Activators of mitophagy and uses thereof

Abstract

The present invention is related to compound of formula (I) or a salt thereof: (I) or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of formula (I), which are useful for preventing and / or treating Mitophagy related diseases.

Description

[0001] 123276-03120

[0002] ACTIVATORS OF MITOPHAGY AND USES THEREOF

[0003] RELATED APPLICATIONS

[0004] This application claims priority to U.S. Provisional Application No. 63 / 759,819, filed on February 18, 2025. The entire contents of the foregoing application are expressly incorporated herein by reference.

[0005] FIELD OF THE INVENTION

[0006] The present invention relates to compounds which are useful as activators of mitophagy and are expected to be useful as an active ingredient in a pharmaceutical composition, for example, a pharmaceutical composition for preventing and / or treating mitophagy related disorders.

[0007] BACKGROUND OF THE INVENTION

[0008] Mitophagy is a cellular process that removes damaged or dysfunctional mitochondria via autophagy. Decreased or insufficient mitophagy results in an increase or accumulation of poorly functioning or damaged mitochondria, and decreased levels of ATP synthesis and production. This accumulation of poorly functioning mitochondria has been liked to a number of diseases, such as Parkinson’s disease, Alzheimer’s disease, dementia, Amyotrophic Lateral Sclerosis, Huntington’s disease, diabetes, and Atherosclerosis. Doblado L, etal. Int J Mol Sci. 2021 Apr 9;22(8):3903 and Wang S, etal. Signal Transduct Target Ther. 2023 Aug 16;8(l):304. doi: 10.1038 / s41392-023-01503-7.

[0009] It has been shown that compounds which enhance mitophagy have the potential to treat diseases associated with decreased mitophagy, such as Alzheimer’s disease.

[0010] Pradeepkiran JA, etal. Biomed Pharmacother. 2022 May;149: 112918. doi:

[0011] 10.1016 / j.biopha.2022.112918. Epub 2022 Apr 4. Further, mitophagy enhancement correlates with normalization of damage-induced metabolic dysfunction.

[0012] Thus, there is a need for compounds which activate mitophagy as potential therapeutic agents for treating diseases or disorders which are responsive to mitophagy activation.

[0013] SUMMARY OF THE INVENTION

[0014] The present invention relates to compounds of formula (I), or a salt thereof123276-03120

[0015]

[0016] wherein:

[0017] Z is (Z-l), (Z-2), or (Z-3),

[0018]

[0019] (Z-1 ) (Z-2 ) ( Z-3 )

[0020] Ring A is phenylene, 6-membered heteroarylene containing one to two nitrogen atoms, (A-l), (A-2), or (A-3),

[0021]

[0022] (*L represents the attachment point to L)

[0023] R1is halo, C1-3 alkyl, -ORla, -CF3, Cs-scycloalkyl, -CN, or 5-membered heteroaryl, Rlais Ci-3alkyl, -CF3, or -CHF2,

[0024] n is 1 or 2,

[0025] R2is C1-5 alkyl, C3-5 cycloalkyl, -CH2OR2a, -OR2a, or (R2-1),

[0026]

[0027] ( R2-1 )

[0028] R2ais 4 to 6-membered heterocycloalkyl or C1-5 alkyl, wherein the C1-5 alkyl is optionally substituted with 1 or 2 groups selected from -OH, -O(Ci-5 alkyl), -CF3, and 4 to 6-membered heterocycloalkyl optionally substituted with -C(=O)-Ci-5 alkyl,

[0029] L is (L-l), (L-2), (L-3), (L-4),(L-5), or (L-6), provided that L is not (L-4) when Z is (Z-3),123276-03120

[0030]

[0031] (* A represents the attachment point to Ring A)

[0032] LI is Ci alkylene optionally substituted with 1 or 2 C1-3 alkyl,

[0033] each L2, L3, and L4 are independently a bond or Ci alkylene optionally substituted with 1 or 2 C1-3 alkyl,

[0034] RLais -N(CI-3alkyl)2, (RLA-1), (RLA-2), (RLA-3), or (RLA-4),

[0035]

[0036] (RLA-1 ) (RLA-2 ) (RLA-3 ) (RLA-4 )

[0037] RLbis H or Ci-3 alkyl, -CH2CH2OH or -CH2CH2O(CI-3 alkyl),

[0038] RLCis H or C1-3 alkyl,

[0039] RLdis H or C1-3 alkyl,

[0040] RLeis H, C1-3 alkyl, or oxo,

[0041] or Ring A, L, and R2may together form (LA-1),

[0042]

[0043] ( LA-1 )

[0044] RLAis C3-4 alkyl.

[0045] Further, unless specifically described otherwise, when symbols in one formula in the present specification are also used in other formulae, same symbols denote same meanings.

[0046] Further, the present invention relates to a pharmaceutical composition for treatment of a mitophagy related disease, comprising the compound of formula (I) or a salt thereof.

[0047] Here, the pharmaceutical composition includes an agent for treatment of a mitophagy related disease, comprising the compound of formula (I) or a salt thereof.

[0048] Furthermore, the present invention relates to a compound of formula (I) or a salt thereof for use as a mitophagy activator; a mitophagy activator comprising a compound of123276-03120

[0049] formula (I) or a salt thereof; use of the compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treatment of a mitophagy related disease; use of the compound of formula (I) or a salt thereof for treatment of a mitophagy related disease; the compound of formula (I) or a salt thereof for use in treatment of a mitophagy related disease; and a method for treatment of a mitophagy related disease, comprising administering to a subject an effective amount of the compound of formula (I) or a salt thereof.

[0050] Here, the “subject” is a human or a non-human animal in need of the treatment, and in one embodiment, a human in need of the treatment.

[0051] DETAILED DESCRIPTION OF THE INVENTION

[0052] Definitions

[0053] In the present specification, “Cnx alkyl” is a linear or branched alkyl group having 1 to X carbon atoms (hereinafter, abbreviated as Cnx), for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or the like. The

[0054] "Ci-x alkyl" is a linear or branched C1-5 alkyl in an embodiment; methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or the like. The "Cnx alkyl" is a linear or branched C1-4 alkyl in an embodiment. The "Cnx alkyl" is a linear or branched Cn 3 alkyl in an another embodiment. The "Cnx alkyl" is a linear or branched C3-4 alkyl in an another embodiment.

[0055] “Cnx alkylene” is a linear or branched Cnx alkylene, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, propylene, 2-m ethyltrimethylene, ethyl ethylene, 1,2-dimethylethylene or 1, 1,2,2-tetramethylethylene. The "Cnx alkylene" is Ci alkylene in an embodiment, i.e. methylene.

[0056] “C3-5 cycloalkyl” is a C3-5 saturated hydrocarbon ring group and may form a bridged bicyclic ring. The "C3-5 cycloalkyl" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, or bicycle[l.l.l]pentanyl. The "C3-5 cycloalkyl" is cyclopropyl in an embodiment.

[0057] “Halogen” or “halo” means F, Cl, Br, or I. The “halogen” or “halo” is F or Cl in an embodiment; F in another embodiment; Cl in yet another embodiment; Br is other embodiment; or I is still other embodiment.

[0058] “5-membered heteroaryl” is a 5-membered aromatic ring which has 1, 2, 3, or 4 heteroatoms selected from N, S, or O, in the ring. Examples of the “5-membered heteroaryl” include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl,123276-03120

[0059] oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. The “5-membered heteroaryl” is isoxazolyl in an embodiment.

[0060] “Oxo” is a group represented by (=0).

[0061] “6-membered heteroarylene containing one to two nitrogen atoms” means a bivalent moiety obtained by removing two hydrogen atoms from a 6-membered aromatic ring which has 1 or 2 nitrogen ring atoms. Examples of “6-membered heteroarylene containing one to two nitrogen atoms” include, but are not limited to, pyridinediyl, pyrazinediyl, pyrimidinediyl or pyridazinediyl. The “6-membered heteroarylene containing one or two nitrogen atoms” is pyridinediyl in an embodiment.

[0062] “4 to 6-membered heterocycloalkyl” is a 4 to 6-membered saturated ring which has 1, 2, 3, or 4 heteroatoms selected from N, S, or O, in the ring. Examples of the

[0063] “4 to 6-membered heterocycloalkyl” include, but are not limited to, oxetanyl, tetrahydropyranyl, morpholinyl, azetidinyl, piperidinyl, pyrrolidinyl, piperazinyl, or tetrahydrofuranyl. The “4 to 6-membered heterocycloalkyl” is oxetanyl or tetrahydropyranyl in an embodiment. The “4 to 6-membered heterocycloalkyl” is morpholinyl, tetrahydropyranyl, or azetidinyl in an embodiment.

[0064] In the present specification, the expression "optionally substituted" includes “which is not substituted" or "which is substituted with one or more substituents”. Substitution may be occurred wherever a hydrogen atom is normally present on the group. In one embodiment, “optionally substituted” is “optionally substituted with 1 to 2 substituents”. In another embodiment, “optionally substituted with one substituent as defined”, for example “optionally substituted with -C(=O)-Ci-5 alkyl”. In case of multiple substitutions, substituents can be the same or different from each other.

[0065] In the present specification, “treatment” includes both “therapeutic treatment” and “prophylactic treatment”. “Therapeutic treatment” means alleviating symptoms, altering the disease course, increasing longevity, etc., and “prophylactic treatment” means reducing the likelihood of contracting the disease in subjects at risk of developing the disease. The “subjects at risk of developing the disease” means individuals with known risk factors that make them more likely to develop the disease than those in the general population.

[0066] The “a mitophagy related disease” or “mitophagy related diseases” herein refers to diseases associated with insufficient mitophagy. The “mitophagy related diseases” include, but is not limited to neurodegenerative diseases, such as Parkinson’s Disease, Dementia, Alzheimer’s Disease, Post-Stroke Cognitive Impairment (PSCI), Amyotrophic Lateral Sclerosis, Huntington’s Disease, Autism, and Epilepsy; Psychiatric Diseases such as123276-03120

[0067] Schizophrenia, Bipolar Disorder, and Depression; Liver Diseases such as Non-Alcoholic Faty Liver Disease and Alcoholic Liver Disease; Kidney Diseases such as Acute Kidney Injury or Chronic Kidney Diseases; Ocular Doseases; Fibrotic Diseases; Metabolic Diseases such as Type 2 Diabetes, Type 1 Diabetes, and Obesity; Cardiovascular Diseases such as Atherosclerosis, Heart Failure, Ischemia-Reperfusion Injury, and Cardiac Hypertrophy; Microvascular Diseases such as Diabetic Retinopathy; Skeletal Muscle Diseases; Aging; Cancer; and Inflammation.

[0068] Some embodiments, including the embodiments described in (1-1) to (3-1) of the compound of formula (I) or a salt thereof in the present invention are described below.

[0069] (1-1) A compound or a salt thereof wherein:

[0070] Ring A is (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), or (A-8),

[0071]

[0072] (A-7 ) (A-8 )

[0073] (* L represents the attachment point to L)

[0074] R1is halo, C1-3 alkyl, -ORla, -CF3, cyclopropyl, -CN, or isoxazolyl,

[0075] Rlais C1-3 alkyl, -CF3, or -CHF2,

[0076] n is 1 or 2,

[0077] R2is C1-5 alkyl, cyclopropyl, -CH2OR2a, -OR2a, or (R2-1),

[0078]

[0079] R2ais oxetanyl, tetrahydropyranyl, or C1-5 alkyl, wherein the C1-5 alkyl is optionally substituted with 1 or 2 groups selected from -OH, -O(Ci-5 alkyl) , -CF3, morpholinyl, tetrahydropyranyl, and azetidinyl optionally substituted with C(=O)-Ci-3 alkyl,

[0080] L is (L-l), (L-2), (L-3), (L-4), (L-5), or (L-6), provided that L is not (L-4) when Z is (Z-3),123276-03120

[0081]

[0082] (* A represents the attachment point to Ring A)

[0083] LI is Ci alkylene optionally substituted with C1-3 alkyl,

[0084] L2, L3 and L4 are the same or different, and are a bond or Ci alkylene optionally substituted with C1-3 alkyl,

[0085] RLais -N(CI-3alkyl)2, (RLA-1), (RLA-2), or (RLA-3),

[0086]

[0087] (RLA-1 ) (RLA-2 ) (RLA-3 )

[0088] RLbis H or Ci-3 alkyl, -CH2CH2OH or -CH2CH2O(CI-3 alkyl),

[0089] RLCis H or C1-3 alkyl,

[0090] RLdis H or C1-3 alkyl,

[0091] RLeis H, C1-3 alkyl, or oxo,

[0092] or Ring A, L and R2may together form (LA-1),

[0093]

[0094] (1-2) A compound or a salt thereof, wherein Z is (z-i), (Z-1 )

[0095]

[0096] (1-3) A compound or a salt thereof, wherein Z is (Z-2), (Z-2 )

[0097]

[0098] (1-4) A compound or a salt thereof, wherein Z is (Z-3), (Z-3 )123276-03120

[0099] (2-1) A compound or a salt thereof, wherein the compound is of Formula (II):

[0100]

[0101] (2-2) A compound or a salt thereof, wherein Lis ° or

[0102]

[0103] RLb, wherein * A represents the attachment point to Ring A.

[0104] (2-3) A compound or a salt thereof, wherein RLais

[0105]

[0106] (2-4) A compound or a salt thereof, wherein

[0107]

[0108]

[0109] , wherein * A represents the attachment point to Ring A.

[0110] (2-5) A compound or a salt thereof, wherein R1is -ORlaor halo, and wherein Rlais Ci-3alkyl or -CF3.

[0111] (2-6) A compound or a salt thereof, wherein R1is -OCF3 or -Cl.

[0112] (2-7) A compound or a salt thereof, wherein Ring A is phenylene

[0113]

[0114] (2-8) A compound or a salt thereof, wherein Ring

[0115]

[0116]

[0117] (2-9) A compound or a salt thereof, wherein R2is -CH2OR2aor -OR2a, and wherein R2ais Ci-4alkyl.123276-03120

[0118] (2-10) A compound or a salt thereof, wherein R2is -CH2OCH(CH3)2, -OCH3, or -OCH2CH(CH3)2.

[0119] (3-1) A compound or a salt thereof which is a combination of two or more embodiments that are not mutually contradictory, among the embodiments of the groups described in (1-1) to (2-10).

[0120] In one embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of formula (I), or a salt thereof:

[0121]

[0122] wherein:

[0123] Z is (Z-l), (Z-2), or (Z-3),

[0124]

[0125] (Z-1 ) (Z-2 ) (Z-3 )

[0126] Ring A is phenylene, 6-membered heteroarylene containing one to two nitrogen atoms, (A-l), (A-2), or (A-3),

[0127]

[0128] (*L represents the attachment point to L)

[0129] R1is halo, C1-3 alkyl, -ORla, -CF3, C3-5 cycloalkyl, -CN, or 5-membered heteroaryl, Rlais Ci-3alkyl, -CF3, or -CHF2,

[0130] n is 1 or 2,

[0131] R2is C1-5 alkyl, C3-5 cycloalkyl, -CH2OR2a, -OR2a, or (R2-1),

[0132]

[0133] ( R2-1 )

[0134] R2ais 4 to 6-membered heterocycloalkyl or C1-5 alkyl, wherein the Ci-salkyl is optionally substituted with 1 or 2 groups selected from -OH, -O(Ci-s alkyl), -CF3, and 4 to 6-membered heterocycloalkyl optionally substituted with -C(=O)-Ci-5 alkyl,123276-03120

[0135] L is (L-1), (L-2), (L-3), (L-4), (L-5), or (L-6), provided that L is not (L-4) when Z is (Z-3),

[0136]

[0137] (* A represents the attachment point to Ring A)

[0138] LI is Ci alkylene optionally substituted with 1 or 2 C1-3 alkyl,

[0139] each L2, L3, and L4 are independently a bond or Ci alkylene optionally substituted with 1 or 2 C1-3 alkyl,

[0140] RLais -N(CI-3alkyl)2, (RLA-1), (RLA-2), (RLA-3), or (RLA-4),

[0141]

[0142] (RLA-1 ) (RLA-2 ) (RLA-3 ) (RLA-4 )

[0143] RLbis H or Ci-3 alkyl, -CH2CH2OH or -CH2CH2O(CI-3 alkyl),

[0144] RLCis H or C1-3 alkyl,

[0145] RLdis H or C1-3 alkyl,

[0146] RLeis H, C1-3 alkyl, or oxo,

[0147] or Ring A, L, and R2may together form (LA-1),

[0148]

[0149] ( LA-1 )

[0150] RLAis C3-4 alkyl.

[0151] Some embodiments, including the embodiments described in (1-1) to (2-10) of the pharmaceutical composition in the present invention are described below.

[0152] (4-1) A pharmaceutical composition, wherein:

[0153] Ring A is (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), or (A-8),123276-03120

[0154]

[0155] (A-7 ) (A-8 )

[0156] (*L represents the attachment point to L)

[0157] R1is halo, C1-3 alkyl, -ORla, -CF3, cyclopropyl, -CN, or isoxazolyl,

[0158] Rlais Ci-3alkyl, -CF3, or -CHF2,

[0159] n is 1 or 2,

[0160] R2is C1-5 alkyl, cyclopropyl, -CH2OR2a, -OR2a, or (R2-1),

[0161]

[0162] R2ais oxetanyl, tetrahydropyranyl, or C1-5 alkyl, wherein the C1-5 alkyl is optionally substituted with 1 or 2 groups selected from -OH, -O(Ci-5 alkyl) , -CF3, morpholinyl, tetrahydropyranyl, and azetidinyl optionally substituted with C(=O)-Ci-3 alkyl,

[0163] L is (L-l), (L-2), (L-3), (L-4), (L-5), or (L-6), provided that L is not (L-4) when Z is (Z-3),

[0164]

[0165] (* A represents the attachment point to Ring A)

[0166] LI is Ci alkylene optionally substituted with C1-3 alkyl,

[0167] L2, L3 and L4 are the same or different, and are a bond or Ci alkylene optionally substituted with C1-3 alkyl,

[0168] RLais -N(CI-3alkyl)2, (RLA-1), (RLA-2), or (RLA-3),123276-03120

[0169]

[0170] (RLA-1 ) (RLA-2 ) (RLA-3 )

[0171] RLbis H or Ci-3 alkyl, -CH2CH2OH or -CH2CH2O(CI-3 alkyl),

[0172] RLCis H or C1-3 alkyl,

[0173] RLdis H or C1-3 alkyl,

[0174] RLeis H, C1-3 alkyl, or oxo,

[0175] or Ring A, L and R2may together form (LA-1),

[0176]

[0177] (4-2) A pharmaceutical composition, wherein Z IS (z-i), (Z-1 )

[0178]

[0179] (4-3) A pharmaceutical composition, wherein Z IS (Z-2), ( Z-2 )

[0180]

[0181] (4-4) A pharmaceutical composition, wherein Z IS

[0182]

[0183] (Z-3 )

[0184] (5-1) A pharmaceutical composition, wherein the compound is of Formula (II):

[0185]

[0186] (5-2) A pharmaceutical composition, wherein L is0or

[0187]

[0188] RLb, wherein * A represents the attachment point to Ring A.

[0189] (5-3) A pharmaceutical composition, wherein RLais

[0190]

[0191] 123276-03120

[0192] (5-4) A pharmaceutical composition, wherein Lis

[0193]

[0194]

[0195] , wherein * A represents the attachment point to Ring A.

[0196] (5-5) A pharmaceutical composition, wherein R1is -ORlaor halo, and wherein Rlais Ci-3alkyl or -CF3.

[0197] (5-6) A pharmaceutical composition, wherein R1is -OCF3 or -Cl.

[0198] (5-7) A pharmaceutical composition, wherein Ring A is phenylene

[0199]

[0200] (5-8) A pharmaceutical composition, wherein Ring

[0201]

[0202]

[0203] (5-9) A pharmaceutical composition, wherein R2is -CH2OR2aor -OR2a, and wherein R2ais Ci-4alkyl.

[0204] (5-10) A pharmaceutical composition, wherein R2is -CH2OCH(CH3)2, -OCH3, or -OCH2CH(CH3)2.

[0205] (6-1) A pharmaceutical composition which is a combination of two or more embodiments that are not mutually contradictory, among the embodiments of the groups described in (4-1) to (5-10).

[0206] Examples of the specific compounds included in the present invention include the following compounds (Examples 1-97) either in free base form or salts thereof.

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[0294]

[0295] With regard to the compounds of formula (I), tautomers or geometrical isomers thereof may exist, depending on the kinds of the substituents. In the present specification, the compound of formula (I) and salts thereof may be described in only one form of isomers in some cases, but the present invention includes other isomers, isolated forms of the isomers, or a mixture thereof.

[0296] Compounds having one or more chiral centers can exist in various stereoisomeric forms, / .< ., each chiral center can have an R or S configuration, or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.

[0297] When a compound is designated by its chemical name (e.g., where the configuration is indicated in the chemical name by “7?” or “5”) or its structure (e.g., the configuration is indicated by “wedge” bonds) that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

[0298] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the123276-03120

[0299] total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0300] “Peak 1” in the Experimental section refers to an intended reaction product compound obtained from a chromatography separation / purifi cation that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended product compound is referred to as “peak 2”.

[0301] Moreover, the salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I), and the compounds of formula (I) may form an acid addition salt or a salt with a base, depending on the kinds of the substituents in some cases. Specifically, examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and with organic acids such as acetic, benzenesulfonic, benzoic, ethanesulfonic, methanesulfonic, and succinic acids, and salts with metal anions such as sodium, potassium, magnesium, calcium, and aluminum, and with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, salts with various amino acids such as acetyl leucine, or derivatives of amino acids, ammonium salts, and others.

[0302] Pharmaceutically acceptable salts of compounds of any one of the formulae described above may be prepared by one or more of three methods:

[0303] (i) by reacting the compound of any one of the formulae described above with the desired acid or base;

[0304] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of any one of the formulae described above or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or

[0305] (iii) by converting one salt of the compound of any one of the formulae described above to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[0306] All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.

[0307] Pharmaceutical Compositions

[0308] A pharmaceutical composition comprising one or two or more kinds of the compound of formula (I) as an active ingredient can be prepared using a pharmaceutically acceptable carrier or excipient which is usually used in the art, that is, an excipient for a pharmaceutical123276-03120

[0309] preparation, a carrier for a pharmaceutical preparation, and the like, according to a method usually used.

[0310] Administration can be accomplished either by oral administration via tablets, pills, capsules, granules, powders, solutions, and the like, or parenteral administration via injections, such as intraarticular, intravenous, and intramuscular injections, suppositories, ophthalmic solution, ophthalmic ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalers, and the like.

[0311] As a solid composition for oral administration, tablets, powders, granules, and the like are used. In such a solid composition, one kind or two or more kinds of the active ingredients are mixed with at least one excipient. In a conventional method, the composition may contain excipients such as a lubricant, a disintegrating agent, a stabilizer, or a solubilization assisting agent. If necessary, tablets, powders and granule may be coated with a wax, a sugar or with a film of a gastric or enteric coating substance.

[0312] The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and also includes generally used diluents, for example, purified water or ethanol. The liquid composition may also include excipients such as a solubilization assisting agent, a moistening agent, a suspending agent, sweeteners, flavors, aromatics, and antiseptics.

[0313] The injections for parenteral administration include sterile aqueous or non-aqueous solution preparations, suspensions, or emulsions. The aqueous solvent includes, for example, distilled water for injection and saline. Examples of the non-aqueous solvent include alcohols such as ethanol. Such a composition may further include a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing assisting agent. These are sterilized, for example, by filtration through a bacteria retaining filter, blending of a bactericide, or irradiation. In addition, these can also be used by preparing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use.

[0314] Examples of the vehicle for external use include ointments, hard plasters, creams, jellies, cataplasms, sprays, lotions, ophthalmic solution, ophthalmic ointments, and the like. The vehicle further contains generally used ointment bases, lotion bases, aqueous or nonaqueous liquid preparations, suspensions, emulsions, and the like.

[0315] As the transmucosal agents such as an inhaler and a transnasal agent, those in the form of a solid, liquid, or semi-solid state are used, and can be prepared in accordance with a123276-03120

[0316] method known in the related art. For example, a known excipient, and also a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizing agent, a thickening agent, and the like may be appropriately added thereto. For the administration, an appropriate device for inhalation or blowing can be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a known device or sprayer such as a metered administration inhalation device. A dry powder inhaler and the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, this may be in a form such as a pressurized aerosol spray that uses an appropriate propellant agent, for example, a suitable gas such as chlorofluoroalkanes, carbon dioxide, or other forms.

[0317] Usually, in the case of oral administration, the daily dose is from about 0.001 mg / kg to 100 mg / kg, as an embodiment from 0.1 mg / kg to 30 mg / kg, and as another embodiment from 0.1 mg / kg to 10 mg / kg, per body weight, administered in one portion or in 2 to 4 divided portions. In the case of intravenous administration, the daily dose is suitably administered from about 0.0001 mg / kg to 10 mg / kg per body weight, once a day or two or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 mg / kg to 100 mg / kg per body weight, once or plural times a day. The dose is appropriately decided in response to the individual case by taking the symptoms, the age, and the gender, and the like into consideration.

[0318] Although there are differences depending on a route of administration, a dosage form, an administration site, and a type of the excipient or additive, a pharmaceutical composition of the present invention comprises 0.01% by weight to 100% by weight of, as an embodiment, 0.01% by weight to 50% by weight of, one or more of the compound of formula (I) or a salt thereof which is the active ingredient.

[0319] The compound of formula (I) may be used in combination with various agents for treating diseases on which the compound of formula (I) is considered to show the effect. Such combined preparations may be administered simultaneously, or separately and consecutively, or at a desired time interval. The preparations to be co-administered may be a blend, or may be prepared individually.

[0320] Exemplification

[0321] The production process for the compound of formula (I) will be described in more detail below with reference to Examples. The present invention is not limited to the123276-03120

[0322] compounds described in the Examples below. Further, the production processes for the starting compounds will be described in Preparation Examples, and the production processes for the known compounds will be described in Reference Examples. In addition, the production processes for the compound of formula (I) are not limited to the production processes of the specific Examples shown below, but the compound of formula (I) can be prepared by a combination of these production processes or a method that is apparent to a person skilled in the art.

[0323] Example 1: Synthesis of N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxamide

[0324]

[0325] Example 1

[0326] Step-1: Synthesis of ethyl l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxylate To a mixture of ethyl piperidine-4-carboxylate (1.04 g, 6.62 mmol) and triethylamine (1.34 g, 13.24 mmol) in DCM (25 mL) was added 2-(trifluorom ethoxy )benzene-l -sulfonyl chloride (1.81 g, 6.95 mmol) at 0 °C. The reaction was stirred for 2 hours allowing too warm to room temperature. The reaction mixture was diluted with methylene chloride, washed with aqueous sodium carbonate solution (I M) and water. The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound, which was used in consecutive reaction steps without further purification. Yield: 2.46 g. LCMS: m / z 382.0 [M+H]+.

[0327] Step-2: Synthesis of l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxylic acid123276-03120

[0328] To a suspension of crude ethyl l-((2-(trifluorom ethoxy )phenyl)sulfonyl)piperi dine-4-carboxylate (2.46 g) in waterTHF (35 mL; 1:2.5) was added lithium hydroxide monohydrate (0.54 g, 12.87 mmol), and the resulting mixture was stirred at room temperature for 18 hours. After removal of THF under reduced pressure, the residual aqueous solution was diluted with water and acidified to pH 2. The resulting precipitate was filtered, washed with water and dried under reduced pressure to afford the title compound as a colourless solid. Yield: 2.00 g, 5.66 mmol, 85% over 2 steps. LCMS: m / z 354.0 [M+H]+.

