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WO2024168004A1 - Biaryl amide-containing agonists of orexin receptor type 2 - Google Patents

Biaryl amide-containing agonists of orexin receptor type 2 Download PDF

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Publication number
WO2024168004A1
WO2024168004A1 PCT/US2024/014749 US2024014749W WO2024168004A1 WO 2024168004 A1 WO2024168004 A1 WO 2024168004A1 US 2024014749 W US2024014749 W US 2024014749W WO 2024168004 A1 WO2024168004 A1 WO 2024168004A1
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compound
mmol
disease
syndrome
difluoro
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PCT/US2024/014749
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French (fr)
Inventor
Matthew Volgraf
Cameron Rees SMITH
Liang Zhao
Robin LAROUCHE-GAUTHIER
Samir BOUAYAD-GERVAIS
Todd J.A. Ewing
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Vertex Pharmaceuticals Incorporated
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Publication of WO2024168004A1 publication Critical patent/WO2024168004A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • This invention generally relates to compounds that function as agonists of orexin receptor type 2 (Ox2R), particularly biaryl amide-containing compounds thereof, as well as methods of using such compounds for treating conditions or disorders associated with a deficiency in Ox2R signaling, e.g., narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome.
  • Ox2R orexin receptor type 2
  • Orexins are hypothalamic neuropeptides that are implicated in, for example, sleep/wake control and body weight homeostasis.
  • Narcolepsy is a socially debilitating disorder characterized by an inability to properly maintain wakefulness (excessive daytime sleepiness, sleep attacks), and a pathological intrusion of signs of REM sleep into wakefulness (cataplexy, hypnagogic hallucination, sleep paralysis, etc.). Narcolepsy affects an estimated 1 in every 2,000 individuals, and is a non-progressive, life-long condition.
  • a deficiency in orexin/Ox2R signaling causes the sleep disorder narcolepsy in humans, mice, and dogs.
  • a vast majority (>90%) of human narcoleptics lack detectable levels of orexin peptides in the cerebrospinal fluid due to a highly specific (probably autoimmune) degeneration of orexin neurons, indicating that human narcolepsy is an “orexin deficiency syndrome.”
  • Compounds having Ox2R agonism activity have previously been described (see, e.g., Nagahara, et al., J. Med. Chem., 2015, 58, 7931-37).
  • One aspect of the invention provides compounds, compositions, and methods useful for preventing or treating conditions modulated by Ox2R, such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy- like symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with dementia with Lewy body.
  • the compounds disclosed and claimed herein demonstrate, among other things, high potency and selectivity for OX2R, and improved drug-like properties, such as central nervous system penetration (e.g., as determined by a MDR1-MDCK permeability assay) and a favorable pharmacokinetic profile.
  • a compound having the structure of Formula (IA): or a deuterated derivative, thereof; wherein: V and W are independently for each occurrence CH, CF, or N; X is O or absent (i.e., a bond); Y is CH or N; provided that if X is O, then Y is CH; Z is CR 3 R 4 or NR 5 ; R 1 is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C 1- C 6 )alkyl, (C 1- C 6 )alkoxy, (C 1- C 6 )haloalkyl, (C 1- C 6 )hydroxyalkyl, and (C
  • a pharmaceutical composition comprising a compound of formula (I), or deuterated derivative, or pharmaceutically acceptable salt or prodrug thereof, and at least one pharmaceutically acceptable excipient.
  • a disease selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy body, hypersomnia syndrome involving daytime hypersomnia (e.g., Kleine-Levin syndrome, major depression accompanied by hypersomnia, dementia with Lewy body, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction
  • an element means one element or more than one element.
  • the phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified.
  • a reference to “A and/or B”, when 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); etc.
  • “or” should be understood to have the same meaning as “and/or” as defined above.
  • the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. [0017] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • 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, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • “Geometric isomer” means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides 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,” indicate configurations relative to the core molecule.
  • Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.”
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • the compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer.
  • 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% by mole fraction pure relative to the other stereoisomers.
  • the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure.
  • the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure.
  • the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer.
  • Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • “deuterated derivative(s)” refers to a compound having the same chemical structure as a reference compound, with one or more hydrogen atoms replaced by one or more deuterium atoms, respectively.
  • the one or more hydrogens replaced by deuterium are part of an alkyl group.
  • the one or more hydrogens replaced by deuterium are part of a methyl group.
  • prodrug encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue. In some embodiments, the prodrug is converted by an enzymatic activity of the host animal.
  • a common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule.
  • Prodrugs of the compounds of the invention may be, for example, amides.
  • Amides that may be utilized as prodrugs in the present invention are phenyl amides, aliphatic (C1-C24) amides, acyloxymethyl amides, ureas, carbamates, and amino acid amides.
  • a compound of the invention that contains an NH group may be acylated at this position in its prodrug form.
  • Other prodrug forms include esters, such as, for example phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters.
  • the present invention features a prodrug of any one of the formulas or compounds listed herein.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non- pyrogenic.
  • materials which can serve 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower 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) buffering agents, such as magnesium hydroxide and aluminum
  • compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).
  • the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the 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 salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).
  • pharmaceutically acceptable cocrystals refers to solid coformers that do not form formal ionic interactions with the small molecule.
  • a “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions.
  • the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the term “patient” or “subject” refers to a mammal in need of a particular treatment.
  • the patient is typically human. However, in some embodiments, the patient may be a primate, canine, feline, or equine.
  • An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below.
  • a straight aliphatic chain is limited to unbranched carbon chain moieties.
  • the term “aliphatic group” refers to a straight chain (i.e., linear or unbranched), branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.
  • Alkyl refers to a fully saturated cyclic or acyclic, branched or unbranched (i.e., linear) carbon chain moiety having the number of carbon atoms specified, or may be up to 30 carbon atoms if not specified.
  • alkyl of 1 to 8 carbon atoms refers to moieties, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and moieties which 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.
  • a linear or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably, 20 or fewer.
  • Alkyl goups may be substituted or unsubstituted.
  • heteroalkyl refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.
  • haloalkyl refers to an alkyl group as hereinbefore defined substituted with at least one halogen.
  • haloalkoxy refers to an alkoxy group as defined herein substituted with at least one halogen atom.
  • haloalkoxy groups include fluoroalkoxy groups, such as trifluoromethoxy, difluoromethoxy, and the like.
  • hydroxyalkyl refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl.
  • alkylene refers to an alkyl group having the specified number of carbon atoms, such as 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound, typically on its longest carbon chain.
  • Non-limiting examples of alkylene groups include methylene (-(CH2)-), ethylene (-(CH2CH2)-), n-propylene (-(CH 2 CH 2 CH 2 )-), isopropylene (-(CH 2 CH(CH 3 ))-), and the like.
  • Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.
  • Cycloalkyl refers to mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms.
  • cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure.
  • Cycloalkyl groups may be substituted or unsubstituted. Some examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • 1,2-Disubstituted cyclohexyl refers to a cyclohexane ring that contains points of attachment at the 1 and 2 positions of the cyclohexane ring to the rest of the compound.
  • 1,2-disubstituted cyclopentyl refers to a cyclopentane ring that contains points of attachment at the 1 and 2 positions of the cyclopentane ring to the rest of the compound.
  • 1,2-Disubstituted cyclohexyl and 1,2-disubstituted cyclopentyl can also be referred to as 1,2-cyclohexylene and 1,2-cyclopentylene, respectively.
  • halocycloalkyl refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen.
  • Cycloheteroalkyl refers to a cycloalkyl moiety as hereinbefore defined which contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms.
  • Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure.
  • Cycloheteroalkyl groups may be substituted or unsubstituted. Some examples include piperidinyl, piperazinyl, tetrahydrofuranyl, and tetrahydropyranyl groups.
  • lower alkyl means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • preferred alkyl groups are lower alkyls.
  • a substituent designated herein as alkyl is a lower alkyl.
  • Alkenyl refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety.
  • Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).
  • Alkynyl refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more triple bonds in the moiety.
  • aryl as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl).
  • aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings.
  • the term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline groups, and the like.
  • Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, indazole, quinoline, benzofuran, and like groups.
  • Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.
  • halo means halogen, and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms.
  • halo is selected from the group consisting of fluoro, chloro and bromo.
  • halo is fluoro.
  • heterocyclyl or “heterocyclic group” or “heterocycloalkyl” refer to 3- to 12-membered ring structures, more typically 5- to 12-membered rings, more typically 5- to 10- membered rings, whose ring structures include one to four heteroatoms.
  • Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic, and may be saturated, partially unsaturated, 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, o
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amid
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms, such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety
  • the substituents on substituted alkyls are selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.
  • small molecules refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da).
  • the small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 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 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da).
  • a “small molecule” refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000.
  • a small molecule is an organic compound, with a size on the order of 1 nm.
  • small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000.
  • An “effective amount” is an amount sufficient to effect beneficial or desired results.
  • a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms.
  • An effective amount can be administered in one or more administrations, applications or dosages.
  • a therapeutically effective amount of a composition depends on the composition selected.
  • compositions can be administered from one or more times per day to one or more times per week; including once every other day.
  • the skilled artisan will appreciate that certain factors may influence 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 general health and/or age of the subject, and other diseases present.
  • treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments.
  • the terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference.
  • “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter as compared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment.
  • the terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as 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% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10- fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.
  • the term “modulate” includes up-regulation (e.g., activating or enhancing a response) and down-regulation (e.g., inhibiting or deactivating a response).
  • a “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and/or therapy of various diseases.
  • the radiolabelled pharmaceutical agent for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source.
  • RI radioisotope
  • the term “radioisotope” includes metallic and non-metallic radioisotopes.
  • the radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents.
  • a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule.
  • the radioisotope is a non-metallic radioisotope
  • the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule.
  • a compound of Formula (IA) , or a deuterated derivative, thereof; wherein: V and W are independently for each occurrence CH, CF, or N; X is O or absent; Y is CH or N; provided that if X is O, then Y is CH; Z is CR 3 R 4 or NR 5 ; R 1 is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1- C6)haloalkoxy; R
  • the compound of Formula (IA-1) is a compound of the Formula (IA-2) or (IA-3): or or a thereof; wherein R 1 , R 2 , R 6 , R 7 , R 8 , V, W, X, Y, Z, n, and m are as defined anywhere above.
  • the compound of Formula (IA-1) is a compound of the Formula (IA-2) or (IA-3): or or a thereof; wherein R 1 , R 2 , R 6 , R 7 , R 8 , V, W, X, Y, Z, and n are as defined anywhere above.
  • any of the compounds of Formulas (IA-1), (IA-2), or (IA-3) may more particularly be a stereoisomeric version (including enriched or isolated stereoisomers) of any of the following Formulas (IA-1’), (IA-2’), or (IA-3’), such as follows: or or a thereof; wherein R 1 , R 2 , R 6 , R 7 , R 8 , V, W, X, Y, Z, and n are as defined anywhere above.
  • R 1 is 5-membered heteroaryl, 6-membered heteroaryl, 8- membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl; each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy and (C1- C6)hydroxyalkyl.
  • R 1 is 5-membered heteroaryl, 6-membered heteroaryl, 8- membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C 1- C 6 )alkyl, and (C 1- C 6 )alkoxy.
  • R 1 is pyridinyl, isoxazolyl, thiazolyl, pyrazolyl, indazolyl, 2-oxoindolin- 5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl), or benzo[d]imidazolyl; each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C 1- C 6 )alkyl, (C 1- C 6 )alkoxy and (C 1- C 6 )hydroxyalkyl, and in further particular embodiments, R 1 is pyridinyl, isoxazolyl, thiazolyl, pyrazolyl, or indazolyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C 1- C 6 )alkyl, and (C 1- C 6 )alkoxy
  • R 1 is 3-pyridinyl, 5-isoxazolyl, 2-thiazolyl, 1-H-4-pyrazolyl, 1-H-5-indazolyl, 2-oxoindolin-5-yl, 2- oxo-2,3-dihydrobenzo[d]oxazol-6-yl), or 1H-benzo[d]imidazol-5-yl; each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C 1- C 6 )alkyl, and (C 1- C 6 )alkoxy.
  • R 1 is 3-pyridinyl, 5-isoxazolyl, 2-thiazolyl, 1-H-4-pyrazolyl, or 1-H-5-indazolyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C 1- C 6 )alkyl, and (C 1- C 6 )alkoxy. [0069] In some embodiments, R 1 is optionally substituted with one, two, three, or four substituents independently selected from chloro, fluoro, methoxy, hydroxymethyl, and methyl.
  • R 1 is phenyl optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, and cyano.
  • R 1 is phenyl substituted with one, two, three, or four substituents independently selected from chloro, fluoro, cyano, and methoxy.
  • R 1 is phenyl, 3,5-difluorophenyl, 2,6-difluoro, 2-chlorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl, 3-cyano-5-fluorophenyl, 3-methoxyphenyl, or 3-fluoro-5- hyroxyphenyl, while in even more particular R 1 is phenyl, 3,5-difluorophenyl, 2,6-difluoro, 2- chlorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl, 3-cyano-5-fluorophenyl, or 3-methoxyphenyl.
  • the compound has the structure of Formula (IIA): ), or a de ptable salt, or a prodrug thereof.
  • the compounds of Formula (IIA) have the structure of Formula (IIA-1) or Formula (IIA-2), as follows: or a a salt, or a prodrug of any of these.
  • the compound has the structure of Formula (IIB): , or a deuterated a or a thereof.
  • the compound has the structure of Formula (IIB-1) or Formula (IIB-2), as follows: or or a deuterated thereof.
  • the compound has the structure of Formula (IIC) , or a deuterated thereof.
  • the compound has the structure of Formula (IID): , or a deuterated a or a thereof.
  • R 2 is hydrogen.
  • R 2 is fluoro.
  • R 2 is chloro.
  • R 2 is (C 1- C 3 )alkyl, such as methyl.
  • R 2 is (C1-C3)alkoxy, such as methoxy.
  • R 2 is (C1-C6)fluoroalkoxy, such as trifluoromethoxy.
  • R 2 is (C 3- C 6 )cycloalkyl, such as cyclopropyl.
  • R 2 is cyano.
  • R 2 is (C1-C3)fluoroalkyl, such as trifluoromethyl or difluoromethyl.
  • V is CH. In other embodiments, for any of the above formulas, V is CF. In still other embodiments, for any of the above formulas, V is N. [0089] In some embodiments, W is CH. In other embodiments, W is CF, in still other embodiments, W is N. [0090] In some embodiments, for any of the above formulas, X is absent (i.e., is a bond). [0091] In some embodiments, for any of the above formulas, Y is CH, while in other embodiments, Y is N. [0092] In other embodiments, for any of the above formulas, X is O and Y is CH.
  • Z is CR 3 R 4 .
  • R 3 is hydrogen.
  • R 4 is (C1-C3)alkoxy. In particular embodiments, for any of the above formulas, R 4 is isopropyloxy.
  • R 4 is NR a R b .
  • R a and R b are each (C1-C3)alkyl. In certain embodiments, for any of the above formulas, R a and R b are each methyl.
  • R 3 and R 4 together with the carbon atom to which they are attached form a 4- or 5-membered spiro heterocycloalkyl optionally substituted with one, two, three, or four independently selected instances of (C1- C 3 )alkyl.
  • Z is NR 5 .
  • R 5 is (C1-C3)alkyl optionally substituted with (C 3- C 8 )cycloalkyl. In more particular embodiments, for any of the above formulas, R 5 is cyclopropylmethyl.
  • R 5 is isopropyl.
  • R 5 is (C1-C3)fluoroalkyl optionally substituted with (C 3- C 8 )cycloalkyl.
  • R 5 is 1-fluorocyclopropylmethyl.
  • R 5 is (C3-C8)cycloalkyl.
  • R 5 is cyclobutyl and in other particular embodiments, R 5 is cyclopentyl.
  • n is 0, while in other embodiments, n is 1.
  • m is 2.
  • R 6 is fluoro.
  • R 6 is fluoro and m is 2.
  • –N(H)-A-X- is: .
  • R 7 is hydrogen, while in other embodiments, R 7 is fluoro.
  • R 8 is hydrogen. In certain preferred embodiments, . is fluoro.
  • a compound is selected from compounds in Table 1: Table 1. Exemplary compounds of the present disclosure. Cmpd # Structure Cmpd # Structure In more particular embodiments, a compound is selected from compounds in Table 2: Table 2. Exemplary compounds of the present disclosure.
  • a compound is selected from , or deuterated derivative, or pharmaceutically acceptable odiments, the compound is a deuterated derivative, or pharmaceutically acceptable the compound is a deuterated derivative, or pharmaceutically acceptable salt or prodrug thereof. In some embodiments, the or a deuterated derivative, or pharmaceutically or is salt or prodrug thereof.
  • the compoun or a deuterated derivative, or pharmaceutically acceptable salt o embodiments, the compound a deuterated derivative, or pharmaceutically acceptable embodiments, the compound is a deuterated derivative, or pharmaceutically acceptable salt the compound is a deuterated derivative, or pharmaceutically embodiments, the compound is a deuterated derivative, or pharmaceutically acceptable [00113]
  • 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, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13 C- or 14 C- enriched carbon are within the scope of this invention.
  • the (C 1 -C 4 )alkyl or the -O-(C 1 - C4)alkyl can be suitably deuterated (e.g., -CD3, or -OCD3, respectively).
  • Any compound of the invention can also be radiolabeled for the preparation of a radiopharmaceutical agent.
  • this disclosure is directed to compounds disclosed herein (e.g., Formulas IA, IA-1, IA-2, IA-3, IA-1’, IA-2’, IA-3’,IIA, IIA-1, IIA-2, IB, IIB,, IIB-1, IIB-2, IIC, IID) and the compounds described in Tables 1 and 2), deuterated derivatives of those compounds, and pharmaceutically acceptable salts or prodrugs thereof.
  • the disclosure is directed to non-salt forms of the compounds disclosed herein (e.g., Formulas IA, IA-1, IA-2, IA-3, IA-1’, IA-2’, IA-3’,IIA, IIA-1, IIA-2, IB, IIB,, IIB-1, IIB-2, IIC, IID) and the compounds described in Tables 1 and 2).
  • Methods of Treatment [00117] One aspect of the invention provides compounds, compositions, and methods useful for preventing or treating a disease which is at least partially mediated by orexin receptor 2. In certain embodiment, the compounds act as agonists of orexin receptor 2.
  • Another aspect of the invention relates to methods of preventing or treating a disease selected from the group consisting of narcolepsy (e.g., narcolepsy type 1 and/or narcolepsy type 2), idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy body, hypersomnia syndrome involving daytime hypersomnia (e.g., narcolepsy type 1 and/or narcolepsy type 2), idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy body, hypersomnia syndrome involving daytime hypersomnia (e.g.
  • Kleine-Levin syndrome major depression accompanied by hypersomnia, dementia with Lewy body, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen's encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto encephalopathy), coma, loss of consciousness, obesity (e.g.
  • malignant mast cell extrinsic obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophysial obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, alimentary obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer, impaired consciousness such as coma, side effect or complication caused by anesthesia, sleep disturbance, sleep problem, insomnia, intermittent sleep, night myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorder of shift workers, dyssomnia, sleep terror, depression, major depression, sleepwalking, enuresis, sleep disorder, Alzheimer's sundown syndrome, disease associated with circadian rhythm, fibromyalgia, condition resulting from decrease in sleeping quality, bulimia, obsessive eating disorder, obesity-related diseases, hypertension, diabetes, elevated plasma insulin level/insulin resistance, hyperlipemia, hyperlipidaemia, endometrial cancer, breast cancer, prostate cancer, colon cancer
  • the invention relates to methods of treating or preventing a disease selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with dementia with Lewy body in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), (IIC), (IID) or any sub-formula thereof or deuterated derivative, or pharmaceutically acceptable salt or prodrug thereof.
  • a disease selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with dementia with Lewy
  • the disease being treated or prevented is narcolepsy (e.g., narcolepsy type 1 and/or narcolepsy type 2), and a compound of any of the above formulas is administered.
  • the disease being treated or prevented is narcolepsy type 1.
  • the disease being treated or prevented is hypersomnolence, and a compound of any of the above formulas is administered.
  • the disease being treated or prevented is idiopathic hypersomnia, and a compound of any of the above formulas is administered.
  • the disease being treated or prevented is hypersomnia, and a compound of any of the above formulas is administered.
  • the disease being treated or prevented is sleep apnea syndrome, and a compound of any of the above formulas is administered.
  • the disease being treated or prevented is narcolepsy syndrome involving narcolepsy-like symptoms, and a compound of any of the above formulas is administered.
  • the disease being treated or prevented is hypersomnia associated with Parkinson’s disease, and a compound of any of the above formulas is administered.
  • the disease being treated or prevented is Parkinson's disease, and a compound of any of the above formulas is administered.
  • the disease being treated or prevented is traumatic brain injury, and a compound of any of the above formulas is administered.
  • the disease being treated or prevented is hypersomnia associated with dementia with Lewy body, and a compound of any of the above formulas is administered.
  • the compound or deuterated derivative, or pharmaceutically acceptable salt or prodrug thereof is administered orally to the subject. In certain embodiments, the compound is administered orally to the subject.
  • the compound or deuterated derivative, or pharmaceutically acceptable salt or prodrug thereof is administered parenterally to the subject. In certain embodiments, the compound is administered parenterally to the subject. [00132] In certain embodiments, any one or more of the above-mentioned diseases is prevented. In other embodiments, any one or more of the above-mentioned diseases is treated.
  • the compounds disclosed herein e.g., Formulas IA, IA-1, IA-2, IA-3, IA-1’, IA-2’, IA-3’,IIA, IIA-1, IIA-2, IB, IIB,, IIB-1, IIB-2, IIC, IID) and the compounds described in Tables 1 and 2), deuterated derivatives of those compounds, and pharmaceutically acceptable salts or prodrugs thereof, modulate orexin 2 receptor in the subject.
  • the compounds disclosed herein e.g., Formulas IA, IA-1, IA-2, IA-3, IA-1’, IA- 2’, IA-3’,IIA, IIA-1, IIA-2, IB, IIB, IIB-1, IIB-2, IIC, IID) and the compounds described in Tables 1 and 2), deuterated derivatives of those compounds, and pharmaceutically acceptable salts or prodrugs thereof, activates orexin 2 receptor in the subject.
  • the compounds of any of the foregoing formulas activate orexin receptor 2 in the subject.
  • the invention is directed to a pharmaceutical composition, comprising a compound of the invention, e.g., a compound of Formula (IA), (IB), (IIA), (IIB), (IIC), (IID), or any sub-formula thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of any of the disclosed embodiments, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier.
  • compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents.
  • an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect.
  • the effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition.
  • One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and/or other therapeutic agent without necessitating undue experimentation.
  • a maximum dose may be used, that is, the highest safe dose according to some medical judgment.
  • Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein.
  • intravenous administration of a compound may typically be from 0.1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 0.1 mg/kg/day to 2 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 0.5 mg/kg/day to 5 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 1 mg/kg/day to 10 mg/kg/day.
  • daily oral doses of a compound will be, for human subjects, from about 0.01 milligrams/kg per day to 1000 milligrams/kg per day. Oral doses in the range of 0.5 to 50 milligrams/kg, in one or more administrations per day, may yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits.
  • the therapeutically effective amount can be initially determined from animal models.
  • a therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, 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 potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan.
  • compositions of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
  • an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface.
  • Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical.
  • a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration.
  • the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers.
  • oral dosage forms of the above component or components may be chemically modified so that oral delivery of the derivative is efficacious.
  • the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine.
  • the increase in overall stability of the component or components and increase in circulation time in the body are also desired.
  • moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline.
  • Abuchowski and Davis “Soluble Polymer- Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982).
  • Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane.
  • the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine.
  • the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine.
  • a coating impermeable to at least pH 5.0 is essential may facilitate full gastric resistance.
  • cellulose acetate trimellitate cellulose acetate trimellitate
  • HPMCP 50 hydroxypropylmethylcellulose phthalate
  • HPMCP 55 polyvinyl acetate phthalate
  • PVAP polyvinyl acetate phthalate
  • Eudragit L30D Aquateric
  • CAP cellulose acetate phthalate
  • Eudragit S Eudragit S
  • shellac shellac
  • a coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow.
  • Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used.
  • the shell material of cachets could be thick starch or other edible paper.
  • moist massing techniques can be used.
  • the therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm.
  • the formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets.
  • the therapeutic could be prepared by compression.
  • Colorants and flavoring agents may all be included.
  • the compound of the invention may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents.
  • an edible product such as a refrigerated beverage containing colorants and flavoring agents.
  • These diluents could include carbohydrates, especially mannitol, ⁇ -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.
  • Disintegrants may be included in the formulation of the therapeutic into a solid dosage form.
  • Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used.
  • Another form of the disintegrants are the insoluble cationic exchange resins.
  • Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.
  • Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.
  • An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process.
  • Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000. [00156] Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.
  • Non- ionic detergents that could be included in the formulation as surfactants 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 ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios.
  • Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
  • Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration.
  • compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • a powder mix of the compound e.g., gelatin
  • suitable powder base such as lactose or starch.
  • pulmonary delivery of the compounds disclosed herein (or salts thereof) The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream.
  • each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, 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.
  • Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed.
  • Formulations suitable for use with a nebulizer will typically comprise a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution.
  • the formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure).
  • the nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol.
  • Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant.
  • the propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof.
  • Suitable surfactants include sorbitan trioleate and soya lecithin.
  • Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing a compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation.
  • the compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers ( ⁇ m), most preferably 0.5 to 5 ⁇ m, for most effective delivery to the deep lung.
  • Nasal delivery of a pharmaceutical composition of the present invention is also contemplated.
  • Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung.
  • Formulations for nasal delivery include those with dextran or cyclodextran.
  • a useful device is a small, hard bottle to which a metered dose sprayer is attached.
  • the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed.
  • the chamber is compressed to administer the pharmaceutical composition of the present invention.
  • the chamber is a piston arrangement.
  • Such devices are commercially available.
  • a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used.
  • the opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation.
  • the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.
  • the compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi- dose containers, with an added preservative.
  • compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate 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 may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • a compound may also be formulated as a depot preparation.
  • Such long-acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
  • ion exchange resins for example, as an emulsion in an acceptable oil
  • sparingly soluble derivatives for example, as a sparingly soluble salt.
  • the pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin.
  • the pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above.
  • the pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990).
  • the compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal.
  • the salts or cocrystals should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts or cocrystals may conveniently be used to prepare pharmaceutically acceptable salts or cocrystals thereof.
  • Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic.
  • such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
  • Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (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).
  • Pharmaceutical compositions of the invention contain an effective amount of a compound as described herein and optionally therapeutic agents included in a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal.
  • carrier denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application.
  • the components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
  • the therapeutic agent(s) including specifically but not limited to a compound of the invention, may be provided in particles.
  • Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein.
  • the particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating.
  • the therapeutic agent(s) also may be dispersed throughout the particles.
  • the therapeutic agent(s) also may be adsorbed into the particles.
  • the particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc.
  • the particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof.
  • the particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state.
  • the particles may be of virtually any shape.
  • Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired.
  • Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
  • the therapeutic agent(s) may be contained in controlled release systems.
  • controlled release is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations.
  • sustained release also referred to as “extended release” is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • 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 there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.” [00185] Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.
  • Step 2 Preparation of (1S,6R)-2,2-difluoro-6-(4- nitrobenzenesulfonamido)cyclohexyl methanesulfonate
  • N-[(1R,2S)-3,3-difluoro-2-hydroxycyclohexyl]-4- nitrobenzenesulfonamide (6 g, 17.8 mmol) and triethylamine (3.61 g, 35.7 mmol) in tetrahydrofuran (60 mL) was added methanesulfonyl chloride (2.04 g, 17.8 mmol) in portions at 0 °C.
  • Step 3 Preparation of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane
  • (1S,6R)-2,2-difluoro-6-(4-nitrobenzenesulfonamido)cyclohexyl methanesulfonate 9.2 g, 22.2 mmol
  • acetonitrile 100 mL
  • potassium carbonate 9.27 g, 66.6 mmol
  • Step 4 Preparation of N-[(1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl]-4-nitrobenzenesulfonamide
  • (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (4 g, 12.6 mmol) in toluene (30 mL) were added 1-isopropylpiperazine (3.22 g, 25.1 mmol) in portions at room temperature.
  • Step 5 Preparation of (1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexan-1-amine (Intermediate 1)
  • N-[(1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl]-4-nitrobenzenesulfonamide (4 g, 8.96 mmol) in toluene (30 mL) was added sodium benzenethiolate (5.92 g, 44.8 mmol) in portions at room temperature.
  • Step 2 Preparation of (1R,6S)-2,2-difluoro-6-[(1-isopropylpiperidin-4- yl)oxy]cyclohexan-1-amine (Intermediate 2)
  • N-[(1R,6S)-2,2-difluoro-6-[(1-isopropylpiperidin-4- yl)oxy]cyclohexyl]-4-nitrobenzenesulfonamide 800 mg, 1.73 mmol
  • sodium benzenethiolate (1.37 g, 10.4 mmol
  • Step 2 Preparation of ⁇ 2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid [00211] To a solution of methyl 2- ⁇ 2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetate (3 g, 10.7 mmol) in tetrahydrofuran (7 mL), methanol (7 mL) and water (7 mL) was added lithium hydroxide (1.28 g, 53.5 mmol). The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS.
  • Step 3 Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 1) [00213] To a solution of ⁇ 2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid (350 mg, 1.32 mmol) in N,N-dimethylformamide (10 mL) was added Intermediate 1 (343 mg, 1.32 mmol) and HATU (650 mg, 1.71 mmol).
  • N,N-diisopropylethylamine (765 mg, 5.92 mmol) was added at 0 °C.
  • the reaction was stirred at room temperature for 1 h, at which point the reaction was judged complete by LCMS.
  • the reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (3 ⁇ 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated.
  • Step 2 Preparation of 2-(2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 6)
  • Compound 6 2-(2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid (82 mg, 0.290 mmol) and Intermediate 1 (50.6 mg, 0.193 mmol) in N,N-dimethylformamide (2 mL) was added HATU (95.6 mg, 0.251 mmol) and N,N-diisopropylethylamine (112 mg, 0.870 mmol) dropwise at 0 °C.
  • Step 2 Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,6-difluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 7)
  • Compound 7 To a stirred mixture of ⁇ 2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid (82 mg, 0.290 mmol) and Intermediate 1 (50.6 mg, 0.193 mmol) in N,N-dimethylformamide (2 mL) was added HATU (95.6 mg, 0.251 mmol) and N,N-diisopropylethylamine (112 mg, 0.870 mmol) dropwise at 0 °C.
  • Step 2 Preparation of methyl 2- ⁇ 2,3',5,5'-tetrafluoro-[1,1'-biphenyl]-3-yl ⁇ acetate
  • 3-bromo-2,3',5,5'-tetrafluoro-1,1'-biphenyl 400 mg, 1.31 mmol
  • tert-butyl[(1-methoxyethenyl)oxy]dimethylsilane 494 mg, 2.62 mmol
  • cupric fluoride (266 mg, 2.62 mmol
  • XPhos-Pd-G3 111 mg, 0.131 mmol
  • Step 3 Preparation of ⁇ 2,3',5,5'-tetrafluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid
  • methyl 2- ⁇ 2,3',5,5'-tetrafluoro-[1,1'-biphenyl]-3-yl ⁇ acetate 140 mg, 0.469 mmol
  • lithium hydroxide 56.2 mg, 2.35 mmol
  • Step 4 Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,3',5,5'-tetrafluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 9)
  • To a stirred solution of ⁇ 2,3',5,5'-tetrafluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid (100 mg, 0.352 mmol) and HATU (174 mg, 0.458 mmol) in N,N-dimethylformamide (5 mL) were added Intermediate 1 (101 mg, 0.387 mmol) and N,N-diisopropylethylamine (136 mg, 1.06 mmol) dropwise at room temperature.
  • Step 2 Preparation of 2-(3',5'-difluoro-2-methoxy-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 11)
  • Step 2 To a stirred mixture of ⁇ 3',5'-difluoro-2-methoxy-[1,1'-biphenyl]-3-yl ⁇ acetic acid (65 mg, 0.234 mmol) and Intermediate 1 (50.9 mg, 0.195 mmol) in N,N-dimethylformamide (3 mL) was added HATU (96.2 mg, 0.254 mmol) and N,N-diisopropylethylamine (113 mg, 0.878 mmol) dropwise at 0 °C.
  • Step 1 Preparation of tert-butyl 2-(2-chloro-3-fluoropyridin-4-yl)acetate
  • 2-chloro-3-fluoro-4-iodopyridine (1 g, 4.04 mmol) and (2-(tert- butoxy)-2-oxoethyl) zinc(II) bromide (1.01 g, 3.89 mmol) in tetrahydrofuran (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.76 g, 0.660 mmol) in portions at room temperature.
  • Step 2 Preparation of tert-butyl 2-[2-(3,5-difluorophenyl)-3-fluoropyridin-4- yl]acetate
  • tert-butyl 2-(2-chloro-3-fluoropyridin-4-yl)acetate 150 mg, 0.611 mmol
  • 3,5-difluorophenylboronic acid 116 mg, 0.733 mmol
  • 1,4-dioxane/water 10:1, 5.5 mL
  • Step 3 Preparation of [2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]acetic acid
  • tert-butyl 2-[2-(3,5-difluorophenyl)-3-fluoropyridin-4- yl]acetate 140 mg, 0.433 mmol
  • lithium hydroxide 51.9 mg, 2.17 mmol
  • the resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS.
  • Step 4 Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl)acetamide (Compound 13) [00265] To a stirred solution of [2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]acetic acid (67.5 mg, 0.253 mmol) and Intermediate 1 (60.0 mg, 0.230 mmol) in N,N-dimethylformamide (3 mL) was added HATU (114 mg, 0.299 mmol) in portions at room temperature under air atmosphere.
  • N,N-diisopropylethylamine (89.0 mg, 0.690 mmol) dropwise at 0 °C.
  • the resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS.
  • the reaction was quenched with water (10 mL).
  • the resulting mixture was extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated.
  • Step 2 Preparation of tert-butyl 2-[4-(3,5-difluorophenyl)-3-fluoropyridin-2- yl]acetate
  • tert-butyl 2-(4-chloro-3-fluoropyridin-2-yl)acetate 170 mg, 0.692 mmol
  • 3,5-difluorophenylboronic acid 131 mg, 0.830 mmol
  • 1,4-dioxane/water 10:1, 5.5 mL
  • [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) 50.6 mg, 0.069 mmol
  • potassium carbonate 287 mg, 2.08 mmol
  • Step 3 Preparation of [4-(3,5-difluorophenyl)-3-fluoropyridin-2-yl] acetic acid
  • tert-butyl 2-[4-(3,5-difluorophenyl)-3-fluoropyridin-2- yl]acetate 120 mg, 0.371 mmol
  • lithium hydroxide 44.5 mg, 1.86 mmol
  • Step 4 Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(4-(3,5-difluorophenyl)-3-fluoropyridin-2-yl)acetamide (Compound 14) [00275] To a stirred solution of [4-(3,5-difluorophenyl)-3-fluoropyridin-2-yl]acetic acid (60 mg, 0.225 mmol) and Intermediate 1 (53.4 mg, 0.205 mmol) in N,N-dimethylformamide (3 mL) was added HATU (101 mg, 0.266 mmol) in portions at room temperature.
  • N,N-diisopropylethylamine (79.2 mg, 0.614 mmol) in portions at 0 °C.
  • the resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS.
  • the reaction was quenched with water (15 mL).
  • the resulting mixture was extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated.
  • Step 2 Preparation of tert-butyl 4- ⁇ [(1S,2R)-2-amino-3,3- difluorocyclohexyl]oxy ⁇ piperidine-1-carboxylate [00281] To a solution of tert-butyl 4- ⁇ [(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy ⁇ piperidine-1-carboxylate (140 mg, 0.269 mmol) in toluene (5 mL) was added sodium benzenethiolate (285 mg, 2.15 mmol).
  • Step 3 Preparation of tert-butyl 4- ⁇ [(1S,2R)-3,3-difluoro-2-(2- ⁇ 2,3',5'-trifluoro- [1,1'-biphenyl]-3-yl ⁇ acetamido)cyclohexyl]oxy ⁇ piperidine-1-carboxylate [00283] To a solution of ⁇ 2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid (35.8 mg, 0.135 mmol) in N,N-dimethylformamide (2 mL) was added HATU (61.4 mg, 0.162 mmol).
  • Step 4 Preparation of N-[(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl]-2- ⁇ 2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetamide
  • Step 5 Preparation of N-[(1R,6S)-2,2-difluoro-6-[(1-isopropylpiperidin-4- yl)oxy]cyclohexyl]-2- ⁇ 2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetamide (Compound 15) [00287] To a solution of N-[(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl]-2- ⁇ 2,3',5'- trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetamide (100 mg, 0.207 mmol) in methanol (5 mL) was added acetone (120 mg, 2.07 mmol) and sodium cyanoborohydride (39.1 mg, 0.621 mmol).
  • Step 1 Preparation of methyl 2-(3-chloro-2-cyclopropylphenyl) acetate
  • methyl 2-(2-bromo-3-chlorophenyl) acetate 300 mg, 1.14 mmol
  • cyclopropylboronic acid 293 mg, 3.42 mmol
  • palladium (II) acetate 37.9 mg, 0.228 mmol
  • di(1-adamantyl)-n-butylphosphine 81.6 mg, 0.341 mmol
  • sodium carbonate 355 mg, 3.42 mmol
  • Step 2 Preparation of 2-(3-chloro-2-cyclopropylphenyl) acetic acid
  • methanol methanol
  • water mL
  • lithium hydroxide 57.6 mg, 2.40 mmol
  • the reaction was stirred at room temperature for 3 h.
  • Step 3 Preparation of 2-(3-chloro-2-cyclopropylphenyl)-N-((1R,6S)-2,2-difluoro- 6-(4-isopropylpiperazin-1-yl)cyclohexyl) acetamide
  • 3-chloro-2-cyclopropylphenyl) acetic acid 51.3 mg, 0.243 mmol
  • N,N-dimethylformamide 3 mL
  • Intermediate 1 70 mg, 0.268 mmol
  • HATU 139 mg, 0.365 mmol
  • N,N-diisopropylethylamine 126 mg, 0.974 mmol.
  • Step 4 Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 16) [00297] To a solution of 2-(3-chloro-2-cyclopropylphenyl)-N-[(1R,6S)-2,2-difluoro-6-(4- isopropylpiperazin-1-yl)cyclohexyl]acetamide (115 mg, 0.253 mmol) and 3,5- difluorophenylboronic acid (60 mg, 0.380 mmol) in dioxane (5 mL) and water (0.5 mL) was added [2',6'-bis(propan-2-yloxy)-[1,1'-bi
  • Step 2 Preparation of tert-butyl 8-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-1,8- diazaspiro[4.5]decane-1-carboxylate [00311] To a solution of tert-butyl 8-[(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]-1,8-diazaspiro[4.5]decane-1-carboxylate (260 mg, 0.465 mmol) in toluene (10 mL) was added sodium benzenethiolate (308 mg, 2.33 mmol).
  • Step 3 Preparation of tert-butyl 8-[(1S,2R)-3,3-difluoro-2-(2- ⁇ 2,3',5'-trifluoro- [1,1'-biphenyl]-3-yl ⁇ acetamido)cyclohexyl]-1,8-diazaspiro[4.5]decane-1-carboxylate [00313] To a solution of tert-butyl 8-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-1,8- diazaspiro[4.5]decane-1-carboxylate (90 mg, 0.241 mmol) in N,N-dimethylformamide (10 mL) was added ⁇ 2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid (64.2 mg, 0.241 mmol) and HATU (119 mg,
  • N,N-diisopropylethylamine 140 mg, 1.09 mmol was added at 0 °C.
  • the reaction was stirred at room temperature for 1 h, at which point the reaction was judged complete by LCMS.
  • the reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow oil (110 mg, 73.4% yield).
  • Step 4 Preparation of N-((1R,6S)-2,2-difluoro-6-(1,8-diazaspiro[4.5]decan-8- yl)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 21) [00315] To a solution of tert-butyl 8-[(1S,2R)-3,3-difluoro-2-(2- ⁇ 2,3',5'-trifluoro-[1,1'- biphenyl]-3-yl ⁇ acetamido)cyclohexyl]-1,8-diazaspiro[4.5]decane-1-carboxylate (100 mg, 0.161 m
  • Step 2 Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,3',5',6-tetrafluoro-[1,1'-biphenyl]-3-yl)acetamide
  • Compound 22 [00321] To a solution of 2-(3-chloro-2,4-difluorophenyl)-N-[(1R,6S)-2,2-difluoro-6-(4- isopropylpiperazin-1-yl)cyclohexyl]acetamide (46 mg, 0.102 mmol) and 3,5- difluorophenylboronic acid (24.2 mg, 0.153 mmol) in tetrahydrofuran (5 mL) was added X-phos (4.87 mg, 0.010 mmol), XPhos-Pd-G3 (8.65 mg
  • Step 2 Preparation of methyl 2- ⁇ 3',5',6-trifluoro-2-methoxy-[1,1'-biphenyl]-3- yl ⁇ acetate
  • 3-bromo-3',5',6-trifluoro-2-methoxy-1,1'-biphenyl 820 mg, 2.59 mmol
  • tert-butyl[(1-methoxyethenyl)oxy]dimethylsilane (2.44 g, 12.9 mmol)
  • zinc fluoride (1.34 g, 12.9 mmol) and bis(tri-tert- butylphosphine) palladium (264 mg, 0.517 mmol).
  • Step 3 Preparation of ⁇ 3',5',6-trifluoro-2-methoxy-[1,1'-biphenyl]-3-yl ⁇ acetic acid [00329] To a solution of methyl 2- ⁇ 3',5',6-trifluoro-2-methoxy-[1,1'-biphenyl]-3-yl ⁇ acetate (70 mg, 0.226 mmol) in tetrahydrofuran/methanol/water (1/1/1, 4.5 mL) and was added lithium hydroxide (27.0 mg, 1.13 mmol). The reaction was stirred at 25 °C for 1 h.
  • Step 4 Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(3',5',6-trifluoro-2-methoxy-[1,1'-biphenyl]-3-yl)acetamide (Compound 23) [00331] To a solution of ⁇ 3',5',6-trifluoro-2-methoxy-[1,1'-biphenyl]-3-yl ⁇ acetic acid (59.2 mg, 0.199 mmol) and Intermediate 1 (43.5 mg, 0.166 mmol) in N,N-dimethylformamide (5 mL) was added HATU (94.9 mg, 0.249 mmol) and N,N-diisopropylethylamine (64.5 mg, 0.498 mmol).
  • Step 2 Preparation of methyl 2-[2-(3,5-difluorophenyl)-3-methoxypyridin-4- yl]acetate
  • methyl 2-(2-chloro-3-methoxypyridin-4-yl)acetate 190 mg, 0.881 mmol
  • 3,5-difluorophenylboronic acid 348 mg, 2.20 mmol
  • 1,4-dioxane/water 10:1, 5.5 mL
  • [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (64.5 mg, 0.088 mmol)
  • potassium carbonate 365 mg, 2.64 mmol
  • Step 3 Preparation of [2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl]acetic acid
  • methyl 2-[2-(3,5-difluorophenyl)-3-methoxypyridin-4- yl]acetate 150 mg, 0.511 mmol
  • methanol/tetrahydrofuran/water 1:1:1, 6 mL
  • lithium hydroxide 61.25 mg, 2.56 mmol
  • Step 4 Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl)acetamide (Compound 26) [00345] To a stirred solution of [2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl]acetic acid (70 mg, 0.251 mmol) and Intermediate 1 (65.5 mg, 0.251 mmol) in N,N-dimethylformamide (4 mL) was added HATU (124 mg, 0.326 mmol,) in portions at room temperature.
  • N,N-diisopropylethylamine (97.2 mg, 0.753 mmol) in portions at 0 °C.
  • the resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS.
  • the reaction was quenched with water (20 mL), then the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated.
  • Step 2 Preparation of (1R,6S)-6-(4-cyclobutylpiperazin-1-yl)-2,2- difluorocyclohexan-1-amine
  • N-[(1R,6S)-6-(4-cyclobutylpiperazin-1-yl)-2,2-difluorocyclohexyl]-4- nitrobenzenesulfonamide 130 mg, 0.284 mmol
  • sodium benzenethiolate 187 mg, 1.42 mmol.
  • Step 3 Preparation of N-((1R,6S)-6-(4-cyclobutylpiperazin-1-yl)-2,2- difluorocyclohexyl)-2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 27) [00353] To a solution of (1R,6S)-6-(4-cyclobutylpiperazin-1-yl)-2,2-difluorocyclohexan-1- amine (50 mg, 0.183 mmol) in N,N-dimethylformamide (10 mL) was added ⁇ 2-cyclopropyl-3',5'- difluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid (52.7 mg, 0.183 mmol) and HATU (90.4 mg, 0.238 mmol).
  • N,N-diisopropylethylamine (106 mg, 0.824 mmol) was added at 0 °C.
  • the reaction was stirred at room temperature for 1 h, at which point the reaction was judged complete by LCMS.
  • the mixture was diluted with water (10 mL), then extracted with ethyl acetate (3 ⁇ 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated.
  • Step 2 Preparation of methyl 2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3- yl ⁇ acetate
  • methyl 2-(3-chloro-2-cyclopropylphenyl)acetate 1.7 g, 7.57 mmol
  • 3,5-difluorophenylboronic acid 2.39 g, 15.1 mmol
  • X-Phos (0.36 g, 0.757 mmol
  • X-Phos-Pd-G3 (0.64 g, 0.757 mmol
  • Step 3 Preparation of ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid
  • methyl 2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3- yl ⁇ acetate 2.1 g, 6.95 mmol
  • tetrahydrofuran/water/methanol (1:1:1, 12 mL) was added lithium hydroxide (0.83 g, 34.7 mmol) in portions at 0 °C.
