Compounds and methods for the modulation of muscarinic receptors

Abstract

This invention relates to compounds that are agonists of the muscarinic M1 and / or M4 receptors useful in the treatment of diseases mediated by the muscarinic M1 and / or M4 receptors. Also provided are pharmaceutical compositions containing the compounds and the therapeutic applications of the compounds. Specifically, the present disclosure is related to compounds that are useful in treating pain, schizophrenia, Parkinson's disease, Alzheimer's disease, and other neuropsychiatric and neurodegenerative diseases.

Description

Attorney Docket No.: 206602-0001-00WOTITLE OF THE INVENTIONCompounds and Methods for the Modulation of Muscarinic ReceptorsCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U. S. Provisional Application No. 63 / 843,808, filed July 14, 2025, and U. S. Provisional Application No. 63 / 724,541, filed November 25, 2024, the disclosures of which are each incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION

[0002] Muscarinic acetylcholine receptors (mAChRs) are G protein-coupled receptors (GPCRs) which are broadly expressed in the central nervous system (CNS) and other tissues in the periphery. The mAChR family consists of five distinct subtypes, denoted Ml to M5 that are encoded by the genes CHRM1 to CHRM5. Ml, M3 and M5 receptors couple primarily to Gq / n that stimulate phospholipase C and inositol phosphate and mediate an excitatory effect through intracellular calcium influx. M2 and M4 are coupled with Gi / o, resulting in an inhibition of the downstream adenyl cyclase activation. The mAChRs play essential roles in human physiology, regulating heart rate, smooth muscle contraction, glandular secretion and many fundamental functions of the central nervous system (CNS). The Ml mAChR is primarily expressed in the brain and constitutes up to 60% of total mAChR expression in the central nervous system (CNS). Preclinical and clinical evidence highlighted the involvement of muscarinic receptors in many neuropsychiatric illnesses, including major depressive disorder (MDD), bipolar disorder (BP), schizophrenia, dementia, Alzheimer’s disease (AD) and anxiety disorders. Modulation of mAChR for therapeutic mitigation of neuropsychiatric disorders has been hampered by the dose limiting adverse effects associated with M2 and M3 receptor activation in the peripheral. There remains a need for highly selective agonists for MIR or the use of positive allosteric modulators, which selectively enhance the affinity' of the Ml receptor for acetylcholine.SUMMARY OF THE INVENTION

[0003] The compounds of the present invention are muscarinic agonists. More specifically, the compounds of the present invention are selective agonists of the muscarinic Ml receptor. These agonists are potentially useful for treating a variety of disorders of the central nervous system and other body systems that are mediated through muscarinic receptors. These disorders include, for example, cognitive disorders, ADHD, Parkinson’s diseases, Alzheimer’s disease, andAttorney Docket No.: 206602-0001-00WOschizophrenia.

[0004] In one embodiment, the present disclosure provides compounds comprising the structure of Formula (I).Ax, D\ — CFormula (I)or a tautomer, stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, solvate, or derivative thereof.Wherein:R1is O, S, NH, N-OH;Y is N, O, CH,X1is C, or absentR2, R3are each independently absent, hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl-Ci-3alkyl, C3-7 heterocycloalkyl, C3-7heterocycloalkyl-Ci-3alkyl, Ce-ioaryl-Ci-3alk d, C3-9 heteroaryl, or C3-9 heteroaryl-Ci-3 alkyd;A, B, C, D are each independently absent, CH, CH2, CRa;Where in Rais hydrogen, C1-6 alkyd, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl-Ci-3 alkyd, C3-7 heterocycloalkyd, C3-7 heterocycloalkyd-C i-salkyd, Ce-ioaryd-Ci-3alkyd, C3-9 heteroaryd, or C3-9 heteroary I-C1-3 alkyl;m = 0, 1, 2, 3n = l, 2, 3o = 0, 1p = 1 or 2q = 1 or 2R4is H, C1-3 alkyl;Attorney Docket No.: 206602-0001-00WOX5is CH2, C=0, or O;R5is selected from -Rb, -ORb, -NRcRd:Rb, Rc, and Rdare each independently hydrogen, Ci-6 alky l, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl-Ci-salkyl, C3-7 heterocycloalkyl, C3-7heterocycloalkyl-Ci-3alkyl, Ce-ioaryl-Ci-salkyl, C3-9 heteroaryl, or C3-9 heteroaryl-Ci-3 alkyl;R6is absent, hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl-Ci-salkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl-Ci-3alkyl. Ce-io aryl-Ci-3alkyl, C3-9 heteroaryl, or C3-9 heteroaryl-Ci-3 alkyd;

[0005] In one embodiment, the method of treating diseases or conditions ameliorated by the muscarinic system comprises administering to subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or iso topic derivative thereof.

[0006] In one embodiment, the compound of Formula (I) is administered to patients of neurological disorder, including Alzheimer’s disease psychosis. Parkinson’s disease psychosis, dementia related psychosis, dementia with Lewy Bodies, Schizophrenia, brief psychotic disorder or acute delirium.

[0007] In one embodiment, the compound of Formula (I) is administered orally to the subject, in the form of tablets, troches, liquids, drops, capsules, caplets and gel caps or other such formulations known to one skilled in the art.

[0008] In one embodiment, the method of treatment comprises administering the compound of Formula (I) and a muscarinic antagonist to alleviate the side effects associated with use of the muscarinic activators.

[0009] In one embodiment, the compound of Formula (I) may be taken sequentially with a muscarinic antagonist. In another embodiment, the muscarinic agonist may be taken concurrently with the muscarinic antagonist. In a preferred embodiment, the compound of Formula (I) and the muscarinic antagonist are formulated to be contained in the same dosage form or dosage vehicle.

[0010] In one embodiment, the compound of Formula (I) may be taken sequentially with a muscarinic antagonist. In another embodiment, the muscarinic agonist may be taken concurrently with the antagonist. In a preferred embodiment, the agonist and the antagonist are formulated to be contained in the same dosage form or dosage.

[0011] In one embodiment, the compound of Formula (I) and a muscarinic antagonist areAttorney Docket No.: 206602-0001-00WOformulated to be in separate dosage forms or dosage vehicles. In one embodiment, the muscarinic agonist and antagonist are formulated in an immediate release dosage form. In a preferred embodiment, the muscarinic antagonist is trospium.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] For a further understanding of the nature, objects, and advantages of the present disclosure, reference should be had to the following detailed description, read in conjunction with the following drawings, wherein like reference numerals denote like elements.

[0013] The following detailed description of exemplary' embodiments of the disclosure will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the disclosure is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings.

[0014] FIG. 1 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 2.

[0015] FIG. 2 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 6.

[0016] FIG. 3 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 13.

[0017] FIG. 4 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 31.

[0018] FIG. 5 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 35.

[0019] FIG. 6 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 46.

[0020] FIG. 7 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 49.

[0021] FIG. 8 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 50.

[0022] FIG. 9 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 67.

[0023] FIG. 10 shows representative results demonstrating the dose-dependent activation ofAttorney Docket No.: 206602-0001-00WOmuscarinic Ml, M2, M3, M4 receptors by example compound 69.

[0024] FIG. 11 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 74.

[0025] FIG. 12 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 78

[0026] FIG. 13 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 81.

[0027] FIG. 14 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 83.

[0028] FIG. 15 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 109

[0029] FIG. 16 shows representative results demonstrating the dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compound 110.DETAILED DESCRIPTION OF THE DISCLOSUREDefinitions

[0030] As used herein, the term “treatment" or “treating"’ is defined as the application or administration of a therapeutic agent, i.e.. a compound of the present disclosure (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder contemplated herein, a sign or symptom of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a disease or disorder contemplated herein, the signs or symptoms of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics. To “treat” a disease as the term is used herein, means to reduce the frequency or severity of at least one sign or symptom of a disease or disorder experienced by a subject.

[0031] “Oral” administration of a composition includes through mouth and swallow, buccal,Attorney Docket No.: 206602-0001-00WOsublabial, or sublingual method.

[0032] “Parenteral” administration of a composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m), or intrastemal injection, or infusion techniques.

[0033] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0034] As used herein, “pharmaceutically acceptable salts” refer to derivatives of the compounds disclosed herein wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to. those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxy ethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxy naphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicyclic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc.

[0035] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-l -carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary7buty lacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine,Attorney Docket No.: 206602-0001-00WOtromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt may be 1:1, or any ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0036] It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt.

[0037] '‘Solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0038] The compounds according to the present disclosure and their salts can exist in the form of tautomers which are included in the embodiments of the present disclosure.

[0039] The term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH conditions. The concept of tautomers that are interconvertible by tautomerizations is called tautomerism.

[0040] Where the present disclosure depicts a compound prone to tautomerization, but only depicts one of the tautomers, it is understood that all tautomers are included as part of the meaning of the chemical depicted. It is to be understood that the compounds disclosed herein may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included, and the naming of the compounds does not exclude any tautomer form.

[0041] Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group ( — CHO) in a sugar chain molecule reacting with one of the hydroxy groups ( — OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.Attorney Docket No.: 206602-0001-00WO

[0042] Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), imine-enamine and enamine-enamine.

[0043] As used herein, the term '“pharmaceutical composition” refers to a mixture of at least one compound useful within the present disclosure with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration. The term “pharmacological composition,” “therapeutic composition,” “therapeutic formulation” or “pharmaceutically acceptable formulation” can mean, but is in no way limited to, a composition or formulation that allows for the effective distribution of an agent provided by the present disclosure, which is in a form suitable for administration to the physical location most suitable for their desired activity, e.g., systemic administration.

[0044] Non-limiting examples of agents suitable for formulation with the, e.g., compounds provided by the instant disclosure include: cinnamoyl, PEG, phospholipids or lipophilic moieties, phosphorothioates, P-glycoprotein inhibitors (such as Pluronic P85) which can enhance entry of drugs into various tissues, for example the CNS (Jolliet-Riant and Tillement, 1999, Fundam. Clin. Pharmacol., 13. 16-26); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after implantation (Emerich, D F et al, 1999, Cell Transplant, 8, 47-58) Alkermes, Inc. Cambridge, Mass.; and loaded nanoparticles, such as those made of polybutylcyanoacrylate, which can deliver drugs across the blood brain barrier and can alter neuronal uptake mechanisms (Prog Neuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999).

[0045] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs or symptoms of pathology disease or disorder, for the purpose of diminishing or eliminating those signs or symptoms.

[0046] As used herein, the terms “effective amount,” “‘pharmaceutically effective amount” and “‘therapeutically effective amount” refer to a sufficient amount of an agent to provide the desired biological or physiologic result. That result may be reduction and / or alleviation of a sign, a symptom, or a cause of a disease or disorder, or any other desired alteration of a biological system. An appropriate effective amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0047] As used herein, the term “pharmaceutically acceptable carrier” means aAttorney Docket No.: 206602-0001-00WOpharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the present disclosure within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the present disclosure, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0048] As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the present disclosure, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the present disclosure.

[0049] As used herein, the term “prodrugs” means any compound that is converted in vivo into a biologically active compound of the formula (I). For example, some prodrugs are esters of the active of any hydroxyl groups present in the parent compound with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required. Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

[0050] Accordingly, in another embodiment, the invention provides a prodrug of a compound as defined in any embodiment wherein the compound contains a functional group which isAttorney Docket No.: 206602-0001-00WOconvertible under physiological conditions to form a hydroxyl group or amino group.

[0051] As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherw ise stated, a fluorine, chlorine, bromine, or iodine atom.

[0052] As used herein, the term “alkyl.” by itself or as part of another substituent means, unless otherwise stated, a linear or branched chain hydrocarbon having the number of carbon atoms designated (i.e. Ci-6 means one to six carbon atoms) and includes linear, branched chain, or cyclic substituent groups. Examples include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl. isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyL n-heptyl, n-octyl, and the like. The term “alkyl,” unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below, such as “heteroalkyl”, “haloalkyl” and “homoalkyl”.

[0053] As used herein, the term “substituted alkyl” means alkyl, as defined above, substituted by one, two or three substituents selected from the group consisting of halogen, -OH, alkoxy, -NH2, -N(CH3)2, -C(=O)OH, trifluoromethyl, -C=N, -C(=O)O(Ci-C4)alkyl, -C(=O)NH2, -SO2NH2, -C(=NH)NH2, and -NO2, for example, containing one or two substituents selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(=O)OH, selected, for example, from halogen, alkoxy and -OH. Examples of substituted alky ls include, but are not limited to, 2,2-difluoropropyl, 2-carboxy cyclopentyl and 3-chloropropyl.

[0054] Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycyclic cycloalkyls include adamantine and norbomane. The term cycloalkyl includes “unsaturated nonaromatic carbocyclyl” or “nonaromatic unsaturated carbocyclyl” groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon double bond or one carbon triple bond.

[0055] As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group. The term “substituted” further refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. In one embodiment, the substituents van,' in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two. The substituents are independently selected, and substitution may be at any chemically accessible position. In oneAttorney Docket No.: 206602-0001-00WOembodiment, the substituents vary in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two. In yet another embodiment, the substituents are independently selected from the group consisting of Ci-6 alkyl, -OH, Ci-6 alkoxy, halo, amino, acetamido and nitro. In yet another embodiment, the substituents are independently selected from the group consisting of Ci-6 alkyl, Ci-6 alkoxy, halo, acetamido, and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, linear or cyclic. For example, in one embodiment, the carbon chain is linear.

[0056] As used herein, the term '‘optionally substituted’’ means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

[0057] In one embodiment, the substituents are independently selected from the group consisting of oxo, halogen, -CN, -NH2, -OH, -NH(CH?), -N(CH?)2, alkyl (including linear chain, branched and / or unsaturated alkyl), substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, fluoro alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted alkoxy, fluoroalkoxy, -S-alkyl, S(=O)2alkyl, -C(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -C(=O)N[H or alkyl]2, -OC(=O)N[substituted or unsubstituted alkyl]2, -NHC(=O)NH[substituted or unsubstituted alkyl, or substituted or unsubstituted phenyl], -NHC(=O)alkyl, -N[substituted or unsubstituted alkyl] C(=O)[substituted or unsubstituted alkyl], -NHC(=O)[substituted or unsubstituted alkyl], -C(OH)[substituted or unsubstituted alkyl]2. and -C(NH2) [substituted or unsubstituted alkyl]2. In another embodiment, by way of example, an optional substituent is selected from oxo, fluorine, chlorine, bromine, iodine, -CN, -NH2, -OH, -NH(CH.3), -N(CH3)2, -CH3, -CH2CH3, -CH(CHs)2, -CF3, -CH2CF3, -0CH3, -OCH2CH3, -OCH(CH3)2, -0CF3, - OCH2CF3, -S(=O)2-CH3, -C(=O)NH2, -C(=O)-NHCH3, -NHC(=O)NHCH3. -C(=O)CH3, -ON(O)2, and -C(=O)OH. In yet one embodiment, the substituents are independently selected from the group consisting of C1-6 alkyl, -OH, C1-6 alkoxy, halo, amino, acetamido, oxo and nitro. In yet another embodiment, the substituents are independently selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, halo, acetamido, and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, linear, or cyclic.

[0058] As used herein, the term "analog.” “analogue,” or “derivative” is meant to refer to aAttorney Docket No.: 206602-0001-00WOchemical compound or molecule made from a parent compound or molecule by one or more chemical reactions. As such, an analog can be a structure having a structure similar to that of the small molecule therapeutic agents described herein or can be based on a scaffold of a small molecule therapeutic agents described herein, but differing from it in respect to certain components or structural makeup, which may have a similar or opposite action metabolically. An analog or derivative can also be a small molecule that differs in structure from the reference molecule, but retains the essential properties of the reference molecule. An analog or derivative may change its interaction with certain other molecules relative to the reference molecule. An analog or derivative molecule may also include a salt, an adduct, tautomer, isomer, or other variant of the reference molecule.

[0059] Ranges: throughout this disclosure, various aspects of the present disclosure can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4. from 1 to 5, from 2 to 4. from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.Compounds

[0060] In one aspect, the present disclosure provides compounds comprising the structure of Formula (I).Formula (I)or a tautomer, stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, solvate, or derivative thereof.Wherein:Attorney Docket No.: 206602-0001-00WOR1is O, S;Y is N, O, CH,X1is C, or absentR2, R3are each independently absent, hydrogen, Ci-6 alkyl. Ci-6 haloalkyl. C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl-Ci-salkyl, C3-7 heterocycloalkyl, C3-7heterocycloalkyl-Ci-3alkyl, Ce-ioaryl-Ci-salkyl, C3-9 heteroaryl, or C3-9 heteroaryl-Ci-3 alkyl;A, B, C, D are each independently absent, CH, CH2, CRa,Wherein Rais hydrogen, C1-6 alkyl, C1-6 haloalky l, C2-6 alkenyl, C2-6 alky nyl, C3-7 cycloalkyl-Ci-3 alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalky l-Ci-salkyl, Ce-ioaryl-Ci-salkyl, C3-9 heteroaryl, or C3-9 heteroaryl-Ci-3 alkyl;m = 0, 1, 2, 3n = l, 2, 3o = 0, 1p = 1 or 2q = 1 or 2R4is H, C1-3 alkyl;X5is CH2, C=O, or O;R5is selected from -Rb, -ORb, -NRcRd;Rb, Rc, and Rdare each independently hydrogen, C1-6 alkyl, C1-6 haloalkyl. C2-6 alkenyl, C2-6 alkynyl, C3-7cycloalkyl-Ci-3alkyl, C3-7 heterocycloalkyl, C3-7heterocycloalkyl-Ci-3alkyl, Ce-ioaryl-Ci-salkyl, C3-9 heteroaryl, or C3-9 heteroaryl-Ci-s alkyl;R6is absent, hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl-Ci-salkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl-Ci-salkyl, Ce-io aryl-Ci-3alkyl, C3-9 heteroaryl, or C3-9 heteroaryl-Ci-3 alkyl.

