Thiazolopyridine derivatives as positive allosteric modulators of muscarinic acetylcholine receptor M4

Abstract

6, 7-dihydrothiazolo [5, 4-c] pyridines substituted in position 5 by a heterocyclic ring are positive allosteric modulators of muscarinic acetylcholine receptor M4 (mAChR M4) and are useful in the treatment of neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction.

Description

[0001] Cross-references to related applications This application claims priority to U.S. Provisional Application No. 63 / 496,808, filed April 18, 2023, and U.S. Provisional Application No. 63 / 610,205, filed December 14, 2023, each of which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure relates to compounds, compositions, and methods for treating neurological and mental disorders associated with muscarinic acetylcholine receptor dysfunction. Background Technology

[0003] Cholinergic neurotransmission involves the activation of nicotinic acetylcholine receptors (nAChR) or muscarinic acetylcholine receptors (mAChR) via the binding of the endogenous ortho-agonist acetylcholine (ACh). Conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by a decrease in acetylcholine levels in the brain. This is thought to be a result of the degeneration of basal forebrain cholinergic neurons, which extensively innervate multiple brain regions, including the associative cortex and hippocampus, which play key roles in higher processes. Clinical data support that cholinergic dysfunction contributes to cognitive deficits in patients with schizophrenia. Efforts to increase acetylcholine levels have focused on increasing choline levels (the precursor to acetylcholine synthesis) and blocking acetylcholinesterase (AChE) (the enzyme that metabolizes acetylcholine). Therefore, acetylcholinesterase (AChE) inhibitors, which inhibit the hydrolysis of ACh, have been approved in the United States for palliative treatment of cognitive deficits in patients with AD, but not for disease-modifying therapy.

[0004] Attempts to enhance central cholinergic function through the administration of choline or phosphatidylcholine have not been successful. AChE inhibitors have shown therapeutic efficacy, but frequent cholinergic side effects, including abdominal cramps, nausea, vomiting, and diarrhea, have been observed due to peripheral acetylcholine stimulation. These gastrointestinal side effects have been observed in approximately one-third of treated patients. Furthermore, some AChE inhibitors, such as tacrine, have been found to cause significant hepatotoxicity, with elevated liver transaminases observed in approximately 30% of patients. The side effects of AChE inhibitors have severely limited their clinical application. An alternative pharmacological approach to targeting cholinergic dysfunction is to activate mAChR, which is widely expressed throughout the body.

[0005] mAChR is a member of the G protein-coupled receptor (GPCR) family A, and includes five subtypes, named M1-M5. Subtypes M1, M3, and M5 are primarily associated with G... q It couples with and activates phospholipase C, while the M2 and M4 isoforms are mainly associated with G. i / oand related effector systems. The five different mAChR subtypes have been identified in the mammalian central nervous system, where they are ubiquitous and differentially expressed. M1-M5 have different roles in cognitive, sensory, motor, and autonomic functions. Thus, without wishing to be bound by a particular theory, it is believed that selective agonists of mAChR subtypes involved in the processes that modulate cognitive function can prove to be superior therapies for the treatment of psychoses, schizophrenia, and related disorders. Muscarinic M4 receptors have been shown to have an important role in cognitive processes and are believed to have an important role in the pathophysiology of psychotic disorders, including schizophrenia.

[0006] There is evidence that the most prominent side effects of AChE inhibitors and other cholinergic agents are mediated through the activation of peripheral M2 and M3 mAChRs, and include bradycardia, gastrointestinal upset, excessive salivation, and sweating. In contrast, M4 is believed to be the most likely subtype to mediate the role of muscarinic acetylcholine receptor dysfunction in psychotic disorders, including schizophrenia, cognitive disorders, and neuropathic pain. Thus, a great deal of effort has been focused on developing selective M4 agonists for the treatment of these disorders. Unfortunately, these efforts have largely been unsuccessful due to the inability to develop compounds with high selectivity for mAChR M4. Thus, mAChR agonists that have been tested in clinical studies induce a range of side effects through the activation of peripheral mAChRs. To fully understand the physiological roles of individual mAChR subtypes and further explore the therapeutic utility of mAChR ligands in psychoses, including schizophrenia, cognitive disorders, and other disorders, it can be important to develop compounds that are highly selective activators of mAChR M4 and other individual mAChR subtypes.

[0007] Previous attempts to develop agonists with high selectivity for individual mAChR subtypes have failed because the orthosteric ACh binding site is highly conserved. To circumvent the problems associated with targeting the highly conserved orthosteric ACh binding site, it is believed that compounds that act at allosteric sites on mAChRs were developed, which are remote from the orthosteric site and are less highly conserved. This approach has proven very successful in developing selective ligands for a variety of GPCR subtypes. In the case of mAChRs, the primary goal 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 at a site different from the orthosteric site to directly activate the receptor in the absence of ACh, and positive allosteric modulators (PAMs), which do not directly activate the receptor but enhance the activation of the receptor by the endogenous orthosteric agonist, ACh. Furthermore, a single molecule can have both allosteric potentiator and allosteric agonist activity.

[0008] More recently, muscarinic agonists, including xanomeline, have been shown in animal models to have similar activity to known antipsychotic drugs, but without causing catalepsy (Bymaster et al, Eur. J. Pharmacol. [European Journal of Pharmacology] 1998, 356, 109, Bymaster et al, Life Sci. [Life Sciences] 1999, 64, 527; Shannon et al, J. Pharmacol. Exp. Ther. [Journal of Pharmacology and Experimental Therapeutics] 1999, 290, 901; Shannon et al, Schizophrenia Res. [Schizophrenia Research] 2000, 42, 249). In addition, xanomeline has been shown to reduce psychotic behavioral symptoms such as delusions, suspiciousness, sound blasts, and hallucinations in Alzheimer's patients (Bodick et al, Arch. Neurol. [Archives of Neurology] 1997, 54, 465), however, side effects (e.g., gastrointestinal effects) associated with treatment have severely limited the clinical utility of this compound.

[0009] Despite advances in the study of muscarinic acetylcholine receptors, there remains a need for potent, efficacious, and selective M4 mAChR activators, and compounds effective in treating neurological and psychiatric disorders related to cholinergic activity and diseases involving muscarinic M4 receptors. SUMMARY

[0010] In one aspect, disclosed are compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 is or ; X 1 is N or CR 1a ; R 1a is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or C 1-4 fluoroalkyl; X 2 is N or CR 1b ; R 1b is cyano, halogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or hydrogen; R 1c and R 1e are hydrogen, C 1-4 alkyl, halogen, C1-4 fluoroalkyl, C 3-6 cycloalkyl, or –OC 1-4 alkyl; R 1d and R 1f It is hydrogen, C 1-4 Alkyl, halogen, C 1-4 fluoroalkyl, or C 3-6 cycloalkyl; Alternatively, R 1a and R 1b Together with the atoms to which they are attached, or R 1c and R 1d Together with their respective attached atoms, they form optionally substituted 6-membered aromatic hydrocarbons, 5- to 6-membered heteroaromatic hydrocarbons containing 1 to 3 heteroatoms, 5- to 7-membered heterocycles containing 1 heteroatom, or 5- to 7-membered carbocyclic rings, wherein these heteroatoms are independently selected from the group consisting of N, O, and S, wherein the optional substitution is 1 to 3 optional substituents independently selected from the group consisting of: C 1-4 Alkyl, halogen, –OC 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl and C 1-2 Alkylene-C 3-4 cycloalkyl; G 1 It is a 5- to 6-membered aromatic or partially unsaturated heterocyclic system containing 1-3 nitrogen atoms, wherein Z 1 Is it N or C, Z? 2 It is N or C, and Z 1 and Z 2 Not both N; R 10 Choose from the following groups: C 1-4 Alkyl, C 1-4 Fluoroalkyl, halogen, C 3-4 cycloalkyl, C 1-2 Alkylene-C 3-4 Cycloalkyl, –C(O)OC 1-4 Alkyl groups and –C(O)NR a R b ; R 11 Each time it appears, independently select from the following groups: C 1-6 Alkyl, C 1-6 Fluoroalkyl, halogen, –C 1-6 Alkylene–R y –C 1-6 Fluoride-R y G 11 、or –C 1-3 Alkylene–G 11; R 12 is oxo; m is 0 or 1; n is 0, 1, or 2; p is 0 or 1; R a is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; R b is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, G 10 , or –C 1-3 alkylene–G 10 ; wherein alternatively, R a and R b , together with the nitrogen to which they are attached, form a 4- to 10-membered heterocyclic ring containing the nitrogen to which R a and R b are attached and optionally containing 1-2 additional heteroatoms that are independently O, N, or S, which heterocyclic ring is optionally substituted with 1-3 first substituents selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, –OR 50 , –N(R 50 )2, G 10a , and –C 1-3 alkylene–G 10a ; and is optionally further substituted with 1-3 substituents that are independently halogen or C 1-4 alkyl; G 10 is phenyl, 5- to 6-membered heteroaryl containing 1-3 heteroatoms, 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, or C 3-6 cycloalkyl, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G 10 is optionally substituted with 1-3 first substituents selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, –OR 50 , –N(R 50 )2, G 10a , and –C 1-3 alkylene–G 10a ; and is optionally further substituted with 1-3 substituents that are independently halogen or C 1-4 alkyl; G10a is phenyl, 5- to 6-membered heteroaryl containing 1-3 heteroatoms, 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, or 3- to 8-membered carbocyclyl, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G 10a is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, OH, -OC 1-4 alkyl, -OC 1-4 fluoroalkyl, C 3-4 cycloalkyl, and -C 1-3 alkylene-C 3-4 cycloalkyl; R 50 is independently at each occurrence hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, or -C 1-3 alkylene-C 3-6 cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, and C 1-4 fluoroalkyl; R y is -OR c , -N(R c )2, -C(O)R c , -C(O)OR c , or -C(O)N(R c )2; R c is independently at each occurrence hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or -C 1-3 alkylene-C 3-4 cycloalkyl, wherein alternatively, two R c together with the nitrogen to which they are attached form a 4- to 8-membered heterocyclic ring containing the nitrogen to which R c is attached and optionally containing 1 additional heteroatom that is O, N, or S, which heterocyclic ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-2 alkyl, and C 1-2 fluoroalkyl; G 11 is phenyl, 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, 5- to 6-membered heteroaryl containing 1-4 heteroatoms, or C 3-6cycloalkyl, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G 11 optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, halo, cyano, oxo, -OC 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, and -C 1-2 alkylene-C 3-4 cycloalkyl; R 2 is G 2 , -NR 2a R 2b , halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -OR 2a , -NR 2a C(O)R 2b , -C(O)OR 2a , -C(O)NR 2a R 2b , or hydrogen; R 2a and R 2b are independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, G 2 , or -C 1-3 alkylene-G 2 , provided that R 2 is not -N(CH3)2; G 2 is independently in each occurrence 5- to 6-membered heteroaryl containing 1-4 heteroatoms, phenyl, 4- to 7-membered heterocyclyl containing 1-2 heteroatoms, or 3- to 7-membered carbocyclyl, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G 2 optionally substituted with 1-4 substituents independently selected from the group consisting of halo, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, -OR x , -N(R x )2, -C(O)R x , -C(O)OR x , -C(O)N(R x )2, -C 1-6 alkylene-OR x , -C 1-6 alkylene-N(R x )2, G 2a , and -C 1-3 alkylene-G 2asubstituted with 1-4 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, and C 1-4 fluoroalkyl; R x independently at each occurrence is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, or -C 1-3 alkylene-C 3-6 cycloalkyl; G 2a is C 3-6 cycloalkyl; R 8 independently at each occurrence is halogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or C 3-4 cycloalkyl; and o is 0, 1, 2, 3, or 4; wherein G 2a and R 8 each cycloalkyl at each occurrence is independently unsubstituted or substituted with 1-4 substituents independently selected from C 1-4 alkyl (e.g., methyl) and halogen (e.g., fluoro); provided that the compound is not: 4,5,6,7-tetrahydro-5-(2-pyridyl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-tetrahydro-5-(4-pyrimidinyl)-thiazolo[5,4-c]pyridin-2-amine; 5-(6-chloro-2-cyclopropyl-5-methyl-4-pyrimidinyl)-4,5,6,7-tetrahydro-2-methyl- thiazolo[5,4-c]pyridine; 2-[2-(4-ethyl-piperazin-1-yl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-quinoline; 4,5,6,7-tetrahydro-5-[5-(trifluoromethyl)-thiazolo[5,4- c ]pyridin-2-amine; N-(2-aminophenyl)-4,5,6,7-tetrahydro-5-[5-(trifluoromethyl)-2-pyridyl]- thiazolo[5,4- c ]pyridine-2-carboxamide; 5-(2,5-dimethyloxazolo[5,4- d ]pyrimidin-7-yl)-4,5,6,7-tetrahydro-thiazolo[5,4-c ]pyridin-2-amine; 5-(2-cyclopentyl-6,7-dihydro-5 H -pyrrolo[3,4- d ]pyrimidin-4-yl)-4,5,6,7-tetrahydro- thiazolo[5,4- c ]pyridin-2-amine; 5-(5,6-dimethylthieno[2,3- d ]pyrimidin-4-yl)-4,5,6,7-tetrahydro- thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-tetrahydro-5-thieno[2,3- d ]pyrimidin-4-yl-thiazolo[5,4- c ]pyridin-2-amine; 5-[2,6-bis(1,1-dimethylethyl)-4-pyrimidinyl]-4,5,6,7-tetrahydro- thiazolo[5,4- c ]pyridine; 7-(6,7-dihydrothiazolo[5,4-c]pyridin-5(4 H )-yl)-2-(trifluoromethyl)-thiazolo[5,4- d ]pyrimidine; 4,5,6,7-tetrahydro-5-(2-pyridinyl)-thiazolo[5,4-c]pyridine-2-carboxylic acid or a salt thereof; 4-(6,7-dihydrothiazolo[5,4-c]pyridin-5(4 H )-yl)-[1,2,5]thiadiazolo[3,4- c ]pyridine; 4,5,6,7-tetrahydro-5-[6-methyl-2-(1-methylpropyl)-4-pyrimidinyl]- thiazolo[5,4- c ]pyridin-2-amine; 5-(4-chloro-2-pyridinyl)-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine; 5-[2-(1,1-dimethylethyl)-4-pyrimidinyl]-4,5,6,7-tetrahydro- thiazolo[5,4- c ]pyridin-2-amine; 5-[6-(1,1-dimethylethyl)-1-methyl-1H-pyrrolo[3,4- d ]pyrimidin-4-yl]-4,5,6,7-tetrahydro- thiazolo[5,4- c ]pyridin-2-amine; 5-(2-ethyl-7-methylthieno[3,2- d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-thiazolyl[5,4- c ]Pyridine; 4,5,6,7-Tetrahydro-5-(2-methyl-7-) H -pyrrolo[2,3- d ]pyrimidin-4-yl)-thiazolyl[5,4- c ]Pyridine-2-amine; 5-(6-cyclopentyl-1-methyl-1-yl) H -pyrazolo[3,4- d ]pyrimidin-4-yl)-4,5,6,7-tetrahydro-thiazolyl[5,4- c ]Pyridine-2-amine; 4,5,6,7-Tetrahydro-5-[3-(trifluoromethyl)-1,2,4-triazolo[4,3- b ]pyridazine-6-yl]-thiazolyl[5,4- c ]Pyridine-2-amine; 6-(6,7-dihydrothiazo[5,4-c]pyridine-5(4) H )-yl)-2-(trifluoromethyl)-9 H -purine; 5-(2,6-Dicyclopropyl-4-pyrimidinyl)-4,5,6,7-tetrahydro-thiazo[5,4- c ]Pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(5-iodo-2-pyridyl)-thiazo[5,4- c ]Pyridine; 4,5,6,7-Tetrahydro-5-(7-methylthiopheno[3,2- d ]pyrimidin-4-yl)-thiazolyl[5,4- c ]Pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(2-methyl-4-pyrimidinyl)-thiazo[5,4- c ]Pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(4-quinazolinyl)-thiazolyl[5,4- c ]Pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-thiazolyl[5,4- c ]Pyridine; 4,5,6,7-Tetrahydro-5-(3-pyridazinyl)-thiazo[5,4- c ]Pyridine-2-amine; 4,5,6,7-Tetrahydro-5-[6-methyl-2-(1-methylethyl)-4-pyrimidinyl]- thiazolo[5,4- c ]pyridin-2-amine; 5-(6-Ethyl-5-fluoro-4-pyrimidinyl)-4,5,6,7-thiazolo[5,4- c ]pyridin-2-amine; 5-(7-Chloro-4-quinazolinyl)-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridin-2-amine; 5-(5-Bromo-2-pyridinyl)-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridine; 4,5,6,7-Tetrahydro-5-(2-methylthieno[3,2- d ]pyrimidin-4-yl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-Tetrahydro-5-(1 H -pyrrolo[2,3- b ]pyridin-6-yl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-Tetrahydro-5-(2-methyl-6-propyl-4-pyrimidinyl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-Tetrahydro-5-(5-methylthieno[2,3- d ]pyrimidin-4-yl)-thiazolo[5,4- c ]pyridin-2-amine; 5-(6-Cyclohexyl-4-pyrimidinyl)-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridine; 4,5,6,7-Tetrahydro-5-[6-methyl-2-(1-methylpropyl)-4-pyrimidinyl]- thiazolo[5,4- c ]pyridine; or 5-(6-Bromo-4-quinazolinyl)-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridin-2-amine.

[0011] In another aspect, the present application provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] ​​​​​​​​​​​​​​Another aspect provides a method of treating a neurological and / or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or composition thereof.

[0013] Another aspect provides a compound of Formula (I), or a pharmaceutically acceptable salt or composition thereof, for use in treating a neurological and / or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal.

[0014] Another aspect provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt or composition thereof, in the manufacture of a medicament for treating a neurological and / or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal.

[0015] In another aspect, the present application provides a kit comprising a compound of Formula (I), or a pharmaceutically acceptable salt or composition thereof, and instructions for use. BRIEF DESCRIPTION OF DRAWINGS

[0016] The figure shows the effect of compound 70 in an amphetamine-induced locomotor assay. DETAILED DESCRIPTION

[0017] Disclosed herein are positive allosteric modulators (i.e., potentiators) of the muscarinic acetylcholine receptor M4 (mAChR M4), methods of making the same, pharmaceutical compositions comprising the same, and methods of using the same to treat neurological and psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. The compounds include naphthyridine-substituted pyridazine compounds.

[0018] The human muscarinic acetylcholine receptor M4 (mAChR M4) is a 479 amino acid protein encoded by the CHRM4 gene. The molecular weight of the unglycosylated protein is about 54 kDa, and it is a transmembrane GPCR. As noted above, mAChR M4 is a member of the GPCR A class or rhodopsin-like GPCRs, which are characterized by structural features similar to rhodopsin, such as seven transmembrane segments. The N-terminus of the muscarinic acetylcholine receptor is extracellular, facing the membrane surface, and the C-terminus is located in the cytoplasmic surface.

[0019] Previous attempts to develop agonists with high selectivity for individual mAChR subtypes have failed because the orthosteric ACh binding site is highly conserved. To circumvent the problems associated with targeting the highly conserved orthosteric ACh binding site, it is believed that compounds were developed that act at allosteric sites on mAChRs that are distal from the orthosteric site and are less highly conserved. Without wishing to be bound by a particular theory, it is believed that the disclosed compounds and products of the disclosed methods bind to allosteric sites that are different from the orthosteric binding site.

[0020] 1. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the application belongs. In the case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present application. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0021] As used herein, the terms "comprise(s)," "include(s)," "having," "has," "can," "contain(s)," and variants thereof, are open-ended transitional phrases, terms, or words that are intended to encompass the possibility that there are additional items, for example, acts, or structures, in addition to the ones explicitly recited. Unless otherwise explicitly stated, the singular forms "a," "an," and "the" include plural referents. The present disclosure also contemplates other embodiments "comprising," "consisting of," and "consisting essentially of," the embodiments or elements presented herein, whether explicitly set forth or not.

[0022] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., it includes the degree of error associated with the measurement of the particular quantity). The modifier "about" should also be considered in its normal sense as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "about 2 to about 4" also discloses the range "2 to 4." The term "about" can mean plus or minus 10% of the indicated number. For example, "about 10%" can mean a range of 9% to 11%, and "about 1" can mean 0.9-1.1. Other meanings of "about" can be apparent from the context, such as rounding, thus, for example, "about 1" can also mean 0.5 to 1.4.

[0023] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional group terms are generally defined as in Organic Chemistry [Organic Chemistry], Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, [March’s Advanced Organic Chemistry], 5thEd., John Wiley & Sons, Inc., New York, 2001; Larock, [Comprehensive Organic Transformations], VCH Publishers, Inc., New York, 1989; Carruthers, [Some Modern Methods of Organic Synthesis], 3rdEd., Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. March's Advanced Organic Chemistry Comprehensive Organic Transformations [Organic Chemistry], Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, [March’s Advanced Organic Chemistry], 5thEd., John Wiley & Sons, Inc., New York, 2001; Larock, [Comprehensive Organic Transformations], VCH Publishers, Inc., New York, 1989; Carruthers, [Some Modern Methods of Organic Synthesis], 3rdEd., Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference. Some Modern Methods of Organic Synthesis

[0024] As used herein, the term “alkoxy” refers to an alkyl group as defined herein attached through an oxygen atom to the parent molecular moiety. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propyloxy, 2-propyloxy, butoxy, and t-butoxy.

[0025] As used herein, the term “alkyl” means a straight or branched chain saturated hydrocarbon chain. The term “lower alkyl” or “C 1-6 alkyl” means a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms. The term “C 1-4 alkyl” means a straight or branched chain saturated hydrocarbon containing 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to: methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0026] As used herein, the term “alkenyl” means a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond.

[0027] ​​As used herein, the term "alkoxyalkyl" refers to an alkoxy group as defined herein attached to the parent molecular moiety through an alkyl group as defined herein.

[0028] As used herein, the term "alkoxyalkyl" refers to an alkoxy group as defined herein attached to the parent molecular moiety through an alkyl group as defined herein.

[0029] As used herein, the term "alkylene" refers to a divalent group derived from a straight-chain or branched saturated hydrocarbon (e.g., a straight-chain or branched saturated hydrocarbon having 1 to 6 carbon atoms). Representative examples of alkylene groups include, but are not limited to: -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH2CH2-, -CH2CH(CH3)CH2CH2-, and -CH2CH2CH2CH2CH2-.

[0030] As used herein, the term "alkylamino" means at least one alkyl group as defined herein attached to the parent molecular moiety through an amino group as defined herein.

[0031] As used herein, the term "amide" means -C(O)NR- or -NRC(O)-, where R can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0032] As used herein, the term "aminoalkyl" means at least one amino group as defined herein attached to the parent molecular moiety through an alkylene group as defined herein.

[0033] As used herein, the term "amino" means -NR x R y , where R x and R y may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any other moiety where an amino group is attached to two other moieties, the amino group can be -NR x , where R x may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

[0034] As used herein, the term "aryl" refers to a phenyl group or a phenyl group that is attached to the parent molecular moiety and is fused to a cycloalkane group (e.g., the aryl group can be an indan-4-yl group), fused to a 6-membered aromatic hydrocarbon group (i.e., the aryl group is a naphthyl group), or fused to a non-aromatic heterocyclic ring (e.g., the aryl group can be a benzo[d][l,3]dioxol-5-yl group). The term "phenyl" is used when referring to a substituent group and the term 6-membered aromatic hydrocarbon is used when referring to a fused ring. The 6-membered aromatic hydrocarbon is monocyclic (e.g., benzene or benzo). The aryl group can be monocyclic (phenyl) or bicyclic (e.g., a 9- to 12-membered fused bicyclic ring system).

[0035] As used herein, the term "cyanoalkyl" means at least one -CN group attached to the parent molecular moiety through an alkylene group as defined herein.

[0036] As used herein, the term "cyanoalkyl" means at least one -CN group attached to the parent molecular moiety through an alkylene group as defined herein.

[0037] As used herein, the term "cycloalkoxy" refers to a cycloalkyl group as defined herein attached to the parent molecular moiety through an oxygen atom.

[0038] As used herein, the term "cycloalkyl" or "cycloalkane" refers to a saturated ring system containing all carbon atoms as ring members and no double bonds. The term "cycloalkyl" as used herein when present as a substituent group refers to a cycloalkane. The cycloalkyl group can be a monocyclic cycloalkyl group (e.g., cyclopropyl), a fused bicyclic cycloalkyl group (e.g., decahydronaphthyl), or a bridged cycloalkyl group in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptanyl). Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[l.l.l]pentanyl.

[0039] As used herein, the term "cycloalkenyl" or "cycloalkene" means a non-aromatic monocyclic or polycyclic ring system containing all carbon atoms as ring members and at least one carbon-carbon double bond, and preferably each ring has 5-10 carbon atoms. The term "cycloalkenyl" as used herein when present as a substituent group refers to a cycloalkene. The cycloalkenyl group can be a monocyclic cycloalkenyl group (e.g., cyclopentenyl), a fused bicyclic cycloalkenyl group (e.g., octahydropentalenyl), or a bridged cycloalkenyl group in which two non-adjacent atoms of the ring are connected 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.

[0040] The term "carbocyclyl" means "cycloalkyl" or "cycloalkenyl". The term "carbocyclic" means "cycloalkane" or "cycloalkene". The term "carbocyclyl" when present as a substituent means "carbocyclic".

[0041] 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 with 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.

[0042] 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 with 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-tetrafluoropropene, 1,1,2,3,3-pentafluoropropene, and perfluoropropene, such as 1,1,2,2,3,3-hexafluoropropene.

[0043] The term "fluoroalkoxy" as used herein means at least one fluoroalkyl group as defined herein attached to the parent molecular moiety through an oxygen atom. Representative examples of fluoroalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

[0044] The term "halogen" or "halo" as used herein means Cl, Br, I, or F.

[0045] 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 with halogen.

[0046] The term "haloalkoxy" as used herein means at least one haloalkyl group as defined herein attached to the parent molecular moiety through an oxygen atom.

[0047] The term "halocycloalkyl" as used herein means a cycloalkyl group as defined herein in which one or more hydrogen atoms are replaced with halogen.

[0048] The term "heteroalkyl" as used herein means an alkyl group as defined herein in which one or more carbon atoms are replaced with a heteroatom selected from S, O, P, and N. Representative examples of heteroalkyl include, but are not limited to, alkyl ethers, secondary alkyl amines, tertiary alkyl amines, amides, and alkyl sulfides.

[0049] As used herein, the term "heteroaryl" refers to a ring containing an aromatic monocyclic heteroatom (monocyclic heteroaryl) or a bicyclic system containing at least one monocyclic heteroaromatic ring (bicyclic heteroaryl). As present as a substituent, the term "heteroaryl" as used herein refers to a heteroarene. Monocyclic heteroaryl is a five- or six-membered ring 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). A five-membered aromatic monocycle has two double bonds, and a six-membered aromatic monocycle has three double bonds. Bicyclic heteroaryl is an 8- to 12-membered ring system and includes fused bicyclic heteroaromatic ring systems (i.e., 10 pi-electron systems), such as monocyclic heteroaryl rings fused to a 6-membered arene (e.g., quinolin-4-yl, indol-1-yl), monocyclic heteroaryl rings fused to a monocyclic heteroarene (e.g., naphthyridinyl), and phenyl groups fused to a monocyclic heteroarene (e.g., quinolin-5-yl, indol-4-yl). Bicyclic heteroaryl / heteroarene groups include 9-membered fused bicyclic heteroaromatic ring systems having four double bonds and at least one heteroatom contributing a lone pair of electrons to the fully aromatic 10 pi-electron system, such as ring systems having a nitrogen atom at the ring junction (e.g., imidazopyridine) or benzoxadiazolyl. Bicyclic heteroaryl also includes fused bicyclic systems consisting of one heteroaromatic ring and one non-aromatic ring, such as monocyclic heteroaryl rings fused to a monocyclic carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[b]pyridinyl) or monocyclic heteroaryl rings fused to a monocyclic heterocyclic ring (e.g., 2,3-dihydrofuro[3,2-b]pyridinyl). Bicyclic heteroaryl is attached to the parent molecular moiety at an aromatic ring atom. Other representative examples of heteroaryl include, but are not limited to: indolyl (e.g., indol-1-yl, indol-2-yl, indol-4-yl), pyridyl (including pyrid-2-yl, pyrid-3-yl, pyrid-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl (e.g., pyrazol-4-yl), pyrrolyl, benzopyrazolyl, 1,2,3-triazolyl (e.g., triazol-4-yl), 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, imidazolyl, thiazolyl (e.g., thiazol-4-yl), isothiazolyl, thienyl, benzimidazolyl (e.g., benzimidazol-5-yl), benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl, isoindolyl, quinoxalinyl, indazolyl (e.g., indazol-4-yl, indazol-5-yl), quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl, imidazo[1,2- a ]pyridyl (e.g., imidazo[1,2-a]pyridin-6-yl), naphthyridinyl, pyridinoimidazolyl, thiazolo[5,4- b ]pyridin-2-yl, and thiazolo[5,4- dpyrimidin-2-yl.

