Substituted macrocyclic amine modulators of orexin receptor 2

Abstract

Disclosed are compounds, compositions, and methods useful for preventing or treating diseases mediated at least in part by orexin receptor 2. One aspect of the present invention provides compounds, compositions, and methods useful for preventing or treating diseases mediated at least in part by orexin receptor 2. Surprisingly, it has been discovered that the compounds disclosed and claimed herein demonstrate improved drug-like properties, such as, inter alia, high potency and selectivity for Ox2R, as well as central nervous system penetration (e.g., as determined by an MDR1-MDCK permeability assay) and a favorable pharmacokinetic profile.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 471,848, filed June 8, 2023, and U.S. Provisional Patent Application No. 63 / 427,672, filed November 23, 2022, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present disclosure relates generally to modulating compounds (more specifically, agonists or antagonists) of orexin receptor 2 (OX2R) and methods of their use in treating conditions mediated at least in part by OX2R. [Background technology]

[0003] Orexins are hypothalamic neuropeptides involved in, for example, sleep / wake regulation and body weight homeostasis. The peptides act on two G protein-coupled receptors, called orexin 1 receptor (Ox1R) and orexin 2 receptor (Ox2R). Although orexin-producing neurons are exclusively located in the lateral hypothalamic region, their receptors are expressed in many regions of the brain.

[0004] Narcolepsy is a socially debilitating disorder characterized by an inability to maintain wakefulness (excessive daytime sleepiness, narcolepsy) and pathological intrusion of REM sleep into wakefulness (e.g., cataplexy, hypnagogic hallucinations, sleep paralysis). Narcolepsy affects an estimated 1 in 2,000 people and is a non-progressive, lifelong condition. Defects in orexin / Ox2R signaling cause the sleep disorder narcolepsy in humans, mice, and dogs. The majority of human narcoleptics (>90%) lack detectable levels of orexin peptides in the cerebrospinal fluid due to highly specific (presumably autoimmune) degeneration of orexin neurons, indicating that human narcolepsy is an "orexin deficiency syndrome." Compounds with Ox2R agonistic activity have been previously described (see, e.g., Nagahara, et al., J. Med. Chem., 2015, 58, 7931-37); however, these compounds may have some undesirable properties (e.g., poor pharmacokinetic properties and / or central nervous system penetration, poor selectivity for Ox2R, etc.). Thus, there remains a need for Ox2R agonist compounds with improved properties. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Nagahara, et al., J. Med. Chem., 2015, 58, 7931-37 Summary of the Invention

[0006] One aspect of the present invention provides compounds, compositions, and methods useful for preventing or treating diseases mediated at least in part by orexin receptor 2. Surprisingly, it has been discovered that the compounds disclosed and claimed herein demonstrate improved drug-like properties, such as, inter alia, high potency and selectivity for Ox2R, as well as central nervous system penetration (e.g., as determined by an MDR1-MDCK permeability assay) and a favorable pharmacokinetic profile.

[0007] Thus, in some embodiments, a compound having the structure of formula (I):

[0008] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, During the ceremony, A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl; n is 0, 1, 2, or 3; R 1 is (C1-C6) alkyl, (C3-C8) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, and each (C1-C6) alkyl is optionally selected from one or more R 1a , C(O)NR 1b R 1c , halo, cyano, hydroxy, or (C1-C6)alkoxy, and each (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl; R 1a is (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy(C1-C6)alkyl, or (C1-C6)alkoxy; R 1b and R 1c is independently H, or (C1-C6)alkyl, each (C1-C6)alkyl optionally substituted with one or more halo, cyano, hydroxy, or (C1-C6)alkoxy, or R 1a and R 1b together with the nitrogen to which they are attached form a 3- to 7-membered heterocyclyl ring, R 2 is H, R 3 is halo, cyano, (C1-C6) alkyl, or (C1-C6) haloalkyl; m is 0, 1, 2, 3, or 4; q is 0, 1, or 2; R 4is halo, (C1-C6) alkyl, or (C1-C6) haloalkyl; X is CH; Y is O or absent (i.e., a bond); Z is O or (CR 7 R 8 ) p and p is 1, 2, 3, or 4; R 7 and R 8 is, in each occurrence, independently H, (C1-C3) alkyl, or (C1-C3) haloalkyl; or R 7 and R 8 together with the carbons to which they are attached form a 3- to 6-membered cycloalkyl, T is CR 9 R 10 or does not exist, U is CR 11 R 12 and V is CR 13 R 14 and W is CR 15 R 16 or absent, provided that exactly one of T or W is absent, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is each independently H or fluoro.

[0009] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used to practice or test the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references described herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will prevail. Furthermore, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0010] Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims. DETAILED DESCRIPTION OF THE INVENTION

[0011] definition For convenience, before further description of the present invention, certain terms used in the specification, examples, and appended claims are provided herein.These definitions should be read in light of the remainder of this disclosure and understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0012] In order that the present invention may be more readily understood, certain terms and phrases are defined below and throughout the specification.

[0013] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of an article. By way of example, "an element" means one element or more than one element.

[0014] As used herein in the specification and claims, the term "and / or" should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some instances and disjunctively present in other instances. Multiple elements listed with "and / or" should be construed in the same manner, i.e., "one or more" of the elements so conjoined. Other elements, whether related or unrelated to those elements specifically identified, may optionally be present beyond the elements specifically identified by the "and / or" clause. Thus, as a non-limiting example, a reference to "A and / or B" used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); and so forth.

[0015] In the specification and claims, when used herein, "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as being inclusive, i.e., the inclusion of at least one of a number or list of elements, but including two or more, and optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one," or when used in the claims, "consisting of" refers to the inclusion of exactly one element of a number or list of elements. Generally, when used herein, the term "or" should be interpreted as indicating exclusive alternatives (i.e., "one or the other, but not both") only when preceded by terms of exclusion, such as "either," "one," "only one," or "exactly one." When used in the claims, "consisting essentially of" shall have its ordinary meaning as used in the field of patent law.

[0016] As used herein in the specification and claims, the phrase "at least one," in connection with a list of one or more elements, should be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including at least one of each and every element specifically listed in the list of elements, nor excluding any combinations of elements in the list of elements. This definition also allows for elements to optionally be present other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") refers in one embodiment to at least one, optionally including two or more, A (and optionally including elements other than B) in the absence of B; in another embodiment to at least one, optionally including two or more, B (and optionally including elements other than A) in the absence of A; and in yet another embodiment to at least one, optionally including two or more, A and at least one, optionally including two or more, B (and optionally including other elements).

[0017] It should also be understood that, unless expressly stated to the contrary, in any method claimed herein which includes more than one step or action, the order of the method steps or actions is not necessarily limited to the order in which the method steps or actions are recited.

[0018] In the claims, as well as in the above specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "comprising," and the like, are to be understood to be open-ended, i.e., including, but not limited to: Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed-ended or semi-closed-ended transitional phrases, respectively, as set forth in U.S. Manual of Patent Examining Procedure Section 2111.03.

[0019] Certain compounds contained in the compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof, within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0020] "Geometric isomer" means an isomer that differs in the orientation of substituent atoms in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic ring system. The atoms (other than H) on either side of the carbon-carbon double bond may be in the E (substituents are on either side of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. "R", "S", "S" * ", "R *"," "E," "Z," "cis," and "trans" refer to configurations relative to the core molecule. Some of the compounds of the present disclosure may exist in or as "atropisomeric" forms. Atropisomers are stereoisomers resulting from hindered rotation about a single bond, where the steric strain, the barrier to rotation, is high enough to allow isolation of the stereoisomers. The compounds of the present invention may be prepared as individual isomers either by isomer-specific synthesis or by resolution from a mixture of isomers. Traditional resolution techniques include forming a salt of the free base of each isomer of the isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming a salt of the acid form of each isomer of the isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each isomer of the isomeric pair using an optically pure acid, amine, or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving isomeric mixtures of either the starting materials or the final products using a variety of well-known chromatographic methods.

[0021] For example, if a specific enantiomer of a compound of this invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, the resulting diastereomeric mixture separated, and the auxiliary cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino, or an acidic functional group such as carboxyl, a diastereomeric salt is formed with a suitable optically active acid or base, followed by fractional crystallization or chromatographic means well known in the art, and the pure enantiomer is then recovered.

[0022] Percent purity by mole fraction is the ratio of moles of enantiomers (or diastereomers), or moles of enantiomer (or diastereomer) plus moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure mole fraction relative to other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure mole fraction. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99%, or about 99.9% pure mole fraction.

[0023] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it should be understood that if the compound has at least one chiral center, the name or structure encompasses either an enantiomer of the compound free of the corresponding optical isomer, a racemic mixture of the compound or a mixture enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating stereochemistry, it should be understood that if the compound has two or more chiral centers, the name or structure encompasses a diastereomer free of the other diastereomer, multiple diastereomers free of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers enriched in one diastereomer relative to the other diastereomer(s), or mixtures of diastereomers enriched in one or more diastereomers relative to the other diastereomers. The present invention encompasses all of these forms.

[0024] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with 13 C or 14 Compounds produced by substitution with C-enriched carbons are within the scope of the present invention. As used herein, "deuterated derivative(s)" refers to a compound having the same chemical structure as a reference compound, in which one or more hydrogen atoms have been replaced with deuterium atoms. In some embodiments, the one or more hydrogens replaced with deuterium are part of an alkyl group. In some embodiments, the one or more hydrogens replaced with deuterium are part of a methyl group. In chemical structures, deuterium may be represented by "D."

[0025] As used herein, the term "prodrug" encompasses compounds that are converted into therapeutically active agents under physiological conditions. Such conversion can be affected, for example, by hydrolysis in blood or enzymatic conversion of the prodrug form to the parent form in blood or tissues. In other embodiments, the prodrug is converted by enzymatic activity in the host animal.

[0026] A common method for making a prodrug is to include a selected moiety that is hydrolyzed under physiological conditions to reveal the desired molecule. A prodrug of a compound of the present invention may be, for example, an amide. Amides that can be utilized as prodrugs in the present invention include phenylamides, aliphatic (C1-C6) amides, and the like. 24 ) amides, acyloxymethylamides, ureas, carbamates, and amino acid amides. For example, compounds of the invention containing an NH group may be acylated at this position in their prodrug forms. Other prodrug forms include esters, e.g., phenyl esters, aliphatic (C1-C 24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and Judkins et al., Synthetic Communications 26(23):4351-4367, 1996, each of which is incorporated herein by reference in its entirety. In some embodiments, the invention features a prodrug of any one of the formulas or compounds listed herein.

[0027] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting a chemical substance of interest from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients in the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials that can function as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil; Examples of suitable pharmaceutical compositions include cottonseed oil, saffron oil, sesame oil, olive oil, corn oil, and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters, such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer, and (21) other non-toxic, compatible substances used in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce a significant temperature increase when administered to a patient.

[0028] The term "pharmaceutically acceptable salt" refers to relatively non-toxic inorganic and organic acid addition salts of a compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in their free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulfonate. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19.)

[0029] In other cases, compounds useful in the methods of the present invention may contain one or more acidic functional groups and, therefore, can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these cases, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic inorganic and organic base addition salts of the compound(s). These salts can also be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in their free acid form with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, e.g., Berge et al., supra).

[0030] The term "pharmaceutically acceptable cocrystal" refers to a solid coformer that does not form formal ionic interactions with a small molecule.

[0031] A "therapeutically effective amount" (or "effective amount") of a compound for use in therapy refers to the amount of compound in a preparation that, when administered (to a mammal, preferably a human) as part of a desired dosing regimen, alleviates the symptoms, improves the condition, or delays the onset of a disease state according to clinically acceptable criteria for the disorder or condition being treated or for cosmetic purposes, e.g., at a reasonable benefit / risk ratio applicable to any treatment.

[0032] The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to a host of one or more of the subject compositions. When administered prior to clinical manifestation of an undesired condition (e.g., a disease or other undesired condition in a host animal), the treatment is prophylactic (i.e., protects the host from the occurrence of the undesired condition), whereas when administered after the manifestation of the undesired condition, the treatment is therapeutic (i.e., intended to reduce, ameliorate, or stabilize an existing undesired condition or its side effects).

[0033] The term "patient" or "subject" refers to a mammal in need of a particular treatment. In certain embodiments, the patient is a primate, dog, cat, or horse. In certain embodiments, the patient is human.

[0034] Aliphatic chains include the classes alkyl, alkenyl, and alkynyl, as defined below. Straight-chain aliphatic chains are limited to unbranched carbon chain moieties. As used herein, the term "aliphatic group" refers to a straight-chain, branched, or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups, such as alkyl, alkenyl, or alkynyl groups.

[0035] "Alkyl" refers to a fully saturated, cyclic or acyclic, branched or unbranched (straight-chain) carbon chain moiety having the specified number of carbon atoms, or up to 30 carbon atoms if unspecified. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, as well as moieties that are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, and tetracosyl. In certain embodiments, a straight-chain or branched-chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C6 for straight-chain). 30 , C3 to C for branched 30 ), more preferably having 20 or fewer carbon atoms. Alkyl groups can be substituted or unsubstituted.

[0036] As used herein, the term "heteroalkyl" refers to an alkyl moiety, as defined above, that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of a carbon atom.

[0037] As used herein, the term "haloalkyl" refers to an alkyl group, as defined above, that is substituted with at least one halogen.

[0038] As used herein, the term "hydroxyalkyl" refers to an alkyl group, as defined above, substituted with at least one hydroxyl.

[0039] As used herein, the term "alkylene" refers to an alkyl group having a specified number of carbons, e.g., 2 to 12 carbon atoms, and containing two points of attachment to the remainder of the compound on the longest carbon chain. Non-limiting examples of alkylene groups include methylene-(CH)-, ethylene-(CHCH)-, n-propylene-(CHCHCH)-, isopropylene-(CHCH(CH))-, and the like. Alkylene groups may be cyclic or acyclic, branched or unbranched carbon chain moieties, and may be optionally substituted with one or more substituents.

[0040] "Cycloalkyl" means mono- or bicyclic, or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3-12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups can be substituted or unsubstituted. Some examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0041] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group, as defined above, that is substituted with at least one halogen.

[0042] "Cycloheteroalkyl" refers to a cycloalkyl moiety, as defined above, that contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms instead of carbon atoms. Preferred cycloheteroalkyls have from 4 to 8 carbon atoms and heteroatoms in their ring structure, and more preferably 4 to 6 carbon atoms and heteroatoms in the ring structure. Cycloheteroalkyl groups can be substituted or unsubstituted. Some examples include piperidinyl, piperazinyl, tetrahydrofuranyl, and tetrahydropyranyl groups.

[0043] Unless the number of carbons is otherwise specified, as used herein, "lower alkyl" refers to an alkyl group, as defined above, but having 1 to 10 carbons, more preferably 1 to 6 carbon atoms in its backbone structure, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Throughout this application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0044] "Alkenyl" refers to any cyclic or acyclic, branched or unbranched (straight-chain) unsaturated carbon chain moiety having the specified number of carbon atoms, or up to 26 carbon atoms if no limit is specified, and having one or more double bonds. Alkenyls of 6 to 26 carbon atoms are exemplified in their various isomeric forms by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, where the unsaturated bond(s) can be located anywhere within the moiety and can have either the (Z) or (E) configuration around the double bond(s).

[0045] "Alkynyl" refers to a hydrocarbyl moiety within the scope of alkenyl, but which contains one or more triple bonds.

[0046] As used herein, the term "aryl" includes 3- to 12-membered substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, the aryl group contains a 5- to 12-membered ring, more preferably a 6- to 10-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, and at least one of the rings is aromatic; for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline groups. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, and more preferably 5- to 10-membered rings, and the ring structures contain one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine groups, etc. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.

[0047] As used herein, the terms "halo," "halide," or "halogen" mean halogen, including, but not limited to, fluoro, chloro, bromo, iodo, and the like, in both radioactive and non-radioactive forms. In preferred embodiments, halo is selected from the group consisting of fluoro, chloro, and bromo.

[0048] The terms "heterocyclyl" or "heterocyclyl group" or "heterocycloalkyl" refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, and more preferably 5- to 10-membered rings, which ring structures include one to four heteroatoms. The heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic, and can be saturated or unsaturated. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sulfones, and the like. The heterocyclyl ring may be substituted at one or more positions with such substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF3, -CN, etc.

[0049] The term "substituted" refers to a moiety having substituents replacing a hydrogen on one or more backbone carbons. It should be understood that "substituted" or "substituted" implicitly includes the provision that such substitution is in accordance with the permissible valences of the replacing atom and substituent, and that the substitution results in a stable compound that does not undergo spontaneous transformations, such as rearrangement, cyclization, elimination, and the like. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for suitable organic compounds. For purposes of this invention, heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Substituents can include any of the substituents described herein, including, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxy, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituent on the substituted alkyl is C 1~6 Alkyl, C 3~6 In a more preferred embodiment, the substituent on the substituted alkyl is selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that the substituent itself can be substituted, if appropriate. Unless specifically described as "unsubstituted," reference to a chemical moiety herein is understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants.

[0050] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0051] As used herein, "small molecule" refers to a small organic or inorganic molecule with a molecular weight of less than about 3,000 Daltons. Generally, small molecules useful in the present invention have a molecular weight of less than 3,000 Daltons (Da). The small molecule can be, for example, at least about 100 Da to about 3,000 Da (e.g., about 100 to about 3,000 Da, about 100 to about 2,500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1,500, about 500 to about 1,000, about 300 to about 1,000 Da, or about 100 to about 250 Da).

[0052] In some embodiments, "small molecule" refers to an organic, inorganic, or organometallic compound that typically has a molecular weight of less than about 1000. In some embodiments, small molecules are organic compounds with a size on the order of 1 nm. In some embodiments, small molecule agents of the present invention include oligopeptides and other biomolecules with a molecular weight of less than about 1000.

[0053] An "effective amount" is an amount sufficient to produce a beneficial or desired effect. For example, a therapeutic amount is an amount that achieves a desired therapeutic effect. This amount may be the same as or different from a prophylactically effective amount, which is the amount necessary to prevent the onset of a disease or disease symptoms. An effective amount can be administered in one or more administrations, applications, or dosages. The therapeutically effective amount of a composition will depend on the composition selected. The composition can be administered from once or more times daily to once or more times weekly, including once every other day. One of skill in the art will understand that certain factors can affect the dosage and timing required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, previous treatments, the subject's general health and / or age, and other diseases present. Furthermore, treatment of a subject with a therapeutically effective amount of a composition described herein can include a single treatment or a series of treatments.

[0054] The terms "decrease," "reduce," "reduced," "reduction," "decrease," and "inhibit" are generally used herein to mean to decrease by a statistically significant amount compared to a reference. However, for the avoidance of doubt, "reduce", "reduction", or "decrease", or "inhibit" typically means a decrease of at least 10% compared to a reference level, e.g., at least about a 20% decrease, at least about a 25%, at least about a 30%, at least about a 35%, at least about a 40%, at least about a 45%, at least about a 50%, at least about a 55%, at least about a 60%, at least about a 65%, at least about a 70%, at least about a 75%, at least about a 80%, at least about a 85%, at least about a 90%, at least about a 95%, at least about a 98%, at least about a 99% (maximum) decrease, including, for example, any decrease from 10-99% compared to the complete absence of a given entity or parameter, or the absence of a given treatment, compared to a reference level.

[0055] The terms "increased," "increase," or "enhance," or "activate" are all used herein to generally mean an increase by a statistically significant amount, and for the avoidance of doubt, the terms "increased," "increase," or "enhance," or "activate" mean an increase of at least 10% compared to a reference level, for example, an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% increase, or up to a 100% increase, or including any increase between 10-100% compared to a reference level, or at least about a 2-fold, or at least about 3-fold, or at least about 4-fold, or at least about 5-fold, or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or more compared to a reference level.

[0056] As used herein, the term "modulate" includes upregulation (eg, activating or enhancing a response) and downregulation (eg, inhibiting or inactivating a response).

[0057] As defined herein, a "radiopharmaceutical" refers to a pharmaceutical containing at least one radiation-emitting radioisotope. Radiopharmaceuticals are routinely used in nuclear medicine for the diagnosis and / or therapy of various diseases. Radiolabeled pharmaceuticals, such as radiolabeled antibodies, contain a radioisotope (RI) that functions as a radiation source. As contemplated herein, the term "radioisotope" includes metallic and non-metallic radioisotopes. The radioisotope is selected based on the medical application of the radiolabeled pharmaceutical. When the radioisotope is a metallic radioisotope, a chelating agent is typically used to bind the metallic radioisotope to the remainder of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked to the remainder of the molecule directly or via a linker.

[0058] For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.

[0059] Compounds of the Invention One aspect of the present invention is a compound of formula (A):

[0060] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, During the ceremony, A (i.e., ring A) is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl; n is 0, 1, 2, or 3; R 1 is (C1-C6) alkyl, (C3-C8) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, and each (C1-C6) alkyl is optionally selected from one or more R 1a , C(O)NR 1b R1c , halo, cyano, hydroxy, or (C1-C6)alkoxy, and each (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl; R 1a is (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy(C1-C6)alkyl, or (C1-C6)alkoxy; R 1b and R 1c is independently H, or (C1-C6)alkyl, each (C1-C6)alkyl optionally substituted with one or more halo, cyano, hydroxy, or (C1-C6)alkoxy, or R 1a and R 1b together with the nitrogen to which they are attached form a 3- to 7-membered heterocyclyl ring, R 2 is H, R 3 is halo, cyano, (C1-C6) alkyl, or (C1-C6) haloalkyl; m is 0, 1, 2, 3, or 4; q is 0, 1, or 2; R 4 is, at each occurrence, independently selected from hydrogen (H), halo, (C1-C6) alkyl, and (C1-C6) haloalkyl; X is CH; Y is O or absent (i.e., a bond); Z is O or (CR 7 R 8) p and p is 1, 2, 3, or 4; R 7 and R 8 is, in each occurrence, independently H, (C1-C3) alkyl, or (C1-C3) haloalkyl; or R 7 and R 8 together with the carbons to which they are attached form a 3- to 6-membered cycloalkyl, T is CR 9 R 10 or does not exist, U is CR 11 R 12 and V is CR 13 R 14 and W is CR 15 R 16 or absent, provided that exactly one of T or W is absent, and R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is each independently H or fluoro.

[0061] One aspect of the present invention is a compound of formula (I):

[0062] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, During the ceremony, A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl; n is 0, 1, 2, or 3; R 1is (C1-C6) alkyl, (C3-C8) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, and each (C1-C6) alkyl is optionally selected from one or more R 1a , C(O)NR 1b R 1c , halo, cyano, hydroxy, or (C1-C6)alkoxy, and each (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl is optionally substituted with one or more halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl; R 1a is (C3-C8)cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy(C1-C6)alkyl, or (C1-C6)alkoxy; R 1b and R 1c is independently H, or (C1-C6)alkyl, each (C1-C6)alkyl optionally substituted with one or more halo, cyano, hydroxy, or (C1-C6)alkoxy, or R 1a and R 1b together with the nitrogen to which they are attached form a 3- to 7-membered heterocyclyl ring, R 2 is H, R 3 is halo, cyano, (C1-C6) alkyl, or (C1-C6) haloalkyl; m is 0, 1, 2, 3, or 4; q is 0, 1, or 2; R 4 is halo, (C1-C6) alkyl, or (C1-C6) haloalkyl; X is CH; Y is O or absent (i.e., a bond); Z is O or (CR 7 R 8 ) p and p is 1, 2, 3, or 4; R 7 and R 8 is, in each occurrence, independently H, (C1-C3) alkyl, or (C1-C3) haloalkyl; or R 7 and R 8 together with the carbons to which they are attached form a 3- to 6-membered cycloalkyl, T is CR 9 R 10 or does not exist, U is CR 11 R 12 and V is CR 13 R 14 and W is CR 15 R 16 or absent, provided that exactly one of T or W is absent, R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 is each independently H, or fluoro. For clarity, in Formula (I) and other formulas described herein, the presence of a capital letter h (“H”) in a structure is intended to refer to a hydrogen atom.

