WO2019104011A1

WO2019104011A1 - Ceramide galactosyltransferase inhibitors for the treatment of disease

Info

Publication number: WO2019104011A1
Application number: PCT/US2018/061965
Authority: WO
Inventors: Bing Wang
Original assignee: Biomarin Pharmaceutical Inc.
Priority date: 2017-11-21
Filing date: 2018-11-20
Publication date: 2019-05-31

Abstract

Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with the enzyme ceramide galactosyltransferase (CGT), such as, for example, lysosomal storage diseases. Examples of lysosomal storage diseases include, for example, Krabbe disease and Metachromatic Leukodystrophy.

Description

CERAMIDE GALACTOSYLTRANSFERASE INHIBITORS FOR THE

TREATMENT OF DISEASE

CROSS REFERENCE

[0001] This application claims the benefit of priority of U.S. Provisional Patent

Application No. 62/589,496, filed November 21, 2017, the content of which is incorporated herein by reference in its entirety.

FIELD

[0002] Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods to treat or prevent diseases or disorders associated with the enzyme ceramide

galactosyltransferase (CGT). Also described herein is that such compounds are for use in said methods for treating or preventing diseases or disorders. Such diseases or disorders include, for example, lysosomal storage diseases (LSDs). Examples of lysosomal storage diseases include Krabbe disease and Metachromatic Leukodystrophy.

BACKGROUND

[0003] Ceramide galactosyltransferase (CGT) is a key enzyme in glycosphingolipid

(GSL) biosynthesis in eukaryotic cells. Glycosphingolipids (GSLs) are believed to be integral in many cell membrane events, including cellular interactions, signaling, and trafficking. Ceramides play a central role in sphingolipid metabolism, and CGT facilitates conversion of ceramides to galactosylceramides. Galactosylceramides can be further modified by the enzyme cerebroside sulfotransferase (CST) to form sulfatides.

Galactosylceramides and sulfatides are primarily produced by the myelin generating cells of the central and peripheral nervous systems, oligodendrocytes and Schwann cells respectively, where these glycolipids make up a large proportion of the lipids in the myelin sheath.

Galactosylceramide and sulfatide are also found on the extracellular leaflet of the plasma membrane of other cells in eukaryotic organisms where they have been reported to be involved in a diverse range of functions.

[0004] Degradation of galactosylceramides is catalyzed in the lysosome by galactosylceramidase (GALC). Insufficient degradation of galactosylceramides caused by a deficiency of GALC, can lead to an accumulation of galactosylceramides and its partially degraded product psychosine (also called galactosylsphingosine). In humans, deficiency of GALC results in Krabbe disease (also known as globoid cell leukodystrophy or galactosylceramide lipidosis). See , e.g., Ezoe et al., J. Neurosci. Res. 59:170-178 (2000); Ezoe et al., J. Neurosci. Res. 59:179-187 (2000). Increased psychosine levels are believed to be the primary toxic molecule in Krabbe disease leading to widespread destruction of oligodendrocytes in the CNS and Schwann cells in the PNS and subsequent demyelination. See , e.g., Suzuki et al., Proc. Natl. Acad. Sci. U.S.A. 66(2):302-9 (1970); Graziano et al., Gene 555(l):2-l3 (2015). Similarly, turnover of sulfatides occurs in lysosome via the enzyme arylsulfatase A (ASA) and defects in ASA can lead to the accumulation of sulfatides and its partially degraded product lyso-sulfatides. ASA deficiency can lead to the

development of an autosomal recessive disease called metachromatic leukodystrophy (MLD). See, e.g., Kohlschutter, Handb. Clin. Neurol. 113: 1611-1618 (2013).

[0005] Krabbe disease detrimentally affects the myelin sheath, which protects nerves and facilitates the sending and receiving of nerve signals. The accumulation of

unmetabolized galactosylceramides and psychosine detrimentally affects the growth and development of the myelin sheath. Damage to the myelin sheath can lead to a severe degeneration of motor skills, cognitive deficits, and seizures, and is often fatal. Similarly, in MLD, accumulation of sulfatides and lyso-sulfatides detrimentally affects the myelin sheath, disrupting neuronal functions and leads to seizures, progressive coordination and speech problems, and other behavioral disturbances.

[0006] An approach to treatment of such diseases resulting from an abnormal accumulation of galactosylceramides, psychosine, sulfatides, lyso-sulfatides and related GSLs is to inhibit the CGT enzyme to reduce the synthesis of galactosylceramides and other downstream molecules. Accordingly, molecules that inhibit the activity of CGT are useful as therapeutic agents in the treatment of lysosomal storage diseases relating to defects in sphingolipid metabolism, such as Krabbe disease and MLD. In addition,

abnormal metabolism of galactosylceramides and sulfatides has been associated with other pathological conditions such as Parkinson's Disease. See, e.g, Marshall and Bongarzone, J. Neurosci. Res., 94: 1328 (2016); Smith et al., J. Pathol. 232:509 (2014). Overexpression of sulfatide has also been linked to epilepsy and audiogenic seizures as well as

other pathological states in the nervous system. Accordingly, molecules that inhibit the activity of CGT may be used to treat Parkinson's disease, epilepsy and audiogenic seizures that are associate with overexpression or accumulation of galactosylceramides/sulfatides. SUMMARY

[0007] In one aspect, provided herein is a compound of Formula (IA):

Formula (I A),

wherein:

ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms;

ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups;

provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R³ groups;

L is a bond, -O-, C(O), or -[C(R⁴R⁵)]_P-;

p is 1 or 2;

R¹ is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 groups

independently selected from alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

alkylcarbonylamino, alkoxycarbonylamino, cycloalkyloxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy and (cycloalkyl)alkoxy;

R² is aryl or heteroaryl, each of which is optionally substituted with 1 or 2 R⁶ groups;

each R³ is independently alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, or alkoxycarbonylamino;

each R⁴ is independently H or alkyl;

each R⁵ is independently H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl are independently and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

alkylcarbonylamino, or alkoxycarbonylamino;

each R⁶ is independently alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxyl, haloalkyl,

hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

alkylcarbonylamino, alkoxycarbonylamino, (haloalkyl)cycloalkyl, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, aryl, aryloxy, or heteroaryl, wherein each aryl or heteroaryl is independently and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, haloalkyl, hydroxyalkyl, alkoxy,

hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy, alkylaminocarbonyloxy,

dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, or

alkoxycarbonylamino;

provided when ring B is piped dinyl or pyrrolidinyl, then R² is not amino-substituted

imidazolyl;

or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally

optionally a pharmaceutically acceptable salt thereof.

[0008] In another aspect, provided herein is a compound of Formula (I):

Formula (I),

wherein:

L is a bond, C(O), or -[C(R⁴R⁵)]_P-;

p is 1 or 2;

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

alkylcarbonylamino, or alkoxycarbonylamino;

each R⁴ is independently H or alkyl; each R⁵ is independently H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl are independently and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

alkylcarbonylamino, or alkoxycarbonylamino;

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, or

alkoxycarbonylamino;

provided that the compound of Formula (I) is that when ring B is piperidinyl or pyrrolidinyl, then R² is not amino-substituted imidazolyl;

optionally a pharmaceutically acceptable salt thereof.

[0009] In another aspect, provided herein is a compound of Formula (II):

Formula (II),

wherein, ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms;

ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic

heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups;

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

alkylcarbonylamino, or alkoxycarbonylamino;

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, or

alkoxycarbonylamino;

optionally a pharmaceutically acceptable salt thereof.

[0010] In another aspect, provided herein is a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

[0011] In another aspect, provided herein is a method of treating a lysosomal storage disease with a compound or composition disclosed herein. Thus, a compound or composition disclosed herein is for use in a method of treating a lysosomal storage disease.

[0012] In certain embodiments, the lysosomal storage disease is Krabbe disease or

Metachromatic Leukodystrophy.

DETAILED DESCRIPTION

Abbreviations

Definitions

[0013] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art.

[0014] “About” preceding a numerical value refers to a range of values ±10% of the value specified.

[0015] “Acceptable” with respect to a formulation, composition or ingredient, means having no persistent detrimental effect on the general health of the subject being treated.

[0016] Whenever a group is described as being“optionally substituted,” it is meant that the referenced group can be“unsubstituted or substituted.”

[0017] “Alkenyl” means a straight or branched hydrocarbon group having from 2 to 8 carbon atoms and at least one double bond. In certain embodiments, alkenyl includes ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, or l-hex-5-enyl.

[0018] “Alkoxy” means a group of the formula -OR, where R is alkyl. In certain embodiments, alkoxy includes methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy.

[0019] “Alkoxycarbonyl” means a group of the formula -C(0)R, where R is alkoxy, as defined herein.

