IL323959A - History of pyrrolopyridines as positive allosteric modulators of the m4 muscarinic acetylcholine receptor - Google Patents

Description

WO 2024/220633 PCT/US2024/025144 PYRROLOPYRIDINE DERIVATIVES AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE RECEPTOR M4 Related Applications [0001]This application claims priority to U.S. Provisional Application No. 63/496,806, filed April 18, 2023, and U.S. Provisional Application No. 63/610,184, filed December 14, 2023, each of which is hereby incorporated by reference in its entirety.

Technical Field [0002]The present disclosure relates to compounds, compositions, and methods for treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.

Background [0003]Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChRs) or the muscarinic acetylcholine receptors (mAChRs) by the binding of the endogenous orthosteric agonist acetylcholine (ACh). Conditions associated with cognitive impairment, such as Alzheimer ’s disease, are accompanied by a reduction of acetylcholine content in the brain. This is believed to be the result of degeneration of cholinergic neurons of the basal forebrain, which widely innervate multiple areas of the brain, including the association cortices and hippocampus, which are critically involved in higher processes. Clinical data supports that cholinergic hypofunction contributes to the cognitive deficits of patients suffering from schizophrenia. Efforts to increase acetylcholine levels have focused on increasing levels of choline, the precursor for acetylcholine synthesis, and on blocking acetylcholinesterase (AChE), the enzyme that metabolizes acetylcholine. As a result, 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 AD patients. [0004]Attempts to augment central cholinergic function through the administration of choline or phosphatidylcholine have not been successful. AChE inhibitors have shown therapeutic efficacy, but have been found to have frequent cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal cramps, nausea, vomiting, and diarrhea. These gastrointestinal side effects have been observed in about a third of the patients treated. In addition, some AChE inhibitors, such as tacrine, have also been found to cause — 1 — WO 2024/220633 PCT/US2024/025144 significant hepatotoxicity with elevated liver transaminases observed in about 30% of patients. The adverse effects of AChE inhibitors have severely limited their clinical utility. An alternative approach to pharmacologically target cholinergic hypofunction is the activation of mAChRs, which are widely expressed throughout the body. [0005]The mAChRs are members of the family A G protein-coupled receptors (GPCRs) and include five subtypes, designated M1-M5. The M1, M3 and M5 subtypes mainly couple to Gq and activate phospholipase C, whereas the M2 and M4 subtypes mainly couple to Gi/o and associated effector systems. These five distinct mAChR subtypes have been identified in the mammalian central nervous system where they are prevalent and differentially expressed. Mi-Ms have varying roles in cognitive, sensory, motor and autonomic functions. Thus, without wishing to be bound by a particular theory, it is believed that selective agonists of mAChR subtypes that regulate processes involved in cognitive function could prove to be superior therapeutics for treatment of psychosis, schizophrenia and related disorders. The muscarinic M4 receptor has been shown to have a major role in cognitive processing and is believed to have a major role in the pathophysiology of psychotic disorders, including schizophrenia. [0006]Evidence suggests that the most prominent adverse effects of AChE inhibitors and other cholinergic agents are mediated by activation of peripheral M2 and M3 mAChRs and include bradycardia, GI distress, excessive salivation, and sweating. In contrast, M4 has been viewed as the most likely subtype for mediating the effects of muscarinic acetylcholine receptor dysfunction in psychotic disorders, including schizophrenia, cognition disorders, and neuropathic pain. Because of this, considerable effort has been focused on developing selective M4 agonists for treatment of these disorders. Unfortunately, these efforts have been largely unsuccessful because of an inability to develop compounds that are highly selective for the mAChR M4. Because of this, mAChR agonists that have been tested in clinical studies induce a range of adverse effects by activation of peripheral mAChRs. To fully understand the physiological roles of individual mAChR subtypes and to further explore the therapeutic utility of mAChR ligands in psychosis, including schizophrenia, cognition disorders and other disorders, it can be important to develop compounds that are highly selective activators of mAChR M4 and other individual mAChR subtypes. [0007]Previous attempts to develop agonists that are highly selective for individual mAChR subtypes have failed because of the high conservation of the orthosteric ACh binding site. To — 2 — WO 2024/220633 PCT/US2024/025144 circumvent problems associated with targeting the highly conserved orthosteric ACh binding site, it is believed that developing compounds that act at allosteric sites on mAChRs that are removed from the orthosteric site and are less highly conserved. This approach is proving to be highly successful in developing selective ligands for multiple GPCR subtypes. In the case of mAChRs, a major goal has been to develop allosteric ligands that selectively increase activity of mAChR M4 or other mAChR subtypes. Allosteric activators can include allosteric agonists, that act at a site removed from the orthosteric site to directly activate the receptor in the absence of ACh as well as positive allosteric modulators (PAMs), which do not activate the receptor directly but potentiate activation of the receptor by the endogenous orthosteric agonist ACh. Also, it is possible for a single molecule to have both allosteric potentiator and allosteric agonist activity. [0008]More recently, muscarinic agonists including xanomeline have been shown to be active in animal models with similar profiles to known antipsychotic drugs, but without causing catalepsy (Bymaster et al., Eur. J. Pharmacol. 1998, 356, 109, Bymaster et al., Life Set. 1999, 64, 527; Shannon et al., J. Pharmacol. Exp. Ther. 1999, 290, 901; Shannon et al.. Schizophrenia Res. 2000, 42, 249). Further, xanomeline was shown to reduce psychotic behavioral symptoms such as delusions, suspiciousness, vocal outbursts, and hallucinations in Alzheimer ’s disease patients (Bodick et al., Arch. Neurol. 1997, 54, 465), however treatment induced side effects, e.g., gastrointestinal effects, have severely limited the clinical utility of this compound. [0009]Despite advances in muscarinic acetylcholine receptor research, there is still a scarcity of compounds that are potent, efficacious, and selective activators of the M4 mAChR and also effective in the treatment of neurological and psychiatric disorders associated with cholinergic activity and diseases in which the muscarinic M4 receptor is involved.

Summary [0010]In one aspect, disclosed are compounds of formula (I), or a pharmaceutically acceptable salt thereof, — 3 — WO 2024/220633 PCT/US2024/025144 (1)wherein:X1 is NR5, 0, or CR5AR5B;R2 is G2, -NR2aR2b , halogen, cyano, C1-6alkyl, C1-6haloalkyl, -OR2a, -NR2aC(O)R2b , -C(O)OR2a, -C(O)NR2aR2b , or hydrogen;R2a and R2b are independently hydrogen, C1-6alkyl, C1-6haloalkyl, G2, or -Ci-alkylene-G;G2, at each occurrence, is independently a 5- to 6-membered heteroaryl containing 1-4heteroatoms, a phenyl, a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms, or a 3- to 7-membered carbocyclyl, wherein the heteroatoms are independently selected from the group consisting of 0, N, and S, and G2 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1- 4fluoroalkyl, oxo, -ORX, -N(RX)2, -C(O)RX, -C(0)0Rx, -C(0)N(Rx)2, -C1-6alkylene-OR x, -C1-6alkylene-N(R x)2, G2a, and -C1-3alkylene-G 2a;Rx, at each occurrence, is independently hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-6cycloalkyl, or -C1-3alkylene-C3-6cycloalkyl;G2a is a C3-6cycloalkyl;R4a and R4b are independently hydrogen, C1-4alkyl, C3-4cycloalkyl, or -C1-3alkylene-OH; or R4A and R4b together with the carbon to which they attach form a C3-6cycloalkyl;R5 is hydrogen, C1-6alkyl, Cuefluoroalkyl, -C1-6alkylene-R y , -C1-6fluoroalkylene-R y , G5, or -C1-3alkylene-G 5; — 4 — WO 2024/220633 PCT/US2024/025144 R5a and R3B are independently hydrogen, halogen, C1-4alkyl, C1-4fluoroalkyl, or -C1-4alkylene- OH;Ry is -OR53, -N(R5a)2, -C(O)R5a, -C(O)OR5a, or -C(O)N(R5a)2;R5a, at each occurrence, is independently hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-4cycloalkyl, or -C1-3alkylene-C3-4cycloalkyl;G3 is phenyl, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, 5- to 6-membered heteroaryl containing 1-4 heteroatoms, or a C3-6cycloalkyl, wherein the heteroatoms are independently selected from the group consisting of 0, N, and S, and G5 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-2fluoroalkyl, -OC1-4alkyl, OH, and oxo;R6 is hydrogen, halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, C2-4alkenyl, -OR6a, -N(R6a)2, -C1-3alkylene-OR 6a, or C3-4cycloalkyl;R6a, at each occurrence, is independently hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-4cycloalkyl, or -C1-3alkylene-C3-4cycloalkyl;wherein alternatively, two R6a, together with the nitrogen to which they attach form a 4- to 8- membered heterocyclic ring containing the nitrogen attached to R6a and optionally additional heteroatom that is O, N, or S, the heterocyclic ring being optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-2alkyl, and C1-2fluoroalkyl;R7 is C1-4alkyl, hydrogen, halogen, cyano, C1-4fluoroalkyl, C2-4alkenyl, -OR7a, -C1-3alkylene-OR 7a, CO2R7a, COR73, or C3-6cycloalkyl;R7a is hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-4cycloalkyl, or -C1-3alkylene-C3-4cycloalkyl;R8, at each occurrence, is independently halogen, C1-4alkyl, C1-4fluoroalkyl, or C3-4cycloalkyl; andn is 0, 1, 2, 3, or 4;wherein each cycloalkyl at Rx, G2a, R6, R6a, R7, R7a, and R8 is independently unsubstituted or substituted with 1-4 substituents independently selected from C1-4alkyl (e.g., methyl) and halogen (e.g., fluoro). [0011]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. — 5 — WO 2024/220633 PCT/US2024/025144

[0012]Another aspect provides a method of treating a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of formula (I), or pharmaceutically acceptable salt or composition thereof. [0013]Another aspect provides a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal. [0014]Another aspect provides use of a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, for the preparation of a medicament for the treatment of a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal. [0015]In another aspect, the invention provides kits comprising a compound of formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use.

Detailed Description [0016]Disclosed herein are positive allosteric modulators (i.e. potentiators) of the muscarinic acetylcholine receptor M4 (mAChR M4), methods of making same, pharmaceutical compositions comprising same, and methods of treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using same. The compounds include naphthyridine-substituted pyridazine compounds. [0017]The human muscarinic acetylcholine receptor M4 (mAChR M4) is a protein of 4amino acids encoded by the CHRM4 gene. The molecular weight of the unglycosylated protein is about 54 kDa and it is a transmembrane GPCR. As described above, the mAChR M4 is a member of the GPCR Class A family, or the rhodopsin-like GPCRs, which are characterized by structural features similar to rhodopsin such as seven transmembrane segments. The muscarinic acetylcholine receptors have the N-terminus oriented to the extracellular face of the membrane and the C-terminus located on the cytoplasmic face. [0018]Previous attempts to develop agonists that are highly selective for individual mAChR subtypes have failed because of the high conservation of the orthosteric ACh binding site. To circumvent problems associated with targeting the highly conserved orthosteric ACh binding site, it is believed that developing compounds that act at allosteric sites on mAChRs that are removed from the orthosteric site and are less highly-conserved. Without wishing to be bound by — 6 — WO 2024/220633 PCT/US2024/025144 a particular theory, the disclosed compounds and products of the disclosed methods are believed to bind to an allosteric site distinct from the orthosteric binding site. 1. Definitions [0019]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. [0020]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. [0021]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. [0022]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, 75th Ed., inside cover, and specific functional groups are generally defined as described therein. — ר — WO 2024/220633 PCT/US2024/025144 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, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. [0023]The term “alkoxy, ” as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert- butoxy. [0024]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 “Cwalkyl ” 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, zz-propyl, z.w-propyl, n-butyl, sec-butyl, zso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, zz-heptyl, zz-octyl, n-nonyl, and zz-decyl. [0025]The term “alkenyl, ” as used herein, means a straight or branched, hydrocarbon chain containing at least one carbon-carbon double bond. [0026]The term “alkoxyalkyl, ” as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. [0027]The term “alkoxyfluoroalkyl, ” as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein. [0028]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-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2CH2-, and -CH2CH2CH2CH2CH2-. [0029]The term “alkylamino, ” as used herein, means at least one alkyl group, as defined herein, is appended to the parent molecular moiety through an amino group, as defined herein. — 8 — WO 2024/220633 PCT/US2024/025144

[0030]The term “amide, ” as used herein, means -C(O)NR- or -NRC(O)-, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. [0031]The term “aminoalkyl, ” as used herein, means at least one amino group, as defined herein, is appended to the parent molecular moiety through an alkylene group, as defined herein. [0032]The term “amino, ” as used herein, means -NRxRy, wherein Rx and Ry may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any other moiety where amino appends together two other moieties, amino may be -NRX-, wherein Rx may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. [0033]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][l,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). [0034]The term “cyanoalkyl, ” as used herein, means at least one -CN group, is appended to the parent molecular moiety through an alkylene group, as defined herein. [0035]The term “cyanofluoroalkyl, ” as used herein, means at least one -CN group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein. [0036]The term “cycloalkoxy, ” as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. [0037]The term “cycloalkyl ” or “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., decahydronaphthal enyl), or 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).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 . — 9 — WO 2024/220633 PCT/US2024/025144

[0038]The term "cycloalkenyl" or “cycloalkene, ” as used herein, means a non-aromatic monocyclic or multicyclic ring system containing all carbon atoms as ring members and 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. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. [0039]The term "carbocyclyl" means a "cycloalkyl" or a “cycloalkenyl. ” The term “carbocycle ” means a “cycloalkane ” or a “cycloalkene. ” The term “carbocyclyl ” refers to a “carbocycle ” when present as a substituent. [0040]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 fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2- trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl such as 3,3,3 -trifluoropropy 1. [0041]The term “fluoroalkylene, ” as used herein, means an alkylene group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkylene include, but are not limited to -CF2-, -CH2CF2-, 1,2-difluoroethylene, 1,1,2,2-tetrafluoroethylene, 1,3,3,3-tetrafluoropropylene, 1,1,2,3,3-pentafluoropropylene, and perfluoropropylene such as 1,1,2,2,3,3-hexafluoropropylene. [0042]The term “fluoroalkoxy, ” as used herein, means at least one fluoroalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom. Representative examples of fluoroalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy. [0043] The term “halogen ” or “halo, ” as used herein, means Cl, Br, I, or F. [0044] The term "haloalkyl," as used herein, means an alkyl group, as defined herein, inwhich one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen. — 10 — WO 2024/220633 PCT/US2024/025144

[0045]The term “haloalkoxy, ” as used herein, means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom. [0046]The term "halocycloalkyl," as used herein, means a cycloalkyl group, as defined herein, in which one or more hydrogen atoms are replaced by a halogen. [0047]The term “heteroalkyl, ” as used herein, means an alkyl group, as defined herein, in which one or more of the carbon atoms has been replaced by a heteroatom selected from S, O, P and N. Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides, and alkyl sulfides. [0048]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 heteroaromatic ring (bicyclic heteroaryl). The term “heteroaryl ” is used herein to refer to a heteroarene when present as a substituent. 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 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., 10electron system) such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indol-l-yl), a monocyclic heteroaryl ring fused to a monocyclic heteroarene (e.g., naphthyridinyl), and a phenyl fused to a monocyclic 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 heteroatom contributing a lone electron pair to a fully aromatic 1071 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. Other representative examples of heteroaryl include, but are not limited to, indolyl (e.g., indol-l-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), — 11 — WO 2024/220633 PCT/US2024/025144 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[l,2-،z]pyridinyl (e.g., imidazo[l,2- a]pyridin-6-yl), naphthyridinyl, pyridoimidazolyl, thiazolo[5,4-Z>]pyridin-2-yl, and thiazolo[5,4- ،7]pyrimidin-2-yl. [0049]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 0, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of 0, 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 0, 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 0, 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 0, N, and S. Representative examples of monocyclic heterocyclyls include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-di oxol any 1, 1,3-di thiol any 1, 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 — 12 — WO 2024/220633 PCT/US2024/025144 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-l-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, l,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, octahydropyrrol opyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2.2.1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2- oxaspiro[3.3]heptanyl, 3-oxaspiro[5.5]undecanyl, 6-oxaspiro[2.5]octan-l-yl, and 3- oxabicyclo[3.1.0]hexan-6-yl. 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-2//-2,5-methanocyclopenta[A]furan, hexahydro- 1/7-1,4-methanocy cl openta[c]furan, aza-adamantane (1-azatricyclo[3.3. 1.13,?]decane), and oxa-adamantane (2-oxatricyclo[3. 3.1.13,?]decane). The monocyclic, bicyclic, and tricyclic heterocyclyls are connected to the parent molecular moiety at a non-aromatic ring atom. [0050]The term “hydroxyl ” or “hydroxy, ” as used herein, means an -OH group. [0051]The term “hydroxyalkyl, ” as used herein, means at least one -OH group, is appended to the parent molecular moiety through an alkylene group, as defined herein. [0052]The term “hydroxyfluoroalkyl, ” as used herein, means at least one -OH group, is appended to the parent molecular moiety through a fluoroalkyl group, as defined herein. [0053]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 — 13 — WO 2024/220633 PCT/US2024/025144 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. 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). [0054]The terms "parent molecule" or "parent molecular moiety" refer to the entire portion of a molecule to which a substituent is attached, i.e., the remainder of the molecule. [0055]The term “sulfonamide, ” as used herein, means -S(O)2NRZ- or -NRZS(O)-, wherein Rz may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. [0056]The term “substituents ” refers to a group “substituted" on a group such as an alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, or heterocycle group, at any atom of that group. Any atom can be substituted. [0057]The term “substituted ” refers to a group that may be further substituted with one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, =0 (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. In some embodiments, a group is optionally substituted. In some embodiments, a group is optionally substituted with 1, 2, 3, 4, or substituents. In some embodiments, an aryl, heteroaryl, cycloalkyl, or heterocycle is optionally substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, an aryl, heteroaryl, cycloalkyl, or heterocycle may be independently unsubstituted or substituted with 1, 2, or substituents. [0058]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. — 14 — WO 2024/220633 PCT/US2024/025144

[0059]The term “allosteric site” as used herein refers to a ligand binding site that is topographically distinct from the orthosteric binding site. [0060]The term “modulator ” as used herein refers to a molecular entity (e.g., but not limited to, a ligand and a disclosed compound) that modulates the activity of the target receptor protein. [0061]The term “ligand ” as used herein refers to a natural or synthetic molecular entity that is capable of associating or binding to a receptor to form a complex and mediate, prevent or modify a biological effect. Thus, the term “ligand ” encompasses allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates and analogs of natural substrates. [0062]The terms “natural ligand ” and “endogenous ligand ” as used herein are used interchangeably, and refer to a naturally occurring ligand, found in nature, which binds to a receptor. [0063]The term “orthosteric site” as used herein refers to the primary binding site on a receptor that is recognized by the endogenous ligand or agonist for that receptor. For example, the orthosteric site in the mAChR M4 receptor is the site that acetylcholine binds. [0064]The term “mAChR M4 receptor positive allosteric modulator ” as used herein refers to any exogenously administered compound or agent that directly or indirectly augments the activity of the mAChR M4 receptor in the presence or in the absence of acetylcholine, or another agonist, in an animal, in particular a mammal, for example a human. For example, a mAChR Mreceptor positive allosteric modulator can increase the activity of the mAChR M4 receptor in a cell in the presence of extracellular acetylcholine. The cell can be Chinese hamster ovary (CHO- KI) cells transfected with human mAChR M4. The cell can be Chinese hamster ovary (CHO-K1) cells transfected with rat mAChR M4 receptor. The cell can be Chinese hamster ovary (CHO-K1) cells transfected with a mammalian mAChR M4. The term “mAChR M4 receptor positive allosteric modulator ” includes a compound that is a “mAChR M4 receptor allosteric potentiator ” or a “mAChR M4 receptor allosteric agonist, ” as well as a compound that has mixed activity comprising pharmacology of both an “mAChR M4 receptor allosteric potentiator ” and an “mAChR M4 receptor allosteric agonist. ” The term “mAChR M4 receptor positive allosteric modulator also includes a compound that is a “mAChR M4 receptor allosteric enhancer. ” [0065]The term “mAChR M4 receptor allosteric potentiator ” as used herein refers to any exogenously administered compound or agent that directly or indirectly augments the response produced by the endogenous ligand (such as acetylcholine) when the endogenous ligand binds to — 15 — WO 2024/220633 PCT/US2024/025144 the orthosteric site of the mAChR M4 receptor in an animal, in particular a mammal, for example a human. The mAChR M4 receptor allosteric potentiator binds to a site other than the orthosteric site, that is, an allosteric site, and positively augments the response of the receptor to an agonist or the endogenous ligand. In some embodiments, an allosteric potentiator does not induce desensitization of the receptor, activity of a compound as an mAChR M4 receptor allosteric potentiator provides advantages over the use of a pure mAChR M4 receptor orthosteric agonist. Such advantages can include, for example, increased safety margin, higher tolerability, diminished potential for abuse, and reduced toxicity. [0066]The term “mAChR M4 receptor allosteric enhancer ” as used herein refers to any exogenously administered compound or agent that directly or indirectly augments the response produced by the endogenous ligand (such as acetylcholine) in an animal, in particular a mammal, for example a human. In some embodiments, the allosteric enhancer increases the affinity of the natural ligand or agonist for the orthosteric site. In some embodiments, an allosteric enhancer increases the agonist efficacy. The mAChR M4 receptor allosteric enhancer binds to a site other than the orthosteric site, that is, an allosteric site, and positively augments the response of the receptor to an agonist or the endogenous ligand. An allosteric enhancer has no effect on the receptor by itself and requires the presence of an agonist or the natural ligand to realize a receptor effect. [0067]The term “mAChR M4 receptor allosteric agonist ” as used herein refers to any exogenously administered compound or agent that directly activates the activity of the mAChR M4 receptor in the absence of the endogenous ligand (such as acetylcholine) in an animal, in particular a mammal, for example a human. The mAChR M4 receptor allosteric agonist binds to a site that is distinct from the orthosteric acetylcholine site of the mAChR M4 receptor. Because it does not require the presence of the endogenous ligand, activity of a compound as an mAChR M4 receptor allosteric agonist provides advantages if cholinergic tone at a given synapse is low. [0068]The term “mAChR M4 receptor neutral allosteric ligand ” as used herein refers to any exogenously administered compound or agent that binds to an allosteric site without affecting the binding or function of agonists or the natural ligand at the orthosteric site in an animal, in particular a mammal, for example a human. However, a neutral allosteric ligand can block the action of other allosteric modulators that act via the same site. — 16 — WO 2024/220633 PCT/US2024/025144

