Compounds, compositions, and methods for the treatment of diseases

Abstract

Provided herein are compounds, or pharmaceutically acceptable salts thereof having the structure selected from the group consisting of Formula (I), Formula (II), and Formula (III). The disclosure also provides pharmaceutical compositions comprising the disclosed compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or excipient and further provides methods of treating, inhibiting, and / or diseases (e.g., cancer or a CNS disease).

Description

COMPOUNDS, COMPOSITIONS, AND METHODS FOR THE TREATMENT OF DISEASESSTATEMENT OF U.S. GOVERNMENT SUPPORT

[0001] This invention was made with government support under Grant No R01 NS119266 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0002] Dopamine D4 receptor and Sigma-1 receptor antagonists represent important therapeutic targets. Current treatments for conditions like Parkinson's disease, dyskinesia, addiction, cancer, schizophrenia, pain, ADHD, bipolar disorder, and eating disorders have significant limitations. For example, while levodopa remains the most potent drug for controlling Parkinson's disease symptoms, it is associated with complications such as dyskinesia and motor fluctuations. Similarly, existing treatments for conditions like schizophrenia and bipolar disorder often have suboptimal efficacy and problematic side effects.

[0003] Accordingly, there remains a need for improved therapeutic compounds that can effectively treat these conditions while minimizing adverse effects.SUMMARY

[0004] There remains a need for compounds that are inhibitors of D4 dopamine receptors and / or sigma-1 receptors to treat and prevent diseases and disorders modulated by inhibiting these receptors.

[0005] The disclosure provides compounds or pharmaceutically acceptable salt thereof, having the structure selected from the group of Formula (I), Formula (II), and Formula (III):wherein each X and X’ is independently O, CH2, SO2, NH, NCi-Cealkyl, or CF2;

[0006] each Ring A and Ring B is independently selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, C3-Ci2cycloalkyl, and3 to 12-membered cycloheteroalkyl containing 1-3 ring heteroatoms independently selected from N, O, and S;

[0007] R1is H or Ci-C6alkyl;

[0008] each b is independently -CH2-, C=O, -CH2-CO-NH-, or -NH-CO-CH2-;

[0009] n and p are independently 0, 1 , 2, or 3; and

[0010] m is 1 , 2, or 3.

[0011] The disclosure also provides pharmaceutical compositions comprising the disclosed compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier or excipient. The disclosure further provides methods of treating, inhibiting, and / or diseases in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the disclosed compounds or pharmaceutically acceptable salts thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 shows mean plasma and brain concentrations vs. time profile for compound 21 in CD1 mice after 10 mg / kg intraperitoneal (IP) injection.

[0013] Figure 2 shows plasma concentration vs. time profile for compound 28 in Sprague Dawley rats after 0.25 mg / kg intravenous (IV) injection.

[0014] Figure 3 shows plasma concentration vs. time profile for compound 19 in Sprague Dawley rats after 0.25 mg / kg intravenous (IV) injection.

[0015] Figure 4 shows plasma concentration vs. time profile for compound 40 in Sprague Dawley rats after 0.25 mg / kg intravenous (IV) injection.DETAILED DESCRIPTION

[0016] The present disclosure provides compounds useful for treating, inhibiting, and / or preventing diseases associated with the overexpression of D4 dopamine receptors and / or sigma-1 receptors.

[0017] The compounds and pharmaceutical salts disclosed herein provide several advantages over conventional compounds and treatment regimens. The disclosed compounds are suitable for the inhibition of the D4 dopamine receptor and / or the sigma-1 receptor systems. Without wishing to be bound to any particular theory, it is believed that inhibiting D4 dopamine receptors and / or sigma-1 represents a promising, novel therapeutic strategy to treat or prevent diseases and disorders such as, for example, cancer and CNS disorders and diseases.

[0018] As further described herein, the disclosure provides compounds of Formula (I), Formula (II), and Formula (III), pharmaceutical compositions comprising the disclosed compounds, and methods of using the disclosed compounds and compositions.Definitions

[0019] The term “alkyl” as used herein refers to straight chained and branched saturated hydrocarbon groups containing one to thirty carbon atoms, for example, one to twenty carbon atoms, one to ten carbon atoms, one to six carbon atoms, or one to three carbon atoms. The term Cnmeans the alkyl group has “n” carbon atoms. For example, C4alkyl refers to an alkyl group that has 4 carbon atoms. Ci-Csalkyl refers to an alkyl group having a number of carbon atoms encompassing the entire range (e.g., 1 to 8 carbon atoms), as well as all subgroups (e.g., 1 -8, 2-8, 3-8, 4-8, 5-8, 6-8, 7-8, 1 , 2, 3, 4, 5, 6, 7, and 8 carbon atoms). Nonlimiting examples of alkyl groups include, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl (2- methylpropyl), t-butyl (1 ,1 -dimethylethyl), 3,3-dimethylpentyl, and 2-ethylhexyl. Unless otherwise indicated, an alkyl group can be an unsubstituted alkyl group or a substituted alkyl group.

[0020] The term “alkylene” as used herein refers to an alkyl group having a substituent. For example, the term “alkylenehalo” refers to an alkyl group substituted with a halo group. For example, an alkylene group can be -CH2CH2- or -CH2-. The term Cnmeans the alkylene group has “n” carbon atoms. For example, Ci- alkylene refers to an alkylene group having a number of carbon atoms encompassing the entire range, as well as all subgroups, as previously described for “alkyl” groups. Unless otherwise indicated, an alkylene group can be an unsubstituted alkylene group or a substituted alkylene group.

[0021] The term “cycloalkyl” as used herein refers to an aliphatic cyclic hydrocarbon group containing three to eleven carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, or 1 1 carbon atoms). The term Cnmeans the cycloalkyl group has “n” carbon atoms. For example, Cscycloalkyl refers to a cycloalkyl group that has 5 carbon atoms in the ring. Ce-Cucycloalkyl refers to cycloalkyl groups having a number of carbon atoms encompassing the entire range (e.g., 6 to 1 1 carbon atoms), as well as all subgroups (e.g., 6-7, 6-8, 7-8, 6-9, 6, 7, 8, 9, 10, and 1 1 carbon atoms). Nonlimiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise indicated, a cycloalkyl group can be an unsubstituted cycloalkyl group or a substituted cycloalkyl group. The cycloalkyl groups described herein can be isolated or fused to another cycloalkyl group. When a cycloalkyl group is fused to another cycloalkyl group, then each of the cycloalkyl groups can contain three to twelve carbon atoms unless specified otherwise. Unless otherwise indicated, a cycloalkyl group can be unsubstituted or substituted.

[0022] The terms “heterocycloalkyl” and “cycloheteroalkyl” are used interchangeably herein, and are used similarly as cycloalkyl, except the ring contains one to three heteroatoms independently selected from oxygen, nitrogen, and sulfur. In particular, the term “heterocycloalkyl” refers to a ring containing a total of three to twelve atoms (e.g., three to seven, or five to twelve), of which 1 , 2, 3 or three of those atoms are heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, and the remaining atoms in the ring are carbon atoms. Nonlimiting examples of heterocycloalkyl groups include piperdine, pyrazolidine, tetrahydrofuran, tetrahydropyran, dihydrofuran, morpholine, and the like. The heterocycloalkyl groups described herein can be isolated or fused (e.g., fused or spiro) to another heterocycloalkyl group. Heterocycloalkyl groups can be saturated or partially unsaturated ring systems. Unless otherwise indicated, a heterocycloalkyl group can be unsubstituted or substituted.

[0023] The term “aryl” as used herein refers to a monocyclic aromatic hydrocarbon group, such as phenyl or a bicyclic aromatic hydrocarbon group, such as naphthyl. Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more groups. Aryl groups can be isolated (e.g., phenyl) or fused to another aryl group (e.g., naphthyl, anthracenyl), a cycloalkyl group (e.g. tetraydronaphthyl), a heterocycloalkyl group, and / or a heteroaryl group. Exemplary aryl groups include, but are not limited to, phenyl, chlorophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, 2,4-methoxychlorophenyl, and the like. Throughout, the abbreviation “Ph” refers to phenyl and “Bn” refers to benzyl (i.e., CH2phenyl).

[0024] The term “heteroaryl” as used herein refers to a monocyclic or bicyclic aromatic ring having 5 to 14 total ring atoms, and containing one to three heteroatoms selected from nitrogen, oxygen, and sulfur atom in the aromatic ring. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, pyridyl, pyrrolyl, oxazolyl, triazinyl, triazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyrimidinyl, thiazolyl, and thiadiazolyl.

[0025] The term “oxo” as used herein refers to a =0 group.

[0026] The term “halo” as used herein refers to a F (fluoro), Cl (chloro), Br (bromo), or I (iodo) group.

[0027] As used herein, the term “substituted” when used to modify a chemical functional group, refers to the replacement of at least one hydrogen radical on the functional group with a substituent. Substituents can include, but are not limited to, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, oxy, alkoxy, heteroalkoxy, ester, thioester, carboxy, cyano, nitro, amino, amido, acetamide, and halo (e.g., fluoro, chloro,bromo, or iodo). When a chemical functional group includes more than one substituent, the substituents can be bound to the same carbon atom or to two or more different carbon atoms.

[0028] The phrase “optionally substituted” as used herein means unsubstituted (e.g., substituted with a H) or substituted. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. It is understood that substitution at a given atom is limited by valency. The use of a substituent (radical) prefix name such as alkyl without the modifier “optionally substituted” or “substituted” is understood to mean that the particular substituent is unsubstituted.

[0029] The compounds disclosed herein include isotopically-labeled compounds wherein one or more atoms of the compounds disclosed herein are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature, examples of which include isotopes of hydrogen, such as2H and3H, isotopes of carbon, such as11C and13C, and isotopes of fluorine, such as18F. Unless otherwise specifically indicated, an “H” substituent refers to any isotope of hydrogen,1H,2H, or3H. In some cases, one or more hydrogen atoms of the compounds disclosed herein are specifically2H (“D” or deuterium). Isotopically-labeled compounds as disclosed herein can be prepared by techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and schemes using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed.

[0030] Compounds of the disclosure can exist in various isomeric forms, including configurational, geometric, and conformational isomers, including, for example, cis- or transconformations. The compounds may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term “isomer” is intended to encompass all isomeric forms of a compound of this disclosure, including tautomeric forms of the compound. All forms are included in the disclosure.

[0031] As used herein, the term “therapeutically effective amount” means an amount of a compound or combination of therapeutically active compounds (e.g., more than one of the compounds disclosed herein) that ameliorates, attenuates or eliminates one or more symptoms of a particular disease or condition (e.g., cancer), or prevents or delays the onset of one of more symptoms of a particular disease or condition.

[0032] As used herein, the terms “patient” and “subject” may be used interchangeably and mean animals, such as dogs, cats, cows, horses, and sheep (e.g., non-human animals) and humans. Particular patients or subjects are mammals (e.g., humans). The terms patient and subject include males and females.

[0033] The term “pharmaceutically acceptable” as used herein means that the referenced substance, such as a compound of the present disclosure, or a formulation containing thecompound, or a particular excipient, are safe and suitable for administration to a patient or subject. The term “pharmaceutically acceptable excipient” refers to a medium that does not interfere with the effectiveness of the biological activity of the active ingredient(s) and is not toxic to the host to which it is administered.

[0034] The terms “treating”, “treat” or “treatment” and the like as used herein include preventative (e.g., prophylactic) and palliative treatment.

[0035] As used herein, the term “excipient” means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API).

[0036] The compounds disclosed herein can be in the form of a pharmaceutically acceptable salt. As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1 -19, which is incorporated herein by reference.

[0037] Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutamate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts of compounds containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such salts include, but are not limited to, alkali metal, alkaline earth metal, aluminum salts, ammonium, N+(Ci-4alkyl)4salts, and salts of organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline,dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyl)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.Compounds of Formula (I), Formula (II), and Formula (III)

[0038] The disclosure provides compounds, or pharmaceutically acceptable salts thereof, having the structure of Formula (I), Formula (II), and Formula (III), as described herein:

[0039] Compounds of Formula (I), Formula (II), and Formula (III) disclosed herein comprise a nitrogen-containing bicyclic heterocycle moiety (e.g., a nitrogen-containing bicyclic, spiro, or bridged heterocyclic moiety), a linker moiety b, a Ring A moiety, and a Ring B moiety, as described herein.

[0040] In some embodiments, Ring A, Ring B, and b of compounds of Formula (II) and (III) are as described for compounds of Formula (I).Compounds of Formula (I)

[0041] In some embodiments, the disclosure provides compounds of Formula (I),wherein X is O, CH2, SO2, NH, NCi-Cealkyl, or CF2; Ring A is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, C3-C12 cycloalkyl, and 3 to 12-membered cycloheteroalkyl containing 1 -3 ring heteroatoms independently selected from N, O, and S; Ring B is selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, C3-Ci2cycloalkyl, and 3 to 12-membered cycloheteroalkyl containing 1 -3 ring heteroatoms independently selected from N, O, and S; b is -CH2-, C=O, -CH2-CO-NH-, or -NH-CO-CH2-; and n and p are independently 0, 1 , 2, or 3.Ring comprising “X”

[0042] Compounds of Formula (I) comprise a substituted pyrrolidine moiety fused to a cycloalkyl or heterocycloalkyl moiety. The “X” moiety of Formula (I) is selected from the group consisting of O, CH2, SO2, NH, NCi-Cealkyl, and CF2. In some embodiments, X is CH2 or O. In some embodiments, X is CH2. In some embodiments, X is O.

[0043] The size of the ring comprising X has a suitable number of methylene units as defined by “n” and “p”, wherein each n and p is independently selected from 0, 1 , 2, or 3. In some embodiments, the ring comprising the X moiety is a 3 to 6-membered ring. In some embodiments, the ring comprising the X moiety is a 3-membered ring. In some embodiments, the ring comprising the X moiety is a 5-membered ring. In some embodiments, the ring comprising the X moiety is a 6-membered ring.embodiments, Formula (I) comprises. In some embodiments, Formula (I) comprisesIn some embodiments, Formula (I) comprises * &** . In some embodiments,Formula (I) comprises.Linker “b”

[0045] Compounds of Formula (I) comprise a linker moiety “b” which links the fused bicyclic structure with the Ring A moiety. In some embodiments, b is -CH2-, C=O, -CH2-CO-NH-, or .NH-CO-CH2-. In some embodiments, b is -CH2-. In some embodiments, b is C=O. In some embodiments, b is -CH2-CO-NH-. In some embodiments, b is -NH-CO-CH2-.Ring A and Ring B

[0046] Compounds of Formula (I) comprise a Ring A moiety and a Ring B moiety, wherein Ring A and Ring B are each independently selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, C3-C12 cycloalkyl, and 3 to 12- membered cycloheteroalkyl containing 1 -3 ring heteroatoms independently selected from N, O, and S.

[0047] In some embodiments, Ring A is selected from the group consisting ofOCH3; s is 0, 1 , or 2; R2and R3are each independently H or Cvsalkyl; and R4is halo.

[0048] In some embodiments, Ring A is selected from the group consisting of

[0049] In some embodiments, the “b-Ring A” moiety is selected from the group consisting of

[0050] In some embodiments, Ring B is selected from the group consisting ofCH3; Z2is H or halo; R5is H or CH3; and t is 0, 1 , or 2.

[0051] In some embodiments, Ring B is selected from the group consisting ofCompounds of Formula (II)

[0052] In some embodiments, the disclosure provides compounds of Formula (II)wherein X’ is O, CH2, SO2, NH, NCi-Cealkyl, or CF2.Ring comprising “ X’ ”

[0053] The size of the ring comprising X’ comprises a suitable number of methylene units as defined by “m”, wherein m is 1 , 2, or 3. In some embodiments, the ring comprising the X’ moiety is a 4 to 6-membered ring. In some embodiments, the ring comprising the X’ moiety is a 4-membered ring. In some embodiments, the ring comprising the X’ moiety is a 5-membered ring. In some embodiments, the ring comprising the X’ moiety is a 6-membered ring.

[0055] In some embodiments, Formula (II) comprises. In some embodiments,Formula (II) comprises. In some embodiments, Formula (II) comprisesIn some embodiments, Formula (II) comprisesCompounds of Formula (III)

[0056] In some embodiments, the disclosure provides compounds of Formula (II),

[0057] In some embodiments, R1is H. In some embodiments, R1is Ci-Cealkyl. In some embodiments, R1is methyl. In some embodiments, R1is ethyl.

[0058] In some embodiments, the disclosure provides a compound selected from the group consisting of the compounds listed in Table A.Table A:

[0059] In some embodiments, the disclosure provides a compound selected from the groupPharmaceutical formulations, dosing, and routes of administration

[0060] Further provided are pharmaceutical formulations comprising a compound as described herein (e.g., compounds of Formula (I) Formula (II), Formula (II), the compounds of Table A, or pharmaceutically acceptable salts of the compounds) and a pharmaceutically acceptable excipient.

[0061] The compounds described herein can be administered to a subject in a therapeutically effective amount (e.g., in an amount sufficient to prevent or relieve the symptoms of a disorder capable of being modulated by inhibiting dopamine D4 receptors and / or sigma-1 receptors). The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds can be administered all at once, multiple times, or delivered substantially uniformly over a period of time. It is also noted that the dose of the compound can be varied over time.

[0062] A particular administration regimen for a particular subject will depend, in part, upon the compound, the amount of compound administered, the route of administration, and the cause and extent of any side effects. The amount of compound administered to a subject (e.g., a mammal, such as a human) in accordance with the disclosure should be sufficient to effect the desired response over a reasonable time frame. Dosage typically depends upon the route, timing, and frequency of administration. Accordingly, the clinician titers the dosage and modifies the route of administration to obtain the optimal therapeutic effect, and conventional rangefinding techniques are known to those of ordinary skill in the art.

[0063] Purely by way of illustration, the method comprises administering, e.g., from about 0.1 mg / kg up to about 100 mg / kg of compound or more, depending on the factors mentionedabove. In other embodiments, the dosage ranges from 1 mg / kg up to about 100 mg / kg; or 5 mg / kg up to about 100 mg / kg; or 10 mg / kg up to about 100 mg / kg. Some conditions require prolonged treatment, which may or may not entail administering lower doses of compound over multiple administrations. If desired, a dose of the compound is administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. The treatment period will depend on the particular condition and type of pain, and may last one day to several months.

[0064] Suitable methods of administering a physiologically-acceptable composition, such as a pharmaceutical composition comprising the compounds disclosed herein (e.g., compounds of compounds of Formula (I), Formula (II), Formula (III), the compounds of Table A, or pharmaceutically acceptable salts of the compounds), are well known in the art. Although more than one route can be used to administer a compound, a particular route can provide a more immediate and more effective reaction than another route. Depending on the circumstances, a pharmaceutical composition comprising the compound is applied or instilled into body cavities, absorbed through the skin or mucous membranes, ingested, inhaled, and / or introduced into circulation. For example, in certain circumstances, it will be desirable to deliver a pharmaceutical composition comprising the agent orally, through injection by intravenous, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, intralesional, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, urethral, vaginal, or rectal means, by sustained release systems, or by implantation devices. If desired, the compound is administered regionally via intrathecal administration, intracerebral (intra- parenchymal) administration, intracerebroventricular administration, or intraarterial or intravenous administration feeding the region of interest. Alternatively, the composition is administered locally via implantation of a membrane, sponge, or another appropriate material onto which the desired compound has been absorbed or encapsulated. Where an implantation device is used, the device is, in one aspect, implanted into any suitable tissue or organ, and delivery of the desired compound is, for example, via diffusion, timed-release bolus, or continuous administration.

[0065] To facilitate administration, the compound is, in various aspects, formulated into a physiologically-acceptable composition comprising a carrier (e.g., vehicle, adjuvant, or diluent). The particular carrier employed is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. Physiologically- acceptable carriers are well known in the art. Illustrative pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (for example, see U.S. Patent No. 5,466,468). Injectable formulations are further described in, e.g.,Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia. Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986)). A pharmaceutical composition comprising the compound is, in one aspect, placed within containers, along with packaging material that provides instructions regarding the use of such pharmaceutical compositions. Generally, such instructions include a tangible expression describing the reagent concentration, as well as, in certain embodiments, relative amounts of excipient ingredients or diluents (e.g., water, saline or PBS) that may be necessary to reconstitute the pharmaceutical composition.

[0066] Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0067] These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Microorganism contamination can be prevented by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0068] Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution retarders, as for example, paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, and tablets, the dosage forms may also comprise buffering agents. Solid compositions of a similartype may also be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols, and the like.

[0069] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. The solid dosage forms may also contain opacifying agents. Further, the solid dosage forms may be embedding compositions, such that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compound can also be in micro-encapsulated form, optionally with one or more excipients.

[0070] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[0071] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compound, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

[0072] Compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds of the disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary room temperature, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity and release the active component.

[0073] The compositions used in the methods of the invention may be formulated in micelles or liposomes. Such formulations include sterically stabilized micelles or liposomes and sterically stabilized mixed micelles or liposomes. Such formulations can facilitate intracellular delivery, since lipid bilayers of liposomes and micelles are known to fuse with the plasma membrane of cells and deliver entrapped contents into the intracellular compartment.

[0074] Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms such as injectable solutions, drug releasecapsules and the like. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.

[0075] The frequency of dosing will depend on the pharmacokinetic parameters of the agents and the routes of administration. The optimal pharmaceutical formulation will be determined by one of skill in the art depending on the route of administration and the desired dosage. See, for example, Remington’s Pharmaceutical Sciences, 18th Ed. (1990) Mack Publishing Co., Easton, PA, pages 1435-1712, incorporated herein by reference. Such formulations may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the administered agents. Depending on the route of administration, a suitable dose may be calculated according to body weight, body surface areas or organ size. Further refinement of the calculations necessary to determine the appropriate treatment dose is routinely made by those of ordinary skill in the art without undue experimentation, especially in light of the dosage information and assays disclosed herein, as well as the pharmacokinetic data observed in animals or human clinical trials.

[0076] The precise dosage to be employed depends upon several factors including the host, whether in veterinary medicine or human medicine, the nature and severity of the condition, e.g., disease or disorder, being treated, the mode of administration and the particular active substance employed. The compounds may be administered by any conventional route, in particular enterally, and, in one aspect, orally in the form of tablets or capsules. Administered compounds can be in the free form or pharmaceutically acceptable salt form as appropriate, for use as a pharmaceutical, particularly for use in the prophylactic or curative treatment of a disease of interest. These measures will slow the rate of progress of the disease state and assist the body in reversing the process direction in a natural manner.

[0077] It will be appreciated that the pharmaceutical compositions and treatment methods of the invention are useful in fields of human medicine and veterinary medicine. Thus, the subject to be treated is in one aspect a mammal. In another aspect, the mammal is a human.

[0078] In jurisdictions that forbid the patenting of methods that are practiced on the human body, the meaning of “administering” of a composition to a human subject shall be restricted to prescribing a controlled substance that a human subject will self-administer by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation that is consistent with laws or regulations defining patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods that are practiced on the human body, the “administering” of compositions includes both methods practiced on the human body and also the foregoing activities.Methods of use

[0079] The compounds disclosed herein are particularly advantageous for the treatment of diseases or disorders caused by overexpression or activity of D4 dopamine receptors and / or sigmai-1 receptors. The incidence and / or intensity of diseases or disorders associated with aberrant overexpression or activity of D4 dopamine receptors and / or sigma- 1 receptors can be reduced. The disclosed compounds can be used for cancer prevention and treatment, as well as in CNS diseases.

[0080] The disclosure provides methods of using the disclosed compounds. In some cases, the disclosure provides a method of inhibiting a dopamine D4 receptor comprising contacting the receptor with the compound or salt of any of the disclosed compounds in an amount effective to inhibit the receptor. In some embodiments, the disclosure provides a method of inhibiting a sigma-1 receptor comprising contacting the receptor with the compound or salt of any of the disclosed compounds in an amount effective to inhibit the receptor. In some instances, compounds of the disclosure inhibit both dopamine D4 receptors and sigma-1 receptors.

[0081] In some embodiments, the disclosure provides methods of treating or preventing a disease or disorder capable of being modulated by inhibiting a dopamine D4 receptor or a sigma-1 receptor comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising the disclosed compounds or salts.

[0082] In some embodiments, the disorder is dyskinesia. In some embodiments, the dyskinesia is L-DOPA-induced dyskinesia (LID).

[0083] In some embodiments, the disorder is pain.

[0084] In some embodiments, the disease is cancer.

[0085] In some embodiments, the disease is a CNS disease.

[0086] In some embodiments, the disease or disorder is selected from the group consisting of neuropsychiatric disorders, neurodegenerative disorders, Parkinson’s disease, Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD), bipolar disorder, glioblastoma, and Dopamine D4 Receptor Antagonism.

[0087] As described herein, any of the disclosed methods can comprise administering (or contacting) one or more the compounds disclosed herein. In some cases, the disclosed methods comprise administering one or more of the compounds disclosed herein in combination with one or more additional active agent (e.g., additional anti-cancer drug or CNS agent).

[0088] Uses of the compounds disclosed herein in the preparation of a medicament for treating diseases or disorders related to inhibiting dopamine D4 and / or sigma-1 receptors also are provided herein.EMBODIMENTS1 . A compound, or pharmaceutically acceptable salt thereof, having the structure selected from the group consisting of Formula (I), Formula (II), and Formula (III):whereinX and X’ are independently O, CH2, SO2, NH, NCi-Cealkyl, or CF2; each Ring A and Ring B is independently selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, C3-Ci2cycloalkyl, and 3 to 12-membered cycloheteroalkyl containing 1 -3 ring heteroatoms independently selected from N, O, and S;R1is H or Ci-Cealkyl; each b is independently -CH2-, C=O, -CH2-CO-NH-, or -NH-CO-CH2-; n and p are independently 0, 1 , 2, or 3; and m is 1 , 2, or 3.3. The compound of embodiment 2, whereinof Formula (I) is5. The compound of any one of embodiments 1 -4, wherein R1of Formula (III) is H,CH3, or -CH2CH3.6. The compound of any one of embodiment 1 -5, wherein Ring A is selected fromwhereinY is H, halo, or -OCH3; s is 0, 1 , or 2;R2and R3are each independently H or Ci-3alkyl; andR4is halo.7. The compound of embodiment 6, wherein Ring A is selected from the group consisting of:9. The compound of any one of embodiments 1 -8, wherein the “b-Ring A” moiety is10. The compound of any one of embodiments 1 -9, wherein Ring B is selected fromwhereinZ1is H, halo, or CH3;Z2is H or halo;R5is H or CH3; and t is 0, 1 , or 2.1 1 . The compound of embodiment 10, wherein Ring B is selected from the group12. The compound of any one of embodiments 1 -11 , wherein the compound is selected from the compounds listed in Table A:13. The compound of embodiment 12, wherein the compound is selected from the14. A pharmaceutical composition comprising the compound or salt of any one of embodiments 1-13 and a pharmaceutically acceptable carrier or excipient.15. A method of inhibiting a receptor selected from a dopamine D4 receptor, sigma-1 receptor, and a combination thereof comprising contacting the receptor with the compound or salt of any one of embodiments 1-13 in an amount effective to inhibit the receptor.16. A method of treating or preventing a disease or disorder capable of being modulated by inhibiting a dopamine D4 receptor or a sigma-1 receptor comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising the compound or salt of any one of embodiments 1-13.17. The method of embodiment 16, wherein the disorder is dyskinesia.18. The method of embodiment 17, wherein the dyskinesia is L-DOPA-induced dyskinesia (LID).19. The method of embodiment 16, wherein the disorder is pain.20. The method of embodiment 16, wherein the disease is cancer.21 . The method of embodiment 16, wherein the disease is a CNS disease.22. The method of embodiment 16, wherein the disease or disorder is selected from the group consisting of neuropsychiatric disorders, neurodegenerative disorders, Parkinson’s disease, Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD), bipolar disorder, glioblastoma, and Dopamine D4 Receptor Antagonism.23. A pharmaceutical composition comprising the compound of any one of embodiment s 1-13 and a pharmaceutically acceptable carrier or excipient for use in for use treating or preventing a disease or disorder capable of being modulated by inhibiting a dopamine D4 receptor or a sigma- 1 receptor.

[0089] The foregoing summary is not intended to define every aspect of the disclosure, and additional aspects are described in other sections of the disclosure. The entire document is intended to be related as a unified disclosure, and it should be understood that all combinations of features described herein are contemplated, even if the combination of features are not found together in the same sentence, or paragraph, or section of this document.

[0090] In addition to the foregoing, the disclosure includes, as an additional aspect, all embodiments of the disclosure narrower in scope in any way than the variations specifically mentioned above. With respect to aspects of the disclosure described or claimed with “a” or “an,” these terms mean “one or more” unless context unambiguously requires a more restricted meaning. With respect to elements described as one or more within a set, all combinations within the set are contemplated as combination inventions. If aspects of the disclosure are described as “comprising” a feature, embodiments also are contemplated “consisting of” or “consisting essentially of” the feature.

[0091] Aspects of the disclosure described as methods of treatment should also be understood to include first or subsequent “medical use” aspects of the disclosure or “Swiss use” of compositions for the manufacture of a medicament for treatment of the same disease or condition.

