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WO2025037036A1 - Pyridyl imidazoles, their preparation and their therapeutic application - Google Patents

Pyridyl imidazoles, their preparation and their therapeutic application Download PDF

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Publication number
WO2025037036A1
WO2025037036A1 PCT/EP2024/073181 EP2024073181W WO2025037036A1 WO 2025037036 A1 WO2025037036 A1 WO 2025037036A1 EP 2024073181 W EP2024073181 W EP 2024073181W WO 2025037036 A1 WO2025037036 A1 WO 2025037036A1
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Prior art keywords
chloro
methyl
imidazol
fluoro
alkyl
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French (fr)
Inventor
Lothar Schwink
Hans Matter
Anika TARASEWICZ
Marcel BALTRUSCHAT
Anna SIB
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Sanofi SA
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Sanofi SA
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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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • MRGPRX2 is a G-protein coupled receptor (GPCR) expressed on mast cells involved in inflammation pathways, including the non-histaminergic activation of mast cells. See Meixong, J., et al., Immunity, 50, 1163-1171 (2019). MRGPRX2 is a member of the X subfamily of the Mas family of GPCRs. MRGPRX2 is activated by numerous secretagogues, including neuropeptides, eosinophil granule proteins, and antimicrobial peptides.
  • GPCR G-protein coupled receptor
  • mast cells may undergo degranulation and release tryptase, which preferentially triggers non-histaminergic itch, as well as chymase, carboxipeptidases, histamine, serotonin, chemokines, and cytokines.
  • tryptase preferentially triggers non-histaminergic itch, as well as chymase, carboxipeptidases, histamine, serotonin, chemokines, and cytokines.
  • This activation can lead to type 2 inflammation, pruritis, and pain.
  • Preclinical data demonstrates that blocking the activation of MRGPRX2 has the potential to effectively treat a range of mast-cell-mediated diseases. See, e.g., Meixong, J., et al.; Ogasawara, H.
  • MRGPRX2 antagonists of the present disclosure may provide safe, oral, and efficacious treatments for diseases, disorders and conditions involving inflammation, itch, and/or pain.
  • A is selected from , each is a single or a double bond, provided two adjacent are not both double bonds; each instance of R1 is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R2 is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C 1 -C 6 haloalkyl; each instance of R 3 is independently selected from halogen, cyano, -OR 11 , -NR 11 R 12
  • A is selected from R1 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl;
  • R 2 is selected from halogen, -OR 11 , -NR 11 R 12 , C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, and C 1 - C 3 haloalkyl; each instance of R 3 is independently selected from halogen, -OR 11 , -NR 11 R 12 , C 1 -C 6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl;
  • R4 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl;
  • R 4P is selected from halogen, -OR 11 , -NR 11
  • One embodiment is a compound of formula I, wherein the compound is of formula I-A or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I according to any one of claims 1-4, wherein the compound is of formula I-B , or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, wherein the compound is of formula I-D , I-D, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, wherein the compound is of formula I-G1
  • L1 is selected from -CH2- and -N(R11)-;
  • One embodiment is a compound of formula I, wherein the compound is of formula I-H or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, wherein the compound is of any one of formulas -J1 to I-J5,
  • each instance of E1 is independently selected from -CH- and -N-;
  • E2 is selected from -NH-, -O-, and -S-;
  • E3 is selected from -CH2-, -NH-, and -O-; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, wherein R1 is selected from halogen and C1-C4 alkyl; R 2 is selected from halogen and C 1 -C 4 alkyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • R1 is fluoro; R 2 is chloro; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, wherein R4 is selected from halogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • R4P is selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound selected from the compounds listed in Table 1, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present disclosure is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Another aspect of the present disclosure is a method of treating a disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is selected from an inflammatory disorder, an allergic disorder, a skin disorder, a mast cell disorder, a pain disorder, and an itch disorder.
  • Another aspect of the present disclosure is a method of treating a disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is selected from atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation
  • the disease, disorder, or condition is selected from atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma.
  • Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder.
  • Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, heriditary alpha tryptasemia, chronic itch, and chronic
  • the disease, disorder, or condition is selected from atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma.
  • Another aspect of the present disclosure is a medicament, characterized in that it comprises the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present disclosure is the use of a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for preparing a medicament intended for the treatment of a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder.
  • a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder.
  • H hydrogen atom or radical.
  • the hydrogen is an isotope of hydrogen.
  • the hydrogen is deuterium (D), for example a methyl, Me, or CH3 group may be CD3.
  • D deuterium
  • alkyl refers to a linear or branched saturated hydrocarbon group.
  • a C X -C Y alkyl group refers to an alkyl group having between X and Y carbon atoms, for example a C 1 -C 6 alkyl group refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.
  • Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and the like.
  • haloalkyl refers to an alkyl group in which one or more hydrogen atoms have been substituted by a halogen atom.
  • a CX-CY haloalkyl group refers to a haloalkyl group having between X and Y carbon atoms, for example a C 1 -C 6 haloalkyl group refers to a haloalkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms (in addition to one or more halogen atoms).
  • Exemplary haloalkyl groups include chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 1,2-difluoroethyl, 1,1,2,2-tetrafluoroethyl, and the like.
  • halogen refers to fluoro, chloro, bromo, or iodo.
  • heteroalkyl refers to a linear or branched, non-cyclic saturated group containing 1, 2, or 3 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different.
  • Heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylthio, and alkylthioalkyl groups.
  • a C X - C Y heteroalkyl group refers to a heteroalkyl group having between X and Y carbon atoms, for example a C1-C6 heteroalkyl group refers to a heteroalkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms (in addition to 1, 2, or 3 heteroatoms).
  • heteroalkyl groups include methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxymethyl, 2-methoxyethyl, 2-methoxyethoxy, (2-hydroxyethoxy)ethyl, (2- methoxyethoxy)ethyl, 3-hydroxy-2-(hydroxymethyl)propyl, 3-methoxy-2- (methoxymethyl)propyl, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, methanethiolato, ethanethiolato, or the like.
  • aryl refers to an aromatic monocyclic or bicyclic ring system containing between 5 and 10 carbon atoms. Exemplary aryl groups include phenyl and naphthyl.
  • arylalkyl refers to an alkyl group substituted with an aryl group.
  • a CX-CY arylalkyl group refers to an arylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C1-C3 arylalkyl group refers to an arylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with an aryl group.
  • arylalkyl groups include benzyl and phenethyl.
  • cycloalkyl refers to a non-aromatic monocyclic ring system containing between 3 and 8 carbon atoms.
  • a CX-CY cycloalkyl group (or an X- to Y- membered cycloalkyl group) refers to a cycloalkyl group having between X and Y carbon atoms, for example a C3-C6 cycloalkyl group (or a 3- to 6-membered cycloalkyl group) to refers to a cycloalkyl group having 3, 4, 5, or 6 carbon atoms.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and the like.
  • cycloalkylalkyl refers to an alkyl group substituted with a cycloalkyl group.
  • a CX-CY M- to N-membered cycloalkylalkyl group refers to a cycloalkylalkyl group having between X and Y carbon atoms in the alkyl chain and between M and N carbon atoms in the cycloalkyl ring, for example a C1-C3 3- to 6-membered cycloalkylalkyl group refers to a cycloalkylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with a cycloalkyl group of 3, 4, 5, or 6 carbon atoms.
  • cycloalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.
  • heteroaryl refers to a cyclic aromatic group containing between 1 and 10 carbon atoms and containing between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different, wherein the group contains between 5 and 10 carbon atoms or heteroatoms.
  • Heteroaryl groups include those where a nitrogen atom of the heteroaryl ring is substituted with an oxide (-O-), for example, pyridinyl N-oxide and the like, where the context so permits. Heteroaryl groups may be monocyclic or bicyclic. As used herein, the term “monocyclic heteroaryl” means a cyclic aromatic group containing 1 to 5 carbon atoms and containing between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more hetero atoms may be the same or different, wherein the monocyclic ring contains between 5 and 6 carbon atoms or heteroatoms.
  • heteroaryl groups include benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzotriazolyl, benzoxazolyl, furanyl, furazanyl, indolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridinyl N-oxide, pyrimidinyl, pyrrolo[2,3- b]pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrrolyl, 1,2,4-thiadiazolyl, 1,2,4-triazinyl, 1,3,4-thiadiazolyl, thiazolyl, triazolyl, tetrazolyl, thiophenyl, and the like.
  • heteroarylalkyl refers to an alkyl group substituted with a heteroaryl group.
  • a CX-CY heteroarylalkyl group refers to a heteroarylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C1-C3 heteroarylalkyl group refers to a heteroarylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with a heteroaryl group.
  • a “monocyclic heteroarylalkyl” group refers to an alkyl group substituted with a monocyclic heteroaryl group.
  • heteroarylalkyl groups include pyridylmethyl, pyrrolylmethyl, furanylmethyl, and the like.
  • heterocyclyl refers to a non-aromatic (saturated or unsaturated) monocyclic group containing between 1 and 5 carbon atoms and between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different, wherein the monocyclic ring contains between 3 and 6 carbon atoms or heteroatoms.
  • oxide pyrrolidinyl N-oxide
  • An X- to Y-membered heterocyclyl group refers to a heterocyclyl group having between X and Y ring atoms (which may be carbon or heteroatoms).
  • exemplary heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyridinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocyclyl group.
  • a CX-CY heterocyclylalkyl group refers to a heterocyclylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C 1 -C 3 heterocyclylalkyl group refers to a heterocyclylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with a heterocyclyl group.
  • heterocyclylalkyl groups include piperidinylmethyl, pyrrolidinylmethyl, azetidinylmethyl, 2-(oxo-4,5- dihydrotetrazolyl)ethyl, and the like.
  • substituted refers to a hydrogen radical of the designated moiety being replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound.
  • a substituent can be in any position, provided that the respective compound is sufficiently stable and is suitable as a pharmaceutical active compound.
  • the prerequisite that a specific group and a compound of the formula I are sufficiently stable and suitable as a pharmaceutical active compound applies in general with respect to the definitions of all groups in the compounds of the formula I, and compounds of a subformula of formula I.
  • the terms “independently” or “independently selected” means that the same or different values may be selected for multiple instances of a given variable in a single compound.
  • the term “unsubstituted” indicates that the respective group does not carry any of the specified non-hydrogen substituents.
  • the term “pharmaceutically acceptable salt” refers to the relatively non-toxic, inorganic and organic acid and base addition salts of a compound of formula I, or a compound of a subformula of formula I. These salts can be prepared in situ during the final isolation and purification of the compounds.
  • “ ” indicates the bond between two atoms may be either a single or a double bond.
  • the carbon atoms When is a single bond between two carbon atoms, the carbon atoms each are bonded to one more hydrogen atom (or substituent in place of a hydrogen atom) than if had been a double bond.
  • the carbon atoms when is a double bond, the carbon atoms each are bonded to one fewer hydrogen atom (or substituent in place of a hydrogen atom) than if had been a single bond. If two bonds are adjacent, both bonds may be a single bond, either may be single and the other a double bond, but both bonds may not be a double bond.
  • the compounds of the formula I, or compounds of a subformula of formula I comprise one or more acidic or basic groups, for example basic heterocyclic groups
  • the corresponding physiologically or toxicologically acceptable salts are also included in the disclosure, especially the pharmaceutically acceptable salts.
  • the compounds of the formula I, or compounds of a subformula of formula I may thus be deprotonated on an acidic group and be used for example as alkali metal salts or as ammonium salts.
  • Compounds of formula I, or compounds of a subformula of formula I, comprising at least one basic group may also be prepared and used in the form of their acid addition salts, for example in the form of pharmaceutically acceptable salts with inorganic acids and organic acids.
  • Salts can in general be prepared from acidic and basic compounds of the formula I, or compounds of a subformula of formula I, by reaction with an acid or base in a solvent or diluent according to customary procedures. If the compounds of the formula I, or compounds of a subformula of formula I, simultaneously contain an acidic and a basic group in the molecule, the disclosure also includes internal salts (betaines, zwitterions) in addition to the salt forms mentioned.
  • the present disclosure also comprises all salts of the compounds of the formula I, or compounds of a subformula of formula I, which, because of low physiological tolerability, are not directly suitable for use as a pharmaceutical, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange.
  • pharmaceutically acceptable excipient refers to a non- toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compound of the present disclosure to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the subject.
  • the said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.
  • the term “therapeutically effective amount” refers to an amount of a compound/composition according to the present disclosure effective in producing the desired therapeutic effect.
  • the term “subject” refers to a human or animal subject. In some embodiments, the subject is human (i.e., a “patient”). In some embodiments, the subject is an animal.
  • the term “compounds of formula I”, or “compounds of a subformula of formula I,” and equivalent expressions, include racemic compounds of formula I, or compound of a subformula of formula I, and their enantiomers, diastereoisomers, tautomers, atropisomers, and mixtures thereof, where the context so permits.
  • Tautomeric compounds of formula I are exemplified by formulas I (tautomer 1) an I (tautomer 2).
  • substitution of the tautomeric proton may generate a mixture of discrete regioisomers.
  • the alkylating agent is SEM-Cl
  • such a mixture will be referred to as “mixture of SEM-regioiosmers” herein.
  • subformula refers to subsets of compound of formula I, such as compounds of formula I which are a compound of formula I-A, I-A1, I-A2, I-A3, I- A4, I-A5, I-A6, I-A7, I-B, I-B1, I-B2, I-B3, I-B4, I-B5, I-B6, I-B7, I-C, I-C1, I-C2, I-C3, I-D, I-D1, I-D2, I-D3, I-D4, I-D5, I-D6, I-D7, I-E, I-E1, I-E2, I-E3, I-E4, I-E5, I-E6, I-E7, I-F, I- F1, I-F2, I-F3, I-F4, I-F5, I-F6, I-F7, I-G1, I-G2, I-H, any one of I-J1 to I-J21, or any one of I- K1
  • isomers refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space.
  • the labels “isomer 1” and “isomer 2,” or the like, can be assigned to isomers of known absolute configuration or can be used to describe stereoisomers of unknown absolute configuration.
  • the labels “R*” or “S*” may be assigned to stereocenters of some enantiomeric compounds of unknown absolute configuration. The use of the labels “isomer 1,” “isomer 2,” R*, and S* is not to be interpreted as indicating that the absolute configuration of both isomers is known.
  • isomeric mixture refers to a mixture of isomers.
  • stereoisomers is a general term used for all isomers of the individual molecules that differ only in the orientation of their atoms in space.
  • diastereomers refers to stereoisomers that are not mirror images of one another and the term “enantiomers” refers to stereoisomers that are non-superimposable mirror images of each other.
  • An enantiomer can be characterized by the absolute configurations of its asymmetric centers, chiral axes and planes, and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or ( ⁇ )-isomers respectively).
  • a chiral compound can exist as either individual enantiomer, individual diastereomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a “racemic mixture.”
  • a mixture containing any proportions of the diastereomers is called a “diastereomeric mixture”.
  • trans refers to the substituents (other than hydrogen) of the chiral centers are on opposite sides of the ring;
  • cis refers to the substituents of the chiral centers are on the same sides of the ring.
  • Racemic trans refers to equal proportions of two trans enantiomers and “racemic cis” refers to equal proportions of two cis enantiomers.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can also be directly separated using chiral chromatographic techniques or indirectly using enzymatic methods. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present disclosure.
  • A is selected from
  • One embodiment is a compound of formula I, wherein: A is selected from R1 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R2 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C 3 haloalkyl; each instance of R 3 is independently selected from halogen, -OR 11 , -NR 11 R 12 , C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, and C 1 -C 6 haloalkyl; R 4 is selected from halogen, -OR 11 , -NR 11 R 12 , C 1 -C 4 alkyl, C 1 -C 4 heteroalkyl, and C 1 - C 3 haloalkyl; R4P is selected from halogen,
  • R1 is selected from halogen;
  • R2 is selected from halogen and C1-C4 alkyl;
  • R4 is selected from halogen and C1-C4 alkyl;
  • R 4P is selected from hydrogen and C 1 -C 4 alkyl;
  • R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3
  • R1 is fluoro;
  • R2 is selected from chloro, bromo, methyl, and ethyl;
  • R4 is selected from fluoro, chloro, and methyl;
  • R 4P is selected from hydrogen and methyl;
  • R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylal
  • One embodiment is a compound of formula I which is a compound of formula I-A , I-A wherein R1, R2, R3, R4, R5, n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-A1 , wherein R 1 , R 2 , R 4 , and R 5 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-A2 , I-A2 wherein: each instance of X is independently selected from halogen; and R 5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- A2, wherein each instance of X is independently selected from fluoro and chloro;
  • One embodiment is a compound of formula I which is a compound of formula I-A3 , wherein R 5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-A4 , I-A4 wherein: L is selected from -R 6 and -NR 7 R 8 ; and R 1 , R 2 , R 4 , R 6 , R 7 , and R 8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-A5 , wherein: each instance of X is independently selected from halogen; L is selected from -R 6 and -NR 7 R 8 ; and R 6 , R 7 , and R 8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-A6 , wherein: L is selected from -R 6 , -OR 7 , and -NR 7 R 8 ; and R 1 , R 2 , R 4 , R 6 , R 7 , and R 8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-A7 , I-A7 wherein: each instance of X is independently selected from halogen; L is selected from -R 6 , -OR 7 , and -NR 7 R 8 ; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- A7, wherein each instance of X is independently selected from fluoro and chloro;
  • One embodiment is a compound of formula I which is a compound of formula I-B , wherein R 1 , R 2 , R 3 , R 4 , R 5 , n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-B, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are joined, such that hydrogen other radicals of the two moieties are replaced with a bond between the two moieties, provided that the joining results in a stable or chemically feasible compound.
  • a compound of formula wherein R 1 , R 2 , R 7 , and n are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-B1 , wherein R1, R2, R4, and R5 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- B1, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are joined, such that hydrogen other radicals of the two moieties are replaced with a bond between the two moieties, provided that the joining results in a stable or chemically feasible compound.
  • a compound of formula I which is a compound of formula I- B1, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are joined, such that hydrogen other radicals of the two moieties are replaced with a bond between the two moieties, provided that the joining results in a stable or chemically feasible compound.
  • a compound of formula I which is a compound of formula I- B1, or an enantiomer, diastereomer, or tautomer thereof, or a
  • R1, R2, and R7 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • R1, R2, and R7 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-B2 , wherein: each instance of X is independently selected from halogen; and R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-B3 , I-B3 wherein R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • L is selected from -R 6 and -NR 7 R 8 ; and R 1 , R 2 , R 4 , R 6 , R 7 , and R 8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- B4, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R4 and L are joined, such that hydrogen other radicals of the two moieties are replaced with a bond between the two moieties, provided that the joining results in a stable or chemically feasible compound.
  • a compound of formula wherein R 1 , R 2 , and R 7 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-B5 , I-B5 wherein: each instance of X is independently selected from halogen; L is selected from -R 6 and -NR 7 R 8 ; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- B5, wherein each instance of X is independently selected from fluoro and chloro;
  • One embodiment is a compound of formula I which is a compound of formula I-B6 , wherein: L is selected from -R 6 , -OR 7 , and -NR 7 R 8 ; and R 1 , R 2 , R 4 , R 6 , R 7 , and R 8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-B7 , wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and wherein R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- B7, wherein each instance of X is independently selected from fluoro and chloro;
  • One embodiment is a compound of formula I which is a compound of formula I-C , wherein R1, R2, R3, X1, n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-C, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R3 is selected from halogen and C1-C4 alkyl; m is 0 or 1; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-C, wherein R1 is fluoro; R 2 is selected from chloro, bromo, methyl, and ethyl; R 3 is selected from fluoro, chloro, and methyl; X 1 is selected from fluoro and chloro; m is 1; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-C1 , I-C1 wherein R1, R2, R3, X1, and m are as defined for a compound of formula I; and or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- C1, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R3 is selected from halogen and C1-C4 alkyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- C1, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R3 is selected from fluoro, chloro, and methyl; X 1 is selected from fluoro and chloro; and m is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-C2 , I-C2 wherein each instance of X is independently selected from halogen; and R 3 , X 1 , and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- C2, wherein R 3 is selected from halogen and C 1 -C 4 alkyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- C2, wherein each instance of X is independently selected from fluoro, chloro, and bromo; R 3 is selected from fluoro, chloro, and methyl; and m is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-C3 , I-C3 wherein R3, X1, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- C3, wherein R 3 is selected from halogen and C 1 -C 4 alkyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I- C3, wherein each instance of X is independently selected from fluoro, chloro, and bromo; R3 is selected from fluoro, chloro, and methyl; and m is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-D , I-D wherein R 1 , R 2 , R 3 , R 4P , R 5 , n, m, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-D1 , I-D1 wherein R 1 , R 2 , R 4P , R 5 , and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-D2 , I-D2 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4 alkyl; and R5 and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-D3 , I-D3 wherein R 5 and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-D4 , I-D4 wherein L is selected from -R6 and -NR7R8; and R1, R2, R4P, R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-D5 , I-D5 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C 1 -C 4 alkyl; and L is selected from -R 6 and -NR 7 R 8 ; and R 6 , R 7 , R 8 , and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-D6 , I-D6 wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4P, R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-D7 , I-D7 wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-E , I-E wherein R1, R2, R3, R4P, R5, n, m, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-E1 , I-E1 wherein R1, R2, R4P, R5, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-E2 , I-E2 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C 1 -C 4 alkyl; and R 5 and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-E3 , I-E3 wherein R5 and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-E4 , I-E4 wherein L is selected from -R6 and -NR7R8; and R 1 , R 2 , R 4P , R 6 , R 7 , R 8 , and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-E5 , I-E5 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4 alkyl; L is selected from -R 6 and -NR 7 R 8 ; and R 6 , R 7 , R 8 , and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-E6 , I-E6 wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4P, R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-E7 , I-E7 wherein: each instance of X is independently selected from halogen; L is selected from -R 6 , -OR 7 , and -NR 7 R 8 ; and R 6 , R 7 , R 8 , and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-F , I-F wherein R 1 , R 2 , R 3 , R 4P , R 5 , n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-F1 , I-F1 wherein R 1 , R 2 , R 4P , and R 5 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-F2 , I-F2 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C 1 -C 4 alkyl; and R 5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-F3 , wherein R 5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-F4 , I-F4 wherein L is selected from -R6 and -NR7R8; and R1, R2, R4P, R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-F5 , I-F5 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C 1 -C 4 alkyl; and L is selected from -R6 and -NR7R8; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-F6 , I-F6 wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4P, R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-F7 , I-F7 wherein: each instance of X is independently selected from halogen; L is selected from -R 6 , -OR 7 , and -NR 7 R 8 ; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I which is a compound of formula I-H , wherein: R 1 , R 2 , R 4P , and R 6 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • a compound of formula I is a compound of any one of formulas I-J1 to I-J5:
  • a compound of formula I is a compound of any one of formulas I-K1 to I-K8: wherein: y is 0, 1, or 2 where valency permits; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; E3 is selected from -CH2-, -NH-, and -O-; and R1, R2, R4P, R9, R10, R11, R12 and R13 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • a compound of formula I is a compound of any one of formulas I-K1 to I-K8, wherein: R1 is fluoro; R2 is chloro; R 4P is methyl; y is 0, 1, or 2 where valency permits; each instance of E 1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; E3 is selected from -CH2-, -NH-, and -O-; and each instance of R9 is H; each instance of R10 is independently selected from C1-C4 alkyl and C3-C6 cycloalkyl; which groups are unsubstituted or substituted with one or two R 13 ; each instance of R 11 and R 12 is independently selected from hydrogen, C 1 -C 4 alkyl, C 1 - C 4 heteroalkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 3-to 6-membered cycloalkyl
  • One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1 is selected from halogen and C1-C4 alkyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1 is fluoro; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R2 is selected from halogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R2 is selected from chloro, bromo, methyl, and ethyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R2 is chloro; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1 is selected from halogen and C1-C4 alkyl; R 2 is selected from chloro, bromo, methyl, and ethyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R 1 is fluoro; R 2 is selected from chloro, bromo, methyl, and ethyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R 1 is fluoro; R 2 is chloro; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, wherein: ; R 4 is selected from halogen and C 1 -C 4 alkyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • R 4 is selected from fluoro, chloro, and methyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, wherein: ; R 4 is chloro; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • X 1 is selected from halogen
  • R3 is selected from halogen and C1-C4 alkyl
  • m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, wherein: X1 is selected from fluoro and chloro; R 3 is selected from fluoro, chloro, and methyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [226] One embodiment is a compound of formula I, wherein: X 1 is selected from fluoro and chloro; R3 is selected from fluoro, chloro, and methyl; and m is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, wherein: R4P is selected from hydrogen and C1-C4 alkyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • R4P is selected from hydrogen and methyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, wherein: R4P is methyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F,
  • One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, or I-F6, wherein R5 is selected from , , , , or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [237] All these subgroups taken alone or in combination are part of the description.
  • One embodiment is a compound of formula I, selected from the compounds listed in Table 1, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a compound of formula I, selected from: Methyl 3-(((3S*,4S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)propanoate; 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)propan-1-ol; 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyri
  • One embodiment is a compound of formula I, or a compound of a subformula of formula I, that has sufficient solubility to avoid, for example, advanced formulations or advanced delivery systems, which include but are not limited to liposomal suspensions, inclusion complexes solid dispersions in polymers mechano-chemically activated systems, microparticles or nanoparticles, micro- or nano-emulsions, and vesicular systems.
  • a compound of formula I, or a compound of a subformula of formula I has a solubility of 20 ⁇ M or greater at pH 7.4.
  • a compound of formula I, or a compound of a subformula of formula I has a solubility of 100 ⁇ M or greater at pH 7.4. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 500 ⁇ M or greater at pH 7.4. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 1000 ⁇ M or greater at pH 7.4. [241]
  • the compounds of formula I, and subformulas thereof may comprise one or more asymmetric atoms and/or chiral axes. They may thus exist in the form of enantiomers or diastereoisomers.
  • Some of the compounds of formula I, and subformulas thereof may exist in the form of acids or of base-addition salts. Such addition salts form part of the disclosure. These salts are advantageously prepared with pharmaceutically acceptable bases or cations, but the salts of other bases or cations that are useful, for example, for purification or isolation of the compounds of formula I, and subformulas thereof, also form part of the disclosure.
  • Some of the compounds of formula I, and subformulas thereof may exist in the form of bases or of acid-addition salts. Such addition salts form part of the disclosure.
  • Another aspect of the present disclosure is a process for preparing a compound of formula I, or a subformula thereof, comprising reacting an intermediate of formula B*-PG with an intermediate of formula D1 in the presence of a catalyst and a base to give an intermediate of formula C2:
  • R 1 , A, and n are as defined for a compound of formula I
  • R 2 * is as defined for a compound of formula I or hydrogen
  • PG is a protecting group
  • X is selected from halogen.
  • C2 may be obtained as a mixture of positional isomers, where A is adjacent to the protected nitrogen atom in a first isomer and not adjacent to the protected nitrogen isomer in a second isomer.
  • the protecting group is 2-(trimethylsilyl)ethoxymethyl.
  • the catalyst is selected from bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl2) and bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2).
  • the base is selected from potassium carbonate, potassium acetate, and sodium carbonate.
  • the protecting group is 2- (trimethylsilyl)ethoxymethyl
  • the catalyst is selected from Pd(dtbpf)Cl 2 and Pd(dppf)Cl 2
  • the base is selected from potassium carbonate, potassium acetate, and sodium carbonate.
  • an intermediate of formula C2 is subsequently deprotected to give a compound of formula I.
  • an intermediate of formula C2, wherein R2 * is hydrogen is subsequently halogenated and deprotected to give a compound of formula I, wherein R 2 is selected from halogen.
  • compositions comprise a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient.
  • excipients may be selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.
  • compositions for oral, inhalative, topical, or transdermal administration the active ingredient of formula I, or a compound of a subformula of formula I, or its pharmaceutically acceptable salt, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals or to human beings for the treatment of a disease, disorder, or condition.
  • Appropriate unit administration forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, forms for inhalative administration, and forms for topical or transdermal administration.
  • topical and transdermal administration it is possible to use the herein described compounds in creams, gels, ointments, or lotions.
  • the dose of active principle per day may reach 2000 mg/day, taken all at once or in portions.
  • the dose of active principle per day may reach 50 mg/day.
  • the dose of active principle per day may reach 400 mg/day.
  • the dosage that is appropriate for each subject is determined by the doctor according to the mode of administration and the weight and response of the said subject.
  • Compounds described herein have an antagonistic activity for MRGPRX2.
  • the compounds according to the present disclosure can, therefore, be used for preparing medicaments, especially medicaments which are antagonists of MRGPRX2.
  • yet another aspect of the present disclosure is a medicament, characterized in that it comprises a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the medicaments of the present disclosure can be employed therapeutically, especially in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders.
  • a compound of formula I for preparing a medicament for the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders.
  • the disease, disorder, or condition is selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, hereditary alpha tryptasemia, chronic itch, and chronic pain.
  • atopic dermatitis chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea
  • the disease, disorder, or condition is selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma.
  • the disease, disorder, or condition is atopic dermatitis.
  • the disease, disorder, or condition is chronic spontaneous urticaria.
  • the disease, disorder, or condition is prurigo nodularis.
  • the disease, disorder, or condition is asthma.
  • Yet another aspect of the present disclosure is a method of treating a disease, disorder, or condition associated with MRGPRX2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a method for treating a disease, disorder, or condition associated with undesired mast cell activity or mast cell degranulation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a method for treating a disease, disorder, or condition for which modulation of MRGPRX2 is indicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • Modes of modulating MRGPRX2 include antagonism, inhibition, blocking, agonism, partial agonism, inverse agonism, and combinations thereof.
  • One embodiment is a method for treating a disease, disorder, or condition for which antagonism of MRGPRX2 is indicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, mast cell disorders, pain disorders, and itch disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis systemic mastocytosis cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, hereditary alpha tryptasemia, chronic itch, and chronic pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an en
  • One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a method for treating atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a method for treating chronic spontaneous urticaria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a method for treating prurigo nodularis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • One embodiment is a method for treating asthma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof or a mixture thereof or a pharmaceutically acceptable salt thereof.
  • a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of a disease disorder or condition associated with MRGPRX2.
  • One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition associated with undesired mast cell activity or mast cell degranulation.
  • One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition for which modulation of MRGPRX2 is indicated.
  • Modes of modulating MRGPRX2 include antagonism, inhibition, blocking, agonism, partial agonism, inverse agonism, and combinations thereof.
  • One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition for which antagonism of MRGPRX2 is indicated.
  • One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders.
  • One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction allergy rheumatoid arthritis inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis
  • One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma.
  • One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of atopic dermatitis.
  • One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic spontaneous urticaria.
  • One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of prurigo nodularis.
  • One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of asthma.
  • One embodiment is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the compound of formula I is selected from the compounds listed in Table 1.
  • One embodiment is a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof or a mixture thereof or a pharmaceutically acceptable salt thereof, for use as a medicament, wherein the compound of formula I is selected from one of the above three lists.
  • One embodiment is the use of a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, wherein the compound of formula I is selected from one of the above three lists.
  • One embodiment is a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, wherein the compound of formula I is selected from one of the above three lists.
  • One embodiment is a method of treating a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from one of the above three lists.
  • each X is independently selected from halogen.
  • Carbamimidoyl pyridine intermediates of formula A1 may be commercially available, such as 5- fluoropyridine-2-carboxamidine, or can be prepared according to Scheme 5 or by methods known to those skilled in the art.
  • Haloacetyl intermediates of formula A2 may be commercially available or can be prepared by methods known to those skilled in the art.
  • a carbamimidoyl pyridine intermediate of formula A1 can be cyclized to a pyridyl-imidazole intermediate of formula A3 by reacting with a haloacetyl intermediate of formula A2 in the presence of a base, such as potassium carbonate, in a solvent, such as ethanol.
  • the pyridyl- imidazole intermediate of formula A3 can be converted to a compound of formula I, wherein R2 is selected from halogen (e.g., -Cl), by reacting with a halogenation reagent, such as N- chlorosuccinimide, in a solvent such as DMF.
  • the preparation of the compounds of formula I can be carried out according to Schemes 2-6.
  • Schemes 2-6 depict methods of preparing different pyridyl-imidazole halide intermediates which can be coupled with boronic ester intermediates to give compounds of formula I or other intermediates which can be converted to compounds of formula I.
  • Picolinaldehyde intermediates of formula B1 may be commercially available, such as 5-fluoropicolinaldehyde, or can be prepared by methods known to those skilled in the art.
  • a picolinaldehyde intermediate of formula B1 can be converted to a pyridyl-imidazole intermediate of formula B2 by reacting with oxalaldehyde and ammonium hydroxide in a solvent, such as ethanol.
  • the pyridyl-imidazole intermediate of formula B2 can be converted to a protected pyridyl-imidazole intermediate of formula B3 by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.
  • a protected pyridyl-imidazole intermediate of formula B3 can be converted to a protected pyridyl-imidazole bromide intermediate of formula B4 (an isomeric mixture) by reacting with a bromination reagent, such as N-bromosuccinimide, in a solvent, such as chloroform.
  • a bromination reagent such as N-bromosuccinimide
  • a protected pyridyl imidazole intermediate of formula B2 can be converted to a pyridyl-imidazole dibromide intermediate of formula B5 by reacting with a bromination reagent, such as N-bromosuccinimide, in a solvent, such as chloroform.
  • the pyridyl-imidzole dibromide intermediate of formula B5 can be converted to a protected pyridyl-imidazole dibromide intermediate of formula B6 by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.
  • a protecting group such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.
  • a pyridyl-imidazole intermediate of formula B2 can be converted to a pyridyl- imidazole chloride intermediate of formula B7 by reacting with a chlorination reagent, such as N-chlorosuccinimide, in a solvent, such as DMF.
  • a chlorination reagent such as N-chlorosuccinimide
  • the pyridyl-imidazole chloride intermediate of formula B7 can be converted to a pyridyl-imidazole chloride bromide intermediate of formula B8 by reacting with a bromination reagent, such as N-bromosuccinimide, in a solvent, such as THF.
  • the pyridyl-imidazole chloride bromide intermediate of formula B8 can be converted to a protected pyridyl-imidazole chloride bromide intermediate of formula B9 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.
  • a protecting group such as by reacting with a base, such as sodium hydride
  • a protecting group reagent such as SEM-Cl
  • a pyridyl-imidazole intermediate of formula B2 can be converted to a pyridyl- imidazole diiodide intermediate of formula B10 by reacting with an iodination reagent, such as N-iodosuccinimide, in a solvent, such as acetonitrile.
  • the pyridyl-imidazole diiodide intermediate of formula B10 can be converted to a pyridyl-imidazole iodide intermediate of formula B11 by reacting with a reducing agent, such as sodium sulfite (Na2SO3), in the presence of water, in a solvent such as DMF, water, or a mixture thereof.
  • a reducing agent such as sodium sulfite (Na2SO3)
  • the pyridyl- imidazole iodide intermediate of formula B11 can be converted to a protected pyridyl- imidazole iodide intermediate of formula B12 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.
  • a protecting group such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.
  • the protected pyridyl-imidazole iodide intermediate of formula B12 (an isomeric mixture) can be converted to a protected pyridyl-imidazole chloride iodide intermediate of formula B13 (an isomeric mixture) by reacting with a chlorination reagent, such as N-chlorosuccinimide.
  • a chlorination reagent such as N-chlorosuccinimide.
  • a picolinonitrile intermediate of formula A0 can be converted to a carbamimidoyl pyridine intermediate of formula A1 by reacting with a base, such as LiHMDS, in a solvent such as THF, and quenching with ammonium chloride.
  • a base such as LiHMDS
  • a solvent such as THF
  • Haloacetyl intermediates of formula D2 may be commercially available, such as when R 2 is methyl or ethyl, or can be prepared by methods known to those skilled in the art.
  • a carbamimidoyl pyridine intermediate of formula A1 can be converted to a pyridyl-imidazole intermediate of formula B14 by reacting with a haloacetyl intermediate of formula D2 in the presence of a base, such as potassium carbonate, in a solvent, such as ethanol.
  • a pyridyl- imidazole intermediate of formula B14 can be converted to a pyridyl-imidazole bromide intermediate of formula B15 by reacting with a bromination reagent, such as N- bromosuccinimide, in a solvent, such as acetonitrile.
  • a pyridyl-imidazole bromide intermediate of formula B15 can be converted to a protected pyridyl-imidazole bromide intermediate of formula B16 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.
  • a protecting group such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.
  • Picolinaldehyde intermediates of formula B1 may be commercially available, such as 5-fluoropicolinaldehyde, or can be prepared by methods known to those skilled in the art.
  • An oxoacetyl intermediate of formula D13 may be commercially available, such as wherein R2 is methyl or ethyl, or can be prepared by methods known to those skilled in the art.
  • a picolinaldehyde intermediate of formula B1 can be converted to a pyridyl-imidazole intermediate of formula B17 by reacting with an oxoacetyl intermediate of formula D13 in the presence of ammonium acetate in a solvent, such as methanol.
  • a pyridyl-imidazole intermediate of formula B17 can be converted to a pyridyl-imidazole iodide intermediate of formula B18 by reacting with an iodination reagent, such as N-iodosuccinimide, in a solvent, such as acetonitrile.
  • an iodination reagent such as N-iodosuccinimide
  • a pyridyl-imidazole iodide intermediate of formula B18 can be converted to a protected pyridyl-imidazole iodide intermediate of formula B19 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.
  • a protecting group to the imidazole such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.
  • the preparation of the compounds of formula I can be carried out according to Scheme 7, which depicts the coupling of various pyridyl-imidazole halide intermediates (such as those prepared according to Schemes 2-6) with a boronic acid intermediate.
  • R2* is R2 as defined for a compound of
  • the coupling can be accomplished in the presence of a catalyst, such as bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl 2 ) bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl 2 ), and a base, such as potassium carbonate, potassium acetate, or sodium carbonate, in a solvent, such as NMP, DMF, dioxane, or DMSO, or a mixture with water thereof.
  • a catalyst such as bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl 2 ) bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl 2 )
  • a base such as potassium carbonate, potassium acetate, or sodium carbonate
  • a solvent such as NMP, DMF, dioxane, or DMSO
  • An intermediate of formula B*-PG (an isomeric mixture) can be converted to an intermediate of formula C2 (an isomeric mixture) by coupling with a boronic acid intermediate of formula D1, which may be commercially available or can be prepared by methods known to those skilled in the art.
  • the coupling can be accomplished in the presence of a catalyst, such as bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl 2 ) bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2), and a base, such as potassium carbonate, potassium acetate, or sodium carbonate, in a solvent, such as NMP, DMF, dioxane, or DMSO, or a mixture with water thereof.
  • a catalyst such as bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl 2 ) bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2)
  • a base such as potassium carbonate, potassium acetate, or sodium carbonate
  • An intermediate of formula C2 may be deprotected to convert to an intermediate of formula C1 (which may also
  • an intermediate of formula C1 may be converted to a compound of formula I, wherein R 2 is selected from halogen by reacting with a halogenation agent, such as N-chlorosuccinimide, N-bromosuccinimide, or N- iodosuccinimide, in a solvent, such as THF, acetonitrile, DMF, or chloroform.
  • a halogenation agent such as N-chlorosuccinimide, N-bromosuccinimide, or N- iodosuccinimide
  • an intermediate of formula C2 (an isomeric mixture) may be converted to an intermediate of formula C3 (an isomeric mixture), wherein R 2 is selected from halogen by reacting with a halogenation agent, such as N- chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide, in a solvent, such as THF, acetonitrile, DMF, or chloroform.
  • a halogenation agent such as N- chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide
  • An intermediate of formula C3 may be deprotected to convert to a compound of formula I by reacting with an acid such as TFA
  • the preparation of compounds of formula I can be carried out according to Scheme 8.
  • An intermediates of formula E1 may be prepared according to Scheme 8 (as an intermediate of formula C2 (an isomeric mixture)).
  • An intermediate of formula E1 can be converted to an intermediate of formula E2 (an isomeric mixture) by reacting with a hydrogen source, such as molecular hydrogen (H2), in the presence of a catalyst, such as palladium on carbon (Pd/C), in a solvent, such as methanol or ethanol.
  • a hydrogen source such as molecular hydrogen (H2)
  • H2 molecular hydrogen
  • a catalyst such as palladium on carbon (Pd/C)
  • solvent such as methanol or ethanol.
  • An intermediate of formula E2, wherein R5 is an acid cleavable group (e.g., BOC), can be converted to a piperidine intermediate of formula E3, or an acid addition salt thereof, by reacting with an acid, such as TFA or HCl.
  • an acid such as TFA or HCl.
  • a piperidine intermediate of formula E3, or an acid additional salt thereof, can be converted to a compound of formula I, wherein A is reacting with an electrophilic reagent, such as acetyl chloride, methanesulfonyl chloride, or (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)- yl)sulfonyl)amide, in the presence of a base, such as DIEA, in a solvent, such as DCM.
  • an electrophilic reagent such as acetyl chloride, methanesulfonyl chloride, or (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)- yl)sulfonyl)amide
  • An intermediate of formula E1 (an isomeric mixture) can be converted to an intermediate of formula E4, , wherein R5 is an acid cleavable group (e.g., BOC), or an acid addition salt thereof, by reacting with an acid, such as TFA or HCl.
  • R5 is an acid cleavable group (e.g., BOC), or an acid addition salt thereof, by reacting with an acid, such as TFA or HCl.
  • An intermediate of formula E4, or an acid addition salt thereof can be converted to a to a compound of formula I, wherein one is a double bond, by reacting with an electrophilic reagent, such as acetyl chloride, methanesulfonyl chloride, (tert- butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide, in the presence of a base, such as DIEA, in a solvent, such as THF or DCM.
  • an electrophilic reagent such as acetyl chloride, methanesulfonyl chloride, (tert- butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide
  • a compound of formula I for example a compound of formula I prepared according to methods depicted in Schemes 1 to 8, or any combination thereof, can also be an intermediate to one or more additional compounds of formula I.
  • additional compounds of formula I can be prepared by modifying R 5 by methods known to those skilled in the art. The synthetic examples herein provide exemplary modifications of R 5 .
  • LCMS analysis or separation was performed using the following methods or methods described for specific examples.
  • Method A [321] A: H 2 O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95%B in 1.5min; Flow Rate: 1.8ml/min; Column: SunFire C18, 3.5 ⁇ m, 4.6x50mm; Column Temperature: 50°C [322] Method B [323] A: H 2 O (10mM NH 4 HCO 3 ), B: MeCN; Gradient: 5%-95%B in 1.3min, 95%B for 1.7min; Flow Rate: 1.8ml/min; Column: XBridge C18, 3.5 ⁇ m, 4.6x50mm; Column Temperature: 50°C [324] Method C [325] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95%B in 1.3min, 95%B for 1.7min; Flow Rate:
  • Example 1 Tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]piperidine-1-carboxylate [355] Step 1: Preparation of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]piperidine-1-carboxylate [356] A mixture of 5-fluoropyridine-2-carboxamidine (100.0 mg, 0.7188 mmol), tert- butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (330.1 mg, 1.078 mmol) and K2CO3 (397.3 mg, 2.875 mmol) was stirred in ethanol (3 mL) at 80°C for 2 hours.
  • Step 2 Preparation of tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]piperidine-1-carboxylate
  • Example 2 1-[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-1- piperidyl]ethanone [360] Step 1: Preparation of 2-[4-chloro-5-(4-piperidyl)-1H-imidazol-2-yl]-5-fluoro- pyridine (hydrochloride) [361] Tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]piperidine-1- carboxylate (10.0 mg, 0.0263 mmol) was dissolved in 1,4-dioxane (2 mL).
  • Step 2 Preparation of 1-[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-1- piperidyl]ethanone
  • 2-[4-Chloro-5-(4-piperidyl)-1H-imidazol-2-yl]-5-fluoro-pyridine hydrochloride (10.0 mg, 0.0315 mmol) was added to dichloromethane (2 mL).
  • Example 3 2-[4-Chloro-5-(1-methylsulfonyl-4-piperidyl)-1H-imidazol-2-yl]-5- fluoro-pyridine
  • Example 4 Example 5, and Example 6: (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2- yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 4), (3S,4S)-4-(4-chloro-2- (5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 5), and (3R*,4S*/3S*,4R*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (Example 6) [367] Step 1: Preparation of
  • Step 2 Preparation of 5-fluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)pyridine
  • a solution of 5-fluoro-2-(1H-imidazol-2-yl)pyridine (102 g, ⁇ 0.63 mol) in THF (2000 mL) was added NaH (60% in oil, 37.55 g, 0.94 mol) in several portions at 0°C under N2 atmosphere. ⁇ The reaction was stirred at 0°C for 1 hour. Then, SEM-Cl (125.4 g, 0.75 mol) was added dropwise maintaining the temperature at 0°C. The reaction mixture was stirred at room temperature for another 6 hours.
  • Step 3 Preparation of a mixture of 2-(5-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine
  • 5-Fluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine (156 g, ⁇ 0.53 mol) was dissolved in chloroform (1000 mL) under N2 atmosphere.
  • NBS 94.77 g, 0.53 mol
  • the reaction was stirred at room temperature for 16 hours. Then the solvent was removed.
  • the mixture was poured into water (2000 mL) and extracted with ethyl acetate (1000 mL x 3). The organic layers were washed with brine (1000 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 4 Preparation of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3- methyl-3,6-dihydro-2H-pyridine-1-carboxylate [374] To a solution of a mixture of 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine
  • Step 5 Preparation of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1- carboxylate [376] To a solution of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol
  • Step 6 Preparation of a mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate [378] To a solution of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [2-(5-fluoro-2-pyridyl)
  • the reaction was stirred at 40°C for 16 hours. Then the solvent was removed. The mixture was poured into water (500 mL) and extracted with ethyl acetate (800 mL x 3). The combined organic layers were washed with brine (1000 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 7 Preparation of 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (hydrochloride) [380] To a solution of a mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate (44 g, 84 mmol) in THF (40 mL) was added 4 M HCl in 1,4-dioxane (80 m
  • Step 8 Preparation of tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate
  • 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine hydrochloride 44 g, crude, 84 mmol
  • DIEA 54 g, 0.42 mol
  • (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide 27.8 g, 92.4 mmol).
  • Step 9 Preparation of 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide
  • tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate (33 g, 69.8 mmol) in THF (30 mL) was added 4 M HCl in dioxane (60 mL). The reaction was stirred at room temperature for 16 hours.
  • Step 10 Preparation of (3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidine-1-sulfonamide and (3S,4S)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidine-1-sulfonamide and (3R*,4S*/3S*,4R*)-4-(4-chloro-2-(5- fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide [386] The mixture of isomers of 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methylpiperidine-1-sulfonamide (24.3 g, purity: 95%)
  • Step 2 Preparation of tert-butyl 4-(2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4- methylpiperidine-1-carboxylate
  • Step 3 Preparation of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl) -1H-imidazol- 5-yl)-4-methylpiperidine-1-carboxylate
  • tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4-methyl- piperidine-1-carboxylate 544 mg, 1.5 mmol
  • MeCN 5 mL
  • NCS 202 mg, 1.8 mmol
  • Step 4 Preparation of 2-(4-chloro-5-(4-methylpiperidin-4-yl)-1H-imidazol -2-yl)- 5-fluoropyridine
  • tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4- methyl-piperidine-1-carboxylate (96 mg, 0.243 mmol) in DCM (2 mL) was added TFA (1 mL) at 0°C. The reaction was stirred at room temperature for 2 h.
  • Step 5 Preparation of tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-4–methylpiperidin-1-yl)sulfonyl)carbamate
  • [402] A solution of [1-(ethoxycarbonylsulfamoyl)-4-pyridylidene]-dimethyl-ammonium (54 mg, 0.18 mmol), 2-[4-chloro-5-(4-methyl-4-piperidyl)-1H-imidazol-2-yl]-5-fluoro- pyridine (66 mg, 0.22 mmol) and TEA (36 mg, 0.36 mmol) in DCM (4 mL) was stirred at room temperature for 3 h.
  • reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and ⁇ concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether 50:50 to 70:30) to give tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-methylpiperidin-1- yl)sulfonyl)carbamate (44 mg, 51.7% yield).
  • Step 6 Preparation of 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4- methylpiperidine-1-sulfonamide
  • Step 6 Preparation of 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4- methylpiperidine-1-sulfonamide
  • Step 2 Preparation of 3-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)oxazolidin-2-one [414] To a solution of sulfurisocyanatidic chloride (48 mg, 0.34 mmol) in ⁇ dichloromethane (2 mL) was added 2-bromoethan-1-ol (43 mg, 0.34 mmol) under N2. The solution was cooled to 0°C ⁇ and stirred for 1 hour.
  • Step 3 Preparation of (3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-N-(2-hydroxyethyl)-3-methylpiperidine-1-sulfonamide
  • Step 3 To a solution of 3-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)oxazolidin-2-one (110 mg, 0.25 mmol) in ethanol (2 mL) was added a solution of sodium hydroxide (12 mg, ⁇ 0.3 mmol ) in water
  • Example 10 2-(4-Chloro-5-((3R,4R)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)- 1H-imidazol-2-yl)-5-fluoropyridine [420] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (80 mg, 0.27 mmol) in ⁇ dichloromethane (2 mL) was added DIEA (176 mg, 1.36 mmol) at 0°C and stirred for 10 min.
  • DIEA 176 mg, 1.36 mmol
  • Example 11 1-((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methylpiperidin-1-yl)ethan-1-one [422] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (80 mg, 0.27 mmol) in ⁇ dichloromethane (2 mL) was added DIEA (105 mg, 0.82 mmol) at 0°C and stirred for 10 min.
  • DIEA 105 mg, 0.82 mmol
  • Example 12 and Example 13 (3S*,4S*)-4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 12) and (3R*,4R*)-4-(4-ethyl-2- (5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 13) [424] Step 1: Preparation of 5-fluoropicolinimidamide [425] To a solution of 4-fluoro-benzonitrile (20 g, 164 mmol) in dry THF (300 mL) was added LiHMDS (1M in THF, 328 mL, 328 mmol) slowly at -78°C.
  • Step 2 Preparation of 2-(4-ethyl-1H-imidazol-2-yl)-5-fluoropyridine
  • 5-fluoropicolinimidamide 5 g, 36 mmol
  • EtOH 30 ml
  • 1-bromobutan-2-one 5.6 g, 36 mmol
  • K2CO3 4.9 g, 36 mmol
  • the reaction mixture was stirred at 80°C for 16 h.
  • the resulting mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3).
  • Step 3 Preparation of 2-(5-bromo-4-ethyl-1H-imidazol-2-yl)-5-fluoro-pyridine
  • 2-(4-ethyl-1H-imidazol-2-yl)-5-fluoro-pyridine 3 g, 15 mmol
  • MeCN MeCN
  • N-bromosuccinimide 3.2 g, 18 mmol
  • the reaction was stirred at room temperature for 16 h.
  • the resulting mixture was diluted with EA (200 mL), washed with brine (200 mL x 3), dried over anhydrous sodium sulfate and concentrated.
  • Step 4 Preparation of a mixture of 2-[[5-bromo-4-ethyl-2-(5-fluoro-2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-bromo-5-ethyl-2-(5-fluoro-2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane [431] To a solution of 2-(5-bromo-4-ethyl-1H-imidazol-2-yl)-5-fluoro-pyridine (1 g, 3.7 mmol) in THF (dry, 30 mL) was added NaH (133 mg, 5.5 mmol) and 2-(chloromethoxy)ethyl- trimethyl-silane (926 mg, 5.5 mmol) at 0°C.
  • Step 5 Preparation of a mixture of tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-3- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1- carboxylate and tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate [433] To a solution of a mixture of 2-[[5-bromo-4-ethyl-2-(5-fluoro-2-pyridyl)imidazol- 1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-bromo-5-ethyl-2-(5-fluoro
  • Step 6 Preparation of a mixture of tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-3- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate [435] To a solution of a mixture of tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[5-ethyl-2-(
  • Step 7 Preparation of 2-(4-ethyl-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine
  • Step 8 Preparation of tert-butyl ((4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate
  • 2-(4-ethyl-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine 270 mg, 0.93 mmol
  • DIEA 232 mg, 1.86 mmol
  • (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (308 mg, 0.99 mmol).
  • Step 9 Preparation of 4-[4-ethyl-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-piperidine-1-sulfonamide
  • Step 10 Preparation of (3R*,4R*)-4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidine-1-sulfonamide and (3S*,4S*)-4-(4-ethyl-2-(5- fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide [443] The isomers of 4-[4-ethyl-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- piperidine-1-sulfonamide were separated by chiral SFC to afford the title compounds.
  • Example 14 Methyl (((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidin-1-yl)sulfonyl)glycinate [449] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (150 mg, 0.51 mmol) in ⁇ dichloromethane (3 mL) was added triethylamine (155 mg, 1.53 mmol) under N2.
  • Example 15 (((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)glycine [451] To a solution of methyl (((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)glycinate (90 mg, 0.20 mmol) in THF (2 mL) was added a solution of lithium hydroxide (15 mg, ⁇ 0.6 mmol) in water (2 mL).
  • Example 16 2-(4-Chloro-5-((3S,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)- 1H-imidazol-2-yl)-5-fluoropyridine [453] To a solution of 2-(4-chloro-5-((3S,4S)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (100 mg, 0.34 mmol) in ⁇ dichloromethane (2 mL) was added DIEA (132 mg, 1.02 mmol) at 0°C and stirred for 10 min.
  • DIEA 132 mg, 1.02 mmol
  • Example 17 2-(4-Chloro-5-((3R*,4S*/3S*,4R*)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine [455] To a solution of 2-(4-chloro-5-((3R*,4S*/3S*,4R*)-3-methylpiperidin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (200 mg, 0.68 mmol) in ⁇ THF (4 mL) was added DIEA (263 mg, 2.04 mmol) at 0°C and stirred for 10 min.
  • Example 18 1-(((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxamide [457] Step 1: Preparation of methyl-1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)- 1H-imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate [458] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (190 mg, 0.65 mmol) in ⁇ THF (2 mL) was added DIEA (167 mg,
  • Step 2 Preparation of 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylic acid
  • a solution of methyl 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate 180 mg, 0.38 mmol
  • MeOH 2-aquexide
  • sodium hydroxide 76 mg, ⁇ 1.91 mmol
  • Step 3 Preparation of 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxamide
  • DCM dimethyl methacrylate
  • DIEA 225 mg, 1.75 mmol
  • NH4Cl 59 mg, 1.09 mmol
  • EDCI 83 mg, 0.44 mmol
  • HOBt 60 mg, 0.44 mmol
  • Step 2 Preparation of 2-(4,5-diiodo-1H-imidazol-2-yl)-5-fluoropyridine
  • 5-Fluoro-2-(1H-imidazol-2-yl)pyridine 100 g, 612.91 mmol
  • acetonitrile 1000 ml
  • NIS 303.4 g, 1.35 mol
  • the reaction mixture was stirred at room temperature for 6 hours.
  • the solvent was removed.
  • the residue was poured into water (2000 mL) and extracted with ethyl acetate (1000 mL x 3).
  • Step 3 Preparation of 5-fluoro-2-(4-iodo-1H-imidazol-2-yl)pyridine [469] To a solution of 2-(4,5-diiodo-1H-imidazol-2-yl)-5-fluoropyridine (219 g, 527.78 mmol) in DMF (2000 mL) and water (1000 mL) was added Na2SO3 (399 g, ⁇ 3.166 mol) in several portions.
  • Step 4 Preparation of a mixture of 5-fluoro-2-(4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine and 5-fluoro-2-(5-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine [471] To a solution of 5-fluoro-2-(4-iodo-1H-imidazol-2-yl)pyridine (130 g, ⁇ 0.45 mol) in THF (2000 mL) was added NaH (26.99 g, 0.675 mol, 60%) in several portions at 0°C under N2 atmosphere. ⁇ The resulting mixture was stirred at 0°C for 1 hour.
  • Step 5 Preparation of a mixture of 2-(5-chloro-4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-chloro-5-iodo-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine [473] To a solution of a mixture of 5-fluoro-2-(4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine and 5-fluoro-2-(5-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine (10 g, ⁇ 23.9 mmol) in THF (100 mL) was added NCS (3.81 g, 28.6 m
  • the reaction mixture was stirred at 40°C for 16 h.
  • the mixture was poured into water (150 mL) and extracted with EA (150 mL x 3).
  • the organic layers were washed with brine (150 mL x 2), dried with Na2SO4 and concentrated.
  • Step 6 Preparation of a mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1- carboxylate and tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate [475] To a solution of a mixture of 2-(5-chloro-4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-chloro-5-iodo-1- ((2-(trimethylsilyl)ethoxy)
  • Step 7 Preparation of 2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine
  • Step 8 Preparation of (S*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4- yl)-1H-imidazol-2-yl)-5-fluoropyridine and (R*)-2-(4-chloro-5-(3-methyl-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine [479] The enantiomeric mixture 2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)- 1H-imidazol-2-yl)-5-fluoropyridine (270 mg) was separated by chiral HPLC to give (S*)-2-(4- chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine (
  • Example 20 (R*)-2-(4-Chloro-5-(3-methyl-1-(methylsulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine [485] To a solution of (R*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (60 mg, 0.21 mmol) in DCM (2 mL) was added DIEA (80 mg, 0.62 mmol) at 0°C.
  • Step 2 Preparation of (S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methyl-3,6-dihydropyridine-1(2H)-sulfonamide
  • Step 2 Preparation of (R*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methyl-3,6-dihydropyridine-1(2H)-sulfonamide
  • R* tert-butyl
  • R* tert-butyl
  • 4 M HCl in 1,4-dioxane (4 mL) was stirred at room temperature for 16 hours.
  • Example 23 2-(5-((3R,4R)-1-((1H-Pyrazol-4-yl)sulfonyl)-3-methylpiperidin-4-yl)- 4-chloro-1H-imidazol-2-yl)-5-fluoropyridine [497] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (60 mg, 0.20 mmol) in ⁇ THF (2 mL) was added DIEA (53 mg, 0.41 mmol) at 0°C and stirred for 10 min.
  • Example 24 Methyl 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate [499] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (190 mg, 0.65 mmol) in ⁇ THF (2 mL) was added DIEA (167 mg, 1.3 mmol) at 0°C and stirred for 10 min.
  • DIEA 167 mg, 1.3 mmol
  • Example 25 1-(((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylic acid [501] To a solution of methyl 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate (180 mg, 0.38 mmol) in MeOH (2 mL) was added a solution of sodium hydroxide (76 mg, ⁇ 1.91 mmol ) in water (2 mL).
  • Step 2 Preparation of 2-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine
  • 2-(4,5-dibromo-1H-imidazol-2-yl)-5-fluoropyridine 300 mg, ⁇ 0.93 mmol
  • THF 10 mL
  • NaH 45 mg, 1.12 mmol, 60%
  • Step 3 Preparation of a mixture of 2-(4-bromo-5-(2,3-difluorophenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(5-bromo-4-(2,3- difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine [508] To a solution of 2-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol- 2-yl)-5-fluoropyridine (300 mg, ⁇ 0.67 mmol) in 1,4-dioxane (6 mL) and water (1.2 mL) were added (2,3-difluorophenyl)boronic acid (105 mg, 0.67 mmol), sodium carbonate (211
  • Example 28 2-[4-Chloro-5-(2-chloro-4-methylsulfinyl-phenyl)-1H-imidazol-2-yl]- 5-fluoro-pyridine
  • Step 1 Preparation of 2-(4-chloro-1H-imidazol-2-yl)-5-fluoropyridine
  • 5-Fluoro-2-(1H-imidazol-2-yl)pyridine (3 g, 18.4 mmol) was dissolved in N,N- dimethylformamide (40 mL). Then N-chlorosuccinimide (2.4 g, 18.4 mmol) and acetic acid (1.1 g, 18.4 mmol) were added.
  • Step 2 Preparation of 2-(5-bromo-4-chloro-1H-imidazol-2-yl)-5-fluoropyridine
  • 2-(4-Chloro-1H-imidazol-2-yl)-5-fluoropyridine (1.9 g, 9.6 mmol) was dissolved in tetrahydrofuran (20 mL). The solution was ⁇ cooled to 0°C. Then N-bromosuccinimide (2.1 g, 11.57 mmol) was added. The reaction was stirred at room temperature for ⁇ 3 hours. Then water (80 mL) was added. The resulting mixture was extracted with dichloromethane (80 mL x 3).
  • Step 3 Preparation of a mixture of 2-(5-bromo-4-chloro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-5-chloro- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine
  • 2-(5-Bromo-4-chloro-1H-imidazol-2-yl)-5-fluoropyridine (1.8 g, 6.55 mmol) was dissolved in tetrahydrofuran (20 mL). The solution was ⁇ cooled to 0°C.
  • Step 4 Preparation of a mixture of 2-(4-chloro-5-(2-chloro-4- (methylsulfinyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5- fluoropyridine and 2-(5-chloro-4-(2-chloro-4-(methylsulfinyl)phenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine [521] To a solution of a mixture of 2-(5-bromo-4-chloro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-5-chloro- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyr
  • the ⁇ crude product ⁇ was purified by flash column chromatography (ethyl acetate / petroleum ether 40:60) to give a mixture of 2-(4-chloro-5-(2- chloro-4-(methylsulfinyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5- fluoropyridine and 2-(5-chloro-4-(2-chloro-4-(methylsulfinyl)phenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (130 mg, 0.248 mmol, yield: ⁇ 20.1%).
  • Step 5 Preparation of 2-[4-chloro-5-(2-chloro-4-methylsulfinyl-phenyl)-1H- imidazol-2-yl]-5-fluoro-pyridine
  • Example 29 2-[4-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-1H-imidazol-2- yl]-5-fluoro-pyridine
  • Step 1 Preparation of a mixture of 2-[[4-chloro-5-(2-chloro-4-methylsulfonyl- phenyl)-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro- 4-(2-chloro-4-methylsulfonyl-phenyl)-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane [526] A mixture of 2-(4-chloro-5-(2-chloro-4-(methylsulfinyl)phenyl)-1-((2- (trimethyl)
  • potassium monopersulfate triple salt (Oxone) (172 mg, 0.28 mmol) was added in one portion. The reaction was stirred at room temperature for 2 hours. Then the mixture was poured into water (5 mL) and extracted with EA (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated.
  • Step 2 Preparation of 2-[4-chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-1H- imidazol-2-yl]-5-fluoro-pyridine
  • Example 30 2-[4-Chloro-5-(2-chloro-4-(methylsulfonimidoyl)phenyl)-1H- imidazol-2-yl]-5-fluoro-pyridine [530] Step 1: Preparation of a mixture of 2-[[4-chloro-5-[2-chloro-4- (methylsulfonimidoyl)phenyl]-2-(5-fluoro- 2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl- silane and 2-[[5-chloro-4-[2-chloro-4-(methylsulfonimidoyl)phenyl]-2-(5-fluoro- 2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane [531] To a solution of a mixture of 2-(4-chloro-5-(2-chloro-4-(methylsulfin
  • Step 2 Preparation of 2-[4-chloro-5-(2-chloro-4-(methylsulfonimidoyl)phenyl)- 1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 31 Methyl 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzoate
  • Step 1 Preparation of a mixture of methyl 3-chloro-4-[5-chloro-2-(5-fluoro-2- pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate and methyl 3-chloro-4-[5- chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate [536] To a mixture of 2-(5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-5-chloro-1-(
  • reaction was stirred at 70°C for 16 h under nitrogen. LCMS indicated the reaction was completed.
  • the reaction mixture was cooled to room temperature, diluted with water (10 mL), acidified with 1 M HCl solution until pH 5 and extracted with ethyl acetate (15 mL x 3).
  • Step 2 Preparation of methyl 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]benzoate
  • Example 32 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzoic acid
  • a solution of methyl 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]benzoate (40 mg, 0.109 mmol) in MeOH (1 mL) was added a solution of lithium hydroxide monohydrate (91.7 mg, 2.18 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was completed.
  • reaction mixture was diluted with water (10 mL), acidified with 1 M HCl solution until pH 5 and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous sodium sulfate and concentrated to give the residue, which was purified by prep-HPLC to afford the title compound (23.2 mg, 0.064 mmol, yield: 59.1%).
  • Step 2 Preparation of 4-bromo-3-chloro-N,N-bis[(2,4- dimethoxyphenyl)methyl]benzenesulfonamide
  • Step 3 Preparation of [4-[bis[(2,4-dimethoxyphenyl)methyl]sulfamoyl]-2-chloro- phenyl]boronic acid
  • [547] To a solution of 3-chloro-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (11 g, 16.9 mmol) in acetone (100 mL) and water (30 mL) was added ammonium acetate (3.6 g, 47.3 mmol) and sodium periodate (11.9 g, 55.8 mmol) in potions.
  • Step 4 Preparation of a mixture of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4- [2-(5-fluoro-2-pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzenesulfonamide and 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]benzenesulfonamide [549] A mixture of 2-[[5-bromo-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane and 2-[[4-bromo-2-(5-fluoro-2-pyridyl)imidazol-1-yl]me
  • Step 5 Preparation of 3-chloro-4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzenesulfonamide
  • Step 6 Preparation of 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzenesulfonamide
  • Step 6 To a solution of 3-chloro-4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzenesulfonamide (230 mg, 0.652 mmol) in DMF (2 mL) was added NCS (113 mg, 0.848 mmol). The reaction mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was completed.
  • reaction mixuture was stirred at 0°C for 10 min. Then tert-butyl 2-bromoacetate (185 mg, 0.948 mmol) was added into the reaction mixture. The reaction was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was quenched with sat. ammonium chloride solution, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3).