[0061] In some embodiments, provided herein is a compound, or pharmaceutically acceptable salt thereof, chosen from the compounds listed in Table 1:

[0062] TABLE 1. Exemplary Compound of the Disclosure.Exemplary Compound of the DisclosureAttorney Docket No.: 206602-0001-00WOCompoundChemical Structure IUPAC name MW #1 o / Ethyl 4'-methyl-4-(2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l- 386.50 y l)-l 1,4'-bipiperidine] - 1 '- 6 ^0carboxylateIsopropyl 4'-methyl-4-(2-oxo-2,3- 2dihydro-lH-benzo[d]imidazol-l- 400.52 6 y l)-[ 1,4'-bipiperidine] - 1'- carboxylated Prop-2-yn-l-yl 4'-methyl-4-(2-oxo-0J3 2,3-dihydro-lH-benzo[d]imidazol- 396.491 -yl)- [ 1,4'-bipiperidine] - 1'- carboxylatepHN^\ / -.., _. Methyl 4'-methyl-4-(6-methyl-2- 1N~< N-V A, O~4 oxo-2, 3 -dihy dro- 1 H- 386.50 benzo[d]imidazol- 1 -yl)-[ 1,4'- bipiperidine] - l'-carboxylateoHN^ / — i. _ _. / Ethyl 4'-methyl-4-(6-methyl-2-oxo- / N— ( V \5 2,3-dihydro-lH-benzo[d]imidazol- 400.521 -yl)- [ 1,4'-bipiperidine] - 1'- carboxylatepHN' x. / Isopropyl 4'-methyl-4-(6-methyl-2- 6 oxo-2.3-dihy dro- 1 H- 414.55 benzo [d] imidazol- 1 -yl)-[ 1,4'- bipiperidine] - l'-carboxy lateJ Prop-2-yn-l-yl 4'-methyl-4-(6- 1 N— / KI A / \ P~~~^7 methyl-2-oxo-2,3-dihydro-lH- 410.52 n benzo[d]imidazol-l-yl)-[l,4'- bipiperidine] - l'-carboxylatepHN^\ / —^., _. / Ethyl 4-(6-fluoro-2-oxo-2,3- 1 N — ( KI-\ / P — '8 dihydro-lH-benzo[d]imidazol-l- 404.49 yl)-4'-methyl-[1.4'-bipiperidine]-r- F carboxylateO HN^\ / — v > / Isopropyl 4-(6-fluoro-2-oxo-2,3- 9 dihy dro- lH-benzo[d]imidazol- 1 - 418.51 yl)-4'-methyl-[l,4'-bipiperidine]-r- F carboxylateAttorney Docket No.: 206602-0001-00WOProp-2-yn-l-yl 4-(6-fluoro-2-oxo- 1 N-( NA / \ ' 2,3-dihydro-lH-benzo[d]imidazol- 414.481 -yl)-4'-methy 1- [ 1,4'-bipiperidine] - F 1 '-carboxylateO HN"^ / \ \ / — x O— Methyl 4-(5-fluoro-2-oxo-2?3- £ / N~ < N-¥ N-Z dihydro-lH-benzo[d]imidazol-l- 390.46 yl)-4'-methyl-[ 1.4'-bipiperidine]- 1'- X? °F carboxylate0HN-X / \ \ / - \ O—^ Ethyl 4-(5-fluoro-2-oxo-2,3- L zN— ( N-¥ N-Z dihydro-lH-benzo[d]imidazol-l- 404.49 yl)-4'-methyl-[1.4'-bipiperidine]-r- JO °F carboxylateO HN-^x / ~ \ \ J — X O— ( Isopropyl 4-(5-fluoro-2-oxo-2,3- f / N - / N-¥ W \ dihydro-lH-benzo[d]imidazol-l- 418.51 fjOy l)-4'-methy 1- [ 1.4'-bipiperidine] - 1'- F carboxylateOHlX / \ \ / — \ 0— x Prop-2-y n- 1 -y 14-(5 -fluoro-2-oxo- 2,3-dihydro-lH-benzo[d]imidazol- 414.48 l-yl)-4'-methyl-[l,4'-bipiperidine]- l'-carboxylateoHN"^ / \ \ / — x O— Methyl 4-(5-fluoro-6-methyl-2- oxo-2, 3 -dihy dro- 1 H- 404.49 benzo [d] imi dazol- 1 -y 1 ) -4 ' -methyl - x ° [ 1,4'-bipiperidine] - l'-carboxy late oHN"^ / \ \ J — x O-^ Ethyl 4-(5-fluoro-6-methyl-2-oxo- 2,3-dihydro-lH-benzo[d]imidazol- 418.51 1 -yl)-4'-methy 1- [ 1,4'-bipiperidine] - H01 '-carboxylate0HN^x / \ \ / — X 0— / Isopropyl 4-(5-fluoro-6-methyl-2- 2 / V / A_7HAoxo-2, 3 -dihy dro- 1 H- 432.54 benzoldJimidazol-l-yl)-4'-methyl- x [ 1,4'-bipiperidine] - 1 '-carboxylate I" J Prop-2-yn-l-yl 4-(5-fluoro-6- methyl-2-oxo-2,3 -dihydro- 1H- 428.51 benzo [d] imi dazol- 1 -y 1 )-4' -methyl - X ° [ 1,4'-bipiperidine] - l'-carboxy lateAttorney Docket No.: 206602-0001-00WO1HNQN-^X>V'Ny°^' Ethyl 3 -((4-(2-oxo-2, 3-dihy dro- 1 H- benzo [d]imidazol- 1 -y l)piperidin- 1 - 358.44 y l)methyl)azetidine- 1 -carboxylateEthyl 3-methyl-3-((4-(2-oxo-2,3- „NW \ o^ dihydro-lH-benzo[d]imidazol-l- 372.47 yl)piperidin-l-yl)methyl)azetidine- t5 ° 1 -carboxylateHNUN\<-0.. Ethyl 3-((4-(5-fluoro-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l- 376.43 0ryl)piperidin-l-yl)methyl)azetidine- F 1 -carboxylateEthyl 3-((4-(5-fluoro-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l- 390.46 0!y 1 )pi pendm- 1 -yl)methyl)-3- F methylazetidine- 1 -carboxylateI HN0., Ethyl 3-((4-(6-fluoro-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l- 376.43 yl)piperidin-l-yl)methyl)azetidine- 01F 1 -carboxylateEthyl 3-((4-(6-fluoro-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l- 390.46 y 1 )pi pendm- 1 -yl)methyl)-3- 0rmethylazetidine- 1 -carboxylateFEthyl 3-((4-(5-fluoro-6-methyl-2- oxo-2, 3-dihy dro- 1 H- 390.46 0 • benzo [d]imidazol- 1 -y l)piperidin- 1 - F y l)methyl)azetidine- 1 -carboxylateEthyl 3-((4-(5-fluoro-6-methyl-2-HNW "h oxo-2, 3 -dihy dro- 1 H- benzo [d]imidazol- 1 -y l)piperidin- 1 - 404.49 yl)methyl)-3-methylazetidine- 1 - ArcarboxylatenNy° o / "'' Ethyl 3-((4-(2-oxo-2, 3-dihy dro-lH- benzo[d]imidazol-l-yl)piperidin-l- 372.47 y l)methyl)pyrrolidine- 1 -carboxylateAttorney Docket No.: 206602-0001-00WOEthyl 3-methyl-3-((4-(2-oxo-2,3- HN^° VcC dihydro-lH-benzo[d]imidazol-l- yl)piperidin-l- 386.50 y l)methyl)pyrrolidine- 1 - carboxylateIsopropyl 4-(6-fluoro-2-oxoindolin- 1 -yl)-4'-methy 1- [ 1,4'-bipiperidine] - 417.53 1 '-carboxylateFIsopropyl 4'-methyl-4-(3-methyl-2- oxoindolin- 1 -yl)-[ 1,4'- 413.56 bipiperidine] - l'-carboxylateoHN^ / \ \ / - \ O—Z Isopropyl 4-(6-fluoro-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l- 418.51 y^-d'-methyl-fl.d'-bipiperidine]-!'- F carboxylate,0Ethyl 3-methyl-3-(4-(3-methyl-2-XN"'Z / - \ < / uH p-' ox o-2, 3 -dihy dro- 1 H - 386.50 benzo [d]imidazol- 1 -y l)piperidin- 1 - U y l)pyrrolidine- 1 -carboxylate0Ethyl 3-(4-(6-fluoro-3-methyl-2- oxoindolin- 1 -y l)piperidin- 1 -y l)-3 - 403.50 methy Ipy rrolidine- 1 -carboxyl ateFoL / N\,NP N- / \ Isopropyl 4-(3,6-dimethyl-2- 427.59 oxoindolin- 1 -y l)-4'-methy 1- [ 1,4'- ° bipiperidine] - l'-carboxylateO HN^\ / \ \ / — \ p— ( Isopropyl 4-(5-fluoro-6-methyl-2- oxo-2, 3 -dihy dro- 1 H- 432.54 benzo[d]imidazol-l-yl)-4'-methyl- [ 1,4'-bipiperidine] - 1 '-carboxylateoEthyl 4'-methyl-4-((3aS,7aS)-3- / - \ / - y O— / methy 1-2-oxooctahy dro- 1 H- X / ~\,N7\ 406.57 benzo[d]imidazol-l-yl)-[l,4'- \ J ' - / '°bipiperidine] - l'-carboxy lateAttorney Docket No.: 206602-0001-00WOoIsopropyl 4'-methyl-4-((3aS,7aS)-3- \ \ o-Z methy 1-2-oxooctahy ^dro- 1 H- AZ V_ / NT\ M ' 420.60 \ J ' — / ° benzo[d]imidazol-l-yl)-[l,4'- bipiperidine] - l'-carboxylateo Ethyl 3-methyl-3-(4-((3aS,7aS)-3- methy 1-2-oxooctahy dro-lH- 392.54 benzo [d]imidazol- 1 -y 1 )pi peri din- 1 - yl)pyrrolidine-l -carboxylate0 Isopropyl 3-methyl-3-(4-((3aS,7aS)-3-methyl-2-oxooctahydro-lH- 406.57 benzo [d]imidazol- 1 -y l)piperidin- 1 - y 1 )py rrolidine- 1 -carboxylateoMN\ / ^ Ethyl 4'-methyl-4-((7aS)-3-methyl- L > ~\^N-X N-^ 2-oxooctahydro-lH-indol-l-yl)- 405.58 \ 3 ' — / '° [ 1,4'-bipiperidine] - 1 '-carboxylate oIsopropyl 4'-methyl-4-((7aS)-3- v — \ °~( methyl-2-oxooctahydro-lH-indol- v_ / N\NZ ' 419.61 \ J ' —z'° 1 -yl)_[ 1,4'-bipiperidine] - 1'- carboxylateoEthyl 3-methyl-3-(4-((7aS)-3- methyl-2-oxooctahydro-lH-indol- Af \ _ / 1 N— \ 391.56 I \ o 1 -y 1 )pi peridin- 1 -yl )pyrrolidine- 1 - carboxylateIsopropyl 3-methyl-3-(4-((7aS)-3- methy 1-2-oxooctahy dro-lH- 406.57 benzo[d]imidazol- 1 -y l)piperidin- 1 - yl)pyrrolidine-l -carboxylateNH2Isopropyl 4-((3aS,7aS)-2-amino- NZ / \ / — \ O— ( 3a.4.5.6.7.7a-he.xahydro-IH- \_ / NA M ' 405.59 benzo[d]imidazol-l-yl)-4'-methyl- \ 3 ' — '[L4'-bipiperidine]- l'-carboxylateHOsNH Isopropyl 4-((3aS,7aS)-2- NZ / \ / - \ O— ( (hy droxy amino)-3 a, 4, 5,6,7,7a- hexahydro-lH-benzo[d]imidazol-l- 421.59 AANV / NA W '\ J ' - ' '° y l)-4'-methy 1- [ 1,4'-bipiperidine] - 1'- carboxylateSEthyl 4'-methyl-4-((3aS,7aS)-2- HN^ / - \ - v o- / 0N~CNACHOthioxooctahydro-lH- 408.61 benzo[d]imidazol-l-yl)-[l,4'- bipiperidine] - l'-carboxylateAttorney Docket No.: 206602-0001-00WOsIsopropyl 4'-methyl-4-((3aS,7aS)-2- / - \ \ / - \ O- / thi oxooctahydro- 1 H- A / N~V_VN\ ' 422.63 benzo[d]imidazol-l-yl)-[l,4'- \ i ' — / x°bipiperidine] - l'-carboxylatep J / — \ / — \ ° \ Isopropyl 4'-methyl-4-(3-oxo-2- N— \ N-T( N— ' azaspiro[4.5]decan-2-yl)-[1.4'- 419.61 < p- / ' —! ' ' —fObipiperidine] - l'-carboxy lateO / Isopropyl 4'-methyl-4-(2-oxo-l,4- 414.55 ^50 X3^ dihydroquinazolin-3(2H)-yl)-[l,4'- bipiperidine] - l'-carboxylateo / Isopropyl 4'-methyl-4-(2-oxo-2,3-HNI ^\ N,—\ / N— v \ \ N — P \ ' dihy dro- IH-thieno [3,4-d] imidazol- 406.551 -yl)-[ 1,4'-bipiperidine] - l'- carboxylate0 / Isopropyl 4'-methyl-4-(2- HN^\ _ / X / X _P \1 N— ( N-Z N— \xoxohexahydrocyclopenta[d]imidazo 392.541- 1 (2H)-y 1)- [ 1,4'-bipiperidine] - 1'- carboxylateIsopropyl 4'-methyl-4-(6-methyl-2- oxohexahydrocyclopenta[d]imidazo 406.57 1-1 (2H)-y 1)- [ 1,4'-bipiperidine] - 1'- carboxylateo / Isopropyl 4'-methyl-4-(4-methyl-2- oxohexahydrocyclopenta[d]imidazo 406.57 1- 1 (2H)-y 1)- [ 1.4'-bipiperidine] - 1'- carboxylateIsopropyl 4-(4,4-dimethyl-2- HN"^ / X / X / O—\__7 N— < N-Z N— ' oxoimidazolidin-l-yl)-4'-methyl- 380.53 / "y' —f' ' —fo [ 1,4'-bipiperidine] - 1 '-carboxylate0 / HN"^ _ / X _ / / ^ X Isopropyl 4-(4,5-dimethyl-2- JLN\N-7\n“4xoxoimidazolidin- 1 -yl)-4'-methyl- 380.53[ 1.4'-bipiperidine] - 1 '-carboxylate0 / HN-A / X / \ / ° \ Isopropyl 4'-methyl-4-(5-methyl-2- 1 N— < N-Z N^<xoxoimidazolidin- 1 -y 1)- [ 1,4'- 366.51 bipiperidine] - l'-carboxylate0 / Isopropyl 4'-methyl-4-(2- HM I "^ N— / < \ N-y \ N— / ° \xoxoimidazolidin- 1 -yl)- [ 1,4'- 352.48 X — / / \ — / o bipiperidine] - l'-carboxy lateAttorney Docket No.: 206602-0001-00WO0 / HN"^ / \ \ \ Isopropyl 4-(5-ethyl-2- 1 N— < N-X N— A 'oxoimidazolidin-l-yl)-4'-methyl- 380.53.[ 1,4'-bipiperidine] - 1 '-carboxylateIsopropyl 4'-methyl-4-(2- ■rfc-zC-^ ox otetrahydropyri midin- l(2H)-yl)- 366.51[ 1,4'-bipiperidine] - 1 '-carboxylatep / HN— z \ / — \ p \ Isopropyl 4'-methyl-4-(5-methyl-2- < N-( N-X N-<xox otetrahydropyri midin- 1 (2H)-yl)- 380.53 \ — / \ - / / \ — / o[ 1,4'-bipiperidine] - 1 '-carboxylate Isopropyl 4-(5,6-dimethyl-2- oxotetrahydropyrimidin-l(2H)-yl)- 394.56 4'-methyl-[ 1,4'-bipiperidine] - 1'- carboxylateIsopropyl 4'-methyl-4-(2-oxo-3,6- dc-TC-^ dihydropyrimidin-l(2H)-yl)-[l,4'- 364.49 bipiperidine] - l'-carboxylatep / Isopropyl 4'-methyl-4-(6-methyl-2- HN~Z / — \ / — \ P—( oxo-3, 6-dihydropyrimi din- 1(2H)- <\ 378.5 v — / N-\ \ — / N“ / A N — >,n2 o yl)-[ 1,4'-bipiperidine] -1'- carboxylateIsopropyl 4-(6-ethyl-5-methyl-2- oxo-3,6-dihydropyrimidin-l(2H)- 406.57 y l)-4'-methyl- [ 1,4'-bipiperidine] - 1'- carboxylateIsopropyl 4-(6-ethyl-5-methyl-2- oxotetrahydropyrimidin-l(2H)-yl)- X C-TC-^ 408.594'-methyl-[ 1,4'-bipiperi dine] - l'- carboxylateoIsopropyl 4-(5,6-dimethyl-2-oxo- HN^ / — \ / — v o-ZXNX> TC> V 2,3-dihydro-lH-benzo[d]imidazol- 428.54 l-yl)-4'-methyl-[l,4'-bipiperidine]- l'-carboxylateo / Isopropyl 4'-methyl-4-(4-methyl-2- HN-X / \ / \ 0— (l yN \ N”7\ N - ' oxo-2, 3 -dihy dro- 1 H- 414.55 benzo [d] imidazol- 1 -yl )-[ 1,4'- bipiperidine] - l'-carboxylate0HN— \ Isopropyl 4'-methyl-4-(2-oxo-6- (trifluoromethyl)-2,3-dihydro-lH- 468.52 benzo|djimidazol-l-yl)-[l,4'- bipiperidine] - l'-carboxylateF3C OAttorney Docket No.: 206602-0001-00WOo Isopropyl 4-(4,6-difluoro-2-oxo- R J. \ _ _ 2,3-dihydro-lH-benzo[d]imidazol- 436.50 1 -yl)-4'-methyl-[l,4'-bipiperidine]- F01 '-carboxylateo Isopropyl 4-(5,7-dimethyl-2-oxo- HN-^ / ~\o / 2,3-dihydro-lH-benzo[d]imidazol- vJN7V H 428.581 -yl)-4'-methy 1- [ 1,4'-bipiperidine] -01 '-carboxylateIsopropyl 4'-methy 1 -4- (7 -methy 1-2-HNA-rN7r^°^ oxo-2, 3 -dihydro- 1 H- / W \ ' — / o 414.55 benzo [d] imidazol- 1 -yl)-[ 1,4'- bipiperidine] - l'-carboxy lateIsopropyl 4-(7-fluoro-2-oxo-2,3- dihydro-lH-benzo[d]imidazol-l- / W ' —1> ' — ' o 418.51 yl)-4'-methyl-[l,4'-bipiperidine]-r- kA carboxylateo Isopropyl 4-(6,7-dimethyl-2-oxo- YV2,3-dihydro-lH-benzo[d]imidazol- 428.58 1 -yl)-4'-methy 1- [ 1,4'-bipiperidine] - P 1 '-carboxylateMethyl 4'-methyl-4-(2-oxo-2,3- PY _1 2 / n.NY3NTCY dihydro-lH-benzo[d]imidazol-l- 372.47 yl)-[ 1,4'-bipiperidine] -1'- O I \ J0carboxylateo Isopropyl 4'-methyl-4-((3aR,7aR)- HN-^ / \ \ / v O— / 2-oxohexahydropyrano[3.4- 408.54 I \ ' —Zo d] imidazol- 1 (4H)-y 1)- [1,4'- 0^ / bipiperidine] - l'-carboxy lateIsopropyl 4'-methyl-4-((3aR,7aS)- 2-oxohexahydropyrano[3,4- 408.54 d] imidazol- 1 (4H)-y 1)- [1,4'- bipiperidine] - l'-carboxylateIsopropyl 4'-methyl-4-((3aS,8aS)-2- oxooctahydrocyclohepta[d]imidazo 420.60 1- 1 (2H)-y 1)- [ 1,4'-bipiperidine] - 1'- carboxylate(3aS,7aS)-l-(l-(4- (isopropoxymethyl)cyclohexyl)pipe 377.57 ridin-4-yl)octahydro-2H- benzo[d]imidazol-2-oneIsopropyl 4'-methyl-4-((4S,5S)-2- oxo-4, 5 -dipheny limidazolidin- 1 - 504.68 y l)-[ 1,4'-bipiperidine] - 1 '- -Y Ph c-xY0carboxylateAttorney Docket No.: 206602-0001-00WOo _ ( Isopropyl 4’-methyl-4-((3aS,7aR)- HN^ / \ \ / - \ O 2-oxohexahydropyrano[3,4- A'N\_VNA / H 408.54 0 d]imidazol-3(2H)-yl)-[l,4'- bipiperidine] - l'-carboxylateco p (3aS,7aS)-l-(l-(4- HN"\ / —, „ / (ethoxymethyl)cyclohexyl)piperidi 363.54 n-4-yl)octahydro-2H- benzo[d]imidazol-2-one(3aS,7aS)-l-(l-(3- (isopropoxymethyl)cyclopentyl)pip 363.55 eridin-4-yl)octahydro-2H- benzo[d]imidazol-2-one(3aS,7aS)-l-(l-(3- (ethoxymethyl)cyclopentyl)piperidi 349.52 n-4-yl)octahydro-2H- benzo[d]imidazol-2-oneIsopropyl 4-(4-((3aS,7aS)-2- H^0 / =\ oxooctahydro-lH- 386.50 0NVZ'O'4 benzo[d]imidazol-l- yl)phenyl)piperazine- 1 -carboxylate o / Ehyl 4-methyl-4-(4-((3aS,7aS)-2- HN^ / =\ oxooctahydro- 1H- 385.51 benzo [d]imidazol- 1 - \ \ 0yl)phenyl)piperidine-l -carboxylateo / Isopropyl 4-methyl-4-(4- HN^ z=\. _ _ \ ((3aS,7aS)-2-oxooctahydro-lH- >N~z X-y ~\ 399.54 / v w vi benzo[d]imidazol-l- 1^9 oy l)phenyl)piperidine- 1 -carboxylatep / Isopropyl 4-(4-((3aS,7aS)-2- HN^ / =. (?. N-Z \ / ~~\ O oxooctahydro-lH- 385.51 / v \y~v^N-< benzo[d]imidazol-l-0y l)phenyl)piperidine- 1 -carboxylate,0 1 Isopropyl 3-(4-((3aS,7aS)-2- HN-^ 1 oxooctahydro-lH- 371.48 benzo[d]imidazol-l- °yl)phenyl)pyrrolidine-l -carboxylate Isopropyl 4'-methyl-4-((4aS,8aS)-3- oxooctahydro-4H- 421.29 benzo[b][l,4]oxazin-4-yl)-[l,4'- bipiperidine] - l'-carboxylate' _ o Ethyl 4'-methyl-4-((4aS?8aS)-3- oxooctahydro-4H- 407.28 benzo [b] [1,4] oxazin-4-yl)- [ 1,4'- bipiperidine] - l'-carboxylateAttorney Docket No.: 206602-0001-00WOO ( (3aS,7aS)-l-(4-(4- HNX / — \ \ p (ethoxymethy l)piperidin- 1 - ^p_^N— ' 363.55 yl)cyclohexyl)octahydro-2H- benzo[d]imidazol-2-oneO _ / (3aS,7aS)-l-(4-(4-HN"^ / — \ ' — \ / ° (isopropoxymethyl)piperidin-l- \ / — 377.57 yl)cyclohexyl)octahydro-2H- benzo[d]imidazol-2-oneIsopropyl 4-(4-((3aS,7aS)-2- HKT\ p —P oxooctahydro-lH- ZVNVvN\N-< benzo[d]imidazol-l- 392.54 yl)cyclohexyl)piperazine-l - carboxylateS _ Isopropyl 4-(4-((4aS,8aS)-3- oxooctahydro-4H- benzo [b] [1,4] oxazin-4- 407.56 ^"1 yl)cyclohexyl)piperazine-l - carboxylate / p ( (4aS,8aS)-4-(4-(4- O S ' N / — \ N ~ \ P-7o (ethoxymethyl)piperidin- 1 - 378.56 yl)cyclohexyl)hexahydro-2H- O benzo[b][l,4]oxazin-3(4H)-one(4aS,8aS)-4-(4-(4- (isopropoxymethyl)piperidin-l- > Jo-o5 392.30 yl)cyclohexyl)hexahydro-2H- benzo [b] [ 1,4] oxazin-3(4H)-one(3aS,7aS)-l-(l-(tetrahydro-2H- pyran-4-yl)piperidin-4- ^p_^N — \ p — \ p 307.44 yl)octahydro-2H-benzo[d]imidazol- 2-oneP (3aS,7aS)-l-(l-(4- HN^\ / — >. _ _ methyltetrahydro-2H-pyran-4- 321.46 yl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one(3aS,7aS)-l-(l-(4- (hydroxymethyl)cyclohexyl)piperid 335.49 pf-O-O ™ in-4-y 1 )octahy dro-2H- benzo[d]imidazol-2-oneP (3aS,7aS)-l-(l-(3- HN-< _ OH (hydroxymethyl)cyclopentyl)piperi 321.46 din-4-yl)octahydro-2H- benzo[d]imidazol-2-oneAttorney Docket No.: 206602-0001-00WO0 (3aS,7aS)-l-(l-(3- HN-< (methoxymethyl)cyclopentyl)piperi 101 335.49 din-4-yl)octahydro-2H- benzo[d]imidazol-2-oneO r— I (3aS,7aS)-l-(l-(4- HN" N, ~ ((cyclobutylmethoxy)methyl)cyclo 102 403.61 hexyl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-oneo (3aS,7aS)-1-(1-(4- ((cyclopropylmethoxyjmethyljcycl103 389.58 ohexyl)piperidin-4-yl)octahydro- 2H-benzo[d]imidazol-2-one0 (3aS,7aS)-l-(l-(4- (methoxymethyl)cyclohexyl)piperi104 349.52 din-4-yl)octahydro-2H- benzo[d]imidazol-2-one0 (3aS,7aS)-l-(l-(4-((2- HN"^ / — >,, „105 fluoroethoxy)methyl)cyclohexyl)pi 381.54 peridin-4-yl)octahydro-2H- benzo[d]imidazol-2-onep (3aS,7aS)-l-(l-(4-((2,2,2- HN-AFVF trifluoroethoxy)methyl)cyclohexyl) 106 417.56 piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-oneo (3aS,7aS)-l-(l-(4-((2,2- HN^<L; difluoroethoxy)methyl)cyclohexyl) 108 399.53 piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one0Isopropyl 4-(5,6-difluoro-2-oxo- 2,3-dihydro-lH-benzo[d]imidazol- 109 436.50FZZ-OTO-^p 1 -yl)-4'-methyl-[ 1,4'-bipiperidine] - F 1 '-carboxylate0 / Isopropyl 4'-methyl-4-(5-methyl-2- HN^\ _ / \ / \ P \ oxo-2, 3 -dihy dro- 1 H- 110 414.55 benzo [d] imidazol- 1 -yl )-[ 1,4'- bipiperidine] - 1 '-carboxylate