[0020] “Alkoxycarbonylamino” means a group of the formula -NHC(0)R, where R is alkoxy, as defined herein.

[0021] “Alkoxycarbonyloxy” means a group of the formula -OC(0)R, where R is alkoxy, as defined herein.

[0022] “Alkyl” means a straight or branched saturated hydrocarbon group containing from 1-10 carbon atoms, and in certain embodiments includes 1-6 carbon atoms. In certain embodiments, alkyl includes 1-4 carbon atoms (“Ci-4 alkyl”). In certain embodiments alkyl includes 1-3 carbon atoms (“C1-3 alkyl”). In certain embodiments, alkyl includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n- hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.

[0023] “Alkylaminocarbonyl” means a group of the formula -C(0)R, where R is alkylamino, as defined herein. [0024] “Alkylaminocarbonyloxy” means a group of the formula -OC(0)R, where R is alkylamino, as defined herein.

[0025] “Alkylcarbonylamino” means a group of the formula -NHC(0)R, where R is alkyl, as defined herein.

[0026] “Alkylene” refers to a divalent group formed by removal of a hydrogen atom from alkyl.

[0027] “Alkynyl” means a straight or branched hydrocarbon group having from 2 to 8 carbon atoms and at least one triple bond. In certain embodiments, alkynyl includes ethynyl, propynyl, l-but-3-ynyl, l-pent-3-ynyl, or l-hex-5-ynyl.

[0028] “Amino” means an -NIL· group.

[0029] “Aminocarbonyl” means an -C(0)ML· group.

[0030] “Aminocarbonyloxy” means a group of formula -0C(0)ML·

[0031] “Alkylamino” means a group of the formula -NHR, where R is alkyl as defined herein. In certain embodiments, alkylamino includes methylamino, ethylamino, //-propylamino, Ao-propylamino, //-butyl ami no, Ao-butylamino, or A 7-butylamino.

[0032] “Alkylcarbonyl” means a group of the formula -C(0)R, where R is alkyl, as defined herein.

[0033] “Alkylcarbonyloxy” means a group of the formula -OC(0)R, where R is alkyl, as defined herein.

[0034] “Aryl” means a monovalent six- to fourteen-membered, mono-, bi-, or tri- carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic or tricyclic ring is aromatic. In certain embodiments, aryl includes phenyl, naphthyl, indanyl, or anthracenyl.

[0035] “(Aryl)alkylene” means an alkylene group, as defined herein, substituted with aryl group as defined herein. In certain embodiments, the (aryl)alkylene is benzyl.

[0036] “Aryloxy” means a group of the formula -OR, where R is aryl, as defined herein. In certain embodiments, aryloxy is phenoxy.

[0037] “Carbonyl” means an -C=(0) group.

[0038] “Carboxy” means an -C(0)OH group.

[0039] “Cyano” means an -CN group.

[0040] “Cycloalkyl” means a monocyclic or bicyclic, saturated or partially unsaturated (but not aromatic), hydrocarbon ring of three to ten carbon ring atoms.

Cycloalkyl groups include fused and bridged bicyclic rings. For example, when fused, the cycloalkyl group may comprise two rings that share adjacent atoms ( e.g ., one covalent bond). When bridged, the cycloalkyl group may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom. When a cycloalkyl group contains from 3-10 carbon atoms, it may be referred to herein as C3-1₀ cycloalkyl. When a cycloalkyl group contains from 5-6 carbon atoms, it may be referred to herein as C5-₆ cycloalkyl. In certain embodiments, cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0041] “(Cycloalkyl)alkyl” means an alkyl group, as defined herein, substituted with at least one cycloalkyl groups as defined herein. In certain embodiments, alkyl is substituted with 1 cycloalkyl group. In certain embodiments, alkyl is substituted with 1 or 2 cycloalkyl groups. In certain embodiments, (cycloalkyl)alkyl includes cyclobutylmethyl,

cyclopentylmethyl, and cyclohexylmethyl.

[0042] “(Cycloalkyl)alkoxy” means a group of the formula -OR, where R is a

(cycloalkyl)alkyl group as defined herein. In certain embodiments, (cycloalkyl)alkoxy includes cyclobutylmethoxy, cyclopentylmethoxy, and cyclohexylmethoxy.

[0043] “Cycloalkyloxy” means a group of the formula -OR, where R is cycloalkyl, as defined herein. In certain embodiments, cycloalkyloxy includes cyclobutyloxy,

cyclopentyloxy, and cyclohexyloxy.

[0044] “Dialkylamino” means a group of the formula -NRR', where R and R' are independently alkyl as defined herein. In certain embodiments, dialkylamino includes dimethylamino, diethylamino, A', A^f-m ethyl propyl am i n o or N, A - m et h y 1 et h y 1 am i n o .

[0045] “Dialkylaminocarbonyl” means a group of the formula -C(0)R, where R is dialkylamino, as defined herein.

[0046] “Dialkylaminocarbonyloxy” means a group of the formula -OC(0)R, where R is dialkylamino, as defined herein.

[0047] “Halo” means a fluoro, chloro, bromo, or iodo group.

[0048] “Haloalkoxy” means an alkoxy group, substituted with one or more halo atoms. In certain embodiments, the alkoxy is substituted with 1, 2, or 3 halo atoms. Certain embodiments of haloalkoxy include difluoromethoxy, trifluorom ethoxy, or 1,1,1 - trifluoroethoxy.

[0049] “Haloalkyl” means an alkyl group substituted with one or more halo atoms. In certain embodiments, haloalkyl is an alkyl group substituted by 1, 2, 3, 4, 5, or 6 halo atoms. In certain embodiments, haloalkyl is an alkyl group substituted by 1, 2, or 3 halo atoms. In certain other embodiments, haloalkyl is an alkyl group substituted with 2 halo atoms. In certain embodiments, haloalkyl is an alkyl group substituted with 1 halo atom. In certain embodiments, haloalkyl includes trifluoromethyl, fluoromethyl, perfluoroethyl, or chloromethyl. Certain other embodiments of haloalkyl include chloromethyl, fluoromethyl, difluorom ethyl, trifluoromethyl, or l,l,l-trifluoroethanyl.

[0050] “(Haloalkyl)cycloalkyl” means a cycloalkyl group substituted with one or more haloalkyl groups, as defined herein. In certain embodiment, (haloalkyl)cycloalkyl includes l-(haloalkyl)cyclopropyl, 2-(haloalkyl)cyclopropyl, l-(haloalkyl)cyclobutyl, 2- (haloalkyl)cyclobutyl, 3-(haloalkyl)cyclobutyl, l-(haloalkyl)cyclopentyl, 2- (haloalkyl)cyclopentyl, 3-(haloalkyl)cyclopentyl, l-(haloalkyl)cyclohexyl, 2- (haloalkyl)cyclohexyl, 3-(haloalkyl)cyclohexyl, 4-(haloalkyl)cyclohexyl, 2,3- bis(haloalkyl)cyclopropyl, 2,4-bis(haloalkyl)cyclobutyl, 3,4-bis(haloalkyl)cyclopentyl, or 3,5-bis(haloalkyl)cyclohexyl. In certain embodiment, (haloalkyl)cycloalkyl groups include

[0051] “Heteroaryl” means a monocyclic, bicyclic, or tricyclic ring of 5 to 14 ring atoms containing one or more ring heteroatoms independently selected from -0-, -S-, -N= (trivalent nitrogen), and -N(H)-, and the remaining ring atoms being carbon atoms, wherein the monocyclic ring is aromatic and wherein at least one of the rings in the bicyclic or tricyclic rings is aromatic (but does not have to be a ring which contains a heteroatom, e.g. 2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl). Unless stated otherwise, the valency may be located on any atom of any ring of the heteroaryl group, valency rules permitting.

[0052] In certain embodiments, heteroaryl includes, but is not limited to, triazolyl, tetrazolyl, pyrrolyl, imidazolyl, thienyl, furanyl, pyrazolyl, oxazolyl, isooxazolyl,

oxadiazolyl, thiadiazolyl (including, for example, l,3,4-thiadiazolyl), indolyl, 2,3-dihydro- l//-indolyl (including, for example, 2, 3 -di hydro- 1 //-i ndol -2-y 1 or 2,3-dihydro- l//-indol-5- yl), indazolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or

tetrahydroisoquinolin-6-yl), pyrrolo[3,2-c]pyridinyl (including, for example, pyrrolo[3,2- c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl), pyrrolo[l,2-Z>]pyridazinyl, imidazo[l,2- a]pyridinyl, thiazolyl, benzo[i/][l,3]dioxolyl, 2,3-dihydrobenzo[£][l,4]dioxinyl, furo[2,3- i/]thiazolyl, thieno[2,3-_<i]oxazolyl, thieno[3,2-Z>]furanyl, furo[2,3-_<i]pyrimidinyl, furo[3,2- L] pyridinyl, furo[3,2-c]pyridinyl, 6,7-dihydro-5//-cyclopenta[Z>]pyridinyl, or 7,8-dihydro-6//- cyclopenta[g]quinoxalinyl. [0053] “Heterocycloalkyl” means a saturated or partially unsaturated (but not aromatic) monocyclic ring of 3 to 9 ring atoms, or a saturated or partially unsaturated (but not aromatic) bicyclic ring of 5 to 12 ring atoms in which one or more ring atoms is a heteroatom independently selected from -0-, -S-, -N= (trivalent nitrogen), or -NH-, and the remaining ring atoms are carbon. In certain embodiments, heterocycloalkyl is a saturated or partially unsaturated monocyclic group of 4 to 7 rings atoms, or a saturated or partially unsaturated bicyclic group of 7 to 9 ring atoms.