  • Step 2 Preparation of a mixture of tert-butyl 2-[[3-chloro-4-[5-chloro-2-(5-fluoro- 2-pyridyl)-3-(2-trime-thylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate and tert-butyl 2-[[3-chloro-4-[5-chloro-2-(5-fluoro-2- pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate [559] To a solution of a mixture of tert-butyl 2-[[3-chloro-4-[2-(5-fluoro- 2-pyridyl)-3-(2-trime
  • reaction mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was completed.
  • the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried with anhydrous sodium sulfate and concentrated.
  • Step 3 Preparation of 2-[[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]phenyl]sulfonylamino]acetic acid [561] A solution of a mixture of tert-butyl 2-[[3-chloro-4-[5-chloro-2-(5-fluoro-2- pyridyl)-3-(2-trime-thylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate and tert-butyl 2-[[3-chloro-4-[5-chloro-2-(5-fluoro-2- pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-y
  • Step 2 Preparation of 4-bromo-3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-N-(2- hydroxyethyl)benzenesulfonamide
  • Step 3 Preparation of 2-[(4-bromo-3-chloro-phenyl)sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl acetate
  • 4-bromo-3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-N-(2- hydroxyethyl)benzenesulfonamide (1.9 g, 4.09 mmol)
  • N,N-diethylethanamine (1.65 g, 16.36 mmol) in DCM (20 mL) was added acetyl chloride (0.642 g, 8.18 mmol) dropwise at 0°C.
  • Step 4 Preparation of 2-[[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]sulfonyl-[(2,4-dimethoxyphenyl)methyl]amino]ethyl acetate
  • Step 5 Preparation of [4-[2-acetoxyethyl-[(2,4- dimethoxyphenyl)methyl]sulfamoyl]-2-chloro-phenyl]boronic acid
  • Step 6 Preparation of a mixture of 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl acetate and 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl acetate [574] A mixture of [4-[2-acetoxyethyl-[(2,4-dimethoxyphenyl)methyl]sulfamoyl]-2- chloro-phenyl]boronic acid (500 mg, 1.
  • Step 7 Preparation of 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylamino]ethyl acetate
  • Step 8 Preparation of 2-[[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]phenyl]sulfonylamino]ethyl acetate
  • 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylamino]ethyl acetate (117 mg, 0.267 mmol) in DMF (3 mL) was added NCS (53.4 mg, 0.400 mmol) slowly.
  • Step 9 Preparation of 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-N-(2-hydroxyethyl)benzenesulfonamide
  • 2-[[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylamino]ethyl acetate (108 mg, 0.228 mmol) in MeOH (2 mL) was added a solution of lithium hydroxide monohydrate (95.7 mg, 2.28 mmol) in water (1 mL).
  • Example 36 2-[5-(2-Chloro-4-methylsulfonyl-phenyl)-4-methyl-1H-imidazol-2- yl]-5-fluoro-pyridine [582]
  • Step 1 Preparation of 5-fluoro-2-(4-methyl-1H-imidazol-2-yl)pyridine [583] To a solution of 5-fluoropyridine-2-carbaldehyde (3.5 g, 28.0 mmol) in MeOH (250 mL) were added ammonium acetate (21.6 g, 280.0 mmol), 2-oxopropanal (25.2 g of 40% aq. solution, 140 mmol). The reaction was stirred at 70°C for 2 h.
  • Step 2 Preparation of 5-fluoro-2-(5-iodo-4-methyl-1H-imidazol-2-yl)pyridine
  • NIS NIS
  • Step 3 Preparation of a mixture of 2-[[2-(5-fluoro-2-pyridyl)-5-iodo-4-methyl- imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[2-(5-fluoro-2-pyridyl)-4-iodo-5-methyl- imidazol-1-yl]methoxy]ethyl-trimethyl-silane [587] To a solution of 5-fluoro-2-(5-iodo-4-methyl-1H-imidazol-2-yl)pyridine (4.75 g, 15.7 mmol) in THF (50 mL) was added 60% NaH in mineral oil (940 mg, 23.5 mmol) slowly at 0°C.
  • Step 4 Preparation of a mixture of 2-[[5-(2-chloro-4-methylsulfonyl-phenyl)-2-(5- fluoro-2-pyridyl)-4-methyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-(2-chloro- 4-methylsulfonyl-phenyl)-2-(5-fluoro-2-pyridyl)-5-methyl-imidazol-1-yl]methoxy]ethyl- trimethyl-silane [589] A mixture of 2-[[2-(5-fluoro-2-pyridyl)-5-iodo-4-methyl-imidazol-1- yl]methoxy]ethyl-trimethyl-silane and 2-[[2-(5-fluoro-2-pyridyl)-4-iodo-5-methyl-methyl-
  • Step 5 Preparation of 2-[5-(2-chloro-4-methylsulfonyl-phenyl)-4-methyl-1H- imidazol-2-yl]-5-fluoro-pyridine
  • Example 37 Methyl 1-((3-chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)phenyl)sulfonyl)azetidine-3-carboxylate [593] Step 1: Preparation of methyl 1-((4-bromo-3-chlorophenyl)sulfonyl) azetidine-3- carboxylate [594] To a solution of 4-bromo-3-chloro-benzenesulfonyl chloride (8.0 g, 27.6 mmol) and methyl azetidine-3-carboxylate (3.5 g, 30.3 mmol) ⁇ in the DCM (100 mL) was added TEA (5.58 g, 55.2 mmol) in several portions.
  • Step 2 Preparation of methyl 1-((3-chloro-4-(4,4,5,5-tetramethyl-1,3,2– dioxaborolan-2-yl)phenyl)sulfonyl)azetidine-3-carboxylate [596] To a solution of methyl 1-(4-bromo-3-chloro-phenyl)sulfonylazetidine-3- carboxylate (11.2 g, 30.4 mmol) and 4,4,5,5-tetramethyl-2-(3,3,4,4-tetramethylborolan-1-yl)- 1,3,2-dioxaborolane (8.35 g, 33.4 mmol) in 1,4-dioxane (120 mL) was added potassium acetate (5.96 g, 60.8 mmol) in several portions.
  • Step 3 Preparation of a mixture of 1-[3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)- 3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonylazetidine-3-carboxylic acid and 1-[3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4- yl]phenyl]sulfonylazetidine-3-carboxylic acid [598] To a solution of a mixture of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-iodo-imidazol- 1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-2-(5-fluoro-2-pyridyl
  • Step 4 Preparation of methyl 1-((3-chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)- 1H-imidazol-5-yl)phenyl)sulfonyl)azetidine-3-carboxylate
  • Example 38 1-((3-Chloro-4-(4-chloro-2-(5-fluoro-pyridin-2-yl)-1H-imidazol-5- yl)-phenyl) sulfonyl)azetidine-3-carboxylic acid
  • Example 39 1-((3-Chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)phenyl)sulfonyl)azetidine-3-carboxamide
  • EDCI 59 mg, 0.31 mmol
  • HOBt 42 mg, 0.31 mmol
  • DIEA 54 mg, 0.42 mmol
  • ammonium chloride 22.5 mg, 0.42 mmol.
  • Example 40 Methyl 2-chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)benzoate
  • Step 1 Preparation of a mixture of methyl 2-chloro-3-[5-chloro-2-(5-fluoro-2- pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate and methyl 2-chloro-3-[5- chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate [607] To a solution of a mixture of 2-[[5-chloro-2-(5-fluoro-2-pyridyl)-4-iodo-imidazol- 1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-
  • Step 2 Preparation of methyl 2-chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)benzoate
  • Example 41 2-Chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)benzoic acid [611] To a solution of methyl 2-chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)benzoate (180 mg, 0.49 mmol) in MeOH (2 mL) was added a solution of sodium hydroxide (98 mg, ⁇ 2.46 mmol) in water (2 mL). The mixture was ⁇ stirred at room temperature ⁇ for ⁇ 16 h.
  • Example 42 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-2,3-dihydro- 1,2-benzothiazole 1,1-dioxide [613]
  • Step 1 Preparation of 1-benzylsulfanyl-3-bromo-2-methyl-benzene [614] A mixture of 1,3-dibromo-2-methyl-benzene (25 g, 100 mmol), phenylmethanethiol (9.94 g, 80 mmol), DIEA (20.7 g, 160 mmol), Pd2(dba)3 (2.29 g, 2.5 mmol) and Xantphos (2.49 g, 5 mmol) in 1,4-dioxane (600 mL) was stirred at 100°C for 6 h.
  • Step 2 Preparation of 3-bromo-2-methyl-benzenesulfonyl chloride
  • a mixture of 1-benzylsulfanyl-3-bromo-2-methyl-benzene (12.2 g, 41.6 mmol), H2O (3.0 g, 166 mmol) and acetic acid (12.5 g, 208 mmol) in DCM (400 mL) was stirred at 0°C for 5 min.
  • sulfuryl chloride (22.5 g, 166 mmol) was added dropwise. After addition, the mixture was stirred at 0°C for 5 min, then warmed to room temperature and stirred for 20 min.
  • Step 3 Preparation of 3-bromo-N-tert-butyl-2-methyl-benzenesulfonamide
  • Step 5 Preparation of 4-bromo-2-tert-butyl-3H-1,2-benzothiazole 1,1-dioxide
  • Step 6 Preparation of 2-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3H-1,2-benzothiazole 1,1-dioxide
  • Step 7 Preparation of (2-tert-butyl-1,1-dioxo-3H-1,2-benzothiazol-4-yl)boronic acid
  • 2-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-1,2- benzothiazole 1,1-dioxide 430 mg, 1.2 mmol
  • ammonium acetate 264 mg, 3.4 mmol
  • acetone/H2O 10 mL / 2 mL
  • Step 8 Preparation of a mixture of 2-[[5-(2-tert-butyl-1,1-dioxo-3H-1,2- benzothiazol-4-yl)-4-chloro-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl- silane and 2-[[4-(2-tert-butyl-1,1-dioxo-3H-1,2-benzothiazol-4-yl)-5-chloro-2-(5-fluoro-2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane [628] A mixture of (2-tert-butyl-1,1-dioxo-3H-1,2-benzothiazol-4-yl)boronic acid (240 mg, 0.89 mmol), a mixture of 2-[[4-chloro-2-(5-fluoro-2-pyr
  • Step 9 Preparation of 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-2,3- 30 dihydro-1,2-benzothiazole 1,1-dioxide
  • Step 2 Preparation of N,N-bis(2,4-dimethoxybenzyl)-2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide
  • Step 2 To a solution of 3-bromo-N,N-bis(2,4-dimethoxybenzyl)-2- methylbenzenesulfonamide (8.1 g, 14.8 mmol) in 1,4-dioxane (100 mL) were added bis(pinacolato)diboron (5.64 g, 22.2 mmol), potassium carbonate (2.9 g, 29.6 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.07 g, 1.48 mmol) under nitrogen atmosphere.
  • Step 3 Preparation of (3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)-2- methylphenyl)boronic acid
  • N,N-bis(2,4-dimethoxybenzyl)-2-methyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzenesulfonamide 8 g, 13.3 mmol
  • acetone 50 mL
  • water 50 mL
  • ammonium acetate 2.9 g, 37.2 mmol
  • sodium periodate 9.4 g, 43.9 mmol.
  • Step 4 Preparation of mixture of 3-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-methyl- benzenesulfonamide and 3-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-methyl- benzenesulfonamide [639] To a solution of (3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)-2- methylphenyl)boronic acid (200 mg, 0.38 mmol) in 1,4-dioxane (10 mL) and water (2 mL) were added
  • reaction mixture was stirred at 80°C for 8 hours. Then the mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 5 Preparation of 3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-2- methylbenzenesulfonamide
  • Example 44 2-Chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)benzamide
  • 2-chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)benzoic acid 60 mg, 0.17 mmol
  • DIEA 176 mg, 1.36 mmol
  • NH4Cl 46 mg, 0.85 mmol
  • EDCI 65 mg, 0.34 mmol
  • HOBt 46 mg, 0.34 mmol
  • Example 45 2-(4-Chloro-5-(2-fluoro-6-methylphenyl)-1H-imidazol-2-yl)-5- fluoropyridine
  • Step 1 Preparation of a mixture of 2-[[4-chloro-5-(2-fluoro-6-methyl-phenyl)-2-(5- fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-4-(2-fluoro-6- methyl-phenyl)-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane [646] A mixture of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-
  • Step 2 Preparation of 2-(4-chloro-5-(2-fluoro-6-methylphenyl)-1H-imidazol-2-yl)- 5-fluoropyridine
  • Step 2 Preparation of methyl 3-bromo-4-fluoro-2-methylbenzoate
  • 3-bromo-4-fluoro-2-methyl- benzoic acid 33 g, 0.142 mol
  • potassium carbonate 58.7 g, 0.425 mol
  • methyl iodide 40.2 g, 0.283 mmol
  • the reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (200 mL x 3).
  • Step 3 Preparation of methyl 4-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate
  • Pd(dppf)Cl2 903 mg, 1.23 mmol
  • potassium acetate 3.63 g, 37.0 mmol
  • Step 4 Preparation of (6-fluoro-3-(methoxycarbonyl)-2-methylphenyl)boronic acid [657] To a mixture of methyl 4-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate (2.0 g, 6.80 mmol), acetone (20 mL) and water (6 mL) was added ammonium acetate (1.47 g, 19.0 mmol), sodium periodate (4.8 g, 22.4 mmol) successively under cooling with an ice ⁇ water bath. The resulting mixture was stirred at room temperature for 16 h.
  • Step 5 Preparation of methyl 4-fluoro-3-(2-(5-fluoropyridin-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-methylbenzoate (mixture of SEM- regioisomers)
  • Pd(dtbpf)Cl2 335 mg, 0.519 mmol
  • potassium carbonate (2.15 g, 15.6 mmol) in dioxane (20 mL) and water (4 mL)
  • Step 6 Preparation of methyl 3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-4-fluoro-2-methylbenzoate [661] To a mixture of methyl 4-fluoro-3-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-2-methyl-benzoate (1.3 g, 2.83 mmol) and TsOH.H2O (53.8 mg, 0.283 mmol) in MeCN (13 mL) was added NCS (453 mg, 3.39 mmol) 30 in portions.
  • the reaction mixture was stirred at room temperature for 16 h.
  • the reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (80 mL x 2), brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under pressure.
  • the residue was purified by preparative HPLC to give the title compound (76.1 mg, 0.128 mmol, yield: 60.6%) as white solid.1H NMR.
  • Example 49 2-(4-Chloro-5-(2-fluoro-6-methyl-4-(methylthio)phenyl)-1H- imidazol-2-yl)-5-fluoropyridine [667] Step 1: Preparation of 2-bromo-1-fluoro-3-methyl-5-methylsulfanyl-benzene [668] 4-bromo-3-fluoro-5-methyl-aniline (5 g, 24.5 mmol) was dissolved in 1,2- dimethyldisulfane (35 mL, 394 mmol) and heated to 75°C under nitrogen.
  • Step 2 Preparation of 2-(2-fluoro-6-methyl-4-methylsulfanyl-phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane [670] To a solution of 2-bromo-1-fluoro-3-methyl-5-methylsulfanyl-benzene (3.5 g, 14.9 mmol) in 1,4-dioxane (35 mL) ⁇ were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.16 g, 16.4 mmol) and KOAc (2.92 g, 29.8 mmol).
  • Step 3 Preparation of 2-(4-chloro-5-(2-fluoro-6-methyl-4-(methylthio)phenyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (mixture of SEM- regioisomers)
  • 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-iodo-imidazol-1- yl]methoxy]ethyl-trimethyl-silane 400 mg, 0.88 mmol, mixture of SEM-regioisomers) in 1,4- dioxane (4 mL) were added 2-(2-fluoro-6-methyl-4-methylsulfanyl-phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (373 mg, 1.32 mmol) and K3PO4 (561 mg,
  • Step 4 Preparation of 2-(4-chloro-5-(2-fluoro-6-methyl-4-(methylthio)phenyl)-1H- imidazol-2-yl)-5-fluoropyridine
  • Example 50 2-[4-Chloro-5-(2-fluoro-6-methyl-4-methylsulfonyl-phenyl)-1H- imidazol-2-yl]-5-fluoro-pyridine [676] MCPBA (50 mg) was added to a mixture of 2-[4-chloro-5-(2-fluoro-6-methyl-4- methylsulfanyl-phenyl)-1H-imidazol-2-yl]-5-fluoro-pyridine (55 mg) and DCM (3 mL). After 2 hours, the mixture was concentrated and purified by preparative HPLC to afford the title compound.
  • Example 51 3-[3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylpropan-1-ol [678] Step 1: Preparation of 3-((4-bromo-3-chlorophenyl)sulfonyl)propan-1-ol [679] A mixture of 4-bromo-3-chloro-benzenesulfonyl chloride (8.3 g, 28.6 mmol), Na2SO3 ⁇ (7.22 g, 57.2 mmol), NaHCO3 ⁇ (4.81 g, 57.2 mmol) and water (60 mL) was stirred at 100 ⁇ °C for 1.5 h.
  • Step 2 Preparation of (3-((4-bromo-3-chlorophenyl)sulfonyl)propoxy)(tert- butyl)dimethylsilane
  • Step 3 Preparation of tert-butyl(3-((3-chloro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)sulfonyl)propoxy)dimethylsilane
  • 3-(4-bromo-3-chloro-phenyl)sulfonylpropoxy-tert-butyl-dimethyl- silane 5 g, 11.7 mmol
  • 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,3,2-dioxaborolane 3.86 g, 15.2 mmol
  • 1,4-dioxane 75 mL
  • Pd(dppf)Cl2 855 mg, 0.1 eq.
  • Step 4 Preparation of 2-(5-(4-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)-2- chlorophenyl)-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5- fluoropyridine (mixture of SEM-regioisomers) [685] To a solution of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-iodo-imidazol-1- yl]methoxy]ethyl- trimethyl-silane (3 g, 6.61 mmol, mixture of SEM-regioisomers) and tert- butyl-[3-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl] sulfon
  • Step 5 Preparation of 3-[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]phenyl]sulfonylpropan-1-ol
  • Step 2 Preparation of 3-bromo-4-fluoro-2-methylaniline
  • 2-Bromo-1-fluoro-3-methyl-4-nitro-benzene (17.5 g, 74.8 mmol) was dissolved in 30 MeOH (170 mL) and HOAc (80 mL). Iron powder (41.8 g, 748 mmol) was added with several portions. The reaction mixture was stirred at RT for 16 hrs. The reaction was monitored by LCMS. The solid was filtered out and washed with MeOH (1000 mL). The filtrate was concentrated.
  • Step 3 Preparation of ⁇ 3-bromo-4-fluoro-2-methylbenzenesulfonyl chloride
  • 3-bromo-4-fluoro-2-methyl-aniline 13 g, 0.0637 mol was dissolved in HCl (9 N, 150 mL). NaNO2 (5.71 g, 82.8 mmol) in water (25 mL) was added dropwise at 0 °C.
  • Step 4 Preparation of 3-bromo-N,N-bis(2,4-dimethoxybenzyl)-4-fluoro-2- methylbenzenesulfonamide
  • 1-(2,4-dimethoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]methanamine (8.5 g, 26.8 mmol) and DIEA (14.8 g, 0.115 mol) were dissolved in DCM (150 mL).
  • 3-bromo-4- fluoro-2-methyl- benzenesulfonyl chloride 11 g, 0.0383 mol was added with several portions. The reaction mixture was stirred at RT for 16 hrs.
  • Step 5 Preparation of N,N-bis(2,4-dimethoxybenzyl)-4-fluoro-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide
  • Step 5 To a solution of 3-bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-fluoro-2- methyl- benzenesulfonamide (12 g, 21.1 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,3,2-dioxaborolane (6.97 g, 27.4 mmol) in 1,4-dioxane (150 mL) under N2 atmosphere, KOAc (6.22 g, 63.3 mmol) was added followed by 30 Pd(dppf)Cl2 (1.54 ).
  • Step 6 Preparation of (3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)-6-fluoro-2- methylphenyl)boronic acid
  • N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-fluoro-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide 7 g, 11.4 mmol
  • NH4OAc (2.45 g, 31.8 mmol
  • acetone 100 mL
  • H2O 30 mL
  • sodium periodate 8.03 g, 37.5 mmol
  • Step 7 Preparation of N,N-bis(2,4-dimethoxybenzyl)-4-fluoro-3-(2-(5- fluoropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2- methylbenzenesulfonamide (mixture of SEM-regioisomers)
  • [702] To a mixture of 2-[[5-bromo-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane (1.5 g, 4.03 mmol, mixture of SEM-regioisomers), ⁇ [3-[bis[(2,4- dimethoxyphenyl)methyl]sulfamoyl]-6-fluoro-2-methyl-phenyl] boronic acid (2.58 g, 4.83 mmol) and K2CO3 (1.67 g,
  • Step 8 Preparation of 4-fluoro-3-(2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-2- methylbenzenesulfonamide
  • Step 9 Preparation of 3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4- fluoro-2-methylbenzenesulfonamide
  • Step 9 To a solution of 4-fluoro-3-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-2-methyl- benzenesulfonamide (130 mg, 0.371 mmol) in THF (3 mL) was added NCS (59.5 mg, 0.445 mmol) in portions. The resulting mixture was stirred at 40 °C for 16 hrs.
  • Step 2 Preparation of 3-[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]phenyl]sulfonylpropanamide [711] A mixture of 3-[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylpropanoic acid (15 mg), ammonium chloride (7.2 mg), DMF (0.5 mL) and DIPEA (35 mg) was added EDC (12.9 mg) and HOBt (4.6 mg).
  • Step 2 Preparation of methyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylbenzoate
  • Example 55 4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylbenzoic acid
  • a solution of methyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-benzoate (0.4 g, 1.2 mmol) in MeOH (4 mL) was added NaOH (0.28 g, 6.9 mmol) in H2O (20 mL).
  • the reaction was stirred at room temperature for 16 h.
  • Example 56 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- benzamide
  • Example 57 N-(2-Amino-2-oxo-ethyl)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-benzamide
  • the reaction was stirred at 100°C for 16 h.
  • the reaction mixture was quenched with water (200 mL) and extracted with DCM (200 mL x 3). The organic layers were combined, washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated.
  • the crude product was purified by silica gel column chromatography with petroleum ether to afford the subtitle compound (7 g, yield 61%) as a colorless oil.
  • Step 2 Preparation of (2-methyl-4-methylsulfanyl-phenyl)boronic acid
  • 1-bromo-2-methyl-4-methylsulfanyl-benzene (5 g, 23 mmol) was dissolved in tetrahydrofuran (30 mL). Then 2.5 M n-butyllithium (13.8 mL, 34.5 mmol) was added slowly at -78°C under N2 atmosphere. After stirring for 1h, trimethyl borate (7.2 g, 69.1 mmol) was added dropwise at -78°C. The mixture stirred at -78°C for another 2 h and at RT for 16 h.
  • Step 3 Preparation of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-(2-methyl-4- methylsulfanyl-phenyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (mixture of SEM- regioisomers)
  • Step 4 Preparation of 2-[4-chloro-5-(2-methyl-4-methylsulfanyl-phenyl)-1H- imidazol-2-yl]-5-fluoro-pyridine
  • 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-(2-methyl-4-methylsulfanyl- phenyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (0.5 g) was added 4M HCl in 1,4- dioxane (5 mL). The reaction was stirred at RT for 4 h.
  • Example 59 N-(2-Amino-2-oxo-ethyl)-3-chloro-4-[4-chloro-2-(5-fluoro-2- pyridyl)-1H-imidazol-5-yl]benzamide
  • a mixture of 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzoic acid (17.5 mg), DMF (0.5 mL) and DIPEA (26 mg) was added HATU (24 mg). After 5 min, 2-aminoacetamide (hydrochloride, 7.4 mg) was added.
  • Example 60 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzamide
  • Example 61 and Example 62 2-[4-Chloro-5-(2-methyl-4-methylsulfonyl-phenyl)- 1H-imidazol-2-yl]-5-fluoro-pyridine and 2-[4-chloro-5-(2-methyl-4-methylsulfinyl-phenyl)- 1H-imidazol-2-yl]-5-fluoro-pyridine [737] MCPBA (78 mg) was added to a mixture of 2-[4-chloro-5-(2-methyl-4- methylsulfanyl-phenyl)-1H-imidazol-2-yl]-5-fluoro-pyridine (100 mg) and DCM (2 mL).
  • Example 63 and Example 64 Tert-butyl (S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)- 1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (R*)-4-(4- chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)- carboxylate [739] Step 1: Preparation of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1-
  • Step 2 Preparation of 2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (hydrochloride)
  • a solution of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1-((2-30 (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)- carboxylate (10.8 g, 20.7 mmol, mixture of SEM-regioisomers) in 1,4-dioxane (20 mL) was added 4M HCl in 1,4-dioxane (40 mL) and stirred at room temperature for 16 hours.
  • Step 3 Preparation of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate [744] To a solution of 2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (11 g, crude hydrochloride) in DCM (100 mL) were added TEA (10.4 g, 103.4 mmol) and tert-butoxycarbonyl tert-butyl carbonate (4.7 g, 21.7 mmol).
  • Step 4 Preparation of tert-butyl (S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (R*)-4-(4- chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)- carboxylate [746] Tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-carboxylate (10 g) was separated by chiral-HPLC to afford tert-butyl (S*)-4-(4-chloro-2-(5-fluoro
  • Example 65 (3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- N,N,3-trimethyl-piperidine-1-carboxamide
  • Example 66 Methyl (3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-piperidine-1-carboxylate
  • Example 67 [2-(Dimethylamino)-2-oxo-ethyl] (3R,4R)-4-[4-chloro-2-(5-fluoro-2- pyridyl)-1H-imidazol-5-yl]-3-methyl-piperidine-1-carboxylate
  • Example 68 Methyl 3-[[(3S*)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoate [758] A mixture of 2-[4-chloro-5-[(3S*)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H- imidazol-2-yl]-5-fluoro-pyridine (250 mg), DCM (5 mL) and DIPEA (0.41 mL) was added methyl 3-(chlorosulfonyl)propanoate (186 mg).
  • Example 69 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3-pyridylsulfonyl)-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 70 and Example 71 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3- pyridylsulfonyl)-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-1-oxido-pyridin-1-ium and 2-[4- chloro-5-[(3R,4R)-3-methyl-1-(1-oxidopyridin-1-ium-3-yl)sulfonyl-4-piperidyl]-1H-imidazol- 2-yl]-5-fluoro-pyridine [762] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(3-pyridylsulfonyl)-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-
  • Example 72 2-[5-[(3R,4R)-1-(Azetidin-3-ylsulfonyl)-3-methyl-4-piperidyl]-4- chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride)
  • Step 1 Preparation of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]azetidine-1-carboxylate
  • Step 2 Preparation of 2-[5-[(3R,4R)-1-(azetidin-3-ylsulfonyl)-3-methyl-4- piperidyl]-4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride)
  • Example 73 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]azetidin-1-yl]ethanone [769] A mixture of 2-[5-[(3R,4R)-1-(Azetidin-3-ylsulfonyl)-3-methyl-4-piperidyl]-4- chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride, 80 mg), DIPEA (1.5 mL), DCM (5 mL) and 1,4-dioxane (5 mL) was added acetyl chloride (30 mg).
  • Example 74 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]azetidine-1-carboxamide [771] A mixture of 2-[5-[(3R,4R)-1-(azetidin-3-ylsulfonyl)-3-methyl-4-piperidyl]-4- chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride, 50 mg), triethylamine (70 mg) and DCM (2 mL) was added isocyanato(trimethyl)silane (18 mg).
  • Example 75 Methyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]butanoate [773] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (1.8 mL) and DCM (6 mL) was added methyl 4- chlorosulfonylbutanoate (120 mg).
  • Example 76 Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]-2,2-dimethyl-propanoate [775] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (2 mL) and DCM (6 mL) was added methyl 3- chlorosulfonyl-2,2-dimethyl-propanoate (160 mg).
  • Example 77 Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate [777] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (2 mL) and DCM (7 mL) was added tert-butyl 3- (chlorosulfonylmethyl)azetidine-1-carboxylate (180 mg).
  • Example 78 2-[5-[(3R,4R)-1-(Azetidin-3-ylmethylsulfonyl)-3-methyl-4- piperidyl]-4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride) [779] A mixture of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate (102 mg) and DCM (3 mL) was added HCl (6N in iPrOH, 5 mL).
  • Example 79 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-2-methyl-pyridine [781] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (90 mg), DIPEA (1.5 mL), DCM (6 mL) was added 6-methylpyridine-3- sulfonyl chloride (115 mg).
  • Example 80 2-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethoxy]ethanol [783] Step 1: Preparation of 2-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethanol [784] To a stirred solution of 2-(2-hydroxyethoxy)ethanol (46.3 g, 437.0 mmol) in pyridine (34.5 g, 437.0 mmol) was added tert-butyl-chloro-diphenyl-silane (20.0 g, 72.8 mmol) dropwise at 0°C under nitrogen atmosphere.
  • Step 2 Preparation of S-[2-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethyl] ethanethioate
  • DIAD 1,3-bis(triphenyl)-2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethanol
  • Step 3 Preparation of 2-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethane sulfonyl chloride
  • S-[2-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethyl] 30 ethanethioate (10.6 g, 26.3 mmol) in acetonitrile (100 mL) was added 2 M HCl (4.74 mL) and NCS (14.1 g, 105.0 mmol) slowly at 0°C. The reaction mixture was stirred at 0°C for 15 min.
  • Step 4 Preparation of tert-butyl-[2-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2- pyridyl)-1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethoxy]ethoxy]-diphenyl-silane [790] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (85 mg), DIPEA (1.5 mL) and DCM (6 mL) was added 2-[2-[tert- butyl(diphenyl)silyl]oxyethoxy]ethanesulfonyl chloride (290 mg).
  • Step 5 Preparation of 2-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethoxy]ethanol [792] A mixture of tert-butyl-[2-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethoxy]ethoxy]-diphenyl-silane (170 mg) and THF (10 mL) was added TBAF (1M in THF, 1 mL).
  • Example 81 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]butanoic acid [794] A mixture of methyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]butanoate (115 mg), water (1.5 mL) and THF (6 mL) was added LiOH (22 mg).
  • Example 82 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- 30 methyl-1-piperidyl]sulfonyl]-2,2-dimethyl-propanoic acid [796] A mixture of methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]-2,2-dimethyl-propanoate (132 mg), water (1.5 mL) and THF (6 mL) was added LiOH (45 mg).
  • Example 83 2-[4-Chloro-5-[(3R,4R)-1-[(6-methoxy-3-pyridyl)sulfonyl]-3-methyl- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [798] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (80 mg), DIPEA (1.5 mL) and DCM (6 mL) was added 6-methoxypyridine-3- sulfonyl chloride (100 mg).
  • Example 84 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]butanamide [800] A mixture of 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]butanoic acid (92 mg), DIPEA (0.15 mL) and DMF (5 mL) was added EDC (55 mg) and HOBt (50 mg).
  • Example 85 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-2,2-dimethyl-propanamide [802] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-2,2-dimethyl-propanoic acid (112 mg), DIPEA (0.15 mL) and DMF (5 mL) was added EDC (65 mg) and HOBt (60 mg).
  • Example 86 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- 30 methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxamide [804] A mixture of 2-[5-[(3S,4S)-1-(azetidin-3-ylmethylsulfonyl)-3-methyl-4-piperidyl]- 4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride, 75 mg), triethylamine (0.3 mL) and DCM (3 mL) was added isocyanato(trimethyl)silane (50 mg).
  • Example 87 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-1H-pyridin-2-one [806] A mixture of 2-[4-chloro-5-[(3R,4R)-1-[(6-methoxy-3-pyridyl)sulfonyl]-3-methyl- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (50 mg), MeCN (3 mL) and NaI (50 mg) was added TMSCl (40 ⁇ L).
  • Example 88 2-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethoxy]acetic acid [808] A mixture of 2-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]ethoxy]ethanol (70 mg) and acetone (3 mL) was added Jones reagent (0.1 mL).
  • Example 89 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-tetrahydrofuran-3-ylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [810] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (50 mg), DIPEA (0.8 mL) and DCM (3 mL) was added tetrahydrofuran-3- sulfonyl chloride (55 mg).
  • Step 2 Preparation of oxetane-3-sulfonyl chloride
  • aqueous solution of NaClO (7.5%, 160 g, 0.161 mol) was added 1 M HCl (161 mL, 0.161 mol) dropwise at 0°C.
  • This solution was added into another solution of S- (oxetan-3-yl) ethanethioate (7.1 g, 53.7 mmol) in DCM (70 mL) at 0°C slowly.
  • the reaction mixture was stirred at 0°C for 0.5 h.
  • the reaction mixture was extracted with DCM (100 mL x 3).
  • Step 3 Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(oxetan-3-ylsulfonyl)-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 91 2-[4-Chloro-5-[(3R,4R)-1-[(2-methoxy-4-pyridyl)sulfonyl]-3-methyl- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 92 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-1H-pyridin-2-one [821] A mixture of 2-[4-chloro-5-[(3R,4R)-1-[(2-methoxy-4-pyridyl)sulfonyl]-3-methyl- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (100 mg), MeCN (5 mL) and NaI (100 mg) was added TMSCl (80 ⁇ L).
  • Example 93 Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoate [823] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (hydrochloride, 200 mg), DIPEA (0.43 mL) and DCM (4 mL) was added methyl 3-chlorosulfonylpropanoate (175 mg).
  • Example 94 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid [825] A mixture of methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoate (400 mg) and THF (5 mL) was added LiOH 2M (1 mL).
  • Example 95 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanamide [827] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (200 mg), DMF (2 mL) and DIPEA (0.33 mL) was added EDC (116 mg), HOBt (69 mg) and ammonium chloride (50 mg).
  • Step 2 Preparation of methyl (1r,3r)-3-(chlorosulfonyl)cyclobutane-1-carboxylate
  • Step 2 To a solution of methyl (1r,3r)-3-(chlorosulfonyl)cyclobutane-1-carboxylate (6 g, 32 mmol) in MeCN (30 mL) was added NCS (4.3 g, 32 mmol) and aqueous HCl (16 mL, 1M) at 0°C. The reaction mixture was stirred at 0°C for 1 h. The resulting mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3).
  • Step 3 Preparation of methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylate (isomer 1) and methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]cyclobutanecarboxylate (isomer 2) [834] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (120 mg), DIPEA (2 mL) and DCM (6 mL) was added methyl 3- chlorosulfon
  • Step 4 Preparation of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 1)
  • Example 97 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 2)
  • Example 98 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-N-methyl-propanamide [840] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (500 mg), DMF (3 mL) and DIPEA (1.25 mL) was added EDC (278 mg), HOBt (157 mg) and methanamine (hydrochloride, 200 mg).
  • Example 99 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]cyclobutanecarboxamide (isomer 1) [842] A mixture of 3-[[(3S,4S)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 1, 100 mg), DMF (4 mL) and DIPEA (0.2 mL) was stirred for 15 min, and added EDC (90 mg), HOBt (75 mg) and ammonium chloride (50 mg).
  • Example 100 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]cyclobutanecarboxamide (isomer 2)
  • Step 2 Preparation of (3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- N,N-bis(2-hydroxyethyl)-3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide
  • a mixture of 2-(2-hydroxyethylamino)ethanol (45 mg), DIPEA (0.3 mL) and DCM (4 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (35 mg).
  • Example 102 (3R,4R)-1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]pyrrolidine-3,4-diol [851] A mixture of (3R,4R)-pyrrolidine-3,4-diol (50 mg), DIPEA (0.2 mL) and DCM (4 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (35 mg).
  • Example 102 (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-N-(1H-tetrazol-5-ylmethyl)-3,6-dihydro-2H-pyridine-1-sulfonamide
  • a mixture of 1H-tetrazol-5-ylmethanamine (50 mg), DIPEA (0.5 mL) and DMF (4 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (35 mg).
  • Example 104 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]propyl acetate
  • Example 105 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]propan-1-ol [857] A mixture of methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]propyl acetate (61 mg) and THF (1 mL) was added LiOH (2M, 1 mL).
  • Example 106 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(3-hydroxyazetidin-1-yl)propan-1-one [859] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (500 mg), azetidin-3-ol (170 mg), DMF (5 mL) and DIPEA (0.83 mL) was added HATU (552 mg).
  • Example 107 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-methylsulfonyl-propanamide [861] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (50 mg), DMF (1 mL), DIPEA (0.15 mL) was added EDC (30 mg) and HOBt (20 mg).
  • Example 108 (5R)-5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]imidazolidine-2,4-dione [863] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (50 mg), DIPEA (0.8 mL) and DCM (3 mL) was added [(4R)-2,5- dioxoimidazolidin-4-yl]methanesulfonyl chloride (70 mg).
  • Example 109 (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N-[2- hydroxy-1-(hydroxymethyl)ethyl]-3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide
  • a mixture of (3R,4R)-pyrrolidine-3,4-diol (40 mg), DIPEA (0.5 mL) and DCM (4 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (40 mg).
  • Example 110 4-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]piperazin-2-one [867] A mixture of piperazin-2-one (30 mg), DIPEA (0.6 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (30 mg).
  • Example 111 (2S)-2-Amino-N-[[(3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanamide
  • Example 112 1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]azetidin-3-ol [871] A mixture of azetidin-3-ol (20 mg), DIPEA (0.6 mL), DMF (1 mL) and DCM (330 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (30 mg).
  • Example 113 (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-N-(2-oxopyrrolidin-3-yl)-3,6-dihydro-2H-pyridine-1-sulfonamide
  • Example 114 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetic acid [875] Step 1: Preparation of methyl 2-[[(3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetate [876] dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetic acid [877] A mixture of methyl 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-
  • Step 2 Preparation of 2-[[(3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetic acid [879] A mixture of methyl 2-[[(3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetate (36 mg), water (0.5 mL) and THF (2 mL) was added LiOH (7 mg).
  • Step 2 Preparation of 2-methoxypyrimidine-5-sulfonyl chloride
  • 2-methoxy-5-[(4-methoxyphenyl)methylsulfanyl]pyrimidine 5.9 g, 22.5 mmol
  • acetic acid 60 mL
  • water 20 mL
  • NCS 12.0 g, 90.0 mmol
  • the reaction mixture was stirred at room temperature for 2 h.
  • the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (80 mL x 3).
  • Step 3 Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]-2-methoxy-pyrimidine [886] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (71 mg), DIPEA (0.8 mL) and DCM (3 mL) was added 2-methoxypyrimidine- 5-sulfonyl chloride (105 mg).
  • Example 116 Methyl 2-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrazol-1-yl]acetate
  • Example 117 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetamide [890] A mixture of 2-[[(3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetic acid (40 mg), DMF (2.5 mL) and DIPEA (0.1 mL) was stirred for 15 min, and added EDC (25 mg), HOBt (22 mg) and ammonium chloride (15
  • Step 2 Preparation of pyrimidine-5-sulfonyl chloride [895] To a solution of aqueous HCl solution (1 N, 206 mL), NaClO (206 g) was added in portions.
  • Step 3 Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidine [897] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (50 mg), DIPEA (0.8 mL), DMF (0.5 mL) and DCM (2 mL) was added pyrimidine-5-sulfonyl chloride (100 mg).
  • Example 119 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-methyl-pyridin-2-one [899]
  • Step 1 Preparation of 4-[(4-methoxyphenyl)methylsulfanyl]-1 -methyl-pyridin-2- one [900] To a solution of 4-bromo-1-methyl-pyridin-2-one (4.0 g, 21.3 mmol) and (4- methoxyphenyl)methanethiol (3.61 g, 23.4 mmol) in toluene (50 mL) was added DIPEA (5.5 g, 42.5 mL).
  • Step 2 Preparation of 1-methyl-2-oxo-pyridine-4-sulfonyl chloride
  • Step 3 Preparation of 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]-1-methyl-pyridin-2-one [904] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (43 mg), DIPEA (0.7 mL), DMF (0.5 mL) and DCM (2 mL) was added 1- methyl-2-oxo-pyridine-4-sulfonyl chloride (95 mg).
  • Step 2 Preparation of 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]ethanol
  • ethyl 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]acetate 6.8 g, 24.6 mmol
  • LiAlH4 1.49 g, 39.4 mmol
  • the reaction mixture was stirred overnight at RT.
  • LCMS showed the reaction was completed.
  • the mixture was quenched with water (1.49 mL), NaOH (20%, 1.49 mL), water (4.5 mL) and was filtrated to afford the crude product.
  • Step 3 Preparation of 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]ethyl 4- methylbenzenesulfonate
  • 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]ethanol 3.6 g, 15.6 mmol
  • N,N-diethylethanamine 3.11 g, 30.7 mmol
  • 4-methylbenzenesulfonyl chloride (4.39 g, 23.1 mmol) slowly at 0°C.
  • the reaction mixture was stirred overnight. LCMS showed the reaction was completed.
  • Step 4 Preparation of S-[2-[(4-methoxyphenyl)methyl]tetrazol -5-yl]ethyl] ethanethioate
  • 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]ethyl 4- methylbenzenesulfonate (4.3 g, 11.1 mmol) in DMF (30 mL) ⁇ were added ethanethioic S-acid (1.69 g, 22.1 mmol) and potassium carbonate (6.12 g, 44.3 mmol). The reaction mixture was stirred at 60°C for 16 hours. LCMS showed the reaction was completed.
  • Step 5 Preparation of 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]ethanesulfonyl chloride [915] To a solution of 1-chloropyrrolidine-2,5-dione (333 mg) in ACN (5 mL) was added hydrogen chloride (3 mL) slowly, the mixture was stirred at 0°C for 15 mins. S-[2-[(4- methoxyphenyl)methyl]tetrazol-5-yl]ethyl] ethanethioate (292 mg) was added. The reaction 30 was stirred at 0°C for 30 mins. LCMS showed the reaction was completed.
  • Step 6 Preparation of 2-[4-chloro-5-[(3R,4R)-1-[2-[2-[(4- methoxyphenyl)methyl]tetrazol-5-yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]- 5-fluoro-pyridine
  • a mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine 70 mg
  • DIPEA 1.5 mL
  • DMF 1.0 mL
  • DCM 4- mL
  • Example 121 2-[4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrazol-1-yl]acetic acid [919] A mixture of methyl 2-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrazol-1-yl]acetate (56 mg), water (1 mL) and THF (4 mL) was added LiOH (10 mg).
  • Example 122 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-ol [921] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-2-methoxy-pyrimidine (60 mg), water (1 mL) and THF (4 mL) was added LiOH (11 mg).
  • Example 124 Methyl 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoate [926] Step 1: Preparation of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-5-methyl-3,6-dihydro-2H-pyridine-1-carboxylate [927] To a solution of 2-[[5-bromo-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane (5 g, 13.4 mmol) in 1,4-
  • Step 2 Preparation of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-5-methyl-3,6-dihydro-2H-pyridine-1-carboxylate [929] To a solution of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-5-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (2 g, ⁇ 4.09 mmol) in THF (20 mL) was added NCS (653 mg, 4.91 mmol) in several portions at RT (water bath).
  • Step 3 Preparation of 2-[4-chloro-5-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl]-5-fluoro-pyridine
  • Step 4 Preparation of methyl 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-5-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoate [933] A mixture of 2-[4-chloro-5-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol- 2-yl]-5-fluoro-pyridine (150 mg), DIPEA (0.3 mL) and DCM (5 mL) was added methyl 3- chlorosulfonylpropanoate (105 mg).
  • Step 2 Preparation of 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanamide [938] A mixture of 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl- 3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was stirred for 15 min, and added EDC (20 mg), HOBt (9.5 mg) and ammonium chloride (7.5 mg).
  • Example 126 3-[[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl- 3,6-dihydro-2H-pyridin-1-yl]sulfonyl]-1-(3-hydroxyazetidin-1-yl)propan-1-one [940] A mixture of 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl- 3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was stirred for 15 min, and added EDC (20 mg), HOBt (9.5 mg) and azetidin-3-ol (10 mg
  • Example 127 3-[[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl- 3,6-dihydro-2H-pyridin-1-yl]sulfonyl]-N-cyclopropyl-propanamide
  • Example 128 (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-3,6-dihydro-2H-pyridine-1-sulfonamide
  • Example 129 [1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]azetidin-3-yl]methanol [946] A mixture of azetidin-3-ylmethanol (30 mg), DIPEA (0.8 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride (40 mg).
  • Example 130 N-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]piperidine-3-carboxamide [948] A mixture of piperidine-3-carboxamide (45 mg), DIPEA (0.8 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride (40 mg).
  • Example 131 (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N-[(2S)- 2-hydroxypropyl]-3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide
  • a mixture of (2S)-1-aminopropan-2-ol (25 mg), DIPEA (0.8 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride (40 mg).
  • Example 132 and Example 133 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonylamino]-N,N-dimethyl- acetamide and 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylamino]-N,N-dimethyl-acetamide [952] A mixture of 2-amino-N,N-dimethyl-acetamide (35 mg), DIPEA (0.8 mL), DMF (1 mL) and DCM (3
  • Example 134 Tert-butyl (3S,4S)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-piperidine-1-carboxylate
  • Step 1 Preparation of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidine-1-carboxylate
  • Step 2 Preparation of tert-butyl (3S,4S)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-piperidine-1-carboxylate
  • the isomeric mixture tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidine-1-carboxylate (85 g, crude) was separated by preparative chiral HPLC to afford tert-butyl (3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H
  • Example 135 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6- dihydro-2H-pyridine-1-sulfonamide
  • Step 1 Preparation of tert-butyl N-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-5-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]carbamate
  • Step 2 Preparation of 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5- methyl-3,6-dihydro-2H-pyridine-1-sulfonamide
  • Example 136 2-Chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidine
  • Example 137 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylpyrazol-4-yl)sulfonyl- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [970] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (63 mg), DIPEA (1 mL) and DCM (3 mL) was added 1-methylpyrazole-4- sulfonyl chloride (100 mg).
  • Example 138 (3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N,3- dimethyl-piperidine-1-carboxamide
  • Example 139 1-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]azetidin-3-ol [974] A mixture of azetidin-3-ol (17 mg), DIPEA (0.5 mL) and DMF (2 mL) was added 2-chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine (33 mg).
  • Example 140 2-[[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]amino]ethanol [976] A mixture of 2-aminoethanol (15 mg), DIPEA (0.5 mL) and DMF (2 mL) was added 2-chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine (33 mg).
  • Step 2 Preparation of 2-(1-methyltetrazol-5-yl)ethanol
  • ethyl 2-(1-methyltetrazol-5-yl)acetate 6.1 g, 35.8 mmol
  • MeOH 60 mL
  • sodium borohydride 2.71 g, 71.7 mmol
  • the resulting solution was stirred at room temperature for 1 h.
  • the reaction mixture was quenched with water (20 mL) and concentrated.
  • Step 3 Preparation of O-[2-(1-methyltetrazol-5-yl)ethyl] ethanethioate [983] To a solution of triphenylphosphine (20.3 g, 77.3 mol) in dry THF (200 mL) was added DIAD (15.6 g, 77.3 mmol) dropwise at 0°C under nitrogen atmosphere.
  • Step 5 Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-[2-(1-methyltetrazol-5- yl)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 142 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-amine [989]
  • Step 2 Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-amine
  • Example 143 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyridin-2-amine [994]
  • Step 1 Preparation of 2-aminopyrimidine-5-sulfonyl chloride
  • a mixture of pyrimidin-2-amine (5.0 g, ⁇ 52.6 mmol) and sulfurochloridic acid (50 mL) was stirred at 150°C for 4 hrs. The mixture was poured into water (50 mL) and extracted with DCM (50 mL x 3).
  • Step 2 Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyridin-2-amine [997] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (65 mg), DIPEA (1 mL) and DCM (3 mL) was added 6-aminopyridine-3- sulfonyl chloride (192 mg).
  • Example 144 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-cyclopropyl-pyrimidin-2-amine [999] A mixture of cyclopropanamine (14 mg), DIPEA (0.5 mL) and DMF (2 mL) was added 2-chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine (33 mg).
  • Example 145 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-methyl-pyrrolidin-2-one [1001] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (65 mg), DIPEA (1 mL) and DCM (3 mL) was added 1-methyl-5-oxo- pyrrolidine-3-sulfonyl chloride (100 mg).
  • Example 146 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-methyl-pyrimidin-2-amine [1003] A mixture of methanamine (10 mg), DIPEA (1 mL) and DMF (1.5 mL) was added 2-chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine (33 mg).
  • Example 147 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N,N-bis(trideuteriomethyl)propanamide [1005] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 ⁇ L) was added EDC (20 mg) and HOBt (9.4 mg).
  • Example 148 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(2-hydroxy-2-methyl-propyl)propanamide [1007] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 ⁇ L) was added EDC (20 mg) and HOBt
  • Example 149 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-cyclopropyl-propanamide [1009] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 ⁇ L) was added EDC (20 mg) and HOBt (9.4 mg).
  • Example 150 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-[(3R)-3-hydroxypyrrolidin-1-yl]propan-1-one [1011] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 ⁇ L) was added EDC (20 mg) and HOBt (9.4 mg).
  • Example 151 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-[(3S)-3-hydroxypyrrolidin-1-yl]propan-1-one [1013] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 ⁇ L) was added EDC (20 mg) and HOBt (9.
  • Example 152 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(3-methoxyazetidin-1-yl)propan-1-one [1015] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 ⁇ L) was added EDC (20 mg) and HOBt (9.4 mg
  • Example 153 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(3-hydroxy-3-methyl-azetidin-1-yl)propan-1-one [1017] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 ⁇ L) was added EDC (20 mg) and HOBt (9.4 mg).
  • Example 154 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-1-(4-hydroxy-1-piperidyl)propan-1-one [1019] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 ⁇ L) was added EDC (20 mg) and HOBt (9.4 mg).
  • Example 155 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(2-methoxyethyl)propanamide [1021] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 ⁇ L) was added EDC (20 mg) and HOBt (9.4 mg).
  • Example 156 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(2-methyltetrazol-5- yl)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1023] Step 1: Preparation of ethyl 2-(2-methyltetrazol-5-yl)acetate [1024] To a stirred suspension of ethyl 2-(1H-tetrazol-5-yl)acetate (10.5 g, 67.2 mmol) in MeCN (100 mL) was added potassium carbonate (9.29 g, 67.2 mmol) slowly.
  • Step 2 Preparation of 2-(1-methyltetrazol-5-yl)ethanol
  • ethyl 2-(1-methyltetrazol-5-yl)acetate 4.2 g, 24.7 mmol
  • MeOH 40 mL
  • sodium borohydride 1.87 g, 49.4 mmol
  • the resulting mixture was stirred at room temperature for 1 h.
  • the reaction was quenched with water (30 mL) and concentrated.
  • Step 3 Preparation of O-[2-(2-methyltetrazol-5-yl)ethyl] ethanethioate [1028] To a stirred solution of triphenylphosphine (14.0 g, 53.2 mol) in dry THF (140 mL) was added DIAD (10.8 g, 53.2 mmol) dropwise at 0 °C under nitrogen atmosphere.
  • Step 4 Preparation of (2-(2-methyltetrazol-5-yl)ethanesulfonyl chloride [1030] To a stirred solution of O-[2-(2-methyltetrazol-5-yl)ethyl] ethanethioate (11.5 g, crude) in MeCN (100 mL) was added 2 M HCl (72.6 mL, 145.2 mmol) dropwise followed by NCS (8.08 g, 60.5 mmol) in portions at 0 °C. The reaction mixture was stirred at 0 °C for 2 h.
  • the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage 80 g silica gel column, eluting with 0%-25% ethyl acetate in petroleum ether) to give the crude product, into which was added water (100 mL). The mixture was stirred at 100 °C for 1 h, cooled to room temperature and extracted with ethyl acetate (50 mL x 3). The aqueous phase was concentrated under reduced pressure. The residue was dissolved in POCl3 (37.1 g, 242.0 mmol).
  • Step 5 Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-[2-(2-methyltetrazol-5- yl)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 157 Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]azetidine-1-carboxylate [1034] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (2 mL) and DCM (6 mL) was added tert-butyl 3- chlorosulfonylazetidine-1-carboxylate (120 mg).
  • Example 158 2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]acetamide
  • Step 1 Preparation of methyl 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]acetate
  • Step 2 Preparation of 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]acetic acid [1039] A mixture of methyl 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]acetate (42 mg), water (1.0 mL) and THF (4 mL) was added LiOH (8 mg).
  • Step 3 Preparation of 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]acetamide
  • Example 159 Tert-butyl N-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]thiazol-2-yl]carbamate [1043] Step 1: Preparation of tert-butyl N-[4-(chloromethyl)thiazol-2-yl]carbamate [1044] A mixture of 4-(chloromethyl)thiazol-2-amine (hydrochloride, 10 g, 54 mmol), TEA (16.4 g, 162 mmol) and DMAP (cat.) in THF (150 mL) was stirred at room temperature for 5 min.
  • Boc2O (14.2 g, 64.8 mmol) was added in portions. After addition, the mixture was stirred at room temperature for 16 h. The mixture was concentrated. The residue was poured into 150 mL water. The water layer was extracted with EtOAc (150 mL x 3). Organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (30% EtOAc in PE) to afford the subtitle compound (5.4 g, 40% yield) as yellow solid. MS m/z 249 [M+H]+.
  • Step 2 Preparation of S-[[2-(tert-butoxycarbonylamino)thiazol-4-yl]methyl] ethanethioate
  • Step 3 Preparation of [2-(tert-butoxycarbonylamino)thiazol-4-yl]methanesulfonic acid
  • a mixture of S-[[2-(tert-butoxycarbonylamino)thiazol-4-yl]methyl] ethanethioate (100 mg, 0.35 mmol) in HCOOH/ H2O (10/10 mL) was stirred at room temperature.
  • H2O2 (4 g, 35 mmol) was added dropwise. After addition, the mixture was stirred at room temperature for 3 h.
  • Step 4 Preparation of tert-butyl N-[4-(chlorosulfonylmethyl)thiazol-2- yl]carbamate
  • a mixture of [2-(tert-butoxycarbonylamino)thiazol-4-yl]methanesulfonic acid (600 mg, 2 mmol mmol) in DCM (10 mL) was stirred at room temperature.
  • DMF cat.
  • the mixture was stirred at 0°C.
  • Step 5 Preparation of tert-butyl N-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]thiazol-2-yl]carbamate
  • Example 160 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[(1-methylsulfonylazetidin-3- yl)methylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Step 1 Preparation of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate [1055] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-
  • Step 2 Preparation of 2-[5-[(3R,4R)-1-(azetidin-3-ylmethylsulfonyl)-3-methyl-4- piperidyl]-4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine
  • a mixture of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate (135 mg) and DCM (5 mL) was added HCl (6M in iPrOH, 10 mL).
  • Step 3 Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-[(1- methylsulfonylazetidin-3-yl)methylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • a mixture of 2-[5-[(3R,4R)-1-(azetidin-3-ylmethylsulfonyl)-3-methyl-4-piperidyl]- 4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (30 mg), DIPEA (0.4 mL) and DCM (2 mL) was added methanesulfonyl chloride (15 mg).
  • Example 161 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylsulfonylazetidin-3- yl)sulfonyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Step 1 Preparation of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate
  • Step 2 Preparation of 2-[5-[(3R,4R)-1-(azetidin-3-ylsulfonyl)-3-methyl-4- piperidyl]-4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Step 3 Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(1- methylsulfonylazetidin-3-yl)sulfonyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • a mixture of 2-[5-[(3R,4R)-1-(azetidin-3-ylsulfonyl)-3-methyl-4-piperidyl]-4- chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (30 mg), DIPEA (0.4 mL) and DCM (2 mL) was added methanesulfonyl chloride (15 mg).
  • Example 162 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonylmethyl]thiazol-2-amine [1068] A mixture of tert-butyl N-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]thiazol-2-yl]carbamate (50 mg) and DCM (3 mL) was added HCl (6M in iPrOH, 6 mL).
  • Example 163 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidin-1-yl]ethanone [1070] A mixture of 2-[5-[(3R,4R)-1-(azetidin-3-ylmethylsulfonyl)-3-methyl-4-piperidyl]- 4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (30 mg), DIPEA (0.4 mL) and DCM (2 mL) was added acetyl chloride (10 mg).
  • Example 164 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(trideuteriomethyl)propanamide [1072] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg).
  • Example 165 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(oxetan-3-yl)propanamide [1074] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg).
  • Example 166 2-[4-Chloro-5-[(3R,4R)-1-(1H-imidazol-4-ylsulfonyl)-3-methyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1076] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (28 mg), DIPEA (0.4 mL) and DCM (2 mL) was added 1H-imidazole-4- sulfonyl chloride (15 mg).
  • Example 167 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-ethyl-propanamide [1078] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg).
  • Example 168 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(4-hydroxy-4-methyl-1-piperidyl)propan-1-one [1080] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU
  • Example 169 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-morpholino-propan-1-one [1082] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), morpholine (12 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg
  • Example 170 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(cyclopropylmethyl)propanamide [1084] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), cyclopropylmethanamine (10 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg).
  • Example 171 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-pyrrolidin-1-yl-propan-1-one [1086] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), pyrrolidine (10 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg).
  • Example 172 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(2,2,2-trifluoroethyl)propanamide [1088] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 2,2,2-trifluoroethanamine (14 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg).
  • Example 173 Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate [1090] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (45 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added methyl carbonochloridate (12 mg).
  • Example 174 Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]azetidine-1-carboxylate [1092] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (33 mg), DIPEA (0.4 mL) and DCM (2 mL) was added methyl carbonochloridate (12 mg).
  • Example 175 N-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethyl]acetamide [1094] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (35 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added acetyl chloride (10 mg).
  • Example 176 N-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethyl]methanesulfonamide [1096] A mixture of 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]ethanamine (27 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added methanesulfonyl chloride (15 mg).
  • Example 177 Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]furan-2-carboxylate [1098] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (35 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added methyl 5- chlorosulfonylfuran-2-carboxylate (25 mg).
  • Example 178 5-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethyl]-3-methyl-1,2,4-oxadiazole [1100] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (122 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (110 mg).
  • Example 179 Tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-lH- imidazol-5-yl]-3-methyl-l-piperidyl]sulfonyl]ethyl]carbamate
  • Step 1 Preparation of tetrabutylammonium 2-(tert-butoxycarbonylamino) ethanesulfonate
  • Step 2 Preparation of tert-butyl N-(2-chlorosulfonylethyl)carbamate
  • Step 3 Preparation of tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1 H-imidazol-5-yl] -3 -methyl- 1 -piperidyl] sulfonyl] ethyl] carbamate
  • Example 180 2-[4-Chloro-5-[(3R,4R)-l-[2-[l-[(4-methoxyphenyl)methyl]triazol-
  • Step 1 Preparation of 4-(2-bromoethyl)-l-[(4-methoxyphenyl)methyl]triazole
  • Step 2 Preparation of S-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethyl] ethanethioate
  • Step 3 Preparation of 2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl] ethanesulfonic acid
  • a mixture of S-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethyl] ethanethioate (2.0 g, 6.9 mmol) in HCOOH (10 mL) was stirred at room temperature.
  • H2O2 (30% aqueous solution, 4 g, 35 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 6 h. Then water (50 mL) was added.
  • Step 4 Preparation of 2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethanesulfonyl chloride
  • a mixture of [2-(tert-butoxycarbonylamino)thiazol-4-yl]methanesulfonic acid (1.8 g, 6 mmol) in DCM (30 mL) was stirred at room temperature.
  • DMF cat.
  • the mixture was stirred at 0°C.
  • Step 5 Preparation of 2-[4-chloro-5-[(3R,4R)-1-[2-[1-[(4- methoxyphenyl)methyl]triazol-4-yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine
  • Example 181 2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]ethanamine (hydrochloride)
  • Example 182 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-[(1-hydroxycyclopropyl)methyl]propanamide [1122] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 1-(aminomethyl)cyclopropanol (12 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg).
  • Example 183 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]propan-1-one [1124] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 3-(trifluoromethyl)pyrrolidin-3-ol (hydrochloride, 27 mg), (DMF (0.5 mL) and
  • Example 184 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(oxetan-3-ylmethyl)propanamide [1126] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), oxetan-3-ylmethanamine (12 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg).
  • Example 185 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-1-one [1128] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 2-oxa-7-azaspiro[3.5]nonane (18 mg), (DMF (0.5 mL) and DIPEA (0.05
  • Example 186 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(4-methoxy-1-piperidyl)propan-1-one [1130] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 4-methoxypiperidine (16 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg).
  • Example 187 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-tetrahydropyran-4-yl-propanamide [1132] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), tetrahydropyran-4-amine (14 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg).
  • Example 188 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-[(3S)-tetrahydropyran-3-yl]propanamide [1134] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), (S)-tetrahydro-2H-pyran-3-amine (hydrochloride, 20 mg), (DMF (0.5 mL) and DIPEA (
  • Example 189 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propan-1-one [1136] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 2-oxa-6-azaspiro[3.3]heptane (14 mg), (DMF (0.5 mL) and DIPEA (
  • Example 190 2-[4-Chloro-5-[(3R,4R)-1-(2-methoxyethylsulfonyl)-3-methyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 191 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-tetrahydropyran-4-ylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 192 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(tetrahydrofuran-3- ylmethylsulfonyl)-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 193 N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]thiazol-2-yl]acetamide [1144] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (60 mg), DIPEA (1 mL) and DCM (5 mL) was added 2-acetamidothiazole-5- sulfonyl chloride (100 mg).
  • Example 194 N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]-4-methyl-thiazol-2-yl]acetamide [1146] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (60 mg), DIPEA (1 mL) and DCM (5 mL) was added 2-acetamido-4-methyl- thiazole-5-sulfonyl chloride (100 mg).
  • Example 195 Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]pyridine-2-carboxylate [1148] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (1 mL) and DCM (5 mL) was added methyl 5- chlorosulfonylpyridine-2-carboxylate (100 mg).
  • Example 196 Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrrolidine-1-carboxylate [1150] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (120 mg), DIPEA (1.2 mL) and DCM (6 mL) was added tert-butyl 3- chlorosulfonylpyrrolidine-1-carboxylate (150 mg).
  • Example 197 Tert-butyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]piperidine-1-carboxylate [1152] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (120 mg), DIPEA (1.2 mL) and DCM (6 mL) was added tert-butyl 4- chlorosulfonylpiperidine-1-carboxylate (150 mg).
  • Example 198 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(1H-triazol-4- yl)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1154] A mixture of 2-[4-chloro-5-[(3R,4R)-1-[2-[1-[(4-methoxyphenyl)methyl]triazol-4- yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (50 mg) and TFA (5 mL) was stirred at 80°C for 8h.
  • Example 199 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(4-piperidylsulfonyl)-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride)
  • Example 200 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-pyrrolidin-3-ylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride)
  • Example 201 Tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethylsulfamoyl]carbamate [1160] A mixture of 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]ethanamine (hydrochloride, 30 mg) and DCM (2 mL) was added DIPEA (0.3 mL).
  • Example 202 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]thiazol-2-amine [1162] A mixture of N-[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]thiazol-2-yl]acetamide (49 mg) and EtOH (2 mL) was added HCl (6N, 2 mL).
  • Example 203 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-4-methyl-thiazol-2-amine [1164] A mixture of N-[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]-4-methyl-thiazol-2-yl]acetamide (45 mg) and EtOH (2 mL) was added HCl (6N, 2 mL).
  • Example 204 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyridine-2-carboxylic acid [1166] A mixture of methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]pyridine-2-carboxylate (120 mg), water (1.5 mL) and THF (6 mL) was added LiOH (20 mg).
  • Example 205 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonylmethyl]-5-methyl-1,2,4-oxadiazole
  • Example 206 1-[4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]-1-piperidyl]ethanone [1170] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(4-piperidylsulfonyl)-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (30 mg), DIPEA (0.5 mL) and DCM (2 mL) was added acetyl chloride (10 mg).
  • Example 207 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[(1-methylsulfonyl-4- piperidyl)sulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1172] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(4-piperidylsulfonyl)-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (30 mg), DIPEA (0.5 mL) and DCM (2 mL) was added methanesulfonyl chloride (15 mg).
  • Example 208 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2- (sulfamoylamino)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 209 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylsulfonylpyrrolidin-3- yl)sulfonyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 210 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrrolidin-1-yl]ethanone [1178] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-pyrrolidin-3-ylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride, 45 mg), DIPEA (0.5 mL) and DCM (3 mL) was added acetyl chloride (15 mg).
  • Example 211 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyridine-2-carboxamide
  • Example 212 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyrrolidine-1-carboxamide [1182] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-pyrrolidin-3-ylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride, 50 mg), triethylamine (0.35 mL) and DCM (5 mL) was added isocyanato(trimethyl)silane (20 mg).
  • Step 2 Preparation of 1H-1,2,3-triazole-4-sulfonyl chloride
  • a solution of 4-(1H-triazol-4-yldisulfanyl)-1H-triazole (3.2 g, 16 mmol) in CHCl3 (30 mL) were added potassium nitrate (4.04 g, 40 mmol) and trimethylsilyl chloride (4.34 g, 40 mmol) and stirred vigorously at 50°C for 48 h.
  • the reaction mixture was cooled to room temperature and filtered.
  • the filtrate was concentrated under reduced pressure to afford the subtitle compound (1.21 g, 45%) as a white solid.
  • Step 3 Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(1H-triazol-4- ylsulfonyl)-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine 40 mg
  • DIPEA 0.5 mL
  • DCM 2.5 mL
  • Example 214 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]furan-2-carboxamide
  • Step 1 Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]furan-2-carboxylic acid [1192] A mixture of methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulf
  • Step 2 Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]furan-2-carboxamide
  • Example 215 2-[4-Chloro-5-[(3R,4R)-3-methyl-1- (methylsulfonylmethylsulfonyl)-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 216 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3- methylsulfonylpropylsulfonyl)-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine
  • Example 217 [5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-2-furyl]-(3-hydroxyazetidin-1-yl)methanone [1200] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]furan-2-carboxylic acid (50 mg), azetidin-3-ol (25 mg), (DMF (1 mL) and DIPEA (0.1 mL) was added HATU (80 mg).
