BR112018004154B1 - DELTA OPIOID RECEPTOR MODULATOR COMPOUNDS CONTAINING 6-MEMBER AZAHETEROCYLICS, COMPOSITIONS COMPRISING THE SAME AND THEIR USES - Google Patents

Abstract

DELTA OPIOID RECEPTOR MODULATOR COMPOUNDS CONTAINING 6-MEMBER AZA-HETEROCYLICS, METHODS OF USE AND PRODUCTION THEREOF. The present embodiments are directed, in part, to compounds, or a pharmaceutically acceptable salt thereof or pharmaceutical compositions thereof for partial and/or impartial modulation of delta opioid receptor activity, and/or methods for treating pain, migraines , headaches, depression, Parkinson's disease, anxiety and/or overactive bladder and other conditions and disorders described herein or any combination thereof.

Description

Cross Reference to Related Requests

[0001] The present application claims priority to United States Provisional Application No. 62/213,203, filed on September 2, 2015, which is incorporated herein by reference in its entirety. Reference to Government Concessions

[0002] The present invention was supported by funds from the United States government (NIH Grants Nos. 5U01NS074480-02 and 1RC2MH090877-01) and the United States government may therefore have certain rights to the invention. Field

[0003] The embodiments described here are directed, in part, to compounds, or pharmaceutically acceptable salts thereof, for modulating delta opioid receptor activity and/or methods for treating pain (e.g., neuropathic pain), migraines ( e.g., episodic, chronic, or acute), headaches (e.g., episodic, chronic, or acute), depression, Parkinson's disease, PTSD, anxiety, and/or overactive bladder, or any combination thereof. Background

[0004] Opioid receptors (ORs) mediate the actions of morphine and morphine-like opioids, including most clinical analgesics. Three molecularly and pharmacologically distinct types of opioid receptors have been described: δ, K and μ. Furthermore, each type is believed to have subtypes. All three types of opioid receptors appear to share the same functional mechanisms at a cellular level. For example, certain activation of opioid receptors causes inhibition of adenylate cyclase and recruits β-arrestin.

[0005] The delta opioid receptor (DOR) has long been of interest as a target for potentially non-addictive treatments for a variety of CNS disorders. Recent evidence suggests that DOR activation may be beneficial in the treatment of migraine, neuropathic pain, Parkinson's disease, depression, anxiety, and several other indications. However, some DOR agonists have caused seizures in preclinical species, making it difficult to develop selective drugs targeting DOR. Therefore, it is necessary to identify a PAIN modulator for the treatment of these and other conditions. The present embodiments described here satisfy these needs and others.

Summary of Achievements

[0006] In some embodiments, the present invention provides a compound as described herein or a compound of a formula described herein or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the present invention provides pharmaceutical compositions comprising one or more compounds described herein or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, there is provided a compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: B1049, B0704, B0707, B0720, B0876, B1079, B1145, B1194, B1205, B1211, B1365 and B1401. In some embodiments, the opposite stereochemistry is provided. In some embodiments, the racemic mixture is provided.

[0009] In some embodiments, the present embodiments provide methods for treating pain, migraines (e.g., episodic, chronic, or acute), headaches (e.g., episodic, chronic, or acute), depression, anxiety, and/or bladder pain. hyperactive in an individual. In some embodiments, the methods comprise administering to the individual one or more compounds described herein, or a salt thereof, or a pharmaceutical composition comprising one or more compounds, or a salt thereof, of a compound described herein. In some embodiments, methods of preventing the conditions described herein are provided. In some embodiments, methods for treating and/or preventing major depressive disorders, treatment-resistant anxiety, post-traumatic stress disorder, neuropathic pain, including diabetic peripheral neuropathy, postherpetic neuralgia, chemotherapy-induced neuropathic pain, prevention of induced neuropathy by chemotherapy, prevention of chemotherapy-induced neuropathic pain, trigeminal neuralgia, inflammatory pain, including osteoarthritis, rheumatoid arthritis, Rett syndrome, autism spectrum disorders, migraine, cluster headaches, acute abortive treatment, prophylaxis of acute intermittent migraine, prophylaxis of chronic migraine, treatment of episodic and chronic cluster headache, treatment or prevention of acute episodic and chronic headache, Charcot-Marie Tooth disease, traumatic brain injury, fibromyalgia, stroke, acute ischemic syndrome, ischemia injury/ reperfusion, substance abuse intervention, and/or alcohol abuse treatment in an individual. In some embodiments, the methods comprise administering to the individual one or more compounds described herein, or a salt thereof, or a pharmaceutical composition comprising one or more compounds, or a salt thereof, of a compound described herein. In some embodiments, the individual is a mammal. In some embodiments, the individual is a human being in need of it.

Brief Description of the Drawings

[0010] Figure 1 illustrates compounds prepared according to the examples, including LCMS data.

[0011] Figure 2 illustrates the in vitro data for the compounds described here and as cited in the examples.

[0012] Figure 3 illustrates that the compounds of the present description are effective in treating medication overuse headache.

[0013] Figure 4 illustrates that the compounds of the present description are effective in the treatment of opioid-induced hyperalgesia.

[0014] Figure 5 illustrates that the compounds of the present description do not lead to headaches due to excessive medication use.

Description of Achievements

[0015] Unless otherwise defined, all technical and scientific terms have the same meaning as commonly understood by those skilled in the art to which the described embodiments belong.

[0016] As used herein, the terms "a" or "an" mean "at least one" or "one or more", unless the context clearly indicates otherwise.

[0017] As used herein, the term "about" means that the numerical value is approximate and small variations will not significantly affect the practice of the described embodiments. When a numerical limitation is used, unless otherwise indicated by the context, "about" means that the numerical value may vary by ± 10% and remain within the scope of the described embodiments.

[0018] As used herein, the term "acylamino" means an amino group substituted by an acyl group (e.g., -O-C(=O)-H or -O-C(=O)-alkyl). An example of an acylamino is -NHC(=O)H or -NHC(=O)CH3. The term "lower acylamino" refers to an amino group substituted by a lower acyl group (e.g., -O-C(=O)-H or -O-C(=O)-C1-6alkyl). An example of a lower acylamino is -NHC(=O)H or -NHC(=O)CH3.

[0019] As used herein, the term "alkenyl" means a linear or branched alkyl group that has one or more carbon-carbon double bonds and 2-20 carbon atoms including, but not limited to, ethenyl, 1-propenyl, 2- propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and so on. In some embodiments, the alkenyl chain is from 2 to 10 carbon atoms long, from 2 to 8 carbon atoms long, from 2 to 6 carbon atoms long, or from 2 to 4 carbon atoms long.

[0020] The terms "alkoxy", "phenyloxy", "benzoxy" and "pyrimidinyloxy" refer to an alkyl group, benzyl group or pyrimidinyl group, respectively, each optionally substituted, which is linked through an oxygen atom. For example, the term "alkoxy" means a linear or branched -O-alkyl group of 1 to 20 carbon atoms including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy and so on. In some embodiments, the alkoxy chain is from 1 to 10 carbon atoms long, from 1 to 8 carbon atoms long, from 1 to 6 carbon atoms long, from 1 to 4 carbon atoms long, from 2 to 10 carbon atoms long, from 2 to 8 carbon atoms long, from 2 to 6 carbon atoms long, or from 2 to 4 carbon atoms long long carbon.

[0021] As used herein, the term "alkyl" means a straight or branched chain saturated hydrocarbon group. An alkyl group can contain from 1 to 20, from 2 to 20, from 1 to 10, from 2 to 10, from 1 to 8, from 2 to 8, from 1 to 6, from 2 to 6, from 1 to 4, from 2 to 4, from 1 to 3 or 2 or 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, t-butyl, isobutyl), pentyl ( e.g., n-pentyl, isopentyl, neopentyl), hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, 2-methyl-1- propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 2,2-dimethyl-1- propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl and so on.

[0022] As used herein, the term "alkylamino" means an amino group substituted by an alkyl group having from 1 to 6 carbon atoms. An example of an alkylamino group is -NHCH2CH3.

[0023] As used herein, the term "alkylene" or "alkylenyl" means a divalent alkyl linking group. An example of an alkylene (or alkylenyl) group is methylene or methyleneyl (-CH2-).

[0024] As used herein, the term "alkylthio" means a -S-alkyl group having from 1 to 6 carbon atoms. An example of an alkylthio group is - SCH2CH3.

[0025] As used herein, the term "alkynyl" means a linear or branched alkyl group that has one or more carbon-carbon triple bonds and 2-20 carbon atoms including, but not limited to, acetylene, 1-propylene, 2- propylene and so on. In some embodiments, the alkynyl chain is 2 to 10 carbon atoms long, 2 to 8 carbon atoms long, 2 to 6 carbon atoms long, or 2 to 4 carbon atoms long.

[0026] As used here, the term "amidino" means -C(=NH)NH2.

[0027] As used here, the term "amino" means -NH2.

[0028] As used herein, the term "aminoalkoxy" means an alkoxy group substituted by an amino group. An example of an aminoalkoxy group is -OCH2CH2NH2.

[0029] As used herein, the term "aminoalkyl" means an alkyl group substituted by an amino group. An example of an aminoalkyl group is -CH2CH2NH2.

[0030] As used here, the term "aminosulfonyl" means -S(=O)2NH2.

[0031] As used herein, the term "aminoalkylthio" means an alkylthio group substituted by an amino group. An example of an aminoalkylthio group is -SCH2CH2NH2.

[0032] As used here, the term "amphiphilic" means a three-dimensional structure with distinct hydrophobic and hydrophilic regions. An amphiphilic compound suitably has the presence of hydrophobic and hydrophilic members.

[0033] As used herein, the term "animal" includes, but is not limited to, humans and non-human vertebrates, such as wild, domestic and farmed animals.

[0034] As used herein, the term "antagonize" or "antagonism" means to reduce or completely eliminate an effect, such as delta opioid receptor activity.

[0035] As used herein, the phrase "anti-receptor effective amount" of a compound can be measured by the anti-receptor effectiveness of the compound. In some embodiments, an antireceptor effective amount inhibits a receptor activity by at least 10%, by at least 20%, by at least 30%, by at least 40%, by at least 50%, by at least 60%, in at least 70%, at least 80%, at least 90% or at least 95%. In some embodiments, an "antireceptor effective amount" is also a "therapeutically effective amount" whereby the compound reduces or eliminates at least one effect of a delta opioid receptor. In some embodiments, the effect is the effect on beta-arrestin. In some embodiments, the effect is the effect mediated by the G protein.

[0036] As used herein, the term "aryl" means monocyclic, bicyclic or polycyclic aromatic hydrocarbons (e.g., having 2, 3 or 4 fused rings). In some embodiments, the aryl groups have from 6 to 20 carbon atoms or from 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, and so on. Examples of aryl groups include, but are not limited to:

[0037] As used herein, the term "arylalkyl" means an aryl-substituted C1-6alkyl.

[0038] As used herein, the term "arylamino" means an amino group substituted by an aryl group. An example of an arylamino group is -NH(phenyl).

[0039] As used herein, the term "arylene" means an aryl linking group, that is, an aryl group that links one group to another group in a molecule.

[0040] As used herein, the term "cancer" means a spectrum of pathological symptoms associated with the initiation or progression, as well as metastasis, of malignant tumors.

[0041] As used here, the term "carbamoyl" means -C(=O)-NH2.

[0042] As used herein, the term "carbocycle" means a saturated or unsaturated 5- or 6-membered cyclic ring that optionally contains O, S or N atoms as part of the ring. Examples of carbocycles include, but are not limited to, cyclopentyl, cyclohexyl, cyclopenta-1,3-diene, phenyl and any of the aforementioned heterocycles.

[0043] As used herein, the term "carrier" means a diluent, adjuvant or excipient with which a compound is administered. Pharmaceutical carriers can be liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and so on. Pharmaceutical carriers can also be saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea and so on. Additionally, auxiliary agents, stabilizers, thickeners, lubricants and coloring agents can be used.

[0044] As used herein, the term "compound" means all stereoisomers, tautomers and isotopes of the compounds described herein.

[0045] As used herein, the terms "comprising" (and any form of understanding, such as "comprises", "comprises" and "consisting of"), "have" ( and any form of have, such as "has" and "have"), "which includes" (and any form of including, such as "includes" and "include") or "which contains" (and any form of contain, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional members, unnamed members, or method steps.

[0046] As used herein, the term "contact" means bringing together two members in an in vitro system or an in vivo system. For example, "contacting" a δ-opioid compound with a δ-opioid receptor in an individual or patient or cell includes administering the compound to an individual or patient, such as a human, as well as, for example, introducing a compound in a sample that contains a cellular or purified preparation that contains the δ-opioid receptor.

[0047] As used herein, the term "cyan" means -CN.

[0048] As used herein, the term "cycloalkyl" means non-aromatic cyclic hydrocarbons, including cyclized alkyl, alkenyl and alkynyl groups that contain up to 20 ring-forming carbon atoms. Cycloalkyl groups may include mono- or polycyclic ring systems, such as fused ring systems, bridged ring systems and spiro ring systems. In some embodiments, polycyclic ring systems include 2, 3 or 4 fused rings. A cycloalkyl group may contain 3 to 15, 3 to 10, 3 to 8, 3 to 6, 4 to 6, 3 to 5, or 5 or 6 ring-forming carbon atoms. Ring-forming carbon atoms of a cycloalkyl group may be optionally substituted by oxo or sulfide. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl and so on. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused to (having a bond in common with) the cycloalkyl ring, e.g., benzo or thienyl derivatives of pentane, pentene, hexane, and so on (e.g., 2,3-dihydro-1H-indene-1-yl or 1H-inden-2(3H)-one-1-yl).

[0049] As used herein, the term "cycloalkylalkyl" means a C1-6alkyl substituted by cycloalkyl.

[0050] As used herein, the term "dialkylamino" means an amino group substituted by two alkyl groups, each having from 1 to 6 carbon atoms.

[0051] As used here, the term "diazamino" means -N(NH2)2.

[0052] As used herein, the term "facially amphiphilic" or "facial amphiphilicity" means compounds with polar (hydrophilic) and non-polar (hydrophobic) side chains that adopt conformation(s) that lead to the segregation of polar side chains and nonpolar on opposite faces or separate regions of the structure or molecule.

[0053] As used here, the term "guanidino" means -NH(=NH)NH2.

[0054] As used herein, the term "halo" means halogen groups including, but not limited to, fluorine, chlorine, bromine and iodine.

[0055] As used herein, the term "haloalkoxy" means a -O-haloalkyl group. An example of a haloalkoxy group is OCF3.

[0056] As used herein, the term "haloalkyl" means a C1-6alkyl group that has one or more halogen substituents. Examples of haloalkyl groups include, but are not limited to, CF3, C2F5, CH2F, CHF2, CCl3, CHCl2, CH2CF3 and so on.

[0057] As used herein, the term "heteroaryl" means an aromatic heterocycle that has up to 20 ring-forming atoms (e.g., C) and that has at least one heteroatom member in the ring (ring-forming atom), such such as sulfur, oxygen or nitrogen. In some embodiments, the heteroaryl group has at least one or more ring-forming heteroatoms, each of which is independently sulfur, oxygen or nitrogen. In some embodiments, the heteroaryl group has 3 to 20 ring-forming atoms, 3 to 10 ring-forming atoms, 3 to 6 ring-forming atoms, or 3 to 5 ring-forming atoms. In some embodiments, the heteroaryl group contains 2 to 14 carbon atoms, 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic systems (e.g., having 2, 3, or 4 fused rings). Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (such as indole-3-yl), pyrrolyl, oxazolyl, benzofuryl, groups. benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4- thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, pyrazolyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furanyl, phenoxazinyl and so on. Suitable heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino-1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2, 4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine and 2-aminopyridine.

[0058] As used herein, the term "heteroarylalkyl" means a C1-6alkyl group substituted by a heteroaryl group.

[0059] As used herein, the term "heteroarylamino" means an amino group substituted by a heteroaryl group. An example of a heteroarylamino group is -NH- (2-pyridyl).

[0060] As used herein, the term "heteroarylene" means a heteroaryl linkage group, that is, a heteroaryl group that links one group to another group in a molecule.

[0061] As used herein, the term "heterocycle" or "heterocyclic ring" means a 5- to 7-membered monocyclic or 7 to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated and unsaturated and which consists of carbon atoms and one to three heteroatoms chosen from N, O and S and wherein the N and S heteroatoms may be optionally oxidized and the N heteroatom may be optionally quaternized and including any bicyclic group in which any of the heterocyclic rings defined above is fused to a benzene ring. Particularly useful are rings that contain one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. The heterocyclic ring can be attached to any heteroatom or carbon atom that results in the creation of a stable structure. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzo xazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl. Morpholino is the same as morpholinil.

[0062] As used herein, the term "heterocycloalkyl" means non-aromatic heterocycles that have up to 20 ring-forming atoms, including cyclized alkyl, alkenyl and alkynyl groups, where one or more of the ring-forming carbon atoms are replaced by a heteroatom, such as an O, N, or S atom. Heterocycloalkyl groups may be mono- or polycyclic (e.g., fused, bridged, or spiro systems). In some embodiments, the heterocycloalkyl group has 1 to 20 carbon atoms or 3 to 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl and so on. Furthermore, ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group may be optionally substituted by oxo or sulfide. For example, a ring-forming S atom can be replaced by 1 or 2 oxo (forms an S(O) or S(O)2 group). For another example, a ring-forming C atom can be replaced by oxo (carbonyl form). Also included in the definition of heterocycloalkyl are moieties having one or more aromatic rings fused to (having a common bond with) the non-aromatic heterocyclic ring including, but not limited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl and benzo derivatives of heterocycles, such as indolene, isoindolene, 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl, 5,6-dihydrothieno[2,3-c]pyridin-7(4H) )-one-5-yl, isoindolin-1-one-3-yl and 3,4-dihydroisoquinolin-1(2H)-one-3-yl. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally substituted by oxo or sulfide.

[0063] As used herein, the term "heterocycloalkylalkyl" refers to a C1-6alkyl substituted by heterocycloalkyl.

[0064] As used herein, the term "hydroxy" or "hydroxyl" means an -OH group.

[0065] As used herein, the term "hydroxyalkyl" or "hydroxylalkyl" means an alkyl group substituted by a hydroxyl group. Examples of a hydroxylalkyl group include, but are not limited to, -CH2OH and -CH2CH2OH.

[0066] As used herein, the term "individual" or "patient", used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses or primates, such as humans.

[0067] As used herein, the phrase "inhibitory activity", such as enzyme or receptor activity, means reducing, by any measurable amount, the activity of an enzyme or receptor, such as the δ-opioid receptor.

[0068] As used herein, the phrase "in need of the same" means that the animal or mammal has been identified as having a need for the particular method or treatment. In some embodiments, identification may be by any diagnostic means. In any of the methods and treatments described here, the animal or mammal may need it. In some embodiments, the animal or mammal is in an environment or will be traveling to an environment in which a particular disease, disorder or condition is prevalent.

[0069] As used herein, the phrase "gelable in situ" means to encompass not only low-viscosity liquids that form gels upon contact with the eye or with tear fluid outside the eye, but also more viscous liquids, such as gels. semi-fluids and thixotropics, which exhibit substantially greater gel viscosity or rigidity upon administration to the eye.

[0070] As used herein, the phrase "integer from X to Y" means any integer that includes the full stops. For example, the phrase "integer from X to Y" means 1, 2, 3, 4, or 5.

[0071] As used herein, the term "isolated" means that the compounds described herein are separated from other components of (a) a natural source, such as a plant or cell or (b) a synthetic organic chemical reaction mixture, such as through conventional techniques.

[0072] As used herein, the term "mammal" means a rodent (i.e., a mouse, a rat, or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or a human being . In some embodiments, the mammal is a human being.

[0073] As used herein, the term "N-alkyl" refers to an alkyl chain that is substituted with an amine group. Non-limiting examples include, but are not limited to, and so on. The alkyl chain may be linear, branched, cyclic or any combination thereof. In some embodiments, the alkyl comprises 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3 or 1-2 carbons.

[0074] As used herein, the term "nitro" means -NO2.

[0075] As used herein, the term "n-members", where n is an integer, typically describes the number of ring-forming atoms in a portion, where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl ring.

[0076] As used herein, the phrase "ophthalmically acceptable" means having no persistent harmful effect on the treated eye or its operation, nor on the general health of the individual being treated. However, it will be recognized that transient effects, such as minor irritation or a "stinging" sensation, are common with topical administration of ophthalmic drugs and the existence of such transient effects is not inconsistent with the composition, formulation or ingredient (e.g. example, excipient) in question be "ophthalmically acceptable" as defined herein.

[0077] As used herein, the phrase "optionally substituted" means that the substitution is optional and therefore includes unsubstituted and substituted atoms and moieties. A "substituted" atom or moiety indicates that any hydrogen on the designated atom or moiety may be replaced by a selection of the indicated substituent groups, provided that the normal valence of the designated atom or moiety is not exceeded and that the substitution results in a stable compound . For example, if a methyl group is optionally substituted, then 3 hydrogen atoms on the carbon atom can be replaced by substituent groups.

[0078] As used herein, the phrase "pharmaceutically acceptable" means compounds, materials, compositions and/or dosage forms that are, within the scope of good medical judgment, suitable for use in contact with tissues of humans and animals. In some embodiments, "pharmaceutically acceptable" means approved by a federal or state government regulatory agency or listed in the North American Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and, more particularly, in humans.

[0079] In some embodiments, the salt of a compound described herein is a pharmaceutically acceptable salt thereof. As used herein, the phrase "pharmaceutically acceptable salt(s)" includes, but is not limited to, salts of acidic or basic groups. Compounds of a basic nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts that contain pharmacologically acceptable anions including, but not limited to, sulfuric, thiosulfuric acids. , citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, iodhydrate, nitrate, sulfate, bisulfate, bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate , bitartrate, ascorbate, succinate, maleate, gentilinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, bicarbonate, malonate, mesylate, esylate, napsidisylate, tosylate, besylate, orthophosphate , trifluoroacetate and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) salts). Compounds that include an amino moiety can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Compounds that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include, but are not limited to, salts of alkali metals or alkaline earth metals and, in particular, salts of calcium, magnesium, ammonium, sodium, lithium, zinc, potassium and iron. The present invention also includes quaternary ammonium salts of the compounds described herein, wherein the compounds have one or more tertiary amine moieties.

[0080] As used here, the term "phenyl" means -C6H5. A phenyl group may be unsubstituted or substituted by one, two or three suitable substituents.

[0081] As used herein, the term "prodrug" means a derivative of a known direct-acting drug, which derivative has improved administration characteristics and therapeutic value compared to the drug and is transformed into the active drug through a enzymatic or chemical process.

[0082] As used herein, the term "purified" means that, when isolated, the isolate contains at least 90%, at least 95%, at least 98% or at least 99% of a compound described herein by weight of the isolate.

[0083] As used herein, the phrase "quaternary ammonium salts" means derivatives of the described compounds with one or more tertiary amine moieties in which at least one of the tertiary amine moieties in the original compound is modified by converting the tertiary amine moiety into a quaternary ammonium cation through alkylation (and the cations are balanced by anions such as Cl-, CH3COO- and CF3COO-), for example, methylation or ethylation.

[0084] As used here, the term "semicarbazone" means =NNHC(=O)NH2.

[0085] As used herein, the phrase "solubilizing agent" means agents that result in the formation of a micellar solution or a true solution of the drug.

[0086] As used herein, the term "solution/suspension" means a liquid composition in which a first portion of the active agent is present in solution and a second portion of the active agent is present in particle form, suspended in a liquid matrix. .

[0087] As used herein, the phrase "substantially isolated" means a compound that is at least partially or substantially separated from the environment in which it is formed or detected.

[0088] As used here, the phrase "suitable substituent" or "substituent" means a group that does not nullify the synthetic or pharmaceutical utility of the compounds described here or of intermediates useful for their preparation. Examples of suitable substituents include, but are not limited to: C1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, C5-C6aryl, C1-C6alkyloxy, C3-C5heteroaryl, C3-C6cycloalkyl, C5-C6aryloxy, -CN, -OH, oxo, halo, haloalkyl, -NO2, -CO2H, -NH2, -NH(C1-C8alkyl), -N(C1-C8alkyl)2, -NH(C6aryl), -N(C5-C6aryl)2, -CHO, -CO (C1-C6alkyl), -CO((C5-C6)aryl), -CO2((C1-C6)alkyl) and - CO2((C5-C6)aryl). Those skilled in the art can easily choose a suitable substituent based on the stability and pharmacological and synthetic activity of the compounds described herein.

[0089] As used herein, the phrase "therapeutically effective amount" means the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response being sought in a tissue, system, animal, individual or human being by a researcher, veterinarian, doctor or other clinician. The therapeutic effect depends on the disorder being treated or the desired biological effect. As such, the therapeutic effect may be a decrease in the severity of symptoms associated with the disorder and/or inhibition (partial or complete) of the progression of the disorder or improvement in the treatment, cure, prevention or elimination of a disorder or side effects. The amount needed to elicit a therapeutic response can be determined based on the age, health, size and sex of the individual. Optimal amounts can also be determined based on monitoring the individual's response to treatment.

[0090] As used herein, the terms "treatment", "treated" or "treat" mean therapeutic treatment and prophylactic measures in which the objective is to alleviate (lessen) an undesirable physiological condition, disorder or disease or to obtain beneficial or desired clinical results . For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, relief of symptoms; decrease in the extent of the condition, disorder or disease; stabilized (i.e., not worsening) state of the disease, disorder or condition; delay in the onset or slowing of the progression of the condition, disorder or disease; improvement or remission (partial or total) of the condition, disorder or disease, whether detectable or undetectable; an improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or increase or improvement in condition, disorder or disease. Treatment includes achieving a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival compared to the expected survival if not receiving treatment. Thus, "pain treatment" means an activity that alleviates or improves any primary phenomenon or secondary symptoms associated with pain or another condition described herein.

[0091] As used here, the term "ureido" means -NHC(=O)-NH2.

[0092] In various places in the present description, the substituents of the compounds can be described in groups or in ranges. It is specifically intended that embodiments include each individual sub-combination of members of such groups and bands. For example, the term "C 1-6 alkyl" is specifically intended to describe individually, methyl, ethyl, propyl, C4alkyl, C5alkyl and C6alkyl.

[0093] For compounds in which a variable appears more than once, each variable may be a different portion selected from the Markush group that defines the variable. For example, where a structure is described as having two R groups that are simultaneously present in the same compound, the two R groups may represent different moieties selected from the Markush groups defined for R. In another example, when an optionally multiple substituent is designated in the form, for example, then, it is understood that the substituent R can occur any number of times in the ring and R can be a different moiety in each occurrence. Furthermore, in the example above, where the variable T1 is defined to include hydrogens, such as when T1 is CH2, NH, etc., any H can be replaced by a substituent.

[0094] It is further appreciated that certain features described here that are, for greater clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. On the other hand, several features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0095] It should be understood that the present invention covers the use, when applicable, of stereoisomers, diastereomers and optical stereoisomers of the compounds of the invention, as well as mixtures thereof. Furthermore, it should be understood that stereoisomers, diastereomers and optical stereoisomers of the compounds of the invention and mixtures thereof are within the scope of the invention. By way of non-limiting example, the mixture may be a racemate or the mixture may comprise unequal proportions of a particular stereoisomer relative to the other. Additionally, the compounds can be provided as substantially pure stereoisomers, diastereomers and optical stereoisomers (such as epimers).

[0096] The compounds described here may be asymmetric (for example, having one or more stereocenters). It is intended that all stereoisomers, such as enantiomers and diastereomers, are included within the scope of the invention unless otherwise indicated. Compounds containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods of preparing optically active forms from optically active starting materials are known in the art, such as by decomposition of racemic mixtures or through stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds and so on may also be present in the compounds described herein and all of these stable isomers are considered in the present invention. Cis and trans geometric isomers of the compounds are also included within the scope of the invention and can be isolated as a mixture of isomers or as separate isomeric forms. When a compound capable of stereoisomerism or geometric isomerism is designated in its structure or name without reference to specific R/S or cis/trans configurations, it is intended that all such isomers be considered.

[0097] The decomposition of racemic mixtures of compounds can be carried out by any of numerous methods known in the art including, for example, chiral HPLC, fractional recrystallization using a chiral decomposition acid which is an optically active salt-forming organic acid. Suitable decomposition agents for fractional recrystallization methods include, but are not limited to, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid and the various camphorsulfonic acids. optically active, such as β-camphorsulfonic acid. Other suitable decomposition agents for fractional crystallization methods include, but are not limited to, stereoisomerically pure forms of α-methyl benzyl amine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N -methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and so on. Decomposition of racemic mixtures can also be accomplished by elution on a packed column with an optically active decomposition agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0098] Compounds may also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond along with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactime pairs, enamine-imine pairs, and ring forms in which a proton can occupy two or more positions of a system. heterocyclic including, but not limited to, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form through appropriate substitution.

[0099] Compounds also include hydrates and solvates, as well as anhydrous and unsolvated forms.

[0100] Compounds can also include all isotopes of atoms that occur in intermediates or final compounds. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0101] In some embodiments, the compounds, or salts thereof, are substantially isolated. Partial separation may include, for example, a composition enriched in the compound of the invention. Substantial separation may include compositions that contain at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about at least about 97% or at least about 99% by weight of the compound of the invention, or a salt thereof. Methods for isolating compounds and their salts are routine in the art.

[0102] Although the described compounds are suitable, other functional groups can be incorporated into the compound with an expectation of similar results. In particular, thioamides and thioesters are considered to have very similar properties. The distance between the aromatic rings can have an impact on the geometric pattern of the compound and this distance can be altered by incorporating aliphatic chains of variable length, which can be optionally substituted or can comprise an amino acid, a dicarboxylic acid or a diamine. The distance between and the relative orientation of monomers within compounds can also be changed by replacing the amide bond with a substitute that has additional atoms. Therefore, replacing a carbonyl group with a dicarbonyl changes the distance between the monomers and the propensity of the dicarbonyl moiety to adopt an opposite configuration of the two carbonyl moieties and alter the periodicity of the compound. Pyromellitic anhydride represents yet another alternative to simple amide bonds that can alter the conformation and physical properties of the compound. Modern methods of solid phase organic chemistry (E. Atherton and R.C. Sheppard, Solid Phase Peptide Synthesis A Practical Approach, IRL Press Oxford, 1989) now allow the synthesis of homodisperse compounds with molecular weights approaching 5,000 Daltons. Other replacement patterns are equally effective.

[0103] The compounds also include derivatives said to be prodrugs.

[0104] Compounds that contain an amine function can also form N-oxides. A reference herein to a compound containing an amine function also includes the N-oxide. When a compound contains multiple amine functions, one or more of the nitrogen atoms can be oxidized to form an N-oxide. Examples of N-oxides include N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid) (see Advanced Organic Chemistry, Jerry March, 4th Edition, Wiley Interscience) .

[0105] Embodiments of various compounds and salts thereof are provided. When a variable is not specifically cited, the variable can be any option described here unless otherwise noted or dictated by context.

[0106] In some embodiments, compounds having Formula I, I-1 or Ib-2 or a pharmaceutically acceptable salt thereof are provided: or a pharmaceutically acceptable salt thereof, wherein: BB is cycloalkyl, heterocycle, imidazole, such as Z is C, S, N, S(O)2 or O; R35 is a protecting group, C(=O)OR81b, H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, -R63R64, C1-C6 optionally substituted branched or unbranched alkyl, C2-C6 optionally substituted alkenyl, C2- C6 optionally substituted haloalkenyl -(CH2)nR65, optionally substituted heterocycle, C1-C6 optionally substituted ester, optionally substituted cycloalkyl, C1-C6 optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, C3-C6 optionally substituted cyclic ether or optionally piperidyl replaced; R36 is absent, is H, halo, optionally substituted C1-C6 haloalkyl, -SO2C1-C6alkyl, -OCF3, optionally substituted C1-C6 alkyl or -OR75; wherein R75 is H or optionally substituted C1-C6 alkyl; R37 is absent, is H, halo, C1-C6 optionally substituted haloalkyl, -SO2C1-C6alkyl, -OCF3, optionally substituted sulfonamide, optionally substituted cyclic sulfonamide, -(CH2)q-R38, -NH-(CH2)q-R38 , -S- (CH2)q-R38, -C(=O)R38 or -O-(CH2)q-R38 R38 is H, C1-C6 alkyl, halo, C1-C6 haloalkyl, C(=O)C1-C6 alkyl, –OR66, S(O)2R67 optionally substituted cycloalkyl, (CH2)pR65 or optionally substituted heterocycle; or R37 is -(CH2)q-R38 or R36 and R37 form a heterocycle that is fused to the phenyl ring; R41 is absent, is H or C1-C6 alkyl, provided that when Z is S, O or S(O)2, R41 is absent; or, when Z is C, the bond connecting Z to the adjacent carbon is a double bond and R41 is H, wherein R39 is H or C1-C6 alkyl; R40 is H, C1-C6 alkyl, halo or alkoxy; R42 is absent, H, C1-C6 alkyl, a member of a carbocycle that includes the atom to which it is attached or =O; Xa is C or O, provided that, when Xa is O, R42 is absent; Xb is S or O; Xc is C or N; R43 is -OH, -CN, -C(=O)NR45R46, where: R44 is H or C1-C6 alkyl; R45 is H or C1-C6 alkyl; and R46 is H or C1-C6 alkyl; R47 is H or C1-C6 alkyl; R48 is H or C1-C6 alkyl; each R49 is independently H or C1-C6 alkyl; R50 is H or C1-C6 alkyl; R51 is H or C1-C6 alkyl; R52 is H or C1-C6 alkyl; R53 is H or C1-C6 alkyl; R55 is H or C1-C6 alkyl; R56 is H or C1-C6 alkyl; R57 is H or C1-C6 alkyl; R58 is missing or H; R59 is H or OH; R60 is H or N(R54)2; each R54 is independently H or C1-C6 alkyl; R61 is H, C1-C6 alkyl, C1-C6 optionally substituted haloalkyl, gem-dimethyl, cyclopropyl, spirocycle or CF3; R62 is absent, is H or C1-C6 alkyl; each R63 and R64 are independently H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, C1-C6 optionally substituted branched or unbranched alkyl, C2-C6 optionally substituted alkenyl, -(CH2)vR65, optionally substituted cycloalkyl, - OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl; or R63 and R64 together form an optionally substituted 510-membered heterocycle or 5-10-membered heteroaryl optionally substituted with the atom to which R63 and R64 are attached; each R65 is, independently, H, -C(=O)R65A, C1-C6 optionally substituted haloalkyl, optionally substituted nitrogen, C1-C6 optionally substituted branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, C2-C6 alkenyl optionally substituted, optionally substituted cycloalkyl, optionally substituted heterocycle, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted phenyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted morpholinyl or optionally substituted piperidyl; R65A is phenyl or branched or unbranched C1-C6 alkyl; R66 is H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, -NR63R64, C1-C6 optionally substituted branched or unbranched alkyl, C2C6 optionally substituted alkenyl, -(CH2)wR65, optionally substituted cycloalkyl, -OH, optionally substituted alkoxy , optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl; R67 is C1-C6 optionally substituted branched or unbranched alkyl, C1-C6 optionally substituted haloalkyl; R81a and R82a are each independently H or optionally substituted C1-C6 alkyl; R81b is H or optionally substituted branched or unbranched C1-C6 alkyl; z is 1 or 2, each n, p, v, w and q is independently an integer from 0-6.

[0107] In some embodiments, R81b is t-butyl. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, when z is 2, one of R61 is H. In some embodiments, when z is 2, one of R61 is methyl. In some embodiments, when z is 2, each R61 is independently methyl or gem-dimethyl. In some embodiments, each R61 is the same.

[0108] In some embodiments, R35 is -CH2CH2R76, where R76 is an optionally substituted aryl, heteroaryl or heterocycle. In some embodiments, R76 is phenyl. In some embodiments, R35 is C1-C6 optionally substituted branched or unbranched alkyl, -CH2R76 or -CH2CH2R76, wherein R76 is optionally substituted aryl, optionally substituted ketone, optionally substituted cycloalkyl, C2-C6 optionally substituted alkenyl, C2C6 optionally substituted haloalkenyl or optionally substituted heteroaryl. In some embodiments, R76 is optionally substituted cyclopropyl. In some embodiments, R76 is difluorocyclopropyl. In some embodiments, R76 is 2,2-difluorocyclopropyl. In some embodiments R76 is C2 substituted haloalkenyl. The substitution can be mono- or di-substituted. In some embodiments, R76 is -C=CF2. In some embodiments, R76 is optionally substituted pyrrole or optionally substituted alkenyl. In some embodiments, R76 is . In some embodiments, R76 is cyclopropyl, halo-substituted cyclopropyl, phenyl, - -C(=O)RXA, wherein RXA is optionally substituted phenyl or optionally substituted C1-C6 branched or unbranched alkyl.

[0109] As used here, the phrase "R36 and R37 form a heterocycle that is fused to the phenyl ring" refers to a structure that results in a fused ring structure. Non-limiting examples of such a structure include and so on. In some embodiments, the fused ring is a 6-membered ring with or without the oxygen shown here. In some embodiments, the fused ring is aromatic. In some embodiments, the fused ring is non-aromatic. For example, the fused ring may form a structure including, but not limited to, Other non-limiting examples include benzofuran and benzopyran. The structure can also be represented using the following formulas in context with the remaining compound These are non-limiting examples. Examples of such structures are also shown in Figure 1. The location of the fusion can change depending on the heteroatom. For example, the oxygen atom shown in this example could also be a nitrogen. Additionally, the ring structures can be replaced.

[0110] In some embodiments, compounds of Formulas I, Ia or Ib, or pharmaceutically acceptable salts thereof, have Formulas II, III, IV and V:

[0111] In some embodiments, compounds of Formulas I, Ia or Ib, or pharmaceutically acceptable salts thereof, have Formula VI:

[0112] In some embodiments, compounds of Formulas I, Ia or Ib, or pharmaceutically acceptable salts thereof, have Formula VII or VIIa:

[0113] In some embodiments of the compounds of Formulas I, Ia or Ib, II, III, IV, V, VI, VII, VIIA, Z is O. In some embodiments, Z is C or N. In some embodiments, Z is The e R41 is missing.

[0114] In some embodiments of compounds of Formulas I, Ia or Ib, II, III, IV, V, VI, VII or VIIa, R37 is halo. In some embodiments, R37 is absent. In some embodiments, when R37 is halo, Z is O and R41 is absent. In some embodiments R37 is alkoxy, which may be optionally substituted. In some embodiments, z is 1.

[0115] In some embodiments of compounds of Formulas I, Ia or Ib, II, III, IV, V, VI, VII or VIIa, q is 0. In some embodiments, q is 1-4.

[0116] In some embodiments of compounds of Formulas I, Ia or Ib, II, III, IV, V, VI, VII or VIIa, R38 is absent or is H. In some embodiments, R38 is haloalkyl. In some embodiments, R38 is -C(=O)C1-C6 alkyl. In some embodiments, R38 is OR66, S(O)2 R67, , optionally substituted cycloalkyl, -(CH2)pR65 or optionally substituted heterocycle.