[0092] Multiple embodiments are contemplated for combinations described herein. For example, some aspects of the disclosure that are described as a method of treatment (or medical use) combining two or more compounds or agents, whether administered separately (sequentially or simultaneously) or in combination (co-formulated or mixed). For each aspect described in this manner, the disclosure further includes a composition comprising the two or more compounds or agents co-formulated or in admixture with each other; and the disclosure further includes a kit or unit dose containing the two or more compounds / agents packaged together, but not in admixture. Optionally, such compositions, kits or doses further include one or more carriers in admixture with one or both agents or co-packaged for formulation prior to administration to a subject. The reverse also is true: some aspects of the disclosure are described herein as compositions useful for therapy and containing two or more therapeutic agents. Equivalent methods and uses are specifically contemplated.

[0093] Although the applicant(s) invented the full scope of the claims appended hereto, the claims appended hereto are not intended to encompass within their scope the prior art.Therefore, in the event that statutory or judicially recognized prior art within the scope of a claim is brought to the attention of the applicants by a Patent Office or other entity or individual, the applicant(s) reserve the right to exercise amendment rights under applicable patent laws to redefine the subject matter of such a claim to specifically exclude such prior art or obvious variations of statutory prior art from the scope of such a claim. Variations of the disclosure defined by such amended claims also are intended as aspects of the invention. Additional features and variations of the invention will be apparent to those skilled in the art from the entirety of this application, and all such features are intended as aspects of the disclosure.

[0094] The disclosure herein will be understood more readily by reference to the following examples, below.EXAMPLES

[0095] The following examples are provided for illustration and are not intended to limit the scope of the disclosure.General Experimental Procedures:

[0096] General Chemistry Procedures. All reactions were carried out in oven-dried glassware under positive nitrogen pressure unless otherwise noted. Reaction progress was monitored by thin-layer chromatography carried out on silica gel plates (2.5 cm x 7.5 cm, 200 pm thick, 60 F254) and visualized by using UV (254 nm) or by dragendorff solution as indicator. Flash column chromatography was performed with silica gel (40-63 pm, 60 A) using the mobile phase indicated. Commercial grade solvents and reagents were purchased from Fisher Scientific (Houston, TX) or Sigma-Aldrich (Milwaukee, Wl) and were used without further purification. Anhydrous solvents were purchased from Across Organics and stored under an atmosphere of dry nitrogen over molecular sieves.

[0097] 1H and13C NMR spectra were recorded in the indicated solvent on a Broker 400 MHz Advance III HD spectrometer at 400 and 100 MHz for1H and13C, respectively. Multiplicities are indicated by s (single), d (doublet), t (triplet), m (multiplet), and br (broad). Chemical shifts (5) are reported in parts per million (ppm) and coupling constants (J), in hertz.

[0098] High-resolution mass spectra (HRMS) were recorded with an Agilent 6230 LC / TOF spectrometer using an ESI source coupled to an Agilent Infinity 1260 system running in reverse phase with a ZORBAX RRHT Extend-C18 (80 A, 2.1 x 50 mm, 1 .8 pm) column using solvent A (water with 0.1 % Formic acid), solvent B (acetonitrile with 0.1 % Formic acid), and a flow rate of 0.6 mL / min starting a mixture of 95% A and 5% B. Solvent B is gradually increased to 95% at 5 min, held at 95% until 6 min, then gradually ramped back down to 5% at 8.0 min. The purity analysis of final compounds were determined >95% pure using a Waters ACQUITY ultraperformance liquid chromatography (UPLC) H-Class System with TUV (254 nm) detector and Empower 2 software (Milford, MA, USA) using an Agilent Eclipse plus C18 5p column (4.6 X150 mm). Chromatography was performed using solvent A (water with 0.1 % Trifluoroacetic acid), solvent B (methanol with 0.1 % Trifluoroacetic acid), and a flow rate of 1 .0 mL / min for 20 min. with an isocratic system (20:80, A:B).Synthesis of Compounds

[0099] The following illustrative procedures can be used to prepare compounds of the disclosure.

[0100] Compounds of Formula (I)

[0101] Compounds of Formula (I) were prepared using one or more of the following Generals Procedures depicted below with illustrative compounds of the disclosure.

[0102] General Procedure A.

[0103] (3-(3-Fluoro-4-methoxybenzyl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol (A). To a room temperature solution of (3-azabicyclo[3.1 ,0]hexan-1 -yl)methanol (205 mg; 1.37 mmol) in MeOH (8 mL) was added Na2COs (319 mg; 3.00 mmol) followed by 4-(bromomethyl)-2-fluoro-1 - methoxybenzene (360 mg; 1 .6 mmol) and the mixture was stirred at room temperature overnight. Next, the MeOH was evaporated and then dissolved in EtOAc and washed with water. The organic layer was dried and evaporated and then purified by Biotage to obtain KVA- B-29. Yield = 258 mg; 74%. LCMS: RT = 1.913 min, m / z [M + H]+, calc’d 252.1 for C14H19FNO2, found 252.0 .

[0104] 3-(3-f luoro-4-methoxybenzyl)-1 -(((6-f luoropyridin-2-yl)oxy)methyl)-3- azabicyclo[3.1.0]hexane (1). The starting material, KVA-B-29 (25.0 mg; 0.099 mmol) was dissolved in DMF (0.5 mL) and then NaH (2.85 mg; 0.1 19 mmol) was added portionwise and the reaction was stirred for 1 h. To this mixture was added 2-chloro-6-fluoropyridine (18.7 mL; 0.189 mmol) and the reaction was stirred for 12 h. The mixture was quenched with H2O and then EtOAc was added an then extracted with additional EtOAc. The organic layer was dried, evaporated and purified by Biotage to yield KVA-B-105. Yield = 12.0 mg, 19%. LCMS: RT = 2.78 min, m / z [M + H]+, calc’d 363.1 for C19H21CIFN2O2, found 363.1 .1H NMR (500 MHz, CDCI3) 5 7.65 (q, J= 8.0 Hz, 1 H), 7.07 (d, J = 12.4 Hz, 1 H), 7.00 (d, J = 7.9 Hz, 1 H), 6.90 (t, J = 8.4 Hz, 1 H), 6.61 (dd, J= 7.8, 1 .7 Hz, 1 H), 6.46 (dd, J= 7.7, 2.5 Hz, 1 H), 4.42 (d, J= 1 1 .4 Hz, 1 H), 4.26 (d, J= 1 1.3 Hz, 1 H), 3.89 (s, 3H), 3.58 (q, J= 13.3 Hz, 2H), 3.04 (dd, J= 55.1 , 8.7 Hz, 2H), 2.47 (s, 2H), 1.40 (d, J = 7.8 Hz, 1 H), 1.25 (s, 1 H), 0.63 (d, J= 8.0 Hz, 1 H).13C NMR (125MHz, CDCI3) 6 163.05, 161.14, 153.27, 151.32, 142.53, 142.47, 113.02, 107.22, 107.18, 99.96, 99.68, 70.17, 58.02, 56.70, 56.33, 54.58, 41.03, 26.65, 20.69, 12.59.

[0105] General Procedure B.

[0106] General Procedure C.

[0107] To ter -butyl 1 -(hydroxymethyl)-3-azabicyclo[3.1 .0]hexane-3-carboxylate (E, 1.0 equiv.) in DMF (10 mL) was slowly added sodium hydride (1 .5 equiv.) at 0eC and stirred for 1 h at room temperature. Then the 1 -(iodomethyl)-2-oxabicyclo[2.1.1 ]hexane (F, 1.0 equiv.) was added, and the reaction was stirred at 60eC for overnight. The reaction was quenched with distilled water (100 mL), extracted with ethyl acetate (30 mL x 3), combined organic phases washed with brine (20 mL), dried with sodium sulfate, concentrated in vacuo, and purified by normal phase chromatography (0-25% hexanes / ethyl acetate) to yield the desired compound.

[0108] General Procedure D.

[0109] To G (1.0 equiv.) in CH2CI2 (1 mL) was added TFA (1 mL) at room temperature and stirred for 15 min. The reaction was quenched with NaOH aqueous solution (1 M, 100 mL), extracted with ethyl acetate (30 mL x 3). Organic phases were combined, dried with sodium sulfate, and concentrated in vacuo. The crude product was dissolved in MeOH (5 mL). Then Na2COs (3.0 equiv.) and 4-(bromomethyl)-2-fluoro-1 -methoxybenzene (H, 1.1 equiv.) were added to the reaction mixture sequentially. The reaction was stirred at room temperature for overnight. The reaction was quenched with NaHCOs aqueous solution (sat., 100 mL), and extracted with ethyl acetate (30 mL x 3). Organic phases were combined, dried with sodium sulfate and concentrated in vacuo. The residue was purified by normal phase chromatography (0-100% hexanes / ethyl acetate) to yield the desired compound.

[0110] Example Compounds Prepared Using General Procedure B.

[0111] (3-(3-Fluoro-4-methoxybenzyl)-3-azabicyclo[3.1.0]hexan-1 -yl)methyl methanesulfonate (C). To a solution of KVA-B-29 (150 mg; 0.60 mmol) in CH2CI2 (6.0 mL) was added methanesulfonyl chloride (69.3 mL; 1.19 mmol) followed by Et3N (1.2 mL; 1.2 mmol) and the reaction was stirred for 2 h. The reaction mixture was carefully quenched with sat. NaHCOs and the compound was extracted into CH2CI2. The organic layer was evaporated and used without further purification (KVA-B-11 1 ).

[0112] 1 -((3,4-dif luorophenoxy)methyl)-3-(3-f luoro-4-methoxybenzyl)-3- azabicyclo[3.1.0]hexane (5). To KVA-B-111 (30.0 mg; 0.091 mmol) in DMF (1.0 mL) was added CS2CO3 (24.1 mg; 0.228 mmol) and 3,4-difluorophenol (23.7 mg; 0.182 mmol) and the mixture was stirred at room temperature for 6 h. Next, H2O and EtOAc was added and the aqueous layer was extracted with additional EtOAc. The organic layer was dried, evaporated and purified by Gilson prep-HPLC to yield KVA-B-113. Yield = 8.0 mg; 24%. LCMS: RT = 2.96 min, m / z [M + H]+, calc’d 364.1 for C20H21F3NO2, found 364.1.1H NMR (500 MHz, CDCI3) 5 7.16 - 7.03 (m, 2H), 7.03 - 6.94 (m, 1 H), 6.71 (ddd, J= 12.1 , 6.6, 3.0 Hz, 1 H), 6.58 (dtd, J= 9.4, 3.1 , 1.6 Hz, 1 H), 4.02 (d, J = 9.7 Hz, 1 H), 3.90 (s, 4H), 3.57 (dt, J = 27.9, 14.1 Hz, 2H), 3.04 (d, J = 49.8 Hz, 2H), 2.46 (s, 2H), 1.39 (s, 1 H), 1.27 (d, J = 10.4 Hz, 1 H), 0.60 (d, J = 7.1 Hz, 1 H).13C NMR (125 MHz, CDCI3) 5 153.29, 151.33, 146.51 , 145.99, 143.98, 117.04, 1 16.10, 1 13.02, 104.29, 104.14, 99.98, 72.60, 57.99, 56.33, 54.52, 26.84, 20.55, 12.52.

[0113] 2-((3-(3-fluoro-4-methoxybenzyl)-3-azabicyclo[3.1.0]hexan-1 - yl)methoxy)thiazole (2). General Procedure. Yield = 8.0 mg; 24%. LCMS: RT = 2.58 min, m / z [M + H]+, calc’d 345.1 for C17H19FN2O2S, found 345.1.1H NMR (500 MHz, CDCI3) 5 7.1 1 (d, J = 3.8 Hz, 1 H), 7.10 - 6.83 (m, 3H), 6.68 (d, J = 3.8 Hz, 1 H), 4.55 - 4.35 (m, 2H), 3.90 (s, 4H), 3.59 (s, 2H), 3.04 (d, J = 55.5 Hz, 2H), 2.46 (s, 2H), 1.45 (s, 1 H), 1.29 (d, J = 15.1 Hz, 1 H), 0.66 (s, 1 H).13C NMR (125 MHz, CDCI3) 5 146.68, 142.53, 142.47, 1 13.02, 107.22, 107.18, 104.76 99.96, 99.68, 57.96, 56.33, 54.49, 41.03, 26.69, 20.81 , 17.69, 12.69.

[0114] 3-(3-fluoro-4-methoxybenzyl)-1 -((3-fluorophenoxy)methyl)-3- azabicyclo[3.1.0]hexane (3). General Procedure. Yield = 9.0 mg; 21 %. LCMS: RT = 3.44 min, m / z [M + H]+, calc’d 345.2 for C20H21F2NO2, found 335.1 .1H NMR (500 MHz, CDCI3) 5 7.22 (td, J = 8.3, 6.9 Hz, 1 H), 7.10 - 7.05 (m, 1 H), 7.03 - 6.98 (m, 1 H), 6.90 (t, J = 8.4 Hz, 1 H), 6.70 - 6.63 (m, 2H), 6.61 (dt, J= 1 1 .0, 2.4 Hz, 1 H), 4.00 (dd, J= 65.8, 9.9 Hz, 2H), 3.90 (s, 3H), 3.59 (q, J = 13.0 Hz, 2H), 3.16 - 2.95 (m, 2H), 2.47 (t, J = 8.2 Hz, 2H), 1.40 (dt, J = 7.9, 3.8 Hz, 1 H), 1 .27 (d, J = 8.2 Hz, 1 H), 0.61 (dd, J = 7.9, 4.4 Hz, 1 H).13C NMR (125 MHz, CDCI3) 5 164.57, 162.62, 153.29, 151.34, 130.16, 130.08, 1 16.10, 1 13.02, 1 13.00, 1 10.39, 1 10.37, 107.55, 107.39, 102.37, 102.18, 72.00, 58.01 , 56.57, 56.33, 54.56, 26.85, 20.55, 12.51.

[0115] 2-((3-(3-fluoro-4-methoxybenzyl)-3-azabicyclo[3.1.0]hexan-1-yl)methoxy)-4- methylthiazole (4). General Procedure. Yield = 7.0 mg; 21%. LCMS: RT = 2.70 min, m / z [M + H]+, calc’d 349.1 for C18H22FN2O2S, found 349.1.1H NMR (500 MHz, CDCI3) 5 7.04 (d, J = 42.6 Hz, 2H), 6.90 (t, J = 8.5 Hz, 1 H), 6.22 (d, J = 1 .7 Hz, 1 H), 4.53 - 4.32 (m, 2H), 3.90 (s, 3H), 3.58 (s, 2H), 3.03 (d, J = 52.2 Hz, 2H), 2.46 (s, 2H), 2.26 (d, J = 1 .3 Hz, 3H), 1 .43 (s, 1 H), 1 .29 (d, J = 14.9 Hz, 1 H), 0.64 (s, 1 H).13C NMR (125 MHz, CDCI3) 5 146.68, 142.53, 142.47, 1 13.02, 107.22, 107.18, 104.76 99.96, 99.68, 57.96, 56.33, 54.49, 41.03, 26.69, 20.81 , 17.69, 12.69.

[0116] 1 -((4-chloro-3-f luorophenoxy)methyl)-3-(3-f luoro-4-methoxybenzyl)-3- azabicyclo[3.1.0]hexane (6). General Procedure. Yield = 7.0 mg; 21%. LCMS: RT = 3.59 min, m / z [M + H]+, calc’d 380.1 for C20H21CIF2NO2, found 380.1 .1H NMR (500 MHz, CDCI3) 5 7.27 - 7.19 (m, 1 H), 7.08 (dd, J = 22.3, 10.1 Hz, 2H), 6.92 (t, J = 8.4 Hz, 1 H), 6.69 (dd, J = 10.8, 2.6 Hz, 1 H), 6.63 (ddd, J = 9.2, 2.7, 1 .3 Hz, 1 H), 4.06 - 3.93 (m, 2H), 3.90 (s, 3H), 3.80 - 3.59 (m, 2H), 3.15 (d, J = 46.6 Hz, 2H), 2.61 (s, 1 H), 1.47 (s, 1 H), 1 .34 (s, 2H), 0.67 (s, 1 H).13C NMR (125 MHz, CDCI3) 5 159.38, 157.40, 153.24, 151.28, 130.55, 1 13.18, 1 11.25, 103.62, 103.43, 66.96, 57.94, 56.32, 54.53, 26.86, 20.52.

[0117] 3-(3-fluoro-4-methoxybenzyl)-1 -((3-fluoro-4-methylphenoxy)methyl)-3- azabicyclo[3.1.0]hexane (7). General Procedure. Yield = 8.0 mg; 25%. LCMS: RT = 3.55 min, m / z [M + H]+, calc’d 360.2 for C21H24F2NO2, found 360.1.1H NMR (500 MHz, CDCI3) 5 7.14 - 7.02 (m, 2H), 7.00 (d, J = 8.3 Hz, 1 H), 6.90 (t, J = 8.4 Hz, 1 H), 6.64 - 6.52 (m, 2H), 4.04 (d, J = 9.8 Hz, 1 H), 3.91 (s, 1 H), 3.90 (s, 4H), 3.58 (q, J = 13.2 Hz, 2H), 3.04 (dd, J = 55.7, 8.6 Hz, 2H), 2.46 (t, J = in Hz, 2H), 2.21 (d, J= 1.9 Hz, 3H), 1.42 - 1.22 (m, 2H), 0.59 (dd, J = 7.9, 4.3 Hz, 1 H).13C NMR (125 MHz, CDCI3) 5 162.50, 160.55, 158.40, 153.29, 151 .34, 146.49, 131 .34, 123.88, 1 16.24, 1 16.09, 1 13.01 , 1 10.08, 101 .99, 72.08, 58.02, 56.60, 56.33, 54.57, 26.93, 20.52, 13.74, 12.49.

[0118] 1 -((4-f luoro-3-methylphenoxy)methyl)-3-(3-f luoro-4-methoxybenzyl)-3- azabicyclo[3.1.0]hexane (8). General Procedure. Yield = 8.0 mg; 25%. LCMS: RT = 3.51 min, m / z [M + H]+, calc’d 360.2 for C21H24F2NO2, found 360.1.1H NMR (500 MHz, CDCI3) 5 7.1 1 - 7.03 (m, 1 H), 6.99 (d, J = 8.3 Hz, 1 H), 6.90 (t, J = 9.0 Hz, 2H), 6.71 (dd, J = 6.3, 3.0 Hz, 1 H), 6.64 (dt, J = 8.8, 3.5 Hz, 1 H), 4.03 (d, J= 9.9 Hz, 1 H), 3.90 (s, 4H), 3.58 (q, J = 13.2 Hz, 2H), 3.04 (dd, J= 55.3, 8.6 Hz, 2H), 2.46 (d, J = 8.4 Hz, 2H), 2.25 (d, J= 2.0 Hz, 3H), 1.37 (dt, J = 7.8, 3.9 Hz, 1 H), 1 .24 (s, 1 H), 0.59 (dd, J = 8.0, 4.3 Hz, 1 H).13C NMR (125 MHz, CDCI3) 5 156.79, 154.90, 153.29, 151.34, 125.56, 125.41 , 123.87, 1 17.45, 1 17.41 , 1 16.24, 1 16.10, 1 15.28, 1 15.09, 1 13.00, 1 12.99, 1 12.65, 1 12.59, 72.38, 58.04, 56.62, 56.34, 54.60, 27.05, 20.48, 14.80, 14.77, 12.48.

[0119] 1 -(((2-oxab i cy clo [2.1.1 ]hexan-1 -yl)methoxy)methyl)-3-(3-f luoro-4- methoxybenzyl)-3-azabicyclo[3.1.0]hexane (9). Prepared using General Procedure. Yield = 154.6 mg (47%, colorless oil). LCMS: RT = 1 .880 min, ESI-MS: m / z [M + H]+, calc’d 348.2 for C20H26FNO3 + H+, found 348.1 .1H NMR (600 MHz, CDCI3) 5 7.02 (d, J= 12.3 Hz, 1 H), 6.94 (d, J = 8.3 Hz, 1 H), 6.86 (td, J = 8.5, 2.5 Hz, 1 H), 3.86 (d, J = 2.7 Hz, 3H), 3.78 (d, J = 2.2 Hz, 2H), 3.73 - 3.63 (m, 3H), 3.57 - 3.41 (m, 3H), 2.98 (d, J = 8.5 Hz, 1 H), 2.89 (dd, J= 8.4, 5.4 Hz, 2H), 2.37 (d, J = 8.9 Hz, 2H), 1 .75 (dq, J = 4.6, 2.0 Hz, 2H), 1.52 - 1 .42 (m, 2H), 1 .20 (dd, J = 7.9, 3.9 Hz, 1 H), 1.10 (s, 1 H), 0.46 (dd, J= 7.8, 4.1 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 152.49 (d, JC-F = 245.2 Hz), 146.56 (d, JC-F = 11.0 Hz), 133.10, 124.04, 116.33 (d, J= 18.5 Hz), 113.17, 88.75, 75.34, 70.03, 69.77, 58.28, 56.93, 56.53, 54.72, 40.60, 40.58, 37.82, 27.38, 20.33, 12.65.

[0120] 1 -(((2-oxabicyclo[2.1.1 ]hexan-1 -yl)methoxy)methyl)-3-(3-f luoro-4- methoxybenzyl)-3-azabicyclo[3.1.0]hexane (10). Prepared using General Procedure. Yield = 40.9 mg (22%, colorless oil). LCMS: RT = 1.987 min, ESI-MS: m / z [M + H]+, calc’d 362.2 for C21H28FNO3 + H+, found 362.1.1H NMR (600 MHz, CDCI3) 5 7.02 (dd, J = 12.3, 2.0 Hz, 1 H), 6.94 (d, J = 8.3 Hz, 1 H), 6.86 (t, J = 8.4 Hz, 1 H), 3.86 (s, 3H), 3.72 - 3.61 (m, 3H), 3.60 - 3.45 (m, 5H), 2.98 (d, J = 8.5 Hz, 1 H), 2.90 (d, J= 8.6 Hz, 1 H), 2.43 - 2.28 (m, 2H), 1.60 - 1 ,50f (m, 4H), 1.31 (s, 3H), 1.22 - 1.16 (m, 1 H), 1.09 (t, J= 4.1 Hz, 1 H), 0.45 (dd, J= 7.9, 4.2 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 152.49 (d, JC-F = 245.2 Hz), 146.56 (d, JC-F= 11 .0 HZ), 132.99, 124.06 (d, JC-F = 3.4 Hz), 116.35 (d, JC-F = 18.3 Hz), 113.18 (d, JC-F = 2.2 HZ), 87.11 , 75.30, 74.42, 69.91 , 58.27, 56.92, 56.53, 54.70, 45.86, 45.30, 27.38, 20.34, 15.61 , 12.66.

[0121] ferf-butyl 1 -((3,4-dif luorophenoxy)methyl)-3-azabicyclo[3.1 ,0]hexane-3- carboxylate (11). Prepared using General Procedure. Yield = 35.7 mg (19%, colorless oil). LCMS: RT = 2.172 min, ESI-MS: m / z [M + H]+, calc’d 322.2 for C18H21F2NO2 + H+, found 322.1 .1H NMR (600 MHz, CDCI3) 5 7.03 (q, J = 9.3 Hz, 1 H), 6.73 - 6.66 (m, 1 H), 6.60 - 6.54 (m, 1 H), 4.05 - 3.96 (m, 1 H), 3.88 (d, J = 9.7 Hz, 1 H), 3.75 (s, 2H), 3.28 - 3.03 (m, 2H), 2.87 - 2.79 (m, 2H), 2.52 (s, 2H), 2.20 - 1 .88 (m, 1 H), 1 .73 (s, 2H), 1.51 - 1 .42 (m, 2H), 1 .34 (s, 1 H), 1 .23 - 1.09 (m, 1 H), 0.56 (s, 1 H).13C NMR (150 MHz, CDCI3) 5 155.65 (d, JC-F = 10.1 Hz), 150.55 (d, Jc-F= 247.3 Hz), 145.15 (dd, JC-F = 240.0, 12.8 Hz), 117.28 (d, JC-F = 19.0 Hz), 110.15 (dd, JC-F = 5.9, 3.4 Hz), 104.45 (d, JC-F = 20.3 Hz), 89.35, 72.87, 69.90, 58.38, 56.36, 56.21 , 41.73, 41.65, 37.62, 27.22, 20.89, 12.83.

[0122] 2-((1 -(((2-oxabicyclo[2.1.1 ]hexan-1 -yl)methoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)methyl)imidazo[1,2-a]pyridine (12). Prepared using General Procedure. Yield = 15.6 mg (18%, colorless oil). LCMS: RT = 0.511 min, ESI-MS: m / z [M + H]+, calc’d 340.2 for C20H25N3O2 + H+, found 340.1 .1H NMR (600 MHz, CDCI3) 5 8.04 (d, J= 6.7 Hz, 1 H), 7.51 (d, J = 9.0 Hz, 1 H), 7.46 (s, 1 H), 7.13 - 7.06 (m, 1 H), 6.75 - 6.69 (m, 1 H), 3.83 (d, J = 5.0 Hz, 2H), 3.76 (s, 2H), 3.71 - 3.62 (m, 3H), 3.49 (d, J = 10.9 Hz, 1 H), 3.14 (d, J = 8.7 Hz,1H), 3.06 (d, J = 8.9 Hz, 1H), 2.86 (t, J = 3.2 Hz, 1H), 2.61 -2.52 (m, 2H), 1.80- 1.67 (m, 2H), 1.44 (dd, J=4.6, 1.9 Hz, 2H), 1.23- 1.20 (m, 1H), 1.14 (t, J=4.2 Hz, 1H), 0.48 (dd, J =8.0, 4.3 Hz, 1H).13C NMR (150 MHz, CDCI3) 5145.02, 125.66, 124.36, 124.27, 117.51, 112.26, 112.20, 110.81, 88.70, 75.25, 69.98, 69.73, 57.16, 54.99, 53.02, 40.53, 40.52, 37.77, 27.49, 20.44, 12.77.

[0123] 5-((1 -(((2-oxabicyclo[2.1.1 ]hexan-1 -yl)methoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)methyl)-1-methyl-1 / 7-benzo[d]imidazole (13). Prepared usingGeneral Procedure. Yield = 18.7 mg (21%, colorless oil). LCMS: RT = 1.418 min, ESI-MS: m / z [M + H]+, calc’d 354.2 for C21H27N3O2 + H+, found 354.1.1H NMR (600 MHz, CDCI3) 57.78 (s, 1 H), 7.63 (s, 1 H), 7.25 - 7.20 (m, 2H), 3.77 (s, 3H), 3.73 (s, 2H), 3.69 (s, 2H), 3.63 (q, J = 11.4 Hz, 3H), 3.44 (d, J = 10.9 Hz, 1H), 2.97 (d, J = 8.7 Hz, 1H), 2.88 (d, J = 8.7 Hz, 1H), 2.83 (t, J = 3.2 Hz, 1 H), 2.38 (dd, J = 8.7, 4.5 Hz, 2H), 1.73- 1.66 (m, 2H), 1.41 (dd, J = 4.7, 1.9 Hz, 2H), 1.14 (dt, J =7.8, 3.8 Hz, 1H), 1.08 (t, J=4.1 Hz, 1H), 0.40 (dd, J =7.9, 4.1 Hz, 1H).13C NMR (150 MHz, CDCI3) 5143.91, 143.79, 133.84, 133.77, 124.22, 120.21, 109.03, 88.77, 75.40, 70.00, 69.72, 59.43, 56.98, 54.66, 40.56, 37.80, 31.27, 27.37, 20.38, 12.69.

[0124] 5-((1 -(((2-oxabicyclo[2.1.1 ]hexan-1 -yl)methoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)methyl)-1H-indazole (14). Prepared using General Procedure.Yield = 18.3 mg (22%, colorless oil). LCMS: RT = 1.891 min, ESI-MS: m / z[M + H]+, calc’d 340.2 for C20H25N3O2 + H+, found 340.1.1H NMR (600 MHz, CDCI3) 510.02 (br, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.35 (d, J =8.5 Hz, 1H), 7.28 (dd, J= 8.6, 1.5 Hz, 1H), 3.77 (s, 2H), 3.73-3.63 (m, 5H), 3.51 (d, J=10.9 Hz, 1H), 3.03 (d, J=8.8 Hz, 1H), 2.96 (d, J=8.9 Hz, 1H), 2.86 (t, J = 3.2 Hz, 1 H), 2.49 - 2.44 (m, 2H), 1.75- 1.72 (m, 2H), 1.46 (dd, J= 4.7, 1.9 Hz, 2H), 1.23 - 1.20 (m, 1H), 1.12 (t, J=4.2 Hz, 1H), 0.46 (dd, J=7.9, 4.3 Hz, 1H).13C NMR (150 MHz, CDCI3) 5139.80, 134.47, 131.40, 128.28, 123.30, 120.39, 109.85, 88.69, 75.19, 69.94, 69.75, 59.25, 56.79, 54.73, 40.53, 37.77, 27.40, 20.35, 12.80.