[0054] In certain embodiments, the heterocycloalkyl group comprises one, two, three, or four ring heteroatoms, independently selected from -0-, -S-, -N= (trivalent nitrogen), or -NH-, and the remaining ring atoms are carbon. In certain embodiments, the

heterocycloalkyl group contains only one or two nitrogen atoms, and the remaining ring atoms are carbon. When a heterocycloalkyl group contains from 4 to 7 ring atoms, it may be referred to herein as 4-7 membered heterocycloalkyl. When a heterocycloalkyl group contains from 7 to 9 ring atoms, it may be referred to herein as 7-9 membered

heterocycloalkyl.

[0055] Heterocycloalkyl groups include fused or bridged heterocycloalkyl bicyclic rings. For example, a fused heterocycloalkyl group may comprise two rings that share adjacent atoms ( e.g ., one covalent bond). When bridged, the heterocycloalkyl group may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom.

[0056] In certain embodiments, heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2,5-dihydro- 1 //-pyrrol inyl, 2,5-dihydro- 1 //-pyrrolyf piperidinyl, morpholinyl, piperazinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, l,3-dioxinyl, l,3-dioxanyl, l,4-dioxinyl, l,4-dioxanyl, thiomorpholinyl, thiamorpholinyl,

perhydroazepinyl,pyrazolidinyl, imidazolinyl, imidazolidinyl, dihydropyridinyl,

tetrahydropyridinyl, oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl, octahydropyrrolo[3,4- c] pyrrol inyl, decahydroisoquinolyl, tetrahydrofuryl, 2-azaspiro[3.3]heptanyl, 4,7- diazaspiro[2.5]octanyl, l,6-diazaspiro[3.3]heptanyl, 7-azabicyclo[2.2. l]heptanyl, 3- azabicyclo[3.2. l]octanyl, and 8-azabicyclo[3.2.l]octanyl.

[0057] “(Heterocycloalkyl)alkyl” means an alkyl group, as defined herein, substituted with at least one, in another example 1 or 2, heterocycloalkyl groups as defined herein.

[0058] “Heterocycloalkyloxy” means a group of the formula -OR, where R is heterocycloalkyl group, as defined herein. [0059] “(Hetercycloalkyl)alkoxy” means a group of the formula -OR, where R is a

(heterocycloalkyl)alkyl group as defined herein.

[0060] “Hydroxy alkyl” means an alkyl group, as defined herein, substituted with at least one, or in other embodiments 1, 2, or 3 hydroxy groups.

[0061] “Hydroxyalkoxy” means an alkoxy group, as defined herein, substituted with at least one, or in other embodiments 1, 2, or 3 hydroxy groups.

[0062] “Hydroxy” means an -OH group. The terms“hydroxy” and“hydroxyl” are used interchangeably and mean an -OH group.

[0063] “Nitro” means an -NO2 group.

[0064] In some embodiments, compounds of the described herein exist as stereoisomers, wherein asymmetric or chiral centers are present. The term (R) and (S) used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem ., (1976), 45: 13-30, hereby incorporated by reference. The embodiments described herein specifically includes the various stereoisomers and mixtures thereof.

[0065] Stereoisomers” include (but are not limited to) geometric isomers, enantiomers, diastereomers, and mixtures of geometric isomers, enantiomers or

diastereomers. In some embodiments, individual stereoisomers of compounds are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic column.

[0066] “Amelioration” of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.

[0067] The terms“effective amount” or“therapeutically effective amount,” refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

[0068] “Excipient” or“pharmaceutically acceptable excipient” means a

pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof. In one embodiment, each component is“pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed .; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of

Pharmaceutical Excipients, 6th ed. ; Rowe el al. , Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed !; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed !; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

[0069] “Pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or salicylic acid. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D- glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, or lysine, or by other methods previously determined. The pharmacologically acceptable salts are not specifically limited as far as it can be used in medicaments. Examples of a salt that the compound forms with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

[0070] The term“pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components, such as an excipient. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.

[0071] “Subject” refers to an animal, including, but not limited to, a primate ( e.g ., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and“patient” are used interchangeably. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a human child.

[0072] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a human child.

[0073] Treat,”“treating,” and“treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof. Often, the beneficial effects that a subject derives from a therapeutic agent do not result in a complete cure of the disease, disorder or condition.

Embodiments

[0074] The following paragraphs present a number of embodiments of the compounds disclosed herein. In each instance the embodiment includes both the recited compound(s) as well as a single stereoisomer or mixture of stereoisomers thereof, as well as a pharmaceutically acceptable salt thereof.

[0075] In certain embodiments, the compound of Formula (I) is that wherein:

L is a bond, C(O), or -[C(R⁴R⁵)]_P-;

p is 1 or 2;

R¹ is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy,

cycloalkyloxy, or (cycloalkyl)alkoxy;

each R³ is independently halo or amino;

R⁴ is H;

R⁵ is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl; and

each R⁶ is independently haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with halo, haloalkoxy, or haloalkyl;

or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[0076] In certain embodiments, ring A is a 4-7 membered monocyclic

heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups; provided that when ring A is piperazinyl then ring A is optionally substituted with 1, 2, or 3 R³ groups.

[0077] In certain embodiments, ring A is a 4-7 membered monocyclic

heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups; provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R³ groups.

[0078] In certain embodiments, ring A is a 4-7 membered monocyclic

heterocycloalkyl ring, other than piperazinyl, which ring contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups; or ring A a 7-9 membered bicyclic heterocycloalkyl ring, which contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups; or ring A is piperazinyl which is optionally substituted with 1, 2, or 3 R³ groups. [0079] In certain embodiments, ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms.

[0080] In certain embodiments, ring B is piperazinyl, piperidinyl, or pyrrolidinyl. In certain embodiments, ring B is piperazinyl.

[0081] In certain embodiments, the compound of Formula (I) is according to

Formula (la), (lb), or (Ic):

Formula (la); Formula (lb); or Formula (Ic); where all groups are as defined in the Summary or as defined in any of the embodiments described herein, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[0082] In certain embodiments, the compound of Formula (I) is according to

Formula (la), (lb), or (Ic),

wherein:

cycloalkyloxy, or (cycloalkyl)alkoxy; each R³ is independently halo or amino; R⁴ is H; R⁵ is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl; and each R⁶ is independently haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with halo, haloalkoxy, or haloalkyl; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[0083] In certain embodiments, the compound of Formula (I) is according to

Formula (la):

Formula (la);

wherein: R¹ is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy; each R³ is independently halo or amino; R⁴ is H; R⁵ is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl; and each R⁶ is independently haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl group is each optionally substituted with halo, haloalkoxy, or haloalkyl; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[0084] In certain embodiments, the compound of Formula (I) is according to

Formula

Formula (Id); Formula (Ie); or Formula (If); wherein:

cycloalkyloxy, or (cycloalkyl)alkoxy; each R³ is independently halo or amino; R⁴ is H; R⁵ is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl; and each R⁶ is independently haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl group is each optionally substituted with halo, haloalkoxy, or haloalkyl; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[0085] In certain embodiments, the compound or pharmaceutically acceptable salt of

Formula (I) is that wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups; L is C(O); R¹ is aryl optionally substituted with cycloalkyloxy or (cycloalkyl)alkoxy; R² is aryl, optionally substituted with 1 or 2 R⁶ groups; each R³ is independently halo or amino; and each R⁶ is independently haloalkyl, haloalkoxy, or aryl, wherein the aryl is optionally substituted with halo.

[0086] In certain embodiments, the compound or pharmaceutically acceptable salt of

Formula (I) is according to Formula (Id) wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups; R¹ is aryl optionally substituted with cycloalkyloxy or (cycloalkyl)alkoxy; R² is aryl, optionally substituted with 1 or 2 R⁶ groups; each R³ is independently halo or amino; and each R⁶ is independently haloalkyl, haloalkoxy, or aryl, wherein the aryl is optionally substituted with halo.