  • Step 2 Preparation of 3-((4-methoxybenzyl)thio)propanoic acid [1205] To a solution of ethyl 3-[(4-methoxyphenyl)methylsulfanyl]propanoate (8 g, 31.5 mmol) in THF (100 mL) and H2O (50 mL) was added NaOH (12.6 g, 315.6 mmol), and the mixture was stirred at RT for 16hours.
  • Step 3 Preparation of 3-((4-methoxybenzyl)thio)propanoyl chloride
  • 3-((4-methoxybenzyl)thio)propanoic acid 5 g, 22.1 mmol
  • DMF 0.5 mL
  • (COCl)2 3.4 g, 26.5 mmol
  • the mixture was concentrated to afford the subtitle compound (5.2 g, yield: 100%) as a colorless oil.
  • Step 4 Preparation of 2-(3-((4-methoxybenzyl)thio)propanoyl)hydrazine-1- carboxamide
  • DIPEA 11.0 g, 85.2 mmol
  • H2O 20 mL
  • 3-((4-methoxybenzyl)thio)propanoyl chloride 5.2 g, 21.3 mmol
  • the mixture was concentrated and diluted with EtOAc (100 mL) and H2O (100 mL).
  • Step 5 Preparation of 2-(3-((4-methoxybenzyl)thio)propanoyl)hydrazine-1- carboxamide
  • 2-(3-((4-methoxybenzyl)thio)propanoyl)hydrazine-1-carboxamide 6.0 g, 21.2 mmol
  • NaOH 2M, 150 mL
  • the mixture was stirred at 100°C for 16 hours.
  • the mixture was concentrated and diluted with EtOAc (100 mL) and H2O (100 mL).
  • the organic phase was separated.
  • the aqueous layer was extracted with EA (100 mL ⁇ 2).
  • Step 6 Preparation of 2-(5-oxo-1,4-dihydro-1,2,4-triazol-3-yl)ethanesulfonyl chloride [1213] To a solution of NCS (1.12 g, 13.4 mmol), HCl (1M, 0.671 mL, 0.671 mmol) in MeCN (9 mL) was added 3-[2-[(4-methoxyphenyl)methylsulfanyl]ethyl]-1,4-dihydro-1,2,4- triazol-5-one (890.0 mg, 3.35 mmol) in portions under ice/water bath cooling.
  • Step 7 Preparation of 3-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethyl]-1,4-dihydro-1,2,4-triazol-5-one [1215] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (40 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added 2-(5-oxo-1,4- dihydro-1,2,4-triazol-3-yl)ethanesulfonyl chloride (35 mg).
  • Example 219 Tert-butyl N-[6-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyridazin-3-yl]carbamate
  • Step 1 Preparation of tert-butyl N-(6-carbamimidoylsulfanylpyridazin-3- yl)carbamate
  • Step 2 Preparation of tert-butyl N-(3-thioxo-4H-pyridazin-6-yl)carbamate
  • Step 3 Preparation of tert-butyl N-(6-chlorosulfonylpyridazin-3-yl)carbamate
  • NaClO (13.1 g, 132 mmol) was stirred at 0°C.
  • HCl 0.1 M, 132 mL, 132 mmol
  • the mixture was stirred at 0°C for 15 min.
  • a solution of tert-butyl N-(3-thioxo-4H-pyridazin-6-yl)carbamate (1.0 g, 4.4 mmol) in CH3CN (5 mL) was prepared.
  • the NaClO-HCl mixture was added dropwise at 0°C.
  • Step 4 Preparation of tert-butyl N-[6-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyridazin-3-yl]carbamate
  • Example 220 6-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyridazin-3-amine
  • Step 2 Preparation of methyl 5-chlorosulfonylpyrimidine-2-carboxylate [1231] To a solution of NCS (3.68 g, 27.6 mmol), 2 M HCl (0.7 mL, 1.4 mmol) in MeCN (40 mL) was added methyl 5-[(4-methoxyphenyl)methylsulfanyl]pyrimidine-2-carboxylate (2.0 g, 6.89 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure (water bath temperature below 30 °C). The mixture was poured into water (40 mL) and extracted with DCM (40 mL x 3).
  • Step 3 Preparation of methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidine-2-carboxylate [1233] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (1.5 mL) and DCM (6 mL) was added methyl 5- chlorosulfonylpyrimidine-2-carboxylate (100 mg).
  • Example 222 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyrimidine-2-carboxylic acid [1235] A mixture of methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidine-2-carboxylate (112 mg), water (2 mL) and THF (8 mL) was added LiOH (20 mg).
  • Example 223 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyrimidine-2-carboxamide [1237] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyrimidine-2-carboxylic acid (50 mg), DMF (2 mL) and DIPEA (0.3 mL) was added HATU (80 mg).

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Abstract

Disclosed are compounds of formula (I), or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R1, R2, A, and n are defined herein. Also disclosed are methods of preparing such compounds, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders.

Description

PYRIDYL IMIDAZOLES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
CROSS-REFERENCE TO RELATED APPLICATIONS
[1] This application claims priority to European Application No. 23306385.8, filed August 17, 2023, the disclosure of which is incorporated by reference herein in its entirety.
TECHNICAL FIELD
[2] Disclosed herein are substituted pyridyl imidazole compounds, processes for their preparation, pharmaceutical compositions containing the compounds, as well as therapeutic uses thereof.
BACKGROUND
[3] MRGPRX2 is a G-protein coupled receptor (GPCR) expressed on mast cells involved in inflammation pathways, including the non-histaminergic activation of mast cells. See Meixong, J., et al., Immunity, 50, 1163-1171 (2019). MRGPRX2 is a member of the X subfamily of the Mas family of GPCRs. MRGPRX2 is activated by numerous secretagogues, including neuropeptides, eosinophil granule proteins, and antimicrobial peptides. In response to MRGPRX2 activation, mast cells may undergo degranulation and release tryptase, which preferentially triggers non-histaminergic itch, as well as chymase, carboxipeptidases, histamine, serotonin, chemokines, and cytokines. See Corbiere, A., et al., Experimental Dermatology 30, 193-200 (2020). This activation can lead to type 2 inflammation, pruritis, and pain. Preclinical data demonstrates that blocking the activation of MRGPRX2 has the potential to effectively treat a range of mast-cell-mediated diseases. See, e.g., Meixong, J., et al.; Ogasawara, H. & Noguchi, M., Cells, 10, 2906 (2021); Quan, P.L., et al., Inti. J. Molecular Sciences, 22, 4421 (2021); Al Hamwi, G., et al., Pharmacology & Therapeutics, 2:38, 108529 (2022).
[4] Currently used treatments for inflammatory diseases typically have one or more of the following drawbacks: limited efficacy, need for injection, or significant side effects. MRGPRX2 antagonists of the present disclosure may provide safe, oral, and efficacious treatments for diseases, disorders and conditions involving inflammation, itch, and/or pain.
BRIEF SUMMARY [5] The present disclosure describes substituted pyridyl imidazole compounds, processes for their preparation, pharmaceutical compositions containing the compounds, as well as therapeutic uses thereof. [6] One aspect of the present disclosure is a compound of formula I
Figure imgf000003_0001
, wherein: A is selected from ,
Figure imgf000003_0002
each
Figure imgf000003_0003
is a single or a double bond, provided two adjacent are not both
Figure imgf000003_0004
double bonds; each instance of R1 is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R2 is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; each instance of R3 is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R4 is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R4P is selected from hydrogen, halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, - OC(=O)R6, -OC(=O)OR7, -OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, - NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, - S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, aryl, C1-C3 arylalkyl, monocyclic heteroaryl, and C1-C3 heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, - (CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(arylene)R13, heterocyclyl, or -(heterocyclylene)R13; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, aryl, C1-C3 arylalkyl, heteroaryl, and C1-C3 heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, - OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, or -NR9S(=O)2NR11R12; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or more R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C3 3-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or more R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), - C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)OH, -OC(=O)O(C1-C4 alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), - NHC(=O)(C1-C4 alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4 alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4 alkyl), -NHC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)(C1- C4 alkyl), -N(C1-C4 alkyl)C(=O)OH, -N(C1-C4 alkyl)C(=O)O(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)NH2, -N(C1-C4 alkyl)C(=O)NH(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qOH, -(CH2)qO(C1-C4 alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4 alkyl), -(CH2)qN(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qC(=O)(C1-C4 alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4 alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4 alkyl), - (CH)qC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a heterocyclyl ring; X1 is halogen; m is 0 or 1; n is 1 or 2; each p is independently 1, 2, or 3; and each q is independently 1, 2, or 3; wherein when
Figure imgf000006_0001
, R4 and R5 may be taken together with the carbons connecting them to form a 5- or 6-membered heterocyclyl ring; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure imgf000006_0002
. [7] One embodiment is a compound of formula I, wherein:
A is selected from
Figure imgf000007_0001
R1 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R2 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; each instance of R3 is independently selected from halogen, -OR11, -NR11R12, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R4 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R4P is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -SR7, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, phenyl, C1-C3 phenylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O- )R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, - (CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(phenylene)R13, 4- to 6- membered heterocyclyl, or -(4- to 6-membered heterocyclene)R13; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, phenyl, C1-C3 phenylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, or - S(=O)(=NR9)NR11R12; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C3 3-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), - C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)OH, -OC(=O)O(C1-C4 alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), - NHC(=O)(C1-C4 alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4 alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4 alkyl), -NHC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)(C1- C4 alkyl), -N(C1-C4 alkyl)C(=O)OH, -N(C1-C4 alkyl)C(=O)O(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)NH2, -N(C1-C4 alkyl)C(=O)NH(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qOH, -(CH2)qO(C1-C4 alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4 alkyl), -(CH2)qN(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qC(=O)(C1-C4 alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4 alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4 alkyl), - (CH)qC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4- to 6-membered heterocyclyl ring; m is 0 or 1; n is 1; each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [8] One embodiment is a compound of formula I, wherein: A is selected from
Figure imgf000009_0001
R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10, - NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pC(=O)OR11, -(CH2)p(phenylene)R13, or –(4- to 6- membered heterocyclene)R13; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, 4- to 6-membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6- membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -OC(=O)(C1-C4 alkyl), -OC(=O)O(C1-C4 alkyl), -(CH2)qOH, and - S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4-membered heterocyclyl ring; m is 0; n is 1; each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [9] One embodiment is a compound of formula I, wherein: A is selected from
Figure imgf000011_0001
R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro, chloro, and methyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, - (CH2)OR11, -(CH2)C(=O)OR11, -(CH2)(phenylene)R13, or –(4- to 6-membered heterocyclene)R13; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, 4 to 6-membered heterocyclyl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, or -C(=O)NR11R12,; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, 4- to 6- membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C33- to 6-membered cycloalkylalkyl, 4- to 6- membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, -C(=O)OtBu, -OC(=O)Me, -OC(=O)OMe, -OC(=O)OEt, -(CH2)OH, and -S(=O)2(Me), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form:
Figure imgf000012_0001
; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [10] One embodiment is a compound of formula I, wherein the compound is of formula I-A
Figure imgf000012_0002
or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [11] One embodiment is a compound of formula I according to any one of claims 1-4, wherein the compound is of formula I-B ,
Figure imgf000013_0001
or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [12] One embodiment is a compound of formula I, wherein the compound is of formula I-D
Figure imgf000013_0002
, I-D, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [13] One embodiment is a compound of formula I, wherein the compound is of formula I-G1
Figure imgf000014_0002
wherein: L1 is selected from -CH2- and -N(R11)-; G1 is selected from -OR11, NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12,, - S(=O)2R10, -S(=O)2NR11R12, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl; and j is 0, 1, or 2; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [14] One embodiment is a compound of formula I, wherein the compound is of formula I-H
Figure imgf000014_0001
or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [15] One embodiment is a compound of formula I, wherein the compound is of any one of formulas -J1 to I-J5,
Figure imgf000015_0001
Figure imgf000016_0001
wherein: z is 0, 1, or 2 where valency permits; each instance of Z1 is independently selected from halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, - S(=O)(=NR9)R10, -S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, -(CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, - (CH2)p(arylene)R13, heterocyclyl, or -(heterocyclene)R13; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; and E3 is selected from -CH2-, -NH-, and -O-; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [16] One embodiment is a compound of formula I, wherein the compound is of any one of formulas I-K1 to I-K8
Figure imgf000016_0002
Figure imgf000017_0001
Figure imgf000018_0001
wherein: y is 0, 1, or 2 where valency permits; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; and E3 is selected from -CH2-, -NH-, and -O-; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [17] One embodiment is a compound of formula I, wherein R1 is selected from halogen and C1-C4 alkyl; R2 is selected from halogen and C1-C4 alkyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [18] One embodiment is a compound of formula I, wherein R1 is fluoro; R2 is chloro; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [19] One embodiment is a compound of formula I, wherein R4 is selected from halogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [20] One embodiment is a compound of formula I according to any one of claims 1 to 7, wherein R4P is selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [21] One embodiment is a compound of formula I, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [22] One embodiment is a compound of formula I, wherein R5 is -S(=O)2R6; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [23] One embodiment is a compound selected from the compounds listed in Table 1, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [24] Another aspect of the present disclosure is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. [25] Another aspect of the present disclosure is a method of treating a disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is selected from an inflammatory disorder, an allergic disorder, a skin disorder, a mast cell disorder, a pain disorder, and an itch disorder. [26] Another aspect of the present disclosure is a method of treating a disease, disorder, or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is selected from atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, heriditary alpha tryptasemia, chronic itch, and chronic pain. [27] In one embodiment, the disease, disorder, or condition is selected from atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma. [28] Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament. [29] Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder. [30] Another aspect of the present disclosure is a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, heriditary alpha tryptasemia, chronic itch, and chronic pain. [31] In one embodiment, the disease, disorder, or condition is selected from atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma. [32] Another aspect of the present disclosure is a medicament, characterized in that it comprises the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [33] Another aspect of the present disclosure is the use of a compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for preparing a medicament intended for the treatment of a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder. DETAILED DESCRIPTION [34] It is to be understood that the disclosed embodiments are merely examples of the disclosure, which may be embodied in various forms. Well-known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed structure. [35] As used herein “H,” “-H,” or “hydrogen” refer to a hydrogen atom or radical. In some embodiments, the hydrogen is an isotope of hydrogen. In some embodiments, the hydrogen is deuterium (D), for example a methyl, Me, or CH3 group may be CD3. [36] As used herein, the term “alkyl” refers to a linear or branched saturated hydrocarbon group. A CX-CY alkyl group refers to an alkyl group having between X and Y carbon atoms, for example a C1-C6 alkyl group refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and the like. [37] As used herein, the term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms have been substituted by a halogen atom. A CX-CY haloalkyl group refers to a haloalkyl group having between X and Y carbon atoms, for example a C1-C6 haloalkyl group refers to a haloalkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms (in addition to one or more halogen atoms). Exemplary haloalkyl groups include chloromethyl, dichloromethyl, trichloromethyl, trifluoromethyl, 1,2-difluoroethyl, 1,1,2,2-tetrafluoroethyl, and the like. [38] As used herein, the term “halogen” refers to fluoro, chloro, bromo, or iodo. [39] As used herein, the term “heteroalkyl” refers to a linear or branched, non-cyclic saturated group containing 1, 2, or 3 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different. Heteroalkyl groups include alkoxy, alkoxyalkyl, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylthio, and alkylthioalkyl groups. A CX- CY heteroalkyl group refers to a heteroalkyl group having between X and Y carbon atoms, for example a C1-C6 heteroalkyl group refers to a heteroalkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms (in addition to 1, 2, or 3 heteroatoms). Exemplary heteroalkyl groups include methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxymethyl, 2-methoxyethyl, 2-methoxyethoxy, (2-hydroxyethoxy)ethyl, (2- methoxyethoxy)ethyl, 3-hydroxy-2-(hydroxymethyl)propyl, 3-methoxy-2- (methoxymethyl)propyl, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, 1-aminoethyl, 2-aminoethyl, methanethiolato, ethanethiolato, or the like. [40] As used herein, the term “aryl” refers to an aromatic monocyclic or bicyclic ring system containing between 5 and 10 carbon atoms. Exemplary aryl groups include phenyl and naphthyl. [41] As used herein, the term “arylalkyl” refers to an alkyl group substituted with an aryl group. A CX-CY arylalkyl group refers to an arylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C1-C3 arylalkyl group refers to an arylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with an aryl group. Exemplary arylalkyl groups include benzyl and phenethyl. [42] As used herein, the term “cycloalkyl” refers to a non-aromatic monocyclic ring system containing between 3 and 8 carbon atoms. A CX-CY cycloalkyl group (or an X- to Y- membered cycloalkyl group) refers to a cycloalkyl group having between X and Y carbon atoms, for example a C3-C6 cycloalkyl group (or a 3- to 6-membered cycloalkyl group) to refers to a cycloalkyl group having 3, 4, 5, or 6 carbon atoms. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and the like. [43] As used herein, the term “cycloalkylalkyl” refers to an alkyl group substituted with a cycloalkyl group. A CX-CY M- to N-membered cycloalkylalkyl group refers to a cycloalkylalkyl group having between X and Y carbon atoms in the alkyl chain and between M and N carbon atoms in the cycloalkyl ring, for example a C1-C3 3- to 6-membered cycloalkylalkyl group refers to a cycloalkylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with a cycloalkyl group of 3, 4, 5, or 6 carbon atoms. Exemplary cycloalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl. [44] As used herein, the term “heteroaryl” refers to a cyclic aromatic group containing between 1 and 10 carbon atoms and containing between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different, wherein the group contains between 5 and 10 carbon atoms or heteroatoms. Heteroaryl groups include those where a nitrogen atom of the heteroaryl ring is substituted with an oxide (-O-), for example, pyridinyl N-oxide and the like, where the context so permits. Heteroaryl groups may be monocyclic or bicyclic. As used herein, the term “monocyclic heteroaryl” means a cyclic aromatic group containing 1 to 5 carbon atoms and containing between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more hetero atoms may be the same or different, wherein the monocyclic ring contains between 5 and 6 carbon atoms or heteroatoms. Exemplary heteroaryl groups include benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzotriazolyl, benzoxazolyl, furanyl, furazanyl, indolyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridinyl N-oxide, pyrimidinyl, pyrrolo[2,3- b]pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrrolyl, 1,2,4-thiadiazolyl, 1,2,4-triazinyl, 1,3,4-thiadiazolyl, thiazolyl, triazolyl, tetrazolyl, thiophenyl, and the like. [45] As used herein, the term “heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group. A CX-CY heteroarylalkyl group refers to a heteroarylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C1-C3 heteroarylalkyl group refers to a heteroarylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with a heteroaryl group. A “monocyclic heteroarylalkyl” group refers to an alkyl group substituted with a monocyclic heteroaryl group. Exemplary heteroarylalkyl groups include pyridylmethyl, pyrrolylmethyl, furanylmethyl, and the like. [46] As used herein, the term “heterocyclyl” refers to a non-aromatic (saturated or unsaturated) monocyclic group containing between 1 and 5 carbon atoms and between 1 and 4 heteroatoms, such as nitrogen, oxygen, or sulfur, which in the case of a group containing 2 or more heteroatoms the heteroatoms may be the same or different, wherein the monocyclic ring contains between 3 and 6 carbon atoms or heteroatoms. Heterocyclyl groups include those where one or more carbon atoms of the heterocyclyl ring is substituted with an oxo (=O), for example, lactones, lactams, oxopyrrolidinyl, oxopiperidinyl, oxoimidazolidinyl, oxo-4,5- dihydrotetrazolyl, and the like; or a nitrogen atom of the heterocyclyl ring is substituted with an oxide (-O-), for example, pyrrolidinyl N-oxide, piperidinyl N-oxide, and the like, where the context so permits. An X- to Y-membered heterocyclyl group refers to a heterocyclyl group having between X and Y ring atoms (which may be carbon or heteroatoms). Exemplary heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyridinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, lactones, lactams, oxopyrrolidinyl, oxopiperidinyl, oxoimidazolidinyl, oxo-4,5-dihydrotetrazolyl, pyrrolidinyl N-oxide, piperidinyl N-oxide, and the like. [47] As used herein, the term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl group. A CX-CY heterocyclylalkyl group refers to a heterocyclylalkyl group having between X and Y carbon atoms in the alkyl chain, for example a C1-C3 heterocyclylalkyl group refers to a heterocyclylalkyl group having an alkyl group of 1, 2, or 3 carbon atoms substituted with a heterocyclyl group. Exemplary heterocyclylalkyl groups include piperidinylmethyl, pyrrolidinylmethyl, azetidinylmethyl, 2-(oxo-4,5- dihydrotetrazolyl)ethyl, and the like. [48] As used herein, the term “acyl” refers to a group attached through a carbonyl (- C(=O)-) linker, wherein the linker is bonded to an alkyl, hydroxy, alkoxy, amino, alkylamino, or dialkylamino group. A CX-CY acyl group refers to an acyl group wherein any alkyl, if present in the acyl group, has between X and Y carbon atoms, for example, a C1-C4 acyl group refers to an acyl group selected from -C(=O)(C1-C4-alkyl), -C(=O)OH, -C(=O)O(C1-C4-alkyl), -C(=O)NH2, -C(=O)NH(C1-C4-alkyl), and -C(=O)N(C1-C4-alkyl)2. [49] As used herein, the term “sulfonyl” refers to a group attached through a sulfonyl (-S(=O)2-) linker, wherein the linker is bonded to an alkyl, amino, alkylamino, or dialkylamino group. A CX-CY sulfonyl group refers to a sulfonyl group wherein any alkyl, if present in the sulfonyl group, has between X and Y carbon atoms, for example, a C1-C4 sulfonyl group refers to a sulfonyl group selected from -S(=O)2(C1-C4-alkyl), -S(=O)2NH2, -S(=O)2NH(C1-C4- alkyl), and -S(=O)2N(C1-C4-alkyl)2. [50] As used herein, the term “substituted” refers to a hydrogen radical of the designated moiety being replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise noted, a substituent can be in any position, provided that the respective compound is sufficiently stable and is suitable as a pharmaceutical active compound. The prerequisite that a specific group and a compound of the formula I are sufficiently stable and suitable as a pharmaceutical active compound applies in general with respect to the definitions of all groups in the compounds of the formula I, and compounds of a subformula of formula I. [51] As used herein, the terms “independently” or “independently selected” means that the same or different values may be selected for multiple instances of a given variable in a single compound. [52] As used herein, the term “unsubstituted” indicates that the respective group does not carry any of the specified non-hydrogen substituents. [53] As used herein, the term “pharmaceutically acceptable salt” refers to the relatively non-toxic, inorganic and organic acid and base addition salts of a compound of formula I, or a compound of a subformula of formula I. These salts can be prepared in situ during the final isolation and purification of the compounds. [54] As used herein, “ ” indicates the bond between two atoms may be either a single or a double bond. When is a single bond between two carbon atoms, the carbon atoms each are bonded to one more hydrogen atom (or substituent in place of a hydrogen atom) than if had been a double bond. Correspondingly, when is a double bond, the carbon atoms each are bonded to one fewer hydrogen atom (or substituent in place of a hydrogen atom) than if had been a single bond. If two bonds are adjacent, both bonds may be a single bond, either may be single and the other a double bond, but both bonds may not be a double bond. [55] If the compounds of the formula I, or compounds of a subformula of formula I, comprise one or more acidic or basic groups, for example basic heterocyclic groups, the corresponding physiologically or toxicologically acceptable salts are also included in the disclosure, especially the pharmaceutically acceptable salts. The compounds of the formula I, or compounds of a subformula of formula I, may thus be deprotonated on an acidic group and be used for example as alkali metal salts or as ammonium salts. Compounds of formula I, or compounds of a subformula of formula I, comprising at least one basic group may also be prepared and used in the form of their acid addition salts, for example in the form of pharmaceutically acceptable salts with inorganic acids and organic acids. Salts can in general be prepared from acidic and basic compounds of the formula I, or compounds of a subformula of formula I, by reaction with an acid or base in a solvent or diluent according to customary procedures. If the compounds of the formula I, or compounds of a subformula of formula I, simultaneously contain an acidic and a basic group in the molecule, the disclosure also includes internal salts (betaines, zwitterions) in addition to the salt forms mentioned. The present disclosure also comprises all salts of the compounds of the formula I, or compounds of a subformula of formula I, which, because of low physiological tolerability, are not directly suitable for use as a pharmaceutical, but are suitable as intermediates for chemical reactions or for the preparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange. [56] As used herein, the term “pharmaceutically acceptable excipient” refers to a non- toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compound of the present disclosure to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the subject. The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art. [57] As used herein, the term “therapeutically effective amount” refers to an amount of a compound/composition according to the present disclosure effective in producing the desired therapeutic effect. [58] As used herein, the term “subject” refers to a human or animal subject. In some embodiments, the subject is human (i.e., a “patient”). In some embodiments, the subject is an animal. [59] As used herein, the term “compounds of formula I”, or “compounds of a subformula of formula I,” and equivalent expressions, include racemic compounds of formula I, or compound of a subformula of formula I, and their enantiomers, diastereoisomers, tautomers, atropisomers, and mixtures thereof, where the context so permits. Tautomeric compounds of formula I are exemplified by formulas I (tautomer 1) an I (tautomer 2).
Figure imgf000028_0001
[60] Generally, in an imidazole with different substituents in the 3- and 4- position, substitution of the tautomeric proton, e.g., by alkylation, may generate a mixture of discrete regioisomers. For example, in the case of the alkylating agent is SEM-Cl, such a mixture will be referred to as “mixture of SEM-regioiosmers” herein. [61] As used herein, the term “subformula” refers to subsets of compound of formula I, such as compounds of formula I which are a compound of formula I-A, I-A1, I-A2, I-A3, I- A4, I-A5, I-A6, I-A7, I-B, I-B1, I-B2, I-B3, I-B4, I-B5, I-B6, I-B7, I-C, I-C1, I-C2, I-C3, I-D, I-D1, I-D2, I-D3, I-D4, I-D5, I-D6, I-D7, I-E, I-E1, I-E2, I-E3, I-E4, I-E5, I-E6, I-E7, I-F, I- F1, I-F2, I-F3, I-F4, I-F5, I-F6, I-F7, I-G1, I-G2, I-H, any one of I-J1 to I-J21, or any one of I- K1 to I-K8 where the context so permits. [62] As used herein, the term "isomers" refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space. The labels “isomer 1” and “isomer 2,” or the like, can be assigned to isomers of known absolute configuration or can be used to describe stereoisomers of unknown absolute configuration. Likewise, the labels “R*” or “S*” may be assigned to stereocenters of some enantiomeric compounds of unknown absolute configuration. The use of the labels “isomer 1,” “isomer 2,” R*, and S* is not to be interpreted as indicating that the absolute configuration of both isomers is known. The term “isomeric mixture” refers to a mixture of isomers. [63] As used herein, the term "stereoisomers" is a general term used for all isomers of the individual molecules that differ only in the orientation of their atoms in space. The term “diastereomers” refers to stereoisomers that are not mirror images of one another and the term “enantiomers” refers to stereoisomers that are non-superimposable mirror images of each other. An enantiomer can be characterized by the absolute configurations of its asymmetric centers, chiral axes and planes, and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer, individual diastereomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.” A mixture containing any proportions of the diastereomers is called a “diastereomeric mixture”. For a compound with two chiral centers in a cyclic system, "trans" refers to the substituents (other than hydrogen) of the chiral centers are on opposite sides of the ring; "cis" refers to the substituents of the chiral centers are on the same sides of the ring. “Racemic trans” refers to equal proportions of two trans enantiomers and “racemic cis” refers to equal proportions of two cis enantiomers. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can also be directly separated using chiral chromatographic techniques or indirectly using enzymatic methods. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present disclosure. [64] One aspect of the present disclosure is a compound of formula I
Figure imgf000029_0001
wherein: A is selected from
Figure imgf000030_0001
each is a single or a double bond, provided two adjacent are not both double bonds; each instance of R1 is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R2 is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; each instance of R3 is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R4 is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R4P is selected from hydrogen, halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, - OC(=O)R6, -OC(=O)OR7, -OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, - NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, - S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, aryl, C1-C3 arylalkyl, monocyclic heteroaryl, and C1-C3 heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, - (CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(arylene)R13, heterocyclyl, or -(heterocyclylene)R13; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, aryl, C1-C3 arylalkyl, heteroaryl, and C1-C3 heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, - OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, or -NR9S(=O)2NR11R12; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or more R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C3 3-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or more R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), - C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)OH, -OC(=O)O(C1-C4 alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), - NHC(=O)(C1-C4 alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4 alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4 alkyl), -NHC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)(C1- C4 alkyl), -N(C1-C4 alkyl)C(=O)OH, -N(C1-C4 alkyl)C(=O)O(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)NH2, -N(C1-C4 alkyl)C(=O)NH(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qOH, -(CH2)qO(C1-C4 alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4 alkyl), -(CH2)qN(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qC(=O)(C1-C4 alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4 alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4 alkyl), - (CH)qC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a heterocyclyl ring; X1 is halogen; m is 0 or 1; n is 1 or 2; each p is independently 1, 2, or 3; and each q is independently 1, 2, or 3; wherein when
Figure imgf000032_0001
, R4 and R5 may be taken together with the carbons connecting them to form a 5- or 6-membered heterocyclyl ring; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, provided the compound of formula I is not of formula
Figure imgf000033_0001
. [65] One embodiment is a compound of formula I, wherein: A is selected from
Figure imgf000033_0002
R1 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R2 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; each instance of R3 is independently selected from halogen, -OR11, -NR11R12, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R4 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R4P is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -SR7, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, phenyl, C1-C3 phenylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O- )R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, - (CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(phenylene)R13, 4- to 6- membered heterocyclyl, or -(4- to 6-membered heterocyclene)R13; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, phenyl, C1-C3 phenylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, or - S(=O)(=NR9)NR11R12; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C3 3-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), - C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)OH, -OC(=O)O(C1-C4 alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), - NHC(=O)(C1-C4 alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4 alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4 alkyl), -NHC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)(C1- C4 alkyl), -N(C1-C4 alkyl)C(=O)OH, -N(C1-C4 alkyl)C(=O)O(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)NH2, -N(C1-C4 alkyl)C(=O)NH(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qOH, -(CH2)qO(C1-C4 alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4 alkyl), -(CH2)qN(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qC(=O)(C1-C4 alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4 alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4 alkyl), - (CH)qC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4- to 6-membered heterocyclyl ring; m is 0 or 1; n is 1; each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [66] One embodiment is a compound of formula I, wherein: A is selected from
Figure imgf000036_0001
R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10, - NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pC(=O)OR11, -(CH2)p(phenylene)R13, or –(4- to 6- membered heterocyclene)R13; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, 4- to 6-membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6- membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -OC(=O)(C1-C4 alkyl), -OC(=O)O(C1-C4 alkyl), -(CH2)qOH, and - S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4-membered heterocyclyl ring; m is 0; n is 1; each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [67] One embodiment is a compound of formula I, wherein: A is selected from
Figure imgf000038_0001
R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro, chloro, and methyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, - (CH2)OR11, -(CH2)C(=O)OR11, -(CH2)(phenylene)R13, or –(4- to 6-membered heterocyclene)R13; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, 4 to 6-membered heterocyclyl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, or -C(=O)NR11R12,; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, 4- to 6- membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C33- to 6-membered cycloalkylalkyl, 4- to 6- membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, -C(=O)OtBu, -OC(=O)Me, -OC(=O)OMe, -OC(=O)OEt, -(CH2)OH, and -S(=O)2(Me), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form:
Figure imgf000039_0001
; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [68] One embodiment is a compound of formula I which is a compound of formula I-A
Figure imgf000039_0002
, I-A wherein R1, R2, R3, R4, R5, n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [69] One embodiment is a compound of formula I which is a compound of formula I-A, wherein: R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [70] One embodiment is a compound of formula I which is a compound of formula I-A, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [71] One embodiment is a compound of formula I which is a compound of formula I-A1 ,
Figure imgf000041_0001
wherein R1, R2, R4, and R5 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [72] One embodiment is a compound of formula I which is a compound of formula I- A1, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [73] One embodiment is a compound of formula I which is a compound of formula I- A1, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [74] One embodiment is a compound of formula I which is a compound of formula I-A2
Figure imgf000043_0001
, I-A2 wherein: each instance of X is independently selected from halogen; and R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [75] One embodiment is a compound of formula I which is a compound of formula I- A2, wherein: R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [76] One embodiment is a compound of formula I which is a compound of formula I- A2, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [77] One embodiment is a compound of formula I which is a compound of formula I-A3 ,
Figure imgf000045_0001
wherein R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [78] One embodiment is a compound of formula I which is a compound of formula I- A3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [79] One embodiment is a compound of formula I which is a compound of formula I- A3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [80] One embodiment is a compound of formula I which is a compound of formula I-A4
Figure imgf000047_0001
, I-A4 wherein: L is selected from -R6 and -NR7R8; and R1, R2, R4, R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [81] One embodiment is a compound of formula I which is a compound of formula I- A4, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [82] One embodiment is a compound of formula I which is a compound of formula I- A4, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [83] One embodiment is a compound of formula I which is a compound of formula I-A5 ,
Figure imgf000049_0001
wherein: each instance of X is independently selected from halogen; L is selected from -R6 and -NR7R8; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [84] One embodiment is a compound of formula I which is a compound of formula I- A5, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [85] One embodiment is a compound of formula I which is a compound of formula I- A5, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [86] One embodiment is a compound of formula I which is a compound of formula I-A6 ,
Figure imgf000051_0001
wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4, R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [87] One embodiment is a compound of formula I which is a compound of formula I- A6, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [88] One embodiment is a compound of formula I which is a compound of formula I- A6, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [89] One embodiment is a compound of formula I which is a compound of formula I-A7
Figure imgf000053_0001
, I-A7 wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [90] One embodiment is a compound of formula I which is a compound of formula I- A7, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [91] One embodiment is a compound of formula I which is a compound of formula I- A7, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [92] One embodiment is a compound of formula I which is a compound of formula I-B ,
Figure imgf000055_0001
wherein R1, R2, R3, R4, R5, n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [93] One embodiment is a compound of formula I which is a compound of formula I-B, wherein: R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [94] One embodiment is a compound of formula I which is a compound of formula I-B, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [95] One embodiment is a compound of formula I which is a compound of formula I-B, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are joined, such that hydrogen other radicals of the two moieties are replaced with a bond between the two moieties, provided that the joining results in a stable or chemically feasible compound. For example, a compound of formula
Figure imgf000057_0001
, wherein R1, R2, R7, and n are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [96] One embodiment is a compound of formula I which is a compound of formula I-B1 ,
Figure imgf000057_0002
wherein R1, R2, R4, and R5 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [97] One embodiment is a compound of formula I which is a compound of formula I- B1, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [98] One embodiment is a compound of formula I which is a compound of formula I- B1, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [99] One embodiment is a compound of formula I which is a compound of formula I- B1, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 are joined, such that hydrogen other radicals of the two moieties are replaced with a bond between the two moieties, provided that the joining results in a stable or chemically feasible compound. For example, a compound of formula
Figure imgf000060_0001
, wherein R1, R2, and R7 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [100] One embodiment is a compound of formula I which is a compound of formula I-B2 ,
Figure imgf000060_0002
wherein: each instance of X is independently selected from halogen; and R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [101] One embodiment is a compound of formula I which is a compound of formula I- B2, wherein: R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [102] One embodiment is a compound of formula I which is a compound of formula I- B2, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [103] One embodiment is a compound of formula I which is a compound of formula I-B3
Figure imgf000062_0001
, I-B3 wherein R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [104] One embodiment is a compound of formula I which is a compound of formula I- B3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [105] One embodiment is a compound of formula I which is a compound of formula I- B3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [106] One embodiment is a compound of formula I which is a compound of formula I-B4
Figure imgf000064_0001
, I-B4 wherein: L is selected from -R6 and -NR7R8; and R1, R2, R4, R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [107] One embodiment is a compound of formula I which is a compound of formula I- B4, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [108] One embodiment is a compound of formula I which is a compound of formula I- B4, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [109] One embodiment is a compound of formula I which is a compound of formula I- B4, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R4 and L are joined, such that hydrogen other radicals of the two moieties are replaced with a bond between the two moieties, provided that the joining results in a stable or chemically feasible compound. For example, a compound of formula
Figure imgf000066_0001
, wherein R1, R2, and R7 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [110] One embodiment is a compound of formula I which is a compound of formula I-B5
Figure imgf000066_0002
, I-B5 wherein: each instance of X is independently selected from halogen; L is selected from -R6 and -NR7R8; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [111] One embodiment is a compound of formula I which is a compound of formula I- B5, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [112] One embodiment is a compound of formula I which is a compound of formula I- B5, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [113] One embodiment is a compound of formula I which is a compound of formula I-B6 ,
Figure imgf000068_0001
wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4, R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [114] One embodiment is a compound of formula I which is a compound of formula I- B6, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [115] One embodiment is a compound of formula I which is a compound of formula I- B6, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro and chloro; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [116] One embodiment is a compound of formula I which is a compound of formula I-B7 ,
Figure imgf000070_0001
wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and wherein R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [117] One embodiment is a compound of formula I which is a compound of formula I- B7, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [118] One embodiment is a compound of formula I which is a compound of formula I- B7, wherein each instance of X is independently selected from fluoro and chloro; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [119] One embodiment is a compound of formula I which is a compound of formula I-C ,
Figure imgf000072_0001
wherein R1, R2, R3, X1, n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [120] One embodiment is a compound of formula I which is a compound of formula I-C, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R3 is selected from halogen and C1-C4 alkyl; m is 0 or 1; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [121] One embodiment is a compound of formula I which is a compound of formula I-C, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R3 is selected from fluoro, chloro, and methyl; X1 is selected from fluoro and chloro; m is 1; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [122] One embodiment is a compound of formula I which is a compound of formula I-C1
Figure imgf000073_0001
, I-C1 wherein R1, R2, R3, X1, and m are as defined for a compound of formula I; and or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [123] One embodiment is a compound of formula I which is a compound of formula I- C1, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R3 is selected from halogen and C1-C4 alkyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [124] One embodiment is a compound of formula I which is a compound of formula I- C1, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R3 is selected from fluoro, chloro, and methyl; X1 is selected from fluoro and chloro; and m is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [125] One embodiment is a compound of formula I which is a compound of formula I-C2
Figure imgf000074_0001
, I-C2 wherein each instance of X is independently selected from halogen; and R3, X1, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [126] One embodiment is a compound of formula I which is a compound of formula I- C2, wherein R3 is selected from halogen and C1-C4 alkyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [127] One embodiment is a compound of formula I which is a compound of formula I- C2, wherein each instance of X is independently selected from fluoro, chloro, and bromo; R3 is selected from fluoro, chloro, and methyl; and m is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [128] One embodiment is a compound of formula I which is a compound of formula I-C3
Figure imgf000075_0001
, I-C3 wherein R3, X1, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [129] One embodiment is a compound of formula I which is a compound of formula I- C3, wherein R3 is selected from halogen and C1-C4 alkyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [130] One embodiment is a compound of formula I which is a compound of formula I- C3, wherein each instance of X is independently selected from fluoro, chloro, and bromo; R3 is selected from fluoro, chloro, and methyl; and m is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [131] One embodiment is a compound of formula I which is a compound of formula I-D
Figure imgf000075_0002
, I-D wherein R1, R2, R3, R4P, R5, n, m, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [132] One embodiment is a compound of formula I which is a compound of formula I-D, wherein: R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [133] One embodiment is a compound of formula I which is a compound of formula I-D, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [134] One embodiment is a compound of formula I which is a compound of formula I-D1
Figure imgf000077_0001
, I-D1 wherein R1, R2, R4P, R5, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [135] One embodiment is a compound of formula I which is a compound of formula I- D1, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [136] One embodiment is a compound of formula I which is a compound of formula I- D1, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [137] One embodiment is a compound of formula I which is a compound of formula I-D2
Figure imgf000079_0001
, I-D2 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4 alkyl; and R5 and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [138] One embodiment is a compound of formula I which is a compound of formula I- D2, wherein: R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [139] One embodiment is a compound of formula I which is a compound of formula I- D2, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [140] One embodiment is a compound of formula I which is a compound of formula I-D3
Figure imgf000081_0001
, I-D3 wherein R5 and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [141] One embodiment is a compound of formula I which is a compound of formula I- D3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [142] One embodiment is a compound of formula I which is a compound of formula I- D3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [143] One embodiment is a compound of formula I which is a compound of formula I-D4
Figure imgf000083_0001
, I-D4 wherein L is selected from -R6 and -NR7R8; and R1, R2, R4P, R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [144] One embodiment is a compound of formula I which is a compound of formula I- D4, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [145] One embodiment is a compound of formula I which is a compound of formula I- D4, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [146] One embodiment is a compound of formula I which is a compound of formula I-D5
Figure imgf000085_0001
, I-D5 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4 alkyl; and L is selected from -R6 and -NR7R8; and R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [147] One embodiment is a compound of formula I which is a compound of formula I- D5, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [148] One embodiment is a compound of formula I which is a compound of formula I- D5, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [149] One embodiment is a compound of formula I which is a compound of formula I-D6
Figure imgf000087_0001
, I-D6 wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4P, R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [150] One embodiment is a compound of formula I which is a compound of formula I- D6, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [151] One embodiment is a compound of formula I which is a compound of formula I- D6, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [152] One embodiment is a compound of formula I which is a compound of formula I-D7
Figure imgf000089_0001
, I-D7 wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [153] One embodiment is a compound of formula I which is a compound of formula I- D7, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [154] One embodiment is a compound of formula I which is a compound of formula I- D7, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [155] One embodiment is a compound of formula I which is a compound of formula I-E
Figure imgf000091_0001
, I-E wherein R1, R2, R3, R4P, R5, n, m, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [156] One embodiment is a compound of formula I which is a compound of formula I-E, wherein: R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [157] One embodiment is a compound of formula I which is a compound of formula I-E, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [158] One embodiment is a compound of formula I which is a compound of formula I-E1
Figure imgf000093_0001
, I-E1 wherein R1, R2, R4P, R5, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [159] One embodiment is a compound of formula I which is a compound of formula I- E1, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [160] One embodiment is a compound of formula I which is a compound of formula I- E1, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [161] One embodiment is a compound of formula I which is a compound of formula I-E2
Figure imgf000095_0001
, I-E2 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4 alkyl; and R5 and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [162] One embodiment is a compound of formula I which is a compound of formula I- E2, wherein: R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [163] One embodiment is a compound of formula I which is a compound of formula I- E2, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [164] One embodiment is a compound of formula I which is a compound of formula I-E3
Figure imgf000097_0001
, I-E3 wherein R5 and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [165] One embodiment is a compound of formula I which is a compound of formula I- E3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [166] One embodiment is a compound of formula I which is a compound of formula I- E3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [167] One embodiment is a compound of formula I which is a compound of formula I-E4
Figure imgf000098_0001
, I-E4 wherein L is selected from -R6 and -NR7R8; and R1, R2, R4P, R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [168] One embodiment is a compound of formula I which is a compound of formula I- E4, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [169] One embodiment is a compound of formula I which is a compound of formula I- E4, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [170] One embodiment is a compound of formula I which is a compound of formula I-E5
Figure imgf000100_0001
, I-E5 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4 alkyl; L is selected from -R6 and -NR7R8; and R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [171] One embodiment is a compound of formula I which is a compound of formula I- E5, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [172] One embodiment is a compound of formula I which is a compound of formula I- E5, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [173] One embodiment is a compound of formula I which is a compound of formula I-E6
Figure imgf000102_0001
, I-E6 wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4P, R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [174] One embodiment is a compound of formula I which is a compound of formula I- E6, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [175] One embodiment is a compound of formula I which is a compound of formula I- E6, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [176] One embodiment is a compound of formula I which is a compound of formula I-E7
Figure imgf000104_0001
, I-E7 wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and R6, R7, R8, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [177] One embodiment is a compound of formula I which is a compound of formula I- E7, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [178] One embodiment is a compound of formula I which is a compound of formula I- E7, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [179] One embodiment is a compound of formula I which is a compound of formula I-F
Figure imgf000106_0001
, I-F wherein R1, R2, R3, R4P, R5, n, and m are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [180] One embodiment is a compound of formula I which is a compound of formula I-F, wherein: R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [181] One embodiment is a compound of formula I which is a compound of formula I-F, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [182] One embodiment is a compound of formula I which is a compound of formula I-F1
Figure imgf000108_0001
, I-F1 wherein R1, R2, R4P, and R5 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [183] One embodiment is a compound of formula I which is a compound of formula I- F1, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [184] One embodiment is a compound of formula I which is a compound of formula I- F1, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [185] One embodiment is a compound of formula I which is a compound of formula I-F2
Figure imgf000110_0001
, I-F2 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4 alkyl; and R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [186] One embodiment is a compound of formula I which is a compound of formula I- F2, wherein: R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [187] One embodiment is a compound of formula I which is a compound of formula I- F2, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [188] One embodiment is a compound of formula I which is a compound of formula I-F3 ,
Figure imgf000112_0001
wherein R5 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [189] One embodiment is a compound of formula I which is a compound of formula I- F3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [190] One embodiment is a compound of formula I which is a compound of formula I- F3, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [191] One embodiment is a compound of formula I which is a compound of formula I-F4
Figure imgf000113_0001
, I-F4 wherein L is selected from -R6 and -NR7R8; and R1, R2, R4P, R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [192] One embodiment is a compound of formula I which is a compound of formula I- F4, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [193] One embodiment is a compound of formula I which is a compound of formula I- F4, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [194] One embodiment is a compound of formula I which is a compound of formula I-F5
Figure imgf000115_0001
, I-F5 wherein: each instance of X is independently selected from halogen; M is selected from hydrogen and C1-C4 alkyl; and L is selected from -R6 and -NR7R8; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [195] One embodiment is a compound of formula I which is a compound of formula I- F5, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [196] One embodiment is a compound of formula I which is a compound of formula I- F5, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [197] One embodiment is a compound of formula I which is a compound of formula I-F6
Figure imgf000117_0001
, I-F6 wherein: L is selected from -R6, -OR7, and -NR7R8; and R1, R2, R4P, R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [198] One embodiment is a compound of formula I which is a compound of formula I- F6, wherein R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4P is selected from hydrogen and C1-C4 alkyl; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [199] One embodiment is a compound of formula I which is a compound of formula I- F6, wherein R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; R4P is selected from hydrogen and methyl; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [200] One embodiment is a compound of formula I which is a compound of formula I-F7
Figure imgf000119_0001
, I-F7 wherein: each instance of X is independently selected from halogen; L is selected from -R6, -OR7, and -NR7R8; and R6, R7, and R8 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [201] One embodiment is a compound of formula I which is a compound of formula I- F7, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [202] One embodiment is a compound of formula I which is a compound of formula I- F7, wherein each instance of X is independently selected from fluoro and chloro; M is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl, which groups are unsubstituted or substituted with one or more of C1- C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, and C1-C4 heteroalkyl, which groups are unsubstituted or substituted with one or more of -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, - S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [203] One embodiment is a compound of formula I which is a compound of formula I-G1 ,
Figure imgf000121_0001
wherein: L1 is selected from -CH2- and -N(R11)-; G1 is selected from -OR11, NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12,, - S(=O)2R10, -S(=O)2NR11R12, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl; j is 0, 1, or 2; and R10, R11, R12, and are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [204] One embodiment is a compound of formula I which is a compound of formula I-G2
Figure imgf000121_0002
, I-G2 wherein: L1 is selected from -CH2- and -N(R11)-; G1 is selected from -OR11, NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12,, - S(=O)2R10, -S(=O)2NR11R12, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl; j is 0, 1, or 2; and R10, R11, and R12 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [205] One embodiment is a compound of formula I which is a compound of formula I-H ,
Figure imgf000122_0001
wherein: R1, R2, R4P, and R6 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [206] One embodiment is a compound of formula I which is a compound of formula I-H, wherein: R1 is fluoro; R2 is chloro; R4P is methyl; R6 is C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6- membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, - OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, S(=O)R10, - S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)OR11, - (CH2)NR11R12, -(CH2)C(=O)R10, -(CH2)C(=O)OR11, -(CH2)C(=O)NR11R12, - (CH2)p(phenylene)R13, 4- to 6-membered heterocyclyl, or –(4- to 6-membered heterocyclene)R13; and R10, R11, R12, and R13 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [207] One embodiment is a compound of formula I which is a compound of formula I-H, wherein: R1 is fluoro; R2 is chloro; R4P is methyl; R6 is C1-C6 alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6- membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three C1-C4 alkyl, -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)OR11, -NR9C(=O)R10, - NR9C(=O)OR11, -NR9C(=O)NR11R12, -S(=O)2R10, -NR9S(=O)2R10, -(CH2)C(=O)OR11, - (CH2)(phenylene)R13, or -(4- to 6-membered heterocyclene)R13; and R10, R11, R12, and R13 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
[208] In other embodiments, a compound of formula I is a compound of any one of formulas I-J1 to I-J5:
Figure imgf000124_0001
Figure imgf000125_0001
wherein: z is 0, 1, or 2 where valency permits; each instance of Z1 is independently selected from halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, - S(=O)(=NR9)R10, -S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, -(CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, - (CH2)p(arylene)R13, heterocyclyl, and -(heterocyclene)R13; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; E3 is selected from -CH2-, -NH-, and -O-; and R1, R2, R4P, R10, R11, R12 and R13 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [209] In other embodiments, a compound of formula I is a compound of any one of formulas I-J1 to I-J5, wherein: R1 is fluoro; R2 is chloro; R4P is methyl; z is 0, 1, or 2 where valency permits; each instance of Z1 is independently selected from halogen, C1-C4 alkyl, -OR11, - NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)OR11, -NR9C(=O)R10, - NR9C(=O)OR11, -NR9C(=O)NR11R12, -S(=O)2R10, -NR9S(=O)2R10, -(CH2)C(=O)OR11, - (CH2)(phenylene)R13, and -(4- to 6-membered heterocyclene)R13; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; E3 is selected from -CH2-, -NH-, and -O-; and R10, R11, R12 and R13 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [210] In other embodiments, a compound of formula I is a compound of any one of formulas I-J1 to I-J5, wherein: R1 is fluoro; R2 is chloro; R4P is methyl; z is 0, 1, or 2 where valency permits; each instance of Z1 is independently selected from chloro, C1-C4 alkyl, -OH, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -NH(C1-C4 heteroalkyl), -NH(C3-C6 cycloalkyl), -C(=O)Me, - C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)OtBu, -C(=O)NH2, -OC(=O)O(C1-C4 alkyl), - NHC(=O)Me, -NHC(=O)O(C1-C4 alkyl), -NHC(=O)NH2, -S(=O)2Me, -NHS(=O)2Me, - CH2C(=O)OH, -(CH2)C(=O)O(C1-C4 alkyl), -(CH2)(phenylene)R13, or -(4- to 6-membered heterocyclene)R13; wherein if z is 2, the second instance of Z1 is C1-C4 alkyl; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; E3 is selected from -CH2-, -NH-, and -O-; and R13 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [211] In other embodiments, a compound of formula I is a compound of any one of formulas I-K1 to I-K8:
Figure imgf000127_0001
Figure imgf000128_0001
wherein: y is 0, 1, or 2 where valency permits; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; E3 is selected from -CH2-, -NH-, and -O-; and R1, R2, R4P, R9, R10, R11, R12 and R13 are as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [212] In other embodiments, a compound of formula I is a compound of any one of formulas I-K1 to I-K8, wherein: R1 is fluoro; R2 is chloro; R4P is methyl; y is 0, 1, or 2 where valency permits; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; E3 is selected from -CH2-, -NH-, and -O-; and each instance of R9 is H; each instance of R10 is independently selected from C1-C4 alkyl and C3-C6 cycloalkyl; which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C3 3-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; and R13 is as defined for a compound of formula I; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [213] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1 is selected from halogen and C1-C4 alkyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [214] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1 is fluoro; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [215] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R2 is selected from halogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [216] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R2 is selected from chloro, bromo, methyl, and ethyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [217] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R2 is chloro; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [218] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1 is selected from halogen and C1-C4 alkyl; R2 is selected from chloro, bromo, methyl, and ethyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [219] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1 is fluoro; R2 is selected from chloro, bromo, methyl, and ethyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [220] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, I-F6, I-H, any one of I-J1 to I-J5, or any one of I-K1 to I-K8, wherein: R1 is fluoro; R2 is chloro; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [221] One embodiment is a compound of formula I, wherein:
Figure imgf000132_0001
; R4 is selected from halogen and C1-C4 alkyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [222] One embodiment is a compound of formula I, wherein:
Figure imgf000132_0002
; R4 is selected from fluoro, chloro, and methyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [223] One embodiment is a compound of formula I, wherein:
Figure imgf000132_0003
; R4 is chloro; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [224] One embodiment is a compound of formula I, wherein:
Figure imgf000133_0001
X1 is selected from halogen; R3 is selected from halogen and C1-C4 alkyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [225] One embodiment is a compound of formula I, wherein:
Figure imgf000133_0002
X1 is selected from fluoro and chloro; R3 is selected from fluoro, chloro, and methyl; and m is 0 or 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [226] One embodiment is a compound of formula I, wherein:
Figure imgf000133_0003
X1 is selected from fluoro and chloro; R3 is selected from fluoro, chloro, and methyl; and m is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [227] One embodiment is a compound of formula I, wherein:
Figure imgf000134_0001
R4P is selected from hydrogen and C1-C4 alkyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [228] One embodiment is a compound of formula I, wherein:
Figure imgf000134_0002
R4P is selected from hydrogen and methyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [229] One embodiment is a compound of formula I, wherein:
Figure imgf000134_0003
R4P is methyl; and m is 0; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [230] One embodiment is a compound of formula I, wherein: A is selected from
Figure imgf000135_0001
; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; each instance of R10 is independently selected from C1-C4 alkyl and C1-C4 heteroalkyl; and each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C1-C3 acyl, and C1-C3 sulfonyl, provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [231] One embodiment is a compound of formula I, wherein:
Figure imgf000136_0001
; R5 is selected from -C(=O)NR7R8, -S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [232] One embodiment is a compound of formula I, wherein:
Figure imgf000136_0002
R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [233] One embodiment is a compound of formula I, wherein:
Figure imgf000137_0001
R5 is selected from -C(=O)NR7R8, -S(=O)2R6, and -S(=O)2NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1- C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, - NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [234] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F,
Figure imgf000138_0001
,
Figure imgf000139_0001
Figure imgf000140_0001
. [236] One embodiment is a compound of formula I, or a compound of formula I-A, I-A1, I-A4, I-A6, I-B, I-B1, I-B4, I-B6, I-C, I-C1, I-D, I-D1, I-D4, I-D6, I-E, I-E1, I-E4, or I-E6, I-F, I-F1, I-F4, or I-F6, wherein R5 is selected from ,
Figure imgf000140_0002
, , ,
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [237] All these subgroups taken alone or in combination are part of the description. [238] One embodiment is a compound of formula I, selected from the compounds listed in Table 1, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [239] One embodiment is a compound of formula I, selected from: Methyl 3-(((3S*,4S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)propanoate; 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)propan-1-ol; 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)propanoic acid; 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)propanamide; 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)-N-methylpropanamide; Methyl N-(((3S*,4S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)-N-methylglycinate; (3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N-(2- hydroxyethyl)-N,3-dimethylpiperidine-1-sulfonamide; N-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)-N-methylglycine; 2-((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N,3- dimethylpiperidine-1-sulfonamido)acetamide; 2-((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N,3- dimethylpiperidine-1-sulfonamido)-N-methylacetamide; Methyl (S*)-3-((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)propanoate; (S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)propan-1-ol; (S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)propanoic acid; (S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)propanamide; (S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)-N-methylpropanamide; Methyl (S*)-N-((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)-N-methylglycinate; (S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N-(2-hydroxyethyl)-N,3- dimethyl-3,6-dihydropyridine-1(2H)-sulfonamide; (S*)-N-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridin-1(2H)-yl)sulfonyl)-N-methylglycine; (S*)-2-(4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N,3-dimethyl-1,2,3,6- tetrahydropyridine-1-sulfonamido)acetamide; (S*)-2-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N,3-dimethyl- 1,2,3,6-tetrahydropyridine)-1-sulfonamido)-N-methylacetamide; (S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-carboxamide; 3-((3-Chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)phenyl)sulfonyl)propan-1-ol; and 3-((3-Chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)phenyl)sulfonyl)propanoic acid; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [240] One embodiment is a compound of formula I, or a compound of a subformula of formula I, that has sufficient solubility to avoid, for example, advanced formulations or advanced delivery systems, which include but are not limited to liposomal suspensions, inclusion complexes solid dispersions in polymers mechano-chemically activated systems, microparticles or nanoparticles, micro- or nano-emulsions, and vesicular systems. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 20 µM or greater at pH 7.4. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 100 µM or greater at pH 7.4. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 500 µM or greater at pH 7.4. In some embodiments a compound of formula I, or a compound of a subformula of formula I, has a solubility of 1000 µM or greater at pH 7.4. [241] The compounds of formula I, and subformulas thereof, may comprise one or more asymmetric atoms and/or chiral axes. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures are provided herein. [242] Some of the compounds of formula I, and subformulas thereof, may exist in the form of acids or of base-addition salts. Such addition salts form part of the disclosure. These salts are advantageously prepared with pharmaceutically acceptable bases or cations, but the salts of other bases or cations that are useful, for example, for purification or isolation of the compounds of formula I, and subformulas thereof, also form part of the disclosure. [243] Some of the compounds of formula I, and subformulas thereof, may exist in the form of bases or of acid-addition salts. Such addition salts form part of the disclosure. These salts are advantageously prepared with pharmaceutically acceptable acids or anions, but the salts of other acids or anions that are useful, for example, for purification or isolation of the compounds of formula I, and subformulas thereof, also form part of the disclosure. [244] Another aspect of the present disclosure is a process for preparing a compound of formula I, or a subformula thereof, comprising reacting an intermediate of formula B*-PG with an intermediate of formula D1 in the presence of a catalyst and a base to give an intermediate of formula C2:
Figure imgf000160_0001
wherein R1, A, and n are as defined for a compound of formula I, R2 * is as defined for a compound of formula I or hydrogen, PG is a protecting group, and X is selected from halogen. C2 may be obtained as a mixture of positional isomers, where A is adjacent to the protected nitrogen atom in a first isomer and not adjacent to the protected nitrogen isomer in a second isomer. In some embodiments, the protecting group is 2-(trimethylsilyl)ethoxymethyl. In some embodiments, the catalyst is selected from bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl2) and bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2). In some embodiments, the base is selected from potassium carbonate, potassium acetate, and sodium carbonate. In some embodiments, the protecting group is 2- (trimethylsilyl)ethoxymethyl, the catalyst is selected from Pd(dtbpf)Cl2 and Pd(dppf)Cl2, and the base is selected from potassium carbonate, potassium acetate, and sodium carbonate. In some embodiments, an intermediate of formula C2 is subsequently deprotected to give a compound of formula I. In some embodiments, an intermediate of formula C2, wherein R2* is hydrogen is subsequently halogenated and deprotected to give a compound of formula I, wherein R2 is selected from halogen. [245] Yet another aspect of the present disclosure is a pharmaceutical composition that includes a compound described herein as an active ingredient. These pharmaceutical compositions comprise a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and also at least one pharmaceutically acceptable excipient. [246] The said excipients may be selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art. [247] In these pharmaceutical compositions for oral, inhalative, topical, or transdermal administration, the active ingredient of formula I, or a compound of a subformula of formula I, or its pharmaceutically acceptable salt, may be administered in a unit administration form, in a mixture with conventional pharmaceutical excipients, to animals or to human beings for the treatment of a disease, disorder, or condition. [248] Appropriate unit administration forms include oral forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, forms for inhalative administration, and forms for topical or transdermal administration. For topical and transdermal administration, it is possible to use the herein described compounds in creams, gels, ointments, or lotions. [249] By the oral route, the dose of active principle per day may reach 2000 mg/day, taken all at once or in portions. By the inhalative route, the dose of active principle per day may reach 50 mg/day. By parenteral routes, the dose of active principle per day may reach 400 mg/day. [250] There may be particular cases in which higher or lower dosages are appropriate; such dosages do not depart from the scope of the disclosure. According to usual practice, the dosage that is appropriate for each subject is determined by the doctor according to the mode of administration and the weight and response of the said subject. [251] Compounds described herein have an antagonistic activity for MRGPRX2. The compounds according to the present disclosure can, therefore, be used for preparing medicaments, especially medicaments which are antagonists of MRGPRX2. [252] Accordingly, yet another aspect of the present disclosure is a medicament, characterized in that it comprises a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [253] The medicaments of the present disclosure can be employed therapeutically, especially in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders. In yet another aspect, also provided is the use of a compound of formula I, or a compound of a subformula of formula I, for preparing a medicament for the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders. [254] In one embodiment, the disease, disorder, or condition is selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, hereditary alpha tryptasemia, chronic itch, and chronic pain. [255] In one embodiment, the disease, disorder, or condition is selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma. In one embodiment, the disease, disorder, or condition is atopic dermatitis. In one embodiment, the disease, disorder, or condition is chronic spontaneous urticaria. In one embodiment, the disease, disorder, or condition is prurigo nodularis. In one embodiment, the disease, disorder, or condition is asthma. [256] Yet another aspect of the present disclosure is a method of treating a disease, disorder, or condition associated with MRGPRX2, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [257] One embodiment is a method for treating a disease, disorder, or condition associated with undesired mast cell activity or mast cell degranulation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [258] One embodiment is a method for treating a disease, disorder, or condition for which modulation of MRGPRX2 is indicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. Modes of modulating MRGPRX2 include antagonism, inhibition, blocking, agonism, partial agonism, inverse agonism, and combinations thereof. [259] One embodiment is a method for treating a disease, disorder, or condition for which antagonism of MRGPRX2 is indicated, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [260] One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of inflammatory disorders, autoimmune disorders, allergic disorders, mast cell disorders, pain disorders, and itch disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [261] One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction, allergy, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis systemic mastocytosis cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, hereditary alpha tryptasemia, chronic itch, and chronic pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [262] One embodiment is a method for treating a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [263] One embodiment is a method for treating atopic dermatitis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [264] One embodiment is a method for treating chronic spontaneous urticaria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [265] One embodiment is a method for treating prurigo nodularis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. [266] One embodiment is a method for treating asthma, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof or a mixture thereof or a pharmaceutically acceptable salt thereof. [267] According to another aspect, also provided is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease disorder or condition associated with MRGPRX2. [268] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition associated with undesired mast cell activity or mast cell degranulation. [269] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition for which modulation of MRGPRX2 is indicated. Modes of modulating MRGPRX2 include antagonism, inhibition, blocking, agonism, partial agonism, inverse agonism, and combinations thereof. [270] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition for which antagonism of MRGPRX2 is indicated. [271] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders. [272] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic urticaria, chronic spontaneous urticaria, inducible urticaria, prurigo, prurigo nodularis, pruritus, asthma, rosacea, contact dermatitis, allergic contact dermatitis, anaphylaxis, anaphylactoid drug reaction allergy rheumatoid arthritis inflammatory bowel disease, ulcerative colitis, allergic rhinitis, chronic rhinosinusitis, aggressive periodontitis, systemic mastocytosis, cutaneous mastocytosis, mastocytic enterocolitis, mast cell activation syndrome, interstitial cystitis, hereditary alpha tryptasemia, chronic itch, and chronic pain. [273] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma. [274] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of atopic dermatitis. [275] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of chronic spontaneous urticaria. [276] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of prurigo nodularis. [277] One embodiment is a compound of formula I, or a compound of a subformula of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of asthma. [278] One embodiment is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the compound of formula I is selected from the compounds listed in Table 1. [279] One embodiment is a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof or a mixture thereof or a pharmaceutically acceptable salt thereof, for use as a medicament, wherein the compound of formula I is selected from one of the above three lists. [280] One embodiment is the use of a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, wherein the compound of formula I is selected from one of the above three lists. [281] One embodiment is a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, wherein the compound of formula I is selected from one of the above three lists. [282] One embodiment is a method of treating a disease, disorder, or condition selected from the group consisting of inflammatory disorders, allergic disorders, skin disorders, mast cell disorders, pain disorders, and itch disorders, for example, atopic dermatitis, chronic spontaneous urticaria, prurigo nodularis, and asthma, comprising administering to a subject in need thereof, in particular a human, a therapeutically effective amount of a compound of formula I, or an enantiomer, diastereomer, or tautomer, or atropisomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula I is selected from one of the above three lists. [283] GENERAL SYNTHETIC METHODS [284] The compounds of formula I herein can be prepared by the methods outlined in the following reaction schemes and examples. In the schemes and examples, the addition of a protecting group (PG) to an imidazole ring nitrogen may lead to positional isomers, which are depicted herein as two structures. A given substituent on the adjacent carbon atoms of the imidazole ring may be either adjacent or not adjacent to the protected nitrogen atom. Because protected imidazoles do not typically tautomerize, these intermediates may be prepared, isolated, characterized, and modified as a mixture of discrete positional isomers. After removal of the protecting group, the imidazole ring of the resulting intermediate or compound of formula I will no longer be restricted from tautomerization and may no longer exist as discrete positional isomers or a mixture thereof. [285] In certain embodiments, the preparation of the compounds of formula I can be carried out according to Scheme 1.