[0069]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. [0070]Abbreviations;AIBN is 2,2'-azobis(2-methylpropionitrile);aq is aqueous;BINAP is 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl;Boc is tert-butoxycarbonyl;BrettPhos is 2-(dicyclohexylphosphino)3,6-dimethoxy-26,'4, ׳'-triisopropyl-l,r ־biphenyl;BrettPhos Pd G3 is [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl- 1,1'- biphenyl)-2-(2'-amino-l,r-biphenyl)]palladium(II) methanesulfonate;t-BuOH is te/7-butanol;Celite® is diatomaceous earth;DCE is 1,2-dichloroethane;DCM is dichloromethane;DEA is diethylamine;DMAP is 4-dimethylaminopyridine;DMF is A,A-dimethylformamide;DMP or Dess-Martin periodinane is l,l,l-tris(acetyloxy)-l,l-dihydro-l,2-benziodoxol-3-(l//)- one;DIAD is diisopropyl azodicarboxylate;DIPEA or DIEA is diisopropylethylamine;DMSO is dimethyl sulfoxide;Dowtherm™ A is a eutectic mixture of 26.5% diphenyl + 73.5% diphenyl oxide;DfBAD is di-/c/7-butyl-azodicarboxylate;eq or eq. is equivalent(s);EtOAC is ethyl acetate;(4,4'-dtbbpy)NiC12 is 4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine] nickel (II) dichloride;EtOH is ethanol;h or hr is hour(s); — 17 — WO 2024/220633 PCT/US2024/025144 Hex is hexane(s);IP A is isopropyl alcohol;KO Ac is potassium acetate;LAH is lithium aluminum hydride;Lawesson’s Reagent is 2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-l,3,2,4-dithiadiphosphetane;mCPBA is meta-chloroperoxy benzoic acid;MeCN or ACN is acetonitrile;MeOH is methanol;min is minute(s);NaOAc is sodium acetate;NaOMe is sodium methoxide;NBS is N-bromosuccinimide;NCS is N-chlorosuccinimide;NMO is 4-methylmorpholine N-oxide;NMP is A-methyl-2-pyrrolidone;[Pd(allyl)(tBuBrettPhos)]OTf is trifluoromethanesulfonate allyl[(2-Di-tert-butylphosphino-3,6- dimethoxy-2',4',6'-triisopropyl-l,r-biphenyl)-2-(2'-amino-l,r ־biphenyl)] palladium(!!);Pd(dppf)C12 is [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II);Pd(OAc)2 is palladium(II)acetate;Pd(PPh3)4 is tetrakis(triphenylphosphine)palladium(0);PPA is polyphosphoric acid;PPh3 is triphenylphosphine;PPTS is pyridiniump-toluenesulfonate;rt is room temperature;sat. is saturated;sec is second(s);SCX cartridge or HF SCX cartridge is a strong cation exchanger cartridge (i.e. Agilent part# 14256027);SFC is supercritical fluid chromatography;TBAC or TBAC1 is tetrabutylammonium chloride;/-BuXPhos i s 2-di-ter/-butylphosphino-2 ',46 '-trii sopropylbiphenyl ; — 18 — WO 2024/220633 PCT/US2024/025144 TEA or Et3N is triethyamine;TFA is trifluoroacetic acid;THE is tetrahydrofuran;TMB is trimethylboroxine;TosCI ispara-toluenesulfonyl chloride; and tosyl is para-toluenesulfonyl. 2. Compounds [0071]In one aspect, the invention provides compounds of formula (1), wherein R2, R4A, R4B, R6, R7, R8, X1, and n are as defined herein. [0072]Unsubstituted or substituted rings (i.e., optionally substituted) such as aryl, heteroaryl, etc. are composed of both a ring system and the ring system's optional substituents. Accordingly, the ring system may be defined independently of its substituents, such that redefining only the ring system leaves any previous optional substituents present. For example, a 5- to 12-membered heteroaryl with optional substituents may be further defined by specifying the ring system of the 5- to 12-membered heteroaryl is a 5- to 6-membered heteroaryl (i.e., 5- to 6-membered heteroaryl ring system), in which case the optional substituents of the 5- to 12- membered heteroaryl are still present on the 5- to 6-membered heteroaryl, unless otherwise expressly indicated. [0073]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. [0074]In the following, numbered embodiments of the invention are disclosed. The first embodiment is denoted El, subsequent embodiments are denoted E1.1, El.2, E2, E3, E4, E4.1, and so forth. [0075]El. A compound of formula (I), or a pharmaceutically acceptable salt thereof, — 19 — WO 2024/220633 PCT/US2024/025144 (1)wherein:X1 is NR5, 0, or CR5AR5B;R2 is G2, -NR2aR2b , halogen, cyano, C1-6alkyl, C1-6haloalkyl, -OR2a, -NR2aC(O)R2b ,-C(O)OR2a, -C(O)NR2aR2b , or hydrogen;R2a and R2b are independently hydrogen, C1-6alkyl, C1-6haloalkyl, G2, or -Ci-alkylene-G;G2, at each occurrence, is independently a 5- to 6-membered heteroaryl containing 1-4heteroatoms, a phenyl, a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms, or a 3- to 7-membered carbocyclyl, wherein the heteroatoms are independently selected from the group consisting of 0, N, and S, and G2 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1- 4fluoroalkyl, oxo, -ORX, -N(RX)2, -C(O)RX, -C(0)0Rx, -C(0)N(Rx)2, -C1-6alkylene-OR x, -C1-6alkylene-N(R x)2, G2a, and -C1-3alkylene-G 2a;Rx, at each occurrence, is independently hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-6cycloalkyl, or -C1-3alkylene-C3-6cycloalkyl;G2a is a C3-6cycloalkyl;R4a and R4b are independently hydrogen, C1-4alkyl, C3-4cycloalkyl, or -C1-3alkylene-OH; or R4A and R4b together with the carbon to which they attach form a C3-6cycloalkyl;R5 is hydrogen, C1-6alkyl, Cnefluoroalkyl, -C1-6alkylene-R y , -C1-6fluoroalkylene-R y , G5, or -C1-3alkylene-G 5; — 20 — WO 2024/220633 PCT/US2024/025144 R5a and R3B are independently hydrogen, halogen, C1-4alkyl, C1-4fluoroalkyl, or -C1-4alkylene- OH;Ry is -OR53, -N(R5a)2, -C(O)R5a, -C(O)OR5a, or -C(O)N(R5a)2;R5a, at each occurrence, is independently hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-4cycloalkyl, or -C1-3alkylene-C3-4cycloalkyl;G3 is phenyl, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, 5- to 6-membered heteroaryl containing 1-4 heteroatoms, or a C3-6cycloalkyl, wherein the heteroatoms are independently selected from the group consisting of 0, N, and S, and G5 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-2fluoroalkyl, -OC1-4alkyl, OH, and oxo;R6 is hydrogen, halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, C2-4alkenyl, -OR6a, -N(R6a)2, -C1-3alkylene-OR 6a, or C3-4cycloalkyl;R6a, at each occurrence, is independently hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-4cycloalkyl, or -C1-3alkylene-C3-4cycloalkyl;wherein alternatively, two R6a, together with the nitrogen to which they attach form a 4- to 8- membered heterocyclic ring containing the nitrogen attached to R6a and optionally additional heteroatom that is O, N, or S, the heterocyclic ring being optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-2alkyl, and C1-2fluoroalkyl;R7 is C1-4alkyl, hydrogen, halogen, cyano, C1-4fluoroalkyl, C2-4alkenyl, -OR7a, -C1-3alkylene-OR 7a, CO2R7a, COR73, or C3-6cycloalkyl;R7a is hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-4cycloalkyl, or -C1-3alkylene-C3-4cycloalkyl;R8, at each occurrence, is independently halogen, C1-4alkyl, C1-4fluoroalkyl, or C3-4cycloalkyl; andn is 0, 1, 2, 3, or 4;wherein each cycloalkyl at Rx, G2a, R6, R6a, R7, R7a, and R8 is independently unsubstituted or substituted with 1-4 substituents independently selected from C1-4alkyl (e.g., methyl) and halogen (e.g., fluoro). [0076]El.l. The compound of El, or a pharmaceutically acceptable salt thereof, wherein G5 is phenyl, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, 5- to 6-membered heteroaryl containing 1-4 heteroatoms, or a C3-6cycloalkyl, wherein the heteroatoms are — 21 — WO 2024/220633 PCT/US2024/025144 independently selected from the group consisting of 0, N, and S, and G3 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-4alkyl, C1- 2fluoroalkyl, -OC1-4alkyl, OH, and oxo. [0077] El. 2. The compound ofEl orEl.l, or a pharmaceutically acceptable salt thereof,wherein X1 is NR5 or 0. [0078] E2. The compound of any of El-El.2, or a pharmaceutically acceptable saltthereof, wherein R2 is G2, -NR2aR2b , halogen, cyano, C1-6alkyl, C1-6haloalkyl, -OR2a, -C(O)OR2a, -C(O)NR2aR2b , or hydrogen. [0079] E3. The compound of E2, or a pharmaceutically acceptable salt thereof, whereinR2 is G2. [0080] E4. The compound of any of E1-E3, or a pharmaceutically acceptable saltthereof, wherein G2 is the optionally substituted 3- to 7-membered carbocyclyl. [0081] E4.1. The compound of any of E1-E4, or a pharmaceutically acceptable saltthereof, wherein the ring system of the optionally substituted 3- to 7-membered carbocyclyl at Gis a C3-7cycloalkyl. [0082] E4.2. The compound of E4.1, or a pharmaceutically acceptable salt thereof,wherein the ring system of the optionally substituted 3- to 7-membered carbocyclyl at G2 is a cyclopropyl or cyclobutyl. [0083] E4.3. The compound of any of E4-E4.2, or a pharmaceutically acceptable saltthereof, wherein G2 is optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl and halogen. [0084] E4.4. The compound of E4.3, or a pharmaceutically acceptable salt thereof,wherein G2 is optionally substituted with 1-4 substituents independently selected from the group consisting of methyl and fluoro. [0085] E4.5. The compound of E4.4, or a pharmaceutically acceptable salt thereof, wherein G2 is [0086] E5. The compound of any of E1-E3, or a pharmaceutically acceptable saltthereof, wherein G2 is the optionally substituted 5- to 6-membered heteroaryl. — 22 — WO 2024/220633 PCT/US2024/025144

[0087] E5.1. The compound of any of El -E3 or E5, or a pharmaceutically acceptable saltthereof, wherein the ring system of the optionally substituted 5- to 6-membered heteroaryl at Gis a 5-membered heteroaryl. [0088] E5.2. The compound of E5 or E5.1, or a pharmaceutically acceptable salt thereof,wherein the ring system of the optionally substituted heteroaryl at G2 contains 1-2 heteroatoms independently selected from the group consisting of N and S. [0089] E5.3. The compound of E5.2, or a pharmaceutically acceptable salt thereof,wherein the ring system of the optionally substituted heteroaryl at G2 is thiophenyl or pyrazolyl. [0090] E5.4. The compound of E5.3, or a pharmaceutically acceptable salt thereof,wherein the ring system of the optionally substituted heteroaryl at G2 is thiophen-2-yl or pyrazol- 5-yl. [0091] E5.5. The compound of any of E5-E5.4, or a pharmaceutically acceptable saltthereof, wherein G2 is optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl and halogen. [0092] E5.6. The compound of E5.5, or a pharmaceutically acceptable salt thereof,wherein G2 is optionally substituted with 1-4 substituents independently selected from the group consisting of methyl and fluoro. [0093] E5.7. The compound of E5.6, or a pharmaceutically acceptable salt thereof, h. KJ

[0094] E6. The compound of any of E1-E5.7, or a pharmaceutically acceptable salt thereof, wherein G2 is [0095] E7. The compound of E2, or a pharmaceutically acceptable salt thereof, whereinR2 is -NR2aR2b . [0096] E8.R2 is C1-6alkyl. [0097] E8.1.

The compound of E2, or a pharmaceutically acceptable salt thereof, wherein The compound of E8, or a pharmaceutically acceptable salt thereof, whereinR2 is methyl or tert-butyl. — 23 — WO 2024/220633 PCT/US2024/025144 R2 is C(O)NR2aR2b .

[0098] E9.R2 is halogen.The compound of E2, or a pharmaceutically acceptable salt thereof, wherein

[0099] E9.1.R2 is chloro.The compound of E9, or a pharmaceutically acceptable salt thereof, wherein

[00100] E10.R2 is hydrogen.The compound of E2, or a pharmaceutically acceptable salt thereof, wherein

[00101]Ell.R2 is -C(O)OR2a.The compound of E2, or a pharmaceutically acceptable salt thereof, wherein

[00102]E12. The compound of E2, or a pharmaceutically acceptable salt thereof, wherein

[00103] E13. The compound of any of El, El.1, El.2, E2, E4.1-E4.4, E5.1-E5.6, E7, orEl 1-E12, or a pharmaceutically acceptable salt thereof, wherein R2a is hydrogen or C1-6alkyl. [00104] E13.1. The compound of E13, or a pharmaceutically acceptable salt thereof,wherein R2a is hydrogen. [00105] E13.2. The compound of E13, or a pharmaceutically acceptable salt thereof,wherein R2a is C1-4alkyl. [00106] E13.3. The compound of E13.2, or a pharmaceutically acceptable salt thereof,wherein R2a is ethyl. [00107] E14. The compound of any of El, El.1, El.2, E2, E4.1-E4.4, E5.1-E5.6, E7, orE12-E13.3, or a pharmaceutically acceptable salt thereof, wherein R2b is hydrogen. [00108]El 5. The compound of any of El-El 4, or a pharmaceutically acceptable salt thereof, wherein R4A and R4B are hydrogen. [00109]El 5.1. The compound of El 5, or a pharmaceutically acceptable salt thereof, wherein the hydrogen at R4A and R4B are deuterium (2H). [00110]E16. The compound of any of E1-E15.1, or a pharmaceutically acceptable salt thereof, wherein X1 is NR3. [00111] E17. The compound of any of E1-E16, or a pharmaceutically acceptable saltthereof, wherein R5 is hydrogen, C1-6alkyl, G or-C1-3alkylene-G 5. [00112] E17.1. The compound of E17, or a pharmaceutically acceptable salt thereof,wherein R5 is hydrogen, C1-6alkyl, or G5. — 24 — WO 2024/220633 PCT/US2024/025144

[00113]El 7.2. The compound of El 7.1, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen. [00114] E17.3. The compound of E17.1, or a pharmaceutically acceptable salt thereof,wherein R5 is C1-6alkyl. [00115] E17.4. The compound of E17.3, or a pharmaceutically acceptable salt thereof,wherein R5 is C1-3alkyl. [00116] E17.5. The compound of E17.4, or a pharmaceutically acceptable salt thereof,wherein R5 is methyl. [00117] E17.6. The compound of E17.1, or a pharmaceutically acceptable salt thereof,wherein R5 is G5. [00118] E17.7. The compound of E17, or a pharmaceutically acceptable salt thereof,wherein R5 is -C1-3alkylene-G 5. [00119] E17.8. The compound of any 0fEl-E17.1 or E17.6-E17.7, or pharmaceuticallyacceptable salt thereof, wherein G5 is the optionally substituted C3-6cycloalkyl. [00120] E17.9. The compound of any of E1-E17.1 or E17.6-E17.8, or a pharmaceuticallyacceptable salt thereof, wherein the ring system of the optionally substituted C3-6cycloalkyl at Gis cyclopropyl, cyclobutyl, or cyclopentyl. [00121] E17.10. The compound of any of El-El 7.1 or E17.6-E17.9, or a pharmaceuticallyacceptable salt thereof, wherein the C3-6cycloalkyl at G5 is optionally substituted with 1-substituents independently selected from the group consisting of halogen, cyano, and C1-4alkyl. [00122] E17.11. The compound of E17.10, or a pharmaceutically acceptable salt thereof,wherein the C3-6cycloalkyl at G5 is optionally substituted with 1-2 substituents independently selected from the group consisting of fluoro, cyano, and methyl. [00123] E17.12. The compound of E17.11, or pharmaceutically acceptable salt thereof,wherein G5 is cyclopropyl or cyclopentyl. [00124] E17.13. The compound of any of E1-E17.1 or E17.6-E17.7, or pharmaceuticallyacceptable salt thereof, wherein G5 is the optionally substituted phenyl. [00125]E17.14. The compound of any of E1-E17.1, E17.6-E17.7, 0rE17.13, orpharmaceutically acceptable salt thereof, wherein the phenyl at G5 is optionally substituted with 1-2 substituents independently selected from the group consisting of fluoro, chloro, cyano, methyl, and -OCH3 — 25 — WO 2024/220633 PCT/US2024/025144

[00126] E17.15. The compound 0fE17.14, or a pharmaceutically acceptable salt thereof,wherein G5 is 2,4-dimethoxyphenyl. [00127] E18. The compound of any of E1-E15.1, or a pharmaceutically acceptable saltthereof, wherein X1 is O. [00128] E19. The compound of any of E1-E15.1, or a pharmaceutically acceptable saltthereof, wherein X1 is CR5AR5B. [00129]E19.1. The compound of any of E1 -E15.1 or E19, or a pharmaceutically acceptable salt thereof, wherein R5A and R5B are hydrogen. [00130] E20 The compound of any of E1-E19.1, or a pharmaceutically acceptable saltthereof, wherein R6 is hydrogen. [00131] E20.1. The compound of any of E1-E19.1, or a pharmaceutically acceptable saltthereof, wherein R6 is C1-4alkyl. [00132] E20.2. Compound of E20.1, or a pharmaceutically acceptable salt thereof, whereinR6 is methyl. [00133] E21. The compound of any of E1-E20.2, or a pharmaceutically acceptable saltthereof, wherein R7 is C1-4alkyl, halogen, cyano, C2-4alkenyl, CO2R7a, or the unsubstituted or substituted C3-6cycloalkyl. [00134] E21.1. The compound of E21, or a pharmaceutically acceptable salt thereof,wherein R7 is C1-4alkyl, halogen, cyano, or the unsubstituted or substituted C3-6cycloalkyl. [00135] E21.2. The compound of E21.1, or a pharmaceutically acceptable salt thereof,wherein R7 is C1-4alkyl. [00136] E21.3. The compound of any of E1-E21.2, or a pharmaceutically acceptable saltthereof, wherein the C1-4alkyl at R7 is methyl. [00137] E21.4. The compound of any of E1-E21.2, or a pharmaceutically acceptable saltthereof, wherein the C1-4alkyl at R7 is ethyl. [00138] E21.5. The compound of E21.1, or a pharmaceutically acceptable salt thereof,wherein R7 is cyano. [00139] E21.6. The compound of E21.1, or a pharmaceutically acceptable salt thereof,wherein R7 is the unsubstituted C3-6cycloalkyl. [00140] E21.7. The compound of any 0fEl-E21.1 0rE21.6, or a pharmaceuticallyacceptable salt thereof, wherein R7 is cyclopropyl. — 26 — WO 2024/220633 PCT/US2024/025144

