WO2024126777A1 - Heteroaromatic compounds - Google Patents

Heteroaromatic compounds Download PDF

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Publication number
WO2024126777A1
WO2024126777A1 PCT/EP2023/086034 EP2023086034W WO2024126777A1 WO 2024126777 A1 WO2024126777 A1 WO 2024126777A1 EP 2023086034 W EP2023086034 W EP 2023086034W WO 2024126777 A1 WO2024126777 A1 WO 2024126777A1
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methyl
ethyl
phenyl
imidazol
urea
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PCT/EP2023/086034
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French (fr)
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Perla Breccia
Maria Angel PALOMERO VAZQUEZ
Rebecca Elizabeth Jarvis
Stig Jonas BOSTRÖM
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Astrazeneca Ab
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Publication of WO2024126777A1 publication Critical patent/WO2024126777A1/en

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    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • SARM1 is an NAD-hydrolysing enzyme which is enriched in neurons and activated in response to neuronal injury. Activation of SARM1 leads to programmed axonal degeneration and inhibitors of SARM1 may be used to treat axonal degeneration disorders (see, e.g., Coleman et al., “Programmed axon degeneration: from mouse to mechanism to medicine” Nature Reviews Neuroscience (2020) 21(4):1-14). SARM1 is an evolutionarily conserved protein which incorporates distinct domains.
  • an N- terminal targeting sequence there is an N- terminal targeting sequence, an ARM (armadillo/HEAT repeat) domain, two SAM (sterile alpha motif) domains and a C-terminal TIR (toll interleukin receptor) domain which has catalytic NADase activity.
  • the ARM domain is autoinhibitory and modulates the activity of SARM1 (see, e.g., Jiang et al., “The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1” Nature (2020) 588(7839):658-663). Constructs without the ARM domain are constitutively active.
  • the SAM domains are believed to mediate oligomerization of SARM1 monomers.
  • the SARM1 TIR domain catalyses the conversion of nicotinamide adenine dinucleotide (NAD+, also called “NAD” herein) to nicotinamide (NAM) and ADP-ribose (ADPR) / cyclic ADP-ribose (cADPR).
  • NAD+ nicotinamide adenine dinucleotide
  • ADPR ADP-ribose
  • cADPR cyclic ADP-ribose
  • Inhibitors of SARM1 may, for example, act by blocking or interfering with the catalytic activity of the enzyme, or they may stabilise the autoinhibited state or block activation.
  • Neuropathies associated with axonal degeneration may be due to neuronal injury such as, e.g., chemical injury, physical injury, or genetic mutation, or they may arise as a result of disease.
  • CIPN chemotherapy induced peripheral neuropathy
  • PDN painful diabetic neuropathy
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • demyelinating disease Parkinson’s Disease
  • AD Alzheimer’s Disease
  • CMT Charcot Marie Tooth Disease
  • SARM1 genetic knock out has shown to be protective in several models of CIPN.
  • SARM1 inhibitors may be useful in the treatment or prevention of CIPN caused by chemotherapeutic agents such as, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, vincristine, vinblastine, bortezomib and carfilzomib (see, e.g., Geisler, “Vincristine- and bortezomib-induced neuropathies – from bedside to bench and back” Experimental Neurology (2021) 336:113519).
  • chemotherapeutic agents such as, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, vincristine, vinblastine, bortezomib and carfilzomib (see, e.g., Geisler, “Vincristine- and bortezomib-induced neuropathies – from bedside to bench and back” Experimental Neurology (2021)
  • Inhibitors of SARM1 may also be useful for the treatment or prevention of anaesthesia induced neuroinflammation and cognitive impairment (see, e.g., Lin et al., “SARM1 is Essential for Anesthesia-Induced Neuroinflammation and Cognitive Impairment in Aged Mice” Cell Mol Neurobiol (2022 Jul;42(5):1465-1476) Inhibitors of SARM1 may also be useful for the treatment of cardiomyopathy (see e.g. Light et al., “Cardiomyopathy Induced by Metabolic and Hypertensive Stresses is alleviated by SARM1 Deficiency” Circulation.2021;144:A13316.
  • the compounds of the disclosure provide an anti-neurodegenerative effect by, as a minimum, acting as SARM1 inhibitors.
  • the compounds of the specification may also exhibit advantageous physical properties (for example, lower lipophilicity, higher aqueous solubility, higher permeability, lower plasma protein binding, and/or greater chemical stability), and/or favourable toxicity profiles (for example a decreased activity at hERG, or a decreased inhibition of Cytochrome P450 enzymes), and/or favourable metabolic or pharmacokinetic profiles, in comparison with other known SARM1 inhibitors.
  • Such compounds may therefore be especially suitable as therapeutic agents, such as for the treatment of chemotherapy induced peripheral neuropathy (CIPN).
  • CIPN chemotherapy induced peripheral neuropathy
  • a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a neurodegenerative condition.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a neurodegenerative condition.
  • a method of treating neurodegenerative conditions in a patient comprising administering to the patient an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • intermediates useful for the synthesis of a compound of Formula (I) or a pharmaceutically acceptable salt thereof are set forth as appropriate throughout the detailed description.
  • alkyl refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms.
  • Cx-y indicates the numerical range of carbon atoms that are present in the group.
  • suitable C 1-4 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
  • X-Y membered indicates the numerical range of atoms (i.e. carbon atoms and heteroatoms) that are present in the group.
  • alkylene refers to a diradical of a saturated, linear or branched hydrocarbon having the specified number of carbon atoms, obtained by removing two hydrogen atoms from the hydrocarbon.
  • the two hydrogen atoms may either both from the same carbon atom, or one from each of two different carbon atoms.
  • Examples of C 1-3 alkylene groups include methylene (i.e. -(CH 2 )-), 1,1-ethylene (i.e. -(CH(CH 3 ))-), 1,2- ethylene (i.e. -(CH 2 CH 2 )-) and 1,3- propylene (i.e. - (CH2CH2CH2)-).
  • alkoxy refers to a saturated group comprising the specified number of carbon atoms and one oxygen atom.
  • the alkoxy group may be a straight chain or a branched chain.
  • suitable C1-4 alkoxy groups include methoxy (OMe), ethoxy (OEt), n-propoxy (O n Pr), i-propoxy (O i Pr), n-butoxy (O n Bu), i-butoxy (O i Bu), s-butoxy (O s Bu) and t- butoxy (O t Bu).
  • cycloalkyl refers to saturated cyclic hydrocarbon radicals having the specified number of carbon atoms.
  • C 3-4 cycloalkyl groups include cyclopropyl and cyclobutyl.
  • C1-4 fluoroalkyl refers to a saturated hydrocarbon radical having 1 to 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom.
  • suitable C1-4 fluoroalkyl groups include fluoromethyl (CFH2), difluoromethyl (CF2H), trifluoromethyl (CF3), 1,1- difluoroethyl (CF 2 CH 3 ), 2,2,2-trifluoroethyl (CH 2 CF 3 ) and 3-fluoropropyl (CH 2 CH 2 CH 2 F).
  • C 3-4 cyclofluoroalkyl refers to a saturated cyclic hydrocarbon radical having 3 or 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom.
  • suitable C3-4 fluorocycloalkyl groups include 2-fluorocyclopropyl, 2,2- difluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 2,2,3-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,3-difluorocyclobutyl, 2,4- difluorocyclobutyl and 2,3,4-trifluorocyclobutyl.
  • heteromatic ring refers to an aromatic, monocyclic or bicyclic, ring having the specified number of atoms, containing at least one N atom and optionally one or more additional heteroatoms independently selected from O, S and N.
  • a heteroaromatic ring may be a 5 or 6 membered monocyclic heteroaromatic ring.
  • Examples of a suitable 5 membered heteroaromatic ring include pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, furazan, 1,3,4-thiadiazole and tetrazole.
  • Examples of a suitable 6 membered heteroaromatic ring include pyridine, pyridazine, pyrimidine, pyrazine and 1,3,4-triazine.
  • a heteroaryl may be a 9-membered bicyclic heteroaromatic ring.
  • a suitable 9 membered heteroaromatic ring examples include pyrazolo[1,5-a]pyridine, benzimidazole, indole, isoindole, indazole, benzthiazole, purine and benzo[d]oxazole.
  • Ring C 1 , C 2 or C 3 may be fused with a benzene or pyridine ring.
  • “fused with a benzene ring” means that a “CH2CH2” diradical of said Ring C 1 , C 2 or C 3 is replaced with .
  • fused with a pyridine ring means that a “CH 2 CH 2 ” diradical of said Ring C 1 , C 2 or C 3 ” is replaced way of illustration only, a ring fused with a benzene ring may In embodiments of the disclosure, Ring C 1 , C 2 or C 3 may be bridged by a C1-3 alkylene group.
  • bridged by a C1-3 alkylene group means that two H atoms attached to different carbon atoms of said Ring C 1 , C 2 or C 3 are replaced with a C 1-3 alkylene group.
  • a ring bridged with a methylene (-(CH 2 )-) group may be , , .
  • the bonding of an atom or group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.
  • the selected substituents may comprise the same substituents or different substituents from within the given group.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof as defined above.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein A and L are independently CR 2 , and E and G are independently CR 2 or N.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein A, E and L are independently CR 2 , and G is independently CR 2 or N.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein A, E, G and L are CH.
  • each R 2 is independently H, OH, C 1-4 alkyl, F or Cl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein each R 2 is independently H, OH, CH3, F or Cl. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R 2 is H. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that is a compound of Formula (II) wherein each R 2A is independently selected from F, Cl, cyano, C1-4 fluoroalkyl, O(C1-4 fluoroalkyl), OH, R 4 , OR 4 , R 5 and OR 5 , and q is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof wherein X is absent, Q is R 3 and R 1 is H.
  • -X-Q- is CH2CH2CH2- or -CH2OCH2-.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof wherein X is absent, Y is CH, and Z is N, such that Ring V 1 , together with Y and Z with which it is fused, is an imidazole or thiazole ring.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof wherein X is present, Y is C, and Z is N, such that Ring V 1 , together with Y and Z with which it is fused, is an imidazole or thiazole ring.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof wherein X is absent, Y is NH, and Z is C, such that Ring V 1 , together with Y and Z with which it is fused, is an imidazole or thiazole ring.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof wherein X is present, Y is N, and Z is C, such that Ring V 1 , together with Y and Z with which it is fused, is an imidazole or thiazole ring.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof wherein X is absent, Y is C, and Z is C, such that Ring V 1 , together with Y and Z with which it is fused, is a thiazole ring.
  • a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof wherein x is 0, 1 or 2. In further embodiments, x is 0 or 1. In further embodiments, x is 0.
  • a compound of Formula (II), or a pharmaceutically acceptable salt thereof that is a compound of Formula (III) wherein V 2 is selected from wherein x2 is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (II), or a pharmaceutically acceptable salt thereof wherein V 2 is selected from wherein R V2 is H, C1-4 alkyl or C3-4 cycloalkyl.
  • R v2 is C1-4 alkyl.
  • R V2 is CH3.
  • a compound of Formula (III), or a pharmaceutically acceptable salt thereof that is a compound of Formula (IIIA) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (III), or a pharmaceutically acceptable salt thereof that is a compound of Formula (IIIB) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (III), or a pharmaceutically acceptable salt thereof that is a compound of Formula (IIIC) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (III), or a pharmaceutically acceptable salt thereof that is a compound of Formula (IIID) or a pharmaceutically acceptable salt thereof.
  • R 3 is C1-4 fluoroalkyl, C1-4 alkyl and C3-4 cycloalkyl.
  • V 3 is selected from wherein R V3 is H, C1-4 alkyl or C1-4 fluoroalkyl.
  • R V3 is C1-4 alkyl.
  • R V3 is CH 3 .
  • a compound of Formula (IV), or a pharmaceutically acceptable salt thereof that is a compound of Formula (IVA) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (IV), or a pharmaceutically acceptable salt thereof that is a compound of Formula (IVB) or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (IV), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof wherein x3 is 0 or 1.
  • Q B is O or CH2.
  • each R V is independently C1-4 alkyl, C3-4 cycloalkyl, C1-4 alkoxy, C1-4 fluoroalkyl or F. In further embodiments, each R V is independently selected from C 1-4 alkyl and C 3-4 cycloalkyl.
  • each R V is CH 3 , CH 2 CH 2 or CH(CH2)2. In further embodiments, each R V is CH3. In embodiments, there is provided a compound of Formula (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein each R 2A is independently OH, C1-4 alkyl, F or Cl.
  • each R 2A is independently OH, CH3, F or Cl.
  • a compound of Formula (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof wherein q is 0, 1 or 2. In further embodiments, q is 0.
  • Ring C 1 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R 9 groups.
  • X A is CH2. In further embodiments, X A is a covalent bond. In further embodiments, Y A is CH2. In further embodiments, Y A is a covalent bond.
  • X A is CH 2 .
  • X A is a covalent bond.
  • Y A is CH 2 .
  • Y A is a covalent bond.
  • X A is CH2.
  • X A is a covalent bond.
  • Y A is CH2.
  • Y A is a covalent bond.
  • X A is a covalent bond.
  • Z A is a covalent bond or CH2.
  • Z A is a covalent bond.
  • Ring C 2 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R 9 groups.
  • X B is CH2. In further embodiments, X B is a covalent bond. In further embodiments, Y B is CH2. In further embodiments, Y B is a covalent bond.
  • Ring C 2 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R 9 groups.
  • X B is CH 2 .
  • X B is a covalent bond.
  • Y B is CH2.
  • Y B is a covalent bond.
  • X B is CH2.
  • X B is a covalent bond.
  • X B is CH2.
  • X B is a covalent bond.
  • X B is CH2.
  • X B is a covalent bond.
  • Y B is CH 2 .
  • Y B is a covalent bond.
  • X B is CH 2 .
  • X B is a covalent bond.
  • Y B is CH2.
  • Y B is a covalent bond.
  • X B is CH2. In further embodiments, X B is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is In further embodiments, X B is CH 2 . In further embodiments, X B is a covalent bond.
  • Z B is a covalent bond or CH2.
  • Z B is a covalent bond.
  • Ring C 3 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R 9 groups.
  • X C is CH2.
  • X C is a covalent bond.
  • Y C is CH 2 .
  • Y C is a covalent bond.
  • Ring C 3 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R 9 groups.
  • X C is CH 2 .
  • X C is a covalent bond.
  • Y C is CH 2 .
  • Y C is a covalent bond.
  • X C is CH 2 .
  • X C is a covalent bond.
  • Y C is CH 2 .
  • Y C is a covalent bond.
  • X C is CH2.
  • X C is a covalent bond.
  • Y C is CH2.
  • Y C is a covalent bond.
  • X C is CH2.
  • X C is a covalent bond.
  • X C is CH2.
  • X C is a covalent bond.
  • Ring D 1 is a 5 or 6 membered heteroaromatic ring.
  • Ring D 1 is an imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring.
  • Z C is a covalent bond, CH2, O or NH.
  • Z C is a covalent bond or CH 2 .
  • Z C is a covalent bond.
  • Ring D 2 is an imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring.
  • Ring D 3 is an imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring.
  • Ring D 4 is an imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring.
  • Ring D 4 is an imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring.
  • R 6A is H, C 1-4 alkyl, F or OH.
  • R 6A is H, F or CH 3 .
  • R 6A is H.
  • R 7 is H, C1-4 alkyl, F or OH.
  • R 7 is H, F or CH3.
  • R 7 is H.
  • R 7A is H, C 1-4 alkyl, C 1-4 fluoroalkyl, C 3-4 cycloalkyl, C 3-4 fluorocycloalkyl, F, OH or C 1-4 alkoxy.
  • R 7A is H, C 1-4 alkyl, F or OH.
  • R 7A is H, F or CH 3 .
  • R 7A is H.
  • each R 8 is independently C1-4 alkyl, R 11 , C1-4 alkoxy, C3-4 cycloalkyl, OH or F.
  • each R 8 is independently C1-4 alkyl, C1-4 alkoxy, OH or F.
  • each R 8 is independently C1-4 alkyl or F.
  • each R 8 is independently CH3 or F.
  • each R 8 is CH3.
  • each R 9 is independently C 1-4 alkyl, R 11 , C 1-4 alkoxy, C 3-4 cycloalkyl, NH(R 10 ), N(R 10 ) 2 , OH, F, Cl or Br.
  • each R 9 is independently C1-4 alkyl, C1-4 alkoxy, C3-4 cycloalkyl, OH, F or Cl.
  • each R 9 is independently C1-4 alkyl or F.
  • each R 9 is independently C1-4 alkyl. In further embodiments, each R 9 is CH3. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2. In further embodiments, m is 0 or 1. In further embodiments, m is 0.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein the compound is selected from, 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((4-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(3-methyl-1H-pyrazol-5-yl)urea, 1-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-3-1H-pyrazol-3-ylurea, 1-(4-((1H-imidazol-5-yl)
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof wherein the compound is selected from, 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((4-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(3-methyl-1H-pyrazol-5-yl)urea, 1-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-3-1H-pyrazol-3-ylurea, 1-(4-((1H-imidazol-5-yl)
  • a further feature is any of the embodiments described in the specification with the proviso that any of the specific Examples are individually disclaimed.
  • a further feature is any of the embodiments described in the specification with the proviso that any one or more of the compounds selected from the above list of Examples of compounds of the specification are individually disclaimed.
  • the compounds disclosed herein may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e. as individual enantiomers, diastereoisomers, or as a stereoisomerically enriched mixture. All such stereoisomer (and enriched) mixtures are included within the scope of the embodiments, unless otherwise stated.
  • stereoisomers may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers, diastereoisomers, conformers, rotamers and tautomers of the compound depicted.
  • a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of the enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereoisomers including (R,R), (S,S), (R,S) and (S,R).
  • a pharmaceutical composition which comprises a compound of the Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of ⁇ 90% and a diastereomeric excess (%de) of ⁇ 90%.
  • the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), and pharmaceutically acceptable salts thereof may be prepared, used or supplied in amorphous form, crystalline form, or semicrystalline form and any given compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or pharmaceutically acceptable salt thereof, may be capable of being formed into more than one crystalline / polymorphic form, including hydrated (e.g.
  • the present specification is intended to include all isotopes of atoms occurring in the present compounds. Isotopes will be understood to include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopes of nitrogen include 15 N.
  • Isotopes of fluorine include 18 F.
  • a suitable pharmaceutically acceptable salt of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) is, for example, a base addition salt.
  • a base addition salt of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) may be formed by bringing the compound into contact with a suitable inorganic or organic base under conditions known to the skilled person.
  • a base addition salt may for example be an alkali metal salt (such as a sodium, potassium, or lithium salt) or an alkaline earth metal salt (such as a calcium salt), which may be formed using an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., an ethoxide or methoxide).
  • a base addition salt may also be formed using a suitably basic organic amine (e.g., a choline or meglumine salt).
  • a suitable pharmaceutically acceptable salt of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) is, for example, an acid addition salt.
  • An acid addition salt of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person.
  • An acid addition salt may for example be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid.
  • An acid addition salt may also be formed using an organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.
  • organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid.
  • a further suitable pharmaceutically acceptable salt of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) is, for example, a salt formed within a patient’s body after administration of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) to the patient.
  • the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or pharmaceutically acceptable salt thereof may be prepared as a co-crystal solid form.
  • a pharmaceutically acceptable co-crystal of an compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or pharmaceutically acceptable salts thereof form an aspect of the present specification.
  • a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • composition refers to a preparation which is in such form as to permit the biological activity of the active ingredient, and which contains no additional components which are unacceptably toxic to a patient to which the composition would be administered. Such compositions can be sterile.
  • a pharmaceutical composition according to the present specification will comprise a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the composition may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • Such compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V),or a pharmaceutically acceptable salt thereof will normally be administered via the oral route though parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form may be possible.
  • the compositions may be administered at varying doses.
  • the pharmaceutical formulations of the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) described above may be prepared e.g. for parenteral, subcutaneous, intramuscular or intravenous administration.
  • the pharmaceutical formulations of the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) described above may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).
  • compositions suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with binding agents, fillers, lubricants and surfactants. Liquid compositions may contain conventional additives such as suspending agents, emulsifying agents and preservatives. Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules.
  • SEG soft elastic gelatin
  • An exemplary oral composition would comprise a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) and at least one pharmaceutically acceptable excipient filled into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule.
  • SEG soft elastic gelatin
  • the compounds of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), and pharmaceutically acceptable salts thereof are expected to be useful in therapy, for example in the treatment of diseases or medical conditions mediated at least in part by SARM1, such as a neuropathy associated with axonal degeneration.
  • SARM1 such as a neuropathy associated with axonal degeneration.
  • chemotherapy induced peripheral neuropathy CIPN
  • painful diabetic neuropathy PDN
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • demyelinating disease Parkinson’s Disease
  • AD Alzheimer’s Disease
  • CMT Charcot
  • the CIPN is caused by a chemotherapeutic agent selected from cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, vincristine, vinblastine, bortezomib and carfilzomib.
  • the term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.
  • the term “prophylaxis” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • treatment is used synonymously with “therapy”.
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • the disease mediated by SARM1 is chemotherapy induced peripheral neuropathy (CIPN).
  • CIPN chemotherapy induced peripheral neuropathy
  • the medicament is for the treatment of chemotherapy induced peripheral neuropathy (CIPN).
  • a method of treating disease in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof.
  • Terms such as “treating” or “treatment” refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder.
  • those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented.
  • the term "effective amount” means an amount of an active ingredient which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • patient refers to any animal (e.g., a mammal), including, but not limited to humans, non- human primates, rodents, and the like, which is to be the recipient of a particular treatment.
  • the term “patient” refers to a human subject.
  • a method of treating disease in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein the disease is selected from chemotherapy induced peripheral neuropathy (CIPN), painful diabetic neuropathy (PDN), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), demyelinating disease, Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Charcot Marie Tooth Disease (CMT), hereditary spastic paraplegia, ischemia, stroke, traumatic brain injury (TBI), traumatic neuronal injury, carpal tunnel syndrome, glaucoma, retinal degeneration, viral infection, and viral encephalitis.
  • chemotherapy induced peripheral neuropathy CIPN
  • painful diabetic neuropathy PDN
  • ALS amyotroph
  • a method of treating a SARM1 mediated disease in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof.
  • the SARM1 mediated disease is chemotherapy induced peripheral neuropathy (CIPN).
  • a method of treating chemotherapy induced peripheral neuropathy (CIPN) in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof.
  • the compounds of the present disclosure may or may not form a covalent adduct with ADP-ribose (ADPR), wherein said adduct inhibits SARM1 activity.
  • ADPR ADP-ribose
  • the compounds of the present disclosure may be used in the methods described above as either as single pharmacological agents or in combination with other pharmacological agents or techniques.
  • Such combination therapies may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • These combination therapies employ the compounds of the present disclosure and the other pharmacological agent(s).
  • the compounds of the Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) are primarily of value as therapeutic agents for use in patients, they are also useful whenever it is required to inhibit SARM1. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Examples The specification will now be illustrated by the following non-limiting Examples. General Experimental Details Unless stated otherwise, starting materials were commercially available.
  • LCMS experiments were performed using a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector.
  • LCMS was run in one of three set ups: method 1 [Halo C18 column (2.0 ⁇ m 3.0 x 30 mm) in combination with a gradient (5-100% B in 1.2 min.) of water and FA (0.1%) (A) and MeCN and FA (0.1%) (B) at a flow rate of 1.5 mL/min]; method 2 [Halo C18 column (2.0 ⁇ m 3.0 x 30 mm) in combination with a gradient (5-100% B in 1.2 min.) of water and TFA (0.05%) (A) and MeCN and TFA (0.05%)(B) at a flow rate of 1.5 mL/min]; method 3 [Poroshell HPH C18 column (2.7 ⁇ m 3.0 x 50 mm) in combination with a gradient (10-95% B in 2 min.) of aqueous 46 mM ammonium carbonate/ammonia buffer at pH 10 (A) and MeCN (B) at a flow rate of 1.2 mL/min].
  • the Column Oven (CTO-20AC) temperature was 40 °C.
  • the injection volume was 1 ⁇ L.
  • PDA (SPD-M20A) detection was in the range ⁇ (190–400) nm.
  • the MS detector was configured with electrospray ionization as ionizable source; acquisition mode: Scan; nebulizing gas flow:1.5 L/min; drying gas flow:15 L/min; detector voltage: 0.95-1.25 kv; DL T: 250 °C; heat block T: 250 °C; scan range: 90.00 - 900.00 m/z.
  • Preparative reverse phase HPLC was performed on a Waters instrument (2545 or 2767 or 2489) fitted with a QDa or SQ Detector 2 ESCi mass spectrometers and a Waters X-Bridge or Waters Xselect or Waters SunFire reverse-phase column (C-18, 5um, 30 mm diameter and 150 mm length with a flow rate of 60 ml/min or C-18, 5um, 19 mm diameter and 250 mm length with a flow rate of 25 ml/min).
  • Preparative Chiral SFC was performed on a Waters instrument SFC (80 or 100 or 150 or 350) fitted with UV2489 (or mass spectrometer) and a Daicel or YMC or Phenomenex chiral column (CHIRALPAK IC / CHIRALPAK IG/ Phenomenex Lux Cellulose-3/ Phenomenex Lux Cellulose-4, 5 microns silica, 20 mm or 50 mm diameter, 250 mm length, flow rate of 40 –250 ml/min).
  • CHIRALPAK IC / CHIRALPAK IG/ Phenomenex Lux Cellulose-3/ Phenomenex Lux Cellulose-4 5 microns silica, 20 mm or 50 mm diameter, 250 mm length, flow rate of 40 –250 ml/min.
  • ChemDraw Professional version 20.0 generates the names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules as closely as possible when generating chemical names. Stereoisomers are differentiated from each other by stereodescriptors cited in names and assigned in accordance with the CIP rules. ChemDraw is optionally using labels in the graphical representation of stereocenters such as and 'or' to describe the configuration of the stereochemical centers present in the structure.
  • CIP Cahn-Ingold-Prelog
  • Examples and Intermediates containing the label '&' at a stereocenter means the configuration of such Example or Intermediate at that stereocenter is a mixture of both (R) and (S); and a label 'or' means the configuration of such Example or Intermediate at that stereocenter is either (S) or (R).
  • Absolute, unspecified, '&', and 'or' stereocenters can all be present in a single structure.
  • the '&' and 'or' label at each stereocenter present in a structure may also include a number. The numbers indicate that stereocenters may or may not vary independently to each other, so that if two or more stereocenters do not vary independently of each other.
  • the label “Isomer 1” corresponds to the first eluted isomer
  • “Isomer 2” corresponds to the second eluted isomer, on a given chiral HPLC column and eluent, and are used to distinguish two isomers containing one or more stereocenters with absolute unknown configuration.
  • the relative stereochemistry is described using configurational descriptors ‘S’ and ‘R’ for the stereogenic centers and using the “rac-“ or “rel-“ prefix cited at the front of the name.
  • Example 13 is named “rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3- yl)urea”
  • Example 13 may be “(S)-1-(2-(4,4-Difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5- tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one”.
  • Example 27 is named “(rac)-(R)-1- (2-fluorophenyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea”
  • Example 27 also contains “(S)-1-(2-fluorophenyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea”.
  • Step 2 SOCl2 (1.5 ml, 20.68 mmol) was added dropwise to a solution of tert-butyl (4-(1- hydroxyethyl)phenyl)carbamate (3 g, 12.64 mmol) and 2-methyl-1H-imidazole (7.5 g, 91.35 mmol) in DCM (90 mL). The reaction mixture was stirred at 40 °C for 2 hours. The solvent was removed under reduced pressure.
  • Step 3 (4-(1-(2-Methyl-1H-imidazol-1-yl)ethyl)phenyl)carbamate (9.7 g, 32.18 mmol) was purified by preparative chiral-HPLC, Column: Venusil Chiral OD-H, 2.11*25 cm, 5 ⁇ m; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2 M NH3-MeOH); RT1 (min): 8.4; RT2 (min): 11.6; Sample Solvent: MeOH (0.1% 2 M NH3-MeOH), to afford: ISOMER 1: (R)-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)carbamate (4.53 g, 46.7%) RT1 (8.47 min) as a colourless oil.
  • Step 4 (S)-(4-(1-(2-Methyl-1H-imidazol-1-yl)ethyl)phenyl)carbamate (3.95 g, 13.11 mmol) was added to a 4 M HCl solution in EtOH (40 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to afford (S)-4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)aniline dihydrochloride (3.80 g) as a yellow solid.
  • Procedure B Synthesis of (S)-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)aniline (Intermediate I-1) – chiral Procedure Step 1 Glyoxal (5.24 g, 90.27 mmol), acetaldehyde (3.98 g, 90.27 mmol) and ammonium acetate (6.96 g, 90.27 mmol) were added to a solution of (1S)-1-(4-nitrophenyl)ethan-1-amine (5.0 g, 30.09 mmol) in MeOH (50 mL). The reaction mixture was stirred at 65 °C for 48 hours, then it was cooled to room temperature and concentrated under reduced pressure.
  • Step 2 10% Pd-C (w/w) (0.78 g, 0.74 mmol) was added to a solution of 2-methyl-1-(4-nitrobenzyl)-1H- imidazole (1.6 g, 7.37 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 2 hours, then it was filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure to afford 4-((2-methyl-1H-imidazol-1- yl)methyl)aniline (1.0 g, 72.5%).
  • Procedure D Synthesis of (S)-2-chloro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)aniline (Intermediate I-10) NCS (50 mg, 0.37 mmol) was added to a solution of (1H-imidazol-2-yl)methanol (100 mg, 0.36 mmol) and pyridine (60 mg, 0.75 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 16 hours and then it was concentrated under reduced pressure.
  • Step 2 DIEA (10.9 mL, 62.48 mmol) was added to a solution of ethyl 2-bromo-2-(4-nitrophenyl)acetate (6.0 g, 20.83 mmol) and 2-methyl-1H-imidazole (6.84 g, 83.31 mmol) in MeCN (70 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 80 °C for 15 hours, then concentrated under reduced pressure.
  • Step 3 Ethyl 2-(2-methyl-1H-imidazol-1-yl)-2-(4-nitrophenyl)acetate (2.2 g, 7.60 mmol) was added to a suspension of iron (2.1 g, 38.02 mmol) and NH4Cl (10 mL) in EtOH (20 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 60 °C for 3 hours, then cooled down and filtered through a pad of CELITE.
  • Step 4 Methyl-2-(4-aminophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetate (500 mg, 2.04 mmol) was added to a solution of LiAlH 4 (93 mg, 2.45 mmol) in THF (10 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 0 °C for 2 hours. The reaction was quenched by successive addition of water (0.08 mL), NaOH (15%, 0.088 mL) and water (0.264 mL). The reaction mixture was stirred for 5 minutes and filtered through a pad of CELITE.
  • Procedure F Synthesis of (rac)-(R)-(1-(1-(4-aminophenyl)ethyl)-1H-imidazol-2-yl)methanol (Intermediate I-13) Step 1: SOCl 2 (0.921 mL, 12.62 mmol) was added to a solution of tert-butyl (4-(1- hydroxyethyl)phenyl)carbamate (2.140 g, 9.02 mmol) and 2-(((tert-butyldimethylsilyl)oxy)methyl)- 1H-imidazole (3.83 g, 18.03 mmol) in DCM (20 mL) at 0 °C under one atmosphere of nitrogen.
  • the reaction mixture was stirred at 40 °C for 3 hours, then it was cooled down and poured into water (50 mL).
  • the crude mixture was extracted with DCM (20 mL x 3) and the combined organic layers were dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
  • the crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 5% MeOH in DCM, to afford tert-butyl (4-(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-1H-imidazol-1-yl)ethyl)phenyl)carbamate (0.447 g) as a yellow oil.
  • Step 2 A 4 M HCl solution in EtOH (5 mL) was added to tert-butyl (4-(1-(2-(((tert- butyldimethylsilyl)oxy)methyl)-1H-imidazol-1-yl)ethyl)phenyl)carbamate (430 mg, 1.00 mmol) under one atmosphere of nitrogen and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to afford (1-(1-(4-aminophenyl)ethyl)-1H- imidazol-2-yl)methanol (380 mg) as a pale yellow foam.
  • Step 2 Bromo-4-(1-chloroethyl)benzene (5.1 g, 23.23 mmol) was added to a suspension of 1H-imidazole-2- carbaldehyde (5.58 g, 58.08 mmol) and Cs 2 CO 3 (15.14 g, 46.47 mmol) in DMF (40 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 60 °C for 16 hours, then it was cooled down and poured into water (200 mL). The crude mixture was extracted with EtOAc (75 mL x 3), and the combined organic layers were dried over Na2SO4, filtered and evaporated.
  • 1H-imidazole-2- carbaldehyde 5.58 g, 58.08 mmol
  • Cs 2 CO 3 15.14 g, 46.47 mmol
  • Step 3 NaBH4 (1.49 g, 39.41 mmol) was added portionwise into a solution a 1-(1-(4-bromophenyl)ethyl)-1H- imidazole-2-carbaldehyde (5.5 g, 19.70 mmol) in ethanol (50 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, then it was concentrated under reduced pressure. The residue was diluted with water (100 mL), extracted with EtOAc (100 mL x 2) and the combined organic layers were dried over Na 2 SO 4 , filtered and evaporated.
  • Step 4 BAST (1.57 mL, 8.54 mmol) was added dropwise to a solution of (1-(1-(4-bromophenyl)ethyl)-1H- imidazol-2-yl)methanol (2.0 g, 7.11 mmol) in DCM (20 mL) at 0 °C under one atmosphere of nitrogen.
  • the reaction mixture was stirred at room temperature for 2 hours, then it was quenched with saturated NaHCO3 (20 mL) and extracted with DCM (25 mL). The organic layer was dried over Na2SO4, filtered and evaporated.
  • Step 5 BrettPhos-Pd-G3 (311 mg, 0.34 mmol) was added to a suspension of 1-(1-(4-bromophenyl)ethyl)-2- (fluoromethyl)-1H-imidazole (970 mg, 3.43 mmol), tert-butyl carbamate (602 mg, 5.14 mmol) and Cs 2 CO 3 (2.2 g, 6.85 mmol) in 1,4-dioxane (15 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 100 °C for 3 hours, then it was cooled down and poured into water (100 mL).
  • Step 6 A 4 M HCl solution in EtOH (5 mL) was added to tert-butyl (4-(1-(2-(fluoromethyl)-1H-imidazol-1- yl)ethyl)phenyl)carbamate (400 mg, 1.25 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure to afford 4-(1-(2- (fluoromethyl)-1H-imidazol-1-yl)ethyl)aniline (307 mg, 84%) as a white solid.
  • Procedure H Synthesis of 4-(1-(2-methyl-1H-imidazol-1-yl)cyclopropyl)aniline (Intermediate I-15) Step 1 1-(4-Bromophenyl)cyclopropan-1-amine (500 mg, 2.36 mmol, 1.0 equiv) was added to a stirred mixture of acetaldehyde (104 mg, 2.36 mmol, 1.0 equiv), oxalaldehyde (342 mg, 2.36 mmol, 1.0 equiv), acetic acid (142 mg, 2.36 mmol, 1.0 equiv) and ammonium acetate (750 mg, 9.73 mmol, 4.1 equiv) in CHCl3 (2 mL).
  • Step 3 4-(1-(2-Methyl-1H-imidazol-1-yl)cyclopropyl)aniline was prepared using the Procedure G, step 6 described above and used directly without further purification. MS (ES+, m/z): 213.9 [M + H] + .
  • Step 2 5% Pd-C (w/w) (120 mg, 0.45 mmol) was added to a solution of 4-(1-(2-(difluoromethyl)-1H-imidazol- 1-yl)ethyl)aniline (1.2 g, 4.49 mmol) in MeOH (20 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen until spectral data of an aliquot revealed consumption of the starting material, then it was filtered through a pad of CELITE.
  • Step 2 Carbon tetrabromide (32.71 g, 98.62 mmol) was added portionwise to a solution of (rac)-1-(5- chloropyrazin-2-yl)ethan-1-ol (9.2 g, 58.01 mmol) and triphenylphosphine (25.87 g, 98.62 mmol) in DCM (200 mL) at 0 °C. The reaction mixture stirred at room temperature for 2 hours and concentrated under reduced pressure.
  • Step 3 A mixture of 2-(1-bromoethyl)-5-chloropyrazine (2.7 g, 12.19 mmol), 2-methyl-1H-imidazole (1.1 g, 13.41 mmol) and Cs2CO3 (19.86 g, 60.96 mmol, 4.88 mL, 5.0 eq) in MeCN (250 mL) was stirred at 80 o C for 16 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was partitioned between EtOAc (300 mL) and water (100 mL).
  • Step 4 A degassed suspension of 2-chloro-5-[1-(2-methyl-1H-imidazol-1-yl)ethyl]pyrazine (2.3 g, 10.33 mmol), tert-butyl carbamate (1.45 g, 12.39 mmol), Cs 2 CO 3 (16.82 g, 51.64 mmol), XantPhos (597.58 mg, 1.03 mmol) and Pd(OAc) 2 (116 mg, 516 ⁇ mol) in dry dioxane (50 mL) was stirred at 100 o C overnight. After cooling down, the reaction mixture was evaporated under reduced pressure.
  • Step 5 Acetyl chloride (4.14 g, 52.76 mmol, 3.76 mL, 10.0 eq) was added dropwise to a solution of MeOH (2.03 g, 63.31 mmol, 2.54 mL, 12.0 eq) in dioxane (100 mL) at 15 o C and the resulting mixture was stirred for 1 hour.
  • tert-Butyl N-5-[1-(2-methyl-1H-imidazol-1-yl)ethyl]pyrazin-2-ylcarbamate (1.6 g, 5.27 mmol) in dioxane (20 mL) was added and the reaction mixture was stirred at room temperature overnight.
  • Procedure K Synthesis of (rac)-(R)-6-(1-(4-methyl-1H-imidazol-5-yl)ethyl)pyridin-3-amine (Intermediate I-18) Step 1 n-Butyllithium solution in hexanes (13.62 mL, 34.05 mmol) was added dropwise to a solution of 2- bromo-5-chloropyridine (6.55 g, 34.05 mmol) in DCM (100 mL) at -78 °C under one atmosphere of nitrogen and the resulting mixture was stirred at -78 °C for 30 minutes.5-Methyl-1-trityl-1H- imidazole-4-carbaldehyde (10 g, 28.37 mmol) was added and stirring continued at -78 °C for 1 hour.
  • Step 2 PCC (2.96 g, 13.73 mmol) was added to a suspension of (5-chloropyridin-2-yl)(5-methyl-1-trityl-1H- imidazol-4-yl)methanol (3.2 g, 6.87 mmol), sodium acetate (2.99 g, 36.40 mmol) and silica gel (2.96 g) in DCM (35 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours.
  • Step 3 A 1 M solution of K t BuO in THF (8.08 mL, 8.08 mmol) was added to a solution of methyltriphenylphosphonium bromide (2.89 g, 8.08 mmol) in THF (25 mL) at 0 °C under one atmosphere of nitrogen. The reaction mixture was stirred at 0 °C for 45 minutes, then a solution of (5-chloropyridin-2-yl)(5-methyl-1-trityl-1H-imidazol-4-yl)methanone (2.5 g, 5.39 mmol) in THF (25 mL) was added and the mixture was stirred at 0 °C for one hour and at room temperature overnight.
  • Step 4 tert-Butyl (6-(1-(5-methyl-1-trityl-1H-imidazol-4-yl)vinyl)pyridin-3-yl)carbamate was prepared using the Procedure G, step 5 described above.
  • Step 5 10% Pd-C (w/w) (0.353 g, 0.33 mmol) was added to a solution of tert-butyl (6-(1-(5-methyl-1-trityl- 1H-imidazol-4-yl)vinyl)pyridin-3-yl)carbamate (1.8 g, 3.32 mmol) in MeOH (30 mL) and THF (3 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 3 hours, then it was filtered through a pad of CELITE.
  • Step 6 6-(1-(4-Methyl-1H-imidazol-5-yl)ethyl)pyridin-3-amine was prepared using the Procedure G, step 6 described above.
  • Procedure L Synthesis of (rac)-4-(1-(4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5- yl)ethyl)aniline (Intermediate I-19) Step 1 Sodium nitrite (19.88 g, 288.14 mmol) in water (250.0 mL) was added dropwise to a solution of methyl 3-oxopentanoate (25 g, 192.10 mmol) in AcOH (250 mL) at -15 °C.
  • reaction mixture was stirred at -15 °C for 4 hours, then it was warmed to 0 °C and formaldehyde (20.19 g, 672.34 mmol) and 12 M HCl (108 mL) were successively added, maintaining the reaction mixture at 0 °C. After the addition was complete, the mixture was stirred at -15 °C for 15 hours. Then, 28% aqueous ammonia solution (124.8 mL) was added and the resulting mixture was stirred at 70 °C for 1.5 hours. The reaction mixture was cooled down, quenched with water (200 mL) and extracted with EtOAc (100 mL x 3).
  • Step 3 Methyl 4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (9.82 g, 34.53 mmol) was added to a solution of NaOH (6.90 g, 172.63 mmol) in water (25 mL) and MeOH (75 mL). The reaction mixture was stirred at room temperature for 4 hours, then it was diluted with water (100 mL), acidified with 2 M HCl and extracted with EtOAc (100 mL x 3).
  • N,O-dimethylhydroxylamine hydrochloride (7.54 g, 77.29 mmol) was added portionwise to a solution of HATU (14.69 g, 38.65 mmol), DIEA (13.62 g, 105.40 mmol) and 4-ethyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-imidazole-5-carboxylic acid (9.5 g, 35.13 mmol) in DMF (100 mL) at room temperature under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 15 hours, then it was quenched with water (300 mL) and extracted with EtOAc (100 mL x 3).
  • Step 5 (4-Chlorophenyl) magnesium bromide (24.56 mL, 24.56 mmol) was added dropwise to a solution of 4-ethyl-N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxamide (7.0 g, 22.33 mmol) in THF (70 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 2 hours, then it was quenched with water (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step 6 Potassium 2-methylpropan-2-olate (13.48 mL, 13.48 mmol) was added dropwise to a solution of methyltriphenylphosphonium bromide (4.82 g, 13.48 mmol) in THF (50 mL) at 0 °C under one atmosphere of nitrogen. After the addition was complete, (4-chlorophenyl)(4-ethyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methanone (4.1g, 11.23 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours.
  • Step 7 Brettphos Pd G3 (0.89 g, 0.99 mmol) was added to a suspension of 5-(1-(4-chlorophenyl)vinyl)-4- ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (3.6 g, 9.92 mmol), Cs2CO3 (6.46 g, 19.84 mmol) and tert-butyl carbamate (1.39 g, 11.90 mmol) in 1,4-dioxane (50 mL) under one atmosphere of nitrogen.
  • the reaction mixture was stirred at 90 °C for 3 hours, then it was was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3 The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure.
  • the crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 50% EtOAc in petroleum ether, to afford tert- butyl (4-(1-(4-ethyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-imidazol-5-yl) vinyl) phenyl) carbamate (3.50 g, 80%) as an orange oil.
  • Step 8 10% Pd-C (w/w) (1.2 g, 0.11 mmol) was added to a solution of tert-butyl (4-(1-(4-ethyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)vinyl)phenyl)carbamate (5 g, 0.11 mmol) in MeOH (50 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 3 hours, then it was filtered through a pad of CELITE.
  • Step 9 A solution of tert-butyl (4-(1-(4-ethyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-imidazol-5-yl) ethyl) phenyl) carbamate (1 g, 2.24 mmol) in 4 M HCl in EtOH (10 mL, 2.24 mmol) were stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to afford (rac)-4-(1-(4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethyl)aniline (0.750 g, 97%) as a green oil.
  • Procedure M Synthesis of the mixture of rel-(R)-4-(1-(4-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethyl)aniline and rel-(R)-4-(1-(5-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)aniline (Intermediate I-20)
  • Step 1 5-Bromo-4-methyl-1H-imidazole (8.6 g, 53.42 mmol) was added to a suspension of NaH (1.41 g, 58.76 mmol) in THF (100 mL) at 0 °C and the reaction mixture was stirred for 30 minutes.
  • (2- (Chloromethoxy)ethyl)trimethylsilane (8.91 g, 53.42 mmol) was added and the mixture was stirred at room temperature 3 hours, then it was concentrated under reduced pressure and the residue was diluted with EtOAc (200 mL) and washed with water (100 mL x 3) and brine (100 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure.
  • the crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 10% MeOH in DCM, to afford a mixture of 5-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 4- bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (10.8 g, 69.4%) as a yellow oil.
  • Step 2 5-Bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (4 g, 13.73 mmol) was added to a solution of tert-butyl (Z)-(4-(1-(2-tosylhydrazineylidene)ethyl)phenyl)carbamate (5.54 g, 13.73 mmol), SPhos (0.56 g, 1.37 mmol), Pd(OAc) 2 (0.15 g, 0.69 mmol) and LiO t Bu (2.41 g, 30.21 mmol) in CPME (100 mL, 13.73 mmol) under one atmosphere of nitrogen.
  • the reaction mixture was stirred at 100 o C for 4 hours, then it was concentrated under reduced pressure.
  • the residue was diluted with EtOAc (100 mL) and washed with water (100 mL x 3) and brine (100 mL x 3).
  • the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure.
  • the crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 80% EtOAc in petroleum ether, to afford a mixture of tert-butyl (4-(1-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-5-yl)vinyl)phenyl)carbamate and tert-butyl (4-(1-(5-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)vinyl)phenyl)carbamate (3.0 g, 50.8%) as a yellow oil.
  • Step 3 tert-Butyl (4-(1-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5- yl)vinyl)phenyl)carbamate (3 g, 6.98 mmol) was added to a suspension of 10% Pd-C (w/w) (0.74 g, 6.98 mmol) in MeOH (30 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 16 hours, then it was filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure.
  • the crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 10% MeOH in DCM, to afford a mixture of tert-butyl (4-(1-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethyl)phenyl)carbamate and tert-butyl (4-(1-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4- yl)vinyl)phenyl)carbamate (1.7 g, 56.4%) as a yellow oil.
  • Step 4 A mixture of tert-butyl (4-(1-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5- yl)ethyl)phenyl)carbamate and tert-butyl (4-(1-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-4-yl)vinyl)phenyl)carbamate (1.7 g, 3.94 mmol) was added to a 4 M HCl solution in EtOH (20 mL, 658 mmol). The resulting solution was stirred at room temperature for 1 hour.
  • the above mixture was purified by preparative chiral HPLC, Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hexane (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH, to give three fractions: a mixture of ISOMER 1&2, ISOMER 3 and ISOMER 4.
  • the mixture of ISOMER 1&2 was re-purified by preparative chiral HPLC, Column: CHIRALPAK IG, 2*25 cm, 5 ⁇ m; Mobile Phase A: Hexane (0.5% 2 M NH 3 -MeOH), Mobile Phase B: EtOH), to afford ISOMER 1 and ISOMER 2.
  • the reaction mixture was stirred at 110 °C for 16 hours, then it was cooled to room temperature, filtered through a pad of CELITE and the filtrate was concentrated under reduced pressure.
  • the crude product was purified by flash C18-flash chromatography, eluting with a mixture of 0 to 80% MeCN in water (0.1% NH4HCO3), to afford (rac)-tert-butyl (4-(1-(thiazol-5-yl)ethyl)phenyl)carbamate (0.18 g, 48.5%) as a yellow solid.
  • Step 2 A 4 M HCl solution in 1,4-dioxane (10 ml, 40.00 mmol) was added to tert-butyl (4-(1-(thiazol-5- yl)ethyl)phenyl)carbamate (160 mg, 0.53 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to afford (rac)-4-(1- (thiazol-5-yl)ethyl)aniline (0.14 g) as a light red solid.
  • Step 2 10% Pd-C (w/w) (630 mg, 5.92 mmol) was added to a solution of 3-methyl-5-(4- nitrophenyl)imidazo[1,5-a]pyridine (500 mg, 1.97 mmol) and TEA (19.98 mg, 0.20 mmol) in EtOH (2 mL). The reaction mixture was placed under 13 atmospheres of hydrogen and stirred at 80 °C for 16 hours. The reaction mixture was cooled down, filtered through a pad of CELITE and the filtrate was concentrated under reduced pressure to afford 4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin- 5-yl)aniline (0.3 g, 66.8%).
  • Procedure Q Synthesis of (rac)-(R)-4-(3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5- yl)aniline (Intermediate I-35)
  • Step 1 (2-Methyl-1-trityl-1H-imidazol-4-yl)methanol (5.70 g, 71.7%) was prepared using the Procedure A, step 1 described above.
  • Step 2 K t OBu (1.18 g, 10.58 mmol) was added to a solution of (2-methyl-1-trityl-1H-imidazol-4-yl)methanol (2.5 g, 7.05 mmol) in DMSO (100 mL) at room temperature and the reaction mixture was stirred for 30 minutes.2-(4-Bromophenyl)oxirane (1.54 g, 7.76 mmol) was added and stirring continued for 16 hours. The reaction mixture was poured into water (300 mL), extracted with EtOAc (100 mL x 3) and the combined organic layers were washed with water (75 mL x 2), brine (75 mL), dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
  • Steps 3-4 Methanesulfonyl chloride (0.621 g, 5.42 mmol) was added dropwise to a solution of 1-(4- bromophenyl)-2-((2-methyl-1-trityl-1H-imidazol-4-yl)methoxy)ethan-1-ol (2.5 g, 4.52 mmol) and TEA (1.88 mL, 13.55 mmol) in DCM (30 mL) at 0 °C under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 16 hours, then it was poured into water (100 mL), extracted with EtOAc (100 mL x 3) and the combined organic layers were dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
  • Step 1 A 2.5 M solution of nBuLi in hexanes (25 mL, 61.69 mmol) was added dropwise to a solution of 1,4- dibromobenzene (14.55 g, 61.69 mmol) in THF (100 mL) at -78 °C under one atmosphere of nitrogen and the reaction mixture was stirred for 30 minutes.6,7-Dihydroimidazo[1,5-a]pyridin-8(5H)-one (2.8 g, 20.56 mmol) was added and stirring continued at -78 °C for 1 hour. The reaction mixture was warmed to room temperature and concentrated under reduced pressure.
  • Step 2 8-(4-Bromophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol (1.3 g, 4.43 mmol) was added to a 5 M HCl aqueous solution (13 mL, 4.43 mmol) . The reaction mixture was stirred at 100 °C for 1 hour and concentrated under reduced pressure to afford 8-(4-bromophenyl)-5,6-dihydroimidazo[1,5- a]pyridine (1.100 g, 90 %) as a yellow solid.
  • Step 3 Pd 2 (dba) 3 (542 mg, 0.22 mmol) was added to a solution of 8-(4-bromophenyl)-5,6- dihydroimidazo[1,5-a]pyridine (600 mg, 2.18 mmol), tert-butyl carbamate (1.02 g, 8.72 mmol), 2-di- t-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl (93 mg, 0.22 mmol) and ethyl bromodifluoroacetate t-butoxide (1.25 g, 13.08 mmol) in toluene (10 mL) under one atmosphere of nitrogen.
  • Step 4 Pd(OH)2 - C (w/w) (451 mg, 1.93 mmol) was added to a solution of to tert-butyl (4-(5,6- dihydroimidazo[1,5-a]pyridin-8-yl)phenyl)carbamate (600 mg, 1.93 mmol) in MeOH (6 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 2 hours. The reaction mixture was filtered through a pad of CELITE.
  • Step 5 A mixture of tert-butyl (4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)carbamate (300 mg, 0.96 mmol) and 4 M HCl in EtOAc (3 mL, 0.96 mmol) was stirred at room temperature under one atmosphere of hydrogen for 1 hour. The solvent was removed under reduced pressure to afford 4- (5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)aniline (180 mg, 88 %) as a yellow solid.
  • Step 3 A mixture of tert-butyl (1-(3-bromopyridin-2-yl)ethyl)carbamate (10.8 g, 35.86 mmol) and 4 M HCl in EtOH (100 mL) was stirred at room temperature for 8 hours, then it was concentrated under reduced pressure. The crude product was purified by trituration with diethyl ether (50 mL), collected by filtration and dried to afford 1-(3-bromopyridin-2-yl)ethan-1-amine (7.0 g, 97%) as a white solid.
  • Step 4 A mixture of 1-(3-bromopyridin-2-yl)ethan-1-amine (8.6 g, 42.77 mmol) and FA (90 mL) was stirred at 60 °C under one atmosphere of nitrogen for 3 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash C18-flash chromatography, eluting with a mixture of 0 to 80% MeCN in water (0.1% FA), to afford N-(1-(3-bromopyridin-2- yl)ethyl)formamide (4.93 g, 50.3 %) as a purple solid.
  • Step 5 POCl 3 (2.68 g, 17.46 mmol) was added to a solution of N-(1-(3-bromopyridin-2-yl)ethyl)formamide (2 g, 8.73 mmol) in toluene (20 mL) and the reaction mixture was stirred at 80 °C under one atmosphere of nitrogen for 2 hours. The solvent was removed under reduced pressure and the residue was basified with saturated Na2CO3 solution and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step 6 A suspension of 8-bromo-1-methylimidazo[1,5-a]pyridine (1.85 g, 8.77 mmol), (4- nitrophenyl)boronic acid (1.75 g, 10.52 mmol), Pd(PPh3)4 (1.01 g, 0.88 mmol) and K2CO3 (1.96 g, 14.21 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was stirred at 90 °C under one atmosphere of nitrogen for 3 hours. The reaction mixture was cooled down and the solvent was removed under reduced pressure.
  • Step 7 10% Pd-C (w/w) (0.546 g, 5.13 mmol) was added to a solution of 1-methyl-8-(4- nitrophenyl)imidazo[1,5-a]pyridine (1.3 g, 5.13 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 24 hours. The reaction mixture was filtered through a pad of CELITE and the filtrate was concentrated under reduced pressure to afford (rac)-4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)aniline (0.68 g, 58.9%) as a brown oil.
  • Steps 2-3 1-(4-Chloro-3-methoxyphenyl)ethan-1-ol (4.8g, 25.72 mmol) was added to SOCl2 (5 mL, 68.51 mmol) at room temperature and the reaction mixture was stirred at 80 °C for 2 hours. The solvent was removed under reduced pressure. The residue was taken up in DMF (20 mL) and 2-methyl-1H- imidazole (4.22 g, 51.44 mmol) and Cs 2 CO 3 (25.1 g, 77.16 mmol) were added.
  • Steps 4-5 Pd 2 (dba) 3 (3.65 mg, 3.99 ⁇ mol) and t-BuBrettPhos (3.87 mg, 7.98 ⁇ mol) were suspended in toluene (2 mL) at room temperature under one atmosphere of nitrogen.