[0063] The compounds according to the disclosure are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material. Furthermore, reverse phase preparative HPLC of compounds of the present disclosure which possess a sufficiently basic or acidic functionality, mayAttorney Docket No.: 206602-0001-00WOresult in the formation of a salt, such as, in the case of a compound of the present disclosure which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present disclosure which is sufficiently acidic, an ammonium salt for example. Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. Additionally, the drying process during the isolation of compounds of the present disclosure may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognize which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g., salt, free base, solvate, inclusion complex) of a compound of the present disclosure as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity’.

[0064] The compounds of the disclosure may, depending on their structure, exist in different stereoisomeric forms. These forms include configurational isomers or optically conformational isomers (enantiomers and / or diastereoisomers including those of atropisomers). The present disclosure therefore includes enantiomers, diastereoisomers as well as mixtures thereof. From those mixtures of enantiomers and / or disastereoisomers pure stereoisomeric forms can be isolated with methods known in the art, for example, methods of chromatography, especially high performance liquid chromatography (HPLC) using achiral or chiral phase. The disclosure further includes all mixtures of the stereoisomers mentioned above independent of the ratio, including the racemates.

[0065] The compounds of the present disclosure may, depending on their structure, exist in various stable isotopic forms. These forms include those in which one or more hydrogen atoms have been replaced with deuterium atoms, those in which one or more nitrogen atoms have been replaced with15N atoms, or those in which one or more atoms of carbon, fluorine, chlorine, bromine, sulfur, or oxygen have been replaced by the stable isotope of the respective, original atoms.

[0066] Some of the compounds and salts according to the present disclosure may exist in different crystalline forms (polymorphs) which are within the scope of the present disclosure.

[0067] One aspect of the present disclosure is salts of the compounds according to the present disclosure including all inorganic and organic salts, especially all pharmaceutically acceptableAttorney Docket No.: 206602-0001-00WOinorganic and organic salts, particularly all pharmaceutically acceptable inorganic and organic salts customarily used in pharmacy.

[0068] Salts of the compounds of Formula (I) according to the disclosure can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methyl ethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art.

[0069] According to the person skilled in the art the compounds of Formula (I) according to this disclosure as well as their salts may contain, e g., when isolated in crystalline form, varying amounts of solvents. Included within the scope of the present disclosure are therefore all solvates and in particular all hydrates of the compounds of Formula (I) according to this present disclosure as well as all solvates and in particular all hydrates of the salts of the compounds of Formula (I) according to this present disclosure.

[0070] Examples of salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, meglumine, ammonium, salts optionally derived from NHs or organic amines having from 1 to 16 C-atoms such as, e.g., ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, ethylendiamine, N-methylpiperindine, arginine, lysine, and guanidinium salts.

[0071] The salts of the disclosed compounds include pharmaceutically acceptable waterinsoluble and, particularly, water-soluble salts.Pharmaceutical Compositions

[0072] This disclosure also describes, in part, a composition which comprises a compoundAttorney Docket No.: 206602-0001-00WOcomprising the structure of Formula (I), or a tautomer, stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, solvate, or derivative thereof.

[0073] This disclosure also describes, in part, a pharmaceutical composition which comprises a compound comprising the structure of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0074] This disclosure also describes, in part, a compound comprising the structure of Formula (I), or a pharmaceutically acceptable salt thereof, for use in modulating the activity of a muscarinic receptor (e.g.. Ml and / or M4).

[0075] This disclosure also describes, in part, a compound comprising the structure of Formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy of Schizophrenia.

[0076] This disclosure also describes, in part, a compound comprising the structure of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of neurological disorders.

[0077] This disclosure also describes, in part, a method for treating cancer in a subject in need of such treatment, which comprises administering to the subject a therapeutically effective amount of a compound comprising the structure of Formula (I), or a pharmaceutically acceptable salt thereof. For example, this disclosure also describes, in part, a method for treating neurological disorders in patients in need of such treatment, which comprises administering a therapeutically effective amount of a compound comprising the structure of Formula (I), or a pharmaceutically acceptable salt thereof.|0078| In one embodiment, the disclosure provides for a pharmaceutical composition comprising at least one compound comprising the structure of Formula (I) or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutical compound is for use in treatment of a proliferative disease, such as a cancer, for example, non-small cell lung cancer. A further embodiment may provide a method of treating lung cancer comprising administering to a subject in need of treatment or amelioration a compound according to any one of the preceding paragraphs. In some embodiments a compound as presented above is used in the preparation of a medicament for treatment of lung cancer in a patient or subject, such as a human or animal.

[0079] The pharmaceutical compositions of the present disclosure can be in any form known to those of skill in the art, and a suitable dosage form of the compound(s) can be administered by an appropriate route. For instance, in some embodiments the pharmaceutical compositions are in a form of a product for oral delivery. said product form being selected from a group consisting of a concentrate, dried powder, liquid, capsule, pellet, and pill. In other embodiments, the pharmaceutical compositions of the present disclosure are in the form of a product for parenteralAttorney Docket No.: 206602-0001-00WOadministration including intravenous, intradermal, intramuscular, intraarticular, intra-synovial, intrastemal, intrathecal and subcutaneous administration. The compounds described herein may be administered as a single dose or a divided dose over a period of time. The pharmaceutical compositions disclosed herein may also further comprise carriers, binders, diluents, and excipients. The described carriers, diluents and excipients may include dried com starch or lactose, the binder may include microcrystalline cellulose, gum tragacanth or gelatin, in addition, the excipients may also include a dispersing agent, a lubricant, a glidant, a sweetening agent or a flavoring agent.Methods of Use and Treatment

[0080] The methods for treating a clinical indication by the muscarinic Ml and / or M4 receptor agonists disclosed herein, may be effectuated by administering a therapeutically effective amount of the Ml and / or M4 agonists to a patient in need thereof.

[0081] In one embodiment, the method of treating diseases or conditions ameliorated by the muscarinic system comprises administering to subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, prodrug, or isotopic derivative thereof., this therapeutically effective amount may comprise administration of the compound to the patient at about 1 mg / kg / day, about 2 mg / kg / day, about 3 mg / kg / day, about 4 mg / kg / day. about 5 mg / kg / day, about 10 mg / kg / day and about 20mg / kg / day. Alternatively, amounts ranging from about 0.001 mg / kg / day to about 0.01 mg / kg / day, or about 0.01 mg / kg / day to about 0.1 mg / kg / day, or about 0.1 mg / kg / day to about 1 mg / kg / day, or about 1 mg / kg / day to about 10 mg / kg / day, or about 10 mg / kg / day to about 100 mg / kg / day, or about 100 mg / kg / day to about 1000 mg / kg / day are also contemplated.

[0082] In one embodiment, the compound of Formula (I) is administered to patients of neurological disorder, including Alzheimer’s disease psychosis. Parkinson’s disease psychosis, dementia related psychosis, dementia with Lewy Bodies, Schizophrenia, brief psychotic disorder or acute delirium.

[0083] In one embodiment, the compound of Formula (I) is administered orally to the subject, in the form of tablets, troches, liquids, drops, capsules, caplets and gel caps or other such formulations known to one skilled in the art.

[0084] In one embodiment, the method of treatment comprises administering the compound of Formula (I) and a muscarinic antagonist to alleviate the side effects associated with use of the muscarinic agonists. In one embodiment, the muscarinic antagonist is aclidinium bromide,Attorney Docket No.: 206602-0001-00WOglycopyrronium bromide, ipratropium bromide, oxitropium bromide, tiotropium bromide, trospium chloride, umeclidinium bromide. In a preferred embodiment, the muscarinic antagonist is trospium.100851 In one embodiment, the compound of Formula (I) may be taken sequentially with a muscarinic antagonist. In another embodiment, the muscarinic agonist may be taken concurrently with the muscarinic antagonist. In a preferred embodiment, the compound of Formula (I) and the muscarinic antagonist are formulated to be contained in the same dosage form or dosage vehicle.

[0086] In one embodiment, the compound of Formula (I) may be taken sequentially with a muscarinic antagonist. In another embodiment, the muscarinic agonist may be taken concurrently with the antagonist. In a preferred embodiment, the agonist and the antagonist are formulated to be contained in the same dosage form or dosage.

[0087] In one embodiment, the compound of Formula (I) and a muscarinic antagonist are formulated to be in separate dosage forms or dosage vehicles. In one embodiment, the muscarinic agonist and antagonist are formulated in an immediate release dosage form.

[0088] A further object of the disclosure is a kit comprising a composition containing at least one Ml and / or M4 receptor agonist compound for treatment of schizophrenia and other CNS disorders. The composition of the kit may comprise at least one carrier, at least one binder, at least one diluent, at least one excipient, at least one other therapeutic agent, or mixtures thereof. The kits may also include instructions to customers for proper usage of the kit to treat patients exhibiting the symptoms of the desired disease or disorder, e.g., Schizophrenia or Alzheimer’s disease.

[0089] One aspect of the present disclosure is the compounds disclosed herein as w ell as the intermediates as used for their synthesis, and the synthetic schemes for the preparation of the disclosed final compounds and the intermediates resulted before the final compound is generated.

[0090] While certain features of this present disclosure shown and described below are pointed out in the annexed claims, the present disclosure is not intended to be limited to the details specified, since a person of ordinary skill in the relevant art will understand that various omissions, modifications, substitutions, and changes in the forms and details of the present disclosure illustrated and in its operation may be made without departing in any way from the spirit of the present disclosure. No feature of the present disclosure is critical or essential unless it is specifically stated as being '‘critical” or “essential”.

[0091] These and other features, aspects, and advantages of embodiments of the disclosure will become more evident with regard to the following descriptions, claims, and accompanyingAttorney Docket No.: 206602-0001-00WOdrawings explained below.EXAMPLES

[0092] Hereby are provided non-limiting examples of embodiments of compounds disclosed herein. The examples and preparations provided below further illustrate and exemplify the compounds as disclosed herein and methods of preparing such compounds. It is to be understood that the scope of the disclosure is not limited in any way by the scope of the following examples and preparations. Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received.