[0050] As used herein, the term "heterocycle" or "heterocyclic" means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. As present as a substituent, the term "heterocyclyl" as used herein means a heterocycle. 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 bonds and one heteroatom selected from the group consisting of O, N, and S. A five-membered ring contains zero or one double bonds 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. A seven-membered ring and an eight-membered ring 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 heterocyclyl groups include, but are not limited to: azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothiophenyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. A bicyclic heterocycle is a monocyclic heterocycle fused to a 6-membered aromatic hydrocarbon, 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 heteroaromatic hydrocarbon, or a spiro heterocyclyl group, or a bridged monocyclic heterocyclic ring system in which two non-adjacent atoms of the ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms or by an alkenylene bridge of two, three, or four carbon atoms. A bicyclic heterocyclyl group is attached to the parent molecular moiety at a non-aromatic ring atom (e.g., indolin-1-yl).Representative examples of bicyclic heterocyclyl groups include, but are not limited to: chroman-4-yl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzothiophen-2-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]heptan-2-yl), azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl), 2,3-dihydro-1. H - indol-1-yl, isoindolin-2-yl, octahydrocyclopenta[ c ]pyrrolopyridinyl, 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 heterocyclyl groups are exemplified by bicyclic heterocycles fused to a 6-membered aromatic hydrocarbon, or bicyclic heterocycles fused to a monocyclic cycloalkane, or bicyclic heterocycles fused to a monocyclic cycloalkene, or bicyclic heterocycles fused to a monocyclic heterocycle, or bicyclic heterocycles wherein two non-adjacent atoms of the bicyclic ring are connected by an alkylene bridge of 1, 2, 3, or 4 carbon atoms or by an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocyclyl groups include, but are not limited to, octahydro-2,5-epoxycyclopenta-2 H - 2,5-methylenecyclopenta[ b ]dieno[2,3-b]furan, hexahydro-1 H - 1,4-methylenecyclopenta[ c ]dieno[2,3-b]furan, azadamantane (1-azatricyclo[3.3.1.13,7]decane), and oxadamantane (2-oxatricyclo[3.3.1.13,7]decane). Monocyclic, bicyclic, and tricyclic heterocyclyl groups are attached to the parent molecular moiety at a non-aromatic ring atom.

[0051] As used herein, the term “hydroxyl” or “hydroxy” means an -OH group.

[0052] As used herein, the term “hydroxyalkyl” means at least one -OH group attached to the parent molecular moiety through an alkylene group, as defined herein.

[0053] As used herein, the term “hydroxyfluoroalkyl” means at least one -OH group attached to the parent molecular moiety through a fluoroalkyl group, as defined herein.

[0054] Terms such as "alkyl", "cycloalkyl", and "alkylene" may be preceded by a designation indicating the number of atoms present in the group under specific conditions (e.g., "C"). 1-4 Alkyl", C 3-6 cycloalkyl, C 1-4 Alkylene). These designations are used as commonly understood by those skilled in the art. For example, a subscript number following "C" indicates the number of carbon atoms present in the subsequent group. Thus, "C3 alkyl" is an alkyl group having three carbon atoms (i.e., n-propyl, isopropyl). In the case of a given range, such as in "C 1-4 In the phrase "", the subsequent group members can have any number of carbon atoms falling within the range described. For example, "C 1-4 "Alkyl" is an alkyl group having 1 to 4 carbon atoms (regardless of the arrangement, i.e., straight chain or branched chain).

[0055] The term "parent molecule" or "parent molecule portion" refers to the entire molecule portion with the substituents attached, i.e., the remaining part of the molecule.

[0056] As used herein, the term "sulfonamide" refers to -S(O)2NR z -or–NR z S(O)-, where R z It can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, alkenyl, or heteroalkyl.

[0057] The term "substituent" refers to a group that "substitutes" on any atom of a group such as alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, or heterocyclic groups. Any atom can be substituted.

[0058] The term "substituted" refers to a group that can be further substituted with one or more non-hydrogen substituent groups. Substituent groups include, but are not limited to, halogen, =0 (oxo), =S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate, and acyl. In some embodiments, a group is optionally substituted. In some embodiments, a group is optionally substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, an aryl, heteroaryl, cycloalkyl, or heterocycle is optionally substituted with 1, 2, 3, 4, or 5 substituents. In some embodiments, an aryl, heteroaryl, cycloalkyl, or heterocycle can be independently unsubstituted or substituted with 1, 2, or 3 substituents.

[0059] For the compounds described herein, the groups and substituents thereof can be selected in accordance with the allowed valence of the atoms and substituents so that the selection and substitution results in a stable compound, e.g., the compound does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, etc.).

[0060] As used herein, the term "allosteric site" refers to a ligand binding site that is topologically distinct from the orthosteric binding site.

[0061] As used herein, the term "modulator" refers to a molecular entity (e.g., but not limited to, a ligand and a disclosed compound) that modulates the activity of a targeted receptor protein.

[0062] As used herein, the term "ligand" refers to a natural or synthetic molecular entity that is capable of associating or binding with a receptor to form a complex and mediate, prevent, or alter a biological effect. Thus, the term "ligand" includes allosteric modulators, inhibitors, activators, agonists, antagonists, natural substrates, and analogs of natural substrates.

[0063] As used herein, the terms "natural ligand" and "endogenous ligand" are used interchangeably and refer to a naturally occurring ligand found in nature that binds to a receptor.

[0064] As used herein, the term "orthosteric site" refers to the primary binding site on a receptor that is recognized by the endogenous ligand or agonist of that receptor. For example, the orthosteric site in the mAChR M4 receptor is the site of acetylcholine binding.

[0065] As used herein, the term "mAChR M4 receptor positive allosteric modulator" refers to any exogenously administered compound or agent that directly or indirectly enhances the activity of a mAChR M4 receptor of an animal, particularly a mammal, e.g., a human, in the presence or absence of acetylcholine or another agonist. For example, in the presence of extracellular acetylcholine, a mAChR M4 receptor positive allosteric modulator can increase the activity of a mAChR M4 receptor in a cell. The cell can be a Chinese hamster ovary (CHO-K1) cell transfected with a human mAChR M4. The cell can be a Chinese hamster ovary (CHO-K1) cell transfected with a rat mAChR M4 receptor. The cell can be a Chinese hamster ovary (CHO-K1) cell transfected with a mammalian mAChR M4. The term "mAChR M4 receptor positive allosteric modulator" includes compounds that are "mAChR M4 receptor allosteric potentiators" or "mAChR M4 receptor allosteric agonists," as well as compounds with mixed activity that include the pharmacology of both "mAChR M4 receptor allosteric potentiators" and "mAChR M4 receptor allosteric agonists." The term "mAChR M4 receptor positive allosteric modulator" also includes compounds that are "mAChR M4 receptor allosteric enhancers."

[0066] As used herein, the term "mAChR M4 receptor allosteric potentiator" refers to any exogenously administered compound or agent that, when an endogenous ligand binds to the orthosteric site of a mAChR M4 receptor of an animal, particularly a mammal, e.g., a human, directly or indirectly enhances the response produced by the endogenous ligand, such as acetylcholine. The mAChR M4 receptor allosteric potentiator binds to a site other than the orthosteric site, i.e., an allosteric site, and positively enhances the response of the receptor to an agonist or endogenous ligand. In some embodiments, the allosteric potentiator does not induce receptor desensitization, providing advantages over the use of a pure mAChR M4 receptor orthosteric agonist for compounds that are mAChR M4 receptor allosteric potentiators. Such advantages can include, for example, increased safety margin, greater tolerability, reduced potential for abuse, and reduced toxicity.

[0067] As used herein, the term "mAChR M4 receptor allosteric enhancer" refers to any exogenously administered compound or agent that directly or indirectly enhances the response produced by an animal's (particularly a mammal's, such as a human's) endogenous ligand (such as acetylcholine). In some embodiments, the allosteric enhancer increases the affinity of the natural ligand or agonist for the orthosteric site. In some embodiments, the allosteric enhancer increases the efficacy of the agonist. The mAChR M4 receptor allosteric enhancer binds to a site other than the orthosteric site, the allosteric site, and positively enhances the response of the receptor to an agonist or endogenous ligand. The allosteric enhancer has no effect on the receptor by itself and requires the presence of an agonist or natural ligand to effect a receptor action.

[0068] As used herein, the term "mAChR M4 receptor allosteric agonist" refers to any exogenously administered compound or agent that directly activates the activity of the mAChR M4 receptor in the absence of an endogenous ligand (such as acetylcholine) in an animal (particularly a mammal, such as a human). The site to which the mAChR M4 receptor allosteric agonist binds is different from the orthosteric acetylcholine site of the mAChR M4 receptor. Because the presence of the endogenous ligand is not required, the activity of the compound as a mAChR M4 receptor allosteric agonist provides an advantage if cholinergic tone is low at a given synapse.

[0069] As used herein, the term "mAChR M4 receptor neutral allosteric ligand" refers to any exogenously administered compound or agent that binds to an allosteric site without affecting the binding or function of an agonist or natural ligand at the orthosteric site of an animal (particularly a mammal, such as a human). However, the neutral allosteric ligand can block the action of other allosteric modulators that act via the same site.

[0070] For recitations of numerical ranges of values, such ranges are intended to include each and every value within the range. For example, for a range of 6-9, this would include the values 6, 7, 8, and 9, in addition to the range of values from 6-9. For a range of 6.0-7.0, the values 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are expressly included in the range.

[0071] Abbreviations: aq is aqueous solution BINAP is 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl Boc is tert-butyloxycarbonyl Boc2O is di-tert-butyl dicarbonate BrettPhos is 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- biphenyl BrettPhos Pd G3 is [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl- 1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate n-BuLi is n-butyllithium t t-BuOH is tert-butanol CDI is 1,1'-carbonyldiimidazole Celite ® is diatomaceous earth DCE is 1,2-dichloroethane DCM is dichloromethane DEA is diethylamine DIAD is diisopropyl azodicarboxylate DIPEA or DIEA is diisopropylethylamine DMA is N , N dimethylacetamide DMAP is 4-dimethylaminopyridine DMF is N , N dimethylformamide DMP or Dess-Martin periodinane is 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2- benzenediol-3-(1 H )-one 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 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 is hour(s) HATU is 1-[bis(dimethylamino)methylene]-1 H -1,2,3-triazolo[4,5- b ]pyridinium 3-oxide hexafluorophosphate Hex is hexane IPA is isopropyl alcohol Ir[dF(CF3)ppy]2(dtbpy))PF6 is [4,4'- (5'-fluoro-2,2'-bipyridyl)bis[2-(4,6- difluorophenyl)pyridine]iridium(III) hexafluorophosphate bis1,1-Dimethylethyl)-2,2′-Bipyridine- N 1, N 1′] bis [3,5-Difluoro-2-[5-(trifluoromethyl)-2-pyridyl- N ]Phenyl-C]iridium(III) hexafluorophosphate KOAc is potassium acetate. Lawson's reagent is 2,4-bis(4-methoxyphenyl)-2,4-dithio-1,3,2,4-dithiodiphosphine heterocyclic butane (CAS# 19172-47-5). LAH is lithium aluminum hydride. m CPBA is m-chloroperoxybenzoic acid Me is a methyl group. MeCN or ACN is acetonitrile. MeOH is methanol. min is minutes. MW stands for microwave (referring to microwave reactors). NaOAc is sodium acetate. NaOMe is sodium methoxide. NBS is N - Bromosuccinimide NCS is N -Chlorosuccinimide NMP is N 2-Methyl-2-pyrrolidone [Pd(allyl)(tBuBrettPhos)]OTf is allyl trifluoromethanesulfonate[(2-di-tert-butylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II). Pd2(dba)3 is tris(dibenzylacetone)dipalladium(0) Pd(dppf)Cl2 is [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium(II) Pd(OAc)₂ is palladium(II) acetate. Pd(PPh3)4 is tetra(triphenylphosphine)palladium(0) PPA is polyphosphoric acid. PPh3 is triphenylphosphine PPTS is pyridinium p-toluenesulfonate rt is room temperature Rxn is the reaction sat. means saturated. sec is a second SCX cartridge or HF SCX cartridge is a strong cation exchange cartridge (i.e., Agilent part number 14256027) SFC is supercritical fluid chromatography TBAC or TBACl is tetrabutylammonium chloride t -BuXPhos is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl TEA or Et3N is triethylamine TFA is trifluoroacetic acid THF is tetrahydrofuran TosCl is p-toluenesulfonyl chloride tosyl is p-toluenesulfonyl Xantphos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0072] 2. Compound In one aspect, the present application provides a compound of Formula (I), wherein R 1 , R 2 , R 8 , and o are as defined herein.

[0073] Unsubstituted or substituted ring (i.e., optionally substituted), such as aryl, heteroaryl, and the like, consists of a ring system and optional substituents of the ring system. Thus, the ring system can be defined independently of its substituents, such that redefining the ring system only preserves any prior optional substituents. For example, a 5- to 12-membered heteroaryl having optional substituents can be further defined by specifying the ring system of the 5- to 12-membered heteroaryl as 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 still exist on the 5- to 6-membered heteroaryl, unless otherwise explicitly stated.

[0074] In cases where a heterocyclic and heteroaromatic ring system is defined as "containing" (contain or containing) a specified heteroatom (e.g., 1-3 heteroatoms independently selected from the group consisting of O, N, and S), any ring atom of the heterocyclic and heteroaromatic ring system that is not one of the specified heteroatoms is a carbon atom.

[0075] Hereinafter, numbered embodiments of the present application are disclosed. The first embodiment is labeled E1, and subsequent embodiments are labeled E1.1, E1.2, E2, E3, E4, E5, E6, E7, E7.1, and so on.

[0076] E1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: R 1 is or ; X 1 is N or CR 1a ; R 1a is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, or C 1-4 fluoroalkyl; X 2 is N or CR 1b ; R 1b is cyano, halogen, C 1-4 alkyl, C 1-4 fluoroalkyl, or hydrogen; R 1c and R 1e are hydrogen, C 1-4 alkyl, halogen, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, or -OC 1-4 alkyl; R 1d and R 1f are hydrogen, C 1-4 alkyl, halogen, C 1-4 fluoroalkyl, or C 3-6 cycloalkyl; alternatively, R 1a and R 1b together with the atom to which each is attached, or R 1c and R 1d together with the atom to which each is attached, form an optionally substituted 6-membered aromatic, 5- to 6-membered heteroaromatic containing 1-3 heteroatoms, 5- to 7-membered heterocycle containing 1 heteroatom, or 5- to 7-membered carbocyclic ring, wherein the heteroatoms are independently selected from the group consisting of N, O, and S, wherein the optional substitution is 1-3 optional substituents independently selected from the group consisting of C 1-4 alkyl, halogen, -OC 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, and C 1-2 alkylene-C 3-4 cycloalkyl; G 1 is a 5- to 6-membered aromatic or partially unsaturated heterocyclic ring system containing 1-3 nitrogen atoms, wherein Z 1 is N or C, Z 2 is N or C, and Z 1 and Z 2 are not simultaneously N; R10 selected from the group consisting of C 1-4 alkyl, C 1-4 fluoroalkyl, halogen, C 3-4 cycloalkyl, C 1-2 alkylene-C 3-4 cycloalkyl, -C(O)OC 1-4 alkyl, and -C(O)NR a R b ; R 11 is independently selected at each occurrence from the group consisting of C 1-6 alkyl, C 1-6 fluoroalkyl, halogen, -C 1-6 alkylene-R y , -C 1-6 fluoroalkylene-R y , G 11 , or -C 1-3 alkylene-G 11 ; R 12 is oxo; m is 0 or 1; n is 0, 1, or 2; p is 0 or 1; R a is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or -C 1-3 alkylene-C 3-4 cycloalkyl; R b is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, G 10 , or -C 1-3 alkylene-G 10 ; wherein alternatively, R a and R b together with the nitrogen to which they are attached form a 4- to 10- membered heterocyclic ring containing the nitrogen to which R a and R b are attached and optionally containing 1-2 additional heteroatoms that are independently O, N, or S, which heterocyclic ring is optionally substituted with a first substituent selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, -OR 50 , -N(R 50 )2, G 10a , and -C 1-3 alkylene-G 10a; and optionally further substituted with 1-3 substituents independently halogen or C 1-4 alkyl; G 10 is phenyl, 5- to 6-membered heteroaryl containing 1-3 heteroatoms, 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, or C 3-6 cycloalkyl, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G 10 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, -OR 50 , -N(R 50 )2, G 10a , and -C 1-3 alkylene-G 10a alkyl; 1-4 alkyl; G 10a is phenyl, 5- to 6-membered heteroaryl containing 1-3 heteroatoms, 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, or 3- to 8-membered carbocyclyl, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G 10a is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, OH, -OC 1-4 alkyl, -OC 1-4 fluoroalkyl, C 3-4 cycloalkyl, and -C 1-3 alkylene-C 3-4 cycloalkyl; R 50 is, at each occurrence, independently hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, or -C 1-3 alkylene-C 3-6 cycloalkyl, wherein each cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, and C 1-4 fluoroalkyl; R y is -OR c , -N(R c )2, -C(O)R c , -C(O)OR c , or -C(O)N(R c )2; Rc independently at each occurrence is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl, wherein alternatively, two R c form, together with the nitrogen to which they are attached, a 4- to 8-membered heterocyclic ring, which heterocyclic ring contains the nitrogen to which R c is attached and optionally contains 1 additional heteroatom that is O, N, or S, which heterocyclic ring is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-2 alkyl, and C 1-2 fluoroalkyl; G 11 is phenyl, 4- to 8-membered heterocyclyl containing 1-2 heteroatoms, 5- to 6-membered heteroaryl containing 1-4 heteroatoms, or C 3-6 cycloalkyl, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G 11 is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, halogen, cyano, oxo, –OC 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, and –C 1-2 alkylene–C 3-4 cycloalkyl; R 2 is G 2 , –NR 2a R 2b , halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, –OR 2a , –NR 2a C(O)R 2b , –C(O)OR 2a , –C(O)NR 2a R 2b , or hydrogen; R 2a and R 2b are independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, G 2 , or –C 1-3 alkylene–G 2 , provided that R 2 is not –N(CH3)2; G 2independently at each occurrence is a 5- to 6-membered heteroaryl containing 1-4 heteroatoms, phenyl, 4- to 7-membered heterocyclyl containing 1-2 heteroatoms, or 3- to 7-membered carbocyclyl, wherein the heteroatoms are independently selected from the group consisting of O, N, and S, and G 2 optionally substituted by a first substituent selected from the group consisting of halo, cyano, C 1-4 alkyl, C 1-4 fluoroalkyl, oxo, -OR x , -N(R x )2, -C(O)R x , -C(O)OR x , -C(O)N(R x )2, -C 1-6 alkylene-OR x , -C 1-6 alkylene-N(R x )2, G 2a , and -C 1-3 alkylene-G 2a , and optionally further substituted by 1-4 substituents independently selected from the group consisting of halo, cyano, C 1-4 alkyl, and C 1-4 fluoroalkyl; R x is, at each occurrence, independently hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, or -C 1-3 alkylene-C 3-6 cycloalkyl; G 2a is C 3-6 cycloalkyl; R 8 is, at each occurrence, independently halo, C 1-4 alkyl, C 1-4 fluoroalkyl, or C 3-4 cycloalkyl; and o is 0, 1, 2, 3, or 4; wherein each cycloalkyl at G 2a and R 8 is independently unsubstituted or substituted by 1-4 substituents independently selected from C 1-4 alkyl (e.g., methyl) and halo (e.g., fluoro); provided that the compound is not: 4,5,6,7-Tetrahydro-5-(2-pyridyl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-Tetrahydro-5-(4-pyrimidinyl)-thiazolo[5,4-c]pyridin-2-amine; 5-(6-Chloro-2-cyclopropyl-5-methyl-4-pyrimidinyl)-4,5,6,7-tetrahydro-2-methyl- thiazolo[5,4-c]pyridine; 2-[2-(4-Ethyl-piperazin-1-yl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-quinoline; 4,5,6,7-Tetrahydro-5-[5-(trifluoromethyl)-thiazolo[5,4- c ]pyridin-2-amine; N-(2-Aminophenyl)-4,5,6,7-tetrahydro-5-[5-(trifluoromethyl)-2-pyridinyl]- thiazolo[5,4- c ]pyridine-2-carboxamide; 5-(2,5-Dimethyloxazolo[5,4- d ]pyrimidin-7-yl)-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridin-2-amine; 5-(2-Cyclopentyl-6,7-dihydro-5 H -pyrrolo[3,4- d ]pyrimidin-4-yl)-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridin-2-amine; 5-(5,6-Dimethyl-thieno[2,3- d ]pyrimidin-4-yl)-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-Tetrahydro-5-thieno[2,3- d ]pyrimidin-4-yl-thiazolo[5,4- c ]pyridin-2-amine; 5-[2,6-Bis(1,1-dimethylethyl)-4-pyrimidinyl]-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridine; 7-(6,7-Dihydrothiazolo[5,4-c]pyridin-5(4 H )-yl)-2-(trifluoromethyl)-thiazolo[5,4- d ]pyrimidine; 4,5,6,7-Tetrahydro-5-(2-pyridinyl)-thiazolo[5,4-c]pyridine-2-carboxylic acid or a salt thereof; 4-(6,7-Dihydrothiazolo[5,4-c]pyridin-5(4 H )-yl)-[1,2,5]thiadiazolo[3,4-c ]Pyridine; 4,5,6,7-Tetrahydro-5-[6-methyl-2-(1-methylpropyl)-4-pyrimidinyl]-thiazo[5,4- c ]Pyridine-2-amine; 5-(4-chloro-2-pyridyl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine; 5-[2-(1,1-dimethylethyl)-4-pyrimidinyl]-4,5,6,7-tetrahydro-thiazo[5,4- c ]Pyridine-2-amine; 5-[6-(1,1-dimethylethyl)-1-methyl-1H-pyrazolo[3,4-] d [Pyrimidin-4-yl]-4,5,6,7-tetrahydro-thiazolyl[5,4-] c ]Pyridine-2-amine; 5-(2-ethyl-7-methylthiopheno[3,2-) d ]pyrimidin-4-yl)-4,5,6,7-tetrahydro-thiazolyl[5,4- c ]Pyridine; 4,5,6,7-Tetrahydro-5-(2-methyl-7-) H -pyrrolo[2,3- d ]pyrimidin-4-yl)-thiazolyl[5,4- c ]Pyridine-2-amine; 5-(6-cyclopentyl-1-methyl-1-yl) H -pyrazolo[3,4- d ]pyrimidin-4-yl)-4,5,6,7-tetrahydro-thiazolyl[5,4- c ]Pyridine-2-amine; 4,5,6,7-Tetrahydro-5-[3-(trifluoromethyl)-1,2,4-triazolo[4,3- b ]pyridazine-6-yl]-thiazolyl[5,4- c ]Pyridine-2-amine; 6-(6,7-dihydrothiazo[5,4-c]pyridine-5(4) H )-yl)-2-(trifluoromethyl)-9 H -purine; 5-(2,6-Dicyclopropyl-4-pyrimidinyl)-4,5,6,7-tetrahydro-thiazo[5,4- c ]Pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(5-iodo-2-pyridyl)-thiazo[5,4- c ]Pyridine; 4,5,6,7-Tetrahydro-5-(7-methylthiopheno[3,2-d ]pyrimidin-4-yl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-tetrahydro-5-(2-methyl-4-pyrimidinyl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-tetrahydro-5-(4-quinazolinyl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-tetrahydro-5-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)-thiazolo[5,4- c ]pyridine; 4,5,6,7-tetrahydro-5-(3-pyridazinyl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-tetrahydro-5-[6-methyl-2-(l-methylethyl)-4-pyrimidinyl]-thiazolo[5,4- c ]pyridin-2-amine; 5-(6-ethyl-5-fluoro-4-pyrimidinyl)-4,5,6,7-thiazolo[5,4- c ]pyridin-2-amine; 5-(7-chloro-4-quinazolinyl)-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridin-2-amine; 5-(5-bromo-2-pyridinyl)-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridine; 4,5,6,7-tetrahydro-5-(2-methylthieno[3,2- d ]pyrimidin-4-yl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-tetrahydro-5-(l H -pyrrolo[2,3- b ]pyridin-6-yl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-tetrahydro-5-(2-methyl-6-propyl-4-pyrimidinyl)-thiazolo[5,4- c ]pyridin-2-amine; 4,5,6,7-tetrahydro-5-(5-methylthieno[2,3- d ]pyrimidin-4-yl)-thiazolo[5,4- c ]pyridin-2-amine; 5-(6-cyclohexyl-4-pyrimidinyl)-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridine; 4,5,6,7-tetrahydro-5-[6-methyl-2-(1-methylpropyl)-4-pyrimidinyl]-thiazolo[5,4- c ]pyridine; or 5-(6-bromo-4-quinazolinyl)-4,5,6,7-tetrahydro-thiazolo[5,4- c ]pyridin-2-amine.

[0077] E1.1. The compound of E1 or a pharmaceutically acceptable salt thereof, wherein G 11 is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, halogen, oxo, -OC 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, and -C 1-2 alkylene-C 3-4 cycloalkyl.

[0078] E1.2. The compound of E1 or E1.1 or a pharmaceutically acceptable salt thereof, wherein R 11 is independently selected from the group consisting of C 1-4 alkyl, C 1-4 fluoroalkyl, halogen, C 3-4 cycloalkyl, and C 1-2 alkylene-C 3-4 cycloalkyl.

[0079] E2. The compound of any one of E1-E1.2 or a pharmaceutically acceptable salt thereof, wherein R 1 is .

[0080] E3. The compound of any one of E1-E2 or a pharmaceutically acceptable salt thereof, wherein X 1 is N.

[0081] E4. The compound of any one of E1-E2 or a pharmaceutically acceptable salt thereof, wherein X 1 is CR 1a .

[0082] E5. The compound of any one of E1-E4 or a pharmaceutically acceptable salt thereof, wherein X 2 is N.

[0083] E6. The compound of any one of E1-E4 or a pharmaceutically acceptable salt thereof, wherein X 2 is CR​​​1b .

[0084] E7. The compound of any one of E1-E2 or E4-E6, or a pharmaceutically acceptable salt thereof, wherein R 1a is hydrogen or C 1-4 alkyl.

[0085] E7.1. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R 1a is hydrogen.

[0086] E7.2. The compound of E7, or a pharmaceutically acceptable salt thereof, wherein R 1a is C 1-4 alkyl.

[0087] E7.3. The compound of E7.2, or a pharmaceutically acceptable salt thereof, wherein R 1a is methyl.

[0088] E8. The compound of any one of E1-E4 or E6-E7.3, or a pharmaceutically acceptable salt thereof, wherein R 1b is cyano.

[0089] E9. The compound of any one of E1-E2, E4, or E6, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b together with the atom to which each is attached form an optionally substituted 6-membered aromatic, 5- to 6-membered heteroaromatic containing 1-3 heteroatoms, 5- to 7-membered heterocycle containing 1 heteroatom, or 5- to 7-membered carbocyclic ring.

[0090] E9.1. The compound of E9, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b together with the atom to which each is attached form an optionally substituted 5- to 6-membered heteroaromatic.

[0091] E9.2. The compound of any one of E1-E9.1, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b together with the atom to which each is attached form a ring system of the 5- to 6-membered heteroaromatic is imidazole, pyrazole, pyrrole, furan, thiophene, or pyrazine.

[0092] E9.3. The compound of E9.2, or a pharmaceutically acceptable salt thereof, wherein R 1 is and R 10a , R 11a , and R 11b are independently hydrogen, C 1-4alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or C 1-2 alkylene-C 3-4 cycloalkyl.

[0093] E9.4. The compound of E9.2, or a pharmaceutically acceptable salt thereof, wherein R 1 is and R 11a and R 11b are independently hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or C 1-2 alkylene-C 3-4 cycloalkyl.

[0094] E9.5. The compound of E9.3 or E9.4, or a pharmaceutically acceptable salt thereof, wherein R 10a , R 11a , and R 11b are hydrogen.

[0095] E10. The compound of any one of E1-E9.5, or a pharmaceutically acceptable salt thereof, wherein R 1c is hydrogen, C 1-4 alkyl, or halogen.

[0096] E10.1. The compound of E10, or a pharmaceutically acceptable salt thereof, wherein R 1c is hydrogen.

[0097] E10.2. The compound of E10, or a pharmaceutically acceptable salt thereof, wherein R 1c is C 1-4 alkyl.

[0098] E10.3. The compound of E10.2, or a pharmaceutically acceptable salt thereof, wherein R 1c is methyl.

[0099] E10.4. The compound of E10, or a pharmaceutically acceptable salt thereof, wherein R 1c is halogen.

[0100] E10.5. The compound of E10.4, or a pharmaceutically acceptable salt thereof, wherein R 1c is chloro.

[0101] E11. The compound of any one of E1-E10.5, or a pharmaceutically acceptable salt thereof, wherein R 1d is hydrogen or C 1-4 alkyl.

[0102] E11.1. The compound of E11 or a pharmaceutically acceptable salt thereof, wherein R 1d is hydrogen.

[0103] E11.2. The compound of E11 or a pharmaceutically acceptable salt thereof, wherein R 1d is C 1-4 alkyl.

[0104] E11.3. The compound of E11.2 or a pharmaceutically acceptable salt thereof, wherein R 1d is methyl.

[0105] E12. The compound of any one of E1-E8 or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d together with the atoms to which they are attached form an optionally substituted 6-membered aromatic, 5- to 6-membered heteroaromatic containing 1-3 heteroatoms, 5- to 7-membered heterocycle containing 1 heteroatom, or 5- to 7-membered carbocyclic ring.

[0106] E12.1. The compound of E12 or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d together with the atoms to which they are attached form an optionally substituted 6-membered aromatic.

[0107] E12.2. The compound of any one of E1-E8 or E12-E12.1 or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d together with the atoms to which they are attached form the 6-membered aromatic is optionally substituted with methyl, fluoro, chloro, or methoxy.