[0117] In some embodiments of compounds of Formulas I, Ia or Ib, II, III, IV, V, VI, VII or VIIa, R34 is In some embodiments, R34 is

[0118] In some embodiments, R34 is . In some embodiments, when R34 is Z is O. In some embodiments R34 is , wherein R77 and R78 are each independently H or C1-C6 alkyl or R77 and R78 form a C3-C6 cycloalkyl, including the carbon to which R77 and R78 are attached.

[0119] In some embodiments of the compounds, or pharmaceutically acceptable salts thereof, of Formulas I, Ia or Ib, II, III, IV, V, VI, VII or VIIa or any other formula described herein, the compound is selected from of the group consisting of a compound described herein.

[0120] In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, having Formula VIII, VIII-a or VIII-b is provided: wherein: R79 is optionally substituted C1-C6 alkyl; R80 is optionally substituted C1-C6 alkyl; R81 is O, NH, S or CH2; R82 is optionally substituted C1-C6 alkyl; R83 is optionally substituted C1-C6 alkyl; and R84 is optionally substituted aryl or heteroaryl.

[0121] In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, having Formulas VIII, VIII-a or VIII-b, R79 is methyl or ethyl, with the other variables as described. In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, having Formulas VIII, VIII-a or VIII-b, R80 is C2, C3 or C4 alkyl with the other variables as described. In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, having Formulas VIII, VIII-a or VIII-b, R81 is O or S with the other variables as described. In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, having Formulas VIII, VIII-a or VIII-b, R82 is methyl or ethyl, with the other variables as described. In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, having Formulas VIII, VIII-a or VIII-b, R83 is C2 alkyl with the other variables as described. In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, having Formulas VIII, VIII-a, or VIII-b, R84 is an optionally substituted phenyl, optionally substituted pyrrole, or optionally substituted pyrrolidine, with the other variables as described. here. In some embodiments, R84 is In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, having Formulas VIII, VIII-a or VIII-b, R79 is methyl, R80 is C2 alkyl, R81 is O, R82 is methyl, R83 is C2 alkyl and R84 is

[0122] The compounds described here can be prepared according to any method. Examples of methods used to prepare the compounds described herein are provided herein. Those skilled in the art may modify the procedures to produce compounds not specifically exemplified in the present description without undue experimentation.

[0123] In some embodiments, a compound or a salt thereof is chosen from a compound illustrated and exemplified in Figure 1 and as described here or in the tables in the Examples section of the present description. The compounds described herein can be synthesized according to the schemes described herein. The schemes can also be readily modified if necessary to prepare a compound described herein.

[0124] In some embodiments, the present invention provides a compound having Formula I00, Formula I00A, Formula I00B or Formula I00C or pharmaceutically acceptable salts thereof:

[0125] In some embodiments, R100, R200 and R1400 are each independently H, cyano, optionally substituted C1-C6 branched or unbranched alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkyl, C2-C6 alkenyl optionally substituted, optionally substituted pyrimidine, optionally substituted pyridyl, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyridinone, optionally substituted -CH2-pyridinone, optionally substituted aryl, halo, -NC(=O)R300, -C(=O) NR300R400 , -C(=O)OR300 , S(=O)2NR300R400, -C(=O)R300 , -OR300, —(CH2)nR500, =O or

[0126] In some embodiments, R1500 is absent, C2-C6 alkenyl, a protecting group or C(=O)OR81b, wherein R81b is H or optionally substituted branched or unbranched C1-C6 alkyl. In some embodiments, R81b is t-butyl.

[0127] In some embodiments, when R1500 is absent, R600 is H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, -R700R800, C1-C6 optionally substituted branched or unbranched alkyl, C2-C6 optionally substituted alkenyl, - ( CH2)nR500, optionally substituted cycloalkyl, -OH, optionally substituted C1-C6 alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl.

[0128] In some embodiments, when R1500 is C2C6 alkenyl, R600 is C2-C6 alkenyl.

[0129] In some embodiments, R300 and R400 are each, independently, H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, -R700R800, C1-C6 optionally substituted branched or unbranched alkyl, C2-C6 optionally substituted alkenyl, - (CH2)nR500, optionally substituted cycloalkyl, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl; or R300 and R400 together form an optionally substituted 5-10 membered heterocycle or optionally substituted 5-10 membered heteroaryl with the atom to which R300 and R400 are attached.

[0130] In some embodiments R1200 is, independently, H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, -R700R800, C1-C6 optionally substituted branched or unbranched alkyl, C2-C6 optionally substituted alkenyl, - (CH2)nR500 , optionally substituted cycloalkyl, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl; or R300 and R400 together form an optionally substituted 5-10 membered heterocycle or optionally substituted 5-10 membered heteroaryl with the atom to which R300 and R400 are attached.

[0131] In some embodiments, each R500 is, independently, H, C1-C6 optionally substituted haloalkyl, -NR700R800, C1-C6 optionally substituted branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, C2-C6 optionally substituted alkenyl , optionally substituted cycloalkyl, optionally substituted heterocycle, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl.

[0132] In some embodiments, R700 and R800 are each independently H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, C1-C6 optionally substituted branched or unbranched alkyl, C2C6 optionally substituted alkenyl, -(CH2)nR5oo , optionally substituted cycloalkyl, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl; or R700 and R800 together form an optionally substituted 5-10 membered heterocycle or optionally substituted 5-10 membered heteroaryl with the atom to which R700 and R800 are attached.

[0133] In some embodiments, R900 is absent, H, haloalkyl, -OR300 or optionally substituted cycloalkyl, -(CH2)pR500 or optionally substituted heterocycle.

[0134] In some embodiments, R1100 is H, halo or optionally substituted C1-C6 alkyl.

[0135] In some embodiments, R1300 is a bond, C, N, S or O.

[0136] In some embodiments, R1400 is an optionally substituted pyridinone or —CH2—optionally substituted pyridinone.

[0137] In some embodiments, each n, p and y is independently an integer from 0-6.

[0138] In some embodiments, each Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 is, independently, C, N or O.

[0139] In some embodiments, each Re00, Rf00 and Rg00 is independently C, N, S, O or is absent.

[0140] In some embodiments, each Z100, Z200 and Z300 is independently a bond, C(=O), C, N, S or O.

[0141] In some embodiments, the compound or pharmaceutically acceptable salts thereof are not:

[0142] In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: The compounds can be used, in some embodiments, to prepare other compounds described herein.

[0143] In some embodiments, the present invention provides a compound or salt thereof that has Formula I00D or Formula I00E: wherein: R100, R200, R600, R900 and R1500 are as described herein, Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C; R1100 is H; R1300 and Z100 is O; Z200 is C; Z300 is a link; ey = 2.

[0144] In some embodiments, a compound as described herein is provided in which R100 is -C(=0)NR3OQR4QQ.

[0145] In some embodiments, there is provided a compound or salt thereof as described herein wherein each R300 and R400 is independently H, halo, optionally substituted C1-C6 haloalkyl or optionally substituted C1-C6 alkyl.

[0146] In some embodiments, a compound or salt thereof is provided, wherein R100 is H, halo, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3) 2 -COOH, -C(=O)OCH3, cyano, S(=O)2NH2, optionally substituted alkoxy, -OCF3, CF3, -NC(=O)CH3, pyridyl,

[0147] In some embodiments, a compound or salt thereof is provided, wherein R100 and R200 are each independently H, halo or optionally substituted C1-C6 haloalkyl.

[0148] In some embodiments, a compound or salt thereof is provided, wherein R100 and R200 are independently halo.

[0149] In some embodiments, a compound or salt thereof is provided, wherein the optionally substituted C1-C6 haloalkyl is trifluoromethyl.

[0150] In some embodiments, a compound or salt thereof is provided, wherein R100 is fluoro and R200 is trifluoromethyl.

[0151] In some embodiments, a compound or salt thereof is provided, in which R100 and R200 are linked to different atoms in the ring.

[0152] In some embodiments, a compound or salt thereof is provided, wherein R200 is H.

[0153] In some embodiments, a compound or salt thereof is provided, wherein: R600 is H, optionally substituted C1-C6 alkyl or -C(=O)OR3oo; and R300 is an optionally substituted C1-C6 branched or unbranched alkyl.

[0154] In some embodiments, a compound or salt thereof is provided, wherein: R100 is -C(=O)NH2 and R600 is H or optionally substituted C1-C6 alkyl; or R100 is - C(=O)NR300R400, wherein R300 is H and R400 is C1-C6 optionally substituted branched or unbranched alkyl or C2-C6 optionally substituted branched or unbranched alkenyl and R600 is H or optionally C1-C6 alkyl replaced; or R100 is -C(=O)NR300R400, wherein R300 and R400 are each independently optionally substituted C1-C6 branched or unbranched alkyl and R600 is H, optionally substituted C1-C6 alkyl or optionally substituted alkaryl.

[0155] In some embodiments, a compound or salt thereof is provided, wherein R100 is -C(=O)NR300R400, wherein: R300 and R400 are H; R300 is H and R400 is optionally substituted branched or unbranched C1-C6 alkyl; or R300 is H and R400 is optionally substituted branched or unbranched C2-C6 alkenyl; or R300 is H and R400 is optionally substituted C1-C6 cycloalkyl; or R300 is H and R400 is - (CH2)nR500; wherein n is 1-6 and R500 is an optionally substituted cycloalkyl; or R300 is H and R400 is -(CH2)nR500, wherein n is 1-6 and R500 is an optionally substituted alkoxy; or R300 and R400 are each independently optionally substituted C1-C6 alkyl.

[0156] In some embodiments, a compound or salt thereof is provided, wherein R100 is -C(=O)NR300R400, wherein R300 and R400 together form an optionally substituted 5-10 membered heterocycle or 5-10 heteroaryl members optionally substituted with the atom to which R300 and R400 are attached.

[0157] In some embodiments, a compound or salt thereof is provided, wherein Rb00 is N. In some embodiments, a compound or salt thereof is provided, wherein Ra00 is N. In some embodiments, a compound or salt thereof is provided. salt thereof, wherein Rc00 is N. In some embodiments, a compound or salt thereof is provided, wherein Rd00 is N. In some embodiments, a compound or salt thereof is provided, wherein R1100 is H, R1300 is O, Ri00 is C, Z100 is O, Z200 is C, Z300 is a bond, and y = 2. In some embodiments, R100, R200, and R600 are each H and Z is O. In some embodiments, R100 is =O and R200 is H.

[0158] In some embodiments, a compound or salt thereof is provided, wherein R100 is -C(=O)NR3ooR4oo; and R600 is H, C1-C6 alkyl or -C(=O)OR3, wherein R300 is an optionally substituted branched or unbranched C1-C6 alkyl. In CH3 r CH3 some embodiments, R300 is

[0159] In some embodiments, a compound or salt thereof is provided in which R600 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, -OR3 or (CH2)n-aryl, n is an integer from 0-6; R900 is R1100 is H or halo; R1300 is O; Ri00 is C; y =2; and R1500 is C2-C6 optionally substituted alkenyl when R600 is C2-C6 optionally substituted alkenyl.

[0160] In some embodiments, a compound or salt thereof is provided in which R1100 is fluorine.

[0161] In some embodiments, a compound or salt thereof is provided, wherein R100 is -C(=O)NH2.

[0162] In some embodiments, a compound or salt thereof is provided, wherein R100 is cyano.

[0163] In some embodiments, a compound or salt thereof is provided, wherein: Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C; Z100 is O, Z200 is C, Z300 is a bond; y=0; R900 is branched or unbranched C1-C6 optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocycle; and R1300 is O. In some embodiments, R600 is H or optionally substituted branched or unbranched C1-C6 alkyl. In some embodiments, R900 is In some embodiments, R100 is -C(=O)NR300R400 or cyano. In some embodiments, R200 is H. In some embodiments, R1100 is H.

[0164] In some embodiments, a compound or salt thereof is provided, wherein one of Ra00, Rb00, Rc00 and Rd00 is N; Z100 is a bond or O; Z200 is C, Z300 is a bond and y=0; Rh00 and Ri00 are C; R100 is H, -C(=O)NR300R400 or =O; R200 is H; R600 is H, C1-C6 alkyl or C2-C6 alkenyl; R900 is C1-C6 alkyl, haloalkyl or cycloalkyl; R1100 is H; and R1300 is O. In some embodiments, Z100 is a bond and R100 is =O. In some embodiments, R400 is H. In some embodiments, Rd00 is N and R100 is =O.

[0165] In some embodiments, a compound or salt thereof is provided, wherein Ra00, Rb00, Rc00 and Rd00 are C; Rh00 and Ri00 are C; Z100 is O, Z200 is C, Z300 is a bond; R1100 is halo or C1-C6 alkyl; y=0; R900 is H, haloalkyl or C1-C6 alkyl; R1300 is O; R600 is H, C1-C6 alkyl or C2-C6 alkenyl; and R200 is H. In some embodiments, R100 is H, cyano or - C(=O)NR300R400.

[0166] In some embodiments, a compound or salt thereof having Formula I00E is provided. where R100, R200. R600. and R900 are as described herein, Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C; R1300 is O; Z100 is O, Z200 is C, Z300 is a bond; ey=0. In some embodiments, R900 is H, haloalkyl or C1-C6 alkyl. In some embodiments, R200 is H. In some embodiments, R1100 is H. In some embodiments, R600 is H, C1-C6 alkyl or C2-C6 alkenyl. In some embodiments, R100 is H, cyano or -C(=O)NR300R400. In some embodiments, R900 is H or C1-C6 alkyl.

[0167] In some embodiments, there is provided a compound or salt thereof that has the structure of Formula I00A according to claim i, wherein Ra00, Rb00, Rc00, Rd00, Re00 and Ri00 are C, Rg00 is C or O ; Rf00 is missing; Ri300 is O; and Zi00 is O, Z200 is C and Z300 is a bond. In some embodiments, R200 is H. In some embodiments, R100 is H. In some embodiments, R600 is H, optionally substituted C1-C6 alkyl, or optionally substituted C2-C6 alkenyl. In some embodiments, R100 is H, cyano, -C(=O)NR300R400 or C1-C6 alkyl. In some embodiments, Rg00 is O.

[0168] In some embodiments, a compound or salt thereof is provided, where y = 1. In some embodiments, R900 is an optionally substituted C1-C6 alkyl or optionally substituted cycloalkyl.

[0169] In some embodiments, Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C. In some embodiments, R1300 is O. In some embodiments, Z100 is O, Z200 is C and Z300 is a bond. In some embodiments, R200 and R1100 are H. In some embodiments, R100 is -C(=O)NR3ooR4oo. In some embodiments, R600 is H or optionally substituted C1-C6 alkyl.

[0170] In some embodiments, a compound or salt thereof is provided in which Rh00 is N. In some embodiments, Ra00, Rb00, Rc00, Rd00, Ri00 are C. In some embodiments, R200 is H. In some embodiments, R1300 is O. In some embodiments, Z100 is O, Z200 is C, and Z300 is a bond. In some embodiments, R1100 is H. In some embodiments, R600 is optionally substituted C2-C6 alkenyl, optionally substituted C1-C6 alkyl, or H. In some embodiments, R100 is H or -C(=O)NR300R400.

[0171] In some embodiments, a compound or salt thereof is provided in which R1100 is H or halo. In some embodiments, Ra00, Rb00, Rc00, Rd00 and Ri00 are C. In some embodiments, Z100 is O, Z200 is C, Z300 is a bond. In some embodiments, R1300 is a bond or C. In some embodiments, y = 1. In some embodiments, R900 is H. In some embodiments, R600 is H, optionally substituted C1-C6 alkyl, or optionally substituted C2-C6 alkenyl. In some embodiments, R200 is H. In some embodiments, R100 is H, -C(=O)NR300R400, or cyano. In some embodiments, y=0, R1300 is a bond and R900 is H. In some embodiments, the compound is of Formula 00X: wherein R100, R200, R600, and R900 are as defined in claim 1; Z100 is O, Z200 is C, Z300 is a bond; Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C; R200 is H; R1100 is halo; R1300 is O; y=0-6; and R900 is C1-C6 alkyl. In some embodiments, R600 is H, optionally substituted C1-C6 alkyl or optionally substituted C2-C6 alkenyl. In some embodiments, R100 is H, cyano or -C(=O)NR3ooR4oo.

[0172] In some embodiments, a compound or salt thereof is provided, where Z100 is O, Z200 and Z300 is C. In some embodiments, R100 is C. In some embodiments, R200 and/or R1100 are H. In some embodiments, R600 is H. In some embodiments, R100 is H, halo, cyano, -C(=O)OR3, or -C (=O)NR300R400. In some embodiments, R1300 is O; R900 is H or -OR3; and y is 0-6.

[0173] In some embodiments, a compound or salt thereof is provided, wherein Z100 is S or O; Z300 is missing; Z200 is C; R200 and/or R1100 are H; Ri00 is C; R1300 is O; R900 is H or -OR3; and y=0-6. In some embodiments, Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C. In some embodiments, R600 is H or -C(=O)OR3. In some embodiments, R100 is H or — C(=O)NR300R400.

[0174] In some embodiments, a compound or salt thereof is provided, wherein Ri00 is N; R200 and/or R1100 are H; Z300 is a bond or C; Z100 is N or O; and Z200 is C or C(=O). In some embodiments, Ra00, Rb00, Rc00, Rd00, Rh00 are C. In some embodiments, R1300 is O. In some embodiments, R900 is H and y=0-6. In some embodiments, wherein R100 is halo, H, cyano, -C(=O)NR300R400 or -OR3. In some embodiments, R600 is H, optionally substituted C1-C6 alkyl or -(CH2)p-aryl, where p is an integer from 0-6. In some embodiments, Z200 is C(=O), Z100 is N and Z300 is C.

[0175] In some embodiments, a compound or salt thereof is provided, wherein Z200 is C(=O) or C; Z100 is N or O; and Z300 is C or absent. In some embodiments, Ra00, Rb00, Rc00, Rd00 and Rh00 are C. In some embodiments, R200 is H. In some embodiments, R100 is H, halo, cyano or -C(=O)NR300R400. In some embodiments, R1100 is H. In some embodiments, R1300 is O; and R900 is H or -OR3. In some embodiments, R600 is H, C1-C6 alkyl or -(CH2)pR500. In some embodiments, Z100 is O; Z300 is missing; and Z200 is C. In some embodiments, the compound or salt thereof has a structure of Formula I00B.

[0176] In some embodiments, a compound or salt thereof of Formula I00C is provided, wherein Z100 is C and R1400 is a pyridinone. In some embodiments, Z100 is O and R1400 is optionally substituted-CH2-pyridinone. In some embodiments, R600 is H. In some embodiments, Ri00 and Rh00 are C. In some embodiments, R1300 is O. In some embodiments, y is an integer from 1-6.

[0177] In some embodiments, a compound or a salt thereof is chosen from a compound as shown in Figure 1 and described herein, including in the Examples section of the present description. Data for the compounds can be found in Figure 2 and the Examples. As described herein, compounds can be prepared according to the schemes and methods described herein and below.

[0178] Although the compounds described here can be shown to have specific stereochemistry around certain atoms, such as cis or trans, the compounds can also be made in the opposite orientation or in a racemic mixture. Such racemic isomers or mixtures are encompassed by the present description.

[0179] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt thereof of any compound described herein.

[0180] The compounds described here can be made according to the methods described here and in the Examples. The methods described here can be adapted based on the desired compounds described here. In some embodiments, the method is carried out according to the following schemes, wherein Q and L are the substituents as shown and described herein and will be apparent to those skilled in the art based on the present description. In some embodiments, this method can be used to produce one or more compounds as described herein and it will be apparent to those skilled in the art which compounds can be prepared in accordance with the methods described herein.

[0181] In some embodiments, the compounds are made according to Scheme I. Scheme I

[0182] The conditions and temperatures can be varied, or the synthesis can be carried out according to the Examples described here.

[0183] In some embodiments, one or more compounds are made according to Scheme II. Scheme II

[0184] Conditions and temperatures can be varied, as shown in the Examples described here. These schemes are non-limiting synthetic schemes and the synthetic routes may be modified, as will be apparent to one skilled in the art when reading the present specification. Compounds can also be prepared according to the schemes described in the Examples.

[0185] Compounds can be used to modulate the δ-opioid receptor. Thus, in some embodiments, the compounds can be said to be δ-opioid receptor modulating compounds.

[0186] Although the compounds in the tables above or in the Examples section are shown with specific stereochemistry around certain atoms, such as cis or trans, the compounds can also be made in the opposite orientation or in a racemic mixture.

[0187] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt thereof of any compound described herein.

[0188] The compounds described here can be made according to the methods described here and in the Examples. The methods described here can be adapted based on the desired compounds described here. In some embodiments, the method is carried out according to the following schemes, wherein Q and L are the substituents as shown and described herein and will be apparent to those skilled in the art based on the present description. In some embodiments, this method can be used to produce one or more compounds as described herein and it will be apparent to those skilled in the art that the compounds can be prepared in accordance with the methods described herein.

[0189] In some embodiments, the compounds are made according to schemes described in the examples. The schemes can be used to prepare the compounds and compositions described herein. Conditions and temperatures can be varied, or the synthesis can be carried out according to the examples described here, with modifications that are readily evident based on the compound being synthesized.

[0190] Conditions and temperatures can be varied, as shown in the examples described here. These schemes are non-limiting synthetic schemes and the synthetic routes may be modified, as will be apparent to one skilled in the art when reading the present specification.

[0191] The compounds described here can be administered in any conventional manner via any route where they are active. Administration can be systemic, topical or oral. For example, administration may be, but is not limited to, via parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, sublingual or ocular routes, or intravaginally, via inhalation, depot injections or implants. The mode of administration may depend on the conditions or diseases being targeted or treated. Selection of the specific route of administration can be chosen or adjusted by the clinician according to methods known to the clinician to obtain the desired clinical response.

[0192] In some embodiments, it may be desirable to administer one or more compounds, or a pharmaceutically acceptable salt thereof, locally to an area in need of treatment. This can be achieved, for example, and not by way of limitation, through local infusion during surgery, topical application, for example, in conjunction with a dressing after surgery, through injection, through a catheter, through a suppository or by means of an implant, wherein the implant is of a porous, non-porous or gelatinous material, including membranes, such as Sialastic membranes or fibers.

[0193] The compounds described here can be administered individually or in combination (simultaneously or in series) with other pharmaceutical products. For example, the compounds can be administered in combination with other analgesics, antidepressants, anxiolytic compounds, overactive bladder compounds, compounds for treating Parkinson's disease, and so on. In some embodiments, the compounds can be administered in combination with other therapies for PTSD. Examples of other pharmaceutical products or medicaments are known to those skilled in the art and include, but are not limited to, those described herein.

[0194] The means and methods of administration are known in the art and those skilled in the art can refer to various pharmacological references for guidance (see, for example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979) and Goodman & Gilman, The Pharmaceutical Basis of Therapeutics, 6th edition, MacMillan Publishing Co., New York (1980)).

[0195] The amount of compound to be administered is that amount that is therapeutically effective. The dosage to be administered will depend on the characteristics of the individual being treated, for example, the particular animal treated, the age, weight, health, types of concomitant treatments, if any, and the frequency of treatments, and can be easily determined by those skilled in the art (e.g., by the clinician). The standard dosage for protamine can be used and adjusted (i.e., increased or decreased) depending on the factors described above. Selection of the specific dose regimen may be chosen or adjusted or titrated by the clinician according to methods known to the clinician to obtain the desired clinical response.

[0196] The amount of a compound described here that will be effective in treating and/or preventing a particular disease, condition or disorder will depend on the nature and extent of the disease, condition or disorder and can be determined by a clinician using standard techniques. Additionally, in vitro or in vivo assays can optionally be used to help identify optimal dosage ranges. The precise dose to be used in the compositions will also depend on the route of administration and the severity of the disorder, and must be decided according to the physician's judgment and the circumstances of each patient. However, a suitable dosage range for oral administration is, in general, from about 0.001 milligram to about 200 milligrams per kilogram of body weight, from about 0.01 milligram to about 100 milligrams per kilogram. of body weight, from about 0.01 milligram to about 70 milligrams per kilogram of body weight, from about 0.1 milligram to about 50 milligrams per kilogram of body weight, from 0.5 milligrams to about 20 milligrams per kilogram of body weight or from about 1 milligram to about 10 milligrams per kilogram of body weight. In some embodiments, the oral dose is about 5 milligrams per kilogram of body weight.

[0197] In some embodiments, suitable dosage ranges for intravenous (iv) administration are from about 0.01 mg to about 500 mg per kg of body weight, from about 0.1 mg to about 100 mg per kg of body weight, from about 1 mg to about 50 mg per kg of body weight or from about 10 mg to about 35 mg per kg of body weight. Suitable dosage ranges for other modes of administration can be calculated based on preceding dosages as known to those skilled in the art. For example, recommended dosages for intranasal, transmucosal, intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal or inhalation administration range from about 0.001 mg to about 200 mg per kg of body weight, from about 0.01 mg to about 100 mg per kg of body weight, from about 0.1 mg to about 50 mg per kg of body weight, or from about 1 mg at about 20 mg per kg of body weight. Effective doses can be extrapolated from dose-response curves derived from animal or in vitro model test systems. Such animal models and systems are well known in the art.

[0198] The compounds described here can be formulated for parenteral administration via injection, such as bolus injection or continuous infusion. The compounds can be administered by continuous infusion subcutaneously over a period of about 15 minutes to about 24 hours. Formulations for injection may be presented in unit dosage form, such as in ampoules or multi-dose containers, optionally with an added preservative. The compositions may take forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. In some embodiments, the injectable is in the form of short-acting, depot or implant forms, and pellets injected subcutaneously or intramuscularly. In some embodiments, the parenteral dosage form is in the form of a solution, suspension, emulsion or dry powder.

[0199] For oral administration, the compounds described here can be formulated by combining the compounds with pharmaceutically acceptable carriers well known in the art. Such carriers allow compounds to be formulated as tablets, pills, dragees, capsules, emulsions, liquids, gels, syrups, sachets, granules, pellets, suspensions, lozenges, aqueous or oily suspensions, and so on, for oral ingestion by a patient. to be treated. Pharmaceutical preparations for oral use can be obtained, for example, by adding a solid excipient, optionally grinding the resulting mixture and processing the mixture into granules, after adding suitable auxiliaries, if desired, to obtain tablets or tablet cores. Suitable excipients include, but are not limited to, fillers such as sugars including, but are not limited to, lactose, sucrose, mannitol and sorbitol; cellulose preparations such as, but not limited to, corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP). If desired, disintegrating agents such as, but not limited to, cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate, may be added.

[0200] Orally administered compositions may contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents, such as mint, orange or cherry oil; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Furthermore, when in tablet or lozenge form, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active conducting compound are also suitable for orally administered compounds. Oral compositions may include standard carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Such carriers are suitably of pharmaceutical grade.

[0201] Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Colorants or pigments can be added to tablet or dragee coatings to identify or characterize different dose combinations of active compounds.

[0202] Pharmaceutical preparations that can be used orally include, but are not limited to, "push-fit" capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules may contain the active ingredients in admixture with a filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. Additionally, stabilizers can be added.

[0203] For buccal administration, the compositions may take the form of, for example, tablets or lozenges formulated in a conventional manner.

[0204] For administration by inhalation, the compounds described herein can be administered in the form of an aerosol spray presentation from pressurized packaging or a nebulizer, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, dioxide carbon or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to dispense a metered amount. Capsules and cartridges, such as gelatin, for use in an inhaler or insufflator may be formulated which contain a powder mixture of the compound and a suitable powder base, such as lactose or starch.

[0205] The compounds described here can also be formulated in rectal compositions, such as suppositories or retention enemas, for example, which contain conventional suppository bases, such as cocoa butter or other glycerides. The compounds described herein can also be formulated into vaginal compositions, such as vaginal creams, suppositories, pessaries, vaginal rings and intrauterine devices.

[0206] In transdermal administration, the compounds can be applied to a patch or can be applied through therapeutic transdermal systems which, consequently, are delivered to the body. In some embodiments, the compounds are present in creams, solutions, powders, fluid emulsions, fluid suspensions, semisolids, ointments, pastes, gels, jellies and foams, or in patches containing any of the same.

[0207] The compounds described here can also be formulated as a depot preparation. Such long-acting formulations can be administered via implantation (e.g., via the subcutaneous or intramuscular route) or intramuscular injection. Depot injections can be administered at intervals of approximately 1 to approximately 6 months or longer. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as poorly soluble derivatives, for example as a distinctly soluble salt.

[0208] In some embodiments, the compounds can be administered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng., 1987, 14, 201; Buchwald et al., Surgery, 1980, 88, 507 Saudek et al., N. Engl. J. Med., 1989, 321, 574). In some embodiments, polymeric materials may be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger et al., J. Macromol. Sci. Rev. Macromol. Chem., 1983, 23, 61; see also Levy et al., Science, 1985, 228 , 190; During et al., Ann. Neurol., 1989, 25, 351; Howard et al., J. Neurosurg., 1989, 71, 105). In yet another embodiment, a controlled release system can be placed in proximity to the target of the compounds described herein, such as the liver, thereby requiring only a fraction of the systemic dose (see, for example, Goodson, in Medical Applications of Controlled Release, supra, vol 2, pages 115-138 (1984)). Other controlled release systems discussed in the review by Langer, Science, 1990, 249, 1527-1533) can be used.

[0209] It is also known in the art that compounds may be contained in such formulations with diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic carriers, water-soluble carriers, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and so on. The pharmaceutical compositions may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols. In some embodiments, the compounds described herein can be used with agents including, but not limited to, topical analgesics (e.g., lidocaine), barrier devices (e.g., GelClair), or rinses (e.g., Caphosol).

[0210] In some embodiments, the compounds described herein can be administered in a vesicle, in particular a liposome (see Langer, Science, 1990, 249, 1527-1533; Treat et al. in Liposomes in the Therapy of Infectious Disease and Cancer , Lopez-Berestein and Fidler (eds.), Liss, New York, pages 353-365 (1989); Lopez-Berestein, ibid., pages 317-327, see generally ibid.).

[0211] Suitable compositions include, but are not limited to, non-absorbed oral compositions. Suitable compositions also include, but are not limited to, saline, water, cyclodextrin solutions and buffered solutions at a pH of 3-9.

[0212] The compounds described herein, or pharmaceutically acceptable salts thereof, can be formulated with various excipients including, but not limited to, purified water, propylene glycol, PEG 400, glycerin, DMA, ethanol, benzyl alcohol, citric acid / citric acid. sodium (pH of 3), citric acid/sodium citrate (pH of 5), tris(hydroxymethyl)amino methane HCl (pH of 7.0), 0.9% saline and 1.2% saline and any combination thereof. In some embodiments, the excipient is chosen from propylene glycol, purified water and glycerin.

[0213] In some embodiments, the formulation can be freeze-dried to a solid and reconstituted, for example, with water before use.

[0214] When administered to a mammal (for example, to an animal for veterinary use or to a human for clinical use), the compounds can be administered in isolated form.

[0215] When administered to a human being, the compounds may be sterile. Water is a suitable carrier when the compound of Formula I is administered intravenously. Saline solutions and aqueous solutions of dextrose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene, glycol, water, ethanol and so on. The present compositions, if desired, may also contain small amounts of wetting or emulsifying agents, or pH buffering agents.

[0216] The compositions described herein may take the form of a solution, suspension, emulsion, tablet, pill, lozenges, capsules, liquid-containing capsules, powder, sustained-release formulation, suppository, aerosol, spray or any other suitable form For use. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. R. Gennaro (Editor) Mack Publishing Co.

[0217] In some embodiments, the compounds are formulated according to routine procedures as a pharmaceutical composition adapted for administration to humans. Typically, the compounds are solutions in sterile isotonic aqueous buffer. When necessary, the compositions may also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic, such as lidocaine, to relieve pain at the injection site. In general, the ingredients are supplied separately or mixed in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container, such as an ampoule or sachet, indicating the amount of active agent. Where the compound is to be administered by infusion, it may be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. When the compound is administered by injection, an ampoule of sterile water for injection or saline solution may be provided so that the ingredients can be mixed before administration.

[0218] The pharmaceutical compositions may be in unit dosage form. In such form, the composition can be divided into unit doses containing appropriate amounts of the active component. The unit dosage form may be a packaged preparation, the packaging containing distinct quantities of the preparations, for example tablets, capsules and powders packaged in vials or ampoules. The unit dosage form may also be a capsule, capsule or tablet, or may be the appropriate number of any of these packaged forms.

[0219] In some embodiments, a composition of the present invention is in the form of a liquid in which the active agent (i.e., one of the facially amphiphilic polymers or oligomers described herein) is present in solution, suspension, as an emulsion or as a solution/suspension. In some embodiments, the liquid composition is in the form of a gel. In other embodiments, the liquid composition is aqueous. In other embodiments, the composition is in the form of an ointment.

[0220] In some embodiments, the composition is in the form of a solid article. For example, in some embodiments, the ophthalmic composition is a solid article that can be inserted into a suitable location in the eye, such as between the eye and the eyelid or in the conjunctival sac, where it releases the active agent as described, e.g. in United States Patent No. 3,863,633; United States Patent No. 3,867,519; United States Patent No. 3,868,445; United States Patent No. 3,960,150; United States Patent No. 3,963,025; United States Patent No. 4,186,184; United States Patent No. 4,303,637; United States Patent No. 5,443,505; and United States Patent No. 5,869,079. The release of such an article is generally into the cornea, either through the tear fluid bathing the surface of the cornea or directly into the cornea itself, with which the solid article is usually in intimate contact. Solid articles suitable for implantation in the eye in such a manner are generally composed primarily of polymers and may be biodegradable or non-biodegradable. Biodegradable polymers that can be used in the preparation of ocular implants bearing one or more of the antimicrobial, facially amphiphilic polymers or active oligomers in accordance with the present invention include, but are not limited to, aliphatic polyesters, such as poly(glycolide) polymers and copolymers. ), poly(lactide), poly(epsilon-caprolactone), poly(hydroxybutyrate) and poly(hydroxyvalerate), polyamino acids, polyorthoesters, polyanhydrides, aliphatic polycarbonates and polyether lactones. Suitable non-biodegradable polymers include silicone elastomers.

[0221] The compositions described here may contain preservatives. Suitable preservatives include, but are not limited to, substances containing mercury, such as phenylmercuric salts (e.g., phenylmercuric acetate, borate and nitrate) and thimerosal; stabilized chlorine dioxide; quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride; imidazolidinyl urea; parabens, such as methylparaben, ethylparaben, propylparaben and butylparaben and salts thereof; phenoxyethanol; chlorophenoxyethanol; phenoxypropanol; chlorobutanol; chlorocresol; phenylethyl alcohol; disodium EDTA; and sorbic acid and salts thereof.

[0222] Optionally, one or more stabilizers may be included in the compositions to increase chemical stability when necessary. Suitable stabilizers include, but are not limited to, chelating agents or complexing agents such as, for example, the calcium complexing agent ethylene diamine tetraacetic acid (EDTA). For example, an appropriate amount of EDTA or a salt thereof, e.g., disodium salt, may be included in the composition to complex with excess calcium ions and prevent gel formation during storage. EDTA or a salt thereof may suitably be included in an amount of from about 0.01% to about 0.5%. In those embodiments that contain a preservative other than EDTA, the EDTA or a salt thereof, more particularly disodium EDTA, may be present in an amount from about 0.025% to about 0.1% by weight.

[0223] One or more antioxidants may also be included in the compositions. Suitable antioxidants include, but are not limited to, ascorbic acid, sodium metabisulfite, sodium bisulfite, acetylcysteine, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, or other agents known to those skilled in the technique. Such preservatives are typically employed at a level of from about 0.001% to about 1.0% by weight.

[0224] In some embodiments, the compounds are solubilized, at least in part, by an acceptable solubilizing agent. Certain acceptable non-ionic surfactants, for example, polysorbate 80, may be useful as solubilizing agents, such as glycols, ophthalmically acceptable polyglycols, for example, polyethylene glycol 400 (PEG-400) and glycol ethers.

[0225] Suitable solubilizing agents for solutions and solution/suspension compositions are cyclodextrins. Suitable cyclodextrins can be chosen from α-cyclodextrin, β-cyclodextrin, Y-cyclodextrin, alkylcyclodextrins (e.g. methyl-β-cyclodextrin, dimethyl-β-cyclodextrin, diethyl-β-cyclodextrin), hydroxyalkylcyclodextrins (e.g. , hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin), carboxyalkylcyclodextrins (e.g., carboxymethyl-β-cyclodextrin), sulfoalkyl ether cyclodextrins (e.g., sulfobutyl ester of β-cyclodextrin) and so on. The ophthalmic applications of cyclodextrins were reviewed in Rajewski et al., Journal of Pharmaceutical Sciences, 1996, 85, 11551159.

[0226] In some embodiments, the composition optionally contains a suspending agent. For example, in embodiments in which the composition is a suspension or aqueous solution/suspension, the composition may contain one or more polymers as suspending agents. Useful polymers include, but are not limited to, water-soluble polymers, such as cellulosic polymers, for example, hydroxypropylmethylcellulose, and water-insoluble polymers, such as carboxyl-containing cross-linked polymers.

[0227] One or more acceptable pH adjusting agents and/or buffering agents may be included in the compositions, including acids, such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and trishydroxymethylaminomethane; and buffers, such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount necessary to maintain the pH of the composition in an acceptable range.

[0228] One or more acceptable salts may be included in the compositions of the invention in an amount necessary to bring the osmolality of the composition to an acceptable range. Such salts include, but are not limited to, those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions. In some embodiments, the salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite, and ammonium sulfate. In some embodiments, the salt is sodium chloride.

[0229] Optionally, one or more acceptable surfactants, preferably nonionic surfactants, or co-solvents, may be included in the compositions to increase the solubility of the components of the compositions or impart physical stability, or for other purposes. Suitable non-ionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, for example, polyoxyethylene hydrogenated castor oil (60); and alkyl ethers and alkylphenyl ethers of polyoxyethylene, for example, octoxynol 10, octoxynol 40; polysorbate 20, 60 and 80; polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic® F-68, F84 and P-103); cyclodextrin; or other agents known to those skilled in the art. Typically, such cosolvents or surfactants are used in the compositions at a level of from about 0.01% to about 2% by weight.

[0230] The present invention also provides pharmaceutical packages or kits comprising one or more containers filled with one or more compounds described herein. Optionally associated with this container(s) may be a label in the form prescribed by a governmental agency that regulates the manufacture, use or sale of pharmaceutical or biological products, which label reflects the agency's approval of the manufacture, use or or sale for human administration for treatment of a condition, disease or disorder described herein. In some embodiments, the kit contains more than one compound described herein. In some embodiments, the kit comprises a compound described herein in a single injectable dosage form, such as a single dose within an injectable device, such as a syringe with a needle.

[0231] Modulation of the δ-opioid receptor has been considered a target for the treatment of brain disorders (Trends Pharmacol Sci., October 2011; 32(10): 581-90. Epub September 17, 2011). Specifically, preclinical data confirmed that delta opioid receptor activation reduces persistent pain and improves negative emotional states. (Id.). Compounds that modulate δ-opioid receptors have also been found to have anxiolytic activities. Next, the compounds described here can be used to treat brain disorders such as depression, Parkinson's disease or anxiety. The compounds can also be used to treat pain. The compounds can also be used to treat overactive bladder.