[0093] Example 1

[0094] General Synthesis

[0095] The chemical entities described herein can be synthesized according to one or more illustrative schemes herein and / or techniques well known in the art. Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from about -10 °C. to about 200 °C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -10 °C to about 200 °C over a period that can be, for example, about 1 to about 24 hours; reactions left to run overnight in some embodiments can average a period of about 16 hours. Isolation and purification of the chemical entities and intermediates described herein can be implemented, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. See, e.g., Carey et al. Advanced Organic Chemistry, 3rd Ed., 1990 New York: Plenum Press; Mundy et al., Name Reaction and Reagents in Organic Synthesis, 2nd Ed., 2005 Hoboken, N. J.: J. Wiley & Sons. Specific illustrations of suitable separation and isolation procedures are given by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can also be used.

[0096] In all of the methods, it is well understood that protecting groups for sensitive or reactive groups may be employed where necessary, in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons). These groups may be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.Attorney Docket No.: 206602-0001-00WO

[0097] In some embodiments, disclosed compounds can generally be synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful in synthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure. Many of the optionally substituted starting compounds and other reactants are commercially available, or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.

[0098] The discussion below is offered to illustrate certain of the diverse methods available for use in making the disclosed compounds and is not intended to limit the scope of reactions or reaction sequences that can be used in preparing the compounds provided herein. The skilled artisan will under- stand that standard atom valencies apply to all compounds disclosed herein in genus or named compound for unless otherwise specified.

[0099] TABLE 3. A list of abbreviations.BINAP 2,2'-bis(diphenylphosphino)-1, 1 '-binaphthyl DCM DichloromethaneDIPEA N. N-DiisopropylethylamineDMF Dimethvl formami deDMSO Dimethvl sulfoxideEA Ethyl acetateESI Electrospray ionizationEtOH EthanolHE n-HexaneHOAc Acetic acidLC-MS Liquid chromatography-mass spectrometry NBS N-BromosuccinimideNMP N-Methyl-2-pyrrolidonePPA Polyphosphoric acidPrep-LC Preparative liquid chromatographySM Starting materialr.t Room temperatureTFA Trifluoroacetic acidNEt3 TriethylamineDIEA N, N- DiethylpropylamineCDI 1,1'-CarbonyldiimidazoleK2CO3 Potassium carbonateDPPA Diphenyl azidophosphateTHF TetrahydrofuranTM Target materialSTAB Sodium triacetoxvborohydride

[0100] General scheme to synthesize the exemplary compounds in the present disclosure isAttorney Docket No.: 206602-0001-00WOshown below.

[0101] Example 2

[0102] Ethyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[1.4'-bipiperidine]- 1 '-carboxylate (1) and isopropyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)- [1,4'-bipiperidine]-l '-carboxylate (Compound 2)K2CO3, EtOH. reflux STAB, HOAc, DCM, rtTFA, DCM, rt

[0103] Preparation of tert-butyl 4'-methyl-4-oxo- [ 1,4'-bipiperi dine] -l'-carboxy late

[0104] To a suspension of tert-butyl 4-amino-4-methylpiperidine-l -carboxylate (4.28 g, 20 mmol) and K2CO3 (0.4 g, cat.) in 80 mL of EtOH was added l-ethyl-l-methyl-4-oxopiperidin-l-ium iodide (10.8 g, 40 mmol) in 20 mL of water dropwise at 80 °C. The resulting solution was stirred for 2 hours and the reaction was monitored by LCMS. After completion, the solvent residue was removed in vacuo. The mixture was diluted with 50 mL of brine, extracted with DCM (50 mLx3). The combined organic layers were dried over Na2SO4, filtered, evaporated to dryness to provide tert-butyl 4'-methyl-4-oxo-[1,4'-bipiperidine]-1'-carboxylate 5.5 g as an orange oil, which was used in the next step without further purification. LCMS [M+H]+: 297 found.

[0105] Step 1. Preparation of tert-butyl 4-((2-aminophenyl)amino)-4'-methyl-[l,4'-bipiperidine] - 1 '-carboxylate

[0106] To a stirred solution of tert-butyl 4'-methyl-4-oxo-[l,4'-bipiperidine]-r-carboxylate (300 mg, 1 mmol), benzene- 1,2-diamine (216 mg, 2 mmol) and one drop of HOAc in 20 mL of DCM was added STAB (424 mg, 2 mmol) portionwise at rt. After stirring for 2 hours, the mixture was subjected onto silica gel column chromatography with EA:n-hexane and EA: MeOH as eluent.220 mg of tert-butyl 4-((2-aminophenyl)amino)-4'-methyl-[ l,4'-bipiperi dine] -1 '-carboxylate wasAttorney Docket No.: 206602-0001-00WOobtained as a brown oil. LCMS [M+H]+: 389 found.

[0107] Step 2. Preparation of tert-butyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-l '-carboxylate

[0108] To a stirred solution of above obtained tert-butyl 4-((2-aminophenyl)amino)-4'-methyl-[l,4'-bipiperidine]-l'-carboxylate (220 mg, 0.57 mmol) in 10 mL of THF was added 0.5 mL of NEt3 followed by CDI (0.16 g, 1 mmol) at rt. After completion, the mixture was subjected onto silica gel column chromatography with EA:n-hexane and EA: MeOH as eluent. 205 mg of tertbutyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-T-carboxylate was obtained as brown oil. LCMS [M+H]+: 415 found.

[0109] Step 3. Preparation of isopropyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-r-carboxylate (Compound 2)

[0110] 2 mL of TFA was added to a solution of above obtained tert-butyl 4'-methyl-4-(2-oxo- 2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-l'-carboxylate (205 mg) in 5 mL of DCM at rt. After stirring for 1 hour, the mixture was concentrated in vacuo. The crude product was re-dissolved into 5 mL of DCM, cooled to 0 °C by ice-water. A solution of isopropyl carbonochloridate (0.3 mL, 1 mol / L in toluene) was added dropwise. After stirring at rt for 2 hours, the mixture was concentrated in vacuo. The residue was subjected onto silica gel column chromatography with EA:n-hexane and EA: MeOH as eluent and then further purified by prep-HPLC (C18, 0.5% FA in H2O-MeCN). 110 mg of isopropyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-l'-carboxylate was obtained as brown oil. LCMS [M+H]+401 found. 1H NMR: δ 1.07 (3H, s), 1.42 (6H, d, J= 7.1 Hz), 1.53-1.69 (4H, m), 1.87 (4H, dd), 2.62 (4H, m), 3.20-3.36 (4H, m), 3.97 (1H, t), 4.75 (1H, sept, J= 7.1 Hz), 6.98-7.17 (3H, m), 7.60 (1H, d).

[0111] Example 3

[0112] Synthesis of ethyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[1,4'-bipiperidine]-1'-carboxylate (Compound 1)

[0113] Following the process of Example 2, ethyl 4'-methyl-4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-[1,4'-bipiperidine]-1'-carboxylate was obtained by using ethyl chloroformate in the final step. LCMS [M+H]+387 found. 1H NMR: δ 1.07 (3H, s), 1.28 (3H,Attorney Docket No.: 206602-0001-00WOt, J= 7.1 Hz), 1.53-1.69 (4H, m), 1.87 (4H, d), 2.61 (4H, d), 3.19-3.35 (4H, m), 3.97 (1H, t, J= 10.2 Hz), 4.25 (2H, s), 6.98-7.17 (3H, m), 7.60 (1H, d).

[0114] Example 4

[0115] Synthesis of isopropyl 4-(5,6-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)- 4'-methyl-[l,4'-bipiperidine]-T-carboxylate (Compound 66)TFA, DCM, rt NEt3, DCM, 0 °C to rt STAB, NEt3, DCM, rt

[0116] Preparation of isopropyl 4'-methyl-4-oxo-[l,4'-bipiperidine]-r-carboxylate

[0117] To a stirred solution of tert-butyl 4'-methyl-4-oxo-[l,4'-bipiperidine]-T-carboxylate (2.97 g, 10 mmol) in 20 mL of DCM was added 5 mL of TFA at r.t. After stirring for 2 hours, the mixture was concentrated in vacuo. 20 mL of DCM was added to dissolve the residue, followed by addition of 3 mL of NEt3 slowly at 0 °C. isopropyl carbonochloridate (20 mL, 20 mmol, 1 mol / L in toluene) was added dropwise. After completion, the reaction was quenched by saturated NaHCO3 aqueous solution, extracted with DCM (100 mL x3). Combined organic layers were dried over Na2SO4, filtered, evaporated to provide 2.4 g of isopropyl 4'-methyl-4-oxo-[l,4'-bipiperidine]- l'-carboxylate as a light orange oil without further purification. LCMS [M+H]+283 found.

[0118] Preparation of isopropyl 4-((2-amino-4,5-dimethylphenyl)amino)-4'-methyl-[l,4'-bipiperidine] - l'-carboxylateAttorney Docket No.: 206602-0001-00WO

[0119] To a stirred solution of isopropyl 4'-methyl-4-oxo- [l,4'-bipiperi dine] -1 '-carboxy late (300 mg, 1 mmol), 4,5-dimethylbenzene-l,2-diamine (216 mg, 2 mmol) and one drop of HOAc in 20 mL of DCM was added STAB (424 mg, 2 mmol) portionwise at rt. After stirring for 2 hours, the mixture was subjected onto silica gel column chromatography with EA:n-hexane and EA: MeOH as eluent. 130 mg of isopropyl 4-((2-amino-4,5-dimethylphenyl)amino)-4'-methyl-[l,4'-bipiperidine]-l'-carboxylate was obtained as a brown oil. LCMS [M+H]+: 403 found.

[0120] Preparation of isopropyl 4-(5,6-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine]-r-carboxylate (Compound 66)

[0121] To a stirred solution of above obtained isopropyl 4-((2-amino-4,5-dimethylphenyl)amino)-4'-methyl-[l,4'-bipiperidine]-r-carboxylate (100 mg) in 10 mL of THF was added 0.5 mL of NEt3 followed by CDI (0.16 g, 1 mmol) at rt. After completion, the mixture was subjected onto silica gel column chromatography with EA:n-hexane and EA: MeOH as eluent.20 mg of isopropyl 4-(5,6-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine]-l'-carboxylate was obtained as a brown oil. LCMS [M+H]+429 found. 1H NMR: δ 1.07 (3H, s), 1.42 (6H, d, J= 7.1 Hz), 1.53-1.69 (4H, m), 1.87 (4H, m), 2.15-2.27 (6H, m), 2.62 (4H, m), 3.20-3.36 (4H, m), 4.05 (1H, t, J= 10.2 Hz), 4.75 (1H, sept, J = 7.1 Hz), 7.46 (1H, d, J= 0.5 Hz), 7.68 (1H, d, J= 0.5 Hz).

[0122] Example 5

[0123] Synthesis of isopropyl 4'-methyl-4-(4-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol- l-yl)-[l,4'-bipiperidine]-l'-carboxylate (Compound 67)Attorney Docket No.: 206602-0001-00WO

[0124] Preparation of 2-((T-(isopropoxycarbonyl)-4'-methyl-[l,4'-bipiperidin]-4-yl)amino)-6-methylbenzoic acid

[0125] To a stirred solution of isopropyl 4'-methyl-4-oxo-[ 1,4' -bipiperidine]-! '-carboxylate (300 mg, 1 mmol), 2-amino-6-methylbenzoic acid (300 mg, 2 mmol) and one drop of HO Ac in 20 mL of DCM was added STAB (424 mg, 2 mmol) portionwise at rt. After stirring for 2 hours, the mixture was subjected onto silica gel column chromatography with EA:n-hexane and EA: MeOH as eluent. 180 mg of 2-((r-(isopropoxycarbonyl)-4'-methyl-[l,4'-bipiperidin]-4-yl)amino)-6-methylbenzoic acid was obtained as a white solid. LCMS [M+H]+: 418 found.

[0126] Preparation of isopropyl 4'-methyl-4-(4-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-T-carboxylate

[0127] A mixture of 2-((T-(isopropoxycarbonyl)-4'-methyl-[l,4'-bipiperidin]-4-yl)amino)-6-methylbenzoic acid (180 mg, 0.4 mmol), NEts (0.1 mL, 1 mmol) and DPPA (0.3 g, 1 mmol) in 5 mL of DCE was stirred at 70 °C overnight. After completion, the mixture was concentrated and subjected onto silica gel column chromatography with EA:n-hexane and EA: MeOH as eluent. 23 mg of isopropyl 4'-methyl-4-(4-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-l'-carboxylate was obtained as a brown solid. LCMS [M+H]+415 found. 'H NMR: δ 1.07 (3H, s), 1.42 (6H, d, J= 7.1 Hz), 1.53-1.69 (4H, d), 1.87 (4H, d), 2.21 (3H, s), 2.62 (4H, d), 3.20-3.36 (4H, m). 3.98 (1H, t). 4.75 (1H, sept, J= 7.1 Hz), 6.71-6.95 (2H, m), 7.16 (1H, dd, J = 8.0 Hz).

[0128] Example 6

[0129] Isopropyl 4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'- methyl-[l,4'-bipiperidine]-r-carboxylate (Compound 35)Attorney Docket No.: 206602-0001-00WOo

[0130] Following the process of Example 5, the title compound was obtained as a white solid. LC-MS: 433, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 432.2537 for C23H33FN4O3[M + H]+; found, 433.2622;NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 7.09 (d, J = 6.4 Hz, 1H), 6.76 (d, J = 9.6 Hz, 1H), 4.76 (sept, J = 7.2 Hz, 1H), 4.01-4.12 (m, 1H), 3.41-3.60 (m, 2H), 3.01-3.11 (m, 2H), 2.19-2.35 (m, 4H), 1.62-1.83 (m, 4H), 1.31-1.42 (m, 2H), 1.19 (d, J = 6.4 Hz, 6H), 0.93 (s, 3H).

[0131] Example 7

[0132] Isopropyl 4'-methyl-4-((3aS,7aS)-3-methyl-2-oxooctahydro-lH-benzo[d]imidazol-l- yl)-[l,4'-bipiperidine]-l'-carboxylate (Compound 43)NaH, DMF, 0°C NEt3, DCM, 0 °C to rt

[0133] Following the standard reductive amination step as example 1, tert-butyl 4'-methyl-4-oxo-[1,4'-bipiperidine]-1'-carboxylate (6 g, 20 mmol), (1S,2S)-cyclohexane-1,2-diamine (4.6 g, 40 mmol) and a drop of HOAc in 100 mL of DCM was added STAB (8.4 g, 40 mmol) portionwise at room temperature. After completion, CDI (4.8 g, 30 mmol) was added for cyclization. After another 2 hours, 100 mL of brine was added to quench the reaction. Organic extract was dried over Na2SO4, filtered, and evaporated to dryness. The residue was subjected onto silica gel column (eluent: EA: MeOH, 80:20) to provide 6.8 g tert-butyl 4'-methyl-4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-l'-carboxylate as a yellow solid.Attorney Docket No.: 206602-0001-00WO

[0134] A solution of tert-butyl 4'-methyl-4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-l'-carboxylate (6.2 g, 14.7 mmol) in DCM was added 10 mL of TFA at room temperature. After completion, the solvent was removed in vacuo. 100 mL of DCM was added, followed by 6.3 g of NEt3 at 0 °C. Isopropyl chloroformate (15 mL, 30 mmol, 2 M in toluene) was added dropwise at 0 °C. After completion, 100 mL of brine was added to quench the reaction. Organic extract was dried over NazSCL, filtered, and evaporated to dryness. The residue was subjected onto silica gel column (eluent: EA: MeOH, 80:20) to provide 2.8 g of isopropyl 4'-methyl-4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-l'-carboxylate as a white solid.

[0135] To a solution of isopropyl 4'-methyl-4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-T-carboxylate (0.2 g, 0.5 mmol) in 5 mL of DMF was added NaH (0.1 g. excess) at 0 °C. After completion, 10 mL of brine was added to quench the reaction. EA was added for extraction. Organic extract was dried over Na2SO4, filtered, and evaporated to dryness. The residue was subjected onto silica gel column (eluent: EA: MeOH, 80:20) to provide isopropyl 4'-methyl-4-((3aS,7aS)-3-methyl-2-oxooctahydro-1H-benzo[d]imidazol-1-yl)-[1,4'-bipiperidine]-1'-carboxylate as light yellow oil. LC-MS: 421, [M+H]+, ESI+; HRMS (ESI) m / z: calcd. 420.3100 for C23H40N4O3 [M + H]+; found, 421.3178; 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 4.75 (sept, J = 7.2 Hz, 1H), 2.79-3.01 (m, 3H), 2.54 (s, 3H), 1.95-2.15 (m, 4H), 1.41-1.89 (m, 8H), 1.17-1.41 (m, 6H), 1.16 (t, J = 6.4 Hz, 6H), 0.87 (s, 3H).

[0136] Example 8

[0137] Isopropyl 4-((3aS,7aS)-2-amino-3a,4,5,6,7,7a-hexahydro-lH-benzo[d]imidazol-l-yl)- 4'-methyl-[l,4'-bipiperidine]-l'-carboxylate (Compound 44)Attorney Docket No.: 206602-0001-00WO

[0138] The synthetic process followed Example 7 with minor modifications.

[0139] A solution of tert-butyl 4-(((lS,2S)-2-aminocyclohexyl)amino)-4'-methyl-[l,4'-bipiperidine]-T-carboxylate (2.0 g, 5 mmol) andNEts (1 g, 10 mmol) in 50 mL of DCM was added 1,1 ’-Thiocarbonyldiimidazole (1.5 g, 7.5 mmol) at 0 °C. After completion, the mixture was evaporated to dryness. The residue was sub] ected onto silica gel column (eluent: n-hexane-EA, 50-50) to provide tert-butyl 4'-methyl-4-((3aS,7aS)-2-thioxooctahydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-l'-carboxylate (0.7 g) as a yellow solid.

[0140] After de-Boc by TFA / DCM and protected by Isopropyl chloroformate as in example 7, isopropyl 4'-methyl-4-((3aS,7aS)-2-thioxooctahydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-T-carboxylate was obtained as a yellow solid.

[0141] Isopropyl 4'-methyl-4-((3aS,7aS)-2-thioxooctahydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-l'-carboxylate was converted to isopropyl 4'-methyl-4-((3aS,7aS)-2-(methylthio)-3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazol-1-yl)-[1,4'-bipiperidine]-1'-carboxylate by methylation by using the condition in example 7.