[0108] E12.3. The compound of E12.1 or a pharmaceutically acceptable salt thereof, wherein R 1 is .

[0109] E12.4. The compound of E12.2 or E12.3 or a pharmaceutically acceptable salt thereof, wherein R 1 is .

[0110] E12.5. The compound of E12 or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d together with the atoms to which they are attached form an optionally substituted 5- to 6-membered heteroaromatic.

[0111] E12.6. The compound of any one of E1-E12 or E12.5, or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d The ring system of the optionally substituted 5- to 6-membered heteroarene formed is furan, thiophene, pyrrole, or isoxazole.

[0112] E12.7. The compound of any one of E1-E12 or E12.5-E12.6, or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d The 5- to 6-membered heteroarene formed is optionally substituted with C 1-4 alkyl.

[0113] E12.8. The compound of E12.7, or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d The 5- to 6-membered heteroarene formed is optionally substituted with methyl.

[0114] E12.9. The compound of E12.7, or a pharmaceutically acceptable salt thereof, wherein R 1 is .

[0115] E12.10. The compound of E12.8 or E12.9, or a pharmaceutically acceptable salt thereof, wherein R 1 is .

[0116] E12.11. The compound of E12, or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d together with the atom to which each is attached form an optionally substituted 5- to 7-membered heterocycle containing 1 heteroatom.

[0117] E12.12. The compound of E12.11, or a pharmaceutically acceptable salt thereof, wherein R 1 is (e.g., ).

[0118] E12.13. The compound of E12, or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d together with the atom to which each is attached form an optionally substituted 5- to 7-membered carbocycle.

[0119] E12.14. The compound of E12.13 or a pharmaceutically acceptable salt thereof, wherein R 1 is (e.g., , ).

[0120] E13. The compound of any one of E1-E12.9 or a pharmaceutically acceptable salt thereof, wherein R 1 is .

[0121] E14. The compound of any one of E1-E1.2 or a pharmaceutically acceptable salt thereof, wherein R 1 is .

[0122] E15. The compound of any one of E1-E1.2 or E14 or a pharmaceutically acceptable salt thereof, wherein Z 1 is N and Z 2 is C.

[0123] E16. The compound of any one of E1-E1.2 or E14 or a pharmaceutically acceptable salt thereof, wherein Z 1 is C and Z 2 is N.

[0124] E17. The compound of any one of E1-E1.2 or E14 or a pharmaceutically acceptable salt thereof, wherein Z 1 is C and Z 2 is C.

[0125] E18. The compound of any one of E1-E1.2 or E14-E17 or a pharmaceutically acceptable salt thereof, wherein G 1 is a 5-membered aromatic heterocyclic ring system.

[0126] E18.1. The compound of any one of E1-E1.2 or E14-E18 or a pharmaceutically acceptable salt thereof, wherein G 1 the 5- to 6-membered heterocyclic ring system is imidazole, pyrazole, pyrrole, furan, or thiophene.

[0127] E18.2. The compound of E18.1 or a pharmaceutically acceptable salt thereof, wherein R 1 is and R 10a , R11a , and R 11b is independently hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or C 1-2 alkylene-C 3-4 cycloalkyl.

[0128] E19. The compound of any one of E1-E1.2 or E14-E17, or a pharmaceutically acceptable salt thereof, wherein G 1 is a 5-membered partially unsaturated heterocyclic ring system.

[0129] E19.1. The compound of E19, or a pharmaceutically acceptable salt thereof, wherein R 1 is ; and R 11a is hydrogen, C 1-6 alkyl, C 1-6 fluoroalkyl, -C 1-6 alkylene-R y , -C 1-6 fluoroalkylene-R y , G 11 , or -C 1-3 alkylene-G 11 .

[0130] E19.2. The compound of E19.1, or a pharmaceutically acceptable salt thereof, wherein R 11a is hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or C 1-2 alkylene-C 3-4 cycloalkyl.

[0131] E19.3. The compound of E19.1 or E19.2, or a pharmaceutically acceptable salt thereof, wherein R 11a is hydrogen.

[0132] E19.4. The compound of E19.1 or E19.2, or a pharmaceutically acceptable salt thereof, wherein R 11a is C 1-4 alkyl.

[0133] E19.5. The compound of E19.4, or a pharmaceutically acceptable salt thereof, wherein R 11a is methyl.

[0134] E19.6. The compound of E19.5, or a pharmaceutically acceptable salt thereof, wherein the methyl at R 11a is CD3.

[0135] E19.7. The compound of E19.1 or a pharmaceutically acceptable salt thereof, wherein R 11a is -C 1-6 alkylene-R y .

[0136] E19.8. The compound of E19.1 or E19.7 or a pharmaceutically acceptable salt thereof, wherein R 11a is -C 1-6 alkylene-R y is -CH2CH2-R y or -CH(CH3)CH2-R y .

[0137] E19.9. The compound of E19.1 or a pharmaceutically acceptable salt thereof, wherein R 11a is G 11 .

[0138] E19.10. The compound of E19.1 or a pharmaceutically acceptable salt thereof, wherein R 11a is -C 1-3 alkylene-G 11 .

[0139] E19.11. The compound of E19.1 or E19.10 or a pharmaceutically acceptable salt thereof, wherein R 11a is -C 1-3 alkylene-G 11 is -CH2-G 11 .

[0140] E19.12. The compound of any one of E19.1, E19.7-E19.8, or E19.11 or a pharmaceutically acceptable salt thereof, wherein R y is -OR c .

[0141] E19.13. The compound of any one of E19.1, E19.7-E19.8, or E19.11-E19.12 or a pharmaceutically acceptable salt thereof, wherein R c is C 1-4 alkyl.

[0142] E19.14. The compound of any one of E19.1, E19.7-E19.8, or E19.11-E19.13 or a pharmaceutically acceptable salt thereof, wherein the C c alkyl at R 1-4 is methyl.

[0143] E19.15. The compound of any one of E19.1 or E19.8-E19.14, or a pharmaceutically acceptable salt thereof, wherein G 11 is an optionally substituted 4 to 8 membered heterocyclyl containing 1-2 heteroatoms.

[0144] E19.16. The compound of any one of E19.1 or E19.8-E19.15, or a pharmaceutically acceptable salt thereof, wherein G 11 the ring system of the optionally substituted 4 to 8 membered heterocyclyl at the is tetrahydrofuran or morpholine.

[0145] E19.17. The compound of E19.16, or a pharmaceutically acceptable salt thereof, wherein G 11 the ring system of the optionally substituted 4 to 8 membered heterocyclyl at the is tetrahydrofuran-3-yl or morpholin-2-yl.

[0146] E19.18. The compound of E19.17, or a pharmaceutically acceptable salt thereof, wherein G 11 or .

[0147] E19.19. The compound of E19.17, or a pharmaceutically acceptable salt thereof, wherein G 11 .

[0148] E19.20. The compound of E19.19, or a pharmaceutically acceptable salt thereof, wherein G 11 .

[0149] E19.21. The compound of any one of E19.1 or E19.8-E19.14, or a pharmaceutically acceptable salt thereof, wherein G 11 is an optionally substituted C 3-6 cycloalkyl.

[0150] E19.22. The compound of any one of E19.1, E19.8-E19.14, E19.16-E19.17, or E19.21, or a pharmaceutically acceptable salt thereof, wherein G 11 the ring system of the optionally substituted C 3-6 cycloalkyl at the is cyclopropyl or cyclopentyl.

[0151] E19.23. The compound of any one of E19.1, E19.8-E19.14, E19.16-E19.17, or E19.21, or a pharmaceutically acceptable salt thereof, wherein G 11 the ring system of the optionally substituted C 3-6 ​​​The ring system of cycloalkyl is cyclobutyl.

[0152] E19.24. The compound of E19.22 or a pharmaceutically acceptable salt thereof, wherein G 11 is cyclopropyl or cyclopentyl.

[0153] E19.25. The compound of any one of E19.1, E19.8-E19.14, E19.16-E19.17, or E19.21, or a pharmaceutically acceptable salt thereof, wherein G 11 is the C 3-6 cycloalkyl is optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, cyano, and C 1-4 alkyl.

[0154] E19.26. The compound of E19.25 or a pharmaceutically acceptable salt thereof, wherein G 11 is the C 3-6 cycloalkyl is optionally substituted with 1-2 substituents independently selected from the group consisting of fluorine, cyano, and methyl.

[0155] E19.27. The compound of E19.26 or a pharmaceutically acceptable salt thereof, wherein G 11 is .

[0156] E20. The compound of any one of E1-E1.2 or E14-E17, or a pharmaceutically acceptable salt thereof, wherein G 1 is a 6-membered partially unsaturated heterocyclic ring system.

[0157] E20.1. The compound of E20 or a pharmaceutically acceptable salt thereof, wherein R 1 is ; R 10a is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, halogen, C 3-4 cycloalkyl, C 1-2 alkylene-C 3-4 cycloalkyl, -C(O)OC 1-4 alkyl, and -C(O)NR a R b ; and R 11a is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, halogen, C 3-4 cycloalkyl, and C 1-2 alkylene-C 3-4 cycloalkyl.

[0158] E20.2. The compound or pharmaceutically acceptable salt thereof of E20.1, wherein R 10a is selected from the group consisting of hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, -C(O)OC 1-4 alkyl, and -C(O)NR a R b ; and R 11a is selected from the group consisting of hydrogen, C 1-4 alkyl, and halo.

[0159] E20.3. The compound or pharmaceutically acceptable salt thereof of E20.2, wherein R 10a is selected from the group consisting of hydrogen, methyl, CHF2, -CO2CH2CH3, and -C(O)NR a R b ; and R 11a is selected from the group consisting of hydrogen, methyl, and fluoro.

[0160] E20.4. The compound or pharmaceutically acceptable salt thereof of any one of E1-E1.2, E14-E18.1, E19, or E20-E20.3, wherein R a is hydrogen.

[0161] E20.5. The compound or pharmaceutically acceptable salt thereof of any one of E1-E1.2, E14-E18.1, E19, or E20-E20.4, wherein R b is G 10 or -C 1-3 alkylene-G 10 (e.g., -CH2-G 10 ).

[0162] E20.6. The compound or pharmaceutically acceptable salt thereof of any one of E1-E1.2, E14-E18.1, E19, or E20-E20.5, wherein G 10 is optionally substituted 5- to 6-membered heteroaryl (e.g., thiazolyl) or C 3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl).

[0163] E20.7. The compound or pharmaceutically acceptable salt thereof of any one of E1-E1.2, E14-E18.1, E19, or E20-E20.6, wherein G 10 is optionally substituted by cyano or C 1-4 fluoroalkyl (e.g., 2,2,2-trifluoroethyl).

[0164] E20.8. A compound as described in E20.7 or a pharmaceutically acceptable salt thereof, wherein R b yes .

[0165] E20.9. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E1.2, E14-E18.1, E19, or E20-E20.3, wherein R a and R b Together with the nitrogen attached to them, they form optionally substituted 4- to 10-membered heterocycles.

[0166] E20.10. A compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E1.2, E14-E18.1, E19, E20-E20.3, or E20.9, wherein R a and R b The resulting 4- to 10-membered heterocyclic ring system is aza-butane, pyrrolidine, or 2-oxa-6-azaspiro[3,3]heptane.

[0167] E20.11. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E1.2, E14-E18.1, E19, E20-E20.3, or E20.9-E20.10, wherein R a and R b The 4- to 10-membered heterocycle formed is optionally selected from halogens (e.g., fluorine), C 1-4 Alkyl (e.g., methyl), –OR 50 (e.g., OCH3), and G 10a The first substituent of the group consisting of (e.g., pyridyl, such as pyridin-3-yl) is substituted; and optionally further substituted by a halogen (e.g., fluorine) or C 1-4 One substituent of an alkyl group (e.g., methyl) is substituted.

[0168] E20.12. The compound or a pharmaceutically acceptable salt thereof as described in any one of E1-E1.2, E14-E18.1, E19, E20-E20.3, or E20.9-E20.11, wherein R a and R b The 4- to 10-membered heterocycles that are optionally substituted are .

[0169] E20.13. A compound as described in E20 or a pharmaceutically acceptable salt thereof, wherein R 1 yes And R 11a and R 11b Choose independently the following groups: hydrogen, C 1-4alkyl, C 1-4 fluoroalkyl, halogen, C 3-4 cycloalkyl, and C 1-2 alkylene-C 3-4 cycloalkyl.

[0170] E20.14. The compound or pharmaceutically acceptable salt thereof of E20.13, wherein R 11a is hydrogen.

[0171] E20.15. The compound or pharmaceutically acceptable salt thereof of E20.13 or E20.14, wherein R 11b is selected from the group consisting of hydrogen, C 1-4 alkyl (e.g., methyl), and C 1-4 fluoroalkyl (e.g., CHF2, CF3).

[0172] E21. The compound or pharmaceutically acceptable salt thereof of any one of E1-E1.2, E14, or E17, wherein G 1 is a 6-membered aromatic heterocyclic ring system.

[0173] E21.1. The compound or pharmaceutically acceptable salt thereof of any one of E1-E1.2, E14, E17, or E21, wherein G 1 the 6-membered aromatic heterocyclic ring system at is a pyrazine.

[0174] E21.2. The compound or pharmaceutically acceptable salt thereof of E21.1, wherein R 1 is ; and R 11a and R 11b are independently hydrogen, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or C 1-2 alkylene-C 3-4 cycloalkyl.

[0175] E21.3. The compound or pharmaceutically acceptable salt thereof of E21.2, wherein R 11a and R 11b are hydrogen.

[0176] E22. The compound or pharmaceutically acceptable salt thereof of any one of E1-E1.2 or E14-E21.3, wherein R 1e is hydrogen or C 1-4 alkyl.

[0177] E22.1. The compound or pharmaceutically acceptable salt thereof of E22, wherein R 1e is hydrogen.

[0178] E22.2. The compound or pharmaceutically acceptable salt thereof of E22, wherein R 1e is C 1-4 alkyl.

[0179] E22.3. The compound or pharmaceutically acceptable salt thereof of E22.2, wherein R 1e is methyl.

[0180] E23. The compound or pharmaceutically acceptable salt thereof of any one of E1-E1.2 or E14-E22.3, wherein R 1f is C 1-4 alkyl.

[0181] E23.1. The compound or pharmaceutically acceptable salt thereof of E23, wherein R 1f is methyl.

[0182] E24. The compound or pharmaceutically acceptable salt thereof of any one of E1-E1.2 or E14-E23.1, wherein R 1 is .

[0183] E24.1. The compound or pharmaceutically acceptable salt thereof of E24, wherein R 1 is .

[0184] E24.2. The compound or pharmaceutically acceptable salt thereof of E24 or E24.1, wherein R 1 is .

[0185] E25. The compound or pharmaceutically acceptable salt thereof of any one of E1-E24.2, R 2 is G 2 , -NR2a R 2b , halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -OR 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , or hydrogen.

[0186] E26. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R 2 is G 2 .

[0187] E27. The compound of any one of E1-E26, or a pharmaceutically acceptable salt thereof, wherein G 2 is an optionally substituted 3- to 7-membered carbocyclyl.

[0188] E27.1. The compound of any one of E1-E27, or a pharmaceutically acceptable salt thereof, wherein the ring system of the optionally substituted 3- to 7-membered carbocyclyl is C 3-6 cycloalkyl.

[0189] E27.2. The compound of E27.1, or a pharmaceutically acceptable salt thereof, wherein the C 3-6 cycloalkyl ring system is cyclopropyl.

[0190] E27.3. The compound of E27.1, or a pharmaceutically acceptable salt thereof, wherein the C 3-6 cycloalkyl ring system is cyclobutyl.

[0191] E27.4. The compound of any one of E1-E27.3, or a pharmaceutically acceptable salt thereof, wherein G 2 is optionally substituted with 1-2 substituents independently selected from methyl and fluoro.

[0192] E27.5. The compound of E27.4, or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0193] E27.6. The compound of E27.4, or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0194] E27.7. The compound of E27.4, or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0195] E28. The compound of any one of E1-E26, or a pharmaceutically acceptable salt thereof, wherein G 2 is an optionally substituted 5- to 6-membered heteroaryl.

[0196] E28.1. The compound of any one of E1-E26 or E28, or a pharmaceutically acceptable salt thereof, wherein G 2 the optionally substituted 5- to 6-membered heteroaryl ring system at G

[0197] E28.2. The compound of any one of E1-E26 or E28-E28.1, or a pharmaceutically acceptable salt thereof, wherein G 2 is optionally substituted with C 1-4 alkyl (e.g., methyl) or C 3-4 cycloalkyl, and is optionally further substituted with 1-2 C 1-4 alkyl.

[0198] E28.3. The compound of E28.2, or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0199] E29. The compound of any one of E1-E26, or a pharmaceutically acceptable salt thereof, wherein G 2 is an optionally substituted phenyl.

[0200] E30. The compound of any one of E1-E29, or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0201] E30.1. The compound of any one of E1-E30, or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0202] E30.2. The compound of E30.1, or a pharmaceutically acceptable salt thereof, wherein G 2 is .

[0203] E31. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R 2 is -NR 2a R 2b .

[0204] E32. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R 2is -C(O)NR 2a R 2b .

[0205] E33. The compound or pharmaceutically acceptable salt thereof of any one of E1-E25 or E31-E32, wherein R 2b is hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, G 2 , or -C 1-3 alkylene-G 2 .

[0206] E33.1. The compound or pharmaceutically acceptable salt thereof of E33, wherein R 2b is hydrogen.

[0207] E33.2. The compound or pharmaceutically acceptable salt thereof of E33, wherein R 2b is G 2 .

[0208] E33.3. The compound or pharmaceutically acceptable salt thereof of E33, wherein R 2b is -C 1-3 alkylene-G 2 .

[0209] E33.4. The compound or pharmaceutically acceptable salt thereof of E33.3, wherein R 2b is -CH2-G 2 .

[0210] E33.5. The compound or pharmaceutically acceptable salt thereof of any one of E1-E25, E31-E33, or E33.2-E33.4, wherein G 2 is optionally substituted 5- to 6-membered heteroaryl.

[0211] E33.6. The compound or pharmaceutically acceptable salt thereof of any one of E1-E25, E31-E33, or E33.2-E33.4, wherein G 2 is optionally substituted phenyl.

[0212] E33.7. The compound or pharmaceutically acceptable salt thereof of any one of E1-E25, E31-E33, or E33.2-E33.6, wherein G 2 is optionally substituted with 1-3 halogens independently selected from the group consisting of fluorine and chlorine.

[0213] E33.8. The compound or pharmaceutically acceptable salt thereof of E33.7, wherein G 2is 2-fluorophenyl, 3-fluorophenyl, or 4-fluorophenyl.

[0214] E34. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R 2 is -C(O)OR 2a .

[0215] E35. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R 2 is -OR 2a .

[0216] E36. The compound of any one of E1-E25 or E31-E35, or a pharmaceutically acceptable salt thereof, wherein R 2a is hydrogen or C 1-6 alkyl.

[0217] E36.1. The compound of E36, or a pharmaceutically acceptable salt thereof, wherein R 2a is hydrogen.

[0218] E36.2. The compound of E36, or a pharmaceutically acceptable salt thereof, wherein R 2a is C 1-4 alkyl.

[0219] E36.3. The compound of E36.2, or a pharmaceutically acceptable salt thereof, wherein R 2a is methyl or ethyl.

[0220] E37. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-6 alkyl.

[0221] E37.1. The compound of E37, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-4 alkyl.

[0222] E37.2. The compound of E37.1, or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl (e.g., CD3), isopropyl, or tert-butyl.

[0223] E38. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen.

[0224] E38.1. The compound of E38, or a pharmaceutically acceptable salt thereof, wherein R 2 is chloro or bromo.

[0225] E39. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

[0226] E40. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-6 haloalkyl.

[0227] E40.1. The compound of E40, or a pharmaceutically acceptable salt thereof, wherein R 2 is CF3.

[0228] E41. The compound of E25, or a pharmaceutically acceptable salt thereof, wherein R 2 is cyano.

[0229] E42. The compound of any one of E1-E41, or a pharmaceutically acceptable salt thereof, wherein o is 0.

[0230] E43. The compound of E1 selected from the group consisting of: 6-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)-5-methylnicotinonitrile 5-methyl-6-(2-(2-methylpyridin-4-yl)-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)nicotinonitrile 5-methyl-6-(2-(thiazol-5-yl)-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)nicotinonitrile 6-(2-(1-cyclobutyl-1-pyrazol-4-yl)-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)-5-methylnicotinonitrile 6-(2-((2-fluorophenyl)amino)-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)-4,5-dimethylpyridazine-3-carbonitrile 6-(2-((3-fluorophenyl)amino)-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)-4,5-dimethylpyridazine-3-carbonitrile 6-(2-((4-fluorophenyl)amino)-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)-4,5-dimethylpyridazine-3-carbonitrile 6-(2-methoxy-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)-4,5-dimethylpyridazine-3-carbonitrile 5-(6-chloro-2,5-dimethylpyrimidin-4-yl)-2-methyl-4,5,6,7-tetrahydrothiazolo[5,4-]pyridine 6-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)-4,5-dimethylpyridazine-3-carbonitrile 2-bromo-5-(6-chloro-2,5-dimethylpyrimidin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-]pyridine 6-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)-4,5-dimethylpyridazine-3-carbonitrile 5-(6-cyano-4,5-dimethylpyridazin-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4-]pyridine-2-carbonitrile 5-(6-chloro-2,5-dimethylpyrimidin-4-yl)-2-fluorophenyl-4,5,6,7-tetrahydrothiazolo[5,4-]pyridine-2-amine 5-methyl-6-(2-methyl-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)nicotinonitrile 6-(2-cyclopropyl-6,7-dihydrothiazolo[5,4-]pyridine-5(4)-yl)-5-methylnicotinonitrile 6-(6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-5-methylnicotinonitrile 6-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-5-methylnicotinonitrile 6-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-5-methylnicotinonitrile 5-methyl-6-(2-(methyl- d 3)-6,7-dihydrothiazolo[5,4- c ]pyridine-5(4 H )-yl)nicotinonitrile 5-(5-cyano-3-methylpyridin-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide 4-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-5-methylfuro[2,3-d]pyrimidine 2-bromo-5-(5-methylthieno[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-bromo-5-(5-methylthieno[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 4-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-methylisothiazolo[5,4-c]pyrimidine 2-bromo-5-(thieno[3,2-d]pyrimidin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-bromo-5-(thieno[3,2-d]pyrimidin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-bromo-5-(7-methyl-7-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-bromo-5-(6-fluoroquinazolin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-bromo-5-(6-fluoroquinazolin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-bromo-5-(6-fluoroquinazolin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-bromo-5-(6-fluoroquinazolin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-bromo-5-(6-fluoroquinazolin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-bromo-5-(6-fluoroquinazolin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-bromo-5-(6-fluoroquinazolin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 7-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-8-methyl-4-pyrimido[1,2-a]pyrimidin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-8-methyl-2-(trifluoromethyl)-4-pyrimido[1,2-a]pyrimidin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-8-methyl-2-(trifluoromethyl)-4-pyrimido[1,2-a]pyrimidin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)-3-fluoro-2,8,9-trimethyl-4H-pyrimido[1,2-a]pyrimidin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-2,3,8-trimethyl-4- pyrimido[1,2-]pyridazin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-2-(difluoromethyl)-8- methyl-4-pyrimido[1,2-]pyridazin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-3-fluoro-2,8-dimethyl-4- pyrimido[1,2-]pyridazin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-8-methyl-2-(3-(pyridin-3- yl)pyrrolidine-1-carbonyl)-4-pyrimido[1,2-]pyridazin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-8-methyl-4-oxo-N-(thiazol-5- ylmethyl)-4-pyrimido[1,2-]pyridazine-2-carboxamide 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-8-methyl-2-(3-methylazetidine- 1-carbonyl)-4-pyrimido[1,2-]pyridazin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-2-(3-methoxyazetidine-1- carbonyl)-8-methyl-4-pyrimido[1,2-]pyridazin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-2-(3-fluoro-3-methylazetidine- 1-carbonyl)-8-methyl-4-pyrimido[1,2-]pyridazin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-8-methyl-2-(2-oxa-6- azaspiro[3.3]heptane-6-carbonyl)-4-pyrimido[1,2-]pyridazin-4-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-8-methyl-4-oxo-(3-(2,2,2- trifluoroethyl)cyclobutyl)-4-pyrimido[1,2-]pyridazine-2-carboxamide 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-8-methyl-4-(trifluoromethyl)- 2-pyrimido[1,2-]pyridazin-2-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-8-methyl-2-pyrimido[1,2-] pyridazin-2-one 7-(2-bromo-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-4,8-dimethyl-2- pyrimido[1,2-]pyridazin-2-one ​ 7-(2-bromo-6,7-dihydrothiazolo[5,4-c]pyridin-5(4)-yl)-8-methyl-4-oxo-4-pyrimido[1,2-]pyridazine-2-carboxylic acid ethyl ester 5-(7-methylpyrido[2,3-]pyrazin-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-cyclopropyl-5-(7-methylpyrido[2,3-]pyrazin-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-(1-methylcyclopropyl)-5-(7-methylpyrido[2,3-]pyrazin-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 5-(7-methylpyrido[2,3-]pyrazin-6-yl)-2-(thiophen-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-methyl-5-(7-methylpyrido[2,3-]pyrazin-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 5-(7-methylpyrido[2,3-]pyrazin-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid ethyl ester 2-(1-methyl-1-pyrazol-5-yl)-5-(7-methylpyrido[2,3-]pyrazin-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 5-(7-methylpyrido[2,3-]pyrazin-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-amine 2-chloro-5-(7-methylpyrido[2,3-]pyrazin-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 5-(7-methylpyrido[2,3-]pyrazin-6-yl)-2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-(2,2-dimethylcyclopropyl)-5-(7-methylpyrido[2,3-]pyrazin-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-isopropyl-5-(7-methylpyrido[2,3-]pyrazin-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-(tert-butyl)-5-(7-methylpyrido[2,3-]pyrazin-6-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 7-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4)-yl)-6-methyl-[1,2,4]triazolo[4,3-]pyrimidin-3(2)-one 7-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4)-yl)-2,6-dimethyl-[1,2,4]triazolo[4,3-]pyrimidin-3(2)-one 5,6-dimethyl-7-(2-(1-methylcyclopropyl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4)-yl)-[1,2,4]triazolo[4,3-]pyrimidin-3(2)-one 7-(2-(1-Fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-5,6-dimethyl- [1,2,4]triazolo[4,3-]pyrimidin-3(2)-one 7-(2-(1-Fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-2,5,6-trimethyl- [1,2,4]triazolo[4,3-]pyrimidin-3(2)-one 7-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4- c ]pyridine-5(4 H )-yl)-5,6-dimethyl-2-(methyl- d 3)-[1,2,4]triazolo[4,3- a ]pyrimidine-3(2 H )-one]]> 7-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-5,6-dimethyl-[1,2,4]triazolo[4,3-]pyrimidin-3(2)-one 1-((7-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-5,6-dimethyl-3-oxo- [1,2,4]triazolo[4,3-]pyrimidin-2(3)-yl)methyl)cyclopropane-1-carbonitrile 7-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-2-((2,2-difluorocyclopropyl)methyl)-5,6-dimethyl-[1,2,4]triazolo[4,3-]pyrimidin-3(2)-one 7-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-2-(cyclopropylmethyl)-5,6- dimethyl-[1,2,4]triazolo[4,3-]pyrimidin-3(2)-one 7-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-2-((3,3-difluorocyclobutyl)methyl)-5,6-dimethyl-[1,2,4]triazolo[4,3-]pyrimidin-3(2)-one 7-(2-Cyclopropyl-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-2,5,6-trimethyl-[1,2,4]triazolo[4,3-]pyrimidin-3(2)-one 2-(Cyclopropylmethyl)-7-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazolo[5,4-]pyridin-5(4)-yl)-5,6-dimethyl-[1,2,4]triazolo[4,3-]pyrimidin-3(2)-one or a pharmaceutically acceptable salt thereof.

[0231] E44. A pharmaceutical composition comprising a compound of any one of E1-E43, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0232] E45. A method of treating a neurological and / or psychiatric disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound of any one of E1-E43, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E44.

[0233] E46. The method of E45, wherein the disorder is associated with mAChR M4 dysfunction.

[0234] E47. The method of E45 or E46, wherein the disorder is a neurological and / or psychiatric disorder associated with mAChR M4 dysfunction.

[0235] E48. The method of any one of E45-E47, wherein the disorder is selected from the group consisting of Alzheimer’s disease, schizophrenia, a sleep disorder, a pain disorder, and a cognitive disorder.

[0236] E49. The method of E48, wherein the disorder is Alzheimer’s disease.

[0237] E50. The method of any one of E45-E47, wherein the disorder is selected from the group consisting of: psychosis, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, anxiety psychotic episodes, 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 intellectual disability, autism disorder, movement disorder, Tourette syndrome, akinesia-rigidity syndrome, movement disorder associated with Parkinson's disease, tardive dyskinesia, movement difficulties based on drug-induced and neurodegenerative changes, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[0238] E51. A kit comprising a compound as described in any one of E1-E43 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 disorders related to cholinergic activity; (d) instructions for treating disorders related to cholinergic activity; (e) instructions for treating disorders related to mAChR M4 receptor activity; and (f) instructions for administering the compound in combination with cognitive or behavioral therapy.

[0239] E52. The compound of any one of E1-E43 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of E44, for use in the treatment of neurological and / or mental disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors.