[0232] The present invention also provides methods of treating pain including, but not limited to, neuropathic pain, migraines (chronic, episodic or acute), headache (e.g., episodic, chronic, acute, cluster and so on) , Parkinson's disease, depression, anxiety, overactive bladder including but not limited to major depressive disorder, treatment-resistant depression, anxiety, post-traumatic stress disorder, neuropathic pain including diabetic peripheral neuropathy, postherpetic neuralgia, neuropathic pain chemotherapy-induced, prevention of chemotherapy-induced neuropathy, prevention of chemotherapy-induced neuropathic pain, trigeminal neuralgia, inflammatory pain, including osteoarthritis, rheumatoid arthritis, Rett syndrome, autism spectrum disorders, migraine (chronic, episodic or acute), cluster headaches (e.g., episodic, chronic, acute, cluster, and so on), acute abortive treatment, acute intermittent migraine prophylaxis, chronic migraine prophylaxis, treatment of episodic and chronic cluster headache, acute headache prevention episodic and chronic, Charcot-Marie Tooth disease, traumatic brain injury, fibromyalgia, stroke, acute ischemic syndrome, ischemia/reperfusion injury, substance abuse intervention and/or alcohol abuse treatment in an individual who understands administering , to the individual, one or more compounds described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some embodiments, the subject is an individual in need of such treatment. As described herein, in some embodiments, the subject is a mammal such as, but not limited to, a human being.

[0233] The present invention also provides one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, for the treatment in methods of treating, but without limitation, neuropathic pain. , migraines (chronic, episodic, or acute), headache (e.g., episodic, chronic, acute, cluster, and so on), Parkinson's disease, depression, anxiety, overactive bladder including, but not limited to, major depressive disorder, treatment-resistant depression, anxiety, post-traumatic stress disorder, neuropathic pain, including diabetic peripheral neuropathy, postherpetic neuralgia, chemotherapy-induced neuropathic pain, prevention of chemotherapy-induced neuropathy, prevention of chemotherapy-induced neuropathic pain, neuralgia of trigeminal, inflammatory pain, including osteoarthritis, rheumatoid arthritis, Rett syndrome, autism spectrum disorders, migraine (chronic, episodic, or acute), cluster headaches (e.g., episodic, chronic, acute, cluster, and so on), treatment acute abortive, acute intermittent migraine prophylaxis, chronic migraine prophylaxis, treatment of episodic and chronic cluster headache, prevention of acute episodic and chronic headache, Charcot-Marie Tooth disease, traumatic brain injury, fibromyalgia, stroke, acute ischemic syndrome, ischemia/reperfusion injury, substance abuse intervention and/or alcohol abuse treatment in an individual, such as a mammal or human. In some embodiments, the compounds are for the treatment of, but without limitation, neuropathic pain, migraines (chronic, episodic, or acute), headache (e.g., episodic, chronic, acute, cluster, and so on). , Parkinson's disease, depression, anxiety, overactive bladder including but not limited to major depressive disorder, treatment-resistant depression, anxiety, post-traumatic stress disorder, neuropathic pain including diabetic peripheral neuropathy, post-herpetic neuralgia, neuropathic pain chemotherapy-induced, prevention of chemotherapy-induced neuropathy, prevention of chemotherapy-induced neuropathic pain, trigeminal neuralgia, inflammatory pain, including osteoarthritis, rheumatoid arthritis, Rett syndrome, autism spectrum disorders, migraine (chronic, episodic or acute), cluster headaches (e.g., episodic, chronic, acute, cluster, and so on), acute abortive treatment, acute intermittent migraine prophylaxis, chronic migraine prophylaxis, treatment of episodic and chronic cluster headache, acute headache prevention episodic and chronic, Charcot-Marie Tooth disease, traumatic brain injury, fibromyalgia, stroke, acute ischemic syndrome, ischemia/reperfusion injury, substance abuse intervention and/or alcohol abuse treatment in an individual (e.g. , mammal or human and others described here) that needs the same.

[0234] The present invention also provides one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, for the treatment of hyperalgesia in an individual comprising administering, to the individual , one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein, or a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein. In some embodiments, the hyperalgesia is opioid-induced hyperalgesia. In some embodiments, opioid-induced hyperalgesia is hyperalgesia induced by morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone and/or heroin. In some embodiments, the subject has received an opioid prior to receiving one or more compounds, or a pharmaceutically acceptable salt thereof, of the pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof.

[0235] The present invention also provides one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, for decreasing nociceptive sensitization in an individual comprising administering, to the individual , one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein, or a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein. In some embodiments, the subject has opioid-induced nociceptive sensitization. In some embodiments, opioid-induced nociceptive sensitization is nociceptive sensitization induced by morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone and/or heroin, or a pharmaceutically acceptable salt thereof. .

[0236] The present invention also provides one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, for the treatment of pain in an individual comprising administering, to the individual , one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein, or a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein. In some embodiments, the method comprises administering an opioid agonist to the subject until the opioid increases nociceptive sensitization in the subject; and administering to the individual one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein, or a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein. In some embodiments, the opioid agonist is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone and/or heroin, or a pharmaceutically acceptable salt thereof.

[0237] The present invention also provides one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, for the treatment of pain in an opioid-exposed individual comprising administering , to the individual, one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein, or a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein. In some embodiments, the methods comprise: a) administering an opioid agonist to the subject; and b) administering to the subject of step a), in the absence of the opioid administered in step a), one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein, or a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein. In some embodiments, the opioid that is administered in step a) is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone and/or heroin or a pharmaceutically acceptable salt thereof.

[0238] The present invention also provides one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, for the treatment of medication overuse headache in a subject comprising administering to the subject one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein, or a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein. here. In some embodiments, the medication overuse headache is caused by acetaminophen, aspirin, a mu-opioid agonist, a nonsteroidal anti-inflammatory drug (NDAID), or a triptan. In some embodiments, the triptan is sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, avitriptan or donitriptan, or a pharmaceutically acceptable salt thereof. In some embodiments, the mu-opioid agonist is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone or heroin, or a pharmaceutically acceptable salt thereof.

[0239] The present invention also provides one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, for the treatment of migraines in an individual comprising administering a triptan to an individual; and administering to the individual one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein, or a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein. In some embodiments, the one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein, or a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein is administered. in the absence of triptan. In some embodiments, the triptan is sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, avitriptan or donitriptan, or a pharmaceutically acceptable salt thereof. In some embodiments, the individual develops a medication overuse headache prior to receiving one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein, or a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, of a compound described herein.

[0240] The present invention also provides one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, for use in the manufacture of a medicament for the treatment in methods of treatment of pain including, but not limited to, neuropathic pain, migraines (chronic, episodic, or acute), headache (e.g., episodic, chronic, acute, cluster, and so on), Parkinson's disease, depression, anxiety, overactive bladder including, but not limited to, major depressive disorder, treatment-resistant depression, anxiety, post-traumatic stress disorder, neuropathic pain, including diabetic peripheral neuropathy, postherpetic neuralgia, chemotherapy-induced neuropathic pain, prevention of chemotherapy-induced neuropathy, prevention of chemotherapy-induced neuropathic pain, trigeminal neuralgia, inflammatory pain including osteoarthritis, rheumatoid arthritis, Rett syndrome, autism spectrum disorders, migraine (chronic, episodic, or acute), cluster headaches (e.g., episodic, chronic, acute, cluster and so on), acute abortive treatment, acute intermittent migraine prophylaxis, chronic migraine prophylaxis, treatment of episodic and chronic cluster headache, prevention of acute episodic and chronic headache, Charcot-Marie Tooth disease, traumatic brain injury, fibromyalgia, stroke, acute ischemic syndrome, ischemia/reperfusion injury, substance abuse intervention and/or alcohol abuse treatment in an individual, such as those described herein. In some embodiments, the mammal is a mammal in need thereof.

[0241] The present invention also provides the use of one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, in modulating a δ-opioid receptor. In some embodiments, the compounds, the pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof modulates the beta-arrestin modulated pathway of the δ-opioid receptor. In some embodiments, the compounds, the pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof modulates the G protein-modulated pathway of the δ-opioid receptor.

[0242] As used herein, "modulation" may refer to the inhibition or enhancement of a specific activity. For example, δ-opioid receptor modulation may refer to the inhibition and/or activation of the δ-opioid receptor G protein-mediated pathway. In some embodiments, the modulation refers to the inhibition or activation of the β-arrestin-mediated pathway of the δ-opioid receptor. The activity of a δ-opioid receptor can be measured by any method including, but not limited to, the methods described herein.

[0243] The compounds described here are agonists or antagonists of delta opioid receptors (DORs). The ability of compounds to stimulate or inhibit DOR-mediated signaling can be measured using any assay known in the art used to detect DOR-mediated signaling or DOR activity or the absence of such signaling/activity. "DOR activity" refers to the ability of a DOR to transduce a signal. Such activity can be measured, for example, in a heterologous cell, by coupling a DOR (or a chimeric DOR) to a downstream effector such as adenylate cyclase.

[0244] A "natural ligand-induced activity", as used herein, refers to the activation of DOR by a natural DOR ligand. Activity can be assessed using any number of parameters to measure DOR activity.

[0245] In general, assays to test compounds that modulate DOR-mediated signal transduction include determining any parameter that is indirectly or directly under the influence of a DOR, for example, a functional, physical or chemical effect.

[0246] Samples or assays comprising DORs that are treated with a potential activator, inhibitor, or modulator are compared to control samples without the inhibitor, activator, or modulator to examine the extent of inhibition. Control samples (not treated with inhibitors) are assigned a relative DOR activity value of 100%. Inhibition of a DOR is achieved when the DOR activity value relative to the control is about 80%, 50% or 25%. Activation of a DOR is achieved when the DOR activity value relative to the control (not treated with activators) is 110%, 150%, or 200-500% (i.e., two to five times greater relative to the control) or 1000-3000% or higher.

[0247] The effects of compounds on the function of a DOR can be measured by examining any of the parameters described above. Any suitable physiological change that affects DOR activity can be used to evaluate the influence of a compound on DORs and natural ligand-mediated DOR activity. When functional consequences are determined using intact cells or animals, one can also measure a variety of effects, such as changes in intracellular second messengers such as cAMP.

[0248] In some embodiments, the compound or a pharmaceutically acceptable salt thereof selectively inhibits the beta-arrestin-mediated pathway of the delta-opioid receptor. In some embodiments, the compound or a pharmaceutically acceptable salt thereof selectively inhibits the cAMP-mediated pathway of the delta-opioid receptor. In some embodiments, the compound or a pharmaceutically acceptable salt thereof selectively activates the beta-arrestin-mediated pathway of the delta-opioid receptor. In some embodiments, the compound or a pharmaceutically acceptable salt thereof selectively activates the cAMP-mediated pathway of the delta-opioid receptor.

[0249] Modulators of DOR activity can be tested using DOR polypeptides as described herein, whether recombinant or naturally occurring. The protein can be isolated, expressed in a cell, expressed in a cell-derived membrane, expressed in tissue or in an animal. For example, neuronal cells, immune cells, transformed cells or membranes can be used to test the GPCR polypeptides described above. Modulation is tested using one of the in vitro or in vivo assays described here. Signal transduction can also be examined in vitro with soluble or solid-state reactions using a chimeric molecule, such as an extracellular domain of a receptor covalently linked to a heterologous signal transduction domain or a heterologous extracellular domain covalently linked to the transmembrane and cytoplasmic domain of a receptor. Furthermore, the ligand-binding domains of the protein of interest can be used in vitro in soluble or solid-state reactions to assay ligand binding.

[0250] Ligand binding to a DOR, a domain or chimeric protein can be tested in several formats. Binding can be carried out in solution, in a bilayer membrane, attached to a solid phase, in a lipid monolayer or in vesicles. For example, in one assay, the binding of the natural ligand to its receptor is measured in the presence of a candidate modulator, such as the compound described here. Alternatively, binding of the candidate modulator can be measured in the presence of the natural ligand. Competitive assays are often used to measure the ability of a compound to compete with natural ligand binding to the receptor. Binding can be tested by measuring, for example, changes in spectroscopic characteristics (e.g., fluorescence, absorbance, refractive index), hydrodynamic changes (e.g., shape), or changes in chromatographic properties or solubility.

[0251] The activity of compounds can also be measured using assays that involve the recruitment of β-arrestin. β-arrestin serves as a regulatory protein that is distributed throughout the cytoplasm in non-activated cells. Ligand binding to an appropriate DOR is associated with the redistribution of β-arresin from the cytoplasm to the cell surface, where it associates with the DOR. Thus, receptor activation and the effect of candidate modulators on ligand-induced receptor activation can be assessed by monitoring the recruitment of β-arrestin to the cell surface. This is often accomplished by transfecting a tagged β-arrestin fusion protein (e.g., β-arrestin-green fluorescent protein (GFP)) into cells and monitoring its distribution via confocal microscopy (see , for example, Groarke et al., J. Biol. Chem. 274 (33): 2326369 (1999)).

[0252] Another technology that can be used to evaluate DOR protein interactions in living cells involves bioluminescent resonance energy transfer (BRET). A detailed discussion of BRET can be found in Kroeger et al., J. Biol. Chem., 276 (16): 12736 43 (2001).

[0253] Other assays may involve determining the activity of receptors that, when activated by ligand binding, result in a change in the level of intracellular cyclic nucleotides, e.g., cAMP, through activation or inhibition of downstream effectors, such such as adenylate cyclase. In one embodiment, changes in intracellular AMP can be measured using immunoassays. The method described in Offermanns & Simon, J. Biol. Chem. 270: 15175 15180 (1995) can be used to determine the level of cAMP. Furthermore, the method described in Felley-Bosco et al., Am. J. Resp. Cell and Mol. Biol. 11: 159 164 (1994) can be used to determine the cGMP level. Additionally, an assay kit for measuring cAMP is described in United States Patent No. 4,115,538, incorporated herein by reference.

[0254] In another embodiment, transcription levels can be measured to evaluate the effects of a test compound on ligand-induced signal transduction. A host cell containing the protein of interest is contacted with a test compound in the presence of the natural ligand for a time sufficient to effect any interactions, and then the level of gene expression is measured. The amount of time to effect such interactions can be determined empirically, such as by running a time course and measuring the level of transcription as a function of time. The amount of transcription can be measured using any method known to those skilled in the art to be suitable. For example, mRNA expression of the protein of interest can be detected using Northern blots or its polypeptide products can be identified using immunoassays. Alternatively, transcription-based assays that use reporter genes can be used, as described in U.S. Pat. United States No. 5,436,128, incorporated herein by reference. Reporter genes can be, for example, chloramphenicol acetyltransferase, firefly luciferase, bacterial luciferase, β-galactosidase and alkaline phosphatase. Furthermore, the protein of interest can be used as an indirect reporter by binding to a second reporter, such as green fluorescent protein (see, for example, Mistili & Spector, Nature Biotechnology 15: 961 964 (1997)).

[0255] The amount of transcription is then compared to the amount of transcription in the same cell in the absence of the test compound or can be compared to the amount of transcription in a substantially identical cell that does not have the protein of interest. A substantially identical cell can be derived from the same cells from which the recombinant cell was prepared, but which has not been modified by the introduction of heterologous DNA. Any difference in the amount of transcription indicates that the test compound has altered the activity of the protein of interest in some way.

[0256] Additional assays may also be used. For example, the activity of the compound can be measured in a cell-based assay. For example, a nucleic acid molecule encoding the delta-opioid receptor (Accession NP_000902) can be incorporated into an expression vector and transfected or transformed into a cell. In some embodiments, the expression vector is a plasmid or virus. In some embodiments, expression of the nucleic acid molecule is operably linked to a promoter. The promoter may be constitutive or responsive to a drug or other response member so that expression can be controlled. The type of expression vector is not critical and any expression vector that is suitable for the cell type can be used. In some embodiments, the plasmid is pCMV-Prolink. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a Chinese Hamster Ovary (CHO-1) cell. In some embodiments, the cell is a CHO-1 cell of the parental EA-arrestin lineage, which is available from DiscoveRx Corporation (Fremont, CA). Receptor expression can be stable, so that stable cell lines can be selected. The selection of cell lines that stably express the receptor can be done using routine methods, such as selection for expression in G418 (Geneticin). Receptor expression may also be transient.

[0257] After the receptor is expressed in a cell, the cells can be cultured in appropriate media in the appropriate cell plate. Cells can be plated, for example, at 5000-10000 cells per well in a 384-well plate. In some embodiments, cells are placed in the plates at about 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 or 10,000 cells/well. The plates can have any number of wells and the number of cells can be modified accordingly.

[0258] In some embodiments, to measure cAMP activity that is mediated by the receptor, responses can be determined by measuring changes in intracellular AMP. cAMP can be measured using any known method or kit. Examples of a kit that can be used include, but are not limited to, the CisBio HTRF cAMP HiRange kit (cat# 62AM6PEJ) based on time-decomposed fluorescence resonance energy transfer (TR-FRET). Compounds (e.g., test or control) can be contacted with cells for a period of time and then cAMP can be measured.

[0259] In some embodiments, the effect of a compound on the beta-arrestin activity of the receptor is measured. Activity can be measured using any method or kit. For example, beta-arrestin recruitment or activity was determined using the DiscoveRx betaarrestin PathHunter Detection kit (cat# 93-0001). In this system, beta-arrestin is fused to an N-terminal deletion mutant of beta-galactosidase (called the EA enzyme acceptor) and the GPCR of interest is fused to a smaller (42 amino acids), weakly complementary fragment called ProLink™ . In cells stably expressing such fusion proteins, ligand stimulation results in the interaction of beta-arrestin and Prolink-tagged GPCR, forcing complementation of the two betagalactosidase fragments and resulting in the formation of a functional enzyme that converts the substrate into a signal. detectable. Compounds that enhance this activity will lead to an increase in functional enzyme and an increase in detectable signal. Compounds that inhibit this activity will decrease the detectable signal. The compounds may also have no effect on beta-arrestin recruitment.

[0260] The present invention also provides the use of one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, in the treatment of pain treatment methods including, but not limited to, without limitation, pain including, but not limited to, neuropathic pain, migraines (chronic, episodic, or acute), headache (e.g., episodic, chronic, acute, cluster, and so on), Parkinson's disease, depression, anxiety, overactive bladder including, but not limited to, major depressive disorder, treatment-resistant depression, anxiety, post-traumatic stress disorder, neuropathic pain, including diabetic peripheral neuropathy, post-herpetic neuralgia, chemotherapy-induced neuropathic pain, prevention of chemotherapy-induced neuropathy chemotherapy, prevention of chemotherapy-induced neuropathic pain, trigeminal neuralgia, inflammatory pain including osteoarthritis, rheumatoid arthritis, Rett syndrome, autism spectrum disorders, migraine (chronic, episodic, or acute), cluster headaches (e.g., episodic, chronic, acute, cluster and so on), acute abortive treatment, acute intermittent migraine prophylaxis, chronic migraine prophylaxis, treatment of episodic and chronic cluster headache, prevention of acute episodic and chronic headache, Charcot-Marie disease Tooth, traumatic brain injury, fibromyalgia, stroke, acute ischemic syndrome, ischemia/reperfusion injury, substance abuse intervention and/or alcohol abuse treatment in an individual or an individual in need thereof, such as the one described here.

[0261] Any medicine that has utility in an application described here can be used in cotherapy, coadministration or coformulation with a composition as described above. These additional medications include medications for Parkinson's disease such as, among others, injections of levodopa, carbidopa, Catechol-O-methyl transferase (e.g., Entacapone or Tolcapone), dopamine agonists, ropinirole, bromocriptine, pramipexole, Monoamine Oxidase inhibitors (in English, MAOi) (for example, rasagiline or selegiline), anti-cholinergics (for example, Benztropine or Trihexyphenidyl) and amantadine. Examples of overactive bladder medications include, but are not limited to, tolterodine (Detrol), oxybutynin (Ditropan), an oxybutynin dermal patch (Oxytrol), trospium (Sanctura), solifenacin (Vesicare), and darifenacin (Enablex). Examples of medications for treating depression and/or anxiety include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), paroxetine (Paxil) and sertraline (Zoloft); tricyclic and tetracyclic antidepressants, such as doxepin (Sinequan) and nortriptyline (Aventyl, Pamelor); other antidepressants, such as bupropion (Wellbutrin, Wellbutrin SR), mirtazapine (Remeron), and trazodone and venlafaxine (Effexor, Effexor XR); monoamine oxidase inhibitors (MAOis), such as isocarboxazid (Marplan), phenelzine sulfate (Nardil), and selegiline (Emsam), Ativan, Celexa, Cymbalta, Klonopin, Lexapro, Luvox CR, Norpramin, Paxil, Remeron, Tofranil , Valium and Xanax.

[0262] Examples of pain medications include, but are not limited to, non-steroidal anti-inflammatory agents, opioids, non-narcotic analgesics, topical analgesics, topical anesthetics. Examples of suitable non-steroidal anti-inflammatory agents include, but are not limited to, prostaglandin H synthetase (Cos I or Cox II) inhibitors, also said to be type I and type II cyclooxygenase inhibitors, such as diclofenac, flurbiprofen, ketorolac , suprofen, naprofen, ibuprofen, bronfenac, ketoprofen, meclofenamate, piroxicam, sulindac, mefanamic acid, diflusinal, oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumetome, etodolac, phenylbutazone, aspirin, oxyphenbutazone, tenoxicam and carprofen; selective type II cyclooxygenase inhibitors, such as vioxx, celecoxib, etodolac; PAF antagonists such as apafante, bepafante, minopafante, nupafante and modipafante; PDE II inhibitors such as ariflo, torbafilin, rolipram, filaminast, piclamilast, cipanfilin and roflumilast; cytokine production inhibitors, such as NFkB transcription factor inhibitors; or other anti-inflammatory agents known to those skilled in the art. Other examples of pain medications include, but are not limited to, acetaminophen, buprenorphine, butorphanol, codeine, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, tramadol, butalbital, capsaicin, benzocaine , dibucaine, prilocaine and lidocaine.

[0263] The additional medicament can be administered in cotherapy (including coformulation) with one or more of the compounds described here.

[0264] In some embodiments, the response of the disease or disorder to treatment is monitored and the treatment regimen is adjusted, if necessary, in light of this monitoring.

[0265] The frequency of administration is typically such that the dosage interval, for example, the period of time between one dose and the next, during waking hours is from about 2 to about 12 hours, from about 3 to about 8 hours or from about 4 to about 6 hours. It will be understood by those skilled in the art that an appropriate dosage interval depends, to some extent, on the time during which the selected composition is capable of maintaining a concentration of the compound(s) in the subject and/or target tissue ( for example, above the EC50 (the minimum concentration of the compound that modulates receptor activity by 90%). Ideally, the concentration remains above the EC50 for at least 100% of the dosing interval. When this is not possible, it is It is desirable that the concentration remains above the EC50 for at least about 60% of the dosing interval or remains above the EC50 for at least about 40% of the dosing interval.

[0266] The present description also provides the following non-limiting embodiments: 1. A compound having Formula I, I-1, Ia, I-a1 or Ib, Ib-1 or Ib-2 or pharmaceutically acceptable salts thereof, wherein Z is C, S, N, S(O)2 or O; R35 is a protecting group, C(=O)OR81b, H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, -R63R64, C1-C6 optionally substituted branched or unbranched alkyl, C2-C6 optionally substituted alkenyl, C2- C6 optionally substituted haloalkenyl -(CH2)nR65, optionally substituted heterocycle, C1-C6 optionally substituted ester, optionally substituted cycloalkyl, C1-C6 optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl, C3-C6 optionally substituted cyclic ether or optionally piperidyl replaced; R36 is absent, is H, halo, optionally substituted C1-C6 haloalkyl, -SO2C1-C6alkyl, -OCF3, optionally substituted C1-C6 alkyl or -OR75; wherein R75 is H or optionally substituted C1-C6 alkyl; R37 is absent, is H, halo, optionally substituted C1-C6 haloalkyl, -SO2C1-C6alkyl, -OCF3, optionally substituted sulfonamide, optionally substituted cyclic sulfonamide or -(CH2)q-R38, -NH-(CH2)q-R38 , -S- (CH2)q-R38, -C(=O)R38 or -O-(CH2)q-R38, R38 is H, C1-C6 alkyl, halo, C1-C6 haloalkyl, -C(=O)C1- C6 alkyl, –OR66, S(O)2R67, optionally substituted cycloalkyl, -(CH2)pR65 or optionally substituted heterocycle; or R37 is -(CH2)q-R38 or R36 and R37 form a heterocycle that is fused to the phenyl ring; R41 is absent, is H or C1-C6 alkyl, provided that when Z is S, O or S(O)2, R41 is absent; or, when Z is C, the bond connecting Z to the adjacent carbon is a double bond and R41 is H, wherein, R39 is H or C1-C6 alkyl; R40 is H, C1-C6 alkyl, halo or alkoxy; R42 is absent, it is H, C1-C6 alkyl, a member of a carbocycle that includes the atom to which it is attached, =O; Xa is C or O, provided that, when Xa is O, R42 is absent; Xb is S or O; Xc is C or N; R43 is -OH, -CN, -C(=O)NR45R46, where: R44 is H or C1-C6 alkyl; R45 is H or C1-C6 alkyl; and R46 is H or C1-C6 alkyl; R47 is H or C1-C6 alkyl; R48 is H or C1-C6 alkyl; each R49 is independently H or C1-C6 alkyl; R50 is H or C1-C6 alkyl; R51 is H or C1-C6 alkyl; R52 is H or C1-C6 alkyl; R53 is H or C1-C6 alkyl; R55 is H or C1-C6 alkyl; R56 is H or C1-C6 alkyl; R57 is H or C1-C6 alkyl; R58 is missing or H; R59 is H or OH; R60 is H or N(R54)2; each R54 is independently H or C1-C6 alkyl; R61 is H, C1-C6 alkyl, C1-C6 optionally substituted haloalkyl, gem-dimethyl, cyclopropyl, spirocycle or CF3; R62 is absent, is H or C1-C6 alkyl; each R63 and R64 are independently H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, C1-C6 optionally substituted branched or unbranched alkyl, C2-C6 optionally substituted alkenyl, -(CH2)vR65, optionally substituted cycloalkyl, - OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl; or R63 and R64 together form an optionally substituted 510-membered heterocycle or 5-10-membered heteroaryl optionally substituted with the atom to which R63 and R64 are attached; each R65 is, independently, H, -C(=O)R65A, C1-C6 optionally substituted haloalkyl, optionally substituted nitrogen, C1-C6 optionally substituted branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, C2-C6 alkenyl optionally substituted, optionally substituted cycloalkyl, optionally substituted heterocycle, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted phenyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted morpholinyl or optionally substituted piperidyl; R65A is phenyl or branched or unbranched C1-C6 alkyl; R66 is H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, -NR63R64, C1-C6 optionally substituted branched or unbranched alkyl, C2C6 optionally substituted alkenyl, -(CH2)wR65, optionally substituted cycloalkyl, -OH, optionally substituted alkoxy , optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl; R67 is C1-C6 optionally substituted branched or unbranched alkyl, C1-C6 optionally substituted haloalkyl; R81a and R82a are each independently H or optionally substituted C1-C6 alkyl; R81b is H or optionally substituted branched or unbranched C1-C6 alkyl; z is 1 or 2, each n, p, v, w and q is independently an integer from 0-6. 2. The compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, having Formula II, III, IV or V: 3. The compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, having Formula VI: 4. The compound, according to embodiment 1 pharmaceutically acceptable salt thereof, having Formula VII or VIIa: 5. The compound according to any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein z is 1. 6. The compound according to any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof. acceptable thereof, wherein each R61 is methyl. 7. The compound according to embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein each R61 is gem-dimethyl. 8. The compound according to any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein Z is O. 9. The compound according to any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof. acceptable of the same, where Z is S(O)2. 10. The compound according to any one of embodiments 1-9, or a pharmaceutically acceptable salt thereof, wherein R41 is absent. 11. The compound according to any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein R37 is alkoxy, halo, optionally substituted sulfonamide, optionally substituted cyclic sulfonamide. 12. The compound according to any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein R36 and R37 form a heterocycle that is fused to the phenyl ring. 13. The compound of embodiment 12, or a pharmaceutically acceptable salt thereof, wherein the fused ring structure is an optionally substituted benzofuran or benzopyran. 14. The compound according to embodiment 12, or a pharmaceutically acceptable salt thereof, wherein the fused ring has the formula: 15. The compound according to any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein R37 is absent. 16. The compound according to any one of embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein q is 0. 17. The compound according to any one of embodiments 1-15, or a pharmaceutically acceptable salt thereof , where q is 1-4. 18. The compound according to any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, in which R38 is absent or H. 19. The compound according to any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein R38 is C1-C6 haloalkyl. 20. The compound according to any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein R38 is -C(=O)C1-C6 alkyl. 21. The compound according to any one of embodiments 1-17, or a pharmaceutically acceptable salt thereof, wherein R38 is -OR66, -S(O)2R67 optionally substituted cycloalkyl, -(CH2)pR65 or optionally substituted heterocycle. 22. The compound according to any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein R34 is 23. The compound according to any one of embodiments 1-21, or a pharmaceutically acceptable salt thereof, wherein R34 is 24. The compound according to any one of embodiments 1-23, or a pharmaceutically acceptable salt thereof, wherein R34 is 25. The compound according to any one of embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein R61 is H, C1-C6 alkyl, C1-C6 optionally substituted haloalkyl, gem-dimethyl, cyclopropyl, spirocycle or CF3. 26. The compound according to any one of embodiments 1-25, or a pharmaceutically acceptable salt thereof, wherein R35 is C1-C6 optionally substituted branched or unbranched alkyl, -CH2R76 or -CH2CH2R76, wherein R76 is aryl optionally substituted, optionally substituted ketone, optionally substituted cycloalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2C6 haloalkenyl or optionally substituted heteroaryl. 27. The compound according to embodiment 26, or a pharmaceutically acceptable salt thereof, wherein R76 is cyclopropyl. 28. The compound according to embodiment 26, or a pharmaceutically acceptable salt thereof, wherein R76 is difluorocyclopropyl. 29. The compound according to embodiment 26, or a pharmaceutically acceptable salt thereof, wherein R76 is 2,2-difluorocyclopropyl. 30. The compound according to embodiment 26, or a pharmaceutically acceptable salt thereof, wherein R76 is - CH=CF2. 31. The compound according to any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of a compound illustrated in Figure 1 and/or described herein. 32. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of a compound described herein including, but not limited to, those in Figure 1. 33. A compound, or a pharmaceutically acceptable salt acceptable thereof, selected from the group consisting of: B1049, B0704, B0707, B0720, B0876, B1079, B1145, B1194, B1205, B1211, B1365, B1401, 34. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-33. 35. A method of treating or preventing pain, neuropathic pain, migraine, headache, depression, Parkinson's disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreased nociceptive sensitization, pain in a individual exposed to opioids, PTSD or other condition or disorder described herein in an individual comprising administering, to the individual, one or more compounds, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 133 or a pharmaceutical composition comprising one or more compounds, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-33. 36. The method, according to embodiment 35, in which the individual is an individual who needs it. 37. A method of preparing a compound, or a pharmaceutically acceptable salt thereof, the method comprising preparing a compound according to one of the schemes described herein. 38. A compound having Formula I00, Formula I00A, Formula I00B or Formula I00C, or pharmaceutically acceptable salts thereof: wherein: R100, R200 and R1400 are each independently H, cyano, C1-C6 optionally substituted branched or unbranched alkyl, C1-C6 optionally substituted alkoxy, C1-C6 optionally substituted haloalkyl, C2-C6 optionally substituted alkenyl, pyrimidine optionally substituted, optionally substituted pyridyl, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyridinone, optionally substituted aryl, halo, -NC(=O)R300, -C(=O)NR300R400,-C(=O)OR3, S (=O)2NR300R400 , -C(=O)R300 , -OR3, — (CH2)nR500, =O or R1500 is a protecting group, C(=O)OR81b, is absent or is C2-C6 alkenyl, wherein R81b is H or C1-C6 optionally substituted branched or unbranched alkyl; when R1500 is absent, R600 is H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, -NR700R800, C1-C6 optionally substituted branched or unbranched alkyl, C2-C6 optionally substituted alkenyl, -(CH2)nR5oo, optionally substituted cycloalkyl , -OH, optionally substituted C1-C6 alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl; when R1500 is C2-C6 alkenyl, R600 is C2-C6 alkenyl; R300, R400 and R1200 are each, independently, H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, -NR700R800, C1-C6 optionally substituted branched or unbranched alkyl, C2-C6 optionally substituted alkenyl, -(CH2)nR5oo, optionally substituted cycloalkyl, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl; or R300 and R400 together form an optionally substituted 5-10 membered heterocycle or 5-10 membered heteroaryl optionally substituted with the atom to which R300 and R400 are attached; each R500 is, independently, H, C1-C6 optionally substituted haloalkyl, -NR700R800, C1-C6 optionally substituted branched or unbranched alkyl, optionally substituted aryl, optionally substituted heteroaryl, C2-C6 optionally substituted alkenyl, optionally substituted cycloalkyl, optionally heterocycle substituted, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl; R700 and R800 are each independently H, optionally substituted aryl, C1-C6 optionally substituted haloalkyl, C1-C6 optionally substituted branched or unbranched alkyl, C2-C6 optionally substituted alkenyl, -(CH2)nR5oo, optionally substituted cycloalkyl, -OH, optionally substituted alkoxy, optionally substituted pyrrolinyl, optionally substituted morpholinyl or optionally substituted piperidyl; or R700 and R800 together form an optionally substituted 5-10 membered heterocycle or optionally substituted 5-10 membered heteroaryl with the atom to which R700 and R800 are attached, R900 is absent, is H, haloalkyl, –OR3 or optionally substituted cycloalkyl, -(CH2)pR500 or optionally substituted heterocycle; R1100 is H, -SO2C1-C6alkyl, -OCF3, halo or optionally substituted C1-C6alkyl; R1300 is a bond, C, N, S or O; R1400 is an optionally substituted pyridinone or optionally substituted-CH2-pyridinone; each n, p and y is independently an integer from 0-72; each Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 is independently C, N or O, provided that the compound or pharmaceutically acceptable salt thereof is not: 39. The compound according to embodiment 38, or a pharmaceutically acceptable salt thereof, having Formula I00D or Formula I00E: wherein: R100, R200, R600, R900 and R1500 are as defined in embodiment 67; Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C; R1100 is H; R1300 and Z100 is O; Z200 is C; Z300 is a link; ey = 2. 40. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38 or 39, wherein R100 is -C(=O)NR3ooR4oo. 41. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 3840, wherein each R300 and R400 is independently H, halo, optionally substituted C1C6 haloalkyl, or optionally substituted C1-C6 alkyl. 42. The compound, or a pharmaceutically acceptable salt thereof, according to embodiments 38 or 39, wherein R100 is H, halo, -C(=O)NH2, -C(=O)NHCH3, -C(= O)N(CH3)68 -COOH, -C(=O)OCH3, cyano, S(=O)2NH2, optionally substituted alkoxy, -OCF3, CF3, -NC(=O)CH3, pyridyl, 43. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 38, 39 or 42, wherein R100 and R200 is each independently H, halo or optionally substituted C1-C6 haloalkyl. 44. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 43, wherein R100 and R200 are independently halo. 45. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 43, wherein the optionally substituted C1-C6 haloalkyl is trifluoromethyl. 46. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 43, wherein R100 is fluorine and R200 is trifluoromethyl. 47. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 3846, wherein R100 and R200 are attached to different atoms in the ring. 48. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38 or 39, wherein R200 is H. 49. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38 or 39, where: R600 is H, C1-C6 optionally substituted alkyl or - C(=O)OR3; and R300 is an optionally substituted C1-C6 branched or unbranched alkyl. 50. The compound, or a pharmaceutically acceptable salt thereof, according to embodiments 38 or 39, wherein: R100 is -C(=O)NH2 and R600 is H or optionally substituted C1-C6 alkyl; or R100 is -C(=O)NR300R400, wherein R300 is H and R400 is C1-C6 optionally substituted branched or unbranched alkyl or C2-C6 alkenyl and R600 is H or optionally substituted C1-C6 alkyl; or R100 is -C(=O)NR300R400, wherein R300 and R400 are each independently optionally substituted C1-C6 branched or unbranched alkyl and R600 is H, optionally substituted C1-C6 alkyl or optionally substituted alkaryl. 51. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38 or 39, wherein R100 is -C(=O)NR300R400, wherein: R300 and R400 are H; R300 is H and R400 is optionally substituted branched or unbranched C1-C6 alkyl; or R300 is H and R400 is optionally substituted branched or unbranched C2-C6 alkenyl; or R300 is H and R400 is optionally substituted C1-C6 cycloalkyl; or R300 is H and R400 is - (CH2)nR5oo; wherein n is 1-6 and R500 is an optionally substituted cycloalkyl; or R300 is H and R400 is -(CH2)nR500, wherein n is 1-6 and R500 is an optionally substituted alkoxy; or R300 and R400 are each independently optionally substituted C1-C6 alkyl. 52. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38 or 39, wherein R100 is -C(=O)NR300R400, wherein R300 and R400 together form an optionally substituted 5-10 membered heterocycle or 5-10 membered heteroaryl optionally substituted with the atom to which R300 and R400 are attached. 53. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein Rb00 is N. 54. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein Ra00 is No. 55. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein Rc00 is N. 56. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein Rd00 is N. 57. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 53-55 wherein R1100 is H, R1300 is O, R100 is C, Z100 is O, Z200 is C, Z300 is a bond and y = 2. 58. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 5358, wherein R100, R200 and R600 are each H and Z is O. 59. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 53-58, wherein R100 is =O and R200 is H. 60. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38 or 39, where Rioo is -C(=O)NR3ooR4oo; and R600 is H, C1-C6 alkyl or -C(=O)ORs, wherein R300 is an optionally substituted branched or unbranched C1-C6 alkyl. 61. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 60, wherein R300 is 62. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 3861, wherein: R600 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, -OR3 or (CH2)n -arila, n is an integer from 0-2; R900 is R1100 is H or halo; R1300 is O; Ri00 is C; y = 2; and optionally, R1500 is C2-C6 optionally substituted alkenyl when R600 is C2-C6 optionally substituted alkenyl. 63. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 3862, wherein R1100 is fluorine. 64. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 38-42, 48, 49, 53-57 or 60-63, wherein R100 is -C(=O)NH2. 65. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 38, 39, 42 or 53-57, wherein R100 is cyano. 66. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38 wherein: Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C; Z100 is O, Z200 is C, Z300 is a bond; y=0; R900 is C1-C6 optionally substituted branched or unbranched alkyl, optionally substituted haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocycle; and R1300 is O. 67. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 66, wherein R600 is H or optionally substituted branched or unbranched C1-C6 alkyl. 68. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 66 or 67, wherein R900 69. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 6668, wherein R100 is -C(=O)NR3ooR4oo or cyano. 70. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 6669, wherein R200 is H. 71. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 6670, wherein R1100 is H. 72. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein: one of Ra00, Rb00, Rc00 and Rd00 is N; Z100 is a bond or O; Z200 is C, Z300 is a bond and y=0; Rh00 and Ri00 are C; R100 is H, -C(=O)NR300R400 or =O; R200 is H; R600 is H, C1-C6 alkyl or C2-C6 alkenyl; R900 is C1-C6 alkyl, haloalkyl or cycloalkyl; R1100 is H; and R1300 is O. 73. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 72, wherein Z100 is a bond and R100 is =O. 74. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 72, wherein R400 is H. 75. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 72 or 74, wherein Rd00 is N and R100 is =O. 76. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein: Ra00, Rb00, Rc00 and Rd00 are C; Rh00 and Ri00 are C; Z100 is O, Z200 is C, Z300 is a bond; R1100 is halo or C1-C6 alkyl; y=0; R900 is H, haloalkyl or C1-C6 alkyl; R1300 is O; R600 is H, C1-C6 alkyl or C2-C6 alkenyl; R200 is H. 77. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 76, wherein R100 is H, cyano or -C(=O)NR3ooR4oo. 78. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 77 having Formula I00E: where: R100, R200. R600. and R900 are as defined in embodiment 77; Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C; R1300 is O; Z100 is O, Z200 is C, Z300 is a bond; ey=0. 79. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 78, wherein R900 is H, haloalkyl or C1-C6 alkyl. 80. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 68 or 79, wherein R200 is H. 81. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiment 7880, wherein R1100 is H. 82. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 7881, wherein R600 is H, C1-C6 alkyl or C2-C6 alkenyl. 84. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 7882, wherein R100 is H, cyano or -C(=O)NR3ooR4oo. 85. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 7883, wherein R900 is H or C1-C6 alkyl. 86. The compound, or a pharmaceutically acceptable salt thereof, of Formula I00A according to embodiment 38, wherein: Ra00, Rb00, Rc00, Rd00, Re00 and Ri00 are C, Rg00 is C or O; Rf00 is missing; R1300 is O; and Z100 is O, Z200 is C and Z300 is a bond. 87. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 86, wherein R200 is H. 88. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 86 or 87, wherein R1100 is H. 89. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiment 8688, wherein R600 is H, optionally substituted C1-C6 alkyl or optionally substituted C2-C6 alkenyl. 90. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 8488, wherein R100 is H, cyano, -C(=O)NR300R400 or C1-C6 alkyl. 91. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiment 8489, wherein Rg00 is O. 92. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein y = 1. 93. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 92, wherein R900 is an optionally substituted C1-C6 alkyl or optionally substituted cycloalkyl. 94. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 92 or 93, wherein Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C. 95. The compound, or a pharmaceutically acceptable salt thereof , according to any one of embodiments 9194, wherein R1300 is O. 96. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 9195, wherein Z100 is O, Z200 is C, and Z300 is a call. 97. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 9196, wherein R200 and R1100 are H. 98. The compound, or a pharmaceutically acceptable salt thereof, according to any one of the embodiments 9197, where R100 is -C(=O)NR3ooR4oo. 99. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 9198, wherein R600 is H or optionally substituted C1-C6 alkyl. 100. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein Rh00 is N. 101. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 100, wherein Ra00, Rb00, Rc00, Rd00, Ri00 are C. 102. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 100 or 101, wherein R200 is H. 103. The compound, or a pharmaceutically acceptable salt thereof , according to any one of embodiments 100102, wherein R1300 is O. 104. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 100103, wherein Z100 is O, Z200 is C, and Z300 is a call. 105. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 100104, wherein R1100 is H. 106. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 100105, wherein R600 is C2-C6 optionally substituted alkenyl, C1-C6 optionally substituted alkyl, or H. 107. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 100106, wherein R100 is H or -C (=O)NR300R400. 108. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein R1100 is H or halo. 109. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 108, wherein Ra00, Rb00, Rc00, Rd00 and Ri00 are C. 110. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 108 or 109, wherein Z100 is O, Z200 is C, Z300 is a bond. 111. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 108110, wherein R1300 is a bond or C. 112. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 108 -111, wherein y = 1. 113. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 108 -112, wherein R900 is H. 114. The compound, or a pharmaceutically acceptable salt acceptable thereof, according to any one of embodiments 108113, wherein R600 is H, optionally substituted C1-C6 alkyl or optionally substituted C2-C6 alkenyl. 115. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 108114, wherein R200 is H. 116. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 108115, where R100 is H, -C(=O)NR300R400 or cyan. 117. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 108, wherein y=0, R1300 is a bond, and R900 is H. 118. The compound, or a pharmaceutically acceptable salt thereof, according to with embodiment 108, which has Formula 00X: where: R100, R200. R600. and R900 are as defined above; Z100 is O, Z200 is C, Z300 is a bond; Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C; R200 is H; R1100 is halo; R1300 is O; y=0-72; and R900 is C1-C6 alkyl. 119. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 118, wherein R600 is H, optionally substituted C1-C6 alkyl or optionally substituted C2-C6 alkenyl. 120. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 118 or 119, wherein Rio is H, cyano or -C(=O)NR3ooR4oo. 121. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein Z100 is O, Z200 and Z300 is C. 122. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 121, wherein Ri00 is C. 123. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 121 or 122, wherein R200 and/or R1100 are H. 124. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 121123, wherein R600 is H. 125. The compound, or a pharmaceutically acceptable salt thereof, of according to any one of embodiments 121124, wherein R100 is H, halo, cyano, -C(=O)OR3 or -C(=O)NR300R400. 126. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 121125, wherein: R1300 is O; R900 is H or -OR3; ey is 0-72. 127. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein: Z100 is S or O; Z300 is missing; Z200 is C; R200 and/or R1100 are H; Ri00 is C; R1300 is O; R900 is H or -OR3; ey=0-72. 128. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 127, wherein Ra00, Rb00, Rc00, Rd00, Rh00 and Ri00 are C. 129. The compound, or a pharmaceutically acceptable salt thereof, of according to embodiment 127 or 128, wherein R600 is H or -C(=O)OR3. 130. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 127129, wherein R100 is H or -C(=O)NR300R400. 131. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein: Ri00 is N; R200 and/or R1100 are H; Z300 is a bond or C; Z100 is N or O; and C or C(=O). The compound, or a pharmaceutically acceptable salt according to embodiment 131, wherein Ra00, Rd00, Rh00 are C. The compound, or a pharmaceutically acceptable salt according to embodiment 131 or 132, wherein the compound, or a pharmaceutically acceptable salt pharmaceutically acceptable according to any one of embodiments 131133, wherein R900 is H and y=0-72. 135. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 131134, wherein R100 is halo, H, cyano, -C(=O)NR300R400, or -OR3. 136. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 131135, wherein R600 is H, optionally substituted C1-C6 alkyl or -(CH2)p-aryl, wherein p is an integer from 0-2. 137. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 131136, wherein Z200 is C(=O), Z100 is N, and Z300 is C. 138. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 38, wherein: Z200 is C(=O) or C; Z100 is N or O; and Z300 is C or absent. The compound, or a pharmaceutically acceptable salt according to embodiment 138, wherein Ra00, Rd00 and Rh00 are C. The compound, or a pharmaceutically acceptable salt according to any one of embodiment 138139, wherein R200 is H. 141. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 138140, wherein R100 is H, halo, cyano or -C(=O)NR3ooR4oo. 142. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 138141, wherein R1100 is H. 143. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 138142, where: R1300 is O; and R900 is H or -OR3. 144. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 138143, wherein R600 is H, C1-C6 alkyl or -(CH2)pR500. 145. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 138144, wherein: Z100 is O; Z300 is missing; and Z200 is C. 146. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 138145, which has Formula I00B. 147. The compound, or a pharmaceutically acceptable salt thereof, of Formula I00C according to embodiment 38, wherein Z100 is C or O and R1400 is an optionally substituted pyridinone or -CH2-pyridinone. 148. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 147, wherein R600 is H. 149. The compound, or a pharmaceutically acceptable salt thereof, according to embodiment 147 or 148, wherein R100 and Rh00 are C. 150. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 147149, wherein R1300 is O. 151. The compound, or a pharmaceutically acceptable salt thereof, according to any of embodiments 147150, wherein y is an integer from 1-4. 152. The compound according to embodiment 38, wherein the compound is chosen from a compound of Figure 1. 153. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of of embodiments 38-152. 154. A method of treating pain, neuropathic pain, migraine, headache, depression, Parkinson's disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreased nociceptive sensitization, pain in an exposed individual to opioids, PTSD or other condition or disorder described herein in a mammal comprising administering to the mammal one or more compounds or a salt thereof according to any one of embodiments 38-152 or a pharmaceutical composition comprising one or more compounds or a salt thereof according to any one of embodiments 38-152. 155. The method according to embodiment 154, wherein the mammal is a mammal in need thereof. 156. A method of treating hyperalgesia in an individual comprising administering to the mammal one or more compounds or a salt thereof according to any one of embodiments 38-152 or a pharmaceutical composition comprising one or more compounds or a salt thereof according to any of embodiments 38-152. 157. The method according to embodiment 156, wherein the hyperalgesia is opioid-induced hyperalgesia. 158. The method according to embodiment 157, wherein the opioid-induced hyperalgesia is hyperalgesia induced by morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone and/or heroin . 159. The method of embodiment 156, wherein the subject has received an opioid prior to receiving one or more compounds, or a salt thereof, of the pharmaceutical composition comprising one or more compounds or a salt thereof. 160. A method of decreasing nociceptive sensitization in an individual comprising administering to the individual one or more compounds or a salt thereof according to any one of embodiments 38-152 or a pharmaceutical composition comprising one or more compounds or a salt thereof according to any one of embodiments 38-152. 161. The method, according to embodiment 160, wherein the subject has opioid-induced nociceptive sensitization. 162. The method according to embodiment 161, wherein the opioid-induced nociceptive sensitization is nociceptive sensitization induced by morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone and/or or heroin or pharmaceutically acceptable salts thereof. 163. A method of treating pain in an individual comprising: administering an opioid agonist to the individual until the opioid increases nociceptive sensitization in the individual; and administering to the individual one or more compounds or a salt thereof according to any one of embodiments 38-152 or a pharmaceutical composition comprising one or more compounds or a salt thereof according to any one of embodiments 38-152 . 164. The method of embodiment 163, wherein the opioid agonist is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone and/or heroin or pharmaceutically acceptable salts thereof. same. 165. A method of treating pain in an individual exposed to opioids comprising: a) administering an opioid agonist to the individual; b) administering to the subject of step a), in the absence of the opioid administered in step a), one or more compounds or a salt thereof according to any one of embodiments 38-152 or a pharmaceutical composition comprising one or more compounds or a salt thereof according to any one of embodiments 38-152. 166. The method according to embodiment 165, wherein the opioid is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone and/or heroin or pharmaceutically acceptable salts thereof . 167. A method of treating medication overuse headache in an individual comprising administering to the individual one or more compounds or a salt thereof according to any one of embodiments 38152 or a pharmaceutical composition comprising one or more further compounds or a salt thereof according to any one of embodiments 38-152. 168. The method according to embodiment 167, wherein the medication overuse headache is caused by acetaminophen, aspirin, a mu-opioid agonist, a non-steroidal anti-inflammatory drug (NSAID), or a triptan. 169. The method of embodiment 168, wherein the triptan is sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, avitriptan or donitriptan or a pharmaceutically acceptable salt thereof. 170. The method of embodiment 168, wherein the mu-opioid agonist is morphine, oxycodone, hydrocodone, hydromorphone, fentanyl, meperidine, alfentanil, remifentanil, sufentanil, etorphine, buprenorphine, methadone or heroin or a pharmaceutically acceptable salt of the same. 171. A method of treating a migraine in an individual, the method comprising: administering a triptan to an individual; and administering to the individual one or more compounds or a salt thereof according to any one of embodiments 38-152 or a pharmaceutical composition comprising one or more compounds or a salt thereof according to any one of embodiments 38-152 . 172. The method according to embodiment 171, wherein one or more compounds or a salt thereof according to any one of embodiments 38-152 or the pharmaceutical composition comprising one or more compounds or a salt thereof according to with either embodiment 38152 is administered in the absence of the triptan. 173. The method of embodiment 171, wherein the triptan is sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, avitriptan or donitriptan or a pharmaceutically acceptable salt thereof. 174. The method according to embodiment 171, wherein the subject develops a medication overuse headache before receiving one or more compounds or a salt thereof according to any one of embodiments 38-152 or the composition pharmaceutical comprising one or more compounds or a salt thereof according to any one of embodiments 38-152. 175. The method according to any one of embodiments 154-174, wherein the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: B1049, B0704, B0707, B0720, B0876, B1079, B1145, B1194, B1205, B1211, B1365, B1401 or the pharmaceutical composition comprises a compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of: B1049, B0704, B0707, B0720, B0876, B1079, B1145 , B1194, B1205, B1211, B1365, B1401.