[0063] Since X is CH, compounds of formula (I) may also be represented as:

[0064] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0065] The compounds of Formula (A), (I), or (I-1) may also be enriched or isolated chiral forms (e.g., enantiomeric or diastereomeric forms), or racemic mixtures of two or more chiral forms.

[0066] In some embodiments, the compound of Formula A is in enriched or isolated chiral form having the structure of Formula Ia:

[0067] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt or prodrug thereof, while in another embodiment, the present invention provides a compound of formula Ib:

[0068] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt or prodrug thereof. Racemic mixtures of the above are also contemplated.

[0069] In some embodiments, the compound of Formula I is in enriched or isolated chiral form having the structure of Formula Ia-1:

[0070] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt or prodrug thereof, while in another embodiment, the present invention provides a compound of formula Ib-1:

[0071] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt or prodrug thereof. Racemic mixtures of the above are also contemplated.

[0072] In certain embodiments of Formula (I), the compounds of the invention are compounds of formula I-2:

[0073] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein Q is selected from (C1-C6) alkyl, (C3-C8) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, as provided above for R1, and any of the examples and R 1 In some embodiments, Q is a (C1-C6) alkyl substituted with a (C3-C8) cycloalkyl. In the above formula, R 2 is taken as H. The group CN is a nitrile group.

[0074] Since X is CH, compounds of formula (I-2) can also be represented as:

[0075] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0076] Chiral forms of formulas (I-2) and (I-3) are also contemplated herein, compounds represented by the following formula:

[0077] [ka] or

[0078] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt or prodrug thereof. Racemic mixtures of the above are also contemplated.

[0079] Since X is CH, compounds of formula (I-4) and (I-5) can also be represented as:

[0080] [ka] or

[0081] [ka] or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0082] In some embodiments, for any of the above formulas, n is 1, while in other embodiments, n is 2.

[0083] In some embodiments, for any of the above formulas, A (ie, ring A) is phenyl.

[0084] In some embodiments, for any of the above formulas, m is 0, while in other embodiments, m is 1, and in still other embodiments, m is 2.

[0085] In some embodiments, for any of the above formulas, R 3 is halo. In certain preferred embodiments, R 3 is fluoro.

[0086] In some embodiments, for any of the above formulas, A is

[0087] [ka] is.

[0088] In some embodiments, for any of the above formulas, A is

[0089] [ka] while in other embodiments, A is

[0090] [ka] is.

[0091] In some embodiments, for any of the above formulas, R 1 optionally one or more of fluoro, cyano, hydroxy, R a , or C(O)NR1 b R 1c In some embodiments, R 1 is (C1-C6) alkyl substituted with at least one fluoro or cyano. In some embodiments, R 1 is (C1-C6) alkyl substituted with cyano. In other embodiments, R 1 is a (C1-C6) alkyl substituted with a (C3-C8) cycloalkyl group.

[0092] In some embodiments, for any of the above formulas, R 1 optionally, one or more of fluoro, cyano, hydroxy, R 1a , or C(O)NR 1b R 1c substituted with methyl.

[0093] In some embodiments, for any of the above formulas, R 1ais (C3-C8)cycloalkyl, phenyl, 4- to 5-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more fluoro, cyano, (C1-C3)alkyl, (C1-C3)fluoroalkyl, or (C1-C3)alkoxy. 1a is cyclopropyl, phenyl, 4- to 5-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more fluoro, cyano, cyclopropyl, methyl, or trifluoromethyl. 1a is cyclopropyl, cyclobutyl, phenyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is optionally substituted with one or more fluoro, cyano, cyclopropyl, methyl, or trifluoromethyl.

[0094] In some embodiments, for any of the above formulas, R 1 is C(O)NR 1b R 1c In certain embodiments, R 1b and R 1c are H, respectively.

[0095] In certain embodiments, R 1 is the following:

[0096] [ka] is.

[0097] In further particular embodiments, R 1 is the following:

[0098] [ka] is.

[0099] In other embodiments, R 1is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazinyl, pyrazinyl, or diazoyl, each of which is optionally substituted with one or more halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, or 4 to 7 membered heterocycloalkyl.

[0100] In some embodiments, R 1 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazinyl, pyrazinyl, or diazoyl, each of which is optionally substituted with one or more fluoro, cyano, hydroxy, (C1-C3)alkyl, (C1-C3)fluoroalkyl, or (C1-C3)alkoxy. 1 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or diazoyl, each of which is optionally substituted with one or more fluoro, cyano, hydroxy, (C1-C3)alkyl, (C1-C3)fluoroalkyl, (C1-C3)alkoxy, or 4- to 7-membered heterocycloalkyl. 1 is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or diazoyl, each of which is optionally substituted with one or more fluoro, cyano, methyl, trifluoromethyl, methoxy, or oxetane.

[0101] In some embodiments, R 1 is the following:

[0102] [ka] is.

[0103] In some embodiments, R 1 is the following:

[0104] [ka] is.

[0105] In other embodiments, R 1 is a (C3-C5)cycloalkyl, or a 4- to 6-membered heterocycloalkyl, each of which is optionally substituted with one or more halo, cyano, hydroxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxyalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, or a 4- to 7-membered heterocycloalkyl.

[0106] In some embodiments, R 1 is the following:

[0107] [ka] is.

[0108] In other embodiments, R 1 is the following:

[0109] [ka] is.

[0110] In still other embodiments, R1 is:

[0111] [ka] is.

[0112] In some embodiments, R 1 is substituted with at least one fluoro or cyano. 1 is substituted with cyano.

[0113] In some embodiments, for any of the above formulas, Y is O. In other embodiments, Y is absent (i.e., a bond).

[0114] In some embodiments, for any of the above formulas, R 7 and R 8 are each CH3, or R 7 and R 8 together with the atom to which they are attached form a cyclopropyl. In another embodiment, R 7 and R 8 are H, respectively.

[0115] In some embodiments, for any of the above formulas, p is 1.

[0116] In some embodiments, for any of the above formulas, R 9 , R 10 , R 11 , R 12 , R1 3 , R1 4 , R 15 , and R 16 are H, respectively.

[0117] In some embodiments, R 4 For any of the above formulas where there are two occurrences of R 4 Both groups are hydrogen atoms (H).

[0118] In some embodiments, the compound is a compound of Table 1A, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. In other embodiments, the compound is a compound of Table 1A, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Table 1A.

[0119] [Table 1A-1] [Table 1A-2] [Table 1A-3]

[0120] In some embodiments, the compound is a compound of Table 1B, or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. In other embodiments, the compound is a compound of Table 1B, or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound of Table 1B.

[0121] [Table 1B-1] [Table 1B-2]

[0122] In certain embodiments, the compounds are atropisomers. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or the replacement of carbon by 13 C or 14 Compounds produced by substitution with C-enriched carbons are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. For example, 1 In this case, the (C1-C4) alkyl, or -O-(C1-C4) alkyl may be suitably deuterated (for example, -CD3, -OCD3).

[0123] Any of the compounds of the present invention may also be radiolabeled for the preparation of radiopharmaceuticals.

[0124] For the avoidance of doubt, the present disclosure is directed to the compounds disclosed herein (e.g., of Formulas A, I, I-1, Ia, Ib, Ia-1, Ib-1, I-2, I-3, I-4, I-5, I-6, and I-7), and compounds set forth in Tables 1A and 1B, deuterated derivatives of those compounds, and pharmaceutically acceptable salts thereof or prodrugs thereof. In some embodiments, the present disclosure is directed to the compounds disclosed herein (e.g., of Formulas A, I, I-1, Ia, Ib, Ia-1, Ib-1, I-2, I-3, I-4, I-5, I-6, and I-7), and compounds set forth in Tables 1A and 1B, and / or pharmaceutically acceptable salts thereof. In other embodiments, the present disclosure is directed to compounds disclosed herein (e.g., of Formulas A, I, I-1, Ia, Ib, Ia-1, Ib-1, I-2, I-3, I-4, I-5, I-6, and I-7), and compounds set forth in Tables 1A and 1B. In still other embodiments, the present disclosure is directed to non-salt forms of compounds disclosed herein (e.g., of Formulas A, I, I-1, Ia, Ib, Ia-1, Ib-1, I-2, I-3, I-4, I-5, I-6, and I-7), and compounds set forth in Tables 1A and 1B.

[0125] Treatment method One aspect of the present invention provides compounds, compositions, and methods useful for preventing or treating diseases mediated at least in part by orexin receptor 2. In certain embodiments, the compounds act as agonists of orexin receptor 2. In other embodiments, the compounds act as antagonists of orexin receptor 2.

[0126] Another aspect of the present invention is directed to the treatment of narcolepsy (e.g., narcolepsy type 1 and / or narcolepsy type 2), idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy bodies, hypersomnia syndrome with excessive daytime sleepiness (e.g., Kleine-Levin syndrome, major depression with hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscle dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperinsulinemic obesity, hyperplastic obesity, pituitary obesity, hypoplastic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, diet-induced obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, disorders of consciousness such as stupor, side effects or complications caused by anesthesia , sleep disorders, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep interruptions, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep disorders, sleep terrors, depression, major depression, sleepwalking, bedwetting, sleep disorders, Alzheimer's sundowning syndrome, circadian rhythm related disorders, fibromyalgia, conditions resulting from poor sleep quality, bulimia, compulsive eating disorder, obesity related disorders, hypertension, diabetes, elevated plasma insulin levels / insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, Cholelithiasis, gallstones, heart disease, cardiac arrhythmias, myocardial infarction, congestive heart failure, heart failure, coronary artery disease, cardiovascular disease, sudden death, polycystic ovary syndrome, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, sexual / reproductive dysfunction such as hirsutism in women, fetal defects associated with prenatal obesity, gastrointestinal motility disorders such as gastroesophageal reflux disease associated with obesity, obesity hypoventilation syndrome (Pickwickian syndrome),Respiratory diseases such as shortness of breath, inflammation such as vascular systemic inflammation, secondary risks of obesity such as atherosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, hot flushes, night sweats, reproductive / urinary tract diseases, diseases related to sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as brain defects developed after cardiac bypass surgery or heart transplant, stroke , ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, intrapartum hypoxia, cardiac arrest, hypoglycemia, nerve damage, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye disorders, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders related to muscle spasms, delirium, memory impairment, age-related cognitive decline, schizophrenia affective disorder, delusions, drug dependence, movement disorders, chronic fatigue syndrome, fatigue, drug-induced Parkinsonism, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, neuropathy, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain

[0010] The present invention relates to a method for preventing or treating a disease selected from the group consisting of toothache, cataplexy, and traumatic brain injury in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein. In certain embodiments, the method comprises administering to the subject an effective amount of a compound of formula (I).

[0127] In certain embodiments, the present invention relates to a method for preventing or treating a disease selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy with narcoleptic symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with dementia with Lewy bodies in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein. In certain embodiments, the method comprises administering to the subject an effective amount of a compound of Formula (I).

[0128] In certain embodiments, the disease is narcolepsy. In certain embodiments, the disease is narcolepsy type 1.

[0129] In certain embodiments, the disorder is hypersomnolence.

[0130] In certain embodiments, the disease is idiopathic hypersomnia.

[0131] In certain embodiments, the disorder is hypersomnia.

[0132] In certain embodiments, the disease is sleep apnea.

[0133] In certain embodiments, the disease is narcolepsy syndrome accompanied by narcolepsy-like symptoms.

[0134] In certain embodiments, the disorder is hypersomnia associated with Parkinson's disease.

[0135] In certain embodiments, the disease is hypersomnia associated with dementia with Lewy bodies.

[0136] In some embodiments, the compound or deuterated derivative, or a pharmaceutically acceptable salt or prodrug thereof, is orally administered to the subject. In certain embodiments, the compound is orally administered to the subject.

[0137] In some embodiments, the compound or deuterated derivative, or a pharmaceutically acceptable salt or prodrug thereof, is administered parenterally to the subject. In certain embodiments, the compound is administered parenterally to the subject.

[0138] In certain embodiments, the disease is prevented. In other embodiments, the disease is treated.

[0139] In certain embodiments of any one of the methods of the present disclosure, the compound of formula (I) is a compound of Table 1.

[0140] In some embodiments, compounds disclosed herein (e.g., compounds of Formulas A, I, I-1, Ia, Ib, Ia-1, Ib-1, I-2, I-3, I-4, I-5, I-6, and I-7), and compounds described in Tables 1A and 1B, deuterated derivatives of these compounds, and pharmaceutically acceptable salts or prodrugs thereof, modulate orexin 2 receptors in a subject. In other embodiments, compounds disclosed herein (e.g., compounds of Formulas A, I, I-1, Ia, Ib, Ia-1, Ib-1, I-2, I-3, I-4, I-5, I-6, and I-7), and compounds described in Tables 1A and 1B, deuterated derivatives of these compounds, and pharmaceutically acceptable salts or prodrugs thereof, activate orexin 2 receptors in a subject. In certain embodiments, a compound of Formula (I) activates orexin receptor 2 in a subject.

[0141] Pharmaceutical Compositions, Routes of Administration, and Dosages In certain embodiments, the present invention is directed to a pharmaceutical composition comprising a compound of the present invention, or a deuterated derivative thereof, or a pharmaceutically acceptable salt or prodrug thereof, e.g., a compound of Formula (I), and a pharmaceutically acceptable carrier.

[0142] In certain embodiments, the present invention is directed to a pharmaceutical composition comprising a compound according to any one of the disclosed embodiments and a pharmaceutically acceptable carrier.

[0143] In some embodiments, the present invention is directed to pharmaceutical compositions comprising one or more of the compounds disclosed herein (e.g., Formulas A, I, I-1, Ia, Ib, Ia-1, Ib-1, I-2, I-3, I-4, I-5, I-6, and I-7), as well as compounds set forth in Tables 1A and 1B, deuterated derivatives of these compounds, and pharmaceutically acceptable salts or prodrugs thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the present invention is directed to pharmaceutical compositions comprising a compound of Table 1A or 1B, or a deuterated derivative thereof, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the present invention is directed to pharmaceutical compositions comprising a compound of Table 1, or a deuterated derivative thereof, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

[0144] In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier.

[0145] In certain embodiments, the pharmaceutical compositions of the present invention further comprise at least one additional pharmaceutically active agent other than the compound of the present invention. The at least one additional pharmaceutically active agent can be an agent useful in the treatment of ischemia-reperfusion injury.

[0146] Pharmaceutical compositions of the present invention can be prepared by combining one or more compounds of the present invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.

[0147] As stated above, "effective amount" refers to any amount sufficient to achieve a desired biological effect. In combination with the teachings provided herein, by selecting from various active compounds and weighting factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and mode of administration, an effective prophylactic or therapeutic treatment regimen can be designed that does not cause substantial undesirable toxicity and is effective for treating a particular subject. The effective amount for any particular application may vary depending on such factors as the disease or condition being treated, the particular compound of the present invention being administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art can empirically determine the effective amount of a particular compound of the present invention and / or other therapeutic agent without undue experimentation. A maximum dose, i.e., the maximum safe dose according to some medical judgment, may be used. Multiple administrations per day may be contemplated to achieve a suitable systemic level of the compound. A suitable systemic level may be determined, for example, by measuring the patient's peak or sustained plasma levels of the drug. "Dose" and "dosage" are used interchangeably herein.

[0148] In certain embodiments, intravenous administration of the compound may typically be from 0.1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be from 0.1 mg / kg / day to 2 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be from 0.5 mg / kg / day to 5 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be from 1 mg / kg / day to 20 mg / kg / day. In one embodiment, intravenous administration of the compound may typically be from 1 mg / kg / day to 10 mg / kg / day.

[0149] Generally, the daily oral dose of the compound for a human subject is about 0.01 milligrams / kg / day to 1000 milligrams / kg / day. Oral administration in the range of 0.5 to 50 milligrams / kg in one or more doses per day can produce therapeutic results. The dose can be appropriately adjusted to achieve the desired drug level, local or systemic, depending on the mode of administration. For example, intravenous administration is expected to require a dose one to several orders of magnitude lower per day. If the subject's response is inadequate at such a dose, a higher dose (or a higher effective dose via a different, more localized delivery route) can be employed, as tolerated by the patient. Multiple doses per day are contemplated to achieve suitable systemic levels of the compound.

[0150] For any compound described herein, the therapeutically effective amount can be first determined from animal models. The therapeutically effective dose can also be determined from human data for compounds that have been tested in humans and are known to exhibit similar pharmacological activity, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and efficacy of the administered compound. Based on the above-mentioned methods and other methods known in the art, it is within the ability of a person skilled in the art to adjust the dose to achieve maximum efficacy.

[0151] The formulations of the present invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salts, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.

[0152] For use in therapy, an effective amount of compound can be administered to a subject by any mode that delivers the compound to the desired surface.The administration of pharmaceutical compositions can be achieved by any means known to those skilled in the art.Administration routes include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (e.g., tumor or abscess), mucosal (e.g., topical to ocular), inhalation, and topical.

[0153] For intravenous and other parenteral administration routes, the compounds of the present invention can be formulated as lyophilized preparations, as lyophilized preparations of liposome-mediated or encapsulated active compound, as lipid complexes in aqueous suspension, or as salt complexes. Lyophilized preparations are generally reconstituted in a suitable aqueous solution, such as sterile water or physiological saline, immediately prior to administration.

[0154] For oral administration, the compound can be easily formulated by combining the active compound(s) with a pharmaceutically acceptable carrier well known in the art. Such carriers allow the compound of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipients, optionally after adding suitable excipients, to obtain tablets or dragee cores, and optionally milling the resulting mixture, and processing the granular mixture. Suitable excipients are, in particular, sugars including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or fillers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate. Optionally, the oral formulations may also be formulated in saline or buffers, such as EDTA, to neutralize internal acid conditions, or may be administered without any carrier.

[0155] Oral dosage forms of the above component(s) are also specifically contemplated. The component(s) may be chemically modified to enable oral delivery of the derivative. Generally, contemplated chemical modifications involve the attachment of at least one moiety to the component molecule itself, said moiety (a) inhibiting acid hydrolysis and (b) enabling uptake from the stomach or intestine into the bloodstream. Increasing the overall stability of the component(s) and increasing their circulation time in the body is also desirable. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts," In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that can be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. For pharmaceutical applications, as mentioned above, polyethylene glycol moieties are preferred.

[0156] For the component (or derivative), the location of release may be the stomach, the small intestine (duodenum, jejunum, or ileum), or the large intestine. Those skilled in the art have available formulations that do not dissolve in the stomach but release the substance in the duodenum or elsewhere in the intestine. Preferably, the release avoids the adverse effects of the stomach environment, either by protecting the compound (or derivative) of the present invention or by releasing the bioactive substance beyond the stomach environment, such as in the intestine.

[0157] Coatings that are impermeable to at least pH 5.0 can ensure complete gastric resistance. Examples of more common inactive ingredients used as enteric coatings include cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMP 50, HPMP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, aqueous cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings can be used as mixed films.

[0158] Coatings or mixtures of coatings may also be used on tablets that are not intended for protection against the stomach. This may include sugar coatings or coatings that make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic agents (e.g., powders), or for liquid forms, a soft gelatin shell may be used. The shell material for cachets may be thick starch or other edible paper. For pills, lozenges, molded tablets, or tablet triturates, wet mass techniques may be used.

[0159] The therapeutic agent may be included in the formulation as fine multiparticulates in the form of granules or pellets with a particle size of about 1 mm. The formulation of the material for capsule administration may also be a powder, slightly compressed plugs, or tablets. The therapeutic agent may be prepared by compression.

[0160] Colorants and flavoring agents may all be included. For example, the compounds (or derivatives) of the present invention may be formulated (e.g., by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage, containing colorants and flavoring agents.

[0161] Inert materials may be used to dilute or increase the volume of the therapeutic agent. These diluents may include carbohydrates, particularly mannitol, α-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, and starch. Certain inorganic salts may also be used as fillers, including calcium triphosphate, magnesium carbonate, and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress, and Avicell.

[0162] Disintegrants may be included in the formulation of solid dosage forms of therapeutic agents. Materials used as disintegrants include, but are not limited to, starch and the commercially available starch-based disintegrant Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, carboxymethylcellulose acid, natural sponge, and bentonite can all be used. Another form of disintegrant is insoluble cation exchange resin. Powdered gums may be used as disintegrants and binders, including powdered gums such as agar, Karaya, or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0163] Binders hold the therapeutic agent together to form a hard tablet and may include materials from natural products such as acacia, tragacanth, starch, and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC), both in alcoholic solution, can be used to granulate the therapeutic agent.

[0164] Antifriction agents may be included in the therapeutic agent formulation to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic agent wall and the die wall, and these may include, but are not limited to, stearic acid, including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oil, and wax. Soluble lubricants, such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols of various molecular weights, Carbowax 4000 and 6000, may also be used.

[0165] Lubricants may be added which may improve the flow properties of the drug in the formulation and aid in reconstitution during compression. Lubricants may include starch, talc, pyrogenic silica, and hydrated silicoaluminate.

[0166] To aid in dissolving the therapeutic agent in the aqueous environment, a surfactant may be added as a wetting agent. Surfactants may include anionic surfactants such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic surfactants that may be used include benzalkonium chloride and benzethonium chloride. Nonionic surfactants that may be included in the formulation include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glycerol monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants may be present alone or in a mixture of different ratios in the formulation of the compound or derivative of the present invention.

[0167] Orally usable pharmaceutical preparations include push-fit capsules made of gelatin and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally, a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. Microspheres formulated for oral administration can also be used. Such microspheres are well defined in the art. All formulations for oral administration should be in a dosage suitable for such administration.

[0168] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0169] For topical administration, the compounds may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art. Systemic formulations include formulations designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as formulations designed for transdermal, transmucosal, oral, or pulmonary administration.

[0170] For administration by inhalation, the compounds for use according to the present invention can be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer by using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges, for example, of gelatin, for use in an inhaler or insufflator can be formulated to contain a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0171] Also contemplated herein is pulmonary delivery of the compounds disclosed herein (or salts thereof). The compounds are delivered to the lungs of a mammal upon inhalation and cross the lung epithelial lining into the bloodstream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990), Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate), Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) (endothelin-1), Hubbard et al., Annal Int Med 3:206-212 (1989) (α1-antitrypsin), Smith et al., 1989, J Clin Invest 84:1145-1146 (α1-proteinase), and Oswein et al., 1990, “Aerosolization of Proteins”, Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone), Debs et al., 1988, J Immunol 140:3482-3488 (interferon gamma and tumor necrosis factor alpha), and Platz et al., U.S. Patent No. 5,284,656 (granulocyte colony-stimulating factor, incorporated by reference). Methods and compositions for pulmonary delivery of drugs for systemic effect are described in U.S. Patent No. 5,451,569 (incorporated by reference), September 19, 1995, Wong et al.