[00141] E21.8. The compound of E21.1, or a pharmaceutically acceptable salt thereof,wherein R7 is halogen. [00142] E21.9. The compound of any of El-E21.1, E21.3, E21.4, 0rE21.8, orapharmaceutically acceptable salt thereof, wherein the halogen at R7 is bromo. [00143] E21.10. The compound of E21, or a pharmaceutically acceptable salt thereof,wherein R7 is C2-4alkenyl. [00144] E21.11. The compound of any of E1-E21, E21.3, E21.4, E21.9, orE21.10, orapharmaceutically acceptable salt thereof, wherein the C2-4alkenyl at R7 is vinyl or prop-l-en-2-yl. [00145] E21.12. The compound of E21, or a pharmaceutically acceptable salt thereof,wherein R7 is CO2R7a. [00146] E21.13. The compound of any of E1-E21, E21.3, E21.4, E21.9, E21.10, E21.11, orE21.12, or a pharmaceutically acceptable salt thereof, wherein R7a is C1-4alkyl. [00147] E21.14. The compound of any of E1-E21, E21.3, E21.4, E21.9, E21.10, E21.11, orE21.12-E21.13, or a pharmaceutically acceptable salt thereof, wherein the C1-4alkyl at R7a is methyl. [00148] E21.15. The compound of any of E1-E20.2, or a pharmaceutically acceptable saltthereof, wherein R7 is hydrogen. [00149] E22 The compound of any of E1-E21.15, or a pharmaceutically acceptable saltthereof, wherein n is 0. [00150] E23. The compound of El selected from the group consisting of: 2-(6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)-3-methyl-6,7-dihydro-577-pyrrolo[3,4- Z>]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z7)-yl)-3-methyl-6,7-dihydro-5/7- pyrrolo[3,4-Z>]pyridin-5-one;3-methyl-2-(2-(l-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(47T)-yl)-6,7- dihydro-5/7-pyrrolo[3,4-5]pyridin-5-one;3-methyl-2-(2-(thiophen-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6,7-dihydro- 5//-pyrrolo[3,4-Z>]pyridin-5-one;ethyl 5-(3-methyl-5-oxo-6,7-dihydro-5/7-pyrrolo[3,4-6]pyridin-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate; — 27 — WO 2024/220633 PCT/US2024/025144 3-methyl-2-(2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)-6,7-dihydro-5/7- pyrrolo[3,4-Z>]pyridin-5-one;3-methyl-2-(2-(l-methyl-lZ/-pyrazol-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z/)-yl)- 6,7-dihydro-5//-pyrrolo[3,4-Z>]pyridin-5-one;2-(2-amino-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-3-methyl-6,7-dihydro-5//- pyrrolo[3,4-Z>]pyridin-5-one;2-(2-chl oro-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)-3-methyl-6,7-dihydro-5//- pyrrolo[3,4-Z>]pyridin-5-one;2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-3-methyl- 6,7-dihydro-5//-pyrrolo[3,4-Z>]pyridin-5-one;2-(2-(tert-butyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(47/)-yl)-3-methyl-6,7-dihydro-57f- pyrrolo[3,4-Z>]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)-3,6-dimethyl-6,7-dihydro- 5//-pyrrolo[3,4-Z)]pyridin-5-one;3,6-dimethyl-2-(2-(l-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)- 6,7-dihydro-57/-pyrrolo[3,4-6]pyridin-5-one;6-cyclopropyl-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(47/)-yl)-3-methyl- 6,7-dihydro-5//-pyrrolo[3,4-/>]pyridin-5-one;6-cyclopropyl-3-methyl-2-(2-(l-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin- 5(4Z/)-yl)-6,7-dihydro-5//-pyrrolo[3,4-Z>]pyridin-5-one;6-cyclopentyl-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-3-methyl- 6,7-dihydro-5//-pyrrolo[3,4-6]pyridin-5-one;6-cyclopentyl-3-methyl-2-(2-(l-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin- 5(4//)-yl)-6,7-dihydro-577-pyrrolo[3,4-Z>]pyridin-5-one;2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)-3,6- dimethyl-6,7-dihydro-5//-pyrrolo[3,4-/>]pyridin-5-one;6-cyclopropyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)- yl)-3-methyl-6,7-dihydro-57f-pyrrolo[3,4-/)]pyridin-5-one;6-cyclopentyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)- yl)-3-methyl-6,7-dihydro-57f-pyrrolo[3,4-6]pyridin-5-one; — 28 — WO 2024/220633 PCT/US2024/025144 2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-3,6-dimethyl-6,7-dihydro- 5Z/-pyrrolo[3,4-Z>]pyridin-5-one;2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z/)-yl)-3-methylfuro[3,4-6]pyridin- 5(7//)-one;2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-3,6-dimethyl- 6,7-dihydro-5//-pyrrolo[3,4-Z>]pyridin-5-one;3-methyl-2-(2-(l-methyl cy cl opropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z/)- yl)furo[3,4-/>]pyridin-5(7Z/)-one;2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)-3-methyl-6,7-dihydro-5//- pyrrolo[3,4-Z)]pyridin-5-one;3-cyclopropyl-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z/)-yl)-6-methyl- 6,7-dihydro-57/-pyrrolo[3,4-Z)]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z/)-yl)-6-methyl-5-oxo-6,7- dihydro-577-pyrrolo[3,4-6]pyridine-3-carbonitrile;2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(41/)-yl)-3-methyl-6,7- dihydro-5//-pyrrolo[3,4-6]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6-methyl-3-vinyl-6,7- dihydro-5//-pyrrolo[3,4-/>]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6-methyl-3-(prop-l-en-2- yl)-6,7-dihydro-5/7-pyrrolo[3,4-Z>]pyri din-5-one;methyl 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6-methyl-5-oxo-6,7-dihydro-5//-pyrrolo[3,4-6]pyridine-3-carboxylate;5-(3-methyl-5-oxo-6,7-dihydro-5//-pyrrolo[3,4-Z>]pyridin-2-yl)-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4 ־c]pyridin-5(4/7)-yl)-6-(2,4-dimethoxybenzyl)- 3-ethyl-6,7-dihydro-577-pyrrolo[3,4-/>]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4 ־c]pyridin-5(4/7)-yl)-3-ethyl-6,7-dihydro-5/7- pyrrolo[3,4-Z>]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)-3-methyl-6,7-dihydro-5/7- cyclopenta[Z>]pyridin-5-one; — 29 — WO 2024/220633 PCT/US2024/025144 2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-3,4-dimethyl- 6,7-dihydro-5//-pyrrolo[3,4-Z>]pyridin-5-one;2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-4-methyl-6,7- dihydro-5//-pyrrolo[3,4-6]pyridin-5-one;2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-3,4,6-trimethyl- 6,7-dihydro-5//-pyrrolo[3,4-Z>]pyridin-5-one;or a pharmaceutically acceptable salt thereof.

[00151] E24. A pharmaceutical composition comprising the compound of any of E1-E23,or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [00152] E25. A method for treating a neurological and/or psychiatric disorder associatedwith muscarinic acetylcholine receptor dysfunction in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of any of E1-E23, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition ofE24. [00153] E26. The method of E25, wherein the disorder is associated with a mAChR M4dysfunction. [00154] E27. The method of E25 or E26, wherein the disorder is a neurological and/orpsychiatric disorder associated with mAChR M4 dysfunction. [00155] E28. The method of any of E25-E27, wherein the disorder is selected from thegroup consisting of Alzheimer's disease, schizophrenia, a sleep disorder, a pain disorder, and a cognitive disorder. [00156] E29. The method of E28, wherein the disorder is Alzheimer's disease. [00157] E30. The method of any of E25-E27, wherein the disorder is selected from thegroup consisting of psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as 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, autistic disorder, movement disorders, Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug induced and neurodegeneration — 30 — WO 2024/220633 PCT/US2024/025144 based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders. [00158]E31. A kit comprising the compound of any of E1-E23, or a pharmaceutically acceptable salt thereof, and one or more of: (a) at least one agent known to increase mAChR Mactivity; (b) at least one agent known to decrease mAChR M4 activity; (c) at least one agent known to treat a disorder associated with cholinergic activity; (d) instructions for treating a disorder associated with cholinergic activity; (e) instructions for treating a disorder associated with mAChR M4 receptor activity; and (f) instructions for administering the compound in connection with cognitive or behavioral therapy. [00159] E32. The compound of any of E1-E23, or a pharmaceutically acceptable saltthereof, or the pharmaceutical composition of E24, for use in the treatment of a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal. [00160] E33. The use of the compound of any of E1-E23, or a pharmaceuticallyacceptable salt thereof, or the pharmaceutical composition of E24 for the preparation of a medicament for the treatment of a neurological and/or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal. [00161]The compound may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “7?” or “5” depending on the configuration of substituents around the chiral carbon atom. The terms “7?” and “5” 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 include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. 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 — 31 — WO 2024/220633 PCT/US2024/025144 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. [00162]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. [00163]In the compounds of formula (I), and any subformulas, any "hydrogen" or "H," whether explicitly recited or implicit in the structure, encompasses hydrogen isotopes 1H (protium) and 2H (deuterium). [00164]The present disclosure also includes an isotopically-labeled compound, which is identical to those recited in formula (1), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. 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 to 2H, 3H, 13C, 14c, I5N, 180, 17O, 31P, 32P, 35s, 18F, and 36Cl, respectively. Substitution with heavier isotopes such as deuterium, i.e. 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron- emitting isotopes that can be incorporated in compounds of formula (I) are nC, 13N, 15O, and 18F. [00165]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 of isotopic 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). a. Pharmaceutically Acceptable Salts [00166]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 — 32 — WO 2024/220633 PCT/US2024/025144 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. [00167]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, A.A-dimethylaniline, N- methylpiperidine, A-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine and N, N ’-dibenzyl ethylenedi ami ne, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. b. General Synthesis [00168]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. [00169]Compounds of formula (I) may be synthesized as shown in Schemes 1-10. — 33 — WO 2024/220633 PCT/US2024/025144 Scheme 1

[00170]As shown in Scheme 1, tert-butyl 3-bromo-4-oxopiperidine-l -carboxylate (i)may be subjected to a thioamide in solvent (e.g., ethanol) with heating to about 70-80 °C to provide intermediate (ii).Intermediate (iii)may be formed from subjecting intermediate (ii)to acid (e.g., TFA, HCI, etc.). Scheme 2 (iv) ORRO"B'R21. Suzuki Reaction 2. H+

[00171]As shown in Scheme 2, tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4//)- carboxylates (iv)may be subjected to Suzuki reaction conditions with the appropriate substituted boronic acid or ester reagent, palladium catalyst (e.g., Pd(PPh3)4, Pd(dppf)Ch) in the presence of a base (e.g., sodium carbonate, cesium carbonate) and solvents such as dioxane or dioxane/water mixtures. Subsequent deprotection under acidic conditions (e.g., TFA, HCI) may form intermediate compound (iii). Scheme 3

[00172]As illustrated in Scheme 3, intermediate compounds of formula (iii)may be subjected to standard nucleophilic substitution conditions with 2-chloro-3-methyl-6,7-dihydro-5//- — 34 — WO 2024/220633 PCT/US2024/025144 pyrrolo[3,4-/>]pyridin-5-ones (vi),base (e.g., DIPEA),solvent (e.g., DMSO)with heating to about 90-120 °C to provide compounds with the formula (vii). Scheme 4 (viii) (ix) [00173]As shown in Scheme 4, ester intermediate (viii)(wherein Y, Y1 and Y2 are a Cl,Br, or 1) may be subjected to amines, base (e.g., DIEA) and solvent (e.g., THE) with no heating or heating up to 40-50 °C to provide (ix). Scheme 5

[00174]As illustrated in Scheme 5, intermediate compounds (iii)may be subjected to standard nucleophilic substitution conditions with an intermediate (x) (wherein Y is a halogen), base (e.g., DIPEA), solvent (e.g., DMSO) with heating to about 90-120 °C to provide compounds with the formula (xi). — 35 — WO 2024/220633 PCT/US2024/025144 Scheme 6 RO-^ORR7Suzuki reaction (xi)

[00175] As shown in Scheme 6, intermediates of formula (xi)(wherein Visa halogen) may be coupled with a boronic acid or ester (e.g., trimethylboroxine) under Suzuki coupling conditions, generally known in the art to provide (xii).Coupling reactions may be conducted with a palladium catalyst, such as Pd(dppf)C12, 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 70-°C. Reactions may be facilitated with microwave irradiation. Scheme 7 (xi) solvent, heatcatalyst, Zn(CN) 2

[00176] As shown in Scheme 7, intermediates of formula (xi)(wherein Visa halogen) may be subjected to catalyst (e.g., Pd(PPh3)4), a cyanide source (e.g., Zn(CN)2) and solvent (e.g., DMF) with heating up to 120-140 °C to afford compounds of formula (xiii). Scheme 8 R2aHN'R2b Xantphos, Pd2(dba) 3, Cs 2CO31,4-dioxane, 110 °C — 36 — WO 2024/220633 PCT/US2024/025144

[00177]As shown in Scheme 8, intermediates (xiv)may be coupled with an amine under Buchwald coupling conditions, generally known in the art, to provide products (xv).An analogous reaction may be carried out with intermediate (iv)to provide -NR2aR2b substituted intermediate compounds. Scheme 9 NaOR23 nW 100 °Cr4b (xvi) [00178]As shown in Scheme 9, intermediates (xiv)may be coupled with an alkoxide-type reagent in an appropriate solvent to provide products (xvi).An analogous reaction may be carried out with intermediate (iv)to provide -OR2a substituted intermediate compounds. Scheme 10 Zn(CN) 2, Zn°, Pd(dppf)CI2 R6 DMF, 160 °C

[00179]As shown in Scheme 10, intermediates (xiv)may be reacted with zinc metal and Zn(CN)2 with a palladium catalyst (e.g. Pd(dppf)Ch) and heating in an appropriate solvent to provide (xvii).An analogous reaction may be carried out with intermediate (iv)to provide cyano substituted intermediate compounds. [00180]Suitable boronic acids/esters, amines, and alcohols for coupling reactions described herein may be readily obtained from commerical sources or prepared by standard methods well known to those skilled in the art. [00181]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 — 37 — S R2a WO 2024/220633 PCT/US2024/025144 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 CM20 2JE, England. [00182]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. [00183]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 the art 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. [00184]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 — 38 — WO 2024/220633 PCT/US2024/025144 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 (4th ed.), 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. [00185]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). [00186]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. [00187]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. c. Muscarinic Acetylcholine Receptor M4 Activity [00188]In some embodiments, the disclosed compounds potentiate the agonist response (e.g., acetylcholine) of mAChR M4. In some embodiments, the disclosed compounds increase mAChR M4 response 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 M4 activity can be demonstrated by methodology known in the art. For example, activation of mAChR Mactivity 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) and co- expression of a chimeric or promiscuous G protein. In some embodiments, the calcium flux was measured as an increase in fluorescent static ratio. In some embodiments, positive allosteric modulator activity was analyzed as a concentration-dependent increase in the EC20 acetylcholine response (i.e. the response of mAChR M4 at a concentration of acetylcholine that yields 20% of the maximal response). — 39 — WO 2024/220633 PCT/US2024/025144

[00189]In some embodiments, the disclosed compounds activate mAChR M4 response as an increase in calcium fluorescence in mAChR M4-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. In some embodiments, a disclosed compound activates the mAChR M4 response with an EC 50 of less than about 10 pM, less than about 5 pM, less than about 1 pM, less than about 500 nM, of less than about 100 nM, or less than about 50 nM. In some embodiments, the mAChR M4-transfected CHO-K1 cells are transfected with human mAChR M4 In some embodiments, the mAChR M4-transfected CHO-K1 cells are transfected with rat mAChR M4. [00190]The disclosed compounds may exhibit positive allosteric modulation of mAChR Mresponse to acetylcholine as an increase in response to non-maximal concentrations of acetylcholine in CHO-K1 cells transfected with a mAChR M4 in the presence of the compound, compared to the response to acetylcholine in the absence of the compound. In some embodiments, the disclosed compounds exhibit positive allosteric modulation of the mAChR Mresponse to acetylcholine with an EC50 of less than about 10 pM, less than about 5 pM, less than about 1 pM, less than about 500 nM, or less than about 100 nM. In some embodiments, the ECfor positive allosteric modulation is determined in CHO-K1 cells are transfected with a mAChR M4. In some embodiments, the mAChR M4 transfected human mAChR M4. In some embodiments, the mAChR M4 transfected rat mAChR M4. [00191]A disclosed compound can have selectivity for the mAChR M4 receptor vis-a-vis one or more of the mAChR M1, M2, M3 or M5 receptors. For example, the disclosed compounds may activate mAChR M4 response in mAChR M4 -transfected CHO-K1 cells with an EC50 less than the EC50 for one or more of mAChR M1, M2, M3 or Ms-transfected CHO-K1 cells. In some embodiments, a disclosed compound can activate mAChR M4 response with an EC50 of about 5- fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100- fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500- fold less than that for mAChR M1. In some embodiments, a disclosed compound can activate mAChR M4 response with an EC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M2. In some embodiments, a disclosed compound can activate mAChR M4 response with an EC50 of about 5- fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100- — 40 — WO 2024/220633 PCT/US2024/025144 fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500- fold less than that for mAChR M3. In some embodiments, a disclosed compound can activate mAChR M4 response with an EC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M5. In some embodiments, a disclosed compound can activate mAChR M4 response with an EC50 of 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less than that for the M2-Ms receptors, of about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400- fold less, or greater than about 500-fold less than that for the mAChR M1, M2, M3, or Mreceptors. [00192]The disclosed compounds may activate mAChR M4 response in M4-transfected CHO- KI cells with an EC50 of less than about 10 pM and exhibits a selectivity for the M4 receptor vis- a-vis one or more of the mAChR M1, M2, M3, or M5 receptors. For example, in some embodiments, the compound can have an EC50 of less than about 10 pM, of less than about pM, of less than about 1 pM, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also activate mAChR M4 response with an EC50 of about 5-fold less, 10-fold less, 20-fold less, 30-fold less, 50-fold less, 100-fold less, 200-fold less, 300-fold less, 400-fold less, or greater than about 500-fold less than that for mAChR M1. In some embodiments, the compound can have an EC50 of less than about 10 pM, of less than about pM, of less than about 1 pM, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also activate mAChR M4 response with an EC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M2. In some embodiments, the compound can have an EC50 of less than about 10 pM, of less than about 5 |1M, of less than about 1 pM, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also activate mAChR M4 response with an EC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR M3. In some embodiments, the compound can have an EC50 of less than about 10 pM, of less than about 5 pM, of less than about 1 pM, of less than about 500 nM, of less than about 100 nM, — 41 — WO 2024/220633 PCT/US2024/025144 or of less than about 50 nM; and the compound can also activate mAChR M4 response with an EC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for mAChR Ms. In some embodiments, the compound can have an EC50 of less than about 10 pM, of less than about 5 pM, of less than about 1 pM, of less than about 500 nM, of less than about 100 nM, or of less than about 50 nM; and the compound can also activate mAChR M4 response with ECso of 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less than that for the M2-M5 receptors, of about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, M2, M3, or Ms receptors, or greater than about 500-fold less than that for the mAChR M1, M2, M3, or Ms receptors. [00193]In vivo efficacy for disclosed compounds can be measured in a number of preclinical rat behavioral models where known, clinically useful antipsychotics display similar positive responses. For example, disclosed compounds may reverse amphetamine-induced hyperlocomotion in male Sprague-Dawley rats at doses ranging from 1 to 100 mg/kg p.o. 3. Pharmaceutical Compositions and Formulations [00194]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. [00195]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 — 42 — WO 2024/220633 PCT/US2024/025144 earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount. [00196]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. [00197]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 fdler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable 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. [00198]Thus, the compounds and their pharmaceutically acceptable salts 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, — 43 — WO 2024/220633 PCT/US2024/025144 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. [00199]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). [00200]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. [00201]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%. [00202]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%. [00203]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%. [00204]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%. [00205]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%. — 44 — WO 2024/220633 PCT/US2024/025144