[0267] So that the embodiments described here can be better understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting embodiments in any way. Throughout these examples, there may be molecular cloning reactions and other standard recombinant DNA techniques described and these were performed in accordance with the methods described in Maniatis et al., Molecular Cloning - A Laboratory Manual, 2nd ed., Cold Spring Harbor Press (1989), using commercially available reagents unless otherwise indicated. EXAMPLES Example 1 General Procedures A1: Preparation of 3,4-Piperidine NH Analogs Scheme 1 Scheme 2 Preparation of (+)-6-{[trans-4-(4-Methoxyphenyl)piperidin -3-yl]methoxy}isoindolin-1-one [(+)B0515] and (-)-6-{[trans-4 - (4-Methoxyphenyl)piperidin-3-yl]methoxy}isoindolin-1-one [(- )B0523] (Scheme 1) 4-(Trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1,3 (2H)- 1-tert-Butyl 3-Ethyl dicarboxylate (2)

[0268] Trifluoromethanesulfonic anhydride (33.3 mL, 203 mmol) was added little by little to a mixture of commercially available (+/-)-1-tert-butyl 3-ethyl 4-oxopiperidine-1,3-dicarboxylate [( +/-) 1, 50.0 g, 184 mmol] and N,N-diisopropylethylamine (48.3 mL, 277 mmol) in anhydrous toluene (922 mL) at 0°C under nitrogen, at a rate at which kept the internal reaction temperature below 40°C. The mixture was stirred at 0°C for 2 h, after which it was warmed to room temperature and the solids were removed by filtration. The solvents in the filtrate were removed under reduced pressure to give crude 2 as a brown oil which was used in the next step without purification (74 g, 99%). The 1H NMR spectral data were consistent with the literature (III. I. Elitzin, et al. Org. Process Res. Dev. 2010, 14, 912-917). 1-tert-Butyl 3-Ethyl 4-Phenyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate (3)

[0269] Tetrakis(triphenylphosphine)palladium (4.2 g, 3.7 mmol) was added to a degassed mixture of 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate de1- crude tert-butyl 3-ethyl (2.74 g, 184 mmol), 4-methoxyphenylboronic acid (36.0 g, 239 mmol) and potassium phosphate (48 g, 276 mmol) in anhydrous THF (915 mL) at temperature room under nitrogen, after which the mixture was heated to 70 ° C and stirred for 12 h. The cold mixture was diluted with ethyl acetate (200 mL) and the solids were removed by filtration through a Celite pad. The solvents in the filtrate were removed under reduced pressure to half the volume (about 600 mL) and then washed with water (200 mL) and brine (200 mL). The solvents were removed under reduced pressure and the crude product was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (9:1), to give 3 as a yellow solid which was suitable for use. without further purification (63 g, 95%): LCMS (M+H) 362. (+/- )-cis-1-tert-Butyl 3-Ethyl 4-(4-Methoxyphenyl)piperidine-1,3-dicarboxylate [(+/-) 4]

[0270] A mixture of 1-tert-butyl 3-ethyl 4-phenyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate (3, 60.0 g, 166 mmol) and palladium on carbon 10% (50% wet, 6.0 g) in anhydrous ethanol (60 mL) at room temperature under nitrogen was exchanged with a hydrogen atmosphere (flask), after which the mixture was stirred for 48 h. The atmosphere was exchanged for nitrogen, the mixture was diluted with methylene chloride (150 mL) and the solids were removed by filtration under reduced pressure through a Celite plug, eluting with methylene chloride (150 mL). The organic extract solvents were removed under reduced pressure to provide (+/-) 4 as a grayish solid (56.6 g, 94%): LCMS (M+H) 364. 4-(4-Methoxyphenyl)piperidine-1, (+/- )-trans-1-tert-Butyl 3-Ethyl 3-dicarboxylate [(+/-) 5]

[0271] Sodium ethoxide (36 mL, 21 wt% solution in ethanol) was added to a solution of (+/-)-cis-1-4-(4-methoxyphenyl)piperidine-1,3-dicarboxylate tert-butyl 3-ethyl [(+/-) 4, 10.0 g, 27.5 mmol] in anhydrous ethanol (150 mL) at room temperature under nitrogen, after which the mixture was heated to 50°C and stirred for 12 hours. The cold mixture was treated with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with a brine solution (100 mL), dried over sodium sulfate and filtered. The solvents were removed under reduced pressure to provide (+/-) 5 as a yellow oil that was suitable for use without further purification (9.8 g, 98%): LCMS (M+H) 364. 3-(Hydroxymethyl) (+/-)-trans-tert-Butyl-4-(4-methoxyphenyl)-piperidine-1-carboxylate [(+/-) 6]

[0272] Lithium aluminum hydride (41.2 mL, 41.2 mmol, 1 M in tetrahydrofuran) was added dropwise to a solution of 4-(4-methoxyphenyl)piperidine-1,3-dicarboxylate. (+/-)-trans-1-tert-butyl 3-ethyl [(+/-) 5, 11.2 g, 27.5 mmol] in anhydrous tetrahydrofuran (225 mL) at - 20°C under nitrogen , after which the mixture was heated to 0°C. The mixture was stirred for 4 h and then slowly warmed to room temperature with stirring for a total of 12 h. The mixture was cooled to 0°C and slowly treated with water (2 mL) and then 1N sodium hydroxide solution (2 mL) and stirred for a further 1 h. The solids were removed by filtration under reduced pressure and the solvents in the filtrate were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (2:3), to give (+/-) 6 as a colorless oil (3.8 g, 58%) : LCMS (M+H) 322. (+/-)-trans-tert-Butyl 4-(4-Methoxyphenyl)-3-{[(methylsulfonyl)oxy]-methyl} piperidine-1-carboxylate [(+/ -) 7]

[0273] Methanesulfonyl chloride (1.4 mL, 18.1 mmol) was added dropwise to a solution of (+/-) 3-(hydroxymethyl)-4-(4-methoxyphenyl)piperidine-1-carboxylate -trans-tert-butyl [(+/-) 6, 4.40 g, 13.7 mmol] and triethylamine (2.3 mL, 16.5 mmol) in anhydrous methylene chloride (150 mL) at 0°C under nitrogen, after which the mixture was slowly warmed to room temperature with stirring for a total of 5 h. The mixture was treated with brine solution (100 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were washed with a brine solution (100 mL), dried over sodium sulfate and filtered. The solvents were removed under reduced pressure to provide (+/-)7 as a yellow oil that was suitable for use without further purification (5.08 g, 88%). 4-(4-Methoxyphenyl)-3-{[(3-oxoisoindolin-5-yl)oxy]methyl} (+/-)-trans-tert-Butyl piperidine-1-carboxylate [(+/-) 8]

[0274] Potassium carbonate (727 mg, 5.3 mmol) [Note: An equivalent amount of sodium hydride can also be used alternately] was added to a solution of 6-hydroxy-isoindolin-1-one (523 mg, 3.5 mmol) and (+/-)-trans-tert-butyl 4-(4-methoxyphenyl)-3-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate [(+/-) 7, 600 mg, 1.8 mmol] in anhydrous N,N-dimethylformamide (30 mL) at room temperature under nitrogen, after which the mixture was heated to 80 ° C and stirred for 18 h. The cold mixture was diluted with ethyl acetate (200 ml) and the solids were removed by filtration under reduced pressure. The solvents in the filtrate were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with methylene chloride/methanol (9:1), to give (+/-)8 as a solid white (240 mg, 35%): LCMS (M+H) 453. (+/-)-6-{[trans-4-(4-Methoxyphenyl)piperidin-3-yl]methoxy}isoindolin-1- hydrochloride one [(+/-) B0356]

[0275] Trifluoroacetic acid (0.70 mL, 10 mmol) was added dropwise to a solution of 4-(4-methoxyphenyl)- 3-{[(3-oxoisoindolin-5-yl)oxy]methyl}piperidine- 1- (+/-)-trans-tert-butyl carboxylate [(+/-) 8.432 mg, 1.0 mmol] in anhydrous methylene chloride (30 mL) at 0°C under nitrogen, after which the mixture was slowly warmed to room temperature with stirring for a total of 5 h. The solvents were removed under reduced pressure and the residue was dissolved in methanol for purification by reverse phase preparative HPLC, eluting with 0.05% TFA in acetonitrile/water (gradient from 2% to 60%, Fenomenex column Luna). The isolated residue was acidified with HCl (2 mL, 2M in diethyl ether), diluted with acetonitrile/water and lyophilized to provide (+/-) B0356 as a white solid (91 mg, 24%): LCMS (M+H) 353; 1H NMR (500 MHz, CD3OD) δ 7.43 (dd, J = 8.5, 0.5 Hz, 1H), 7.18 (d, J = 11.5 Hz, 2H), 7.12-7 .09 (m, 2H), 6.88 (d, J = 8.5 Hz, 2H), 4.36 (s, 2H), 3.82 (dd, J = 10.0, 3.0 Hz, 1H), 3.75 (s, 3H), 3.72-3.69 (m, 2H), 3.56-3.49 (m, 1H), 3.21-3.15 (m, 2H) , 2.96-2.90 (m, 1H), 2.46-2.40 (m, 1H), 2.08-2.00 (m, 2H). Separation of [(+/-) B0356] into (+)-6-{[trans-4-(4- Methoxyphenyl)piperidin-3-yl]methoxy}isoindolin-1-one [(+)B0515] and (- )-6-{[trans-4-(4-Methoxyphenyl)piperidin-3- yl]methoxy}isoindolin-1-one [(-)B0523]

[0276] A solution of (+/-)-6-{[trans-4-(4-Methoxyphenyl)piperidin-3-yl]methoxy}isoindolin-1-one [(+/-) B0356, 48 mg] in methanol was separated using chiral preparative HPLC (10 μM CHIRALPAK AD, 2 cm x 25 cm, flow rate 5 mL/min, 3 mg/injection), eluting with 0.1% diethylamine in methanol, to give ( +) B0515 as a white solid (12 mg, 25%), followed by (-)B0523, (11 mg, 23%) as a white solid. Alternative preparation of 4-(4-Methoxyphenyl)-3-{[ (3-oxoisoindolin-5-yl)oxy]methyl}piperidine-1-carboxylate of (+/-)-trans-tert-Butyl [(+/-) 8] (Scheme 2)

[0277] 1,1'-(Azodicarbonyl)dipiperidine (5.9 g, 23.4 mmol) was added to a solution of 3-(hydroxymethyl)-4-(4-methoxyphenyl)piperidine-1-carboxylate (+ /-)-trans-tert-butyl [(+/-) 6, 3.75 g, 11.7 mmol], 6-hydroxy-isoindolin- 1-one (1.74 g, 11.7 mmol) and tributylphosphine (4.73 g, 23.4 mmol) in anhydrous tetrahydrofuran (100 mL) at 0 ° C under nitrogen, after which the mixture was slowly warmed to room temperature with stirring for a total of 12 h. The mixture was cooled to 0°C and the solids were removed by filtration under reduced pressure. The solvents in the filtrate were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with methylene chloride/methanol (9:1), to give [(+/-) 8] as a white solid (3.01 g, 57%). General Procedure A2: Alternative preparation of 3,4-Piperidine NH analogues Scheme 3 Preparation of (+/-)-6-{[trans-4-(4-Bromophenyl)piperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one [(+/- ) B0614] (+/-)-trans-Ethyl 4-(4-Bromophenyl)-2,6-dioxopiperidine-3-carboxylate [(+/-) 10]

[0278] A solution of ethyl 3-amino-3-oxopropanoate (13.1 g, 100 mmol) in anhydrous DMF (100 mL) was added to a suspension of sodium hydride (6.0 g, 150 mmol, 60 % in mineral oil) in anhydrous DMF (200 mL) at 0°C under nitrogen. The mixture was stirred at 0°C for 30 min, after which commercially available (E)-methyl 3-(4-bromophenyl)acrylate (9, 24.0 g, 100 mmol) was added gradually and the mixture was slowly warmed to room temperature with stirring for a total of 2 h. The mixture was further heated to 60°C and stirred for 5 h, after which the mixture was cooled to room temperature and treated with saturated aqueous ammonium chloride solution (50 mL) and then 2N HCl (200 mL). The mixture was extracted with ethyl acetate (3 x 200 mL) and the combined organic extracts were dried over sodium sulfate and filtered. The solvents were removed under reduced pressure to give (+/-) 10 as a grayish semi-solid which was used in the next step without purification (26.2 g): LCMS (M-H) 338. (+/-)-[trans-4 -(4-Bromophenyl)piperidin-3-yl]methanol [(+/-) 11]

[0279] Borane (269 mL, 269 mmol, 1.0 M solution in THF) was slowly added to a solution of (+/-) 4-(4-bromophenyl)-2,6-dioxopiperidine-3-carboxylate - crude (3S,4R)-ethyl [(+/-) 10, 26.2 g, 67.2 mmol] in anhydrous THF (400 mL) at room temperature under nitrogen, after which the mixture was heated to 60° C and stirred for 16 h. The cold mixture was treated with anhydrous methanol (30 mL), followed by 2 N HCl (250 mL), after which the organic layer was collected. The solvent was removed under reduced pressure to (+/-)11 as a white solid which was used in the next step without purification (25.6 g): LCMS (M+H) 270. 4-(4-Bromophenyl)-3 (+/-)-trans-tert-Butyl-(hydroxymethyl)-piperidine-1-carboxylate [(+/-) 12]

[0280] Triethylamine (47 mL, 335 mmol) was added to a solution of (+/-)-[trans-4-(4-bromophenyl)piperidin-3-yl] crude methanol [(+/-) 11.25 .6 g, 83.8 mmol] in anhydrous THF (200 mL) at room temperature under nitrogen, after which the mixture was cooled to 0 ° C. A solution of di-tert-butyl dicarbonate (18.3 g, 83.8 mmol) in anhydrous THF (100 mL) was slowly added, after which the mixture was stirred at 0°C for 4 h. The mixture was warmed to room temperature, washed with water (300 mL) and the organic layer was collected. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (2:3), to give (+/-) 12 as a white solid ( 15.8 g, 50% over three steps): LCMS (M+H) 370. 4-(4-Bromophenyl)-3-{[(3-oxoisoindolin-5-yl)oxy]methyl} piperidine-1 -(+/-)-trans-tert-Butyl carboxylate [(+/-) 13]

[0281] Prepared according to General Procedure A1 to provide (+/-) 13 as a grayish semisolid that was used in the next step without further purification (700 mg):LCMS (M+H) 501, (+/-) -6-{[trans-4-(4-Bromophenyl)piperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one [(+/-) B0614]

[0282] Prepared according to General Procedure A1 to provide (+/-) B0614 as a white solid (87 mg, 54% over two steps): LCMS (M+H) 401; 1H NMR (500 MHz, CD3OD) δ 7.49 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8 .5 Hz, 2H), 7.14 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 8.5, 2.5 Hz, 1H), 4.37 (s, 2H ), 3.83 (dd, J = 9.5, 3.0 Hz, 1H), 3.74-3.70 (m, 2H), 3.54 (m, 1H), 3.233.16 (m, 2H), 3.02 (dt, J = 12.0, 4.0 Hz, 1H), 2.46 (m, 1H), 2.11-2.00 (m, 2H). General Procedure A3: Preparation of N-Alkyl Analogs Scheme 4 Preparation of (-)-6-{[(trans,trans)-4-(4-methoxyphenyl)-2-methyl-1-(2-phenylethyl)piperidin-3-yl]methoxy}-2,3-di- hydro-1H- isoindole-1-one [(-)B0707]

[0283] A solution of (-)-6-{[(trans, trans)-4-(4-methoxyphenyl)-2-methylpiperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindole -1-one [(-)B0699, 2.6 g, 7.09 mmol] and sodium triacetoxyborohydride (4.5 g, 21.3 mmol) in DCE (80 mL) were allowed to stir at rt for 30 min. To this was added phenylacetaldehyde (1.3 mL, 10.6 mmol). After stirring for three days, LCMS indicated no remaining initiation material. The reaction was quenched with the addition of methanol (~10 mL) and concentrated. The crude product was purified using reversed-phase chromatography (Fenomenex Luna 5μ column, C18, 10% MeCN - 50%/water/0.1% TFA. The product-containing fractions were combined and concentrated. The concentrate was treated with sat. NaHCO3 solution to basic and extracted with DCM (X3). The combined extracts were passed through a hydrophobic frit and concentrated to provide 2.6 g (71%) of [(-)B0707]. The hydrochloride salt can be formed by dissolving the free base in MeCN/water, adding 1.05 eq of 1N HCl and lyophilizing to provide a white powder. LCMS (M+H) 471.2; HCl Salt 1H NMR (400 MHz , MeOD) δ 7.52 — 7.37 (m, 5H), 7.37 — 7.25 (m, 1H), 7.23 - 7.10 (m, 4H), 6.86 (dd, 2H ), 4.39 (s, 2H), 4.10 (d, 1H), 3.99 — 3.42 (m, 9H), 3.29 - 3.02 (m, 3H), 2.45 - 1.97 (m, 3H), 1.68 - 1.44 (m, 3H) Scheme 5a Preparation of (-)-6-{[(trans, trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methyl-1-[2-(1H-pyrrol-1-yl)ethyl]piperidin -3-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one [(-)B1049]

[0284] To a solution of (-)-6-{[(trans, trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methylpiperidin-3-yl]methoxy}-2,3-di - hydro-1H-isoindol-1-one [(-)B1415, 5.10 g, 12.42 mmol] in anhydrous acetonitrile (25 mL) was added potassium carbonate (3.43 g, 24.85 mmol, 2 .0 eq.) and 1-pyrrolthyl bromide (4.32 g, 24.85 mmol, 2.0 eq.) and the reaction heated to 50 ° C for 168 hr. The reaction was cooled to room temperature, the inorganics filtered off and concentrated. The crude product was purified using reversed-phase chromatography (Fenomenex Luna 5μ column, C18, 30% - 50% MeCN/water/0.1% TFA. The product fractions were concentrated and the residue dissolved in 25 mL of DCM and washed with 1N NaOH (ensuring a basic aqueous layer through pH paper). The layers were separated and the aqueous layer extracted 3X 10 mL of DCM. The combined organics were washed with brine, filtered through cotton wool and concentrated to provide 6.4 g (84%) of [(- )B1049] as a white solid. The hydrochloride salt can be formed by dissolving the free base in MeCN/water, adding 1.05 eq. HCl to 1 N and lyophilizing to give a white powder. LCMS (M+H) 504.3; HCl Salt 1H NMR (400 MHz, DMSO) δ 11.15 - 10.65 (m, 1H), 8.55 (s, 1H), 7.48 - 7.42 (m, 1H), 7.25 - 7.08 (m, 2H), 7.07 - 6.96 (m, 3H), 6.95 - 6.67 ( m, 3H), 6.10 - 6.05 (m, 2H), 4.55 - 4.31 (m, 2H), 4.27 (s, 2H), 4.09 (d, J = 8, 7, 1H), 4.03 - 3.82 (m, 3H), 3.76 - 3.62 (m, 1H), 3.61 - 3.48 (m, 5H), 3.27 - 3, 23 (m, 3H), 3.22 - 2.96 (m, 2H), 2.46 - 2.12 (m, 2H), 1.95 - 1.71 (m, 1H), 1.48 - 1.37 (m, 3H). Scheme 5b Preparation of (-)-6-{[(trans,methoxyethoxy)phenyl]-2-methyl-1-[2-(3-methyl-1H-pyrrol-1-yl)ethyl]piperidin-3-yl]methoxy} Ethyl -2,3-dihydro-1H-isoindol-1-one [(-)14] 1-(2-bromoethyl)-3-methyl-1H-pyrrole-2-carboxylate (14)

[0285] To a mixture of potassium hydroxide (431 mg, 7.84 mmol) and 1,2-dibromoethane (2453 mg, 13.06 mmol) in 5 mL of acetonitrile, a solution of 3-methyl-1-H Ethyl-pyrrole carboxylate (727 mg, 5.22 mmol) in 20 mL of acetonitrile was slowly added over 2 h. After 1h, the reaction mixture was quenched with water and extracted with hexanes (3X10 mL). The organics were combined, concentrated and subjected to Biotage purification under flash chromatography (45 g silica gel column, eluted with EtOAc in hexane: 2% - 20%, 10 CV; 100% EtOAc, 10 CV) to provide 316 14 mg in a 23% yield. LCMS (M+H = 262.0). Ethyl 1-(2-bromoethyl)-5-methyl-1H-pyrrole-2-carboxylate was also made via the above procedure in a 7% yield. LCMS (M+H = 262.2). 1-{2 - [(trans, trans) -4- [3- (2-methoxyethoxy)phenyl] -2-methyl-3- {[(3-oxo-2,3-dihydro-1H-isoindole- (-)-Ethyl 5-yl)oxy]methyl}piperidin-1-yl]ethyl}-3-methyl-1H-pyrrole-2-carboxylate [ (- )B1374]

[0286] The title compound was prepared from ethyl 1-(2-bromoethyl)-3-methyl-1H-pyrrole-2-carboxylate (14) according to Scheme 5. LCMS (M+H = 590 ,two). (-)-6-{[(trans,trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methyl-1-[2-(3-methyl-1H-pyrrol-1-yl)ethyl ]piperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one [(-)B1396]

[0287] To a suspension of 1-{2-[(trans, trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methyl-3-{[(3-oxo-2,3-di (-)-ethyl-hydro-1H-isoindol-5-yl)oxy]methyl}piperidin-1-yl]ethyl}-3-methyl-1H-pyrrole-2-carboxylate [(-) B1374, 94 mg, 0.13 mmol) in MeOH (6.69 mL) 50% NaOH (aq) (1.5 mL) was added and the reaction heated at 50°C for 30 minutes. The reaction was cooled to room temperature, acidified to a pH of 2, then heated at 50°C for 4 hours. The reaction mixture was filtered and subjected to HPLC purification. HPLC purification method: Luna Acid Medium column, 5% - 55% acetonitrile in H2O over 15 min, followed by 100% acetonitrile modifier, 0.1% TFA used. Lyophilization of the combined fractions provided 26.93 mg of (-)B1396 as a light pink solid. LCMS (M+H = 518.2); 1H NMR (400 MHz, CD3CN) δ 7.43 (d, J = 8.3, 1H), 7.20 (t, J = 7.8, 1H), 7.11 (dd, J = 8.3 , 2.4, 1H), 7.06 (s, 1H), 6.77 (dd, J = 16.2, 8.1, 5H), 6.62 (s, 1H), 5, 99 — 5 , 93 (m, 1H), 4.43 - 4.33 (m, 2H), 4.30 (s, 2H), 4.06 (d, J = 9.9, 1H), 4.02 - 3 , 80 (m, 3H), 3.70 - 3.39 (m, 7H), 3.31 (s, 3H), 3.10 (dd, J = 20.2, 10.9, 2H), 2 .37 (d, J = 11.2, 2H), 2.06 (s, 3H), 1.45 (dd, J = 28.0, 6.1, 3H).