[0087] In certain embodiments, the compound or pharmaceutically acceptable salt of

Formula (I) is that wherein: L is -[C(R⁴R⁵)]_P-; R¹ is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy; each R³ is independently halo or amino; p is 1 or 2; each R⁴ is H; each R⁵ is independently H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl; and each R⁶ is independently haloalkyl, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with halo, haloalkoxy, or haloalkyl.

[0088] In certain embodiments, the compound or pharmaceutically acceptable salt of

Formula (I) is according to Formula (Ie) wherein: R¹ is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy; each R³ is independently halo or amino; p is 1 or 2; each R⁴ is H; each R⁵ is independently H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl; and each R⁶ is independently haloalkyl, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl group is each optionally substituted with halo, haloalkoxy, or haloalkyl.

[0089] In certain embodiments, the compound or pharmaceutically acceptable salt of

Formula (I) is according to Formula (Ie) wherein: R¹ is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy; each R³ is independently halo or amino; p is 1 or 2; each R⁴ is H; each R⁵ is H; and each R⁶ is independently haloalkyl, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl group is each optionally substituted with halo, haloalkoxy, or haloalkyl.

[0090] In certain embodiments, the compound or pharmaceutically acceptable salt of

Formula (I) is according to Formula (Ie) wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups; R¹ is aryl optionally substituted with (cycloalkyl)alkoxy; R² is aryl, optionally substituted with an R⁶ group; each R³ is independently halo or amino; p is 1; R⁴ is H; R⁵ is alkyl; and R⁶ is aryl optionally substituted with halo.

[0091] In certain embodiments, the compound or pharmaceutically acceptable salt of

Formula (I) is according to Formula (Ie) wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups R¹ is aryl optionally substituted with (cycloalkyl)alkoxy; R² is aryl, optionally substituted with 1 or 2 R⁶ groups; each R³ is independently halo or amino; p is 1; R⁴ is H; R⁵ is cycloalkyl; and R⁶ is haloalkyl.

[0092] In certain embodiments, the compound or pharmaceutically acceptable salt of

Formula (I) is according to Formula (Ie) wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups R¹ is aryl optionally substituted with (cycloalkyl)alkoxy; R² is aryl optionally substituted with 1 or 2 R⁶ groups; each R³ is independently halo or amino; p is 1; R⁴ is H; R⁵ is aryl optionally substituted with haloalkyl; and R⁶ is haloalkyl. In certain embodiments, R⁵ is unsubstituted aryl. In certain embodiments, R⁵ is substituted aryl.

[0093] In certain embodiments, ring A is a 4-7 membered monocyclic

heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups; L is a bond; R¹ is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or

(cycloalkyl)alkoxy; R² is aryl, wherein the aryl is optionally substituted with 1 or 2 R⁶ groups; each R³ is independently halo or amino; and each R⁶ is independently haloalkyl.

[0094] In certain embodiments, the compound or pharmaceutically acceptable salt of

Formula (I) is according to Formula (If) wherein: ring A is a 4-7 membered monocyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups; L is a bond; R¹ is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or

[0095] In another aspect, provided herein is a compound of Formula (II):

Formula (II),

wherein:

ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms; ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups;

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

alkylcarbonylamino, or alkoxycarbonylamino;

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, or alkoxycarbonylamino;

optionally a pharmaceutically acceptable salt thereof.

[0096] In certain embodiments, the compound of Formula (II) is that wherein: R¹ is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or (cycloalkyl)alkoxy; R² is aryl, wherein the aryl is optionally substituted with 1 or 2 R⁶ groups; each R³ is

independently halo or amino; and each R⁶ is independently halo, haloalkyl, alkoxy, aryl, or aryloxy, wherein aryl is optionally substituted with halo; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[0097] In certain embodiments, the compound of Formula (II) is that wherein ring B is piperazinyl, piperidinyl, or pyrrolidinyl. In certain embodiments, ring B is piperidinyl or pyrrolidinyl. In certain embodiments, ring B is piperidinyl. In certain embodiments, ring B is pyrrolidinyl.

[0098] In certain embodiments, the compound of Formula (II) is according to

Formula (Ila) or (lib):

Formula (Ila); or Formula (lib);

where all groups are as defined in the Summary or as defined in any of the embodiments described herein, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[0099] In certain embodiments, the compound of Formula (II) is according to

Formula (Ila) or (lib) wherein:

R¹ is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or cycloalkyl)alkoxy; R² is aryl, wherein the aryl is optionally substituted with 1 or 2 R⁶ groups; each R³ is independently halo or amino; and each R⁶ is independently halo, haloalkyl, alkoxy, aryl, or aryloxy, wherein aryl is optionally substituted with halo; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. [00100] In certain embodiments, the compound of Formula (II) is according to Formula (Ha):

Formula (Ha);

wherein:

R¹ is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or

(cycloalkyl)alkoxy; R² is aryl, wherein the aryl is optionally substituted with 1 or 2 R⁶ groups; each R³ is independently halo or amino; and each R⁶ is independently halo, haloalkyl, or aryl, wherein aryl is optionally substituted with halo; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[00101] In certain embodiments, the compound of Formula (II) is according to Formula (lib):

Formula (lib);

wherein: R¹ is aryl, wherein the aryl is optionally substituted with cycloalkyloxy or

(cycloalkyl)alkoxy; R² is aryl, wherein the aryl is optionally substituted with 1 or 2 R⁶ groups; each R³ is independently amino; and each R⁶ is independently halo, alkoxy, aryl, or aryloxy; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[00102] In certain embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is that where L is C(O). In certain embodiments, L is a bond. In certain embodiments, L is -[C(R⁴R⁵)]_P-, wherein p is 1 or 2. In certain embodiments, L is C(O) or a bond. In certain embodiments, L is -[C(R⁴R⁵)]_P- or C(O), wherein p is 1 or 2. In certain embodiments, L is -[C(R⁴R⁵)]_P- or a bond, wherein p is 1 or 2. [00103] In certain embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is that where L is -[C(R⁴R⁵)]_P-, wherein, p is 1 or 2, wherein each R⁴ is H and each R⁵ is independently H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, L is -CH2-. In certain embodiments, L is -CH2CH2-. In certain embodiments, L is -C(R⁴R⁵)-, wherein R⁴ is H and R⁵ is alkyl. In certain embodiments, L is -C(R⁴R⁵)-, wherein R⁴ is H and R⁵ is methyl. In certain

embodiments, L is -C(R⁴R⁵)-, wherein R⁴ is H and R⁵ is cycloalkyl. In certain embodiments, L is -C(R⁴R⁵)-, wherein R⁴ is H and R⁵ is cyclopropyl, cyclopentyl, or cyclohexyl. In certain embodiments, L is -C(R⁴R⁵)-, wherein R⁴ is H and R⁵ is aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, L is -C(R⁴R⁵)-, wherein R⁴ is H and R⁵ is phenyl, wherein the phenyl is optionally substituted with haloalkyl. In certain embodiments, L is -C(R⁴R⁵)-, wherein R⁴ is H and R⁵ is phenyl, wherein the phenyl is optionally substituted with trifluorom ethyl. In certain embodiments, L is -C(R⁴R⁵)-, wherein R⁴ is H and R⁵ is phenyl, wherein the phenyl is substituted with trifluoromethyl. In certain embodiments, L is - C(R⁴R⁵)-, wherein R⁴ is H and R⁵ is unsubstituted aryl. In certain embodiments, L is - C(R⁴R⁵)-, wherein R⁴ is H and R⁵ is unsubstituted phenyl.

[00104] In certain embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is that where each R⁴ is independently H. In certain embodiments, R⁴ is alkyl. In certain embodiments, each R⁴ is independently H or alkyl.

[00105] In certain embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is that wherein p is 1 or 2. In certain embodiments, p is 1. In certain embodiments, p is 2.

