Pyrropyridine derivatives as positive allosteric modulators of the m4 muscarinic acetylcholine receptor

Description

1 / 140 PYRROPYRIDINE DERIVATIVES AS POSITIVE ALLOSTERIC MODULATORS OF THE MUSCARINIC ACETYLCHOLINE M4 RECEPTOR RELATED ORDERS

[0001] This application claims priority over Provisional Application No. U.S. 63 / 496,806, filed April 18, 2023, and Provisional Application No. U.S. 63 / 610,184, filed December 14, 2023, each of which is incorporated herein by reference in its entirety. FIELD OF TECHNIQUE

[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 muscarinic acetylcholine receptors (mAChRs) by the binding of endogenous orthosteric acetylcholine agonist (ACh). Conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by a reduction in acetylcholine content in the brain. This is believed to be a result of the degeneration of cholinergic neurons in the forebrain, which extensively innervate various brain areas, including the association cortices and the hippocampus, which are critically involved in higher-level processes. Clinical data support 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 to acetylcholine synthesis, and blocking acetylcholinesterase (AChE), the enzyme that metabolizes acetylcholine.As a result, acetylcholinesterase (AChE) inhibitors... Petition 870250094048, dated 10 / 14 / 2025, pp. 360 / 509 2 / 140 inhibitors that inhibit ACh hydrolysis have been approved in the United States for use in the palliative, but not disease-modifying, treatment of cognitive deficits in patients with AD.

[0004] Attempts to increase central cholinergic function through the administration of choline or phosphatidylcholine have been unsuccessful. AChE inhibitors have shown therapeutic efficacy but have been shown to have frequent cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal cramps, nausea, vomiting, and diarrhea. These gastrointestinal side effects were observed in about one-third of treated patients. In addition, some AChE inhibitors, such as tacrine, have also been shown to cause 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 targeted cholinergic hypofunction is the activation of mAChRs, which are widely expressed throughout the body.

[0005] mAChRs are members of the G protein-coupled receptors family A (GPCRs) and include five subtypes designated MiM5. Subtypes M1, M3, and M5 primarily couple to Gq and activate phospholipase C, while subtypes M2 and M4 primarily couple to Gi / oe 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. M1-M5 have variable roles in cognitive, sensory, motor, and autonomic functions. Thus, without wishing to adhere to any 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 the treatment of psychosis, schizophrenia, and related disorders. The muscarinic M4 receptor has been shown to play an important role in cognitive processing and is believed Petition 870250094048, dated 10 / 14 / 2025, pp. 361 / 509 3 / 140 that plays an important 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 the activation of peripheral M2 and M3 mAChRs and include bradycardia, GI discomfort, excessive salivation, and sweating. In contrast, M4 has been seen as the most likely subtype to mediate the effects of muscarinic acetylcholine receptor dysfunction in psychotic disorders, including schizophrenia, cognitive disorders, and neuropathic pain. For this reason, considerable effort has been focused on the development of selective M4 agonists for the treatment of these disorders. Unfortunately, these efforts have been largely unsuccessful due to the inability to develop compounds highly selective for the M4 mAChR. For this reason, the mAChR agonists that have been tested in clinical studies induce a range of adverse effects by activating 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, cognitive disorders, and other disorders, it may be important to develop compounds that are highly selective activators of mAChR M4 and other individual mAChR subtypes.

[0007] Previous attempts to develop highly selective agonists for individual mAChR subtypes have failed due to the high conservation of the ACh orthosteric binding site. To circumvent the problems associated with targeting the highly conserved ACh orthosteric binding site, it is believed that compounds acting on allosteric sites in mAChRs that are removed from the orthosteric site and are less highly conserved have been developed. This approach has proven highly successful in developing ligands selective for multiple mAChRs. Petition 870250094048, dated 10 / 14 / 2025, pp. 362 / 509 4 / 140 subtypes of GPCR. In the case of mAChRs, the main objective has been to develop allosteric ligands that selectively increase the activity of mAChR M4 or other mAChR subtypes. Allosteric activators can include allosteric agonists, which act on 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 receptor activation by endogenous orthosteric agonist ACh. Furthermore, it is possible for a single molecule to have both allosteric enhancer and allosteric agonist activity.

[0008] More recently, muscarinic agonists, including xanomeline, have been shown to be active in animal models with profiles similar to known antipsychotic drugs, but without causing catalepsy (Bymaster et al., Eur. J. Pharmacol. 1998, 356, 109; Bymaster et al., Life Sci. 1999, 64, 527; Shannon et al., J. Pharmacol. Exp. Ther. 1999, 290, 901; Shannon et al., Schizophrenia Res. 2000, 42, 249). Furthermore, xanomeline has been shown to reduce psychotic behavioral symptoms, such as delusions, suspiciousness, vocal outbursts, and hallucinations in patients with Alzheimer's disease (Bodick et al., Arch. Neurol. 1997, 54, 465); however, the treatment induced side effects, for example, gastrointestinal effects, which severely limited the clinical usefulness of this compound.

[0009] Despite advances in research on muscarinic acetylcholine receptors, there is still a shortage of compounds that are potent, effective and selective activators of the M4 mAChR and also effective in treating neurological and psychiatric disorders associated with cholinergic activity and diseases in which the muscarinic M4 receptor is involved. SUMMARY

[0010] In one aspect, compounds of formula (I) are revealed, Petition 870250094048, dated 10 / 14 / 2025, pp. 363 / 509 5 / 140 or a pharmaceutically acceptable salt thereof, (I) where: X1 is NR5, O or CR5AR5B; R2 is G2, -NR2aR2b, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, -OR2a, NR2aC(O)R2b, -C(O)OR2a, -C(O)NR2aR2b or hydrogen; R2ae R2bsão, independently, hydrogen, C1-6 alkyl, C1-6 haloalkyl, G2 or -C1-3 alkylene-G2; G2, in each occurrence, is independently a 5- to 6-membered heteroaryl containing 1-4 heteroatoms, 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 O, N, and S, and G2 is optionally substituted by 1-5 substituents independently selected from the group consisting of halogen, cyano, C1-4-alkyl, C1-4-fluoroalkyl, oxo, -ORx, -N(Rx)2, C(O)Rx, -C(O)ORx, -C(O)N(Rx)2, -C1-6-alkylene-ORx, -C1-6-alkylene-N(Rx)2, G2a and -C1-3-alkylene-G2a; Rx, in each occurrence, is independently hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C3-6 cycloalkyl, or C1-3 alkylene-C3-6 cycloalkyl; Petition 870250094048, dated 10 / 14 / 2025, pp. 364 / 509 6 / 140 G2a is a C3-6 Cycloalkyl group; R4A and R4B are independently hydrogen, C1-4 alkyl, C3-4 cycloalkyl, or C1-3 alkylene-OH; or R4A and R4B together with the carbon to which they are attached form a C3-6 cycloalkyl; R5 is hydrogen, C1-6 alkyl, C1-6 fluoroalkyl, -C1-6 alkylene-Ry, -C1-6 fluoroalkylene-Ry, G5 or -C1-3 alkylene-G5; R5Ae R5B are independently hydrogen, halogen, C1-4 alkyl, C1-4 fluoroalkyl or -C1-4 alkylene-OH; Ry is -OR5a, -N(R5a)2, -C(O)R5a, -C(O)OR5aor -C(O)N(R5a)2; R5a, in each occurrence, is independently hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, or C1-3 alkylene-C3-4 cycloalkyl; G5 is a phenyl, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, a 5- to 6-membered heteroaryl containing 1-4 heteroatoms, or a C3-6 cycloalkyl, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G5 is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, cyano, C1-4 alkyl, C1-2 fluoroalkyl, -OC1-4 alkyl, OH, and oxo; R6 is hydrogen, halogen, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C2-4 alkenyl, -OR6a, -N(R6a)2, -C1-3 alkylene-OR6a or C3-4 cycloalkyl; R6a, in each occurrence, is independently hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, or C1-3 alkylene-C3-4 cycloalkyl; wherein, alternatively, two R6a, together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclic ring containing the nitrogen attached to R6a and optionally 1 additional heteroatom which is O, N or S, wherein the heterocyclic ring is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C1-2 alkyl and C1-2 fluoroalkyl; R7 is C1-4 alkyl, hydrogen, halogen, cyano, C1-4 fluoroalkyl, C2-4 alkenyl, Petition 870250094048, dated 10 / 14 / 2025, pp. 365 / 509 7 / 140 -OR7a, -Ci-3alkylene-OR7a, CO2R7a, COR7aor Cs-ecycloalkyl; R7a is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, Cs-4 cycloalkyl or C1-3 alkylene-Cs-4 cycloalkyl; R8, in each occurrence, is independently halogen, C1-4 alkyl, C1-4 fluoroalkyl, or C3-4 cycloalkyl; en is 0, i, 2, 3 or 4; wherein each cycloalkyl group in Rx, G2a, R6, R6a, R7, R7a and R8 is unsubstituted or substituted by i-4 substituents independently selected from among C1-4 alkyl (e.g., methyl) and halogen (e.g., fluoro). [00ii] 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. [00i2] Another aspect provides a method for 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 a pharmaceutically acceptable salt or composition thereof. [00i3] 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. [00i4] Another aspect provides for the 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. Petition 870250094048, dated 10 / 14 / 2025, pp. 366 / 509 8 / 140

[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] Positive allosteric modulators (i.e., enhancers) of the muscarinic acetylcholine receptor M4 (mAChR M4), methods for producing them, pharmaceutical compositions comprising them, and methods for treating neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction using them are disclosed in this document. The compounds include naphthyridine-substituted pyridazine compounds.

[0017] The human muscarinic acetylcholine receptor M4 (mAChR M4) is a 479-amino acid protein encoded by the CHRM4 gene. The molecular weight of the non-glycosylated protein is approximately 54 kDa and it is a transmembrane GPCR. As described above, mAChR M4 is a member of the Class A family of GPCRs, or rhodopsin-like GPCRs, which are characterized by structural features similar to rhodopsin, such as seven transmembrane segments. Muscarinic acetylcholine receptors have the N-terminal oriented towards the extracellular face of the membrane, and the C-terminal located on the cytoplasmic face.

[0018] Previous attempts to develop highly selective agonists for individual mAChR subtypes have failed due to the high conservation of the ACh orthosteric binding site. To circumvent the problems associated with targeting the highly conserved ACh orthosteric binding site, it is believed that compounds acting on allosteric sites on mAChRs that are removed from the orthosteric site and are less highly conserved have been developed. Without wishing to be bound to any particular theory, it is believed that the compounds and products disclosed from the disclosed methods bind to an allosteric site distinct from the orthosteric site. Petition 870250094048, dated 10 / 14 / 2025, pp. 367 / 509 9 / 140 orthosteric connection. 1. Definitions

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by a person of ordinary skill in the art. In case of conflict, this document, including the definitions, shall prevail. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein may be used in the practice or experimentation of the present invention. All publications, patent applications, patents and other references mentioned herein are incorporated in their entirety by reference. The materials, methods and examples disclosed herein are for illustrative purposes only and are not intended to be limiting.

[0020] The terms “comprises”, “includes”, “having”, “has”, “may”, “contains”, and their variants, as used in this document, are intended to be open transitional phrases, terms, or words that do not exclude the possibility of additional acts or structures. The singular forms “a”, “an”, and “the” include references made in the plural, unless the context explicitly indicates otherwise. This disclosure also contemplates other modalities “comprising”, “consisting of”, and “consisting essentially of” the modalities or elements presented in this document, whether explicitly mentioned or not.

[0021] The approximately modifier used in connection with a quantity is inclusive of the determined value and has a meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The approximately modifier should be considered as revealing the range defined by the absolute values ​​of the two points of Petition 870250094048, dated 10 / 14 / 2025, pp. 368 / 509 10 / 140 extreme. For example, the expression "about 2 to about 4" also reveals the range of 2 to 4. The term "about" can refer to more or less 10% of the indicated number. For example, "about 10%" can indicate a range of 9% to 11%, and "about 1" can mean from 0.9 to 1.1. Other meanings of "about" may be evident from the context, such as around, approximately, for example "about 1" can also mean from 0.5 to 1.4.

[0022] Definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified in accordance with the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, back cover, and specific functional groups are generally defined as described therein. Additionally, the general principles of organic chemistry, as well as specific functional chemical moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March's Advanced Organic Chemistry, 5th Edition, John Wiley and 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 into this document by way of reference.

[0023] The term alkoxy, as used herein, refers to an alkyl group, as defined herein, linked to the original molecular chemical 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 in this document, means a saturated hydrocarbon chain, straight or Petition 870250094048, dated 10 / 14 / 2025, pp. 369 / 509 11 / 140 branched. The term “lower alkyl” or “C1-6 alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “C1-4 alkyl” means a straight or branched chain saturated hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0025] The term “alkenyl”, as used in this document, 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, linked to the original molecular chemical portion via an alkyl group, as defined herein.

[0027] The term “alkoxyfluoroalkyl”, as used herein, refers to an alkoxy group, as defined herein, linked to the original molecular chemical moiety via 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 hydrocarbon chain, 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 in this document, means at least one alkyl group, as defined in this document, is attached to the original molecular chemical portion through Petition 870250094048, dated 10 / 14 / 2025, pp. 370 / 509 12 / 140 of an amino group, as defined in this document.

[0030] The term “amide”, as used in this document, means -C(O)NR- or -NRC(O)-, where R can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl or heteroalkyl.

[0031] The term “aminoalkyl”, as used in this document, means at least one amino group, as defined in this document, is linked to the original molecular chemical portion through an alkylene group, as defined in this document.

[0032] The term “amino”, as used in this document, 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 chemical moiety where the amino is linked to two other chemical moieties, the amino may be -NRx-, wherein Rx may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl or heteroalkyl.

[0033] The term “aryl”, as used in this document, refers to a phenyl or a phenyl group attached to the original molecular chemical moiety and fused to a cycloalkane group (for example, 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 (for example, the aryl may be benzo[d][1,3]dioxol-5-yl). The term “phenyl” is used in reference to a substituent, and the term 6-membered arene is used in reference to a fused ring. The 6-membered arene is monocyclic (for example, benzene or benzo). The aryl may be monocyclic (phenyl) or bicyclic (for example, a 9- to 12-membered fused bicyclic system).

[0034] The term “cyanoalkyl”, as used in this document, means at least one -CN group is linked to the original molecular chemical portion through an alkylene group, as defined in this document. Petition 870250094048, dated 10 / 14 / 2025, pp. 371 / 509 13 / 140

[0035] The term “cyanofluoroalkyl”, as used in this document, means at least one -CN group is linked to the original molecular chemical portion through a fluoroalkyl group, as defined in this document.

[0036] The term “cycloalkoxy”, as used herein, refers to a cycloalkyl group, as defined herein, linked to the original molecular chemical moiety via 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., decahydronaphthalenyl), 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]heptanil). Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0038] The term “cycloalkenyl” or “cycloalkene”, as used herein, means a monocyclic or multicyclic non-aromatic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond and preferably having 5-10 carbon atoms per ring. The term “cycloalkenyl” is used herein to refer to a cycloalkene when present as a substituent. A cycloalkenyl can be a monocyclic cycloalkenyl (e.g., cyclopentenyl), a Petition 870250094048, dated 10 / 14 / 2025, pp. 372 / 509 14 / 140 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 “carbocyclo” means a “cycloalkane” or a “cycloalkene”. The term “carbocyclyl” refers to a “carbocyclo” 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-trifluoropropyl.

[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, attached to the original molecular chemical moiety through Petition 870250094048, dated 10 / 14 / 2025, pp. 373 / 509 15 / 140 of 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 in this document, means Cl, Br, I or F.

[0044] The term “haloalkyl”, as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.

[0045] The term “haloalkoxy”, as used herein, means at least one haloalkyl group, as defined herein, linked to the original molecular chemical 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 a ring containing a monocyclic aromatic heteroatom (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 Petition 870250094048, dated 10 / 14 / 2025, pp. 374 / 509 16 / 140 heteroarene when present as a substituent. Monocyclic heteroaryls 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). Five-membered monocyclic aromatic rings have two double bonds, and six-membered monocyclic aromatic rings have three double bonds. A bicyclic heteroaryl is an 8- to 12-membered ring system and includes a fused bicyclic heteroaromatic ring system (i.e., 10π electron system), such as a monocyclic heteroaryl ring fused to a 6-membered arene (e.g., quinolin-4-yl, indole-1-yl), a monocyclic heteroaryl ring fused to a monocyclic heteroarene (e.g., naphthyridinyl), and a phenyl group fused to a monocyclic heteroarene (e.g., quinolin-5-yl, indole-4-yl).A bicyclic heteroaryl / heteroarene group includes a 9-membered bicyclic fused heteroaromatic ring system having four double bonds and at least one heteroatom contributing an electron pair to a fully aromatic 10π electron system, such as ring systems with a nitrogen atom at the ring junction (e.g., imidazopyridine) or a benzoxadiazolyl. A bicyclic heteroaryl also includes a fused bicyclic ring system composed of a heteroaromatic ring and a 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[3,2b]pyridinyl). The bicyclic heteroaryl group is attached to the original molecular chemical portion at an aromatic ring atom.Other representative examples of heteroaryl groups include, but are not limited to, indole (e.g., indole-1-yl, indole-2-yl, indole-4-yl), pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl). Petition 870250094048, dated 10 / 14 / 2025, pp. 375 / 509 17 / 140 pyrrolila, benzopyrazolila, 1,2,3-triazolila (for example, triazol-4-ila), 1,3,4tiadiazolila, 1,2,4-tiadiazolila, 1,3,4-oxadiazolila, 1,2,4-oxadiazolila, imidazolila, tiazolila (for example, tiazol-4-ila), isotiazolila, thienila, benzimidazolila (for example, benzimidazol-5-ila), benzothiazolila, benzoxazolila, benzoxadiazolila, benzotienila, benzofuranila, isobenzofuranila, furanila, oxazolila, isoxazolila, purinila, isoindolila, quinoxalinila, indazolila (for example, indazol-4-ila, indazol-5-ila), quinazolinila, 1,2,4-triazinila, 1,3,5-triazinila, isoquinolinila, quinolinila, imidazo[1,2-a ]piridinila (for example, imidazo[1,2-a]piridin-6-ila), naftiridinila, piridoimidazolila, tiazolo[5,4-b ]piridin-2-ila e thiazolo[5,4-d]pyrimidin-2-ila.

[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. A monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. A three- or four-membered ring contains zero or one double bond and one heteroatom selected from the group consisting of O, N, and S. A five-membered ring contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. A six-membered ring contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.Seven- and eight-membered rings contain zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocyclides include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-ditianyl, imidazolinyl, isothiazolinyl, isoxazolinyl. Petition 870250094048, dated 10 / 14 / 2025, pp. 376 / 509 18 / 140 isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetra-hydrofuranyl, tetra-hydropyranyl, tetra-hydropyridinyl, tetra-hydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2thiazinyl, 1,3-thiazinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1dioxidthiomorpholinyl (thiomorpholin sulfone), thiopyranyl and trithianyl.A bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered arene, or a monocyclic heterocycle fused to a monocyclic cycloalkane, or a monocyclic heterocycle fused to a monocyclic cycloalkene, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a monocyclic heterocycle fused to a monocyclic heteroarene, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent ring atoms 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 linked to the original molecular chemical moiety at a non-aromatic ring atom (e.g., indolin-1-yl). Representative examples of bicyclic heterocyclides include, but are not limited to, chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, hydroisoquinolin-2-yl, azaspiro[3,3]heptan-6-yl, azabicyclo[2,2,1]hept-2-yl). 2,3-dihydrobenzotien-2-yl, 1,2,3,4-tetra2-azaspiro[3,3]heptan-2-yl, 2-oxa-6azabicyclo[2,2,1]heptyl (including 2azabicyclo[3,1,0]hexanyl (including 3azabicyclo[3,1,0]hexan-3-yl), 2,3-dihydro-1 H-indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[ c ]pyrrolyl, octahydropyrrolopyridinyl, tetrahydroisoquinolinyl, 7-oxabicyclo[2,2,1]heptanyl, hexahydro-2H-cyclopenta[b]furanyl, 2 oxaspiro[3,3]heptanyl, 3-oxaspiro[5,5]undecanyl, 6-oxaspiro[2,5]octan-1-yl and 3-oxabicyclo[3,1,0]hexan-6-yl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a 6-arene. Petition 870250094048, dated 10 / 14 / 2025, pp. 377 / 509 19 / 140 members, or a bicyclic heterocycle fused to a monocyclic cycloalkane, or a bicyclic heterocycle fused to a monocyclic cycloalkene, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non-adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3 or 4 carbon atoms, or an alkenylene bridge of two, three or four carbon atoms. Examples of tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanecyclopenta[b]furan, hexahydro1H-1,4-methanecyclopenta[c]furan, aza-adamantane (1azatricyclo[3,3,1,13,7]decane) and oxa-adamantane (2oxatricyclo[3,3,1,13,7]decane). Monocyclic, bicyclic and tricyclic heterocycles are connected to the original molecular chemical portion at a non-aromatic ring atom.

[0050] The term “hydroxyl” or “hydroxyl”, as used in this document, means an -OH group.

[0051] The term “hydroxyalkyl”, as used herein, means at least one -OH group is attached to the original molecular chemical portion via an alkylene group, as defined herein.

[0052] The term “hydroxyfluoroalkyl”, as used herein, means at least one -OH group is attached to the original molecular chemical moiety via 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 occurrence (e.g., C1-4alkyl, C3-6cycloalkyl, C1-4alkylene). These designations are used as generally understood by those skilled in the art. For example, the representation C followed by a subscript number indicates the number of Petition 870250094048, dated 10 / 14 / 2025, pp. 378 / 509 20 / 140 carbon atoms are present in the next group. Thus, C1-4 alkyl is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). When a range is given, as in C1-4, the members of the next group can have any number of carbon atoms within the mentioned range. A C1-4 alkyl, for example, is an alkyl group that has from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

[0054] The terms original molecule or original molecular chemical portion refer to the entire portion of a molecule to which a substituent is attached, that is, the remainder of the molecule.

[0055] The term “sulfonamide”, as used in this document, means -S(O)2NRz- or -NRzS(O)-, where R can 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, on any atom of that group. Any atom can be substituted.