[0329] Step-3 : Synthesis of N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxamide, Example 1

[0330] A mixture of (3-[(ethylimino)methylidene]aminopropyl)dimethylamine hydrochloride (0.42 g, 2.18 mmol), 2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethan-l -amine (0.40 g, 1.82 mmol), and lH-l,2,3-benzotriazol-l-ol (0.32 g, 2.36 mmol) in DMF (4 mL) was stirred at room temperature for 10 minutes before l-((2-(trifluorom ethoxy )phenyl)sulfonyl)piperidine-4-carboxylic acid (0.67 g, 1.91 mmol) was added. The resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 10 mL). The organic phases were combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC to afford Example 1. Yield: 0.457 g, 0.82 mmol, 42%. LCMS: m / z 556.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.91 (dd, J= 8.0, 1.5 Hz, 1H), 7.80 (td, J= 8.0, 1.5 Hz, 1H), 7.63-7.55 (m, 2H), 7.47 (t, J= 6.0 Hz, 1H), 7.18-7.14 (m, 1H), 6.78-6.73 (m, J= 7.0 Hz, 3H), 3.69 (s, 3H), 3.60-3.48 (m, 3H), 3.22-3.18 (m, 1H), 3.16-3.10 (m, 1H), 2.62-2.54 (m, 2H), 2.47-2.40 (m, 2H), 2.31-2.24 (m, 2H), 2.14-2.06 (m, 1H), 1.64-1.48 (m, 6H), 1.44-1.28 (m, 2H).123276-03120

[0331] Example 2: 7V-[2-(3-methoxyphenyl)-2-(piperidin-l-yl)ethyl]-l-(4-methylbenzenesulfonyl)piperidine-4-carboxamide

[0332]

[0333] Example 2

[0334] Step 1: 2-(3-methoxyphenyl)-2-(piperidin-l-yl)acetonitrile

[0335] To a stirred solution of 3 -methoxybenzaldehyde (1.99 g, 14.65 mmol) and 2 -hydroxy -2-methylpropanenitrile (1.23 g, 14.65 mmol) in water (50 mL), piperidine (1.25 g, 14.65 mmol) was added and stirred at room temperature for 18 hours. The mixture was extracted with MTBE (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. Yield: 2.85 g, 12.37 mmol, 84%). 'H NMR (400 MHz, CDC13) 87.27 (m, 1H), 7.18-7.05 (m, 2H), 6.94-6.83 (m, 1H), 4.77 (s, 1H), 3.81 (s, 3H), 2.59-2.45 (m, 4H), 1.70- 1.45 (m, 6H).

[0336] Step 2: Synthesis of 2-(3-m ethoxyphenyl)-2-(piperi din- l-yl)ethan-l -amine

[0337] A stirred solution of lithium aluminium hydride (0.20 g, 5.27 mmol) in dry THF (10 mL) was cooled to 0 °C before the dropwise addition of 2-(3-methoxyphenyl)-2-(piperidin-l-yl)acetonitrile (1.04 g, 4.52 mmol) in THF (10 mL). The mixture was then heated to 60 °C and stirred 2 hours. The reaction mixture was cooled to 0 °C before the dropwise addition of water (1.2 mL) followed by 2M NaOH (2 mL). The mixture was allowed to warm to room temperature and stirred for 30 minutes. The solid was filtered and washed with ethyl acetate (3 x 10 mL) and concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield 0.07 g. LCMS: m / z'. 235.2 [M+H]+.

[0338] Step 3: Synthesis of A-[2-(3-methoxyphenyl)-2-(piperidin-l-yl)ethyl]-l-(4-methylbenzenesulfonyl)piperidine-4-carboxamide, Example 2123276-03120

[0339] To a stirred solution of crude 2-(3-methoxyphenyl)-2-(piperidin-l-yl)ethan-l -amine (70 mg), l-(4-methylbenzenesulfonyl)piperidine-4-carboxylic acid (84 mg, 0.29 mmol) and diisopropylethylamine (192 mg, 1.49 mmol) in anhydrous DMF (10 mL), HATU (136 mg, 0.36 mmol) was added in one portion. The resulting mixture was stirred for 18 hours at room temperature. The mixture was concentration under reduced pressure. The residue was purified by HPLC to afford Example 2. Yield: 63 mg, 0.12 mmol, 2% over 2 steps. LCMS: m / z 500.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.58 (d, J= 8.0 Hz, 2H), 7.45-7.35 (m, 3H), 7.18 (t, J= 8.0 Hz, 1H), 6.79 (d, J= 7.5 Hz, 1H), 6.75-6.65 (m, 2H), 3.71 (s, 3H), 3.55-3.40 (m, 5H), 2.39 (s, 3H), 2.35-2.12 (m, 6H), 2.05-1.95 (m, 1H), 1.65-1.51 (m, 2H), 1.48-1.18 (m, 9H).

[0340] Example 5: l-((4-chlorophenyl)sulfonyl)-N-(2-(pyrrolidin-l-yl)-2-(3- (trifluoromethoxy)phenyl)ethyl)piperidine-4-carboxamide

[0341] <

[0342]

[0343] Example 5

[0344] Step 1 : 2-(pyrrolidin-l-yl)-2-(3-(trifluoromethoxy)phenyl)acetonitrile

[0345] The title compound was synthesized in the same manner as step 1 of Example 2. Yield: 1.47 g, 5.45 mmol, 88%. 'HNMR (500 MHz, CDC13) 67.49 (d, J= 7.5 Hz, 1H), 7.45-7.40 (m, 2H), 7.22 (d, J= 8.0 Hz, 1H), 5.07 (s, 1H), 2.72-2.59 (m, 4H), 1.92-1.77 (m, 4H). Step 2: Synthesis of 2-(pyrrolidin-l-yl)-2-(3-(trifluoromethoxy)phenyl)ethan-l -amine dihydrochloride

[0346] A stirred solution of cobalt(II) chloride hexahydrate (131.5 mg, 0.55 mmol) in methanol (30 mL) was cooled to -10 °C before the addition of 2-(pyrrolidin-l-yl)-2-(3-(trifluoromethoxy)phenyl)acetonitrile (0.50 g, 1.85 mmol). After 10 minutes, sodium borohydride (422.4 mg, 11.16 mmol) was added in 3 equal portions over a period of 30123276-03120

[0347] minutes. To the reaction mixture, di -tert-butyl dicarbonate (445.2 mg, 2.04 mmol) was added and stirred for 18 hours at room temperature. The reaction was quenched by the slow addition of ammonium hydroxide (10 mL). The mixture was filtered, and the solid washed with methanol (10 mL) before the filtrate was concentrated under reduced pressure. The aqueous residue was extracted with EtOAc (4 x 10 mL), the combined organic phases were washed with brine (2 x 10 mL), dried over sodium sulfate and concentrated under reduced pressure. To the crude residue, 1,4-di oxane (2 mL) was added followed by hydrogen chloride solution in dioxane (4M, 10 mL). The reaction mixture was stirred at room temperature for 5 hours. The solution was concentrated under reduced pressure to afford the title compound which was used without further purification. Yield: 0.20 g. LCMS: m / z'. 275.0 [M+H]+.

[0348] Step 3: Synthesis of l-((4-chlorophenyl)sulfonyl)-N-(2-(pyrrolidin-l-yl)-2-(3-(trifluoromethoxy)phenyl)ethyl)piperidine-4-carboxamide, Example 5.

[0349] Example 5 was synthesized in the same manner of step 3 for Example 2. Yield: 0.03 g, 0.05 mmol, 3% over 2 steps. LCMS: m z 560.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.74-7.66 (m, 4H), 7.55-7.50 (m, 1H), 7.41-7.36 (m, 1H), 7.25-7.16 (m, 2H), 7.14 (s, 1H), 3.59-3.38 (m, 3H), 3.22-3.14 (m, 1H), 2.30-2.22 (m, 4H), 2.02-1.93 (m, 1H), 1.67-1.57 (m, 4H), 1.54-1.45 (m, 2H), 1.44-1.30 (m, 2H).

[0350] Example 6: l-((4-chlorophenyl)sulfonyl)-N-(2-(3-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0351]

[0352]

[0353]

[0354] Example 6

[0355] Step 1: 2-(3-isobutoxyphenyl)-2-(pyrrolidin-l-yl)acetonitrile

[0356] The title compund was synthesized in the same manner as step 1 of Example 2. Yield: 0.85 g, 3.29 mmol, 59%. 'H NMR (400 MHz, CDC13) 87.33-7.25 (m, 1H), 7.14-7.05 (m,123276-03120

[0357] 1H), 6.95-6.86 (m, 1H), 5.05-5.01 (m, 1H), 3.77-3.69 (m, 2H), 2.74-2.60 (m, 4H), 2.17-2.03 (m, 1H), 1.90-1.80 (m, 4H), 1.11-1.01 (m, 6H).

[0358] Step 2: Synthesis of 2-(3-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethan-l-amine dihydrochloride The title compound was synthesized in the same manner as step 2 of Example 5. Yield: 0.65 g. LCMS: m / z 263.0 [M+H]+.

[0359] Step 3: Synthesis of l-((4-chlorophenyl)sulfonyl)-N-(2-(3-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 6.

[0360] Example 6 was synthesized in the same manner of step 3 for Example 2. Yield: 0.03 g, 0.06 mmol, 4% over 2 steps. LCMS: m / z 554.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 8 7.90 (dd, J= 8.0, 1.5 Hz, 1H), 7.87-7.76 (m, 1H), 7.70-7.54 (m, 2H), 7.46 (t, J= 6.0 Hz, 1H), 7.12-7.05 (m, 4H), 3.62-3.45 (m, 3H), 3.24-3.1 (m, 2H), 2.63-2.51 (m, 4H), 2.45-2.30 (m, 5H), 2.13- .03 (m, 1H), 1.64-1.20 (m, 8H), 1.13 (t, J= 7.5 Hz, 3H).

[0361] Example 7: N-(2-(4-ethylphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2- (trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxamide

[0362]

[0363] Example 7 was synthesized in the same manner of step 3 for Example 1. Yield: 0.07 g, 0.14 mmol, 49%. LCMS: m / z 554.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.90 (dd, J= 8.0, 1.5 Hz, 1H), 7.87-7.76 (m, 1H), 7.70-7.54 (m, 2H), 7.46 (t, J= 6.0 Hz, 1H), 7.12-7.05 (m, 4H), 3.62-3.45 (m, 3H), 3.24-3.1 (m, 2H), 2.63-2.51 (m, 4H), 2.45-2.30 (m, 5H), 2.13- .03 (m, 1H), 1.64-1.20 (m, 8H), 1.13 (t, J= 7.5 Hz, 3H).123276-03120

[0364] Example 8: l-((2-chlorophenyl)sulfonyl)-N-(2-(4-ethylphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0365]

[0366] Example 8

[0367] Step 1: ethyl l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxylate

[0368] The title compound was synthesized in the same manner as step 1 of Example 1. Yield: 1.65 g. LCMS: m / z 332.0 [M+H]+.

[0369] Step 2: Synthesis of l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxylic acid

[0370] The title compound was synthesized in the same manner as step 2 of Example 1. Yield: 1.50 g, 4.94 mmol, 66% over 2 steps. LCMS: m / z 304.0 [M+H]+.

[0371] Step 3: Synthesis of l-((2-chlorophenyl)sulfonyl)-N-(2-(4-ethylphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 8.

[0372] Example 8 was synthesized in the same manner of step 3 for Example 1. Yield: 4.6 mg, 0.009 mmol, 1.2%. LCMS: m / z 504.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.94 (dd, J= 8.0, 1.5 Hz, 1H), 7.71-7.61 (m, 2H), 7.57-7.45 (m, 2H), 7.09 (m, 4H), 3.61-3.48 (m, 3H), 3.24-3.09 (m, 2H), 2.74-2.64 (m, 2H), 2.54 (q, J= 7.5 Hz, 2H), 2.44-2.22 (m, 5H), 2.16- 2.06 (m, 1H), 1.64-1.43 (m, 6H), 1.41-1.25 (m, 2H), 1.13 (t, J= 7.5 Hz, 3H).123276-03120

[0373] Example 9: l-((2-chlorophenyl)sulfonyl)-N-(2-(4-cyclopropylphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0374]

[0375] Step 1: Synthesis of l-((2-chlorophenyl)sulfonyl)-N-(2-(4-cyclopropylphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 9.

[0376] Example 9 was synthesized in the same manner of step 3 for Example 2. Yield: 0.03 g, 0.07 mmol, 7%. LCMS: m / z 516.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.76-7.62 (m, 2H), 7.54 (m, 1H), 7.49-7.44 (m, 1H), 7.06 (d, J= 8.0 Hz, 2H), 6.95 (d, J= 8.0 Hz, 2H), 3.62-3.50 (m, 3H), 3.20-3.05 (m, 2H), 2.72-2.66 (m, 2H), 2.44-2.37 (m, 2H), 2.28-2.20 (m, 2H), 2.20-2.02 (m, 1H), 1.88-1.80 (m, 1H), 1.62-1.45 (m, 6H), 1.42-1.26 (m, 2H), 0.90-0.84 (m, 2H), 0.62-0.57 (m, 2H).

[0377] Example 10: l-((2-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0378]

[0379] 123276-03120

[0380] Step 1: ethyl l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxylate

[0381] The title compound was synthesized in the same manner as step 1 of Example 1. Yield: 1.65 g. LCMS: m / z 332.0 [M+H]+.

[0382] Step 2: Synthesis of l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxylic acid

[0383] The title compound was synthesized in the same manner as step 2 of Example 1. Yield: 1.50 g, 4.94 mmol, 67% over 2 steps. LCMS: m / z 304.0 [M+H]+.

[0384] Step 3: Synthesis of l-((2-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 10.

[0385] Example 10 was synthesized in the same manner of step 3 for Example 1. Yield: 0.04 g, 0.08 mmol, 6%. LCMS: m / z 506.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.94 (d, J = 8.0 Hz, 1H), 7.71-7.62 (m, 2H), 7.56-7.46 (m, 2H), 7.16 (t, J= 8.0 Hz, 1H), 6.82-6.74 (m, 3H), 3.69 (s, 3H), 3.62-3.50 (m, 3H), 3.24-3.09 (m, 2H), 2.74-2.66 (m, 2H), 2.32-2.25 (m, 2H), 2.18-2.10 (m, 1H), 1.65-1.45 (m, 6H), 1.42-1.30 (m, 2H).

[0386] Example 11: l-((2-ethylphenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0387]

[0388] Example 11

[0389] Step 1: Synthesis of l-((2-ethylphenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 11.

[0390] Example 11 was synthesized in the same manner of step 3 for Example 2. Yield: 0.10 g, 0.19 mmol, 29%. LCMS: m / z 500.2 [M+H]+. 'll NMR (500 MHz, d6-DMSO) 67.74 (dd, J= 8.0, 1.0 Hz, 1H), 7.62-7.56 (m, 1H), 7.51-7.43 (m, 2H), 7.39 (t, J= 7.5 Hz, 1H), 7.20-7.14 (m, 1H), 6.82-6.68 (m, 3H), 3.69 (s, 3H), 3.58-3.40 (m, 3H), 3.23-3.19 (m, 1H), 3.16-3.10 (m, 1H), 2.91 (q, J= 7.5 Hz, 2H), 2.63-2.51 (m, 4H), 2.47-2.39 (m, 3H), 2.32-2.25 (m, 2H), 2.15-2.08 (m, 1H), 1.66-1.47 (m, 6H), 1.43-1.31 (m, 2H), 1.18 (t, J= 7.5 Hz, 3H).123276-03120

[0391] Example 12: l-((2-chlorophenyl)sulfonyl)-N-(2-(dimethylamino)-2-(4-isobutoxyphenyl)ethyl)piperidine-4-carboxamide

[0392]

[0393] Step 1: 2-(dimethylamino)-2-(4-isobutoxyphenyl)acetonitrile

[0394] The title compound was synthesized in the same manner as step 1 of Example 2. Yield: 0.99 g, 4.26 mmol, 76%. 'H NMR (400 MHz, CDC13) 87.46-7.40 (m, 2H), 6.96-6.89 (m, 2H), 4.82 (s, 1H), 3.75 (d, J= 6.5 Hz, 2H), 2.34 (s, 6H), 2.17-2.06 (m, 1H), 1.05 (d, J = 6.5 Hz, 6H).

[0395] Step 2: Synthesis of l-(4-isobutoxyphenyl)-Nl,Nl -dimethylethane- 1,2-diamine dihydrochloride

[0396] The title compound was synthesized in the same manner as step 2 of Example 5. Yield: 0.70 g. LCMS: m / z 237.0 [M+H]+.

[0397] Step 3: Synthesis of l-((2-chlorophenyl)sulfonyl)-N-(2-(dimethylamino)-2-(4-isobutoxyphenyl)ethyl)piperidine-4-carboxamide, Example 12.

[0398] Example 12 was synthesized in the same manner of step 3 for Example 2. Yield: 0.05 g, 0.09 mmol, 5% over 2 steps. LCMS: m / z 522.2 [M+H]+. 'll NMR (500 MHz, d6-DMSO) 67.94 (dd, J= 8.0, 1.5 Hz, 1H), 7.71-7.62 (m, 2H), 7.56-7.45 (m, 2H), 7.06 (d, J= 8.5 Hz, 2H), 6.83 (d, J= 8.5 Hz, 2H), 3.69 (d, J= 6.5 Hz, 2H), 3.62-3.56 (m, 2H), 3.48-3.42 (m, 1H), 2.73-2.65 (m, 2H), 2.19-2.12 (m, 1H), 2.03-1.92 (m, 7H), 1.60-1.50 (m, 2H), 1.43-1.32 (m, 2H), 0.95 (d, J = 6.5 Hz, 6H).123276-03120

[0399] Example 13: 1 -((2-chl orophenyl)sulfonyl)-N-(2-(3-(2 -methoxy ethoxy)phenyl)-2-(pyrrolidin- l-yl)ethyl)piperidine-4-carboxamide

[0400]

[0401] Step 1: 3-(2-methoxyethoxy)benzaldehyde

[0402] To a stirred solution of 3 -hydroxybenzaldehyde (1.50 g, 12.28 mmol) and l-bromo-2-methoxyethane (1.87 g, 13.50 mmol) in DMF (30 mL), potassium carbonate (2.54 g, 18.42 mmol) was added. The reaction mixture was heated to 80 °C and stirred for 18 h. The reaction mixture was cooled before dilution with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (3 x 15 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. Yield: 1.61 g, 8.96 mmol, 73%. 'H NMR (400 MHz, CDC13) 89.98 (s, 1H), 7.52-7.35 (m, 3H), 7.30-7.20 (m, 1H), 4.24-4.09 (m, 2H), 3.86-3.76 (m, 2H), 3.48 (s, 3H).

[0403] Step 2 : 2-(3 -(2-methoxy ethoxy)phenyl)-2-(pyrroli din- 1 -yl)acetonitrile

[0404] The title compound was synthesized in the same manner as step 1 of Example 2.

[0405] Yield: 1.35 g, 5.22 mmol, 52%. Hl NMR (400 MHz, CDCI3) 67.33-7.18 (m, 1H), 7.18-7.03 (m, 2H), 7.01-6.79 (m, 1H), 4.99 (s, 1H), 4.20-4.08 (m, 2H), 3.83-3.70 (m, 2H), 3.44 (s, 3H), 2.69-2.58 (m, 4H), 1.86-1.75 (m, 4H).

[0406] Step 3: Synthesis of 2-(3 -(2 -methoxy ethoxy)phenyl)-2-(pyrrolidin-l-yl)ethan-l -amine dihydrochloride

[0407] The title compound was synthesized in the same manner as step 2 of Example 5.

[0408] Yield: 0.41 g. LCMS: m / r. 265.0 [M+H]+.123276-03120

[0409] Step 4: Synthesis of l-((2-chlorophenyl)sulfonyl)-N-(2-(3-(2-methoxy ethoxy )phenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 13.

[0410] Example 13 was synthesized in the same manner of step 3 for Example 2. Yield: 0.04 g, 0.06 mmol, 2% over 2 steps. LCMS: m / z 550.2 [M+H]+. 'll NMR (500 MHz, d6-DMSO) 67.94 (d, J= 8.0 Hz, 1H), 7.71-7.62 (m, 2H), 7.56-7.47 (m, 2H), 7.15 (t, J= 8.0 Hz, 1H), 6.79-6.73 (m, 3H), 4.06-3.98 (m, 2H), 3.64-3.51 (m, 6H), 3.24-3.09 (m, 2H), 2.72-2.63 (m, 2H), 2.32-2.24 (m, 2H), 2.16-2.09 (m, 1H), 1.65-1.45 (m, 6H), 1.40-1.30 (m, 2H).

[0411] Example 14: (R or S)-l-((2-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0412]

[0413] Step 1: Synthesis of (R or S)-l-((2-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 14.

[0414] Example 14 was synthesized in the same manner of step 3 for Example 1.

[0415] Yield: 0.04 g, 0.08 mmol, 6%. LCMS: m / z 506.2 [M+H]+.1H NMR (500 MHz, d6-DMSO) 87.94 (d, J= 8.0 Hz, 1H), 7.71-7.62 (m, 2H), 7.58-7.46 (m, 2H), 7.16 (t, J= 8.0 Hz, 1H), 6.79-6.73 (m, 3H), 3.69 (s, 3H), 3.60-3.50 (m, 3H), 3.24-3.10 (m, 2H), 2.74-2.68 (m, 2H), 2.32-2.26 (m, 2H), 2.18-2.09 (m, 1H), 1.65-1.45 (m, 6H), 1.42-1.30 (m, 2H).

[0416] Example 15: (R or S)-l-((2-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0417]

[0418] Step 1: Synthesis of (R or S)-l-((2-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 15.123276-03120

[0419] Example 15 was synthesized in the same manner of step 3 for Example 1.

[0420] Yield: 0.04 g, 0.08 mmol, 6%. LCMS: m / z 506.2 [M+H]+.1H NMR (500 MHz, d6-DMSO) 67.94 (d, J= 8.0 Hz, 1H), 7.72-7.61 (m, 2H), 7.58-7.46 (m, 2H), 7.16 (t, J= 8.0 Hz, 1H), 6.79-6.72 (m, 3H), 3.69 (s, 3H), 3.61-3.50 (m, 3H), 3.24-3.10 (m, 2H), 2.74-2.68 (m, 2H), 2.32-2.26 (m, 2H), 2.18-2.09 (m, 1H), 1.65-1.45 (m, 6H), 1.42-1.29 (m, 2H).

[0421] Example 16: l-((2-chlorophenyl)sulfonyl)-N-(2-(6-methoxypyri din-2 -yl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0422]

[0423] Step 1 : 2-(6-methoxypyri din-2 -yl)-2-(pyrrolidin-l-yl)acetonitrile

[0424] The title compound was synthesized in the same manner as step 1 of Example 2. Yield: 1.26 g, 5.80 mmol, 79%. 'H NMR (400 MHz, CDC13) 67.62-7.53 (m, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.69 (d, J= 8.0 Hz, 1H), 5.06 (s, 1H), 3.95 (s, 3H), 2.77-2.67 (m, 4H), 1.89-1.80 (m, 4H).

[0425] Step 2: Synthesis of 2-(6-m ethoxypyri din-2 -yl)-2-(pyrrolidin-l-yl)ethan-l -amine dihydrochloride

[0426] The title compound was synthesized in the same manner as step 2 of Example 5. Yield: 0.50 g. LCMS: m / z 1Q [M+H]+.

[0427] Step 3: Synthesis of l-((2-chlorophenyl)sulfonyl)-N-(2-(6-methoxypyridin-2-yl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 16.

[0428] Example 16 was synthesized in the same manner of step 3 for Example 2. Yield: 0.08 g, 0.15 mmol, 1% over 2 steps. LCMS: m / z 507.2 [M+H]+. 'll NMR (500 MHz, d6-DMSO) 87.94 (d, J= 7.5 Hz, 1H), 7.70-7.45 (m, 5H), 6.82 (d, J= 7.5 Hz, 1H), 6.63 (d, J= 8.0 Hz, 1H), 3.80 (s, 3H), 3.61-3.55 (m,3H), 3.49-3.45 (m, 1H), 2.70-2.65 (m, 2H), 2.38-2.33 (m, 2H), 2.18-2.12 (m, 1H), 1.60-1.50 (m, 6H), 1.40-1.30 (m, 2H).123276-03120

[0429] Example 17: l-((2-chlorophenyl)sulfonyl)-N-(2-(3,3-dimethylazetidin-l-yl)-2-(3-methoxyphenyl)ethyl)piperidine-4-carboxamide

[0430]

[0431] Example 17 Step 1 : 2-(3,3-dimethylazetidin-l-yl)-2-(3-methoxyphenyl)acetonitrile

[0432] The title compound was synthesized in the same manner as step 1 of Example 2. Yield: 1.22 g, 5.31 mmol, 77%. 'H NMR (400 MHz, CDC13) 67.33-7.24 (m, 1H), 7.10-6.98 (m, 2H), 6.93-6.85 (m, 1H), 4.69 (s, 1H), 3.82 (s, 3H), 3.23-2.98 (m, 4H), 1.25 (s, 6H). Step 2 : 2-(3 , 3 -dimethylazetidin- 1 -yl)-2-(3 -methoxyphenyl)ethan- 1 -amine

[0433] A stirred solution of cobalt(II) chloride hexahydrate (0.42 g, 1.77 mmol) in methanol (100 mL) was cooled to -10 °C before the addition of 2-(3, 3 -dimethylazetidin- 1 -yl)-2-(3 -methoxyphenyl)acetonitrile (1.22 g, 5.31 mmol). After 10 minutes, sodium borohydride (1.35 g, 35.44 mmol) was added in 3 equal portions over a period of 30 minutes. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched by the slow addition of IM sodium hydroxide solution (50 mL). The mixture was filtered, and the solid washed with methanol (30 mL) before the filtrate was concentrated under reduced pressure. The aqueous residue was extracted with EtOAc (3 x 30 mL), the combined organic phases were washed with brine (2 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound which was used in consecutive reaction steps without further purification. Yield: 0.20 g. LCMS: m / r. 235.0 [M+H]+.

[0434] Step 3: Synthesis of l-((2-chlorophenyl)sulfonyl)-N-(2-(3, 3 -dimethylazetidin- l-yl)-2-(3-methoxyphenyl)ethyl)piperidine-4-carboxamide, Example 17.123276-03120

[0435] Example 17 was synthesized in the same manner of step 3 for Example 2. Yield: 0.06 g, 0.10 mmol, 1% over 2 steps. LCMS: m / z 520.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.95 (d, J= 8.0 Hz, 1H), 7.70-7.62 (m, 2H), 7.60-7.50 (m, 2H), 7.16 (t, J= 8.0 Hz, 1H), 6.86-6.72 (m, 3H), 3.69 (s, 3H), 3.65-3.55 (m, 2H), 3.27-3.20 (m, 2H), 2.88-2.79 (m, 3H), 2.78-2.67 (m, 4H), 2.20-2.12 (m, 1H), 1.65-1.58 (m, 2H), 1.49-1.35 (m, 2H), 1.12 (s, 6H).

[0436] Example 18: l-((2-chlorophenyl)sulfonyl)-N-(2-(6-isobutoxypyridin-3-yl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0437]

[0438] Step 1 : 2-(6-isobutoxypyridin-3-yl)-2-(pyrrolidin-l-yl)acetonitrile

[0439] The title compound was synthesized in the same manner as step 1 of Example 2. Yield: 0.84 g, 3.24 mmol, 53%. 'H NMR (500 MHz, CDC13) 88.25 (d, J= 2.5 Hz, 1H), 7.68 (dd, J= 8.5, 2.5 Hz, 1H), 6.75 (d, J= 8.6 Hz, 1H), 4.95 (s, 1H), 4.06 (d, J= 6.5 Hz, 2H), 2.69-2.57 (m, 4H), 2.12-2.04 (m, 1H), 1.90-1.79 (m, 4H), 1.01 (d, J= 6.5 Hz, 6H).