[0142] A solution of isopropyl 4'-methyl-4-((3aS,7aS)-2-(methylthio)-3a,4,5,6,7,7a-hexahydro-lH-benzo[d]imidazol-l-yl)-[I,4'-bipiperidine]-r-carboxylate (0.22 g, 0.5 mmol) and K2CO3 (0.14 g, 1 mmol) in 5 mL of EtOH was added NH2OH (excess). After stirring for 5 hours at 80 °C, the solvent was removed in vacuo. The residue was subjected to silica gel column chromatography to provide isopropyl 4-((3aS,7aS, Z)-2-(hydroxyimino)octahydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine]-r-carboxylate (examples 9) as a white solid.Attorney Docket No.: 206602-0001-00WO

[0143] A mixture of isopropyl 4-((3aS,7aS,Z)-2-(hydroxyimino)octahydro-1H-benzo[d]imidazol-1-yl)-4'-methyl-[1,4'-bipiperidine]-1'-carboxylate (0.1 g) and Raney-Ni (0.1 g, wet) in 10 mL of MeOH, 1 mL ofHOAc was stirred under hydrogen atmosphere for 2 hours. After filtration through celite, the filtrate was evaporated to dryness. The residue was subjected onto silica gel column chromatography to provide isopropyl 4-((3aS,7aS)-2-iminooctahydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine]-l'-carboxylate as awhite solid. LC-MS: 406, [M+H]+, ESI+; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (br, 2H), 8.20 (s, 1H), 4.75 (sept, J = 7.2 Hz, 1H), 3.52-3.65 (m, 1H), 2.81-3.32 (m, 7H), 1.97-2.33 (m, 4H), 1.60-1.82 (m, 8H), 1.22-1.57 (m, 7H), 1.15 (d, J = 6.4 Hz, 6H), 0.87 (s, 3H).

[0144] Example 9

[0145] Isopropyl (E)-4-(2-(hydroxyimino)octahydro-lH-benzo[d]imidazol-l-yl)-4'-methyl- [1,4'-bipi peri dine]- I'-carboxylate (Compound 45)HO,NH

[0146] Compound 45 was prepared similarly as in example 8. White solid. LC-MS: 422, [M+H]+, ESI+; 1H NMR (400 MHz, DMSO-d6) δ 4.77 (sept, J = 7.2 Hz, 1H), 3.62-3.73 (m, 1H), 3.07-3.25 (m, 6H), 2.53-2.82 (m, 4H), 1.85-2.21 (m, 4H), 1.62-1.81 (m, 8H), 1.21-1.36 (m, 4H), 1.18 (d, J = 6.4 Hz, 6H), 1.15 (s, 3H).|00147| Example 10

[0148] Isopropyl 4'-methyl-4-((3aS,7aS)-2-thioxooctahydro-lH-benzo[d]imidazol-l-yl)-[1.4'- bipiperidinej- 1 '-carboxylate (Compound 46)

[0149] This compound was synthesized as in example 8. White solid. LC-MS: 408.61, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 408.2559 for C22H38N4O2S [M + H]+; found, 408.2564; 1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 4.74 (sept, J = 7.2 Hz, 1H), 4.46-4.57 (m, 1H), 3.21-3.33 (m,Attorney Docket No.: 206602-0001-00WO2H), 2.91-3.11 (m, 4H), 2.29-2.33 (m, 1H), 2.03-2.17 (m, 2H), 1.89-1.98 (m, 1H), 1.62-1.77 (m, 7H), 1.39-1.47 (m, 3H), 1.26-1.38 (m. 5H), 1.17 (d, J = 6.4 Hz, 6H), 0.90 (s, 3H).

[0150] Example 11

[0151] Isopropyl 4,-methyl-4-(3-oxo-2-azaspiro[4.5]decan-2-yl)-[l,4'-bipiperidine]-l'- carboxylate (Compound 48)

[0152] By using standard reductive amination as show in example 7, tert-butyl 4'-methyl-4-(3-oxo-2-azaspiro[4.5]decan-2-yl)-[l,4'-bipiperidine]-l'-carboxylate was obtained as a white solid.

[0153] After de-Boc by TFA / DCM and protected by isopropyl chloroformate as example 7, isopropyl 4'-methyl-4-(3-oxo-2-azaspiro[4.5]decan-2-yl)-[1.4'-bipiperidine]-r-carboxylate was obtained as a light yellow oil. LC-MS: 420, [M+H]+, ESE; HRMS (ESI) m / z: calcd, 419.3148 for C24H41N3O3 [M + H]+; found, 420.3230; 'H NMR (400 MHz, DMSO-tfc) 54.75 (sept, J = 7.2 Hz, 1H), 3.71-3.89 (m, 1H), 3.47-3.53 (m, 4H), 3.22-3.29 (m, 2H), 3.09-3.17 (m, 2H), 3.05 (s, 2H), 2.33-2.48 (m, 2H). 2.09 (s, 2H). 1.67-1.82 (m, 4H), 1.53-1.65 (m, 2H), 1.32-1.52 (m, 12H). 1.18 (d, J = 6.4 Hz, 6H), 1.03 (s, 3H).

[0154] Example 12

[0155] Isopropyl 4'-methyl-4-(2-oxo-l,4-dihydroquinazolin-3(2H)-yl)-[l,4'-bipiperidine]-r- carboxylate (Compound 49)Attorney Docket No.: 206602-0001-00WO

[0156] Following the process of example 7, isopropyl 4'-methyl-4-(2-oxo-l,4-dihydroquinazolin-3(2H)-yl)-[l,4'-bipiperidine]-l'-carboxylate was obtained as a yellow oil. LC-MS: 415, [M+H]+, ESC; HRMS (ESI) m / z: calcd, 414.2631 for C23H34N4O3 [M + H]+; found, 415.2709;NMR (400 MHz, DMSO-c / c) 5 9.16 (s, 1H), 7.09-7.13 (m, 2H), 6.86 (t, J = 7.2 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 4.75 (sept, J = 7.2 Hz, 1H), 4.27-4.32 (m, 2H), 4.09-4.20 (m, 1H), 3.21-3.45 (m, 4H), 2.91-3.03 (m, 4H), 1.30-2.20 (m, 8H), 1.16 (d, J = 6.4 Hz, 6H), 0.90 (s. 3H).

[0157] Example 13

[0158] Isopropyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-thieno[3,4-d]imidazol-l-yl)-[l,4'- bipiperidine]-! '-carboxylate (Compound 50)

[0159] Following the process of example 7, isopropyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-thieno[3,4-d]imidazol-l-yl)-[l,4'-bipiperidine]-r-carboxylate was formed as a brown solid. LC-MS: 407, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 406.2039 for C20H30N4O3S [M + H]+; found, 407.2114; 'H NMR (400 MHz, DMSO-tfc) 5 10.55 (s. 1H), 6.75 (s. 1H), 6.52 (s, 1H), 4.75 (sept. J = 7.2 Hz, 1H), 3.94-4.03 (m, 1H), 3.27-3.62 (m, 4H), 3.01-3.12 (m, 2H), 2.17-2.29 (m, 2H), 2.05-2.16 (m, 2H), 1.75-1.82 (m, 2H), 1.68-1.73 (m, 2H), 1.30-1.41 (m, 2H), 1.33 (t, J = 6.4 Hz, 6H), 0.91 (s, 3H).

[0160] Example 14

[0161] Isopropyl 4'-methyl-4-(2-oxohexahydrocyclopenta[d]imidazol-l(2H)-yl)-[l,4'- bipiperidine]-l'-carboxylate (Compound 51)

[0162] Following the process of example 7, Isopropyl 4'-methyl-4-(2-oxohexahydrocyclopenta[d]imidazol-l(2H)-yl)-[l,4'-bipipendine]-l'-carboxylate was obtained asAttorney Docket No.: 206602-0001-00WOa white solid. LC-MS: 393, [M+H]+. ESI+; HRMS (ESI) m / z: calcd, 392.2787 for C21H36N4O3 [M + H]+; found, 393.2864; 'H NMR (400 MHz, DMSO-dd) 54.75 (sept, J = 7.2 Hz, 1H), 3.89-4.10 (m, 2H), 3.54-3.62 (m, 1H), 3.21-3.34 (m, 4H), 2.91-2.99 (m, 4H), 1.81-2.21 (m, 4H), 1.32-1.77 (m, 10 H), 1.18 (d, J = 6.4 Hz, 6H), 0.95 (s, 3H).

[0163] Example 15

[0164] Isopropyl 4-(4,4-dimethy 1-2-oxoimidazolidin- 1 -y l)-4'-methy l-[ 1,4'-bipiperidine] - 1 '- carboxylate (Compound 54)

[0165] Following the process of example 7, Isopropyl 4-(4,4-dimethyl-2-oxoimidazolidin-l-yl)-4'-methyl-[l,4'-bipiperidine]-l'-carboxylate was obtained as a light yellow solid. LC-MS: 381, [M+H]+, ESC; HRMS (ESI) m / z: calcd, 380.2787 for C20H36N4O3 [M + H]+; found, 381.2866; ’H NMR (400 MHz, DMSO-tL) 5 8.25 (br. 1H), 6.32 (s. 1H), 4.75 (sept, J = 7.2 Hz, 1H), 3.45-3.62 (m, 3H), 2.89-3.30 (m, 8H), 2.01-2.12 (m, 2H), 1.71-1.79 (m, 2H), 1.45-1.56 (m, 4H), 1.23 (s, 6H), 1.16 (d, t = 6.4 Hz, 6H), 0.87 (s, 3H).

[0166] Example 16

[0167] Isopropyl 4'-methyl-4-(2-oxoimidazolidin-l-yl)-[l,4'-bipiperidine]-r-carboxylate (Compound 57)

[0168] Following the process of example 7, Isopropyl 4'-methyl-4-(2-oxoimidazolidin-l-yl)-[l,4'-bipiperidine]-I'-carboxylate was obtained as a light yellow oil. LC-MS: 353, |M+H|. ESI+; HRMS (ESI) m / z: calcd, 352.2474 for C18H32N4O3 [M + H]+; found. 353.2552; 'H NMR (400 MHz, DMSO-tL) 86.19 (s, 1H), 4.75 (sept, J = 7.2 Hz, 1H), 3.15-3.37 (m, 9H), 2.86-2.93 (m, 3H), 2.32-2.40 (m, 1H), 2.01-2.13 (m, 2H), 1.71-1.78 (m, 2H), 1.49-1.57 (m, 4H), 1.22-1.35 (m, 2H), 1.16 (d, J = 6.4 Hz, 6H), 0.86 (s, 3H).Attorney Docket No.: 206602-0001-00WO

[0169] Example 17

[0170] Isopropyl 4'-methyl-4-(2-oxotetrahydropyrimidin- 1 (2H)-yl)-[ 1,4'-bipiperidine] -1'- carboxylale (Compound 59)

[0171] Following the process of example 7, Isopropyl 4'-methyl-4-(2-oxotetrahydropyrimidin-l(2H)-yl)-[I.4'-bipiperidine]-r-carboxylate was obtained as a light yellow oil. LC-MS: 367, [M+H]+, ESI; HRMS (ESI) m / z: calcd. 366.2631 for C19H34N4O3 [M + H]+; found, 367.2709; 'H NMR (400 MHz, DMSO-tL) 8 6.01 (s, 1H), 4.75 (sept, J = 7.2 Hz, 1H), 3.92-4.06 (m, 1H), 3.15-3.37 (m, 9H), 2.86-2.93 (m, 3H), 2.01-2.12 (m, 2H), 1.61-1.69 (m, 4H), 1.21-1.38 (m, 4H), 1.16 (d, J = 6.4 Hz, 6H), 0.87 (s, 3H).

[0172] Example 18

[0173] Isopropyl 4'-methyl-4-(2-oxo-5-(trifluoromethyl)-2,3-dihydro-lH-benzo[d]imidazol-l- yl)-[l,4'-bipiperidine]-r-carboxylale (Compound 68)F3C O

[0174] Following the process of Example 5, the title compound was obtained as a white solid. LC-MS: 469, [M+H]+, ESI+; HRMS (ESI) m / z: calcd. 468.2348 for C23H31F3N4O3 [M + H]+; found, 469.2431; 'H NMR (400 MHz. DMSO-de) 6 10.97 (s, 1H), 6.93-7.22 (m, 3H), 4.77 (sept, J = 7.2 Hz, 1H), 4.02-4.15 (m, 1H), 3.41-3.60 (m, 2H), 3.01-3.11 (m, 2H), 2.19-2.35 (m, 4H), 1.62-1.83 (m, 4H), 1.31-1.42 (m, 2H), 1.19 (d, J = 6.4 Hz, 6H), 0.92 (s, 3H).

[0175] Example 19

[0176] Isopropyl 4-(4,6-difluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl- [1,4'-bipi peri dine]- l'-carboxylate (Compound 69)Attorney Docket No.: 206602-0001-00WO

[0177] Following the process of Example 5. the title compound was obtained as a white solid. LC-MS: 437, [M+H]+, ESI; HRMS (ESI) m / z: calcd, 436.2286 for C22H30F2N4O3 [M + H]+; found, 437.2366; 'H NMR (400 MHz, DMSO-tfc) 5 11.45 (s, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.91 (t, J = 8.4 Hz, 1H), 4.76 (sept, J = 7.2 Hz, 1H), 4.01-4.12 (m, 1H), 3.41-3.60 (m, 2H), 3.01-3.11 (m, 2H), 2.19-2.35 (m, 4H), 1.62-1.83 (m, 4H), 1.31-1.42 (m, 2H), 1.19 (d, J = 6.4 Hz, 6H), 0.91 (s, 3H).

[0178] Example 20

[0179] Isopropyl 4-(5,7-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl- [l,4'-bipi peri dine]- I'-carboxylate (Compound 70)

[0180] Following the process of Example 5, the title compound was obtained as a white solid. LC-MS: 429, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 428.2787 for C24H36N4O3 [M + H]+; found, 429.2866; ’H NMR (400 MHz, DMSO-cL) 5 10.62 (s, 1H), 7.23 (s, 1H), 7.19 (s, 1H), 4.77 (sept, J = 7.2 Hz, 1H), 4.01-4.12 (m, 1H), 3.41-3.60 (m, 2H), 3.01-3.11 (m, 2H), 2.19-2.35 (m, 4H), 2.15 (s, 3H), 2.08 (s, 3H), 1.62-1.83 (m, 4H), 1.31-1.42 (m, 2H), 1.19 (d, J = 6.4 Hz, 6H), 0.91 (s. 3H).

[0181] Example 21

[0182] Isopropyl 4'-methyl-4-(7-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'- bipiperidine]- l'-carboxylate (Compound 71)

[0183] Following the process of Example 5, the title compound was obtained as a yellow solid. LC-MS: 415. [M+H]+, ESI+; HRMS (ESI) m / z: calcd. 414.2631 for C23H34N4O3 [M + H]+; found, 415.2712; 'H NMR (400 MHz, DMSO-cfc) 5 10.74 (s, 1H). 6.72-6.89 (m, 3H). 4.77 (sept. J = 7.2 Hz, 1H), 4.01-4.12 (m, 1H), 3.41-3.60 (m, 2H), 3.01-3.11 (m, 2H), 2.34 (s, 3H), 2.19-2.35 (m, 4H),Attorney Docket No.: 206602-0001-00WO2.15 (s, 3H), 2.08 (s, 3H), 1.62-1.83 (m, 4H), 1.31-1.42 (m, 2H), 1.18 (d, J = 6.4 Hz, 6H), 0.89 (s, 3H).

[0184] Example 22

[0185] Isopropyl 4-(7-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[1,4'-bipiperidine]-l'-carboxylate (Compound 72)

[0186] Following the process of Example 5, the title compound was obtained as a yellow solid. LC-MS: 419, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 418.2380 for C22H31FN4O3 [M + H]+; found, 419.2456; ’H NMR (400 MHz, DMSO- e) 6 11.19 (s, 1H), 6.93-6.99 (m, 1H), 6.79-6.82 (m, 2H), 4.76 (sept, J = 7.2 Hz, 1H), 4.19-4.32 (m, 1H), 3.09-3.23 (m, 2H), 2.98-3.07 (m, 2H), 2.12-2.23 (m, 4H), 1.67-1.83 (m. 4H), 1.25-1.32 (m. 2H), 1.18 (d. J = 6.4 Hz. 6H), 0.90 (s. 3H).

[0187] Example 23

[0188] Isopropyl 4-(6,7-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl- [l,4'-bipi peri dine]- l'-carboxylate (Compound 73)

[0189] Following the process of Example 5, the title compound was obtained as ayellow solid. LC-MS: 429, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 428.2787 for C24H36N4O3 [M + H]+; found, 429.2867; ’H NMR (400 MHz, DMSO-cL) 5 10.61 (s, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H), 4.76 (sept, J = 7.2 Hz, 1H), 4.19-4.32 (m, 1H), 3.09-3.23 (m, 2H), 2.98-3.07 (m. 2H), 2.41 (s, 3H), 2.30 (s. 3H), 2.12-2.23 (m, 4H). 1.67-1.83 (m, 4H), 1.25-1.32 (m, 2H), 1.18 (d, J = 6.4 Hz, 6H), 0.89 (s, 3H).

[0190] Example 24

[0191] Methyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-l'-carboxylate (Compound 74)Attorney Docket No.: 206602-0001-00WO

[0192] Following the process of Example 2, the title compound was obtained by using methyl chloroformate in the final step as a yellow solid. LC-MS: 373, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 372.2161 for C20H28N4O3 [M + H]+; found, 373.2233;NMR (400 MHz, DMSO-cfe) 5 10.83 (s, 1H), 7.20-7.25 (m, 1H), 6.93-7.02 (m, 3H), 4.12 (sept, J = 7.2 Hz, 1H), 3.60 (s, 3H), 2.98-3.11 (m, 2H), 2.83-2.92 (m, 4H), 2.18-2.32 (m, 4H), 1.67-1.83 (m, 4H), 1.25-1.40 (m, 2H), 1.09-1.17 (m, 4H). 0.92 (s. 3H).

[0193] Example 25

[0194] Isopropyl 4'-methyl-4-((3aR,7aR)-2-oxohexahydropyrano[3,4-d]imidazol-l(4H)-yl)- [1,4'-bipi peri dine]- I'-carboxylate (Compound 75)

[0195] Following the process of example 7, the title compound was obtained as a yellow solid. LC-MS: 409. [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 408.2737 for C21H36N4O4 [M + H]+; found, 409.2813; 'H NMR (400 MHz, CDCh) 6 4.85-4.92 (m, 2H), 4.59 (s, 1H), 3.33-3.92 (m, 10H), 2.32-2.49 (m, 4H), 1.83-2.11 (m, 8H), 1.58-1.67 (m, 2H), 1.23 (d, J = 6.4 Hz, 6H), 1.21 (s, 3H).