  • Step 6 A 1 M solution of BBr 3 in DCM (0.1 mL, 0.10 mmol) was added dropwise to a solution of 1-((5- fluoropyridin-2-yl)methyl)-3-(2-methoxy-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea (20 mg, 0.05 mmol) in DCM (1 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 2 hours, then it was quenched with water (1 mL) and concentrated under reduced pressure.
  • Step 2 LiBH 4 (0.458 g, 21.03 mmol) was added to a solution of ethyl 4-(3-(pyridin-2-yl)ureido)benzoate (1.2 g, 4.21 mmol) in THF (30 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 10% MeOH in DCM, to afford 1-(4-(hydroxymethyl)phenyl)-3-(pyridin- 2-yl)urea (0.80 g, 78%) as a yellow solid.
  • Step 3 SOCl2 (450 ⁇ l, 6.17 mmol) was added to a solution of 1-(4-(hydroxymethyl)phenyl)-3-(pyridin-2- yl)urea (500 mg, 2.06 mmol) and pyridine (16.62 ⁇ l, 0.21 mmol) in DCM (5 mL) and THF (15 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes.
  • Step 4 1-(4-(Chloromethyl)phenyl)-3-(pyridin-2-yl)urea (50 mg, 0.19 mmol) was added to a suspension of 2- methyl-1H-imidazole (15.69 mg, 0.19 mmol) and K 2 CO 3 (52.8 mg, 0.38 mmol) in MeCN (3 mL) under one atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 2 hours and then it was concentrated under reduced pressure. The reaction mixture was purified by flash C18- flash chromatography, eluting with a mixture of 0 to 70% MeCN in water, to afford crude product.
  • Step 2 10% Pd-C (w/w) (50 mg, 0.47 mmol) was added to a solution of 1-(5-(benzyloxy)pyridin-2-yl)-3-(4-(1- (2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea (50 mg, 0.12 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 2 hours, then it was filtered through a pad of CELITE.
  • Step 2 (rac)-(R)-1-(5-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)urea (87 mg, 0.19 mmol) was added to a 4 M HCl solution in EtOH (1 mL, 4.00 mmol). The resulting mixture was stirred at room temperature for 1 hour, then it was concentrated under reduced pressure.
  • Steps 4-5 rel-(R)-4-(1-(2-Methyl-1H-imidazol-1-yl)ethyl)benzoic acid (118.7 mg, 0.52 mmol) was added to a solution of DPPA (156 mg, 0.57 mmol) and TEA (156 mg, 1.55 mmol) in toluene (1.5 mL) at 0 °C under one atmosphere of nitrogen.
  • reaction mixture was stirred at 0 °C for 1.5 hour, then at 90 °C for 1 hour.4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (63.9 mg, 0.26 mmol) was added and stirring at 90 °C continued for 15 hours. The solvent was removed under reduced pressure and the reaction mixture was quenched with water (5 mL), extracted with DCM (5 mL x 3), the combined organic layers were dried over Na2SO4, and evaporated.
  • Step 6 rel-(R)-1-(4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3-(4-(1-(2-methyl-1H- imidazol-1-yl)ethyl)phenyl)urea (55 mg, 0.12 mmol) was added to a solution of TBAF (151 mg, 0.58 mmol) in THF (1 mL) under one atmosphere of nitrogen. The resulting mixture was stirred at 65 °C for 2 hours, then concentrated under reduced pressure.
  • reaction mixture was stirred at 0 °C for 3 hours, then quenched by successive addition of water (0.15 mL), 15% NaOH (0.15 mL) and water (0.45 mL).
  • the reaction mixture was filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure and the crude product was purified by C18-flash chromatography, eluting with a mixture of 0 to 30% MeCN in water (0.1% NH 4 HCO 3 ), to afford 2-(4-aminophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethan-1-ol (0.31 g, 36.9%) as a yellow solid.
  • Step 2 2-(4-Aminophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethan-1-ol (279 mg, 1.28 mmol) was added to a solution of imidazole (219 mg, 3.21 mmol) and tert-butylchlorodimethylsilane (406 mg, 2.70 mmol) in THF (3 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 3 hours.
  • Step 3 (rac)-(R)-1-(4-(2-((tert-Butyldimethylsilyl)oxy)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5- fluoropyridin-2-yl)methyl)urea was made using the Procedures O and 3 described above.
  • Step 4 TBAF (570 mg, 2.18 mmol) was added to a solution of (rac)-(R)-1-(4-(2-((tert-Butyldimethylsilyl)oxy)- 1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-fluoropyridin-2-yl)methyl)urea (527 mg, 1.09 mmol) in THF (1 mL) . The reaction mixture was stirred at room temperature for 3 hours, then the solvent was removed under reduced pressure. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3).
  • Step 5 (rac)-(R)-1-((5-Fluoropyridin-2-yl)methyl)-3-(4-(2-hydroxy-1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)urea (100 mg, 0.27 mmol) was added to a solution of BAST (120 mg, 0.54 mmol) in DCM (1 mL) at -78 °C under one atmosphere of nitrogen. The reaction mixture was warmed to room temperature and stirred for 15 hours, then it was quenched by addition of MeOH.
  • Step 2 A mixture of (rac)-(R)-2,2,2-trifluoroethyl N-(4-5H,6H,7H,8H-imidazo[1,5-a]pyridine-8- ylphenyl)carbamate 2 (250 mg, 821.01 ⁇ mol), (5-fluoropyridin-2-yl)methanamine 1.2 (124.27 mg, 985.21 ⁇ mol) and DIPEA (159.16 mg, 1.23 mmol) in dry MeCN (5 mL) was stirred at room temperature overnight and then concentrated under reduced pressure.
  • Step 3 The stereoisomers were separated on a Chiralcel OD (250x30 mm, 10 ⁇ m), eluting with hexane: IPA: MeOH: DEA, 60:20:20:0.05, at a flow rate of 30 mL / min., to afford: ISOMER 1 rel-(R)- 3-[(5-fluoropyridin-2-yl)methyl]-1-(4-5H,6H,7H,8H-imidazo[1,5-a]pyridine-8- ylphenyl)urea (20.7 mg), RT1 (8.76 min), MS (ES+, m/z): 366.2 [M+H] + .
  • Step 2 The stereoisomers were separated on a Chiralpak AD-H (250x20 mm, 5 ⁇ m), eluting with hexane: IPA: MeOH: DEA, 50:25:25:0.05, at a flow rate of 12 mL/min., to afford: ISOMER 1 rel-(R)-2,2-Difluoro-2-(pyridin-3-yl)-N-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)acetamide (22.3 mg), RT1 (29.40 min), MS (ES+, m/z): 369.0 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) ⁇ 1.78 – 1.62 (m, 1H), 1.84 (ddt, 1H), 2.08 – 1.94 (m, 2H), 3.94 (ddd, 1H), 4.03 (dd, 1H), 4.13 (
  • the reaction mixture was stirred at 80 °C for 5 hours, then it was cooled, poured into water (25 mL), extracted with EtOAc (20 mL x 3) and the combined organic layers were dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
  • the crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 20% EtOAc in petroleum ether, to afford benzyl N-(tert-butoxycarbonyl)-N-(pyridin-2-yl)glycinate (1.3 g, 81%) as a colourless oil.
  • Step 2 10% Pd-C (w/w) (0.37 g, 0.35 mmol) was added to a solution of benzyl N-(tert-butoxycarbonyl)-N- (pyridin-2-yl)glycinate (1.2 g, 3.50 mmol) in MeOH (15 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 3 hours, then it was filtered through a pad of CELITE and the filtrate was concentrated under reduced pressure to afford N-(tert-butoxycarbonyl)- N-(pyridin-2-yl)glycine (0.87 g, 98%) as a green oil.
  • Steps 3-4 tert-Butyl (S)-(2-((4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)amino)-2-oxoethyl)(pyridin-2- yl)carbamate was prepared using the Procedure 14 described above and used without further purification. TFA (1.5 mL) was added to the solution of crude product in DCM (3 mL) and stirred for 1 hour.
  • Step 2 The enantiomers were separated on a CHIRALPAK AD (250x30 mm, 10 mkm), eluting with Hexane:IPA:MeOH, 50:25:25, at a flow rate of 40 mL/min, to afford: ISOMER 1 (eutomer): N-(5-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyrazin-2-yl)-2-((R)- tetrahydrofuran-3-yl)acetamide (35.1 mg) RT1 (24.8 min), MS (ES+, m/z): 316.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d 6 ) ⁇ 1.50 (dq, 1H), 1.75 (d, 3H), 1.99 (dtd, 1H), 2.28 (s, 3H), 2.50 – 2.57 (m, 2H), 3.24 – 3.30 (m, 2H), 3.61
  • Step 2 A solution of N-(4-(1-(4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethyl)phenyl)-2,2- difluoro-2-(pyridin-3-yl)acetamide (75 mg, 0.15 mmol) was added and TFA (0.5 mL) in DCM (0.5 mL) was stirred at room temperature for 15 hour.
  • Biochemical NADase assay A biochemical enzyme inhibition assay was used to measure the SARM1-mediated conversion of NAD to ADPR (and other metabolites) using mass spectrometry.
  • Materials and methods Expression and purification of SARM1
  • SARM1 cDNA corresponding to residues 28-724 with N-terminal polyhistidine (6xHN) and AVI tags was synthesised (GenScript) and cloned into a pFastBac1 vector.
  • Spodoptera frugiperda 9 (Sf9) cells were infected and grown in ExpiSf CD Medium (ThermoFisher) according to standard protocols.
  • Cells were harvested 48 h post-infection by centrifugation (3400 g, 15 min, 4 °C) and resuspended in Buffer A (40 mM HEPES pH 8, 0.4 M NaCl, 8 mM imidazole, 0.008 % Tween-20, 4% glycerol and 5 mM TCEP) supplemented with 0.04 ⁇ L/mL DNAse I and Complete protease inhibitor (1 tablet/50 mL; Roche). The sample was lysed by sonication and clarified by centrifugation (38400 g, 45 min, 4 °C).
  • Buffer A 40 mM HEPES pH 8, 0.4 M NaCl, 8 mM imidazole, 0.008 % Tween-20, 4% glycerol and 5 mM TCEP
  • Buffer A 40 mM HEPES pH 8, 0.4 M NaCl, 8 mM imidazole, 0.008 % Tween-20,
  • the supernatant was loaded onto a 5 mL HisTrap Crude FF column (Cytiva) pre-equilibrated with Buffer A and eluted with 300 mM imidazole in Buffer A.
  • the eluate was pooled and concentrated to ⁇ 11 mL using a 10 kDa MWCO centrifugal device (Pall).
  • the sample was subsequently purified using a Superdex 20026/60 column (Cytiva) pre-equilibrated with Buffer B (40 mM HEPES pH 8, 0.4 M NaCl, 5 % glycerol and 1 mM TCEP).
  • Buffer B 40 mM HEPES pH 8, 0.4 M NaCl, 5 % glycerol and 1 mM TCEP.
  • the peak fractions containing pure SARM1 were pooled, flash- frozen and stored at - 80 °C.
  • AMI-MS Acoustic mist ionization mass spectroscopy
  • the misting event repetition rate was set at 1400 Hz with a power of 11.5 dB, polarity switching every 10 nl, charging cone voltage at ⁇ 3 kV, and transfer interface heated at 200 °C.
  • the transit velocity of droplets within the interface was controlled by allowing cone gas flow at 50 L/h.
  • the mass spectrometer was operated in positive ion sensitivity mode with a source temperature of 100 °C, cone voltage of 20 V, and target enhancement at 550. Data were acquired over a range of 500 – 700 m/z. Samples were written into a single data acquisition file and automatically post-processed into an individual mass spectrum for each sample.
  • NAD and ADPR were quantified by measuring the intensities of [M+H] + at 664.1287 ⁇ 0.04 m/z and 560.0991 ⁇ 0.04 m/z, respectively.
  • LC-MS/MS measurements Samples (1 ⁇ l) were injected into an UPLC system (ACQUITY; Waters) containing an ACQUITY UPLC HSS T3 column (2.1 x 30 mm, 1.8 ⁇ m; Waters) kept at 40 °C at a flow rate of 1 ml/min in 0.2% MeCN with 0.1% FA. Mobile phase A was water containing 0.1% FA and mobile phase B was MeCN containing 0.1% FA.
  • DRG neuron culture The dorsal root ganglia (DRG) were isolated from rat embryos obtained from pregnant female SD rats (15.5 days postcoitus) and were kept on ice in Leibovitz's 15 medium. DRGs were dissociated by incubation in TrypLE Express at 37 °C for about 30 min.
  • L-15 medium containing 10% FBS was added and DRGs were filtered by 100 ⁇ m cell strainer. DRGs were centrifuged at 1000 rpm for 5 min and resuspend in 15 mL complete medium containing neurobasal medium, 2% B-27, 2 mM L-glutamine, 2 ⁇ M 5-Fluoro-2'-deoxyuridine, 2 ⁇ M uridine, 50 ng/mL 2.5S NGF and 100 U/mL Penicillin- Streptomycin. Cells were counted and diluted in complete medium to a final concentration of 1 x 10 7 cells/mL. 0.5 ⁇ L of cell suspension was dripped into each well of pre-coated 96-well plate.
  • Compound treatment Test compounds were initially prepared in DMSO with final concentration of 10 mM as a stock solution.8 doses (intermediate solutions) of test compounds were prepared, starting from 10 mM stock solution by 3-fold serial dilutions with 100% (v/v) DMSO. Compound solutions were prepared by dilution of the intermediate solutions in 50 fold steps using complete medium, while 1 mM and 0.3 mM compound solutions were prepared by 5-fold and 16.67-fold dilution of 10 mM DMSO stock, respectively.
  • Vincristine solution was prepared by dilution in 50 fold steps of 100 ⁇ M DMSO stock solution using complete medium. 5.55 ⁇ L of compound solution and 5.55 ⁇ L Vincristine solution was added to each well (10% of final culture volume) of the cell plate, in which final concentrations of test compounds were 100, 30, 10, 3.33, 1.11, 0.37, 0.12, 0.041, 0.014 and 0.005 ⁇ M. High control and low control was prepared by dilution of 100% DMSO, respectively. Then 11.1 ⁇ L was added to each well of the cell plate, in which the final concentration of DMSO was 0.1%. The cell plate was incubated with the compound treatment for 48 hours at 37 °C.
  • Results Results from the rat DRG neurodegeneration assay are shown below in Table 23.
  • Table 23 Activity in rat DRG neurodegeneration assay.
  • Example Protection of neurite degeneration in rDRG EC 50 ( ⁇ M) 1 0.627 44 0.084 110 3.98 132 0.659 220 0.299 The above description of illustrative embodiments is intended only to acquaint others skilled in the art with the Applicant's specification, its principles, and its practical application so that others skilled in the art may readily adapt and apply the specification in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples, while indicating embodiments of this specification, are intended for purposes of illustration only.

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Abstract

The specification relates to compounds of Formula (I) and to pharmaceutically acceptable salts thereof, to processes and intermediates used for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of diseases such as chemotherapy induced peripheral neuropathy (CIPN).

Description

HETEROAROMATIC COMPOUNDS Cross‑Reference to Related Patent Applications This specification claims the benefit of priority to U.S. Provisional Patent Application No.63/387,742 (filed December 162022). The entire text of the above-referenced patent application is incorporated by reference into this specification. This specification relates to certain heteroaromatic compounds and pharmaceutically acceptable salts thereof that inhibit Sterile Alpha and toll/interleukin Receptor motif-containing protein 1 (SARM1), and their use in treating diseases such as chemotherapy induced peripheral neuropathy (CIPN). This specification also relates to processes and intermediate compounds involved in the preparation of the heteroaromatic compounds and to pharmaceutical compositions containing them. Introduction SARM1 is an NAD-hydrolysing enzyme which is enriched in neurons and activated in response to neuronal injury. Activation of SARM1 leads to programmed axonal degeneration and inhibitors of SARM1 may be used to treat axonal degeneration disorders (see, e.g., Coleman et al., “Programmed axon degeneration: from mouse to mechanism to medicine” Nature Reviews Neuroscience (2020) 21(4):1-14). SARM1 is an evolutionarily conserved protein which incorporates distinct domains. There is an N- terminal targeting sequence, an ARM (armadillo/HEAT repeat) domain, two SAM (sterile alpha motif) domains and a C-terminal TIR (toll interleukin receptor) domain which has catalytic NADase activity. The ARM domain is autoinhibitory and modulates the activity of SARM1 (see, e.g., Jiang et al., “The NAD+-mediated self-inhibition mechanism of pro-neurodegenerative SARM1” Nature (2020) 588(7839):658-663). Constructs without the ARM domain are constitutively active. The SAM domains are believed to mediate oligomerization of SARM1 monomers. The SARM1 TIR domain catalyses the conversion of nicotinamide adenine dinucleotide (NAD+, also called “NAD” herein) to nicotinamide (NAM) and ADP-ribose (ADPR) / cyclic ADP-ribose (cADPR). Under normal cellular conditions SARM1 exists in an autoinhibited state with very low NADase activity (see, e.g., Sasaki et al., “cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons” Exp. Neurol. (2020) 329:113252). Inhibitors of SARM1 may, for example, act by blocking or interfering with the catalytic activity of the enzyme, or they may stabilise the autoinhibited state or block activation. Neuropathies associated with axonal degeneration may be due to neuronal injury such as, e.g., chemical injury, physical injury, or genetic mutation, or they may arise as a result of disease. Diseases and disorders associated with axonal degeneration include, but are not limited to, chemotherapy induced peripheral neuropathy (CIPN), painful diabetic neuropathy (PDN), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), demyelinating disease, Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Charcot Marie Tooth Disease (CMT), hereditary spastic paraplegia, ischemia, stroke, traumatic brain injury (TBI), traumatic neuronal injury, carpal tunnel syndrome, glaucoma, retinal degeneration, viral infection, and viral encephalitis. SARM1 genetic knock out has shown to be protective in several models of CIPN. Thus, SARM1 inhibitors may be useful in the treatment or prevention of CIPN caused by chemotherapeutic agents such as, cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, vincristine, vinblastine, bortezomib and carfilzomib (see, e.g., Geisler, “Vincristine- and bortezomib-induced neuropathies – from bedside to bench and back” Experimental Neurology (2021) 336:113519). Inhibitors of SARM1 may also be useful for the treatment or prevention of anaesthesia induced neuroinflammation and cognitive impairment (see, e.g., Lin et al., “SARM1 is Essential for Anesthesia-Induced Neuroinflammation and Cognitive Impairment in Aged Mice” Cell Mol Neurobiol (2022 Jul;42(5):1465-1476) Inhibitors of SARM1 may also be useful for the treatment of cardiomyopathy (see e.g. Light et al., “Cardiomyopathy Induced by Metabolic and Hypertensive Stresses is alleviated by SARM1 Deficiency” Circulation.2021;144:A13316. The compounds of the disclosure provide an anti-neurodegenerative effect by, as a minimum, acting as SARM1 inhibitors. The compounds of the specification may also exhibit advantageous physical properties (for example, lower lipophilicity, higher aqueous solubility, higher permeability, lower plasma protein binding, and/or greater chemical stability), and/or favourable toxicity profiles (for example a decreased activity at hERG, or a decreased inhibition of Cytochrome P450 enzymes), and/or favourable metabolic or pharmacokinetic profiles, in comparison with other known SARM1 inhibitors. Such compounds may therefore be especially suitable as therapeutic agents, such as for the treatment of chemotherapy induced peripheral neuropathy (CIPN). General Description According to one aspect of the specification there is provided a compound of Formula (I): wherein 0, 1 or 2 of A, E, L and G are N, and the others of A, E, L and G are independently CR2, Q, X and R1 are such that (i) X is absent, Q is R3 and R1 is H, (ii) X is absent, and Q and R1 together with the carbon atom to which they are attached form a cyclopropane or cyclobutane ring, or (iii) -X-Q- is -(CH2)a1(QA)a2(CH2)a3- and R1 is H, wherein a1 and a3 are independently 0, 1, or 2, and a2 is 0 or 1, such that a1+a2+a3 is 2, 3 or 4, and QA is O, CH2, NH, N(C1-4 alkyl) or N(C=O)( C1-4 alkyl), where X is absent, Y is selected from N, NH and CH, and where -X-Q- is -(CH2)a1(QA)a2(CH2)a3-, Y is selected from N and C, Ring V1, together with Y and Z with which it is fused, is an imidazole, thiazole or pyrazole ring, such that Z is N or C, each R2 is independently selected from H, F, Cl, cyano, C1-4 fluoroalkyl, O(C1-4 fluoroalkyl), OH, R4, OR4, R5 and OR5, R3 is H, C1-4 fluoroalkyl, O(C1-4 fluoroalkyl), R4A or R5A, each RV is independently selected from F, Cl, cyano, OH, C1-4 alkoxy, C1-4 fluoroalkyl, O(C1-4 fluoroalkyl), R4A and R5A, each R4 and R4A is independently C1-4 alkyl optionally substituted with one OH, C1-4 alkoxy or C3-4 cycloalkyl, each R5 and R5A is independently C3-4 cycloalkyl optionally substituted with one OH, C1-4 alkoxy or C1-4 fluoroalkyl, J is selected from
Figure imgf000004_0001
R6 and R6A are independently H, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl, F, OH or C1-4 alkoxy, R7 and R7A and independently H, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl or F, Rings C1, C2 and C3 are either (i) optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups, or (ii) optionally bridged by a C1-3 alkylene group, wherein the C1-3 alkylene group is optionally substituted by one or more R8 groups, each R8 is independently C1-4 alkyl, R11, C1-4 alkoxy, C3-4 cycloalkyl, OH or F, each R9 is independently C1-4 alkyl, R11, C1-4 alkoxy, C3-4 cycloalkyl, NH(R10), N(R10)2, OH, F, Cl or Br, each R10 is independently H, C1-4 alkyl, C(=O)C1-4 alkyl, C3-4 cycloalkyl or C(=O)C3-4 cycloalkyl, each R11 is independently C1-4 alkyl substituted with OH, XA, XB and XC are CH2, O, or a covalent bond, YA, YB and YC are CH2 or a covalent bond, ZA, ZB and ZD are a covalent bond or C(R6A)(R7A), Zc is a covalent bond, C(R6A)(R7A), O or NH, Ring D1 is a 5-9 membered heteroaromatic ring, Rings D2, D3 and D4 are a 5 or 6 membered heteroaromatic ring, x is 0, 1 or 2, and m is 0, 1, 2 or 3, wherein a C1-4 fluoroalkyl is a saturated hydrocarbon radical having 1 to 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom, wherein a C3-4 cyclofluoroalkyl is a saturated cyclic hydrocarbon radical having 3 or 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom, and wherein a heteroaromatic ring is independently an aromatic ring containing at least one N atom and optionally one or more additional heteroatoms independently selected from O, S and N, or a pharmaceutically acceptable salt thereof. In a further aspect there is provided a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In a further aspect there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in therapy. In a further aspect there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative condition. In a further aspect there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament. In a further aspect there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative condition. In a further aspect there is provided a method of treating neurodegenerative conditions in a patient comprising administering to the patient an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In a further aspect there is provided intermediates useful for the synthesis of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Definitions So that the present specification may be more readily understood, certain terms are explicitly defined below. In addition, definitions are set forth as appropriate throughout the detailed description. As used herein the term “alkyl” refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. In this specification the prefix Cx-y, as used in terms such as “Cx-y alkyl” and the like where x and y are integers, indicates the numerical range of carbon atoms that are present in the group. Examples of suitable C1-4 alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. In this specification the prefix X-Y membered, as used in terms such as “X-Y membered ring” and the like where X and Y are integers, indicates the numerical range of atoms (i.e. carbon atoms and heteroatoms) that are present in the group. As used herein the term “alkylene” refers to a diradical of a saturated, linear or branched hydrocarbon having the specified number of carbon atoms, obtained by removing two hydrogen atoms from the hydrocarbon. The two hydrogen atoms may either both from the same carbon atom, or one from each of two different carbon atoms. Examples of C1-3 alkylene groups include methylene (i.e. -(CH2)-), 1,1-ethylene (i.e. -(CH(CH3))-), 1,2- ethylene (i.e. -(CH2CH2)-) and 1,3- propylene (i.e. - (CH2CH2CH2)-). As used herein the term “alkoxy” refers to a saturated group comprising the specified number of carbon atoms and one oxygen atom. For the avoidance of doubt, the alkoxy group may be a straight chain or a branched chain. Examples of suitable C1-4 alkoxy groups include methoxy (OMe), ethoxy (OEt), n-propoxy (OnPr), i-propoxy (OiPr), n-butoxy (OnBu), i-butoxy (OiBu), s-butoxy (OsBu) and t- butoxy (OtBu). As used herein the term “cycloalkyl” refers to saturated cyclic hydrocarbon radicals having the specified number of carbon atoms. Examples of suitable C3-4 cycloalkyl groups include cyclopropyl and cyclobutyl. As used herein the term “C1-4 fluoroalkyl” refers to a saturated hydrocarbon radical having 1 to 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom. Examples of suitable C1-4 fluoroalkyl groups include fluoromethyl (CFH2), difluoromethyl (CF2H), trifluoromethyl (CF3), 1,1- difluoroethyl (CF2CH3), 2,2,2-trifluoroethyl (CH2CF3) and 3-fluoropropyl (CH2CH2CH2F). As used herein the term “C3-4 cyclofluoroalkyl” refers to a saturated cyclic hydrocarbon radical having 3 or 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom. Examples of suitable C3-4 fluorocycloalkyl groups include 2-fluorocyclopropyl, 2,2- difluorocyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, 2,2,3-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclopropyl, 2-fluorocyclobutyl, 3-fluorocyclobutyl, 2,3-difluorocyclobutyl, 2,4- difluorocyclobutyl and 2,3,4-trifluorocyclobutyl. Unless otherwise stated, the term “heteroaromatic ring” refers to an aromatic, monocyclic or bicyclic, ring having the specified number of atoms, containing at least one N atom and optionally one or more additional heteroatoms independently selected from O, S and N. A heteroaromatic ring may be a 5 or 6 membered monocyclic heteroaromatic ring. Examples of a suitable 5 membered heteroaromatic ring include pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,3-oxadiazole, furazan, 1,3,4-thiadiazole and tetrazole. Examples of a suitable 6 membered heteroaromatic ring include pyridine, pyridazine, pyrimidine, pyrazine and 1,3,4-triazine. A heteroaryl may be a 9-membered bicyclic heteroaromatic ring. Examples of a suitable 9 membered heteroaromatic ring include pyrazolo[1,5-a]pyridine, benzimidazole, indole, isoindole, indazole, benzthiazole, purine and benzo[d]oxazole. The term “oxo” refers to a oxygen atom forming a double bond (i.e. =O) to a suitable atom, such as carbon. In embodiments of the disclosure, Ring C1, C2 or C3 may be fused with a benzene or pyridine ring. In this context, “fused with a benzene ring” means that a “CH2CH2” diradical of said Ring C1, C2 or C3 is replaced with
Figure imgf000008_0001
. Likewise, fused with a pyridine ring means that a “CH2CH2” diradical of said Ring C1, C2 or C3” is replaced
Figure imgf000008_0002
way of illustration only, a
Figure imgf000008_0003
ring fused with a benzene ring may
Figure imgf000008_0004
In embodiments of the disclosure, Ring C1, C2 or C3 may be bridged by a C1-3 alkylene group. In this context, “bridged by a C1-3 alkylene group” means that two H atoms attached to different carbon atoms of said Ring C1, C2 or C3 are replaced with a C1-3 alkylene group. By way of illustration only, a
Figure imgf000008_0006
ring bridged with a methylene (-(CH2)-) group may be
Figure imgf000008_0005
, , . Unless specifically stated, the bonding of an atom or group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl. For the avoidance of doubt, where multiple substituents are independently selected from a given group, the selected substituents may comprise the same substituents or different substituents from within the given group. For the avoidance of doubt, the use of “ ” in formulas of this specification denotes the point of attachment between different groups. For the avoidance of doubt, the use of a bond between a substituent and the centre of a ring denotes that the substituent may replace any hydrogen atom directly attached to the ring, whether that hydrogen atom be attached to a C or N atom. Where any embodiment within this specification includes a group which is said to be “optionally substituted”, then a further embodiment will include that embodiment wherein the said group is unsubstituted. For the avoidance of doubt, where multiple substituents are independently selected from a given group, the selected substituents may comprise the same substituents or different substituents from within the given group. Units, prefixes, and symbols are denoted in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Unless defined otherwise, 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 disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure. Detailed Description In one aspect there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined above. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein A and L are independently CR2, and E and G are independently CR2 or N. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein A, E and L are independently CR2, and G is independently CR2 or N. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein A, E, G and L are independently CH, C(C1-4 alkyl), CF or CCl. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein A, E, G and L are CH. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R2 is independently H, OH, C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl, O(C1-4 fluoroalkyl), F or Cl. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R2 is independently H, OH, C1-4 alkyl, F or Cl. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R2 is independently H, OH, CH3, F or Cl. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein each R2 is H. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that is a compound of Formula (II)
Figure imgf000010_0001
wherein each R2A is independently selected from F, Cl, cyano, C1-4 fluoroalkyl, O(C1-4 fluoroalkyl), OH, R4, OR4, R5 and OR5, and q is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X is absent, Q is R3 and R1 is H. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X is absent, and Q and R1 together with the carbon atom to which they are attached form a cyclopropane or cyclobutane ring. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein -X-Q- is -(CH2)a1(QA)a2(CH2)a3- and R1 is H, wherein a1 and a3 are independently 0, 1, or 2, and a2 is 0 or 1, such that a1+a2+a3 is 2, 3 or 4, and QA is O, NH, N(C1-4 alkyl) or N(C=O)( C1-4 alkyl). In further embodiments, a1+a2+a3 is 3. In further embodiments, QA is O. In further embodiments, -X-Q- is CH2CH2CH2- or -CH2OCH2-. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X is absent and Y is selected from N, NH and CH. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X is present and Y is selected from N and C. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein Z is C. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein Z is N. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein Ring V1, together with Y and Z with which it is fused, is an imidazole ring. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein Ring V1, together with Y and Z with which it is fused, is a thiazole ring. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X is absent, Y is CH, and Z is N, such that Ring V1, together with Y and Z with which it is fused, is an imidazole or thiazole ring. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X is present, Y is C, and Z is N, such that Ring V1, together with Y and Z with which it is fused, is an imidazole or thiazole ring. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X is absent, Y is NH, and Z is C, such that Ring V1, together with Y and Z with which it is fused, is an imidazole or thiazole ring. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X is present, Y is N, and Z is C, such that Ring V1, together with Y and Z with which it is fused, is an imidazole or thiazole ring. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein X is absent, Y is C, and Z is C, such that Ring V1, together with Y and Z with which it is fused, is a thiazole ring. In embodiments, there is provided a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, wherein x is 0, 1 or 2. In further embodiments, x is 0 or 1. In further embodiments, x is 0. In embodiments, there is provided a compound of Formula (II), or a pharmaceutically acceptable salt thereof, that is a compound of Formula (III)
Figure imgf000011_0001
wherein V2 is selected from wherein x2 is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. In embodiments, there is provided a compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein V2 is selected from
Figure imgf000012_0001
wherein RV2 is H, C1-4 alkyl or C3-4 cycloalkyl. In further embodiments, Rv2 is C1-4 alkyl. In further embodiments, RV2 is CH3. In embodiments, there is provided a compound of Formula (II), or a pharmaceutically acceptable salt thereof, wherein V2 is selected from
Figure imgf000012_0002
. In embodiments, there is provided a compound of Formula (III), or a pharmaceutically acceptable salt thereof, that is a compound of Formula (IIIA)
Figure imgf000012_0003
or a pharmaceutically acceptable salt thereof. In embodiments, there is provided a compound of Formula (III), or a pharmaceutically acceptable salt thereof, that is a compound of Formula (IIIB) or a pharmaceutically acceptable salt thereof. In embodiments, there is provided a compound of Formula (III), or a pharmaceutically acceptable salt thereof, that is a compound of Formula (IIIC)
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof. In embodiments, there is provided a compound of Formula (III), or a pharmaceutically acceptable salt thereof, that is a compound of Formula (IIID)
Figure imgf000013_0002
or a pharmaceutically acceptable salt thereof. In embodiments, there is provided a compound of Formula (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof, wherein x2 is 0 or 1. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof, wherein R3 is H, C1-4 fluoroalkyl, C1-4 alkyl and C3-4 cycloalkyl. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof, wherein R3 is C1-4 fluoroalkyl, C1-4 alkyl and C3-4 cycloalkyl. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof, wherein R3 is C1-4 alkyl. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof, wherein R3 is H or CH3. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC) or (IIID), or a pharmaceutically acceptable salt thereof, wherein R3 is CH3. In embodiments, there is provided a compound of Formula (II), or a pharmaceutically acceptable salt thereof, that is a compound of Formula (IV)
Figure imgf000014_0001
wherein V3 is selected from
Figure imgf000014_0002
wherein x3 is 0, 1 or 2, and QB is O, CH2, NH, N(C1-4 alkyl), N(C=O)(C1-4 alkyl) or a covalent bond, or a pharmaceutically acceptable salt thereof. In embodiments, there is provided a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein V3 is selected from
Figure imgf000014_0003
wherein RV3 is H, C1-4 alkyl or C1-4 fluoroalkyl. In further embodiments, RV3 is C1-4 alkyl. In further embodiments, RV3 is CH3. In embodiments, there is provided a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, that is a compound of Formula (IVA) or a pharmaceutically acceptable salt thereof. In embodiments, there is provided a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, that is a compound of Formula (IVB)
Figure imgf000015_0001
or a pharmaceutically acceptable salt thereof. In embodiments, there is provided a compound of Formula (IV), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, wherein x3 is 0 or 1. In embodiments, there is provided a compound of Formula (IV), (IVA) or (IVB), or a pharmaceutically acceptable salt thereof, wherein QB is O or CH2. In embodiments, there is provided a compound of Formula (IV), or a pharmaceutically acceptable salt thereof, wherein V3 is selected from
Figure imgf000015_0002
. In embodiments, there is provided a compound of Formula (II), or a pharmaceutically acceptable salt thereof, that is a compound of Formula (V) wherein V4 is selected from
Figure imgf000016_0001
wherein x4 is 0, 1 or 2, and wherein QX is a covalent bond or CH2, or a pharmaceutically acceptable salt thereof. In embodiments, there is provided a compound of Formula (V), or a pharmaceutically acceptable salt thereof, wherein x4 is 0 or 1. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein each RV is independently C1-4 alkyl, C3-4 cycloalkyl, C1-4 alkoxy, C1-4 fluoroalkyl or F. In further embodiments, each RV is independently selected from C1-4 alkyl and C3-4 cycloalkyl. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein each RV is CH3, CH2CH2 or CH(CH2)2. In further embodiments, each RV is CH3. In embodiments, there is provided a compound of Formula (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein each R2A is independently OH, C1-4 alkyl, F or Cl. In further embodiments, each R2A is independently OH, CH3, F or Cl. In embodiments, there is provided a compound of Formula (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein q is 0, 1 or 2. In further embodiments, q is 0. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein each R4 and R4A is independently C1-4 alkyl optionally substituted with one OH. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein each R4 and R4A is independently C1-4 alkyl. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000017_0001
wherein Ring C1 is either (i) optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups, or (ii) optionally bridged by a C1-3 alkylene group, wherein the C1-3 alkylene group is optionally substituted by one or more R8 groups. In further embodiments, Ring C1 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XA is CH2. In further embodiments, XA is a covalent bond. In further embodiments, YA is CH2. In further embodiments, YA is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000017_0002
wherein Ring C1 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XA is CH2. In further embodiments, XA is a covalent bond. In further embodiments, YA is CH2. In further embodiments, YA is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000017_0003
wherein Ring C1 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XA is CH2. In further embodiments, XA is a covalent bond. In further embodiments, YA is CH2. In further embodiments, YA is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000018_0001
wherein Ring C1 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XA is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000018_0002
. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000018_0003
In further embodiments, XA is CH2. In further embodiments, XA is a covalent bond. In further embodiments, YA is CH2. In further embodiments, YA is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is In further embodiments, XA is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000019_0001
wherein n is 0, 1, 2 or 3. In further embodiments, n is 0 or 1. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000019_0002
wherein n is 0, 1, 2 or 3. In further embodiments, n is 0 or 1. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein ZA a covalent bond or C(R6A)(R7A). In further embodiments, ZA is a covalent bond or CH2. In further embodiments, ZA is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000020_0001
wherein Ring C2 , wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups, or (ii) optionally bridged by a C1-3 alkylene group, wherein the C1-3 alkylene group is optionally substituted by one or more R8 groups. In further embodiments, Ring C2 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XB is CH2. In further embodiments, XB is a covalent bond. In further embodiments, YB is CH2. In further embodiments, YB is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000020_0002
wherein Ring C2 , wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups, or (ii) optionally bridged by a C1-3 alkylene group, wherein the C1-3 alkylene group is optionally substituted by one or more R8 groups. In further embodiments, Ring C2 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XB is CH2. In further embodiments, XB is a covalent bond. In further embodiments, YB is CH2. In further embodiments, YB is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000021_0001
wherein Ring C2 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XB is CH2. In further embodiments, XB is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000021_0002
wherein Ring C2 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XB is CH2. In further embodiments, XB is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000021_0003
. In further embodiments, XB is CH2. In further embodiments, XB is a covalent bond. In further embodiments, YB is CH2. In further embodiments, YB is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000021_0004
In further embodiments, XB is CH2. In further embodiments, XB is a covalent bond. In further embodiments, YB is CH2. In further embodiments, YB is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000022_0001
. In further embodiments, XB is CH2. In further embodiments, XB is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000022_0002
In further embodiments, XB is CH2. In further embodiments, XB is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000022_0003
wherein n is 0, 1, 2 or 3. In further embodiments, n is 0 or 1. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein ZB a covalent bond or C(R6A)(R7A). In further embodiments, ZB is a covalent bond or CH2. In further embodiments, ZB is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000023_0001
wherein Ring C3 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups, or (ii) optionally bridged by a C1-3 alkylene group, wherein the C1-3 alkylene group is optionally substituted by one or more R8 groups. In further embodiments, Ring C3 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XC is CH2. In further embodiments, XC is a covalent bond. In further embodiments, YC is CH2. In further embodiments, YC is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000023_0002
wherein Ring C3 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups, or (ii) optionally bridged by a C1-3 alkylene group, wherein the C1-3 alkylene group is optionally substituted by one or more R8 groups. In further embodiments, Ring C3 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XC is CH2. In further embodiments, XC is a covalent bond. In further embodiments, YC is CH2. In further embodiments, YC is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000024_0001
wherein Ring C3 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XC is CH2. In further embodiments, XC is a covalent bond. In further embodiments, YC is CH2. In further embodiments, YC is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000024_0002
wherein Ring C3 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XC is CH2. In further embodiments, XC is a covalent bond. In further embodiments, YC is CH2. In further embodiments, YC is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000024_0003
wherein Ring C3 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XC is CH2. In further embodiments, XC is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000025_0001
wherein Ring C3 is optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups. In further embodiments, XC is CH2. In further embodiments, XC is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000025_0002
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000025_0003
In further embodiments, XC is CH2. In further embodiments, XC is a covalent bond. In further embodiments, YC is CH2. In further embodiments, YC is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is In further embodiments, XC is CH2. In further embodiments, XC is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000026_0001
In further embodiments, XC is CH2. In further embodiments, XC is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000026_0002
wherein n is 0, 1, 2 or 3. In further embodiments, n is 0 or 1. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is wherein n is 0, 1, 2 or 3. In further embodiments, n is 0 or 1. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000027_0001
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000027_0002
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein Ring D1 is a pyrazolo[1,5- a]pyridine, benzimidazole, imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring. In further embodiments, Ring D1 is a 5 or 6 membered heteroaromatic ring. In further embodiments, Ring D1 is an imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000027_0003
. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000027_0004
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000028_0001
. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein ZC is a covalent bond, C(R6A)(R7A), O or NH. In further embodiments, ZC is a covalent bond, CH2, O or NH. In further embodiments, ZC is a covalent bond or CH2. In further embodiments, ZC is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000028_0002
. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein Ring D2 is an imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000028_0003
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000029_0001
. In further embodiments, Ring D3 is an imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000029_0002
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000030_0001
. In further embodiments, Ring D4 is an imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein ZD a covalent bond or C(R6A)(R7A). In further embodiments, ZD is a covalent bond or CH2, In further embodiments, ZD is a covalent bond. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000030_0002
. In further embodiments, Ring D4 is an imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000031_0001
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is
Figure imgf000031_0002
In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is selected from
Figure imgf000031_0003
wherein m is 0, 1 or 2. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein J is selected from
Figure imgf000032_0001