[0440] Step 2: Synthesis of 2-(6-isobutoxypyridin-3-yl)-2-(pyrrolidin-l-yl)ethan-l-amine

[0441] A stirred solution of cobalt(II) chloride hexahydrate (300.9 mg, 1.27 mmol) in methanol (45 mL) was cooled to -10 °C before the addition of 2-(6-isobutoxypyridin-3-yl)-2-(pyrrolidin-l-yl)acetonitrile (0.84 g, 3.24 mmol). After 10 minutes, sodium borohydride (0.96 g, 25.4 mmol) was added in 3 equal portions over a period of 30 minutes. To the reaction mixture, di-tert-butyl dicarbonate (1.38 g, 6.35 mmol) was added and stirred for 18 hours at room temperature. The reaction was quenched by the slow addition of ammonium hydroxide (20 mL). The mixture was filtered, and the solid washed with methanol (20 mL) before the filtrate was concentrated under reduced pressure. The aqueous residue was extracted with EtOAc (4 x 10 mL), the combined organic phases were washed with brine (2 x 10 mL), dried over sodium sulfate and concentrated under reduced pressure. To the crude residue, 1,4-123276-03120

[0442] dioxane (2 mL) was added followed by hydrogen chloride solution in dioxane (4M, 18 mL). The reaction mixture was stirred at room temperature for 5 hours. The solution was concentrated under reduced pressure before dilution with IM sodium hydroxide (10 mL). The resulting mixture was extracted with methylene chloride (3 x 10 mL), combined, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound which was used in consecutive reaction steps without further purification. Yield: 0.17 g. LCMS: m / z 264.0 [M+H]+.

[0443] Step 3: Synthesis of l-((2-chlorophenyl)sulfonyl)-N-(2-(6-isobutoxypyridin-3-yl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 18.

[0444] Example 18 was synthesized in the same manner of step 3 for Example 2. Yield: 0.10 g, 0.17 mmol, 4% over 2 steps. LCMS: m / z 549.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.93 (d, J= 8.0 Hz, 1H), 7.88 (m, 1H), 7.70-7.61 (m, 2H), 7.59-7.49 (m, 3H), 6.71 (d, J = 8.5 Hz, 1H), 4.00-3.90 (m, 2H), 3.63-3.50 (m, 3H), 3.24-3.10 (m, 2H), 2.73-2.64 (m, 2H), 2.29-2.22 (m, 2H), 2.15-2.08 (m, 1H), 2.01-1.92 (m, 1H), 1.64-1.44 (m, 6H), 1.40-1.26 (m, 2H), 0.93 (d, J= 6.5 Hz, 6H).

[0445] Example 19: l-((4-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(2-oxopyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0446]

[0447] NHBoc

[0448] BOC2O, NEt3, THF COCI2.6H2O, NaBH4, Step-3 Step-4

[0449]

[0450]

[0451]

[0452] Example 19123276-03120

[0453] Step 1: 2-(3-methoxyphenyl)-2-((trimethylsilyl)oxy)acetonitrile

[0454] To a mixture of trimethyl silanecarbonitrile (6.17 g, 62.3 mmol, 7.78 ml, 1.6 eq) and anhydrous Znh (catalytic amount), 3 -methoxybenzaldehyde (5.30 g, 38.9 mmol) was slowly added. The mixture was heated at 95 °C for 4 hours before concentrating under reduce pressure to afford crude title compound as a yellow liquid, which was subsequently used without further purification. Yield: 9.20 g.1H NMR (400 MHz, CDCh) 87.30 (t, J = 8.0 Hz, 1H), 7.12-6.94 (m, 2H), 6.9 (d, J= 8.0 Hz, 1H), 5.45 (s, 1H), 3.82 (s, 4H), 0.22 (s, 9H).

[0455] Step 2: 2-amino-2-(3-methoxyphenyl)acetonitrile

[0456] To a saturated solution of methanolic ammonia (35 mL), 2-(3-methoxyphenyl)-2-((trimethylsilyl)oxy)acetonitrile (5.2 g, 22.1 mmol) was added in one portion. The mixture was warmed to 40°C and stirred for 2 hours before concentrating under reduced pressure to afford crude title compound as yellow oil was obtained, which was subsequently used without further purification. Yield: 2.40 g. 'H NMR (500 MHz, CDCI3) 87.32 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.91 (d, J = 8.0 Hz 1H), 4.91 (s, 1H), 3.82 (s, 3H), 2.75-2.45 (m, 2H).

[0457] Step 3: tert-butyl (cyano(3-methoxyphenyl)methyl)carbamate

[0458] To a stirred solution of 2-amino-2-(3-methoxyphenyl)acetonitrile (3.6 g, 22.3 mmol) in THF (40 mL) was added di-tert-butyl dicarbonate (5.3 g, 24.5 mmol) followed by triethylamine (2.3 g, 22.3 mmol). The mixture was stirred at room temperature for 70 hours before concentrating under reduced pressure. The crude material was purified by flash column chromatography eluting with 0%-100% ethyl acetate in petroleum ether to afford the title compound. Yield: 2.90 g, 11.0 mmol, 3% over 3 steps. LCMS: m / z 285.0 [M+Na]+. Step 4: tert-butyl (2-amino-l-(3-methoxyphenyl)ethyl)carbamate

[0459] A stirred solution of cobalt(II) chloride hexahydrate (5.20 g, 21.8 mmol) in methanol (150 mL) was cooled to 0 °C before the addition of tert-butyl (cyano(3-methoxyphenyl)methyl)carbamate (5.20 g, 19.8 mmol). After 10 minutes, sodium borohydride (7.5 g, 198 mmol) was added in 3 equal portions over a period of 30 minutes. The mixture was stirred for a further hour before the additional of, 1 M hydrochloric acid (170 mL) and allowed to further stir for 10 minutes at room temperature, before the slow addition of 5 M aqueous sodium hydroxide solution (150 mL). The mixture was filtered using Celite, before the filtrate was extracted with MTBE (3x40 mL). The extract was washed with 5% NH4OH (80 mL), and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to afford the title compound as yellow oil, which was used in the next step without further purification. Yield: 5.20 g. LCMS: m / z 267.4 [M+H]+.123276-03120

[0460] Step 5: tert-butyl (2-(l-((4-chlorophenyl)sulfonyl)piperidine-4-carboxamido)-l-(3-methoxyphenyl)ethyl)carbamate

[0461] To solution of crude tert-butyl (2-amino-l-(3-methoxyphenyl)ethyl)carbamate (3.00 g), l-(4-chlorobenzenesulfonyl)piperidine-4-carboxylic acid (3.42 g, 11.3 mmol) and triethylamine (2.85 g, 28.2 mmol) and N,N-dimethylpyridin-4-amine (0.28 g, 2.25 mmol) in methylene chloride (120 mL) was cooled to 0 °C before the addition of (3-[(ethylimino)methylidene]aminopropyl)dimethylamine hydrochloride (3.23 g, 16.91 mmol). The mixture was allowed to warm to room temperature over 15 min, then stirred for an additional 18 hours. The mixture was diluted with EtOAc (400 mL) and washed with brine (2 x 50 mL), 1% citric acid (50 mL), and brine (50 mL). The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as brown oil which was used in the next step without further purification. Yield: 6.20 g. LCMS: m / z 574.2 [M+Na]+.

[0462] Step 6: N-(2-amino-2-(3-methoxyphenyl)ethyl)-l-((4-chlorophenyl)sulfonyl)piperi dinercarb oxami de

[0463] To a stirred solution of crude tert-butyl (2-(l-((4-chlorophenyl)sulfonyl)piperidine-4-carboxamido)-l-(3-methoxyphenyl)ethyl)carbamate (6.20 g) in MeOH (50 mL) was added 6N HC1 (20 mL). The mixture was stirred at reflux for 30 min, before evaporated under reduced pressure. The mixture was then diluted with aqueous 8 N sodium hydroxide solution to adjust the pH to 9-10, before the aqueous mixture was extracted with MTBE (3 x 50 mL). The organic layer dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude material was purified by flash column chromatography eluting with 0%-100% THF in CHCh to afford the title compound (0.9 g, 59.1% yield) as yellow oil. Yield: 0.90 g, 1.99 mmol, 18% over 3 steps. LCMS: m / z 452.2 [M+H]+.

[0464] Step 7: l-((4-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(2-oxopyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 19

[0465] To a solution of N-(2-amino-2-(3-methoxyphenyl)ethyl)-l-((4-chlorophenyl)sulfonyl)piperidine-4-carboxamide (400 mg, 0.885 mmol) in methylene chloride (2.0 mL) was added diisopropylamine (171 mg, 1.33 mmol) and 4-chlorobutyryl chloride (0.12 g, 0.88 mmol). The reaction mixture was stirred for 15 minutes before the addition of benzyltri ethyl azanium chloride (20.1 mg, 0.088 mmol), sodium hydroxide (0.17 g, 4.42 mmol) and water (0.2 mL). The mixture was stirred at room temperature for 20 hours. The di chloromethane layer was diluted and dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on preparative HPLC to afford123276-03120

[0466] Example 19. Yield: 0.32 g, 0.62 mmol, 69%. LCMS: m / z: 520.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.85 (t, J= 5.5 Hz, 1H), 7.79-7.64 (m, 4H), 7.24 (t, J= 8 Hz, 1H), 6.84 (dd, J= 8.5, 2.5 Hz, 1H), 6.79 (d, J= 7.5 Hz, 1H), 6.73 (s, 1H), 5.17-5.06 (m, 1H), 3.72 (s, 3H), 3.67-3.58 (m, 1H), 3.56-3.50 (m, 2H), 3.48-3.33 (m, 2H), 2.96-2.73 (m, 2H), 2.41-2.29 (m, 2H), 2.23-2.12 (m, 2H), 2.10-1.94 (m, 1H), 1.83-1.71 (m, 2H), 1.70-1.59 (m, 2H), 1.57- 1.37 (m, 2H).

[0467] Example 20: (R or S)-l-((4-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin- l-yl)ethyl)piperidine-4-carboxamide

[0468]

[0469] Example 20

[0470] Step 1: (Ror S)-l-((4-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 20

[0471] To a stirred solution of l-(4-chlorobenzenesulfonyl)piperidine-4-carboxylic acid (0.40 g, 1.32 mmol), 2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethan-l -amine (0.29 g, 1.32 mmol), and diisopropylethylamine (0.68 g, 5.28 mmol) in anhydrous DMF (4 mL), HATU (0.75 g, 1.98 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 18 hours. The crude obtained was directly purified by HPLC. Pure racemic mixture was separated by chiral chromatography (Chiralpak IC (250 x 4.6 mm, 5 um), eluting with 2:1:1 (Hexane:IPA:MeOH), 0.6 mL / min). Peak 1 from the chiral chromatography was assigned as Example 20. Yield: 0.11 g, 0.22 mmol, 16%. LCMS: m / r. 506.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.75-7.66 (m, 4H), 7.52-7.39 (m, 1H), 7.23-7.11 (m, 1H), 6.83-6.67 (m, 3H), 3.70 (s, 3H), 3.60-3.38 (m, 3H), 3.23-3.06 (m, 2H), 2.44-2.38 (m, 2H), 2.32-2.19 (m, 4H), 2.05-1.94 (m, 1H), 1.69-1.30 (m, 8H).123276-03120

[0472] Example 21: (R or S)-l-((4-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0473]

[0474] Step 1: (Ror S)-l-((4-chlorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 21

[0475] Example 21 was prepared with Example 20. Peak 2 from the chiral chromatography was assigned as Example 21. Yield: 0.11 g, 0.22 mmol, 16%. LCMS: m / z 506.2 [M+H]+.1H NMR (500 MHz, d6-DMSO) 87.75-7.66 (m, 4H), 7.52-7.39 (m, 1H), 7.23-7.11 (m, 1H), 6.83-6.67 (m, 3H), 3.70 (s, 3H), 3.60-3.38 (m, 3H), 3.23-3.06 (m, 2H), 2.44-2.38 (m, 2H), 2.32-2.19 (m, 4H), 2.05-1.94 (m, 1H), 1.69-1.30 (m, 8H).

[0476] Example 22: (R or S)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2- (trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxamide

[0477]

[0478] Step 1: (Ror S)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxamide, Example 22

[0479] Example 22 was prepared from Example 1 using chiral chromatography (Chiralpak IG (250 x 4.6 mm, 5 um), eluting with 2:1:1 (Hexane:IPA:MeOH), 0.6 mL / min). Peak 1 from the chiral chromatography was assigned as Example 22. Yield: 0.09 g, 0.22 mmol. LCMS: m / z 556.2 [M+H]+. 'll NMR (500 MHz, d6-DMSO) 67.91 (dd, J= 8.0, 1.5 Hz, 1H), 7.80 (td,J= 8.0, 1.5 Hz, 1H), 7.63-7.55 (m, 2H), 7.47 (t, J = 6.0 Hz, 1H), 7.18-7.14 (m, 1H), 6.78-6.73 (m, J= 7.0 Hz, 3H), 3.69 (s, 3H), 3.60-3.48 (m, 3H), 3.22-3.18 (m, 1H), 3.16-3.10 (m, 1H), 2.62-2.54 (m, 2H), 2.47-2.40 (m, 2H), 2.31-2.24 (m, 2H), 2.14-2.06 (m, 1H), 1.64-1.48 (m, 6H), 1.44-1.28 (m, 2H).123276-03120

[0480] Example 23: (R or S)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2- (trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxamide

[0481]

[0482] Step 1: (Ror S)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carboxamide, Example 23

[0483] Example 23 was prepared from Example 1 using chiral chromatography (Chiralpak IG (250 x 4.6 mm, 5 um), eluting with 2:1:1 (Hexane:IPA:MeOH), 0.6 mL / min). Peak 2 from the chiral chromatography was assigned as Example 23. Yield: 0.9 g, 0.15 mmol. LCMS: m / z 556.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.91 (dd, J= 8.0, 1.5 Hz, 1H), 7.80 (td,J= 8.0, 1.5 Hz, 1H), 7.63-7.55 (m, 2H), 7.47 (t, = 6.0 Hz, 1H), 7.18-7.14 (m, 1H), 6.78- 6.73 (m, J= 7.0 Hz, 3H), 3.69 (s, 3H), 3.60-3.48 (m, 3H), 3.22-3.18 (m, 1H), 3.16-3.10 (m, 1H), 2.62-2.54 (m, 2H), 2.47-2.40 (m, 2H), 2.31-2.24 (m, 2H), 2.14-2.06 (m, 1H), 1.64-1.48 (m, 6H), 1.44-1.28 (m, 2H).

[0484] Example 24: l-((2-chloro-6-methylphenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0485]

[0486] Example 24123276-03120

[0487] Step 1: tert-butyl 4-((2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)carbamoyl)piperidine-l-carboxylate

[0488] The title compound was synthesized in the same manner of step 3 for Example 2. Yield: 9.0 g, 20.8 mmol, 63%. LCMS: m / z 432.4 [M+H]+.

[0489] Step 2: N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide dihydrochloride

[0490] To a saturated solution of hydrogen chloride in 1,4-dioxane (2.3 mL), tert-butyl 4-((2-(3 -methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)carbamoyl)piperidine-l -carboxylate (9.0 g, 20.8 mmol) was added and stirred at room temperature for 18 hours. The mixture was diluted with methyl tert-butyl ether (5 mL) before filtering. The solid was washed with methyl tert-butyl ether (2 x 20 mL) and dried to afford the title compound. Yield: 7.00 g, 15.6 mmol, 74%. LCMS: m / r. 332.2 [M+H]+.

[0491] Step 3 : l-((2-chloro-6-methylphenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 24

[0492] To a solution of N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide dihydrochloride (0.20 g, 0.49 mmol) and tri ethylamine (0.15 g, 1.48 mmol) in methylene chloride, 2-chloro-6-m ethylbenzene- 1 -sulfonyl chloride (0.16 g, 0.74 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, washed with water, brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by HPLC to afford Example 24. Yield: 0.10 g, 0.19 mmol, 39%. LCMS: m / z 520.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.59-7.44 (m, 3H), 7.42-7.36 (m, 1H), 7.21-7.14 (m, 1H), 6.81-6.68 (m, 3H), 3.69 (s, 3H), 3.59-3.47 (m, 3H), 3.24-3.17 (m, 1H), 3.15-3.11 (m, 1H), 2.79-2.69 (m, 2H), 2.61 (s, 3H), 2.47-2.40 (m, 2H), 2.31-2.24 (m, 2H), 2.19-2.13 (m, 1H), 1.64-1.57 (m, 4H), 1.56-1.47 (m, 2H), 1.41-1.29 (m, 2H).

[0493] Example 25: N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2-methoxyphenyl)sulfonyl)piperidine-4-carboxamide

[0494]

[0495] 123276-03120

[0496] Step 1: N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2-methoxyphenyl)sulfonyl)piperidine-4-carboxamide, Example 25

[0497] Example 25 was synthesized in the same manner of step 3 for Example 24. Yield: 0.10 g, 0.19 mmol, 38%. LCMS: m / z 502.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.70 (d, J = 7.5 Hz, 1H), 7.62-7.55 (m, 1H), 7.50-7.43 (m, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.84-6.66 (m, 3H), 3.84 (s, 3H), 3.70 (s, 3H), 3.62-3.46 (m, 3H), 3.23-3.10 (m, 2H), 2.58-2.52 (m, 1H), 2.46-2.38 (m, 2H), 2.30-2.24 (m, 2H), 2.13-2.02 (m, 2H), 1.71-1.43 (m, 6H), 1.38-1.30 (m, 2H).

[0498] Example 26: l-((2-chloro-4-fluorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin- l-yl)ethyl)piperidine-4-carboxamide

[0499]

[0500] Example 26

[0501] Step 1 : l-((2-chloro-4-fluorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 26

[0502] Example 26 was synthesized in the same manner of step 3 for Example 24. Yield: 0.10 g, 0.19 mmol, 31%. LCMS: m / z 524.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 6 8.07-7.97 (m, 1H), 7.78-7.68 (m, 1H), 7.55-7.49 (m, 1H), 7.46-7.39 (m, 1H), 7.19-7.12 (m, 1H), 6.86-6.59 (m, 3H), 3.70 (s, 3H), 3.58-3.50 (m, 3H), 3.25-3.11 (m, 2H), 2.75-2.64 (m, 2H), 2.45-2.38 (m, 2H), 2.34-2.24 (m, 2H), 2.19-2.09 (m, 1H), 1.81-1.14 (m, 8H)

[0503] Example 27 : 1 -((2-isopropylphenyl)sulfonyl)-N-(2-(3 -methoxyphenyl)-2-(pyrrolidin- 1 -yl)ethyl)piperidine-4-carboxamide

[0504]

[0505] Example 27123276-03120

[0506] Step 1 : l-((2-isopropylphenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 27

[0507] Example 27 was synthesized in the same manner of step 3 for Example 24. Yield: 0.09 g, 0.17 mmol, 37%. LCMS: m / z 514.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.76 (d, J = 7.5 Hz, 1H), 7.65-7.57 (m, 2H), 7.54-7.48 (m, 1H), 7.40-7.33 (m, 1H), 7.19-7.13 (m, 1H), 6.83-6.68 (m, 3H), 3.69 (s, 3H), 3.58-3.38 (m, 2H), 3.23-3.09 (m, 2H), 2.63-2.55 (m, 2H), 2.47-2.39 (m, 2H), 2.32-2.25 (m, 2H), 2.17-2.10 (m, 1H), 1.65-1.24 (m, 8H), 1.19 (d, J = 7.0 Hz, 6H).

[0508] Example 28: 1 -((2-cyclopropylphenyl)sulfonyl)-N-(2-(3 -methoxyphenyl)-2-(pyrrolidin- 1 -yl)ethyl)piperidine-4-carboxamide

[0509]

[0510] Example 28

[0511] Step 1 : l-((2-cyclopropylphenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 28

[0512] Example 28 was synthesized in the same manner of step 3 for Example 24. Yield: 0.11 g, 0.20 mmol, 41%. LCMS: m / z 512.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.76 (dd, J= 8.0, 1.5 Hz, 1H), 7.59-7.40 (m, 2H), 7.32 (t, J= 7.5 Hz, 1H), 7.22-7.11 (m, 1H), 7.03 (d, J= 8.0 Hz, 1H), 6.86-6.64 (m, 3H), 3.69 (s, 3H), 3.57-3.45 (m, 3H), 3.25-3.10 (m, 2H), 2.70-2.64 (m, 1H), 2.56-2.53 (m, 1H), 2.43-2.38 (m, 2H), 2.33-2.27 (m, 2H), 2.14-2.05 (m, 1H), 1.72-1.27 (m, 8H), 1.07-1.01 (m, 2H), 0.82-0.73 (m, 2H).

[0513] Example 29: N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-(o-tolylsulfonyl)piperidine-4-carboxamide

[0514]

[0515] Example 29123276-03120

[0516] Step 1 : N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-(o-tolylsulfonyl)piperidine-4-carboxamide, Example 29

[0517] Example 29 was synthesized in the same manner of step 3 for Example 24. Yield: 0.13 g, 0.26 mmol, 44%. LCMS: m / z 486.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.76 (d, J = 8.0 Hz, 1H), 7.57-7.52 (m, 1H), 7.51-7.45 (m, 1H), 7.45-7.36 (m, 2H), 7.16 (t, J = 8.0 Hz, 1H), 6.81-6.68 (m, 3H), 3.69 (s, 3H), 3.61-3.39 (m, 3H), 3.23-3.09 (m, 2H), 2.60-2.53 (m, 4), 2.42-2.38 (m, 3H), 2.33-2.25 (m, 2H), 2.15-2.06 (m, 1H), 1.65-1.26 (m, 8H).

[0518] Example 30: l-((2-chloro-4-methylphenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0519]

[0520] Example 30

[0521] Step 1 : l-((2-chloro-4-methylphenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 30

[0522] Example 30 was synthesized in the same manner of step 3 for Example 24. Yield: 0.10 g, 0.17 mmol, 36%. LCMS: m / z 520.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.81 (d, J = 8.0 Hz, 1H), 7.56-7.44 (m, 2H), 7.34 (d, J = 8.5 Hz, 1H), 7.20-7.13 (m, 1H), 6.83-6.70 (m, 3H), 3.69 (s, 3H), 3.59-3.50 (m, 3H), 3.24-3.11 (m, 2H), 2.68-2.61 (m, 2H), 2.46-2.40 (m, 2H), 2.36 (s, 3H), 2.32-2.27 (m, 2H), 2.18-2.05 (m, 1H), 1.70-1.25 (m, 8H).

[0523] Example 31: l-((2-chloro-5-fluorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0524]

[0525] Example 31123276-03120

[0526] Step 1 : l-((2-chloro-5-fluorophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 31

[0527] Example 31 was synthesized in the same manner of step 3 for Example 24. Yield: 0.14 g, 0.25 mmol, 51%. LCMS: m / z 524.4 [M+H]+. 'll NMR (500 MHz, d6-DMSO) 8 7.80-7.69 (m, 2H), 7.62-7.55 (m, 1H), 7.55-7.47 (m, 1H), 7.20-7.13 (m, 1H), 6.84-6.65 (m, 3H), 3.70 (s, 3H), 3.66-3.52 (m, 3H), 3.24-3.08 (m, 2H), 2.82-2.67 (m, 2H), 2.46-2.38 (m, 2H), 2.33-2.26 (m, 2H), 2.19-2.10 (m, 1H), 1.69-1.25 (m, 8H).

[0528] Example 32: l-((2-(difluoromethoxy)phenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2- (pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0529]

[0530] Example 32

[0531] Step 1 : l-((2-(difluoromethoxy)phenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 32

[0532] Example 32 was synthesized in the same manner of step 3 for Example 24. Yield: 0.11 g, 0.20 mmol, 41%. LCMS: m / z 538.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.84 (d, J = 8.0 Hz, 1H), 7.77-7.68 (m, 1H), 7.51-7.12 (m, 5H), 6.86-6.65 (m, 3H), 3.69 (s, 3H), 3.63-3.48 (m, 3H), 3.23-3.18 (m, 1H), 3.17-3.09 (m, 1H), 2.63-2.53 (m, 2H), 2.45-2.38 (m, 2H), 2.34-27 (m, 2H), 2.13-2.05 (m, 1H), 1.72-1.21 (m, 8H).

[0533] Example 33: l-((2-(isoxazol-4-yl)phenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0534]

[0535] Example 33123276-03120

[0536] Step 1 : l-((2-(isoxazol-4-yl)phenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 33

[0537] Example 33 was synthesized in the same manner of step 3 for Example 24. Yield: 0.002 g, 0.004 mmol, 6%. LCMS: m / z 539.2 [M+H]+. 'H NMR (500 MHz, CD3OD) 68.91-8.78 (m, 1H), 8.65-8.55 (m, 1H), 8.07-8.03 (m, 1H), 7.74-7.64 (m, 1H), 7.63-7.58 (m, 1H), 7.53-7.48 (m, 1H), 7.41-7.36 (m, 1H), 7.09-6.94 (m, 3H), 4.39-4.34 (m, 1H), 3.95-3.90 (m, 2H), 3.82 (s, 3H), 3.73-3.67 (m, 1H), 3.37-3.34 (m, 2H), 3.18-3.10 (m, 1H), 3.00-2.92 (m, 1H), 2.52-2.44 (m, 2H), 2.27-1.83 (m, 5H), 1.58-1.26 (m, 5H).

[0538] Example 34: l-((2-chloro-4-methoxyphenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0539]

[0540] Example 34

[0541] Step 1 : l-((2-chloro-4-methoxyphenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 34

[0542] Example 34 was synthesized in the same manner of step 3 for Example 24. Yield: 0.29 g, 0.52 mmol, 42%. LCMS: m / z 536.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.85 (d, J = 8.5 Hz, 1H), 7.51-7.47 (m, 1H), 7.27-7.23 (m, 1H), 7.19-7.14 (m, 1H), 7.06 (dd, J = 8.5, 2.5 Hz, 1H), 6.83-6.66 (m, 3H), 3.85 (s, 3H), 3.70 (s, 3H), 3.58-3.49 (m, 3H), 3.24-3.18 (m, 1H), 3.17-3.08 (m, 1H), 2.67-2.58 (m, 2H), 2.46-2.40 (m, 2H), 2.32-2.27 (m, 2H), 2.15-2.08 (m, 1H), 1.74-1.22 (m, 8H).123276-03120

[0543] Example 35: 2-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxyphenethyl)propan-2-amine

[0544]

[0545] Step 1: tert-butyl 4-(2-(2-(4-isobutoxyphenyl)acetamido)propan-2-yl)piperidine-l-carboxylate

[0546] To a stirred solution of 2-(4-isobutoxyphenyl)acetic acid (0.86 g, 4.13 mmol) and triethylamine (1.25 g, 12.4 mmol) in anhydrous methylene chloride (30 mL), (3- [(ethylimino)methylidene]aminopropyl)dimethylamine hydrochloride (0.95 g, 4.96 mmol) and lH-l,2,3-benzotriazol-l-ol (0.67 g, 4.96 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour before the addition of tert-butyl 4-(2-aminopropan-2-yl)piperidine-l -carboxylate (1.00 g, 4.13 mmol). The resulting mixture was further stirred at room temperature for 16 hours before being washed with aqueous IM sodium hydrogen sulfate (50 mL), aqueous IM potassium carbonate (50 mL) and brine (50 mL) before being dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by normal phase flash column chromatography eluting with 5%-100% ethyl acetate in hexane to afford the title compound. Yield: 0.32 g, 0.74 mmol, 18%. LCMS: m / z'. 455.2 [M+Na]+. Step 2: 2-(4-isobutoxyphenyl)-N-(2-(piperidin-4-yl)propan-2-yl)acetamide

[0547] To a stirred solution of tert-butyl 4-(2-(2-(4-isobutoxyphenyl)acetamido)propan-2-yl)piperidine-l -carboxylate (0.32 g, 0.74 mmol) in methylene chloride (5 mL), trifluoroacetic123276-03120

[0548] acid (5 mL) in one portion. The reaction mixture was stirred for 2 hours at 40 °C, concentrated under reduced pressure and diluted with IM NaOH (50 mL). The aqueous layer was extracted with methylene chloride (2 x 50 mL). The combined organics were washed with brine (50 mL) before being dried over sodium sulfate and concentrated under reduced pressure to afford the title copound. Yield: 0.25 g, 0.74 mmol, 99%. LCMS: m / z'. 333.2 [M+H]+.