[0240] E53. Use of any compound of any one of E1-E43 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in E44 in the preparation of a medicament for treating neurological and / or mental disorders in mammals associated with dysfunction of muscarinic acetylcholine receptors.

[0241] Compounds can exist as stereoisomers with asymmetric or chiral centers. Stereoisomers are classified according to the configuration of the substituents surrounding the chiral carbon atom. R "or" S The term "" as used in this article R "and" S" is the configuration as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry [IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry], Pure Appl. Chem. [Pure and Applied Chemistry], 1976, 45: 13-30. The present disclosure contemplates various stereoisomers and mixtures thereof, and these are specifically included within the scope of the invention. Stereoisomers include enantiomers and diastereomers and mixtures of enantiomeric or diastereomeric forms. Single stereoisomers of compounds can be synthesized from commercially available starting materials, either by using asymmetric synthesis or by preparing racemic mixtures followed by resolution methods well known to one of ordinary skill in the art. These resolution methods are exemplified by (1) attachment of the enantiomeric mixture to a chiral auxiliary, separation of the resulting diastereomeric mixture by chromatography or other standard techniques, and optionally, release of the optically pure product from the auxiliary, as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry”, 5thEd. (1989), Longman Scientific & Technical [Longman Scientific & Technical], CM20 2JE, Essex, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods.

[0242] It is understood that compounds can have tautomeric forms as well as geometric isomers, and these are also contemplated as embodiments of the disclosure.

[0243] In compounds of Formula (I) and any subformula, any "hydrogen" or "H", whether explicitly listed in a structure or implied, includes hydrogen isotopes 1 H (protium) and 2 H (deuterium).

[0244] The present disclosure also includes isotopically-labeled compounds, which are identical to those recited in Formula (I) but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the application are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, and chlorine, for example, and include 2 H, 3 H, 13 C, 14 C, 15N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F、and 36 Cl. Substitution with heavier isotopes such as deuterium (i.e., 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence can be preferred in some circumstances. Compounds can contain 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 11 C、 13 N、 15 O, and 18 F.

[0245] Isotopically enriched forms of compounds of Formula (I) or any subformulae can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically enriched reagents in place of non-isotopically enriched reagents. The degree of isotopic enrichment can be characterised as the percentage incorporation of a particular isotope at the isotopically labelled atom (e.g., % deuterium incorporation at a deuterium label).

[0246] a. pharmaceutically acceptable salts The disclosed compounds can exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" means a salt or zwitterion of a compound that is water or oil-soluble or dispersible, that is suitable for use in treating disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio, and effective for its intended use. These salts can be prepared during the final isolation and purification of the compounds or separately by reacting the amino groups of the compounds with appropriate acids. For example, the compound can 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 can be precipitated out and isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid can be removed under reduced pressure to provide the salt. Representative salts include: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, bisulfate, butyrate, camphorate, camphorsulfonate, di gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, hydroxyethanesulfonate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, new- pamoate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, p-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfate, phosphate, and the like. The amino groups of the compounds can be quaternized with alkyl chlorides, bromides and iodides (e.g., methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like).

[0247] Base addition salts can be prepared during the final isolation and purification of the disclosed compounds by reacting a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation (e.g., lithium, sodium, potassium, calcium, magnesium, or aluminum), or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, for example, from those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N- dimethyl aniline, N- methyl piperidine, N- methyl morpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzyl phenethylamine, 1 -di- phenyl- hydroxymethylamine, and N,N’- dibenzyl ethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0248] b. General Synthesis Compounds of Formula (I) can be prepared by synthetic or metabolic methods. Preparation of compounds by metabolic methods includes those occurring in the human or animal body (in vivo) or methods occurring in vitro.

[0249] Compounds of Formula (I) can be synthesized as shown in Schemes 1-11.

[0250] Scheme 1 As shown in Scheme 1, 3-bromo-4-oxopiperidine-1-carboxylic acid tert-butyl ester of Formula (i) can be reacted with R 2 substituted thioamide under suitable conditions to provide 6,7-dihydrothiazolo[5,4- c ]pyridine-5(4 H )-carboxylic acid tert-butyl ester (ii), which can then be subjected to suitable acidic Boc deprotection conditions (e.g., TFA, HC1, etc.) to provide 4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine (iii).

[0251] Scheme 2 As shown in Scheme 2, 2-bromo-6,7-dihydrothiazolo[5,4- c ]pyridine-5(4 H )-carboxylic acid tert-butyl ester of Formula (iv) can be subjected to a Suzuki reaction condition with an appropriate R 2 substituted boronic acid or ester reagent and a palladium catalyst (e.g., Pd(PPh3)4, Pd(dppf)Cl2), followed by subsequent Boc-deprotection under acidic conditions (e.g., TFA, HC1) to form 4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine (iii).

[0252] Scheme 3 As shown in Scheme 3, 2-bromo-6,7-dihydrothiazolo[5,4- c ]pyridine-5(4 H )-carboxylic acid tert-butyl ester of Formula (iv) can be reacted with R 2 substituted (1,10-phenanthroline)copper (e.g., trifluoromethyl(1,10-phenanthroline)copper) under suitable conditions, followed by subsequent Boc-deprotection under acidic conditions (e.g., TFA, HC1) to provide 4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine (iii).

[0253] Scheme 4 As shown in Scheme 4, 2-bromo-6,7-dihydrothiazolo[5,4-c ]pyridine-5(4 H )-carboxylic acid tert-butyl ester can be treated with a metalating reagent (e.g., n-BuLi, -78 °C) followed by reaction with R 2 substituted halide (e.g., CD3I) to provide 6,7-dihydrothiazolo[5,4- c ]pyridine-5(4 H )-carboxylic acid tert-butyl ester (ii).

[0254] Scheme 5 As shown in Scheme 5, R 1 substituted halide can be reacted with 4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine (iii) under suitable nucleophilic substitution conditions (e.g., amine, base (e.g., DIEA, Et3N, etc.) and solvent (e.g., NMP) heated to about 70 °C-110 °C to provide R 1 substituted 4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine of formula (vi).

[0255] Scheme 6 As shown in Scheme 6, the intermediate of formula (vii) can be heated with hydrazine in ethanol to 70 °C-80 °C to give the intermediate of formula (viii).

[0256] Scheme 7 As shown in Scheme 7, the intermediate of formula (viii) can be treated with a solvent (e.g., 1,4-dioxane, THF, etc.), CDI (CAS# 530-62-1) and heated to 60 °C-80 °C to form the compound of formula (ix).

[0257] Scheme 8 As shown in Scheme 8, the intermediate (x) can be coupled with an amine under the well-known Borchwald coupling conditions to provide the product (xi). Similar reactions can be performed on the intermediate (iv) to provide -NR 2a R 2b substituted intermediate compound.

[0258] Scheme 9 As shown in Scheme 9, intermediate (x) can be coupled with an alkoxide-type reagent in a suitable solvent to provide product (xii). Similar reactions can be performed on intermediate (iv) to provide -OR 2a substituted intermediate compounds.

[0259] Scheme 10 As shown in Scheme 10, intermediate (x) can be reacted with zinc metal and Zn(CN)2in the presence of a palladium catalyst (e.g., Pd(dppf)Cl2) and heated in a suitable solvent to provide (xiii). Similar reactions can be performed on intermediate (iv) to provide cyano-substituted intermediate compounds.

[0260] Scheme 11 As shown in Scheme 11, intermediates of formula (ix) can be treated with a base (e.g., K2CO3, Cs2CO3, and the like), R 11a -X (where X is a halogen, mesylate, and the like) and heated to 45-50 °C to form compounds of formula (xiv).

[0261] Suitable boronic acids / esters, amines, and alcohols for the coupling reactions described herein can be readily obtained from commercial sources or prepared by standard methods well known to those skilled in the art.

[0262] Compounds and intermediates can be isolated and purified by methods well known to one skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can include, but are not limited to, chromatography on solid supports (e.g., silica gel, alumina, or silica derivatized with alkylsilane groups), recrystallization (optionally preceded by pretreatment with activated charcoal) at high or low temperature, thin layer chromatography, distillation at various pressures, sublimation under vacuum, and trituration, as described in, for example, “Vogel’s Textbook of Practical Organic Chemistry,” 5thEdition (1989), Furniss, Hannaford, Smith, and Tatchell, Longman Scientific & Technical Publishers, Essex CM20 2JE, England.

[0263] The disclosed compounds can have at least one basic nitrogen, and the compound can be treated with an acid to form the desired salt. For example, the compound can be reacted with an acid at room temperature or above to provide the desired salt, which is precipitated and collected by filtration upon cooling. Examples of acids suitable for the reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, and mandelic acid, arthritic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid, and the like.

[0264] The reaction conditions and reaction times for each individual step can vary depending on the particular reactants employed and the substituents present in the reactants used. The Examples section provides specific procedures. The reactions can be worked up in the conventional manner, for example by removing the solvent from the residue and further purified according to methods generally known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise stated, the starting materials and reagents are commercially available, or can be prepared from commercially available materials by methods described in the chemical literature by one skilled in the art. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemistry techniques, techniques analogous to those used to synthesize similarly structured compounds known in the art, or techniques analogous to the procedures described in the above schemes or the Synthetic Examples section.

[0265] Conventional experimentation, including reaction conditions, reagents, the order of a synthesis route, protection of any chemical functionality that is incompatible with the reaction conditions, and appropriate manipulation of protecting groups at suitable points in the reaction sequence of the process, are included in the scope of the application. Suitable protecting groups and methods for their use to protect and deprotect different substituents are well known to those skilled in the art; examples of which can be found in PGM Wuts and TW Greene, Greene’s book entitled Protective Groups in Organic Synthesis (4th Ed.), John Wiley & Sons, New York (2006), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the present application can be accomplished by methods analogous to those described in the above synthesis schemes and specific examples.

[0266] When an optically active form of a disclosed compound is desired, it can be obtained by using an optically active starting material (e.g., by asymmetric induction by suitable reaction steps), one of the procedures described herein, or by resolution of a mixture of stereoisomers of the compound or intermediate by using standard procedures such as chromatographic separation, recrystallization or enzymatic resolution.

[0267] Similarly, when a pure geometric isomer of a compound is desired, it can be obtained by using a pure geometric isomer as a starting material, one of the procedures above, or by resolution of a mixture of geometric isomers of the compound or intermediate by using standard procedures such as chromatographic separation.

[0268] It is understood that the synthetic schemes and specific examples are illustrative and should not be construed as limiting the scope of the application as defined in the appended claims. All alternatives, modifications, and equivalents thereof are included within the scope of the claims.

[0269] c. Muscarinic acetylcholine receptor M4 activity 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 mAChR M4 to a non-maximal concentration of agonist in the presence of the compound compared to the response to the agonist in the absence of the compound. Potentiation of mAChR M4 activity can be demonstrated by methods known in the art. For example, activation of mAChR M4 activity can be determined by measuring calcium flux in response to agonist (e.g., acetylcholine) and co-expression of chimeric or promiscuous G proteins in cells loaded with a calcium-sensitive fluorescent dye (e.g., Fluo-4). In some embodiments, calcium flux is measured as an increase in the fluorescence static ratio. In some embodiments, positive allosteric modulator activity is analyzed as the EC 2+ Agonist (e.g., acetylcholine) and co-expression of chimeric or promiscuous G proteins in cells loaded with a calcium-sensitive fluorescent dye (e.g., Fluo-4). In some embodiments, calcium flux is measured as an increase in the fluorescence static ratio. In some embodiments, positive allosteric modulator activity is analyzed as the EC 20 Concentration-dependent increase in acetylcholine response (i.e., response of mAChR M4 at acetylcholine concentrations that produce 20% of the maximal response).

[0270] In some embodiments, the disclosed compounds activate mAChR M4 response in the presence of the compound, exhibited as a decrease in calcium fluorescence in mAChR M4 transfected CHO-K1 cells, compared to the response of CHO-K1 cells in the absence of the compound. In some embodiments, the disclosed compounds activate mAChR M4 response with an EC 50less than about 10 μΜ, less than about 5 μΜ, less than about 1 μΜ, less than about 500 nM, less than about 100 nM, or less than about 50 nM. In some embodiments, the mAChR M4 transfected CHO-K1 cells are transfected with human mAChR M4. In some embodiments, the mAChR M4 transfected CHO-K1 cells are transfected with rat mAChR M4.

[0271] The disclosed compounds can exhibit positive allosteric modulation of the mAChR M4 response to acetylcholine in mAChR M4 transfected CHO-K1 cells in the presence of the compound as compared to the response to acetylcholine in the absence of the compound as an increase in the response to a non-maximal concentration of acetylcholine. In some embodiments, the disclosed compounds exhibit positive allosteric modulation of the mAChR M4 response to acetylcholine with an EC 50 less than about 10 μΜ, less than about 5 μΜ, less than about 1 μΜ, less than about 500 nM, or less than about 100 nM. In some embodiments, the EC 50 In some embodiments, the mAChR M4 transfected human mAChR M4. In some embodiments, the mAChR M4 transfected rat mAChR M4.

[0272] The disclosed compounds can exhibit selectivity for the mAChR M4 receptor over one or more of the mAChR M1, M2, M3, or M5 receptors. For example, the disclosed compounds can activate the mAChR M4 response in mAChR M4 transfected CHO-K1 cells with an EC 50 less than the EC of one or more of the mAChR M1, M2, M3, or M5 transfected CHO-K1 cells 50 In some embodiments, the disclosed compounds can activate the mAChR M4 response with an EC 50 about 5 fold, about 10 fold, about 20 fold, about 30 fold, about 50 fold, about 100 fold, about 200 fold, about 300 fold, about 400 fold, or more than about 500 fold. In some embodiments, the disclosed compounds can activate the mAChR M4 response with an EC 50about 400-fold, or more than about 500-fold. In some embodiments, the disclosed compounds can activate mAChR M4 responses with an EC 50 about 400-fold, or more than about 500-fold. In some embodiments, the disclosed compounds can activate mAChR M4 responses with an EC 50 about 400-fold, or more than about 500-fold. In some embodiments, the disclosed compounds can activate mAChR M4 responses with an EC 50 about 400-fold, or more than about 500-fold. In some embodiments, the disclosed compounds can activate mAChR M4 responses with an EC 50 about 400-fold, or more than about 500-fold. In some embodiments, the disclosed compounds can activate mAChR M4 responses with an EC

[0273] The disclosed compounds can activate mAChR M4 responses in M4-transfected CHO-K1 cells with an EC 50 less than about 10 μΜ, and exhibit selectivity for the M4 receptor over one or more of mAChR M1, M2, M3, or M5 receptors. For example, in some embodiments, the EC 50 may be less than about 10 μΜ, less than about 5 μΜ, less than about 1 μΜ, less than about 500 nM, less than about 100 nM, or less than about 50 nM; and the compound can also activate mAChR M4 responses with an EC 50 about 400-fold, or more than about 500-fold. In some embodiments, the disclosed compounds can activate mAChR M4 responses with an EC 50 may be less than about 10 μΜ, less than about 5 μΜ, less than about 1 μΜ, less than about 500 nM, less than about 100 nM, or less than about 50 nM; and the compound can also activate mAChR M4 responses with an EC 50The reduction is approximately 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, or more than 500-fold. In some embodiments, the EC of the compound... 50 The concentrations can be 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; and the compound can also activate the mAChR M4 response, with an EC50 greater effect than that of activating the mAChR M3 response. 50 The reduction is approximately 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, or more than 500-fold. In some embodiments, the EC of the compound... 50 The concentrations can be 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; and the compound can also activate the mAChR M4 response, with an EC5 value lower than that activating the mAChR M5 response. 50 The reduction is approximately 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, or more than 500-fold. In some embodiments, the EC of the compound... 50 The concentrations can be 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; and the compound can also activate the mAChR M4 response, with an EC5 value lower than that of the M2-M5 receptor response. 50 A 5-fold reduction, a 10-fold reduction, a 20-fold reduction, and a 30-fold reduction, compared to the activation of M2, M3, or M5 receptor responses, resulted in lower ECGs. 50 A reduction of approximately 50-fold, 100-fold, 200-fold, 300-fold, or 400-fold, or compared to the activation of mAChR M1, M2, M3, or M5 receptor responses, its EC 50 It has been reduced by more than 500 times.

[0274] The in vivo efficacy of the disclosed compounds can be measured in many preclinical rat behavioral models, where known, clinically useful antipsychotic drugs show similar positive responses. For example, the disclosed compounds can reverse excitatory movement induced by oral administration of amphetamines at doses ranging from 1 to 100 mg / kg in male Spratly-Dowley rats.

[0275] 3. Pharmaceutical compositions and formulations The disclosed compounds can be incorporated into pharmaceutical compositions suitable for administration to a subject (e.g., a patient, which can be a human or non-human). The disclosed compounds can also be provided as a formulation (e.g., a spray-dried dispersion formulation).

[0276] Pharmaceutical compositions and formulations can include a "therapeutically effective amount" or a "prophylactically effective amount" of an agent. A "therapeutically effective amount" refers to the amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a composition can be determined by one of skill in the art, and can vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compounds of the present application (e.g., compounds of Formula (I)) are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, a prophylactically effective amount will be less than a therapeutically effective amount since the prophylactic dose is used before or at the early stages of disease in the subject.

[0277] For example, a therapeutically effective amount of a compound of Formula (I) can 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.

[0278] Pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or any type of formulation aid. Some examples of materials that can be used as pharmaceutically acceptable carriers are sugars, such as, but not limited to, lactose, glucose, and sucrose; starches, such as, but not limited to, corn starch and potato starch; cellulose and its derivatives, such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered astragalus gum; malt; gelatin; talc; excipients, such as, but not limited to, cocoa butter and suppository waxes; oils, such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; esters, such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffers, such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffer solutions, as well as other non-toxic and compatible lubricants, such as, but not limited to, sodium dodecyl sulfate and magnesium stearate, and colorants, release agents, coating agents, sweeteners, flavoring agents, and flavoring agents. Preservatives and antioxidants may also be included in the composition at the discretion of the formulator.

[0279] Therefore, compounds and their pharmaceutically acceptable salts can be formulated for administration via, for example, solid dosage forms, eye drops, in topical oil-based formulations, injection, inhalation (through the mouth or nose), implantation, or for oral, oral, parenteral, or rectal administration. Technologies and formulations are generally available in Remington's Pharmaceutical Sciences (Meade Publishing Co., Easton, Pennsylvania). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0280] The route of administration of the disclosed compound and the form of the composition determine the type of carrier to be used. The composition may be in a variety of forms suitable for, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, oral, implant, or parenteral) or topical administration (e.g., skin, lung, nose, ear, eye, liposome delivery system, or iontophoresis).

[0281] Carriers for systemic application typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, antioxidants, preservatives, flow aids, solvents, suspending agents, wetting agents, surfactants, and combinations thereof. All carriers are optional in the composition.

[0282] Suitable diluents include sugars such as dextrose, lactose, dextrates, and sucrose; glycols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50% to about 90%.

[0283] Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and coconut oil. The amount of lubricant(s) in a systemic or topical composition is typically about 5% to about 10%.

[0284] Suitable binders include polyvinylpyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and celluloses and their derivatives such as sodium carboxymethylcellulose, ethyl cellulose, methyl cellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5% to about 50%.

[0285] Suitable disintegrants include agar-agar, alginic acid and its sodium salt, effervescent mixtures, crosscarmellose, crospovidone, sodium starch glycolate, starch, sodium starch glycolate, hydroxypropyl starch, clay, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1% to about 10%.

[0286] Suitable colorants include FD&C dyes and the like colorants. When used, the amount of colorant(s) in a systemic or topical composition is typically about 0.005% to about 0.1%.

[0287] Suitable flavoring agents include menthol, peppermint, and fruit flavors. When used, the amount of flavoring agent(s) in a systemic or topical composition is typically about 0.1% to about 1.0%.

[0288] Suitable sweetening agents include aspartame and saccharin. The amount of sweetening agent(s) in a systemic or topical composition is typically about 0.001% to about 1%.

[0289] Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1% to about 5%.

[0290] Suitable preservatives include benzalkonium chloride, methyl paraben, and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01% to about 5%.

[0291] Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically from about 1% to about 5%.

[0292] Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oil, alcohols such as ethanol, and phosphate buffered solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0% to about 100%.

[0293] Suitable suspending agents include AVICEL RC-591 (from FMC Corporation, Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically from about 1% to about 8%.

[0294] Suitable surfactants include lecithin, polysorbate 80, and sodium lauryl sulfate, as well as TWEENS (from Atlas Powder Company, Wilmington, DE). Suitable surfactants include those disclosed in C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant(s) in a systemic or topical composition is typically from about 0.1% to about 5%.

[0295] While the amount of components in a systemic composition can vary depending on the type of systemic composition being prepared, generally, a systemic composition includes from 0.01% to 50% of an active compound (e.g., a compound of Formula (I)) and from 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include from 0.1% to 10% of an active and from 90% to 99.9% of a carrier, including diluents and solvents.

[0296] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount (typically at least about 5%, more particularly from about 25% to about 50%) of an active. Oral dosage compositions include from about 50% to about 95% of a carrier, and more particularly, from about 50% to about 75%.

[0297] Tablets can be compressed, tablet triturates, enteric coated, sugar coated, film coated, or multiple compressed. Tablets typically include the active ingredient and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, coloring agents, flavoring agents, sweetening agents, glidants, and combinations thereof. Particular diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Particular binders include starch, gelatin and sucrose. Particular disintegrants include alginic acid and crosscarmellose. Particular lubricants include magnesium stearate, stearic acid and talc. Particular coloring agents are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain a sweetening agent (such as aspartame and saccharin), or a flavoring agent (such as menthol, peppermint, fruit flavors), or combinations thereof.

[0298] Capsules (including implants, timed release and sustained release formulations) typically include the active compound (e.g., a compound of Formula (I)) and a carrier comprising one or more diluents disclosed above in the capsules comprising gelatin. Granules typically contain the disclosed compound, preferably a glidant (such as silicon dioxide) to improve flow properties. Implants can be of the biodegradable or non-biodegradable type.

[0299] The choice of ingredients in the carrier for oral compositions depends on secondary considerations, such as taste, cost, and shelf stability, which do not affect the efficacy of the application.

[0300] Solid compositions can be coated by conventional means (typically with pH or time dependent coatings) to provide sustained release of the disclosed compound in the gastrointestinal tract at the desired location, or at different points and times, to prolong the desired effect. The coating typically includes one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries of Essen, Germany), waxes, and shellac.

[0301] Compositions for oral administration can have a liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent formulations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid compositions for oral administration typically include the disclosed compound and a carrier, i.e., a carrier selected from diluents, coloring agents, flavoring agents, sweetening agents, preservatives, solvents, suspending agents, and surface active agents. Oral liquid compositions preferably include one or more ingredients selected from coloring agents, flavoring agents, and sweetening agents.

[0302] Other compositions for achieving systemic delivery of the subject compounds 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. Such compositions can further include lubricants, colorants, flavorants, sweeteners, antioxidants, and glidants.

[0303] The disclosed compounds can be administered topically. Topical compositions that can be applied to the skin can be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-in and rinse-off conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. The topical compositions include a disclosed compound (e.g., a compound of Formula (I)) and a carrier. The carrier of the topical composition preferably aids in penetration of the compound into the skin. The carrier can further include one or more optional components.

[0304] The amount of carrier used in combination with the disclosed compounds is sufficient to provide a practical amount of the composition for administration of the compound per unit dose. Techniques and compositions for making dosage forms useful in the methods of the present application are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker and Rhodes, Editors (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2ndEdition, (1976).

[0305] The carrier can 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 the group consisting of: 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.

[0306] The carrier of the topical composition can further include one or more ingredients selected from the group consisting of: emollients, propellants, solvents, humectants, thickening agents, powders, fragrances, pigments, and preservatives, all of which are optional.

[0307] Suitable emollients include stearyl alcohol, glycerol monoricinoleate, glycerol monostearate, propane- 1,2-diol, butane- 1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Particular emollients for the skin include stearyl alcohol and dimethicone. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%.

[0308] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95%.

[0309] Suitable solvents include water, ethanol, dichloromethane, isopropyl alcohol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Particular solvents include ethanol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%.

[0310] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. A particular humectant includes glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%.

[0311] The amount of thickening agent(s) in a topical composition is typically about 0% to about 95%.

[0312] Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, whiting, talc, fullers earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectites, trialkylaryl ammonium smectites, chemically modified magnesium aluminum silicate, organically modified smectite clay, hydrated aluminum silicate, fumed silicon dioxide, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.

[0313] The amount of perfume in the topical composition is typically from about 0% to about 0.5%, specifically, from about 0.001% to about 0.1%.

[0314] Suitable pH adjusting additives include HC1 or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.

[0315] The pharmaceutical composition or formulation can exhibit positive allosteric modulation of mAChR M4 with an EC 50 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 can exhibit positive allosteric modulation of mAChR M4 with an EC 50 between about 10 µM and about 1 nM, between about 1 µM and about 1 nM, between about 100 nM and about 1 nM, or between about 10 nM and about 1 nM.

[0316] a. Spray-dried dispersion formulation The disclosed compounds can be formulated into a spray-dried dispersion (SDD). An SDD is a single-phase, amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution in which the compound molecules are “dissolved” in the solid matrix. SDDs are obtained by dissolving the drug and polymer in an organic solvent and then spray-drying the solution. The use of spray-drying for pharmaceutical applications can result in amorphous dispersions with increased solubility for Biopharmaceutics Classification System (BCS) Class II (high permeability, low solubility) and Class IV (low permeability, low solubility) drugs. Formulation and process conditions are selected to allow rapid evaporation of the solvent from the droplets, leaving insufficient time for phase separation or crystallization. SDDs have demonstrated long-term stability and manufacturability. For example, SDDs have demonstrated over 2 years of shelf life. Advantages of SDDs include, but are not limited to, enhanced oral bioavailability of poorly water-soluble compounds, delivery using traditional solid dosage forms (e.g., tablets and capsules), reproducible, controllable, and scalable manufacturing processes, and broad applicability to structurally diverse insoluble compounds with a wide range of physical properties.

[0317] Thus, in one embodiment, the disclosure can provide a spray-dried dispersion formulation comprising a compound of Formula (I).

[0318] 4. Methods of use The disclosed compounds, pharmaceutical compositions, and formulations can be used in methods of treating disorders associated with muscarinic acetylcholine receptor dysfunction (e.g., neurological and / or psychiatric disorders). The disclosed compounds and pharmaceutical compositions can also be used in methods of enhancing muscarinic acetylcholine receptor activity in a mammal, and in methods of enhancing cognition in a mammal. These methods further include combination therapy methods for improving treatment outcomes in the context of cognitive or behavioral therapy. In the methods of use described herein, additional therapeutic agents can be administered simultaneously or sequentially with the disclosed compounds and compositions.

[0319] a. Treating a disorder The disclosed compounds, pharmaceutical compositions, and formulations can be used in methods of treating disorders, or in methods of treating disorders associated with muscarinic acetylcholine receptor dysfunction (e.g., neurological and / or psychiatric disorders). The methods of treatment can include administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I).

[0320] In some embodiments, the present disclosure provides a method for enhancing cognition in a mammal, the method comprising the step of administering to the mammal a therapeutically effective amount of a compound of Formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I).

[0321] The compounds and compositions disclosed herein can be used to treat, prevent, ameliorate, manage, or reduce the risk of a variety of disorders associated with selective mAChR M4 receptor activation. For example, treatment can include selective mAChR M4 receptor activation to an extent effective to influence cholinergic activity. The disorder can be associated with cholinergic activity, e.g., hypocholinergic function. Accordingly, a method of treating or preventing a disorder in a subject is provided, the method comprising the step of administering to the subject at least one disclosed compound or at least one disclosed pharmaceutical composition in an amount effective to treat the disorder in the subject.

[0322] Also provided is a method for treating one or more disorders associated with mAChR M4 receptor activity in a subject, the method comprising the step of administering to the subject a therapeutically effective amount of a 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.

[0323] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating a disorder associated with mAChR M4 receptors. 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 of treating a disorder associated with mAChR M4 receptors.

[0324] 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 treating a disorder associated with mAChR M4 receptors.

[0325] 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.

[0326] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal.

[0327] In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal.

[0328] 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 treating a disorder associated with muscarinic acetylcholine receptor dysfunction in a mammal.

[0329] In some embodiments, the disclosed compounds and compositions are useful in treating a variety of neurological, psychotic, and cognitive disorders associated with mAChR M4 receptors, including one or more of the following conditions or diseases: schizophrenia, psychotic disorder NOS, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic breakdown, 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 embodiments, the psychotic disorder is psychosis associated with a disease selected from major depressive disorder, mood disorder, bipolar disorder, electrolyte disturbance, Alzheimer’s disease, neurological disorder, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder.

[0330] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurological, psychotic, or cognitive disorder associated with mAChR M4 receptors, particularly a disorder described herein. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating a neurological, psychotic, or cognitive disorder associated with mAChR M4 receptors, particularly a disorder 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 treating a neurological, psychotic, or cognitive disorder associated with mAChR M4 receptors, particularly a disorder described herein.

[0331] In some embodiments, the disorder is a neurological disorder selected from brain tumor, Lewy body dementia, multiple sclerosis, sarcoidosis, Lyme disease, syphilis, Alzheimer’s disease, Parkinson’s disease, and anti-NMDA receptor encephalitis.