[00206]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%. [00207]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%. [00208]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%. [00209]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%. [00210]Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%. [00211]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%. [00212]Suitable suspending agents include AVICEL RC-591 (from EMC 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%. [00213]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%. [00214]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. [00215]Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms — 45 — WO 2024/220633 PCT/US2024/025144 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%. [00216]Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, fdm-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. [00217]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. [00218]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. [00219]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. [00220]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 — 46 — WO 2024/220633 PCT/US2024/025144 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. [00221]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. [00222]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. [00223]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). [00224]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 — 47 — WO 2024/220633 PCT/US2024/025144 particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols. [00225]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. [00226]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. Specific emollients 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%. [00227]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%. [00228]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%. [00229]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%. [00230]The amount of thickener(s) in a topical composition is typically about 0% to about 95%. [00231]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 — 48 — WO 2024/220633 PCT/US2024/025144 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%. [00232]The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%. [00233]Suitable pH adjusting additives include HCI or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition. [00234]The pharmaceutical composition or formulation may exhibit positive allosteric modulation of mAChR M4 with an EC50 of less than about 10 pM, less than about 5 pM, less than about 1 pM, less than about 500 nM, or less than about 100 nM. The pharmaceutical composition or formulation may exhibit positive allosteric modulation of mAChR M4 with an EC50 of between about 10 pM and about 1 nM, about 1 pM and about 1 nM, about 100 nM and about 1 nM, or between about 10 nM and about 1 nM. a. Spray-Dried Dispersion Formulations [00235]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 obtained by 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. — 49 — WO 2024/220633 PCT/US2024/025144

[00236]Thus, in one embodiment, the disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (1). 4. Methods of Use [00237]The disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treatment of disorders, such as neurological and/or psychiatric disorders, associated with muscarinic acetylcholine receptor dysfunction. The disclosed compounds and pharmaceutical compositions may also be used in methods for the potentiation of muscarinic acetylcholine receptor activity in a mammal, and in methods for enhancing cognition in a mammal. The methods further include cotherapeutic methods for improving treatment outcomes in the context of cognitive or behavioral therapy. In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. a. Treating disorders [00238]The disclosed compounds, pharmaceutical compositions and formulations may be used for treating disorders, or used in methods for treatment of disorders, such as neurological and/or psychiatric disorders, associated with muscarinic acetylcholine receptor dysfunction. The methods of treatment may comprise administering to a subject in need of such treatment a therapeutically effective amount of the compound of formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (1). [00239]In some embodiments, the disclosure provides a method for enhancing cognition in a mammal comprising the step of administering to the mammal a therapeutically effective amount of the compound of formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (1). [00240]The compounds and compositions disclosed herein may be useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with selective mAChR M4 receptor activation. For example, a treatment can include selective mAChR M4 receptor activation to an extent effective to affect cholinergic activity. A disorder can be associated with cholinergic activity, for example cholinergic hypofunction. Thus, 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 or at least one disclosed pharmaceutical composition, in an amount effective to treat the disorder in the subject. — 50 — WO 2024/220633 PCT/US2024/025144

[00241]Also provided is a method for the treatment of one or more disorders associated with mAChR M4 receptor activity in a subject comprising the step of administering to the subject a therapeutically effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. [00242]In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a disorder associated with the mAChR M4 receptor. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a disorder associated with the mAChR M4 receptor. [00243]In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disorder associated with the mAChR M4 receptor. [00244]In some embodiments, the disclosure provides a method for the treatment of a disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or pharmaceutically acceptable salt thereof. [00245]In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal. [00246]In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal. [00247]In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal. — 51 — WO 2024/220633 PCT/US2024/025144

[00248]In some embodiments, the disclosed compounds and compositions have utility in treating a variety of neurological, psychiatric and cognitive disorders associated with the mAChR M4 receptor, including one or more of the following conditions or diseases; schizophrenia, psychotic disorder NOS, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic break, tardive psychosis, myxedematous psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar I disorder with psychotic features, and substance-induced psychotic disorder. In some embodiments, the psychotic disorder is a psychosis associated with an illness selected from major depressive disorder, affective disorder, bipolar disorder, electrolyte disorder, Alzheimer ’s disease, neurological disorder, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder. [00249]In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a neurological, psychiatric, or cognitive disorder associated with the mAChR M4 receptor, in particular, the disorders described herein. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the treatment of a neurological, psychiatric, or cognitive disorder associated with the mAChR M4 receptor, in particular, the disorders described herein. In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a neurological, psychiatric, or cognitive disorder associated with the mAChR M4 receptor, in particular, the disorders described herein. [00250]In some embodiments, the disorder is a neurological disorder selected from brain tumor, dementia with Lewy bodies, multiple sclerosis, sarcoidosis, Lyme disease, syphilis, Alzheimer ’s disease, Parkinson ’s disease, and anti-NMD A receptor encephalitis. [00251]In some embodiments, the disorder is a psychotic disorder selected from schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, and shared psychotic disorder. In some embodiments, the schizophrenia is selected from catastrophic schizophrenia, catatonic schizophrenia, paranoid schizophrenia, residual schizophrenia, disorganized schizophrenia, and undifferentiated schizophrenia. In some embodiments, the disorder is selected from schizoid personality disorder, schizotypal personality — 52 — WO 2024/220633 PCT/US2024/025144 disorder, and paranoid personality disorder. In some embodiments, the psychotic disorder is due to a general medical condition and is substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants, and cocaine). [00252]In some embodiments, the present disclosure provides a method for treating a cognitive disorder, comprising administering to a patient in need thereof an effective amount of a compound or a composition of the present disclosure. In some embodiments, cognitive disorders include 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 disorder, substance-induced persisting delirium, dementia due to HIV disease, dementia due to Huntington ’s disease, dementia due to Parkinson ’s disease, Parkinsonian-ALS demential complex, dementia of the Alzheimer ’s type, age-related cognitive decline, and mild cognitive impairment. [00253]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. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (2013, American Psychiatric Association, Washington DC) provides a diagnostic tool for neurocognitive disorders (NCDs) that include delirium, followed by the syndromes of major NCD, mild NCD, and their etiological subtypes. The major or mild NCD subtypes include NCD due to Alzheimer ’s disease, vascular NCD, NCD with Lewy bodies, NCD due to Parkinson ’s disease, frontotemporal NCD, NCD due to traumatic brain injury, NCD due to HIV infection, substance/medication-inducedNCD, NCD due to Huntington ’s disease, NCD due to prion disease, NCD due to another medical condition, NCD due to multiple etiologies, and unspecified NCD. The NCD category in DSM-5 encompasses the group of disorders in which the primary clinical deficit is in cognitive function, and that are acquired rather than developmental. As used herein, the term “cognitive disorders ” includes treatment of those cognitive disorders and neurocognitive disorders as described in DSM-IV-TR or DSM-5. 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 — 53 — WO 2024/220633 PCT/US2024/025144 scientific progress. Thus the term “cognitive disorders ” is intended to include like disorders that are described in other diagnostic sources. [00254]In some embodiments, 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 or composition of the present disclosure. Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder. DSM-IV-TR provides a diagnostic tool that includes paranoid, disorganized, catatonic, undifferentiated or residual schizophrenia, and substance- induced psychotic disorder. DSM-5 eliminated the subtypes of schizophrenia, and instead includes a dimensional approach to rating severity for the core symptoms of schizophrenia, to capture the heterogeneity in symptom type and severity expressed across individuals with psychotic disorders. As used herein, the term “schizophrenia or psychosis ” includes treatment of those mental disorders as described in DSM-IV-TR or DSM-5. 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. [00255]In some embodiments, the present disclosure provides a method for treating pain, comprising administering to a patient in need thereof an effective amount of a compound or composition 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. [00256]The compounds and compositions may be 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 and compositions may be 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. [00257]In the treatment of conditions which require activation of mAChR M4, an appropriate dosage level may be about 0.01 to 500 mg per kg patient body weight per day, which can be administered in single or multiple doses. The dosage level may be about 0.1 to about 250 mg/kg — 54 — WO 2024/220633 PCT/US2024/025144 per day, or about 0.5 to about 100 mg/kg per day. A suitable dosage level can be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 10milligrams of the active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. [00258]Thus, in some embodiments, the disclosure relates to a method for activating mAChR M4 receptor activity in at least one cell, comprising the step of contacting the at least one cell with at least one disclosed compound or at least one product of a disclosed method in an amount effective to activate mAChR M4 in the at least one cell. In some embodiments, the cell is mammalian, for example, human. In some embodiments, the cell has been isolated from a subject prior to the contacting step. In some embodiments, contacting is via administration to a subject. [00259]In some embodiments, the invention relates to a method for activating mAChR Mactivity in a subject, comprising the step of administering to the subject at least one disclosed compound or at least one product of a disclosed method in a dosage and amount effective to activating mAChR M4 activity in the subject. In some embodiments, the subject is mammalian, for example, human. In some embodiments, the mammal has been diagnosed with a need for mAChR M4 agonism prior to the administering step. In some embodiments, the mammal has been diagnosed with a need for mAChR M4 activation prior to the administering step. In some embodiments, the method further comprises the step of identifying a subject in need of mAChR M4 agonism. — 55 — WO 2024/220633 PCT/US2024/025144

[00260]In some embodiments, the invention relates to a method for the treatment of a disorder associated with selective mAChR M4 activation, for example, a disorder associated with cholinergic activity, in a mammal comprising the step of administering to the mammal at least one disclosed compound or at least one product of a disclosed method in a dosage and amount effective to treat the disorder in the mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed with a need for treatment for the disorder prior to the administering step. In some embodiments, the method further comprises the step of identifying a subject in need of treatment for the disorder. [00261]In some embodiments, the disorder can be selected from psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as 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, 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. [00262]In some embodiments, the disorder is Alzheimer ’s disease. b. Potentiation of Muscarinic Acetylcholine Receptor Activity [00263]In some embodiments, the disclosure relates to a method for potentiation of muscarinic acetylcholine receptor activity in a mammal comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or pharmaceutically acceptable salt thereof. [00264]In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in a method for the potentiation of muscarinic acetylcholine receptor activity in a mammal. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the potentiation of muscarinic acetylcholine receptor activity in a mammal. — 56 — WO 2024/220633 PCT/US2024/025144

[00265]In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the potentiation of muscarinic acetylcholine receptor activity in a mammal. [00266]In some embodiments, potentiation of muscarinic acetylcholine receptor activity increases muscarinic acetylcholine receptor activity. In some embodiments, potentiation of muscarinic acetylcholine receptor activity is partial agonism of the muscarinic acetylcholine receptor. In some embodiments, potentiation of muscarinic acetylcholine receptor activity is positive allosteric modulation of the muscarinic acetylcholine receptor. [00267]In some embodiments, the compound administered exhibits potentiation of mAChR M4 with an EC 50 of less than about 10 pM, less than about 5 pM, less than about 1 pM, less than about 500 nM, or less than about 100 nM. In some embodiments, the compound administered exhibits potentiation of mAChR M4 with an EC50 of between about 10 pM and about 1 nM, about 1 pM and about 1 nM, about 100 nM and about 1 nM, or about 10 nM and about 1 nM. [00268]In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed with a need for potentiation of muscarinic acetylcholine receptor activity prior to the administering step. In some embodiments, the method further comprises the step of identifying a mammal in need of potentiating muscarinic acetylcholine receptor activity. In some embodiments, the potentiation of muscarinic acetylcholine receptor activity treats a disorder associated with muscarinic acetylcholine receptor activity in the mammal. In some embodiments, the muscarinic acetylcholine receptor is mAChR M4. [00269]In some embodiments, potentiation of muscarinic acetylcholine receptor activity in a mammal is associated with the treatment of a neurological and/or psychiatric disorder associated with a muscarinic receptor dysfunction, such as a neurological or psychiatric disorder disclosed herein. In some embodiments, the muscarinic receptor is mAChR M4. [00270]In some embodiments, the disclosure provides to a method for potentiation of muscarinic acetylcholine receptor activity in a cell, comprising the step of contacting the cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is mammalian (e.g., human). In some embodiments, the cell has been isolated from a mammal prior to the contacting step. In some embodiments, contacting is via administration to a mammal. — 57 — WO 2024/220633 PCT/US2024/025144 c. Enhancing Cognition [00271]In some embodiments, the invention relates to a method for enhancing cognition in a mammal comprising the step of administering to the mammal an effective amount of least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. [00272]In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in a method for the enhancment of cognition in a mammal. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for the enhancment of cognition in a mammal. [00273]In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the enhancment of cognition in a mammal. [00274]In some embodiments, the mammal is a human. In some embodiments, the mammal has been diagnosed with a need for cognition enhancement prior to the administering step. In some embodiments, the method further comprises the step of identifying a mammal in need of cognition enhancement. In some embodiments, the need for cognition enhancement is associated with a muscarinic receptor dysfunction. In some embodiments, the muscarinic receptor is mAChR M4. [00275]In some embodiments, the cognition enhancement is a statistically significant increase in Novel Object Recognition. In some embodiments, the cognition enhancement is a statistically significant increase in performance of the Wisconsin Card Sorting Test. d. Cotherapeutic methods [00276]The present invention is further directed to administration of a selective mAChR Mactivator for improving treatment outcomes in the context of cognitive or behavioral therapy. That is, in some embodiments, the invention relates to a cotherapeutic method comprising a step of administering to a mammal an effective amount and dosage of at least one disclosed compound, or a pharmaceutically acceptable salt thereof. [00277]In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in a cotherapeutic method with cognitive or behaviorial therapy in a mammal. In some embodiments, the disclosure provides a — 58 — WO 2024/220633 PCT/US2024/025144 pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a cotherapeutic method with cognitive or behaviorial therapy in a mammal. [00278]In some embodiments, the disclosure provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for a cotherapeutic method with cognitive or behaviorial therapy in a mammal. [00279]In some embodiments, 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 a still further 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. [00280]It is understood that the disclosed cotherapeutic methods can be used in connection with the disclosed compounds, compositions, kits, and uses. e. Combination Therapies [00281]In the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed compounds. In some embodiments, administration of an additional therapeutic agent with a disclosed compound may allow lower doses of the other therapeutic agents and/or administration at less frequent intervals. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula (I). The above combinations include — 59 — WO 2024/220633 PCT/US2024/025144 combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. [00282]The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefor, 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 may be used. 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. Thus, when used in combination with one or more other active ingredients, the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly. [00283]The pharmaceutical compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. [00284]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 invention. When a compound of the present invention 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 invention. [00285]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 — 60 — WO 2024/220633 PCT/US2024/025144 each will be used. Thus, for example, when a compound of the present invention 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 invention 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. [00286]In such combinations a disclosed compound 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). [00287]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. [00288]In some embodiments, the compound can be employed in combination with anti- Alzheimer ’s agents, beta-secretase inhibitors, cholinergic agents, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, Mi allosteric agonists, Mi positive allosteric modulators, NSAIDs including ibuprofen, vitamin E, and anti-amyloid antibodies. In another embodiment, the subject compound can be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), 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, busprione, 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, — 61 — WO 2024/220633 PCT/US2024/025144 ni sobamate, 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. [00289]In some embodiments, the compound 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 will be 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. [00290]In some embodiments, the compound can be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indoIone 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 — 62 — WO 2024/220633 PCT/US2024/025144 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. [00291]In some embodiments, the compound 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 (CRT) antagonists, a-adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypical anti- depressants, benzodiazepines, 5-HT1A agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRT) 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. [00292]In some embodiments, the compounds can be coadministered with orthosteric muscarinic agonists, muscarinic potentiators, or cholinesterase inhibitors. In some embodiments, the compounds can be coadministered with GlyTI inhibitors and the like such as, but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbitol, and salts thereof and combinations thereof. f. Modes of Administration [00293]Methods of treatment may include any number of modes of administering a disclosed — 63 — WO 2024/220633 PCT/US2024/025144 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 oral administration, 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. Gelucire.TM.). In the pharmaceutical composition, the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition. [00294]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. [00295]The term “parenterally, ” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. 5. Kits [00296]In one aspect, the disclosure provides kits comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, and one or more of:(a) at least one agent known to increase mAChR M4 activity;(b) at least one agent known to decrease mAChR M4 activity;(c) at least one agent known to treat a disorder associated with cholinergic activity;(d) instructions for treating a disorder associated with cholinergic activity;(e) instructions for treating a disorder associated with M4 receptor activity; or (f) instructions for administering the compound in connection with cognitive or — 64 — WO 2024/220633 PCT/US2024/025144 behavioral therapy. [00297]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. [00298]The disclosed kits can be employed in connection with disclosed methods of use. [00299]The kits may further comprise information, instructions, or both that use of the kit may 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. In addition 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, for example with the benefit of treating or preventing medical conditions in mammals (e.g., humans). [00300]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. Examples [00301]All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer. 1H chemical shifts are reported in 6 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, hold at 95% acetonitrile for 0.1 min, 0.5 mL/min, 55° C (“90 sec method ”). Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 pm, 1.0 x 50 mm) at 0.5 mL/min, with column and solvent temperatures maintained at 55 °C. The DAD was set to scan from 190 to 300 nm, — 65 — WO 2024/220633 PCT/US2024/025144 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 °C 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. a. Preparation of Intermediates Na2CO3, THF, 70°C Lawesson's Reagent

[00302] 1-Methylcyclopropanecarbothioamide.To a suspension of 1-methylcyclopropanecarboxamide (1.1 g, ll.lmmol) and sodium carbonate (1.2 g, ll.lmmol) in THF (55 mL) was added Lawesson’s reagent (4.5 g, 1 l.lmmol), and the reaction mixture was heated to 70 °C. After 2 h, the reaction mixture was concentrated and the resulting residue was diluted with EtOAc and washed with water (2x) and brine. The organic layer was concentrated and dried under high vacuum to afford the title compound (1.2 g). ES-MS [M+l]+: 116.9. 9 p Lawesson's Reagenth2NXA7־ " h2NV Na2CO3, THF, 70°C

[00303] 1-Fluorocyclopropane-l-carbothioamide.To a suspension of 1- fluorocyclopropanecarboxamide (500 mg, 4.85 mmol) and sodium carbonate (524 mg, 4.mmol) in THF (24 mL) was added Lawesson's reagent (1.96 g, 4.85 mmol). The resulting mixture was heated to 70 °C. After 36 hr, the reaction mixture was concentrated and the resulting residue was diluted with EtOAc and washed with water (2x) and brine. The organic layer was concentrated to afford the desired compound, which was carried forward to the next step without further purification. *HNMR (400 MHz, DMSO) 8 9.74 (d, J = 194.7 Hz, 2H), 1.(td, .1= 8.7, 5.2 Hz, 2H), 1.49 - 1.38 (m, 2H). — 66 — WO 2024/220633 PCT/US2024/025144 2. TFA, DCM

[00304] 2-(l-Methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine.To a suspension of 1-methylcyclopropanecarbothioamide (1.0 g, 9.0 mmol) in ethanol (46 mL) was added A-Boc-3-bromo-4-oxopiperidine (2.5 g, 9.0 mmol), and the reaction was subsequently heated to 80 °C for 48 h. The crude reaction mixture was concentrated in vacuo. To the residue was added DCM (25 mL) and TFA (6.9 mL). After lb at rt, the reaction mixture was concentrated. The residue was dissolved in EtOAc and saturated Na2CO3 solution. The mixture was separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified via normal phase column chromatography (0-70% EtOAc/Hexanes followed by 0-10% DCM:MeOH; 1% NHOH gradient) to afford the title compound (1.59 g). 1H NMR of title compound (400 MHz, CDC13) 4.00 (t, J= 1.8 Hz, 2H), 3.71 (t, J= 5.8 Hz, 2H), 2.80-2.76 (m, 2H), 1.54 (s, 3H), 1.23 (dd, J= 6.8, 4.4 Hz, 2H), 0.91 (dd, J= 6.5, 4.1 Hz, 2H); ES-MS [M+l]+: 295.1 and 195.1. 1. EtOH, 80°C 2. HCI, 1,4-dioxane

[00305] 2-Cyclopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine hydrochloride. Cyclopropanecarbothioamide (1.8 g, 18.0 mmol) and A-Boc-3-bromo-4-oxopiperidine (5.0 g, 18.0 mmol) in ethanol (30 mL) was stirred at 80 °C for 2 h. The solution was concentrated, then 1,4-dioxane (8 mL) and AM hydrochloric acid solution in 1,4-dioxane (40 mL) were added.After ih at rt, the solution was concentrated in vacuo to afford the title compound (4.0 g). 1H NMR (400 MHz, DMSO-d6) 8 4.30 (s, 2H), 2.91 (t, J= 6.0 Hz, 2H), 2.59 (t, J= 6.5 Hz, 2H), 2.41-2.35 (m, IH), 1.13-1.08 (m, 2H), 0.95-0.91 (m, 2H); ES-MS [M+l]+: 181.4. 1. EtOH, 80°C2. TFA, DCM