[0288] The following compounds were prepared using General Procedures A1 and A3: (-)-6-{[trans, trans-4-(1-benzofuran-6-yl)-2-methyl-1- [2 -(1H-pyrrol-1-yl)ethyl]piperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one [(-)B1400] LCMS (MH+ = 471.2) ; 1H NMR (400 MHz, DMSO) δ 9.88 - 9.68 (m, 1H), 8.56 (s, 1H), 7.57 - 7.32 (m, 1H), 7.27 - 7, 46 (m, 1H), 7.14 - 7.08 (m, 1H), 7.05 - 7.01 (m, 1H), 7.00 - 6.95 (m, 2H), 6.94 - 6.46 (m, 3H), 6.12 — 6.06 (m, 2H), 5.16 - 5.01 (m, 1H), 4.88 - 4.80 (m, 1H), 4, 80 - 4.69 (m, 1H), 4.66 - 4.31 (m, 5H), 4.28 (s, 2H), 4.13 - 3.14 (m, 8H), 3.10 - 2.97 (m, 1H), 2.28 - 1.70 (m, 4H), 1.45 - 1.30 (m, 3H). (+/-)-6-{[(trans, trans)-4-(1-acetylpiperidin-4-yl)-2-methyl-1-(2-phenylethyl)piperidin-3-yl]methoxy}-2, 3-dihydro-1H-isoindol-1-one [(+/-) B1413] LCMS (MH+ = 490.2); 1H NMR (400MHz ,CD3OD): 7.53 (d, J = 8.4Hz, 1H), 7.27-7.38 (m, 7H), 4.61 (t, J = 13.2Hz, 1H) , 4.42 (s, 2H), 4.27-4.38 (m, 2H), 3.97 (t, J = 12.4Hz, 1H), 3.80 (m, 1H), 3.61 (m, 1H), 3.58 (m, 1H), 3.30 (m, 1H), 3.20 (m, 1H), 3.10 (m, 2H), 2.56 (m, 1H) , 1.90-2.20 (m, 7H), 1.70 (m, 2H), 1.56 (d, J = 6.0Hz, 3H), 1.40-1.50 (m, 2H) , 1.20-1.40 (m, 1H). (+/-)-6-{[(trans, trans)-4-(1-acetylpiperidin-4-yl)-2-methyl-1-[2-(1H-pyrrol-1-yl)ethyl]piperidin- 3-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one [(+/-) B1413] LCMS (MH+ = 490.2); 1H NMR (400MHz ,CD3OD): 7.53 (d, J = 8.0Hz, 1H), 7.37(s, 1H), 7.27 (d, J = 7.6Hz, 1H), 6.88 (s, 2H), 6.17 (s, 2H), 4.60 (t, J = 12.0Hz, 1H), 4.30-4.50 (m, 5H), 4.10-4.30 (m, 1H), 3.96 (t, J = 14.0Hz, 1H), 3.77 (m, 1H), 3.65 (m, 1H), 3.51 (m, 2H), 3, 07 (m, 2H), 2.54 (m, 1H), 1.88-2.15 (m, 7H), 1.60-1.85 (m, 2H), 1.35-1.55 ( m, 5H), 1.10-1.35 (m, 1H). (-)-6-{[trans, trans-4-(3-hydroxyphenyl)-2-methyl-1-[2-(1H-pyrrol-1-yl)ethyl]piperidin-3-yl]methoxy}-2 ,3-dihydro-1H-isoindol-1-one [(-)B1416] LCMS (MH+ = 446.2); 1H NMR (400 MHz, DMSO) δ 9.53 (s, 1H), 9.35 — 9.20 (m, 1H), 8.46 (s, 1H), 7.46 — 7.28 (m, 1H), 7.05 — 6.86 (m, 5H), 6.68 — 6.45 (m, 3H), 6.01 (s, 2H), 4.40 — 4.23 (m, 2H) , 4.20 (s, 2H), 3.98 (d, J = 10.0, 1H), 3.89 — 3.12 (m, 15H), 2.95 — 2.81 (m, 1H) , 2.15 — 1.65 (m, 4H), 1.34 — 1.24 (m, 3H). (-)-6-{[trans, trans-4-[3-(2-hydroxyethoxy)phenyl]-2-methylpiperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindole-1- ona [(-)B1417] LCMS (MH+ = 397.1); 1H NMR (400 MHz, DMSO) δ 8.80 (d, J = 10.0, 1H), 8.65 — 8.46 (m, 2H), 7.44 (d, J = 8.3, 1H ), 7.21 (t, J = 7.9, 1H), 7.09 (dd, J = 8.3, 2.3, 1H), 7.02 (d, J = 2.2, 1H) , 6.79 (dd, J = 8.1, 2.0, 1H), 6.73 (d, J = 7.6, 1H), 6.69 (s, 1H), 4.27 (s, 2H), 4.02 (d, J = 8.7, 1H), 3.93 - 3.86 (m, 1H), 3.82 - 3.74 (m, 1H), 3.64 (t, J = 4.9, 2H), 3.51 (dd, J = 10.2, 2.3, 1H), 3.48 - 3.35 (m, 2H), 3.14 (d, J = 9 .1, 1H), 3.07 - 2.98 (m, 1H), 2.11 (t, J = 11.1, 1H), 2.04 - 1.86 (m, 2H), 1.35 (d, J = 6.4, 3H). (-)-6-{[trans, trans-4-(3,4-dihydro-2H-1-benzopyran-7-yl)-2-methyl-1-[2-(1H-pyrrole-1- yl)ethyl]piperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one [(-)-B1365] LCMS (MH+ = 486.2); 1H NMR (400 MHz, DMSO) δ 10.93 - 10.45 (m, 1H), 8.56 (s, 1H), 7.50 — 7.40 (m, 1H), 7.17 — 7, 07 (m, 1H), 7.05 - 7.01 (m, 1H), 7.00 - 6.88 (m, 3H), 6.78 - 6.49 (m, 2H), 6.15 - 6.00 (m, 2H), 4.54 - 4.31 (m, 2H), 4.28 (s, 2H), 4.19 - 3.80 (m, 8H), 3.77 - 3, 61 (m, 1H), 3.60 - 3.43 (m, 4H), 3.39 - 2.85 (m, 3H), 2.67 (t, J = 6.0, 2H), 2, 41 - 2.04 (m, 3H), 1.96 - 1.66 (m, 4H), 1.46 - 1.33 (m, 3H). (-)-6-{[trans,trans-4-(4-methoxyphenyl)-2-methyl-1-[2-(1H-pyrrol-1-yl)ethyl]piperidin-3-yl]methoxy}-2 ,3-dihydro-1H-isoindol-1-one [(-)B0876] LCMS (MH+ = 460.3); 1H NMR (400 MHz, MeOD) δ 7.36 (d, J = 9.1, 1H), 7.17 - 6.92 (m, 4H), 6.81 (t, J = 2.1, 2H ), 6.74 (d, J = 8.8, 2H), 6.08 (t, J = 2.1, 2H), 4.47 - 4.13 (m, 4H), 4.02 - 3 .32 (m, 9H), 3.06 - 2.86 (m, 1H), 2.32 - 1.69 (m, 4H), 1.53 - 1.05 (m, 4H). (-)-6-{[trans,trans-4-[3-fluoro-4-(2-methoxyethoxy)phenyl]-2-methyl-1-[2-(1H-pyrrol-1-yl)ethyl]piperidin -3-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one [(-)B1205] LCMS (MH+ = 522.2); 1H NMR (400 MHz, MeOD) δ 7.49 (d, J = 9.1, 1H), 7.25 - 6.80 (m, 7H), 6.20 (s, 2H), 4.63 - 4.31 (m, 4H), 4.19 - 3.36 (m, 13H), 3.30 - 3.04 (m, 2H), 2.40 - 1.85 (m, 3H), 1, 67 - 1.31 (m, 3H). (-)-6-{[trans,trans-4-[3-fluoro-4-(2-methoxyethoxy)phenyl]-2-methyl-1-(2-phenylethyl)piperidin-3-yl]methoxy}-2 ,3-dihydro-1H-isoindol-1-one [(-)B1194] LCMS (MH+ = 533.2); 1H NMR (400 MHz, MeOD) δ 7.41 — 7.15 (m, 6H), 7.06 (d, J = 7.9, 2H), 7.03 - 6.79 (m, 3H), 4.28 (s, 2H), 4.02 (dd, J = 5.4, 3.7, 3H), 3.95 - 3.32 (m, 8H), 3.29 (s, 3H), 3.19 - 2.89 (m, 3H), 2.39 - 1.81 (m, 3H), 1.62 - 1.25 (m, 3H). [(+/-) -6-{[(trans, trans)-4-(3-fluoro-5-methoxyphenyl)- 2-methyl-1-[2-(1H-pyrrol-1-yl)ethyl]piperidin -3-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one [(+/-) B1274] LCMS (MH+ = 478.3); 1H NMR (300MHz ,CD3OD): 7.48 (m, 1H), 7.18 (m, 2H), 6.91 (t, J = 2.1Hz, 2H), 6.58 (m, 3H), 6.19 (t, J = 2.1Hz, 2H), 4.49 (m, 2H), 4.39 (s, 2H), 4.10 (m, 1H), 3.90 (m, 1H) , 3.65-3.80 (m, 2H), 3.61 (s, 3H), 3.55 (m, 1H), 3.40 (m, 1H), 3.20 (m, 2H), 2.00-2.40 (m, 3H), 1.20-1.28 (m, 3H). (-)-6-{[trans, trans-1-(4,4-difluorobut-3-en-1-yl)-4-(4-methoxyphenyl)-2-methylpiperidin-3-yl]methoxy}-2 ,3-dihydro-1H-isoindol-1-one [(-)B1145] LCMS (MH+ = 457.2); 1H NMR (400 MHz, DMSO) δ 10.75 - 10.40 (m, 1H), 8.53 (s, 1H), 7.45 (d, J = 8.3, 1H), 7.27 - 7.06 (m, 3H), 7.04 - 7.00 (m, 1H), 6.91 - 6.80 (m, 2H), 4.68 (dt, J = 26.6, 7.6 , 1H), 4.27 (s, 2H), 4.11 - 3.88 (m, 1H), 3.72 - 3.68 (m, 3H), 3.64 - 3.45 (m, 3H ), 3.42 - 3.12 (m, 3H), 3.06 - 2.96 (m, 1H), 2.40 - 2.08 (m, 2H), 1.97 - 1.75 (m , 1H), 1.50 - 1.35 (m, 3H). General Procedure A4: Preparation of 3,4-Piperidine NH analogues: Example of Reverse Coupling and Hydrolysis Scheme 6 Preparation of (+/-)-2-{[trans-4-(4-methoxyphenyl) piperidin-3-yl]methoxy}-isonicotinamide [(+/-) B0354] 3-{[(4-Cyanopyridin-2- (+/-)-trans-tert-Butyl yl)oxy]methyl}-4-(4-methoxyphenyl) piperidine-1-carboxylate [(+/-) 15]

[0289] A solution of (+/-)-trans-tert-butyl 3-(hydroxymethyl)-4-(4-methoxyphenyl)piperidine-1-carboxylate [(+/-) 6, 500 mg, 1.6 mmol, prepared as described in General Procedure A1, Scheme 1] in anhydrous tetrahydrofuran (2 mL) was added dropwise to a solution of sodium hydride (73 mg, 1.8 mmol, 60% dispersion in mineral oil ) in anhydrous tetrahydrofuran (8 mL) at 0°C under nitrogen, after which the mixture was stirred for 15 min. A solution of 2-chloroisonicotinonitrile (251 mg, 1.8 mmol) in anhydrous tetrahydrofuran (2 mL) was added, after which the mixture was heated to reflux and stirred for 3 h. The cold mixture was treated with water (0.5 mL), diluted with ethyl acetate (60 mL), dried over sodium sulfate and filtered. The solvents in the filtrate were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (1:1), to give (+/-) 15 as a solid white (132 mg, 52%): LCMS (M+H) 424. (+/-)-2-{[trans-4-(4-Methoxyphenyl)piperidin-3-yl] methoxy}-isonicotinonitrile [(+/ -) B0344]

[0290] Prepared according to General Procedure A2, to provide (+/-)B0344 as a grayish solid (95 mg, 92%): LCMS (M+H) 324; 1H NMR (500 MHz, CD3OD) δ 8.23 (d, J = 5.0 Hz, 1H), 7.20 (dd, J = 5.0, 1.0 Hz, 1H), 7.16 (d , J = 9.0 Hz, 2H), 7.11 (d, J = 1.0 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 4.17 (dd, J = 11.0, 3.0 Hz, 1H), 3.99 (dd, J = 11.0, 7.0 Hz, 1H), 3.76 (s, 3H), 3.66 (dd, J = 12.5, 3.0 Hz, 1H), 3.54-3.48 (m, 1H), 3.17-3.07 (m, 2H), 2.84 (dt, J = 12.0, 4.5Hz, 1H), 2.47-2.43 (m, 1H), 2.06-1.96 (m, 2H).

[0291] (+/-)-2-{[trans-4-(4-Methoxyphenyl)piperidin-3-yl]methoxy}-isonicotinamide [(+/-) B0354]

[0292] A solution of (+/-)-2-{[trans-4-(4-methoxyphenyl)piperidin-3-yl]methoxy}-isonicotinonitrile [(+/) B0344, 100 mg, 0.31 mmol] in ethanol (1 mL) was added to a mixture of hydrogen peroxide (0.2 mL, 30% solution in water) and 2N sodium hydroxide solution (0.2 mL) at 0°C, after which the mixture was stirred for 1 h. A 1M solution of monobasic potassium phosphate was added (1 mL), after which the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methylene chloride/methanol/concentrated ammonium chloride (6:3:1), to provide (+/-)B0354 as a white solid (31 mg, 29%). LCMS (MH) 340; 1H NMR (500 MHz, CD3OD) δ 8.15 (d, J = 5.0 Hz, 1H), 7.29 (dd, J = 5.0, 1.0 Hz, 1H), 7.19 (d , J = 9.0 Hz, 2H), 7.14 (d, J = 1.0 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H), 4.08 (dd, J = 11.0, 3.0 Hz, 1H), 3.90 (dd, J = 11.0, 2.5 Hz, 1H), 3.78 (s, 3H), 3.41 (dd, J = 12.5, 3.5 Hz, 1H), 3.18 (m, 1H), 2.81-2.62 (m, 3H), 2.25-2.21 (m, 1H), 1.83 -1.78 (m, 2H). General Procedure A5: Preparation of syn - 3,4-Piperidine analogues Scheme 7 Preparation of (+/-)-3-{[cis-4-(4-Methoxyphenyl) piperidin-3-yl]methoxy}-benzonitrile [(+/-) B0550] 3-(Hydroxymethyl)-4-(4- methoxyphenyl)-piperidine-1- (+/-)-cis-tert-Butyl carboxylate [(+/-) 16]

[0293] Prepared according to General Procedure A1 to provide (+/-)16 as a light yellow oil (3.56 g, 80%): LCMS (M+H) 322. 4-(4-Methoxyphenyl)- (+/-)-cis-tert-Butyl 3-{[(methylsulfonyl)oxy]-methyl}piperidine-1-carboxylate [(+/-) 17]

[0294] Prepared according to General Procedure A1 to provide (+/-)17 as a yellow oil (1.2 g, 99%).

[0295] (+/-)-cis-tert-Butyl 3-[(3-Cyanophenoxy)methyl]-4-(4-methoxyphenyl) piperidine-1-carboxylate [(+/-) 18]

[0296] A solution of 3-hydroxybenzonitrile (268 mg, 2.2 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added dropwise to a solution of sodium hydride (90 mg, 2.2 mmol, 60% dispersion in mineral oil) in anhydrous N,N-dimethylformamide (4 mL) at 0°C under nitrogen, after which the mixture was stirred for 15 min. A solution of (+/-)-cis-tert-butyl 4-(4-methoxyphenyl)-3-{[(methylsulfonyl)oxy]-methyl}piperidine-1-carboxylate [(+/-) 17, 300 mg , 0.75 mmol] in anhydrous N,N-dimethylformamide (4 ml) was added, after which the mixture was heated to 80°C and stirred for 3 h. The cold mixture was treated with water (0.5 mL), diluted with ethyl acetate (60 mL), dried over sodium sulfate and filtered. The solvents in the filtrate were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with methylene chloride/methanol (9:1), to give (+/-) 18 as an oil light yellow (116 mg, 29%): LCMS (M+H) 423. (+/-)-3-{[cis-4-(4-Methoxyphenyl)piperidin-3-yl]methoxy}-benzonitrile [(+ /-) B0550].

[0297] Prepared according to General Procedure A2 to provide (+/-)B0550 as a grayish solid (40 mg, 87%): LCMS (M+H) 323; 1H NMR (500 MHz, CD3OD) δ 7.42-7.40 (m, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.21 (d, J = 8.5 Hz , 2H), 7.14-7.13 (m, 2H), 6.92 (d, J = 8.5 Hz, 2H), 4.06 (dd, J = 9.5, 3.0 Hz, 1H), 3.81-3.78 (m, 4H), 3.71-3.67 (m, 1H), 3.573.53 (m, 1H), 3.37-3.32 (m, 2H) , 3.16 (dt, J = 13.0, 3.5 Hz, 1H), 2.58-2.54 (m, 1H), 2.35 (ddd, J = 27.0, 13.0, 4.0Hz, 1H), 2.02-1.98 (m, 1H). Preparation of 3,4-NH O-Substituted Piperidine Analogs Scheme 8 Preparation of (+/-)-6-{[trans-4-[4-(2-Fluoroethoxy)phenyl]piperidin-3-yl]methoxy}isoindolin-1-one [(+/-) B0466] (+/ -)-6-{[trans-4-(4-Hydroxyphenyl)piperidin-3-yl] methoxy}isoindolin-1-one [(+/-) 19]

[0298] Boron tribromide (1.3 mL, 13.3 mmol) was added dropwise to a solution of 4-(4-methoxyphenyl)- 3-{[(3-oxoisoindolin-5-yl)oxy]methyl (+/-)-trans-tert-butyl }-piperidine-1-carboxylate [(+/-) 8, 2.0 g, 4.4 mmol] in anhydrous methylene chloride (80 mL) at 0°C under nitrogen, after which the mixture was stirred for 2 h. The mixture was slowly diluted with 10% aqueous potassium carbonate solution (50 mL) and warmed to room temperature. The organic layer was collected and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methylene chloride/methanol (1:1), to give (+/-) 19 as a white solid (748 mg, 50%): LCMS (M+H) 339; 1H NMR (500 MHz, CD3OD) δ 7.44 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 7.10 (dd, J = 8 .5, 2.5 Hz, 1H), 7.07 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 8.5 Hz, 2H), 4.36 (s, 2H ), 3.82 (dd, J = 9.5, 3.0 Hz, 1H), 3.75-3.69 (m, 2H), 3.54-3.50 (m, 1H), 3, 20-3.13 (m, 2H), 2.88 (dt, J = 11.5, 4.5 Hz, 1H), 2.41-2.37 (m, 1H), 2.07-1, 99 (m, 2H). (+/-)-trans-tert-Butyl 4-(4-Hydroxyphenyl)-3-{[(3-oxoisoindolin-5-yl)oxy] methyl}piperidine-1-carboxylate [(+/-) 20]

[0299] Triethylamine (1.4 mL, 10.0 mmol) was added to a solution of 6-{[trans-4-(4-hydroxyphenyl)piperidin-3-yl]methoxy}isoindolin-1-one [(+ /-) 19.672 mg, 2.0 mmol] in anhydrous THF (10 mL) and dioxane (10 mL) at room temperature under nitrogen, after which the mixture was cooled to 0 ° C. Di-tert-butyl dicarbonate (434 mg, 2.0 mmol) was added, after which the mixture was stirred at 0°C for 3 h. The mixture was warmed to room temperature, diluted with 10% aqueous citric acid solution (30 mL) and extracted with ethyl acetate (2 x 70 mL). The combined organic extracts were dried over sodium sulfate, filtered and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with methylene chloride/methanol (4:1), to give (+/-) 20 as a white solid (643 mg, 74%): LCMS (M+H) 439. 4-[4-(2-Fluoroethoxy)phenyl]-3-{[(3-oxoisoindolin-5-yl)oxy]methyl}piperidine-1-carboxylate of (+/-)-trans -tert- Butyl [(+/-) 21].

[0300] 1-Fluoro-2-iodoethane (16 mg, 0.091 mmol) was added to a mixture of potassium carbonate (38 mg, 0.27 mmol) and 4-(4-hydroxyphenyl)-3-{[(3 (+/-)-trans-tert-butyl-oxoisoindolin-5-yl)oxy]methyl}piperidine-1-carboxylate [(+/-) 20, 40 mg, 0.091 mmol] in anhydrous N,N-dimethylformamide ( 2 mL) at room temperature under nitrogen, after which the mixture was stirred for 24 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were washed with 10% aqueous lithium chloride solution (30 mL), dried over sodium sulfate and filtered. The solvents in the filtrate were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with methylene chloride/methanol (4:1), to give (+/-)21 as a semisolid colorless (36 mg, 87%): LCMS (M+H) 485. (+/-)-6-{[trans-4-[4-(2-Fluoroethoxy)phenyl]piperidin-3- yl]methoxy}- isoindolin-1-one [(+/-) B0466]

[0301] Prepared according to General Procedure A2 to provide (+/-) B0466 as a white solid (10 mg, 35%): LCMS (M+H) 385; 1H NMR (500 MHz, CD3OD) δ 7.34 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 2 .0 Hz, 1H), 7.00 (dd, J = 8.5, 2.0 Hz, 1H), 6.83 (d, J = 9.0 Hz, 2H), 4.63 (t, J = 4.0 Hz, 1H), 4.54 (t, J = 4.0 Hz, 1H), 4.26 (s, 2H), 4.11 (t, J = 4.0 Hz, 1H), 4.05 (t, J = 4.0 Hz, 1H), 3.73 (dd, J = 9.5, 4.0 Hz, 1H), 3.65-3.59 (m, 2H), 3.454 .41 (m, 1H), 3.10-3.05 (m, 2H), 2.83 (dt, J = 11.5, 4.0 Hz, 1H), 2.33-2.29 (m , 1H), 1.96-1.90 (m, 2H). General Procedure A7: Preparation of N-Substituted 3,4-Piperidine NH Analogs Scheme 9 Scheme 10 Preparation of (+/-)-N-[4-(trans-3-{[(3-Oxoisoindolin-5-yl)oxy]methyl}piperidin-4-yl)phenyl] methanesulfonamide hydrochloride [(+/-) B0529] (Scheme 9) 3-{[(3-Oxoisoindolin-5-yl)oxy]methyl}-4-(4-{[(perfluorobutyl)sulfonyl]oxy}phenyl)piperidine-1-carboxylate (+/ -)- trans-tert-Butyl [(+/-) 22]

[0302] Perfluorobutanesulfonyl fluoride (nonafluorobutanesulfonyl fluoride, 0.42 mL, 2.4 mmol) was added to a solution of 4-(4-hydroxyphenyl)-3-{[(3-oxoisoindolin-5-yl)oxy] (+/-)-trans-tert-butyl methyl}piperidine-1-carboxylate [(+/-) 19, 870 mg, 2.0 mmol] and triethylamine (0.33 mL, 2.4 mmol) in chloride of anhydrous methylene (20 mL) at room temperature under nitrogen, after which the mixture was stirred for 24 h. The mixture was washed with 2N NaOH (30 ml) and water (20 ml) and dried over sodium sulfate and filtered. The solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (gradient from 1:1 to 0:100), to give (+/ -) 22 as a white solid (1.24 g, 87%): LCMS (M+H) 721. 6-{[trans-1-(tert-Butoxycarbonyl)-4-(4-{[(perfluorobutyl) (+/-)-tert-Butyl sulfonyl]oxy}phenyl)piperidin-3-yl]methoxy}-1-oxo isoindoline-2-carboxylate [(+/-) 23]

[0303] A solution of (+/ -)-trans-tert-butyl [(+/-) 22, 1.24 g, 1.72 mmol] in anhydrous THF (10 mL) was added to a suspension of sodium hydride (83 mg, 2.1 mmol , 60% dispersion in mineral oil) in anhydrous THF (30 mL) at room temperature under nitrogen, after which the mixture was stirred for 5 min. Di-tert-butyl dicarbonate (752 mg, 3.4 mmol) was added, followed by 4-dimethylaminopyridine (201 mg, 1.7 mmol), after which the mixture was stirred for 12 h. Water (0.5 mL) was added and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (gradient from 1:1 to 0:100), to give (+/- )23 as a light yellow solid (1.28 g, 91 %): LCMS (M+H) 821. 6-{[4-(4-Aminophenyl)-1-(tert-butoxycarbonyl)piperidin- 3-yl]methoxy}-1-oxoisoindoline- (+/-)-trans-tert-Butyl 2-carboxylate [(+/-) 24]

[0304] A mixture of 6-{[trans-1-(tert-butoxycarbonyl)-4-(4-{[(perfluorobutyl)sulfonyl]oxy} phenyl)piperidin-3-yl]methoxy}-1-oxoisoindoline-2 -(+/-)-tert-butyl carboxylate [(+/-) 23, 400 mg, 0.49 mmol], benzophenone imine (132 mg, 0.75 mmol), tris(dibenzylideneacetone)dipalladium(0) ( 45 mg, 10 mol %), 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl (BINAP, 60 mg, 20 mol %) and cesium carbonate (318 mg, 2.0 mmol) in anhydrous dioxane (20 mL) was heated at 100°C under nitrogen for 3 h. The cold mixture was diluted with ethyl acetate (120 mL), dried over sodium sulfate and filtered. The solvents were removed under reduced pressure and the residue was dissolved in methanol (5 mL) and stirred at room temperature under nitrogen. Hydroxylamine hydrochloride (170 mg, 2.4 mmol) was added and the mixture was stirred for 3 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (gradient from 1:1 to 0:100), to give (+/ ) 24 as a yellow oil (121 mg, 41% over two steps): LCMS (M+H) 538. 4-[4-(Methylsulfonamido)phenyl]-3-{[(3-oxoisoindolin-5-yl )oxy]methyl}piperidine-1-carboxylate of (+/-)-trans-tert-Butyl [(+/-) 25]

[0305] Sodium bis(trimethylsilyl)amide (0.45 mL, 0.45 mmol, 1.0 M in THF) was added to a solution of 6-{[4-(4-aminophenyl)-1-(tert (+/-)-trans-tert-butyl-butoxycarbonyl)piperidin-3-yl]methoxy}-1-oxoisoindoline-2-carboxylate [(+/-) 24, 120 mg, 0.23 mmol] in chloride anhydrous methylene (5 mL) and the mixture was stirred for 15 min. Methanesulfonyl chloride (93 mg, 0.81 mmol) was added, after which the mixture was stirred for a further 3 h. The mixture was treated with water (0.5 mL), diluted with methylene chloride (50 mL), dried over sodium sulfate and filtered. The solvents were removed under reduced pressure and the residue was dissolved in methanol (5 ml) at room temperature. 2N NaOH solution (2 mL) was added and the mixture was stirred for 2 h. The solvents were removed under reduced pressure and the residue was diluted with methylene chloride (50 ml), washed with 10% citric acid solution (20 ml), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography over neutral alumina, eluting with methylene chloride/methanol (gradient from 19:1 to 4:1), to give (+/- ) 25 as a yellow solid (59 mg, 51% over two steps): LCMS (M+H) 516. (+/-)-N-[4-(trans-3-{[(3-) hydrochloride Oxoisoindolin-5-yl)oxy]methyl}piperidin-4-yl)phenyl]methanesulfonamide [(+/) B0529]

[0306] Hydrochloric acid (0.30 mL, 4M in dioxane) was added to a solution of 4-[4-(methylsulfonamido)phenyl]- 3-{[(3-oxoisoindolin-5-yl)oxy]methyl}- (+/-)-trans-tert-butyl piperidine-1-carboxylate [(+/-) 25.39 mg, 0.076 mmol] in anhydrous dioxane (2 mL) at room temperature under nitrogen, after which the mixture was stirred for 2 h. The solvents were removed under reduced pressure and the residue was dissolved in methanol for purification by reverse phase preparative HPLC, eluting with 0.05% TFA in acetonitrile/water (gradient from 2% to 60%, Fenomenex column Luna). The isolated residue was acidified with HCl (2 mL, 2M in diethyl ether), diluted with acetonitrile/water and lyophilized to provide (+/-) B0529 as a yellow solid (28 mg, 82%): LCMS (M+H) 416; 1H NMR (500 MHz, CD3OD) δ 7.43 (d, J = 8.5 Hz, 1H), 7.27-7.21 (m, 4H), 7.12-7.01 (m, 2H) , 4.36 (s, 2H), 3.84 (dd, J = 9.5, 3.0 Hz, 1H), 3.76-3.65 (m, 3H), 3.60-3.53 (m, 2H), 3.22-3.18 (m, 1H), 2.99 (dt, J = 11.5, 4.0 Hz, 1H), 2.93 (s, 3H), 2.472, 43 (m, 1H), 2.11-2.03 (m, 2H). Alternative preparation of (+/-)-N-[4-(trans-3-{[(3-Oxoisoindolin-5-yl)oxy]methyl}piperidin-4-yl)phenyl]methanesulfonamide hydrochloride [(+/- ) B0529] (Scheme 10) 6-{[trans-4-(4-Bromophenyl)-1-(tert-butoxycarbonyl)-piperidin-3-yl]methoxy}-1-oxoisoindoline-2-carboxylate (+/- )-tert-Butyl [(+/-) 26]

[0307] Prepared according to General Procedure A7, Scheme 9 to provide (+/-) 26 as a white solid (645 mg, 53%): LCMS (M+H) 601. 6-{[trans-1- (tert-Butoxycarbonyl)-4-(4-[methyl sulfonamido]phenyl)piperidin-3-yl]methoxy}-1-oxoisoindoline-2-carboxylate of (+/-)-tert-Butyl [(+/-) 27 ]

[0308] A mixture of (+/-) 6-{[trans-4-(4-bromophenyl)-1-(tert-butoxycarbonyl)-piperidin-3-yl]methoxy}-1-oxoisoindoline-2-carboxylate -tert-butyl [(+/-) 26, 150 mg, 0.25 mmol], methanesulfonamide (29 mg, 0.30 mmol), allylpalladium(II) chloride dimer (2.3 mg, 5 mol%) , 2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl (tBu-XPhos, 21 mg, 20 mol%) and potassium carbonate (69 mg, 0.50 mmol) in 2-methyltetra -anhydrous hydrofuran (5 mL) was heated at 80 °C under nitrogen for 12 h. The cold mixture was diluted with ethyl acetate (120 mL), dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (gradient from 1:1 to 0:100), to give (+/ -) 27 as a yellow oil (91 mg, 59%): LCMS (M+H) 616. (+/-)-N-[4-(trans-3-{[(3-Oxoisoindolin-5-) hydrochloride yl)oxy]methyl}piperidin-4-yl)phenyl]methanesulfonamide [(+/) B0529]

[0309] Prepared according to General Procedure A1 to provide (+/-)B0529 as a yellow solid (54 mg, 61%): LCMS (M+H) 416; 1H NMR (500 MHz, CD3OD) δ 7.43 (d, J = 8.5 Hz, 1H), 7.27-7.21 (m, 4H), 7.12-7.01 (m, 2H) , 4.36 (s, 2H), 3.84 (dd, J = 9.5, 3.0 Hz, 1H), 3.76-3.65 (m, 3H), 3.60-3.53 (m, 2H), 3.22-3.18 (m, 1H), 2.99 (dt, J = 11.5, 4.0 Hz, 1H), 2.93 (s, 3H), 2, 47-2.43 (m, 1H), 2.11-2.03 (m, 2H). General Procedure A8: Preparation of 3,4-Tetrahydropyridine NH analogues Scheme 11 Preparation of 3-{[4-(4-Methoxyphenyl)-1,2,5,6-tetrahydropyridin-3-yl]methoxy}benzonitrile [B0412] 3-(Hydroxymethyl)-4-(4-methoxyphenyl)- tert-Butyl 5,6-dihydropyridine-1(2H)-carboxylate [28]

[0310] Prepared according to General Procedure A1 to provide 28 as a colorless oil (1.9 g, 71%): LCMS (M+H) 320. 4-(4-Methoxyphenyl)-3-{[(methylsulfonyl )oxy]methyl}-5,6- tert-Butyl dihydropyridine-1(2H)-carboxylate [29]

[0311] Prepared according to General Procedure A1 to provide 29 as a light yellow oil that was suitable for use without further purification (2.4 g, 99%): LCMS (M+H) 398. 3-[(3 -Cyanophenoxy)methyl]-4-(4-methoxyphenyl)-5,6-dihydropyridine-1(2H)-tert-Butyl carboxylate [30]

[0312] Prepared according to General Procedure A5 to provide 30 as a yellow oil (506 mg, 97%): LCMS (M+H) 421. 3-{[4-(4-Methoxyphenyl)-1,2, 5,6-tetrahydropyridin-3-yl]methoxy}-benzonitrile [B0412]

[0313] Prepared according to General Procedure A2 to provide B0412 as a white solid (51 mg, 61%): LCMS (M+H) 321; 1H NMR (500 MHz, CD3OD) δ 7.41 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 8 .5 Hz, 2H), 7.12 (dd, J = 7.5, 2.5 Hz, 1H), 7.09-7.05 (m, 1H), 6.95 (d, J = 8, 5 Hz, 2H), 4.54 (s, 2H), 3.84 (s, 2H), 3.80 (s, 3H), 3.36 (t, J = 6.0 Hz, 2H), 2 .68 (t, J = 6.0 Hz, 2H). General Procedure A9: Preparation of 3-Methyl-3,4-Piperidine NH analogues Scheme 12 Preparation of 3-{[(+/-)-cis-4-(4-Methoxyphenyl)-3-methylpiperidin-3-yl]methoxy}benzonitrile hydrochloride [(+/-) B0568]. (+/-)-1-tert-Butyl 3-Ethyl 3-Methyl-4-oxopiperidine-1,3-dicarboxylate [(+/-) 32]

[0314] A mixture of iodomethane (4.6 mL, 73.7 mmol), potassium carbonate (10.2 g, 73.7 mmol) and 4-oxopiperidine-1,3-dicarboxylate (+/-)- Commercially available 1-tert-butyl 3-ethyl [(+/-) 31, 10.0 g, 36.9 mmol] in anhydrous acetone (150 mL) was heated at reflux under nitrogen for 12 h. The cold mixture was filtered and the solvent in the filtrate was removed under reduced pressure to give (+/-) 32 as a light yellow oil (8.6 g, 82%): LCMS (M+H) 286. 3-Methyl- (+/-)-1-tert-Butyl 3-Ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydropyridine-1,3(6H)-dicarboxylate [(+/-) 33 ]

[0315] Sodium hydride (2.3 g, 60.3 mmol, 60% in mineral oil) was added little by little to a solution of (+/-) 3-methyl-4-oxopiperidine-1,3-dicarboxylate -1-tert-butyl 3-ethyl [(+/-) 32, 8.6 g, 30.1 mmol] in anhydrous THF (100 mL) at 0 °C under nitrogen. The mixture was stirred at 0°C for 5 min, after which N-phenylbis(trifluoromethanesulfonamide) (16.2 g, 45.2 mmol) was added gradually. The mixture was warmed to room temperature and then further heated to 60 °C and stirred for 1 h. The cold mixture was treated with saturated aqueous sodium chloride solution (150 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over sodium sulfate and filtered and the solvents were removed under reduced pressure to give (+/-)33 as a dark amber oil (7.2 g, 57%): LCMS (M+H) 418 4-(4-Methoxyphenyl)-3-methyl-2,3-dihydropyridine-1,3(6H)-dicarboxylate of (+/-)-1-tert-Butyl 3-Ethyl [(+/-) 34]

[0316] Prepared according to General Procedure A1 to provide (+/-) 34 as a dark amber oil (5.8 g, 89%): LCMS (M+H) 376. cis-4-(4-Methoxyphenyl (+/-)-1-tert-Butyl 3-Ethyl)-3-methylpiperidine-1,3-dicarboxylate [(+/-) 35]

[0317] Prepared according to General Procedure A1 to provide (+/-) 35 as a crude amber oil (4.6 g) that was suitable for use in the next step without purification: LCMS (M+H) 377, cis (+/-)-1-tert-Butyl -3-(Hydroxymethyl)-4-(4-methoxyphenyl)-3-methylpiperidine-1-carboxylate [(+/-) 36]

[0318] Prepared according to General Procedure A1 to provide (+/-) 36 as a light yellow oil (2.5 g, 62% over two steps): LCMS (M+H) 336. cis-4 (+/-)-1- tert-Butyl -(4-Methoxyphenyl)-3-methyl-3-({[(trifluoromethyl)sulfonyl]oxy}methyl)piperidine-1-carboxylate [(+/-) 37]

[0319] Prepared in accordance with General Procedure A9 to provide (+/-) 37 as a dark amber oil (1.4 g, 43%): LCMS (M+H) 468. 3-[(3-Cyanophenoxy) (+/-)-tert-Butyl methyl]-4-(4-methoxyphenyl)-3-methylpiperidine-1-carboxylate [(+/-) 38]

[0320] Prepared in accordance with General Procedure A5 to provide (+/-) 38 as a crude amber oil (120 mg) that was suitable for use in the next step without purification: LCMS (M+H) 437. Hydrochloride of 3 -{[(+/-) -cis-4-(4-Methoxyphenyl)-3- methylpiperidin-3-yl]methoxy}benzonitrile [(+/-) B0568]

[0321] Prepared according to General Procedure A1 to provide (+/-) B0568 as a white solid (84 mg, 40% over two steps): LCMS (M+H) 337; 1H NMR (500 MHz, CD3OD) δ 7.51-7.48 (m, 1H), 7.41-7.40 (m, 1H), 7.38-7.33 (m, 2H), 7, 16 (d, J = 9.5 Hz, 2H), 6.88 (d, J = 9.5 Hz, 2H), 4.17 (d, J = 9.5 Hz, 1H), 3.79 ( s, 3H), 3.743.70 (m, 2H), 3.62-3.59 (m, 1H), 2.34-3.16 (m, 1H), 3.07 (d, J = 13, 0 Hz, 1H), 2.96 (dd, J = 13.5, 3.5 Hz, 1H), 1.94-1.90 (m, 1H), 1.00 (m, 3H). General Procedure A10: Preparation of 5-Methyl-3,4-Piperidine NH analogues Scheme 13 Preparation of 3-{[(+/-)-trans,cis-4-(4-Methoxyphenyl)-5-methylpiperidin-3-yl]methoxy}benzonitrile hydrochloride [(+/-) B0548] and 3- hydrochloride {[(+/-)-trans,trans-4-(4-Methoxyphenyl)-5-methylpiperidin-3-yl]methoxy}benzonitrile [(+/-) B0573]. (+/-)-1-tert-Butyl 3-Ethyl 5-Methyl-4-oxopiperidine-1,3-dicarboxylate [(+/-) 40]

[0322] Triethylamine (2.2 mL, 13.8 mmol) was added to a commercially available (+/-)-ethyl 5-methyl-4-oxopiperidine-3-carboxylate hydrochloride solution [(+/-) 39, 2.5 g, 9.2 mmol] and 4-dimethylaminopyridine (DMAP, 20 mg) in anhydrous methylene chloride (10 mL) at room temperature under nitrogen, after which a solution of di-tert-butyl dicarbonate (3.0 g, 13.8 mmol) in anhydrous methylene chloride (10 mL) was slowly added. The mixture was stirred for 4 h, after which it was diluted with water (30 ml) and the organic layer was collected. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (2:3) to give (+/-) 40 as a white solid (3 .0 g, 87%): LCMS (M+H) 286. 5-Methyl-4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydropyridine-1,3(2H)-dicarboxylate ( +/-)-1-tert-Butyl 3-Ethyl [(+/-) 41]

[0323] Prepared in accordance with General Procedure A9 to provide (+/-) 41 as a dark amber oil (3.8 g, 86%): LCMS (M+H) 418. 4-(4-Methoxyphenyl)- (+/-)-1-tert-Butyl 3-Ethyl 5-methyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate [(+/-) 42]

[0324] Prepared according to General Procedure A1 to provide (+/-) 42 as a crude amber oil (2.9 g) which was used without further purification in the next step: LCMS (M+H) 376. cis, cis/trans-4-(4-Methoxyphenyl)-5-methylpiperidine-1,3-(+/-)-1-tert-Butyl 3-Ethyl dicarboxylate [(+/-) 43]

[0325] Prepared according to General Procedure A1 to provide (+/-) 43 as an amber oil (1.6 g, 53% over two steps): LCMS (M+H) 378. trans, cis/ trans-4-(4-Methoxyphenyl)-5-methylpiperidine- (+/-)-1-tert-Butyl 3-Ethyl 1,3-dicarboxylate [(+/-) 44]

[0326] Prepared according to General Procedure A1 to provide (+/-) 44 as a crude amber oil (1.6 g) which was used without further purification in the next step: LCMS (M+H) 378. trans, (+/-)-1-tert-Butyl cis/trans-3-(Hydroxymethyl)-4-(4-methoxyphenyl)-5-methylpiperidine-1-carboxylate [(+/-) 45]

[0327] Prepared according to General Procedure A1 to provide (+/-) 45 as a crude amber oil (900 mg) which was used without further purification in the next step: LCMS (M+H) 336. trans, cis/ trans-4-(4-Methoxyphenyl)-3-methyl-5- {[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate of (+/- )-1-tert-Butyl [(+/-) 46]

[0328] Prepared according to General Procedure A1 to provide (+/-) 46 as a light yellow oil (600 mg, 56% over three steps): LCMS (M+H) 414. trans, cis/trans (+/-)-tert-Butyl-3-[(3-Cyanophenoxy)methyl]-4-(4-methoxyphenyl)-5-methylpiperidine-1-carboxylate [(+/-) 47]

[0329] Prepared in accordance with General Procedure A5 to provide (+/-) 47 as a crude amber oil (155 mg) that was suitable for use in the next step without purification: LCMS (M+H) 437. Hydrochloride of 3 -{[(+/-) -trans,cis-4-(4-Methoxyphenyl)- 5-methylpiperidin-3-yl]methoxy}benzonitrile [(+/-) B0548] and 3-{[(+/ -) -trans,trans-4-(4-Methoxyphenyl)-5-methylpiperidin-3-yl]methoxy}benzonitrile [(+/-) B0573].