[0196] Example 26

[0197] 4'-methyl-4-((3aR,7aS)-2-oxohexahydropyrano[3,4-d]imidazol-l(4H)-yl)-[l,4'- bipiperidine]- I'-carboxylate (Compound 76)o

[0198] Following the process of example 7 the title compound was obtained as a yellow solid. LC-MS: 409, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 408.2737 for C21H36N4O4 [M + H]+; found, 409.2812; ’HNMR (400 MHz, CDCls) 88.31 (s, 1H), 4.80-4.92 (m, 2H), 3.21-3.32 (m, 8H), 3.01-3.09 (m, 2H), 2.48-2.63 (m, 2H), 2.09-2.28 (m, 2H), 1.80-2.03 (m, 4H), 1.62-1.68 (m, 2H), 1.23 (d, J = 6.4 Hz, 6H), 1.21 (s, 3H).Attorney Docket No.: 206602-0001-00WO

[0199] Example 27

[0200] (Trans)-isopropyl 4'-methyl-4-(2-oxooctahydrocyclohepta[d]imidazol-l(2H)-yl)-[l,4'-bipiperidine]-l'-carboxylate (Compound 77)

[0201] Following the process of example 7 the title compound was obtained as a white solid. LC-MS: 421, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 420.3100 for C23H40N4O3 [M + H]+; found, 421.3175; ’H NMR (400 MHz, CDCh) 5 4.90 (sept, J = 7.2 Hz, 1H), 4.69-4.74 (m, 1H), 3.91-4.12 (m. 4H), 3.44-3.72 (m, 7H), 2.88-3.03 (m, 4H). 2.61-2.72 (m, 5H), 2.23-2.40 (m, 4H), 1.92-2.12 (m, 4H), 1.87-1.90 (m, 3H), 1.41-1.68 (m, 8H), 1.24 (d, J = 6.4 Hz, 6H), 1.05 (s, 3H).

[0202] Example 28

[0203] (3aS,7aS)-l-(l-(4-(isopropoxymethyl)cyclohexyl)piperidin-4-yl)octahydro-2H-benzo [d]imidazol-2-one (Compound 78)

[0204] Preparation of tert-butyl 4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)piperidine-l -carboxylate:

[0205] To a stirred solution of (lS.2S)-cyclohexane-1.2-diamine (16.0 g, 160 mmol), tert-butyl 4-oxopiperidine-l -carboxylate (16.0 g, 80 mmol) and HOAc (9.6 g, 160 mmol) in 200 rnL of DCMAttorney Docket No.: 206602-0001-00WOwas added STAB (25.4 g, 120 mmol) portionwise at room temperature. After stirring at room temperature overnight. CDI (24.0 g. 200 mmol) was added. After stirring for additional 2 hours and detected by LCMS to make sure full conversion. 2M KOH aqueous solution was added to quench the reaction. 2x200 mL of DCM was added to extract the product. Combined organic layers were washed with IM HC1 solution till pH<5. The organic layer was further washed with NaHCOs aqueous solution and brine. After drying over Na2SO4, the organic layer was fdtered and evaporated to dryness. The residue was stirred in EA (-300 mL) for 1 hour. The solids were collected by fdtration. Most of the di-substituted byproduct from the first step was dissolved in mother liquor. Finally, 12 g of tert-butyl 4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)piperidine-l -carboxylate was obtained as a white solid.

[0206] Preparation of 4-(ethoxymethyl)cyclohexan-l-one:

[0207] A solution of (l,4-dioxaspiro[4.5]decan-8-yl)methanol (3.4 g, 20 mmol), KOH (5.6 g, 100 mmol) and ethyl iodide (15.6 g, 100 mmol) in 15 mL of DMSO was stirred at room temperature overnight. After completion, the mixture was extracted with 100 mL of ether 3 times. Combined extracts were dried over Na2SO4, filtered, evaporated to provide 3.2 g of 8-(ethoxymethyl)-l,4-dioxaspiro[4.5]decane as a yellow oil.

[0208] The obtained 3.2 g of 8-(ethoxymethyl)-l,4-dioxaspiro[4.5] decane in 10 mL of THF was added 10 mL of 6 M aquous HC1 solution and stirred overnight. After completion, the mixture was extracted with 100 mL of ether 3 times. Combined extracts were dried over Na2SO4, filtered, evaporated to provide 2.1 g of 4-(ethoxymethyl)cyclohexan-l-one as a colorless oil.

[0209] By using standard reductive amination process and the general work-up is as follows: After completion, 2M KOH aqueous solution was added to the mixture to quench the reductive amination reaction. Combined organic layers were washed with NH4C1 (aq.), brine and dried over Na2SO4. The layer was filtered and evaporated to dryness. The residue was titrated with EA. The solids were collected to provide the title compound as white solid. LC-MS: 378, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 377.3042 for C22H39N3O2 [M + H]+; found. 378.3109; 'H NMR (400 MHz, CDCh) 5 11.80 (s, 1H), 4.91-5.13 (m, 1H), 4.01-4.16 (m, 2H), 3.42-3.65 (m, 5H), 3.34-3.39 (m, 3H), 2.97-3.20 (m, 8H), 2.73-2.91 (m, 7H), 2.27-2.42 (m, 5H), 1.75-2.03 (m, 10H), 1.50-1.74 (m, 4H), 1.31-1.48 (m, 6H), 1.14 (d, J = 6.0 Hz, 6H).

[0210] Example 29

[0211] Isopropyl 4'-methyl-4-((4S,5S)-2-oxo-4,5-diphenylimidazolidin-l-yl)-[l,4'- bipiperidine]-l'-carboxylate (Compound 79)Attorney Docket No.: 206602-0001-00WO

[0212] Following the process of example 7 the title compound was obtained as a white solid. LC-MS: 505, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 504.3100 for C30H40N4O3 [M + H]+; found, 505.3178; ’H NMR (400 MHz. CDCh) 57.26-7.40 (m, 8H), 7.13-7.19 (m, 2H), 5.35 (s, 1H), 4.87 (sept. J = 7.2 Hz. 1H), 4.76-4.85 (m. 1H), 4.49 (d. J = 6.0 Hz. 1H), 4.38 (d. J = 6.0 Hz. 1H), 3.81-3.98 (m, 3H), 3.20-3.25 (m. 2H), 2.86-2.97 (m. 2H), 2.53 (t, J = 6.0 Hz. 1H), 2.42 (t, J = 6.0 Hz.1H), 2.12-2.23 (m, 1H), 1.79-1.93 (m, 3H), 1.42-1.63 (m, 4H), 1.20 (d, J = 6.4 Hz, 6H), 1.18 (s, 3H).

[0213] Example 30

[0214] Isopropyl 4'-methyl-4-((3aS,7aR)-2-oxohexahydropyrano[3,4-d]imidazol-3(2H)-yl)- [L4'-bipiperidine]-l '-carboxylate (Compound 80)

[0215] Following the process of example 7 the title compound was obtained as a white solid. LC-MS: 409, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 408.2737 for C21H36N4O4 [M + H]+; found, 409.2816; ’H NMR (400 MHz, CDCh) 5 5.09 (s, 1H), 4.90(sept, J = 7.2 Hz, 1H), 4.30-4.43 (m, 2H), 4.00-4.21 (m. 2H), 3.85-3.97 (m, 2H), 3.39-3.52 (m, 5H). 3.15-3.30 (m, 2H), 2.99-3.10 (m, 2H), 2.51-2.60 (m, 2H), 2.06-2.32 (m, 2H), 1.71-2.03 (m, 7H), 1.41-1.70 (m, 2H), 1.25 (s, 3H), 1.24 (d, J = 6.4 Hz, 6H).

[0216] Example 31

[0217] (3aS,7aS)-l-(l-(4-(ethoxymethyl)cyclohexyl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one (Compound 81)

[0218] Following the process of example 28 the title compound was obtained as a white solid. LC-MS: 364, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 363.2886 for C21H37N3O2 [M + H]+; found, 364.2955; *HNMR (400 MHz, CDCh) 58.59 (s, 1H), 5.04 (s, 1H), 3.97-4.09 (m, 1H), 3.51-3.62Attorney Docket No.: 206602-0001-00WO(m, 2H), 3.42-3.51 (m, 2H), 3.39-3.41 (m, 2H), 3.08-3.22 (m, 2H), 2.97-3.06 (m, 2H), 2.78-2.89 (m. 2H), 2.28-2.43 (m. 3H), 1.78-2.03 (m. 9H), 1.50-1.71 (m. 4H), 1.31-1.49 (m. 4H), 1.21 (t, J = 7.2 Hz, 3H).1002191 Example 32

[0220] (3aS,7aS)-l-(l-(3-(isopropoxymethyl)cyclopentyl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one (Compound 82)

[0221] Following the process of example 28 the title compound was obtained as a light yellow solid. LC-MS: 364, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 363.2886 for C21H37N3O2 [M + H]+; found, 364.2953; 'H NMR (400 MHz, CDCh) 5 12.32 (s, 1H), 4.64 (s, 1H), 3.90-4.12 (m. 1H), 3.21-3.80 (m, 6H), 2.92-3.11 (m, 2H), 2.56-2.98 (m, 4H), 2.10-2.41 (m, 2H), 1.63-2.09 (m, 4H), 1.22-1.53 (m, 6H), 1.13 (d, J = 6.0 Hz, 6H).

[0222] Example 33

[0223] (3aS,7aS)-l-(l-(3-(ethoxymethyl)cyclopentyl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one (Compound 83)

[0224] Following the process of example 28 the title compound was obtained as a light yellow solid. LC-MS: 350, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 349.2729 for C20H35N3O2 [M + H]+; found, 350.2803; ’H NMR (400 MHz, CDCls) 54.43 (s, 1H), 3.72-3.83 (m, 1H), 3.46 (q, J = 7.0 Hz, 2H), 3.25-3.32 (m, 2H), 2.93-3.12 (m, 4H). 2.45-2.54 (m, 1H), 2.12-2.36 (m, 2H), 1.91-2.01 (m. 4H), 1.70-1.90 (m. 7H), 1.29-1.52 (m. 6H), 1.19 (t, J = 7.0 Hz, 3H), 1.05-1.13 (m, 1H).

[0225] Example 34

[0226] Isopropyl 4-(4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l- yl)phenyl)piperazine-l -carboxyl ate (Compound 84)Attorney Docket No.: 206602-0001-00WO

[0227] A mixture of tert-butyl 4-(4-iodophenyl)piperazine-l -carboxylate (3.9 g, 10 mmol), (lS,2S)-cyclohexane-l,2-diamine (1.3 g, 12 mmol), Cui (0.19 g, 1 mmol) and K3PO4 (4.2 g, 20 mmol) in 50 mL of 1,4-dioxane was heated at 100 °C under argon for 2 hours. After cooling to room temperature, the mixture was filtered through celite. The filtrate was evaporated to dryness. The residue was subjected onto silica gel column chromatography to provide 1.17 g of tert- butyl 4-(4-(((lS,2S)-2-aminocyclohexyl)amino)phenyl)piperazine-l-carboxylate as a brown foam.

[0228] Obtained amine in 10 mL of DCM was added CDI (2 g, excess) and NEt? at room temperature. After completion, the solvent was evaporated to dryness. The residue was subjected onto silica gel column chromatography (eluent: n-hexane-EA, 50:50) to provide 1.0 g of tert-butyl 4-(4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)phenyl)piperazine-l -carboxylate as a yellow solid.

[0229] Following the process of example 7, after de-Boc and isopropyl chloroformate reaction, 0.28 g of tert-butyl 4-(4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)phenyl)piperazine-l -carboxylate converted to the title compound as a white solid. LC-MS: 387, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 386.2318 for C21H30N4O3 [M + H]+; found, 387.2395; 'H NMR (400 MHz, CDCh) 5 7.13 (d, J = 8.8 Hz, 2H), 6.92 (d. J = 8.8 Hz, 2H), 4.95 (sept, J = 7.2 Hz. 1H), 4.74 (s, 1H), 3.52-3.64 (m, 4H), 3.31-3.42 (m, 1H). 3.20-3.29 (m, 1H). 3.05-3.13 (m, 4H), 2.01-2.09 (m, 2H), 1.80-1.92 (m, 2H), 1.31-1.59 (m, 5H), 1.26 (d, J = 6.0 Hz, 6H).

[0230] Example 35

[0231] Ethyl 4-methyl-4-(4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l- yl)phenyl)piperidine-l -carboxylate (Compound 85)Attorney Docket No.: 206602-0001-00WO

[0232] To a solution of ethyl 4-oxopiperidine-l -carboxylate (5.1 g, 30 mmol) in 100 mL of THF was added MeMgBr (15 mL. 45 mmol, 3M in ether) dropwise at 0°C. After completion, the mixture was quenched with saturated NH4CI solution and extracted with 2x100 mL of EA. The solvent was evaporated to dryness. The residue was subjected onto silica gel column chromatography (eluent: n-hexane-EA, 0-100%) to provide 2.6 g of ethyl 4-hydroxy-4-methylpiperidine-1 -carboxylate as a light yellow oil.

[0233] To a mixture of ethyl 4-hydroxy-4-methylpiperidine-l-carboxylate (564 mg, 3 mmol) in iodobenzene (6 g. 30 mmol, 10 eq.) was added TfOH (4.5 g, 30 mmol, 10 eq.) at 0 °C. After completion, the reaction mixture was poured into ice-water and extracted with 2x50 mL of EA. Combined extracts were dried over Na2SO4, filtered, evaporated to dryness. The residue was subjected onto silica gel column chromatography (eluent: n-hexane-EA, 0-30%) to provide 0.35 g of ethyl 4-(4-iodophenyl)-4-methylpiperidine-l -carboxylate as a colorless oil.

[0234] Following the process of example 34, the title compound was obtained as white solid. LC-MS: 386, [M+H]+. ESI+; HRMS (ESI) m / z: calcd. 385.2365 for C22H31N3O3 [M + H]+; found, 386.2432; H NMR (400 MHz, CDCh) 5 7.31 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 4.81 -4.92 (m, 1H), 4.10 (q, J = 7.0 Hz, 2H), 3.21-3.60 (m, 7H), 1.95-2.21 (m, 5H), 1.61-1.92 (m, 6H), 1.35-1.59 (m, 5H), 1.13-1.31 (m, 8H).

[0235] Example 36

[0236] Isopropyl 4-methyl-4-(4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l- yl)phenyl)piperidine-l -carboxylate (Compound 86)

[0237] Following the process of example 34 and 35, the title compound was obtained as a white solid. LC-MS: 400, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 399.2522 for C23H33N3O3 [M + H]+; found. 400.2597; 'H NMR (400 MHz, CDCh) 5 7.12-7.33 (m, 4H), 4.82-4.95 (m, 1H), 4.61-4.72 (m, 1H), 4.19-4.31 (m, 1H), 3.16-3.60 (m, 7H), 1.95-2.21 (m. 5H), 1.61-1.92 (m. 6H), 1.35-1.59 (m, 5H), 1.13-1.32 (m, 8H).

[0238] Example 37

[0239] Isopropyl 4-(4-((3 aS,7aS)-2-oxooctahy dro- 1 H-benzo [d] imidazol- 1 - yl)phenyl)piperidine-l -carboxylate (Compound 87)Attorney Docket No.: 206602-0001-00WO

[0240] Following the process of example 34 and 35, the title compound was obtained as white solid. LC-MS: 386, [M+H]+, ESC; HRMS (ESI) m / z: calcd, 385.2365 for C22H31N3O3 [M + H]+; found, 386.2442; 'H NMR (400 MHz, CDCh) 67.11-7.22 (m, 4H), 4.83-5.00 (m, 2H), 4.21-4.32 (m, 1H), 3.39-3.45 (m, 1H), 3.21-3.29 (m, 1H), 2.75-2.89 (m, 2H), 2.60-2.69 (m, 1H), 2.01-2.18 (m, 2H), 1.75-1.89 (m, 4H), 1.50-1.69 (m, 5H), 1.32-1.49 (m, 3H), 1.26 (d, J = 6.0 Hz, 6H).

[0241] Example 38

[0242] Isopropyl 3 -(4-((3 aS, 7 aS)-2-oxooctahy dro- 1 H-benzo [d] imidazol- 1 - yl)phenyl)pyrrolidine-l -carboxylate (Compound 88)

[0243] Following the process of example 34 and 35, the title compound was obtained as a white solid. LC-MS: 372, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 371.2209 for C21H29N3O3 [M + H]+; found. 372.2284; 'H NMR (400 MHz, CDCh) 57.11-7.26 (m. 4H), 4.81-5.00 (m, 2H), 3.71-3.92 (m, 1H), 3.52-3.70 (m, 1H), 3.21-3.49 (m, 5H), 2.21-2.30 (m, 1H), 2.00-2.17 (m, 2H), 1.80-2.00 (m, 3H), 1.31-1.62 (m, 4H), 1.25 (d, J = 6.0 Hz, 6H).

[0244] Example 39

[0245] Isopropyl 4'-methyl-4-((4aS,8aS)-3-oxooctahydro-4H-benzo[b][l,4]oxazin-4-yl)- [1.4'-bipi peri dine]- l'-carboxylate (Compound 89)

[0246] Following the standard reductive amination process, tert-butyl 4'-methyl-4-oxo-[l,4'-bipiperidine]- l'-carboxylate (0.4 g, 1.2 mmol) reacted with (lS.2S)-2-aminocyclohexan-l-ol (0.16 g, 1.5 mmol) and STAB (0.42 g, 2 mmol) to provide 0.41 g of tert-butyl 4-(((l S,2S)-2-Attorney Docket No.: 206602-0001-00WOhydroxycyclohexyl)amino)-4'-methyl-[l,4'-bipiperidine]-r-carboxylate as a yellow solid, which reacted with 2-chloroacetyl chloride (0.3 g, 1.5 mmol) and NEt3 (0.3 g, 2 mmol) as base, tert-butyl 4-(2-chloro-N-((lS,2S)-2-hydroxycyclohexyl)acetamido)-4'-methyl-[l,4'-bipiperidine]-r-carboxylate was obtained as a yellow solid. The cyclization reaction was carried out by using sodium hydride in THF. tert-butyl 4'-methyl-4-((4aS,8aS)-3-oxooctahydro-4H-benzo[b][l,4]oxazin-4-yl)-[l,4'-bipiperidine]-T-carboxylate was obtained as a brown oil.