[0172] Contemplated for use in the practice of the present invention are mechanical devices designed for pulmonary delivery of therapeutic products, including, but not limited to, nebulizers, metered dose inhalers, and dry powder inhalers, all of which are well known to those skilled in the art.

[0173] Some specific examples of commercially available devices suitable for the practice of the present invention are the Ultravent nebulizer manufactured by Mallinckrodt, Inc. of St. Louis, Massachusetts, the Acorn II nebulizer manufactured by Marquest Medical Products of Engelwood, Colorado, the Ventlin metered dose inhaler manufactured by Glaxo Inc. of Tryon Park, North Carolina, and the Spinhaler powder inhaler manufactured by Fisons Corp. of Bedford, Massachusetts.

[0174] All such devices require the use of suitable formulations for dispensing the compounds of the present invention. Typically, each formulation is specific to the type of device used and may involve the use of suitable propellant materials in addition to the usual diluents, adjuvants, and / or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. The chemically modified compounds of the present invention may also be prepared in different formulations depending on the type of chemical modification or the type of device used.

[0175] Formulations suitable for use in either jet or ultrasonic nebulizers typically contain a compound (or derivative) of the present invention dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the present invention per mL of solution. The formulation may also contain a buffer and a simple sugar (e.g., for inhibitor stabilization and osmotic pressure regulation). Nebulizer formulations may also contain a surfactant to reduce or prevent surface-induced aggregation of the compound of the present invention caused by atomization of the solution during aerosol formation.

[0176] Formulations for use in metered dose inhalers generally comprise a finely divided powder containing the compound (or derivative) of the present invention suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material used for this purpose, such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, or hydrocarbons, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soybean lecithin. Oleic acid may also be useful as a surfactant.

[0177] Formulations for dispensing from powder inhalation devices comprise a finely divided dry powder containing a compound (or derivative) of the invention, and may also contain a bulking agent such as lactose, sorbitol, sucrose, or mannitol in an amount to facilitate dispersion of the powder from the device, e.g., 50-90% by weight of the formulation. The compound (or derivative) of the invention should advantageously be prepared in particulate form, with an average particle size of less than 10 micrometers (μm), most preferably 0.5-5 μm, for most effective delivery to the deep lung.

[0178] Nasal delivery of the pharmaceutical compositions of the present invention is also contemplated. Nasal delivery allows the pharmaceutical compositions of the present invention to pass into the bloodstream immediately after administration of the therapeutic product to the nose, without the need for product deposition in the lungs. Formulations for nasal delivery include formulations with dextran or cyclodextran.

[0179] For nasal administration, a useful device is a small, hard bottle equipped with a metered-dose sprayer. In one embodiment, the metered dose is delivered by drawing the solution pharmaceutical composition of the present invention into a chamber of a defined volume, the chamber having an opening sized to aerosolize the liquid in the chamber by forming a spray when compressed, and the aerosol formulation. The chamber is compressed to administer the pharmaceutical composition of the present invention. In certain embodiments, the chamber is a piston arrangement. Such devices are commercially available.

[0180] Alternatively, a plastic squeeze bottle is used that has an opening or openings sized to aerosolize the aerosol formulation by forming a spray when squeezed. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit into the nasal cavity for efficient administration of the aerosol formulation. Preferably, the nasal inhaler provides a metered amount of the aerosol formulation for administration of a measured dose of medication.

[0181] When it is desired to deliver the compound systemically, it can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion.The preparation for injection can be presented in a unit dosage form, for example, in an ampule or in a multi-dose container, with the addition of a preservative.The composition can take such forms as a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain formulatory agents such as suspending agents, stabilizing agents, and / or dispersing agents.

[0182] Pharmaceutical preparations for parenteral administration include aqueous solutions of water-soluble active compounds.In addition, suspensions of active compounds can be prepared as suitable oily injection suspensions.Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.Optionally, suspensions can also contain suitable stabilizers or agents that increase the solubility of compounds, allowing the preparation of highly concentrated solutions.

[0183] Alternatively, the active compound may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0184] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0185] In addition to the formulations described above, the compounds may also be formulated as depot preparations. Such long-acting preparations may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil), or ion exchange resins, or, for example, as a sparingly soluble salt or sparingly soluble derivative.

[0186] 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 such as starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0187] Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulation, encapsulation, coating on microscopic gold particles, inclusion in liposomes, nebulization, aerosolization, pellets for skin implantation, or drying on a sharp object that is scratched on the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with extended release of active compounds, and their preparation excipients, as well as additives and / or adjuvants such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners, or solubilizers, are commonly used as described above. Pharmaceutical compositions are suitable for use in various drug delivery systems. For a brief review of drug delivery methods, see Langer R, Science 249:1527-33 (1990).

[0188] The compounds of the present invention and, optionally, other therapeutic agents may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in pharmaceuticals, the salt or cocrystal should be pharmaceutically acceptable; however, non-pharmaceutically acceptable salts or cocrystals may be conveniently used to prepare pharmaceutically acceptable salts or cocrystals thereof. Such salts include, but are not limited to, those prepared from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Such salts may also be prepared as alkali metal or alkaline earth salts, such as sodium, potassium, or calcium salts, of the carboxylic acid group.

[0189] Suitable buffering agents include acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (0.8-2% w / v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v), chlorobutanol (0.3-0.9% w / v), parabens (0.01-0.25% w / v), and thimerosal (0.004-0.02% w / v).

[0190] The pharmaceutical compositions of the present invention contain an effective amount of a compound described herein and, optionally, a therapeutic agent contained in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers, diluents, or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic organic or inorganic ingredient with which the active ingredient is combined to facilitate application. The components of the pharmaceutical composition can also be mixed with the compound of the present invention, and with each other, in a manner such that there is no interaction that would substantially impair the desired pharmaceutical effect.

[0191] Therapeutic agent(s), including but not limited to, the compounds of the present invention, may be provided in particles. As used herein, particle refers to nanoparticles or microparticles (or in some cases, larger particles) that may consist, in whole or in part, of the compounds of the present invention or other therapeutic agent(s) described herein. The particles may contain the therapeutic agent(s) within a core surrounded by a coating, including but not limited to, an enteric coating. The therapeutic agent(s) may also be dispersed throughout the particle. The therapeutic agent(s) may also be adsorbed within the particle. The particles may have release kinetics of any order, including zero-order, first-order, second-order, delayed, sustained, immediate, and any combination thereof. In addition to the therapeutic agent(s), the particles may contain any of the materials routinely used in the pharmaceutical and medicinal arts, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable materials, or combinations thereof. The particles may be microcapsules containing the compounds of the present invention in solution or in a semi-solid state. The particles may be of virtually any shape.

[0192] Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for delivering therapeutic agent(s). Such polymers may be natural or synthetic. The polymer is selected based on the desired release period. Bioadhesive polymers of particular interest are described in Sawhney HS et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acid, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).

[0193] The therapeutic agent(s) may be contained in a controlled-release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation is controlled. This refers to immediate and non-immediate release formulations, with non-immediate release formulations including, but not limited to, sustained and delayed release formulations. The term "sustained release" (also called "extended release") is used in its conventional sense to refer to a drug formulation that provides a gradual release of drug over an extended period of time, preferably, but not necessarily, resulting in substantially constant blood levels of drug over an extended period of time. The term "delayed release" is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom. "Delayed release" may or may not involve a gradual release of drug over an extended period of time, and therefore may or may not be a "sustained release."

[0194] The use of long-term sustained-release implants may be particularly suitable for treating chronic conditions. As used herein, "long-term" release means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30 to 60 days. Long-term sustained-release implants are well known to those skilled in the art and include some of the release systems described above.

[0195] Those skilled in the art will appreciate that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description of the invention contained herein, in view of the information known to those skilled in the art, and can be made without departing from the scope of the invention or any of its embodiments. Having now described the invention in detail, the specification will be more clearly understood by reference to the following examples, which are not intended to limit the invention and are included herein for illustrative purposes only. [Example]

[0196] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0197] Intermediate 1: Synthesis of 4-(2-benzyloxyphenyl)cyclohexanol Scheme 1

[0198] [ka]

[0199] Step 1: Preparation of 2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol 2-Iodophenol (200 g, 909.06 mmol, 102.56 mL, 1 equiv.) was charged to a 2500 mL glass flask, followed by the addition of dioxane (1400 mL) and HO (140 mL) at 25 °C. 2-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (290.33 g, 1.09 mol, 1.2 equiv.), potassium carbonate (251.28 g, 1.82 mol, 2 equiv.), and Pd(dppf)Cl (6.65 g, 9.09 mmol, 0.01 equiv.) were added, followed by the addition of nitrogen, which was then bubbled through the reaction mixture for 15 minutes. The reaction was then stirred at 90 °C for 12 hours. Three parallel reactions were performed. The reactions were then cooled to room temperature, combined, and then diluted with water (1800 mL) and extracted with ethyl acetate (3 x 2000 mL). The combined organic layers were then washed with brine (2 x 1500 mL), dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel column chromatography (5% to 7%, ethyl acetate in heptane gradient). The isolated product was triturated with a 20:1 mixture of petroleum ether and ethyl acetate (1500 mL) at room temperature for 1.5 hours. The resulting mixture was filtered, and the filter cake was dried to give the title compound (550 g) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.20 - 7.07 (m, 2H), 6.96 - 6.82 (m, 2H), 5.85 - 5.75 (m, 1H), 5.70 - 5.48 (m, 1H), 4.04 (s, 4H), 2.55 (t, J = 7 Hz, 2H), 2.50 - 2.42 (m, 2H), 1.94 (t, J = 7 Hz, 2H).

[0200] Step 2: Preparation of 2-(1,4-dioxaspiro[4.5]decan-8-yl)phenol 2-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)phenol (91 g, 391.78 mmol, 1 equiv.) was added to 1.2 L of methanol, followed by the addition of palladium on carbon (9.1 g, 10% Pd on carbon, 50% in water) and palladium(II) acetate (1.82 g, 8.11 mmol, 0.0207 equiv.) under a nitrogen atmosphere. The reaction was then purged with hydrogen and stirred under hydrogen (50 Psi) at room temperature for 12 hours. Four parallel reactions were performed. The reactions were then combined and filtered through Celite, and the combined filtrate was concentrated. The crude product was then triturated with a 20:1 mixture of petroleum ether and ethyl acetate at room temperature for 1.5 hours. The resulting mixture was filtered, and the filter cake was dried to give the title compound (285 g, 1.22 mol, 77.62% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8 Hz, 1H), 7.06 (t, J = 8 Hz, 1H), 6.90 (t, J = 8 Hz, 1H), 6.75 (d, J = 8 Hz, 1H), 5.75 - 5.30 (m, 1H), 4.02 (s, 4H), 2.96 (s, 1H), 1.92 - 1.85 (m, 4H), 1.82 - 1.69 (m, 4H).

[0201] Step 3: Preparation of 4-(2-hydroxyphenyl)cyclohexanone 2-(1,4-Dioxaspiro[4.5]decan-8-yl)phenol (94 g, 401.21 mmol, 1 equiv.) was dissolved in 1.2 L of methanol, and then hydrochloric acid (6 M, 768.99 mL, 11.5 equiv.) was added. The resulting solution was stirred at room temperature under a nitrogen atmosphere for 12 hours. Three parallel reactions were performed. The resulting reaction mixtures were then combined and concentrated under reduced pressure to remove methanol. The resulting mixture was then filtered, and the filter cake was then collected and triturated with a 20:1 mixture of petroleum ether and ethyl acetate at room temperature for 1.5 hours. The mixture was then filtered, and the filter cake was dried under reduced pressure to give the title compound (182 g, 956.70 mmol, 79.48% yield) as a white solid.1 H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8 Hz, 1H), 7.11 (t, J = 8 Hz, 1H), 6.93 (t, J = 8 Hz, 1H), 6.77 (d, J = 8 Hz, 1H), 5.11 (s, 1H), 3.50 - 3.35 (m, 1H), 2.62 - 2.48 (m, 4H), 2.35 - 2.18 (m, 2H), 2.05 - 1.82 (m, 2H).

[0202] Step 4: Preparation of 4-(2-benzyloxyphenyl)cyclohexanone 4-(2-Hydroxyphenyl)cyclohexanone (91 g, 478.35 mmol, 1 equiv.) was added to 1 L of acetonitrile, followed by potassium carbonate (132.22 g, 956.70 mmol, 2 equiv.) and benzyl bromide (77.72 g, 454.43 mmol, 53.97 mL, 0.95 equiv.), and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours. Two parallel reactions were performed. The reactions were then combined, the solids were removed by filtration, and the resulting solution was concentrated under reduced pressure. The resulting residue was triturated with a 10:1 mixture of petroleum ether and ethyl acetate at room temperature for 1 hour. The resulting mixture was then filtered, and the filter cake was dried under reduced pressure to give the title compound (180 g, 642.03 mmol, 67.11% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.55 - 7.32 (m, 5H), 7.25 - 7.16 (m, 2H), 7.02 - 6.89 (m, 2H), 5.14 (s, 2H), 3.61 - 3.44 (m, 1H), 2.61 - 2.41 (m, 4H), 2.30 - 2.16 (m, 2H), 2.00 - 1.85 (m, 2H).

[0203] Step 5: Preparation of 4-(2-benzyloxyphenyl)cyclohexanol (Intermediate 1) A solution of triethylamine (75.07 g, 741.90 mmol, 103.26 mL, 2.6 equiv.) in dichloromethane (700 mL) was cooled to 0° C., and then formic acid (31.52 g, 684.83 mmol, 25.84 mL, 2.4 equiv.) and N-[(1S,2S)-2-amino-1,2-diphenyl-ethyl]-4-methyl-benzenesulfonamide; chlororuthenium; 1-isopropyl-4-methyl-benzene (909.14 mg, 1.43 mmol, 0.005 equiv.) were added. The reaction was then warmed to room temperature and stirred under a nitrogen atmosphere for 30 minutes. 4-(2-benzyloxyphenyl)cyclohexanone (80 g, 285.35 mmol, 1 equiv.) was then added, and the reaction mixture was stirred under a nitrogen atmosphere at 50° C. for 3 hours. Two parallel reactions were performed. The reactions were then combined and concentrated under reduced pressure. The resulting residue was diluted with water (2000 mL) and then extracted with ethyl acetate (3 x 1600 mL). The combined organic layers were then washed with brine (2 x 1000 mL), dried over sodium sulfate, then filtered and concentrated under reduced pressure. The crude product was then purified by silica gel chromatography (20-33%, ethyl acetate in petroleum ether gradient) to afford the title compound (105 g, 371.84 mmol, 65.16% yield) as a white solid. LCMS (ESI): m / z [M+H] + C 19 H 23 Calculated O2: 283.2, measured 265.2 (M-OH). 1 H NMR (400 MHz, DMSO-d6) δ 7.50 - 7.37 (m, 4H), 7.35 - 7.27 (m, 1H), 7.19 (d, J = 8 Hz, 1H), 7.16 - 7.09 (m, 1H), 7.00 (d, J = 8 Hz, 1H), 6.95 - 6.82 (m, 1H), 5.12 (s, 2H), 4.33 (d, J = 2 Hz, 1H), 3.90 (d, J = 2 Hz, 1H), 3.05 - 2.85 (m, 1H), 1.86 - 1.68 (m, 4H), 1.59 - 1.38 (m, 4H).

[0204] Synthesis of intermediate 2 (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -Amino-3,8-dioxa-5(2,1)piperidina-1(1,2)-benzen-2(1,4)cyclohexanaoctaphan-6-one Scheme 2

[0205] [ka]

[0206] Step 1: Preparation of 3-bromo-2-(bromomethyl)pyridine A mixture of 2-methyl-3-bromopyridine (30.1 mL, 256 mmol), Luperox A98, benzoyl peroxide (3.17 g, 12.8 mmol), and N-bromosuccinimide (50.2 g, 282 mmol) in carbon tetrachloride (427 mL) was degassed with nitrogen for 15 minutes, and then the solution was heated under reflux (85° C.) for 18 hours. The reaction mixture was cooled to room temperature and filtered. The residue was washed with 10% EtOAc / heptane. The filtrate was concentrated and purified by flash column chromatography (silica gel, 0-15% EtOAc / heptane) to give the title compound as a purple oil (67.0 g, 67% yield), which solidified upon storage in the refrigerator. LCMS (ESI): m / z [M+H] + Calculated for C6H5Br2N: 253.87, found 253.9.

[0207] Step 2: Preparation of 2-((((1s,4s)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-bromopyridine Under nitrogen, to a solution of (1s,4s)-4-(2-(benzyloxy)phenyl)cyclohexanol (Intermediate 1) (15.0 g, 53.1 mmol) in THF (150 mL) was added sodium tert-butoxide (10.5 g, 106 mmol), and the solution was stirred at room temperature for 20 minutes. 3-Bromo-2-(bromomethyl)pyridine (20.0 g, 79.7 mmol) in THF (45.3 mL) was slowly added to the solution and stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (26.0 g, 108% yield), which was used in the next step without further purification. LCMS(ESI):m / z[M+H] + C 25 H 26 Calculated BrNO2 value: 452.11, found value 452.2.

[0208] Step 3: Preparation of tert-butyl (2-(((((1s,4s)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)carbamate To a solution of 2-((((1s,4s)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)-3-bromopyridine (26.0 g, 57.5 mmol) in dioxane (160 mL) under nitrogen, cesium carbonate (26.2 g, 80.5 mmol) and tert-butyl carbamate (10.3 g, 86.2 mmol) were added. Nitrogen was bubbled through for 15 minutes, and 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (3.39 g, 5.75 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (2.69 g, 2.87 mmol) were added. Bubbling was continued for 5 minutes, and then the solution was stirred under nitrogen at 100° C. for 17 hours. The reaction was then diluted with ethyl acetate (200 mL) / brine (100 mL). The reaction was filtered, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography (silica, 0-70% EtOAc / heptane) to afford the title compound in 70% purity (27.0 g, 96% yield). LCMS (ESI): m / z [M+H] + C 30 H 36 Calculated N2O4: 489.27, measured 489.5.

[0209] Step 4: Preparation of tert-butyl (2-(((((1s,4s)-4-(2-hydroxyphenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)carbamate To a solution of tert-butyl (2-((((1s,4s)-4-(2-(benzyloxy)phenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)carbamate (27.0 g, 55.3 mmol) in ethanol (216 mL) and methanol (216 mL) was added ammonium formate (52.3 g, 829 mmol), followed by 10% wet palladium on carbon (2.64 g, 24.8 mmol). The reaction mixture was stirred at 70° C. for 2 hours. Heating was stopped and the reaction was stirred at room temperature for 2 days. The reaction mixture was filtered through Celite, washed with methanol, and the filtrate was concentrated. The crude product was diluted with water / EtOAc (300 mL / 500 mL) and stirred at room temperature for 10 minutes. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated to give the title compound which was used crude in the next step as is (21.9 g, 98% yield). LCMS (ESI): m / z [M+H] + C 23 H 30 Calculated N2O4: 399.22, measured 399.4.

[0210] Step 5: Preparation of ethyl 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)pyridin-2-yl)methoxy)cyclohexyl)phenoxy)acetate To tert-butyl (2-((((1s,4s)-4-(2-hydroxyphenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)carbamate (23.2 g, 58.3 mmol) in acetone (194 mL) was added potassium carbonate (24.2 g, 175 mmol) and potassium iodide (494 mg, 2.92 mmol), followed by the dropwise addition of ethyl bromoacetate (8.6 mL, 76.0 mmol). The solution was stirred at 50° C. for 21 hours. The solution was cooled to room temperature, and the precipitate was filtered, rinsed with acetone, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0% to 80% EtOAc / heptane) to give the title compound as a brown oil (17.9 g, 63% yield). LCMS (ESI): m / z [M+H] + C 27 H 36Calculated N2O6: 485.26, measured 485.5.

[0211] Step 6: Preparation of ethyl 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetate To a solution of ethyl 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)pyridin-2-yl)methoxy)cyclohexyl)phenoxy)acetate (17.9 g, 36.9 mmol) in a mixture of ethanol (160 mL) and acetic acid (18.0 mL) under nitrogen was added platinum(IV) oxide (2.09 g, 9.22 mmol). The reaction was subjected to five vacuum / hydrogen cycles and then left under hydrogen for 21 hours. The hydrogen was replaced with nitrogen with five vacuum / nitrogen cycles. The solution was filtered through Celite, rinsed well with ethanol, dichloromethane, and ethyl acetate, and then concentrated to dryness. The crude product was purified by flash column chromatography (silica gel, 0%-8% MeOH / DCM) and the fractions corresponding to the cis product were concentrated to give the title compound as a mixture of enantiomers (10.7 g, 59% yield). LCMS (ESI): m / z [M+H] + C 27 H 42 Calculated N2O6: 491.3, measured 491.5.

[0212] Step 7: Preparation of 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetic acid To a solution of ethyl 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetate (10.7 g, 21.9 mmol) in a mixture of ethanol (27.0 mL), water (27.0 mL), and tetrahydrofuran (54.0 mL), lithium hydroxide (920.4 mg, 37.7 mmol) was added, the solution was stirred under nitrogen for 5.5 hours, and then the reaction was concentrated to remove most of the organic solvent. The slurry was diluted with acetonitrile (100 mL). 1 M aqueous hydrochloric acid (15.8 mL, 15.8 mmol) was added dropwise, and the resulting suspension was concentrated again. Additional acetonitrile (50 mL) was added, and the suspension was concentrated again. To the residue was added water (75 mL) and acetonitrile (20 mL), frozen, and lyophilized to give the crude title compound as an off-white solid (10.1 g, 100% yield). LCMS (ESI): m / z [M+H] + C 25 H 38 Calculated N2O6: 463.27, measured 463.5.

[0213] Step 8: tert-Butyl ((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)piperidina-1(1,2)-benzena-2(1,4)cyclohexanacyclooctaphane-5 3 Preparation of (-yl)carbamates To a solution of 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)phenoxy)acetic acid (1.00 g, 2.16 mmol) in dichloromethane (216 mL) under nitrogen at 0° C. was added N,N-diisopropylethylamine (1.51 mL, 8.65 mmol), followed by HATU (1.26 g, 3.24 mmol) in one portion. The solution was stirred under nitrogen in an ice-water bath for 18 hours, allowing the ice-water bath to slowly warm to room temperature. Saturated aqueous sodium bicarbonate (200 mL) was added, the phases were separated, the aqueous phase was extracted with dichloromethane (100 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the title compound, which was used crude in the next step.