[0125] 5-((1 -(((2-oxabicyclo[2.1.1 ]hexan-1 -yl)methoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)methyl)-1H-benzo[cf]imidazole (15). Prepared using General Procedure. Yield = 12.3 mg (11%, colorless oil). LCMS: RT = 1.119 min, ESI-MS: m / z [M + H]+, calc’d 340.2 for C20H25N3O2 + H+, found 340.1.1H NMR (500 MHz, CDCI3) 58.10 (s, 1 H), 7.82 - 7.27 (br, 1 H), 7.72 (s, 1 H), 7.56 (d, J= 8.2 Hz, 1 H), 7.29 (dd, J= 8.4, 1.5 Hz, 1 H), 4.03 (d, J = 2.1 Hz, 2H), 3.77 (s, 2H), 3.71 - 3.65 (m, 2H), 3.62 - 3.50 (m, 2H), 3.26 (dd, J= 24.0, 10.1 Hz, 2H), 3.02-2.90 (m, 2H), 2.89 (t, J= 3.2 Hz, 1H), 1.71 (dt, J =5.0, 2.8 Hz, 2H), 1.48-1.40 (m, 3H), 1.37 (t, J= 4.9 Hz, 1H), 0.64 (dd, J = 8.1, 5.4 Hz, 1H).13C NMR (125 MHz, CDCI3) 5 142.23, 138.22, 137.79, 128.19, 124.63, 117.25, 116.16, 88.51, 73.86, 70.11 , 70.01 , 59.43, 56.35, 55.10, 40.64, 40.58, 37.95, 27.90, 20.33, 13.33.

[0126] 5-((1 -(((2-oxabicyclo[2.1.1 ]hexan-1 -yl)methoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)methyl)-1-methyl-1 / - / -indazole (16). Prepared using General Procedure. Yield = 66.1 mg (58%, colorless oil). LCMS: RT = 1.830 min, ESI-MS: m / z [M + H]+, calc’d 354.2 for C21H27N3O2 + H+, found 354.1.1H NMR (600 MHz, CDCI3) 67.91 (d, J = 0.9 Hz, 1 H), 7.58 (s, 1 H), 7.40 - 7.34 (m, 1 H), 7.31 (d, J = 8.6 Hz, 1 H), 4.05 (s, 3H), 3.77 (s, 2H), 3.76 -3.64 (m, 5H), 3.51 (d, J=11.0 Hz, 1H), 3.03 (d, J =8.8 Hz, 1H), 2.96 (d, J =8.9 Hz, 1H), 2.88 (t, J = 3.2 Hz, 1 H), 2.47 (s, 2H), 1.76-1.71 (m, 2H), 1.46 (dd, J = 4.7, 1.9 Hz, 2H), 1.25 - 1.20 (m, 1H), 1.15 (t, J =4.4 Hz, 1H), 0.49 (s, 1H).13C NMR (126 MHz, CDCI3) 5139.62, 132.73, 127.95, 124.15, 120.63, 120.60, 108.86, 88.72, 75.22, 70.01, 69.79, 59.27, 56.91, 54.78, 40.56, 37.81, 35.75, 27.46, 20.37, 12.75.

[0127] 3-((1 -(((2-oxabicyclo[2.1.1 ]hexan-1 -yl)methoxy)methyl)-3- azabicyclo[3.1.0]hexan-3-yl)methyl)imidazo[1,5-a]pyridine (17). Prepared using General Procedure. Yield = 65.7 mg (60%, red oil). LCMS: RT = 1.830 min, ESI-MS: m / z [M + H]+, calc’d340.2 for C20H25N3O2 + H+, found 340.2.1H NMR (500 MHz, CDCI3) 68.07 (d, J= 7.2 Hz, 1 H), 7.38 (dd, J =9.1, 1.3 Hz, 1H), 7.29 (s, 1H), 6.67 (dd, J =9.2, 6.3 Hz, 1 H), 6.53 - 6.44 (m, 1H), 4.04 (d, J= 1.9 Hz, 2H), 3.76 (s, 2H), 3.69 - 3.62 (m, 3H), 3.46 (d, J= 10.8 Hz, 1 H), 2.87 (q, J = 4.3, 3.2 Hz, 2H), 2.77 (d, J= 8.7 Hz, 1 H), 2.52 (d, J = 8.6 Hz, 2H), 1.75-1.70 (m, 2H), 1.45 (dd, J =4.7, 1.9 Hz, 2H), 1.24-1.21 (m, 1H), 0.97 (t, J =4.2 Hz, 1H), 0.46 (dd, J =8.0, 4.3 Hz, 1H).13C NMR (125 MHz, CDCI3) 6136.18, 131.33, 122.44, 118.64, 118.35, 112.03, 88.71, 75.18, 69.99, 69.90, 56.92, 54.56, 51.54, 40.57, 40.53, 37.79, 27.65, 20.47, 12.54.

[0128] 2-((1-((3,4-difluorophenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3- yl)methyl)imidazo[1 ,2-a]pyridine (18). Prepared using General Procedure. Yield = 96.3 mg (98%, yellow oil). LCMS: RT = 2.088 min, ESI-MS: m / z [M + H]+, calc’d 356.2 for C20H19F2N3O + H+, found 356.1.1H NMR (600 MHz, CDCI3) 68.05 (dd, J= 6.8, 1.3 Hz, 1 H), 7.53 (dd, J= 9.1 ,1.2 Hz, 1H), 7.49 (s, 1H), 7.16-7.08 (m, 1H), 7.06-6.96 (m, 1H), 6.76-6.72 (m, 1H), 6.71 - 6.63 (m, 1H), 6.54 (dtd, J= 9.1 , 3.2, 1.7 Hz, 1H), 4.01 (d, J =9.8 Hz, 1 H), 3.92 - 3.80 (m, 3H), 3.23 (d, J= 8.7 Hz, 1H), 3.12 (d, J= 8.9 Hz, 1H), 2.70-2.57 (m, 2H), 1.41 - 1.35 (m, 1H), 1.28 (t, J= 4.3 Hz, 1H), 0.59 (dd, J= 8.0, 4.5 Hz, 1H).13C NMR (150 MHz, CDCI3) 6155.57 (d, JC-F = 7.3 Hz), 150.58 (dd, JC-F= 247.4, 13.8 Hz), 145.15 (dd, JC-F= 239.9, 12.5 Hz), 145.11, 125.68, 124.37, 117.59, 117.28 (d, JC-F= 18.2 Hz), 112.28, 110.85, 110.13 (dd, JC-F=5.7, 3.3 Hz), 110.10, 104.44 (d, JC-F = 20.3 Hz), 72.81 , 57.01 , 54.99, 52.91, 27.15, 20.83, 12.87.

[0129] 5-((1 -((3,4-dif luorophenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-1 - methyl-1H-benzo[cf]imidazole (19). Prepared using General Procedure. Yield = 80.4 mg (79%, orange solid). LCMS: RT = 1.898 min, ESI-MS: m / z[M + H]+, calc’d 370.2 for C21H21F2N3O + H+, found 370.1.1H NMR (600 MHz, CDCI3) 57.84 (s, 1 H), 7.69 (s, 1 H), 7.40 - 7.29 (m, 2H), 7.06-6.92 (m, 1H), 6.68-6.60 (m, 1H), 6.55-6.48 (m, 1H), 3.96 (d, J= 9.8 Hz, 1 H), 3.90 - 3.78 (m, 6H), 3.15 (d, J= 9.0 Hz, 1 H), 3.06 (d, J= 9.2 Hz, 1 H), 2.60 (s, 2H), 1.43 -I.37 (m, 1H), 1.35 (s, 1H), 0.60 (dd, J = 8.1, 4.6 Hz, 1H).13C NMR (150 MHz, CDCI3) 5155.51, 150.56 (d, JC-F= 260.8 Hz), 145.12 (d, JC-F= 240.1 Hz), 144.01, 143.86, 134.11, 124.43,120.54, 119.02, 117.28 (d, JC-F = 18.3 Hz), 110.07 (dd, JC-F = 5.9, 3.2 Hz), 109.33, 104.41 (d, JC-F= 20.1 Hz), 72.57, 65.78, 59.26, 56.54, 54.67, 31.28, 27.07, 20.71, 12.90.

[0130] 3-((1 -((3,4-dif luorophenoxy)methyl)-3-azabicyclo[3.1 ,0]hexan-3- yl)methyl)imidazo[1 ,5-a]pyridine (20). Prepared using General Procedure. Yield = 38.0 mg (40%, red oil). LCMS: RT = 2.202 min, ESI-MS: m / z[M + H]+, calc’d 356.2 for C20H19F2N3O + H+, found 356.1.1H NMR (600 MHz, CDCI3) 58.06 (d, J =7.2 Hz, 1H), 7.40 (dd, J =9.2, 1.4 Hz, 1 H), 7.31 (s, 1 H), 7.01 (q, J= 9.4 Hz, 1 H), 6.75 - 6.60 (m, 2H), 6.60 - 6.46 (m, 2H), 4.07 (d, J= 3.2 Hz, 2H), 4.02 (d, J= 9.7 Hz, 1H), 3.82 (d, J= 9.7 Hz, 1H), 2.88 (dd, J= 50.4, 8.6 Hz, 2H), 2.58 (dd, J= 8.7, 2.8 Hz, 2H), 1.41 - 1.35 (m, 1H), 1.09 (t, J=4.3 Hz, 1H), 0.56 (dd, J = 8.0, 4.4 Hz, 1H).13C NMR (150 MHz, CDCI3) 5155.50 (d, JC-F= 8.4 Hz), 150.58 (dd, JC-F = 247.3, 13.7 Hz), 145.17 (dd, JC-F = 240.0, 12.8 Hz), 136.06, 131.36, 122.30, 118.70, 118.43, 118.41, 117.30 (d, JC-F= 18.5 Hz), 112.16, 110.07 (dd, JC-F= 5.8, 3.3 Hz), 104.37 (d, JC-F= 20.3 Hz).72.61, 56.72, 54.59, 51.42, 27.18, 20.87, 12.63.

[0131] 5-((1 -((3,4-dif luorophenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3-yl)methyl)-1 - methyl-1 / 7-benzo[d]imidazole (21). Prepared using General Procedure. Yield = 63.6 mg (65%, colorless oil). LCMS: RT = 2.136 min, ESI-MS: m / z [M + H]+, calc’d 356.2 for C20H19F2N3O + H+, found 356.1.1H NMR (600 MHz, CDCI3) 510.86 (br, 1H), 8.04 (s, 1H), 7.64 (s, 1H), 7.48 - 7.35 (m, 2H), 7.09 - 6.95 (m, 1 H), 6.72 - 6.63 (m, 1 H), 6.58 - 6.49 (m, 1 H), 4.00 (d, J = 9.7 Hz, 1 H), 3.86 (d, J= 9.7 Hz, 1 H), 3.84 - 3.68 (m, 2H), 3.08 (dd, J= 57.1 , 8.9 Hz, 2H), 2.54 (t, J = 11.1 Hz, 2H), 1.44- 1.35 (m, 1H), 1.29 (s, 1H), 0.59 (dd, J= 8.1, 4.5 Hz, 1H).13C NMR (150 MHz, CDCI3) 5155.52 (d, JC-F= 8.4 Hz), 150.57 (dd, JC-F= 247.4, 13.8 Hz), 145.16 (dd, JC-F = 240.1, 12.9 Hz), 139.82, 134.78, 128.47, 123.40, 120.48, 117.30 (d, JC-F= 18.3 Hz), 110.10 (dd, JC-F= 5.7, 3.4 Hz), 109.83, 104.40 (d, JC-F= 20.0 Hz), 72.73, 59.23, 56.75, 54.81, 27.08, 20.77, 12.89.

[0132] 2-((3-(imidazo[1,2-a]pyridin-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-1- yl)methoxy)-5-methylthiazole (22). Prepared using General Procedure. Yield = 49.1 mg (14%, orange oil). LCMS: RT = 1.867 min, ESI-MS: m / z [M + H]+, calc’d 341.1 for C18H20N4OS + H+, found 341.1.1H NMR (600 MHz, CDCI3) 58.05 (dd, J= 6.8, 1.2 Hz, 1 H), 7.58 - 7.52 (m, 1H), 7.49 (s, 1H), 7.15-7.08 (m, 1H), 6.76-6.71 (m, 1H), 6.71 -6.63 (m, 1H), 4.44 (d, J =II.0 Hz, 1H), 4.33 (d, J= 10.9 Hz, 1H), 3.88 (q, J= 14.0 Hz, 2H), 3.23 (d, J =8.8 Hz, 1H), 3.12 (d, J =8.9 Hz, 1H), 2.65 (d, J =8.9 Hz, 2H), 2.28 (s, 3H), 1.45-1.37 (m, 1H), 1.27 (t, J =4.5 Hz, 1 H), 0.62 (dd, J = 8.1 , 4.6 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5173.32, 145.06, 133.42, 125.70, 125.47, 124.45, 117.56, 112.33, 110.92, 74.84, 56.84, 54.90, 52.78, 27.03, 21.12, 13.04, 12.52.

[0133] 5-methyl-2-((3-((1-methyl-1 / 7-indazol-5-yl)methyl)-3-azabicyclo[3.1.0]hexan-1- yl)methoxy)thiazole (23). Prepared using General Procedure. Yield = 58.1 mg (62%, yellow oil). LCMS: RT = 2.050 min, ESI-MS: m / z [M + H]+, calc’d 355.2 for C19H22N4OS + H+, found355.1 .1H NMR (600 MHz, CDCI3) 6 7.91 (s, 1 H), 7.57 (s, 1 H), 7.38 - 7.29 (m, 2H), 6.70 (d, J = 1.5 Hz, 1 H), 4.44 (d, J = 10.9 Hz, 1 H), 4.32 (d, J = 10.9 Hz, 1 H), 4.05 (s, 3H), 3.75 - 3.63 (m, 2H), 3.05 (d, J = 8.6 Hz, 1 H), 2.95 (d, J = 8.7 Hz, 1 H), 2.50 - 2.41 (m, 2H), 2.28 (s, 3H), 1.42 -1 .33 (m, 1 H), 1 .23 (d, J = 4.3 Hz, 1 H), 0.59 (dd, J = 8.0, 4.3 Hz, 1 H).13C NMR (150 MHz, CDCI3) 6 173.20, 139.40, 133.25, 132.51 , 127.64, 125.23, 123.97, 120.18, 108.65, 74.90, 58.98, 56.55, 54.55, 35.56, 26.73, 20.90, 12.74, 12.34.

[0134] 2-((3-(imidazo[1 ,5-a]pyridin-3-ylmethyl)-3-azabicyclo[3.1.0]hexan-1- yl)methoxy)-5-methylthiazole (24). Prepared using General Procedure. Yield = 38.0 mg (40%, red oil). LCMS: RT = 2.038 min, ESI-MS: m / z [M + Na]+, calc’d 363.1 for C18H20N4OS + Na+, found 363.0.1H NMR (600 MHz, CDCI3) 6 8.04 (d, J= 7.2 Hz, 1 H), 7.44 - 7.35 (m, 1 H), 7.30 (s, 1 H), 6.79 - 6.63 (m, 2H), 6.57 - 6.43 (m, 1 H), 4.44 (d, J = 10.9 Hz, 1 H), 4.29 (d, J = 11.0 Hz, 1 H), 4.05 (s, 2H), 2.90 (d, J= 8.5 Hz, 1 H), 2.80 (d, J = 8.7 Hz, 1 H), 2.63 - 2.50 (m, 2H), 2.27 (s, 3H), 1.39 (dt, J= 7.8, 3.8 Hz, 1 H), 1.06 (t, J= 4.3 Hz, 1 H), 0.58 (dd, J = 8.0, 4.4 Hz, 1 H).13C NMR (150 MHz, CDCI3) 6 173.23, 136.09, 133.39, 131 .32, 125.48, 122.29, 118.63, 118.38, 112.09, 74.65, 56.58, 54.51 , 51.40, 27.04, 21.16, 12.78, 12.49.

[0135] 5-((1 -((3-f luoro-4-methylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3- yl)methyl)-1H-indazole (25). Prepared using General Procedure. Yield = 45.5 mg (62%, white solid). LCMS: RT = 2.106 min, ESI-MS: m / z [M + H]+, calc’d 352.2 for C21H22FN3O + H+, found352.1.1H NMR (600 MHz, CDCI3) 6 10.86 (s, 1 H), 8.04 (s, 1 H), 7.65 (s, 1 H), 7.46 - 7.32 (m, 2H), 7.02 (t, J= 8.8 Hz, 1 H), 6.63 - 6.48 (m, 2H), 3.99 (d, J= 9.9 Hz, 1 H), 3.90 (d, J= 9.9 Hz, 1 H), 3.87 - 3.72 (m, 2H), 3.17 (d, J= 8.9 Hz, 1 H), 3.12 - 3.02 (m, 1 H), 2.59 (s, 2H), 2.18 (d, J =1.8 Hz, 3H), 1.45 - 1.36 (m, 1 H), 1.29 (s, 1 H), 0.61 (dd, J= 8.1 , 4.6 Hz, 1 H).13C NMR (150 MHz, CDCI3) 6 161.70 (d, JC-F = 244.3 Hz), 158.43 (d, JC-F = 10.5 Hz), 139.85, 134.77, 131.58 (d, JC-F = 7.0 Hz), 128.47, 123.39, 120.65, 116.79 (d, JC-F = 17.5 Hz), 110.26 (d, JC-F = 3.2 Hz), 109.89, 102.28 (d, JC-F = 25.6 Hz), 72.06, 59.26, 56.73, 54.86, 27.20, 20.72, 13.92 (d, JC-F = 3.1 Hz), 12.87.

[0136] 5-((1 -((3-f luoro-4-methylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3- yl)methyl)-1H-indazole (26). Prepared using General Procedure. Yield = 37.0 mg (49%, colorless oil). LCMS: RT = 1 .917 min, ESI-MS: m / z [M + H]+, calc’d 366.2 for C22H24FN3O + H+, found 366.1 .1H NMR (600 MHz, CDCI3) 6 7.93 (s, 1 H), 7.60 (s, 1 H), 7.39 (d, J= 8.5 Hz, 1 H),7.33 (d, J= 8.6 Hz, 1 H), 7.02 (t, J= 8.8 Hz, 1 H), 6.63 - 6.48 (m, 2H), 4.06 (s, 3H), 4.01 (d, J =9.9 Hz, 1 H), 3.88 (d, J = 9.8 Hz, 1 H), 3.82 - 3.68 (m, 2H), 3.05 (dd, J= 63.5, 8.8 Hz, 2H), 2.51 (s, 2H), 2.18 (d, J= 1.8 Hz, 3H), 1.40 - 1.34 (m, 1 H), 1.26 (s, 1 H), 0.58 (dd, J= 8.1 , 4.4 Hz, 1 H).13C NMR (150 MHz, CDCI3) 6 161.71 (d, JC-F = 244.3 Hz), 158.54 (d, JC-F = 10.6 Hz),139.62, 132.72, 131.55 (d, JC-F = 7.0 Hz), 127.90, 124.16, 120.54, 116.70 (d, JC-F = 17.3 Hz), 110.28 (d, JC-F = 3.3 Hz), 108.88, 102.28 (d, JC-F = 25.7 Hz), 72.26, 59.21 , 56.82, 54.81 , 35.75, 27.15, 20.73, 13.93 (d, JC-F = 3.2 Hz), 12.76.

[0137] 3-((1 -((3-f luoro-4-methylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3- yl)methyl)imidazo[1 ,5-a]pyridine (27). Prepared using General Procedure. Yield = 37.7 mg (52%, red oil). LCMS: RT = 2.145 min, ESI-MS: m / z [M + H]+, calc’d 352.2 for C21H22FN3O + H+, found 352.1 .1H NMR (600 MHz, CDCI3) 5 8.09 (d, J = 7.2 Hz, 1 H), 7.40 (d, J = 9.1 Hz, 1 H), 7.31 (s, 1 H), 7.01 (t, J = 8.8 Hz, 1 H), 6.69 (dd, J = 9.2, 6.3 Hz, 1 H), 6.53 (ddd, J= 12.3, 5.6, 2.8 Hz, 3H), 4.09 (s, 2H), 4.03 (d, J = 9.8 Hz, 1 H), 3.83 (d, J = 9.9 Hz, 1 H), 2.96 (d, J = 8.6 Hz, 1 H), 2.85 (d, J = 8.8 Hz, 1 H), 2.61 (t, J= 8.4 Hz, 2H), 2.17 (d, J = 1.8 Hz, 3H), 1.41 - 1.35 (m, 1 H), 1 .10 (t, J = 4.4 Hz, 1 H), 0.58 (dd, J = 8.1 , 4.4 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 161 .69 (d, JC-F = 244.3 Hz), 158.42 (d, JC-F = 10.8 Hz), 131 .56 (d, JC-F = 6.9 Hz), 131 .38, 122.35, 118.74, 118.42 (d, JC-F = 5.1 Hz), 116.75 (d, JC-F = 17.5 Hz), 112.18, 110.24 (d, JC-F = 3.3 HZ), 102.24 (d, JC-F = 25.5 Hz), 72.01 , 56.76, 54.60, 51.36, 27.29, 20.82, 13.91 (d, JC-F = 3.3 Hz), 12.61.

[0138] 5-((1 -((4-f luoro-3-methylphenoxy)methyl)-3-azabicyclo[3.1 ,0]hexan-3- yl)methyl)-1 / 7-benzo[d]imidazole (28). Prepared using General Procedure. Yield = 61 .8 mg (75%, colorless oil). LCMS: RT = 1 .874 min, ESI-MS: m / z [M + H]+, calc’d 352.2 for C21H22FN3O + H+, found 352.1 .1H NMR (600 MHz, CDCI3) 5 9.77 (s, 1 H), 8.09 (s, 1 H), 7.67 (s, 1 H), 7.54 (d, J = 8.3 Hz, 1 H), 7.29 - 7.19 (m, 1 H), 6.85 (t, J = 9.0 Hz, 1 H), 6.64 (dd, J = 6.3, 3.1 Hz, 1 H), 6.57 (dt, J= 8.7, 3.6 Hz, 1 H), 3.96 (d, J= 2.6 Hz, 2H), 3.90 (s, 2H), 3.30 (d, J= 9.6 Hz, 1 H), 3.18 (d, J= 9.8 Hz, 1 H), 2.92 - 2.74 (m, 2H), 2.20 (d, J= 1.9 Hz, 3H), 1.47 (dt, J= 8.2, 4.0 Hz, 1 H), 1 .33 (t, J = 4.7 Hz, 1 H), 0.68 (dd, J = 8.2, 5.2 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 156.17 (d, JC-F = 237.4 Hz), 154.68 (d, JC-F = 2.2 Hz), 141.88, 137.70, 130.30, 125.82 (d, JC-F =18.8 Hz), 124.57, 117.56 (d, JC-F = 4.8 Hz), 116.54, 115.73, 115.47 (d, JC-F = 24.1 Hz), 112.82 (d, JC-F = 7.8 Hz), 71.53, 59.45, 56.56, 55.02, 27.54, 20.56, 14.94 (d, JC-F = 3.3 Hz), 13.31.

[0139] 5-((1-((4-fluoro-3-methylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3- yl)methyl)-1 -methy 1-1 H-benzo[cf] imidazole (29). Prepared using General Procedure. Yield =69.8 mg (81%, light orange solid). LCMS: RT = 1.874 min, ESI-MS: m / z [M + H]+, calc’d 352.2 for C21H22FN3O + H+, found 352.1 .1H NMR (600 MHz, CDCI3) 5 7.85 (s, 1 H), 7.70 (s, 1 H), 7.41 - 7.30 (m, 2H), 6.86 (t, J= 9.0 Hz, 1 H), 6.66 (dd, J= 6.4, 3.1 Hz, 1 H), 6.59 (dt, J= 8.9, 3.5 Hz, 1 H), 3.97 (d, J= 9.9 Hz, 1 H), 3.90 - 3.75 (m, 6H), 3.16 (d, J= 8.9 Hz, 1 H), 3.08 - 2.97 (m, 1 H), 2.59 (s, 2H), 2.21 (s, 3H), 1 .42 - 1 .34 (m, 1 H), 1 .32 (s, 1 H), 0.59 (dd, J = 8.1 , 4.5 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 156.04 (d, JC-F = 237.1 Hz), 154.98, 143.91 (d, JC-F = 20.4 Hz), 134.10, 125.64 (d, JC-F = 18.7 Hz), 124.47, 120.54, 117.61 (d, JC-F = 4.6 Hz), 115.35 (d, JC-F =23.9 Hz), 112.83 (d, JC-F = 8.0 Hz), 109.31 , 72.28, 59.30, 56.61 , 54.72, 31 .26, 27.29, 20.63, 14.93 (d, JC-F = 3.3 Hz), 12.83.

[0140] 5-((1-((4-fluoro-3-methylphenoxy)methyl)-3-azabicyclo[3.1.0]hexan-3- yl)methyl)-1-methyl-1 / - / -indazole (30). Prepared using General Procedure. Yield = 56.2 mg (56%, colorless oil). LCMS: RT = 2.181 min, ESI-MS: m / z [M + H]+, calc’d 366.2 for C22H24FN3O + H+, found 366.1 .1H NMR (600 MHz, CDCI3) 6 7.93 (s, 1 H), 7.59 (s, 1 H), 7.38 (dd, J = 8.5, 1 .5 Hz, 1 H), 7.32 (d, J = 8.6 Hz, 1 H), 6.87 (t, J = 9.0 Hz, 1 H), 6.68 (dd, J = 6.4, 3.1 Hz, 1 H), 6.61 (dt, J = 8.8, 3.6 Hz, 1 H), 4.06 (s, 3H), 4.01 (d, J = 9.8 Hz, 1 H), 3.86 (d, J = 9.8 Hz, 1 H), 3.80 - 3.65 (m, 2H), 3.09 (d, J= 8.5 Hz, 1 H), 2.98 (d, J= 8.7 Hz, 1 H), 2.53 - 2.43 (m, 2H), 2.22 (d, J = 2.0 Hz, 3H), 1.35 (dt, J = 7.8, 3.8 Hz, 1 H), 1.24 (t, J= 4.0 Hz, 1 H), 0.57 (dd, J= 8.0, 4.3 Hz, 1 H).13C NMR (150 MHz, CDCI3) 6 156.02 (d, JC-F = 236.7 Hz), 155.10 (d, JC-F = 2.2 Hz), 139.59, 132.69, 127.87, 125.64 (d, JC-F = 18.7 Hz), 124.16, 120.42, 117.61 (d, JC-F = 4.5 HZ), 115.36 (d, JC-F = 24.0 Hz), 112.80 (d, JC-F = 7.9 Hz), 108.82, 72.63, 59.23, 56.89, 54.83, 35.74, 27.25, 20.70, 14.95 (d, JC-F = 3.3 Hz), 12.72.

[0141] 2-((1 -((4-f luoro-3-methylphenoxy)methyl)-3-azabicyclo[3.1 ,0]hexan-3- yl)methyl)imidazo[1 ,2-a]pyridine (31). Prepared using General Procedure. Yield = 24.3 mg (29%, red oil). LCMS: RT = 2.116 min, ESI-MS: m / z [M + H]+, calc’d 352.2 for C22H24FN3O + H+, found 352.1 .1H NMR (600 MHz, CDCI3) 6 8.02 (s, 1 H), 7.85 (d, J= 7.0 Hz, 1 H), 7.53 (d, J= 9.2 Hz, 1 H), 6.85 (t, J= 9.0 Hz, 1 H), 6.70 - 6.64 (m, 2H), 6.58 (dt, J= 8.8, 3.6 Hz, 1 H), 6.52 (t, J = 6.7 Hz, 1 H), 4.02 (d, J= 5.0 Hz, 2H), 3.98 (d, J= 10.0 Hz, 1 H), 3.85 (d, J= 9.9 Hz, 1 H), 3.18 (d, J= 8.9 Hz, 1 H), 3.07 (d, J= 9.0 Hz, 1 H), 2.69 (d, J= 8.6 Hz, 2H), 2.20 (d, J= 2.0 Hz, 3H), 1.36 (dt, J= 8.0, 3.9 Hz, 1 H), 1.26 (s, 1 H), 0.58 (dd, J= 8.1 , 4.6 Hz, 1 H).13C NMR (150 MHz, CDCI3) 6 156.03 (d, JC-F = 237.1 Hz), 155.00, 128.42, 126.51 , 125.63 (d, JC-F = 18.8 Hz), 122.26, 118.82, 118.45, 117.63 (d, JC-F = 4.9 HZ), 115.34 (d, JC-F = 24.1 Hz), 112.94, 112.87 (d, JC-F = 7.9 Hz), 72.34, 56.51 , 54.51 , 51 .29, 29.87, 27.35, 20.72, 14.93 (d, JC-F = 3.4 Hz), 12.76.