[0247] Following the process of example 2, the title compound was obtained as a white solid. LC-MS: 422. [M+H]+, ESI+; HRMS (ESI) m / z: calcd. 421.2941 for C23H39N3O4 [M + H]+; found, 422.3018; 'H NMR (400 MHz, CDCh) 5 4.91 (sept, J = 7.2 Hz, 1H), 4.24 (d, J = 16.4 Hz, 1H), 4.16 (d, J = 16.4 Hz, 1H), 3.89-4.08 (m, 1H), 3.31-3.59 (m, 3H), 3.15-3.29 (m, 2H), 2.98-3.13 (m, 1H), 2.09-2.42 (m, 4H), 1.99-2.08 (m, 2H), 1.63-1.92 (m, 5H), 1.32-1.51 (m, 7H), 1.21-1.31 (m, 7H), 1.03 (s, 3H).

[0248] Example 40

[0249] (3aS,7aS)-l-(4-(4-(ethoxymethyl)piperidin-l-yl)cyclohexyl)octahydro-2H- benzo[d]imidazol-2-one (Compound 91)

[0250] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 364. [M+H]+, ESI+; HRMS (ESI) m / z: calcd. 363.2886 for C21H37N3O2 [M + H]+; found, 364.2962; 'H NMR (400 MHz, CDCh) 5 4.39-4.45 (m, 1H). 3.55-3.89 (m, 1H), 3.45 (q, J = 6.4 Hz, 2H), 3.15-3.36 (m, 4H), 2.92-3.03 (m, 2H), 2.00-2.21 (m, 4H), 1.87-1.98 (m, 5H), 1.45-1.62 (m, 5H), 1.31-1.43 (m, 4H), 1.18 (t, J = 6.0 Hz, 3H).

[0251] Example 41

[0252] (3aS,7aS)-l-(4-(4-(isopropoxymethyl)piperidin-l-yl)cyclohexyl)octahydro-2H- benzo[d]imidazol-2-one (Compound 92)Attorney Docket No.: 206602-0001-00WO

[0253] Following the process of example 28 and example 40, the title compound was obtained as a white solid. LC-MS: 378, [M+H]+, ESI+; HRMS (ESI) m / z: calcd. 377.3042 for C22H39N3O2 [M + H]+; found. 378.3119.

[0254] Example 42

[0255] Isopropyl 4-(4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l- yl)cyclohexyl)piperazine- 1 -carboxylate (Compound 93)

[0256] Following the process of example 28 and example 40, the title compound was obtained as a white solid. LC-MS: 393, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 392.2787 for C21H36N4O3 [M + H]+; found, 393.2853; 'H NMR (400 MHz, CDCh) 54.91 (sept, J = 7.2 Hz, 1H), 3.71-3.90 (m, 2H), 3.42-3.50 (m, 3H). 3.12-3.19 (m, 2H). 2.98-3.10 (m, 3H), 2.43-2.49 (m, 3H), 2.15-2.26 (m, 2H), 1.97-2.13 (m, 5H), 1.77-1.90 (m, 6H), 1.21-1.55 (m, 11H), 1.24 (m, J = 6.4 Hz, 6H).Example 43

[0257] Isopropyl 4-(4-((4aS,8aS)-3 -oxooctahy dro-4H-benzo [b] [1,4] oxazin-4- yl)cyclohexyl)piperazine-l-carboxylate (Compound 94)

[0258] Following the process of example 28 and example 40, the title compound was obtained as a white solid. LC-MS: 408, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 407.2784 for C22H37N3O4 [M + H]+; found, 408.2854; 'H NMR (400 MHz, CDCI3) 54.92 (sept, J = 7.2 Hz, 1H), 4.11-4.32 (m, 3H), 3.38-3.71 (m, 6H), 3.22-3.31 (m, 4H), 2.52-2.73 (m, 2H), 2.35-2.49 (m, 4H), 1.95-2.25 (m. 8H), 1.74-1.86 (m. 3H), 1.25-1.58 (m. 9H), 1.24 (d. J = 6.4 Hz, 6H), 1.15-1.23 (m. 3H).

[0259] Example 44Attorney Docket No.: 206602-0001-00WO

[0260] (4aS,8aS)-4-(4-(4-(ethoxymethyl)piperidin-l-yl)cyclohexyl)hexahydro-2H- benzo[b][1.4]oxazin-3(4H)-one (Compound 95)

[0261] Following the process of example 28 and example 40, the title compound was obtained as a white solid. LC-MS: 379, [M+H]+, ESC; HRMS (ESI) m / z: calcd, 378.2882 for C22H38N2O3 [M + H]+; found, 379.2959; 'H NMR (400 MHz, CDCh) 54.21 (d, J = 15.4 Hz, 1H), 4.15 (d, J = 15.4 Hz, 1H), 4.02-4.09 (m, 1H), 3.78-3.85 (m, 1H), 3.44-3.53 (m, 2H), 3.15-3.33 (m, 3H), 2.45-2.69 (m, 2H), 1.92-2.35 (m, 8H), 1.77-1.91 (m, 4H), 1.21-1.15 (m, 10 H), 1.18 (t, J = 7.0 Hz. 3H).

[0262] Example 45

[0263] (4aS,8aS)-4-(4-(4-(isopropoxymethyl)piperidin-l-yl)cyclohexyl)hexahydro-2H- benzo[b][l,4]oxazin-3(4H)-one (Compound 96)

[0264] Following the process of example 28 and example 40, the title compound was obtained as a white solid. LC-MS: 393, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 392.3039 for C23H40N2O3 [M + H]+; found, 393.3109; ’H NMR (400 MHz, CDCh) 55.72 (s, 2H), 4.83 (br, 1H), 4.23 (d, J = 16.4 Hz, 1H), 4.15 (d, J = 16.4 Hz, 1H), 3.89-4.02 (m, 1H), 3.50-3.58 (m, 1H), 3.15-3.32 (m, 6H), 2.55-2.77 (m, 2H), 1.98-2.30 (m, 7H), 1.72-1.90 (m. 4H), 1.22-1.69 (m. 10 H), 1.13 (d, J = 6.4 Hz, 6H).

[0265] Example 46

[0266] (3aS,7aS)-l -(1 -(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one (Compound 97)

[0267] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 308, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 307.2260 for C17H29N3O2 [M + H]+; found, 308.2336;NMR (400 MHz, CDCh) 5 8.45 (s, 1H), 7.61 (br, 2H), 4.89 (s, 1H), 3.89-4.18 (m,Attorney Docket No.: 206602-0001-00WO3H), 3.31-3.55 (m, 5H), 2.92-3.14 (m, 3H), 2.51-2.68 (m, 2H), 2.12-2.40 (m, 4H), 1.62-2.05 (m, 10H), 1.21-1.52 (m, 5H).

[0268] Example 47|00269| (3aS.7aS)-l-(l-(4-methyltetrahydro-2H-pyran-4-yl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one (Compound 98)

[0270] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 322, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 321.2416 for C18H31N3O2 [M + H]+; found, 322.2484; 'H NMR (400 MHz, CDCls) 58.389s, 1H), 4.63-4.78 (m, 1H), 3.92-4.02 (m, 2H), 3.42-3.56 (m, 4H), 2.93-3.21 (m, 4H), 2.51-2.63 (m, 2H), 2.15-2.31 (m, 4H), 1.73-2.00 (m, 5H), 1.60-1.67 (m, 2H), 1.32-1.51 (m, 4H), 1.28 (s, 3H).

[0271] Example 48

[0272] (3aS,7aS)-l-(l-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one (Compound 99)pHN-X

[0273] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 336, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 335.2573 for C19H33N3O2 [M + H]+; found, 336.2650; 'HNMR (400 MHz, CDCls) 54.49 (s, 1H), 4.01-4.12 (m, 1H), 3.42-3.69 (m, 3H), 2.91-3.11 (m, 2H), 2.65-2.89 (m, 1H), 2.42-2.61 (m, 2H), 1.72-2.01 (m, 6H). 1.23-1.61 (m, 11H), 0.71-0.91 (m, 4H).

[0274] Example 49

[0275] (3aS,7aS)-l-(l-(3-(hydroxymethyl)cyclopentyl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one (Compound 100)Attorney Docket No.: 206602-0001-00WO

[0276] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 322. [M+H]+, ESI+; HRMS (ESI) m / z: calcd. 321.2416 for C18H31N3O2 [M + H]+; found, 322.2490; 'H NMR (400 MHz, CDCh) 54.42 (s, 1H), 3.72-3.89 (m, 1H), 3.45-3.56 (m, 2H), 3.06-3.22 (m, 2H), 2.91-3.05 (m, 2H), 2.51-2.67 (m, 1H), 2.22-2.40 (m, 2H), 1.93-2.13 (m, 6H), 1.52-1.90 (m, 7H), 1.22-1.50 (m, 4H).

[0277] Example 50

[0278] (3aS,7aS)-l-(l-(3-(methoxymethyl)cyclopentyl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one (Compound 101)HN

[0279] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 336. [M+H]+. ESI+; HRMS (ESI) m / z: calcd. 335.2573 for C19H33N3O2 [M + H]+; found, 336.2651; *HNMR (400 MHz, CDCh) 88.41 (s, 1H), 4.47 (s, 1H), 3.87-3.93 (m, 1H), 3.35-3.51 (m, 2H), 3.42 (s, 3H), 3.18-3.22 (m, 2H), 2.96-3.15 (m, 3H), 2.26-2.43 (m, 4H), 2.01-2.22 (m, 2H), 1.84-2.00 (m, 5H), 1.21-1.45 (m, 7H).

[0280] Example 51

[0281] (3aS,7aS)-l-(l-(4-((cyclobutylmethoxy)methyl)cyclohexyl)piperidin-4-yl)octahydro- 2H-benzo[d]imidazol-2-one (Compound 102)

[0282] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 390, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 403.3199 for C24H41N3O2 [M + H]+; found, 404.3275; 'H NMR (400 MHz, CDCh) 84.69 (s, 1H), 3.92-4.01 (m, 1H), 3.15-3.61 (m, 5H), 2.91-3.13 (m, 4H), 2.66-2.82 (m, 2H), 2.43-2.58 (m, 1H), 2.21-2.35 (m, 3H), 1.25-2.12 (m, 22H).

[0283] Example 52

[0284] (3aS,7aS)-l-(l-(4-((cyclopropylmethoxy)methyl)cyclohexyl)piperidin-4- yl)octahydro-2H-benzo[d]imidazol-2-one (Compound 103)Attorney Docket No.: 206602-0001-00WOo

[0285] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 404. [M+H]+, ESI+; HRMS (ESI) m / z: calcd. 389.3042 for C23H39N3O2 [M + H]+; found, 390.3120; 'H NMR (400 MHz, CDCl3) 54.69 (s, 1H). 3.92-4.01 (m, 1H). 3.15-3.61 (m, 5H), 2.91-3.13 (m, 4H), 2.66-2.82 (m, 2H), 2.43-2.58 (m, 1H), 2.21-2.35 (m, 3H), 1.21-2.12 (m, 18H), 0.93-1.11 (m, 2H), 0.42-0.55 (m, 2H), 0.13-0.19 (m, 2H).

[0286] Example 53

[0287] (3aS,7aS)-l-(l-(4-(methoxymethyl)cyclohexyl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one (Compound 104)HN-A oty-o-o-

[0288] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 350. [M+H]+, ESI+; HRMS (ESI) m / z: calcd. 349.2729 for C20H35N3O2 [M + H]+; found, 350.2806; *HNMR (400 MHz, CDCh) 58.48 (s, 1H), 4.47 (s, 1H), 3.82-3.93 (m, 1H), 3.33-3.42 (m, 2H), 3.31 (s, 3H), 3.22-3.28 (m, 2H), 2.91-3.07 (m, 2H), 2.71-2.91 (m, 1H), 2.63-2.70 (m, 2H), 2.19-2.41 (m, 3H), 2.01-2.17 (m, 3H), 1.82-1.98 (m, 7H), 1.02-1.97 (m, 14H).

[0289] Example 54

[0290] (3aS,7aS)-l-(l-(4-((2-fluoroethoxy)methyl)cyclohexyl)piperidin-4-yl)octahydro-2H- benzo[d]imidazol-2-one (Compound 105)o

[0291] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 382, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 381.2792 for C21H36FN3O2 [M + H]+; found, 382.2869; 'H NMR (400 MHz, CDCh) 54.61 (t, J = 6.3 Hz, 1H), 4.33-4.42 (m, 2H), 3.71-3.92 (m, 1H), 3.67-3.71 (m, 1H), 3.58-3.66 (m, 1H), 3.46 (d, J = 7.2 Hz, 1H). 3.30 (d, J = 7.2 Hz. 1H), 2.92-3.21 (m, 4H), 2.29-2.66 (m, 4H), 1.89-2.07 (m, 5H), 1.23-1.87 (m, 15 H), 0.92-1.08 (m, 1H).

[0292] Example 55Attorney Docket No.: 206602-0001-00WO

[0293] (3aS,7aS)-l-(l-(4-((2,2,2-trifluoroethoxy)methyl)cyclohexyl)piperidin-4- yl)octahydro-2H-benzo[d]imidazol-2-one (Compound 106)

[0294] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 418, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 417.2603 for C21H34F3N3O2 [M + H]+; found, 418.2681; 'H NMR (400 MHz, CDCI3) 5 4.53 (s, 1H), 3.90-4.01 (m, 1H), 3.72-3.83 (m, 2H), 3.58 (d, J = 7.2 Hz, 1H), 3.31-3.42 (m, 3H), 2.81-3.03 (m, 3H), 2.51-2.70 (m, 2H), 2.16-2.28 (m, 4H), 1.60-2.11 (m, 15H), 0.78-1.57 (m, 8H).

[0295] Example 56

[0296] (3aS,7aS)-l-(l-(4-((2,2-difluoroethoxy)methyl)cyclohexyl)piperidin-4-yl)octahydro- 2H-benzo[d]imidazol-2-one (Compound 108)

[0297] Following the process of example 28, the title compound was obtained as a white solid. LC-MS: 400, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 399.2697 for C21H35F2N3O2 [M + H]+; found, 400.2774; 'H NMR (400 MHz, CDCh) 5 8.27 (s. 1H), 5.85 (dt, 1H), 5.06 (s, 1H), 3.92-4.07 (m, 1H), 3.30-3.65 (m, 5H), 2.72-3.13 (m, 4H), 2.10-2.38 (m, 3H), 1.71-2.00 (m, 7H), 1.22-1.67 (m, 6H).

[0298] Example 57

[0299] ethyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]- l'-carboxylate (compound 1)

[0300] Following the process of example 2, the title compound was obtained as a white solid. LC-MS: 387. [M+H]+, ESI+; HRMS (ESI) m / z: calcd. 386.2318 for C21H30N4O3 [M + H]+; found, 387.2394; *HNMR (400 MHz, DMSO-d<5) 57.20-7.24 (m, 1H), 7.04-7.21 (m, 3H), 4.25-4.33 (m,Attorney Docket No.: 206602-0001-00WO1H), 4.16 (sept. J = 7.2 Hz, 1H), 3.56-3.71 (m, 2H), 3.38-3.47 (m, 2H), 3.04-3.12 (m, 2H), 2.25-2.43 (m, 4H), 1.61-1.93 (m, 4H), 1.43-1.49 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 0.98 (s. 3H).

[0301] Example 581003021 Isopropyl 4-(5-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[1.4'- bipiperidinej-l'-carboxylate (Compound 13)o

[0303] Following the process of example 2. the title compound was obtained as a white solid. LC-MS: 419, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 418.2380 for C22H31FN4O3 [M + H]+; found, 419.2455.

[0304] Example 59

[0305] Isopropyl 4-(6-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'- bipiperidine]-l'-carboxylate (Compound 31)HN‘

[0306] Following the process of example 2, the title compound was obtained as a light yellow solid. LC-MS: 419, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 418.2380 for C22H31FN4O3 [M + H]+; found, 419.2457; 'H NMR (400 MHz, DMSO-tfe) 5 10.90 (s, 1H). 7.19 (d, J = 9.6Hz, 1H). 6.94 (dd, J = 8.4, 4.8 Hz, 1H), 6.73-6.82 (m, 1H), 4.77 (sept, J = 7.2 Hz, 1H), 4.02-4.15 (m, 1H), 3.41-3.60 (m, 2H), 3.01-3.11 (m, 2H), 2.19-2.35 (m, 4H), 1.62-1.83 (m, 4H), 1.31-1.42 (m, 2H), 1.19 (d, J = 6.4 Hz, 6H), 0.92 (s, 3H).

[0307] Example 60

[0308] Isopropyl 4-(5,6-difluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl- [l,4'-bipiperidine]-r-carboxylate (Compound 109)HN"\NFAttorney Docket No.: 206602-0001-00WO

[0309] Following the process of example 2, the title compound was obtained as a red solid. LC-MS: 437. [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 436.2286 for C22H30F2N4O3 [M + H]+; found.437.2369; 'H NMR (400 MHz, DMSO-dd) 5 11.04 (s, 1H), 7.43 (dd, J = 10.8, 7.2 Hz, 1H), 7.03 (dd, J = 10.8 Hz, 7.2 Hz, 1H), 4.76 (sept, J = 7.2 Hz, 1H), 4.02-4.15 (m, 1H), 3.41-3.60 (m, 2H), 3.01-3.11 (m, 2H), 2.20-2.33 (m, 4H), 1.62-1.83 (m, 4H), 1.31-1.42 (m, 2H), 1.18 (d, J = 6.4 Hz, 6H), 0.95 (s, 3H).

[0310] Example 61

[0311] Isopropyl 4'-methyl-4-(6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'- bipiperidine]-l'-carboxylate (Compound 6)o

[0312] Following the process of example 2. the title compound was obtained as a white solid. LC-MS: 415, [M+H]+, ESI+; HRMS (ESI) m / z: calcd, 414.2631 for C23H34N4O3 [M + H]+; found, 415.2715.

[0313] Example 62

[0314] Human Ml - M4 calcium mobilization FLIPR assay

[0315] CHO (Chinese hamster ovary cells, ATCC) cells stably expressing the human muscarinic Ml, M2, M3 or M4 receptor were plated in 384-well tissue culture plates (10000 cells / well / 50pL) in DMEM / F12 medium containing 10% FBS, lx penicillin-streptomycin, and 600 pg / ml hygromycin B at 37 °C, 5% (v / v) CO2. Prior to assay experiments, cell culture medium was removed from the plates. A loading solution of 30 pL of Hank’s balanced salt solution, 10 mM Hepes and 2.5 mM Probenicid at pH7.4 with 2 pM calcium indicator dye was added to the wells. Plates were incubated at 37 °C for 60 minutes prior to start of assay. Incubation was terminated by washing the cells in assay buffer, leaving a residual 25 pL buffer per well. Cell plates were transferred to the Fluorescent Imaging Plate Reader (FLIPR) for treatment with test compounds.