[00306] 2-(2,2-Dimethylcyclopropyl)-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine.In a vialwere combined 2,2-dimethylcyclopropanecarbothioamide (232 mg, 1.8 mmol) and A-Boc-3- — 67 — 1. EtOH, 80°C WO 2024/220633 PCT/US2024/025144 bromo-4-oxopiperidine (500 mg, 1.8 mmol) in ethanol (2 mL). After 2 h at 80 °C, the reaction mixture was concentrated. To the crude residue was added DCM (2 mL) and trifluoroacetic acid (1.38 mL). After 1 h at rt, the solution was concentrated, diluted with saturated aqueous Na2COsolution, and extracted with DCM (3x). The combined organic layers were passed through a hydrophobic phase separator and concentrated to afford the title compound (195 mg). 1H NMR(400 MHz, DMSO) 5 3.83 (d, J= 1.8 Hz, 2H), 2.96 (t, J= 5.8 Hz, 2H), 2.61 (t, J= 4.1. 2H), 2.(dd, J =8.4, 5.6 Hz, 1H), 1.17 (s, 3H), 1.11-1.01 (m, 2H), 0.97 (s, 3H); ES-MS [M+l]+: 209.3. 2. TEA, DCM

[00307] 2-Isopropyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine.A vial containing 2- methylpropanethioamide (185 mg, 1.8 mmol) and/V-Boc-3-bromo-4-oxopiperidine (500 mg, 1.mmol) in ethanol (2 mL) was heated at 80 °C for 2 h. The reaction mixture was concentrated.To the crude residue was added DCM (2 mL) and tri fluor oacetic acid (1.38 mL). After l h, the solution was concentrated, diluted with saturated Na2C03 solution, and the aqueous layer was extracted with DCM (3x). The combined organic layers were passed through a hydrophobic phase separator and concentrated to afford the title compound (372 mg). 1H NMR (400 MHz, CDC13) 5 4.40 (s, 2H), 3.53 (t, J= 6.1 Hz, 2H), 3.29 (p, J= 6.9 Hz, 1H), 3.17 (t, J= 5.8 Hz, 2H), 1.38 (d, J= 6.9 Hz, 6H); ES-MS [M+l]+: 183.2. 2. TEA, DCM

[00308] 2-(/(,/7-Butyl)-4.5.6.7-letrahydrothiazolo|5.4-c|pyridine.A vial containing 2,2- dimethylpropanethioamide (211 mg, 1.8 mmol) and/V-Boc-3-bromo-4-oxopiperidine (500 mg, 1.8 mmol) in Ethanol (2 mL) was heated at 80 °C for 2 h. The solution was concentrated. To the crude residue was added DCM (2 mL) and trifluoroacetic acid (1.4 mL). After 1 h at rt, the reaction mixture was concentrated and purified by SCX cartridge. After elution with IN NH/MeOH solution, the solvents were removed to afford the title compound (238 mg). 1H NMR — 68 — 1. EtOH, 80°C 1. EtOH, 80°C WO 2024/220633 PCT/US2024/025144 (400 MHz, DMSO)8 3.83 (t, J= 1.9 Hz, 2H), 2.96 (t, J= 5.8 Hz, 2H), 2.61 (t, J=5.8, 1.9 Hz, 2H), 1.34 (s, 9H); ES-MS [M+l]+: 197.1. 1. EtOH, 80 °C2. TEA, DCM

[00309] 2-(l-Fluorocyclopropyl)-4,5,6,7-tetrahydrothiazolo [5,4-c] pyridine.1 -Fluorocyclopropane- 1-carbothioamide (114 mg, 0.72 mmol) and jV-boc-3-bromo-4- oxopiperidine (200 mg, 0.72 mmol) in ethanol (2.3 mL) was heated to 80 °C for 18 h. The reaction mixture was concentrated and the residue was purified by normal phase column chromatography (0-80% EtOAc/hexanes). To the intermediate residue was added DCM and trifluoroacetic acid (2.0 mL; 2:1) at room temperature. After 3 hr, the solution was concentrated and the material was purified using an SCX cartridge. After elution with 2N NH3/M60H solution, the solvents were removed to afford the title compound. ES-MS [M+l]+: 199; 1HNMR (400 MHz, DMSO) 5 3.92 (t, J= 1.9 Hz, 2H), 2.99 (t, J= 5.8 Hz, 2H), 2.63 (tt, J = 5.9, 1.9 Hz, 2H), 1.70- 1.55 (m, 2H), 1.40- 1.28 (m, 2H). 1. EtOH, 80 °C2. TEA, DCM

[00310] 2-Cyclobutyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. Cyclobutanecarbothioamide (203 mg, 1.76 mmol) and 7V-boc-3-bromo-4-oxopiperidine (490 mg, 1.76 mmol) in ethanol (4.5 mL) was stirred at 80 °C for 2 hr. The solution was concentrated then DCM (4.0 mL) and trifluoroacetic acid (1.35 mL) were added at room temperature for hr. The solution was concentrated then diluted with EtOAc and saturated Na2CO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound (3mg). ES-MS [M+l]+: 195; 1HNMR (400 MHz, CDC13) 8 4.21 (s, 2H), 3.83 - 3.72 (m, 2H), 3.(t, .7 = 6.0 Hz, 2H), 2.94 (t, .7 = 5.8 Hz, 2H), 2.49 - 2.37 (m, 2H), 2.37 - 2.24 (m, 2H), 2.12 - 1.84 (m, 2H). — 69 — WO 2024/220633 PCT/US2024/025144 oh 2. DOM, TFA 1. Pd(PPh 3)4, Na2CODioxane/Water, 80°C

[00311] 2-(Thiophen-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine.In a vial were combined thiophene-2-boronic acid (105 mg, 0.82 mmol), tert-butyl 2-bromo-6,7- dihydrothiazolo[5,4-c]pyridine-5(477)-carboxylate (175 mg, 0.55 mmol), sodium carbonate (1mg, 1.37 mmol), and tetrakis(triphenylphosphine)palladium(0) in 1,4-dioxane (2 mL) and water (0.5 mL). After the reaction was purged with nitrogen (3x), the reaction was heated to 80 °C for h. The reaction was filtered over Celite® and the Celites was washed with DCM (2 x 25 mL). The filtrate was concentrated and purified by normal-phase chromatography (0-40% EtOAc/Hexanes) to afford the desired Boc-protected amine. The Boc-protected amine was dissolved in DCM (2 mL) and tri fluoroacetic acid (0.59 mL). After l h, the reaction was concentrated, basified with saturated Na2CO3, extracted with DCM (3x), passed through a hydrophobic phase separator, and concentrated to afford the title compound (112 mg). 1H NMR (400 MHz, CDC13) 5 7.44 (dd, J =3.1, 1.2 Hz, 1H), 7.36 (dd, J= 5.1, 1.2 Hz, 1H), 7.06 (dd, J= 5.1, 3.7 Hz, 1H), 4.10 (s, 2H), 3.24 (t, J= 5.9 Hz, 2H), 2.90 (ddd, J= 6.0, 4.1, 1.8 Hz, 2H); ES- MS [M+l]+: 223.1. 2. DCM, TFA 1. Pd(dppf)CI2,Cs2CO 3Dioxane/Water, 100°C

[00312] 2-( 1-Methyl-1//-pyr1؛zol-5-yl)-4.5.6.7-1 etr:111ydrothi1؛zolo|5,4-c|pyridine,tert-butyl2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(477)-carboxylate (300 mg, 0.94 mmol), cesium carbonate (924 mg, 2.82 mmol), Pd(dppf)C12 (69 mg, 0.09 mmol), and l-methylpyrazole-5- boronic acid pinacol ester (391 mg, 1.88 mmol) in 1,4-dioxane (2.3 mL) and water (0.mL) were heated at 100 °C for 18 h. The mixture was filtered through a pad of Celite®, and the filtrate was concentrated. The residue was purified by normal-phase chromatography (0-40% EtOAc/Hexanes) to afford Boc-amine, which was dissolved in DCM (2 mL) and trifluoroacetic acid (1.1 mL). After l h, the reaction was concentrated, basified with saturated Na2CO3 solution, extracted with DCM (3x), passed through a hydrophobic phase separator, and concentrated to afford the title compound (162 mg). 1H NMR (400 MHz, CDC13) 5 7.47 (d, J= 2.0 Hz, 1H), 6.60 — 70 — WO 2024/220633 PCT/US2024/025144 (d, J= 2.1 Hz, 1H), 4.26 (d, J= 1.6 Hz, 2H), 4.22 (s, 3H), 3.39 (t, J = 5.9 Hz, 2H), 3.10-3.(m, 2H); ES-MS [M+l]+: 221.2.

NaOH, EtOH

[00313] tert-Butyl 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2- carboxylic acid.To a solution of 5-(tert-butyl) 2-ethyl 6,7-dihydrothiazolo[5,4-c]pyridine- 2,5(4/7)-dicarboxylate (300 mg, 0.96 mmol) in ethanol (4.8 mL) was added a 5Maqueous solution of NaOH (384 pL, 1.92 mmol). After 3 h, the reaction mixture was concentrated and carried forward without further purification. ES-MS [M + H]+= 285.

NH4CI, HATUDIEA, THE, 75 °C

[00314] tert-Butyl 2-carbamoyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate. To a solution of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (273 mg, 0.96 mmol) in THE (3.2 mL) was added A,A-diisopropylethylamine (1.7 mL, 9.mmol), HATU (1.09 g, 2.88 mmol), and NHCl (285 mg, 5.76 mmol). The mixture was heated to °C for 18 hours. At room temperature, the reaction was diluted with water and extracted with chloroform/IPA (3:1) (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude material was purified using normal-phase column chromatography (0- 2% MeOH/DCM). 1HNMR (400 MHz, CDCI3) 5 7.01 (s, 1H), 5.46 (s, 1H), 4.71 (s, 2H), 3.(t, J= 5.3 Hz, 2H), 2.90 (t, J= 5.1 Hz, 2H), 1.49 (s, 9H); ES-MS [M + H]+= 284.

[00315] 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide.To a solution of tert- butyl 2-carbamoyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4/7)-carboxylate (272 mg, 0.96 mmol)in DCM (6.4 mL) was added TFA (735 pL, 9.6 mmol). After 18 hours at room temperature, the — 71 — WO 2024/220633 PCT/US2024/025144 reaction was concentrated then dissolved in MeOH and loaded onto a SCX cartridge (HF bond). After flushing the cartridge with MeOH, the cartridge was eluted with 7NNHs/MeOH solution. The solvents were removed in vacuo to afford the title compound. 1H NMR (400 MHz, DMSO) 7.15 (s, 1H), 6.80 (s, 1H), 3.05 (t, J= 1.7 Hz, 2H), 2.10 (t, J = 5.8 Hz, 2H), 1.83 (ddd, J=1A, 3.8, 1.5 Hz, 2H); ES-MS [M + H]+= 184.

HO N

[00316]Ethyl 5-br01B0-6-hydr0xy-2-methyhii£0tmate. To a solution of ethyl-2-methyl-6- oxo-1,6-dihydropyridine-3-carboxyate (10 g, 55.2 mmol) in DMF (185 mL) at 0 °C was slowly added N-bromosuccinimide (10.8 g, 60.7 mmol) portionwise. The ice bath was removed. After h, to the reaction was added saturated sodium bisulfite (aq) and stirred for 30 min. The reaction was filtered and the collected solid was dried by vacuum oven to afford the title compound (14.2 g). 1HNMR (400 MHz, DMSO) 8 8.15 (s, 1H), 4.20 (q, J= 7.1 Hz, 2H), 3.(s, 3H), 2.55 (s, 1H), 1.27 (t, J= 7.1 Hz, 3H); ES-MS [M+l]+: 260.0/262.0. 0MeCN, 85OC Bn w * VIHO Ncr n

[00317]Ethyl 5-bromo-6-cWoro-2-methyh1kotinate. To a 500 mL round bottom flask was added ethyl 5-bromo-6-hydroxy-2-methylnicotinate (14.2 g, 54.6 mmol) in MeCN (300 mL) followed by phosphorous (V) oxychloride (29.4 mL, 316 mmol). The reaction was equipped with a condenser and heated at 85 °C. After 18 h, the mixture was cooled to room temperature and concentrated. The residue was dissolved in DCM (10 mL) and slowly added dropwise to a stirred solution of saturated aqueous NaHCO3 solution, keeping the pH >7. Additional DCM (mL) was added and the mixture was allowed to stir for 30 min. The organic layer was separated and the aqueous layer was re-extracted with 3:1 chloroform/IPA (3 x 20 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-25% EtOAc/Hexanes) to afford the title compound (12 g). 1H — 72 — DMF, 0°C WO 2024/220633 PCT/US2024/025144 NMR (400 MHz, CDC13) 6 8.40 (s, 1H), 4.38 (q, J= 7.1 Hz, 2H), 2.76 (s, 3H), 1.40 (t, J= 1AHz, 3H). ES-MS [M+l]+: 277.9/279.9.

[00318]Ethyl 5-bromo~2-(bromomethyl)-6~£hIor H2N— THF, 000

[00319] 3-Bromo-2-£hIon)-6-methyl-6,7-dihydro-5/f-pyrroio[3,46 ־]pyi ־idin-5-one. To asolution of ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate (2.5 g, 6.99 mmol) in THF (1mL) at 0 °C was added a 2.0 Absolution of methylamine (17.5 mL, 35.0 mmol) and the reaction stirred for 30 min. The reaction was concentrated at it and purified by normal-phase chromatography (0-30% EtOAc/DCM) to afford the title compound (948 mg). 1H NMR (4MHz, DMSO) 5 8.49 (s, 1H), 4.50 (s, 2H), 3.09 (s, 3H). ES-MS [M+l]+: 261.1/263.1.

NMP, DIPEA160°C — 73 — WO 2024/220633 PCT/US2024/025144

[00320] 3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6-methyl- 6,7-dihydro-51/-pyrrolo[3,4-6]pyridin-5-one.To a solution of 3-bromo-2-chloro-6-methyl-777- pyrrolo[3,4-/)]pyridin-5-one (262 mg, 1.0 mmol) andN,N-diisopropylethylamine (0.87 mL, 5.mmol) in NMP (3.7 mL) was added 2-cyclopropyl-4,5,6,7-tetrahydro-[l,3]thiazolo[5,4- c]pyridine (271 mg, 1.5 mmol). The reaction was heated to 160 °C. After 18 h, the reaction cooled to rt and water was added to generate a precipitate. The suspension was filtered, rinsed with water, and dried under N2. The residue was purified by normal-phase chromatography (0- 5% MeOH/DCM/0.1% NHOH) to afford the title compound (225 mg). 1H NMR (400 MHz, CDCL) 5 8.15 (s, 1H), 4.60 (s, 2H), 4.25 (s, 2H), 3.80 (t, J= 5.6 Hz, 2H), 3.42 -3.32 (m, 2H), 2.84 (s, 3H), 2.36 (q, J= 9.0 Hz, 2H), 2.29 (dt, J= 8.4, 4.8 Hz, 1H), 2.08 - 1.95 (m, 2H); ES-MS [M+l]+: 405.1/407.1.

[00321] 3-Bromo-2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)- 6-methyl-6,7-dihydro-5Jf-pyrroIo[3,4-6]pyridin-5-one.To a solution of 3-bromo-2-chloro-6- methyl-7/7-pyrrolo[3,4-6]pyridin-5-one (30 mg, 0.11 mmol) and N,N-diisopropylethylamine (0.mL, 0.57 mmol) in DMSO (0.57 mL) was added 2-(l-fluorocyclopropyl)-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridine (27.0 mg, 0.14 mmol). The reaction was heated to 70 °C for h. The reaction was purified by reverse-phase HPLC (18-58% MeCN/Water/0.05% NHJOH) to afford the title compound. ES-MS [M+l ]+: 425/426; 1H NMR (400 MHz, CDCL) 5 8.17 (d, J= 1.5 Hz, 1H), 4.68 (q.1.8 Hz, 2H), 4.26 (d, J= 1.5 Hz, 2H), 3.82 (td, J- 5.7, 1.6 Hz, 2H), 3.19 (d, J= 1.5 Hz, 3H), 3.09 (ddd, J= 7.6, 3.8, 1.8 Hz, 2H), 1.65 - 1.54 (m, 2H), 1.51-1.(m, 2H). — 74 — DIEA, DMSO 70 °C WO 2024/220633 PCT/US2024/025144

[00322] 3-Bromo-2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5J/-pyrrolo[3,4- 6]pyridin-5-one.To a solution of ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate (1300 mg, 2.8 mmol) in THE (55 mL) was slowly added 2,4-dimethoxybenzylamine (2.1mL, 14.0 mmol) and the reaction stirred for 30 min at RT. Triethylamine (0.58 mL, 4.2 mmol) was added. After h at room temperature, the reaction was concentrated over Celite® and purified by normal- phase chromatography (0-25% EtOAc/DCM) to afford the title compound. 1H NMR (400 MHz, CDCI) 8 8.30 (s, 1H), 7.22 (dd, J-7.8, 0.7 Hz, 1H), 6.46-6.43 (m, 2H), 4.74 (s, 2H), 4.30 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H). ES-MS [M+l]+: 397/399.

[00323] 3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z/)-yI)-6-(2,4- dimethoxybenzyl)-6,7-dihydro-57/-pyrrolo [3,4-6] pyridin-5-one.To a solution of 3-bromo-2- chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5//-pyrrolo[3,4-6]pyridin-5-one (888 mg, 2.mmol) and A,A-diisopropylethylamine (1.94mL, 11.2 mmol) in NMP (5.6 mL) was added 2- cyclopropyl-4,5,6,7-tetrahydro-[l,3]thiazolo[5,4-c]pyridine (604 mg, 3.4 mmol). The reaction heated to 120 °C. After 18 h, water was added and the precipitate was filtered, rinsed with water, and dried under N2 to afford the title compound. 1H NMR (400 MHz, CDCL) 8 8.16 (s, 1H), 7.20 (d, J= 8.1 Hz, 1H), 6.45-6.43 (m, J = 2.4 Hz, 2H), 4.72 (s, 2H), 4.56 (s, 2H), 4.16 (s, 2H), — 75 — WO 2024/220633 PCT/US2024/025144 3.83 (s, 3H), 3.81-3.75 (s, 5H), 3.05 (td, J = 5.6, 1.9 Hz, 2H), 2.25 (tt, J= 8.2, 4.9 Hz, 1H), 1.- 1.07 (m, 2H), 1.03 -0.97 (m, 2H). ES-MS [M+l]+; 541/543.

[00324] 2-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6-(2,4- dimethoxybenzyl)-3-vinyl-6,7-dihydro-5Z/-pyrrolo[3,4-6]pyridin-5-one.A mixture of 3- bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6-(2,4-dimethoxybenzyl)- 6,7-dihydro-5//-pyrrolo[3,4-Z>]pyridin-5-one (200 mg, 0.37 mmol), vinylboronic acid pinacol ester (0.09 mL, 0.55 mmol), Pd(dppf)C12 (14 mg, 0.02 mmol) and cesium carbonate (363 mg, 1.11 mmol) in THE (2.2 mL) and water (0.22 mL) was subjected to microwave irradiation at 1°C for 30 min. The reaction mixture was filtered over Celite®, washed with 3:1 CHCh/IPA, and the solvents were removed in vacuo. The crude sample was purified by reverse-phase chromatography (15-65% MeCN/Water/0.05% NH40H) to afford the title compound. ES-MS [M+l]+: 489.