[0330] Prepared according to General Procedure A1: (+/-) B0548 was isolated as a white solid (15 mg, 16% over two steps): LCMS (M+H) 337; 1H NMR (500 MHz, CD3OD) δ 7.40-7.37 (m, 1H), 7.27-7.25 (m, 1H), 7.18-7.14 (m, 2H), 7, 11-7.09 (m, 2H), 6.91 (d, J = 10.5 Hz, 2H), 3.96 (dd, J = 10.0, 3.0 Hz, 1H), 3.84 -3.79 (m, 1H), 3.77 (s, 3H), 3.67 (dd, J = 12.5, 4.0 Hz, 1H), 3.38 (d, J = 2.9 Hz, 2H), 3.19-3.12 (m, 2H), 2.91-2.84 (m, 1H), 2.27-2.22 (m, 1H), 0.99 (d, J = 7.5 Hz, 3H). Also, (+/-)B0573 was isolated as a white solid (17 mg, 18% over two steps): LCMS (M+H) 337; 1H NMR (500 MHz, CD3OD) δ 7.40 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.16-7.08 (m , 4H), 6.92-6.90 (m, 1H), 3.77-3.73 (m, 4H), 3.67-3.62 (m, 2H), 3.49-3.44 (m, 1H), 3.38-3.33 (m, 1H), 3.18-3.12 (m, 1H), 2.85 (t, J = 12.5 Hz, 1H), 2, 51 (t, J = 11.5 Hz, 1H), 2.48-2.34 (m, 1H), 2,102.07 (m, 1H), 0.76 (d, J = 6.5 Hz, 3H ). General Procedure A11: Preparation of 3,4-Piperidine NH 2-Substituted Analogs Scheme 14a Preparation of (-)-6-{[(trans,trans)-4-(4-methoxyphenyl)-2-methylpiperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one Ethyl [(-)B0699] (2Z)-3-[[(4-methoxyphenyl)methyl]amino]but-2-enoate (48)

[0331] In a 100 mL round bottom flask, a mixture of ethyl 3-oxobutanoate (1 g, 7.68 mmol, 1.00 equiv.), (4-methoxyphenyl)methanamine (1.05 g) was placed , 7.65 mmol, 1.00 equiv.), iodine (195 mg, 0.77 mmol, 0.10 equiv.). The resulting mixture was stirred for 1 h at room temperature. The mixture was diluted with 20 mL of DCM. The resulting solution was washed with 2x30 mL of H2O. The organic solution was dried over sodium sulfate and concentrated in vacuo. This resulted in 2 g (crude) of 48 as a yellow oil. Ethyl 4-(4-methoxyphenyl)-1-[(4-methoxyphenyl)methyl]-2-methyl-1,4-dihydropyridine-3-carboxylate (49)

[0332] In a 100 mL round bottom flask, a solution of ethyl (2Z)-3-[(4-methoxyphenyl)amino]but-2-enoate (48.1 g, 4.25 mmol, 1.00 equiv.) and (3E)-4-(4-methoxyphenyl)but-3-en-2-one (1.54 g, 8.74 mmol, 2.06 equiv.) in ethanol (20 mL) . The resulting solution was stirred overnight at 60°C. The resulting solution was concentrated under vacuum. This resulted in 2.4 g (crude) of 49 as a yellow oil. (cis,cis)-4-(4-methoxyphenyl)-2-methylpiperidine-3-(+/-)-ethyl carboxylate [(+/-) 50]

[0333] In a 2000 mL pressure tank reactor, a solution of 4-(4-methoxyphenyl)-1-[(4-methoxyphenyl)methyl]-2-methyl-1,4-dihydropyridine- 3- ethyl carboxylate (49.77 g, 195.69 mmol, 1.00 equiv.) and PtO2 (7 g) in ethanol (1000 mL). The resulting solution was hydrogenated to 1.5 MPa and stirred overnight at room temperature. The solids were filtered. The filtrate was concentrated under vacuum. The residue was dissolved in MeOH (700 mL), then Pd(OH)2 (77 g) and AcOH (70 mL) were added to the solution. The resulting mixture was hydrogenated at 50 psi and stirred at rt for 3h. The solids were filtered. The filtrate was concentrated under vacuum. This resulted in 60 g (77%) of (+/-) 50 as a light yellow oil. (cis,cis)-4-(4-methoxyphenyl)-2-methylpiperidine-1,3-(+/-)-3-Ethyl dicarboxylate [(+/-) 51]

[0334] In a 100 mL round bottom flask, a solution of ethyl (2S,3S,4S)-4-(4-methoxyphenyl)-2-methylpiperidine-3-carboxylate [(+/-) 50 , 200 mg, 0.72 mmol, 1.00 equiv.], Boc2O (318.4 mg, 1.46 mmol, 2.02 equiv.) and TEA (145.8 mg, 1.44 mmol, 2.00 equiv.) in DCM (10 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, EA:PE=05 increasing to EA:PE = 60% within 30 min; Detector, UV 254 nm. 100 mg of product was obtained. This resulted in 100 mg (37%) of (+/-)51 as a yellow oil. (trans,trans)-4-(4-methoxyphenyl)-2-methylpiperidine-1,3-dicarboxylate of (+/-)-1-tert-butyl 3-ethyl [(+/-) 52]

[0335] In a 500 mL round bottom flask, a solution of (cis, cis)-4-(4-methoxyphenyl)-2-methylpiperidine-1,3-dicarboxylate of (+/-)-1- tert-butyl 3-ethyl [(+/-) 51.10 g, 26.49 mmol, 1.00 equiv.) and sodium ethoxide (3.6 g, 52.90 mmol, 2.00 equiv.) in ethanol (200 mL). The resulting solution was stirred for 2 h at 60 °C. The resulting solution was extracted with 2x200 mL of DCM and the organic layers combined. The organic solution was washed with 2x200 mL of H2O and concentrated in vacuo. This resulted in 10 g (100%) of (+/-) 52 as a yellow oil. (trans,trans)-3-(hydroxymethyl)-4-(4-methoxyphenyl)-2-methylpiperidine-1-carboxylate of (+/-)-tert-butyl [(+/-) 53]

[0336] In a 100 mL round bottom flask with 3 necks, a mixture of (trans, trans)-4-(4-methoxyphenyl)-2-methylpiperidine-1,3-dicarboxylate (+/-) was placed - 1-tert-butyl 3-ethyl [(+/-) 52.5 g, 13.25 mmol, 1.00 equiv.) and LiAlH4 (680 mg, 17.89 mmol, 1.51 equiv.) in THF (50 mL). The resulting mixture was stirred for 2 h at 0°C. The reaction was then quenched by adding 100 mL of water. The resulting solution was extracted with 2x100 mL of dichloromethane and the combined organic layers then concentrated in vacuo. The residue was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, EA:PE=0% increasing to EA:PE = 100% within 50 min; Detector, UV 254 nm. 2.8675 g of product were obtained. This resulted in 2.86 g (64%) of (+/-) 53 as a white solid. LC-MS (ES, m/z): 280[M- 55]; 1H-NMR (400MHz, CD3OD,ppm): 7.17 (d, J = 8.8Hz, 2H),7.85 (m, J = 8.4Hz, 2H), 4.39 (t, J = 4 .4Hz, 1H), 4.14(t, J = 6.4Hz, 1H), 3.73(s, 3H), 3.62~3.57(m, 1H), 3.34~3.21 (m, 2H), 3.07~3.01(m, 1H), 2.52~2.45(m, 1H), 1.89~1.74(m, 2H), 1.73~1 .60(m, 1H), 1.55~1.53(m, 9H), 1.15(d, J = 6.4Hz, 3H). (trans,trans)-3-(hydroxymethyl)-4-(4-methoxyphenyl)-2-methylpiperidine-1-carboxylate of (-)-tert-butyl [(-)53]

[0337] 11.04 g of (trans, trans)-3-(hydroxymethyl)- 4-(4-methoxyphenyl)-2-methylpiperidine-1-carboxylate of (+/-)- tert-butyl [(+/- ) 53] were purified by supercritical fluid chromatography (Thar 350 Preparative SFC, ChiralPak AD-10Ü 300x50mm, 25% isopropanol/0.05% DEA/CO2) to provide 4.42 g of (-) 53 as a white solid. LC-MS (ES, m/z): 280[M-55]; 1H NMR (400 MHz, DMSO) δ 7.25 - 7.03 (m, J = 8.6, 2H), 6.86 (d, J = 8.6, 2H), 4.37 (s, 1H ), 4.13 (p, J = 6.6, 1H), 3.73 (s, 3H), 3.64 - 3.52 (m, 1H), 3.33 (s, 4H), 3, 22 (dt, J = 13.4, 6.8, 2H), 3.04 (d, J = 4.7, 1H), 2.48 - 2.41 (m, 1H), 1.91 - 1 .67 (m, 2H), 1.61 (tt, J = 10.0, 5.0, 1H), 1.42 (s, 9H), 1.17 (d, J = 6.7, 3H) ; or = -40.3° (5.4 mg/mL in MeOH). 6-{[(trans, trans) -1- [(tert-butoxy)carbonyl] -4- (4-methoxyphenyl) -2-methylpiperidin-3-yl]methoxy}-1-oxo-2,3-di- (-)-tert-butyl hydro-1H-isoindole-2-carboxylate [(-)54]

[0338] An oven-dried flask was brought to room temperature under vacuum, then purged with nitrogen. (trans, trans)-3-(hydroxymethyl)-4-(4-methoxyphenyl)-2-methylpiperidine-1-carboxylate of (-)-tert-butyl [(-)53, previously dried in a vacuum oven at 50 °C overnight, 4.5 g, 13.4 mmol) was dissolved in dry THF (100 mL) and cooled in an ice bath. Tri-n-butyl phosphine (5.0 mL, 20.1 mmol, 1.5 eq.) was added, followed by 1,1'-(azodicarbonyl)dipiperidine (5.1 g, 20.1 mmol, 1. 5 eq.) and the resulting mixture stirred cold for two hours. Tert-butyl 6-hydroxy-1-oxo-2,3-dihydro-1H-isoindol-2-carboxylate (4.0 g, 16.1 mmol, 1.2 eq.) was added, the water bath Ice was removed and the reaction was stirred at rt overnight. The mixture was filtered and concentrated. The residue was taken up in a minimal amount of EtOAc and purified by flash column chromatography (5%-40% EtOAc/hexanes) to provide 7.4 g of (-)54 as a white solid (97%). LCMS (M-Boc-tBu) 411. (-) -6-{[(trans, trans) -4- (4-methoxyphenyl) -2-methylpiperidin- 3-yl]methoxy}-2,3-dihydro -1H-isoindole-1-one [(-)B0699)]

[0339] To a solution of 6-{[(trans, trans)-1-[(tert-butoxy)carbonyl]-4-(4-methoxyphenyl)-2-methylpiperidin-3-yl]methoxy}-1-oxo (-)-tert-butyl-2,3-dihydro-1H-isoindole-2-carboxylate [(-)54, 1.7 g, 3.0 mmol] in DCM (20 mL) was added TFA ( 10 mL). After 90 minutes, the reaction was concentrated and the residue was dissolved in DCM (20 mL) and stirred with 1 N NaOH (10 mL). The layers were separated and the aqueous layer extracted twice more with DCM. The combined organics were washed with brine, filtered through cotton wool and concentrated to provide 0.86 g (78%) of (-) B0699 as a white solid. LCMS (MH+) 367, 1H NMR (400 MHz, DMSO) δ 8.88 — 8.71 (m, J = 9.5, 1H), 8.70 - 8.45 (m, 2H), 7.44 (d, J = 8.3, 1H), 7.08 (d, J = 8.5, 3H), 7.00 (d, J = 2.2, 1H), 6.87 (d, J = 8.6, 2H), 4.27 (s, 2H), 3.99 (d, J = 8.5, 1H), 3.70 (s, 3H), 3.52 (d, J = 7, 7, 1H), 3.48 — 3.34 (m, 2H), 3.20 — 3.05 (m, 1H), 3.00 (dt, J = 16.5, 8.4, 1H), 2.06 (t, J = 11.0, 1H), 2.0 — 1.85 (m, 2H), 1.34 (d, J = 6.4, 3H). Scheme 14b Preparation of (-)-6-{[(trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methylpiperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindole- 1-one [(-) B1415] 1-Iodo-3-(2-methoxyethoxy)benzene (55)

[0340] In a 2000 mL round bottom flask, a solution of 3-iodophenol (50 g, 227.26 mmol, 1.00 equiv.), potassium carbonate (94.1 g, 680.85 mmol) was placed. , 3.00 equiv.) and 1-bromo-2-methoxyethane (94.1 g, 677.02 mmol, 3.00 equiv.) in ACN (1000 mL). The resulting solution was stirred overnight at 80°C. The resulting solution was diluted with 500 mL of water. The resulting solution was extracted with 3x200 mL of ethyl acetate and the combined organic layers then dried over anhydrous magnesium sulfate and concentrated in vacuo. This resulted in 50 g (79%) of 55 as a light yellow oil. (2E)-3-[3-(2-methoxyethoxy)phenyl]prop-2-enal (56)

[0341] In a 2000 mL round bottom flask, which was purged and maintained with an inert nitrogen atmosphere, a solution of 1-iodo-3-(2-methoxyethoxy)benzene (55.63 g, 226 .55 mmol, 1.00 equiv.), n- BuNOAc (136.5 g, 451.99 mmol, 2.00 equiv.), potassium carbonate (46.8 g, 338.62 mmol, 1.50 equiv. .), KCl (16.84 g, 226.04 mmol, 1.00 equiv.), Pd(OAc)2 (1.52 g, 6.77 mmol, 0.03 equiv.) and 3,3-diethoxyprop -1-ene (88.4 g, 679.03 mmol, 3.00 equiv.) in DMF (500 mL). The resulting solution was stirred overnight at 90°C. The reaction mixture was cooled to room temperature with a water/ice bath. The pH value of the solution was adjusted to 4 with 1N hydrogen chloride. The mixture was stirred at rt for 20 min. The resulting solution was extracted with 3x200 mL of ethyl acetate and the combined organic layers then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:2) as eluent. This resulted in 30 g (64%) of 56 as a yellow semisolid. Ethyl 4-[4-(2-methoxyethoxy)phenyl]-1-[(4-methoxyphenyl)methyl]-2-methyl-1,4-dihydropyridine-3-carboxylate (57)

[0342] In a 1000 mL round bottom flask, a solution of (2E)-3-[4-(2-methoxyethoxy)phenyl]prop-2-enal (56.35 g, 169.71 mmol) was placed. 1.00 equiv.), proline (3.4 g, 29.53 mmol, 0.17 equiv.) and ethyl (2E)-3-[[(4-methoxyphenyl)methyl]amino]but-2-enoate (50.8 g, 203.77 mmol, 1.20 equiv.) in ethanol (500 mL). The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by adding 200 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and the combined organic layers then dried over anhydrous magnesium sulfate and concentrated. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 44 g (59%) of 57 as a yellow oil. (cis, cis) -4- [3- (2-methoxyethoxy)phenyl] -2-methylpiperidine- (+/-)-Ethyl 3-carboxylate [(+/-) 58]

[0343] In a reactor with a 2 L pressure tank, a mixture of 4-[3-(2-methoxyethoxy)phenyl]-1-[(4-methoxyphenyl)methyl]-2-methyl-1,4 was placed ethyl -dihydropyridine-3- carboxylate (57.50 g, 114.28 mmol, 1.00 equiv.) and PtO2 (4 g) in ethanol (1000 mL). The resulting solution was hydrogenated to 1.5 MPa and stirred overnight at room temperature. The solids were filtered. The filtrate was concentrated and the residue was dissolved in MeOH (500 mL), then Pd(OH)2 (50 g) and AcOH (50 mL) were added. The resulting mixture was hydrogenated at 50 psi and stirred for 3h at room temperature. The solids were filtered. The filtrate was concentrated under vacuum. This resulted in 23 g (63%) of (+/-) 58 as a yellow oil. (cis,cis)-1-tert-butyl 3-ethyl 4-(3-(2-methoxyethoxy)phenyl)-2-methylpiperidine-1,3-dicarboxylate (+/-)-1-tert-Butyl 3- ethyl [(+/-) 59]

[0344] In a 1000 mL round bottom flask, a solution of (cis, cis)-4-[3-(2-methoxyethoxy)phenyl]-2-methylpiperidine-3-carboxylate (+/-) was placed. -ethyl [(+/-) 58.23 g, 71.56 mmol, 1.00 equiv.], (Boc)2O (31.24 g, 143.30 mmol, 2.00 equiv.) and TEA (21 .3 g, 210.47 mmol, 3.00 equiv.) in DCM (300 mL). The resulting solution was stirred for 3 h at room temperature, then concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:2) as eluent. This resulted in 26 g (86%) of (+/-) 59 as a yellow oil. (trans,trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methylpiperidine-1,3-dicarboxylate of (+/-)-1-tert-Butyl 3-ethyl [(+/-) 60 ]

[0345] In a 500 mL round bottom flask, a solution of (cis, cis)-1-tert-butyl 3-ethyl 4- (3-(2-methoxyethoxy)phenyl)-2-methylpiperidine-1 was placed (+/-)-1-tert-butyl 3-ethyl ,3-dicarboxylate [(+/-) 59.22 g, 52.19 mmol, 1.00 equiv.] in freshly distilled ethanol (100 mL). EtONa (104 mL, 1 mol/L, 2.00 equiv.) was added at 60°C. The resulting solution was stirred for 2 h at 60°C, then cooled to rt with a water/ice bath. The reaction was then quenched by adding 300 mL of saturated NH4Cl. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The organic solution was washed with brine (3x200 mL) and dried over anhydrous magnesium sulfate, then concentrated in vacuo. This resulted in 19.8 g (90%) of (+/-)60 as a light yellow oil. (trans, trans)-3-(hydroxymethyl)-4-[3-(2-methoxyethoxy)phenyl]-2-methylpiperidine-1-carboxylate (+/-)-tert-Butyl [(+/-)61]

[0346] In a 1000 mL 3-neck round bottom flask purged and maintained with an inert nitrogen atmosphere, a suspension of LAH (5.59 g, 147 mmol, 2.00 equiv.) in THF (200 mL). This was followed by the addition of a solution of (trans,trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methylpiperidine-1,3-dicarboxylate (+/-)-1-tert-butyl 3 -ethyl [(+/-) 60.31 g, 73.54 mmol, 1.00 equiv.) in THF (300 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 30 min at room temperature. The reaction mixture was cooled to 0°C with a water/ice bath. The reaction was then quenched by adding 5.9 mL of water (0.04 mL of water per mmol of LAH) and stirred at rt for 15 min., then 5.9 mL of 15% NaOH ( 0.04 mL of 15% NaOH per mmol of LAH) was added and stirred at rt for 15min. To this was added 14.7 ml of water (0.1 ml of water per mmol of LAH) and the mixture was stirred at rt for 15min. Solids were filtered through Celite. The filtrate was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The organic solution was washed with brine (3x200 mL) and dried over anhydrous magnesium sulfate, then concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 23 g (82%) of (+/-)61 as a pink semisolid. LCMS (ES, m/z): 380 [M+H]+; 1H NMR, 400 MHz ,CD3OD, ppm): 7.2(t, J = 8.0Hz, 1H), 6.8(d, J = 6.4Hz, 2H), 6.7(d, J = 8 ,0Hz, 1H),4.4(t, J = 4.4Hz, 1H), 4.1(m, 3H), 3.6(m, 3H), 3.3(s, 3H), 3, 2(m, 2H), 3.0(m, 1H), 2.5 (s, 1H), 1.8(m, 2H), 1.7(m, 1H), 1.68(m, 1H ), 1.6(s, 9H), 1.1(d, J = 6.0Hz, 3H). (trans, trans)-3- (hydroxymethyl) -4- [3- (2-methoxyethoxy) phenyl]-2-methylpiperidine-1-carboxylate of (-)-tert-Butyl [(-)61]

[0347] 14.7 g of tert-butyl (trans, trans)-3-(hydroxymethyl)-4-[3-(2-methoxyethoxy)phenyl]-2-methylpiperidine-1-carboxylate [(+/-) 61] was purified by supercritical fluid chromatography (Thar 200 Preparative SFC, ChiralPak AD-10Ü 300x50mm, 25% isopropanol/0.05% DEA/CO2) to provide 6.3 g (-) 61 as a solid white. LC-MS (ES, m/z, M-tBu): 324.1; 1H NMR (400 MHz, CDCl3) δ 7.24 (t, J = 8.1, 1H), 6.88 — 6.82 (m, 2H), 6.80 (dd, J = 7.9, 2 .0, 1H), 4.24 - 4.16 (m, 1H), 4.16 - 4.10 (m, 2H), 3.91 - 3.80 (m, 1H), 3.78 (dd , J = 5.4, 3.9, 2H), 3.51 (dd, J = 11.3, 3.6, 1H), 3.48 (s, 3H), 3.39 (dd, J = 11.4, 4.7, 1H), 3.34 - 3.23 (m, 1H), 2.69 - 2.59 (m, 1H), 2.14 - 1.99 (m, 1H), 1.92 - 1.80 (m, 1H), 1.78 - 1.69 (m, 1H), 1.51 (s, 9H), 1.29 (d, J = 6.8, 3H); or = -33.1 (4.1 mg/mL in MeOH). (trans, trans) -4- [3- (2-methoxyethoxy) phenyl] -2-methyl-3-{ [(3- oxo-2,3-dihydro-1H-isoindol-5-yl)oxy] (-)-tert-Butyl methyl}piperidine-1-carboxylate [(-)62]

[0348] To an ice-cold solution of (trans, trans)-3-(hydroxymethyl)-4-[3-(2-methoxyethoxy)phenyl]-2-methylpiperidine-1-(-)-tert-butyl carboxylate [( -) 61, 5.3 g, 14.0 mmol] in tert-butylmethyl ether (25 mL) trimethylamine (2.5 mL, 18.2 mmol, 1.3 eq.) was added, followed by mesyl chloride dropwise drop (1.4 mL, 18.2 mmol, 1.3 eq.) to provide a thick white suspension. The ice bath was removed and the reaction was stirred at rt for 2 hr. 25 mL of ice water were added to the reaction and the mixture was stirred vigorously for 45 minutes and then for another 15 minutes in an ice bath. The mixture was filtered and washed with 3X 20 mL of water and dried under vacuum in the filter funnel, then at rt in a vacuum oven for 24 hours to provide 5.5 g of the mesylate as a white solid. A 250 mL 2-neck flask was dried in an oven, taken to rt under vacuum, and purged with nitrogen. Cesium carbonate (7.8 g, 24.0 mmol, 2.0 eq.) and 6-hydroxy-2,3-dihydro-1H-isoindol-1-one (2.2 g, 15.0 mmol , 1.25 eq.) were added, followed by isopropyl alcohol (previously dried over 3 angstrom molecular sieves, 75 mL). The resulting mixture was stirred with an overhead mechanical stirrer under nitrogen for 2.5 hr and then the mesylate was added (5.5 g, 12.0 mmol). The mixture was heated to 70°C overnight. The reaction was cooled to rt, the inorganics filtered and concentrated. The crude product was purified by normal phase chromatography (120 g Biotage Zip Sfere column; 8% - 70% acetone/hexanes) to provide 3.7 g (60%) of (-)62 as a white solid . LC-MS (ES, m/z, M-tBu): 455.3. (-)-6-{[(trans,trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methylpiperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindole- 1-one [(-)B1415]

[0349] To a solution of (trans, trans)-4-[3-(2-methoxyethoxy)phenyl]-2-methyl-3-{[(3-oxo-2,3-dihydro-1H-isoindole - (-)-tert-butyl 5-yl)oxy]methyl}piperidine-1-carboxylate [(-) 62, 6.2 g, 12.1 mmol] in methanol (20 mL) was added 1N HCl /EtOAc (61 mL, 61 mmol, 5 eq.) and the resulting solution was stirred at rt overnight. The reaction was concentrated to a white foam, which was triturated with diethyl ether, then dried under high vacuum overnight to provide 5.8 g (quant.) of (-) B1415 as a white solid. LCMS (ES, m/z, MH+): 411.2, 1H NMR (400 MHz, DMSO) δ 8.93 (d, J = 20.5, 2H), 8.54 (s, 1H), 7. 44 (d, J = 8.3, 1H), 7.21 (t, J = 7.9, 1H), 7.10 (dd, J = 8.3, 2.3, 1H), 7.02 (d, J = 2.2, 1H), 6.79 (dd, J = 8.2, 2.1, 1H), 6.75 (d, J = 7.6, 1H), 6.69 ( s, 1H), 4.26 (s, 2H), 4.07 - 3.92 (m, 2H), 3.91 - 3.79 (m, 1H), 3.56 (t, J = 4, 5, 2H), 3.50 (d, J = 7.8, 1H), 3.25 (s, 3H), 3.18 - 2.93 (m, 2H), 2.18 (t, J = 10.9, 1H), 2.06 (ddd, J = 16.0, 13.3, 3.4, 1H), 1.92 (d, J = 12.3, 1H), 1.37 (d , J = 6.4, 3H). Scheme 14c Preparation of (+/-)-6-{[(trans, trans)-2-methyl-4-[3-(methylsulfanyl)phenyl]piperidin-3-yl]methoxy}-2,3-dihydro-1H - isoindol-1-one [(+/-) 71] (+/-)-3-[(trans,trans)-3-(hydroxymethyl)-2-methylpiperidin-4-yl]phenol [(+/-) 64]

[0350] In a 500 mL round bottom flask with 3 necks purged and maintained with an inert nitrogen atmosphere, a solution of (trans, trans)-3-(hydroxymethyl)-4-(3-methoxyphenyl)- was placed (+/-)-tert-butyl 2-methylpiperidine-1-carboxylate [(+/-)63, prepared according to Scheme 14a, 10.5 g, 31.30 mmol, 1.00 equiv.] in DCM (100 mL). This was followed by the addition of BBr3 (19.59 g, 78.36 mmol, 2.50 equiv.) dropwise with stirring at 0 °C. The resulting solution was stirred for 1h at room temperature. The reaction was then quenched by adding water. The pH value of the mixture was adjusted to 8 with 1N sodium hydroxide. The resulting mixture was extracted with 100 mL of DCM. The organic solution was concentrated under vacuum. This resulted in 6 g (87%) of (+/-)64 as a grayish solid. (trans,trans)-3-(hydroxymethyl)-4-(3-hydroxyphenyl)-2-methylpiperidine-1-carboxylate of (+/-)-tert-Butyl [(+/-) 65]

[0351] In a 500 mL round bottom flask, a solution of (+/-)-3-[(trans, trans)-3-(hydroxymethyl)-2-methylpiperidin-4-yl]phenol [( +/-) 64, 6.85 g, 30.95 mmol, 1.00 equiv.] and TEA (9.58 g, 94.67 mmol, 3.00 equiv.) in DCM (200 mL). This was followed by the addition of tert-butyl dicarbonate (8.78 g, 40.23 mmol, 1.30 equiv.) at 0°C. The resulting solution was stirred for 2 h at room temperature and diluted with 100 mL of water. The resulting mixture was extracted with 3x60 mL of DCM and the combined organic layers then concentrated in vacuo. This resulted in 9 g (90%) of (+/-)65 as a grayish solid. (trans,trans)-3-(hydroxymethyl)-2-methyl-4-[3- [(trifluoromethane)sulfonyloxy]phenyl]piperidine-1- (+/-)-tert-butyl carboxylate [(+/-) 66]

[0352] In a 200 mL round bottom flask, a solution of (trans, trans)-3-(hydroxymethyl)-4-(3-hydroxyphenyl)-2-methylpiperidine-1-carboxylate of (+/- )- tert-butyl [(+/-) 65.9 g, 28.00 mmol, 1.00 equiv.)] and TEA (8.57 g, 84.69 mmol, 3.00 equiv.) in DCM ( 200 mL). This was followed by the addition of (trifluoromethane)sulfonyl trifluoromethanesulfonate (15.82 g, 56.07 mmol, 2.00 equiv.) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by adding 100 mL of water. The resulting solution was extracted with 3x100 mL of dichloromethane and the combined organic layers then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 6 g (47%) of (+/-)66 as a yellow oil. (trans, trans)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-2-methyl-4-[3-[(trifluoromethane)sulfonyloxy]phenyl] (+/-)-tert piperidine-1-carboxylate -Butyl [(+/-) 67]

[0353] In a 250 mL round bottom flask, a solution of (trans, trans)-3-(hydroxymethyl)-2-methyl-4-[3-[(trifluoromethane)sulfonyloxy]phenyl]piperidine-1 was placed -(+/-)-tert-butyl carboxylate [(+/-) 66.3 g, 6.62 mmol, 1.00 equiv.], imidazole (1.35 g, 19.85 mmol, 3.00 equiv.) and tert-butyl(chloro)dimethylsilane (2.99 g, 19.84 mmol, 3.00 equiv.) in DCM (80 mL). The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by adding 100 mL of water. The resulting solution was extracted with 3x100 mL of dichloromethane and the combined organic layers then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 3 g (80%) of (+/-)67 as a yellow oil. (trans, trans)-4-[3-(acetylsulfanyl)phenyl]-3-[[(tert-butyldimethylsilyl)oxy]methyl]-2-methylpiperidine-1-(+/-)-tert-Butyl carboxylate [( +/-) 68]

[0354] In a 5 mL vial purged and maintained with an inert argon atmosphere, a solution of (trans, trans)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-2-methyl-4- [(+/-)-tert-butyl [3-[(trifluoromethane)sulfonyloxy]phenyl]piperidine-1-carboxylate [(+/-) 67.1 g, 1.76 mmol, 1.00 equiv.], Pd2 (dba)3,CHCl3 (45.54 mg, 0.04 mmol, 0.03 equiv.), 1-(potassiumsulfanyl)ethan-1-one (300.96 mg, 2.64 mmol, 1.50 equiv. ), Xantphos (59.92 mg, 0.10 mmol, 0.05 equiv.) and DIEA (454.93 mg, 3.52 mmol, 2.00 equiv.) in dioxane (3 mL). The final reaction mixture was irradiated with microwave radiation for 30 min at 160 °C. The reaction was then dissipated with water. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. The organic solution was washed with 2x100 mL of brine and dried over anhydrous magnesium sulfate, then concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 260 mg (30%) of (+/-)68 as a yellow oil. (trans, trans)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-2-methyl-4-[3-(methylsulfanyl)phenyl]piperidine-1-carboxylate of (+/-)-tert-Butyl [ (+/-) 69]

[0355] In a 50 mL round bottom flask purged and maintained with an inert nitrogen atmosphere, a solution of (trans, trans)-4-[3-(acetylsulfanyl)phenyl]-3-[[(tert) was placed - butyldimethylsilyl)oxy]methyl]-2-methylpiperidine-1- (+/-)-tert-butyl carboxylate [(+/-) 68, 600 mg, 1.22 mmol, 1.00 equiv.] and CH3I ( 205.9 mg, 1.45 mmol, 1.20 equiv.) in ethanol (6 mL), then 1N sodium hydroxide (1.46 mL, 1.20 equiv.) was added to the solution. The resulting solution was stirred for 1 h at 0°C. The reaction was then dissipated with water. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. The organic solution was washed with 3x60 mL of brine and dried over anhydrous magnesium sulfate, then concentrated in vacuo. This resulted in 450 mg (80%) of (+/-)69 as a yellow oil. (trans,trans)-3-(hydroxymethyl)-2-methyl-4-[3-(methylsulfanyl)phenyl]piperidine-1-carboxylate of (+/-)-tert-butyl [(+/-) 70]

[0356] In a 50 mL round bottom flask purged and maintained with an inert nitrogen atmosphere, a solution of (trans, trans)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-2-methyl was placed (+/-)-tert-butyl-4-[3-(methylsulfanyl)phenyl]piperidine-1-carboxylate [(+/-) 69.465 mg, 1.00 mmol, 1.00 equiv.] in THF (5 mL). This was followed by addition of TBAF (1mol/L in tetrahydrofuran) (2 mL, 2.00 equiv.) dropwise with stirring at 0 °C. The resulting solution was stirred overnight at room temperature. The reaction was then dissipated with water/ice. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers combined. The organic solution was washed with 3x50 mL of brine and dried over anhydrous magnesium sulfate, then concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 320 mg (91%) of (+/-) 70 as a yellow oil. (+/-)-6-{[(trans, trans)-2-methyl-4-[3-(methylsulfanyl)phenyl]piperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindole -1-one [(+/-) 71]

[0357] (+/-)71 can be prepared from (trans, trans)-3-(hydroxymethyl)-2-methyl-4-[3-(methylsulfanyl)phenyl]piperidine-1-carboxylate of (+/ -)- tert-butyl [(+/-) 70] according to Scheme 14a. LCMS (M+H) 383.1. 14d scheme Preparation of (+/-)-6-{[(trans, trans)-4-(3-methanesulfonylphenyl)-2-methylpiperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindole-1 -one (74) (2E)-3-(3-methanesulfonylphenyl)-N-methoxy-N-methylprop- 2-enamide (72)

[0358] In a 1000 mL round bottom flask purged and maintained with an inert nitrogen atmosphere, a solution of 1-bromo-3-methanesulfonylbenzene (40 g, 170.14 mmol, 1.00 equiv.) was placed, N-methoxy-N-methylprop-2-enamide (29.52 g, 256.40 mmol, 1.50 equiv.) and sodium acetate (27.88 g, 339.86 mmol, 2.00 equiv.) in DMF (500 mL). The resulting solution was stirred for 30 min., then P(o-Tol)3 (5.175 g, 17.00 mmol, 0.10 equiv.) and Pd(OAc)2 (1.9 g, 8.46 mmol , 0.05 equiv.) were added to the solution. The resulting solution was stirred overnight at 120°C. The reaction was then quenched by adding 500 mL of water. The resulting mixture was extracted with 3x200 mL of ethyl acetate and the organic layers combined. The organic solution was washed with 3x500 mL of brine and dried over anhydrous magnesium sulfate. The solids were filtered. The filtrate was concentrated under vacuum. The residue was recrystallized from ethyl acetate:hexane in a ratio of 1:20. This gave 36.6 g (80%) of 72 as a yellow solid. (2E)-3-(3-methanesulfonylphenyl)prop-2-enal (73)

[0359] In a 100 mL round bottom flask purged and maintained with an inert nitrogen atmosphere, a solution of (2E)-3-(3-methanesulfonylphenyl)- N-methoxy-N-methylprop-2-enamide was placed (72, 2.69 g, 9.99 mmol, 1.00 equiv.) and DIBAL-H (1N in hexane, 20 mL, 2.00 equiv.) in THF (30 mL, distilled). The resulting solution was stirred for 2h at -78oC. The reaction was then quenched by adding 50 mL of 1N hydrogen chloride at -78oC. The resulting mixture was extracted with 3x20 mL of ethyl acetate and the combined organic layers then dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 1.6 g (76%) of 73 as a yellow solid. (+/-) -6-{[(trans, trans) -4- (3-methanesulfonylphenyl) -2- methylpiperidin-3-yl]methoxy} -2,3-dihydro-1H-isoindol-1-one [(+/-) 74]

[0360] (+/-)74 can be prepared from (2E)-3-(3-methanesulfonylphenyl)prop-2-enal (73) according to Scheme 14a. LCMS (M+H) 415.1. Scheme 14e Preparation of (+/-)-6-{[(2R,3S)-4-(3,4-dihydro-2H-1-benzopyran-7-yl)-2-methylpiperidin-3-yl]methoxy} -2,3-dihydro- 1H-isoindol-1-one [(+/-) 79] 3-(3-Bromophenoxy)propanoic acid (75)

[0361] In a 2 L round bottom flask with 3 necks, a solution of NaOH (120 g) in water (2000 mL), 3-bromophenol (519 g, 3.00 mol, 1.00 equiv. ). This was followed by adding a solution of 3-bromopropanoic acid (459 g, 3.00 mol, 1.00 equiv.) and NaOH (120 g) in water (3000 mL) dropwise with stirring at 100 °C. The resulting solution was stirred for 48 h at 100 °C. The reaction mixture was cooled to 0 °C with a water/ice bath. The pH value of the solution was adjusted to 1 with hydrogen chloride (12 mol/L). Solids were collected through filtration. The crude product was washed with water and n-pentane. This resulted in 110 g (15%) of 75 as a grayish solid. 7-Bromo-3,4-dihydro-2H-1-benzopyran-4-one (76)

[0362] In a 250 mL round bottom flask with 3 necks purged and maintained in an inert nitrogen atmosphere, 3-(3-bromophenoxy)propanoic acid (75, 20 g, 81.61 mmol, 1.00 equiv.), PCl5 (25.57 g, 122.79 mmol, 1.50 equiv.). The mixture was stirred for 30 min at room temperature. This was followed by the addition of trichloroaluminum (21.89 g, 164.17 mmol, 2.00 equiv.). The resulting solution was stirred for 1 h at 130 °C. The reaction mixture was cooled to room temperature. The reaction was then quenched by adding ice. The resulting solution was extracted with 3x60 mL of ethyl acetate and the organic layers combined. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 9.3 g (50%) of 76 as a yellow solid. 7-Bromo-3,4-dihydro-2H-1-benzopyran (77)

[0363] In a 1000 mL round bottom flask, a solution of 7-bromo-3,4-dihydro-2H-1-benzopyran-4-one (76.60 g, 264.25 mmol, 1.00 equiv.) in trifluoroacetic acid (600 mL), triethylsilane (154.2 g, 1.33 mol, 5.00 equiv.). The resulting solution was stirred overnight at 65°C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 8 with sodium bicarbonate. The resulting solution was extracted with 3x100 mL of dichloromethane and the organic layers combined. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:15). This resulted in 35 g (62%) of 77 as a colorless oil. (2E)-3-(3,4-Dihydro-2H-1-benzopyran-7-yl)prop-2-enal (78)

[0364] In a 1000 mL round bottom flask purged and maintained with an inert nitrogen atmosphere, a solution of 7-bromo-3,4-dihydro-2H-1-benzopyran (77.35 g, 164.26 mmol, 1.00 equiv.) in N,N-dimethylformamide (500 mL), n-Bu4NOAc (99.7 g, 330.13 mmol, 2.00 equiv.), potassium carbonate (34.15 g, 247.09 mmol, 1.50 equiv.), KCl (12.3 g, 165.10 mmol, 1.00 equiv.), Pd(OAc)2 (1.1 g, 4.90 mmol, 0 .03 equiv.), 3,3-diethoxyprop-1-ene (64.38 g, 494.53 mmol, 3.00 equiv.). The resulting solution was stirred overnight at 90°C. The reaction mixture was cooled to room temperature with a water/ice bath. The pH value of the solution was adjusted to 4 with hydrogen chloride (2 mol/L). The mixture was stirred for 30 minutes at room temperature. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x500 mL of brine. The mixture was dried over anhydrous magnesium sulfate. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 9.3 g (30%) of 78 as a yellow oil. (-) -6-{[(2R,3S) -4-(3,4-dihydro-2H-1-benzopyran-7-yl) -2-methylpiperidin-3-yl]methoxy} -2,3 -dihydro-1H-isoindol-1-one [(+/-) 79]

[0365] (+/-)79 can be prepared from (2E)-3-(3,4-dihydro-2H-1-benzopyran-7-yl)prop-2-enal (78) according with Scheme 14a. LCMS (M+H) 393.1. Scheme 14f Preparation of (+/-)-6-{[(trans, trans)-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2-methylpiperidin-3-yl]methoxy} -2,3-dihydro-1H-isoindol-1-one [(+/-) 83] 3,4-Dihydro-2H-1-benzopyran (80)

[0366] In a 1000 mL round bottom flask, a solution of 3,4-dihydro-2H-1-benzopyran-4-one (45 g, 303.73 mmol, 1.00 equiv.) was placed. and Et3SiH (176.63 g, 1.52 mol, 5.00 equiv.) in trifluoroacetic acid (450 mL). The resulting solution was stirred overnight at 65oC. The reaction was then quenched by adding water (500 mL). The resulting solution was extracted with 2X300 mL of DCM and the combined organic layers then concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 28.77 g (71%) of 80 as a colorless oil. 6-Iodo-3,4-dihydro-2H-1-benzopyran (81)