wherein m is 0, 1 or 2. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein R6 is H, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl, F, OH or C1-4 alkoxy. In further embodiments, R6 is H, C1-4 alkyl, F or OH. In further embodiments, R6 is H, F or CH3. In further embodiments, R6 is H. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein R6A is H, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl, F, OH or C1-4 alkoxy. In further embodiments, R6A is H, C1-4 alkyl, F or OH. In further embodiments, R6A is H, F or CH3. In further embodiments, R6A is H. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein R7 is H, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl, F, OH or C1-4 alkoxy. In further embodiments, R7 is H, C1-4 alkyl, F or OH. In further embodiments, R7 is H, F or CH3. In further embodiments, R7 is H. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein R7A is H, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl, F, OH or C1-4 alkoxy. In further embodiments, R7A is H, C1-4 alkyl, F or OH. In further embodiments, R7A is H, F or CH3. In further embodiments, R7A is H. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein R6 and R7 are independently H, F or CH3. In further embodiments, R6 is H and R7 is H. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein R6A and R7A are independently H, F or CH3. In further embodiments, R6A is H and R7A is H. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein each R8 is independently C1-4 alkyl, R11, C1-4 alkoxy, C3-4 cycloalkyl, OH or F. In further embodiments, each R8 is independently C1-4 alkyl, C1-4 alkoxy, OH or F. In further embodiments, each R8 is independently C1-4 alkyl or F. In further embodiments, each R8 is independently CH3 or F. In further embodiments, each R8 is CH3. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein each R9 is independently C1-4 alkyl, R11, C1-4 alkoxy, C3-4 cycloalkyl, NH(R10), N(R10)2, OH, F, Cl or Br. In further embodiments, each R9 is independently C1-4 alkyl, C1-4 alkoxy, C3-4 cycloalkyl, OH, F or Cl. In further embodiments, each R9 is independently C1-4 alkyl or F. In further embodiments, each R9 is independently C1-4 alkyl. In further embodiments, each R9 is CH3. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2. In further embodiments, m is 0 or 1. In further embodiments, m is 0. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from, 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((4-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(3-methyl-1H-pyrazol-5-yl)urea, 1-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-3-1H-pyrazol-3-ylurea, 1-(4-((1H-imidazol-5-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-cyclobutyl-1H-pyrazol-5-yl)-3-(4-((1H-imidazol-1-yl)methyl)phenyl)urea, 1-(4-cyclopropyl-1H-pyrazol-3-yl)-3-(4-[(1H-imidazol-1-yl)methyl]phenyl)urea, 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(4-methyl-1H-pyrazol-5-yl)urea, 1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(4-methyl-1H-pyrazol-3-yl)urea, 1-(2-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1-methyl-1H-pyrazol-3-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)propyl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)propyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(6-((2-methyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-3-(1H-pyrazol-3-yl)urea, 1-(4-(1-(2-methyl-1H-imidazol-1-yl)cyclopropyl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-(isoxazol-3-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-( pyridin-2-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxazol-2-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxetan-3-yl)urea, (rac)-(R)-1-(2-fluorophenyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, 1-(4-(1-(2-methyl-1H-imidazol-1-yl)cyclopropyl)phenyl)-3-(pyridin-2-yl)urea, (rac)-(R)-1-(5-hydroxypyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (rac)-(R)-1-(5-(hydroxymethyl)pyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (rac)-(R)-1-(4-(cyclopropyl(2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (rac)-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrazin-2-yl)urea, (rac)-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrimidin-4-yl)urea, rel-(R)-1-(4-(cyclopropyl(2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(4-methyl-1H-pyrazol-3-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol-4-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxazol-4-yl)urea, rel-(R)-1-(5-fluoropyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-(3-fluoropyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-(4-chloro-1H-pyrazol-3-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridazin-3-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-3-ylmethyl)urea, rel-(R)-1-((5-fluoropyrimidin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-ylmethyl)urea, rel-(R)-1-(5-bromopyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (rac)-(R)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (rac)-(R)-1-(4-(1-(2-cyclopropyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (rac)-(R)-1-(4-(1-(2-(hydroxymethyl)-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((SR)-1-(pyridin-2-yl)ethyl)urea, rel-(R)-1-((1H-pyrazol-3-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-((4-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-((3-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, 1-((R)-1-(5-fluoropyridin-2-yl)ethyl)-3-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (rac)-(R)-1-(4-(2-hydroxy-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (rac)-(R)-1-(4-(2,2-difluoro-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrimidin-4-ylmethyl)urea, rel-1-((R)-1-(1H-pyrazol-3-yl)ethyl)-3-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-1-((R)-1-(1H-pyrazol-3-yl)ethyl)-3-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridazin-3-ylmethyl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-methyl-1H-pyrazol-3-yl)methyl)urea, rel-(R)-1-((6-methoxypyrimidin-4-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((4-methyl-1H-pyrazol-3-yl)methyl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol-2-ylmethyl)urea, (rac)-(R)-1-(4-(1-(5-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol-2-ylmethyl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(3-methyloxetan-3-yl)urea, rel-(R)-1-(4-chlorobenzyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrazin-2-ylmethyl)urea, rel-(R)-1-((5-methoxypyrazin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, rel-(R)-1-(2-chloro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((S)-tetrahydrofuran-3-yl)urea, 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((R)-tetrahydrofuran-3-yl)urea, rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1-methyl-1H-imidazol-4-yl)urea, rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (rac)-(R)-1-(2-chloro-6-fluoro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((S)-tetrahydrofuran-3-yl)methyl)urea, 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((S)-tetrahydro-2H-pyran-3-yl)urea, (rac)-(R)-1-(4-(1-(2-(fluoromethyl)-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-fluoropyridin-2- yl)methyl)urea, rel-(R)-1-(4-(1-(2-(fluoromethyl)-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-fluoropyridin-2-yl)methyl)urea, rel-1-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((3S,4R)-4-methyltetrahydrofuran-3- yl)urea, (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(2-hydroxy-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((S)-tetrahydrofuran-2-yl)methyl)urea, 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((R)-tetrahydrofuran-2-yl)methyl)urea, rel-(R)-1-(4-(2-fluoro-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-fluoropyridin-2- yl)methyl)urea, 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((2R*,5R*)-5-methyltetrahydrofuran-2- yl)methyl)urea, rel-(R)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, rel-(R)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((1H-imidazol-5-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (rac)-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)urea, 1-(4-((1H-imidazol-5-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((RS)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-((S)-tetrahydrofuran-3-yl)urea, (rac)-(R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (rac)-(R)-1-(4-(1-(1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, rel-(R)-1-(4-(1-(1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((4-methyl-1H-imidazol-5-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, rel-(R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)urea, rel-(R)-1-(6-(1-(4-methyl-1H-imidazol-5-yl)ethyl)pyridin-3-yl)-3-(pyridin-2-yl)urea, rel-(R)-1-(1H-pyrazol-3-yl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)urea, rel-(R)-1-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5- yl)phenyl)urea, rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5- yl)phenyl)urea, rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5- yl)phenyl)urea, 1-(4-((RS)-3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)phenyl)-3-((S)-tetrahydrofuran-3- yl)urea, 1-(4-((R*)-3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)phenyl)-3-((S)-tetrahydrofuran-3- yl)urea, rel-(R)-1-(4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-3-(pyridin-2-yl)urea, rel-(R)-1-(pyridin-2-yl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)urea, 1-((S)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-3-(4-((RS)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyridin-8-yl)phenyl)urea, rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)urea, rel-(R)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, rel-(R)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-ylmethyl)urea, (rac)-(R)-1-(4-(1-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-3-(pyridin-2- yl)urea, (rac)-(R)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)-3-fluorophenyl)-3-(pyridin-2-yl)urea, (rac)-(R)-1-[4-[1-[2-(difluoromethyl)imidazol-1-yl]ethyl]phenyl]-3-(2-pyridyl)urea, rel-(R)-1-[(5-fluoropyridin-2-yl)methyl]-3-(4-[5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl]phenyl)urea, 1-(pyridin-2-yl)-3-(4-(thiazol-5-ylmethyl)phenyl)urea, (rac)-(R)-1-(1H-pyrazol-3-yl)-3-(4-(1-(thiazol-5-yl)ethyl)phenyl)urea, 1-(1H-pyrazol-3-yl)-3-(4-(thiazol-5-ylmethyl)phenyl)urea, rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((RS)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-((S)-tetrahydrofuran-3-yl)urea, 1-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-((S)-tetrahydrofuran-3-yl)urea, rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyridin-2-ylmethyl)urea, rel-(R)-1-((1H-pyrazol-3-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(thiazol-2-ylmethyl)urea, rel-(R)-1-((4-methyl-1H-pyrazol-3-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, 1-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-((S)-tetrahydro-2H-pyran-3-yl)urea, rel-(R)-1-((5-methyl-1H-pyrazol-3-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyrimidin-4-ylmethyl)urea, rel-(R)-1-((4-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyrazin-2-ylmethyl)urea, rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(oxazol-2-yl)urea, 1-(4-((1-methyl-1H-pyrazol-5-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (rac)-(R)-1-(4-(1-(1-methyl-1H-pyrazol-5-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(1-methyl-1H-pyrazol-5-yl)ethyl)phenyl)urea, rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(thiazol-2-yl)acetamide, rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-1H-pyrrole-2-carboxamide, rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(1H-pyrazol-3-yl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)nicotinamide, rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-2-yl)acetamide, rel-(R)-2-(5-fluoropyridin-3-yl)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)acetamide, rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)propanamide, rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(5-methylpyridin-3-yl)acetamide, 4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl-3-(2H-1,2,3-triazol-2-yl)propanamide, rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yloxy)acetamide, rel-(R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)propanamide, 4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl-2-(pyrimidin-5-yl)acetamide , rel-(R)-N-(4-(2-hydroxy-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-2-ylamino)acetamide, rel-(R)-N-(2-fluoro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, rel-(R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)butanamide, (R*)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(oxolan-3-(R)-yl)acetamide, rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(oxetan-3-yl)acetamide, (RS)-2-hydroxy-N-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, rel-2-((R)-3-hydroxytetrahydrofuran-3-yl)-N-(4-((R)-1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)acetamide, (RS)-2-fluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((RS)-tetrahydrofuran-3- yl)acetamide, (RS)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((RS)-tetrahydrofuran-3-yl)propanamide, (R*)-2-methoxy-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (R*)-2-methoxy-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((R*)-tetrahydrofuran-3- yl)acetamide, (RS)-2-hydroxy-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((RS)-tetrahydrofuran-3- yl)propanamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(4-methyl-1H-pyrazol-3-yl)propanamide, 2,2-difluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((R*)-tetrahydrofuran-3- yl)acetamide, 2,2-difluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((R*)-tetrahydrofuran-3- yl)acetamide, (R*)-2-fluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((R*)-tetrahydrofuran-3- yl)acetamide, N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((R*)-tetrahydrofuran-2-yl)propanamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)isonicotinamide, 2-((R*)-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)acetamide, (S)-2,2-difluoro-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)tetrahydrofuran-3-carboxamide, (S)-3-chloro-4-fluoro-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)benzamide, (rac)-(R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)isonicotinamide, (S)-4-fluoro-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)benzamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)oxetane-3-carboxamide, N-(5-((RS)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-((R)-tetrahydrofuran-3-yl)acetamide, (rac)-(R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-(pyridin-3-yl)acetamide, (R*)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)tetrahydro-2H-pyran-3-carboxamide, 2-((R*)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)isoxazole-4-carboxamide, N-(5-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyrazin-2-yl)-2-((R)-tetrahydrofuran-3-yl)acetamide, N-(5-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-((R)-tetrahydrofuran-3-yl)acetamide, rel-(R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-(pyridin-3-yl)acetamide, rel-(R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)isonicotinamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(4H-1,2,4-triazol-3-yl)acetamide, (R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-2- carboxamide, (R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)chromane-3-carboxamide, rel-(R)-N-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-2,2-difluoro-2-(pyridin-3-yl)acetamide, N-(4-((R*)-1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((R)-tetrahydrofuran-3-yl)acetamide, (R*)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)isochromane-4-carboxamide, (rac)-(R)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(thiazol-2-yl)propanamide, rel-(R)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(4-methyl-1H-pyrazol-3-yl)propanamide, N-(4-((R*)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((R)-tetrahydrofuran-3-yl)acetamide, rel-(R)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (rac)-(R)-2,2-difluoro-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, N-(6-((R*)-1-(4-methyl-1H-imidazol-5-yl)ethyl)pyridin-3-yl)-2-((R)-tetrahydrofuran-3-yl)acetamide, (RS)-N-(4-((S*)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((R)-tetrahydrofuran-3-yl)propanamide, 2,2-difluoro-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)-tetrahydrofuran-3- yl)acetamide, rel-(R)-2,2-difluoro-N-(4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-2-(pyridin-3- yl)acetamide, (R)-N-(4-((R*)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)tetrahydro-2H-pyran-3- carboxamide, 2-((R)-tetrahydrofuran-3-yl)-N-(4-((R*)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)acetamide, N-(4-((R*)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-2-((R)-tetrahydrofuran-3- yl)acetamide, 2-((R)-tetrahydrofuran-3-yl)-N-(4-((RS)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)acetamide, 2-(2,3-dihydro-1-benzofuran-3-yl)-N-[4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl]acetamide, (rac)-(R)-N-(4-(3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)phenyl)-2-(pyridin-3- yl)acetamide, rel-(R)-2-(pyridin-3-yl)-N-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)acetamide, rel-(R)-N-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)-2-(pyridin-3- yl)acetamide, 2,2-difluoro-2-(oxolan-3-yl)-N-[4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl]acetamide, 3-(RS)-methyl-N-(4-[(S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)oxane-3-carboxamide, 6,6-dimethyl-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)oxane-3-(RS)-carboxamide, (1R*,5S*)-6,6-difluoro-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)-3- oxabicyclo[3.1.0]hexane-1-carboxamide, rel-(1S,4S)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane- 4-carboxamide, rel-(1S,4S)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane- 4-carboxamide, 4,4-difluoro-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)oxane-3-(RS)-carboxamide, 7-hydroxy-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)-2,3-dihydro-1,4-benzodioxine-2- (RS)-carboxamide , rel-(R)-2,2-difluoro-2-(pyridin-3-yl)-N-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)acetamide, (R)-N-(4-((RS)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine- 2-carboxamide, 2,2-difluoro-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)-tetrahydrofuran-3- yl)acetamide, 2,2-difluoro-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)-tetrahydrofuran-3- yl)acetamide, rel-2-((R)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyridin-8-yl)phenyl)acetamide, rel-(R)-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)-tetrahydrofuran-3- yl)propanamide, rel-(R)-N-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-2,2-difluoro-2-(pyridin-3-yl)acetamide, rel-(R)-N-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-2,2-difluoro-2-(pyridin-3-yl)acetamide, rel-(R)-N-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, N-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-((R)-tetrahydrofuran-3-yl)acetamide, rel-(R)-N-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)isonicotinamide, (S)-2,2-difluoro-N-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (R)-N-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)tetrahydro-2H-pyran-3-carboxamide, 2,2-difluoro-N-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-((RS)-tetrahydrofuran-3-yl)acetamide, and rel-2-((R)-2,3-dihydrobenzofuran-3-yl)-N-(4-((R)-1-(4-methylthiazol-5-yl)ethyl)phenyl)acetamide. In embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is selected from, 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((4-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(3-methyl-1H-pyrazol-5-yl)urea, 1-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-3-1H-pyrazol-3-ylurea, 1-(4-((1H-imidazol-5-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-cyclobutyl-1H-pyrazol-5-yl)-3-(4-((1H-imidazol-1-yl)methyl)phenyl)urea, 1-(4-cyclopropyl-1H-pyrazol-3-yl)-3-(4-[(1H-imidazol-1-yl)methyl]phenyl)urea, 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(4-methyl-1H-pyrazol-5-yl)urea, 1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(4-methyl-1H-pyrazol-3-yl)urea, 1-(2-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1-methyl-1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)propyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)propyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(6-((2-methyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-3-(1H-pyrazol-3-yl)urea, 1-(4-(1-(2-methyl-1H-imidazol-1-yl)cyclopropyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(isoxazol-3-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-(isoxazol-3-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-( pyridin-2-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxazol-2-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxazol-2-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxetan-3-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxetan-3-yl)urea, (R)-1-(2-fluorophenyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-(2-fluorophenyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, 1-(4-(1-(2-methyl-1H-imidazol-1-yl)cyclopropyl)phenyl)-3-(pyridin-2-yl)urea, (R)-1-(5-hydroxypyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-(5-hydroxypyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(5-(hydroxymethyl)pyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-(5-(hydroxymethyl)pyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(4-(cyclopropyl(2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(cyclopropyl(2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrazin-2-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrazin-2-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrimidin-4-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrimidin-4-yl)urea, (R)-1-(4-(cyclopropyl(2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(cyclopropyl(2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(4-methyl-1H-pyrazol-3-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(4-methyl-1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol-4-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol-4-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxazol-4-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxazol-4-yl)urea, (R)-1-(5-fluoropyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-(5-fluoropyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(3-fluoropyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-(3-fluoropyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(4-chloro-1H-pyrazol-3-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-(4-chloro-1H-pyrazol-3-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridazin-3-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridazin-3-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-3-ylmethyl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-3-ylmethyl)urea, (R)-1-((5-fluoropyrimidin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-((5-fluoropyrimidin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-ylmethyl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-ylmethyl)urea, (R)-1-(5-bromopyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-(5-bromopyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(2-cyclopropyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(1-(2-cyclopropyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(2-(hydroxymethyl)-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (s)-1-(4-(1-(2-(hydroxymethyl)-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((SR)-1-(pyridin-2-yl)ethyl)urea, (R)-1-((1H-pyrazol-3-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-((1H-pyrazol-3-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-((4-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-((4-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-((3-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-((3-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, 1-((R)-1-(5-fluoropyridin-2-yl)ethyl)-3-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(4-(2-hydroxy-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(2-hydroxy-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(4-(2,2-difluoro-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(2,2-difluoro-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrimidin-4-ylmethyl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrimidin-4-ylmethyl)urea, 1-((R)-1-(1H-pyrazol-3-yl)ethyl)-3-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, 1-((S)-1-(1H-pyrazol-3-yl)ethyl)-3-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, 1-((S)-1-(1H-pyrazol-3-yl)ethyl)-3-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, 1-((R)-1-(1H-pyrazol-3-yl)ethyl)-3-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridazin-3-ylmethyl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridazin-3-ylmethyl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-methyl-1H-pyrazol-3-yl)methyl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-methyl-1H-pyrazol-3-yl)methyl)urea, (R)-1-((6-methoxypyrimidin-4-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-((6-methoxypyrimidin-4-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((4-methyl-1H-pyrazol-3-yl)methyl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((4-methyl-1H-pyrazol-3-yl)methyl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol-2-ylmethyl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol-2-ylmethyl)urea, (R)-1-(4-(1-(5-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol-2-ylmethyl)urea, (S)-1-(4-(1-(5-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol-2-ylmethyl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(3-methyloxetan-3-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(3-methyloxetan-3-yl)urea, (R)-1-(4-chlorobenzyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-(4-chlorobenzyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrazin-2-ylmethyl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrazin-2-ylmethyl)urea, (R)-1-((5-methoxypyrazin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-((5-methoxypyrazin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(2-chloro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(2-chloro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((S)-tetrahydrofuran-3-yl)urea, 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((R)-tetrahydrofuran-3-yl)urea, (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1-methyl-1H-imidazol-4-yl)urea, (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1-methyl-1H-imidazol-4-yl)urea, (R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, (R)-1-(2-chloro-6-fluoro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(2-chloro-6-fluoro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((S)-tetrahydrofuran-3-yl)methyl)urea, 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((S)-tetrahydro-2H-pyran-3-yl)urea, (R)-1-(4-(1-(2-(fluoromethyl)-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-fluoropyridin-2-yl)methyl)urea, (S)-1-(4-(1-(2-(fluoromethyl)-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-fluoropyridin-2-yl)methyl)urea, 1-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((3S,4R)-4-methyltetrahydrofuran-3-yl)urea, 1-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((3S,4S)-4-methyltetrahydrofuran-3-yl)urea, 1-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((3R,4R)-4-methyltetrahydrofuran-3-yl)urea, 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((3S,4R)-4-methyltetrahydrofuran-3-yl)urea, 1-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((3R,4S)-4-methyltetrahydrofuran-3-yl)urea, 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((3S,4S)-4-methyltetrahydrofuran-3-yl)urea, 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((3R,4R)-4-methyltetrahydrofuran-3-yl)urea, 1-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((3R,4S)-4-methyltetrahydrofuran-3-yl)urea, 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((3R,4S)-4-methyltetrahydrofuran-3-yl)urea, (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(2-hydroxy-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea, 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((S)-tetrahydrofuran-2-yl)methyl)urea, 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((R)-tetrahydrofuran-2-yl)methyl)urea, (R)-1-(4-(2-fluoro-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-fluoropyridin-2-yl)methyl)urea, (S)-1-(4-(2-fluoro-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-fluoropyridin-2-yl)methyl)urea, 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((2R*,5R*)-5-methyltetrahydrofuran-2- yl)methyl)urea, (R)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (S)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((1H-imidazol-5-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)urea, (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)urea, 1-(4-((1H-imidazol-5-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((RS)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-((S)-tetrahydrofuran-3-yl)urea, (R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (S)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (R)-1-(4-(1-(1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (S)-1-(4-(1-(1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((4-methyl-1H-imidazol-5-yl)methyl)phenyl)-3-(pyridin-2-yl)urea, (R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (S)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)urea, (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)urea, (R)-1-(6-(1-(4-methyl-1H-imidazol-5-yl)ethyl)pyridin-3-yl)-3-(pyridin-2-yl)urea, (S)-1-(6-(1-(4-methyl-1H-imidazol-5-yl)ethyl)pyridin-3-yl)-3-(pyridin-2-yl)urea, (R)-1-(1H-pyrazol-3-yl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)urea, (S)-1-(1H-pyrazol-3-yl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)urea, (R)-1-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)urea, (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)urea, (R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5- yl)phenyl)urea, (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5- yl)phenyl)urea, 1-(4-((RS)-3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)phenyl)-3-((S)-tetrahydrofuran-3- yl)urea, 1-(4-((R*)-3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)phenyl)-3-((S)-tetrahydrofuran-3- yl)urea, (R)-1-(4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-3-(pyridin-2-yl)urea, (S)-1-(4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-3-(pyridin-2-yl)urea, (R)-1-(pyridin-2-yl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)urea, (S)-1-(pyridin-2-yl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)urea, 1-((S)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-3-(4-((RS)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyridin-8-yl)phenyl)urea, (R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)urea, (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)urea, (R)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (S)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (R)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-ylmethyl)urea, (S)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-ylmethyl)urea, (R)-1-(4-(1-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-3-(pyridin-2- yl)urea, (S)-1-(4-(1-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-3-(pyridin-2- yl)urea, (R)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)-3-fluorophenyl)-3-(pyridin-2-yl)urea, (S)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)-3-fluorophenyl)-3-(pyridin-2-yl)urea, (R)-1-[4-[1-[2-(difluoromethyl)imidazol-1-yl]ethyl]phenyl]-3-(2-pyridyl)urea, (S)-1-[4-[1-[2-(difluoromethyl)imidazol-1-yl]ethyl]phenyl]-3-(2-pyridyl)urea, (R)-1-[(5-fluoropyridin-2-yl)methyl]-3-(4-[5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl]phenyl)urea, (S)-1-[(5-fluoropyridin-2-yl)methyl]-3-(4-[5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl]phenyl)urea, 1-(pyridin-2-yl)-3-(4-(thiazol-5-ylmethyl)phenyl)urea, (R)-1-(1H-pyrazol-3-yl)-3-(4-(1-(thiazol-5-yl)ethyl)phenyl)urea, (S)-1-(1H-pyrazol-3-yl)-3-(4-(1-(thiazol-5-yl)ethyl)phenyl)urea, 1-(1H-pyrazol-3-yl)-3-(4-(thiazol-5-ylmethyl)phenyl)urea, (R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, (S)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea, 1-(4-((RS)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-((S)-tetrahydrofuran-3-yl)urea, 1-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-((S)-tetrahydrofuran-3-yl)urea, (R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyridin-2-ylmethyl)urea, (S)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyridin-2-ylmethyl)urea, (R)-1-((1H-pyrazol-3-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, (S)-1-((1H-pyrazol-3-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, (R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(thiazol-2-ylmethyl)urea, (S)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(thiazol-2-ylmethyl)urea, (R)-1-((4-methyl-1H-pyrazol-3-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, (S)-1-((4-methyl-1H-pyrazol-3-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, 1-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-((S)-tetrahydro-2H-pyran-3-yl)urea, (R)-1-((5-methyl-1H-pyrazol-3-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, (S)-1-((5-methyl-1H-pyrazol-3-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, (R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, (R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyrimidin-4-ylmethyl)urea, (S)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyrimidin-4-ylmethyl)urea, (R)-1-((4-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, (S)-1-((4-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)urea, (R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyrazin-2-ylmethyl)urea, (S)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyrazin-2-ylmethyl)urea, (R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(oxazol-2-yl)urea, (S)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(oxazol-2-yl)urea, 1-(4-((1-methyl-1H-pyrazol-5-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-(4-(1-(1-methyl-1H-pyrazol-5-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (S)-1-(4-(1-(1-methyl-1H-pyrazol-5-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea, (R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(1-methyl-1H-pyrazol-5-yl)ethyl)phenyl)urea, (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(1-methyl-1H-pyrazol-5-yl)ethyl)phenyl)urea, (R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(thiazol-2-yl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(thiazol-2-yl)acetamide, (R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-1H-pyrrole-2-carboxamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-1H-pyrrole-2-carboxamide, (R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(1H-pyrazol-3-yl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(1H-pyrazol-3-yl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)nicotinamide, (R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-2-yl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-2-yl)acetamide, (R)-2-(5-fluoropyridin-3-yl)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)acetamide, (S)-2-(5-fluoropyridin-3-yl)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)acetamide, (R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)propanamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)propanamide, (R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(5-methylpyridin-3-yl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(5-methylpyridin-3-yl)acetamide, 4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl-3-(2H-1,2,3-triazol-2-yl)propanamide, (R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yloxy)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yloxy)acetamide, (R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)propanamide, (S)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)propanamide, 4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl-2-(pyrimidin-5-yl)acetamide, (R)-N-(4-(2-hydroxy-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (S)-N-(4-(2-hydroxy-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-2-ylamino)acetamide, (R)-N-(2-fluoro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (S)-N-(2-fluoro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)butanamide, (S)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)butanamide, (R*)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(oxolan-3-(R)-yl)acetamide, (R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(oxetan-3-yl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(oxetan-3-yl)acetamide, (RS)-2-hydroxy-N-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, 2-((R)-3-hydroxytetrahydrofuran-3-yl)-N-(4-((R)-1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)acetamide, 2-((R)-3-hydroxytetrahydrofuran-3-yl)-N-(4-((S)-1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)acetamide, 2-((S)-3-hydroxytetrahydrofuran-3-yl)-N-(4-((R)-1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)acetamide, 2-((S)-3-hydroxytetrahydrofuran-3-yl)-N-(4-((S)-1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)acetamide, (RS)-2-fluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((RS)-tetrahydrofuran-3- yl)acetamide, (RS)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((RS)-tetrahydrofuran-3-yl)propanamide, (R*)-2-methoxy-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (R*)-2-methoxy-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((R*)-tetrahydrofuran-3- yl)acetamide, (RS)-2-hydroxy-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((RS)-tetrahydrofuran-3- yl)propanamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(4-methyl-1H-pyrazol-3-yl)propanamide, 2,2-difluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((R*)-tetrahydrofuran-3- yl)acetamide, 2,2-difluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((R*)-tetrahydrofuran-3- yl)acetamide, (R*)-2-fluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((R*)-tetrahydrofuran-3- yl)acetamide, N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((R*)-tetrahydrofuran-2-yl)propanamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)isonicotinamide, 2-((R*)-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)acetamide, (S)-2,2-difluoro-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)tetrahydrofuran-3-carboxamide, (S)-3-chloro-4-fluoro-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)benzamide, (R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)isonicotinamide, (S)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)isonicotinamide, (S)-4-fluoro-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)benzamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)oxetane-3-carboxamide, N-(5-((RS)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-((R)-tetrahydrofuran-3-yl)acetamide, (R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-(pyridin-3-yl)acetamide, (S)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-(pyridin-3-yl)acetamide, (R*)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)tetrahydro-2H-pyran-3-carboxamide, 2-((R*)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)acetamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)isoxazole-4-carboxamide, N-(5-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyrazin-2-yl)-2-((R)-tetrahydrofuran-3-yl)acetamide, N-(5-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-((R)-tetrahydrofuran-3-yl)acetamide, (R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-(pyridin-3-yl)acetamide, (S)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-(pyridin-3-yl)acetamide, (R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)isonicotinamide, (S)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)isonicotinamide, (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(4H-1,2,4-triazol-3-yl)acetamide, (R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine-2- carboxamide, (R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)chromane-3-carboxamide, (R)-N-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-2,2-difluoro-2-(pyridin-3-yl)acetamide, (S)-N-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-2,2-difluoro-2-(pyridin-3-yl)acetamide, N-(4-((R*)-1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((R)-tetrahydrofuran-3-yl)acetamide, (R*)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)isochromane-4-carboxamide, (R)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(thiazol-2-yl)propanamide, (S)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(thiazol-2-yl)propanamide, (R)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(4-methyl-1H-pyrazol-3-yl)propanamide, (S)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(4-methyl-1H-pyrazol-3-yl)propanamide, N-(4-((R*)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((R)-tetrahydrofuran-3-yl)acetamide, (R)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (S)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (R)-2,2-difluoro-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (S)-2,2-difluoro-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, N-(6-((R*)-1-(4-methyl-1H-imidazol-5-yl)ethyl)pyridin-3-yl)-2-((R)-tetrahydrofuran-3-yl)acetamide, (RS)-N-(4-((S*)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((R)-tetrahydrofuran-3-yl)propanamide, 2,2-difluoro-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)-tetrahydrofuran-3- yl)acetamide, (R)-2,2-difluoro-N-(4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-2-(pyridin-3- yl)acetamide, (S)-2,2-difluoro-N-(4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-2-(pyridin-3- yl)acetamide, (R)-N-(4-((R*)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)tetrahydro-2H-pyran-3- carboxamide, 2-((R)-tetrahydrofuran-3-yl)-N-(4-((R*)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)acetamide, N-(4-((R*)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-2-((R)-tetrahydrofuran-3- yl)acetamide, 2-((R)-tetrahydrofuran-3-yl)-N-(4-((RS)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)acetamide, 2-(2,3-dihydro-1-benzofuran-3-yl)-N-[4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl]acetamide, (R)-N-(4-(3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)phenyl)-2-(pyridin-3-yl)acetamide, (S)-N-(4-(3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)phenyl)-2-(pyridin-3-yl)acetamide, (R)-2-(pyridin-3-yl)-N-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)acetamide, (S)-2-(pyridin-3-yl)-N-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)acetamide, (R)-N-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)-2-(pyridin-3-yl)acetamide, (S)-N-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)-2-(pyridin-3-yl)acetamide, 2,2-difluoro-2-(oxolan-3-yl)-N-[4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl]acetamide, 3-(RS)-methyl-N-(4-[(S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)oxane-3-carboxamide, 6,6-dimethyl-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)oxane-3-(RS)-carboxamide, (1R*,5S*)-6,6-difluoro-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)-3- oxabicyclo[3.1.0]hexane-1-carboxamide, (1S,4S)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1S,4S)-1-ethyl-N-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1S,4R)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (RS,4S)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1S,4R)-1-ethyl-N-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1R,4S)-1-ethyl-N-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1R,4R)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1R,4R)-1-ethyl-N-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1R,4R)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1R,4S)-1-ethyl-N-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1S,4R)-1-ethyl-N-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1R,4S)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1S,4R)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1S,4R)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, (1S,4S)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4- carboxamide, 4,4-difluoro-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)oxane-3-(RS)-carboxamide, 7-hydroxy-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)-2,3-dihydro-1,4-benzodioxine-2- (RS)-carboxamide , (R)-2,2-difluoro-2-(pyridin-3-yl)-N-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)acetamide, (S)-2,2-difluoro-2-(pyridin-3-yl)-N-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)acetamide, (R)-N-(4-((RS)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine- 2-carboxamide, 2,2-difluoro-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)-tetrahydrofuran-3- yl)acetamide, 2,2-difluoro-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)-tetrahydrofuran-3- yl)acetamide, 2-((R)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyridin-8-yl)phenyl)acetamide, 2-((R)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-N-(4-((R)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyridin-8-yl)phenyl)acetamide, 2-((S)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyridin-8-yl)phenyl)acetamide, 2-((S)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-N-(4-((R)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5- a]pyridin-8-yl)phenyl)acetamide, (R)-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)-tetrahydrofuran-3-yl)propanamide, (R)-N-(4-((R)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)-tetrahydrofuran-3-yl)propanamide, (S)-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)-tetrahydrofuran-3-yl)propanamide, (S)-N-(4-((R)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)-tetrahydrofuran-3-yl)propanamide, (R)-N-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-2,2-difluoro-2-(pyridin-3-yl)acetamide, (S)-N-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-2,2-difluoro-2-(pyridin-3-yl)acetamide, (R)-N-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (S)-N-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, N-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-((R)-tetrahydrofuran-3-yl)acetamide, (R)-N-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)isonicotinamide, (S)-N-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)isonicotinamide, (S)-2,2-difluoro-N-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide, (R)-N-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)tetrahydro-2H-pyran-3-carboxamide, 2,2-difluoro-N-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-((RS)-tetrahydrofuran-3-yl)acetamide, 2-((R)-2,3-dihydrobenzofuran-3-yl)-N-(4-((R)-1-(4-methylthiazol-5-yl)ethyl)phenyl)acetamide, 2-((R)-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-(4-methylthiazol-5-yl)ethyl)phenyl)acetamide, 2-((S)-2,3-dihydrobenzofuran-3-yl)-N-(4-((R)-1-(4-methylthiazol-5-yl)ethyl)phenyl)acetamide, and 2-((S)-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-(4-methylthiazol-5-yl)ethyl)phenyl)acetamide. A further feature is any of the embodiments described in the specification with the proviso that any of the specific Examples are individually disclaimed. A further feature is any of the embodiments described in the specification with the proviso that any one or more of the compounds selected from the above list of Examples of compounds of the specification are individually disclaimed. The compounds disclosed herein may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e. as individual enantiomers, diastereoisomers, or as a stereoisomerically enriched mixture. All such stereoisomer (and enriched) mixtures are included within the scope of the embodiments, unless otherwise stated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name is intended to embrace all possible stereoisomers, diastereoisomers, conformers, rotamers and tautomers of the compound depicted. For example, a compound containing a chiral carbon atom is intended to embrace both the (R) enantiomer and the (S) enantiomer, as well as mixtures of the enantiomers, including racemic mixtures; and a compound containing two chiral carbons is intended to embrace all enantiomers and diastereoisomers including (R,R), (S,S), (R,S) and (S,R). In embodiments, there is provided a pharmaceutical composition which comprises a compound of the Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or pharmaceutically acceptable salt thereof, wherein the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or pharmaceutically acceptable salt thereof is present within the composition with an enantiomeric excess (%ee) of ^ 90% and a diastereomeric excess (%de) of ^ 90%. The compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), and pharmaceutically acceptable salts thereof, may be prepared, used or supplied in amorphous form, crystalline form, or semicrystalline form and any given compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or pharmaceutically acceptable salt thereof, may be capable of being formed into more than one crystalline / polymorphic form, including hydrated (e.g. hemi hydrate, a mono hydrate, a di hydrate, a tri hydrate or other stoichiometry of hydrate) and/or solvated forms. It is to be understood that the present specification encompasses any and all such solid forms of the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), and pharmaceutically acceptable salts thereof. In further embodiments there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or pharmaceutically acceptable salts thereof, which is obtainable by the methods described in the ‘Examples” section hereinafter. The present specification is intended to include all isotopes of atoms occurring in the present compounds. Isotopes will be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include 13C and 14C. Isotopes of nitrogen include 15N. Isotopes of fluorine include 18F. A suitable pharmaceutically acceptable salt of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) is, for example, a base addition salt. A base addition salt of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) may be formed by bringing the compound into contact with a suitable inorganic or organic base under conditions known to the skilled person. A base addition salt may for example be an alkali metal salt (such as a sodium, potassium, or lithium salt) or an alkaline earth metal salt (such as a calcium salt), which may be formed using an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., an ethoxide or methoxide). A base addition salt may also be formed using a suitably basic organic amine (e.g., a choline or meglumine salt). A suitable pharmaceutically acceptable salt of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) is, for example, an acid addition salt. An acid addition salt of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) may be formed by bringing the compound into contact with a suitable inorganic or organic acid under conditions known to the skilled person. An acid addition salt may for example be formed using an inorganic acid selected from hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid. An acid addition salt may also be formed using an organic acid selected from trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonic acid and para-toluenesulfonic acid. A further suitable pharmaceutically acceptable salt of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) is, for example, a salt formed within a patient’s body after administration of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) to the patient. The compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or pharmaceutically acceptable salt thereof, may be prepared as a co-crystal solid form. It is to be understood that a pharmaceutically acceptable co-crystal of an compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or pharmaceutically acceptable salts thereof, form an aspect of the present specification. In a further aspect there is provided a pharmaceutical composition comprising a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The term "pharmaceutical composition" refers to a preparation which is in such form as to permit the biological activity of the active ingredient, and which contains no additional components which are unacceptably toxic to a patient to which the composition would be administered. Such compositions can be sterile. A pharmaceutical composition according to the present specification will comprise a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. For example, the composition may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). Such compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. An effective amount of the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, will normally be present in the composition. The compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V),or a pharmaceutically acceptable salt thereof, will normally be administered via the oral route though parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form may be possible. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses. The pharmaceutical formulations of the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) described above may be prepared e.g. for parenteral, subcutaneous, intramuscular or intravenous administration. The pharmaceutical formulations of the compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) described above may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985). Pharmaceutical formulations suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with binding agents, fillers, lubricants and surfactants. Liquid compositions may contain conventional additives such as suspending agents, emulsifying agents and preservatives. Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. An exemplary oral composition would comprise a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) and at least one pharmaceutically acceptable excipient filled into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule. As a result of their SARM1 inhibitory activity, the compounds of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), and pharmaceutically acceptable salts thereof are expected to be useful in therapy, for example in the treatment of diseases or medical conditions mediated at least in part by SARM1, such as a neuropathy associated with axonal degeneration. In one aspect of the present specification there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, for use in therapy. In one aspect of the present specification there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases and disorders associated with axonal degeneration. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative condition. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, for use in the treatment of chemotherapy induced peripheral neuropathy (CIPN), painful diabetic neuropathy (PDN), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), demyelinating disease, Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Charcot Marie Tooth Disease (CMT), hereditary spastic paraplegia, ischemia, stroke, traumatic brain injury (TBI), traumatic neuronal injury, carpal tunnel syndrome, glaucoma, retinal degeneration, viral infection, or viral encephalitis. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, for use in the treatment of neuropathy. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, for use in the treatment of acute peripheral neuropathy. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, for use in the treatment of chemotherapy induced peripheral neuropathy (CIPN). In further embodiments, the CIPN is caused by a chemotherapeutic agent selected from cisplatin, carboplatin, oxaliplatin, paclitaxel, docetaxel, vincristine, vinblastine, bortezomib and carfilzomib. The term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology. The term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be interpreted in a corresponding manner. The term “prophylaxis” is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease. The term “treatment” is used synonymously with “therapy”. Similarly the term “treat” can be regarded as “applying therapy” where “therapy” is as defined herein. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, for use in providing an inhibitory effect on SARM1. In embodiments, there is provided a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease mediated by SARM1. In embodiments, the disease mediated by SARM1 is chemotherapy induced peripheral neuropathy (CIPN). In one aspect of the present specification there is provided the use of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, as described herein, in the manufacture of a medicament. In embodiments, the medicament is for the treatment of chemotherapy induced peripheral neuropathy (CIPN). In one aspect of the present specification there is provided a method of treating disease in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof. Terms such as “treating” or “treatment” refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. The term "effective amount" means an amount of an active ingredient which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician. The term “patient” refers to any animal (e.g., a mammal), including, but not limited to humans, non- human primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the term “patient” refers to a human subject. In embodiments, there is provided a method of treating disease in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof, wherein the disease is selected from chemotherapy induced peripheral neuropathy (CIPN), painful diabetic neuropathy (PDN), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), demyelinating disease, Parkinson’s Disease (PD), Alzheimer’s Disease (AD), Charcot Marie Tooth Disease (CMT), hereditary spastic paraplegia, ischemia, stroke, traumatic brain injury (TBI), traumatic neuronal injury, carpal tunnel syndrome, glaucoma, retinal degeneration, viral infection, and viral encephalitis. In embodiments, there is provided a method of treating a SARM1 mediated disease in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof. In embodiments, the SARM1 mediated disease is chemotherapy induced peripheral neuropathy (CIPN). In embodiments, there is provided a method of treating chemotherapy induced peripheral neuropathy (CIPN) in a patient comprising administering to the patient an effective amount of a compound of Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V), or a pharmaceutically acceptable salt thereof. The compounds of the present disclosure may or may not form a covalent adduct with ADP-ribose (ADPR), wherein said adduct inhibits SARM1 activity. The compounds of the present disclosure may be used in the methods described above as either as single pharmacological agents or in combination with other pharmacological agents or techniques. Such combination therapies may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. These combination therapies (and corresponding combination products) employ the compounds of the present disclosure and the other pharmacological agent(s). Although the compounds of the Formula (I), (II), (III), (IIIA), (IIIB), (IIIC), (IIID), (IV), (IVA), (IVB) or (V) are primarily of value as therapeutic agents for use in patients, they are also useful whenever it is required to inhibit SARM1. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Examples The specification will now be illustrated by the following non-limiting Examples. General Experimental Details Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received. Abbreviations AcOH: acetic acid; AIBN: azobisisobutyronitrile; BAST: bis(2-methoxyethyl)aminosulfur trifluoride (DEOXO-FLUOR); BBr3: boron tribromide; Boc2O: di-tert-butyl decarbonate; BrettPhos-Pd-G3: [(2-di- cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′- triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′ - biphenyl)]palladium(ii) methanesulfonate methanesulfonate; CDCl3: deuterated chloroform; CHCl3: chloroform; CPME: cyclopentyl methyl ether; Cs2CO3: cesium carbonate; DCM: dichloromethane; DEA: diethylamine; DIEA: N,N-diisopropylethylamine; DIPEA: N,N-diisopropylethylamine; DMF: N,N- dimethylformamide; DMSO: dimethylsulfoxide; D2O: deuterium oxide; DPPA: diphenylphosphoryl azide; ES+: electrospray positive ionization; EtOAc: ethyl acetate; EtOH: ethanol; FA: formic acid; HATU: [bis(dimethylamino)methylene]-1h-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; HCl: hydrogen chloride; HPLC: high performance liquid chromatography; IPA: isopropanol; K2CO3: potassium carbonate; KtBuO: potassium tert-butoxide; LiAlH4: lithium aluminium hydride; LiBH4: lithium borohydride; LiOtBu: lithium tert-butoxide; MeCN: acetonitrile; MeOH: methanol; MtBE: methyl tert-butyl ether; Na2CO3: sodium carbonate; Na2SO4: sodium sulfate; NaBH4: sodium borohydride; NaH: sodium hydride; NaHCO3: sodium bicarbonate; NaOH: sodium hydroxide; NBS: N-bromosuccinimide; NCS: N-chlorosuccinimide; NH3: ammonia; NH4Cl: ammonium chloride; NH4HCO3: ammonium bicarbonate; NMM: N-methylmorpholine; NMR: nuclear magnetic resonance; PCC: pyridinium chlorochromate; Pd(OAc)2: palladium (II) acetate; Pd(OH)2: palladium (II) hydroxide; Pd(PPh3)4: tetrakis(triphenylphosphine)palladium(0); Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0); Pd-C: palladium (0) on carbon; PdCl2(dppf): [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II); POCl3: phosphorous oxychloride; RT: retention time; SFC: supercritical fluid chromatography; SOCl2: thionyl chloride; SPhos: 2- dicyclohexylphosphino-2′,6′-dimethoxybiphenyl; TBAF: tetra-N-butylammonium fluoride; t- BuBrettPhos: di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine; TCFH: chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate; TEA: triethylamine; TFA: trifluoroacetic acid; THF: tetrahydrofuran; XantPhos: 5-(diphenylphosphanyl)-9,9-dimethyl-9H- xanthen-4-yl]diphenylphosphane. Analytical and Purification Methods LCMS experiments were performed using a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector. LCMS was run in one of three set ups: method 1 [Halo C18 column (2.0 µm 3.0 x 30 mm) in combination with a gradient (5-100% B in 1.2 min.) of water and FA (0.1%) (A) and MeCN and FA (0.1%) (B) at a flow rate of 1.5 mL/min]; method 2 [Halo C18 column (2.0 µm 3.0 x 30 mm) in combination with a gradient (5-100% B in 1.2 min.) of water and TFA (0.05%) (A) and MeCN and TFA (0.05%)(B) at a flow rate of 1.5 mL/min]; method 3 [Poroshell HPH C18 column (2.7 µm 3.0 x 50 mm) in combination with a gradient (10-95% B in 2 min.) of aqueous 46 mM ammonium carbonate/ammonia buffer at pH 10 (A) and MeCN (B) at a flow rate of 1.2 mL/min]. The Column Oven (CTO-20AC) temperature was 40 ℃. The injection volume was 1 µL. PDA (SPD-M20A) detection was in the range λ (190–400) nm. The MS detector was configured with electrospray ionization as ionizable source; acquisition mode: Scan; nebulizing gas flow:1.5 L/min; drying gas flow:15 L/min; detector voltage: 0.95-1.25 kv; DL T: 250 ℃; heat block T: 250 ℃; scan range: 90.00 - 900.00 m/z. NMR Spectra were recorded on a Bruker AVANCE III HD 400 (400 MHz) or Bruker AVANCE NEO 400 (400 MHz) or Bruker AVANCE III 400 (400 MHz) or Bruker AVANCE II 300 (300 MHz) or Bruker AVANCE III 300 (300 MHz) or Bruker AVANCE III HD 300(300 MHz). Preparative reverse phase HPLC was performed on a Waters instrument (2545 or 2767 or 2489) fitted with a QDa or SQ Detector 2 ESCi mass spectrometers and a Waters X-Bridge or Waters Xselect or Waters SunFire reverse-phase column (C-18, 5um, 30 mm diameter and 150 mm length with a flow rate of 60 ml/min or C-18, 5um, 19 mm diameter and 250 mm length with a flow rate of 25 ml/min). Preparative Chiral SFC was performed on a Waters instrument SFC (80 or 100 or 150 or 350) fitted with UV2489 (or mass spectrometer) and a Daicel or YMC or Phenomenex chiral column (CHIRALPAK IC / CHIRALPAK IG/ Phenomenex Lux Cellulose-3/ Phenomenex Lux Cellulose-4, 5 microns silica, 20 mm or 50 mm diameter, 250 mm length, flow rate of 40 –250 ml/min). Chemical Drawings and Chirality In general Examples and Intermediate compounds are named using ChemDraw Professional version 20.0 from PerkinElmer. ChemDraw Professional version 20.0 generates the names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules as closely as possible when generating chemical names. Stereoisomers are differentiated from each other by stereodescriptors cited in names and assigned in accordance with the CIP rules. ChemDraw is optionally using labels in the graphical representation of stereocenters such as
Figure imgf000063_0001
and 'or' to describe the configuration of the stereochemical centers present in the structure. In general chemical structures of Examples and Intermediates containing the label '&' at a stereocenter, means the configuration of such Example or Intermediate at that stereocenter is a mixture of both (R) and (S); and a label 'or' means the configuration of such Example or Intermediate at that stereocenter is either (S) or (R). Absolute, unspecified, '&', and 'or' stereocenters can all be present in a single structure. In general, the '&' and 'or' label at each stereocenter present in a structure may also include a number. The numbers indicate that stereocenters may or may not vary independently to each other, so that if two or more stereocenters do not vary independently of each other. i.e., are fixed relative to each other, they have the same number, but if they do vary independently of each other they have different numbers. For example, if a compound has two stereocenters in a ring which are independent of each other, the one stereocenter will be labelled “or1” (or “&1”) and the other labelled “or2” (or “&2”) whereas if a compound has two stereocenters in a ring and they are fixed relative to each other and do not vary independently of each other, both stereocenters would be labelled “or1” (or “&1”) and if a compound had two stereocenters that are fixed relative to each other and a third stereocenter that varies independently to the former stereocenters, the first two stereocenters would both be labelled “or1” (or “&1”) and the third labeled “or2” (or “&2”) It is further noted that as an artifact of this automatic labelling from ChemDraw, in some examples, two isomers are represented side by side, with the stereocenter(s) in isomer 1 labelled with a “or1” and the stereocenter(s) in isomer 2 labelled with a “or2”. It is to be understood that these two compounds are believed to be isomers of each other, as demonstrated by different properties, e.g., different elution times on a chiral HPLC. In general, for chemical structures of Examples and Intermediates where all stereocenters present are racemic, no flag is designated to the stereocenter(s) and the structure is drawn with a straight bond at each stereocenter. In general for structures of Examples and Intermediates where all of the stereocenters are designated as the structure is named with a “rac-” prefix. For structures of Examples and Intermediates where all of the stereocenters are designated as 'or', the structure is named with a “rel-” prefix. In general the label “Isomer 1” corresponds to the first eluted isomer, and “Isomer 2” corresponds to the second eluted isomer, on a given chiral HPLC column and eluent, and are used to distinguish two isomers containing one or more stereocenters with absolute unknown configuration. In general, for Examples or Intermediates containing more than one stereocenter the relative stereochemistry is described using configurational descriptors ‘S’ and ‘R’ for the stereogenic centers and using the “rac-“ or “rel-“ prefix cited at the front of the name. It is to be understood that an Example or Intermediate named with the “rel-“ prefix is a single isomer, and while the stereocenter(s) in the isomer have been designated as “R” or “S”, the actual stereochemistry of that particular isomer could be the opposite of the label. For example, while Example 13 is named “rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3- yl)urea”, Example 13 may be “(S)-1-(2-(4,4-Difluoropiperidin-2-yl)benzyl)-2-thioxo-1,2,3,5- tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one”. It is to be understood that an Example or Intermediate named with the “rac-“ prefix is a mixture of isomers, and while the relative stereochemistry of the stereocenters in the isomer have been designated with “R” or “S” descriptors, the actual stereochemistry of that particular isomer mixture contains also the opposite of said descriptors. For example, while Example 27 is named “(rac)-(R)-1- (2-fluorophenyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea”, Example 27 also contains “(S)-1-(2-fluorophenyl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea”. Intermediate Synthesis Procedure A: Synthesis of (S)-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)aniline (Intermediate I-1) – racemic Procedure
Figure imgf000065_0001
Step 1 NaBH4 (3.54 g, 93.50 mmol) was added to a solution of tert-butyl (4-acetylphenyl)carbamate (11 g, 46.75 mmol) in MeOH (300 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours, then it was concentrated under reduced pressure. The residue was dissolved in DCM (200 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 10% MeOH in DCM, to afford tert-butyl (4-(1- hydroxyethyl)phenyl)carbamate (10 g, 90%) as a white solid. MS (ES+, m/z): 164.1 [M - OtBu]+; 1H NMR (300 MHz, CDCl3) δ 1.47 (d, J = 6.4 Hz, 3H), 1.52 (s, 9H), 4.86 (q, J = 6.4 Hz, 1H), 6.48 (s, 1H), 7.23 – 7.38 (m, 4H), OH proton is not visible. Step 2 SOCl2 (1.5 ml, 20.68 mmol) was added dropwise to a solution of tert-butyl (4-(1- hydroxyethyl)phenyl)carbamate (3 g, 12.64 mmol) and 2-methyl-1H-imidazole (7.5 g, 91.35 mmol) in DCM (90 mL). The reaction mixture was stirred at 40 °C for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 10% MeOH in DCM, to afford (rac)-tert-butyl (R)-(4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)carbamate (2.60 g, 68.2%) as a white solid. MS (ES+, m/z): 302.1 [M +H]+; 1H NMR (400 MHz, CDCl3) δ 1.51 (s, 9H), 1.79 (d, J = 7.1 Hz, 3H), 2.35 (s, 3H), 5.28 (q, J = 7.0 Hz, 1H), 6.48 (s, 1H), 6.94 – 7.03 (m, 4H), 7.29 – 7.36 (m, 2H). Step 3 (4-(1-(2-Methyl-1H-imidazol-1-yl)ethyl)phenyl)carbamate (9.7 g, 32.18 mmol) was purified by preparative chiral-HPLC, Column: Venusil Chiral OD-H, 2.11*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (0.1% 2 M NH3-MeOH); RT1 (min): 8.4; RT2 (min): 11.6; Sample Solvent: MeOH (0.1% 2 M NH3-MeOH), to afford: ISOMER 1: (R)-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)carbamate (4.53 g, 46.7%) RT1 (8.47 min) as a colourless oil. MS (ES+, m/z): 302.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.46 (s, 9H), 1.69 (d, J = 7.0 Hz, 3H), 2.20 (s, 3H), 3.18 (d, J = 5.0 Hz, 2H), 6.76 (d, J = 1.4 Hz, 1H), 7.03 – 7.12 (m, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.35 – 7.45 (m, 2H), ee: 99.56%. ISOMER 2: (S)-(4-(1-(2-Methyl-1H-imidazol-1-yl)ethyl)phenyl)carbamate (3.95 g, 40.7%) RT2 (11.67 min) as a colourless oil. MS (ES+, m/z): 302.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.46 (s, 9H), 1.69 (d, J = 7.0 Hz, 3H), 2.20 (s, 3H), 5.37 (q, J = 7.0 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 7.03 – 7.12 (m, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.36 – 7.44 (m, 2H), 9.35 (s, 1H), ee: 98.7%. The absolute stereochemistry of ISOMER 2 was determined to be S by comparison with chirally pure material synthesised by an alternative procedure. Step 4 (S)-(4-(1-(2-Methyl-1H-imidazol-1-yl)ethyl)phenyl)carbamate (3.95 g, 13.11 mmol) was added to a 4 M HCl solution in EtOH (40 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to afford (S)-4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)aniline dihydrochloride (3.80 g) as a yellow solid. MS (ES+, m/z): 202.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.84 (d, J = 6.9 Hz, 3H), 2.62 (d, J = 1.5 Hz, 3H), 5.82 (d, J = 7.4 Hz, 1H), 7.35 – 7.52 (m, 4H), 7.66 (d, J = 2.1 Hz, 1H), 7.88 (q, J = 2.3 Hz, 1H). Table 1. The following compounds were made using a method analogous to the Procedure A, described above. Intermediate Structure MS (ES+, m/z) NMR I-2 188.25 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.81 (d, J = 7.1 H]+ Hz, 3H), 5.58 (q, J = 7.0 Hz, 1H), 6.52 – 6.61 (m, 2H), 7.01 – 7.16 (m, 2H), 7.63 – 7.72 (m, 1H), 7.77 (t, J = 1.8 Hz, 1H), 9.18 (t, J = 1.5 Hz, 1H), the exchangeable protons are not visible. I-3 216.05 [M + 1H NMR (300 MHz, CDCl3) δ 0.97 (t, J = 7.3 Hz, H]+ 3H), 2.09 – 2.32 (m, 2H), 2.71 (s, 3H), 4.98 (t, J = 7.7 Hz, 1H), 6.63 – 6.72 (m, 2H), 6.95 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 2.1 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), the exchangeable protons are not visible. I-4 228.05 [M + 1H NMR (300 MHz, DMSO-d6) δ 0.30 – 0.39 (q, H]+ J = 6.1 Hz, 1H), 0.49 – 0.69 (m, 3H), 0.91 – 0.96 (t, J = 7.0 Hz, 2H), 4.74 – 4.85 (d, J = 10.0 Hz, 1H), 7.04 – 7.14 (d, J = 8.1 Hz, 2H), 7.22 – 7.30 (d, J = 8.4 Hz, 2H), 7.55 – 7.61 (d, J = 2.1 Hz, 1H), 7.92 – 7.97 (d, J = 2.1 Hz, 1H), the exchangeable protons are not visible. I-5 228.05 [M + 1H NMR (300 MHz, DMSO-d6) δ 0.90 – 1.13 (m, H]+ 2H), 1.16 – 1.38 (m, 2H), 1.83 – 1.93 (d, J = 7.0 Hz, 3H), 2.28 – 2.41 (m, 1H), 5.95 – 6.07 (q, J = 6.9 Hz, 1H), 7.29 – 7.40 (d, J = 8.5 Hz, 2H), 7.42 – 7.51 (d, J = 8.5 Hz, 2H), 7.57 – 7.68 (d, J = 2.2 Hz, 1H), 7.87 – 7.94 (d, J = 2.2 Hz, 1H), the exchangeable protons are not visible. I-6 238.11 [M + 1H NMR (300 MHz, DMSO-d6) δ 2.71 (s, 3H), H]+ 6.20-6.35 (m, 1H), 6.90-7.30 (m, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.65 (d, J = 7.7 Hz, 2H), 7.75 (s, 1H).7.80 (s, 1H). Procedure B: Synthesis of (S)-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)aniline (Intermediate I-1) – chiral Procedure Step 1 Glyoxal (5.24 g, 90.27 mmol), acetaldehyde (3.98 g, 90.27 mmol) and ammonium acetate (6.96 g, 90.27 mmol) were added to a solution of (1S)-1-(4-nitrophenyl)ethan-1-amine (5.0 g, 30.09 mmol) in MeOH (50 mL). The reaction mixture was stirred at 65 °C for 48 hours, then it was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) and washed with water (25 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 15% MeOH in EtOAc, to afford 2-methyl-1-[(1S)-1-(4- nitrophenyl)ethyl]-1H-imidazole (3.5 g, 32.7%) as an orange solid. MS (ES+, m/z): 232.0 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 1.76 (d, 3H), 2.16 (d, 3H), 5.64 (d, 1H), 6.82 (s, 1H), 7.33 (d, 1H), 7.36 – 7.42 (m, 2H), 8.11 – 8.26 (m, 2H). Step 2 5% Pd-C (w/w) (138.06 mg, 1.3 mmol) was added to a solution of 2-methyl-1-((1S)-1-(4- nitrophenyl)ethyl)-1H-imidazole (3.0 g, 12.97 mmol) in MeOH (30 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen until the starting material had been consumed, then it was filtered through a pad of CELITE and the filtrate was concentrated under reduced pressure. The crude product was recrystallised from MtBE to afford (S)-4-(1-(2-methyl-1H- imidazol-1-yl)ethyl)aniline (1.5 g, 54.6%) as a yellow solid. MS (ES+, m/z): 202.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 1.71 (dd, 3H), 2.27 (d, 3H), 3.67 (s, 2H), 5.17 (qd, 1H), 6.58 (dd, 2H), 6.83 (dd, 2H), 6.90 (q, 2H). Procedure C: Synthesis of 4-((2-methyl-1H-imidazol-1-yl)methyl)aniline (Intermediate I-7)
Figure imgf000068_0001
Step 1 2-Methyl-1H-imidazole (3.04 g, 37.03 mmol) was added to a solution of 1-(bromomethyl)-4- nitrobenzene (2 g, 9.26 mmol) and K2CO3 (3.84 g, 27.77 mmol) in MeCN (5 mL) at room temperature. The reaction mixture was stirred at 80 °C for 3 hours, cooled down and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 10% MeOH in DCM, to afford 2-methyl-1-(4- nitrobenzyl)-1H-imidazole (1.7 g, 85%) as an orange solid.1H NMR (300 MHz, MeOH-d4) δ 2.29 (s, 3H), 5.33 (s, 2H), 6.90 (d, J = 1.5 Hz, 1H), 7.10 (d, J = 1.4 Hz, 1H), 7.27 – 7.38 (m, 2H), 8.17 – 8.27 (m, 2H). Step 2 10% Pd-C (w/w) (0.78 g, 0.74 mmol) was added to a solution of 2-methyl-1-(4-nitrobenzyl)-1H- imidazole (1.6 g, 7.37 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 2 hours, then it was filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure to afford 4-((2-methyl-1H-imidazol-1- yl)methyl)aniline (1.0 g, 72.5%). MS (ES+, m/z): 188.3 [M + H]+; 1H NMR (300 MHz, MeOH-d4) δ 2.29 (s, 3H), 4.97 (s, 2H), 6.65 – 6.72 (m, 2H), 6.86 – 6.96 (m, 4H), the exchangeable protons are not visible. Table 2. The following compounds were made using a method analogous to the Procedure C, described above. Intermediate Structure MS (ES+, m/z) NMR I-8 206.05 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 2.25 (s, 3H), 4.93 (s, 2H), 5.15 (s, 2H), 6.71 – 6.79 (m, 3H), 6.82 – 6.87 (m, 1H), 7.07 – 7.10 (d, J = 1.3 Hz, 1H). I-9 189.30 [M + H]+ 1H NMR (400 MHz, MeOH-d4) δ 2.34 (s, 3H), 5.07 (s, 2H), 6.83 (d, J = 1.5 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 7.01 (d, J = 1.5 Hz, 1H), 7.06 (dd, J = 2.8, 8.4 Hz, 1H), 7.96 (dd, J = 0.6, 2.8 Hz, 1H), two exchangeable protons are not seen. Procedure D: Synthesis of (S)-2-chloro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)aniline (Intermediate I-10) NCS (50 mg, 0.37 mmol) was added to a solution of (1H-imidazol-2-yl)methanol (100 mg, 0.36 mmol) and pyridine (60 mg, 0.75 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 16 hours and then it was concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 5 to 10% MeOH in DCM, to afford (S)-2-chloro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)aniline (82 mg) as a yellow solid. MS (ES+, m/z): 235.8 [M + H]+. Table 3. The following compound was made using a method analogous to the Procedure D and Procedures described above. Intermediate Structure MS (ES+, m/z) NMR I-11 254.10 [M + H]+ 1H NMR (300 MHz, DMSO-d6) δ 1.63 (d, J = 6.4 Hz, 3H), 2.38 (s, 2H), 5.48 (d, J = 6.7 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 7.42 (s, 1H), 7.63 (s, 1H), the exchangeable protons are not visible. Procedure E: Synthesis of (rac)-(R)-2-(4-aminophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethan-1-ol (Intermediate I-12)
Figure imgf000070_0001
Step 1 Ethyl 2-(4-nitrophenyl)acetate (10 g, 47.80 mmol) was added to a solution of NBS (9.36 g, 52.58 mmol) and AIBN (0.235 g, 1.43 mmol) in MeCN (120 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 75 °C for 15 hours, then it was cooled down and concentrated under reduced pressure. The residue was diluted with water (150 mL) and extracted with DCM (150 mL x 3). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 9% EtOAc in petroleum ether, to afford ethyl 2-bromo-2-(4-nitrophenyl)acetate (7.21 g, 52.4%) as a yellow liquid. MS (ES+, m/z): 286.0 [M - H]-; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (t, J = 7.1 Hz, 3H), 4.20 (q, 7.1 Hz, 2H), 6.15 (s, 1H), 7.80 – 7.87 (m, 2H), 8.25 – 8.31 (m, 2H). Step 2 DIEA (10.9 mL, 62.48 mmol) was added to a solution of ethyl 2-bromo-2-(4-nitrophenyl)acetate (6.0 g, 20.83 mmol) and 2-methyl-1H-imidazole (6.84 g, 83.31 mmol) in MeCN (70 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 80 °C for 15 hours, then concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 70% EtOAc in petroleum ether, to afford ethyl 2-(2-methyl-1H-imidazol-1-yl)-2-(4- nitrophenyl)acetate (4.43 g, 73.5%) as a red oil. MS (ES+, m/z): 290.1 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, J = 7.1 Hz, 3H), 2.30 (s, 3H), 4.27 (q, J = 7.1 Hz, 2H), 6.60 (s, 1H), 6.80 (d, J = 1.5 Hz, 1H), 7.02 (d, J = 1.5 Hz, 1H), 7.58 – 7.68 (m, 2H), 8.25 – 8.32 (m, 2H). Step 3 Ethyl 2-(2-methyl-1H-imidazol-1-yl)-2-(4-nitrophenyl)acetate (2.2 g, 7.60 mmol) was added to a suspension of iron (2.1 g, 38.02 mmol) and NH4Cl (10 mL) in EtOH (20 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 60 °C for 3 hours, then cooled down and filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure and the crude product was purified by flash C18-flash chromatography, eluting with a mixture of 0 to 5% MeCN in water (0.1% NH4HCO3), to afford ethyl 2-(4-aminophenyl)-2-(2-methyl-1H-imidazol-yl) acetate (1.2 g, 63.9%) as a red oil. MS (ES+, m/z): 260.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.18 (t, J = 7.1 Hz, 3H), 2.25 (s, 3H), 4.20 (q, J = 7.1 Hz, 2H), 5.35 (s, 2H), 5.98 (s, 1H), 6.56 (d, 2H), 6.65 (d, J = 1.4 Hz, 1H), 6.69 (d, J = 1.4 Hz, 1H), 7.00 (d, 2H). Step 4 Methyl-2-(4-aminophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetate (500 mg, 2.04 mmol) was added to a solution of LiAlH4 (93 mg, 2.45 mmol) in THF (10 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 0 °C for 2 hours. The reaction was quenched by successive addition of water (0.08 mL), NaOH (15%, 0.088 mL) and water (0.264 mL). The reaction mixture was stirred for 5 minutes and filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure and the crude product was purified by flash C18-flash chromatography, eluting with a mixture of 0 to 8% MeCN in water, to afford 2-(4-aminophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethan-1-ol (345 mg, 78%) as a yellow solid. MS (ES+, m/z): 218.0 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 2.22 (s, 3H), 3.80 – 3.99 (m, 2H), 4.98 – 5.14 (m, 4H), 6.46 – 6.54 (m, 2H), 6.71 (d, J = 1.4 Hz, 1H), 6.86 – 6.92 (m, 2H), 7.20 (d, J = 1.4 Hz, 1H). Procedure F: Synthesis of (rac)-(R)-(1-(1-(4-aminophenyl)ethyl)-1H-imidazol-2-yl)methanol (Intermediate I-13)
Figure imgf000072_0001
Step 1: SOCl2 (0.921 mL, 12.62 mmol) was added to a solution of tert-butyl (4-(1- hydroxyethyl)phenyl)carbamate (2.140 g, 9.02 mmol) and 2-(((tert-butyldimethylsilyl)oxy)methyl)- 1H-imidazole (3.83 g, 18.03 mmol) in DCM (20 mL) at 0 °C under one atmosphere of nitrogen. The reaction mixture was stirred at 40 °C for 3 hours, then it was cooled down and poured into water (50 mL). The crude mixture was extracted with DCM (20 mL x 3) and the combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 5% MeOH in DCM, to afford tert-butyl (4-(1-(2-(((tert-butyldimethylsilyl)oxy)methyl)-1H-imidazol-1-yl)ethyl)phenyl)carbamate (0.447 g) as a yellow oil. MS (ES+, m/z): 432.1 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.00 (d, J = 1.6 Hz, 6H), 0.84 (s, 9H), 1.46 (s, 9H), 1.72 (d, J = 7.1 Hz, 3H), 4.54 – 4.76 (m, 2H), 5.57 (q, J = 7.0 Hz, 1H), 6.83 (d, J = 1.3 Hz, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 1.3 Hz, 1H), 7.40 (d, J = 8.3 Hz, 2H), 9.34 (s, 1H). Step 2: A 4 M HCl solution in EtOH (5 mL) was added to tert-butyl (4-(1-(2-(((tert- butyldimethylsilyl)oxy)methyl)-1H-imidazol-1-yl)ethyl)phenyl)carbamate (430 mg, 1.00 mmol) under one atmosphere of nitrogen and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to afford (1-(1-(4-aminophenyl)ethyl)-1H- imidazol-2-yl)methanol (380 mg) as a pale yellow foam. MS (ES+, m/z): 218.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.71 (d, J = 6.9 Hz, 3H), 4.64 (d, J = 15.2 Hz, 1H), 4.76 (d, J = 15.2 Hz, 1H), 5.72 (d, J = 6.8 Hz, 1H), 7.08 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 2.1 Hz, 1H), 7.78 (d, J = 2.1 Hz, 1H), the exchangeable protons are not visible. Procedure G: Synthesis of (rac)-(R)-4-(1-(2-(fluoromethyl)-1H-imidazol-1-yl)ethyl)aniline (Intermediate I-14)
Figure imgf000073_0001
Step 1 SOCl2 (4.54 mL, 62.17 mmol) was added dropwise to a solution of 1-(4-bromophenyl)ethan-1-ol (5.0 g, 24.87 mmol) in DCM (50 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure to afford 1-bromo-4-(1- chloroethyl)benzene (5.10 g, 93%) as a colourless oil that was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ 1.85 (d, J = 6.8 Hz, 3H), 5.07 (q, J = 6.8 Hz, 1H), 7.28 – 7.36 (m, 2H), 7.46 – 7.55 (m, 2H). Step 2 Bromo-4-(1-chloroethyl)benzene (5.1 g, 23.23 mmol) was added to a suspension of 1H-imidazole-2- carbaldehyde (5.58 g, 58.08 mmol) and Cs2CO3 (15.14 g, 46.47 mmol) in DMF (40 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 60 °C for 16 hours, then it was cooled down and poured into water (200 mL). The crude mixture was extracted with EtOAc (75 mL x 3), and the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash C18-flash chromatography, eluting with a mixture of 20 to 60% MeCN in water (0.1% FA), to afford 1-(1-(4-bromophenyl)ethyl)-1H-imidazole-2-carbaldehyde (5.65 g, 87%) as a yellow oil. MS (ES+, m/z): 278.9 [M + H]+; 1H NMR (400 MHz, CDCl3) δ 1.84 (d, J = 7.1 Hz, 3H), 6.55 (q, J = 7.1 Hz, 1H), 7.07 – 7.15 (m, 2H), 7.28 (d, J = 1.0 Hz, 1H), 7.34 (d, J = 1.0 Hz, 1H), 7.45 – 7.53 (m, 2H), 9.85 (d, J = 1.0 Hz, 1H). Step 3 NaBH4 (1.49 g, 39.41 mmol) was added portionwise into a solution a 1-(1-(4-bromophenyl)ethyl)-1H- imidazole-2-carbaldehyde (5.5 g, 19.70 mmol) in ethanol (50 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour, then it was concentrated under reduced pressure. The residue was diluted with water (100 mL), extracted with EtOAc (100 mL x 2) and the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 20% EtOAc in petroleum ether, to afford (1-(1-(4-bromophenyl)ethyl)-1H-imidazol-2-yl)methanol (5.00 g, 90%) as a white solid. MS (ES+, m/z): 281.0 [M + H]+; 1H NMR (300 MHz, CDCl3) δ 1.83 (d, J = 7.1 Hz, 3H), 3.96 (s, 2H), 5.72 (q, J = 7.1 Hz, 1H), 6.89 – 7.00 (m, 2H), 7.01 – 7.11 (m, 2H), 7.42 – 7.53 (m, 2H), the exchangeable protons are not visible. Step 4 BAST (1.57 mL, 8.54 mmol) was added dropwise to a solution of (1-(1-(4-bromophenyl)ethyl)-1H- imidazol-2-yl)methanol (2.0 g, 7.11 mmol) in DCM (20 mL) at 0 °C under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 2 hours, then it was quenched with saturated NaHCO3 (20 mL) and extracted with DCM (25 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a mixture of 5 to 7% MeOH in DCM, to afford 1-(1-(4-bromophenyl)ethyl)-2- (fluoromethyl)-1H-imidazole (0.87 g, 43.2%) as a yellow oil. MS (ES+, m/z): 283.0 [M + H]+; 1H NMR (400 MHz, CDCl3) δ 1.86 (d, J = 7.1 Hz, 3H), 3.42 – 3.45 (m, 1H), 3.54 (s, 2H), 5.22 – 5.39 (m, 1H), 5.47 – 5.64 (m, 1H), 7.01 – 7.06 (m, 2H), 7.47 – 7.52 (m, 2H). Step 5 BrettPhos-Pd-G3 (311 mg, 0.34 mmol) was added to a suspension of 1-(1-(4-bromophenyl)ethyl)-2- (fluoromethyl)-1H-imidazole (970 mg, 3.43 mmol), tert-butyl carbamate (602 mg, 5.14 mmol) and Cs2CO3 (2.2 g, 6.85 mmol) in 1,4-dioxane (15 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 100 °C for 3 hours, then it was cooled down and poured into water (100 mL). The residue was extracted with EtOAc (50 mL x 3) and the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with a mixture of 20 to 90% EtOAc in petroleum ether, to afford tert-butyl (4-(1-(2- (fluoromethyl)-1H-imidazol-1-yl)ethyl)phenyl)carbamate (408 mg, 37.3%) as a white solid. MS (ES+, m/z): 320.1 [M + H]+; 1H NMR (300 MHz, CDCl3) δ 1.53 (s, 9H), 1.85 (d, J = 7.0 Hz, 3H), 5.24 – 5.63 (m, 3H), 6.58 (s, 1H), 7.05 – 7.08 (m, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.10 – 7.13 (m, 2H), 7.36 (d, J = 8.5 Hz, 2H). Step 6 A 4 M HCl solution in EtOH (5 mL) was added to tert-butyl (4-(1-(2-(fluoromethyl)-1H-imidazol-1- yl)ethyl)phenyl)carbamate (400 mg, 1.25 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure to afford 4-(1-(2- (fluoromethyl)-1H-imidazol-1-yl)ethyl)aniline (307 mg, 84%) as a white solid. MS (ES+, m/z): 220.1 [M + H]+; 1H NMR (300 MHz, MeOH-d4) δ 2.02 (d, J = 7.0 Hz, 3H), 5.67 – 5.83 (m, 1H), 5.83 – 6.02 (m, 1H), 6.08 (q, J = 6.9 Hz, 1H), 7.46 – 7.55 (m, 2H), 7.59 – 7.70 (m, 2H), 7.77 (d, J = 2.1 Hz, 1H), 7.97 (d, J = 2.1 Hz, 1H), the exchangeable protons are not visible. Procedure H: Synthesis of 4-(1-(2-methyl-1H-imidazol-1-yl)cyclopropyl)aniline (Intermediate I-15)
Figure imgf000075_0001
Step 1 1-(4-Bromophenyl)cyclopropan-1-amine (500 mg, 2.36 mmol, 1.0 equiv) was added to a stirred mixture of acetaldehyde (104 mg, 2.36 mmol, 1.0 equiv), oxalaldehyde (342 mg, 2.36 mmol, 1.0 equiv), acetic acid (142 mg, 2.36 mmol, 1.0 equiv) and ammonium acetate (750 mg, 9.73 mmol, 4.1 equiv) in CHCl3 (2 mL). The reaction mixture was stirred at 100 ℃ for 1 hour, then it was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluting with a mixture of 0 to 5% MeOH in DCM, to afford 1-(1-(4- bromophenyl)cyclopropyl)-2-methyl-1H-imidazole (600 mg, 92%) as a black solid. MS (ES+, m/z): 276.9 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.54 – 1.59 (m, 2H), 1.61 – 1.64 (m, 2H), 2.17 (s, 3H), 6.61 – 6.67 (m, 2H), 6.82 (d, J = 1.4 Hz, 1H), 7.20 (d, J = 1.4 Hz, 1H), 7.44 – 7.52 (m, 2H). Step 2 tert-Butyl (4-(1-(2-methyl-1H-imidazol-1-yl)cyclopropyl)phenyl)carbamate was prepared using the Procedure G, step 5 described above. MS (ES+, m/z): 314.1 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.42 – 1.47 (s, 9H), 1.51 – 1.63 (m, 4H), 2.16 – 2.18 (s, 3H), 6.60 – 6.66 (d, J = 8.7 Hz, 2H), 6.77 – 6.80 (d, J = 1.4 Hz, 1H), 7.18 – 7.21 (d, J = 1.4 Hz, 1H), 7.32 – 7.38 (d, J = 8.6 Hz, 2H), 9.28 – 9.34 (s, 1H). Step 3 4-(1-(2-Methyl-1H-imidazol-1-yl)cyclopropyl)aniline was prepared using the Procedure G, step 6 described above and used directly without further purification. MS (ES+, m/z): 213.9 [M + H]+. Procedure I: Synthesis of (rac)-4-(1-(2-(difluoromethyl)-1H-imidazol-1-yl)ethyl)aniline (Intermediate I-16)
Figure imgf000076_0001
Step 1 1-(1-Bromoethyl)-4-nitrobenzene (2.15 g, 9.3 mmol) and Cs2CO3 (4.14 g, 12.7 mmol) were added to a solution 2-(difluoromethyl)-1H-imidazole (1 g, 8.47 mmol) in DMF (20 mL). The reaction mixture was stirred at 50 oC for 18 hours, then diluted water (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with a 2:1 mixture of hexane and EtOAc, to afford 4-(1-(2-(difluoro methyl)-1H-imidazol-1-yl)ethyl)aniline (1.2 g, 53%). MS (ES+, m/z): 268.0 [M+H]+. Step 2 5% Pd-C (w/w) (120 mg, 0.45 mmol) was added to a solution of 4-(1-(2-(difluoromethyl)-1H-imidazol- 1-yl)ethyl)aniline (1.2 g, 4.49 mmol) in MeOH (20 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen until spectral data of an aliquot revealed consumption of the starting material, then it was filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure and the crude product was recrystallised from EtOH to afford 4-(1-(2-(difluoro methyl)-1H-imidazol-1-yl)ethyl)aniline (1.0 g, 95.6%) as a yellow solid. MS (ES+, m/z): 238.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.71 (dd, 3H), 5.12 (s, 2H), 5.56 (q, 1H), 6.46 – 7.55 (m, 7H). Procedure J: Synthesis of (rac)-5-[1-(2-methyl-1H-imidazol-1-yl)ethyl]pyrazin-2-amine (Intermediate I-17)
Figure imgf000077_0001
Step 1 A 3 M solution of methylmagnesium chloride in THF (6.3 g, 84.18 mmol) was added dropwise to a solution of 5-chloropyrazine-2-carbaldehyde (10.0 g, 70.15 mmol) in THF (250 mL) at -60oC. The reaction mixture was warmed to room temperature, stirred for 1.5 hours and quenched with saturated NH4Cl solution (50 mL). The organic layer was washed with brine (100 mL x 2), dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford 1-(5-chloropyrazin-2-yl)ethan- 1-ol (10.1 g, 90%) as a brown oil. MS (ES+, m/z): 159.0 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 1.58 (d, 3H), 2.92 – 3.13 (m, 1H), 4.93 – 5.07 (m, 1H), 8.49 (dd, 1H), 8.54 (d, 1H). Step 2 Carbon tetrabromide (32.71 g, 98.62 mmol) was added portionwise to a solution of (rac)-1-(5- chloropyrazin-2-yl)ethan-1-ol (9.2 g, 58.01 mmol) and triphenylphosphine (25.87 g, 98.62 mmol) in DCM (200 mL) at 0 °C. The reaction mixture stirred at room temperature for 2 hours and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with a mixture of 50% EtOAc in hexane to afford 2-(1-bromoethyl)-5-chloropyrazine (6.2 g, 48.8%) as a yellow oil. MS (ES+, m/z): 221.0 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 2.11 (d, 3H), 5.25 (q, 1H), 8.51 (d, 1H), 8.57 (d, 1H). Step 3 A mixture of 2-(1-bromoethyl)-5-chloropyrazine (2.7 g, 12.19 mmol), 2-methyl-1H-imidazole (1.1 g, 13.41 mmol) and Cs2CO3 (19.86 g, 60.96 mmol, 4.88 mL, 5.0 eq) in MeCN (250 mL) was stirred at 80 oC for 16 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was partitioned between EtOAc (300 mL) and water (100 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and evaporated under the reduced pressure to afford (rac)-2-chloro-5-[1-(2-methyl-1H-imidazol-1-yl)ethyl]pyrazine (1.2 g, 44.4%) as a light yellow solid.1H NMR (300 MHz, CDCl3) δ 1.90 (d, 3H), 2.39 (s, 3H), 5.45 (q, 1H), 7.04 (dd, 2H), 7.99 (dd, 1H), 8.58 (d, 1H). Step 4 A degassed suspension of 2-chloro-5-[1-(2-methyl-1H-imidazol-1-yl)ethyl]pyrazine (2.3 g, 10.33 mmol), tert-butyl carbamate (1.45 g, 12.39 mmol), Cs2CO3 (16.82 g, 51.64 mmol), XantPhos (597.58 mg, 1.03 mmol) and Pd(OAc)2 (116 mg, 516 µmol) in dry dioxane (50 mL) was stirred at 100 oC overnight. After cooling down, the reaction mixture was evaporated under reduced pressure. The residue was partitioned between EtOAc (100 mL) and water (100 mL), the organic layer was washed with water and the combined aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 5 to 30% MeOH in CHCl3 / MeCN to afford (rac)-tert-butyl N-5-[1-(2-methyl-1H-imidazol-1-yl)ethyl]pyrazin-2- ylcarbamate (1.6 g, 48%). MS (ES+, m/z): 304.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 3.81 (d, 9H), 4.08 (d, 3H), 4.63 (d, 3H), 7.89 (d, 1H), 9.08 (s, 1H), 9.46 – 9.58 (m, 1H), 10.50 (s, 1H), 11.32 (s, 1H), 12.55 (s, 1H). Step 5 Acetyl chloride (4.14 g, 52.76 mmol, 3.76 mL, 10.0 eq) was added dropwise to a solution of MeOH (2.03 g, 63.31 mmol, 2.54 mL, 12.0 eq) in dioxane (100 mL) at 15 oC and the resulting mixture was stirred for 1 hour. tert-Butyl N-5-[1-(2-methyl-1H-imidazol-1-yl)ethyl]pyrazin-2-ylcarbamate (1.6 g, 5.27 mmol) in dioxane (20 mL) was added and the reaction mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with diethyl ether (50 mL x 2) and dried to afford 5-[1-(2-methyl-1H-imidazol-1-yl)ethyl]pyrazin-2-amine dihydrochloride (1.3 g, 89%). 1H NMR (300 MHz, D2O) δ 1.80 (d, 3H), 2.58 (s, 3H), 5.66 (q, 1H), 7.26 (d, 1H), 7.38 (d, 1H), 7.90 (dd, 1H), 8.20 (d, 1H). Procedure K: Synthesis of (rac)-(R)-6-(1-(4-methyl-1H-imidazol-5-yl)ethyl)pyridin-3-amine (Intermediate I-18)