[0332] In some embodiments, the disorder is a psychotic disorder selected from schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, and shared psychotic disorder. In some embodiments, the schizophrenia is selected from catastrophic schizophrenia, catatonic schizophrenia, paranoid schizophrenia, residual schizophrenia, disorganized schizophrenia, and undifferentiated schizophrenia. In some embodiments, the disorder is selected from schizoid personality disorder, schizotypal personality disorder, and paranoid personality disorder. In some embodiments, the psychotic disorder is due to a general medical condition and is substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamines and other psychostimulants, and cocaine).

[0333] In some embodiments, the disclosure provides a method for treating a cognitive disorder comprising administering to a patient in need thereof an effective amount of a compound or composition of the disclosure. In some embodiments, the cognitive disorder comprises dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, other general medical conditions, or substance abuse), delirium, amnestic disorder, substance-induced persisting delirium, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, Parkinson's disease-dementia complex of Alzheimer's type, age-related cognitive decline, and mild cognitive impairment.

[0334] The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington, D.C.) provides a diagnostic tool that includes cognitive impairments, including dementia, delirium, amnesia, and age-related cognitive decline. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (2013, American Psychiatric Association, Washington, D.C.) provides a diagnostic tool for neurocognitive disorders (NCDs), including delirium, followed by syndromic severe NCD, mild NCD, and their etiological subtypes. Subtypes of severe or mild NCD include NCD caused by Alzheimer's disease, vascular NCD, Lewy body NCD, NCD caused by Parkinson's disease, frontotemporal NCD, NCD caused by traumatic brain injury, NCD caused by HIV infection, substance / drug-induced NCD, NCD caused by Huntington's disease, NCD caused by prion diseases, NCD caused by other medical conditions, NCD caused by multiple etiologies, and unspecified NCD. The NCD categories in DSM-5 encompass a group of disorders in which the primary clinical deficit is cognitive function and is acquired rather than developmental. As used herein, the term "cognitive impairment" includes those cognitive impairments and treatments of mental cognitive impairments as described in DSM-IV-TR or DSM-5. Those skilled in the art will recognize that alternative nomenclature, disease taxonomy, and classification systems exist for mental disorders, and that these systems have evolved with advances in medicine and science. Therefore, the term "cognitive impairment" is intended to include similar impairments described in other diagnostic sources.

[0335] In some embodiments, the disclosure provides methods for treating schizophrenia or psychosis, comprising administering to a patient in need thereof an effective amount of a compound or composition of the disclosure. Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic, or undifferentiated schizophrenia and substance-induced psychotic disorder. The DSM-IV-TR provides a diagnostic tool, including paranoid, disorganized, catatonic, undifferentiated, or residual schizophrenia, and substance-induced psychotic disorder. The DSM-5 eliminates subtypes of schizophrenia in favor of a dimensional approach to assess the severity of schizophrenia core symptoms to capture the heterogeneity of types and severity of symptoms exhibited in individuals with psychotic disorders. As used herein, the term "schizophrenia or psychosis" includes treatment of those psychiatric disorders as described in the DSM-IV-TR or DSM-5. Those skilled in the art will recognize that alternative nomenclature, nosology, and classification systems exist for psychiatric disorders, and that these systems evolve with medical and scientific advances. Thus, the term "schizophrenia or psychosis" is intended to include similar disorders described in other diagnostic sources.

[0336] In some embodiments, the disclosure provides methods for treating pain, comprising administering to a patient in need thereof an effective amount of a compound or composition of the disclosure. Particular pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecological surgery), chronic pain, and neuropathic pain.

[0337] The compounds and compositions can further be used in methods for preventing, treating, managing, ameliorating, or reducing the risk of the diseases, disorders, and conditions described herein. The compounds and compositions can further be used in combination with other agents in methods for preventing, treating, managing, ameliorating, or reducing the risk of the diseases, disorders, and conditions described above.

[0338] In the treatment of disorders requiring activation of mAChR M4, an appropriate dosage level can be about 0.01 to 500 mg / kg patient body weight per day which can be administered in single or multiple doses. Dosage levels can be about 0.1 to about 250 mg / kg per day, or about 0.5 to about 100 mg / kg per day. A suitable dosage level can be about 0.01 to 250 mg / kg per day, about 0.05 to 100 mg / kg per day, or about 0.1 to 50 mg / kg per day. Within this range the dosage can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg / kg per day. For oral administration, the compositions can be provided in the form of tablets containing 1.0 to 1000 milligrams, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900 or 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. This dosage regimen can be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0339] Thus, in some embodiments, the disclosure relates to a method of activating mAChR M4 receptor activity in at least one cell, the method comprising the step of: contacting the at least one cell with at least one disclosed compound, or at least one product of the disclosed method, in an amount effective to activate mAChR M4 in the at least one cell. In some embodiments, the cell is mammalian, e.g., human. In some embodiments, the cell has been isolated from a subject prior to the contacting step. In some embodiments, the contacting is performed via administration to a subject.

[0340] In some embodiments, the present application relates to a method for activating mAChR M4 activity in a subject, the method comprising the step of administering to the subject at least one disclosed compound, or at least one product of a disclosed method, in a dose and amount effective to activate mAChR M4 activity in the subject. In some embodiments, the subject is a mammal, e.g., a human. In some embodiments, prior to the administering step, the mammal has been diagnosed as in need of mAChR M4 agonism. In some embodiments, prior to the administering step, the mammal has been diagnosed as in need of mAChR M4 activation. In some embodiments, the method further comprises the step of identifying a subject in need of mAChR M4 agonism.

[0341] In some embodiments, the present application relates to a method for treating a disorder associated with selective mAChR M4 activation (e.g., a disorder associated with cholinergic activity) in a mammal, the method comprising the step of administering to the mammal at least one disclosed compound, or at least one product of a disclosed method, in a dose and amount effective to treat the disorder in the mammal. In some embodiments, the mammal is a human. In some embodiments, prior to the administering step, the mammal has been diagnosed as in need of treatment for the disorder. In some embodiments, the method further comprises the step of identifying a subject in need of treatment for the disorder.

[0342] In some embodiments, the disorder can be 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 disorder such as major depressive disorder severe; mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral manifestations of mental retardation, autism disorder, movement disorder, Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, motor difficulties based on drug induction and neurodegeneration, attention deficit hyperactivity disorder, cognitive disorders, dementia, and memory disorders.

[0343] In some embodiments, the disorder is Alzheimer's disease.

[0344] b. Enhancement of muscarinic acetylcholine receptor activity In some embodiments, the present disclosure relates to a method for enhancing muscarinic acetylcholine receptor activity in a mammal, the method 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.

[0345] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of enhancing 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 of enhancing muscarinic acetylcholine receptor activity in a mammal.

[0346] 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 muscarinic acetylcholine receptor activity in a mammal.

[0347] In some embodiments, the enhancement of muscarinic acetylcholine receptor activity increases muscarinic acetylcholine receptor activity. In some embodiments, the enhancement of muscarinic acetylcholine receptor activity is partial agonism of the muscarinic acetylcholine receptor. In some embodiments, the enhancement of muscarinic acetylcholine receptor activity is positive allosteric modulation of the muscarinic acetylcholine receptor.

[0348] In some embodiments, the administered compound exhibits an enhancement of mAChR M4 with an EC 50 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 an enhancement of mAChR M4 with an EC 50 between about 10 µM and about 1 nM, between about 1 µM and about 1 nM, between about 100 nM and about 1 nM, or between about 10 nM and about 1 nM.

[0349] In some embodiments, the mammal is a human. In some embodiments, prior to the administering step, the mammal has been diagnosed as in need of enhancement of muscarinic acetylcholine receptor activity. In some embodiments, the method further comprises the step of identifying a mammal in need of enhancement of muscarinic acetylcholine receptor activity. In some embodiments, the enhancement of muscarinic acetylcholine receptor activity treats a disorder associated with muscarinic acetylcholine receptor activity in the mammal. In some embodiments, the muscarinic acetylcholine receptor is mAChR M4.

[0350] In some embodiments, the enhancement of muscarinic acetylcholine receptor activity in the mammal is associated with treating a neurological and / or psychiatric disorder associated with muscarinic receptor dysfunction (e.g., a neurological or psychiatric disorder disclosed herein). In some embodiments, the muscarinic receptor is mAChR M4.

[0351] In some embodiments, the disclosure provides a method for enhancing muscarinic acetylcholine receptor activity in a cell, the method comprising the step of: contacting the cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is mammalian (e.g., human). In some embodiments, the cell has been isolated from a mammal prior to the contacting step. In some embodiments, the contacting is performed via administration to the mammal.

[0352] c. Enhancing cognition In some embodiments, the present invention relates to a method for enhancing cognition in a mammal, the method 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.

[0353] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of enhancing 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 of enhancing cognition in a mammal.

[0354] 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.

[0355] In some embodiments, the mammal is human. In some embodiments, the mammal has been diagnosed as needing cognition enhancement prior to the administering step. In some embodiments, the method further comprises the step of: identifying a mammal in need of cognition enhancement. In some embodiments, the need for cognition enhancement is associated with muscarinic receptor dysfunction. In some embodiments, the muscarinic receptor is mAChR M4.

[0356] In some embodiments, the cognition enhancement is a statistically significant increase in Novel Object Recognition. In some embodiments, the cognition enhancement is a statistically significant increase in Wisconsin Card Sorting Test performance.

[0357] d. Combination therapy methods The present invention further relates to administering a selective mAChR M4 activator for improving the outcome of a cognitive or behavioral therapy context. That is, in some embodiments, the present invention relates to a combination therapy method, the method comprising the step of: administering to a mammal an effective amount and dose of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of combination therapy for the treatment of a disease or condition 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 of combination therapy for the treatment of a disease or condition in a mammal.

[0359] In some embodiments, the disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of combination therapy for the treatment of a disease or condition in a mammal.

[0360] In some embodiments, administration in the context of cognitive or behavioral therapy improves treatment outcomes. Administration in conjunction with cognitive or behavioral therapy can be continuous or intermittent. Administration need not be concurrent with therapy and can precede, during, and / or follow therapy. For example, cognitive or behavioral therapy can be provided within 1, 2, 3, 4, 5, 6, 7 days prior to or following administration of a compound. As a further example, cognitive or behavioral therapy can be provided within 1, 2, 3, or 4 weeks prior to or following administration of a compound. As yet a further example, cognitive or behavioral therapy can be provided prior to or following administration within a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 half-lives of the administered compound.

[0361] It will be appreciated that the disclosed methods of combination therapy can be used in conjunction with the disclosed compounds, compositions, kits, and uses.

[0362] e. Combination therapy In the methods of use described herein, the additional therapeutic agent(s) can be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration encompasses administration prior to or following the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent(s) can be administered in the same composition as the disclosed compounds. In other embodiments, there can be a time interval between administration of the additional therapeutic agent(s) and the disclosed compounds. In some embodiments, administration of the additional therapeutic agent(s) with the disclosed compounds can allow for lower dosages and / or less frequent interval administration of the other therapeutic agent(s). When used in combination with one or more other active ingredients, the compounds of the present application, as well as the other active ingredients, can be used in lower doses than when each is used alone. Thus, the pharmaceutical compositions of the present application include those that contain one or more other active ingredients, in addition to a compound of Formula (I). The combinations referred to above can include a compound of the present application with one other active compound, as well as a compound of the present application with two or more other active compounds.

[0363] The disclosed compounds can be used in the treatment, prevention, control, amelioration, or reduction of risk of the above diseases, disorders and conditions for which the disclosed compounds or the other drugs are useful, as single agents or in combination with one or more other drugs. The drug combination can be more effective than either drug used alone, or can be less toxic, or have greater efficacy, or have different side effects. The one or more other drugs can be administered simultaneously or sequentially with the disclosed compounds. When the disclosed compounds are used as combinations with one or more other drugs, pharmaceutical compositions of such drugs and the disclosed compounds in unit dosage form can be used. However, the combination therapy can also be administered on overlapping or non-overlapping dosage schedules. It is also contemplated that the combination of one or more active ingredients with the disclosed compounds can be more effective than either as a single agent. Thus, the disclosed compounds and other active ingredients can be used in smaller doses that when used alone, when used in combination.

[0364] The pharmaceutical compositions and methods of the present application can further comprise other therapeutically active compounds known to be useful in the treatment of the disease or condition of interest.

[0365] The combinations above include not only the disclosed compounds with one other active compound, but also with two or more other active compounds. Likewise, the disclosed compounds can be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of diseases or conditions for which the disclosed compounds can be useful. Such other drugs can be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with the disclosed compounds. When the disclosed compounds are used as a combination with one or more other drugs, pharmaceutical compositions containing these other drugs in addition to the disclosed compounds are preferred. Accordingly, pharmaceutical compositions include those that also contain one or more other active ingredients in addition to the compounds of the present application.

[0366] The weight ratio of the disclosed compound to the second active ingredient can be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present application is combined with another agent, the weight ratio of the disclosed compound to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably about 200: 1 to about 1 : 200. Combinations of a compound of the present application and other active ingredients will generally also fall within the aforementioned range, but in each case the effective dose of each active ingredient should be

[0367] In such combination therapy, the disclosed compounds and other drugs can be administered simultaneously or sequentially. In addition, administration of one element can be prior to, simultaneous with, or sequential to the administration of the other.

[0368] Thus, the disclosed compounds can be used alone or in combination with other agents known to be beneficial in the subject indication or other drugs that affect receptors or enzymes that can increase the efficacy, safety, convenience of the disclosed compounds or reduce unwanted side effects or toxicity of the disclosed compounds. The subject compounds and other agents can be co-administered in a concomitant therapy or in a fixed combination.

[0369] In some embodiments, the compounds can be used in combination with anti- Alzheimer's agents, beta-secretase inhibitors, cholinergic agents, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, Ml allosteric agonists, Ml positive allosteric modulators, NSAIDs (including ibuprofen), vitamin E, and anti-amyloid antibodies. In another embodiment, the subject compounds can be used in combination with sedatives, hypnotics, anxiolytics, antipsychotic drugs (typical and atypical), anxiolytic agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, etc., such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, clonidine, clorazepate, chlordiazepoxide, desipramine, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etodolac, flurazepam, flutemazine, fluoxetine, flurazepam, geabarbital, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone, melatonin, mephobarbital, methaqualone, methyprylon, midafural, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraflutizol, paroxetine, pentobarbital, perlapine, perphenazine, phenazodine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, tiotixene, tracazolate, tranylcypromaine, triazolam, trichloromethylphenyl sulfone, trifluoperazine, triptergine, trimipramine, ultrazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zopiclone, and salts thereof, combinations thereof, and the like, or the subject compounds can be used in conjunction with physical methods such as light therapy or electrostimulation.

[0370] In some embodiments, the compounds can be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor, e.g., carbidopa or benserazide), an anticholinergic agent (e.g., biperiden (optionally as its hydrochloride or lactate salt) and trihexephendyl (benztropine) hydrochloride), a COMT inhibitor (e.g., entacapone), a MOA-B inhibitor, an antioxidant, an A2a adenosine receptor antagonist, a cholinergic agonist, an NMDA receptor antagonist, a serotonin receptor antagonist and a dopamine receptor agonist (e.g., alentemol, bromocriptine, fenoldopam, lysuride, naxagolide, pergolide, and pramipexole). It will be appreciated that the dopamine agonists can be in the form of a pharmaceutically acceptable salt, e.g., alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride, and pergolide mesylate. Lysuride and pramipexole are generally used in non-salt form.

[0371] In some embodiments, the compounds can be used in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolone classes of antipsychotic agents. Suitable examples of phenothiazines include chloφromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, peφhenazine and trifluoperazine. Suitable examples of thioxanthenes include chloφrothixene 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 molindone. Other antipsychotic agents include loxapine, sulpiride and risperidone. It will be appreciated that the antipsychotic agents can be in the form of a pharmaceutically acceptable salt when used in combination with the subject compounds, e.g., chloφromazine hydrochloride, mesoridazine benzenesulfonate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine enanthate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Peφhenazine, chloφrothixene, clozapine, haloperidol, pimozide and risperidone are generally used in non-salt form. Thus, the subject compounds can be used in combination with acetophenazine, alentemol, aripiprazole, amiserodone, benztropine, bromocriptine, biperiden, chloφromazine, chloφrothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lysuride, loxapine, mesoridazine, molindone, naxagolide, olanzapine, pergolide, peφhenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexephendyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.

[0372] In some embodiments, the compounds can 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 inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, alpha-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1Aagonists or antagonists (especially 5-HT1Apartial agonists), and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, despramine, imipramine, and trimipramine; amoxapine, desvenlafaxine, maprotiline, nortriptyline, and protriptyline; fluoxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazid, phenazine, tranylcypromine, and selegiline; moclobemide; venlafaxine; duloxetine; aripiprazole; bupropion, lithium, nefazodone, trazodone, and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlordiazepoxide, diazepam, halazepam, lorazepam, oxazepam, and prazepam; buspirone, flurazepam, gepirone, and ipsapirone, and pharmaceutically acceptable salts thereof.

[0373] In some embodiments, the compounds can be co-administered with orthosteric muscarinic agonists, muscarinic potentiators, or cholinesterase inhibitors. In some embodiments, the compounds can be co-administered with GlyT1 inhibitors, among others, such as, but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbital, and salts thereof, and combinations thereof.

[0374] f. Mode of administration The methods of treatment can include any number of ways of administering the disclosed compositions. The modes of administration can include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions (e.g., oil-in-water emulsions), liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. To prepare the pharmaceutical compositions for oral administration, the agents can be mixed with commonly known and used adjuvants and excipients, such as gum arabic, talc, starch, sugars (e.g., mannitol, methylcellulose, lactose), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, preservatives, flavorings (e.g., ether oil), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g., Gelucire.TM.). In the pharmaceutical compositions, the agents can also be dispersed in microparticles (e.g., nanoparticulate compositions).

[0375] For parenteral administration, the agents can be dissolved or suspended in physiologically acceptable diluents, such as water, buffers, oils, surfactants, dispersants or emulsifiers, with or without solubilizers. As oils, for example, but not limited to, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil can be used. More generally, for parenteral administration, the agents can be in the form of aqueous, lipid, oily or other kinds of solutions or suspensions, or even in the form of liposomes or nanosuspensions.

[0376] As used herein, the term "parenteral" refers to modes of administration that include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injections and infusions.

[0377] 5. Kits In one aspect, the disclosure provides kits comprising at least one disclosed compound, or a pharmaceutically acceptable salt thereof, and one or more of: (a) at least one agent known to increase mAChR M4 activity; (b) at least one agent known to decrease mAChR M4 activity; (c) at least one agent known to treat a disorder associated with cholinergic activity; (d) instructions for treating a disorder associated with cholinergic activity; (e) instructions for treating a disorder associated with M4 receptor activity; or (f) instructions for administering the compound in conjunction with cognitive or behavioral therapy.

[0378] In some embodiments, the at least one disclosed compound and the at least one agent are co-formulated. In some embodiments, the at least one disclosed compound and the at least one agent are co-packaged. Kits can also include compounds and / or products that are co-packaged, co-formulated, and / or co-delivered with other components. For example, a pharmaceutical manufacturer, a pharmaceutical distributor, a physician, a compounding shop, or a pharmacist can provide a kit that includes a disclosed compound and / or product and another component for delivery to a patient.

[0379] The disclosed kits can be used in conjunction with the disclosed methods of use.

[0380] The kits can further include information, instructions, or both, for using the kit to provide treatment for a medical condition in a mammal, particularly a human. The information and instructions can be in the form of text, pictures, or both, among others. Additionally or alternatively, the kits can include a compound, a composition, or both; and information, instructions, or both, regarding methods of use of the compound or composition, for example, having a benefit of treating or preventing a medical condition in a mammal, for example, a human.

[0381] The compounds and methods of the present application will be better understood by reference to the following examples, which are intended to illustrate but not limit the scope of the present application.

[0382] 6. Example All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer. 1H Chemical shifts are reported in ppm downfield from TMS as delta values. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq = AB quartet), coupling constant, integration. Reverse phase LCMS analysis was performed using the following parameters using an Agilent 1200 system consisting of a binary pump with degasser, high performance autosampler, constant temperature column compartment, C18 column, diode array detector (DAD), and Agilent 6150 MSD. The gradient conditions were 5% to 95% acetonitrile in 1.4 minutes with the aqueous phase being 0.1% TFA in water, 0.1 min hold at 95% acetonitrile, 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 set to scan from 190 nm 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 the low resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13 cycles / second with a peak width of 0.008 minutes. The dry gas flow was set to 13 liters per minute at 300 °C, and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set to 3000 V, and the fragmentation voltage was set to 100 V. Data acquisition was performed using Agilent Chemstation and Analytical Studio Reviewer software.

[0383] a. Preparation of intermediates 1 -Methylcyclopropane thioformamide. To a suspension of 1 -methylcyclopropane carboxamide (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 give the title compound (1.2 g). ES-MS [M+1] + : 116.9.

[0384] 1 -fluorocyclopropane- 1 -thiocarboxamide. To a suspension of 1 -fluorocyclopropanecarboxamide (500 mg, 4.85 mmol) and sodium carbonate (524 mg, 4.85 mmol) in THF (24 mL) was added Lawesson's reagent (1.96 g, 4.85 mmol). The resulting mixture was heated to 70 °C. After 36 hr, the reaction mixture was concentrated and the resulting residue was diluted with EtOAc and washed with water (2x) and brine. The organic layer was concentrated to give the desired compound which was carried on to the next step without further purification. 1 H 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).

[0385] 2-( 1 -methylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine. To a suspension of 1 -methylcyclopropanethiocarboxamide (1.0 g, 9.0 mmol) in ethanol (46 mL) was added N -Boc-3-bromo-4-oxopiperidine (2.5 g, 9.0 mmol) and then the reaction was heated to 80 °C for 48 h. The crude reaction mixture was concentrated in vacuo. To the residue was added DCM (25 mL) and TFA (6.9 mL). After 1 h at room temperature, the reaction mixture was concentrated. The residue was dissolved in EtOAc and saturated Na2CO3solution. The mixture was separated and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified via normal phase column chromatography (0%-70% EtOAc / hexanes, then 0%-10% DCM:MeOH:1% NH4OH gradient) to give the title compound (1.59 g). The 1 H NMR (400MHz, CDCl3) 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.

[0386] 2-cyclopropyl-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine hydrochloride. Cyclopropanethioamide (1.8 g, 18.0 mmol) and N -Boc-3-bromo-4-oxopiperidine (5.0 g, 18.0 mmol) were stirred at 80 °C for 2 h. The solution was concentrated, then 1,4-dioxane (8 mL) and 4 M hydrochloric acid solution. After 1 h at room temperature, the solution was concentrated in vacuo to give the title compound (4.0 g). 1 H NMR (400 MHz, DMSO-d6) 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.

[0387] 2-(2,2-dimethylcyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine. In a vial, 2,2-dimethylcyclopropanethioamide (232 mg, 1.8 mmol) and N -Boc-3-bromo-4-oxopiperidine (500 mg, 1.8 mmol) were combined in ethanol (2 mL). After 2 h at 80 °C, the reaction mixture was concentrated. To the crude residue was added DCM (2 mL) and trifluoroacetic acid (1.38 mL). After 1 h at room temperature, the solution was concentrated, diluted with saturated aqueous Na2CO3, and extracted with DCM (3x). The combined organic layers were passed through a hydrophobic phase separator and concentrated to give the title compound (195 mg). 1 H NMR (400MHz, 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.

[0388] 2-Isopropyl-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine. A vial containing 2-methylpropane thioamide (185 mg, 1.8 mmol) and N -Boc-3-bromo-4-oxopiperidine (500 mg, 1.8 mmol) was heated at 80 °C for 2 h. The reaction mixture was concentrated. To the crude residue was added DCM (2 mL) and trifluoroacetic acid (1.38 mL). After 1 h, the solution was concentrated, diluted with saturated Na2CO3solution, and the aqueous layer was extracted with DCM (3x). The combined organic layers were passed through a hydrophobic phase separator and concentrated to give the title compound (372 mg). 1 H NMR (400 MHz, CDCl3) 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.

[0389] 2-(tert-Butyl)-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine. A vial containing 2,2-dimethylpropane thioamide (211 mg, 1.8 mmol) and N -Boc-3-bromo-4-oxopiperidine (500 mg, 1.8 mmol) was heated at 80 °C for 2 h. The solution was concentrated. To the crude residue was added DCM (2 mL) and trifluoroacetic acid (1.38 mL). After 1 h at room temperature, the reaction mixture was concentrated and purified through a SCX cartridge. After elution with 2 N NH3 / MeOH solution, the solvent was removed to give the title 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.

[0390] 2-(1-Fluorocyclopropyl)-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine. 1-Fluorocyclopropane-1-thiocarboxamide (114 mg, 0.72 mmol) and N Boc-3-bromo-4-oxopiperidine (200 mg, 0.72 mmol) were heated to 80 °C for 18 h. The reaction mixture was concentrated and the residue was purified by normal phase column chromatography (0%-80% EtOAc / hexanes). To the residue was added DCM and trifluoroacetic acid (2.0 mL; 2:1) at room temperature. After 3 hr, the solution was concentrated and the material was purified using an SCX cartridge. After elution with 2 N NH3 / MeOH solution, the solvent was removed to give the title compound. ES-MS [M+1] + : 199; 1 H 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).

[0391] 2-Cyclobutyl-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine. Cyclobutane thioicarboxamide (203 mg, 1.76 mmol) and N- boc-3-bromo-4-oxopiperidine (490 mg, 1.76 mmol) was stirred at 80 °C for 2 hr. The solution was concentrated, then DCM (4.0 mL) and trifluoroacetic acid (1.35 mL) were added at room temperature for 1 hr. The solution was concentrated, then diluted with EtOAc and saturated Na2CO3 solution. The layers were separated, and the aqueous layer was extracted with EtOAc (2x). The combined organic layers were dried (MgSO4), filtered, and concentrated to give the title compound (300 mg). ES-MS [M+1] + : 195; 1 HNMR (400 MHz, CDCl3) 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).

[0392] 2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine 2,2,2-trifluoroacetate. A vial containing 6-Boc-2-bromo-4,5,6,7-tetrahydro-6- azabenzo thiazole (170 mg, 0.53 mmol) and trifluoromethyl(l,10-phenanthroline)copper (200 mg, 0.64 mmol) in DMA (2 mL) was heated at 100 °C for 18 h. The reaction was diluted with water and EtOAc. The organics were extracted with water (3x), brine (3x), dried (MgSO4), filtered and concentrated. The crude residue was purified by normal phase chromatography (0%-30% EtOAc / hexanes) to give Boc protected 2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine which was dissolved in DCM (2 mL) and trifluoroacetic acid (0.49 mL) and stirred for 2 h. The reaction was concentrated to give the title compound (58 mg). 1 H NMR (400 MHz, CDCl3) δ 4.52 (s, 2H), 3.60 (t, J = 6.0 Hz,2H), 3.28 (t, J = 5.9 Hz, 2H); ES-MS [M+1] + : 209.1.

[0393] 2-(methyl- d 3)-6,7-dihydrothiazolo[5,4- c ]pyridine-5(4 H )-carboxylic acid tert-butyl ester. To a solution of 2-bromo-6,7-dihydrothiazolo[5,4- 1 c ]pyridine-5(4 H )-carboxylic acid tert-butyl ester (100 mg, 0.31 mmol) in THF (3.1 mL) was added n -BuLi (150 μL, 0.38 mmol) at -78 °C. After 10 min at -78 °C, iodomethane- 1 d 3 (97.5 μL, 1.57 mmol) was added. After a further 1 h, water was added to the reaction mixture and the mixture was warmed to ambient temperature. The mixture was extracted with EtOAc (1x) then chloroform / IPA (3:1) (2x). The organic phases were combined, dried (MgS04), filtered, and concentrated. The crude material was purified using normal phase column chromatography (0%-50% EtOAc / hexane) to give the title compound (49 mg). ES-MS [M + H] + = 358.

[0394] 2-(methyl- d 3)-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine. To a solution of 2-(methyl- 1 d 3)-6,7-dihydrothiazolo[5,4- c ]pyridine-5(4 H )-carboxylic acid tert-butyl ester (49.3 mg, 0.19 mmol) dissolved in DCM (2 mL) was added hydrochloric acid (4 M in 1,4-dioxane) (61 μL, 2.0 mmol). After 18 h at room temperature, additional HCl (4 M in 1,4-dioxane) (61 μL, 2.0 mmol) was added and the reaction stirred for 1 h then concentrated. The residue was dissolved in MeOH and purified by SCX cartridge (eluted with 2 N NH3 / MeOH solution). The solvent was removed to give the title compound (24 mg). ES-MS [M + H] + = 158.

[0395] 2-chloro-4,5,6,7-tetrahydro-[l,3]thiazolo[5,4- c ]pyridine, 2,2,2-trifluoroacetate. To a solution of 6-Boc-2-chloro-4,5,6,7- tetrahydro-6-azabenzothiazole (250 mg, 0.91 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.7 mL, 9.1 mmol). After 1 h, the reaction was concentrated to give the title compound (195 mg). ES-MS [M+1] + : 175.0.

[0396] 4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridin-2-amine, 2,2,2-trifluoroacetate. To a solution of 6-Boc-2-amino-4,5,6,7- tetrahydro-6-azabenzothiazole (100 mg, 0.39 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.3 mL, 3.92 mmol). After 1 h, the reaction was concentrated to give the title compound (48 mg). ES-MS [M+1] + : 156.1.