  • Step 5 Preparation of 2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ -N- [(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl]acetamide [00369] To a stirred solution of tert-butyl 4- ⁇ [(1S,2R)-2-(2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'- biphenyl]-3-yl ⁇ acetamido)-3,3-difluorocyclohexyl]oxy ⁇ piperidine-1-carboxylate (300 mg, 0.496 mmol) in 1,4-dioxane (3 mL
  • Step 6 Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 30) [00371] To a stirred solution of 2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ -N- [(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl]acetamide (200 mg, 0.396 mmol) in methanol (6 mL) was added acetone (69.1 mg, 1.19 mmol) at room temperature.
  • Step 2 Preparation of tert-butyl (3R,4S)-4-(((1S,2R)-2-amino-3,3- difluorocyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate
  • tert-butyl (3R,4S)-4- ⁇ [(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy ⁇ -3-fluoropiperidine-1-carboxylate 100 mg, 0.186 mmol
  • sodium benzenethiolate 147 mg, 1.12 mmol
  • Step 3 Preparation of tert-butyl (3R,4S)-4-(((1S,2R)-3,3-difluoro-2-(2-(2,3',5'- trifluoro-[1,1'-biphenyl]-3-yl) acetamido)cyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00385] To a solution of tert-butyl (3R,4S)-4- ⁇ [(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy ⁇ - 3-fluoropiperidine-1-carboxylate (60 mg, 0.170 mmol) in N,N-dimethylformamide (4 mL) was added ⁇ 2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid (54.4 mg, 0.204 mmol), HATU (97.1 mg,
  • Step 4 Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide
  • Step 5 Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 34) [00389] To a solution of N-[(1R,6S)-2,2-difluoro-6- ⁇ [(3R,4S)-3-fluoropiperidin-4- yl]oxy ⁇ cyclohexyl]-2- ⁇ 2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetamide (80 mg, 0.160 mmol) in methanol (3 mL) was added acetone (92.8 mg, 1.60 mmol) and sodium cyanoborohydride (40.2 mg, 0.639 m
  • Step 2 Preparation of tert-butyl (3S,4S)-4-(((1S,2R)-2-amino-3,3- difluorocyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00395] To a solution of tert-butyl (3S,4S)-4- ⁇ [(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy ⁇ -3-fluoropiperidine-1-carboxylate (240 mg, 0.446 mmol) in toluene (5 mL) was added sodium benzenethiolate (359 mg, 2.72 mmol).
  • Step 3 Preparation of tert-butyl (3S,4S)-4-(((1S,2R)-3,3-difluoro-2-(2-(2,3',5'- trifluoro-[1,1'-biphenyl]-3-yl)acetamido)cyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00397] To a solution of tert-butyl (3S,4S)-4- ⁇ [(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy ⁇ - 3-fluoropiperidine-1-carboxylate (240 mg, 0.681 mmol) in N,N-dimethylformamide (4 mL) was added ⁇ 2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid (218 mg, 0.817 mmol), HATU (388 mg,
  • Step 4 Preparation of N-((1R,6S)-2,2-difluoro-6-(((3S,4S)-3-fluoropiperidin-4- yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide
  • Step 5 Preparation of N-((1R,6S)-2,2-difluoro-6-(((3S,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 35) [00401] To a solution of N-[(1R,6S)-2,2-difluoro-6- ⁇ [(3S,4S)-3-fluoropiperidin-4- yl]oxy ⁇ cyclohexyl]-2- ⁇ 2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl ⁇ acetamide (100 mg, 0.200 mmol) in methanol (5 mL) was added acetone (116 mg, 2.00 mmol) and sodium cyanoborohydride (50.2 mg, 0.799 mmol).
  • Step 1 Preparation of tert-butyl 4- ⁇ [(1S,2R)-2- ⁇ 2-[2-(3,5-difluorophenyl)-3- methoxypyridin-4-yl]acetamido ⁇ -3,3-difluorocyclohexyl]oxy ⁇ piperidine-1-carboxylate [00405] To a stirred solution [2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl]acetic acid (60 mg, 0.215 mmol) and tert-butyl 4- ⁇ [(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy ⁇ piperidine-1- carboxylate (71.9 mg, 0.215 mmol) in N,N-dimethylformamide (3 mL) was added HATU (106 mg, 0.280 mmol) in portions at room temperature.
  • HATU 106 mg, 0.280 mmol
  • Step 2 Preparation of N-[(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy) cyclohexyl]- 2-[2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl]acetamide [00407] To a stirred solution of tert-butyl 4- ⁇ [(1S,2R)-2- ⁇ 2-[2-(3,5-difluorophenyl)-3- methoxypyridin-4-yl]acetamido ⁇ -3,3-difluorocyclohexyl]oxy ⁇ piperidine-1-carboxylate (120 mg, 0.201 mmol) in 1,4-dioxane (3 mL) was added 4M hydrochloric acid
  • Step 3 Preparation of N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl)acetamide (Compound 36) [00409] To a stirred solution of N-[(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl]-2-[2- (3,5-difluorophenyl)-3-methoxypyridin-4-yl]acetamide (60 mg, 0.121 mmol) in dichloroethane (3 mL) was added acetone (21.1 mg, 0.363 mmol) at room temperature.
  • Step 2 Preparation of 2- ⁇ 2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ -N-[(1R,6S)- 2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl]acetamide
  • ⁇ 2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid 117 mg, 0.414 mmol
  • N,N-dimethylformamide 13 mL
  • Intermediate 1 108 mg, 0.414 mmol
  • N,N-diisopropylethylamine 80.2 mg, 0.621 mmol.
  • Step 3 Preparation of 2-(2-cyano-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 39) [00422] To a solution of 2- ⁇ 2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ -N-[(1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl]acetamide (130 mg, 0.247 mmol) in N,N- dimethylformamide (13 mL) was added zinc cyanide (34.8 mg, 0.296 mmol), BrettPhos-Pd-G3 (44.4 mg, 0.049 mmol) and BrettPhos (
  • Step 2 Preparation of 3-cyclopropyl-2-(3,5-difluorophenyl)pyridine-4- carbaldehyde
  • 2-chloro-3-cyclopropylpyridine-4-carbaldehyde 320 mg, 1.76 mmol
  • 3,5-difluorophenylboronic acid 556 mg, 3.52 mmol
  • 1,4-dioxane/water 10:1, 6.6 mL
  • [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 129 mg, 0.176 mmol
  • potassium carbonate 731 mg, 5.29 mmol
  • Step 3 Preparation of 3-cyclopropyl-2-(3,5-difluorophenyl)-4-[(E)-2- methanesulfinyl-2-(methylsulfanyl)ethenyl] pyridine
  • E 2- methanesulfinyl-2-(methylsulfanyl)ethenyl
  • pyridine-4-carbaldehyde 400 mg, 1.54 mmol
  • methyl (methylthio)methyl sulfoxide 230 mg, 1.85 mmol
  • benzyltrimethylammonium hydroxide 258 mg, 1.54 mmol
  • Step 4 Preparation of ethyl 2-[3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4- yl]acetate
  • 3-cyclopropyl-2-(3,5-difluorophenyl)-4-[(E)-2- methanesulfinyl-2-(methylsulfanyl)ethenyl]pyridine 250 mg, 0.684 mmol
  • ethanol 5 mL
  • 4M hydrochloric acid in 1,4-dioxane (0.86 mL, 3.42 mmol
  • Step 5 Preparation of [3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4-yl]acetic acid
  • ethyl 2-[3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4- yl]acetate 180 mg, 0.567 mmol
  • tetrahydrofuran/methanol/water 1:1:1.
  • 6 mL lithium hydroxide (67.9 mg, 2.84 mmol) in portions at 0 °C.
  • the resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS.
  • Step 6 Preparation of 2-(3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 40)
  • [00436] To a stirred solution of [3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4-yl]acetic acid (60 mg, 0.207 mmol) and Intermediate 2 (57.3 mg, 0.207 mmol) in N,N-dimethylformamide (3 mL) was added HATU (103 mg, 0.269 mmol) in portions at room temperature.
  • N,N-diisopropylethylamine (80.4 mg, 0.621 mmol) in portions at 0 °C.
  • the resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS.
  • the reaction was quenched with water (15 mL), then the resulting mixture was extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated.
  • Step 1 Preparation of methyl 2-[2-cyclopropyl-3-(5-fluoropyridin-3-yl) phenyl] acetate
  • methyl 2-(3-chloro-2-cyclopropylphenyl) acetate 200 mg, 0.890 mmol
  • 5-fluoropyridin-3-ylboronic acid 188 mg, 1.34 mmol
  • XPhos 42.4 mg, 0.089 mmol
  • XPhos-Pd-G3 7.5.4 mg, 0.089 mmol
  • potassium phosphate tribasic 378 mg, 1.78 mmol
  • Step 2 Preparation of [2-cyclopropyl-3-(5-fluoropyridin-3-yl) phenyl] acetic acid
  • a solution of methyl 2-[2-cyclopropyl-3-(5-fluoropyridin-3-yl) phenyl] acetate (120 mg, 0.421 mmol) and lithium hydroxide (50.4 mg, 2.11 mmol) in methanol/tetrahydrofuran/water (1:1:1, 5 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 4 with 2M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 30 mL).
  • Step 3 Preparation of 2-(2-cyclopropyl-3-(5-fluoropyridin-3-yl)phenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 41)
  • [2-cyclopropyl-3-(5-fluoropyridin-3-yl) phenyl] acetic acid (58.9 mg, 0.217 mmol) and HATU (89.4 mg, 0.235 mmol) in N,N-dimethylformamide (10 mL) were added Intermediate 2 (50 mg, 0.181 mmol) and N,N-diisopropylethylamine (93.5 mg, 0.724 mmol) in portions at 0 °C.
  • Step 1 Preparation of methyl 2-[2-cyclopropyl-3-(5-methoxypyridin-3-yl)phenyl] acetate
  • Step 2 To a stirred solution of methyl 2-(3-chloro-2-cyclopropylphenyl) acetate (200 mg, 0.890 mmol) and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (314 mg, 1.34 mmol) in tetrahydrofuran/water (4:1, 10 mL) were added XPhos (42.4 mg, 0.089 mmol), XPhos-Pd-G3 (75.4 mg, 0.089 mmol) and potassium phosphate tribasic (378 mg, 1.78 mmol) at room temperature.
  • Step 2 Preparation of [2-cyclopropyl-3-(5-methoxypyridin-3-yl)phenyl] acetic acid
  • a solution of methyl 2-[2-cyclopropyl-3-(5-methoxypyridin-3-yl) phenyl] acetate (170 mg, 0.572 mmol) and lithium hydroxide (68.5 mg, 2.86 mmol) in methanol/tetrahydrofuran/water (1:1:1, 5 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 4 with 2M hydrochloric acid.
  • Step 3 Preparation of 2-(2-cyclopropyl-3-(5-methoxypyridin-3-yl)phenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 42)
  • [2-cyclopropyl-3-(5-methoxypyridin-3-yl)phenyl] acetic acid (73.8 mg, 0.260 mmol) and HATU (107 mg, 0.282 mmol) in N,N-dimethylformamide (5 mL) were added Intermediate 2 (60 mg, 0.217 mmol) and N,N-diisopropylethylamine (112 mg, 0.868 mmol) dropwise at 0 °C.
  • Step 2 3-bromo-2-(trifluoromethoxy)benzaldehyde
  • [3-bromo-2-(trifluoromethoxy)phenyl]methanol 1.6 g, 5.90 mmol
  • dichloromethane 10 mL
  • pyridinium chlorochromate 3.82 g, 17.7 mmol
  • the resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by TLC.
  • the reaction was quenched with water (30 mL), then the resulting mixture was extracted with ethyl acetate (3 x 30 mL).
  • Step 3 Preparation of 1-bromo-3-[(E)-2-methanesulfinyl-2- (methylsulfanyl)ethenyl]-2(trifluoromethoxy)benzene
  • benzyltrimethylammonium hydroxide 311 mg, 1.86 mmol
  • Step 4 Preparation of ethyl 2-[3-bromo-2-(trifluoromethoxy)phenyl]acetate
  • 1-bromo-3-[(E)-2-methanesulfinyl-2-(methylsulfanyl)ethenyl]- 2-(trifluoromethoxy)benzene 250 mg, 0.666 mmol
  • 4M hydrochloric acid in 1,4-dioxane (0.83 mL, 3.33 mmol
  • Step 5 Preparation of [3-bromo-2-(trifluoromethoxy)phenyl]acetic acid
  • ethyl 2-[3-bromo-2-(trifluoromethoxy)phenyl]acetate 160 mg, 0.489 mmol
  • lithium hydroxide 58.6 mg, 2.45 mmol
  • the resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS.
  • Step 6 Preparation of 2-[3-bromo-2-(trifluoromethoxy) phenyl]-N-[(1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl]acetamide
  • HATU 198 mg, 0.521 mmol
  • Step 7 Preparation of 2-(3',5'-difluoro-2-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)- N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 45) [00472] To a stirred solution of 2-[3-bromo-2-(trifluoromethoxy)phenyl]-N-[(1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl]acetamide (80 mg, 0.147 mmol) and 3,5- difluorophenylboronic acid (116 mg, 0.735
  • Step 1 Preparation of 3-bromo-2-(trifluoromethyl)benzaldehyde
  • pyridinium chlorochromate (2.54 g, 11.8 mmol) in portions at 0 °C.
  • the resulting mixture was stirred for 3 h at room temperature, at which point the reaction was judged complete by TLC.
  • the reaction was quenched with water (30 mL), then the resulting mixture was extracted with dichloromethane (3 x 30 mL).
  • Step 2 Preparation of 1-bromo-3-[(E)-2-methanesulfinyl-2- (methylsulfanyl)ethenyl]-2-(trifluoromethyl)benzene
  • 3-bromo-2-(trifluoromethyl)benzaldehyde 550 mg, 2.17 mmol
  • methyl (methylthio)methyl sulfoxide 324 mg, 2.61 mmol
  • benzyltrimethylammonium hydroxide 364 mg, 2.17 mmol
  • Step 3 Preparation of ethyl 2-[3-bromo-2-(trifluoromethyl)phenyl]acetate
  • 1-bromo-3-[(E)-2-methanesulfinyl-2-(methylsulfanyl)ethenyl]- 2-(trifluoromethyl)benzene 300 mg, 0.835 mmol
  • 4M HCl in 1,4- dioxane 4.175 mmol
  • Step 4 [3-bromo-2-(trifluoromethyl)phenyl]acetic acid
  • ethyl 2-[3-bromo-2-(trifluoromethyl)phenyl]acetate 250 mg, 0.804 mmol
  • lithium hydroxide 96.2 mg, 4.02 mmol
  • Step 5 2-[3-bromo-2-(trifluoromethyl)phenyl]-N-[(1R,6S)-2,2-difluoro-6-(4- isopropylpiperazin-1-yl)cyclohexyl]acetamide
  • [3-bromo-2-(trifluoromethyl)phenyl]acetic acid 70 mg, 0.247 mmol
  • Intermediate 1 64.6 mg, 0.247 mmol
  • N,N-dimethylformamide 5 mL
  • HATU 122 mg, 0.321 mmol
  • N,N-diisopropylethylamine 95.9 mg, 0.741 mmol
  • Step 6 Preparation of 2-(3',5'-difluoro-2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)- N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 46) [00486] To a stirred solution of 2-[3-bromo-2-(trifluoromethyl)phenyl]-N-[(1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl]acetamide (60 mg, 0.114 mmol) and 3,5- difluorophenylboronic acid (36.0 mg, 0.228 mmol) in 1,4-dioxane/water (4:1, 5 mL) were added [1,1′-bis(diphenylphosphino)ferroc
  • the resulting mixture was stirred for 3 h at 90 °C under a nitrogen atmosphere.
  • the reaction was cooled to room temperature, then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated.
  • the crude product was purified by Prep-HPLC using a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 ⁇ m column (55-65% methanol/water with 0.05% ammonium bicarbonate) to provide the title compound as an off-white solid (45.9 mg, 71.4% yield).
  • Step 1 Preparation of methyl 2-[3-(5-chloropyridin-3-yl)-2-cyclopropylphenyl] acetate
  • Step 1 To a stirred solution of methyl 2-(3-chloro-2-cyclopropylphenyl) acetate (150 mg, 0.668 mmol) and 5-chloropyridin-3-ylboronic acid (158 mg, 1.00 mmol) in 1,4-dioxane/water (4:1, 5 mL) were added bis(acetonitrile)dichloropalladium(II) (17.3 mg, 0.067 mmol) and potassium phosphate tribasic (283 mg, 1.34 mmol) in portions at room temperature.
  • Step 2 Preparation of [3-(5-chloropyridin-3-yl)-2-cyclopropylphenyl] acetic acid
  • a solution of methyl 2-[3-(5-chloropyridin-3-yl)-2-cyclopropylphenyl] acetate (40 mg, 0.133 mmol) and lithium hydroxide (15.9 mg, 0.665 mmol) in methanol/tetrahydrofuran/water (1:1:1, 4 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH 4 with 2N hydrochloric acid, then the resulting mixture was extracted with ethyl acetate (3 x 20 mL).
  • Step 3 Preparation of 2-(3-(5-chloropyridin-3-yl)-2-cyclopropylphenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 47)
  • [3-(5-chloropyridin-3-yl)-2-cyclopropylphenyl] acetic acid (40 mg, 0.139 mmol) and HATU (68.7 mg, 0.181 mmol) in N,N-dimethylformamide (4 mL) were added Intermediate 2 (38.4 mg, 0.139 mmol) and N,N-diisopropylethylamine (71.9 mg, 0.556 mmol) in portions at 0°C.
  • Step 2 Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl)acetamide
  • Step 3 Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-(1-fluoropropan-2-yl)piperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 50) [00506] To a solution of 2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ -N-[(1R,6S)-2,2- difluoro-6-(piperidin-4-yloxy)cyclohexyl]acetamide (145 mg, 0.287 mmol) and fluoroacetone (109 mg, 1.44 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (609 mg, 2.87 mmol)
  • Step 2 Preparation of ⁇ 2-cyclopropyl-3'-methoxy-[1,1'-biphenyl]-3-yl ⁇ acetic acid
  • Step 3 Preparation of 2-(2-cyclopropyl-3'-methoxy-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 52)
  • acetic acid 50 mg, 0.177 mmol
  • HATU 87.5 mg, 0.230 mmol
  • N,N-dimethylformamide 5 mL
  • Step 2 Preparation of [2-cyclopropyl-3-(3-methyl-1,2-oxazol-5-yl)phenyl]acetic acid
  • methyl 2-[2-cyclopropyl-3-(3-methyl-1,2-oxazol-5-yl)phenyl]acetate 100 mg, 0.369 mmol
  • methanol 2 mL
  • water 1 mL
  • lithium hydroxide 53.0 mg, 2.21 mmol
  • Step 3 Preparation of 2-(2-cyclopropyl-3-(3-methylisoxazol-5-yl)phenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 54)
  • [2-cyclopropyl-3-(3-methyl-1,2-oxazol-5-yl)phenyl]acetic acid 40 mg, 0.155 mmol
  • N,N-dimethylformamide (2 mL ) was added Intermediate 2 (43.0 mg, 0.155 mmol), HATU (88.7 mg, 0.232 mmol) and N,N-diisopropylethylamine (60.3 mg, 0.465 mmol) at room temperature.
  • Step 2 Preparation of tert-butyl (3R,4R)-4- ⁇ [(1S,2R)-2-amino-3,3- difluorocyclohexyl]oxy ⁇ -3-fluoropiperidine-1-carboxylate [00534] To a solution of tert-butyl (3R,4R)-4- ⁇ [(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy ⁇ -3-fluoropiperidine-1-carboxylate (120 mg, 0.223 mmol) in toluene (0.12 mL) was added sodium benzenethiolate (29.5 mg, 0.223 mmol).
  • Step 3 Preparation of tert-butyl (3R,4R)-4- ⁇ [(1S,2R)-2-(2- ⁇ 2-cyclopropyl-3',5'- difluoro-[1,1'-biphenyl]-3-yl ⁇ acetamido)-3,3-difluorocyclohexyl]oxy ⁇ -3-fluoropiperidine-1- carboxylate [00536] To a solution of tert-butyl (3R,4R)-4- ⁇ [(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy ⁇ - 3-fluoropiperidine-1-carboxylate (122 mg, 0.346 mmol) in N,N-dimethylformamide (10 mL) was added ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid (99.8 mg, 0.3
  • Step 4 Preparation of 2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ -N- [(1R,6S)-2,2-difluoro-6- ⁇ [(3R,4R)-3-fluoropiperidin-4-yl]oxy ⁇ cyclohexyl]acetamide
  • Step 5 Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(((3R,4R)-3-fluoro-1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide (Compound 56) [00540] To a solution of 2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ -N-[(1R,6S)-2,2- difluoro-6- ⁇ [(3R,4R)-3-fluoropiperidin-4-yl]oxy ⁇ cyclohexyl]acetamide (50 mg, 0.096 mmol) in methanol (3 mL) was added acetone (65 mg, 1.12 mmol) and sodium cyanoboronitrile (50
  • Step 2 Preparation of tert-butyl (3S,4R)-4-(((1S,2R)-2-amino-3,3- difluorocyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00546] To a solution of tert-butyl (3S,4R)-4- ⁇ [(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy ⁇ -3-fluoropiperidine-1-carboxylate (240 mg, 0.446 mmol) in toluene (5 mL) was added sodium benzenethiolate (354 mg, 2.68 mmol).
  • Step 3 Preparation of tert-butyl (3S,4R)-4-(((1S,2R)-2-(2-(2-cyclopropyl-3',5'- difluoro-[1,1'-biphenyl]-3-yl)acetamido)-3,3-difluorocyclohexyl)oxy)-3-fluoropiperidine-1- carboxylate [00548] To a solution of tert-butyl (3S,4R)-4- ⁇ [(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy ⁇ - 3-fluoropiperidine-1-carboxylate (102 mg, 0.289 mmol) and ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'- biphenyl]-3-yl ⁇ acetic acid (100 mg, 0.347 mmol) in N,N-dimethylformamide (5 mL)
  • Step 4 Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(((3S,4R)-3-fluoropiperidin-4-yl)oxy)cyclohexyl)acetamide
  • Step 5 Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(((3S,4R)-3-fluoro-1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide (Compound 57)
  • [00552] To a solution of 2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ -N-[(1R,6S)-2,2- difluoro-6- ⁇ [(3S,4R)-3-fluoropiperidin-4-yl]oxy ⁇ cyclohexyl]acetamide (60 mg, 0.115 mmol) in methanol (3 mL) was added acetone (67 mg, 1.15 mmol) and sodium cyano
  • Step 2 Preparation of [2-cyclopropyl-3-(1,3-thiazol-2-yl)phenyl]acetic acid
  • methanol 1 mL
  • water 2 mL
  • lithium hydroxide 52.6 mg, 2.20 mmol
  • Step 3 Preparation of 2-(2-cyclopropyl-3-(thiazol-2-yl)phenyl)-N-((1R,6S)-2,2- difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 58) [00560] To a solution of [2-cyclopropyl-3-(1,3-thiazol-2-yl)phenyl]acetic acid (37.5 mg, 0.145 mmol) and Intermediate 2 (40 mg, 0.145 mmol) in N,N-dimethylformamide (3 mL) was added HATU (82.5 mg, 0.217 mmol) and N,N-diisopropylethylamine (93.5 mg, 0.724 mmol).
  • Step 2 Preparation of 2-(2-cyclopropyl-3-(1H-indazol-5-yl)phenyl)acetic acid
  • Step 3 Preparation of 2-(2-cyclopropyl-3-(1H-indazol-5-yl)phenyl)-N-((1R,6S)- 2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 59)
  • [2-cyclopropyl-3-(1H-indazol-5-yl) phenyl] acetic acid (52.9 mg, 0.181 mmol) and Intermediate 2 (50 mg, 0.181 mmol) in N,N-dimethylformamide (3 mL) was added HATU (103 mg, 0.271 mmol) and N,N-diisopropylethylamine (111 mg, 0.855 mmol).
  • Step 2 Preparation of 2-(3,5-difluorophenyl)-4-[(E)-2-ethoxyethenyl]-3- (trifluoromethyl) pyridine
  • Step 2 To a stirred solution of 2-chloro-4-[(E)-2-ethoxyethenyl]-3-(trifluoromethyl) pyridine (550 mg, 2.19 mmol) and 3,5-difluorophenylboronic acid (414 mg, 2.62 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (178 mg, 0.219 mmol) and potassium carbonate (604 mg, 4.37 mmol) in portions at room temperature.
  • Step 3 Preparation of 2-[2-(3,5-difluorophenyl)-3-(trifluoromethyl) pyridin-4-yl] acetaldehyde
  • Step 4 Preparation of [2-(3,5-difluorophenyl)-3-(trifluoromethyl) pyridin-4-yl] acetic acid
  • 2-[2-(3,5-difluorophenyl)-3-(trifluoromethyl) pyridin-4-yl] acetaldehyde (120 mg, 0.398 mmol) in a mixture of tert-butanol (2.5 mL) and tetrahydrofuran (2.5 mL) was added 2-methyl-2-butene (168 mg, 2.39 mmol) and sodium chlorite (43.2 mg, 0.478 mmol) in portions at 0 °C.
  • Step 5 Preparation of N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl)acetamide (Compound 61)
  • [00582] To a stirred solution of [2-(3,5-difluorophenyl)-3-(trifluoromethyl) pyridin-4-yl] acetic acid (70 mg, 0.221 mmol) and HATU (109 mg, 0.287 mmol) in N,N-dimethylformamide (3 mL) were added Intermediate 2 (60.99 mg, 0.221 mmol, 1 equiv) and
  • Step 2 Preparation of 3-[(E)-2-ethoxyethenyl]-3',5'-difluoro-[1,1'-biphenyl]-2- carbonitrile
  • Step 2 To a solution of 3-bromo-3',5'-difluoro-[1,1'-biphenyl]-2-carbonitrile (200 mg, 0.680 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added 2-[(E)-2-ethoxyethenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (269 mg, 1.36 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (49.8 mg, 0.068 mmol) and potassium carbonate (235 mg, 1.70 mmol) under a nitrogen atmosphere.
  • the reaction was stirred at 90 °C for 3 h under a nitrogen atmosphere, then the mixture was allowed to cool to room temperature. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulsfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound as a yellow oil (160 mg, 82.5% yield).
  • Step 3 Preparation of 3',5'-difluoro-3-(2-oxoethyl)-[1,1'-biphenyl]-2-carbonitrile
  • Step 3 To a solution of 3-[(E)-2-ethoxyethenyl]-3',5'-difluoro-[1,1'-biphenyl]-2-carbonitrile (160 mg, 0.561 mmol) in 1,4-dioxane (2 mL) was added 2N hydrochloric acid (2 mL). The reaction was stirred at 50 °C for 16 h, then was cooled to room temperature.
  • Step 4 Preparation of ⁇ 2-cyano-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid
  • 3-methyl-2-butene 204 mg, 2.92 mmol
  • sodium chlorite 63.3 mg, 0.700 mmol
  • sodium phosphate monobasic (83.9 mg, 0.700 mmol) in water (0.5 mL) was added at 0°C.
  • the reaction was stirred at 0 °C for 0.5 h, then was stirred at room temperature for 1 h.
  • the reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow oil, which was used without further purification (130 mg, 81.6% yield).
  • Step 5 Preparation of 2-(2-cyano-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 62)
  • ⁇ 2-cyano-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ acetic acid 150 mg, 0.549 mmol
  • HATU 250 mg, 0.659 mmol
  • N,N-dimethylformamide 3 mL
  • Step 2 Preparation of tert-butyl 2-[2-chloro-3-(trifluoromethoxy)pyridin-4- yl]acetate
  • 2-chloro-4-iodo-3-(trifluoromethoxy)pyridine (1 g, 3.09 mmol) in N,N-dimethylformamide (10 mL) was added ⁇ [1-(tert-butoxy)ethenyl]oxy ⁇ (tert- butyl)dimethylsilane (3.56 g, 15.5 mmol), bis(tri-t-butylphosphine)palladium(0) (316 mg, 0.618 mmol) and zinc fluoride (1.60 g, 15.5 mmol) under a nitrogen atmosphere.
  • Step 3 Preparation of tert-butyl 2-[2-(3,5-difluorophenyl)-3- (trifluoromethoxy)pyridin-4-yl]acetate
  • tert-butyl 2-[2-chloro-3-(trifluoromethoxy)pyridin-4-yl]acetate 390 mg, 1.25 mmol
  • 1,4-dioxane 5 mL
  • water 1 mL
  • 3,5-difluorophenylboronic acid 395 mg, 2.50 mmol
  • [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 91.6 mg, 0.125 mmol
  • potassium carbonate 432 mg, 3.13 mmol
  • Step 4 Preparation of [2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4- yl]acetic acid
  • tert-butyl 2-[2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4- yl]acetate 320 mg, 0.822 mmol
  • lithium hydroxide 118 mg, 4.93 mmo
  • Step 5 Preparation of N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4-yl)acetamide (Compound 63)
  • the reaction was stirred at 90 °C under a nitrogen atmosphere for 5 h.
  • the reaction was cooled to room temperature, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL).
  • the combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated.
  • the residue was purified by preparative HPLC (YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 ⁇ m column, 49-73% acetonitrile/water gradient with 10 mM ammonium formate) to provide the formic acid salt of the title compound as a white solid (24.9 mg, 21.4% yield.
  • Step 2 Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4-yl)acetamide
  • Step 3 Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3- (trifluoromethoxy)pyridin-4-yl)acetamide (Compound 67) [00621] To a solution of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4-yl)acetamide (150 mg, 0.287 mmol) and acetone (81.9 mg, 1.41 mmol) in methanol (3 mL) was added sodium cyanoborohydride
  • Step 2 Preparation of [3-(1H-1,3-benzodiazol-5-yl)-2-cyclopropylphenyl] acetic acid
  • a solution of methyl 2-[3-(1H-1,3-benzodiazol-5-yl)-2-cyclopropylphenyl] acetate (190 mg, 0.620 mmol) and lithium hydroxide (74.3 mg, 3.10 mmol) in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL) was stirred for 1 h at room temperature. The mixture was neutralized to pH 7 with 1N hydrochloric acid, then the solution was concentrated.
  • Step 3 Preparation of 2-(3-(1H-benzo[d]imidazol-5-yl)-2-cyclopropylphenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 69)
  • [00632] To a stirred solution of [3-(1H-1,3-benzodiazol-5-yl)-2-cyclopropylphenyl] acetic acid (60 mg, 0.205 mmol) and HATU (101 mg, 0.267 mmol) in N,N-dimethylformamide (3 mL) was added Intermediate 2 (56.7 mg, 0.205 mmol) and N,N-diisopropylethylamine (106 mg, 0.820 mmol) in portions at 0 °C.
  • Step 2 Preparation of 5- ⁇ 4-[(E)-2-ethoxyethenyl]-3-(trifluoromethyl) pyridin-2- yl ⁇ -1H-indazole
  • 2-chloro-4-[(E)-2-ethoxyethenyl]-3-(trifluoromethyl) pyridine 540 mg, 2.15 mmol
  • 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (629 mg, 2.58 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (175 mg, 0.215 mmol) and potassium carbonate (593 mg, 4.29 mmol) in portions at room temperature.
  • Step 3 Preparation of 2-[2-(1H-indazol-5-yl)-3-(trifluoromethyl) pyridin-4-yl] acetaldehyde
  • Step 4 Preparation of [[2-(1H-indazol-5-yl)-3-(trifluoromethyl) pyridin-4-yl] acetic acid
  • 2-[2-(1H-indazol-5-yl)-3-(trifluoromethyl) pyridin-4-yl] acetaldehyde 100 mg, 0.328 mmol
  • 2-methyl-2-butene 138 mg, 1.97 mmol
  • sodium chlorite 35.6 mg, 0.394 mmol
  • Step 5 Preparation of 2-(2-(1H-indazol-5-yl)-3-(trifluoromethyl)pyridin-4-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 70) [00644] To a stirred solution of [2-(1H-indazol-5-yl)-3-(trifluoromethyl) pyridin-4-yl] acetic acid (50 mg, 0.156 mmol) and HATU (76.9 mg, 0.203 mmol) in N,N-dimethylformamide (3 mL) was added Intermediate 2 (43.0 mg, 0.156 mmol) and N,N-diis
  • Step 2 Preparation of methyl 2-[2-(3,5-difluorophenyl)-3- (trifluoromethyl)pyridin-4-yl]acetate
  • methyl 2-[2-chloro-3-(trifluoromethyl)pyridin-4-yl]acetate 280 mg, 1.10 mmol
  • 3,5-difluorophenylboronic acid 349 mg, 2.21 mmol
  • 1,4-dioxane 5 mL
  • water 0.5 mL
  • Step 3 Preparation of [2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4- yl]acetic acid
  • methyl 2-[2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4- yl]acetate 300 mg, 0.906 mmol
  • tetrahydrofuran 2 mL
  • water 2 mL
  • methanol methanol
  • Step 4 Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3- (trifluoromethyl)pyridin-4-yl)acetamide (Compound 71)
  • [00654] To a stirred mixture of [2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl]acetic acid (100 mg, 0.315 mmol) and (1R,6S)-2,2-difluoro-6- ⁇ [(3R,4S)-3-fluoro-1-isopropylpiperidin- 4-yl]oxy ⁇ cyclohexan-1-amine (92.8 mg, 0.315 mmol) in N,N-dimethylformamide (5 mL)
  • Step 2 Preparation of N-[(1R,6S)-2,2-difluoro-6- ⁇ [(3S,4R)-3-fluoropiperidin-4- yl]oxy ⁇ cyclohexyl]-4-nitrobenzenesulfonamide
  • tert-butyl (3S,4R)-4- ⁇ [(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy ⁇ -3-fluoropiperidine-1-carboxylate 440 mg, 0.819 mmol
  • 1,4-dioxane 5 mL
  • 4N hydrogen chloride in 1,4-dioxane (5 mL).
  • Step 3 Preparation of N-[(1R,6S)-2,2-difluoro-6- ⁇ [(3S,4R)-3-fluoro-1- isopropylpiperidin-4-yl]oxy ⁇ cyclohexyl]-4-nitrobenzenesulfonamide
  • N-[(1R,6S)-2,2-difluoro-6- ⁇ [(3S,4R)-3-fluoropiperidin-4- yl]oxy ⁇ cyclohexyl]-4-nitrobenzenesulfonamide 400 mg, 0.914 mmol
  • acetone 4.25 g, 73.1 mmol
  • sodium cyanoborohydride 17.4 mg, 0.276 mmol
  • Step 4 Preparation of (1R,6S)-2,2-difluoro-6- ⁇ [(3S,4R)-3-fluoro-1- isopropylpiperidin-4-yl]oxy ⁇ cyclohexan-1-amine [00664] To a solution of N-[(1R,6S)-2,2-difluoro-6- ⁇ [(3S,4R)-3-fluoro-1-isopropylpiperidin-4- yl]oxy ⁇ cyclohexyl]-4-nitrobenzenesulfonamide (300 mg, 0.626 mmol) in toluene (15 mL) was added sodium thiophenolate (413 mg, 3.13 mmol), and the reaction was stirred at 100 °C for 2 h.
  • Step 5 Preparation of N-((1R,6S)-2,2-difluoro-6-(((3S,4R)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3- (trifluoromethyl)pyridin-4-yl)acetamide (Compound 72) [00666] To a solution of (1R,6S)-2,2-difluoro-6- ⁇ [(3S,4R)-3-fluoro-1-isopropylpiperidin-4- yl]oxy ⁇ cyclohexan-1-amine (110 mg, 0.374 mmol) in N,N-dimethylformamide (10 mL) was added [2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl]acetic acid (119 mg, 0.374 mmol) and HA
  • Step 2 Preparation of methyl 2-[2-chloro-3-(difluoromethoxy)pyridin-4- yl]acetate
  • 2-chloro-3-(difluoromethoxy)-4-iodopyridine 800 mg, 2.62 mmol
  • tert-butyl[(1-methoxyethenyl)oxy]dimethylsilane 2.47 g, 13.1 mmol
  • zinc fluoride (1.35 g, 13.1 mmol
  • bis(tri-tert- butylphosphine) palladium(0) 268 mg, 0.524 mmol
  • Step 3 Preparation of methyl 2-[3-(difluoromethoxy)-2-(3,5- difluorophenyl)pyridin-4-yl]acetate
  • methyl 2-[2-chloro-3-(difluoromethoxy)pyridin-4-yl]acetate (320 mg, 1.27 mmol) and 3,5-difluorophenylboronic acid (502 mg, 3.18 mmol) in 1,4-dioxane and water (10:1 mixture, 5.5 mL) were added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (93.1 mg, 0.127 mmol) and potassium carbonate (527 mg, 3.82 mmol) in portions at room temperature.
  • Step 4 Preparation of [3-(difluoromethoxy)-2-(3,5-difluorophenyl)pyridin-4- yl]acetic acid
  • methyl 2-[3-(difluoromethoxy)-2-(3,5-difluorophenyl)pyridin- 4-yl]acetate 320 mg, 0.972 mmol
  • lithium hydroxide 116 mg, 4.86 mmol
  • Step 5 Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(3-(difluoromethoxy)-2-(3,5- difluorophenyl)pyridin-4-yl)acetamide (Compound 73) [00678] To a stirred solution of [3-(difluoromethoxy)-2-(3,5-difluorophenyl)pyridin-4-yl]acetic acid (80 mg, 0.254 mmol) and (1R,6S)-2,2-difluoro-6- ⁇ [(3R,4S)-3-fluoro-1-isopropylpiperidin-4- yl]oxy ⁇ cyclohexan-1-amine (62.3 mg, 0.212 mmol) in N,N-dimethylformamide (5
  • the reaction was stirred at 150 °C for 1 h, at which point the reaction was judged complete by LCMS.
  • the reaction mixture was cooled to room temperature, quenched by addition of water (10 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound (85 mg, 21.9% yield).
  • Step 2 Preparation of tert-butyl (4S)-4- ⁇ [(1S,2R)-2-amino-3,3- difluorocyclohexyl]oxy ⁇ -3,3-difluoropiperidine-1-carboxylate [00684] To a solution of tert-butyl (4S)-4- ⁇ [(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy ⁇ -3,3-difluoropiperidine-1-carboxylate (80 mg, 0.144 mmol) in toluene (10 mL) was added sodium thiophenolate (95.2 mg, 0.720 mmol), and the reaction was stirred at 100 °C for 2
  • Step 3 Preparation of tert-butyl (4S)-4- ⁇ [(1S,2R)-2-(2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'- biphenyl]-3-yl ⁇ acetamido)-3,3-difluorocyclohexyl]oxy ⁇ -3,3-difluoropiperidine-1- carboxylate
  • tert-butyl (4S)-4- ⁇ [(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy ⁇ -3,3- difluoropiperidine-1-carboxylate 45 mg, 0.121 mmol
  • N,N-dimethylformamide 10 mL
  • Step 4 Preparation of 2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ -N- [(1R,6S)-6- ⁇ [(4S)-3,3-difluoropiperidin-4-yl]oxy ⁇ -2,2-difluorocyclohexyl]acetamide [00686] To a solution of tert-butyl (4S)-4- ⁇ [(1S,2R)-2-(2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'- biphenyl]-3-yl ⁇ acetamido)-3,3-difluorocyclohexyl]oxy ⁇ -3,3-difluoropiperidine-1-carboxylate (40 mg, 0.062 mmol) in 1,4-dioxane (5 mL) was added 4M hydrogen chloride in 1,4-dioxan
  • Step 5 Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-6-((3,3-difluoro-1-isopropylpiperidin-4-yl)oxy)-2,2-difluorocyclohexyl)acetamide (Compound 74)
  • [00688] To a solution of 2- ⁇ 2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl ⁇ -N-[(1R,6S)-6- ⁇ [(4S)-3,3-difluoropiperidin-4-yl]oxy ⁇ -2,2-difluorocyclohexyl]acetamide (50 mg, 0.092 mmol) in methanol (10 mL) was added acetone (429 mg, 7.36 mmol).
  • the reaction was stirred at room temperature for 0.5 h, then the reaction was cooled to 0 °C and sodium cyanoborohydride (17.4 mg, 0.276 mmol) was added. The reaction was stirred at room temperature for 3 h, at which point the reaction was judged complete by LCMS. The mixture was diluted with water (30 mL), then extracted with dichloromethane (3 ⁇ 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated.
  • Step 2 Preparation of methyl 2-[2-chloro-3-(difluoromethyl)pyridin-4-yl]acetate
  • 2-chloro-3-(difluoromethyl)-4-iodopyridine 800 mg, 2.76 mmol
  • tert-butyl[(1-methoxyethenyl)oxy]dimethylsilane 2.60 g, 13.8 mmol
  • zinc fluoride (1.43 g, 13.8 mmol
  • bis(tri-tert- butylphosphine) palladium(0) 282 mg, 0.553 mmol
  • Step 3 Preparation of methyl 2-[3-(difluoromethyl)-2-(3,5- difluorophenyl)pyridin-4-yl]acetate
  • Step 3 Preparation of methyl 2-[3-(difluoromethyl)-2-(3,5- difluorophenyl)pyridin-4-yl]acetate
  • methyl 2-[2-chloro-3-(difluoromethyl)pyridin-4-yl]acetate 300 mg, 1.27 mmol
  • 3,5-difluorophenylboronic acid 502 mg, 3.18 mmol
  • 1,4- dioxane and water 10:1, 5.5 mL
  • Step 4 Preparation of [3-(difluoromethyl)-2-(3,5-difluorophenyl)pyridin-4- yl]acetic acid
  • methyl 2-[3-(difluoromethyl)-2-(3,5-difluorophenyl)pyridin-4- yl]acetate 300 mg, 0.958 mmol
  • lithium hydroxide 115 mg, 4.79 mmol
  • Step 5 Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(3-(difluoromethyl)-2-(3,5- difluorophenyl)pyridin-4-yl)acetamide (Compound 75) [00700] To a stirred solution of [3-(difluoromethyl)-2-(3,5-difluorophenyl)pyridin-4-yl]acetic acid (50 mg, 0.167 mmol) and (1R,6S)-2,2-difluoro-6- ⁇ [(3R,4S)-3-fluoro-1-isopropylpiperidin-4- yl]oxy ⁇ cyclohexan-1-amine (49.2 mg, 0.167 mmol) in N,N-dimethylformamide (3 mL)
  • Step 3 Preparation of [2-chloro-3-(trifluoromethyl)pyridin-4-yl]acetic acid
  • tert-butyl 2-[2-chloro-3-(trifluoromethyl)pyridin-4-yl]acetate 370 mg, 1.25 mmol
  • methanol 2 mL
  • water 1 mL
  • lithium hydroxide 180 mg, 7.51 mmol
  • Step 4 Preparation of 2-[2-chloro-3-(trifluoromethyl)pyridin-4-yl]-N-[(1R,6S)- 2,2-difluoro-6- ⁇ [(3R,4S)-3-fluoro-1-isopropylpiperidin-4-yl]oxy ⁇ cyclohexyl]acetamide
  • [2-chloro-3-(trifluoromethyl)pyridin-4-yl]acetic acid 190 mg, 0.793 mmol
  • N,N-dimethylformamide 5 mL
  • (1R,6S)-2,2-difluoro-6- ⁇ [(3R,4S)-3-fluoro- 1-isopropylpiperidin-4-yl]oxy ⁇ cyclohexan-1-amine 280 mg, 0.952 mmol
  • HATU 362 mg, 0.952 mmol
  • Step 5 Preparation of 2-(2-(1H-indazol-5-yl)-3-(trifluoromethyl)pyridin-4-yl)-N- ((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide (Compound 76) [00710] To a solution of 2-[2-chloro-3-(trifluoromethyl)pyridin-4-yl]-N-[(1R,6S)-2,2-difluoro- 6- ⁇ [(3R,4S)-3-fluoro-1-isopropylpiperidin-4-yl]oxy ⁇ cyclohexyl]acetamide (190 mg, 0.368 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added 5-(4,4,5,5-tetra
  • Step 2 Preparation of N-[(1R,6S)-6-[(4R)-azepan-4-yloxy]-2,2- difluorocyclohexyl]-4-nitrobenzenesulfonamide
  • tert-butyl (4R)-4- ⁇ [(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy ⁇ azepane-1-carboxylate 300 mg, 0.562 mmol
  • 1,4- dioxane 3 mL
  • 4M hydrogen chloride in 1,4-dioxane (3 mL) at room temperature.
  • Step 3 Preparation of N-[(1R,6S)-2,2-difluoro-6- ⁇ [(4R)-1-isopropylazepan-4- yl]oxy ⁇ cyclohexyl]-4-nitrobenzenesulfonamide
  • N-[(1R,6S)-6-[(4R)-azepan-4-yloxy]-2,2-difluorocyclohexyl]- 4-nitrobenzenesulfonamide (220 mg, 0.508 mmol) in methanol (4 mL) was added acetone (88.4 mg, 1.52 mmol) and the resulting mixture was stirred at room temperature for 30 min.
  • Step 4 Preparation of (1R,6S)-2,2-difluoro-6- ⁇ [(4R)-1-isopropylazepan-4- yl]oxy ⁇ cyclohexan-1-amine
  • N-[(1R,6S)-2,2-difluoro-6- ⁇ [(4R)-1-isopropylazepan-4- yl]oxy ⁇ cyclohexyl]-4-nitrobenzenesulfonamide 180 mg, 0.379 mmol
  • sodium thiophenolate 250 mg, 1.89 mmol
  • Step 5 Preparation of N-((1R,6S)-2,2-difluoro-6-(((R)-1-isopropylazepan-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl)acetamide (Compound 77)
  • (1R,6S)-2,2-difluoro-6- ⁇ [(4R)-1-isopropylazepan-4- yl]oxy ⁇ cyclohexan-1-amine 60 mg, 0.207 mmol
  • [2-(3,5-difluorophenyl)-3- (trifluoromethyl)pyridin-4-yl]acetic acid (32.8 mg, 0.103 mmol) in N,N-dimethylformamide (4 mL) was added HATU (51.1 mg, 0.135 mmol) in portions at room temperature
  • reaction mixture was then cooled to 0 °C and N,N-diisopropylethylamine (40.1 mg, 0.310 mmol) was added dropwise.