Figure imgf000079_0001
Step 1 n-Butyllithium solution in hexanes (13.62 mL, 34.05 mmol) was added dropwise to a solution of 2- bromo-5-chloropyridine (6.55 g, 34.05 mmol) in DCM (100 mL) at -78 °C under one atmosphere of nitrogen and the resulting mixture was stirred at -78 °C for 30 minutes.5-Methyl-1-trityl-1H- imidazole-4-carbaldehyde (10 g, 28.37 mmol) was added and stirring continued at -78 °C for 1 hour. The reaction mixture was warmed to room temperature over 3 hours, poured into saturated NH4Cl (200 mL) and extracted with DCM (125 mL x 3). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 20 to 80% EtOAc in petroleum ether, to afford (5- chloropyridin-2-yl)(5-methyl-1-trityl-1H-imidazol-4-yl)methanol (5.80 g, 43.9%) as a yellow foam. MS (ES+, m/z): 465.9 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.42 (s, 3H), 5.63 (d, J = 4.7 Hz, 1H), 5.77 (s, 1H), 6.97 (s, 1H), 7.06 (dd, J = 2.1, 7.7 Hz, 6H), 7.34 – 7.47 (m, 9H), 7.69 (d, J = 8.5 Hz, 1H), 7.90 (dd, J = 2.5, 8.5 Hz, 1H), 8.48 (d, J = 2.5 Hz, 1H). Step 2 PCC (2.96 g, 13.73 mmol) was added to a suspension of (5-chloropyridin-2-yl)(5-methyl-1-trityl-1H- imidazol-4-yl)methanol (3.2 g, 6.87 mmol), sodium acetate (2.99 g, 36.40 mmol) and silica gel (2.96 g) in DCM (35 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash silica chromatography, eluting with a mixture of 20 to 50% EtOAc in petroleum ether, to afford (5-chloropyridin-2-yl)(5-methyl-1-trityl-1H-imidazol-4- yl)methanone (1.6 g, 50.2%) as a pale yellow foam. MS (ES+, m/z): 463.9 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.81 (s, 3H), 7.09 – 7.18 (m, 6H), 7.26 (s, 1H), 7.44 (t, J = 7.4 Hz, 9H), 7.97 (d, J = 8.4 Hz, 1H), 8.09 (dd, J = 2.4, 8.4 Hz, 1H), 8.73 (d, J = 2.4 Hz, 1H). Step 3 A 1 M solution of KtBuO in THF (8.08 mL, 8.08 mmol) was added to a solution of methyltriphenylphosphonium bromide (2.89 g, 8.08 mmol) in THF (25 mL) at 0 °C under one atmosphere of nitrogen. The reaction mixture was stirred at 0 °C for 45 minutes, then a solution of (5-chloropyridin-2-yl)(5-methyl-1-trityl-1H-imidazol-4-yl)methanone (2.5 g, 5.39 mmol) in THF (25 mL) was added and the mixture was stirred at 0 °C for one hour and at room temperature overnight. The reaction mixture was quenched with saturated NH4Cl (100 mL), extracted with EtOAc (75 mL x 3) and the combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 10 to 40% EtOAc in petroleum ether, to afford 5-chloro-2-(1-(5-methyl-1-trityl-1H-imidazol-4- yl)vinyl)pyridine (2.400 g, 96%) as a pale yellow solid. MS (ES+, m/z): 462.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.29 (s, 3H), 5.41 (d, J = 2.3 Hz, 1H), 6.16 (d, J = 2.3 Hz, 1H), 7.12 – 7.16 (m, 7H), 7.37 – 7.50 (m, 10H), 7.87 (dd, J = 2.6, 8.5 Hz, 1H), 8.61 (d, J = 2.5 Hz, 1H). Step 4 tert-Butyl (6-(1-(5-methyl-1-trityl-1H-imidazol-4-yl)vinyl)pyridin-3-yl)carbamate was prepared using the Procedure G, step 5 described above. MS (ES+, m/z): 543.0 [M + H]+; 1H NMR (300 MHz, DMSO- d6) δ 1.22 (s, 3H), 1.48 (s, 9H), 5.30 (d, J = 2.6 Hz, 1H), 6.02 (d, J = 2.6 Hz, 1H), 7.15 (dd, J = 1.7, 3.4 Hz, 5H), 7.41 – 7.45 (m, 6H), 7.59 – 7.65 (m, 6H), 7.82 (d, J = 8.2 Hz, 1H), 8.57 (d, J = 2.6 Hz, 1H), 9.60 (s, 1H). Step 5 10% Pd-C (w/w) (0.353 g, 0.33 mmol) was added to a solution of tert-butyl (6-(1-(5-methyl-1-trityl- 1H-imidazol-4-yl)vinyl)pyridin-3-yl)carbamate (1.8 g, 3.32 mmol) in MeOH (30 mL) and THF (3 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 3 hours, then it was filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure and the crude product was purified by flash silica chromatography, eluting with a mixture of 5 to 80% MeCN in water (0.1% NH4HCO3), to afford tert-butyl-(6-(1-(4-methyl-1-trityl-1H-imidazol- 5-yl)ethyl)pyridin-3-yl)carbamate (0.83 g, 45.7%) as a white solid. MS (ES+, m/z): 545.2 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (s, 3H), 1.48 (s, 9H), 1.52 (d, J = 7.1 Hz, 3H), 4.06 (q, J = 7.1 Hz, 1H), 7.03 – 7.08 (m, 8H), 7.36 – 7.42 (m, 9H), 7.75 (d, J = 8.2 Hz, 1H), 8.44 (d, J = 2.6 Hz, 1H), 9.41 (s, 1H). Step 6 6-(1-(4-Methyl-1H-imidazol-5-yl)ethyl)pyridin-3-amine was prepared using the Procedure G, step 6 described above. MS (ES+, m/z): 203.1 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.54 (d, J = 7.2 Hz, 3H), 2.16 (s, 3H), 4.25 (q, J = 7.2 Hz, 1H), 5.26 (s, 2H), 6.89 (dd, J = 2.7, 8.3 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 2.7 Hz, 1H), 8.76 (s, 1H), one exchangeable proton is not visible. Procedure L: Synthesis of (rac)-4-(1-(4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5- yl)ethyl)aniline (Intermediate I-19)
Figure imgf000081_0001
Step 1 Sodium nitrite (19.88 g, 288.14 mmol) in water (250.0 mL) was added dropwise to a solution of methyl 3-oxopentanoate (25 g, 192.10 mmol) in AcOH (250 mL) at -15 °C. The reaction mixture was stirred at -15 °C for 4 hours, then it was warmed to 0 °C and formaldehyde (20.19 g, 672.34 mmol) and 12 M HCl (108 mL) were successively added, maintaining the reaction mixture at 0 °C. After the addition was complete, the mixture was stirred at -15 °C for 15 hours. Then, 28% aqueous ammonia solution (124.8 mL) was added and the resulting mixture was stirred at 70 °C for 1.5 hours. The reaction mixture was cooled down, quenched with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford methyl 4-ethyl-1H-imidazole-5-carboxylate (7.34 g) as a yellow oil. MS (ES+, m/z): 155.0 [M + H]+. Step 2 DIEA (28.7 mL, 164.11 mmol) was added to a solution of methyl 4-ethyl-1H-imidazole-5-carboxylate (12.65 g, 82.05 mmol) and (2-(chloromethoxy) ethyl) trimethylsilane (16.42 g, 98.46 mmol) in DCM (80 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 4 hours, then it was quenched with water (200 mL) and extracted with DCM (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 80% EtOAc in petroleum ether, to afford methyl 4-ethyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H- imidazole-5-carboxylate (9.82 g) as a yellow oil. MS (ES+, m/z): 285.0 [M + H]+; 1H NMR (300 MHz, MeOH-d4) δ 0.01 (s, 9H), 0.85 – 0.98 (m, 2H), 1.23 – 1.26 (m, 3H), 3.05 (q, J = 7.5 Hz, 2H), 3.50 – 3.63 (m, 2H), 3.87 (s, 3H), 5.41 (s, 2H), 7.79 (s, 1H). Step 3 Methyl 4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (9.82 g, 34.53 mmol) was added to a solution of NaOH (6.90 g, 172.63 mmol) in water (25 mL) and MeOH (75 mL). The reaction mixture was stirred at room temperature for 4 hours, then it was diluted with water (100 mL), acidified with 2 M HCl and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford 4-ethyl-1-((2-( trimethylsilyl) ethoxy)methyl)-1H-imidazole-5-carboxylic acid (9.50 g) as a yellow solid. MS (ES+, m/z): 271.1 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 0.03 (s, 9H), 0.76 – 0.91 (m, 2H), 1.13 (t, J = 7.4 Hz, 3H), 2.72 – 2.96 (m, 2H), 3.40 – 3.53 (m, 2H), 5.35 (s, 1H), 7.77 (s, 1H), one exchangeable proton is not visible. Step 4 N,O-dimethylhydroxylamine hydrochloride (7.54 g, 77.29 mmol) was added portionwise to a solution of HATU (14.69 g, 38.65 mmol), DIEA (13.62 g, 105.40 mmol) and 4-ethyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-imidazole-5-carboxylic acid (9.5 g, 35.13 mmol) in DMF (100 mL) at room temperature under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 15 hours, then it was quenched with water (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography, eluting with a mixture of 5 to 30% MeCN in water (0.1% NH4HCO3), to afford 4-ethyl-N-methoxy-N-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxamide (8.45 g, 77%) as a yellow solid. MS (ES+, m/z): 314.1 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 0.03 (s, 9H), 0.74 – 0.91 (m, 2H), 1.12 (td, J = 1.1, 7.5 Hz, 4H), 2.80 (q, J = 7.5 Hz, 2H), 3.35 (s, 3H), 3.42 – 3.54 (m, 2H), 3.72 (s, 3H), 5.34 (s, 2H), 7.76 (s, 1H). Step 5 (4-Chlorophenyl) magnesium bromide (24.56 mL, 24.56 mmol) was added dropwise to a solution of 4-ethyl-N-methoxy-N-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxamide (7.0 g, 22.33 mmol) in THF (70 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 2 hours, then it was quenched with water (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 30% EtOAc in petroleum ether, to afford (4-chlorophenyl) (4-ethyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-imidazol-5-yl) methanone (4.17 g, 51.2%) as a yellow solid. MS (ES+, m/z): 365.1 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 0.02 (s, 9H), 0.82 – 0.93 (m, 2H), 1.19 (t, J = 7.3 Hz, 3H), 3.00 (q, J = 7.4 Hz, 2H), 3.46 – 3.58 (m, 2H), 5.44 (s, 2H), 7.55 – 7.61 (m, 2H), 7.92 (s, 1H), 8.18 – 8.28 (m, 2H). Step 6 Potassium 2-methylpropan-2-olate (13.48 mL, 13.48 mmol) was added dropwise to a solution of methyltriphenylphosphonium bromide (4.82 g, 13.48 mmol) in THF (50 mL) at 0 °C under one atmosphere of nitrogen. After the addition was complete, (4-chlorophenyl)(4-ethyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methanone (4.1g, 11.23 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 30% EtOAc in petroleum ether, to afford 5-(1-(4-chlorophenyl) vinyl)-4-ethyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-imidazole (3.70 g, 91 %) as a yellow solid. MS (ES+, m/z): 363.10 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 0.02 (s, 9H), 0.80 – 0.91 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H), 2.43 – 2.50 (m, 2H), 3.49 (t, J = 8.0 Hz, 2H), 5.32 (s, 2H), 5.36 (d, J = 1.7 Hz, 1H), 5.50 (d, J = 1.7 Hz, 1H), 7.30 – 7.36 (m, 2H), 7.36 – 7.41 (m, 2H), 7.74 (s, 1H). Step 7 Brettphos Pd G3 (0.89 g, 0.99 mmol) was added to a suspension of 5-(1-(4-chlorophenyl)vinyl)-4- ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (3.6 g, 9.92 mmol), Cs2CO3 (6.46 g, 19.84 mmol) and tert-butyl carbamate (1.39 g, 11.90 mmol) in 1,4-dioxane (50 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 90 °C for 3 hours, then it was was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3 The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 50% EtOAc in petroleum ether, to afford tert- butyl (4-(1-(4-ethyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-imidazol-5-yl) vinyl) phenyl) carbamate (3.50 g, 80%) as an orange oil. MS (ES+, m/z): 444.30 [M + H]+; 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 0.90 – 0.98 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H), 1.54 (s, 9H), 2.51 (q, J = 7.5 Hz, 2H), 3.47 – 3.59 (m, 2H), 5.25 (s, 2H), 5.46 (q, J = 1.7 Hz, 2H), 6.55 (s, 1H), 7.30 – 7.34 (m, 3H), 7.56 (s, 1H), one exchangeable proton is not visible. Step 8 10% Pd-C (w/w) (1.2 g, 0.11 mmol) was added to a solution of tert-butyl (4-(1-(4-ethyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)vinyl)phenyl)carbamate (5 g, 0.11 mmol) in MeOH (50 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 3 hours, then it was filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure to afford tert-butyl (4-(1-(4-ethyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H- imidazol-5-yl) ethyl) phenyl) carbamate (3.200 g, 63.71 %) as a yellow oil. MS (ES+, m/z): 446.15 [M + H]+; δ 0.09 (s, 9H), 0.81 – 0.96 (m, 2H), 1.03 (t, J = 7.5 Hz, 3H), 1.52 (d, J = 2.0 Hz, 9H), 1.66 (d, J = 7.2 Hz, 3H), 2.58 (q, J = 7.5 Hz, 2H), 3.42 – 3.62 (m, 2H), 4.10 (dq, J = 28.1, 7.1 Hz, 1H), 5.18 (s, 2H), 6.46 (d, J = 22.4 Hz, 1H), 7.28 (s, 4H), 7.52 (s, 1H). Step 9 A solution of tert-butyl (4-(1-(4-ethyl-1-((2-(trimethylsilyl) ethoxy) methyl)-1H-imidazol-5-yl) ethyl) phenyl) carbamate (1 g, 2.24 mmol) in 4 M HCl in EtOH (10 mL, 2.24 mmol) were stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to afford (rac)-4-(1-(4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethyl)aniline (0.750 g, 97%) as a green oil. MS (ES+, m/z): 346.15 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ -0.12 – 0.05 (s, 9H), 0.71 – 0.92 (m, 2H), 1.50 – 1.73 (d, J = 7.1 Hz, 3H), 1.51 – 1.63 (d, J = 7.2 Hz, 3H), 3.37 – 3.47 (t, J = 7.0 Hz, 2H), 3.52 – 3.63 (t, J = 8.1 Hz, 2H) ,4.08 – 4.32 (s, 1H), 4.38 – 4.55 (d, J = 7.3 Hz, 2H), 5.38 – 5.61 (d, J = 15.8 Hz, 2H), 7.27 – 7.44 (d, J = 8.2 Hz, 2H), 7.44 – 7.61 (d, J = 8.3 Hz, 2H),8.79 – 9.08 (s, 1H). Procedure M: Synthesis of the mixture of rel-(R)-4-(1-(4-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethyl)aniline and rel-(R)-4-(1-(5-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)aniline (Intermediate I-20)
Step 1 5-Bromo-4-methyl-1H-imidazole (8.6 g, 53.42 mmol) was added to a suspension of NaH (1.41 g, 58.76 mmol) in THF (100 mL) at 0 °C and the reaction mixture was stirred for 30 minutes. (2- (Chloromethoxy)ethyl)trimethylsilane (8.91 g, 53.42 mmol) was added and the mixture was stirred at room temperature 3 hours, then it was concentrated under reduced pressure and the residue was diluted with EtOAc (200 mL) and washed with water (100 mL x 3) and brine (100 mL x 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 10% MeOH in DCM, to afford a mixture of 5-bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole and 4- bromo-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (10.8 g, 69.4%) as a yellow oil. MS (ES+, m/z): 290.9 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ -0.04 (s, 9H), 0.76 – 0.93 (m, 2H), 2.11 (d, J = 34.5 Hz, 3H), 3.46 (dt, J = 8.0, 11.5 Hz, 2H), 5.28 (d, J = 20.2 Hz, 2H), 7.84 (d, J = 61.5 Hz, 1H). Step 2 5-Bromo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (4 g, 13.73 mmol) was added to a solution of tert-butyl (Z)-(4-(1-(2-tosylhydrazineylidene)ethyl)phenyl)carbamate (5.54 g, 13.73 mmol), SPhos (0.56 g, 1.37 mmol), Pd(OAc)2 (0.15 g, 0.69 mmol) and LiOtBu (2.41 g, 30.21 mmol) in CPME (100 mL, 13.73 mmol) under one atmosphere of nitrogen. The reaction mixture was stirred at 100 oC for 4 hours, then it was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL) and washed with water (100 mL x 3) and brine (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 80% EtOAc in petroleum ether, to afford a mixture of tert-butyl (4-(1-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-5-yl)vinyl)phenyl)carbamate and tert-butyl (4-(1-(5-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)vinyl)phenyl)carbamate (3.0 g, 50.8%) as a yellow oil. MS (ES+, m/z): 430.15 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ -0.03 (s, 9H), 0.80 – 0.88 (m, 2H), 1.48 (s, 9H), 1.99 (s, 3H), 3.44 – 3.52 (m, 2H), 5.27 (d, J = 2.1 Hz, 1H), 5.28 (s, 2H), 5.35 (d, J = 2.1 Hz, 1H), 7.08 – 7.15 (m, 2H), 7.15 – 7.25 (m, 2H), 7.73 (s, 1H). Step 3 tert-Butyl (4-(1-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5- yl)vinyl)phenyl)carbamate (3 g, 6.98 mmol) was added to a suspension of 10% Pd-C (w/w) (0.74 g, 6.98 mmol) in MeOH (30 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 16 hours, then it was filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 10% MeOH in DCM, to afford a mixture of tert-butyl (4-(1-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethyl)phenyl)carbamate and tert-butyl (4-(1-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4- yl)vinyl)phenyl)carbamate (1.7 g, 56.4%) as a yellow oil. MS (ES+, m/z): 432.1 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ -0.06 (s, 9H), 0.76 - 0.82 (m, 2H), 1.46 (s, 9H), 1.54 (d, J = 7.3 Hz, 3H), 2.06 (s, 3H), 3.31 (dd, J = 7.4, 9.0 Hz, 2H), 3.96 (q, J = 7.0 Hz, 1H), 5.76 (s, 2H), 7.01 - 7.08 (m, 2H), 7.26 - 7.32 (m, 2H), 7.52 (s, 1H), 9.16 (s, 1H). Step 4 A mixture of tert-butyl (4-(1-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5- yl)ethyl)phenyl)carbamate and tert-butyl (4-(1-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-4-yl)vinyl)phenyl)carbamate (1.7 g, 3.94 mmol) was added to a 4 M HCl solution in EtOH (20 mL, 658 mmol). The resulting solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give a mixture of 4-(1-(4-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethyl)aniline and 4-(1-(5-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)vinyl)aniline (1.5 g) as a pale yellow solid. The above mixture was purified by preparative chiral HPLC, Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; Mobile Phase A: Hexane (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH, to give three fractions: a mixture of ISOMER 1&2, ISOMER 3 and ISOMER 4. The mixture of ISOMER 1&2 was re-purified by preparative chiral HPLC, Column: CHIRALPAK IG, 2*25 cm, 5μm; Mobile Phase A: Hexane (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH), to afford ISOMER 1 and ISOMER 2. Chiral analysis and biological testing on the final compounds derived from pure isomers 1-4 were allowed the determination of ISOMER 1 and 4 as regiosomeric precursors of the distomers and ISOMER 2 and 3 as regiosomeric precursors of the eutomers. The ISOMERS 2 and 3 (with the same stereochemistry at the chiral centre) were combined to afford a mixture of rel-(R)-4-(1-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethyl)aniline and rel-(R)-4-(1-(5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)aniline (600 mg). MS (ES+, m/z): 332.10 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ -0.05 (s, 9H), 0.82–0.91 (m, 2H), 1.67 (d, J = 7.3 Hz, 3H), 2.29 (s, 3H), 3.39–3.49 (m, 2H), 4.50–4.60 (m, 1H), 5.50 (s, 2H), 5.50 (s, 2H), 7.32–7.36 (m, 2H), 7.45–7.52 (m, 2H), 9.26 (s, 1H). Table 4. The following compounds were made using a method analogous to the Procedure M, described above. Intermediate Structure MS (ES+, m/z) NMR I-21 219.06 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.60 H]+ (d, J = 7.1 Hz, 3H), 2.30 (s, 3H), 4.56 (q, J = 6.8 Hz, 1H), 7.33 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 8.98 (s, 1H). I-22 318.05 [M + 1H NMR (300 MHz, DMSO-d6) δ -0.04 H]+ (s, 9H), 0.67 - 0.75 (m, 2H), 1.55 (d, J = 7.1 Hz, 3H), 3.41 – 3.48 (m, 2H), 4.32 – 4.37 (m, 1H), 5.52 (s, 2H), 7.08 (d, 2H), 7.19 (d, 2H), 7.81 (s, 1H), 9.25 (s, 1H). I-23 364.20 [M + 1H NMR (400 MHz, MeOH-d4) δ 0.04 H]+ (s, 9H), 0.93 – 0.99 (m, 2H), 1.11 (t, J = 7.5 Hz, 3H), 1.76 (d, J = 7.4 Hz, 3H), 2.78 – 2.85 (m, 2H), 3.60 – 3.71 (m, 2H), 4.72 (q, J = 7.2 Hz, 1H), 5.58 (s, 2H), 7.25 (dd, J = 2.2, 10.6 Hz, 1H), 7.30 – 7.38 (m, 1H), 7.67 (t, J = 8.2 Hz, 1H), 9.13 (s, 1H), two exchangeable protons are not visible. Procedure N: Synthesis of (rac)-4-(1-(thiazol-5-yl)ethyl)aniline (Intermediate I-24)
Figure imgf000088_0001
Step 1 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (785 mg, 3.72 mmol) was added to a suspension of tert-butyl (E)-(4-(1-(2-tosylhydrazineylidene)ethyl)phenyl)carbamate (500 mg, 1.24 mmol) and K2CO3 (514 mg, 3.72 mmol) in 1,4-dioxane (5 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 110 °C for 16 hours, then it was cooled to room temperature, filtered through a pad of CELITE and the filtrate was concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography, eluting with a mixture of 0 to 80% MeCN in water (0.1% NH4HCO3), to afford (rac)-tert-butyl (4-(1-(thiazol-5-yl)ethyl)phenyl)carbamate (0.18 g, 48.5%) as a yellow solid. MS (ES+, m/z): 304.9 [M + H]+; 1H NMR (300 MHz, CDCl3) δ 1.41 (s, 9H), 1.59 (d, J = 7.2 Hz, 3H), 4.23 (q, J = 7.1 Hz, 1H), 6.40 (s, 1H), 7.00 – 7.11 (m, 2H), 7.15 – 7.25 (m, 2H), 7.50 (t, J = 1.0 Hz, 1H), 8.56 (d, J = 0.8 Hz, 1H), the exchangeable protons are not visible. Step 2: A 4 M HCl solution in 1,4-dioxane (10 ml, 40.00 mmol) was added to tert-butyl (4-(1-(thiazol-5- yl)ethyl)phenyl)carbamate (160 mg, 0.53 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure to afford (rac)-4-(1- (thiazol-5-yl)ethyl)aniline (0.14 g) as a light red solid. MS (ES+, m/z): 204.8 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.53 (d, J = 7.1 Hz, 3H), 4.44 (q, J = 7.1 Hz, 1H), 7.15 – 7.25 (m, 3H), 7.30 (d, J = 8.4 Hz, 2H), 8.93 (s, 1H), the exchangeable protons are not visible. Table 5. The following compounds were made using a method analogous to the Procedure N, described above. Intermediate Structure MS (ES+, m/z) NMR I-25 191.06 [M + H]+ 1H NMR (300 MHz, DMSO-d6) δ 4.12 (s, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 1.0 Hz, 1H), 8.84 (d, J = 0.8 Hz, 1H), the exchangeable protons are not visible. I-26 188.11 [M + H]+ 1H NMR (300 MHz, DMSO-d6) δ 3.59 (s, 3H), 3.65 (s, 2H), 5.89 (d, J = 1.9 Hz, 1H), 7.19 (d, J = 4.9 Hz, 2H), 7.22 (d, J = 4.9 Hz, 2H), 7.27 (d, J = 2.0 Hz, 1H), the exchangeable protons are not visible. I-27 201.90 [M + H]+ 1H NMR (300 MHz, DMSO-d6) δ 1.40 (d, J = 7.1 Hz, 3H), 3.43 (s, 3H), 4.21 (q, J = 7.1 Hz, 1H), 6.16 (d, J = 1.9 Hz, 1H), 7.19 (d, J = 2.4 Hz, 2H), 7.21 (d, J = 3.0 Hz, 2H), 7.27 (d, J = 1.9 Hz, 1H), the exchangeable protons are not visible. I-28 188.10 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 4.03 (s, 2H), 7.20 – 7.43 (m, 4H), 8.94 (s, 1H), 10.15 (s, 2H), 14.41 (s, 1H). Procedure O: Synthesis of tert-butyl 3-((phenoxycarbonyl)amino)-1H-pyrazole-1-carboxylate (Intermediate I-29) Phenyl carbonochloridate (411 µl, 3.27 mmol) was added dropwise to a solution of pyridine (439 µl, 5.46 mmol) and tert-butyl 3-amino-1H-pyrazole-1-carboxylate (500 mg, 2.73 mmol) in DCM (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours, then it was diluted with DCM (50 mL) and washed with water (15 mL x 3). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by silica column, eluting with a mixture of 0 to 20% EtOAc in petroleum ether to afford tert-butyl 3- ((phenoxycarbonyl)amino)-1H-pyrazole-1-carboxylate (400 mg) as a white solid. MS (ES+, m/z): 304.2 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.45 (s, 9H), 6.54 (d, 1H), 7.05 – 7.19 (m, 3H), 7.21 – 7.37 (m, 2H), 8.07 (d, 1H), 11.01 (s, 1H). Table 6. The following compounds were made using a method analogous to the Procedure O, described above. Intermediate Structure MS (ES+, m/z) NMR I-30 18.05 [M + H]+ 1H NMR (300 MHz, DMSO-d6) δ 3.64 – 3.78 (m, 3H), 7.12 – 7.22 (m, 4H), 7.38-7.46 (m, 3H). I-31 204.80 [M + 1H NMR (300 MHz, DMSO-d6) δ H]+ 7.12 (d, J = 0.9 Hz, 1H), 7.15 – 7.4 (m, 3H), 7.38 – 7.5 (m, 2H), 7.88 (s, 1H), 11.51 (s, 1H). I-32 317.90 [M + 1H NMR (300 MHz, DMSO-d6) δ H]+ 1.44 (s, 9H), 1.86 (d, J = 1.1 Hz, 3H), 7.05 – 7.09 (m, 2H), 7.11 – 7.17 (m, 1H), 7.28 – 7.34 (m, 2H), 7.91 (d, J = 1.1 Hz, 1H), 10.09 (s, 1H). Procedure P: Synthesis of (rac)-4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)aniline (Intermediate I-33)
Figure imgf000091_0001
Step 1 5-Bromo-3-methylimidazo[1,5-a]pyridine (1g, 4.74 mmol) was added to (4-nitrophenyl)boronic acid (0.791 g, 4.74 mmol), PdCl2(dppf) (0.347 g, 0.47 mmol) and K2CO3 (1.964 g, 14.21 mmol) in 1,4- dioxane (40 mL) and water (10 mL) at room temperature under one atmosphere of nitrogen. The reaction mixture and stirred at 90 °C for 6 hours. The solvent was removed under reduced pressure and the crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 50% EtOAc in petroleum ether, to afford 3-methyl-5-(4-nitrophenyl)imidazo[1,5-a]pyridine (1.1 g, 92%) as a white solid. MS (ES+, m/z): 254.2 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.93 (s, 3H), 6.56 (dd, J = 1.3, 6.5 Hz, 1H), 6.79 (dd, J = 6.5, 9.1 Hz, 1H), 7.45 – 7.51 (m, 1H), 7.61 (dd, J = 1.2, 9.1 Hz, 1H), 7.75 – 7.84 (m, 2H), 8.28 – 8.39 (m, 2H). Step 2 10% Pd-C (w/w) (630 mg, 5.92 mmol) was added to a solution of 3-methyl-5-(4- nitrophenyl)imidazo[1,5-a]pyridine (500 mg, 1.97 mmol) and TEA (19.98 mg, 0.20 mmol) in EtOH (2 mL). The reaction mixture was placed under 13 atmospheres of hydrogen and stirred at 80 °C for 16 hours. The reaction mixture was cooled down, filtered through a pad of CELITE and the filtrate was concentrated under reduced pressure to afford 4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin- 5-yl)aniline (0.3 g, 66.8%). MS (ES+, m/z): 228.25 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.48-1.65 (m, 2H), 1.85 (s, 3H), 1.95 – 2.21 (m, 2H), 2.53 – 2.88 (m, 2H), 4.98 (s, 2H), 5.22 (dd, J = 3.3, 5.5 Hz, 1H), 6.39 – 6.53 (m, 4H), 6.52 (s, 1H). Table 7. The following compound was made using a method analogous to the Procedure P, described above. Intermediate Structure MS (ES+, m/z): NMR I-34 214.25 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 1.80 (dd, 1H), 1.95 (qd, 1H), 2.08 (dd, 2H), 3.16 (s, 2H), 4.05 (dd, 1H), 4.12 – 4.25 (m, 1H), 4.36 (d, 1H), 6.76 (d, 2H), 6.95 – 7.10 (m, 3H), 9.05 (s, 1H). Procedure Q: Synthesis of (rac)-(R)-4-(3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5- yl)aniline (Intermediate I-35)
Figure imgf000092_0001
Step 1 (2-Methyl-1-trityl-1H-imidazol-4-yl)methanol (5.70 g, 71.7%) was prepared using the Procedure A, step 1 described above. MS (ES+, m/z): 355.3 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.47 (s, 3H), 4.28 (d, J = 5.2 Hz, 2H), 4.80 (t, J = 5.6 Hz, 1H), 6.50 (s, 1H), 7.02 – 7.10 (m, 6H), 7.34 – 7.47 (m, 9H). Step 2 KtOBu (1.18 g, 10.58 mmol) was added to a solution of (2-methyl-1-trityl-1H-imidazol-4-yl)methanol (2.5 g, 7.05 mmol) in DMSO (100 mL) at room temperature and the reaction mixture was stirred for 30 minutes.2-(4-Bromophenyl)oxirane (1.54 g, 7.76 mmol) was added and stirring continued for 16 hours. The reaction mixture was poured into water (300 mL), extracted with EtOAc (100 mL x 3) and the combined organic layers were washed with water (75 mL x 2), brine (75 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by silica column, eluting with a mixture of 0 to 30% EtOAc in petroleum ether, to afford 300 mg 1-(4-bromophenyl)-2- ((2-methyl-1-trityl-1H-imidazol-4-yl)methoxy)ethan-1-ol. MS (ES+, m/z): 553.2 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.43 – 1.52 (m, 3H), 3.36 – 3.52 (m, 1H), 4.28 (s, 1H), 4.61 – 4.76 (m, 1H), 5.52 (d, J = 4.6 Hz, 1H), 5.77 (s, 1H), 6.55 (s, 1H), 7.03 – 7.08 (m, 7H), 7.21 – 7.32 (m, 1H), 7.35 – 7.48 (m, 12H). Steps 3-4 Methanesulfonyl chloride (0.621 g, 5.42 mmol) was added dropwise to a solution of 1-(4- bromophenyl)-2-((2-methyl-1-trityl-1H-imidazol-4-yl)methoxy)ethan-1-ol (2.5 g, 4.52 mmol) and TEA (1.88 mL, 13.55 mmol) in DCM (30 mL) at 0 °C under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 16 hours, then it was poured into water (100 mL), extracted with EtOAc (100 mL x 3) and the combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was added to a solution of DIEA (1.99 mL, 11.40 mmol) in MeCN (25 mL) at room temperature and the resulting mixture was stirred at 70 °C for 16 hours, then concentrated under reduced pressure. The crude product was purified by flash C18-flash chromatography, eluting with a mixture of 5 to 50% MeCN in water (0.1% NH4HCO3), to afford 5-(4-bromophenyl)-3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazine (0.292 g, 26.2%) as a colourless oil. MS (ES+, m/z): 293.15 [M + H]+; 1H NMR (400 MHz, CDCl3) δ 2.16 (s, 3H), 4.02 (dd, J = 3.0, 12.0 Hz, 1H), 4.19 (dd, J = 4.0, 12.1 Hz, 1H), 4.84 (d, J = 14.4 Hz, 1H), 5.03 (d, J = 14.4 Hz, 1H), 5.16 (t, J = 3.5 Hz, 1H), 6.88 – 6.96 (m, 3H), 7.47 – 7.55 (m, 2H). Steps 5-6 4-(3-Methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5-yl)aniline was prepared using the Procedure G, steps 5-6 described above. MS (ES+, m/z): 230.1 [M + H]+; 1H NMR (300 MHz, MeOH-d4) δ 2.32 (s, 3H), 4.15 (dd, J = 2.6, 12.4 Hz, 1H), 4.33 (dd, J = 4.0, 12.4 Hz, 1H), 4.92 (d, J = 15.7 Hz, 1H), 5.08 – 5.22 (m, 1H), 5.72 (t, J = 3.2 Hz, 1H), 7.37 – 7.47 (m, 3H), 7.43 – 7.54 (m, 2H), the exchangeable protons are not visible. Procedure R: Synthesis of (rac)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)aniline (Intermediate I-36)
Figure imgf000093_0001
Step 1 A 2.5 M solution of nBuLi in hexanes (25 mL, 61.69 mmol) was added dropwise to a solution of 1,4- dibromobenzene (14.55 g, 61.69 mmol) in THF (100 mL) at -78 °C under one atmosphere of nitrogen and the reaction mixture was stirred for 30 minutes.6,7-Dihydroimidazo[1,5-a]pyridin-8(5H)-one (2.8 g, 20.56 mmol) was added and stirring continued at -78 °C for 1 hour. The reaction mixture was warmed to room temperature and concentrated under reduced pressure. The residue was taken up in EtOAc (200 mL) and washed with water (50 mL x 3) and brine (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 9% MeOH in DCM, to afford 8-(4-bromophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol (1.32 g, 22.03%) as a white solid. MS (ES+, m/z): 293.02 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.67 – 1.87 (m, 1H), 1.88 – 2.04 (m, 2H), 2.20 (m, J = 4.9, 9.6, 14.1 Hz, 1H), 3.96 (m, J = 4.8, 11.5, 12.3 Hz, 1H), 4.18 (m, J = 4.8, 12.4 Hz, 1H), 5.79 (s, 1H), 6.43 (s, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.58 (s, 1H). Step 2 8-(4-Bromophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-ol (1.3 g, 4.43 mmol) was added to a 5 M HCl aqueous solution (13 mL, 4.43 mmol) . The reaction mixture was stirred at 100 °C for 1 hour and concentrated under reduced pressure to afford 8-(4-bromophenyl)-5,6-dihydroimidazo[1,5- a]pyridine (1.100 g, 90 %) as a yellow solid. MS (ES+, m/z): 275.01 [M + H]+ ; 1H NMR (300 MHz, DMSO-d6) δ 2.74 (q, J = 6.6 Hz, 2H), 4.32 (t, J = 7.1 Hz, 2H), 6.43 (t, J = 4.8 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.58 – 7.74 (m, 3H), 9.20 (s, 1H). Step 3 Pd2(dba)3 (542 mg, 0.22 mmol) was added to a solution of 8-(4-bromophenyl)-5,6- dihydroimidazo[1,5-a]pyridine (600 mg, 2.18 mmol), tert-butyl carbamate (1.02 g, 8.72 mmol), 2-di- t-butylphosphino-2',4',6'-tri-i-propyl-1,1'-biphenyl (93 mg, 0.22 mmol) and ethyl bromodifluoroacetate t-butoxide (1.25 g, 13.08 mmol) in toluene (10 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 60 °C for 16 hours, then it was cooled down and concentrated under reduced pressure. The residue was taken up in EtOAc (75 mL) and washed with water (15 mL x 3) and brine (15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 10% MeOH in DCM, to afford tert-butyl (4-(5,6- dihydroimidazo[1,5-a]pyridin-8-yl)phenyl)carbamate (650 mg, 96%) as a yellow oil. MS (ES+, m/z): 312.16 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.49 (s, 9H), 2.56 – 2.67 (m, 2H), 4.08 (t, J = 7.0 Hz, 2H), 5.90 (t, J = 4.7 Hz, 1H), 6.81 (s, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.70 (s, 1H), 9.47 (s, 1H). Step 4 Pd(OH)2 - C (w/w) (451 mg, 1.93 mmol) was added to a solution of to tert-butyl (4-(5,6- dihydroimidazo[1,5-a]pyridin-8-yl)phenyl)carbamate (600 mg, 1.93 mmol) in MeOH (6 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 2 hours. The reaction mixture was filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure to afford tert-butyl (4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)carbamate (480 mg, 79%) as a yellow solid. MS (ES+, m/z): 314.17 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.47 (s, 9H), 1.68 – 2.06 (m, 4H), 3.90 – 4.00 (m, 2H), 4.15 (d, J = 12.6 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.53 (s, 1H), 8.32 (s, 1H), 9.28 (s, 1H). Step 5 A mixture of tert-butyl (4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)carbamate (300 mg, 0.96 mmol) and 4 M HCl in EtOAc (3 mL, 0.96 mmol) was stirred at room temperature under one atmosphere of hydrogen for 1 hour. The solvent was removed under reduced pressure to afford 4- (5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)aniline (180 mg, 88 %) as a yellow solid. MS (ES+, m/z): 214.17 [M + H]+ ; 1H NMR (300 MHz, DMSO-d6) δ 1.80 – 2.00 (m, 2H), 2.10 (d, J = 12.6 Hz, 2H), 4.24 (m, J = 4.4, 10.0 Hz, 2H), 4.34 – 4.43 (m, 1H), 7.14 (d, J = 1.4 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 9.11 (d, J = 1.5 Hz, 1H). Procedure S: Synthesis of (rac)-(R)-4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)aniline (Intermediate I-37)
Figure imgf000095_0001
Steps 1-2 3-Bromopicolinonitrile (10.98 g, 60.0 mmol) was added to a 1 M solution of methyl magnesium bromide (60 mL, 60.0 mmol) in THF (100 mL) at 0 °C under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes. NaBH4 (2.72 g, 72.0 mmol) was added, followed by MeOH (30 mL) and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was taken up in MeOH (150 mL) and water (50 mL), treated with Boc2O (13 g, 59.56 mmol) and stirred at room temperature for 3 hours. The MeOH was removed under reduced pressure and the aqueous phase was extracted with EtOAc (60 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 40% petroleum ether in EtOAc, to afford tert-butyl (1-(3-bromopyridin-2- yl)ethyl)carbamate (10.90 g) as a yellow solid. MS (ES+, m/z): 300.9 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.31 (d, J = 22.5 Hz, 12H), 5.00 – 5.11 (m, 1H), 7.14 (d, J = 7.9 Hz, 1H), 7.25 (dd, J = 4.6, 8.0 Hz, 1H), 8.04 (dd, J = 1.5, 8.0 Hz, 1H), 8.54 (dd, J = 1.5, 4.7 Hz, 1H). Step 3 A mixture of tert-butyl (1-(3-bromopyridin-2-yl)ethyl)carbamate (10.8 g, 35.86 mmol) and 4 M HCl in EtOH (100 mL) was stirred at room temperature for 8 hours, then it was concentrated under reduced pressure. The crude product was purified by trituration with diethyl ether (50 mL), collected by filtration and dried to afford 1-(3-bromopyridin-2-yl)ethan-1-amine (7.0 g, 97%) as a white solid. MS (ES+, m/z): 202.95 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.02 (t, J = 7.0 Hz, 2H), 1.45 (d, J = 6.8 Hz, 1H), 3.41 (q, J = 7.0 Hz, 1H), 7.39 (dd, J = 4.7, 8.1 Hz, 1H), 8.16 (dd, J = 1.4, 8.2 Hz, 1H), 8.62 (dd, J = 1.4, 4.7 Hz, 1H), 8.74 (s, 2H). Step 4 A mixture of 1-(3-bromopyridin-2-yl)ethan-1-amine (8.6 g, 42.77 mmol) and FA (90 mL) was stirred at 60 °C under one atmosphere of nitrogen for 3 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by flash C18-flash chromatography, eluting with a mixture of 0 to 80% MeCN in water (0.1% FA), to afford N-(1-(3-bromopyridin-2- yl)ethyl)formamide (4.93 g, 50.3 %) as a purple solid. MS (ES+, m/z): 229.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.33 (d, J = 6.8 Hz, 3H), 5.44 (p, J = 7.1 Hz, 1H), 7.29 (dd, J = 4.6, 8.1 Hz, 1H), 8.00 (s, 1H), 8.07 (dd, J = 1.5, 8.1 Hz, 1H), 8.55 – 8.61 (m, 1H), one exchangeable proton is not visible. Step 5 POCl3 (2.68 g, 17.46 mmol) was added to a solution of N-(1-(3-bromopyridin-2-yl)ethyl)formamide (2 g, 8.73 mmol) in toluene (20 mL) and the reaction mixture was stirred at 80 °C under one atmosphere of nitrogen for 2 hours. The solvent was removed under reduced pressure and the residue was basified with saturated Na2CO3 solution and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 10% MeOH in DCM, to afford (rac)-8-bromo-1-methylimidazo[1,5-a]pyridine (1.85 g, 100%) as a yellow solid.MS (ES+, m/z): 212.95 [M + H]+.1H NMR (300 MHz, DMSO-d6) δ 2.67 (s, 3H), 6.44 (t, J = 6.9 Hz, 1H), 6.96 (d, J = 6.9 Hz, 1H), 8.26 (d, J = 7.0 Hz, 1H), 8.32 (s, 1H). Step 6 A suspension of 8-bromo-1-methylimidazo[1,5-a]pyridine (1.85 g, 8.77 mmol), (4- nitrophenyl)boronic acid (1.75 g, 10.52 mmol), Pd(PPh3)4 (1.01 g, 0.88 mmol) and K2CO3 (1.96 g, 14.21 mmol) in 1,4-dioxane (40 mL) and water (10 mL) was stirred at 90 °C under one atmosphere of nitrogen for 3 hours. The reaction mixture was cooled down and the solvent was removed under reduced pressure. The crude product was purified by C18-flash chromatography, eluting with mixtures of 0 to 80% MeCN in water (0.1% FA), to afford (rac)-1-methyl-8-(4- nitrophenyl)imidazo[1,5-a]pyridine (1.3 g, 58.6%) as a brown solid. MS (ES+, m/z): 254.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.98 (s, 3H), 6.59 – 6.74 (m, 2H), 7.74 (d, J = 8.5 Hz, 2H), 8.15 (s, 1H), 8.34 (d, J = 4.7 Hz, 2H), 8.42 (s, 1H). Step 7 10% Pd-C (w/w) (0.546 g, 5.13 mmol) was added to a solution of 1-methyl-8-(4- nitrophenyl)imidazo[1,5-a]pyridine (1.3 g, 5.13 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 24 hours. The reaction mixture was filtered through a pad of CELITE and the filtrate was concentrated under reduced pressure to afford (rac)-4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)aniline (0.68 g, 58.9%) as a brown oil. MS (ES+, m/z): 228.1 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.58 (s, 3H), 1.60 – 1.92 (m, 2H), 1.98 (d, J = 6.2 Hz, 1H), 2.04 (d, J = 6.8 Hz, 1H), 3.89 (t, J = 6.3 Hz, 1H), 3.97 (t, J = 5.8 Hz, 2H), 4.89 (s, 2H), 6.36 – 6.52 (m, 2H), 6.73 (d, J = 8.1 Hz, 2H), 7.40 (s, 1H). Synthesis of Final Compounds Procedure 1 Example 1: 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea
Figure imgf000098_0001
2-Isocyanatopyridine (29.3 mg, 0.24 mmol) was added to a solution of 4-((1H-imidazol-1- yl)methyl)aniline dihydrochloride (50 mg, 0.20 mmol) and TEA (0.142 mL, 1.02 mmol) in toluene (1 mL) at room temperature under one atmosphere of nitrogen. The reaction mixture was stirred at 100 °C for 16 hours, then cooled down and concentrated under reduced pressure. The crude product was purified by preparative HPLC, Column: XBridge Prep OBD C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3), Mobile Phase B: MeCN; RT (min): 6.83, to afford 1- (pyridin-2-yl)-3-(4-(imidazo-1-ylmethyl)phenyl)urea (20.9 mg, 35.1%) as a white solid. MS (ES+, m/z): 294.0 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 5.13 (s, 2H), 6.89 (s, 1H), 7.01 (dd, J = 5.1, 7.2 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 7.19 – 7.27 (m, 2H), 7.46 – 7.55 (m, 3H), 7.69 – 7.77 (m, 2H), 8.24 – 8.30 (m, 1H), 9.46 (s, 1H), 10.53 (s, 1H). Some compounds containing a chiral centre were synthesised as racemic mixtures and separated into the corresponding enantiomers using chiral preparative HPLC or SFC. Table 8. The following compounds were made from the appropriate Intermediate and isocyanate, using a method analogous to the Procedure 1, described above. Example Structure MS (ES+, m/z) NMR 12 308.15 [M + 1H NMR (300 MHz, MeOH-d4) δ 1.87 (d, J = H]+ 7.1 Hz, 3H), 5.51 (q, J = 7.1 Hz, 1H), 6.85 – 7.13 (m, 2H), 7.15 – 7.36 (m, 4H), 7.50 – 7.60 (m, 2H), 7.65 – 7.80 (m, 1H), 7.88 (s, 1H), 8.22 – 8.34 (m, 1H). exchangeable protons are not visible. 322.25 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.71 (d, J = H]+ 7.2 Hz, 3H), 2.21 (s, 3H), 5.41 (q, J = 6.6 Hz, 1H), 6.77 (d, J = 1.5 Hz, 1H), 7.05 – 6.95 (m, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 1.4 Hz, 1H), 7.49 (dd, J = 8.4, 6.9 Hz, 3H), 7.74 (td, J = 7.8, 7.2, 2.1 Hz, 1H), 8.30 – 8.22 (m, 1H), 9.41 (s, 1H), 10.45 (s, 1H). 322.05 [M + 1H NMR (400 MHz, MeOH-d4) δ 1.86 (d, J = H]+ 7.0 Hz, 3H), 2.46 (s, 3H), 5.60 (q, J = 7.0 Hz, 1H), 7.01 (dd, J = 5.1, 7.2 Hz, 1H), 7.18 (dd, J = 1.2, 8.2 Hz, 2H), 7.20 – 7.26 (m, 2H), 7.45 (d, J = 1.7 Hz, 1H), 7.53 – 7.61 (m, 2H), 7.72 (dd, J = 7.3, 8.3 Hz, 1H), 8.28 (dd, J = 1.9, 5.1 Hz, 1H), the exchangeable protons are not visible. 339.00 1H NMR (300 MHz, DMSO-d6) δ 1.71 (d, J = [M+H]+ 7.0 Hz, 3H), 2.21 (s, 3H), 5.40 (q, J = 6.9 Hz, 1H), 6.77 (d, J = 1.4 Hz, 1H), 6.93 – 7.06 (m, 1H), 7.07 – 7.29 (m, 5H), 7.36 – 7.45 (m, 2H), 8.14 (td, J = 8.3, 1.7 Hz, 1H), 8.53 (d, J = 2.7 Hz, 1H), 9.09 (s, 1H). 334.20 [M + 1H NMR (300 MHz, DMSO-d6) δ 2.18 – 2.33 H]+ (s, 3H), 4.47 – 5.50 (m, 4H), 6.64 – 6.75 (d, J = 1.3 Hz, 1H), 6.94 – 7.07 (m, 2H), 7.35 – 7.56 (m, 5H), 7.69 – 7.80 (ddd, J = 2.0, 7.3, 8.9 Hz, 1H), 8.19 – 8.34 (dd, J = 1.9, 5.3 Hz, 1H), 9.37 – 9.52 (s, 1H), 10.49 – 10.66 (s, 1H). 294.00 [M + 1H NMR (300 MHz, DMSO-d6) δ 3.79 (s, 2H), H]+ 6.72 (s, 1H), 7.00 (dd, J = 5.2, 7.2 Hz, 1H), 7.17 (d, J = 8.2 Hz, 2H), 7.38 – 7.47 (m, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.68 – 7.80 (m, 1H), 8.24 – 8.32 (m, 1H), 9.41 (s, 1H), 10.44 (s, 1H). 322.95 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.54 (t, J = H]+ 7.6 Hz, 3H), 2.04 (d, J = 10.0 Hz, 3H), 4.03 – 4.36 (m, 1H), 6.97 – 7.07 (m, 1H), 7.18 (dd, J = 8.5, 18.8 Hz, 1H), 7.37 (d, J = 6.3 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.70 – 7.80 (m, 1H), 7.80 – 7.95 (m, 1H), 8.24 – 8.32 (m, 1H), 8.56 (dd, J = 2.6, 22.2 Hz, 1H), 9.50 (d, J = 7.7 Hz, 1H), 10.51 (d, J = 17.8 Hz, 1H), 11.60 (d, J = 19.3 Hz, 1H). 336.20 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.11 (t, J = H]+ 7.5 Hz, 3H), 1.72 (d, J = 7.0 Hz, 3H), 2.40 – 2.48 (m, 1H), 2.58 – 2.76 (m, 1H), 5.36 – 5.52 (m, 1H), 6.81 (d, J = 1.3 Hz, 1H), 7.01 (ddd, J = 1.0, 5.0, 7.3 Hz, 1H), 7.10 – 7.17 (m, 2H), 7.26 (d, J = 1.4 Hz, 1H), 7.49 (dd, J = 6.5, 8.5 Hz, 3H), 7.75 (ddd, J = 1.9, 7.3, 9.0 Hz, 1H), 8.27 (ddd, J = 0.9, 2.0, 5.1 Hz, 1H), 9.41 (s, 1H), 10.46 (s, 1H). 336.15 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.11 (t, J = H] 7.5 Hz, 3H), 1.72 (d, J = 7.0 Hz, 3H), 2.45 (d, J = 7.7 Hz, 1H), 2.58 – 2.76 (m, 1H), 5.35 – 5.53 (m, 1H), 6.81 (d, J = 1.3 Hz, 1H), 7.01 (dd, J = 5.1, 7.2 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.26 (s, 1H), 7.49 (dd, J = 6.5, 8.5 Hz, 3H), 7.66 – 7.84 (m, 1H), 8.27 (dd, J = 1.6, 5.5 Hz, 1H), 9.41 (s, 1H), 10.46 (s, 1H). 308.05 [M + 1H NMR (300 MHz, MeOH-d4) δ 2.35 (s, 3H), H]+ 4.06 (s, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.56 (d, J = 8.5 Hz, 2H), 8.17 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 8.73 (s, 1H), the exchangeable protons are not visible. 347.95 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.59 (s, 3H), H]+ 1.67 – 2.16 (m, 4H), 4.04 (dt, J = 17.2, 6.4 Hz, 3H), 7.02 (dd, J = 14.2, 7.4 Hz, 3H), 7.39 – 7.54 (m, 4H), 7.74 (ddd, J = 8.9, 7.1, 1.9 Hz, 1H), 8.27 (dd, J = 5.4, 1.9 Hz, 1H), 9.41 (s, 1H), 10.46 (s, 1H). 334.15 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.69 – 1.94 H]+ (m, 2H), 1.96 – 2.13 (m, 2H), 3.92 – 4.05 (m, 2H), 4.17 (d, J = 12.6 Hz, 1H), 6.29 (s, 1H), 6.97 – 7.06 (m, 1H), 7.18 (d, J = 8.3 Hz, 2H), 7.42 – 7.53 (m, 3H), 7.56 (s, 1H), 7.69 – 7.80 (m, 1H), 8.25 – 8.31 (m, 1H), 9.43 (s, 1H), 10.49 (s, 1H). 336.00 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.04 (t, J = H]+ 7.5 Hz, 3H), 1.54 (d, J = 7.2 Hz, 3H), 2.46 – 2.50 (m, 3H), 4.15 (q, J = 7.2 Hz, 1H), 6.96 – 7.07 (m, 1H), 7.22 (d, J = 8.5 Hz, 2H), 7.33 – 7.45 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.65 – 7.78 (m, 1H), 7.88 (s, 1H), 8.27 (dd, J = 1.9, 4.8 Hz, 1H), 9.40 (s, 1H), 10.42 (s, 1H). 311.15 [M + 1H NMR (400 MHz, DMSO-d6) δ 4.16 (s, 2H), H]+ 6.95-7.06 (m, 1H), 7.17 – 7.25 (m, 2H), 7.42 – 7.52 (m, 3H), 7.68 – 7.79 (m, 2H), 8.24-8.30 (m, 1H), 8.93 (d, J = 0.8 Hz, 1H), 9.41 (s, 1H), 10.47 (s, 1H). 124 339.00 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.58 (d, J = H]+ 7.2 Hz, 3H), 2.31 (s, 3H), 4.44 (q, J = 7.1 Hz, 1H), 7.01 (dd, J = 5.2, 7.0 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.40 – 7.54 (m, 3H), 7.68 – 7.80 (m, 1H), 8.23 – 8.31 (m, 1H), 8.82 (s, 1H), 9.39 (s, 1H), 10.42 (s, 1H). 125 339.00 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.58 (d, J = H]+ 7.1 Hz, 3H), 2.31 (s, 3H), 4.44 (q, J = 7.1 Hz, 1H), 6.95 – 7.06 (m, 1H), 7.17 – 7.27 (m, 2H), 7.48 (dd, J = 8.4, 11.1 Hz, 3H), 7.68 – 7.80 (m, 1H), 8.23 – 8.31 (m, 1H), 8.82 (s, 1H), 9.39 (s, 1H), 10.42 (s, 1H). Procedure 2 Example 84: 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((S)-tetrahydrofuran-2- yl)methyl)urea
Figure imgf000102_0001