[0316] Test compounds and positive control were diluted in three-fold concentration range for 10 points serial dilutions. For all calcium assays, a baseline reading was taken for 30 seconds followed by the addition of 12.5 -25 pL of compounds, resulting in a total well volume of 37.5 to 50 pL. Data were collected every 1.6 seconds for 300 seconds. The fluorescence emission was read using filter 1 (emission 520-545 nm) by the FLIPR on board CCD camera.Attorney Docket No.: 206602-0001-00WO

[0317] The dose-dependent activation of muscarinic Ml, M2, M3, M4 receptors by example compounds are shown in FIG. 1 to 16.

Claims

Attorney Docket No.: 206602-0001-00WOCLAIMSWhat is claimed is:

1. A compound comprising the structure of Formula (I):Formula (I)or a tautomer, stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, solvate, or derivative thereof.wherein:R1is O, S, NH. NH-OH;Y is N, O, CH,X1is C, or absentR2, R3are each independently absent, hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl-Ci-3alkyl, C3-7 heterocycloalkyl, C3-7heterocycloalkyl-Ci-3alkyl, Ce-ioaryl-Ci-3alkyl, C3-9 heteroaryl, or C3-9 heteroaryl-Ci-3 alkyl;A, B. C, D are each independently absent, CH, CH2, CRa;Rais hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl-Ci-3 alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl-Ci-3alkyl, Cs-io aryl-Ci-3alkyl, C3-9 heteroaryl, or C3-9 heteroaryl-Ci-3 alkyl;m = 0, 1.2, 3n = l, 2, 3o = 0, 1p = 1 or 2q = 1 or 2R4is H, C1-3 alkyl;X5is CH2, C=O, or O;Attorney Docket No.: 206602-0001-00WOR5is selected from -Rb, -ORb, -NRcRd:Rb, Rc, and Rdare each independently hydrogen, Ci-6 alkyl, Ci-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl-Ci-3alkyl, C3-7 heterocycloalkyl, C3-7heterocycloalkyl-Ci-3alkyl, Ce-ioaryl-Ci-3alkyl, C3-9 heteroaryl, or C3-9 heteroaryl-Ci-3 alkyl;R6is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl. C3-7 cycloalkyl-Ci-3alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl-Ci-3alkyl, Ce-io aryl-Ci-3alkyl, C3-9 heteroaryl, or C3-9 heteroaryl-Ci-3 alkyl;2. The compound of claim 1, or a pharmaceutically acceptable salt form thereof, or a prodrug thereof, wherein Y is N, R1is O, and R6is H.

3. The compound of claim 1, or a pharmaceutically acceptable salt form thereof, or a prodrug thereof, wherein R1is S.

4. The compound of claim 1, or a pharmaceutically acceptable salt form thereof, or a prodrug thereof, wherein R1is O.

5. The compound of claim 1, or a pharmaceutically acceptable salt form thereof, or a prodrug thereof, wherein R1is O, Y is N. R6is H, X1is absent, X5is O.

6. The compounds of claim 1, wherein the compound comprising the structure of Formula (I) is selected from the group consisting of:ethyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-r-carboxylate;isopropyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[1.4'-bipiperidine]-T-carboxylate;prop-2-yn-l-yl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-T-carboxylate;methyl 4'-methyl-4-(6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[1.4'-bipiperidine]-1 '-carboxylate;ethyl 4'-methyl-4-(6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-r-carboxylate;isopropyl 4'-methyl-4-(6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine] - 1 '-carboxylate;Attorney Docket No.: 206602-0001-00WOprop-2-yn-l-yl 4'-methyl-4-(6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine] - l'-carboxy late;ethyl 4-(6-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine]-r-carboxylate;isopropyl 4-(6-fluoro-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - 1 '-carboxylate;prop-2-yn-l-yl 4-(6-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - 1 '-carboxylate;methyl 4-(5-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine]-l'-carboxylate;ethyl 4-(5-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine]-l'-carboxylate;isopropyl 4-(5-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - l'-carboxylate;prop-2-yn-l-yl 4-(5-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - l'-carboxylate;methyl 4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - l'-carboxy late;ethyl 4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - l'-carboxy late;isopropyl 4-(5-fluoro-6-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - l'-carboxy late;prop-2-yn-l-yl 4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[ 1,4'-bipiperidine] - l'-carboxylate;ethyl 3-((4-(2-oxo-2.3-dihydro-lH-benzo[d]imidazol-l-yl)piperidin-l-yl)methyl)azetidine-l-carboxylate;ethyl 3-methyl-3-((4-(2-oxo-2.3-dihydro-lH-benzo[d]imidazol-l-yl)piperidin-l-y l)methy l)azetidine- 1 -carboxylate;ethyl 3-((4-(5-fluoro-2-oxo-2,3-dihydro-lH-benzo|d]imidazol-l-yl)piperidin-l-Attorney Docket No.: 206602-0001-00WOyl)methyl)azetidine-l -carboxylate;ethyl 3-((4-(5-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidin-l-yl)methyl)-3-methylazetidine- 1 -carboxylate;ethyl 3-((4-(6-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidin-l-yl)methy l)azetidine- 1 -carboxylate;ethyl 3-((4-(6-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidin-l-yl)methyl)-3-methylazetidine- 1 -carboxylate;ethyl 3-((4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidin-l-yl)methyl)azetidine-l -carboxylate;ethyl 3-((4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidin-l-yl)methyl)-3-methylazetidine- 1 -carboxylate;ethyl 3-((4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidin-l-yl)methyl)pyrrolidine-l-carboxylate;ethyl 3-methyl-3-((4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidin-l-yl)methyl)pyrrolidine- 1 -carboxylate;isopropyl 4-(6-fluoro-2-oxoindolin-l-yl)-4'-methyl-[l,4'-bipiperidine]-l'-carboxylate; isopropyl 4'-methyl-4-(3-methyl -2-oxoindohn- 1 -y 1)- [ 1,4'-bi piperidine] - 1 '-carboxylate; isopropyl 4-(6-fluoro-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - 1 '-carboxylate;ethyl 3-methyl-3-(4-(3-methyl-2-oxoindohn-l-yl)piperidin-l-yl)pyrrolidine-l-carboxylate; ethyl 3-(4-(6-fluoro-3-methyl-2-oxoindolin-l-yl)piperidin-l-yl)-3-methylpyrrolidine-l-carboxylate;isopropyl 4-(3,6-dimethyl-2-oxoindolin-l-yl)-4'-methyl-[L4'-bipiperidine]-r-carboxylate; isopropyl 4-(5-fluoro-6-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - 1 '-carboxylate;ethyl 4'-methyl-4-((3aS,7aS)-3-methyl-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)-[L4'-bipiperidine] - 1 '-carboxylate;isopropyl 4'-methyl-4-((3aS,7aS)-3-methyl-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine] - 1 '-carboxylate;Attorney Docket No.: 206602-0001-00WOethyl 3-methyl-3-(4-((3aS,7aS)-3-methyl-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)piperidin-l-y l)py rrolidine- 1 -carboxylate;isopropyl 3-methyl-3-(4-((3aS,7aS)-3-methyl-2-oxooctahydro-lH-benzo[d]imidazol-l-y l)piperidin- 1 -yl)py rrolidine- 1 -carboxylate;ethyl 4'-methyl-4-((7aS)-3-methyl-2-oxooctahydro-lH-indol-l-yl)-[l,4'-bipiperidine]-l'-carboxylate;isopropyl 4'-methyl-4-((7aS)-3-methyl-2-oxooctahydro-lH-indol-l-yl)-[l,4'-bipiperidine]-r-carboxylate;ethyl 3-methyl-3-(4-((7aS)-3-methyl-2-oxooctahydro-lH-indol-l-yl)pipendin-l-yl)pyrrolidine-l-carboxylate;isopropyl 4'-methyl-4-((3aS,7aS)-3-methyl-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine] - 1 '-carboxylate;isopropyl 4-((3aS,7aS)-2-amino-3a,4,5,6,7,7a-hexahydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine]-l'-carboxylate;isopropyl 4-((3aS,7aS)-2-(hydroxyamino)-3a,4,5,6,7,7a-hexahydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine]-r-carboxylate;ethyl 4'-methyl-4-((3aS,7aS)-2-thioxooctahydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]-l'-carboxylate;isopropyl 4'-methyl-4-((3aS,7aS)-2-thioxooctahydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine] - l'-carboxy late;isopropyl 4'-methyl-4-(3-oxo-2-azaspiro[4.5]decan-2-yl)-[l,4'-bipiperidine]- l'-carboxylate; isopropyl 4'-methy l-4-(2-oxo- 1,4-dihy droquinazolin-3(2H)-yl)-[ 1,4'-bipiperidine] - l'-carboxy late; isopropyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-thieno[3,4-d]imidazol-l-yl)-[l,4'-bipiperidine]-r-carboxylate;isopropyl 4'-methyl-4-(2-oxohexahydrocyclopenta[d]imidazol-l(2H)-yl)-[l,4'-bipiperidine]-r-carboxylate;isopropyl 4'-methyl-4-(6-methyl-2-oxohexahydrocyclopenta[d]imidazol-l(2H)-yl)-[l,4'-bipiperidine] - l'-carboxy late;isopropyl 4'-methyl-4-(4-methyl-2-oxohexahydrocyclopenta[d]imidazol-l(2H)-yl)-[l, 4'-Attorney Docket No.: 206602-0001-00WObipiperidine] - l'-carboxy late;isopropyl 4-(4,4-dimethyl-2-oxoimidazolidin-l-yl)-4'-methyl-[l,4'-bipiperidine]-r-carboxylate; isopropyl 4-(4,5-dimethyl-2-oxoimidazolidin-l-yl)-4'-methyl-[l,4'-bipiperidine]-r-carboxylate; isopropyl 4'-methyl-4-(5-methyl-2-oxoimidazolidin-l-yl)-[l,4'-bipiperidine]-r-carboxylate; isopropyl 4'-methyl-4-(2-oxoimidazolidin-l-yl)-[l,4'-bipiperi dine] -l'-carboxylate; isopropyl 4-(5-ethyl-2-oxoirmdazolidin-l-yl)-4'-methyl-[l,4'-bipiperidine]-l '-carboxylate; isopropyl 4'-methyl-4-(2-oxotetrahydropyrimidin-l(2H)-yl)-[l,4'-bipiperidine]-r-carboxylate; isopropyl 4'-methyl-4-(5-methyl-2-oxotetrahydropyrimidin-l(2H)-yl)-[l,4'-bipiperidine]-r-carboxylate;isopropyl 4-(5,6-dimethyl-2-oxotetrahydropyrimidin-l(2H)-yl)-4'-methyl-[1.4'-bipiperidine]-r-carboxylate;isopropyl 4'-methyl-4-(2-oxo-3,6-dihydropyrimidin-l(2H)-yl)-[1.4'-bipiperidine]-r-carboxylate; isopropyl 4'-methyl-4-(6-methyl-2-oxo-3,6-dihydropyrimi din- l(2H)-yl)-[l,4'-bipiperi dine] -1'-carboxylate;isopropyl 4-(6-ethyl-5-methyl-2-oxo-3,6-dihydropyrimidin-l(2H)-yl)-4'-methyl-[l,4'-bipiperidine] - 1 '-carboxylate;isopropyl 4-(6-ethyl-5-methyl-2-oxotetrahydropyrimidin-l(2H)-yl)-4'-methyl-[L4'-bipiperidine]-l'-carboxylate;isopropyl 4-(5,6-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - 1 '-carboxylate;isopropyl 4'-methyl-4-(4-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine] - l'-carboxylate;isopropyl 4'-methyl-4-(2-oxo-6-(trifluoromethyl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine] - l'-carboxylate;isopropyl 4-(4,6-difluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - l'-carboxy late;isopropyl 4-(5,7-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - l'-carboxy late;Attorney Docket No.: 206602-0001-00WOisopropyl 4'-methyl-4-(7-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine] - l'-carboxy late;isopropyl 4-(7-fluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - l'-carboxylate;isopropyl 4-(6,7-dimethyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l 4'-bipiperidine] - 1 '-carboxylate;methyl 4'-methyl-4-(2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine]- l'-carboxylate;isopropyl 4'-methyl-4-((3aR aR)-2-oxohexahydropyrano[3,4-d]imidazol-l(4H)-yl)-[l,4'-bipiperidine] - 1 '-carboxylate;isopropyl 4'-methyl-4-((3aR,7aS)-2-oxohexahydropyrano[3,4-d]imidazol-l(4H)-yl)-[l,4'-bipiperidine] - 1 '-carboxylate;isopropyl 4'-methyl-4-((3aS,8aS)-2-oxooctahydrocyclohepta[d]imidazol-l(2H)-yl)-[l,4'-bipiperidine] - l'-carboxylate;(3aS,7aS)-l-(l-(4-(isopropoxymethyl)cyclohexyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;isopropyl 4'-methyl-4-((4S,5S)-2-oxo-4,5-diphenylimidazolidin-l-yl)-[l,4'-bipiperidine]-r-carboxylate;isopropyl 4'-methyl-4-((3aS,7aR)-2-oxohexahydropyrano[3,4-d]imidazol-3(2H)-yl)-[l,4'-bipiperidine] - l'-carboxy late;(3aS,7aS)-l-(l-(4-(ethoxymethyl)cyclohexyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;(3aS,7aS)-l-(l-(3-(isopropoxymethyl)cyclopentyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;(3aS,7aS)-l-(l-(3-(ethoxymethyl)cyclopentyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;isopropyl 4-(4-((3aS,7aS)-2-oxooctahydro-1H-benzo[d]imidazol-1-yl)phenyl)piperazine-1-carboxylate;ethyl 4-methyl-4-(4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)phenyl)piperidine-l-Attorney Docket No.: 206602-0001-00WOcarboxylate;isopropyl 4-methyl-4-(4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)phenyl)piperidine-l -carboxylate;isopropyl 4-(4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)phenyl)piperidine-l-carboxylate;isopropyl 3-(4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)phenyl)pyrrolidine-l-carboxylate;isopropyl 4'-methyl-4-((4aS,8aS)-3-oxooctahydro-4H-benzo[b][l,4]oxazin-4-yl)-[l,4'-bipiperidine] - 1 '-carboxylate;ethyl 4'-methyl-4-((4aS,8aS)-3-oxooctahydro-4H-benzo[b][1,4]oxazin-4-yl)-[l,4'-bipiperidine]-l'-carboxylate;(3aS,7aS)-l-(4-(4-(ethoxymethyl)piperidin-l-yl)cyclohexyl)octahydro-2H-benzo[d]imidazol-2-one;(3aS,7aS)-l-(4-(4-(isopropoxymethyl)piperidin-l-yl)cyclohexyl)octahydro-2H-benzo[d]imidazol-2-one;isopropyl 4-(4-((3aS,7aS)-2-oxooctahydro-lH-benzo[d]imidazol-l-yl)cyclohexyl)piperazine-l-carboxylate;isopropyl 4-(4-((4aS,8aS)-3-oxooctahydro-4H-benzo[b][l,4]oxazin-4-yl)cyclohexyl)piperazine-1 -carboxylate;(4aS,8aS)-4-(4-(4-(ethoxymethyl)piperidin- 1 -yl)cy clohexyl)hexahydro-2H-benzo[b] [ 1,4] oxazin-3(4H)-one;(4aS,8aS)-4-(4-(4-(isopropoxymethyl)piperidin-l-yl)cyclohexyl)hexahydro-2H-benzo[b][l,4]oxazin-3(4H)-one;(3aS,7aS)-l-(l-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one; (3aS,7aS)-l-(l-(4-methyltetrahydro-2H-pyran-4-yl)piperidin-4-yl)octahydro-2H-benzo [d] imidazol-2-one;(3aS,7aS)-l-(l-(4-(hydroxymethyl)cyclohexyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;(3aS,7aS)-l-(l-(3-(hydroxymethyl)cyclopentyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-Attorney Docket No.: 206602-0001-00WO2-one;(3aS,7aS)-l-(l-(3-(methoxymethyl)cyclopentyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;(3aS,7aS)-l-(l-(4-((cyclobutylmethoxy)methyl)cyclohexyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;(3aS,7aS)-l-(l-(4-((cyclopropylmethoxy)methyl)cyclohexyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;(3aS,7aS)-l-(l-(4-(methoxymethyl)cyclohexyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;(3aS,7aS)-l-(l-(4-((2-fluoroethoxy)methyl)cyclohexyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;(3aS,7aS)-l-(l-(4-((2,2,2-trifluoroethoxy)methyl)cyclohexyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;(3aS,7aS)-l-(l-(4-((2,2-difluoroethoxy)methyl)cyclohexyl)piperidin-4-yl)octahydro-2H-benzo[d]imidazol-2-one;isopropyl 4-(5,6-difluoro-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-4'-methyl-[l,4'-bipiperidine] - l'-carboxylate;isopropyl 4'-methyl-4-(5-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-[l,4'-bipiperidine] - l'-carboxylate;and any combination thereof.

7. A pharmaceutical composition comprising an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

8. A method of treating or lessening the severity of a disease mediated by the muscarinic Ml or M4 receptor, wherein the disease is a cognitive disorder, a psychotic disorder, or cute, chronic, neuropathic, or inflammatory pain, comprising administering to the subject an effective amount of at least one compound of claim 1 or a composition thereof.

9. A method of treating or lessening the severity of a disease mediated by the muscarinic Ml or M4 receptor suffering from said disease in a subject, wherein the disease is selected from the group consisting of Alzheimer’s Disease, dementia with Lewy bodies, other cognitiveAttorney Docket No.: 206602-0001-00WOdisorders, acute, chronic, neuropathic, and inflammatory pain, addiction and movement disorders, comprising administering to the subject the compound according to claim 1 that exhibits selectivity for the Ml receptor and / or the Ml and M4 receptor relative to the M2 and M3 receptor subtypes.

10. A method of treating or lessening the severity of a disease mediated by the muscarinic Ml or M4 receptor, comprising administering the compound of claim 1 and a muscarinic antagonist to alleviate the side effects associated with use of the muscarinic activators.

11. A method of treating or lessening the severity of a disease mediated by the muscarinic Ml or M4 receptor, comprising administering the compound of claim 1 and a muscarinic antagonist wherein the compound of claim 1 and the muscarinic antagonist are formulated to be contained in the same dosage form or dosage.

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