  • the resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS.
  • the reaction was quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated.
  • Step 2 Preparation of N-[(1R,6S)-6-[(4S)-azepan-4-yloxy]-2,2- difluorocyclohexyl]-4-nitrobenzenesulfonamide
  • Step 3 Preparation of N-[(1R,6S)-2,2-difluoro-6- ⁇ [(4S)-1-isopropylazepan-4- yl]oxy ⁇ cyclohexyl]-4-nitrobenzenesulfonamide
  • N-[(1R,6S)-6-[(4S)-azepan-4-yloxy]-2,2-difluorocyclohexyl]-4- nitrobenzenesulfonamide 190 mg, 0.438 mmol
  • acetone 255 mg, 4.38 mmol
  • sodium cyanoborohydride 275 mg, 4.38 mmol
  • Step 4 Preparation of (1R,6S)-2,2-difluoro-6- ⁇ [(4S)-1-isopropylazepan-4- yl]oxy ⁇ cyclohexan-1-amine
  • N-[(1R,6S)-2,2-difluoro-6- ⁇ [(4S)-1-isopropylazepan-4- yl]oxy ⁇ cyclohexyl]-4-nitrobenzenesulfonamide (170 mg, 0.357 mmol) in toluene (5 mL) was added sodium thiophenolate (283 mg, 2.14 mmol).
  • Step 5 Preparation of N-((1R,6S)-2,2-difluoro-6-(((S)-1-isopropylazepan-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl)acetamide (Compound 78)
  • [00734] To a solution of [2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl]acetic acid (81.9 mg, 0.258 mmol) and HATU (147 mg, 0.387 mmol) in N,N-dimethylformamide (3 mL) was added (1R,6S)-2,2-difluoro-6- ⁇ [(4S)-1-isopropylazepan-4-yl]oxy ⁇ cyclohexan-1-amine (75 mg, 0.258 mmol) and N,N-d
  • IP1 generated within the cell by OX2R agonism competes with the IP1 analog coupled to a d2 fluorophore (FRET acceptor) for binding to an anti-IP1 monoclonal antibody labeled with Eu cryptated (FRET donor).
  • FRET acceptor d2 fluorophore
  • the measured HTRF-FRET based signal is inversely proportional to the IP1 concentration produced.
  • HTRF- FRET values were measured using a ClarioStar Plus (BMG Labtech) plate reader and the data were expressed as the standard 665nm/620nm ratio.
  • exemplary compounds, characterization data, and orexin 2 activation activity is provided in Table 3. Table 3.

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Abstract

Disclosed are compounds, compositions, and methods useful for preventing or treating a disease which is at least partially mediated by orexin receptor 2.

Description

BIARYL AMIDE-CONTAINING AGONISTS OF OREXIN RECEPTOR TYPE 2 CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of priority from U.S. Provisional Application No. 63/444,057, filed February 8, 2023, and U.S. Provisional Application No. 63/528,113, filed July 21, 2023, which are herein incorporated by reference in their entirety. FIELD OF THE INVENTION [0002] This invention generally relates to compounds that function as agonists of orexin receptor type 2 (Ox2R), particularly biaryl amide-containing compounds thereof, as well as methods of using such compounds for treating conditions or disorders associated with a deficiency in Ox2R signaling, e.g., narcolepsy, idiopathic hypersomnia, hypersomnia, and sleep apnea syndrome. BACKGROUND [0003] Orexins are hypothalamic neuropeptides that are implicated in, for example, sleep/wake control and body weight homeostasis. The peptides act on two G protein-coupled receptors termed Orexin receptor type 1 (Ox1R) and Orexin receptor type 2 (Ox2R). Orexin producing neurons are exclusively localized in the lateral hypothalamic area, but their receptors are expressed in many areas of the brain. [0004] Narcolepsy is a socially debilitating disorder characterized by an inability to properly maintain wakefulness (excessive daytime sleepiness, sleep attacks), and a pathological intrusion of signs of REM sleep into wakefulness (cataplexy, hypnagogic hallucination, sleep paralysis, etc.). Narcolepsy affects an estimated 1 in every 2,000 individuals, and is a non-progressive, life-long condition. A deficiency in orexin/Ox2R signaling causes the sleep disorder narcolepsy in humans, mice, and dogs. A vast majority (>90%) of human narcoleptics lack detectable levels of orexin peptides in the cerebrospinal fluid due to a highly specific (probably autoimmune) degeneration of orexin neurons, indicating that human narcolepsy is an “orexin deficiency syndrome.” [0005] Compounds having Ox2R agonism activity have previously been described (see, e.g., Nagahara, et al., J. Med. Chem., 2015, 58, 7931-37). However, those compounds may possess 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 having improved properties. SUMMARY [0006] One aspect of the invention provides compounds, compositions, and methods useful for preventing or treating conditions modulated by Ox2R, such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy- like symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with dementia with Lewy body. It was surprisingly discovered that the compounds disclosed and claimed herein demonstrate, among other things, high potency and selectivity for OX2R, and improved drug-like properties, such as central nervous system penetration (e.g., as determined by a MDR1-MDCK permeability assay) and a favorable pharmacokinetic profile. [0007] Accordingly, provided herein in some embodiments is a compound having the structure of Formula (IA): , or a deuterated derivative,
Figure imgf000003_0001
thereof; wherein: V and W are independently for each occurrence CH, CF, or N; X is O or absent (i.e., a bond); Y is CH or N; provided that if X is O, then Y is CH; Z is CR3R4 or NR5; R1 is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1- C6)haloalkoxy; R2 is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)fluoroalkoxy, 4- to 7-membered heterocycloalkyl, cyano, or halo; R3 and R4 are independently hydrogen, -OH, (C1-C6)alkyl, (C1-C6)alkoxy, or NRaRb; or R3 and R4 taken together with the carbon atom to which they are attached form a 4- to 7-membered spiro heterocycloalkyl optionally substituted with one, two, three, or four substituents independently selected from the group consisting of (C1-C6)alkyl; Ra and Rb are each independently hydrogen or (C1-C6)alkyl; R5 is H or (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl; wherein (C1-C6)alkyl and (C1-C6)haloalkyl are each optionally substituted with hydroxy, (C1-C6)alkoxy, or (C3-C8)cycloalkyl; A is a cyclohexyl or cyclopentyl ring, also herein referred to as a disubstituted cyclohexyl or disubstituted cyclopentyl not counting the possible R6 substitution on A, or more particularly, a 1,2-disubstituted cyclohexyl or 1,2-disubstituted cyclopentyl; wherein one carbon of the 1,2- disubstituted cyclohexyl or 1,2-disubstituted cyclopentyl is optionally replaced with oxygen; R6 is independently for each occurrence halo, cyano, or oxetanyl; R7 is hydrogen or fluoro; R8 is hydrogen or fluoro; n is 0, 1, or 2; and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; provided that, if A is 1,2-disubstituted cyclohexyl, then m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; or if A is 1,2-disubstituted cyclopentyl, then m is 0, 1, 2, 3, 4, 5, or 6. [0008] Other aspects of the present disclosure provide a pharmaceutical composition comprising a compound of formula (I), or deuterated derivative, or pharmaceutically acceptable salt or prodrug thereof, and at least one pharmaceutically acceptable excipient. [0009] In still other aspects, provided herein is a method for treating or preventing a disease selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy body, hypersomnia syndrome involving daytime hypersomnia (e.g., Kleine-Levin syndrome, major depression accompanied by hypersomnia, dementia with Lewy body, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen's encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cell, extrinsic obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophysial obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, alimentary obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer, impaired consciousness such as coma, side effect or complication caused by anesthesia, sleep disturbance, sleep problem, insomnia, intermittent sleep, night myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorder of shift workers, dyssomnia, sleep terror, depression, major depression, sleepwalking, enuresis, sleep disorder, Alzheimer's sundown syndrome, disease associated with circadian rhythm, fibromyalgia, condition resulting from decrease in sleeping quality, bulimia, obsessive eating disorder, obesity-related diseases, hypertension, diabetes, elevated plasma insulin level/insulin resistance, hyperlipemia, hyperlipidaemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstone, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disease, sudden death, polycystic ovary, craniopharyngioma, Prader Willi syndrome, Froehlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormality, decrease of fecundability, infertility, hypogonadism in men, sexual/reproductive-function dysfunction such as hirsutism in women, fetal defect associated with maternity obesity, gastrointestinal motility disorder such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory disease such as respiratory distress, inflammation such as vascular systemic inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, renal cancer, secondary risk of obesity such as risk of left ventricle hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweat, disease in genitalium/urinary system, disease associated with sexual function or fecundability, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorder such as cerebral deficiency developed after heart bypass surgery or heart transplant, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head injury, periparturient hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorder associated with muscle spasm, delirium, amnestic disorder, age-associated cognitive decline, schizoaffective disorder, paranoia, drug addiction, movement disorder, chronic fatigue syndrome, fatigue, medication-induced parkinsonian syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptom, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, and traumatic brain injury, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or deuterated derivative, or pharmaceutically acceptable salt or prodrug thereof. [0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. [0011] Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims. DETAILED DESCRIPTION Definitions [0012] For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are provided here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. [0013] In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification. [0014] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., they refer to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. [0015] The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when 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); etc. [0016] As used herein in the specification and in the claims, “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” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. [0017] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. 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”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. [0018] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. [0019] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03. [0020] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, 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, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. [0021] “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides 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," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.” Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. [0022] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. [0023] Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the 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% by mole fraction pure relative to the 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% by mole fraction pure. 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% by mole fraction pure. [0024] When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound, or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s), or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention encompasses all of these forms. [0025] Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13C- or 14C-enriched carbon are within the scope of this invention. As used herein, “deuterated derivative(s)” refers to a compound having the same chemical structure as a reference compound, with one or more hydrogen atoms replaced by one or more deuterium atoms, respectively. In some embodiments, the one or more hydrogens replaced by deuterium are part of an alkyl group. In some embodiments, the one or more hydrogens replaced by deuterium are part of a methyl group. In chemical structures, deuterium is typically represented as “D.” [0026] The term “prodrug,” as used herein, encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. Such a transformation can be affected, for example, by hydrolysis in blood or enzymatic transformation of the prodrug form to the parent form in blood or tissue. In some embodiments, the prodrug is converted by an enzymatic activity of the host animal. [0027] A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. Prodrugs of the compounds of the invention may be, for example, amides. Amides that may be utilized as prodrugs in the present invention are phenyl amides, aliphatic (C1-C24) amides, acyloxymethyl amides, ureas, carbamates, and amino acid amides. For example, a compound of the invention that contains an NH group may be acylated at this position in its prodrug form. Other prodrug forms include esters, such as, for example phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. 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 in its entirety herein by reference. In some embodiments, the present invention features a prodrug of any one of the formulas or compounds listed herein. [0028] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non- pyrogenic. Some examples of materials which can serve 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower 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) buffering agents, 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 solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient. [0029] The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). [0030] In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the 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 salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra). [0031] The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule. [0032] A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment. [0033] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). [0034] The term “patient” or “subject” refers to a mammal in need of a particular treatment. The patient is typically human. However, in some embodiments, the patient may be a primate, canine, feline, or equine. [0035] An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain (i.e., linear or unbranched), branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group. [0036] “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched (i.e., linear) carbon chain moiety having the number of carbon atoms specified, or may be up to 30 carbon atoms if not specified. For example, alkyl of 1 to 8 carbon atoms refers to moieties, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and moieties which 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 linear or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C3-C30 for branched chains), and more preferably, 20 or fewer. Alkyl goups may be substituted or unsubstituted. [0037] As used herein, the term “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. [0038] As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one halogen. [0039] As used herein, the term “haloalkoxy” refers to an alkoxy group as defined herein substituted with at least one halogen atom. For example, haloalkoxy groups include fluoroalkoxy groups, such as trifluoromethoxy, difluoromethoxy, and the like. [0040] As used herein, the term “hydroxyalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl. [0041] As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbon atoms, such as 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound, typically on its longest carbon chain. Non-limiting examples of alkylene groups include methylene (-(CH2)-), ethylene (-(CH2CH2)-), n-propylene (-(CH2CH2CH2)-), isopropylene (-(CH2CH(CH3))-), and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents. [0042] "Cycloalkyl" refers to mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 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 may be substituted or unsubstituted. Some examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. [0043] “1,2-Disubstituted cyclohexyl,” as used herein, refers to a cyclohexane ring that contains points of attachment at the 1 and 2 positions of the cyclohexane ring to the rest of the compound. Similarly, “1,2-disubstituted cyclopentyl,” as used herein, refers to a cyclopentane ring that contains points of attachment at the 1 and 2 positions of the cyclopentane ring to the rest of the compound. 1,2-Disubstituted cyclohexyl and 1,2-disubstituted cyclopentyl can also be referred to as 1,2-cyclohexylene and 1,2-cyclopentylene, respectively. [0044] As used herein, the term “halocycloalkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen. [0045] "Cycloheteroalkyl" refers to a cycloalkyl moiety as hereinbefore defined which contains one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure. Cycloheteroalkyl groups may be substituted or unsubstituted. Some examples include piperidinyl, piperazinyl, tetrahydrofuranyl, and tetrahydropyranyl groups. [0046] Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl. [0047] “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s). [0048] “Alkynyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more triple bonds in the moiety. [0049] The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, and aniline groups, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, indazole, quinoline, benzofuran, and like groups. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic. [0050] The term “halo”, “halide”, or “halogen,” as used herein, means halogen, and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo. In a further preferred embodiment, halo is fluoro. [0051] The terms “heterocyclyl” or “heterocyclic group” or “heterocycloalkyl” refer to 3- to 12-membered ring structures, more typically 5- to 12-membered rings, more typically 5- to 10- membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic, and may be saturated, partially unsaturated, 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, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like. [0052] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated 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 non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms, such as nitrogen, may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. [0053] 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. [0054] As used herein, “small molecules” refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da). The small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 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 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da). [0055] In some embodiments, a “small molecule” refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound, with a size on the order of 1 nm. In some embodiments, small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000. [0056] An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence 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 general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments. [0057] The terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter as compared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment. [0058] The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as 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% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10- fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. [0059] As used herein, the term “modulate” includes up-regulation (e.g., activating or enhancing a response) and down-regulation (e.g., inhibiting or deactivating a response). [0060] A “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and/or therapy of various diseases. The radiolabelled pharmaceutical agent, for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source. As contemplated herein, the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule. [0061] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Compounds of the Invention [0062] In some embodiments, provided herein is a compound of Formula (IA): , or a deuterated derivative, thereof; wherein:
Figure imgf000021_0001
V and W are independently for each occurrence CH, CF, or N; X is O or absent; Y is CH or N; provided that if X is O, then Y is CH; Z is CR3R4 or NR5; R1 is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1- C6)haloalkoxy; R2 is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)fluoroalkoxy, 4- to 7-membered heterocycloalkyl, cyano, or halo; R3 and R4 are independently hydrogen, -OH, (C1-C6)alkyl, (C1-C6)alkoxy, or NRaRb; or R3 and R4 taken together with the carbon atom to which they are attached form a 4- to 7-membered spiro heterocycloalkyl optionally substituted with one, two, three, or four substituents independently selected from the group consisting of (C1-C6)alkyl; Ra and Rb are each independently hydrogen or (C1-C6)alkyl; R5 is H or (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl; wherein (C1-C6)alkyl and (C1-C6)haloalkyl are each optionally substituted with hydroxy, (C1-C6)alkoxy, or (C3-C8)cycloalkyl; A is a cyclohexyl or cyclopentyl ring, also herein referred to as a disubstituted cyclohexyl or disubstituted cyclopentyl not counting the possible R6 substitution on A, or more particularly, A is a 1,2-disubstituted cyclohexyl or 1,2-disubstituted cyclopentyl; wherein one carbon of the 1,2- disubstituted cyclohexyl or 1,2-disubstituted cyclopentyl is optionally replaced with oxygen; R6 is independently for each occurrence halo, cyano, or oxetanyl; R7 is hydrogen or fluoro; R8 is hydrogen or fluoro; n is 0, 1, or 2; and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; provided that, if A is 1,2-disubstituted cyclohexyl, then m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; or if A is 1,2-disubstituted cyclopentyl, then m is 0, 1, 2, 3, 4, 5, or 6. [0063] In particular embodiments, the compound of Formula (IA) is a compound of the Formula (IA-1):
(IA-1) or a deuterated derivative, a pharmaceutically acceptable salt, or a prodrug thereof; wherein R1, R2, R6, R7, R8, V, W, X, Y, Z, n, and m are as defined anywhere above. [0064] In more particular embodiments, the compound of Formula (IA-1) is a compound of the Formula (IA-2) or (IA-3): or or a
Figure imgf000023_0001
thereof; wherein R1, R2, R6, R7, R8, V, W, X, Y, Z, and n are as defined anywhere above. [0065] In further particular embodiments, any of the compounds of Formulas (IA-1), (IA-2), or (IA-3) may more particularly be a stereoisomeric version (including enriched or isolated stereoisomers) of any of the following Formulas (IA-1’), (IA-2’), or (IA-3’), such as follows: or or a
Figure imgf000024_0001
thereof; wherein R1, R2, R6, R7, R8, V, W, X, Y, Z, and n are as defined anywhere above. [0066] In other embodiments, provided herein is a compound of Formula (IB): B), or a deuterated derivative, rodrug thereof; wherein: V and W are independently for each occurrence CH, CF, or N; X is O or absent; Y is CH or N; provided that if X is O, then Y is CH; Z is CR3R4 or NR5; R1 is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1- C6)haloalkoxy; R2 is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)fluoroalkoxy, 4- to 7-membered heterocycloalkyl, cyano, or halo; R3 and R4 are independently hydrogen, -OH, (C1-C6)alkyl, (C1-C6)alkoxy, or NRaRb; or R3 and R4 taken together with the carbon atom to which they are attached form a 4- to 7-membered spiro heterocycloalkyl optionally substituted with one, two, three, or four independently selected instances of (C1-C6)alkyl; Ra and Rb are each independently hydrogen or (C1-C6)alkyl; R5 is H or (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein (C1-C6)alkyl and (C1-C6)haloalkyl are each optionally substituted with hydroxy, (C1-C6)alkoxy, or (C3-C8)cycloalkyl; A is a cyclohexyl or cyclopentyl ring, also herein referred to as a disubstituted cyclohexyl or disubstituted cyclopentyl not counting the possible R6 substitution on A, or more particularly, A is a 1,2-disubstituted cyclohexyl or 1,2-disubstituted cyclopentyl, wherein one carbon atom of the 1,2-disubstituted cyclohexyl or 1,2-disubstituted cyclopentyl is optionally replaced with an oxygen atom; R6 is independently for each occurrence halo, cyano, or oxetanyl; R7 is hydrogen or fluoro; n is 0, 1, or 2; and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; provided that, if A is 1,2-disubstituted cyclohexyl, then m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; or if A is 1,2-disubstituted cyclopentyl, then m is 0, 1, 2, 3, 4, 5, or 6. [0067] In certain embodiments, R1 is 5-membered heteroaryl, 6-membered heteroaryl, 8- membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl; each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy and (C1- C6)hydroxyalkyl. [0068] In certain embodiments, R1 is 5-membered heteroaryl, 6-membered heteroaryl, 8- membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, and (C1-C6)alkoxy. In more particular embodiments, R1 is pyridinyl, isoxazolyl, thiazolyl, pyrazolyl, indazolyl, 2-oxoindolin- 5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl), or benzo[d]imidazolyl; each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy and (C1-C6)hydroxyalkyl, and in further particular embodiments, R1 is pyridinyl, isoxazolyl, thiazolyl, pyrazolyl, or indazolyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, and (C1-C6)alkoxy. In still more particular embodiments, R1 is 3-pyridinyl, 5-isoxazolyl, 2-thiazolyl, 1-H-4-pyrazolyl, 1-H-5-indazolyl, 2-oxoindolin-5-yl, 2- oxo-2,3-dihydrobenzo[d]oxazol-6-yl), or 1H-benzo[d]imidazol-5-yl; each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, and (C1-C6)alkoxy. In yet more particular embodiments, R1 is 3-pyridinyl, 5-isoxazolyl, 2-thiazolyl, 1-H-4-pyrazolyl, or 1-H-5-indazolyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, and (C1-C6)alkoxy. [0069] In some embodiments, R1 is optionally substituted with one, two, three, or four substituents independently selected from chloro, fluoro, methoxy, hydroxymethyl, and methyl. In some other embodiments, R1 is optionally substituted with one, two, three, or four substituents independently selected from chloro, fluoro, cyano, methoxy, and methyl. [0070] In some embodiments, R1 is phenyl optionally substituted with one, two, three, or four substituents independently selected from chloro, fluoro, methoxy, methyl, and hydroxymethyl . In some other embodiments, R1 is phenyl optionally substituted with one, two, three, or four substituents independently selected from chloro, fluoro, methoxy, and methyl. [0071] In other embodiments, R1 is phenyl optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, and cyano. [0072] In still other embodiments, R1 is phenyl substituted with one, two, three, or four substituents independently selected from chloro, fluoro, cyano, and methoxy. [0073] In some embodiments, R1 is phenyl, 3,5-difluorophenyl, 2,6-difluoro, 2-chlorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl, 3-cyano-5-fluorophenyl, 3-methoxyphenyl, or 3-fluoro-5- hyroxyphenyl, while in even more particular R1 is phenyl, 3,5-difluorophenyl, 2,6-difluoro, 2- chlorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl, 3-cyano-5-fluorophenyl, or 3-methoxyphenyl. [0074] In some embodiments, the compound has the structure of Formula (IIA): ), or a de ptable salt, or a prodrug thereof. [0075] In particular embodiments, the compounds of Formula (IIA) have the structure of Formula (IIA-1) or Formula (IIA-2), as follows:
Figure imgf000028_0002
or a a salt, or a prodrug of any of these. [0076] In more particular embodiments, the compound has the structure of Formula (IIB): ,
Figure imgf000028_0001
or a deuterated a or a thereof. [0077] In more particular embodiments, the compound has the structure of Formula (IIB-1) or Formula (IIB-2), as follows: or or a deuterated
Figure imgf000029_0001
thereof. [0078] In other embodiments, the compound has the structure of Formula (IIC) , or a deuterated
Figure imgf000029_0002
thereof. [0079] In more particular embodiments, the compound has the structure of Formula (IID): ,
Figure imgf000029_0003
or a deuterated a or a thereof. [0080] In some embodiments, for any of the above formulas, R2 is hydrogen. [0081] In other embodiments, for any of the above formulas, R2 is fluoro. In other embodiments, for any of the above formulas, R2 is chloro. [0082] In still other embodiments, for any of the above formulas, R2 is (C1-C3)alkyl, such as methyl. [0083] In other embodiments, for any of the above formulas, R2 is (C1-C3)alkoxy, such as methoxy. [0084] In yet other embodiments, for any of the above formulas, R2 is (C1-C6)fluoroalkoxy, such as trifluoromethoxy. [0085] In other embodiments, for any of the above formulas, R2 is (C3-C6)cycloalkyl, such as cyclopropyl. [0086] In other embodiments, for any of the above formulas, R2 is cyano. [0087] In some embodiments, for any of the above formulas, R2 is (C1-C3)fluoroalkyl, such as trifluoromethyl or difluoromethyl. [0088] In some embodiments, for any of the above formulas, V is CH. In other embodiments, for any of the above formulas, V is CF. In still other embodiments, for any of the above formulas, V is N. [0089] In some embodiments, W is CH. In other embodiments, W is CF, in still other embodiments, W is N. [0090] In some embodiments, for any of the above formulas, X is absent (i.e., is a bond). [0091] In some embodiments, for any of the above formulas, Y is CH, while in other embodiments, Y is N. [0092] In other embodiments, for any of the above formulas, X is O and Y is CH. [0093] In some embodiments, for any of the above formulas, Z is CR3R4. [0094] In some embodiments, for any of the above formulas, R3 is hydrogen. [0095] In some embodiments, for any of the above formulas, R4 is (C1-C3)alkoxy. In particular embodiments, for any of the above formulas, R4 is isopropyloxy. [0096] In other embodiments, for any of the above formulas, R4 is NRaRb. [0097] In some embodiments, for any of the above formulas, Ra and Rb are each (C1-C3)alkyl. In certain embodiments, for any of the above formulas, Ra and Rb are each methyl. [0098] In some embodiments, for any of the above formulas, R3 and R4 together with the carbon atom to which they are attached form a 4- or 5-membered spiro heterocycloalkyl optionally substituted with one, two, three, or four independently selected instances of (C1- C3)alkyl. [0099] In some embodiments, for any of the above formulas, Z is NR5. [00100] In some embodiments, for any of the above formulas, R5 is (C1-C3)alkyl optionally substituted with (C3-C8)cycloalkyl. In more particular embodiments, for any of the above formulas, R5 is cyclopropylmethyl. In other embodiments, for any of the above formulas, R5 is isopropyl. [00101] In other embodiments, for any of the above formulas, R5 is (C1-C3)fluoroalkyl optionally substituted with (C3-C8)cycloalkyl. In more particular embodiments, for any of the above formulas, R5 is 1-fluorocyclopropylmethyl. [00102] In some embodiments, for any of the above formulas, R5 is (C3-C8)cycloalkyl. In more particular embodiments, for any of the above formulas, R5 is cyclobutyl and in other particular embodiments, R5 is cyclopentyl. [00103] In some embodiments, for any of the above formulas, n is 0, while in other embodiments, n is 1. [00104] In some embodiments, for any of the above formulas, m is 2. [00105] In some embodiments, for any of the above formulas, R6 is fluoro. [00106] In certain embodiments, for any of the above formulas, R6 is fluoro and m is 2. [00107] In certain embodiments, for any of the above formulas, –N(H)-A-X- is: . [00108] In some embodiments, for any of the above formulas, R7 is hydrogen, while in other embodiments, R7 is fluoro. [00109] In some embodiments, for any of the above formulas, R8 is hydrogen. In certain preferred embodiments, .
Figure imgf000032_0001
is fluoro. [00111] In some embodiments, a compound is selected from compounds in Table 1: Table 1. Exemplary compounds of the present disclosure. Cmpd # Structure Cmpd # Structure
Figure imgf000032_0002
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
In more particular embodiments, a compound is selected from compounds in Table 2: Table 2. Exemplary compounds of the present disclosure. Cmpd # Structure IUPAC - - -
Figure imgf000038_0002
2-(2'-hlr-2-fl r-[11'-bihnl]- - - - -
Figure imgf000039_0001
N-((1R,6S)-2,2-difluoro-6-(4- - - - -
Figure imgf000040_0001
2-(2-cyclopropyl-3'5'-difluoro-[11'- - -
Figure imgf000041_0001
N-((1R,6S)-2,2-difluoro-6-(4- - - - - - -
Figure imgf000042_0001
2-(2-cyclopropyl-3',5'-difluoro-[1,1'- bihnl]-3-l)-N-((1R6S)-22- - n- - - - - - -
Figure imgf000043_0001
N-((1R,6S)-6-((1- cyclopentylpiperidin-4-yl)oxy)-2,2- - o- - - -
Figure imgf000044_0001
2-(3',5'-difluoro-2-(trifluoromethoxy)- - - - - - - - - - - -
Figure imgf000045_0001
2-(2-cyclopropyl-3'-methoxy-[1,1'- biphenyl]-3-yl)-N-((1R,6S)-2,2- - - - - - - 6-
Figure imgf000046_0001
2-(2-cyclopropyl-3-(1H-indazol-5- 6- - or deu
Figure imgf000047_0001
terate ervatve, or p armaceutca y accepta e sat or pro rug t ereo. [00112] In some embodiments, a compound is selected from , or deuterated derivative, or pharmaceutically acceptable odiments, the compound is a deuterated derivative, or pharmaceutically acceptable the compound is
Figure imgf000048_0001
a deuterated derivative, or pharmaceutically acceptable salt
Figure imgf000048_0002
or prodrug thereof. In some embodiments, the or a deuterated derivative, or pharmaceutically
Figure imgf000048_0003
or
Figure imgf000048_0004
is salt or prodrug thereof. In some embodiments, the compoun or a deuterated derivative, or pharmaceutically acceptable salt o embodiments, the compound a deuterated derivative, or pharmaceutically acceptable
Figure imgf000049_0001
embodiments, the compound is a deuterated derivative, or pharmaceutically acceptable salt
Figure imgf000049_0002
the compound is a deuterated derivative, or pharmaceutically
Figure imgf000049_0003
embodiments, the compound is a deuterated derivative, or pharmaceutically acceptable
Figure imgf000049_0004
[00113] 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, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13C- or 14C- enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. For example, in the case of variable R1, the (C1-C4)alkyl or the -O-(C1- C4)alkyl can be suitably deuterated (e.g., -CD3, or -OCD3, respectively). [00114] Any compound of the invention can also be radiolabeled for the preparation of a radiopharmaceutical agent. [00115] For the avoidance of doubt, this disclosure is directed to compounds disclosed herein (e.g., Formulas IA, IA-1, IA-2, IA-3, IA-1’, IA-2’, IA-3’,IIA, IIA-1, IIA-2, IB, IIB,, IIB-1, IIB-2, IIC, IID) and the compounds described in Tables 1 and 2), deuterated derivatives of those compounds, and pharmaceutically acceptable salts or prodrugs thereof. In other embodiments, the disclosure is directed to non-salt forms of the compounds disclosed herein (e.g., Formulas IA, IA-1, IA-2, IA-3, IA-1’, IA-2’, IA-3’,IIA, IIA-1, IIA-2, IB, IIB,, IIB-1, IIB-2, IIC, IID) and the compounds described in Tables 1 and 2). [00116] Methods of Treatment [00117] One aspect of the invention provides compounds, compositions, and methods useful for preventing or treating a disease which is at least partially mediated by orexin receptor 2. In certain embodiment, the compounds act as agonists of orexin receptor 2. [00118] Another aspect of the invention relates to methods of preventing or treating a disease selected from the group consisting of narcolepsy (e.g., narcolepsy type 1 and/or narcolepsy type 2), idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy body, hypersomnia syndrome involving daytime hypersomnia (e.g. Kleine-Levin syndrome, major depression accompanied by hypersomnia, dementia with Lewy body, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen's encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto encephalopathy), coma, loss of consciousness, obesity (e.g. malignant mast cell, extrinsic obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophysial obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, alimentary obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer, impaired consciousness such as coma, side effect or complication caused by anesthesia, sleep disturbance, sleep problem, insomnia, intermittent sleep, night myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorder of shift workers, dyssomnia, sleep terror, depression, major depression, sleepwalking, enuresis, sleep disorder, Alzheimer's sundown syndrome, disease associated with circadian rhythm, fibromyalgia, condition resulting from decrease in sleeping quality, bulimia, obsessive eating disorder, obesity-related diseases, hypertension, diabetes, elevated plasma insulin level/insulin resistance, hyperlipemia, hyperlipidaemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstone, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disease, sudden death, polycystic ovary, craniopharyngioma, Prader Willi syndrome, Froehlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormality, decrease of fecundability, infertility, hypogonadism in men, sexual/reproductive-function dysfunction such as hirsutism in women, fetal defect associated with maternity obesity, gastrointestinal motility disorder such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory disease such as respiratory distress, inflammation such as vascular systemic inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, renal cancer, secondary risk of obesity such as risk of left ventricle hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweat, disease in genitalium/urinary system, disease associated with sexual function or fecundability, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorder such as cerebral deficiency developed after heart bypass surgery or heart transplant, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head injury, periparturient hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorder associated with muscle spasm, delirium, amnestic disorder, age- associated cognitive decline, schizoaffective disorder, paranoia, drug addiction, movement disorder, chronic fatigue syndrome, fatigue, medication-induced parkinsonian syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptom, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, and traumatic brain injury, in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), (IIC), (IID) or any sub-formula thereof or deuterated derivative, or pharmaceutically acceptable salt or prodrug thereof. [00119] In certain embodiments, the invention relates to methods of treating or preventing a disease selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with dementia with Lewy body in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (IA), (IB), (IIA), (IIB), (IIC), (IID) or any sub-formula thereof or deuterated derivative, or pharmaceutically acceptable salt or prodrug thereof. [00120] In certain embodiments, the disease being treated or prevented is narcolepsy (e.g., narcolepsy type 1 and/or narcolepsy type 2), and a compound of any of the above formulas is administered. In particular embodiments, the disease being treated or prevented is narcolepsy type 1. [00121] In certain embodiments, the disease being treated or prevented is hypersomnolence, and a compound of any of the above formulas is administered. [00122] In certain embodiments, the disease being treated or prevented is idiopathic hypersomnia, and a compound of any of the above formulas is administered. [00123] In certain embodiments, the disease being treated or prevented is hypersomnia, and a compound of any of the above formulas is administered. [00124] In certain embodiments, the disease being treated or prevented is sleep apnea syndrome, and a compound of any of the above formulas is administered. [00125] In certain embodiments, the disease being treated or prevented is narcolepsy syndrome involving narcolepsy-like symptoms, and a compound of any of the above formulas is administered. [00126] In certain embodiments, the disease being treated or prevented is hypersomnia associated with Parkinson’s disease, and a compound of any of the above formulas is administered. [00127] In certain embodiments, the disease being treated or prevented is Parkinson's disease, and a compound of any of the above formulas is administered. [00128] In certain embodiments, the disease being treated or prevented is traumatic brain injury, and a compound of any of the above formulas is administered. [00129] In certain embodiments, the disease being treated or prevented is hypersomnia associated with dementia with Lewy body, and a compound of any of the above formulas is administered. [00130] In some embodiments, the compound or deuterated derivative, or pharmaceutically acceptable salt or prodrug thereof, is administered orally to the subject. In certain embodiments, the compound is administered orally to the subject. [00131] In some embodiments, the compound or deuterated derivative, or pharmaceutically acceptable salt or prodrug thereof, is administered parenterally to the subject. In certain embodiments, the compound is administered parenterally to the subject. [00132] In certain embodiments, any one or more of the above-mentioned diseases is prevented. In other embodiments, any one or more of the above-mentioned diseases is treated. [00133] In some embodiments, the compounds disclosed herein (e.g., Formulas IA, IA-1, IA-2, IA-3, IA-1’, IA-2’, IA-3’,IIA, IIA-1, IIA-2, IB, IIB,, IIB-1, IIB-2, IIC, IID) and the compounds described in Tables 1 and 2), deuterated derivatives of those compounds, and pharmaceutically acceptable salts or prodrugs thereof, modulate orexin 2 receptor in the subject. In other embodiments, the compounds disclosed herein (e.g., Formulas IA, IA-1, IA-2, IA-3, IA-1’, IA- 2’, IA-3’,IIA, IIA-1, IIA-2, IB, IIB, IIB-1, IIB-2, IIC, IID) and the compounds described in Tables 1 and 2), deuterated derivatives of those compounds, and pharmaceutically acceptable salts or prodrugs thereof, activates orexin 2 receptor in the subject. In certain embodiments, the compounds of any of the foregoing formulas activate orexin receptor 2 in the subject. Pharmaceutical Compositions, Routes of Administration, and Dosing [00134] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the invention, e.g., a compound of Formula (IA), (IB), (IIA), (IIB), (IIC), (IID), or any sub-formula thereof, and a pharmaceutically acceptable carrier. [00135] In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of any of the disclosed embodiments, and a pharmaceutically acceptable carrier. [00136] In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier. [00137] Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents. [00138] As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and/or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein. [00139] In certain embodiments, intravenous administration of a compound may typically be from 0.1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 0.1 mg/kg/day to 2 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 0.5 mg/kg/day to 5 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 1 mg/kg/day to 10 mg/kg/day. [00140] Generally, daily oral doses of a compound will be, for human subjects, from about 0.01 milligrams/kg per day to 1000 milligrams/kg per day. Oral doses in the range of 0.5 to 50 milligrams/kg, in one or more administrations per day, may yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound. [00141] For any compound described herein, the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, 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 potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan. [00142] The formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. [00143] For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical. [00144] For intravenous and other parenteral routes of administration, a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration. [00145] For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers. [00146] Also specifically contemplated are oral dosage forms of the above component or components. The component or components may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer- Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable. [00147] For the component (or derivative) the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine. [00148] A coating impermeable to at least pH 5.0 is essential may facilitate full gastric resistance. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films. [00149] A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used. [00150] The therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression. [00151] Colorants and flavoring agents may all be included. For example, the compound of the invention (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents. [00152] One may dilute or increase the volume of the therapeutic with an inert material. These diluents could include carbohydrates, especially 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. [00153] Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants. [00154] Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic. [00155] An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000. [00156] Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate. [00157] To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non- ionic detergents that could be included in the formulation as surfactants 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 ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios. [00158] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration. [00159] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. [00160] For topical administration, the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration. [00161] For administration by inhalation, compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. [00162] Also contemplated herein is pulmonary delivery of the compounds disclosed herein (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. 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) (α-1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1-proteinase); 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. Pat. No. 5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No. 5,451,569 (incorporated by reference), issued Sep. 19, 1995 to Wong et al. [00163] Contemplated for use in the practice of this invention are mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art. [00164] Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass. [00165] All such devices require the use of formulations suitable for the dispensing of the compounds of the invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, 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. Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed. [00166] Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol. [00167] Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant. [00168] Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing a compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers (µm), most preferably 0.5 to 5 µm, for most effective delivery to the deep lung. [00169] Nasal delivery of a pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran. [00170] For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In one embodiment, the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available. [00171] Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug. [00172] The compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi- dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. [00173] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate 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 may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [00174] Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. [00175] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. [00176] In addition to the formulations described above, a compound may also be formulated as a depot preparation. Such long-acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. [00177] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. [00178] Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990). [00179] The compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in medicine the salts or cocrystals should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts or cocrystals may conveniently be used to prepare pharmaceutically acceptable salts or cocrystals thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group. [00180] Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (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). [00181] Pharmaceutical compositions of the invention contain an effective amount of a compound as described herein and optionally therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency. [00182] The therapeutic agent(s), including specifically but not limited to a compound of the invention, may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state. The particles may be of virtually any shape. [00183] Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate). [00184] The therapeutic agent(s) may be contained in controlled release systems. 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 are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. 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 there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.” [00185] Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above. [00186] It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention. EXAMPLES [00187] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. [00188] Synthesis of Intermediate 1: (1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexan-1-amine [00189] Scheme 1
Figure imgf000067_0001
nitrobenzenesulfonamide [00191] To a stirred solution of (1S,6R)-6-amino-2,2-difluorocyclohexan-1-ol (5 g, 33.1 mmol) and 2-nitrobenzenesulfonyl chloride (14.7 g, 66.2 mmol) in tetrahydrofuran (50 mL) was added sodium bicarbonate (16.7 g, 198 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature under, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to afford the title compound as a yellow oil (10 g, 89.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C12H14F2N2O5S: 337.06, found 337.10. [00192] Step 2: Preparation of (1S,6R)-2,2-difluoro-6-(4- nitrobenzenesulfonamido)cyclohexyl methanesulfonate [00193] To a stirred solution of N-[(1R,2S)-3,3-difluoro-2-hydroxycyclohexyl]-4- nitrobenzenesulfonamide (6 g, 17.8 mmol) and triethylamine (3.61 g, 35.7 mmol) in tetrahydrofuran (60 mL) was added methanesulfonyl chloride (2.04 g, 17.8 mmol) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to afford the title compound as a yellow oil (6 g, 81.2% yield). LCMS (ESI): m/z [M+H]+ calcd for C13H16F2N2O7S2: 415.04, found 415.10. [00194] Step 3: Preparation of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane [00195] To a stirred solution of (1S,6R)-2,2-difluoro-6-(4-nitrobenzenesulfonamido)cyclohexyl methanesulfonate (9.2 g, 22.2 mmol) in acetonitrile (100 mL) was added potassium carbonate (9.27 g, 66.6 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at 80 °C, at which point the reaction was judged complete by LCMS. After cooling to room temperature, the reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to afford the title compound as a yellow oil (5 g, 70.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C12H12F2N2O4S: 319.05, found 319.10. [00196] Step 4: Preparation of N-[(1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl]-4-nitrobenzenesulfonamide [00197] To a stirred solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (4 g, 12.6 mmol) in toluene (30 mL) were added 1-isopropylpiperazine (3.22 g, 25.1 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at 110 °C, at which point the reaction was judged complete by LCMS. After cooling to room temperature, the reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to afford the title compound as a yellow solid (4 g, 71.3% yield). LCMS (ESI): m/z [M+H]+ calcd for C19H28F2N4O4S: 447.18, found 447.10. [00198] Step 5: Preparation of (1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexan-1-amine (Intermediate 1) [00199] To a stirred solution of N-[(1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl]-4-nitrobenzenesulfonamide (4 g, 8.96 mmol) in toluene (30 mL) was added sodium benzenethiolate (5.92 g, 44.8 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at 100 °C, at which point the reaction was judged complete by LCMS. After cooling to room temperature, the reaction was quenched with water (50 mL). The resulting mixture was extracted with dichloromethane (3 x 100 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (5:1 dichloromethane/methanol) to afford the title compound as a yellow solid (2 g, 85.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C13H25F2N3: 2612.21, found 262.10. [00200] Synthesis of Intermediate 2: (1R,6S)-2,2-difluoro-6-[(1-isopropylpiperidin-4- yl)oxy]cyclohexan-1-amine [00201] Scheme 2 yl)oxy]cyclohexyl]-4-nitrobenzenesulfonamide [00203] To a solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (800 mg, 2.51 mmol) in N-methyl-2-pyrrolidone (0.8 mL) was added 1-isopropylpiperidin-4-ol (720 mg, 5.03 mmol). The reaction was stirred at 150 °C for 2 h. The reaction was then quenched with water (40 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow solid (900 mg, 77.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C20H29F2N3O5S: 462.18, found 462.25. [00204] Step 2: Preparation of (1R,6S)-2,2-difluoro-6-[(1-isopropylpiperidin-4- yl)oxy]cyclohexan-1-amine (Intermediate 2) [00205] To a solution of N-[(1R,6S)-2,2-difluoro-6-[(1-isopropylpiperidin-4- yl)oxy]cyclohexyl]-4-nitrobenzenesulfonamide (800 mg, 1.73 mmol) in toluene (15 mL) was added sodium benzenethiolate (1.37 g, 10.4 mmol). The reaction was stirred at 110 °C for 2 h. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-50% methanol/dichloromethane) to provide the title compound as a yellow solid (400 mg, 83.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C14H26F2N2O: 277.20, found 277.25. [00206] Synthesis of Compound 1: N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide [00209] To a solution of methyl 2-(3-bromo-2-fluorophenyl)acetate (3 g, 12.1 mmol) in dioxane (20 mL) and water (2 mL) was added 3,5-difluorophenylboronic acid (1.92 g, 12.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.89 g, 1.21 mmol) and potassium carbonate (5.03 g, 36.4 mmol) in portions at room temperature. The reaction was stirred at 90 °C for 2 h under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (3 g, 83.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H11F3O2: 281.07, found 281.05. [00210] Step 2: Preparation of {2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}acetic acid [00211] To a solution of methyl 2-{2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}acetate (3 g, 10.7 mmol) in tetrahydrofuran (7 mL), methanol (7 mL) and water (7 mL) was added lithium hydroxide (1.28 g, 53.5 mmol). The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was acidified to pH = 4 with 2 N hydrochloric acid and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide the title compound which was used without further purification (1.6 g, 53.3% yield). LCMS (ESI): m/z [M-H]- calcd for C14H9F3O2: 265.06, found 265.00. [00212] Step 3: Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 1) [00213] To a solution of {2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}acetic acid (350 mg, 1.32 mmol) in N,N-dimethylformamide (10 mL) was added Intermediate 1 (343 mg, 1.32 mmol) and HATU (650 mg, 1.71 mmol). Then N,N-diisopropylethylamine (765 mg, 5.92 mmol) was added at 0 °C. The reaction was stirred at room temperature for 1 h, at which point the reaction was judged complete by LCMS. The reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a Xselect CSH Prep Fluoro-Phenyl 30 mm x 250 mm x 5 μm column (2-30% acetonitrile/water with 0.1% formic acid) to afford the title compound as a light-yellow solid (211.5 mg, 31.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C27H32F5N3O: 510.25, found 510.05. 1H NMR (300 MHz, Acetonitrile-d3) δ 8.30 (s, 1H), 7.29 – 7.45 (m, 2H), 7.09 – 7.27 (m, 3H), 6.85 – 6.99 (m, 1H), 6.48 – 6.70 (m, 1H), 4.02 – 4.28 (m, 1H), 3.52 – 3.75 (m, 2H), 2.71 – 2.96 (m, 3H), 2.68 (s, 3H), 2.42 – 2.55 (m, 3H), 1.98 – 2.16 (m, 1H), 1.50 – 1.80 (m, 3H), 1.37 – 1.10 (m, 2H), 0.90 – 1.09 (m, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -96.60, -111.48, -112.81, -122.82. [00214] Compound 2: N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)-2- (2-fluoro-[1,1'-biphenyl]-3-yl)acetamide [00215] The title compound 1. LCMS (ESI): m/z [M+H]+
Figure imgf000073_0001
calcd for C27H34F3N3O: 474.27, found 474.30. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.58 – 7.70 (m, 2H), 7.50 – 7.60 (M, 2H), 7.35 – 7.50 (m, 3H), 7.20 – 7.35 (m, 1H), 6.35 – 6.70 (d, 1H), 4.20 – 4.50 (m, 1H), 3.60 – 3.81 (m, 2H), 2.50 – 2.73 (m, 4H), 2.23 – 2.43 (m, 6H), 1.70 – 1.90 (m, 3H), 1.30 – 1.45 (m, 2H), 0.90 – 1.00 (m, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -96.66, - 113.00, -123.55. [00216] Compound 3: 2-(2'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)-2,2-difluoro- 6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide [00217] The title compound
Figure imgf000073_0002
1. LCMS (ESI): m/z [M+H]+ calcd for C27H33ClF3N3O: 208.23, found 208.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.53 – 7.65 (m, 1H), 7.37 – 7.52 (m, 4H), 7.27 – 7.36 (m, 2H), 6.31 – 6.71 (d, 1H), 4.10 – 4.40 (m, 1H), 3.60 – 3.80 (m, 2H), 2.60 – 2.72 (m, 2H), 2.50 – 2.60 (m, 2H), 2.30 – 2.50 (m, 6H), 1.75 – 1.98 (m, 4H), 1.30 – 1.50 (m, 2H), 0.95 – 1.02 (m, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ - 96.66, -113.05, -119.60. [00218] Preparation of Compound 4: N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(3',5'-difluoro-[1,1'-biphenyl]-3-yl)acetamide N [00219] To a solution of acid (68.4 mg, 0.276 mmol)
Figure imgf000074_0001
in N,N-dimethylformamide (4 mL) was added Intermediate 1 (60 mg, 0.230 mmol), HATU (131 mg, 0.345 mmol) and N,N-diisopropylethylamine (89 mg, 0.690 mmol). The reaction was stirred for 1 h at room temperature. The reaction mixture was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Prep OBD C18 Column 150 mm x 30 mm x 5 μm column (49-73% acetonitrile/water with 10 mM ammonium formate) to afford the title compound as white solid (35.7 mg, 31.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C27H33F4N3O: 492.26, found 492.20.1H NMR (300 MHz, DMSO-d6) δ 8.09 (d, J = 9.5 Hz, 1H), 7.69 (s, 1H), 7.56 – 7.64 (m, 1H) - 7.46 (m, 4H), 7.17 – 7.31 (m, 1H), 4.10 – 4.31 (m, 2H), 3.45 – 3.73 (m, 2H), 2.46 – 2.54 (m, 1H), 2.13 – 2.19 (m, 4H), 2.03 – 2.09 (m, 5H), 1.74 – 1.80 (m, 3H), 1.21 – 1.32 (m, 3H), 0.76 – 0.85 (m, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -94.91, -95.75, -109.58, - 109.96, -110.80, -221.05. [00220] Compound 5: 2-([1,1'-biphenyl]-3-yl)-N-((1R,6S)-2,2-difluoro-6-(4- isopropylpiperazin-1-yl)cyclohexyl)acetamide
[00221] The title compound was prepared similarly to Compound 4. LCMS (ESI): m/z [M+H]+ calcd for C27H35F2N3O: 456.28, found 456.30. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.59 - 7.71 (m, 3H), 7.32 - 7.42 (m, 3H), 7.42 - 7.59 (m, 3H), 6.33 - 6.62 (m,1H), 4.15 - 4.32 (m,1H), 3.53 - 3.70 (m, 2H), 2.47 - 2.66 (m, 3H), 2.27 - 2.45 (m, 5H), 2.02 - 2.17 (m, 3H), 1.63 - 1.93 (m, 3H), 1.28 - 1.48 (m, 2H), 0.76 - 0.98 (m, 6H).19F NMR (282 MHz, Acetonitrile-d3) δ -96.59, -112.88. [00222] Synthesis of Compound 6: 2-(2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide
Figure imgf000075_0001
[00225] To a stirred mixture of (3-bromo-2-chlorophenyl)acetic acid (800 mg, 3.21 mmol) in dimethoxyethane (8 mL) and water (2 mL) was added 3,5-difluorophenylboronic acid (608 mg, 3.85 mmol), sodium bicarbonate (673 mg, 8.02 mmol) and bis(triphenylphosphine)palladium(II) chloride (225 mg, 0.321 mmol) in portions at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C, at which point the reaction was judged complete by LCMS. The mixture was diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate) to provide the title compound as a white solid (100 mg, 11% yield). [00226] Step 2: Preparation of 2-(2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 6) [00227] To a stirred mixture of {2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl}acetic acid (82 mg, 0.290 mmol) and Intermediate 1 (50.6 mg, 0.193 mmol) in N,N-dimethylformamide (2 mL) was added HATU (95.6 mg, 0.251 mmol) and N,N-diisopropylethylamine (112 mg, 0.870 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a X Bridge Prep OBD C18150 mm x 30 mm x 5μm column (45-66% acetonitrile/water with 10 mM ammonium bicarbonate) to afford the title as a white solid compound (21.0 mg, 20.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C27H32ClF4N3O: 526.22, found 526.10.1H NMR (300 MHz, Acetonitrile-d3) δ 7.45 – 7.54 (m, 1H), 7.35 – 7.44 (m, 1H), 7.27 – 7.33 , 6.96 – 7.14 (m, 3H), 6.56 (d, J = 9.6 Hz, 1H), 4.13 – 4.40 (m, 1H), 3.81 (d, J = 3.1 Hz, 2H), 2.49 – 2.69 (m, 4H), 2.33 – 2.47 (m, 6H), 2.25 (s, 1H), 1.76 – 1.92 (m, 3H), 1.26 – 1.44 (m, 2H), 0.92 – 1.00 (m, 6H).19F NMR (282 MHz, Acetonitrile-d3) δ -96.54, - 111.88, -113.36. [00228] Synthesis of Compound 7: N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,6-difluoro-[1,1'-biphenyl]-3-yl)acetamide [00229] Scheme 5
Figure imgf000076_0001
[00231] To a stirred mixture of (3-chloro-2,4-difluorophenyl)acetic acid (600 mg, 2.91 mmol) in tetrahydrofuran (8 mL) and water (2 mL) was added phenyl boronic acid (531 mg, 4.36 mmol), potassium phosphate tribasic (1.85 g, 8.72 mmol), palladium(II) acetate (65.2 mg, 0.290 mmol) and SPhos (238 mg, 0.581 mmol) in portions at 25 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C, at which point the reaction was judged complete by LCMS. The mixture was diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate) to afford the title compound as a white solid (300 mg, 41.6% yield). [00232] Step 2: Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,6-difluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 7) [00233] To a stirred mixture of {2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl}acetic acid (82 mg, 0.290 mmol) and Intermediate 1 (50.6 mg, 0.193 mmol) in N,N-dimethylformamide (2 mL) was added HATU (95.6 mg, 0.251 mmol) and N,N-diisopropylethylamine (112 mg, 0.870 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The mixture was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a X Bridge Prep OBD C18150 mm x 30 mm x 5μm column (45-66% acetonitrile/water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (24.7 mg, 25.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C27H33F4N3O: 492.26, found 492.15.1H NMR (300 MHz, Acetonitrile-d3) δ 7.36 – 7.58 (m, 6H), 7.01 – 7.13 (m, 1H), 6.55 (d, J = 9.6 Hz, 1H), 4.13 – 4.36 (m, 1H), 3.54 – 3.72 (m, 2H), 2.44 – 2.65 (m, 3H), 2.39 – 2.43 (m, 1H), 2.27 – 2.39 (m, 5H), 2.03 – 2.16 (m, 1H), 1.86 – 1.95 (m, 1H), 1.76 – 1.85 (m, 2H), 1.27 – 1.48 (m, 2H), 0.93 (d, J = 6.5 Hz, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -96.54, -112.84, - 118.27. [00234] Compound 8: 2-(3',5'-dichloro-2-fluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide [00235] The title compound +
Figure imgf000078_0001
1. LCMS (ESI): m/z [M+H] calcd for C27H32Cl2F3N3O: 542.19, found 542.20. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.50- 7.62 (m, 3H), 7.35-7.49 (m, 2H), 7.18-7.31 (m, 1H), 6.41-6.61 (m, 1H), 4.07-4.35 (m, 1H), 3.50- 3.80 (m, 2H), 2.59-2.73 (m, 2H), 2.36-2.59 (m, 8H), 1.65-1.87 (m, 4H), 1.27-1.42 (m, 2H), 0.97 (s, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -96.55, -112.87, -122.65. [00236] Synthesis of Compound 9: N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,3',5,5'-tetrafluoro-[1,1'-biphenyl]-3-yl)acetamide [00237] Scheme 6
Figure imgf000078_0002
[00239] To a stirred mixture of 1,3-dibromo-2,5-difluorobenzene (2 g, 7.36 mmol) and 3,5- difluorophenylboronic acid (1.05 g, 6.62 mmol) in dioxane/water (10:1, 20 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.85 g, 0.736 mmol) and potassium carbonate (0.10 g, 0.736 mmol) in portions at room temperature. The resulting mixture was stirred at 90 °C for overnight under nitrogen atmosphere, at which point the reaction was judged complete by TLC. The aqueous layer was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate) to afford the title compound as a yellow oil (1.2 g, 53.5% yield). [00240] Step 2: Preparation of methyl 2-{2,3',5,5'-tetrafluoro-[1,1'-biphenyl]-3-yl}acetate [00241] To a stirred solution of 3-bromo-2,3',5,5'-tetrafluoro-1,1'-biphenyl (400 mg, 1.31 mmol) and tert-butyl[(1-methoxyethenyl)oxy]dimethylsilane (494 mg, 2.62 mmol) in tetrahydrofuran (10 mL) was added cupric fluoride (266 mg, 2.62 mmol) and XPhos-Pd-G3 (111 mg, 0.131 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere, at which point the reaction was judged complete by TLC. The reaction was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate) to afford the title compound as a yellow oil (150 mg, 38.4% yield). [00242] Step 3: Preparation of {2,3',5,5'-tetrafluoro-[1,1'-biphenyl]-3-yl}acetic acid [00243] To a stirred solution of methyl 2-{2,3',5,5'-tetrafluoro-[1,1'-biphenyl]-3-yl}acetate (140 mg, 0.469 mmol) in a mixture of tetrahydrofuran/methanol/water (1:1:1, 10 mL) was added lithium hydroxide (56.2 mg, 2.35 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for 2 h, at which point the reaction was judged complete by LCMS. The mixture was acidified to pH = 4 with 1M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated, to provide the title compound as a yellow oil (100 mg, 75.0% yield), which was used without further purification. LCMS (ESI): m/z [M+H]+ calcd for C14H8F4O2: 285.05, found 285.10. [00244] Step 4: Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,3',5,5'-tetrafluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 9) [00245] To a stirred solution of {2,3',5,5'-tetrafluoro-[1,1'-biphenyl]-3-yl}acetic acid (100 mg, 0.352 mmol) and HATU (174 mg, 0.458 mmol) in N,N-dimethylformamide (5 mL) were added Intermediate 1 (101 mg, 0.387 mmol) and N,N-diisopropylethylamine (136 mg, 1.06 mmol) dropwise at room temperature. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (15 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column (55- 65% methanol/water with 0.05% ammonium bicarbonate) to afford the title compound as a white solid (10.9 mg, 5.86% yield). LCMS (ESI): m/z [M+H]+ calcd for C27H31F6N3O: 528.24, found 528.25.1H NMR (400 MHz, Acetonitrile-d3) δ 7.29 – 7.18 (m, 4H), 7.07 – 7.02 (m, 1H), 6.55 (d, J = 9.6 Hz, 1H), 4.30 – 4.20 (m, 1H), 3.71 – 3.60 (m, 1H), 2.66 – 2.51 (m, 3H), 2.45 – 2.27 (m, 7H), 2.15 – 2.05 (m, 1H), 1.97 – 1.87 (m, 3H), 1.45 – 1.30 (m, 2H), 0.95 – 0.88 (m, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -96.61, -111.30, -113.57, -120.05, -127.64. [00246] Compound 10: 2-(3'-chloro-2-fluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)-2,2-difluoro- 6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide [00247] The title compound 1. LCMS (ESI): m/z [M+H]+
Figure imgf000081_0001
calcd for C27H33ClF3N3O: 508.23, found 508.25. 1H NMR (300 MHz, Acetonitrile-d3) δ7.57 – 7.71 (m, 1H), 7.32-7.57 (m, 5H), 7.12-7.32 (m, 1H), 6.32-6.60 (m, 1H), 4.09-4.43 (m, 1H), 2.59- 3.77 (m, 2H), 2.49-2.59 (m, 3H), 2.42-2.49 (m, 1H), 2.22-2.42 (m,6H), 1.68-1.96 (m, 4H), 1.26- 1.51 (m, 2H), 0.80-1.01 (m, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -96.54, -112.89, - 123.08. [00248] Synthesis of Compound 11: 2-(3',5'-difluoro-2-methoxy-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide
Figure imgf000081_0002
- [00251] To a stirred mixture of (3-bromo-2-methoxyphenyl)acetic acid (700 mg, 2.86 mmol) in dimethoxyethane (8 mL) and water (2 mL) was added 3,5-difluorophenylboronic acid (541 mg, 3.43 mmol), sodium bicarbonate (600 mg, 7.14 mmol) and bis(triphenylphosphine)palladium(II) chloride (200 mg, 0.286 mmol) in portions at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 90 °C, at which point the reaction was judged complete by LCMS. The mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate) to afford the title compound as a white solid (500 mg, 62.9% yield). [00252] Step 2: Preparation of 2-(3',5'-difluoro-2-methoxy-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 11) [00253] To a stirred mixture of {3',5'-difluoro-2-methoxy-[1,1'-biphenyl]-3-yl}acetic acid (65 mg, 0.234 mmol) and Intermediate 1 (50.9 mg, 0.195 mmol) in N,N-dimethylformamide (3 mL) was added HATU (96.2 mg, 0.254 mmol) and N,N-diisopropylethylamine (113 mg, 0.878 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The mixture was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a X Bridge Prep OBD C18150 mm x 30 mm x 5μm column (42-64% acetonitrile/water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (28.4 mg, 27.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H35F4N3O2: 522.27, found 522.10. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.36 – 7.46 (m, 1H), 7.26 – 7.33 (m, 1H), 7.13 – 7.29 (m, 3H), 6.85 – 6.91 (m, 1H), 6.57 (d, J = 9.7 Hz, 1H), 4.14 – 4.36 (m, 1H), 3.64 (s, 2H), 2.40 – 2.64 (m, 4H), 2.13 – 2.39 (m, 6H), 1.91 – 2.05 (m, 2H), 1.73 – 1.84 (m, 1H), 1.67 – 1.78 (m, 2H), 1.53 – 1.67 (m, 1H), 1.29 – 1.38 (m, 3H), 0.95 (d, J = 6.5 Hz, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -97.39, -112.03, -113.76. [00254] Compound 12: 2-(3'-cyano-2,5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide [00255] The title compound w ound 1. LCMS (ESI): m/z [M+H]+ calcd for C28H32F4N4O: 517.25, found 517.20. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.71 – 7.89 (m, 1H), 7.61 – 7.71 (m, 1H), 7.54 – 7.61 (m, 1H), 7.42 – 7.54 (m, 2H), 7.25 – 7.34 (m, 1H), 6.48 – 6.55 (m, 1 H), 4.16 – 4.33 (m, 1H), 3.68 – 3.76 (m, 2H), 2.51 – 2.69 (m, 3H), 2.25 – 2.51 (m, 7H), 2.08 – 2.12 (m, 1H), 1.70 – 1.93 (m, 3H), 1.28 – 1.44 (m, 2H), 0.88 – 0.96 (m, 6H).19F NMR (376 MHz, Acetonitrile-d3) δ -96.63, -112.06, -122.87. [00256] Synthesis of Compound 13: N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl)acetamide
[00258] Step 1: Preparation of tert-butyl 2-(2-chloro-3-fluoropyridin-4-yl)acetate [00259] To a stirred solution 2-chloro-3-fluoro-4-iodopyridine (1 g, 4.04 mmol) and (2-(tert- butoxy)-2-oxoethyl) zinc(II) bromide (1.01 g, 3.89 mmol) in tetrahydrofuran (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.76 g, 0.660 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 70 °C under nitrogen atmosphere, at which point the reaction was judged complete by LCMS. After cooling down to room temperature, the reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate) to afford the title compound as a yellow oil (170 mg, 17.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C11H13ClFNO2: 246.06, found 246.05. [00260] Step 2: Preparation of tert-butyl 2-[2-(3,5-difluorophenyl)-3-fluoropyridin-4- yl]acetate [00261] To a stirred solution of tert-butyl 2-(2-chloro-3-fluoropyridin-4-yl)acetate (150 mg, 0.611 mmol) and 3,5-difluorophenylboronic acid (116 mg, 0.733 mmol) in 1,4-dioxane/water (10:1, 5.5 mL) were added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44.7 mg, 0.061 mmol) and potassium carbonate (253 mg, 1.83 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere, at which point the reaction was judged complete by LCMS. After cooling down to room temperature, the reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate) to afford the title compound as a yellow oil (150 mg, 76% yield). LCMS (ESI): m/z [M+H]+ calcd for C17H16F3NO2: 324.12, found 324.00. [00262] Step 3: Preparation of [2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]acetic acid [00263] To a stirred solution of tert-butyl 2-[2-(3,5-difluorophenyl)-3-fluoropyridin-4- yl]acetate (140 mg, 0.433 mmol) in tetrahydrofuran/methanol/water (1:1:1, 6 mL) was added lithium hydroxide (51.9 mg, 2.17 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The residue was acidified to pH = 5 with 1 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to provide the title compound as a yellow oil (110 mg, 95.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C13H8F3NO2: 268.05, found 268.00. [00264] Step 4: Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl)acetamide (Compound 13) [00265] To a stirred solution of [2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]acetic acid (67.5 mg, 0.253 mmol) and Intermediate 1 (60.0 mg, 0.230 mmol) in N,N-dimethylformamide (3 mL) was added HATU (114 mg, 0.299 mmol) in portions at room temperature under air atmosphere. To the above mixture was added N,N-diisopropylethylamine (89.0 mg, 0.690 mmol) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column (55- 65% methanol/water with 0.05% ammonium bicarbonate) to afford the title compound as a white solid (33.0 mg, 28.0% yield). LCMS (ESI): m/z [M+H]+ calcd for C26H31F5N4O: 511.25, found 511.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.47 (dd, J = 4.7, 0.9 Hz, 1H), 7.56 – 7.71(m, 2H), 7.46 – 7.53(m, 1H), 7.08 (tt, J = 9.1, 2.4 Hz, 1H), 6.64 (d, J = 9.6 Hz,1H), 4.18 – 4.33(m, 1H), 3.78 (dt, J = 15.3, 0.8 Hz, 2H), 2.51 – 2.66(m, 3H), 2.22 – 2.49(m, 6H), 2.17 (s, 2H), 1.68 – 1.93(m, 3H), 1.24 – 1.51(m, 2H), 0.87 – 0.95(m, 6H).19F NMR (376 MHz, Acetonitrile-d3) δ -96.57, -112.88, - 129.08. [00266] Synthesis of Compound 14: N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(4-(3,5-difluorophenyl)-3-fluoropyridin-2-yl)acetamide te [00269] To a stirred solution of 2-bromo-4-chloro-3-fluoropyridine (900 mg, 4.28 mmol) and (2-(tert-butoxy)-2-oxoethyl) zinc(II) bromide (1.11 g, 4.28 mmol) in tetrahydrofuran (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (840 mg, 0.727 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 70 °C under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. After cooling down to room temperature, the reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate) to afford the title compound as a yellow oil (170 mg, 16.2% yield). LCMS (ESI): m/z [M+H]+ calcd for C11H13ClFNO2: 246.06, found 246.05. [00270] Step 2: Preparation of tert-butyl 2-[4-(3,5-difluorophenyl)-3-fluoropyridin-2- yl]acetate [00271] To a stirred solution of tert-butyl 2-(4-chloro-3-fluoropyridin-2-yl)acetate (170 mg, 0.692 mmol) and 3,5-difluorophenylboronic acid (131 mg, 0.830 mmol) in 1,4-dioxane/water (10:1, 5.5 mL) were added [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (50.6 mg, 0.069 mmol) and potassium carbonate (287 mg, 2.08 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. After cooling to room temperature, the reaction was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 petroleum ether/ethyl acetate) to provide the title compound as a yellow oil (80 mg, 35.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C17H16F3NO2: 324.12, found 323.90. [00272] Step 3: Preparation of [4-(3,5-difluorophenyl)-3-fluoropyridin-2-yl] acetic acid [00273] To a stirred solution of tert-butyl 2-[4-(3,5-difluorophenyl)-3-fluoropyridin-2- yl]acetate (120 mg, 0.371 mmol) in tetrahydrofuran/methanol/water (1:1:1, 6 mL) was added lithium hydroxide (44.5 mg, 1.86 mmol) in portions at 0 °C. The resulting mixture was stirred for 5 h at room temperature, at which point the reaction was judged complete by LCMS. The residue was acidified to pH = 5 with 2N hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to provide the title compound as a yellow oil which was used without further purification (140 mg, 141% crude yield). LCMS (ESI): m/z [M+H]+ calcd for C13H8F3NO2: 268.05, found 268.05. [00274] Step 4: Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(4-(3,5-difluorophenyl)-3-fluoropyridin-2-yl)acetamide (Compound 14) [00275] To a stirred solution of [4-(3,5-difluorophenyl)-3-fluoropyridin-2-yl]acetic acid (60 mg, 0.225 mmol) and Intermediate 1 (53.4 mg, 0.205 mmol) in N,N-dimethylformamide (3 mL) was added HATU (101 mg, 0.266 mmol) in portions at room temperature. To the above mixture was added N,N-diisopropylethylamine (79.2 mg, 0.614 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (15 mL). The resulting mixture was extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column (55-65% methanol/water with 0.05% ammonium bicarbonate) to provide the title compound as a white solid (10.6 mg, 10.0% yield). LCMS (ESI): m/z [M+H]+ calcd for C26H31F5N4O: 511.25, found 511.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.46 (d, J = 5.0 Hz, 1H), 7.52 – 7.71 (m, 1H), 7.42 – 7.49 (m, 1H), 7.24 – 7.33 (m, 2H), 7.09 – 7.17 (m, 1H), 6.74 – 6.83 (m, 1H), 4.17 – 4.31 (m, 1H), 3.82 – 3.97 (m, 2H), 2.42 – 2.61 (m, 4H), 2.24 – 2.38 (m, 5H), 2.17 – 2.22 (m, 2H), 1.71 – 1.92 (m, 3H), 1.29 – 1.45 (m, 2H), 0.89 (d, J = 6.5 Hz, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -97.19, -113.10, -131.06. [00276] Synthesis of Compound 15: N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide [00277] Scheme 10
Figure imgf000088_0001
nitrobenzenesulfonamido)cyclohexyl]oxy}piperidine-1-carboxylate [00279] To a solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (100 mg, 0.314 mmol) in N-methyl-2-pyrrolidone (0.1 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (126 mg, 0.628 mmol). The reaction was stirred at 110 °C for 2 h under a nitrogen atmosphere. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow solid (110 mg, 67.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C22H31F2N3O7S: 520.19, found 520.2. [00280] Step 2: Preparation of tert-butyl 4-{[(1S,2R)-2-amino-3,3- difluorocyclohexyl]oxy}piperidine-1-carboxylate [00281] To a solution of tert-butyl 4-{[(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy}piperidine-1-carboxylate (140 mg, 0.269 mmol) in toluene (5 mL) was added sodium benzenethiolate (285 mg, 2.15 mmol). The reaction was stirred at 110 °C for 2 h under a nitrogen atmosphere. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-30% gradient) to the title compound as a yellow solid (80 mg, 88.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C16H28F2N2O3: 335.21, found 335.2. [00282] Step 3: Preparation of tert-butyl 4-{[(1S,2R)-3,3-difluoro-2-(2-{2,3',5'-trifluoro- [1,1'-biphenyl]-3-yl}acetamido)cyclohexyl]oxy}piperidine-1-carboxylate [00283] To a solution of {2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}acetic acid (35.8 mg, 0.135 mmol) in N,N-dimethylformamide (2 mL) was added HATU (61.4 mg, 0.162 mmol). The reaction was stirred at 25 °C for 15 min. Then tert-butyl 4-{[(1S,2R)-2-amino-3,3- difluorocyclohexyl]oxy}piperidine-1-carboxylate (45 mg, 0.135 mmol) and N,N- diisopropylethylamine (69.6 mg, 0.540 mmol) was added. The reaction was stirred at 25 °C for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow solid (65 mg, 82.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C30H35F5N2O4: 583.26, found 583.3. [00284] Step 4: Preparation of N-[(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl]-2- {2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}acetamide [00285] tert-butyl 4-{[(1S,2R)-3,3-difluoro-2-(2-{2,3',5'-trifluoro-[1,1'-biphenyl]-3- yl}acetamido)cyclohexyl]oxy}piperidine-1-carboxylate (60 mg, 0.103 mmol) was dissolved in 4 M hydrochloric acid in 1,4-dioxane (5 mL). The reaction was stirred at 0 °C for 1 h. The solvent was removed to provide the title compound as yellow solid, which was used without purification (45 mg, 90.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C25H27F5N2O2: 483.20, found 483.2. [00286] Step 5: Preparation of N-[(1R,6S)-2,2-difluoro-6-[(1-isopropylpiperidin-4- yl)oxy]cyclohexyl]-2-{2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}acetamide (Compound 15) [00287] To a solution of N-[(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl]-2-{2,3',5'- trifluoro-[1,1'-biphenyl]-3-yl}acetamide (100 mg, 0.207 mmol) in methanol (5 mL) was added acetone (120 mg, 2.07 mmol) and sodium cyanoborohydride (39.1 mg, 0.621 mmol). The reaction was stirred at 25 °C for 16 h. The reaction was then quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Prep OBD C18 Column 150 mm x 30 mm x 5 μm column (eluent: 17- 42% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (40.3 mg, 36.5%). LCMS (ESI): m/z [M+H]+ calcd for C28H33F5N2O2: 525.25, found 525.3. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.39 – 7.49 (m, 2H), 7.17 – 7.32 (m, 3H), 6.97 – 7.07 (m, 1H), 6.71 (d, J = 9.8 Hz, 1H), 4.04 – 4.22 (m, 1H), 3.61 – 3.75 (m, 2H), 3.31 – 3.41 (m, 2H), 2.55 – 2.72 (m, 3H), 2.04 – 2.14 (m, 4H), 1.65 – 1.84 (m, 4H), 1.22 – 1.50 (m, 4H), 0.96 (d, J = 6.4 Hz, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.39, -111.59, -112.67, -122.95. [00288] Synthesis of Compound 16: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)- N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide
[00290] Step 1: Preparation of methyl 2-(3-chloro-2-cyclopropylphenyl) acetate [00291] To a solution of methyl 2-(2-bromo-3-chlorophenyl) acetate (300 mg, 1.14 mmol) and cyclopropylboronic acid (293 mg, 3.42 mmol) in toluene (5 mL) and water (0.5 mL) was added palladium (II) acetate (37.9 mg, 0.228 mmol), di(1-adamantyl)-n-butylphosphine (81.6 mg, 0.341 mmol), and sodium carbonate (355 mg, 3.42 mmol). The reaction was stirred at 90 °C under nitrogen for 3 h. The reaction was then quenched with water (15 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-100% gradient) to provide the title compound as a yellow oil (220 mg, 86% yield). LCMS (ESI): m/z [M+H]+ calcd for C12H13ClO2: 225.06, found 225.15. [00292] Step 2: Preparation of 2-(3-chloro-2-cyclopropylphenyl) acetic acid [00293] To a solution of methyl 2-(3-chloro-2-cyclopropylphenyl) acetate (180 mg, 0.801 mmol) in tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL) was added lithium hydroxide (57.6 mg, 2.40 mmol). The reaction was stirred at room temperature for 3 h. The residue was acidified to pH = 4 with 2 N hydrochloric acid and extracted with dichloromethane (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated, to provide the title compound as a yellow oil (150 mg, 90% yield). LCMS (ESI): m/z [M+H]- calcd for C11H11ClO2: 209.04, found 209.00. [00294] Step 3: Preparation of 2-(3-chloro-2-cyclopropylphenyl)-N-((1R,6S)-2,2-difluoro- 6-(4-isopropylpiperazin-1-yl)cyclohexyl) acetamide [00295] To a solution of (3-chloro-2-cyclopropylphenyl) acetic acid (51.3 mg, 0.243 mmol) in N,N-dimethylformamide (3 mL) was added Intermediate 1 (70 mg, 0.268 mmol), HATU (139 mg, 0.365 mmol) and N,N-diisopropylethylamine (126 mg, 0.974 mmol). The reaction was stirred at room temperature for 3 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-100% gradient) to provide the title compound as a yellow oil (120 mg, 90% yield). LCMS (ESI): m/z [M+H]+ calcd for C24H34ClF2N3O: 454.24, found 454.10. [00296] Step 4: Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 16) [00297] To a solution of 2-(3-chloro-2-cyclopropylphenyl)-N-[(1R,6S)-2,2-difluoro-6-(4- isopropylpiperazin-1-yl)cyclohexyl]acetamide (115 mg, 0.253 mmol) and 3,5- difluorophenylboronic acid (60 mg, 0.380 mmol) in dioxane (5 mL) and water (0.5 mL) was added [2',6'-bis(propan-2-yloxy)-[1,1'-biphenyl]-2-yl]dicyclohexylphosphane (11.8 mg, 0.025 mmol), RuPhos-Pd-G3 (21.2 mg, 0.025 mmol) and potassium carbonate (87.5 mg. 0.633 mmol). The reaction was stirred at 90 °C under nitrogen for 5 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 μm column (49- 73% acetonitrile/water with 10 mM ammonium bicarbonate) to afford the title compound as a white solid (26.7 mg, 19.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C30H37F4N3O: 532.29, found 532.25.1H NMR (300 MHz, Acetonitrile-d3) δ 7.20 - 7.29 (m, 1H), 7.10 - 7.19 (m, 1H), 7.00 - 7.09 , 6.88 - 6.99 (m, 2H), 6.76 - 6.86 (m, 1H), 6.36 (d, J = 9.0 Hz, 1H), 4.19 - 4.42 (m, 1H), 3.80 - 3.98 (m, 2H), 2.51 - 2.62 (m, 2H), 2.35 - 2.50 (m, 2H), 2.15 - 2.34 (m, 6H), 1.88 - 2.00 (m, 2H), 1.73 - 1.79 (m, 1H), 1.52 - 1.72 (m, 2H), 1.10 - 1.36 (m, 2H), 0.96 (d, J = 6.0 Hz, 6H), 0.74 - 0.86 (m, 2H), 0.06 - 0.18 (m, 2H). 19F NMR (282 MHz, Acetonitrile-d3) δ - 96.55, -112.79, -113.62. [00298] Compound 17: N-((1R,6S)-6-(4-cyclopentylpiperazin-1-yl)-2,2- difluorocyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide
[00299] The title compound was prepared similarly to Compound 1. LCMS (ESI): m/z [M+H]+ calcd for C29H34F5N3O: 536.27, found 536.30. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.42 – 7.51 (m, 2H), 7.19 – 7.31 (m, 3H), 6.97 – 7.08 (m, 1H), 6.47 – 6.51 (m, 1H), 4.18 – 4.32 (m, 1H), 3.58 – 3.77 (m, 2H), 2.58 – 2.64 (m, 3H), 2.22 – 2.42 (m, 5H), 2.11 – 2.20 (m, 2H), 2.09 – 2.17 (m, 1H), 1.87 – 1.96 (m, 1H), 1.58 – 1.76 (m, 6H), 1.43 – 1.52 (m, 2H), 1.12 – 1.42 (m, 4H).19F NMR (376 MHz, Acetonitrile-d3) δ -97.24, -111.63, -112.97, -122.23. [00300] Compound 18: N-((1R,6S)-6-(4-cyclobutylpiperazin-1-yl)-2,2-difluorocyclohexyl)- 2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide [00301] The title
Figure imgf000094_0001
1. LCMS (ESI): m/z [M+H]+ calcd for C28H32F5N3O: 522.25, found 522.05. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.41 – 7.60 (m, 2H), 7.19 – 7.40 (m, 3H), 6.91 – 7.10 (m, 1H), 6.47 – 6.75 (m, 1H), 4.16 – 4.37 (m, 1H), 3.59 – 3.90 (m, 2H), 2.68 – 2.84 (m, 3H), 2.21 – 2.68 (m, 7H), 2.01 – 2.21 (m, 4H), 1.77 – 1.91 (m, 3H), 1.58 – 1.77 (m, 3H), 1.26 – 1.58 (m, 2H). 19F NMR (376 MHz, Acetonitrile- d3) δ -96.65, -111.46, -112.96, -122.28. [00302] Compound 19: N-((1R,6S)-2,2-difluoro-6-(((S)-1-isopropylpyrrolidin-3- yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide [00303] The title
Figure imgf000094_0002
15. LCMS (ESI): m/z [M+H]+ calcd for C27H31F5N2O2: 511.23, found 511.20. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.37 – 7.50 (m, 2H), 7.14 – 7.33 (m, 3H), 6.95 – 7.09 (m, 1H), 6.77 (d, J = 9.8 Hz, 1H), 4.03 – 4.25 (m, 2H), 3.60 – 3.77 (m, 2H), 3.25 – 3.38 (m, 1H), 2.72 – 2.84 (m, 1H), 2.38 – 2.51 (m, 3H), 2.32 – 2.43 (m, 1H), 2.19 – 2.37 (m, 2H), 1.72 – 1.97 (m, 1H), 1.74 – 1.80 (m, 2H), 1.47 – 1.67 (m, 1H), 1.47 – 1.22 (m, 2H), 0.96 – 1.05 (m, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ - 98.33, -111.27, -112.67, -122.88. [00304] Compound 20: N-((1R,6S)-2,2-difluoro-6-(1,7-diazaspiro[3.5]nonan-7- yl)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide [00305] The title compound