Phenylchloroformate (40 mg, 0.26 mmol) was added to a solution of (S)-4-(1-(2-methyl-1H-imidazol- 1-yl)ethyl)aniline dihydrochloride (50 mg, 0.18 mmol) and TEA (0.076 mL, 0.55 mmol) in CHCl3 (2 mL) and the reaction mixture was stirred at 0 °C under one atmosphere of nitrogen for 1 hour. (S)- (Tetrahydrofuran-3-yl)methanamine (20.29 mg, 0.20 mmol) and TEA (0.076 mL, 0.55 mmol) were added and the mixture was stirred at 60 °C for 16 hours. The solvent was removed under reduced pressure. The crude product was purified by preparative HPLC, Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3), Mobile Phase B: MeCN; RT (min): 7.0, to afford 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((S)- tetrahydrofuran-2-yl)methyl)urea (39.9 mg, 66.6%) as a white solid. MS (ES+, m/z): 329.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.44 – 1.58 (m, 1H), 1.69 (d, J = 7.0 Hz, 3H), 1.84 (ddd, J = 12.9, 10.8, 5.8 Hz, 3H), 2.20 (s, 3H), 3.00 – 3.15 (m, 1H), 3.22 (dt, J = 13.5, 5.7 Hz, 1H), 3.63 (q, J = 7.2 Hz, 1H), 3.72 – 3.92 (m, 2H), 5.36 (q, J = 6.9 Hz, 1H), 6.17 (t, J = 5.8 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.27 – 7.41 (m, 2H), 8.54 (s, 1H). Table 9. The following compounds were made from the appropriate Intermediate, using a method analogous to the Procedure 2 described above. Example Structure MS (ES+, NMR m/z) 142 305.20 1H NMR (300 MHz, DMSO-d6) δ 1.47 (d, J = [M + H]+ 7.1 Hz, 3H), 3.50 (s, 3H), 4.13 (q, J = 7.0 Hz, 1H), 4.36 (d, J = 5.7 Hz, 2H), 6.19 (dd, J = 0.6, 1.8 Hz, 1H), 6.70 (t, J = 5.8 Hz, 1H), 6.95 – 7.05 (m, 2H), 7.26 – 7.45 (m, 4H), 7.62 – 7.78 (m, 1H), 8.45 – 8.53 (m, 1H), 8.70 (s, 1H). 26 301.00 1H NMR (400 MHz, MeOH-d4) δ 1.78 (d, J = [M + H]+ 7.0 Hz, 3H), 2.25 (s, 3H), 4.49 – 4.61 (m, 2H), 4.87 (d, J = 2.6 Hz, 3H), 5.36 – 5.46 (m, 1H), 6.87 (s, 1H), 7.02 – 7.10 (m, 2H), 7.18 (s, 1H), 7.29 – 7.37 (m, 2H), the exchangeable protons are not visible. 36 328.00 1H NMR (300 MHz, DMSO-d6) δ 1.72 (d, J = [M + H]+ 7.0 Hz, 3H), 2.21 (s, 3H), 5.41 (q, J = 7.0 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 7.07 – 7.18 (m, 2H), 7.27 (dd, J = 1.8, 15.9 Hz, 2H), 7.38 – 7.50 (m, 2H), 8.17 (s, 1H), 8.84 – 8.96 (m, 2H), 9.49 (s, 1H). 42 336.05 1H NMR (300 MHz, DMSO-d6) δ 1.56 (d, J = [M + H]+ 7.0 Hz, 3H), 2.08 (s, 3H), 4.18 (d, J = 5.9 Hz, 2H), 5.23 (q, J = 7.0 Hz, 1H), 6.57 (t, J = 6.0 Hz, 1H), 6.63 (d, J = 1.4 Hz, 1H), 6.89 – 6.98 (m, 2H), 7.09 (d, J = 1.4 Hz, 1H), 7.18 – 7.29 (m, 3H), 7.52 – 7.62 (m, 1H), 8.33 (dd, J = 1.7, 4.8 Hz, 1H), 8.39 (dd, J = 0.9, 2.3 Hz, 1H), 8.53 (s, 1H). 355.25 1H NMR (300 MHz, DMSO-d6) δ 1.70 (d, J = [M + H]+ 7.0 Hz, 3H), 2.20 (s, 3H), 4.45 – 4.56 (m, 2H), 5.36 (q, J = 6.9 Hz, 1H), 6.68 – 6.81 (m, 2H), 7.05 (d, J = 8.6 Hz, 2H), 7.23(d, J = 1.4 Hz, 1H), 7.32 – 7.41 (m, 2H), 8.80 – 8.96 (m, 3H). 336.41 1H NMR (300 MHz, DMSO-d6) δ 1.57 (d, J = [M + H]+ 7.0 Hz, 3H), 2.08 (s, 3H), 4.27 (d, J = 5.6 Hz, 2H), 5.24 (q, J = 7.0 Hz, 1H), 6.58 – 6.68 (m, 2H), 6.88 – 6.99 (m, 2H), 7.06 – 7.30 (m, 5H), 7.58 – 7.70 (m, 1H), 8.35 – 8.44 (m, 1H), 8.68 (s, 1H). 354.40 1H NMR (400 MHz, DMSO-d6) δ 1.69 (d, J = [M + H]+ 7.0 Hz, 3H), 2.21 (s, 2H), 4.38 (d, J = 5.6 Hz, 2H), 5.37 (q, J = 7.0 Hz, 1H), 6.76 (dd, J = 5.0, 11.0 Hz, 2H), 7.03 – 7.10 (m, 2H), 7.23 (s, 1H), 7.32 – 7.44 (m, 3H), 7.66 – 7.76 (m, 1H), 8.51 (d, J = 2.9 Hz, 1H), 8.79 (s, 1H). 350.10 1H NMR (300 MHz, DMSO-d6) δ 1.25 (d, J = [M+H]+ 6.8 Hz, 3H), 1.56 (d, J = 7.0 Hz, 3H), 2.07 (s, 3H), 4.77 (p, J = 7.0 Hz, 1H), 5.23 (q, J = 7.0 Hz, 1H), 6.59 – 6.68 (m, 2H), 6.88 – 6.96 (m, 2H), 7.04 – 7.31 (m, 5H), 7.59 – 7.70 (m, 1H), 8.42 (dt, J = 1.4, 4.7 Hz, 1H), 8.57 (s, 1H). 325.05 1H NMR (300 MHz, DMSO-d6) δ 1.57 (d, J = [M + H]+ 7.0 Hz, 3H), 2.09 (s, 3H), 4.14 (d, J = 5.4 Hz, 2H), 5.24 (q, J = 7.0 Hz, 1H), 6.02 (d, J = 2.1 Hz, 1H), 6.37 (t, J = 5.6 Hz, 1H), 6.65 (d, J = 1.4 Hz, 1H), 6.88 – 6.99 (m, 2H), 7.10 (d, J = 1.4 Hz, 1H), 7.18 – 7.28 (m, 2H), 7.45 (d, J = 2.1 Hz, 1H), 8.08 (s, 1H), 8.50 (s, 1H). 354.05 1H NMR (300 MHz, DMSO-d6) δ 1.64 – 1.73 [M + H]+ (d, J = 7.0 Hz, 3H), 2.19 – 2.23 (s, 3H), 4.46 – 4.53 (d, J = 4.9 Hz, 2H), 5.32 – 5.42 (d, J = 6.9 Hz, 1H), 6.69 – 6.79 (m, 2H), 7.03 – 7.09 (d, J = 8.5 Hz, 2H), 7.20 – 7.25 (d, J = 1.4 Hz, 1H), 7.32 – 7.38 (d, J = 8.5 Hz, 2H), 7.39 – 7.47 (dt, J = 4.4, 8.5 Hz, 1H), 7.68 – 7.76 (t, J = 8.6 Hz, 1H), 8.38 – 8.44 (d, J = 4.8 Hz, 1H), 8.82 – 8.87 (s, 1H). 354.10 1H NMR (300 MHz, MeOH-d4) δ 1.85 (d, J = [M + H]+ 7.0 Hz, 3H), 2.47 (s, 3H), 4.50 (s, 2H), 5.52 – 5.65 (m, 1H), 7.05 – 7.18 (m, 1H), 7.13 – 7.26 (m, 4H), 7.37 – 7.50 (m, 3H), 8.50 (dd, J = 5.7, 8.3 Hz, 1H). 368.43 1H NMR (300 MHz, DMSO-d6) δ -0.12 (s, 9H), [M + H]+ 1.24 (d, J = 6.9 Hz, 3H), 1.56 (d, J = 7.0 Hz, 3H), 2.08 (s, 3H), 4.79 (p, J = 6.9 Hz, 1H), 5.23 (q, J = 7.0 Hz, 1H), 6.55 – 6.67 (m, 2H), 6.92 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 1.4 Hz, 1H), 7.14 – 7.25 (m, 2H), 7.34 (dd, J = 4.5, 8.7 Hz, 1H), 7.52 – 7.65 (m, 1H), 8.41 (d, J = 3.0 Hz, 1H), 8.53 (s, 1H). 337.10 1H NMR (300 MHz, DMSO-d6) δ 1.57 (d, J = [M + H]+ 7.0 Hz, 3H), 2.08 (s, 3H), 4.27 (d, J = 5.8 Hz, 2H), 5.24 (q, J = 7.0 Hz, 1H), 6.60 – 6.73 (m, 2H), 6.94 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 1.4 Hz, 1H), 7.19 – 7.30 (m, 2H), 7.30 (dd, J = 1.4, 5.3 Hz, 1H), 8.61 (d, J = 5.2 Hz, 1H), 8.77 (s, 1H), 8.98 (d, J = 1.4 Hz, 1H). 339.05 1H NMR (400 MHz, DMSO-d6) δ 1.38 (d, J = [M + H]+ 6.8 Hz, 3H), 1.68 (d, J = 7.0 Hz, 3H), 2.20 (d, J = 1.7 Hz, 3H), 4.87 (s, 1H), 5.36 (q, J = 7.0 Hz, 1H), 6.15 (d, J = 2.1 Hz, 1H), 6.44 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 1.6 Hz, 1H), 7.30 – 7.36 (m, 2H), 7.62 (s, 1H), 8.50 (s, 1H), 12.59 (s, 1H). 339.05 1H NMR (400 MHz, DMSO-d6) δ 1.38 (d, J = [M + H]+ 6.8 Hz, 3H), 1.68 (d, J = 7.0 Hz, 3H), 2.20 (d, J = 1.7 Hz, 3H), 4.87 (s, 1H), 5.36 (q, J = 7.0 Hz, 1H), 6.15 (d, J = 2.1 Hz, 1H), 6.44 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 1.6 Hz, 1H), 7.30 – 7.36 (m, 2H), 7.62 (s, 1H), 8.50 (s, 1H), 12.59 (s, 1H). 337.05 1H NMR (300 MHz, DMSO-d6) δ 1.57 (d, J = [M+H]+ 7.0 Hz, 3H), 2.08 (s, 3H), 4.47 (d, J = 5.7 Hz, 2H), 5.24 (q, J = 7.0 Hz, 1H), 6.63 (d, J = 1.4 Hz, 1H), 6.80 (t, J = 5.8 Hz, 1H), 6.94 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 1.4 Hz, 1H), 7.20 – 7.29 (m, 2H), 7.43 – 7.60 (m, 2H), 8.73 (s, 1H), 9.01 (dd, J = 1.8, 4.8 Hz, 1H). 339.10 1H NMR (300 MHz, DMSO-d6) δ 1.67 (d, J = [M + H]+ 7.0 Hz, 3H), 2.17 (d, J = 9.9 Hz, 6H), 4.15 (d, J = 5.3 Hz, 2H), 5.34 (q, J = 7.0 Hz, 1H), 5.86 (s, 1H), 6.36 (s, 1H), 6.74 (s, 1H), 7.04 (d, J = 8.2 Hz, 2H), 7.20 (s, 1H), 7.32 (d, J = 8.3 Hz, 2H), 8.53 (s, 1H), 12.23 (s, 1H). 367.10[M 1H NMR (300 MHz, DMSO-d6) δ 1.56 (d, J = +H]+ 7.0 Hz, 3H), 2.08 (s, 3H), 3.78 (s, 3H), 4.18 (d, J = 5.7 Hz, 2H), 5.24 (q, J = 7.0 Hz, 1H), 6.64 (d, J = 4.5 Hz, 3H), 6.94 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 1.4 Hz, 1H), 7.24 (d, J = 8.3 Hz, 2H), 8.60 (s, 1H), 8.73 (s, 1H). 339.42 1H NMR (300 MHz, DMSO-d6) δ 1.68 (d, J = [M + H]+ 7.0 Hz, 3H), 1.97 (d, J = 0.8 Hz, 3H), 2.23 (s, 3H), 4.20 (d, J = 5.1 Hz, 2H), 5.39 (t, J = 6.9 Hz, 1H), 6.83 (s, 1H), 7.06 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H), 7.33 (d, J = 8.5 Hz, 2H), 8.51 (s, 1H). 342.05 1H NMR (300 MHz, DMSO-d6) δ 1.75 (d, J = [M + H]+ 7.1 Hz, 3H), 2.00 (d, J = 1.1 Hz, 3H), 4.58 (d, J = 6.0 Hz, 2H), 5.30 (q, J = 7.1 Hz, 1H), 6.63 (t, J = 1.1 Hz, 1H), 6.94 (t, J = 6.0 Hz, 1H), 6.99 – 7.07 (m, 2H), 7.32 – 7.43 (m, 2H), 7.60 (d, J = 3.3 Hz, 1H), 7.69 – 7.80 (m, 2H), 8.84 (s, 1H). 342.10 1H NMR (400 MHz, CDCl3) δ 1.83 (d, J = 7.1 [M + H]+ Hz, 3H), 2.11 (d, J = 1.0 Hz, 3H), 3.16 (s, 2H), 4.71 – 4.86 (m, 2H), 5.23 (q, J = 7.0 Hz, 1H), 6.85 (d, J = 8.6 Hz, 3H), 6.97 – 7.08 (m, 1H), 7.23 – 7.29 (m, 2H), 7.69 (d, J = 3.3 Hz, 1H), 7.84 (s, 1H), 8.66 (s, 1H). 315.00 1H NMR (300 MHz, DMSO-d6) δ 1.54 (s, 3H), [M + H]+ 1.69 (d, J = 7.0 Hz, 3H), 2.20 (s, 3H), 4.29 (d, J = 6.0 Hz, 2H), 4.60 (d, J = 6.0 Hz, 2H), 5.36 (q, J = 7.0 Hz, 1H), 6.61 (s, 1H), 6.76 (d, J = 1.4 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.28 – 7.38 (m, 2H), 8.52 (s, 1H). 369.00 1H NMR (300 MHz, DMSO-d6) δ 1.69 (d, J = [M + H]+ 6.9 Hz, 3H), 2.20 (s, 3H), 4.27 (d, J = 6.0 Hz, 2H), 5.36 (d, J = 7.1 Hz, 1H), 6.64 (s, 1H), 6.76 (s, 1H), 7.05 (d, J = 8.6 Hz, 2H), 7.22 (s, 1H), 7.26 – 7.43 (m, 6H), 8.63 (s, 1H). 337.05 1H NMR (300 MHz, DMSO-d6) δ 1.69 (d, J = [M + H]+ 7.0 Hz, 3H), 2.21 (s, 3H), 4.42 (dd, J = 5.8, 19.5 Hz, 2H), 5.36 (q, J = 7.0 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 6.86 (q, J = 4.3, 5.8 Hz, 1H), 7.01 – 7.11 (m, 2H), 7.22 (d, J = 1.4 Hz, 1H), 7.31 – 7.41 (m, 2H), 8.19 (s, 1H), 8.54 (d, J = 2.6 Hz, 1H), 8.57 – 8.63 (m, 2H), 8.87 (s, 1H). 367.43 1H NMR (300 MHz, DMSO-d6) δ 1.69 (d, J = [M + H]+ 7.0 Hz, 3H), 2.20 (s, 3H), 3.89 (s, 3H), 4.35 (d, J = 5.7 Hz, 2H), 5.36 (q, J = 6.9 Hz, 1H), 6.69 (t, J = 5.8 Hz, 1H), 6.75 (d, J = 1.3 Hz, 1H), 7.00 – 7.10 (m, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.29 – 7.39 (m, 2H), 8.16 (d, J = 1.4 Hz, 1H), 8.27 (d, J = 1.4 Hz, 1H), 8.71 (s, 1H). 315.05 1H NMR (300 MHz, DMSO-d6) δ 1.67 (d, J = [M + H]+ 7.0 Hz, 4H), 2.00 – 2.15 (m, 1H), 2.18 (s, 3H), 3.44 (dd, J = 3.6, 8.7 Hz, 1H), 3.61 – 3.83 (m, 3H), 4.17 (s, 1H), 5.34 (d, J = 7.3 Hz, 1H), 6.38 (d, J = 6.9 Hz, 1H), 6.74 (s, 1H), 7.03 (d, J = 8.2 Hz, 2H), 7.19 (s, 1H), 7.31 (d, J = 8.1 Hz, 2H), 8.34 (s, 1H). 315.00 1H NMR (300 MHz, DMSO-d6) δ 1.67 (d, J = [M + H]+ 7.0 Hz, 4H), 2.05 – 2.11 (m, 1H), 2.18 (s, 3H), 3.45 (s, 1H), 3.65 – 3.79 (m, 3H), 4.16 (s, 1H), 5.34 (q, J = 6.9 Hz, 1H), 6.37 (d, J = 6.9 Hz, 1H), 6.74 (d, J = 1.4 Hz, 1H), 7.03 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 1.4 Hz, 1H), 7.27 – 7.35 (m, 2H), 8.32 (s, 1H). 354.00 1H NMR (300 MHz, DMSO-d6) δ 1.69 (d, J = [M + H]+ 7.0 Hz, 3H), 2.20 (s, 3H), 4.39 (d, J = 5.7 Hz, 2H), 5.36 (q, J = 7.0 Hz, 1H), 6.71 – 6.81 (m, 2H), 7.00 – 7.11 (m, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.31 – 7.46 (m, 3H), 7.71 (td, J = 8.8, 3.0 Hz, 1H), 8.51 (d, J = 2.9 Hz, 1H), 8.79 (s, 1H). 329.21 1H NMR (300 MHz, DMSO-d6) δ 1.45 – 1.62 [M + H]+ (m, 1H), 1.69 (d, J = 7.0 Hz, 3H), 1.83 – 2.00 (m, 1H), 2.22 (s, 3H), 2.24 – 2.41 (m, 1H), 3.07 (t, J = 6.4 Hz, 2H), 3.39 (dd, J = 5.6, 8.5 Hz, 1H), 3.54 – 3.79 (m, 3H), 5.37 (q, J = 6.9 Hz, 1H), 6.32 (t, J = 5.9 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 7.01 – 7.10 (m, 2H), 7.23 (d, J = 1.4 Hz, 1H), 7.30 – 7.39 (m, 2H), 8.18 (s, 1H), 8.50 (s, 1H). MS (ES+, 1H NMR (300 MHz, DMSO-d6) δ 1.49 (q, J = m/z): 8.0 Hz, 2H), 1.69 (d, J = 7.0 Hz, 4H), 1.81 (d, J 329.20 = 10.8 Hz, 1H), 2.20 (s, 3H), 3.20 (dd, J = 6.8, [M + H]+ 10.8 Hz, 1H), 3.40 – 3.48 (m, 1H), 3.53 – 3.62 (m, 2H), 3.70 (dd, J = 3.5, 10.8 Hz, 1H), 5.36 (q, J = 6.9 Hz, 1H), 6.26 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 1.3 Hz, 1H), 7.02 – 7.08 (m, 2H), 7.22 (d, J = 1.4 Hz, 1H), 7.27 – 7.38 (m, 2H), 8.45 (s, 1H). 372.00 1H NMR (400 MHz, DMSO-d6) δ 1.74 (d, J = [M + H]+ 7.0 Hz, 3H), 4.39 (d, J = 5.7 Hz, 2H), 5.22 – 5.78 (m, 3H), 6.78 (t, J = 5.8 Hz, 1H), 6.96 (d, J = 1.2 Hz, 1H), 7.13 – 7.24 (m, 2H), 7.33 – 7.44 (m, 4H), 7.71 (td, J = 3.0, 8.8 Hz, 1H), 8.51 (d, J = 2.9 Hz, 1H), 8.83 (s, 1H). 372.10 1H NMR (400 MHz, DMSO-d6) δ 1.75 (d, J = [M + H]+ 7.0 Hz, 3H), 4.39 (d, J = 5.7 Hz, 2H), 5.32 – 5.64 (m, 3H), 6.76 (t, J = 5.8 Hz, 1H), 6.97 (d, J = 1.2 Hz, 1H), 7.13 – 7.23 (m, 2H), 7.33 – 7.44 (m, 4H), 7.71 (td, J = 3.0, 8.8 Hz, 1H), 8.51 (d, J = 3.0 Hz, 1H), 8.81 (s, 1H). 329.20 1H NMR (300 MHz, DMSO-d6) δ 1.01 (d, J = [M + H]+ 6.9 Hz, 3H), 1.69 (d, J = 7.1 Hz, 3H), 1.95 – 2.15 (m, 1H), 2.20 (s, 3H), 3.28 (dd, J = 6.6, 8.4 Hz, 1H), 3.41 (dd, J = 4.8, 8.7 Hz, 1H), 3.76 (p, J = 5.8 Hz, 1H), 3.84 – 3.98 (m, 2H), 5.36 (q, J = 6.9 Hz, 1H), 6.40 (d, J = 7.0 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.28 – 7.37 (m, 2H), 8.39 (s, 1H). 329.42 1H NMR (300 MHz, DMSO-d6) δ 1.46 – 1.54 [M + H]+ (m, 1H), 1.69 (d, J = 7.0 Hz, 3H), 1.77 – 1.91 (m, 3H), 2.20 (s, 3H), 3.02 – 3.12 (m, 1H), 3.17 – 3.27 (m, 1H), 3.58 – 3.67 (m, 1H), 3.73 – 3.80 (m, 1H), 3.80 – 3.88 (m, 1H), 5.36 (q, J = 7.0 Hz, 1H), 6.17 (t, J = 5.7 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 7.02 – 7.07 (m, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.30 – 7.35 (m, 2H), 8.54 (s, 1H). 343.00 1H NMR (400 MHz, DMSO-d6) δ 1.16 (dd, J = [M + H]+ 6.1, 18.1 Hz, 3H), 1.33 – 1.43 (m, 1H), 1.47 – 1.62 (m, 1H), 1.69 (d, J = 7.0 Hz, 3H), 1.80 – 1.99 (m, 2H), 2.20 (s, 3H), 3.01 – 3.12 (m, 1H), 3.18 – 3.28 (m, 1H), 3.79 – 4.03 (m, 2H), 5.36 (q, J = 7.0 Hz, 1H), 6.14 (t, J = 5.8 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 6.99 – 7.08 (m, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.27 – 7.37 (m, 2H), 8.56 (d, J = 9.4 Hz, 1H). 366.20 1H NMR (400 MHz, DMSO-d6) δ 1.65 (s, 1H), [M + H]+ 1.71 – 1.79 (m, 1H), 1.88 (q, J = 10.5, 9.8 Hz, 1H), 2.14 (s, 1H), 2.77 (t, J = 6.4 Hz, 2H), 4.39 (d, J = 5.7 Hz, 2H), 5.23 (dd, J = 7.5, 5.0 Hz, 1H), 6.67 (s, 1H), 6.78 (d, J = 6.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 2H), 7.07 (s, 1H), 7.35 – 7.45 (m, 3H), 7.71 (td, J = 8.8, 3.0 Hz, 1H), 8.51 (d, J = 2.9 Hz, 1H), 8.82 (s, 1H). 380.18 1H NMR (300 MHz, MeOH-d4) δ 1.59 – 1.71 [M + H]+ (m, 2H), 1.96 (s, 4H), 2.23 – 2.35 (m, 1H), 2.64 – 2.78 (m, 1H), 2.88 – 2.98 (m, 1H), 4.48 (s, 2H), 5.39 (dd, J = 3.2, 5.6 Hz, 1H), 6.65 (t, J = 1.1 Hz, 1H), 6.70 – 6.77 (m, 2H), 7.31 – 7.37 (m, 2H), 7.42 – 7.49 (m, 1H), 7.55 – 7.63 (m, 1H), 8.37 – 8.42 (m, 1H). 380.18 1H NMR (300 MHz, MeOH-d4) δ 1.60 – 1.73 [M + H]+ (m, 2H), 1.96 (s, 3H), 2.00 – 2.08 (m, 1H), 2.23 – 2.35 (m, 1H), 2.66 – 2.77 (m, 1H), 2.87 – 2.97 (m, 1H), 4.48 (s, 2H), 5.40 (dd, J = 3.2, 5.6 Hz, 1H), 6.65 (s, 1H), 6.74 (d, J = 8.5 Hz, 2H), 7.31 – 7.37 (m, 2H), 7.45 (dd, J = 4.5, 8.7 Hz, 1H), 7.55 – 7.63 (m, 1H), 8.38 – 8.42 (m, 1H). 343.10 1H NMR (400 MHz, DMSO-d6) δ 1.64 – 1.76 [M + H]+ (m, 1H), 1.88 (s, 3H), 2.05 – 2.18 (m, 1H), 3.46 (dd, J = 3.5, 8.9 Hz, 1H), 3.65 – 3.83 (m, 3H), 3.86 (dd, J = 3.2, 11.9 Hz, 1H), 4.05 (dd, J = 4.0, 11.9 Hz, 1H), 4.16 – 4.23 (m, 1H), 4.72 (d, J = 13.9 Hz, 1H), 4.92 (d, J = 14.2 Hz, 1H), 5.25 (t, J = 3.5 Hz, 1H), 6.42 (d, J = 6.9 Hz, 1H), 6.63 (s, 1H), 6.81 – 6.89 (m, 2H), 7.29 – 7.37 (m, 2H), 8.38 (s, 1H). 343.00 1H NMR (300 MHz, DMSO-d6) δ 1.62 – 1.78 [M + H]+ (m, 1H), 1.88 (s, 3H), 2.02 – 2.20 (m, 1H), 3.46 (dd, J = 3.5, 8.9 Hz, 1H), 3.65 – 3.80 (m, 3H), 3.81 – 3.90 (m, 1H), 4.06 (dd, J = 4.0, 11.8 Hz, 1H), 4.16 – 4.22 (m, 1H), 4.72 (d, J = 14.2 Hz, 1H), 4.92 (d, J = 14.1 Hz, 1H), 5.25 (t, J = 3.5 Hz, 1H), 6.44 (d, J = 6.9 Hz, 1H), 6.63 (d, J = 1.1 Hz, 1H), 6.85 (d, J = 8.6 Hz, 2H), 7.28 – 7.37 (m, 2H), 8.40 (s, 1H). 407.05 1H NMR (300 MHz, DMSO-d6) δ 1.58 (s, 3H), [M + H]+ 1.64 – 1.92 (m, 3H), 2.08 (d, J = 10.2 Hz, 1H), 3.99 (d, J = 6.5 Hz, 3H), 4.30 (dd, J = 9.7, 4.6 Hz, 1H), 4.70 (dd, J = 9.7, 8.2 Hz, 1H), 5.38 (q, J = 6.8, 6.2 Hz, 1H), 6.77 (d, J = 7.0 Hz, 1H), 6.86 (dd, J = 8.7, 4.1 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 7.06 (td, J = 8.9, 2.8 Hz, 1H), 7.22 (dd, J = 8.1, 2.7 Hz, 1H), 7.31 (d, J = 8.4 Hz, 2H), 7.43 (s, 1H), 8.35 (s, 1H). 380.44 1H NMR (300 MHz, DMSO-d6) δ 1.58 (s, 3H), [M + H]+ 1.63 – 1.82 (m, 2H), 1.83 (d, J = 5.2 Hz, 1H), 2.03 – 2.12 (m, 1H), 4.01 (q, J = 6.0, 6.7 Hz, 3H), 4.42 (d, J = 5.7 Hz, 2H), 6.76 (t, J = 5.8 Hz, 1H), 6.91 – 7.00 (m, 2H), 7.17 – 7.28 (m, 2H), 7.28 – 7.37 (m, 2H), 7.48 (s, 1H), 8.50 – 8.61 (m, 1H), 8.75 (s, 1H). 332.00 1H NMR (300 MHz, DMSO-d6) δ 1.55 (d, J = [M + H]+ 7.1 Hz, 3H), 1.62 – 1.77 (m, 1H), 2.02 – 2.20 (m, 1H), 2.29 (s, 3H), 3.46 (dd, J = 3.6, 8.9 Hz, 1H), 3.63 – 3.85 (m, 3H), 4.11 – 4.25 (m, 1H), 4.39 (q, J = 7.1 Hz, 1H), 6.37 (d, J = 6.9 Hz, 1H), 7.06 – 7.17 (m, 2H), 7.25 – 7.35 (m, 2H), 8.29 (s, 1H), 8.80 (s, 1H). 332.00 1H NMR (300 MHz, DMSO-d6) δ 1.55 (d, J = [M + H]+ 7.1 Hz, 3H), 1.62 – 1.77 (m, 1H), 2.02 – 2.20 (m, 1H), 2.29 (s, 3H), 3.46 (dd, J = 3.6, 8.9 Hz, 1H), 3.63 – 3.85 (m, 3H), 4.11 – 4.25 (m, 1H), 4.39 (q, J = 7.1 Hz, 1H), 6.37 (d, J = 6.9 Hz, 1H), 7.06 – 7.17 (m, 2H), 7.25 – 7.35 (m, 2H), 8.29 (s, 1H), 8.80 (s, 1H). 353.00 1H NMR (300 MHz, DMSO-d6) δ 1.55 (d, J = [M + H]+ 7.1 Hz, 3H), 2.29 (s, 3H), 4.32 – 4.45 (m, 3H), 6.72 (t, J = 5.7 Hz, 1H), 7.07 – 7.18 (m, 2H), 7.24 – 7.30 (m, 1H), 7.31 – 7.37 (m, 3H), 7.71 – 7.83 (m, 1H), 8.48 – 8.56 (m, 1H), 8.74 (s, 1H), 8.80 (s, 1H). 342.13 1HNMR(300 MHz, DMSO-d6) δ 1.55 (d, J = 7.1 [M + H]+ Hz, 3H), 2.29 (s, 3H), 4.26 (d, J = 5.4 Hz, 2H), 4.39 (d, J = 7.0 Hz, 1H), 6.14 (d, J = 2.1 Hz, 1H), 6.44 (t, J = 5.5 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 7.29 – 7.35 (m, 2H), 7.58 (d, J = 2.1 Hz, 1H), 8.53 (s, 1H), 8.80 (s, 1H), 12.84 (s, 1H). 358.95 1H NMR (300 MHz, DMSO-d6) δ 1.56 (d, J = [M + H]+ 7.1 Hz, 3H), 2.30 (s, 3H), 4.40 (q, J = 7.1 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 6.92 (t, J = 6.1 Hz, 1H), 7.09 – 7.18 (m, 2H), 7.30 – 7.41 (m, 2H), 7.61 (d, J = 3.3 Hz, 1H), 7.72 (d, J = 3.3 Hz, 1H), 8.79 (d, J = 11.7 Hz, 2H). 356.00 1H NMR (400 MHz, DMSO-d6) δ 1.55 (d, J = [M + H]+ 7.1 Hz, 3H), 2.00 (s, 3H), 2.30 (s, 3H), 4.24 (d, J = 5.1 Hz, 2H), 4.39 (q, J = 7.1 Hz, 1H), 6.30 (s, 1H), 7.07 – 7.17 (m, 2H), 7.26 – 7.35 (m, 2H), 7.45 (s, 1H), 8.47 (s, 1H), 8.80 (s, 1H), 12.40 (s, 1H). 346.15 1H NMR (400 MHz, DMSO-d6) δ 1.48 (d, J = [M + H]+ 7.8 Hz, 1H), 1.55 (d, J = 7.1 Hz, 3H), 1.62 – 1.72 (m, 1H), 1.82 (d, J = 11.0 Hz, 1H), 2.29 (s, 3H), 3.16 – 3.24 (m, 1H), 3.31 (s, 1H), 3.46 (d, J = 7.9 Hz, 1H), 3.55 – 3.65 (m, 2H), 3.66 – 3.74 (m, 1H), 4.38 (q, J = 7.1 Hz, 1H), 6.23 (d, J = 7.9 Hz, 1H), 7.09 – 7.14 (m, 2H), 7.27 – 7.32 (m, 2H), 8.38 (s, 1H), 8.80 (s, 1H). 356.15 1H NMR (300 MHz, DMSO-d6) δ 1.55 (d, J = [M + H]+ 7.1 Hz, 3H), 2.15 – 2.21 (m, 3H), 2.29 (s, 3H), 4.16 (s, 2H), 4.39 (q, J = 7.1 Hz, 1H), 5.88 (s, 1H), 6.34 (s, 1H), 7.07 – 7.16 (m, 2H), 7.28 – 7.35 (m, 2H), 8.49 (s, 1H), 8.80 (s, 1H), 12.26 (s, 1H). 371.10 1H NMR (300 MHz, DMSO-d6) δ 1.55 (d, J = [M + H]+ 7.1 Hz, 3H), 2.29 (s, 3H), 4.39 (d, J = 5.9 Hz, 3H), 6.72 (t, J = 5.8 Hz, 1H), 7.07 – 7.18 (m, 2H), 7.28 – 7.39 (m, 2H), 7.35 – 7.46 (m, 1H), 7.71 (td, J = 3.0, 8.8 Hz, 1H), 8.51 (dd, J = 0.7, 3.0 Hz, 1H), 8.72 (s, 1H), 8.80 (s, 1H). 353.95 1H NMR (300 MHz, DMSO-d6) δ 1.55 (d, J = [M + H]+ 7.1 Hz, 3H), 2.29 (s, 3H), 4.39 (d, J = 6.1 Hz, 3H), 6.79 (t, J = 5.8 Hz, 1H), 7.08 – 7.17 (m, 2H), 7.30 – 7.39 (m, 2H), 7.43 (dd, J = 1.4, 5.2 Hz, 1H), 8.74 (d, J = 5.2 Hz, 1H), 8.82 (d, J = 9.8 Hz, 2H), 9.11 (d, J = 1.4 Hz, 1H). 371.00 1H NMR (300 MHz, DMSO-d6) δ 1.55 (d, J = [M + H]+ 7.1 Hz, 3H), 2.29 (s, 3H), 4.40 (t, J = 6.1 Hz, 3H), 6.76 (t, J = 5.9 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.22 (dd, J = 5.5, 9.3 Hz, 2H), 7.30 – 7.38 (m, 2H), 8.50 – 8.61 (m, 1H), 8.78 (d, J = 12.0 Hz, 2H). 138 354.10 1H NMR (300 MHz, DMSO-d6) δ 1.55 (d, J = [M + H]+ 7.1 Hz, 3H), 2.29 (s, 3H), 4.42 (dd, J = 6.4, 19.2 Hz, 3H), 6.81 (t, J = 5.8 Hz, 1H), 7.08 – 7.17 (m, 2H), 7.28 – 7.38 (m, 2H), 8.54 (d, J = 2.6 Hz, 1H), 8.56 – 8.65 (m, 2H), 8.80 (d, J = 3.7 Hz, 2H). 15 311.20 1H NMR (400 MHz, DMSO-d6) δ 1.92 (s, 3H), [M + H]+ 2.23 (s, 3H), 5.05 (s, 2H), 6.74 (d, J = 1.3 Hz, 1H), 7.05 – 7.12 (m, 3H), 7.40 – 7.47 (m, 3H), 8.48 (s, 1H), 9.62 (s, 1H), 12.20 (s, 1H). Procedure 3 Example 17: 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1-methyl-1H-pyrazol-3-yl)urea
Figure imgf000115_0001
4-((2-Methyl-1H-imidazol-1-yl)methyl)aniline (190 mg, 1.01 mmol) was added to a solution of phenyl (1-methyl-1H-pyrazol-3-yl)carbamate (200 mg, 0.92 mmol) and TEA (385 µl, 2.76 mmol) in DMF (5 mL) at room temperature under one atmosphere of nitrogen. The resulting mixture was stirred at 90 °C for 3 hours, then it was cooled down and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC, Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3), Mobile Phase B: MeCN; RT (min): 10.0, to afford 1-(4-((2-methyl-1H-imidazol-1- yl)methyl)phenyl)-3-(1-methyl-1H-pyrazol-3-yl)urea (0.130 g, 45.5%) as a white solid. MS (ES+, m/z): 311.00 [M + H]+; 1H NMR (400 MHz, MeOH-d4) δ 2.23 (s, 3H), 3.72 (s, 3H), 5.05 (s, 2H), 6.19 (d, J = 2.2 Hz, 1H), 6.74 (d, J = 1.3 Hz, 1H), 7.04 – 7.12 (m, 3H), 7.38 – 7.46 (m, 2H), 7.52 (d, J = 2.2 Hz, 1H), 8.88 (s, 1H), 8.98 (s, 1H). Table 10. The following compounds were made from the appropriate Intermediate and isocyanate, using a method analogous to the Procedure 3 described above. Example Structure MS (ES+, NMR m/z) 22 312.20 [M + 1H NMR (300 MHz, MeOH-d4) δ 1.82 – 1.91 (m, H]+ 3H), 2.42 – 2.51 (m, 3H), 5.60 (t, J = 6.8 Hz, 1H), 6.73 (d, J = 1.8 Hz, 1H), 7.12 – 7.30 (s, 3H), 7.42 – 7.59 (m, 3H), 8.25 – 8.40 (m, 1H), 8.48 (s, 1H, formic acid salt), two exchangeable protons not visible. 25 312.05 [M + 1H NMR (400 MHz, MeOH-d4) δ 1.86 (d, J = 7.0 H]+ Hz, 3H), 2.44 (s, 3H), 5.60 (q, J = 7.0 Hz, 1H), 7.05 (d, J = 1.1 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 7.20 – 7.27 (m, 2H), 7.43 (d, J = 1.9 Hz, 1H), 7.52 – 7.60 (m, 3H), 8.43 (s, 1H). Procedure 4 Example 7: 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea
Figure imgf000116_0001
tert-Butyl 3-((phenoxycarbonyl)amino)-1H-pyrazole-1-carboxylate (292 mg, 0.96 mmol) was added to a solution of 4-((2-methyl-1H-imidazol-1-yl)methyl)aniline (150 mg, 0.80 mmol) and TEA (162 mg, 1.60 mmol) in DMF (3 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 40 °C for 12 hours, then it was diluted with water and was extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and evaporated to afford crude tert-butyl 3-(3-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)ureido)-1H-pyrazole-1-carboxylate (190 mg, 0.47 mmol), which was dissolved in DCM (10 mL) and treated with TFA (6 mL). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC, Column: Xselect CSH OBD 30*150mm, 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN, to afford 1-(4-((2-methyl-1H-imidazol-1- yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea (39 mg, 40.1 %) as a white solid. MS (ES+, m/z): 296.9 [M + H]+; 1H NMR (400 MHz, MeOH-d4) δ 2.66 (s, 3H), 5.33 (s, 2H), 6.23 (s, 1H), 7.27 – 7.35 (m, 2H), 7.42 – 7.53 (m, 2H), 7.53 – 7.63 (m, 3H), the exchangeable protons are not visible. Table 11. The following compounds were made from the appropriate Intermediate using a method analogous to the Procedure 4 described above. Example Structure MS (ES+, NMR m/z) 140 297.33 [M + 1H NMR (300 MHz, DMSO-d6) δ 3.68 (s, 3H), H]+ 3.96 (s, 2H), 5.97 (d, J = 1.8 Hz, 1H), 6.23 (s, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 1.8 Hz, 1H), 7.36 – 7.43 (m, 2H), 7.59 (s, 1H), 8.93 (s, 1H), 9.05 (s, 1H), 12.23 (s, 1H). 141 310.95 [M + 1H NMR (300 MHz, MeOH-d4) δ 1.18 (s, 1H), H]+ 1.49 (d, J = 7.1 Hz, 3H), 3.45 (s, 3H), 4.08 (q, J = 7.1 Hz, 1H), 6.10 (s, 1H), 6.20 (dd, J = 0.7, 2.0 Hz, 1H), 6.92 – 7.03 (m, 2H), 7.24 – 7.35 (m, 3H), 7.42 (d, J = 2.4 Hz, 1H), the exchangeable protons are not visible. 11 297.05 [M + 1H NMR (300 MHz, MeOH-d4) δ 1.93 (d, J = 7.1 H]+ Hz, 3H), 5.63 (q, J = 7.0 Hz, 1H), 6.23 (d, J = 2.4 Hz, 1H), 7.26 – 7.37 (m, 3H), 7.45 (s, 1H), 7.48 – 7.59 (m, 3H), 8.21 (s, 0.324H, FA, salt), 8.47 (s, 1H), the exchangeable protons are not visible. 13 311.15 [M + 1H NMR (300 MHz, MeOH-d4) δ 1.80 (d, J = 7.1 H]+ Hz, 3H), 2.27 (s, 3H), 5.44 (q, J = 6.9 Hz, 1H), 6.21 (s, 1H), 6.87 (d, J = 1.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 1.5 Hz, 1H), 7.39 – 7.49 (m, 2H), 7.53 (d, J = 2.4 Hz, 1H), the exchangeable protons are not visible. 311.15 [M + 1H NMR (300 MHz, MeOH-d4) δ 1.80 (d, J = 7.1 H]+ Hz, 3H), 2.27 (s, 3H), 5.44 (q, J = 6.9 Hz, 1H), 6.21 (s, 1H), 6.87 (d, J = 1.5 Hz, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 1.5 Hz, 1H), 7.39 – 7.49 (m, 2H), 7.53 (d, J = 2.4 Hz, 1H), the exchangeable protons are not visible. 315.20 [M + 1H NMR (300 MHz, DMSO-d6) δ 2.14 – 2.30 (s, H]+ 3H), 4.92 – 5.19 (s, 2H), 6.06 – 6.27 (s, 1H), 6.71 – 6.79 (d, J = 1.3 Hz, 1H), 6.90 – 7.05 (m, 2H), 7.07 – 7.18 (d, J = 1.3 Hz, 1H), 7.56 – 7.68 (d, J = 2.4 Hz, 1H), 8.07 – 8.20 (t, J = 8.4 Hz, 1H), the exchangeable protons are not visible. 325.20 [M + 1H NMR (400 MHz, MeOH-d4) δ 0.86 (t, J = 7.3 H]+ Hz, 3H), 2.18 (dq, J = 7.4, 7.3 Hz, 2H), 2.39 (s, 3H), 5.18 (t, J = 7.7 Hz, 1H), 6.11 (s, 1H), 7.10 (d, J = 1.8 Hz, 1H), 7.13 – 7.21 (m, 2H), 7.36 – 7.46 (m, 4H), 8.30 (s, 0.7H, formic acid salt). 325.20 [M + 1H NMR (400 MHz, MeOH-d4) δ 0.93 (t, J = 7.3 H]+ Hz, 3H), 2.20 (dq, J = 7.4, 7.3 Hz, 2H), 2.32 (s, 3H), 5.12 (t, J = 7.7 Hz, 1H), 6.18 – 6.23 (m, 1H), 6.89 (d, J = 1.5 Hz, 1H), 7.14 – 7.22 (m, 2H), 7.24 (d, J = 1.6 Hz, 1H), 7.41 – 7.49 (m, 2H), 7.53 (d, J = 2.4 Hz, 1H). 298.05 [M + 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), H]+ 3.31 (s, 1H), 5.14 (s, 2H), 6.25 (s, 1H), 6.74 (d, J = 1.3 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 1.2 Hz, 1H), 7.58 – 7.63 (m, 1H), 7.93 (dd, J = 2.6, 8.5 Hz, 1H), 8.55 (d, J = 2.7 Hz, 1H), 9.09 (s, 1H), 9.20 (s, 1H), 12.27 (s, 1H). 323.2 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.50 – 1.79 (m, H]+ 4H), 2.41 (s, 3H), 6.24 (d, J = 2.3 Hz, 1H), 6.80 – 6.94 (m, 2H), 7.35 – 7.50 (m, 3H), 7.56 (d, J = 2.3 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 9.01 (s, 1H), 9.30 (s, 1H), 12.25 (s, 1H). 337.05 [M + 1H NMR (300 MHz, DMSO-d6) δ 0.20 (dd, J = 4.3, H]+ 9.0 Hz, 1H), 0.32 – 0.66 (m, 3H), 1.51 (d, J = 6.8 Hz, 1H), 2.01 (s, 3H), 4.38 (d, J = 9.6 Hz, 1H), 6.13 (s, 1H), 6.67 (d, J = 1.3 Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 7.29 (dd, J = 3.6, 5.1 Hz, 3H), 7.48 (s, 1H), 8.90– 9.03 (m, 2H), 12.16 (s, 1H). 337.05 [M + 1H NMR (300 MHz, DMSO-d6) δ 0.20 (dd, J = 4.3, H]+ 9.0 Hz, 1H),δ 0.50 – 0.69 (m, 3H), 1.24 (s, 1H), 1.63 (s, 1H), 2.11 (s, 4H), 4.49 (d, J = 9.6 Hz, 1H), 6.25 (s, 1H), 6.79 (d, J = 1.3 Hz, 1H), 7.09 (d, J = 8.5 Hz, 2H), 7.35 – 7.44 (m, 3H), 7.57 (s, 1H), 8.95 (s, 1H), 9.06 (s, 1H), 12.23 (s, 1H). MS (ES+, 1H NMR (300 MHz, DMSO-d6) δ 1.58 (dd, J = 7.4, m/z): 3.5 Hz, 3H), 1.80 (d, J = 3.4 Hz, 3H), 2.09 (d, J = 325.20 [M + 3.7 Hz, 3H), 5.27 (s, 1H), 6.64 (d, J = 3.3 Hz, 1H), H]+ 6.91 – 7.20 (m, 3H), 7.29 (dd, J = 8.7, 3.5 Hz, 3H), 8.35 (s, 1H), 9.36 – 9.60 (m, 1H), 12.08 (s, 1H). 297.33 [M + 1H NMR (400 MHz, DMSO-d6) δ 1.76 (d, J = 7.1 H]+ Hz, 3H), 5.47 (q, J = 7.1 Hz, 1H), 6.23 (s, 1H), 6.89 (t, J = 1.1 Hz, 1H), 7.17 – 7.26 (m, 3H), 7.37 – 7.45 (m, 2H), 7.59 (s, 1H), 7.77 (d, J = 1.2 Hz, 1H), 8.95 (s, 1H), 9.08 (s, 1H), 12.24 (s, 1H). 297.33 [M + 1H NMR (400 MHz, DMSO-d6) δ 1.76 (d, J = 7.1 H]+ Hz, 3H), 5.46 (q, J = 7.0 Hz, 1H), 6.22 (s, 1H), 6.88 (t, J = 1.2 Hz, 1H), 7.16 – 7.25 (m, 3H), 7.37 – 7.45 (m, 2H), 7.58 (s, 1H), 7.76 (t, J = 1.2 Hz, 1H), 8.94 (s, 1H), 9.08 (s, 1H), 12.23 (s, 1H). 325.05 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.11 (t, J = 7.5 H]+ Hz, 3H), 1.71 (d, J = 7.0 Hz, 3H), 2.38 – 2.57 (m, 1H), 2.66 (dq, J = 15.0, 7.5 Hz, 1H), 5.42 (q, J = 7.1 Hz, 1H), 6.23 (s, 1H), 6.80 (d, J = 1.4 Hz, 1H), 7.10 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 1.4 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.59 (s, 1H), 8.94 (s, 1H), 9.07 (s, 1H), 12.24 (s, 1H). 337.05 [M + 1H NMR (300 MHz, DMSO-d6) δ 0.58 – 0.69 (m, H]+ 1H), 0.71 – 0.88 (m, 3H), 1.72 (d, J = 7.0 Hz, 3H), 1.83 – 1.94 (m, 1H), 5.64 (d, J = 7.0 Hz, 1H), 6.21 (s, 1H), 6.69 (d, J = 1.3 Hz, 1H), 7.18 (m, 3H), 7.39 (d, J = 8.5 Hz, 2H), 7.58 (s, 1H), 8.91 (s, 1H), 9.06 (s, 1H), 12.21 (s, 1H). 310.95 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.61 (d, J = 7.0 H]+ Hz, 3H), 4.25 – 4.43 (m, 2H), 5.24 (t, J = 5.6 Hz, 1H), 5.54 (q, J = 6.8 Hz, 1H), 6.11 (s, 1H), 6.69 (d, J = 1.3 Hz, 1H), 7.04 – 7.14 (m, 3H), 7.28 (d, J = 8.5 Hz, 2H), 7.47 (s, 1H), 8.81 (s, 1H), 8.96 (s, 1H), 12.11 (s, 1H). 327.15 [M + 1H NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3H), H]+ 3.89 – 4.04 (m, 2H), 5.12 – 5.23 (m, 2H), 6.23 (s, 1H), 6.76 (d, J = 1.3 Hz, 1H), 7.12 – 7.17 (m, 2H), 7.27 (d, J = 1.5 Hz, 1H), 7.38 – 7.43 (m, 2H), 7.59 (s, 1H), 8.94 (s, 1H), 9.08 (s, 1H), 12.24 (s, 1H). 467.34 [M + 1H NMR (300 MHz, DMSO-d6) δ 2.31 (s, 3H), H]+ 5.71 – 5.84 (m, 1H), 6.25 (s, 1H), 6.62 – 7.03 (m, 2H), 7.24 (d, J = 1.4 Hz, 1H), 7.30 – 7.38 (m, 2H), 7.45 – 7.53 (m, 2H), 7.59 (d, J = 2.3 Hz, 1H), 8.97 (s, 1H), 9.15 (s, 1H), 12.24 (s, 1H). 345.10 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.60 (d, J = 7.0 H]+ Hz, 3H), 2.10 (s, 3H), 5.31 (q, J = 7.0 Hz, 1H), 6.03 (s, 1H), 6.67 (d, J = 1.4 Hz, 1H), 6.98 – 7.07 (m, 1H), 7.09 – 7.20 (m, 2H), 7.50 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 9.51 (s, 1H), 12.23 (s, 1H). 363.15 [M + 1H NMR (300 MHz, MeOH-d4) δ 1.88 (d, J = 7.0 H]+ Hz, 3H), 2.43 (s, 3H), 5.64 (q, J = 7.0 Hz, 1H), 6.20 (s, 1H), 7.07 (dd, J = 2.0, 10.2 Hz, 1H), 7.13 – 7.28 (m, 2H), 7.43 – 7.49 (m, 1H), 7.53 – 7.59 (m, 1H), 8.43 (s, 2H). 283.10 1H NMR (300 MHz, DMSO-d6) δ 5.09 (s, 2H), + 6.21 (d, J = 2.3 Hz, 1H), 6.87 (d, J = 1.2 Hz, 1H), [M + H] 7.11 – 7.22 (m, 3H), 7.37 – 7.46 (m, 2H), 7.57 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 1.4 Hz, 1H), 8.19 (s, 1H), 8.98 (s, 1H), 9.12 (s, 1H). 325.20 [M + 1H NMR (400 MHz, DMSO-d6) δ 1.11 (t, J = 7.5 H]+ Hz, 3H), 1.71 (d, J = 7.0 Hz, 3H), 2.42 – 2.49 (m, 1H), 2.60 – 2.74 (m, 1H), 5.43 (q, J = 7.0 Hz, 1H), 6.23 (s, 1H), 6.83 (d, J = 1.4 Hz, 1H), 7.07 – 7.14 (m, 2H), 7.27 (d, J = 1.4 Hz, 1H), 7.37 – 7.43 (m, 2H), 7.59 (s, 1H), 8.95 (s, 1H), 9.08 (s, 1H), 12.25 (s, 1H). 323.30 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.60 – 1.81 (m, H]+ 2H), 1.83 – 1.96 m, 1H), 2.04 – 2.19 (m, 1H), 2.78 (t, J = 6.4 Hz, 2H), 5.22 – 5.29 (m, 1H), 6.21 (s, 1H), 6.68 (s, 1H), 6.99 (d, J = 8.3 Hz, 2H), 7.09 (s, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.57 (s, 1H), 8.94 (s, 1H), 9.10 (s, 1H), 12.22 (s, 1H). 337.25 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.39 – 1.68 (m, H]+ 2H), 1.85 (s, 3H), 1.89 – 2.00 (m, 1H), 2.10 – 2.28 (m, 1H), 2.55 – 2.70 (m, 1H), 2.85 (d, J = 16.0 Hz, 1H), 5.42 (d, J = 5.1 Hz, 1H), 6.25(d, J = 2.2 Hz, 1H), 6.58 (s, 1H), 6.72 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 2.3 Hz, 1H), 8.92 (s, 1H), 9.10 (s, 1H), 12.10 (s, 1H). 122 313.95 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.50 (d, J = 7.1 H]+ Hz, 3H), 4.30 (q, J = 7.0 Hz, 1H), 6.11 (s, 1H), 7.07 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.47 (s, 1H), 7.58 (s, 1H), 8.81 (d, J = 3.4 Hz, 2H), 8.94 (s, 1H), 12.11 (s, 1H). 123 300.35 [M + 1H NMR (300 MHz, DMSO-d6) δ 4.15 (s, 2H), H]+ 6.23 (s, 1H), 7.17 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.60 (s, 1H), 7.72 (d, J = 0.9 Hz, 1H), 8.93 (d, J = 1.0 Hz, 1H), 9.06 (s, 1H), 12.24 (s, 1H). 128 328 [M+H]+ 1H NMR (300 MHz, MeOH-d4) δ 1.65 (d, J = 7.1 Hz, 3H), 2.33 (s, 3H), 4.44 (q, J = 7.1 Hz, 1H), 6.20 (d, J = 2.4 Hz, 1H), 7.14 – 7.25 (m, 2H), 7.35 – 7.46 (m, 2H), 7.53 (d, J = 2.4 Hz, 1H), 8.74 (s, 1H), the exchangeable protons are not visible. 98 441.24 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.48 (d, J = 7.2 H]+ Hz, 3H), 2.02 (s, 3H), 4.01 (d, J = 7.4 Hz, 1H), 6.19 (s, 1H), 7.15 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.37 (s, 1H), 7.56 (d, J = 2.3 Hz, 1H), 8.87 (s, 1H), 8.97 (s, 1H), 11.64 (s, 1H), 12.20 (s, 1H). 99 441.24 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.48 (d, J = 7.2 H]+ Hz, 3H), 2.01 (s, 3H), 4.00 (s, 1H), 6.19 (s, 1H), 7.15 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.35 (s, 1H), 7.56 (d, J = 2.3 Hz, 1H), 8.87 (s, 1H), 8.97 (s, 1H), 11.54 (s, 1H), 12.20 (s, 1H). Procedure 5 Example 37: (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxazol-4-yl)urea Step 1 Diphenyl phosphorazidate (2.68 g, 9.73 mmol) was added dropwise to a solution of oxazole-4- carboxylic acid (1.0 g, 8.84 mmol) and TEA (3.70 ml, 26.53 mmol) in THF (10 mL) at 0 °C under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with mixtures of 0 to 5% THF in DCM, to afford oxazole-4-carbonyl azide (0.809 g, 66.2%) as a white solid. MS (ES+, m/z): 139.0 [M+H]+; 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 1.0 Hz, 1H), 8.23 (d, J = 1.0 Hz, 1H). Step 2 A solution of oxazole-4-carbonyl azide (284 mg, 2.06 mmol) in toluene (2 mL) was stirred at 90 °C for 1 hour. TEA (956 µl, 6.86 mmol) and rel-(R)-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)aniline dihydrochloride (100 mg, 1.37 mmol) were added and the resulting mixture was stirred at 100 °C for 2.5 hours. The mixture was concentrated under reduced pressure. The crude product was purified The crude product was purified by flash C18-flash chromatography, eluting with a mixture of 30 to 50% MeCN in water (0.1% NH4HCO3), to afford (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)- 3-(oxazol-4-yl)urea (45 mg, 2.1%) as a yellow oil. MS (ES+, m/z): 312.3 [M+H]+; 1H NMR (300 MHz, MeOH-d4) δ 1.79 (d, J = 7.1 Hz, 3H), 2.26 (s, 3H), 5.43 (q, J = 7.0 Hz, 1H), 6.86 (d, J = 1.5 Hz, 1H), 7.05 – 7.15 (m, 2H), 7.18 (d, J = 1.5 Hz, 1H), 7.36 – 7.47 (m, 2H), 7.86 (d, J = 1.2 Hz, 1H), 7.97 (d, J = 1.2 Hz, 1H), the exchangeable protons are not visible. Table 12. The following compounds were made from the appropriate Intermediate using a method analogous to the Procedure 5 described above. Example Structure MS (ES+, m/z) NMR 339.95 [M + 1H NMR (300 MHz, DMSO-d6) δ 1.72 (d, J = H]+ 7.0 Hz, 3H), 2.21 (s, 3H), 5.40 (t, J = 7.0 Hz, 1H), 6.77 (d, J = 1.3 Hz, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 1.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.73 (dd, J = 1.9, 6.4 Hz, 2H), 8.27 (s, 1H), 9.36 (s, 1H), 9.73 (s, 1H). 339.95 [M + 1H NMR (400 MHz, DMSO-d6) δ 1.75 (d, J = H]+ 7.0 Hz, 3H), 2.20 (s, 3H), 5.42 (q, J = 7.0 Hz, 1H), 6.78 (d, J = 1.4 Hz, 1H), 7.11 – 7.19 (m, 3H), 7.25 (d, J = 1.4 Hz, 1H), 7.49 – 7.55 (m, 2H), 7.70 – 7.79 (m, 1H), 8.18 (d, J = 4.9 Hz, 1H), 9.43 (s, 1H), 11.01 (s, 1H). 323.10 1H NMR (400 MHz, DMSO-d6) δ 1.72 (d, J = + 7.0 Hz, 3H), 2.21 (s, 3H), 5.42 (q, J = 6.9 Hz, [M + H] 1H), 6.78 (d, J = 1.4 Hz, 1H), 7.11 – 7.18 (m, 2H), 7.25 (d, J = 1.4 Hz, 1H), 7.42 – 7.49 (m, 2H), 7.64 (dd, J = 4.7, 9.1 Hz, 1H), 8.02 (dd, J = 1.5, 9.1 Hz, 1H), 8.88 (dd, J = 1.5, 4.7 Hz, 1H), 9.73 (s, 1H), 9.78 (s, 1H). 401.80 [M + 1H NMR (400 MHz, DMSO-d6) δ 1.72 (d, J = H]+ 7.0 Hz, 3H), 2.21 (s, 3H), 5.41 (d, J = 6.9 Hz, 1H), 6.77 (d, J = 1.4 Hz, 1H), 7.06 – 7.27 (m, 3H), 7.45 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.9 Hz, 1H), 7.96 (dd, J = 8.9, 2.6 Hz, 1H), 8.38 (d, J = 2.5 Hz, 1H), 9.44 (s, 1H), 9.78 (s, 1H). 322.05 [M + 1H NMR (400 MHz, DMSO-d6) δ 1.70 (d, J = H]+ 7.0 Hz, 3H), 2.20 (s, 3H), 3.59 (s, 3H), 5.38(q, J = 7.0 Hz, 1H), 6.77 (d, J = 1.5 Hz, 1H), 6.90 (s, 1H), 7.09 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 1.5 Hz, 1H), 7.37 (m, 3H), 8.61 (s, 1H), 8.90 (s, 1H). 139 328.95[M + H]+ 1H NMR (300 MHz, DMSO-d6) δ 1.58 (d, J = 7.1 Hz, 3H), 2.30 (s, 3H), 4.45 (q, J = 7.0 Hz, 1H), 7.14 (d, J = 1.1 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.82 (s, 1H), 8.82 (s, 1H), 10.29 (s, 1H), 10.85 (s, 1H). Procedure 6 Example 83: (rac)-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(2-hydroxy-4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)urea
Figure imgf000125_0001
Step 1 Methylmagnesium bromide (29.31 mmol) was added dropwise to a solution of 4-chloro-3- methoxybenzaldehyde (5g, 29.31 mmol) in THF (50 mL) at -78 °C under one atmosphere of nitrogen. The reaction mixture was stirred at -78 °C for 1 hour, then it was warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated NH4Cl (100 mL), extracted with EtOAc (100 mL x 2) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 5% MeOH in DCM, to afford 1-(4-chloro-3- methoxyphenyl)ethan-1-ol (5.00 g, 91%) as a light-yellow oil. MS (ES+, m/z): 187.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.32 (d, J = 6.4 Hz, 3H), 3.85 (s, 3H), 4.66 – 4.78 (m, 1H), 5.22 – 5.29 (m, 1H), 6.87 – 6.97 (m, 1H), 7.12 (d, J = 1.9 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H). Steps 2-3 1-(4-Chloro-3-methoxyphenyl)ethan-1-ol (4.8g, 25.72 mmol) was added to SOCl2 (5 mL, 68.51 mmol) at room temperature and the reaction mixture was stirred at 80 °C for 2 hours. The solvent was removed under reduced pressure. The residue was taken up in DMF (20 mL) and 2-methyl-1H- imidazole (4.22 g, 51.44 mmol) and Cs2CO3 (25.1 g, 77.16 mmol) were added. The reaction mixture was stirred at 80 °C for 24 hours, then additional 2-methyl-1H-imidazole (4.22 g, 51.44 mmol) was added and stirring continued at 80 °C for 48 hours. The solvent was removed under reduced pressure and the crude product was purified by flash C18-flash chromatography, eluting with a mixture of 0 to 50% MeCN in water (0.1% NH4HCO3), to afford 1-(1-(4-chloro-3- methoxyphenyl)ethyl)-2-methyl-1H-imidazole (3.50 g, 54.3%) as a white solid. MS (ES+, m/z): 251.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.74 (d, J = 7.0 Hz, 3H), 2.21 (s, 3H), 3.83 (s, 3H), 5.39 – 5.52 (m, 1H), 6.63 – 6.72 (m, 1H), 6.81 (d, J = 1.4 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 7.29 – 7.42 (m, 2H). Steps 4-5 Pd2(dba)3 (3.65 mg, 3.99 µmol) and t-BuBrettPhos (3.87 mg, 7.98 µmol) were suspended in toluene (2 mL) at room temperature under one atmosphere of nitrogen. The mixture was stirred at room temperature for 3 minutes, then it was added to a solution of 1-(1-(4-chloro-3- methoxyphenyl)ethyl)-2-methyl-1H-imidazole (100mg, 0.40 mmol), sodium cyanate (51.9 mg, 0.80 mmol), phenol (75 mg, 0.80 mmol) and TEA (0.014 mL, 0.10 mmol) in toluene (2 mL) at room temperature under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 16 hours. (5-Fluoropyridin-2-yl)methanamine (60.4 mg, 0.48 mmol) was added and the reaction mixture was stirred at room temperature for 5 hours. The crude product was successively purified by flash silica chromatography, eluting with a mixture of 0 to 4% MeOH in DCM, and by preparative HPLC, Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3), Mobile Phase B: MeCN; RT (min): 6.63, to afford 1-((5- fluoropyridin-2-yl)methyl)-3-(2-methoxy-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea (30.0 mg, 9.78%) as a white solid. MS (ES+, m/z): 384.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.71 (d, J = 7.0 Hz, 3H), 2.23 (s, 3H), 3.81 (s, 3H), 4.37 (d, J = 5.7 Hz, 2H), 5.29 – 5.42 (m, 1H), 6.67 (dd, J = 1.9, 8.4 Hz, 1H), 6.76 (d, J = 1.3 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 7.34 – 7.42 (m, 1H), 7.46 (t, J = 5.9 Hz, 1H), 7.64 – 7.77 (m, 1H), 8.00 (d, J = 8.3 Hz, 1H), 8.15 (s, 1H), 8.51 (d, J = 3.0 Hz, 1H). Step 6 A 1 M solution of BBr3 in DCM (0.1 mL, 0.10 mmol) was added dropwise to a solution of 1-((5- fluoropyridin-2-yl)methyl)-3-(2-methoxy-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea (20 mg, 0.05 mmol) in DCM (1 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 2 hours, then it was quenched with water (1 mL) and concentrated under reduced pressure. The crude product was purified by preparative HPLC, Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3), Mobile Phase B: MeCN; RT (min): 6.52, to afford 1-((5-fluoropyridin-2-yl)methyl)-3-(2-hydroxy-4-(1-(2- methyl-1H-imidazol-1-yl)ethyl)phenyl)urea (15 mg, 78%) as a white solid. MS (ES+, m/z): 370.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.67 (d, J = 7.0 Hz, 3H), 2.19 (s, 3H), 4.37 (d, J = 5.8 Hz, 2H), 5.24 – 5.37 (m, 1H), 6.51 (d, J = 2.1 Hz, 1H), 6.58 (dd, J = 2.1, 8.4 Hz, 1H), 6.77 (d, J = 1.4 Hz, 1H), 7.18 (d, J = 1.4 Hz, 1H), 7.34 – 7.41 (m, 1H), 7.41 – 7.47 (m, 1H), 7.64 – 7.77 (m, 1H), 7.83 (d, J = 8.3 Hz, 1H), 8.13 (s, 1H), 8.50 (d, J = 2.9 Hz, 1H), 9.90 (s, 1H). Procedure 7 Example 2: 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea
Figure imgf000127_0001
Step 1 Ethyl 4-(3-(pyridin-2-yl)ureido)benzoate made using the Procedure 1 described above. MS (ES+, m/z): 286.2 [M + H]+1H NMR (400 MHz, DMSO-d6) δ 1.31 (t, J = 7.1 Hz, 3H), 4.29 (d, J = 7.1 Hz, 2H), 6.96 – 7.08 (m, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.63 – 7.73 (m, 2H), 7.77 (dd, J = 8.9, 7.3 Hz, 1H), 7.86 – 7.96 (m, 2H), 8.30 (dd, J = 5.1, 2.0 Hz, 1H), 9.58 (s, 1H), 10.81 (s, 1H). Step 2 LiBH4 (0.458 g, 21.03 mmol) was added to a solution of ethyl 4-(3-(pyridin-2-yl)ureido)benzoate (1.2 g, 4.21 mmol) in THF (30 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 16 hours. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 10% MeOH in DCM, to afford 1-(4-(hydroxymethyl)phenyl)-3-(pyridin- 2-yl)urea (0.80 g, 78%) as a yellow solid. MS (ES+, m/z): 244.2 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 4.44 (d, J = 5.6 Hz, 2H), 5.10 (t, J = 5.7 Hz, 1H), 7.00 (dd, J = 7.3, 5.0 Hz, 1H), 7.22 – 7.31 (m, 2H), 7.43 – 7.52 (m, 3H), 7.74 (dd, J = 9.0, 7.3 Hz, 1H), 8.25 – 8.31 (m, 1H), 9.43 (s, 1H), 10.51 (s, 1H). Step 3 SOCl2 (450 µl, 6.17 mmol) was added to a solution of 1-(4-(hydroxymethyl)phenyl)-3-(pyridin-2- yl)urea (500 mg, 2.06 mmol) and pyridine (16.62 µl, 0.21 mmol) in DCM (5 mL) and THF (15 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes. The crude product was purified by flash C18-flash chromatography, eluting with a mixture of 0 to 100% MeCN in water (0.1% NH4HCO3), to afford 1-(4-(chloromethyl)phenyl)-3-(pyridin-2- yl)urea (0.30 g, 55.8%) as a yellow solid. MS (ES+, m/z): 262.2 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 4.74 (s, 2H), 7.19 (t, J = 3.4 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.41 (s, 1H), 7.53 (dd, J = 8.6, 3.2 Hz, 3H), 8.00 (q, J = 8.1 Hz, 1H), 8.30 (d, J = 5.3 Hz, 1H), 10.47 (s, 1H), 10.56 (s, 1H). Step 4 1-(4-(Chloromethyl)phenyl)-3-(pyridin-2-yl)urea (50 mg, 0.19 mmol) was added to a suspension of 2- methyl-1H-imidazole (15.69 mg, 0.19 mmol) and K2CO3 (52.8 mg, 0.38 mmol) in MeCN (3 mL) under one atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 2 hours and then it was concentrated under reduced pressure. The reaction mixture was purified by flash C18- flash chromatography, eluting with a mixture of 0 to 70% MeCN in water, to afford crude product. The crude product was purified by preparative HPLC, Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: MeCN; RT (min): 6.15, to afford 1-(4-((2- methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea (8 mg, 13%) as a white solid. MS (ES+, m/z): 308.3 [M + H]+; 1H NMR (300 MHz, MeOH-d4) δ 2.40 (s, 3H), 5.18 (s, 2H), 6.96 – 7.06 (m, 2H), 7.17 (dd, J = 1.2, 8.7 Hz, 4H), 7.51 – 7.61 (m, 2H), 7.72 (dd, J = 7.2, 8.4 Hz, 1H), 8.28 (dd, J = 1.8, 5.1 Hz, 1H). Table 13. The following compounds were made from the appropriate Intermediate using a method analogous to the Procedure 7 described above. Example Structure MS (ES+, NMR m/z) 3 308.20 [M + 1H NMR (300 MHz, MeOH-d4) δ 2.15 (s, 3H), H]+ 5.09 (s, 2H), 6.79 (s, 1H), 6.96 – 7.08 (m, 1H), 7.13 – 7.25 (m, 3H), 7.49 – 7.59 (m, 2H), 7.62 (s, 1H), 7.67 – 7.80 (m, 1H), 8.24 – 8.32 (m, 1H). Procedure 8 Example 29: (rac)-(R)-1-(5-hydroxypyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)urea
Figure imgf000129_0001
Step 1 1-(5-(Benzyloxy)pyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea was made using the Procedure 2 described above. MS (ES+, m/z): 428.10 [M + H]+; 1H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H), 7.87 (d, J = 3.0 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.32 (d, J = 1.2 Hz, 1H), 7.30 (d, J = 1.8 Hz, 2H), 7.25 (d, J = 3.0 Hz, 1H), 7.22 (d, J = 3.0 Hz, 1H), 7.00 – 6.90 (m, 4H), 6.79 (d, J = 9.0 Hz, 1H), 5.24 (q, J = 9.0, 7.8 Hz, 1H), 4.99 (s, 2H), 2.35 (s, 3H), 1.72 (d, J = 7.2 Hz, 3H). Step 2 10% Pd-C (w/w) (50 mg, 0.47 mmol) was added to a solution of 1-(5-(benzyloxy)pyridin-2-yl)-3-(4-(1- (2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea (50 mg, 0.12 mmol) in MeOH (5 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 2 hours, then it was filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure and the crude product was purified by preparative HPLC, Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3), Mobile Phase B: MeCN; RT (min): 10.45, to afford 1-(5-hydroxypyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea (4.00 mg, 10.14%) as a white solid. MS (ES+, m/z): 337.95 [M + H]+; 1H NMR (300 MHz, MeOH-d4) δ 7.74 (d, J = 2.9 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H), 7.10 (d, J = 3.0 Hz, 2H), 7.02 (d, J = 8.4 Hz, 3H), 6.77 (s, 1H), 5.35 (d, J = 7.2 Hz, 1H), 2.17 (s, 3H), 1.70 (d, J = 7.2 Hz, 3H), the exchangeable proton is not visible. Procedure 9 Example 30: (rac)-(R)-1-(5-(hydroxymethyl)pyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)urea
Figure imgf000130_0001
Step 1 (rac)-Phenyl (R)-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)carbamate 5-(((tert- butyldimethylsilyl)oxy)methyl) pyridin-2-amine was prepared using the Procedure 8, step 1 described above. MS (ES+, m/z): 446.0 [M + H]+; 1H NMR (300 MHz, CDCl3) δ 0.01 (s, 6H), 0.69 – 0.87 (m, 1H), 0.83 (s, 7H), 1.15 (s, 1H), 1.71 (d, J = 7.0 Hz, 3H), 2.24 (s, 3H), 3.34 (s, 1H), 3.60 (s, 1H), 4.59 (s, 2H), 5.20 (q, J = 7.1 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 6.87 – 6.98 (m, 4H), 7.42 – 7.57 (m, 3H), 8.05 – 8.12 (m, 1H), 8.86 (s, 1H), 11.75 (s, 1H). Step 2 (rac)-(R)-1-(5-(((tert-Butyldimethylsilyl)oxy)methyl)pyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)urea (87 mg, 0.19 mmol) was added to a 4 M HCl solution in EtOH (1 mL, 4.00 mmol). The resulting mixture was stirred at room temperature for 1 hour, then it was concentrated under reduced pressure. The crude product was purified by preparative HPLC, Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3), Mobile Phase B: MeCN; RT (min): 7.45, to afford (rac)-(R)-1-(5-(hydroxymethyl)pyridin-2-yl)-3-(4-(1-(2-methyl-1H- imidazol-1-yl)ethyl)phenyl)urea (10.93 mg, 16.65%) as a white solid. MS (ES+, m/z): 352.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.59 (d, J = 7.0 Hz, 3H), 2.09 (s, 3H), 4.32 (d, J = 5.6 Hz, 2H), 5.08 (t, J = 5.6 Hz, 1H), 5.29 (q, J = 7.0 Hz, 1H), 6.65 (d, J = 1.4 Hz, 1H), 6.97 – 7.06 (m, 2H), 7.12 (d, J = 1.4 Hz, 1H), 7.35 (dd, J = 4.0, 8.5 Hz, 3H), 7.57 (dd, J = 2.3, 8.5 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 9.26 (s, 1H), 10.33 (s, 1H). Procedure 10 Example 40: rel-(R)-1-(4-chloro-1H-pyrazol-3-yl)-3-(4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)urea
Figure imgf000131_0001
Steps 1-2 tert-Butyl 4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)benzoate was made using the Procedure A, step 2 described above. MS (ES+, m/z): 287.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.41 (d, J = 2.6 Hz, 9H), 1.62 (d, J = 7.0 Hz, 3H), 2.02 (d, J = 28.4 Hz, 3H), 7.06 – 7.25 (m, 3H), 7.61 – 7.77 (m, 2H), 8.04 (s, 2H). Step 3 tert-Butyl 4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)benzoate (1 g, 3.49 mmol) was added to a 4 M HCl solution in in 1,4-dioxane (5 mL). The resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to afford 4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)benzoic acid (0.80 g, 99 %) as a white solid. MS (ES+, m/z): 230.8 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.74 (d, J = 7.0 Hz, 3H), 2.18 (s, 3H), 5.54 (q, J = 7.0 Hz, 1H), 6.81 (d, J = 1.4 Hz, 1H), 7.24 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 1.4 Hz, 1H), 7.90 (d, 2H). Steps 4-5 rel-(R)-4-(1-(2-Methyl-1H-imidazol-1-yl)ethyl)benzoic acid (118.7 mg, 0.52 mmol) was added to a solution of DPPA (156 mg, 0.57 mmol) and TEA (156 mg, 1.55 mmol) in toluene (1.5 mL) at 0 °C under one atmosphere of nitrogen. The reaction mixture was stirred at 0 °C for 1.5 hour, then at 90 °C for 1 hour.4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-amine (63.9 mg, 0.26 mmol) was added and stirring at 90 °C continued for 15 hours. The solvent was removed under reduced pressure and the reaction mixture was quenched with water (5 mL), extracted with DCM (5 mL x 3), the combined organic layers were dried over Na2SO4, and evaporated. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 5.3% MeOH in DCM, to afford rel-(R)-1-(4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3-(4-(1-(2-methyl-1H- imidazol-1-yl)ethyl)phenyl)urea (55 mg, 22.5 %) as a yellow solid. MS (ES+, m/z): 475.20 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ -0.08 – -0.02 (s, 9H), 0.79 – 0.86 (m, 2H), 1.19 – 1.25 (s, 2H), 1.65 – 1.73 (d, J = 7.0 Hz, 3H), 2.18 – 2.24 (s, 3H), 3.50 – 3.57 (m, 2H), 5.35 – 5.47 (m, 1H), 6.77 – 6.84 (d, J = 1.4 Hz, 1H), 7.05 – 7.14 (d, J = 8.7 Hz, 2H), 7.22 – 7.29 (d, J = 1.5 Hz, 1H), 7.35 – 7.44 (m, 2H), 8.07 – 8.13 (s, 1H), 8.44 – 8.50 (s, 1H), 9.01 – 9.07 (s, 1H). Step 6 rel-(R)-1-(4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-3-(4-(1-(2-methyl-1H- imidazol-1-yl)ethyl)phenyl)urea (55 mg, 0.12 mmol) was added to a solution of TBAF (151 mg, 0.58 mmol) in THF (1 mL) under one atmosphere of nitrogen. The resulting mixture was stirred at 65 °C for 2 hours, then concentrated under reduced pressure. The crude product was purified by preparative HPLC, Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3), Mobile Phase B: MeCN), to afford rel-(R)-1-(4-chloro-1H- pyrazol-3-yl)-3-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)urea (6.36 mg, 15.93 %) as a white solid. MS (ES+, m/z): 345.20 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 0.92 (t, J = 7.3 Hz, 0H), 1.72 (d, J = 7.0 Hz, 3H), 2.18 (s, 3H), 5.37 (q, J = 7.0 Hz, 1H), 6.75 (d, J = 1.3 Hz, 1H), 7.08 (m, 2H), 7.22(d, J = 1.4 Hz, 1H), 7.31 – 7.46 (m, 2H), 8.98 (s, 1H), 12.84 (s, 1H). Procedure 11 Example 86: (R)-1-(4-(2-fluoro-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-fluoropyridin-2- yl)methyl)urea
Figure imgf000132_0001