Figure imgf000168_0001
[287] In Scheme 1, each X is independently selected from halogen. Carbamimidoyl pyridine intermediates of formula A1 may be commercially available, such as 5- fluoropyridine-2-carboxamidine, or can be prepared according to Scheme 5 or by methods known to those skilled in the art. Haloacetyl intermediates of formula A2 may be commercially available or can be prepared by methods known to those skilled in the art. A carbamimidoyl pyridine intermediate of formula A1 can be cyclized to a pyridyl-imidazole intermediate of formula A3 by reacting with a haloacetyl intermediate of formula A2 in the presence of a base, such as potassium carbonate, in a solvent, such as ethanol. The pyridyl- imidazole intermediate of formula A3 can be converted to a compound of formula I, wherein R2 is selected from halogen (e.g., -Cl), by reacting with a halogenation reagent, such as N- chlorosuccinimide, in a solvent such as DMF. [288] In certain embodiments, the preparation of the compounds of formula I can be carried out according to Schemes 2-6. Schemes 2-6 depict methods of preparing different pyridyl-imidazole halide intermediates which can be coupled with boronic ester intermediates to give compounds of formula I or other intermediates which can be converted to compounds of formula I.
Figure imgf000169_0001
[290] Picolinaldehyde intermediates of formula B1 may be commercially available, such as 5-fluoropicolinaldehyde, or can be prepared by methods known to those skilled in the art. A picolinaldehyde intermediate of formula B1 can be converted to a pyridyl-imidazole intermediate of formula B2 by reacting with oxalaldehyde and ammonium hydroxide in a solvent, such as ethanol. The pyridyl-imidazole intermediate of formula B2 can be converted to a protected pyridyl-imidazole intermediate of formula B3 by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF. [291] A protected pyridyl-imidazole intermediate of formula B3 can be converted to a protected pyridyl-imidazole bromide intermediate of formula B4 (an isomeric mixture) by reacting with a bromination reagent, such as N-bromosuccinimide, in a solvent, such as chloroform. [292] A protected pyridyl imidazole intermediate of formula B2 can be converted to a pyridyl-imidazole dibromide intermediate of formula B5 by reacting with a bromination reagent, such as N-bromosuccinimide, in a solvent, such as chloroform. The pyridyl-imidzole dibromide intermediate of formula B5 can be converted to a protected pyridyl-imidazole dibromide intermediate of formula B6 by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF. [293] Scheme 3
Figure imgf000170_0001
[294] Pyridyl-imidazole intermediates of formula B2 can be prepared according to Scheme 2. A pyridyl-imidazole intermediate of formula B2 can be converted to a pyridyl- imidazole chloride intermediate of formula B7 by reacting with a chlorination reagent, such as N-chlorosuccinimide, in a solvent, such as DMF. The pyridyl-imidazole chloride intermediate of formula B7 can be converted to a pyridyl-imidazole chloride bromide intermediate of formula B8 by reacting with a bromination reagent, such as N-bromosuccinimide, in a solvent, such as THF. The pyridyl-imidazole chloride bromide intermediate of formula B8 can be converted to a protected pyridyl-imidazole chloride bromide intermediate of formula B9 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF. [295] Scheme 4
Figure imgf000171_0001
[296] Pyridyl-imidazole intermediates of formula B2 can be prepared according to Scheme 2. A pyridyl-imidazole intermediate of formula B2 can be converted to a pyridyl- imidazole diiodide intermediate of formula B10 by reacting with an iodination reagent, such as N-iodosuccinimide, in a solvent, such as acetonitrile. The pyridyl-imidazole diiodide intermediate of formula B10 can be converted to a pyridyl-imidazole iodide intermediate of formula B11 by reacting with a reducing agent, such as sodium sulfite (Na2SO3), in the presence of water, in a solvent such as DMF, water, or a mixture thereof. The pyridyl- imidazole iodide intermediate of formula B11 can be converted to a protected pyridyl- imidazole iodide intermediate of formula B12 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF. The protected pyridyl-imidazole iodide intermediate of formula B12 (an isomeric mixture) can be converted to a protected pyridyl-imidazole chloride iodide intermediate of formula B13 (an isomeric mixture) by reacting with a chlorination reagent, such as N-chlorosuccinimide. [297] Scheme 5
Figure imgf000172_0001
[298] Picolinonitrile intermediates of formula A0 may be commercially available, such as 5-methyl-picolinonitrile, or may be prepared by methods known to those skilled in the art. A picolinonitrile intermediate of formula A0 can be converted to a carbamimidoyl pyridine intermediate of formula A1 by reacting with a base, such as LiHMDS, in a solvent such as THF, and quenching with ammonium chloride. [299] Haloacetyl intermediates of formula D2 may be commercially available, such as when R2 is methyl or ethyl, or can be prepared by methods known to those skilled in the art. A carbamimidoyl pyridine intermediate of formula A1 can be converted to a pyridyl-imidazole intermediate of formula B14 by reacting with a haloacetyl intermediate of formula D2 in the presence of a base, such as potassium carbonate, in a solvent, such as ethanol. A pyridyl- imidazole intermediate of formula B14 can be converted to a pyridyl-imidazole bromide intermediate of formula B15 by reacting with a bromination reagent, such as N- bromosuccinimide, in a solvent, such as acetonitrile. A pyridyl-imidazole bromide intermediate of formula B15 can be converted to a protected pyridyl-imidazole bromide intermediate of formula B16 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF.
[300] Scheme 6
Figure imgf000174_0001
[301] Picolinaldehyde intermediates of formula B1 may be commercially available, such as 5-fluoropicolinaldehyde, or can be prepared by methods known to those skilled in the art. An oxoacetyl intermediate of formula D13 may be commercially available, such as wherein R2 is methyl or ethyl, or can be prepared by methods known to those skilled in the art. A picolinaldehyde intermediate of formula B1 can be converted to a pyridyl-imidazole intermediate of formula B17 by reacting with an oxoacetyl intermediate of formula D13 in the presence of ammonium acetate in a solvent, such as methanol. A pyridyl-imidazole intermediate of formula B17 can be converted to a pyridyl-imidazole iodide intermediate of formula B18 by reacting with an iodination reagent, such as N-iodosuccinimide, in a solvent, such as acetonitrile. A pyridyl-imidazole iodide intermediate of formula B18 can be converted to a protected pyridyl-imidazole iodide intermediate of formula B19 (an isomeric mixture) by addition of a protecting group to the imidazole, such as by reacting with a base, such as sodium hydride, and a protecting group reagent, such as SEM-Cl, in an aprotic solvent, such as THF. [302] In certain embodiments, the preparation of the compounds of formula I can be carried out according to Scheme 7, which depicts the coupling of various pyridyl-imidazole halide intermediates (such as those prepared according to Schemes 2-6) with a boronic acid intermediate. In Scheme 7, R2* is R2 as defined for a compound of formula I, but may also be selected from hydrogen.
[303] Scheme 7
Figure imgf000176_0001
[304] Intermediates of formula B* are non-protected pyridyl-imidazoles including intermediates of formula B5, B7, B8, B10, B11, B15, and B18, which can be prepared according to Schemes 2-6. Intermediates of formula B*-PG are protected pyridyl-imidazoles including intermediates of formula B4, B6, B9, B12, B13, B16, and B19, which can be prepared according to Schemes 2-6. [305] An intermediate of formula B* can be converted to an intermediate of formula C1 (which may also be a compound of formula I) by coupling with a boronic acid intermediate of formula D1, which may be commercially available or can be prepared by methods known to those skilled in the art. The coupling can be accomplished in the presence of a catalyst, such as bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl2) bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2), and a base, such as potassium carbonate, potassium acetate, or sodium carbonate, in a solvent, such as NMP, DMF, dioxane, or DMSO, or a mixture with water thereof. [306] An intermediate of formula B*-PG (an isomeric mixture) can be converted to an intermediate of formula C2 (an isomeric mixture) by coupling with a boronic acid intermediate of formula D1, which may be commercially available or can be prepared by methods known to those skilled in the art. The coupling can be accomplished in the presence of a catalyst, such as bis(di-tert-butylphosphino)palladium dichloride (Pd(dtbpf)Cl2) bis(diphenylphosphino)palladium dichloride (Pd(dppf)Cl2), and a base, such as potassium carbonate, potassium acetate, or sodium carbonate, in a solvent, such as NMP, DMF, dioxane, or DMSO, or a mixture with water thereof. An intermediate of formula C2 may be deprotected to convert to an intermediate of formula C1 (which may also be a compound of formula I) by reacting with an acid, such as TFA. [307] In embodiments wherein R2* is hydrogen, an intermediate of formula C1 may be converted to a compound of formula I, wherein R2 is selected from halogen by reacting with a halogenation agent, such as N-chlorosuccinimide, N-bromosuccinimide, or N- iodosuccinimide, in a solvent, such as THF, acetonitrile, DMF, or chloroform. [308] In embodiments wherein R2* is hydrogen, an intermediate of formula C2 (an isomeric mixture) may be converted to an intermediate of formula C3 (an isomeric mixture), wherein R2 is selected from halogen by reacting with a halogenation agent, such as N- chlorosuccinimide, N-bromosuccinimide, or N-iodosuccinimide, in a solvent, such as THF, acetonitrile, DMF, or chloroform. An intermediate of formula C3 may be deprotected to convert to a compound of formula I by reacting with an acid such as TFA [309] In certain embodiments, wherein
Figure imgf000178_0001
one is a double bond,
Figure imgf000178_0002
, the preparation of compounds of formula I can be carried out according to Scheme 8.
[310] Scheme 8
Figure imgf000179_0001
[311] An intermediates of formula E1 (an isomeric mixture) may be prepared according to Scheme 8 (as an intermediate of formula C2 (an isomeric mixture)). An intermediate of formula E1 (an isomeric mixture) can be converted to an intermediate of formula E2 (an isomeric mixture) by reacting with a hydrogen source, such as molecular hydrogen (H2), in the presence of a catalyst, such as palladium on carbon (Pd/C), in a solvent, such as methanol or ethanol. An intermediate of formula E2, wherein R5 is an acid cleavable group (e.g., BOC), can be converted to a piperidine intermediate of formula E3, or an acid addition salt thereof, by reacting with an acid, such as TFA or HCl. A piperidine intermediate of formula E3, or an acid additional salt thereof, can be converted to a compound of formula I, wherein A is
Figure imgf000180_0001
reacting with an electrophilic reagent, such as acetyl chloride, methanesulfonyl chloride, or (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)- yl)sulfonyl)amide, in the presence of a base, such as DIEA, in a solvent, such as DCM. [312] An intermediate of formula E1 (an isomeric mixture) can be converted to an intermediate of formula E4, , wherein R5 is an acid cleavable group (e.g., BOC), or an acid addition salt thereof, by reacting with an acid, such as TFA or HCl. An intermediate of formula E4, or an acid addition salt thereof, can be converted to a to a compound of formula I, wherein
Figure imgf000180_0002
one is a double bond, by reacting with an electrophilic reagent, such as acetyl chloride, methanesulfonyl chloride, (tert- butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide, in the presence of a base, such as DIEA, in a solvent, such as THF or DCM. [313] In certain embodiments, a compound of formula I, for example a compound of formula I prepared according to methods depicted in Schemes 1 to 8, or any combination thereof, can also be an intermediate to one or more additional compounds of formula I. In certain embodiments, such additional compounds of formula I, can be prepared by modifying R5 by methods known to those skilled in the art. The synthetic examples herein provide exemplary modifications of R5. [314] In another aspect, also provided are compounds of formula A0, A1, A2, A3, B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B15, B16, B17, B18, B19, B*, B*-PG, C1, C2, C3, D1, D2, D3, E1, E2, E3, or E4. These compounds are useful as synthetic intermediates for the compounds of formula I, or compounds of a subformula of formula I. EXAMPLES [315] The embodiments provided herein will be explained more specifically with reference to the following examples, however, the scope of the embodiments provided herein is not limited to these examples. The isomeric configuration for stereocenters of some enantiomeric compounds described in the Examples has been assigned as R* or S*, but the absolute configuration has not been determined. [316] ABBREVIATIONS [317] Unless otherwise stated, the following abbreviations have the stated meanings: dba dibenzylideneacetone DCM dichloromethane DIEA N,N-diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dppf 1,1’-bis(diphenylphosphino)ferrocene dtbpf 1,1’-bis(di-tert-butyl-phosphino)ferrocene eq. equivalent EA ethyl acetate EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et ethyl EtOH ethanol FA formic acid HOBt hydroxybenzotriazole HPLC hi h f li id h h LCMS liquid chromatography-mass spectrometry LDA lithium diisopropylamide NMP N-methyl-2-pyrrolidone Me methyl MeCN acetonitrile MeOH methanol MOPS 3-(N-morpholino)propanesulfonic acid MS mass spectrometry NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMR nuclear magnetic spectroscopy OAc acetate Pd/C palladium on carbon PE petroleum ether RT room temperature SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride t-Bu tert-butyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran Xantphos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) [318] Generally, crude products were purified by column chromatography or flash chromatography. LCMS analysis or separation was performed using the following methods or methods described for specific examples. [319] LCMS METHODS [320] Method A [321] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95%B in 1.5min; Flow Rate: 1.8ml/min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C [322] Method B [323] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95%B in 1.3min, 95%B for 1.7min; Flow Rate: 1.8ml/min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C [324] Method C [325] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95%B in 1.3min, 95%B for 1.7min; Flow Rate: 2.0ml/min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C [326] Method D [327] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95%B in 1.3min, 95%B for 1.7min; Flow Rate: 2.0ml/min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 45°C [328] Method E [329] A: H2O (10mmol NH4HCO3), B: MeCN; Gradient: 10-95%B in 1.5min; Flow Rate: 1.8mL/min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C [330] Method F [331] A: H2O (0.05% TFA), B: MeCN (0.05% TFA); Gradient: 5%-95%B in 1.3min, 95%B for 2.9min, 95%-5%B in 0.1min; Flow Rate: 2ml/min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 45°C [332] Method G [333] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95%B in 1.4min, 95%B for 1.6min; Flow Rate: 1.8ml/min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 45°C [334] Method H [335] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 5%-95%B in 1.3.min, 95%B for 1.7min; Flow Rate: 1.8ml/min; Column: XBridge C18, 3.5μm, 4.6x50mm; Column Temperature: 45°C [336] Method I [337] A: H2O (10mM NH4HCO3), B: MeCN; Gradient: 10-95%B in 1.5min; Flow Rate: 1.8ml/min; Column: XBridge C18 35μm 46x50mm; Column Temperature: 45°C [338] Method J [339] A: H2O (0.01% TFA), B: MeCN(0.01% TFA); Gradient: 5%B-95%B in 1min, 95%B for 1min; Flow Rate: 1.6ml/min; Column: Agilent Poroshell 2.7μm, 3.0mmx30mm; Column Temperature: 50°C [340] Method K [341] A: H2O (0.1% FA), B: MeCN (0.1% FA); Gradient: 10%B for 0.2min, increase to 90%B in 1.3min, 90%B for 1.5min; Flow Rate: 2ml/min; Column: Agilent Poroshell 120 C18, 4.0μm, 4.6x50mm; Column Temperature: 50°C [342] Method L: [343] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 5%-95%B in 1.3min; Flow Rate: 2.0ml/min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C [344] Method M: [345] A: H2O (0.01% TFA), B: MeCN (0.01% TFA); Gradient: 10%-90%B in 1.5min, 95%B for 3min, 95%-10%B in 0.01 min; Flow Rate: 2.0ml/min; Column: SunFire C18, 3.5μm, 4.6x50mm; Column Temperature: 50°C [346] Method N: [347] A: H2O (0.05% FA), B: MeCN (0.035% FA); Gradient: 2%B for 0.2min, 2-98%B in 3.6min, 98%B for 0.5min, 98%-2%B in 0.2min; Flow Rate: 1.0ml/min; Column: Waters ACQUITY UPLC BEH C18, 1.7μm, 2.1x50mm; Column Temperature: 55°C [348] Method O: [349] A: H2O (0.05% FA), B: MeCN (0.035% FA); Gradient: 2%B for 0.2min, 2-98%B in 8.3min, 98%B for 1min, 98%-2%B in 0.5min; Flow Rate: 0.6ml/min; Column: Waters ACQUITY UPLC BEH C18, 1.7μm, 2.1x50mm; Column Temperature: 55°C [350] Method P: [351] A: H2O (0.05% FA), B: MeCN (0.045% TFA); Gradient: 2%B for 1min, 2-98%B in 22.5min, 98%B for 4min, 98%-2%B in 2.5min; Flow Rate: 0.6ml/min; Column: Waters ACQUITY UPLC CSHC18, 1.7µm, 2.1x100mm; Column Temperature: 55°C [352] SYNTHETIC METHODS [353] Table 1: Structure and analytical data of examples
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[354] Example 1: Tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]piperidine-1-carboxylate [355] Step 1: Preparation of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]piperidine-1-carboxylate [356] A mixture of 5-fluoropyridine-2-carboxamidine (100.0 mg, 0.7188 mmol), tert- butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (330.1 mg, 1.078 mmol) and K2CO3 (397.3 mg, 2.875 mmol) was stirred in ethanol (3 mL) at 80°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (10 mL) and separated by vacuum filtration. The filtrate was concentrated and purified by flash chromatography (n-heptane / ethyl acetate 100:0 to 50:50) to give tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]piperidine-1-carboxylate (151 mg, purity: 95%, yield: 58%). MS m/z 347.2 [M+H]+. [357] Step 2: Preparation of tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]piperidine-1-carboxylate [358] A mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]piperidine-1- carboxylate (129.0 mg, 0.3724 mmol) and N-chlorosuccinimide (54.70 mg, 0.4096 mmol) was stirred in dimethylformamide (3 mL) at 70°C for 3 hours. After cooling to room temperature, the solution was purified by flash chromatography (n-heptane / ethyl acetate 100:0 to 50:50) to give 170 mg crude product. Flash chromatography was repeated (n-heptane / ethyl acetate 100:0 to 90:10 to 75:25) to afford the title compound (11 mg, purity: 95%, yield: 7.4%). [359] Example 2: 1-[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-1- piperidyl]ethanone [360] Step 1: Preparation of 2-[4-chloro-5-(4-piperidyl)-1H-imidazol-2-yl]-5-fluoro- pyridine (hydrochloride) [361] Tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]piperidine-1- carboxylate (10.0 mg, 0.0263 mmol) was dissolved in 1,4-dioxane (2 mL). 4M HCl in 1,4- dioxane (1 mL) was added and the reaction was stirred for 21 hours. The crude product was concentrated in vacuo and used in the next step without further purification. [362] Step 2: Preparation of 1-[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-1- piperidyl]ethanone [363] 2-[4-Chloro-5-(4-piperidyl)-1H-imidazol-2-yl]-5-fluoro-pyridine hydrochloride (10.0 mg, 0.0315 mmol) was added to dichloromethane (2 mL). Diisopropylethylamine (0.00824 mL, 0.0473 mmol) was added, and the mixture was cooled to 0°C. Acetyl chloride (2.97 mg, 0.0378 mmol) was dissolved in dichloromethane (1 mL) and added via syringe to the mixture within 1 min. The mixture was allowed to reach room temperature and stirred for 16 hours. The mixture was concentrated in vacuo and purified by prep-HPLC to afford the title compound (11.5 mg, purity: 95%, yield: quantitative). [364] Example 3: 2-[4-Chloro-5-(1-methylsulfonyl-4-piperidyl)-1H-imidazol-2-yl]-5- fluoro-pyridine [365] A mixture of 2-[4-chloro-5-(4-piperidyl)-1H-imidazol-2-yl]-5-fluoro-pyridine hydrochloride (14.0 mg, 0.0441 mmol), dichloromethane (2 ml), N-ethyl-N-isopropyl-propan- 2-amine (19.2 µl, 0.110 mmol) and methane sulfonyl chloride (6.13 mg, 0.0530 mmol) dissolved in dichloromethane (1 ml) was stirred for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC to afford the title compound (3.5 mg, purity: 95%, yield: 22%). [366] Example 4, Example 5, and Example 6: (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2- yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 4), (3S,4S)-4-(4-chloro-2- (5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 5), and (3R*,4S*/3S*,4R*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (Example 6) [367] Step 1: Preparation of 5-fluoro-2-(1H-imidazol-2-yl)pyridine [368] To a mixture of 5-fluoropicolinaldehyde (100.0 g, 799.35 mmol) and oxalaldehyde (463.91 g,^7.99 mol) in EtOH (2000 mL) was added NH3*H2O (560.28 g,^15.99 mol)^dropwise at 0°C under N2 atmosphere. The reaction mixture was stirred at room temperature for 16 hours. Then the solvent was removed under reduced pressure. The residue was poured into water (2000 mL) and extracted with DCM (1000 mL x 3). The combined organic layers were washed with brine (3000 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated to give 5-fluoro-2-(1H-imidazol-2-yl)pyridine (102 g, purity: 98%, yield: 78%) which was used directly in the next step. MS m/z 164.1 [M+H]+. [369] Step 2: Preparation of 5-fluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)pyridine [370] To a solution of 5-fluoro-2-(1H-imidazol-2-yl)pyridine (102 g,^0.63 mol) in THF (2000 mL) was added NaH (60% in oil, 37.55 g, 0.94 mol) in several portions at 0°C under N2 atmosphere.^ The reaction was stirred at 0°C for 1 hour. Then, SEM-Cl (125.4 g, 0.75 mol) was added dropwise maintaining the temperature at 0°C. The reaction mixture was stirred at room temperature for another 6 hours. Then the mixture was quenched with water (2000 mL) and extracted with ethyl acetate (2000 mL x 3). The combined organic layers were washed with brine (2000 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 30:70) to give 5- fluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine (156 g, purity: 85%, yield:^84%). MS m/z 294.0 [M+H]+. [371] Step 3: Preparation of a mixture of 2-(5-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine [372] 5-Fluoro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine (156 g,^0.53 mol) was dissolved in chloroform (1000 mL) under N2 atmosphere. Then, NBS (94.77 g, 0.53 mol) was added in several portions at 0°C. The reaction was stirred at room temperature for 16 hours. Then the solvent was removed. The mixture was poured into water (2000 mL) and extracted with ethyl acetate (1000 mL x 3). The organic layers were washed with brine (1000 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash chromatography (ethyl acetate / petroleum ether 10:90) to give the desired crude product as a mixture of 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine (150 g, purity: 85%, yield: 76%). MS m/z 372.0 [M+H]+. [373] Step 4: Preparation of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3- methyl-3,6-dihydro-2H-pyridine-1-carboxylate [374] To a solution of a mixture of 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine (65 g, 0.18 mol) in THF (500 mL) and water (50 mL) were added (1-tert-butoxycarbonyl-3-methyl-3,6-dihydro-2H-pyridin-4-yl)boronic acid (55 g, 0.23 mol), potassium carbonate (72.5 g, 0.53 mol) and Pd(dtbpf)Cl2 (17.4 g, 0.027 mol) under nitrogen atmosphere. The reaction was stirred at 80°C for 16 hours. Then the mixture was quenched with water (500 mL) and extracted with ethyl acetate (1000 mL x 3). The combined organic layers were washed with brine (1000 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether 30:70) to afford the subtitle mixture of compounds (54 g,^purity: 85%, yield:^63%). MS m/z 489.2 [M+H]+. [375] Step 5: Preparation of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1- carboxylate [376] To a solution of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3- methyl-3,6-dihydro-2H-pyridine-1-carboxylate (9 g, 0.02 mol) in methanol (150 mL) was added Pd/C (10%, 0.9 g). The reaction was stirred under hydrogen at room temperature for 72 hours. This reaction was performed in 6 batches in parallel. The mixtures were filtered and washed with methanol (100 mL x 3). The combined filtrates were concentrated and purified by flash chromatography (ethyl acetate / petroleum ether 40:60) to give a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine- 1-carboxylate and tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate (35 g, purity: 90%, yield:^65%). MS m/z 491.4 [M+H]+. [377] Step 6: Preparation of a mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate [378] To a solution of a mixture of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1- carboxylate (54 g,^0.11 mol) in chloroform (500 mL) was added NCS (17.59 g, 0.13 mol) in several portions at 0°C. The reaction was stirred at 40°C for 16 hours. Then the solvent was removed. The mixture was poured into water (500 mL) and extracted with ethyl acetate (800 mL x 3). The combined organic layers were washed with brine (1000 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash chromatography (ethyl acetate / petroleum ether 25:75) to give the desired product as a mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate (55 g, purity: 85%, yield: 90%). MS m/z 525.3 [M+H]+. [379] Step 7: Preparation of 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (hydrochloride) [380] To a solution of a mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate (44 g, 84 mmol) in THF (40 mL) was added 4 M HCl in 1,4-dioxane (80 mL). The reaction was stirred at room temperature for 16 hours. Then the mixture was concentrated and 4 M HCl in dioxane (80 mL) was added again. The reaction was stirred at room temperature for another 8 hours. LCMS showed the reaction was completed. Then the mixture was concentrated to give 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine hydrochloride (44 g, crude), which was used in the next step without further purification. MS m/z 295.2 [M+H]+. [381] Step 8: Preparation of tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate [382] To a solution of 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine hydrochloride (44 g, crude, 84 mmol) in THF (150 mL) were added DIEA (54 g, 0.42 mol) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (27.8 g, 92.4 mmol). The reaction was stirred at room temperature for 36 hours. Then the mixture was quenched with water (200 mL) and extracted with ethyl acetate (400 mL x 3). The organic layers were combined, washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by silica gel column chromatography (ethyl acetate / petroleum ether 40:60) to give tert-butyl ((4-(4-chloro-2-(5- fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate (25 g, purity: 95%, yield (2 steps): 70%). MS m/z 474.4 [M+H]+. [383] Step 9: Preparation of 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide [384] To a mixture of tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate (33 g, 69.8 mmol) in THF (30 mL) was added 4 M HCl in dioxane (60 mL). The reaction was stirred at room temperature for 16 hours. Then the mixture was concentrated, and water (100 mL) was added. The mixture was basified with saturated K2CO3 solution to pH 9 and extracted with ethyl acetate (300 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidine-1-sulfonamide (24 g, purity: 95%, yield: 92%). The product is subjected to chiral-HPLC without further purification. MS m/z 374.2 [M+H]+. [385] Step 10: Preparation of (3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidine-1-sulfonamide and (3S,4S)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidine-1-sulfonamide and (3R*,4S*/3S*,4R*)-4-(4-chloro-2-(5- fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide [386] The mixture of isomers of 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methylpiperidine-1-sulfonamide (24.3 g, purity: 95%) was separated by SFC to afford the title compounds. [387] Preparative chiral HPLC conditions: Instrument: SFC-200 (Waters); Column: AS 25x250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2/MeOH [0.2% NH3 (7M in MeOH)] 75:25; Flow rate: 120 ml/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 8.6 min; Sample solution: 24 g dissolved in 700 ml methanol; Injection volume: 6.0 ml. [388] Analytical chiral HPLC conditions: Column: AS-3 4.6*100mm 3µm, Column temperature: 40°C; Mobile phase: CO2/MeOH [0.2% NH3 (7M in MeOH)] 85:15; Flow rate: 3 ml/min; Back pressure: 2000 psi; Detection wavelength: 254 nm; Run time: 6 min; Injection volume: 5.00 µl. [389] (3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (9.055 g, yield 38%). Chiral HPLC t=2.53min. [390] (3S,4S)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (9.5 g, yield 40%). Chiral HPLC t=4.47min. [391] (3R*,4S*/3S*,4R*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (1.1 g, yield 4.6%). Chiral HPLC t=2.04/2.11min. [392] Example 7: 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4- methylpiperidine-1-sulfonamide [393] Step 1: Preparation of tert-butyl 4-(2-chloroacetyl)-4-methyl-piperidine-1- carboxylate [394] To a solution of 1-(tert-butyl) 4-ethyl 4-methylpiperidine-1,4-dicarboxylate (1.0 g, 3.69 mmol) and chloro(iodo)methane (2.59 g, 14.76 mmol) in THF (40 mL), LDA (2 M in THF, 9.23 mL) was added at -78°C.^ After addition, the reaction was stirred for 10 minutes, and then a solution of acetic acid (2 mL) in THF (20 mL) was added while keeping the reaction mixture temperature below -65°C. The mixture was stirred for an additional 10 minutes, quenched with water (80 mL) and extracted with ethyl acetate (60 mL x 2). The organic layers were combined, washed with brine (60 mL x 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether = 0:100 to 10:90) to give tert-butyl 4-(2-chloroacetyl)-4-methyl-piperidine-1- carboxylate (864 mg, 85.0% yield). MS m/z 220.1 [M-55]+. [395] Step 2: Preparation of tert-butyl 4-(2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4- methylpiperidine-1-carboxylate [396] A mixture of 5-fluoropyridine-2-carboxamidine (764 mg, 2.77 mmol), KHCO3 (1.09 g, 10.98 mmol) and tert-butyl 4-(2-chloroacetyl)-4-methyl-piperidine-1-carboxylate (1.51 g, 5.49 mmol) in DMF (20 mL) was stirred at 50°C for 16 h. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product tert-butyl 4-(2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-4- methylpiperidine-1-carboxylate (544 mg, 54.5% yield). MS m/z 361.6 [M+H]+. [397] Step 3: Preparation of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl) -1H-imidazol- 5-yl)-4-methylpiperidine-1-carboxylate [398] To a solution of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4-methyl- piperidine-1-carboxylate (544 mg, 1.5 mmol) in MeCN (5 mL) was added NCS (202 mg, 1.8 mmol). The reaction was stirred at room temperature for 4 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer were combined, washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate / petroleum ether 70:30 to 100:0) to give tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-4-methylpiperidine-1-carboxylate (338 mg, 57% yield). MS m/z 395.3 [M+H]+. [399] Step 4: Preparation of 2-(4-chloro-5-(4-methylpiperidin-4-yl)-1H-imidazol -2-yl)- 5-fluoropyridine [400] To a solution of tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4- methyl-piperidine-1-carboxylate (96 mg, 0.243 mmol) in DCM (2 mL) was added TFA (1 mL) at 0°C. The reaction was stirred at room temperature for 2 h. The resulting mixture was concentrated to give the crude product 2-(4-chloro-5-(4-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (54 mg, 75% yield). MS m/z 295.3 [M+H]+. [401] Step 5: Preparation of tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-4–methylpiperidin-1-yl)sulfonyl)carbamate [402] A solution of [1-(ethoxycarbonylsulfamoyl)-4-pyridylidene]-dimethyl-ammonium (54 mg, 0.18 mmol), 2-[4-chloro-5-(4-methyl-4-piperidyl)-1H-imidazol-2-yl]-5-fluoro- pyridine (66 mg, 0.22 mmol) and TEA (36 mg, 0.36 mmol) in DCM (4 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and^concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether 50:50 to 70:30) to give tert-butyl ((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-methylpiperidin-1- yl)sulfonyl)carbamate (44 mg, 51.7% yield). MS m/z 474.1 [M+H]+. [403] Step 6: Preparation of 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4- methylpiperidine-1-sulfonamide [404] To a solution of tert-butyl N-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-4-methyl-1- piperidyl]sulfonyl]carbamate (44 mg, 0.093 mmol) in DCM (0.9 mL) was added TFA (0.3 mL) at 0°C. The reaction was stirred at room temperature for 1 h. The resulting mixture was concentrated and purified by prep-HPLC to afford title compound (4.2 mg, 12.1% yield). [405] Example 8: (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N-(2- hydroxyethyl)-3-methylpiperidine-1-sulfonamide [406] Step 1: Resolution of 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine: Preparation of 2-(4-chloro-5-((3S*,4R*/3R*,4S*)-3-methylpiperidin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine, 2-(4-chloro-5-((3S,4S)-3-methylpiperidin-4-yl)-1H-imidazol- 2-yl)-5-fluoropyridine and 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2-yl)- 5-fluoropyridine [407] The mixture of isomers of 2-(4-chloro-5-(3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (1.6 g) was separated by SFC to afford the title compounds. [408] Preparative chiral HPLC conditions: Instrument: Instrument: SFC-150 (Waters); Column: AS 20x250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2/EtOH (0.5% NH3 (7M in MeOH) 80:20; Flow rate: 100 ml/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 4.3 min; Sample solution: 1600 mg dissolved in 100 ml methanol; Injection volume: 2.0 ml. [409] Analytical chiral HPLC conditions: Column: AS-H 4.6*100mm 5µm; Column temperature: 40°C; Mobile phase: CO2/EtOH (0.5% NH3 (7M in MeOH) 90:10; Flow rate: 3 ml/min; Back pressure: 2000 psi; Detection wavelength: 214 nm; Run time: 7 min; Injection volume: 5.00 µl. [410] 2-(4-Chloro-5-((3S*,4R*/3R*,4S*)-3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (500 mg, impure). MS (method A) 295.1 (M+H)+, t=1.48min. 1H NMR (500 MHz, DMSO-d6) δ (selected signals) 8.61 – 8.54 (m, 1H), 8.03 (m, 1H), 7.85 – 7.76 (m, 1H), 3.31 – 3.22 (m, 2H), 3.20 – 2.73 (m, 2H), 2.48 – 2.26 (m, 1H), 2.19 – 1.90 (m, 2H), 1.73 – 1.45 (m, 1H), 0.99 – 0.54 (m, 3H) ppm. Chiral HPLC t=1.32min. [411] 2-(4-Chloro-5-((3S,4S)-3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (400 mg, purity: 99%, yield 25%). MS (method A) m/z 295.1 (M+H)+, t=1.41min. 1H NMR (500 MHz, DMSO-d6) δ 8.60 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 8.5, 4.5 Hz, 1H), 7.82 (td, J = 9.0, 3.0 Hz, 1H), 3.03 (d, J = 13.0 Hz, 2H), 2.77 (d, J = 2.0 Hz, 2H), 2.57 – 2.51 (m, 1H), 2.39 – 2.23 (m, 1H), 1.94 – 1.84 (m, 1H), 1.40 (d, J = 11.0 Hz, 1H), 0.86 (d, J = 7.0 Hz, 3H) ppm. Chiral HPLC t=2.74min. [412] 2-(4-Chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (420 mg, purity: 100%, yield 26%). MS (method A) m/z 295.2 (M+H)+, t=1.41min. 1H NMR (500 MHz, DMSO-d6) δ 8.60 (d, J = 2.5 Hz, 1H), 7.99 (dd, J = 8.5, 4.5 Hz, 1H), 7.82 (td, J = 9.0, 3.0 Hz, 1H), 3.03 (d, J = 13.0 Hz, 2H), 2.77 (d, J = 2.0 Hz, 2H), 2.56 – 2.51 (m, 1H), 2.38 – 2.23 (m, 1H), 1.90 (s, 1H), 1.39 (d, J = 11.0 Hz, 1H), 0.86 (d, J = 7.0 Hz, 3H) ppm. Chiral HPLC t=3.64min. [413] Step 2: Preparation of 3-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)oxazolidin-2-one [414] To a solution of sulfurisocyanatidic chloride (48 mg, 0.34 mmol) in^dichloromethane (2 mL) was added 2-bromoethan-1-ol (43 mg, 0.34 mmol) under N2. The solution was cooled to 0°C^and stirred for 1 hour. Then 2-(4-chloro-5-((3R,4R)-3- methylpiperidin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine (100 mg, 0.34 mmol) and triethylamine (103 mg, 1.02 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (ethyl acetate / petroleum ether 40:60) to afford the title compound (110 mg, yield: 73%). MS m/z 444.1 [M+H]+. [415] Step 3: Preparation of (3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-N-(2-hydroxyethyl)-3-methylpiperidine-1-sulfonamide [416] To a solution of 3-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)oxazolidin-2-one (110 mg, 0.25 mmol) in ethanol (2 mL) was added a solution of sodium hydroxide (12 mg,^0.3 mmol ) in water (2 mL). The reaction was^stirred at room temperature^for^2 h. Then the mixture was concentrated under reduced pressure and then water (20 mL) was added. The resulting mixture was extracted with ethyl acetate (25 mL x 3), washed with brine (20 mL x 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to afford the title compound (68.5 mg, 0.16 mmol, yield: 66%). [417] Example 9: (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-carboxamide [418] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (80 mg, 0.27 mmol) in^dichloromethane (2 mL) was added DIEA (70 mg, 0.54 mmol) at 0°C and stirred for 10 min. Then trimethylsilylisocyanate (31 mg, 0.41 mmol) was added slowly. The reaction was stirred at room temperature for 16 h. The mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (57.3 mg, 0.17 mmol, yield: 62%). [419] Example 10: 2-(4-Chloro-5-((3R,4R)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)- 1H-imidazol-2-yl)-5-fluoropyridine [420] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (80 mg, 0.27 mmol) in^dichloromethane (2 mL) was added DIEA (176 mg, 1.36 mmol) at 0°C and stirred for 10 min. Then methanesulfonyl chloride (47 mg, 0.41 mmol) was added slowly. The reaction was stirred at room temperature for 2 h. The mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (45.3 mg, 0.12 mmol, yield: 45%). [421] Example 11: 1-((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methylpiperidin-1-yl)ethan-1-one [422] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (80 mg, 0.27 mmol) in^dichloromethane (2 mL) was added DIEA (105 mg, 0.82 mmol) at 0°C and stirred for 10 min. And then acetyl chloride (25 mg, 0.33 mmol) was added slowly. The reaction was stirred at room temperature for 2 h. The mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (50.6 mg, 0.15 mmol, yield: 56%). [423] Example 12 and Example 13: (3S*,4S*)-4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 12) and (3R*,4R*)-4-(4-ethyl-2- (5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide (Example 13) [424] Step 1: Preparation of 5-fluoropicolinimidamide [425] To a solution of 4-fluoro-benzonitrile (20 g, 164 mmol) in dry THF (300 mL) was added LiHMDS (1M in THF, 328 mL, 328 mmol) slowly at -78°C. The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride (300 mL) and extracted with dichloromethane (300 mL x 3). The organic layers were combined, washed with brine (200 mL x 3), dried over anhydrous sodium sulfate and concentrated to give 5-fluoropicolinimidamide (8 g, 35% yield). MS m/z 140 [M+H]+. [426] Step 2: Preparation of 2-(4-ethyl-1H-imidazol-2-yl)-5-fluoropyridine [427] To a solution of 5-fluoropicolinimidamide (5 g, 36 mmol) in EtOH (30 ml) was added 1-bromobutan-2-one (5.6 g, 36 mmol) and K2CO3 (4.9 g, 36 mmol). The reaction mixture was stirred at 80°C for 16 h. The resulting mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give 2-(4-ethyl-1H-imidazol-2-yl)-5- fluoropyridine (3 g, crude), which was used for the next step without further purification. MS m/z 192 [M+H]+. [428] Step 3: Preparation of 2-(5-bromo-4-ethyl-1H-imidazol-2-yl)-5-fluoro-pyridine [429] To a solution of 2-(4-ethyl-1H-imidazol-2-yl)-5-fluoro-pyridine (3 g, 15 mmol) in MeCN (100 mL) was added N-bromosuccinimide (3.2 g, 18 mmol). The reaction was stirred at room temperature for 16 h. The resulting mixture was diluted with EA (200 mL), washed with brine (200 mL x 3), dried over anhydrous sodium sulfate and concentrated. The crude was purified by column chromatography on silica gel (ethyl acetate/petroleum ether 20:80) to give 2-(5-bromo-4-ethyl-1H-imidazol-2-yl)-5-fluoro-pyridine (3.2 g, 75.5% yield). MS m/z 270 [M+H]+. [430] Step 4: Preparation of a mixture of 2-[[5-bromo-4-ethyl-2-(5-fluoro-2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-bromo-5-ethyl-2-(5-fluoro-2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane [431] To a solution of 2-(5-bromo-4-ethyl-1H-imidazol-2-yl)-5-fluoro-pyridine (1 g, 3.7 mmol) in THF (dry, 30 mL) was added NaH (133 mg, 5.5 mmol) and 2-(chloromethoxy)ethyl- trimethyl-silane (926 mg, 5.5 mmol) at 0°C. The reaction was stirred at room temperature for 4 h. The mixture was diluted with EA (100 mL), washed with brine (100 mL x 3), dried over anhydrous sodium sulfate and concentrated. The crude was purified by column chromatography (petroleum ether/ethyl acetate = 1/5) to afford the subtitle compounds (700 mg, 47.2% yield). MS m/z 400 [M+H]+. [432] Step 5: Preparation of a mixture of tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-3- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1- carboxylate and tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate [433] To a solution of a mixture of 2-[[5-bromo-4-ethyl-2-(5-fluoro-2-pyridyl)imidazol- 1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-bromo-5-ethyl-2-(5-fluoro-2-pyridyl)imidazol- 1-yl]methoxy]ethyl-trimethyl-silane (700 mg, 1.7 mmol) in dioxane (30 mL) and water (3 mL) were added (1-(tert-butoxycarbonyl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (750 mg, 2.5 mmol), potassium carbonate (470 mg, 3.4 mmol) and Pd(tbdpf)Cl2 (115 mg, 0.17 mmol) under nitrogen atmosphere. The reaction was stirred at 70°C for 4 hours. Then the mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 20:80) to afford the subtitle compounds (741 mg, 1.43 mmol, yield:^85%). MS m/z 517 [M+H]+. [434] Step 6: Preparation of a mixture of tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-3- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate [435] To a solution of a mixture of tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4- yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (741 mg, 1.43 mmol) in methanol (10 mL) was added Pd/C (10%, 100 mg). The reaction was stirred under hydrogen at room temperature for 16 hours. The mixture was filtered and the solid washed with methanol (10 mL x 3). The combined filtrates were concentrated and the residue purified by flash chromatography (ethyl acetate / petroleum ether 30:70) to give a mixture of tert-butyl 4-[5- ethyl-2-(5-fluoro-2-pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate and tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate (703 mg, 1.35 mmol, 95% yield). MS m/z 519 [M+H]+. [436] Step 7: Preparation of 2-(4-ethyl-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine [437] To a solution of a mixture of tert-butyl 4-[5-ethyl-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl 4- [5-ethyl-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate (800 mg, 1.54 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in dioxane (20 mL). The reaction was stirred at room temperature for 16 hours. LCMS showed the reaction was completed. Then the mixture was concentrated to give the product 2-(4- ethyl-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine (400 mg, 1.38 mmol, crude), which was used in the next step without further purification. MS m/z 289 [M+H]+. [438] Step 8: Preparation of tert-butyl ((4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate [439] To a solution of 2-(4-ethyl-5-(3-methylpiperidin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (270 mg, 0.93 mmol) in DCM (10 mL) were added DIEA (232 mg, 1.86 mmol) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (308 mg, 0.99 mmol). The reaction was stirred at room temperature for 4 hours. Then the mixture was quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by silica gel column chromatography (ethyl acetate / petroleum ether 50:50) to give tert-butyl ((4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)carbamate (340 mg, 0.72 mmol, 78% yield). MS m/z 468 [M+H]+. [440] Step 9: Preparation of 4-[4-ethyl-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-piperidine-1-sulfonamide [441] To a solution of tert-butyl N-[[4-[4-ethyl-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]carbamate (370 mg, 1 mmol) in 1,4-dioxane (5 mL) was added 4 M HCl in dioxane (5 mL). The reaction was stirred at room temperature for 2 hours. Then the mixture was concentrated, and water (40 mL) was added. The mixture was basified with saturated K2CO3 solution to pH = 9 and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (60 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 4-[4-ethyl-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-piperidine-1-sulfonamide (250 mg, 0.68 mmol, 68% yield). [442] Step 10: Preparation of (3R*,4R*)-4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidine-1-sulfonamide and (3S*,4S*)-4-(4-ethyl-2-(5- fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonamide [443] The isomers of 4-[4-ethyl-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- piperidine-1-sulfonamide were separated by chiral SFC to afford the title compounds. [444] Preparative chiral separation conditions: Instrument: SFC-150 (Waters); Column: AS 25x250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2/MeOH [0.2% NH3 (7M in MeOH) 70:30; Flow rate: 100ml/min; Back pressure: 100bar; Detection wavelength: 214nm; Cycle time: 4.5min; Sample solution: 270mg dissolved in 25ml methanol; Injection volume: 1ml. [445] Analytical chiral separation conditions: Column: AS3 4.6x100mm, 3μm; Column temperature: 40°C; Mobile phase: CO2/MeOH [0.2% NH3 (7M in MeOH) 80:20; Flow rate: 3ml/min; Back pressure: 2000psi; Detection wavelength: 214nm; Run time: 5min; Injection volume: 5µl. [446] (3R*,4R*)-4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (70 mg, 28% yield). Chiral HPLC 1.54min. [447] (3S*,4S*)-4-(4-ethyl-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide (90 mg, 36% yield). Chiral HPLC 1.23min. [448] Example 14: Methyl (((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidin-1-yl)sulfonyl)glycinate [449] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (150 mg, 0.51 mmol) in^dichloromethane (3 mL) was added triethylamine (155 mg, 1.53 mmol) under N2. And then methyl (chlorosulfonyl)glycinate (954 mg, 5.10 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 40:60) to afford the title compound (120 mg, 0.27 mmol, yield: 53%). [450] Example 15: (((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)glycine [451] To a solution of methyl (((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)glycinate (90 mg, 0.20 mmol) in THF (2 mL) was added a solution of lithium hydroxide (15 mg,^0.6 mmol) in water (2 mL). The reaction was^stirred at room temperature^for^2 h. The mixture was extracted with ethyl acetate (15 mL x 3), washed with brine (10 mL x 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to afford the title compound (74 mg, 0.17 mmol, yield: 85%). [452] Example 16: 2-(4-Chloro-5-((3S,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)- 1H-imidazol-2-yl)-5-fluoropyridine [453] To a solution of 2-(4-chloro-5-((3S,4S)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (100 mg, 0.34 mmol) in^dichloromethane (2 mL) was added DIEA (132 mg, 1.02 mmol) at 0°C and stirred for 10 min. And then methanesulfonyl chloride (58 mg, 0.51 mmol) was added slowly. The reaction was stirred at room temperature for 2 h. The mixture was quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (19.6 mg, 0.05 mmol, yield: 15%). [454] Example 17: 2-(4-Chloro-5-((3R*,4S*/3S*,4R*)-3-methyl-1- (methylsulfonyl)piperidin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine [455] To a solution of 2-(4-chloro-5-((3R*,4S*/3S*,4R*)-3-methylpiperidin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (200 mg, 0.68 mmol) in^THF (4 mL) was added DIEA (263 mg, 2.04 mmol) at 0°C and stirred for 10 min. And then methanesulfonyl chloride (116 mg, 1.02 mmol) was added slowly. The reaction was stirred at room temperature for 2 h. The mixture was quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (16.3 mg, 0.04 mmol, yield: 6%). [456] Example 18: 1-(((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxamide [457] Step 1: Preparation of methyl-1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)- 1H-imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate [458] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (190 mg, 0.65 mmol) in^THF (2 mL) was added DIEA (167 mg, 1.3 mmol) at 0°C and stirred for 10 min. And then methyl-1-(chlorosulfonyl)azetidine-3- carboxylate (96 mg, 0.78 mmol) was added slowly. The reaction was stirred at room temperature for 16 h. The mixture was quenched with water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether 30:70) to afford the subtitle compound (180 mg, 0.38 mmol, yield: 59%). MS m/z 472.1 [M+H]+. [459] Step 2: Preparation of 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylic acid [460] To a solution of methyl 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate (180 mg, 0.38 mmol) in MeOH (2 mL) was added a solution of sodium hydroxide (76 mg,^1.91 mmol ) in water (2 mL). The reaction was^stirred at room temperature^for^16 h. Then the mixture was diluted with water (20 mL), acidified with 1 M HCl solution to pH 4, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine (20 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuum to afford the subtitle compound (130 mg, 0.28 mmol, yield: 74%). MS m/z 458.0 [M+H]+. [461] Step 3: Preparation of 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxamide [462] To a solution of 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylic acid (100 mg, 0.22 mmol) in DCM (2 mL) were added DIEA (225 mg, 1.75 mmol), NH4Cl (59 mg, 1.09 mmol), EDCI (83 mg, 0.44 mmol) and HOBt (59 mg, 0.44 mmol). The reaction was stirred at room temperature for 16 hours. Then the crude product was purified by prep-HPLC to afford the title compound (83.6 mg, 0.18 mmol, yield: 84%). [463] Example 19: (S*)-2-(4-Chloro-5-(3-methyl-1-(methylsulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine [464] Step 1: Preparation of 5-fluoro-2-(1H-imidazol-2-yl)pyridine [465] To a mixture of 5-fluoropicolinaldehyde (100.0 g, 799.35 mmol) and oxalaldehyde (463.91 g,^7.99 mol) in EtOH (2000 mL) was added NH3*H2O (560.28 g,^15.99 mol)^dropwise at 0°C under N2 atmosphere. The reaction mixture was stirred at room temperature for 16 hours. Then the solvent was removed under reduced pressure. The residue was poured into water (2000 mL) and extracted with DCM (1000 mL x 3). The combined organic layers were washed with brine (3000 mL x 2), dried with Na2SO4, filtered and concentrated to give the crude product 5-fluoro-2-(1H-imidazol-2-yl)pyridine (100 g) which was used directly in the next step. MS m/z 164.1 (M+H)+. [466] Step 2: Preparation of 2-(4,5-diiodo-1H-imidazol-2-yl)-5-fluoropyridine [467] 5-Fluoro-2-(1H-imidazol-2-yl)pyridine (100 g, 612.91 mmol) was dissolved acetonitrile (1000 ml) under N2 atmosphere. Then, NIS (303.4 g, 1.35 mol) was added in several portions at 0°C. The reaction mixture was stirred at room temperature for 6 hours. Then the solvent was removed. The residue was poured into water (2000 mL) and extracted with ethyl acetate (1000 mL x 3). The organic layers were washed with brine (1000 mL x 3), dried with Na2SO4, filtered and concentrated to afford the crude subtitle compound (219 g) which was used directly in the next step. MS m/z 415.8 (M+H)+. [468] Step 3: Preparation of 5-fluoro-2-(4-iodo-1H-imidazol-2-yl)pyridine [469] To a solution of 2-(4,5-diiodo-1H-imidazol-2-yl)-5-fluoropyridine (219 g, 527.78 mmol) in DMF (2000 mL) and water (1000 mL) was added Na2SO3 (399 g,^3.166 mol) in several portions. The reaction was stirred at^120°C for 16 hours. Then the reaction mixture was poured into water (5000 mL) and extracted with ethyl acetate (3000 mL x 3). The combined organic layers were washed with brine (5000 mL x 3), dried with Na2SO4, filtered and concentrated to give the crude product 5-fluoro-2-(4-iodo-1H-imidazol-2-yl)pyridine (130 g) which was used directly in the next step. MS m/z 289.9 (M+H)+. [470] Step 4: Preparation of a mixture of 5-fluoro-2-(4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine and 5-fluoro-2-(5-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine [471] To a solution of 5-fluoro-2-(4-iodo-1H-imidazol-2-yl)pyridine (130 g,^0.45 mol) in THF (2000 mL) was added NaH (26.99 g, 0.675 mol, 60%) in several portions at 0°C under N2 atmosphere.^The resulting mixture was stirred at 0°C for 1 hour. Then, SEM-Cl (90 g, 0.54 mol) was added dropwise maintaining the temperature at 0°C. The reaction was stirred at room temperature for another 6 hours. The reaction mixture was quenched by adding water (2000 mL) slowly and extracted with ethyl acetate (2000 mL x 3). The combined organic layers were washed with brine (5000 mL x 2), dried with Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (Biotage Flash, ethyl acetate/petroleum ether 25:75) to afford the subtitle compounds (170 g, 0.405 mol, yield:^50.7% in 4 steps). MS m/z 420.0 (M+H)+. [472] Step 5: Preparation of a mixture of 2-(5-chloro-4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-chloro-5-iodo-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine [473] To a solution of a mixture of 5-fluoro-2-(4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine and 5-fluoro-2-(5-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyridine (10 g,^23.9 mmol) in THF (100 mL) was added NCS (3.81 g, 28.6 mmol) in several portions. The reaction mixture was stirred at 40°C for 16 h. The mixture was poured into water (150 mL) and extracted with EA (150 mL x 3). The organic layers were washed with brine (150 mL x 2), dried with Na2SO4 and concentrated. The crude was purified by flash chromatography (ethyl acetate / petroleum ether 20:80) to give the desired mixture of 2-(5-chloro-4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-chloro-5-iodo-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (5.6 g, 12.4 mmol, yield: 52%). MS m/z 454.0 [M+H]+. [474] Step 6: Preparation of a mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1- (2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1- carboxylate and tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate [475] To a solution of a mixture of 2-(5-chloro-4-iodo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-chloro-5-iodo-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (1 g, 2.2 mmol) in THF (10 mL)^ were added (1-(tert-butoxycarbonyl)-3-methyl-1,2,3,6-tetrahydropyridin-4- yl)boronic acid (798 mg, 3.3 mmol) and potassium carbonate (914 mg, 6.6 mmol) in water (2 mL). And then Pd(dtbpf)Cl2 (285 mg, 0.44 mmol) was added under N2 atmosphere. The reaction was stirred at 80°C for 16 h. The reaction mixture was quenched with adding water (80 mL) and extracted with EA (80 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether 30:70) to give a mixture of tert-butyl 4-[5- chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6- dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (500 mg, 0.96 mmol, yield:^43 %). MS m/z 523.2 [M+H]+. [476] Step 7: Preparation of 2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine [477] A mixture of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate and tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4- yl]-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (500 mg, 0.96 mmol) and TFA (4 mL) was stirred at room temperature for 2 hours. Then the mixture was concentrated, diluted with water (20 mL), basified with saturated K2CO3 solution to pH 9 and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-(4-chloro-5-(3-methyl- 1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine (200 mg, 0.68 mmol, yield: 72%). The crude product is subjected to chiral HPLC without further purification. MS m/z 293.1 [M+H]+. [478] Step 8: Preparation of (S*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4- yl)-1H-imidazol-2-yl)-5-fluoropyridine and (R*)-2-(4-chloro-5-(3-methyl-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine [479] The enantiomeric mixture 2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)- 1H-imidazol-2-yl)-5-fluoropyridine (270 mg) was separated by chiral HPLC to give (S*)-2-(4- chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine (130 mg) and (R*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5- fluoropyridine (125 mg). [480] Preparative chiral HPLC conditions: Instrument: SFC-150 (Waters); Column: AD 25x250mm, 10μm (Daicel); Column temperature: 35°C; Mobile phase: CO2/ MeOH (0.2% NH3(7M in MeOH) 75:25; Flow rate: 100 ml/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 3.0 min; Sample solution: 300 mg dissolved in 35 ml methanol; Injection volume: 1.0 ml. [481] Analytical chiral HPLC conditions: Column: AD-H 4.6x100µm, 5μm; Column temperature: 40°C; Mobile phase: CO2/ MeOH (0.2% NH3(7M in MeOH) 75:25; Flow rate: 3ml/min; Back pressure: 2000psi; Detection wavelength: 214 nm; Run time: 4.0 min; Injection volume: 7.00 µl. (S*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine. Chiral HPLC 0.87 min. (R*)-2-(4-chloro-5-(3-methyl-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine. Chiral HPLC 1.12min. [482] Step 9: Preparation of (S*)-2-(4-chloro-5-(3-methyl-1-(methylsulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine [483] To a solution of (S*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (65 mg, 0.22 mmol) in DCM (2 mL) was added DIEA (86 mg, 0.67 mmol) at 0°C. Then methanesulfonyl chloride (30 mg, 0.27 mmol) was added dropwise. The reaction was stirred at room temperature for 3 hours. Then the mixture was quenched with water (10 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (36.5 mg, 0.10 mmol, yield: 44%). [484] Example 20: (R*)-2-(4-Chloro-5-(3-methyl-1-(methylsulfonyl)-1,2,3,6- tetrahydropyridin-4-yl)-1H-imidazol-2-yl)-5-fluoropyridine [485] To a solution of (R*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (60 mg, 0.21 mmol) in DCM (2 mL) was added DIEA (80 mg, 0.62 mmol) at 0°C. Then methanesulfonyl chloride (28 mg, 0.25 mmol) was added slowly. The reaction was stirred at room temperature for 3 hours. Then the mixture was quenched with water (10 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (28.1 mg, 0.08 mmol, yield: 37%). [486] Example 21: (S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-sulfonamide [487] Step 1: Preparation of tert-butyl (S*)-((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate [488] To a solution of (S*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (65 mg, 0.22 mmol) in DCM (2 mL) were added DIEA (86 mg, 0.67 mmol) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)- yl)sulfonyl)amide (67 mg, 0.22 mmol). The reaction was stirred at room temperature for 2 hours. Then the mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether 50:50) to give tert-butyl (S*)-((4- (4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridin-1(2H)- yl)sulfonyl)carbamate (72 mg, 0.15 mmol, yield: 68%). MS m/z 472.0 [M+H]+. [489] Step 2: Preparation of (S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methyl-3,6-dihydropyridine-1(2H)-sulfonamide [490] A mixture of tert-butyl (S*)-((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (72 mg, 0.15 mmol) and 4 M HCl in dioxane (4 mL) was stirred at room temperature for 16 hours. Then the mixture was concentrated, diluted with water (10 mL), basified with saturated K2CO3 solution to pH 9, and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (27.6 mg, 0.07 mmol, yield: 49%). [491] Example 22: (R*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-sulfonamide [492] Step 1: Preparation of tert-butyl (R*)-((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate [493] To a solution of (R*)-2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (80 mg, 0.27 mmol) in DCM (2 mL) were added DIEA (106 mg, 0.82 mmol) and (tert-butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)- yl)sulfonyl)amide (82 mg, 0.27 mmol). The reaction was stirred at room temperature for 2 hours. Then the mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether 50:50) to give tert-butyl (R*)-((4- (4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridin-1(2H)- yl)sulfonyl)carbamate (88 mg,0.19 mmol, yield 68%). MS m/z 472.1 [M+H]+. [494] Step 2: Preparation of (R*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methyl-3,6-dihydropyridine-1(2H)-sulfonamide [495] A mixture of tert-butyl (R*)-((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (88 mg, 0.19 mmol) and 4 M HCl in 1,4-dioxane (4 mL) was stirred at room temperature for 16 hours. Then the mixture was concentrated, diluted with water (10 mL), basified with saturated K2CO3 solution to pH 9, and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (44.4 mg, 0.12 mmol, yield: 64%). [496] Example 23: 2-(5-((3R,4R)-1-((1H-Pyrazol-4-yl)sulfonyl)-3-methylpiperidin-4-yl)- 4-chloro-1H-imidazol-2-yl)-5-fluoropyridine [497] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (60 mg, 0.20 mmol) in^THF (2 mL) was added DIEA (53 mg, 0.41 mmol) at 0°C and stirred for 10 min. And then 1H-pyrazole-4-sulfonyl chloride (41 mg, 0.24 mmol) was added slowly. The reaction was stirred at room temperature for 16 h. The mixture was quenched with water (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by prep-HPLC to afford the title compound (22.1 mg, 0.05 mmol, yield: 25%). [498] Example 24: Methyl 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate [499] To a solution of 2-(4-chloro-5-((3R,4R)-3-methylpiperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine (190 mg, 0.65 mmol) in^THF (2 mL) was added DIEA (167 mg, 1.3 mmol) at 0°C and stirred for 10 min. And then methyl 1-(chlorosulfonyl)azetidine-3- carboxylate (96 mg, 0.78 mmol) was added slowly. The reaction was stirred at room temperature for 16 h. The mixture was quenched with water (30 mL) and extracted with EA (30 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether 30:70) to afford the title compound (180 mg, 0.38 mmol, yield: 59%). [500] Example 25: 1-(((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylic acid [501] To a solution of methyl 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate (180 mg, 0.38 mmol) in MeOH (2 mL) was added a solution of sodium hydroxide (76 mg,^1.91 mmol ) in water (2 mL). The reaction was^stirred at room temperature^for^16 h. Then the mixture was diluted with water (20 mL), acidified with 1 M HCl solution to pH 4 and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine (20 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuum to afford the title compound (130 mg, 0.28 mmol, yield: 74%). [502] Example 26: 2-(4-Bromo-5-(2,3-difluorophenyl)-1H-imidazol-2-yl)-5- fluoropyridine [503] Step 1: Preparation of 2-(4,5-dibromo-1H-imidazol-2-yl)-5-fluoro-pyridine [504] To a solution of 5-fluoro-2-(1H-imidazol-2-yl)pyridine (350 mg, 2.15 mmol) in chloroform (7 mL) was added NBS (764 mg,^4.29 mmol) under N2 atmosphere. The reaction was stirred at^room temperature for 2 h. The mixture was quenched with water (20 mL) and extracted with^ethyl acetate (30 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash chromatography (ethyl acetate / petroleum ether 30:70) to give 2-(4,5- dibromo-1H-imidazol-2-yl)-5-fluoro-pyridine (650 mg, 2.03 mmol, 94% yield). MS m/z 321.6 [M+H]+. [505] Step 2: Preparation of 2-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine [506] To a solution of 2-(4,5-dibromo-1H-imidazol-2-yl)-5-fluoropyridine (300 mg,^0.93 mmol) in THF (10 mL)^at 0°C under N2 atmosphere was added NaH (45 mg, 1.12 mmol, 60%) slowly.^The reaction mixture was stirred at 0°C for 30 min. Then, SEM-Cl (202 mg, 1.21 mmol) was added dropwise maintaining the temperature at 0°C and the reaction mixture was stirred at room temperature for another 2 h. The reaction mixture was quenched with adding water (30 mL) slowly and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether 15:85) to give 2- (4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (355 mg,^ 0.79 mmol, yield:^84%). MS m/z 450.0 [M+H]+. [507] Step 3: Preparation of a mixture of 2-(4-bromo-5-(2,3-difluorophenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(5-bromo-4-(2,3- difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine [508] To a solution of 2-(4,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol- 2-yl)-5-fluoropyridine (300 mg,^ 0.67 mmol) in 1,4-dioxane (6 mL) and water (1.2 mL) were added (2,3-difluorophenyl)boronic acid (105 mg, 0.67 mmol), sodium carbonate (211 mg, 2 mmol), and Pd(dppf)Cl2 (49 mg, 0.07 mmol) under nitrogen atmosphere. The reaction was stirred at 80°C for 18 hours. Then the mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The^crude product^was purified by flash column chromatography (ethyl acetate / petroleum ether 40:60) to give a mixture of 2-(4-bromo-5-(2,3-difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine and 2-(5-bromo-4-(2,3-difluorophenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (180 mg, 0.37 mmol, yield:^56%) [509] Step 4: Preparation of 2-(4-bromo-5-(2,3-difluorophenyl)-1H-imidazol-2-yl)-5- fluoropyridine [510] A mixture of 2-(4-bromo-5-(2,3-difluorophenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(5-bromo-4-(2,3- difluorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (180 mg, 0.37 mmol) and TFA (5 mL) was stirred at room temperature for 2 hours. Then the mixture was concentrated, and the^crude product was purified by prep-HPLC to afford the title compound (80 mg, 0.23 mmol, yield:^61 %). [511] Example 27: 2-(4-Bromo-5-(2-chlorophenyl)-1H-imidazol-2-yl)-5-fluoropyridine [512] To a solution of 2-(4,5-dibromo-1H-imidazol-2-yl)-5-fluoropyridine (600 mg, 1.87 mmol) in 1,4-dioxane (6 mL) and water (1.2 mL) were added (2-chlorophenyl)boronic acid (292 mg, 1.87 mmol), potassium carbonate (774 mg, 5.6 mmol), CataCXium A (161 mg, 0.45 mmol) and Pd(OAc)2 (42 mg, 0.19 mmol) under nitrogen atmosphere. The reaction was stirred at 80°C for 18 hours. Then the mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The^crude product was purified by prep-HPLC to afford the title compound (45.9 mg, 0.13 mmol, yield:^7%). [513] Example 28: 2-[4-Chloro-5-(2-chloro-4-methylsulfinyl-phenyl)-1H-imidazol-2-yl]- 5-fluoro-pyridine [514] Step 1: Preparation of 2-(4-chloro-1H-imidazol-2-yl)-5-fluoropyridine [515] 5-Fluoro-2-(1H-imidazol-2-yl)pyridine (3 g, 18.4 mmol) was dissolved in N,N- dimethylformamide (40 mL). Then N-chlorosuccinimide (2.4 g, 18.4 mmol) and acetic acid (1.1 g, 18.4 mmol) were added. The reaction was stirred at 60°C for 16 hours. Then water (80 mL) was added. The mixture was extracted with dichloromethane (100 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 25:75) to afford 2-(4-chloro-1H-imidazol-2-yl)-5-fluoropyridine (1.9 g, 9.6 mmol, yield: 52%). MS m/z 198 [M+H]+. [516] Step 2: Preparation of 2-(5-bromo-4-chloro-1H-imidazol-2-yl)-5-fluoropyridine [517] 2-(4-Chloro-1H-imidazol-2-yl)-5-fluoropyridine (1.9 g, 9.6 mmol) was dissolved in tetrahydrofuran (20 mL). The solution was^cooled to 0°C. Then N-bromosuccinimide (2.1 g, 11.57 mmol) was added. The reaction was stirred at room temperature for^3 hours. Then water (80 mL) was added. The resulting mixture was extracted with dichloromethane (80 mL x 3). The combined organic layer was washed with brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 25:75) to afford 2-(5-bromo-4-chloro-1H-imidazol-2-yl)-5- fluoropyridine (2 g, 7.3 mmol, yield: 76%). MS m/z 278 [M+H]+. [518] Step 3: Preparation of a mixture of 2-(5-bromo-4-chloro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-5-chloro- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine [519] 2-(5-Bromo-4-chloro-1H-imidazol-2-yl)-5-fluoropyridine (1.8 g, 6.55 mmol) was dissolved in tetrahydrofuran (20 mL). The solution was^cooled to 0°C. Then sodium hydride (236 mg, 9.82 mmol) was added. The mixture was stirred at 0°C for^30 min. Then 2- (trimethylsilyl)ethoxymethyl chloride (1.64 g, 9.82 mmol) was added. The reaction was stirred at room temperature for another 2 hours. Then water (50 mL) was added. The mixture was extracted with ethyl acetate (80 mL x 3). The combined organic layer was washed with brine (80 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 25:75) to afford a mixture of 2-(5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-5-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5- fluoropyridine (2.5 g, 6.2 mmol, yield: 94%). MS m/z 349.9 [M+H]+. [520] Step 4: Preparation of a mixture of 2-(4-chloro-5-(2-chloro-4- (methylsulfinyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5- fluoropyridine and 2-(5-chloro-4-(2-chloro-4-(methylsulfinyl)phenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine [521] To a solution of a mixture of 2-(5-bromo-4-chloro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-5-chloro- 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (500 mg,^ 1.23 mmol) in 1,4-dioxane (6 mL) and water (1.2 mL) were added (2,3-difluorophenyl)boronic acid (443 mg, 1.48 mmol), sodium carbonate (263 mg, 2.46 mmol), and Pd(dtbpf)Cl2 (160 mg, 0.246 mmol) under nitrogen atmosphere. The reaction was stirred at 50°C for 2 hours. Then the mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The^crude product^was purified by flash column chromatography (ethyl acetate / petroleum ether 40:60) to give a mixture of 2-(4-chloro-5-(2- chloro-4-(methylsulfinyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5- fluoropyridine and 2-(5-chloro-4-(2-chloro-4-(methylsulfinyl)phenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (130 mg, 0.248 mmol, yield:^20.1%). MS m/z 499.7 [M+H]+. [522] Step 5: Preparation of 2-[4-chloro-5-(2-chloro-4-methylsulfinyl-phenyl)-1H- imidazol-2-yl]-5-fluoro-pyridine [523] The mixture of 2-(4-chloro-5-(2-chloro-4-(methylsulfinyl)phenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(5-chloro-4-(2- chloro-4-(methylsulfinyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5- fluoropyridine (100 mg, 0.2 mmol) was dissolved in trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 4 h. Then, the solvent was removed, and water (10 mL) was added. The mixture was basified with saturated K2CO3 solution to pH 9 and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product which was purified by column chromatography (ethyl acetate / petroleum ether 50:50) to afford the title compound (60 mg, 0.162 mmol, yield: 81.1%). [524] Example 29: 2-[4-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-1H-imidazol-2- yl]-5-fluoro-pyridine [525] Step 1: Preparation of a mixture of 2-[[4-chloro-5-(2-chloro-4-methylsulfonyl- phenyl)-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro- 4-(2-chloro-4-methylsulfonyl-phenyl)-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane [526] A mixture of 2-(4-chloro-5-(2-chloro-4-(methylsulfinyl)phenyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(5-chloro-4-(2- chloro-4-(methylsulfinyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5- fluoropyridine (70 mg, 0.14 mmol) was dissolved in acetone (1 mL) and water (0.3 mL). Then potassium monopersulfate triple salt (Oxone) (172 mg, 0.28 mmol) was added in one portion. The reaction was stirred at room temperature for 2 hours. Then the mixture was poured into water (5 mL) and extracted with EA (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether 50:50) to give a mixture of 2-[[4-chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-2-(5-fluoro-2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-4-(2-chloro-4- methylsulfonyl-phenyl)-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (70 mg, 0.129 mmol, yield: 92.1%). MS m/z 515.7 [M+H]+. [527] Step 2: Preparation of 2-[4-chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-1H- imidazol-2-yl]-5-fluoro-pyridine [528] A mixture of 2-[[4-chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-2-(5-fluoro-2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-4-(2-chloro-4- methylsulfonyl-phenyl)-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 0.194 mmol) was dissolved in trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 4 h. Then, the solvent was removed, and water (10 mL) was added. The mixture was basified with saturated K2CO3 solution to pH 9 and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by column chromatography (ethyl acetate / petroleum ether 50:50) to afford the title compound (28.5 mg, 0.162 mmol, yield: 54.8%). [529] Example 30: 2-[4-Chloro-5-(2-chloro-4-(methylsulfonimidoyl)phenyl)-1H- imidazol-2-yl]-5-fluoro-pyridine [530] Step 1: Preparation of a mixture of 2-[[4-chloro-5-[2-chloro-4- (methylsulfonimidoyl)phenyl]-2-(5-fluoro- 2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl- silane and 2-[[5-chloro-4-[2-chloro-4-(methylsulfonimidoyl)phenyl]-2-(5-fluoro- 2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane [531] To a solution of a mixture of 2-(4-chloro-5-(2-chloro-4-(methylsulfinyl)phenyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(5-chloro-4-(2- chloro-4-(methylsulfinyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5- fluoropyridine (120 mg, 0.24 mmol) and (NH4)2CO3 (46.1 mg, 0.48 mmol) in MeOH (2 mL), [acetoxy(phenyl)-lambda3-iodanyl] acetate (178 mg, 0.551 mmol) was added in one portion under N2 atmosphere. The reaction mixture was stirred at room temperature for 3 h. The solvent was removed. The resulting mixture was poured into water (10 mL) and extracted with EA (20 mL x 3). The organic layers were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by column chromatography (ethyl acetate / petroleum ether 50:50). This provided a mixture of 2-[[4-chloro-5-[2-chloro-4-(methylsulfonimidoyl)phenyl]-2-(5-fluoro- 2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-4-[2-chloro-4- (methylsulfonimidoyl)phenyl]-2-(5-fluoro- 2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl- silane (100 mg, 0.194 mmol, yield: 80.9%). MS m/z 514.7 [M+H]+. [532] Step 2: Preparation of 2-[4-chloro-5-(2-chloro-4-(methylsulfonimidoyl)phenyl)- 1H-imidazol-2-yl]-5-fluoro-pyridine [533] A mixture of 2-[[4-chloro-5-[2-chloro-4-(methylsulfonimidoyl)phenyl]-2-(5- fluoro- 2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-4-[2-chloro- 4-(methylsulfonimidoyl)phenyl]-2-(5-fluoro- 2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane (100 mg, 0.194 mmol) was dissolved in trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 4 h. Then, the solvent was removed, and water (10 mL) was added. The mixture was basified with saturated K2CO3 solution to pH 9 and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product which was purified by column chromatography (ethyl acetate / petroleum ether 50:50) to afford the title compound (20.3 mg, 0.053 mmol, yield: 27.2%). [534] Example 31: Methyl 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzoate [535] Step 1: Preparation of a mixture of methyl 3-chloro-4-[5-chloro-2-(5-fluoro-2- pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate and methyl 3-chloro-4-[5- chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate [536] To a mixture of 2-(5-bromo-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-5-chloro-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (250 mg, 0.615 mmol) and (2-chloro-4-methoxycarbonyl-phenyl)boronic acid (158 mg, 0.738 mmol) in THF (5 mL) and water (0.5 mL) were added Pd(dtbpf)Cl2 (80.1 mg, 0.123 mmol) and K2CO3 (170 mg, 1.23 mmol). The reaction was stirred at 70°C for 16 h under nitrogen. LCMS indicated the reaction was completed. The reaction mixture was cooled to room temperature, diluted with water (10 mL), acidified with 1 M HCl solution until pH 5 and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous sodium sulfate and concentrated to give the residue, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether 20:80) to give a mixture of methyl 3-chloro- 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate and methyl 3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]benzoate (133 mg, 0.255 mmol, yield: 41.4%). MS m/z 497 [M+H]+. [537] Step 2: Preparation of methyl 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]benzoate [538] A solution of a mixture of methyl 3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]benzoate and methyl 3-chloro-4-[5-chloro-2-(5- fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate (133 mg, 0.268 mmol) in 4 M HCl in 1,4-dioxane (4 mL) was stirred at room temperature for 16 h. Then the reaction mixture was concentrated. The residue was diluted with water (5 mL), basified with sat. ammonium bicarbonate solution until pH 7 and extracted with ethyl acetate (15 ml x 3). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to afford the title compound (84.5 mg, 0.219 mmol, yield: 81.8%). [539] Example 32: 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzoic acid [540] To a solution of methyl 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]benzoate (40 mg, 0.109 mmol) in MeOH (1 mL) was added a solution of lithium hydroxide monohydrate (91.7 mg, 2.18 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was diluted with water (10 mL), acidified with 1 M HCl solution until pH 5 and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over anhydrous sodium sulfate and concentrated to give the residue, which was purified by prep-HPLC to afford the title compound (23.2 mg, 0.064 mmol, yield: 59.1%). [541] Example 33: 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzenesulfonamide [542] Step 1: Preparation of 4-bromo-3-chloro-N,N-bis[(2,4- dimethoxyphenyl)methyl]benzenesulfonamide [543] To a solution of 4-bromo-3-chloro-benzenesulfonyl chloride (5.0 g, 17.2 mmol) in dichloromethane (50 mL) was added 1-(2,4-dimethoxyphenyl)-N-[(2,4- dimethoxyphenyl)methyl]methanamine (6.57 g, 20.7 mmol) and triethylamine (6.98 g, 69.0 mmol) slowly. The reaction was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether 50:50) to afford 4-bromo-3-chloro-N,N-bis[(2,4- dimethoxyphenyl)methyl]benzenesulfonamide (9.8 g, 17.2 mmol, yield: 99.5%). MS (method B) 2.51min. [544] Step 2: Preparation of 4-bromo-3-chloro-N,N-bis[(2,4- dimethoxyphenyl)methyl]benzenesulfonamide [545] A mixture of 4-bromo-3-chloro-N,N-bis[(2,4- dimethoxyphenyl)methyl]benzenesulfonamide (9.8 g, 17.2 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (5.23 g, 20.6 mmol), Pd(dppf)Cl2*DCM (628 mg, 0.858 mmol) and potassium acetate (5.05 g, 51.5 mmol) in dry 1,4-dioxane (100 mL) was stirred at 80°C for 6 h under nitrogen atmosphere. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (Biotage, ethyl acetate / petroleum ether 40:60) to afford 4-bromo-3-chloro-N,N-bis[(2,4- dimethoxyphenyl)methyl]benzenesulfonamide (11 g, 16.9 mmol, yield: 98.5%). MS (method E) 1.99min. [546] Step 3: Preparation of [4-[bis[(2,4-dimethoxyphenyl)methyl]sulfamoyl]-2-chloro- phenyl]boronic acid [547] To a solution of 3-chloro-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (11 g, 16.9 mmol) in acetone (100 mL) and water (30 mL) was added ammonium acetate (3.6 g, 47.3 mmol) and sodium periodate (11.9 g, 55.8 mmol) in potions. The reaction was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine^(200 mL), dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (Biotage, ethyl acetate / petroleum ether 50:50) to give [4-[bis[(2,4- dimethoxyphenyl)methyl]sulfamoyl]-2-chloro-phenyl]boronic acid (2.5 g, 4.43 mmol, yield: 26.2%). MS (method E) 1.98min. [548] Step 4: Preparation of a mixture of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4- [2-(5-fluoro-2-pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzenesulfonamide and 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]benzenesulfonamide [549] A mixture of 2-[[5-bromo-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane and 2-[[4-bromo-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane (1.1 g, 2.95 mmol), [4-[bis[(2,4-dimethoxyphenyl)methyl]sulfamoyl]-2- chloro-phenyl]boronic acid (1.58 g, 2.95 mmol), Pd(dtbpf)Cl2 (385 mg, 0.591 mmol) and potassium carbonate (817 mg, 5.91 mmol) were added to 1,4-dioxane (15 ml) and water (3 ml). The reaction mixture was stirred at 70°C for 16 h under nitrogen. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Biotage, ethyl acetate / petroleum ether 15:85) to give a mixture of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[2-(5-fluoro-2- pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzenesulfonamide and 3-chloro-N- [(2,4-dimethoxyphenyl)methyl]-4-[2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]benzenesulfonamide (1.37 g, 1.95 mmol, yield: 65.2%). MS m/z 633 [M+H]+. [550] Step 5: Preparation of 3-chloro-4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzenesulfonamide [551] A mixture of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[2-(5-fluoro-2- pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzenesulfonamide and 3-chloro-N- [(2,4-dimethoxyphenyl)methyl]-4-[2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]benzenesulfonamide (870 mg, 1.24 mol) in TFA (10 mL) was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was basified with sat. sodium bicarbonate solution until pH 8, extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether 70:30) to give 3-chloro-4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzenesulfonamide (230 mg, 0.652 mmol, yield: 50.1%). MS m/z 353 [M+H]+. [552] Step 6: Preparation of 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzenesulfonamide [553] To a solution of 3-chloro-4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzenesulfonamide (230 mg, 0.652 mmol) in DMF (2 mL) was added NCS (113 mg, 0.848 mmol). The reaction mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was purified by prep-HPLC to afford title compound (140 mg, 0.343 mmol, yield: 52.6%). [554] Example 34: 2-[[3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylamino]acetic acid [555] Step 1: Preparation of a mixture of tert-butyl 2-[[3-chloro-4-[2-(5-fluoro-2- pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate and tert-butyl 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)- 1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate [556] [557] To a solution of a mixture of 3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[2-(5- fluoro-2-pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzenesulfonamide and 3- chloro-N-[(2,4-dimethoxyphenyl)methyl]-4-[2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]benzenesulfonamide (500 mg, 0.790 mmol) in dry THF (5 ml) was added NaH (47.4 mg, 1.18 mmol) at 0°C. The reaction mixuture was stirred at 0°C for 10 min. Then tert-butyl 2-bromoacetate (185 mg, 0.948 mmol) was added into the reaction mixture. The reaction was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was quenched with sat. ammonium chloride solution, diluted with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried with anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel chromatography (ethyl acetate / petroleum ether 20:80) to afford a mixture of tert-butyl 2-[[3- chloro-4-[2-(5-fluoro-2-pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4- yl]phenyl]sulfonyl-[(2,4-dimethoxyphenyl)methyl]amino]acetate and tert-butyl 2-[[3-chloro- 4-[2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl- [(2,4-dimethoxyphenyl)methyl]amino]acetate (224 mg, 0.285 mmol, yield: 36.1%). MS m/z 747 [M+H]+. [558] Step 2: Preparation of a mixture of tert-butyl 2-[[3-chloro-4-[5-chloro-2-(5-fluoro- 2-pyridyl)-3-(2-trime-thylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate and tert-butyl 2-[[3-chloro-4-[5-chloro-2-(5-fluoro-2- pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate [559] To a solution of a mixture of tert-butyl 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate and tert-butyl 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)- 1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate (220 mg, 0.294 mmol) in dry DMF (3 mL) was added NCS (59.0 mg, 0.442 mmol). The reaction mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried with anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (Biotage Flash, ethyl acetate / petroleum ether 10:90) to give a mixture of tert-butyl 2-[[3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2-trime- thylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate and tert-butyl 2-[[3-chloro-4-[5-chloro-2-(5-fluoro-2- pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate (190 mg, 0.231 mmol, yield: 78.4%). MS m/z 747 [M+H]+. [560] Step 3: Preparation of 2-[[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]phenyl]sulfonylamino]acetic acid [561] A solution of a mixture of tert-butyl 2-[[3-chloro-4-[5-chloro-2-(5-fluoro-2- pyridyl)-3-(2-trime-thylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate and tert-butyl 2-[[3-chloro-4-[5-chloro-2-(5-fluoro-2- pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]acetate (100 mg, 0.128 mol) in TFA (5 ml) was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford title compound (5.2 mg, 0.014 mmol, yield: 8.95%). MS (method E) m/z 445 [M+H]+, t=1.32min. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 2.8 Hz, 1H), 8.10 (dd, J = 8.8, 4.4 Hz, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.92 – 7.86 (m, 1H), 7.86 – 7.82 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 3.25 (s, 2H) ppm. [562] Example 35: 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N-(2- hydroxyethyl)benzenesulfonamide [563] Step 1: Preparation of 2-[(2,4-dimethoxyphenyl)methylamino]ethanol [564] To a solution of 2,4-dimethoxybenzaldehyde (6.0 g, 0.0361 mol) and 2- aminoethanol (2.21 g, 0.0361 mmol) in methanol (44 mL), anhydrous sodium sulfate (2.31 g, 0.0162 mol) was added. The mixture was stirred at room temperature for 16 hours. Then sodium borohydride (0.683 g, 0.0181 mol) was added over 15 minutes, and the mixture was stirred at room temperature for 30 minutes. After that, acetic acid (1.08 g, 0.0181 mol) was added. The mixture was stirred for 10 minutes and concentrated to approximately 1/2 of the volume under reduced pressure. The concentrated mixture was diluted with sat. sodium carbonate solution and extracted with dicholoromethane (150 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried with anhydrous sodium sulfate and concentrated. The residue was triturated with petroleum ether (40 mL) and ethyl acetate (1.6 mL). The precipitate was filtered, washed with petroleum ether (50 mL) and dried in vacuo to give 2-[(2,4-dimethoxyphenyl)methylamino]ethanol (5.6 g, yield: 73%). MS m/z 212 [M+H]+. [565] Step 2: Preparation of 4-bromo-3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-N-(2- hydroxyethyl)benzenesulfonamide [566] To a solution of 2-[(2,4-dimethoxyphenyl)methylamino]ethanol (1.1 g, 5.21 mmol) and DIEA (2.02 g, 15.6 mmol) in DCM (20 mL) was added 4-bromo-3-chloro- benzenesulfonyl chloride (1.51 g, 5.21 mmol). The reaction mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether 15:85) to give 4-bromo-3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-N-(2- hydroxyethyl)benzenesulfonamide (2.05 g, yield: 85%). MS (method B) 1.30min. [567] Step 3: Preparation of 2-[(4-bromo-3-chloro-phenyl)sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl acetate [568] To a solution of 4-bromo-3-chloro-N-[(2,4-dimethoxyphenyl)methyl]-N-(2- hydroxyethyl)benzenesulfonamide (1.9 g, 4.09 mmol), N,N-diethylethanamine (1.65 g, 16.36 mmol) in DCM (20 mL) was added acetyl chloride (0.642 g, 8.18 mmol) dropwise at 0°C. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water (100 mL), extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried with anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (ethyl acetate / petroleum ether 10:90) to afford 2-[(4-bromo-3- chloro-phenyl)sulfonyl-[(2,4-dimethoxyphenyl)methyl]amino]ethyl acetate (1.65 g, yield: 80%). MS m/z 508 [M+H]+. [569] Step 4: Preparation of 2-[[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]sulfonyl-[(2,4-dimethoxyphenyl)methyl]amino]ethyl acetate [570] A mixture of 2-[(4-bromo-3-chloro-phenyl)sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl acetate (1.55 g, 3.06 mmol), bis(pinacolato)diboron (932 mg, 3.67 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (224 mg, 0.306 mmol) and potassium acetate (900 mg, 9.18 mmol) in dry 1,4-dioxane (15 mL) was stirred at 80°C for 16 hours under nitrogen atmosphere. LCMS indicated the reaction was completed. The reaction was diluted with water (100 mL), extracted with ethyl actate (100 mL x 3). The organic layers were washed with brine (100 mL), dried with anhydrous sodium sulfate and concentrated under reduced pressure to give 2-[[3-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]sulfonyl-[(2,4-dimethoxyphenyl)methyl]amino]ethyl acetate (1.6 g, yield: 94%). MS (method G) 1.76min. [571] Step 5: Preparation of [4-[2-acetoxyethyl-[(2,4- dimethoxyphenyl)methyl]sulfamoyl]-2-chloro-phenyl]boronic acid [572] To a solution of 2-[[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]sulfonyl-[(2,4-dimethoxyphenyl)methyl]amino]ethyl acetate (1.6 g, 2.89 mmol) in acetone (20 mL) and water (10 mL) were added ammonium acetate (623 mg, 8.09 mmol) and sodium periodate (2.06 g, 9.54 mmol). The reaction was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine (100 mL), dried with anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether 50:50) to give [4-[2-acetoxyethyl-[(2,4- dimethoxyphenyl)methyl]sulfamoyl]-2-chloro-phenyl]boronic acid (660 mg, yield: 48%). MS (method I) 1.77min. [573] Step 6: Preparation of a mixture of 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl acetate and 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl acetate [574] A mixture of [4-[2-acetoxyethyl-[(2,4-dimethoxyphenyl)methyl]sulfamoyl]-2- chloro-phenyl]boronic acid (500 mg, 1.06 mmol), a mixture of 2-(5-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine and 2-(4-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (395 mg, 1.06 mmol), 1,1'- bis (di-t-butylphosphino)ferrocene palladium dichloride (68.4 mg, 0.106 mmol) and potassium carbonate (293 mg, 2.12 mmol) in THF (5 mL) and water (1 mL) was stirred at 65°C for 16 hours under nitrogen atmosphere. LCMS indicated the reaction was completed. The reaction was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried with anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether 10:90) to give a mixture of 2-[[3-chloro-4-[2- (5-fluoro-2-pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl acetate and 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl acetate (354 mg, yield: 46%). MS m/z 719 [M+H]+. [575] Step 7: Preparation of 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylamino]ethyl acetate [576] A solution of a mixture of 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl acetate and 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonyl-[(2,4- dimethoxyphenyl)methyl]amino]ethyl acetate (354 mg, 0.492 mmol) in TFA (5 mL) was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was concentrated, diluted with water (10 mL), basified with sat. sodium bicarbonate solution until pH 8 and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried with anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether 10:90) to give 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylamino]ethyl acetate (117 mg, yield: 54%). MS m/z 349 [M+H]+. [577] Step 8: Preparation of 2-[[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]phenyl]sulfonylamino]ethyl acetate [578] To a solution of 2-[[3-chloro-4-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylamino]ethyl acetate (117 mg, 0.267 mmol) in DMF (3 mL) was added NCS (53.4 mg, 0.400 mmol) slowly. The reaction mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried with anhydrous sodium sulfate, and concentrated to give 2-[[3- chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]phenyl]sulfonylamino]ethyl acetate (108 mg, crude). MS m/z 473 [M+H]+. [579] Step 9: Preparation of 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-N-(2-hydroxyethyl)benzenesulfonamide [580] To a solution of 2-[[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylamino]ethyl acetate (108 mg, 0.228 mmol) in MeOH (2 mL) was added a solution of lithium hydroxide monohydrate (95.7 mg, 2.28 mmol) in water (1 mL). The reaction was stirred at room temperature for 16 h. The mixture was diluted with water (10 mL), acidified with 1 M HCl solution to pH 7 and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC to afford the title compound (45.3 mg, yield: 46%). [581] Example 36: 2-[5-(2-Chloro-4-methylsulfonyl-phenyl)-4-methyl-1H-imidazol-2- yl]-5-fluoro-pyridine [582] Step 1: Preparation of 5-fluoro-2-(4-methyl-1H-imidazol-2-yl)pyridine [583] To a solution of 5-fluoropyridine-2-carbaldehyde (3.5 g, 28.0 mmol) in MeOH (250 mL) were added ammonium acetate (21.6 g, 280.0 mmol), 2-oxopropanal (25.2 g of 40% aq. solution, 140 mmol). The reaction was stirred at 70°C for 2 h. LCMS indicated the reaction was completed. The reaction mixture was concentrated and purified by silica gel column chromatography (ethyl acetate / petroleum ether 70:30) to give 5-fluoro-2-(4-methyl-1H- imidazol-2-yl)pyridine (4.25 g, 23.98 mmol, yield: 86%). MS m/z 178 [M+H]+. [584] Step 2: Preparation of 5-fluoro-2-(5-iodo-4-methyl-1H-imidazol-2-yl)pyridine [585] To a solution of 5-fluoro-2-(4-methyl-1H-imidazol-2-yl)pyridine (4.25 g, 24.0 mmol) in MeCN (40 mL) was added NIS (5.94 g, 26.4 mmol) slowly at room temperature. The reaction mixture was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried with anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether 20:80) to afford 5- fluoro-2-(5-iodo-4-methyl-1H-imidazol-2-yl)pyridine (4.7 g, 15.5 mmol, yield: 65%). MS m/z 304 [M+H]+. [586] Step 3: Preparation of a mixture of 2-[[2-(5-fluoro-2-pyridyl)-5-iodo-4-methyl- imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[2-(5-fluoro-2-pyridyl)-4-iodo-5-methyl- imidazol-1-yl]methoxy]ethyl-trimethyl-silane [587] To a solution of 5-fluoro-2-(5-iodo-4-methyl-1H-imidazol-2-yl)pyridine (4.75 g, 15.7 mmol) in THF (50 mL) was added 60% NaH in mineral oil (940 mg, 23.5 mmol) slowly at 0°C. The mixture was stirred at 0°C for 10 min. Then SEM-Cl (3.9 g, 23.5 mmol) was added. The reaction was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried with anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether 30:70) to afford a mixture of 2-[[2-(5-fluoro-2-pyridyl)-5-iodo-4-methyl-imidazol-1-yl]methoxy]ethyl-trimethyl- silane and 2-[[2-(5-fluoro-2-pyridyl)-4-iodo-5-methyl-imidazol-1-yl]methoxy]ethyl-trimethyl- silane (5.6 g, 12.9 mmol, yield: 82%). MS m/z 434 [M+H]+. [588] Step 4: Preparation of a mixture of 2-[[5-(2-chloro-4-methylsulfonyl-phenyl)-2-(5- fluoro-2-pyridyl)-4-methyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-(2-chloro- 4-methylsulfonyl-phenyl)-2-(5-fluoro-2-pyridyl)-5-methyl-imidazol-1-yl]methoxy]ethyl- trimethyl-silane [589] A mixture of 2-[[2-(5-fluoro-2-pyridyl)-5-iodo-4-methyl-imidazol-1- yl]methoxy]ethyl-trimethyl-silane and 2-[[2-(5-fluoro-2-pyridyl)-4-iodo-5-methyl-imidazol-1- yl]methoxy]ethyl-trimethyl-silane (110 mg, 0.346 mmol), Pd(dtbpf)Cl2 (22.6 mg, 0.0346 mmol) and potassium carbonate (95.7 mg, 0.692 mmol) in 1,4-dioxane (1.5 mL) and water (0.3 mL) was stirred at 70°C for 16 h under nitrogen atmosphere. LCMS indicated the reaction was completed. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether 30:70) to afford a mixture of 2-[[5-(2-chloro-4-methylsulfonyl-phenyl)-2-(5-fluoro-2-pyridyl)-4-methyl-imidazol-1- yl]methoxy]ethyl-trimethyl-silane and 2-[[4-(2-chloro-4-methylsulfonyl-phenyl)-2-(5-fluoro- 2-pyridyl)-5-methyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane (130 mg, 0.262 mmol, yield: 76%). MS m/z 496 [M+H]+. [590] Step 5: Preparation of 2-[5-(2-chloro-4-methylsulfonyl-phenyl)-4-methyl-1H- imidazol-2-yl]-5-fluoro-pyridine [591] A solution of a mixture of 2-[[5-(2-chloro-4-methylsulfonyl-phenyl)-2-(5-fluoro-2- pyridyl)-4-methyl-imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-(2-chloro-4- methylsulfonyl-phenyl)-2-(5-fluoro-2-pyridyl)-5-methyl-imidazol-1-yl]methoxy]ethyl- trimethyl-silane (130 mg, 0.262 mmol) in TFA (3 mL) was stirred at room temperature for 16 h. LCMS indicated the reaction was completed. The reaction mixture was concentrated to give the crude product, which was purified by prep-HPLC to afford title compound (54.4 mg, 0.148 mmol, yield: 56%). MS (method E) m/z 366 [M+H]+, t=1.61min. 1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.62 (t, J = 2.8 Hz, 1H), 8.14-8.07 (m, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.92 (dd, J = 8.0, 2.0 Hz, 1H), 7.84 (td, J = 8.8, 2.8 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 3.33 (s, 3H), 2.25 (s, 3H) ppm. [592] Example 37: Methyl 1-((3-chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)phenyl)sulfonyl)azetidine-3-carboxylate [593] Step 1: Preparation of methyl 1-((4-bromo-3-chlorophenyl)sulfonyl) azetidine-3- carboxylate [594] To a solution of 4-bromo-3-chloro-benzenesulfonyl chloride (8.0 g, 27.6 mmol) and methyl azetidine-3-carboxylate (3.5 g, 30.3 mmol)^in the DCM (100 mL) was added TEA (5.58 g, 55.2 mmol) in several portions. The reaction was stirred at room temperature for 2 h. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography (EA/PE 70:30 to 100:0) to give methyl 1-((4-bromo-3-chlorophenyl)sulfonyl)azetidine-3- carboxylate (9.7 g, 95.4% yield). MS m/z 369.9 [M+H]+. [595] Step 2: Preparation of methyl 1-((3-chloro-4-(4,4,5,5-tetramethyl-1,3,2– dioxaborolan-2-yl)phenyl)sulfonyl)azetidine-3-carboxylate [596] To a solution of methyl 1-(4-bromo-3-chloro-phenyl)sulfonylazetidine-3- carboxylate (11.2 g, 30.4 mmol) and 4,4,5,5-tetramethyl-2-(3,3,4,4-tetramethylborolan-1-yl)- 1,3,2-dioxaborolane (8.35 g, 33.4 mmol) in 1,4-dioxane (120 mL) was added potassium acetate (5.96 g, 60.8 mmol) in several portions. Then 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.22 g, 3.04 mmol) was added. The reaction was stirred at 90°C for 16h under nitrogen. The reaction mixture was poured into water (100 mL) and extracted with EA (100 mL x 2). The organic layers were combined, washed with brine (100 mL x 2), dried with anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (EA/PE 10:90) to give methyl 1-((3-chloro-4-(4,4,5,5- tetramethyl-1,3,2–dioxaborolan-2-yl)phenyl)sulfonyl)azetidine-3-carboxylate (6.8 g, 53.8% yield). MS m/z 334.0 [M-82+H]+. [597] Step 3: Preparation of a mixture of 1-[3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)- 3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonylazetidine-3-carboxylic acid and 1-[3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4- yl]phenyl]sulfonylazetidine-3-carboxylic acid [598] To a solution of a mixture of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-iodo-imidazol- 1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-2-(5-fluoro-2-pyridyl)-4-iodo-imidazol- 1-yl]methoxy]ethyl-trimethyl-silane (1.23 g, 2.7 mmol) and methyl 1-((3-chloro-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl)sulfonyl)azetidine-3-carboxylate (1.25 g, 3.0 mmol) in 1,4-dioxane/H2O (20 mL, 10:1) was added potassium carbonate (829 mg, 6.0 mmol). Then 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (195 mg, 0.3 mmol) was added under N2. The reaction was stirred at 80°C for 16 h. Then the mixture was poured into water (100 mL) and extracted with EA (100 mL x 2). The organic layers were combined, washed with brine (100 mL x 2), dried with anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (MeOH/DCM 0:100 to 10:90) to give a mixture of 1-[3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonylazetidine-3-carboxylic acid and 1- [3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4- yl]phenyl]sulfonylazetidine-3-carboxylic acid (172 mg, 9.54% yield). MS m/z 601.0 [M+H]+. [599] Step 4: Preparation of methyl 1-((3-chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)- 1H-imidazol-5-yl)phenyl)sulfonyl)azetidine-3-carboxylate [600] A solution of a mixture of 1-[3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonylazetidine-3-carboxylic acid and 1- [3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4- yl]phenyl]sulfonylazetidine-3-carboxylic acid (59 mg, 0.09 mmol) in HCl/MeOH (4 M, 4 mL) was stirred at room temperature for 4 h. The reaction mixture was concentrated and purified by prep-HPLC to afford the title compound (5.9 mg, 12.4% yield). [601] Example 38: 1-((3-Chloro-4-(4-chloro-2-(5-fluoro-pyridin-2-yl)-1H-imidazol-5- yl)-phenyl) sulfonyl)azetidine-3-carboxylic acid [602] A solution of 1-[3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl) imidazol-4-yl]phenyl]sulfonylazetidine-3-carboxylic acid (82 mg, 0.14 mmol) in HCl/1,4-dioxane (4 M, 4 mL) was stirred at room temperature for 6 h. Then the mixture was concentrated and purified by prep-HPLC to afford title compound (6.6 mg, 10.2% yield). [603] Example 39: 1-((3-Chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)phenyl)sulfonyl)azetidine-3-carboxamide [604] To a solution of 1-[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylazetidine-3-carboxylic acid (97 mg, 0.21 mmol), EDCI (59 mg, 0.31 mmol) and HOBt (42 mg, 0.31 mmol) in DMF (4 mL) were added DIEA (54 mg, 0.42 mmol) and ammonium chloride (22.5 mg, 0.42 mmol). The reaction was stirred at room temperature for 6 h. Then the mixture was poured into water (20 mL) and extracted with EA (20 mL x 2). The organic layers were combined, washed with brine (20 mL x 2), dried with anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the title compound (2.9 mg, 3.33% yield). [605] Example 40: Methyl 2-chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)benzoate [606] Step 1: Preparation of a mixture of methyl 2-chloro-3-[5-chloro-2-(5-fluoro-2- pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate and methyl 2-chloro-3-[5- chloro-2-(5-fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate [607] To a solution of a mixture of 2-[[5-chloro-2-(5-fluoro-2-pyridyl)-4-iodo-imidazol- 1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-iodo-imidazol- 1-yl]methoxy]ethyl-trimethyl-silane (1.3 g, 2.9 mmol) in 1,4-dioxane (13 mL)^ were added methyl 2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.7 g, 5.7 mmol) and potassium carbonate (1.2 g, 8.6 mmol) in water (2.6 mL). And then Pd(dtbpf)Cl2 (185 mg, 0.29 mmol) was added under N2 atmosphere. The reaction was stirred at 80°C for 16 h. The reaction mixture was quenched with water (80 mL) and extracted with EA (80 mL x 3). The combined organic layers were washed with brine (80 mL x 2), dried and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether 20:80) to give a mixture of methyl 2-chloro-3-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]benzoate and methyl 2-chloro-3-[5-chloro-2-(5- fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate (465 mg, 0.94 mmol, yield:^33%). MS m/z 496.0 [M+H]+. [608] Step 2: Preparation of methyl 2-chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)benzoate [609] A mixture of methyl 2-chloro-3-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]benzoate and methyl 2-chloro-3-[5-chloro-2-(5- fluoro-2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]benzoate (465 mg,^ 0.94 mmol) and 4 M HCl in 1,4-dioxane (10 mL) was stirred at room temperature for 16 hours. Then the mixture was diluted with water (20 mL), basified with saturated K2CO3 solution until pH 9 and extracted with ethyl acetate (40 mL x 3). The organic layers were combined, washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether 30:70) to afford the title compound (190 mg, 0.52 mmol, yield:^55%). 30 [610] Example 41: 2-Chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)benzoic acid [611] To a solution of methyl 2-chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)benzoate (180 mg, 0.49 mmol) in MeOH (2 mL) was added a solution of sodium hydroxide (98 mg,^2.46 mmol) in water (2 mL). The mixture was^stirred at room temperature^for^16 h. Then the mixture was diluted with water (20 mL), acidified with 1 M HCl solution to pH 4 and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine (20 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuum to afford title compound (105 mg, 0.30 mmol, yield: 61%). [612] Example 42: 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-2,3-dihydro- 1,2-benzothiazole 1,1-dioxide [613] Step 1: Preparation of 1-benzylsulfanyl-3-bromo-2-methyl-benzene [614] A mixture of 1,3-dibromo-2-methyl-benzene (25 g, 100 mmol), phenylmethanethiol (9.94 g, 80 mmol), DIEA (20.7 g, 160 mmol), Pd2(dba)3 (2.29 g, 2.5 mmol) and Xantphos (2.49 g, 5 mmol) in 1,4-dioxane (600 mL) was stirred at 100°C for 6 h. The resulting mixture was cooled to room temperature and water (300 mL) was added. The aqueous layer was extracted with DCM (300 mL x 3). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE) to give 1-benzylsulfanyl-3-bromo-2-methyl-benzene (17.2 g, 58% yield). MS (method M) 2.23min. [615] Step 2: Preparation of 3-bromo-2-methyl-benzenesulfonyl chloride [616] A mixture of 1-benzylsulfanyl-3-bromo-2-methyl-benzene (12.2 g, 41.6 mmol), H2O (3.0 g, 166 mmol) and acetic acid (12.5 g, 208 mmol) in DCM (400 mL) was stirred at 0°C for 5 min. Then sulfuryl chloride (22.5 g, 166 mmol) was added dropwise. After addition, the mixture was stirred at 0°C for 5 min, then warmed to room temperature and stirred for 20 min. Then the mixture was cooled to 0°C and water (50 mL) was added. The mixture was stirred at room temperature for another 1 h. The resulting mixture was washed with water (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-bromo-2-methyl-benzenesulfonyl chloride (16.2 g, crude). The crude product was used for the next step without further purification. MS m/z 320 [M+H]+. [617] Step 3: Preparation of 3-bromo-N-tert-butyl-2-methyl-benzenesulfonamide [618] A mixture of 3-bromo-2-methyl-benzenesulfonyl chloride (8.1 g, crude) and^DMAP (2.44 g, 20 mmol) in DCM (200 mL) was stirred at room temperature. Then 2- methylpropan-2-amine (8.78 g, 120 mmol) and DIEA (15.5 g, 120 mmol) was added. The mixture was stirred at room temperature for 16 h. Then DCM (300 mL) was added. The organic layer was washed with brine (200 mL x 2), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (DCM / PE 50:50) to give 3-bromo- N-tert-butyl-2-methyl-benzenesulfonamide (4.8 g, yield: 78%). MS m/z 250 [M-55]+. [619] Step 4: Preparation of 3-bromo-2-(bromomethyl)-N-tert-butyl-benzenesulfonamide [620] A mixture of 3-bromo-N-tert-butyl-2-methyl-benzenesulfonamide (4.8 g, 15.6 mmol) in DCM (150 mL) was stirred at room temperature. NBS (16.7 g, 94 mmol) was added. The mixture was stirred at room temperature for 72 h. The resulting mixture was filtered. The solution was concentrated and purified by silica gel column chromatography (DCM / PE 50:50) to give 3-bromo-2-(bromomethyl)-N-tert-butyl-benzenesulfonamide (5.2 g, yield: 86%). MS m/z 330 [M-55]+. [621] Step 5: Preparation of 4-bromo-2-tert-butyl-3H-1,2-benzothiazole 1,1-dioxide [622] A mixture of 3-bromo-2-(bromomethyl)-N-tert-butyl-benzenesulfonamide (5.2 g, 13.5 mmol), K2CO3 (3.73 g, 27 mmol) and tetra-n-butylammonium iodide (1.0 g, 1.35 mmol) in CH3CN (100 mL) was stirred at 50°C for 16 h. The resulting mixture was cooled to room temperature and filtered. The solution was concentrated and purified by silica gel column chromatography (DCM / PE 50:50) to give 4-bromo-2-tert-butyl-3H-1,2-benzothiazole 1,1- dioxide (3.7 g, yield: 90%). MS m/z 248 [M-55]+. [623] Step 6: Preparation of 2-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3H-1,2-benzothiazole 1,1-dioxide [624] A mixture of 4-bromo-2-tert-butyl-3H-1,2-benzothiazole 1,1-dioxide (3.7 g, 12.2 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (3.71 g, 14.6 mmol), KOAc (2.98 g, 30 mmol) and Pd(dppf)Cl2 (890 mg, 1.22 30 mmol) in 1,4-dioxane (80 mL) was stirred at 80°C for 6 h under N2. The resulting mixture was cooled to room temperature and filtered. The solution was concentrated and the residue was purified by silica gel column chromatography (DCM / PE 60:40) to afford the subtitle compound (3.6 g, yield: 84%). MS m/z 296 [M-55]+. [625] Step 7: Preparation of (2-tert-butyl-1,1-dioxo-3H-1,2-benzothiazol-4-yl)boronic acid [626] A mixture of 2-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-1,2- benzothiazole 1,1-dioxide (430 mg, 1.2 mmol) and ammonium acetate (264 mg, 3.4 mmol) in acetone/H2O (10 mL / 2 mL) was stirred at room temperature. Then NaIO4 (916 mg, 4.3 mmol) was added. The mixture was stirred at room temperature for 16 h. The resulting mixture was poured into water (20 mL). The aqueous layer was extracted with EA (20 mL x 3). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (MeOH / DCM 5:95) to give (2-tert-butyl-1,1- dioxo-3H-1,2-benzothiazol-4-yl)boronic acid (240 mg, 72% yield). MS m/z 214 [M-55]+. [627] Step 8: Preparation of a mixture of 2-[[5-(2-tert-butyl-1,1-dioxo-3H-1,2- benzothiazol-4-yl)-4-chloro-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl- silane and 2-[[4-(2-tert-butyl-1,1-dioxo-3H-1,2-benzothiazol-4-yl)-5-chloro-2-(5-fluoro-2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane [628] A mixture of (2-tert-butyl-1,1-dioxo-3H-1,2-benzothiazol-4-yl)boronic acid (240 mg, 0.89 mmol), a mixture of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-iodo-imidazol-1- yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-2-(5-fluoro-2-pyridyl)-4-iodo-imidazol-1- yl]methoxy]ethyl-trimethyl-silane (243 mg, 0.53 mmol), Pd(dtbpf)Cl2 (117 mg, 0.178 mmol) and K2CO3 (246 mg, 1.78 mmol) in 1,4-dioxane/H2O (8 mL/2 mL) was stirred at 80°C for 16 h under N2. The resulting mixture was cooled to room temperature, filtered and concentrated. The residue was purified by silica gel column chromatography (MeOH / DCM 4:96) to give a mixture of 2-[[5-(2-tert-butyl-1,1-dioxo-3H-1,2-benzothiazol-4-yl)-4-chloro-2-(5-fluoro-2- pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-(2-tert-butyl-1,1-dioxo-3H- 1,2-benzothiazol-4-yl)-5-chloro-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl- silane (110 mg, 22.4% yield). MS m/z 551 [M+H]+. [629] Step 9: Preparation of 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-2,3- 30 dihydro-1,2-benzothiazole 1,1-dioxide [630] A mixture of 2-[[5-(2-tert-butyl-1,1-dioxo-3H-1,2-benzothiazol-4-yl)-4-chloro-2- (5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[4-(2-tert-butyl-1,1- dioxo-3H-1,2-benzothiazol-4-yl)-5-chloro-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane (110 mg, 0.2 mmol) in TFA (5 mL) was stirred at 40°C for 16 h. The resulting mixture was cooled to room temperature and concentrated. The residue was purified by reversed-phase column chromatography to afford the title compound (27 mg, 37% yield). [631] Example 43: 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-2- methylbenzenesulfonamide [632] Step 1: Preparation of 3-bromo-N,N-bis(2,4-dimethoxybenzyl)-2- methylbenzenesulfonamide [633] To a solution of 3-bromo-2-methylbenzenesulfonyl chloride (8.0 g, 29.8 mmol) and pyridine (4.77 g, 59.6 mmol) in DCM (100 mL) was added 1-(2,4-dimethoxyphenyl)-N- [(2,4-dimethoxyphenyl)methyl]methanamine (9.45 g, 29.8 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was poured into water (300 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by flash chromatography (ethyl acetate / petroleum ether 10:90) to give 3-bromo- N,N-bis(2,4-dimethoxybenzyl)-2-methylbenzenesulfonamide (8.1 g, 14.7 mmol, 49% yield). MS m/z 574 [M+Na]+. [634] Step 2: Preparation of N,N-bis(2,4-dimethoxybenzyl)-2-methyl-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [635] To a solution of 3-bromo-N,N-bis(2,4-dimethoxybenzyl)-2- methylbenzenesulfonamide (8.1 g, 14.8 mmol) in 1,4-dioxane (100 mL) were added bis(pinacolato)diboron (5.64 g, 22.2 mmol), potassium carbonate (2.9 g, 29.6 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.07 g, 1.48 mmol) under nitrogen atmosphere. The reaction was stirred at 80°C for 16 hours. Then the mixture was quenched with water (200 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (400 mL x 2), dried over anhydrous sodium sulfate, filtered and 30 concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 20:80) to give N,N-bis(2,4-dimethoxybenzyl)-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzenesulfonamide (8 g, 13 mmol, yield: 87%). MS m/z 620 [M+Na]+. [636] Step 3: Preparation of (3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)-2- methylphenyl)boronic acid [637] To a solution of N,N-bis(2,4-dimethoxybenzyl)-2-methyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzenesulfonamide (8 g, 13.3 mmol) in acetone (50 mL) and water (50 mL) were added ammonium acetate (2.9 g, 37.2 mmol) and sodium periodate (9.4 g, 43.9 mmol). The reaction was stirred at room temperature for 16 h. Then the mixture was quenched with water (200 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (400 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 40:60) to give (3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)-2-methylphenyl)boronic acid (4.5 g, 8.7 mmol, 65.4% yield). MS m/z 538 [M+Na]+. [638] Step 4: Preparation of mixture of 3-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-methyl- benzenesulfonamide and 3-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-methyl- benzenesulfonamide [639] To a solution of (3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)-2- methylphenyl)boronic acid (200 mg, 0.38 mmol) in 1,4-dioxane (10 mL) and water (2 mL) were added a mixture of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-iodo-imidazol-1- yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-2-(5-fluoro-2-pyridyl)-4-iodo-imidazol-1- yl]methoxy]ethyl-trimethyl-silane (171 mg, 0.38 mmol), potassium carbonate (104 g, 0.76 mmol) and Pd(dtbpf)Cl2 (24.8 mg, 0.038 mmol) under nitrogen atmosphere. The reaction mixture was stirred at 80°C for 8 hours. Then the mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 20:80) to give a mixture of 3-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-N,N-30 bis[(2,4-dimethoxyphenyl)methyl]-2-methyl-benzenesulfonamide and 3-[5-chloro-2-(5-fluoro- 2-pyridyl)-1-(2-trimethylsilylethoxymethyl)imidazol-4-yl]-N,N-bis[(2,4- dimethoxyphenyl)methyl]-2-methyl-benzenesulfonamide (50 mg, 0.06 mmol, 16.5% yield). MS m/z 797 [M+H]+. [640] Step 5: Preparation of 3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-2- methylbenzenesulfonamide [641] A solution of a mixture of 3-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-methyl- benzenesulfonamide and 3-[5-chloro-2-(5-fluoro-2-pyridyl)-1-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-N,N-bis[(2,4-dimethoxyphenyl)methyl]-2-methyl- benzenesulfonamide (50 mg, 0.06 mmol) in acetic acid (3 mL) was stirred at RT for 16 h. LCMS indicated the reaction was completed. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep- HPLC to afford the title compound (15 mg, 0.04 mmol, 68% yield). [642] Example 44: 2-Chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)benzamide [643] To a solution of 2-chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)benzoic acid (60 mg, 0.17 mmol) in DMF (2 mL) were added DIEA (176 mg, 1.36 mmol), NH4Cl (46 mg, 0.85 mmol), EDCI (65 mg, 0.34 mmol) and HOBt (46 mg, 0.34 mmol). The reaction was stirred at room temperature for 16 hours. Then the crude product was purified by prep-HPLC to afford the title compound (23.8 mg, 0.07 mmol, yield: 40%). [644] Example 45: 2-(4-Chloro-5-(2-fluoro-6-methylphenyl)-1H-imidazol-2-yl)-5- fluoropyridine [645] Step 1: Preparation of a mixture of 2-[[4-chloro-5-(2-fluoro-6-methyl-phenyl)-2-(5- fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-4-(2-fluoro-6- methyl-phenyl)-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane [646] A mixture of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-iodo-imidazol-1-30 yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-2-(5-fluoro-2-pyridyl)-4-iodo-imidazol-1- yl]methoxy]ethyl-trimethyl-silane (200 mg, 0.441 mmol), (2-fluoro-6-methylphenyl)boronic acid (81.43 mg, 0.529 mmol), Pd(dtbpf)Cl2 (32.9 mg, 0.044 mmol) and K2CO3 (121.8 mg, 0.881 mmol) in THF (2 mL) and water (0.4 mL) was stirred at 80°C for 16 hours under nitrogen atmosphere. LCMS indicated the reaction was completed. Then the mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether 0:100 to 10:90) to give a mixture of 2-[[4-chloro-5-(2-fluoro- 6-methyl-phenyl)-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2- [[5-chloro-4-(2-fluoro-6-methyl-phenyl)-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane (101 mg, 0.232 mmol, yield: 52%). MS m/z 436 [M+H]+. [647] Step 2: Preparation of 2-(4-chloro-5-(2-fluoro-6-methylphenyl)-1H-imidazol-2-yl)- 5-fluoropyridine [648] A solution of a mixture of 2-[[4-chloro-5-(2-fluoro-6-methyl-phenyl)-2-(5-fluoro- 2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane and 2-[[5-chloro-4-(2-fluoro-6- methyl-phenyl)-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (101 mg, 0.232 mmol) in TFA (2 mL) was stirred at room temperature for 2 h. LCMS indicated the reaction was completed. Then the mixture was concentrated under reduced pressure and purified by prep-HPLC to afford the title compound (31.5 mg, 0.103 mmol, yield: 44%). [649] Example 46: Methyl 3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4- fluoro-2-methylbenzoate [650] Step 1: Preparation of 3-bromo-4-fluoro-2-methylbenzoic acid [651] To a stirred solution of 2,2,6,6-tetramethylpiperidine (42.6 g, 0.301 mol) in dry THF (400 mL) was added n-BuLi (2.5 M, 121 mL, 0.301 mol) dropwise at -5 °C under nitrogen atmosphere. The mixture was stirred at this temperature for 15 min. The reaction mixture was cooled to -50 °C. A solution of 3-bromo-4-fluoro-benzoic acid (30.0 g, 0.137 mmol) in dry THF (300 mL) was added dropwise into the reaction system. The resulting mixture was stirred at -50 °C for 2.5 h. The reaction mixture was cooled to -70 °C. Methyl 30 iodide (42.8 g, 0.301 mol) was added dropwise into the reaction system. The reaction mixture was allowed to warm to room temperature for 16 h. The reaction mixture was quenched with water (100 mL) under cooling with an ice/water bath, concentrated under reduced pressure, acidified with HCl (4M, 200 mL), until pH = 1 was reached, diluted with water (500 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the subtitle compound (33 g crude) as white solid which was used directly in the next step. [652] Step 2: Preparation of methyl 3-bromo-4-fluoro-2-methylbenzoate [653] To a suspension, cooled with an ice/water batch, of 3-bromo-4-fluoro-2-methyl- benzoic acid (33 g, 0.142 mol) and potassium carbonate (58.7 g, 0.425 mol) in DMF (300 mL) was added methyl iodide (40.2 g, 0.283 mmol) dropwise under nitrogen atmosphere. The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with water (500 mL x 2), brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the subtitle compound (7.176 g, 29.0 mmol, yield: 20.5%) as white solid which was used in the next step directly. [654] Step 3: Preparation of methyl 4-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate [655] Under nitrogen, a mixture of methyl 3-bromo-4-fluoro-2-methyl-benzoate (3.05 g, 12.3 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (3.76 g, 14.8 mmol), Pd(dppf)Cl2 (903 mg, 1.23 mmol) and potassium acetate (3.63 g, 37.0 mmol) in dry 1,4-dioxane (50 mL) was prepared. The resulting mixture was stirred at 100 °C for 40 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified with flash chromatography (Biotage, 40 g silica gel column, eluting with 0%-10% ethyl acetate in petroleum ether) to give the subtitle compound (2.8 g, 9.52 mmol, yield: 77.1%) as colorless oil. MS m/z 295 [M+H]+. 30 [656] Step 4: Preparation of (6-fluoro-3-(methoxycarbonyl)-2-methylphenyl)boronic acid [657] To a mixture of methyl 4-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzoate (2.0 g, 6.80 mmol), acetone (20 mL) and water (6 mL) was added ammonium acetate (1.47 g, 19.0 mmol), sodium periodate (4.8 g, 22.4 mmol) successively under cooling with an ice\water bath. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage, 25 g silica gel column, eluting with 0%-75% ethyl acetate in petroleum ether) to give the subtitle compound (1.4 g, 6.60 mmol, yield: 97.1%) as white solid. MS m/z 212 [M+H]+. [658] Step 5: Preparation of methyl 4-fluoro-3-(2-(5-fluoropyridin-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-methylbenzoate (mixture of SEM- regioisomers) [659] A mixture of (6-fluoro-3-methoxycarbonyl-2-methyl-phenyl)boronic acid (1.1 g, 5.19 mmol), 2-[[5-bromo-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (1.93 g, 5.19 mmol, mixture of SEM-regioisomers), Pd(dtbpf)Cl2 (335 mg, 0.519 mmol) and potassium carbonate (2.15 g, 15.6 mmol) in dioxane (20 mL) and water (4 mL) was prepared under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 25 g silica gel column, eluting with 0%-30% ethyl acetate in petroleum ether) to give the subtitle compound (1.4 g, 3.05 mmol, yield: 58.7%) as colorless oil. MS m/z 460 [M+H]+. [660] Step 6: Preparation of methyl 3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-4-fluoro-2-methylbenzoate [661] To a mixture of methyl 4-fluoro-3-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-2-methyl-benzoate (1.3 g, 2.83 mmol) and TsOH.H2O (53.8 mg, 0.283 mmol) in MeCN (13 mL) was added NCS (453 mg, 3.39 mmol) 30 in portions. The resulting mixture was stirred at 50 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage 25 g silica gel column, eluting with 0%-60% ethyl acetate in petroleum ether) to give the title compound (740 mg, 2.03 mmol, yield: 71.9%) as white solid. [662] Example 47: 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-fluoro-2- methylbenzoic acid [663] To a stirred solution of methyl 3-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-4-fluoro-2-methyl-benzoate (230 mg, 0.632 mmol) in MeOH (3 mL) was added a solution of sodium hydroxide (253 mg, 6.32 mmol) in water (2 mL) dropwise. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The remaining aqueous phase was acidified with 1 M HCl until pH = 5 was reached. The precipitate formed was filtered off and washed with water. The filter cake was dried in vacuum to afford the title compound (295 mg, 0.844 mmol, yield: 95.9%) as white solid. 1H NMR. [664] Example 48: 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-fluoro-2- methylbenzamide [665] To a stirred mixture of 3-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4- fluoro-2-methyl-benzoic acid (126 mg, 0.360 mmol) in DMF (2 mL) was added HOBt (97.4 mg, 0.721 mmol), EDCI (138 mg, 0.721 mmol), then ammonium chloride (96.4 mg, 1.80 mmol) and DIPEA (373 mg, 2.88 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (80 mL x 2), brine (80 mL), dried over anhydrous sodium sulfate, and concentrated under pressure. The residue was purified by preparative HPLC to give the title compound (76.1 mg, 0.128 mmol, yield: 60.6%) as white solid.1H NMR. [666] Example 49: 2-(4-Chloro-5-(2-fluoro-6-methyl-4-(methylthio)phenyl)-1H- imidazol-2-yl)-5-fluoropyridine [667] Step 1: Preparation of 2-bromo-1-fluoro-3-methyl-5-methylsulfanyl-benzene [668] 4-bromo-3-fluoro-5-methyl-aniline (5 g, 24.5 mmol) was dissolved in 1,2- dimethyldisulfane (35 mL, 394 mmol) and heated to 75°C under nitrogen. Isoamyl nitrite (8.52 mL, 63.7 mmol) was added dropwise to the reaction via an addition funnel through a reflux condenser (about 1 drop/sec). After the addition was complete, the reaction was heated to 95°C for 1 hour and allowed to cool to ambient temperature. The reaction was concentrated and purified by chromatography over silica gel (100% hexanes) to the subtitle compound (3.5 g, yield: 61%) as an orange solid. MS m/z 234.1 [M+H]+. [669] Step 2: Preparation of 2-(2-fluoro-6-methyl-4-methylsulfanyl-phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane [670] To a solution of 2-bromo-1-fluoro-3-methyl-5-methylsulfanyl-benzene (3.5 g, 14.9 mmol) in 1,4-dioxane (35 mL)^ were added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.16 g, 16.4 mmol) and KOAc (2.92 g, 29.8 mmol). And then Pd(dppf)Cl2 (1.09 g, 1.49 mmol) was added under N2 atmosphere. The reaction was stirred at 90°C for 16 hrs. The reaction mixture was quenched by adding water (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether = 30%) to afford the subtitle compound (1.22 g, yield:^29%) as a white solid. MS m/z 283.2 [M+H]+. [671] Step 3: Preparation of 2-(4-chloro-5-(2-fluoro-6-methyl-4-(methylthio)phenyl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5-fluoropyridine (mixture of SEM- regioisomers) [672] To a solution of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-iodo-imidazol-1- yl]methoxy]ethyl-trimethyl-silane (400 mg, 0.88 mmol, mixture of SEM-regioisomers) in 1,4- dioxane (4 mL) were added 2-(2-fluoro-6-methyl-4-methylsulfanyl-phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (373 mg, 1.32 mmol) and K3PO4 (561 mg, 2.64 mmol) in water (0.8 mL). Pd(PPh3)2Cl2 (62 mg, 0.09 mmol) was added under N2 atmosphere. The 30 reaction was stirred at 110°C for 16 hrs. The reaction mixture was quenched with water (30 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL x 2), dried and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether = 40%) to give the subtitle compound (180 mg, yield:^42%) as a yellow oil. MS m/z 482.1 [M+H]+. [673] Step 4: Preparation of 2-(4-chloro-5-(2-fluoro-6-methyl-4-(methylthio)phenyl)-1H- imidazol-2-yl)-5-fluoropyridine [674] A solution of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-5-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (180 mg, 0.4 mmol) in 1,4-dioxane (1 mL) was added 4M HCl in 1,4-dioxane (2 mL) and stirred at room temperature for 4 hours. Then the mixture was concentrated and diluted with water (10 mL). The mixture was basified with saturated K2CO3 solution to pH = 9 and extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (56.1 mg, yield 40%) as a white solid. [675] Example 50: 2-[4-Chloro-5-(2-fluoro-6-methyl-4-methylsulfonyl-phenyl)-1H- imidazol-2-yl]-5-fluoro-pyridine [676] MCPBA (50 mg) was added to a mixture of 2-[4-chloro-5-(2-fluoro-6-methyl-4- methylsulfanyl-phenyl)-1H-imidazol-2-yl]-5-fluoro-pyridine (55 mg) and DCM (3 mL). After 2 hours, the mixture was concentrated and purified by preparative HPLC to afford the title compound. [677] Example 51: 3-[3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylpropan-1-ol [678] Step 1: Preparation of 3-((4-bromo-3-chlorophenyl)sulfonyl)propan-1-ol [679] A mixture of 4-bromo-3-chloro-benzenesulfonyl chloride (8.3 g, 28.6 mmol), Na2SO3^(7.22 g, 57.2 mmol), NaHCO3^(4.81 g, 57.2 mmol) and water (60 mL) was stirred at 100^°C for 1.5 h. Then the mixture was cooled to 50^°C. TBAB (9.23 g, 28.6 mmol) and 3- bromopropan-1-ol (11.9 g, 85.9 mmol) were added. The mixture was stirred at 50^°C for 3 h. 30 The resulting mixture was cooled to room temperature and extracted with chloroform (30 mL x 3). The organic layers were combined, dried over Na2SO4^and concentrated. The residue was purified by silica gel column (70% EtOAc in PE) to give the subtitle compound (7.0 g, 78% yield) as white solid. MS m/z 335 [M+Na]+. [680] Step 2: Preparation of (3-((4-bromo-3-chlorophenyl)sulfonyl)propoxy)(tert- butyl)dimethylsilane [681] A mixture of 3-(4-bromo-3-chloro-phenyl)sulfonylpropan-1-ol (5.0 g, 15.9 mmol) and imidazole (3.26 g, 47.8 mmol) in DCM (50 mL) was stirred at room temperature. TBS-Cl (3.6 g, 23.9 mmol) was added. The mixture was stirred at room temperature for 4 h. The resulting mixture was poured into 100 mL DCM. The organic layer was washed with water (50 mL), dried over Na2SO4^and concentrated. The residue was purified by silica gel column (100% PE) to give the subtitle compound (5.5 g, 80% yield) as white solid. MS m/z 445 [M+Na]+. [682] Step 3: Preparation of tert-butyl(3-((3-chloro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)sulfonyl)propoxy)dimethylsilane [683] To a solution of 3-(4-bromo-3-chloro-phenyl)sulfonylpropoxy-tert-butyl-dimethyl- silane (5 g, 11.7 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1,3,2-dioxaborolane (3.86 g, 15.2 mmol) in 1,4-dioxane (75 mL) under N2 atmosphere, was added KOAc (2.29 g, 23.4 mmol) followed by Pd(dppf)Cl2 (855 mg, 0.1 eq). The reaction mixture was stirred at 60 °C for 6 hrs. The mixture was poured into water (200 mL) and extracted with EA (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried and concentrated. The residue was purified by flash column on silica gel (PE/EA= 3:1) to afford the desired product (4.1 g, 73.9% yield) as a white solid. MS m/z 475 [M+H]+. [684] Step 4: Preparation of 2-(5-(4-((3-((tert-butyldimethylsilyl)oxy)propyl)sulfonyl)-2- chlorophenyl)-4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)-5- fluoropyridine (mixture of SEM-regioisomers) [685] To a solution of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-iodo-imidazol-1- yl]methoxy]ethyl- trimethyl-silane (3 g, 6.61 mmol, mixture of SEM-regioisomers) and tert- butyl-[3-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)phenyl] sulfonylpropoxy]- 30 dimethyl-silane (4.40 g, 9.26 mmol) in 1,4-dioxane (50 mL), K3PO4 (4.21 g, 19.8 mmol) was added followed by Pd(PPh3)2Cl2 (464 mg. The reaction mixture was stirred at 110 °C for 16 hrs. The mixture was poured into water (200 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (500 mL), dried and concentrated. The residue was purified by flash column on silica gel (PE/EA=3:1) to afford the subtitle compound (2.1 g, 47.1% yield) as a light-yellow oil. MS m/z 674.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 2.8 Hz, 1H), 8.19-8.16 (m, 2H), 8.03-8.00 (m, 1H), 7.94-7.91 (m, 2 H), 5.87-5.76 (ABq, 2 H), 3.65-3.62 (t, J=6.0 Hz, 2H), 3.51-3.47 (m, 2H), 3.24-3.20 (t, J=5.6 Hz, 1H), 4.46-4.44 (d, J=6.4 Hz, 2H), 1.78-1.74 (m, 2H), 0.83 (s, 9 H), 0.60-0.56 (t, J=8.4 Hz, 2 H), 0.01 (s, 6 H), -0.22 (s, 9 H) ppm. [686] Step 5: Preparation of 3-[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]phenyl]sulfonylpropan-1-ol [687] Tert-butyl-[3-[3-chloro-4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]phenyl]sulfonylpropoxy]-dimethyl-silane (200 mg) was added TFA (2 mL). After 48 hours, the mixture was concentrated. The crude was dissolved in MeOH (10 mL) and heated to 50°C for 1 hour. After 14 hours at RT, the precipitate formed was collected by filtration. The solid was washed with EA and dried in vacuo to afford the title compound. [688] Example 52: 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-fluoro-2- methylbenzenesulfonamide [689] Step 1: Preparation of 2-bromo-1-fluoro-3-methyl-4-nitrobenzene [690] 2-Bromo-1-fluoro-3-methyl-benzene (21 g, 0.111 mmol) was dissolved in HOAc (105 mL) and HNO3 (105 mL). The reaction mixture was stirred at 80 °C for 5 hrs. The mixture was poured into ice-water (1500 mL) and extracted with EA (1000 mL x 3). The organic layers were washed with brine and concentrated to give the crude product. The residue was purified by flash column chromatography on silica gel (PE:EA=1:20) to the subtitle compound (17.5 g, 67.3%) as a yellow solid. MS m/z 235.8 [M+H]+. [691] Step 2: Preparation of 3-bromo-4-fluoro-2-methylaniline [692] 2-Bromo-1-fluoro-3-methyl-4-nitro-benzene (17.5 g, 74.8 mmol) was dissolved in 30 MeOH (170 mL) and HOAc (80 mL). Iron powder (41.8 g, 748 mmol) was added with several portions. The reaction mixture was stirred at RT for 16 hrs. The reaction was monitored by LCMS. The solid was filtered out and washed with MeOH (1000 mL). The filtrate was concentrated. The residue was purified by flash column on silica gel (PE/EA=3/1) to afford the subtitle compound (13 g, 63.7 mmol) as a light-yellow solid. MS m/z 205.0 [M+H]+. [693] Step 3: Preparation of ^ 3-bromo-4-fluoro-2-methylbenzenesulfonyl chloride [694] 3-bromo-4-fluoro-2-methyl-aniline (13 g, 0.0637 mol) was dissolved in HCl (9 N, 150 mL). NaNO2 (5.71 g, 82.8 mmol) in water (25 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 h (solution 1). NaHSO3 (13.1 g, 0.127 mol) was dissolved in water (43 mL) and aliquoted into two portions. To one portion, CuSO4.5H2O (1.02 g, 6.37 mmol) dissolved in HCl (112 mL, 12 N) was added (solution 2). Solution 1 and solution 2 were added dropwise simultaneously to the other portion of the NaHSO3 solution. The reaction mixture was stirred at RT for 16 hrs. The reaction mixture was poured into water and extracted with^DCM. The organic layer was dried and concentrated to afford the subtitle compound (11 g, crude) as a brown oil which was used directly in the next step. [695] Step 4: Preparation of 3-bromo-N,N-bis(2,4-dimethoxybenzyl)-4-fluoro-2- methylbenzenesulfonamide [696] 1-(2,4-dimethoxyphenyl)-N-[(2,4-dimethoxyphenyl)methyl]methanamine (8.5 g, 26.8 mmol) and DIEA (14.8 g, 0.115 mol) were dissolved in DCM (150 mL). 3-bromo-4- fluoro-2-methyl- benzenesulfonyl chloride (11 g, 0.0383 mol) was added with several portions. The reaction mixture was stirred at RT for 16 hrs. The mixture was poured into water (200 mL). The aqueous layer was extracted with DCM (100 mL x 3), dried and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA=1:10) to afford the subtitle compound (13 g, yield 59.8%) as a light-yellow solid. MS m/z 590.0 [M+Na]+. ^ [697] Step 5: Preparation of N,N-bis(2,4-dimethoxybenzyl)-4-fluoro-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide [698] To a solution of 3-bromo-N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-fluoro-2- methyl- benzenesulfonamide (12 g, 21.1 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,3,2-dioxaborolane (6.97 g, 27.4 mmol) in 1,4-dioxane (150 mL) under N2 atmosphere, KOAc (6.22 g, 63.3 mmol) was added followed by 30 Pd(dppf)Cl2 (1.54 g, 2.11 mmol). The reaction mixture was stirred at 80 °C for 16 hrs. The mixture was poured into water (300 mL) and extracted with EA (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried and concentrated. The residue was purified by flash chromatography on silica gel (PE/EA=1:5) to afford the subtitle compound (10.5 g, 80.8% yield) as a white solid. MS m/z^616.3 [M+H]+. [699] Step 6: Preparation of (3-(N,N-bis(2,4-dimethoxybenzyl)sulfamoyl)-6-fluoro-2- methylphenyl)boronic acid [700] To a mixture of N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-fluoro-2-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (7 g, 11.4 mmol), NH4OAc (2.45 g, 31.8 mmol), acetone (100 mL) ^and H2O (30 mL), sodium periodate (8.03 g, 37.5 mmol) was added with several portions. The mixture was stirred at RT for 16 hrs. The mixture was poured into water (200 mL) and filtered. The filter cake was washed with EA and the filtrate was extracted with EA (200 mL x 3). The organic layers were washed with brine (500 mL), dried and concentrated. The residue was purified by flash chromatography on silica gel to afford the subtitle compound (6.1 g, 9.72 mmol, 85.5% yield) as a white solid. MS m/z^556.0 [M+Na]+. [701] Step 7: Preparation of N,N-bis(2,4-dimethoxybenzyl)-4-fluoro-3-(2-(5- fluoropyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2- methylbenzenesulfonamide (mixture of SEM-regioisomers) [702] To a mixture of 2-[[5-bromo-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane (1.5 g, 4.03 mmol, mixture of SEM-regioisomers), ^[3-[bis[(2,4- dimethoxyphenyl)methyl]sulfamoyl]-6-fluoro-2-methyl-phenyl] boronic acid (2.58 g, 4.83 mmol) and K2CO3 (1.67 g, 12.1 mmol),1,4-dioxane (15 mL) and H2O (3 mL) under N2 atmosphere, Pd(dtbpf)Cl2 (263 mg, 0.403 mmol) was added. The reaction was stirred at 80 °C for 16 hrs. The mixture was poured into water (100 mL) and extracted with EA (50 mL x 3). The combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel to afford the subtitle compound (1.1 g, 35% yield) as a light yellow solid. MS m/z^781.0 [M+H]+. [703] Step 8: Preparation of 4-fluoro-3-(2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-2- methylbenzenesulfonamide [704] A solution of N,N-bis[(2,4-dimethoxyphenyl)methyl]-4-fluoro-3-[2-(5-fluoro-2- pyridyl)-3-(2-trimethylsilylethoymethyl)imidazol-4-yl]-2-methyl-benzenesulfonamide (600 mg, 0.768 mmol) in 4 M HCl in 1,4-dioxane (9.6 mL) was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure. The residue was dissolved with water (50 mL), basified with sat. sodium bicarbonate solution, until pH = 8, and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 25 g silica gel column, eluting with 0%-40% ethyl acetate in petroleum ether) to afford the subtitle compound (130 mg, 0.371 mmol, yield: 48.3%) as white solid. MS m/z 351 [M+H]+. 1H NMR (500 MHz, DMSO) δ 13.11 (s, 1H), 8.65 (d, J = 2.5 Hz, 0.80H), 8.62 (d, J = 2.5 Hz, 0.20H), 8.15 (dd, J = 8.5, 4.5 Hz, 0.20H), 8.10 (dd, J = 8.5, 4.5 Hz, 0.80H), 8.01 – 7.96 (m, 0.20H), 7.94 (dd, J = 9.0, 6.0 Hz, 0.80H), 7.862-7.821 (m, 1H), 7.55 (s, 0.40H), 7.49 (s, 1.60H), 7.41 (s, 0.80H), 7.35 (d, J = 9.0 Hz, 0.20H), 7.29 (t, J = 8.5 Hz, 0.80H), 7.17 (s, 0.20H), 2.58 (s, 2.40H), 2.52 (s, 0.60H) ppm. [705] Step 9: Preparation of 3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4- fluoro-2-methylbenzenesulfonamide [706] To a solution of 4-fluoro-3-[2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-2-methyl- benzenesulfonamide (130 mg, 0.371 mmol) in THF (3 mL) was added NCS (59.5 mg, 0.445 mmol) in portions. The resulting mixture was stirred at 40 °C for 16 hrs. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (23.0 mg, 0.0597 mmol, yield: 16.1%) as white solid. [707] Example 53: 3-[3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylpropanamide [708] Step 1: Preparation of 3-[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]phenyl]sulfonylpropanoic acid [709] A mixture of 3-[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylpropan-1-ol (105 mg), MeCN (15 mL) and H2O (1.5 mL) was added TEMPO (11.4 mg) and diacetoxyiodo-benzene (160 mg). After stirring overnight, more 30 diacetoxyiodo-benzene (160 mg) was added and stirring continued for 1 day. The mixture was concentrated and purified by preparative HPLC to afford the subtitle compound. MS m/z 444 [M+H]+. [710] Step 2: Preparation of 3-[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]phenyl]sulfonylpropanamide [711] A mixture of 3-[3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylpropanoic acid (15 mg), ammonium chloride (7.2 mg), DMF (0.5 mL) and DIPEA (35 mg) was added EDC (12.9 mg) and HOBt (4.6 mg). After stirring for 14 hours, the mixture was diluted with MeOH (1 mL), filtrated, and purified by preparative HPLC to afford the title compound. [712] Example 54: Methyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylbenzoate [713] Step 1: Preparation of methyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-3-methylbenzoate (mixture of SEM- regioisomers) [714] To a solution of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-iodo-imidazol-1- yl]methoxy]ethyl-trimethyl-silane (1 g, 2.2 mmol, mixture of SEM-regioisomers) in 1,4- dioxane (10 mL) and water (2 mL) under N2 atmosphere was added (4-methoxycarbonyl-2- methyl-phenyl)boronic acid (641 mg, 3.31 mmol) and K2CO3 (920 mg, 6.6 mmol) followed by Pd(dtbpf)Cl2 (144 mg, 0.22 mmol). The mixture was stirred at 80°C for 16 hrs. The reaction mixture was quenched with water (20 mL), concentrated and extracted with DCM (30 mL x 3). The organic layers were combined, washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 19:1) to afford the subtitle compound (570 mg, yield: 54%) as a white solid. MS m/z 476.0 [M+H]+. [715] Step 2: Preparation of methyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylbenzoate [716] A mixture of methyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-3-methyl-benzoate (0.85 g, 1.8 mmol) and 4 M 30 HCl in 1,4-dioxane (5 mL) was kept at RT for 16 h. The reaction mixture was concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 9:1) to afford the title compound (502 mg, yield: 81%) as a white solid. [717] Example 55: 4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylbenzoic acid [718] To a solution of methyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-benzoate (0.4 g, 1.2 mmol) in MeOH (4 mL) was added NaOH (0.28 g, 6.9 mmol) in H2O (20 mL). The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated and acidified with 1 M HCl solution until pH=4, and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated to afford the title compound (354 mg) as a white solid. [719] Example 56: 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- benzamide [720] A mixture of 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- benzoic acid (30 mg), DMF (0.5 mL) and DIPEA (48 mg) was added HATU (52 mg). After 20 min, ammonium chloride (9.7 mg) was added. After 1 hour, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [721] Example 57: N-(2-Amino-2-oxo-ethyl)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-benzamide [722] A mixture of 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- benzoic acid (30 mg), DMF (0.5 mL) and DIPEA (48 mg) was added HATU (52 mg). After 20 min, 2-aminoacetamide (hydrochloride, 20 mg) was added. After 1 hour, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [723] Example 58: 2-(4-Chloro-5-(2-methyl-4-(methylthio)phenyl)-1H-imidazol-2-yl)-5- fluoropyridine [724] Step 1: Preparation of 1-bromo-2-methyl-4-methylsulfanyl-benzene [725] To a solution of 1-bromo-4-fluoro-2-methyl-benzene (10 g, 53 mmol) in DMF (80 mL) was added methylsulfanylsodium (4.08 g, 58.2 mmol). The reaction was stirred at 100°C for 16 h. The reaction mixture was quenched with water (200 mL) and extracted with DCM (200 mL x 3). The organic layers were combined, washed with brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography with petroleum ether to afford the subtitle compound (7 g, yield 61%) as a colorless oil. [726] Step 2: Preparation of (2-methyl-4-methylsulfanyl-phenyl)boronic acid [727] 1-bromo-2-methyl-4-methylsulfanyl-benzene (5 g, 23 mmol) was dissolved in tetrahydrofuran (30 mL). Then 2.5 M n-butyllithium (13.8 mL, 34.5 mmol) was added slowly at -78°C under N2 atmosphere. After stirring for 1h, trimethyl borate (7.2 g, 69.1 mmol) was added dropwise at -78°C. The mixture stirred at -78°C for another 2 h and at RT for 16 h. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x3). The organic layers were washed with brine (50 ml x 2), dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash chromatography (ethyl acetate / petroleum ether = 50%) to afford the subtitle compound (800 mg, 19% yield) as a white solid. MS m/z 183.1 [M+H]+. [728] Step 3: Preparation of 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-(2-methyl-4- methylsulfanyl-phenyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (mixture of SEM- regioisomers) [729] To a solution of (2-methyl-4-methylsulfanyl-phenyl)boronic acid (800 mg, 4.4 mmol) in 1,4-dioxane (20 mL) and water (4 mL) were added 2-[[4-chloro-2-(5-fluoro-2- pyridyl)-5-iodo-imidazol-1-yl]methoxy]ethyl-trimethyl-silane (2.0 g, 4.4 mmol, mixture of SEM-regioisomers), potassium carbonate (1.84 g, 13.2 mmol) and Pd(dtbpf)Cl2 (286 mg, 0.44 mmol) under nitrogen atmosphere. The reaction was stirred at 100°C for 16 hours. Then the mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The 30 combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether = 15%) to afford the title compound (0.5 g, yield: 18%) as a brown oil. MS m/z 464.0 [M+H]+. [730] Step 4: Preparation of 2-[4-chloro-5-(2-methyl-4-methylsulfanyl-phenyl)-1H- imidazol-2-yl]-5-fluoro-pyridine [731] 2-[[4-chloro-2-(5-fluoro-2-pyridyl)-5-(2-methyl-4-methylsulfanyl- phenyl)imidazol-1-yl]methoxy]ethyl-trimethyl-silane (0.5 g) was added 4M HCl in 1,4- dioxane (5 mL). The reaction was stirred at RT for 4 h. The reaction was concentrated and basified with 1 M NaOH solution until pH=10, and then extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether = 30%) to afford the title compound (233.9 mg, yield: 90%) as a white solid. [732] Example 59: N-(2-Amino-2-oxo-ethyl)-3-chloro-4-[4-chloro-2-(5-fluoro-2- pyridyl)-1H-imidazol-5-yl]benzamide [733] A mixture of 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzoic acid (17.5 mg), DMF (0.5 mL) and DIPEA (26 mg) was added HATU (24 mg). After 5 min, 2-aminoacetamide (hydrochloride, 7.4 mg) was added. After 1 hour, the mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [734] Example 60: 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzamide [735] A mixture of 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzoic acid (17.5 mg), DMF (0.5 mL) and DIPEA (26 mg) was added HATU (24 mg). After 5 min, ammonium chloride (5.3 mg) was added. After 1 hour, the mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [736] Example 61 and Example 62: 2-[4-Chloro-5-(2-methyl-4-methylsulfonyl-phenyl)- 1H-imidazol-2-yl]-5-fluoro-pyridine and 2-[4-chloro-5-(2-methyl-4-methylsulfinyl-phenyl)- 1H-imidazol-2-yl]-5-fluoro-pyridine [737] MCPBA (78 mg) was added to a mixture of 2-[4-chloro-5-(2-methyl-4- methylsulfanyl-phenyl)-1H-imidazol-2-yl]-5-fluoro-pyridine (100 mg) and DCM (2 mL). After 30 min, more MCPBA (25 mg) was added. After standing overnight, the mixture was concentrated, and the residue dissolved in DMF (0.5 mL) and MeOH (0.5 mL). The mixture was separated by preparative HPLC to afford the title compounds. [738] Example 63 and Example 64: Tert-butyl (S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)- 1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (R*)-4-(4- chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)- carboxylate [739] Step 1: Preparation of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)- carboxylate (mixture of SEM-regioisomers) [740] To a solution of 2-(5-chloro-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)-5-fluoropyridine (18 g, 39.7 mmol, mixture of SEM-regioisomers) in 1,4- dioxane (180 mL)^ were added (1-(tert-butoxycarbonyl)-3-methyl-1,2,3,6-tetrahydropyridin-4- yl)boronic acid (14.4 g, 59.6 mmol) and potassium carbonate (16.5 g, 119 mmol) in water (36 mL). And then Pd(dtbpf)Cl2 (5.2 g, 8.0 mmol) was added under N2 atmosphere. The reaction was stirred at 80°C for 16 hrs. The reaction mixture was quenched by adding water (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether = 30%) to afford the subtitle compound (10.8 g, yield:^52%) as a yellow oil. MS m/z 523.3 [M+H]+. [741] Step 2: Preparation of 2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (hydrochloride) [742] A solution of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1-((2-30 (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)- carboxylate (10.8 g, 20.7 mmol, mixture of SEM-regioisomers) in 1,4-dioxane (20 mL) was added 4M HCl in 1,4-dioxane (40 mL) and stirred at room temperature for 16 hours. The mixture was concentrated to afford the subtitle compound (11 g) as an off-white solid. The crude product is used for the next step without further purification. MS m/z 293.1 [M+H]+. [743] Step 3: Preparation of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate [744] To a solution of 2-(4-chloro-5-(3-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine (11 g, crude hydrochloride) in DCM (100 mL) were added TEA (10.4 g, 103.4 mmol) and tert-butoxycarbonyl tert-butyl carbonate (4.7 g, 21.7 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into water (200 mL) and extracted with DCM (150 mL x 3). The organic layers were washed with brine (150 mL x 2), dried with Na2SO4 and concentrated. The crude was purified by flash chromatography (ethyl acetate / petroleum ether = 30%) to afford the subtitle compound (6.4 g, yield: 79% two steps) as a white solid. MS m/z 393.1 [M+H]+. [745] Step 4: Preparation of tert-butyl (S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate and tert-butyl (R*)-4-(4- chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)- carboxylate [746] Tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-carboxylate (10 g) was separated by chiral-HPLC to afford tert-butyl (S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6-dihydropyridine- 1(2H)-carboxylate (4.989 g) and tert-butyl (R*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)-carboxylate (4.878 g). [747] Preparative chiral HPLC conditions: instrument: SFC-150 (Waters); column: AD 25x250mm, 10μm (Daicel); column temperature: 35°C; mobile phase: CO2/ MeOH (0.2% NH3(7M in MeOH) 80:20; flow rate: 100 ml/min; back pressure: 100 bar; detection wavelength: 214 nm; cycle time: 4.1 min; sample solution: 10 g dissolved in 200 ml methanol; injection volume: 2.5 ml. [748] Analytical chiral HPLC conditions: column: AD-3 4.6*100mm, 3µm; column 30 temperature: 40°C; mobile phase: CO2/ MeOH (0.2% NH3(7M in MeOH) 85:15; flow rate: 3ml/min; back pressure: 2000psi; detection wavelength: 214 nm; run time: 4.0 min; injection volume: 5.00 µl. [749] Tert-butyl (S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl- 3,6-dihydropyridine-1(2H)-carboxylate. Chiral HPLC 1.005 min. [750] Tert-butyl (R*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl- 3,6-dihydropyridine-1(2H)-carboxylate. Chiral HPLC 1.384 min. [751] Example 65: (3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- N,N,3-trimethyl-piperidine-1-carboxamide [752] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (60 mg) and DCM (4 mL) was added DIPEA (1.2 mL) followed by N,N- dimethylcarbamoyl chloride (60 mg). After 1 hour at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [753] Example 66: Methyl (3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-piperidine-1-carboxylate [754] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (60 mg) and DCM (3 mL) was added DIPEA (1 mL) followed by methyl carbonochloridate (90 mg). After 1 hour at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [755] Example 67: [2-(Dimethylamino)-2-oxo-ethyl] (3R,4R)-4-[4-chloro-2-(5-fluoro-2- pyridyl)-1H-imidazol-5-yl]-3-methyl-piperidine-1-carboxylate [756] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (70 mg) and THF (4 mL) was added DIPEA (1.5 mL) followed by [2- (dimethylamino)-2-oxo-ethyl] imidazole-1-carboxylate (200 mg). After 8 hours at 90°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [757] Example 68: Methyl 3-[[(3S*)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoate [758] A mixture of 2-[4-chloro-5-[(3S*)-3-methyl-1,2,3,6-tetrahydropyridin-4-yl]-1H- imidazol-2-yl]-5-fluoro-pyridine (250 mg), DCM (5 mL) and DIPEA (0.41 mL) was added methyl 3-(chlorosulfonyl)propanoate (186 mg). The mixture was stirred overnight, diluted with EA (20 mL) and washed with 1N HCl (5 mL x2) and brine (5 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to afford the title compound. [759] Example 69: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3-pyridylsulfonyl)-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine [760] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (200 mg), DIPEA (3.5 mL) and DCM (12 mL) was added pyridine-3-sulfonyl chloride (150 mg). After 20 min at 40°C, the reaction mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [761] Example 70 and Example 71: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3- pyridylsulfonyl)-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-1-oxido-pyridin-1-ium and 2-[4- chloro-5-[(3R,4R)-3-methyl-1-(1-oxidopyridin-1-ium-3-yl)sulfonyl-4-piperidyl]-1H-imidazol- 2-yl]-5-fluoro-pyridine [762] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(3-pyridylsulfonyl)-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine (200 mg) and DCM (5 mL) was added MCPBA (75% purity, 50 mg). After 2 hours, the reaction mixture was concentrated, and the residue purified by preparative HPLC to afford the title compounds. [763] Example 72: 2-[5-[(3R,4R)-1-(Azetidin-3-ylsulfonyl)-3-methyl-4-piperidyl]-4- chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride) [764] Step 1: Preparation of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]azetidine-1-carboxylate [765] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (302 mg), DIPEA (5 mL) and DCM (15 mL) was added tert-butyl 3- chlorosulfonylazetidine-1-carboxylate (300 mg). After 20 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the subtitle compound. [766] Step 2: Preparation of 2-[5-[(3R,4R)-1-(azetidin-3-ylsulfonyl)-3-methyl-4- piperidyl]-4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride) [767] A mixture of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]azetidine-1-carboxylate (294 mg) and DCM (3 mL) was added HCl (6N in iPrOH, 5 mL). After 0.5 h, the mixture was concentrated to afford the title compound. [768] Example 73: 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]azetidin-1-yl]ethanone [769] A mixture of 2-[5-[(3R,4R)-1-(Azetidin-3-ylsulfonyl)-3-methyl-4-piperidyl]-4- chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride, 80 mg), DIPEA (1.5 mL), DCM (5 mL) and 1,4-dioxane (5 mL) was added acetyl chloride (30 mg). After 15 min, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [770] Example 74: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]azetidine-1-carboxamide [771] A mixture of 2-[5-[(3R,4R)-1-(azetidin-3-ylsulfonyl)-3-methyl-4-piperidyl]-4- chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride, 50 mg), triethylamine (70 mg) and DCM (2 mL) was added isocyanato(trimethyl)silane (18 mg). After 15 min, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [772] Example 75: Methyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]butanoate [773] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (1.8 mL) and DCM (6 mL) was added methyl 4- chlorosulfonylbutanoate (120 mg). After 20 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [774] Example 76: Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]-2,2-dimethyl-propanoate [775] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (2 mL) and DCM (6 mL) was added methyl 3- chlorosulfonyl-2,2-dimethyl-propanoate (160 mg). After 20 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [776] Example 77: Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate [777] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (2 mL) and DCM (7 mL) was added tert-butyl 3- (chlorosulfonylmethyl)azetidine-1-carboxylate (180 mg). After 30 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [778] Example 78: 2-[5-[(3R,4R)-1-(Azetidin-3-ylmethylsulfonyl)-3-methyl-4- piperidyl]-4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride) [779] A mixture of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate (102 mg) and DCM (3 mL) was added HCl (6N in iPrOH, 5 mL). After 0.5 h, the mixture was concentrated to afford the title compound. [780] Example 79: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-2-methyl-pyridine [781] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (90 mg), DIPEA (1.5 mL), DCM (6 mL) was added 6-methylpyridine-3- sulfonyl chloride (115 mg). After 30 min at 40°C, the mixture was concentrated, and the 30 residue purified by preparative HPLC to afford the title compound. [782] Example 80: 2-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethoxy]ethanol [783] Step 1: Preparation of 2-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethanol [784] To a stirred solution of 2-(2-hydroxyethoxy)ethanol (46.3 g, 437.0 mmol) in pyridine (34.5 g, 437.0 mmol) was added tert-butyl-chloro-diphenyl-silane (20.0 g, 72.8 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 120 g silica gel column, eluting with 0%-40% ethyl acetate in petroleum ether) to afford the subtitle compound (24.0 g, 69.66 mmol, yield: 95.7%) as colorless oil. [785] Step 2: Preparation of S-[2-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethyl] ethanethioate [786] To a stirred solution of triphenylphosphine (16.7 g, 63.9 mmol) in dry THF (130 mL) was added DIAD (12.9 g, 63.9 mmol) dropwise at 0°C under nitrogen atmosphere. After 20 min, a solution of 2-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethanol (10.0 g, 29.0 mmol) in dry THF (10 mL) was added into the reaction system. After 10 min, neat ethanethioic S-acid (4.86 g, 63.9 mmol) was added into the reaction system. The reaction mixture was stirred at 0°C for 1 h, and at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. To the residue was added petroleum ether (200 mL), and the mixture stirred for 10 min. The filter cake obtained after filtration was washed with petroleum ether (100 mL). The filtrate was concentrated. The residue was purified by flash chromatography (Biotage 80 g silica gel column, eluting with 0%-40% dichloromethane in petroleum ether) to afford the subtitle compound (10.6 g, 26.3 mmol, yield: 90.7%) as colorless oil. [787] Step 3: Preparation of 2-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethane sulfonyl chloride [788] To a stirred solution of S-[2-[2-[tert-butyl(diphenyl)silyl]oxyethoxy]ethyl] 30 ethanethioate (10.6 g, 26.3 mmol) in acetonitrile (100 mL) was added 2 M HCl (4.74 mL) and NCS (14.1 g, 105.0 mmol) slowly at 0°C. The reaction mixture was stirred at 0°C for 15 min. The reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 80 g silica gel column, eluting with 0%-40% dichloromethane in petroleum ether) to afford the subtitle compound (4.1 g, 9.6 mmol, yield: 36.5%) as colorless oil. MS m/z 449 [M+Na]+. [789] Step 4: Preparation of tert-butyl-[2-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2- pyridyl)-1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethoxy]ethoxy]-diphenyl-silane [790] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (85 mg), DIPEA (1.5 mL) and DCM (6 mL) was added 2-[2-[tert- butyl(diphenyl)silyl]oxyethoxy]ethanesulfonyl chloride (290 mg). After 20 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the subtitle compound. MS m/z 685.4 [M+H]+. [791] Step 5: Preparation of 2-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethoxy]ethanol [792] A mixture of tert-butyl-[2-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethoxy]ethoxy]-diphenyl-silane (170 mg) and THF (10 mL) was added TBAF (1M in THF, 1 mL). After 30 min, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [793] Example 81: 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]butanoic acid [794] A mixture of methyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]butanoate (115 mg), water (1.5 mL) and THF (6 mL) was added LiOH (22 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [795] Example 82: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- 30 methyl-1-piperidyl]sulfonyl]-2,2-dimethyl-propanoic acid [796] A mixture of methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]-2,2-dimethyl-propanoate (132 mg), water (1.5 mL) and THF (6 mL) was added LiOH (45 mg). After 2 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [797] Example 83: 2-[4-Chloro-5-[(3R,4R)-1-[(6-methoxy-3-pyridyl)sulfonyl]-3-methyl- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [798] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (80 mg), DIPEA (1.5 mL) and DCM (6 mL) was added 6-methoxypyridine-3- sulfonyl chloride (100 mg). After 30 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [799] Example 84: 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]butanamide [800] A mixture of 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]butanoic acid (92 mg), DIPEA (0.15 mL) and DMF (5 mL) was added EDC (55 mg) and HOBt (50 mg). After 15 min, ammonium chloride (30 mg) was added. After 2d, the mixture was filtered, the filtrate concentrated, and the residue purified by preparative HPLC to afford the title compound. [801] Example 85: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-2,2-dimethyl-propanamide [802] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-2,2-dimethyl-propanoic acid (112 mg), DIPEA (0.15 mL) and DMF (5 mL) was added EDC (65 mg) and HOBt (60 mg). After 15 min, ammonium chloride (35 mg) was added. After 2d, the mixture was filtered, the filtrate concentrated, and the residue purified by preparative HPLC to afford the title compound. [803] Example 86: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- 30 methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxamide [804] A mixture of 2-[5-[(3S,4S)-1-(azetidin-3-ylmethylsulfonyl)-3-methyl-4-piperidyl]- 4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride, 75 mg), triethylamine (0.3 mL) and DCM (3 mL) was added isocyanato(trimethyl)silane (50 mg). After 3h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [805] Example 87: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-1H-pyridin-2-one [806] A mixture of 2-[4-chloro-5-[(3R,4R)-1-[(6-methoxy-3-pyridyl)sulfonyl]-3-methyl- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (50 mg), MeCN (3 mL) and NaI (50 mg) was added TMSCl (40 µL). After 2h at 60°C, the mixture was filtered, the filtrate concentrated, and the residue purified by preparative HPLC to afford the title compound. [807] Example 88: 2-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethoxy]acetic acid [808] A mixture of 2-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]ethoxy]ethanol (70 mg) and acetone (3 mL) was added Jones reagent (0.1 mL). After 1 h, the mixture was diluted with EA and washed with water. The organic phase was dried (Na2SO4), concentrated, and the residue purified by preparative HPLC to afford the title compound. [809] Example 89: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-tetrahydrofuran-3-ylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [810] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (50 mg), DIPEA (0.8 mL) and DCM (3 mL) was added tetrahydrofuran-3- sulfonyl chloride (55 mg). After 30 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [811] Example 90: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(oxetan-3-ylsulfonyl)-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine 30 [812] Step 1: Preparation of S-(oxetan-3-yl) ethanethioate [813] A mixture of 3-iodooxetane (12.0 g, 65.2 mmol) and potassium thioacetate (14.9 g, 130.5 mmol) in DMF (60 mL) in a sealed tube was stirred at 50°C for 16 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 80 g silica gel column, eluting with 0%-10% ethyl acetate in petroleum ether) to afford the subtitle compound (7.1 g, 53.7 mmol, yield: 82.4%) as light yellow oil. MS m/z 133 [M+H]+. [814] Step 2: Preparation of oxetane-3-sulfonyl chloride [815] To a stirred aqueous solution of NaClO (7.5%, 160 g, 0.161 mol) was added 1 M HCl (161 mL, 0.161 mol) dropwise at 0°C. This solution was added into another solution of S- (oxetan-3-yl) ethanethioate (7.1 g, 53.7 mmol) in DCM (70 mL) at 0°C slowly. The reaction mixture was stirred at 0°C for 0.5 h. The reaction mixture was extracted with DCM (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Biotage 80 g silica gel column, eluting with 0%-45% dichloromethane in petroleum ether) to afford the subtitle compound (2.5 g, 1.60 mmol, yield: 29.7%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.48 – 4.53 (m, 5H) ppm. [816] Step 3: Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(oxetan-3-ylsulfonyl)-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [817] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (50 mg), DIPEA (1 mL) and DCM (3 mL) was added oxetane-3-sulfonyl chloride (55 mg). After 30 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [818] Example 91: 2-[4-Chloro-5-[(3R,4R)-1-[(2-methoxy-4-pyridyl)sulfonyl]-3-methyl- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [819] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (2 mL) and DCM (6 mL) was added 2-methoxypyridine-4- sulfonyl chloride (95 mg). After 30 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [820] Example 92: 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-1H-pyridin-2-one [821] A mixture of 2-[4-chloro-5-[(3R,4R)-1-[(2-methoxy-4-pyridyl)sulfonyl]-3-methyl- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (100 mg), MeCN (5 mL) and NaI (100 mg) was added TMSCl (80 µL). After 2 h at 60°C, the mixture was filtered, the filtrate concentrated, and the residue purified by preparative HPLC to afford the title compound. [822] Example 93: Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoate [823] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (hydrochloride, 200 mg), DIPEA (0.43 mL) and DCM (4 mL) was added methyl 3-chlorosulfonylpropanoate (175 mg). After 45 min, the mixture was diluted with NH4Cl solution (2M, 3 mL). The pH was adjusted to 1 with 1M HCl. The mixture was extracted with EA (10 mL). The organic layer was washed with brine (2 mL), dried (Na2SO4) and concentrated. The residue purified by chromatography (15 g silica gel, n-heptane/EA 100:0 to 0:100) to afford the title compound. [824] Example 94: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid [825] A mixture of methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoate (400 mg) and THF (5 mL) was added LiOH 2M (1 mL). After 3 h, the mixture was adjusted to pH = 1 by addition of HCl (1M) and extracted with EA (30 mL). The organic phase was washed with HCl (0.1M, 5 mL) and brine (5 mL), dried (Na2SO4) and concentrated. The residue was stirred with MeCN. The mixture was filtered to afford the title compound as solid. [826] Example 95: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanamide [827] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (200 mg), DMF (2 mL) and DIPEA (0.33 mL) was added EDC (116 mg), HOBt (69 mg) and ammonium chloride (50 mg). After stirring overnight, the mixture was added an additional amount of EDC (23 mg) and stirring was continued for 1 h. The mixture was filtered and purified by preparative HPLC. The product (146 mg) was dissolved in EA (1.5 mL). After 5 min, a precipitate formed. The suspension was stirred overnight. The solid was filtered off and dried in vacuo to afford the title compound. [828] Example 96: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 1) [829] Step 1: Preparation of methyl (1r,3r)-3-(acetylthio)cyclobutane-1-carboxylate [830] To a solution of methyl (1s,3s)-3-hydroxycyclobutane-1-carboxylate (8 g, 61.5 mmol) in dry THF (50 mL) was added ethanethioic S-acid (7 g, 92 mmol) and PPh3 (35 g, 135 mmol). The reaction was stirred at 0°C under nitrogen atmosphere for 10 min. Then DIAD (27 g, 135 mmol) was added slowly. The reaction mixture was stirred at 0°C for 16 h. The reaction was quenched with saturated ammonium chloride solution (300 mL) and extracted with dichloromethane (300 mL x 3). The crude product was purified by flash chromatography (ethyl acetate / petroleum ether = 10%) to afford the subtitle compound (6 g, 32 mmol, yield: 52%) as a colorless oil. MS m/z 189 [M+H]+. [831] Step 2: Preparation of methyl (1r,3r)-3-(chlorosulfonyl)cyclobutane-1-carboxylate [832] To a solution of methyl (1r,3r)-3-(chlorosulfonyl)cyclobutane-1-carboxylate (6 g, 32 mmol) in MeCN (30 mL) was added NCS (4.3 g, 32 mmol) and aqueous HCl (16 mL, 1M) at 0°C. The reaction mixture was stirred at 0°C for 1 h. The resulting mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (ethyl acetate / petroleum ether = 10%) to afford the subtitle compound (3.9 30 g, 18.3 mmol, yield:57%) as a colorless oil. MS m/z 213 [M+H]+. [833] Step 3: Preparation of methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylate (isomer 1) and methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]cyclobutanecarboxylate (isomer 2) [834] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (120 mg), DIPEA (2 mL) and DCM (6 mL) was added methyl 3- chlorosulfonylcyclobutanecarboxylate (190 mg). After 30 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the subtitle compounds. Isomer 1: MS (method N) m/z 471.1 [M+H]+, t=2.01min. Isomer 2: MS (method N) m/z 471.1 [M+H]+, t=2.07min. [835] Step 4: Preparation of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 1) [836] A mixture of methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylate (isomer 1, 137 mg), THF (4 mL) and water (1.5 mL) was added LiOH (25 mg). After 3 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [837] Example 97: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 2) [838] A mixture of methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylate (isomer 2, 118 mg), THF (4 mL) and water (1 mL) was added LiOH (22 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [839] Example 98: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-N-methyl-propanamide [840] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (500 mg), DMF (3 mL) and DIPEA (1.25 mL) was added EDC (278 mg), HOBt (157 mg) and methanamine (hydrochloride, 200 mg). After 30 stirring overnight, the mixture was diluted with MeOH (6.5 mL), filtered and purified by preparative HPLC. The solid obtained was suspended with MTBE (5 mL) for 48 h. The suspension was filtered, and the solid dried (stream of air) to afford the title compound. [841] Example 99: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]cyclobutanecarboxamide (isomer 1) [842] A mixture of 3-[[(3S,4S)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 1, 100 mg), DMF (4 mL) and DIPEA (0.2 mL) was stirred for 15 min, and added EDC (90 mg), HOBt (75 mg) and ammonium chloride (50 mg). After stirring overnight, the mixture was filtered and purified by preparative HPLC to afford the title compound. [843] Example 100: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]cyclobutanecarboxamide (isomer 2) [844] A mixture of 3-[[(3S,4S)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 2, 105 mg), DMF (4 mL) and DIPEA (0.3 mL) was stirred for 15 min, and added EDC (90 mg), HOBt (75 mg) and ammonium chloride (50 mg). After stirring overnight, the mixture was filtered and purified by preparative HPLC to afford the title compound. [845] Example 101: (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N,N- bis(2-hydroxyethyl)-3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide [846] Step 1: Preparation of (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride [847] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (360 mg), DCM (5 mL) and DIPEA (0.3 mL) under argon was cooled to - 78°C. Sulfuryl chloride (440 mg) as solution in DCM (5 mL) was added dropwise. The cooling bath was removed. The mixture was stirred at RT for 1 h, diluted with EA and washed with HCl (1N) and brine. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to afford the subtitle compound. [848] Step 2: Preparation of (3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- N,N-bis(2-hydroxyethyl)-3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide [849] A mixture of 2-(2-hydroxyethylamino)ethanol (45 mg), DIPEA (0.3 mL) and DCM (4 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (35 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [850] Example 102: (3R,4R)-1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]pyrrolidine-3,4-diol [851] A mixture of (3R,4R)-pyrrolidine-3,4-diol (50 mg), DIPEA (0.2 mL) and DCM (4 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (35 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [852] Example 102: (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-N-(1H-tetrazol-5-ylmethyl)-3,6-dihydro-2H-pyridine-1-sulfonamide [853] A mixture of 1H-tetrazol-5-ylmethanamine (50 mg), DIPEA (0.5 mL) and DMF (4 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (35 mg). After 6 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [854] Example 104: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]propyl acetate [855] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (hydrochloride, 100 mg), DIPEA (0.22 mL) and DCM (2 mL) was added 3- chlorosulfonylpropyl acetate (76 mg). After 45 min, the mixture was diluted with NH4Cl solution (2M, 3 mL). The pH was adjusted to 1 with 1M HCl. The mixture was extracted with EA (10 mL). The organic layer was washed with HCl (0.1M, 2mL) and brine (2 mL), dried (Na2SO4) and concentrated. The residue purified by chromatography (15 g silica gel, n- 30 heptane/EA 100:0 to 0:100) to afford the title compound. [856] Example 105: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]propan-1-ol [857] A mixture of methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]propyl acetate (61 mg) and THF (1 mL) was added LiOH (2M, 1 mL). After 2 h, the mixture was diluted with ammonium chloride solution (2M, 2 mL) and HCl (1M, 2 mL) and extracted with EA (10 mL). The organic phase was washed with HCl (0.1M, 2 mL) and brine (2 mL), dried (Na2SO4) and concentrated to afford the title compound. [858] Example 106: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(3-hydroxyazetidin-1-yl)propan-1-one [859] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (500 mg), azetidin-3-ol (170 mg), DMF (5 mL) and DIPEA (0.83 mL) was added HATU (552 mg). After stirring overnight, the mixture was diluted with MeOH (1 mL), filtered and purified by preparative HPLC. The oily material obtained (337 mg) was suspended with MTBE (5 mL) for 48 h. The solid was isolated by filtration to afford the title compound. [860] Example 107: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-methylsulfonyl-propanamide [861] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (50 mg), DMF (1 mL), DIPEA (0.15 mL) was added EDC (30 mg) and HOBt (20 mg). After 15 min, the mixture was added methanesulfonamide (30 mg). After 2 h, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [862] Example 108: (5R)-5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]imidazolidine-2,4-dione [863] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (50 mg), DIPEA (0.8 mL) and DCM (3 mL) was added [(4R)-2,5- dioxoimidazolidin-4-yl]methanesulfonyl chloride (70 mg). After 30 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [864] Example 109: (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N-[2- hydroxy-1-(hydroxymethyl)ethyl]-3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide [865] A mixture of (3R,4R)-pyrrolidine-3,4-diol (40 mg), DIPEA (0.5 mL) and DCM (4 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (40 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [866] Example 110: 4-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]piperazin-2-one [867] A mixture of piperazin-2-one (30 mg), DIPEA (0.6 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (30 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [868] Example 111: (2S)-2-Amino-N-[[(3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanamide [869] A mixture of (2S)-2-aminopropanamide (20 mg), DIPEA (0.6 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride (30 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [870] Example 112: 1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]azetidin-3-ol [871] A mixture of azetidin-3-ol (20 mg), DIPEA (0.6 mL), DMF (1 mL) and DCM (330 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonyl chloride (30 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [872] Example 113: (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-N-(2-oxopyrrolidin-3-yl)-3,6-dihydro-2H-pyridine-1-sulfonamide [873] A mixture of 3-aminopyrrolidin-2-one (27 mg), DIPEA (0.6 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride (30 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [874] Example 114: 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetic acid [875] Step 1: Preparation of methyl 2-[[(3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetate [876] dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetic acid [877] A mixture of methyl 2-(methylamino)acetate (110 mg), DIPEA (1.5 mL), DMF (2 mL) and DCM (10 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride (130 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the subtitle compound. MS m/z 458.1 [M+H]+. [878] Step 2: Preparation of 2-[[(3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetic acid [879] A mixture of methyl 2-[[(3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetate (36 mg), water (0.5 mL) and THF (2 mL) was added LiOH (7 mg). After 1 h, the mixture was concentrated to afford the title compound. [880] Example 115: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-2-methoxy-pyrimidine 30 [881] Step 1: Preparation of 2-methoxy-5-[(4-methoxyphenyl)methylsulfanyl]pyrimidine [882] A mixture of 5-bromo-2-methoxy-pyrimidine (5.0 g, 26.5 mmol), (4- methoxyphenyl)methanethiol (6.1 g, 26.5 mmol), Pd2(dba)3 (1.45 g, 1.59 mmol), Xantphos (1.83 g, 3.17 mmol), DIPEA (10.3 g, 79.4 mmol) and toluene (50 mL) was exchanged with nitrogen three times. The reaction mixture was stirred at 100°C for 16 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 40 g silica gel column, eluting with 0%-20% ethyl acetate in petroleum ether) to afford the subtitle compound (6.0 g, 22.9 mmol, yield: 86.5%) as yellow solid. MS m/z 263 [M+H]+. [883] Step 2: Preparation of 2-methoxypyrimidine-5-sulfonyl chloride [884] To a solution of 2-methoxy-5-[(4-methoxyphenyl)methylsulfanyl]pyrimidine (5.9 g, 22.5 mmol) in acetic acid (60 mL) and water (20 mL) was added NCS (12.0 g, 90.0 mmol) slowly at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 40 g silica gel column, eluting with 0%-50% dichloromethane in petroleum ether) to give the crude product, which was triturated with petroleum ether (30 mL). The precipitate formed was isolated by filtration and dried in vacuo to afford the subtitle compound (1.2 g, 5.75 mmol, yield: 25.6%) as white solid. MS m/z 209 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 2H), 4.18 (s, 3H) ppm. [885] Step 3: Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]-2-methoxy-pyrimidine [886] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (71 mg), DIPEA (0.8 mL) and DCM (3 mL) was added 2-methoxypyrimidine- 5-sulfonyl chloride (105 mg). After 60 min, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [887] Example 116: Methyl 2-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrazol-1-yl]acetate [888] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (50 mg), DIPEA (1.0 mL) and DCM (3 mL) was added methyl 2-(4- chlorosulfonylpyrazol-1-yl)acetate (110 mg). After 60 min, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [889] Example 117: 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetamide [890] A mixture of 2-[[(3R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl-methyl-amino]acetic acid (40 mg), DMF (2.5 mL) and DIPEA (0.1 mL) was stirred for 15 min, and added EDC (25 mg), HOBt (22 mg) and ammonium chloride (15 mg). After stirring overnight, the mixture was filtered and purified by preparative HPLC to afford the title compound. [891] Example 118: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyrimidine [892] Step 1: Preparation of 5-((4-methoxybenzyl)thio)pyrimidine [893] To a solution of 5-bromopyrimidine (9 g, 57 mmol) in toluene (50 mL) was added PMB-SH (8.7 g, 57 mmol), DIPEA (22 g, 171 mmol), Pd2(dba)3 (3.1 g, 3.4 mmol) and Xantphos (3.3 g, 5.7 mmol) under nitrogen atmosphere. The reaction was stirred at 80°C under nitrogen atmosphere for 16 h. The reaction was quenched with saturated ammonium chloride (300 mL) and extracted with dichloromethane (500 mL x 3). The crude product was purified by flash chromatography (ethyl acetate / petroleum ether = 10%) to afford the subtitle compound (12 g, 51 mmol, yield: 89%) as a yellow oil. MS m/z 233 [M+H]+. [894] Step 2: Preparation of pyrimidine-5-sulfonyl chloride [895] To a solution of aqueous HCl solution (1 N, 206 mL), NaClO (206 g) was added in portions. The mixture was stirred at -5°C for 30 mins. Then, the mixture was dropwise to a solution of 1,3-dichloro-5,5-dimethyl-imidazolidine-2,4-dione (8 g, 34 mmol) in DCM (100 mL). The reaction mixture was stirred at RT for 30 mins. The desired product was found in LCMS. The mixture was filtered and concentrated. The crude product was purified by flash 30 chromatography (ethyl acetate / petroleum ether = 20%) to afford the subtitle compound (244 mg, yield: 4%) as a colorless oil. MS m/z 179 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 8.90 (s, 2H ) ppm. [896] Step 3: Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidine [897] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (50 mg), DIPEA (0.8 mL), DMF (0.5 mL) and DCM (2 mL) was added pyrimidine-5-sulfonyl chloride (100 mg). After 60 min, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [898] Example 119: 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-methyl-pyridin-2-one [899] Step 1: Preparation of 4-[(4-methoxyphenyl)methylsulfanyl]-1 -methyl-pyridin-2- one [900] To a solution of 4-bromo-1-methyl-pyridin-2-one (4.0 g, 21.3 mmol) and (4- methoxyphenyl)methanethiol (3.61 g, 23.4 mmol) in toluene (50 mL) was added DIPEA (5.5 g, 42.5 mL). Then (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (734 mg, 1.28 mmol) and (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (739 mg, 1.28 mmol) were added under N2 atmosphere. The reaction was stirred at 80°C for 16 h. Then the mixture was poured into water (50 mL) and extracted with EA (50 mL x 2). The organic layers were combined, washed with brine (50 mL x 2), dried with anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (EA/PE= 35%) to afford the subtitle compound (5.4 g, yield: 97.1%) as colorless oil. MS m/z 262.1 [M+H]+. [901] Step 2: Preparation of 1-methyl-2-oxo-pyridine-4-sulfonyl chloride [902] To a solution of 4-[(4-methoxyphenyl)methylsulfanyl]-1-methyl-pyridin-2-one (5.4 g,^20.7 mmol) in AcOH/H2O (100 mL, v/v=1/1) was added 1-chloropyrrolidine-2,5-dione (11.0 g, 827 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hrs. The mixture was poured into water (100 mL) and extracted with DCM (100 mL x 3). The organic layers were washed with brine (100 mL x 2), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (EA: PE= 80%) to afford the subtitle 30 compound (1.44 g, yield: 33.6 %) as a white solid. MS m/z 208.1 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 7.2 Hz, 1 H), 7.20 (d, J = 2.2 Hz, 1 H), 6.64 (dd, J = 7.2, 2.2 Hz, 1 H), 3.63 (s, 3 H). [903] Step 3: Preparation of 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]-1-methyl-pyridin-2-one [904] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (43 mg), DIPEA (0.7 mL), DMF (0.5 mL) and DCM (2 mL) was added 1- methyl-2-oxo-pyridine-4-sulfonyl chloride (95 mg). After 60 min, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [905] Example 120: 2-[4-Chloro-5-[(3R,4R)-1-[2-[2-[(4-methoxyphenyl)methyl]tetrazol- 5-yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [906] Step 1: Preparation of ethyl 2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H- tetrazol-5- yl)acetate [907] To a solution of ethyl 2-(2H-tetrazol-5-yl)acetate (10 g, 64.0 mmol) in DMF (30 mL) under argon atmosphere at 25°C was added potassium carbonate (10.6 g, 76.9 mmol) and 1-(chloromethyl)-4-methoxy-benzene (12.0 g, 76.9 mmol). The reaction mixture was stirred overnight. LCMS showed the reaction was completed. The mixture was extracted with EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (100 mL) and water (50 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (15-48% EtOAc in hexanes) to afford the subtitle compound (7.0 g, 0.0196 mol, yield: 30.6%) as a white solid. MS m/z 277.1 [M+H]+. [908] Step 2: Preparation of 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]ethanol [909] To a solution of ethyl 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]acetate (6.8 g, 24.6 mmol) in THF (70 mL) under argon atmosphere at 0°C was added LiAlH4 (1.49 g, 39.4 mmol). The reaction mixture was stirred overnight at RT. LCMS showed the reaction was completed. The mixture was quenched with water (1.49 mL), NaOH (20%, 1.49 mL), water (4.5 mL) and was filtrated to afford the crude product. The crude product was dissolved in DCM, loaded to a silica column (SanTai, 80 g), purified by flash chromatography (Biotage) and rinsed with EA/PE (0% to 5%) to afford the subtitle compound (3.8 g, 0.0142 mol, yield: 30 57.6%) as a colorless oil. MS m/z 235.1 [M+H]+. [910] Step 3: Preparation of 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]ethyl 4- methylbenzenesulfonate [911] To a solution of 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]ethanol (3.6 g, 15.6 mmol), N,N-diethylethanamine (3.11 g, 30.7 mmol) in THF (40 mL) under argon atmosphere was added 4-methylbenzenesulfonyl chloride (4.39 g, 23.1 mmol) slowly at 0°C. The reaction mixture was stirred overnight. LCMS showed the reaction was completed. The mixture was concentrated and was diluted with EtOAc (100 mL) and H2O (100 mL). ^The organic phase was separated. The aqueous layer was extracted with EA (100 ml ×2). The organic phases were combined, washed with water (100 ml ×2), dried over Na2SO4 and concentrated. The crude product was dissolved in DCM, loaded to a silica column (SanTai, 120 g), purified by flash chromatography (Biotage) and rinsed with EA/PE (0% to 50%, 80 mL/ min) to afford the subtitle compound (4.7 g, 0.012 mol, yield 77.8%) as a colorless oil. MS m/z 389.1 [M+H]+. [912] Step 4: Preparation of S-[2-[2-[(4-methoxyphenyl)methyl]tetrazol -5-yl]ethyl] ethanethioate [913] To a solution of 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]ethyl 4- methylbenzenesulfonate (4.3 g, 11.1 mmol) in DMF (30 mL)^were added ethanethioic S-acid (1.69 g, 22.1 mmol) and potassium carbonate (6.12 g, 44.3 mmol). The reaction mixture was stirred at 60°C for 16 hours. LCMS showed the reaction was completed. The mixture was diluted with EtOAc (100 mL) and H2O (100 mL). ^The organic phase was separated. The aqueous layer was extracted with EA (100 mL ×2). The organic phases were combined, washed with water (100 mL × 2), dried over Na2SO4 and concentrated. The crude product was dissolved in DCM, loaded to a silica column (SanTai, 120 g), purified by flash chromatography (Biotage) and rinsed with EA/PE (0% to 50%) to afford the subtitle compound (3.0 g, 9.67 mmol, yield 87.3%) as a yellow oil.^MS m/z 293.1 [M+H]+. [914] Step 5: Preparation of 2-[2-[(4-methoxyphenyl)methyl]tetrazol-5-yl]ethanesulfonyl chloride [915] To a solution of 1-chloropyrrolidine-2,5-dione (333 mg) in ACN (5 mL) was added hydrogen chloride (3 mL) slowly, the mixture was stirred at 0°C for 15 mins. S-[2-[2-[(4- methoxyphenyl)methyl]tetrazol-5-yl]ethyl] ethanethioate (292 mg) was added. The reaction 30 was stirred at 0°C for 30 mins. LCMS showed the reaction was completed. The mixture was concentrated and purified by reverse flash chromatography (Biotage, gradient: 20%-50% ACN in water (0.01%TFA), flow rate: 30 mL/min; column: Boston C18, 40 g) (reaction was repeated with 3 batches) to afford the subtitle compound (581.4 mg, yield: 42.8%) as a white solid.MS m/z 339.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.29 (m, 2H), 6.92 – 6.87 (m, 2H), 5.66 (s, 2H), 4.16 – 4.11 (m, 2H), 3.80 (s, 3H), 3.62 – 3.57 (m, 2H). [916] Step 6: Preparation of 2-[4-chloro-5-[(3R,4R)-1-[2-[2-[(4- methoxyphenyl)methyl]tetrazol-5-yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]- 5-fluoro-pyridine [917] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (70 mg), DIPEA (1.5 mL), DMF (1.0 mL) and DCM (4 mL) was added 2-[2- [(4-methoxyphenyl)methyl]tetrazol-5-yl]ethanesulfonyl chloride (190 mg). After 30 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [918] Example 121: 2-[4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrazol-1-yl]acetic acid [919] A mixture of methyl 2-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrazol-1-yl]acetate (56 mg), water (1 mL) and THF (4 mL) was added LiOH (10 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [920] Example 122: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-ol [921] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-2-methoxy-pyrimidine (60 mg), water (1 mL) and THF (4 mL) was added LiOH (11 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [922] [923] Example 123: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(2H-tetrazol-5- 30 yl)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [924] A mixture of 2-[4-chloro-5-[(3R,4R)-1-[2-[2-[(4-methoxyphenyl)methyl]tetrazol- 5-yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (65 mg) and TFA (3 mL) was stirred at 50°C for 2h. The mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [925] Example 124: Methyl 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoate [926] Step 1: Preparation of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-5-methyl-3,6-dihydro-2H-pyridine-1-carboxylate [927] To a solution of 2-[[5-bromo-2-(5-fluoro-2-pyridyl)imidazol-1-yl]methoxy]ethyl- trimethyl-silane (5 g, 13.4 mmol) in 1,4-dioxane (50 mL)^ were added tert-butyl 5-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (4.34 g, 13.4 mmol) and potassium carbonate (5.57 g, 40.3 mmol) in water (10 mL). And then Pd(dtbpf)Cl2 (876 mg, 1.34 mmol) was added under N2 atmosphere. The reaction was stirred at 80°C for 48 hrs. The reaction mixture was quenched by adding water (100 mL) and extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried and concentrated. The crude product was purified by flash column chromatography (ethyl acetate / petroleum ether = 30%) to afford the subtitle compound (3.02 g, yield:^46%) as a yellow oil. MS m/z 489.2 [M+H]+. [928] Step 2: Preparation of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-5-methyl-3,6-dihydro-2H-pyridine-1-carboxylate [929] To a solution of tert-butyl 4-[2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-5-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (2 g,^4.09 mmol) in THF (20 mL) was added NCS (653 mg, 4.91 mmol) in several portions at RT (water bath). The reaction mixture was stirred at 40°C for 16 hrs. The solvent was removed, and the residue taken up into water (50 mL) followed by extraction with EA (50 mL x 3). The organic layers were washed with brine, dried with Na2SO4 and concentrated. The crude was purified by flash chromatography (ethyl acetate / petroleum ether = 25%) to afford the subtitle compound (540 mg, yield: 25%) as a yellow oil. MS m/z 523.0 [M+H]+. [930] Step 3: Preparation of 2-[4-chloro-5-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl]-5-fluoro-pyridine [931] A solution of tert-butyl 4-[5-chloro-2-(5-fluoro-2-pyridyl)-3-(2- trimethylsilylethoxymethyl)imidazol-4-yl]-5-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (540 mg, 1.03 mmol) in 1,4-dioxane (2 mL) was added 4M HCl in 1,4-dioxane (4 mL) and stirred at room temperature for 4 hours. Then the mixture was concentrated and diluted with water (10 mL). The mixture was basified with saturated K2CO3 solution to pH = 9 and was extracted with ethyl acetate (15 mL x 3). The organic layers were combined, washed with brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated to afford the subtitle compound (174.5 mg, yield 57.6%) as a white solid. MS m/z 293.2 [M+H]+.1H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 2.5 Hz, 1H), 8.15 (dd, J = 8.5, 4.5 Hz, 1H), 7.49 (td, J = 8.5, 2.5 Hz, 1H), 3.43 (s, 2H), 3.10 (t, J = 5.5 Hz, 2H), 2.35 (s, 2H), 1.68 (s, 3H) ppm. [932] Step 4: Preparation of methyl 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-5-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoate [933] A mixture of 2-[4-chloro-5-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol- 2-yl]-5-fluoro-pyridine (150 mg), DIPEA (0.3 mL) and DCM (5 mL) was added methyl 3- chlorosulfonylpropanoate (105 mg). After stirring overnight, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [934] Example 125: 3-[[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl- 3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanamide [935] Step 1: Preparation of 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoic acid [936] A mixture of methyl 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoate (100 mg) and THF (1 mL) was added LiOH (2M, 0.17 mL). After stirring overnight, the mixture was diluted with ammonium chloride solution (2M, 2 mL), acidified with 1M HCl and extracted with EA (5 mL). The organic phase was washed with HCl (0.1M, 2 mL) and brine (2 mL x2), dried (Na2SO4) and concentrated to afford the subtitle compound. [937] Step 2: Preparation of 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanamide [938] A mixture of 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl- 3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was stirred for 15 min, and added EDC (20 mg), HOBt (9.5 mg) and ammonium chloride (7.5 mg). After stirring overnight, the mixture was filtered and purified by preparative HPLC to afford the title compound. [939] Example 126: 3-[[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl- 3,6-dihydro-2H-pyridin-1-yl]sulfonyl]-1-(3-hydroxyazetidin-1-yl)propan-1-one [940] A mixture of 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl- 3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was stirred for 15 min, and added EDC (20 mg), HOBt (9.5 mg) and azetidin-3-ol (10 mg). After stirring overnight, the mixture was filtered and purified by preparative HPLC to afford the title compound. [941] Example 127: 3-[[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl- 3,6-dihydro-2H-pyridin-1-yl]sulfonyl]-N-cyclopropyl-propanamide [942] A mixture of 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl- 3,6-dihydro-2H-pyridin-1-yl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was stirred for 15 min, and added EDC (20 mg), HOBt (9.5 mg) and cyclopropanamine (8 mg). After stirring overnight, the mixture was filtered and purified by preparative HPLC to afford the title compound. [943] Example 128: (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-3,6-dihydro-2H-pyridine-1-sulfonamide [944] A mixture of (5-methyl-1,3,4-oxadiazol-2-yl)methanamine (40 mg), DIPEA (0.6 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride (25 mg). After 1 h at 50°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the subtitle compound. [945] Example 129: [1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]azetidin-3-yl]methanol [946] A mixture of azetidin-3-ylmethanol (30 mg), DIPEA (0.8 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride (40 mg). After 1 h at 50°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [947] Example 130: N-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]piperidine-3-carboxamide [948] A mixture of piperidine-3-carboxamide (45 mg), DIPEA (0.8 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride (40 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [949] Example 131: (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N-[(2S)- 2-hydroxypropyl]-3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide [950] A mixture of (2S)-1-aminopropan-2-ol (25 mg), DIPEA (0.8 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride (40 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [951] Example 132 and Example 133: 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonylamino]-N,N-dimethyl- acetamide and 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylamino]-N,N-dimethyl-acetamide [952] A mixture of 2-amino-N,N-dimethyl-acetamide (35 mg), DIPEA (0.8 mL), DMF (1 mL) and DCM (3 mL) was added (R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- 3-methyl-3,6-dihydropyridine-1(2H)-sulfonyl chloride (40 mg, containing (3R,4R)-4-(4- chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1-sulfonyl chloride as impurity). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compounds. [953] Example 134: Tert-butyl (3S,4S)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-piperidine-1-carboxylate [954] Step 1: Preparation of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidine-1-carboxylate [955] A mixture of tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-3-methylpiperidine-1-carboxylate (147 g, 0.28 mol, mixture of SEM-regioisomers) and 1 M HCl in dioxane (365 mL) was stirred at room temperature for 4 hours. Then solution was concentrated by rotary evaporator and slurried with MTBE/PE=10/1 three times to afford the subtitle compound (85 g, crude) as a yellow solid. MS m/z 395.0 [M+H]+. [956] Step 2: Preparation of tert-butyl (3S,4S)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-piperidine-1-carboxylate [957] The isomeric mixture tert-butyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methylpiperidine-1-carboxylate (85 g, crude) was separated by preparative chiral HPLC to afford tert-butyl (3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-carboxylate (35.448 g) and the title compound (36.128 g). [958] Preparative chiral HPLC conditions: instrument: SFC-150 (Waters); column: OD 25x250mm, 10μm (Daicel); column temperature: 35°C; mobile phase: CO2/ MeOH (0.2% NH3(7M in MeOH) 85:15; flow rate: 100 ml/min; back pressure: 100 bar; detection wavelength: 214 nm; cycle time: 3.5 min; sample solution: 85 g dissolved in 1000 ml methanol; injection volume: 1 ml. [959] Analytical chiral HPLC conditions: column: IG 4.6*100mm, 5µm; column temperature: 40°C; mobile phase: CO2/ MeOH (0.2% NH3(7M in MeOH) 90:10; flow rate: 3ml/min; back pressure: 2000psi; detection wavelength: 214 nm; run time: 4.0 min; injection volume: 5.00 µl. [960] Tert-butyl (3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-carboxylate. Chiral HPLC 2.060 min. 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.60 (d, J = 2.8 Hz, 1H), 7.99 (dd, J = 8.8, 4.4 Hz, 1H), 7.82 (td, J = 8.8, 2.8 Hz, 1H), 4.10 (s, 1H), 3.87 (s, 1H), 3.21 – 2.60 (m, 3H), 2.38 (dd, J = 22.0, 12.4 Hz, 1H), 2.00 (s, 1H), 1.55 – 1.30 (m, 10H), 0.76 (d, J = 6.4 Hz, 3H) ppm. [961] Tert-butyl (3S,4S)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- piperidine-1-carboxylate. Chiral HPLC 2.343 min. [962] Example 135: 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6- dihydro-2H-pyridine-1-sulfonamide [963] Step 1: Preparation of tert-butyl N-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-5-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]carbamate [964] A mixture of 2-[4-chloro-5-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-imidazol- 2-yl]-5-fluoro-pyridine (25 mg), DIPEA (30 µL) and DCM (1 mL) was added (tert- butoxycarbonyl)(4-dimethylimino)pyridine-1(4H)-yl)sulfamoyl)amide (39 mg). After stirring overnight, the mixture was diluted with ammonium chloride solution (2M, 2 mL), acidified with 1M HCl and extracted with EA (5 mL). The organic phase was washed with HCl (0.1M, 1 mL) and brine (1 mL x2), dried (Na2SO4) and concentrated to afford the crude subtitle compound. [965] Step 2: Preparation of 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5- methyl-3,6-dihydro-2H-pyridine-1-sulfonamide [966] A mixture of tert-butyl N-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 5-methyl-3,6-dihydro-2H-pyridin-1-yl]sulfonyl]carbamate (40 mg, crude) and DCM (1 mL) was added HCl (6M in iPrOH, 1 mL). After 3d, the mixture was concentrated and purified by preparative HPLC to afford the title compound. [967] Example 136: 2-Chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidine [968] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (230 mg), DIPEA (2 mL) and DCM (5 mL) was added 2-chloropyrimidine-5- sulfonyl chloride (220 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [969] Example 137: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylpyrazol-4-yl)sulfonyl- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [970] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (63 mg), DIPEA (1 mL) and DCM (3 mL) was added 1-methylpyrazole-4- sulfonyl chloride (100 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [971] Example 138: (3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N,3- dimethyl-piperidine-1-carboxamide [972] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (60 mg), DIPEA (1 mL) and DCM (3 mL) was added N-methylcarbamoyl chloride (50 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [973] Example 139: 1-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]azetidin-3-ol [974] A mixture of azetidin-3-ol (17 mg), DIPEA (0.5 mL) and DMF (2 mL) was added 2-chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine (33 mg). After 1 h at 60°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [975] Example 140: 2-[[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]amino]ethanol [976] A mixture of 2-aminoethanol (15 mg), DIPEA (0.5 mL) and DMF (2 mL) was added 2-chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine (33 mg). After 1 h at 60°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [977] Example 141: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(1-methyltetrazol-5- yl)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [978] Step 1: Preparation of ethyl 2-(1-methyltetrazol-5-yl)acetate [979] To a stirred suspension of ethyl 2-(1H-tetrazol-5-yl)acetate (10.5 g, 67.2 mmol) in MeCN (100 mL) was added potassium carbonate (9.29 g, 67.2 mmol) in portions. Then methyl iodide (11.5 g, 81.7 mmol) was added into the reaction system dropwise. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the solid washed with ethyl acetate (100 mL). The filtrate was concentrated. The residue was purified by flash chromatography (Biotage 120 g silica gel column, eluting with 0%-50% ethyl acetate in petroleum ether) to the subtitle compound (6.1 g, 35.8 mmol, yield: 53.3%) as white solid. MS m/z 171 [M+H]+. [980] Step 2: Preparation of 2-(1-methyltetrazol-5-yl)ethanol [981] To a stirred solution of ethyl 2-(1-methyltetrazol-5-yl)acetate (6.1 g, 35.8 mmol) in MeOH (60 mL) was added sodium borohydride (2.71 g, 71.7 mmol) in portions at 0°C. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was quenched with water (20 mL) and concentrated. The residue was purified by flash chromatography (Biotage 40 g silica gel column, eluting with 0%-20% MeOH in DCM) to afford the subtitle compound (4.5 g, 35.1 mmol, yield: 98%) as colorless oil. MS m/z 129 [M+H]+. [982] Step 3: Preparation of O-[2-(1-methyltetrazol-5-yl)ethyl] ethanethioate [983] To a solution of triphenylphosphine (20.3 g, 77.3 mol) in dry THF (200 mL) was added DIAD (15.6 g, 77.3 mmol) dropwise at 0°C under nitrogen atmosphere. After 20 min, a solution of 2-(1-methyltetrazol-5-yl)ethanol (4.5 g, 35.1 mmol) in dry THF (20 mL) was added into the reaction system. After 10 min, neat ethanethioic S-acid (5.88 g, 77.3 mmol) was added into the reaction system. The resulting mixture was stirred at 0°C for 1 h and at room temperature for 4 h. The reaction mixture was concentrated. The residue was purified by flash chromatography (Biotage 120 g silica gel column, eluting with 0%-30% ethyl acetate in petroleum ether) to afford the subtitle compound (12.5 g, crude) as light-yellow solid. MS m/z 187 [M+H]+. [984] Step 4: Preparation of 2-(1-methyltetrazol-5-yl)ethanesulfonyl chloride [985] To a solution of O-[2-(1-methyltetrazol-5-yl)ethyl] ethanethioate (12.5 g, crude) in MeCN (65 mL) were added HCl (2 M, 105 mL, 0.209 mmol) slowly and NCS (11.7 g, 87.3 mmol) in portions at 0°C. The resulting mixture was stirred at 0°C for 2 h. The reaction mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried with anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage 80 g silica gel column, eluting with 0%-30% ethyl acetate in petroleum ether) to afford the subtitle compound (3.8 g, 18.04 mmol, yield: 51.4%) as white solid. MS m/z 211 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 4.46 – 4.24 (m, 2H), 4.10 (s, 3H), 3.74 – 3.39 (m, 2H) ppm. [986] Step 5: Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-[2-(1-methyltetrazol-5- yl)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [987] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (65 mg), DIPEA (1 mL) and DCM (3 mL) was added 2-(1-methyltetrazol-5- yl)ethanesulfonyl chloride (165 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [988] Example 142: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-amine [989] Step 1: Preparation of 2-aminopyrimidine-5-sulfonyl chloride [990] A mixture of pyrimidin-2-amine (20 g,^210 mmol) and SOCl2/ClSO2OH (280 mL, v/v=9/5) was stirred at 150°C for 96 hrs. The mixture was poured into water (200 mL) and extracted with DCM (200 mL x 3). The organic layers were washed with brine (200 mL x 2), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (EA: PE= 40%) to give to afford the subtitle compound (4.2 g, yield: 10.3%) as a white solid. MS m/z 193.9 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 2H), 5.95 (s, 2H) ppm. [991] Step 2: Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-amine [992] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (500 mg), DIPEA (5 mL) and DCM (20 mL) was added 2-aminopyrimidine-5- sulfonyl chloride (550 mg). After 2 h, the mixture was concentrated, and the residue purified by preparative HPLC. The solid obtained (610 mg) was dissolved in EA. The solution was washed with sat. NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was suspended with EA/n-heptane. The solid was isolated by filtration and dried in vacuo to afford the title compound. [993] Example 143: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyridin-2-amine [994] Step 1: Preparation of 2-aminopyrimidine-5-sulfonyl chloride [995] A mixture of pyrimidin-2-amine (5.0 g,^52.6 mmol) and sulfurochloridic acid (50 mL) was stirred at 150°C for 4 hrs. The mixture was poured into water (50 mL) and extracted with DCM (50 mL x 3). The organic layers were washed with brine (50 mL x 2), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (EA: PE= 70%) to give to afford the subtitle compound (1.96 g, yield: 19.3%) as a white solid. MS m/z 192.9 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 9.2, 2.8 Hz, 1H), 6.56 (dd, J = 9.2, 0.4 Hz, 1H), 5.30 (s, 2H). [996] Step 2: Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyridin-2-amine [997] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (65 mg), DIPEA (1 mL) and DCM (3 mL) was added 6-aminopyridine-3- sulfonyl chloride (192 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [998] Example 144: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-cyclopropyl-pyrimidin-2-amine [999] A mixture of cyclopropanamine (14 mg), DIPEA (0.5 mL) and DMF (2 mL) was added 2-chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine (33 mg). After 1 h at 60°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1000] Example 145: 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-methyl-pyrrolidin-2-one [1001] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (65 mg), DIPEA (1 mL) and DCM (3 mL) was added 1-methyl-5-oxo- pyrrolidine-3-sulfonyl chloride (100 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1002] Example 146: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-methyl-pyrimidin-2-amine [1003] A mixture of methanamine (10 mg), DIPEA (1 mL) and DMF (1.5 mL) was added 2-chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine (33 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1004] Example 147: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N,N-bis(trideuteriomethyl)propanamide [1005] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 µL) was added EDC (20 mg) and HOBt (9.4 mg). After 10 min, the mixture was added 1,1,1- trideuterio-N-(trideuteriomethyl)methanamine (7.1 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1006] Example 148: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(2-hydroxy-2-methyl-propyl)propanamide [1007] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 µL) was added EDC (20 mg) and HOBt (9.4 mg). After 10 min, the mixture was added 1-amino-2- methyl-propan-2-ol (12 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1008] Example 149: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-cyclopropyl-propanamide [1009] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 µL) was added EDC (20 mg) and HOBt (9.4 mg). After 10 min, the mixture was added cyclopropanamine (8 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1010] Example 150: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-[(3R)-3-hydroxypyrrolidin-1-yl]propan-1-one [1011] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 µL) was added EDC (20 mg) and HOBt (9.4 mg). After 10 min, the mixture was added (3R)- pyrrolidin-3-ol (12 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1012] Example 151: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-[(3S)-3-hydroxypyrrolidin-1-yl]propan-1-one [1013] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 µL) was added EDC (20 mg) and HOBt (9.4 mg). After 10 min, the mixture was added (3S)-pyrrolidin- 3-ol (12 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1014] Example 152: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(3-methoxyazetidin-1-yl)propan-1-one [1015] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 µL) was added EDC (20 mg) and HOBt (9.4 mg). After 10 min, the mixture was added 3- methoxyazetidine (12 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1016] Example 153: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(3-hydroxy-3-methyl-azetidin-1-yl)propan-1-one [1017] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 µL) was added EDC (20 mg) and HOBt (9.4 mg). After 10 min, the mixture was added 3- methylazetidin-3-ol (12 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1018] Example 154: 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-1-(4-hydroxy-1-piperidyl)propan-1-one [1019] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 µL) was added EDC (20 mg) and HOBt (9.4 mg). After 10 min, the mixture was added piperidin-4-ol (14 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1020] Example 155: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(2-methoxyethyl)propanamide [1021] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL), DIPEA (50 µL) was added EDC (20 mg) and HOBt (9.4 mg). After 10 min, the mixture was added 2- methoxyethanamine (10 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1022] Example 156: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(2-methyltetrazol-5- yl)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1023] Step 1: Preparation of ethyl 2-(2-methyltetrazol-5-yl)acetate [1024] To a stirred suspension of ethyl 2-(1H-tetrazol-5-yl)acetate (10.5 g, 67.2 mmol) in MeCN (100 mL) was added potassium carbonate (9.29 g, 67.2 mmol) slowly. Then methyl iodide (11.5 g, 81.7 mmol) was added into the reaction system dropwise. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was filtered and the cake washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 120 g silica gel column, eluting with 0%-50% ethyl acetate in petroleum ether) to afford the subtitle compound (4.2 g, 24.7 mmol, yield: 36.7%) as colorless oil. MS m/z 171 [M+H]+. [1025] Step 2: Preparation of 2-(1-methyltetrazol-5-yl)ethanol [1026] To a stirred solution of ethyl 2-(1-methyltetrazol-5-yl)acetate (4.2 g, 24.7 mmol) in MeOH (40 mL) was added sodium borohydride (1.87 g, 49.4 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (30 mL) and concentrated. The residue was purified by flash chromatography (Biotage 40 g silica gel column, eluting with 0%-20% MeOH in DCM) to afford the subtitle compound (3.1 g, 24.2 mmol, yield: 98%) as colorless oil. MS m/z 129 [M+H]+. [1027] Step 3: Preparation of O-[2-(2-methyltetrazol-5-yl)ethyl] ethanethioate [1028] To a stirred solution of triphenylphosphine (14.0 g, 53.2 mol) in dry THF (140 mL) was added DIAD (10.8 g, 53.2 mmol) dropwise at 0 °C under nitrogen atmosphere. After 20 min, a solution of 2-(2-methyltetrazol-5-yl)ethanol (3.1 g, 24.2 mmol) in dry THF (30 mL) was added into the reaction system. After 10 min, neat ethanethioic S-acid (4.05 g, 53.2 mmol) was added into the reaction system. The resulting mixture was stirred at 0 °C for 1 h and at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 80 g silica gel column, eluting with 0%-30% ethyl acetate in petroleum ether) to afford the subtitle compound (11.5 g, crude) as light yellow oil. MS m/z 187 [M+H]+. [1029] Step 4: Preparation of (2-(2-methyltetrazol-5-yl)ethanesulfonyl chloride [1030] To a stirred solution of O-[2-(2-methyltetrazol-5-yl)ethyl] ethanethioate (11.5 g, crude) in MeCN (100 mL) was added 2 M HCl (72.6 mL, 145.2 mmol) dropwise followed by NCS (8.08 g, 60.5 mmol) in portions at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage 80 g silica gel column, eluting with 0%-25% ethyl acetate in petroleum ether) to give the crude product, into which was added water (100 mL). The mixture was stirred at 100 °C for 1 h, cooled to room temperature and extracted with ethyl acetate (50 mL x 3). The aqueous phase was concentrated under reduced pressure. The residue was dissolved in POCl3 (37.1 g, 242.0 mmol). The resulting mixture was stirred at 70 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 40 g silica gel column, eluting with 0%-30% ethyl acetate in petroleum ether) to afford the subtitle compound (2.0 g, 9.49 mmol, two steps’ yield: 39.2%) as light yellow oil. MS m/z 211 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 4.35 (s, 3H), 4.18- 4.15 (m, 2H), 3.72-3.57 (m, 2H) ppm. [1031] Step 5: Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-[2-(2-methyltetrazol-5- yl)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1032] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (50 mg), DIPEA (1 mL) and DCM (3 mL) was added 2-(2-methyltetrazol-5- yl)ethanesulfonyl chloride (120 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1033] Example 157: Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]azetidine-1-carboxylate [1034] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (2 mL) and DCM (6 mL) was added tert-butyl 3- chlorosulfonylazetidine-1-carboxylate (120 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1035] Example 158: 2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]acetamide [1036] Step 1: Preparation of methyl 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]acetate [1037] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (2 mL) and DCM (6 mL) was added methyl 2- chlorosulfonylacetate (210 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the subtitle compound. [1038] Step 2: Preparation of 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]acetic acid [1039] A mixture of methyl 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]acetate (42 mg), water (1.0 mL) and THF (4 mL) was added LiOH (8 mg). After 1 h, the mixture was concentrated to afford the crude subtitle compound. [1040] Step 3: Preparation of 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]acetamide [1041] A mixture of 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]acetic acid (40 mg, crude), DMF (2 mL), DIPEA (0.3 mL) was added EDC (25 mg) and HOBt (22 mg). After 15 min, the mixture was added ammonium chloride (18 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1042] Example 159: Tert-butyl N-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]thiazol-2-yl]carbamate [1043] Step 1: Preparation of tert-butyl N-[4-(chloromethyl)thiazol-2-yl]carbamate [1044] A mixture of 4-(chloromethyl)thiazol-2-amine (hydrochloride, 10 g, 54 mmol), TEA (16.4 g, 162 mmol) and DMAP (cat.) in THF (150 mL) was stirred at room temperature for 5 min. Then Boc2O (14.2 g, 64.8 mmol) was added in portions. After addition, the mixture was stirred at room temperature for 16 h. The mixture was concentrated. The residue was poured into 150 mL water. The water layer was extracted with EtOAc (150 mL x 3). Organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (30% EtOAc in PE) to afford the subtitle compound (5.4 g, 40% yield) as yellow solid. MS m/z 249 [M+H]+. [1045] Step 2: Preparation of S-[[2-(tert-butoxycarbonylamino)thiazol-4-yl]methyl] ethanethioate [1046] A mixture of tert-butyl N-[4-(chloromethyl)thiazol-2-yl]carbamate (2.5 g, 10 mmol) in acetone (50 mL) was stirred at room temperature. Potassium ethanethioate (2.3 g, 20 mmol) was added. The mixture was stirred at 40°C for 4 h. The mixture was cooled to room temperature and concentrated. The residue was poured into water (50 mL). The water layer was extracted with EtOAc (50 mL x 3). The organic layers were combined, dried over Na2SO4 and concentrated to afford the subtitle compound (3.0 g, crude) as yellow solid. MS m/z 289 [M+H]+. [1047] Step 3: Preparation of [2-(tert-butoxycarbonylamino)thiazol-4-yl]methanesulfonic acid [1048] A mixture of S-[[2-(tert-butoxycarbonylamino)thiazol-4-yl]methyl] ethanethioate (100 mg, 0.35 mmol) in HCOOH/ H2O (10/10 mL) was stirred at room temperature. H2O2 (4 g, 35 mmol) was added dropwise. After addition, the mixture was stirred at room temperature for 3 h. Then water (50 mL) was added. The mixture was freeze-dried directly to afford the subtitle compound (1.8 g, 88%) as white solid which was used without further purification. MS m/z 239 [M-tBu+H]+. [1049] Step 4: Preparation of tert-butyl N-[4-(chlorosulfonylmethyl)thiazol-2- yl]carbamate [1050] A mixture of [2-(tert-butoxycarbonylamino)thiazol-4-yl]methanesulfonic acid (600 mg, 2 mmol mmol) in DCM (10 mL) was stirred at room temperature. DMF (cat.) was added. The mixture was stirred at 0°C. Oxalyl dichloride (310 mg, 2.4 mmol) was added dropwise. After addition, the mixture was warmed to room temperature and stirred at room temperature for 5 h. The mixture was washed with water (10 mL). The organic layer was dried over Na2SO4 and concentrated to afford the subtitle compound (420 mg, 52% yield) as off-white solid. MS m/z 355 [M+Na]+. 1H NMR (400 MHz, DMSO) δ 7.02 (s, 1H), 3.82 (s, 2H), 1.49 (s, 9H). [1051] Step 5: Preparation of tert-butyl N-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]thiazol-2-yl]carbamate [1052] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (80 mg), DIPEA (1.5 mL) and DCM (6 mL) was added tert-butyl N-[4- (chlorosulfonylmethyl)thiazol-2-yl]carbamate (170 mg). After 30 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1053] Example 160: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[(1-methylsulfonylazetidin-3- yl)methylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1054] Step 1: Preparation of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate [1055] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (130 mg), DIPEA (3 mL) and DCM (10 mL) was added tert-butyl 3- (chlorosulfonylmethyl)azetidine-1-carboxylate (230 mg). After 30 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the subtitle compound. [1056] Step 2: Preparation of 2-[5-[(3R,4R)-1-(azetidin-3-ylmethylsulfonyl)-3-methyl-4- piperidyl]-4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine [1057] A mixture of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate (135 mg) and DCM (5 mL) was added HCl (6M in iPrOH, 10 mL). After 30 min at RT, the mixture was concentrated to afford the crude subtitle compound. [1058] Step 3: Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-[(1- methylsulfonylazetidin-3-yl)methylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1059] A mixture of 2-[5-[(3R,4R)-1-(azetidin-3-ylmethylsulfonyl)-3-methyl-4-piperidyl]- 4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (30 mg), DIPEA (0.4 mL) and DCM (2 mL) was added methanesulfonyl chloride (15 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1060] Example 161: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylsulfonylazetidin-3- yl)sulfonyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1061] Step 1: Preparation of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate [1062] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (2 mL) and DCM (6 mL) was added tert-butyl 3- chlorosulfonylazetidine-1-carboxylate (120 mg). After 20 min at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the subtitle compound. [1063] Step 2: Preparation of 2-[5-[(3R,4R)-1-(azetidin-3-ylsulfonyl)-3-methyl-4- piperidyl]-4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine [1064] A mixture of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]azetidine-1-carboxylate (90 mg) and DCM (4 mL) was added HCl (6M in iPrOH, 8 mL). After 3 h at RT, the mixture was concentrated to afford the crude subtitle compound. [1065] Step 3: Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(1- methylsulfonylazetidin-3-yl)sulfonyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1066] A mixture of 2-[5-[(3R,4R)-1-(azetidin-3-ylsulfonyl)-3-methyl-4-piperidyl]-4- chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (30 mg), DIPEA (0.4 mL) and DCM (2 mL) was added methanesulfonyl chloride (15 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1067] Example 162: 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonylmethyl]thiazol-2-amine [1068] A mixture of tert-butyl N-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]thiazol-2-yl]carbamate (50 mg) and DCM (3 mL) was added HCl (6M in iPrOH, 6 mL). After stirring overnight, the mixture was concentrated, and the residue purified by preparative HPLC to afford the crude title compound. [1069] Example 163: 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidin-1-yl]ethanone [1070] A mixture of 2-[5-[(3R,4R)-1-(azetidin-3-ylmethylsulfonyl)-3-methyl-4-piperidyl]- 4-chloro-1H-imidazol-2-yl]-5-fluoro-pyridine (30 mg), DIPEA (0.4 mL) and DCM (2 mL) was added acetyl chloride (10 mg). After 1 h at RT, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1071] Example 164: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(trideuteriomethyl)propanamide [1072] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 min, trideuteriomethanamine (hydrochloride, 10 mg) was added. After 16 hours, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1073] Example 165: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(oxetan-3-yl)propanamide [1074] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 min, oxetan-3-amine (10 mg) was added. After 16 hours, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1075] Example 166: 2-[4-Chloro-5-[(3R,4R)-1-(1H-imidazol-4-ylsulfonyl)-3-methyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1076] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (28 mg), DIPEA (0.4 mL) and DCM (2 mL) was added 1H-imidazole-4- sulfonyl chloride (15 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1077] Example 167: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-ethyl-propanamide [1078] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 min, ethanamine (hydrochloride,11 mg) was added. After 1 hour, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1079] Example 168: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(4-hydroxy-4-methyl-1-piperidyl)propan-1-one [1080] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 min, 4-methylpiperidin-4-ol (16 mg) was added. After 1 hour, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1081] Example 169: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-morpholino-propan-1-one [1082] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), morpholine (12 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 1 hour, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1083] Example 170: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(cyclopropylmethyl)propanamide [1084] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), cyclopropylmethanamine (10 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 1 hour, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1085] Example 171: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-pyrrolidin-1-yl-propan-1-one [1086] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), pyrrolidine (10 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 1 hour, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1087] Example 172: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(2,2,2-trifluoroethyl)propanamide [1088] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 2,2,2-trifluoroethanamine (14 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 1 hour, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1089] Example 173: Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate [1090] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (45 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added methyl carbonochloridate (12 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1091] Example 174: Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]azetidine-1-carboxylate [1092] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (33 mg), DIPEA (0.4 mL) and DCM (2 mL) was added methyl carbonochloridate (12 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1093] Example 175: N-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethyl]acetamide [1094] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (35 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added acetyl chloride (10 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1095] Example 176: N-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethyl]methanesulfonamide [1096] A mixture of 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]ethanamine (27 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added methanesulfonyl chloride (15 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1097] Example 177: Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]furan-2-carboxylate [1098] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (35 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added methyl 5- chlorosulfonylfuran-2-carboxylate (25 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1099] Example 178: 5-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethyl]-3-methyl-1,2,4-oxadiazole [1100] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (122 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (110 mg). After 1 hour, N'-hydroxyacetamidine (21.5 mg) was added. After 1 h, the mixture was heated to 100°C for 1h. The mixture was diluted with MeOH (1.5 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1101] Example 179: Tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-lH- imidazol-5-yl]-3-methyl-l-piperidyl]sulfonyl]ethyl]carbamate
[1102] Step 1: Preparation of tetrabutylammonium 2-(tert-butoxycarbonylamino) ethanesulfonate
[1103] To a solution of 2-aminoethanesulfonic acid (30 g, 0.24 mol) and tetrabutylammonium hydroxide (62.2 g, 0.24 mol) in acetone/ H2O (400 mL, 1:1), was added tert-butoxycarbonyl tert-butyl carbonate (52.3 g, 0.24 mol). The reaction mixture was stirred at room temperature for 4 hrs. The mixture was poured into water (400 mL) and extracted with DCM (400 mL x 3). The organic layers were washed with brine (400 mL x 2), dried with Na2SO4 and concentrated. The crude product purified by flash chromatography (EA: PE= 20%) to afford the subtitle compound (86 g, yield: 76.9%) as a colorless oil. 1H NMR (400 MHz, CDC13) 8 6.12 (s, 1H), 3.57-3.55 (m, 2H), 3.32-3.27 (m, 8 H), 2.94-2.91 (m, 2H), 1.70- 1.62 (m, 8H), 1.50-1.47 (m, 17H), 1.03-0.99 (m, 12H) ppm.