[0057] The term “substituted” refers to a group that can be further replaced by one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, =O (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclo, 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. Petition 870250094048, dated 10 / 14 / 2025, pp. 379 / 509 21 / 140 In some embodiments, a group is optionally substituted by 1, 2, 3, 4 or 5 substituents. In some embodiments, an aryl, a heteroaryl, a cycloalkyl or a heterocycle is optionally substituted by 1, 2, 3, 4 or 5 substituents. In some embodiments, an aryl, a heteroaryl, a cycloalkyl or a heterocycle may be independently unsubstituted or substituted by 1, 2 or 3 substituents.

[0058] For the compounds described in this document, groups and substituents thereof may be selected according to the permitted valence of the atoms and substituents, so that the selections and substitutions result in a stable compound, for example, that does not spontaneously undergo transformation, such as rearrangement, cyclization, elimination, etc.

[0059] The term “allosteric site”, as used in this document, refers to a ligand binding site that is topographically distinct from the orthosteric binding site.

[0060] The term “modulator”, as used in this document, refers to a molecular entity (for example, 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 in this document, refers to a natural or synthetic molecular entity that is capable of associating with 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 in this document, are used interchangeably and refer to a naturally occurring ligand, found in nature, that binds to a receptor. Petition 870250094048, dated 10 / 14 / 2025, pp. 380 / 509 22 / 140

[0063] The term “orthosteric site,” as used in this document, 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 on the mAChR M4 receptor is the site to which acetylcholine binds.

[0064] The term “positive allosteric modulator of mAChR M4 receptor”, as used in this document, refers to any exogenously administered compound or agent that directly or indirectly increases the activity of the mAChR M4 receptor in the presence or absence of acetylcholine, or another agonist, in an animal, in particular a mammal, for example, a human. For example, a positive allosteric modulator of the mAChR M4 receptor may increase the activity of the mAChR M4 receptor in a cell in the presence of extracellular acetylcholine. The cell may be Chinese hamster ovary (CHO-K1) cells transfected with human mAChR M4. The cell may be Chinese hamster ovary (CHO-K1) cells transfected with rat mAChR M4 receptor. The cell may be Chinese hamster ovary (CHO-K1) cells transfected with mammalian mAChR M4.The term “positive allosteric modulator of mAChR M4 receptor” includes a compound that is either an “allosteric enhancer of mAChR M4 receptor” or an “allosteric agonist of mAChR M4 receptor”, as well as a compound that has mixed activity comprising pharmacology of both an “allosteric enhancer of mAChR M4 receptor” and an “allosteric agonist of mAChR M4 receptor”. The term “positive allosteric modulator of mAChR M4 receptor” also includes a compound that is an “allosteric enhancer of mAChR M4 receptor”.

[0065] The term “mAChR M4 receptor allosteric enhancer”, as used herein, refers to any exogenously administered compound or agent that directly or indirectly enhances the response produced by the endogenous ligand (such as acetylcholine) when the Petition 870250094048, dated 10 / 14 / 2025, pp. 381 / 509 23 / 140 An endogenous ligand binds to the orthosteric site of the mAChR M4 receptor in an animal, particularly a mammal, for example, a human. An allosteric mAChR M4 receptor enhancer binds to a site other than the orthosteric site, i.e., an allosteric site, and positively increases the receptor's response to an agonist or endogenous ligand. In some embodiments, an allosteric enhancer does not induce receptor desensitization; the activity of a compound as an allosteric mAChR M4 receptor enhancer provides advantages over the use of a pure mAChR M4 receptor orthosteric agonist. Such advantages may include, for example, increased safety margin, higher tolerability, decreased 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 enhances the response produced by the endogenous ligand (such as acetylcholine), particularly in 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 efficacy of the agonist. The mAChR M4 receptor allosteric enhancer binds to a site other than the orthosteric site, i.e., an allosteric site, and positively enhances the receptor response 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 achieve a receptor effect.

[0067] The term “allosteric agonist of the mAChR M4 receptor”, as used in this document, 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. Petition 870250094048, dated 10 / 14 / 2025, pp. 382 / 509 24 / 140 mAChR M4 receptor allosteric agonist binds to a site that is different from the orthosteric acetylcholine site of the mAChR M4 receptor. Because it does not require the presence of the endogenous ligand, the activity of a compound as an mAChR M4 receptor allosteric agonist offers advantages if the cholinergic tone at a given synapse is low.

[0068] The term “mAChR M4 receptor allosteric ligand”, as used in this document, 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 may block the action of other allosteric modulators acting at the same site.

[0069] In the case of reciting numerical ranges in this document, each intermediate number between them with the same degree of precision is explicitly contemplated. For example, in the case of the range from 6 to 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and in the case of the range from 6.0 to 7.0, the numbers 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(diphenylphosphine)-1,1'-binaphthyl; Boc and iron-butoxicarbonyl; BrettPhos is 2-(dicyl-hexylphosphine)3,6-dimethoxy-2',4',6'-tri-isopropyl-1,1'biphenyl; BrettPhos Pd G3 is methanosulfonate of [(2-di-cyclo-hexylphosphine-3,6dimethoxy-2',4',6'- tri-isopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II); f-BuOH is ferric-butanol; Celite®é diatomaceous earth; Petition 870250094048, dated 10 / 14 / 2025, p. 383 / 509 25 / 140 ECD is 1,2-dichloroethane; DCM is dichloromethane; AED is diethylamine; DMAP is 4-dimethylaminopyridine; DMF and N, N-dimethylformamide; DMP or periodinane from Dess-Martin is 1,1,1-tris(acetyloxy)-1,1-di-hydro-1,2benziodoxol-3-(1 H)-one; DIAD is di-isopropyl azodicarboxylate; DIPEA or DIEA is diisopropylethylamine; DMSO is dimethyl sulfoxide; Dowtherm™ A is a eutectic mixture of 26.5% diphenyl + 73.5% diphenyl oxide; D t BAD is di-tert-butyl-azodicarboxylate; eq or eq. is equivalent(s); EtOAC is ethyl acetate; (4,4'-dtbbpy)NiCl2 is 4,4'-bis(1,1-dimethylethyl)-2,2'bipyridine]nickel(II) dichloride; EtOH is ethanol; h or hr means hour(s); Hex is hexane(s); IPA stands for isopropyl alcohol; KOAc is potassium acetate; LAH stands for lithium aluminum hydride; Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4dithiadiphosphetan; m CPBA is meta-chloroperoxy benzoic acid; MeCN or ACN stands for acetonitrile; MeOH is methanol; min means minute(s); Petition 870250094048, dated 10 / 14 / 2025, pp. 384 / 509 26 / 140 NaOAc is sodium acetate; NaOMe is sodium methoxide; NBS stands for N-bromosuccinimide; NCS stands for N-chlorosuccinimide; NMO is 4-methylmorpholine N-oxide; NMP stands for N-methyl-2-pyrrolidone; [Pd(allyl)(tBuBrettPhos)]OTf is allyl[(2-Di-tertbutylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'biphenyl)]palladium(II) trifluoromethanesulfonate; Pd(dppf)Cl2 is [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II); Pd(OAc)2 is palladium(II)acetate; Pd(PPhs)4 is tetrakis(triphenylphosphine)palladium(0); PPA stands for polyphosphoric acid; PPh3 is triphenylphosphine; PPTS is pyridinium p-toluenesulfonate; rt is ambient temperature; sat. means saturated; s is second(s); SCX cartridge or HF SCX cartridge is a strong cation exchange cartridge (i.e., Agilent part no. 14256027); SFC stands for supercritical fluid chromatography; TBAC or TBACl is tetrabutylammonium chloride; t-BuXPhos is 2-di-tert-óüt / / phosphino-2',4',6'-triisopropylbiphenyl; TEA or EtsN is triethiamin; TFA stands for trifluoroacetic acid; THF stands for tetrahydrofuran; TMB stands for trimethylboroxine; TosCl stands for para-toluenesulfonyl chloride; and tosila stands for para-toluenesulfonyl. Petition 870250094048, dated 10 / 14 / 2025, pp. 385 / 509 27 / 140 2. Compounds

[0071] In one aspect, the invention provides compounds of formula (I), wherein R2, R4A, R4B, R6, R7, R8, X1 and n are as defined herein.

[0072] Unsubstituted or substituted (i.e., optionally substituted) rings, such as aryl, heteroaryl, etc., are composed of both a ring system and the optional substituents of the ring system. Consequently, the ring system can be defined independently of its substituents, so that redefining only the ring system leaves only the previous optional substituents present. For example, a 5- to 12-membered heteroaryl with optional substituents can still be defined by specifying that the ring system of the 5- to 12-membered heteroaryl is a 5- to 6-membered heteroaryl (i.e., a 5- to 6-membered heteroaryl ring system), in which case the optional substituents of the 5- to 12-membered heteroaryl are still present in the 5- to 6-membered heteroaryl, unless expressly indicated otherwise.

[0073] When heterocyclic and heteroaromatic ring systems are defined as containing or having specific 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] The numbered embodiments of the invention are disclosed below. The first embodiment is denoted E1, subsequent embodiments are denoted E1.1, E1.2, E2, E3, E4, E4.1 and so forth.

[0075] E1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, Petition 870250094048, dated 10 / 14 / 2025, pp. 386 / 509 28 / 140 (R8)n (I) where: X1 is NR5, O or CR5AR5B; R2e G2, -NR2aR2b, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, -OR2a, NR2aC(O)R2b, -C(O)OR2a, -C(O)NR2aR2bou hydrogen; R2ae R2bsão, independently, hydrogen, C1-6 alkyl, C1-6 haloalkyl, G2 or -C1-3 alkylene-G2; G2, in each occurrence, is independently a 5- to 6-membered heteroaryl containing 1-4 heteroatoms, 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 O, N, and S, and G2 is optionally substituted by 1-5 substituents independently selected from the group consisting of halogen, cyano, C1-4-alkyl, C1-4-fluoroalkyl, oxo, -ORx, -N(Rx)2, C(O)Rx, -C(O)ORx, -C(O)N(Rx)2, -C1-6-alkylene-ORx, -C1-6alkylene-N(Rx)2, G2ae -C1-3alkylene-G2a; Rx, in each occurrence, is independently hydrogen, C1-4 alkyl, C14 fluoroalkyl, C3-6 cycloalkyl, or C1-3 alkylene-C3-6 cycloalkyl; G2a is a C3-6 cycloalkyl group; Petition 870250094048, dated 10 / 14 / 2025, pp. 387 / 509 29 / 140 R4A and R4B are independently hydrogen, C1-4 alkyl, C3-4 cycloalkyl, or C1-3 alkylene-OH; or R4A and R4B together with the carbon to which they are attached form a C3-6 cycloalkyl; R5 is hydrogen, C1-6 alkyl, C1-6 fluoroalkyl, -C1-6 alkylene-Ry, -C1-6 fluoroalkylene-Ry, G5 or -C1-3 alkylene-G5; R5Ae R5B are independently hydrogen, halogen, C1-4 alkyl, C1-4 fluoroalkyl or -C1-4 alkylene-OH; Ry is -OR5a, -N(R5a)2, -C(O)R5a, -C(O)OR5aor -C(O)N(R5a)2; R5a, in each occurrence, is independently hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, or C1-3 alkylene-C3-4 cycloalkyl; G5 is a phenyl, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, a 5- to 6-membered heteroaryl containing 1-4 heteroatoms, or a C3-6 cycloalkyl, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G5 is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, cyano, C1-4 alkyl, C1-2 fluoroalkyl, -OC1-4 alkyl, OH, and oxo; R6 is hydrogen, halogen, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C2-4 alkenyl, -OR6a, -N(R6a)2, -C1-3 alkylene-OR6a or C3-4 cycloalkyl; R6a, in each occurrence, is independently hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, or C1-3 alkylene-C3-4 cycloalkyl; wherein, alternatively, two R6a, together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclic ring containing the nitrogen attached to R6a and optionally 1 additional heteroatom which is O, N or S, wherein the heterocyclic ring is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C1-2 alkyl and C1-2 fluoroalkyl; R7 is C1-4 alkyl, hydrogen, halogen, cyano, C1-4 fluoroalkyl, C2-4 alkenyl, -OR7a, Petition 870250094048, dated 10 / 14 / 2025, pp. 388 / 509 30 / 140 -Ci-3alkylene-OR7a, CO2R7a, COR7aor C3-6Cycloalkyl; R7a is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl or -C13-alkylene-C3-4 cycloalkyl; R8, in each occurrence, is independently halogen, C1-4 alkyl, C1-4 fluoroalkyl, or C3-4 cycloalkyl; en is 0, 1, 2, 3 or 4; wherein each cycloalkyl group in Rx, G2a, R6, R6a, R7, R7a and R8 is unsubstituted or substituted by 1-4 substituents independently selected from C1-4 alkyl (e.g., methyl) and halogen (e.g., fluoro).

[0076] E1.1. The compound of E1, or a pharmaceutically acceptable salt thereof, wherein G5 is a phenyl, a 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, a 5- to 6-membered heteroaryl containing 1-4 heteroatoms or a C3-6-cycloalkyl, wherein the heteroatoms are independently selected from the group consisting of O, N and S, and G5 is optionally substituted by 1-4 substituents independently selected from the group consisting of halogen, C1-4-alkyl, C1-2-fluoroalkyl, -OC1-4-alkyl, OH and oxo.

[0077] E1.2. The compound of any one of E1 or E1.1, or a pharmaceutically acceptable salt thereof, wherein X1 is NR5 or 0.

[0078] E2. The compound of any one of E1-E1.2, or a pharmaceutically acceptable salt thereof, wherein R2 is G2, -NR2aR2b, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, -OR2a, -C(O)OR2a, -C(O)NR2aR2b or hydrogen.

[0079] E3. The compound of E2, or a pharmaceutically acceptable salt thereof, wherein R2 is G2.

[0080] E4. The compound from any one of E1-E3, or a pharmaceutically acceptable salt thereof, wherein G2 is the optionally substituted 3- to 7-membered carbocyclyl. Petition 870250094048, dated 10 / 14 / 2025, pp. 389 / 509 31 / 140

[0081] E4.1. The compound of any one of E1-E4, or a pharmaceutically acceptable salt thereof, characterized in that the optionally substituted 3- to 7-membered carbocyclyl ring system at G2 is Cs-cycloalkyl.

[0082] E4.2. The compound of E4.1, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 3- to 7-membered carbocyclyl ring system at G2 is a cyclopropyl or cyclobutyl.

[0083] E4.3. The compound of any one of E4-E4.2, or a pharmaceutically acceptable salt thereof, wherein G2 is optionally substituted by 1-4 substituents independently selected from the group consisting of C1-4 alkyl and halogen.

[0084] E4.4. The compound of E4.3, or a pharmaceutically acceptable salt thereof, wherein G2 is optionally substituted by 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, where G2 is I, F, or XZ.

[0086] E5. The compound from any one of E1-E3, or a pharmaceutically acceptable salt thereof, wherein G2 is the optionally substituted 5- to 6-membered heteroaryl.

[0087] E5.1. The compound of any one of E1-E3 or E5, or a pharmaceutically acceptable salt thereof, characterized in that the optionally substituted 5- to 6-membered heteroaryl ring system in G2 is a 5-membered heteroaryl.

[0088] E5.2. The compound of any one of E5 or E5.1, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl ring system in G2 contains 1-2 heteroatoms independently selected from the group consisting of N and S. Petition 870250094048, dated 10 / 14 / 2025, pp. 390 / 509 32 / 140

[0089] E5.3. The compound of E5.2, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl ring system at G2 is thiophenyl or pyrazolyl.

[0090] E5.4. The compound of E5.3, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted heteroaryl ring system at G2 is thiophen-2-yl or pyrazol-5-yl.

[0091] E5.5. The compound of any one of E5-E5.4, or a pharmaceutically acceptable salt thereof, wherein G2 is optionally substituted by 1-4 substituents independently selected from the group consisting of C1-4 alkyl and halogen.

[0092] E5.6. The compound of E5.5, or a pharmaceutically acceptable salt thereof, wherein G2 is optionally substituted by 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, where G2 is or

[0094] E6. The compound of any one of E1-E5.7, or a pharmaceutically acceptable salt thereof, wherein G2 is or

[0095] E7. The compound of E2, or a pharmaceutically acceptable salt thereof, wherein R2 is -NR2aR2b.

[0096] E8. The compound of E2, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-6 alkyl.

[0097] E8.1. The compound of E8, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl or tert-butyl.

[0098] E9. The compound of E2, or a pharmaceutically available salt Petition 870250094048, dated 10 / 14 / 2025, pp. 391 / 509 33 / 140 acceptable of the same, where R2 is a halogen.

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

[0100] E10. The compound of E2, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

[0101] E11. The compound of E2, or a pharmaceutically acceptable salt thereof, wherein R2 is -C(O)OR2a.

[0102] E12. The compound of E2, or a pharmaceutically acceptable salt thereof, wherein R2 is -C(O)NR2aR2b.

[0103] E13. The compound of any one of E1, E1.1, E1.2, E2, E4.1-E4.4, E5.1-E5.6, E7 or E11-E12, or a pharmaceutically acceptable salt thereof, wherein R2a is hydrogen or C1-6 alkyl.

[0104] E13.1. The compound of E13, or a pharmaceutically acceptable salt thereof, wherein R2a is hydrogen.

[0105] E13.2. The compound of E13, or a pharmaceutically acceptable salt thereof, wherein R2a is C1-4 alkyl.

[0106] E13.3. The compound of E13.2, or a pharmaceutically acceptable salt thereof, wherein R2a is ethyl.

[0107] E14. The compound of any one of E1, E1.1, E1.2, E2, E4.1-E4.4, E5.1-E5.6, E7 or E12-E13.3, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

[0108] E15. The compound of any one of E1-E14, or a pharmaceutically acceptable salt thereof, wherein R4A and R4B are hydrogen.

[0109] E15.1. The compound of E15, or a pharmaceutically acceptable salt thereof, in which the hydrogen in R4Ae R4Be is deuterium (2H).

[0110] E16. The compound of any one of E1-E15.1, or a pharmaceutically acceptable salt thereof, wherein X1 is NR5. Petition 870250094048, dated 10 / 14 / 2025, pp. 392 / 509 34 / 140

[0111] E17. The compound of E1-E16, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen, C1-6 alkyl, G5 or -C1-3 alkylene-G5.

[0112] E17.1. The compound of E17, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen, C1-6 alkyl or G5.

[0113] E17.2. The compound of E17.1, or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen.

[0114] E17.3. The compound of E17.1, or a pharmaceutically acceptable salt thereof, wherein R5 is C1-6 alkyl.

[0115] E17.4. The compound of E17.3, or a pharmaceutically acceptable salt thereof, wherein R5 is C1-3 alkyl.

[0116] E17.5. The compound of E17.4, or a pharmaceutically acceptable salt thereof, wherein R5 is methyl.

[0117] E17.6. The compound of E17.1, or a pharmaceutically acceptable salt thereof, wherein R5 is G5.

[0118] E17.7. The compound of E17, or a pharmaceutically acceptable salt thereof, wherein R5 is -C1-3alkylene-G5.

[0119] E17.8. The compound of any one of E1E17.1 or E17.6-E17.7, or a pharmaceutically acceptable salt thereof, wherein G5 is the optionally substituted C3-6cycloalkyl.

[0120] E17.9. The compound of any one of E1-E17. 1 or E17.6-E17.8, or a pharmaceutically acceptable salt thereof, wherein the optionally substituted C3-6 cycloalkyl ring system at G5 is cyclopropyl, cyclobutyl or cyclopentyl.

[0121] E17.10. The compound of any one of E1E17.1 or E17.6-E17.9, or a pharmaceutically acceptable salt thereof, wherein the C3-6-cycloalkyl in G5 is optionally substituted by 1-2 substituents independently selected from the group consisting Petition 870250094048, dated 10 / 14 / 2025, pp. 393 / 509 35 / 140 in halogen, cyano and C1-4 alkyl.

[0122] E17.11. The compound of E17.10, or a pharmaceutically acceptable salt thereof, wherein the C3-6 Cycloalkyl in G5 is optionally substituted by 1-2 substituents independently selected from the group consisting of fluoro, cyano and methyl.

[0123] E17.12. The compound of E17.11, or a pharmaceutically acceptable salt thereof, wherein G5 is cyclopropyl and cyclopentyl.

[0124] E17.13. The compound of any one of E1E17.1 or E17.6-E17.7, or a pharmaceutically acceptable salt thereof, wherein G5 is the optionally substituted phenyl group.

[0125] E17.14. The compound of any one of E1E17.1, E17.6-E17.7 or E17.13, or a pharmaceutically acceptable salt thereof, wherein the phenyl in G5 is optionally replaced by 1-2 substituents independently selected from the group consisting of fluoro, chlorine, cyano, methyl and -OCH3.

[0126] E17.15. The compound of E17.14, or a pharmaceutically acceptable salt thereof, wherein G5 is 2,4-dimethoxyphenyl.

[0127] E18. The compound of any one of E1-E15.1, or a pharmaceutically acceptable salt thereof, wherein X1 is 0.

[0128] E19. The compound of any one of E1-E15.1, or a pharmaceutically acceptable salt thereof, wherein X1 is CR5AR5B.

[0129] E19.1. The compound of any one of E1E15.1 or E19, or a pharmaceutically acceptable salt thereof, wherein R5A and R5B are hydrogen.

[0130] E20 The compound of any one of E1-E19, or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen.

[0131] E20.1. The compound of any one of E1E19.1, or a pharmaceutically acceptable salt thereof, wherein R6 is C1 Petition 870250094048, of 14 / 10 / 2025, page 394 / 509 36 / 140 4-alkyl.

[0132] E20.2. The compound of E20.1, or a pharmaceutically acceptable salt thereof, wherein R6 is methyl.

[0133] E21. The compound of any one of E1-E20.2, or a pharmaceutically acceptable salt thereof, wherein R7 is C1-4 alkyl, halogen, cyano, C2-4 alkenyl, CO2R7a or unsubstituted or substituted C3-6 cycloalkyl.

[0134] E21.1. The compound of E21, or a pharmaceutically acceptable salt thereof, wherein R7 is C1-4 alkyl, halogen, cyano or C3-6 cycloalkyl unsubstituted or substituted.

[0135] E21.2. The compound of E21.1, or a pharmaceutically acceptable salt thereof, wherein R7 is C1-4 alkyl.

[0136] E21.3. The compound of any one of E1E21.2, or a pharmaceutically acceptable salt thereof, wherein the C14 alkyl in R7 is methyl.

[0137] E21.4. The compound of any one of E1E21.2, or a pharmaceutically acceptable salt thereof, wherein the C14 alkyl in R7 is ethyl.