Figure imgf000095_0001
21. LCMS (ESI): m/z [M+H]+ calcd for C27H30F5N3O: 508.23, found 508.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.45 (s, 1H), 7.39 – 7.49 (m, 2H), 7.19 – 7.31 (m, 3H), 6.98 – 7.06 (m, 1H), 6.52 – 6.61 (m, 1H), 4.19 – 4.31 (m, 1H), 3.61 – 3.74 (m, 4H), 2.74 (s, 1H), 2.56 (s, 2H), 2.28 – 2.42 (m, 2H), 2.06 – 2.17 (m, 3H), 1.96 – 1.99 (m, 1H), 1.54 – 1.90 (m, 7H), 1.25 – 1.42 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -97.29, -111.54, -113.04, -122.89. [00306] Synthesis of Compound 21: N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,3',5',6-tetrafluoro-[1,1'-biphenyl]-3-yl)acetamide [00307] Scheme 12
Figure imgf000095_0002
F NBoc F
Figure imgf000096_0001
nitrobenzenesulfonamido)cyclohexyl]-1,8-diazaspiro[4.5]decane-1-carboxylate [00309] To a solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (180 mg, 0.566 mmol) in toluene (10 mL) was added tert-butyl 1,8- diazaspiro[4.5]decane-1-carboxylate (109 mg, 0.453 mmol). The reaction was stirred at 110 °C for 2 h, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow oil (270 mg, 85.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C25H36F2N4O6S: 559.24, found 559.25. [00310] Step 2: Preparation of tert-butyl 8-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-1,8- diazaspiro[4.5]decane-1-carboxylate [00311] To a solution of tert-butyl 8-[(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]-1,8-diazaspiro[4.5]decane-1-carboxylate (260 mg, 0.465 mmol) in toluene (10 mL) was added sodium benzenethiolate (308 mg, 2.33 mmol). The reaction was stirred at 100 °C for 2 h, then was quenched with water (20 mL) and extracted with dichloromethane (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-100% gradient) to provide the title compound as a yellow oil (100 mg, 57.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C19H33F2N3O2: 374.26, found 374.25. [00312] Step 3: Preparation of tert-butyl 8-[(1S,2R)-3,3-difluoro-2-(2-{2,3',5'-trifluoro- [1,1'-biphenyl]-3-yl}acetamido)cyclohexyl]-1,8-diazaspiro[4.5]decane-1-carboxylate [00313] To a solution of tert-butyl 8-[(1S,2R)-2-amino-3,3-difluorocyclohexyl]-1,8- diazaspiro[4.5]decane-1-carboxylate (90 mg, 0.241 mmol) in N,N-dimethylformamide (10 mL) was added {2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}acetic acid (64.2 mg, 0.241 mmol) and HATU (119 mg, 0.313 mmol). Then N,N-diisopropylethylamine (140 mg, 1.09 mmol) was added at 0 °C. The reaction was stirred at room temperature for 1 h, at which point the reaction was judged complete by LCMS. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow oil (110 mg, 73.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C33H40F5N3O3: 622.30, found 622.30. [00314] Step 4: Preparation of N-((1R,6S)-2,2-difluoro-6-(1,8-diazaspiro[4.5]decan-8- yl)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 21) [00315] To a solution of tert-butyl 8-[(1S,2R)-3,3-difluoro-2-(2-{2,3',5'-trifluoro-[1,1'- biphenyl]-3-yl}acetamido)cyclohexyl]-1,8-diazaspiro[4.5]decane-1-carboxylate (100 mg, 0.161 mmol) in 1,4-dioxane (5 mL) was added 4M hydrochloric acid in 1,4-dioxane (5 mL). The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The resulting mixture was concentrated, and the residue was purified by preparative HPLC using a Agilent Poroshell HPH-C18 (42-75% acetonitrile/water with 10 mM ammonium bicarbonate) to afford the title compound as an off-white solid (31.9 mg, 37.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F5N3O: 522.25, found 522.05. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.25 – 7.46 (m, 2H), 7.02 – 7.25 (m, 3H), 6.81 – 7.00 (m, 1H), 6.36 – 6.54 (m, 1H), 4.04 – 4.29 (m, 1H), 3.48 – 3.70 (m, 2H), 2.68 – 2.80 (m, 2H), 2.50 – 2.68 (m, 1H), 2.29 – 2.50 (m, 3H), 2.14 – 2.29 (m, 1H), 1.94 – 1.99 (m, 1H), 1.69 – 1.85 (m, 3H), 1.50 – 1.61 (m, 2H), 1.15 – 1.34 (m, 8H). 19F NMR (282 MHz, Acetonitrile-d3) δ -96.47, -111.63, - 113.76, -122.91. [00316] Synthesis of Compound 22: N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,3',5',6-tetrafluoro-[1,1'-biphenyl]-3-yl)acetamide N N
Figure imgf000098_0001
6- (4-isopropylpiperazin-1-yl)cyclohexyl]acetamide [00319] To a solution of (3-chloro-2,4-difluorophenyl)acetic acid (75.9 mg, 0.367 mmol) and Intermediate 1 (80 mg, 0.306 mmol) in N,N-dimethylformamide (3 mL) was added HATU (175 mg, 0.459 mmol) and N,N-diisopropylethylamine (119 mg, 0.918 mmol). The reaction was stirred at 25 °C for 1 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow solid (56 mg, 40.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C21H28ClF4N3O: 450.19, found 450.10. [00320] Step 2: Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2,3',5',6-tetrafluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 22) [00321] To a solution of 2-(3-chloro-2,4-difluorophenyl)-N-[(1R,6S)-2,2-difluoro-6-(4- isopropylpiperazin-1-yl)cyclohexyl]acetamide (46 mg, 0.102 mmol) and 3,5- difluorophenylboronic acid (24.2 mg, 0.153 mmol) in tetrahydrofuran (5 mL) was added X-phos (4.87 mg, 0.010 mmol), XPhos-Pd-G3 (8.65 mg, 0.010 mmol) and potassium phosphate tribasic (65.1 mg, 0.306 mmol). The reaction was stirred at 90 °C under nitrogen for 3 h. The reaction was then cooled to room temperature, quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a X Bridge Prep OBD C18150 mm x 30 mm x 5 μm column (40-70% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (7.8 mg, 14.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C27H31F6N3O: 528.24, found 528.20. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.39 - 7.61 (m, 1H), 6.92 - 7.29 (m, 4H), 6.38 - 6.75 (m, 1H), 4.10 - 4.32 (m, 1H), 3.40 - 3.87 (m, 2H), 2.50 - 2.68 (m, 3H), 2.41 - 2.50 (m, 1H), 2.31 - 2.41 (m, 4H), 2.22 - 2.31 (m, 2H), 2.07 - 2.13 (m, 1H), 1.68 - 1.94 (m, 3H), 1.2 - 1.5 (m, 2H), 0.79 - 1.01 (m, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -96.64, -111.62, -112.94, -113.58, -117.72. [00322] Synthesis of Compound 23: N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(3',5',6-trifluoro-2-methoxy-[1,1'-biphenyl]-3-yl)acetamide [00323] Scheme 14
Figure imgf000099_0001
[00325] To a solution of 3,5-difluorophenylboronic acid (500 mg, 3.17 mmol) and 1-bromo-4- fluoro-3-iodo-2-methoxybenzene (1.15 g, 3.48 mmol) in 1,4-dioxane (7 mL) and water (0.7 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (232 mg, 0.317 mmol) and potassium carbonate (1.31 g, 9.50 mmol). The reaction was stirred at 90 °C under nitrogen for 3 h, then was cooled to room temperature, quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a white solid (850 mg, 84.7% yield). GC/MS (EI): m/z [M]+ calcd for C13H8BrF3O: 315.97, found 316.00. [00326] Step 2: Preparation of methyl 2-{3',5',6-trifluoro-2-methoxy-[1,1'-biphenyl]-3- yl}acetate [00327] To a solution of 3-bromo-3',5',6-trifluoro-2-methoxy-1,1'-biphenyl (820 mg, 2.59 mmol) and tert-butyl[(1-methoxyethenyl)oxy]dimethylsilane (2.44 g, 12.9 mmol) in N,N- dimethylformamide (20 mL) was added zinc fluoride (1.34 g, 12.9 mmol) and bis(tri-tert- butylphosphine) palladium (264 mg, 0.517 mmol). The reaction was stirred at 100 °C under nitrogen for 3 h, then was cooled to room temperature, quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a white solid (77 mg, 9.60% yield). GC/MS (ESI): m/z [M+H]+ calcd for C16H13F3O3: 311.09, found 311.08. [00328] Step 3: Preparation of {3',5',6-trifluoro-2-methoxy-[1,1'-biphenyl]-3-yl}acetic acid [00329] To a solution of methyl 2-{3',5',6-trifluoro-2-methoxy-[1,1'-biphenyl]-3-yl}acetate (70 mg, 0.226 mmol) in tetrahydrofuran/methanol/water (1/1/1, 4.5 mL) and was added lithium hydroxide (27.0 mg, 1.13 mmol). The reaction was stirred at 25 °C for 1 h. The mixture was acidified to pH = 4 with 2N hydrochloric acid, then was diluted with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide the title compound as a white solid, which was used without further purification (59 mg, 88.3% yield). [00330] Step 4: Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(3',5',6-trifluoro-2-methoxy-[1,1'-biphenyl]-3-yl)acetamide (Compound 23) [00331] To a solution of {3',5',6-trifluoro-2-methoxy-[1,1'-biphenyl]-3-yl}acetic acid (59.2 mg, 0.199 mmol) and Intermediate 1 (43.5 mg, 0.166 mmol) in N,N-dimethylformamide (5 mL) was added HATU (94.9 mg, 0.249 mmol) and N,N-diisopropylethylamine (64.5 mg, 0.498 mmol). The reaction was stirred at 25 °C for 1 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Prep OBD C1830*150 mm, 5μm Column (41-71% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (20.4 mg, 22.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H34F5N3O2: 540.26, found 540.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.35-7.41 (m, 1H), 6.92-7.20 (m, 4H), 6.35-6.70 (m, 1H), 4.09-4.40 (m, 1H), 3.50-3.70 (s, 2H), 3.33-3.49 (s, 3H), 2.50-2.68 (m, 4H), 2.33-2.47 (m, 4H), 2.25-2.33 (m, 2H), 2.07-2.15 (m, 1H), 1.65-1.92 (m, 3H), 1.27-1.50 (m, 2H), 0.9-1.03 (m, 6H).19F NMR (376 MHz, Acetonitrile-d3) δ -112.05, -112.10, -112.97, -113.58, -118.02. [00332] Compound 24: 2-(3',5'-difluoro-2-methyl-[1,1'-biphenyl]-3-yl)-N-((1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide [00333] The title compound 1. LCMS (ESI): m/z [M+H]+
Figure imgf000102_0001
calcd for C28H35F4N3O: 506.27, found 506.15. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.28 – 7.37 (m, 1H), 7.18 – 7.27 (m, 1H), 7.10 – 7.17 (m, 1H), 6.86 – 7.03 (m, 3H), 6.38 (d, J = 12.0 Hz, 1H), 4.14 – 4.36 (m, 1H), 3.64 (s, 2H), 2.49 – 2.58 (m, 2H), 2.35 – 2.48 (m, 2H), 2.20 – 2.31 (m, 5H), 1.96 – 2.10 (m, 5H), 1.78 – 1.85 (m, 1H), 1.54 – 1.71 (m, 2H), 1.12 – 1.32 (m, 2H), 0.92 (d, J = 9.0, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -96.57, -112.09, -112.87. [00334] Compound 25: 2-(2',6'-difluoro-2-methoxy-[1,1'-biphenyl]-3-yl)-N-((1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide [00335] The title compound
Figure imgf000102_0002
11. LCMS (ESI): m/z [M+H]+ calcd for C28H35F4N3O2: 522.27, found 522.10. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.42 – 7.55 (m, 2H), 7.19 – 7.27 (m, 2H), 7.09 – 7.17 (m, 2H), 6.52 – 6.67 (m, 1H), 4.21 – 4.36 (m, 1H), 3.61 – 3.72 (m, 2H), 3.45 (s, 3H), 2.51 – 2.68 (m, 4H), 2.31 – 2.48 (m, 6H), 2.07 – 2.18 (m, 1H), 1.69 – 1.98 (m, 3H), 1.27 – 1.51 (m, 2H), 0.92 – 1.08 (m, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -97.26, -113.03, -113.58. [00336] Synthesis of Compound 26: N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl)acetamide [00339] To a stirred solution of 2-chloro-4-iodo-3-methoxypyridine (500 mg, 1.86 mmol) and tert-butyl[(1-methoxyethenyl)oxy]dimethylsilane (1.75 g, 9.28 mmol) in N,N- dimethylformamide (8 mL) were added zinc fluoride (959 mg, 9.28 mmol) and bis(tri-tert- butylphosphine) palladium (190 mg, 0.371 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 110 °C under nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction was cooled to room temperature, then was quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (170 mg, 42.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C9H10ClNO3: 216.03, found 216.05. [00340] Step 2: Preparation of methyl 2-[2-(3,5-difluorophenyl)-3-methoxypyridin-4- yl]acetate [00341] To a stirred solution of methyl 2-(2-chloro-3-methoxypyridin-4-yl)acetate (190 mg, 0.881 mmol) and 3,5-difluorophenylboronic acid (348 mg, 2.20 mmol) in 1,4-dioxane/water (10:1, 5.5 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (64.5 mg, 0.088 mmol) and potassium carbonate (365 mg, 2.64 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction was cooled to room temperature, then was quenched with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 dichloromethane/methanol) to provide the title compound as a yellow oil (180 mg, 69.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H13F2NO3: 294.09, found 293.95. [00342] Step 3: Preparation of [2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl]acetic acid [00343] To a stirred solution of methyl 2-[2-(3,5-difluorophenyl)-3-methoxypyridin-4- yl]acetate (150 mg, 0.511 mmol) in methanol/tetrahydrofuran/water (1:1:1, 6 mL) was added lithium hydroxide (61.25 mg, 2.56 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The mixture was acidified to pH = 4 with 2 M hydrochloric acid, then the resulting mixture was extracted with 10:1 dichloromethane/methanol (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated, to provide the title compound as a yellow oil (100 mg, 70.0% yield). LCMS (ESI): m/z [M+H]+ calcd for C14H11F2NO3: 280.07, found 280.15. [00344] Step 4: Preparation of N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1- yl)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl)acetamide (Compound 26) [00345] To a stirred solution of [2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl]acetic acid (70 mg, 0.251 mmol) and Intermediate 1 (65.5 mg, 0.251 mmol) in N,N-dimethylformamide (4 mL) was added HATU (124 mg, 0.326 mmol,) in portions at room temperature. To the above mixture was added N,N-diisopropylethylamine (97.2 mg, 0.753 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (20 mL), then the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column (55-65% methanol/water with 0.05% ammonium bicarbonate) to provide the title compound as a white solid (33.6 mg, 25.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C27H34F4N4O2: 523.27, found 523.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.37 – 8.47 (m, 1H), 7.59 – 7.67 (m, 2H), 7.41– 7.46 (m, 1H), 7.02 – 7.11 (m, 1H), 6.63 – 6.72 (m, 1H), 4.17 – 4.31 (m, 1H), 3.64– 3.77 (m, 2H), 3.53 – 3.61 (m, 3H), 2.49 – 2.69 (m, 4H), 2.21 – 2.42 (m, 6H), 2.03 – 2.17 (m, 1H), 1.63 – 1.97 (m, 3H), 1.13 – 1.51 (m, 2H), 0.86 – 1.03 (m, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -96.40, -111.87, -112.86. [00346] Synthesis of Compound 27: N-((1R,6S)-6-(4-cyclobutylpiperazin-1-yl)-2,2- difluorocyclohexyl)-2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)acetamide [00347] Scheme 16
Figure imgf000105_0001
erazin-1-yl)-2,2- difluorocyclohexyl]-4-nitrobenzenesulfonamide [00349] To a solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (100 mg, 0.314 mmol) in toluene (10 mL) was added 1- cyclobutylpiperazine (52.9 mg, 0.377 mmol). The reaction was stirred at 110 °C for 2 h, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow oil (140 mg, 87.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C20H28F2N4O4S: 459.18, found 459.15. [00350] Step 2: Preparation of (1R,6S)-6-(4-cyclobutylpiperazin-1-yl)-2,2- difluorocyclohexan-1-amine [00351] To a solution of N-[(1R,6S)-6-(4-cyclobutylpiperazin-1-yl)-2,2-difluorocyclohexyl]-4- nitrobenzenesulfonamide (130 mg, 0.284 mmol) in toluene (10 mL) was added sodium benzenethiolate (187 mg, 1.42 mmol). The reaction was stirred at 100 °C for 2 h, then was quenched with water (10 mL) and extracted with dichloromethane (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0- 100% gradient) to provide the title compound (55 mg, 70.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C19H33F2N3O2: 274.21, found 274.20. [00352] Step 3: Preparation of N-((1R,6S)-6-(4-cyclobutylpiperazin-1-yl)-2,2- difluorocyclohexyl)-2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 27) [00353] To a solution of (1R,6S)-6-(4-cyclobutylpiperazin-1-yl)-2,2-difluorocyclohexan-1- amine (50 mg, 0.183 mmol) in N,N-dimethylformamide (10 mL) was added {2-cyclopropyl-3',5'- difluoro-[1,1'-biphenyl]-3-yl}acetic acid (52.7 mg, 0.183 mmol) and HATU (90.4 mg, 0.238 mmol). Then N,N-diisopropylethylamine (106 mg, 0.824 mmol) was added at 0 °C. The reaction was stirred at room temperature for 1 h, at which point the reaction was judged complete by LCMS. The mixture was diluted with water (10 mL), then extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP 18 OBD 30 mm x 150 mm x 5 μm column (53-83% acetonitrile/water with 10 mM ammonium bicarbonate and 0.1% aqueous ammonia) to provide the title compound as a white solid (20.7 mg, 20.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C31H37F4N3O: 544.29, found 544.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.36 – 7.47 (m, 1H), 7.28 – 7.36 (m, 1H), 7.16 – 7.28 (m, 1H), 7.01 – 7.15 (m, 2H), 6.88 – 7.01 (m, 1H), 6.18 – 6.57 (m, 1H), 4.19 – 4.51 (m, 1H), 4.69 – 4.06 (m, 2H), 2.53 – 2.71 (m, 4H), 2.38 – 2.49 (m, 2H), 2.21 – 2.31 (m, 2H), 2.01 – 2.17 (m, 4H), 1.87 – 1.96 (m, 2H), 1.70 – 1.87 (m, 4H), 1.59 – 1.70 (m, 2H), 1.31 – 1.48 (m, 2H), 1.29 – 1.31 (m, 1H), 0.72 – 0.95 (m, 2H), 0.07 – 0.20 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -96.65, -112.83, -113.53. [00354] Compound 28: 2-(2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)-2,2- difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide [00355] The title compo 15. LCMS (ESI): m/z [M+H]+ calcd for C28H33ClF4N2O2: 541.22, found 541.15. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.23 – 7.42 (m, 2H), 7.08 – 7.21 (m, 1H), 6.81 – 7.05 (m, 3H), 6.68 (d, J = 9.0 Hz, 1H), 4.02 – 4.27 (m, 1H), 3.79 (s, 2H), 3.28 – 3.46 (m, 2H), 2.62 – 2.74 (m, 3H), 1.97 – 2.08 (m, 3H), 1.57 – 1.79 (m, 4H), 1.02 – 1.45 (m, 5H), 0.96 (d, J = 6 Hz, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -98.97, -111.81, -111.86. [00356] Compound 29: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-(1,8-diazaspiro[4.5]decan-8-yl)cyclohexyl)acetamide [00357] The title compound
Figure imgf000108_0001
21. LCMS (ESI): m/z [M+H]+ calcd for C31H37F4N3O: 544.29, found 544.10. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.39 (s, 1H), 7.38 – 7.43 (m, 1H), 7.29-7.38 (m, 1H), 7.09 – 7.29 (m, 1H), 7.01 – 7.09 (m, 2H), 6.84 – 7.01 (m, 1H), 6.29 – 6.58 (m, 1H), 4.19 – 4.46 (m, 1H), 3.71 – 4.09 (m, 2H), 3.10 – 3.16 (m, 2H), 2.80 – 2.84 (m, 1H), 2.54 – 2.58 (m, 2H), 2.39 – 2.41 (m, 1H), 2.00 – 2.18 (m, 3H), 1.84 – 1.92 (m, 3H), 1.16 – 1.83 (m, 7H), 1.52 – 1.61 (m, 1H), 1.31 – 1.48 (m, 2H), 0.75 – 0.87 (m, 2H), 0.02 – 0.29 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -96.55, -112.77, -113.63. [00358] Synthesis of Compound 30: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)- N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide [00361] To a stirred solution of methyl 2-(2-bromo-3-chlorophenyl)acetate (2.00 g, 7.59 mmol) and cyclopropylboronic acid (1.96 g, 22.8 mmol) in toluene/water (7:1, 16 mL) were added sodium carbonate (2.01 g, 19.0 mmol) and palladium (II) acetate (0.17 g, 0.759 mmol) in portions at room temperature. To the above mixture was added di(1-adamantyl)-n- butylphosphine (0.54 g, 1.52 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at 90 °C under a nitrogen atmosphere, at which point the reaction was judged complete by GCMS. After cooling down to room temperature, the reaction was quenched with water (50 mL), and the resulting mixture was extracted with ethyl acetate (5 x 40 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography(1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (1.7 g, 99.7% yield). GC/MS (EI): m/z [M]+ calcd for C12H13ClO: 224.06, found 224.09. [00362] Step 2: Preparation of methyl 2-{2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3- yl}acetate [00363] To a stirred solution of methyl 2-(3-chloro-2-cyclopropylphenyl)acetate (1.7 g, 7.57 mmol) and 3,5-difluorophenylboronic acid (2.39 g, 15.1 mmol) in tetrahydrofuran/water (4:1, 10 mL) were added X-Phos (0.36 g, 0.757 mmol) and X-Phos-Pd-G3 (0.64 g, 0.757 mmol) in portions at room temperature. To the above mixture was added potassium phosphate tribasic (4.02 g, 18.9 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 80 °C under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction was cooled to room temperature, then quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 methanol/dichloromethane) to provide the title compound as a yellow oil (2.1 g, 91.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C18H16F2O2: 303.12, found 303.10. [00364] Step 3: Preparation of {2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}acetic acid [00365] To a stirred solution of methyl 2-{2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3- yl}acetate (2.1 g, 6.95 mmol) in tetrahydrofuran/water/methanol (1:1:1, 12 mL) was added lithium hydroxide (0.83 g, 34.7 mmol) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature, at which point the reaction was judged complete by LCMS. The mixture was acidified to pH = 4 with 2 M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated, to provide the title compound as a yellow oil (2.0 g, 99.9% yield). LCMS (ESI): m/z [M-H]- calcd for C17H14F2O2: 287.10, found 287.05. [00366] Step 4: Preparation of tert-butyl 4-{[(1S,2R)-2-(2-{2-cyclopropyl-3',5'-difluoro- [1,1'-biphenyl]-3-yl} acetamido)-3,3-difluorocyclohexyl]oxy}piperidine-1-carboxylate [00367] To a stirred solution of {2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl} acetic acid (280 mg, 0.971 mmol) and tert-butyl 4-{[(1S,2R)-2-amino-3,3- difluorocyclohexyl]oxy}piperidine-1-carboxylate (325 mg, 0.971 mmol) in N,N- dimethylformamide (8 mL) was added HATU (480 mg, 1.26 mmol) in portions at room temperature. To the above mixture was added N,N-diisopropylethylamine (377 mg, 2.91 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (30 mL), then the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:5 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (300 mg, 51.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C33H40F4N2O4: 605.30, found 605.25. [00368] Step 5: Preparation of 2-{2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}-N- [(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl]acetamide [00369] To a stirred solution of tert-butyl 4-{[(1S,2R)-2-(2-{2-cyclopropyl-3',5'-difluoro-[1,1'- biphenyl]-3-yl}acetamido)-3,3-difluorocyclohexyl]oxy}piperidine-1-carboxylate (300 mg, 0.496 mmol) in 1,4-dioxane (3 mL) was added 4 M hydrochloride acid in 1,4-dioxane (3 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature, at which point the reaction was judged complete by LCMS. The resulting mixture was concentrated under vacuum to provide the title compound as a yellow oil, which was used without purification (230 mg, 91.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F4N2O2: 505.24, found 505.25. [00370] Step 6: Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 30) [00371] To a stirred solution of 2-{2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}-N- [(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl]acetamide (200 mg, 0.396 mmol) in methanol (6 mL) was added acetone (69.1 mg, 1.19 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature. To the above mixture was then added sodium cyanoborohydride (125 mg, 1.98 mmol) in portions at 0 °C. The resulting mixture was stirred overnight at room temperature, after which the reaction was judged complete by LCMS. The reaction was quenched with water (30 mL), then the resulting mixture was extracted with dichloromethane (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column (55-65% methanol/water with 0.05% ammonium bicarbonate) to provide the title compound as a white solid (81.8 mg, 36.2% yield). LCMS (ESI): m/z [M+H]+ calcd for C31H38F4N2O2: 547.29, found:547.30. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.26 – 7.37 (m, 2H), 7.13 – 7.23 (m, 1H), 7.01 – 7.10 (m, 2H), 6.88 – 6.99 (m, 1H), 6.58 – 6.71 (m, 1H), 4.09 – 4.26 (m, 1H), 3.78 – 4.04 (m, 2H), 3.31 – 3.50 (m, 2H), 2.68 – 2.79 (m, 3H), 2.07 – 2.14 (m, 2H), 1.99 – 2.04 (m, 1H), 1.68 – 1.92 (m, 5H), 1.22 – 1.58 (m, 5H), 0.88 – 1.09 (m, 6H), 0.71 – 0.88 (m, 2H), 0.03 – 0.21 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.66, -112.57, -112.79. [00372] Compound 31: N-((1R,6S)-6-((1-cyclobutylpiperidin-4-yl)oxy)-2,2- difluorocyclohexyl)-2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)acetamide [00373] The title
Figure imgf000112_0001
30. LCMS (ESI): m/z [M+H]+ calcd for C32H38F4N2O2: 559.29, found 559.30. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.27 - 7.37 (m, 2H), 7.13 – 7.24 (m, 1H), 7.02 – 7.11 (m, 2H), 6.91 – 7.01 (m, 1H), 6.51 – 6.63 (m, 1H), 4.09 – 4.24 (m, 1H), 3.78 – 4.03 (m, 2H), 3.17 – 3.51 (m, 2H), 2.47 – 2.72 (m, 3H), 2.08 – 2.19 (m, 4H), 1.98 – 2.07 (m, 2H), 1.70 – 1.91 (m, 7H), 1.59 – 1.68 (m, 2H), 1.27 – 1.48 (m, 4H), 0.72 – 0.88 (m, 2H), 0.05 – 0.18 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.67, -112.59, -112.80. [00374] Compound 32: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-((1-methylpiperidin-4-yl)oxy)cyclohexyl)acetamide [00375] The title compou d 30. LCMS (ESI): m/z [M+H]+ calcd for C29H34F4N2O2: 519.26, found 519.30. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.28 – 7.37 (m, 2H), 7.14 – 7.25 (m, 1H), 7.01 – 7.13 – 7.00 (m, 1H), 6.41 – 6.70
Figure imgf000113_0001
(m, 1H), 4.11 – 4.24 (m, 1H), 3.74 – 4.04 (m, 2H), 3.32 – 3.58 (m, 2H), 2.54 – 2.71 (m, 2H), 2.14 – 2.21 (m, 3H), 1.99 – 2.14 (m, 4H), 1.70 – 1.92 (m, 4H), 1.24 – 1.53 (m, 5H), 0.71 – 0.87 (m, 2H), 0.06 – 0.17 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.68, -111.76, -112.60. [00376] Compound 33: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-(1-methyl-1,8-diazaspiro[4.5]decan-8-yl)cyclohexyl)acetamide [00377] The title compound
Figure imgf000113_0002
21. LCMS (ESI): m/z [M+H]+ calcd for C32H39F4N3O: 558.31, found 558.35. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.29 – 7.45 (m, 2H), 7.19 – 7.29 (m, 1H), 7.00 – 7.14 (m, 2H), 6.88 – 7.00 (m, 1H), 6.29 – 6.47 (m, 1H), 4.17 – 4.50 (m, 1H), 3.75 – 4.10 (m, 2H), 2.53 – 2.85 (m, 6H), 2.21 – 2.31 (m, 2H), 2.13 – 2.19 (m, 2H), 1.98 – 2.13 (m, 2H), 1.74 – 1.95 (m, 3H), 1.60 – 1.74 (m, 5H), 1.35 – 1.50 (m, 3H), 1.20 – 1.29 (m, 1H), 1.11 – 1.20 (m, 1H), 0.73 – 0.89 (m, 2H), 0.02 – 0.24 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -96.59, -112.79, -113.60. [00378] Synthesis of Compound 34: N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide H nitrophenyl) sulfonamido)cyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00381] To a solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7-azabicyclo [4.1.0] heptane (140 mg, 0.440 mmol) in N-methyl-2-pyrrolidone (0.1 mL) was added tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (193 mg, 0.880 mmol). The reaction was stirred at 150 °C for 2 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-100% gradient) to provide the title compound as a yellow oil (106 mg, 42% yield). [00382] Step 2: Preparation of tert-butyl (3R,4S)-4-(((1S,2R)-2-amino-3,3- difluorocyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00383] To a solution of tert-butyl (3R,4S)-4-{[(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate (100 mg, 0.186 mmol) in toluene (5 mL) was added sodium benzenethiolate (147 mg, 1.12 mmol). The reaction was stirred at 100 °C for 3 h, then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-100% gradient) to provide the title compound as a black solid (300 mg, 78.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C16H27F3N2O3: 353.20, found 353.15. [00384] Step 3: Preparation of tert-butyl (3R,4S)-4-(((1S,2R)-3,3-difluoro-2-(2-(2,3',5'- trifluoro-[1,1'-biphenyl]-3-yl) acetamido)cyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00385] To a solution of tert-butyl (3R,4S)-4-{[(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy}- 3-fluoropiperidine-1-carboxylate (60 mg, 0.170 mmol) in N,N-dimethylformamide (4 mL) was added {2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}acetic acid (54.4 mg, 0.204 mmol), HATU (97.1 mg, 0.255 mmol) and N,N-diisopropylethylamine (110 mg, 0.851 mmol). The reaction was stirred at room temperature for 3 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-100% gradient) to provide the title compound as a yellow oil (80 mg, 67% yield). LCMS (ESI): m/z [M+H]+ calcd for C30H34F6N2O4: 601.25, found 501.10 [M+H-Boc]+. [00386] Step 4: Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide [00387] To a solution of tert-butyl (3R,4S)-4-{[(1S,2R)-3,3-difluoro-2-(2-{2,3',5'-trifluoro- [1,1'-biphenyl]-3-yl}acetamido)cyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate (75 mg, 0.125 mmol) in 1,4-dioxane (2 mL) was added 4M hydrochloric acid in 1,4-dioxane (2 mL). The reaction was stirred at room temperature for 2 h, then was concentrated to provide the title compound as a yellow oil, which was used without purification (55 mg, 88% yield). LCMS (ESI): m/z [M+H]+ calcd for C25H26F6N2O2: 501.19, found 501.15. [00388] Step 5: Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 34) [00389] To a solution of N-[(1R,6S)-2,2-difluoro-6-{[(3R,4S)-3-fluoropiperidin-4- yl]oxy}cyclohexyl]-2-{2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}acetamide (80 mg, 0.160 mmol) in methanol (3 mL) was added acetone (92.8 mg, 1.60 mmol) and sodium cyanoborohydride (40.2 mg, 0.639 mmol). The reaction was stirred at room temperature for 12 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 μm column (49-73% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (23.5 mg, 26.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F6N2O2: 543.24, found 543.10. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.37 - 7.50 (m, 2H), 7.14 - 7.36 (m, 3H), 6.95 - 7.09 (m, 1H), 6.80 (d, J = 12.0 Hz, 1H), 4.47 - 4.73 (m, 1H), 4.08 - 4.30 (m, 1H), 3.38 - 3.69 (m, 3H), 3.20 - 3.35 (m, 1H), 2.50 - 2.79 (m, 2H), 2.22 - 2.49 (m, 2H), 2.03 - 2.19 (m, 2H), 1.90 - 2.00 (m, 1H), 1.62 - 1.83 (m, 2H), 1.50 - 1.61 (m, 1H), 1.38 - 1.49 (m, 1H), 1.18 - 1.37 (m, 2H), 0.90 - 1.00 (m, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -98.43, -111.54, - 111.86, -122.58. [00390] Synthesis of Compound 35: N-((1R,6S)-2,2-difluoro-6-(((3S,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide
[00391] Scheme 19 F NBoc F
Figure imgf000117_0001
- - nitrophenyl) sulfonamido)cyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00393] To a solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (150 mg, 0.471 mmol) in N-methyl-2-pyrrolidone (0.1 mL) was added tert-butyl (3S,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (207 mg, 0.943 mmol). The reaction was stirred at 150 °C for 3 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-100% gradient) to provide the title compound as a yellow oil (280 mg, 98% yield). [00394] Step 2: Preparation of tert-butyl (3S,4S)-4-(((1S,2R)-2-amino-3,3- difluorocyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00395] To a solution of tert-butyl (3S,4S)-4-{[(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate (240 mg, 0.446 mmol) in toluene (5 mL) was added sodium benzenethiolate (359 mg, 2.72 mmol). The reaction was stirred at 100 °C for 3 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-100% gradient) to provide the title compound as a yellow oil (160 mg, 89% yield). LCMS (ESI): m/z [M+H]+ calcd for C16H27F3N2O3: 353.20, found 353.20. [00396] Step 3: Preparation of tert-butyl (3S,4S)-4-(((1S,2R)-3,3-difluoro-2-(2-(2,3',5'- trifluoro-[1,1'-biphenyl]-3-yl)acetamido)cyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00397] To a solution of tert-butyl (3S,4S)-4-{[(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy}- 3-fluoropiperidine-1-carboxylate (240 mg, 0.681 mmol) in N,N-dimethylformamide (4 mL) was added {2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}acetic acid (218 mg, 0.817 mmol), HATU (388 mg, 1.02 mmol) and N,N-diisopropylethylamine (440 mg, 3.41 mmol). The reaction was stirred at room temperature for 3 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-100% gradient) to provide the title compound as a yellow oil (120 mg, 44% yield). [00398] Step 4: Preparation of N-((1R,6S)-2,2-difluoro-6-(((3S,4S)-3-fluoropiperidin-4- yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide [00399] To a solution of tert-butyl (3S,4S)-4-{[(1S,2R)-3,3-difluoro-2-(2-{2,3',5'-trifluoro- [1,1'-biphenyl]-3-yl}acetamido)cyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate (110 mg, 0.183 mmol) in 1,4-dioxane (2.0 mL) was added 4M hydrochloric acid in 1,4-dioxane (2.0 mL). The reaction was stirred at room temperature for 3 h, then was concentrated to provide the title compound as a yellow oil, which was used without purification (85 mg, 93% yield). LCMS (ESI): m/z [M+H]+ calcd for C25H26F6N2O2: 501.19, found 501.15. [00400] Step 5: Preparation of N-((1R,6S)-2,2-difluoro-6-(((3S,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide (Compound 35) [00401] To a solution of N-[(1R,6S)-2,2-difluoro-6-{[(3S,4S)-3-fluoropiperidin-4- yl]oxy}cyclohexyl]-2-{2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl}acetamide (100 mg, 0.200 mmol) in methanol (5 mL) was added acetone (116 mg, 2.00 mmol) and sodium cyanoborohydride (50.2 mg, 0.799 mmol). The reaction was stirred at room temperature for 12 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 μm column (49-73% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (24.4 mg, 22.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F6N2O2: 543.24, found 543.15. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.39 - 7.50 (m, 2H), 7.17 - 7.38 (m, 3H), 6.95 - 7.08 (m, (d, J = 12.0 Hz, 1H), 3.90 - 4.30 (m, 2H), 3.50 - 3.73 (m, 2H),
Figure imgf000119_0001
3.21 - 3.48 (m, 2H), 2.80 - 3.00 (m, 1H), 2.55 - 2.72 (m, 1H), 2.38 - 2.50 (m, 1H), 1.92 - 2.05 (m, 3H), 1.56 - 1.79 (m, 3H), 1.22 - 1.41 (m, 2H), 1.00 - 1.21 (m, 2H), 0.75 - 0.98 (m, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -98.44, -111.54, -111.86, -122.91, -187.89. [00402] Synthesis of Compound 36: N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl)acetamide
[00404] Step 1: Preparation of tert-butyl 4-{[(1S,2R)-2-{2-[2-(3,5-difluorophenyl)-3- methoxypyridin-4-yl]acetamido}-3,3-difluorocyclohexyl]oxy}piperidine-1-carboxylate [00405] To a stirred solution [2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl]acetic acid (60 mg, 0.215 mmol) and tert-butyl 4-{[(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy}piperidine-1- carboxylate (71.9 mg, 0.215 mmol) in N,N-dimethylformamide (3 mL) was added HATU (106 mg, 0.280 mmol) in portions at room temperature. To the above mixture was added N,N- diisopropylethylamine (83.3 mg, 0.645 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (15 mL), then the resulting mixture was extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (120 mg, 93.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C30H37F4N3O5: 596.27, found 596.30. [00406] Step 2: Preparation of N-[(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy) cyclohexyl]- 2-[2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl]acetamide [00407] To a stirred solution of tert-butyl 4-{[(1S,2R)-2-{2-[2-(3,5-difluorophenyl)-3- methoxypyridin-4-yl]acetamido}-3,3-difluorocyclohexyl]oxy}piperidine-1-carboxylate (120 mg, 0.201 mmol) in 1,4-dioxane (3 mL) was added 4M hydrochloric acid in 1,4-dioxane (3 mL) in portions at room temperature. Once the reaction was judged complete by LCMS the solution was concentrated to provide the title compound as a yellow oil, which was used without purification (90 mg, 90.2% yield). LCMS (ESI): m/z [M+H]+ calcd for C25H29F4N3O3: 496.22, found 496.1. [00408] Step 3: Preparation of N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-methoxypyridin-4-yl)acetamide (Compound 36) [00409] To a stirred solution of N-[(1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl]-2-[2- (3,5-difluorophenyl)-3-methoxypyridin-4-yl]acetamide (60 mg, 0.121 mmol) in dichloroethane (3 mL) was added acetone (21.1 mg, 0.363 mmol) at room temperature. The resulting mixture was stirred for 30 min at room temperature. To the above mixture was added sodium triacetoxyborohydride (128 mg, 0.605 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (15 mL), then the resulting mixture was extracted with dichloromethane (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column (55-65% methanol/water with 0.05% ammonium bicarbonate) to provide the title compound as a white solid (7.4 mg, 11.3% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H35F4N3O3: 538.26, found 538.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.23 – 8.55 (m, 1H), 7.53 – 7.81 (m, 2H), 7.21 – 7.48 –7.19 (m, 1H), 6.74 –6.98
Figure imgf000121_0001
(m, 1H), 3.98 –4.39 (m, 1H), 3.69 –3.88 (m, 2H), 3.48 –3.62 (m, 3H), 3.27 –3.46 (m, 2H), 2.58 – 2.81 (m, 3H), 2.09 –2.11 (m, 1H), 1.69 –1.92 (m, 5H), 1.32 –1.52 (m, 5H), 1.28 –1.31 (m, 1H), 0.89 –1.08 (m, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.87, -111.94, -112.58. [00410] Synthesis of Compound 37: N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl)acetamide
[00412] To a stirred solution of [2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl]acetic acid (30 mg, 0.112 mmol) and Intermediate 2 (31.0 mg, 0.112 mmol) in N,N-dimethylformamide (2 mL) was added HATU (55.5 mg, 0.146 mmol) in portions at room temperature. To the above mixture was added N,N-diisopropylethylamine (43.5 mg, 0.336 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (15 mL), then the resulting mixture was extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column (55-65% methanol/water with 0.05% ammonium bicarbonate) to provide the title compound as an off-white solid (20.5 mg, 33.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C27H32F5N3O2: 526.24, found 526.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.39 – 8.68 (m, 1H), 7.58 – 7.69 (m, 2H), 7.38 – 7.52 (m, 1H), 7.01 – 7.17 (m, 1H), 7.72 – 7.91 (m, 1H), 4.06 – 4.29 (m, 1H), 3.63 – 3.81 (m, 2H), 3.25 – 3.43 (m, 2H), 2.53 – 2.72 (m, 3H), 2.07 – 2.11 (m, 3H), 1.67 – 1.88 (m,4H), 1.28 – 1.49 (m, 5H), 0.92 – 0.99 (m, 6H).19F NMR (376 MHz, Acetonitrile-d3) δ -99.02, -111.29, 129.26. [00413] Compound 38: N-((1R,6S)-6-((1-cyclopentylpiperidin-4-yl)oxy)-2,2- difluorocyclohexyl)-2-(2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)acetamide [00414] The title
Figure imgf000122_0001
LCMS (ESI): m/z [M+H]+ calcd for C30H35F5N2O2: 551.27, found 551.35. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.25-7.41 (s, 2H), 7.01-7.41 (m, 3H), 6.82-6.99 (m, 1H), 6.69 (d, J = 9.8 Hz), 3.91-4.18 (m, 1H), 3.50-3.68 (m, 2H), 3.38-3.50 (m, 1H), 3.18-3.38 (m, 1H), 2.65-2.80 (s, 3H), 2.26-2.32 (m, 1H), 1.93-2.11 (m, 2H), 1.60-1.80 (m, 6H), 1.50-1.60 (m, 2H), 1.32-1.50 (m, 7H), 1.10-1.32 (m, 2H). 19F NMR (282 MHz, Acetonitrile-d3) δ -98.37, -111.53, -111.87, -122.96. [00415] Synthesis of Compound 39: 2-(2-cyano-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide
Figure imgf000123_0001
acid [00418] To a solution of (3-bromo-2-chlorophenyl)acetic acid (500 mg, 2.00 mmol) in dimethoxyethane (12 mL) and water (1.2 mL) was added 3,5-difluorophenylboronic acid (316 mg, 2.00 mmol) and sodium bicarbonate (421 mg, 5.01 mmol). The reaction was stirred at 90 °C for 2 h under a nitrogen atmosphere, then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 μm column (49-73% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (240 mg, 42.4% yield). [00419] Step 2: Preparation of 2-{2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl}-N-[(1R,6S)- 2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl]acetamide [00420] To a solution of {2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl}acetic acid (117 mg, 0.414 mmol) in N,N-dimethylformamide (13 mL) was added Intermediate 1 (108 mg, 0.414 mmol) and N,N-diisopropylethylamine (80.2 mg, 0.621 mmol). The reaction was stirred at room temperature for 2 h, then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow oil (150 mg, 68.9% yield). [00421] Step 3: Preparation of 2-(2-cyano-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 39) [00422] To a solution of 2-{2-chloro-3',5'-difluoro-[1,1'-biphenyl]-3-yl}-N-[(1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl]acetamide (130 mg, 0.247 mmol) in N,N- dimethylformamide (13 mL) was added zinc cyanide (34.8 mg, 0.296 mmol), BrettPhos-Pd-G3 (44.4 mg, 0.049 mmol) and BrettPhos (26.53 mg, 0.049 mmol). The reaction was stirred at 120 °C for 2 h under a nitrogen atmosphere, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 μm column (49-73% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (9.9 mg, 7.49% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F4N4O: 517.25, found 517.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.67 – 7.76 (m, 1H), 7.60 – 7.67 (m, 1H), 7.46 – 7.53 (m, 1H), 7.28 – 7.18 (m, 2H), 7.11–7.18 (m, 1H), 6.64 (d, J = 9.7 Hz, 1H), 4.18 – 4.35 (m, 1H), 3.91 (s, 2H), 2.50 – 2.70 (m, 4H), 2.26 – 2.45 (m, 6H), 1.67 – 1.97 (m, 4H), 1.28 – 1.47 (m, 2H), 0.92 – 0.99 (m, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -96.52, -110.96, -112.91. [00423] Synthesis of Compound 40: 2-(3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4-yl)- N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide [00426] To a stirred solution of 3-bromo-2-chloropyridine-4-carbaldehyde (1 g, 4.54 mmol) and cyclopropylboronic acid (0.47 g, 5.44 mmol) in toluene/water (20:1. 10.5 mL) were added palladium (II) acetate (0.20 g, 0.907 mmol) and potassium phosphate tribasic (3.85 g, 18.1 mmol) in portions at room temperature. To the above mixture was added tricyclohexylphosphine (0.51 g, 1.81 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 100 °C under a nitrogen atmosphere, then was cooled to room temperature and quenched with water (30 mL). The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 methanol/dichloromethane) to provide the title compound as a yellow oil (350 mg, 42.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C9H8ClNO: 182.03, found 182.15. [00427] Step 2: Preparation of 3-cyclopropyl-2-(3,5-difluorophenyl)pyridine-4- carbaldehyde [00428] To a stirred solution of 2-chloro-3-cyclopropylpyridine-4-carbaldehyde (320 mg, 1.76 mmol) and 3,5-difluorophenylboronic acid (556 mg, 3.52 mmol) in 1,4-dioxane/water (10:1, 6.6 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (129 mg, 0.176 mmol) and potassium carbonate (731 mg, 5.29 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction was cooled to room temperature, then quenched with water (30 mL), and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 methanol/dichloromethane) to provide the title compound as a yellow oil (420 mg, 92.0% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H11F2NO: 260.08, found 260.05. [00429] Step 3: Preparation of 3-cyclopropyl-2-(3,5-difluorophenyl)-4-[(E)-2- methanesulfinyl-2-(methylsulfanyl)ethenyl] pyridine [00430] To a stirred solution of 3-cyclopropyl-2-(3,5-difluorophenyl)pyridine-4-carbaldehyde (400 mg, 1.54 mmol) and methyl (methylthio)methyl sulfoxide (230 mg, 1.85 mmol) in tetrahydrofuran (7 mL) was added benzyltrimethylammonium hydroxide (258 mg, 1.54 mmol) in portions at room temperature. The resulting mixture was stirred for 5 h at 60 °C, at which point the reaction was judged complete by TLC. The reaction was cooled to room temperature, then was quenched with water (30 mL). The resulting mixture was extracted with 10:1 dichloromethane/methanol (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (300 mg, 53.2% yield). [00431] Step 4: Preparation of ethyl 2-[3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4- yl]acetate [00432] To a stirred solution of 3-cyclopropyl-2-(3,5-difluorophenyl)-4-[(E)-2- methanesulfinyl-2-(methylsulfanyl)ethenyl]pyridine (250 mg, 0.684 mmol) in ethanol (5 mL) was added 4M hydrochloric acid in 1,4-dioxane (0.86 mL, 3.42 mmol) in portions at room temperature. The resulting mixture was stirred overnight at 80 °C, at which point the reaction was judged complete by LCMS. The reaction was cooled to room temperature, then was quenched with water (30 mL). The resulting mixture was extracted with 10:1 dichloromethane/methanol (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated, to provide the title compound as a yellow oil (180 mg, 82.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C18H17F2NO2: 318.13, found: 318.05. [00433] Step 5: Preparation of [3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4-yl]acetic acid [00434] To a stirred solution of ethyl 2-[3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4- yl]acetate (180 mg, 0.567 mmol) in tetrahydrofuran/methanol/water (1:1:1. 6 mL) was added lithium hydroxide (67.9 mg, 2.84 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The mixture was acidified to pH = 5 with 2M hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated, to provide the title compound as a yellow oil (160 mg, 97.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C16H13F2NO2: 290.09, found 290.05. [00435] Step 6: Preparation of 2-(3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 40) [00436] To a stirred solution of [3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4-yl]acetic acid (60 mg, 0.207 mmol) and Intermediate 2 (57.3 mg, 0.207 mmol) in N,N-dimethylformamide (3 mL) was added HATU (103 mg, 0.269 mmol) in portions at room temperature. To the above mixture was added N,N-diisopropylethylamine (80.4 mg, 0.621 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (15 mL), then the resulting mixture was extracted with ethyl acetate (3 x 15 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column (55-65% methanol/water with 0.05% ammonium bicarbonate) to provide the title compound as a white solid (18.4 mg, 16.2% yield). LCMS (ESI): m/z [M+H]+ calcd for C30H37F4N3O2: 548.29, found 548.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.32 – 8.56 (m, 1H), 7.19 – 7.35 (m, 3H), 6.94 – 7.11 (m, 1H), 6.68 – 6.88 (m, 1H), 4.11 – 4.31 (m, 1H), 3.82 – 4.01 (m, 2H), 3.32 – 3.52 (m,2H), 2.61– 2.79 (m, 3H), 2.21 – 2.25 (m, 1H), 1.99 – 2.18 (m, 3H), 1.72 – 1.87 (m, 4H), 1.29 – 1.51 (m, 5H),0.93 – 1.06 (m, 6H), 0.79 – 0.92 (m, 2H), 0.08 – 0.21 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.70, -111.83, -112.47. [00437] Synthesis of Compound 41: 2-(2-cyclopropyl-3-(5-fluoropyridin-3-yl)phenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide
[00439] Step 1: Preparation of methyl 2-[2-cyclopropyl-3-(5-fluoropyridin-3-yl) phenyl] acetate [00440] To a stirred solution of methyl 2-(3-chloro-2-cyclopropylphenyl) acetate (200 mg, 0.890 mmol) and 5-fluoropyridin-3-ylboronic acid (188 mg, 1.34 mmol) in tetrahydrofuran/water (4:1, 10 mL) were added XPhos (42.4 mg, 0.089 mmol), XPhos-Pd-G3 (75.4 mg, 0.089 mmol) and potassium phosphate tribasic (378 mg, 1.78 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (120 mg, 47.3% yield). LCMS (ESI): m/z [M+H]+ calcd for C17H16FNO2: 286.12, found 286.05. [00441] Step 2: Preparation of [2-cyclopropyl-3-(5-fluoropyridin-3-yl) phenyl] acetic acid [00442] A solution of methyl 2-[2-cyclopropyl-3-(5-fluoropyridin-3-yl) phenyl] acetate (120 mg, 0.421 mmol) and lithium hydroxide (50.4 mg, 2.11 mmol) in methanol/tetrahydrofuran/water (1:1:1, 5 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH = 4 with 2M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the title compound as a white solid, which was used without further purification (110 mg, 96.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C16H14FNO2: 272.10, found 272.10. [00443] Step 3: Preparation of 2-(2-cyclopropyl-3-(5-fluoropyridin-3-yl)phenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 41) [00444] To a stirred solution of [2-cyclopropyl-3-(5-fluoropyridin-3-yl) phenyl] acetic acid (58.9 mg, 0.217 mmol) and HATU (89.4 mg, 0.235 mmol) in N,N-dimethylformamide (10 mL) were added Intermediate 2 (50 mg, 0.181 mmol) and N,N-diisopropylethylamine (93.5 mg, 0.724 mmol) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature, then was quenched by addition of water. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC using a XBridge Prep OBD C18 Column 150 mm x 30 mm x 5 μm column (25-55% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (24.2 mg, 24.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C30H38F3N3O2: 530.29, found 530.35. 1H NMR (300 MHz, Acetonitrile-d3) δ 8.30 – 8.50 (m, 2H), 7.52 (ddd, J = 10.0, 2.8, 1.8 Hz, 1H), 7.23 – 7.35 (m, 2H), 7.15 (dd, J = 5.7, 3.5 Hz, 1H), 6.53 (d, J = 9.8 Hz, 1H), 4.18 (dtd, J = 24.5, 10.1, 3.9 Hz, 1H), 3.70 – 4.00 (m, 2H), 3.40 (dq, J = 10.2, 5.7, 5.2 Hz, 2H), 2.52 – 2.76 (m, 3H), 2.12 – 2.22 (m, 2H), 1.97 – 2.08 (m, 2H), 1.93 (s, 1H), 1.62 – 1.82 (m, 4H), 1.20 – 1.45 (m, 4H), 0.82 – 0.99 (m, 6H), 0.60 – 0.78 (m, 2H), 0.16 – 0.03 (m, 2H). 19F NMR (282 MHz, Acetonitrile-d3) δ -97.903, -111.825, - 130.289. [00445] Synthesis of Compound 42: 2-(2-cyclopropyl-3-(5-methoxypyridin-3-yl)phenyl)- N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide
[00447] Step 1: Preparation of methyl 2-[2-cyclopropyl-3-(5-methoxypyridin-3-yl)phenyl] acetate [00448] To a stirred solution of methyl 2-(3-chloro-2-cyclopropylphenyl) acetate (200 mg, 0.890 mmol) and 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (314 mg, 1.34 mmol) in tetrahydrofuran/water (4:1, 10 mL) were added XPhos (42.4 mg, 0.089 mmol), XPhos-Pd-G3 (75.4 mg, 0.089 mmol) and potassium phosphate tribasic (378 mg, 1.78 mmol) at room temperature. The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. The mixture was then cooled to room temperature, quenched by addition of water, and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (170 mg, 64.2% yield). LCMS (ESI): m/z [M+H]+ calcd for C18H19NO3: 298.14, found 298.25. [00449] Step 2: Preparation of [2-cyclopropyl-3-(5-methoxypyridin-3-yl)phenyl] acetic acid [00450] A solution of methyl 2-[2-cyclopropyl-3-(5-methoxypyridin-3-yl) phenyl] acetate (170 mg, 0.572 mmol) and lithium hydroxide (68.5 mg, 2.86 mmol) in methanol/tetrahydrofuran/water (1:1:1, 5 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH = 4 with 2M hydrochloric acid. The reaction was then diluted with water, and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated, to provide the title compound as a white solid, which was used without further purification (120 mg, 74.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C17H17NO3: 284.12, found 284.10. [00451] Step 3: Preparation of 2-(2-cyclopropyl-3-(5-methoxypyridin-3-yl)phenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 42) [00452] To a stirred solution of [2-cyclopropyl-3-(5-methoxypyridin-3-yl)phenyl] acetic acid (73.8 mg, 0.260 mmol) and HATU (107 mg, 0.282 mmol) in N,N-dimethylformamide (5 mL) were added Intermediate 2 (60 mg, 0.217 mmol) and N,N-diisopropylethylamine (112 mg, 0.868 mmol) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with water, then the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP 18 OBD Column 150 mm x 30 mm x 5 μm column (30-60% acetonitrile/water with 10 mM ammonium bicarbonate + 0.1% aqueous ammonia) to provide the title compound as a white solid (34.0 mg, 28.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C31H41F2N3O3: 542.31, found 542.35.1H NMR (300 MHz, Acetonitrile-d3) δ 8.15 (dd, J = 12.6, 2.3 Hz, 2H), 7.22 – 7.40 (m, 3H), J = 4.6, 4.1 Hz, 1H), 6.60 (d, J = 9.7 Hz, 1H), 4.18 (dtd, J = 24.4, 10.1, 3.9 Hz, 1H), 3.78 – 3.98 (m, 5H), 3.20 – 3.40 (m, 2H), 2.55 – 2.70 (m, 3H), 2.15 – 2.00 (m, 1H), 1.98 – 2.10 (m, 3H), 1.90 – 1.98 (m, 1H), 1.60 – 1.80 (m, 4H), 1.20 – 1.39 (m, 4H), 0.88 – 1.00 (m, 6H), 0.66 (dtd, J = 7.9, 4.8, 3.3 Hz, 2H), 0.08 (dq, J = 5.6, 1.2 Hz, 2H). 19F NMR (282 MHz, Acetonitrile-d3) δ -97.879, -112.680. [00453] Compound 43: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)-6- (((S)-1-(cyclopropylmethyl)pyrrolidin-3-yl)oxy)-2,2-difluorocyclohexyl)acetamide [00454] The title
Figure imgf000132_0001
LCMS (ESI): m/z [M+H]+ calcd for C31H36F4N2O2: 545.27, found 545.30. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.26 – 7.36 (m, 2H), 7.18 – 7.24 (m, 1H), 7.01 – 7.10 (m, 2H), 6.91 – 7.01 (m, 1H), 6.68 (d, J = 9.8 Hz), 4.11 – 4.27 (m, 2H), 3.84 – 3.99 (m, 2H), 3.31 – 3.39 (m, 1H), 2.76 – 2.85 (m, 1H), 2.57 – 2.67 (m, 1H), 2.42 – 2.57 (m, 2H), 2.25 – 2.32 (m, 2H), 1.61 – 1.87 (m, 4H), 1.28 – 1.50 (m, 4H), 0.76 – 0.94 (m, 4H), 0.44 – 0.52 (m, 2H), 0.06 – 0.15 (m, 4H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.14, -111.84, -112.79. [00455] Compound 44: N-((1R,6S)-6-(4-cyclobutylpiperazin-1-yl)-2,2-difluorocyclohexyl)- 2-(3-cyclopropyl-2-(3,5-difluorophenyl)pyridin-4-yl)acetamide [00456] The title compound w ound 40. LCMS (ESI): m/z [M+H]+ calcd for C30H36F4N4O: 545.29, found 545.15. 1H NMR (300 MHz, Acetonitrile-d3) δ 8.19 – 8.40 (m, 1H), 7.14 – 7.28 (m, 1H), 6.99 – 7.14 (m, 2H), 6.69 – 6.96 (m, 1H), 6.32 – 6.52 (m, 1H), 4.00 – 4.32 (m, 1H), 3.75 (s, 2H), 2.38 – 2.51 (m, 4H), 2.19 – 2.30 (m, 2H), 1.85 – 2.01 (m, 5H), 1.68 – 1.77 (m, 4H), 1.41 – 1.69 (m, 6H), 1.12 – 1.31 (m, 2H), 0.67 – 0.81 (m, 2H), 0.08 – 0.25 (m, 2H). 19F NMR (282 MHz, Acetonitrile-d3) δ -96.50, -112.62, -113.47. [00457] Synthesis of Compound 45: 2-(3',5'-difluoro-2-(trifluoromethoxy)-[1,1'-biphenyl]- 3-yl)-N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide [00458] Scheme 26
Figure imgf000133_0001
O OCF3 O OCF3 OCF3 OCF O S 3 Br BH3-THF Br PCC S Br Br S
Figure imgf000134_0001
[00460] To a stirred solution of 3-bromo-2-(trifluoromethoxy)benzoic acid (2.0 g, 7.02 mmol) in tetrahydrofuran (3 mL) was added borane-tetrahydrofuran, 1M in tetrahydrofuran (40 mL) in portions at 0 °C. The resulting mixture was stirred overnight at room temperature, at which point the reaction was judged complete by TLC. The reaction was quenched by the addition of water (30 mL) at 0 °C, then the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a colorless oil (1.3 g, 68.4% yield). [00461] Step 2: 3-bromo-2-(trifluoromethoxy)benzaldehyde [00462] To a stirred solution of [3-bromo-2-(trifluoromethoxy)phenyl]methanol (1.6 g, 5.90 mmol) in dichloromethane (10 mL) was added pyridinium chlorochromate (3.82 g, 17.7 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by TLC. The reaction was quenched with water (30 mL), then the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (1.3 g, 81.9% yield) [00463] Step 3: Preparation of 1-bromo-3-[(E)-2-methanesulfinyl-2- (methylsulfanyl)ethenyl]-2(trifluoromethoxy)benzene [00464] To a stirred solution of 3-bromo-2-(trifluoromethoxy)benzaldehyde (500 mg, 1.86 mmol) and methyl (methylthio)methyl sulfoxide (277 mg, 2.23 mmol) in tetrahydrofuran (6 mL) was added benzyltrimethylammonium hydroxide (311 mg, 1.86 mmol) in portions at room temperature. The resulting mixture was stirred overnight at 60 °C, at which point the reaction was judged complete by TLC. The reaction was cooled to room temperature, quenched with water (30 mL), and the resulting mixture was extracted with 10:1 dichloromethane/methanol (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (250 mg, 35.9% yield). [00465] Step 4: Preparation of ethyl 2-[3-bromo-2-(trifluoromethoxy)phenyl]acetate [00466] To a stirred solution of 1-bromo-3-[(E)-2-methanesulfinyl-2-(methylsulfanyl)ethenyl]- 2-(trifluoromethoxy)benzene (250 mg, 0.666 mmol) in ethanol (5 mL) was added 4M hydrochloric acid in 1,4-dioxane (0.83 mL, 3.33 mmol) at room temperature. The resulting mixture was stirred for 5 h at 80 °C, at which point the reaction was judged complete by GCMS. The reaction was cooled to room temperature, then was quenched with water (30 mL), and the resulting mixture was extracted with 10:1 dichloromethane/methanol (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated, to provide the title compound as a yellow oil, which was used without further purification (150 mg, 68.8% yield). GC/MS (EI): m/z [M]+ calcd for C11H10BrF3O3: 325.98, found 326.00. [00467] Step 5: Preparation of [3-bromo-2-(trifluoromethoxy)phenyl]acetic acid [00468] To a stirred solution of ethyl 2-[3-bromo-2-(trifluoromethoxy)phenyl]acetate (160 mg, 0.489 mmol) in tetrahydrofuran/methanol/water (1:1:1, 6 mL) was added lithium hydroxide (58.6 mg, 2.45 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The mixture was acidified to pH = 5 with 2M hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated, to provide the title compound as a yellow oil, which was used without further purification (100 mg, 68.4% yield). LCMS (ESI): m/z [M-H]- calcd for C9H6BrF3O3: 296.95, found 297.15. [00469] Step 6: Preparation of 2-[3-bromo-2-(trifluoromethoxy) phenyl]-N-[(1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl]acetamide
Figure imgf000136_0001
[00470] To a stirred solution of [3-bromo-2-(trifluoromethoxy)phenyl]acetic acid (120 mg, 0.401 mmol) and Intermediate 1 (105 mg, 0.401 mmol) in N,N-dimethylformamide (5 mL) was added HATU (198 mg, 0.521 mmol) in portions at room temperature. To the above mixture was added N,N-diisopropylethylamine (156 mg, 1.20 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (30 mL), then the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 methanol/dichloromethane) to provide the title compound as a yellow oil (150 mg, 68.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C22H29BrF5N3O2: 542.14, found 542.10. [00471] Step 7: Preparation of 2-(3',5'-difluoro-2-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)- N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 45) [00472] To a stirred solution of 2-[3-bromo-2-(trifluoromethoxy)phenyl]-N-[(1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl]acetamide (80 mg, 0.147 mmol) and 3,5- difluorophenylboronic acid (116 mg, 0.735 mmol) in tetrahydrofuran/water (4:1, 5 mL) were added X-Phos (7.03 mg, 0.015 mmol) and X-Phos-Pd-G3 (12.5 mg, 0.015 mmol) in portions at room temperature. To the above mixture was added potassium phosphate tribasic (78.3 mg, 0.367 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 80 °C under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction was cooled to room temperature, then was quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column (55- 65% methanol/water with 0.05% ammonium bicarbonate) to provide the title compound as a white solid (12.5 mg, 14.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F7N3O2: 576.24, found 576.25. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.48 – 7.59 (m, 1H), 7.24 – 7.41 (m, 2H), 6.99 – 7.12 , 6.84 – 6.98 (m, 1H), 6.37 – 6.58 (m, 1H), 4.04 – 4.34 (m, 1H), 3.59 – 3.71 (m, 2H), – (m, 4H), 2.18 – 2.39 (m, 6H), 1.96 – 2.03 (m, 1H), 1.51 – 1.92 (m, 3H), 1.15 – 1.38 (m, 2H), 0.81 – 0.94 (m, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -57.10, -97.44, -111.63, -112.86. [00473] Synthesis of Compound 46: 2-(3',5'-difluoro-2-(trifluoromethyl)-[1,1'-biphenyl]- 3-yl)-N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide
[00475] Step 1: Preparation of 3-bromo-2-(trifluoromethyl)benzaldehyde [00476] To a stirred solution of [3-bromo-2-(trifluoromethyl)phenyl]methanol (1 g, 3.92 mmol) in dichloromethane (15 mL) were added pyridinium chlorochromate (2.54 g, 11.8 mmol) in portions at 0 °C. The resulting mixture was stirred for 3 h at room temperature, at which point the reaction was judged complete by TLC. The reaction was quenched with water (30 mL), then the resulting mixture was extracted with dichloromethane (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (700 mg, 42.3% yield). [00477] Step 2: Preparation of 1-bromo-3-[(E)-2-methanesulfinyl-2- (methylsulfanyl)ethenyl]-2-(trifluoromethyl)benzene [00478] To a stirred solution of 3-bromo-2-(trifluoromethyl)benzaldehyde (550 mg, 2.17 mmol) and methyl (methylthio)methyl sulfoxide (324 mg, 2.61 mmol) in tetrahydrofuran (10 mL) was added benzyltrimethylammonium hydroxide (364 mg, 2.17 mmol) in portions at room temperature. The resulting mixture was stirred for 12 h at 60 °C, at which point the reaction was judged complete by TLC. The reaction was quenched with water (20 mL), then the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:6 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (300 mg, 38.4% yield). [00479] Step 3: Preparation of ethyl 2-[3-bromo-2-(trifluoromethyl)phenyl]acetate [00480] To a stirred solution of 1-bromo-3-[(E)-2-methanesulfinyl-2-(methylsulfanyl)ethenyl]- 2-(trifluoromethyl)benzene (300 mg, 0.835 mmol) in ethanol (5 mL) were added 4M HCl in 1,4- dioxane (4.175 mmol) in portions at room temperature. The resulting mixture was stirred for 8 h at 80 °C, at which point the reaction was judged complete by TLC. The reaction was cooled to room temperature then concentrated, to provide the title compound as a yellow oil (200 mg, 77.0% yield), which was used without further purification. [00481] Step 4: [3-bromo-2-(trifluoromethyl)phenyl]acetic acid [00482] To a stirred solution of ethyl 2-[3-bromo-2-(trifluoromethyl)phenyl]acetate (250 mg, 0.804 mmol) in tetrahydrofuran/methanol/water (1:1:1, 5 mL) was added lithium hydroxide (96.2 mg, 4.02 mmol) in portions at 0 °C. The resulting mixture was stirred for 3 h at room temperature, at which point the reaction was judged complete by TLC. The mixture was acidified to pH = 5 with 2M hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated, to provide the title compound as a yellow oil (70 mg, 30.8% yield), which was used without further purification. [00483] Step 5: 2-[3-bromo-2-(trifluoromethyl)phenyl]-N-[(1R,6S)-2,2-difluoro-6-(4- isopropylpiperazin-1-yl)cyclohexyl]acetamide [00484] To a stirred solution of [3-bromo-2-(trifluoromethyl)phenyl]acetic acid (70 mg, 0.247 mmol) and Intermediate 1 (64.6 mg, 0.247 mmol) in N,N-dimethylformamide (5 mL) were added HATU (122 mg, 0.321 mmol) and N,N-diisopropylethylamine (95.9 mg, 0.741 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (30 mL), then the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (1:5 methanol/dichloromethane) to provide the title compound as a yellow oil (60 mg, 46.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C22H29BrF5N3O: 526.14, found 526.25. [00485] Step 6: Preparation of 2-(3',5'-difluoro-2-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)- N-((1R,6S)-2,2-difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl)acetamide (Compound 46) [00486] To a stirred solution of 2-[3-bromo-2-(trifluoromethyl)phenyl]-N-[(1R,6S)-2,2- difluoro-6-(4-isopropylpiperazin-1-yl)cyclohexyl]acetamide (60 mg, 0.114 mmol) and 3,5- difluorophenylboronic acid (36.0 mg, 0.228 mmol) in 1,4-dioxane/water (4:1, 5 mL) were added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.34 mg, 0.011 mmol) and potassium carbonate (47.3 mg, 0.342 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at 90 °C under a nitrogen atmosphere. The reaction was cooled to room temperature, then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by Prep-HPLC using a XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column (55-65% methanol/water with 0.05% ammonium bicarbonate) to provide the title compound as an off-white solid (45.9 mg, 71.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F7N3O: 560.25, found 560.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.53 – 7.66 (m, 2H), 7.23 – 7.30 (m, 1H), 6.90 – 7.02 (m, 3H), 6.50 (d, J = 9.6 Hz, 2H), 4.19 – 4.35 (m, 1H), 3.80 – 3.92 (m, 2H), 2.51 – 2.70 (m, 4H), 2.30 – 2.51 (m, 6H), 2.05 – 2.15 (m, 1H), 1.70 – 1.98 (m, 3H), 1.28 – 1.56 (m, 2H), 0.99 (dd, J = 6.6, 1.7 Hz, 6H).19F NMR (376 MHz, Acetonitrile- d3) δ -50.85, -96.75, -112.33. [00487] Synthesis of Compound 47: 2-(3-(5-chloropyridin-3-yl)-2-cyclopropylphenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide
[00489] Step 1: Preparation of methyl 2-[3-(5-chloropyridin-3-yl)-2-cyclopropylphenyl] acetate [00490] To a stirred solution of methyl 2-(3-chloro-2-cyclopropylphenyl) acetate (150 mg, 0.668 mmol) and 5-chloropyridin-3-ylboronic acid (158 mg, 1.00 mmol) in 1,4-dioxane/water (4:1, 5 mL) were added bis(acetonitrile)dichloropalladium(II) (17.3 mg, 0.067 mmol) and potassium phosphate tribasic (283 mg, 1.34 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 110 °C under a nitrogen atmosphere. The reaction was then cooled to room temperature, quenched by addition of water, and the resulting mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (1:5 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (50 mg, 24.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C17H16ClNO2: 302.09, found 302.10. [00491] Step 2: Preparation of [3-(5-chloropyridin-3-yl)-2-cyclopropylphenyl] acetic acid [00492] A solution of methyl 2-[3-(5-chloropyridin-3-yl)-2-cyclopropylphenyl] acetate (40 mg, 0.133 mmol) and lithium hydroxide (15.9 mg, 0.665 mmol) in methanol/tetrahydrofuran/water (1:1:1, 4 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH = 4 with 2N hydrochloric acid, then the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated, to provide the title compound as a white solid (36 mg, 94.4% yield), which was used without further purification. LCMS (ESI): m/z [M+H]+ calcd for C16H14ClNO2: 288.07, found 288.10. [00493] Step 3: Preparation of 2-(3-(5-chloropyridin-3-yl)-2-cyclopropylphenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 47) [00494] To a stirred solution of [3-(5-chloropyridin-3-yl)-2-cyclopropylphenyl] acetic acid (40 mg, 0.139 mmol) and HATU (68.7 mg, 0.181 mmol) in N,N-dimethylformamide (4 mL) were added Intermediate 2 (38.4 mg, 0.139 mmol) and N,N-diisopropylethylamine (71.9 mg, 0.556 mmol) in portions at 0°C. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched by addition of water, then the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC using a Xselect CSH Prep Fluoro- Phenyl Column 250 mm x 19 mm x 5 μm column (25-55% acetonitrile/water with 10 mM formic acid) to provide the title compound as a white solid (5.5 mg, 6.92% yield). LCMS (ESI): m/z [M+H]+ calcd for C30H38ClF2N3O2: 546.27, found 546.25. 1H NMR (400 MHz, Acetonitrile- d3) δ 8.57 (dd, J = 3.3, 2.1 Hz, 2H), 7.86 (t, J = 2.2 Hz, 1H), 7.35 (d, J = 4.6 Hz, 2H), 7.25 (q, J = 4.5, 4.0 Hz, 1H), 6.76 (d, J = 9.8 Hz, 1H), 4.22 (dtd, J = 24.3, 10.1, 3.8 Hz, 1H), 4.09 – 3.80 (m, 2H), 3.71 (s, 1H), 3.40 (d, J = 11.4 Hz, 1H), 3.15 – 3.28 (m, 1H), 2.97 – 3.07 (m, 2H), 2.82 (s, 2H), 2.09 – 2.17 (m, 4H), 1.72 – 1.90 (m, 4H), 1.39 – 1.55 (m, 2H), 1.26 – 1.36 (m, 1H), 1.10 – 1.26 (m, 6H), 0.72 – 0.86 (m, 2H), 0.03 – 0.16 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.0907, -111.7662. [00495] Compound 48: N-((1R,6S)-6-(((S)-1-(cyclopropylmethyl)pyrrolidin-3-yl)oxy)-2,2- difluorocyclohexyl)-2-(2-(3,5-difluorophenyl)-3-fluoropyridin-4-yl)acetamide [00496] The title
Figure imgf000142_0001
LCMS (ESI): m/z [M+H]+ calcd for C27H30F5N3O2: 524.23, found 524.20. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.32 – 8.56 (m, 1H), 7.57 – 7.62 (m, 2H), 7.39 – 7.51 (m, 1H), 7.04 – 7.17 (m, 1H), 6.79 – 6.99 (m, 1H), 4.01 – 4.29 (m, 2H), 3.71 – 3.82 (m, 2H), 3.22 – 3.41 (m, 1H), 2.69 – 2.88 (m, 1H), 2.32 – 2.62 (m, 3H), 2.19 – 2.22 (m, 1H), 1.71 – 1.86 (m, 2H), 1.55 – 1.69 (m, 1H), 1.28 – 1.49 (m, 4H), 0.71 – 0.96 (m, 2H), 0.36 – 0.59 (m, 2H), 0.02 – 0.18 (m, 3H). 19F NMR (376 MHz, Acetonitrile-d3) δ -99.07, -111.24, -111.84, -129.25. [00497] Compound 49: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-(((S)-1-((1-fluorocyclopropyl)methyl)pyrrolidin-3- yl)oxy)cyclohexyl)acetamide [00498] The title compo 50. LCMS (ESI): m/z [M+H]+ calcd for C31H35F5N2O2: 563.27, found 563.25. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.25 – 7.35 (m, 2H), 7.05 – 7.18 (m, 1H), 6.90 – 7.04 – 6.90 (m, 1H), 6.69 (d, J =
Figure imgf000143_0001
9.7 Hz, 1H), 4.05 – 4.33 (m, 2H), 3.82 – 3.92 (m, 2H), 3.15 – 3.25 (m, 1H), 2.83 – 2.95 (m, 1H), 2.79 (s, 1H), 2.58 – 2.65 (m, 1H), 2.45 – 2.63 (m, 2H), 2.35 – 2.45 (m, 1H), 1.94 – 2.02 (m, 4H), 1.54 – 1.73 (m, 3H), 1.15 – 1.40 (m, 2H), 0.93 – 1.06 (m, 2H), 0.75 – 0.85 (m, 2H), 0.57 – 0.71 (m, 2H), 0.05 – 0.15 (m, 2H). 19F NMR (282 MHz, Acetonitrile-d3) δ -98.02, -111.75, -112.61, -183.32. [00499] Synthesis of Compound 50: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)- N-((1R,6S)-2,2-difluoro-6-((1-(1-fluoropropan-2-yl)piperidin-4-yl)oxy)cyclohexyl)acetamide [00500] Scheme 29
Figure imgf000143_0002
[1,1'-biphenyl]-3-yl)acetamido)-3,3-difluorocyclohexyl)oxy)piperidine-1-carboxylate [00502] To a solution of tert-butyl 4-{[(1S,2R)-2-amino-3,3- difluorocyclohexyl]oxy}piperidine-1-carboxylate (150 mg, 0.449 mmol) in N,N- dimethylformamide (4 mL) was added {2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}acetic acid (155 mg, 0.538 mmol), HATU (256 mg, 0.672 mmol) and N,N-diisopropylethylamine (290 mg, 2.24 mmol). The reaction was stirred at room temperature for 2 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-100% gradient) to provide the title compound as a yellow oil (210 mg,77% yield). LCMS (ESI): m/z [M+H]+ calcd for C33H40F4N2O4: 605.30, found 605.20. [00503] Step 2: Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(piperidin-4-yloxy)cyclohexyl)acetamide [00504] To a solution of tert-butyl 4-{[(1S,2R)-2-(2-{2-cyclopropyl-3',5'-difluoro-[1,1'- biphenyl]-3-yl}acetamido)-3,3-difluorocyclohexyl]oxy}piperidine-1-carboxylate (210 mg, 0.347 mmol) in 1,4-dioxane (2.0 mL) was added 4N hydrochloric acid in 1,4-dioxane (2.0 mL). The reaction was stirred at room temperature for 2 h, then was concentrated to provide the title compound as a yellow oil (300 mg, 78.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F4N2O2: 505.24, found 505.20. [00505] Step 3: Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-(1-fluoropropan-2-yl)piperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 50) [00506] To a solution of 2-{2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}-N-[(1R,6S)-2,2- difluoro-6-(piperidin-4-yloxy)cyclohexyl]acetamide (145 mg, 0.287 mmol) and fluoroacetone (109 mg, 1.44 mmol) in dichloromethane (5 mL) was added sodium triacetoxyborohydride (609 mg, 2.87 mmol) at 0°C. The reaction was stirred at 25 °C for 3 h, then was quenched with water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Shield RP 18 OBD Column 150 mm x 30 mm x 5 μm column (35-65% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (24.3 mg, 15.0% yield). LCMS (ESI): m/z [M+H]+ calcd for C31H37F5N2O2: 565.28, found 565.35. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.26 – 7.35 (m, 2H), 7.18 – 7.24 (m, 1H), 7.01 – 7.10 (m, 2H), 6.91 – 7.00 (m, 1H), 6.60 (d, J = 9.8 Hz, 1H), 4.26 – 4.50 (m, 2H), 4.10 – 4.25 (m, 1H), 3.91 (q, J = 15.7 Hz, 2H), 3.34 – 3.48 (m, 2H), 2.82 – 2.96 (m, 1H), 2.73 – 2.81 (m, 2H), 2.35 – 2.41 (m, 3H), 1.72 – 1.88 (m, 4H), 1.26 – 1.50 (m, 6H), 1.01 (dt, J = 6.9, 1.6 Hz, 3H), 0.73 – 0.87 (m, 2H), 0.04 – 0.17 (m, 2H).19F NMR (376 MHz, Acetonitrile-d3) δ -98.03, -111.94, -112.58. [00507] Compound 51: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-(1,9-diazaspiro[5.5]undecan-9-yl)cyclohexyl)acetamide [00508] The title compound
Figure imgf000145_0001
16. LCMS (ESI): m/z [M+H]+ calcd for C32H39F4N3O: 558.31, found 558.35. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.37-7.45 (s, 1H), 7.25-7.37 (m, 1H), 7.17-7.25 (m, 1H), 7.01-7.10 (m, 2H), 6.87-7.01 (m, 1H), 6.32-6.58 (m, 1H), 4.31 (dt, J = 24.5, 10.8 Hz, 1H), 3.87-4.01 (m, 2H), 2.72-2.95 (m, 5H), 2.50- 2.63 (m, 4H), 2.30-2.46 (m, 5H), 1.71-1.86 (m, 4H), 1.50 (m, 5H), 1.34-1.43 (m, 2H), 0.75-0.85 (m, 2H), 0.12 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -96.48, -112.77, -113.64. [00509] Synthesis of Compound 52: 2-(2-cyclopropyl-3'-methoxy-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide
Figure imgf000146_0001
acetate [00512] To a stirred solution of methyl 2-(3-chloro-2-cyclopropylphenyl) acetate (150 mg, 0.668 mmol) and 3-methoxyphenylboronic acid (152 mg, 1.00 mmol) in 1,4-dioxane/water (4:1, 6 mL) were added potassium phosphate tribasic (283 mg, 1.34 mmol) and XPhos (31.8 mg, 0.067 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at 90 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched by addition of water, then the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (160 mg, 80.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C19H20O3: 297.14, found 297.10. [00513] Step 2: Preparation of {2-cyclopropyl-3'-methoxy-[1,1'-biphenyl]-3-yl} acetic acid [00514] A solution of methyl 2-{2-cyclopropyl-3'-methoxy-[1,1'-biphenyl]-3-yl} acetate (160 mg, 0.540 mmol) and lithium hydroxide (64.7 mg, 2.70 mmol) in methanol/tetrahydrofuran/water (1:1:1, 5 mL) was stirred for 1 h at room temperature. The mixture was acidified to pH = 5 with 2N hydrochloric acid, then the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated, to provide the title compound as a white solid(120 mg, 78.7% yield), which was used without further purification. LCMS (ESI): m/z [M+H]+ calcd for C18H18O3: 283.13, found 283.05. [00515] Step 3: Preparation of 2-(2-cyclopropyl-3'-methoxy-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 52) [00516] To a stirred solution of {2-cyclopropyl-3'-methoxy-[1,1'-biphenyl]-3-yl} acetic acid (50 mg, 0.177 mmol) and HATU (87.5 mg, 0.230 mmol) in N,N-dimethylformamide (5 mL) were added Intermediate 2 (48.9 mg, 0.177 mmol) and N,N-diisopropylethylamine (68.7 mg, 0.531 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature, then the reaction was quenched by addition of water and the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC using a Xselect CSH C18 OBD Column 150 mm x 30 mm x 5 μm column (20-45% acetonitrile/water with 10 mM formic acid) to provide the formic acid salt of the title compound as a pink solid (17.3 mg, 16.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C33H44F2N2O5: 541.32, found 541.35. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.34 (t, J = 7.8 Hz, 1H), 7.15 – 7.30 (m, 3H), 6.89 – 7.02 (m, 3H), 6.61 (d, J = 9.8 Hz, 1H), 4.19 (dtd, J = 24.3, 10.0, 3.9 Hz, 1H), 3.85 – 4.05 (m, 2H), 3.83 (s, 3H), 3.46 – 3.52 (m, 1H), 3.25 – 3.46 (m, 1H), 2.78 – 2.90 (m, 3H), 2.11 (d, J = 10.7 Hz, 2H), 1.78 – 1.95 (m, 4H), 1.30 – 1.60 (m, 4H), 1.40 – 1.27 (m, 1H), 1.06 (d, J = 6.6 Hz, 6H), 0.67 – 0.80 (m, 2H), 0.0 – 0.1 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.015, -111.903. [00517] Compound 53: 2-(3',5'-difluoro-2-methoxy-[1,1'-biphenyl]-3-yl)-N-((1R,6S)-2,2- difluoro-6-(1,8-diazaspiro[4.5]decan-8-yl)cyclohexyl)acetamide [00518] The title compound 11. LCMS (ESI): m/z
Figure imgf000148_0001
[M+H]+ calcd for C29H35F4N3O2: 534.27, found 534.15. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.31 – 7.36 (m, 1H), 7.19 – 7.28 (m, 1H), 7.08 – 7.17 (m, 3H), 6.86 – 6.92 (m, 1H), 6.49 – 6.59 (m, 1H), 4.09 – 4.23 (m, 1H), 3.29 – 3.37 (m, 4H), 3.02 – 3.16 (m, 2H), 2.62 – 2.70 (m, 1H), 2.45 – 2.58 (m, 3H), 2.36 – 2.44 (m, 2H), 1.81 – 1.86 (m, 2H), 1.71 – 1.79 (m, 1H), 1.68 – 1.74 (m, 2H), 1.60 – 1.67 (m, 3H), 1.54 – 1.59 (m, 1H), 1.39 – 1.52 (m, 3H), 1.22 – 1.36 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -97.27, -111.92, -113.12. [00519] Synthesis of Compound 54: 2-(2-cyclopropyl-3-(3-methylisoxazol-5-yl)phenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide [00520] Scheme 31
Figure imgf000148_0002
yl)phenyl]acetate [00522] To a solution of methyl 2-(3-chloro-2-cyclopropylphenyl)acetate (150 mg, 0.668 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (140 mg, 0.668 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was added XPhos-Pd-G3 (56.5 mg, 0.067 mmol), X-Phos (31.8 mg, 0.067 mmol) and potassium phosphate tribasic (283 mg, 1.34 mmol). The reaction was stirred at 100 °C under a nitrogen atmosphere for 3 h. The reaction was then cooled to room temperature, quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow solid (100 mg, 55.2% yield). LCMS (ESI): m/z [M+H]+ calcd for C16H17NO3: 272.12, found 272.15. [00523] Step 2: Preparation of [2-cyclopropyl-3-(3-methyl-1,2-oxazol-5-yl)phenyl]acetic acid [00524] To a solution of methyl 2-[2-cyclopropyl-3-(3-methyl-1,2-oxazol-5-yl)phenyl]acetate (100 mg, 0.369 mmol) in tetrahydrofuran (2 mL), methanol (2 mL) and water (1 mL) was added lithium hydroxide (53.0 mg, 2.21 mmol). The reaction was stirred at 25 °C for 2 h. The mixture was acidified to pH = 4 with 1N hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide the title compound as a yellow solid (70 mg, 73.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H15NO3: 258.11, found 258.15. [00525] Step 3: Preparation of 2-(2-cyclopropyl-3-(3-methylisoxazol-5-yl)phenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 54) [00526] To a solution of [2-cyclopropyl-3-(3-methyl-1,2-oxazol-5-yl)phenyl]acetic acid (40 mg, 0.155 mmol) in N,N-dimethylformamide (2 mL ) was added Intermediate 2 (43.0 mg, 0.155 mmol), HATU (88.7 mg, 0.232 mmol) and N,N-diisopropylethylamine (60.3 mg, 0.465 mmol) at room temperature. The resulting mixture was stirred for 16 h at room temperature, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a XBridge Prep OBD C18 Column 150 mm x 30 mm x 5 μm column (32-62% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (8.1 mg, 9.60% yield). LCMS (ESI): m/z [M+H]+ calcd for C29H39F2N3O3: 516.30, found 516.20. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.45 – 7.51 (m, 1H), 7.29 – 7.41 (m, 2H), 6.65 (d, J = 9.6 Hz, 1H), 6.43 (s, 1H), 4.09 – 4.24 (m, 1H), 3.81 – 4.00 (m, 2H), 3.33 – 3.45 (m, 2H), 2.68 – 2.83 (m, 3H), 2.34 (s, 3H), 2.21 – 2.27 (m, 2H), 2.00 – 2.10 (m, 3H), 1.72 – 1.84 (m, 4H), 1.32 – 1.47 (m, 4H), 1.28 – 1.32 (m, 1H), 0.88 – 1.02 (m, 7H), 0.18-0.26 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.11, -111.91. [00527] Compound 55: 2-(2-cyclopropyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-((1R,6S)- 2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide [00528] The title
Figure imgf000150_0001
54. LCMS (ESI): m/z [M+H]+ calcd for C29H40F2N4O2: 515.32, found 515.30. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.68 (s, 1H), 7.58 – 7.62 (m, 1H), 7.24 – 7.33 (m, 1H), 7.18 – 7.24 (m, 1H), 7.12 – 7.18 (m, 1H), 6.54 (d, J = 9.7 Hz, 1H), 4.08 – 4.25 (m, 1H), 3.80 – 4.02 (m, 5H), 3.45 – 3.31 (m, 2H), 2.62 – 2.77 (m, 3H), 2.05 – 2.18 (m, 4H), 1.85 – 1.97 (m, 2H), 1.71 – 1.85 (m, 3H), 1.28 – 1.51 (m, 4H), 1.03 – 0.89 (m, 8H), 0.15 – 0.27 (m, 2H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.02, - 111.99. [00529] Synthesis of Compound 56: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)- N-((1R,6S)-2,2-difluoro-6-(((3R,4R)-3-fluoro-1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide
Figure imgf000151_0001
nitrobenzenesulfonamido)cyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate [00532] To a solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (150 mg, 0.471 mmol) in N-methyl-2-pyrrolidone (0.15 mL) was added tert-butyl (3R,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (155 mg, 0.706 mmol). The reaction was stirred at 150 °C for 2 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow oil (130 mg, 51.3% yield). LCMS (ESI): m/z [M+H]+ calcd for C22H30F3N3O7S: 538.18, found 438.05 [M+H-Boc]+. [00533] Step 2: Preparation of tert-butyl (3R,4R)-4-{[(1S,2R)-2-amino-3,3- difluorocyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate [00534] To a solution of tert-butyl (3R,4R)-4-{[(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate (120 mg, 0.223 mmol) in toluene (0.12 mL) was added sodium benzenethiolate (29.5 mg, 0.223 mmol). The reaction was stirred at 100 °C for 2 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel with (methanol/dichloromethane, 0-30% gradient) to provide the title compound as a yellow oil (65 mg, 82.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C16H27F3N2O3: 353.20, found 353.30. [00535] Step 3: Preparation of tert-butyl (3R,4R)-4-{[(1S,2R)-2-(2-{2-cyclopropyl-3',5'- difluoro-[1,1'-biphenyl]-3-yl}acetamido)-3,3-difluorocyclohexyl]oxy}-3-fluoropiperidine-1- carboxylate [00536] To a solution of tert-butyl (3R,4R)-4-{[(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy}- 3-fluoropiperidine-1-carboxylate (122 mg, 0.346 mmol) in N,N-dimethylformamide (10 mL) was added {2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}acetic acid (99.8 mg, 0.346 mmol), HATU (197 mg, 0.519 mmol) and N,N-diisopropylethylamine (134 mg, 1.04 mmol). The reaction was stirred at room temperature for 2 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow oil (49 mg, 22.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C33H39F5N2O4: 623.29, found 623.30. [00537] Step 4: Preparation of 2-{2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}-N- [(1R,6S)-2,2-difluoro-6-{[(3R,4R)-3-fluoropiperidin-4-yl]oxy}cyclohexyl]acetamide [00538] To a solution of tert-butyl (3R,4R)-4-{[(1S,2R)-2-(2-{2-cyclopropyl-3',5'-difluoro- [1,1'-biphenyl]-3-yl}acetamido)-3,3-difluorocyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate (45 mg, 0.072 mmol) in 1,4-dioxane (3 mL) was added 4N hydrochloric acid in 1,4-dioxane (3 mL). The reaction was stirred at room temperature for 2 h, then was concentrated to provide the title compound as a yellow solid (35 mg, 92.7% yield), which was used without purification. LCMS (ESI): m/z [M+H]+ calcd for C28H31F5N2O2: 523.23, found 523.25. [00539] Step 5: Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(((3R,4R)-3-fluoro-1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide (Compound 56) [00540] To a solution of 2-{2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}-N-[(1R,6S)-2,2- difluoro-6-{[(3R,4R)-3-fluoropiperidin-4-yl]oxy}cyclohexyl]acetamide (50 mg, 0.096 mmol) in methanol (3 mL) was added acetone (65 mg, 1.12 mmol) and sodium cyanoborohydride (32 mg, 0.509 mmol). The reaction was stirred at room temperature for 12 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 μm column (49-73% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (8.5 mg, 15.1%). LCMS (ESI): m/z [M+H]+ calcd for C31H37F5N2O2: 565.28, found 565.25. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.18 - 7.30 (m, 2H), 7.02 - 7.17 (m, 1H), 6.76 - 7.02 (m, 3H), 6.45 (d, J = 12.0 Hz, 1H), 3.91 - 4.29 (m, 2H), 3.63 - 3.90 (m, 2H), 3.28 - 3.48 (m, 2H), 2.78 - 2.97 (m, 1H), 2.47 - 2.77 (m, 2H), 2.10 - 2.20 (m, 2H), 1.89 - 2.04 (m, 2H), 1.61 - 1.86 (m, 3H), 1.12 - 1.41 (m, 4H), 0.81 - 0.97 (m, 6H), 0.60 - 0.80 (m, 2H), 0.03 - 0.20 (m, 2H). 19F NMR (282 MHz, Acetonitrile-d3) δ -98.14, -112.08, -113.30, -186.86. [00541] Synthesis of Compound 57: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)- N-((1R,6S)-2,2-difluoro-6-(((3S,4R)-3-fluoro-1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide
Figure imgf000154_0001
nitrophenyl)sulfonamido)cyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00544] To a solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (200 mg, 0.628 mmol) in N-methyl-2-pyrrolidone (0.2 mL) was added tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (276 mg, 1.26 mmol). The reaction was stirred at 150 °C for 2 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow oil (250 mg, 74.0% yield). LCMS (ESI): m/z [M+H]+ calcd for C22H30F3N3O7S: 538.18, found 560.30 [M+Na]+. [00545] Step 2: Preparation of tert-butyl (3S,4R)-4-(((1S,2R)-2-amino-3,3- difluorocyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate [00546] To a solution of tert-butyl (3S,4R)-4-{[(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate (240 mg, 0.446 mmol) in toluene (5 mL) was added sodium benzenethiolate (354 mg, 2.68 mmol). The reaction was stirred at 100 °C for 2 h, then was cooled to room temperature, quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-30% gradient) to provide the title compound as a yellow oil (110 mg, 69.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C16H27F3N2O3: 353.20, found 353.30. [00547] Step 3: Preparation of tert-butyl (3S,4R)-4-(((1S,2R)-2-(2-(2-cyclopropyl-3',5'- difluoro-[1,1'-biphenyl]-3-yl)acetamido)-3,3-difluorocyclohexyl)oxy)-3-fluoropiperidine-1- carboxylate [00548] To a solution of tert-butyl (3S,4R)-4-{[(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy}- 3-fluoropiperidine-1-carboxylate (102 mg, 0.289 mmol) and {2-cyclopropyl-3',5'-difluoro-[1,1'- biphenyl]-3-yl}acetic acid (100 mg, 0.347 mmol) in N,N-dimethylformamide (5 mL) was added HATU (165 mg, 0.433 mmol) and N,N-diisopropylethylamine (112 mg, 0.867 mmol). The reaction was stirred at 25 °C for 2 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow solid. LCMS (ESI): m/z [M+H]+ calcd for C33H39F5N2O4: 623.29, found 623.20. [00549] Step 4: Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(((3S,4R)-3-fluoropiperidin-4-yl)oxy)cyclohexyl)acetamide [00550] To a solution of tert-butyl (3S,4R)-4-{[(1S,2R)-2-(2-{2-cyclopropyl-3',5'-difluoro- [1,1'-biphenyl]-3-yl}acetamido)-3,3-difluorocyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate (70 mg, 0.112 mmol) in 1,4-dioxane (5 mL) was added 4N hydrochloric acid in 1,4-dioxane (5 mL). The reaction was stirred at 25 °C for 1 h, then was concentrated to provide the title compound as a yellow solid (55 mg, 93.5% yield), which was used without purification. LCMS (ESI): m/z [M+H]+ calcd for C28H31F5N2O2: 523.23, found: 523.15. [00551] Step 5: Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-(((3S,4R)-3-fluoro-1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide (Compound 57) [00552] To a solution of 2-{2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}-N-[(1R,6S)-2,2- difluoro-6-{[(3S,4R)-3-fluoropiperidin-4-yl]oxy}cyclohexyl]acetamide (60 mg, 0.115 mmol) in methanol (3 mL) was added acetone (67 mg, 1.15 mmol) and sodium cyanoborohydride (36 mg, 0.573 mmol). The reaction was stirred at room temperature for 12 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 μm column (49-73% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (1.1 mg, 1.66% yield). LCMS (ESI): m/z [M+H]+ calcd for C31H37F5N2O2: 565.28, found 565.20. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.12 - 7.22 (m, 2H), 7.01 - 7.11 (m, 1H), 6.78 - 7.00 (m,
Figure imgf000156_0001
(d, J = 12.0 Hz, 1H), 4.38 - 4.69 (m, 1H), 3.99 - 4.29 (m, 1H), 3.62 - 3.95 (m, 2H), 3.41 - 3.60 (m, 1H), 3.26 - 3.40 (m, 1H), 2.72 - 2.87 (m, 1H), 2.51 - 2.71 (m, 2H), 2.29 - 2.48 (m, 1H), 2.12 - 2.22 (m, 1H), 1.90 - 2.05 (m, 3H), 1.49 - 1.76 (m, 4H), 1.24 - 1.42 (m, 2H), 0.85 - 0.98 (m, 6H), 0.61 - 0.78 (m, 2H), 0.2 - 0.18 (m, 2H). 19F NMR (282 MHz, Acetonitrile-d3) δ -98.05, -98.91, -111.85, -112.80. [00553] Synthesis of Compound 58: 2-(2-cyclopropyl-3-(thiazol-2-yl)phenyl)-N-((1R,6S)- 2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide
Figure imgf000157_0001