[1104] Step 2: Preparation of tert-butyl N-(2-chlorosulfonylethyl)carbamate
[1105] To a solution of tetrabutylammonium 2-(tert-butoxycarbonylamino) ethanesulfonate (4.7 g) in DCM (42 mL) was added DMF (77 pL) followed by a solution of triphosgene in DCM (0.5M, 8 mL at 0°C). The mixture was warmed to RT and stirred for 0.5h. The solution was concentrated and used in the next step directly.
[1106] Step 3: Preparation of tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1 H-imidazol-5-yl] -3 -methyl- 1 -piperidyl] sulfonyl] ethyl] carbamate
[1107] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-lH-imidazol-2-yl]-5- fluoro-pyridine (500 mg), DIPEA (6 mL) and DCM (20 mL) was added tert-butyl N-(2- chlorosulfonylethyl)carbamate (1000 mg, crude). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound.
[1108] Example 180: 2-[4-Chloro-5-[(3R,4R)-l-[2-[l-[(4-methoxyphenyl)methyl]triazol-
4-yl] ethylsulfonyl] -3 -methyl-4-piperidyl] - 1 H-imidazol-2-yl] -5-fluoro-pyridine
[1109] Step 1: Preparation of 4-(2-bromoethyl)-l-[(4-methoxyphenyl)methyl]triazole
[1110] A mixture of l-(azidomethyl)-4-methoxy-benzene (1.6 g, 10 mmol) and 4- bromobut-l-yne (1.95 g, 15 mmol) in EtOH/H2O (50 mL/50 mL) was stirred at room temperature. CuSO4.5H2O (50 mg, 0.2 mmol) and sodium (2R)-2-[(1S)-1,2-dihydroxyethyl]- 4-hydroxy-5-oxo-2H-furan-3-olate (117 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 40 h. The result mixture was extracted with EtOAc (100 mL x 3). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography on a silica gel column (30% EtOAc in PE) to afford the subtitle compound (2.7 g, 93% yield) as white solid. MS m/z 296 [M+H]+. [1111] Step 2: Preparation of S-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethyl] ethanethioate [1112] A mixture of 4-(2-bromoethyl)-1-[(4-methoxyphenyl)methyl]triazole (2.7 g, 9 mmol) in acetone (40 mL) was stirred at room temperature. Ethanethioyloxypotassium (2.08 g, 18 mmol) was added. The mixture was stirred at 50°C for 4 h. Then the mixture was cooled to room temperature and poured into water (100 mL). The water layer was extracted with EtOAc (100 mL x 3). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (silica gel, 60% EtOAc in PE) to afford the subtitle compound (2.5 g, 94% yield) as light yellow solid. MS m/z 292 [M+H]+. [1113] Step 3: Preparation of 2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl] ethanesulfonic acid [1114] A mixture of S-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethyl] ethanethioate (2.0 g, 6.9 mmol) in HCOOH (10 mL) was stirred at room temperature. H2O2 (30% aqueous solution, 4 g, 35 mmol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 6 h. Then water (50 mL) was added. The mixture was freeze- dried directly to afford the title compound (1.83 g, 88%) as white solid without further purification. MS m/z 298 [M+H]+. [1115] Step 4: Preparation of 2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethanesulfonyl chloride [1116] A mixture of [2-(tert-butoxycarbonylamino)thiazol-4-yl]methanesulfonic acid (1.8 g, 6 mmol) in DCM (30 mL) was stirred at room temperature. DMF (cat.) was added. The mixture was stirred at 0°C. Oxalyl dichloride (1.15 g, 9 mmol) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred at room temperature for 6 h. Then the mixture was washed with water (20 mL). The organic layer was dried over Na2SO4 and concentrated to afford the subtitle compound (1.82 g, 76% yield) as yellow solid without further purification. MS m/z 316 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 5.45 (s, 2H), 4.11-4.07 (m, 2H), 3.81 (s, 3H), 3.48 – 3.35 (m, 2H). [1117] Step 5: Preparation of 2-[4-chloro-5-[(3R,4R)-1-[2-[1-[(4- methoxyphenyl)methyl]triazol-4-yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine [1118] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (60 mg), DIPEA (1 mL) and DMF (5 mL) was added 2-[1-[(4- methoxyphenyl)methyl]triazol-4-yl]ethanesulfonyl chloride (130 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1119] Example 181: 2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]ethanamine (hydrochloride) [1120] A mixture of tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethyl]carbamate (245 mg) and DCM (10 mL) was added HCl (6N in iPrOH, 20 mL). After 1 h at 40°C, the mixture was concentrated to afford the title compound. [1121] Example 182: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-[(1-hydroxycyclopropyl)methyl]propanamide [1122] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 1-(aminomethyl)cyclopropanol (12 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 1 hour, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1123] Example 183: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]propan-1-one [1124] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 3-(trifluoromethyl)pyrrolidin-3-ol (hydrochloride, 27 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After standing overnight, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1125] Example 184: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(oxetan-3-ylmethyl)propanamide [1126] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), oxetan-3-ylmethanamine (12 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After standing overnight, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1127] Example 185: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-1-one [1128] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 2-oxa-7-azaspiro[3.5]nonane (18 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After standing overnight, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1129] Example 186: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(4-methoxy-1-piperidyl)propan-1-one [1130] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 4-methoxypiperidine (16 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After standing overnight, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1131] Example 187: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-tetrahydropyran-4-yl-propanamide [1132] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), tetrahydropyran-4-amine (14 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After standing overnight, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1133] Example 188: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-[(3S)-tetrahydropyran-3-yl]propanamide [1134] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), (S)-tetrahydro-2H-pyran-3-amine (hydrochloride, 20 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After standing overnight, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1135] Example 189: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propan-1-one [1136] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 2-oxa-6-azaspiro[3.3]heptane (14 mg), (DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After standing overnight, the reaction was complete. The mixture was diluted with MeOH (1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1137] Example 190: 2-[4-Chloro-5-[(3R,4R)-1-(2-methoxyethylsulfonyl)-3-methyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1138] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (35 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added 2- methoxyethanesulfonyl chloride (25 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1139] Example 191: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-tetrahydropyran-4-ylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1140] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (35 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added tetrahydropyran-4- sulfonyl chloride (25 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1141] Example 192: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(tetrahydrofuran-3- ylmethylsulfonyl)-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1142] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (35 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added tetrahydrofuran-3- ylmethanesulfonyl chloride (27 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1143] Example 193: N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]thiazol-2-yl]acetamide [1144] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (60 mg), DIPEA (1 mL) and DCM (5 mL) was added 2-acetamidothiazole-5- sulfonyl chloride (100 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1145] Example 194: N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]-4-methyl-thiazol-2-yl]acetamide [1146] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (60 mg), DIPEA (1 mL) and DCM (5 mL) was added 2-acetamido-4-methyl- thiazole-5-sulfonyl chloride (100 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1147] Example 195: Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]pyridine-2-carboxylate [1148] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (1 mL) and DCM (5 mL) was added methyl 5- chlorosulfonylpyridine-2-carboxylate (100 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1149] Example 196: Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrrolidine-1-carboxylate [1150] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (120 mg), DIPEA (1.2 mL) and DCM (6 mL) was added tert-butyl 3- chlorosulfonylpyrrolidine-1-carboxylate (150 mg). After 3 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1151] Example 197: Tert-butyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]piperidine-1-carboxylate [1152] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (120 mg), DIPEA (1.2 mL) and DCM (6 mL) was added tert-butyl 4- chlorosulfonylpiperidine-1-carboxylate (150 mg). After 3 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1153] Example 198: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(1H-triazol-4- yl)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1154] A mixture of 2-[4-chloro-5-[(3R,4R)-1-[2-[1-[(4-methoxyphenyl)methyl]triazol-4- yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (50 mg) and TFA (5 mL) was stirred at 80°C for 8h. The mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1155] Example 199: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(4-piperidylsulfonyl)-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride) [1156] A mixture of tert-butyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]piperidine-1-carboxylate (70 mg) and DCM (2 mL) was added HCl (6M in iPrOH, 8 mL). After 1 h at 40°C, the mixture was concentrated to afford the title compound. [1157] Example 200: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-pyrrolidin-3-ylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride) [1158] A mixture of tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrrolidine-1-carboxylate (135 mg) and DCM (12 mL) was added HCl (6M in iPrOH, 12 mL). After 1 h at 40°C, the mixture was concentrated to afford the title compound. [1159] Example 201: Tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethylsulfamoyl]carbamate [1160] A mixture of 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]ethanamine (hydrochloride, 30 mg) and DCM (2 mL) was added DIPEA (0.3 mL). After 10 min, tert-butoxycarbonyl-[(4-dimethyliminio-1- pyridyl)sulfonyl]azanide (32 mg) was added. After stirring overnight, the mixture was diluted with EA, washed with sat. NH4Cl solution and brine. The organic layer was dried (Na2SO4) and concentrated, and the residue purified by preparative HPLC to afford the title compound. [1161] Example 202: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]thiazol-2-amine [1162] A mixture of N-[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]thiazol-2-yl]acetamide (49 mg) and EtOH (2 mL) was added HCl (6N, 2 mL). After 1 h at 80°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1163] Example 203: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-4-methyl-thiazol-2-amine [1164] A mixture of N-[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]-4-methyl-thiazol-2-yl]acetamide (45 mg) and EtOH (2 mL) was added HCl (6N, 2 mL). After 1 h at 80°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1165] Example 204: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyridine-2-carboxylic acid [1166] A mixture of methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]pyridine-2-carboxylate (120 mg), water (1.5 mL) and THF (6 mL) was added LiOH (20 mg). After 1 h, the mixture was concentrated to afford the title compound. [1167] Example 205: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonylmethyl]-5-methyl-1,2,4-oxadiazole [1168] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (50 mg), DIPEA (0.6 mL) and DCM (3 mL) was added (5-methyl-1,2,4- oxadiazol-3-yl)methanesulfonyl chloride (110 mg). After 2 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1169] Example 206: 1-[4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]-1-piperidyl]ethanone [1170] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(4-piperidylsulfonyl)-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (30 mg), DIPEA (0.5 mL) and DCM (2 mL) was added acetyl chloride (10 mg). After 2 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1171] Example 207: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[(1-methylsulfonyl-4- piperidyl)sulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1172] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(4-piperidylsulfonyl)-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (30 mg), DIPEA (0.5 mL) and DCM (2 mL) was added methanesulfonyl chloride (15 mg). After 2 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1173] Example 208: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2- (sulfamoylamino)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1174] A mixture of tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethylsulfamoyl]carbamate (50 mg), DCM (1.5 mL) and MeOH (1.5 mL) was added HCl (6N in iPrOH, 5 mL). After 1 h at 40°C, the mixture was concentrated to afford the title compound. [1175] Example 209: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylsulfonylpyrrolidin-3- yl)sulfonyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1176] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-pyrrolidin-3-ylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride, 45 mg), DIPEA (0.5 mL) and DCM (3 mL) was added methanesulfonyl chloride (15 mg). After 2 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1177] Example 210: 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrrolidin-1-yl]ethanone [1178] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-pyrrolidin-3-ylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride, 45 mg), DIPEA (0.5 mL) and DCM (3 mL) was added acetyl chloride (15 mg). After 2 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1179] Example 211: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyridine-2-carboxamide [1180] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyridine-2-carboxylic acid (100 mg, crude), DMF (4 mL), DIPEA (0.3 mL) was added EDC (55 mg) and HOBt (50 mg). After 15 min, the mixture was added ammonium chloride (70 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1181] Example 212: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyrrolidine-1-carboxamide [1182] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-pyrrolidin-3-ylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (hydrochloride, 50 mg), triethylamine (0.35 mL) and DCM (5 mL) was added isocyanato(trimethyl)silane (20 mg). After 2h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1183] Example 213: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1H-triazol-4-ylsulfonyl)-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1184] Step 1: Preparation of disulfide 4-(1H-triazol-4-yldisulfanyl)-1H-triazole [1185] Sodium 1H-1,2,3-triazole-4-thiolate (14 g, 0.11 mmol) was added in small portions to ice-cooled methanol (100 mL) followed by NH4Cl (9.12 g, 0.17 mmol) in H2O (40 mL). The reaction mixture was air bubbled for 16 hours at room temperature. It was then concentrated under reduced pressure. The mixture was poured into DCM (300 mL) and the solid was removed, the filtrate was concentrated to dryness to afford the subtitle compound (3.2 g, yield 14%) as a white solid. MS m/z 201.1 [M+H]+. [1186] Step 2: Preparation of 1H-1,2,3-triazole-4-sulfonyl chloride [1187] A solution of 4-(1H-triazol-4-yldisulfanyl)-1H-triazole (3.2 g, 16 mmol) in CHCl3 (30 mL) were added potassium nitrate (4.04 g, 40 mmol) and trimethylsilyl chloride (4.34 g, 40 mmol) and stirred vigorously at 50°C for 48 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to afford the subtitle compound (1.21 g, 45%) as a white solid. MS m/z 168.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 14.62 (s, 1H), 7.77 (s, 1H) ppm. [1188] Step 3: Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-(1H-triazol-4- ylsulfonyl)-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1189] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (40 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added 1H-triazole-4- sulfonyl chloride (15 mg). After 2 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1190] Example 214: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]furan-2-carboxamide [1191] Step 1: Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]furan-2-carboxylic acid [1192] A mixture of methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]furan-2-carboxylate (240 mg), water (3 mL) and THF (12 mL) was added LiOH (50 mg). After 1 h, the mixture was concentrated to afford the title compound. [1193] Step 2: Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]furan-2-carboxamide [1194] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]furan-2-carboxylic acid (60 mg, crude), DMF (2.5 mL), DIPEA (0.3 mL) was added EDC (50 mg) and HOBt (50 mg). After 15 min, the mixture was added ammonium chloride (40 mg). After stirring overnight, the mixture was filtered, and the filtrate purified by preparative HPLC to afford the title compound. [1195] Example 215: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1- (methylsulfonylmethylsulfonyl)-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1196] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (40 mg), DIPEA (0.5 mL) and DCM (2 mL) was added methylsulfonylmethanesulfonyl chloride (40 mg). After 2 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1197] Example 216: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3- methylsulfonylpropylsulfonyl)-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1198] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (40 mg), DIPEA (0.5 mL) and DCM (2 mL) was added 3- methylsulfonylpropane-1-sulfonyl chloride (40 mg). After 2 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1199] Example 217: [5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-2-furyl]-(3-hydroxyazetidin-1-yl)methanone [1200] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]furan-2-carboxylic acid (50 mg), azetidin-3-ol (25 mg), (DMF (1 mL) and DIPEA (0.1 mL) was added HATU (80 mg). After 16h at 40°C, the mixture was diluted with MeOH (0.5 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1201] Example 218: 3-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethyl]-1,4-dihydro-1,2,4-triazol-5-one [1202] Step 1: Preparation of ethyl 3-[(4-methoxyphenyl)methylsulfanyl]propanoate [1203] To a solution of (4-methoxyphenyl)methanethiol (7.5 g, 48.7 mmol) in DMF (70 mL) were added cesium carbonate (31.7 g, 97.4 mmol) and tetrabutylammonium iodide (21.6 g, 58.4 mmol). The mixture was stirred at RT for 1 hour. Then, under ice-cooling, ethyl 3- bromopropanoate (9.68 g, 53.5 mmol) was added and the mixture was stirred overnight while returning to room temperature gradually. LCMS showed the reaction was completed. After addition of saturated aqueous ammonium chloride (300 mL) to the reaction mixture, it was extracted with ethyl acetate (200 mL x 3). The organic layer was washed with brine (500 mL x 3) and then water (500 mL), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated to dryness. The residue was purified by medium pressure silica gel column chromatography (n-hexane: ethyl acetate = 95:5) to afford the subtitle compound (8 g, yield: 75 %) as a colorless liquid. [1204] Step 2: Preparation of 3-((4-methoxybenzyl)thio)propanoic acid [1205] To a solution of ethyl 3-[(4-methoxyphenyl)methylsulfanyl]propanoate (8 g, 31.5 mmol) in THF (100 mL) and H2O (50 mL) was added NaOH (12.6 g, 315.6 mmol), and the mixture was stirred at RT for 16hours. The mixture was quenched with HCl (2M) to pH=7 and diluted with EtOAc (100 mL). The organic phase was separated. The aqueous layer was extracted with EA (100 ml ×2). The organic phases were combined, washed with water (100 ml ×2), dried over Na2SO4 and concentrated to the subtitle compound (6 g, yield: 84%) as a white solid. MS m/z 249 [M+Na]+. [1206] Step 3: Preparation of 3-((4-methoxybenzyl)thio)propanoyl chloride [1207] To a solution of 3-((4-methoxybenzyl)thio)propanoic acid (5 g, 22.1 mmol) in THF (50 mL) and DMF (0.5 mL) was added (COCl)2 (3.4 g, 26.5 mmol) slowly at 0°C, the mixture was stirred at RT for 2 hours. The mixture was concentrated to afford the subtitle compound (5.2 g, yield: 100%) as a colorless oil. [1208] Step 4: Preparation of 2-(3-((4-methoxybenzyl)thio)propanoyl)hydrazine-1- carboxamide [1209] To a solution of hydrazinecarboxamide (2.72 g, 36.3 mmol), DIPEA (11.0 g, 85.2 mmol) in THF (50 mL) and H2O (20 mL) was added 3-((4-methoxybenzyl)thio)propanoyl chloride (5.2 g, 21.3 mmol) slowly at 0°C, and the mixture was stirred at RT for 16 hours. The mixture was concentrated and diluted with EtOAc (100 mL) and H2O (100 mL). The organic phase was separated. The aqueous layer was extracted with EA (100 ml ×2). The organic phases were combined, washed with water (100 ml ×2), dried over Na2SO4 and concentrated to afford the subtitle compound (6 g, yield: 100%) as a colorless oil. MS m/z 284 [M+H]+. [1210] Step 5: Preparation of 2-(3-((4-methoxybenzyl)thio)propanoyl)hydrazine-1- carboxamide [1211] To a solution of 2-(3-((4-methoxybenzyl)thio)propanoyl)hydrazine-1-carboxamide (6.0 g, 21.2 mmol) in THF (50 mL) was added NaOH (2M, 150 mL), the mixture was stirred at 100°C for 16 hours. The mixture was concentrated and diluted with EtOAc (100 mL) and H2O (100 mL). The organic phase was separated. The aqueous layer was extracted with EA (100 mL ×2). The organic phases were combined, washed with water (100 mL ×2), dried over Na2SO4 and concentrated to afford the subtitle compound (1 g, yield: 18%) as a colorless oil. MS m/z 266 [M+H]+. [1212] Step 6: Preparation of 2-(5-oxo-1,4-dihydro-1,2,4-triazol-3-yl)ethanesulfonyl chloride [1213] To a solution of NCS (1.12 g, 13.4 mmol), HCl (1M, 0.671 mL, 0.671 mmol) in MeCN (9 mL) was added 3-[2-[(4-methoxyphenyl)methylsulfanyl]ethyl]-1,4-dihydro-1,2,4- triazol-5-one (890.0 mg, 3.35 mmol) in portions under ice/water bath cooling. The resulting mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure (water bath temperature below 30°C). The residue was purified by flash chromatography (Biotage 25 g silica gel column, eluting with 0%-100% ethyl acetate in petroleum ether) to afford the subtitle compound (515.1 mg, 2.43 mmol, yield: 72.6%) as white solid. MS m/z 212 [M+H]+. 1H NMR (500 MHz, DMSO) δ 14.57 (s, 1H), 12.52 (s, 1H), 2.79 (m, 2H), 2.74 – 2.60 (m, 2H) ppm. [1214] Step 7: Preparation of 3-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]ethyl]-1,4-dihydro-1,2,4-triazol-5-one [1215] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (40 mg), DIPEA (0.5 mL) and DCM (2.5 mL) was added 2-(5-oxo-1,4- dihydro-1,2,4-triazol-3-yl)ethanesulfonyl chloride (35 mg). After 2 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1216] Example 219: Tert-butyl N-[6-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyridazin-3-yl]carbamate [1217] Step 1: Preparation of tert-butyl N-(6-carbamimidoylsulfanylpyridazin-3- yl)carbamate [1218] A mixture of tert-butyl N-(6-chloropyridazin-3-yl)carbamate (4.6 g, 20 mmol) in 1,4-dioxane (100 mL) was stirred at room temperature. Thiourea (1.52 g, 20 mmol) was added. The mixture was stirred at 75°C for 48 h. The^mixture was cooled to room temperature and concentrated to afford the subtitle compound (4.3 g, crude) as brown solid. The residue was used for the next step directly without further purification. [1219] Step 2: Preparation of tert-butyl N-(3-thioxo-4H-pyridazin-6-yl)carbamate [1220] A mixture of tert-butyl N-(6-carbamimidoylsulfanylpyridazin-3-yl)carbamate (4.3 g, crude) in water (20 mL) was stirred at room temperature for 5 min. NaOH (5 g, 125 mmol) in water (80 mL) was added. The mixture was stirred at room temperature for 30 min. Then the mixture was extracted with EtOAc (100 mL x 6). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (40% EtOAc in PE) to afford the subtitle compound (1.3 g, 57% yield) as yellow solid. MS m/z 228 [M+H]+. [1221] Step 3: Preparation of tert-butyl N-(6-chlorosulfonylpyridazin-3-yl)carbamate [1222] NaClO (13.1 g, 132 mmol) was stirred at 0°C. HCl (0.1 M, 132 mL, 132 mmol) was added dropwise. After addition, the mixture was stirred at 0°C for 15 min. A solution of tert-butyl N-(3-thioxo-4H-pyridazin-6-yl)carbamate (1.0 g, 4.4 mmol) in CH3CN (5 mL) was prepared. The NaClO-HCl mixture was added dropwise at 0°C. After addition, the mixture was stirred at 0°C for 4 h. Then the mixture was filtered and the solid was washed with water and dried by lyophilization to afford the subtitle compound (1.1 g, 85% yield) as white solid. MS m/z 238 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.53 (d, J = 9.5 Hz, 1H), 8.19 (s, 1H), 8.13 (d, J = 9.5 Hz, 1H), 1.57 (s, 9H). [1223] Step 4: Preparation of tert-butyl N-[6-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyridazin-3-yl]carbamate [1224] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (70 mg), DIPEA (1 mL) and DCM (4 mL) was added tert-butyl N-(6- chlorosulfonylpyridazin-3-yl)carbamate (70 mg). After 2 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1225] Example 220: 6-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyridazin-3-amine [1226] A mixture of tert-butyl N-[6-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyridazin-3-yl]carbamate (70 mg), DCM (4 mL) and MeOH (4 mL) was added HCl (6N in iPrOH, 15 mL). After 4 h at 40°C, the mixture was concentrated and purified by preparative HPLC to afford the title compound. [1227] Example 221: Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidine-2-carboxylate [1228] Step 1: Preparation of methyl 5-[(4-methoxyphenyl)methylsulfanyl]pyrimidine-2- carboxylate [1229] To a solution of methyl 5-bromopyrimidine-2-carboxylate (5 g, 23.0 mmol) and (4- methoxyphenyl) methanethiol (4.26 g, 27.6 mmol) in toluene (80 mL) was added DIPEA (7.9 mL, 46.1 mmol). Xantphos (1.33 g, 2.3 mmol) was added followed by Pd2(dba)3 (2.11 g, 2.3 mmol) under N2. The mixture was heated to 80°C for 12 h. The mixture was poured into water (100 mL) and extracted with DCM (200 mL x 3). The organic layers were washed with brine (100 mL x 2), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (EA: PE= 20%) to afford the subtitle compound (4.7 g, yield: 70.3 %) as a yellow oil. MS m/z 291.1 [M+H]+. [1230] Step 2: Preparation of methyl 5-chlorosulfonylpyrimidine-2-carboxylate [1231] To a solution of NCS (3.68 g, 27.6 mmol), 2 M HCl (0.7 mL, 1.4 mmol) in MeCN (40 mL) was added methyl 5-[(4-methoxyphenyl)methylsulfanyl]pyrimidine-2-carboxylate (2.0 g, 6.89 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 10 min. The reaction mixture was concentrated under reduced pressure (water bath temperature below 30 °C). The mixture was poured into water (40 mL) and extracted with DCM (40 mL x 3). The organic layers were washed with brine (40 mL x 2), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (EA: PE= 60%) to the subtitle compound (220 mg, yield: 13.5%) as white solid. MS m/z 237.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.47 (s, 2 H), 4.13 (s, 3 H) ppm. [1232] Step 3: Preparation of methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidine-2-carboxylate [1233] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (1.5 mL) and DCM (6 mL) was added methyl 5- chlorosulfonylpyrimidine-2-carboxylate (100 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1234] Example 222: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyrimidine-2-carboxylic acid [1235] A mixture of methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidine-2-carboxylate (112 mg), water (2 mL) and THF (8 mL) was added LiOH (20 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1236] Example 223: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]pyrimidine-2-carboxamide [1237] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyrimidine-2-carboxylic acid (50 mg), DMF (2 mL) and DIPEA (0.3 mL) was added HATU (80 mg). After 15 min, ammonium chloride (100 mg) was added. After 16h, the mixture was filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1238] Example 224: [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]propanoyl]azetidin-3-yl] methyl carbonate [1239] Step 1: Preparation of tert-butyl 3-((methoxycarbonyl)oxy)azetidine-1-carboxylate [1240] To^a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (10.0 g, 57.7 mmol) in DCM (150 mL) was added^pyridine (9.13 g, 115 mol) at -50°C. After 15 min, methyl carbonochloridate (8.18 g, 86.6 mmol) was added to the reaction mixture and stirring continued for^another 30 minutes. The mixture was warmed to room temperature and stirred for 4 hrs. LCMS indicated the reaction was completed. The reaction was diluted with DCM (60 mL) and washed with saturated citric acid solution (50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (Biotage, 80 g silica gel column, 50 mL/min, eluting with 0-20% ethyl acetate in petroleum ether for 40 min) to afford the subtitle compound (9.8 g, 42.4 mmol, yield: 73.4%) as a colorless oil. [1241] Step 2: Preparation of azetidin-3-yl methyl carbonate (hydrochloride) [1242] To a solution of tert-butyl 3-methoxycarbonyloxyazetidine-1-carboxylate (9.8 g, 42.4 mmol) in DCM (100 mL) was added hydrogen chloride (4N in 1,4-dioxane, 63.6 mL, 254 mmol) at 0°C. The mixture was warmed to room temperature for 16 hrs. LCMS indicated the reaction was completed. Volatiles were removed to afford the subtitle compound (7.80 g, 46.5 mmol, yield: 90%) as a white solid. MS m/z 132 [M+H]+^. 1H NMR (500 MHz, DMSO) δ 9.65 (s, 2H), 5.30 – 5.08 (m, 1 H), 4.23 (dd, J = 12.6, 7.0 Hz, 2 H), 4.00 (dd, J = 12.6, 5.3 Hz, 2 H), 3.75 (d, J = 7.5 Hz, 3 H) ppm.^ [1243] Step 3: Preparation of [1-[3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoyl]azetidin-3-yl] methyl carbonate [1244] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), azetidin-3-yl methyl carbonate (18 mg of hydrochloride were treated with K2CO3 (19 mg) in DMF (0.2 mL)), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH/water (9:1, 1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1245] Example 225: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(3-methoxy-3-methyl-azetidin-1-yl)propan-1-one [1246] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 3-methoxy-3-methyl-azetidine (19 mg of hydrochloride were treated with K2CO3 (19 mg) in DMF (0.2 mL)), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH/water (9:1, 1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1247] Example 226: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-[(3S)-3-methoxypyrrolidin-1-yl]propan-1-one [1248] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), (3S)-3-methoxypyrrolidine (14 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH/water (9:1, 1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1249] Example 227: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-[dimethyl(oxo)-λ⁶-sulfanylidene]propanamide [1250] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), imino-dimethyl-oxo-λ⁶-sulfane (13 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH/water (9:1, 1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1251] Example 228: [2-(Aminomethyl)-3-hydroxy-2-methyl-propyl] 3-[[(3R,4R)-4-[4- chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoate (2,2,2-trifluoroacetic acid salt) [1252] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), (3-methyloxetan-3-yl)methanamine (13 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH/water (9:1, 1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1253] Example 229: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(3-methyloxetan-3-yl)propanamide [1254] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 3-methyloxetan-3-amine (hydrochloride, 13 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH/water (9:1, 1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1255] Example 230: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(1-methylcyclopropyl)propanamide [1256] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 3-methyloxetan-3-amine (hydrochloride, 13 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH/water (9:1, 1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1257] Example 231: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(2-methoxy-2-methyl-propyl)propanamide [1258] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 2-methoxy-2-methyl-propan-1-amine (14 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH/water (9:1, 1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1259] Example 232: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-[(3R)-3-methoxypyrrolidin-1-yl]propan-1-one [1260] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), (3R)-3-methoxypyrrolidine (14 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH/water (9:1, 1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1261] Example 233: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-[[(2S)-oxetan-2-yl]methyl]propanamide [1262] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), [(2S)-oxetan-2-yl]methanamine (12 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH/water (9:1, 1 mL), filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1263] Example 234: 2-[4-Chloro-5-[(3R,4R)-1-[2-[4-[(4-methoxyphenyl)methyl]-1,2,4- triazol-3-yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1264] Step 1: Preparation of ethyl 2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3- yl]acetate [1265] To a stirred suspension of ethyl 2-(4H-1,2,4-triazol-3-yl)acetate (5.0 g, 32.2 mmol) and potassium carbonate (5.34 g, 38.7 mmol) in DMF (30 mL) was added 1-(chloromethyl)-4- methoxy-benzene (6.06 g, 38.7 mmol) dropwise. After the addition, the mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage 80 g silica gel, eluting with 0%-60% ethyl acetate in petroleum ether) to afford the subtitle compound (6.7 g, 24.3 mmol, yield: 75.5%) as brown oil. MS m/z 276 [M+H]+. [1266] Step 2: Preparation of ethyl 2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3- yl]ethanol [1267] To a solution of ethyl 2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]acetate (6.7 g, 24.3 mmol) in THF (70 mL) was added 2.5 M lithium aluminum hydride in THF (19.5 mL, 48.7 mmol) dropwise under cooling with an ice/water bath. The mixture was stirred at room temperature for 4 h. The mixture was quenched with water (200 mL), concentrated under reduced pressure to remove THF. The remaining aqueous layer was extracted with ethyl acetate (100 mL x 3). The combined organic layers were concentrated. The residue was purified by flash chromatography (Biotage 80 g silica gel, eluting with 0%-70% ethyl acetate in petroleum ether) to afford the subtitle compound (3.3 g, 14.1 mmol, yield: 58.1%) as yellow solid. MS m/z 234 [M+H]+. [1268] Step 3: Preparation of 2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl 4- methylbenzenesulfonate [1269] To a solution of 2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethanol (3.3 g, 14.1 mmol) and triethylamine (4.29 g, 42.4 mmol) in THF (30 mL) was added TosCl (4.05 g, 21.2 mmol) in portions at 0°C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage 40 g silica gel, eluting with 0%-100% ethyl acetate in petroleum ether) to afford the subtitle compound (1.224 g, 3.16 mmol, yield: 22.3%) as light-yellow solid. MS m/z 388 [M+H]+. [1270] Step 4: Preparation of S-[2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl] ethanethioate [1271] A mixture of 2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl 4- methylbenzenesulfonate (1.24 g, 3.20 mmol), ethanethioic S-acid (448 mg, 6.40 mmol) and potassium carbonate (1.77 g, 12.8 mmol) in DMF (6 mL) was stirred at 60°C for 16 h. The reaction mixture was cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (40 mL x 3), dried over anhydrous sodium sulfate, and concentrated to afford the subtitle compound (860 mg, 2.95 mmol, yield: 92.2%) as brown oil. MS m/z 294 [M+H]+. [1272] Step 5: Preparation of S-[2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl] ethanethioate [1273] To a solution of S-[2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethyl] ethanethioate (860.0 mg, 2.95 mmol) in formic acid (10 mL) was added 30% hydrogen peroxide (1.34 g, 11.8 mmol) dropwise at 0°C. The reaction was stirred at room temperature for 4 h. The reaction mixture was diluted with water (20 mL) and then lyophilized to afford the subtitle compound (850 mg, 2.86 mmol, yield: 96.9%) as light yellow solid. MS m/z 298 [M+H]+. [1274] Step 6: Preparation of 2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3- yl]ethanesulfonyl chloride [1275] To a suspension of 2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3- yl]ethanesulfonic acid (277.0 mg, 0.932 mmol) in DCM (5 mL) was added DMF (6.81 mg, 0.093 mmol) and oxalyl chloride (177 mg, 1.44 mmol) dropwise under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to afford the subtitle compound (303 mg, crude) as light yellow solid. MS m/z 316 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.49 – 7.27 (m, 5H), 5.13 (s, 2H), 4.07 – 4.04 (m, 1H), 3.97 (d, J = 3.5 Hz, 1H), 3.76 – 3.64 (m, 2H), 3.41 – 3.24 (m, 1H), 3.15-3.08 (m, 1H), 2.21-2.10 (m, 1H), 1.97 (d, 1H), 1.26 (s, 1H), 1.02 (t, J = 6.5 Hz, 3H) ppm. [1276] Step 7: Preparation of 2-[4-chloro-5-[(3R,4R)-1-[2-[4-[(4-methoxyphenyl)methyl]- 1,2,4-triazol-3-yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1277] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (80 mg), DIPEA (1 mL) and DCM (3 mL) was added 2-[4-[(4- methoxyphenyl)methyl]-1,2,4-triazol-3-yl]ethanesulfonyl chloride (115 mg). After 3 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1278] Example 235: N-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]ethyl]cyclopropanesulfonamide [1279] A mixture of 2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]ethanamine (hydrochloride, 80 mg), DIPEA (0.3 mL) and DCM (2 mL) was added cyclopropanesulfonyl chloride (15 mg). After 2 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1280] Example 236: [5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]thiazol-2-yl]urea [1281] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]thiazol-2-amine (35 mg), triethylamine (0.5 mL) and DMF (3 mL) was added isocyanato(trimethyl)silane (150 mg). After 16h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1282] Example 237: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(4H-1,2,4-triazol-3- yl)ethylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1283] A mixture of 2-[4-chloro-5-[(3R,4R)-1-[2-[4-[(4-methoxyphenyl)methyl]-1,2,4- triazol-3-yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (55 mg) and TFA (10 mL) was stirred at 80°C for 8h. The mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1284] Example 238: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[(3-methyloxetan-3- yl)methylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1285] Step 1: Preparation of S-((3-methyloxetan-3-yl)methyl) ethanethioate [1286] To a solution of (3-methyloxetan-3-yl)methanol (10.0 g, 98 mmol) in dry THF (100 mL) was added ethanethioic S-acid (14.9 g,196 mmol) and PPh3 (51.0 g, 196 mmol). The reaction was stirred at 0°C under nitrogen atmosphere for 10 min. Then, DIAD (39.6 g, 196 mmol) was added slowly. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated ammonium chloride (300 mL) and extracted with dichloromethane (300 mL x 3). The organic layer was concentrated. The crude product was purified by flash chromatography (dichloromethane / petroleum ether = 20%) to afford the subtitle compound (8 g, 50 mmol, yield:51%) as a colorless oil. MS m/z 161 [M+H]+. [1287] Step 2: Preparation of (3-methyloxetan-3-yl)methanesulfonyl chloride [1288] To a solution of S-((3-methyloxetan-3-yl)methyl) ethanethioate (8.0 g, 50 mmol) in MeCN (30 ml) was added NCS (3.3 g, 25 mmol) and aqueous HCl (1 M, 5 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 min. The resulting mixture was diluted with water (200 mL) and extracted with EA (200 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (dichloromethane / petroleum ether = 10%) to afford the subtitle compound (1.0 g, 5.4 mmol, yield:10.8%) as colorless oil. MS m/z 185 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 4.36 (d, J=9.2 Hz, 1H), 4.24 (d, J=9.6 Hz, 1H), 8.23 (s, 3 H), 3.53-3.45 (m, 2H), 1.33 (s, 3H) ppm. [1289] Step 3: Preparation of 2-[4-chloro-5-[(3R,4R)-3-methyl-1-[(3-methyloxetan-3- yl)methylsulfonyl]-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1290] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (50 mg), DIPEA (0.6 mL) and DCM (3 mL) was added (3-methyloxetan-3- yl)methanesulfonyl chloride (300 mg). After 2 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1291] Example 239: Tert-butyl 3-[3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoylamino]azetidine-1-carboxylate [1292] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (300 mg), tert-butyl 3-aminoazetidine-1- carboxylate (240 mg), DMF (3 mL) and DIPEA (0.5 mL) was added HATU (331 mg). After 16 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 4.5 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1293] Example 240: [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]propanoyl]-4-piperidyl] methyl carbonate [1294] Step 1: Preparation of tert-butyl 4-methoxycarbonyloxypiperidine-1-carboxylate [1295] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10.0 g, 49.7 mmol) in DCM (100 mL) was added pyridine (9.83 g, 124 mmol). The reaction was stirred at -50°C under nitrogen atmosphere for 10 min. Then methyl carbonochloridate (8.45 g, 89.4 mmol) was added dropwise. The reaction mixture was stirred at RT for 16 h. The reaction was quenched with saturated ammonium chloride (100 mL) and extracted with dichloromethane (200 mL x 3). The combined organic layers were washed with brine (500 mL), dried and concentrated. The residue was purified by flash chromatography (ethyl acetate / petroleum ether = 10%) to afford the subtitle compound (9.1 g,^yield: 70.6%) as a colorless oil. MS m/z 260.2 [M+H]+. [1296] Step 2: Preparation of methyl 4-piperidyl carbonate (hydrochloride) [1297] Tert-butyl 4-methoxycarbonyloxypiperidine-1-carboxylate (9.1 g,^35.1 mmol) was dissolved in HCl (4 M in 1,4-dioxane, 100 mL). The reaction mixture was stirred at room temperature for 2 hrs. Then, the mixture was concentrated to give the subtitle compound (7.34 g) as a white solid. MS m/z 196.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 4.94 (s, 1H), 3.80 (s, 3 H), 3.27 (s, 4H), 2.27-2.76 (m, 2H), 2.12-2.09 (m, 2H) ppm. [1298] Step 3: Preparation of [1-[3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoyl]-4-piperidyl] methyl carbonate [1299] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), methyl 4-piperidyl carbonate (22 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (40 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1300] Example 241: [(3R)-1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoyl]pyrrolidin-3-yl] methyl carbonate [1301] Step 1: Preparation of tert-butyl (3R)-3-methoxycarbonyloxypyrrolidine-1- carboxylate [1302] To a solution of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (8.0 g, 42.7 mmol) in DCM (50 mL) was added^pyridine (6.76 g, 85.5 mmol) at -50°C. After 15 minutes, methyl carbonochloridate (8.18 g, 86.6 mmol) was added to the reaction mixture and stirring was continued for 30 minutes. The mixture was warmed to room temperature for 4 hrs. LCMS indicated the reaction was completed. The reaction was extracted with dichloromethane (50 mL x 3). The combined organic layer was washed with water (100 mL x 3) and brine (200 mL), dried over anhydrate sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage, 120 g silica gel column, 80 mL/min, eluting with 0-50% ethyl acetate in petroleum ether for 1 h) to afford the subtitle compound (6.0 g, 24.5 mmol, yield: 57 %) as a white solid. MS m/z 268 [M+Na]+. [1303] Step 2: Preparation of methyl [(3R)-pyrrolidin-3-yl] carbonate (hydrochloride) [1304] To a solution of tert-butyl (3R)-3-methoxycarbonyloxypyrrolidine-1-carboxylate (6.0 g, 24.5 mmol) in DCM (40 mL) was added hydrogen chloride (4 N in 1,4-dioxane, 36.7 mL, 147 mmol) at 0°C. The mixture was warmed to room temperature with stirring for 16 hrs. LCMS indicated the reaction was completed. Volatiles were removed under reduced pressure to afford the subtitle compound (4.20 g, 23.1 mmol, yield: 94.5%) as a white solid. MS m/z 146 [M+H]+. 1H NMR (500 MHz, DMSO) δ 9.50 (s, 2H), 5.23 (t, J = 4.8 Hz, 1H), 3.73 (s, 3H), 3.46 – 3.24 (m, 4H), 3.17 (dt, J = 18.7, 9.3 Hz, 1H), 2.21 – 2.03 (m, 2H) ppm. [1305] Step 3: Preparation of [(3R)-1-[3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoyl]pyrrolidin-3-yl] methyl carbonate [1306] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), methyl [(3R)-pyrrolidin-3-yl] carbonate (20 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1307] Example 242: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-[[(2S)-tetrahydrofuran-2-yl]methyl]propanamide [1308] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), [(2S)-tetrahydrofuran-2-yl]methanamine (14 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1309] Example 243: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-[[(2R)-tetrahydrofuran-2-yl]methyl]propanamide [1310] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), [(2R)-tetrahydrofuran-2-yl]methanamine (14 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1311] Example 244: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-[(3R)-tetrahydrofuran-3-yl]propanamide [1312] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), (3R)-tetrahydrofuran-3-amine (4- methylbenzenesulfonic acid salt, 36 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1313] Example 245: 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]propanoyl]piperidin-4-one [1314] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), piperidin-4-one (hydrate, hydrochloride; 36 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1315] Example 246: 1-(Azetidin-1-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propan-1-one [1316] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), azetidine (8 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1317] Example 247: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(3-methylsulfonylazetidin-1-yl)propan-1-one [1318] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 3-methylsulfonylazetidine (hydrochloride, 24 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1319] Example 248: 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-N-[1-(hydroxymethyl)cyclobutyl]propanamide [1320] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), (1-aminocyclopentyl)methanol (14 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1321] Example 249: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-[1-(hydroxymethyl)cyclopentyl]propanamide [1322] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), (1-aminocyclopentyl)methanol (16 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1323] Example 250: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(4-hydroxycyclohexyl)propanamide [1324] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 4-aminocyclohexanol (16 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1325] Example 251: 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-N-(5-methyl-1,3,4-oxadiazol-2-yl)propanamide [1326] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 5-methyl-1,3,4-oxadiazol-2-amine (14 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1327] Example 252: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(5-fluoro-2-pyridyl)propanamide [1328] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 5-fluoropyridin-2-amine (16 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1329] Example 253: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(2-methylpyrazol-3-yl)propanamide [1330] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 2-methylpyrazol-3-amine (14 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1331] Example 254: 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]-1-[4-(hydroxymethyl)-1-piperidyl]propan-1-one [1332] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 4-piperidylmethanol (16 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1333] Example 255: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(3-fluoroazetidin-1-yl)propan-1-one [1334] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 3-fluoroazetidine (10 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1335] Example 256: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1-(6-oxa-1-azaspiro[3.3]heptan-1-yl)propan-1-one [1336] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 6-oxa-1-azaspiro[3.3]heptane (2,2,2- trifluoroacetic acid salt, 10 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1337] Example 257: [1-[3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]propanoyl]-4-piperidyl] acetate [1338] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), 4-piperidyl acetate (hydrochloride, 25 mg), DMF (0.5 mL) and DIPEA (0.05 mL) was added HATU (33 mg). After 2 h, the reaction was complete. The mixture was diluted with MeOH to a total volume of 1 mL, filtrated and the filtrate purified by preparative HPLC to afford the title compound. [1339] Example 258: 5-[[(3S*,4S*)-4-[4-Fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-amine [1340] Step 1: Preparation of 4-fluoro-1-(methoxymethyl)imidazole [1341] To a stirred solution of 4-fluoro-1H-imidazole (7.0 g, 81.3 mmol) in dry THF (140 mL) was added 60% sodium hydride (4.88 g, 122.0 mmol) in portions at 0°C under nitrogen atmosphere. After 10 min, MOMBr (11.2 g, 81.5 mmol) was added dropwise into the reaction system at 0°C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water (10 mL) under ice/water bath cooling and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage, 80 g silica gel, eluting with 0%-10% DCM in MeOH) to afford the subtitle compound (7.8 g, 59.9 mmol, yield: 73.7%) as light-yellow oil. MS m/z 131 [M+H]+. [1342] Step 2: Preparation of 4-fluoro-5-iodo-1-(methoxymethyl)imidazole [1343] To a solution of 4-fluoro-1-(methoxymethyl)imidazole (7.8 g, 59.9 mmol) in acetonitrile (80 mL) was added NIS (15.5 g, 68.9 mmol) in portions. The reaction mixture was stirred at room temperature for 72 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (Biotage, 80 g silica gel, eluting with 0%-30% ethyl acetate in petroleum ether) to afford the subtitle compound (3.4 g, 13.3 mmol, yield: 22.2%) as brown solid. MS m/z 257 [M+H]+. [1344] Step 3: Preparation of tert-butyl 4-[5-fluoro-3-(methoxymethyl)imidazol-4-yl]-3- methyl-3,6-dihydro-2H-pyridine-1-carboxylate [1345] A mixture of 4-fluoro-5-iodo-1-(methoxymethyl)imidazole (3.4 g, 13.3 mmol), (1- tert-butoxycarbonyl-3-methyl-3,6-dihydro-2H-pyridin-4-yl)boronic acid (3.52 g, 14.6 mmol), Pd(dtbpf)Cl2 (429.0 mg, 0.664 mmol) and potassium carbonate (5.51 g, 39.8 mmol) in 1,4- dioxane (30 mL) and water (6 mL) was exchanged with nitrogen three times, and the mixture was stirred at 80°C under nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature and diluted with water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined^organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Biotage 40 g silica gel column, eluting with 0%-60% ethyl acetate in petroleum ether) to afford the subtitle compound (4.11 g, 12.6 mmol, yield: 95.1%) as brown oil. MS m/z 326 [M+H]+. [1346] Step 4: Preparation of tert-butyl 4-[5-fluoro-3-(methoxymethyl)imidazol-4-yl]-3- methyl-piperidine-1-carboxylate [1347] To a solution of tert-butyl 4-[5-fluoro-3-(methoxymethyl)imidazol-4-yl]-3-methyl- 3,6-dihydro-2H-pyridine-1-carboxylate (4.11 g, 12.6 mmol) in EtOH (50 mL) was added 10% Pd/C (wet, 600 mg). The mixture was exchanged with hydrogen three times. The resulting mixture was stirred at room temperature under hydrogen atmosphere for 16 h. The reaction mixture was filtered through celite and washed with EtOH (50 mL). The filtrate was concentrated under reduced pressure to afford the subtitle compound^(3.7 g, 11.3 mmol, yield: 89.5%) as white solid. MS m/z 328 [M+H]+. [1348] Step 5: Preparation of tert-butyl 4-[5-fluoro-2-(5-fluoro-2-pyridyl)-3- (methoxymethyl)imidazol-4-yl]-3-methyl-piperidine-1-carboxylate [1349] To a solution of 1,1,2,2-tetramethylpiperidine (1.55 g, 11.0 mmol) in dry THF (10 mL) was added n-Bu2Mg (1 M in heptane, 5.55 mL, 5.55 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction was stirred at 70°C under nitrogen atmosphere. A solution of tert-butyl 4-[5-fluoro-3-(methoxymethyl)imidazol-4-yl]-3-methyl- piperidine-1-carboxylate (1.8 g, 5.55 mmol) in dry THF (20 mL) was added into the reaction system. After 2 at RT, ZnCl2 (2 M in THF, 5.55 mL, 11.0 mmol) was added into the reaction system. The resulting mixture was stirred at room temperature for another 2 h. To the reaction system were added 2-bromo-5-fluoro-pyridine (1.94 g, 11.0 mmol) and Pd(PPh3)4 (318.0 mg, 0.275 mmol). The mixture was exchanged with nitrogen three times. The resulting mixture was stirred at 70°C for 16 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (Biotage 25 g silica gel column, eluting with 0%-25% ethyl acetate in petroleum ether) to afford the subtitle compound (530.0 mg, 1.25 mmol, yield: 22.8%) as light-yellow solid. MS m/z 423 [M+H]+. [1350] Step 6: Preparation of 5-fluoro-2-(4-fluoro-5-(3-methylpiperidin-4-yl)-1H- imidazol-2-yl)pyridine (hydrochloride) [1351] A mixture of tert-butyl 4-[5-fluoro-2-(5-fluoro-2-pyridyl)-3- (methoxymethyl)imidazol-4-yl]-3- methyl-piperidine-1-carboxylate (655 mg, 1.42 mmol) and HCl (4 M in 1,4-dioxane, 1.78 mL, 7.10 mmol) was stirred at 80°C for 16 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and dried under vacuum to afford the subtitle compound (520 mg, crude) as light-yellow solid. MS m/z 279 [M+H]+. [1352] Step 7: Preparation of tert-butyl 4-[4-fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-piperidine-1-carboxylate [1353] To a solution of 5-fluoro-2-[4-fluoro-5-(3-methyl-4-piperidyl)-1H-imidazol-2- yl]pyridine (520 mg, crude) and triethylamine (784 mg, 7.75 mmol) in dry DCM (15 mL) was added di-tert-butyl carbonate (0.372 mg, 1.71 mmol) at room temperature. The reaction was stirred at room temperature. The reaction mixture was diluted with water (50 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography (Biotage 25 g silica gel column, eluting with 0%-30% ethyl acetate in petroleum ether) to afford the subtitle compound (517.0 mg, 1.37 mmol, two steps’ yield: 88.1%) as light-yellow solid. MS m/z 379 [M+H]+. [1354] Step 8: Preparation of tert-butyl (3S*,4S*)-4-[4-fluoro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-piperidine-1-carboxylate and tert-butyl (3R*,4R*)-4-[4-fluoro-2-(5- fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-piperidine-1-carboxylate [1355] Tert-butyl 4-[4-fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- piperidine-1-carboxylate (517.0 mg, 1.37 mmol) was separated by chiral SFC to give tert- butyl (3S*,4S*)-4-[4-fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-piperidine-1- carboxylate (210.4 mg, 0.556 mmol, yield: 40.7%) as white solid and tert-butyl (3R*,4R*)-4- [4-fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-piperidine-1-carboxylate (204.3 mg, 0.538 mmol, yield: 39.4%) as white solid. [1356] Preparative chiral HPLC conditions: Instrument: SFC-150 (Waters); Column: IG 25*250mm, 10μm (Daicel); Column temperature: RT; Mobile phase: CO2/MeOH [0.2% NH3 (7M in MeOH)] 90:10; Flow rate: 85 ml/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 8.75 min; Sample solution: 500 mg dissolved in 25 ml methanol; Injection volume: 1.0 ml. [1357] Analytical chiral HPLC conditions: Column: IG 4.6*100mm 5µm, Column temperature: 40°C; Mobile phase: CO2/MeOH [0.2% NH3 (7M in MeOH)] 90:10; Flow rate: 3 ml/min; Back pressure: 2000 psi; Detection wavelength: 214 nm; Run time: 6 min; Injection volume: 7.5 µl. [1358] Tert-butyl (3S*,4S*)-4-[4-fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-piperidine-1-carboxylate. MS m/z 379 [M+H]+. Chiral HPLC tR = 2.19 min. 1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 8.33 (d, J = 2.8 Hz, 1H), 7.98 (dd, J = 8.8, 4.4 Hz, 1H), 7.4- 7.44 (m, 1H), 4.29 (s, 1H), 3.96 (s, 1H), 3.20 – 3.00 (m, 2H), 2.88 (s, 1H), 2.12 (s, 1H), 2.05 – 1.97 (m, 1H), 1.84 – 1.76 (m, 1H), 1.47 (s, 9H), 0.90 (d, J = 7.2 Hz, 3H) ppm. [1359] Tert-butyl (3R*,4R*)-4-[4-fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-piperidine-1-carboxylate. MS m/z 379 [M+H]+. Chiral HPLC tR = 2.62 min.1H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 8.33 (d, J = 2.8 Hz, 1H), 7.98 (dd, J = 8.8, 4.4 Hz, 1H), 7.4- 7.44 (m, 1H), 4.29 (s, 1H), 3.96 (s, 1H), 3.20 – 3.00 (m, 2H), 2.88 (s, 1H), 2.12 (s, 1H), 2.05 – 1.97 (m, 1H), 1.84 – 1.76 (m, 1H), 1.47 (s, 9H), 0.90 (d, J = 7.2 Hz, 3H) ppm. [1360] Step 9: Preparation of 5-fluoro-2-[4-fluoro-5-[(3S*,4S*)-3-methyl-4-piperidyl]- 1H-imidazol-2-yl]pyridine (hydrochloride) [1361] A mixture of tert-butyl (3S*,4S*)-4-[4-fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-piperidine-1-carboxylate (200 mg) and DCM (1 mL) was added HCl (6M in 1,4-dioxane, 2 mL). After 1h, the mixture was concentrated to afford the subtitle compound. [1362] Step 10: Preparation of 5-[[(3S*,4S*)-4-[4-fluoro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-amine [1363] A mixture of 5-fluoro-2-[4-fluoro-5-[(3S*,4S*)-3-methyl-4-piperidyl]-1H- imidazol-2-yl]pyridine (hydrochloride, 50 mg), DIPEA (0.07 mL) and DCM (0.5 mL) was added 2-aminopyrimidine-5-sulfonyl chloride (23 mg). After 2 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1364] Example 259: 5-[[(3R*,4R*)-4-[4-Fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-amine [1365] Step 1: Preparation of 5-fluoro-2-[4-fluoro-5-[(3S*,4S*)-3-methyl-4-piperidyl]- 1H-imidazol-2-yl]pyridine (hydrochloride) [1366] A mixture of tert-butyl (3R*,4R*)-4-[4-fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-piperidine-1-carboxylate (200 mg) and DCM (1 mL) was added HCl (6M in 1,4-dioxane, 2 mL). After 1h, the mixture was concentrated to afford the subtitle compound. [1367] Step 2: Preparation of 5-[[(3R*,4R*)-4-[4-fluoro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-amine [1368] A mixture of 5-fluoro-2-[4-fluoro-5-[(3R*,4R*)-3-methyl-4-piperidyl]-1H- imidazol-2-yl]pyridine (hydrochloride, 50 mg), DIPEA (0.07 mL) and DCM (0.5 mL) was added 2-aminopyrimidine-5-sulfonyl chloride (23 mg). After 2 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1369] Example 260: N-(Azetidin-3-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)- 1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propenamide (hydrochloride) [1370] A mixture of tert-butyl 3-[3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoylamino]azetidine-1-carboxylate (360 mg) and EtOH (2 mL) was added HCl (6N in iPrOH, 3 mL). After 0.5 h, the mixture was concentrated to afford the title compound. [1371] Example 261: 2-[4-Chloro-5-[(3R,4R)-1-[[1-[(4-methoxyphenyl)methyl]triazol-4- yl]methylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1372] Step 1: Preparation of 1-[(4-methoxyphenyl)methyl] triazol-4-yl]methanesulfonic acid [1373] To a mixture of sodium prop-2-ynylsulfonyloxysodium (5.0 g, 35.2 mmol), sodium rac-(2R)-3-hydroxy-5-oxo-2-[rac-(1S)-1,2-dihydroxyethyl]-2H-furan-4-olate (1.39 g, 7.04 mmol) and CuSO4.5H2O (0.878 g, 3.52 mmol) in t-BuOH/ H2O (50/ 50 mL) at room temperature was added 1-(azidomethyl)-4-methoxy-benzene (6.03 g, 36.9 mmol). The mixture was warmed to room temperature and stirred for 16 hrs. The mixture was washed with water (20 mL). The organic layer was dried over Na2SO4 and concentrated to afford the subtitle compound (3.20 g, yield: 32.1%) as yellow solid. MS m/z 284 [M+H]+. [1374] Step 2: Preparation of [1-[(4-methoxyphenyl)methyl]triazol-4-yl]methanesulfonyl chloride [1375] A mixture of [1-[(4-methoxyphenyl)methyl]triazol-4-yl]methanesulfonic acid (3.0 g, 10.6 mmol ) in chloroform (80 mL) was stirred at room temperature. DMF (cat.) was added. The mixture was stirred at 0°C. Oxalyl dichloride (1.34 mL, 15.9 mmol) was added dropwise. The mixture was warmed to room temperature and stirred at room temperature for 16 hrs. The mixture was washed with water (20 mL). The organic layer was dried over Na2SO4 and concentrated. The crude residue obtained was purified by silica gel column chromatography using PE/EA (50%) as eluent to afford^the subtitle compound (0.5 g, 15.6% yield) as yellow solid. MS m/z 324 [M+Na]+. 1H NMR (400 MHz, DMSO) δ 7.99 (s, 1H), 7.32 (d, J = 8.7 Hz, 2H), 7.05 – 6.75 (m, 2H), 5.50 (s, 2H), 3.77 (d, J = 23.4 Hz, 5H) ppm. [1376] Step 3: Preparation of 2-[4-chloro-5-[(3R,4R)-1-[[1-[(4- methoxyphenyl)methyl]triazol-4-yl]methylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]- 5-fluoro-pyridine [1377] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (200 mg), DIPEA (2.5 mL) and DCM (10 mL) was added [1-[(4- methoxyphenyl)methyl]triazol-4-yl]methanesulfonyl chloride (300 mg). After 3 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1378] Example 262: 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1H-triazol-4- ylmethylsulfonyl)-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine [1379] A mixture of 2-[4-chloro-5-[(3R,4R)-1-[[1-[(4-methoxyphenyl)methyl]triazol-4- yl]methylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine (25 mg) and TFA (8 mL) was stirred at 80°C for 5h. The mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1380] Example 263: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-3-methoxy-pyridazine [1381] Step 1: Preparation of 5-iodo-2-methylpyridazin-3(2H)-one [1382] A mixture of 5-iodopyridazin-3-ol (3.3 g, 15 mmol), MeOH (950 mg, 30 mmol) and PPh3 (7.8 g, 30 mmol) in THF (100 mL) was stirred at 0 °C for 15 min. DTBAD (5.13 g, 45 mmol) in THF (30 mL) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred at room temperature for 16 h. The resulting mixture was poured into water (200 mL). The water layer was extracted with EtOAc (100 mL x 3). The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (40% EtOAc in PE) to afford the subtitle compound (6.2 g, crude) as yellow solid.^MS m/z 237 [M+H]+. [1383] Step 2: Preparation of 5-((4-methoxybenzyl)thio)-2-methylpyridazin-3(2H)-one [1384] A mixture of 5-iodo-2-methylpyridazin-3(2H)-one (6.0 g, crude, 15 mmol), (4- methoxyphenyl)methanethiol (2.31 g, 15 mmol), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one palladium (234 mg, 0.26 mmol), Xantphos (148 mg, 0.3 mmol) and DIEA (5.8 g, 45 mmol) in toluene (100 mL) was stirred under N2 at 80 °C for 16 h. The resulting mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (3% MeOH in DCM) to afford the subtitle compound (2.9 g, yield: 73%) as yellow solid. MS m/z 263 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 2.