[0142] 5-((1 -((4-chloro-3-f luorophenoxy)methyl)-3-azabicyclo[3.1 ,0]hexan-3-yl)methyl)-1 H-benzo[d]imidazole (32). Prepared using General Procedure. Yield = 33.4 mg (39%, colorless oil). LCMS: RT = 2.094 min, ESI-MS: m / z [M + H]+, calc’d 372.1 for C2oHigCI35°FN03 + H+, found 372.1 ; calc’d 374.1 for C2oHigCI37°FN03 + H+, found 374.1 .1H NMR (600 MHz, CDCI3) 6 8.86 (s, 1 H), 8.07 (s, 1 H), 7.65 - 7.52 (m, 2H), 7.25 - 7.14 (m, 2H), 6.69 - 6.48 (m, 2H), 4.01 (d, J= 9.8 Hz, 1 H), 3.86 (d, J = 9.8 Hz, 1 H), 3.82 - 3.70 (m, 2H), 3.11 (d, J = 8.6 Hz, 1 H), 3.01 (d, J = 8.9 Hz, 1 H), 2.56 - 2.42 (m, 2H), 1.37 (dt, J = 7.9, 3.8 Hz, 1 H), 1.24 (t, J = 4.3 Hz, 1 H), 0.56 (dd, J = 8.0, 4.4 Hz, 1 H).13C NMR (150 MHz, CDCI3) 6 159.02 (d, JC-F = 9.4 Hz), 158.55 (d, JC-F = 247.9 Hz), 141.10, 137.63, 134.15, 130.67, 124.06, 115.41 , 112.35 (d, JC-F = 17.9 Hz), 111.48 (d, JC-F = 3.2 Hz), 103.69 (d, JC-F = 24.1 Hz), 72.61 , 59.40, 56.81 , 54.79, 26.98, 20.80, 12.87.

[0143] 5-((1 -((4-chloro-3-f luorophenoxy)methyl)-3-azabicyclo[3.1 ,0]hexan-3-yl)methyl)-1-methyl-1 / 7-benzo[c / ]imidazole (33). Prepared using General Procedure. Yield = 60.7 mg (68%, light orange solid). LCMS: RT = 1 .962 min, ESI-MS: m / z [M + H]+, calc’d 386.1 forC2I H2ICI350FNO3+ H+, found 386.1 ; calc’d 388.1 for C2I H2ICI370FNO3+ H+, found 388.1 .1H NMR (600 MHz, CDCI3) 5 7.84 (s, 1 H), 7.70 (s, 1 H), 7.32 (s, 2H), 7.22 (t, J = 8.7 Hz, 1 H), 6.64 (dd, J= 10.9, 2.8 Hz, 1 H), 6.62 - 6.55 (m, 1 H), 4.01 (d, J= 9.8 Hz, 1 H), 3.87 (d, J= 9.8 Hz, 1 H), 3.82 (s, 5H), 3.12 (d, J= 8.7 Hz, 1 H), 3.02 (d, J = 8.9 Hz, 1 H), 2.54 (s, 2H), 1.37 (dt, J =7.9, 3.8 Hz, 1 H), 1.31 (s, 1 H), 0.58 (dd, J = 8.1 , 4.5 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5159.02 (d, JC-F = 9.4 Hz), 158.54 (d, JC-F = 247.7 Hz), 143.95, 133.71 , 130.64, 124.30, 120.40, 112.33 (d, JC-F=17.8 Hz), 111.48 (d, JC.F= 3.1 Hz), 109.22, 103.70 (d, JC.F = 24.2 HZ), 72.52, 59.26, 56.60, 54.65, 31.27, 26.96, 20.76, 12.82.

[0144] 5-((1 -((4-chloro-3-f luorophenoxy)methyl)-3-azabicyclo[3.1 ,0]hexan-3-yl)methyl)-1 H-indazole (34). Prepared using General Procedure. Yield = 26.4 mg (30%, colorless oil). LCMS: RT= 2.137 min, ESI-MS: m / z [M + H]+, calc’d 372.1 for C20HI9CI350FNO3+ H+, found 372.0; calc’d 374.1 for C20HI9CI37 0FNO3+ H+, found 374.0.1H NMR (600 MHz, CDCI3) 5 8.04 (s, 1 H), 7.63 (s, 1 H), 7.45 - 7.34 (m, 2H), 7.23 (t, J = 8.7 Hz, 1 H), 6.66 (dd, J = 10.9, 2.8 Hz, 1 H), 6.60 (dd, J = 9.0, 2.8 Hz, 1 H), 4.02 (d, J = 9.8 Hz, 1 H), 3.88 (d, J = 9.8 Hz, 1 H), 3.82 - 3.69 (m, 2H), 3.11 (d, J = 8.7 Hz, 1 H), 3.02 (d, J = 8.9 Hz, 1 H), 2.58 - 2.44 (m, 2H), 1.41 - 1.36 (m, 1 H), 1 .30 - 1 .27 (m, 1 H), 0.59 (dd, J = 8.0, 4.5 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 159.02 (d, JC-F = 9.6 Hz), 158.56 (d, JC-F = 247.9 Hz), 139.78, 134.84, 130.67, 128.46, 123.42, 120.38, 112.38 (d, J= 17.9 Hz), 111.49 (d, JC-F = 3.3 HZ), 109.77, 103.69 (d, JC-F = 24.1 Hz), 72.60, 59.22, 56.76, 54.79, 29.89, 27.00, 20.82, 12.87.

[0145] 3-((1 -((4-chloro-3-f luorophenoxy)methyl)-3-azabicyclo[3.1 ,0]hexan-3- yl)methyl)imidazo[1 ,5-a]pyridine (35). Prepared using General Procedure. Yield = 62.4 mg (72%, red oil). LCMS: RT = 2.185 min, ESI-MS: m / z [M + H]+, calc’d 372.1 for C2oHi9CI35°FN03+ H+, found 372.0; calc’d 374.1 for C2oHi9CI37°FN03+ H+, found 374.0.1H NMR (600 MHz, CDCI3) 5 8.04 (s, 1 H), 7.63 (s, 1 H), 7.45 - 7.34 (m, 2H), 7.23 (t, J= 8.7 Hz, 1 H), 6.66 (dd, J =10.9, 2.8 Hz, 1 H), 6.60 (dd, J= 9.0, 2.8 Hz, 1 H), 4.02 (d, J= 9.8 Hz, 1 H), 3.88 (d, J= 9.8 Hz,1 H), 3.82 - 3.69 (m, 2H), 3.11 (d, J= 8.7 Hz, 1 H), 3.02 (d, J= 8.9 Hz, 1 H), 2.58 - 2.44 (m, 2H), 1.41 - 1.36 (m, 1 H), 1.30 - 1.27 (m, 1 H), 0.59 (dd, J= 8.0, 4.5 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 159.02 (d, JC-F = 9.6 Hz), 158.56 (d, JC-F = 247.9 Hz), 139.78, 134.84, 130.67, 128.46, 123.42, 120.38, 112.38 (d, JC-F = 17.9 Hz), 111 .49 (d, JC-F = 3.3 Hz), 109.77, 103.69 (d, JC-F = 24.1 Hz), 72.60, 59.22, 56.76, 54.79, 29.89, 27.00, 20.82, 12.87.

[0146] Illustrative Procedures for Compounds having [3.3.0] bicyclic structure

[0147] Compounds of the disclosure comprising a [3.3.0] bicyclic structure were prepared using the following illustrative general procedures.

[0148] To methyl cyclopent- 1 -ene-1 -carboxylate (I, 1 .0 equiv) and A / -benzyl-1 -methoxy- / V- ((trimethylsilyl)methyl)methanamine (J, 1.5 equiv) was added lithium fluoride (3 equiv.) at room temperature. Then the reaction was stirred at 120 °C - 140 °C overnight (~16 h). Conversion was checked by LCMS and TLC. Then the reaction was cooled to room temperature, rinsed with acetone, filtered, concentrated in vacuo, and purified by normal phase chromatography (0- 40% hexanes / ethyl acetate) to yield the desired compound.

[0149] Methyl 2-benzylhexahydrocyclopenta[c]pyrrole-3a(1 H)-carboxylate (K).Prepared using general procedure. Yield = 6.90 g (74.6%, yellow oil). LCMS: RT = 1.804 min, ESI-MS: m / z [M + H]+, calc’d 260.16 for C16H21NO2, found 260.1.1H NMR (600 MHz, CDCI3) 6 7.38 - 7.27 (m, 4H), 7.25 - 7.20 (m, 1 H), 3.68 (s, 3H), 3.59 (d, J= 13.2 Hz, 1 H), 3.53 (d, J= 13.2 Hz, 1 H), 2.93 (d, J = 9.4 Hz, 1 H), 2.88 (tt, J = 8.2, 4.3 Hz, 1 H), 2.68 (dd, J = 9.0, 7.5 Hz, 1 H), 2.44 (d, J = 9.3 Hz, 1 H), 2.32 (dd, J = 9.1 , 4.3 Hz, 1 H), 2.07 - 1.97 (m, 1 H), 1.86 (dtd, J= 12.0, 7.9, 6.4 Hz, 1 H), 1.81 - 1 .69 (m, 2H), 1.67 - 1 .60 (m, 1 H), 1.55 - 1 .47 (m, 1 H).13C NMR (125 MHz, CDCI3) 6 177.91 , 139.26, 128.59, 128.27, 126.90, 63.71 , 61 .26, 59.67, 59.62, 52.07, 47.75, 38.39, 33.54, 26.83.

[0150] A solution of methyl 2-benzylhexahydrocyclopenta[c]pyrrole-3a(1 H)-carboxylate K (1 equiv.) in MeOH and catalytic amount of acetic acid was hydrogenated in the presence of 10% Pd / C, for 24 h. Conversion is checked by LCMS and TLC. After full conversion, the reaction was filtered through a pad of celite. The solution was concentrated and dissolved in DCE. Then Ar-CHO (R2) was added at room temperature and the mixture was stirred for 2 h. Followed by slow addition of sodium triacetoxyborohydride (4 equiv.) at room temperature and stirred overnight. The reaction was quenched with sodium bicarbonate solution, extracted with DCM, washed with brine, dried with magnesium sulfate, concentrated, and purified by column chromatography to yield the desired compound.

[0151] Methyl 2-(imidazo[1 ,2-a]pyridin-2-ylmethyl)hexahydrocyclopenta[c]pyrrole- 3a(1 H)-carboxylate (L). Prepared using general procedure B. Yield = 1.66 g (27%-41%, brown oil). LCMS: RT = 1 .544 min, ESI-MS: m / z [M + H]+, calc’d 300.16 for C17H21N3O2, found 300.1 .1H NMR (600 MHz, CDCI3) 6 8.08 - 8.03 (m, 1 H), 7.55 - 7.50 (m, 2H), 7.14 - 7.08 (m, 1 H), 6.76 - 6.70 (m, 1 H), 3.85 - 3.79 (m, 1 H), 3.78 - 3.71 (m, 1 H), 3.67 (s, 3H), 3.24 (d, J = 9.5 Hz, 1 H), 2.95 - 2.88 (m, 2H), 2.45 (d, J = 9.6 Hz, 1 H), 2.38 - 2.32 (m, 1 H), 2.03 - 1 .94 (m, 1 H), 1.88 - 1 .79 (m, 1 H), 1.79 - 1 .69 (m, 2H), 1.69 - 1 .60 (m, 1 H), 1.58 - 1 .49 (m, 1 H).13C NMR (125 MHz, CDCI3) 6 177.92, 144.95, 144.64, 125.67, 124.29, 117.43, 112.18, 110.70, 63.64, 61.44, 59.72, 53.55, 52.19, 47.90, 38.01 , 32.98, 26.55.

[0152] Methyl 2-((1 -methyl-1 / 7-indazol-5-yl)methyl)hexahydrocyclopenta[c]pyrrole- 3a(1 H)-carboxylate (M). Prepared using general procedure B. Yield: 2.60 g (55%, brown oil). LCMS: RT = 1 .801 min, ESI-MS: m / z [M + H]+, calc’d 314.18 for C18H23N3O2, found 314.1 .1H NMR (600 MHz, CDCI3) 6 7.92 (s, 1 H), 7.61 (s, 1 H), 7.43 - 7.38 (m, 1 H), 7.33 (d, J = 8.6 Hz, 1 H), 4.06 (s, 3H), 3.67 (s, 5H), 2.95 (d, J = 9.4 Hz, 1 H), 2.88 (ft, J = 8.2, 4.4 Hz, 1 H), 2.70 (t, J =8.3 Hz, 1 H), 2.43 (d, J = 9.5 Hz, 1 H), 2.32 (s, 1 H), 2.05 - 1 .97 (m, 1 H), 1 .85 (dtd, J = 12.0, 7.8,6.3 Hz, 1 H), 1.80 - 1 .69 (m, 2H), 1 .64 (dp, J = 11 .2, 5.7 Hz, 1 H), 1.54 - 1 .47 (m, 1 H).13C NMR (125 MHz, CDCI3) 6 177.92, 139.54, 132.64, 131.48, 127.82, 124.12, 120.43, 108.82, 63.65, 61.19, 59.74, 59.62, 52.14, 47.78, 38.39, 35.68, 33.50, 26.82.

[0153] To a solution of L,M (1 equiv.) in THF was added lithium borohydride at room temperature. Then the reaction was warmed to 50 °C and stirred overnight. Conversion was checked by LCMS and TLC. The mixture was quenched with deionized water (25 mL), extracted with dichloromethane (50 mL x 3), combined organic phases washed with brine (25 mL), dried with magnesium sulfate, and concentrated in vacuo. The residue was dissolved in DMF and NaH (2 equiv) was added. The mixture was stirred for 1 h Then Ar-X (R1, 1.1 equiv.) was added, and the reaction was heated to 120 °C and stirred overnight. The reaction was quenched with deionized water (5 mL), extracted with ethyl acetate (30 mL x 3), washed with water (10 mL x 5), combined organic phases washed with brine (15 mL), dried with magnesium sulfate, concentrated in vacuo, and purified by normal phase chromatography (0-5% methanol / dichloromethane) to yield the desired compound.

[0154] 2-((3a-(((6-Chloropyridin-2-yl)oxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 H)- yl)methyl)imidazo[1 ,2-a]pyridine (36). Prepared using general procedure C. Yield: 1.9 mg (4.5%, yellow oil). LCMS: RT = 2.068 min, ESI-MS: m / z [M + H]+, calc’d 383.16 for C21H23CIN4O, found 383.1.1H NMR (600 MHz, CDCI3) 6 8.05 (d, J = 6.8 Hz, 1 H), 7.66 (s, 1 H), 7.50 (d, J = 9.1 Hz, 1 H), 7.46 (t, J = 7.8 Hz, 1 H), 7.16 - 7.04 (m, 1 H), 6.84 (d, J = 7.5 Hz, 1 H), 6.73 (t, J = 6.7 Hz, 1 H), 6.63 (d, J = 8.2 Hz, 1 H), 4.26 - 4.09 (m, 2H), 3.99 - 3.85 (m, 2H), 3.06 (t, J= 8.8 Hz, 1 H), 2.95 (d, J= 10.1 Hz, 1 H), 2.65 (d, J= 10.1 Hz, 1 H), 2.56 - 2.46 (m, 1 H), 2.41 (t, J= 5.4Hz, 1 H), 1.82 - 1.72 (m, 2H), 1 .72 - 1 .65 (m, 2H), 1.61 - 1.53 (m, 2H).13C NMR (150 MHz, CDCI3) 5 163.94, 148.35, 144.98, 142.79, 140.72, 125.88, 124.61 , 117.46, 116.43, 112.42, 111.78, 109.28, 72.24, 63.67, 60.96, 53.94, 53.42, 45.90, 36.40, 32.47, 25.89.

[0155] 5-((3a-(((6-Chloropyridin-2-yl)oxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 H)- yl)methyl)-1-methyl-1H-indazole (37). Prepared using general procedure C. Yield: 2.7 mg (4.4%, brown oil). LCMS: RT = 2.179 min, ESI-MS: m / z [M + H]+, calc’d for 397.17 C22H25CIN4O, found 397.1.1H NMR (600 MHz, CDCI3) 5 7.91 (d, J = 1.0 Hz, 1 H), 7.61 (s, 1 H), 7.47 (t, J = 7.8 Hz, 1 H), 7.44 - 7.40 (m, 1 H), 7.34 - 7.30 (m, 1 H), 6.86 (d, J = 7.5 Hz, 1 H), 6.60 (d, J = 8.2 Hz, 1 H), 4.24 - 4.11 (m, 2H), 4.05 (s, 2H), 3.65 (s, 2H), 2.73 (t, J= 8.0 Hz, 1 H), 2.62 (d, J= 9.3 Hz, 1 H), 2.38 (d, J = 9.3 Hz, 1 H), 2.33 - 2.24 (m, 1 H), 1.81 - 1.66 (m, 4H), 1 .66 - 1 .54 (m, 2H), 1.51 - 1.45 (m, 1 H).13C NMR (125 MHz, CDCI3) 5 164.16, 148.36, 140.55, 139.49, 132.59, 131.81 , 127.84, 124.07, 120.32, 116.17, 109.23, 108.75, 72.84, 64.17, 61.23, 59.94, 53.82, 46.01 , 36.55, 35.64, 32.98, 26.13.

[0156] To a solution of L,M (1 equiv.) in THF was added lithium borohydride at room temperature. Then the reaction was warmed to 50 °C and stirred overnight. Conversion was checked by LCMS and TLC. The mixture was quenched with deionized water (25 mL), extracted with dichloromethane (50 mL x 3), combined organic phases washed with brine (25 mL), dried with magnesium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane (5 mL) and triethylamine (2 equiv.) was added. The reaction was cooled to 0°C and methanesulfonyl chloride (2 equiv.) was added slowly. The mixture was brought to room temperature and stirred for 2 hours. Conversion was checked by LCMS and TLC. The mixture was quenched with deionized water (2 mL), extracted with dichloromethane (5 mL x 3), combined organic phases washed with brine (5 mL), dried with magnesium sulfate, and concentrated in vacuo. The residue was dissolved in DMF and CS2CO3 (4 equiv) was added. The mixture was stirred for 1 h Then Phenol (R1, 1 .0 equiv.) was added, and the reaction was heated to 120 °C and stirred 24 to 48 h. The reaction was quenched with deionized water (5 mL), extracted with ethyl acetate (30 mL x 3), washed with water (10 mL x 5), combined organic phases washed with brine (15 mL), dried with magnesium sulfate, concentrated in vacuo, and purified by normal phase chromatography (0-10% methanol / dichloromethane) to yield the desired compound.

[0157] 2-((3a-((3,4- Dif luorophenoxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 / - / )- yl)methyl)imidazo[1 ,2-a]pyridine (38). Prepared using general procedure D. Yield: 3.1 mg (13%, yellow oil). LCMS: RT = 2.331 min, ESI-MS: m / z [M + H]+, calc’d 384.18 for C22H23F2N3O,found 384.1 .1H NMR (600 MHz, CDCI3) 6 8.09 - 8.03 (m, 1 H), 7.57 - 7.51 (m, 2H), 7.16 - 7.09 (m, 1 H), 7.01 (dt, J = 10.0, 9.1 Hz, 1 H), 6.80 - 6.72 (m, 1 H), 6.72 - 6.65 (m, 1 H), 6.59 - 6.53 (m, 1 H), 3.94 - 3.76 (m, 3H), 3.72 (d, J = 8.3 Hz, 1 H), 3.05 (s, 1 H), 2.95 - 2.90 (m, 1 H), 2.45 (d, J= 9.4 Hz, 1 H), 2.34 (s, 2H), 1.80 - 1.58 (m, 5H), 1.58 - 1.49 (m, 1 H).13C NMR (125 MHz, CDCI3) 6 155.90, 151 .57, 151 .46, 149.49, 145.07, 144.02, 125.71 , 124.43, 117.57, 117.25, 117.23, 117.10, 112.31 , 111.03, 109.95, 109.92, 109.90, 109.88, 104.34, 104.18, 75.03, 63.96, 61 .35, 54.27, 53.57, 46.01 , 36.20, 32.36, 25.84. (Additional peaks due to F splitting)

[0158] 2-((3a-((4-Chloro-3-fluorophenoxy)rnethyl)hexahydrocyclopenta[c]pyrrol-2(1 H)- yl)methyl)imidazo[1 ,2-a]pyridine (39). Prepared using general procedure D. Yield: 1.1 mg (4.3%, yellow oil). LCMS: RT = 2.476 min, ESI-MS: m / z [M + H]+, calc’d 400.15 for C22H23CIFN3O, found 400.1 .1H NMR (600 MHz, CDCI3) 5 8.06 - 8.01 (m, 1 H), 7.57 - 7.50 (m, 1 H), 7.48 (s, 1 H), 7.20 (t, J = 8.7 Hz, 1 H), 7.13 - 7.08 (m, 1 H), 6.75 - 6.69 (m, 1 H), 6.67 (dd, J = 11.0, 2.8 Hz, 1 H), 6.62 - 6.57 (m, 1 H), 3.89 (d, J = 8.3 Hz, 1 H), 3.81 - 3.69 (m, 3H), 2.99 (t, J = 7.7 Hz, 1 H), 2.85 (d, J = 9.5 Hz, 1 H), 2.38 (d, J = 9.5 Hz, 1 H), 2.33 - 2.24 (m, 2H), 1 .78 - 1 .57 (m, 5H), 1 .55 - 1 .47 (m, 1 H).13C NMR (125 MHz, CDCI3) 6 159.44, 159.41 , 159.34, 157.47, 145.01 , 144.81 , 130.47, 125.59, 124.23, 117.50, 112.15, 112.04, 111.90, 111.35, 111.32, 110.61 , 103.63, 103.44, 74.97, 64.15, 61.53, 54.18, 53.68, 46.03, 36.11 , 32.38, 25.84. (Additional peaks due to F splitting)

[0159] 5-((3a-((3,4-Dif luorophenoxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 H)- yl)methyl)-1-methyl-1 / -indazole (40). Prepared using general procedure D. Yield: 3.5 mg (5.9%, yellow oil). LCMS: RT = 2.246 min, ESI-MS: m / z [M + H]+, calc’d 398.20 for C23H25F2N3O, found 398.1 .1H NMR (600 MHz, CDCI3) 5 7.92 (s, 1 H), 7.62 (s, 1 H), 7.42 (d, J = 8.6 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 1 H), 7.07 - 6.98 (m, 1 H), 6.73 - 6.65 (m, 1 H), 6.59 - 6.53 (m, 1 H), 4.06 (s, 3H), 3.85 (d, J = 8.3 Hz, 1 H), 3.73 - 3.64 (m, 3H), 2.85 - 2.82 (m, 1 H), 2.71 - 2.66 (m, 1 H), 2.35 - 2.27 (m, 1 H), 2.23 (d, J = 8.5 Hz, 1 H), 1.82 - 1 .58 (m, 4H), 1 .55 - 1 .47 (m, 1 H), 1 .26 (s, 2H).13C NMR (125 MHz, CDCI3) 6 155.95, 155.88, 151 .56, 151 .45, 149.59, 149.49, 145.99, 145.89, 144.08, 143.97, 139.54, 132.64, 127.89, 124.12, 120.57, 117.24, 117.22, 117.09, 117.09, 109.92, 109.90, 109.88, 109.85, 108.86, 104.26, 104.10, 75.17, 63.85, 61.20, 59.93, 54.17, 45.99, 36.31 , 35.69, 32.69, 26.00. (additional peaks due to F splitting)

[0160] 5-((3a-((4-Chloro-3-fluorophenoxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 H)- yl)methyl)-1-methy 1-1 / -indazole (41). Prepared using general procedure D. Yield: 4.0 mg (6.7%, yellow oil). LCMS: RT = 2.361 min, ESI-MS: m / z [M + H]+, calc’d 414.17 for C23H25CIFN3O, found 414.1.1H NMR (600 MHz, CDCI3) 5 7.92 (s, 1 H), 7.61 (s, 1 H), 7.42 (d, J = 8.6 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 1 H), 7.22 (t, J= 8.7 Hz, 1 H), 6.68 (dd, J= 10.9, 2.8 Hz, 1 H), 6.64 - 6.59 (m, 1 H), 4.06 (s, 3H), 3.86 (d, J = 8.5 Hz, 1 H), 3.72 (d, J= 8.3 Hz, 1 H), 3.67 (s, 2H), 2.83 (s, 1 H), 2.68 (s, 1 H), 2.31 - 2.20 (m, 2H), 1.79 - 1 .58 (m, 6H), 1 .50 (s, 1 H).13C NMR (125 MHz, CDCI3) 5 155.95, 155.88, 151.56, 151.45, 149.59, 149.49, 145.99, 145.89, 144.08,143.97, 139.54, 132.64, 131.78, 127.89, 124.12, 120.57, 117.24, 117.22, 117.09, 117.09, 109.92, 109.90, 109.88, 109.85, 108.86, 104.26, 104.10, 75.17, 63.85, 61.20, 59.93, 54.17, 45.99, 36.31, 35.69, 32.69, 26.00. (additional peaks due to F splitting)

[0161] 5-((3a-((4-Fluoro-3-methylphenoxy)rnethyl)hexahydrocyclopenta[c]pyrrol-2(1 / 7)-y l)methyl)-1-methy 1-1 / -indazole (42). Prepared using general procedure D. Yield: 1.6 mg (3.7%, yellow oil). LCMS: RT = 2.295 min, ESI-MS: m / z [M + H]+, calc’d 394.22 for C24H28FN3O, found 394.2.1H NMR (500 MHz, CDCI3) 57.93 (s, 1H), 7.63 (s, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.34 (d, J =8.6 Hz, 1H), 6.87 (t, J =9.0 Hz, 1H), 6.71 -6.65 (m, 1 H), 6.65 - 6.59 (m, 1 H), 4.06 (s, 3H), 3.85 (d, J = 8.4 Hz, 1 H), 3.76 - 3.65 (m, 3H), 2.89 - 2.79 (m, 1 H), 2.72 (d, J=9.5 Hz, 1H), 2.37 (d, J=9.4 Hz, 1 H), 2.34 - 2.18 (m, 5H), 1.80-1.58 (m, 5H), 1.54-1.46 (m, 1 H).13C NMR (125 MHz, CDCI3) 5156.80, 155.37, 155.35, 154.91 , 139.54, 132.65, 131.21,127.94, 125.60, 125.45, 124.11, 120.67, 117.33, 117.29, 115.35, 115.16, 112.58, 112.52, 108.86, 74.88, 63.89, 61.14, 59.92, 54.26, 45.98, 36.41, 35.67, 32.73, 26.03, 14.89, 14.86. (additional peaks due to F splitting)

[0162] 5-((3a-((3-Fluoro-4-methylphenoxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 / 7)-yl)methyl)-1-methyl-1 / 7-indazole (43). Prepared using general procedure D. Yield: 7.8 mg (8.1%, yellow oil). LCMS: RT = 2.345 min, ESI-MS: m / z [M + H]+, calc’d 394.22 for C24H28FN3O , found 394.2.1H NMR (600 MHz, CDCI3) 57.92 (d, J= 1.0 Hz, 1 H), 7.62 (s, 1 H), 7.42 (d, J= 9.4 Hz, 1 H), 7.33 (d, J= 8.5 Hz, 1 H), 7.02 (t, J= 8.7 Hz, 1 H), 6.59 - 6.53 (m, 2H), 4.06 (s, 3H), 3.85 (d, J= 8.3 Hz, 1 H), 3.72 (d, J= 8.4 Hz, 1H), 3.66 (s, 2H), 2.74 (d, J= 74.8 Hz, 2H), 2.36 - 2.25 (m, 3H), 2.18 (d, J = 1.8 Hz, 4H), 1.79-1.66 (m, 3H), 1.66 - 1.57 (m, 1 H), 1.50 (s, 1 H).13C NMR (125 MHz, CDCI3) 5162.53, 160.72, 158.03, 157.96, 139.5, 132.64, 131.32, 127.9, 125.3, 120.66, 117.15, 117.18, 109.99, 109.97, 108.88, 102.25, 102.09, 74.84, 63.87, 61.16, 59.9, 54.22, 45.97, 36.37, 35.66, 32.71 , 25.99, 13.82, 13.8. (additional peaks due to F splitting)

[0163] 2-benzyl-3a-((3,4-dif luorophenoxy)methyl)octahydrocyclopenta[c]pyrrole. (44)General Procedure. Yield = 1.14g (52.1%, yellow oil). LCMS: RT = 2.251 min, ESI-MS: m / z [M+H]+, calc’d 344.17 for C21H23F2NO, found 344.1.1H NMR (600 MHz, CDCI3) 57.39 - 7.27 (m, 4H), 7.24 (dd, J= 13.1, 6.1 Hz, 1H), 7.03 (q, J= 9.4 Hz, 1H), 6.70 (ddd, J= 12.1, 6.6, 3.0 Hz, 1H), 6.57 (dtd, J= 8.6, 3.2, 1.7 Hz, 1H), 3.84 (d, J= 8.3 Hz, 1H), 3.71 (d, J= 8.3 Hz, 1H), 3.57 (s, 2H), 2.83-2.77 (m, 1H), 2.68-2.64 (m, 1H), 2.33-2.26 (m, 2H), 2.23-2.16 (m, 1H), 1.82-1.57 (m, 5H), 1.53- 1.46 (m, 1 H).13C NMR (150 MHz, CDCI3) 5155.94 (dd, J = 8.7, 2.2 Hz), 150.54 (dd, J =247.1, 13.7 Hz), 144.99 (dd, J =239.5, 12.7 Hz), 139.15, 128.77, 128.35, 127.04, 117.16 (d, J= 18.0 Hz), 109.89 (dd, J =5.6, 3.3 Hz), 104.20 (d, J= 20.1 Hz).75.19,63.94, 61.26, 59.89, 54.19, 46.01, 36.30, 32.71, 26.02.