NMOMeCN

[00325] Ethyl 5-bromo-6-chloro-2-formylnicotinate.To a solution of ethyl 5-bromo-2- (bromomethyl)-6-chloronicotinate (1.36 g, 3.8 mmol) in MeCN (21.5 mL) was added 4- methylmorpholine N-oxide (893 uL, 8.6 mmol) and the mixture was stirred at ambient temperature for 2 hr. The solution was diluted with EtOAc and washed with water. The organic layer was separated, dried (MgSO4), filtered, and concentrated. The crude product was purified via normal phase column chromatography (0-30% EtOAc/Hexanes) to give the title compound (668 mg). ES-MS [M+l]+: 292/294; 1H NMR (400 MHz, CDCh) 5 10.22 (s, 1H), 8.34 (d, J= 0.5 Hz, 1H), 4.45 (q, J= 7.2 Hz, 2H), 1.41 (t, J= 7.1 Hz, 3H). — 76 — WO 2024/220633 PCT/US2024/025144 2) HCI, 1,4-dioxanes 1) NaBH4, THF

[00326] 3-Bromo-2-chlorofuro[3,4-6]pyridin-5(7//)-one.To a solution of ethyl 5-bromo-6- chloro-2-formylnicotinate (668 mg, 1.76 mmol) in THF (8.8 mL) at -40 °C was added sodium borohydride (27 mg, 0.70 mmol). The reaction was allowed to stir at -40 °C for 45 minutes. To the reaction mixture was added water and the reaction was warmed to room temperature. After the reaction was extracted with EtOAc (3x), the combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was taken up in 1,4-dioxane (4 mL), then hydrochloric acid (879 pL, 3.52 mmol; 4ATin 1,4-dioxane) was added and the mixture was heated to 50 °C for hr. Additional AMHCI in 1,4-dioxane (400 pL, 1.6 mmol) was added and the mixture was heated to 50 °C. After 4 hr, the mixture was concentrated under vacuum and the residue was dissolved in DCM. The solution was washed with an aqueous saturated NaHCO3 solution. The organic layer was separated, dried (MgSO4), and concentrated. The crude residue was purified via normal phase column chromatography (0 - 0.5% MeOH/DCM) to give the title compound. ES-MS [M+l]+: 248/250; 1HNMR (400 MHz, CDCI) 8 8.42 (t, J= 0.5 Hz, 1H), 5.28 (d, J =0.5 Hz, 2H).

DIEA, NMP, 50°C

[00327] 3-Bromo-2-(2-(l-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(47/)- yl)furo [3,4-6] pyridin-5(7FZ)-one.To a solution of 3-bromo-2-chlorofuro[3,4-6]pyridin-5(7Z/)- one (40 mg, 0.13 mmol) in NMP (1 mL) was added 3-bromo-2-chloro-72/-furo[3,4-6]pyridin-5- one hydrochloride (40 mg, 0.13 mmol) and ApV-diisopropylethylamine (0.07 mL, 0.39 mmol). The mixture heated at 50 °C for 18 hr. The mixture was cooled to ambient temperature, diluted with water, and extracted with EtOAc (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The product was carried forward without further purification. ES-MS [M+l]+: 406/408. — 77 — WO 2024/220633 PCT/US2024/025144 Bromine

[00328] 3-Bromo-6,7-dihydro-5Z/-cyclopenta[6]pyridin-2-ol.To a vial containing 6,7- dihydro-5.H-cyclopenta[£>]pyridin-2-ol (500 mg, 3.7 mmol) and acetic acid (5.3 mL) at 0 °C was added bromine (150 pL, 2.9 mmol). The reaction was allowed to come to it over 3h. The reaction mixture was concentrated in vacuo and to the residue was added sat. sodium thiosulfate solution and neutralized with aqueous saturated sodium carbonate solution. The mixture was extracted with EtOAc (3x). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by normal phase column chromatography (0-10% DCM/MeOH with 1% NHOH additive) to afford the desired compound (493 mg). 1H NMR (400 MHz, CDCI3) 5 7.74 (s, 1H), 2.91 (tt, J= 8.1, 1.Hz, 2H), 2.79 - 2.70 (m, 2H), 2.21 - 2.09 (m, 2H); ES-MS [M+l]+: 214/216.

[00329] 3-Bromo-2-chloro-6,7-dihydro-5H-cyclopenta[6]pyridine.3-Bromo-6,7-dihydro- 5Lf-cyclopenta[Z>]pyridin-2-ol (493 mg, 2.3 mmol) in POC13 (1.2 mL, 13.2 mmol). The solution is heated to 90 °C for 18 h. The reaction mixture was concentrated. Aqueous saturated sodium carbonate was slowly added to the residue. The mixture was extracted with DCM (3x). The combined organic layers were washed with water (3x). The organics were dried with sodium sulfate, filtered, and concentrated. The crude residue was purified using normal phase column chromatography (0 - 60% EtOAc/Hex) to produce the title compound (316 mg). 1H NMR (4MHz, CDCI3) 5 7.72 (t, J= 1.2 Hz, 1H), 3.00 - 2.88 (m, 4H), 2.17 (p, J= 7.7 Hz, 2H); ES-MS [M+l]+: 232/234. — 78 — Acetic acid WO 2024/220633 PCT/US2024/025144 BrKMnO 4, MgSO4 t-BuOH, H2O 40 °C Br

[00330] 3-Bromo-2-chloro-6,7-dihydro-5/Z-cyclopenta[6]pyridin-5-one.To a solution of magnesium sulfate (833 mg, 6.8 mmol) and potassium permanganate (430 mg, 2.7mmol) in water (1.7 mL) and tert-butanol (5 mL) was added 3-bromo-2-chloro-6,7-dihydro-5/7- cyclopenta[Z>]pyridine (316 mg, 1.36 mmol). The mixture was stirred at 40 °C for 3 h. The reaction mixture was filtered over Celite®, washing with EtOAc and MeOH. The filtrate was concentrated. The residue was dissolved in water/EtOAc (1:1; 50 mL). The organic layer was separated, and the aqueous layer re-extracted with EtOAc (2x). The combined organic layers were washed with brine, filtered, and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (0-60% EtOAc/Hexanes) to afford the title compound. ES-MS [M+l]+: 246/248; 1HNMR (400 MHz, CDC13) 5 8.22 (s, 1H), 3.26 - 3.(m, 2H), 2.87-2.80 (m, 2H).

[00331] 3-B1־omo-2-(2-cyclop1־opyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6,7- dihydro-5Jf-cyclopenta[6]pyridin-5-one.To a solution of 3-bromo-2-chloro-6,7-dihydro-5/7- cyclopenta[Z>]pyridin-5-one (13 mg, 0.05 mmol) in DMSO (0.5 mL) was added 2-cyclopropyl- 4,5,6,7-tetrahydro-[l,3]thiazolo[5,4-c]pyridine (10 mg, 0.06 mmol) and N,N- diisopropylethylamine (55 pL, 0.32 mmol). The mixture was heated to 120 °°C. After 18 h, the mixture was poured into water and extracted with EtOAc (3x). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude residue was purified using normal phase column chromatography (0-80% EtOAc/Hexanes) to afford the title compound. [M+l]+: 390/392. — 79 — WO 2024/220633 PCT/US2024/025144 nh2 0־ 0 ־toluene 4MHCI in 1,4-dioxane

[00332] Ethyl 6-hydroxy-2,4-dimethylnicotinate.To a solution of ethyl (Z)-3-aminobut-2- enoate (1.96 mL, 15.5 mmol) in toluene (11.6 mL) was added a solution of hydrochloric acid (4M in dioxanes) (7.74 mL, 30.9 mmol) and the reaction was heated to 115 °C for 18 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the crude residue was purified by normal-phase chromatography (0-90% EtOAc/DCM) to afford the title compound. 1HNMR (400 MHz, CDC13) 5 6.25 (s, 1H), 4.34 (q, J= 7.1 Hz, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 1.37 (t, J= 7.1 Hz, 3H). ES-MS [M+l]+: 196.

[00333] Ethyl 5-bromo-6-hydroxy-2,4-dimethylnicotinate.Prepared in a similar manner as ethyl 5־bromo-6-hydroxy-2-methylnicotinate. 1H NMR (400 MHz, CDCI3) 5 4.36 (q, J= 7.1 Hz, 2H), 2.43 (s, 3H), 2.42 (s, 3H), 1.38 (t, J= 7.1 Hz, 3H). ES-MS [M+l]+: 274/276. 0Cl 61Cl

[00334] Ethyl 5-bromo-6-chloro-2,4-dimethylnicotinate:Prepared in a similar manner as ethyl 5-bromo-6-chloro-2-methylnicotinate. 1HNMR (400 MHz, CDCI3) 5 4.43 (q, J= 7.1 Hz, 2H), 2.47 (s, 3H), 2.43 (s, 3H), 1.40 (t, J= 7.1 Hz, 3H). ES-MS [M+l]+: 292/294.

[00335] Ethyl 5-bromo-2-(bromomethyl)-6-chloro-4-methylnicotinate:Prepared in asimilar manner as ethyl 5-bromo-2-(bromomethyr)-6-chloronicotinate. 1H NMR (400 MHz, — 80 — WO 2024/220633 PCT/US2024/025144 CDC13) S 4.53 (s, 2H), 4.48 (q, J = 7.2 Hz, 2H), 2.48 (s, 3H), 1.43 (t, J= 7.2 Hz, 3H). ES-MS [M+l]+: 370/372/374. h2n— THF, 0°C

[00336] 3-Bromo-2-chloro-4,6-dimethyl-6,7-dihydro-5/f-pyrrolo[3,4-6]pyridin-5-one: Prepared in a similar manner as 3-bromo-2-chloro-6-methyl-6,7-dihydro-577-pyrrolo[3,4- />]pyridim50 ״ne. 1HNMR (400 MHz, DMSO) 5 4.43 (s, 2H), 3.07 (s, 3H), 2.75 (s, 3H). ES-MS [M+l]+: 275/277.

[00337] 3-Bromo-2-chloro-4-methyl-6,7-dihydro-517-pyrrolo[3,4-6]pyridin-5-one:To a solution of ethyl 5-bromo-2-(bromomethyl)-6-chloro-4-methylnicotinate (320 mg, 0.86 mmol) in methanol (15.4 mL) was added ammonia (7Ain MeOH) (615 pL, 4.31 mmol) and the reaction stirred for 18 hours at room temperature. Additional ammonia (7A in MeOH) (615 pL, 4.mmol) was added and the reaction was allowed to stir for an additional 18 hours. The reaction was concentrated in vacuo then resuspended in IPA. The solution was sonicated and the precipitate was collected by vacuum filtration to afford title compound. 1H NMR (400 MHz, DMSO) 5 8.93 (s, 1H), 4.33 (d, J= 1.2 Hz, 2H), 2.75 (s, 3H). ES-MS [M+l]’: 261/263.

DIEA, DMSO 70 °C

[00338] 3-Bromo-2-(2-(l-fluorocydopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)- 4,6-dimethyl-6,7-dihydro-5Jf-pyrrolo[3,4-6]pyridin-5-one.Prepared in a similar manner as 3- bromo-2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)-6-methyl-6,7- — 81 — WO 2024/220633 PCT/US2024/025144 dihydro-5/7-pyrrolo[3,4-Z)]pyridin-5-one. 1H NMR (400 MHz, CDC13) 8 4.63 (d, J= 1.9 Hz, 2H), 4.20 (s, 2H), 3.75 (t, J= 5.6 Hz, 2H), 3.17 (s, 3H), 3.12 - 3.07 (m, 2H), 2.78 (s, 3H), 1.65 - 1.58 (m, 2H), 1.50- 1.40 (m, 2H). ES-MS [M+l]+: 437/439.

DIEA, DMSO 70 °C

[00339] 3-Bromo-2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)- 4-methyl-6,7-dihydro-5H-pyrroIo[3,4-6]pyridin-5-one.Prepared in a similar manner as 3- bromo-2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)-6-methyl-6,7- dihydro-5//-pyrrolo[3,4-/>]pyridin-5-one. 1H NMR (400 MHz, CDCI3) 8 5.90 (s, 1H), 4.65 (t, J = 1.8 Hz, 2H), 4.28 (d, J= 1.1 Hz, 2H), 3.78 (t, J= 5.6 Hz, 2H), 3.11 (t, J= 5.7 Hz, 2H), 2.79 (s, 3H), 1.65 - 1.58 (m, 2H), 1.49 - 1.42 (m, 2H). ES-MS [M+l]+: 423/425.

Table 1. Commercial Starting Materials Name CAS# Supplier tert-Butyl 6,7-dihydrothiazolo[5,4-c]pyridine- 5(47/)-carboxylate165948-24-3 Combi-Blocks, Inc. -(te77-Butyl) 2-ethyl 6,7-dihydrothiazolo[5,4- c]pyridine-2,5(4//)-dicarboxylate1053656-51-1 J & W PharmLab 4,5,6,7-Tetrahydrothiazolo[5,4-c]pyridine 165948-23-2 Enamine terAButyl 2-chloro-6,7-dihydrothiazolo[5,4- c]pyridine-5(4/7)-carboxylate1221931-40-3 Combi-Blocks, Inc. terAButyl 2-amino-6,7-dihydrothiazolo[5,4- c]pyridine-5(477)-carboxylate365996-05-0 Combi-Blocks, Inc.

Ethyl 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine- 2-carboxylate hydrochloride1186663-33-1 AstaTech, Inc. 2-Bromo-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridine hydrochloride949922-52-5 Synthonix — 82 — WO 2024/220633 PCT/US2024/025144 2-Methyl-4,5,6,7-tetrahydrothiazolo[5,4- c]pyridine124458-27-1 Aurum Pharmatech tert-Butyl 2-bromo-6,7-dihydrothiazolo[5,4- c]pyridine-5(4/7)-carboxylate365996-06-1 Combi-Blocks, Inc. l/:Z,2//,5//,6/7(7/7-cydopeiua[6]pyridin-2-one 88499-85-8 Enamine 1-Fluorocyclopropanecarboxamide 1445686-01-7 eNovation Chemicals b. Representative synthesis of compounds of the invention

[00340] 2-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z7)-yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-6]pyridin-5-one (Compound 2).To a solution of 2-chioro-3-methyl- 6,7-dihydropyrrolo[3,4-6]pyridin-5-one (15 mg, 0.08 mmol) and AJV-diisopropylethylamine (0.07 mL, 0.41 mmol) in DMSO (0.8 mL) was added 2-cyclopropyl-4,5,6,7-tetrahydro- [l,3]thiazolo[5,4-c]pyridine;hydrochloride (21 mg, 0.10 mmol). The reaction heated at 120 °C for 18 h. The reaction was purified by reverse-phase HPLC (5-45% MeCN/Water/0.05% NH4OH). The desired fractions were concentrated to afford the title compound (2.1 mg). 1H NMR (400 MHz, CDCI) 5 7.82 (s, 1H), 6.50 (s, 1H), 4.52 (s, 2H), 4.35 (s, 2H), 3.57 (t, J= 5.Hz, 2H), 3.02 (t, J= 5.6 Hz, 2H), 2.40 (s, 3H), 2.30-2.23 (m, 1H), 1.14-1.09 (m, 2H), 1.04-1.(m, 2H); ES-MS [M+l]+: 327.0. — 83 — WO 2024/220633 PCT/US2024/025144

[00341] 3-Methyl-2-(2-(l-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)- yl)-6,7-dihydro-51/-pyrrolo [3,4-6] pyridin-5-one (Compound 3).To a solution of 2-chloro-3- methyl-6,7-dihydropyrrolo[3,4-6]pyridin-5-one (15 mg, 0.08 mmol) and N,N-di isopropyl ethyl ami ne (0.07 mL, 0.41 mmol) in DMSO (0.8 mL) was added 2-(l- methylcyclopropyl)-4,5,6,7-tetrahydro-[l,3]thiazolo[5,4-c]pyridine (19 g, 0.10 mmol). The reaction heated at 120 °C for 18 h. The reaction was purified by reverse-phase HPLC (5-45% MeCN/Water/0.05% NH4OH). Desired fractions were concentrated to afford the title compound (9.4mg). 1HNMR(400 MHz, DMSO-d6) 5 8.37 (s, 1H), 7.77 (s, 1H), 4.49 (s, 2H), 4.25 (s, 2H), 3.54 (t, J= 5.5 Hz, 2H), 2.91 (t, J= 5.4 Hz, 2H), 2.37 (s, 3H), 1.50 (s, 3H), 1.13 (dd, J= 6.7, 2.Hz, 2H), 0.96 (dd, J= 6.3, 3.7 Hz, 2H); ES-MS [M+l]341.0 :־. 1,4-dioxanes, 80°C

[00342] 2-(2-Cyclopropyl-6,7-dihydro-4//-[l,3]thiazolo[5,4-c]pyridin-5-yl)-3,6-dimethyl- 7//-pyrrolo [3,4-6] pyridin-5-one (Compound 12).3-Bromo-2-(2-cyclopropyl-6,7- dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6-methyl-6,7-dihydro-5//-pyrrolo[3,4-6]pyridin-5-one (225 mg, 0.56 mmol), cesium carbonate (543 mg, 1.67 mmol), trimethylboroxine (50% wt in THE) (0.47 mL, 1.67 mmol), [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (mg, 0.11 mmol), and 1,4-dioxane (2.9 mL) were charged into a vial. The mixture was evacuated and purged with nitrogen and stirred at 80 °C for 18 h. The reaction was filtered through a pad of Celite®, which was rinsed thoroughly with 3:1 CHC13/IPA. Solvents were removed and the crude sample was purified by reverse-phase chromatography (5-40% MeCN/Water/0.1% TFA).Desired fractions were basified with saturated NaHCO3, extracted with 3:1 CHCl/IPA and were concentrated to give the title compound (36 mg). 1H NMR (400 MHz, CDC13) 8 7.79 (s, 1H), 4.50 (s, 2H), 4.26 (s, 2H), 3.55 (t, J= 5.6 Hz, 2H), 3.18 (s, 3H), 3.06 - 2.99 (m, 2H), 2.39 (s, H), 2.31 (d, J = 4.7 Hz, 1H), 1.14 (dd, J = 7.9, 3.1 Hz, 2H), 1.09- 1.00 (m, 2H) ; ES-MS [M+l]+: 341.2. — 84 — Pd(dppf)CI2,Cs 2CO3 WO 2024/220633 PCT/US2024/025144

[00343] 2-(2-(l-Fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,6- dimethyl-6,7-dihydro-51/-pyrrolo [3,4-6] pyridin-5-one (Compound 23).3-Bromo-2-[2-(l- fluorocyclopropyl)-6,7-dihydro-4//-[l,3]thiazolo[5,4-c]pyridin-5-yl]-6-methyl-7//-pyrrolo[3,4- 6]pyridin-5-one (21.0 mg, 0.05 mmol), cesium carbonate (48.0 mg, 0.15mmol), trimethylboroxine (50% wt in THF) (40.0 pL, 0.15 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.0 mg, 0.01 mmol), and 1,4-dioxane (0.5 mL) were charged into a microwave vial. The mixture was evacuated and purged with nitrogen and stirred at 80 °C for 18 h. The reaction was fdtered through a pad of Celite®, which was rinsed thoroughly with EtOAc. Solvents were removed and the crude sample was purified by reverse-phase chromatography (15-55% MeCN/Water/0.1% TFA). Desired fractions were basified with saturated NaHCOa, extracted with 3:1 CHCla/IPA and were concentrated to give the title compound. ES-MS [M+l]+: 359.2; 1HNMR (400 MHz, CDCI3) 5 7.80 (d, J= 0.9 Hz, 1H), 4.57 (t, J = 1.9 Hz, 2H), 4.27 (s, 2H), 3.56 (t, J= 5.7 Hz, 2H), 3.18 (s, 3H), 3.02 (tt, J= 5.7, 1.8 Hz, 2H), 2.40 (d, J= 0.9 Hz, 3H), 1.65 - 1.52 (m, 2H), 1.52 - 1.41 (m, 2H).

I I /B^B- Pd(dppf)CI2,Cs 2CO3 1,4-dioxanes, 80°C

[00344] 3-Methyl-2-(2-( l-methylcyclopropyl)-6,7-dihydrothiazolo [5,4-c] pyridin-5(4/T)- yl)furo[3,4-6]pyridin-5(7H)-one (Compound 24).A solution of 3-bromo-2-(2-(l-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)furo[3,4-6]pyridin-5(7/7)-one — 85 — WO 2024/220633 PCT/US2024/025144 (57 mg, 0.13 mmol), cesium carbonate (126 mg, 0.39 mmol), trimethylboroxine (50% wt. in THE) (108 pL, 0.39 mmol), and [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.025 mmol) in 1,4-dioxane (1 mL) was charged into a vial. The mixture was evacuated and purged with nitrogen (3x) and stirred at 80 °C. After 4 h, the mixture was cooled to ambient temperature and additional cesium carbonate (126 mg, 0.39 mmol), trimethylboroxine (50% wt. in THE) (108 pL, 0.39 mmol), and [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.025 mmol) were added to the mixture and stirred at 85 °C for another 4 hours. The reaction was filtered through a pad of Celite®, washing thoroughly with DCM/MeOH then concentrated. The crude product was purified via reverse-phase chromatography (10-60% MeCN/Water/0. 1% TEA) and desired fractions were basified with saturated NaHCO3 then extracted with chloroform/IPA (3:1) (3x). The organics were combined, passed through a phase separator, and concentrated. The product was then purified using normal-phase column chromatography (0-70% EtOAc/Hex) to afford the title compound. ES-MS [M+l]+: 342.