Step 1 Ethyl 2-(4-aminophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetate (1 g, 3.86 mmol) was added to a solution of LiAlH4 (0.16 g, 4.24 mmol) in THF (10 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at 0 °C for 3 hours, then quenched by successive addition of water (0.15 mL), 15% NaOH (0.15 mL) and water (0.45 mL). The reaction mixture was filtered through a pad of CELITE. The filtrate was concentrated under reduced pressure and the crude product was purified by C18-flash chromatography, eluting with a mixture of 0 to 30% MeCN in water (0.1% NH4HCO3), to afford 2-(4-aminophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethan-1-ol (0.31 g, 36.9%) as a yellow solid. MS (ES+, m/z): 218.0 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 2.20 (s, 3H), 3.44 (d, J = 7.4 Hz, 1H), 3.84 (dd, J = 10.9, 40.6 Hz, 2H), 5.02 – 5.09 (m, 3H), 6.48 (d, J = 8.0 Hz, 2H), 6.73 (s, 1H), 6.88 (d, J = 8.0 Hz, 2H), 7.21 (s, 1H). Step 2 2-(4-Aminophenyl)-2-(2-methyl-1H-imidazol-1-yl)ethan-1-ol (279 mg, 1.28 mmol) was added to a solution of imidazole (219 mg, 3.21 mmol) and tert-butylchlorodimethylsilane (406 mg, 2.70 mmol) in THF (3 mL) under one atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the crude product was purified by flash C18-flash chromatography, eluting with a mixture of 0 to 4% MeCN in water (0.1% NH4HCO3), to afford 4-(2-((tert-butyldimethylsilyl)oxy)-1-(2-methyl-1H-imidazol-1- yl)ethyl)aniline (391 mg, 92%) as a colourless oil. MS (ES+, m/z): 332.1 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ -0.05 (s, 6H), 0.77 (s, 9H), 2.24 (s, 3H), 3.97 – 4.20 (m, 2H), 5.10 (s, 3H), 6.51 (d, J = 8.0 Hz, 2H), 6.71 (s, 1H), 6.94 (d, J = 7.9 Hz, 2H), 7.16 (s, 1H). Step 3 (rac)-(R)-1-(4-(2-((tert-Butyldimethylsilyl)oxy)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5- fluoropyridin-2-yl)methyl)urea was made using the Procedures O and 3 described above. MS (ES+, m/z): 484.1 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ -0.05 (s, 6H), 0.78 (s, 9H), 2.30 (s, 3H), 4.04 – 4.25 (m, 2H), 4.41 (d, J = 5.7 Hz, 2H), 5.30 (d, J = 7.4 Hz, 1H), 6.80 (s, 1H), 6.96 (s, 1H), 7.18 (d, J = 8.2 Hz, 2H), 7.30 – 7.47 (m, 4H), 7.70 (t, J = 8.6 Hz, 1H), 8.44 – 8.57 (m, 1H), 8.90 (s, 1H). Step 4 TBAF (570 mg, 2.18 mmol) was added to a solution of (rac)-(R)-1-(4-(2-((tert-Butyldimethylsilyl)oxy)- 1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5-fluoropyridin-2-yl)methyl)urea (527 mg, 1.09 mmol) in THF (1 mL) . The reaction mixture was stirred at room temperature for 3 hours, then the solvent was removed under reduced pressure. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na2SO4 to afford (rac)-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(2-hydroxy-1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)urea (400 mg, 99%) as white solid. MS (ES+, m/z): 370.05 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 2.21 (s, 3H), 3.87 – 4.02 (m, 2H), 4.14(d, J = 6.9 Hz, 1H), 4.36 (d, J = 5.6 Hz, 2H), 5.14 – 5.20 (m, 1H), 6.73 (s, 1H), 7.06 (d, J = 8.1 Hz, 2H), 7.24 (s, 1H), 7.33 – 7.47 (m, 4H), 7.68 (t, J = 9.1 Hz, 1H), 8.47 (d, J = 2.9 Hz, 1H), 9.37 (s, 1H). Step 5 (rac)-(R)-1-((5-Fluoropyridin-2-yl)methyl)-3-(4-(2-hydroxy-1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)urea (100 mg, 0.27 mmol) was added to a solution of BAST (120 mg, 0.54 mmol) in DCM (1 mL) at -78 °C under one atmosphere of nitrogen. The reaction mixture was warmed to room temperature and stirred for 15 hours, then it was quenched by addition of MeOH. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC, Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3), Mobile Phase B: MeOH; RT (min): 7.88, to afford (rac)-(R) -1- (4- (2-fluoro-1-(2- methyl-1H- imidazol -1-yl) ethyl) phenyl) -3-((5 -fluoropyridin-2-yl) methyl) urea (33.0 mg, 32.8%) as a white solid. The enantiomers were separated by preparative chiral-HPLC, Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: MtBE ( 0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH; RT1 (min): 20.01; RT2 (min): 29.2, to afford (R)-1-(4-(2-fluoro-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5- fluoropyridin-2-yl)methyl)urea ISOMER 1 (2.92 mg, 7.30%) as a white solid. MS (ES+, m/z): 372.0 [M + H]+; 1H NMR (300 MHz, MeOH-d4) δ 1.33 (s, 1H), 2.21 (s, 3H), 3.47 – 3.60 (m, 1H), 4.49 (s, 2H), 6.40 (dt, J = 6.6, 48.6 Hz, 1H), 6.91 (s, 1H), 7.10 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 1.7 Hz, 1H), 7.48 (dd, J = 4.4, 8.7 Hz, 1H), 7.62 (td, J = 2.9, 8.6 Hz, 1H), 8.42 (d, J = 2.9 Hz, 1H). Procedure 12 Example 91: (rac)-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methyl-1H-imidazol-5- yl)ethyl)phenyl)urea
Figure imgf000134_0001
(rac)-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-5-yl)ethyl)phenyl)urea was made using the Procedures 2 and 10, step 6 described above. MS (ES+, m/z): 354.30 [M + H]+; 1H NMR (400 MHz, DMSO-d6) δ 1.50 (d, J = 7.2 Hz, 3H), 2.06 (s, 3H), 4.05 (d, J = 7.1 Hz, 1H), 4.38 (d, J = 5.7 Hz, 2H), 6.72 (d, J = 5.8 Hz, 1H), 7.12 (d, J = 8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.40 (dd, J = 4.5, 8.7 Hz, 1H), 7.64 – 7.77 (m, 2H), 8.15 (s, 1H), 8.51 (d, J = 3.0 Hz, 1H), 8.68 (s, 1H). Table 14. The following compounds were made from the appropriate Intermediate using a method analogous to the Procedure 12 described above. Example Structure MS (ES+, m/z) NMR 93 315.10 [M + H]+ 1H NMR (300 MHz, MeOH-d4) δ 1.59 (d, J = 7.3 Hz, 3H), 1.84 (d, J = 14.2 Hz, 1H), 2.09 (s, 3H), 2.25 (dq, J = 7.6, 13.1 Hz, 1H), 3.58 (dd, J = 3.4, 9.1 Hz, 1H), 3.72 – 4.01 (m, 3H), 4.15 (q, J = 7.3 Hz, 1H), 4.33 (p, J = 3.8 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.48 (s, 1H). 101 354.10 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 1.48 (d, J = 7.2 Hz, 3H), 2.02 (s, 3H), 3.99 (s, 1H), 4.38 (d, J = 5.7 Hz, 2H), 6.69 (t, J = 5.9 Hz, 1H), 7.11 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 7.34 – 7.44 (m, 2H), 7.71 (dd, J = 3.0, 8.8 Hz, 1H), 8.51 (d, J = 2.9 Hz, 1H), 8.63 (s, 1H), 11.56 (s, 1H). 116 350.19 [M + H]+ 1H NMR (400 MHz, DMSO-d6) δ 1.01 (t, J = 7.5 Hz, 3H), 1.49 (d, J = 7.2 Hz, 3H), 2.42 – 2.46 (m, 2H), 4.03 (q, J = 7.7 Hz, 1H), 4.38 (d, J = 5.6 Hz, 2H), 6.70 (t, J = 5.7 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 7.24 – 7.30 (m, 4H), 7.33 (d, J = 7.9 Hz, 1H), 7.74 – 7.79 (m, 1H), 8.52 (d, J = 4.9 Hz, 1H), 8.66 (s, 1H), one exchangeable proton is not visible. 118 354.10 [M + H]+ H NMR (300 MHz, DMSO-d6) δ 1.02 (t, J = 7.4 Hz, 3H), 1.49 (d, J = 7.1 Hz, 3H), 2.40 – 2.51 (m, 2H), 4.21 – 4.47 (m, 1H), 6.97 – 7.10 (m, 2H), 7.10 – 7.29 (m, 1H), 7.29 – 7.44 (m, 1H), 7.44 – 7.53 (m, 2H), 7.75 (t, J = 7.9 Hz, 1H), 8.28 (d, J = 5.2 Hz, 1H), 9.44 (s, 1H), 10.54 (s, 1H), 11.63 (s, 1H). Procedure 13 Example 94: (rac)-(R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea (4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea
Figure imgf000136_0001
(rac)-(R)-1-(4-(1-(4-Methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(136yridine-2-yl)urea was made using the Procedures 1 and 10, step 6 described above. MS (ES+, m/z): 322.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (dd, J = 12.0, 7.2 Hz, 3H), 2.03 (d, J = 8.4 Hz, 3H), 3.90 – 4.21 (m, 1H), 6.93 – 7.12 (m, 1H), 7.20 (dd, J = 17.1, 8.3 Hz, 2H), 7.32 – 7.58 (m, 4H), 7.74 (t, J = 7.3 Hz, 1H), 8.27 (d, J = 5.1 Hz, 1H), 9.38 (d, J = 5.6 Hz, 1H), 10.37 (d, J = 15.8 Hz, 1H), 11.61 (d, J = 40.4 Hz, 1H). The enantiomers were separated by preparative chiral-HPLC, Column: CHIRAL Amylose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2 M NH3-MeOH)-HPLC, Mobile Phase B: EtOH; RT1 (min): 12.03; RT2 (min): 15.02, to afford rel-(R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridine-2- yl)urea ISOMER 2 (50.0 mg, 30.6%) as a white solid. MS (ES+, m/z): 332.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (d, J = 7.2 Hz, 3H), 2.04 (s, 3H), 4.04 (q, J = 7.1 Hz, 1H), 7.00 (ddd, J = 7.2, 5.0, 1.0 Hz, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.35 – 7.43 (m, 3H), 7.49 (d, J = 8.4 Hz, 1H), 7.74 (ddd, J = 8.9, 7.3, 1.9 Hz, 1H), 8.22 – 8.31 (m, 1H), 9.38 (s, 1H), 10.37 (s, 1H). Table 15. The following compounds were made from the appropriate Intermediate using a method analogous to the Procedure 13 described above. Example Structure MS (ES+, m/z) NMR 95 308.00 [M + H]+ 1H NMR (300 MHz, DMSO-d6) δ 1.53 (d, J = 7.2 Hz, 3H), 4.09 (q, J = 7.1 Hz, 1H), 6.97 – 7.06 (m, 2H), 7.18 (d, J = 8.4 Hz, 3H), 7.48 (dd, J = 17.7, 8.4 Hz, 3H), 7.74 (ddd, J = 8.8, 7.2, 2.0 Hz, 1H), 8.11 (s, 1H), 8.27 (dd, J = 5.1, 1.9 Hz, 1H), 9.42 (s, 1H), 10.44 (s, 1H). 96 308.00 [M + H]+ 1H NMR (300 MHz, DMSO-d6) δ 1.24 (s, 1H), 1.55 (d, J = 7.2 Hz, 3H), 4.13 (q, J = 7.3 Hz, 1H), 7.01 (dd, J = 7.2, 5.1 Hz, 1H), 7.15 – 7.23 (m, 3H), 7.48 (t, J = 8.5 Hz, 3H), 7.75 (td, J = 7.9, 7.1, 1.9 Hz, 1H), 8.23 – 8.32 (m, 1H), 8.39 (s, 1H), 9.42 (s, 1H), 10.46 (s, 1H). Procedure 14 Example 120: rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5- a]pyridine-8-yl)phenyl)urea
Figure imgf000138_0001
Step 1 2,2,2-Trifluoroethyl chloroformate (263.39 mg, 1.62 mmol) was added to a mixture of (rac)-(R)-4- (5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-8-yl)aniline (314.28 mg, 1.47 mmol) and pyridine (349.68 mg, 4.42 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at room temperature overnight, then it was diluted with water (5 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude (rac)-(R)-2,2,2-trifluoroethyl N-(4-5H,6H,7H,8H-imidazo[1,5- a]pyridine-8-ylphenyl)carbamate 2 (250.0 mg, 40%), which was used in the next step without further purification. Step 2 A mixture of (rac)-(R)-2,2,2-trifluoroethyl N-(4-5H,6H,7H,8H-imidazo[1,5-a]pyridine-8- ylphenyl)carbamate 2 (250 mg, 821.01 µmol), (5-fluoropyridin-2-yl)methanamine 1.2 (124.27 mg, 985.21 µmol) and DIPEA (159.16 mg, 1.23 mmol) in dry MeCN (5 mL) was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by preparative HPLC, Column: Waters Sun Fire C18 OBD, 100×19mm, 5μm; Mobile Phase A: Water, Mobile Phase B: MeOH; RT (min) 0.47, to afford (rac)-(R)-3-[(5-fluoropyridin-2-yl)methyl]-1- (4-5H,6H,7H,8H-imidazo[1,5-a]138yridine-8-ylphenyl)urea (51.5 mg, 16.8%) as a beige solid. MS (ES+, m/z): 366.0 [M+H]+ . Step 3 The stereoisomers were separated on a Chiralcel OD (250x30 mm, 10 µm), eluting with hexane: IPA: MeOH: DEA, 60:20:20:0.05, at a flow rate of 30 mL / min., to afford: ISOMER 1 rel-(R)- 3-[(5-fluoropyridin-2-yl)methyl]-1-(4-5H,6H,7H,8H-imidazo[1,5-a]pyridine-8- ylphenyl)urea (20.7 mg), RT1 (8.76 min), MS (ES+, m/z): 366.2 [M+H]+.1H NMR (500 MHz, DMSO-d6) δ 1.70 (q, 1H), 1.92 – 1.79 (m, 1H), 1.98 (d, 2H), 3.93 (q, 2H), 4.12 (d, 1H), 4.42 – 4.36 (m, 2H), 6.23 (s, 1H), 6.79 – 6.64 (m, 1H), 7.06 (dd, 2H), 7.32 (dd, 2H), 7.39 (dt, 1H), 7.51 (d, 1H), 7.69 (tt, 1H), 8.49 (t, 1H), 8.69 (d, 1H). ISOMER 2 rel-(R)- 3-[(5-fluoropyridin-2-yl)methyl]-1-(4-5H,6H,7H,8H-imidazo[1,5-a]pyridine-8- ylphenyl)urea (24 mg), RT2 (11.32 min), MS (ES+, m/z): 366.2 [M+H] +; 1H NMR (500 MHz, DMSO-d6) δ 1.70 (q, 1H), 1.92 – 1.79 (m, 1H), 1.98 (d, 2H), 3.93 (q, 2H), 4.12 (d, 1H), 4.42 – 4.36 (m, 2H), 6.23 (s, 1H), 6.79 – 6.64 (m, 1H), 7.06 (dd, 2H), 7.32 (dd, 2H), 7.39 (dt, 1H), 7.51 (d, 1H), 7.69 (tt, 1H), 8.49 (t, 1H), 8.69 (d, 1H). Table 16. The following compounds were made from the appropriate Intermediate using a Procedure analogous to the Procedure 14 described above. Example Structure MS (ES+, m/z) NMR 119 358.2 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 1.78 (d, 3H), 5.69 (q, 1H), 6.99 (ddd, 1H), 7.01 – 7.28 (m, 4H), 7.44 – 7.51 (m, 3H), 7.56 (s, 1H), 7.72 (ddd, 1H), 8.25 (dd, 1H), 9.39 (s, 1H), 10.45 (s, 1H). Procedure 15 Example 174: (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)isonicotinamide TCFH (84 mg, 0.30 mmol) was added to a stirred mixture of isonicotinic acid (36.7 mg, 0.30 mmol), 1- methylimidazole (102 mg, 1.24 mmol) and (S)-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)aniline (50 mg, 0.25 mmol) in MeCN (2 mL). The mixture was stirred at room temperature for 15 hours. The crude product was purified by preparative HPLC, Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Gradient: 21% B to 26% B in 13 min, 26% B; Wave Length: 220 nm; RT (min): 11, to afford (S)-N-(4-(1- (2-methyl-1H-imidazol-1-yl)ethyl)phenyl)isonicotinamide (42.0 mg, 55.2%) as a white solid. MS (ES+, m/z): 307.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.73 (d, J = 7.1 Hz, 3H), 2.22 (s, 3H), 5.45 (d, J = 7.2 Hz, 1H), 6.79 (s, 1H), 7.20 (d, J = 8.2 Hz, 2H), 7.27 (s, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 5.1 Hz, 2H), 8.79 (d, J = 5.0 Hz, 2H), 10.53 (s, 1H). Table 17. The following compounds were made from the appropriate racemic or enantiomerically pure intermediate using an amide coupling analogous to the Procedure 15 described above. For those examples in which a racemic starting material was used, the enantiomers of the final compounds were separated by chiral preparative HPLC or chiral SFC. Exampl Structure MS NMR e (ES+, m/z) 143 321.16 1H NMR (300 MHz, DMSO-d6) δ 1.68 (d, J = 7.0 Hz, 3H), [M + H]+ 2.18 (s, 3H), 3.67 (s, 2H), 5.38 (q, J = 7.0 Hz, 1H), 6.75 (d, J = 1.3 Hz, 1H), 7.11 (d, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.30 – 7.39 (m, 1H), 7.53 (d, 2H), 7.71 (dt, J = 7.9, 2.0 Hz, 1H), 8.41 – 8.54 (m, 2H), 10.26 (s, 1H). 144 327.20 1H NMR (300 MHz, DMSO-d6) δ 1.69 (d, J = 7.0 Hz, 3H), [M + H]+ 2.18 (s, 3H), 4.12 (s, 2H), 5.39 (q, J = 7.0 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 7.13 (d, 2H), 7.22 (d, J = 1.4 Hz, 1H), 7.54 (d, 2H), 7.64 (d, J = 3.3 Hz, 1H), 7.73 (d, J = 3.3 Hz, 1H), 10.38 (s, 1H). 295.18 1H NMR (300 MHz, DMSO-d6) δ 1.71 (d, J = 7.0 Hz, 3H), [M + H]+ 2.21 (s, 3H), 5.40 (q, J = 7.0 Hz, 1H), 6.12 – 6.21 (m, 1H), 6.77 (d, J = 1.4 Hz, 1H), 6.94 (td, J = 2.7, 1.4 Hz, 1H), 7.01 – 7.07 (m, 1H), 7.14 (d, 2H), 7.24 (d, J = 1.4 Hz, 1H), 7.68 (d, 2H), 9.76 (s, 1H), 11.64 (s, 1H). 310.17 1H NMR (300 MHz, DMSO-d6) δ 1.70 (d, J = 7.0 Hz, 3H), [M + H]+ 2.20 (s, 3H), 3.63 (s, 2H), 5.40 (d, J = 6.9 Hz, 1H), 6.16 (s, 1H), 6.77 (d, J = 1.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 1.4 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 10.15 (s, 1H). 307.03 1H NMR (300 MHz, DMSO-d6) δ 1.73 (d, J = 7.0 Hz, 3H), [M + H]+ 2.22 (s, 3H), 5.45 (q, J = 7.0 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 7.19 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 1.4 Hz, 1H), 7.52 – 7.62 (m, 1H), 7.74 (d, J = 8.6 Hz, 2H), 8.23 – 8.33 (m, 1H), 8.72 – 8.81 (m, 1H), 9.09 (d, J = 2.3 Hz, 1H), 10.47 (s, 1H). 321.05 1H NMR (300 MHz, DMSO-d6) δ 1.70 (d, J = 7.0 Hz, 3H), [M+H]+ 2.19 (s, 3H), 3.82 (s, 2H), 5.39 (q, J = 7.0 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 7.06 – 7.17 (m, 2H), 7.19 – 7.31 (m, 2H), 7.38 (dt, J = 1.1, 7.8 Hz, 1H), 7.51 – 7.61 (m, 2H), 7.69 – 7.81 (m, 1H), 8.44 – 8.53 (m, 1H), 10.26 (s, 1H). 339.25 1H NMR (300 MHz, DMSO-d6) δ 1.67 (d, J = 7.0 Hz, 3H), [M+H]+ 2.17 (s, 3H), 3.74 (s, 2H), 5.38 (q, J = 7.0 Hz, 1H), 6.74 (d, J = 1.4 Hz, 1H), 7.06 – 7.15 (m, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.47 – 7.57 (m, 2H), 7.66 (dt, J = 2.4, 9.9 Hz, 1H), 8.37 (t, J = 1.8 Hz, 1H), 8.46 (d, J = 2.8 Hz, 1H), 10.26 (s, 1H). 335.05 1H NMR (300 MHz, DMSO-d6) δ 1.69 (d, J = 7.0 Hz, 3H), [M+H]+ 2.19 (s, 3H), 2.74 (dd, J = 6.7, 8.4 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H), 5.38 (q, J = 7.0 Hz, 1H), 6.76 (d, J = 1.4 Hz, 1H), 7.05 – 7.14 (m, 2H), 7.14 – 7.24 (m, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.63 – 7.74 (m, 1H), 8.47 (dd, J = 1.6, 4.7 Hz, 1H), 9.98 (s, 1H). 335.00 1H NMR (400 MHz, DMSO-d6) δ 1.70 (d, J = 7.0 Hz, 3H), [M + H]+ 2.19 (s, 3H), 2.29 (s, 3H), 3.64 (s, 2H), 5.35 – 5.44 (m, 1H), 6.76 (d, J = 1.4 Hz, 1H), 7.09 – 7.16 (m, 2H), 7.23 (d, J = 1.4 Hz, 1H), 7.51 – 7.58 (m, 3H), 8.30 (t, J = 2.9 Hz, 2H), 10.25 (s, 1H). 337.16 1H NMR (300 MHz, DMSO-d6) δ 1.69 (d, J = 7.0 Hz, 3H), [M + H]+ 2.18 (s, 3H), 4.77 (s, 2H), 5.40 (q, J = 6.9 Hz, 1H), 6.75 (d, J = 1.4 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 1.4 Hz, 1H), 7.30-7.40 (m, 2H), 7.57 (d, J = 8.6 Hz, 2H), 8.18 (dd, J = 4.5, 1.5 Hz, 1H), 8.34 (dd, J = 2.9, 0.8 Hz, 1H), 10.15 (s, 1H). 335.18 1H NMR (300 MHz, DMSO-d6) δ 1.42 (d, J = 7.0 Hz, 3H), [M + H]+ 1.69 (d, J = 7.0 Hz, 3H), 2.24 (s, 3H), 3.85 (q, J = 7.0 Hz, 1H), 5.44 (q, J = 7.0 Hz, 1H), 6.92 (s, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.29 – 7.39 (m, 2H), 7.48 – 7.59 (m, 2H), 7.70 – 7.80 (m, 1H), 8.44 (dd, J = 1.6, 4.8 Hz, 1H), 8.56 (d, J = 2.3 Hz, 1H), 10.18 (s, 1H). 337.05 1H NMR (400 MHz, DMSO-d6) δ 2.20 (s, 3H), 3.68 (s, [M + H]+ 2H), 3.87 – 3.96 (m, 1H), 3.99 (d, J = 8.3 Hz, 1H), 5.13 (d, J = 5.4 Hz, 1H), 5.17 – 5.25 (m, 1H), 6.75 (d, J = 1.3 Hz, 1H), 7.13 – 7.19 (m, 2H), 7.25 (d, J = 1.1 Hz, 1H), 7.31 – 7.39 (m, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.68 – 7.76 (m, 1H), 8.42 – 8.48 (m, 1H), 8.50 (d, J = 2.3 Hz, 1H), 10.30 (s, 1H). 339.10 1H NMR (300 MHz, DMSO-d6) δ 1.59 (d, J = 7.0 Hz, 3H), [M + H]+ 2.08 (s, 3H), 3.65 (s, 2H), 5.32 (q, J = 7.0 Hz, 1H), 6.67 (d, J = 1.4 Hz, 1H), 6.84 (dd, J = 2.0, 8.4 Hz, 1H), 6.97 (dd, J = 2.0, 12.0 Hz, 1H), 7.16 (d, J = 1.4 Hz, 1H), 7.19 – 7.28 (m, 1H), 7.60 (dt, J = 2.0, 7.9 Hz, 1H), 7.69 (t, J = 8.3 Hz, 1H), 8.30 – 8.42 (m, 2H), 9.94 (s, 1H). 349.20 1H NMR (300 MHz, DMSO-d6) δ 0.74 (t, J = 7.3 Hz, 3H), [M+H]+ 1.52 – 1.70 (m, 4H), 1.93 (ddd, J = 7.5, 14.0, 15.9 Hz, 1H), 2.06 (s, 3H), 3.49 (dd, J = 6.6, 8.6 Hz, 1H), 5.26 (q, J = 7.0 Hz, 1H), 6.64 (d, J = 1.4 Hz, 1H), 6.94 – 7.04 (m, 2H), 7.09 (d, J = 1.4 Hz, 1H), 7.24 (ddd, J = 0.8, 4.7, 7.8 Hz, 1H), 7.37 – 7.48 (m, 2H), 7.66 (dt, J = 2.0, 7.9 Hz, 1H), 8.34 (dd, J = 1.6, 4.8 Hz, 1H), 8.44 (dd, J = 0.9, 2.3 Hz, 1H), 10.08 (s, 1H). 314.05 1H NMR (300 MHz, DMSO-d6) δ 1.52 (dd, J = 7.4, 12.5 [M + H]+ Hz, 1H), 1.70 (d, J = 7.0 Hz, 3H), 1.92 – 2.06 (m, 1H), 2.20 (s, 3H), 2.34 – 2.43 (m, 2H), 3.30 (d, J = 8.3 Hz, 2H), 3.57 – 3.85 (m, 3H), 5.33 – 5.44 (m, 1H), 6.77 (d, J = 1.4 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 1.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 9.97 (s, 1H). 300.16 1H NMR (300 MHz, DMSO-d6) δ 1.68 (d, J = 7.0 Hz, 3H), [M + H]+ 2.17 (s, 3H), 2.70 (d, J = 7.8 Hz, 2H), 3.19 – 3.32 (m, 1H), 4.31 (t, J = 6.2 Hz, 2H), 4.60 – 4.71 (m, 2H), 5.37 (q, J = 7.0 Hz, 1H), 6.74 (d, J = 1.4 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 1.4 Hz, 1H), 7.50 (d, J = 8.5 Hz, 2H), 9.98 (s, 1H). 337.05 1H NMR (300 MHz, DMSO-d6) δ 1.70 (d, J = 7.0 Hz, 3H), [M + H]+ 2.21 (s, 3H), 5.18 (d, J = 4.6 Hz, 1H), 5.35 – 5.45 (m, 1H), 6.66 (d, J = 4.8 Hz, 1H), 6.81 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.27 (s, 1H), 7.39 (dd, J = 4.7, 7.9 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.87 (d, J = 8.2 Hz, 1H), 8.50 (dd, J = 1.7, 4.9 Hz, 1H), 8.69 (d, J = 2.3 Hz, 1H), 10.06 (s, 1H). 330.00 1H NMR (300 MHz, DMSO-d6) δ 1.70 (d, J = 7.0 Hz, 3H), [M+H]+ 1.82 – 2.05 (m, 2H), 2.20 (s, 3H), 2.59 (d, J = 14.1 Hz, 1H), 2.67 (d, J = 14.1 Hz, 1H), 3.34 (s, 1H), 3.63 (d, J = 9.1 Hz, 1H), 3.68 – 3.87 (m, 2H), 5.00 (s, 1H), 5.40 (q, J = 7.0 Hz, 1H), 6.77 (s, 1H), 7.12 (d, J = 8.5 Hz, 2H), 7.23 (s, 1H), 7.50 – 7.60 (m, 2H), 9.93 (s, 1H). 322.00 1H NMR (300 MHz, DMSO-d6) δ 1.71 (d, J = 7.0 Hz, 3H), [M + H]+ 1.75 – 2.04 (m, 2H), 2.20 (s, 3H), 2.66 – 2.88 (m, 1H), 3.55 – 3.86 (m, 4H), 4.83 – 5.15 (m, 1H), 5.42 (q, J = 7.0 Hz, 1H), 6.78 (d, J = 1.4 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 1.4 Hz, 1H), 7.62 (dd, J = 3.0, 8.6 Hz, 2H), 10.23 (d, J = 20.3 Hz, 1H). 328.05 1H NMR (300 MHz, DMSO-d6) δ 1.11 (dd, J = 6.1, 20.1 [M+H]+ Hz, 3H), 1.45 – 1.63 (m, 1H), 1.70 (d, J = 7.0 Hz, 3H), 2.20 (s, 3H), 2.24 – 2.43 (m, 2H), 3.35 (ddd, J = 6.7, 8.4, 17.5 Hz, 1H), 3.54 – 3.86 (m, 3H), 5.39 (q, J = 7.0 Hz, 1H), 6.77 (d, J = 1.4 Hz, 1H), 7.11 (dd, J = 1.3, 8.7 Hz, 2H), 7.23 (d, J = 1.4 Hz, 1H), 7.50 – 7.61 (m, 2H), 9.92 (d, J = 4.0 Hz, 1H), the exchangeable proton not seen. 351.00 1H NMR (300 MHz, DMSO-d6) δ 1.69 (d, J = 7.0 Hz, 3H), [M + H]+ 2.18 (s, 3H), 3.39 (s, 3H), 4.94 (s, 1H), 5.40 (q, J = 7.0 Hz, 1H), 6.77 (d, J = 1.3 Hz, 1H), 7.08 – 7.17 (m, 2H), 7.24 (d, J = 1.4 Hz, 1H), 7.43 (dd, J = 4.9, 8.0 Hz, 1H), 7.57 – 7.68 (m, 2H), 7.85 (dt, J = 2.0, 7.9 Hz, 1H), 8.55 (dd, J = 1.7, 4.8 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 10.18 (s, 1H). 344.00 1H NMR (300 MHz, DMSO-d6) δ 1.57 – 1.68 (m, 1H), [M + H]+ 1.71 (d, J = 6.9 Hz, 4H), 1.79 – 1.88 (m, 1H), 2.20 (s, 3H), 3.28 (s, 3H), 3.49 – 3.67 (m, 3H), 3.67 – 3.79 (m, 2H), 5.41 (q, J = 7.1 Hz, 1H), 6.77 (d, J = 1.4 Hz, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 1.4 Hz, 1H), 7.60 – 7.69 (m, 2H), 10.05 (s, 1H). 344.10 1H NMR (300 MHz, DMSO-d6) δ 1.25 – 1.32 (s, 1H), [M + H]+ 1.33 – 1.41 (s, 2H), 1.65 – 1.74 (d, J = 7.0 Hz, 3H), 1.78 – 1.94 (m, 2H), 2.15 – 2.25 (s, 3H), 2.59 – 2.69 (t, J = 8.0 Hz, 1H), 3.52 – 3.83 (m, 4H), 5.34 – 5.47 (d, J = 7.1 Hz, 1H), 5.74 – 5.80 (s, 1H), 6.75 – 6.80 (d, J = 1.4 Hz, 1H), 7.07 – 7.16 (d, J = 8.4 Hz, 2H), 7.19 – 7.29 (d, J = 1.4 Hz, 1H), 7.63 – 7.71 (m, 2H), 9.56 – 9.63 (s, 1H). 338.20 1H NMR (300 MHz, DMSO-d6) δ 1.70 (d, J = 7.0 Hz, 3H), [M + 1.96 (s, 3H), 2.20 (s, 3H), 2.60 (t, J = 7.7 Hz, 2H), 2.81 H]+. (t, J = 7.7 Hz, 2H), 3.18 (s, 0H), 5.39 (d, J = 7.2 Hz, 1H), 6.77 (s, 1H), 7.11 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 17.6 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 9.96 (s, 1H), 12.13 (s, 1H). 350.16 1H NMR (400 MHz, DMSO-d6) δ 1.72 (d, J = 7.0 Hz, 3H), [M + H]+ 1.85 – 1.97 (m, 1H), 1.97 – 2.10 (m, 1H), 2.21 (s, 3H), 3.06 – 3.23 (m, 1H), 3.64 (q, J = 7.6 Hz, 1H), 3.78 (dd, J = 6.1, 11.8 Hz, 3H), 5.44 (q, J = 7.0 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 7.15 – 7.22 (m, 2H), 7.27 (d, J = 1.4 Hz, 1H), 7.61 – 7.67 (m, 2H), 10.65 (s, 1H). 350.16 1H NMR (400 MHz, DMSO-d6) δ 1.72 (d, J = 7.0 Hz, 3H), [M + H]+ 1.85 – 1.98 (m, 1H), 1.98 – 2.10 (m, 1H), 2.20 (s, 3H), 3.05 – 3.21 (m, 1H), 3.64 (q, J = 7.6 Hz, 1H), 3.78 (dd, J = 6.0, 11.8 Hz, 3H), 5.44 (q, J = 7.0 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 7.15 – 7.21 (m, 2H), 7.27 (d, J = 1.5 Hz, 1H), 7.60 – 7.68 (m, 2H), 10.65 (s, 1H). 332.00 1H NMR (300 MHz, DMSO-d6) δ 1.71 (d, J = 7.0 Hz, 3H), [M + H]+ 1.77 – 2.03 (m, 2H), 2.20 (s, 3H), 2.66 – 2.91 (m, 1H), 3.55 – 3.86 (m, 4H), 4.90 – 5.15 (m, 1H), 5.42 (q, J = 7.0 Hz, 1H), 6.78 (d, J = 1.4 Hz, 1H), 7.10 – 7.19 (m, 2H), 7.25 (d, J = 1.4 Hz, 1H), 7.57 – 7.67 (m, 2H), 10.19 (s, 1H). 328.05 1H NMR (400 MHz, DMSO-d6) δ 1.38 – 1.51 (m, 1H), [M + H]+ 1.66 – 1.78 (m, 5H), 1.80 – 2.00 (m, 3H), 2.21 (s, 3H), 2.26 – 2.46 (m, 2H), 3.52 – 3.65 (m, 1H), 3.69 – 3.82 (m, 2H), 5.32 – 5.47 (m, 1H), 6.77 (d, J = 1.4 Hz, 1H), 7.04 – 7.17 (m, 2H), 7.25 (d, J = 1.4 Hz, 1H), 7.49 – 7.64 (m, 2H), 9.91 (s, 1H). 362.12 1H NMR (300 MHz, DMSO-d6) δ 1.71 (d, J = 7.0 Hz, 3H), [M + H]+ 2.21 (s, 3H), 2.61 (dd, J = 15.2, 8.6 Hz, 1H), 2.82 (dd, J = 15.3, 6.1 Hz, 1H), 3.88 (d, J = 8.1 Hz, 1H), 4.18 – 4.30 (m, 1H), 4.69 (t, J = 9.1 Hz, 1H), 5.42 (t, J = 7.0 Hz, 1H), 6.73 – 6.89 (m, 3H), 7.06 – 7.18 (m, 3H), 7.18 – 7.28 (m, 2H), 7.56 (d, J = 8.4 Hz, 2H), 10.05 (s, 1H). 357.00 1H NMR (300 MHz, DMSO-d6) δ 1.69 – 1.75 (m, 3H), [M + H]+ 2.21 (d, J = 3.6 Hz, 3H), 5.40 – 5.53 (m, 1H), 6.82 (d, J = 3.4 Hz, 1H), 7.16 – 7.23 (m, 2H), 7.28 (d, J = 3.4 Hz, 1H), 7.58 – 7.68 (m, 3H), 8.04 – 8.14 (m, 1H), 8.75 – 8.94 (m, 2H), 10.94 (s, 1H). 300.16 1H NMR (400 MHz, DMSO-d6) δ 1.70 (d, J = 7.0 Hz, 3H), [M + H]+ 1.99 – 2.12 (m, 2H), 2.20 (s, 3H), 3.06 – 3.18 (m, 1H), 3.65 – 3.82 (m, 3H), 3.92 (t, J = 8.2 Hz, 1H), 5.40 (q, J = 7.0 Hz, 1H), 6.77 (d, J = 1.4 Hz, 1H), 7.08 – 7.15 (m, 2H), 7.23 (d, J = 1.4 Hz, 1H), 7.51 – 7.58 (m, 2H), 10.05 (s, 1H). 357.95 1H NMR (300 MHz, DMSO-d6) δ 1.73 (d, J = 7.0 Hz, 3H), [M+H]+ 2.22 (s, 3H), 5.44 (d, J = 7.0 Hz, 1H), 6.79 (s, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H), 7.60 (t, J = 8.9 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 6.4 Hz, 1H), 8.19 (dd, J = 2.2, 7.2 Hz, 1H), 10.38 (s, 1H). 308.03 1H NMR (300 MHz, DMSO-d6) δ 1.78 (d, J = 7.0 Hz, 3H), [M + H]+ 2.28 (d, J = 4.5 Hz, 3H), 5.56 (d, J = 7.0 Hz, 1H), 6.82 (s, 1H), 7.33 (s, 1H), 7.74 (dd, J = 2.6, 8.8 Hz, 1H), 7.90 (d, J = 5.3 Hz, 2H), 8.16 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 2.5 Hz, 1H), 8.77 (d, J = 5.3 Hz, 2H). 324.10 1H NMR (300 MHz, DMSO-d6) δ 1.75 (d, J = 7.0 Hz, 3H), [M + H]+ 2.21 (s, 3H), 5.37 – 5.51 (m, 1H), 6.80 (s, 1H), 7.18(d, J = 8.4 Hz, 2H), 7.28 (d, J = 1.4 Hz, 1H), 7.40 (t, J = 8.8 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.95 – 8.14 (m, 2H), 10.31 (s, 1H). 286.05 1H NMR (300 MHz, DMSO-d6) δ 1.70 (d, J = 7.0 Hz, 3H), [M + H]+ 2.20 (s, 3H), 3.93 (p, J = 7.4 Hz, 1H), 4.61 – 4.75 (m, 4H), 5.40 (q, J = 7.0 Hz, 1H), 6.77 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 7.24 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 9.97 (s, 1H). 315.05 1H NMR (300 MHz, CDCl3) δ 1.58 – 1.73 (m, 1H), 1.85 [M + H]+ （J = 7.1 Hz, 3H), 2.15 – 2.27 (m, 1H), 2.36(s, 3H), 2.58 （d, J = 7.4 Hz, 2H), 2.71 – 2.85 (m, 1H), 3.46 – 3.56 (m, 1H), 3.75 – 3.87 (m, 1H), 3.87 – 4.05 (m, 2H), 5.28 – 5.39 (m, 1H), 6.94 – 7.07 (m, 2H), 7.38 – 7.46 (m, 1H), 8.05 (s, 2H), 8.18 (d, J = 8.7 Hz, 1H). 322.10 1H NMR (400 MHz, DMSO-d6) δ 1.74 (d, J = 7.0 Hz, 3H), [M + H]+ 2.24 (s, 3H), 3.77 (s, 2H), 5.49 (q, J = 7.0 Hz, 1H), 6.78 (d, J = 1.4 Hz, 1H), 7.27 (d, J = 1.5 Hz, 1H), 7.35 (ddd, J = 1.0, 4.9, 7.8 Hz, 1H), 7.64 (dd, J = 2.5, 8.7 Hz, 1H), 7.73 (dt, J = 2.0, 7.9 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.46 (dd, J = 1.7, 4.8 Hz, 1H), 8.49 – 8.54 (m, 1H), 10.88 (s, 1H). 314.05 1H NMR (300 MHz, DMSO-d6) δ 1.42 – 1.64 (m, 2H), [M + H]+ 1.64 – 1.79 (d, J = 7.0 Hz, 4H), 1.84 – 1.99 (d, J = 12.5 Hz, 1H), 2.13 – 2.23 (s, 3H), 2.54 – 2.67 (m, 1H), 3.23 – 3.33 (m, 1H), 3.36 – 3.43 (d, J = 10.7 Hz, 1H), 3.74 – 3.88 (d, J = 11.1 Hz, 1H), 3.89 – 4.00 (m, 1H), 5.31 – 5.45 (m, 1H), 6.72 – 6.80 (d, J = 1.3 Hz, 1H), 7.05 – 7.15 (d, J = 8.4 Hz, 2H), 7.18 – 7.27 (d, J = 1.4 Hz, 1H), 7.48 – 7.58 (d, J = 8.4 Hz, 2H), 9.90 – 10.04 (s, 1H). 380.00 1H NMR (300 MHz, DMSO-d6) δ 1.69 (d, J = 7.0 Hz, 3H), [M + H]+ 2.19 (s, 3H), 2.61 (dd, J = 15.4, 9.0 Hz, 1H), 2.83 (dd, J = 15.5, 5.8 Hz, 1H), 3.80 – 3.91 (m, 1H), 4.25 (dd, J = 9.0, 6.7 Hz, 1H), 4.70 (t, J = 9.1 Hz, 1H), 5.39 (q, J = 7.0 Hz, 1H), 6.69 – 6.80 (m, 2H), 6.91 (td, J = 9.0, 2.9 Hz, 1H), 7.05 (dd, J = 8.3, 2.7 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 1.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 10.04 (s, 1H). 397.05 1H NMR (300 MHz, DMSO-d6) δ 1.72 (t, J = 7.2 Hz, 3H), [M+H]+ 2.25 (d, J = 9.3 Hz, 3H), 5.45 (p, J = 7.0 Hz, 1H), 6.83 (d, J = 1.4 Hz, 1H), 7.16 – 7.26 (m, 2H), 7.29 (d, J = 1.4 Hz, 1H), 7.61 – 7.70 (m, 2H), 9.08 (s, 1H), 9.57 (s, 1H), 10.26 (s, 1H). 315.00 1H NMR (300 MHz, CDCl3) δ 1.65(m, 1H), 1.88 (d, J = [M + H]+ 7.0 Hz, 3H), 2.23 (m, 1H), 2.52 (d, J = 12.6 Hz, 5H), 2.69 – 2.87 (m, 1H), 3.48 – 3.56 (m, 1H), 3.73 – 3.86 (m, 1H), 3.87 – 4.05 (m, 2H), 5.33 – 5.45 (m, 1H), 7.04 (s, 1H), 7.11 – 7.17 (s, 1H), 7.38 – 7.50 (m, 1H), 7.96 – 8.02 (s, 1H), 8.09 (d, J = 2.5 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H). 322.04 1H NMR (400 MHz, DMSO-d6) δ 1.74 (d, J = 7.1 Hz, 3H), [M + H]+ 2.24 (s, 3H), 3.77 (s, 2H), 5.50 (q, J = 7.0 Hz, 1H), 7.35 (ddd, J = 0.9, 4.8, 7.8 Hz, 1H), 6.78 (d, J = 1.4 Hz, 1H), 7.27 (d, J = 1.4 Hz, 1H), 7.61 – 7.76 (m, 2H), 8.01 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 2.5 Hz, 1H), 8.43 – 8.53 (m, 2H), 10.87 (s, 1H). 308.10 1H NMR (300 MHz, DMSO-d6) δ 1.78 (d, J = 7.0 Hz, 3H), [M + H]+ 2.28 (s, 3H), 5.49 – 5.64 (m, 1H), 6.84 (s, 1H), 7.33 (s, 1H), 7.74 (dd, J = 2.5, 8.7 Hz, 1H), 7.85 – 7.98 (m, 2H), 8.17 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.72 – 8.88 (m, 2H). 311 [M 1H NMR (300 MHz, DMSO-d6) δ 1.74 (d, J = 7.0 Hz, 3H), + H]+ 2.33 (s, 3H), 3.80 (d, J = 39.5 Hz, 2H), 5.51 (q, J = 6.9 Hz, 1H), 7.04 (s, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 1.6 Hz, 1H), 7.52 – 7.62 (m, 2H), 8.16 (d, J = 181.5 Hz, 1H), 10.34 (d, J = 32.7 Hz, 1H), 13.84 (s, 1H). 364.00 1H NMR (400 MHz, DMSO-d6) δ 1.71 (d, J = 7.0 Hz, 3H), [M + H]+ 2.19 (s, 3H), 4.33 (dd, J = 5.8, 11.6 Hz, 1H), 4.44 (dd, J = 2.8, 11.6 Hz, 1H), 4.97 (dd, J = 2.7, 5.8 Hz, 1H), 5.42 (q, J = 7.1 Hz, 1H), 6.77 (d, J = 1.4 Hz, 1H), 6.81 – 6.94 (m, 3H), 7.03 (dd, J = 1.9, 8.1 Hz, 1H), 7.11 – 7.18 (m, 2H), 7.24 (d, J = 1.4 Hz, 1H), 7.56 – 7.63 (m, 2H), 10.16 (s, 1H). 360.00 1H NMR (300 MHz, DMSO-d6) δ 1.62 (d, J = 7.0 Hz, 3H), [M + H]+ 2.22 (s, 3H), 2.83 – 3.08 (m, 3H), 3.98 (t, J = 9.8 Hz, 1H), 4.43 (d, J = 11.1 Hz, 1H), 5.33 – 5.49 (m, 1H), 6.70 – 6.94 (m, 3H), 7.02 – 7.21 (m, 4H), 7.25 (d, J = 1.4 Hz, 1H), 7.51 – 7.65 (m, 2H), 10.23 (s, 1H). 371.15 1H NMR (300 MHz, MeOH-d4) δ 1.08 – 1.26 (m, 3H), [M + H]+ 1.82 (d, J = 7.3 Hz, 3H), 2.50 – 2.79 (m, 2H), 5.44 – 5.60 (m, 1H), 6.93 (d, J = 1.6 Hz, 1H), 7.09 – 7.27 (m, 3H), 7.53 – 7.70 (m, 3H), 8.11 – 8.22 (m, 1H), 8.75 (d, J = 4.9 Hz, 1H), 8.84 – 8.94 (m, 1H). 328.10 1H NMR (300 MHz, DMSO-d6) δ 1.09 (t, J = 7.5 Hz, 3H), [M + H]+ 1.44 – 1.59 (m, 1H), 1.69 (d, J = 6.9 Hz, 3H), 1.89 – 2.12 (m, 1H), 2.30 – 2.48 (m, 3H), 2.53 – 2.72 (m, 2H), 3.26 – 3.33 (m, 1H), 3.55 – 3.90 (m, 3H), 5.30 – 5.52 (m, 1H), 6.79 (d, J = 1.4 Hz, 1H), 7.10 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 1.4 Hz, 1H), 7.43 – 7.67 (m, 2H), 9.95 (s, 1H). 362.07 1H NMR (300 MHz, MeOH-d4) δ 1.33 (d, J = 11.9 Hz, [M + H]+ 1H), 1.81 (d, J = 7.0 Hz, 3H), 2.27 (s, 3H), 3.93 (t, J = 5.4 Hz, 1H), 4.12 – 4.30 (m, 2H), 4.84 (q, J = 15.1 Hz, 2H), 5.47 (q, J = 7.0 Hz, 1H), 6.89 (d, J = 1.5 Hz, 1H), 7.13 (dd, J = 5.8, 8.1 Hz, 3H), 7.19 – 7.33 (m, 4H), 7.52 – 7.62 (m, 2H). 376.15 1H NMR (300 MHz, DMSO-d6) δ 1.71 – 1.92 (m, 2H), [M + H]+ 1.95 – 2.11 (m, 2H), 3.89 – 4.05 (m, 2H), 4.16 (d, J = 12.3 Hz, 1H), 4.35 (m, J = 5.8, 11.6 Hz, 1H), 4.45 (m, J = 2.8, 11.6 Hz, 1H), 4.97 (m, J = 2.7, 5.8 Hz, 1H), 6.26 (d, J = 1.2 Hz, 1H), 6.84 – 6.94 (m, 3H), 7.00 – 7.07 (m, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.52 – 7.60 (m, 3H), 10.12 (s, 1H). 338.10 1H NMR (300 MHz, DMSO-d6) δ 1.44 (d, J = 7.1 Hz, 3H), [M + H]+ 2.16 (s, 3H), 3.55 (s, 2H), 4.30 (q, J = 7.1 Hz, 1H), 7.07 (d, J = 8.3 Hz, 2H), 7.23 (dd, J = 4.8, 7.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.55 – 7.65 (m, 1H), 8.33 (dd, J = 1.6, 5.1 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.69 (s, 1H), 10.08 (s, 1H). 331.00 1H NMR (300 MHz, DMSO-d6) δ 1.46 – 1.62 (m, 4H), [M + H]+ 1.92 – 2.10 (m, 1H), 2.29 (s, 3H), 2.35 – 2.42 (m, 2H), 2.55 – 2.62 (m, 1H), 3.64 (q, J = 7.5 Hz, 1H), 3.69 – 3.74 (m, 1H), 3.76 (d, J = 7.1 Hz, 1H), 3.81 (d, J = 7.6 Hz, 1H), 4.42 (q, J = 7.1 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 8.81 (s, 1H), 9.90 (s, 1H). 324.15 1H NMR (400 MHz, DMSO-d6) δ 1.60 (d, J = 7.1 Hz, 3H), [M + H]+ 2.31 (s, 3H), 4.48 (q, J = 7.1 Hz, 1H), 7.25 – 7.31 (m, 2H), 7.67 – 7.74 (m, 2H), 7.82 – 7.88 (m, 2H), 8.77 – 8.84 (m, 3H), 10.48 (s, 1H). 374 [M 1H NMR (300 MHz, DMSO-d6) δ 1.57 (d, J = 7.0 Hz, 3H), + H]+ 2.29 (s, 3H), 4.47 (q, J = 7.1 Hz, 1H), 7.21 – 7.32 (m, 2H), 7.56 – 7.67 (m, 3H), 8.04 – 8.14 (m, 1H), 8.76 – 8.85 (m, 2H), 8.85 – 8.92 (m, 1H), 10.88 (s, 1H) 331.00 1H NMR (300 MHz, DMSO-d6) δ 1.55 (d, J = 7.1 Hz, 3H), [M + H]+ 1.60 (s, 2H), 1.62 – 1.79 (m, 1H), 1.92 (d, J = 12.6 Hz, 1H), 2.28 (s, 3H), 2.51 – 2.67 (m, 1H), 3.22 – 3.43 (m, 2H), 3.81 (d, J = 11.2 Hz, 1H), 3.88 – 3.99 (m, 1H), 4.42 (q, J = 7.1 Hz, 1H), 7.14 – 7.22 (m, 2H), 7.46 – 7.55 (m, 2H), 8.81 (s, 1H), 9.91 (s, 1H). 367.05 1H NMR (300 MHz, MeOH-d4) δ 1.68 (d, J = 7.1 Hz, [M + H]+ 3H), 1.97 – 2.23 (m, 2H), 2.34 (s, 3H), 3.03 – 3.27 (m, 1H), 3.77 (q, J = 7.6 Hz, 1H), 3.83 – 4.02 (m, 3H), 4.50 (q, J = 7.1 Hz, 1H), 7.17 – 7.36 (m, 2H), 7.49 – 7.62 (m, 2H), 8.77 (s, 1H). 367.05 1H NMR (400 MHz, DMSO-d6) δ 1.57 (d, J = 7.1 Hz, 3H), [M + H]+ 2.30 (s, 3H), 2.60 (dd, J = 15.2, 8.8 Hz, 1H), 2.81 (dd, J = 15.2, 6.0 Hz, 1H), 3.86 (p, J = 8.2 Hz, 1H), 4.24 (dd, J = 9.1, 6.6 Hz, 1H), 4.43 (q, J = 7.1 Hz, 1H), 4.69 (t, J = 9.1 Hz, 1H), 6.76 – 6.86 (m, 2H), 7.11 (dd, J = 8.5, 7.2 Hz, 1H), 7.18 – 7.24 (m, 3H), 7.53 (d, J = 8.5 Hz, 2H), 8.82 (s, 1H), 10.00 (s, 1H). 341.10 1H NMR (300 MHz, DMSO-d6) δ 1.50 (d, J = 7.2 Hz, 3H), [M + H]+ 2.05 (s, 3H), 2.79 (t, J = 7.2 Hz, 2H), 3.28 (t, J = 7.2 Hz, 2H), 4.06 (q, J = 7.1 Hz, 1H), 7.18 (d, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.53 – 7.62 (m, 2H), 7.69 (d, J = 3.3 Hz, 1H), 8.16 (s, 1H), 9.96 (s, 1H). 338.10 1H NMR (300 MHz, DMSO-d6) δ 1.50 (d, J = 7.2 Hz, 3H), [M + H]+ 1.95 (s, 3H), 2.03 (s, 3H), 2.50 (t, J = 7.7 Hz, 2H), 2.80 (t, J = 7.6 Hz, 2H), 3.98 (d, J = 7.8 Hz, 1H), 7.15 (d, J = 8.2 Hz, 2H), 7.30 (s, 1H), 7.38(s, 1H), 7.46 (d, J = 8.3 Hz, 2H), 9.83 (s, 1H), 11.47 (s, 2H). 314.10 1H NMR (300 MHz, DMSO-d6) δ 1.43 – 1.62 (m, 4H), [M + H]+ 1.93 – 2.08 (m, 4H), 2.32 – 2.41 (m, 2H), 2.53 – 2.61 (m, 1H), 3.26 – 3.33 (m, 1H), 3.58 – 3.84 (m, 3H), 3.94 – 4.12 (s, 1H), 7.10 – 7.23 (d, J = 8.2 Hz, 2H), 7.34 – 7.39 (s, 1H), 7.39 – 7.50 (d, J = 8.2 Hz, 2H), 9.76 – 9.93 (s, 1H), 11.43 – 11.80 (s, 1H). 321.05 1H NMR (300 MHz, DMSO-d6) δ 1.49 (d, J = 7.2 Hz, 3H), [M+H]+ 2.02 (s, 3H), 3.67 (s, 2H), 4.02 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 11.0 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.68 – 7.78 (m, 1H), 8.42 – 8.55 (m, 2H), 10.12 (s, 1H), 11.57 (s, 1H). 357.13 1H NMR (300 MHz, DMSO-d6) δ 1.49 (d, J = 7.2 Hz, 3H), [M + H]+ 2.03 (s, 3H), 4.06 (s, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.38 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.57 – 7.66 (m, 1H), 8.09 (d, J = 8.0 Hz, 1H), 8.80 (d, J = 4.8 Hz, 1H), 8.88 (d, J = 2.3 Hz, 1H), 10.81 (s, 1H), 11.63 (s, 1H). 315.14 1H NMR (300 MHz, DMSO-d6) δ 1.45 – 1.62 (m, 4H), [M + H]+ 1.93 – 2.10 (m, 1H), 2.03 (s, 3H), 2.35 – 2.46 (m, 2H), 2.51 – 2.66 (m, 1H), 3.27 – 3.36 (m, 1H), 3.57 – 3.71 (m, 1H), 3.68 – 3.86 (m, 2H), 4.16 (q, J = 7.2 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 7.40 (s, 1H), 7.84 – 7.94 (m, 1H), 8.60 (d, J = 2.5 Hz, 1H), 10.07 (s, 1H), 11.70 (s, 1H). 328.15 1H NMR (400 MHz, MeOH-d4) δ 1.24 (dd, J = 6.6, 27.4 [M + H]+ Hz, 3H), 1.58 – 1.75 (m, 4H), 2.11 (s, 4H), 2.32 – 2.54 (m, 2H), 3.48 (ddd, J = 7.3, 8.6, 19.8 Hz, 1H), 3.70 – 3.82 (m, 1H), 3.82 – 4.00 (m, 2H), 4.16 (q, J = 7.3 Hz, 1H), 7.17 – 7.25 (m, 2H), 7.41 – 7.50 (m, 3H). 349.95 1H NMR (300 MHz, MeOH-d4) δ 1.62 (d, J = 7.3 Hz, [M + H]+ 3H), 2.00 – 2.21 (m, 5H), 3.04 – 3.27 (m, 1H), 3.68 – 3.83 (m, 1H), 3.83 – 3.99 (m, 3H), 4.18 (q, J = 7.3 Hz, 1H), 7.20 – 7.30 (m, 2H), 7.48 (s, 1H), 7.49 – 7.58 (m, 2H). 383.10 1H NMR (300 MHz, DMSO-d6) δ 1.26 (s, 1H), 1.58 (s, [M + H]+ 3H), 1.67 – 1.93 (m, 3H), 2.10 (d, J = 8.9 Hz, 1H), 4.00 (d, J = 6.1 Hz, 2H), 4.10 (t, J = 6.1 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 7.46 (s, 1H), 7.61 (t, J = 7.9 Hz, 3H), 8.10 (d, J = 7.9 Hz, 1H), 8.81 (d, J = 4.9 Hz, 1H), 8.87 – 8.93 (m, 1H), 10.86 (s, 1H). 340.05 1H NMR (300 MHz, DMSO-d6) δ 1.56 (s, 4H), 1.62 – [M + H]+ 1.86 (m, 5H), 1.93 (d, J = 13.4 Hz, 1H), 2.06 (s, 1H), 2.58 – 2.66 (m, 1H), 3.30 (s, 1H), 3.39 (d, J = 10.7 Hz, 1H), 3.81 (d, J = 9.1 Hz, 1H), 3.90 – 4.10 (m, 4H), 7.01 (d, J = 8.4 Hz, 2H), 7.38 – 7.57 (m, 3H), 9.90 (s, 1H). 326.10 1H NMR (300 MHz, DMSO-d6) δ 1.47 – 1.62 (m, 1H), [M + H]+ 1.70 -1.76 (m, 1H), 1.81 – 1.94 (m, 1H), 1.94 – 2.09 (m, 3H), 2.35 – 2.43 (m, 2H), 2.54 – 2.61 (m, 1H), 3.31 (s, 1H), 3.60 – 3.70 (m, 1H), 3.70 – 3.84 (m, 2H), 3.90 – 4.06 (m, 2H), 4.10 – 4.21 (m, 1H), 6.26 (d, J = 1.2 Hz, 1H), 7.09 – 7.20 (m, 2H), 7.45 – 7.57 (m, 3H), 9.91 (s, 1H). 340.00 1H NMR (400 MHz, DMSO-d6) δ 1.46 – 1.56 (m, 1H), [M + H]+ 1.65 – 1.90 (m, 3H), 1.94 – 2.16 (m, 2H), 2.32 – 2.45 (m, 2H), 2.47 – 2.64 (m, 3H), 3.31 (s, 1H), 3.35 (s, 1H), 3.65 (q, J = 7.6 Hz, 1H), 3.70 – 3.87 (m, 2H), 3.95 - 4.05 (m, 3H), 7.01 (d, J = 8.3 Hz, 2H), 7.37 – 7.59 (m, 3H), 9.88 (s, 1H). 326.05 1H NMR (300 MHz, DMSO-d6) δ 1.48 – 1.61 (m, 1H), [M + H]+ 1.74 (t, J = 10.8 Hz, 1H), 1.81 – 1.94 (m, 1H), 1.94 – 2.09 (m, 3H), 2.36 – 2.43 (m, 2H), 2.57 (d, J = 7.0 Hz, 1H), 3.32 (d, J = 6.4 Hz, 1H), 3.64 (q, J = 7.6 Hz, 1H), 3.69 – 3.84 (m, 2H), 3.89 – 4.05 (m, 2H), 4.15 (d, J = 12.8 Hz, 1H), 6.25 (d, J = 1.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.48 – 7.58 (m, 3H), 9.93 (s, 1H). 349.10 1H NMR (300 MHz, DMSO-d6) δ 1.88 (s, 3H), 3.69 (s, [M + H]+ 2H), 3.88 (dd, J = 3.0, 11.9 Hz, 1H), 4.07 (dd, J = 4.0, 11.9 Hz, 1H), 4.72 (d, J = 14.2 Hz, 1H), 4.93 (d, J = 14.2 Hz, 1H), 5.26 – 5.33 (m, 1H), 6.65 (s, 1H), 6.92 (d, J = 8.5 Hz, 2H), 7.36 (dd, J = 4.8, 7.8 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.68 – 7.78 (m, 1H), 8.42 – 8.55 (m, 2H), 10.30 (s, 1H). 212 333.05 1H NMR (300 MHz, DMSO-d6) δ 1.63 – 1.76 (m, 2H), [M + H]+ 1.80 – 1.96 (m, 1H), 2.06 – 2.25 (m, 1H), 2.78 (t, J = 6.4 Hz, 2H), 3.70 (s, 2H), 5.29 (dd, J = 5.1, 7.3 Hz, 1H), 6.68 (s, 1H), 7.02 (d, J = 8.5 Hz, 2H), 7.09 (s, 1H), 7.36 (dd, J = 4.7, 7.9 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.69 – 7.79 (m, 1H), 8.42 – 8.56 (m, 2H), 10.29 (s, 1H). 213 347.18 1H NMR (300 MHz, MeOH-d4) δ 1.67 (s, 2H), 1.95 (s, [M + H]+ 3H), 2.04 (dd, J = 4.2, 13.6 Hz, 1H), 2.19 – 2.39 (m, 1H), 2.62 – 2.79 (m, 1H), 2.86 – 3.00 (m, 1H), 3.74 (s, 2H), 5.42 (dd, J = 3.2, 5.7 Hz, 1H), 6.65 (t, J = 1.1 Hz, 1H), 6.74 – 6.84 (m, 2H), 7.36 – 7.47 (m, 1H), 7.47 – 7.58 (m, 2H), 7.79 – 7.89 (m, 1H), 8.44 (dd, J = 1.6, 4.9 Hz, 1H), 8.52 (dd, J = 0.9, 2.3 Hz, 1H). 152 325.15 + n/a [M + H] 155 322.20 [M + H] + n/a Procedure 16 Example 217: (1R*,5S*)-6,6-difluoro-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)-3- oxabicyclo[3.1.0]hexane-1-carboxamide
Figure imgf000154_0001
HATU (471 mg, 1.46 mmol) was added to a solution of (rac)-(1R,5S)-6,6-difluoro-3- oxabicyclo[3.1.0]hexane-1-carboxylic acid (200 mg, 1.22 mmol) and DIPEA (0.63 ml, 3.66 mmol) in DMF (4 mL). The reaction mixture was stirred for 15 minutes and (S)-4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)aniline (245 mg, 1.22 mmol) was added in one portion. The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The crude product was purified by preparative HPLC, Column: XBridge BEH C18, 100×19mm, 5μm; Mobile Phase A: Water (+ 0.1% NH3), Mobile Phase B: MeOH; RT (min) 0.806, to afford (1R*,5S*)-6,6-difluoro-N-(4-[(1S)-1-(2- methyl-1H-imidazol-1-yl)ethyl]phenyl)-3-oxabicyclo[3.1.0]hexane-1-carboxamide (106.2 mg, 25%) as a white solid. MS (ES+, m/z): 348.1 [M + H]+; 1H NMR (500 MHz, DMSO-d6) δ 1.68 (d, 3H), 2.17 (s, 3H), 3.10 (dd, 1H), 4.05 (dd, 2H), 4.12 (d, 1H), 4.37 (d, 1H), 5.40 (q, 1H), 6.75 (s, 1H), 7.13 (d, 2H), 7.21 (s, 1H), 7.54 (d, 2H), 10.13 (s, 1H). Table 18. The following compound was made using a method analogous to the Procedure 16 described above. Example Structure MS (ES+, m/z) NMR 221 380.1 [M + H]+ 1H NMR (500 MHz, DMSO-d6) δ 1.72 (q, 1H), 1.91 (dq, 3H), 2.11 – 1.96 (m, 3H), 3.18 – 3.10 (m, 1H), 3.63 (q, 1H), 3.77 – 3.71 (m, 1H), 3.79 (d, 2H), 3.94 (td, 1H), 4.03 (dd, 1H), 4.20 – 4.08 (m, 1H), 6.24 (s, 1H), 7.20 (d, 2H), 7.52 (s, 1H), 7.59 (d, 2H), 10.55 (s, 1H). Procedure 17 Example 222: rel-(R)-2,2-difluoro-2-(pyridin-3-yl)-N-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)acetamide
Figure imgf000155_0001
Step 1 HATU (247.72 mg, 651.5 µmol) was added to a solution of 2,2-difluoro-2-(pyridin-3-yl)acetic acid (94 mg, 543 µmol), and NMM (137 mg, 1.36 mmol) in DMF (2 mL) at -10 °C. The reaction mixture was stirred for 10 minutes and (rac)-(R)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)aniline (139 mg, 651.5 µmol) was added in one portion. The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by preparative HPLC, Column: Waters Sun Fire C18 OBD, 100×19mm, 5μm; Mobile Phase A: Water (0.1% NH4OH), Mobile Phase B: MeOH; RT (min) 0.94, to afford (rac)- 2,2-difluoro-N-(4-5H,6H,7H,8H- imidazo[1,5-a]pyridin-8-ylphenyl)-2-(pyridin-3-yl)acetamide (60.5 mg; 23.2%) as a light-brown solid. MS (ES+, m/z): 369.0; 1H NMR (500 MHz, DMSO-d6) δ 1.72 (d, 1H), 1.85 (dd, 1H), 1.92 – 2.08 (m, 2H), 3.94 (ddd, 1H), 4.03 (dd, 1H), 4.13 (dt, 1H), 6.23 (d, 1H), 7.12 – 7.27 (m, 2H), 7.52 (s, 1H), 7.54 – 7.64 (m, 3H), 8.08 (dt, 1H), 8.78 (dd, 1H), 8.87 (d, 1H), 10.84 (s, 1H). Step 2 The stereoisomers were separated on a Chiralpak AD-H (250x20 mm, 5 µm), eluting with hexane: IPA: MeOH: DEA, 50:25:25:0.05, at a flow rate of 12 mL/min., to afford: ISOMER 1 rel-(R)-2,2-Difluoro-2-(pyridin-3-yl)-N-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)acetamide (22.3 mg), RT1 (29.40 min), MS (ES+, m/z): 369.0 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 1.78 – 1.62 (m, 1H), 1.84 (ddt, 1H), 2.08 – 1.94 (m, 2H), 3.94 (ddd, 1H), 4.03 (dd, 1H), 4.13 (dt, 1H), 6.24 (s, 1H), 7.29 – 7.12 (m, 2H), 7.53 (s, 1H), 7.59 (dt, 3H), 8.08 (dt, 1H), 8.78 (dd, 1H), 8.87 (d, 1H), 10.84 (s, 1H). ISOMER 2 rel-(R)-2,2-Difluoro-2-(pyridin-3-yl)-N-(4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl)acetamide (22.7 mg), RT2 (92.83 min), MS (ES+, m/z): 369.0 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 1.78 – 1.62 (m, 1H), 1.84 (ddt, 1H), 2.08 – 1.94 (m, 2H), 3.94 (ddd, 1H), 4.03 (dd, 1H), 4.13 (dt, 1H), 6.24 (s, 1H), 7.29 – 7.12 (m, 2H), 7.53 (s, 1H), 7.59 (dt, 3H), 8.08 (dt, 1H), 8.78 (dd, 1H), 8.87 (d, 1H), 10.84 (s, 1H). Table 19. The following compounds were made using a method analogous to the Procedure 17, step 1 described above. Example Structure MS (ES+, m/z) NMR 215 382.1 [M + H]+ 1H NMR (500 MHz, DMSO-d6) δ 1.10 (s, 3H), 1.63 – 1.43 (m, 3H), 1.68 (d, 3H), 2.10 (d, 1H), 2.17 (s, 3H), 3.44 (ddd, 1H), 3.58 (dt, 1H), 4.02 (d, 1H), 5.38 (q, 1H), 6.74 (d, 1H), 7.12 – 7.02 (m, 2H), 7.20 (d, 1H), 7.63 – 7.47 (m, 2H), 9.26 (s, 1H). 216 342.2 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 1.13 (d, 6H), 1.36 (td, 1H), 1.55 (dt, 1H), 1.67 (d, 3H), 1.77 – 1.71 (m, 1H), 1.85 – 1.77 (m, 1H), 2.17 (s, 3H), 2.45 (dd, 1H), 3.58 (t, 1H), 3.68 (ddd, 1H), 5.36 (q, 1H), 6.74 (d, 1H), 7.16 – 7.04 (m, 2H), 7.19 (d, 1H), 7.55 – 7.48 (m, 2H), 9.92 (s, 1H). 218 354.2 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 0.91 (td, 3H), 1.60 – 1.53 (m, 1H), 1.74 – 1.63 (m, 6H), 1.78 (dq, 1H), 1.85 (d, 1H), 1.94 – 1.87 (m, 1H), 2.02 (dddd, 1H), 2.17 (d, 3H), 3.73 (dd, 1H), 3.84 (ddd, 1H), 5.37 (q, 1H), 6.74 (d, 1H), 7.15 – 7.01 (m, 2H), 7.19 (d, 1H), 7.57 (dd, 2H), 9.43 (s, 1H). 219 358.2 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 1.68 (d, 4H), 1.76 (td, 1H), 1.89 – 2.00 (m, 3H), 2.00 – 2.13 (m, 1H), 2.17 (s, 3H), 3.80 (d, 1H), 3.90 (dd, 1H), 4.55 (s, 1H), 4.65 (s, 1H), 5.38 (q, 1H), 6.74 (d, 1H), 7.09 (d, 2H), 7.20 (d, 1H), 7.53 – 7.63 (m, 2H), 9.50 (s, 1H). 220 350.0 [M + H] + 1H NMR (500 MHz, DMSO-d6) δ 1.73 – 1.65 (m, 3H), 1.97 (s, 1H), 2.17 (d, 3H), 2.30 (s, 1H), 3.19 – 2.95 (m, 1H), 3.95 – 3.62 (m, 3H), 4.25 (dd, 1H), 5.38 (q, 1H), 6.75 (d, 1H), 7.15 – 7.06 (m, 2H), 7.27 – 7.17 (m, 1H), 7.54 – 7.44 (m, 1H), 7.64 – 7.54 (m, 1H), 10.12 (s, 1H). Procedure 18 Example 214: 2,2-difluoro-2-(oxolan-3-yl)-N-[4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- yl)phenyl]acetamide
Figure imgf000158_0001
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (127.31 mg, 664.11 µmol) was added to a suspension of (rac)-(R)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)aniline (118.03 mg, 553.42 µmol), sodium 2,2-difluoro-2-(oxolan-3-yl)acetate (104.1 mg, 553.42 µmol), and 3H- [1,2,3]triazolo[4,5-b]pyridin-3-ol (90.39 mg, 664.11 µmol) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The crude product was purified by preparative HPLC, Column: XBridge BEH C18, 100×19mm, 5μm; Mobile Phase A: Water (+ 0.1% NH3), Mobile Phase B: MeCN; RT (min) 1.56, to afford 2,2-difluoro-2-(oxolan- 3-yl)-N-[4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl]acetamide (13.9 mg, 7% yield) as a beige solid. MS (ES+, m/z): 362.2 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 1.72 (q, 1H), 1.91 (dq, 3H), 2.11 – 1.96 (m, 3H), 3.18 – 3.10 (m, 1H), 3.63 (q, 1H), 3.77 – 3.71 (m, 1H), 3.79 (d, 2H), 3.94 (td, 1H), 4.03 (dd, 1H), 4.20 – 4.08 (m, 1H), 6.24 (s, 1H), 7.20 (d, 2H), 7.52 (s, 1H), 7.59 (d, 2H), 10.55 (s, 1H). Procedure 19 Example 157: (S)- N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-2- ylamino)acetamide
Figure imgf000158_0002
Step 1 Cs2CO3 (4.60 g, 14.06 mmol) was added to a solution of tert-butyl pyridin-2-ylcarbamate (910 mg, 4.69 mmol) and benzyl 2-bromoacetate (1.28 g, 5.62 mmol) in DMF (10 mL) at room temperature under one atmosphere of nitrogen. The reaction mixture was stirred at 80 °C for 5 hours, then it was cooled, poured into water (25 mL), extracted with EtOAc (20 mL x 3) and the combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by flash silica chromatography, eluting with a mixture of 0 to 20% EtOAc in petroleum ether, to afford benzyl N-(tert-butoxycarbonyl)-N-(pyridin-2-yl)glycinate (1.3 g, 81%) as a colourless oil. MS (ES+, m/z): 343.1 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.39 (s, 9H), 4.66 (s, 2H), 5.17 (s, 2H), 6.94–7.16 (m, 1H), 7.25–7.43 (m, 2H), 7.35 (s, 3H), 7.64–7.83 (m, 2H), 8.29 (dt, J = 4.9, 1.5 Hz, 1H). Step 2 10% Pd-C (w/w) (0.37 g, 0.35 mmol) was added to a solution of benzyl N-(tert-butoxycarbonyl)-N- (pyridin-2-yl)glycinate (1.2 g, 3.50 mmol) in MeOH (15 mL). The reaction mixture was stirred at room temperature under one atmosphere of hydrogen for 3 hours, then it was filtered through a pad of CELITE and the filtrate was concentrated under reduced pressure to afford N-(tert-butoxycarbonyl)- N-(pyridin-2-yl)glycine (0.87 g, 98%) as a green oil. MS (ES+, m/z): 253.0 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.36 (s, 1H), 1.38–1.48 (m, 1H), 1.43 (s, 9H), 4.47 (s, 2H), 7.07 (td, J = 5.0, 2.8 Hz, 1H), 7.66–7.79 (m, 2H), 8.28 (dt, J = 4.9, 1.5 Hz, 1H). Steps 3-4 tert-Butyl (S)-(2-((4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)amino)-2-oxoethyl)(pyridin-2- yl)carbamate was prepared using the Procedure 14 described above and used without further purification. TFA (1.5 mL) was added to the solution of crude product in DCM (3 mL) and stirred for 1 hour. The solvent was removed under reduced pressure and purified by preparative HPLC, Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3 + 0.1% NH3), Mobile Phase B: MeCN; RT (min): 8.78, to afford (S)-N-(4-(1-(2-methyl-1H-imidazol-1- yl)ethyl)phenyl)-2-(pyridin-2-ylamino)acetamide (13.0 mg) as a white solid. MS (ES+, m/z): 336 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.68 (d, J = 7.0 Hz, 3H), 2.18 (s, 3H), 4.01 (d, J = 6.0 Hz, 2H), 5.36 (t, J = 7.0 Hz, 1H), 6.46–6.51 (m, 1H), 6.58 (dt, J = 8.4, 1.0 Hz, 1H), 6.75 (d, J = 1.4 Hz, 1H), 6.83 (t, J = 6.0 Hz, 1H), 7.06–7.15 (m, 2H), 7.21 (d, J = 1.4 Hz, 1H), 7.37 (ddd, J = 8.7, 7.0, 1.9 Hz, 1H), 7.49–7.57 (m, 2H), 7.92 (ddd, J = 5.1, 2.0, 0.8 Hz, 1H), 9.97 (s, 1H). Procedure 20 Example 187: N-(5-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyrazin-2-yl)-2-((R)-tetrahydrofuran-3- yl)acetamide
Figure imgf000160_0001