[0367] In a 1000 mL round bottom flask, a mixture of 3,4-dihydro-2H-1-benzopyran (80, 40.7 g, 303.33 mmol, 1.00 equiv.) was placed. and AgNO3 (51.6 g, 303.89 mmol, 1.12 equiv.), I2 (85.3 g, 335.83 mmol, 1.00 equiv.) in methanol (400 mL). The resulting mixture was stirred for 1 h at room temperature. The reaction was then quenched by adding saturated sodium thiosulfate (400 mL). The resulting solution was extracted with 3X200 mL of dichloromethane and the combined organic layers then dried and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane/petroleum ether (1:1). This resulted in 39 g (49%) of 81 as a yellow oil. (2E)-3-(3,4-Dihydro-2H-1-benzopyran-6-yl)prop-2-enal (82)

[0368] In a 2 L round bottom flask purged and maintained with an inert nitrogen atmosphere, a solution of 6-iodo-3,4-dihydro-2H-1-benzopyran (81.52 g, 199.94 mmol, 1.00 equiv.), n-BuNOAc (120.8 g, 400.00 mmol, 2.00 equiv.), potassium carbonate (41.4 g, 299.54 mmol, 1.50 equiv.), KCl (14.9 g, 200.00 mmol, 1.00 equiv.), Pd(OAc)2 (1.35 g, 6.01 mmol, 0.03 equiv.) and 3.3- diethoxyprop-1-ene (78 g, 599.15 mmol, 3.00 equiv.) in DMF (500 mL). The resulting solution was stirred overnight at 90°C. The reaction solution was cooled to room temperature with a water/ice bath. The pH value of the solution was adjusted to 4 with 2N hydrogen chloride. The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x500 mL of water. The mixture was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 24 g (64%) of 82 as a yellow solid. ( + /-)-6-{[(trans, trans)-4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2-methylpiperidin-3-yl]methoxy }-2 ,3-dihydro-1H-isoindole-1-one [(+/-) 83]

[0369] (+/-)83 can be prepared from (2E)-3-(3,4-dihydro-2H-1-benzopyran-6-yl)prop-2-enal (82) according with Scheme 14a. LCMS (M+H) 393.3. Scheme 14g Preparation of (+/-)-6-{[(trans, trans)-4-(1-acetylpiperidin-4-yl)-2-methylpiperidin-3-yl]methoxy}-2,3-dihydro-1H -isoindol-1-one [(+/-) 90] tert-Butyl 4-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]piperidine-1-carboxylate (84)

[0370] In a 1000 mL round bottom flask with 3 necks purged and maintained with an inert nitrogen atmosphere, a solution of sodium hydride (18.24 g, 760.00 mmol, 1.80 equiv.) was placed. in ethylene glycol dimethyl ether (300 mL). This was followed by the addition of ethyl 2-(diethoxyphosphoryl)acetate (102.22 g, 455.95 mmol, 1.80 equiv.) dropwise with stirring at 0 °C. The resulting solution was stirred for 15 min at 0°C. To this was added a solution of tert-butyl 4-formylpiperidine-1-carboxylate (54 g, 253.20 mmol, 1.00 equiv.) in ethylene glycol dimethyl ether (200 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 10 min at 0°C. The reaction was then quenched by adding water/ice. The resulting solution was extracted with 3x300 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1x300 mL of brine. The mixture was dried over anhydrous magnesium sulfate. This resulted in 71 g (99%) of 84 as a yellow oil. tert-Butyl 4-[(1E)-3-hydroxyprop-1-en-1-yl]piperidine-1-carboxylate (85)

[0371] In a 2000 mL round bottom flask with 3 necks purged and maintained with an inert nitrogen atmosphere, a solution of tert-butyl 4-[(1E)- 3-ethoxy-3-oxoprop-1- en-1-yl]piperidine-1-carboxylate (84.65.1 g, 229.74 mmol, 1.00 equiv.) in tetrahydrofuran (distillate) (600 mL). This was followed by addition of DIBAL-H (1M in hexane, 460 mL, 2.00 equiv.) dropwise with stirring at 0°C. The resulting solution was stirred for 1h at 0°C. The reaction was poured into ice/water and filtered through Celite. The product was extracted with 3x100 mL of ethyl acetate and the organic layers combined, then washed with 2x300 mL of brine. The organic solution was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 32 g (58%) of 85 as a light yellow oil. tert-Butyl 4-[(1E)-3-oxoprop-1-en-1-yl]piperidine-1-carboxylate (86)

[0372] In a 1000 mL round bottom flask purged and maintained with an inert nitrogen atmosphere, a solution of 4-[(1E)-3-hydroxyprop-1-en-1-yl]piperidine-1- tert-butyl carboxylate (85.18 g, 74.59 mmol, 1.00 equiv.) in DCM (500 mL). This was followed by the addition of Dess-Martin reagent (38 g, 89.62 mmol, 1.20 equiv.) little by little at 0 °C. The resulting solution was stirred for 30 min at room temperature. The reaction was then quenched by the addition of saturated sodium bicarbonate. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x100 mL of brine. The organic solution was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:2). The resulting mixture was concentrated under vacuum. This resulted in 14.3 g (80%) of 86 as a colorless oil. (+/-)-Ethyl 4-[1-[(tert-butoxy)carbonyl]piperidin-4-yl]-1-[(4-methoxyphenyl)methyl]-2-methylpiperidine-3-carboxylate [(+/ -) 87]

[0373] (+/-)87 can be prepared from tert-butyl 4-[(1E)-3-oxoprop-1-en-1-yl]piperidine-1-carboxylate (86) according to the Scheme 14a. (+/-)-Ethyl 1-[(4-methoxyphenyl)methyl]-2-methyl-4-(piperidin-4-yl)piperidine-3-carboxylate [(+/-) 88]

[0374] In a 50 mL round bottom flask, a solution of 4-[1-[(tert-butoxy)carbonyl]piperidin-4-yl]-1-[(4-methoxyphenyl)methyl]-2 was placed - (+/-)-ethyl methylpiperidine-3-carboxylate [(+/-) 87.474 mg, 1.00 mmol, 1.00 equiv.] in ethyl acetate (10 mL). HCl (gas) was introduced to the resulting solution and stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 340 mg (91%) of (+/-)88 as a grayish solid. (+/-)-Ethyl 4-(1-acetylpiperidin-4-yl)-1-[(4-methoxyphenyl)methyl]-2-methylpiperidine-3-carboxylate [(+/-) 89]

[0375] In a 250 mL round bottom flask with 3 necks purged and maintained with an inert nitrogen atmosphere, a solution of 1-[(4-methoxyphenyl)methyl]-2-methyl-4-(piperidin- (+/-)-ethyl 4-yl)piperidine-3-carboxylate [(+/-) 88.5 g, 13.35 mmol, 1.00 equiv.] and pyridine (2.11 g, 26.68 mmol, 2.00 equiv.) in DCM (100 mL). This was followed by addition of acetic anhydride (2.7 g, 26.47 mmol, 1.98 equiv.) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum to remove the pyridine. This resulted in 3.8 g (68%) of (+/-) 89 as a yellow oil. (+/-) -6-{[(trans, trans) -4- (1-Acetylpiperidin-4-yl) -2- methylpiperidin-3-yl]methoxy} -2,3-dihydro-1H-isoindole -1-one [(+/-) 90]

[0376] (+/-)90 can be prepared from 4-(1-acetylpiperidin-4-yl)-1-[(4-methoxyphenyl)methyl]-2-methylpiperidin-3-carboxylate (+/- )-ethyl [(+/-) 89] via Scheme 14a. LCMS (M+H) 386.1, Scheme 14h Synthesis of (+/-)-6-{[(trans, trans)-4-(2,3-dihydro-1-benzofuran-5-yl)-2-methylpiperidin-3-yl]methoxy}-2 ,3-dihydro-1H-isoindol-1-one [(+/-) B0856] (2E)-3-(2,3-dihydro-1-benzofuran-5-yl)prop-2-enal (91)

[0377] In a 1000 mL round bottom flask, a solution of 5-bromo-2,3-dihydro-1-benzofuran (70 g, 351.68 mmoles, 1.00 equiv.) in N was placed ,N-dimethylformamide (500 mL), nBu4NOAc (213.5 g, 706.95 mmol, 2.01 equiv.), K2CO3 (73.2 g, 529.63 mmol, 1.51 equiv.), KCl (26 .3 g, 353.02 mmol, 1.00 equiv.), Pd(OAc)2 (2.35 g, 10.47 mmol, 0.03 equiv.), 1,1-diethoxypropane (137.8 g, 1.04 mol, 2.96 equiv.). The resulting solution was stirred overnight at 90°C. The pH value of the solution was adjusted to 4 with hydrogen chloride (2 M). The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers combined and concentrated in vacuo. The crude product (25 g) was purified using Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, EA/PE (0-50%) within 50 min; Detector, UV 254 nm. 18 g of product were obtained. This resulted in 18 g (29%) of (2E)-3-(2,3-dihydro-1-benzofuran-5-yl)prop-2-enal (91) as a yellow oil. (+/-)-6-{[(trans, trans)-4-(2,3-dihydro-1-benzofuran-5-yl)-2-methylpiperidin-3-yl]methoxy}-2.3 -dihydro-1H-isoindole-1-one [(+/-) B0856]

[0378] (+/-)B0856 can be prepared from (2E)-3-(3,4-dihydro-2H-1-benzopyran-6-yl)prop-2-enal (91) according with Scheme 14a. LCMS (M+H) 379.2. Scheme 14i Synthesis of (+/-)-6-{[(trans, trans)-2-(fluoromethyl)-4-(4-methoxyphenyl)-1-(2-phenylethyl)piperidin-3-yl]methoxy}-2, Ethyl 3-dihydro-1H-isoindol-1-one [(+/-) B1216] 4-fluoro-3-oxobutanoate (92)

[0379] In a 500 mL 3-neck round bottom flask purged and maintained with an inert nitrogen atmosphere, a solution of ethyl acetate (16 g, 181.60 mmol, 1.10 equiv.) in tetra -hydrofuran (100 mL). This was followed by addition of LDA (freshly prepared) (120 mL, 1.20 equiv.) dropwise with stirring at -78oC. The resulting solution was stirred for 0.5 at -78°C. To this was added ethyl 2-fluoroacetate (18 g, 169.66 mmol, 1.00 equiv.) dropwise with stirring at -78°C. The resulting solution was stirred overnight at r.t. The reaction was then quenched by adding 200 mL of 10% hydrogen chloride. The resulting solution was extracted with 3x500 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 17.6 g (70%) of (92) as a brown liquid. (2E)-4-fluoro-3-[[(4-methoxyphenyl)methyl]amino]but-2-ethyl enoate

[0380] In a 250 mL round bottom flask purged and maintained with an inert nitrogen atmosphere, (4-methoxyphenyl)methanamine (16.3 g, 118.82 mmol, 1.00 equiv.), dichloromethane (16.3 g, 118.82 mmol, 1.00 equiv.) was placed. 100 mL), 92 (17.6 g, 118.81 mmol, 1.00 equiv.), I2 (3.1 g, 0.10 equiv.). The resulting solution was stirred overnight at room temperature. The resulting mixture was washed with 2x300 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:20). This resulted in 17.5 g (55%) of ethyl (2E)-4-fluoro-3-[[(4-methoxyphenyl)methyl]amino]but-2-enoate as a light yellow oil. Ethyl 2-(fluoromethyl)-4-(4-methoxyphenyl)-1-[(4-methoxyphenyl)methyl]-1,4-dihydropyridine-3-carboxylate (93)

[0381] In a 500 mL round bottom flask, (2E)-3-(4-methoxyphenyl)prop-2-enal (17.5 g, 107.90 mmol, 1.00 equiv.) was placed, ( 2E)-4-fluoro-3-[(4-methoxyphenyl)methyl]aminobut-2-enoate (10.6 g, 39.66 mmol, 1.00 equiv.), ethanol (200 mL). The resulting solution was stirred for 3 days at 60°C. The resulting mixture was concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:15). This resulted in 12 g (27%) of 93 as a brown oil. ( + /-) -6-{[(trans, trans) -2- (fluoromethyl) -4- (4-methoxy phenyl)piperidin-3-yl]methoxy} -2,3-dihydro-1H-isoindole -1-one [(+/-) 94]

[0382] (+/-)94 can be prepared from 2-(fluoromethyl)-4-(4-methoxyphenyl)-1-[(4-methoxyphenyl)methyl]-1,4-dihydropyridine-3- ethyl carboxylate (93) according to Scheme 14a. (+/-)-6-{[(trans,trans)-2-(fluoromethyl)-4-(4-methoxy phenyl)-1-(2-phenylethyl)piperidin-3-yl]methoxy}-2,3 -dihydro- 1H-isoindol-1-one [(+/-) B1216]

[0383] (+/-)B1216 can be prepared from (+/- )94 according to Scheme 4, LCMS (M+H) 489.1. Scheme 14j Synthesis of (-)-6-{[trans, trans-4-(3-fluoro-5-methoxyphenyl)-2-methyl-1-[2-(1H-pyrrol-1-yl)ethyl]piperidin-3- yl]methoxy}-2,3-dihydro-1H-isoindol-1-one [(+/-) B1401] (2E)-3-(3-fluoro-5-methoxyphenyl)prop-2-enal (95 )

[0384] In a 2 L round bottom flask purged and maintained with an inert nitrogen atmosphere, 1-bromo-3-fluoro-5-methoxybenzene (45 g, 219.49 mmol, 1.00 equiv.) was placed. , nBu4NOAc (132.9 g, 2.00 equiv.), potassium carbonate (45.5 g, 329.21 mmol, 1.50 equiv.), KCl (16.4 g, 1.00 equiv.), Pd(OAc)2 (1.32 g, 5.88 mmol, 0.03 equiv.), N,N-dimethylformamide (1 L), 3,3-diethoxyprop-1-ene (85.8 g, 659. 06 mmol, 3.00 equiv.). The resulting solution was stirred overnight at 90°C. The reaction was then quenched by adding 500 mL of 2N hydrogen chloride. The resulting solution was extracted with 3x1 L of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3x1 L of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was recrystallized from hexane. This resulted in 13 g (33%) of 95 as a yellow solid. (+/-)-6-{[(trans, trans)-4-(3-fluoro-5-methoxyphenyl)-2-methylpiperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindole -1-one [(+/-) 96]

[0385] (+/-)96 can be prepared from (2E)-3-(3-fluoro-5-methoxyphenyl)prop-2-enal (95) according to Scheme 14a. (-)-6-{[trans, trans-4-(3-fluoro-5-methoxyphenyl)-2-methyl-1-[2-(1H-pyrrol-1-yl)ethyl]piperidin-3-yl] methoxy}-2,3-dihydro-1H-isoindol-1-one [(+/-) B1401]

[0386] (-)B1401 can be prepared from (+/- )96 according to Scheme 5a. LCMS (M+H) 478.2. 14k scheme Synthesis of ( + /-)-6-{[(trans, trans)-2-ethyl-4-(4-methoxyphenyl)piperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindole- Ethyl 1-one [(+/-) B0770] (2Z)-3-{[(4-methoxyphenyl)methyl]amino}pent-2-enoate (97)

[0387] In a 100 mL round bottom flask, (4-methoxyphenyl)methanamine (10 g, 72.90 mmol, 1.00 equiv.), ethyl 3-oxopentanoate (10.5 g, 72.00 equiv.) were placed. 83 mmol, 1.00 equiv.), iodide (1.9 g, 7.49 mmol, 0.20 equiv.). The resulting solution was stirred for 20 min at 25°C. The resulting solution was diluted with 50 mL of brine. The resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined and concentrated in vacuo. This resulted in 20 g (crude) of 97 as a red oil. (+/-)-6-{[(trans, trans)-2-ethyl-4-(4-methoxyphenyl)piperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindole- 1- one [(+/-) B0770]

[0388] (+/-)B0770 can be prepared from ethyl (2Z)-3-{[(4-methoxyphenyl)methyl]amino}pent-2-enoate (97) according to Scheme 14a. LCMS (M+H) 381.2. Scheme 14l Synthesis of (+/-)-6-{[(2R,3S,4R)-4-(1H-indol-6-yl)-2-methyl- 1- [2- (1H-pyrrol-1-yl) ethyl]piperidin-3-yl]methoxy}-2,3-dihydro- 1H-isoindol-1-one [(+/-) B1330 4-(1H-indol-6-yl)-2-methyl-1 ,2,5,6-tetrahydropyridine- (+/-)-1-tert-Butyl 3-ethyl 1,3-dicarboxylate [(+/-) 98]

[0389] In a 250 mL round bottom flask, 2-methyl-4-[(trifluoromethane)sulfonyloxy]-1,2,5,6-tetrahydropyridine-1,3-dicarboxylate of 1-tert- butyl 3-ethyl (7.5 g, 17.97 mmol, 1.00 equiv.), CH3COOK (5.25 g, 53.50 mmol, 3.00 equiv.), a solution of dioxane (75 mL) in water (75 mL), Pd(dppf)Cl2 (680 mg, 0.93 mmol, 0.05 equiv.), (1H-indol-5-yl)boronic acid (2.88 g, 17.89 mmol, 1 .00 equiv.). The resulting solution was stirred for 1 h at 100 °C in an oil bath, then extracted with 3x50 mL of DCM and the organic layers combined. The resulting mixture was washed with 2x50 mL of sodium chloride. The solution was dried and concentrated under vacuum. This resulted in 5.5 g (80%) of (+/-) 98 as a white solid. (+/-) 4-[1-[(tert-butoxy)carbonyl]-1H-indol-6-yl]-2-methyl-1,2,5,6-tetrahydropyridine-1,3-dicarboxylate -1- tert-Butyl 3-ethyl [(+/-) 99]

[0390] In a 500 mL round bottom flask, a solution of (+/-) 98 (5.4 g, 14.05 mmol, 1.00 equiv.) in dichloromethane (200 mL) was placed, di-tert-butyl (3.37 g, 15.44 mmol, 1.10 equiv.), 4-dimethylaminopyridine (514 mg, 4.21 mmol, 0.30 equiv.), DIEA (3.63 g, 28 .09 mmol, 2.00 equiv.). The resulting solution was stirred overnight at room temperature, then washed with 2x100 mL of hydrogen chloride (1M). The resulting solution was extracted with 3x200 mL of dichloromethane and the organic layers combined and dried and concentrated in vacuo. This resulted in 6 g (88%) of (+/-) 99 as a white solid. (trans, trans)-4-[1-[(tert-butoxy)carbonyl]-1H-indol-6-yl]-2-methylpiperidine-1,3-dicarboxylate (+/-)-1-tert-Butyl 3-ethyl [(+/-) 100]

[0391] In a 25 mL round bottom flask, a solution of (+/-) 99 (80 mg, 0.17 mmol, 1.00 equiv.) in EA (5 mL), Rh/C ( 60 mg), H2 (3 atm). The resulting solution was stirred overnight at room temperature. The solids were filtered. The resulting mixture was concentrated under vacuum. This resulted in 70 mg (87%) of (+/-) 100 as a yellow oil. (+/-)-6-[[(trans, trans)-4-(1H-indol-6-yl)-2-methylpiperidin-3-yl]methoxy]-2,3-dihydro-1H-isoindole -1-one [(+/-) 101]

[0392] [(+/-) 101] can be prepared from (trans, trans)-4-[1-[(tert-butoxy)carbonyl]-1H-indol-6-yl]-2-methylpiperidine- (+/-)-1-tert-Butyl 3-ethyl 1,3-dicarboxylate according to Scheme 14a. ( + /-) -6-{[(2R,3S,4R)-4-(1H-indol-6-yl)-2-methyl-1-[2-(1H-pyrrol-1-yl)ethyl] piperidin-3-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one [(+/-) B1330]

[0393] (+/-)B1330 can be prepared from (+/-)-6-[[(trans, trans)-4-(1H-indol-6-yl)-2-methylpiperidin-3-yl ]methoxy]-2,3-dihydro-1H-isoindol-1-one according to Scheme 5a. LCMS Scheme14m Synthesis of ( + /-)-6-{[(trans)-7-(4-methoxyphenyl)-4-(2-phenylethyl)-4-azaspiro[2,5]octan-8-yl]methoxy}-2 ,3-dihydro-1H-isoindol-1-one [(+/-) B1126] 4-t-Butyl 6-methyl 7-oxo-4-azaspiro[2,5]octane-4,6-dicarboxylate , 4-t-butyl 8-methyl 7-oxo-4-azaspiro[2,5]octane-4,6-dicarboxylate (103)

[0394] In a 100 mL round bottom flask, a solution of methyl 3-[[(tert-butoxy)carbonyl][1-(2-methoxy-2-oxoethyl)cyclopropyl]amino]propanoate (3 .15 g, 9.99 mmol, 1.00 equiv.) in toluene (30 mL), t-BuOK (3.37 g, 30.09 mmol, 3.00 equiv.). The resulting solution was stirred for 10 h at 80 °C. The residue was applied to a silica gel column with ethyl acetate/petroleum ether (1:3). This resulted in 1.7 g (60%) of a mixture of # and # as a yellow oil. The mixture was purified using Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, ACN in water to 0% ACN increasing to 90% ACN within 40 min; Detector, UV 220 nm. This resulted in 300 mg of 102 and 600 mg of 103. (+/-)-6-{ [(trans) -7- (4-methoxyphenyl) -4-azaspiro[2.5]octan- 8-yl]methoxy }-2,3-dihydro-1H-isoindol-1-one [(+/-) 104]

[0395] [(+/-) 104] can be prepared from 4-tert-butyl 8-methyl 7-oxo-4-azaspiro[2,5]octane-4,8-dicarboxylate according to the Schemes 1 and 14a. (+/-)-6-{[(trans)-7-(4-methoxyphenyl)-4-(2-phenylethyl)-4- azaspiro[2.5]octan-8-yl]methoxy}-2.3 -dihydro-1H-isoindole-1-one [(+/-) B1126]

[0396] (+/-)B1126 can be prepared from ( + /-) -6-{[(trans) -7- (4-methoxyphenyl) -4-azaspiro[2,5]octan-8- yl ]methoxy}-2,3-dihydro-1H-isoindol-1-one according to Scheme 4, LCMS (M+H) 483.2. General Procedure A12: Preparation of bridged bicyclic 3,4-Piperidine NH analogues Scheme 15 Preparation of (+/-)-exo-trans-6-{[3-(4-Methoxyphenyl)-8-azabicyclo[3,2,1]octan-2-yl]methoxy}isoindolin-1-one [(+ /-) B0631] and (+/-)-endo-trans-6-{[3-(4-Methoxyphenyl)-8- azabicyclo[3,2,1]octan-2-yl]methoxy}isoindolin-1- onea [(+/-) B0630] 3-Oxo-8-azabicyclo[3,2,1]octane-2,8-dicarboxylate of (+/-)- 8-tert-Butyl 2-Methyl [(+/- ) 105]

[0397] A solution of dimethyl carbonate (4.0 g, 44.4 mmol) in anhydrous toluene (20 mL) was added dropwise over 30 min to a suspension of sodium hydride (3.2 g, 82.1 mmol, 60% dispersion in mineral oil) in anhydrous toluene (60 mL) at room temperature under nitrogen, after which the mixture was heated to 80 ° C. Anhydrous methanol (0.5 mL) was added, followed by dropwise addition of a solution of (+/-)-tert-butyl 3-oxo-8-azabicyclo[3,2,1]octane-8-carboxylate commercially available [5.0 g, 22.2 mmol] in anhydrous toluene (20 mL) over 30 min. Stirring at 80 °C was continued for 12 h, after which the mixture was cooled to room temperature, slowly diluted with water (5 mL) and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (1:1), to give (+/-) 105 as a light yellow oil (5.4 g, 82% ): LCMS (M+H) 284. 3-{[(Trifluoromethyl)sulfonyl]oxy}-8-azabicyclo[3,2,1]oct-2-ene-2,8-dicarboxylate (+/-)- 8-tert-Butyl 2-Methyl [(+/-) 106]

[0398] Prepared in accordance with General Procedure A9 to provide (+/-) 106 as a crude amber oil (8.4 g) that was suitable for use in the next step without purification: LCMS (M+H) 416.3 -(4-Methoxyphenyl)-8-azabicyclo[3,2,1]oct-2-ene-2,8- (+/-)-8-tert-Butyl 2-Methyl dicarboxylate [(+/-) 107 ]

[0399] Prepared according to General Procedure A1 to provide (+/-) 107 as a light yellow oil (5.4 g, 71% over two steps): LCMS (M+H) 374. 3-( 4-Methoxyphenyl)-8-azabicyclo[3,2,1]octane-2,8-dicarboxylate of (+/-)-exo-cis-8-tert-Butyl 2-Methyl [(+/-) 108] and 3-(4-Methoxyphenyl)-8-azabicyclo[3,2,1]octane-2,8-(+/-)-endo-cis-8-tert-Butyl 2-Methyl dicarboxylate [(+/) 109 ]

[0400] Prepared according to General Procedure A1 to provide (+/-)108 and (+/-)109 as an inseparable mixture in an indeterminate proportion as a colorless oil (840 mg) that was suitable for use in the next step without purification: LCMS (M+H) 376. (+/-)-exo-trans-8-tert 3-(4-Methoxyphenyl)-8-azabicyclo[3,2,1]octane-2,8-dicarboxylate -Butyl 2-Methyl [(+/) 110] and 3-(4-Methoxyphenyl)-8-azabicyclo[3,2,1]octane-2,8- (+/-)-endo-trans-8 dicarboxylate -tert-Butyl 2-Methyl [(+/-) 111]

[0401] Prepared according to General Procedure A1 to provide (+/-) 110 and (+/-) 111 as an inseparable mixture in an indeterminate proportion as a colorless oil (730 mg, 97% over two steps) : LCMS (M+H) 376. (+/-)-exo-trans-tert 2-(Hydroxymethyl)-3-(4-methoxyphenyl)-8-azabicyclo[3,2,1]octane-8-carboxylate -Butyl [(+/-) 112] and 2-(Hydroxymethyl)-3-(4-methoxyphenyl)-8-azabicyclo[3,2,1]octane-8-carboxylate of (+/-)-endo-trans - tert-Butyl [(+/-) 113]

[0402] Prepared according to General Procedure A1 to provide (+/-) 112 and (+/-) 113 as an inseparable mixture in an indeterminate proportion as a colorless oil (510 mg, 78%): LCMS (M+ H) 348. 3-(4-Methoxyphenyl)-2-{[(3-oxoisoindolin-5-yl)oxy]methyl}-8-azabicyclo[3,2,1]octane-8-carboxylate (+/- )-exo-trans-tert-Butyl [(+/-) 114] and 3-(4-Methoxyphenyl)-2-{[(3-oxoisoindolin-5-yl)oxy]methyl}-8-azabicyclo[3, 2,1]octane-8- (+/-)-endo-trans-tert-Butyl carboxylate [(+/-) 115]

[0403] Prepared according to General Procedure A1 to provide (+/-) 114 and (+/-) 115 as an inseparable mixture in an indeterminate proportion as a colorless oil (162 mg) that was suitable for use in the next step without purification: LCMS (M+H) 479. (+/-)-exo-trans-6-{[3-(4-Methoxyphenyl)-8-azabicyclo [3,2,1]octan-2-yl]methoxy }isoindolin-1-one [(+/-) B0631] and (+/-)-endo-trans-6-{[3-(4-Methoxyphenyl)-8- azabicyclo[3,2,1]octan-2 -yl]methoxy}isoindolin-1-one [(+/-) B0630].

[0404] Prepared according to General Procedure A1: (+/-) B0631 was isolated as a white solid (22 mg, 8% over two steps): LCMS (M+H) 379; 1H NMR (500 MHz, CD3OD) δ 7.47 (d, J = 9.0 Hz, 1H), 7.23-7.19 (m, 4H), 6.84 (d, J = 7.0 Hz , 2H), 4.41-4.38 (m, 3H), 4.28-4.25 (m, 1H), 3.91 (dd, J = 10.0, 3.5 Hz, 1H), 3.82 (dd, J = 10.0, 6.5 Hz, 1H), 3.73 (s, 3H), 3.59-3.54 (m, 1H), 2.62 (dt, J = 14.0, 2.5 Hz, 1H), 2.45-2.44 (m, 1H), 2.36-2.33 (m, 2H), 2.25-2.20 (m, 2H) , 1.97-1.92 (m, 1H). Also, (+/-) B0630 was isolated as a white solid (18 mg, 7% over two steps): LCMS (M+H) 379; 1H NMR (500 MHz, CD3OD) δ 7.47 (d, J = 9.0 Hz, 1H), 7.25-7.19 (m, 4H), 6.89 (d, J = 7.0 Hz , 2H), 4.38 (s, 2H), 4.17-4.11 (m, 2H), 3.95-3.90 (m, 1H), 3.84-3.81 (m, 1H) ), 3.76 (s, 3H), 2.96-2.89 (m, 1H), 2.61-2.55 (m, 1H), 2.36-2.29 (m, 2H), 2.27-2.16 (m, 2H), 2.10-2.04 (m, 1H), 1.80-1.75 (m, 1H). General Procedures A13: Preparation of ligand-modified 3,4-Piperidine NH analogs Scheme 16 Scheme 17 Scheme 18 Scheme 19 Scheme 20 Scheme 21 Preparation of (+/-)-3-({[trans-4-(4-Methoxyphenyl)piperidin-3-yl]methyl}thio)benzonitrile hydrochloride [(+/-) B0513], Scheme 16 3-{[ (3-Cyanophenyl)thio]methyl}-4-(4-methoxyphenyl)piperidine-1-carboxylate (+/-)-trans-tert-Butyl [(+/-) 116]

[0405] Prepared according to General Procedure A1 to provide (+/-) 116 as a yellow oil (170 mg, 77%): LCMS (M+H) 439. Methoxyphenyl)piperidin-3-yl]methyl}thio )benzonitrile [(+/-) B0513]

[0406] Prepared according to General Procedure A1 to provide (+/-) B0513 as a white hygroscopic solid (94 mg, 64%): LCMS (M+H) 339; 1H NMR (300 MHz, CD3OD) δ 7.58-7.53 (m, 1H), 7.43-7.39 (m, 2H), 7.32-7.29 (m, 1H), 7, 09 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 3.77 (d, J = 2.3 Hz, 1H), 3.44 (d, J = 12.6 Hz, 1H), 3.16-2.86 (m, 3H), 2.73-2.55 (m, 2H), 2.19 -1.81 (m, 3H). Preparation of (+/-)-3-({[trans-4-(4-Methoxyphenyl)piperidin-3-yl]methyl}sulfonyl)-benzonitrile hydrochloride [(+/-) B0538], Scheme 17 3-{ [(3-Cyanophenyl)sulfonyl]methyl}-4-(4-methoxyphenyl)piperidine-1-carboxylate of (+/-)-trans-tert-Butyl [(+/-) 117].

[0407] A solution of (+/-)-trans-tert-butyl 3-{[(3-cyanophenyl)thio]methyl}-4-(4-methoxyphenyl)piperidine-1-carboxylate [(+/-) 116, 210 mg, 0.48 mmol] in methanol (3 mL) was added dropwise to a solution of Oxone (590 mg, 0.96 mmol) in water (3 mL) at 0 °C, after which the The mixture was slowly warmed to room temperature with stirring for a total of 12 h. Methanol was removed under reduced pressure and the aqueous layer mixture was diluted with saturated aqueous sodium bicarbonate (50 ml) and extracted with methylene chloride (3 x 25 ml). The combined organic extracts were washed with brine (20 ml), the solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (1:1) to provide (+/-) 117 as a white solid (148 mg, 59%): LCMS (M+H) 471. (+/-)-3-({[trans-4-(4-Methoxyphenyl)piperidine hydrochloride -3-yl]methyl}sulfonyl)-benzonitrile [(+/-) B0538]

[0408] Prepared according to General Procedure A1 to provide (+/-) B0538 as a white solid (101 mg, 83%): LCMS (M+H) 371; 1H NMR (500 MHz, CD3OD) δ 8.12 (d, J = 7.8 Hz, 1H), 8.03 (s, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.79 (t, J = 7.9 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 4, 04 (dd, J = 12.8, 4.0 Hz, 1H), 3.80 (s, 3H), 3.49 (d, J = 12.8 Hz, 1H), 3.23 (dd, J = 4.8, 3.2 Hz, 1H), 3.14-2.98 (m, 3H), 2.62 (dt, J = 11.8, 4.0 Hz, 1H), 2.39 ( dq, J = 10.2, 1.2 Hz, 1H), 2.03-1.84 (m, 2H). Preparation of (+/-)-6-{[trans-4-(4-Methoxyphenyl)piperidin-3-yl)methyl]amino}isoindolin-1-one hydrochloride [(+/-) B0492], Scheme 18 6 (+/-)-trans-tert-Butyl -({[1-(tert-Butoxycarbonyl)-4-(4-methoxyphenyl)-piperidin-3-yl]methyl}amino)-1-oxoisoindoline-2-carboxylate [(+/-) 118]

[0409] Prepared in accordance with General Procedure A5 to provide (+/-)118 as a crude orange oil (85 mg) that was suitable for use in the next step without purification: LCMS (M+H) 552, Hydrochloride ( +/-)-6-{[trans-4-(4-Methoxyphenyl) piperidin-3-yl)methyl]amino}isoindolin-1-one [(+/-) B0492]

[0410] Prepared according to General Procedure A1 to provide (+/-) B0492 as a yellow solid (8 mg, 4% over two steps): LCMS (M+H) 352; 1H NMR (500 MHz, CD3OD) δ 7.67 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 8 .2 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 4.44 (d, J = 17.4 Hz, 1H), 4.29 (d, J = 17.4 Hz, 1H), 3.72 (s, 3H), 3.62-3.53 (m, 1H), 3.47 (d, J = 11.9 Hz, 2H), 3.18-3.09 (m, 1H), 2.96 (t, J = 11.6 Hz, 1H), 2.79-2.62 (m, 2H), 1.98 (s, 2H). Preparation of (+/-)-6-{[(trans-4-(4-Methoxyphenyl)piperidin-3-yl)methyl](methyl)-amino}isoindolin-1-one dihydrochloride [(+/-) B0504 ], Scheme 19 6-({[-1-(tert-Butoxycarbonyl)-4-(4-methoxyphenyl)-piperidin-3-yl]methyl}[methyl]amino)-1-oxoisoindoline-2-carboxylate (+ /-)-trans-tert-Butyl [(+/-) 119]

[0411] Paraformaldehyde (13 mg, 0.45 mmol) was added to a solution of 6-({[1-(tert-butoxycarbonyl)-4-(4-methoxyphenyl)piperidin-3-yl]methyl}amino)- (+/-)-trans-tert-butyl 1-oxoisoindoline-2-carboxylate [(+/-) 118.83 mg, 0.15 mmol] in methanol (5 mL) at room temperature under nitrogen and the mixture was stirred for 10 min. Sodium cyanoborohydride (28 mg, 0.45 mmol) was then added, after which the mixture was stirred at room temperature for 12 h. The mixture was diluted with water (60 mL) and extracted with methylene chloride (3 x 30 mL). The combined organic extracts were washed with brine (20 mL) and the solvents were removed under reduced pressure. The residue was purified twice by rapid column chromatography on silica gel, the first time eluting with hexanes/ethyl acetate (1:9) and the second time eluting with methylene chloride/methanol (4:2), to provide (+/-)119 as an orange oil (18 mg) that was suitable for use in the next step without purification: LCMS (M+H) 566. (+/-)-6-{[(trans-4) dihydrochloride -(4-Methoxyphenyl)piperidin-3-yl)methyl](methyl)-amino}isoindolin-1-one [(+/-) B0504]

[0412] Prepared according to General Procedure A1 to provide (+/-) B0504 as a yellow solid (10 mg, 15% over two steps): LCMS (M+H) 366; 1H NMR (500 MHz, CD3OD) δ 7.72 (s, 1H), 7.67 (s, 2H), 7.24 (d, J = 8.2 Hz, 2H), 6.87 (d, J = 8.2 Hz, 2H), 4.44 (d, J = 17.6 Hz, 1H), 4.28 (d, J = 17.6 Hz, 1H), 3.70 (s, 3H), 3.59-3.54 (m, 1H), 3.46 (d, J = 11.7 Hz, 2H), 3.38-3.34 (m, 1H), 3.18-3.09 ( m, 1H), 2.96 (t, J = 11.8 Hz, 1H), 2.78-2.62 (m, 2H), 2,021.93 (m, 2H). Preparation of (+/-)-3-{(E)-2-[trans-4-(4-Methoxyphenyl)piperidin-3-yl]vinyl}benzonitrile hydrochloride [(+/-) B0524], Scheme 20 3 -Formyl-4-(4-methoxyphenyl)piperidine-1-carboxylate of (+/-)-trans-tert-Butyl [(+/-) 120]

[0413] Dess-Martin periodinane (1.74 g, 4.1 mmol) was added to a solution of (+/-)-3-(hydroxymethyl)-4-(4-methoxyphenyl)piperidine-1-carboxylate trans-tert-butyl [(+/-) 6, 880 mg, 2.7 mmol, prepared as described in General Procedure A] in methylene chloride (30 mL) at room temperature under nitrogen and the mixture was stirred for 12 h . The mixture was washed with saturated sodium bicarbonate and sodium bisulfite solutions (20 ml each) and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (2:1), to give (+/-) 120 as a yellow oil (470 mg, 53%): LCMS (M+H) 320. 3-[(E)-3-Cyanostyryl]-4-(4-methoxyphenyl)piperidine-1-(+/-)-trans-tert-Butyl carboxylate [(+/-) 121 ]

[0414] Sodium hydride (50 mg, 1.2 mmol, 60% in mineral oil) was added to a solution of [(3-cyanophenyl)methyl]triphenylphosphonium bromide (574 mg, 1.2 mmol) in anhydrous DMSO (5 mL) at room temperature under nitrogen and the mixture was heated to 60 ° C and stirred for 2 h. The mixture was cooled to room temperature for the addition of a solution of (+/-)-trans-tert-butyl 3-formyl-4-(4-methoxyphenyl)piperidine-1-carboxylate [(+/-) 120 , 200 mg, 0.63 mmol] in anhydrous DMSO (5 mL), after which the mixture was heated again to 60 °C and stirred for 12 h. The cold mixture was treated with water (0.5 mL), further diluted with saturated sodium bicarbonate solution (40 mL) and extracted with ethyl acetate (3 x 20 mL). The organic extracts were combined and the solvents were removed under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (1:1), to give (+/-) 121 as an amber oil (179 mg, 68%): LCMS (M+H) 419. (+/-)-3-{(E)-2-[trans-4-(4-Methoxyphenyl)piperidin-3-yl]vinyl}benzonitrile hydrochloride [(+/-) B0524 ]

[0415] Prepared according to General Procedure A1 to provide (+/-) B0524 as a white solid (20 mg, 90%): LCMS (M+H) 319; 1H NMR (300 MHz, CD3OD) δ 7.57-7.38 (m, 4H), 7.16 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.8 Hz , 2H), 6.31 (d, J = 16.1 Hz, 1H), 6.02 (dd, J = 16.0, 7.7 Hz, 1H), 3.72 (s, 3H), 3 .49 (t, J = 10.9 Hz, 2H), 3.22-3.03 (m, 2H), 2.89-2.78 (m, 2H), 2.10-1.93 (m , 2H). Preparation of (+/-)-3-{2-[trans-4-(4-Methoxyphenyl) piperidin-3-yl]ethyl}benzonitrile [(+/-) B0530], Scheme 21 3-(3-Cyanophenethyl) (+/-)-trans-tert-Butyl-4-(4-methoxyphenyl)piperidine-1-carboxylate [(+/-) 122]

[0416] A mixture of (+/-)-trans-tert-butyl 3-[(E)-3-cyanostyryl]-4-(4-methoxyphenyl)piperidine-1-carboxylate [(+/-) 121, 150 mg, 0.35 mmol] and 10% palladium on barium sulfate (100 mg) in anhydrous ethanol (10 mL) at room temperature under nitrogen was exchanged with a hydrogen atmosphere (balloon), after which the mixture was stirred for 12 hours. The atmosphere was exchanged for nitrogen, the mixture was diluted with methylene chloride (50 mL) and the solids were removed by filtration under reduced pressure through a Celite buffer, eluting with methylene chloride (50 mL). The solvents in the organic extract were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (1:1), to give (+/-) 122 as a amber oil (52 mg, 35%): LCMS (M+H) 421. (+/-)-3-{2-[trans-4-(4-Methoxyphenyl)piperidin-3-yl]ethyl}benzonitrile [( +/-) B0530]

[0417] Prepared according to General Procedure A1 to provide (+/-) B0530 as a white solid (27 mg, 70%): LCMS (M+H) 321; 1H NMR (300 MHz, CD3OD) δ 7.51 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.32-7.26 (m , 2H), 7.04 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 3.78 (s, 3H), 3.48 (dd , J = 12.5, 3.1 Hz, 1H), 3.28-3.22 (m, 1H), 3.92 (dt, J = 12.5, 3.5 Hz, 1H), 2, 71-2.56 (m, 2H), 2.50-2.33 (m, 2H), 1.92-1.66 (m, 3H), 1.58-1.47 (m, 1H), 1.38-1.23 (m, 1H). General Procedure A14: Preparation of 6-Methyl-3,4-Piperidine NH analogues Scheme 22 Preparation of (+/-)-6-{[trans,trans-4-(4-Methoxyphenyl)-6-methylpiperidin-3-yl]methoxy}isoindolin-1-one [(+/-) B0655], Scheme 22 (+/-)-tert-Butyl 3-Methyl 6-Methyl-4-oxopiperidine-1,3-dicarboxylate [(+/-) 124]

[0418] Prepared in accordance with General Procedure A12 to provide (+/-) 124 as an amber oil (3.7 g, 58%): LCMS (M+H) 272. 6-Methyl-4-{[( (+/-)-1-tert-Butyl 3-Methyl trifluoromethyl)sulfonyl]oxy}-5,6-dihydropyridine-1,3(2H)-dicarboxylate [(+/-) 125]

[0419] Prepared according to General Procedure A9 to provide crude (+/-)125 as an amber oil (5.2 g) which was used in the next step without purification: LCMS (M+H) 404. 4-( (+/-)-1-tert-Butyl 3-Methyl 4-Methoxyphenyl)-6-methyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate [(+/-) 126]

[0420] Prepared according to General Procedure A1 to provide (+/-)126 as a light brown oil (3.7 g, 81% over two steps): LCMS (M+H) 362. 4-( 4-Methoxyphenyl)-6-methylpiperidine-1,3-dicarboxylate of (+/-)-1-tert-Butyl cis,trans-3-Methyl [(+/-) -cis,trans- 127] and 4-( (+/-)-1-tert-Butyl cis,cis-3-Methyl 4-Methoxyphenyl)-6-methylpiperidine-1,3-dicarboxylate [(+/-) -cis,cis-128]

[0421] Prepared in accordance with General Procedure A1 to provide (+/-)-cis,trans-127 and (+/-)-cis,ci s-128 as an inseparable mixture of an indeterminate proportion as a colorless oil ( 3.2 g, 85 %): LCMS (M+H) 364. (+/-)-1-tert-Butyl trans, trans- 4-(4-Methoxyphenyl)-6-methylpiperidine-1,3-dicarboxylate 3-Methyl [(+/-) - trans,trans-129] and 4-(4-Methoxyphenyl)-6-methylpiperidine-1,3- dicarboxylate of (+/-)-1-tert-Butyl trans,cis- 3-Methyl [(+/) -trans,cis-130]

[0422] Prepared in accordance with General Procedure A1 to provide (+/-)-trans,trans-129 and (+/-)-trans,cis-130 as an inseparable mixture of an indeterminate proportion as an amber oil (2 .3 g, 73 %): LCMS (M+H) 364. trans,trans-5-(Hydroxymethyl)-4-(4-methoxyphenyl)-2-methylpiperidine-1-carboxylate (+/-)-1- tert-Butyl [(+/-) -trans,trans-131] and trans,cis-5-(Hydroxymethyl)-4-(4-methoxyphenyl)-2-methylpiperidine-1-carboxylate of (+/-)-1 - tert-Butyl [(+/-) -trans,cis-132]

[0423] Prepared in accordance with General Procedure A1 to provide (+/-)-trans,trans-131 and (+/-)-trans,cis-132 as an inseparable mixture of an indeterminate proportion as an amber oil (900 mg, 74%): LCMS (M+H) 336.