[0164] 5-((3a-((3,4-d if luorophenoxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 H)- yl)methyl)benzo[cf]thiazole. (45) General Procedure. Yield = 54.4 mg (46.2%, brown oil). LCMS: RT = 2.240 min, ESI-MS: m / z [M+H]+, calc’d 401.14 for C22H22F2N2OS, found 401.1.1H NMR (600 MHz, CDCI3) 58.97 (s, 1 H), 8.08 (s, 1 H), 7.87 (d, J = 8.2 Hz, 1 H), 7.46 (dd, J = 8.2, 1.6 Hz, 1H), 7.01 (dt, J= 9.9, 9.1 Hz, 1H), 6.69 (ddd, J= 12.1, 6.6, 3.0 Hz, 1H), 6.59-6.53 (m, 1H), 3.83 (d, J=8.3 Hz, 1H), 3.75-3.67 (m, 3H), 2.81 (t, J = 7.6 Hz, 1H), 2.67 (d, J = 9.3 Hz, 1H), 2.37 (d, J =9.3 Hz, 1H), 2.31 -2.22 (m, 2H), 1.82-1.55 (m, 5H), 1.55- 1.47 (m, 1H).13C NMR (150 MHz, CDCI3) 5155.89 (dd, J = 8.7, 2.1 Hz), 154.17, 153.62, 150.49 (dd, J = 247.1, 13.8 Hz), 144.94 (dd, J =239.8, 12.8 Hz), 138.18, 132.21, 126.57, 123.29, 121.56, 117.12 (d, J = 18.5 Hz), 109.83 (dd, J=6.0, 3.3 Hz), 104.16 (d, J=20.0 Hz).75.15, 64.03, 61.27, 59.63, 54.19, 46.03, 36.32, 32.81, 26.06.

[0165] 6-chloro-2-((3a-((3,4-difluorophenoxy)methyl)hexahydrocyclopenta[c]pyrrol- 2(1H)-yl)methyl)imidazo[1,2-b]pyridazine. (46) General Procedure. Yield = 20.7 mg (29.3%, brown oil). LCMS: RT = 2.273 min, ESI-MS: m / z [M+H]+, calc’d 419.14 for C21H21CIF2N4O, found 419.1.1H NMR (600 MHz, CDCI3) 57.85 (s, 1H), 7.81 (d, J=9.4 Hz, 1H), 7.01 (dd, J =9.3, 1.4 Hz, 2H), 6.67 (ddd, J = 12.1, 6.6, 3.0 Hz, 1H), 6.58-6.52 (m, 1H), 3.85 (d, J = 8.3 Hz, 1H), 3.78 (q, J = 14.0 Hz, 2H), 3.70 (d, J = 8.3 Hz, 1H), 2.97-2.90 (m, 1H), 2.80 (d, J=9.4 Hz, 1H), 2.39 (d, J = 9.4 Hz, 1H), 2.33-2.26 (m, 2H), 1.79-1.56 (m, 5H), 1.55- 1.47 (m, 1H).13C NMR (150 MHz, CDCI3) 5155.85 (dd, J = 8.8, 2.2 Hz), 150.50 (dd, J = 247.1, 13.7 Hz), 146.55, 146.40144.97 (dd, J = 239.5, 12.8 Hz), 137.24, 126.51, 118.60, 117.14 (d, J = 18.3 Hz), 115.68, 109.82 (dd, J = 5.9, 3.3 Hz), 104.18 (d, J = 20.1 Hz), 75.09, 64.18, 61.53, 54.27, 53.79, 46.05, 36.24, 32.53, 25.91.

[0166] 3a-((3,4-difluorophenoxy)methyl)-2-(3-fluoro-4- methoxybenzyl)octahydrocyclopenta[c]pyrrole. (47) General Procedure. Yield = 22.6 mg (40.6%, brown oil). LCMS: RT = 2.370 min, ESI-MS: m / z [M+H]+, calc’d 392.18 for C22H24F3NO2, found 392.2.1H NMR (600 MHz, CDCI3) 57.11 - 6.97 (m, 3H), 6.88 (t, J = 8.5 Hz, 1 H), 6.70 (ddd, J = 12.1, 6.6, 3.0 Hz, 1H), 6.60-6.54 (m, 1H), 3.87 (s, 3H), 3.83 (d, J=8.3 Hz, 1H), 3.70 (d, J = 8.3 Hz, 1 H), 3.48 (s, 2H), 2.76 (t, J = 8.3 Hz, 1 H), 2.62 (d, J = 9.3 Hz, 1 H), 2.28 (dd, J = 18.2, 9.7 Hz, 2H), 2.21 -2.15 (m, 1H), 1.84-1.55 (m, 5H), 1.53- 1.45 (m, 1H).13C NMR (150 MHz, CDCI3) 5155.94 (d, J = 8.3 Hz), 152.44 (d, J = 245.0 Hz), 150.55 (dd, J = 247.3, 13.6 Hz), 146.59 (d, J = 10.5 Hz), 145.01 (dd, J = 239.5, 12.8 Hz), 132.71, 124.10, 117.19 (d, J = 18.1 Hz), 116.37 (d, J = 18.1 Hz), 113.18 (d, J = 2.1 Hz), 109.89 (dd, J = 5.9, 3.3 Hz), 104.22 (d, J = 20.0 Hz), 75.19, 63.91, 61.18, 58.90, 56.44, 54.19, 46.03, 36.35, 32.78, 26.05.

[0167] 5-((3a-((3,4-difluorophenoxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1H)- yl)methyl)-1 / 7-indazole. (48) General Procedure. Yield = 42.8 mg (38.1%, brown oil). LCMS: RT = 2.043 min, ESI-MS: m / z [M+H]+, calc’d 384.18 for C22H23F2N3O, found 384.1.1H NMR (600 MHz, CDCI3) 510.37 (s, 2H), 8.00 (s, 1 H), 7.66 (s, 1 H), 7.38 (s, 2H), 6.98 (q, J = 9.4 Hz, 1 H),6.65 (ddd, J = 12.1 , 6.6, 3.0 Hz, 1 H), 6.52 (dtd, J= 9.1 , 3.1 , 1.6 Hz, 1 H), 3.87 (d, J= 8.4 Hz, 1 H), 3.80 (q, J= 12.8 Hz, 1 H), 3.70 (d, J= 8.4 Hz, 1 H), 3.08 - 2.99 (m, 1 H), 2.89 (d, J= 10.0 Hz, 1 H), 2.43 (d, J = 10.0 Hz, 1 H), 2.40 - 2.29 (m, 2H), 1.82 - 1 .58 (m, 5H), 1 .57 - 1 .49 (m, 1 H).13C NMR (150 MHz, CDCI3) 5 155.60 (dd, J= 8.7, 2.2 Hz), 150.36 (dd, J = 247.2, 13.8 Hz), 144.90 (dd, J = 239.8, 12.7 Hz), 139.76, 134.35, 129.78, 128.38, 123.24, 120.96, 117.04 (d, J = 18.6 Hz), 109.97, 109.75 (dd, J = 5.9, 3.3 Hz), 104.11 (d, J = 20.1 Hz), 74.64, 63.12, 60.50,59.55, 53.96, 45.68, 36.20, 32.19, 25.67.

[0168] 2-(3a-((3,4-difluorophenoxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 / 7)-yl)-A / - (4-fluoro-3-methylphenyl)acetamide. (49) General Procedure. Yield = 7.2 mg (17.1%, clear oil). LCMS: RT = 2.341 min, ESI-MS: m / z [M+H]+, calc’d 419.19 for C23H25F3N2O2, found 419.1 .1H NMR (600 MHz, CDCI3) 5 9.02 (s, 1 H), 7.35 (dd, J = 6.9, 2.7 Hz, 1 H), 7.32 - 7.25 (m, 1 H), 7.08 (q, J= 9.3 Hz, 1 H), 6.95 (t, J= 9.0 Hz, 1 H), 6.75 (ddd, J = 12.0, 6.5, 3.0 Hz, 1 H), 6.65 - 6.59 (m, 1 H), 3.84 (d, J = 2.9 Hz, 2H), 3.37 - 3.13 (m, 2H), 2.90 (d, J = 51.8 Hz, 2H), 2.68 - 2.36 (m, 3H), 2.25 (d, J = 2.0 Hz, 3H), 1 .96 - 1 .76 (m, 3H), 1 .76 - 1 .67 (m, 2H), 1.60 - 1 .50 (m, 1 H).13C NMR (150 MHz, CDCI3) 5 168.48, 158.05 (d, J = 242.2 Hz), 155.59 (d, J = 7.4 Hz), 150.61 (dd, J = 248.0, 13.8 Hz), 145.24 (dd, J = 240.6, 12.7 Hz), 133.43 (d, J = 3.1 Hz), 125.56 (d, J = 18.3 Hz), 122.60 (d, J= 4.7 Hz), 118.49 (d, J = 7.8 Hz), 117.38 (dd, J = 18.1 , 1.2 Hz), 115.33 (d, J = 23.3 Hz), 110.00 (dd, J = 5.8, 3.3 Hz), 104.27 (d, J = 20.4 Hz), 74.87, 64.37, 61.57, 58.55, 54.55, 46.30, 36.77, 33.11 , 26.18, 14.75 (d, J = 3.3 Hz).

[0169] 1 -(3a-((3,4-difluorophenoxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 H)-yl)-2- (3,4-difluorophenyl)ethan-1-one. (50) General Procedure. Yield = 30.7 mg (19.1%, brown oil). LCMS: RT = 2.911 min, ESI-MS: m / z [M+H]+, calc’d 408.15 for C22H21F4NO2, found 408.1.1H NMR (600 MHz, CDCI3) 5 7.15 - 6.92 (m, 8H), 6.68 - 6.61 (m, 2H), 6.55 - 6.48 (m, 2H), 3.84 - 3.64 (m, 8H), 3.58 (d, J = 10.6 Hz, 4H), 3.51 - 3.29 (m, 4H), 2.60 - 2.36 (m, 2H), 1 .99 - 1 .87 (m, 2H), 1.84 - 1 .63 (m, 5H), 1.57 - 1 .42 (m, 2H).13C NMR (150 MHz, CDCI3) 5 168.76,168.73, 155.28, 155.20, 155.14, 151.43, 151.34, 151.21 , 151.12, 150.31 , 149.79, 149.69,149.55, 148.63, 146.08, 144.55, 144.48, 131.87, 131.83, 131.80, 125.14, 125.04, 118.20,118.11 , 118.09, 118.00, 117.42, 117.40, 117.35, 117.29, 117.24, 109.82, 109.70, 104.25,104.19, 104.11 , 104.06, 77.37, 77.16, 76.95, 73.69, 73.54, 55.61 , 55.31 , 54.79, 53.25, 53.19, 51.86, 46.62, 44.87, 41.04, 40.89, 35.48, 35.42, 32.65, 32.33, 24.96. (Additional Peaks and Hydrogens due to rotamers)

[0170] 3-((3a-((3,4-d if luorophenoxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 H)- yl)methyl)-6-fluoro-1H-indole. (51) General Procedure. Yield = 17.2 mg (23.5%, brown oil). LCMS: RT = 2.177 min, ESI-MS: m / z [M+H]+, calc’d 401.18 for C23H23F3N2O, found 401.1.1H NMR (600 MHz, CDCI3) 5 8.80 (s, 1 H), 7.59 (dd, J = 8.7, 5.2 Hz, 1 H), 7.24 (s, 1 H), 7.07 (dd, J = 9.5, 2.3 Hz, 1 H), 6.98 (q, J = 9.3 Hz, 1 H), 6.88 (td, J = 9.1 , 2.3 Hz, 1 H), 6.65 (ddd, J = 12.0, 6.6, 3.0 Hz, 1 H), 6.57 - 6.47 (m, 1 H), 4.04 - 3.84 (m, 3H), 3.71 (d, J = 8.5 Hz, 1 H), 3.14 - 2.89 (m,2H), 2.61 - 2.36 (m, 3H), 1.80 - 1.52 (m, 6H).13C NMR (150 MHz, CDCI3) 6 159.98 (d, J = 237.9 Hz), 155.42 (d, J = 8.5 Hz), 150.37 (dd, J = 247.3, 13.8 Hz), 144.99 (dd, J = 240.3, 12.9 Hz), 136.16 (d, J = 12.5 Hz), 124.95, 124.02, 120.91 , 119.61 (d, J = 11.0 Hz), 117.09 (d, J = 18.3 Hz), 109.74 (dd, J = 5.8, 3.3 Hz), 108.59 (d, J = 24.9 Hz), 104.18 (d, J = 20.2 Hz), 97.76 (d, J = 26.1 Hz), 74.36, 62.72, 60.23, 54.00, 49.93, 45.67, 36.19, 32.14, 25.66.

[0171] 3a-((3,4-d if luorophenoxy)methyl)-2-(pyridin-3- ylmethyl)octahydrocyclopenta[c]pyrrole. (52) General Procedure. Yield = 10.4 mg (10.2%, brown oil). LCMS: RT = 2.003 min, ESI-MS: m / z [M+H]+, calc’d 345.17 for C20H22F2N2O, found 345.3.1H NMR (600 MHz, CDCI3) 5 8.59 - 8.45 (m, 2H), 7.71 (s, 1 H), 7.27 - 7.22 (m, 1 H), 7.03 (dt, J = 10.1 , 9.1 Hz, 1 H), 6.69 (ddd, J = 12.0, 6.6, 3.0 Hz, 1 H), 6.57 (dtd, J= 9.0, 3.2, 1.7 Hz, 1 H), 3.84 (d, J= 8.6 Hz, 1 H), 3.71 (d, J = 8.3 Hz, 1 H), 3.61 (s, 2H), 2.76 (d, J = 75.2 Hz, 2H), 2.30 (t, J = 34.7 Hz, 3H), 1.80 - 1 .42 (m, 6H).13C NMR (150 MHz, CDCI3) 5 155.78 (d, J = 8.5 Hz), 150.55 (dd, J = 247.5, 13.8 Hz), 150.19, 148.81 , 145.07 (dd, J= 239.8, 12.8 Hz), 144.71 , 136.62, 123.55, 117.23 (dd, J= 18.4, 1.3 Hz), 109.87 (dd, J= 5.8, 3.3 Hz), 104.22 (d, J= 20.3 Hz), 74.91 , 63.80, 61.12, 57.04, 54.23, 45.96, 36.38, 32.68, 26.00.

[0172] 1-(3a-((3,4-difluorophenoxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 H)-yl)-2- (3-fluoro-4-methoxyphenyl)ethan-1-one. (53) General Procedure. Yield = 48.3 mg (25.4%, yellow oil). LCMS: RT = 2.861 min, ESI-MS: m / z [M+H]+, calc’d 420.17 for C23H24F3NO3, found 420.2.1H NMR (600 MHz, CDCI3) 5 7.09 - 6.94 (m, 5H), 6.94 - 6.85 (m, 2H), 6.80 (t, J= 8.5 Hz, 1 H), 6.65 - 6.59 (m, 2H), 6.54 - 6.47 (m, 2H), 3.89 - 3.77 (m, 7H), 3.77 - 3.61 (m, 7H), 3.55 (d, J = 12.2 Hz, 4H), 3.45 (d, J = 12.8 Hz, 1 H), 3.38 - 3.27 (m, 3H), 2.52 (ft, J = 8.3, 4.2 Hz, 1 H), 2.39 (ft, J = 8.6, 4.9 Hz, 1 H), 1.91 (tq, J= 14.5, 7.3 Hz, 2H), 1.82 - 1.60 (m, 8H), 1.52 (dq, J= 12.3, 5.8 Hz, 1 H), 1.43 (dq, J= 12.9, 6.2 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 169.30, 169.26, 155.33, 155.27, 155.21 , 155.16, 153.17, 153.12, 151.54, 151.49, 151.34,151.25, 149.70, 149.61 , 146.61 , 146.57, 146.54, 146.50, 146.03, 145.99, 145.94, 145.91 ,144.43, 144.40, 144.35, 144.31 , 127.83, 127.79, 127.77, 127.73, 124.70, 124.67, 124.56,124.53, 117.35, 117.31 , 117.23, 117.19, 116.88, 116.76, 116.63, 113.61 , 113.43, 109.79,109.75, 109.72, 109.69, 109.66, 104.20, 104.14, 104.07, 104.00, 73.69, 73.49, 56.36, 56.22, 55.46, 55.23, 54.71 , 53.19, 53.12, 51.74, 46.60, 44.82, 41.10, 40.93, 35.41 , 35.30, 32.59, 32.33, 24.93. (Additional Peaks and Hydrogens due to rotamers)

[0173] (3-bromophenyl)(3a-((3,4- difluorophenoxy)methyl)hexahydrocyclopenta[c]pyrrol-2(1 / 7)-yl)methanone. (54) General Procedure. Yield = 40.0 mg (18.7%, clear oil). LCMS: RT = 3.061 min, ESI-MS: m / z [M+H]+, calc’d 436.06 for C2iH20BrF2NO2, found 436.1.1H NMR (600 MHz, CDCI3) 5 7.61 (d, J= 14.4 Hz, 2H), 7.56 - 7.51 (m, 2H), 7.43 - 7.35 (m, 2H), 7.30 - 7.22 (m, 2H), 7.10 - 7.00 (m, 2H), 6.74 - 6.63 (m, 2H), 6.61 - 6.51 (m, 2H), 4.01 - 3.93 (m, 1 H), 3.90 - 3.60 (m, 8H), 3.55 (dd, J = 13.0, 4.5 Hz, 1 H), 3.35 (d, J= 11.5 Hz, 1 H), 3.27 (dd, J= 11.5, 4.1 Hz, 1 H), 2.54 - 2.48 (m,2H), 2.00 - 1 .67 (m, 9H), 1 .66 - 1 .58 (m, 2H), 1 .48 - 1 .40 (m, 1 H).13C NMR (150 MHz, CDCI3) 5 167.96, 167.94, 167.91 , 155.35, 155.30, 155.22, 155.16, 151.41 , 151.32, 149.77, 149.68, 146.10, 146.02, 144.51 , 144.42, 138.75, 138.72, 133.02, 130.33, 130.09, 125.81 , 125.79, 122.57, 1 17.42, 1 17.42, 1 17.30, 1 17.30, 109.86, 104.28, 104.15, 73.77, 73.53, 57.93, 55.46, 55.30, 54.68, 53.43, 51.87, 46.82, 45.05, 35.86, 35.31 , 32.55, 32.40, 25.16. (Additional Peaks and Hydrogens due to rotamers)

[0174] 5-benzyl-3a-((3,4-difluorophenoxy)methyl)hexahydro-1 / 7-furo[3,4-c]pyrrole. (55) General Procedure. Yield = 236 mg (37.5%, yellow oil). LCMS: RT = 2.018 min, ESI-MS: m / z [M+H]+, calc’d 346.15 for C20H21F2NO2, found 346.2.1H NMR (600 MHz, CDCI3) 6 7.37 - 7.29 (m, 4H), 7.29 - 7.23 (m, 1 H), 7.08 - 7.00 (m, 1 H), 6.74 - 6.67 (m, 1 H), 6.61 - 6.54 (m, 1 H), 3.99 (dd, J = 8.8, 7.2 Hz, 1 H), 3.92 - 3.84 (m, 3H), 3.70 (d, J = 9.0 Hz, 1 H), 3.66 - 3.56 (m, 3H), 2.72 - 2.67 (m, 1 H), 2.66 - 2.61 (m, 1 H), 2.60 - 2.56 (m, 1 H), 2.51 - 2.43 (m, 2H).13C NMR (150 MHz, CDCI3) 6 155.42 (dd, J= 8.7, 2.3 Hz), 150.54 (dd, J= 247.6, 13.8 Hz), 145.20 (dd, J = 240.3, 12.8 Hz), 139.01 , 128.65, 128.41 , 127.14, 1 17.27 (d, J = 17.2 Hz), 109.82 (dd, J = 5.7, 3.4 Hz), 104.24 (d, J = 20.3 Hz), 76.14, 73.98, 72.93, 61.59, 59.35, 58.65, 56.02, 47.1 1.

[0175] 5-(benzo[cf]thiazol-5-ylmethyl)-3a-((3,4-dif luorophenoxy)methyl)hexahydro-1 H- furo[3,4-c]pyrrole. (56) General Procedure. Yield = 33.0 mg (41.9%, brown oil). LCMS: RT = 2.001 min, ESI-MS: m / z [M+H]+, calc’d 403.12 for C21H20F2N2O2S, found 403.1 .1H NMR (600 MHz, CDCI3) 6 8.98 (s, 1 H), 8.07 (s, 1 H), 7.89 (d, J = 8.3 Hz, 1 H), 7.50 - 7.42 (m, 1 H), 7.08 - 6.98 (m, 1 H), 6.72 - 6.64 (m, 1 H), 6.59 - 6.52 (m, 1 H), 3.98 (t, J = 8.1 Hz, 1 H), 3.92 - 3.84 (m, 3H), 3.81 - 3.74 (m, 2H), 3.70 (d, J= 9.0 Hz, 1 H), 3.60 (dd, J= 8.8, 5.3 Hz, 1 H), 2.76 - 2.70 (m, 1 H), 2.68 - 2.64 (m, 1 H), 2.63 - 2.59 (m, 1 H), 2.53 - 2.49 (m, 1 H), 2.49 - 2.43 (m, 1 H).13C NMR (150 MHz, CDCI3) 6 155.36 (dd, J = 8.5, 2.3 Hz), 154.34, 153.64, 150.52 (dd, J = 247.7, 13.8 Hz), 145.19 (dd, J = 240.2, 12.7 Hz), 137.72, 132.44, 126.51 , 123.31 , 121.72, 1 17.26 (d, J = 18.5 Hz), 109.79 (dd, J= 5.6, 3.3 Hz), 104.23 (d, J = 20.0 Hz), 76.12, 73.96, 72.89, 61.56, 59.12, 58.62, 56.04, 47.10.

[0176] 5-((6-chloroimidazo[1 ,2-b]pyridazin-2-yl)methyl)-3a-((3,4- difluorophenoxy)methyl)hexahydro-1 / 7-furo[3,4-c]pyrrole. (57) General Procedure. Yield = 12.5 mg (16.4%, brown oil). LCMS: RT = 1.999 min, ESI-MS: m / z [M+H]+, calc’d 421.12 for C20H19CIF2N4O2, found 421 .1 .1H NMR (600 MHz, CDCI3) 6 7.93 - 7.78 (m, 2H), 7.09 - 6.98 (m, 2H), 6.71 - 6.64 (m, 1 H), 6.59 - 6.51 (m, 1 H), 3.97 - 3.80 (m, 6H), 3.76 - 3.70 (m, 1 H), 3.67 - 3.59 (m, 1 H), 2.97 - 2.74 (m, 2H), 2.74 - 2.65 (m, 1 H), 2.60 - 2.45 (m, 2H).13C NMR (150 MHz, CDCI3) 6 155.55 - 155.01 (m), 150.55 (dd, J = 247.7, 13.8 Hz), 146.74, 146.70, 145.25 (dd, J = 240.4, 13.0 Hz), 137.38, 126.61 , 1 18.87, 1 17.30 (d, J= 19.0 Hz), 115.78, 109.80 (dd, J = 5.7, 3.3 Hz), 104.28 (d, J = 20.3 Hz), 76.15, 73.67, 72.81 , 61.89, 59.04, 56.07, 53.15, 47.14.

[0177] 2-((3a-((3,4-difluorophenoxy)methyl)octahydro-2 / 7-isoindol-2- yl)methyl)imidazo[1 ,2-a]pyridine. (58) General Procedure. Yield = 41.8 mg (51%, yellow oil). LCMS: RT = 2.226 min, ESI-MS: m / z [M+H]+, calc’d 398.20 for C23H25F2N3O, found 398.1.1H NMR (600 MHz, CDCI3) 68.07-7.98 (m, 1H), 7.52 (d, J = 9.1 Hz, 1H), 7.48 (s, 1H), 7.15- 7.07 (m, 1H), 7.00 (dt, J = 10.1, 9.1 Hz, 1H), 6.75-6.69 (m, 1H), 6.70-6.63 (m, 1H), 6.57- 6.51 (m, 1H), 3.93 (d, J =3.0 Hz, 2H), 3.79 (d, J =8.6 Hz, 1H), 3.65 (d, J =8.6 Hz, 1H), 3.03 (dd, J= 9.4, 7.7 Hz, 1 H), 2.89 (d, J= 9.8 Hz, 1 H), 2.78 (dd, J= 9.4, 7.3 Hz, 1 H), 2.73 (d, J= 9.8 Hz, 1H), 2.10-2.01 (m, 1H), 1.73 (ddd, J= 14.0, 5.9, 3.8 Hz, 1H), 1.65 - 1.46 (m, 5H), 1.43- 1.32 (m, 2H).13C NMR (150 MHz, CDCI3) 6155.85 (dd, J = 8.6, 2.2 Hz), 150.50 (dd, J = 247.3, 13.8 Hz), 145.31, 145.02, 144.95 (dd, J= 239.5, 12.8 Hz), 125.58, 124.25, 117.46, 117.14 (d, J = 18.6 Hz), 112.14, 110.64, 109.85 (dd, J= 5.9, 3.4 Hz), 104.11 (d, J= 20.3 Hz), 73.82, 62.66, 58.02, 54.63, 43.94, 39.22, 28.88, 25.63, 21.72, 21.26.

[0178] 2-benzyl-3a-((3,4-difluorophenoxy)methyl)octahydro-1 H-isoindole. (59) General Procedure. Yield = 734.3 mg (52.3%, yellow oil). LCMS: RT = 2.384 min, ESI-MS: m / z [M+H]+, calc’d 358.19 for C22H25F2NO, found 358.1.1H NMR (600 MHz, CDCI3) 57.43 - 7.32 (m, 4H), 7.31 -7.25 (m, 1H), 7.11 -7.03 (m, 1H), 6.76 (ddd, J= 12.1, 6.6, 3.0 Hz, 1H), 6.65-6.60 (m, 1H), 3.86 (d, J =8.6 Hz, 1H), 3.77 (s, 2H), 3.73 (d, J= 8.6 Hz, 1H), 2.90 (dd, J= 9.3, 7.9 Hz, 1H),2.77 (d, J=9.5 Hz, 1 H), 2.73 - 2.63 (m, 2H), 2.13 - 2.05 (m, 1H), 1.85- 1.77 (m, 1H), 1.74-1.66 (m, 1 H), 1.66 - 1.52 (m, 4H), 1.52- 1.40 (m, 2H).13C NMR (150 MHz, CDCI3) 6 155.90 (dd, J= 8.6, 2.2 Hz), 150.51 (dd, J= 247.2, 13.8 Hz), 144.95 (dd, J= 239.9, 12.7 Hz), 139.85, 128.60, 128.27, 126.85, 117.12 (dd, J= 18.4, 1.1 Hz), 109.90 (dd, J= 5.8, 3.2 Hz), 104.14 (d, J= 20.0 Hz), 73.97, 62.72, 60.78, 57.95, 43.83, 39.09, 28.85, 25.86, 21.59, 21.14.

[0179] 5-((3a-((3,4-difluorophenoxy)methyl)octahydro-2H-isoindol-2- yl)methyl)benzo[cf]thiazole. (60) General Procedure. Yield = 15.6 mg (19.5%, brown oil).LCMS: RT = 2.177 min, ESI-MS: m / z [M+H]+, calc’d 415.16 for C23H24F2N2OS, found 415.2.1H NMR (600 MHz, CDCI3) 68.98 (s, 1H), 8.09 (s, 1H), 7.88 (d, J= 8.2 Hz, 1H), 7.47 (d, J= 8.3 Hz, 1H), 7.03 (dt, J= 10.0, 9.1 Hz, 1H), 6.70 (ddd, J= 12.1, 6.6, 3.0 Hz, 1H), 6.57 (dtd, J= 9.1, 3.2, 1.7 Hz, 1H), 3.89 (s, 2H), 3.82 (d, J =8.6 Hz, 1H), 3.69 (d, J =8.6 Hz, 1H), 2.89 (t, J =8.7 Hz, 1H), 2.79-2.60 (m, 3H), 2.10 - 2.03 (m, 1H), 1.75 (dt, J= 14.2, 4.9 Hz, 1H), 1.66 (ddd, J = 14.1, 9.7, 4.0 Hz, 1H), 1.59-1.17 (m, 6H).13C NMR (150 MHz, CDCI3) 6155.81 (dd, J= 8.4, 1.7 Hz), 154.27, 153.64, 150.53 (dd, J = 247.3, 13.7 Hz), 145.02 (dd, J = 239.7, 12.8 Hz), 137.94, 132.32, 126.64, 123.36, 121.67, 117.19 (dd, J= 18.3, 1.2 Hz), 109.90 (dd, J= 6.0, 3.3 Hz), 104.19 (d, J= 20.0 Hz), 73.81 , 62.71 , 60.56, 57.88, 43.91, 39.06, 28.86, 25.76, 21.55, 21.18.