[0138] E21.5. The compound of E21.1, or a pharmaceutically acceptable salt thereof, where R7 is cyan.

[0139] E21.6. The compound of E21.1, or a pharmaceutically acceptable salt thereof, wherein R7 is the unsubstituted C3-6 cycloalkyl.

[0140] E21.7. The compound of any one of E1E21.1 or E21.6, or a pharmaceutically acceptable salt thereof, wherein R7 is cyclopropyl.

[0141] E21.8. The compound of E21.1, or a pharmaceutically acceptable salt thereof, wherein R7 is a halogen.

[0142] E21.9. The compound of any one of E1 Petition 870250094048, dated 10 / 14 / 2025, pp. 395 / 509 37 / 140 E21.1, E21.3, E21.4 or E21.8, or a pharmaceutically acceptable salt thereof, wherein the halogen in R7 is bromine.

[0143] E21.10. The compound of E21, or a pharmaceutically acceptable salt thereof, wherein R7 is C2-4 alkenyl.

[0144] E21.11. The compound of any one of E1-E21, E21.3, E21.4, E21.9, or E21.10, or a pharmaceutically acceptable salt thereof, wherein C2-4-cycloalkyl in R7 is vinyl or propen-1,2-yl.

[0145] E21.12. The compound of E21, or a pharmaceutically acceptable salt thereof, wherein R7 is CO2R7a.

[0146] E21.13. The compound of any one of E1-E21, E21.3, E21.4, E21.9, E21.10, E21.11 or E21.12, or a pharmaceutically acceptable salt thereof, wherein R7a is C1-4 alkyl.

[0147] E21.14. The compound of any one of E1-E21, E21.3, E21.4, E21.9, E21.10, E21.11 or E21.12-E21.13, or a pharmaceutically acceptable salt thereof, wherein the C1-4 alkyl in R7a is methyl.

[0148] E21.15. The compound of any one of E1E20.2, or a pharmaceutically acceptable salt thereof, wherein R7 is hydrogen.

[0149] E22 The compound of any one of E1-E21.15, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0150] E23. The compound of E1 selected from the group consisting of: 2-(6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-methyl-6,7-dihydro-5Hpyrrolo[3,4-b]pyridin-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; Petition 870250094048, dated 10 / 14 / 2025, pp. 396 / 509 38 / 140 3-methyl-2-(2-(thiophen-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 5-(3-methyl-5-oxo-6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-2-yl)-4,5,6,7-tetrahidrothiazolo[5,4-c ]pyridin-2-carboxylate de ethyla; 3-methyl-2-(2-methyl-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-6,7-di-hidro-5 Hpirrolo[3,4-b ]pyridin-5-one; 3-methyl-2-(2-(1-methyl-1 H-pyrazol-5-yl)-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H) yl)-6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-5-ona; 2-(2-amino-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3-methyl-6,7-di-hidro5 H-pyrrolo[3,4-b ]pyridin-5-one; 2-(2-chloro-6,7-di-hydrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3-methyl-6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5-one; 2-(2-(2,2-dimethylcyclopropyl)-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3methyl-6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 2-(2-(terc-butyl)-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3-methyl-6,7-dihydro-5 H-pyrrolo[3,4-b ]pyridin-5-ona; 2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3,6-dimethyl-6,7-dihydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 3,6-dimethyl-2-(2-(1-methylcyclopropyl)-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H )yl)-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 6-cyclopropyl-2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3methyl-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 6-cyclopropyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-di-hydrothiazolo[5,4c ]pyridine-5(4 H)-yl)-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridin-5-one; 6-cyclopentyl-2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3methyl-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 6-cyclopentyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-di-hydrothiazolo[5,4c ]pyridine-5(4 H)-yl)-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridin-5-one; Petition 870250094048, dated 10 / 14 / 2025, p. 397 / 509 39 / 140 2-(2-(2,2-dimethylcyclopropyl)-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3,6dimethyl-6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 6-cyclopropyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-di-hidrothiazolo[5,4-c ]pyridin5(4 H)-yl)-3-methyl-6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 6-cyclopentyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-di-hidrothiazolo[5,4-c ]pyridin5(4 H)-yl)-3-methyl-6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 2-(2-cyclobutyl-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3,6-dimethyl-6,7-dihydro-5 H-pyrrolo[3,4-b ]pyridin-5-ona; 2-(2-cyclobutyl-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3-methylfuro[3,4b]pyridin-5(7H)-ona; 2-(2-(1-fluorocyclopropyl)-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3,6dimethyl-6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 3-methyl-2-(2-(1-methylcyclopropyl)-6,7-di-hydrothiazolo[5,4-c ]pyridin-5(4 H) yl)furo[3,4-b ]pyridin-5(7 H)-one; 2-(2-cyclobutyl-6,7-di-hydrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3-methyl-6,7-di-hydro5 H-pyrrolo[3,4-b ]pyridin-5-one; 3-cyclopropyl-2-(2-cyclopropyl-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-6methyl-6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 2-(2-cyclopropyl-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-6-methyl-5-oxo-6,7di-hidro-5 H-pyrrolo[3,4-b ]pyridine-3-carbonitrila; 2-(2-(1-fluorocyclopropyl)-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3-methyl6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-6-methyl-3-vinyl-6,7di-hydro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 2-(2-cyclopropyl-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-6-methyl-3-(prop-1en-2-yl)-6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-5-ona; 2-(2-cyclopropyl-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-6-methyl-5-oxo-6,7di-hidro-5 H-pyrrolo[3,4-b ]pyridine-3-carboxylate de methyl; Petition 870250094048, dated 10 / 14 / 2025, p. 398 / 509 40 / 140 5-(3-methyl-5-oxo-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridin-2-yl)-4,5,6,7-tetrahydrothiazole[5,4-c ]pyridine-2-carboxamide; 2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-6-(2,4dimethoxybenzyl)-3-ethyl-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridin-5-one; 2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3-ethyl-6,7-di-hydro5 H-pyrrole[3,4-b ]pyridine-5-one; 2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3,4dimethyl-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-4-methyl6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,4,6trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

[0151] E24. A pharmaceutical composition comprising any one of E1-E23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0152] E25. A method for 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 any compound from E1-E23, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of E24.

[0153] E26. The E25 method, in which the disorder is associated with a dysfunction of mAChR M4.

[0154] E27. The E25 or E26 method, where the disorder is a neurological and / or psychiatric disorder associated with mAChR M4 dysfunction.

[0155] E28. The method of any one of E25-E27, in Petition 870250094048, dated 10 / 14 / 2025, pp. 399 / 509 41 / 140 that the disorder is selected from the group that consists of Alzheimer's disease, schizophrenia, a sleep disorder, a pain disorder, and a cognitive disorder.

[0156] E29. The method of E28, where the disorder is Alzheimer's disease.

[0157] E30. The method of any one of E25-E27, wherein the disorder is selected from the group 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 syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, neurodegeneration-based and drug-induced dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders.

[0158] E31. A kit comprising any one of E1-E23 compounds, 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 mAChR M4 receptor activity; and (f) instructions for administering the compound in connection with cognitive or behavioral therapy.

[0159] E32. The compound of any one of E1-E23, or one Petition 870250094048, dated 10 / 14 / 2025, pp. 400 / 509 42 / 140 pharmaceutically acceptable salt thereof, 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.

[0160] E33. The use of any compound of E1E23, or a pharmaceutically acceptable 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.

[0161] The compound can exist as a stereoisomer in which asymmetric or chiral centers are present. The stereoisomer is R or S depending on the configuration of substituents around the chiral carbon atom. The terms R and S used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof, and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers and diastereomers. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparing racemic mixtures followed by resolution methods well known to those of common skill in the art.These resolution methods are exemplified by (1) binding a mixture of enantiomers to a chiral auxiliary, separating the resulting mixture of diastereomers by recrystallization or chromatography and optionally releasing the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith and Tatchell, Vogel's Textbook of Practical Organic Chemistry, 5th edition (1989), Longman Scientific & Technical, Essex CM20. Petition 870250094048, dated 10 / 14 / 2025, pp. 401 / 509 43 / 140 2JE, England or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods.

[0162] It should be understood that the compound may possess tautomeric forms as well as geometric isomers, and that these also constitute modes of disclosure.

[0163] In compounds of formula (I), and any subformulas, any hydrogen or H, whether explicitly mentioned or implied in the structure, encompasses hydrogen isotopes 1H (protium) and 2H (deuterium).

[0164] The present disclosure also includes an isotopically labeled compound, which is identical to those mentioned in formula (I), except 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 normally found in nature. Examples of suitable isotopes 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, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl, respectively. Substitution by heavier isotopes, such as deuterium, i.e., 2H, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances.The compound can incorporate positron-emitting isotopes for medical imaging and positron emission tomography (PET) studies to determine receptor distribution. Suitable positron-emitting isotopes that can be incorporated into compounds of formula (I) are 11C, 13N, 15O and 18F.

[0165] Isotopically enriched forms of compounds of formula (I), or any subformulas, can generally be prepared by conventional techniques known to those skilled in the art or by Petition 870250094048, dated 10 / 14 / 2025, pages 402 / 509 44 / 140 processes analogous to those described in the appended Examples, using a suitable isotopically enriched reagent in place of a non-isotopically enriched reagent. The extent of isotopic enrichment can be characterized as a percentage of incorporation of a specific isotope into an isotopically labeled atom (e.g., % incorporation of deuterium into a deuterium label). a. Pharmaceutically acceptable salts

[0166] The disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds that are soluble in water or oil or dispersible, suitable for the treatment of disorders without undue toxicity, irritation, and allergic response, proportionate to a reasonable benefit / risk ratio, and effective for the intended use. The salts may be prepared during the isolation and final 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, such as hydrochloric acid. The resulting salt may precipitate 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. Petition 870250094048, dated 10 / 14 / 2025, pp. 403 / 509 45 / 140 can also be quaternized with alkyl chlorides, bromides and iodides, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0167] Basic addition salts can be prepared during the isolation and final purification of compounds revealed by the reaction of a carboxyl group with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a metallic cation, such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or a primary, secondary, or tertiary organic amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, A / ^ / V-dimethylaniline, / V-methylpiperidine, Λ / methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine and Λ / ,Λ / '-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. b. General System

[0168] Compounds of formula (I) can be prepared by synthetic processes or by metabolic processes. The preparation of compounds by metabolic processes includes those that occur in the human or animal body (in vivo) or processes that occur in vitro.

[0169] Compounds of formula (I) can be synthesized as shown in Schemes 1-10. Scheme 1 (i) (ii) (iii)

[0170] As shown in Scheme 1, 3-bromo-4 Petition 870250094048, dated 10 / 14 / 2025, pp. 404 / 509 46 / 140 tert-butyl oxopiperidine-1-carboxylate (i) can be subjected to a thioamide in solvent (e.g., ethanol) with heating to about 7080 °C to give intermediate (ii). Intermediate (ii) can be formed by subjecting intermediate (ii) to acid (e.g., TFA, HCl, etc.). Scheme 2

[0171] As shown in Scheme 2, 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4 / - / )-tert-butyl carboxylates (iv) can be subjected to Suzuki reaction conditions with the appropriate substituted ester or boronic acid reagent, palladium catalyst (e.g., Pd(PPhs)4, Pd(dppf)Cb) 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, HCl) can form the intermediate compound (iii). Scheme 3

[0172] As illustrated in Scheme 3, intermediate compounds of formula (iii) can be subjected to standard nucleophilic substitution conditions with 2-chloro-3-methyl-6,7-dihydro-5 / - / pyrrolo[3,4-b]pyridin-5-ones (vi), base (e.g., DIPEA), solvent (e.g., DMSO) with heating to about 90-120 °C to provide Petition 870250094048, dated 10 / 14 / 2025, pp. 405 / 509 47 / 140 compounds with formula (vii). Scheme 4 r4E(v ii i}

[0173] As shown in Scheme 4, the ester intermediate (viii) (where Y, Y1 and Y2 are Cl, Br or I) can be subjected to amines, base (e.g. DIEA) and solvent (e.g. THF) without heating or with heating up to 40-50 °C to give (ix). Scheme 5 (*) (xi)

[0174] As illustrated in Scheme 5, intermediate compounds (iii) can be subjected to standard nucleophilic substitution conditions with an intermediate (x) (where Y is a halogen), base (e.g., DIPEA), solvent (e.g., DMSO) with heating to about 90-120 °C to give compounds with formula (xi). Petition 870250094048, dated 10 / 14 / 2025, pp. 406 / 509 48 / 140 Scheme 6 CPR...OR □ R7 Suzuki reaction (xi) ---------------------

[0175] As shown in Scheme 6, intermediates of formula (xi) (wherein Y is a halogen) can be coupled to a boronic acid or ester (e.g., trimethylboroxine) under Suzuki coupling conditions, generally known in the art as providing (xii). The coupling reactions can be carried out with a palladium catalyst, such as Pd(dppf)Cb, and a base (e.g., K2CO3, CS2CO3) in a mixture of organic solvents, such as DMF or 1,4-dioxane, and water with heating to about 70-90 °C. The reactions can be facilitated by microwave irradiation. Scheme 7 (xi) catalyst, Zn(CN)2 solvent, heat

[0176] As shown in Scheme 7, intermediates of formula (xi) (where Y is a halogen) can be subjected to a catalyst (e.g., Pd(PPhs)4), a cyanide source (e.g., Zn(CN)2) and a solvent (e.g., DMF) with heating up to 120-140 °C to provide compounds of formula (xiii). Petition 870250094048, dated 10 / 14 / 2025, pp. 407 / 509 49 / 140 Xanlphos. 11d2(tiba)3. Cbi2CO31.4-dioKano. 110°C

[0177] As shown in Scheme 8, the intermediates (xiv) can be coupled with an amine under Buchwald coupling conditions, generally known in the art, to give the products (xv). An analogous reaction can be carried out with the intermediate (iv) to give the intermediate compounds substituted by -NR2aR2b. Scheme 9

[0178] As shown in Scheme 9, the intermediates (xiv) can be coupled to an alkoxide-type reagent in a suitable solvent to give the products (xvi). An analogous reaction can be carried out with the intermediate (iv) to give the -OR2a substituted intermediate compounds. Scheme 10

[0179] As shown in Scheme 10, intermediaries (xiv) Petition 870250094048, dated 10 / 14 / 2025, pages 408 / 509 50 / 140 can be reacted with zinc metal and Zn(CN)2 with a palladium catalyst (e.g. Pd(dppf)Cb) and heating in a suitable solvent to give (xvii). An analogous reaction can be carried out with intermediate (iv) to give the cyano-substituted intermediate compounds.

[0180] Boronic acids / esters, amines and alcohols suitable for coupling reactions described in this document can be easily obtained from commercial sources or prepared by standard methods well known to those skilled in the art.

[0181] Compounds and intermediates can 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 may include, but are not limited to, chromatography on solid supports such as silica gel, alumina or silica-derived alkylsilane groups, by recrystallization at high or low temperature with an optional pretreatment with activated carbon, thin-layer chromatography, distillation at various pressures, vacuum sublimation and trituration, as described, for example, 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.

[0182] A disclosed compound may have at least one basic nitrogen, so that 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 give the desired salt, which is deposited and collected by filtration after cooling. Examples of suitable acids for the reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic, atrolatic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic, carbonic, fumaric, maleic acids, Petition 870250094048, dated 10 / 14 / 2025, pages 409 / 509 51 / 140 gluconic, acetic, propionic, salicylic, hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric, camphorsulfonic, malic, phenylacetic, aspartic or glutamic, and similar.

[0183] The reaction conditions and reaction times for each individual step may vary depending on the specific reagents employed and the substituents present in the reagents used. Specific procedures are provided in the Examples section. Reactions may be carried out conventionally, for example, by removing the solvent from the residue and further purifying it 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 commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.If starting materials are not commercially available, they can be prepared by procedures selected from standard organic chemical techniques, techniques analogous to the synthesis of known and structurally similar compounds, or techniques analogous to the schemes described above or to the procedures described in the synthetic examples section.

[0184] Routine experimentation, including proper manipulation of reaction conditions, reagents, and the sequence of the synthetic pathway, protection of any chemical functionality that may not be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included within the scope of the invention. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, in Greene's book entitled Petition 870250094048, dated 10 / 14 / 2025, pp. 410 / 509 52 / 140 Protective Groups in Organic Synthesis (4th edition), John Wiley and Sons, NY (2006), which is incorporated herein by reference in its entirety. The synthesis of the compounds of the invention can be carried out by methods analogous to those described in the synthetic schemes described above and in specific examples.

[0185] When an optically active form of a revealed compound is required, it can be obtained by carrying out one of the procedures described in this document using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step) or by resolving a mixture of the compound's stereoisomers or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).

[0186] Similarly, when a pure geometric isomer of a compound is required, it can be obtained by performing one of the above procedures using a pure geometric isomer as starting material, or by resolving a mixture of the compound's geometric isomers or intermediates using a standard procedure, such as chromatographic separation.

[0187] It may be understood that the synthetic schemes and specific examples described are illustrative and should not be interpreted as limiting the scope of the invention as 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

[0188] In some embodiments, the disclosed compounds potentiate the agonist response (e.g., acetylcholine) of mAChR M4. In some embodiments, the disclosed compounds increase the response of Petition 870250094048, dated 10 / 14 / 2025, pp. 411 / 509 53 / 140 mAChR M4 at non-maximal agonist concentrations in the presence of the compound compared with the agonist response in the absence of the compound. The potentiation of mAChR M4 activity can be demonstrated by methodologies known in the art. For example, the activation of mAChR M4 activity can be determined by measuring calcium flux in response to the agonist, e.g., acetylcholine, in cells loaded with a Ca2+-sensitive fluorescent dye (e.g., Fluo4) and co-expressing a chimeric or promiscuous G protein. In some embodiments, calcium flux was measured as an increase in static fluorescent ratio. In some embodiments, positive allosteric modulator activity was analyzed as a concentration-dependent increase in the acetylcholine response to EC20 (i.e., the mAChR M4 response to an acetylcholine concentration that produces 20% of the maximal response).

[0189] In some embodiments, the disclosed compounds activate the mAChR M4 response as an increase in calcium fluorescence in CHO-K1 cells transfected with mAChR M4 in the presence of the compound, compared with 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 EC50 less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. In some embodiments, CHO-K1 cells transfected with mAChR M4 are transfected with human mAChR M4. In some embodiments, CHO-K1 cells transfected with mAChR M4 are transfected with mouse mAChR M4.

[0190] The disclosed compounds may exhibit positive allosteric modulation of the mAChR M4 response to acetylcholine as an increase in response to non-maximal acetylcholine concentrations in Petition 870250094048, dated 10 / 14 / 2025, pp. 412 / 509 54 / 140 CHO-K1 cells transfected with an mAChR M4 in the presence of the compound, compared with the response to acetylcholine in the absence of the compound. In some embodiments, the disclosed compounds exhibit positive allosteric modulation of the mAChR M4 response to acetylcholine with an EC50 less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, or less than about 100 nM. In some embodiments, the EC50 for positive allosteric modulation is determined in CHO-K1 cells that are transfected with an mAChR M4. In some embodiments, the mAChR M4 transfected human mAChR M4. In some embodiments, the mAChR M4 transfected mouse mAChR M4.

[0191] A disclosed compound may have selectivity for the mAChR M4 receptor vis-à-vis one or more of the mAChR M1, M2, M3, or M5 receptors. For example, the disclosed compounds may activate the mAChR M4 response in CHO-K1 cells transfected with mAChR M4 with an EC50 lower than the EC50 for one or more of the CHO-K1 cells transfected with mAChR M1, M2, M3, or M5. In some embodiments, a revealed compound may activate the mAChR M4 response with an EC50 approximately 5 times lower, approximately 10 times lower, approximately 20 times lower, approximately 30 times lower, approximately 50 times lower, approximately 100 times lower, approximately 200 times lower, approximately 300 times lower, approximately 400 times lower, or more than approximately 500 times lower than that for mAChR M1.In some embodiments, a disclosed compound may activate the mAChR M4 response with an EC50 approximately 5 times smaller, approximately 10 times smaller, approximately 20 times smaller, approximately 30 times smaller, approximately 50 times smaller, approximately 100 times smaller, approximately 200 times smaller, approximately 300 times smaller, approximately 400 times smaller, or more than approximately 500 times smaller than that for mAChR M2. In some embodiments, a disclosed compound may activate the mAChR M4 response with an EC50 approximately 5 times smaller, approximately 10 times smaller, approximately 20 times smaller, approximately 30 times smaller. Petition 870250094048, dated 10 / 14 / 2025, pp. 413 / 509 55 / 140 approximately 50 times smaller, approximately 100 times smaller, approximately 200 times smaller, approximately 300 times smaller, approximately 400 times smaller, or more than approximately 500 times smaller than that for mAChR M3. In some embodiments, a revealed compound may activate the mAChR M4 response with an EC50 approximately 5 times smaller, approximately 10 times smaller, approximately 20 times smaller, approximately 30 times smaller, approximately 50 times smaller, approximately 100 times smaller, approximately 200 times smaller, approximately 300 times smaller, approximately 400 times smaller, or more than approximately 500 times smaller than that for mAChR M5.In some embodiments, a revealed compound may activate the mAChR M4 response with an EC50 5 times lower, about 10 times lower, about 20 times lower, about 30 times lower than that for M2-M5 receptors, about 50 times lower, about 100 times lower, about 200 times lower, about 300 times lower, about 400 times lower, or more than about 500 times lower than that for mAChR M1, M2, M3, or M5 receptors.