acetate [00556] To a solution of methyl 2-(3-chloro-2-cyclopropylphenyl)acetate (200 mg, 0.890 mmol) in toluene (4 mL) was added 2-(tripropylstannyl)-1,3-thiazole (591 mg, 1.78 mmol), XPhos (42.4 mg, 0.089 mmol) and XPhos-Pd-G3 (75.35 mg, 0.089 mmol). The reaction was stirred at 100 °C under a nitrogen atmosphere for 2 h., then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 0-100% gradient) to provide the title compound as a yellow solid (120 mg, 49.3% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H15NO2S: 274.09, found 274.10. [00557] Step 2: Preparation of [2-cyclopropyl-3-(1,3-thiazol-2-yl)phenyl]acetic acid [00558] To a solution of methyl 2-[2-cyclopropyl-3-(1,3-thiazol-2-yl)phenyl]acetate (100 mg, 0.366 mmol) in tetrahydrofuran (2 mL), methanol (1 mL) and water (2 mL) was added lithium hydroxide (52.6 mg, 2.20 mmol). The reaction was stirred at 25 °C for 2 h, then the mixture was acidified to pH = 4 with 2N hydrochloric acid. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide the title compound as a yellow solid (80 mg, 84.3% yield). LCMS (ESI): m/z [M+H]+ calcd for C14H13NO2S: 260.07, found 260.00. [00559] Step 3: Preparation of 2-(2-cyclopropyl-3-(thiazol-2-yl)phenyl)-N-((1R,6S)-2,2- difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 58) [00560] To a solution of [2-cyclopropyl-3-(1,3-thiazol-2-yl)phenyl]acetic acid (37.5 mg, 0.145 mmol) and Intermediate 2 (40 mg, 0.145 mmol) in N,N-dimethylformamide (3 mL) was added HATU (82.5 mg, 0.217 mmol) and N,N-diisopropylethylamine (93.5 mg, 0.724 mmol). The reaction was stirred at room temperature for 2 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 μm column (49- 73% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (2.9 mg, 3.85% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H37F2N3O2S: 518.26, found 518.20.1H NMR (300 MHz, Acetonitrile-d3) δ 7.90 (d, J = 3.0 Hz, 1H), 7.64 (d, J = 3.0 Hz, 1H), (m, 1H), 7.26 - 7.42 (m, 2H), 6.66 (d, J = 9.0 Hz, 1H), 3.88 - 4.12 (m, 1H), 3.59 - 3.88 (m, 2H), 3.09 - 3.11 (m, 2H), 2.40 - 2.60 (m, 3H), 1.81 - 2.00 (m, 4H), 1.52 - 1.75 (m, 4H), 1.02 - 1.37 (m, 5H), 0.99 (d, J = 6.0 Hz, 6H), 0.80 - 0.94 (m, 2H), 0.12 - 0.27 (m, 2H).19F NMR (282 MHz, Acetonitrile-d3) δ -97.96, -111.79. [00561] Synthesis of Compound 59: 2-(2-cyclopropyl-3-(1H-indazol-5-yl)phenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide ate [00564] To a solution of methyl 2-(3-chloro-2-cyclopropylphenyl)acetate (200 mg, 0.890 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (435 mg, 1.78 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was added X-Phos (42.4 mg, 0.089 mmol), XPhos-Pd- G3 (75.3 mg, 0.089 mmol) and potassium phosphate tribasic (472 mg, 2.23 mmol). The reaction was stirred at 90 °C under a nitrogen atmosphere for 5 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane, 0-100% gradient) to provide the title compound as a yellow oil (175 mg, 64% yield). LCMS (ESI): m/z [M+H]+ calcd for C19H18N2O2: 307.14, found 307.20. [00565] Step 2: Preparation of 2-(2-cyclopropyl-3-(1H-indazol-5-yl)phenyl)acetic acid [00566] To a solution of methyl 2-[2-cyclopropyl-3-(1H-indazol-5-yl)phenyl]acetate (165 mg, 0.539 mmol) in tetrahydrofuran\methanol\water (1:1:1, 3 mL) was added lithium hydroxide (64.5 mg, 2.69 mmol) .The reaction was stirred at room temperature for 2 h, then the residue was acidified to pH = 4 with 2 N hydrochloric acid and extracted with dichloromethane (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated, to provide the title compound as a yellow oil (140 mg, 89% yield). LCMS (ESI): m/z [M+H]+ calcd for C18H16N2O2: 293.12, found 293.20. [00567] Step 3: Preparation of 2-(2-cyclopropyl-3-(1H-indazol-5-yl)phenyl)-N-((1R,6S)- 2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 59) [00568] To a solution of [2-cyclopropyl-3-(1H-indazol-5-yl) phenyl] acetic acid (52.9 mg, 0.181 mmol) and Intermediate 2 (50 mg, 0.181 mmol) in N,N-dimethylformamide (3 mL) was added HATU (103 mg, 0.271 mmol) and N,N-diisopropylethylamine (111 mg, 0.855 mmol). The reaction was stirred at room temperature for 3 h, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 μm column (49- 73% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (33.1 mg, 32.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C32H40F2N4O2: 551.32, found 551.25. 1H NMR (300 MHz, Acetonitrile-d3) δ 8.45 (s, 1H), 8.03 – 8.09 (m, 1H), 7.73 (s, 1H), 7.54 – 7.63 (m, 1H), 7.40 – 7.49 (m, 1H), 7.20 – 7.35 (m, 3H), 6.76 (d, J = 12.0 Hz, 1H), 4.16 – 4.34 (m, 1H), 3.86 – 4.02 (m, 2H), 3.60 – 3.81 (m, 1H), 3.36 – 3.47 (m, 1H), 3.12 – 3.23 (m, 1H), 2.96 – 3.09 (m, 2H), 2.71 – 2.88 (m, 2H), 2.05 – 2.21 (m, 2H), 1.97 – 2.06 (m, 2H), 1.85 – 1.94 (m, 1H), 1.68 – 1.78 (m, 4H), 1.32 – 1.52 (m, 2H), 1.19 (d, J = 6.0 Hz, 6H), 0.59 – 0.75 (m, 2H), 0.01 – 0.07 (m, 2H). 19F NMR (282 MHz, Acetonitrile-d3) δ -98.82, -112.52. [00569] Compound 60: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-(4-hydroxy-4-isopropylpiperidin-1-yl)cyclohexyl)acetamide
[00570] The title compound und 16. LCMS (ESI): m/z [M+H]+ calcd for C31H38F4N2O2: 547.29, found 547.15. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.00 – 7.38 (m, 3H), 6.72 – 7.00 (m, 3H), 6.98 – 6.87 (m, 1H), 6.20 (d, J = 9.5 Hz, 1H), 4.00- 4.40 (m, 1H), 3.42 – 3.98 (m, 3H), 2.38 – 2.85 (m, 3H), 2.20 – 2.38 (m, 2H), 1.84 – 2.00 (m, 2H), 1.52 – 1.80 (m, 3H), 1.20 – 1.40 (m, 5H), 1.03 – 1.16 (m, 1H), 0.51 – 0.80 (m, 8H), 0.08 – 0.11 (m, 2H). 19F NMR (282 MHz, Acetonitrile-d3) δ -96.36, -112.81, -113.75. [00571] Synthesis of Compound 61: N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl)acetamide [00572] Scheme 36
Figure imgf000161_0001
pyridine [00574] To a stirred solution of 2-chloro-4-iodo-3-(trifluoromethyl) pyridine (1 g, 3.25 mmol) and 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.77 g, 3.90 mmol) in 1,4- dioxane (10 mL) and water (1 mL) was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.26 g, 0.325 mmol) and potassium carbonate (0.90 g, 6.51 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature, then the reaction was quenched by addition of water. The resulting mixture was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel (1:1 petroleum ether/ethyl acetate) to provide the title compound as a yellow oil (600 mg, 73.3% yield). LCMS (ESI): m/z [M+H]+ calcd for C10H9ClF3NO: 252.03, found 252.10. [00575] Step 2: Preparation of 2-(3,5-difluorophenyl)-4-[(E)-2-ethoxyethenyl]-3- (trifluoromethyl) pyridine [00576] To a stirred solution of 2-chloro-4-[(E)-2-ethoxyethenyl]-3-(trifluoromethyl) pyridine (550 mg, 2.19 mmol) and 3,5-difluorophenylboronic acid (414 mg, 2.62 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (178 mg, 0.219 mmol) and potassium carbonate (604 mg, 4.37 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. The mixture was allowed to cool to room temperature, then was quenched by addition of water. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 petroleum ether/ethyl acetate) to provide the title compound as a yellow oil (640 mg, 88.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C16H12F5NO: 330.08, found 330.15. [00577] Step 3: Preparation of 2-[2-(3,5-difluorophenyl)-3-(trifluoromethyl) pyridin-4-yl] acetaldehyde [00578] A solution of 2-(3,5-difluorophenyl)-4-[(E)-2-ethoxyethenyl]-3-(trifluoromethyl) pyridine (300 mg, 0.911 mmol) and 2N hydrochloric acid (2 mL, 65.8 mmol) in 1,4-dioxane (4 mL) was stirred for 1 h at room temperature. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow oil, which was used without further purification (240 mg, 87.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C14H8F5NO: 302.06, found 302.15. [00579] Step 4: Preparation of [2-(3,5-difluorophenyl)-3-(trifluoromethyl) pyridin-4-yl] acetic acid [00580] To a stirred solution of 2-[2-(3,5-difluorophenyl)-3-(trifluoromethyl) pyridin-4-yl] acetaldehyde (120 mg, 0.398 mmol) in a mixture of tert-butanol (2.5 mL) and tetrahydrofuran (2.5 mL) was added 2-methyl-2-butene (168 mg, 2.39 mmol) and sodium chlorite (43.2 mg, 0.478 mmol) in portions at 0 °C. To the above mixture was added sodium phosphate monobasic (57.4 mg, 0.478 mmol) in 1 mL of water dropwise over 1 min at 0 °C. The resulting mixture was stirred for an additional 30 min at 0 °C, then was stirred for 3 h at room temperature. The reaction was quenched with water, and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow oil, which was used without further purification (70 mg, 55.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C14H8F5NO2: 318.05, found 317.90. [00581] Step 5: Preparation of N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl)acetamide (Compound 61) [00582] To a stirred solution of [2-(3,5-difluorophenyl)-3-(trifluoromethyl) pyridin-4-yl] acetic acid (70 mg, 0.221 mmol) and HATU (109 mg, 0.287 mmol) in N,N-dimethylformamide (3 mL) were added Intermediate 2 (60.99 mg, 0.221 mmol, 1 equiv) and N,N-diisopropylethylamine (114 mg, 0.884 mmol) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature, then the reaction was quenched by addition of water. The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Xselect CSH OBD Column 150 mm x 30 mm x 5 μm column, 17-40% acetonitrile/water gradient with 10 mM formic acid) to provide the formic acid salt of the title compound as a white solid (24.6 mg, 17.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F7N3O2: 576.24, found 576.20. 1H NMR (300 MHz, Acetonitrile-d3) δ 8.76 (d, J = 5.0 Hz, 1H), 7.00 – 7.25 (m, 3H), 6.94 (d, J = 9.8 Hz, 1H), 4.21 (s, 1H), 3.85 – 4.00 (m, 2H), 3.65 (s, 1H), 3.41 (s, 1H), 3.11 (s, 1H), 2.90 – 3.05 (m, 2H), 2.69 (s, 2H), 2.12 (s, 2H), 2.00 – 2.07 (m, 1H), 1.89 – 1.98 (m, 1H), 1.65 – 1.85 (m, 4H), 1.40 – 1.52 (m, 2H), 1.05 – 1.25 (m, 6H).19F NMR (282 MHz, Acetonitrile- d3) δ -51.995, -98.470, -111.806, -111.882. [00583] Synthesis of Compound 62: 2-(2-cyano-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide [00584] Scheme 37
Figure imgf000164_0001
[00586] To a solution of 2-bromo-6-iodobenzonitrile (500 mg, 1.62 mmol) in a mixture of ethanol (4 mL), toluene (4 mL), and water (2 mL) was added 3,5-difluorophenylboronic acid (256 mg, 1.62 mmol), tetrakis(triphenylphosphine)palladium(0) (188 mg, 0.162 mmol) and sodium carbonate (430 mg, 4.06 mmol) under a nitrogen atmosphere. The reaction was stirred at 90 °C for 2 h, then was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound as a yellow solid (400 mg, 83.8% yield). GC/MS (EI): m/z [M]+ calcd for C13H6BrF2N: 292.97, found 292.97. [00587] Step 2: Preparation of 3-[(E)-2-ethoxyethenyl]-3',5'-difluoro-[1,1'-biphenyl]-2- carbonitrile [00588] To a solution of 3-bromo-3',5'-difluoro-[1,1'-biphenyl]-2-carbonitrile (200 mg, 0.680 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added 2-[(E)-2-ethoxyethenyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (269 mg, 1.36 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (49.8 mg, 0.068 mmol) and potassium carbonate (235 mg, 1.70 mmol) under a nitrogen atmosphere. The reaction was stirred at 90 °C for 3 h under a nitrogen atmosphere, then the mixture was allowed to cool to room temperature. The reaction was then quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulsfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound as a yellow oil (160 mg, 82.5% yield). [00589] Step 3: Preparation of 3',5'-difluoro-3-(2-oxoethyl)-[1,1'-biphenyl]-2-carbonitrile [00590] To a solution of 3-[(E)-2-ethoxyethenyl]-3',5'-difluoro-[1,1'-biphenyl]-2-carbonitrile (160 mg, 0.561 mmol) in 1,4-dioxane (2 mL) was added 2N hydrochloric acid (2 mL). The reaction was stirred at 50 °C for 16 h, then was cooled to room temperature. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow oil, which was used without further purification (130 mg, 90.1% yield). [00591] Step 4: Preparation of {2-cyano-3',5'-difluoro-[1,1'-biphenyl]-3-yl}acetic acid [00592] To a solution of 3',5'-difluoro-3-(2-oxoethyl)-[1,1'-biphenyl]-2-carbonitrile (150 mg, 0.583 mmol) in tert-butanol (2 mL) and tetrahydrofuran (2 mL) was added 2-methyl-2-butene (204 mg, 2.92 mmol) and sodium chlorite (63.3 mg, 0.700 mmol). Then sodium phosphate monobasic (83.9 mg, 0.700 mmol) in water (0.5 mL) was added at 0°C. The reaction was stirred at 0 °C for 0.5 h, then was stirred at room temperature for 1 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow oil, which was used without further purification (130 mg, 81.6% yield). [00593] Step 5: Preparation of 2-(2-cyano-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N-((1R,6S)- 2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 62) [00594] To a solution of {2-cyano-3',5'-difluoro-[1,1'-biphenyl]-3-yl}acetic acid (150 mg, 0.549 mmol) and HATU (250 mg, 0.659 mmol) in N,N-dimethylformamide (3 mL) was added Intermediate 2 (152 mg, 0.549 mmol) and N,N-diisopropylethylamine (213 mg, 1.65 mmol). The reaction was stirred at room temperature for 2 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Xselect CSH Prep C18 Column 250 mm x 19 mm x 5 μm, 51-62% methanol/water gradient with 0.1% formic acid) to provide the title compound as an off-white solid (29.2 mg, 8.54% yield). LCMS (ESI): m/z [M+H]+ calcd for C29H33F4N3O2: 532.25, found 532.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.72 (t, J = 7.8 Hz, 1H), 7.56 – 7.60 (m, 1H), 7.47 – 7.53 1H), 7.18 – 7.29 (m, 2H), 7.06 – 7.16 (m, 1H), 6.83 (d, J = 9.8 Hz, 1H), 7.07 – 7.23 (m, 1H), 3.91 (d, J = 1.6 Hz, 2H), 3.32 – 3.46 (m, 2H), 2.62 – 2.74 (m, 3H), 2.05 – 2.14 (m, 2H), 1.71 – 1.86 (m, 5H), 1.26 – 1.52 (m, 5H), 0.98 (d, J = 6.6 Hz, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -98.31, -110.93, -112.54. [00595] Synthesis of Compound 63: N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4-yl)acetamide [00596] Scheme 38
Figure imgf000167_0001
[00598] To a solution of 2-chloro-3-(trifluoromethoxy)pyridine (2 g, 10.1 mmol) in tetrahydrofuran (20 mL) was added lithium diisopropylamide (1.30 g, 12.2 mmol) at -78 °C under a nitrogen atmosphere. The reaction was stirred at -78 °C for 2 h, then iodine (3.85 g, 15.2 mmol) was added, and the reaction was stirred at -78 °C for an additional 2 h. The reaction was allowed to warm to room temperature and stirred at 25 °C for 16 h. The reaction was then quenched with water (60 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound as a yellow solid (1.7 g, 51.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C6H2ClF3INO: 323.88, found 324.00. [00599] Step 2: Preparation of tert-butyl 2-[2-chloro-3-(trifluoromethoxy)pyridin-4- yl]acetate [00600] To a solution of 2-chloro-4-iodo-3-(trifluoromethoxy)pyridine (1 g, 3.09 mmol) in N,N-dimethylformamide (10 mL) was added {[1-(tert-butoxy)ethenyl]oxy}(tert- butyl)dimethylsilane (3.56 g, 15.5 mmol), bis(tri-t-butylphosphine)palladium(0) (316 mg, 0.618 mmol) and zinc fluoride (1.60 g, 15.5 mmol) under a nitrogen atmosphere. The reaction was stirred at 100 °C for 3 h under nitrogen, then was cooled to room temperate, quenched with water (50 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound as a yellow oil (400 mg, 41.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C12H13ClF3NO3: 312.05, found 312.15. [00601] Step 3: Preparation of tert-butyl 2-[2-(3,5-difluorophenyl)-3- (trifluoromethoxy)pyridin-4-yl]acetate [00602] To a solution of tert-butyl 2-[2-chloro-3-(trifluoromethoxy)pyridin-4-yl]acetate (390 mg, 1.25 mmol) in 1,4-dioxane (5 mL) and water (1 mL) was added 3,5-difluorophenylboronic acid (395 mg, 2.50 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (91.6 mg, 0.125 mmol), and potassium carbonate (432 mg, 3.13 mmol) under a nitrogen atmosphere. The reaction was stirred at 90 °C for 3 h. The reaction was then cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound as a yellow solid (330 mg, 67.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C18H16F5NO3: 390.11, found 390.20. [00603] Step 4: Preparation of [2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4- yl]acetic acid [00604] To a solution of tert-butyl 2-[2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4- yl]acetate (320 mg, 0.822 mmol) in a mixture of tetrahydrofuran (4 mL), methanol (4 mL), and water (2 mL) was added lithium hydroxide (118 mg, 4.93 mmo). The reaction was stirred at room temperature °C for 3 h. The solvent was removed, then the mixture was acidified to pH = ~7 with 1N hydrochloric acid and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow solid, which was used without further purification (245 mg, 89.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C14H8F5NO3: 334.05, found 334.15. [00605] Step 5: Preparation of N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4-yl)acetamide (Compound 63) [00606] To a solution of [2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4-yl]acetic acid (150 mg, 0.450 mmol) and HATU (205 mg, 0.540 mmol) in N,N-dimethylformamide (3 mL) was added Intermediate 2 (124 mg, 0.450 mmol) and N,N-diisopropylethylamine (175 mg, 1.35 mmol). The reaction was stirred at room temperature for 2 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Xselect CSH Prep C18 Column 250 mm x 19 mm x 5 μm, 51-62% methanol/water gradient with 0.1% formic acid) to provide the formic acid salt of the title compound as a white solid (62.7 mg, 21.3% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F7N3O3: 592.24, found 592.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.63 (d, J = 4.9 Hz, 1H), 7.54 (d, J = 4.9 Hz, 1H), 7.38 –
Figure imgf000170_0001
2H), 7.06 – 7.15 (m, 1H), 6.97 (d, J = 9.7 Hz, 1H), 4.12 – 4.27 (m, 1H), 3.82 (q, J = 16.1 Hz, 2H), 3.54 – 3.67 (m, 1H), 3.36 – 3.45 (m, 2H), 2.84 – 3.16 (m, 4H), 2.63 – 2.75 (m, 2H), 2.07 – 2.17 (m, 2H), 1.60 – 1.84 (m, 4H), 1.33 – 1.49 (m, 2H), 1.13 (d, J = 6.6 Hz, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -57.54, -98.53, -111.33, -111.86. [00607] Preparation of Compound 64: 2-(2-cyclopropyl-3-(2-oxoindolin-5-yl)phenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide [00608] Scheme 39
Figure imgf000170_0002
- [(1-isopropylpiperidin-4-yl)oxy]cyclohexyl]acetamide (80 mg, 0.171 mmol) and 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydroindol-2-one (66.3 mg, 0.257 mmol) in tetrahydrofuran (4 mL) and water (1 mL) was added potassium phosphate tribasic (109 mg, 0.513 mmol), X-phos (8.13 mg, 0.017 mmol) and Pd-XPhos-G3 (14.4 mg, 0.017 mmol). The resulting mixture was stirred for 2 h at 90 °C. After cooling to room temperature, the reaction was diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (X Bridge Prep OBD C18150 mm x 30 mm x 5μm column, 23-53% acetonitrile/water with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (30.6 mg, 31.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C33H41F2N3O3: 566.31, found 566.15. 1H NMR (300 MHz, Acetonitrile-d3) δ 8.34 (s, 1H), 7.06 – 7.23 (m, 5H), 6.84 (d, J = 8.0 Hz,
Figure imgf000171_0001
J = 9.7 Hz, 1H), 3.99 – 4.20 (m, 1H), 3.68 – 3.92 (m, 2H), 3.35 – 3.54 (m, 2H), 3.15 – 3.32 (m, 2H), 2.50 – 2.79 (m, 3H), 1.97 – 2.06 (m, 3H), 1.61 – 1.82 (m, 5H), 1.20 – 1.41 (m, 5H), 0.92 (d, J = 6.6 Hz, 6H), 0.64 – 0.74 (m, 2H), 0.01 – 0.05 (m, 2H). 19F NMR (282 MHz, Acetonitrile-d3) δ -98.78, -112.74. [00610] Preparation of Compound 65: 2-(2-cyclopropyl-3'-fluoro-5'-(hydroxymethyl)- [1,1'-biphenyl]-3-yl)-N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide
[00611] To a solution of 2-(3-chloro-2-cyclopropylphenyl)-N-[(1R,6S)-2,2-difluoro-6-[(1- isopropylpiperidin-4-yl)oxy]cyclohexyl]acetamide (90 mg, 0.192 mmol) and 3-fluoro-5- (hydroxymethyl)phenylboronic acid (65.2 mg, 0.384 mmol) in tetrahydrofuran (0.8 mL) and water (0.2 mL) was added XPhos (18.3 mg, 0.038 mmol), Pd-XPhos-G3 (32.5 mg, 0.038 mmol), and potassium phosphate tribasic (102 mg, 0.480 mmol). The reaction was stirred at 90 °C under a nitrogen atmosphere for 5 h. The reaction was cooled to room temperature, then was quenched with water (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 μm column, 49-73% acetonitrile/water gradient with 10 mM ammonium formate) to provide the formic acid salt of the title compound as a white solid (24.9 mg, 21.4% yield. LCMS (ESI): m/z [M+H]+ calcd for C32H41F3N2O3: 559.31, found 559.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.25 - 7.35 (m, 2H), 7.18 - 7.24 (m, 2H), 7.01 - 7.12
Figure imgf000172_0001
(d, J = 8.0 Hz, 1H), 4.64 (s, 2H), 4.12 - 4.29 (m, 1H), 3.84 - 3.98 (m, 2H), 3.29 - 3.59 (m, 3H), 2.92 - 3.00 (m, 1H), 2.78 - 2.89 (m, 2H), 2.42 - 2.60 (m, 2H), 2.02 - 2.11 (m, 2H), 1.70 - 1.89 (m, 4H), 1.44 – 1.65 (m, 2H), 1.30 - 1.43 (m, 2H), 1.00 - 1.12 (m, 6H), 0.70 - 0.85 (m, 2H), 0.04 - 0.14 (m, 2H). 19F NMR (377 MHz, Acetonitrile-d3) δ -98.12, -111.85, -116.50. [00612] Preparation of Compound 66: 2-(2-cyclopropyl-3-(2-oxo-2,3- dihydrobenzo[d]oxazol-6-yl)phenyl)-N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide [00613] To a solution
Figure imgf000172_0002
-2,2-difluoro-6-[(1- isopropylpiperidin-4-yl)oxy]cyclohexyl]acetamide (80 mg, 0.171 mmol) and 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-1,3-benzoxazol-2-one (53.4 mg, 0.205 mmol) in tetrahydrofuran (2 mL) and water (0.5 mL) was added potassium phosphate tribasic (90.5 mg, 0.428 mmol), XPhos (8.13 mg, 0.017 mmol) and Pd-XPhos-G3 (14.4 mg, 0.017 mmol). The reaction was stirred at 90 °C for 2 hours under a nitrogen atmosphere. The reaction was then cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD 150 mm x 30 mm x 5 μm colum, 27-50% acetonitrile/water gradient with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (20.5 mg, 21.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C32H39F2N3O4: 568.29, found 568.30. 1H NMR (400 MHz, Acetonitrile-d3) δ 7.26 (t, J = 4.2 Hz, 2H), 7.07 – 7.27 (m, 3H), 6.60 (d, 9.8 Hz, 1H), 4.10 –
Figure imgf000173_0001
4.27 (m, 1H), 3.82 – 3.99 (m, 2H), 3.34 – 3.47 (m, 2H), 2.68 – 2.79 (m, 3H), 2.06 – 2.30 (m, 4H), 1.87 – 1.97 (m, 1H), 1.78 – 1.82 (m, 4H), 1.28 – 1.50 (m, 4H), 1.00 (d, J = 6.5 Hz, 6H), 0.67 – 0.81 (m, 2H), 0.04 – 0.08 (m, 2H).19F NMR (376 MHz, Acetonitrile-d3) δ: -98.00, -112.58. [00614] Synthesis of Compound 67: N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3- (trifluoromethoxy)pyridin-4-yl)acetamide [00615] Scheme 40
Figure imgf000173_0002
l)- 3-(trifluoromethoxy)pyridin-4-yl)acetamido)-3,3-difluorocyclohexyl)oxy)-3- fluoropiperidine-1-carboxylate [00617] To a solution of [2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4-yl]acetic acid (60 mg, 0.180 mmol) in N,N-dimethylformamide (3 mL) was added tert-butyl (3R,4S)-4- (((1S,2R)-2-amino-3,3-difluorocyclohexyl)oxy)-3-fluoropiperidine-1-carboxylate (76.2 mg, 0.216 mmol,), HATU (103 mg, 0.270 mmol), and N,N-diisopropylethylamine (93.1 mg, 0.720 mmol). The reaction was stirred at 25 °C for 1 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound as a yellow solid (90 mg, 74.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C30H33F8N3O5: 668.23, found 668.20. [00618] Step 2: Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4-yl)acetamide [00619] tert-Butyl (3R,4S)-4-(((1S,2R)-2-(2-(2-(3,5-difluorophenyl)-3- (trifluoromethoxy)pyridin-4-yl)acetamido)-3,3-difluorocyclohexyl)oxy)-3-fluoropiperidine-1- carboxylate (85 mg, 0.127 mmol) was dissolved in 4N hydrogen chloride in 1,4-dioxane (3 mL). The reaction was stirred at 25 °C for 2 h. The solvent was then removed under reduced pressure to provide the title compound as a yellow solid (70 mg, 96.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C25H25F8N3O3: 568.18, found 568.05. [00620] Step 3: Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3- (trifluoromethoxy)pyridin-4-yl)acetamide (Compound 67) [00621] To a solution of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoropiperidin-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethoxy)pyridin-4-yl)acetamide (150 mg, 0.287 mmol) and acetone (81.9 mg, 1.41 mmol) in methanol (3 mL) was added sodium cyanoborohydride (44.3 mg, 0.705 mmol) at 0°C. The reaction was warmed to room temperature and stirred for 3 h, then was quenched with water (20 mL) and extracted with dichloromethane (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (XBridge Shield RP 18 OBD 150 mm x 30 mm x 5 μm column, 46-76% acetonitrile/water gradient with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (42.3 mg, 25.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H31F8N3O3: 610.23, found 610.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.62 (d, J = 4.9 Hz, 1H), 7.54 (d, J = 4.9 Hz, 1H),
Figure imgf000175_0001
(m, 2H), 7.05 – 7.15 (m, 1H), 6.94 (d, J = 9.8 Hz, 1H), 4.53 – 4.73 (m, 1H), 4.14 – 4.31 (m, 1H), 3.73 – 3.89 (m, 2H), 3.57 – 3.71 (m, 1H), 3.39 – 3.48 (m, 1H), 2.69 – 2.87 (m, 2H), 2.44 – 2.64 (m, 2H), 2.23 – 2.33 (m, 1H), 2.07 – 2.15 (m, 2H), 1.69 – 1.87 (m, 3H), 1.57 – 1.66 (m, 1H), 1.32 – 1.52 (m, 2H), 0.94 – 1.01 (m, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -57.35, -98.56, -111.37, -112.59. [00622] Preparation of Compound 68: 2-(2-cyclopropyl-3-(1H-indazol-5-yl)phenyl)-N- ((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide
[00623] Scheme 41
Figure imgf000176_0001
yl)oxy)cyclohexan-1-amine (60 mg, 0.204 mmol) and 2-(2-cyclopropyl-3-(1H-indazol-5- yl)phenyl)acetic acid (66.3 mg, 0.227 mmol) in N,N-dimethylformamide (4 mL) was added HATU (116 mg, 0.306 mmol) and N,N-diisopropylethylamine (132 mg, 1.02 mmol). The reaction was stirred at room temperature for 2 hm then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (YMC-Actus Triart C18 ExRS 150 mm x 30 mm x 5 μm column, 49-73% acetonitrile/water gradient with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (14.5 mg, 12.0% yield). LCMS (ESI): m/z [M+H]+ calcd for C32H39F3N4O2: 569.31, found 569.25.1H NMR (400 MHz, Acetonitrile-d3) δ 11.28 (s, 1H), 8.06 (d, J = 4.0 Hz, 1H), 7.72 - 7.77 (m, 1H), 7.55 - 7.62 (m, 1H), 7.42 - 7.49 (m, 1H), 7.22 - 7.33 (m, 3H), 6.68 (d, J = 8.0 Hz, 1H), 4.66 - 4.73 (m, 1H), 4.54 - 4.61 (m, 1H), 3.80 - 4.00 (m, 2H), 3.55 - 3.74 (m, 1H), 3.35 - 3.48 (m, 1H), 2.78- 2.88 (m, 1H), 2.70 - 2.77 (m, 1H), 2.57 - 2.68 (m, 1H), 2.42 - 2.56 (m, 1H), 2.25 - 2.34 (m, 2H), 1.98 - 2.02 (m, 1H), 1.85 - 1.94 (m, 1H), 1.70 - 1.81 (m, 3H), 1.55 - 1.66 (m, 1H), 1.32 - 1.50 (m, 2H), 0.97 - 1.06 (m, 6H), 0.61 - 0.73 (m, 2H), 0.01 - 0.08 (m, 2H). 19F NMR (377 MHz, Acetonitrile-d3) δ -98.10, -98.75, -111.87, -112.52. [00625] Synthesis of Compound 69: 2-(3-(1H-benzo[d]imidazol-5-yl)-2- cyclopropylphenyl)-N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide cyclopropylphenyl] acetate [00628] To a stirred solution of methyl 2-(3-chloro-2-cyclopropylphenyl) acetate (200 mg, 0.890 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,3-benzodiazole (261 mg, 1.07 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL) was added XPhos (42.4 mg, 0.089 mmol), Pd-XPhos-G3 (75.4 mg, 0.089 mmol), and potassium phosphate tribasic (378 mg, 1.78 mmol). The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. The reaction was cooled to room temperature, then was quenched with water. The resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (190 mg, 69.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C19H18N2O2: 307.14, found 307.25. [00629] Step 2: Preparation of [3-(1H-1,3-benzodiazol-5-yl)-2-cyclopropylphenyl] acetic acid [00630] A solution of methyl 2-[3-(1H-1,3-benzodiazol-5-yl)-2-cyclopropylphenyl] acetate (190 mg, 0.620 mmol) and lithium hydroxide (74.3 mg, 3.10 mmol) in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL) was stirred for 1 h at room temperature. The mixture was neutralized to pH = 7 with 1N hydrochloric acid, then the solution was concentrated. The residue was purified by preparative HPLC (C18 column, 5-20% acetonitrile/water gradient) to provide the title compound as a yellow solid (80 mg, 44.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C18H16N2O2: 293.12, found 293.05. [00631] Step 3: Preparation of 2-(3-(1H-benzo[d]imidazol-5-yl)-2-cyclopropylphenyl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 69) [00632] To a stirred solution of [3-(1H-1,3-benzodiazol-5-yl)-2-cyclopropylphenyl] acetic acid (60 mg, 0.205 mmol) and HATU (101 mg, 0.267 mmol) in N,N-dimethylformamide (3 mL) was added Intermediate 2 (56.7 mg, 0.205 mmol) and N,N-diisopropylethylamine (106 mg, 0.820 mmol) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature, then the reaction was quenched by addition of water and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD C18150 mm x 30 mm x 5 μm column, 27-39% acetonitrile/water gradient with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (4.8 mg, 4.07% yield). LCMS (ESI): m/z [M+H]+ calcd for C32H40F2N4O2: 551.32, found 551.35. 1H NMR (300 MHz, Acetonitrile-d3) δ 8.07 (s, 1H), 7.65 (d, J = 9.5 Hz, 2H), 7.12 – 7.34 (m, 4H), 6.56 (d, J = 9.8 Hz, 1H), 4.02 – 4.30 (m, 1H), 3.80 – 4.00 (m, 2H), 3.28 – 3.50 (m, 2H), 2.60 – 2.83 (m, 3H), 2.00 – 2.09 (m, 2H), 1.75 – 1.85 (m, 3H), 1.68 – 1.75 (m, 1H), 1.30 – 1.53 (m, 5H), 1.30 (s, 1H), 0.97 – 1.03 (m, 6H), 0. 78 – 0.92 (m, 1H), 0.55 – 0.72 (m, 2H), 0. 01 – 0.08 (m, 2H).19F NMR (282 MHz, Acetonitrile-d3) δ -97.949, -111.862. [00633] Synthesis of Compound 70: 2-(2-(1H-indazol-5-yl)-3-(trifluoromethyl)pyridin-4- yl)-N-((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide pyridine [00636] To a stirred solution of 2-chloro-4-iodo-3-(trifluoromethyl) pyridine (1 g, 3.25 mmol) and 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.77 g, 3.90 mmol) in 1,4- dioxane (10 mL) and water (1 mL) was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.26 g, 0.325 mmol) and potassium carbonate (0.90 g, 6.51 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. The reaction was cooled to room temperature, quenched by addition of water, then was extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentarted. The residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (600 mg, 73.3% yield). LCMS (ESI): m/z [M+H]+ calcd for C10H9ClF3NO: 252.03, found 252.15. [00637] Step 2: Preparation of 5-{4-[(E)-2-ethoxyethenyl]-3-(trifluoromethyl) pyridin-2- yl}-1H-indazole [00638] To a stirred solution of 2-chloro-4-[(E)-2-ethoxyethenyl]-3-(trifluoromethyl) pyridine (540 mg, 2.15 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (629 mg, 2.58 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (175 mg, 0.215 mmol) and potassium carbonate (593 mg, 4.29 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, quenched by addition of water, and was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (380 mg, 53.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C17H14F3N3O: 334.11, found 334.05. [00639] Step 3: Preparation of 2-[2-(1H-indazol-5-yl)-3-(trifluoromethyl) pyridin-4-yl] acetaldehyde [00640] A solution of 5-{4-[(E)-2-ethoxyethenyl]-3-(trifluoromethyl) pyridin-2-yl}-1H- indazole (200 mg, 0.600 mmol) and hydrochloric acid (2 mL, 65.8 mmol) in 1,4-dioxane (4 mL) was stirred for 1 h at room temperature. The reaction was diluted with water, and the resulting mixture was then extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow oil, which was used without further purification (120 mg, 65.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H10F3N3O: 306.08, found 306.10. [00641] Step 4: Preparation of [[2-(1H-indazol-5-yl)-3-(trifluoromethyl) pyridin-4-yl] acetic acid [00642] To a stirred solution of 2-[2-(1H-indazol-5-yl)-3-(trifluoromethyl) pyridin-4-yl] acetaldehyde (100 mg, 0.328 mmol) in tert-butyl alcohol (2.5 mL) and tetrahydrofuran (2.5 mL) was added 2-methyl-2-butene (138 mg, 1.97 mmol) and sodium chlorite (35.6 mg, 0.394 mmol) in portions at 0 °C. To the above mixture was added sodium phosphate monobasic (47.2 mg, 0.394 mmol) in 1 mL of water dropwise over 1 min at 0 °C. The resulting mixture was stirred for an additional 30 min at 0 °C, then was stirred at room temperature for 3 h. The reaction was quenched by addition of water, and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow oil, which was used without further purification (60 mg, 57.0% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H10F3N3O2: 322.08, found 322.00. [00643] Step 5: Preparation of 2-(2-(1H-indazol-5-yl)-3-(trifluoromethyl)pyridin-4-yl)-N- ((1R,6S)-2,2-difluoro-6-((1-isopropylpiperidin-4-yl)oxy)cyclohexyl)acetamide (Compound 70) [00644] To a stirred solution of [2-(1H-indazol-5-yl)-3-(trifluoromethyl) pyridin-4-yl] acetic acid (50 mg, 0.156 mmol) and HATU (76.9 mg, 0.203 mmol) in N,N-dimethylformamide (3 mL) was added Intermediate 2 (43.0 mg, 0.156 mmol) and N,N-diisopropylethylamine (80.5 mg, 0.624 mmol) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature then the reaction mixture was quenched by addition of water and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (YMC Triart C18 ExRs 250 mm x 20 mm x 5 μm column, 25-50% acetonitrile/water gradient with 10 mM ammonium bicarbonate) to provide the title compound as a white solid (4.8 mg, 4.94% yield). LCMS (ESI): m/z [M+H]+ calcd for C29H34F5N5O2: 580.27, found 580.30. 1H NMR (300 MHz, Acetonitrile-d3) δ 11.39 (s, 1H), 8.74 (d, J = 5.0 Hz, 1H), 8.10 (d, J = 1.0
Figure imgf000181_0001
(t, J = 1.1 Hz, 1H), 7.64 (dt, J = 8.6, 1.0 Hz, 1H), 7.21 – 7.45 (m, 2H), 6.83 (d, J = 9.8 Hz, 1H), 3.95 – 4.20 (m, 1H), 3.68 – 3.95 (m, 2H), 3.15 – 3.50 (m, 2H), 2.49 – 2.79 (m, 3H), 2.15 – 2.19 (m, 1H), 2.12 (d, J = 11.3 Hz, 2H), 1.60 – 1.80 (m, 4H), 1.12 – 1.40 (m, 5H), 0.85 – 0.93 (m, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -51.608, -98.315, -111.892. [00645] Synthesis of Compound 71: N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3- (trifluoromethyl)pyridin-4-yl)acetamide te [00648] To a stirred solution of 2-chloro-4-iodo-3-(trifluoromethyl)pyridine (1 g, 3.25 mmol) and tert-butyl[(1-methoxyethenyl)oxy]dimethylsilane (3.06 g, 16.3 mmoL) in N,N- dimethylformamide (5 mL) were added bis(tri-tert-butylphosphine)palladium(0) (0.33 g, 0.651 mmoL), and zinc fluoride (1.68 g, 16.3 mmol) in portions at room temperature. The resulting mixture was stirred for 4 h at 100 °C under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction was cooled to room temperature, quenched with water (50 mL), and the resulting mixture was extracted with ethyl acetate (3 x 60 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (400 mg, 48.5% yield). LCMS (ESI): m/z [M-H]- calcd for C9H7ClF3NO2: 252.01, found 251.95. [00649] Step 2: Preparation of methyl 2-[2-(3,5-difluorophenyl)-3- (trifluoromethyl)pyridin-4-yl]acetate [00650] To a stirred solution of methyl 2-[2-chloro-3-(trifluoromethyl)pyridin-4-yl]acetate (280 mg, 1.10 mmol) and 3,5-difluorophenylboronic acid (349 mg, 2.21 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (162 mg, 0.221 mmol) and potassium carbonate (458 mg, 3.31 mmol) in portions at room temperature. The resulting mixture was then stirred for 3 h at 90 °C under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction was cooled to room temperature, quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (300 mg, 82.0% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H10F5NO2: 332.07, found 332.10. [00651] Step 3: Preparation of [2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4- yl]acetic acid [00652] To a stirred mixture of methyl 2-[2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4- yl]acetate (300 mg, 0.906 mmol) in a mixture of tetrahydrofuran (2 mL), water (2 mL), and methanol (2 mL) were added lithium hydroxide (108 mg, 4.53 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature, at which point the reaction was judged complete by LMCS. The mixture was acidified with 2N hydrochloric acid to pH = 5 and the resulting mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow solid, which was used without further purification (250 mg, 87.0% yield). LCMS (ESI): m/z [M+H]+ calcd for C14H8F5NO2: 318.05, found 317.95. p [00653] Step 4: Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3- (trifluoromethyl)pyridin-4-yl)acetamide (Compound 71) [00654] To a stirred mixture of [2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl]acetic acid (100 mg, 0.315 mmol) and (1R,6S)-2,2-difluoro-6-{[(3R,4S)-3-fluoro-1-isopropylpiperidin- 4-yl]oxy}cyclohexan-1-amine (92.8 mg, 0.315 mmol) in N,N-dimethylformamide (5 mL) were added HATU (240 mg, 0.630 mmol) and N,N-diisopropylethylamine (122 mg, 0.945 mmol) dropwise at room temperature. The resulting mixture was stirred for 1 h at room temperature, then the reaction was quenched by addition of water (10 mL) and the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column, 55-65% methanol/water with 0.05% ammonium carbonate) to provide the title compound as a yellow solid (16.9 mg, 8.91% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H31F8N3O2: 594.23, found 594.05. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.75 (d, J = 5.1 Hz, 1H), 7.51 (d, J = 5.0 Hz, 1H), 7.03 – 7.14 (m, 3H), 6.87 (d, J = 9.8 Hz, 1H), 4.55 – 4.74 (m, 1H), 4.12 – 4.27 (m, 1H), 3.80 – 4.00 (m, 2H), 3.55 – 3.71 (m, 1H), 3.40 – 3.50 (m, 1H), 2.70 – 2.90 (m, 2H), 2.59 – 2.70 (m, 1H), 2.41 – 2.59 (m, 1H), 2.24 – 2.36 (m, 1H), 2.08 – 2.12 (m, 2H), 1.70 – 1.90 (m, 3H), 1.59 – 1.70 (m, 1H), 1.30 – 1.50 (m, 2H), 1.00 (dd, J = 6.6, 4.6 Hz, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -52.01, - 98.64, -99.28, -111.90. [00655] Synthesis of Compound 72: N-((1R,6S)-2,2-difluoro-6-(((3S,4R)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3- (trifluoromethyl)pyridin-4-yl)acetamide [00656] Scheme 45
Figure imgf000184_0001
nitrobenzenesulfonamido)cyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate [00658] To a solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (300 mg, 0.943 mmol) in N-methyl-2-pyrrolidone (0.1 mL) was added tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (207 mg, 0.943 mmol). The reaction was stirred at 150 °C for 1 h, at which point it was judged complete by LCMS. The reaction was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography 0- 100% ethyl acetate/petroleum ether gradient) to provide the title compound (450 mg, 79.9% yield). LCMS (ESI): m/z [M+H-Boc]+ calcd for C22H30F3N3O7S: 438.13, found 438.15. [00659] Step 2: Preparation of N-[(1R,6S)-2,2-difluoro-6-{[(3S,4R)-3-fluoropiperidin-4- yl]oxy}cyclohexyl]-4-nitrobenzenesulfonamide [00660] To a solution of tert-butyl (3S,4R)-4-{[(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy}-3-fluoropiperidine-1-carboxylate (440 mg, 0.819 mmol) in 1,4-dioxane (5 mL) was added 4N hydrogen chloride in 1,4-dioxane (5 mL). The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The resulting mixture was concentrated to provide the title compound, which was used without purification (400 mg, 89.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C17H22F3N3O5S: 438.13, found 438.10. [00661] Step 3: Preparation of N-[(1R,6S)-2,2-difluoro-6-{[(3S,4R)-3-fluoro-1- isopropylpiperidin-4-yl]oxy}cyclohexyl]-4-nitrobenzenesulfonamide [00662] To a solution of N-[(1R,6S)-2,2-difluoro-6-{[(3S,4R)-3-fluoropiperidin-4- yl]oxy}cyclohexyl]-4-nitrobenzenesulfonamide (400 mg, 0.914 mmol) in methanol (10 mL) was added acetone (4.25 g, 73.1 mmol) and sodium cyanoborohydride (17.4 mg, 0.276 mmol). The reaction was stirred at room temperature for 0.5 h, then was cooled to 0 °C, addition sodium cyanoborohydride (172 mg, 2.74 mmol) was added, and the reaction was allowed to warm to room temperature and was stirred for 3 h. The mixture was diluted with water (30 mL), then extracted with dichloromethane (3 × 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound (310 mg, 63.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C20H28F3N3O5S: 480.17, found 480.10. [00663] Step 4: Preparation of (1R,6S)-2,2-difluoro-6-{[(3S,4R)-3-fluoro-1- isopropylpiperidin-4-yl]oxy}cyclohexan-1-amine [00664] To a solution of N-[(1R,6S)-2,2-difluoro-6-{[(3S,4R)-3-fluoro-1-isopropylpiperidin-4- yl]oxy}cyclohexyl]-4-nitrobenzenesulfonamide (300 mg, 0.626 mmol) in toluene (15 mL) was added sodium thiophenolate (413 mg, 3.13 mmol), and the reaction was stirred at 100 °C for 2 h. The reaction was then cooled to room temperature, quenched with water (30 mL), and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% methanol/dichloromethane gradient) to provide the title compound (120 mg, 65.2% yield). LCMS (ESI): m/z [M+H]+ calcd for C14H25F3N2O: 295.20, found 295.25. [00665] Step 5: Preparation of N-((1R,6S)-2,2-difluoro-6-(((3S,4R)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3- (trifluoromethyl)pyridin-4-yl)acetamide (Compound 72) [00666] To a solution of (1R,6S)-2,2-difluoro-6-{[(3S,4R)-3-fluoro-1-isopropylpiperidin-4- yl]oxy}cyclohexan-1-amine (110 mg, 0.374 mmol) in N,N-dimethylformamide (10 mL) was added [2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl]acetic acid (119 mg, 0.374 mmol) and HATU (185 mg, 0.486 mmol). Then the reaction was cooled to 0 °C and N,N- diisopropylethylamine (217 mg, 1.68 mmol). The reaction was stirred at room temperature for 1 h, at which point it was judged complete by LCMS. The mixture was diluted with water (30 mL), then extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD C1830 mm x 150 mm x 5 μm column, 41-53% acetonitrile/water gradient with 10 mM ammonium carbonate and 0.1% aqueous ammonia) to provide the title compound as a white solid (50.1 mg, 22.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H31F8N3O2: 594.23, found 594.10.1H NMR (400 MHz, Acetonitrile-d3) δ 8.69 – 8.79 (d, J = 5.0 Hz, 1H), 7.42 – 7.58 (m, 1H), 7.03 – 7.13 (m, 3H), 6.70 – 6.82 (m, 1H), 4.59 – 4.80 (m, 1H), 4.01 – 4.30 (m, 1H), 3.80 – 4.00 (m, 2H), 3.50 – 3.70 (m, 1H), 3.33 – 3.50 (m, 1H), 2.91 (s, 1H), 2.61 – 2.80 (m, 2H), 2.38 – 2.58 (m, 1H), 2.22 – 2.32 (m, 1H), 2.08 – 2.15 (m, 2H), 1.70 – 1.92 (m, 3H), 1.62 – 1.70 (m, 1H), 1.32 – 1.50 (m, 2H), 0.92 – 1.02 (dd, J = 6.6, 4.6 Hz, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -52.03, -98.66, -99.30, -111.91. [00667] Synthesis of Compound 73: N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(3-(difluoromethoxy)-2-(3,5- difluorophenyl)pyridin-4-yl)acetamide [00668] Scheme 46
Figure imgf000187_0001
[00670] To a stirred solution of 2-chloro-4-iodopyridin-3-ol (1.2 g, 4.69 mmol) and sodium chlorodifluoroacetate (1.43 g, 9.39 mmol) in N,N-dimethylformamide and water (8:1 mixture, 9 mL) was added potassium carbonate (0.78 g, 5.64 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 100 °C, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (20 mL), extracted with ethyl acetate (3 x 20 mL), and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (800 mg, 55.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C6H3ClF2INO: 305.89, found 305.80. [00671] Step 2: Preparation of methyl 2-[2-chloro-3-(difluoromethoxy)pyridin-4- yl]acetate [00672] To a stirred solution of 2-chloro-3-(difluoromethoxy)-4-iodopyridine (800 mg, 2.62 mmol) and tert-butyl[(1-methoxyethenyl)oxy]dimethylsilane (2.47 g, 13.1 mmol) in N,N- dimethylformamide (10 mL) were added zinc fluoride (1.35 g, 13.1 mmol) and bis(tri-tert- butylphosphine) palladium(0) (268 mg, 0.524 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 100 °C under a nitrogen atmosphere. The reaction was cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (320 mg, 48.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C9H8ClF2NO3: 252.02, found 251.95. [00673] Step 3: Preparation of methyl 2-[3-(difluoromethoxy)-2-(3,5- difluorophenyl)pyridin-4-yl]acetate [00674] To a stirred solution of methyl 2-[2-chloro-3-(difluoromethoxy)pyridin-4-yl]acetate (320 mg, 1.27 mmol) and 3,5-difluorophenylboronic acid (502 mg, 3.18 mmol) in 1,4-dioxane and water (10:1 mixture, 5.5 mL) were added [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (93.1 mg, 0.127 mmol) and potassium carbonate (527 mg, 3.82 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction mixture was cooled to room temperature, quenched with water (40 mL), and extracted with ethyl acetate (3 x 40 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (350 mg, 83.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H11F4NO3: 330.07, found 329.95. [00675] Step 4: Preparation of [3-(difluoromethoxy)-2-(3,5-difluorophenyl)pyridin-4- yl]acetic acid [00676] To a stirred solution of methyl 2-[3-(difluoromethoxy)-2-(3,5-difluorophenyl)pyridin- 4-yl]acetate (320 mg, 0.972 mmol) in a mixture of methanol, tetrahydrofuran, and water (1:1:1, 6 mL) was added lithium hydroxide (116 mg, 4.86 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The mixture was acidified to pH = 5 with 1N hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated, to provide the title compound as a yellow oil which was used without further purification (280 mg, 91.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C14H9F4NO3: 316.06, found 315.95. [00677] Step 5: Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(3-(difluoromethoxy)-2-(3,5- difluorophenyl)pyridin-4-yl)acetamide (Compound 73) [00678] To a stirred solution of [3-(difluoromethoxy)-2-(3,5-difluorophenyl)pyridin-4-yl]acetic acid (80 mg, 0.254 mmol) and (1R,6S)-2,2-difluoro-6-{[(3R,4S)-3-fluoro-1-isopropylpiperidin-4- yl]oxy}cyclohexan-1-amine (62.3 mg, 0.212 mmol) in N,N-dimethylformamide (5 mL) were added HATU (105 mg, 0.275 mmol) and N,N-diisopropylethylamine (82.0 mg, 0.635 mmol) in portions at 0 °C. The resulting mixture was stirred for 1 h at room temperature, at which point the reaction was judged complete by LCMS. The resulting mixture was quenched with water and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD C1830 mm x 150 mm x 5 μm column, 56-70% acetonitrile/water gradient with 10 mM ammonium carbonate and 0.05% aqueous ammonia) to provide the title compound as a white solid (24.1 mg, 18.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F7N3O3: 592.24, found 592.1. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.56 (d, J = 4.9 Hz, 1H), 7.30 – 7.63 (m, 3H), 7.02 – 7.20 (m, 1H), 6.93 (d, J = 9.8 Hz, 1H), 6.45 (t, J = 73.5 Hz, 1H) , 4.50 – 4.76 (m, 1H), 4.12 – 4.40 (m, 1H), 3.75 – 3.97 (m, 2H), 3.55 – 3.75 (s, 1H), 3.45 – 3.50 (m, 1H), 2.70 – 2.99 (m, 2H), 2.40 – 2.72 (m, 2H), 2.25 – 2.35 (m, 1H), 2.10 – 2.13 (m, 1H), 1.70 – 1.95 (m, 4H), 1.55 – 1.70 (m, 1H), 1.32 – 1.47 (m, 2H), 0.98 (t, J = 6.6, 5.4 Hz, 6H).19F NMR (376 MHz, Acetonitrile-d3) δ -81.81, -98.53, -99.18, -111.59, -111.91, -112.55. [00679] Synthesis of Compound 74: 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)- N-((1R,6S)-6-((3,3-difluoro-1-isopropylpiperidin-4-yl)oxy)-2,2- difluorocyclohexyl)acetamide [00680] Scheme 47