[00106] In certain embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is that wherein p is 1 or 2, wherein each R⁵ is independently H, alkyl, alkenyl, alkynyl, or haloalkyl. In certain embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is that wherein p is 1 or 2, wherein each R⁵ is H. In certain embodiments, p is 1, wherein R⁵ is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl is each independently and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, haloalkyl, hydroxyalkyl, alkoxy,

hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl,

alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,

alkylcarbonyloxy, alkoxycarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, or alkoxycarbonylamino. [00107] In certain embodiments, the compound of Formula (I) or pharmaceutically acceptable salt thereof is that wherein p is 1, wherein R⁵ is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R⁵ is H. In certain embodiments, R⁵ is alkyl. In certain embodiments, R⁵ is methyl, ethyl propyl, butyl, pentyl, or hexyl. In certain embodiments, R⁵ is methyl. In certain embodiments, R⁵ is cycloalkyl. In certain embodiments, R⁵ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R⁵ is cyclopropyl. In certain embodiments, R⁵ is cyclopentyl. In certain embodiments, R⁵ is cyclohexyl. In certain embodiments, R⁵ is aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R⁵ is phenyl, wherein the phenyl is optionally substituted with haloalkyl. In certain embodiments, R⁵ is phenyl, wherein the phenyl is optionally substituted with trifluoromethyl,

difluorom ethyl, l,l,l-trifluoroethyl, or trichloromethyl. In certain embodiments, R⁵ is phenyl, wherein the phenyl is optionally substituted with trifluoromethyl. In certain embodiments, R⁵ is aryl, wherein the aryl is optionally substituted with trifluoromethyl, difluorom ethyl, l,l,l-trifluoroethyl, or trichloromethyl. In certain embodiments, R⁵ is aryl, wherein the aryl is optionally substituted with trifluoromethyl. In certain embodiments, R⁵ is aryl, wherein the aryl is substituted with haloalkyl. In certain embodiments, R⁵ is phenyl, wherein the phenyl is substituted with haloalkyl. In certain embodiments, R⁵ is phenyl, wherein the phenyl is substituted with trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl, or trichloromethyl. In certain embodiments, R⁵ is phenyl, wherein the phenyl is substituted with trifluoromethyl. In certain embodiments, R⁵ is aryl, wherein the aryl is substituted with trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl, or trichloromethyl. In certain embodiments, R⁵ is aryl, wherein the aryl is substituted with trifluoromethyl. In certain embodiments, R⁵ is unsubstituted aryl. In certain embodiments, R⁵ is unsubstituted phenyl.

In certain embodiments, R⁵ is H, alkyl, or cycloalkyl. In certain embodiments, R⁵ is H, alkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R⁵ is H, alkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R⁵ is alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R⁵ is alkyl or cycloalkyl. In certain embodiments, R⁵ is H or alkyl. In certain embodiments, R⁵ is H or cycloalkyl. In certain embodiments, R⁵ is H or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R⁵ is alkyl or aryl, wherein the aryl is optionally substituted with haloalkyl. In certain embodiments, R⁵ is cycloalkyl or aryl, wherein the aryl is optionally substituted with haloalkyl. [00108] In certain embodiments, R¹ is aryl optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is aryl optionally substituted with cycloalkyloxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is aryl optionally substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is aryl optionally substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R¹ is aryl optionally substituted with haloalkoxy. In certain embodiments, R¹ is aryl optionally substituted with cycloalkyloxy. In certain embodiments, R¹ is aryl optionally substituted with (cycloalkyl)alkoxy. In certain embodiments, R¹ is aryl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is aryl substituted with cycloalkyloxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is aryl substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is aryl substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R¹ is aryl substituted with haloalkoxy. In certain embodiments, R¹ is aryl substituted with cycloalkyloxy. In certain embodiments,

R¹ is aryl substituted with (cycloalkyl)alkoxy.

[00109] In certain embodiments, R¹ is unsubstituted aryl.

[00110] In certain embodiments, R¹ is optionally substituted phenyl, napthyl, or indanyl. In certain embodiments, R¹ is optionally substituted phenyl. In certain

embodiments, R¹ is optionally substituted napthyl. In certain embodiments, R¹ is optionally substituted indanyl.

[00111] In certain embodiments, R¹ is phenyl or napththyl, each of which is optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,

alkylcarbonyloxy, alkoxycarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, alkoxy carbonylamino, cycloalkyloxy,

heterocycloalkyloxy, (heterocycloalkyl)alkoxy or (cycloalkyl)alkoxy.

[00112] In certain embodiments, R¹ is phenyl, optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is phenyl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is phenyl substituted with trifluorom ethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, trichloromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cylcohexyloxy, cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy. In certain embodiments, R¹ is phenyl substituted with trifluoromethoxy, cyclopentyloxy, or cyclohexylmethoxy. In certain embodiments, R¹ is phenyl substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is phenyl substituted with trifluoromethoxy or cyclohexylmethoxy. In certain embodiments, R¹ is phenyl substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R¹ is phenyl substituted with cycloalkyloxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is phenyl substituted with cyclopentyloxy or cyclohexylmethoxy. In certain embodiments, R¹ is phenyl substituted with cycloalkyloxy or haloalkoxy. In certain embodiments, R¹ is phenyl substituted with cyclopentyloxy or trifluoromethoxy. In certain embodiments, R¹ is phenyl substituted with haloalkoxy. In certain embodiments, R¹ is phenyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or trichloromethoxy. In certain embodiments, R¹ is phenyl substituted with trifluoromethoxy.

In certain embodiments, R¹ is phenyl substituted with cycloalkyloxy. In certain

embodiments, R¹ is phenyl substituted with cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cylcohexyloxy. In certain embodiments, R¹ is phenyl substituted with cyclopentyloxy. In certain embodiments, R¹ is phenyl substituted with (cycloalkyl)alkoxy. In certain

embodiments, R¹ is phenyl substituted with cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy. In certain embodiments, R¹ is phenyl substituted with cyclohexylmethoxy.

[00113] In certain embodiments, R¹ is unsubstituted phenyl.

[00114] In certain embodiments, R¹ is ortho substituted phenyl. In certain

embodiments, R¹ is meta substituted phenyl. In certain embodiments, R¹ is para substituted phenyl.

[00115] In certain embodiments, R¹ is naphthyl optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is naphthyl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, trichloromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cylcohexyloxy, cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy. In certain embodiments, R¹ is naphthyl substituted with trifluoromethoxy, cyclopentyloxy, or cyclohexylmethoxy. In certain embodiments, R¹ is naphthyl substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R¹ is naphthyl substituted with trifluoromethoxy or cyclopentyloxy. In certain embodiments, R¹ is naphthyl substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is naphthyl substituted with trifluoromethoxy or cyclohexylmethoxy. In certain embodiments, R¹ is naphthyl substituted with

cycloalkyloxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is naphthyl substituted with cyclopentyloxy or cyclohexylmethoxy. In certain embodiments, R¹ is naphthyl substituted with haloalkoxy. In certain embodiments, R¹ is naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or trichloromethoxy. In certain embodiments, R¹ is naphthyl substituted with trifluoromethoxy. In certain embodiments, R¹ is naphthyl substituted with trifluoromethoxy. In certain embodiments, R¹ is naphthyl substituted cycloalkyloxy. In certain embodiments, R¹ is naphthyl substituted with cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyl cohexyl oxy. In certain embodiments, R¹ is naphthyl substituted with cyclopentyloxy. In certain embodiments, R¹ is naphthyl substituted with (cycloalkyl)alkoxy. In certain embodiments, R¹ is naphthyl substituted with

cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy. In certain embodiments, R¹ is naphthyl substituted with cyclohexylmethoxy.

[00116] In certain embodiments, R¹ is 1 -naphthyl optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, trichloromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cylcohexyloxy, cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with trifluoromethoxy, cyclopentyloxy, or cyclohexylmethoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R¹ is 1 -naphthyl substituted with trifluoromethoxy or cyclopentyloxy. In certain embodiments, R¹ is 1 -naphthyl substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with

trifluoromethoxy or cyclohexylmethoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with cycloalkyloxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is 1- naphthyl substituted with cyclopentyloxy or cyclohexylmethoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with haloalkoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or

trichloromethoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with

trifluoromethoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with

trifluoromethoxy. In certain embodiments, R¹ is 1 -naphthyl substituted cycloalkyloxy. In certain embodiments, R¹ is 1 -naphthyl substituted with cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cylcohexyloxy. In certain embodiments, R¹ is 1 -naphthyl substituted with cyclopentyloxy. In certain embodiments, R¹ is 1 -naphthyl substituted with

(cycloalkyl)alkoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with cyclohexylmethoxy.

[00117] In certain embodiments, R¹ is 2-naphthyl optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is 2-naphthyl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is 2-naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, trichloromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cylcohexyloxy, cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy. In certain embodiments, R¹ is 1 -naphthyl substituted with trifluoromethoxy, cyclopentyloxy, or cyclohexylmethoxy. In certain embodiments, R¹ is 2-naphthyl substituted with haloalkoxy or cycloalkyloxy. In certain embodiments, R¹ is 2-naphthyl substituted with trifluoromethoxy or cyclopentyloxy. In certain embodiments, R¹ is 2-naphthyl substituted with haloalkoxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is 2-naphthyl substituted with

trifluoromethoxy or cyclohexylmethoxy. In certain embodiments, R¹ is 2-naphthyl substituted with cycloalkyloxy or (cycloalkyl)alkoxy. In certain embodiments, R¹ is 2- naphthyl substituted with cyclopentyloxy or cyclohexylmethoxy. In certain embodiments, R¹ is 2-naphthyl substituted with haloalkoxy. In certain embodiments, R¹ is 2-naphthyl substituted with trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or

trichloromethoxy. In certain embodiments, R¹ is 2-naphthyl substituted with

trifluoromethoxy. In certain embodiments, R¹ is 2-naphthyl substituted with

trifluoromethoxy. In certain embodiments, R¹ is 2-naphthyl substituted cycloalkyloxy. In certain embodiments, R¹ is 2-naphthyl substituted with cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cylcohexyloxy. In certain embodiments, R¹ is 2-naphthyl substituted with cyclopentyloxy. In certain embodiments, R¹ is 2-naphthyl substituted with

(cycloalkyl)alkoxy. In certain embodiments, R¹ is 2-naphthyl substituted with

cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy. In certain embodiments, R¹ is 2-naphthyl substituted with cyclohexylmethoxy.