[0192] The disclosed compounds can activate the mAChR M4 response in CHO-K1 cells transfected with M4 with an EC50 less than about 10 pM and exhibit selectivity for the M4 receptor vis-à-vis one or more of the mAChR M1, M2, M3, or M5 receptors. For example, in some embodiments, the compound may have an EC50 less than about 10 pM, less than about 5 pM, less than about 1 pM, less than about 500 nM, less than about 100 nM, or less than about 50 nM; The compound may also activate the mAChR M4 response with an EC50 approximately 5 times smaller, 10 times smaller, 20 times smaller, 30 times smaller, 50 times smaller, 100 times smaller, 200 times smaller, 300 times smaller, 400 times smaller, or more than approximately 500 times smaller than that for mAChR M1. In some modalities, the compound may have an EC50 smaller than approximately 10 pM, smaller than approximately 5 pM, smaller than approximately 1 pM, smaller than approximately 500 nM, smaller than approximately 100 nM, or smaller than approximately... Petition 870250094048, dated 10 / 14 / 2025, pp. 414 / 509 56 / 140 of 50 nM; and the compound may also activate the mAChR M4 response with an EC50 approximately 5 times smaller, approximately 10 times smaller, approximately 20 times smaller, approximately 30 times smaller, approximately 50 times smaller, approximately 100 times smaller, approximately 200 times smaller, approximately 300 times smaller, approximately 400 times smaller, or more than approximately 500 times smaller than that for mAChR M2. In some embodiments, the compound may have an EC50 smaller than approximately 10 pM, smaller than approximately 5 pM, smaller than approximately 1 pM, smaller than approximately 500 nM, smaller than approximately 100 nM, or smaller than approximately 50 nM; and the compound can also activate the mAChR M4 response with an EC50 approximately 5 times smaller, approximately 10 times smaller, approximately 20 times smaller, approximately 30 times smaller, approximately 50 times smaller, approximately 100 times smaller, approximately 200 times smaller, approximately 300 times smaller, approximately 400 times smaller, or more than approximately 500 times smaller than that for mAChR M3.In some embodiments, the compound may have an EC50 smaller than about 10 pM, smaller than about 5 pM, smaller than about 1 pM, smaller than about 500 nM, smaller than about 100 nM, or smaller than about 50 nM; and the compound may also activate the mAChR M4 response with an EC50 that is about 5 times smaller, about 10 times smaller, about 20 times smaller, about 30 times smaller, about 50 times smaller, about 100 times smaller, about 200 times smaller, about 300 times smaller, about 400 times smaller, or more than about 500 times smaller than that for mAChR M5.In some modalities, the compound may have an EC50 smaller than about 10 pM, smaller than about 5 pM, smaller than about 1 pM, smaller than about 500 nM, smaller than about 100 nM, or smaller than about 50 nM; and the compound may also activate the mAChR M4 response with an EC50 5 times smaller, about 10 times smaller, about 20 times smaller, about 30 times smaller than that for M2-M5 receptors, about 50 times smaller, about 100 times smaller, about 200 times smaller, about 300 times smaller, about 400 times smaller. Petition 870250094048, dated 10 / 14 / 2025, pp. 415 / 509 57 / 140 smaller, for M2, M3, or M5 receptors, or more than about 500 times smaller than that for mAChR M1, M2, M3, or M5 receptors.

[0193] The in vivo efficacy of the disclosed compounds can be measured in several preclinical behavioral models in rats in which known and clinically useful antipsychotics exhibit similar positive responses. For example, the disclosed compounds can reverse amphetamine-induced hyperlocomotion in male Sprague-Dawley rats at doses in the range of 1 to 100 mg / kg p.o. 3. Pharmaceutical formulations and compositions

[0194] The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to an individual (such as a patient, who may be human or non-human). The disclosed compounds may also be supplied as formulations, such as spray-dried dispersion formulations.

[0195] 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 effective amount, at the dosages and for the time periods required, to achieve the desired therapeutic result. A therapeutically effective amount of the composition can be determined by a person skilled in the art and may vary according to factors such as the disease status, age, sex and weight of the individual, and the ability of the composition to produce a desired response in the individual. A therapeutically effective amount is also that in which any toxic or harmful effects of a compound of the invention (for example, a compound of formula (I)) are offset by the therapeutically beneficial effects.A "prophylactically effective amount" refers to an amount that is effective, at the dosages and for the time periods required, to achieve the desired prophylactic result. Typically, this refers to one dose. Petition 870250094048, dated 10 / 14 / 2025, pp. 416 / 509 If the 58 / 140 prophylactic dose is used in individuals before or at an early stage of the disease, the prophylactically effective dose will be less than the therapeutically effective dose.

[0196] 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.

[0197] Pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. The term pharmaceutically acceptable carrier, as used herein, means a filler, diluent, encapsulating material or formulation aid of any inert, non-toxic solid, semi-solid or liquid type. Some examples of materials that may serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, 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, sunflower oil, sesame oil, olive oil, corn oil, and... Petition 870250094048, dated 10 / 14 / 2025, pp. 417 / 509 59 / 140 soy; glycols; such as, but not limited to, 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 compatible non-toxic lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening agents, flavorings and fragrances, preservatives and antioxidants may also be present in the composition, according to the formulator's judgment.

[0198] Thus, pharmaceutically acceptable compounds and their salts can be formulated for administration by, for example, solid dosage, eye drops, in a topical oil-based formulation, injection, inhalation (by mouth or nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations can generally be found in “Remington's Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions typically need to be sterile and stable under manufacturing and storage conditions.

[0199] The route by which the disclosed compounds are administered and the form of the composition will determine the type of carrier to be used. The composition may be in a variety of suitable forms, 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).

[0200] Carriers for systemic administration typically include at least one of the following: diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, Petition 870250094048, dated 10 / 14 / 2025, pp. 418 / 509 60 / 140 antioxidants, preservatives, anti-caking agents, solvents, suspending agents, humectants, surfactants, combinations thereof and others. All carriers are optional in the compositions.

[0201] 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 (or diluents) in a systemic or topical composition is typically about 50 to about 90%.

[0202] Suitable lubricants include silica, talc, stearic acid and its magnesium 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 theobroma oil. The amount of lubricant (or lubricants) in a systemic or topical composition is typically about 5 to about 10%.

[0203] Suitable binders include polyvinylpyrrolidone; aluminum and magnesium silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder (or binders) in a systemic composition is typically about 5 to about 50%.

[0204] Suitable disintegrants include agar, alginic acid and its sodium salt, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion-exchange resins. The amount of disintegrant (or disintegrants) in a systemic or topical composition is typically about 0.1 to about 10%.

[0205] Suitable dyes include a dye such as a Petition 870250094048, dated 10 / 14 / 2025, pp. 419 / 509 FD&C dye 61 / 140. When used, the amount of dye in a systemic or topical composition is typically about 0.005 to about 0.1%.

[0206] Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavoring (or flavorings) in a systemic or topical composition is typically about 0.1 to about 1.0%.

[0207] Suitable sweeteners include aspartame and saccharin. The amount of sweetener (or sweeteners) in a systemic or topical composition is typically about 0.001 to about 1%.

[0208] Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant (or antioxidants) in a systemic or topical composition is typically about 0.1 to about 5%.

[0209] Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative (or preservatives) in a systemic or topical composition is typically about 0.01 to about 5%.

[0210] Suitable slip agents include silicon dioxide. The amount of anti-adherent agent (or anti-adherent agents) in a systemic or topical composition is typically about 1 to about 5%.

[0211] Suitable solvents include water, isotonic saline solution, ethyl oleate, glycerin, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent (or solvents) in a systemic or topical composition is typically from about 0 to about 100%.

[0212] Suitable suspending agents include AVICEL RC591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent (or suspending agents) in a systemic or topical composition is typically about 1 to about 8%.

[0213] Suitable surfactants include lecithin, polysorbate Petition 870250094048, dated 10 / 14 / 2025, pp. 420 / 509 62 / 140 and sodium lauryl sulfate, in addition to TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the CTFA Cosmetic Ingredient Handbook, 1992, pages 587-592; Remington's Pharmaceutical Sciences, 15th edition, 1975, pages 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American edition, pages 236-239. The amount of surfactant (or surfactants) in a systemic or topical composition is typically about 0.1 to about 5%.

[0214] Although the amounts of components in 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.

[0215] Compositions for oral administration may have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. Oral dosage forms contain a safe and effective amount, usually at least about 5%, and more particularly, from about 25% to about 50% of active ingredients. Oral dosage compositions contain from about 50% to about 95% of carriers and, more particularly, from about 50% to about 75%.

[0216] Tablets may be compressed, crushed tablet, enteric-coated, sugar-coated, film-coated, or multi-tablets. Tablets typically include an active ingredient and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, anti-caking agents, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose. Petition 870250094048, dated 10 / 14 / 2025, pp. 421 / 509 63 / 140 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 FD&C dyes, which may be added to improve appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0217] Capsules (including implants, time-release and extended-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, anti-adherent agents, such as silicon dioxide, to improve flow characteristics. Implants may be of the biodegradable or non-biodegradable type.

[0218] The selection of ingredients in the carrier for oral compositions depends on secondary considerations such as taste, cost and shelf stability, which are not essential for the purposes of this invention.

[0219] Solid compositions can be coated by conventional methods, typically with pH- or time-dependent coatings, so that a revealed compound is released into the gastrointestinal tract in the vicinity of the desired application, or at multiple points and times to extend the desired action. Coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes, and shellac. Petition 870250094048, dated 10 / 14 / 2025, pp. 422 / 509 64 / 140

[0220] Compositions for oral administration may have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid compositions administered orally typically include a disclosing compound and a carrier, i.e., a vehicle selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Oral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0221] Other compositions useful for achieving systemic delivery of the compounds in question include sublingual, buccal, and nasal dosage forms. Such compositions typically include one or more soluble filler substances, such as diluents, including sucrose, sorbitol, and mannitol; and binders, such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. These compositions may also include lubricants, colorants, flavors, sweeteners, antioxidants, and anti-adherent agents.

[0222] The disclosed compounds can be administered topically. 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-in hair conditioners, milks, cleansers, moisturizers, sprays, skin plasters, 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 assists in the penetration of the compounds into the skin. The carrier may also include one or more optional components. Petition 870250094048, dated 10 / 14 / 2025, pp. 423 / 509 65 / 140

[0223] The amount of carrier employed in conjunction with a disclosed compound is sufficient to provide a practical amount of composition for administration per unit dose of the compound. Techniques and compositions for producing 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 edition (1976).

[0224] A carrier may include a single ingredient or a combination of two or more ingredients. In topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide and water, and even more particularly, phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohols and symmetrical alcohols.

[0225] The carrier of a topical composition may also include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments and preservatives, all of which are optional.

[0226] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, vision oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, Petition 870250094048, dated 10 / 14 / 2025, pp. 424 / 509 66 / 140 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, peanut 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. Skin-specific emollients include stearyl alcohol and polydimethylsiloxane. The amount of emollient (or emollients) in a skin-based topical composition is typically about 5% to about 95%.

[0227] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant (or propellants) in a topical composition is typically about 0% to about 95%.

[0228] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent (or solvents) in a topical composition is typically about 0% to about 95%.

[0229] 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 (or humectants) in a topical composition is typically 0% to 95%.

[0230] The amount of thickener (or thickeners) in a topical composition is typically about 0% to about 95%.

[0231] Suitable powders include beta-cyclodextrins, Petition 870250094048, dated 10 / 14 / 2025, pp. 425 / 509 67 / 140 hydroxypropyl cyclodextrins, chalk, talc, Fuller's earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectites, trialkylammonium smectites, chemically modified aluminum magnesium silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder (or powders) in a topical composition is typically 0% to 95%.

[0232] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly about 0.001% to about 0.1%.

[0233] Suitable pH-adjusting additives include HCl or NaOH in sufficient quantities to adjust the pH of a topical pharmaceutical composition.

[0234] The pharmaceutical composition or formulation may exhibit positive allosteric modulation of mAChR M4 with an EC50 less than about 10 μM, less than about 5 μM, less than about 1 μM, 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 between about 10 μM and about 1 nM, about 1 μM 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

[0235] The disclosed compounds can be formulated as a spray-dried dispersion (SDD). An SDD is a single-phase, amorphous molecular dispersion of a drug in a polymeric matrix. It is a solid solution with the compound molecularly “dissolved” in a solid matrix. SDDs are obtained by dissolving a drug and a polymer in an organic solvent and then drying by Petition 870250094048, dated 10 / 14 / 2025, pp. 426 / 509 68 / 140 Spray drying of the solution. The use of spray drying for pharmaceutical applications can result in amorphous dispersions with higher solubility of drugs from the Biopharmaceutical Classification System (BCS) class II (high permeability, low solubility) and class IV (low permeability, low solubility). The formulation and process conditions are selected so that the solvent evaporates rapidly from the droplets, thus allowing insufficient time for phase separation or crystallization. Spray drying solutions (SDDs) have demonstrated long-term stability and manufacturability. For example, shelf lives of more than 2 years have been demonstrated with SDDs.The advantages of SDDs include, but are not limited to, improved oral bioavailability of poorly water-soluble compounds, distribution using traditional solid pharmaceutical 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.

[0236] Thus, in one embodiment, the disclosure may provide a spray-dry dispersion formulation comprising a compound of formula (I). 4. Methods of use

[0237] The disclosed compounds, compositions, and pharmaceutical formulations can be used in methods for treating disorders, such as neurological and / or psychiatric disorders, associated with muscarinic acetylcholine receptor dysfunction. The disclosed compounds and pharmaceutical compositions can also be used in methods for potentiating muscarinic acetylcholine receptor activity in a mammal, and in methods for improving cognition in a mammal. The methods also include co-therapeutic methods to improve treatment outcomes in the context of cognitive or behavioral therapy. In the methods of use described in this document, Petition 870250094048, dated 10 / 14 / 2025, pp. 427 / 509 69 / 140 additional therapeutic agents may be administered simultaneously or sequentially with the disclosed compounds and compositions. a. Treatment of disorders

[0238] The disclosed compounds, compositions and pharmaceutical formulations may be used to treat disorders or used in methods for treating disorders, such as neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. The treatment methods may comprise administering to an individual 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 (I).

[0239] In some embodiments, the disclosure provides a method for improving 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 (I).

[0240] The compounds and compositions disclosed herein may be useful for treating, preventing, improving, controlling, or reducing the risk of a variety of disorders associated with selective mAChR M4 receptor activation. For example, a treatment may involve selective mAChR M4 receptor activation to an extent effective in affecting cholinergic activity. A disorder may be associated with cholinergic activity, for example, cholinergic hypofunction. Thus, a method is provided for treating or preventing a disorder in an individual comprising the step of administering to the individual at least one disclosed compound or at least one disclosed pharmaceutical composition, in an amount effective in treating the disorder in the individual.

[0241] A method for treating a Petition 870250094048, dated 10 / 14 / 2025, pp. 428 / 509 70 / 140 or more disorders associated with mAChR M4 receptor activity in an individual comprising the step of administering to the individual 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.

[0242] In some embodiments, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for treating 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 treating a disorder associated with the mAChR M4 receptor.

[0243] In some embodiments, the disclosure provides a compound of formula (I), 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.

[0244] In some embodiments, the disclosure provides a method for treating 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 a pharmaceutically acceptable salt thereof.

[0245] In some embodiments, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for treating a disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal.

[0246] In some modalities, the revelation provides a Petition 870250094048, dated 10 / 14 / 2025, pp. 429 / 509 71 / 140 pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for treating a disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal.

[0247] In some embodiments, the disclosure provides the compound of formula (I), 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.

[0248] In some embodiments, the disclosed compounds and compositions are useful 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, NOS psychotic disorder, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic break, late-onset psychosis, myxedematous psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar I disorder with psychotic features, and substance-induced psychotic disorder.In some forms, psychotic disorder is a psychosis associated with a disease selected from among major depressive disorder, affective disorder, bipolar disorder, electrolyte disorder, Alzheimer's disease, neurological disorder, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder.

[0249] In some embodiments, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for treating a neurological, psychiatric, or cognitive disorder associated with the mAChR M4 receptor, in particular, the disorders described herein. In some embodiments, the Petition 870250094048, dated 10 / 14 / 2025, pp. 430 / 509 72 / 140 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 (I), 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, disorders described herein.

[0250] In some forms, the disorder is a selected neurological disorder from among brain tumor, dementia with Lewy bodies, multiple sclerosis, sarcoidosis, Lyme disease, syphilis, Alzheimer's disease, Parkinson's disease, and anti-NMDA receptor encephalitis.

[0251] In some modalities, the disorder is a psychotic disorder selected from among schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, and shared psychotic disorder. In some modalities, schizophrenia is selected from among catastrophic schizophrenia, catatonic schizophrenia, paranoid schizophrenia, residual schizophrenia, disorganized schizophrenia, and undifferentiated schizophrenia. In some modalities, the disorder is selected from among schizoid personality disorder, schizotypal personality disorder, and paranoid personality disorder. In some modalities, the psychotic disorder is due to a general medical condition and is substance- or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants, and cocaine).

[0252] In some embodiments, the present disclosure provides a method for treating a cognitive disorder, which comprises administering the Petition 870250094048, dated 10 / 14 / 2025, pp. 431 / 509 73 / 140 a patient who needs an effective amount of a compound or 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-Jakob disease, perinatal hypoxia, other general medical conditions or substance abuse), delirium, amnesic disorder, substance-induced persistent delirium, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, parkinsonian-ALS dementia complex, Alzheimer's-type dementia, age-related cognitive decline and mild cognitive impairment.

[0253] The revised text 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, amnesic 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 major NCD syndromes, mild NCD syndromes, and their etiological subtypes.The major or mild subtypes of NCD 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-induced NCD, 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 the DSM-5 encompasses the group of disorders in which the deficit... Petition 870250094048, dated 10 / 14 / 2025, pp. 432 / 509 74 / 140 primary clinical findings are in cognitive function and are acquired rather than developed. As used in this document, the term “cognitive disorders” includes treatment of those cognitive disorders and neurocognitive disorders as described in DSM-IV-TR or DSM-5. The expert 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 “cognitive disorders” is intended to include similar disorders that are described in other diagnostic sources.

[0254] In some embodiments, the present disclosure provides a method for treating schizophrenia or psychosis, comprising administering to a patient in need an effective amount of a compound or composition of the present disclosure. The specific pathologies of schizophrenia or psychosis 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 residual or substance-induced psychotic disorder. DSM-5 eliminated the subtypes of schizophrenia and instead includes a dimensional approach to classifying the severity of the main symptoms of schizophrenia in order to capture the heterogeneity in the type and severity of symptoms expressed in individuals with psychotic disorders.As used in this document, the term “schizophrenia or psychosis” includes treatment of those mental disorders as described in DSM-IV-TR or DSM-5. Those knowledgeable will recognize that alternative nomenclatures, nosologies, and classification systems for mental disorders exist, and that these systems evolve with medical and scientific progress. Thus, the term “schizophrenia or psychosis” is intended to include similar disorders that are described in other diagnostic sources. Petition 870250094048, dated 10 / 14 / 2025, pp. 433 / 509 75 / 140

[0255] In some embodiments, the present disclosure provides a method for treating pain, comprising administering to a patient in need an effective amount of a compound or composition of the present disclosure. Specific examples of pain are bone and joint pain (osteoarthritis), repetitive motion pain, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecological surgery), chronic pain, and neuropathic pain.

[0256] The compounds and compositions may also be useful in a method for preventing, treating, controlling, improving or reducing the risk of diseases, disorders and conditions indicated in this document. The compounds and compositions may also be useful in a method for preventing, treating, controlling, improving or reducing the risk of the aforementioned diseases, disorders and conditions, in combination with other agents.

[0257] In the treatment of conditions requiring mAChR M4 activation, an appropriate dosage level may be approximately 0.01 to 500 mg per kg of the patient's body weight per day, which may be administered in single or multiple doses. The dosage level may be approximately 0.1 to approximately 250 mg / kg per day, or approximately 0.5 to approximately 100 mg / kg per day. An appropriate dosage level may be approximately 0.01 to 250 mg / kg per day, approximately 0.05 to 100 mg / kg per day, or approximately 0.1 to 50 mg / kg per day. Within this range, the dosage may 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 supplied in the form of tablets containing 1.0 to 1000 milligrams 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 symptomatic dosage adjustment to the patient being treated.The compounds can be administered in a regimen of 1 to 4 times per day, preferably once or twice a day. This dosage regimen can be adjusted accordingly. Petition 870250094048, dated 10 / 14 / 2025, pp. 434 / 509 76 / 140 provide the ideal therapeutic response. However, it should be understood that the specific dose level and dosing frequency for any particular patient may vary and will depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and duration of action of that compound, age, body weight, general health, sex, diet, mode and timing of administration, excretion rate, drug combinations, severity of the specific condition, and the host on therapy.

[0258] Thus, in some embodiments, disclosure refers to a method for activating mAChR M4 receptor activity in at least one cell, comprising the step of bringing at least one cell into contact with at least one disclosed compound or at least one product of a disclosed method in an amount effective to activate mAChR M4 in at least one cell. In some embodiments, the cell is a mammal, for example, a human. In some embodiments, the cell has been isolated from an individual prior to the contact step. In some embodiments, the contact is through administration to an individual.

[0259] In some embodiments, the invention relates to a method for activating mAChR M4 activity in an individual comprising the step of administering to the individual at least one disclosed compound or at least one product of a disclosed method in a dosage and amount effective to activate mAChR M4 activity in the individual. In some embodiments, the individual is a mammal, for example, a human. In some embodiments, the mammal has been diagnosed with a need for mAChR M4 agonism prior to the administration step. In some embodiments, the mammal has been diagnosed with a need for mAChR M4 activation prior to the administration step. In some embodiments, the method further comprises the step of identifying an individual who needs mAChR M4 agonism. Petition 870250094048, dated 10 / 14 / 2025, pp. 435 / 509 77 / 140 mAChR M4.

[0260] In some embodiments, the invention relates to a method for treating a disorder associated with the selective activation of mAChR M4, 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 being. In some embodiments, the mammal has been diagnosed with a need for treatment for the disorder prior to the administration step. In some embodiments, the method further comprises the step of identifying an individual who needs treatment for the disorder.

[0261] In some modalities, the disorder may 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 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 syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, neurodegeneration-based and drug-induced dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders.

[0262] In some forms, the disorder is Alzheimer's disease. Petition 870250094048, dated 10 / 14 / 2025, pp. 436 / 509 78 / 140 b. Potentiation of muscarinic acetylcholine receptor activity

[0263] In some embodiments, disclosure refers to a method for potentiating 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 a pharmaceutically acceptable salt thereof.

[0264] In some embodiments, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for potentiating the 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 potentiating the muscarinic acetylcholine receptor activity in a mammal.

[0265] In some embodiments, the disclosure provides the compound of formula (I), 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.

[0266] In some modalities, potentiation of muscarinic acetylcholine receptor activity increases muscarinic acetylcholine receptor activity. In some modalities, potentiation of muscarinic acetylcholine receptor activity is partial agonist activity of the muscarinic acetylcholine receptor. In some modalities, potentiation of muscarinic acetylcholine receptor activity is positive allosteric modulation of the muscarinic acetylcholine receptor.