[00345] Methyl 2-(2-cyclop1־opyl-6,7-dihyd1־othiazolo[5,4-c]pyridin-5(4//)-yl)-6-methyl-5- oxo-6,7-dihydro-5/f-pyrrolo[3,4-6]pyridine-3-carboxylate (Compound 31).To a solution of 3-bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6-methyl-6,7-dihydro- 5H-pyrrolo[3,4-/)]pyridin-5-one (50 mg, 0.12 mmol) in triethylamine (0.4 mL, 2.8 mmol) and methanol (0.05 mL, 1.2 mmol) were added xantphos (14 mg, 0.02 mmol) and palladium (II) acetate (2.8 mg, 0.01 mmol), and the resulting reaction vial was sealed. The vial was purged with an atmosphere of CO gas. The reaction was then heated at 70 °C for 16 h under a balloon of CO gas. Upon cooling to room temperature, the crude reaction was diluted with 3:1 CHC13/IPA, filtered, and concentrated. The crude oil was purified by reverse-phase chromatography (10-60% MeCN/Water/0. 1 % TEA). Desired fractions underwent basic workup to afford the title compound (3.9 mg). 1HNMR (400 MHz, CDC13) 8 8.39 (s, 1H), 4.51 (s, 2H), 4.27 (s, 2H), 3.94- 3.91 (m, 5H), 3.16 (s, 3H), 3.03 (td, J= 5.5, 2.1 Hz, 2H), 2.26 (tt, J= 8.2, 4.9 Hz, 1H), 1.15 - 1.07 (m, 2H), 1.06-0.97 (m, 2H). ES-MS [M+l]+: 385. — 86 — Pd(OAc)2, Xantphos, TEA, Methanol, 70°C WO 2024/220633 PCT/US2024/025144 DIEA, NMP, 160 °C

[00346] 5-(3-Methyl-5-oxo-6,7-dihydro-577-pyrrolo[3,4-Z>]pyridin-2-yl)-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (Compound 32).To a solution of 4,5,6,7- tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide (23 mg, 0.12 mmol) and 2-chl oro-3-methyl- 6,7-dihydro-5/f-pyrrolo[3,4-Z?]pyridin-5-one (15 mg, 0.08 mmol) in NMP (0.5 mL) was added A,/V-diisopropylethylamine (72 pL, 0.41 mmol) and the reaction heated to 160 °C for 18 hours. The crude residue was purified using RP-HPLC (5-50% ACN/ 0.1% aqueous TFA). The fractions containing the title compound were basified with saturated NaHCO3 then extracted with chloroform/IPA (3:1) (3x). The combined organics were passed through a hydrophobic phase separator and the solvents were removed to afford the title compound. 1H NMR (400 MHz, CDCI) 8 7.86 (s, 1H), 7.04 (s, 1H), 5.88 (s, 1H), 5.46 (s, 1H), 4.68 (s, 2H), 4.35 (s, 2H), 3.63 (t, J= 5.7 Hz, 2H), 3.10 (t, J= 5.7 Hz, 2H), 2.43 (s, 3H); ES-MS [M + H]+= 330.

Pd/C, Pd(OH)2 EtOH, 50°C

[00347] 2-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4FT)-yl)-6-(2,4- dimethoxybenzyl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-6]pyridin-5-one (Compound 33).In a reaction vial, 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-3-vinyl-6,7-dihydro-5H-pyrrolo[3,4-Z1]pyridin-5-one (36 mg, 0.07 mmol) was suspended in ethanol (2 mL) . The mixture was evacuated and purged with nitrogen (3x).Palladium on activated carbon (CAS# 7440-05-3; 8 mg, 0.01 mmol) and palladium hydroxide on activated charcoal (CAS# 12135-22-7; 10 mg, 0.01 mmol) were added. The resulting mixture was purged with H2 gas for 1 min. The balloon was removed, and the reaction stirred at °C for 5 h. The suspension was filtered over a pad of Celite® which was rinsed thoroughly with — 87 — WO 2024/220633 PCT/US2024/025144 % MeOH/DCM. The filtrate was concentrated under reduced pressure and purified by reverse- phase chromatography (15-65% MeCN/Water/0.05% NH4OH) to afford the title compound. 1H NMR (400 MHz, CDCI) 5 7.92 (s, 1H), 7.21 (d, J= 8.2 Hz, 1H), 6.49 - 6.37 (m, 2H), 4.74 (s, 2H), 4.43 (s, 2H), 4.20 (s, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.52 - 3.45 (m, 2H), 3.05 (s, 2H), 2.(q, J=7.5Hz, 2H), 2.38 (s, 1H), 1.29 (t,J=7.4Hz, 3H), 1.21 (s, 2H), 1.10 (s, 2H). ES-MS [M+l]+: 491.

[00348] 2-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z/)-yl)-3-ethyl-6,7- dihydro-5//-pyrrolo|3.4-/)]pyridin-5-one (Compound 34).A mixture of 2-(2-cyclopropyl-6,7- dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-3-ethyl-6,7-dihydro-5H- pyrrolo[3,4-Z>]pyridin-5-one (12 mg, 0.02mmol) in trifluoroacetic acid (75 uL, 0.98 mmol) was stirred at 60 °C for 4 h. The reaction mixture was concentrated to give crude residue which was purified by reverse-phase chromatography (5-45% MeCN/Water/0.1% TFA) to afford the title compound. 1HNMR (400 MHz, CDC13) 8 7.95 (s, 1H), 6.06 (s, 1H), 4.49 (s, 2H), 4.36 (s, 2H), 3.55 (t, J= 5.7 Hz, 2H), 3.09 (t, J= 5.9 Hz, 2H), 2.74 (q, J= 7.5 Hz, 2H), 2.47-2.36 (m, 1H), 1.31 (t, J=7.5Hz, 3H), 1.25-1.21 (m, 2H), 1.18-1.13 (m, 2H). ES-MS [M+l]+: 341.

[00349] 2-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-methyl-6,7- dihydro-5/f-cyclopenta[6]pyridin-5-one (Compound 35).3-Bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(47/)-yl)-6,7-dihydro-577-cyclopenta[Z>]pyridin-5-one (8.0 mg, 0.02 mmol), cesium carbonate (20 mg, 0.06 mmol), trimethylboroxine (50% wt in THF) (20 pL, — 88 — Pd(dppf)CI2C2CO3 1,4-dioxane, 80 °C O WO 2024/220633 PCT/US2024/025144 0.06 mmol), Pd(dppf)C12 (3.0 mg, 0.004 mmol), and 1,4-dioxane (0.5 mL) were charged into a microwave vial. The mixture was evacuated and purged with nitrogen and stirred at 80 °C for h. The reaction mixture was diluted with EtOAc, filtered over Celite® and concentrated. The crude residue was dissolved in DMSO (1.5 mL) and purified using the reverse-phase chromatography (10-40% MeCN/0.1% aqueous TFA). The fractions containing desired product were neutralized with sat. NaHCO3 then extracted with 3:1 chloroform/IPA (3x). The combined organics were passed through a hydrophobic phase separator and the solvents were concentrated to afford the title compound. 1H NMR (400 MHz, CDCI3) 5 7.69 (s, 1H), 4.61 (t, J= 1.9 Hz, 2H), 3.66 (t, J= 5.6 Hz, 2H), 3.04 (dt, J= 9.4, 6.0 Hz, 4H), 2.73 - 2.66 (m, 2H), 2.36 (d, J= 0.9Hz, 3H), 2.27 (ddd, J= 13.1, 8.3, 4.9 Hz, 1H), 1.17 - 0.98 (m, 4H). ES-MS [M+l]+: 326.2.

[00350] 2-(2-(l-Fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-3,4- dimethyl-6,7-dihydro-5H-pyrrolo[3,4-6]pyridin-5-one (Compound 36).Prepared in a similar manner as Compound 23.1H NMR (400 MHz, CDCI3) 8 5.82 (s, 1H), 4.56 - 4.51 (m, 2H), 4.(s, 2H), 3.51 (t, J= 5.7 Hz, 2H), 3.04 (t, J= 5.8 Hz, 2H), 2.66 (s, 3H), 2.29 (s, 3H), 1.67 - 1.55(m, 2H), 1.51-1.39 (m, 2H). ES-MS [M+l]+: 359.

[00351] 2-(2-(l-Fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,4,6- trimethyl-6,7-dihydro-5Ff-pyrrolo [3,4-6] pyridin-5-one (Compound 38).Prepared in a similar manner as Compound 23. 1HNMR (400 MHz, CDC13) 8 4.51 (t, J= 1.8 Hz, 2H), 4.21 (s, — 89 — WO 2024/220633 PCT/US2024/025144 2H), 3.48 (t, J= 5.7 Hz, 2H), 3.16 (s, 3H), 3.03 (tt, J = 5.7, 1.8 Hz, 2H), 2.65 (s, 3H), 2.27 (s, 3H), 1.68- 1.56 (m, 2H), 1.49 - 1.42 (m, 2H). ES-MS [M+l]+: 373.

[00352]The compounds shown in Table 2 may be prepared using the methods shown in the preceding Schemes and Examples with the appropriate starting materials.

Table 2 Cpd. No. Name Structure ES-MS [M+l]+ 2-(6,7-dihydrothiazolo[5,4- c]pyridin-5(4//)-yl)-3-methyl-6,7- dihydro-577-pyrrolo[3,4-6]pyridin- 5-one r T x> /^N N^s/HN 1 II 287 2-(2-cyclopropyl-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4//)-yl)-3-methyl-6,7-dihydro- 5//-pyrrolo[3,4-Z>]pyridin-5-one । T HN 1 II 327 3-methyl-2-(2-(l- methylcyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(47/)-yl)-6,7-dihydro-577- pyrrolo[3,4-Z>]pyridin-5-one HN 1 II 341 3-methyl-2-(2-(thiophen-2-yl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-6,7-dihydro-5/7- pyrrolo[3,4-Z>]pyridin-5-one HN 1 II 369 ethyl 5-(3-methyl-5-oxo-6,7- dihydro-5//-pyrrolo[3,4-6]pyridin- 2-yl)-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridine-2- carboxylate 0 , ץ 1HN 1 11 359 — 90 — WO 2024/220633 PCT/US2024/025144 3-methyl-2-(2-methyl-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-6,7-dihydro-5Z7- pyrrolo[3,4-Z>]pyridin-5-one XX-Nr T x>- HN 1 II 301 3-methyl-2-(2-(l-methyl- 1/7- pyrazol-5-yl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-6,7-dihydro-5/7- pyrrolo[3,4-6]pyridin-5-one N* T/^NHN 1 II 'N367 2-(2-amino-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-3-methyl-6,7-dihydro- 5//-pyrrolo[3,4-Z>]pyridin-5-one Jhn Y 302 2-(2-chloro-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-3-methyl-6,7-dihydro- 5/7-pyrrolo[3,4-Z)]pyridin-5-one 1 T HN 1 II0' 31321 2-(2-(2,2-dimethylcyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-3-methyl-6,7-dihydro- 5/7-pyrrolo[3,4-Z>]pyridin-5-one । 11 x^- 355 2-(2-(tert-butyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-3-methyl-6,7-dihydro- 5/7-pyrrolo[3,4-Z>]pyridin-5-one /___.N nJIs^hn Jr T 343 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)-3,6-dimethyl-6,7-di hydro- 5/7-py rrol 0 [3,4-/>] py ri din- 5-one XX-NT x>— ־NCXX o 341 — 91 — WO 2024/220633 PCT/US2024/025144 3,6-dimethyl-2-(2-(l- methylcyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-6,7-dihydro-5Z7- pyrrolo[3,4-Z>]pyridin-5-one ־NxXl 355 6-cyclopropyl-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin- 5(4//)-yl)-3-methyl-6,7-dihydro- 5//-pyrrolo[3,4-6]pyridin-5-one 1 > — א< ץ 1-./ 1 ע ______ _ ' 0 367 6-cyclopropyl-3-methyl-2-(2-(l- methylcyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(477)-yl)-6,7-dihydro-577- pyrrolo[3,4-/>]pyridin-5-one O 0' 381 6-cyclopentyl-2-(2-cyclopropyl-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-3-methyl-6,7-dihydro- 577-pyrrolo[3,4-6]pyridin-5-one |/"N /I 395 6-cyclopentyl-3 -methyl-2-(2-( 1 - methylcyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4//)-yl)-6,7-dihydro-5/7- pyrrolo[3,4-6]pyridin-5-oneo 409 2-(2-(2,2-dimethylcyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-3,6-dimethyl-6,7- dihydro-5//-pyrrolo[3,4-/>]pyridin- 5-one /X/N /,n. JLy-N00C 369 — 92 — WO 2024/220633 PCT/US2024/025144 6-cyclopropyl-2-(2-(2,2- dimethylcyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-3-methyl-6,7-dihydro- 5//-pyrrolo[3,4-Z>]pyridin-5-one T y>־׳^CCX 395 6-cyclopentyl-2-(2-(2,2- dimethylcyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(477)-yl)-3-methyl-6,7-dihydro- 5//-pyrrolo[3,4-/>]pyridin-5-one 1 T ל—<_ _ NN.e 0' 423 2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-3,6-dimethyl-6,7- dihydro-5Z/-pyrrolo[3,4-6]pyridin-5-one ' T yxא __________ _NP،X ־ 355.3 2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridin- 5(477)-yl)-3-methylfuro[3,4- Z>]pyridin-5(77/)-one ץ 1_ _NN 342.2 2-(2-( 1 -fluorocyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- (4//)-yl )-3, 6-di methyl -6,7 - dihydro- 577-py rrol o [3,4-Z>] py ri din- 5-one l II ־nv^JL 359.2 3-methyl-2-(2-(l- methylcyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(477)-yl)furo[3,4-Z>]pyridin-5(7/7)- one °vOC 342.2 — 93 — WO 2024/220633 PCT/US2024/025144 2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridin- 5(4//)-yl)-3-methyl-6,7-dihydro- 57/-pyrrolo[3,4-6]pyridin-5-one /XN zj W) HN 1 II 341.2 3-cyclopropyl-2-(2-cyclopropyl-6,7-di hy drothi azolo[5,4-c]pyridin-5(4/7)-yl)-6-methyl-6,7-dihydro-577-pyrrolo[3,4-6]pyridin-5-one XX/NT >—<|_ _ OZ V 367 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin- 5(47/)-yl)-6-methyl-5-oxo-6,7- dihydro-5//-pyrrolo[3,4-/>]pyridine- 3-carbonitrile । T x>—<נ ־NPCX 352 2-(2-(l -fluorocyclopropyl)-6,7- dihy drothi azolo[5,4-c]pyri din- 5(4//)-yl)-3-methyl-6,7-dihydro-5//-pyrrolo[3,4-6]pyridin-5-one 1 T_ __XHNCCX o z 345.2 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)-6-methyl-3-vinyl-6,7-di hydro- H-pyrrol 0 [3,4-6] py ri din- 5-one /^/Nl II x>—-NPC، 353 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin- 5(47/)-yl)-6-methyl-3 -(prop- 1 -en-2- yl)-6,7-dihydro-57/-pyrrolo[3,4- 6]pyridin-5-one XX/NT xyxl ־N00Cx o z 1 367 — 94 — WO 2024/220633 PCT/US2024/025144 methyl 2-(2-cyclopropyl-6,7- dihydrothiazolo[5,4-c]pyridin- 5(477)-yl)-6-methyl-5-oxo-6,7- dihydro-57/-pyrrolo[3,4-Z?]pyridine-3-carboxylate 1 T <1־NpOCo ° /O 385 -(3-methyl-5-oxo-6,7-dihydro-5Z/- pyrrolo[3,4-/>]pyridin-2-yl)-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridine-2- carboxamide HN 1 II 330.2 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-6-(2,4-dimethoxybenzyl)-3-ethyl-6,7-dihydro-5//-pyrrolo[3,4-/>]pyridin-5-one oo- 0' 491 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-3-ethyl-6,7-dihydro-5/7- pyrrolo[3,4- ؛]pyridin-5-one 1 ץ xy_<4 HN 1 II 341 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin- 5(4/7)-yl)-3-methyl-6,7-dihydro- 5//-cyclopenta[/>]pyridin-5-one 1 T xv^ 326.2 2-(2-( 1 -fluorocyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(477)-yl)-3,4-dimethyl-6,7- dihydro- 5 //-py rrol o [3,4-Z>] py ri din- 5-one ""״n 1359.2 2-(2-( 1 -fluorocyclopropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(477)-yl)-4-methyl-6,7-dihydro-5//-pyrrolo[3,4-6]pyridin-5-one । IIHN 1 l| 1 345.1 — 95 — WO 2024/220633 PCT/US2024/025144 2-(2-( 1 -fluorocycl opropyl)-6,7- dihydrothiazolo[5,4-c]pyridin- 5(4//)-yl)-3,4,6-trimethyl-6,7- dihydro-57/-pyrrolo[3,4-Z)]pyridin- 5-one ZX/N .Rr '373.2 Biological Activity A. Cell Lines Expressing Muscarinic Acetylcholine Receptors [00353]Human and rat M4 cDNAs, along with the chimeric G protein Gqi5, were transfected into Chinese hamster ovary (CHO-K1) cells purchased from the American Type Culture Collection using Lipofectamine2000. The transfected cells were subjected to selection antbiotic treatment to generate stable cell lines; G418 sulfate (I mg/ml) for selecting M4 expressing cells and Hygromycin B (500 ug/mL) for selecting Gqi5 expressing cells. The resulting polyclones were further screened to obtain monoclones of hM4-G qi5 and rM4-G qi5 for compound screening assay. Stable monoclone cells were maintained in Ham ’s F-12 medium containing 10% heat- inactivated fetal bovine serum (FBS), IX Antibiotic/Antimycotic, 20 mM HEPES, 500 ug/mL G418sulfate, and 200 ug/mL Hygromycin Bin 37 °Chumidified incubators in the presence of 5% CO2. B. Cell-Based Functional Assay of Muscarinic Acetylcholine Receptor Activity [00354]The high throughput assay was employed to measure receptor-induced mobilization of intracellular calcium to determine compound activity. Test compound was added to cells expressing the muscarinic receptors that were loaded with calcium sensitive fluorescent dye. After a -2.5 minute incubation period, a submaximal (EC20) concentration of acetylcholine was added, and the response measured. This kinetic assay allows for simultaneous screening and potency determination of multiple pharmacological modes of action including agonist and potentiator activity. CHO-K1 cells stably expressing muscarinic receptors were plated in growth medium lacking G418 and hygromycin at 15,000 cells/20 uL/well in Greiner 384-well black- walled, tissue culture (TC)-treated, clear-bottom plates (Greiner Bio-One). Cells were incubated overnight at 37 °C and 5% CO2. The next day, calcium assay buffer (Hank’s balanced salt solution (HBSS), 20 mM HEPES, 2.5 mM Probenecid, 4.16 mM sodium bicarbonate (Sigma- Aldrich, St. Louis, MO)) was prepared to dilute compounds, agonists, and Fluo-4- — 96 — WO 2024/220633 PCT/US2024/025144 acetom ethoxy ester (Fluo-4-AM), fluorescent calcium indicator dye. Compounds were serially diluted 1 ;3 into 10 point concentration response curves in DMSO using the Bravo Liquid Handler (Agilent, Santa Clara, CA), transferred to a 384 well daughter plates using an Echo acoustic liquid handler (Beckman Coulter, Indianapolis, Indiana), and diluted in assay Buffer to a 2X final concentration. The agonist plates were prepared using acetylcholine (ACh, Sigma- Aldrich, St. Louis, MO) concentrations for the EC20 and ECMAX responses by diluting in assay buffer to a 5X final concentration. The 2X dye solution (2.3 pM) was prepared by mixing a 2.mM Fluo-4-AM stock in DMSO with 10% (w/v) pluronic acid F-127 in a 1:1 ratio in assay buffer. Using a microplate washer (BioTek, Winooski, VT), cells were washed with assay buffer for 3 times to remove medium. After the final wash, 20 pL of assay buffer remained in the cell plates. Immediately, 20 pL of the 2X dye solution (final 1.15 pM) was added to each well of the cell plate using a Multidrop Combi dispenser (Thermo Fisher, Waltham, MA). After cells were incubated with the dye solutions for 45 min at 37 °C in the presence of 5% CO2, the dye solutions were removed and replaced with assay buffer using a microplate washer, leaving 20 pL of assay buffer in the cell plate. [00355]The prepared compound, agonist, and cell plates were placed inside the Functional Drug Screening System uCell (FDSS uCell, Hamamatsu, Japan) to measure the calcium flux. The triple add protocol was used to measure Ca kinetics; Compound, ACh for EC20, and ACh for EC80 adds in an order. Briefly, after establishment of a fluorescence baseline for 2 seconds (excitation, 480 nm; emission, 530 nm), first add occurred by adding 20 pL of test compound to the cells, and the response was measured for 140 seconds. This is followed by second add; 10 pL (5X) of an EC 20 concentration of ACh agonist was added to the cells, and the response of the cells was measured for 125 seconds. Immediately, the third add occurred by adding 12 ul (5X) of an EC80 concentration of ACh and the response of the cells was measured for 90 seconds. Acetylcholine-mediated maximum response (ECmax) was measured by adding 1 mM ACh as third add in the control wells. DMSO vehicle was added to the control wells in the first add for assessing ACh EC20, EC80, and ECmax responses. Calcium fluorescence was recorded as fold over basal fluorescence and raw data were normalized to the maximal response to ACh agonist. Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition. Positive allosteric modulator activity was analyzed as a concentration- dependent increase in the EC20 acetylcholine response. Antagonist activity was analyzed as a — 97 — WO 2024/220633 PCT/US2024/025144 concentration-dependent decrease in the ECs0 acetylcholine response. Concentration-response curves were generated using a four-parameter logistical equation using GraphPad Prism (La Jolla, CA) or the Dotmatics software platform (Woburn, MA). [00356]The above-described assay was also operated in a second mode where an appropriate fixed concentration of the present compounds was 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 the calcium response (maximum-local minima response) was measured. 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 at a 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. Activity of Compounds in a mAChR M4 Cell-Based Assay [00357]Compounds were synthesized as described above. Activity (EC50 and Emax) W3.S determined in the M4 cell-based functional assay as described above and the data are shown in Table 3. The compound number corresponds to the compound numbers used in Table 2. Table 3.