[0424] trans,trans-4-(4-Methoxyphenyl)-2-methyl-5-{[(3-oxoisoindolin-5-yl)oxy]methyl}piperidine-1-carboxylate of (+/-)-1- tert-Butyl [(+/-) 133]

[0425] Prepared according to General Procedure A1 to provide crude (+/-) 133 as an amber oil (224 mg) which was used without purification in the next step: LCMS (M+H) 467. (+/-) -6-{[trans,trans-4-(4-Methoxyphenyl)-6-methylpiperidin-3-yl]methoxy}isoindolin-1-one [(+/-) B0655]

[0426] Prepared according to General Procedure A1 to provide (+/-) B0655 as a white solid (12 mg, 6% over two steps): LCMS (M+H) 367; 1H NMR (300 MHz, CD3OD) δ 7.45 (d, J = 9.3 Hz, 1H), 7.16-7.08 (m, 4H), 6.83 (d, J = 8.7 Hz , 2H), 4.37 (s, 2H), 4.04-4.00 (m, 1H), 3.73 (s, 3H), 3.67-3.48 (m, 3H), 3. 27-3.04 (m, 2H), 2,101.96 (m, 3H), 1.46 (d, J = 6.6 Hz, 3H). General Procedure A15: Preparation of Tetramethyl-3,4-Tetrahydropyridine NH Analogs Scheme 23 Preparation of 6-{[4-(4-Methoxyphenyl)-2,2,6,6-tetramethyl-1,2,5,6-tetrahydropyridin-3-yl]methoxy}isoindolin-1-one [B0645] , Scheme 23 (+/-)-Methyl 2,2,6,6-Tetramethyl-4-oxopiperidine-3-carboxylate [(+/-) 134]

[0427] Prepared according to General Procedure A12 to provide (+/-) 134 as a brown oil (5.6 g, 77%): LCMS (M+H) 214. 2,2,6,6-Tetramethyl Methyl -4-{[(trifluoromethyl)sulfonyl]oxy}- 1,2,5,6-tetrahydropyridine-3-carboxylate (135)

[0428] Prepared according to General Procedure A9 to provide crude 135 as a colorless oil (7.5 g) which was used in the next step without purification: LCMS (M+H) 346. 4-(4-Methoxyphenyl)- Methyl 2,2,6,6-tetramethyl-1,2,5,6-tetrahydropyridine-3-carboxylate (136)

[0429] Prepared according to General Procedure A1 to provide 136 as a brown oil (3.5 g, 53% over two steps): LCMS (M+H) 304. [4-(4-Methoxyphenyl)- 2,2,6,6-tetramethyl-1,2,5,6-tetrahydropyridin-3-yl]methanol (137)

[0430] Prepared according to General Procedure A1 to provide 137 as a grayish solid (2.3 g, 76%): LCMS (M+H) 276. 6-{[4-(4-Methoxyphenyl)-2, 2,6,6-tetramethyl-1,2,5,6-tetrahydropyridin-3-yl]methoxy}isoindolin-1-one (B0645)

[0431] Prepared according to General Procedure A1 to provide B0645 as a white solid (92 mg, 31%): LCMS (M+H) 407; 1H NMR (300 MHz, CD3OD) δ 7.45 (d, J = 8.1 Hz, 1H), 7.23 (d, J = 8.7 Hz, 2H), 7.15-7.11 (m , 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.76-4.72 (m, 2H), 4.39-4.35 (m, 2H), 3.73 ( s, 3H), 2.69-2.65 (m, 2H), 1.74 (s, 6H), 1.57 (s, 6H). General Procedure A16: Preparation of piperazine analogues Scheme 24 Preparation of (+/-)-3-{[4-benzyl-1-(4-methoxyphenyl)piperazin-2-yl]methoxy}benzamide [(+/-) B0194] 4-benzyl-1-(4-methoxyphenyl )Ethyl piperazine-2-carboxylate [(+/-) 138]

[0432] A solution of ({2-[(4-methoxyphenyl)amino]ethyl}) benzyl amine (137.8.15 g) and diethylamine (18 mL) in toluene was added dropwise to a solution of 2, Ethyl 3-dibromopropanoate (9 mL) in toluene at 50 °C. The reaction was heated to 1000C for 6h, then cooled to room temperature. The reaction was partitioned between EtOAc (250 mL) and water (9100 mL). The organics were separated, washed with brine and dried over Na2SO4. Evaporation of the solvent provided an oil which was purified over silica gel to provide 2.5 g of (+/-)138. 3-{[4-Benzyl-1-(4-Methoxyphenyl)piperazin-2-yl]methoxy}benzamide [(+/-) B0194]

[0433] The title compound was prepared using General Procedure A1 to provide (+/-) B0194, LCMS (M+H) 432. Scheme 25 Preparation of (+/-)-4-benzyl-N-[(4-cyanophenyl)methyl]-1-(4-methoxyphenyl)piperazine-2-carboxamide 4-Benzyl-1-(4-methoxyphenyl)piperazine-2 acid - carboxylic [(+/-) 141]

[0434] A solution of (+/-)-ethyl 4-benzyl-1-(4-methoxyphenyl)piperazine-2-carboxylate [(+/-) 138, 0.32 g, 0.9 mmol] in THF was added to a solution of LiOH (60 mg, 3 mmol) in EtOH-water and stirred for 18h at room temperature. The reaction mixture was treated to a pH of 5 with 10% HCl and then extracted with three 20 mL portions of EtOAc. The organics were combined and washed with brine and dried over Na2SO4. The solvent was evaporated to give (+/-)141 as an oil. (+/-) -4-Benzyl-N- [(4-cyanophenyl)methyl] -1- (4-methoxyphenyl)piperazine-2-carboxamide [(+/-) B0117]

[0435] (+/-)-4-Benzyl-1-(4-methoxyphenyl) piperazine-2-carboxylic acid [(+/-) 141, 87.5 mg, 0.23 mmol] and CDI were stirred together in 2 mL of ACN for 2 h. 4-cyanobenzylamine (37.8 μL, 0.35 mmol) was added and the reaction stirred overnight. The solvent was then evaporated under vacuum and the residue passed through a silica gel column with 1:1 DCM:EtOAc to provide 99.6 mg (98%) of (+/-) B0117 as an oil. LCMS (M+H) 441. General Procedure A17: Preparation of 1,1-Disubstituted Piperidine Analogs Scheme 26 Preparation of 6-{[4-(4-Fluorophenyl)piperidin-4-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one (B0677) 4-(4-fluorophenyl)-4- tert-Butyl [(methanesulfonyloxy)methyl] piperidine-1-carboxylate (142)

[0436] To a solution of commercially available tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (68 mg, 0.22 mmol) and triethylamine (92 mL, 0.66 mmol ) in dichloromethane at 0°C was added methanesulfonyl chloride (26 mL, 0.33 mmol) dropwise. After 30 min, the mixture was heated to rt. After 1h, the mixture was dissipated with 1 mL of saturated NH4Cl solution and the aqueous layer was extracted with dichloromethane (3X5 mL). The organics were passed through a phase separator and concentrated to provide 142 in a quantitative yield. LCMS (M+Na = 410.1). tert-Butyl 4-(4-fluorophenyl)-4-{[(3-oxo-2,3-dihydro-1H-isoindol-5-yl)oxy]methyl}piperidine-1-carboxylate (143)

[0437] A solution of tert-butyl 4-(4-fluorophenyl)-4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (142.85 mg, 0.22 mmol), isoindolinone (45 mg, 0. 22 mmol) and Cs2CO3 (358 mg, 1.1 mmol) in 2.2 mL of N,N-dimethylformamide was stirred at rt. After 30 min, the mixture was gradually heated to 120°C over 10 h with a 2 h interval every 20°C from 20°C. Then, the mixture was dissipated with 1 mL of saturated NH4Cl solution and the aqueous layer was extracted with dichloromethane (3X5 mL). The organics were passed through a phase separator and concentrated to provide 143 in a 40% yield. LCMS (M+Na = 463.1). 6-{[4-(4-Fluorophenyl)piperidin-4-yl]methoxy}-2,3-dihydro-1H-isoindol-1-one (B0677)

[0438] The title compound was prepared using General Procedure A1 from 4-(4-fluorophenyl)-4-{[(3-oxo-2,3-dihydro-1H-isoindol-5-yl tert-butyl)oxy]methyl}piperidine-1-carboxylate (B0677) on the 5 mg scale in a 12% yield. LCMS of peak product (M+H = 341.1); 1H NMR (400 MHz, CD3CN) δ 7.53 (dd, J = 8.7, 5.3, 2H), 7.40 (d, J = 8.3, 1H), 7.17 (t, J = 8.8, 3H), 7.07 (d, J = 8.2, 1H), 6.77 (s, 1H), 4.29 (s, 2H), 4.05 (s, 2H), 3.33 (s, 2H), 2.98 (s, 2H), 2.49 (d, J = 13.9, 2H), 2.33 (d, J = 12.1, 2H).

[0439] The compounds depicted in Figure 1 were prepared according to the methods described herein or the schemes were modified through routine modifications to prepare the compounds depicted in Figure 1. Example 2: Compounds are effective as modulators of the delta receptor (δ)-opioids

[0440] The compounds described here have been tested as modulators of the δ-opioid receptor. The compounds were found to be modulators of receptor activity. Some of the compounds inhibited the β-arrestin pathway and the G-protein-mediated pathway, while others agonized or enhanced the β-arrestin-mediated pathway or the G-protein-mediated pathway. Activity was measured according to the methods described here . The compounds described here have also been tested as μ- and K-opioid receptor modulators.

In vitro assay

[0441] Plasmids encoding the delta-opioid receptor (Accession NP_000902), the mu-opioid receptor (Accession NP_000905) and the kappa-opioid receptor (Accession NP_000903) were generated on the pCMV-Prolink base plasmid and transfected to an EA-arrestin parental human embryonic kidney cell line (HEK -293) from DiscoveRx Corporation. Stable clonal lines were subsequently selected under G418.

Cell culture and plating

[0442] The cell lines were cultured adherently in Minimum Essential Medium (Cellgro cat# 10-010-CM) containing 10% fetal bovine serum (Hyclone cat# SH30071.03), 4 mM glutamine (Cellgro cat # 25-005-CI), 150 μg/ml hygromycin B (Cellgro cat# 30-240-CR), 150 μg/ml G418 (Cellgro cat# 30-234-CR) and penicillin/streptomycin at 50 μg/ml 50 μg (Lonza cat# 17-603E). Prior to assay, cells were removed from flasks with CellStripper (Cellgro cat# 25-056-CI), pipetted repeatedly to disperse cells, and centrifuged at low speed for 5 minutes at room temperature. The cells were then resuspended at 250,000 cells/ml in growth medium and plated at 5,000 cells/well in 384-well plates (Greiner cat# 784080). Plates were incubated overnight at 37°C, 5% CO2 in a humidified incubator.

cAMP assay

[0443] G protein-mediated receptor responses were determined by measuring changes in intracellular cAMP using the CISBio HTRF cAMP HiRange kit (cat# 62AM6PEJ) based on time-decomposed fluorescence resonance energy transfer. , TR-FRET). The growth medium was removed and replaced with Ham's F12 containing IBMX (500 μM), NKH-477 (1 μM, a water-soluble forskolin derivative), and test or control compounds at desired concentrations. After a 30-min incubation at 37°C, cAMP HiRange kit components were added as indicated and plates were read after 1 hour on a BMG PheraStar plate reader. Responses were measured as the ratio of fluorescence at 665 nm/620 nm according to the manufacturer's instructions.

β-arrestin assay

[0444] Receptor-mediated beta-arrestin recruitment was determined using the DiscoveRx β-Arrestin PathHunter Detection kit (cat# 93-0001). In this system, β-arrestin is fused to an N-terminal deletion mutant of β-galactosidase (termed the EA enzyme acceptor) and the GPCR of interest is fused to a smaller (42 amino acids), weakly complementary fragment termed ProLink™. . In cells stably expressing these fusion proteins, ligand stimulation results in the interaction of β-arrestin and Prolink-labeled GPCR, forcing complementation of the two β-galactosidase fragments and resulting in the formation of a functional enzyme that converts the substrate into a detectable signal. The growth medium was removed and replaced with Ham's F12 containing HEPES (10 mM), IBMX (500 μM), NKH-477 (1 μM), and test or control compounds at desired concentrations. After a 60-min incubation at 37°C, the DiscoveRx β-Arrestin PathHunter Detection kit components were added as indicated and plates were read after 1 hour on a BMG PheraStar plate reader.

[0445] Data for the compounds described here are shown in Figure 2.

[0446] In vitro experiments for paroxetine were also performed with a non-selective agonist. Representative data is shown here:

[0447] It was revealed that many of the compounds are selective against the delta-opioid receptor, as indicated by the data, which contrasts with the lack of selectivity of paroxetine. Example 3: Compounds are effective for the treatment of depression and anxiety Activity Assessment in the tail suspension test (TST):

[0448] The compounds indicated below were determined to be effective and were evaluated for side effects in an in vivo model.

[0449] Experiments were performed using adult C57 mice (6-10 weeks old, 20-30 g, Hilltop Lab, PA). Mice were housed in standard rodent cages with stainless steel mesh bar covers in groups of 4 with controlled temperature and light cycles (6:00 am to 6:00 pm). Animals had free access to food (Harlan Teklad Global, 18% protein (Madison, WI)) and water during a minimum 2-day laboratory habituation period. Animals that were used in the study were handled, housed, and euthanized (using compressed CO2 in accordance with current NIH guidelines on the use and care of laboratory animals and all applicable local, state, and federal regulations and guidelines. Animals are identified by cage number and by tags applied to the proximal tip of the tail using a permanent marker. Group sizes (n = 8 and therefore 30-50 animals per study) provide reliable estimates of treatment effects, and this species and This type of mouse is recognized as appropriate for pharmacology studies.

[0450] To measure the effectiveness of the compounds, the compounds were tested using a tail suspension test. The tail suspension test is a behavioral test used to evaluate the effectiveness of antidepressant drugs in rodents. In the TST, mice (n = 8/group) were suspended by their tail with a ribbon approximately 30-50 cm above the laboratory bench. The mice are positioned such that the base of the tail is perpendicular to the laboratory bench. Each mouse does 1 test that takes 6 minutes. The total duration of immobility is calculated as the percentage of time during which the mouse is immobile. The duration of immobility is the main parameter measured. This is calculated from the accumulated time during which the animals do not exhibit initiated movements, including passive rocking. When antidepressant medications are administered, immobility is decreased by a variety of antidepressant drug classes. One or more of the compounds shows antidepressant activity.

[0451] The compounds were also tested for side effects. The tested side effect is Acute Depression Liability. The animals will be acclimatized to the vivarium for at least 48 hours before the behavioral test. Mice were placed in a glass jar (8 cm wide x 17 cm high for mice, 17 cm wide x 31 cm high for rats). Animals receive various doses of test compounds at certain times before testing. Test drugs are administered via any of the following routes: sc, po, iv, or ip using an injection volume of 1-2 ml/100 g (mice) or an injection volume of 1-5 ml/kg ( rats). Volumes will not exceed 2 ml and the tail vein is used for injection. Immediately after the injection, the animal is placed in the observation glass container. Animals are observed for a minimum of 30 minutes for the presence of seizure-like behaviors. The behavior will be assessed as absent, mild or severe. One or more of the compounds did not exhibit significant side effects at the relevant doses.

[0452] The compounds have been shown to be effective in the TST model at the indicated doses, although other doses may also be active. Other compounds described here have not necessarily been tested, but are expected to have some level of efficacy. Data for TST activity is shown in the following table. Example 4: Compounds are effective for treating inflammation and pain Assessment of Tactile Allodynia Produced by Intraplantar Freund's Complete Adjuvant in Mice and Rats:

[0453] The animals were acclimated to the vivarium for at least 48 hours before the behavioral test. Inflammation was induced for both rodent species with the administration of an intraplantar injection (subcutaneous injection into the plantar surface of the hind paw, i.pl.) of 0.10 ml of Complete Freund's Adjuvant (FCA).

[0454] For mouse studies, experiments were conducted 48 hours after FCA administration. Tactile allodynia was measured using a series of von Frey monofilaments. These filaments are flexible, plastic and designed to prick, not penetrate, the skin. The animals were placed in a Plexiglas chamber (approximately 10 cm x 20 cm x 25 cm) and allowed to habituate for 5 to 10 minutes. The camera was placed over a mesh screen so that the von Frey monofilaments could be displayed over the plantar surface of the inflamed hind paw. Measurement of tactile sensitivity for the injected hind paw is obtained using the up/down method (LaBuda and Little, 2005, J Neurosci. Methods, 144, 175) with seven von Frey monofilaments (0.07, 0.16 , 0.4, 0.6, 1, and 2 grams). Each test will begin with a von Frey force of 0.6 grams applied to the hind paw for approximately 1 to 2 seconds. If there is no withdrawal response, the next force majeure will be applied. If there is a response, the next lowest force is applied. This procedure was carried out until no response was obtained at maximum force (2 grams) or until four stimuli were administered after the initial response. The 50% paw withdrawal limit for the hind paw will be calculated using the following formula: [Xth]log = [vFr]log + ky, where [vFr] is the strength of the last von Frey microfilament used, k is the Average range (in log units) between von Frey monofilaments and y is a value that depends on the pattern of withdrawal responses (Dixon, Annual Review Pharmacol Toxicol, 1980, 20, 441).

[0455] For rat studies, experiments were performed 24 hours after CFA administration. Rats are tested for mechanical allodynia in a Randall-Selitto device. The inflamed paw is placed on a pedestal and a sharp force of increasing intensity (0 to 250 grams) is applied to the paw. When the animal struggles to free itself from the force, the test is stopped and the force to induce such a struggle is recorded. Data can be presented as average grams of withdrawal force or a percentage of the maximum possible effect.

[0456] The compounds below have been shown to be effective in the CFA model at the doses indicated, although other doses may also be active. Other compounds described here have not necessarily been tested, but are expected to have some level of efficacy. Example 5: Compounds are effective for treating migraine Assessment of tactile allodynia produced by nitroglycerin:

[0457] The compounds were tested for efficacy in rodent nitroglycerin-induced migraine models. In this model, rats and mice can be induced to have a behavioral response consistent with the progression of a migraine attack by intraperitoneal injection of nitroglycerin. In this test, mice or rats (n = 8/group) receive an intraperitoneal injection of nitroglycerin at 10 mg/kg. After 90 minutes, animals are dosed subcutaneously with the test compound. A measure of mechanical allodynia will be obtained using the up/down method with seven von Frey monofilaments. There is a specific series used for mice and rats. Each monofilament is applied to the hind paw for approximately 1-2 seconds. If there is a response, the next lowest force will be applied. This procedure will be carried out until no response is obtained at maximum strength or until four stimuli are administered after the initial response. The 50% paw withdrawal limit for the hind paw will be calculated using the following formula: [Xth]log = [vFr]log + ky, where [vFr] is the strength of the last von Frey microfilament used, k is the Average range (in log units) between von Frey and y monofilaments is a value that depends on the pattern of withdrawal responses. Tactile sensitivity testing will be performed and a withdrawal value will be assigned as the tactile sensitivity (expressed in grams of force required to elicit a response) for the injected paw for each animal. Data are presented as average grams required to produce a von Frey stimulus hindpaw withdrawal. The compounds below have been shown to have antiallodynic activity. Data for some of the compounds are included below. The compounds were found to be effective in this migraine model at the indicated doses, although other doses may also be active. Other compounds described here have not necessarily been tested, but are expected to have some level of efficacy. Example 6: Compounds are effective in Parkinson's disease

[0458] The compounds were tested for efficacy in reversing akinesia and bradykinesia in two well-accepted Parkinson's disease (PD) models: the haloperidol-induced rat catalepsy model [1] and 6-OHDA rats with hemi-lesions [3].

[0459] In the haloperidol-induced catalepsy model, compounds were administered subcutaneously and motor deficiencies (akinesia/bradykinesia) were measured in the "bar test" [1], which measures the ability of rats to respond to a externally imposed static posture, as well as in the "drag test", a modification of the "wheelbarrow" test [2], which measures the ability of rats to balance their body posture using the forelimbs in response to a dynamic stimulus (drag) externally imposed. The compounds were administered subcutaneously and efficacy was assessed within 60 minutes of administration.

[0460] The compounds below have been shown to be effective in the haloperidol-induced catalepsy model at the indicated doses, although other doses may also be active. Other compounds described here have not necessarily been tested, but are expected to have some level of efficacy.

[0461] In the 6-OHDA model of rats with hemi-injury, the effect of the compound on the akinetic response to injury of the contralateral forelimb in the bar test and on stepping activity measured by the drag test was determined. L-DOPA has been shown to be effective at relevant doses in this model. This trial examines the effectiveness in reversing the motor symptoms of Parkinson's disease (i.e., akinesia/bradykinesia and gait abilities). Behavioral readings will include time spent immobile in the bar test (akinesia), number of steps in the drag test (akinesia/bradykinesia), and time spent on the rod in the Rotarod test (general gait ability, gross motor behavior). The compounds were administered subcutaneously and efficacy was assessed between 30 and 90 minutes after administration.

[0462] The references cited in the paragraphs above are: [1] Marti M., Mela F, Guerrini R., Calo G., Bianchi C., Morari M. (2004). Blockade of nociceptin/orphanin FQ transmission in rat substantia nigra reverses haloperidol- induced akinesia and normalizes nigral glutamate release. J Neurochem 91(6): 1501-1504. [2] Mabrouk, O.S. et al., Stimulation of delta opioid receptors located in substantia nigra reticulata but not globus pallidus or striatum restores motor activity in 6-hydroxypamine lesioned rats: new insights into the role of delta receptors in parkinsonism. Journal of Neurochemistry, 2008. 107(6): pages 1647-1659. [3] Sanberg, P.R. et al., The catalepsy test: its ups and downs. Behav Neurosci, 1988. 102(5): pages 748-59.

[0463] The compounds below have been found to be effective in the 6-OHDA hemi-lesion rat model at the indicated doses, although other doses may also be active. Other compounds described here have not necessarily been tested, but are expected to have some level of efficacy. Thus, the compounds can be used to treat Parkinson's disease. Example 7: Compounds are effective in treating medication overuse headache and opioid-induced hyperalgesia

[0464] Compounds were evaluated for their ability to treat medication overuse headache ("MOH"). Assessment of reversal of tactile allodynia produced by repeated dosing of sumatriptan in mice: Mice (44 male c57bl6J mice, n = 8-9/group) were habituated for 2 days in the test cage before injections. Mice were treated with vehicle (VEH-VEH (saline) VEH-B1049 (BCD-10% saline)) or sumatriptan (SUMA) (0.6 mg/kg, i.p.) daily for 11 days. Mechanical sensitivity was measured as the 50% withdrawal threshold for manual stimulation of von Frey monofilaments on day 12. Baseline measurement was taken 24 hours after the final SUMA/VEH injection and, 3 h later, measurements post-drug administration were performed after administration of B1049 (10 mg/kg, s.c., 30 min before the test) or SNC80 (10 mg/kg, i.p., 45 min before the test). (*** p < 0.001 compared to post-drug SUMA-VEH). The results are illustrated in Figure 3. It was found that B1049, a compound of the present disclosure, can reverse the tactile allodynia produced by repeated dosing of sumatriptan, which means that it can be used to reverse the overuse headache of medicines.

[0465] Next, it was determined whether B1049 could reverse opioid-induced hyperalgesia. Mice (44 male c57bl6J mice, n = 8-9/group) were habituated for 2 days in the test cage before injections. Mice were treated with vehicle (VEH-VEH (saline), VEH-B1049 (BCD-10% saline)) or morphine (MORPH) (20 mg/kg, s.c. days 1-3, 40 mg/kg s.c. day 4) twice a day (9am and 5pm) for 4 days. Mechanical sensitivity was measured as the 50% withdrawal threshold for manual stimulation of von Frey monofilaments on day 5. Baseline measurements were taken 16 hours after the final injection of MORPH/VEH and, 3 h later, measurements post-drug administration were performed after administration of B1049 (10 mg/kg, s.c., 30 min before the test) or SNC80 (10 mg/kg, i.p., 45 min before the test). (*** p < 0.001 compared to post-drug SUMA-VEH). The results are illustrated in Figure 4. It was found that B1049, a compound of the present disclosure, can reverse opioid-induced hyperalgesia. Example 8: Compounds do not induce headaches due to excessive medication use

[0466] Evaluation of tactile allodynia produced by repeated dosing of B1049 in mice demonstrated that it does not induce medication overuse headache. Mice (25 male c57bl6J mice, n = 4-5/group) were habituated for 2 days in the test cage before injections. Mice were treated with vehicle (VEH-VEH (saline), VEH-B1049 (BCD-10% saline)), sumatriptan (SUMA) (0.6 mg/kg, i.p.), SNC80 (10 mg/kg , i.p.) or B1049 (10 mg/kg, s.c.) per day for 11 days. Mechanical sensitivity was measured as the 50% withdrawal threshold for manual stimulation of von Frey monofilaments on days 1 and 11. On these days, mice were habituated to the cage for 15 to 20 minutes, after which initial mechanical thresholds were measured. determined before administration of the drug or control. On day 1 after baseline mechanical threshold assessment, mice were weighed and injected with drug or control and returned to their home cage. The results are illustrated in Figure 5. Figure 5 illustrates that sumatriptan causes medication overuse headache, whereas B1049 does not and is the same as the vehicle control (negative control). Consequently, it was surprisingly discovered that not only is B1049 effective for treating migraines, but it also does not have the side effects of other medications currently used for migraines.

[0467] The compounds described here have been found to be active and effective against various conditions, such as those described herein. The experiments described herein are exemplary and are not intended, nor should they be used, to limit the scope of embodiments. All references, publications, accession numbers, patents, documents, etc., are incorporated herein by reference in full for their intended purpose.

Claims (18)

1. Compound or a pharmaceutically acceptable salt thereof characterized by having Formula I, I-1, Ia, I-a1, Ib, on what: Z is C, S, N, S(O)2 or O; R35 is C(=O)OR81b, H, optionally substituted aryl, C1-C6 haloalkyl, -R63R64, C1-C6 branched or unbranched alkyl, C2-C6 alkenyl, C2-C6 haloalkenyl-(CH2)nR65, heterocycle, C1 -C6 ester, cycloalkyl, C1-C6 alkoxy, pyrrolinyl, morpholinyl, C3-C6 cyclic ether or piperidyl; R36 is H, halo, optionally substituted C1-C6 haloalkyl, -SO2C1-C6alkyl, -OCF3, C1-C6 alkyl or -OR75; wherein R75 is H or optionally substituted C1-C6 alkyl; R37 is H, halo, optionally substituted C1-C6 haloalkyl, -SO2C1-C6alkyl, -OCF3, sulfonamide, cyclic sulfonamide or -(CH2)q-R38, -NH-(CH2)q-R38, -S-(CH2) q- R38, -C(=O)R38 or -O-(CH2)q-R38, R38 is H, C1-C6 alkyl, halo, C1-C6 haloalkyl, -C(=O)C1- C6 alkyl, –OR66, S(O)2R67, optionally substituted cycloalkyl, -(CH2)pR65 or heterocycle; or R37 is -(CH2)q-R38 or R36 and R37 form a heterocycle that is fused to the phenyl ring; R41 is absent, is H or C1-C6 alkyl, provided that when Z is S, O or S(O)2, R41 is absent; or, when Z is C, the bond connecting Z to the adjacent carbon is a double bond and R41 is H, R34 is wherein R39 is H or C1-C6 alkyl; R42 is absent, is H, C1-C6 alkyl, a member of a carbocycle that includes the atom to which it is bonded, or =O; Xa is C or O, provided that, when Xa is O, R42 is absent; R61 is H, C1-C6 alkyl, C1-C6 optionally substituted haloalkyl, gem-dimethyl, cyclopropyl spirocycle or CF3; R62 is absent, is H or C1-C6 alkyl; each R63 and R64 are independently H, optionally substituted aryl, C1-C6 haloalkyl, C1-C6 branched or unbranched alkyl, C2-C6 alkenyl, -(CH2)vR65, cycloalkyl, -OH, alkoxy, pyrrolinyl, morpholinyl or piperidyl; or R63 and R64 together form a 5-10 membered heterocycle or 5-10 membered heteroaryl with the atom to which R63 and R64 are attached; each R65 is, independently, H, -C(=O)R65A, C1-C6 optionally substituted haloalkyl, nitrogen, C1-C6 branched or unbranched alkyl, aryl, heteroaryl, C2-C6 alkenyl, cycloalkyl, heterocycle, -OH, alkoxy, pyrrolyl, pyrrolinyl, phenyl, pyrrolidinyl, imidazolidinyl, morpholinyl or piperidyl; R65A is phenyl or branched or unbranched C1-C6 alkyl; R66 is H, optionally substituted aryl, C1-C6 haloalkyl, -R63R64, -NR63R64, C1-C6 branched or unbranched alkyl, C2-C6 alkenyl, -(CH2)wR65, cycloalkyl, -OH, alkoxy, pyrrolinyl, morpholinyl or piperidyl; R67 is optionally substituted C1-C6 branched or unbranched alkyl, or C1-C6 haloalkyl; R81b is H or optionally substituted branched or unbranched C1-C6 alkyl; z is 1 or 2, each n, p, v, weq is independently an integer from 0-6, where “optionally substituted” refers to an optional substituent selected from C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkynyl, C5-C6 aryl, C1-C6 alkoxy, C3-C5 heteroaryl, C3-C6 cycloalkyl, C5-C6 aryloxy, -CN, -OH, oxo, halo, C1-C6 haloalkoxy, -NO2, -CO2H, -NH2, -NH(C1-C8 alkyl), -N(C1-C8 alkyl)2, -NH(C6 aryl), -N(C5-C6 aryl)2, -CHO, -CO(C1- C6 alkyl), -CO((C5-C6) aryl), -CO2((C1-C6) alkyl) and -CO2((C5-C6) aryl); and wherein: “aryl” refers to monocyclic, bicyclic or polycyclic aromatic hydrocarbons having 6 to 20 carbon atoms; “heterocycle” refers to 5- to 7-membered monocyclic or bicyclic or 7 to 10-membered bicyclic heterocyclic ring systems, any ring of which may be saturated or unsaturated, and which consist of carbon atoms and one to three chosen heteroatoms from N, O and S; “Cycloalkyl” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl and alkynyl groups containing from 3 to 15 ring-forming carbon atoms and includes mono- or polycyclic ring systems such as fused ring systems, bridged ring systems and spiro ring systems; “carbocycle” refers to saturated or unsaturated 5- to 6-membered cyclic rings, optionally containing O, S or N atoms as part of the ring; “alkyl” refers to saturated hydrocarbon groups with a straight or branched chain, which may contain from 1 to 6 carbon atoms; “alkoxy” refers to linear or branched -O-alkyl groups of 1 to 6 carbon atoms; “haloalkyl” refers to C1-C6 alkyl groups with one or more halogen substituents; and “alkenyl” refers to linear or branched alkyl groups having one or more carbon-carbon double bonds and 2 to 6 carbon atoms. 2. Compound or a pharmaceutically acceptable salt thereof, according to claim 1, characterized by having Formula II, III, IV, V, VI, VII or VIII: 3. Compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 or 2, characterized in that R62 is H. 4. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 3, characterized in that each R61 is methyl or gem-dimethyl. 5. Compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, characterized in that Z is O or S(O)2. 6. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 5, characterized in that each of: (i) R37 is alkoxy, halo, optionally substituted sulfonamide, or cyclic sulfonamide; or (ii) R36 and R37 form a heterocycle that is fused to the phenyl ring, preferably wherein the fused ring structure is an optionally substituted benzofuran or benzopyran, or wherein the fused ring has the formula of: (iii) R37 is absent. 7. Compound or a pharmaceutically acceptable salt thereof, according to claim 1, characterized by having Formula VIV, VV, VVI, VVII, VVIII: 8. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 7, characterized in that q is 0 or 1-4. 9. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 8, characterized in that each of: (i) R38 is absent or is H; or (ii) R38 is C1-C6 haloalkyl; or (iii) R38 is -C(=O)C1-C6 alkyl; or (iv) R38 is -OR66, -S(O)2R67, optionally substituted cycloalkyl, -(CH2)pR65 or heterocycle. 10. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9, characterized in that R35 is C1-C6 optionally substituted branched or unbranched alkyl, -CH2R76 or -CH2CH2R76, wherein R76 is aryl, ketone, cycloalkyl, C2-C6 alkenyl, C2C6 haloalkenyl or heteroaryl; preferably wherein each of: (i) R76 is cyclopropyl; (ii) R76 is difluorocyclopropyl; (iii) R76 is 2,2-difluorocyclopropyl; (iv) R76 is -CH=CF2; or (v) R76 is pyrrole. 11. Compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, characterized in that it is selected from the group consisting of: 12. Compound or a pharmaceutically acceptable salt thereof, according to claim 1, characterized in that it has the formula: 13. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 12, characterized in that the pharmaceutically acceptable salt is a hydrochloride salt. 14. Pharmaceutical composition characterized by comprising a compound, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 13 and pharmaceutically suitable carriers or excipients. 15. Pharmaceutical composition according to claim 14, characterized in that the pharmaceutically acceptable salt is a hydrochloride salt. 16. Use of a compound as defined in any one of claims 1 to 13 or of a pharmaceutical composition as defined in claims 14 to 15 characterized in that it is for the manufacture of a medicament for the treatment or prevention of pain, neuropathic pain, including peripheral neuropathy diabetic and chemotherapy-induced neuropathic pain, migraine, headache, depression, Parkinson's disease, anxiety, overactive bladder, medication overuse headache, hyperalgesia, decreased nociceptive sensitization, pain in an individual exposed to opioids, PTSD in an individual. 17. Use of a compound as defined in any one of claims 1 to 13 or of a pharmaceutical composition as defined in claims 14 and 15 for the manufacture of a medicament for treating migraine in an individual. 18. Use according to claims 16 or 17, characterized in that the pharmaceutically acceptable salt is a hydrochloride salt.