[0549] Step 3 : N-(2-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)propan-2-yl)-2-(4-i sobutoxyphenyl)acetami de

[0550] A stirred solution of 2-(4-isobutoxyphenyl)-N-(2-(piperidin-4-yl)propan-2-yl)acetamide (0.25 g, 0.74 mmol) and triethylamine (0.22 g, 2.17 mmol) in anhydrous methylene chloride (10 mL) was cooled to 0 °C, before the addition of 2-chlorobenzenesulfonyl chloride (0.17 g, 0.79 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours before being diluted with 1.0 M aqueous hydrochloric acid (20 mL). The resulting mixture was extracted with methylene chloride (10 mL). The organic layer was washed with aqueous 1.0 M sodium hydrogencarbonate (20 mL), brine (20 mL) before being dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. Yield: 0.35 g, 0.69 mmol, 93%. LCMS: m z 507.4 [M+H]+.

[0551] Step 4: 2-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxyphenethyl)propan-2-amine, Example 35

[0552] To a stirred solution of N-(2-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)propan-2-yl)-2-(4-isobutoxyphenyl)acetamide (0.35 g, 0.69 mmol) in THF (15 mL), borane dimethyl sulfide complex (10.0 M, 0.30 mL, 3.0 mmol) was added in one portion. The reaction mixture was stirred for 16 h at 60 °C. The mixture was then cooled to 0°C before the dropwise addition of methanol (1.0 mL). The mixture was concentrated under reduced pressure. The residue was taken up in methanol (10 mL) before the addition of 10.0 M aqueous hydrochloric acid (5 mL) and the resulting mixture was stirred at 60 °C for 3 hours. The mixture was concentrated under reduced pressure and diluted with IM NaOH (40 mL). The resulting mixture was extracted with methylene chloride (2 x 20 mL), the organic layers were combined, washed with brine (50 mL) before being dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 35. Yield: 0.19 g, 0.38 mmol, 55%. LCMS: m z 493.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.93 (d, J = 8.0 Hz, 1H), 7.70-7.61 (m, 2H), 7.57-7.51 (m, 1H), 7.06 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 3.76-3.62 (m, 4H), 2.60-2.52 (m, 6H), 2.01-1.91 (m,123276-03120

[0553] 1H), 1.62-1.56 (m, 2H), 1.34-1.27 (m, 1H), 1.11-1.00 (m, 3H), 0.94 (d, J = 7.0 Hz, 6H), 0.83 (s, 6H).

[0554] Example 36: l-((2-chlorophenyl)sulfonyl)-N-(2-(4-(2 -morpholinoethoxy )phenyl)-2- (pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0555]

[0556] Step 1 : l-((2-chlorophenyl)sulfonyl)-N-(2-(4-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0557] To a stirred solution of 2-(4-methoxyphenyl)-2-(pyrrolidin-l-yl)ethan-l -amine (20.6 g, 93.5 mmol), l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxylic acid (15.0 g, 49.5 mmol) and diisopropylethylamine (35.2 g, 272.5 mmol) in anhydrous DMF (200 mL), HATU (38.8 g, 102.2 mmol) was added in one portion. The resulting mixture was stirred for 18 hours at room temperature. The mixture was concentration under reduced pressure to afford the title compound which was subsequently used without further purification. Yield: 15.0 g. LCMS: m / z 506.0 [M+H]+.

[0558] Step 2: l-((2-chlorophenyl)sulfonyl)-N-(2-(4-hydroxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide123276-03120

[0559] To a stirred solution of crude l-((2-chlorophenyl)sulfonyl)-N-(2-(4-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide (15.0 g) in dichloroethane (50 mL), boron tribromide (36.7 g, 148.2 mmol) was added dropwise at -10 °C. The reaction mixture was stirred at room temperature for 18 hours. The mixture was quenched by the dropwise addition of an aqueous saturated solution of sodium hydrogen carbonate. The organic layer was washed with water (50 mL), brine (50 mL) and evaporated under reduced pressure to obtain crude product which was purified by normal phase flash column chromatography eluting with 5%-100% ethyl acetate in hexane to afford the title compound. Yield: 4.0 g, 8.1 mmol, 11% over 2 steps. LCMS: m / z 492.0 [M+H]+.

[0560] Step 3 : N-(2-(4-(2-chloroethoxy)phenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxamide

[0561] To a stirred mixture of l-((2-chlorophenyl)sulfonyl)-N-(2-(4-hydroxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide (0.30 g, 0.61 mmol) and potassium carbonate (0.42 g, 3.05 mmol), in DMF (2 mL), l-bromo-2-chloroethane (0.13 g, 0.91 mmol) was added. The reaction mixture was stirred at 60 °C for 18 hours. The mixture was concentration under reduced pressure before the resulting residue diluted with water (15 mL) and extracted with methylene chloride (2 x 15 mL). The organic layer was evaporated under reduced pressure to obtain crude product which was purified by HPLC to afford the title compound. Yield: 0.03 g, 0.05 mmol, 8%. LCMS: m / z 554.0 [M+H]+.

[0562] Step 4: l-((2-chlorophenyl)sulfonyl)-N-(2-(4-(2-morpholinoethoxy)phenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 36.

[0563] To a stirred solution of N-(2-(4-(2-chloroethoxy)phenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxamide (27.0 mg, 0.05 mmol), potassium carbonate (13 mg, 0.1 mmol) and sodium iodide (7.3 mg, 0.048 mmol) in DMF (2 mL), morpholine (4.4 mg, 0.051 mmol) was added. The reaction mixture was stirred at 100 °C for 24 hours. The mixture was concentration under reduced pressure before the resulting residue diluted with water (15 mL) and extracted with methylene chloride (2 x 15 mL). The organic layer was evaporated under reduced pressure to obtain crude product which was purified by HPLC to afford Example 36. Yield: 9.9 mg, 0.02 mmol, 31%. LCMS: m / z 303.2 [M+2H]2+.1H NMR (500 MHz, CD3OD) 88.01 (d, J = 7.5 Hz, 1H), 7.63-7.52 (m, 2H), 7.50-7.45 (m, 1H), 7.20 (d, J= 8.5 Hz, 2H), 6.89 (d, J= 8.5 Hz, 2H), 4.16-4.07 (m, 2H), 3.79-3.67 (m, 6H), 3.39-3.32 (m, 2H), 2.83-2.66 (m, 4H), 2.62-2.550 (m, 5H), 2.46-2.34 (m, 2H), 2.14-2.05 (m, 1H), 1.83-1.65 (m, 4H), 1.65-1.39 (m, 4H).123276-03120

[0564] Example 37: l-((2-chlorophenyl)sulfonyl)-N-(2-(pyrrolidin-l-yl)-2-(4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)ethyl)piperidine-4-carboxamide

[0565]

[0566] Example 37

[0567] Step 1 : l-((2-chlorophenyl)sulfonyl)-N-(2-(pyrrolidin-l-yl)-2-(4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)phenyl)ethyl)piperidine-4-carboxamide, Example 37.

[0568] To a stirred mixture of l-((2-chlorophenyl)sulfonyl)-N-(2-(4-hydroxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide (0.20 g, 0.40 mmol) and potassium carbonate (0.28 g, 2.04 mmol), in DMF (2 mL), 4-(2-bromoethyl)oxane (0.12 g, 0.61 mmol) was added. The reaction mixture was stirred at 85 °C for 24 hours. The mixture was concentration under reduced pressure before the resulting residue diluted with water (20 mL) and extracted with methylene chloride (2 x 15 mL). The organic layer was evaporated under reduced pressure to obtain crude product which was purified by HPLC to afford Example 37.

[0569] Yield: 0.05 g, 0.08 mmol, 19%. LCMS: m / z 604.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 8 7.93 (d, J = 8.0 Hz, 1H), 7.73-7.62 (m, 2H), 7.57-7.51 (m, 1H), 7.50-7.41 (m, 1H), 7.08 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 3.98-3.91 (m, 2H), 3.83-3.76 (m, 2H), 3.63-3.46 (m, 3H), 3.28-3.05 (m, 5H), 2.73-2.62 (m, 2H), 2.42-2.34 (m, 2H), 2.30-2.21 (m, 2H), 2.18-2.08 (m, 1H), 1.72-1.44 (m, 10H), 1.41-1.30 (m, 2H), 1.24-1.15 (m, 2H).

[0570] Example 38: N-(2-(4-((l-acetylazeti din-3 -yl)methoxy)phenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxamide

[0571]

[0572] Step 1 : N-(2-(4-((l-acetylazetidin-3-yl)methoxy)phenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxamide, Example 38.

[0573] Example 38 was synthesized in the same manner of step 1 for Example 37. Yield: 0.08 g, 0.13 mmol, 33%. LCMS: m / z 603.2 [M+H]+. 'H NMR (500 MHz, CD3OD) 68.01123276-03120

[0574] (d, J = 8.0 Hz, 1H), 7.64-7.54 (m, 2H), 7.50-7.44 (m, 1H), 7.21 (d, J = 8.5 Hz, 2H), 6.91 (d, J= 8.5 Hz, 2H), 4.36-4.30 (m, 1H), 4.18-4.03 (m, 4H), 3.87-3.81 (m, 1H), 3.79-3.66 (m, 3H), 3.41-3.32 (m, 2H), 3.09-3.03 (m, 1H), 2.76-2.68 (m, 2H), 2.62-2.55 (m, 2H), 2.46-2.38 (m, 2H), 2.16-2.08 (m, 1H), 1.87 (s, 3H), 1.78-1.70 (m, 4H), 1.61-1.44 (m, 4H).

[0575] Example 39: l-((2-chlorophenyl)sulfonyl)-N-(2-(pyrrolidin-l-yl)-2-(4-((tetrahydro-2H- pyran-4-yl)oxy)phenyl)ethyl)piperidine-4-carboxamide

[0576]

[0577] Example 39

[0578] Step 1 : l-((2-chlorophenyl)sulfonyl)-N-(2-(pyrrolidin-l-yl)-2-(4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)ethyl)piperidine-4-carboxamide, Example 39.

[0579] Example 39 was synthesized in the same manner of step 1 for Example 37. Yield: 0.01 g, 0.02 mmol, 5%. LCMS: m / z 576.2 [M+H]+. 'H NMR (500 MHz, CD3OD) 88.05- 7.93 (m, 1H), 7.65-7.53 (m, 2H), 7.53-7.45 (m, 1H), 7.20 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.5 Hz, 2H), 4.58-4.5 (m, 1H), 3.99-3.89 (m, 2H), 3.79-3.67 (m, 3H), 3.66-3.52 (m, 2H), 3.43- 3.35 (m, 2H), 2.84-2.58 (m, 4H), 2.49-2.40 (m, 2H), 2.16-2.08 (m, 1H), 2.05-1.94 (m, 2H), 1.82-1.39 (m, 10H).

[0580] Example 40: l-((2-chlorophenyl)sulfonyl)-N-(2-(4-(2,3-dihydroxypropoxy)phenyl)-2- (pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0581]

[0582] Example 40 Step 1 : l-((2-chlorophenyl)sulfonyl)-N-(2-(4-(2,3-dihydroxypropoxy)phenyl)-2-(pyrrolidin- l-yl)ethyl)piperidine-4-carboxamide, Example 40.

[0583] Example 40 was synthesized in the same manner of step 3 for Example 36. Yield: 0.01 g, 0.01 mmol, 3%. LCMS: m / z 566.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.97- 7.89 (m, 1H), 7.72-7.61 (m, 2H), 7.57-7.52 (m, 1H), 7.50-7.42 (m, 1H), 7.09 (d, J = 8.0 Hz,123276-03120

[0584] 2H), 6.82 (d, J = 8.0 Hz, 2H), 4.89 (d, J = 5.0 Hz, 1H), 4.65-4.60 (m, 1H), 3.95-3.89 (m, 1H), 3.82-3.72 (m, 2H), 3.66-3.52 (m, 3H), 3.47-3.38 (m, 2H), 3.20-3.14 (m, 1H), 3.12-3.05 (m, 1H), 2.72-2.64 (m, 2H), 2.42-2.38 (m, 1H), 2.28-2.23 (m, 2H), 2.18-2.09 (m, 1H), 1.74-1.18 (m, 9H).

[0585] Examples 41 and 42: (Ror S)-l-((2-chlorophenyl)sulfonyl)-N-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0586]

[0587] Step 1 : l-((2-chlorophenyl)sulfonyl)-N-(2-(4-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0588] To a stirred solution of 2-(4-methoxyphenyl)-2-(pyrrolidin-l-yl)ethan-l -amine (20.6 g, 93.5 mmol), l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxylic acid (15.0 g, 49.5 mmol) and diisopropylethylamine (35.2 g, 272.5 mmol) in anhydrous DMF (200 mL), HATU (38.8 g, 102.2 mmol) was added in one portion. The resulting mixture was stirred for 18 hours at room temperature. The mixture was concentration under reduced pressure to afford the title compound which was subsequently used without further purification. Yield: 15.0 g. LCMS: m / z 506.0 [M+H]+.123276-03120

[0589] Step 2: l-((2-chlorophenyl)sulfonyl)-N-(2-(4-hydroxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0590] To a stirred solution of crude l-((2-chlorophenyl)sulfonyl)-N-(2-(4-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide (15.0 g) in dichloroethane (50 mL), boron tribromide (36.7 g, 148.2 mmol) was added dropwise at -10 °C. The reaction mixture was stirred at room temperature for 18 hours. The mixture was quenched by the dropwise addition of an aqueous saturated solution of sodium hydrogen carbonate. The organic layer was washed with water (50 mL), brine (50 mL) and evaporated under reduced pressure to obtain crude product which was purified by normal phase flash column chromatography eluting with 5%-100% ethyl acetate in hexane to afford the title compound. Yield: 4.0 g, 8.1 mmol, 11% over 2 steps. LCMS: m / z 492.0 [M+H]+.

[0591] Step 3: (R or 5)-l-((2-chlorophenyl)sulfonyl)-N-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Examples 41 and 42.

[0592] To a stirred mixture of l-((2-chlorophenyl)sulfonyl)-N-(2-(4-hydroxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide (0.69 g, 1.42 mmol) and potassium carbonate (0.98 g, 7.11 mmol), in DMF (6 mL), l-bromo-2-methylpropane (0.29 g, 2.13 mmol) was added. The reaction mixture was stirred at 60 °C for 18 hours. The mixture was concentration under reduced pressure before the resulting residue diluted with water (15 mL) and extracted with methylene chloride (2 x 15 mL). The organic layer was evaporated under reduced pressure to obtain crude product which was purified by HPLC, followed by chiral chromatography (Chiralpak AD-H (250 x 4.6 mm, 5 um), eluting with 70:15:15 (Hexane + 0.1% EDA):IPA:MeOH), 0.6 mL / min). Peak 1 from the chiral chromatography was assigned as Example 41. Yield: 0.03 g, 0.06 mmol, 4%. LCMS: m / z: 548.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.94 (d, J= 8.0 Hz, 1H), 7.72-7.61 (m, 2H), 7.57-7.51 (m, 1H), 7.49-7.42 (m, 1H), 7.08 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 3.74-3.42 (m, 5H), 3.22-3.06 (m, 2H), 2.75-2.64 (m, 2H), 2.43-2.36 (m, 2H), 2.32-2.21 (m, 2H), 2.18-2.10 (m, 1H), 1.98-1.90 (m, 1H), 1.69-1.44 (m, 6H), 1.44-1.27 (m, 2H), 0.94 (d, J = 6.5 Hz, 6H). Peak 2 from the chiral chromatography was assigned as Example 42. Yield: 0.03 g, 0.06 mmol, 4%. LCMS: m / z 548.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.94 (d, J = 8.0 Hz, 1H), 7.72-7.61 (m, 2H), 7.57-7.51 (m, 1H), 7.49-7.42 (m, 1H), 7.08 (d, J= 8.0 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 3.74-3.42 (m, 5H), 3.22-3.06 (m, 2H), 2.75-2.64 (m, 2H), 2.43-2.36 (m, 2H), 2.32-2.21 (m, 2H), 2.18-2.10 (m, 1H), 1.98-1.90 (m, 1H), 1.69-1.44 (m, 6H), 1.44-1.27 (m, 2H), 0.94 (d, J = 6.5 Hz, 6H). The stereochemistry of Examples 41 and 42 were arbitrarily assigned.123276-03120

[0593] Example 43: l-((2-chlorophenyl)sulfonyl)-N-(2-(4-(2-hydroxy-2-methylpropoxy)phenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0594]

[0595] Example 43

[0596] Step 1 : l-((2-chlorophenyl)sulfonyl)-N-(2-(4-(2-hydroxy-2-methylpropoxy)phenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 43.

[0597] Example 43 was synthesized in the same manner of step 3 for Example 36. Yield: 0.003 g, 0.005 mmol, 1%. LCMS: m / z 564.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.98-7.90 (m, 1H), 7.72-7.61 (m, 2H), 7.57-7.50 (m, 1H), 7.49-7.40 (m, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 4.58 (s, 1H), 3.68-3.51 (m, 5H), 3.22-3.03 (m, 2H), 2.75-2.64 (m, 2H), 2.43-2.39 (m, 2H), 2.32-2.21 (m, 2H), 2.18-2.09 (m, 1H) 1.62-1.32 (m, 8H), 1.17 (s, 6H). Example 44: 4-((2-(4-(2-isopropoxyethoxy)benzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine

[0598]

[0599] Example 44

[0600] Step 1 : 4-((l-((l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)methyl)pyrrolidin-2-yl)methyl)phenol.

[0601] The title compound was synthesized in the same manner of step 3 for Example 35. Yield: 3.00 g, 5.54 mmol, 77%. LCMS: m / z 499.2 [M+H]+.123276-03120

[0602] Step 2 : 44-((2-(4-(2-isopropoxy ethoxy )benzyl)pyrrolidin- 1 -yl)methyl)- 1 -((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine, Example 44.

[0603] Example 44 was synthesized in the same manner of step 3 for Example 36. Yield: 3.00 g, 5.54 mmol, 77%. LCMS: m / z 585.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.92 (d, J = 8.0 Hz, 1H), 7.84-7.77 (m, 1H), 7.64-7.56 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 4.02-3.94 (m, 2H), 3.70-3.54 (m, 5H), 3.00-2.93 (m, 1H), 2.78-2.70 (m, 1H), 2.60-2.54 (m, 4H), 2.44-2.37 (m, 2H), 2.30-2.22 (m, 1H), 2.05-1.96 (m, 2H), 1.91-1.83 (m, 1H), 1.67-1.59 (m, 1H), 1.55-1.44 (m, 4H), 1.37-1.30 (m, 1H), 1.24-1.01 (m, 6H).

[0604] Example 45: 4-((2-(4-(2-ethoxyethoxy)benzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine

[0605]

[0606] Step 1 : 4-((2-(4-(2-ethoxyethoxy)benzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine, Example 45.

[0607] Example 45 was synthesized in the same manner of step 3 for Example 36. Yield: 0.02 g, 0.03 mmol, 8%. LCMS: m / z 571.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.92 (d, J = 8.0 Hz, 1H), 7.84-7.77 (m, 1H), 7.64-7.56 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 4.04-3.97 (m, 2H), 3.69-3.61 (m, 4H), 3.56-3.46 (m, 2H), 3.02-2.96 (m, 1H), 2.77-2.70 (m, 1H), 2.60-2.54 (m, 4H), 2.42-2.34 (m, 2H), 2.29-2.21 (m, 1H), 2.01-1.83 (m 2H), 1.66-1.23 (m, 6H), 1.14-0.98 (m, 4H).123276-03120

[0608] Example 46: 4-((2-(4-(2-methoxyethoxy)benzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine

[0609]

[0610] Example 46

[0611] Step 1 : 4-((2-(4-(2-methoxyethoxy)benzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine, Example 46.

[0612] Example 46 was synthesized in the same manner of step 3 for Example 36. Yield: 0.24 g, 0.41 mmol, 23%. LCMS: m / z 557.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.92 (d, J = 8.0, 1H), 7.84-7.76 (m, 1H), 7.64-7.57 (m, 2H), 7.05 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 4.05-3.97 (m, 2H), 3.70-3.57 (m, 4H), 3.28 (s, 3H), 3.00-2.92 (m, 1H), 2.77-2.71 (m, 1H), 2.57-2.53 (m, 4H), 2.30-2.22 (m, 1H), 2.02-1.85 (m, 3H), 1.66-1.30 (m, 6H), 1.18-0.91 (m, 2H).

[0613] Example 47 : 4-((2-(4-propoxybenzyl)pyrrolidin- 1 -yl)methyl)- 1 -((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine

[0614]

[0615] Step 1: 4-((2-(4-propoxybenzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine, Example 47.

[0616] Example 47 was synthesized in the same manner of step 3 for Example 36. Yield: 0.02 g, 0.03 mmol, 8%. LCMS: m / z 541.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.92 (d, J = 8.0 Hz, 1H), 7.83-7.77 (m, 1H), 7.63-7.57 (m, 2H), 7.05 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 8.0 Hz, 2H), 3.87-3.81 (m, 2H), 3.71-3.60 (m, 2H), 2.99-2.92 (m, 1H), 2.78-2.70 (m, 1H), 2.59-2.53 (m, 4H), 2.30-2.20 (m, 1H), 2.04-1.94 (m, 2H), 1.91-1.84 (m, 1H), 1.72-1.30 (m, 8H), 1.17-0.92 (m, 5H).123276-03120

[0617] Example 48: l-((2-chlorophenyl)sulfonyl)-4-((2-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)piperidine

[0618]

[0619] Step 1 : (l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)(2-(4-hydroxybenzyl)pyrrolidin-l-yl)methanone

[0620] To a stirred solution of l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxylic acid (2.83 g, 9.30 mmol) in methylene chloride (60 mL), DMF (0.1 mL) was added followed by the dropwise additional of oxalyl chloride (3.52 g, 27.7 mmol). The reaction mixture was stirred at room temperature for 4 hours before being concentrated under reduced pressure. The residue was taken up in methylene chloride (20 mL) and added dropwise to a stirred solution of 4-(pyrrolidin-2-ylmethyl)phenol hydrochloride (1.99 g, 9.3 mmol) and DIPEA (6.01 g, 46.5 mmol) in methylene chloride (100 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. To the solution, 1.0 M aqueous hydrochloric acid (200 mL) was added. The resulting mixture was extracted with methylene chloride (3 x 100 mL). The organic layers were combined and washed with 1.0 M sodium hydrogen carbonate (200 mL), brine (200 mL) before being dried over sodium sulfate and concentrated under reduced pressure to afford the title compound which was used without further purification. Yield: 4.00 g. LCMS: m / r. 463.0 [M+H]+.

[0621] Step 2: (l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)(2-(4-isobutoxybenzyl)pyrrolidin-l-yl)methanone123276-03120

[0622] To a stirred solution of crude (l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)(2-(4-hydroxybenzyl)pyrrolidin-l-yl)m ethanone (4.00 g) and l-bromo-2 -methylpropane (4.71 g, 34.4 mmol) in acetone (120 mL) caesium carbonate (5.63 g, 17.3 mmol) was added in one portion. The reaction mixture was stirred for 72 hours at 55 °C, concentrated under reduced pressure and diluted with water (300 mL). The resulting mixture was extracted with methylene chloride (3 x 100 mL). The organic layers were combined, washed with 1.0 M potassium carbonate (200 mL), brine (200 mL) before being dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by normal phase flash column chromatography eluting with 5%-100% ethyl acetate in hexane to afford the title compound. Yield: 1.80 g, 3.47 mmol, 37%. LCMS: m / z 519.4 [M+H]+.

[0623] Step 3 : l-((2-chlorophenyl)sulfonyl)-4-((2-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)piperidine, Example 48.

[0624] To a stirred solution of (l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)(2-(4-isobutoxybenzyl)pyrrolidin-l-yl)methanone (1.80 g, 3.47 mmol) in THF (60 mL), borane dimethyl sulfide complex (10.0 M, 1.77 mL, 17.7 mmol, 5.0 eq) was added in one portion. The reaction mixture was stirred for 72 hours at 65 °C. The mixture was then cooled to 0°C before the dropwise addition of methanol (3.4 mL). The mixture was concentrated under reduced pressure. The residue was taken up in methanol (20 ml) before the addition of 10.0 M aqueous hydrochloric acid (10 ml) and the resulting mixture was stirred at 60 °C for 3 hours. The mixture was concentrated under reduced pressure and diluted with IM NaOH (100 ml). The resulting mixture was extracted with methylene chloride (3 x 50 mL), the organic layers were combined, washed with brine (100 mL) before being dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 48. Yield: 0.64 g, 1.26 mmol, 36%. LCMS: m / z 505.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.95 (d, J = 7.5 Hz, 1H), 7.70-7.62 (m, 2H), 7.57-7.53 (m, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.78 (d, J = 8.0 Hz, 2H), 3.72-3.62 (m, 4H), 3.01-2.95 (m, 1H), 2.79-2.52 (m, 5H), 2.38-2.34 (m, 1H), 2.29-2.21 (m, 1H), 2.08- 1.92 (m, 3H), 1.90-1.85 (m, 1H), 1.66-1.59 (m, 1H), 1.57-1.48 (m, 4H), 1.41-1.28 (m, 1H), 1.14-0.90 (m, 7H).123276-03120

[0625] Example 49: l-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)-N-methylmethanamine

[0626]

[0627] Step 1: tert-butyl (2-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)ethyl)(methyl)carbamate The title compound was synthesized in the same manner of step 1 for Example 1. Yield: 0.82 g. LCMS: m / z 317.0 [M-100+H]+.

[0628] Step 2: 2-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)-N-methylethan-l-amine hydrochloride To a solution of crude tert-butyl (2-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)ethyl)(methyl)carbamate (0.82 g) in methylene chloride (5 mL), 4M hydrogen chloride in dioxane (15 mL) was added and stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure to afford the title compoud which was used without further purification. Yield: 0.60 g. LCMS: m / z 317.0 [M+H]+.

[0629] Step 3 : l-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)-N-methylmethanamine, Example 49.

[0630] To a solution of crude 2-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)-N-methylethan-1-amine hydrochloride (0.60 g) in methanol (20 mL), acetic acid (3.81 mmol, 220.0 pl) and 4-(2-methylpropoxy)benzaldehyde (0.34 g, 1.91 mmol) were added. The mixture was stirred at room temperature for 1 hour before the addition of sodium cyanoborohydride (0.14 g, 2.29 mmol). The mixture was stirred at room temperature for 18 hours, before being concentrated under reduced pressure. The residue was taken up with water (20 mL), aqueous sodium bicarbonate and extracted with methylene chloride (3 x 15 mL). The organic layers were combined, washed with brine (15 mL) before being dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford123276-03120

[0631] Example 49. Yield: 0.15 g, 0.31 mmol, 8%. LCMS: m / z 479.1 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.94 (d, J = 8.0 Hz, 1H), 7.71-7.61 (m, 2H), 7.57-7.49 (m, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.0 Hz, 2H), 3.70-3.60 (m, 4H), 2.70-2.58 (m, 2H), 2.27-2.20 (m, 2H), 2.03 (s, 3H), 1.98-1.92 (m, 1H), 1.62-1.55 (m, 2H), 1.49-1.25 (m, 3H), 1.08-0.99 (m, 2H), 0.95 (d, J = 7.0 Hz, 6H).

[0632] Example 50: l-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)methanamine

[0633]

[0634] Step 1: tert-butyl (2-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)ethyl)carbamate

[0635] The title compound was synthesized in the same manner of step 1 for Example 1. Yield: 0.80 g. LCMS: m / z 303.0 [M-100+H]+.

[0636] Step 2: 2-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)ethan-l -amine hydrochloride

[0637] The title compound was synthesized in the same manner of step 2 for Example 49. Yield: 0.64 g. LCMS: m / z 303.0 [M+H]+.