[00118] In certain embodiments, R¹ is unsubstituted naphthyl. In certain

embodiments, R¹ is l-naphthyl or 2-naphthyl. In certain embodiments, R¹ is l-naphthyl. In certain embodiments, R¹ is 2-naphthyl.

[00119] In certain embodiments, R¹ is heteroaryl, optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is heteroaryl, optionally substituted with (cycloalkyl)alkoxy. In certain embodiments, R¹ is heteroaryl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is heteroaryl substituted with (cycloalkyl)alkoxy. In certain embodiments, R¹ is 2-pyridyl, 3-pyridyl, or quinolinyl, each of which is substituted with (cycloalkyl)alkoxy. In certain embodiments, R¹ is 2-pyridyl or 3-pyridyl substituted with (cycloalkyl)alkoxy. In certain embodiments, R¹ is 2-pyridyl substituted with (cycloalkyl)alkoxy. In certain embodiments, R¹ is 2-pyridyl, 3-pyridyl, or quinolinyl, each of which is substituted with

cyclohexylmethoxy. In certain embodiments, R¹ is 2-pyridyl, or 3-pyridyl, each of which is substituted with cyclohexylmethoxy. In certain embodiments, R¹ is 2-pyridyl substituted with cyclohexylmethoxy.

[00120] In certain embodiments, R¹ is unsubstituted heteroaryl.

[00121] In certain embodiments, R¹ is 2-pyridyl, optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is 2-pyridyl, substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R¹ is 2-pyridyl substituted with (cycloalkyl)alkoxy. In certain embodiments, R¹ is 2-pyridyl substituted with cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or

cyclopentylethoxy. In certain embodiments, R¹ is 2-pyridyl substituted with

cyclohexylmethoxy.

[00122] In certain embodiments, R¹ is unsubstituted 2-pyridyl.

[00123] In certain embodiments, ring A is a 4-7 membered monocyclic

heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino, provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R³ groups. In certain embodiments, ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino. In certain embodiments, ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing one ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino. In certain embodiments, ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino. In certain embodiments, ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino, provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R³ groups.

[00124] In certain embodiments, ring A is a 5 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino. In certain embodiments, ring A is a 6 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R³ groups wherein each R³ group is independently halo or amino.

[00125] In certain embodiments, ring A is substituted. In certain embodiments, ring A is substituted piperidinyl. In certain embodiments, ring A is substituted pyrrolidinyl.

[00126] In certain embodiments, ring A is optionally substituted piperazinyl.

[00127] In certain embodiments, ring A is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, imidazolidinyl, pyrazolidinyl, hexahydropyrimidinyl, hexahydropyridazinyl, or diazepanyl, each of which is substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino; or ring A is unsubstituted piperazinyl. In certain embodiments, ring A is piperidinyl or pyrrolidinyl, each of which is substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino; or ring A is unsubstituted piperazinyl. In certain embodiments, ring A is unsubstituted piperazinyl or piperidinyl substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino. In certain embodiments, ring A is unsubstituted piperazinyl or pyrrolidinyl substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino.

[00128] In certain embodiments, ring A is piperazinyl optionally substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino. In certain

embodiments, ring A is unsubstituted piperazinyl.

[00129] In certain embodiments, ring A is piperidinyl substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino. In certain embodiments, ring A is piperidinyl substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently selected from fluoro, chloro, bromo, and amino. In certain embodiments, ring A is piperidinyl substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently fluoro or amino. In certain embodiments, ring A is piperidinyl substituted with an amino group. In certain embodiments, ring A is piperidinyl substituted with a halo group. [00130] In certain embodiments, ring A is pyrrolidinyl substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino. In certain embodiments, ring A is pyrrolidinyl substituted with amino.

[00131] In certain embodiments, ring A is:

, wherein n is 1 to 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

[00132] In certain embodiments, ring A is

or optionally a single stereoisomer or mixture of stereoisomers thereof.

[00133] In certain embodiments, ring A is

[00134] In certain embodiments, ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and substituted with 1, 2, or 3 R³ groups, wherein each R³ group is independently halo or amino. In certain embodiments, ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with an amino group. In certain embodiments, ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one ring nitrogen atom, with remaining ring atoms being carbon atoms, and is substituted with an amino group. In certain embodiments, ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with an amino group.

[00135] In certain embodiments, ring A is 8-azabicyclo[3.2. l]octanyl or (lR,5S)-3- azabicyclo[3.2.l] octanyl, each of which is substituted with an amino group. In certain embodiments, ring A is 8-azabicyclo[3.2. l]octanyl substituted with an amino group. In certain embodiments, ring A is (lR,5S)-3-azabicyclo[3.2.l] octanyl substituted with an amino group. [00136] In certain embodiments, ring A is

[00137] In certain embodiments, ring A is

[00138] In certain embodiments, ring A is

[00139] In certain embodiments, ring A is

[00140] In certain embodiments, ring A is:

[00141] In certain embodiments, R³ is independently halo or amino. In certain embodiments, R³ is independently fluoro, chloro, bromo, or amino. In certain embodiments, R³ is independently fluoro or amino. In certain embodiments, R³ is independently halo. In certain embodiments, R³ is independently fluoro, chloro, or bromo. In certain embodiments, R³ is independently fluoro. In certain embodiments, R³ is independently amino.

[00142] In certain embodiments, R² is aryl or heteroaryl, wherein each aryl or heteroaryl is optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is optionally substituted aryl. In certain embodiments, R² is optionally substituted heteroaryl. In certain embodiments, R² is unsubstituted aryl. In certain embodiments, R² is unsubstituted heteroaryl.

[00143] In certain embodiments, R² is aryl optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is aryl optionally substituted with 1 R⁶ group. In certain embodiments, R² is aryl optionally substituted with 2 R⁶ groups. In certain embodiments, R² is aryl substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is aryl substituted with 1 R⁶ group. In certain embodiments, R² is aryl substituted with 2 R⁶ groups.

[00144] In certain embodiments, R² is phenyl, napthyl, or indanyl, each of which is optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is phenyl optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is naphthyl optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is indanyl optionally substituted with 1 or 2 R⁶ groups.

[00145] In certain embodiments, R² is phenyl optionally substituted with 1 R⁶ group.

In certain embodiments, R² is phenyl optionally substituted with 2 R⁶ groups. In certain embodiments, R² is phenyl substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is phenyl substituted with 1 R⁶ group. In certain embodiments, R² is phenyl substituted with 2 R⁶ groups. In certain embodiments, R² is unsubstituted phenyl.

[00146] In certain embodiments, R² is phenyl substituted with 1 or 2 R⁶ groups, wherein each R⁶ group is independently selected from halo, alkoxy, haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, aryloxy, and heteroaryl, wherein each aryl or heteroaryl is independently and optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R² is phenyl substituted with 1 or 2 R⁶ groups, wherein each R⁶ group is independently selected from butoxy, chloro, trifluoromethyl, trifluoromethoxy,

(trifluoromethyl)cyclopropyl, phenyl, phenoxy, and 2-pyridyl, wherein phenyl or 2-pyridyl is each independently and optionally substituted with fluoro, chloro, trifluoromethyl, or trifluoromethoxy .