[0180] Compounds of Formula (III)

[0181] 1 -((3,4-difluorophenoxy)methyl)-3-(imidazo[1 ,2-a]pyridin-2-ylmethyl)-5-methyl-3-azabicyclo[3.1.1]heptane (63). Prepared using General Procedure. Yield = 59.2 mg (94%, red oil). LCMS: RT = 2.1 16 min, ESI-MS: m / z [M + H]+, calc’d 384.2 for C22H24F2N3O, found384.1.1H NMR (600 MHz, CDCI3) 5 8.05 (s, 1 H), 7.86 (dd, J = 7.1 , 1.1 Hz, 1 H), 7.57 (d, J = 9.2 Hz, 1 H), 7.05 - 6.92 (m, 1 H), 6.68 (dd, J= 9.3, 6.3 Hz, 1 H), 6.66 - 6.59 (m, 1 H), 6.56 - 6.46 (m, 2H), 4.07 (s, 2H), 3.65 (s, 2H), 2.90 (s, 2H), 2.77 (s, 2H), 1.71 (dd, J= 6.3, 2.5 Hz, 2H), 1.60 - 1 .49 (m, 2H), 1 .01 (s, 3H).13C NMR (150 MHz, CDCI3) 5 155.73 (d, JC-F = 10.5 Hz), 150.57 (dd, JC-F = 247.1 , 13.8 Hz), 145.08 (dd, JC-F = 239.6, 12.8 Hz), 128.69, 126.67, 122.36,118.80, 118.43, 117.23 (d, JC-F = 18.9 Hz), 112.96, 109.93 (dd, JC-F = 5.9, 3.3 Hz), 104.29 (d, JC-F = 20.2 Hz), 73.63, 61.91 , 57.28, 53.24, 40.16, 38.92, 36.19, 24.62.

[0182] 1 -((3,4-dif luorophenoxy)methyl)-5-methyl-3-((1 -methyl-1 / 7-benzo[d]imidazol-5- yl)methyl)-3-azabicyclo[3.1.1] heptane (64). Prepared using General Procedure. Yield = 47.6 mg (73%, orange oil). LCMS: RT = 1 .938 min, ESI-MS: m / z [M + H]+, calc’d 398.2 for C23H26F2N3O, found 398.1 .1H NMR (600 MHz, CDCI3) 5 7.85 (s, 1 H), 7.76 (s, 1 H), 7.40 (s, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 7.00 (q, J = 9.4 Hz, 1 H), 6.70 - 6.61 (m, 1 H), 6.57 - 6.46 (m, 1 H), 3.87 (s, 2H), 3.83 (s, 3H), 3.65 (s, 2H), 2.80 (s, 2H), 2.67 (s, 2H), 1 .75 (s, 2H), 1 .56 (d, J = 8.1 Hz, 2H), 1.01 (s, 3H).13C NMR (150 MHz, CDCI3) 5 155.76, 150.55 (d, JC-F = 247.5 Hz), 145.03 (d, JC-F = 245.8 Hz), 134.07, 124.55, 120.72, 117.20 (d, JC-F = 18.8 Hz), 109.91 (dd, JC-F = 5.7, 3.4 Hz), 109.27, 104.27 (d, JC-F = 20.2 Hz), 73.74, 62.31 , 61 .31 , 57.75, 40.32, 38.92, 36.21 , 31 .27, 29.89, 24.60.

[0183] 3-((1 H-indazol-5-yl)methyl)-1 -((3,4-dif luorophenoxy)methyl)-5-methyl-3- azabicyclo[3.1.1]heptane (65). Prepared using General Procedure. Yield = 19.1 mg (30%, colorless oil). LCMS: RT = 2.116 min, ESI-MS: m / z [M + H]+, calc’d 384.2 for C22H24F2N3O, found 384.1 .1H NMR (600 MHz, CDCI3) 5 8.06 (s, 1 H), 7.69 (s, 1 H), 7.45 (s, 2H), 7.06 - 6.96 (m, 1 H), 6.74 - 6.63 (m, 1 H), 6.59 - 6.50 (m, 1 H), 3.82 (s, 2H), 3.66 (s, 2H), 2.78 (s, 2H), 2.65 (s, 2H), 1.79 - 1.68 (m, 2H), 1.63 - 1.52 (m, 2H), 1.02 (s, 3H).13C NMR (150 MHz, CDCI3) 5 155.76 (d, JC-F = 9.2 Hz), 150.57 (dd, JC-F = 247.1 , 13.7 Hz), 145.07 (dd, JC-F = 239.5, 12.8 Hz), 139.84, 134.89, 128.67, 123.49, 120.64, 117.23 (d, JC-F = 18.2 Hz), 109.93 (dd, JC-F = 5.7, 3.4 Hz), 109.78, 104.28 (d, JC-F = 20.2 Hz), 73.80, 62.53, 61.20, 57.94, 40.37, 38.98, 36.26, 29.90, 24.67.

[0184] 1 -((3,4-dif luorophenoxy)methyl)-5-ethyl-3-(3-fluoro-4-methoxybenzyl)-3- azabicyclo[3.1.1]heptane (66). Prepared using General Procedure. Yield = 33.4 mg (42%, amber oil). LCMS: RT = 2.440 min, ESI-MS: m / z [M + H]+, calc’d 406.2 for C23H27F3NO2, found406.1.1H NMR (600 MHz, CDCI3) 5 7.12 (dd, J = 12.3, 2.0 Hz, 1 H), 7.06 - 6.98 (m, 2H), 6.90 (t, J = 8.4 Hz, 1 H), 6.70 - 6.64 (m, 1 H), 6.58 - 6.51 (m, 1 H), 3.88 (s, 3H), 3.67 (s, 2H), 3.62 (s, 2H), 2.71 (s, 2H), 2.61 (s, 2H), 1.67 (dd, J= 6.0, 2.5 Hz, 2H), 1.56 - 1.51 (m, 2H), 1.35 (q, J = 7.5 Hz, 2H), 0.79 (t, J = 7.5 Hz, 3H).13C NMR (150 MHz, CDCI3) 5 155.81 (d, JC-F = 7.8 Hz),152.61 (d, JC-F = 245.2 Hz), 150.59 (dd, JC-F = 247.1 , 13.7 Hz), 146.63 (d, JC-F = 10.8 Hz), 145.08 (dd, JC-F = 239.8, 12.7 Hz), 132.56, 124.28 (d, JC-F = 3.2 Hz), 117.24 (d, JC-F = 18.6 Hz), 116.49 (d, JC-F=18.0 Hz), 113.22 (d, JC.F= 2.1 Hz), 109.95 (dd, JC-F = 6.0, 3.3 Hz), 104.27 (d, JC-F=20.2 Hz), 73.95, 60.64, 60.25, 58.27, 56.49, 40.08, 38.77, 38.16, 30.93, 8.87.

[0185] 3-((1 H-indazol-5-yl)methyl)-1 -((3,4-dif luorophenoxy)methyl)-5-ethyl-3- azabicyclo[3.1.1]heptane (67). Prepared using General Procedure. Yield = 23.5 mg (30%, light brown oil). LCMS: RT = 2.254 min, ESI-MS: m / z [M + H]+, calc’d 398.2 for C23H26F2N3O, found 398.1 .1H NMR (600 MHz, CDCI3) 5 8.06 (s, 1 H), 7.70 (s, 1 H), 7.46 (s, 2H), 7.01 (q, J =9.4 Hz, 1 H), 6.73 - 6.61 (m, 1 H), 6.58 - 6.45 (m, 1 H), 3.83 (s, 2H), 3.66 (s, 2H), 2.78 (s, 2H), 2.69 (s, 2H), 1.80 - 1.63 (m, 2H), 1.56 (d, J = 8.1 Hz, 2H), 1.34 (q, J = 7.5 Hz, 2H), 0.78 (t, J =7.5 Hz, 3H).13C NMR (150 MHz, CDCI3) 5 155.78, 150.57 (dd, JC-F = 247.1 , 13.9 Hz), 145.08 (dd, JC-F = 239.7, 12.7 Hz), 139.86, 134.88, 128.68, 123.49, 120.71 , 117.23 (d, JC-F = 19.0 Hz), 109.93 (dd, JC-F=5.9, 3.2 Hz), 109.81 , 104.27 (d, JC-F = 20.1 HZ), 73.89, 61.33, 60.68, 58.30, 43.65, 40.09, 38.77, 38.13, 30.87, 29.90, 8.84.

[0186] 1 -((3,4-dif luorophenoxy)methyl)-5-ethyl-3-((1 -methyl-1 H-indazol-5-yl)methyl)-3- azabicyclo[3.1.1]heptane (68). Prepared using General Procedure. Yield = 48.9 mg (61%, orange oil). LCMS: RT = 2.332 min, ESI-MS: m / z [M + H]+, calc’d 412.2 for C24H28F2N3O, found 412.2.1H NMR (600 MHz, CDCI3) 5 7.94 (s, 1 H), 7.64 (s, 1 H), 7.45 (dd, J = 8.6, 1.5 Hz, 1 H), 7.41 - 7.32 (m, 1 H), 7.07 - 6.93 (m, 1 H), 6.69 - 6.61 (m, 1 H), 6.57 - 6.46 (m, 1 H), 4.07 (s, 3H), 3.80 (s, 2H), 3.66 (s, 2H), 2.74 (s, 2H), 2.64 (s, 2H), 1.73 - 1 .65 (m, 2H), 1 .56 - 1 .51 (m, 2H), 1.34 (q, J= 7.5 Hz, 2H), 0.78 (t, J= 7.5 Hz, 3H).13C NMR (150 MHz, CDCI3) 5 155.80 (d, JC-F =7.6 Hz), 150.57 (dd, JC-F = 247.0, 13.8 Hz), 145.05 (dd, JC-F = 239.6, 12.9 Hz), 139.66, 132.67, 128.03, 124.22, 120.68, 117.21 (d, JC-F = 18.5 Hz), 109.92 (dd, JC-F = 5.9, 3.3 Hz), 108.90, 104.26 (d, J= 19.9 Hz), 73.94, 61.29, 60.73, 58.36, 40.07, 38.78, 38.17, 35.75, 30.94, 8.87.

[0187] 1 -((3, 4-difluorophenoxy)methyl)-5-ethyl-3-((1 -methyl-1 H-benzo[d|imidazol-5- yl)methyl)-3-azabicyclo[3.1.1]heptane (69). Prepared using General Procedure. Yield = 42.3 mg (53%, orange oil). LCMS: RT = 2.113 min, ESI-MS: m / z [M + H]+, calc’d 412.2 for C24H28F2N3O, found 412.1 .1H NMR (600 MHz, CDCI3) 5 7.85 (s, 1 H), 7.76 (s, 1 H), 7.40 (d, J = 8.2 Hz, 1 H), 7.35 (d, J = 8.2 Hz, 1 H), 7.00 (q, J = 9.4 Hz, 1 H), 6.69 - 6.60 (m, 1 H), 6.54 - 6.46 (m, 1 H), 3.88 (s, 2H), 3.83 (s, 3H), 3.65 (s, 2H), 2.80 (s, 2H), 2.71 (s, 2H), 1.75 - 1 .65 (m, 2H), 1.55 (d, J= 8.2 Hz, 2H), 1.33 (q, J= 7.5 Hz, 2H), 0.77 (t, J= 7.5 Hz, 3H).13C NMR (150 MHz, CDCI3) 5 155.73 (d, JC-F = 8.9 Hz), 150.55 (dd, JC-F = 247.0, 13.7 Hz), 145.05 (dd, JC-F = 239.7, 12.8 Hz), 143.91 , 134.04, 124.59, 120.69, 117.20 (d, JC-F = 18.3 Hz), 109.91 (dd, JC-F = 5.7, 3.3 Hz), 109.29, 104.27 (d, JC-F = 20.3 Hz), 73.84, 61 .42, 60.51 , 58.12, 40.04, 38.72, 38.06, 31 .28, 30.82, 8.82.

[0188] 1 -((3,4-difluorophenoxy)methyl)-5-ethyl-3-(imidazo[1 ,2-a]pyridin-2-ylmethyl)-3- azabicyclo[3.1.1]heptane (70). Prepared using General Procedure. Yield = 52.1 mg (67%, red oil). LCMS: RT = 2.309 min, ESI-MS: m / z [M + H]+, calc’d 398.2 for C23H26F2N3O, found 398.1 .1H NMR (600 MHz, CDCI3) 5 8.05 (s, 1 H), 7.86 (dt, J = 7.1 , 1 .2 Hz, 1 H), 7.56 (d, J = 9.2 Hz, 1 H), 6.99 (q, J = 9.4 Hz, 1 H), 6.72 - 6.58 (m, 2H), 6.56 - 6.45 (m, 2H), 4.06 (s, 2H), 3.65 (s, 2H), 2.86 (s, 2H), 2.77 (s, 2H), 1.65 (dd, J = 6.1 , 2.5 Hz, 2H), 1.57 - 1.48 (m, 2H), 1.33 (q, J =7.5 Hz, 2H), 0.77 (t, J = 7.5 Hz, 3H).13C NMR (150 MHz, CDCI3) 5 155.75 (d, JC-F = 8.5 Hz), 150.54 (dd, JC-F=246.8, 13.5 Hz), 145.03 (dd, JC-F = 239.8, 12.7 Hz), 128.53, 128.32, 126.57, 122.31 , 118.64, 118.45, 117.19 (d, JC-F = 18.3 Hz), 112.89, 109.90 (dd, JC-F = 5.7, 3.3 Hz), 104.24 (d, JC-F = 20.0 Hz) 73.74, 60.16, 57.73, 53.44, 40.01 , 38.71 , 37.95, 30.81 , 8.83.

[0189] 1 -((3,4-dif luorophenoxy)methyl)-5-ethyl-3-(imidazo[1 ,5-a]pyridin-3-ylmethyl)-3- azabicyclo[3.1.1]heptane (71). Prepared using General Procedure. Yield = 42.4 mg (55%, red oil). LCMS: RT = 2.309 min, ESI-MS: m / z [M + H]+, calc’d 398.2 for C23H26F2N3O, found 398.1 .1H NMR (600 MHz, CDCI3) 5 8.20 - 8.13 (m, 1 H), 7.42 (dd, J= 9.2, 1.2 Hz, 1 H), 7.34 (s, 1 H), 7.00 (q, J= 9.4 Hz, 1 H), 6.71 (dd, J= 9.2, 6.3 Hz, 1 H), 6.66 - 6.60 (m, 1 H), 6.57 - 6.53 (m, 1 H), 6.52 - 6.45 (m, 1 H), 4.14 (s, 2H), 3.63 (s, 2H), 2.70 (s, 2H), 2.61 (s, 2H), 1 .63 (dd, J = 6.1 ,2.5 Hz, 2H), 1.55 (dd, J = 6.1 , 2.5 Hz, 2H), 1.32 (q, J = 7.5 Hz, 2H), 0.76 (t, J = 7.5 Hz, 3H).13C NMR (150 MHz, CDCI3) 5 155.68 (d, JC-F = 7.8 Hz), 150.56 (dd, JC-F = 247.6, 13.8 Hz), 145.08 (dd, JC-F = 239.9, 12.8 Hz), 135.89, 131 .45, 122.39, 118.68, 118.50, 118.46, 117.22 (d, JC-F = 17.4 Hz), 112.19, 109.91 (dd, JC-F = 5.7, 3.3 Hz), 104.27 (d, JC-F = 20.2 HZ), 73.66, 60.46, 58.00, 53.71 , 40.09, 38.78, 37.87, 30.84, 8.79.

[0190] 1 -cyclopropyl-5-((3,4-dif luorophenoxy)methyl)-3-(3-f luoro-4-methoxybenzyl)-3- azabicyclo[3.1.1]heptane (72). Prepared using General Procedure. Yield = 64.3 mg (83%, light orange oil). LCMS: RT = 2.467 min, ESI-MS: m / z [M + H]+, calc’d 406.2 for C24H27F3NO2, found 406.1 .1H NMR (600 MHz, CDCI3) 5 7.12 (dd, J = 12.3, 2.0 Hz, 1 H), 7.08 - 6.96 (m, 2H), 6.91 (t, J= 8.4 Hz, 1 H), 6.72 - 6.62 (m, 1 H), 6.58 - 6.48 (m, 1 H), 3.88 (s, 3H), 3.64 (d, J = 12.0 Hz, 4H), 2.72 (s, 4H), 1 .52 (dd, J = 6.0, 2.5 Hz, 2H), 1 .48 - 1 .36 (m, 2H), 0.70 (ft, J = 8.3, 5.2 Hz, 1 H), 0.35 - 0.26 (m, 2H), 0.15 (dt, J = 5.4, 2.8 Hz, 2H).13C NMR (150 MHz, CDCI3) 5 155.75 (d, JC-F = 9.7 Hz), 152.61 (d, JC-F = 245.2 Hz), 150.59 (dd, JC-F = 247.5, 13.8 Hz), 146.66 (d, JC-F=10.8 Hz), 145.09 (dd, JC-F = 239.8, 12.7 Hz), 132.45, 124.34 (d, JC-F = 3.1 Hz), 117.25 (d, JC-F=17.6 Hz), 116.54 (d, JC-F = 18.1 Hz), 113.22 (d, JC-F = 2.1 Hz), 109.94 (dd, JC-F = 5.7, 3.3 Hz), 104.26 (d, JC-F = 20.3 Hz), 73.90, 62.06, 60.15, 58.44, 56.49, 39.98, 38.19, 36.21 , 16.34, 0.61.

[0191] 3-((1 H-benzo[cflimidazol-5-yl)methyl)-1 -cyclopropyl-5-((3,4- difluorophenoxy)methyl)-3-azabicyclo[3.1.1] heptane (73). Prepared using General Procedure. Yield = 23.5 mg (31%, colorless oil). LCMS: RT = 2.139 min, ESI-MS: m / z [M + H]+, calc’d 410.2 for C24H26F2N3O, found 410.1.1H NMR (600 MHz, CDCI3) 5 8.09 (s, 1 H), 7.90 -7.02 (br, 1 H), 7.71 (s, 1 H), 7.61 (d, J = 8.2 Hz, 1 H), 7.34 (d, J = 8.3 Hz, 1 H), 6.99 (q, J= 9.4 Hz, 1 H), 6.72 - 6.57 (m, 1 H), 6.49 (dd, J= 8.5, 4.4 Hz, 1 H), 3.92 (s, 2H), 3.63 (s, 2H), 2.88 (s, 4H), 1.67 - 1.55 (m, 2H), 1.43 (d, J= 7.2 Hz, 2H), 0.72 - 0.62 (m, 1 H), 0.30 (d, J= 8.2 Hz, 2H), 0.13 (d, J= 5.3 Hz, 2H).13C NMR (150 MHz, CDCI3) 6 155.38 (d, JC.F= 8.7 Hz), 150.53 (dd, JC.F= 247.6, 13.8 Hz), 145.17 (dd, JC-F= 240.2, 12.3 Hz), 141.71 , 137.88, 137.61 , 124.78, 117.29 (d, Jc-F= 18.5 Hz), 116.74, 115.67, 109.88 (dd, JC-F= 5.8, 3.3 Hz), 104.29 (d, JC-F= 20.2 Hz), 73.42, 61.59, 61.56, 58.11 , 40.05, 38.07, 35.91 , 15.95, 0.68.

[0192] 1 -cyclopropyl-5-((3,4-dif luorophenoxy)methyl)-3-((1 -methyl-1 / - / -indazol-5- yl)methyl)-3-azabicyclo[3.1.1] heptane (74). Prepared using General Procedure D. Yield = 33.0 mg (42%, orange oil). LCMS: RT = 2.359 min, ESI-MS: m / z [M + H]+, calc’d 424.2 for C25H28F2N3O, found 424.1 .1H NMR (600 MHz, CDCI3) 6 7.94 (d, J= 1 .0 Hz, 1 H), 7.65 (s, 1 H), 7.49 - 7.44 (m, 1 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.07 - 6.95 (m, 1 H), 6.68 - 6.61 (m, 1 H), 6.56 - 6.47 (m, 1 H), 4.07 (s, 3H), 3.81 (s, 2H), 3.64 (s, 2H), 2.76 (s, 4H), 1.60 - 1 .50 (m, 2H), 1 .46 - 1.37 (m, 2H), 0.74 - 0.64 (m, 1 H), 0.35 - 0.26 (m, 2H), 0.14 (dd, J= 5.3, 1.3 Hz, 2H).13C NMR (150 MHz, CDCI3) 6 155.73 (d, JC-F= 7.9 Hz), 150.57 (dd, JC-F= 247.2, 13.7 Hz), 145.07 (dd, JC-F= 239.7, 13.0 Hz), 139.67, 132.69, 128.07, 124.22, 120.77, 117.23 (d, J= 18.5 Hz), 109.91 (dd, Jc-F= 5.8, 3.1 Hz), 108.94, 104.25 (d, JC-F= 20.1 Hz), 73.88, 62.14, 61.19, 58.53, 39.98, 38.21 , 36.21 , 35.76, 16.34, 0.61.

[0193] 1 -cyclopropyl-5-((3,4-dif luorophenoxy)methyl)-3-(imidazo[1 ,5-a]pyridin-3- ylmethyl)-3-azabicyclo[3.1.1]heptane (75). Prepared using General Procedure D. Yield = 66.1 mg (87%, red oil). LCMS: RT = 2.381 min, ESI-MS: m / z [M + H]+, calc’d 410.2 for C24H26F2N3O, found 410.1.1H NMR (600 MHz, CDCI3) 6 8.17 (dd, J= 7.2, 1.3 Hz, 1 H), 7.42 (dd, J = 9.2, 1 .3 Hz, 1 H), 7.35 (s, 1 H), 6.99 (q, J = 9.4 Hz, 1 H), 6.74 - 6.68 (m, 1 H), 6.65 - 6.59 (m, 1 H), 6.57 - 6.53 (m, 1 H), 6.51 - 6.47 (m, 1 H), 4.15 (s, 2H), 3.61 (s, 2H), 2.71 (d, J= 12.5 Hz, 4H), 1.48 (dd, J= 6.1 , 2.5 Hz, 2H), 1.41 (dd, J= 6.1 , 2.4 Hz, 2H), 0.71 - 0.64 (m, 1 H), 0.32 - 0.24 (m, 2H), 0.15 - 0.09 (m, 2H).13C NMR (150 MHz, CDCI3) 6 155.61 (d, JC-F= 9.7 Hz), 150.53 (dd, Jc-F= 247.2, 13.7 Hz), 145.07 (dd, JC-F= 240.1 , 12.7 Hz), 135.83, 131.44, 122.35, 118.68, 118.49, 118.45, 117.21 (d, JC-F= 18.4 Hz), 112.21 , 109.89 (dd, JC-F= 5.9, 3.4 Hz), 104.25 (d, JC-F = 20.0 Hz), 73.59, 61.87, 58.15, 53.55, 39.99, 38.19, 35.93, 16.23, 0.61.

[0194] 1 -cyclopropyl-5-((3,4-dif luorophenoxy)methyl)-3-(imidazo[1 ,2-a]pyridin-2- ylmethyl)-3-azabicyclo[3.1.1]heptane (76). Prepared using General Procedure D. Yield = 60.3 mg (79%, red oil). LCMS: RT = 2.309 min, ESI-MS: m / z [M + H]+, calc’d 410.2 for C24H26F2N3O, found 410.1.1H NMR (600 MHz, CDCI3) 6 8.07 (s, 1 H), 7.88 (d, J= 7.1 Hz, 1 H), 7.61 (d, J = 9.2 Hz, 1 H), 6.99 (q, J = 9.3 Hz, 1 H), 6.71 (dd, J = 9.3, 6.3 Hz, 1 H), 6.65 - 6.60 (m, 1 H), 6.55 (t, J= 6.7 Hz, 1 H), 6.52 - 6.46 (m, 1 H), 4.12 (s, 2H), 3.64 (s, 2H), 2.96 (s, 4H), 1 .54 (s, 2H), 1.41 (d, J= 8.2 Hz, 2H), 0.74 - 0.65 (m, 1 H), 0.33 - 0.24 (m, 2H), 0.16 - 0.07 (m, 2H).13C NMR (150 MHz, CDCI3) 6 155.63 (d, JC-F= 8.1 Hz), 150.53 (dd,C- = 247.4, 13.6 Hz),145.06 (dd, JC-F = 240.0, 12.7 Hz), 128.72, 126.69, 122.33, 118.84, 118.40, 117.20 (d, JC-F = 18.3 Hz), 112.94, 109.88 (dd, JC-F = 5.9, 3.4 Hz), 104.24 (d, JC-F = 20.3 Hz), 73.63, 61 .40, 57.77, 53.20, 39.91 , 38.10, 35.97, 16.19, 0.63.

[0195] Compounds of Formula (II)

[0196] Compounds of Formula (II) were prepared using one or more of the following Generals Procedures depicted below with using illustrative compounds of the disclosure.

[0197] To methyl 2-(diethoxyphosphoryl)acetate (O, 1.1 equiv.) in THF (50 mL) was slowly added sodium hydride (1 .2 equiv.) at 0°C and stirred for 1 h. Then the oxetan-3-one (N, 1 .0 equiv.) was slowly added, and the reaction was stirred at room temperature for 2 h. The reaction was quenched with deionized water (250 mL), extracted with dichloromethane (75 mL x 3), combined organic phases washed with brine (50 mL), dried with magnesium sulfate, concentrated in vacuo, and purified by normal phase chromatography (0-40% hexanes / ethyl acetate) to yield the desired compound.

[0198] Methyl 2-(oxetan-3-ylidene)acetate (P). Prepared using General Procedure A.Yield = 10.8 g (51%-72%, white crystals).1H NMR (600 MHz, CDCI3) 5 5.65 (p, J = 2.4 Hz, 1 H), 5.51 (dt, J = 3.7, 2.6 Hz, 2H), 5.33 - 5.28 (m, 2H), 3.71 (s, 3H).13C NMR (125 MHz, CDCI3) 5 165.82, 159.68, 110.86, 81 .22, 78.62, 51 .64.

[0199] To methyl 2-(oxetan-3-ylidene)acetate (P, 1.0 equiv) and / V-benzyl-1-methoxy- / V- ((trimethylsilyl)methyl)methanamine (Q, 1 .5 equiv) was added lithium fluoride (3 equiv.) at room temperature. Then the reaction was stirred at 120°C-140qC overnight (~16 h). Conversion was checked by LCMS and TLC. Then the reaction was cooled to room temperature, rinsed with acetone, filtered, concentrated in vacuo, and purified by normal phase chromatography (0-80% hexanes / ethyl acetate) to yield the desired compounds.

[0200] Methyl 6-benzyl-2-oxa-6-azaspiro[3.4]octane-8-carboxylate (R). Prepared using general procedure B. Yield: 7.38 g (51%-72%, yellow oil). LCMS: RT = 1.488 min, ESI-MS: m / z [M + H]+, 262.14 calc’d for C15H19NO3, found 262.1 .1H NMR (600 MHz, CDCI3) 5 7.36 - 7.22 (m, 5H), 4.70 (d, J = 6.0 Hz, 1 H), 4.61 (d, J = 6.9 Hz, 1 H), 4.51 (d, J = 5.9 Hz, 1 H), 4.45 (d, J =6.9 Hz, 1 H), 3.74 (s, 3H), 3.67 - 3.59 (m, 2H), 3.20 (d, J = 9.3 Hz, 1 H), 3.11 (t, J = 8.0 Hz, 1 H), 3.04 (t, J = 8.9 Hz, 1 H), 2.75 (d, J= 9.3 Hz, 1 H), 2.63 (dd, J= 9.4, 7.1 Hz, 1 H).13C NMR (125 MHz, CDCI3) 5 173.60, 138.57, 128.76, 128.48, 127.31 , 84.03, 78.13, 64.48, 59.76, 56.62, 52.04, 50.52, 48.08.

[0201] A solution of R (1 equiv.) in MeOH and catalytic amount of AcOH was hydrogenated in the presence of 10-20% Pd / C, for 24 h. Conversion is checked by LCMS and TLC. After full conversion, the reaction was filtered through a pad of Celite. Solution was concentrated and proceeded to next reaction without purification.

[0202] To a solution of R’ in DCE, was added Ar-CHO (R2) at room temperature and the mixture was stirred for 2 h. Followed by slow addition of sodium triacetoxyborohydride (4 equiv.) at room temperature and stirred overnight. The reaction was quenched with sodium bicarbonate solution, extracted with DCM, washed with brine, dried with magnesium sulfate, concentrated, and purified by column chromatography.

[0203] Methyl 6-((1 -methyl-1 / 7-indazol-5-yl)methyl)-2-oxa-6-azaspiro[3.4]octane-8- carboxylate (S). Prepared using general procedure C. Yield: 2.37 g (64.4%, yellow oil). LCMS: RT = 1.548 min, ESI-MS: m / z [M + H]+, 316.16 calc’d for C17H21N3O3, found 316.1.1H NMR (600 MHz, CDCI3) 5 7.92 (d, J= 1.0 Hz, 1 H), 7.61 - 7.58 (m, 1 H), 7.36 - 7.31 (m, 2H), 4.67 (d, J = 6.1 Hz, 1 H), 4.58 (d, J = 6.9 Hz, 1 H), 4.49 (d, J = 6.1 Hz, 1 H), 4.42 (d, J = 6.9 Hz, 1 H), 4.04 (s, 3H), 3.75 (s, 2H), 3.72 (s, 3H), 3.25 (d, J= 9.6 Hz, 1 H), 3.15 - 3.05 (m, 2H), 2.78 (d, J= 9.6 Hz, 1 H), 2.70 - 2.64 (m, 1 H).13C NMR (125 MHz, CDCI3) 5 173.27, 139.47, 132.55, 129.88, 127.79, 126.35, 123.94, 120.95, 108.98, 83.63, 77.86, 63.88, 59.50, 56.03, 51.98, 50.20, 47.80, 35.51.