[0214] Step 9: (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 Preparation of -amino-3,8-dioaxa-5(2,1)piperidina-1(1,2)-benzen-2(1,4)cyclohexanaoctaphan-6-one (intermediate 2) tert-Butyl ((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)piperidina-1(1,2)-benzena-2(1,4)cyclohexanacyclooctaphane-5 3To a solution of (4-yl)carbamate (960 mg, 2.16 mmol), trifluoroacetic acid (6 mL, 78.2 mmol) was added, and the mixture was stirred at room temperature for 20 minutes. The reaction was concentrated to dryness, 30 mL of toluene was added, and the solution was concentrated again. The crude product was purified by flash column chromatography (silica gel, 25% to 100% 10% MeOH / DCM with 1% NH4OH in DCM) to give the racemic title compound as a beige solid (618 mg, 83% yield). The above racemic compound was further purified by chiral chromatography (analytical column: ChiralPak IA, 250 mm × 4.6 mm ID, 5 μm, mobile phase: 8:8:84 MeOH:EtOH:hexane, 0.1% DEA, isocratic flow: 1 mL / min, column temperature: 26 °C, run time: 18 min, wavelength: 220 nm) to give the title compound (190 mg, 31% yield). LCMS(ESI):m / z [M+H] + C 20 H 28 Calculated N2O3: 345.21, measured 345.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.13 (td, J = 7.7, 1.7 Hz, 1H), 7.05 (dd, J = 7.3, 1.6 Hz, 1H), 6.81 (t, J = 7.5 Hz, 2H), 5.26 (d, J = 10.4 Hz, 1H), 4.85 (dd, J = 10.7, 5.0 Hz, 1H), 3.91 (d, J = 10.4 Hz, 1H), 3.79 - 3.72 (m, 1H), 3.61 (d, J = 18.6 Hz, 2H), 3.42 (dd, J = 9.1, 3.8 Hz, 1H), 3.22 (s, 1H), 2.85 - 2.93 (m, 1H), 2.62 (dt, J = 12.6, 10.1 Hz, 2H), 2.23 (dt, J = 12.2, 8.8 Hz, 1H), 2.08 (d, J = 11.2 Hz, 1H), 1.69 - 1.10 (m, 10H).

[0215] Preparation of Compound 1: 1-((((2 1 S,24 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)methyl)cyclopropane-1-carbonitrile

[0216] [ka]

[0217] To a solution of intermediate 2 (60.0 mg, 174 μmol) in dichloromethane (1.8 mL) was added 1-formylcyclopropane-1-carbonitrile (34.9 mg, 348 μmol), acetic acid (36.0 μL, 628 μmol), and 4 Å molecular sieves. The mixture was stirred at room temperature for 1 hour, and sodium cyanoborohydride (34.6 mg, 522 μmol) was added. The mixture was stirred at room temperature for 1 hour. The crude product was filtered, rinsed with dichloromethane and methanol, and concentrated. The residue was redissolved in methanol and purified by reverse-phase chromatography (C18, 25-80% MeCN / 10 mM ammonium bicarbonate buffer) to give the title compound (51.5 mg, 70% yield). LCMS (ESI): m / z [M+H] + C 25 H 33 Calculated N3O3: 424.26, measured 424.3. 1H NMR (400 MHz, CD3OD) δ 7.14 (td, J = 7.7, 1.7 Hz, 1H), 7.07 (dd, J = 7.4, 1.6 Hz, 1H), 6.90 - 6.80 (m, 2H), 5.29 (d, J = 10.6 Hz, 1H), 5.24 - 5.14 (m, 1H), 4.11 (d, J = 10.6 Hz, 1H), 3.98 - 3.88 (m, 1H), 3.85 - 3.74 (m, 1H), 3.69 (s, 1H), 3.56 - 3.40 (m, 2H), 2.99 - 2.87 (m, 2H), 2.81 - 2.66 (m, 2H), 2.63 - 2.50 (m, 1H), 2.41 - 2.23 (m, 1H), 2.17 (d, J = 13.2 Hz, 1H), 1.94 - 1.73 (m, 3H), 1.70 - 1.17 (m, 9H), 1.08 - 0.89 (m, 2H).

[0218] Preparation of Compound 2 and Compound 3: 1 S,2 4 S,5 2 R,5 3 S)-5 3 -(((R)-1,1,1-trifluoropropan-2-yl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one and (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -(((S)-1,1,1-trifluoropropan-2-yl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one

[0219] [ka]

[0220] [ka]

[0221] To a solution of Intermediate 2 (25 mg, 72.6 μmol) and 1,1,1-trifluoroacetone (7.8 μL, 87.1 μmol) in dichloromethane (0.75 mL) was added acetic acid (75 μL). The mixture was stirred with 100 mg of 4 Å molecular sieves at room temperature for 1 hour, after which sodium cyanoborohydride (14.4 mg, 218 μmol) was added. The reaction was stirred at room temperature for an additional 20 minutes before being quenched with methanol, filtered through Celite, and concentrated. The crude product was purified by flash column chromatography (C18, 0-100% MeCN / 10 mM ammonium formate buffer) to give a mixture of isomers, which was further purified by chiral chromatography (ChiralPak IA, 250 mm x 4.6 mm ID, 5 μm, 1:3:96 MeOH:EtOH:hexane + 0.1% diethylamine, flow rate 1 mL / min, pressure 51 bar, temperature 26 °C, 16 min run) to give compound 2 as the first eluting isomer (9.6 mg, 30% yield). LCMS (ESI): m / z [M+H] + C 23 H 31 Calculated value of F3N2O3: 441.23, measured value 441.4. 1H NMR (400 MHz, DMSO-d6) δ 7.13 (dd, J = 7.4, 5.9 Hz, 1H), 7.08 - 7.03 (m, 1H), 6.81 (t, J = 7.7 Hz, 2H), 5.26 (d, J = 10.4 Hz, 1H), 5.10 - 4.93 (m, 1H), 3.92 (d, J = 10.4 Hz, 1H), 3.83 - 3.71 (m, 1H), 3.62 (d, J = 18.2 Hz, 2H), 2.86 (d, J = 10.6 Hz, 1H), 2.68 - 2.55 (m, 1H), 2.28 (ddd, J = 22.1, 10.5, 6.6 Hz, 3H), 2.08 (d, J = 14.3 Hz, 1H), 1.71 - 1.59 (m, 3H), 1.51 - 1.01 (m, 12H).

[0222] Compound 3, the second dissolution isomer (2.9 mg, yield 9%) was isolated. LCMS(ESI):m / z[M+H] + C 23 H 31 Calculated value of F3N2O3: 441.23, measured value 441.4. 1 H NMR (400 MHz, DMSO-d6) δ 7.13 (d, J = 7.7 Hz, 1H), 7.05 (d, J = 5.8 Hz, 1H), 6.80 (d, J = 8.5 Hz, 2H), 5.26 (d, J = 10.4 Hz, 1H), 4.84 - 4.89 (m, 1H), 3.92 (d, J = 10.4 Hz, 1H), 3.79 - 3.72 (m, 1H), 3.66 - 3.53 (m, 2H), 3.44 - 3.37 (m, 1H), 2.76 - 2.79 (m, 1H), 2.22 - 1.95 (m, 3H), 1.76 - 1.61 (m, 3H), 1.08 - 1.48 (m, 13H).

[0223] Modulation of compound 4: 2-(((2 1 S,2 4 S,5 2 R,5 3S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)benzonitrile

[0224] [ka] Intermediate 2 (20.0 mg, 58.1 μmol) was dissolved in 1,4-dioxane (0.58 mL), and 2-bromobenzonitrile (20.5 mg, 110 μmol), cesium carbonate (38.6 mg, 116 μmol), and 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (3.43 mg, 5.81 μmol) were added to the solution. The reaction was purged with nitrogen, tris(dibenzylideneacetone)-dipalladium(0) (1.03 mg, 1.12 μmol) was added, and the mixture was heated at 90°C for 18 hours. The reaction was concentrated and purified by flash column chromatography (C18, 50-70% MeCN / 10 mM ammonium bicarbonate buffer) to give the title compound (15.0 mg, 58% yield) as a white powder. LCMS (ESI): m / z [M+H] + C 27 H 31 Calculated N3O3: 446.24, measured 446.4. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (t, J = 8.5 Hz, 2H), 7.13 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.84 - 6.80 (m, 2H), 6.72 (t, J = 7.5 Hz, 1H), 5.70 (d, J = 7.3 Hz, 1H), 5.30 (d, J = 10.4 Hz, 1H), 5.20 - 5.11 (m, 1H), 3.93 (dd, J = 24.1, 10.5 Hz, 2H), 3.71 (d, J = 10.5 Hz, 2H), 3.58 (s, 1H), 3.19 (dd, J = 23.0, 16.9 Hz, 2H), 2.68 - 2.57 (m, 1H), 2.25 - 2.06 (m, 2H), 1.91 (dd, J = 24.0, 12.7 Hz, 1H), 1.79 (d, J = 10.9 Hz, 2H), 1.63 - 1.52 (m, 2H), 1.39 - 1.06 (m, 5H).

[0225] Preparation of Compound 5: (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -(((tetrahydrofuran-2-yl)methyl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one

[0226] [ka] To a solution of intermediate 2 (32.0 mg, 92.9 μmol) in dichloromethane (0.93 mL), tetrahydrofuran-2-carbaldehyde (31.3 mg, 313 μmol), acetic acid (5.3 μL, 92.9 μmol), and 4 Å molecular sieves were added, and the mixture was stirred at 26 °C for 2 h. Sodium triacetoxyborohydride (39.4 mg, 186 μmol) was added, and the solution was stirred at 27 °C for 18 h. The crude product was filtered, rinsed with dichloromethane and methanol, and concentrated. The residue was dissolved in N,N-dimethylformamide and purified by preparative HPLC-MS (40-60% MeCN / 10 mM ammonium bicarbonate buffer) to give the title compound (10.3 mg, 26% yield) as a mixture of diastereomers. LCMS (ESI): m / z [M+H] + C 25 H 36 Calculated N2O4: 429.27, measured 429.5. 1 H NMR (400 MHz, CD3OD) δ 7.18 - 7.12 (m, 1H), 7.08 (dd, J = 7.4, 1.7 Hz, 1H), 6.86 (td, J = 7.4, 1.1 Hz, 1H), 6.80 (dd, J = 8.1, 1.0 Hz, 1H), 5.17 (d, J = 10.3 Hz, 1H), 5.08 (dq, J = 9.1, 4.5 Hz, 1H), 4.03 (d, J = 10.3 Hz, 1H), 3.96 - 3.72 (m, 3H), 3.71 - 3.61 (m, 3H), 3.46 - 3.28 (m, 2H), 2.83 - 2.67 (m, 4H), 2.67 - 2.50 (m, 2H), 2.36 - 2.21 (m, 1H), 1.89 - 1.80 (m, 2H), 1.80 - 1.65 (m, 4H), 1.65 - 1.16 (m, 8H).

[0227] Preparation of Compound 6: (2 1 S,2 4 S,5 2 R,5 3 S)-5 3-((2-Methoxypyridin-3-yl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one

[0228] [ka] Intermediate 2 (20.0 mg, 58.1 μmol) was dissolved in 1,4-dioxane (0.58 mL) and 3-bromo-2-methoxypyridine (13.8 μL, 110 μmol), and cesium carbonate (38.6 mg, 116 μmol) and 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (3.43 mg, 5.81 μmol) were added to the solution. The reaction was purged with nitrogen, and tris(dibenzylideneacetone)-dipalladium(0) (1.03 mg, 1.12 μmol) was added. It was then heated to 90°C for 18 hours. The reaction was concentrated and purified by flash column chromatography (C18, 45-65% MeCN / 10 mM ammonium formate buffer) to give the title compound (8.10 mg, 31% yield) as a white solid. LCMS(ESI):m / z[M+H] + C 26 H 33 Calculated N3O4: 452.25, measured 452.4. 1H NMR (400 MHz, CD3OD) δ 7.40 (dd, J = 5.1, 1.4 Hz, 1H), 7.14 (td, J = 7.8, 1.6 Hz, 1H), 7.06 (d, J = 7.5 Hz, 2H), 6.85 (td, J = 7.1, 1.5 Hz, 3H), 5.42 - 5.35 (m, 1H), 5.32 (d, J = 10.6 Hz, 1H), 4.12 (d, J = 10.6 Hz, 1H), 4.03 - 3.98 (m, 1H), 3.96 (s, 3H), 3.84 (d, J = 13.9 Hz, 1H), 3.73 - 3.66 (m, 1H), 3.62 (s, 1H), 3.55 (td, J = 13.4, 2.5 Hz, 1H), 2.73 (qd, J = 13.1, 4.5 Hz, 1H), 2.60 - 2.49 (m, 1H), 2.26 (ddd, J = 26.1, 13.1, 4.2 Hz, 1H), 2.17 (d, J = 14.0 Hz, 1H), 1.97 - 1.90 (m, 2H), 1.89 - 1.70 (m, 3H), 1.47 - 1.29 (m, 3H), 1.29 - 1.19 (m, 1H).

[0229] Preparation of Compound 7: (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -(Pyridin-2-ylamino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one

[0230] [ka] Intermediate 2 (20.0 mg, 58.1 μmol), cesium carbonate (38.6 mg, 116 μmol), 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (3.43 mg, 5.81 μmol), and tris(dibenzylideneacetone)-dipalladium(0) (2.66 mg, 2.90 μmol) were placed in a vial. 1,4-Dioxane (0.58 mL) was added, and the reaction was degassed with nitrogen for 5 minutes. 2-Bromopyridine (10.7 μL, 110 μmol) was added, and the reaction was sealed and heated at 90 °C for 20 hours. The reaction was concentrated and purified by flash column chromatography (C18 silica, 50-70% MeCN / 10 mM ammonium bicarbonate buffer) to give the title compound (5.8 mg, 24% yield) as a white solid. LCMS(ESI):m / z[M+H] + C 25 H 31 Calculated N3O3: 422.24, measured 422.4. 1H NMR (400 MHz, CD3OD) δ 8.01 - 7.96 (m, 1H), 7.45 (ddd, J = 8.7, 7.1, 1.9 Hz, 1H), 7.14 (td, J = 7.8, 1.7 Hz, 1H), 7.06 (dd, J = 7.5, 1.4 Hz, 1H), 6.86 (dd, J = 11.4, 4.4 Hz, 2H), 6.61 - 6.55 (m, 2H), 5.47 - 5.39 (m, 1H), 5.32 (d, J = 10.5 Hz, 1H), 4.10 (dd, J = 10.0, 7.0 Hz, 2H), 3.98 (dd, J = 10.9, 9.1 Hz, 1H), 3.84 (d, J = 13.2 Hz, 1H), 3.63 (d, J = 3.7 Hz, 1H), 3.55 (t, J = 12.9 Hz, 1H), 3.38 (dd, J = 9.0, 3.9 Hz, 1H), 2.74 (qd, J = 13.2, 4.4 Hz, 1H), 2.55 (ddd, J = 17.3, 12.0, 5.2 Hz, 1H), 2.27 (qd, J = 13.0, 4.1 Hz, 1H), 2.16 (d, J = 13.9 Hz, 1H), 1.96 - 1.86 (m, 2H), 1.80 - 1.71 (m, 3H), 1.45 - 1.37 (m, 2H), 1.33 (dd, J = 13.7, 4.3 Hz, 1H), 1.27 - 1.19 (m, 1H).

[0231] Preparation of Compound 8: (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one

[0232] [ka] Intermediate 2 (20.0 mg, 58.1 μmol), 3-bromo-1-methylpyridin-2(1H)-one (21.8 mg, 110 μmol), cesium carbonate (38.6 mg, 116 μmol), and 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (3.43 mg, 5.81 μmol) were dissolved in anhydrous 1,4-dioxane (0.23 mL). The reaction was purged with nitrogen, and tris(dibenzylideneacetone)-dipalladium(0) (1.03 mg, 1.12 μmol) was added. The reaction was then sealed under nitrogen and heated at 90°C for 18 hours. The mixture was concentrated and purified by flash column chromatography (C18 silica, 50-70% MeCN / 10 mM ammonium bicarbonate buffer) to give the title compound (17.6 mg, 67% yield) as a white solid. LCMS(ESI):m / z[M+H] + C 26 H 33 Calculated N3O4: 452.25, measured 452.4. 1H NMR (400 MHz, DMSO-d6) δ 7.13 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 6.94 (d, J = 6.7 Hz, 1H), 6.82 (dd, J = 7.1, 5.6 Hz, 2H), 6.34 (d, J = 7.3 Hz, 1H), 6.17 (t, J = 7.0 Hz, 1H), 5.29 (d, J = 10.4 Hz, 1H), 5.16 (dd, J = 15.7, 7.0 Hz, 2H), 3.95 (d, J = 10.4 Hz, 1H), 3.91 - 3.84 (m, 1H), 3.69 (d, J = 13.1 Hz, 1H), 3.52 (d, J = 10.3 Hz, 2H), 3.45 (s, 3H), 3.04 (dd, J = 9.1, 3.4 Hz, 1H), 2.68 - 2.52 (m, 2H), 2.24 - 2.05 (m, 2H), 1.90 - 1.73 (m, 3H), 1.57 (d, J = 12.5 Hz, 2H), 1.32 (t, J = 10.7 Hz, 2H), 1.22 (dd, J = 15.6, 11.8 Hz, 1H), 1.11 (d, J = 11.1 Hz, 1H).

[0233] Preparation of Compound 9: (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -((2-Fluorophenyl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one

[0234] [ka] Intermediate 2 (20.0 mg, 58.1 μmol), 2-bromofluorobenzene (7.0 μL, 63.9 μmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (1.84 mg, 2.90 μmol), and sodium tert-butoxide (6.33 mg, 63.9 μmol) were placed in a vial. Toluene (0.15 mL) was added, and the reaction was degassed with nitrogen for 5 minutes. Tris(dibenzylideneacetone)-dipalladium(0) (1.33 mg, 1.45 μmol) was added, and the reaction was sealed and heated at 110° C. for 3 hours. The reaction was concentrated and purified by flash column chromatography (C18 silica, 50-70% MeCN / 10 mM ammonium formate buffer) to give the title compound (12.5 mg, 49% yield). LCMS(ESI):m / z[M+H] + C 26 H 31 Calculated value of FN2O3: 439.24, measured value 439.3. 1H NMR (400 MHz, CD3OD) δ 7.13 (t, J = 7.8 Hz, 1H), 7.08 - 6.92 (m, 4H), 6.88 - 6.81 (m, 2H), 6.62 (dt, J = 13.6, 4.0 Hz, 1H), 5.45 - 5.36 (m, 1H), 5.30 (d, J = 10.6 Hz, 1H), 4.12 (d, J = 10.6 Hz, 1H), 4.02 - 3.94 (m, 1H), 3.81 (d, J = 12.2 Hz, 1H), 3.77 - 3.67 (m, 1H), 3.61 (s, 1H), 3.53 (dd, J = 18.8, 7.6 Hz, 1H), 3.33 (dd, J = 9.1, 3.9 Hz, 1H), 2.73 (qd, J = 13.1, 4.4 Hz, 1H), 2.59 - 2.47 (m, 1H), 2.26 (qd, J = 13.0, 4.1 Hz, 1H), 2.16 (d, J = 13.7 Hz, 1H), 1.90 (dd, J = 21.9, 9.5 Hz, 2H), 1.81 (dd, J = 12.4, 3.5 Hz, 1H), 1.77 - 1.68 (m, 2H), 1.41 (dd, J = 13.2, 3.4 Hz, 2H), 1.36 - 1.28 (m, 1H), 1.27 - 1.18 (m, 1H).

[0235] Preparation of Compound 10: 3-(((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)picolinonitrile

[0236] [ka] Intermediate 2 (30.0 mg, 87.1 μmol), 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (5.14 mg, 8.71 μmol), cesium carbonate (57.9 mg, 174 μmol), and 3-bromopyridine-2-carbonitrile (30.9 mg, 165 μmol) were placed in a vial. 1,4-Dioxane (0.87 mL) was added, and the reaction was degassed with nitrogen for 5 minutes. Tris(dibenzylideneacetone)-dipalladium(0) (3.99 mg, 4.35 μmol) was added, and the reaction was sealed and heated at 90°C for 20 hours. The reaction was purified by reverse-phase flash column chromatography (C18, 40-60% MeCN / 10 mM ammonium formate buffer) to give the title compound (21.4 mg, 55%) as a white solid. LCMS(ESI):m / z[M+H] + C 26 H 30 Calculated N4O3: 447.24, measured 447.3. 1H NMR (400 MHz, CD3OD) δ 7.97 - 7.91 (m, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.51 - 7.45 (m, 1H), 7.14 (t, J = 7.7 Hz, 1H), 7.06 (d, J = 7.3 Hz, 1H), 6.86 (t, J = 8.5 Hz, 2H), 5.32 (dt, J = 10.2, 5.1 Hz, 2H), 4.13 (dd, J = 10.6, 2.0 Hz, 1H), 4.05 (t, J = 9.5 Hz, 1H), 3.86 (d, J = 12.6 Hz, 2H), 3.66 (s, 1H), 3.56 (t, J = 13.3 Hz, 1H), 3.37 - 3.32 (m, 1H), 2.71 (dt, J = 22.3, 11.0 Hz, 1H), 2.56 (dd, J = 14.5, 9.0 Hz, 1H), 2.32 - 2.13 (m, 2H), 1.96 (dd, J = 13.6, 7.6 Hz, 4H), 1.75 (d, J = 12.8 Hz, 2H), 1.44 (d, J = 13.2 Hz, 2H), 1.40 - 1.30 (m, 2H), 1.24 (d, J = 12.5 Hz, 1H).

[0237] Synthesis of Compound 11: (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -((3,3,3-trifluoro-2,2-dimethylpropyl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one

[0238] [ka]

[0239] Step 1: Preparation of 3,3,3-trifluoro-2,2-dimethylpropanol 3,3,3-Trifluoro-2,2-dimethylpropionic acid (300 mg, 1.86 mmol) was dissolved in diethyl ether (4.50 mL) and cooled to 0 °C. Lithium aluminum hydride (1.86 mL, 3.73 mmol) was slowly added at 0 °C, and the mixture was allowed to warm slowly to room temperature and stirred for 18 hours. Water (1 mL) was added to quench the reaction. 2 M sodium hydroxide (2 mL) was added, followed by water (1 mL), and the mixture was stirred for 15 minutes, then filtered over Celite, and the organic phase was partially concentrated under reduced pressure. The crude product was used directly in the next step, assuming quantitative yield.

[0240] Step 2: Preparation of 3,3,3-trifluoro-2,2-dimethylpropanal 3,3,3-Trifluoro-2,2-dimethylpropanol (265 mg, 1.86 mmol) was dissolved in dichloromethane (9.32 mL) and Dess-Martin periodinane (1.03 g, 2.42 mmol) was added. The mixture was stirred at room temperature for 2.5 h. Saturated aqueous sodium carbonate (5 mL) and 1 M sodium thiosulfate (2 mL) were added to the reaction and stirred for 30 min. The aqueous phase was washed with dichloromethane (2 × 10 mL), and the combined organic layers were partially concentrated and used directly in the next step, assuming quantitative yield.