[00147] In certain embodiments, R² is phenyl substituted with 1 or 2 R⁶ groups at the ortho position of the phenyl. In certain embodiments, R² is phenyl substituted with 1 or 2 R⁶ groups at the meta position of the phenyl. In certain embodiments, R² is phenyl substituted with 1 R⁶ group at the para position of the phenyl. In certain embodiments, R² is phenyl substituted with 2 R⁶ groups at the ortho and the meta positions of the phenyl. In certain embodiments, R² is phenyl substituted with 2 R⁶ groups at the ortho and the para positions of the phenyl. In certain embodiments, R² is phenyl substituted with 2 R⁶ groups at the meta and the para positions of the phenyl. In certain embodiments, R² is phenyl substituted with a aryl group at the meta position of the phenyl and a halo group at the para position of the phenyl. In certain embodiments, R² is phenyl substituted with an alkoxy group at the meta position of the phenyl and a halo group at the para position of the phenyl. In certain embodiments, R² is phenyl substituted with an aryloxy group at the meta position of the phenyl and a halo group at the para position of the phenyl. In certain embodiments, R² is phenyl substituted with a phenyl group at the meta position of the phenyl and a chloro group at the the para position of the phenyl. In certain embodiments, R² is phenyl substituted with an n-butoxy group at the meta position of the phenyl and a chloro group at the para position of the phenyl. In certain embodiments, R² is phenyl substituted with a phenoxy group at the meta position of the phenyl and a chloro group at the para position of the phenyl.

[00148] In certain embodiments, R² is phenyl is optionally substituted with an R⁶ group, wherein R⁶ group is selected from consisting of haloalkyl, haloalkoxy,

(haloalkyl)cycloalkyl, aryl, and heteroaryl, wherein each aryl or heteroaryl is independently and optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R² is phenyl substituted with an R⁶ group, wherein R⁶ group is selected from trifluoromethyl, trifluoromethoxy, (trifluoromethyl)cyclopropyl, phenyl, and 2-pyridyl, wherein each phenyl and 2-pyridyl, is independently substituted with fluoro, chloro, trifluoromethyl, or trifluoromethoxy .

[00149] In certain embodiments, R² is phenyl substituted with optionally substituted phenyl. In certain embodiments, R² is phenyl optionally substituted with phenyl , which is optionally substituted with halolakyl. In certain embodiments, R² is phenyl substituted with phenyl , which is optionally substituted with halolakyl. In certain embodiments, R² is phenyl substituted with phenyl, which is substituted with trifluoromethyl. In certain embodiments,

R² is phenyl substituted with chlorophenyl. In certain embodiments, R² is phenyl substituted with fluorophenyl.

[00150] In certain embodiments, R² is phenyl optionally substituted with an R⁶ group, wherein R⁶ group is haloalkyl, haloalkoxy, or aryl, wherein the aryl is optionally substituted with halo. In certain embodiments, R² is phenyl optionally substituted with an R⁶ group, wherein R⁶ group is trifluoromethyl, trifluoromethoxy, or phenyl, wherein the phenyl is optionally substituted with fluoro, chloro or bromo. In certain embodiments, R² is phenyl substituted with haloalkoxy. In certain embodiments, R² is phenyl substituted with trifluoromethoxy. In certain embodiments, R² is phenyl substituted with haloalkyl. In certain embodiments, R² is phenyl substituted with trifluoromethyl. [00151] In certain embodiments, R² is phenyl optionally substituted with an R⁶ group, wherein R⁶ group is selected from haloalkyl, (haloalkyl)cycloalkyl, aryl, and heteroaryl, wherein each aryl or heteroaryl is independently and optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R² is phenyl substituted with an R⁶ group, wherein R⁶ group is selected from trifluoromethyl, (trifluoromethyl)cyclopropyl, phenyl, and 2-pyridyl, wherein each phenyl or 2-pyridyl, is independently substituted with fluoro, chloro, trifluoromethyl, or trifluorom ethoxy. In certain embodiments, R² is phenyl substituted with haloalkyl. In certain embodiments, R² is phenyl substituted with trifluoromethyl. In certain embodiments, R² is phenyl substituted with (haloalkyl)cycloalkyl. In certain embodiments, R² is phenyl substituted with (trifluorom ethyl)cy cl opropyl. In certain embodiments, R² is phenyl substituted with aryl, wherein the aryl is optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R² is phenyl substituted with unsubstituted phenyl. In certain embodiments, R² is phenyl substituted with an R⁶ group, wherein R⁶ group is phenyl optionally substituted with fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, 1,1,1- trifluoroethyl, trichlorom ethyl, trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or trichloromethoxy. In certain embodiments, R² is phenyl substituted with heteroaryl, wherein heteroaryl is optionally substituted with halo or haloalkoxy. In certain embodiments, R² is phenyl substituted with 2-pyridyl or 3-pyridyl, wherein 2-pyridyl or 3-pyridyl is optionally substituted with fluoro, chloro, bromo, trifluoromethoxy, difluoromethoxy, 1,1,1- trifluoroethoxy, or trichloromethoxy. In certain embodiments, R² is phenyl substituted with 2-pyridyl or 3-pyridyl, wherein 2-pyridyl or 3-pyridyl is substituted with fluoro, chloro, or trifluoromethoxy. In certain embodiments, R² is phenyl substituted with 2-pyridyl, which is substituted with fluoro, chloro, or trifluoromethoxy.

[00152] In certain embodiments, R² is phenyl optionally substituted with an R⁶ group, wherein R⁶ group is haloalkoxy. In certain embodiments, R² is phenyl optionally substituted with an R⁶ group, wherein R⁶ group is trifluoromethoxy.

[00153] In certain embodiments, R² is indanyl optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is indanyl optionally substituted with 1 R⁶ group. In certain embodiments, R² is indanyl optionally substituted with 2 R⁶ groups. In certain embodiments, R² is indanyl optionally substituted with haloalkyl. In certain embodiments, R² is indanyl optionally substituted with trifluoromethyl. In certain embodiments, R² is unsubstituted indanyl. In certain embodiments, R² is indanyl substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is indanyl substituted with 1 R⁶ group. In certain embodiments, R² is indanyl substituted with 2 R⁶ groups. In certain embodiments, R² is indanyl substituted with haloalkyl. In certain embodiments, R² is indanyl substituted with trifluoromethyl.

[00154] In certain embodiments, R² is phenyl optionally with 1 or 2 R⁶ groups, wherein R⁶ group is independently selected from halo, haloalkyl, aryloxy, alkoxy, and aryl optionally substituted with halo. In certain embodiments, R² is phenyl optionally substituted with 1 or 2 R⁶ groups, wherein each R⁶ group is independently selected from fluoro, chloro, bromo, trifluorm ethyl, difluorom ethyl, l,l,l-trifluoroethyl, trichloromethyl, phenoxy, methoxy, ethoxy, propoxy, n-butoxy, and phenyl optionally substituted with fluoro, chloro, or bromo. In certain embodiments, R² is phenyl optionally substituted with an R⁶ group selected from chloro, trifluorm ethyl, phenyl, and chlorophenyl. In certain embodiments, R² is phenyl optionally substituted with 2 R⁶ groups, wherein each R⁶ groups are independently selected from chloro, phenoxy, n-butoxy, and phenyl. In certain embodiments, R² is phenyl substituted with halo. In certain embodiments, R² is phenyl substituted with fluoro, chloro, or bromo. In certain embodiments, R² is phenyl substituted with halo substituted phenyl. In certain embodiments, R² is phenyl substituted with chlorophenyl. In certain embodiments, R² is phenyl substituted with haloalkyl. In certain embodiments, R² is phenyl substituted with phenyl substituted with trifluoromethyl. In certain embodiments, R² is phenyl substituted with unsubstituted phenyl. In certain embodiments, R² is unsubstituted phenyl.

[00155] In certain embodiments, R² is phenyl optionally with an R⁶ group, wherein the R⁶ group is selected from halo, haloalkyl, and aryl optionally substituted with halo. In certain embodiments, R² is phenyl optionally with an R⁶ group, wherein the R⁶ group is selected from fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl,

trichloromethyl, and phenyl, wherein the phenyl is optionally substituted with fluoro, chloro, or bromo.

[00156] In certain embodiments, R² is phenyl optionally substituted with 1 or 2 R⁶ groups, wherein each R⁶ group is independently selected from alkoxy, halo, aryl, and aryloxy. In certain embodiments, R² is phenyl optionally substituted with 1 or 2 R⁶ groups, wherein each R⁶ group is independently selected from methoxy, ethoxy, propoxy, butoxy, fluoro, chloro, bromo, phenyl and phenoxy. In certain embodiments, R² is phenyl substituted with 2 R⁶ groups, wherein each R⁶ group is independently alkoxy or halo. In certain embodiments, R² is phenyl substituted with 2 R⁶ groups, wherein each R⁶ group is independently n-butoxy or chloro. In certain embodiments, R² is phenyl substituted with 2 R⁶ groups, wherein each R⁶ group is independently aryl or halo. In certain embodiments, R² is phenyl substituted with 2 R⁶ groups, wherein each R⁶ group is independently phenyl or chloro. In certain embodiments, R² is phenyl substituted with 2 R⁶ groups, wherein each R⁶ group is independently aryloxy or halo. In certain embodiments, R² is phenyl substituted with 2 R⁶ groups, wherein each R⁶ group is independently phenoxy or chloro.