[0267] In some modalities, the administered compound exhibits Petition 870250094048, dated 10 / 14 / 2025, pp. 437 / 509 79 / 140 mAChR M4 potentiation with an EC50 less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, or less than about 100 nM. In some embodiments, the administered compound exhibits mAChR M4 potentiation with an EC50 between about 10 μM and about 1 nM, about 1 μM and about 1 nM, about 100 nM and about 1 nM, or about 10 nM and about 1 nM.

[0268] In some embodiments, the mammal is a human being. In some embodiments, the mammal has been diagnosed with a need for potentiation of muscarinic acetylcholine receptor activity prior to the administration step. In some embodiments, the method further comprises the step of identifying a mammal that needs potentiation of muscarinic acetylcholine receptor activity. In some embodiments, potentiation of muscarinic acetylcholine receptor activity treats a disorder associated with muscarinic acetylcholine receptor activity in mammals. In some embodiments, the muscarinic acetylcholine receptor is mAChR M4.

[0269] 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 muscarinic receptor dysfunction, such as a neurological or psychiatric disorder disclosed in this document. In some embodiments, the muscarinic receptor is mAChR M4.

[0270] In some embodiments, the disclosure provides a method for potentiating the activity of muscarinic acetylcholine receptors in a cell comprising the step of bringing the cell into contact 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 was isolated from a mammal prior to the step. Petition 870250094048, dated 10 / 14 / 2025, pp. 438 / 509 80 / 140 contact. In some modalities, contact is through administration to a mammal. c. Improved cognition

[0271] In some embodiments, the invention relates to a method for improving cognition 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, hydrate, solvate or polymorph thereof.

[0272] In some embodiments, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for improving 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 improving cognition in a mammal.

[0273] In some embodiments, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for enhancing cognition in a mammal.

[0274] In some embodiments, the mammal is a human being. In some embodiments, the mammal has been diagnosed with a need for cognitive enhancement prior to the administration step. In some embodiments, the method also includes the step of identifying a mammal that needs cognitive enhancement. In some embodiments, the need for cognitive enhancement is associated with a dysfunction of a muscarinic receptor. In some embodiments, the muscarinic receptor is mAChR M4.

[0275] In some modalities, the improvement in cognition is a statistically significant increase in Object Recognition Petition 870250094048, dated 10 / 14 / 2025, pp. 439 / 509 81 / 140 New. In some modalities, the improvement in cognition is a statistically significant increase in performance on the Wisconsin Card Sorting Test. d. Co-therapeutic methods

[0276] The present invention is further directed to the administration of a selective mAChR M4 activator to improve 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.

[0277] In some embodiments, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a cotherapeutic method with cognitive or behavioral therapy 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 cotherapeutic method with cognitive or behavioral therapy in a mammal.

[0278] In some embodiments, the disclosure provides the compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for a cotherapeutic method with cognitive or behavioral therapy in a mammal.

[0279] In some modalities, administration improves treatment outcomes in the context of cognitive or behavioral therapy. Administration in connection with cognitive or behavioral therapy may be continuous or intermittent. Administration does not need to be simultaneous with therapy and may be before, during, and / or after therapy. For example, cognitive or behavioral therapy may be Petition 870250094048, dated 10 / 14 / 2025, pp. 440 / 509 82 / 140 provided within 1, 2, 3, 4, 5, 6, or 7 days before or after administration of the compound. As a further example, cognitive or behavioral therapy may be provided within 1, 2, 3, or 4 days before or after administration of the compound. As another example, cognitive or behavioral therapy may be provided before or after administration within a time period of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound.

[0280] It is understood that the disclosed cotherapeutic methods may be used in connection with the disclosed compounds, compositions, kits and uses. e. Combined Therapies

[0281] In the methods of use described herein, additional therapeutic agents 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 a time interval between the administration of the additional therapeutic agent and the disclosed compounds. In some embodiments, the administration of an additional therapeutic agent with a disclosed compound may allow for 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 at lower doses than when each is used alone.Consequently, the pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to a compound of Formula (I). The above combinations include combinations of a compound of the present invention. Petition 870250094048, dated 10 / 14 / 2025, pp. 441 / 509 83 / 140 invention not only with one other active compound, but also with two or more other active compounds.

[0282] The disclosed compounds may be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, improvement, or reduction of the risk of the diseases, disorders, and conditions mentioned above for which the compound or the other drugs are useful, wherein the combination of drugs is safer or more effective than either drug alone. The other drug (or drugs) may be administered by a route and in an amount commonly used for such, simultaneously or sequentially with a disclosed compound. When a disclosed compound is used concomitantly with one or more other drugs, a pharmaceutical composition in the form of a unit dosage containing such drugs and the disclosed compound may be used. However, combination therapy may also be administered in overlapping regimens.It is also anticipated that the combination of one or more active ingredients and a disclosed compound may be more effective than either of them as a single agent. Thus, when used in combination with one or more other active ingredients, the disclosed compounds and the other active ingredients may be used in lower doses than when each is used individually.

[0283] The pharmaceutical compositions and methods of the present invention may also include other therapeutically active compounds as indicated herein, which are commonly used in the treatment of the pathological conditions mentioned above.

[0284] 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. Similarly, the disclosed compounds may be used in combination with other drugs that are Petition 870250094048, dated 10 / 14 / 2025, pp. 442 / 509 84 / 140 used in the prevention, treatment, control, attenuation, or risk reduction of diseases or conditions for which the disclosed compounds are useful. Such other drugs may be administered, by a route and in an amount commonly used for the same, simultaneously or sequentially with a compound of the present invention. When a compound of the present invention is used concomitantly with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to a disclosed compound is preferred. Consequently, pharmaceutical compositions include those that also contain one or more other active ingredients in addition to a compound of the present invention.

[0285] The weight ratio between the disclosed compound and the second active ingredient may vary and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio between a disclosed compound and the other agent will generally be in the range of 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 also generally be within the range mentioned above, but in each case, an effective dose of each active ingredient should be used.

[0286] In such combinations, a disclosed compound and other active agents may be administered separately or together. Additionally, the administration of one element may precede, concurrent with, or follow the administration of another agent (or agents).

[0287] Consequently, the disclosed compounds can be used alone or in combination with other agents that are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that increase efficacy, safety, convenience, or reduce undesirable side effects or toxicity of Petition 870250094048, dated 10 / 14 / 2025, pp. 443 / 509 85 / 140 compounds disclosed. The compound in question and the other agent may be co-administered, in concomitant therapy, or in a fixed combination.

[0288] In some embodiments, the compound may be used in combination with anti-Alzheimer agents, betasecretase inhibitors, cholinergic agents, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, allosteric Mu agonists, positive allosteric Mu modulators, NSAIDs, including ibuprofen, vitamin E and anti-amyloid antibodies. In another embodiment, the compound in question may be used in combination with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), anti-anxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, secondary tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists and similar drugs, such as: adinazolam, alobarbital, alonimide, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbochloral, chloral betaine,chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, chlorethate, chlorpromazine, clozapine, ciprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, phenoban, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, thiothixene, trazolate, tranylcypromain, trazodone, Petition 870250094048, dated 10 / 14 / 2025, pp. 444 / 509 86 / 140 triazolam, trepipam, triketamide, triclofos, trifluoperazine, trimethozin, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem and salts thereof, and combinations thereof, and similar substances, or the compound in question may be administered in conjunction with the use of physical methods, such as phototherapy or electrical stimulation.

[0289] In some embodiments, the compound may be used 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 hydrochloride (benzexole), COMT inhibitors, such as entacapone, MOA-B inhibitors, antioxidants, adenosine A2a 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 understood that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride, and pergolide mesylate. Lisuride and pramipexole are commonly used in a salt-free form.

[0290] In some embodiments, the compound may be used in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine, and indolone classes of neuroleptic agents. 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 Petition 870250094048, dated 10 / 14 / 2025, pp. 445 / 509 87 / 140 risperidone. It will be understood that neuroleptic agents when used in combination with the compound in question may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine enanthate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-saline form.Thus, the compound in question can be used in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzexole, 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.

[0291] In some embodiments, the compound may be used in combination with an antidepressant or anxiolytic agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase inhibitors (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, α-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, especially partial 5-HT1A agonists, and corticotropin-releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, Petition 870250094048, dated 10 / 14 / 2025, pp. 446 / 509 88 / 140 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, clorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxane, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.

[0292] In some embodiments, the compounds may be co-administered with orthosteric muscarinic agonists, muscarinic potentiators, or cholinesterase inhibitors. In some embodiments, the compounds may be co-administered with GlyT1 inhibitors and similar drugs, such as, but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xenomethaline, lithium, phenobarbital, and salts thereof and combinations thereof. f. Modes of administration

[0293] Treatment methods may include any number of modes of administration of a disclosed composition. Modes of administration may include tablets, pills, coated tablets, 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 mixed with commonly known and used adjuvants and excipients, such as gum arabic, talc, starch, sugars (such as mannitol, methylcellulose, lactose), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, preservatives, flavoring agents (e.g., essential oils), solubility enhancers. Petition 870250094048, dated 10 / 14 / 2025, pp. 447 / 509 89 / 140 (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g., Gelucire™). In the pharmaceutical composition, the agent may also be dispersed in a microparticle, for example, a nanoparticulate composition.

[0294] For parenteral administration, the agent may be dissolved or suspended in a physiologically acceptable diluent, such as water, buffer, oils with or without solubilizers, surfactants, dispersants or emulsifiers. Examples of oils, including but not limited to, include olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil. More generally, for parenteral administration, the agent may be in the form of an aqueous, lipid, oily or other type of solution or suspension, or even administered in the form of liposomes or nanosuspensions.

[0295] The term parenteral route, as used in this document, refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injection and infusion. 5. Kits

[0296] In one aspect, the disclosure provides kits comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, and one or more of the following: (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; Petition 870250094048, dated 10 / 14 / 2025, pp. 448 / 509 90 / 140 (e) instructions for treating a disorder associated with M4 receptor activity; or (f) instructions for administering the compound in connection with cognitive or behavioral therapy.

[0297] In some embodiments, at least one disclosed compound and at least one agent are co-formulated. In some embodiments, at least one disclosed compound and at least one agent are co-packaged. Kits may also comprise compounds and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug retailer, a physician, a compounding pharmacy, or a pharmacist may provide a kit comprising a disclosed compound and / or product and another component for delivery to a patient.

[0298] The disclosed kits may be used in connection with the disclosed methods of use.

[0299] The kits may also contain information, instructions, or both, that the 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, images, or both, and so forth. In addition, or alternatively, the kit may include the compound, a composition, or both; and information, instructions, or both; on methods of applying the compound or composition, for example, with the benefit of treating or preventing medical conditions in mammals (e.g., humans).

[0300] The compounds and processes of the invention will be better understood by reference to the following examples, which are intended to be an illustration and not a limitation of the scope of the invention. 6. Examples

[0301] All NMR spectra were recorded in a Petition 870250094048, dated 10 / 14 / 2025, pp. 449 / 509 91 / 140 Bruker AMX 400 MHz NMR spectrometer. 1H chemical shifts are reported as δ values ​​in ppm in the field, with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = wide 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 consisting of a binary pump with degasser, high-performance autosampler, thermostated 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 for 1.4 minutes, maintained at 95% acetonitrile for 0.1 minutes, 0.5 ml / min, 55 °C (“90-second method”).Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 µm, 1.0 x 50 mm) at 0.5 mL / min, with column and solvent temperatures maintained at 55 °C. The DAD was configured to scan from 190 to 300 nm, and the signals used were 220 nm and 254 nm (both with a bandwidth of 4 nm). The MS detector was configured with an electrospray ionization source, and 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 a peak width of 0.008 minutes. The drying gas flow rate was set at 13 liters per minute at 300 °C, and the nebulizer pressure was set to 206.84 kPa (30 psi). The capillary needle voltage was set to 3000 V, and the shredder voltage was set to 100 V. Data acquisition was performed using Agilent Chemstation and Analytical Studio Reviewer software. a. Preparation of Intermediates using Lawesson's Reagent \A~NH2-------------► \. / · -Nh2 Na2CO3, TUF, A Petition 870250094048, dated 10 / 14 / 2025, pp. 450 / 509 92 / 140

[0302] 1-methylcyclopropanecarbothioamide. To a suspension of 1-methylcyclopropanecarboxamide (1.1 g, 11.1 mmol) and sodium carbonate (1.2 g, 11.1 mmol) in THF (55 ml) was added Lawesson's reagent (4.5 g, 11.1 mmol), 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 provide the titrant compound (1.2 g). ES-MS [M+1]+: 116.9. F Lawesson reagent ΗΞΝ'''-ψ-7 ” H2N V NasCO3. THÍ fí),:C

[0303] 1-fluorocyclopropane-1-carbothioamide. Lawesson's reagent (1.96 g, 4.85 mmol) was added to a suspension of 1-fluorocyclopropanecarboxamide (500 mg, 4.85 mmol) and sodium carbonate (524 mg, 4.85 mmol) in THF (24 ml). The resulting mixture was heated to 70 °C. After 36 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 to provide the desired compound, which was carried forward to the next step without further purification. 1H NMR (400 MHz, DMSO) δ 9.74 (d, J= 194.7 Hz, 2H), 1.63 (td, J= 8.7, 5.2 Hz, 2H), 1.49- 1.38 (m, 2H). 2. TFA, DCM 1. EtOH, 80°C

[0304] 2-(1-methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4c]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 at 80 °C for 48 h. The crude reaction mixture was concentrated in vacuo. DCM (25 ml) and TFA (6.9 ml) were added to the residue. After 1 h at rt, the reaction mixture Petition 870250094048, dated 10 / 14 / 2025, pp. 451 / 509 93 / 140 was concentrated. The residue was dissolved in EtOAc and saturated Na2COs 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 by normal phase column chromatography (0-70% EtOAc / Hexanes followed by 0-10% DCM:MeOH:1% NH4OH gradient) to provide the titrant compound (1.59 g). 1H NMR of title compound (400 MHz, CDCb) δ 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+1 ]+: 295.1 and 195.1.

[0305] 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) were stirred at 80 °C for 2 h. The solution was concentrated, then 1,4-dioxane (8 ml) and 4M hydrochloric acid solution in 1,4-dioxane (40 ml) were added. After 1 h at room temperature, the solution was concentrated in vacuo to provide the titrant compound (4.0 g). 1H NMR (400 MHz, DMSO-de) δ 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, 1H), 1.13-1.08 (m, 2H), 0.95-0.91 (m, 2H); ES-MS [M+1]+: 181.4.

[0306] 2-(2,2-dimethylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4c]pyridine. In a flask, 2,2-dimethylcyclopropanecarbothioamide (232 mg, 1.8 mmol) and A / -Boc-3-bromo-4-oxopiperidine (500 mg, 1.8 mmol) were combined in ethanol (2 ml). After 2 hours at 80 °C, the reaction mixture was concentrated. DCM (2 Petition 870250094048, dated 10 / 14 / 2025, pp. 452 / 509 94 / 140 ml) and trifluoroacetic acid (1.38 ml). After 1 h at rt, the solution was concentrated, diluted with saturated aqueous Na2CO3 solution and extracted with DCM (3x). The combined organic layers were passed through a hydrophobic phase separator and concentrated to provide the titrant compound (195 mg). 1H NMR (400 MHz, DMSO) δ 3.83 (d, J = 1.8 Hz, 2H), 2.96 (t, J = 5.8 Hz, 2H), 2.61 (t, J = 4.1, 2H), 2.14 (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+1]+: 209.3. 1. EtOH, 80°C NH2----------- 2. TFA, DCM 2-isopropyl-4,5,6,7-tetrahydrothiazolo[5,4 [c]pyridine. A flask containing 2-methylpropanethioamide (185 mg, 1.8 mmol) and N-Boc-3-bromo-4-oxopiperidine (500 mg, 1.8 mmol) in ethanol (2 ml) was heated to 80 °C for 2 h. The reaction mixture was concentrated. DCM (2 ml) and trifluoroacetic acid (1.38 ml) were added to the crude residue. After 1 h, the solution was concentrated, diluted with saturated Na2CO3 solution, and the aqueous layer was extracted with DCM (3x). The combined organic layers were passed through a hydrophobic phase separator and concentrated to provide the titrant compound (372 mg). 1H NMR (400 MHz, CDCh) δ 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+1]+: 183.2. I θ s Jt Rr \\ 1. EtOH, 80°C / VN / -^cU-N^Y+~U~NH2-------- Γ Y WL 1 TO 2. TFA, DCM ^^S \

[0308] 2-(tert-butyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. A flask containing 2,2-dimethylpropanethioamide (211 mg, 1.8 mmol) and NBoc-3-bromo-4-oxopiperidine (500 mg, 1.8 mmol) in ethanol (2 ml) was heated to 80 °C for 2 h. The solution was concentrated. DCM (2 ml) and trifluoroacetic acid (1.4 ml) were added to the crude residue. After 1 h at room temperature, the Petition 870250094048, dated 10 / 14 / 2025, pp. 453 / 509 The 95 / 140 reaction mixture was concentrated and purified using an SCX cartridge. After elution with 2 N NH3 / MeOH solution, the solvents were removed to provide the titrant compound (238 mg). 1H NMR (400 MHz, DMSO) δ 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+1]+: 197.1. s 2. TFA, DCM 1. EtOH, 80 °C

[0309] 2-(1-fluorocyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4c]pyridine. 1-fluorocyclopropane-1-carbothioamide (114 mg, 0.72 mmol) and Nboc-3-bromo-4-oxopiperidine (200 mg, 0.72 mmol) in ethanol (2.3 ml) was heated at 80 °C for 18 h. The reaction mixture was concentrated and the residue was purified by normal-phase column chromatography (0-80% EtOAc / hexanes). DCM and trifluoroacetic acid (2.0 ml; 2:1) were added to the intermediate residue at room temperature. After 3 h, the solution was concentrated and the material was purified using an SCX cartridge. After elution with 2 N NH3 / MeOH solution, the solvents were removed to provide the titrant compound. ES-MS [M+1]+: 199; 1H NMR (400 MHz, DMSO) δ 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 °C 2. TFA, DCM

[0310] 2-cyclobutyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. Cyclobutanecarbothioamide (203 mg, 1.76 mmol) and N-boc-3-bromo-4-oxopiperidine (490 mg, 1.76 mmol) in ethanol (4.5 ml) were stirred at 80 °C for 2 h. The solution was concentrated, then DCM (4.0 ml) and trifluoroacetic acid (1.35 ml) were added at room temperature for 1 h. The concentrated solution was then diluted with EtOAc and saturated Na2CO3 solution. The layers were separated and the aqueous layer was extracted with Petition 870250094048, dated 10 / 14 / 2025, pp. 454 / 509 96 / 140 EtOAc (2x). The combined organic layers were dried (MgSO4), filtered and concentrated to give the title compound (300 mg). ES-MS [M+1 ]+: 195; 1H NMR (400 MHz, CDCh) δ 4.21 (s, 2H), 3.83 - 3.72 (m, 2H), 3.33 (t, J = 6.0 Hz, 2H), 2.94 (t, J = 5.8 Hz, 2H), 2.49 - 2.37 (m, 2H), 2.37 - 2.24 (m, 2H), 2.12 - 1.84 (m, 2H). DCM. TF A FdtPPhah. NihCOj □ioxane / Water, 80°C

[0311] 2-(thiophen-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine. Thiophene-2-boronic acid (105 mg, 0.82 mmol), 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4 / - / )-tert-butyl carboxylate (175 mg, 0.55 mmol), sodium carbonate (148 mg, 1.37 mmol), and tetrakis(triphenylphosphine)palladium(0) were combined in 1,4-dioxane (2 ml) and water (0.5 ml). After purging the reaction with nitrogen (3x), the reaction was heated to 80 °C for 2 h. The reaction was filtered with Celite® and the Celite® was washed with DCM (2 x 25 ml). The filtrate was concentrated and purified by normal phase chromatography (0-40% EtOAc / hexanes) to provide the desired Boc-protected amine. The amine protected by Boc was dissolved in DCM (2 ml) and trifluoroacetic acid (0.59 ml). After 1 h, the reaction was concentrated, basified with saturated Na2COs, extracted with DCM (3x), passed through a hydrophobic phase separator, and concentrated to provide the titrant compound (112 mg).NMR de1H (400 MHz, CDCh) δ 7.44 (dd, J = 3.7, 1.2 Hz, 1H), 7.36 (dd, 5.1, 1.2 Hz, 1H), 7.06 (dd, J = 5.1,3.7 Hz, 1H, 1H), s = 5.9 Hz, 2H), 2.90 (ddd, J = 6.0, 4.1, 1.8 Hz, 2H); ES-MS [M+1]+: 223.1. DCM. TFA Pd(dpp1)CI2,Cs2CO3□ioxane / Water, 1OÜÚC

[0312] 2-(1 -methyl-1 H-pyrazol-5-yl)-4,5,6,7-tetraPetition 870250094048, dated 14 / 10 / 2025, p. 455 / 509 97 / 140 hydrothiazolo[5,4-c]pyridine. 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine5(4H)-tert-butyl carboxylate (300 mg, 0.94 mmol), cesium carbonate (924 mg, 2.82 mmol), Pd(dppf)Cl2 (69 mg, 0.09 mmol), and pinacol 1-methylpyrazol-5-boronic acid ester (391 mg, 1.88 mmol) in 1,4-dioxane (2.3 ml) and water (0.4 ml) were heated at 100 °C for 18 h. The mixture was filtered through a Celite® filter, and the filtrate was concentrated. The residue was purified by normal phase chromatography (0-40% EtOAc / Hexanes) to provide Boc-amine, which was dissolved in DCM (2 ml) and trifluoroacetic acid (1.1 ml). After 1 h, the reaction was concentrated, basified with saturated Na2CO3 solution, extracted with DCM (3x), passed through a hydrophobic phase separator, and concentrated to provide the titrant compound (162 mg).1H NMR (400 MHz, CDCh) δ 7.47 (d, J = 2.0 Hz, 1H), 6.60 (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 - 3.01 (m, 2H); ES-MS [M+1]+: 221.2.