Figure imgf000190_0001
nitrobenzenesulfonamido)cyclohexyl]oxy}-3,3-difluoropiperidine-1-carboxylate [00682] To a solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (200 mg, 0.628 mmol) in N-methyl-2-pyrrolidone (0.05 mL) was added tert-butyl (4S)-3,3-difluoro-4-hydroxypiperidine-1-carboxylate (298 mg, 1.26 mmol). The reaction was stirred at 150 °C for 1 h, at which point the reaction was judged complete by LCMS. The reaction mixture was cooled to room temperature, quenched by addition of water (10 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound (85 mg, 21.9% yield). LCMS (ESI): m/z [M+H-Boc]+ calcd for C22H29F4N3O7S: 456.12, found 456.10. [00683] Step 2: Preparation of tert-butyl (4S)-4-{[(1S,2R)-2-amino-3,3- difluorocyclohexyl]oxy}-3,3-difluoropiperidine-1-carboxylate [00684] To a solution of tert-butyl (4S)-4-{[(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy}-3,3-difluoropiperidine-1-carboxylate (80 mg, 0.144 mmol) in toluene (10 mL) was added sodium thiophenolate (95.2 mg, 0.720 mmol), and the reaction was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, quenched with water (30 mL), and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% methanol/dichloromethane gradient) to provide the title compound (50 mg, 93.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C16H26F4N2O3: 371.19, found 371.10. Step 3: Preparation of tert-butyl (4S)-4-{[(1S,2R)-2-(2-{2-cyclopropyl-3',5'-difluoro-[1,1'- biphenyl]-3-yl}acetamido)-3,3-difluorocyclohexyl]oxy}-3,3-difluoropiperidine-1- carboxylate To a solution of tert-butyl (4S)-4-{[(1S,2R)-2-amino-3,3-difluorocyclohexyl]oxy}-3,3- difluoropiperidine-1-carboxylate (45 mg, 0.121 mmol) in N,N-dimethylformamide (10 mL) was added {2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}acetic acid (35.0 mg, 0.121 mmol), HATU (60.0 mg, 0.157 mmol), and N,N-diisopropylethylamine (70.7 mg, 0.544 mmol). The reaction was stirred at room temperature for 2 h, then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound (44 mg, 50.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C33H38F6N2O4: 641.28, found 641.30. [00685] Step 4: Preparation of 2-{2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}-N- [(1R,6S)-6-{[(4S)-3,3-difluoropiperidin-4-yl]oxy}-2,2-difluorocyclohexyl]acetamide [00686] To a solution of tert-butyl (4S)-4-{[(1S,2R)-2-(2-{2-cyclopropyl-3',5'-difluoro-[1,1'- biphenyl]-3-yl}acetamido)-3,3-difluorocyclohexyl]oxy}-3,3-difluoropiperidine-1-carboxylate (40 mg, 0.062 mmol) in 1,4-dioxane (5 mL) was added 4M hydrogen chloride in 1,4-dioxane (5 mL). The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The resulting mixture was concentrated to provide the title compound, which was used directly without purification (30 mg, 88.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H30F6N2O2: 541.22, found 541.30. [00687] Step 5: Preparation of 2-(2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl)-N- ((1R,6S)-6-((3,3-difluoro-1-isopropylpiperidin-4-yl)oxy)-2,2-difluorocyclohexyl)acetamide (Compound 74) [00688] To a solution of 2-{2-cyclopropyl-3',5'-difluoro-[1,1'-biphenyl]-3-yl}-N-[(1R,6S)-6- {[(4S)-3,3-difluoropiperidin-4-yl]oxy}-2,2-difluorocyclohexyl]acetamide (50 mg, 0.092 mmol) in methanol (10 mL) was added acetone (429 mg, 7.36 mmol). The reaction was stirred at room temperature for 0.5 h, then the reaction was cooled to 0 °C and sodium cyanoborohydride (17.4 mg, 0.276 mmol) was added. The reaction was stirred at room temperature for 3 h, at which point the reaction was judged complete by LCMS. The mixture was diluted with water (30 mL), then extracted with dichloromethane (3 × 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (XBridge Prep OBD C1830 mm x 150 mm x 5 μm column, 56-70% acetonitrile/water gradient with 10 mM ammonium carbonate and 0.05% aqueous ammonia) to provide the title compound as a white solid (3.6 mg, 6.12% yield). LCMS (ESI): m/z [M+H]+ calcd for C31H36F6N2O2: 583.27, found 583.10. 1H NMR (300 MHz, Acetonitrile-d3) δ 7.16 – 7.28 (m, 2H), 7.06 – 7.16 (m, 1H), 6.90 – 7.00
Figure imgf000193_0001
– 6.90 (m, 1H), 6.49 – 6.70 (m, 1H), 4.01 – 4.22 (m, 1H), 3.69 – 3.94 (m, 2H), 3.43 – 3.65 (m, 1H), 3.32 – 3.43 (m, 1H), 2.60 – 2.82 (m, 2H), 2.38 – 2.59 (m, 3H), 2.19 – 2.29 (m, 2H), 1.65 – 1.71 (m, 1H), 1.43 – 1.59 (m, 3H), 1.28 – 1.35 (m, 3H), 0.88 – 0.90 (m, 6H), 0.67 – 0.70 (m, 2H), 0.00 – 0.03 (m, 2H). 19F NMR (282 MHz, Acetonitrile- d3) δ -98.23, -99.08, -108.78, -109.63, -111.77, -112.63, -112.79. [00689] Synthesis of Compound 75: N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(3-(difluoromethyl)-2-(3,5- difluorophenyl)pyridin-4-yl)acetamide
Figure imgf000194_0001
[00692] To a stirred solution of 2-chloro-4-iodopyridine-3-carbaldehyde (2 g, 7.48 mmol) in dichloromethane (10 mL) was added diethylaminosulfur trifluoride (2.41 g, 14.9 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (30 mL), and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (1.5 g, 69.3% yield). LCMS (ESI): m/z [M+H]+ calcd for C6H3ClF2IN: 289.90, found 289.80. [00693] Step 2: Preparation of methyl 2-[2-chloro-3-(difluoromethyl)pyridin-4-yl]acetate [00694] To a stirred solution of 2-chloro-3-(difluoromethyl)-4-iodopyridine (800 mg, 2.76 mmol) and tert-butyl[(1-methoxyethenyl)oxy]dimethylsilane (2.60 g, 13.8 mmol) in N,N- dimethylformamide (10 mL) were added zinc fluoride (1.43 g, 13.8 mmol) and bis(tri-tert- butylphosphine) palladium(0) (282 mg, 0.553 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 100 °C under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction was cooled to room temperature, quenched with water (50 mL), and the resulting mixture was extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (300 mg, 46.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C9H8ClF2NO2: 236.02, found 235.95. [00695] Step 3: Preparation of methyl 2-[3-(difluoromethyl)-2-(3,5- difluorophenyl)pyridin-4-yl]acetate [00696] To a stirred solution of methyl 2-[2-chloro-3-(difluoromethyl)pyridin-4-yl]acetate (300 mg, 1.27 mmol) and 3,5-difluorophenylboronic acid (502 mg, 3.18 mmol) in a mixture of 1,4- dioxane and water (10:1, 5.5 mL) were added [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (93.2 mg, 0.127 mmol) and potassium carbonate (528 mg, 3.82 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 90 °C under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction mixture was cooled to room temperature, quenched with water (30 mL), and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (300 mg, 75.2% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H11F4NO2: 314.08, found 313.95. [00697] Step 4: Preparation of [3-(difluoromethyl)-2-(3,5-difluorophenyl)pyridin-4- yl]acetic acid [00698] To a stirred solution of methyl 2-[3-(difluoromethyl)-2-(3,5-difluorophenyl)pyridin-4- yl]acetate (300 mg, 0.958 mmol) in a mixture of methanol, tetrahydrofuran, and water (1:1:1, 6 mL) was added lithium hydroxide (115 mg, 4.79 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The mixture was acidified to pH = 5 with 1N hydrochloric acid, and the resulting mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to provide the title compound as a yellow oil which was used without further purification (260 mg, 90.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C14H9F4NO2: 300.06, found 299.95. [00699] Step 5: Preparation of N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1- isopropylpiperidin-4-yl)oxy)cyclohexyl)-2-(3-(difluoromethyl)-2-(3,5- difluorophenyl)pyridin-4-yl)acetamide (Compound 75) [00700] To a stirred solution of [3-(difluoromethyl)-2-(3,5-difluorophenyl)pyridin-4-yl]acetic acid (50 mg, 0.167 mmol) and (1R,6S)-2,2-difluoro-6-{[(3R,4S)-3-fluoro-1-isopropylpiperidin-4- yl]oxy}cyclohexan-1-amine (49.2 mg, 0.167 mmol) in N,N-dimethylformamide (3 mL) was added HATU (82.6 mg, 0.217 mmol) in portions at room temperature. The solution was then cooled to 0 °C and N,N-diisopropylethylamine (64.8 mg, 0.501 mmol) was added in portions. The resulting mixture was stirred for an additional 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column, 55-65% methanol/water gradient with 0.05% ammonium bicarbonate) to provide the title compound as an off-white solid (30.2 mg, 30.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C28H32F7N3O2: 576.24, found 576.15. 1H NMR (300 MHz, Acetonitrile-d3) δ 8.48– 8.69 (m, 1H), 7.28 – 7.42 (m, 1H), 6.98 – 7.13 (m, 3H), 6.50 – 7.97 (m, 2H), 4.40 – 4.71 (m, 1H), 3.99 – 4.27 (m, 1H), 3.68 – 3.98 (m, 2H), 3.41 – 3.62 (m, 1H), 3.22 – 3.40 (m, 1H), 2.59 – 2.84 (m, 2H), 2.29 – 2.57 (m, 2H), 2.12 – 2.28 (m, 1H), 1.97 – 2.05 (m, 1H), 1.58 – 1.78 (m, 3H), 1.43 – 1.53 (m, 1H), 1.20 – 1.40 (m, 2H), 0.88– 0.96 (m, 6H). 19F NMR (282 MHz, Acetonitrile-d3) δ -99.27, -107.51, -110.70, -110.90, -111.05, -111.81, -112.67. [00701] Synthesis of Compound 76: 2-(2-(1H-indazol-5-yl)-3-(trifluoromethyl)pyridin-4- yl)-N-((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide
Figure imgf000197_0001
yl]acetate [00704] To a solution of 2-chloro-4-iodo-3-(trifluoromethyl)pyridine (1 g, 3.25 mmol) in N,N- dimethylformamide (10 mL) was added {[1-(tert-butoxy)ethenyl]oxy}(tert-butyl)dimethylsilane (3.75 g, 16.3 mmol), bis(tri-tert-butylphosphine) palladium(0) (0.33 g, 0.651 mmol) and zinc fluoride (1.68 g, 16.3 mmol) under a nitrogen atmosphere. The reaction was stirred at 100 °C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (3 x 80 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (380 mg, 39.5% yield). LCMS (ESI): m/z [M+H]+ calcd for C12H13ClF3NO2: 296.06, found 296.20. [00705] Step 3: Preparation of [2-chloro-3-(trifluoromethyl)pyridin-4-yl]acetic acid [00706] To a solution of tert-butyl 2-[2-chloro-3-(trifluoromethyl)pyridin-4-yl]acetate (370 mg, 1.25 mmol) in tetrahydrofuran (2 mL), methanol (2 mL), and water (1 mL) was added lithium hydroxide (180 mg, 7.51 mmol). The reaction was stirred at room temperature for 1 h, then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC (C18 column, 5-100% acetonitrile/water gradient) to provide the title compound as a white solid (200 mg, 66.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C8H5ClF3NO2: 240.00, found 240.15. [00707] Step 4: Preparation of 2-[2-chloro-3-(trifluoromethyl)pyridin-4-yl]-N-[(1R,6S)- 2,2-difluoro-6-{[(3R,4S)-3-fluoro-1-isopropylpiperidin-4-yl]oxy}cyclohexyl]acetamide [00708] To a solution of [2-chloro-3-(trifluoromethyl)pyridin-4-yl]acetic acid (190 mg, 0.793 mmol) in N,N-dimethylformamide (5 mL) was added (1R,6S)-2,2-difluoro-6-{[(3R,4S)-3-fluoro- 1-isopropylpiperidin-4-yl]oxy}cyclohexan-1-amine (280 mg, 0.952 mmol), HATU (362 mg, 0.952 mmol) and N,N-diisopropylethylamine (410 mg, 3.17 mmol). The reaction was stirred at room temperature for 1 h, then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound as a yellow solid (200 mg, 48.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C22H28ClF6N3O2: 516.18, found 516.30. [00709] Step 5: Preparation of 2-(2-(1H-indazol-5-yl)-3-(trifluoromethyl)pyridin-4-yl)-N- ((1R,6S)-2,2-difluoro-6-(((3R,4S)-3-fluoro-1-isopropylpiperidin-4- yl)oxy)cyclohexyl)acetamide (Compound 76) [00710] To a solution of 2-[2-chloro-3-(trifluoromethyl)pyridin-4-yl]-N-[(1R,6S)-2,2-difluoro- 6-{[(3R,4S)-3-fluoro-1-isopropylpiperidin-4-yl]oxy}cyclohexyl]acetamide (190 mg, 0.368 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-indazole (180 mg, 0.736 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26.9 mg, 0.037 mmol) and potassium carbonate (127 mg, 0.920 mmol) under a nitrogen atmosphere. The reaction was stirred at 90 °C for 2 h under a nitrogen atmosphere. The mixture was cooled to room temperature, quenched with water (30 mL), and extracted with dichloromethane (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether) to provide the title compound as an off-white solid (118.3 mg, 53.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C29H33F6N5O2: 598.26, found 598.30. 1H NMR (400 MHz, Acetonitrile-d3) δ 11.30 (s, 1H), 8.74 (d, J = 5.0 Hz, 1H), 8.10 – 8.11 (m, 1H), 7.82 (s, 1H), 7.63 – 7.67 (m, 1H), 7.43 – 7.52 (m, 2H), 6.85 (d, J = 9.8 Hz, 1H), 4.55 – 4.73 (m, 1H), 4.14 – 4.29 (m, 1H), 3.81 – 4.03 (m, 2H), 3.59 – 3.73 (m, 1H), 3.39 – 3.49 (m, 1H), 2.69 – 2.87 (m, 2H), 2.42 – 2.67 (m, 2H), 2.19 – 2.38 (m, 1H), 2.05 – 2.15 (m, 2H), 1.71 – 1.88 (m, 3H), 1.59 – 1.69 (m, 1H), 1.34 – 1.50 (m, 2H), 0.99 (dd, J = 6.6, 4.5 Hz, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -51.61, -98.61, -99.25, -111.95, -112.60. [00711] Synthesis of Compound 77: N-((1R,6S)-2,2-difluoro-6-(((R)-1-isopropylazepan-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl)acetamide
[00712] Scheme 50
Figure imgf000200_0001
- - nitrobenzenesulfonamido)cyclohexyl]oxy}azepane-1-carboxylate [00714] To a stirred solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (200 mg, 0.628 mmol) in N-methyl-2-pyrrolidone (0.1 mL) was added tert-butyl (4R)-4-hydroxyazepane-1-carboxylate (203 mg, 0.942 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at 150 °C under a nitrogen atmosphere, at which point the reaction was judged complete by LCMS. The reaction was cooled to room temperature, quenched with water (10 mL), and the resulting mixture was extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 ethyl acetate/petroleum ether) to provide the title compound as a yellow oil (300 mg, 89.5% yield). LCMS (ESI): m/z [M+H-Boc]+ calcd for C23H33F2N3O7S: 434.15, found 434.00. [00715] Step 2: Preparation of N-[(1R,6S)-6-[(4R)-azepan-4-yloxy]-2,2- difluorocyclohexyl]-4-nitrobenzenesulfonamide [00716] To a stirred solution of tert-butyl (4R)-4-{[(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy}azepane-1-carboxylate (300 mg, 0.562 mmol) in 1,4- dioxane (3 mL) was added 4M hydrogen chloride in 1,4-dioxane (3 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature, at which point the reaction was judged complete by LCMS. The resulting mixture was concentrated under reduced pressure to provide the title compound as a yellow oil which was used directly without purification (220 mg, 90.3% yield). LCMS (ESI): m/z [M+H]+ calcd for C18H25F2N3O5S: 434.15, found 434.00. [00717] Step 3: Preparation of N-[(1R,6S)-2,2-difluoro-6-{[(4R)-1-isopropylazepan-4- yl]oxy}cyclohexyl]-4-nitrobenzenesulfonamide [00718] To a stirred solution of N-[(1R,6S)-6-[(4R)-azepan-4-yloxy]-2,2-difluorocyclohexyl]- 4-nitrobenzenesulfonamide (220 mg, 0.508 mmol) in methanol (4 mL) was added acetone (88.4 mg, 1.52 mmol) and the resulting mixture was stirred at room temperature for 30 min. The solution was cooled to 0 °C and sodium cyanoborohydride (159 mg, 2.54 mmol) was added in portions. The resulting mixture was stirred overnight at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (30 mL), and the resulting mixture was extracted with a dichloromethane and methanol mixture (10:1, 3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 methanol/dichloromethane) to provide the title compound as a yellow oil (180 mg, 74.6% yield). LCMS (ESI): m/z [M+H]+ calcd for C21H31F2N3O5S: 476.20, found 476.05. [00719] Step 4: Preparation of (1R,6S)-2,2-difluoro-6-{[(4R)-1-isopropylazepan-4- yl]oxy}cyclohexan-1-amine [00720] To a stirred solution of N-[(1R,6S)-2,2-difluoro-6-{[(4R)-1-isopropylazepan-4- yl]oxy}cyclohexyl]-4-nitrobenzenesulfonamide (180 mg, 0.379 mmol) in toluene (5 mL) was added sodium thiophenolate (250 mg, 1.89 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 100 °C, at which point the reaction was judged complete by LCMS. The reaction mixture was cooled to room temperature, quenched with water (30 mL), and the resulting mixture was extracted with a dichloromethane and methanol mixture (10:1, 3 x 30 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (1:1 methanol/dichloromethane) to provide the title compound as a yellow oil (80 mg, 72.8% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H28F2N2O: 291.22, found 291.15. [00721] Step 5: Preparation of N-((1R,6S)-2,2-difluoro-6-(((R)-1-isopropylazepan-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl)acetamide (Compound 77) [00722] To a stirred solution of (1R,6S)-2,2-difluoro-6-{[(4R)-1-isopropylazepan-4- yl]oxy}cyclohexan-1-amine (60 mg, 0.207 mmol) and [2-(3,5-difluorophenyl)-3- (trifluoromethyl)pyridin-4-yl]acetic acid (32.8 mg, 0.103 mmol) in N,N-dimethylformamide (4 mL) was added HATU (51.1 mg, 0.135 mmol) in portions at room temperature. The reaction mixture was then cooled to 0 °C and N,N-diisopropylethylamine (40.1 mg, 0.310 mmol) was added dropwise. The resulting mixture was stirred for 2 h at room temperature, at which point the reaction was judged complete by LCMS. The reaction was quenched with water (20 mL), and the resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (XBridge Shield RP18 OBD 250 mm x 19 mm x 10 μm column, 55-65% methanol/water gradient with 0.05% ammonium carbonate) to provide the title compound as a white solid (26.4 mg, 42.7% yield). LCMS (ESI): m/z [M+H]+ calcd for C29H34F7N3O2: 590.26, found 590.20. 1H NMR (300 MHz, Acetonitrile-d3) δ 8.75 (d, J = 5.0 Hz, 1H), 7.27 – 7.51 (m, 1H), 6.86 – (m, 3H), 6.58 – 6.84 (m, 1H), 3.91 – 4.17 (m, 1H), 3.70 – 3.89 (m, 2H), 3.46 – 3.69 (m, 1H), 3.12 – 3.38 (m, 1H), 2.62 – 2.88 (m, 1H), 2.33 – 2.60 (m, 4H), 1.98 – 2.01 (m, 2H), 1.62 – 1.81 (m, 5H), 1.19 – 1.51 (m, 5H), 0.98 (d, J = 6.6 Hz, 6H). 19F NMR (282 MHz, Acetonitrile-d3 δ -52.08, -98.31, -99.17, -111.92, -111.98. [00723] Synthesis of Compound 78: N-((1R,6S)-2,2-difluoro-6-(((S)-1-isopropylazepan-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl)acetamide 2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy}azepane-1-carboxylate [00726] To a solution of (1R,6R)-2,2-difluoro-7-(4-nitrobenzenesulfonyl)-7- azabicyclo[4.1.0]heptane (200 mg, 0.628 mmol) in N-methyl-2-pyrrolidone (0.2 mL) was added tert-butyl (4S)-4-hydroxyazepane-1-carboxylate (271 mg, 1.26 mmol) under a nitrogen atmosphere. The reaction was stirred at 150 °C for 2 h under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature, quenched with water (30 mL), and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether gradient) to provide the title compound as a yellow solid (280 mg, 83.5% yield). LCMS (ESI): m/z [M+Na]+ calcd for C23H33F2N3O7S: 556.19, found 556.30. [00727] Step 2: Preparation of N-[(1R,6S)-6-[(4S)-azepan-4-yloxy]-2,2- difluorocyclohexyl]-4-nitrobenzenesulfonamide [00728] tert-Butyl (4S)-4-{[(1S,2R)-3,3-difluoro-2-(4- nitrobenzenesulfonamido)cyclohexyl]oxy}azepane-1-carboxylate (270 mg, 0.506 mmol) was dissolved in 4M hydrogen chloride in 1,4-dioxane (5 mL), and the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to provide the title compound as a yellow solid which was used directly without purification (195 mg, 88.9% yield). LCMS (ESI): m/z [M+H]+ calcd for C18H25F2N3O5S: 434.15, found 434.20. [00729] Step 3: Preparation of N-[(1R,6S)-2,2-difluoro-6-{[(4S)-1-isopropylazepan-4- yl]oxy}cyclohexyl]-4-nitrobenzenesulfonamide [00730] To a solution of N-[(1R,6S)-6-[(4S)-azepan-4-yloxy]-2,2-difluorocyclohexyl]-4- nitrobenzenesulfonamide (190 mg, 0.438 mmol) in methanol (5 mL) was added acetone (255 mg, 4.38 mmol) and sodium cyanoborohydride (275 mg, 4.38 mmol). The reaction was stirred at room temperature for 16 h, then was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-30% methanol/dichloromethane gradient) to provide the title compound as a yellow solid (180 mg, 86.4% yield). LCMS (ESI): m/z [M+H]+ calcd for C21H31F2N3O5S: 476.20, found 476.25. [00731] Step 4: Preparation of (1R,6S)-2,2-difluoro-6-{[(4S)-1-isopropylazepan-4- yl]oxy}cyclohexan-1-amine [00732] To a solution of N-[(1R,6S)-2,2-difluoro-6-{[(4S)-1-isopropylazepan-4- yl]oxy}cyclohexyl]-4-nitrobenzenesulfonamide (170 mg, 0.357 mmol) in toluene (5 mL) was added sodium thiophenolate (283 mg, 2.14 mmol). The reaction was stirred at 110 °C for 2 h, then was cooled to room temperature, quenched with water (50 mL), and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% methanol/dichloromethane gradient) to provide the title compound as a yellow oil (80 mg, 77.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C15H28F2N2O: 291.22, found 291.30. [00733] Step 5: Preparation of N-((1R,6S)-2,2-difluoro-6-(((S)-1-isopropylazepan-4- yl)oxy)cyclohexyl)-2-(2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl)acetamide (Compound 78) [00734] To a solution of [2-(3,5-difluorophenyl)-3-(trifluoromethyl)pyridin-4-yl]acetic acid (81.9 mg, 0.258 mmol) and HATU (147 mg, 0.387 mmol) in N,N-dimethylformamide (3 mL) was added (1R,6S)-2,2-difluoro-6-{[(4S)-1-isopropylazepan-4-yl]oxy}cyclohexan-1-amine (75 mg, 0.258 mmol) and N,N-diisopropylethylamine (134 mg, 1.03 mmol). The reaction was stirred at room temperature for 2 h, then was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Xselect CSH Prep C18250 mm x 19 mm x 5 μm column, 51-62% methanol/water with 0.1% formic acid) to provide the title compound as an off-white solid (24.8 mg, 16.1% yield). LCMS (ESI): m/z [M+H]+ calcd for C29H34F7N3O2: 590.26, found 590.25. 1H NMR (400 MHz, Acetonitrile-d3) δ 8.75 (d, J = 5.0 Hz, 1H), 7.51 (d, J = 5.1, 1H),
Figure imgf000205_0001
– 7.12 (m, 3H), 6.86 (d, J = 9.8 Hz, 1H), 4.06 – 4.21 (m, 1H), 3.82 – 3.98 (m, 2H), 3.63 – 3.71 (m, 1H), 3.29 – 3.39 (m, 1H), 2.80 – 2.92 (m, 1H), 2.56 – 2.70 (m, 3H), 2.46 – 2.55 (m, 1H), 2.05 – 2.15 (m, 2H), 1.81 – 1.96 (m, 3H), 1.69 – 1.80 (m, 2H), 1.55 – 1.67 (m, 2H), 1.26 – 1.54 (m, 3H), 0.98 (d, J = 6.5, 6H). 19F NMR (376 MHz, Acetonitrile-d3) δ -51.98, -98.44, -99.09, -111.95, -112.59. [00735] Human OX2R IP1 assay [00736] The G protein-coupled protein receptor (GPCR) OX2R signals through the Gq/11 signaling pathway. Activation of this pathway can be readily 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 cat #: 62IPAPEB) coupled with a cell line expressing OX2R. IP1 generated within the cell by OX2R agonism competes with the IP1 analog coupled 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 IP1 concentration produced. [00737] Tetracycline-inducible suspension human embryonic kidney cells (Expi293F Inducible; ThermoFisher #A39241) stably expressing tet-responsive human OX2R were induced with 4 µg/mL doxycycline at 32˚C. After 24 hours of induction, cells were harvested, aliquoted, and cryopreserved 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 plated at a concentration of 6,000 cells/well into a 384-well assay plate containing test compounds to give a final concentration of 0.5% DMSO. Following a one-hour incubation at 37˚C, the reaction was terminated by addition of the Cisbio detection mix containing IP1-d2 and anti-IP1-cryptate in lysis buffer. Following a one-hour incubation at room temperature, HTRF- FRET values were measured using a ClarioStar Plus (BMG Labtech) plate reader and the data were expressed as the standard 665nm/620nm ratio. [00738] Exemplary compounds, characterization data, and orexin 2 activation activity is provided in Table 3. Table 3. # Structure IUPAC NMR LCMS pEC50 (MH+) Bin
Figure imgf000206_0001
0.90 – 1.00 (m, 6H).19F NMR (376 MHz, Acetonitrile-d3) δ - 9666 11300 12355
Figure imgf000207_0001
– 1.00 (m, 6H).19F NMR (282 MHz, Acetonitrile-d3) δ -96.54, 11188 11336
Figure imgf000208_0001
(282 MHz, CD3CN) δ -96.54, - 112.89, -123.08. 23'5'difl 2 1H NMR 300 MH
Figure imgf000209_0001
2H), 2.42 – 2.61 (m, 4H), 2.24 – 2.38 (m, 5H), 2.17 – 2.22 (m, 2H 171 192 3H 129
Figure imgf000210_0001
19F NMR (376 MHz, Acetonitrile-d3) δ -97.24, - 11163 11297 12223
Figure imgf000211_0001
biphenyl]-3- (m, 2H), 2.50 – 2.68 (m, 1H), yl)acetamide 2.29 – 2.50 (m, 3H), 2.14 – 2.29 1H 194 199 1H
Figure imgf000212_0001
2-(2',6'-difluoro-2- 1H NMR (400 MHz, methoxy-[1,1'- Acetonitrile-d3) δ 7.42 – 7.55 bih l 3 l N 2H 719 727 2H
Figure imgf000213_0001
2-(2-chloro-3',5'- difluoro-[1,1'- 1H NMR (300 MHz, bih l 3 l N A i il 2 42
Figure imgf000214_0001
N-((1R,6S)-6-((1- cyclobutylpiperidin- 1H NMR (400 MHz, 4 l 22 Acetonitrile-d3) δ 7.27 - 7.37
Figure imgf000215_0001
N-((1R,6S)-2,2- 1H NMR (300 MHz, difluoro-6-(((3R,4S)- Acetonitrile-d3) δ 7.37 - 7.50 3 fl 1 2H 714 736 3H
Figure imgf000216_0001
N-((1R,6S)-2,2- difluoro-6-((1- 1H NMR (400 MHz, i li idi 4
Figure imgf000217_0001
2-(3-cyclopropyl-2- (3,5- difl h l idi 1H MR 4 MH
Figure imgf000218_0001
2-(2-cyclopropyl-3- 1H NMR (300 MHz, (5-methoxypyridin-3- Acetonitrile-d3) δ 8.15 (dd, J = l h l N 12623 H 2H 722 740
Figure imgf000219_0001
2-(3',5'-difluoro-2- 1H NMR (300 MHz, (trifluoromethoxy)- Acetonitrile-d3) δ 7.48 – 7.59 11'bih l 3 l 1H 724 741 2H
Figure imgf000220_0001
N-((1R,6S)-6-(((S)-1- (cyclopropylmethyl)p 1H NMR (400 MHz, lidi 3 l Acetonitrile-d3) δ 832 – 856
Figure imgf000221_0001
2-(2-cyclopropyl- 1H NMR (400 MHz, 3',5'-difluoro-[1,1'- Acetonitrile-d3) δ 7.26 – 7.35 bih l 3 l N 2H 718 724 1H
Figure imgf000222_0001
2-(3',5'-difluoro-2- 1H NMR (400 MHz, methoxy-[1,1'- Acetonitrile-d3) δ 7.31 – 7.36 bih l 3 l N 1H 719 728 1H
Figure imgf000223_0001
2-(2-cyclopropyl- 1H NMR (300 MHz, 3',5'-difluoro-[1,1'- Acetonitrile-d3) δ 7.18 - 7.30 bih l 3 l N
Figure imgf000224_0001
2-(2-cyclopropyl-3- 1H NMR (300 MHz, (1H-indazol-5- Acetonitrile-d3) δ 8.45 (s, 1H), l h l N 803 809 1H 773
Figure imgf000225_0001
1H NMR (400 MHz, Acetonitrile-d3) δ 772 (t J =
Figure imgf000226_0001
1H NMR (400 MHz, Acetonitrile-d3) δ 7.25 - 7.35 2H 718 724 2H
Figure imgf000227_0001
1H NMR (400 MHz, Acetonitrile-d3) δ 11.28 (s, 1H 806 d J 40 H 1H
Figure imgf000228_0001
1H NMR (300 MHz, Acetonitrile-d3) δ 11.39 (s, 1H 874 d J 50 H 1H
Figure imgf000229_0001
1H NMR (400 MHz, Acetonitrile-d3) δ 8.56 (d, J = 49 H 1H 730 763
Figure imgf000230_0001
107.51, -110.70, -110.90, - 111.05, -111.81, -112.67. 1H NMR 400 MH
Figure imgf000231_0001
-98.44, -99.09, -111.95, - 112.59.
Figure imgf000232_0001
** = 1-100 nM (pEC507-9) * = 100 -1000 nM (pEC505-7)
INCORPORATION BY REFERENCE [00739] All of the U.S. patents and U.S. and PCT patent application publications cited herein are hereby incorporated by reference in their entirety. EQUIVALENTS [00740] 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. Such equivalents are intended to be encompassed by the following claims.

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (IA): , or a deuterated derivative, thereof; wherein:
Figure imgf000234_0001
V and W are independently for each occurrence CH, CF, or N; X is O or absent; Y is CH or N; provided that if X is O, then Y is CH; Z is CR3R4 or NR5; R1 is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)haloalkoxy; R2 is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)fluoroalkoxy, 4- to 7-membered heterocycloalkyl, cyano, or halo; R3 and R4 are independently hydrogen, -OH, (C1-C6)alkyl, (C1-C6)alkoxy, or NRaRb; or R3 and R4 taken together with the carbon atom to which they are attached form a 4- to 7-membered spiro heterocycloalkyl optionally substituted with one, two, three, or four substituents independently selected from the group consisting of (C1-C6)alkyl; Ra and Rb are each independently hydrogen or (C1-C6)alkyl; R5 is H or (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl; wherein (C1-C6)alkyl and (C1-C6)haloalkyl are each optionally substituted with hydroxy, (C1-C6)alkoxy, or (C3-C8)cycloalkyl; A is 1,2-disubstituted cyclohexyl or 1,2-disubstituted cyclopentyl; wherein one carbon of the 1,2-disubstituted cyclohexyl or 1,2-disubstituted cyclopentyl is optionally replaced with oxygen; R6 is independently for each occurrence halo, cyano, or oxetanyl; R7 is hydrogen or fluoro; R8 is hydrogen or fluoro; n is 0, 1, or 2; and m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; provided that, if A is 1,2-disubstituted cyclohexyl, then m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; or if A is 1,2-disubstituted cyclopentyl, then m is 0, 1, 2, 3, 4, 5, or 6. 2. A compound of Formula (IB): , or a deuterated derivative,
Figure imgf000235_0001
thereof; wherein: V and W are independently for each occurrence CH, CF, or N; X is O or absent; Y is CH or N; provided that if X is O, then Y is CH; Z is CR3R4 or NR5; R1 is phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, and (C1-C6)haloalkoxy; R2 is hydrogen, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1- C6)fluoroalkoxy, 4- to 7-membered heterocycloalkyl, cyano, or halo; R3 and R4 are independently hydrogen, -OH, (C1-C6)alkyl, (C1-C6)alkoxy, or NRaRb; or R3 and R4 taken together with the carbon atom to which they are attached form a 4- to 7-membered spiro heterocycloalkyl optionally substituted with one, two, three, or four independently selected instances of (C1-C6)alkyl; Ra and Rb are each independently hydrogen or (C1-C6)alkyl; R5 is H or (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein (C1-C6)alkyl and (C1-C6)haloalkyl are each optionally substituted with hydroxy, (C1-C6)alkoxy, or (C3-C8)cycloalkyl; A is 1,2-disubstituted cyclohexyl or 1,2-disubstituted cyclopentyl, wherein one carbon of the 1,2-disubstituted cyclohexyl or 1,2-disubstituted cyclopentyl is optionally replaced with oxygen; R6 is independently for each occurrence halo, cyano, or oxetanyl; R7 is hydrogen or fluoro; n is 0, 1, or 2; m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and if A is 1,2-disubstituted cyclohexyl, then m is 0, 1, 2, 3, 4, 5, 6, 7, or 8; or if A is 1,2- disubstituted cyclopentyl, then m is 0, 1,
2, 3, 4, 5, or 6.
3. The compound of claim 1 or 2, wherein R1 is 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl; each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy and (C1-C6)hydroxyalkyl.
4. The compound of claim 1 or 2, wherein R1 is 5-membered heteroaryl, 6-membered heteroaryl, 8-membered bicyclic heteroaryl, 9-membered bicyclic heteroaryl, or 10-membered bicyclic heteroaryl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, and (C1-C6)alkoxy.
5. The compound of claim 3 or 4, wherein R1 is pyridinyl, isoxazolyl, thiazolyl, pyrazolyl, indazolyl, 2-oxoindolin-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl), or benzo[d]imidazolyl; each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, (C1-C6)alkoxy and (C1-C6)hydroxyalkyl.
6. The compound of any one of claims 1 to 5, wherein R1 is pyridinyl, isoxazolyl, thiazolyl, pyrazolyl, or indazolyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, and (C1-C6)alkoxy.
7. The compound of claim 5 or 6, wherein R1 is 3-pyridinyl, 5-isoxazolyl, 2-thiazolyl, 1-H- 4-pyrazolyl, 1-H-5-indazolyl, 2-oxoindolin-5-yl, 2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl), or 1H- benzo[d]imidazol-5-yl; each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, and (C1-C6)alkoxy.
8. The compound of claim 5 or 6, wherein R1 is 3-pyridinyl, 5-isoxazolyl, 2-thiazolyl, 1-H- 4-pyrazolyl, or 1-H-5-indazolyl, each of which is optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, cyano, (C1-C6)alkyl, and (C1- C6)alkoxy.
9. The compound of any one of claims 1 to 8, wherein R1 is optionally substituted with one, two, three, or four substituents independently selected from chloro, fluoro, methoxy, hydroxymethyl, and methyl.
10. The compound of any one of claims 1 to 9, wherein R1 is optionally substituted with one, two, three, or four substituents independently selected from chloro, fluoro, methoxy, and methyl.
11. The compound of claim 1 or 2, wherein R1 is phenyl optionally substituted with one, two, three, or four substituents independently selected from chloro, fluoro, methoxy, methyl, and hydroxymethyl.
12. The compound of claim 1 or 2, wherein R1 is phenyl optionally substituted with one, two, three, or four substituents independently selected from chloro, fluoro, methoxy, and methyl.
13. The compound of claim 1 or 2, wherein R1 is phenyl optionally substituted with one, two, three, or four substituents independently selected from fluoro, chloro, and cyano.
14. The compound of claim 1 or 2, wherein R1 is phenyl substituted with one, two, three, or four substituents independently selected from chloro, fluoro, cyano, and methoxy.
15. The compound of claim 1 or 2, wherein R1 is phenyl, 3,5-difluorophenyl, 2,6-difluoro, 2- chlorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl, 3-cyano-5-fluorophenyl, 3-methoxyphenyl, or 3-fluoro-5-hyroxyphenyl.
16. The compound of claim 1 or 2, wherein R1 is phenyl, 3,5-difluorophenyl, 2,6-difluoro, 2- chlorophenyl, 3-chlorophenyl, 3,5-dichlorophenyl, 3-cyano-5-fluorophenyl, or 3-methoxyphenyl.
17. The compound of claim 1, having the structure of Formula (IIA): ,
Figure imgf000238_0001
acceptable salt, or a prodrug thereof.
18. The compound of claim 1, having the structure of Formula (IIB): ,
Figure imgf000238_0002
19. The compound of claim 2, having the structure of Formula (IIC): , or a deuterated
Figure imgf000238_0003
thereof.
20. The compound of claim 2, having the structure of Formula (IID): D), or a deuterated derivativ drug thereof.
21. The compound of any one of claims 1 to 20, wherein R2 is hydrogen.
22. The compound of any one of claims 1 to 20, wherein R2 is fluoro.
23. The compound of any one of claims 1 to 20, wherein R2 is chloro.
24. The compound of any one of claims 1 to 20, wherein R2 is (C1-C3)alkyl.
25. The compound of claim 24, wherein R2 is methyl.
26. The compound of any one of claims 1 to 20, wherein R2 is (C1-C3)alkoxy.
27. The compound of claim 26, wherein R2 is methoxy.
28. The compound of any one of claims 1 to 20, wherein R2 is (C1-C6)fluoroalkoxy.
29. The compound of claim 28, wherein R2 is trifluoromethoxy.
30. The compound of any one of claims 1 to 20, wherein R2 is (C3-C6)cycloalkyl.
31. The compound of claim 30, wherein R2 is cyclopropyl.
32. The compound of any one of claims 1 to 20, wherein R2 is cyano.
33. The compound of any one of claims 1 to 20, wherein R2 is (C1-C3)fluoroalkyl.
34. The compound of claim 33, wherein R2 is trifluoromethyl.
35. The compound of claim 33, wherein R2 is difluoromethyl.
36. The compound of any one of claims 1 to 35, wherein V is CH.
37. The compound of any one of claims 1 to 35, wherein V is CF.
38. The compound of any one of claims 1 to 35, wherein V is N.
39. The compound of any one of claims 1 to 38, wherein W is CH.
40. The compound of any one of claims 1 to 38, wherein W is CF.
41. The compound of any one of claims 1 to 38, wherein W is N.
42. The compound of any one of claims 1 to 41, wherein X is absent.
43. The compound of any one of claims 1 to 42, wherein Y is CH.
44. The compound of any one of claims 1 to 42, wherein Y is N.
45. The compound of any one of claims 1 to 41, wherein X is O; and Y is CH.
46. The compound of any one of claims 1 to 45, wherein Z is CR3R4.
47. The compound of claim 46, wherein R3 is hydrogen.
48. The compound of claim 46 or 47, wherein R4 is (C1-C3)alkoxy.
49. The compound of claim 48, wherein R4 is isopropyloxy.
50. The compound of any one of claims 46 or 47, wherein R4 is NRaRb
51. The compound of claim 50, wherein Ra and Rb are each (C1-C3)alkyl.
52. The compound of claim 51, wherein Ra and Rb are each methyl.
53. The compound of claim 46, wherein R3 and R4 together with the carbon atom to which they are attached form a 4- or 5-membered spiro heterocycloalkyl optionally substituted with one, two, three, or four independently selected instances of (C1-C3)alkyl.
54. The compound of any one of claims 1 to 45 wherein Z is NR5.
55. The compound of claim 54, wherein R5 is (C1-C3)alkyl optionally substituted with (C3- C8)cycloalkyl.
56. The compound of claim 55, wherein R5 is cyclopropylmethyl.
57. The compound of claim 55, wherein R5 is isopropyl.
58. The compound of claim 54, wherein R5 is (C1-C3)fluoroalkyl optionally substituted with (C3-C8)cycloalkyl.
59. The compound of claim 58, wherein R5 is 1-fluorocyclopropylmethyl.
60. The compound of claim 55, wherein R5 is (C3-C8)cycloalkyl.
61. The compound of claim 60, wherein R5 is cyclobutyl.
62. The compound of claim 60, wherein R5 is cyclopentyl.
63. The compound of any one of claims 1 to 62, wherein n is 0.
64. The compound of any one of claims 1 to 62, wherein n is 1.
65. The compound of any one of claims 1 to 62, wherein n is 2.
66. The compound of any one of claims 1 to 64, wherein m is 2.
67. The compound of any one of claims 1 to 65, wherein R6 is fluoro.
68. The compound of any one of claims 1 to 66, wherein –N(H)-A-X- is: .
69. The
Figure imgf000241_0001
wherein R7 is hydrogen.
70. The compound of any one of claims 1 to 68, wherein R7 is fluoro.
71. The compound of any one of claims 1 to 70, wherein R8 is hydrogen.
72. The compound of claim 71, wherein .
73.
Figure imgf000241_0002
fluoro.
74. A compound selected from Table 1 of the specification or a deuterated derivative, a pharmaceutically acceptable salt, or a prodrug thereof.
75. A compound selected from Table 2 of the specification or a deuterated derivative, a pharmaceutically acceptable salt, or a prodrug thereof.
76. A pharmaceutical composition comprising a compound of any one of claims 1 to 75; and at least one pharmaceutically acceptable excipient.
77. A method of preventing or treating a disease selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptom, hypersomnia associated with Parkinson's disease, hypersomnia associated with dementia with Lewy body, hypersomnia syndrome involving daytime hypersomnia (e.g., Kleine-Levin syndrome, major depression accompanied by hypersomnia, dementia with Lewy body, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, brain contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, Guillain-Barre syndrome, Rasmussen's encephalitis, Wernicke's encephalopathy, limbic encephalitis, Hashimoto encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cell, extrinsic obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophysial obesity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, alimentary obesity, gonadal obesity, systemic mastocytosis, primary obesity, central obesity), insulin resistance syndrome, Alzheimer, impaired consciousness such as coma, side effect or complication caused by anesthesia, sleep disturbance, sleep problem, insomnia, intermittent sleep, night myoclonus, REM sleep interruption, jet lag, jet lag syndrome, sleep disorder of shift workers, dyssomnia, sleep terror, depression, major depression, sleepwalking, enuresis, sleep disorder, Alzheimer's sundown syndrome, disease associated with circadian rhythm, fibromyalgia, condition resulting from decrease in sleeping quality, bulimia, obsessive eating disorder, obesity-related diseases, hypertension, diabetes, elevated plasma insulin level/insulin resistance, hyperlipemia, hyperlipidaemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstone, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disease, sudden death, polycystic ovary, craniopharyngioma, Prader Willi syndrome, Froehlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children suffering from acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormality, decrease of fecundability, infertility, hypogonadism in men, sexual/reproductive-function dysfunction such as hirsutism in women, fetal defect associated with maternity obesity, gastrointestinal motility disorder such as obesity- related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory disease such as respiratory distress, inflammation such as vascular systemic inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, renal cancer, secondary risk of obesity such as risk of left ventricle hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweat, disease in genitalium/urinary system, disease associated with sexual function or fecundability, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, posttraumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorder such as cerebral deficiency developed after heart bypass surgery or heart transplant, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head injury, periparturient hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye damage, retinopathy, cognitive impairment, muscle spasm, tremor, epilepsy, disorder associated with muscle spasm, delirium, amnestic disorder, age- associated cognitive decline, schizoaffective disorder, paranoia, drug addiction, movement disorder, chronic fatigue syndrome, fatigue, medication-induced parkinsonian syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptom, trigeminal neuralgia, hearing loss, tinnitus, nerve injury, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, cataplexy, and traumatic brain injury, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 75.
78. A method of preventing or treating a disease selected from the group consisting of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome involving narcolepsy-like symptoms, hypersomnia associated with Parkinson's disease, and hypersomnia associated with dementia with Lewy body, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 75.
79. The method of claim 78, wherein the disease is narcolepsy.
80. The method of claim 78, wherein the disease is idiopathic hypersomnia.
81. The method of claim 78, wherein the disease is hypersomnia.
82. The method of claim 78, wherein the disease is sleep apnea syndrome.
83. The method of claim 78, wherein the disease is narcolepsy syndrome involving narcolepsy-like symptoms.
84. The method of claim 78, wherein the disease is hypersomnia associated with Parkinson's disease.
85. The method of claim 78, wherein the disease is hypersomnia associated with dementia with Lewy body.
86. The method of any one of claims 77 to 85, wherein the compound is administered orally.
87. The method of any one of claims 77 to 85, wherein the compound is administered parenterally.
88. The method of any one of claims 77 to 87, wherein the disease is prevented.
89. The method of any one of claims 77 to 87, wherein the disease is treated.
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