[0638] Step 3 : l-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)methanamine, Example 50

[0639] Example 50 was synthesized in the same manner of step 3 for Example 49. Yield: 0.18 g, 0.37 mmol, 16% over 3 steps. LCMS: m / z 465.1 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.94 (d, J = 8.0 Hz, 1H), 7.71-7.61 (m, 2H), 7.57-7.50 (m, 1H), 7.16 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.5 Hz, 2H), 3.70-3.60 (m, 4H), 3.54 (s, 2H), 2.70-2.58 (m, 2H), 2.43-2.37123276-03120

[0640] (m, 2H), 2.00-1.92 (m, 1H), 1.66-1.58 (m, 2H), 1.47-1.25 (m, 3H), 1.08-0.99 (m, 2H), 0.94 (d, J = 7.0 Hz, 6H).

[0641] Example 51: 2-(3-methoxyphenyl)-N-((l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)methyl)ethan- 1 -amine

[0642]

[0643] Example 51

[0644] Step 1 : (l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)m ethanol

[0645] To a solution of (Piperidin-4-yl)methanol (1.63 g, 14.15 mmol) and triethylamine (1.67 g, 16.5 mmol) in 100 mL of dry methylene chloride, cooled to 0 °C a solution of 2-(trifluoromethoxy)benzene-l -sulfonyl chloride (3.06 g, 11.79 mmol) in 5 mL of dry methylene chloride was added dropwise. The mixture was stirred and allowed to warm to room temperature overnight. The mixture was then washed with water (50 mL) followed by 20% aqueous sodium bisulfate (50 mL) before the organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound which was used in consecutive reaction steps without further purification. Yield: 2.76 g. LCMS: m / r. 340.0 [M+H]+.

[0646] Step 2: l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carbaldehyde

[0647] Dimethyl sulfoxide (1.16 g, 14.82 mmol) was dissolved in 50 mL of dry methylene chloride and cooled to -78 °C under argon. A solution of oxalyl chloride (1.13 g, 8.88 mmol) in 5 mL methylene chloride was added dropwise, keeping the temperature below -70 °C. The mixture was stirred for 30 minutes before dropwise addition of crude (l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)methanol (2.76 g) dissolved in 5 mL methylene chloride. The resulting mixture was further stirred for 2 hours at -70 °C, before the123276-03120

[0648] addition of triethylamine (3.00 g, 29.65 mmol) in one portion. The mixture was warmed to room temperature before it was washed with water (50 mL) followed by 20% aqueous sodium bisulfate (50 mL) before the organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. Yield: 1.40 g, 4.15 mmol, 35% over 2 steps. LCMS: m / z 338.0 [M+H]+.

[0649] Step 3 : 2-(3-methoxyphenyl)-N-((l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)methyl)ethan-l -amine, Example 51.

[0650] A mixture of l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carbaldehyde (0.71 g, 2.12 mmol) and 2-(3-methoxyphenyl)ethan-l -amine (0.32 g, 2.12 mmol) in methanol (50 mL) was stirred for 30 minutes at room temperature, followed by addition of sodium cyanoborohydride (0.53 g, 8.47 mmol) and acetic acid (0.21 g, 3.50 mmol). The mixture was stirred at room temperature for 16 hours, before being concentrated under reduced pressure and diluted with chloroform (50 mL). The organic solution was washed with aqueous saturated sodium bicarbonate, before the organic layer was dried over sodium sulfate and concentrated under reduced pressure and purified by HPLC to afford Example 51. Yield: 0.21 g, 0.45 mmol, 21%. LCMS: m / z 473.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.91 (d, J = 8.0, 1H), 7.83-7.76 (m, 1H), 7.64-7.57 (m, 2H), 7.18-7.11 (m, 1H), 6.78-6.66 (m, 3H), 3.69 (s, 3H), 3.67-3.60 (m, 2H), 2.68-2.57 (m, 4H), 2.55-2.51 (m, 2H), 2.34 (d, J = 6.5 Hz, 2H), 1.75-1.67 (m, 2H), 1.50-1.37 (m, 1H), 1.10-1.00 (m, 2H).

[0651] Example 52: N-((l -((2-chlorophenyl )sulfonyl )piperidin-4-yl )methyl )-2-(4-isobutoxyphenyl)ethan- 1 -amine

[0652]

[0653] 123276-03120

[0654] Step 1: (l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)methanol

[0655] The title compound was synthesized in the same manner of step 1 for Example 51. Yield: 1.60 g. LCMS: m / z 290.0 [M+H]+.

[0656] Step 2: l-((2-chlorophenyl)sulfonyl)piperidine-4-carbaldehyde

[0657] The title compound was synthesized in the same manner of step 2 for Example 51. Yield: 0.65 g, 2.26 mmol, 22% over 2 steps. LCMS: m / z 288.0 [M+H]+.

[0658] Step 3 : N-((l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-2-(4-isobutoxyphenyl)ethan-1 -amine, Example 52

[0659] Example 52 was synthesized in the same manner of step 3 for Example 49. Yield: 0.02 g, 0.05 mmol, 4%. LCMS: m / z 465.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.94 (dd, J = 8.0 Hz, 1H), 7.70-7.61 (m, 2H), 7.57-7.50 (m, 1H), 7.06 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 3.70-3.62 (m, 4H), 2.69-2.55 (m, 6H), 2.37-2.32 (m, 2H), 1.99-1.90 (m, 1H), 1.74-1.67 (m, 2H), 1.50-1.39 (m, 2H), 1.09-0.99 (m, 2H), 0.94 (d, J = 6.5 Hz, 6H).

[0660] Example 53: 2-(4-isobutoxyphenyl)-N-((l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)methyl)ethan-l -amine.

[0661]

[0662] Step 1 : (l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)m ethanol

[0663] To a solution of (Piperidin-4-yl)methanol (1.63 g, 14.15 mmol) and triethylamine (1.67 g, 16.5 mmol) in 100 mL of dry methylene chloride, cooled to 0 °C a solution of 2-(trifluoromethoxy)benzene-l -sulfonyl chloride (3.06 g, 11.79 mmol) in 5 mL of dry123276-03120

[0664] methylene chloride was added dropwise. The mixture was stirred and allowed to warm to room temperature overnight. The mixture was then washed with water (50 mL) followed by 20% aqueous sodium bisulfate (50 mL) before the organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound, which was used in consecutive reaction steps without further purification. Yield: 2.76 g. LCMS: m / z 340.0 [M+H]+.

[0665] Step 2: l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carbaldehyde

[0666] Dimethyl sulfoxide (1.16 g, 14.82 mmol) was dissolved in 50 mL of dry methylene chloride and cooled to -78 °C under argon. A solution of oxalyl chloride (1.13 g, 8.88 mmol) in 5 mL methylene chloride was added dropwise, keeping the temperature below -70 °C. The mixture was stirred for 30 minutes before dropwise addition of crude (l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)methanol (2.76 g) dissolved in 5 mL methylene chloride. The resulting mixture was further stirred for 2 hours at -70 °C, before the addition of triethylamine (3.00 g, 29.65 mmol) in one portion. The mixture was warmed to room temperature before it was washed with water (50 mL) followed by 20% aqueous sodium bisulfate (50 mL) before the organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. Yield: 1.40 g, 4.15 mmol, 35% over 2 steps. LCMS: m / z 338.0 [M+H]+.

[0667] Step 3 : 2-(4-isobutoxyphenyl)-N-((l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperi din-4-yl)methyl)ethan-l -amine, Example 53.

[0668] To a solution of 2-(4-isobutoxyphenyl)ethan-l -amine (0.30 g, 1.55 mmol) in methanol (10 mL), l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine-4-carbaldehyde (0.52 g, 1.55 mmol) was added and the mixture was stirred at room temperature for 30 minutes before the addition of sodium cyanoborohydride (0.14 g, 2.29 mmol) and acetic acid (3.80 mmol, 0.22 mL). The mixture was stirred at room temperature for 16 hours, before being concentrated under reduced pressure. The residue was taken up with chloroform (30 mL) and washed with aqueous sodium bicarbonate (3 x 20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 53. Yield: 0.66 g, 1.28 mmol, 82%. LCMS: m / z 515.0 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.91 (d, J = 8.0 Hz, 1H), 7.83-7.76 (m, 1H), 7.62-7.55 (m, 2H), 7.06 (d, J= 8.5 Hz, 2H), 6.77 (d, J= 8.5 Hz, 2H), 3.69-3.61 (m, 4H), 2.63-2.51 (m, 6H), 2.36-2.30 (m, 2H), 1.99-1.90 (m, 1H), 1.74-1.66 (m, 2H), 1.44-1.36 (m, 2H), 1.09-0.98 (m, 2H), 0.94 (d, J = 6.5 Hz, 6H).123276-03120

[0669] Example 54: N-((l -((2-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-l -(4-isobutoxyphenyl)-2-methylpropan-2-amine.

[0670]

[0671] Step 1: isobutyl 3-(4-isobutoxyphenyl)-2,2-dimethylpropanoate

[0672] A stirring mixture of 3-(4-hydroxyphenyl)-2,2-dimethylpropanoic acid (3.17 g, 16.32 mmol), l-iodo-2-m ethylpropane (9.01 g, 48.95 mmol) and dipotassium carbonate (7.88 g, 57.11 mmol) in acetonitrile (40 mL) was heated up to 65 °C for 16 hours. The mixture was cooled, diluted with water (100 mL) and extracted with EtOAc (2x 10 mL). The combined organics were combined, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound which was used without further purification. Yield: 3.70 g.

[0673] LCMS: m / r. 251.2 [M-56+H]+.

[0674] Step 2: 3-(4-isobutoxyphenyl)-2,2-dimethylpropanoic acid

[0675] To a solution of isobutyl 3-(4-isobutoxyphenyl)-2,2-dimethylpropanoate (1.84 g) in methanol (10 mL), water was added (5 mL) followed by sodium hydroxide (0.95 g, 23.97 mmol) and the mixture was refluxed for 18 hours. The mixture was cooled and diluted with water (50 mL) and washed with methylene chloride (2x 50 mL). The aqueous phase was acidified to by addition of 10% aqueous HC1 (10 mL). The aqueous was extracted with EtOAc (2x 50 mL). The organic layer was washed with water, dried over sodium sulfate, concentrated under reduced pressure and the residue was purified by normal phase flash123276-03120

[0676] chromatography eluting with 15%-l 00% EtOAc in hexane to afford the title compound. Yield: 0.35 g, 1.40 mmol, 8% over two steps. LCMS: m / z 251.2 [M-H]'.

[0677] Step 3: l-(4-isobutoxyphenyl)-2-methylpropan-2-amine hydrochloride

[0678] To a solution of 3-(4-isobutoxyphenyl)-2,2-dimethylpropanoic acid (0.33 g, 1.31 mmol) in methylene chloride (10 mL) was treated with oxalyl chloride (0.19 g, 1.57 mmol) in a dropwise fashion at the ambient temperature. After 2 hours, the volatiles were distilled off, and the residue was dissolved in anhydrous THF (5 mL). The solution was added dropwise to a vigorously stirred suspension of sodium azide (0.34 g, 5.24 mmol) in water (3 mL) and THF (17 mL) at 0 °C. The resulting suspension was stirred at room temperature for 18 hours. The mixture was diluted with MTBE (50 mL), washed with water (4x 20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (20 mL) and heated at 100 °C for 2 hours. The mixture was then cooled down to 80 °C and treated with 10% aqueous HC1 (10 mL). The obtained biphasic mixture was stirred at 80 °C for a further 18 hours. Upon cooling to room temperature, the aqueous phase was separated, evaporated to dryness and vacuum-dried to afford the title compound. Yield: 0.19 g, 0.85 mmol, 64%. LCMS: m / z 222:.2 [M+H]+.

[0679] Step 4: N-((l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-l-(4-isobutoxyphenyl)-2-methylpropan-2-amine, Example 54.

[0680] Example 54 was synthesized in the same manner of step 3 for Example 49. Yield: 0.03 g, 0.07 mmol, 8%. LCMS: m / z 493.0 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.95 (d, J = 8.0 Hz, 1H), 7.72-7.59 (m, 2H), 7.57-7.50 (m, 1H), 7.00 (d, J = 8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 3.72-3.64 (m, 4H), 2.72-2.62 (m, 2H), 2.42-2.36 (m, 2H), 2.05-1.90 (m, 1H), 1.79-1.72 (m, 2H), 1.40-1.30 (m, 1H), 1.17-1.03 (m, 2H), 0.95 (d, J = 7.0 Hz, 6H), 0.87 (s, 6H).123276-03120

[0681] Example 55: l-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)methanamine.

[0682]

[0683] Example 55

[0684] Step 1: (l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methanol

[0685] The title compound was synthesized in the same manner of step 1 for Example 51. Yield: 2.00 g. LCMS: m / z 2 [M+H]+.

[0686] Step 2: l-((2-ethylphenyl)sulfonyl)piperidine-4-carbaldehyde

[0687] The title compound was synthesized in the same manner of step 2 for Example 51. Yield: 1.80 g, 6.40 mmol, 64% over 2 steps. LCMS: m / z 282.2 [M+H]+.

[0688] Step 3: l-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)methanamine, Example 55.

[0689] Example 55 was synthesized in the same manner of step 3 for Example 49. Yield: 0.26 g, 0.56 mmol, 30%. LCMS: m / z 445.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.75 (d, J = 8.0 Hz, 1H), 7.60-7.55 (m, 1H), 7.49-7.45 (m, 1H), 7.42-7.36 (m, 1H), 7.16 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.5 Hz, 2H), 3.69-3.66 (m, 2H), 3.59-3.52 (m, 4H), 2.94 (q, J = 7.5 Hz, 2H), 2.60-2.52 (m, 4H), 2.31-2.27 (m, 2H), 1.99-1.90 (m, 1H), 1.77-1.70 (m, 2H), 1.50-1.40 (m, 1H), 1.18 (t, J = 7.5 Hz, 3H) 1.11-0.99 (m, 2H), 0.94 (d, J = 6.5 Hz, 6H).123276-03120

[0690] Example 56: 2-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-6-isobutoxy-l, 2,3,4-tetrahydroisoquinoline

[0691]

[0692] Step 1 : 2-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-6-isobutoxy-l,2,3,4-tetrahydroisoquinoline, Example 56

[0693] Example 56 was synthesized in the same manner of step 3 for Example 49. Yield: 3.0 mg, 0.007 mmol, 2%. LCMS: m / z 471.2 [M+H]+. 'H NMR (500 MHz, CD3OD) 67.86 (d, J = 8.0 Hz, 1H), 7.61-7.55 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.42-7.35 (m, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.87-6.77 (m, 2H), 4.58-4.47 (m, 1H), 4.29-4.17 (m, 1H), 3.83-3.65 (m, 5H), 3.44-3.33 (m, 1H), 3.26-3.07 (m, 4H), 3.02 (q, J= 7.5 Hz, 2H), 2.78-2.70 (m, 2H), 2.16-1.98 (m, 2H), 1.97-1.81 (m, 1H), 1.44-1.32 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H), 1.01 (d, J = 6.5 Hz, 6H).

[0694] Example 57: N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-2-(6-methoxypyri din-2 -yl)ethan-l -amine.

[0695]

[0696] Example 57 Step 1 : N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-2-(6-methoxypyri din-2-yl)ethan-l -amine, Example 57

[0697] Example 57 was synthesized in the same manner of step 3 for Example 49. Yield: 0.22 g, 0.52 mmol, 27%. LCMS: m / z 418.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.75 (d, J = 8.0 Hz, 1H), 7.64-7.51 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.42-7.35 (m, 1H), 6.79 (d, J = 7.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 3.78 (s, 3H), 3.60-3.53 (m, 2H), 2.93 (q, J = 7.5 Hz, 2H), 2.83-2.69 (m, 4H), 2.56-2.52 (m, 2H), 2.38-2.34 (m, 2H), 1.74-1.66 (m, 2H), 1.67- 1.53 (m, 1H), 1.49-1.34 (m, 1H), 1.18 (t, J = 7.5 Hz, 3H), 1.11-1.00 (m, 2H).123276-03120

[0698] Example 58: N-((l -((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-2-(4-isobutoxyphenyl)ethan- 1 -amine

[0699]

[0700] Step 1: N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-2-(4-isobutoxyphenyl)ethan-l-amine, Example 58

[0701] Example 58 was synthesized in the same manner of step 3 for Example 49. Yield: 0.09 g, 0.21 mmol, 38%. LCMS: m / z 459.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.75 (d, J = 8.0 Hz, 1H), 7.62-7.55 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.41-7.36 (m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H), 3.66 (d, J = 6.5 Hz, 2H), 3.58-3.52 (m, 4H), 2.93 (q, J = 7.5 Hz, 2H), 2.63-2.52 (m, 4H), 2.35 (d, J = 6.5 Hz, 2H), 2.01-1.92 (m, 1H), 1.74-1.67 (m, 2H), 1.50-1.40 (m, 1H), 1.18 (t, J = 7.5 Hz, 3H), 1.11-1.01 (m, 2H), 0.94 (d,J= 7.0 Hz, 6H).

[0702] Example 59: N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-2-(4-isobutoxyphenyl)ethan- 1 -amine

[0703]

[0704] Step 1: tert-butyl (2-(6-hydroxypyridin-3-yl)ethyl)carbamate123276-03120

[0705] A solution of 5-(2-aminoethyl)-l,2-dihydropyridin-2-one dihydrochloride (1.36 g, 6.48 mmol) and triethylamine (25.9 mmol, 3.61 mL) in MeOH (15 ml) was cooled to 0 °C. To this stirred solution, di-tert-butyl dicarbonate (1.69 g, 7.77 mmol) was added and the mixture was allowed to warm up to room temperature and stirred for a further 18 hours. The reaction mixture was concentrated under reduced pressure, then was diluted with water (30 mL), extracted with EtOAc (3 x 20 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to afford the title compound. Yield: 1.50 g, 5.98 mmol, 92%. LCMS: m / z 239.2 [M+H]+.

[0706] Step 2: tert-butyl (2-(6-isobutoxypyridin-3-yl)ethyl)carbamate

[0707] To a solution of tert-butyl (2-(6-hydroxypyridin-3-yl)ethyl)carbamate (0.80 g, 3.36 mmol) in toluene (30 mL), l-bromo-2-m ethylpropane (0.68 mg, 5.04 mmol), silver carbonate (0.46 g, 1.68 mmol) was added before the mixture was stirred at 100 °C for 18 hours. The mixture was cooled, filtered and concentrated under reduced pressure. The residue was diluted with water (20 mL) extracted with EtOAc (2 x 20 mL). The combined organics were washed with brine (20 mL), dried over sodium sulfate, concentrated under reduced pressure to afford the title compound. Yield: 0.65 g, 2.19 mmol, 65%. LCMS: m / z'. 295.2 [M+H]+. Step 3: 2-(6-isobutoxypyridin-3-yl)ethan-l -amine

[0708] To a solution of tert-butyl (2-(6-isobutoxypyridin-3-yl)ethyl)carbamate (0.65 g, 2.19 mmol), trifluoroacetic acid (1.69 mL, 21.93 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours before being concentrated under reduced pressure. The residue was diluted with IM NaOH (15 mL), extracted with methylene chloride (3 x 10 mL). The combined organics were dried over sodium sulfate, concentrated under reduced pressure to afford the title compound. Yield: 0.37 g, 1.91 mmol, 87%. LCMS: m z 195.2 [M+H]+.

[0709] Step 4: N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-2-(6-isobutoxypyridin-3-yl)ethan-l -amine, Example 59.

[0710] Example 59 was synthesized in the same manner of step 3 for Example 49. Yield: 0.07 g, 0.14 mmol, 7%. LCMS: m z 460.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.92 (d, J = 2.5 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.61-7.57 (m, 1H), 7.54-7.45 (m, 2H), 7.43-7.35 (m, 1H), 6.68 (d, J = 8.5 Hz, 1H), 3.95 (d, J = 7.0, 2H), 3.58-3.53 (m, 2H), 2.93 (q, J = 7.5 Hz, 2H), 2.64-2.51 (m, 7H), 2.37-2.32 (m, 2H), 2.03-1.93 (m, 1H), 1.77-1.66 (m, 2H), 1.47-1.36 (m, 1H), 1.18 (t, J = 7.5 Hz, 3H), 1.10-1.00 (m, 2H), 0.92 (d, J = 7.0 Hz, 6H).123276-03120

[0711] Example 60: N-((l -((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-2-(4-propoxyphenyl)ethan- 1 -amine

[0712] 1) (COCI)2, DCM

[0713]

[0714] Step 1: 2-(4-propoxyphenyl)ethan-l -amine hydrochloride

[0715] To a solution of 3-(4-propoxyphenyl)propanoic acid (2.01 g, 9.65 mmol) in 10 mL of dry methylene chloride, oxalyl chloride (1.34 g, 10.62 mmol) was added dropwise and stirred for 2 hours at room temperature, before the volatiles were removed under reduced pressure. The residue was dissolved in 5 mL of dry THF and added dropwise to a vigorously stirred suspension of sodium azide (2.51 g, 38.6 mmol) in 3 mL of water and 17 mL of THF at 0 °C. The resulting suspension was stirred for 18 hours at room temperature. The mixture was diluted with 50 mL of MTBE, washed with water (4 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 20 mL of toluene and heated at 100 °C for 2 hours. The mixture was cooled to 80 °C and treated with 10 mL of 10% aqueous hydrochloric acid. The obtained biphasic mixture was stirred at 80 °C for 18 hours. Upon cooling to room temperature, the aqueous phase was separated, evaporated to dryness and vacuum-dried to afford the title compound. Yield: 0.69 g, 3.19 mmol, 33%. LCMS: m / r. 180.2 [M+H]+.

[0716] Step 2: N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-2-(4-propoxyphenyl)ethan-l-amine, Example 60

[0717] Example 60 was synthesized in the same manner of step 3 for Example 49. Yield: 0.07 g, 0.16 mmol, 36%. LCMS: m / z 445.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.75 (d, J = 8.0 Hz, 1H), 7.62-7.56 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.41-7.36 (m, 1H), 7.06 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 3.86-3.82 (m, 2H), 3.58-3.53 (m, 2H), 2.93 (q, J = 7.5 Hz, 2H), 2.65 -2.51 (m, 6H), 2.35 (d, J = 7.0 Hz, 2H), 1.73-1.63 (m, 4H), 1.45-1.37 (m, 1H), 1.18 (t, J = 7.5 Hz, 3H), 1.11-1.00 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H).123276-03120

[0718] Example 61: N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-2-(4-(2,2,2-trifluoroethoxy)phenyl)ethan- 1 -amine

[0719] 1) GDI, NH3ITHF

[0720]

[0721] Step 1: 2-(4-(2,2,2-trifluoroethoxy)phenyl)ethan-l -amine

[0722] To a solution of 2-[4-(2,2,2-trifluoroethoxy)phenyl]acetic acid (1.60 g, 6.84 mmol) in 15 mL of dry THF, l-(lH-imidazole-l-carbonyl)-lH-imidazole (1.44 g, 8.90 mmol) was added and the resulting solution was stirred at room temperature for 3 hours. The solution was saturated with NH3 gas and kept at the ambient temperature for 18 hours, before the volatiles were removed under reduced pressure, the residue was taken up in 20 mL of EtOAc and washed with 15 mL of 20% aqueous sodium bisulfate, dried over sodium sulfate and concentrated under reduced pressure. The solid was dissolved in 5 mL of dry THF and added to a suspension of lithium aluminum hydride (0.93 g, 27.37 mmol) in 30 mL of dry THF under argon. The mixture was stirred at room temperature for 18 hours, before cooling to 0 °C, and carefully quenched by the addition of 40% aqueous NaOH (5 mL). The solids were filtered and discarded, while the filtrate was evaporated to afford the title compound which was used without further purification. Yield: 0.69 g. LCMS: m / z'. 220.0 [M+H]+.

[0723] Step 2: N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-2-(4-(2,2,2-trifluoroethoxy)phenyl)ethan-l -amine, Example 61.

[0724] Example 61 was synthesized in the same manner of step 3 for Example 49. Yield: 0.02 g, 0.05 mmol, 1% over 2 steps. LCMS: m z 485.1 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.75 (d, J = 8.0 Hz, 1H), 7.61-7.56 (m, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.41-7.35 (m, 1H), 7.12 (d, J= 8.5 Hz, 2H), 6.92 (d, J= 8.5 Hz, 2H), 4.71-4.63 (m, 2H), 3.60-3.54 (m, 2H), 2.96-2.89 (m, 2H), 2.66-2.52 (m, 6H), 2.38-2.32 (m, 2H), 1.74-1.67 (m, 2H), 1.46-1.37 (m, 1H), 1.18 (t, J= 7.5 Hz, 3H), 1.11-1.00 (m, 2H).123276-03120

[0725] Example 62: (4-(((4-isobutoxybenzyl)amino)methyl)piperidin-l-yl)(2-(trifluoromethoxy)phenyl)methanone

[0726] 1) (COCI)2, DCM

[0727]

[0728] Example 62

[0729] Step 1 : (4-(hy droxymethyl)piperi din- l-yl)(2-(trifluoromethoxy)phenyl)m ethanone

[0730] To a stirred solution of 2-(trifluoromethoxy)benzoic acid (2.25 g, 10.93 mmol) in methylene chloride (50 mL) and DMF (0.1 mL) was added oxalyl chloride (2.75 g, 21.86 mmol) dropwise. The reaction mixture was stirred for 4 hours at room temperature and concentrated under reduced pressure. The residue was dissolved in methylene chloride (50 mL), and was added dropwise to a stirred solution of (piperidin-4-yl)methanol (1.39 g, 12.05 mmol) and triethylamine (2.21 g, 21.9 mmol) in methylene chloride (50 mL) which was cooled to 0 °C. The reaction mixture was stirred at room temperature for 18 hours before being diluted with 1.0 M aqueous hydrochloric acid (70 mL). The resulting mixture was extracted with methylene chloride (3 x 50 mL). The organic layers were combined, washed with 1.0 M sodium hydrogen carbonate (70 mL), brine (70 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. Yield: 2.47 g, 8.16 mmol, 74%. LCMS: m / z 304.0 [M+H]+.

[0731] Step 2: l-(2-(trifluoromethoxy)benzoyl)piperidine-4-carbaldehyde.

[0732] To a stirred solution of DMSO (26.98 mmol, 1.93 mL) cooled to -78 °C in methylene chloride (50 mL), oxalyl chloride (1.14 mL, 13.49 mmol) was added dropwise, and the mixture was stirred for an additional 30 minutes. To this solution, (4-(hydroxymethyl)piperidin-l-yl)(2-(trifluoromethoxy)phenyl)methanone (2.47 g, 8.16 mmol) in methylene chloride (30 mL) was added a dropwise at -78 ° C and was stirred for 30 minutes. Tri ethylamine (7.83 mL, 56.21 mmol) was added a dropwise and this mixture was stirred for an additional 30 minutes at -78 ° C before the mixture was warmed to room temperature and stirred another 30 minutes. The reaction mixture was quenched with water123276-03120

[0733] (70 mL) and extracted with methylene chloride (3 x 30 mL), the organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. Yield: 2.37 g, 7.90 mmol, 96%. LCMS: m / z 302.0 [M+H]+.

[0734] Step 3: (4-(((4-isobutoxybenzyl)amino)methyl)piperidin-l-yl)(2-(trifluoromethoxy)phenyl)methanone, Example 62.

[0735] Example 62 was synthesized in the same manner of step 3 for Example 49. Yield: 0.22 g, 0.46 mmol, 27%. LCMS: m / z 465.0 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 8 7.58-7.49 (m, 1H), 7.47-7.39 (m, 3H), 7.17 (d, J= 8.5 Hz, 2H), 6.82 (d, J= 8.5 Hz, 2H), 4.49-4.41 (m, 1H), 3.68 (d, J= 6.5 Hz, 2H), 3.57 (s, 2H), 3.26-3.20 (m, 2H), 2.99-2.90 (m, 1H), 2.76-2.68 (m, 1H), 2.37-2.27 (m, 2H), 2.01-1.91 (m, 1H), 1.85-1.75 (m, 1H), 1.70-1.57 (m, 2H), 0.95 (d, J= 6.5 Hz, 6H).