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 6.87 (d, J = 8.5 Hz, 2H), 6.60 (d, J = 2.5 Hz, 1H), 4.09 (s, 2H), 3.80 (s, 3H), 3.71 (s, 3H). [1385] Step 3: Preparation of 1-methyl-6-oxo-1,6-dihydropyridazine-4-sulfonyl chloride [1386] To a stirred solution of 5-((4-methoxybenzyl)thio)-2-methylpyridazin-3(2H)-one (260 mg) in acetonitrile (5 mL) was added 2 M HCl (0.2 mL) and NCS (536 mg) slowly at 0°C. The reaction mixture was stirred at 0°C for 15 min. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the subtitle compound (70 mg, crude), which was used in the next step directly. [1387] Step 4: Preparation of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]-3-methoxy-pyridazine [1388] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (70 mg), DIPEA (1 mL) and DCM (5 mL) was added 6-methoxypyridazine-4- sulfonyl chloride (70 mg, crude). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1389] Example 264: 5-Fluoro-2-[4-fluoro-5-[(3S*,4S*)-3-methyl-1-methylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]pyridine [1390] A mixture of 5-fluoro-2-[4-fluoro-5-[(3S*,4S*)-3-methyl-4-piperidyl]-1H- imidazol-2-yl]pyridine (hydrochloride, 30 mg), DIPEA (70 µL) and DCM (0.5 mL) was added methanesulfonyl chloride (12 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1391] Example 265: 5-Fluoro-2-[4-fluoro-5-[(3R*,4R*)-3-methyl-1-methylsulfonyl-4- piperidyl]-1H-imidazol-2-yl]pyridine [1392] A mixture of 5-fluoro-2-[4-fluoro-5-[(3R*,4R*)-3-methyl-4-piperidyl]-1H- imidazol-2-yl]pyridine (hydrochloride, 30 mg), DIPEA (70 µL) and DCM (0.5 mL) was added methanesulfonyl chloride (12 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1393] Example 266: N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]acetamide [1394] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyrimidin-2-amine (50 mg), pyridine (0.75 mL) and DCM (5 mL) was added acetyl chloride (75 mg). The mixture was stirred at 40° C until a clear solution was obtained. After one additional hour at RT, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1395] Example 267: Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]thiazole-2-carboxylate [1396] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (250 mg), DIPEA (3.5 mL) and DCM (18 mL) was added methyl 5- chlorosulfonylthiazole-2-carboxylate (265 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1397] [1398] Example 268: Methyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]thiazole-2-carboxylate [1399] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (150 mg), DIPEA (2 mL) and DCM (10 mL) was added methyl 4- chlorosulfonylthiazole-2-carboxylate (165 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1400] Example 269: N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]methanesulfonamide [1401] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyrimidin-2-amine (20 mg), pyridine (0.3 mL) and DCM (2 mL) was added methanesulfonyl chloride (10 mg). The mixture was stirred at 40° C until a clear solution was obtained. After one additional hour at RT, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1402] Example 270: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]thiazole [1403] A mixture of methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]thiazole-2-carboxylate (160 mg), water (2 mL) and THF (8 mL) was added LiOH (25 mg). After 2 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1404] Example 271: 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]thiazole-2-carboxylic acid [1405] A mixture of methyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]thiazole-2-carboxylate (160 mg), water (2 mL) and THF (8 mL) was added LiOH (25 mg). After 2 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1406] Example 272: Methyl 3-[3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoylamino]azetidine-1-carboxylate [1407] A mixture of N-(azetidin-3-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propenamide (hydrochloride, 30 mg), DIPEA (41 µL) and DCM (0.5 mL) was added methyl carbonochloridate (6 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1408] Example 273: N-(1-Acetylazetidin-3-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2- pyridyl)-1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propanamide [1409] A mixture of N-(azetidin-3-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propenamide (hydrochloride, 30 mg), DIPEA (41 µL) and DCM (0.5 mL) was added acetyl chloride (5 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1410] Example 274: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(1-methylsulfonylazetidin-3-yl)propanamide [1411] A mixture of N-(azetidin-3-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propenamide (hydrochloride, 30 mg), DIPEA (41 µL) and DCM (0.5 mL) was added methanesulfonyl chloride (7 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1412] Example 275: N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]-1,3,4-thiadiazol-2-yl]acetamide [1413] Step 1: Preparation of 5-acetamido-1,3,4-thiadiazole-2-sulfonyl chloride [1414] A mixture of 2 M HCl in water (20 mL) and acetonitrile (50 mL) was stirred at -10 °C for 30 min. Then N-(5-sulfanyl-1,3,4-thiadiazol-2-yl)acetamide (5 g, 28.5 mmol) and NCS (12.1 g, 91.3 mmol) were added slowly. The reaction was stirred at 10 °C for 2 h. The suspension was filtered through a pad of Celite and silica gel and the filter cake was washed with acetonitrile (20 mL × 2). The combined filtrates were concentrated and poured into water (50 mL), the resulting precipitate was collected by filtration and dried in vacuum to afford the subtitle compound (1.92 g, yield: 28%) as a white solid. MS m/z 242.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 11.08 (s, 2H), 2.17 (d, J = 1.6 Hz, 3H) ppm. [1415] Step 2: Preparation of N-[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]-1,3,4-thiadiazol-2-yl]acetamide [1416] A mixture of 2-[4-chloro-5-[(3R,4R)-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5- fluoro-pyridine (100 mg), DIPEA (1.4 mL) and DCM (7 mL) was added 5-acetamido-1,3,4- thiadiazole-2-sulfonyl chloride (500 mg). After 1 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1417] Example 276: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]thiazole-2-carboxylic acid [1418] A mixture of methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol- 5-yl]-3-methyl-1-piperidyl]sulfonyl]thiazole-2-carboxylate (100 mg), water (1.5 mL) and THF (6 mL) was added LiOH (25 mg). After 2 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1419] Example 277: 2-[[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]amino]propane-1,3-diol [1420] A mixture of 2-chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidine (90 mg), DIPEA (0.5 mL) and DCM (3 mL) was added 2-aminopropane-1,3-diol (40 mg). After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1421] Example 278: Methyl 2-[[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]amino]acetate [1422] A mixture of methyl 2-aminoacetate (hydrochloride, 110 mg), DCM (3 mL) and DMF (2 mL) was added DIPEA (1.2 mL). After 30 min at 40°C, 2-chloro-5-[[(3R,4R)-4-[4- chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidine (250 mg) was added. After 1 h at 40°C, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1423] Example 279: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-1,3,4-thiadiazol-2-amine [1424] A mixture of N-[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]-1,3,4-thiadiazol-2-yl]acetamide (5 mg), EtOH (0.5 mL) and HCl (6N, 0.5 mL) was heated at 80°C for 1h. The mixture was concentrated. The residue was purified by preparative HPLC to afford the title compound. [1425] Example 280: N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]thiazol-2-yl]azetidine-3-carboxamide [1426] Step 1: Preparation of tert-butyl 3-[[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2- pyridyl)-1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]thiazol-2-yl]carbamoyl]azetidine-1- carboxylate (2,2,2-trifluoroacetate) [1427] A mixture of 1-tert-butoxycarbonylazetidine-3-carboxylic acid and DCM (3 mL) was added 1-chloro-N,N,2-trimethyl-1-propenylamine (35 mg). After 30 min at RT, the mixture was added to a solution of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]thiazol-2-amine (55 mg) in DCM (2 mL) and pyridine (1.2 mL). After 2 h, the reaction was quenched with water (0.2 mL). The mixture was concentrated. The residue was purified by preparative HPLC to afford the subtitle compound. MS m/z 640.2 [M+H]+. [1428] Step 2: Preparation of N-[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]thiazol-2-yl]azetidine-3-carboxamide [1429] A mixture of tert-butyl 3-[[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]thiazol-2-yl]carbamoyl]azetidine-1-carboxylate (32 mg) and DCM (2 mL) was added HCl (6N in iPrOH, 5 mL). After 1 h at 40°C, the mixture was concentrated and purified by preparative HPLC to afford the title compound. [1430] Example 281: 2-[[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]amino]acetic acid [1431] A mixture of methyl 2-[[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]amino]acetate (155 mg), water (2 mL) and THF (8 mL) was added LiOH (40 mg). After 2 h, the mixture was concentrated, and the residue purified by preparative HPLC to afford the title compound. [1432] Example 282: 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]thiazole-2-carboxamide [1433] A mixture of 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]thiazole-2-carboxylic acid (80 mg), DMF (3 mL) and DIPEA (0.5 mL) was added HATU (300 mg). After 15 min, ammonium chloride (300 mg) was added. After 14 hours, the mixture was filtrated, and the filtrate purified by preparative HPLC to afford the title compound. [1434] Example 283: 2-[[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]amino]acetamide [1435] A mixture of 2-[[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]amino]acetic acid (100 mg), DMF (6 mL) and DIPEA (0.7 mL) was added EDC (130 mg) and HOBT (100 mG). After 15 min, ammonium chloride (300 mg) was added. After 14 hours, the mixture was filtrated, and the filtrate purified by preparative HPLC to afford the title compound. [1436] Example 284: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(2-hydroxy-1,1-dimethyl-ethyl)propanamide [1437] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (47 µL) was added HATU (33 mg). After 15 min, 2-amino-2-methyl-propan-1-ol (12 mg) was added. After 2 hours, the mixture was filtrated, and the filtrate purified by preparative HPLC to afford the title compound. [1438] Example 285: 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]-N-(3,3-difluorocyclobutyl)propanamide [1439] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (47 µL) was added HATU (33 mg). After 15 min, 3,3-difluorocyclobutaneamine (hydrochloride, 21 mg; mixed with DMF (0.2 mL) and NaHCO3) was added. After 2 hours, the mixture was filtrated, and the filtrate purified by preparative HPLC to afford the title compound. [1440] Example 286: [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]propanoyl]-3-methyl-azetidin-3-yl] acetate [1441] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (47 µL) was added HATU (33 mg). After 15 min, (3-methylazetidin-3-yl) acetate (hydrochloride, 23 mg; mixed with DMF (0.2 mL) and NaHCO3) was added. After 2 hours, the mixture was filtrated, and the filtrate purified by preparative HPLC to afford the title compound. [1442] Example 287: [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]propanoyl]-3-methyl-azetidin-3-yl] methyl carbonate [1443] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (47 µL) was added HATU (33 mg). After 15 min, methyl (3-methylazetidin-3-yl) carbonate (hydrochloride, 25 mg; mixed with DMF (0.2 mL) and NaHCO3) was added. After 2 hours, the mixture was filtrated, and the filtrate purified by preparative HPLC to afford the title compound. [1444] Example 288: [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]-3-methyl-1-piperidyl]sulfonyl]propanoyl]azetidin-3-yl] ethyl carbonate [1445] A mixture of 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoic acid (30 mg), DMF (0.5 mL) and DIPEA (47 µL) was added HATU (33 mg). After 15 min, azetidin-3-yl ethyl carbonate (hydrochloride, 25 mg; mixed with DMF (0.2 mL) and NaHCO3) was added. After 2 hours, the mixture was filtrated, and the filtrate purified by preparative HPLC to afford the title compound. [1446] One embodiment is a compound of formula I selected from Examples V1 to V23 below, which can be prepared according to the procedures described above and methods known to those skilled in the art.
[1447] Example V1: Methyl 3-(((3S*,4S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)propanoate
Figure imgf000470_0001
[1448] Example V2: 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)propan-1-ol
Figure imgf000470_0002
[1449] Example V3: 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)propanoic acid
Figure imgf000470_0003
[1450] Example V4: 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)propanamide
Figure imgf000471_0001
[1451] Example V5: 3-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)-N-methylpropanamide
Figure imgf000471_0002
[1452] Example V6: Methyl N-(((3S*,4S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H- imidazol-5-yl)-3-methylpiperidin-1-yl)sulfonyl)-N-methylglycinate
Figure imgf000471_0003
[1453] Example V7: (3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- N-(2-hydroxyethyl)-N,3-dimethylpiperidine-1-sulfonamide
Figure imgf000472_0001
[1454] Example V8: N-(((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-3-methylpiperidin-1-yl)sulfonyl)-N-methylglycine
Figure imgf000472_0002
[1455] Example V9: 2-((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-N,3-dimethylpiperidine-1-sulfonamido)acetamide
Figure imgf000472_0003
[1456] Example V10: 2-((3S*,4S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)-N,3-dimethylpiperidine-1-sulfonamido)-N-methylacetamide
Figure imgf000473_0001
[1457] Example V11: Methyl (S*)-3-((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)propanoate
Figure imgf000473_0002
[1458] Example V12: (S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)propan-1-ol
Figure imgf000473_0003
[1459] Example V13: (S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)propanoic acid
Figure imgf000474_0001
[1460] Example V14: (S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)propanamide
Figure imgf000474_0002
[1461] Example V15: (S*)-3-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)-N-methylpropanamide
Figure imgf000474_0003
[1462] Example V16: Methyl (S*)-N-((4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol- 5-yl)-3-methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)-N-methylglycinate
Figure imgf000475_0001
[1463] Example V17: (S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N-(2- hydroxyethyl)-N,3-dimethyl-3,6-dihydropyridine-1(2H)-sulfonamide
Figure imgf000475_0002
[1464] Example V18: (S*)-N-((4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridin-1(2H)-yl)sulfonyl)-N-methylglycine
Figure imgf000475_0003
[1465] Example V19: (S*)-2-(4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- N,3-dimethyl-1,2,3,6-tetrahydropyridine-1-sulfonamido)acetamide
Figure imgf000476_0001
[1466] Example V20: (S*)-2-(4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)- N,3-dimethyl-1,2,3,6-tetrahydropyridine-1-sulfonamido)-N-methylacetamide
Figure imgf000476_0002
[1467] Example V21: (S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methyl-3,6-dihydropyridine-1(2H)-carboxamide
Figure imgf000476_0003
[1468] Example V22: 3-((3-Chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)phenyl)sulfonyl)propan-1-ol
Figure imgf000477_0001
[1470] PHARMACOLOGY AND PHYISCOCHEMICAL PROPERTIES [1471] The in vitro potency of compounds described herein in antagonizing MRGPRX2, and solubility and logD of compounds described herein may be determined by the procedures detailed below. [1472] Human MRGPRX2 calcium mobilization assay [1473] The assay employs MRGPRX2 expressing cells pre-labelled with a calcium- sensitive dye. In particular, HEK293T cell line (MultiscreenTM HEK293T, catalog no. C1257a, Multispan, Inc.) stably expressing the human MRGPRX2 receptor (MAS-related G-protein coupled receptor X2; NM_054030 with FLAG tag sequence at N-terminus) and the Calcium 6-QF assay kit (Molecular Devices) were used. Stimulation of the receptor results in an intracellular rise of calcium (Ca2+) levels. In the assay, the Ca2+-influx into cells results in fluorescence changes of a calcium sensitive dye which is included in the Calcium 6-QF assay kit (Molecular Devices). When the dye complexes calcium, a large increase of the fluorescence quantum yield occurs and can be measured with the Fluorometric Imaging Plate Reader (FLIPR Tetra, Molecular Devices). The fluorescent dye enters the cell. Hence, influx of calcium to the cytoplasm can be detected and serve as a proxy for receptor activation. [1474] In brief, frozen assay-ready HEK293T cells stably expressing hMRGPRX2 were plated at 12,500 cells/well (25 µl/well) in 384-well poly-D-Lysin coated plates (Corning # 356697) and incubated overnight at 37°C and 5% CO2. On the second day, culture media was removed and cells were washed two times with a Biotek EL406 plate washer (residual volume 15 µl) (HBSS, 20 mM Hepes, 0,01% Pluronic F68). Subsequently, 10 µl Calcium 6-QF dye solution was added using a Multidrop Combi and cells were incubated for 90 min at 37°C, 5% CO2 without lid. This was followed by incubation for 30 min at RT without lid. Next, 12.5 µl compound solution was added (4x concentrated) within the FLIPR Tetra device while recording fluorescence changes live (Ex 470-495; Em 515-575). Fluorescence changes during the first 15 min indicate agonistic compound activities. After 15 min, 12.5 µl pruritogenic neuropeptide Substance P (Sigma S6883) solution was added (4x concentrated; final concentration EC90 of hMRGPRX2 agonist) in the FLIPR Tetra. Fluorescence was recorded for an additional 240 sec. The maximum signal for each well (time-frame: 30 sec before, 240 sec after Substance P addition) was extracted. [1475] To determine the activity of antagonist compounds, the maximum signal was used and the percent (%) inhibition at each concentration of a test compound was calculated relative to the responses in control wells contained within each assay plate. 0% inhibition was the activity determined from control wells lacking compound and 100% inhibition was derived from the measured activity in control wells containing a reference antagonist (1-(10H- phenazin-5-yl)ethanone) at 100 µM. The concentrations and percent inhibition values for a test compound were plotted and dose-response parameters including relative IC50 values were determined using a four parameter logistic dose-response equation. [1476] Determination of thermodynamic solubility using DMSO stock solution (high throughput method) [1477] In a first run, the actual compound concentration in a DMSO stock solution (nominal concentration 10 mM) is determined after dilution (1:40 with DMSO) using UPLC- UV/ELSD (Evaporative Light Scattering Detector) and quantifying against a standard solution of indometacin. This data point is used for the two-point calibration curve to quantify the solubility sample in a second run. Therefore, the DMSO stock solution on a U-shaped 96-well multi-titer plate is first evaporated to obtain a dry film (~100 µg). The dissolution medium to be tested (160 µL, e.g., phosphate buffer pH 7.4) is added to the dry film together with a stirring bead and the sample is shaken for 16 h at 25 °C on a thermomixer with 600 rpm after sealing the plate. This is followed by a centrifugation (5 min, 4000 rcf) and filtration (filter 0.45 µm) step to obtain a supernatant that is quantified using UPLC-UV (A: H2O (25 mM ammonium acetate), B: MeCN; Gradient: 2%-98% B in 2.3 min, 98% B for 0.6 min; Flow Rate: 0.9 ml/min; Column: Waters Acquity CSH C18 1.7 µm 2.1 x 75 mm; Column Temperature: 50°C) against the calibration curve determined above. [1478] Determination of thermodynamic solubility using solid material [1479] For the calibration samples (in duplicate) and for each buffer medium (selected from pH1.1, pH4.5, pH6.5, pH7.4, pH9.0, FaSSIF, and FeSSIF buffer solution) approx. 1 mg of the test item is accurately (with 3 decimal digits) weighed into a 1 ml HPLC glass vial. An adjusted volume of DMSO is added to the two calibration samples to obtain a starting concentration of 1 mg/ml for the calibration curves. From each calibration sample a DMSO dilution series is created in a U-shaped 96-well multititer plate with the concentration steps 500 µg/ml, 250 µg/ml, 100 µg/ml, 50 µg/ml, 20 µg/ml, 10 µg/ml, 5 µg/ml, 2 µg/ml, and 1 µg/ml. The two dilution series are measured using UPLC-UV (A: H2O (0.05% TFA), B: MeCN (0.045% TFA); Gradient: 2%-98% B in 11.5 min, 98% B for 1 min; Flow Rate: 0.7 ml/min; Column: Waters Acquity CSH C18 1.7 µm 2.1 x 75 mm; Column Temperature: 50°C) and a mean calibration curve (polynomial 2 order) is calculated using these data points. [1480] An adjusted volume of the selected buffers is added to each buffer sample to reach a maximum concentration of 1 mg/ml. The cap sealed samples are then shaken for 16 h at 25 °C on a thermomixer with 600 rpm. This is followed by a centrifugation (10 min, 2500 rcf) and filtration (filter 0.45 µm) step to obtain a supernatant that is quantified using UPLC-UV against the calibration curve determined above. [1481] Determination of logD7.4 by RP-UHPLC [1482] The octanol/water distribution coefficient at pH 7.4 (logD7.4) is determined by a standardized reversed phase UHPLC-UV method (A: H2O, B: MeCN, C: MOPS 100 mmol pH 7.4; Gradient: 95%/0%/5% – 0%/95%/5% in 6.0 min, 0%/95%/5% for 1 min; Flow Rate: 0.7 ml/min; Column: Waters BEH C18 1.7 µm 2.1x50 mm; Column Temperature: 30°C), which allows the fast relative differentiation of test items which are similar to standard compounds. Comparison of the retention times of the test items with those of standard compounds of known distribution coefficient between octanol and water at pH 7.4 (logD7.4) allows the calculation of the logD7.4 value for the test items. The retention times of the reference compounds in the calibration mixture (four basic and four acidic/neutral compounds – see Table 1 & 2) are plotted against their known logD7.4 values. The slope and the intercept of this calibration function are used to calculate the logD7.4 value of the test item from its retention time. The test sample solutions are prepared by diluting 5 µL of a 10 mM stock solution in DMSO with 195 µL of DMSO. [1483] Table 2: HPLC logD7.4 standards for basic compounds
Figure imgf000480_0001
[1484] Table 3: HPLC logD7.4 standards for acidic/neutral compounds
Figure imgf000480_0002
Figure imgf000481_0002
[1485] Biological and Physical Property Data [1486] Table 3 below lists the IC50 values obtained as described for the hMRGPRX2 calcium mobilization assay, logD values at pH 7.4 obtained by RP-HPLC as described herein, thermodynamic solubility values obtained using a DMSO stock solution method, except where otherwise indicated, as described herein, and the molecular weights for exemplified compounds. [1487] Table 4
Figure imgf000481_0001
Figure imgf000482_0001
Figure imgf000483_0001
Figure imgf000484_0001
Figure imgf000485_0001
Figure imgf000486_0001
Figure imgf000487_0001
Figure imgf000488_0001
Figure imgf000489_0001
Figure imgf000490_0001
Figure imgf000491_0001
Figure imgf000492_0001
Figure imgf000493_0001
Figure imgf000494_0001
Figure imgf000495_0001
Figure imgf000496_0001
Figure imgf000497_0001
Figure imgf000498_0001
Figure imgf000499_0001
Figure imgf000500_0001
Figure imgf000501_0001
Figure imgf000502_0001
Figure imgf000503_0001
a Thermodynamic solubility determined from solid as described herein [1488] From the foregoing, those skilled in the art will appreciate that certain modifications can also be made to the present disclosure without departing from the scope of the same. The above description should not be construed as limiting, but merely as exemplifications of particular embodiments. Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

Claims

CLAIMS 1. A compound of formula I
Figure imgf000504_0001
, wherein: A is selected from ,
Figure imgf000504_0002
each is a single or a double bond, provided two adjacent are not both double bonds; each instance of R1 is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R2 is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; each instance of R3 is independently selected from halogen, cyano, -OR11, -NR11R12, - SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R4 is selected from halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R4P is selected from hydrogen, halogen, cyano, -OR11, -NR11R12, -SR11, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, - OC(=O)R6, -OC(=O)OR7, -OC(=O)NR7R8, -NR9C(=O)R6, -NR9C(=O)OR7, - NR9C(=O)NR7R8, -NR9C(=NR9)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, - S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, aryl, C1-C3 arylalkyl, monocyclic heteroaryl, and C1-C3 heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, - (CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(arylene)R13, heterocyclyl, or -(heterocyclylene)R13; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, aryl, C1-C3 arylalkyl, heteroaryl, and C1-C3 heteroarylalkyl, which groups are unsubstituted or substituted with one or more of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, - OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -S(=O)(=NR9)R10, or - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, or -NR9S(=O)2NR11R12; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or more R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C3 3-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or more R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), - C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)OH, -OC(=O)O(C1-C4 alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), - NHC(=O)(C1-C4 alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4 alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4 alkyl), -NHC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)(C1- C4 alkyl), -N(C1-C4 alkyl)C(=O)OH, -N(C1-C4 alkyl)C(=O)O(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)NH2, -N(C1-C4 alkyl)C(=O)NH(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qOH, -(CH2)qO(C1-C4 alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4 alkyl), -(CH2)qN(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qC(=O)(C1-C4 alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4 alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4 alkyl), - (CH)qC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a heterocyclyl ring; X1 is halogen; m is 0 or 1; n is 1 or 2; each p is independently 1, 2, or 3; and each q is independently 1, 2, or 3; wherein when
Figure imgf000507_0001
, R4 and R5 may be taken together with the carbons connecting them to form a 5- or 6-membered heterocyclyl ring; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
Figure imgf000507_0002
.
2. The compound of formula I according to claim 1, wherein: A is selected from
Figure imgf000508_0001
R1 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R2 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; each instance of R3 is independently selected from halogen, -OR11, -NR11R12, C1-C6 alkyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl; R4 is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R4P is selected from halogen, -OR11, -NR11R12, C1-C4 alkyl, C1-C4 heteroalkyl, and C1- C3 haloalkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -C(=NR9)NR7R8, -SR7, - S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, -S(=O)(=NR9)R6, and -S(=O)(=NR9)NR7R8; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, phenyl, C1-C3 phenylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O- )R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, - OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, - NR9C(=NR )NR R S(=O)R S(=O) R S(=O) NR R S(=O)(=NR9)R10, - S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, - (CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, -(CH2)p(phenylene)R13, 4- to 6- membered heterocyclyl, or -(4- to 6-membered heterocyclene)R13; and R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C34- to 6-membered heterocyclylalkyl, phenyl, C1-C3 phenylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, or - S(=O)(=NR9)NR11R12; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C3 3-to 6-membered cycloalkylalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C3 monocyclic heteroarylalkyl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C3 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)(C1-C4 alkyl), - C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -OC(=O)(C1-C4 alkyl), -OC(=O)OH, -OC(=O)O(C1-C4 alkyl), -OC(=O)NH2, -OC(=O)NH(C1-C4 alkyl), -OC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), - NHC(=O)(C1-C4 alkyl), -NHC(=O)OH, -NHC(=O)O(C1-C4 alkyl), -NHC(=O)NH2, - NHC(=O)NH(C1-C4 alkyl), -NHC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)(C1- C4 alkyl), -N(C1-C4 alkyl)C(=O)OH, -N(C1-C4 alkyl)C(=O)O(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)NH2, -N(C1-C4 alkyl)C(=O)NH(C1-C4 alkyl), -N(C1-C4 alkyl)C(=O)N(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qOH, -(CH2)qO(C1-C4 alkyl), -(CH2)qNH2, -(CH2)qNH(C1-C4 alkyl), -(CH2)qN(C1-C4 alkyl)(C1-C4 alkyl), -(CH2)qC(=O)(C1-C4 alkyl), -(CH2)qC(=O)OH, - (CH2)qC(=O)O(C1-C4 alkyl), -(CH2)qC(=O)NH2, -(CH2)qC(=O)NH(C1-C4 alkyl), - (CH)qC(=O)N(C1-C4 alkyl)(C1-C4 alkyl), and -S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4- to 6-membered heterocyclyl ring; m is 0 or 1; n is 1; each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
3. The compound of formula I according to claim 1 or 2, wherein: A is selected from
Figure imgf000510_0001
R1 is selected from halogen; R2 is selected from halogen and C1-C4 alkyl; R4 is selected from halogen and C1-C4 alkyl; R4 is selected from hydrogen and C C alkyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - OC(=O)R10, -NR9C(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10, - NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pC(=O)OR11, -(CH2)p(phenylene)R13, or –(4- to 6- membered heterocyclene)R13; R7 and R8 are independently selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, - C(=O)OR11, -C(=O)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, -NR9C(=O)NR11R12, -S(=O)2R10, -S(=O)2NR11R12, -NR9S(=O)2R10; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, 4- to 6-membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C33-to 6-membered cycloalkylalkyl, 4- to 6- membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -O(C1-C4 alkyl), -NH2, -C(=O)(C1-C4 alkyl), -C(=O)OH, -C(=O)O(C1-C4 alkyl), -C(=O)NH2, -OC(=O)(C1-C4 alkyl), -OC(=O)O(C1-C4 alkyl), -(CH2)qOH, and - S(=O)2(C1-C4 alkyl), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form a 4-membered heterocyclyl ring; m is 0; n is 1; each p is 1; and each q is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof. 4. The compound of formula I according to any one of claims 1-3, wherein: A is selected from
Figure imgf000512_0001
R2 is selected from chloro, bromo, methyl, and ethyl; R4 is selected from fluoro, chloro, and methyl; R4P is selected from hydrogen and methyl; R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -SR7, -S(=O)R6, -S(=O)2R6, -S(=O)2NR7R8, and -S(=O)(=NR9)R6; R6 is selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, and C1-C3 monocyclic heteroarylalkyl which groups are unsubstituted or substituted with one, two, or three of halogen, C1-C4 alkyl, -OR11, -NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, - NHC(=O)R10, -S(=O)2R10, or -S(=O)2NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, - (CH2)OR11, -(CH2)C(=O)OR11, -(CH2)(phenylene)R13, or –(4- to 6-membered heterocyclene)R13; R7 and R8 are independently selected from hydrogen, C1-C4 alkyl, C1-C4 heteroalkyl, 4 to 6-membered heterocyclyl, and C1-C3 monocyclic heteroarylalkyl, which groups are unsubstituted or substituted with one, two, or three of C1-C4 alkyl, -OR11, -NR11R12, - C(=O)R10, -C(=O)OR11, or -C(=O)NR11R12,; each instance of R9 is independently selected from hydrogen and C1-C4 alkyl; each instance of R10 is independently selected from C1-C4 alkyl, C1-C4 heteroalkyl, C3- C6 cycloalkyl, 4- to 6- membered heterocyclyl, and -N=S(Me)2=O, which groups are unsubstituted or substituted with one or two R13; each instance of R11 and R12 is independently selected from hydrogen, C1-C4 alkyl, C1- C4 heteroalkyl, C3-C6 cycloalkyl, C1-C33- to 6-membered cycloalkylalkyl,
4- to 6- membered heterocyclyl, C1-C3 4- to 6-membered heterocyclylalkyl, monocyclic heteroaryl, C1-C4 acyl, and C1-C4 sulfonyl provided R11 is not C1-C4 sulfonyl when R11 is bonded to an oxygen or sulfur atom, which groups are unsubstituted or substituted with one or two R13; each instance of R13 is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OMe, -NH2, -C(=O)Me, -C(=O)OH, -C(=O)OMe, -C(=O)NH2, -C(=O)OtBu, -OC(=O)Me, -OC(=O)OMe, -OC(=O)OEt, -(CH2)OH, and -S(=O)2(Me), and wherein two R13 groups substituting the same carbon of a heterocyclyl ring may be taken together with the carbon to which they are attached to form:
Figure imgf000513_0001
; m is 0; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
5. The compound of formula I according to any one of claims 1-4, wherein the compound is of formula I-A ,
Figure imgf000514_0001
or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
6. The compound of formula I according to any one of claims 1-4, wherein the compound is of formula I-B ,
Figure imgf000514_0002
or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
7. The compound of formula I according to any one of claims 1-4, wherein the compound is of formula I-D ,
Figure imgf000514_0003
or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
8. The compound of formula I according to any one of claims 1-4, wherein the compound is of
Figure imgf000515_0001
I-G1, wherein: L1 is selected from -CH2- and -N(R11)-; G1 is selected from -OR11, NR11R12, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12,, - S(=O)2R10, -S(=O)2NR11R12, 4- to 6-membered heterocyclyl, and monocyclic heteroaryl; and j is 0, 1, or 2; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
9. The compound of formula I according to any one of claims 1-4, wherein the compound is of formula I-H
Figure imgf000515_0002
I-H, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
10. The compound of formula I according to any one of claims 1-4, wherein the compound is of any one of formulas I-J1 to I-J5,
Figure imgf000516_0001
Figure imgf000517_0001
wherein: z is 0, 1, or 2 where valency permits; each instance of Z1 is independently selected from halogen, cyano, C1-C4 alkyl, -OR11, -NR11R12, -N+(O-)R11R12, -SR11, -C(=O)R10, -C(=O)OR11, -C(=O)NR11R12, -C(=NR9)NR11R12, -OC(=O)R10, -OC(=O)OR11, -OC(=O)NR11R12, -NR9C(=O)R10, -NR9C(=O)OR11, - NR9C(=O)NR11R12, -NR9C(=NR9)NR11R12, -S(=O)R10, -S(=O)2R10, -S(=O)2NR11R12, - S(=O)(=NR9)R10, -S(=O)(=NR9)NR11R12, -NR9S(=O)2R10, -NR9S(=O)2NR11R12, -(CH2)pOR11, -(CH2)pNR11R12, -(CH2)pC(=O)R10, -(CH2)pC(=O)OR11, -(CH2)pC(=O)NR11R12, - (CH2)p(arylene)R13, heterocyclyl, or -(heterocyclene)R13; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; and E3 is selected from -CH2-, -NH-, and -O-; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
11. The compound of formula I according to any one of claims 1-4, wherein the compound is of any one of formulas I-K1 to I-K8
Figure imgf000518_0001
Figure imgf000519_0001
wherein: y is 0, 1, or 2 where valency permits; each instance of E1 is independently selected from -CH- and -N-; E2 is selected from -NH-, -O-, and -S-; and E3 is selected from -CH2-, -NH-, and -O-; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
12. The compound of formula I according to any one of claims 1 to 11, wherein R1 is selected from halogen and C1-C4 alkyl; R2 is selected from halogen and C1-C4 alkyl; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
13. The compound of formula I according to any one of claims 1 to 12, wherein R1 is fluoro; R2 is chloro; and n is 1; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
14. The compound of formula I according to any one of claims 1 to 6, wherein R4 is selected from halogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
15. The compound of formula I according to any one of claims 1 to 4, 7, and 9-13, wherein R4P is selected from hydrogen and C1-C4 alkyl; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
16. The compound of formula I according to any one of claims 1 to 15, wherein R5 is selected from -C(=O)R6, -C(=O)OR7, -C(=O)NR7R8, -S(=O)R6, -S(=O)2R6, - S(=O)2NR7R8, and -S(=O)(=NR9)R6; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
17. The compound of formula I according to claim 16, wherein R5 is -S(=O)2R6; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
18. The compound of formula I according to claim 16, wherein R5 is selected from , ,
Figure imgf000521_0001
, , ,
Figure imgf000522_0001
Figure imgf000523_0001
Figure imgf000524_0001
Figure imgf000525_0001
Figure imgf000526_0001
Figure imgf000527_0001
Figure imgf000528_0001
Figure imgf000529_0001
Figure imgf000530_0001
Figure imgf000531_0001
Figure imgf000532_0001
Figure imgf000533_0001
Figure imgf000534_0001
Figure imgf000535_0001
Figure imgf000536_0001
Figure imgf000537_0001
or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
19. A compound selected from: Tert-butyl 4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]piperidine-1- carboxylate; 1-[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-1-piperidyl]ethenone; 2-[4-Chloro-5-(1-methylsulfonyl-4-piperidyl)-1H-imidazol-2-yl]-5-fluoro-pyridine; (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine- 1-sulfonamide; (3S,4S)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine-1- sulfonamide; (3R*,4S*/3S*,4R*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidine-1-sulfonamide; 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-4-methylpiperidine-1- sulfonamide; (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-N-(2-hydroxyethyl)- 3-methylpiperidine-1-sulfonamide; (3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine- 1-carboxamide; 2-(4-Chloro-5-((3R,4R)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine; 1-((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)ethan-1-one; (3S*,4S*)-4-(4-Ethyl-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine- 1-sulfonamide; (3R*,4R*)-4-(4-Ethyl-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidine- 1-sulfonamide; Methyl (((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)glycinate; (((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylpiperidin- 1-yl)sulfonyl)glycine; 2-(4-Chloro-5-((3S,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-1H-imidazol-2- yl)-5-fluoropyridine; 2-(4-Chloro-5-((3R*,4S*/3S*,4R*)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine; 1-(((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxamide; (S*)-2-(4-Chloro-5-(3-methyl-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine; (R*)-2-(4-Chloro-5-(3-methyl-1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H- imidazol-2-yl)-5-fluoropyridine; (S*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonamide; (R*)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-sulfonamide; 2-(5-((3R,4R)-1-((1H-Pyrazol-4-yl)sulfonyl)-3-methylpiperidin-4-yl)-4-chloro-1H- imidazol-2-yl)-5-fluoropyridine; Methyl 1-(((3R,4R)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylate; 1-(((3R,4R)-4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3- methylpiperidin-1-yl)sulfonyl)azetidine-3-carboxylic acid; 2-(4-Bromo-5-(2,3-difluorophenyl)-1H-imidazol-2-yl)-5-fluoropyridine; 2-(4-Bromo-5-(2-chlorophenyl)-1H-imidazol-2-yl)-5-fluoropyridine; 2-[4-Chloro-5-(2-chloro-4-methylsulfinyl-phenyl)-1H-imidazol-2-yl]-5-fluoro- pyridine; 2-[4-Chloro-5-(2-chloro-4-methylsulfonyl-phenyl)-1H-imidazol-2-yl]-5-fluoro- pyridine; 2-[4-Chloro-5-(2-chloro-4-(methylsulfonimidoyl)phenyl)-1H-imidazol-2-yl]-5-fluoro- pyridine; Methyl 3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]benzoate; 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]benzoic acid; 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]benzenesulfonamide; 2-[[3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylamino]acetic acid; 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N-(2- hydroxyethyl)benzenesulfonamide; 2-[5-(2-Chloro-4-methylsulfonyl-phenyl)-4-methyl-1H-imidazol-2-yl]-5-fluoro- pyridine; Methyl 1-((3-chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)phenyl)sulfonyl)azetidine-3-carboxylate; 1-((3-Chloro-4-(4-chloro-2-(5-fluoro-pyridin-2-yl)-1H-imidazol-5-yl)-phenyl) sulfonyl)azetidine-3-carboxylic acid; 1-((3-Chloro-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5- yl)phenyl)sulfonyl)azetidine-3-carboxamide; Methyl 2-chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)benzoate; 2-Chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)benzoic acid; 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-2,3-dihydro-1,2-benzothiazole 1,1-dioxide; 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-2-methylbenzenesulfonamide; 2-Chloro-3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)benzamide; 2-(4-Chloro-5-(2-fluoro-6-methylphenyl)-1H-imidazol-2-yl)-5-fluoropyridine; Methyl 3-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-fluoro-2- methylbenzoate; 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-fluoro-2-methylbenzoic acid; 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-fluoro-2-methylbenzamide; 2-(4-Chloro-5-(2-fluoro-6-methyl-4-(methylthio)phenyl)-1H-imidazol-2-yl)-5- fluoropyridine; 2-[4-Chloro-5-(2-fluoro-6-methyl-4-methylsulfonyl-phenyl)-1H-imidazol-2-yl]-5- fluoro-pyridine; 3-[3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylpropan-1-ol; 3-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-4-fluoro-2- methylbenzenesulfonamide; 3-[3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]phenyl]sulfonylpropanamide; 4-(4-Chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylbenzoic acid; Methyl 4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methylbenzoate; 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-benzamide; N-(2-Amino-2-oxo-ethyl)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-benzamide; 2-(4-Chloro-5-(2-methyl-4-(methylthio)phenyl)-1H-imidazol-2-yl)-5-fluoropyridine; N-(2-Amino-2-oxo-ethyl)-3-chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5- yl]benzamide; 3-Chloro-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]benzamide; 2-[4-Chloro-5-(2-methyl-4-methylsulfonyl-phenyl)-1H-imidazol-2-yl]-5-fluoro- pyridine; 2-[4-Chloro-5-(2-methyl-4-methylsulfinyl-phenyl)-1H-imidazol-2-yl]-5-fluoro- pyridine; Tert-butyl (S*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-carboxylate; Tert-butyl (R*)-4-(4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl)-3-methyl-3,6- dihydropyridine-1(2H)-carboxylate; (3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N,N,3-trimethyl- piperidine-1-carboxamide; Methyl (3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- piperidine-1-carboxylate; [2-(Dimethylamino)-2-oxo-ethyl] (3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-piperidine-1-carboxylate; Methyl 3-[[(3S*)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6- dihydro-2H-pyridin-1-yl]sulfonyl]propanoate; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3-pyridylsulfonyl)-4-piperidyl]-1H-imidazol-2- yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3-pyridylsulfonyl)-4-piperidyl]-1H-imidazol-2- yl]-5-fluoro-1-oxido-pyridin-1-ium; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-oxidopyridin-1-ium-3-yl)sulfonyl-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[5-[(3R,4R)-1-(Azetidin-3-ylsulfonyl)-3-methyl-4-piperidyl]-4-chloro-1H-imidazol- 2-yl]-5-fluoro-pyridine; 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]azetidin-1-yl]ethanone; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]azetidine-1-carboxamide; Methyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]butanoate; Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2,2-dimethyl-propanoate; Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonylmethyl]azetidine-1-carboxylate; 2-[5-[(3R,4R)-1-(Azetidin-3-ylmethylsulfonyl)-3-methyl-4-piperidyl]-4-chloro-1H- imidazol-2-yl]-5-fluoro-pyridine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2-methyl-pyridine; 2-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethoxy]ethanol; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]butanoic acid; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2,2-dimethyl-propanoic acid; 2-[4-Chloro-5-[(3R,4R)-1-[(6-methoxy-3-pyridyl)sulfonyl]-3-methyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]butanamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2,2-dimethyl-propanamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]azetidine-1-carboxamide; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1H-pyridin-2-one; 2-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethoxy]acetic acid; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-tetrahydrofuran-3-ylsulfonyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(oxetan-3-ylsulfonyl)-4-piperidyl]-1H-imidazol-2- yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-1-[(2-methoxy-4-pyridyl)sulfonyl]-3-methyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1H-pyridin-2-one; Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoate; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoic acid; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 1); 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]cyclobutanecarboxylic acid (isomer 2); 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-methyl-propanamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]cyclobutanecarboxamide (isomer 1); 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]cyclobutanecarboxamide (isomer 2); (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N,N-bis(2-hydroxyethyl)- 3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide; (3R,4R)-1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6- dihydro-2H-pyridin-1-yl]sulfonyl]pyrrolidine-3,4-diol; (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-N-(1H-tetrazol- 5-ylmethyl)-3,6-dihydro-2H-pyridine-1-sulfonamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propyl acetate; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propan-1-ol; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-hydroxyazetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-methylsulfonyl-propanamide; (5R)-5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]imidazolidine-2,4-dione; (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N-[2-hydroxy-1- (hydroxymethyl)ethyl]-3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide; 4-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl]piperazin-2-one; (2S)-2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6- dihydro-2H-pyridin-1-yl]sulfonylamino]propenamide; 1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl]azetidin-3-ol; (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-N-(2- oxopyrrolidin-3-yl)-3,6-dihydro-2H-pyridine-1-sulfonamide; 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl-methyl-amino]acetic; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2-methoxy-pyrimidine acid; Methyl 2-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyrazol-1-yl]acetate; 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl-methyl-amino]acetamide; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-methyl-pyridin-2-one; 2-[4-Chloro-5-[(3R,4R)-1-[2-[2-[(4-methoxyphenyl)methyl]tetrazol-5- yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrazol-1-yl]acetic acid; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-ol; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(2H-tetrazol-5-yl)ethylsulfonyl]-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; Methyl 3-[[4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6- dihydro-2H-pyridin-1-yl]sulfonyl]propanoate; 3-[[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6-dihydro-2H- pyridin-1-yl]sulfonyl]propenamide; 3-[[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6-dihydro-2H- pyridin-1-yl]sulfonyl]-1-(3-hydroxyazetidin-1-yl)propan-1-one; 3-[[4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6-dihydro-2H- pyridin-1-yl]sulfonyl]-N-cyclopropyl-propanamide; (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-N-[(5-methyl- 1,3,4-oxadiazol-2-yl)methyl]piperidine-1-sulfonamide; [1-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl]azetidin-3-yl]methanol; N-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonyl]piperidine-3-carboxamide; (3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N-[(2S)-2-hydroxypropyl]- 3-methyl-3,6-dihydro-2H-pyridine-1-sulfonamide; 2-[[(3R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-3,6-dihydro- 2H-pyridin-1-yl]sulfonylamino]-N,N-dimethyl-acetamide; 2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylamino]-N,N-dimethyl-acetamide; Tert-butyl (3S,4S)-4-[4-chloro-2-(5-fluoropyridin-2-yl)-1H-imidazol-5-yl]-3- methylpiperidine-1-carboxylate; 4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-5-methyl-3,6-dihydro-2H- pyridine-1-sulfonamide; 2-Chloro-5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- 1-piperidyl]sulfonyl]pyrimidine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylpyrazol-4-yl)sulfonyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; (3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-N,3-dimethyl- piperidine-1-carboxamide; 1-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]azetidin-3-ol; 2-[[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]amino]ethanol; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(1-methyltetrazol-5-yl)ethylsulfonyl]-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-amine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyridin-2-amine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-cyclopropyl-pyrimidin-2-amine; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-methyl-pyrrolidin-2-one; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-methyl-pyrimidin-2-amine; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N,N-bis(trideuteriomethyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2-hydroxy-2-methyl-propyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-cyclopropyl-propanamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[(3R)-3-hydroxypyrrolidin-1-yl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[(3S)-3-hydroxypyrrolidin-1-yl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-methoxyazetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-hydroxy-3-methyl-azetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(4-hydroxy-1-piperidyl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2-methoxyethyl)propenamide; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(2-methyltetrazol-5-yl)ethylsulfonyl]-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]azetidine-1-carboxylate; 2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]acetamide; Tert-butyl N-[4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonylmethyl]thiazol-2-yl]carbamate; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[(1-methylsulfonylazetidin-3-yl)methylsulfonyl]- 4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylsulfonylazetidin-3-yl)sulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]thiazol-2-amine; 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]azetidin-1-yl]ethenone; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(trideuteriomethyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(oxetan-3-yl)propenamide; 2-[4-Chloro-5-[(3R,4R)-1-(1H-imidazol-4-ylsulfonyl)-3-methyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-ethyl-propanamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(4-hydroxy-4-methyl-1-piperidyl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-morpholino-propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(cyclopropylmethyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-pyrrolidin-1-yl-propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2,2,2-trifluoroethyl)propenamide; Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]azetidine-1-carboxylate; Methyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]azetidine-1-carboxylate; N-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethyl]acetamide; N-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethyl]methanesulfonamide; Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]furan-2-carboxylate; 5-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethyl]-3-methyl-1,2,4-oxadiazole; Tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]ethyl]carbamate; 2-[4-Chloro-5-[(3R,4R)-1-[2-[1-[(4-methoxyphenyl)methyl]triazol-4-yl]ethylsulfonyl]- 3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethanamine; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[(1-hydroxycyclopropyl)methyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[3-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(oxetan-3-ylmethyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(4-methoxy-1-piperidyl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-tetrahydropyran-4-yl-propanamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[(3S)-tetrahydropyran-3-yl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propan-1-one; 2-[4-Chloro-5-[(3R,4R)-1-(2-methoxyethylsulfonyl)-3-methyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-tetrahydropyran-4-ylsulfonyl-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(tetrahydrofuran-3-ylmethylsulfonyl)-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazol-2-yl]acetamide; N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-4-methyl-thiazol-2-yl]acetamide; Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyridine-2-carboxylate; Tert-butyl 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyrrolidine-1-carboxylate; Tert-butyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]piperidine-1-carboxylate; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(1H-triazol-4-yl)ethylsulfonyl]-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(4-piperidylsulfonyl)-4-piperidyl]-1H-imidazol-2- yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-pyrrolidin-3-ylsulfonyl-4-piperidyl]-1H-imidazol- 2-yl]-5-fluoro-pyridine; Tert-butyl N-[2-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]ethylsulfamoyl]carbamate; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazol-2-amine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-4-methyl-thiazol-2-amine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyridine-2-carboxylic acid; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonylmethyl]-5-methyl-1,2,4-oxadiazole; 1-[4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-piperidyl]ethenone; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[(1-methylsulfonyl-4-piperidyl)sulfonyl]-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(sulfamoylamino)ethylsulfonyl]-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1-methylsulfonylpyrrolidin-3-yl)sulfonyl-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrrolidin-1-yl]ethenone; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyridine-2-carboxamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrrolidine-1-carboxamide; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1H-triazol-4-ylsulfonyl)-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]furan-2-carboxamide; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(methylsulfonylmethylsulfonyl)-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(3-methylsulfonylpropylsulfonyl)-4-piperidyl]- 1H-imidazol-2-yl]-5-fluoro-pyridine; [5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-2-furyl]-(3-hydroxyazetidin-1-yl)methanone; 3-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethyl]-1,4-dihydro-1,2,4-triazol-5-one; Tert-butyl N-[6-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyridazin-3-yl]carbamate; 6-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyridazin-3-amine; Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine-2-carboxylate; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine-2-carboxylic acid; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidine-2-carboxamide; [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]azetidin-3-yl] methyl carbonate; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-methoxy-3-methyl-azetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[(3S)-3-methoxypyrrolidin-1-yl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[dimethyl(oxo)-¿6-sulfanylidene]propenamide; [2-(Aminomethyl)-3-hydroxy-2-methyl-propyl] 3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2- pyridyl)-1H-imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propanoate; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(3-methyloxetan-3-yl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(1-methylcyclopropyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2-methoxy-2-methyl-propyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[(3R)-3-methoxypyrrolidin-1-yl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[[(2S)-oxetan-2-yl]methyl]propenamide; 2-[4-Chloro-5-[(3R,4R)-1-[2-[4-[(4-methoxyphenyl)methyl]-1,2,4-triazol-3- yl]ethylsulfonyl]-3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; N-[2-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]ethyl]cyclopropanesulfonamide; [5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazol-2-yl]urea; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[2-(4H-1,2,4-triazol-3-yl)ethylsulfonyl]-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-[(3-methyloxetan-3-yl)methylsulfonyl]-4- piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; Tert-butyl 3-[3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoylamino]azetidine-1-carboxylate; [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]-4-piperidyl] methyl carbonate; [(3R)-1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl- 1-piperidyl]sulfonyl]propanoyl]pyrrolidin-3-yl] methyl carbonate; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[[(2S)-tetrahydrofuran-2-yl]methyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[[(2R)-tetrahydrofuran-2-yl]methyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[(3R)-tetrahydrofuran-3-yl]propenamide; 1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]piperidin-4-one; 1-(Azetidin-1-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-methylsulfonylazetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[1-(hydroxymethyl)cyclobutyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-[1-(hydroxymethyl)cyclopentyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(4-hydroxycyclohexyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(5-methyl-1,3,4-oxadiazol-2-yl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(5-fluoro-2-pyridyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2-methylpyrazol-3-yl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-[4-(hydroxymethyl)-1-piperidyl]propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(3-fluoroazetidin-1-yl)propan-1-one; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1-(6-oxa-1-azaspiro[3.3]heptan-1-yl)propan-1-one; [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]-4-piperidyl] acetate; 5-[[(3S,4S)-4-[4-Fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-amine; 5-[[(3R,4R)-4-[4-Fluoro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-amine; N-(Azetidin-3-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]- 3-methyl-1-piperidyl]sulfonyl]propanamide; 2-[4-Chloro-5-[(3R,4R)-1-[[1-[(4-methoxyphenyl)methyl]triazol-4-yl]methylsulfonyl]- 3-methyl-4-piperidyl]-1H-imidazol-2-yl]-5-fluoro-pyridine; 2-[4-Chloro-5-[(3R,4R)-3-methyl-1-(1H-triazol-4-ylmethylsulfonyl)-4-piperidyl]-1H- imidazol-2-yl]-5-fluoro-pyridine; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-3-methoxy-pyridazine; 5-Fluoro-2-[4-fluoro-5-[(3S,4S)-3-methyl-1-methylsulfonyl-4-piperidyl]-1H-imidazol- 2-yl]pyridine; 5-Fluoro-2-[4-fluoro-5-[(3R,4R)-3-methyl-1-methylsulfonyl-4-piperidyl]-1H- imidazol-2-yl]pyridine; N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]acetamide; Methyl 5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxylate; Methyl 4-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxylate; N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]methanesulfonamide; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxylic acid; 4-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxylic acid; Methyl 3-[3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]propanoylamino]azetidine-1-carboxylate; N-(1-Acetylazetidin-3-yl)-3-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H- imidazol-5-yl]-3-methyl-1-piperidyl]sulfonyl]propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(1-methylsulfonylazetidin-3-yl)propenamide; N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1,3,4-thiadiazol-2-yl]acetamide; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxylic acid; 2-[[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]amino]propane-1,3-diol; Methyl 2-[[5-[[(3R,4R)-4-[4-chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3- methyl-1-piperidyl]sulfonyl]pyrimidin-2-yl]amino]acetate; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-1,3,4-thiadiazol-2-amine; N-[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazol-2-yl]azetidine-3-carboxamide; 2-[[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]amino]acetic acid; 5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]thiazole-2-carboxamide; 2-[[5-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]pyrimidin-2-yl]amino]acetamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(2-hydroxy-1,1-dimethyl-ethyl)propenamide; 3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]-N-(3,3-difluorocyclobutyl)propenamide; [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]-3-methyl-azetidin-3-yl] acetate; [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]-3-methyl-azetidin-3-yl] methyl carbonate; and [1-[3-[[(3R,4R)-4-[4-Chloro-2-(5-fluoro-2-pyridyl)-1H-imidazol-5-yl]-3-methyl-1- piperidyl]sulfonyl]propanoyl]azetidin-3-yl] ethyl carbonate; or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I according to any one of claims 1 to 19, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
21. A compound of formula I according to any one of claims 1 to 19, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament.
22. A compound of formula I according to any one of claims 1 to 19, or an enantiomer, diastereomer, or tautomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease, disorder, or condition selected from an inflammatory disorder, an allergic disorder, skin disorder, a mast cell disorder, a pain disorder, and an itch disorder.
PCT/EP2024/073181 2023-08-17 2024-08-19 Pyridyl imidazoles, their preparation and their therapeutic application Pending WO2025037036A1 (en)

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