[0313] tert-Butyl 5-(tert-butoxycarbonyl)-4,5,6,7tetrahydrothiazolo[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(4H)-dicarboxylate (300 mg, 0.96 mmol) in ethanol (4.8 ml) was added a 5 M aqueous solution of NaOH (384 µl, 1.92 mmol). After 3 h, the reaction mixture was concentrated and carried forward without further purification. ES-MS [M + H]+= 285. nh4ci, HATU Dl EA, THF, 75 °C

[0314] 2-carbamoyl-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H) tert-butyl 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 THF (3.2 ml) was added N,N-diisopropylethylamine (1.7 ml, 9.6 Petition 870250094048, dated 10 / 14 / 2025, pp. 456 / 509 98 / 140 mmol), HATU (1.09 g, 2.88 mmol) and NhUCI (285 mg, 5.76 mmol). The mixture was heated to 75 °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). 1H NMR (400 MHz, CDCb) δ 7.01 (s, 1H), 5.46 (s, 1H), 4.71 (s, 2H), 3.77 (t, J = 5.3 Hz, 2H), 2.90 (t, J = 5.1 Hz, 2H), 1.49 (s, 9H); ES-MS [M + H]+= 284. aN .O \X___HCI .0 ► I II —% / 1 IIS NH2DCMHN^~S NH21o2

[0315] 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide. To a solution of 2-carbamoyl-6,7-dihydrothiazolo[5,4c]pyridine-5(4H)-tert-butyl carboxylate (272 mg, 0.96 mmol) in DCM (6.4 ml) was added TFA (735 μL, 9.6 mmol). After 18 hours at room temperature, the reaction was concentrated, then dissolved in MeOH and loaded onto an SCX cartridge (HF linkage). After rinsing the cartridge with MeOH, the cartridge was eluted with NH3 / MeOH 7Λ solution. The solvents were removed in vacuo to provide the titrant compound. 1H NMR (400 MHz, DMSO) δ 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 = 7.4, 3.8, 1.5 Hz, 2H); ES-MS [M + H]+= 184.

[0316] Ethyl 5-bromo-6-hydroxy-2-methylnicotinate. To a solution of ethyl-2-methyl-6oxo-1,6-dihydropyridine-3-carboxylate (10 g, 55.2 mmol) in DMF (185 ml) at 0 °C, α-bromosuccinimide (10.8 g, 60.7 mmol) was slowly added in portions. The ice bath was removed. After 18 h, saturated sodium bisulfite (aq) was added to the reaction and stirred for 30 min. The reaction was filtered, and the collected solid was dried in a vacuum oven to provide the titrant compound (14.2 g). ¹H NMR (400 MHz, DMSO) δ 8.15 (s, Petition 870250094048, dated 10 / 14 / 2025, pp. 457 / 509 99 / 140 1H), 4.20 (q, J= 7.1 Hz, 2H), 3.32 (s, 3H), 2.55 (s, 1H), 1.27 (t, J= 7.1 Hz, 3H); ES-MS [M+l]+: 260.0 / 262.0.

[0317] Ethyl 5-bromo-6-chloro-2-methylnicotinate. To a 500 ml round-bottom flask, ethyl 5-bromo-6-hydroxy-2-methylnicotinate (14.2 g, 54.6 mmol) was added to MeCN (300 ml) followed by phosphorus oxychloride (V) (29.4 ml, 316 mmol). The reaction was fitted with a condenser and heated to 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, maintaining the pH >7. Additional DCM (25 ml) was added, and the mixture was stirred for 30 min. The organic layer was separated, and the aqueous layer was extracted again with a 3:1 chloroform / IPA solution (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 provide the titrant compound (12 g).1H NMR (400 MHz, CDCh) δ 8.40 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.76 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). ESMS [M+1 ]+: 277.9 / 279.9.

[0318] Ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate. To a solution of ethyl 5-bromo-6-chloro-2-methylnicotinate (12 g, 43.1 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.71 g, 4.3 mmol) in carbon tetrachloride (287 ml) at 50 °C, / V-bromosuccinimide (8.43 g, 47.4 mmol) was added in portions. After 30 min, the reaction was heated to 80 °C. After 18 h, the reaction was cooled to room temperature, diluted with water, and the Petition 870250094048, dated 10 / 14 / 2025, pp. 458 / 509 100 / 140 organic layers were separated. The aqueous layer was extracted with DCM (3 x 50 ml). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0-4% EtOAc / Hexanes) to provide the titrant compound (13.6 g). 1H NMR (400 MHz, CDCl3) ε8.48 (s, 1H), 4.91 (s, 2H), 4.44 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). ES-MS [M+1]+: 357.9 / 359.9. h2n— THF, 0°C

[0319] 3-bromo-2-chloro-6-methyl-6,7-dihydro-5H-pyrrolo[3,4b]pyridin-5-one. To a solution of ethyl 5-bromo-2-(bromomethyl)-6-chloronicotinate (2.5 g, 6.99 mmol) in THF (140 ml) at 0 °C, a 2.0 M methylamine solution (17.5 ml, 35.0 mmol) was added, and the reaction was stirred for 30 min. The reaction was concentrated at rt and purified by normal phase chromatography (0-30% EtOAc / DCM) to provide the titrant compound (948 mg). 1H NMR (400 MHz, DMSO) δ 8.49 (s, 1H), 4.50 (s, 2H), 3.09 (s, 3H). ES-MS [M+1]+: 261.1 / 263.1. NMP, DIPEA 160°C

[0320] 3-bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4c]pyridin-5(4H)-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. To a solution of 3-bromo-2-chloro-6-methyl-7 / - / -pyrrolo[3,4-b]pyridin-5-one (262 mg, 1.0 mmol) and A / , / V-diisopropylethylamine (0.87 ml, 5.0 mmol) in NMP (3.7 ml) was added 2-cyclopropyl-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (271 mg, 1.5 mmol). The reaction was heated to 160 °C. After 18 h, the reaction was cooled to rt and water was added to generate a precipitate. The suspension was filtered, washed with water, and dried under N2. The residue was purified by Petition 870250094048, dated 10 / 14 / 2025, pp. 459 / 509 101 / 140 normal phase chromatography (0-5% MeOH / DCM / 0.1% NH4OH) to provide the title compound (225 mg). 1H NMR (400 MHz, CDCh) δ 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+1]+: 405.1 / 407.1.

[0321] 3-bromo-2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4 H)-yl)-6-methyl-6,7-di-hydro-5 H -pyrrolo[3,4b ]pyridin-5-one. A solution of 3-bromo-2-chloro-6-methyl-7 H-pyrrole[3,4b ]pyridin-5-one (30 mg, 0.11 mmol) and N, N-di-isopropylethylamine (0.1 ml, 0.57 mmol) in DMSO (0.57 ml) was added 2-(1-fluorocyclopropyl)-4,5,6,7-tetrahydrothiazol[5,4-c ]pyridine (27.0 mg, 0.14 mmol). The reaction was heated at 70 °C for 18 h. The reaction was purified by reverse-phase CLAE (18–58% MeCN / water / 0.05% NH4OH) to afford the title compound. ES-MS [M+1]+: 425 / 426; NMR de1H (400 MHz, CDCh) δ 8.17 (d, J = 1.5 Hz, 1H), 4.68 (q, J = 1.8 Hz, 2H), 4.26 (d, J = 1.5 Hz, 2H), 3.82 (td, J = 1.7, Hz, 3.1Hz), (d, J = 1.5 Hz, 3H), 3.09 (ddd, J = 7.6, 3.8, 1.8 Hz, 2H), 1.65 to 1.54 (m, 2H), 1.51 to 1.41 (m, 2H). o— h2n

[0322] 3-bromo-2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro5H-pyrrolo[3,4-b]pyridin-5-one. To a solution of 5-bromo-2-(bromomethyl) Petition 870250094048, of 14 / 10 / 2025, page 460 / 509 102 / 140 Ethyl 6-chloronicotinate (1300 mg, 2.8 mmol) in THF (55 ml) was slowly added, followed by 2,4-dimethoxybenzylamine (2.1 ml, 14.0 mmol), and the reaction was stirred for 30 h at room temperature. Triethylamine (0.58 ml, 4.2 mmol) was then added. After 18 h at room temperature, the reaction was concentrated using Celite® and purified by normal-phase chromatography (0-25% EtOAc / DCM) to provide the titrant compound. 1H NMR (400 MHz, CDCh) δ 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+1]+: 397 / 399.

[0323] 3-bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4c]pyridin-5(4H)-yl)-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4b]pyridin-5-one. To a solution of 3-bromo-2-chloro-6-(2,4-dimethoxybenzyl)6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (888 mg, 2.2 mmol) and N,N-diisopropylethylamine (1.94 ml, 11.2 mmol) in NMP (5.6 ml) was added 2-cyclopropyl-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (604 mg, 3.4 mmol). The reaction was heated to 120 °C. After 18 h, water was added and the precipitate was filtered, rinsed with water, and dried under N2 to provide the titrant compound. 1H NMR (400 MHz, CDCh) δ 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), 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), 1.13 - 1.07 (m, 2H), 1.03 - 0.97 (m, 2H). ES-MS [M+1]+: 541 / 543. Petition 870250094048, dated 10 / 14 / 2025, pp. 461 / 509 103 / 140 PdídpptCIs. CS2CO3 THF / Water, 13 AD

[0324] 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-b]pyridin-5one. A mixture of 3-bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4c]pyridin-5(4 / - / )-yl)-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5 / - / -pyrrolo[3,4-b]pyridin5-one (200 mg, 0.37 mmol), pinacol vinylboronic acid ester (0.09 ml, 0.55 mmol), Pd(dppf)Cl2 (14 mg, 0.02 mmol) and cesium carbonate (363 mg, 1.11 mmol) in THF (2.2 ml) and water (0.22 ml) was subjected to microwave irradiation at 130 °C for 30 min. The reaction mixture was filtered with Celite®, washed with CHCh / IPA 3:1, and the solvents were removed in vacuo. The crude sample was purified by reverse-phase chromatography (15-65% MeCN / Water / 0.05% NH4OH) to provide the titrant compound. ES-MS [M+1]+: 489.

[0325] 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), ΛΖ-4-methylmorpholine oxide (893 μL, 8.6 mmol) was added, and the mixture was stirred at room temperature for 2 h. 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 by normal-phase column chromatography (0-30% EtOAc / hexanes) to yield the titrant compound (668 mg). ES-MS [M+1]+: 292 / 294; 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.34 (d, J = 0.5 Hz, Petition 870250094048, dated 10 / 14 / 2025, pp. 462 / 509 104 / 140 Η), 4.45 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). 1) NaBHi;THF 2) HCl, 1,4-dioxanes THE

[0326] 3-bromo-2-chlorofuro[3,4-b]pyridin-5(7H)-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, sodium borohydride (27 mg, 0.70 mmol) was added. The reaction was stirred at -40 °C for 45 minutes. Water was added to the reaction mixture, and the reaction was warmed to room temperature. After the reaction was extracted with EtOAc (3x), the combined organic layer was dried (MgSO4), filtered, and concentrated. The residue was collected in 1,4-dioxane (4 mL), then hydrochloric acid (879 μL, 3.52 mmol; 4 M mIm 1,4-dioxane) was added, and the mixture was heated to 50 °C for 18 h. Additional 4 M HCl in 1,4-dioxane (400 μL, 1.6 mmol) was added, and the mixture was heated to 50 °C. After 4 h, the mixture was concentrated under vacuum, and the residue was dissolved in DCM. The solution was washed with a saturated aqueous solution of NaHCO3. The organic layer was separated, dried (MgSO4), and concentrated.The crude residue was purified by normal-phase column chromatography (0 - 0.5% MeOH / DCM) to generate the titrant compound. ES-MS [M+1 ]+: 248 / 250; 1H NMR (400 MHz, CDCb) δ 8.42 (t, J = 0.5 Hz, 1H), 5.28 (d, J = 0.5 Hz, 2H).

[0327] 3-bromo-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)furo[3,4-b]pyridin-5(7H)-one. To a solution of 3-bromo-2-chlorofuro[3,4-b]pyridin-5(7 / - / )-one (40 mg, 0.13 mmol) in NMP (1 ml) was added 3-bromo-2-chloro-7 / - / -furo[3,4b]pyridin-5-one hydrochloride (40 mg, 0.13 mmol) and A / , / V-diisopropylethylamine (0.07 ml, 0.39 Petition 870250094048, dated 10 / 14 / 2025, pp. 463 / 509 105 / 140 mmol). The mixture was heated to 50 °C for 18 h. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The product was transported without further purification. ES-MS [M+1]+: 406 / 408.

[0328] 3-Bromo-6,7-dihydro-5H-cyclopenta[ib]pyridin-2-ol. To a flask containing 6,7-dihydro-5 / - / -cyclopenta[b]pyridin-2-ol (500 mg, 3.7 mmol) and acetic acid (5.3 mL) at 0 °C, bromine (150 μL, 2.9 mmol) was added. The reaction was allowed to reach rt for 3 h. The reaction mixture was concentrated in vacuo, and a saturated solution of sodium thiosulfate was added to the residue and neutralized with a saturated aqueous solution of sodium carbonate. The mixture was extracted with EtOAc (3x). The combined organic layers were dried with 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% NH4OH additive) to provide the desired compound (493 mg). 1H NMR (400 MHz, CDCb) δ 7.74 (s, 1H), 2.91 (tt, J = 8.1, 1.2 Hz, 2H), 2.79 - 2.70 (m, 2H), 2.21 - 2.09 (m, 2H); ESMS [M+1 ]+: 214 / 216. Br Br

[0329] 3-Bromo-2-chloro-6,7-dihydro-5Hcyclopenta[b]pyridine. 3-bromo-6,7-dihydro-5 / - / -cyclopenta[b]pyridin-2-ol (493 mg, 2.3 mmol) in POCl3 (1.2 ml, 13.2 mmol). The solution is heated at 90 °C for 18 h. The reaction mixture was concentrated. Aqueous saturated sodium carbonate was slowly added to the residue. The mixture was extracted. Petition 870250094048, dated 10 / 14 / 2025, pp. 464 / 509 106 / 140 with DCM (3x). The combined organic layers were washed with water (3x). The organic layers were dried with sodium sulfate, filtered, and concentrated. The crude material was purified using normal-phase column chromatography (0-60% EtOAc / Hex) to yield the titrant compound (316 mg). 1H NMR (400 MHz, CDCb) δ 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+1]+: 232 / 234.

[0330] 3-Bromo-2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine5-one. To a solution of magnesium sulfate (833 mg, 6.8 mmol), potassium permanganate (430 mg, 2.7 mmol) in water (1.7 ml) and tert-butanol (5 ml), 3-bromo-2-chloro-6,7-dihydro-5Hcyclopenta[b]pyridine (316 mg, 1.36 mmol) was added. The mixture was stirred at 40 °C for 3 h. The reaction mixture was filtered with Celite®, washed 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 provide the titrant compound. ES-MS [M+1]+: 246 / 248; 1H NMR (400 MHz, CDCb) δ 8.22 (s, 1H), 3.26-3.18 (m, 2H), 2.87-2.80 (m, 2H).

[0331] 3-bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4c]pyridin-5(4H)-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one. At one Petition 870250094048, dated 10 / 14 / 2025, pp. 465 / 509 To a solution of 3-bromo-2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one (13 mg, 0.05 mmol) in DMSO (0.5 ml), 2-cyclopropyl-4,5,6,7tetrahydro-[1,3]thiazolo[5,4-c]pyridine (10 mg, 0.06 mmol) and Λ / ,ΛZ-diisopropylethylamine (55 μL, 0.32 mmol) were added. 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 with MgSO4, filtered, and concentrated. The crude residue was purified using normal-phase column chromatography (0-80% EtOAc / hexanes) to provide the titrant compound. [M+1]+: 390 / 392. NHj ü HCI 4 Aí in 1,4-dioxane II] Xjl. xx ' laugh ° <3 toliuene X. JL. HO N '

[0332] 6-Hydroxy-2,4-dimethylnicotinate methyl. To a solution of ethyl (Z)-3-aminobut-2-enoate (1.96 ml, 15.5 mmol) in toluene (11.6 ml), a solution of hydrochloric acid (4 M in dioxanes) (7.74 ml, 30.9 mmol) was added, and the reaction was heated at 115 °C for 18 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, and the crude residue was purified by normal phase chromatography (0-90% EtOAc / DCM) to provide the titrant compound. 1H NMR (400 MHz, CDCb) δ 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+1 ]+: 196.

[0333] Ethyl 5-Bromo-6-hydroxy-2,4-djmetjlnjcotjnate. Prepared in a similar way to ethyl 5-bromo-6-hydroxy-2-methylnicotinate. 1H NMR (400 MHz, CDCb) δ 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+1 ]+: 274 / 276. Petition 870250094048, dated 10 / 14 / 2025, pp. 466 / 509 108 / 140

[0334] 5-Bromo-6-chloro-2,4-dimethylnicotinato de ethyla: Preparada de maneira similar a 5-bromo-6-cloro-2-metilnicotinato de ethyla. NMR de1H (400 MHz, CDCb) δ 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+1 ]+: 292 / 294.

[0335] 5-bromo-2-(bromomethyl)-6-chloro-4-methylnicotinato de etila: Prepared in a similar way to 5-bromo-2-(bromomethyl)-6chloronicotinato de etila. NMR de1H (400 MHz, CDCb) δ 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+1]+: 370 / 372 / 374.

[0336] 3-Bromo-2-chloro-4,6-dimethyl-6,7-di-hidro-5Hpyrrolo[3,4-b]pyridin-5-ona: Prepared in a similar way to 3-bromo-2chloro-6-methyl-6,7-di-hidro-5H-pyrrolo[3,4-b]pyridin-5-ona. NMR de1H (400 MHz, DMSO) δ 4.43 (s, 2H), 3.07 (s, 3H), 2.75 (s, 3H). ES-MS [M+1]+: 275 / 277.

[0337] 3-bromo-2-chloro-4-methyl-6,7-dihydro-5H-pyrrolo[3,4b]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 (7 μL in MeOH) (615 μL, 4.31 mmol), and the reaction was stirred. Petition 870250094048, dated 10 / 14 / 2025, pp. 467 / 509 109 / 140 for 18 hours at room temperature. Additional ammonia (7N in MeOH) (615 pl, 4.31 mmol) was added and the reaction was allowed to be stirred for a further 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 provide the titrant compound. 1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 4.33 (d, J = 1.2 Hz, 2H), 2.75 (s, 3H). ES-MS [M+1]+: 261 / 263. DIEA, DMSO 70 °C

[0338] 3-bromo-2-(2-(1 -fluorociclopropil)-6,7-dihidrotiazolo[5,4-c]piridin-5(4H)-il)-4,6-dimetil-6,7-di-hidro-5H pirrolo[3,4-b]piridin-5-ona. Prepared from similar to 3-bromo-2-(2(1-fluorociclopropil)-6,7-di-hidrotiazolo[5,4-c ]piridin-5(4H)-il)-6-metil-6,7-dihidro-5H-pirrolo[3,4-b]piridin-5-ona. RMN de1H (400 MHz, CDCb) δ 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+1]+: 437 / 439. DIEA, DMSO 70 °C

[0339] 3-bromo-2-(2-(1 -fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4 H)-yl)-4-methyl-6,7-di-hydro-5 H -pyrrolo[3,4b]pyridin-5-one. Prepared similarly to 3-bromo-2-(2-(1fluorocyclopropyl)-6,7-di-hydrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one. de1H NMR (400 MHz, CDCb) δ 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), Petition 870250094048, of 14 / 10 / 2025, p. 468 / 509 110 / 140 3.11 (t, J=5.7Hz, 2H), 2.79 (s, 3H), 1.65-1.58 (m, 2H), 1.49-1.42 (m, 2H). ES-MS [M+1]+: 423 / 425. Table 1. Commercial Starting Materials Name CAS No. Supplier 6,7-Di-hidrothiazolo[5,4-c]piridina-5(4 / - / )carboxylate de terc-butyl 165948-24-3 Combi-Blocks, Inc. 6,7-Di-hidrothiazolo[5,4-c]piridina2,5(4 / - / )-dicacarboxylate de 5-(terc-butyl) 2-ethyl 1053656-51-1 J & W PharmLab 4,5,6,7-tetra-hidrothiazolo[5,4-c]piridina 165948-23-2 Enamine 2-chloro-6,7-di-hidrothiazolo[5,4c]piridina-5(4 / - / )-carboxylate de terc-butyl 1221931-40-3 Combi-Blocks, Inc. 2-amino-6,7-di-hidrothiazolo[5,4c]piridina-5(4 / - / )-carboxylate tertbutyl 365996-05-0 Combi-Blocks, Inc. 4,5,6,7-tetrahidrothiazolo[5,4-c]piridina-2-carboxylate hydrochloride ethyl 1186663-33-1 AstaTech, Inc. 2-bromo-4,5,6,7-tetrahidrothiazolo[5,4-c]piridina hydrochloride 949922-52-5 Synthonix 2-methyl-4,5,6,7-tetra-hidrothiazolo[5,4c]piridina 124458-27-1 Aurum Pharmatech 2-bromo-6,7-di-hidrothiazolo[5,4c]piridina-5(4 / - / )-carboxylate de tercbutila 365996-06-1 Combi-Blocks, Inc.1 H,2H, 5 / - / ,6 / - / , 7 / - / -cyclopenta[b]pyridin2-one 88499-85-8 Enamine 1-fluorocyclopropanecarboxamide 1445686-01-7 eNovation Chemicals. b. Representative synthesis of compounds of the invention DIPEA, DMSO, 120°C Petition 870250094048, dated 10 / 14 / 2025, pp. 469 / 509 111 / 140

[0340] 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 2). To a solution of 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4-b]pyridin-5-one (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 ml, 0.41 mmol) in DMSO (0.8 ml) was added 2-cyclopropyl-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4c]pyridine hydrochloride (21 mg, 0.10 mmol). The reaction was heated at 120 °C for 18 h. The reaction was purified by reversed-phase HPLC (5-45% MeCN / water / 0.05% NH4OH). The desired fractions were concentrated to provide the titrant compound (2.1 mg). 1H NMR (400 MHz, CDCh) δ 7.82 (s, 1H), 6.50 (s, 1H), 4.52 (s, 2H), 4.35 (s, 2H), 3.57 (t, J = 5.6 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), 1.04-1.00 (m, 2H); ES-MS [M+1]+: 327.0.