[0241] Step 3: 1 S,2 4 S,5 2 R,5 3 S)-5 3 Preparation of -((3,3,3-trifluoro-2,2-dimethylpropyl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (compound 14) Intermediate 2 (20.0 mg, 58.1 μmol) was dissolved in methanol (0.15 mL) and a solution of crude 3,3,3-trifluoro-2,2-dimethylpropanal (8.13 mg, 58.1 μmol) in dichloromethane (500 μL) was added and stirred for 1 h. The reaction was cooled to 0 °C and sodium borohydride (22.9 mL, 581 μmol) was added and stirred at 0 °C for 30 min. The reaction was diluted with saturated aqueous sodium carbonate and extracted with dichloromethane (3 × 2 mL). The organic phase was dried over magnesium sulfate, concentrated, and purified by reverse-phase chromatography (C18, 55-75% MeCN / 10 mM ammonium formate buffer) to give the title compound (9.80 mg, 36%). LCMS (ESI): m / z [M+H] + C 25 H 35 Calculated value of F3N2O3: 469.26, measured value 469.3. 1 H NMR (400 MHz, CD3OD) δ 7.13 (td, J = 7.8, 1.4 Hz, 1H), 7.06 (dd, J = 7.4, 1.4 Hz, 1H), 6.88 - 6.79 (m, 2H), 5.28 (d, J = 10.6 Hz, 1H), 5.21 - 5.13 (m, 1H), 4.10 (d, J = 10.6 Hz, 1H), 3.95 - 3.87 (m, 1H), 3.77 (d, J = 14.4 Hz, 1H), 3.67 (s, 1H), 3.54 - 3.41 (m, 2H), 2.80 - 2.68 (m, 4H), 2.55 (ddd, J = 17.5, 12.0, 5.2 Hz, 1H), 2.30 (qd, J = 13.1, 4.1 Hz, 1H), 2.16 (d, J = 14.1 Hz, 1H), 1.87 - 1.78 (m, 3H), 1.67 - 1.57 (m, 1H), 1.43 (qdd, J = 18.3, 15.7, 5.2 Hz, 5H), 1.30 - 1.23 (m, 1H), 1.15 (s, 6H).

[0242] Preparation of Compound 12 and Compound 13: (1S,3r)-3-(((2 1S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)cyclobutane-1-carbonitrile and (1R,3s)-3-(((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)cyclobutane-1-carbonitrile

[0243] [ka]

[0244] [ka] To a solution of intermediate 2 (32.0 mg, 92.9 μmol) in dichloromethane (0.6 mL) was added 3-oxocyclobutanecarbonitrile (11.6 mg, 116 μmol), acetic acid (60.0 μL), and 4 Å molecular sieves. The mixture was stirred at room temperature for 1 hour, and sodium cyanoborohydride (11.5 mg, 174 μmol) was added. The mixture was stirred at room temperature for 1 hour. The crude product was filtered, rinsed with dichloromethane and methanol, and the filtrate was concentrated. The residue was dissolved in methanol and purified by reverse-phase chromatography (C18, 20-80% MeCN / 10 mM ammonium formate buffer) to give a mixture of isomers, which was further purified by chiral chromatography (ChiralPak IA, 250 mm x 4.6 mm ID, 5 μm, 5:25:75 MeOH:IPrOH:hexane, 0.1% diethylamine, flow rate 0.8 mL / min, 61 bar pressure, temperature 26 °C, 15 min run) to give compound 12 as the first eluting isomer (2.26 mg, 9% yield). LCMS (ESI): m / z [M+H]+ C 25 H 33 Calculated N3O3: 424.26, measured 424.3. 1 H NMR (400 MHz, CD3OD) δ 7.19 - 7.11 (m, 1H), 7.07 (d, J = 7.4 Hz, 1H), 6.85 (dd, J = 13.6, 7.4 Hz, 2H), 5.29 (d, J = 10.6 Hz, 1H), 5.15 - 5.05 (m, 1H), 4.10 (d, J = 10.6 Hz, 1H), 3.96 - 3.87 (m, 1H), 3.87 - 3.73 (m, 2H), 3.69 (s, 1H), 3.55 - 3.39 (m, 2H), 3.17 - 3.10 (m, 1H), 2.89 - 2.64 (m, 2H), 2.64 - 2.49 (m, 3H), 2.40 - 2.21 (m, 2H), 2.16 (d, J = 14.7 Hz, 1H), 1.89 - 1.75 (m, 3H), 1.68 - 1.37 (m, 5H), 1.36 - 1.23 (m, 2H), 0.89 (d, J = 7.6 Hz, 1H).

[0245] Compound 13 was obtained as the second eluting isomer (4.82 mg, 20% yield). LCMS (ESI): m / z [M+H] + C 25 H 33 Calculated N3O3: 424.26, measured 424.3. 1H NMR (400 MHz, CD3OD) δ 7.18 - 7.10 (m, 1H), 7.07 (dd, J = 7.4, 1.7 Hz, 1H), 6.89 - 6.79 (m, 2H), 5.29 (d, J = 10.6 Hz, 1H), 5.13 - 5.03 (m, 1H), 4.10 (d, J = 10.6 Hz, 1H), 3.95 - 3.85 (m, 1H), 3.78 (d, J = 10.8 Hz, 1H), 3.68 (s, 1H), 3.54 - 3.38 (m, 3H), 2.99 - 2.79 (m, 2H), 2.77 - 2.63 (m, 3H), 2.62 - 2.50 (m, 1H), 2.36 - 2.22 (m, 1H), 2.15 (ddd, J = 19.2, 13.9, 8.3 Hz, 3H), 1.89 - 1.72 (m, 3H), 1.68 - 1.21 (m, 7H).

[0246] Preparation of Compound 14: 3-(((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)isonicotinonitrile

[0247] [ka] Intermediate 2 (30 mg, 87.1 μmol), cesium carbonate (57.9 mg, 174 μmol), 3-bromo-4-cyanopyridine (16.3 mg, 87.1 μmol), 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (5.14 mg, 8.71 μmol), and tris(dibenzylideneacetone)-dipalladium(0) (3.99 mg, 4.35 μmol) were placed in a vial. 1,4-Dioxane (0.87 mL) was added under nitrogen, and the reaction was degassed for 5 minutes. The reaction was sealed and heated at 90° C. for 22 hours. The reaction was filtered through Celite, rinsed with methanol, concentrated, and purified by reverse-phase flash column chromatography (C18, 25-100% MeCN / 10 mM ammonium formate buffer) to give the title compound (25.1 mg, 65% yield) as a pale yellow solid. LCMS (ESI): m / z [M+H] + C 26 H 30 Calculated N4O3: 447.24, measured 447.3. 1 H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 7.94 (d, J = 4.7 Hz, 1H), 7.44 (d, J = 5.0 Hz, 1H), 7.15 (td, J = 7.7, 1.7 Hz, 1H), 7.07 (dd, J = 7.3, 1.6 Hz, 1H), 6.87 (dd, J = 12.1, 4.6 Hz, 2H), 5.44 - 5.36 (m, 1H), 5.33 (d, J = 10.6 Hz, 1H), 4.14 (d, J = 10.6 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.91 - 3.77 (m, 1H), 3.67 (s, 1H), 3.63 - 3.51 (m, 1H), 3.36 (dd, J = 9.1, 3.7 Hz, 1H), 2.80 - 2.65 (m, 1H), 2.62 - 2.48 (m, 1H), 2.42 - 2.12 (m, 2H), 2.08 - 1.89 (m, 3H), 1.87 - 1.69 (m, 2H), 1.56 - 1.15 (m, 4H).

[0248] Synthesis of Compound 15 (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -(((1-(trifluoromethyl)cyclopropyl)methyl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one

[0249] [ka]

[0250] Step 1: Preparation of N-methoxy-N-methyl-2-(1-(trifluoromethyl)cyclopropyl)acetamide To a solution of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (100 mg, 649 μmol), N,O-dimethylhydroxylamine hydrochloride (64.6 mg, 649 μmol), and N,N-diisopropylethylamine (126 μL, 714 μmol) in dimethylformamide (0.5 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (271 mg, 714 μmol). The reaction was stirred at room temperature for 30 minutes and then quenched with water. Ethyl acetate was added, and the organic phase was washed with water, brine, dried over sodium sulfate, filtered, and concentrated to give the title compound, which was used directly in the next step.

[0251] Step 2: Preparation of 2-(1-(trifluoromethyl)cyclopropyl]acetaldehyde To a solution of N-methoxy-N-methyl-2-(1-(trifluoromethyl)cyclopropyl)acetamide (68.0 mg, 345 μmol) in tetrahydrofuran (2 mL) under nitrogen was added lithium aluminum hydride (19.7 mg, 517 μmol) at 0° C. The reaction was stirred at 0° C. for 10 minutes and then allowed to warm slowly over 1 hour. The reaction was then quenched with sodium sulfate decahydrate (100 mg) and stirred for an additional 20 minutes. The crude reaction was filtered and used directly in the next step.

[0252] Step 3: 1 S,2 4 S,5 2 R,5 3 S)-5 3 Preparation of -(((1-(trifluoromethyl)cyclopropyl)methyl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one (compound 18) To a solution of intermediate 2 (50 mg, 145 μmol) and 2-(1-(trifluoromethyl)cyclopropyl)acetaldehyde (47.6 mg, 345 μmol) in dichloromethane (1.50 mL) was added acetic acid (83.3 μL). The mixture was stirred at room temperature for 5 minutes, after which sodium cyanoborohydride (26.6 mg, 435 μmol) was added. The reaction was stirred at room temperature for 1 hour before being quenched with methanol and concentrated. The crude product was purified by flash column chromatography (C18, 0-100% MeCN / 10 mM ammonium formate buffer) to give the title compound (14.0 mg, 21% yield). LCMS (ESI): m / z [M+H] + C 25 H 33 Calculated value of F3N2O3: 467.25, measured value 467.3. 1H NMR (400 MHz, DMSO-d6) δ 7.10 (ddd, J = 23.1, 12.4, 7.6 Hz, 2H), 6.81 (t, J = 8.4 Hz, 2H), 5.25 (d, J = 10.4 Hz, 1H), 5.04 - 4.92 (m, 1H), 3.92 (d, J = 10.4 Hz, 1H), 3.79 - 3.71 (m, 1H), 3.67 - 3.56 (m, 2H), 2.70 (ddt, J = 35.8, 32.1, 13.5 Hz, 5H), 2.31 - 2.03 (m, 3H), 1.68 (dd, J = 26.3, 14.2 Hz, 3H), 1.50 - 1.07 (m, 8H), 0.90 - 0.79 (m, 4H).

[0253] Preparation of Compound 16: 2-(((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)acetamide

[0254] [ka] Intermediate 2 (20.0 mg, 58.1 μmol) was dissolved in acetonitrile (0.40 mL). N,N-Diisopropylethylamine (15.3 μL, 87.1 μmol) was added, followed by 2-bromoacetamide (8.17 mg, 58.1 μmol). The reaction was heated at 80° C. for 18 hours, then concentrated and purified by flash column chromatography (C18, 0-80% MeCN / 10 mM ammonium formate buffer) to give the title compound (13.00 mg, 56% yield) as a white solid. LCMS (ESI): m / z [M+H] + C 22 H 31 Calculated N3O4: 402.23, measured 402.3. 1H NMR (400 MHz, CD3OD) δ 7.14 (td, J = 7.8, 1.7 Hz, 1H), 7.06 (dd, J = 7.4, 1.6 Hz, 1H), 6.89 - 6.80 (m, 2H), 5.28 (d, J = 10.6 Hz, 1H), 5.20 (s, 1H), 4.10 (d, J = 10.6 Hz, 1H), 3.95 (t, J = 8.9 Hz, 1H), 3.79 (d, J = 13.4 Hz, 1H), 3.70 (s, 1H), 3.60 - 3.35 (m, 4H), 2.94 (d, J = 10.0 Hz, 1H), 2.72 (qd, J = 12.9, 4.3 Hz, 1H), 2.61 - 2.51 (m, 1H), 2.29 (qd, J = 13.0, 4.1 Hz, 1H), 2.16 (d, J = 14.0 Hz, 1H), 2.01 - 1.75 (m, 3H), 1.69 - 1.51 (m, 2H), 1.52 - 1.31 (m, 4H), 1.30 - 1.22 (m, 1H).

[0255] Preparation of Compound 17: 2-(((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)nicotinonitrile

[0256] [ka] To a solution of Intermediate 2 (30.0 mg, 87.1 μmol) and 3-cyano-2-fluoropyridine (16.3 mg, 131 μmol) in N-methyl-2-pyrrolidone (0.99 mL) was added N,N-diisopropylethylamine (46.0 μL, 261 μmol). The resulting solution was heated at 80° C. for 20 hours. The crude product was directly purified by flash column chromatography (C18, 5-100% MeCN / 10 mM ammonium formate buffer) to give the title compound (26.4 mg, 68% yield). LCMS (ESI): m / z [M+H] + C 26 H 30 Calculated N4O3: 447.24, measured 447.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.34 (dd, J = 4.9, 1.9 Hz, 1H), 7.95 (dd, J = 7.6, 1.9 Hz, 1H), 7.15 (td, J = 7.9, 1.7 Hz, 1H), 7.11 - 7.04 (m, 1H), 6.89 - 6.79 (m, 3H), 6.73 (dd, J = 7.6, 4.9 Hz, 1H), 5.32 (d, J = 10.3 Hz, 1H), 5.29 - 5.20 (m, 1H), 4.34 - 4.18 (m, 1H), 3.98 - 3.86 (m, 2H), 3.71 (d, J = 11.8 Hz, 1H), 3.60 (s, 1H), 3.22 (dd, J = 9.4, 3.8 Hz, 1H), 2.69 - 2.58 (m, 2H), 2.27 - 2.03 (m, 2H), 1.96 (t, J = 11.3 Hz, 1H), 1.88 - 1.67 (m, 2H), 1.67 - 1.45 (m, 2H), 1.43 - 1.04 (m, 4H).

[0257] Synthesis of Compound 18 (2 1 S,2 4 S,5 2 R,5 3 S)-5 3-(((1-Fluorocyclopropyl)methyl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzen-2(1,4)-cyclohexanacyclooctaphan-6-one

[0258] [ka]

[0259] Step 1: Preparation of 2-(1-fluorocyclopropyl)-N-methoxy-N-methylacetamide To a solution of 1-fluorocyclopropanecarboxylic acid (67.5 mg, 649 μmol), N,O-dimethylhydroxylamine hydrochloride (64.6 mg, 649 μmol), and N,N-diisopropylethylamine (126 μL, 714 μmol) in dimethylformamide (0.50 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (271 mg, 714 μmol). The reaction was stirred at room temperature for 30 minutes and then quenched with water. Ethyl acetate was added, and the organic phase was washed with water, brine, dried over sodium sulfate, filtered, and concentrated to give the title compound, which was used directly in the next step.

[0260] Step 2: Preparation of 2-(1-fluorocyclopropyl)acetaldehyde To a solution of 2-(1-fluorocyclopropyl)-N-methoxy-N-methylacetamide (50.8 mg, 345 μmol) in tetrahydrofuran (2 mL) under nitrogen was added lithium aluminum hydride (19.7 mg, 517 μmol) at 0° C. The reaction was stirred at 0° C. for 10 minutes and then allowed to warm slowly over 1 hour. The reaction was then quenched with sodium sulfate decahydrate (100 mg) and stirred for an additional 20 minutes. The crude reaction was filtered and used directly in the next step.

[0261] Step 3: 1 S,2 4 S,5 2R,5 3 S)-5 3 Preparation of -(((1-fluorocyclopropyl)methyl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (compound 21) To a solution of intermediate 2 (50 mg, 145 μmol), 2-(1-fluorocyclopropyl)acetaldehyde (20.5 mg, 232 μmol) in dichloromethane (1.50 mL) was added acetic acid (10 μL). The mixture was stirred with 100 mg of 4 Å molecular sieves at room temperature for 1 hour, after which sodium cyanoborohydride (57.6 mg, 870 μmol) was added. The reaction was stirred at room temperature for an additional hour before being quenched with methanol and concentrated. The crude product was purified by flash column chromatography (C18, 0-100% MeCN / 10 mM ammonium formate buffer) to give the title compound (23.0 mg, 38% yield). LCMS (ESI): m / z [M+H] + C 24 H 33 Calculated value of FN2O3: 417.25, measured value 417.4. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 7.24 - 7.04 (m, 2H), 6.95 - 6.78 (m, 2H), 5.32 -5.25 (m, 1H), 4.00 - 3.44 (m, 5H), 2.66-2.61 (m, 1H), 2.38 - 0.07 (m, 21H).

[0262] Preparation of Compound 19: (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -((2-Fluorobenzyl)amino)-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one

[0263] [ka] To a solution of intermediate 2 (20 mg, 58.1 μmol) and 2-fluorobenzaldehyde (9.8 μL, 92.9 μmol) in dichloromethane (0.60 mL) was added acetic acid (4 μL). The mixture was stirred at room temperature for 20 minutes, after which sodium cyanoborohydride (11.5 mg, 174 μmol) was added. The reaction was stirred at room temperature for an additional 20 minutes, after which it was quenched with methanol and concentrated. The crude product was purified by flash column chromatography (C18, 0-100% MeCN / 10 mM ammonium formate buffer) to give the title compound (25.0 mg, 93% yield). LCMS (ESI): m / z [M+H] + C 27 H 33 Calculated value of FN2O3: 453.25, measured value 453.5. 1 H NMR (400 MHz, DMSO-d6) δ 7.48 - 4.43 (m, 1H), 7.21 - 7.12 (m, 4H), 7.06 (d, J = 7.1 Hz, 1H), 6.81 (t, J = 7.7 Hz, 2H), 5.26 (d, J = 9.5 Hz, 1H), 5.05 (s, 1H), 3.97 - 3.58 (m, 6H), 3.45 - 3.40 (m, 1H), 2.80 - 2.62 (m, 2H), 2.33 - 2.01 (m, 3H), 1.78 - 1.61 (m, 3H), 1.42 -1.16 (m, 5H).

[0264] Preparation of Compound 20: 4-(((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)nicotinonitrile

[0265] [ka] Intermediate 2 (30.0 mg, 87.1 μmol), N,N-diisopropylethylamine (50.0 μL, 284 μmol), and 3-bromopyridine-2-carbonitrile (20.6 mg, 110 μmol) were placed in a vial. N-Methyl-2-pyrrolidone (0.44 mL) was added, and the reaction was sealed and heated at 160° C. for 1.5 hours. The crude product was purified directly by reverse-phase chromatography (C18, 35-55% MeCN / 10 mM ammonium formate buffer) to give the title compound (22.7 mg, 58% yield). LCMS (ESI): m / z [M+H] + C 26 H 30 Calculated N4O3: 447.24, measured 447.3. 1 H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.28 (d, J = 6.2 Hz, 1H), 7.14 (td, J = 7.7, 1.6 Hz, 1H), 7.06 (dd, J = 7.3, 1.6 Hz, 1H), 7.01 (d, J = 6.4 Hz, 1H), 6.89 - 6.81 (m, 2H), 5.32 (dd, J = 9.9, 6.4 Hz, 2H), 4.13 (d, J = 10.7 Hz, 1H), 4.08 - 4.01 (m, 1H), 4.01 - 3.93 (m, 1H), 3.90 - 3.82 (m, 1H), 3.66 (s, 1H), 3.55 (td, J = 13.4, 2.3 Hz, 1H), 3.32 (d, J = 4.4 Hz, 1H), 2.72 (qd, J = 13.0, 4.3 Hz, 1H), 2.61 - 2.50 (m, 1H), 2.25 (ddd, J = 32.2, 20.7, 9.6 Hz, 2H), 2.09 - 1.89 (m, 3H), 1.84 - 1.69 (m, 2H), 1.48 - 1.30 (m, 3H), 1.29 - 1.20 (m, 1H).

[0266] Intermediate 3: Synthesis of (1s,4s)-4-(2-(benzyloxy)-3,5-difluorophenyl)cyclohexan-1-ol Scheme 3

[0267] [ka]

[0268] Step 1: Preparation of 2,4-difluoro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol A reaction vessel was charged with 2-bromo-4,6-difluorophenol (580 g, 2.26 mol), 1,4-dioxane (4060 mL), and water (406 mL). 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (886 g, 2.71 mol) and potassium carbonate (767 g, 2.71 mol) were added, followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (227 g, 0.226 mol). The reaction vessel was degassed and purged with nitrogen, and the reaction was stirred at 90°C for 12 hours. The reaction mixture was cooled to room temperature and then filtered through a Celite pad. Water (3V) was added to the filtrate, and the mixture was then extracted with ethyl acetate (3 x 5V). The combined organic layers were washed with brine (5V), then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was filtered through a silica pad with ethyl acetate, and the filtrate was then concentrated and triturated with 20:1 petroleum ether / ethyl acetate (2.5V), and the resulting mixture was stirred for 16 hours. The mixture was then filtered, and the filter cake was washed with 20:1 petroleum ether / ethyl acetate (2.5V). The filter cake was then dried under vacuum to give the title compound (715.5 g, 90.8% purity, 59.2% yield) as a dark gray solid. 1 H NMR (400 MHz, CDCl3) δ 6.73 (m, 2H), 5.86 (s, 1H), 5.29 (s, 1H), 4.03 (s, 4H), 2.58 (m, 2H), 2.47 (m, 2H), 1.92 (m, 2H).

[0269] Step 2: Preparation of 2,4-difluoro-6-(1,4-dioxaspiro[4.5]decan-8-yl)phenol A reaction vessel was charged with 10% palladium on carbon (50% w / w water, 8.35 g) and methanol (1000 mL). 2,4-Difluoro-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol (100 g, 0.373 mol) was then added, followed by palladium(II) acetate (1.67 g, 7.56 mmol), and the reaction vessel was degassed and purged with hydrogen. The reaction mixture was then stirred under hydrogen (50 Psi) at room temperature for 5 days while monitoring the consumption of the starting material. This procedure was carried out over seven batches. The batches were then combined, filtered through a Celite pad, and the filtrate was concentrated to give the crude product (870 g) as a yellow solid. The crude product was triturated with 20:1 petroleum ether / ethyl acetate (3 V) and then filtered. The filter cake was then collected and dried under vacuum to give the title compound (558 g, 90.5% purity, 85.4% yield) as a dark yellow solid. 1 H NMR (400 MHz, CDCl3) δ 6.73 (m, 2H), 5.12 (s, 1H), 3.99 (s, 4H), 3.01 (m, 1H), 1.86 (m, 4H), 1.72 (m, 4H).

[0270] Step 3: Preparation of 4-(3,5-difluoro-2-hydroxyphenyl)cyclohexan-1-one A reaction vessel was charged with 2,4-difluoro-6-(1,4-dioxaspiro[4.5]decan-8-yl)phenol (100 g, 370 mmol) and methanol (1000 mL). 6N hydrochloric acid (709 mL, 4.25 mol) was then added, and the reaction mixture was stirred under a nitrogen atmosphere at room temperature for 14 hours. This procedure was carried out in five batches. The batches were then combined and concentrated to remove the methanol. The resulting suspension was filtered, and the filter cake was dried to give 819 g of crude product. The crude product was triturated with 20:1 petroleum ether / ethyl acetate (3 V), and the resulting mixture was stirred at 15 °C for 1 hour. The mixture was then filtered, and the filter cake was dried under vacuum to give 524 g of a yellow solid. This material was triturated with methyl tert-butyl ether (2.5 V), and the resulting mixture was stirred at 15 °C for 2 hours. The mixture was then filtered and the filter cake was dried under vacuum to give the title compound as a pale yellow solid (385.5 g, 97.0% purity, 80.8% yield). 1 H NMR (400 MHz, CDCl3) δ 6.71 (m, 2H), 5.38 (s, 1H), 3.47 (m, 1H), 2.54 (m, 4H), 2.23 (m, 2H), 1.89 (m, 2H).