No. Human M4 EC50 (nM) Emax (%)* 1 409 91 2 23 88 3 51 73 4 1264 59 707 97 — 98 — WO 2024/220633 PCT/US2024/025144 6 70 95 7 727 71 8 4700 74 9 86 75 39 79 11 406 73 12 15 96 13 70 79 14 14 88 280 72 16 146 66 17 3510 70 18 176 63 19 1166 79 9345 66 21 21 97 22 9 89 23 99 72 24 40 69 5 71 26 201 66 — 99 — WO 2024/220633 PCT/US2024/025144 * %ACh maximum at 30 p.M. 27 154 74 28 76 84 29 52 72 >10,000 42 31 481 80 32 >10,000 56 33 963 44 34 148 78 10 98 36 13 96 37 537 68 38 31 95 D. Functional assessment of M4 activator compounds in cellular cAMP assay Cellular cAMP Gi HTRF Assay [00358]Activation of the M4 receptor leads to the inhibition of cAMP production by coupling to Gi/o proteins. To measure the level of cAMP inhibition by M4 allosteric modulators, a Homogeneous Time-Resolved Fluorescence (HTRF®) cAMP assay was employed using CHO cells stably expressing human or rat M4 receptors. The HTRF cAMP assay is a Time-Resolved Resonance Energy Transfer (TR-FRET) competitive immunoassay. Endogenous intracellular cAMP generated by cells competes with Europium cryptate-labeled cAMP (Europium donor, emission 665 nm) for the binding to a cAMP antibody labeled with d2 (d2-acceptor, emission 620 nm). Thus, the fluorescence emission ratio (665 nm/620 nm) is inversely proportional to the cAMP amount in the cells. Compound-mediated M4 activation results in an increase in HTRF ratio (665 nm/620 nm), indicative of a decrease in intracellular cAMP level. To monitor agonist — 100 — WO 2024/220633 PCT/US2024/025144 activity, compounds were added to the M4 cells in the presence of an EC80 concentration of forskolin (adenylyl cyclase activator) which induces a submaximal intracellular cAMP level. To assess potentiator activity, compounds were added to the M4 cells with an EC80 concentration of forskolin in the presence of an EC20 concentration of acetylcholine. This functional assay allows determination of the potency and efficacy of compounds directly activating or potentiating the Gi/o-coupled M4 receptor. [00359]Functional agonist and potentiator activities of compounds were determined by measuring cAMP levels in Chinese Hamster Ovary (CHO) cells stably expressing human or rat M4 muscarinic receptors using an HTRF cAMP Gi/o kit. Cells were maintained in F12 medium containing 10% FBS, 20 mM HEPES, IX Antibiotic/Antimycotic, and G418 (500 ug/ml) in °C humidified incubators in the presence of 5% CO2. The day before assay, the cells were trypsinized and resuspended in plating medium (growth medium without G418). The cells were plated to white, solid, flat-bottomed, 384 well plates at densities of 4,000 and 6,000 cells/uL/well, of human M4and rat M4 cells, respectively. The cell plates were spun at lOOxg for min, then immediately placed in a 37 °C incubator in the presence of 5% CO2 overnight. [00360]The next day, reagents were freshly diluted at a 2X concentration in assay buffer using F12 basal medium or stimulation buffer. All assay buffers contained 500 pM IBMX to block cAMP degradation. Activation of M4 by compounds was examined in cells stimulated with an EC80 concentration of forskolin to induce submaximal intracellular cAMP levels. Forskolin EC80 concentrations were determined from forskolin concentration response curves (CRCs) and ranged from 1.5 to 2.5 pM. Compounds (10 mM) were prepared in 100% DMSO and further serially diluted either 1:3 or 1:5 into a 13-point CRC in DMSO using a Bravo Liquid Handler in a 384 well microplate. [00361]Agonist assay mode was used to assess the abilities of M4 compounds to directly activate M4 receptors in the absence of the agonist, acetylcholine. The 10-point serially diluted compounds, starting 30 pM as a final concentration, were transferred to a compound plate using an Echo plate reformat protocol. 2X assay buffer containing an EC80 concentration of forskolin concentration was added to the compound plate. Vehicle (1% DMSO) was added to the following control wells; baseline cAMP (no forskolin), forskolin max, and forskolin EC80 pl/well of the prepared 2X assay buffer was immediately added to the cell plates using a Bravo 384 well tip liquid handler. The cell plates were immediately spun for 30 seconds at 100 x g and — 101 — WO 2024/220633 PCT/US2024/025144 incubated at 37 °C for 10 min with gentle shaking at 50 rpm. An acetylcholine CRC was also performed in the presence of an EC80 concentration of forskolin to determine the concentrations of acetylcholine inducing maximal (ECmax) and submaximal (EC20) cAMP inhibition in order to prepare for the subsequent potentiator mode assay. [00362]In potentiator assay mode, the 10-point serially diluted compounds, starting 1.1 pM as a final concentration, were transferred to a compound plate using an Echo plate reformat protocol. 2X assay buffer containing an EC80 concentration of forskolin and an ECconcentration of acetylcholine was added to the compound plate. Vehicle (1% DMSO) was added to the following: (1) for forskolin controls wells - baseline cAMP (no forskolin), forskolin max, and forskolin EC80, (2) for agonist control wells containing forskolin EC80 - basal (no agonist), and acetylcholine EC20 and ECmax. 10 pl/well of the prepared 2X assay buffer was immediately added to the cell plates using a Bravo 384 well tip liquid handler. The cell plates were immediately spun for 30 seconds at lOOx g and incubated at 37 °C for 10 min with gentle shaking at 50 rpm. During the 10-minute incubation period, cAMP Eu-cryptate donor (20X) and anti-cAMP d2 antibody acceptor (20X) were diluted in lysis/detection buffer in separate tubes. Immediately after the incubation, cells were lysed by sequentially adding 10 pl/well of cAMP Eu-crytate solution and 10 pl/well of anti-cAMP d2 antibody solution. The cell plates were immediately spun for 30 seconds at lOOx g and incubated for 60 minutes at 25 °C with gentle shaking at 50 rpm. Immediately after the detection incubation, TR-FRET signals were measured at two channels, 665 and 620 nm, using an EnVision Plate reader (Perkin Elmer). All emission ratios (665/620) were normalized to % acetylcholine max. Individual CRCs were generated using a four-parameter logistical equation using GraphPad Prism (La Jolla, CA), and ECwas extracted from the fitting, and maximal response (% ACh Max) was determined: top — bottomy = bottom + ؛ -y^LogECSO-A^Htllslope where A is the molar concentration of the compound; bottom and top denote the lower and upper plateaus of the concentration-response curve; HillSlope is the Hill coefficient that describes the steepness of the curve; and EC50 is the molar concentration of compound required to generate a response halfway between the top and bottom. — 102 — WO 2024/220633 PCT/US2024/025144 Table 4. Materials and Equipment Item Manufacturer Cat# Cell culture F12 medium Thermo Fisher 11765054Fetal bovine serum Thermo Fisher 16140089Antibiotic/Antimycotic Thermo Fisher 15240062M HEPES (2-[4-(2-hydroxy ethyl) piperazin-1-yl] ethanesulfonic acid)Thermo Fisher 15630080 G418 Sulfate Thermo Fisher 10131027TrypLE Express Thermo Fisher 12605036 cAMP Assay HTRF cAMP-Gi kit Cisbio 62AM9PECCELLSTAR, 384 well plate, TC-treated, White, Solid-flat bottomGreiner 781080 IBMX (3 -i sobuty 1 -1 -methy Ixanthi ne) Sigma 15879Forskolin Sigma F6886Acetylcholine chloride Sigma A6625DMSO (Dimethyl sulfoxide) Sigma D8418Echo 650 liquid handler Beckman 001-16079Bravo liquid handler Agilent G5563AAEnVision plate reader Perkin Elmer 2105-0011 E. In vitro Secondary Pharmacology [00363]Compound 2 was tested using Eurofins LeadProfilingScreen®, which detects potential off-target activity and determines relative selectivity. The screen includes 68 primary molecular targets, including several CNS targets recommended by the EMEA (European Medicines Evaluation Agency) to evaluate drug dependence potential. Compound 70 exhibited - 50% inhibition of each target in the LeadProfilingScreen®, at 10 pM (binding) with the exception of human muscarinic 2 (58% inhibition at 10 pM).

F. In vitro and in vivo Drug Metabolism and Pharmacokinetics [00364]Compound 2 was tested in several in vitro assays to investigate both metabolism and pharmacokinetics. These assays may be performed according to known methods as generally — 103 — WO 2024/220633 PCT/US2024/025144 described in the following references: Conde-Ceide et al. ACS Med. Chem. Lett. 2015, 6, 716- 720; Morris et al. J. Med. Chem. 2014, 57, 10192-10197; and Bubser et al. ACS Chem. Neurosci. 2014, 5, 920-942. In vitro assays include those listed in the following table.

Table 5 Assay Result MDCK-MDR1 ER 2.8 (Papp A^B: 13.8 X IO6־ cm/s)Rat Fu (plasma) 0.117Dog Fu (plasma) 0.054Human Fu (plasma) 0.037Rat Fu (brain) 0.027Rat CLint (mL/min/kg) 83Dog CLint (mL/min/kg) 100Human CLint (mL/min/kg) 6P450 3A4 IC50 (pM) 5P450 2D6 IC50 (pM) 10P450 2C9 IC50 (pM) >30P450 1A2 IC50 (pM) 5

[00365]Compound 2 was tested in several in vivo assays and the pharmacokinetic parameters listed in the following table may be determined from pharmacokinetic studies in rat, or dog, according to known methods as generally described in the following references: Garrison et al. J. Med. Chem. 2022, 65, 6273-6286; Felts et al. J. Med. Chem 2017, 60, 5072-5085; and Yu et al. J. Med. Chem. 2021, 64, 4709-4729.

Table 6 Assay Result Rat CLP (mL/min/kg) 24.2Dog CLP (mL/min/kg) 52.9Rat Vss (L/kg) 0.5 — 104 — WO 2024/220633 PCT/US2024/025144 Dog Vss (L/kg) 0.9Rat Elim, ti/2 (hr) 0.4Dog Elim, ti/2 (hr) 0.2Rat oral F (3 mg/kg) 24%Rat brain: plasma KP 0.8Rat brain: plasma KP־U״ 0.2

[00366]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. [00367]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. — 105 —

Claims (25)

WO 2024/220633 PCT/US2024/025144 ClaimsWhat is claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, (1) R2 wherein:X1 is NR5, 0, or CR5AR5B;R2 is G2, -NR2aR2b , halogen, cyano, C1-6alkyl, C1-6haloalkyl, -OR2a, -NR2aC(O)R2b , -C(O)OR2a, -C(O)NR2aR2b , or hydrogen;R2a and R2b are independently hydrogen, C1-6alkyl, C1-6haloalkyl, G2, or -C-alkylene-G;G2, at each occurrence, is independently a 3- to 7-membered carbocyclyl, a 5- to 6-membered heteroaryl containing 1-4 heteroatoms, a phenyl, or a 4- to 7-membered heterocyclyl containing 1-2 heteroatoms, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G2 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1- 4fluoroalkyl, oxo, -ORX, -N(RX)2, -C(O)RX, -C(0)0Rx, -C(0)N(Rx)2, -C1-6alkylene-ORx, -C1-6alkylene-N(Rx)2, G2a, and -C1-3alkylene-G2a;Rx, at each occurrence, is independently hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-6cycloalkyl, or —C1 3־ alky 1 ene-C 3-6cy cl oal ky 1;G2a is a C3-6cycloalkyl;R4A and R4b are independently hydrogen, C1-4alkyl, C3-4cycloalkyl, or -C1-3alkylene-OH; or R4A — 106 — WO 2024/220633 PCT/US2024/025144 and R4b together with the carbon to which they attach form a C3-6cycloalkyl;R5 is hydrogen, C1-6alkyl, C1-6fluoroalkyl, -C1-6alkylene-Ry, -C1-6fluoroalkylene-Ry, G5, or -C1-3alkylene-G5;R5a and R5B are independently hydrogen, halogen, C1-4alkyl, C1-4fluoroalkyl, or -C1-4alkylene- OH;Ry is -OR53, -N(R5a)2, -C(O)R53, -C(O)OR53, or -C(O)N(R53)2;R53, at each occurrence, is independently hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-4cycloalkyl, or -C1-3alkylene-C3-4cycloalkyl;G5 is phenyl, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, 5- to 6-membered heteroaryl containing 1-4 heteroatoms, or a C3-6cycloalkyl, wherein the heteroatoms are independently selected from the group consisting of 0, N, and S, and G5 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C1-4alkyl, C1-2fluoroalkyl, -OC1-4alkyl, OH, and oxo;R6 is hydrogen, halogen, cyano, C1-4alkyl, C1-4fluoroalkyl, C2-4alkenyl, -OR63, -N(R6a)2, -C1-3alkylene-OR6a, or C3-4cycloalkyl;R63, at each occurrence, is independently hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-4cycloalkyl, or -C1-3alkylene-C3-4cycloalkyl;wherein alternatively, two R63, together with the nitrogen to which they attach form a 4- to 8- membered heterocyclic ring containing the nitrogen attached to R63 and optionally additional heteroatom that is O, N, or S, the heterocyclic ring being optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-2alkyl, and C1-2fluoroalkyl;R7 is C1-4alkyl, hydrogen, halogen, cyano, C1-4fluoroalkyl, C2-4alkenyl, -OR73, -C1-3alkylene-OR7a, CO2R7a, COR73, or C3-6cycloalkyl;R73 is hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-4cycloalkyl, or -C1-3alkylene-C3-4cycloalkyl;R8, at each occurrence, is independently halogen, C1-4alkyl, C1-4fluoroalkyl, or C3-4cycloalkyl; andn is 0, 1, 2, 3, or 4;wherein each cycloalkyl at Rx, G23, R6, R63, R7, R73, and R8 is independently unsubstituted or substituted with 1-4 substituents independently selected from C1-4alkyl and halogen. — 107 — WO 2024/220633 PCT/US2024/025144

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, R2 is G2, -NR2aR2b , halogen, cyano, C1-6alkyl, C1-6haloalkyl, -OR2a, -C(O)OR2a, -C(O)NR2aR2b , or hydrogen.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is G2.

4. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein G2 is the optionally substituted 3- to 7-membered carbocyclyl.

5. The compound of any of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein G2 is the optionally substituted 5- to 6-membered heteroaryl.

6. The compound of any of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein G2 is

7. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is -NR2aR2b .

8. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-6alkyl.

9. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is halogen.

10. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

11. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is -C(O)OR2a. — 108 — WO 2024/220633 PCT/US2024/025144

12. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 is -C(O)NR2aR2b .

13. The compound of any of claims 1, 2, 7, or 11-12, or a pharmaceutically acceptable salt thereof, wherein R2a is hydrogen or C1-6alkyl.

14. The compound of any of claims 1, 2, 7, or 12-13, or a pharmaceutically acceptable salt thereof, wherein R2b is hydrogen.

15. The compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R4A and R4B are hydrogen.

16. The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein X1 is NR5.

17. The compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen, C1-6alkyl, G־, or-C1-3alkylene-G5.

18. The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein X1 is 0.

19. The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein X1 is CR5AR5B.

20. The compound of any of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen.

21. The compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R7 is C1-4alkyl, halogen, cyano, or C3-6cycloalkyl. — 109 — WO 2024/220633 PCT/US2024/025144

22. The compound of any of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein n is 0.

23. The compound of claim 1 selected from the group consisting of:2-(6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)-3-methyl-6,7-dihydro-5/7-pyrrolo[3,4- 6]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-3-methyl-6,7-dihydro-5/7- pyrrolo[3,4-Z>]pyridin-5-one;3-methyl-2-(2-(l-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)-6,7- dihydro-577-pyrrolo[3,4-5]pyridin-5-one;3-methyl-2-(2-(thiophen-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6,7-dihydro- 577-pyrrolo[3,4-Z>]pyridin-5-one;ethyl 5-(3-methyl-5-oxo-6,7-dihydro-5//-pyrrolo[3,4-Z>]pyridin-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate;3-methyl-2-(2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)-6,7-dihydro-5Z7- pyrrolo[3,4-Z>]pyridin-5-one;3-methyl-2-(2-(l-methyl-lZ7-pyrazol-5-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z7)-yl)- 6,7-dihydro-5/7-pyrrolo[3,4-Z>]pyridin-5-one;2-(2-amino-6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)-3-methyl-6,7-dihydro-577- pyrrolo[3,4-Z>]pyridin-5-one;2-(2-chl oro-6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)-3-methyl-6,7-dihydro-5//- pyrrolo[3,4-Z>]pyridin-5-one;2-(2-(2,2-dimethylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)-3-methyl-6,7-dihydro-5/7-pyrrolo[3,4-Z>]pyridin-5-one;2-(2-(tert-butyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-3-methyl-6,7-dihydro-577- pyrrolo[3,4-Z>]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)-3,6-dimethyl-6,7-dihydro- 5Z/-pyrrolo[3,4-Z>]pyridin-5-one;3,6-dimethyl-2-(2-(l-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)-6,7-dihydro-5//-pyrrolo[3,4-Z>]pyridin-5-one; — 110 — M M M M2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-3-methylfuro[3,4-6]pyridin- 5(7//)-one; 2-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)-3,6-dimethyl-6,7-dihydro- WO 2024/220633 PCT/US2024/025144 WO 2024/220633 PCT/US2024/025144 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z/)-yl)-6-methyl-3-vinyl-6,7- dihydro-57Apyrrolo[3,4-6]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(477)-yl)-6-methyl-3-(prop-l-en-2- yl)-6,7-dihydro-5//-pyrrolo[3,4-Z>]pyri din-5-one;methyl 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6-methyl-5-oxo-6,7-dihydro-5//-pyrrolo[3,4-Z>]pyridine-3-carboxylate;5-(3-methyl-5-oxo-6,7-dihydro-5//-pyrrolo[3,4-/>]pyridin-2-yl)-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4//)-yl)-6-(2,4-dimethoxybenzyl)- 3-ethyl-6,7-dihydro-5/7-pyrrolo[3,4-Z>]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z/)-yl)-3-ethyl-6,7-dihydro-57f- pyrrolo[3,4-Z>]pyridin-5-one;2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4Z/)-yl)-3-methyl-6,7-dihydro-57/- cyclopenta[Z>]pyridin-5-one;2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(41/)-yl)-3,4-dimethyl-6,7-dihydro-57f-pyrrolo[3,4-6]pyridin-5-one;2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(41/)-yl)-4-methyl-6,7- dihydro-5//-pyrrolo[3,4-/>]pyridin-5-one;2-(2-(l-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4/7)-yl)-3,4,6-trimethyl- 6,7-dihydro-5/7-pyrrolo[3,4-Z>]pyridin-5-one;or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising the compound of any of claims 1-23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. A compound of any of claims 1-23, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 24, for use in the treatment of a neurological and/or psychiatric disorder, wherein the disorder is selected from Alzheimer's disease, schizophrenia, a sleep disorder, a pain disorder, and a cognitive disorder. — 112 —