[0397] 2-(thiophen-2-yl)-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine. In a vial, thiophene-2-boronic acid (105 mg, 0.82 mmol), 6-Boc-2-bromo-4,5,6,7-tetrahydro-6-azabenzothiazole (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). The reaction was purged with nitrogen (3x), the reaction was heated to 80 °C for 2 h. The reaction was filtered through Celite ® , then the Celite ® was washed with DCM (2 x 25 mL). The reaction was concentrated, and the filtrate was purified by normal phase chromatography (0%-40% EtOAc / hexanes) to give the desired Boc amine. The above residue was dissolved in DCM (2 mL) and trifluoroacetic acid (0.59 mL). After 1 h, the reaction was concentrated, basified with saturated Na2CO3, extracted with DCM (3x), passed through a hydrophobic frit, and concentrated to give the title compound (112 mg). 1 H NMR (400 MHz, CDCl3) δ 7.44 (dd, J ​​​= 3.7, 1.2 Hz, 1H), 7.36 (dd, J = 5.1, 1.2 Hz, 1H), 7.06 (dd, J = 5.1, 3.7 Hz, 1H), 4.10 (s,2H), 3.24 (t, J = 5.9 Hz, 2H), 2.90 (ddd, J = 6.0, 4.1, 1.8 Hz, 2H); ES-MS [M+1] + :223.1.

[0398] 2-(1-methyl-1 H -pyrazol-5-yl)-4,5,6,7-tetrahydrothiazo[5,4- c Pyridine. 6-Boc-2-bromo-4,5,6,7-tetrahydro-6-azabenzothiazole (300 mg, 0.94 mmol), cesium carbonate (924 mg, 2.82 mmol), Pd(dppf)Cl2 (69 mg, 0.09 mmol), and 1-methylpyrazole-5-boronic acid pinacol ester (391 mg, 1.88 mmol) in 1,4-dioxane (2.3 mL) and water (0.4 mL) were heated at 105 °C for 18 h. The mixture was then passed through Celite. ® The mixture was filtered through a pad, and the filtrate was concentrated. The residue was purified by normal-phase chromatography (0%–40% EtOAc / hexane) to obtain Boc-amine, which was dissolved in DCM (2 mL) and trifluoroacetic acid (1.1 mL). After 1 h, the reaction was concentrated, alkalized with saturated Na2CO3 solution, extracted with DCM (3x), passed through a hydrophobic phase separator, and concentrated to obtain the title compound (162 mg). 1 H NMR (400 MHz, CDCl3) δ7.47 (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.

[0399] 2-carbamoyl-6,7-dihydrothiazolo[5,4- c ]pyridine-5(4 H )-carboxylic acid tert-butyl ester. To a solution of 6,7-dihydrothiazolo[5,4- c ]pyridine-2,5(4 H )-dicarboxylic acid 5-(tert-butyl) 2-ethyl ester (300 mg, 0.96 mmol) in ethanol (5 mL) was added a solution of NaOH in water (0.38 mL 5 M ). The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and used without further purification. To the reaction mixture in THF (3.2 mL) was added DIEA (1.67 mL), HATU (1.1 g) and NH4Cl (285 mg). The reaction mixture was heated to 75 °C. After 18 h, water (2 mL) was added and the mixture was extracted with chloroform / IPA (3 : 1) (3x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crude material was purified using normal phase column chromatography (0% - 2% MeOH / DCM) to give the title compound. 1 H NMR (400 MHz, DMSO- J = 5.3 Hz, 2H), 2.90 (t, J = 5.1 Hz, 2H), 1.49 (s, 9H); ES-MS [M + H] + = 284.

[0400] 4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine-2-carboxamide. Prepared in a similar manner to 2-(methyl- d 3)-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine to provide the title compound. 1 H NMR (400 MHz, DMSO- d 6 ) δ7.15 (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.

[0401] 6-Chloro-5-methylpyridin-2,3-diamine. Iron powder (1.79 g, 32.0 mmol) was added to a suspension of 6-chloro-5-methyl-3-nitropyridin-2-amine (2.0 g, 10.7 mmol) and ammonium chloride (1.05 g, 21.3 mmol) in isopropanol (34 mL) / water (17 mL). The resulting mixture was stirred at 90 °C for 3 h. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and passed through Celite. ® The sample was filtered and washed with EtOAc. The filtrate was washed successively with water (3x) and brine. The combined washes were extracted with EtOAc (2x), and the combined organic layers were dried (MgSO4), filtered, and concentrated. The material was used without further purification. ES-MS [M+1] + : 158.

[0402] 6-Chloro-7-methylpyrido[2,3- b Pyrazine. Glyoxal (3.0 mL, 26.7 mmol) (40% w / w aqueous solution) was added to a solution of 6-chloro-5-methylpyridin-2,3-diamine (1.68 g, 10.7 mmol) dissolved in THF (53 mL). The reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel normal-phase column chromatography (0%-45% EtOAc / DCM) to give the title compound (1.15 g). 1 H NMR (400 MHz, MeOD) δ9.02 (d, J = 1.9 Hz, 1H), 9.00 (d, J = 1.9 Hz, 1H), 8.47 (q, J = 1.1 Hz, 1H), 2.66(d, J = 1.0 Hz, 3H). ES-MS [M+1] - : 180.

[0403] 7-Chloro-9-methyl-4 H -pyrimidin[1,2- b Synthesis of pyridazin-4-one.

[0404] (i) 5-(((6-chloro-4-methylpyridazin-3-yl)amino)methylene)-2,2-dimethyl- 1,3-dioxane-4,6-dione. To a solution of 6-chloro-4-methylpyridazin-3-amine (100 mg) in ethanol (1.2 mL) was added triethyl orthoformate (0.174 mL) and isopropylidene malonate (151 mg) at ambient temperature. The reaction mixture was then heated to 60 °C for 18 h. The reaction mixture was filtered and the filter cake was washed with ethanol (3 x 5 mL) to give the title compound which was carried on without further purification. ES-MS [M+1] + : 298.

[0405] (ii) 7-chloro-9-methyl-4 H - pyrimido[1,2- b ]pyridazin-4-one (title compound). A solution of 5-(((6-chloro-4-methylpyridazin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione in Dowtherm™ A (1 mL) was stirred at 220 °C for 1 h. After cooling to room temperature, the mixture was added to water and acidified using 1 M M HCI. The aqueous layer was extracted with hexane (3 x 125 mL). The aqueous layer was neutralised with aqueous NaHC03and the mixture was extracted with chloroform / IPA (4:1) (3x). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give the title compound. 1 H NMR (400MHz, CD3OD) δ 8.34 (d, J = 6.4 Hz, 1H), 7.68 (q, J = 1.3 Hz, 1H), 6.69 (d, J = 6.4 Hz, 1H), 2.60 (d, J = 1.3 Hz, 3H); ES-MS [M+1] + : 196.

[0406] 7-chloro-2,8-dimethyl-4 H - pyrimido[1,2- bPyridazin-4-one. To a solution of 6-chloro-3-amino-5-methylpyridazine (1 g) in polyphosphoric acid (5 mL) was added ethyl acetoacetate (1.76 mL). The mixture was heated to 120 °C for 18 h. The mixture was slowly added to a stirred solution of 150 mL saturated NaHCO3while hot. The aqueous layer was extracted with chloroform: IPA (4: 1) three times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified via silica gel normal phase column chromatography (0% - 70% EtOAc / DCM) to give 1.34 g of the title compound. 1 H NMR (400 MHz, CDC13) δ 7.59 (q, J = 1.3 Hz, 1H), 6.50 (s, 1H), 2.50 (d, J = 1.3 Hz, 3H), 2.43(d, J = 0.7 Hz, 3H). ES-MS [M+1] + : 210.

[0407] 7-chloro-8-methyl-2-(trifluoromethyl)-4 H -pyrimido[1,2- b ]pyridazin-4-one. To a solution of 6-chloro-3-amino-5-methylpyridazine (500 mg) in polyphosphoric acid (5 mL) was added ethyl 4,4,4-trifluoroacetoacetate (1.02 mL). The mixture was heated to 120 °C for 18 h. The mixture was slowly added to a saturated solution of NaHCO3(150 mL) and 50 mL chloroform / IPA (4: 1) while maintaining the pH at ~7. After the addition was complete, the mixture was stirred for 15 min, and the organic layer was separated. The aqueous layer was further extracted with chloroform: IPA (4: 1) three times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was dissolved in 15 mL DMSO, and the filtrate was purified by RP-HPLC (5% -45% MeCN / 0.05% aqueous NH4OH). The fractions containing the product were concentrated to give the title compound. 1 H NMR (400 MHz, CDC13) δ 7.79 (q, J = 1.3 Hz, 1H), 6.98 (s, 1H), 2.56 (d, J = 1.3 Hz, 3H). ES-MS [M+1] + : 264.

[0408] 7-chloro-3-fluoro-2,8,9-trimethyl-4 H - pyrimido[1,2- b ]pyridazine-4-one. To a solution of 6-chloro-3-amino-4,5-dimethylpyridazine (550 mg) in Dowtherm™ A (4 mL) was added 2-fluoro-3-oxo-butyric acid ethyl ester (0.53 mL) and the reaction heated to 150 °C for 18 h. Additional 2-fluoro-3-oxo-butyric acid ethyl ester (0.53 mL) was added and the reaction stirred at 150 °C for an additional 18 h. The reaction mixture was purified directly via silica gel normal phase column chromatography (0% - 20% hexanes / EtOAc; then 0% - 30% EtOAc / DCM) to give 243 mg of the title compound. 1 H NMR (400 MHz, CDCl3) δ 2.62 (d, J = 0.9 Hz, 3H), 2.51 (d, J = 3.6 Hz, 3H), 2.48 (t, J = 0.9 Hz, 3H). ES-MS [M+1] + : 268.

[0409] 7-chloro-2,3,8-trimethyl-4 H - pyrimido[1,2- b ]pyridazine-4-one. To a solution of 6-chloro-3-amino-5-methylpyridazine (500 mg) in Dowtherm™ A (2 mL) was added 2-methyl-3-oxo-butyric acid ethyl ester (0.59 mL) and the reaction heated to 150 °C for 18 h. Additional 2-methyl-3-oxo-butyric acid ethyl ester (0.59 mL) was added and the reaction irradiated in a microwave reactor at 180 °C for 15 min. The solution was purified directly via silica gel normal phase column chromatography (100% Hex, then 0% - 80% EtOAc / DCM) to give 442 mg of the title compound. 1 H NMR (400 MHz, CDCl3) δ 7.53 (q, J = 1.3 Hz, 1H), 2.47 (d, J = 1.3 Hz, 3H), 2.45 (s, 3H), 2.26 (s, 3H). ES-MS [M+1] + : 224.

[0410] 7-chloro-2-(difluoromethyl)-8-methyl-4 H - pyrimido[1,2- b ]pyrimidin-4-one (1-13). To a solution of 6-chloro-3-amino-5-methylpyridazine (500 mg) in polyphosphoric acid (PPA) (5 mL) was added ethyl 4,4-difluoroacetoacetate (0.91 mL). The mixture was heated to 120 °C for 2 h. The mixture was added slowly while hot to a beaker containing 125 mL of saturated NaHC03and 50 mL of chloroform / IPA (4: 1) while maintaining the pH at ~7. After the addition was complete, the mixture was stirred for 15 min, and the organic layer was separated. The aqueous layer was further extracted with chloroform: IPA (4: 1) three times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was dissolved in DMSO (15 mL) and purified by RP-HPLC (0% - 45% MeCN / 0.05% aqueous NH4OH). The fractions containing the product were concentrated to give 640 mg of the title compound. 1 HNMR (400 MHz, CDCl3) δ 7.73 (q, J = 1.3 Hz, 1H), 6.90 (s, 1H), 6.46 (t, J = 54.8Hz, 1H), 2.55 (d, J = 1.3 Hz, 3H). ES-MS [M+1] + : 246.

[0411] 7-chloro-3-fluoro-2,8-dimethyl-4 H - pyrimido[1,2- b ]pyrimidin-4-one. To a solution of 6-chloro-3-amino-5-methylpyridazine (550 mg) in polyphosphoric acid (5.5 mL) was added ethyl 2-fluoroacetoacetate (0.96 mL). The mixture was heated to 120 °C for 2 h. The mixture was then quenched at room temperature by slow addition of saturated sodium bicarbonate (150 mL) and a solution of 4: 1 chloroform / IPA (50 mL). After the addition was complete, the mixture was stirred for 15 min, and the organic layer was separated. The aqueous layer was further extracted with chloroform: IPA (4: 1) three times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by RP-HPLC (0% - 45% MeCN / 0.05% aqueous NH4OH). The fractions containing the product were concentrated to give 627 mg of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.60 (q, J = 1.3 Hz,1H), 2.52 – 2.47 (m, 6H). ES-MS [M+H] + = 228.

[0412] 7-Chloro-8-methyl-4-oxo-4 H -pyrimidin[1,2- b [Ethylpyridinium-2-carboxylate. A mixture of diethyl ethoxymethylene malonate (641 µL) and 6-chloro-3-amino-5-methylpyridinium (500 mg) in Dowtherm™ A (6 mL) was heated to 200 °C for 18 hours. The reaction mixture was cooled to room temperature and purified by normal-phase chromatography (0% - 55% EtOAc / DCM). The fraction containing the desired product was concentrated and further purified by reversed-phase HPLC (5% - 50% ACN / 0.05% aqueous NH4OH). The fraction containing the product was concentrated to give the title compound (250 mg).] 1 H NMR (400MHz, CDCl3) δ 8.93 (s, 1H), 7.75 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.57 (d, J =0.9 Hz, 3H), 1.41 (t, J = 7.1 Hz, 3H). ES-MS [M+1] + : 268.

[0413] 7-Chloro-8-methyl-4-oxo-4 H -pyrimidin[1,2- b ]pyridazine-2-carboxylic acid. At ambient temperature, to 7-(2-bromo-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-yl)-8-methyl-4-oxo-4 H -pyrimidin[1,2- b [Pyridazine-2-ethyl carboxylate (134 mg, 0.30 mmol) in a solution of THF (0.30 mL) was supplemented with sodium hydroxide (293 μL, 0.60 mmol; 2 M (In water). After 3 hours, cool the solution in an ice bath and dilute with water (0.30 mL). Add 1 dropwise... MHCI was added to adjust the pH to pH 5-6 and the product was extracted with CHCI3 / IPA (3: 1) (3x). The combined organic layers were dried (MgS04) and concentrated in vacuo to provide the title compound (114 mg). ES-MS [M + H] + = 422 / 424.

[0414] 7-chloro-8-methyl-2 H - pyrimido[1,2- b ]pyrimidin-2-one. To a microwave vial was added 6-chloro-5-methylpyridazine-3-amine (300 mg, 2.1 mmol) and ethyl propiolate (212 μL, 2.1 mmol) in ethanol (3.1 mL). The vial was sealed and heated to 80 °C for 18 hours. The reaction was concentrated onto Celite® and the crude product was purified using a TeledyneISCO Combi-Flash system (0% - 8% MeOH / DCM / 1% NH4OH) to give the title compound (181 mg). ® 1 HNMR (400 MHz, DMSO) δ 8.39 (dd, J = 7.8, 0.6 Hz, 1H), 7.67 - 7.62 (m, 1H), 6.38 (d, J = 7.8 Hz, 1H), 2.37 (d, J = 1.3 Hz, 3H). ES-MS [M+1] | : 196.

[0415] 7-chloro-8-methyl-2 H - pyrimido[1,2- b ]pyrimidin-2-one. To a microwave vial was added 6-chloro-5-methylpyridazine-3-amine (300 mg, 2.1 mmol) and ethyl propiolate (212 μL, 2.1 mmol) in ethanol (3.1 mL). The vial was sealed and heated to 80 °C for 18 hours. The reaction was concentrated onto Celite® and the crude product was purified using a TeledyneISCO Combi-Flash system (0% - 8% MeOH / DCM / 1% NH4OH) to give the title compound (181 mg). 1 H NMR (400 MHz, DMSO) δ 7.64 (q, J = 1.3 Hz, 1H), 6.39 (d,​J = 1.1Hz, 1H), 2.43 (d, J = 1.0 Hz, 3H), 2.38 (d, J = 1.3 Hz, 3H). ES-MS [M+1] + : 210.

[0416] 7-Chloro-8-methyl-4-(trifluoromethyl)-2 H -pyrimidin[1,2- b [Pyridazin-2-one.] 6-Chloro-5-methylpyridazin-3-amine (300 mg, 2.1 mmol) and ethyl 4,4,4-trifluorobut-2-acetylacetic acid (478 μL, 3.34 mmol) were added to a vial in ethanol (6 mL). The mixture was stirred at ambient temperature for 18 hours, after which a precipitate was observed. The solid was collected by vacuum filtration and washed with EtOH to give the title compound (318 mg). 1 H NMR (400 MHz, DMSO) δ 7.77(q, J = 1.3 Hz, 1H), 7.02 (s, 1H), 2.40 (d, J = 1.3 Hz, 3H). ES-MS [M+1] + : 264.

[0417] 5-(2-chloro-5-methylpyrimidin-4-yl)-2-cyclobutyl-4,5,6,7-tetrahydrothiazo[5,4-] c ]Pyridine. To 2-cyclobutyl-4,5,6,7-tetrahydro-[1,3]thiazo[5,4- c Pyridine (100 mg, 0.51 mmol) was added to a solution of triethylamine (0.36 mL, 2.57 mmol) and 2,4-dichloro-5-methylpyrimidine (92 mg, 0.57 mmol) in DMF (1.56 mL). After 18 hr at room temperature, water was added to the reaction mixture. The reaction mixture was extracted with EtOAc (2x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by normal-phase column chromatography (0%–80% EtOAc / DCM) to give the title compound. ES-MS [M+1] + : 321.

[0418] 2-Cyclobutyl-5-(2-hydrazyl-5-methylpyrimidin-4-yl)-4,5,6,7-tetrahydrothiazo[5,4-] c Pyridine. To 5-(2-chloro-5-methylpyrimidin-4-yl)-2-cyclobutyl-6,7-dihydro-4 H -[1,3]thiazo[5,4- c Pyridine (88 mg, 0.27 mmol) was added to a solution of ethanol (1.8 mL) with hydrazine (172 µL), and the mixture was stirred at 80 °C for 6 hr. After cooling to room temperature, the mixture was concentrated. The crude residue was used without further purification. ES-MS [M+1] + :317.

[0419] 5-(2-chloro-5,6-dimethylpyrimidin-4-yl)-2-(1-fluorocyclopropyl)-4,5,6,7-tetrahydrothiazo[5,4-] c ]Pyridine. To 2-(1-fluorocyclopropyl)-4,5,6,7-tetrahydrothiazo[5,4- c Pyridine (1.19 g, 6.0 mmol) was added to a solution of triethylamine (4.2 mL, 30.1 mmol) and 2,4-dichloro-5,6-dimethylpyrimidine (1.49 g, 8.4 mmol) in DMF (15 mL). The mixture was stirred at 70 °C for 18 h. Water and EtOAc were added to the reaction mixture. The layers were separated, and the aqueous layer was re-extracted with EtOAc (2x). The combined organic matter was washed with water (3x) and brine (2x), dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal-phase chromatography (0%–70% EtOAc / DCM) to give the title compound (1.32 g). 1 H NMR (400 MHz, CDCl3) δ 4.62 (s, 2H), 3.65 (t, J = 5.7 Hz, 2H), 3.03 (ddt, J = 5.7,3.7, 1.9 Hz, 2H), 2.42 (s, 3H), 2.19 (s, 3H), 1.64 – 1.53 (m, 2H), 1.50 –1.40 (m, 2H). ES-MS [M+1] + : 339.

[0420] 2-(1-Fluorocyclopropyl)-5-(2-hydrazino-5,6-dimethylpyrimidin-4-yl)-4,5,6,7-tetrahydrothiazo[5,4-]c ]Pyridine. To 5-(2-chloro-5,6-dimethylpyrimidin-4-yl)-2-(1-fluorocyclopropyl)-4,5,6,7-tetrahydrothiazo[5,4- c Pyridine (1.32 g, 3.9 mmol) was added to a solution of hydrazine (2.4 mL, 77.9 mmol) in ethanol (15 mL), and the mixture was stirred at 80 °C for 18 h. After cooling, the mixture was concentrated and used as is without further purification (1.3 g). ES-MS [M+1] + : 335.

[0421] b. Representative synthesis of the compounds of this invention 6-(2-bromo-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H 6-chloro-5-methylnicotinonitrile (compound 1). Add 150 mg (0.98 mmol) of 6-chloro-5-methylnicotinonitrile (4.8 mL) to a solution of 6-chloro-5-methylnicotinonitrile in NMP (4.8 mL). N,N -Diisopropylethylamine (514 μL, 2.95 mmol) and 2-bromo-4,5,6,7-tetrahydrothiazo[5,4- c Pyridine hydrochloride (327 mg, 1.28 mmol). The mixture was stirred at 110 °C for 18 h, then cooled to room temperature and diluted with water (60 mL), and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude material was purified by normal-phase rapid column chromatography (0% - 50% EtOAc / Hex) to obtain the title compound (110 mg). 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.2 Hz, 1H), 7.61 (dt, J = 2.2, 1.0 Hz, 1H), 4.56 (q, J = 1.6Hz, 3H), 3.63 (t, J = 5.7 Hz, 2H), 3.03 (ddd, J = 7.5, 5.3, 1.8 Hz, 2H), 2.36 (d, J = 0.9 Hz, 3H); ES-MS [M + H] + = 335 / 337.

[0422] 5-Methyl-6-(2-(methyl- d 3)-6,7-dihydrothiazo[5,4- c ]Pyridine-5(4 H )-yl)nicotinonitrile (compound 20). Prepared in a manner similar to compound 1 to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.40(d, J = 2.1 Hz, 1H), 7.61 (dd, J = 2.3, 0.9 Hz, 1H), 4.59 (t, J = 1.9 Hz, 2H), 3.66(t, J = 5.7 Hz, 2H), 3.05 (tt, J = 5.6, 1.9 Hz, 2H), 2.38 (t, J = 0.7 Hz, 3H); ES-MS[M + H] + = 374.

[0423] 4-(2-bromo-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-yl)-5-methylfurano[2,3- d Pyrimidine (compound 22). To 4-chloro-5-methylfurano[2,3- d Pyrimidine (12 mg, 0.07 mmol) was added to a solution of NMP (0.3 mL). N,N -Diisopropylethylamine (51 μL, 0.29 mmol) and 2-bromo-4,5,6,7-tetrahydrothiazo[5,4- c Pyridine hydrochloride (15 mg, 0.06 mmol). The mixture was stirred at 90 °C for 18 h and then cooled to room temperature. The crude material was purified by RP-HPLC (20% - 70% MeCN / 0.05% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and extracted with 3:1 chloroform / IPA. The organic layer was concentrated to provide the title compound (7.9 mg). 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.38 (d, J = 1.4 Hz, 1H), 4.75 (t, J = 1.9 Hz, 2H), 3.96 (t,J = 5.7 Hz, 2H), 3.11 (t, J = 5.7 Hz, 2H), 2.40 (d, J = 1.4 Hz, 3H);ES-MS [M + H] + = 351 / 353.

[0424] 2-Bromo-5-(6-fluoroquinazolin-4-yl)-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine (Compound 28). Prepared in a similar manner to Compound 22 to provide the title compound. 1 H NMR (400 MHz, CDCl3) δ 8.75 (s,1H), 7.96 (dd, J = 9.1, 5.4 Hz, 1H), 7.61 - 7.47 (m, 2H), 4.85 (t, J = 1.9 Hz,2H), 4.03 (t, J = 5.7 Hz, 2H), 3.21 (tt, J = 5.7, 1.9 Hz, 2H);ES-MS [M + H] + =365 / 367.

[0425] 7-(2-Bromo-6,7-dihydrothiazolo[5,4- c ]pyridin-5(4 H )-yl)-8-methyl-4 H -imidazo[1,2- b ]pyridazin-4-one (Compound 34). To a solution of 7-chloro-8-methyl-4 H -imidazo[1,2- b ]pyridazin-4-one (15 mg, 0.08 mmol) and 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4- c ]pyridine hydrochloride (29 mg, 0.12 mmol) in tert-butanol (1 mL) was added N,N -diisopropylethylamine (67 μL, 0.38 mmol). The mixture was stirred at 120 °C for 18 h, then cooled to room temperature. The crude material was purified by RP-HPLC (30%-70% MeCN / 0.05% aqueous NH4OH) to provide the title compound (2.9 mg). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 6.4 Hz, 1H), 7.58 (q, J = 1.2 Hz, 1H), 6.57 (d, J = 6.4 Hz, 1H), 4.67 (t, J = 1.9 Hz, 2H), 3.58 (t, J = 5.7 Hz, 2H), 3.12(tt, J = 5.6, 1.9 Hz, 2H), 2.51 (d, J = 1.2 Hz, 3H); ES-MS [M + H] + = 378 / 380.

[0426] 7-(2-bromo-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-yl)-8-methyl-2 H -pyrimidin[1,2- b ]Pyridazin-2-one (compound 50). Prepared in a manner similar to that of compound 34 to provide the title compound. 1 H NMR (400MHz, CDCl3) δ 7.88 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 1.4 Hz, 1H), 6.50 (d, J = 7.7Hz, 1H), 4.44 (t, J = 1.8 Hz, 2H), 3.54 (t, J = 5.8 Hz, 2H), 3.07 (td, J = 5.8, 2.9Hz, 2H), 2.45 (d, J = 1.3 Hz, 3H); ES-MS [M + H] + = 378 / 380.

[0427] 7-(2-bromo-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-yl)-8-methyl-4-oxo-4 H -pyrimidin[1,2- b[Pyridazine-2-carboxyethyl ester (compound 52). To 7-chloro-8-methyl-4-oxo-4- H -pyrimidin[1,2- b [[Pyridazine-2-ethyl carboxylate (100 mg, 0.37 mmol) and 2-bromo-4,5,6,7-tetrahydrothiazo[5,4-]] c Add pyridine hydrochloride (143 mg, 0.56 mmol) to a solution in tert-butanol (4.9 mL). N,N -Diisopropylethylamine (325 μL, 1.87 mmol). The mixture was stirred at 120 °C for 18 h, then cooled to room temperature. 2-Bromo-4,5,6,7-tetrahydrothiazo[5,4-] was then added to the reaction mixture. c Pyridine hydrochloride (143 mg, 0.56 mmol) and N,N -Diisopropylethylamine (325 μL, 1.87 mmol) and heated to 120 °C for 6 h. The reaction was concentrated. The residue was dissolved in MeOH and purified by SCX column chromatography (eluting with MeOH solution). The solvent was removed to give the title compound (166 mg). 1 H NMR (400 MHz, CDCl3) δ 8.90(s, 1H), 7.66 (q, J = 1.1 Hz, 1H), 4.68 (d, J = 1.9 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H), 3.64 (t, J = 5.7 Hz, 2H), 3.13 (ddt, J = 5.8, 4.3, 2.0 Hz, 2H), 2.56 (d, J =1.2 Hz, 3H), 1.41 (t, J = 7.1 Hz, 3H); ES-MS [M + H] + = 450 / 452.

[0428] 5-Methyl-6-(2-(2-methylpyridin-4-yl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H)-yl)nicotinonitrile (Compound 2). To a vial was added a mixture of 2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (19.6 mg, 0.090 mmol), cesium carbonate (43.7 mg, 0.13 mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (3.3 mg, 0.005 mmol), and 6-(2-bromo-6,7-dihydrothiazolo[5,4-£]pyridin-5(4 c H )-yl)-5-methylnicotinonitrile (15.0 mg, 0.045 mmol), followed by degassed 1,4-dioxane (1.1 mL) and water (0.03 mL). The vial was sealed and the reaction was heated to 80 °C for 18 h. The reaction mixture was filtered through a pad of Celite ® and the pad was washed with DCM / MeOH. The solvent was removed and the residue was dissolved in DMSO (1 mL). The crude material was purified by RP-HPLC (30%-70% MeCN / 0.05% aqueous NH4OH) to provide the title compound (5 mg). 1 H NMR (400 MHz, CDC13) δ 8.60 (dd, J = 5.2, 0.8 Hz, 1H), 8.42 (dd, J = 2.2, 0.6 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.66 - 7.61 (m, 1H), 7.63 - 7.56 (m, 1H), 4.72 (t, J = 1.8 Hz, 2H), 3.72 (t, J = 5.7 Hz, 2H), 3.17 (tt, J = 5.6, 1.7 Hz, 2H), 2.65 (s, 3H), 2.42 (t, J = 0.7 Hz, 3H); ES-MS [M + H] - = 348.

[0429] 5-(6-cyano-4,5-dimethylpyridazin-3-yl)-4,5,6,7-tetrahydrothiazolo[5,4- c ​Pyridine-2-carbonitrile (Compound 13). To a solution of zinc powder (1 mg, 0.015 mmol) and Pd(dppf)Cl2(3.14 mg, 0.0043 mmol) in DMF (1.3 mL) was added 6-(2-bromo-6,7-dihydrothiazolo[5,4- c Pyridine-5(4 H )-yl)-4,5-dimethylpyridazine-3-carbonitrile (15 mg, 0.043 mmol) and zinc cyanide (5.0 mg, 0.043 mmol). The mixture was stirred at 160 °C for 4 h, then cooled to ambient temperature, partitioned between water (8 mL) and EtOAc (8 mL). The organic layer was separated, and the aqueous layer was further extracted with EtOAc twice. The organics were combined, washed with brine, dried (MgS04), filtered, and concentrated. The crude material was purified by RP-HPLC (25% - 70% MeCN / 0.05% aqueous TFA). Fractions containing the desired product were basified with saturated aqueous NaHC03and extracted with 3 : 1 chloroform / IPA. The solvent was concentrated to provide the title compound (3.3 mg). 1 H NMR (400 MHz, CDCl3) δ 4.85 (t, J = 1.6 Hz, 2H), 3.67 (t, J = 5.7 Hz, 2H), 3.17 (t, J =5.8 Hz, 2H), 2.50 (s, 3H), 2.34 (s, 3H); ES-MS [M + H] + = 297.