[0341] 3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 3). To a solution of 2-chloro-3-methyl-6,7-dihydropyrrolo[3,4-b]pyridin-5-one (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 ml, 0.41 mmol) in DMSO (0.8 ml), 2(1-methylcyclopropyl)-4,5,6,7-tetrahydro-[1,3]thiazolo[5,4-c]pyridine (19 mg, 0.10 mmol) was added. The reaction was heated at 120 °C for 18 h. The reaction was purified by reversed-phase HPLC (5-45% MeCN / water / 0.05% NH4OH). The desired fractions were concentrated to provide the titrant compound (9.4 mg). 1H NMR (400 MHz, DMSO-d6) δ 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, 2.6 Hz, 2H), 0.96 (dd, J = 6.3, 3.7 Hz, 2H); ES-MS [M+1]+: 341.0. Petition 870250094048, dated 10 / 14 / 2025, pp. 470 / 509 112 / 140

[0342] 2-(2-cyclopropyl-6,7-dihydro-4H-[1,3]thiazolo[5,4c]pyridin-5-yl)-3,6-dimethyl-7H-pyrrolo[3,4-b]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-t>]pyridin-5-one (225 mg, 0.56 mmol), cesium carbonate (543 mg, 1.67 mmol), trimethylboroxine (50 wt% THF) (0.47 ml, 1.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (81 mg, 0.11 mmol) and 1,4-dioxane (2.9 ml) were loaded into a flask. The mixture was evacuated and purged with nitrogen and stirred at 80 °C for 18 h. The reaction was filtered through a Celite® filter, which was thoroughly rinsed with CHCb / IPA 3:1. The solvents were removed and the crude sample was purified by reverse-phase chromatography (5-40% MeCN / Water / 0.1% TFA). The desired fractions were basified with saturated NaHCO3, extracted with CHCb / IPA 3:1, and concentrated to yield the titrant compound (36 mg).RMN de1H (400 MHz, CDCb) δ 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, 3H), 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+1]+: 341,2. Petition: 870250094048, on 10 / 14 / 2025, page. 471 / 509 113 / 140

[0343] 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4c]pyridin-5(4H)-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-õ]pyridin-5-one (Compound 23). 3-bromo-2-[2-(1-fluorocyclopropyl)-6,7-dihydro-4 / - / [1,3]thiazolo[5,4-c]pyridin-5-yl]-6-methyl-7 / - / -pyrrolo[3,4-b]pyridin-5-one (21.0 mg, 0.05 mmol), cesium carbonate (48.0 mg, 0.15 mmol), trimethylboroxine (50 wt% THF) (40.0 μL, 0.15 mmol), [1,Tbis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.0 mg, 0.01 mmol) and 1,4-dioxane (0.5 mL) were loaded into a microwaveable flask. The mixture was evacuated and purged with nitrogen and stirred at 80 °C for 18 h. The reaction was filtered through a Celite® filter, which was thoroughly rinsed with EtOAc. The solvents were removed and the crude sample was purified by reverse-phase chromatography (15-55% MeCN / Water / 0.1% TFA). The desired fractions were basified with saturated NaHCO3, extracted with CHCh / IPA 3:1, and concentrated to yield the titrant compound.ES-MS [M+1 ]+: 359.2; NMR de1H (400 MHz, CDCh) δ 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, 2H), 3.56 (t, J= 5.7 Hz, 2H, 2H), 3.56 (t, J= 5.7 Hz, 2H, 18). = 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).

[0344] 3-methyl-2-(2-(1 -methylcyclopropyl)-6,7-dihydrothiazol[5,4-c]pyridin-5(4H)-yl)furo[3,4-õ]pyridin-5(7H)-one (Compound 24). A solution of 3-bromo-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazol[5,4-c]pyridin-5(4 / - / )-yl)furo[3,4-b]pyridin-5(7 / - / )-one (57 mg, 0.13 mmol), carbon dioxide (10,639 mg mmol), trimethylboroxine (50 wt % in THF) (108 μΙ, 0.39 mmol), and [1,T Petition 870250094048, of 14 / 10 / 2025, p. 472 / 509 [114 / 140 bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.025 mmol) in 1,4-dioxane (1 ml) was loaded into a flask. The mixture was evacuated and purged with nitrogen (3x) and stirred at 80 °C. After 4 h, the mixture was cooled to room temperature and additional cesium carbonate (126 mg, 0.39 mmol), trimethylboroxine (50 wt% in THF) (108 ml, 0.39 mmol), and [1,1'-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 Celite® filter thoroughly washed with DCM / MeOH then concentrated. The crude product was purified by reversed-phase chromatography (10-60% MeCN / Water / 0.1% TFA) and the desired fractions were basified with saturated NaHCO3 and 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 chromatography (0-70% EtOAc / Hex) to provide the titrant compound. ES-MS [M+1]+: 342.

[0345] Methyl 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)-6-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]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-b]pyridin5-one (50 mg, 0.12 mmol) in triethylamine (0.4 mL, 2.8 mmol) and methanol (0.05 mL, 1.2 mmol) were added xanthos (14 mg, 0.02 mmol) and palladium(II) acetate (2.8 mg, 0.01 mmol), and the resulting reaction flask was sealed. The flask was purged with a CO₂ gas atmosphere. The reaction was then heated to 70 °C for 16 h under a CO₂ gas balloon. Upon cooling to room temperature, the crude reaction was diluted with CH₃Ch / IPA 3:1. Petition 870250094048, dated 10 / 14 / 2025, pp. 473 / 509 115 / 140 filtered and concentrated. The crude oil was purified by reverse-phase chromatography (10-60% MeCN / water / 0.1% TFA). The desired fractions were subjected to basic finishing to provide the titrant compound (3.9 mg). 1H NMR (400 MHz, CDCh) δ 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+1]+: 385. DIEA, NMP, 160 °C

[0346] 5-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]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-chloro-3-methyl-6,7-dihydro-5Hpyrrolo[3,4-b]pyridin-5-one (15 mg, 0.08 mmol) in NMP (0.5 ml) was added N,N-diisopropylethylamine (72 ml, 0.41 mmol) and the reaction was heated at 160 °C for 18 hours. The crude residue was purified using HPLC (5-50% ACN / 0.1% aqueous TFA). The fractions containing the titrant compound were basified with saturated aqueous 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 provide the titrant compound.1H NMR (400 MHz, CDCh) δ 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. Petition 870250094048, dated 10 / 14 / 2025, pp. 474 / 509 116 / 140 Pd / C, Pd(OH)2 EtOH, 50°C

[0347] 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-b]pyridin-5-one (Compound 33). In a reaction flask, 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)-6-(2,4-dimethoxybenzyl)-3-vinyl-6,7-dihydro5H-pyrrolo[3,4-b]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 No. 7440-05-3; 8 mg, 0.01 mmol) and palladium hydroxide on activated charcoal (CAS No. 12135-22-7; 10 mg, 0.01 mmol) were added. The resulting mixture was purged with H2 gas for 1 min. The flask was removed, and the reaction was stirred at 50 °C for 5 h. The suspension was filtered through a Celite® filter that was thoroughly rinsed with 10% MeOH / DCM. The filtrate was concentrated under reduced pressure and purified by reverse-phase chromatography (15-65% MeCN / Water / 0.05% NH4OH) to provide the titrant compound.RMN de1H (400 MHz, CDCh) δ 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), 2.71 (q, J = 7.5 Hz, 2H), 2.38 (s, 1H), 1.29 (t, J = 7.4 Hz, 3H), 1.21 (s, 2H), 1.10 (s, 2H). ES-MS [M+1]+: 491. 0348 117 / 140 il)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-ib]pindin-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-b]pyridin-5-one (12 mg, 0.02 mmol) in trifluoroacetic acid (75 µl, 0.98 mmol) was stirred at 60 °C for 4 h. The reaction mixture was concentrated to generate the crude residue which was purified by reverse-phase chromatography (5-45% MeCN / Water / 0.1% TFA) to provide the titrant compound. 1H NMR (400 MHz, CDCh) δ 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 = 7.5 Hz, 3H), 1.25-1.21 (m, 2H), 1.18-1.13 (m, 2H). ES-MS [M+1]+: 341. Pd(dppf)Ck Cs2CO3 1,4-dioxane BO °C

[0349] 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)yl)-3-methyl-6,7-dihydro-5H-cyclopenta[ib]pindin-5-one (Compound 35). 3-bromo-2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4 / - / )-yl)-6,7-dihydro5 / - / -cyclopenta[b]pyridin-5-one (8.0 mg, 0.02 mmol), cesium carbonate (20 mg, 0.06 mmol), trimethylboroxine (50 wt% THF) (20 μL, 0.06 mmol), Pd(dppf)Ch (3.0 mg, 0.004 mmol), and 1,4-dioxane (0.5 mL) were loaded into a microwaveable flask. The mixture was vacuum-sealed, purged, and stirred at 80 °C for 18 h. The reaction mixture was diluted with EtOAc, filtered with Celite®, and concentrated. The crude residue was dissolved in DMSO (1.5 ml) and purified using reversed-phase chromatography (10-40% MeCN / 0.1% aqueous TFA). The fractions containing the desired product were neutralized with saturated NaHCO3 and then extracted with a 3:1 chloroform / IPA solution (3x).The combined organics were passed through a hydrophobic phase separator, and the solvents were concentrated to provide the titrant compound. 1H NMR (400 MHz, CDCh) δ 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. Petition 870250094048, dated 10 / 14 / 2025, pp. 476 / 509 118 / 140 (m, 2H), 2.36 (d, J= 0.9 Hz, 3H), 2.27 (ddd, J= 13.1,8.3, 4.9 Hz, 1H), 1,170.98 (m, 4H). ES-MS [M+1 ]+: 326.2.

[0350] 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4c]pyridin-5(4H)-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-ib]pyridin-5-one (Compound 36). Prepared in a similar manner to Compound 23. 1H NMR (400 MHz, CDCb) δ 5.82 (s, 1H), 4.56 - 4.51 (m, 2H), 4.28 (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+1 ]+: 359.

[0351] 2-(2-(1-fluorocyclopropyl)-6,7-dj-hjdrotjazolo[5,4c]pyridin-5(4H)-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-ib]pyridin-5one (Compound 38). Prepared in a similar manner to Compound 23. 1H NMR (400 MHz, CDCb) δ 4.51 (t, J = 1.8 Hz, 2H), 4.21 (s, 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+1 ]+: 373.

[0352] The compounds shown in Table 2 can be prepared using the methods shown in the previous Schemes and examples with the appropriate starting materials. Petition 870250094048, dated 10 / 14 / 2025, pp. 477 / 509 119 / 140 Table 2 Compound No. Name Structure ESMS [M+1]+ 1 2-(6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3methyl-6,7-dihydro-5 Hpyrrolo[3,4-b ]pyridin-5ona \ T > ___X, / hnCXX 0 287 2 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3methyl-6,7-dihydro-5 Hpyrrolo[3,4-b ]pyridin-5ona i T v- <i ___.n. hncxx o7 327 3 3-metil-2-(2-(1metilciclopropil)-6,7-dihidrotiazolo[5,4c ]piridin-5(4 h)-il)-6,7di-hidro-5 h-pirrolo[3,4b ]piridin-5-ona hn 1 ii 341 4 3-metil-2-(2-(tiofen-2il)-6,7-dihidrotiazolo[5,4c n ç3 || 0 369 petição 870250094048, de 14 10 2025, pág. 478 509 120 140 5 5-(3-metil-5-oxo-6,7-dihidro-5 ]piridin-2-il)-4,5,6,7tetra-hidrotiazolo[5,4c ]piridina-2-carboxilato etila \ 359 6 3-metil-2-(2-metil-6,7di-hidrotiazolo[5,4c t>— hnCXX o7 301 7 3-methyl-2-(2-(1-methyl- 1H-pyrazol-5-yl)-6,7-dihydrothiazol[5,4c ]pyridin-5(4 H)-yl)-6,7di-hydro-5 H-pyrrolo[3,4b ]pyridin-5-One 36 X 8 X NC 2-(2-amino-6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3methyl-6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5ona / ^N^Nr¥s^NH2HNCXX o7 302 9 2-(2-chloro-6,7-dihydrothiazol[5,4c ]pyridin-5(4 H)-yl)-3methyl-6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5ona hnXI o7 321 Petition 870250094048, of 14 / 10 / 2025, p. 479 / 509 121 / 140 10 2-(2-(2,2dimethylcyclopropyl)-6,7di-hydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3methyl-6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5one. T x>-< HNCXX 0 355 11 2-(2-(tert-butyl)-6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3methyl-6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5one 343 12 2-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3,6dimethyl-6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5one .. 1 341 13 3,6-dimethyl-2-(2-(1methylcyclopropyl)-6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-6,7di-hydro-5 H-pyrrolo[3,4b ]pyridin-5-one NN n'~ T 0 355. Petition 870250094048, 10 / 14 / 2025, p. 480 / 5 122 / 1 14 6-ciclopropil-2-(2ciclopropil-6,7-dihidrotiazolo[5,4c ]piridin-5(4 H)-il)-3metil-6,7-di-hidro-5 Hpirrolo[3,4-b ]piridin-5ona í ¥ V-<1 Λ N. J1- / i^ÇXX 0 367 15 6-ciclopropil-3-metil-2(2-(1-metilciclopropil)6,7-di-hidrotiazolo[5,4c ]piridin-5(4 H)-il)-6,7di-hidro-5 H-pirrolo[3,4b ]piridin-5-ona n OLh-fí 0 381 16 6-ciclopentil-2-(2cyclopentyl-6,7-dihidrotiazolo[5,4c]pyridin-5(4H)-yl)-3methyl-6,7-di-hidro-5Hpirrolo[3,4-b]piridin-5ona ___ ___JLc / 0 395 17 6-ciclopentil-3-methyl-2(2-(1-methylcyclopropyl)6,7-di-hidrotiazolo[5,4c] ]piridin-5(4 H)-yl)-6,7di-hidro-5 H-pyrrolo[3,4b ]piridin-5-ona J. ó 409 Petition 870250094048, of 14 / 10 / 2025, p. 481 / 509 123 / 140 18 2-(2-(2,2- dimethylcyclopropyl)-6,7di-hidrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3,6dimethyl-6,7-di-hidro-5 Hpyrrolo[3,4-b ]pyridin-5ona O 369 19 6-cyclopropyl-2-(2-(2,2dimethylcyclopropyl)-6,7di-hidrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3methyl-6,7-di-hidro-5 Hpyrrolo[3,4-b ]pyridin-5ona ___ / N. JL / o 395 20 6-Cyclopentyl-2-(2-(2,2dimethylcyclopropyl)-6,7di-hydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3methyl-6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5ona 9 u T 423 21 2-(2-Cyclobutyl-6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3,6dimethyl-6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5ona X 9^ zz> A / / z ° 355,3 Petition 870250094048, 14 / 10 / 2025, pág. 482 / 509 124 / 140 22 2-(2-Cyclobutyl-6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3methylfuro[3,4-b ]pyridin5(7 H)-one r T yx > °ÇxX 0 342.2 23 2-(2-(1- fluorocyclopropyl)-6,7di-hydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3,6dimethyl-6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5one Γ II 0 359.2 24. 3-Methyl-2-(2-(1methylcyclopropyl)-6,7-dihydrothiazolo[5,4- c ]pyridin-5(4 H)yl)furo[3,4-b ]pyridin5(7 H)-one ,r.YaH> o7 342.2 25 2-(2-cyclobutyl-6,7-dihydrothiazolo[5.4c ]pyridin-5(4 H)-yl)-3methyl-6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5one ' T yx > hnCXX 0 341.2 Petition 870250094048, 10 / 14 / 2025, p. 483 / 5 125 / 1 26 3-cyclopropyl-2-(2cyclopropyl-6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-6methyl-6,7-dihydro-5 Hpyrrolo[3,4-b ]pyridin-5ona / / \ z T 367 27 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-6methyl-5-oxo-6,7-dihydro-5 H-pyrrolo[3,4b ]pyridin-3-carbonitrila 0 / 352 28 2-(2-(1- fluorocyclopropyl)-6,7dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3methyl-6,7-dihydro-5 Hpyrrolo[3,4-b ]pyridin-5ona Ϊz ω T 345,2 29 2-(2-cyclopropyl-6,7-dihidrothiazolo[5,4c ]pyridin-5(4 H)-yl)-6methyl-3-vinyl-6,7-dihydro-5 H-pyrrolo[3,4b ]pyridin-5-ona 0 353 Petition 870250094048, 14 / 10 / 2025, pág. 484 / 509 126 / 140 30 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-6methyl-3-(prop-1-en-2-yl)6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5ona 0 1 367 31 2-(2-cyclopropyl-6,7-dihydrothiazol[5,4c ]pyridin-5(4 H)-yl)-6methyl-5-oxo-6,7-dihydro-5 H-pyrrole[3,4b ]pyridine-3-methyl carboxylate X z / > Y__ / 7 f O 385 32 5-(3-methyl-5-oxo-6,7-dihydro-5 H-pyrrolo[3,4b ]pyridin-2-yl)-4,5,6,7tetra-hydrothiazol[5,4c ]pyridine-2carboxamide O i T v / o NHo hn\L^ II 0 330.2 33 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-6(2,4-dimethoxybenzyl)-3ethyl-6,7-di-hydro-5 Hpyrrolo[3,4-b ]pyridin-5ona / oo 491 Petition 870250094048, of 14 / 10 / 2025, p. 485 / 509 127 / 140 34 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4- c ]pyridin-5(4 H)-yl)-3-ethyl6,7-dihydro-5 Hpyrrolo[3,4-b ]pyridin-5one ]pyridin-5(4 H)-yl)-3methyl-6,7-dihydro-5 Hcyclopenta[ b ]pyridin-5one Hpyrrolo[3,4-b ]pyridin-5one HN 1 II o 359.2 37 2-(2-(1-fluorocyclopropyl)-6,7dihydrothiazolo[5,4c]pyridin-5(4H)-yl)-4methyl-6,7-dihydro-5 Hpyrrolo[3,4-b]pyridin-5one HN 1 l| The 345.1 Petition 870250094048, dated 10 / 14 / 2025, pp. 486 / 509 128 / 140 38 2-(2-(1-fluorocyclopropyl)-6,7dihydrothiazolo[5,4c ]pyridin-5(4 H)-yl)-3,4,6trimethyl-6,7-dihydro-5 Hpyrrolo[3,4-b ]pyridin-5one ,ü z / >— \\ / / z ° 373.2 Biological activity A. Cell lines that express muscarinic acetylcholine receptors

[0353] Human and mouse M4 cDNAs, along with the chimeric G protein Gqi5, were transfected into Chinese hamster ovary (CHO-K1) cells acquired from the American Type Culture Collection using Lipofectamine2000. Transfected cells were subjected to antibiotic selection treatment to generate stable cell lines; G418 sulfate (1 mg / ml) for selection of M4-expressing cells and Hygromycin B (500 pg / ml) for selection of Gqi5-expressing cells. The resulting polyclones were subsequently screened to obtain hM4-Gqi5 and rM4-Gqi5 monoclones for compound screening assay. Stable monoclonal cells were maintained in Ham F-12 medium containing 10% heat-inactivated fetal bovine serum (FBS), 1X antibiotic / antifungal, 20 mM HEPES, 500 pg / ml G418 sulfate, and 200 pg / ml hygromycin B in humidified incubators at 37 °C in the presence of 5% CO2. B. Cell-based functional assay of muscarinic acetylcholine receptor activity

[0354] The high-throughput assay was employed to measure intracellular calcium receptor-induced mobilization to determine the activity of the compound. The test compound was added to cells expressing muscarinic receptors that were loaded with dye. Petition 870250094048, dated 10 / 14 / 2025, pp. 487 / 509 129 / 140 fluorescent calcium-sensitive. After an incubation period of ~2.5 minutes, a submaximal concentration (EC20) of acetylcholine was added, and the response was measured. This kinetic assay allows for the simultaneous screening and determination of the potency of multiple pharmacological modes of action, including agonist and potentiating activity. CHO-K1 cells that stably express muscarinic receptors were plated in growth medium without G418 and hygromycin at 15,000 cells / 20 μl / well in 384-well Greiner plates with black walls, treated with tissue culture (TC), and a transparent bottom (Greiner Bio-One). The cells were incubated overnight at 37 °C and 5% CO2. The following day, the calcium assay buffer (Hank's Balanced Saline Solution (HBSS), 20 mM HEPES, 2.5 mM Probenecid, 4.16 mM sodium bicarbonate (Sigma-Aldrich, St.A dilution plate was prepared for compounds, agonists, and Fluo-4-acetomethoxyester (Fluo-4-AM), a fluorescent calcium indicator dye. The compounds were serially diluted 1:3 on 10-point concentration response curves in DMSO using the Bravo Liquid Handler (Agilent, Santa Clara, CA), transferred to 384-well daughter plates using an Echo acoustic liquid handler (Beckman Coulter, Indianapolis, Indiana), and diluted in assay buffer to a final concentration of 2X. Agonist plates were prepared using acetylcholine (ACh, Sigma-Aldrich, St. Louis, MO) concentrations for EC20 and ECmax responses by dilution in assay buffer to a final concentration of 5X. The 2X (2.3 pM) dye solution was prepared by mixing a 2.3 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), the cells were washed with assay buffer three times to remove the medium. After the final wash, 20 μL of assay buffer remained in the cell plates. Immediately, 20 μL of 2X dye solution (1.15 pM final) was added to each well. Petition 870250094048, dated 10 / 14 / 2025, pp. 488 / 509 130 / 140 of the cell plate using a Multidrop Combi dispenser (Thermo Fisher, Waltham, MA). After the 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 μL of assay buffer in the cell plate.

[0355] The prepared compound, the agonist, and cell plates were placed within the Functional Drug Screening System uCell (FDSS uCell, Hamamatsu, Japan) to measure calcium flux. The triple addition protocol was used to measure Ca kinetics; compound, ACh at EC20, and ACh at EC80 are added in one order. Briefly, after establishing a fluorescence baseline for 2 seconds (excitation, 480 nm; emission, 530 nm), the first addition occurred by adding 20 µl of the test compound to the cells, and the response was measured for 140 seconds. Then, a second addition was made; 10 µl (5X) of an EC20 concentration of ACh agonist were added to the cells, and the cell response was measured for 125 seconds. Immediately, the third addition occurred by adding 12 µl (5X) of an EC80 concentration of ACh, and the cell response was measured for 90 seconds.The maximum acetylcholine-mediated response (ECmax) was measured by adding 1 mM ACh as a third addition to the control wells. The vehicle DMSO was added to the control wells in the first addition to evaluate the EC20, EC80, and ECmax responses of ACh. Calcium fluorescence was recorded as times the baseline fluorescence, and the raw data were normalized to the maximum response to the ACh agonist. Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization after compound addition. Positive allosteric modulator activity was analyzed as a concentration-dependent increase in acetylcholine response to EC20. Antagonist activity was... Petition 870250094048, dated 10 / 14 / 2025, pp. 489 / 509 131 / 140 analyzed as a concentration-dependent decrease in the acetylcholine response to ECso. Concentration-response curves were generated using a four-parameter logistic equation using GraphPad Prism (La Jolla, CA) or the Dotmatics software platform (Woburn, MA).