[0736] Example 63: 4-((2-(4-isobutoxybenzyl)pyrrolidin- 1 -yl)methyl)- 1 -((2- (trifluoromethoxy)phenyl)sulfonyl)piperidine

[0737]

[0738] Example 63 Me Step 1: tert-butyl 2-(4-isobutoxybenzyl)pyrrolidine-l-carboxylate

[0739] 4-[(Pyrrolidin-2-yl)methyl]phenol hydrochloride (0.76 g, 3.60 mmol) and triethylamine (0.43 g, 4.33 mmol) were dissolved in 30 mL of dry methanol. To this mixture di-tert-butyl dicarbonate (0.86 g, 3.97 mmol) was added and the mixture was stirred for 18 hours at room temperature. The mixture was concentrated under reduced pressure and the residue was taken up in MTBE (50 mL) and washed with water (3x 50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in DMF (20 mL) and potassium carbonate (2.18 g, 15.81 mmol) was added, and the mixture was123276-03120

[0740] stirred at room temperature for 1 hour before the dropwise addition of l-bromo-2-methylpropane (0.86 g , 6.32 mmol). The mixture was stirred at 60 °C for three days (72h). The mixture was cooled to room temperature and filtered. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (3x 20 ml), the organic phases were combined and washed with brine (3x 20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound which was used in the next step without purification. Yield: 1.05 g. LCMS: m / z T&2 [M-'Bu+H] ,

[0741] Step 2: 2-(4-isobutoxybenzyl)pyrrolidine hydrochloride

[0742] tert-butyl 2-(4-isobutoxybenzyl)pyrrolidine-l -carboxylate (1.05 g, 3.13 mmol) was dissolved in Dioxane-HCl (2.2M, 10 mL) and stirred at room temperature for 18 hours, before concentrated under reduced pressure to afford the title compound which was used in the next step without purification. Yield: 0.64 g. LCMS: m / z 233.2 [M+H]+.

[0743] Step 3: 4-((2-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine, Example 63.

[0744] Example 63 was synthesized in the same manner of step 3 for Example 49. Yield: 0.22 g, 0.40 mmol, 11% over 3 steps. LCMS: m / z 554.6 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.91 (d, J= 8.0 Hz, 1H), 7.86-7.75 (m, 1H), 7.67-7.53 (m, 2H), 7.04 (d, J= 8.0 Hz, 2H), 6.74 (d, J= 8.0 Hz, 2H), 3.71-3.59 (m, 4H), 3.01-2.92 (m, 1H), 2.76-2.67 (m, 1H), 2.61-2.53 (m, 4H), 2.30-2.20 (m, 1H), 1.99-1.85 (m, 4H), 1.65-1.57 (m, 1H), 1.55-1.42 (m, 4H), 1.37-1.29 (m, 1H), 1.15-1.00 (m, 2H), 0.95 (d, J= 7.0 Hz, 6H).123276-03120

[0745] Example 64: 4-((2-(4-isobutoxybenzyl)pyrrolidin- 1 -yl)methyl)- 1 -((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine

[0746]

[0747] Step 1: tert-butyl 2-(4-isobutoxybenzyl)pyrrolidine-l-carboxylate

[0748] 4-[(Pyrrolidin-2-yl)methyl]phenol hydrochloride (0.76 g, 3.60 mmol) and triethylamine (0.43 g, 4.33 mmol) were dissolved in 30 mL of dry methanol. To this mixture di-tert-butyl dicarbonate (0.86 g, 3.97 mmol) was added and the mixture was stirred for 18 hours at room temperature. The mixture was concentrated under reduced pressure and the residue was taken up in MTBE (50 mL) and washed with water (3x 50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was in THF (40 mL) and to this solution, oxan-4-ol (0.56 g, 5.53 mmol) and triphenylphosphine (0.80 g, 3.04 mmol) was added and cooled to -20°C before the dropwise addition of (E)-N-[(propan-2-yloxy)carbonyl]imino(propan-2-yloxy)formamide (0.62 g, 3.04 mmol). The mixture was allowed to warm to room temperature and stirred at 18 hours. The mixture was concentrated under reduced pressure and the residue purified by HPLC to afford the title compound. Yield: 0.24 g, 0.66 mmol, 18%. LCMS: m / z 360.2.2 [M-'Bu+H] ,

[0749] Step 2: 2-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidine trifluoroacetate

[0750] To a solution of tert-butyl 2-(4-isobutoxybenzyl)pyrrolidine-l-carboxylate (0.23 g, 0.65 mmol) in methylene chloride (5 mL), trifluoroacetic acid (0.22 g, 1.95 mmol) was added and stirred at room temperature for 18 hours, before concentrated under reduced pressure to afford the title compound. Yield: 0.24 g, 0.64 mmol, 98%. LCMS: m / z 262.2 [M+H]+.

[0751] Step 3 : 4-((2-(4-((tetrahydro-2H-pyran-4-yl)oxy)benzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine, Example 64.123276-03120

[0752] Example 64 was synthesized in the same manner of step 3 for Example 49. Yield: 0.11 g, 0.18 mmol, 26%. LCMS: m / z 583.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.91 (d, J= 8.0 Hz, 1H), 7.86-7.75 (m, 1H), 7.67-7.53 (m, 2H), 7.05 (d, J= 8.0 Hz, 2H), 6.74 (d, J = 8.0 Hz, 2H), 4.54-4.42 (m, 1H), 3.88-3.75 (m, 2H), 3.71-3.60 (m, 2H), 3.48-3.36 (m, 2H), 2.99-2.87 (m, 2H), 2.76-2.68 (m, 1H), 2.59-2.52 (m, 1H), 2.40-2.31 (m, 1H), 2.32-2.24 (m, 1H), 2.02-1.84 (m 5H), 1.67-1.42 (m, 5H), 1.34 (d, J = 8.0 Hz, 1H), 1.05-0.95 (m, 2H).

[0753] Example 65: N-(4-isobutoxybenzyl)-2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l -amine.

[0754]

[0755] Step 1 : 2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l-ol

[0756] The title compound was synthesized in the same manner of step 1 for Example 51. Yield: 3.80 g. LCMS: m / z 354.2 [M+H]+.

[0757] Step 2: 2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)acetaldehyde

[0758] tert-butyl 2-(4-isobutoxybenzyl)pyrrolidine-l -carboxylate was synthesized in the same manner of step 2 for Example 51. Yield: 3.00 g, 8.11 mmol, 62% over 2 steps. LCMS: m / z 352.0.2 [M+H]+.

[0759] Step 3 : N-(4-isobutoxybenzyl)-2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperi din-4-yl)ethan-l -amine, Example 65

[0760] Example 65 was synthesized in the same manner of step 3 for Example 49. Yield: 0.18 g, 0.34 mmol, 24%. LCMS: m / z 515.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.90 (d, J= 8.0 Hz, 1H), 7.82-7.77 (m, 1H), 7.63-7.51 (m, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 3.67 (d, J= 6.5 Hz, 2H), 3.64-3.59 (m, 2H), 3.53 (s, 2H), 3.27 (s, 2H), 2.43-123276-03120

[0761] 2.34 (m, 2H), 2.01-1.92 (m, 1H), 1.68-1.54 (m, 2H), 1.43-1.36 (m, 1H), 1.31-1.25 (m, 2H), 1.16-1.00 (m, 2H), 0.94 (d, J= 7.0 Hz, 6H).

[0762] Example 66: l-(4-isobutoxyphenyl)-N-(2-(l-((2-(tri fl uoromethoxy (phenyl (sulfonyl )pi peri di n-4-yl (ethyl Jethan- 1 -amine

[0763]

[0764] Example 66

[0765] Step 1 : l-(4-isobutoxyphenyl)-N-(2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)ethan-l -amine, Example 66

[0766] Example 66 was synthesized in the same manner of step 3 for Example 49. Yield: 0.24 g, 0.43 mmol, 27%. LCMS: m / z 529.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.90 (d, J= 8.0 Hz, 1H), 7.82-7.77 (m, 1H), 7.62-7.54 (m, 2H), 7.15 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 3.67 (d, J= 6.5 Hz, 2H), 3.64-3.56 (m, 2H), 3.55-3.50 (m, 1H), 3.27 (s, 2H), 2.32-2.26 (m, 1H), 2.22-2.14 (m, 1H), 2.01-1.92 (m, 1H), 1.64-1.50 (m, 2H), 1.41-1.32 (m, 1H), 1.27-1.19 (m, 2H), 1.16-1.11 (d, J= 7.0 Hz, 3H), 1.05-0.92 (m, 7H).123276-03120

[0767] Example 67 : 4-(2-(2-(4-isobutoxyphenyl)pyrrolidin- 1 -yl)ethyl)- 1 -((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine.

[0768]

[0769] Example 67

[0770] Step 1: tert-butyl 2-(4-isobutoxyphenyl)pyrrolidine-l -carboxylate

[0771] To a stirred solution of tert-butyl 2-(4-hydroxyphenyl)pyrrolidine-l -carboxylate (1.59 g, 6.05 mmol) and potassium carbonate (1.67 g, 12.11 mmol) in DMF (20 mL), l-bromo-2-methylpropane (1.24 g , 9.08 mmol) was added. The mixture was stirred at 80 °C for 48 hours. The mixture was cooled to room temperature filtered. The filtrate was diluted with water (30 mL) and extracted with ethyl acetate (3x 20 mL), the organic phases were combined and washed with brine (3x 10 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound which was used in the next step without purification. Yield: 1.70 g. LCMS: m / z Q.l' [M-Boc+H]+.

[0772] Step 2: 2-(4-isobutoxyphenyl)pyrrolidine hydrochloride

[0773] tert-butyl 2-(4-isobutoxyphenyl)pyrrolidine-l-carboxylate (1.70 g, 5.32 mmol) was dissolved in methylene chloride (5mL) and Dioxane-HCl (4M, 20 mL) was added and stirred at room temperature for 5 hours, before concentrated under reduced pressure to afford the title compound which was used in the next step without purification. Yield: 1.30 g. LCMS: m / z 1Q2 [M+H]+.

[0774] Step 3 : 4-(2-(2-(4-isobutoxyphenyl)pyrrolidin-l-yl)ethyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine, Example 67

[0775] Example 67 was synthesized in the same manner of step 3 for Example 49. Yield: 0.16 g, 0.27 mmol, 5% over 3 steps. LCMS: m / z 555.2 [M+H]+. 'H NMR (500 MHz, d6-123276-03120

[0776] DMSO) 87.89 (d, J= 8.0 Hz, 1H), 7.85-7.73 (m, 1H), 7.61-7.56 (m, 2H), 7.15 (d, J= 8.0 Hz, 2H), 6.79 (d, J= 8.0 Hz, 2H), 3.70-3.64 (m, 2H), 3.62-3.51 (m, 2H), 3.20-3.14 (m, 2H), 3.08-3.01 (m, 1H), 2.44-2.31 (m, 2H), 2.08-1.85 (m, 4H), 1.80-1.65 (m, 2H), 1.58-1.51 (m, 1H), 1.51-1.40 (m, 1H), 1.39-1.24 (m, 3H), 1.20-1.10 (m, 1H), 1.04-0.97 (m, 1H), 0.94 (d, J= 7.0 Hz, 6H), 0.89-0.80 (m, 1H).

[0777] Example 68: l-(4-isobutoxyphenyl)-N-(2-(l-((2- (trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)propan-l -amine

[0778]

[0779] Step 1: 1 -(4-isobutoxyphenyl)propan-l -one O-m ethyl oxime

[0780] To a stirred solution of l-[4-(2-methylpropoxy)phenyl]propan-l-one (0.33 g, 1.60 mmol) in ethanol (10 mL) and water (20 mL) were added O-methylhydroxylamine hydrochloride (0.32 g, 3.84 mmol) and sodium acetate (0.58 g, 7.05 mmol). The reaction mixture was refluxed for 18 hours. The reaction mixture was concentrated under reduced pressure before being diluted with water (10 mL) and extracted with EtOAc (3 ^ 15 mL). The combined organic layers were combined and washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. Yield: 0.31 g, 1.32 mmol, 77%. LCMS: m / z 236.4 [M+H]+.

[0781] Step 2: l-(4-isobutoxyphenyl)propan-l -amine

[0782] To a stirred solution l-(4-isobutoxyphenyl)propan-l-one O-methyl oxime (0.31 g, 1.32 mmol) in THF (10 mL) was added borane dimethyl sulfide complex (0.63 mL, 6.58 mmol) in one portion and the mixture was stirred at 60 °C for 18 hours. The reaction mixture was cooled to 0 °C and methanol (5 mL) was added dropwise before the reaction mixture was concentrated under reduced pressure. The residue was diluted with methanol (5 mL) and concentrated aqueous hydrochloric acid (5 mL) and the mixture was stirred at 60 °C for 2123276-03120

[0783] hours. The mixture was concentrated under reduced pressure and diluted with 1 M NaOH (15 mL). The resulting mixture was extracted with methylene chloride (3 x 15 mL). The combined organic layers were combined and dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. Yield: 0.19 g, 0.95 mmol, 72%.1H NMR (500 MHz, CDC13) 87.20 (d, J= 8.0 Hz, 2H), 6.85 (d, J= 8.0 Hz, 2H), 3.82-3.72 (m, 2H), 3.69 (d, J= 6.5 Hz, 3H), 2.69 (s, 3H), 2.12-1,99 (m, 1H), 1.83-1.57 (m, 2H), 1.00 (d, J = 6.5 Hz, 6H), 0.82 (t, J= 7.5 Hz, 3H).

[0784] Step 3 : l-(4-isobutoxyphenyl)-N-(2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperi din-4-yl)ethyl)propan-l -amine, Example 68

[0785] Example 68 was synthesized in the same manner of step 3 for Example 49. Yield: 0.07 g, 0.13 mmol, 13%. LCMS: m / z 543.0 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.89 (d, J= 8.0 Hz, 1H), 7.82-7.76 (m, 1H), 7.62-7.56 (m, 2H), 7.11 (d, J= 8.0 Hz, 2H), 6.80 (d, J = 8.0 Hz, 2H), 3.67 (d, J= 6.5 Hz, 2H), 3.62-3.55 (m, 2H), 2.28-2.10 (m, 2H), 2.00-1.91 (m, 1H), 1.60-1.47 (m, 3H), 1.43-1.27 (m, 2H), 1.25-1.17 (m, 2H), 1.05-0.90 (m, 8H), 0.67 (t, J = 7.5 Hz, 3H).

[0786] Example 69: N-ethyl-N-(4-isobutoxybenzyl)-2-(l-((2- (trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l -amine

[0787]

[0788] 123276-03120

[0789] Step 1 : N-(4-isobutoxybenzyl)ethanamine

[0790] To a solution of [4-(2 -methylpropoxy )phenyl]methanamine (0.29 g, 1.63 mmol) in MeOH (7 mL), acetaldehyde (0.1 mL, 1.79 mmol) and acetic acid (0.19 mL, 3.25 mmol) was added. The mixture was stirred at room temperature for 1 hour before the addition of sodium cyanoborohydride (0.11 g, 1.79 mmol) followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, then diluted with water (10 mL) and extracted with methylene chloride (3 x 10 mL). The combined organic layers were combined and washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound, which was used in the next step without purification. Yield: 0.37 g. LCMS: m / z 208.2 [M+H]+.

[0791] Step 2: N-ethyl-N-(4-isobutoxybenzyl)-2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l -amine, Example 69

[0792] Example 69 was synthesized in the same manner of step 3 for Example 49. Yield: 0.03 g, 0.06 mmol, 3% over 2 steps. LCMS: m / z 543.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.90 (d, J = 8.0 Hz, 1H), 7.83-7.77 (m, 1H), 7.68-7.50 (m, 2H), 7.12 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 3.67 (d, J = 6.5 Hz, 2H), 3.63-3.56 (m, 2H), 3.36 (s, 2H), 2.38-2.22 (m, 4H), 2.01-1.92 (m, 1H), 1.57-1.44 (m, 2H), 1.31-1.25 (m, 2H), 1.11-0.92 (m, 12H).

[0793] Example 70: l-((2-ethylphenyl)sulfonyl)-4-(2-(2-(4-isobutoxyphenyl)pyrrolidin-l-yl)ethyl)piperidine

[0794]

[0795] 123276-03120

[0796] Step 1: 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)ethan-l-ol

[0797] The title compound was synthesized in the same manner of step 1 for Example 51. Yield: 0.70 g. LCMS: m / z 298.2 [M+H]+.

[0798] Step 2: 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)acetaldehyde

[0799] The title compound was synthesized in the same manner of step 2 for Example 51. Yield: 0.60 g, 1.91 mmol, 72% over 2 steps. LCMS: m / z 296.2 [M+H]+.

[0800] Step 3 : l-((2-ethylphenyl)sulfonyl)-4-(2-(2-(4-isobutoxyphenyl)pyrrolidin-l-yl)ethyl)piperidine, Example 70.

[0801] Example 70 was synthesized in the same manner of step 3 for Example 49. Yield: 0.13 g, 0.26 mmol, 25%. LCMS: m / z 499.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.73 (d, J= 8.0 Hz, 1H), 7.61-7.56 (m, 1H), 7.48-7.43 (m, 1H), 7.41-7.36 (m, 1H), 7.15 (d, J= 8.0 Hz, 2H), 6.81 (d, J= 8.0 Hz, 2H), 3.68 (d, J= 6.5 Hz, 2H), 3.53-3.41 (m, 2H), 3.20-3.16 (m, 1H), 3.09-3.04 (m, 1H), 2.90 (q, J= 7.5 Hz, 2H), 2.09-1.84 (m, 4H), 1.80-1.63 (m, 2H), 1.59-1.24 (m, 6H), 1.16 (t, J= 7.5 Hz 3H), 1.04-0.81 (m, 8H).

[0802] Example 71: (2-ethylphenyl)(4-(((4-isobutoxybenzyl)amino)methyl)piperidin-l-yl)methanone

[0803]

[0804] Step-1

[0805] Example 71

[0806] Step 1 : (2-ethylphenyl)(4-(((4-isobutoxybenzyl)amino)methyl)piperidin-l-yl)methanone, Example 71

[0807] Example 71 was synthesized in the same manner of step 3 for Example 49. Yield: 0.29 g, 0.69 mmol, 33%. LCMS: m / z 409.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 8 7.34-7.25 (m, 2H), 7.23-7.14 (m, 3H), 7.13-7.04 (m, 1H), 6.82 (d, J= 8.0 Hz, 2H), 4.50 (d, J = 12.0 Hz, 1H), 3.68 (d, J= 6.5 Hz, 2H), 3.56 (s, 2H), 3.30-3.21 (m, 3H), 2.96-2.83 (m, 1H), 2.74-2.64 (m, 1H), 2.37-2.27 (m, 2H), 2.01-1.92 (m, 1H), 1.82-1.76 (m, 1H), 1.66-1.52 (m, 2H), 1.15-0.81 (m, 12H).123276-03120

[0808] Example 72: l-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)-N-((l-(4-isobutoxyphenyl)cyclopentyl)methyl)methanamine

[0809]

[0810] Step 1: (l-(4-isobutoxyphenyl)cyclopentyl)methanamine

[0811] To a solution of l-(4-isobutoxyphenyl)cyclopentane-l-carbonitrile (1.00 g, 4.11 mmol) in 7M ammonia in methanol (50 mL) Raney nickel (CAS 7440-02-0, wet, approx. 0.5 g) was added, and the mixture was stirred at room temperature for 216 hours under hydrogen atmosphere (50 bar). The reaction mixture was filtered, washed with methanol (2 x 10 mL) and concentrated under reduced pressure to afford the title compound, which was used in the next step without further purification. Yield: 0.75 g. LCMS: m / r. 248.2 [M+H]+.

[0812] Step 2: l-((2-chlorophenyl)sulfonyl)-N-((l-(4-isobutoxyphenyl)cyclopentyl)methyl)piperidine-4-carboxamide

[0813] To a stirred solution of l-((2-chlorophenyl)sulfonyl)piperidine-4-carboxylic acid (0.86 g, 2.85 mmol) and triethylamine (1.01 g, 9.97 mmol) in anhydrous methylene chloride (30 mL), (3-[(ethylimino)methylidene]aminopropyl)dimethylamine hydrochloride (0.60 g, 3.13 mmol) and 1 -hydroxybenzotriazole (0.42 g, 3.13 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour before the addition of crude (l-(4-isobutoxyphenyl)cyclopentyl)methanamine (0.75 g) was added. The resulting mixture was stirred at room temperature for 16 hours, before being washed with aqueous IM sodium hydrogen sulfate (50 mL), aqueous IM potassium carbonate (50 mL) and brine (50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. Yield: 1.00 g, 1.87 mmol, 45% over two steps. LCMS: m / . 533.2 [M+H]+.123276-03120

[0814] Step 3: l-(l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)-N-((l-(4-isobutoxyphenyl)cyclopentyl)methyl)methanamine, Example 72.

[0815] To a stirred solution l-((2-chlorophenyl)sulfonyl)-N-((l-(4-isobutoxyphenyl)cyclopentyl)methyl)piperidine-4-carboxamide (0.50 g, 0.78 mmol) in THF (15 mL) was added borane dimethyl sulfide complex (10 M, 0.47 mL, 4.67 mmol) in one portion and the mixture was stirred at 60 °C for 18 hours. The reaction mixture was cooled to 0 °C and methanol (1 mL) was added dropwise before the reaction mixture was concentrated under reduced pressure. The residue was diluted with methanol (10 mL) and concentrated aqueous hydrochloric acid (5 mL) and the mixture was stirred at 60 °C for 3 hours. The mixture was concentrated under reduced pressure and diluted with 1 M NaOH (40 mL). The resulting mixture was extracted with methylene chloride (2 x 20 mL). The combined organic layers were combined, washed with brine (50 mL) and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 72. Yield: 0.20 g, 0.39 mmol, 49%. LCMS: m / r. 519.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.92 (d, J = 8.0 Hz, 1H), 7.69-7.60 (m, 2H), 7.56-7.50 (m, 1H), 7.13 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz, 2H), 3.66 (d, J = 6.5 Hz, 2H), 3.62-3.57 (m, 2H), 2.63-2.56 (m, 2H), 2.21-2.17 (m, 2H), 2.01-1.93 (m, 1H), 1.91-1.85 (m, 2H), 1.74-1.47 (m, 9H), 1.35-1.28 (m, 1H), 0.99-0.84 (m, 9H).123276-03120

[0816] Example 73: (S)-N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-8-isobutoxy-2,3,4,5-tetrahydrobenzofb] [ 1 ,4]oxazepin-3 -amine

[0817] >NH

[0818]

[0819] Boc

[0820] K2CO3

[0821] Acetone

[0822]

[0823]

[0824]

[0825] Step-1 Step-2

[0826]

[0827]

[0828] Step 1: 2-fluoro-4-isobutoxy-l -nitrobenzene

[0829] To a stirred solution of 3-fluoro-4-nitrophenol (9.50 g, 60.5 mmol) and l-bromo-2-methylpropane (24.7 g, 181.5 mmol) in acetone (200 mL), potassium carbonate (16.7 g, 121.0 mmol) was added, and the mixture was refluxed for 72 hours. The mixture was concentrated under reduced pressure and diluted with water (300 mL) and extracted with methylene chloride (3x 150 mL). The organic phases were combined and washed with brine (200 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the123276-03120

[0830] title compound. Yield: 6.50 g, 30.5 mmol, 50%. 'H NMR (400 MHz, CDC13) 68.15-8.06 (m, 1H), 6.80-6.71 (m, 2H), 3.82 (d, J= 7.0 Hz, 2H), 2.22-2.07 (m, 1H), 1.06 (d, J= 6.5 Hz, 6H). Step 2: N-(tert-butoxycarbonyl)-O-(5-isobutoxy-2-nitrophenyl)-D-serine

[0831] To a stirred suspention of sodium hydride (60.0% dispersion in mineral oil, 1.24 g, 31.1 mmol) in anhydrous DMF (50 mL) (tert-butoxycarbonyl)-D-serine (3.06 g, 14.9 mmol) was added portionwise at 0 °C. The resulting mixture was stirred at room temperature for 1 hour before the addition of 2-fluoro-4-isobutoxy-l-nitrobenzene (3.50 g, 16.4 mmol). The resulting mixture was stirred at room temperature for 16 hours then diluted with brine (300 mL) and acidified with 2N HC1 to pH 2-3. The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The organic phases were combined and washed with brine (2 x 100 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield: 5.50 g. LCMS: m / z 421.2 [M+Na]+. Step 3 : O-(2-amino-5-isobutoxyphenyl)-N-(tert-butoxycarbonyl)-D-serine

[0832] To a solution of crude N-(tert-butoxycarbonyl)-O-(5-isobutoxy-2-nitrophenyl)-D-serine (5.5 g) in THF (100 mL) 10% Pd-C (0.50 g) was added, and the mixture was stirred at room temperature for 48 hours under hydrogen atmosphere (1 bar). The mixture was filtered, washed with THF (2 x 20 mL) and concentrated under reduced pressure afford the title compound, which was used without further purification. Yield: 4.80 g. LCMS: m / z 369.2.2 [M+H]+.

[0833] Step 4: tert-butyl (R)-(8-isobutoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate

[0834] To a stirred solution of crude O-(2-amino-5-isobutoxyphenyl)-N-(tert-butoxycarbonyl)-D-serine (4.8 g) and DIPEA (8.40 g, 65.1 mmol) in anhydrous DMF (50 mL) and ethyl acetate (50 mL) T3P (50% ethyl acetate solution, 16.6 g, 26.1 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with brine (500 mL) and extracted with EtOAc (3 x 200 mL). The organic phases were combined and washed with aqueous potassium carbonate (IM, 300 mL), brine (2 x 300 mL) dried over sodium sulfate and concentrated under reduced pressure and the residue by normal phase flash chromatography eluting with 15%-l 00% EtOAc in hexane to afford the title compund. Yield: 1.60 g, 4.57 mmol, 8% over 3 steps. LCMS: m / z 373.2 [M+Na]+. Step 5: (R)-3-amino-8-isobutoxy-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one

[0835] To a stirred solution tert-butyl (R)-(8-isobutoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate (1.60 g, 4.57 mmol) in methylene chloride (15 mL) was added trifluoroacetic acid (15 mL) in one portion. The reaction mixture was123276-03120

[0836] stirred at room temperature for 2 hours, concentrated under reduced pressure and diluted with IM aqueous sodium hydroxide (100 mL). The aqueous layer was extracted with methylene chloride (2 x 50 mL). The organic phases were combined and washed with brine (50 mL) dried over sodium sulfate and concentrated under reduced pressure to afford the title compoud. Yield: 1.14 g, 4.55 mmol, 99%. LCMS: m / zr\.l' [M+H]+.

[0837] Step 6: (R)-3-(((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)amino)-8-isobutoxy-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one

[0838] To a stirred solution of (R)-3-amino-8-isobutoxy-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (0.60 g, 2.40 mmol) and l-((2-ethylphenyl)sulfonyl)piperidine-4-carbaldehyde (0.67 g, 2.40 mmol) in anhydrous methylene chloride (30 mL), acetic acid (0.72 g, 12.0 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour before the addition of sodium trisacetoxyborohydride (1.02 g, 4.8 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture washed with aqueous potassium carbonate (IM, 50 mL), brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield: 1.10 g. LCMS: m / z 516.2 [M+H]+.

[0839] Step 7: (S)-N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-8-isobutoxy-2,3,4,5-tetrahydrobenzofb] [ 1 ,4]oxazepin-3 -amine, Example73.