[0204] To a solution of S (1 equiv.) in THF was added lithium borohydride at room temperature. Then the reaction was warmed to 50 °C and stirred overnight. Conversion was checked by LCMS and TLC. The mixture was quenched with deionized water (25 mL), extracted with dichloromethane (50 mL x 3), combined organic phases washed with brine (25 mL), dried with magnesium sulfate, and concentrated in vacuo. The residue was dissolved in DMF and NaH (2 equiv) was added. The mixture was stirred for 1 h Then Ar-X (R1, 1.1 equiv.)was added, and the reaction was heated to 120 °C and stirred overnight. The reaction was quenched with deionized water (5 mL), extracted with ethyl acetate (30 mL x 3), washed with water (10 mL x 5), combined organic phases washed with brine (15 mL), dried with magnesium sulfate, concentrated in vacuo, and purified by normal phase chromatography (0-5% methanol / dichloromethane) to yield the desired compound.

[0205] 8-(((6-Chloropyridin-2-yl)oxy)methyl)-6-((1 -methyl-1 H-indazol-5-yl)methyl)-2- oxa-6-azaspiro[3.4]octane (77). Prepared using general procedure. Yield: 17.2 mg (12%, yellow oil). LCMS: RT = 1.980 min, ESI-MS: m / z [M + H]+, calc’d 399.15 for C21H23CIN4O2, found399.1 .1H NMR (600 MHz, CDCI3) 5 7.93 (s, 1 H), 7.61 (s, 1 H), 7.54 - 7.48 (m, 1 H), 7.41 - 7.36 (m, 1 H), 7.35 (d, J= 8.6 Hz, 1 H), 6.90 (d, J = 7.5 Hz, 1 H), 6.64 (d, J = 8.2 Hz, 1 H), 4.87 (d, J = 6.6 Hz, 1 H), 4.70 (d, J = 5.9 Hz, 1 H), 4.53 (d, J = 5.8 Hz, 1 H), 4.44 (dd, J= 10.8, 6.2 Hz, 1 H), 4.38 (d, J= 6.5 Hz, 1 H), 4.34 (dd, J= 10.8, 6.1 Hz, 1 H), 4.07 (s, 3H), 3.75 - 3.67 (m, 2H), 3.20 (d, J= 9.4 Hz, 1 H), 2.98 (t, J = 8.9 Hz, 1 H), 2.72 (d, J= 9.4 Hz, 1 H), 2.65 - 2.57 (m, 1 H), 2.28 (t, J = 8.5 Hz, 1 H).13C NMR (125 MHz, CDCI3) 5 163.27, 148.48, 140.84, 139.57, 132.66, 130.88, 127.83, 124.13, 120.71 , 116.75, 109.36, 108.97, 84.47, 77.46, 66.64, 65.71 , 60.15, 57.08, 47.43, 43.62, 35.71.

[0206] 6-((1 -Methyl-1 H-indazol-5-yl)methyl)-8-(((5-methylthiazol-2-yl)oxy)methyl)-2- oxa-6-azaspiro[3.4]octane (78). Prepared using general procedure. Yield: 17.3 mg (13%, yellow oil). LCMS: RT = 1.879 min, ESI-MS: m / z [M + H]+, calc’d 385.16 for C20H24N4O2S, found385.1 .1H NMR (600 MHz, CDCI3) 5 7.93 (s, 1 H), 7.62 - 7.59 (m, 1 H), 7.41 - 7.36 (m, 1 H), 7.36 - 7.32 (m, 1 H), 6.74 (d, J= 1.4 Hz, 1 H), 4.85 (d, J = 6.6 Hz, 1 H), 4.67 (d, J = 5.9 Hz, 1 H), 4.56 - 4.47 (m, 2H), 4.42 - 4.35 (m, 2H), 4.06 (s, 3H), 3.75 - 3.67 (m, 2H), 3.19 (d, J = 9.4 Hz, 1 H), 2.98 (t, J = 8.9 Hz, 1 H), 2.71 (d, J= 9.4 Hz, 1 H), 2.66 - 2.59 (m, 1 H), 2.33 - 2.26 (m, 4H).13C NMR (125 MHz, CDCI3) 5 172.68, 139.58, 133.46, 132.67, 130.73, 127.80, 125.90, 124.13, 120.74, 108.99, 84.40, 77.20, 70.88, 65.48, 60.05, 56.93, 47.32, 43.63, 35.70, 12.45.

[0207] To a solution of S (1 equiv.) in THF was added lithium borohydride at room temperature. Then the reaction was warmed to 50 °C and stirred overnight. Conversion was checked by LCMS and TLC. The mixture was quenched with deionized water (25 mL), extracted with dichloromethane (50 mL x 3), combined organic phases washed with brine (25 mL), dried with magnesium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane (5 mL) and triethylamine (2 equiv.) was added. The reaction was cooled to 0°C and methanesulfonyl chloride (2 equiv.) was added slowly. The mixture was brought to room temperature and stirred for 2 hours. Conversion was checked by LCMS and TLC. Themixture was quenched with deionized water (2 mL), extracted with dichloromethane (5 mL x 3), combined organic phases washed with brine (5 mL), dried with magnesium sulfate, and concentrated in vacuo. The residue was dissolved in DMF and CS2CO3 (4 equiv) was added. The mixture was stirred for 1 h Then Phenol (R1, 1 .0 equiv.) was added, and the reaction was heated to 120 °C and stirred 24 to 48 h. The reaction was quenched with deionized water (5 mL), extracted with ethyl acetate (30 mL x 3), washed with water (10 mL x 5), combined organic phases washed with brine (15 mL), dried with

[0208] 8-((3,4- Dif luorophenoxy)methyl)-6-((1 -methyl-1 H-indazol-5-yl)methyl)-2-oxa-6- azaspiro[3.4]octane (79). Prepared using general procedure E. Yield: 114 mg (5.4%-25.0%, brown oil). LCMS: RT = 2.055 min, ESI-MS: m / z [M + H]+, calc’d 400.18 for C22H23F2N3O2, found 400.11H NMR (600 MHz, CDCI3) 5 7.93 (s, 1 H), 7.61 (s, 1 H), 7.41 - 7.37 (m, 1 H), 7.37 - 7.32 (m, 1 H), 7.08 - 7.01 (m, 1 H), 6.74 - 6.67 (m, 1 H), 6.61 - 6.55 (m, 1 H), 4.79 (d, J = 6.5 Hz, 1 H), 4.68 (d, J = 5.9 Hz, 1 H), 4.54 (d, J = 5.8 Hz, 1 H), 4.39 (d, J = 6.6 Hz, 1 H), 4.06 (s, 3H), 4.03 - 3.95 (m, 2H), 3.76 - 3.67 (m, 2H), 3.20 (d, J = 9.3 Hz, 1 H), 2.97 (t, J = 8.8 Hz, 1 H), 2.73 (d, J = 9.4 Hz, 1 H), 2.63 - 2.55 (m, 1 H), 2.31 (dd, J= 9.4, 7.4 Hz, 1 H).13C NMR (125 MHz, CDCI3) 5 154.99, 154.97, 154.92, 154.90, 151.57, 151.47, 149.60, 149.49, 146.27, 146.17, 144.35,144.25, 139.53, 132.60, 130.78, 127.76, 124.10, 120.68, 117.41 , 117.40, 117.26, 117.25, 109.85, 109.83, 109.81 , 109.78, 108.95, 104.32, 104.15, 84.42, 77.34, 68.76, 65.69, 60.06, 56.87, 47.34, 43.90, 35.65. (additional peaks due to F splitting)

[0209] 8-((4-Chloro-3-f luorophenoxy)methyl)-6-((1 -methyl-1 / 7-indazol-5-yl)methyl)-2- oxa-6-azaspiro[3.4]octane (80). Prepared using general procedure E. Yield: 10.5 mg (5%, yellow oil). LCMS: RT = 2.135 min, ESI-MS: m / z [M + H]+, calc’d 416.10 for C22H23CIFN3O2, found 416.1 .1H NMR (600 MHz, CDCI3) 5 7.94 (s, 1 H), 7.62 (s, 1 H), 7.42 - 7.37 (m, 1 H), 7.35 (d, J = 8.6 Hz, 1 H), 7.29 - 7.23 (m, 1 H), 6.72 - 6.67 (m, 1 H), 6.65 - 6.61 (m, 1 H), 4.78 (d, J =6.6 Hz, 1 H), 4.69 (d, J= 5.9 Hz, 1 H), 4.55 (d, J = 5.9 Hz, 1 H), 4.39 (d, J = 6.6 Hz, 1 H), 4.14 - 3.94 (m, 5H), 3.72 (s, 2H), 3.20 (d, J= 9.6 Hz, 1 H), 2.98 (t, J= 8.7 Hz, 1 H), 2.74 (d, J= 9.4 Hz, 1 H), 2.61 (t, J = 7.0 Hz, 1 H), 2.32 (s, 1 H).13C NMR (125 MHz, CDCI3) 5 159.56, 158.47, 158.39, 157.58, 139.60, 132.68, 130.79, 127.82, 124.16, 120.79, 112.93, 112.79, 111.28,111.26, 109.03, 103.72, 103.53, 84.46, 77.40, 68.63, 65.70, 60.11 , 56.89, 47.39, 43.91 , 35.73. (additional peaks due to F splitting).

[0210] 8-((4-Fluoro-3-methylphenoxy)methyl)-6-((1 -methyl-1 / 7-indazol-5-yl)methyl)-2- oxa-6-azaspiro[3.4]octane (81). Prepared using general procedure E. Yield: 19.0 mg (9%, yellow oil). LCMS: RT = 2.100 min, ESI-MS: m / z [M + H]+, calc’d 396.20 for C23H26FN3O2, found 396.2.1H NMR (600 MHz, CDCI3) 5 7.94 (s, 1 H), 7.62 (s, 1 H), 7.43 - 7.38 (m, 1 H), 7.35 (d, J =8.6 Hz, 1 H), 6.90 (t, J = 9.0 Hz, 1 H), 6.72 - 6.68 (m, 1 H), 6.67 - 6.61 (m, 1 H), 4.83 (d, J = 6.5 Hz, 1 H), 4.70 (d, J = 5.8 Hz, 1 H), 4.54 (d, J= 5.8 Hz, 1 H), 4.39 (d, J = 6.5 Hz, 1 H), 4.07 (s, 3H), 4.04 - 3.95 (m, 2H), 3.76 - 3.68 (m, 2H), 3.22 (d, J= 9.3 Hz, 1 H), 2.99 (t, J= 8.8 Hz, 1 H), 2.73(d, J= 9.3 Hz, 1 H), 2.62 - 2.55 (m, 1 H), 2.32 (t, J= 8.5 Hz, 1 H), 2.24 (s, 2H).13C NMR (125 MHz, CDCI3) 6 157.10, 155.21 , 154.49, 154.47, 139.58, 132.67, 130.89, 127.85, 125.89,125.74, 124.15, 120.76, 117.37, 117.33, 115.53, 115.34, 112.55, 112.49, 108.98, 84.62, 77.50, 68.48, 65.84, 60.17, 57.03, 47.46, 44.07, 35.71 , 14.92, 14.89. (additional peaks due to F splitting)

[0211] 8-((3-Fluoro-4-methylphenoxy)rnethyl)-6-((1 -methyl-1 / 7-indazol-5-yl)methyl)-2- oxa-6-azaspiro[3.4]octane (82). Prepared using general procedure E. Yield: 54.7 mg (25%, brown oil). LCMS: RT = 2.113 min, ESI-MS: m / z [M + H]+, calc’d 396.20 for C23H26FN3O2, found 396.1 .1H NMR (600 MHz, CDCI3) 6 7.93 (s, 1 H), 7.62 (s, 1 H), 7.42 - 7.37 (m, 1 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.04 (t, J = 8.8 Hz, 1 H), 6.61 - 6.55 (m, 2H), 4.81 (d, J = 6.5 Hz, 1 H), 4.69 (d, J =5.8 Hz, 1 H), 4.54 (d, J = 5.8 Hz, 1 H), 4.38 (d, J= 6.6 Hz, 1 H), 4.06 (s, 3H), 4.03 - 3.96 (m, 2H), 3.75 - 3.67 (m, 2H), 3.21 (d, J = 9.3 Hz, 1 H), 2.99 (t, J = 8.8 Hz, 1 H), 2.73 (d, J = 9.3 Hz, 1 H), 2.62 - 2.55 (m, 1 H), 2.31 (dd, J= 9.5, 7.5 Hz, 1 H), 2.19 (d, J= 1.8 Hz, 3H).13C NMR (125 MHz, CDCI3) 6 162.55, 160.60, 157.89, 157.81 , 139.48, 132.56, 131.57, 131.51 , 130.79,127.74, 124.06, 120.64, 117.03, 116.89, 109.96, 109.93, 108.89, 102.16, 101.95, 84.48, 77.32, 68.17, 65.69, 60.04, 56.90, 47.34, 43.86, 35. 59, 13.80, 13.77. (additional peaks due to F splitting)

[0212] 8-((3-f luorophenoxy)methyl)-6-((1 -methyl-1 / 7-indazol-5-yl)methyl)-2-oxa-6- azaspiro[3.4]octane. (83) General Procedure. Yield: 19.6 mg (12.5%, brown oil). LCMS: RT = 2.015 min, ESI-MS: m / z [M+H]+, calc’d 382.19 for C22H24FN3O2, found 382.1.1H NMR (500 MHz, CDCL3) 5 7.93 (s, 1 H), 7.62 (s, 1 H), 7.46 - 7.31 (m, 2H), 7.21 (td, J = 8.2, 6.8 Hz, 1 H), 6.70 - 6.63 (m, 2H), 6.61 (dt, J = 11 .0, 2.4 Hz, 1 H), 4.81 (d, J = 6.6 Hz, 1 H), 4.70 (d, J = 5.8 Hz, 1 H), 4.54 (d, J = 5.8 Hz, 1 H), 4.39 (d, J = 6.6 Hz, 1 H), 4.14 - 3.99 (m, 5H), 3.76 - 3.67 (m, 2H), 3.21 (d, J = 9.3 Hz, 1 H), 2.99 (t, J = 8.8 Hz, 1 H), 2.73 (d, J = 9.3 Hz, 1 H), 2.65 - 2.56 (m, 1 H), 2.32 (dd, J = 9.4, 7.4 Hz, 1 H).13C NMR (125 MHz, CDCL3) 5 163.73 (d, J= 245.6 Hz), 160.05 (d, J= 10.8 Hz), 139.57, 132.66, 130.96, 130.40 (d, J= 10.0 Hz), 127.83, 124.15, 120.71 , 110.36 (d, J= 2.8 Hz), 108.97, 108.01 (d, J= 21.3 Hz), 102.38 (d, J= 24.8 Hz), 84.59, 77.44, 68.25, 65.82, 60.16, 57.01 , 47.43, 43.95, 35.70.

[0213] 8-((3-f luoro-4-methoxyphenoxy)methyl)-6-((1 -methyl-1 H-indazol-5-yl)methyl)-2- oxa-6-azaspiro[3.4]octane. (84) General Procedure. Yield: 29.9 mg (17.7%, brown oil). LCMS: RT = 2.015 min, ESI-MS: m / z [M+H]+, calc’d 412.20 for C23H26FN3O3, found 412.1.1H NMR (500MHz, CDCL3) 5 7.93 (s, 1 H), 7.61 (s, 1 H), 7.42 - 7.32 (m, 2H), 6.87 (t, J = 9.2 Hz, 1 H),6.68 (dd, J = 12.6, 2.9 Hz, 1 H), 6.59 (ddd, J = 8.8, 2.9, 1 .5 Hz, 1 H), 4.81 (d, J = 6.6 Hz, 1 H),4.69 (d, J = 5.8 Hz, 1 H), 4.53 (d, J = 5.8 Hz, 1 H), 4.38 (d, J = 6.5 Hz, 1 H), 4.06 (s, 3H), 3.98 (qd, J = 9.2, 5.7 Hz, 2H), 3.83 (s, 3H), 3.75 - 3.66 (m, 2H), 3.19 (d, J = 9.3 Hz, 1 H), 2.97 (t, J =8.8 Hz, 1 H), 2.71 (d, J = 9.3 Hz, 1 H), 2.62 - 2.53 (m, 1 H), 2.30 (dd, J = 9.4, 7.4 Hz, 1 H).13C NMR (125 MHz, CDCL3) 5 153.00 (d, J = 9.4 Hz), 152.89 (d, J = 246.2 Hz), 142.17 (d, J = 11.0Hz), 139.54, 132.62, 130.96, 127.81 , 124.11 , 120.68, 114.71 (d, J = 3.1 Hz), 109.36 (d, J = 3.5 Hz), 108.94, 104.18 (d, J = 21.4 Hz), 84.57, 77.45, 68.71 , 65.82, 60.14, 57.20, 57.00, 47.40, 43.99, 35.67.

[0214] 6-benzyl-8-((3,4-dif luorophenoxy)methyl)-2-oxa-6-azaspiro[3.4]octane. (85)General Procedure. Yield: 456 mg (32.5 %, brown oil). LCMS: RT = 1.995 min, ESI-MS: m / z [M+H]+, calc’d 346.15 for C20H21F2NO2, found 346.2.1H NMR (600 MHz, CDCI3) 6 7.36 - 7.24 (m, 5H), 7.06 (q, J = 9.1 Hz, 1 H), 6.72 (ddd, J = 11 .9, 6.5, 3.0 Hz, 1 H), 6.60 (dtd, J = 9.0, 3.2,1 .7 Hz, 1 H), 4.80 (d, J = 6.6 Hz, 1 H), 4.70 (d, J = 5.9 Hz, 1 H), 4.56 (d, J = 5.9 Hz, 1 H), 4.40 (d, J = 6.6 Hz, 1 H), 4.01 (qd, J = 9.1 , 5.8 Hz, 2H), 3.67 - 3.59 (m, 2H), 3.20 (d, J = 9.3 Hz, 1 H), 2.98 (t, J = 8.8 Hz, 1 H), 2.72 (d, J = 9.3 Hz, 1 H), 2.60 (ddd, J = 13.5, 7.8, 5.8 Hz, 1 H), 2.30 (dd, J = 9.4, 7.4 Hz, 1 H).13C NMR (150 MHz, CDCI3) 6 155.00 (dd, J = 8.4, 2.2 Hz), 150.59 (dd, J = 247.7, 13.8 Hz), 145.32 (dd, J = 240.5, 12.7 Hz), 138.54, 128.83, 128.46, 127.29, 117.37 (dd, J = 18.7, 1.7 Hz), 109.86 (dd, J = 5.7, 3.4 Hz), 104.29 (d, J = 20.3 Hz), 84.47, 77.37, 68.82, 65.74, 60.04, 56.97, 47.41 , 43.94.

[0215] 6-(benzo[cf]thiazol-5-ylmethyl)-8-((3,4-difluorophenoxy)methyl)-2-oxa-6- azaspiro[3.4]octane. (86) General Procedure. Yield: 58.3 mg (52.3%, brown oil). LCMS: RT = 1 .949 min, ESI-MS: m / z [M+H]+, calc’d 403.12 for C21H20F2N2O2S, found 403.2.1H NMR (600 MHz, CDCI3) 6 8.98 (s, 1 H), 8.07 (s, 1 H), 7.89 (d, J = 8.3 Hz, 1 H), 7.44 (dd, J = 8.3, 1 .6 Hz, 1 H), 7.04 (q, J = 9.2 Hz, 1 H), 6.70 (ddd, J = 11 .9, 6.5, 3.0 Hz, 1 H), 6.57 (dtd, J = 9.0, 3.2, 1 .6 Hz, 1 H), 4.79 (d, J = 6.6 Hz, 1 H), 4.68 (d, J = 5.9 Hz, 1 H), 4.55 (d, J = 5.9 Hz, 1 H), 4.39 (d, J =6.6 Hz, 1 H), 4.04 - 3.94 (m, 2H), 3.77 (s, 2H), 3.20 (d, J = 9.3 Hz, 1 H), 2.99 (t, J = 8.8 Hz, 1 H), 2.77 (d, J = 9.3 Hz, 1 H), 2.59 (ddd, J = 13.6, 7.7, 5.8 Hz, 1 H), 2.33 (dd, J = 9.4, 7.3 Hz, 1 H).13C NMR (150 MHz, CDCI3) 6 154.91 (dd, J = 8.6, 2.3 Hz), 154.39, 153.60, 150.51 (dd, J = 248.0,13.8 Hz), 145.24 (dd, J = 240.6, 12.7 Hz), 137.23, 132.53, 126.55, 123.42, 121 .73, 1 17.32 (dd, J= 18.7, 1.3 Hz), 109.80 (dd, J = 5.9, 3.3 Hz), 104.22 (d, J = 20.1 Hz), 84.30, 77.27, 68.74, 65.65, 59.70, 56.86, 47.38, 43.88.

[0216] 6-((6-chloroimidazo[1 ,2-b]pyridazin-2-yl)methyl)-8-((3,4- difluorophenoxy)methyl)-2-oxa-6-azaspiro[3.4]octane. (87) General Procedure. Yield: 63.6 mg (55.1%, yellow oil). LCMS: RT = 1.959 min, ESI-MS: m / z [M+H]+, calc’d 421.12 for C20H19CIF2N4O2, found 421 .2.1H NMR (600 MHz, CDCI3) 6 7.85 (s, 1 H), 7.81 (d, J = 9.4 Hz, 1 H), 7.06 - 6.98 (m, 2H), 6.67 (ddd, J = 12.0, 6.6, 2.9 Hz, 1 H), 6.58 - 6.53 (m, 1 H), 4.76 (d, J =6.7 Hz, 1 H), 4.66 (d, J = 6.0 Hz, 1 H), 4.56 (d, J = 5.9 Hz, 1 H), 4.39 (d, J = 6.7 Hz, 1 H), 3.99 (qd, J = 9.2, 5.8 Hz, 2H), 3.87 - 3.80 (m, 2H), 3.33 (d, J = 9.4 Hz, 1 H), 3.10 (t, J = 8.8 Hz, 1 H), 2.83 (d, J = 9.4 Hz, 1 H), 2.65 - 2.57 (m, 1 H), 2.42 (t, J = 8.5 Hz, 1 H).13C NMR (150 MHz, CDCI3) 6 154.86 (dd, J = 8.6, 2.3 Hz), 150.50 (dd, J = 248.0, 13.9 Hz), 146.72, 145.26 (dd, J = 240.6,12.7 Hz), 145.18, 137.37, 126.55, 1 18.93, 1 17.33 (dd, J = 18.6, 1.4 Hz), 1 15.71 , 109.77 (dd, J = 5.8, 3.3 Hz), 104.20 (d, J = 20.3 Hz), 84.32, 77.23, 68.53, 65.84, 57.03, 53.53, 47.39, 43.91.

[0217] 8-((3,4-difluorophenoxy)methyl)-6-(3-fluoro-4-methoxybenzyl)-2-oxa-6- azaspiro[3.4]octane. (88) General Procedure. Yield: 46.2 mg (42.8%, brown oil). LCMS: RT = 2.028 min, ESI-MS: m / z [M+H]+, calc’d 394.16 for C21H22F3NO3, found 394.2.1H NMR (600 MHz, CDCI3) 5 7.09 - 7.02 (m, 2H), 7.01 - 6.97 (m, 1 H), 6.90 (t, J = 8.4 Hz, 1 H), 6.71 (ddd, J = 1 1 .9, 6.5, 3.0 Hz, 1 H), 6.59 (dtd, J = 9.0, 3.1 , 1 .6 Hz, 1 H), 4.79 (d, J = 6.6 Hz, 1 H), 4.68 (d, J = 5.9 Hz, 1 H), 4.54 (d, J = 5.9 Hz, 1 H), 4.39 (d, J = 6.6 Hz, 1 H), 4.04 - 3.95 (m, 2H), 3.87 (s, 3H), 3.53 (s, 2H), 3.16 (d, J = 9.3 Hz, 1 H), 2.94 (t, J = 8.8 Hz, 1 H), 2.70 (d, J = 9.3 Hz, 1 H), 2.58 (ddd, J = 13.5, 7.8, 5.8 Hz, 1 H), 2.27 (dd, J = 9.4, 7.4 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 154.97 (dd, J = 8.6, 2.3 Hz), 152.41 (d, J = 245.6 Hz), 150.57 (dd, J = 248.0, 13.8 Hz), 146.81 (d, J = 10.6 Hz), 145.30 (dd, J = 240.8, 12.7 Hz), 131.78 (d, J = 6.1 Hz), 124.26 (d, J = 3.4 Hz), 1 17.37 (dd, J = 18.7, 1 .5 Hz), 1 16.42 (d, J = 18.2 Hz), 1 13.24 (d, J = 2.0 Hz), 109.84 (dd, J = 6.0, 3.4 Hz), 104.26 (d, J = 20.2 Hz), 84.40, 77.34, 68.75, 65.64, 59.01 , 56.81 , 56.39, 47.39, 43.89.

[0218] 6-((1 H-indazol-5-yl)methyl)-8-((3,4-dif luorophenoxy)methyl)-2-oxa-6- azaspiro[3.4]octane. (89) General Procedure. Yield: 15.3 mg (14.5%, brown oil). LCMS: RT = 1.887 min, ESI-MS: m / z [M+H]+, calc’d 386.16 for C21H21F2N3O2, found 386.2.1H NMR (600 MHz, CDCI3) 5 1 1 .41 (s, 1 H), 8.04 (s, 1 H), 7.65 (s, 1 H), 7.41 - 7.33 (m, 2H), 7.04 (q, J = 9.3 Hz, 1 H), 6.70 (ddd, J = 1 1 .9, 6.5, 3.0 Hz, 1 H), 6.61 - 6.54 (m, 1 H), 4.81 (d, J = 6.6 Hz, 1 H), 4.69 (d, J = 6.0 Hz, 1 H), 4.56 (d, J = 5.9 Hz, 1 H), 4.42 (d, J = 6.6 Hz, 1 H), 4.05 - 3.96 (m, 2H), 3.78 - 3.69 (m, 2H), 3.24 (d, J = 9.5 Hz, 1 H), 3.02 (t, J = 8.9 Hz, 1 H), 2.77 (d, J = 9.5 Hz, 1 H), 2.61 (td, J = 7.8, 3.9 Hz, 1 H), 2.35 (t, J = 8.5 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 154.84 (dd, J = 8.4, 2.4 Hz), 150.47 (dd, J = 247.8, 13.8 Hz), 145.23 (dd, J = 240.6, 12.7 Hz), 139.79, 134.42, 130.64, 128.23, 123.30, 120.65, 1 17.30 (dd, J = 18.3, 1 .2 Hz), 109.98, 109.80 (dd, J = 5.8, 3.3 Hz), 104.21 (d, J = 20.1 Hz), 84.30, 77.32, 68.53, 65.52, 60.04, 56.73, 47.26, 43.78.

[0219] 8-((3,4-d if luorophenoxy)methyl)-6-(imidazo[1 ,2-a]pyridin-2-ylmethyl)-2-oxa-6- azaspiro[3.4]octane, (90) General Procedure. Yield: 56.0 mg (52.9%, brown oil). LCMS: RT =I .825 min, ESI-MS: m / z [M+H]+, calc’d 386.16 for C21H21F2N3O2, found 386.2.1H NMR (600 MHz, CDCI3) 5 8.04 (dt, J = 6.8, 1 .2 Hz, 1 H), 7.52 (d, J = 9.1 Hz, 1 H), 7.49 (s, 1 H), 7.11 (ddd, J = 9.1 , 6.7, 1 .3 Hz, 1 H), 7.01 (q, J = 9.2 Hz, 1 H), 6.73 (td, J = 6.8, 1.1 Hz, 1 H), 6.67 (ddd, J =I I .9, 6.5, 3.0 Hz, 1 H), 6.55 (dtd, J = 9.1 , 3.2, 1 .6 Hz, 1 H), 4.76 (d, J = 6.6 Hz, 1 H), 4.65 (d, J = 5.9 Hz, 1 H), 4.56 (d, J = 5.9 Hz, 1 H), 4.39 (d, J = 6.6 Hz, 1 H), 3.98 (qd, J = 9.1 , 5.7 Hz, 2H), 3.80 (s, 2H), 3.33 (d, J = 9.5 Hz, 1 H), 3.10 (t, J = 8.8 Hz, 1 H), 2.83 (d, J = 9.5 Hz, 1 H), 2.59 (ddd, J = 13.6, 7.9, 5.7 Hz, 1 H), 2.41 (dd, J = 9.5, 7.6 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 154.89 (dd, J = 8.7, 2.2 Hz), 150.47 (dd, J = 247.7, 13.8 Hz), 145.20 (dd, J = 240.5, 12.7 Hz), 145.11 , 143.83, 125.59, 124.51 , 1 17.45, 1 17.28 (dd, J = 18.4, 1.6 Hz), 112.30, 1 10.70, 109.77 (dd, J = 6.0, 3.3 Hz), 104.18 (d, J = 20.1 Hz), 84.39, 77.29, 68.61 , 65.85, 57.00, 53.41 , 47.35, 43.93.