[0430] 6-(2-((4-Fluorophenyl)amino)-6,7-dihydrothiazolo[5,4- c Pyridine-5(4 H )-yl)-4,5-dimethylpyridazine-3-carbonitrile (Compound 7). To a vial was added 6-(2-bromo-6,7-dihydrothiazolo[5,4- c Pyridine-5(4 H ​​​)-yl)-4,5-dimethylpyridazine-3-carbonitrile (15 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.9 mg, 0.004 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.7 mg, 0.01 mmol), 4-fluoroaniline (7.3 μL, 0.09 mmol), and cesium carbonate (42.1 mg, 0.13 mmol). The resulting mixture was heated to 110 °C for 2 h. The reaction mixture was filtered through Celite ® The pad was filtered and the pad was washed with EtOAc / DCM. The solvent was removed, and the residue was dissolved in DMSO (1.5 mL). The crude material was purified by RP-HPLC (30% - 70% MeCN / 0.05% aqueous TFA). The fractions containing the desired product were basified with saturated aqueous NaHC03and extracted with 3: 1 chloroform / IPA. The solvent was concentrated to provide the title compound (4.0 mg). ES-MS [M + H] + = 381.

[0431] 6-(2-methoxy-6,7-dihydrothiazolo[5,4- c ]pyridine-5(4 H )-yl)-4,5-dimethylpyridazine-3-carbonitrile (Compound 8). To a microwave vial containing 6-(2-bromo-6,7-dihydrothiazolo[5,4- c ]pyridine-5(4 H )-yl)-4,5-dimethylpyridazine-3-carbonitrile (10 mg, 0.03 mmol) in methanol (1 mL) was added a solution of sodium methoxide (76 μL, 25 wt.% in methanol). The vial was sealed and the reaction was microwave irradiated at 100 °C for 10 min, then heated to 110 °C for 1 h. The reaction mixture was filtered and concentrated. The crude material was purified by RP-HPLC (30% - 70% MeCN / 0.05% aqueous TFA). The fractions containing the desired product were basified with saturated aqueous NaHC03and extracted with 3: 1 chloroform / IPA. The combined organic layers were concentrated to provide the title compound (3.7 mg). 1 H NMR (400 MHz, CDCl3) δ 4.55 (t, J = 2.1Hz, 2H), 4.06 (s, 3H), 3.64 (t, J = 5.7 Hz, 2H), 2.94 (td, J= 5.6, 2.8 Hz, 2H),2.46 (s, 3H), 2.33 – 2.28 (m, 3H); ES-MS [M + H] + = 302.

[0432] 7-(2-bromo-6,7-dihydrothiazo[5,4-) c ]Pyridine-5(4 H )-yl)-8-methyl-4-oxo- N -(thiazolyl-5-ylmethyl)-4 H -pyrimidin[1,2- b [Pyridazine-2-carboxamide (compound 42). 7-Chloro-8-methyl-4-oxo-4- H -pyrimidin[1,2- b Pyridazine-2-carboxylic acid (10 mg, 0.024 mmol) and HATU (46.7 mg, 0.12 mmol) were dissolved in DMF (1 mL) and stirred for 15 minutes. Add... N,N -Diisopropylethylamine (36 μL, 0.20 mmol) and thiazolyl-5-methylamine hydrochloride (3.5 mg, 0.020 mmol) were added, and the mixture was stirred for 2 h. The reaction mixture was filtered and concentrated. The residue was purified by RP-HPLC (5% - 60% MeCN / 0.05% aqueous TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and extracted with 3:1 chloroform / IPA. The combined organic layers were concentrated to provide the title compound (7.1 mg). 1 H NMR (400 MHz, CDCl3) δ 9.65 (t, J = 5.7 Hz, 1H), 9.23 (s, 1H), 8.73 (d, J = 0.7Hz, 1H), 7.84 (q, J = 0.7 Hz, 1H), 7.73 (q, J = 1.1 Hz, 1H), 4.88 (dd, J = 5.8, 0.9Hz, 2H), 4.68 (t, J = 1.9 Hz, 2H), 3.65 (t, J = 5.7 Hz, 2H), 3.14 (t, J = 5.8 Hz, 2H), 2.58 (d, J= 1.2 Hz, 3H).; ES-MS [M + H] + = 518 / 520.

[0433] 2-(1-Methylcyclopropyl)-5-(7-methylpyridano[2,3-) b ]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazo[5,4- c Pyridine (compound 55). To 6-chloro-7-methylpyridinium[2,3- b Pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) were added to a solution of 2-(1-methylcyclopropyl)-4,5,6,7-tetrahydro-[1,3]thiazo[5,4-]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) in DMSO (0.8 mL). c Pyridine (19 mg, 0.1 mmol). The reaction was heated to 120 °C for 18 h. The reaction was purified by reversed-phase HPLC (5%-45% MeCN / water / 0.05% NH4OH) to give the title compound (9.4 mg). 1 HNMR (400 MHz, CDCl3) δ 8.81 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.07(d, J = 1.2 Hz, 1H), 4.79 (t, J = 1.9 Hz, 2H), 3.72 (t, J = 5.7 Hz, 2H), 3.10 (tt, J = 5.6, 1.9 Hz, 2H), 2.58 (d, J = 1.0 Hz, 3H), 1.57 (s, 3H), 1.29 (q, J = 4.2 Hz, 2H), 0.96 (q, J = 4.3 Hz, 2H); ES-MS [M+1] + : 338.0.

[0434] 2-Cyclopropyl-5-(7-methylpyridino[2,3-] b ]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine (compound 54). To 6-chloro-7-methylpyridinoid [2,3-b Pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) were added to a solution of 2-cyclopropyl-4,5,6,7-tetrahydro-[1,3]thiazo[5,4-]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) in DMSO (0.8 mL). c Pyridine; hydrochloride (21 mg, 0.10 mmol). The reaction was heated to 120 °C for 18 h. The reaction was purified by reversed-phase HPLC (5%–45% MeCN / water / 0.05% NH4OH). The desired fraction was concentrated to give the title compound (7.4 mg). 1 H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 1.2 Hz, 1H), 4.78 (s, 2H), 3.72 (t, J = 5.7 Hz, 2H), 3.14 (d, J =6.0 Hz, 2H), 2.59 (d, J = 1.0 Hz, 3H), 2.38 (s, 1H), 1.26 – 1.15 (m, 2H), 1.11(s, 2H); ES-MS [M+1] + : 324.0.

[0435] 2-(2,2-Dimethylcyclopropyl)-5-(7-methylpyridano[2,3-) b ]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine (compound 63). To 6-chloro-7-methylpyridinoid [2,3- b Pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol) were added to a solution of 2-(2,2-dimethylcyclopropyl)-4,5,6,7-tetrahydro-[1,3]thiazo[5,4-]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol) in DMSO (0.8 mL). c Pyridine (23 mg, 0.11 mmol). The reaction was heated to 120 °C for 18 h. The reaction was purified by reversed-phase HPLC (5%-45% MeCN / water / 0.05% NH4OH) to give the title compound (2.7 mg). 1H NMR (400 MHz, DMSO) δ 8.84 (d, J = 2.0 Hz, 1H), 8.72 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 1.1 Hz, 1H), 4.68 (d, J = 1.5 Hz, 2H), 3.73 (t, J = 5.8 Hz, 2H), 2.99(t, J = 4.7 Hz, 2H), 2.59 – 2.51 (m, 3H), 2.19 (dd, J = 8.3, 5.6 Hz, 1H), 1.18(s, 3H), 1.16 – 1.09 (m, 2H), 0.99 (s, 3H); ES-MS [M+1] + : 352.2.

[0436] 2-(tert-butyl)-5-(7-methylpyridino[2,3-) b] Pyrazin-6-yl)-4,5,6,7-tetrahydrothiazo[5,4- c Pyridine (compound 65). To 6-chloro-7-methylpyridinoid [2,3- b Pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol) were added to a solution of 2-tert-butyl-4,5,6,7-tetrahydro-[1,3]thiazo[5,4-]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol) in NMP (0.8 mL). c Pyridine (21 mg, 0.11 mmol). The reaction was heated at 160 °C for 18 h. The reaction was purified by reversed-phase HPLC (10%–50% MeCN / water / 0.1% TFA). The fraction containing the desired product was alkalized with saturated aqueous NaHCO3 and extracted with 3:1 chloroform / IPA. The combined organic layers were concentrated to provide the title compound (10.7 mg). 1 H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 2.0 Hz, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.07 (d, J =1.1 Hz, 1H), 4.81 (s, 2H), 3.74 (t, J= 5.6 Hz, 2H), 3.15 (td, J = 5.6, 2.8 Hz,2H), 2.59 (s, 3H), 1.45 (s, 9H); ES-MS [M+1] + : 340.4.

[0437] 5-(7-methylpyrido[2,3-) b ]pyrazin-6-yl)-2-(thiophen-2-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine (compound 56). To 6-chloro-7-methylpyridinoid [2,3- b Pyrazine (9.6 mg, 0.05 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.33 mmol) were added to a solution of 2-(thiophene-2-yl)-4,5,6,7-tetrahydrothiazo[5,4-]pyrazine (9.6 mg, 0.05 mmol) and N,N-diisopropylethylamine (0.06 mL, 0.33 mmol) in DMSO (0.8 mL). c Pyridine (17 mg, 0.08 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) to give the title compound (7.4 mg). 1 H NMR (400 MHz, CDCl3) δ 8.82 (d, J = 2.0 Hz, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 1.1 Hz, 1H), 7.48 (dd, J = 3.7, 1.1 Hz, 1H), 7.38 (dd, J = 5.1, 1.1 Hz, 1H), 7.07 (dd, J =5.1, 3.7 Hz, 1H), 4.86 (t, J = 1.8 Hz, 2H), 3.76 (t, J = 5.7 Hz, 2H), 3.19 (tt, J =5.6, 1.8 Hz, 2H), 2.61 (d, J = 1.0 Hz, 3H); ES-MS [M+1] + : 366.0.

[0438] 2-(1-methyl-1 H -pyrazol-5-yl)-5-(7-methylpyridino[2,3-] b ]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine (compound 59). To 6-chloro-7-methylpyridinoid [2,3- b Pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) were added to a solution of 2-(2-methylpyrazol-3-yl)-4,5,6,7-tetrahydro-[1,3]thiazo[5,4-]pyrazol-3-yl)-4,5,6,7-tetrahydro-[1,3]thiazo[5,4- c Pyridine (22 mg, 0.1 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) to give the title compound (5.2 mg). 1 H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 2.0 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.10(d, J = 1.2 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 4.89 (t, J =1.8 Hz, 2H), 4.24 (s, 3H), 3.79 (t, J = 5.7 Hz, 2H), 3.21 (tt, J = 5.6, 1.8 Hz, 2H), 2.62 (d, J = 1.0 Hz, 3H); ES-MS [M+1] + : 364.3.

[0439] 2-Chloro-5-(7-methylpyridano[2,3-) b ]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine (compound 61). To 6-chloro-7-methylpyridinoid [2,3- bPyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) were added to a solution of 2-chloro-4,5,6,7-tetrahydro-[1,3]thiazo[5,4-]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) in DMSO (0.8 mL). c Pyridine (17 mg, 0.1 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) to give the title compound (2.1 mg). 1 H NMR (400 MHz, CDCl3) δ8.74 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 1.2 Hz, 1H), 4.68(t, J = 1.9 Hz, 2H), 3.64 (t, J = 5.7 Hz, 2H), 3.01 (tt, J = 5.6, 1.9 Hz, 2H), 2.50(d, J = 1.0 Hz, 3H); ES-MS [M+1] + : 318.2.

[0440] 5-(7-methylpyrido[2,3-) b ]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine-2-amine (compound 60). To 6-chloro-7-methylpyridino[2,3- b Pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) were added to a solution of 4,5,6,7-tetrahydro-[1,3]thiazo[5,4-]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.07 mL, 0.41 mmol) in DMSO (0.8 mL). c 2,2,2-Pyridine-2-amine 2,2,2-trifluoroacetate (30 mg, 0.11 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) to give the title compound. 1 H NMR (400 MHz, DMSO) δ 8.83 (d, J = 2.0 Hz, 1H), 8.70 (d, J= 2.0 Hz, 1H), 8.13 (d, J = 1.1 Hz,1H), 6.81 (s, 2H), 4.47 (t, J = 2.0 Hz, 2H), 3.68 (t, J = 5.6 Hz, 2H), 2.88 –2.58 (m, 2H), 2.53 (d, J = 1.1 Hz, 3H); ES-MS [M+1] + : 299.2.

[0441] 5-(7-methylpyrido[2,3-) b ]pyrazin-6-yl)-2-(trifluoromethyl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine (compound 62). To 6-chloro-7-methylpyridinoid [2,3- b Pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol) were added to a solution of 2-(trifluoromethyl)-4,5,6,7-tetrahydro-[1,3]thiazo[5,4-]pyrazine (15 mg, 0.08 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.55 mmol) in DMSO (0.8 mL). c 2,2,2-Trifluoroacetate of pyridine (35 mg, 0.11 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) to give the title compound. 1 H NMR (400 MHz, DMSO) δ 8.86 (d, J = 2.0 Hz, 1H), 8.74 (d, J = 2.0 Hz, 1H), 8.20 (d, J =1.1 Hz, 1H), 4.89 (d, J = 1.6 Hz, 2H), 3.81 (t, J = 5.7 Hz, 2H), 3.19 – 3.11 (m,2H), 2.57 (d, J = 1.0 Hz, 3H); ES-MS [M+1] + : 352.2.

[0442] 5-(7-methylpyrido[2,3-) b]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazo[5,4- c ]Pyridine (compound 53). To a solution containing 6-chloro-7-methylpyridine and [2,3-] in NMP (1 mL). b Pyrazine (12 mg, 0.07 mmol) and 4,5,6,7-tetrahydrothiazo[5,4- c N,N-diisopropylethylamine (0.06 mL, 0.34 mmol) was added to a vial of pyridine (9 mg, 0.07 mmol). The mixture was heated at 175 °C for 16 h. After cooling to room temperature, the reaction was purified by reversed-phase HPLC (5%–45% MeCN / water / 0.05% NH4OH) to give the title compound (8.5 mg). 1 H NMR (400 MHz, CDCl3) δ8.83 (d, J = 2.0 Hz, 1H), 8.73 (d, J = 0.7 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.10(s, 1H), 4.90 (s, 2H), 3.77 (t, J = 5.7 Hz, 2H), 3.27 – 3.19 (m, 2H), 2.61 (s, 3H); ES-MS [M+1] + : 284.0.

[0443] 5-(7-methylpyrido[2,3-) b ]pyrazine-6-yl)-4,5,6,7-tetrahydrothiazo[5,4 -c ]Ethyl pyridine-2-carboxylate (compound 58). To 6-chloro-7-methylpyridino[2,3- b Pyrazine (30 mg, 0.17 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.82 mmol) were added to a solution of DMSO (0.8 mL) with 4,5,6,7-tetrahydro-6-azabenzothiazol-2-carboxylic acid ethyl ester hydrochloride (49 mg, 0.2 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) to give the title compound (3.7 mg). 1 H NMR (400 MHz, CDCl3) δ 8.81 (d, J = 2.0 Hz, 1H), 8.66 (d,J = 2.0 Hz, 1H), 8.08 (d, J = 1.1 Hz,1H), 4.90 (t, J = 1.7 Hz, 2H), 4.46 (q, J = 7.1 Hz, 2H), 3.73 (t, J = 5.7 Hz, 2H),3.22 (ddd, J = 5.6, 4.1, 1.6 Hz, 2H), 2.58 (d, J = 1.0 Hz, 3H), 1.41 (t, J = 7.1Hz, 3H);ES-MS [M+1] + : 356.3.

[0444] 7-(2-cyclobutyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4 H )-yl)-6-methyl-[1,2,4]triazolo[4,3-a]pyrimidine-3(2 H )-one (Compound 66). To a solution of [4-(2-cyclobutyl-6,7-dihydro-4 H -[1,3]thiazolo[5,4- c ]pyridin-5-yl)-5-methylpyrimidin-2-yl]hydrazine (86.0 mg, 0.27 mmol) in 1,4-dioxane (1.5 mL) was added 1,1'- carbonyldiimidazole (49.0 mg, 0.3 mmol). The reaction was heated to 85 °C for 6 hr. The mixture was cooled to room temperature and stirred for 18 hr. The reaction was diluted with water and extracted with EtOAc (3x). The organics were dried over sodium sulfate, filtered, and concentrated. The crude product was purified via normal phase column chromatography (0%-100% (10 : 1 : 89) MeOH / NH4OH / DCM and DCM). ES-MS [M+1] + : 343.3; 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.68 (q, J = 1.3 Hz,1H), 4.72 (t, J = 1.9 Hz, 2H), 3.84 – 3.75 (m, 3H), 3.07 (tt, J= 5.5, 1.9 Hz,2H), 2.52 – 2.41 (m, 2H), 2.40 – 2.31 (m, 2H), 2.30 (d, J = 1.3 Hz, 3H), 2.11 –1.88 (m, 2H).

[0445] 7-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-5,6-dimethyl-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-ketone (compound 69). To 2-(1-fluorocyclopropyl)-5-(2-hydrazino-5,6-dimethylpyrimidin-4-yl)-4,5,6,7-tetrahydrothiazo[5,4- c 1,1'-carbonyldiimidazole (0.71 g, 4.4 mmol) was added to a solution of pyridine (1.3 g, 4.0 mmol) in 1,4-dioxane (40 mL). The reaction was heated at 85 °C for 18 h. CDI (515 mg) was then added to the reaction mixture and heated at 85 °C for 4 h. The reaction mixture was diluted with water and extracted with 3:1 CHCl3 / IPA (3x). The organic compounds were combined, dried (MgSO4), filtered, and concentrated. The crude product was purified by normal-phase chromatography (0%–5% MeOH / DCM) to give the title compound (0.6 g). ES-MS [M+1] + 361; 1 H NMR (400 MHz, DMSO) δ 4.57 (s,2H), 3.60 (t, J = 5.6 Hz, 2H), 2.93 (t, J = 5.7 Hz, 2H), 2.68 (s, 3H), 2.07 (s, 3H), 1.71 – 1.57 (m, 2H), 1.42 – 1.31 (m, 2H).

[0446] 7-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-2,5,6-trimethyl-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H)-ketone (compound 70). 7-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4- c ]pyridin-5(4H)-yl)-5,6-dimethyl-[1,2,4]triazolo[4,3- a A solution of pyrimidin-3(2H)-one (0.6 g, 1.7 mmol) and potassium carbonate (0.47 g, 3.4 mmol) in DMF (16 mL) was stirred at room temperature for 20 min. Iodomethane (157 µL, 2.5 mmol) was then added, and the mixture was stirred at 50 °C for 18 h. The reaction was purified by reversed-phase chromatography (10%–50% ACN / 0.05% NH4OH) to give the title compound (390 mg). ES-MS [M+1] + 375; 1 H NMR (400 MHz, DMSO) δ 4.59 (s, 2H), 3.62 (t, J = 5.6 Hz, 2H), 3.36 (s, 3H), 2.93(td, J = 5.5, 2.7 Hz, 2H), 2.68 (s, 3H), 2.08 (s, 3H), 1.73 – 1.56 (m, 2H), 1.44 – 1.29 (m, 2H).

[0447] 7-(2-(1-fluorocyclopropyl)-6,7-dihydrothiazo[5,4-] c ]Pyridine-5(4 H )-yl)-5,6-dimethyl-2-(methyl- d 3)-[1,2,4]triazolo[4,3- a ]Pyrimidine-3(2 H )-Ketone (Compound 71). Prepared in a manner similar to Compound 70 to provide the title compound. ES-MS [M+1] + : 378.2; 1 H NMR (400 MHz, DMSO) δ 4.59 (d, J =1.8 Hz, 2H), 3.62 (t, J = 5.7 Hz, 2H), 2.93 (t, J = 5.7 Hz, 2H), 2.68 (d, J = 0.9Hz, 3H), 2.08 (d, J= 1.0 Hz, 3H), 1.74 - 1.64 (m, 1H), 1.64 - 1.57 (m, 1H), 1.42 - 1.31 (m, 2H).

[0448] Commercial starting materials Name CAS# Supplier -Boc-3-bromo-4-oxopiperidine 188869-05-8 Combi-Blocks, Inc. tert-Butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4)-carboxylate 365996-06-1 Combi-Blocks, Inc. tert-Butyl 2-chloro-6,7-dihydrothiazolo[5,4-c]pyridine-5(4)-carboxylate 1221931-40-3 Combi-Blocks, Inc. tert-Butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4)-carboxylate 365996-05-0 Combi-Blocks, Inc. 6-Chloro-5-methyl-3-nitropyridin-2-amine 202217-19-4 Ambeed 4,5,6,7-Tetrahydrothiazolo[5,4-]pyridine 165948-23-2 Enamine 6,7-dihydrothiazolo[5,4-]pyridine-2,5(4)-dicarboxylic acid 5-(tert-butyl) 2-ethyl ester 1053656-51-1 J & W PharmLab, Inc. 6,7-dihydrothiazolo[5,4-]pyridine-5(4)-carboxylic acid tert-butyl ester 165948-24-3 Combination Blocks, Inc. 4,5,6,7-tetrahydrothiazolo[5,4-]pyridine-2-carboxylic acid ethyl ester hydrochloride 1186663-33-1 AstaTech, Inc. 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-]pyridine hydrochloride 949922-52-5 Synthonix 2-methyl-4,5,6,7-tetrahydrothiazolo[5,4-]pyridine 124458-27-1 Aurum Pharmatech 2,4-dichloro-5,6-dimethylpyrimidine 1780-32-1 ChemScene 1-fluorocyclopropanecarboxamide 1445686-01-7 eNovation Chemicals The compounds shown in Table 1 can be prepared using the methods shown in the foregoing schemes and examples, with appropriate starting materials.

[0449] Table 1

[0450] Biological activity A. Cell lines expressing muscarinic acetylcholine receptors Human (h) and rat (r) M4 cDNAs were transfected into Chinese hamster ovary (CHO-K1) cells purchased from the American Type Culture Collection using Lipofectamine 2000 along with chimeric G proteins G qi5 Transfected cells were subjected to selective antibiotic treatment to generate stable cell lines; cells expressing M4 were selected with G418 sulfate (1 mg / ml) and cells expressing G qi5 were selected with hygromycin B (500 µg / mL). The resulting polyclones were further screened to obtain single clones of hM4-G qi5 and rM4-G qi5 for use in compound screening assays. Stable single clone cells were cultured in Ham’s F-12 medium containing 10% heat inactivated fetal bovine serum (FBS), IX antibiotic / antimycotic, 20 mM HEPES, 500 µg / mL G418 sulfate, and 200 µg / mL hygromycin B in a 37°C humidified incubator in the presence of 5% CO2.

[0451] B. Cell-based functional assay for muscarinic acetylcholine receptor activity A high throughput assay was employed to measure receptor-induced intracellular calcium mobilization to determine compound activity. Test compounds were added to cells expressing muscarinic receptors that were loaded with a calcium-sensitive fluorescent dye. After an incubation period of about 2.5 minutes, a submaximal (EC 20 ) concentration of acetylcholine was added and the response was measured. This kinetic assay can simultaneously screen and determine potency for multiple pharmacological modes of action, including agonist and potentiator activity. CHO-K1 cells stably expressing muscarinic receptors were plated in Greiner 384-well black wall tissue culture (TC) treated clear bottom plates (Greiner Bio-One) at 15,000 cells / 20 μL / well in growth media lacking G418 and hygromycin. Cells were incubated overnight at 37 °C and 5% CO2. The next day, calcium assay buffer (Hank's Balanced Salt Solution (HBSS), 20 mM HEPES, 2.5 mM Probenicid, 4.16 mM Sodium Bicarbonate (Sigma-Aldrich, St. Louis, MO)) was prepared to dilute compounds, agonists, and the fluorescent calcium indicator dye Fluo-4-acetomethoxy ester (Fluo-4-AM). Compounds were serially diluted 1 :3 in DMSO using a Bravo liquid handler (Agilent, Santa Clara, CA) to make a 10-point concentration response curve, transferred to 384-well sub-plates using an Echo acoustic liquid handler (Beckman Coulter, Indianapolis, IN), and diluted to 2x final concentration in assay buffer. Agonist plates were prepared as follows: acetylcholine (ACh, Sigma-Aldrich, St. Louis, MO) was diluted to 5x final concentration in assay buffer corresponding to EC 20 and EC MAXResponse Concentrations. A 2.3 mM stock of Fluo-4-AM in DMSO was mixed 1 : 1 with 10% (w / v) pluronic acid F-127 in assay buffer to make a 2X dye solution (2.3 µM). Using a microplate washer (BioTek, Winooski, VT), cells were washed 3 times with assay buffer to remove culture media. After the final wash, 20 µL of assay buffer remained in the cell plate. Immediately, 20 µL of 2X dye solution (final 1.15 µM) was added to each well of the cell plate using a Multidrop Combi dispenser (Thermo Fisher, Waltham, MA). After incubating the cells with the dye solution for 45 min at 37°C in the presence of 5% CO2, the dye solution was removed using the microplate washer and replaced with assay buffer, leaving 20 µL of assay buffer in the cell plate.

[0452] The prepared compounds, agonists, and cell plates were placed in a functional drug screening system, FDSS uCell (Hamamatsu, Japan) to measure calcium flux. Ca kinetics were measured using a triple add protocol; the test compound, EC 20 ACh, and EC 80 ACh were added sequentially. Briefly, after a 2-second fluorescent baseline (excite, 480 nm; emit, 530 nm) was established, 20 µL of test compound was first added to the cells, and the response was measured for 140 seconds. The second addition followed; 10 µL (5X) EC 20 concentration of ACh agonist was added to the cells, and the cells were measured for 125 seconds. The third addition was made immediately: 12 ul (5X) EC 80 concentration of ACh was added, and the cells were measured for 90 seconds. The acetylcholine-mediated maximal response (EC max ) was measured by adding 1 mM ACh as the third addition in control wells. DMSO vehicle was added in the first addition control wells to assess ACh EC 20 , EC80, and EC max responses. Calcium fluorescence was recorded as a multiple of basal fluorescence, and raw data were normalized to the maximal response to ACh agonist. Agonist activity was analyzed as the concentration-dependent increase in calcium mobilization after compound addition. Positive allosteric modulator activity was analyzed as the concentration-dependent increase in EC 20 acetylcholine response. Antagonist activity was analyzed as the decrease in EC 80Acetylcholine-responsive concentration-dependent decrease. Concentration- response curves were generated by four-parameter logistic equation using GraphPad Prism (La Jolla, CA) or Dotmatics software platform (Woburn, MA).

[0453] The above assay was also performed in a second mode, where a fixed concentration of a compound of the disclosure was added to the cells after the fluorescent baseline was established for about 3 seconds, and the response in the cells was measured. After 140 s, an appropriate concentration of agonist was added, and the calcium response (maxi-min response) was measured. The EC 50 values of the agonist in the presence of the test compound were determined by non-linear curve fitting. A decrease in the EC 50 values of the agonist (leftward shift of the agonist concentration-response curve) with increasing concentration of a compound of the disclosure indicates the degree of muscarinic positive allosteric modulation at a given concentration of a compound of the disclosure. An increase in the EC 50 values of the agonist (rightward shift of the agonist concentration-response curve) with increasing concentration of a compound of the disclosure indicates the degree of muscarinic antagonism at a given concentration of a compound of the disclosure. The second mode also indicates whether a compound of the disclosure also affects the maximal response of the muscarinic receptor to the agonist.

[0454] C. Activity of compounds in mAChR M4 cell-based assays Compounds were synthesized as described above. Activity (EC 50 and E max ) was determined in M4 cell-based functional assays as described above, and the data are shown in Table 2. Compound numbers correspond to the compound numbers used in Table 1.

[0455] Table 2. No. Human M4EC 50 (nM) E max (%)*]] 1 59 92 2 612 59 3 >10,000 45 4 >10,000 54 5 >10,000 43 6 >10,000 41 7 1287 49 8 732 79 9 660 98 10 114 85 11 103 85 12 161 76 13 1213 78 14 5235 51 15 371 87 16 103 84 17 3172 92 18 4110 44 19 851 99 20 243 101 21 301 98 22 106 96 23 204 82 24 50 102 25 1289 113 26 430 98 27 >10,000 43 28 45 101 29 144 96 30 147 91 31 566 68 32 200 91 33 79 99 34 6073 70 35 291 89 36 37 91 37 47 81 38 1178 80 39 75 88 40 94 85 41 2769 74 42 418 87 43 1960 87 44 2394 93 45 752 85 46 360 91 47 1938 66 48 2175 87 49 386 76 50 521 66 51 378 71 52 868 92 53 2789 82 54 32 82 55 253 76 56 2390 50 57 666 90 58 1837 86 59 2781 54 60 >10,000 67 61 414 68 62 93 72 63 738 63 64 119 76 65 1885 57 66 13 76 67 4 71 68 40 97 69 18 88 70 4 77 71 7 83 72 5 91 73 12 91 74 7 94 75 15 111 76 87 105 77 9 121 78 18 109 * %ACh max at 30 mM.