[0271] Step 4: Preparation of 4-(2-(benzyloxy)-3,5-difluorophenyl)cyclohexan-1-one A reaction vessel was charged with 4-(3,5-difluoro-2-hydroxyphenyl)cyclohexan-1-one (142.5 g, 629.9 mmol) and acetonitrile (1.5 L), followed by the addition of potassium carbonate (174.1 g, 1.26 mol) and benzyl bromide (102.35 g, 598.4 mmol) while maintaining the reaction temperature at 15° C. The reaction mixture was then stirred at 25° C. under a nitrogen atmosphere for 12 hours. This procedure was carried out in two batches. The two reactions were then combined, filtered, and the filtrate was concentrated. The crude product was triturated with 10:1 petroleum ether / ethyl acetate (2.5 V), and the resulting mixture was stirred at 15° C. for 1 hour. The mixture was then filtered, and the filter cake was dried under vacuum to give the title compound (330.4 g, 98.2% purity, 82.9% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.38 (m, 5H), 6.77 (m, 1H), 6.63 (m, 1H), 5.09 (s, 2H), 3.25 (t, J = 12 Hz, 1H), 2.34 (m, 4 H), 1.83 (m, 2H), 1.71 (m, 2H).

[0272] Step 5: Preparation of (1s,4s)-4-(2-(benzyloxy)-3,5-difluorophenyl)cyclohexan-1-ol (Intermediate 3) A reaction vessel was charged with triethylamine (83.2 g, 822 mmol) in dichloromethane (500 mL, 5V) and the solution was cooled to 0° C. Formic acid (34.9 g, 759 mmol) was then added, followed by chloro{[(1S,2S)-(+)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amide}(p-cymene)ruthenium(II) (1.01 g, 1.58 mmol), and the solution was stirred at 0° C. for 30 minutes. A solution of 4-(2-(benzyloxy)-3,5-difluorophenyl)cyclohexan-1-one (100 g, 316 mmol) in dichloromethane (500 mL, 5V) was then added at 0° C. The reaction mixture was stirred at 10° C. for 1 hour and then at 30° C. for 16 hours. The reaction mixture was then concentrated under reduced pressure to remove dichloromethane, after which water (10V) was added to the residue, followed by extraction with ethyl acetate (2 x 10V). The combined organic layers were washed with brine (10V), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (40:1 petroleum ether / ethyl acetate) to give the title compound as a yellow oil, which became a white solid upon cooling to 15°C (80g, 99.0% purity, 78.7% yield). 1 H NMR (400 MHz, CDCl3) δ 7.37 (m, 5H), 7.14 (m, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.98 (s, 2H), 4.33 (d, J = 4 Hz, 1H), 3.84 (s, 1H), 1.79 (t, J = 11.6 Hz), 1.68 (m, 4H), 1.42 (m, 2H), 1.21 (m, 2H).

[0273] Synthesis of intermediate 4 (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 3 ,1 5 -Difluoro-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one Scheme 3

[0274] [ka]

[0275] Step 1: Preparation of 3-bromo-2-(bromomethyl)pyridine A mixture of 2-methyl-3-bromopyridine (30.1 mL, 256 mmol), benzoyl peroxide (Luperox A98, 3.17 g, 12.8 mmol), and N-bromosuccinimide (50.2 g, 282 mmol) in carbon tetrachloride (427 mL) was degassed with nitrogen for 15 minutes, and then the solution was heated at reflux (85° C.) for 18 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with 10% ethyl acetate / heptane. The filtrate was concentrated, and the resulting residue was purified by silica gel chromatography (0-15%, ethyl acetate / heptane) to afford the title compound as a purple oil, which solidified upon storage at 4° C. LCMS (ESI): m / z [M+H] + Calculated for C6H5Br2N: 253.87, found 253.9.

[0276] Step 2: Preparation of 2-((((1s,4s)-4-(2-(benzyloxy)-3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-bromopyridine Under nitrogen, to a solution of (1s,4s)-4-(2-(benzyloxy)-3,5-difluorophenyl)cyclohexanol (Intermediate 3) (20.0 g, 62.8 mmol) in tetrahydrofuran (180 mL) was added sodium tert-butoxide (12.4 g, 126 mmol), and the solution was stirred at room temperature for 20 minutes. A solution of 3-bromo-2-(bromomethyl)pyridine (20.0 g, 79.7 mmol) in tetrahydrofuran (50 mL) was added slowly, and the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-30% ethyl acetate / heptane gradient) to give the title compound (25.0 g, 81% yield). LCMS (ESI): m / z [M+H] + C 25 H 24 Calculated value of BrF2NO2: 490.09, found value 490.0.

[0277] Step 3: Preparation of tert-butyl (2-(((((1s,4s)-4-(2-(benzyloxy)-3,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)carbamate To a solution of 2-((((1s,4s)-4-(2-(benzyloxy)-3,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-bromopyridine (8.98 g, 18.4 mmol) in 1,4-dioxane (92 mL) under nitrogen, cesium carbonate (8.39 g, 25.7 mmol) and tert-butyl carbamate (3.30 g, 27.6 mmol) were added. The solution was sparged with nitrogen, and 4,4-bis(diphenylphosphino)-9,9-dimethylxanthene (1.09 g, 1.84 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (859 mg, 0.92 mmol) were added. The infusion was continued for 5 minutes, and then the solution was stirred at 100° C. under a nitrogen atmosphere for 17 hours. The reaction was diluted with ethyl acetate (200 mL) and brine (100 mL). The mixture was filtered, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-70% ethyl acetate / heptane gradient) to give the title compound (9.36 g, 97% yield). LCMS (ESI): m / z [M+H] + C 30 H 34 Calculated value of F2N2O4: 525.25, measured value 525.3.

[0278] Step 4: Preparation of tert-butyl (2-(((((1s,4s)-4-(3,5-difluoro-2-hydroxyphenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)carbamate A solution of tert-butyl (2-((((1s,4s)-4-(2-(benzyloxy)-3,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)carbamate (9.36 g, 17.8 mmol) in ethanol (89.2 mL) was purged with nitrogen for 5 minutes, then palladium on carbon (10 wt % loading, 936 mg, 8.80 mmol) was added. The reaction vessel was evacuated and filled with hydrogen five times, then the reaction was stirred under hydrogen (1 atmosphere) for 18 hours. The hydrogen was removed through four cycles of evacuation and nitrogen filling, then the suspension was filtered over Celite, washed with ethyl acetate, dichloromethane, and ethanol, then concentrated to give the title compound (7.55 g, 97% yield) as a foam. LCMS (ESI): m / z [M+H] + C 23 H2 8F2 Calculated N2O4: 435.20, measured 435.2.

[0279] Step 5: Preparation of ethyl 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)pyridin-2-yl)methoxy)cyclohexyl)-4,6-difluorophenoxy)acetate To tert-butyl (2-((((1s,4s)-4-(3,5-difluoro-2-hydroxyphenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)carbamate (7.55 g, 17.4 mmol) in acetone (86.9 mL) was added potassium carbonate (7.19 g, 52.1 mmol) and potassium iodide (147 mg, 869 μmol), followed by dropwise addition of ethyl bromoacetate (2.56 mL, 22.6 mmol). The solution was stirred at 50° C. for 2 hours. The mixture was cooled to room temperature, then filtered and washed with acetone. The filtrate was then concentrated, and the crude product was purified by silica gel chromatography (0-80% ethyl acetate / heptane gradient, loaded in toluene) to afford the title compound (7.64 g, 84% yield) as a brown oil. LCMS (ESI): m / z [M+H] + C 27 H 34 Calculated value of F2N2O6: 521.24, measured value 521.3.

[0280] Step 6: Preparation of ethyl 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)-4,6-difluorophenoxy)acetate To a solution of ethyl 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)pyridin-2-yl)methoxy)cyclohexyl)-4,6-difluorophenoxy)acetate (7.64 g, 14.7 mmol) in a mixture of ethanol (110 mL) and acetic acid (12.2 mL) under nitrogen was added platinum(IV) oxide (833 mg, 3.67 mmol). The reaction was evacuated and backfilled with hydrogen three times, then the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 16 hours. Additional platinum(IV) oxide (183 mg, 766 μmol) was added and the reaction was stirred under a hydrogen atmosphere for an additional 5 hours. The hydrogen atmosphere was then evacuated and backfilled with nitrogen, after which the reaction mixture was filtered through Celite and rinsed with ethyl acetate, dichloromethane, and ethanol. The filtrate was then concentrated, and the crude product was dissolved in dichloromethane and extracted with saturated sodium bicarbonate solution. The aqueous layer was extracted twice more with dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-10% methanol / dichloromethane gradient) to afford the title compound (4.14 g, 54% yield) as a pale gray gum, isolated as a mixture of cis enantiomers. LCMS (ESI): m / z [M+H] + C 27 H 40 Calculated value of F2N2O6: 527.29, measured value 526.9.

[0281] Step 7: Preparation of 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)-4,6-difluorophenoxy)acetic acid To a solution of ethyl 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)-4,6-difluorophenoxy)acetate (3.34 g, 6.34 mmol) in a mixture of tetrahydrofuran (21.4 mL) and ethanol (10.7 mL) was added 1 M aqueous lithium hydroxide solution (6.98 mL, 6.98 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched by the addition of 1 M aqueous hydrochloric acid (634 μL, 634 μmol), and then the mixture was concentrated. Acetonitrile was added, and the mixture was concentrated again. Water and acetonitrile were added, and the mixture was frozen and lyophilized to give the title compound as a white solid, which was used without further purification (3.25 g, 101% yield). LCMS (ESI): m / z [M+H] + C 25 H 36 Calculated value of F2N2O6: 499.25, measured value 499.2.

[0282] Step 8: (2 1 s,2 4 s)-5 3 -amino-1 3 ,1 5 Preparation of -difluoro-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one To a solution of 2-(2-((1s,4s)-4-((3-((tert-butoxycarbonyl)amino)piperidin-2-yl)methoxy)cyclohexyl)-4,6-difluorophenoxy)acetic acid (800 mg, 1.60 mmol) in dichloroethane (730 mL) at an internal temperature of 70° C. was added N,N-diisopropylethylamine (1.12 mL, 6.42 mmol) followed by HATU (934 mg, 2.41 mmol) in one portion. The solution was stirred at 80° C. for 17 minutes. The solution was concentrated to half its volume and poured into a saturated aqueous solution of sodium bicarbonate. The organic phase was separated and the aqueous phase was extracted with dichloromethane (2×100 mL). The organic layers were combined, dried over sodium sulfate, then filtered and concentrated under reduced pressure to give the crude intermediate. This intermediate (788 mg, 1.64 mmol) was dissolved in dichloromethane (13.5 mL) and trifluoroacetic acid (4.32 mL, 56.4 mmol) was added. The mixture was then stirred at room temperature for 15 minutes. The mixture was concentrated to dryness, after which toluene (20 mL) was added and the solution was concentrated again. The crude product was purified by silica gel chromatography (0-10% methanol / dichloromethane gradient with 1% ammonium hydroxide) to give the title compound (240 mg, 38% yield) as a white solid. LCMS (ESI): m / z [M+H] + C 20 H 26 Calculated value of F2N2O3: 381.19, measured value 381.1.

[0283] Step 9: (2 1 S,2 4 S,5 2 R,5 3 S)-5 3 -amino-1 3 ,1 5 Preparation of -difluoro-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (intermediate 4) Racemic (2 1 s,2 4 s)-5 3 -amino-1 3 ,1 5-Difluoro-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one was purified by chiral chromatography (ChiralPak IA, 250 mm x 4.6 mm ID, 5 μm, 20:20:60 methanol / ethanol / hexanes with 0.1% diethylamine, 0.8 mL / min, column temperature: 22°C, 10 min run time) to give the title compound.

[0284] Preparation of Compound 21: 1-((((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)methyl)cyclobutane-1-carbonitrile

[0285] [ka] To a solution of Intermediate 2 (40.0 mg, 116 μmol) and 1-formylcyclobutanecarbonitrile (25.3 mg, 232 μmol) in dichloromethane (0.8 mL), acetic acid (80 μL) and molecular sieves were added, and the reaction was stirred at room temperature for 18 hours. Sodium cyanoborohydride (38.4 mg, 581 μmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (C18 column, 40-60% acetonitrile / water gradient with 10 mM ammonium formate) to give the title compound (25 mg, 49% yield) as a white solid. LCMS (ESI): m / z [M+H] + C 26 H 35 Calculated N3O3: 438.27, measured 438.3. 1H NMR (400 MHz, methanol-d4) δ 7.14 (td, J = 7.8, 1.7 Hz, 1H), 7.06 (dd, J = 7.4, 1.6 Hz, 1H), 6.87 - 6.81 (m, 2H), 5.29 (d, J = 10.6 Hz, 1H), 5.25 - 5.17 (m, 1H), 4.10 (d, J = 10.6 Hz, 1H), 3.92 (dd, J = 11.0, 9.5 Hz, 1H), 3.79 (d, J = 12.9 Hz, 1H), 3.68 (s, 1H), 3.51 (ddd, J = 15.9, 11.2, 3.4 Hz, 2H), 3.02 (d, J = 6.3 Hz, 2H), 2.94 - 2.87 (m, 1H), 2.74 (ddd, J = 25.6, 12.9, 4.5 Hz, 1H), 2.56 (ddd, J = 17.5, 12.1, 5.3 Hz, 1H), 2.51 - 2.40 (m, 2H), 2.37 - 2.27 (m, 1H), 2.14 (ddddd, J = 25.2, 18.3, 9.2, 4.9, 2.5 Hz, 5H), 1.90 - 1.76 (m, 3H), 1.73 - 1.22 (m, 7H).

[0286] Synthesis of compound 22 4-((((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile

[0287] [ka]

[0288] Step 1: Preparation of 1-formylcyclohexanecarbonitrile 4-(Hydroxymethyl)tetrahydro-2H-pyran-4-carbonitrile (99.9 mg, 708 μmol) was dissolved in dichloromethane (3.5 mL) and Dess-Martin periodinane (360 mg, 849 μmol) was added. The resulting solution was stirred at room temperature for 18 hours. Saturated aqueous sodium carbonate (5 mL) and 1 M aqueous sodium thiosulfate (2 mL) were added to the reaction, and the mixture was stirred for 1 hour. The aqueous phase was extracted with dichloromethane (2 × 10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to give the title compound as a white solid, which was used without further purification.

[0289] Step 2: 4-((((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 Preparation of (-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (compound 22) To a solution of Intermediate 2 (40.0 mg, 116 μmol) in dichloromethane (0.53 mL) and acetic acid (52.8 μL) was added 1-formylcyclohexanecarbonitrile (17.8 mg, 128 μmol) and molecular sieves, and the reaction was then stirred at room temperature for 18 hours. Sodium cyanoborohydride (38.4 mg, 581 μmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (C18 column, 40-60% acetonitrile / water gradient with 10 mM ammonium formate) to give the title compound (22.1 mg, 41% yield) as a white solid. LCMS (ESI): m / z [M+H] + C 27 H 37 Calculated N3O4: 468.28, measured 468.3. 1H NMR (400 MHz, methanol-d4) δ 7.14 (td, J = 7.8, 1.7 Hz, 1H), 7.06 (dd, J = 7.4, 1.6 Hz, 1H), 6.88 - 6.81 (m, 2H), 5.29 (d, J = 10.6 Hz, 1H), 5.23 - 5.15 (m, 1H), 4.10 (d, J = 10.6 Hz, 1H), 4.00 - 3.88 (m, 3H), 3.78 (d, J = 14.9 Hz, 1H), 3.71 - 3.60 (m, 3H), 3.56 - 3.44 (m, 2H), 2.92 - 2.83 (m, 3H), 2.73 (qd, J = 12.7, 4.4 Hz, 1H), 2.61 - 2.51 (m, 1H), 2.31 (ddd, J = 25.9, 13.0, 4.2 Hz, 1H), 2.16 (d, J = 14.2 Hz, 1H), 1.94 - 1.78 (m, 5H), 1.73 - 1.22 (m, 9H).

[0290] Synthesis of compound 23 2-(1-(((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)cyclobutyl)acetonitrile

[0291] [ka]

[0292] Step 1: Preparation of 2-cyclobutylideneacetonitrile Lithium bromide (1.96 g, 22.5 mmol) was flame-dried under vacuum and cooled to room temperature under nitrogen. Tetrahydrofuran (40 mL) was added and the mixture was stirred until homogeneous. Diethyl cyanomethylphosphonate (4.1 mL, 24.1 mmol) was added, followed by triethylamine (3.2 mL, 22.5 mmol). The reaction was stirred at 25°C for 2 hours and then added to a solution of cyclobutanone (1.74 mL, 22.5 mmol) in tetrahydrofuran (5.0 mL). The resulting solution was stirred at room temperature for 20 hours. The mixture was concentrated, dry-loaded onto silica, and purified by silica gel chromatography (0-15% ethyl acetate / heptane gradient) to afford the title compound (581 mg, 28% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 5.12 - 5.08 (m, 1H), 3.00 - 2.91 (m, 2H), 2.90 - 2.81 (m, 2H), 2.09 (dq, J = 11.6, 7.9 Hz, 2H).

[0293] Step 2: 2-(1-(((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 Preparation of (-yl)amino)cyclobutyl)acetonitrile (Compound 23) Intermediate 2 (50.0 mg, 145 μmol) was dissolved in acetonitrile (0.73 mL) in a microwave tube, followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (11.1 μL, 72.6 μmol) and 2-cyclobutylideneacetonitrile (27.0 mg, 290 μmol). The solution was stirred at 110°C for 4 days and then at 130°C for 4 days. The reaction mixture was directly loaded for purification by preparative HPLC (C18 column, 45-65% acetonitrile / water gradient with 10 mM ammonium formate) to give the title compound (24.4 mg, 38% yield) as a beige solid. LCMS (ESI): m / z [M+H] + C 26 H 35 Calculated N3O3: 438.27, measured 438.3. 1H NMR (400 MHz, methanol-d4) δ 7.14 (td, J = 7.7, 1.7 Hz, 1H), 7.06 (dd, J = 7.4, 1.6 Hz, 1H), 6.88 - 6.80 (m, 2H), 5.28 (d, J = 10.6 Hz, 1H), 5.00 - 4.93 (m, 1H), 4.10 (d, J = 10.6 Hz, 1H), 3.96 - 3.89 (m, 1H), 3.75 (d, J = 13.6 Hz, 1H), 3.70 (dd, J = 9.0, 3.8 Hz, 2H), 3.52 - 3.43 (m, 1H), 2.88 (dt, J = 10.2, 5.0 Hz, 1H), 2.84 (d, J = 1.7 Hz, 2H), 2.78 - 2.68 (m, 1H), 2.56 (ddd, J = 17.5, 12.1, 5.2 Hz, 1H), 2.31 (ddd, J = 25.8, 13.0, 4.1 Hz, 1H), 2.12 (ddd, J = 18.3, 15.2, 10.4 Hz, 3H), 2.01 (ddd, J = 16.7, 8.2, 4.3 Hz, 2H), 1.89 - 1.75 (m, 5H), 1.67 - 1.55 (m, 2H), 1.50 - 1.39 (m, 2H), 1.34 (dt, J = 13.9, 7.0 Hz, 1H), 1.26 (dd, J = 10.7, 5.5 Hz, 1H).

[0294] Preparation of Compound 24: 3-(((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)pyridazine-4-carbonitrile

[0295] [ka] A solution of Intermediate 2 (40.0 mg, 116 μmol), triethylamine (98.1 μL, 697 μmol), and 3-chloropyridazine-4-carbonitrile (21.7 mg, 151 μmol) in N-methyl-2-pyrrolidone (0.58 mL) was heated at 100° C. for 18 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (C18 column, 20-80% acetonitrile / water gradient with 10 mM ammonium formate) to give the title compound (22.9 mg, 44% yield) as a mauve solid. LCMS (ESI): m / z [M+H] + C 25 H 29 Calculated N5O3: 448.23, measured 448.2. 1 H NMR (400 MHz, methanol-d4) δ 8.66 (d, J = 4.9 Hz, 1H), 7.71 (d, J = 4.8 Hz, 1H), 7.14 (td, J = 7.8, 1.7 Hz, 1H), 7.08 - 7.04 (m, 1H), 6.88 - 6.83 (m, 2H), 5.62 - 5.51 (m, 1H), 5.34 (d, J = 10.5 Hz, 1H), 4.67 - 4.54 (m, 1H), 4.11 (d, J = 10.5 Hz, 1H), 4.06 (dd, J = 10.8, 9.3 Hz, 1H), 3.87 (d, J = 13.3 Hz, 1H), 3.67 (s, 1H), 3.63 - 3.52 (m, 1H), 3.39 (dd, J = 9.1, 3.9 Hz, 1H), 2.81 - 2.69 (m, 1H), 2.61 - 2.50 (m, 1H), 2.33 - 2.14 (m, 2H), 2.07 - 2.00 (m, 1H), 2.00 - 1.90 (m, 1H), 1.84 - 1.69 (m, 2H), 1.49 - 1.19 (m, 5H).

[0296] Preparation of Compound 25: 3-(((2 1S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)pyrazine-2-carbonitrile

[0297] [ka] A solution of Intermediate 2 (40.0 mg, 116 μmol), triethylamine (98.1 μL, 697 μmol), and 2-chloro-3-cyanopyrazine (21.7 mg, 151 μmol) in N-methyl-2-pyrrolidone (0.58 mL) was heated at 65° C. for 72 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with 1 M hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (C18 column, 25-60% acetonitrile / water gradient with 10 mM ammonium formate) to give the title compound (31 mg, 60% yield). LCMS (ESI): m / z [M+H] + C 25 H 29 Calculated N5O3: 448.23, measured 448.2. 1H NMR (400 MHz, methanol-d4) δ 8.34 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.14 (td, J = 7.7, 1.7 Hz, 1H), 7.06 (dd, J = 7.3, 1.6 Hz, 1H), 6.86 (t, J = 7.5 Hz, 2H), 5.52 - 5.42 (m, 1H), 5.33 (d, J = 10.5 Hz, 1H), 4.38 (dt, J = 12.5, 5.0 Hz, 1H), 4.11 (d, J = 10.6 Hz, 1H), 4.03 (dd, J = 11.0, 9.3 Hz, 1H), 3.85 (d, J = 13.6 Hz, 1H), 3.66 (s, 1H), 3.56 (td, J = 13.4, 2.6 Hz, 1H), 3.35 (dd, J = 9.1, 3.9 Hz, 1H), 2.84 - 2.63 (m, 1H), 2.63 - 2.41 (m, 1H), 2.33 - 2.13 (m, 2H), 2.08 - 1.86 (m, 3H), 1.81 - 1.64 (m, 2H), 1.50 - 1.20 (m, 4H).