[0356] The assay described above was also operated in a second mode, in which a suitable fixed concentration of the compounds present was added to the cells after establishing a baseline of fluorescence for approximately 3 seconds, and the response in the cells was measured. 140 s later, the appropriate concentration of agonist was added, and the calcium response (local maximum-minimum response) was measured. ECso values ​​for the agonist in the presence of the test compound were determined by non-linear curve fitting. A decrease in the ECso value of the agonist with increasing concentrations of the compounds present (a leftward shift of the agonist concentration-response curve) is an indication of the degree of positive muscarinic allosteric modulation at a given concentration of the compound present.An increase in the ECso value of the agonist with increasing concentrations of the compounds present (a rightward shift of the agonist concentration-response curve) is an indication of the degree of muscarinic antagonism at a given concentration of the compound present. The second mode also indicates whether the compounds present also affect the maximum response of the muscarinic receptor to the agonists. C. Activity of compounds in a mAChR M4 cell-based assay

[0357] The compounds were synthesized as described above. The activity (ECso and Emax) was 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. Petition 870250094048, dated 10 / 14 / 2025, pp. 490 / 509 132 / 140 Table 3. Human M4 EC50 Number (nM) Emax (%)* 1 409 91 2 23 88 3 51 73 4 1264 59 5 707 97 6 70 95 7 727 71 8 4700 74 9 86 75 10 39 79 11 406 73 12 15 96 13 70 79 14 14 88 15 280 72 16 146 66 17 3510 70 Petition 870250094048, dated 10 / 14 / 2025, pp. 491 / 509 133 / 140 18 176 63 19 1166 79 20 9345 66 21 21 97 22 9 89 23 99 72 24 40 69 25 5 71 26 201 66 27 154 74 28 76 84 29 52 72 30 >10000 42 31 481 80 32 >10000 56 33 963 44 34 148 78 35 10 98 36 13 96 37 537 68 Petition 870250094048, dated 10 / 14 / 2025, pp. 492 / 509 134 / 140 38 31 95 * Maximum % of ACh at 30 μM. D. Functional evaluation of M4 activating compounds in a cellular cAMP assay. Cellular cAMP Gi HTRF assay.

[0358] Activation of the M4 receptor leads to inhibition of cAMP production by coupling to Gi / o proteins. To measure the level of cAMP inhibition by allosteric M4 modulators, a time-resolved homogeneous fluorescence cAMP assay (HTRF®) was employed using CHO cells that stably express human or mouse M4 receptors. The HTRF cAMP assay is a time-resolved resonance energy transfer competitive immunoassay (TR-FRET). Endogenous intracellular cAMP generated by the cells competes with europium cryptate-labeled cAMP (europium donor, 665 nm emission) for binding to a d2-labeled cAMP antibody (d2 acceptor, 620 nm emission). Thus, the fluorescence emission rate (665 nm / 620 nm) is inversely proportional to the amount of cAMP in the cells. Compound-mediated M4 activation results in an increase in the HTRF ratio (665 nm / 620 nm), indicative of a decrease in intracellular cAMP levels.To monitor agonist activity, compounds were added to M4 cells in the presence of an EC80 concentration of forskolin (adenylyl cyclase activator), which induces a submaximal level of intracellular cAMP. To assess potentiating activity, compounds were added to M4 cells with an EC80 concentration of forskolin in the presence of an EC20 concentration of acetylcholine. This functional assay allows the determination of the potency and efficacy of compounds that directly activate or potentiate the Gi / o-coupled M4 receptor.

[0359] The agonist and functional potentiating activities of the compounds were determined by measuring cAMP levels in stably expressing Chinese hamster ovary (CHO) cells. Petition 870250094048, dated 10 / 14 / 2025, pp. 493 / 509 135 / 140 muscarinic M4 receptors from humans or mice were incubated using a cAMP Gi / o HTRF kit. Cells were maintained in F12 medium containing 10% FBS, 20 mM HEPES, 1X antibiotic / antifungal, and G418 (500 μg / ml) in humidified incubators at 37°C in the presence of 5% CO2. The day before the assay, cells were trypsinized and resuspended in culture medium (growth medium without G418). Cells were placed in white, solid, flat-bottomed, 384-well plates at densities of 4000 and 6000 cells / 10 μl / well, for human and mouse M4 cells, respectively. The cell plates were centrifuged at 100x g for 1 min and immediately placed in an incubator at 37 °C in the presence of 5% CO2 overnight.

[0360] The following day, the reagents were freshly diluted to a 2X concentration in assay buffer using F12 basal medium or stimulation buffer. All assay buffers contained IBMX at 500 μM to block cAMP degradation. M4 activation by compounds was examined in cells stimulated with an ECsü concentration of forskolin to induce submaximal levels of intracellular cAMP. Forskolin ECsü concentrations were determined from forskolin concentration-response curves (CRCs) and ranged from 1.5 to 2.5 μM. Compounds (10 mM) were prepared in 100% DMSO and further serially diluted 1:3 or 1:5 in a 13-point CRC in DMSO using a Bravo Liquid Handler in a 384-well microplate.

[0361] The agonist assay mode was used to evaluate the capabilities of M4 compounds to directly activate M4 receptors in the absence of the agonist, acetylcholine. Compounds diluted in a 10-point serial, starting with 30 μM as the final concentration, were transferred to a compound plate using an Echo plate reformatting protocol. A 2X assay buffer containing Petition 870250094048, dated 10 / 14 / 2025, pp. 494 / 509 136 / 140 an ECso concentration of forskolin. The vehicle (1% DMSO) was added to the following control wells: baseline cAMP (without forskolin), maximum forskolin, and forskolin ECso. 10 µl / well of the prepared 2X assay buffer were immediately added to the cell plates using a Bravo 384 well-tip liquid handler. The cell plates were immediately centrifuged for 30 seconds at 100 x e and incubated at 37 °C for 10 min with gentle shaking at 50 rpm. An acetylcholine CRC was also performed in the presence of an ECso concentration of forskolin to determine the concentrations of acetylcholine inducing maximum (ECmax) and submaximal (EC20) cAMP inhibition, in order to prepare the subsequent enhancer mode assay.

[0362] In enhancer assay mode, compounds diluted in a 10-point series, starting with 1.1 μM as the final concentration, were transferred to a compound plate using an Echo plate reformatting protocol. A 2X assay buffer containing an ECso concentration of forskolin and an EC20 concentration of acetylcholine was added to the compound plate. The vehicle (1% DMSO) was added to the following: (1) for forskolin control wells - baseline cAMP (no forskolin), maximum forskolin, and forskolin ECso, (2) for agonist control wells containing forskolin ECso - baseline (no agonist) and acetylcholine EC20 and ECmax. 10 ql / well of the prepared 2X assay buffer were immediately added to the cell plates using a Bravo 384 well-tip liquid handler. The cell plates were immediately centrifuged for 30 seconds at 100 x e and incubated at 37 °C for 10 min with gentle shaking at 50 rpm.During the 10-minute incubation period, the cAMP Eu-cryptate donor (20X) and the anti-cAMP d2 antibody acceptor (20X) were diluted in lysis / detection buffer in separate tubes. Immediately after incubation, cells were lysed by the sequential addition of 10 µl / well of cAMP Eu-cryptate solution and 10. Petition 870250094048, dated 10 / 14 / 2025, pp. 495 / 509 137 / 140 μL / well of anti-cAMP d2 antibody solution. Cell plates were immediately centrifuged for 30 seconds at 100x g and incubated for 60 minutes at 25 °C with gentle shaking at 50 rpm. Immediately after detection incubation, TR-FRET signals were measured in two channels, 665 and 620 nm, using an EnVision plate reader (Perkin Elmer). All emission rates (665 / 620) were normalized to % acetylcholine max. Individual CRCs were generated using a four-parameter logistic equation using GraphPad Prism (La Jolla, CA), and EC50 was extracted from the fit, and the maximum response (% ACh max) was determined: top — bottom y = bottom + 1 + lo^ogECSO—AjHillslope 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 slope of the curve; and EC50 is the molar concentration of the compound required to generate a response between top and bottom. Table 4. Materials and Equipment Item Manufacturer Cat. No. Cell culture medium F12 Thermo Fisher 11765054 Fetal bovine serum Thermo Fisher 16140089 Antibiotic / Antifungal Thermo Fisher 15240062 HEPES 1 M (2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid) Thermo Fisher 15630080 Sulfate G418 Thermo Fisher 10131027 Petition 870250094048, dated 10 / 14 / 2025, pp. 496 / 509 138 / 140 TrypLE Express Thermo Fisher 12605036 cAMP Assay Kit HTRF cAMP-Gi Cisbio 62AM9PE C CELLSTAR, 384-well plate, TC-treated, white, solid flat bottom Greiner 781080 IBMX (3-isobutyl-1-methylxanthine) Sigma I5879 Forskolin Sigma F6886 Acetylcholine Chloride Sigma A6625 DMSO (Dimethyl Sulfoxide) Sigma D8418 Echo 650 Liquid Handler Beckman 001-16079 Bravo Liquid Handler Agilent G5563AA EnVision Plate Reader Perkin Elmer 2105-0011 E. Secondary Pharmacology In vitro

[0363] Compound 2 was tested using Eurofins LeadProfilingScreen®, which detects off-target activity and determines relative selectivity. The screening included 68 primary molecular targets, including several CNS targets recommended by the EMEA (European Medicines Evaluation Agency) for assessing drug dependence potential. Compound 70 exhibited < 50% inhibition of each target on LeadProfilingScreen®, at 10 μM (binding) with the exception of human muscarinic 2 (58% inhibition at 10 μM). F. Drug Metabolism and Pharmacokinetics in vitro and in vivo

[0364] Compound 2 was tested in several in vitro assays to investigate both metabolism and pharmacokinetics. These assays can be performed according to methods known as Petition 870250094048, dated 10 / 14 / 2025, pp. 497 / 509 139 / 140 generally 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 studies include those listed in the following table. Table 5 Assay Result MDCK-MDR1 ER 2.8 (Papp A> B: 13.8 x 10-6 cm / s) Rat Fu (plasma) 0.117 Dog Fu (plasma) 0.054 Human Fu (plasma) 0.037 Rat Fu (brain) 0.027 Rat CLint (ml / min / kg) 83 Dog CLint (ml / min / kg) 100 Human CLint (ml / min / kg) 6 P450 3A4 IC50 (μM) 5 P450 2D6 IC50 (μM) 10 P450 2C9 IC50 (μM) >30 P450 1A2 IC50 (μM) 5

[0365] Compound 2 was tested in several in vivo assays and the pharmacokinetic parameters listed in the following table can be determined from pharmacokinetic studies in rats or dogs, 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 Trial Result Rat CLp (ml / min / kg) 24.2 Dog CLp (ml / min / kg) 52.9 Petition 870250094048, dated 10 / 14 / 2025, pp. 498 / 509 140 / 140 Rat Vss (l / kg) 0.5 Dog Vss (l / kg) 0.9 Elimination t1 / 2 in Rat (h) 0.4 Elimination t1 / 2 in Dog (h) 0.2 Oral F in Rat (3 mg / kg) 24% Rat brain: Plasma Kp 0.8 Rat brain: Plasma Kp,uu 0.2

[0366] It should be understood that the foregoing detailed description and the accompanying examples are merely illustrative and should not be considered as limitations to the scope of the invention, which is defined only by the appended claims and their equivalents.

[0367] Various alterations 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. Petition 870250094048, dated 10 / 14 / 2025, pp. 499 / 509

Claims

1 / 9 CLAIMS 1. Compound of formula (I), or a pharmaceutically acceptable salt thereof, (I) characterized in that: X1 is NR5, O or CR5AR5B; R2 is G2, -NR2aR2b, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, -OR2a, NR2aC(O)R2b, -C(O)OR2a, -C(O)NR2aR2b or hydrogen; R2a and R2b are independently hydrogen, C1-6 alkyl, C1-6 haloalkyl, G2 or -C1-3 alkylene-G2; G2, in each occurrence, is independently a 3- to 7-membered carbocyclyl, a 5- to 6-membered heteroaryl containing 1-4 heteroatoms, 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 by 1-5 substituents independently selected from the group consisting of halogen, cyano, C1-4-alkyl, C1-4-fluoroalkyl, oxo, -ORx, -N(Rx)2, C(O)Rx, -C(O)ORx, -C(O)N(Rx)2, -C1-6-alkylene-ORx, -C1-6-alkylene-N(Rx)2, G2a, and -C1-3-alkylene-G2a;Petition 870250094048, dated 10 / 14 / 2025, page 500 / 509 2 / 9 Rx, in each occurrence, is independently hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C1-5 cycloalkyl or -C1-3 alkylene-C3-6 cycloalkyl; G2a is a C1-5 cycloalkyl; R4A and R4B are independently hydrogen, C1-4 alkyl, C1-4 cycloalkyl or -C1-5 alkylene-OH; or R4A and R4B together with the carbon to which they are attached form a C3-6 cycloalkyl; R5 is hydrogen, C1-5 alkyl, C1-5 fluoroalkyl, -C1-5 alkylene-Ry, -C1-5 fluoroalkylene-Ry, G5 or -C1-5 alkylene-G5; R5A and R5B are independently hydrogen, halogen, C1-4 alkyl, C1-4 fluoroalkyl, or -C1-4 alkylene-OH; Ry is -OR5a, -N(R5a)2, -C(O)R5a, -C(O)OR5a, or -C(O)N(R5a)2; R5a, in each occurrence, is independently hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, Cs-4 cycloalkyl, or -C1-3 alkylene-Cs-4 cycloalkyl;G5 is a phenyl, a 4- to 8-membered heterocyclyl containing i-2 heteroatoms, a 5- to 8-membered heteroaryl containing i-4 heteroatoms, or a Cs-cycloalkyl, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G5 is optionally substituted by i-4 substituents independently selected from the group consisting of halogen, cyano, C1-4 alkyl, C1-2 fluoroalkyl, -C1-4 alkyl, OH, and oxo; Re is hydrogen, halogen, cyano, C1-4 alkyl, C1-4 fluoroalkyl, C2-4 alkenyl, -ORea, -N(Rea)2, -C1-5 alkylene-ORea, or Cs-4 cycloalkyl; Rea, in each occurrence, is independently hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 cycloalkyl, or C1-5 alkylene-C1-4 cycloalkyl;wherein, alternatively, two Rea, together with the nitrogen to which they are attached, form a 4- to 8-membered heterocyclic ring containing the nitrogen attached to Rea and optionally an additional heteroatom that is O, N or S, wherein the heterocyclic ring is optionally substituted by i-4 substituents independently selected from the group consisting of halogen, C1-2 alkyl and C1-2 fluoroalkyl; R7 is C1-4 alkyl, hydrogen, halogen, cyano, C1-4 fluoroalkyl, C2-4 alkenyl, -OR7a, -C1-3 alkylene-OR7a, CO2R7a, COR7a or C3-6 cycloalkyl; R7a is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl or -C13 alkylene-C3-4 cycloalkyl; R8, in each occurrence, is independently halogen, C1-4 alkyl, C14 fluoroalkyl or C3-4 cycloalkyl; en is 0, 1, 2, 3 or 4;wherein each cycloalkyl group in Rx, G2a, R6, R6a, R7, R7a and R8 is unsubstituted or substituted by 1-4 substituents independently selected from C1-4 alkyl and halogen.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that R2 is G2, -NR2aR2b, halogen, cyano, C1-6-alkyl, C1-6-haloalkyl, -OR2a, -C(O)OR2a, C(O)NR2aR2b, or hydrogen.

3. Compound according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that R2 is G2.

4. A compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, characterized in that G2 is the optionally substituted 3- to 7-membered carbocyclyl.

5. A compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, characterized in that G2 is the optionally substituted 5- to 6-membered heteroaryl. Petition 870250094048, dated 10 / 14 / 2025, pp. 502-509 4 / 9 6. A compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, characterized in that G2 is , , , , 7. Compound according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that R2 is -NR2aR2b.

8. Compound according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that R2 is C1-6 alkyl.

9. Compound according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that R2 is a halogen.

10. Compound according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that R2 is hydrogen.

11. Compound according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that R2 is -C(O)OR2a.

12. Compound according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that R2 is -C(O)NR2aR2b.

13. Compound according to any one of claims 1, 2, 7 or 11-12, or a pharmaceutically acceptable salt thereof, characterized in that R2a is hydrogen or C1-6 alkyl.

14. Compound, according to any one of claims 1, 2, 7 or 12-13, or a pharmaceutically acceptable salt of Petition 870250094048, dated 10 / 14 / 2025, pp. 503 / 509 5 / 9 the same, characterized in that R2b is hydrogen.

15. A compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, characterized in that R4A and R4B are hydrogen.

16. Compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, characterized in that X1 is NR5.

17. Compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, characterized in that R5 is hydrogen, C1-6 alkyl, G5 or -C13-alkylene-G5.

18. Compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, characterized in that X1 is O.

19. A compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, characterized in that X1 is CR5AR5B.

20. A compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, characterized in that R6 is hydrogen.

21. A compound according to any one of claims 1-20, or a pharmaceutically acceptable salt thereof, characterized in that R7 is C1-4 alkyl, halogen, cyano or C36 cycloalkyl.

22. A compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, characterized in that n is 0.

23. Compound according to claim 1, characterized by being selected from the group consisting of: Petition 870250094048, dated 10 / 14 / 2025, page 504 / 509 6 / 9 2-(6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-methyl-6,7-dihydro-5Hpyrrolo[3,4-b]pyridin-5-one; 2-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-methyl-6,7-dihydro-5Hpyrrolo[3,4-b]pyridin-5-one; 3-methyl-2-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 3-methyl-2-(2-(thiophen-2-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; ethyl 5-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]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(4H)-yl)-6,7-dihydro-5Hpyrrolo[3,4-b]pyridin-5-one;3-methyl-2-(2-(1-methyl-1 H-pyrazol-5-yl)-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)yl)-6,7-di-hydro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 2-(2-amino-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3-methyl-6,7-di-hydro5 H-pyrrole[3,4-b ]pyridine-5-one; 2-(2-chloro-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3-methyl-6,7-di-hydro-5 Hpyrrole[3,4-b ]pyridin-5-one; 2-(2-(2,2-dimethylcyclopropyl)-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3methyl-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 2-(2-(tert-butyl)-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3-methyl-6,7-dihydro-5 H-pyrrolo[3,4-b ]pyridine-5-one; 2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3,6-dimethyl-6,7-dihydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 3,6-dimethyl-2-(2-(1-methylcyclopropyl)-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H) il)-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 6-cyclopropyl-2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3methyl-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one;Petition 870250094048, dated 10 / 14 / 2025, p. 505 / 509 7 / 9 6-cyclopropyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-di-hydrothiazolo[5,4c ]pyridine-5(4 H)-yl)-6,7-di-hydro-5 H-pyrrole[3,4-b ];pyridine-one 6-cyclopentyl-2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3methyl-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 6-cyclopentyl-3-methyl-2-(2-(1-methylcyclopropyl)-6,7-di-hydrothiazolo[5,4c ]pyridine-5(4 H)-yl)-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridin-5-one; 2-(2-(2,2-dimethylcyclopropyl)-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3,6dimethyl-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridin-5-one; 6-cyclopropyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-di-hydrothiazolo[5,4-c ]pyridine5(4 H)-yl)-3-methyl-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 6-cyclopentyl-2-(2-(2,2-dimethylcyclopropyl)-6,7-di-hydrothiazolo[5,4-c ]pyridine5(4 H)-yl)-3-methyl-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one;2-(2-cyclobutyl-6,7-di-hydrothiazolo[5,4-c ]pyridin-5(4 H )-yl)-3,6-dimethyl-6,7-dihydro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 2-(2-cyclobutyl-6,7-di-hydrothiazolo[5,4-c ]pyridin-5(4 H )-yl)-3-methylfuro[3,4b]pyridin-5(7H)-one; 2-(2-(1-fluorocyclopropyl)-6,7-di-hydrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3,6dimethyl-6,7-di-hydro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 3-methyl-2-(2-(1-methylcyclopropyl)-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H) yl)furo[3,4-b ]pyridin-5(7 H)-one; 2-(2-cyclobutyl-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H )-yl)-3-methyl-6,7-di-hidro5 H-pyrrolo[3,4-b ]pyridin-5-one; 3-cyclopropyl-2-(2-cyclopropyl-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-6methyl-6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-5-one; 2-(2-cyclopropyl-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-6-methyl-5-oxo-6,7di-hidro-5 H-pyrrolo[3,4-b ]pyridine-3-carbonitrila; 2-(2-(1-fluorocyclopropyl)-6,7-di-hidrothiazolo[5,4-c ]pyridin-5(4 H)-yl)-3-methyl6,7-di-hidro-5 H-pyrrolo[3,4-b ]pyridin-5-one;Petition 870250094048, dated 10 / 14 / 2025, p. 506 / 509 8 / 9 2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-6-methyl-3-vinyl-6,7di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-6-methyl-3-(prop-1en-2-yl)-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridine-5-one; 2-(2-cyclopropyl-6,7-di-hydrothiazole[5,4-c ]pyridine-5(4 H)-yl)-6-methyl-5-oxo-6,7di-hydro-5 H-pyrrole[3,4-b ]pyridine-3-methyl carboxylate; 5-(3-methyl-5-oxo-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridin-2-yl)-4,5,6,7-tetrahydrothiazole[5,4-c ]pyridine-2-carboxamide; 2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-6-(2,4dimethoxybenzyl)-3-ethyl-6,7-di-hydro-5 H-pyrrole[3,4-b ]pyridin-5-one; 2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3-ethyl-6,7-di-hydro5 H-pyrrole[3,4-b ]pyridine-5-one; 2-(2-cyclopropyl-6,7-di-hydrothiazolo[5,4-c ]pyridine-5(4 H)-yl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-5-one;2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,4dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-4-methyl6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 2-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3,4,6trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.

24. Pharmaceutical composition characterized in that it comprises the compound, as defined in any one of claims 1-23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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