[0456] D. Functional evaluation of M4 activator compounds in a cellular cAMP assay (Cellular cAMP G i HTRF assay) Upon activation of the M4 receptor, the production of cAMP is inhibited by coupling to G i / o proteins. To measure the level of inhibition of cAMP by M4 allosteric modulators, CHO cells stably expressing human or rat M4 receptors were utilized, employing a homogeneous time-resolved fluorescence (HTRF ®cAMP assay. The HTRF cAMP assay is a time-resolved, resonance energy transfer (TR-FRET) competitive immunoassay. Endogenous intracellular cAMP produced by the cells competes with europium cryptate labeled cAMP (europium donor, emission 665 nm) for binding to a d2 labeled cAMP antibody (d2-acceptor, emission 620 nm). Thus, the fluorescence emission ratio (665 nm / 620 nm) is inversely proportional to the intracellular cAMP content. Compound-mediated M4 activation results in an increase in the HTRF ratio (665 nm / 620 nm), indicating a decrease in intracellular cAMP levels. To monitor agonist activity, cells are stimulated with EC 80 Concentrations of forskolin (adenylate cyclase activator) in the presence of EC 20 Concentrations of acetylcholine in the presence of EC 80 Concentrations of forskolin. This functional assay can determine direct activation or potentiation of G i / o - the potency and efficacy of compounds that couple to the M4 receptor; representative data are shown in Table 3.

[0457] Functional agonist and potentiator activity of compounds is determined by measuring cAMP levels in Chinese hamster ovary (CHO) cells stably expressing human or rat M4 muscarinic receptors using the HTRF cAMP G i / o Functional agonist and potentiator activity of compounds is determined by measuring cAMP levels in Chinese hamster ovary (CHO) cells stably expressing human or rat M4 muscarinic receptors using the HTRF cAMP G

[0458] The next day, reagents are freshly diluted in assay buffer at 2X concentration using either F12 base medium or stimulation buffer. All assay buffers contain 500 μΜ IBMX to block cAMP degradation. Cells are stimulated with EC 80 Concentrations of forskolin to induce submaximal intracellular cAMP levels. Compounds are tested for activation of M4 in cells stimulated with EC 80Concentrations were determined from a forskolin concentration response curve (CRC) ranging from 1.5 to 2.5 mM. Compounds were prepared in 100% DMSO (10 mM) and then further serially diluted in DMSO at 1 :3 or 1 :5 in 384-well microplates using a Bravo liquid handler to make 13-point CRCs.

[0459] In the agonist assay mode, M4 compounds were evaluated for their ability to directly activate M4 receptors in the absence of an agonist (acetylcholine). A 10-point serial dilution of compound (starting at 30 mM as a final concentration) was transferred to the compound plate using an Echo plate reformat protocol. A 2X assay buffer containing EC 80 Concentrations were determined from a forskolin concentration response curve (CRC) ranging from 1.5 to 2.5 mM. Compounds were prepared in 100% DMSO (10 mM) and then further serially diluted in DMSO at 1 :3 or 1 :5 in 384-well microplates using a Bravo liquid handler to make 13-point CRCs. 80 A 10 pL / well of 2X assay buffer prepared immediately was added to the cell plate using a Bravo 384-tip liquid handler. The cell plate was immediately spun at 100 x g for 30 seconds and incubated at 37 °C with 50 rpm gentle shaking for 10 min. Acetylcholine CRCs were also performed in the presence of EC 80 Concentrations of forskolin to determine the acetylcholine concentrations that induce maximal (EC max ) and submaximal (EC 20 ) cAMP inhibition in preparation for subsequent synergist mode assays.

[0460] In the synergist assay mode, a 10-point serial dilution of compound (starting at 1.1 mM as a final concentration) was transferred to the compound plate using an Echo plate reformat protocol. A 2X assay buffer containing EC 80 Concentrations of forskolin and EC 20 Concentrations of acetylcholine was added to the compound plate. Vehicle (1% DMSO) was added to the following: (1) forskolin control wells: baseline cAMP (no forskolin), maximal forskolin, and forskolin EC 80 ; (2) agonist control wells: containing forskolin EC 80 baseline (no agonist) and acetylcholine EC 20 and EC maxImmediately add 10 μL / well of prepared 2X assay buffer to the cell plate using a Bravo 384 pinhead liquid handler. Immediately spin the cell plate at 100 x g for 30 seconds and incubate at 37 °C with gentle shaking at 50 rpm for 10 min. During the 10 min incubation period, dilute the cAMP Eu-cryptate donor (20X) and anti-cAMP d2 antibody acceptor (20X) in separate tubes with lysis / detection buffer. Immediately after the incubation, add 10 μL / well of the cAMP Eu-cryptate solution and 10 μL / well of the anti-cAMP d2 antibody solution sequentially to lyse the cells. Immediately spin the cell plate at 100 x g for 30 seconds and incubate at 25 °C with gentle shaking at 50 rpm for 60 min. After the detection incubation, immediately measure the TR-FRET signal at both channels 665 and 620 nm using an EnVision plate reader (Perkin Elmer). Normalize all emission ratios (665 / 620) to the maximum acetylcholine %. Use a four-parameter logistic equation in GraphPad Prism (La Jolla, CA) to generate individual CRCs, and EC 50 Extracted from the fit, and determine the maximum response (% ACh Max); where A is the molar concentration of the compound; the minimum ( bottom ) and maximum ( top ) represent the lower and upper plateaus of the concentration-response curve, respectively; the Hill Slope is the Hill coefficient that describes the steepness of the curve; and the EC 50 is the molar concentration of the compound required to produce a response halfway between the maximum and minimum.

[0461] Table 3. hM4_cAMP activity

[0462] Table 4. Materials and equipment

[0463] E. Effect of compounds on amphetamine-induced locomotor stimulation in rats The ability of compound 70 to reverse amphetamine-induced locomotor stimulation, a preclinical model predictive of antipsychotic-like activity, was assessed in male Sprague-Dawley rats (Bubser et al.

[2014] ACS Chemical Neuroscience 5: 920-942).

[0464] Drugs: d- Amphetamine hemisulfate salt (AMP) was obtained from Sigma (St. Louis, MO). Salt correction was used to determine the amount of AMP added to sterile water to make a solution of d - the amount of amphetamine hemisulfate salt (in mg) to produce a solution containing d - a solution of amphetamine (free base) at a concentration of 0.25 mg / mL solution was administered subcutaneously at a volume of 1 mL / kg body weight. On each experimental day, Compound 70 and comparator compound VU0467154, a M4 PAM (Bubser et al.

[2014] ACS Chem. Neurosci. 5: 920-942), were freshly prepared in separate vials with vehicle (10% Tween 80, 90% water, v / v) to obtain a compound concentration of 20 mg / mL (Compound 70) or 1 mg / mL (VU0467154). The resulting mixtures were vortexed vigorously, homogenized using a hand-held tissue homogenizer for 2-3 minutes, and then sonicated in a 39 °C sonication bath for 60 minutes until a microsuspension was formed. These preparations were administered intraperitoneally (i.p.) at a volume of 5 mL / kg body weight (vehicle and Compound 70) or orally (p.o.) at a volume of 10 mL / kg body weight (VU0467154).

[0465] Animals: Male Sprague-Dawley rats (Harlan, Inc., Indianapolis, IN) weighing 268-343 grams (mean 290 grams) were used in this study. Upon arrival, all rats had to be acclimated in the animal housing facility for at least 72 hours prior to testing. Animals were group housed in an American Association for the Accreditation of Laboratory Animal Care (AAALAC) accredited animal care facility and were on a 12-hour light / dark cycle (lights on: 6 AM; lights off: 6 PM) with free access to food and water. Rats used for this experiment were fasted overnight prior to experimental day for oral administration of test compound / vehicle. The experimental procedure performed during the light cycle was approved by the Vanderbilt University Institutional Animal Care and Use Committee and conformed to the guidelines set forth by the National Research Council's Guide for the Care and Use of Laboratory Animals Guide for the Care and Use of Laboratory Animals

[0466] ​Amphetamine-induced excitatory movement: Male rats were tested in a Smart Open Field spontaneous activity testing chamber (Hamilton-Kinder, San Diego, California, USA) using a 16×16 beam for automated recording of spontaneous activity. All rats were acclimatized in the chamber for 30 minutes, followed by intraperitoneal administration of either the vehicle or compound 70, or oral administration of VU0467154. Thirty minutes later, all rats were subcutaneously (sc) injected with 0.25 mg / kg amphetamine, and monitoring continued for another 60 minutes. Spontaneous activity changes were recorded over a total of 120 minutes. Data are expressed as activity counts, defined as the total number of beam interruptions at 5-minute intervals. At the end of this behavioral study, terminal plasma and brain samples were collected for pharmacokinetic analysis to assess exposure levels of compound 70 and VU0467154.

[0467] Data Analysis and Statistics: Behavioral data (beam interruptions every 5 minutes) were analyzed using a two-way ANOVA with GraphPad Prism 10 (version 1, GraphPad Software, San Diego, CA), primarily focusing on the effects of treatment and time. p A probability ≤ 0.05 was used as the statistical significance level. Furthermore, the total number of beam interruptions from amphetamine administration (65-minute chamber) to the end of the study (120-minute chamber) was calculated and plotted. The reversal percentage was calculated using Microsoft Excel. For each rat in each treatment group, its total activity from t = 65 to t = 120 was summed. The mean of each sum was calculated in the mediator group. The reversal percentage for each rat was then calculated using the following formula: Reversal Percentage (%) = 100 - {[(Total activity per animal from t = 65 to t = 120) / (Mean activity of the mediator group from t = 65 to t = 120)] * 100}. The mean reversal percentage ± SEM for each dose group was calculated and expressed using GraphPad Prism 10 (version 1).

[0468] Results: Systemic administration of compound 70 (100 mg / kg (ip)) and positive control compound VU0467154 (10 mg / kg (po)) reversed amphetamine-induced excitatory motor activity (p<0.001), with reversal percentages of 61.1% and 52.7%, respectively. Data are shown in the figure.

[0469] Conclusion: Systemic administration of compound 70 (at a dose of 100 mg / kg, ip) significantly and persistently reversed amphetamine-induced excitatory motor activity (a preclinical model predicting antipsychotic-like activity), with a potency similar to that observed with the comparative compound VU0467154 (at a dose of 10 mg / kg, po) of the M4PAM compound.

[0470] F. In vitro secondary pharmacology and toxicity Compound 70 was tested using Eurofins LeadProfilingScreen®, a assay that detects potential off-target activity and determines relative selectivity. The screening included 68 major molecular targets, including several CNS targets recommended by the European Medicines Evaluation Agency (EMEA) for assessing drug dependence potential. Compound 70 exhibited <50% inhibition of each target in LeadProfilingScreen® at 10 µM (binding), except for human muscarinic 2 (58% inhibition at 10 µM).

[0471] G. In vitro and in vivo drug metabolism and pharmacokinetics Compound 70 has been tested in several in vitro assays to investigate both its metabolism and pharmacokinetics. These assays were performed according to known methods generally described in the following references: Conde-Ceide et al. ACS Med. Chem. Lett. [ACS Medical Chemistry Letters] 2015, 6, 716-720; Morris et al. J. Med. Chem. [Journal of Medicinal Chemistry] 2014, 57, 10192-10197; and Bubser et al. ACS Chem. Neurosci. [ACS Chemical Neuroscience] 2014, 5, 920-942. In vitro assays include those listed in the table below.

[0472] Table 5 Determination Results MDCK-MDR1 ER 0.9 (P app A→ B: 36.7 x 10 -6 cm / s Rat F u (plasma) 0.267 Dog F u (plasma) 0.232 Cynomolgus monkey F u (plasma) 0.177 Human F u (plasma) 0.217 Rat F u (brain) 0.060 Rat CL int (mL / min / kg) 36 Dog CL int (mL / min / kg) 17 Cynomolgus CL int (mL / min / kg) 24 human CL int (mL / min / kg) 9 P450 3A4 IC 50 (µM) >30 P450 2D6 IC 50 (μΜ) >30 P450 2C9 IC 50 (µM) >30 P450 1A2 IC 50 (µM) >30

[0473] Compound 70 has been tested in several in vivo assays, and the pharmacokinetic parameters listed in the table below were determined by pharmacokinetic studies in rats, dogs, or cynomolgus monkeys using known methods generally described in the following references: Garrison et al. J. Med. Chem. [Journal of Medicinal Chemistry] 2022, 65, 6273-6286; Felts et al. J. Med. Chem [Journal of Medicinal Chemistry] 2017, 60, 5072-5085; and Yu et al. J. Med. Chem.J. Med. Chem. 2021, 64, 4709-4729.

[0474] Table 6 Determination Results Rat CL p (mL / min / kg) 4.3 Dog CL p (mL / min / kg) 24.4 Cynomolgus CL p (mL / min / kg) 4.9 Rat V ss (L / kg) 0.7 Dog V ss (L / kg) 3.1 Cynomolgus monkey V ss (L / kg) 1.4 Rat Elim. t 1 / 2 (hr) 3.1 Dog Elim. t 1 / 2 (hr) 2.1 Cynomolgus Elim. t 1 / 2 (hr) 4.2 Rat oral F (3 mg / kg) >100% Dog oral F (3 mg / kg) 83% rat brain:plasma K p ]]> 1.4 rat brain:plasma K p,uu ]]> 0.3

[0475] It is to be understood that the foregoing detailed description and the enclosed figures are only illustrative and should not be considered limiting the scope of the application, which is defined only by the claims and their equivalents.

[0476] Various modifications and changes in the disclosed embodiments can be made by persons of ordinary skill in the art. Such modifications and changes are intended to fall within the scope of the application, which is defined by the following claims and their equivalents.

Claims

1. A compound having formula (I) or a pharmaceutically acceptable salt thereof, in: R 1 yes or ; G 1 It is a 5- to 6-membered partially unsaturated or aromatic heterocyclic system containing 1-3 nitrogen atoms, wherein Z 1 Is it C or N, Z? 2 It is N or C, and Z 1 and Z 2 Not both N; R 10 Choose from the following groups: C 1-4 Alkyl, C 1-4 Fluoroalkyl, halogen, C 3-4 cycloalkyl, C 1-2 Alkylene-C 3-4 Cycloalkyl, –C(O)OC 1-4 Alkyl groups and –C(O)NR a R b ; R 11 Each time it appears, independently select from the following groups: C 1-6 Alkyl, C 1-6 Fluoroalkyl, halogen, –C 1-6 alkylene–R y –C 1-6 Fluoride-R y G 11 、or –C 1-3 Alkylene–G 11 ; R 12 It is oxygenation; m is 0 or 1; n is 1, 0, or 2; p is 1 or 0; R a It is hydrogen, C 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl; R b It is hydrogen, C 1-4 Alkyl, C 1-4 fluoroalkyl, G 10 、or –C 1-3 Alkylene–G 10 ; Alternatively, R a and R b Together with the nitrogen to which they are attached, they form 4- to 10-membered heterocycles containing R a and R b The attached nitrogen and optionally containing 1-2 additional heteroatoms, independently O, N, or S, the heterocycle optionally being substituted by a first substituent selected from the group consisting of: halogen, cyano, C. 1-4 Alkyl, C 1-4 fluoroalkyl, oxo, –OR 50 –N(R) 50 )2、G 10a 、 and –C 1-3 Alkylene–G 10a ; and optionally further independently, is halogen or C 1-4 Alkyl groups are substituted with 1-3 substituents; G 10 It is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a C-shaped group. 3-6 Cycloalkyl groups, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 10 Selected arbitrarily from halogen, cyano, C 1-4 Alkyl, C 1-4 fluoroalkyl, oxo, –OR 50 –N(R) 50 )2、G 10a 、 and –C 1-3 Alkylene–G 10a The first substituent of the group is substituted, and optionally further independently is a halogen or C. 1-4 Alkyl groups are substituted with 1-3 substituents; G 10a It is a phenyl group, a 5- to 6-membered heteroaryl group containing 1-3 heteroatoms, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, or a 3- to 8-membered carbocyclic group, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 10a Optionally substituted by 1-5 substituents independently selected from the group consisting of: halogen, cyano, C 1-4 Alkyl, C 1-4 fluoroalkyl, oxo, OH, –OC 1-4 Alkyl, –OC 1-4 fluoroalkyl, C 3-4 cycloalkyl and –C 1-3 alkylene–C 3-4 cycloalkyl; R 50 Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, or –C 1-3 alkylene–C 3-6 Cycloalkyl groups, wherein each cycloalkyl group is optionally substituted by 1-4 substituents independently selected from the group consisting of: halogens, C... 1-4 Alkyl and C 1-4 fluoroalkyl; R y is –OR c 、–N(R c )2、–C(O)R c 、–C(O)OR c 、or –C(O)N(R c )2; R c Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, or –C 1-3 alkylene–C 3-4 cycloalkyl, wherein alternatively, two R c Together with the nitrogen to which they are attached, they form 4 to 8-membered heterocycles containing R c The attached nitrogen and optionally contain one additional heteroatom, which is O, N, or S, and the heterocycle is optionally substituted by 1-4 substituents independently selected from the group consisting of: halogens, C 1-2 Alkyl and C 1-2 fluoroalkyl; G 11 It is a phenyl group, a 4- to 8-membered heterocyclic group containing 1-2 heteroatoms, a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms, or a C-type heterocyclic group. 3-6 Cycloalkyl groups, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 11 Optionally substituted by 1-4 substituents independently selected from the group consisting of: C 1-4 Alkyl, halogen, cyano, oxo, –OC 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl and –C 1-2 Alkylene-C 3-4 cycloalkyl; X 1 Is it N or CR? 1a ; R 1a It is hydrogen, C 1-4 Alkyl, C 3-6 cycloalkyl, or C 1-4 fluoroalkyl; X 2 Is it N or CR? 1b ; R 1b It is cyano, halogen, C 1-4 Alkyl, C 1-4 fluoroalkyl or hydrogen; R 1c and R 1e It is C 1-4 Alkyl, hydrogen, halogen, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, or –OC 1-4 alkyl; R 1d and R 1f It is C 1-4 Alkyl, hydrogen, halogen, C 1-4 fluoroalkyl, or C 3-6 cycloalkyl; Alternatively, R 1a and R 1b Together with the atoms to which they are attached, or R 1c and R 1d Together with their respective attached atoms, they form optionally substituted 6-membered aromatic hydrocarbons, 5- to 6-membered heteroaromatic hydrocarbons containing 1 to 3 heteroatoms, 5- to 7-membered heterocycles containing 1 heteroatom, or 5- to 7-membered carbocyclic rings, wherein these heteroatoms are independently selected from the group consisting of N, O, and S, wherein the optional substitution is 1 to 3 optional substituents independently selected from the group consisting of: C 1-4 Alkyl, halogen, –OC 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl and C 1-2 Alkylene-C 3-4 cycloalkyl; R 2 It is G 2 –NR 2a R 2b Halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, –OR 2a –NR 2a C(O)R 2b –C(O)OR 2a –C(O)NR 2a R 2b , or hydrogen; R 2a and R 2b Independently, it is hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, G 2 、or –C 1-3 Alkylene–G 2 The condition is R 2 It is not –N(CH3)2; G 2 Each time it appears, it is independently a 3- to 7-membered carbocyclic group, a 5- to 6-membered heteroaryl group containing 1-4 heteroatoms, a phenyl group, or a 4- to 7-membered heterocyclic group containing 1-2 heteroatoms, wherein these heteroatoms are independently selected from the group consisting of O, N, and S, and G 2 Selected arbitrarily from halogen, cyano, C 1-4 Alkyl, C 1-4 fluoroalkyl, oxo, –OR x –N(R) x )2、–C(O)R x –C(O)OR x –C(O)N(R) x )2、–C 1-6 Alkylene – OR x –C 1-6 Alkylene–N(R) x )2、G 2a 、 and –C 1-3 Alkylene–G 2a The first substituent of the group is substituted, and optionally further independently selected from halogen, cyano, C 1-4 Alkyl and C 1-4 The group consisting of fluoroalkyl groups is substituted with 1-4 substituents; R x Each time it appears, it is independently hydrogen and C. 1-4 Alkyl, C 1-4 fluoroalkyl, C 3-6 cycloalkyl, or –C 1-3 alkylene–C 3-6 cycloalkyl; G 2a It is C 3-6 cycloalkyl; R 8 Each time it appears, it is independently halogen, C. 1-4 Alkyl, C 1-4 fluoroalkyl, or C 3-4 cycloalkyl; and o is 0, 1, 2, 3, or 4; Among them G 2a and R 8 Each cycloalkyl group at the position is independently unsubstituted or independently substituted by 1-4 substituents selected from the following: C 1-4 Alkyl groups (e.g., methyl) and halogens (e.g., fluorine); The condition is that the compound is not: 4,5,6,7-Tetrahydro-5-(2-pyridyl)-thiazo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(4-pyrimidinyl)-thiazo[5,4-c]pyridine-2-amine; 5-(6-chloro-2-cyclopropyl-5-methyl-4-pyrimidinyl)-4,5,6,7-tetrahydro-2-methyl-thiazo[5,4-c]pyridine; 2-[2-(4-ethyl-piperazin-1-yl)-6,7-dihydro-4H-thiazo[5,4-c]pyridin-5-yl]-quinoline; 4,5,6,7-Tetrahydro-5-[5-(trifluoromethyl)-thiazo[5,4-c]pyridine-2-amine; N-(2-Aminophenyl)-4,5,6,7-Tetrahydro-5-[5-(trifluoromethyl)-2-pyridyl]-thiazo[5,4-c]pyridine-2-carboxamide; 5-(2,5-dimethyloxazolo[5,4-d]pyrimidin-7-yl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine-2-amine; 5-(2-cyclopentyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine-2-amine; 5-(5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-thieno[2,3-d]pyrimidin-4-yl-thiazo[5,4-c]pyridine-2-amine; 5-[2,6-bis(1,1-dimethylethyl)-4-pyrimidinyl]-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine; 7-(6,7-dihydrothiazo[5,4-c]pyridin-5(4H)-yl)-2-(trifluoromethyl)-thiazo[5,4-d]pyrimidine; 4,5,6,7-Tetrahydro-5-(2-pyridyl)-thiazo[5,4-c]pyridine-2-carboxylic acid or a salt thereof; 4-(6,7-dihydrothiazo[5,4-c]pyridin-5(4H)-yl)-[1,2,5]thiadiazolo[3,4-c]pyridin; 4,5,6,7-Tetrahydro-5-[6-methyl-2-(1-methylpropyl)-4-pyrimidinyl]-thiazo[5,4-c]pyridine-2-amine; 5-(4-chloro-2-pyridyl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine; 5-[2-(1,1-dimethylethyl)-4-pyrimidinyl]-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine-2-amine; 5-[6-(1,1-dimethylethyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine-2-amine; 5-(2-ethyl-7-methylthiopheno[3,2-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine; 4,5,6,7-Tetrahydro-5-(2-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-thiazo[5,4-c]pyridine-2-amine; 5-(6-cyclopentyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-[3-(trifluoromethyl)-1,2,4-triazolo[4,3-b]pyridazin-6-yl]-thiazo[5,4-c]pyridine-2-amine; 6-(6,7-dihydrothiazo[5,4-c]pyridin-5(4H)-yl)-2-(trifluoromethyl)-9H-purine; 5-(2,6-Dicyclopropyl-4-pyrimidinyl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(5-iodo-2-pyridyl)-thiazo[5,4-c]pyridine; 4,5,6,7-Tetrahydro-5-(7-methylthieno[3,2-d]pyrimidin-4-yl)-thiazo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(2-methyl-4-pyrimidinyl)-thiazo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(4-quinazolinyl)-thiazo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-thiazo[5,4-c]pyridine; 4,5,6,7-Tetrahydro-5-(3-pyridazinyl)-thiazo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-[6-methyl-2-(1-methylethyl)-4-pyrimidinyl]-thiazo[5,4-c]pyridine-2-amine; 5-(6-ethyl-5-fluoro-4-pyrimidinyl)-4,5,6,7-thiazo[5,4-c]pyridine-2-amine; 5-(7-chloro-4-quinazolinyl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine-2-amine; 5-(5-bromo-2-pyridyl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine; 4,5,6,7-Tetrahydro-5-(2-methylthieno[3,2-d]pyrimidin-4-yl)-thiazo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(1H-pyrrolo[2,3-b]pyridin-6-yl)-thiazo[5,4-c]pyridin-2-amine; 4,5,6,7-Tetrahydro-5-(2-methyl-6-propyl-4-pyrimidinyl)-thiazo[5,4-c]pyridine-2-amine; 4,5,6,7-Tetrahydro-5-(5-methylthieno[2,3-d]pyrimidin-4-yl)-thiazo[5,4-c]pyridine-2-amine; 5-(6-cyclohexyl-4-pyrimidinyl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine; 4,5,6,7-Tetrahydro-5-[6-methyl-2-(1-methylpropyl)-4-pyrimidinyl]-thiazo[5,4-c]pyridine; or 5-(6-bromo-4-quinazolinyl)-4,5,6,7-tetrahydro-thiazo[5,4-c]pyridine-2-amine.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 yes .

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z 1 It is C and Z 2 It is N.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z 1 It is N and Z 2 It's C.

5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z 1 It is C and Z 2 It's C.

6. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein G 1 It is a 5-membered partially unsaturated heterocyclic system.

7. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein G 1 It is a hexacyclic partially unsaturated heterocyclic system.

8. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein G 1 It is a 5-membered aromatic heterocyclic system.

9. The compound of any one of claims 1, 2, or 5, or a pharmaceutically acceptable salt thereof, wherein G 1 It is a 6-membered aromatic heterocyclic system.

10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R 1e It is C 1-4 Alkyl or hydrogen.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R 1f It is C 1-4 alkyl.

12. The compound of any one of claims 1-11 or a pharmaceutically acceptable salt thereof, wherein R 1 yes 。 13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 yes .

14. The compound of claim 1 or 13 or a pharmaceutically acceptable salt thereof, wherein X 1 It is N.

15. The compound of claim 1 or 13, or a pharmaceutically acceptable salt thereof, wherein X 1 It is CR 1a .

16. The compound of any one of claims 1 or 13-15, or a pharmaceutically acceptable salt thereof, wherein X 2 It is N.

17. The compound of any one of claims 1 or 13-15, or a pharmaceutically acceptable salt thereof, wherein X 2 It is CR 1b .

18. The compound of any one of claims 1, 13, or 15-17, or a pharmaceutically acceptable salt thereof, wherein R 1a Is it hydrogen or C? 1-4 alkyl.

19. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1, 13-15, or 17-18, wherein R 1b It is a cyano group.

20. The compound of any one of claims 1, 13, 15, or 17, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Together with the atoms to which they are attached, they can form optionally substituted 6-membered aromatic hydrocarbons, 5- to 6-membered heteroaromatic hydrocarbons containing 1 to 3 heteroatoms, 5- to 7-membered heterocycles containing 1 heteroatom, or 5- to 7-membered carbon rings.

21. The compound of any one of claims 1 or 13-20, or a pharmaceutically acceptable salt thereof, wherein R 1c It is hydrogen, C 1-4 Alkyl or halogen.

22. The compound of any one of claims 1 or 13-21, or a pharmaceutically acceptable salt thereof, wherein R 1d Is it hydrogen or C? 1-4 alkyl.

23. The compound of any one of claims 1 or 13-19, or a pharmaceutically acceptable salt thereof, wherein R 1c and R 1d Together with the atoms to which they are attached, they can form optionally substituted 6-membered aromatic hydrocarbons, 5- to 6-membered heteroaromatic hydrocarbons containing 1 to 3 heteroatoms, 5- to 7-membered heterocycles containing 1 heteroatom, or 5- to 7-membered carbon rings.

24. The compound of any one of claims 1 or 13-23, or a pharmaceutically acceptable salt thereof, wherein R 1 yes 。 25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, R 2 It is G 2 –NR 2a R 2b Halogen, cyano, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, –OR 2a –C(O)OR 2a –C(O)NR 2a R 2b , or hydrogen.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 2 It is G 2 .

27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 3- to 7-membered carbon cyclogroup that is optionally substituted.

28. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein G 2 It is a 5- to 6-membered heteroaryl group that is optionally substituted.

29. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein G 2 It is an optionally substituted phenyl group.

30. The compound of any one of claims 1-29 or a pharmaceutically acceptable salt thereof, wherein G 2 yes 。 31. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 2 Yes – NR 2a R 2b .

32. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 2 It is –C(O)NR 2a R 2b .

33. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-25 or 31-32, wherein R 2b It is hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, G 2 、or –C 1-3 Alkylene–G 2 .

34. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 2 It is –C(O)OR 2a .

35. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 2 Is – OR 2a .

36. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-25 or 31-35, wherein R 2a Is it hydrogen or C? 1-6 alkyl.

37. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 2 It is C 1-6 alkyl.

38. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 2 It is halogen.

39. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen.

40. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 2 It is C 1-6 Halogenated alkyl groups.

41. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a cyano group.

42. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-41, wherein o is 0.

43. The compound of claim 1, wherein the compound is selected from the group consisting of: Or its pharmaceutically acceptable salt.

44. A pharmaceutical composition comprising the compound of any one of claims 1-43 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

45. The compound of any one of claims 1-43 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 44, for use in the treatment of neurological and / or mental disorders, wherein the disorder is selected from Alzheimer's disease, schizophrenia, sleep disorders, pain disorders, and cognitive impairment.

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