[0840] To a stirred solution of crude (R)-3-(((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)amino)-8-isobutoxy-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one (650 mg) in THF (15 mL) was added borane dimethyl sulfide complex (10.0 M, 0.67 mL, 6.7 mmol) in one portion. The reaction mixture was stirred at 60 °C for 16 hours at 60 °C before cooling to 0 °C. Methanol (1.4 mL) was added dropwise and the reaction mixture was concentrated under reduced pressure. Methanol (10 mL) and concentrated aqueous hydrochloric acid (5 mL) were added and the resulting mixture was stirred at 60 °C for 3 hours. The mixture was concentrated under reduced pressure and diluted with aqueous IM sodium hydroxide (40 mL). The resulting mixture was extracted with methylene chloride (2 x 20 mL). The organic phases were combined and washed with brine (50 mL) dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 73. Yield: 0.17 g, 0.39 mmol, 15% over two steps. LCMS: m / z 502.2 [M+H]+.1H NMR (500 MHz, d6-DMSO) 87.76 (d, J= 7.5 Hz, 1H), 7.59 (t, J= 7.5 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.39 (d, J= 7.5 Hz, 1H), 6.64 (d, J= 8.5 Hz, 1H), 6.40-6.33 (m, 2H), 4.91-4.86 (m, 1H), 3.93 (dd, J= 12.0, 3.5 Hz, 1H), 3.80 (dd, J= 12.0, 5.5 Hz, 1H), 3.61-3.54 (m, 4H), 3.07-3.01 (m, 1H), 2.98-2.86 (m, 3H), 2.76 (s, 1H), 2.57-2.51 (m, 3H), 2.45-2.37 (m, 2H),123276-03120

[0841] 1.96 -1.85 (m, 1H), 1.80-1.71 (m, 2H), 1.42 (s, 1H), 1.19 (t, J= 7.5 Hz, 3H), 1.13-1.04 (m, 2H), 0.91 (d, J= 6.5 Hz, 6H).

[0842] Example 74: (R)-N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-8-isobutoxy-2, 3,4,5-tetrahydrobenzofb] [ 1 ,4]oxazepin-3 -amine

[0843]

[0844]

[0845] 123276-03120

[0846] Step 1 : N-(tert-butoxycarbonyl)-O-(5-isobutoxy-2-nitrophenyl)-L-serine

[0847] The title compound was synthesized in the same manner of step 2 for Example 73. Yield: 5.00

[0848]

[0849] Step 2: O-(2-amino-5-isobutoxyphenyl)-N-(tert-butoxycarbonyl)-L-serine

[0850] The title compound was synthesized in the same manner of step 3 for Example 73. Yield: 4.50 g. LCMS: m / z 369.4 [M+H]+.

[0851] Step 3: tert-butyl (S)-(8-isobutoxy-4-oxo-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3-yl)carbamate

[0852] The title compound was synthesized in the same manner of step 4 for Example 73. Yield: 1.30 g, 3.71 mmol, 29% over three steps. LCMS: m / z 373.2 [M+Na]+.

[0853] Step 4: (S)-3-amino-8-isobutoxy-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one

[0854] The title compound was synthesized in the same manner of step 5 for Example 73. Yield: 0.92 g, 3.70 mmol, 99%. LCMS: m / z 251.2 [M+H]+.

[0855] Step 5: (S)-3-(((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)amino)-8-isobutoxy-2,3-dihydrobenzo[b][l,4]oxazepin-4(5H)-one

[0856] The title compound was synthesized in the same manner of step 6 for Example 73. Yield: 1.00 g. LCMS: m / z 516.0 [M+H]+.

[0857] Step 6: (R)-N-((l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)methyl)-8-isobutoxy-2,3,4,5-tetrahydrobenzo[b][l,4]oxazepin-3 -amine, Example 74.

[0858] Example 74 was synthesized in the same manner of step 7 for Example 73. Yield: 0.10 g, 0.20 mmol, 6% over two steps. LCMS: m / z 502.2 [M+H] .'H NMR (500 MHz, d6-DMSO) 87.76 (d, J= 7.5 Hz, 1H), 7.59 (t, J= 7.5 Hz, 1H), 7.48 (d, J= 7.5 Hz, 1H), 7.39 (t, J= 7.5 Hz, 1H), 6.64 (d, J= 8.5 Hz, 1H), 6.40-6.33 (m, 2H), 4.91-4.86 (m, 1H), 3.95-3.89 (m, 1H), 3.85-3.78 (m, 1H), 3.61-3.54 (m, 4H), 3.07-3.01 (m, 1H), 2.98-2.86 (m, 3H), 2.76 (s, 1H), 2.57-2.51 (m, 3H), 2.45-2.37 (m, 2H), 1.96-1.86 (m, 1H), 1.80-1.71 (m, 2H), 1.42 (s, 1H), 1.19 (t, J= 7.5 Hz, 3H), 1.13-1.04 (m, 2H), 0.90 (d, J= 6.5 Hz, 6H).123276-03120

[0859] Example 75: N-ethyl-N-(4-(oxetan-3-yloxy)benzyl)-2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l -amine

[0860]

[0861] Example 75

[0862] Step 1 : 4-((ethyl(2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)amino)methyl)phenol

[0863] The title compound was synthesized in the same manner of step 3 for Example 49. Yield: 0.22 g, 0.46 mmol, 40%. LCMS: m / z 487.0 [M+H]+.

[0864] Step 2: N-ethyl-N-(4-(oxetan-3-yloxy)benzyl)-2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l-amine , Example 75.

[0865] To a cooled to -10°C stirring solution of 4-((ethyl(2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)amino)methyl)phenol (0.20 g, 0.41 mmol), oxetan-3-ol (45.8 mg, 0.62 mmol), and diethyl azodicarboxylate (0.12 g, 0.72 mmol) in anhydrous THF (5 mL) triphenylphosphine (0.19 g, 0.74 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was triturated with hexane / EtOAc (9:1) mixture, concentrated and purified by HPLC to afford Example 75. Yield: 0.04 g, 0.07 mmol, 18%. LCMS: m / z 543.0 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.90 (d, J= 7.0 Hz, 1H), 7.82-7.77 (m, 1H), 7.63-7.51 (m, 2H), 7.14 (d, J= 8.5 Hz, 2H), 6.67 (d, J= 8.5 Hz, 2H), 5.24-5.14 (m, 1H), 4.88 (t, J= 7.0 Hz, 2H), 4.50 (t, J= 6.0 Hz, 2H), 3.64-3.57 (m, 2H), 3.37 (s, 2H), 2.39-2.23 (m, 5H), 1.59-1.53 (m, 2H), 1.35-1.19 (m, 3H), 1.07-0.95 (m, 2H), 0.91 (t, J= 7.0Hz, 3H).123276-03120

[0866] Example 76: l-((2-chlorophenyl)sulfonyl)-N-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carbothioamide

[0867]

[0868] Example 76

[0869] Step 1 : l-((2-chlorophenyl)sulfonyl)-N-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carbothioamide, Example 76

[0870] To a stirred solution of l-((2-chlorophenyl)sulfonyl)-N-(2-(4-isobutoxyphenyl)-2- (pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide (50.0 mg, 0.09 mmol) in toluene, 2,4-Bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetane-2,4-dithione (73.7 mg, 0.18 mmol) was added. The reaction mixture was heated at 80 °C for 18 hours before being concentration under reduced pressure. The residue was purified by preparative HPLC to afford Example 76.

[0871] Yield: 6.8 mg, 0.011 mmol, 12%. LCMS: m / r. 564.2 [M+H]+. 'H NMR(500 MHz, CD3OD) 88.01 (d, J= 8.0 Hz, 1H), 7.63-7.56 (m, 2H), 7.50-7.45 (m, 1H), 7.20 (d, J= 8.5 Hz, 2H), 6.86 (d, J= 8.5 Hz, 2H), 4.39-4.34 (m, 1H), 3.84-3.63 (m, 6H), 2.73-2.58 (m, 4H), 2.55-2.38 (m, 3H), 2.05-1.99 (m, 1H), 1.84-1.69 (m, 6H), 1.57-1.48 (m, 2H), 1.01 (d, J= 6.5 Hz, 6H).

[0872] Example 77: l-((2-chlorophenyl)sulfonyl)-N-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-N-methylpiperidine-4-carboxamide

[0873]

[0874] Example 77

[0875] Step 1 : l-((2-chlorophenyl)sulfonyl)-N-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-N-methylpiperidine-4-carboxamide, Example 77

[0876] To a stirred solution of l-((2-chlorophenyl)sulfonyl)-N-(2-(4-isobutoxyphenyl)-2- (pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide (49.0 mg, 0.09 mmol) in DMF (0.5 mL), sodium hydride (2.36 mg, 0.10 mmol) was added and stirred for 30 minutes before the dropwise addition of methyl methanesulfonate (29.53 mg, 0.26 mmol). The resulting solution123276-03120

[0877] was stirred at 50 °C for 18 hours before the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 77. Yield: 21.8 mg, 0.036 mmol, 41%. LCMS: m / z 562.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.93 (d, J= 7.5 Hz, 1H), 7.71-7.62 (m, 2H), 7.56-7.52 (m, 1H), 7.17 (d, J= 8.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.83-6.78 (m, 2H), 3.70-3.46 (m, 5H), 3.38-3.35 (m, 2H), 2.75-2.63 (m, 3H), 2.52 (s, 3H), 2.42-2.19 (m, 4H), 2.01-1.90 (m, 1H), 1.65-1.55 (m, 4H), 1.53-1.19 (m, 4H), 1.03-0.83 (m, 6H).

[0878] Example 78: 2-(((l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)(4- i sobutoxyphenethyl)amino)ethan- 1 -ol

[0879]

[0880] Step 1 : 2-(((l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)(4- isobutoxyphenethyl)amino)ethan-l-ol, Example 78

[0881] To a stirred solution of Example 52, (110.0 mg, 0.23 mmol) in acetonitrile (3 mL), 2-bromoethan-l-ol (0.03 g, 0.26 mmol) and potassium carbonate (0.05 g, 0.35 mmol) was added and heated to 50 °C for 16 hours. The mixture was cooled, diluted with water (10 mL) and extracted with EtOAc (2 x 5 mL). The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 78. Yield: 19.5 mg, 0.038 mmol, 16%. LCMS: m / z 509.2 [M+H]+.

[0882] 'H NMR (500 MHz, d6-DMSO) 87.96-7.90 (m, 1H), 7.77-7.61 (m, 2H), 7.57-7.52 (m, 1H), 7.05 (d, J= 8.0 Hz, 2H), 6.77 (d, J= 8.0 Hz, 2H), 4.23-4.17 (m, 1H), 3.69-3.60 (m, 4H), 3.40-3.34 (m, 2H), 2.61-2.52 (m, 6H), 2.25-2.21 (m, 2H), 2.00-1.92 (m, 1H), 1.64-1.57 (m, 2H), 1.41 (s, 1H), 0.98-0.89 (m, 8H).

[0883] Example 79: N-((l -((2-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-2-(4-isobutoxyphenyl)- N-methylethan-1 -amine

[0884]

[0885] 123276-03120

[0886] Step 1 : N-((l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-2-(4-isobutoxyphenyl)-N-methylethan-1 -amine, Example 79

[0887] A mixture of Example 52 (72.8 mg, 0.15 mmol) and formaldehyde (18.8 mg, 0.62 mmol) in MeOH (10 mL) was stirred at room temperature for 30 minutes, followed by addition of sodium triacetoxyborohydride (132.79 mg, 0.62 mmol) and acetic acid (0.2 mL). The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was diluted with chloroform (30 mL), and washed with aqueous saturated sodium bicarbonate (2 x 20 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 79. Yield: 44.3 mg, 0.092 mmol, 59%. LCMS: m / r. 479.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.97-7.91 (m, 1H), 7.71-7.61 (m, 2H), 7.57-7.50 (m, 1H), 7.09-7.03 (m, 2H), 6.80-6.75 (m, 2H), 3.68-3.61 (m, 4H), 2.67-2.2.52 (m, 4H), 2.44-2.38 (m, 2H), 2.15-2.08 (m, 5H), 2.03-1.89 (m, 1H), 1.66-1.60 (m, 2H), 1.56-1.45 (m, 1H), 1.02-0.89 (m, 8H).

[0888] Example 80: l-((2-chlorophenyl)sulfonyl)-4-((3-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)piperidine

[0889]

[0890] Step-4

[0891] Example 80

[0892] Step 1: tert-butyl 4-((3-(4-hydroxybenzyl)pyrrolidin-l-yl)methyl)piperidine-l -carboxylate To a solution of 4-[(pyrrolidin-3-yl)methyl]phenol hydrobromide (1.51 g, 5.86 mmol) in MeOH (30 mL) was added DIPEA (1.02 mL, 5.86 mmol). The mixture was stirred at room123276-03120

[0893] temperature for 10 minutes before the addition of acetic acid (0.704 mL, 11.72 mmol) and tert-butyl 4-formylpiperidine-l -carboxylate (1.31 g, 6.15 mmol). The mixture was stirred at room temperature for 1 hour before sodium cyanoborohydride (0.41 g, 6.45 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, then was diluted with water (15 mL) before extraction with methylene chloride (3 x 15 mL). The organic phases were combined, washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compund. Yield: 1.54 g, 4.13 mmol, 70%. LCMS: m / z 375.2 [M+H]+.

[0894] Step 2: tert-butyl 4-((3-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)piperidine-l-carboxylate The title compound was synthesized in the same manner of step 1 for Example 67. Yield: 0.50 g. LCMS: m / z 431.4 [M+H]+.

[0895] Step 3: 4-((3-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)piperidine dihydrochloride The title compound was synthesized in the same manner of step 2 for Example 49. Yield: 0.20 g. LCMS: m / z 331.2 [M+H]+.

[0896] Step 4: l-((2-chlorophenyl)sulfonyl)-4-((3-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)piperidine, Example 80.

[0897] To a 0 °C stirred solution of crude 4-((3-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)piperidine dihydrochloride (0.20 g) and DIPEA (0.08 mL, 0.44 mmol) in methylene chloride (10 mL) was added a 2-chlorobenzene-l -sulfonyl chloride (0.02 g, 0.093 mmol). The reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was diluted with 1.0 M aqueous sodium hydrogencarbonate (15 mL) and extracted with methylene chloride (3 x 50 mL). The organic phases were combined, washed with brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 80. Yield: 0.03 g, 0.058 mmol, 1% over 3 steps. LCMS: m / z 505.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.94 (d, J = 8.0 Hz, 1H), 7.70-7.60 (m, 2H), 7.56-7.50 (m, 1H), 7.04 (d, J= 8.0 Hz, 2H), 6.78 (d, J= 8.0 Hz, 2H), 3.70-3.64 (m, 4H), 2.70-2.61 (m, 2H), 2.39-2.24 (m, 3H), 2.21-2.10 (m, 2H), 2.05-1.90 (m, 2H), 1.81-1.67 (m, 3H), 1.55-1.41 (m, 1H), 1.38-1.28 (m, 1H), 1.08-0.97 (m, 2H), 0.94 (d, J = 6.5 Hz, 6H).123276-03120

[0898] Example 81: N-((l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-N-(4- isobutoxyphenethyl)-2-methoxyethan-l-amine

[0899]

[0900] Step 1 : N-((l-((2-chlorophenyl)sulfonyl)piperidin-4-yl)methyl)-N-(4-isobutoxyphenethyl)-2- m ethoxy ethan-1 -amine, Example 81.

[0901] Example 81 was synthesized in the same manner of step 1 for Example 78. Yield: 41.0 mg, 0.078 mmol, 34%. LCMS: m / z 527.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 8 7.95-7.90 (m, 1H), 7.69-7.59 (m, 2H), 7.57-7.52 (m, 1H), 7.05 (d, J= 8.0 Hz, 2H), 6.77 (d, J = 8.0 Hz, 2H), 3.69-3.60 (m, 4H), 3.40-3.34 (m, 2H), 3.19 (s, 3H), 2.65-2.52 (m, 8H), 2.25- 2.21 (m, 2H), 2.00-1.90 (m, 1H), 1.64-1.57 (m, 2H), 1.41 (s, 1H), 0.98-0.89 (m, 8H).

[0902] Example 82 : N-(2-(3 -(2-(3 -(but-3 -yn- 1 -y 1 ) -3 H-di azirin-3 -yl)ethoxy)phenyl)-2-(pyrrolidin- 1 -yl)ethyl)-l-((2-ethylphenyl)sulfonyl)piperidine-4-carboxamide.

[0903]

[0904] Example 82

[0905] Step 1: l-((2-ethylphenyl)sulfonyl)-N-(2-(3-hydroxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0906] The title compound was synthesized in the same manner of step 2 for Example 36. Yield: 4.00 g, 7.8 mmol, 50%. LCMS: m / z 486.4 [M+H]+.123276-03120

[0907] Step 2 : N-(2-(3 -(2-(3 -(but-3 -yn- 1 -yl)-3H-diazirin-3 -yl)ethoxy)phenyl)-2-(pyrrolidin- 1 -yl)ethyl)- 1 -((2-ethylphenyl)sulfonyl)piperidine-4-carboxamide, Example 82

[0908] To a stirred mixture of l-((2-ethylphenyl)sulfonyl)-N-(2-(3-hydroxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide (0.36 g, 0.74 mmol) and potassium carbonate (0.51 g, 3.71 mmol) in DMF (10 mL), 3-(2-bromoethyl)-3-(but-3-yn-l-yl)-3H-diazirine (0.14 g, 0.74 mmol) was added. The reaction mixture was heated at 60 °C for 18 hours. The mixture was concentration under reduced pressure before the residue was diluted with water (30 mL) and extracted with methylene chloride (2 x 20 mL). The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford Example 82. Yield: 4.6 mg, 0.007 mmol, 1%. LCMS: m / z 606.4 [M+H]+. 'H NMR (500 MHz, CD3OD) 87.83 (d, J= 8.0 Hz, 1H), 7.60-7.51 (m, 1H), 7.46 (d, J= 7.5 Hz, 1H), 7.40-7.32 (m, 1H), 7.26-7.18 (m, 1H), 6.92-6.75 (m, 3H), 3.86-3.72 (m, 3H), 3.67-3.56 (m, 2H), 3.38-3.31 (m, 2H), 2.99 (q, J= 7.5 Hz, 2H), 2.67-2.54 (m, 4H), 2.49-2.40 (m, 2H), 2.30-2.25 (m, 1H), 2.16-1.97 (m, 3H), 1.87 (t, J= 6.0 Hz, 2H), 1.82-1.73 (m, 4H), 1.70-1.44 (m, 6H), 1.25 (t, J= 7.5 Hz, 3H).123276-03120

[0909] Example 83: N-((6-isobutoxypyridin-3-yl)methyl)-N-methyl-2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l -amine

[0910]

[0911] Example 83

[0912] Step 1 : 6-isobutoxynicotinaldehyde

[0913] To a stirred mixture of 6-hydroxypyridine-3-carbaldehyde (0.99 g, 8.11 mmol) and silver carbonate (1.11 g, 4.06 mmol) in toluene (30 mL) was added l-iodo-2-methylpropane (2.8 mL, 24.34 mmol). The reaction mixture was stirred at 100 °C for 48 hours, filtered and concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield: 0.73 g. LCMS: m / r. 180.2 [M+H]+.

[0914] Step 2: tert-butyl 4-(2-(((6-isobutoxypyridin-3-yl)methyl)(methyl)amino)ethyl)piperidine-l-carboxylate

[0915] To a solution of crude 6-isobutoxynicotinaldehyde (0.73 g) in MeOH (30 mL) were added acetic acid (0.49 gg, 8.15 mmol) and tert-butyl 4-[2-(methylamino)ethyl]piperidine-l-carboxylate (0.98 g, 4.08 mmol). The mixture was stirred at room temperature for 1 hour before the addition of sodium cyanoborohydride (0.29 g, 4.89 mmol) followed by stirring at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, then diluted with water (20 mL), extracted with methylene chloride (3 x 15 mL). The organic phases were combined, washed with brine (15 mL), dried over sodium sulfate123276-03120

[0916] and concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield: 0.97 g. LCMS: m / z 406.4 [M+H]+.

[0917] Step 3 : N-((6-isobutoxypyridin-3-yl)methyl)-N-methyl-2-(piperidin-4-yl)ethan-l-amine trihydrochloride

[0918] To a solution of crude tert-butyl 4-(2-(((6-isobutoxypyridin-3-yl)methyl)(methyl)amino)ethyl)piperidine-l -carboxylate (0.97 g) in MeOH (5 mL) was added Dioxane*HCl (15 mL, 4M). The reaction mixture was then stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield: 0.40 g. LCMS: m z. 306.2 [M+H]+.

[0919] Step 4: N-((6-isobutoxypyridin-3-yl)methyl)-N-methyl-2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l -amine, Example 83.

[0920] Example 83 was synthesized in the same manner of step 4 for Example 80. Yield: 86.0 mg, 0.15 mmol, 4% over 4 steps. LCMS: m z 530.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.94 (d, J= 2.5 Hz, 1H), 7.90 (dd, J= 8.0, 2.0 Hz, 1H), 7.84-7.77 (m, 1H), 7.64-7.50 (m, 3H), 6.71 (d, J= 8.5 Hz, 1H), 3.97 (d, J= 6.5 Hz, 2H), 3.65-3.58 (m, 2H), 3.32 (s, 2H), 2.26-2.20 (m, 2H), 2.04-1.93 (m, 4H), 1.62-1.56 (m, 2H), 1.34-1.28 (m, 3H), 1.12-0.95 (m, 2H), 0.93 (d, J= 6.5 Hz, 6H).

[0921] Example 84: 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-((6-isobutoxypyridin-3-yl)methyl)-N-methylethan-l -amine

[0922]

[0923] Step 1 : 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-((6-isobutoxypyridin-3-yl)methyl)-N-methylethan-1 -amine, Example 84

[0924] Example 84 was synthesized in the same manner of step 4 for Example 80. Yield: 78.0 mg, 0.16 mmol, 4% over 4 steps. LCMS: m / z 474.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.95 (d, J= 2.5 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.62-7.52 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.41-7.35 (m, 1H), 6.72 (d, J= 8.5 Hz, 1H), 3.97 (d, J= 6.5 Hz, 2H), 3.57-3.49 (m, 2H), 3.28 (s, 3H), 2.92 (q, J= 7.5 Hz, 2H), 2.28-2.22 (m, 2H), 2.04 (s, 3H), 1.98 (m, 1H),123276-03120

[0925] 1.64-1.56 (m, 2H), 1.37-1.28 (m, 3H), 1.18 (t, J= 7.5 Hz, 3H), 1.09-0.99 (m, 2H), 0.93 (d, J = 6.5 Hz, 6H).

[0926] Example 85: 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)-N-(2-m ethoxy ethyl)ethan-l -amine

[0927]

[0928] Example 85

[0929] Step 1: 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)acetic acid

[0930] A solution of ethyl 2-(piperidin-4-yl)acetate hydrochloride (1.24 g, 6.42 mmol) and triethylamine (1.62 g, 16.06 mmol) in methylene chloride (40 mL) was cooled to 0 °C. To this solution, 2-ethylbenzene-l -sulfonyl chloride (1.31 g, 6.42 mmol) in 10 mL of DCM was added dropwise, and the mixture was stirred for 2 hours. After that it was washed with saturated aqueous sodium bicarbonate (50 mL), the organic phase was dried over anhydrous sodium sulfate, evaporated and redissolved in 20 ml of EtOH. The solution was then treated with sodium hydroxide (1.03 g, 25.69 mmol) in 5 mL of water. The resulting solution was mixed overnight. It was then concentrated under reduced pressure. The residue was diluted with water (50 mL) and washed with 25 mL of MTBE. The aqueous phase was acidified to pH 4 by adding 20% aqueous sodium bisulfate. The mixture was extracted with methylene123276-03120

[0931] chloride (2x 35 mL). The organic phases were combined, washed with water (30 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound. Yield: 1.40 g, 4.50 mmol, 70%. LCMS: m / z 312.0 [M+H]+.

[0932] Step 2: 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)acetamide A mixture of (3-[(ethylimino)methylidene]aminopropyl)dimethylamine hydrochloride (1.13 g, 5.92 mmol), 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)acetic acid (1.32 g, 4.23 mmol), and lH-l,2,3-benzotriazol-l-ol (0.85 g, 6.35 mmol) in DMF (4 mL) was stirred at room temperature for 10 minutes before the addition of [4-(2-methylpropoxy)phenyl]methanamine (0.75 g, 4.23 mmol). The resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 15 mL). The organic phases were combined, washed with water (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield: 2.20 g. LCMS: m / z 473.2 [M+H]+.

[0933] Step 3 : 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)acetamide To a stirred solution of crude 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)acetamide (2.06 g) in 40 mL of dry THF, borane dimethylsulfide (1.33 g, 17.44 mmol) was added dropwise under argon. The solution was heated at reflux for 18 hours. Upon cooling to room temperature, the excessive borane was quenched by the slow addition of 10% aqueous HC1 (10 mL). The solution was heated at 80 °C for 2 hours. The reaction mixture was then evaporated to half of the initial volume, basified by the addition of 10% aqueous sodium hydroxide (10 mL) and extracted with methylene chloride (3 x 10 mL). The organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield: 1.00 g. LCMS: m / z 459.2 [M+H]+.

[0934] Step 4: 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)-N-(2-m ethoxy ethyl)ethan-l -amine, Example 85

[0935] Example 85 was synthesized in the same manner of step 1 for Example 78. Yield: 67.0 mg, 0.13 mmol, 3% over 3 steps. LCMS: m / z 517.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.74 (d, J= 7.5 Hz, 1H), 7.62-7.56 (m, 1H), 7.47 (d, J= 7.5 Hz, 1H), 7.41-7.35 (m, 1H), 7.13 (d, J= 8.0 Hz, 2H), 6.81 (d, J= 8.0 Hz, 2H), 3.67 (d, J= 6.5 Hz, 2H), 3.54-3.47 (m, 2H), 3.43 (s, 2H), 3.37-3.32 (m, 2H), 3.17 (s, 3H), 2.92 (q, J= 7.5 Hz, 2H), 2.37-2.30 (m, 2H), 2.01-1.91 (m, 1H), 1.57-1.50 (m, 2H), 1.34-1.23 (m, 3H), 1.17 (t, J= 7.5 Hz, 3H), 1.05-0.89 (m, 8H).123276-03120

[0936] Example 86: N-ethyl-2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)ethan- 1 -amine

[0937]

[0938] Step 1 : N-ethyl-2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-(4-isobutoxybenzyl)ethan-l-amine, Example 86

[0939] Example 86 was synthesized in the same manner of step 1 for Example 78. Yield: 80.0 mg, 0.16 mmol, 24%. LCMS: m / r. 487.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 8 7.74 (d, J= 8.0 Hz, 1H), 7.61-7.55 (m, 1H), 7.47 (d, J= 8.0 Hz, 1H), 7.42-7.35 (m, 1H), 7.13 (d, J= 8.0 Hz, 2H), 6.81 (d, J= 8.0 Hz, 2H), 3.70-3.65 (m, 2H), 3.54-3.47 (m, 2H), 3.37 (s, 2H), 2.92 (q, J = 7.5 Hz, 2H), 2.46-2.23 (m, 2H), 2.01-1.91 (m, 1H), 1.58-1.50 (m, 2H), 1.34- 1.26 (m, 3H), 1.18 (t, J = 7.5 Hz, 3H), 1.06-0.85 (m, 12H).

[0940] Example 87: l-(2-ethylphenylsulfonimidoyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[0941]

[0942] Step 1: N-(tert-butyldimethylsilyl)-2-ethylbenzenesulfonamide

[0943] To a stirred solution of 2-ethylbenzene-l -sulfonamide (3.20 g, 17.3 mmol) in THF (50 mL), sodium hydride (0.456 g, 19.0 mmol) was added portion-wise at 0 °C under a nitrogen123276-03120

[0944] atmosphere. The mixture was stirred for 30 minutes before the addition of a solution of tert-butyl(chloro)dimethylsilane (2.85 g, 19.0 mmol) in THF (40 mL). The mixture was then stirred at room temperature for 20 hours. The reaction was quenched by the slow addition of ice cold water (20 mL) and extracted with EtOAc (3 x 50 mL). The organic phases were combined, washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compund. Yield: 5.10 g, 17.0 mmol, 98% LCMS: m / z 300.2 [M+H]+.