[0298] Preparation of Compound 26: 2-(((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)-6-(trifluoromethyl)nicotinonitrile

[0299] [ka] A solution of intermediate 2 (40.0 mg, 116 μmol), N,N-diisopropylethylamine (40.9 μL, 232 μmol), and 2-chloro-6-(trifluoromethyl)nicotinonitrile (49.0 mg, 232 μmol) in N-methyl-2-pyrrolidone (0.3 mL) was stirred at 130° C. for 4 h. The crude reaction mixture was then directly loaded and purified by preparative HPLC (C18 column, 35-100% acetonitrile / water gradient with 10 mM ammonium formate) to afford the title compound (48.8 mg, 82% yield) as a beige solid. LCMS (ESI): m / z [M+H] + C 27 H 29 Calculated value of F3N4O3: 515.22, measured value 515.3. 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 7.8 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.11 - 6.97 (m, 1H), 6.91 - 6.73 (m, 2H), 5.37 - 5.18 (m, 2H), 4.21 (d, J = 4.9 Hz, 1H), 3.97 - 3.86 (m, 2H), 3.71 (d, J = 11.8 Hz, 1H), 3.61 (s, 1H), 3.24 (dd, J = 9.3, 3.7 Hz, 1H), 2.73 - 2.62 (m, 1H), 2.27 - 1.95 (m, 3H), 1.93 - 1.48 (m, 5H), 1.45 - 1.04 (m, 5H).

[0300] Preparation of Compound 27: 1-((((2 1 S,2 4 S,5 2 R,5 3 S)-13,15-Difluoro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)methyl)cyclopropane-1-carbonitrile

[0301] [ka] (2 1 s,2 4 s)-5 3 -amino-1 3 ,1 5 To a solution of 1-difluoro-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-6-one (50 mg, 0.131 mmol) and 1-formylcyclopropane-1-carbonitrile (18.8 mg, 0.197 mmol) was added sodium borohydride (15 mg, 0.349 mmol) at 0° C. The reaction was allowed to warm to 20° C. and stirred for an additional 10 hours, then quenched with water (5 mL) and extracted with ethyl acetate (5 mL×3). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (XBridge C18 OBD column 250 mm x 19 mm x 5 μm, 55-80% acetonitrile / water gradient with 10 mM ammonium formate) to give the racemic title compound (10 mg, 16.26% yield) as a white solid. The mixture of enantiomers was then separated by chiral HPLC (CHIRALPAK IF, 2 x 25 cm, 5 μm, mobile phase A: hexane with 0.5% 2M ammonia in methanol, mobile phase B: ethanol, flow rate: 13 mL / min, 50% isocratic method). The title compound was isolated as the later eluting peak (4.1 mg, 41% yield). LCMS (ESI): m / z [M+H] + C 25 H 31 Calculated value of F2N3O3: 460.24, measured value 460.25. 1H NMR (300 MHz, acetonitrile-d3) δ 6.80 - 6.94 (m, 1H), 6.70 - 6.80 (m, 1H), 5.39 (dd, J = 12.2, 3.4 Hz, 1H), 5.17 - 5.04 (m, 1H), 4.13 (dd, J = 12.2, 1.9 Hz, 1H), 3.76 - 3.89 (m, 2H), 3.70 (s, 1H), 3.35 - 3.61 (m, 2H), 2.77 - 2.91 (m, 2H), 2.71 - 2.77 (m, 1H), 2.47 - 2.70 (m, 2H), 2.08 - 2.16 (m, 1H), 2.00 - 2.08 (m, 1H), 1.68 - 1.85 (m, 3H), 1.29 - 1.65 (m, 7H), 1.17 - 1.22 (m, 2H), 1.10 -1.17 (m, 1H), 0.88 - 1.02 (m, 2H). 19 F NMR (282 MHz, acetonitrile-d3) δ -119.23, -127.68.

[0302] Synthesis of compound 28: 1-((((2 1 S,2 4 S,5 2 R,5 3 S)-1 3 ,1 5 -Difluoro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)methyl)cyclobutane-1-carbonitrile

[0303] [ka]

[0304] Step 1: Preparation of 1-(hydroxymethyl)cyclobutane-1-carbonitrile To a mixture of ethyl 1-cyanocyclobutanecarboxylate (246 mg, 1.53 mmol) in tetrahydrofuran (3.9 mL) and methanol (0.98 mL) at 0° C. was added sodium borohydride (121 mg, 3.08 mmol), and the mixture was slowly warmed to room temperature and stirred for 1 hour. Water (20 mL) was added, and the mixture was extracted with dichloromethane (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the title compound as a colorless oil, which was used without further purification (quantitative yield assumed).

[0305] Step 2: Preparation of 1-formylcyclobutane-1-carbonitrile 1-(Hydroxymethyl)cyclobutane-1-carbonitrile was dissolved in dichloromethane (7.5 mL) and Dess-Martin periodinane (772 mg, 1.82 mmol) was added. The reaction was stirred at room temperature for 21 hours. Saturated sodium bicarbonate solution (10 mL) and 10% sodium thiosulfate solution (10 mL) were added to the reaction, and the mixture was stirred until a clear solution was obtained (1 hour). The aqueous phase was extracted with dichloromethane (2 × 20 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the title compound as a yellow oil, which was used without further purification.

[0306] Step 3:1-((((2 1 S,2 4 S,5 2 R,5 3 S)-1 3 ,1 5 -Difluoro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 Preparation of (-yl)amino)methyl)cyclobutane-1-carbonitrile (compound 28) To a solution of intermediate 4 (100 mg, 263 μmol) and 1-formylcyclobutanecarbonitrile (57.4 mg, 526 μmol) in dichloromethane (1.8 mL) was added acetic acid (181 μL) and molecular sieves. After stirring the reaction for an additional 2 hours, sodium cyanoborohydride (86.9 mg, 1.31 mmol) was then added and the reaction was stirred at room temperature for an additional 1 hour. The reaction was diluted with water (30 mL) and extracted with dichloromethane (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (C18 column, 30-100% acetonitrile / water gradient with 10 mM ammonium formate) to give the title compound (101 mg, 81% yield) as a white solid. LCMS (ESI): m / z [M+H] + C 26 H 33 Calculated value of F2N3O3: 474.25, measured value 474.2. 1 H NMR (400 MHz, methanol-d4) δ 6.86 (ddd, J = 11.5, 8.3, 3.1 Hz, 1H), 6.74 (ddd, J = 9.1, 3.0, 1.9 Hz, 1H), 5.47 (dd, J = 12.4, 3.2 Hz, 1H), 5.26 - 5.16 (m, 1H), 4.14 (dd, J = 12.4, 1.8 Hz, 1H), 3.95 - 3.82 (m, 2H), 3.71 (s, 1H), 3.58 - 3.44 (m, 2H), 3.03 (s, 2H), 2.94 - 2.83 (m, 1H), 2.77 - 2.55 (m, 2H), 2.52 - 2.39 (m, 2H), 2.30 - 2.00 (m, 6H), 1.94 - 1.78 (m, 3H), 1.72 - 1.27 (m, 6H).

[0307] Synthesis of compound 29: 3-((((2 1 S,2 4 S,5 2 R,5 3S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)methyl)oxetane-3-carbonitrile

[0308] [ka]

[0309] Scheme 4

[0310] [ka]

[0311] Step 1: N-(2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-dioxa-5(2,1)piperidina-1(1,2)-benzena-2(1,4)cyclohexanaoctaphane-5 3 Preparation of (-yl)-2-nitrobenzenesulfonamide To a solution of intermediate 2 (120 mg, 348 μmol) in dichloromethane (4.8 mL) was added N,N-diisopropylethylamine (121 μL, 697 μmol), followed by 2-nitrobenzenesulfonyl chloride (78.8 mg, 348 μmol). The reaction was stirred at room temperature for 1 hour, concentrated, and the crude product was purified by preparative HPLC (C18 column, 40-60% acetonitrile / water gradient with 10 mM ammonium formate) to give the title compound (160 mg, 87% yield) as a white solid. LCMS (ESI): m / z [M+H] + C 26 H 31 Calculated value of N3O7S: 530.19, measured value 530.2.

[0312] Step 2: N-(2 1 S,2 4 S,5 2 R,5 3S)-6-Oxo-3,8-dioxa-5(2,1)piperidina-1(1,2)-benzena-2(1,4)cyclohexanaoctaphane-5 3 Preparation of (N-((3-cyanoxetan-3-yl)methyl)-2-nitrobenzenesulfonamide N-(2 1 S,2 4 S,5 2 R,5 3 S)-6-oxo-3,8-diaxa-5(2,1)piperidina-1(1,2)-benzena-2(1,4)cyclohexanaoctaphane-5 3 (-yl)-2-nitrobenzenesulfonamide (136 mg, 256 μmol) was dissolved in toluene (0.13 mL) and to the solution was added 3-(hydroxymethyl)oxetane-3-carbonitrile (64.2 μL, 563 μmol) and triphenylphosphine (5.50 mg, 20.8 μmol). The reaction was heated to 60°C, diisopropyl azodicarboxylate (113 μL, 563 μmol) was added, and the reaction was stirred at 60°C for 20 hours. The reaction mixture was concentrated and the crude product was purified by preparative HPLC (C18 column, 40-60% acetonitrile / water gradient with 10 mM ammonium formate) to give the title compound (45 mg, 28% yield). LCMS (ESI): m / z [M+H] + C 31 H 36 Calculated value of N4O8S: 625.23, measured value 625.2.

[0313] Step 3: 3-((((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 Preparation of (-yl)amino)methyl)oxetane-3-carbonitrile (compound 29) N-(2 1 S,2 4 S,5 2 R,5 3S)-6-oxo-3,8-dioxa-5(2,1)piperidina-1(1,2)-benzena-2(1,4)cyclohexanaoctaphane-5 3 To a solution of (N-((3-cyanoxetan-3-yl)methyl)-2-nitrobenzenesulfonamide (75.0 mg, 120 μmol) was added potassium carbonate (49.8 mg, 360 μmol), followed by thiophenol (39.1 μL, 372 μmol). The reaction was stirred at room temperature for 18 hours, then diluted with 2 M sodium hydroxide and extracted with dichloromethane (3×10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (C18 column, 35-55% acetonitrile / water gradient with 10 mM ammonium formate) to give the title compound (5.7 mg, 11% yield) as an off-white solid. LCMS (ESI): m / z [M+H] + C 25 H 33 Calculated N3O4: 440.25, measured 440.3. 1H NMR (400 MHz, methanol-d4) δ 7.14 (td, J = 7.8, 1.7 Hz, 1H), 7.06 (dd, J = 7.4, 1.6 Hz, 1H), 6.89 - 6.81 (m, 2H), 5.29 (d, J = 10.6 Hz, 1H), 5.25 - 5.17 (m, 1H), 4.86 (dd, J = 6.4, 3.0 Hz, 2H), 4.60 (dd, J = 8.3, 6.4 Hz, 2H), 4.10 (d, J = 10.6 Hz, 1H), 3.93 (dd, J = 10.9, 9.6 Hz, 1H), 3.79 (d, J = 15.0 Hz, 1H), 3.68 (s, 1H), 3.54 - 3.44 (m, 2H), 2.97 - 2.87 (m, 1H), 2.73 (qd, J = 12.9, 4.4 Hz, 1H), 2.61 - 2.50 (m, 1H), 2.31 (ddd, J = 26.0, 13.1, 4.2 Hz, 1H), 2.16 (d, J = 14.0 Hz, 1H), 1.84 (ddd, J = 19.5, 15.2, 4.8 Hz, 3H), 1.71 - 1.20 (m, 8H).

[0314] Preparation of Compound 30 3-(((2 1 S,2 4 S,5 2 R,5 3 S)-6-Oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)pyrazine-2-carbonitrile

[0315] [ka] To a solution of intermediate 4 (70.0 mg, 184 μmol) in N-methyl-2-pyrrolidone (0.92 mL) was added 2-chloro-3-cyanopyrazine (34.1 mg, 239 μmol) and triethylamine (155 μL, 1.10 mmol). The reaction mixture was stirred at 85° C. for 18 hours. The crude reaction mixture was directly loaded and purified by preparative HPLC (C18 column, 30-100% acetonitrile / water gradient with 10 mM ammonium formate) to give the title compound (58 mg, 65% yield) as a beige solid. LCMS (ESI): m / z [M+H] + C 25 H 27 Calculated value of F2N5O3: 484.21, measured value 484.7. 1 H NMR (400 MHz, methanol-d4) δ 8.34 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 2.4 Hz, 1H), 6.86 (ddd, J = 11.5, 8.3, 3.1 Hz, 1H), 6.77 - 6.70 (m, 1H), 5.56 - 5.40 (m, 2H), 4.43 - 4.32 (m, 1H), 4.15 (dd, J = 12.4, 1.7 Hz, 1H), 4.03 - 3.92 (m, 2H), 3.68 (s, 1H), 3.62 - 3.49 (m, 1H), 3.36 (dd, J = 9.0, 3.6 Hz, 1H), 2.80 - 2.53 (m, 2H), 2.20 (d, J = 14.0 Hz, 1H), 2.14 - 1.68 (m, 7H), 1.55 - 1.26 (m, 4H).

[0316] Synthesis of compound 31 3-((((2 1 S,2 4 S,5 2 R,5 3 S)-13,15-Difluoro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)methyl)oxetane-3-carbonitrile

[0317] [ka]

[0318] Step 1: Preparation of (3-cyanoxetan-3-yl)methyl methanesulfonate To a solution of 3-(hydroxymethyl)oxetane-3-carbonitrile (40.0 mg, 354 μmol) in dichloromethane (1.2 mL) was added triethylamine (73.4 μL, 530 μmol), followed by the slow addition of methanesulfonyl chloride (28.7 μL, 371 μmol). The reaction was stirred at room temperature for 1 hour and then diluted with dichloromethane and brine (10 mL / 5 mL). The phases were then separated and the organic phase was washed again with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to near dryness at low temperature to provide the title compound, which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 4.98 (d, J = 7.0 Hz, 2H), 4.64 (s, 2H), 4.58 (d, J = 7.0 Hz, 2H), 3.14 (d, J = 2.7 Hz, 3H).

[0319] Step 2: 3-((((2 1 S,2 4 S,5 2 R,5 3 S)-13,15-Difluoro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 Preparation of (-yl)amino)methyl)oxetane-3-carbonitrile (compound 31) To a solution of intermediate 4 (80.0 mg, 210 μmol) in ethanol (0.6 mL) was added (3-cyanoxetan-3-yl)methyl methanesulfonate (60.3 mg, 315 μmol), followed by N,N-diisopropylethylamine (77.7 μL, 442 μmol). The reaction was stirred at 120° C. for 2 days. The reaction mixture was concentrated, and the resulting residue was purified by preparative HPLC (C18 column, 0-80% acetonitrile / water gradient with 10 mM ammonium formate) to give the title compound (50 mg, 50% yield). LCMS (ESI): m / z [M+H] + C 25 H 31 Calculated value of F2N3O4: 476.23, measured value 476.3. 1 H NMR (400 MHz, methanol-d4) δ 6.85 (ddd, J = 11.5, 8.3, 3.1 Hz, 1H), 6.78 - 6.69 (m, 1H), 5.46 (dd, J = 12.4, 3.2 Hz, 1H), 5.26 - 5.17 (m, 1H), 4.87 - 4.83 (m, 2H), 4.59 (dd, J = 7.9, 6.5 Hz, 2H), 4.14 (dd, J = 12.4, 1.7 Hz, 1H), 3.97 - 3.81 (m, 2H), 3.70 (s, 1H), 3.55 - 3.42 (m, 2H), 3.29 (d, J = 2.1 Hz, 2H), 2.96 - 2.85 (m, 1H), 2.73 - 2.56 (m, 2H), 2.21 - 2.02 (m, 2H), 1.94 - 1.79 (m, 3H), 1.70 - 1.28 (m, 7H).

[0320] Preparation of Compound 32: 2-(((2 1 S,2 4 S,5 2 R,5 3 S)-13,15-Difluoro-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphane-5 3 -yl)amino)-6-(trifluoromethyl)nicotinonitrile

[0321] [ka] A solution of intermediate 4 (50.0 mg, 131 μmol), N,N-diisopropylethylamine (46.2 μL, 263 μmol), and 2-chloro-6-(trifluoromethyl)nicotinonitrile (55.4 mg, 263 μmol) in N-methyl-2-pyrrolidone (340 μL) was stirred at 130° C. for 5 h. The crude reaction mixture was directly loaded and purified by preparative HPLC (C18 column, 40-100% acetonitrile / water with 10 mM ammonium formate) to give the title compound (55 mg, 76% yield) as a beige solid. LCMS (ESI): m / z [M+H] + C 27 H 27 Calculated value of F5N4O3: 551.20, measured value 551.7. 1 H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.22 - 7.10 (m, 2H), 6.88 (d, J = 9.2 Hz, 1H), 5.44 (dd, J = 12.2, 3.0 Hz, 1H), 5.31 - 5.19 (m, 1H), 4.27 - 4.13 (m, 1H), 3.98 (d, J = 12.0 Hz, 1H), 3.89 - 3.73 (m, 2H), 3.62 (s, 1H), 3.36 - 3.22 (m, 1H), 2.64 - 2.56 (m, 2H), 2.17 - 1.88 (m, 3H), 1.88 - 1.68 (m, 2H), 1.68 - 1.50 (m, 2H), 1.46 - 1.16 (m, 4H).

[0322] Synthesis of compound 33: 2-((((21S,24S,52R,53S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-53-yl)amino)methyl)oxetane-2-carbonitrile

[0323] [ka] Scheme 5

[0324] [ka]

[0325] Step 1: Preparation of ethyl 2-cyano-2-diazoacetate To ethyl cyanoacetate (0.47 mL, 4.33 mmol) in acetonitrile (21.7 mL) was added 1H-imidazole-1-sulfonyl azide (1.09 g, 5.20 mmol) and pyridine (1.76 mL, 21.7 mmol). The reaction mixture was stirred at 40° C. for 18 hours. The mixture was then diluted with ethyl acetate, washed with 1 M hydrochloric acid and brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate / heptane gradient) to afford the title compound (255 mg, 37% yield) as an oil. 1 H NMR (400 MHz, CDCl3) δ 4.34 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).

[0326] Step 2: Preparation of ethyl 2-(2-bromoethoxy)-2-cyanoacetate To a solution of ethyl 2-cyano-2-diazoacetate (225 mg, 1.62 mmol) in dichloromethane (14.7 mL) was added 2-bromoethanol (110 μL, 1.47 mmol), followed by rhodium(II) acetate dimer (33.5 mg, 73.5 μmol). The reaction mixture was stirred at room temperature for 21 hours. Water was added, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to give the title compound (340 mg, 98% yield) as a yellow oil. This material was used without further purification.

[0327] Step 3: Preparation of ethyl 2-cyanoxetane-2-carboxylate To ethyl 2-(2-bromoethoxy)-2-cyanoacetate (300 mg, 1.27 mmol) in N,N-dimethylformamide (40.5 mL) at 0° C. was added sodium hydride (60% in mineral oil, 61.0 mg, 1.53 mmol), and the mixture was stirred at 0° C. for 1 hour. The reaction was poured into 10% aqueous ammonium chloride and extracted with dichloromethane (3×7 mL). The organic phases were combined, dried over magnesium sulfate, filtered, and concentrated onto silica gel. This material was dry-loaded and purified by silica gel chromatography (0-50% ethyl acetate / heptane gradient) to afford the title compound (120 mg, 61% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 4.87 (ddd, J = 8.6, 7.1, 5.8 Hz, 1H), 4.77 (ddd, J = 8.6, 6.6, 5.9 Hz, 1H), 4.37 (q, J = 7.2 Hz, 2H), 3.23 (dddd, J = 32.2, 12.0, 8.6, 6.9 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H).

[0328] Step 4: Preparation of 2-(hydroxymethyl)oxetane-2-carbonitrile To ethyl 2-cyanoxetane-2-carboxylate (120 mg, 773 μmol) in methanol (7.7 mL) was added sodium borohydride (152 mg, 3.87 mmol), and the reaction was stirred at room temperature for 18 hours. Water was added, and the reaction was extracted with dichloromethane (30 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound, which was used without further purification (60.0 mg, 69% yield). 1H NMR (400 MHz, CDCl3) δ 4.83 (ddd, J = 8.7, 7.6, 5.9 Hz, 1H), 4.61 - 4.48 (m, 1H), 3.90 (d, J = 12.7 Hz, 1H), 3.77 (d, J = 12.7 Hz, 1H), 3.14 (ddd, J = 11.7, 9.0, 7.6 Hz, 1H), 2.96 (ddd, J = 11.7, 8.7, 6.0 Hz, 1H).

[0329] Step 5: Preparation of (3-cyanoxetan-3-yl)methyl methanesulfonate To a solution of 2-(hydroxymethyl)oxetane-2-carbonitrile (55.0 mg, 486 μmol) in dichloromethane (2.43 mL) were added triethylamine (204 μL, 1.46 mmol) and methanesulfonyl chloride (45.3 μL, 583 μmol). The reaction mixture was stirred at room temperature for 1 hour, and then water was added. The resulting mixture was extracted with dichloromethane (2×10 mL). The combined organic phases were then dried over sodium sulfate, filtered, and concentrated to give the title compound, which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 4.74 (ddd, J = 8.6, 7.4, 6.0 Hz, 1H), 4.55 (dt, J = 8.8, 6.3 Hz, 1H), 4.44 (d, J = 11.7 Hz, 1H), 4.39 (d, J = 11.7 Hz, 1H).

[0330] Step 6: Preparation of 2-((((21S,24S,52R,53S)-6-oxo-3,8-dioxa-5(2,1)-piperidina-1(1,2)-benzena-2(1,4)-cyclohexanacyclooctaphan-53-yl)amino)methyl)oxetane-2-carbonitrile (compound 33) To a solution of intermediate 2 (60.0 mg, 174 μmol) in ethanol (0.5 mL) was added N,N-diisopropylethylamine (61.3 μL, 348 μmol) and (3-cyanoxetan-3-yl)methyl methanesulfonate (46.6 mg, 244 μmol). The reaction mixture was stirred at 120° C. for 18 hours. The reaction mixture was then cooled and added to water. The aqueous phase was extracted with ethyl acetate (three times), washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (C18 column, 0-100% acetonitrile / water with 10 mM ammonium formate) to give the title compound (2.8 mg, 3.7% yield). LCMS (ESI): m / z [M+H] + Calculated value for C25H33N3O4: 440.25, found value 440.8. 1 H NMR (400 MHz, Methanol-d4) δ 7.14 (td, J = 7.8, 1.7 Hz, 1H), 7.06 (dd, J = 7.4, 1.7 Hz, 1H), 6.90 - 6.79 (m, 2H), 5.29 (d, J = 10.6 Hz, 1H), 5.19 (s, 1H), 4.76 (dt, J = 14.2, 7.1 Hz, 1H), 4.62 - 4.49 (m, 1H), 4.10 (d, J = 10.6 Hz, 1H), 3.97 - 3.88 (m, 1H), 3.79 (d, J = 12.8 Hz, 1H), 3.68 (s, 1H), 3.59 - 3.44 (m, 2H), 3.25 - 3.09 (m, 2H), 3.07 - 2.90 (m, 3H), 2.78 - 2.63 (m, 1H), 2.61 - 2.50 (m, 1H), 2.34 - 2.25 (m, 1H), 2.17 (d, J = 12.6 Hz, 1H), 1.85 (dd, J = 28.3, 14.7 Hz, 3H), 1.65 - 1.32 (m, 7H).

[0331] Human OX2R IP1 assay The G protein-coupled receptor (GPCR) OX2R signals through the Gq / 11 signaling pathway. Activation of this pathway can be easily detected by measuring the accumulation of inositol monophosphate (IP-one or IP1) in the presence of excess LiCl. This can be quantified using the commercially available cell-based IP-One Gq Kit (CisBio catalog number: 62IPAPEB) coupled to a cell line expressing OX2R. IP1 generated intracellularly by OX2R agonism competes with an IP1 analog conjugated to a d2 fluorophore (FRET acceptor) for binding to an anti-IP1 monoclonal antibody labeled with Eu cryptated (FRET donor). The measured HTRF-FRET-based signal is inversely proportional to the concentration of IP1 generated.