[0220] 1-(8-((3,4-difluorophenoxy)methyl)-2-oxa-6-azaspiro[3.4]octan-6-yl)-2-(3,4- difluorophenyl)ethan-1-one. (91) General Procedure. Yield: 12.6 mg (11.6%, brown oil). LCMS: RT = 2.573min, ESI-MS: m / z [M+H]+, calc’d 410.13 for C21H19F4NO3, found 410.2.1H NMR (600 MHz, CDCI3) 5 7.15 - 7.00 (m, 6H), 7.00 - 6.90 (m, 2H), 6.72 - 6.60 (m, 2H), 6.57 - 6.49 (m, 2H), 4.89 (d, J = 6.9 Hz, 1 H), 4.80 (d, J= 6.8 Hz, 1 H), 4.69 (d, J = 6.2 Hz, 1 H), 4.63 (s, 2H), 4.57 (d, J = 6.8 Hz, 1 H), 4.50 (d, J= 6.2 Hz, 1 H), 4.45 (d, J= 6.9 Hz, 1 H), 4.12 (dd, J= 9.2, 4.9 Hz, 1 H), 4.03 (dd, J = 9.4, 6.0 Hz, 1 H), 3.98 (dd, J= 9.4, 6.2 Hz, 1 H), 3.92 - 3.79 (m, 6H), 3.70 - 3.63 (m, 2H), 3.63 - 3.54 (m, 4H), 3.51 - 3.43 (m, 2H), 2.82 (ft, J = 7.3, 5.1 Hz, 1 H), 2.73 (dq, J = 7.4, 5.9 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 169.09, 169.01 , 154.60, 154.58, 154.54, 154.49, 154.48, 151.46, 151.43, 151.36, 151.34, 151.25, 151.16, 151.08, 150.49,150.40, 150.32, 149.81 , 149.79, 149.72, 149.69, 149.60, 149.52, 149.44, 148.84, 148.76,148.68, 146.36, 146.32, 146.28, 146.23, 144.76, 144.72, 144.68, 144.63, 131.32, 131.29,131.26, 131.22, 125.18, 125.15, 125.1 1 , 118.20, 118.08, 117.59, 117.55, 117.54, 117.47,117.42, 117.31 , 109.80, 109.78, 109.76, 109.74, 109.72, 109.70, 109.69, 109.66, 104.30,104.29, 104.16, 104.15, 81.33, 81.14, 75.81 , 75.71 , 67.74, 67.03, 56.11 , 54.93, 48.68, 48.06, 48.00, 45.92, 44.53, 42.24, 40.88, 40.60. (Additional peaks due to C-F spliting and Rotamers)

[0221] 5-((8-((3,4-difluorophenoxy)methyl)-6-azaspiro[3.4]octan-6-yl)methyl)-1 -methyl- 1 / 7-indazole. (92) General Procedure. Yield: 3.1 mg (4.6%, brown oil). LCMS: RT = 2.276 min, ESI-MS: m / z [M+H]+, calc’d 398.20 for C23H25F2N3O, found 398.1.1H NMR (500 MHz, CDCI3) 5 7.93 (s, 1 H), 7.63 (s, 1 H), 7.42 (dd, J = 8.6, 1 .6 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.04 (q, J = 9.3 Hz, 1 H), 6.74 - 6.66 (m, 1 H), 6.60 - 6.54 (m, 1 H), 4.07 (s, 4H), 3.99 - 3.92 (m, 1 H), 3.83 - 3.64 (m, 2H), 3.02 - 2.92 (m, 1 H), 2.85 (d, J = 9.1 Hz, 1 H), 2.57 (d, J = 9.1 Hz, 1 H), 2.39 - 2.32 (m, 2H), 2.21 - 2.1 1 (m, 1 H), 2.11 - 2.03 (m, 1 H), 2.03 - 1 .95 (m, 1 H), 1.88 - 1 .76 (m, 2H), 1.75 - 1 .67 (m, 1 H).13C NMR (150 MHz, CDCI3) 5 155.43 (dd, J = 8.5, 2.4 Hz), 150.59 (dd, J = 247.4, 13.6 Hz), 145.12 (dd, J = 240.1 , 12.9 Hz), 139.58, 132.69, 130.99, 127.99, 124.16, 120.77, 1 17.28 (d, J = 18.7 Hz), 109.86 (dd, J = 5.8, 3.3 Hz), 108.92, 104.17 (d, J= 20.2 Hz), 69.83, 67.00, 60.50, 57.50, 47.11 , 46.00, 35.80, 35.71 , 28.57, 17.59.

[0222] 6-benzyl-8-((3,4-difluorophenoxy)methyl)-6-azaspiro[3.4]octane. (93) General Procedure. Yield: 826 mg (24.3%, yellow oil). LCMS: RT = 2.522 min, ESI-MS: m / z [M+H]+, calc’d 342.17 for C21H23F2NO, found 344.1.1H NMR (600 MHz, CDCI3) 5 7.36 - 7.30 (m, 4H),7.30 - 7.23 (m, 1 H), 7.05 (dt, J = 10.2, 9.0 Hz, 1 H), 6.72 (ddd, J = 12.1 , 6.6, 3.0 Hz, 1 H), 6.59 (dtd, J = 9.2, 3.2, 1 .7 Hz, 1 H), 3.97 (dd, J = 8.9, 5.8 Hz, 1 H), 3.80 (dd, J = 8.8, 6.9 Hz, 1 H), 3.68 - 3.57 (m, 2H), 3.00 - 2.92 (m, 1 H), 2.85 (d, J = 9.1 Hz, 1 H), 2.57 (d, J = 9.1 Hz, 1 H), 2.40 -2.30 (m, 2H), 2.18 (dt, J = 1 1 .2, 8.7 Hz, 1 H), 2.12 - 2.04 (m, 1 H), 2.03 - 1 .95 (m, 1 H), 1 .91 - 1.77 (m, 2H), 1.76 - 1.68 (m, 1 H).13C NMR (150 MHz, CDCI3) 5 155.44 (dd, J= 8.6, 2.2 Hz), 150.59 (dd, J = 247.5, 13.8 Hz), 145.12 (dd, J = 240.0, 12.7 Hz), 138.80, 128.95, 128.42,127.19, 117.28 (d, J = 18.5 Hz), 109.87 (dd, J = 5.8, 3.4 Hz), 104.18 (d, J = 20.2 Hz), 69.83, 67.01 , 60.44, 57.53, 47.13, 45.99, 35.69, 28.55, 17.59.

[0223] 5-((8-((3,4-difluorophenoxy)methyl)-6-azaspiro[3.4]octan-6- yl)methyl)benzo[d]thiazole. (94) General Procedure. Yield: 6.8 mg (6.62%, clear oil). LCMS: RT = 2.178 min, ESI-MS: m / z [M+H]+, calc’d 401 .14 for C22H22F2N2OS, found 401 .2.1H NMR (600 MHz, CDCI3) 5 9.36 (s, 1 H), 8.45 (s, 1 H), 8.28 (d, J = 8.2 Hz, 1 H), 7.89 (s, 1 H), 7.40 (q, J = 9.3 Hz, 1 H), 7.06 (ddd, J = 12.0, 6.6, 3.0 Hz, 1 H), 6.97 - 6.91 (m, 1 H), 4.37 - 4.31 (m, 1 H), 4.25 - 4.15 (m, 3H), 3.39 (s, 1 H), 3.27 (d, J = 8.6 Hz, 1 H), 3.04 (s, 1 H), 2.86 - 2.70 (m, 2H), 2.58 - 2.50 (m, 1 H), 2.49 - 2.35 (m, 2H), 2.26 - 2.07 (m, 3H).13C NMR (150 MHz, CDCI3) 5 155.72 - 154.92 (m), 154.42, 153.64, 150.60 (dd, J = 247.5, 13.6 Hz), 145.16 (dd, J = 239.9, 12.9 Hz), 137.23, 132.65, 126.88, 123.71 , 121 .84, 117.31 (dd, J = 18.8, 1 .2 Hz), 109.86 (dd, J = 5.9, 3.4 Hz), 104.19 (d, J = 20.1 Hz), 69.69, 66.82, 60.14, 57.36, 47.15, 45.97, 35.54, 28.49, 17.55.

[0224] 6-chloro-2-((8-((3,4-difluorophenoxy)methyl)-6-azaspiro[3.4]octan-6- yl)methyl)imidazo[1 ,2-b]pyridazine. (95) General Procedure. Yield: 11 .3 mg (11 .4%, brown oil). LCMS: RT = 2.213 min, ESI-MS: m / z [M+H]+, calc’d 419.14 for C21H21CIF2N4O, found 419.2.1H NMR (600 MHz, CDCI3) 5 7.91 (s, 1 H), 7.83 (d, J = 9.4 Hz, 1 H), 7.10 - 6.98 (m, 2H), 6.69 (ddd, J = 12.0, 6.6, 3.0 Hz, 1 H), 6.57 (dtd, J = 9.1 , 3.2, 1.7 Hz, 1 H), 3.97 (dd, J = 8.9, 6.0 Hz, 1 H), 3.88 (q, J = 13.9 Hz, 2H), 3.79 (dd, J = 8.9, 7.2 Hz, 1 H), 3.10 (t, J = 8.9 Hz, 1 H), 3.01 (d, J = 9.2 Hz, 1 H), 2.74 (d, J = 9.2 Hz, 1 H), 2.50 (t, J = 8.4 Hz, 1 H), 2.39 (p, J = 6.9 Hz, 1 H), 2.17 (dt, J = 11 .1 , 8.6 Hz, 1 H), 2.11 - 1 .98 (m, 2H), 1 .92 - 1 .72 (m, 3H).13C NMR (150 MHz, CDCI3) 5 155.35 (dd, J = 8.6, 2.3 Hz), 150.57 (dd, J = 247.6, 13.8 Hz), 145.68, 145.13 (dd, J = 240.0,12.7 Hz), 137.31 , 126.56, 118.79, 117.28 (dd, J = 18.8, 1.6 Hz), 115.97, 109.82 (dd, J = 5.9, 3.4 Hz), 104.14 (d, J = 20.0 Hz), 69.60, 67.12, 57.49, 54.08, 47.19, 46.01 , 35.57, 28.49, 17.54.

[0225] 8-((3,4-difluorophenoxy)methyl)-6-(3-fluoro-4-methoxybenzyl)-6- azaspiro[3.4]octane. (96) General Procedure. Yield: 33.4 mg (33.3%, brown oil). LCMS: RT =2.261 min, ESI-MS: m / z [M+H]+, calc’d 392.18 for C22H24F3NO2, found 392.3.1H NMR (400 MHz, CDCI3) 5 7.13 - 6.98 (m, 3H), 6.89 (t, J = 8.5 Hz, 1 H), 6.71 (ddd, J = 12.1 , 6.6, 3.0 Hz, 1 H), 6.59 (dtd, J = 9.1 , 3.2, 1 .7 Hz, 1 H), 4.02 - 3.91 (m, 1 H), 3.88 (s, 3H), 3.84 - 3.75 (m, 1 H), 3.63 - 3.45 (m, 2H), 2.97 - 2.86 (m, 1 H), 2.81 (d, J = 9.0 Hz, 1 H), 2.55 (d, J = 9.0 Hz, 1 H), 2.41 - 2.27 (m, 2H), 2.22 - 2.12 (m, 1 H), 2.11 - 1.94 (m, 2H), 1.92 - 1.68 (m, 3H).13C NMR (101 MHz, CDCI3) 5 155.44 (dd, J= 8.6, 2.2 Hz), 152.42 (d, J= 245.2 Hz), 150.58 (dd, J= 247.3,13.8 Hz), 146.69 (d, J= 10.8 Hz), 145.11 (dd, J= 239.9, 12.7 Hz), 132.28, 124.29 (d, J= 3.4 Hz), 117.27 (dd, J= 18.2, 1.7 Hz), 116.50 (d, J= 18.2 Hz), 113.22 (d, J= 2.1 Hz), 109.86 (dd, J = 5.7, 3.4 Hz), 104.17 (d, J= 20.2 Hz), 69.84, 66.99, 59.43 (d, J= 1.5 Hz), 57.43, 56.42, 47.12, 45.99, 35.69, 28.55, 17.60.

[0226] 5-((8-((3,4-difluorophenoxy)methyl)-6-azaspiro[3.4]octan-6-yl)methyl)-1 H- indazole. (97) General Procedure. Yield: 10.6 mg (10.8%, yellow oil). LCMS: RT = 2.106 min, ESI-MS: m / z [M+H]+, calc’d 384.18 for C22H23F2N3O, found 384.3.1H NMR (600 MHz, CDCI3) 5 10.44 (s, 1 H), 8.04 (s, 1 H), 7.68 (s, OH), 7.42 (s, 1 H), 7.04 (dt, J = 10.0, 9.1 Hz, 1 H), 6.71 (ddd, J= 12.1 , 6.6, 3.0 Hz, 1 H), 6.58 (dtd, J = 9.1 , 3.2, 1.7 Hz, 1 H), 4.00 - 3.95 (m, 1 H), 3.85 - 3.62 (m, 3H), 2.99 (t, J = 10.9 Hz, 1 H), 2.88 (d, J = 9.1 Hz, 1 H), 2.60 (d, J = 9.2 Hz, 1 H), 2.37 (dt, J = 10.2, 5.1 Hz, 2H), 2.17 (dt, J= 11.1 , 8.8 Hz, 1 H), 2.07 (dt, J= 11.0, 8.8 Hz, 1 H), 2.02 - 1.96 (m, 1 H), 1.91 - 1.69 (m, 3H).13C NMR (150 MHz, CDCI3) 5 155.42 (dd, J= 8.4, 2.0 Hz), 150.59 (dd, J= 247.2, 13.8 Hz), 145.12 (dd, J= 240.0, 12.7 Hz), 139.73, 134.93, 131.74, 128.55,123.44, 120.60, 117.28 (dd, J= 18.5, 1.4 Hz), 109.87 (dd, J= 5.8, 3.3 Hz), 109.70, 104.17 (d, J = 20.0 Hz), 69.82, 67.10, 60.57, 57.54, 47.11 , 46.00, 35.73, 28.59, 17.58.

[0227] 2-((8-((3,4-difluorophenoxy)methyl)-6-azaspiro[3.4]octan-6- yl)methyl)imidazo[1 ,2-a]pyridine. (98) General Procedure. Yield: 9.0 mg (%, brown oil). LCMS: RT = 2.061 min, ESI-MS: m / z [M+H]+, calc’d 384.18 for C22H23F2N3O, found 384.3.1H NMR (600 MHz, CDCI3) 5 8.06 (d, J= 6.8 Hz, 1 H), 7.60 - 7.49 (m, 2H), 7.13 (t, J = 7.8 Hz, 1 H), 7.03 (q, J= 9.4 Hz, 1 H), 6.79 - 6.65 (m, 2H), 6.60 - 6.54 (m, 1 H), 4.01 - 3.73 (m, 4H), 3.17 - 3.01 (m, 2H), 2.78 (d, J= 9.3 Hz, 1 H), 2.52 (t, J= 8.4 Hz, 1 H), 2.39 (p, J = 7.1 Hz, 1 H), 2.21 - 1.99 (m, 3H), 1.91 - 1.72 (m, 3H).13C NMR (150 MHz, CDCI3) 5 155.37 (dd, J= 8.7, 1.7 Hz), 150.56 (dd, J= 247.4, 13.7 Hz), 145.10 (dd, J= 239.9, 12.9 Hz), 145.06, 143.98, 125.69,124.45, 117.54, 117.26 (dd, J = 18.7, 1 .2 Hz), 112.31 , 111 .05, 109.82 (dd, J = 5.7, 3.4 Hz), 104.14 (d, J= 20.0 Hz), 69.60, 67.10, 57.41 , 53.98, 47.15, 46.03, 35.56, 28.46, 17.50.

[0228] 1-(8-((3,4-difluorophenoxy)methyl)-6-azaspiro[3.4]octan-6-yl)-2-(3,4- difluorophenyl)ethan-1-one. (99) General Procedure. Yield: 9.1 mg (9.1%, Clear oil). LCMS: RT = 2.972 min, ESI-MS: m / z [M+H]+, calc’d 408.15 for C22H21F4NO2, found 408.2.1H NMR (600 MHz, CDCI3) 5 7.16 - 6.91 (m, 8H), 6.70 - 6.61 (m, 2H), 6.57 - 6.49 (m, 2H), 4.02 - 3.95 (m, 2H), 3.79 (dd, J= 9.1 , 7.2 Hz, 1 H), 3.70 - 3.53 (m, 11 H), 3.48 (ddd, J= 12.7, 11.4, 4.8 Hz, 2H), 2.49 (ddt, J= 9.1 , 6.5, 4.6 Hz, 1 H), 2.42 (tt, J= 7.2, 5.3 Hz, 1 H), 2.26 - 1.83 (m, 11 H), 1.79 (ddt, J = 11 .7, 8.3, 4.6 Hz, 1 H).13C NMR (150 MHz, CDCI3) 5 169.25, 169.07, 154.89, 151 .51 , 151.48, 151.41 , 151.39, 151.26, 151.22, 151.18, 151.13, 150.45, 150.39, 150.37, 150.31 ,149.86, 149.83, 149.76, 149.74, 149.57, 149.48, 148.82, 148.81 , 148.75, 148.73, 148.67,146.24, 146.16, 146.08, 144.64, 144.57, 144.56, 144.49, 131.77, 131.75, 131.73, 131.70,131.67, 131.66, 131.63, 125.18, 125.16, 125.13, 125.11 , 125.09, 125.07, 118.25, 118.20,118.13, 118.08, 117.53, 117.47, 117.40, 117.35, 117.28, 109.86, 109.84, 109.82, 109.80,109.73, 109.70, 109.66, 104.25, 104.22, 104.11 , 104.08, 68.01 , 67.41 , 58.31 , 56.99, 48.60, 47.93, 47.24, 46.55, 45.22, 44.49, 40.96, 40.77, 32.90, 32.70, 26.55, 26.52, 16.47, 16.44. (Additional peaks due to C-F spliting and Rotamers)

[0229] 2-benzyl-4-((3,4-dif luorophenoxy)methyl)-8-oxa-2-azaspiro[4.5]decane. (100)General Procedure. Yield: 1.2 g (45.3%, yellow oil). LCMS: RT = 2.113 min, ESI-MS: m / z [M+H]+, calc’d 374.19 for C22H25F2NO2, found 374.3.1H NMR (600 MHz, CDCI3) 57.39 - 7.29 (m, 4H), 7.29-7.24 (m, 1H), 7.05 (q, J = 9.3 Hz, 1H), 6.69 (ddd, J = 12.0, 6.6, 3.0 Hz, 1H), 6.60 - 6.54 (m, 1 H), 3.98 (dd, J = 9.0, 6.6 Hz, 1 H), 3.86 - 3.75 (m, 3H), 3.68 (s, 2H), 3.44 (dtd, J=34.0, 11.7, 2.4 Hz, 2H), 3.01 (t, J=8.6 Hz, 1H), 2.85 (d, J =9.5 Hz, 1H), 2.56 (d, J =9.5 Hz, 1H), 2.43 (t, J= 8.7 Hz, 1H), 2.28 (p, J= 7.2 Hz, 1H), 1.88 (ddd, J= 13.3, 11.9, 4.7 Hz, 1H), 1.77 (ddd, J = 12.9, 11.6, 4.5 Hz, 1 H), 1.60 - 1.54 (m, 1 H), 1.53-1.47 (m, 1 H).13C NMR (150 MHz, CDCI3) 5155.20 (dd, J= 8.4, 2.2 Hz), 150.58 (dd, J= 247.6, 13.9 Hz), 145.15 (dd, J = 240.0, 12.7 Hz), 138.87, 128.68, 128.45, 127.20, 117.31 (dd, J= 18.2, 1.2 Hz), 109.82 (dd, J = 5.9, 3.4 Hz), 104.13 (d, J = 20.0 Hz), 68.44, 65.95, 65.32, 63.41, 60.32, 56.50, 47.67, 41.35, 38.43, 32.67.

[0230] 2-benzyl-4-((3,4-difluorophenoxy)methyl)-2-azaspiro[4.4]nonane. (101) General Procedure. Yield: 125.2 mg (10.3%, yellow oil). LCMS: RT = 2.113 min, ESI-MS: m / z [M+H]+, calc’d 358.19 for C22H25F2NO, found 358.3.1H NMR (600 MHz, CDCI3) 57.40 - 7.29 (m, 4H), 7.31-7.25 (m, 1H), 7.04 (dt, J= 10.0, 9.1 Hz, 1H), 6.71 -6.64 (m, 1H), 6.59-6.52 (m, 1H), 3.96-3.89 (m, 1H), 3.87-3.78 (m, 1H), 3.73 (d, J= 39.3 Hz, 2H), 2.60 (s, 1H), 2.50-2.42 (m, 3H), 1.78 (s, 1H), 1.68-1.48 (m, 8H).13C NMR (150 MHz, CDCI3) 5155.38 (dd, J= 8.5, 2.2 Hz), 150.60 (dd, J =247.4, 13.7 Hz), 145.18 (dd, J = 237.7, 11.5 Hz), 129.16, 128.57, 127.59, 117.33 (d, J= 18.2 Hz), 109.84 (dd, J= 5.9, 3.4 Hz), 104.17 (d, J= 20.1 Hz), 69.47, 60.35, 57.49, 51.42, 45.16, 39.94, 32.65, 29.84, 24.47, 23.37.

[0231] 2-benzyl-4-((3,4-difluorophenoxy)methyl)-2-azaspiro[4.5]decane. (102) General Procedure. Yield: 378 mg (13.2%, yellow oil). LCMS: RT = 2.333 min, ESI-MS: m / z [M+H]+, calc’d 372.21 for C23H27F2NO, found 372.3.1H NMR (600 MHz, CDCI3) 57.38 - 7.29 (m, 4H), 7.28-7.21 (m, 1H), 7.04 (dt, J= 10.0, 9.1 Hz, 1H), 6.72-6.66 (m, 1H), 6.59-6.54 (m, 1H), 4.07-3.92 (m, 1H), 3.82 (t, J = 8.5 Hz, 1 H), 3.65 (s, 2H), 3.03 - 2.93 (m, 1H), 2.71 (d, J =9.5 Hz, 1 H), 2.50 - 2.36 (m, 2H), 2.27 - 2.16 (m, 1 H), 1.70- 1.45 (m, 6H), 1.37 - 1.11 (m, 4H).13C NMR (150 MHz, CDCI3) 5155.48 (dd, J= 8.3, 2.1 Hz), 150.59 (dd, J= 247.2, 13.8 Hz), 145.06 (dd, J= 239.9, 12.8 Hz), 139.12, 128.76, 128.41, 127.10, 117.25 (d, J= 19.0 Hz), 109.86 (dd, J = 5.7, 3.4 Hz), 104.12 (d, J= 20.0 Hz), 68.88, 64.02, 60.53, 57.01, 47.96, 43.50, 38.59, 32.30, 26.17, 24.13, 23.40.

[0232] Determination of Binding Affinity.

[0233] The binding affinities of the compounds at the dopamine D4 receptors and sigma-1 receptors were evaluated using the following protocol: values determined by competitive inhibition of PHI / V-methylspiperone (D4R) or [3H1 Pentazocine (S1R) binding in membranes harvested from HEK293 cells. All are run in triplicate.

[0234] The results are shown in Table 1 .Table 1

[0235] The pharmacokinetic properties were evaluated for compounds of the disclosure. The intrinsic and hepatic clearances in human and mice were determined. The results are summarized in Tables 2 and 3.Human or mouse liver microsomes (0.5 mg / mL) and 1 pM test compound were incubated in 100 mM potassium phosphate pH 7.4 buffer with 3 mM MgCI2 at 37eC with constant shaking. After a 5 min preincubation, the reaction was initiated by addition of NADPH (1 mM). At selected time intervals (0, 3,7, 15, 25, and 45 min), 50 pL aliquots were taken and subsequently placed into a 96-well plate containing 150 pL of cold acetonitrile with internal standard (50 ng / mL carbamazepine). Plates were then centrifuged at 3000 ref (4eC) for 10 min, and the supernatant was transferred to a separate 96-well plate and diluted 1 :1 with water for LC / MS / MS analysis. The in vitro half-life (T1 / 2, min), intrinsic clearance (CLINT, mL / min / kg) and subsequent predicted hepatic clearance (CLHEP, mL / min / kg) were determinedThe protein binding of each compound was determined in the plasma of multiple species via equilibrium dialysis employing HTDialysis Teflon dialysis chamber and cellulose membranes (MWCO 12-14 K). Plasma was added to the 96 well plate containing test compound and mixed thoroughly for a final concentration of 5 pM. Subsequently, 150 pL of the plasma-compound mixture was transferred to the dialysis chamber, with an accompanying 150 pL of phosphate buffer (25 mM, pH 7.4) on the other side of the membrane. The device plate was sealed and incubated for 4 hours at 37eC with shaking. At completion, aliquots from each chamber were diluted 1 :1 with either plasma (for the buffer sample) or buffer (for the plasma sample) and transferred to a new 96 well plate, at which time ice-cold acetonitrile containing internal standard (2 volumes) was added to extract the matrices. The plate was centrifuged (3000 ref, 10 min) and supernatants transferred and diluted 1 :1 (supernatant: water) into a new 96 well plate, which was then sealed in preparation for LC / MS / MS analysis. Each compound was assayed in triplicate within the same 96-well plate.

[0236] Table 2Table 3

[0237] Compound 21 IP Plasma concentration-time data

[0238] Blood sampling: 0.167h, 0.5h, 1 h, 3h, 5h, 10h, 24 hours. Vehicle: 10% DMSO / 10%Cremphor EL / 30% PEG400 / 50% Water, 10 mg / kgTable 4. PlasmaTable 5. BrainTable 6. Ratio (Brain / plasma)

[0239] Cassette IV PK: Rat PK, IV, cassette dose, 5 in 1 , n=2, single dose, plasma PK at 8 time points: 5min, 15min, 30min, 1 h, 3h, 4h, 8h, 24h on day 1 ; 2nd dose on day 2 after 24 h collection and collect brain and plasma at 15min (or others) post dose. Vehicle: DMSG:PEG400:EtOH:Saline (5:48:10:37)

[0240] Compound 28:Table 7. Summary of Compound 28 IV pharmacokinetic parameters

[0241] Compound 19:Table 9. Summary of Compound 191V pharmacokinetic parametersTable 10. Ratio between Brain and Plasma following IV Administration

[0242] Compound 40:Table 1 1 . Summary of Compound 40 IV pharmacokinetic parametersTable 12. Ratio between Brain and Plasma following IV Administration

Claims

What is Claimed:1 . A compound, or pharmaceutically acceptable salt thereof, having the structure selected from the group consisting of Formula (I), Formula (II), and Formula (III):whereinX and X’ are independently O, CH2, SO2, NH, NCi-Cealkyl, or CF2; each Ring A and Ring B is independently selected from the group consisting of substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, C3-Ci2cycloalkyl, and 3 to 12-membered cycloheteroalkyl containing 1 -3 ring heteroatoms independently selected from N, O, and S;R1is H or Ci-Cealkyl; each b is independently -CH2-, C=O, -CH2-CO-NH-, or -NH-CO-CH2-; n and p are independently 0, 1 , 2, or 3; and m is 1 , 2, or 3.

2. The compound of claim 1 , whereinThe compound of any one of claims 1 -3, wherein5. The compound of any one of claims 1 -4, wherein R1of Formula (III) is H, CH3, or-CH2CH3.

6. The compound of any one of claim 1 -5, wherein Ring A is selected from thewhereinY is H, halo, or -OCH3; s is 0, 1 , or 2;R2and R3are each independently H or Ci-3alkyl; andR4is halo.

7. The compound of claim 6, wherein Ring A is selected from the group consisting8. The compound of claim 7, wherein Ring9. The compound of any one of claims 1-8, wherein the “b-Ring A” moiety is10. The compound of any one of claims 1 -9, wherein Ring B is selected from thewhereinZ1is H, halo, or CH3;Z2is H or halo;R5is H or CH3; and t is 0, 1 , or 2.

11. The compound of claim 10, wherein Ring B is selected from the group consisting12. The compound of any one of claims 1-11 , wherein the compound is selected from the compounds listed in Table A:Table A13. The compound of claim 12, wherein the compound is selected from the group14. A pharmaceutical composition comprising the compound or salt of any one of claims 1-13 and a pharmaceutically acceptable carrier or excipient.

15. A method of inhibiting a receptor selected from a dopamine D4 receptor, sigma-1 receptor, and a combination thereof comprising contacting the receptor with the compound or salt of any one of claims 1 -13 in an amount effective to inhibit the receptor.

16. A method of treating or preventing a disease or disorder capable of being modulated by inhibiting a dopamine D4 receptor or a sigma-1 receptor comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising the compound or salt of any one of claims 1-13.

17. The method of claim 16, wherein the disorder is dyskinesia.

18. The method of claim 17, wherein the dyskinesia is L-DOPA-induced dyskinesia (LID).

19. The method of claim 16, wherein the disorder is pain.

20. The method of claim 16, wherein the disease is cancer.21 . The method of claim 16, wherein the disease is a CNS disease.

22. The method of claim 16, wherein the disease or disorder is selected from the group consisting of neuropsychiatric disorders, neurodegenerative disorders, Parkinson’s disease, Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD), bipolar disorder, glioblastoma, and Dopamine D4 Receptor Antagonism.

23. A pharmaceutical composition comprising the compound of any one of claims 1 - 13 and a pharmaceutically acceptable carrier or excipient for use in for use treating or preventing a disease or disorder capable of being modulated by inhibiting a dopamine D4 receptor or a sigma-1 receptor.

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