[0945] Step 2: l-(N-(tert-butyldimethylsilyl)-2-ethylphenylsulfonimidoyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin- 1 -yl)ethyl)piperidine-4-carboxamide

[0946] To a stirred suspension of triphenylphosphine oxide (1.80 g, 6.46 mmol) in acetonitrile (20 mL) at 0°C was added oxalyl chloride (0.877 g, 6.96 mmol) and the mixture was stirred at room temperature for 30 minutes, before being concentrated under reduced pressure. The residue was dissolved in methylene chloride (20 mL) and to this solution, N-(tert-butyldimethylsilyl)-2-ethylbenzene-l -sulfonamide (1.49 g, 4.97 mmol) and N,N-diisopropylethylamine (1.28 g, 9.94 mmol) in methylene chloride (20 mL) was added and the reaction mixture was stirred at room temperature for 18 hours. To this reaction mixture, a solution of N-[2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl]piperidine-4-carboxamide (1.45 g, 4.37 mmol) and diisopropylethylamine (1.28 g, 9.94 mmol) in methylene chloride (30 mL) was added. The mixture was stirred at room temperature for 20 hours. The mixture washed with water (2 x 50 mL) and concentrated under reduced pressure. The residue was purified by normal phase flash column chromatography eluting with 5%-100% ethyl acetate in hexane to afford the title compound. Yield: 0.90 g, 1.47 mmol, 28% LCMS: m / z 613.4 [M+H]+.

[0947] Step 3 : l-(2-ethylphenylsulfonimidoyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 87

[0948] To a stirred solution of l-(N-(tert-butyldimethylsilyl)-2-ethylphenylsulfonimidoyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide (0.70 g, 1.14 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (12 mL) and the reaction mixture was stirred at room temperature for 2 hours before being concentrated under reduced pressure. The residue was purified on preparative HPLC to afford Example 87. Yield: 0.38 g, 0.76 mmol, 67%. LCMS: m / z 499.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.79 (d, J = 8.0 Hz, 1H), 7.54-7.45 (m, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.34-7.28 (m, 1H), 7.19-7.14 (m, 1H), 6.79-6.73 (m, 3H), 4.44 (s, 1H), 3.69 (s, 3H), 3.58-3.42 (m, 3H), 3.24-3.18 (m, 1H), 3.16-3.09 (m, 1H), 3.02 (q, J = 7.5 Hz, 2H), 2.48-2.37 (m, 4H), 2.33-2.25 (m, 2H), 2.08-2.00 (m, 1H), 1.65-1.45 (m, 6H), 1.44-1.30 (m, 2H), 1.23 (t, J = 7.5 Hz, 3H).123276-03120

[0949] Example 88: l-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-3-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)urea

[0950]

[0951] Example 88

[0952] Step 1: 2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)acetonitrile

[0953] The title compound was synthesized in the same manner as step 1 of Example 2. Yield: 1.70 g, 6.58 mmol, 75%. 'H NMR (400 MHz, CDC13) 87.54-7.31 (m, 2H), 6.98-6.82 (m, 2H), 4.99 (s, 1H), 3.80-3.67 (m, 2H), 2.71-2.54 (m, 4H), 2.22-2.01 (m, 1H), 1.90-1.75 (m, 4H), 1.16-0.93 (m, 6H).

[0954] Step 2: 2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethan-l -amine123276-03120

[0955] The title compound was synthesized in the same manner as step 2 of Example 2. Yield: 0.50 g. LCMS: m / z 263.2 [M+H]+.

[0956] Step 3: tert-butyl 4-(3-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)ureido)piperidine-l-carboxylate

[0957] To a 0 °C stirred solution of crude 2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethan-l-amine (0.50 g) and tri ethylamine (0.19 g, 1.94 mmol) in methylene chloride (10 mL) was added a solution of tert-butyl 4-isocyanatopiperidine-l -carboxylate (0.36 g, 1.61 mmol). The reaction mixture was stirred at room temperature for 18 hours before the addition of water (20 mL). The resulting mixture was extracted with methylene chloride (3 ^ 15 mL). The organic phases were combined, washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield: 0.78 g. LCMS: m / z 489.4 [M+H]+.

[0958] Step 4: l-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-3-(piperidin-4-yl)urea

[0959] ditri fluoroacetate

[0960] To a 0 °C stirred solution of crude tert-butyl 4-(3-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)ureido)piperidine-l -carboxylate (0.78 g) in methylene chloride (3 mL) was added trifluoroacetic acid (1.26 mL). The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield: 0.70 g. LCMS: m / z 389.2 [M+H]+.

[0961] Step 5: l-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-3-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)urea, Example 88

[0962] To a 0 °C stirred solution of crude l-(2-(4-isobutoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-3-(piperidin-4-yl)urea ditrifluoroacetate (0.70 g) and N-N-diisopropylamine (0.3 mL, 1.71 mmol) in methylene chloride (20 mL) was added a solution of 2-ethylbenzene-l -sulfonyl chloride (0.11 g, 0.57 mmol). The reaction mixture was stirred overnight at room temperature and diluted water (20 mL). The resulting mixture was extracted with methylene chloride (3 x 15 mL). The organic phases were combined, washed with 1.0 M sodium hydrogencarbonate (20 mL), brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on preparative HPLC to afford Example 88. Yield: 0.07 g, 0.12 mmol, 2% over 4 steps. LCMS: m / z 557.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.75 (d, J= 8.0 Hz, 1H), 7.64-7.57 (m, 1H), 7.48 (d, J= 8.0 Hz, 1H), 7.44-7.36 (m, 1H), 7.23-7.09 (m, 2H), 6.85-6.78 (m, 2H), 6.03 (d, J= 7.5 Hz, 1H), 5.32-5.27 (m, 1H), 3.68 (d, J= 6.0 Hz, 2H), 3.58-3.45 (m, 1H), 3.42-3.32 (m, 2H), 3.17-3.00 (m, 3H), 2.92 (q, J= 7.5 Hz, 2H), 2.83-123276-03120

[0963] 2.73 (m, 2H), 2.44-2.22 (m, 4H), 2.01-1.92 (m, 1H), 1.76-1.67 (m, 2H), 1.65-1.55 (m, 4H), 1.28-1.14 (m, 5H), 0.95 (d, J= 6.5 Hz, 6H).

[0964] Example 89: N-((l-(isopropoxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l -amine

[0965]

[0966] Step 1 : (4-(((2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-l-yl)methanol

[0967] A mixture of [4-(aminomethyl)-2-oxabicyclo[2.2.2]octan-l-yl]methanol (0.30 g, 1.75 mmol), 2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)acetaldehyde (0.62 g, 1.75 mmol) and acetic acid (0.21 g, 3.51 mmol) in methanol (10 L) was stirred at room temperature for 30 minutes, before the addition of sodium cyanoborohydride (0.44 g, 7.01 mmol). The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. The residue was dissolved in chloroform (30 mL) and washed with saturated aqueous sodium bicarbonate (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield: 0.55 g. LCMS: m / z'. 507.0 [M+H]+.123276-03120

[0968] Step 2: (4-(((2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-l-yl)methanol

[0969] To a solution of crude (4-(((2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-l-yl)methanol (0.55 g) and triethylamine (0.44 g, 4.38 mmol) in methylene chloride (10 mL), di-tert-butyl dicarbonate (0.48 g, 2.19 mmol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 18 hours. The organic phase was washed with water (15 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound, which was used without further purification. Yield: 0.61 g. LCMS: m / z 629.2 [M+Na]+.

[0970] Step 3: tert-butyl ((l-(isopropoxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)(2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)carbamate

[0971] Silver(I) oxide (0.35 g, 1.52 mmol) was added to a solution of crude (4-(((2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-l-yl)methanol (0.46 g) and 2-iodopropane (0.38 g, 2.28 mmol) in nitromethane (10 mL), and the mixture was stirred at 80 °C for 48 hours. Then the mixture was diluted with methylene chloride (50 mL). The mixture was washed with water (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified on preparative HPLC to afford the title compound. Yield: 65.0 mg, 0.10 mmol, 6% over 3 steps. LCMS: m / z 649.2 [M+H]+.

[0972] Step 4: N-((l-(isopropoxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l -amine, Example 89

[0973] A solution of tert-butyl ((l-(isopropoxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)(2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)carbamate (0.11 g, 0.17 mmol) in 4M hydrogen chloride in dioxane (5 mL) was stirred at room temperature for 18 hours before the mixture was concentrated under reduced pressure. The residue was purified on preparative HPLC to afford Example 89. Yield: 25.5 mg, 0.046 mmol, 27%. LCMS: m / z 549.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.91 (d, J= 8.0 Hz, 1H), 7.83-7.74 (m, 1H), 7.62-7.55 (m, 2H), 3.67-3.56 (m, 2H), 3.50-3.41 (m, 3H), 3.09 (s, 2H), 2.43-2.36 (m, 4H), 2.18-2.11 (m, 2H), 1.78-1.55 (m, 5H), 1.53-1.32 (m, 8H), 1.29-1.22 (m, 2H), 1.02 (d, J= 6.0 Hz, 6H)123276-03120

[0974] Example 90: N-((3-(isopropoxymethyl)bicyclo[l .1 ,l]pentan-l-yl)methyl)-2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l -amine

[0975]

[0976] Example 90

[0977] Step 1: (3-(((2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)amino)methyl)bicyclo[l .1. l]pentan-l-yl)methanol

[0978] The title compound was synthesized in the same manner as step 1 of Example 89. Yield: 0.29 g. LCMS: m / z 463.2 [M+H]+.

[0979] Step 2: tert-butyl ((3-(hydroxymethyl)bicyclo[l.l.l]pentan-l-yl)methyl)(2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)carbamate

[0980] The title compound was synthesized in the same manner as step 2 of Example 89. Yield: 0.28 g. LCMS: m / z 585.2 [M+Na]+.

[0981] Step 3: tert-butyl ((3-(isopropoxymethyl)bicyclo[l.l.l]pentan-l-yl)methyl)(2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethyl)carbamate

[0982] The title compound was synthesized in the same manner as step 3 of Example 89. Yield: 38.0 mg, 0.062 mmol, 8% over 3 steps. LCMS: m / z 627.2 [M+Na]+.123276-03120

[0983] Step 4: N-((3-(isopropoxymethyl)bicyclo[l .1 ,l]pentan-l-yl)methyl)-2-(l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidin-4-yl)ethan-l -amine, Example 90

[0984] Example 90 was synthesized in the same manner as step 4 of Example 89. Yield: 17.9 mg, 0.035 mmol, 17%. LCMS: m / r. 505.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.91 (d, J = 7.5 Hz, 1H), 7.87-7.76 (m, 1H), 7.67-7.49 (m, 2H), 3.71-3.52 (m, 2H), 3.52-3.43 (m, 1H), 3.28-3.26 (m, 6H), 1.73-1.59 (m, 2H), 1.47 (s, 6H), 1.38-1.31 (m, 1H), 1.31-1.21 (m, 2H), 1.13-0.99 (m, 8H).

[0985] Example 91: 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-((l-(isopropoxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-methylethan-l-amine

[0986]

[0987] Example 91

[0988] Step 1 : 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-((l-(hydroxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-methylacetamide

[0989] A mixture of (3-[(ethylimino)methylidene]aminopropyl)dimethylamine hydrochloride (0.56 g, 2.92 mmol), 2-[l-(2-ethylbenzenesulfonyl)piperidin-4-yl]acetic acid (0.65 g, 2.09 mmol), and lH-l,2,3-benzotriazol-l-ol (0.42 g, 3.13 mmol) in DMF (4 mL) was stirred at room temperature for 10 minutes before 4-[(methylamino)methyl]-2-oxabicyclo[2.2.2]octan-1-ylmethanol (0.38 g, 2.09 mmol) was added. The resulting mixture was stirred at room123276-03120

[0990] temperature for 18 hours. The mixture was diluted with water (20 mL), and extracted with ethyl acetate (2x10 mL). The organic phases were combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound which was used without further purification. Yield: 1.10 g. LCMS: m / z'. 479.2 [M+Na]+.

[0991] Step 2: (4-(((2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)ethyl)(methyl)amino)methyl)-2-oxabicyclo[2.2.2]octan-l-yl)methanol

[0992] The title compound was synthesized in the same manner as step 3 of Example 85, followed by purification by preparative HPLC. Yield: 0.14 g, 0.30 mmol, 14% over 2 steps.

[0993] LCMS: m z 465.2 [M+H]+.

[0994] Step 3 : 2-(l-((2-ethylphenyl)sulfonyl)piperidin-4-yl)-N-((l-(isopropoxymethyl)-2-oxabicyclo[2.2.2]octan-4-yl)methyl)-N-methylethan-l-amine, Example 91.

[0995] Example 91 was synthesized in the same manner as step 3 of Example 89. Yield: 9.9 mg, 0.019 mmol, 6%. LCMS: m z 507.2 [M+H]+. 'H NMR (500 MHz, CD3OD) 87.84 (d, J = 8.0 Hz, 1H), 7.59-7.53 (m, 1H), 7.46 (d, J= 8.9 Hz, 1H), 7.38-7.33 (m, 1H), 3.70-3.64 (m, 4H), 3.59-3.50 (m, 1H), 3.20 (s, 2H), 3.01 (q, J= 7.0 Hz, 2H), 2.64-2.56 (m, 2H), 2.37-2.32 (m, 2H), 2.18 (s, 3H), 2.09 (s, 2H), 1.85-1.71 (m, 4H), 1.66-1.50 (m, 5H), 1.39-1.31 (m, 3H), 1.29-1.18 (m, 6H), 1.12 (d, J = 6.5 Hz, 6H).

[0996] Example 92: (R or S)-4-((2-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine

[0997]

[0998] Step 1: (R or S)-4-((2-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine, Example 92

[0999] Racemic Example 92 was synthesized in the same manner of step 3 for Example 49. Pure racemic mixture (50 mg) was than separated by chiral chromatography (Chiralpak AD-H (250 x 4.6 mm, 5 urn) eluting with 1 : 1 (IPA + 0.1% EDA):(MeOH + 0.1% EDA), 0.6 mL / min), . Peak 1 from the chiral chromatography was assigned as Example 92. Yield: 18.1123276-03120

[1000] mg, 0.03 mmol, 17%. LCMS: m / z 555.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.92 (d, J= 7.5 Hz, 1H), 7.87-7.75 (m, 1H), 7.64-7.51 (m, 2H), 7.05 (d, J= 8.5 Hz, 2H), 6.78 (d, J = 8.5 Hz, 2H), 3.72-3.57 (m, 4H), 3.00-2.94 (m, 1H), 2.77-2.70 (m, 1H), 2.59-2.52 (m, 4H), 2.29-2.22 (m, 1H), 2.08-1.80 (m, 4H), 1.66-1.60 (m, 1H), 1.56-1.45 (m, 4H), 1.38-1.29 (m, 1H), 1.14-0.99 (m, 2H), 0.94 (d, J= 7.0 Hz, 6H).

[1001] Example 93: (R or S)-4-((2-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine

[1002]

[1003] Example 93 Step 1: (R or S)-4-((2-(4-isobutoxybenzyl)pyrrolidin-l-yl)methyl)-l-((2-(trifluoromethoxy)phenyl)sulfonyl)piperidine, Example 93

[1004] Example 93 was prepared with Example 92. Peak 2 from the chiral chromatography was assigned as Example 93. Yield: 18.0 mg, 0.03 mmol, 17%. LCMS: m / r. 555.2 [M+H]+.

[1005] 'H NMR (500 MHz, d6-DMSO) 87.92 (d, J= 7.5 Hz, 1H), 7.85-7.77 (m, 1H), 7.64-7.53 (m, 2H), 7.05 (d, J= 8.5 Hz, 2H), 6.78 (d, J= 8.5 Hz, 2H), 3.72-3.57 (m, 4H), 3.00-2.94 (m, 1H), 2.77-2.70 (m, 1H), 2.59-2.52 (m, 4H), 2.29-2.22 (m, 1H), 2.08-1.80 (m, 4H), 1.66-1.60 (m, 1H), 1.56-1.45 (m, 4H), 1.38-1.29 (m, 1H), 1.13-0.98 (m, 2H), 0.94 (d, J= 7.0 Hz, 6H).

[1006] Example 94: N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2- (trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxamide

[1007]

[1008] Example 94123276-03120

[1009] Step 1: N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)-l-((2-(trifluoromethyl)phenyl)sulfonyl)piperidine-4-carboxamide, Example 94

[1010] Example 94 was synthesized in the same manner of step 3 for Example 2. Yield: 0.13 g, 0.22 mmol, 24%. LCMS: m / z 540.4 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 88.06-7.97 (m, 2H), 7.94-7.83 (m, 2H), 7.55-7.48 (m, 1H), 7.19-7.13 (m, 1H), 6.82-6.67 (m, 3H), 3.70 (s, 3H), 3.62-3.49 (m, 3H), 3.24-3.10 (m, 2H), 2.76-2.64 (m, 2H), 2.34-2.24 (m, 2H), 2.20-2.11 (m, 1H), 1.64-1.50 (m, 6H), 1.46-1.30 (m, 2H).

[1011] Example 95: l-((2-cyanophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[1012]

[1013] Step 1 : l-((2-cyanophenyl)sulfonyl)-N-(2-(3-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 95

[1014] Example 95 was synthesized in the same manner of step 3 for Example 2. Yield: 0.15 g, 0.31 mmol, 30%. LCMS: m / z 497.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 68.14 (d, J = 15 Hz, 1H), 8.02-7.97 (m, 1H), 7.95-7.91 (m, 1H), 7.90-7.84 (m, 1H), 7.49 (t, J= 5.5 Hz, 1H), 7.20-7.12 (m, 1H), 6.82-6.70 (m, 3H), 3.69 (s, 3H), 3.62-3.49 (m, 3H), 3.23-3.18 (m, 1H), 3.15-3.10 (m, 1H), 2.64-2.54 (m, 3H), 2.42-2.38 (m, 2H), 2.31-2.25 (m, 2H), 2.12-2.05 (m, 1H), 1.65-1.50 (m, 6H), 1.46-1.30 (m, 2H).

[1015] Example 96: l-((4-chlorophenyl)sulfonyl)-N-(2-(2-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide

[1016]

[1017] 123276-03120

[1018] Step 1 : l-((4-chlorophenyl)sulfonyl)-N-(2-(2-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 96

[1019] Example 96 was synthesized in the same manner of step 3 for Example 2. Yield: 0.16 g, 0.31 mmol, 16%. LCMS: m / z 506.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 67.75-7.66 (m, 4H), 7.40-7.10 (m, 3H), 6.95-6.82 (m, 2H), 3.92-3.79 (m, 1H), 3.71 (s, 3H), 3.63-3.51 (m, 1H), 3.49-3.41 (m, 2H), 3.18-3.12 (m, 1H), 2.45-2.21 (m, 5H), 2.07-1.97 (m, 1H), 1.68-1.47 (m, 6H), 1.44-1.31 (m, 2H).

[1020] Example 97 : 1 -((4-chlorophenyl)sulfonyl)-N-(2-(4-methoxyphenyl)-2-(pyrrolidin- 1 -yl)ethyl)piperidine-4-carboxamide

[1021]

[1022] Step 1 : l-((4-chlorophenyl)sulfonyl)-N-(2-(4-methoxyphenyl)-2-(pyrrolidin-l-yl)ethyl)piperidine-4-carboxamide, Example 97

[1023] Example 97 was synthesized in the same manner of step 3 for Example 2. Yield: 0.08 g, 0.15 mmol, 78%. LCMS: m / z 506.2 [M+H]+. 'H NMR (500 MHz, d6-DMSO) 87.75-7.66 (m, 4H), 7.39 (t, J= 5.5 Hz, 1H), 7.09 (d, J= 8.5 Hz, 2H), 6.81 (d, J= 8.5 Hz, 2H), 3.70 (s, 3H), 3.58-3.42 (m, 3H), 3.20-3.13 (m, 1H), 3.11-3.03 (m, 1H), 2.43-2.36 (m, 2H), 2.32-2.17 (m, 4H), 2.04-1.95 (m, 1H), 1.66-1.50 (m, 6H), 1.46-1.32 (m, 2H)

[1024] Mitophagy cell-based assay

[1025] Abbreviations

[1026] DMEM Dulbecco's Modified Eagle Medium

[1027] GFP green fluorescent protein

[1028] hr(s) hour(s)

[1029] mCherry monomeric red fluorescent protein

[1030] min(s) minute(s)

[1031] mL millilitre

[1032] PBS Phosphate-buff ered saline123276-03120

[1033] Pct Mitophagy Percentage Mitophagy

[1034] PFA Paraformaldehyde

[1035] pL microliter

[1036] pM micromolar

[1037] Mitophagy has been quantified in cells by using mitoQC reporter. MitoQC is a tandem fluorescence, functionally inert, reporter that consists of a fusion protein, green and red fluorescent protein (GFP and mCherry, respectively), with a mitochondrial tag (FIS1101-152) for mitochondrial localisation. In the cytoplasm, both GFP and mCherry emit a fluorescent signal. GFP and mCherry have different sensitivities to pH. Lysosomes have an acidic environment and inside the lysosome, GFP fluorescence is quenched, while mCherry signal is retained. This leads to the appearance of punctate mCherry-only clusters (mitolysosome) that can be quantified as an index of mitophagy.

[1038] Proliferating ARPE- 19, stably expressing mitoQC reporter (mitoQC-ARPE-19), were loaded with CellTracker-DeepRed, washed with PBS, trypsinised and concentration adjusted to 2.5x104 cells / mL in DMEMZF12 Media. Cells were seeded into 384 well PerkinElmer CellCarrierUltra plates using Multidrop Combi (50 uL of cell suspension per well) and transferred to a humidified 37°C incubator with 5% carbon dioxide. Cells were incubated for 24 hours at 37 °C and media was replaced with fresh media. Compound dispensing was performed with Echo liquid handler. Cells were either treated with DMSO (undamaged) or a mix of 1 pM Antimycin and 1 pM Oligomycin (damaged condition). Compounds were dispensed at 8 concentrations, both in basal and damaged conditions. Assay plates were returned to the incubator for 24 hours (or appropriate length of time).

[1039] After compound incubation, cells were washed twice with PBS and fixed with 50 pL 4% PFA, pH 7.0 for 17 mins. PFA was quenched by two washes with 50 pL DMEMZHepes for 3 mins. Nuclear staining was performed with 25 pL Hoechst per well for 17mins. Cells were washed twice with 50 pL PBS and left with PBS in wells and imaged on CV7000 imager. Hoechst (nuclei), Green (mitoQC reporter - mitochondrial network), Red (mitoQC reporter, mitochondrial network and mitolysosomes) and Far Red (CellTracker-DeepRed) were imaged and composite images constructed. Segmentation and quantification of mitophagy was performed on CellProfiler 4.2.1. Nuclei were identified based on the Hoechst signal and cells identified based on expansion from the nuclei, using the signal from CellTracker-DeepRed. Mitophagy index (Pct Mitophagy = % of mitochondria which are undergoing mitophagy) was calculated from the mCherry / GFP ratio for each data point and123276-03120

[1040] normalised against DMSO controls in the same assay plate (Diff Pct Mitophagy). LOESS fit method was applied to all data points to generate dose-response curves and ECthreshold defined as the concentration at which Diff_Pct_Mitophagy=10% for both undamaged and damaged conditions.

[1041] In the table below, assay data (pECthreshold) are presented for the Examples below in accordance with the above-described assay shown in micromolar and negative log of the ECthreshold in molar.

[1042] > <

[1043]

[1044] 123276-03120

[1045] > < > <

[1046]

[1047] 123276-03120

[1048]

Claims

123276-03120CLAIMSWhat is claimed is:

1. A compound of formula (I) or a salt thereof:wherein,Z is (Z-l), (Z-2), or (Z-3),(Z-1 ) (Z-2 ) ( Z-3 )Ring A is phenylene, 6-membered heteroarylene containing one to two nitrogen atoms, (A-l), (A-2), or (A-3),(*L represents the attachment point to L)R1is halo, C1-3 alkyl, -ORla, -CF3, Cs-scycloalkyl, -CN, or 5-membered heteroaryl, Rlais Ci-3alkyl, -CF3, or -CHF2,n is 1 or 2,R2is C1-5 alkyl, C3-5 cycloalkyl, -CH2OR2a, -OR2a, or (R2-1),R2ais 4 to 6-membered heterocycloalkyl or C1-5 alkyl, wherein the Ci-salkyl is optionally substituted with 1 or 2 groups selected from -OH, -O(Ci-5 alkyl), -CF3, and 4 to 6-membered heterocycloalkyl optionally substituted with -C(=O)-Ci-5 alkyl,L is (L-l), (L-2), (L-3), (L-4), (L-5), or (L-6), provided that L is not (L-4) when Z is (Z-3),123276-03120(* A represents the attachment point to Ring A)LI is Ci alkylene optionally substituted with 1 or 2 C1-3 alkyl,each L2, L3, and L4 are independently a bond or Ci alkylene optionally substituted with 1 or 2 C1-3 alkyl,RLais -N(CI-3alkyl)2, (RLA-1), (RLA-2), (RLA-3), or (RLA-4),(RLA-1 ) (RLA-2 ) (RLA-3 ) (RLA-4 )RLbis H or Ci-3 alkyl, -CH2CH2OH or -CH2CH2O(CI-3 alkyl),RLCis H or C1-3 alkyl,RLdis H or C1-3 alkyl,RLeis H, C1-3 alkyl, or oxo,or Ring A, L, and R2may together form (LA-1),( LA-1 )RLAis C3-4 alkyl.

2. The compound or a salt thereof according to claim 1,wherein,Ring A is (A-l), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), or (A-8),123276-03120(A-7 ) (A-8 )(* L represents the attachment point to L)R1is halo, C1-3 alkyl, -ORla, -CF3, cyclopropyl, -CN, or isoxazolyl,Rlais Ci-3alkyl, -CF3, or -CHF2,n is 1 or 2,R2is C1-5 alkyl, cyclopropyl, -CH2OR2a, -OR2a, or (R2-1),R2ais oxetanyl, tetrahydropyranyl, or C1-5 alkyl, wherein the C1-5 alkyl is optionally substituted with 1 or 2 groups selected from -OH, -O(Ci-5 alkyl) , -CF3, morpholinyl, tetrahydropyranyl, and azetidinyl optionally substituted with C(=O)-Ci-3 alkyl,L is (L-l), (L-2), (L-3), (L-4), (L-5), or (L-6), provided that L is not (L-4) when Z is (Z-3),(* A represents the attachment point to Ring A)LI is Ci alkylene optionally substituted with C1-3 alkyl,L2, L3 and L4 are the same or different, and are a bond or Ci alkylene optionally substituted with C1-3 alkyl,RLais -N(CI-3alkyl)2, (RLA-1), (RLA-2), or (RLA-3),123276-03120(RLA-1 ) (RLA-2 ) (RLA-3 )RLbis H or Ci-3 alkyl, -CH2CH2OH or -CH2CH2O(CI-3 alkyl),RLCis H or C1-3 alkyl,RLdis H or C1-3 alkyl,RLeis H, C1-3 alkyl, or oxo,or Ring A, L and R2may together form (LA-1),( LA-1 )RLAis C3-4 alkyl.

3. The compound or a salt thereof according to claim 2, wherein,Z is (Z-l),(Z-1 )4. The compound or a salt thereof according to claim 2, wherein,Z is (Z-2),(Z-2 )5. The compound or a salt thereof according to claim 2, wherein,Z is (Z-3),( Z-3 )6. The compound or a salt thereof according to claim 1, wherein the compound is any one of Example 1-97.123276-031207. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and a pharmaceutically acceptable carrier or excipient.

8. A method for preventing and / or treating Mitophagy related diseases, comprising administering an effective amount of the compound or a salt thereof according to claim 1 to a subject.

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