Step 1 2-[(3R)-Oxolan-3-yl]acetyl chloride (80.57 mg, 542.22 µmol) was added to a solution o of (rac)-5-[1- (2-methyl-1H-imidazol-1-yl)ethyl]pyrazin-2-amine dihydrochloride (100.0 mg, 362.1 µmol) and N,N- dimethylpyridin-4-amine (75 mg, 614.5 µmol, 1.7 eq) in pyridine (143 mg, 1.81 mmol, 150.0 µl, 5.0 eq). The reaction mixture was stirred at room temperature overnight, then it was concentrated under reduced pressure. The residue was partitioned between EtOAc (30 mL) and water (30 mL), the aqueous phase was extracted with EtOAc (30 mL x 3) and the combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by preparative HPLC, Column: XBridge BEH C18, 100*19mm, 5μm; Mobile Phase A: Water, Mobile Phase B: MeCN; RT (min) 1.12, to afford (rac)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyrazin-2-yl)- 2-((R)-tetrahydrofuran-3-yl)acetamide (89.0 mg, 74.2%) as a beige solid. MS (ES+, m/z): 316.2 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (dt, 1H), 1.76 (d, 3H), 2.02 (tt, 1H), 2.29 (s, 3H), 2.55 (d, 1H), 3.39 – 3.46 (m, 2H), 3.57 – 3.84 (m, 4H), 5.58 (q, 1H), 6.75 (d, 1H), 7.20 (d, 1H), 8.22 (d, 1H), 9.27 (d, 1H), 10.85 (s, 1H). Step 2 The enantiomers were separated on a CHIRALPAK AD (250x30 mm, 10 mkm), eluting with Hexane:IPA:MeOH, 50:25:25, at a flow rate of 40 mL/min, to afford: ISOMER 1 (eutomer): N-(5-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyrazin-2-yl)-2-((R)- tetrahydrofuran-3-yl)acetamide (35.1 mg) RT1 (24.8 min), MS (ES+, m/z): 316.2 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 1.50 (dq, 1H), 1.75 (d, 3H), 1.99 (dtd, 1H), 2.28 (s, 3H), 2.50 – 2.57 (m, 2H), 3.24 – 3.30 (m, 2H), 3.61 (q, 1H), 3.71 (td, 1H), 3.78 (dd, 1H), 5.57 (q, 1H), 6.75 (d, 1H), 7.19 (d, 1H), 8.21 (d, 1H), 9.25 (d, 1H), 10.85 (s, 1H). ISOMER 2 (distomer): N-(5-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyrazin-2-yl)-2-((R)- tetrahydrofuran-3-yl)acetamide (38.0 mg) RT1 (50.32 min), MS (ES+, m/z): 316.2 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ 1.50 (dq, 1H), 1.75 (d, 3H), 1.99 (dtd, 1H), 2.28 (s, 3H), 2.50 – 2.57 (m, 2H), 3.24 – 3.30 (m, 2H), 3.61 (q, 1H), 3.71 (td, 1H), 3.78 (dd, 1H), 5.57 (q, 1H), 6.75 (d, 1H), 7.19 (d, 1H), 8.21 (d, 1H), 9.25 (d, 1H), 10.85 (s, 1H). Procedure 21 Examples 228 - 229: rel-(R)-N-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-2,2-difluoro-2-(pyridin- 3-yl)acetamide
Figure imgf000161_0001
Step 1 (rac)-(R)-N-(4-(1-(4-Ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethyl)phenyl)-2,2- difluoro-2-(pyridin-3-yl)acetamide was using the Procedure 15 described above. MS (ES+, m/z): 501.10 [M + H]+. Step 2 A solution of N-(4-(1-(4-ethyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)ethyl)phenyl)-2,2- difluoro-2-(pyridin-3-yl)acetamide (75 mg, 0.15 mmol) was added and TFA (0.5 mL) in DCM (0.5 mL) was stirred at room temperature for 15 hour. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC, Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: MeCN; Gradient: 25% B to 30% B in 13 min, 30% B; RT (min): 11, to afford (rac)-(R)-N-(4-(1-(4-ethyl-1H-imidazol-5- yl)ethyl)phenyl)-2,2-difluoro-2-(pyridin-3-yl)acetamide (41.0 mg, 73.9 %) as a white solid. MS (ES+, m/z): 370.95 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.00 (t, J = 7.5 Hz, 3H), 1.48 (d, J = 7.9 Hz, 3H), 2.46 (d, J = 7.8 Hz, 2H), 4.01 (d, J = 7.2 Hz, 1H), 7.28 (d, J = 8.3 Hz, 2H), 7.39 (s, 1H), 7.47 – 7.66 (m, 3H), 8.09 (d, J = 8.3 Hz, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.88 (s, 1H), 10.79 (s, 1H), 11.63 (s, 1H). Step 3 (rac)-(R)-N-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-2,2-difluoro-2-(pyridin-3-yl)acetamide was resolved by preparative chiral-HPLC on a Column: CHIRALPAK IE, 2*25 cm, 5 μm; Mobile Phase A: MtBE (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH; Gradient: 15% B to 15% B in 14 min; RT1 (min): 7.83; RT2 (min): 11.39, to afford: ISOMER 2 (RT = 11.39 min): rel-(R)-N-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-2,2-difluoro-2- (pyridin-3-yl)acetamide (10.10 mg, 28.9 %) as a white solid. MS (ES+, m/z): 370.95 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.00 (t, J = 7.5 Hz, 3H), 1.50 (t, J = 9.3 Hz, 3H), 2.33 – 2.47 (m, 2H), 3.96 – 4.23 (m, 1H), 7.17 – 7.33 (m, 2H), 7.39 (s, 1H), 7.47 – 7.66 (m, 3H), 8.09 (d, J = 8.4 Hz, 1H), 8.79 (d, J = 4.9 Hz, 1H), 8.88 (s, 1H), 10.79 (s, 1H), 11.63 (s, 1H). ISOMER 1 (RT = 7.83 min): rel-(R)-N-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-2,2-difluoro-2- (pyridin-3-yl)acetamide (10.62 mg, 30.3 %) as a white solid. MS (ES+, m/z): 370.95 [M + H]+; 1H NMR (300 MHz, DMSO-d6) δ 1.00 (t, J = 7.5 Hz, 3H), 1.50 (t, J = 9.3 Hz, 3H), 2.33 – 2.47 (m, 2H), 3.96 – 4.23 (m, 1H), 7.17 – 7.33 (m, 2H), 7.39 (s, 1H), 7.47 – 7.66 (m, 3H), 8.09 (d, J = 8.4 Hz, 1H), 8.79 (d, J = 4.9 Hz, 1H), 8.88 (s, 1H), 10.79 (s, 1H), 11.63 (s, 1H). Table 20. The following compounds were made using a Procedure analogous to the Procedure 21 described above. Example Structure MS (ES+, m/z) NMR 224 350.1 [M + H]+ 1H NMR (300 MHz, MeOH-d4) δ 1.62 (d, J = 7.3 Hz, 3H), 1.96 – 2.23 (m, 5H), 3.03 – 3.27 (m, 1H), 3.77 (q, J = 7.6 Hz, 1H), 3.82 – 4.00 (m, 3H), 4.18 (q, J = 7.3 Hz, 1H), 7.16 – 7.32 (m, 2H), 7.43 – 7.59 (m, 3H), two exchangeable protons are not visible. 225 350.1 [M + H]+ 1H NMR (300 MHz, MeOH-d4) δ 1.62 (d, J = 7.3 Hz, 3H), 1.96 – 2.23 (m, 5H), 3.03 – 3.27 (m, 1H), 3.77 (q, J = 7.6 Hz, 1H), 3.82 – 4.00 (m, 3H), 4.18 (q, J = 7.3 Hz, 1H), 7.16 – 7.32 (m, 2H), 7.43 – 7.59 (m, 3H), two exchangeable protons are not visible. 227 328.1 [M + H]+ 1H NMR (300 MHz, MeOH-d4) δ 1.28 (d, J = 6.6 Hz, 3H), 1.65 (dd, J = 7.7, 23.7 Hz, 4H), 2.11 (s, 4H), 2.31 – 2.53 (m, 2H), 3.46 (dd, J = 7.1, 8.5 Hz, 1H), 3.68 – 3.96 (m, 3H), 4.16 (q, J = 7.3 Hz, 1H), 7.20 (d, J = 8.5 Hz, 2H), 7.32 – 7.57 (m, 3H), the two exchangeable protons are not visible. Biological assays Biochemical NADase assay A biochemical enzyme inhibition assay was used to measure the SARM1-mediated conversion of NAD to ADPR (and other metabolites) using mass spectrometry. Materials and methods Expression and purification of SARM1 The SARM1 cDNA corresponding to residues 28-724 with N-terminal polyhistidine (6xHN) and AVI tags was synthesised (GenScript) and cloned into a pFastBac1 vector. Spodoptera frugiperda 9 (Sf9) cells were infected and grown in ExpiSf CD Medium (ThermoFisher) according to standard protocols. Cells were harvested 48 h post-infection by centrifugation (3400 g, 15 min, 4 °C) and resuspended in Buffer A (40 mM HEPES pH 8, 0.4 M NaCl, 8 mM imidazole, 0.008 % Tween-20, 4% glycerol and 5 mM TCEP) supplemented with 0.04 µL/mL DNAse I and Complete protease inhibitor (1 tablet/50 mL; Roche). The sample was lysed by sonication and clarified by centrifugation (38400 g, 45 min, 4 °C). The supernatant was loaded onto a 5 mL HisTrap Crude FF column (Cytiva) pre-equilibrated with Buffer A and eluted with 300 mM imidazole in Buffer A. The eluate was pooled and concentrated to ~ 11 mL using a 10 kDa MWCO centrifugal device (Pall). The sample was subsequently purified using a Superdex 20026/60 column (Cytiva) pre-equilibrated with Buffer B (40 mM HEPES pH 8, 0.4 M NaCl, 5 % glycerol and 1 mM TCEP). The peak fractions containing pure SARM1 were pooled, flash- frozen and stored at - 80 °C. Biochemical Assay Ten microlitres of purified SARM1 at the indicated concentration (generally 20-100 nM of SARM1) was incubated with 25 µM of NAD and the indicated concentration of compounds in reaction buffer (10 mM Tris-HCl, 25 µM EDTA, 0.01% n-Dodecyl-β-D-maltopyranoside, pH 7.5) at 25 °C in 384 well plates. For testing compounds in concentration response, 100 nL of compound dissolved in DMSO was added to plates prior to addition of SARM1 followed by addition of NAD to initiate reactions. The final DMSO concentration in each reaction was 1%. Reactions were quenched after 30-120 minutes by addition of 40 µl of 0.1% formic acid followed by centrifugation for 2 minutes at 2,500 x g. Concentration response experiments included control samples representing no inhibition (DMSO) and full inhibition (N-ethyl-3-imino-N-phenyl-3H-1,2,4-dithiazol-5-amine; inhibitor control compound). Quenched samples were analysed by AMI-MS or LC-MS/MS. Acoustic mist ionization mass spectroscopy (AMI-MS) measurements Samples in 384 well plates (Labcyte PP-0200) were ionized using an acoustic mist ionization (AMI) source composed of an Echo550 acoustic liquid handler (Labcyte), a high-voltage power supply (RIGOL), and a heated transfer interface (Waters), and introduced into a Xevo G2-XS qToF mass spectrometer (Waters). The transfer interface and mass spectrometer were operated using MassLynx software (Waters). The misting event repetition rate was set at 1400 Hz with a power of 11.5 dB, polarity switching every 10 nl, charging cone voltage at ±3 kV, and transfer interface heated at 200 °C. The transit velocity of droplets within the interface was controlled by allowing cone gas flow at 50 L/h. The mass spectrometer was operated in positive ion sensitivity mode with a source temperature of 100 °C, cone voltage of 20 V, and target enhancement at 550. Data were acquired over a range of 500 – 700 m/z. Samples were written into a single data acquisition file and automatically post-processed into an individual mass spectrum for each sample. NAD and ADPR were quantified by measuring the intensities of [M+H]+ at 664.1287 ± 0.04 m/z and 560.0991 ± 0.04 m/z, respectively. LC-MS/MS measurements Samples (1 µl) were injected into an UPLC system (ACQUITY; Waters) containing an ACQUITY UPLC HSS T3 column (2.1 x 30 mm, 1.8 µm; Waters) kept at 40 °C at a flow rate of 1 ml/min in 0.2% MeCN with 0.1% FA. Mobile phase A was water containing 0.1% FA and mobile phase B was MeCN containing 0.1% FA. Analytes were separated using a linear gradient of 0.2-95% MeCN with 0.1% FA over 0.1-0.7 min and directed into a Xevo TQ-S triple quadrupole mass spectrometer (Waters) with an electrospray ionization (ESI) source. The source temperature and desolvation temperature were set to 150 °C and 450 °C, respectively. Mass analysis was done by multiple reaction monitoring (MRM) and MRM parameters (Table 21, below) were optimized using MassLynx QuanOptimize software (Waters) by flow injection ESI MS of pure analyte standards dissolved in 0.1% formic acid. Peak integration and quantification was done using MassLynx TargetLynx software (Waters). Table 21: MRM parameters for LC-MS/MS measurements Analyte / Parent ion Daughter ion CV (V) CE (V) Compound (m/z) (m/z) NAM 123 80 50 16 ADPR 560 348 26 16 NAD 664 428 40 22 Data analysis The conversion ratio (product/(substrate + product) was calculated using peak areas for the respective analyte according to the formulas: Conversion_ADPR = ADPR / (NAD + ADPR) Conversion_NAM = NAM / (NAD + NAM) Where ADPR is the peak area for ADPR in a well, NAD is the peak area for NAD in a well, and NAM is the peak area for NAM in a well. The data were normalized to the range -100% to 0% relative activity using control samples representing -100% activity (full inhibition; inhibitor control) and 0% activity (no inhibition; DMSO control) according to the formula: Relative activity = -100*(x - <IC>)/(<DC> - <IC>) Where “x” is the conversion ratio of a well, <DC> is the median of conversion ratio values for DMSO control wells, and <IC> is the median of conversion ratio values for inhibitor control wells. Data normalization, curve fitting, and calculations of Z’-factor and IC50 values were done using Genedata Screener (Genedata) and GraphPad Prism (GraphPad). Results Inhibitory activity of compounds The activity of compounds was assessed in the biochemical NADase assays described above based on ADPR activity and using AMI-MS and the results obtained are shown in Table 22. Table 22: Data from Biochemical NADase assay using purified SARM1 SARM1 Example Name IC50 (µM) 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2-yl)urea 1 0.265 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2- 2 0.075 yl)urea 1-(4-((4-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(pyridin-2- 3 2.858 yl)urea 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(3-methyl-1H-pyrazol-5- 4 7.487 yl)urea 5 8.822 1-(5-((1H-imidazol-1-yl)methyl)pyridin-2-yl)-3-1H-pyrazol-3-ylurea 6 0.507 1-(4-((1H-imidazol-5-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H-pyrazol-3- 7 0.217 yl)urea 1-(4-cyclobutyl-1H-pyrazol-5-yl)-3-(4-((1H-imidazol-1- 8 9.609 yl)methyl)phenyl)urea 1-(4-cyclopropyl-1H-pyrazol-3-yl)-3-(4-[(1H-imidazol-1- 9 5.168 yl)methyl]phenyl)urea 1-(4-((1H-imidazol-1-yl)methyl)phenyl)-3-(4-methyl-1H-pyrazol-5- 10 0.868 yl)urea 11 0.732 1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea 12 0.309 1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H- 13 0.020 pyrazol-3-yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H- 14 0.722 pyrazol-3-yl)urea 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(4-methyl-1H- 15 0.594 pyrazol-3-yl)urea 1-(2-fluoro-4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1H- 16 0.415 pyrazol-3-yl)urea 1-(4-((2-methyl-1H-imidazol-1-yl)methyl)phenyl)-3-(1-methyl-1H- 7.015 pyrazol-3-yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)propyl)phenyl)-3-(1H- 31.340 pyrazol-3-yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)propyl)phenyl)-3-(1H- 0.439 pyrazol-3-yl)urea 1-(6-((2-methyl-1H-imidazol-1-yl)methyl)pyridin-3-yl)-3-(1H-pyrazol- 7.450 3-yl)urea 1-(4-(1-(2-methyl-1H-imidazol-1-yl)cyclopropyl)phenyl)-3-(1H- 0.334 pyrazol-3-yl)urea rel-(R)-1-(isoxazol-3-yl)-3-(4-(1-(2-methyl-1H-imidazol-1- 0.585 yl)ethyl)phenyl)urea (R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(-(pyridin-2- 0.594 yl)urea (S)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2- 0.046 yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxazol-2- 0.076 yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxetan- 4.083 3-yl)urea (rac)-(R)-1-(2-fluorophenyl)-3-(4-(1-(2-methyl-1H-imidazol-1- 6.801 yl)ethyl)phenyl)urea 1-(4-(1-(2-methyl-1H-imidazol-1-yl)cyclopropyl)phenyl)-3-(pyridin-2- 8.163 yl)urea (rac)-(R)-1-(5-hydroxypyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1- 0.901 yl)ethyl)phenyl)urea (rac)-(R)-1-(5-(hydroxymethyl)pyridin-2-yl)-3-(4-(1-(2-methyl-1H- 1.880 imidazol-1-yl)ethyl)phenyl)urea (rac)-(R)-1-(4-(cyclopropyl(2-methyl-1H-imidazol-1- 0.926 yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea (rac)-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3- 0.590 (pyrazin-2-yl)urea (rac)-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3- 0.883 (pyrimidin-4-yl)urea rel-(R)-1-(4-(cyclopropyl(2-methyl-1H-imidazol-1-yl)methyl)phenyl)- 0.381 3-(1H-pyrazol-3-yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(4- 0.135 methyl-1H-pyrazol-3-yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol-4- 0.116 yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(oxazol-4- 0.585 yl)urea rel-(R)-1-(5-fluoropyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1- 0.290 yl)ethyl)phenyl)urea rel-(R)-1-(3-fluoropyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1- 0.064 yl)ethyl)phenyl)urea rel-(R)-1-(4-chloro-1H-pyrazol-3-yl)-3-(4-(1-(2-methyl-1H-imidazol-1- 0.443 yl)ethyl)phenyl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3- 1.471 (pyridazin-3-yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin- 3.487 3-ylmethyl)urea rel-(R)-1-((5-fluoropyrimidin-2-yl)methyl)-3-(4-(1-(2-methyl-1H- 0.293 imidazol-1-yl)ethyl)phenyl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin- 0.051 2-ylmethyl)urea rel-(R)-1-(5-bromopyridin-2-yl)-3-(4-(1-(2-methyl-1H-imidazol-1- 2.964 yl)ethyl)phenyl)urea rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H- 0.050 imidazol-1-yl)ethyl)phenyl)urea rel-(R)-1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3- 2.116 yl)urea rel-(R)-1-(4-(1-(1H-imidazol-1-yl)ethyl)phenyl)-3-(1H-pyrazol-3- 0.561 yl)urea (rac)-(R)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H- 0.146 pyrazol-3-yl)urea (rac)-(R)-1-(4-(1-(2-cyclopropyl-1H-imidazol-1-yl)ethyl)phenyl)-3- 1.273 (1H-pyrazol-3-yl)urea (rac)-(R)-1-(4-(1-(2-(hydroxymethyl)-1H-imidazol-1-yl)ethyl)phenyl)- 0.803 3-(1H-pyrazol-3-yl)urea 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((SR)-1- 1.531 (pyridin-2-yl)ethyl)urea rel-(R)-1-((1H-pyrazol-3-yl)methyl)-3-(4-(1-(2-methyl-1H-imidazol-1- 0.127 yl)ethyl)phenyl)urea rel-(R)-1-((4-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H- 0.098 imidazol-1-yl)ethyl)phenyl)urea rel-(R)-1-((3-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H- 1.805 imidazol-1-yl)ethyl)phenyl)urea 1-((R)-1-(5-fluoropyridin-2-yl)ethyl)-3-(4-((R*)-1-(2-methyl-1H- 2.022 imidazol-1-yl)ethyl)phenyl)urea (rac)-(R)-1-(4-(2-hydroxy-1-(2-methyl-1H-imidazol-1- 2.315 yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea (rac)-(R)-1-(4-(2,2-difluoro-1-(2-methyl-1H-imidazol-1- 4.973 yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3- 0.115 (pyrimidin-4-ylmethyl)urea rel-1-((R)-1-(1H-pyrazol-3-yl)ethyl)-3-(4-((S)-1-(2-methyl-1H- 0.782 imidazol-1-yl)ethyl)phenyl)urea rel-1-((R)-1-(1H-pyrazol-3-yl)ethyl)-3-(4-((S)-1-(2-methyl-1H- 0.550 imidazol-1-yl)ethyl)phenyl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3- 8.319 (pyridazin-3-ylmethyl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((5- 0.112 methyl-1H-pyrazol-3-yl)methyl)urea rel-(R)-1-((6-methoxypyrimidin-4-yl)methyl)-3-(4-(1-(2-methyl-1H- 2.758 imidazol-1-yl)ethyl)phenyl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((4- 0.069 methyl-1H-pyrazol-3-yl)methyl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol-2- 0.033 ylmethyl)urea (rac)-(R)-1-(4-(1-(5-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(thiazol- 22.649 2-ylmethyl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(3- 6.609 methyloxetan-3-yl)urea rel-(R)-1-(4-chlorobenzyl)-3-(4-(1-(2-methyl-1H-imidazol-1- 16.173 yl)ethyl)phenyl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyrazin- 0.282 2-ylmethyl)urea rel-(R)-1-((5-methoxypyrazin-2-yl)methyl)-3-(4-(1-(2-methyl-1H- 5.682 imidazol-1-yl)ethyl)phenyl)urea rel-(R)-1-(2-chloro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3- 3.862 (1H-pyrazol-3-yl)urea 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((S)- 0.262 tetrahydrofuran-3-yl)urea 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((R)- 17.955 tetrahydrofuran-3-yl)urea rel-(R)-1-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1- 1.969 methyl-1H-imidazol-4-yl)urea rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(2-methyl-1H- 6.002 imidazol-1-yl)ethyl)phenyl)urea (rac)-(R)-1-(2-chloro-6-fluoro-4-(1-(2-methyl-1H-imidazol-1- 7.828 yl)ethyl)phenyl)-3-(1H-pyrazol-3-yl)urea 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((S)- 7.165 tetrahydrofuran-3-yl)methyl)urea 1-(4-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((S)- 5.420 tetrahydro-2H-pyran-3-yl)urea (rac)-(R)-1-(4-(1-(2-(fluoromethyl)-1H-imidazol-1-yl)ethyl)phenyl)-3- 0.256 ((5-fluoropyridin-2-yl)methyl)urea rel-(R)-1-(4-(1-(2-(fluoromethyl)-1H-imidazol-1-yl)ethyl)phenyl)-3- 0.217 ((5-fluoropyridin-2-yl)methyl)urea rel-1-(4-((R)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((3S,4R)- 0.209 4-methyltetrahydrofuran-3-yl)urea (S)-1-((5-fluoropyridin-2-yl)methyl)-3-(2-hydroxy-4-(1-(2-methyl-1H- 3.840 imidazol-1-yl)ethyl)phenyl)urea 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((S)- 1.859 tetrahydrofuran-2-yl)methyl)urea 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((R)- 4.269 tetrahydrofuran-2-yl)methyl)urea rel-(R)-1-(4-(2-fluoro-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3- 14.442 ((5-fluoropyridin-2-yl)methyl)urea 1-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(((2R*,5R*)- 4.592 5-methyltetrahydrofuran-2-yl)methyl)urea rel-(R)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2- 0.045 yl)urea rel-(R)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin-2- 4.228 yl)urea 22.602 1-(4-((1H-imidazol-5-yl)methyl)phenyl)-3-(1H-pyrazol-3-yl)urea (rac)-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methyl-1H- 0.143 imidazol-5-yl)ethyl)phenyl)urea 5.913 1-(4-((1H-imidazol-5-yl)methyl)phenyl)-3-(pyridin-2-yl)urea 1-(4-((RS)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-((S)- 0.412 tetrahydrofuran-3-yl)urea (rac)-(R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3- 0.069 (pyridin-2-yl)urea 4.477 (rac)-(R)-1-(4-(1-(1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea 1.793 rel-(R)-1-(4-(1-(1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2-yl)urea 1-(4-((4-methyl-1H-imidazol-5-yl)methyl)phenyl)-3-(pyridin-2- 0.161 yl)urea rel-(R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(1H- 4.185 pyrazol-3-yl)urea rel-(R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(1H- 0.035 pyrazol-3-yl)urea rel-(R)-1-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin- 0.040 2-yl)urea rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methyl-1H- 0.071 imidazol-5-yl)ethyl)phenyl)urea rel-(R)-1-(6-(1-(4-methyl-1H-imidazol-5-yl)ethyl)pyridin-3-yl)-3- 0.461 (pyridin-2-yl)urea rel-(R)-1-(1H-pyrazol-3-yl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5- 3.190 a]pyridin-5-yl)phenyl)urea rel-(R)-1-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5- 0.298 yl)phenyl)-3-(1H-pyrazol-3-yl)urea rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(5,6,7,8- 4.373 tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)urea rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(3-methyl-5,6,7,8- >100.000 tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)urea rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(3-methyl-5,6,7,8- 0.182 tetrahydroimidazo[1,5-a]pyridin-5-yl)phenyl)urea 1-(4-((RS)-3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5- 4.419 yl)phenyl)-3-((S)-tetrahydrofuran-3-yl)urea 1-(4-((R*)-3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5- 1.192 yl)phenyl)-3-((S)-tetrahydrofuran-3-yl)urea rel-(R)-1-(4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- 0.040 yl)phenyl)-3-(pyridin-2-yl)urea rel-(R)-1-(pyridin-2-yl)-3-(4-(5,6,7,8-tetrahydroimidazo[1,5- 0.162 a]pyridin-8-yl)phenyl)urea 1-((S)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-3-(4-((RS)-1-methyl- 0.221 5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)urea rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-methyl-5,6,7,8- 0.636 tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)urea rel-(R)-1-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(1H- 0.053 pyrazol-3-yl)urea rel-(R)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2- 0.079 yl)urea rel-(R)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(pyridin-2- 0.121 ylmethyl)urea (rac)-(R)-1-(4-(1-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,5- 0.358 a]pyridin-8-yl)phenyl)-3-(pyridin-2-yl)urea (rac)-(R)-1-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)-3-fluorophenyl)-3- 0.479 (pyridin-2-yl)urea (rac)-(R)-1-[4-[1-[2-(difluoromethyl)imidazol-1-yl]ethyl]phenyl]-3-(2- 0.226 pyridyl)urea rel-(R)-1-[(5-fluoropyridin-2-yl)methyl]-3-(4-[5,6,7,8- 0.550 tetrahydroimidazo[1,5-a]pyridin-8-yl]phenyl)urea 0.694 1-(pyridin-2-yl)-3-(4-(thiazol-5-ylmethyl)phenyl)urea 2.244 (rac)-(R)-1-(1H-pyrazol-3-yl)-3-(4-(1-(thiazol-5-yl)ethyl)phenyl)urea 2.208 1-(1H-pyrazol-3-yl)-3-(4-(thiazol-5-ylmethyl)phenyl)urea rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyridin-2- 0.087 yl)urea rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyridin-2- 4.254 yl)urea 1-(4-((RS)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-((S)- 1.321 tetrahydrofuran-3-yl)urea 1-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-((S)- 0.457 tetrahydrofuran-3-yl)urea rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(1H-pyrazol-3- 0.061 yl)urea rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyridin-2- 0.137 ylmethyl)urea rel-(R)-1-((1H-pyrazol-3-yl)methyl)-3-(4-(1-(4-methylthiazol-5- 0.134 yl)ethyl)phenyl)urea rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(thiazol-2- 0.056 ylmethyl)urea rel-(R)-1-((4-methyl-1H-pyrazol-3-yl)methyl)-3-(4-(1-(4- 0.093 methylthiazol-5-yl)ethyl)phenyl)urea 1-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-((S)-tetrahydro- 7.126 2H-pyran-3-yl)urea rel-(R)-1-((5-methyl-1H-pyrazol-3-yl)methyl)-3-(4-(1-(4- 0.145 methylthiazol-5-yl)ethyl)phenyl)urea rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methylthiazol-5- 0.146 yl)ethyl)phenyl)urea rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyrimidin-4- 0.197 ylmethyl)urea rel-(R)-1-((4-fluoropyridin-2-yl)methyl)-3-(4-(1-(4-methylthiazol-5- 0.194 yl)ethyl)phenyl)urea rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(pyrazin-2- 0.422 ylmethyl)urea rel-(R)-1-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-3-(oxazol-2- 0.139 yl)urea 1-(4-((1-methyl-1H-pyrazol-5-yl)methyl)phenyl)-3-(1H-pyrazol-3- 4.430 yl)urea (rac)-(R)-1-(4-(1-(1-methyl-1H-pyrazol-5-yl)ethyl)phenyl)-3-(1H- 0.921 pyrazol-3-yl)urea rel-(R)-1-((5-fluoropyridin-2-yl)methyl)-3-(4-(1-(1-methyl-1H- 0.249 pyrazol-5-yl)ethyl)phenyl)urea rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin- 0.372 3-yl)acetamide rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(thiazol- 0.924 2-yl)acetamide rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-1H-pyrrole- 6.820 2-carboxamide rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(1H- 0.854 pyrazol-3-yl)acetamide 4.506 (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)nicotinamide rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin- 4.763 2-yl)acetamide rel-(R)-2-(5-fluoropyridin-3-yl)-N-(4-(1-(2-methyl-1H-imidazol-1- 2.775 yl)ethyl)phenyl)acetamide rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(pyridin- 4.997 2-yl)propanamide rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(5- 3.284 methylpyridin-3-yl)acetamide 4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl-3-(2H-1,2,3- 3.529 triazol-2-yl)propanamide rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin- 1.001 3-yloxy)acetamide rel-(R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2- 0.828 (pyridin-3-yl)propanamide 4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl-2-(pyrimidin-5- 2.802 yl)acetamide rel-(R)-N-(4-(2-hydroxy-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)- 9.974 2-(pyridin-3-yl)acetamide (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(pyridin-2- 5.846 ylamino)acetamide rel-(R)-N-(2-fluoro-4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2- 1.335 (pyridin-3-yl)acetamide rel-(R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2- 1.290 (pyridin-3-yl)butanamide (R*)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(oxolan-3- 0.282 (R)-yl)acetamide rel-(R)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(oxetan- 4.342 3-yl)acetamide (RS)-2-hydroxy-N-(4-((R*)-1-(2-methyl-1H-imidazol-1- 0.394 yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide rel-2-((R)-3-hydroxytetrahydrofuran-3-yl)-N-(4-((R)-1-(2-methyl-1H- 1.947 imidazol-1-yl)ethyl)phenyl)acetamide (RS)-2-fluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)- 0.458 2-((RS)-tetrahydrofuran-3-yl)acetamide (RS)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((RS)- 0.844 tetrahydrofuran-3-yl)propanamide (R*)-2-methoxy-N-(4-((S)-1-(2-methyl-1H-imidazol-1- 2.457 yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide (R*)-2-methoxy-N-(4-((S)-1-(2-methyl-1H-imidazol-1- 0.732 yl)ethyl)phenyl)-2-((R*)-tetrahydrofuran-3-yl)acetamide (RS)-2-hydroxy-N-(4-((S)-1-(2-methyl-1H-imidazol-1- 1.886 yl)ethyl)phenyl)-2-((RS)-tetrahydrofuran-3-yl)propanamide (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-(4-methyl- 0.869 1H-pyrazol-3-yl)propanamide 2,2-difluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2- 0.107 ((R*)-tetrahydrofuran-3-yl)acetamide 2,2-difluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2- 2.425 ((R*)-tetrahydrofuran-3-yl)acetamide (R*)-2-fluoro-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)- 0.260 2-((R*)-tetrahydrofuran-3-yl)acetamide N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-3-((R*)- 3.920 tetrahydrofuran-2-yl)propanamide 0.840 (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)isonicotinamide 2-((R*)-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-(2-methyl-1H- 0.134 imidazol-1-yl)ethyl)phenyl)acetamide (S)-2,2-difluoro-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2- 0.090 (pyridin-3-yl)acetamide (R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1- 5.139 yl)ethyl)phenyl)tetrahydrofuran-3-carboxamide (S)-3-chloro-4-fluoro-N-(4-(1-(2-methyl-1H-imidazol-1- 0.798 yl)ethyl)phenyl)benzamide (rac)-(R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2- 4.570 yl)isonicotinamide (S)-4-fluoro-N-(4-(1-(2-methyl-1H-imidazol-1- 0.747 yl)ethyl)phenyl)benzamide (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)oxetane-3- 3.258 carboxamide N-(5-((RS)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-((R)- 1.028 tetrahydrofuran-3-yl)acetamide (rac)-(R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2- 1.934 (pyridin-3-yl)acetamide (R*)-N-(4-((S)-1-(2-methyl-1H-imidazol-1- 0.153 yl)ethyl)phenyl)tetrahydro-2H-pyran-3-carboxamide 2-((R*)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-(2-methyl- 0.083 1H-imidazol-1-yl)ethyl)phenyl)acetamide (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)isoxazole-4- 0.567 carboxamide N-(5-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyrazin-2-yl)-2-((R)- 11.410 tetrahydrofuran-3-yl)acetamide N-(5-((R*)-1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2-((R)- 0.613 tetrahydrofuran-3-yl)acetamide rel-(R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2-yl)-2- 0.518 (pyridin-3-yl)acetamide rel-(R)-N-(5-(1-(2-methyl-1H-imidazol-1-yl)ethyl)pyridin-2- 2.325 yl)isonicotinamide (S)-N-(4-(1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2-(4H-1,2,4- 1.013 triazol-3-yl)acetamide (R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)-2,3- 0.070 dihydrobenzo[b][1,4]dioxine-2-carboxamide (R)-N-(4-((S)-1-(2-methyl-1H-imidazol-1-yl)ethyl)phenyl)chromane- 4.518 3-carboxamide rel-(R)-N-(4-(1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-2,2-difluoro- 0.223 2-(pyridin-3-yl)acetamide N-(4-((R*)-1-(2-ethyl-1H-imidazol-1-yl)ethyl)phenyl)-2-((R)- 1.068 tetrahydrofuran-3-yl)acetamide (R*)-N-(4-((S)-1-(2-methyl-1H-imidazol-1- 2.196 yl)ethyl)phenyl)isochromane-4-carboxamide (rac)-(R)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3- 1.050 (thiazol-2-yl)propanamide rel-(R)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-3-(4- 0.565 methyl-1H-pyrazol-3-yl)propanamide N-(4-((R*)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((R)- 1.723 tetrahydrofuran-3-yl)acetamide rel-(R)-N-(4-(1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-(pyridin- 1.596 3-yl)acetamide (rac)-(R)-2,2-difluoro-N-(4-(1-(4-methyl-1H-imidazol-5- 0.462 yl)ethyl)phenyl)-2-(pyridin-3-yl)acetamide N-(6-((R*)-1-(4-methyl-1H-imidazol-5-yl)ethyl)pyridin-3-yl)-2-((R)- 4.265 tetrahydrofuran-3-yl)acetamide (RS)-N-(4-((S*)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((R)- 0.733 tetrahydrofuran-3-yl)propanamide 2,2-difluoro-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2- 1.118 ((S)-tetrahydrofuran-3-yl)acetamide rel-(R)-2,2-difluoro-N-(4-(1-methyl-5,6,7,8-tetrahydroimidazo[1,5- 0.084 a]pyridin-8-yl)phenyl)-2-(pyridin-3-yl)acetamide (R)-N-(4-((R*)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- 0.193 yl)phenyl)tetrahydro-2H-pyran-3-carboxamide 2-((R)-tetrahydrofuran-3-yl)-N-(4-((R*)-5,6,7,8- 0.347 tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)acetamide N-(4-((R*)-1-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8- 0.359 yl)phenyl)-2-((R)-tetrahydrofuran-3-yl)acetamide 2-((R)-tetrahydrofuran-3-yl)-N-(4-((RS)-5,6,7,8- 0.720 tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)acetamide 2-(2,3-dihydro-1-benzofuran-3-yl)-N-[4-(5,6,7,8- 1.694 tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl]acetamide (rac)-(R)-N-(4-(3-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]oxazin-5- 2.350 yl)phenyl)-2-(pyridin-3-yl)acetamide rel-(R)-2-(pyridin-3-yl)-N-(4-(5,6,7,8-tetrahydroimidazo[1,5- 5.165 a]pyridin-5-yl)phenyl)acetamide rel-(R)-N-(4-(3-methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5- 0.362 yl)phenyl)-2-(pyridin-3-yl)acetamide 2,2-difluoro-2-(oxolan-3-yl)-N-[4-(5,6,7,8-tetrahydroimidazo[1,5- 0.736 a]pyridin-8-yl)phenyl]acetamide 3-(RS)-methyl-N-(4-[(S)-1-(2-methyl-1H-imidazol-1- 4.718 yl)ethyl]phenyl)oxane-3-carboxamide 6,6-dimethyl-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1- 2.401 yl)ethyl]phenyl)oxane-3-(RS)-carboxamide (1R*,5S*)-6,6-difluoro-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1- 1.264 yl)ethyl]phenyl)-3-oxabicyclo[3.1.0]hexane-1-carboxamide rel-(1S,4S)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1- 1.604 yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4-carboxamide rel-(1S,4S)-1-ethyl-N-(4-((S)-1-(2-methyl-1H-imidazol-1- 1.325 yl)ethyl)phenyl)-2-oxabicyclo[2.2.1]heptane-4-carboxamide 4,4-difluoro-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1- 0.175 yl)ethyl]phenyl)oxane-3-(RS)-carboxamide 7-hydroxy-N-(4-[(1S)-1-(2-methyl-1H-imidazol-1-yl)ethyl]phenyl)- 0.272 2,3-dihydro-1,4-benzodioxine-2-(RS)-carboxamide rel-(R)-2,2-difluoro-2-(pyridin-3-yl)-N-(4-(5,6,7,8- 0.117 tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)acetamide (R)-N-(4-((RS)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)- 1.977 2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide 2,2-difluoro-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2- 224 0.099 ((S)-tetrahydrofuran-3-yl)acetamide 2,2-difluoro-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2- 225 1.937 ((S)-tetrahydrofuran-3-yl)acetamide rel-2-((R)-5-fluoro-2,3-dihydrobenzofuran-3-yl)-N-(4-((S)-1-methyl- 226 0.084 5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-8-yl)phenyl)acetamide rel-(R)-N-(4-((S)-1-(4-methyl-1H-imidazol-5-yl)ethyl)phenyl)-2-((S)- 227 0.141 tetrahydrofuran-3-yl)propanamide rel-(R)-N-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-2,2-difluoro- 228 0.548 2-(pyridin-3-yl)acetamide rel-(R)-N-(4-(1-(4-ethyl-1H-imidazol-5-yl)ethyl)phenyl)-2,2-difluoro- 229 6.420 2-(pyridin-3-yl)acetamide rel-(R)-N-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-(pyridin-3- 230 0.587 yl)acetamide N-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-((R)- 231 0.744 tetrahydrofuran-3-yl)acetamide 232 1.081 rel-(R)-N-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)isonicotinamide (S)-2,2-difluoro-N-(4-(1-(4-methylthiazol-5-yl)ethyl)phenyl)-2- 233 0.392 (pyridin-3-yl)acetamide (R)-N-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)tetrahydro-2H- 234 0.554 pyran-3-carboxamide 2,2-difluoro-N-(4-((R*)-1-(4-methylthiazol-5-yl)ethyl)phenyl)-2-((RS)- 235 0.860 tetrahydrofuran-3-yl)acetamide rel-2-((R)-2,3-dihydrobenzofuran-3-yl)-N-(4-((R)-1-(4-methylthiazol- 236 0.272 5-yl)ethyl)phenyl)acetamide Rat DRG neurite degeneration assay Materials and methods Plate preparation 96-well plates were incubated in poly-D-lysine solution at room temperature overnight. Solution was aspirated and plates were briefly washed three times in DPBS solution, then allowed to air dry. Plates were incubated in laminin solution (5μg/mL in DPBS solution) for at least 2 hours at 37 °C. Just prior to plating, laminin solution was aspirated and plates washed once in complete medium. DRG neuron culture The dorsal root ganglia (DRG) were isolated from rat embryos obtained from pregnant female SD rats (15.5 days postcoitus) and were kept on ice in Leibovitz's 15 medium. DRGs were dissociated by incubation in TrypLE Express at 37 °C for about 30 min. L-15 medium containing 10% FBS was added and DRGs were filtered by 100 μm cell strainer. DRGs were centrifuged at 1000 rpm for 5 min and resuspend in 15 mL complete medium containing neurobasal medium, 2% B-27, 2 mM L-glutamine, 2 μM 5-Fluoro-2'-deoxyuridine, 2 μM uridine, 50 ng/mL 2.5S NGF and 100 U/mL Penicillin- Streptomycin. Cells were counted and diluted in complete medium to a final concentration of 1 x 107 cells/mL. 0.5 μL of cell suspension was dripped into each well of pre-coated 96-well plate. Cells were incubated at 37 °C for 10-15 min.100 μL complete medium was then added to each well of the 96- well plate. Plates were incubated at 37 °C for 7 days. Compound treatment Test compounds were initially prepared in DMSO with final concentration of 10 mM as a stock solution.8 doses (intermediate solutions) of test compounds were prepared, starting from 10 mM stock solution by 3-fold serial dilutions with 100% (v/v) DMSO. Compound solutions were prepared by dilution of the intermediate solutions in 50 fold steps using complete medium, while 1 mM and 0.3 mM compound solutions were prepared by 5-fold and 16.67-fold dilution of 10 mM DMSO stock, respectively. Vincristine solution was prepared by dilution in 50 fold steps of 100 μM DMSO stock solution using complete medium. 5.55 μL of compound solution and 5.55 μL Vincristine solution was added to each well (10% of final culture volume) of the cell plate, in which final concentrations of test compounds were 100, 30, 10, 3.33, 1.11, 0.37, 0.12, 0.041, 0.014 and 0.005 μM. High control and low control was prepared by dilution of 100% DMSO, respectively. Then 11.1 μL was added to each well of the cell plate, in which the final concentration of DMSO was 0.1%. The cell plate was incubated with the compound treatment for 48 hours at 37 °C. Immunofluorescence staining, image acquisition and image analysis Media was aspirated from wells and cells were washed twice with 100 µl DPBS before being fixed with 4% paraformaldehyde (PFA) for 10 minutes at room temperature. PFA was aspirated and cells were washed three times with 100µl ice cold DPBS. Cells were then permeabilised with 40 µl 0.5% Triton X-100 and washed a further three times with DPBS. Cells were blocked for 30 min in DPBS with 5% FBS, 2% BSA and 0.1% tween-20. Primary antibodies against NeuN (Abcam ab104225) and beta-III-tubulin (Abcam ab41489) were diluted to 1:1000 and 1:500 respectively in DPBS, and 40 µl was added to each well, the plate was incubated overnight at 4 °C. Wells were washed three times with 100 µl DPBS, five minutes for each wash. Fluorescent secondary antibodies, Goat Anti-Chicken IgY H&L (Abcam ab150169) and Goat Anti-Rabbit IgG H&L (Abcam ab150080) were diluted to 1:500 and 1:1000 respectively in DPBS, and 40 µl was added to each well. Plate was incubated at room temperature for 2 hours. Wells were then washed four times with 100 µl DPBS, five minutes for each wash. Wells were then sealed with 90% glycerol solution. Images were acquired using a Perkin Elmer Operetta CLS high content imaging system using a 20X water immersion lens. Settings were as follows; the 488 nm excitation channel used a 20 ms exposure time and 100% power, the 546 nm excitation channel used a 20 ms exposure time at 20% power. Images were analysed using Harmony 4.9 software. To determine the degeneration index; firstly, all neurites were identified using the beta-III-tubulin stain as a mask then neurites less than 10 µm in length were selected. Neurites less than 10 um with a beta-III-tubulin alexa 488 stain intensity of >10,000 a.u. were defined as degenerated neurites and quantified. The following equations were used to calculate the percentage of degeneration within each image: P= SDeg/STotal ×100% Then % degeneration was corrected following the formula below: Degeneration (%) = (Pcpd-PLC)/(PHC-PLC) × 100% P= Percentage of degeneration SDeg= Number of degenerated segments STotal= Total number of segments Pcpd= Percentage of degeneration in compound treated wells PLC= Percentage of degeneration in Low Control wells (0.1% DMSO treated) PHC= Percentage of degeneration in High Control wells (40nM vincristine treated) IC50 values of compounds were calculated by fitting percent of degeneration against log of compound concentrations with Hill equation using Graphpad Prism 8.0 and fit to a sigmoid dose response curve with a variable slope. Results Results from the rat DRG neurodegeneration assay are shown below in Table 23. Table 23: Activity in rat DRG neurodegeneration assay. Example Protection of neurite degeneration in rDRG EC50 (µM) 1 0.627 44 0.084 110 3.98 132 0.659 220 0.299 The above description of illustrative embodiments is intended only to acquaint others skilled in the art with the Applicant's specification, its principles, and its practical application so that others skilled in the art may readily adapt and apply the specification in its numerous forms, as they may be best suited to the requirements of a particular use. This description and its specific examples, while indicating embodiments of this specification, are intended for purposes of illustration only. This specification, therefore, is not limited to the illustrative embodiments described in this specification, and may be variously modified. In addition, it is to be appreciated that various features of the specification that are, for clarity reasons, described in the context of separate embodiments, also may be combined to form a single embodiment. Conversely, various features of the specification that are, for brevity reasons, described in the context of a single embodiment, also may be combined to form sub-combinations thereof.

Claims

Claims 1. A compound of Formula (I):
Figure imgf000183_0001
wherein 0, 1 or 2 of A, E, L and G are N, and the others of A, E, L and G are independently CR2, Q, X and R1 are such that (i) X is absent, Q is R3 and R1 is H, (ii) X is absent, and Q and R1 together with the carbon atom to which they are attached form a cyclopropane or cyclobutane ring, or (iii) -X-Q- is -(CH2)a1(QA)a2(CH2)a3- and R1 is H, wherein a1 and a3 are independently 0, 1, or 2, and a2 is 0 or 1, such that a1+a2+a3 is 2, 3 or 4, and QA is O, CH2, NH, N(C1-4 alkyl) or N(C=O)( C1-4 alkyl), where X is absent, Y is selected from N, NH and CH, and where -X-Q- is -(CH2)a1(QA)a2(CH2)a3-, Y is selected from N and C, Ring V1, together with Y and Z with which it is fused, is an imidazole, thiazole or pyrazole ring, such that Z is N or C, each R2 is independently selected from H, F, Cl, cyano, C1-4 fluoroalkyl, O(C1-4 fluoroalkyl), OH, R4, OR4, R5 and OR5, R3 is H, C1-4 fluoroalkyl, O(C1-4 fluoroalkyl), R4A or R5A, each RV is independently selected from F, Cl, cyano, OH, C1-4 alkoxy, C1-4 fluoroalkyl, O(C1-4 fluoroalkyl), R4A and R5A, each R4 and R4A is independently C1-4 alkyl optionally substituted with one OH, C1-4 alkoxy or C3-4 cycloalkyl, each R5 and R5A is independently C3-4 cycloalkyl optionally substituted with one OH, C1-4 alkoxy or C1-4 fluoroalkyl, J is selected from R6 and R6A are independently H, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl, F, OH or C1-4 alkoxy, R7 and R7A and independently H, C1-4 alkyl, C1-4 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl or F, Rings C1, C2 and C3 are either (i) optionally fused with a benzene or pyridine ring, wherein the benzene or pyridine ring is optionally substituted with 1, 2 or 3 R9 groups, or (ii) optionally bridged by a C1-3 alkylene group, wherein the C1-3 alkylene group is optionally substituted by one or more R8 groups, each R8 is independently C1-4 alkyl, R11, C1-4 alkoxy, C3-4 cycloalkyl, OH or F, each R9 is independently C1-4 alkyl, R11, C1-4 alkoxy, C3-4 cycloalkyl, NH(R10), N(R10)2, OH, F, Cl or Br, each R10 is independently H, C1-4 alkyl, C(=O)C1-4 alkyl, C3-4 cycloalkyl or C(=O)C3-4 cycloalkyl, each R11 is independently C1-4 alkyl substituted with OH, XA, XB and XC are CH2, O, or a covalent bond, YA, YB and YC are CH2 or a covalent bond, ZA, ZB and ZD are a covalent bond or C(R6A)(R7A), Zc is a covalent bond, C(R6A)(R7A), O or NH, Ring D1 is a 5-9 membered heteroaromatic ring, Rings D2, D3 and D4 are a 5 or 6 membered heteroaromatic ring, x is 0, 1 or 2, and m is 0, 1, 2 or 3, wherein a C1-4 fluoroalkyl is a saturated hydrocarbon radical having 1 to 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom, wherein a C3-4 cyclofluoroalkyl is a saturated cyclic hydrocarbon radical having 3 or 4 carbon atoms, with at least one hydrogen atom substituted for a fluorine atom, and wherein a heteroaromatic ring is independently an aromatic ring containing at least one N atom and optionally one or more additional heteroatoms independently selected from O, S and N, or a pharmaceutically acceptable salt thereof.
2. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein A, E, L are independently CR2 and G is CR2 or N.
3. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in claim 1 or 2, wherein each R2 is independently H, C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl, O(C1-4 fluoroalkyl), OH, F or Cl.
4. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein R3 is H, C1-4 alkyl, C3-4 cycloalkyl, C1-4 fluoroalkyl or O(C1-4 fluoroalkyl).
5. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein R3 is H or CH3.
6. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, wherein each RV is independently C1-4 alkyl, C1-4 alkoxy, C1-4 fluoroalkyl or F.
7. A compound of Formula (I), as claimed in any one of claims 1 to 6, that is a compound of Formula (II)
Figure imgf000185_0001
wherein each R2A is independently selected from F, Cl, cyano, C1-4 fluoroalkyl, O(C1-4 fluoroalkyl), OH, R4, OR4, R5 and OR5, and q is 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof.
8. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, wherein ring V1 is an imidazole ring.
9. A compound of Formula (I), as claimed in claim 7, that is a compound of Formula (III)
Figure imgf000185_0002
wherein V2 is selected from wherein x2 is 0, 1 or 2, or a pharmaceutically acceptable salt thereof.
10. A compound of Formula (III) or a pharmaceutically acceptable salt thereof, as claimed in claim 9, wherein V2 is selected from
Figure imgf000186_0001
wherein RV2 is H, C1-4 alkyl or C3-4 cycloalkyl.
11. A compound of Formula (I), as claimed in claim 7, that is a compound of Formula (IV)
Figure imgf000186_0002
wherein V3 is selected from
Figure imgf000186_0003
wherein x3 is 0, 1 or 2, and QB is O, CH2, NH, N(C1-4 alkyl), N(C=O)( C1-4 alkyl) or a covalent bond, or a pharmaceutically acceptable salt thereof.
12. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, wherein each of Rings D1, D2, D3 and D4 is a imidazole, isoxazole, oxazole, pyrazole, pyrrole, thiazole, triazole, pyridine, pyrimidine, pyridazine or pyrazine ring.
13. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, wherein J is
Figure imgf000187_0001
wherein m is 0, 1 or 2.
14. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 11, wherein J is
Figure imgf000187_0002
wherein m is 0, 1 or 2.
15. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14, wherein R6 and R7 are independently H, F or CH3.
16. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 15, wherein each R8 is independently OH, C1-4 alkyl or F.
17. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 16, wherein each R9 is independently C1-4 alkyl or F.
18. A pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 17, and a pharmaceutically acceptable excipient.
19. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 17, for use in therapy.
20. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 17, for use in the treatment of a neurodegenerative condition.
21. A compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 17, for use in the treatment of chemotherapy induced peripheral neuropathy (CIPN).
22. A method of treating a neurodegenerative condition in a patient comprising administering to the patient an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 17.
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