[0332] Tetracycline-inducible suspension human embryonic kidney cells (Expi293F-inducible, ThermoFisher #A39241) stably expressing the tet-responsive human OX2R were induced with 4 μg / mL doxycycline at 32°C. 24 hours after induction, cells were harvested, aliquoted, and stored frozen in Expi293 medium containing 10% DMSO. On the day of the assay, cells were thawed, washed with PBS, and resuspended in 1X cisbio stimulation buffer. Cells were then seeded at a concentration of 6,000 cells / well into 384-well assay plates containing test compounds, resulting in a final concentration of 0.5% DMSO. After 1 hour of incubation at 37°C, the reaction was terminated by adding cisbio detection mixture containing IP1-d2 and anti-IP1-cryptate in lysis buffer. After 1 hour of incubation at room temperature, HTRF-FRET values ​​were measured using a ClarioStar Plus (BMG Labtech) plate reader, and data were expressed as a standard 665 nm / 620 nm ratio.

[0333] Exemplary compounds, characterization data, and assay data are provided in Table 2.

[0334] [Table 2-1] Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 [Table 2-19] [Table 2-20] [Table 2-21] [Table 2-22]

[0335] pEC 50 Bin *** = 0.01 to 1 nM (pEC 50 11~9) ** = 1 to 100 nM (pEC 50 7~9) * = 100-1000nM (pEC 50 5~7)

[0336] Incorporation by Reference All US patents and US and PCT patent application publications cited herein are hereby incorporated by reference.

[0337] equivalent Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein which equivalents are intended to be encompassed by the following claims.

[0338] While there has been shown and described what are presently considered to be the preferred embodiments of the present invention, those skilled in the art may make various changes and modifications which remain within the scope of the invention as defined by the appended claims.

Claims

1. Compounds according to formula (A): 【Chemistry 71】 or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, During the ceremony, A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl; n is 0, 1, 2, or 3; R １ However, (C １ ~C ６ ) alkyl, (C ３ ~C ８ ) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, and each (C １ ~C ６ ) alkyl optionally contains one or more R １ａ , C(O)NR １ｂ R １ｃ , halo, cyano, hydroxy, or (C １ ~C ６ ) alkoxy, each (C ３ ~C ８ ) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are optionally selected from the group consisting of one or more of halo, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, (C １ ~C ６ ) hydroxyalkyl, (C １ ~C ６ ) alkoxyalkyl, (C １ ~C ６ ) alkoxy, (C ３ ~C ８ ) substituted with cycloalkyl, or 4- to 7-membered heterocycloalkyl; R １ａ However, (C ３ ~C ８ ) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which optionally includes one or more of halo, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, (C １ ~C ６ ) hydroxyalkyl, (C １ ~C ６ ) alkoxy(C １ ~C ６ ) alkyl, or (C １ ~C ６ ) substituted with alkoxy; R １ｂ and R １ｃ are independently H, or (C １ ~C ６ ) alkyl, and each (C １ ~C ６ ) alkyl optionally contains one or more halo, cyano, hydroxy, or (C １ ~C ６ ) substituted with alkoxy, or R １ａ and R １ｂ together with the nitrogen to which they are attached form a 3- to 7-membered heterocyclyl ring; R ２ is H, R ３ but 、 Halo, Cyano, (C １ ~C ６ ) alkyl, and (C １ ~C ６ ) haloalkyl; m is 0, 1, 2, 3, or 4; q is 0, 1, or 2; R ４ In each occurrence, hydrogen atoms (H), halo, (C １ ~C ６ ) alkyl, and (C １ ~C ６ ) haloalkyl; X is CH; Y is O or absent, Z is O or (CR ７ R ８ ) ｐ and p is 1, 2, 3, or 4; R ７ and R ８ Independently, in each occurrence, H,(C １ ~C ３ ) alkyl, or (C １ ~C ３ ) haloalkyl, or R ７ and R ８ together with the carbons to which they are attached form a 3- to 6-membered cycloalkyl; T is CR ９ R １０ or does not exist, U is CR １１ R １２ and V is CR １３ R １４ and W is CR １５ R １６ or absent, provided that exactly one of T or W is absent; R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , and R １６ is each independently H or fluoro.

2. The compound of claim 1 having the structure of Formula Ia: 【Chemistry 72】 or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof or a prodrug thereof.

3. The compound of claim 1 having the structure of formula Ib: 【Transformation 73】 or a deuterated derivative thereof, or a pharmaceutically acceptable salt thereof or a prodrug thereof.

4. The compound according to any one of claims 1 to 3, wherein n is 1.

5. The compound according to any one of claims 1 to 3, wherein n is 2.

6. The compound of any one of claims 1 to 5, wherein A is phenyl.

7. The compound according to any one of claims 1 to 6, wherein m is 0.

8. The compound according to any one of claims 1 to 6, wherein m is 1.

9. The compound according to any one of claims 1 to 6, wherein m is 2.

10. R ３ The compound of any one of claims 1 to 9, wherein is halo.

11. R ３ The compound of claim 10, wherein is fluoro.

12. Compounds according to formula (I): 【Chemistry 74】 or a pharmaceutically acceptable salt thereof, During the ceremony, A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl; n is 0, 1, 2, or 3; R １ However, (C １ ~C ６ ) alkyl, (C ３ ~C ８ ) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, and each (C １ ~C ６ ) alkyl optionally contains one or more R １ａ , C(O)NR １ｂ R １ｃ , halo, cyano, hydroxy, or (C １ ~C ６ ) alkoxy, each (C ３ ~C ８ ) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are optionally selected from the group consisting of one or more of halo, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, (C １ ~C ６ ) hydroxyalkyl, (C １ ~C ６ ) alkoxyalkyl, (C １ ~C ６ ) alkoxy, (C ３ ~C ８ ) substituted with cycloalkyl, or 4- to 7-membered heterocycloalkyl; R １ａ However, (C ３ ~C ８ ) cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which optionally includes one or more of halo, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, (C １ ~C ６ ) hydroxyalkyl, (C １ ~C ６ ) alkoxy(C １ ~C ６ ) alkyl, or (C １ ~C ６ ) substituted with alkoxy; R １ｂ and R １ｃ are independently H, or (C １ ~C ６ ) alkyl, and each (C １ ~C ６ ) alkyl optionally contains one or more halo, cyano, hydroxy, or (C １ ~C ６ ) substituted with alkoxy, or R １ａ and R １ｂ together with the nitrogen to which they are attached form a 3- to 7-membered heterocyclyl ring; R ２ is H, R ３ but 、 Halo, Cyano, (C １ ~C ６ ) alkyl, and (C １ ~C ６ ) haloalkyl; m is 0, 1, 2, 3, or 4; q is 0, 1, or 2; R ４ But, Halo, (C １ ~C ６ ) alkyl, or (C １ ~C ６ ) haloalkyl; X is CH; Y is O or absent, Z is O or (CR ７ R ８ ) ｐ and p is 1, 2, 3, or 4; R ７ and R ８ Independently, in each occurrence, H,(C １ ~C ３ ) alkyl, or (C １ ~C ３ ) haloalkyl, or R ７ and R ８ together with the carbons to which they are attached form a 3- to 6-membered cycloalkyl; T is CR ９ R １０ or does not exist, U is CR １１ R １２ and V is CR １３ R １４ and W is CR １５ R １６ or absent, provided that exactly one of T or W is absent; and R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , and R １６ is each independently H or fluoro.

13. The compound of claim 12 having the structure of formula Ia-1: 【Chemistry 75】 or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 having the structure of formula Ib-1: 【Transformation 76】 or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1 to 3 and 12 to 14, wherein n is 1.

16. The compound of any one of claims 1 to 3 and 12 to 14, wherein n is 2.

17. 17. The compound of any one of claims 1 to 3 and 12 to 16, wherein A is phenyl.

18. The compound according to any one of claims 1 to 6 and 12 to 17, wherein m is 0.

19. The compound of any one of claims 1 to 6 and 12 to 17, wherein m is 1.

20. The compound according to any one of claims 1 to 6 and 12 to 17, wherein m is 2.

21. R ３ The compound of any one of claims 1 to 3 and 12 to 20, wherein is halo.

22. R ３ 22. The compound of claim 21, wherein is fluoro.

23. A is, 【Chemical 77】 The compound according to any one of claims 1 to 5 and 12 to 22,

24. A is, 【Transformation 78】 24. The compound of claim 23, wherein:

25. A is, 【Transformation 79】 24. The compound of claim 23, wherein:

26. R １ However, (C １ ~C ６ ) alkyl, optionally with one or more of fluoro, cyano, hydroxy, R １ａ , or C(O)NR ｂ R １ ｃ 26. The compound of any one of claims 1 to 3 and 12 to 25, substituted with:

27. R １ is methyl, and optionally one or more of fluoro, cyano, hydroxy, R １ａ , or C(O)NR ｂ R １ｃ 27. The compound of claim 26 substituted with:

28. R １ａ However, (C ３ ~C ８ ) cycloalkyl, phenyl, 4- to 5-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which optionally contains one or more of fluoro, cyano, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) fluoroalkyl, or (C １ ~C ３ 28. The compound of any one of claims 1 to 3 and 12 to 27, substituted with alkoxy.

29. R1 ａ is cyclopropyl, phenyl, 4- to 5-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more fluoro, cyano, cyclopropyl, methyl, or trifluoromethyl.

30. R1 ａ is cyclopropyl, cyclobutyl, phenyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl, each of which is optionally substituted with one or more fluoro, cyano, cyclopropyl, methyl, or trifluoromethyl.

31. R １ C(O)NR1 ｂ R １ｃ (C １ ~C ６ 28. The compound of any one of claims 1 to 3 and 12 to 27, wherein:

32. R1 ｂ and R1 ｃ are hydrogen atoms. 、 The compound according to any one of claims 1 to 3, 12 to 27, and 31.

33. R １ but, 【Chemistry 80】 The compound according to any one of claims 12 to 25,

34. R １ but, 【Chemistry 81】 The compound according to any one of claims 12 to 25,

35. R １ is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazinyl, pyrazinyl, or diazoyl, each of which optionally contains one or more of halo, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, (C １ ~C ６ ) hydroxyalkyl, (C １ ~C ６ ) alkoxyalkyl, (C １ ~C ６ ) alkoxy, (C ３ ~C ８ 26. The compound of any one of claims 1 to 3 and 12 to 25, substituted with cycloalkyl, or 4- to 7-membered heterocycloalkyl.

36. R １ is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or diazoyl, each of which optionally contains one or more of halo, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, (C １ ~C ６ ) hydroxyalkyl, (C １ ~C ６ ) alkoxyalkyl, (C １ ~C ６ ) alkoxy, (C ３ ~C ８ 26. The compound of any one of claims 1 to 3 and 12 to 25, substituted with cycloalkyl, or 4- to 7-membered heterocycloalkyl.

37. R １ is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyridazinyl, pyrazinyl, or diazoyl, each of which optionally contains one or more of fluoro, cyano, hydroxy, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) fluoroalkyl, or (C １ ~C ３ 26. The compound of any one of claims 1 to 3 and 12 to 25, substituted with alkoxy.

38. R １ is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or diazoyl, each of which optionally contains one or more of fluoro, cyano, hydroxy, (C １ ~C ３ ) alkyl, (C １ ~C ３ ) fluoroalkyl, (C １ ~C ３ 26. The compound of any one of claims 1 to 3 and 12 to 25, substituted with alkoxy, or 4 to 7 membered heterocycloalkyl.

39. R １ is phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or diazoyl, each of which is optionally substituted with one or more fluoro, cyano, methyl, trifluoromethyl, methoxy, or oxetane.

40. R １ but, 【Chemistry 82】 The compound according to any one of claims 1 to 3 and 12 to 25,

41. R １ but, 【Chemistry 83】 The compound according to any one of claims 1 to 3 and 12 to 25,

42. R １ However, (C ３ ~C ５ ) cycloalkyl, or 4- to 6-membered heterocycloalkyl, each of which optionally includes one or more of halo, cyano, hydroxy, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, (C １ ~C ６ ) hydroxyalkyl, (C １ ~C ６ ) alkoxyalkyl, (C １ ~C ６ ) alkoxy, (C ３ ~C ８ 26. The compound of any one of claims 1 to 3 and 12 to 25, substituted with cycloalkyl, or 4- to 7-membered heterocycloalkyl.

43. R １ but, 【Chemical 84】 43. The compound of claim 42, wherein:

44. R １ but, 【Chemical 85】 43. The compound of claim 42, wherein:

45. R １ but, 【Chemical 86】 43. The compound of claim 42, wherein:

46. R １ is substituted with at least one fluoro or cyano.

47. The compound of any one of claims 1 to 3 and 12 to 46, wherein Y is O.

48. R ７ and R ８ However, each ３ or R ７ and R ８ 48. The compound of any one of claims 1 to 47, wherein together with the atom to which they are attached form a cyclopropyl.

49. R ７ and R ８ The compound of any one of claims 1 to 47, wherein each is H.

50. 50. The compound of any one of claims 1 to 49, wherein p is 1.

51. R ９ , R １０ , R １１ , R １２ , R １３ , R １４ , R １５ , and R １６ The compound of any one of claims 1 to 50, wherein each is H.

52. A compound selected from the following table: Table 3-1 Table 3-2 Table 3-3 or a pharmaceutically acceptable salt thereof.

53. A compound selected from the following table: Table 4-1 Table 4-2 or a pharmaceutically acceptable salt thereof.

54. A pharmaceutical composition comprising a compound according to any one of claims 1 to 53 and at least one pharmaceutically acceptable excipient.

55. Narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcoleptic syndrome with narcoleptic-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy bodies, hypersomnia syndrome with daytime hypersomnia (e.g., Kleine-Levin syndrome, major depression with hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's syndrome) encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperinsulinemic obesity, hyperplastic obesity, pituitary obesity, hypoplastic obesity, hypothyroid obesity, hypothalamic obesity, syndromic obesity, childhood obesity, upper body obesity, diet-induced obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as stupor, side effects or complications caused by anesthesia, sleep disorders, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep interruptions, jet lag Lag, jet lag syndrome, sleep disorders in shift workers, sleep disorders, sleep terrors, depression, major depression, sleepwalking, bedwetting, sleep disorders, Alzheimer's sundowning syndrome, circadian rhythm related disorders, fibromyalgia, conditions resulting from poor sleep quality, bulimia, compulsive eating disorder, obesity related disorders, hypertension, diabetes, elevated plasma insulin levels / insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, cardiac arrhythmias, myocardial infarction, congestive heart failure, coronary artery disease, cardiovascular disease Disease, sudden death, polycystic ovary syndrome, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, sexual / reproductive dysfunction such as hirsutism in women, fetal defects associated with prenatal obesity, gastrointestinal motility disorders such as gastroesophageal reflux disease associated with obesity, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory diseases such as dyspnea, inflammation such as vascular systemic inflammation, atherosclerosis, hypercholesterolemia,Secondary risks of obesity such as hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, hot flushes, night sweats, reproductive / urinary tract disorders, disorders related to sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as brain defects occurring after cardiac bypass surgery or heart transplant, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, external cerebral infarction Injury, intrapartum hypoxia, cardiac arrest, hypoglycemia nerve damage, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye disorders, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders related to muscle spasms, delirium, memory impairment, age-related cognitive decline, schizophrenia affective disorder, delusions, drug dependence, movement disorders, chronic fatigue syndrome, fatigue, drug-induced Parkinsonism, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, neuropathy, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain A method for preventing or treating a disease selected from the group consisting of toothache, cataplexy, and traumatic brain injury, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 53 or a pharmaceutical composition according to claim 54.

56. 55. A method for preventing or treating a disease selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy with narcoleptic symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with dementia with Lewy bodies, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 53 or a pharmaceutical composition of claim 54.

57. 57. The method of claim 56, wherein the disease is narcolepsy.

58. 57. The method of claim 56, wherein the disease is idiopathic hypersomnia.

59. 57. The method of claim 56, wherein the disorder is hypersomnia.

60. 57. The method of claim 56, wherein the disease is sleep apnea syndrome.

61. 57. The method of claim 56, wherein the disease is narcolepsy syndrome with narcolepsy-like symptoms.

62. 57. The method of claim 56, wherein the disorder is hypersomnia associated with Parkinson's disease.

63. 57. The method of claim 56, wherein the disease is hypersomnia associated with dementia with Lewy bodies.

64. 64. The method of any one of claims 55 to 63, wherein the compound is administered orally.

65. 64. The method of any one of claims 55 to 63, wherein the compound is administered parenterally.

66. 64. The method of any one of claims 55 to 63, wherein the disease is prevented.

67. 64. The method of any one of claims 55 to 63, wherein the disease is treated.

68. 55. A method for preventing or treating a disease associated with defective orexin 2 receptor signaling, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 53 or a pharmaceutical composition according to claim 54.

69. The disease associated with a defect in orexin 2 receptor signaling is narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy bodies, hypersomnia syndrome with daytime hypersomnia (e.g., Kleine-Levin syndrome, major depression with hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, syndrome, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperinsulinemic obesity, hyperplastic obesity, pituitary obesity, hypoplastic obesity, hypothyroid obesity, hypothalamic obesity, syndromic obesity, childhood obesity, upper body obesity, diet-induced obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as stupor, side effects or complications caused by anesthesia, sleep disorders, sleep problems, insomnia disorder, intermittent sleep, nocturnal myoclonus, REM sleep interruptions, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep disorders, sleep terrors, depression, major depression, sleepwalking, nocturnal enuresis, sleep disorders, Alzheimer's sundowning syndrome, circadian rhythm related disorders, fibromyalgia, conditions resulting from poor sleep quality, bulimia, compulsive eating disorder, obesity related disorders, hypertension, diabetes, elevated plasma insulin levels / insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, irregular heartbeat Heart failure, myocardial infarction, congestive heart failure, heart failure, coronary artery disease, cardiovascular disease, sudden death, polycystic ovary syndrome, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, sexual / reproductive dysfunction such as hirsutism in women, fetal defects associated with prenatal obesity, gastrointestinal motility disorders such as gastroesophageal reflux disease associated with obesity, obesity-hypoventilation syndrome (Pickwickian syndrome), respiratory disorders such as dyspnea,Inflammation such as vascular systemic inflammation, secondary risks of obesity such as atherosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, hot flushes, night sweats, reproductive / urinary tract disorders, disorders related to sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as brain defects that develop after cardiac bypass surgery or heart transplantation, stroke, ischemic brain 69. The method of claim 68, wherein the condition is selected from the group consisting of stroke, cerebral ischemia, spinal cord trauma, head trauma, intrapartum hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye disorders, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, memory impairment, age-related cognitive decline, schizoaffective disorder, delusions, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, drug-induced Parkinsonism, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, neuropathy, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, and traumatic brain injury.

70. 69. The method of claim 68, wherein the disease associated with a defect in orexin 2 receptor signaling is selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy with narcoleptic symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with dementia with Lewy bodies.

71. Narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcoleptic syndrome with narcoleptic-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy bodies, hypersomnia syndrome with daytime hypersomnia (e.g., Kleine-Levin syndrome, major depression with hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's syndrome) encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperinsulinemic obesity, hyperplastic obesity, pituitary obesity, hypoplastic obesity, hypothyroid obesity, hypothalamic obesity, syndromic obesity, childhood obesity, upper body obesity, diet-induced obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as stupor, side effects or complications caused by anesthesia, sleep disorders, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep interruptions, jet lag Lag, jet lag syndrome, sleep disorders in shift workers, sleep disorders, sleep terrors, depression, major depression, sleepwalking, bedwetting, sleep disorders, Alzheimer's sundowning syndrome, circadian rhythm related disorders, fibromyalgia, conditions resulting from poor sleep quality, bulimia, compulsive eating disorder, obesity related disorders, hypertension, diabetes, elevated plasma insulin levels / insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, cardiac arrhythmias, myocardial infarction, congestive heart failure, coronary artery disease, cardiovascular disease Disease, sudden death, polycystic ovary syndrome, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, sexual / reproductive dysfunction such as hirsutism in women, fetal defects associated with prenatal obesity, gastrointestinal motility disorders such as gastroesophageal reflux disease associated with obesity, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory diseases such as dyspnea, inflammation such as vascular systemic inflammation, atherosclerosis, hypercholesterolemia,Secondary risks of obesity such as hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, hot flushes, night sweats, reproductive / urinary tract disorders, disorders related to sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as brain defects occurring after cardiac bypass surgery or heart transplant, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, external cerebral infarction Injury, intrapartum hypoxia, cardiac arrest, hypoglycemia nerve damage, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye disorders, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders related to muscle spasms, delirium, memory impairment, age-related cognitive decline, schizophrenia affective disorder, delusions, drug dependence, movement disorders, chronic fatigue syndrome, fatigue, drug-induced Parkinsonism, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, neuropathy, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain Use of a compound according to any one of claims 1 to 53 or a pharmaceutical composition according to claim 54 in the manufacture of a medicament for the treatment of a disease selected from the group consisting of toothache, cataplexy, and traumatic brain injury.

72. Narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcoleptic syndrome with narcoleptic-like symptoms, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy bodies, hypersomnia syndrome with daytime hypersomnia (e.g., Kleine-Levin syndrome, major depression with hypersomnia, dementia with Lewy bodies, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's syndrome) encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cells, exogenous obesity, hyperinsulinemic obesity, hyperplastic obesity, pituitary obesity, hypoplastic obesity, hypothyroid obesity, hypothalamic obesity, syndromic obesity, childhood obesity, upper body obesity, diet-induced obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as stupor, side effects or complications caused by anesthesia, sleep disorders, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep interruptions, jet lag Lag, jet lag syndrome, sleep disorders in shift workers, sleep disorders, sleep terrors, depression, major depression, sleepwalking, bedwetting, sleep disorders, Alzheimer's sundowning syndrome, circadian rhythm related disorders, fibromyalgia, conditions resulting from poor sleep quality, bulimia, compulsive eating disorder, obesity related disorders, hypertension, diabetes, elevated plasma insulin levels / insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, cardiac arrhythmias, myocardial infarction, congestive heart failure, coronary artery disease, cardiovascular disease Disease, sudden death, polycystic ovary syndrome, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, sexual / reproductive dysfunction such as hirsutism in women, fetal defects associated with prenatal obesity, gastrointestinal motility disorders such as gastroesophageal reflux disease associated with obesity, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory diseases such as dyspnea, inflammation such as vascular systemic inflammation, atherosclerosis, hypercholesterolemia,Secondary risks of obesity such as hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, hot flushes, night sweats, reproductive / urinary tract disorders, disorders related to sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders, acute neurological and psychiatric disorders such as brain defects occurring after cardiac bypass surgery or heart transplant, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, external cerebral infarction 55. The compound of any one of claims 1 to 53 or the pharmaceutical composition of claim 54 for use in treating a disease selected from the group consisting of: trauma, birth hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye disorders, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, memory impairment, age-related cognitive decline, schizoaffective disorder, delusions, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, drug-induced Parkinsonism, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, neuropathy, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, and traumatic brain injury. ,

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