[00157] In certain embodiments, R² is heteroaryl, optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is heteroaryl optionally substituted with 1 R⁶ group. In certain embodiments, R² is heteroaryl optionally substituted with 2 R⁶ groups. In certain embodiments, R² is heteroaryl substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is heteroaryl substituted with 1 R⁶ group. In certain embodiments, R² is heteroaryl substituted with 2 R⁶ groups. In certain embodiments, R² is unsub stitutedheteroaryl.

[00158] In certain embodiments, R² is pyridyl, thiazolyl, or l,3,4-thiadiazolyl, wherein each R² is independently optionally substituted with 1 or 2 R⁶ groups. In certain

embodiments, R² is 2-pyridyl, 3-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 2-pyridyl, 3-pyridyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 2-pyridyl, 3-pyridyl, or thiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 2-pyridyl, 3- pyridyl, or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 3-pyridyl, thiazolyl, or 1,3,4- thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 2-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 2-pyridyl or 3-pyridyl, wherein each of which is independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 2-pyridyl or thiazolyl, wherein each of whchis independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 2-pyridyl or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 3- pyridyl or thiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 3-pyridyl or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is thiazolyl or l,3,4-thiadiazolyl, wherein each of which is independently optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is pyridyl optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 2-pyridyl optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 3-pyridyl optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is thiazolyl optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 2-thiazolyl optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 4-thiazolyl optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 5-thiazolyl optionally substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is l,3,4-thiadiazolyl optionally substituted with 1 or 2 R⁶ groups.

[00159] In certain embodiments, R² is 2-pyridyl substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 3-pyridyl substituted with 1 or 2 R⁶ groups. In certain

embodiments, R² is 2-thiazolyl substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 3-thiazolyl substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is 4-thiazolyl substituted with 1 or 2 R⁶ groups. In certain embodiments, R² is l,3,4-thiadiazolyl substituted with 1 or 2 R⁶ groups.

[00160] In certain embodiments, R² is selected from:

[00161] In certain embodiments, R² is 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, each of which is optionally substituted with R⁶, wherein R⁶ is aryl or heteroaryl, each of which is optionally substituted with halo, haloalkyl, or haloalkoxy. In certain embodiments, R² is 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, each of which is optionally substituted with phenyl, wherein the phenyl is optionally substituted with a group selected from fluoro, chloro, trifluoromethyl, and trilfuorom ethoxy. In certain embodiments, R² is 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, each of which is optionally substituted with 2-pyridyl, 3-pyridyl, or 4-pyridyl, wherein 2- pyridyl is optionally substituted with chloro. In certain embodiments, R² is 2-pyridyl optionally substituted with aryl, wherein the aryl is optionally substituted with halo. In certain embodiments, R² is 2-pyridyl optionally substituted with chlorophenyl. In certain

embodiments, R² is 3-pyridyl optionally substituted with aryl, wherein the aryl is optionally substituted with halo, haloalkyl or haloalkoxy. In certain embodiments, R² is 3-pyridyl optionally substituted with phenyl, wherein the phenyl is optionally substituted with fluoro, chloro, trifluoromethyl, or trilfuorom ethoxy. In certain embodiments, R² is 3-pyridyl optionally substituted with heteroaryl, wherein heteroaryl is optionally substituted with halo. In certain embodiments, R² is 3-pyridyl optionally substituted with 2-pyridyl, wherein 2- pyridyl is optionally substituted with chloro. In certain embodiments, R² is thiazolyl or 1,3,4- thiadiazolyl, each of which is optionally substituted with aryl, wherein the aryl is optionally substituted with halo. In certain embodiments, R² is thiazolyl or l,3,4-thiadiazolyl, each of which is optionally substituted with phenyl, wherein the phenyl is optionally substituted with chloro.

[00162] In certain embodiments, R⁶ is independently halo, alkoxy, haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, aryloxy, or heteroaryl, wherein each aryl or heteroaryl is each independently optionally substituted with halo, haloalkoxy, or haloalkyl.

In certain embodiments, R⁶ is independently methoxy, ethoxy, propoxy, butoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl, trichlorom ethyl, trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, trichlorom ethoxy,

(trifluoromethyl)cyclopropyl, phenyl, phenoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, wherein phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, is each independently optionally substituted with fluoro, chloro, trifluoromethyl, or trifluoromethoxy. In certain embodiments, R⁶ is independently n-butoxy, chloro, trifluoromethyl, trifluoromethoxy,

(trifluoromethyl)cyclopropyl, phenyl, phenoxy, 2-pyridyl, wherein phenyl or 2-pyridyl is each independently optionally substituted with fluoro, chloro, trifluoromethyl, or

trifluoromethoxy.

[00163] In certain embodiments, each R⁶ is independently halo, alkoxy, haloalkyl, haloalkoxy, or (haloalkyl)cycloalkyl. In certain embodiments, each R⁶ is independently methoxy, ethoxy, propoxy, butoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl, trichloromethyl, trifluoromethoxy, difluoromethoxy, 1,1,1- trifluoroethoxy, trichloromethoxy, or (trifluoromethyl)cyclopropyl. In certain embodiments, R⁶ is independently butoxy, chloro, trifluoromethyl, trifluoromethoxy, or

(trifluoromethyl)cyclopropyl. In certain embodiments, R⁶ is independently halo or alkoxy. In certain embodiments, R⁶ is independently n-butoxy or chloro. In certain embodiments, R⁶ is independently halo, alkoxy, or haloalkyl. In certain embodiments, R⁶ is independently, n- butoxy, chloro, or trifluoromethyl. In certain embodiments, R⁶ is independently halo, alkoxy, or (haloalkyl)cycloalkyl. In certain embodiments, R⁶ is independently n-butoxy, chloro, trifluoromethoxy, or (trifluoromethyl)cyclopropyl. In certain embodiments, R⁶ is

independently halo or (haloalkyl)cycloalkyl. In certain embodiments, R⁶ is independently chloro or (trifluoromethyl)cyclopropyl. In certain embodiments, R⁶ is independently halo. In certain embodiments, R⁶ is independently fluoro, chloro, or bromo. In certain embodiments, R⁶ is independently alkoxy. In certain embodiments, R⁶ is independently methoxy, ethoxy, propoxy, or n-butoxy. In certain embodiments, R⁶ is independently haloalkyl. In certain embodiments, R⁶ is independently trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl, or trichlorom ethyl. In certain embodiments, R⁶ is independently haloalkoxy. In certain embodiments, R⁶ is independently trifluoromethoxy, difluoromethoxy, l,l,l-trifluoroethoxy, or trichloromethoxy. In certain embodiments, R⁶ is independently (haloalkyl)cycloalkyl. In certain embodiments, R⁶ is independently (trifluoromethyl)cyclopropyl.

[00164] In certain embodiments, R⁶ is independently aryl, aryloxy, or heteroaryl, wherein each aryl or heteroaryl is each independently optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R⁶ is independently aryl or heteroaryl, wherein each aryl or heteroaryl is independently optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R⁶ is independently aryl, or aryloxy, wherein each aryl is independently optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R⁶ is independently heteroaryl, or aryloxy, wherein each aryl or heteroaryl is independently optionally substituted with halo, haloalkoxy, or haloalkyl.

[00165] In certain embodiments, R⁶ is aryl substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R⁶ is aryl substituted with halo. In certain embodiments, R⁶ is aryl substituted with haloalkoxy. In certain embodiments, R⁶ is aryl substituted with haloalkyl.

[00166] In certain embodiments, R⁶ is phenyl substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R⁶ is phenyl substituted with fluoro, chloro,

trifluoromethyl, or trifluoromethoxy. In certain embodiments, R⁶ is phenyl substituted with halo. In certain embodiments, R⁶ is phenyl substituted with fluoro or chloro. In certain embodiments, R⁶ is phenyl substituted with haloalkoxy. In certain embodiments, R⁶ is phenyl substituted with trifluoromethoxy. In certain embodiments, R⁶ is phenyl substituted with haloalkyl. In certain embodiments, R⁶ is phenyl substituted with trifluoromethyl.

[00167] In certain embodiments, R⁶ is unsubstituted phenyl.

[00168] In certain embodiments, R⁶ is heteroaryl substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R⁶ is heteroaryl substituted with halo or haloalkoxy. In certain embodiments, R⁶ is heteroaryl substituted with halo. In certain embodiments, R⁶ is heteroaryl substituted with haloalkoxy. In certain embodiments, R⁶ is heteroaryl substituted with chloro. In certain embodiments, R⁶ is heteroaryl substituted with fluoro. In certain embodiments, R⁶ is heteroaryl substituted with trifluoromethoxy.

[00169] In certain embodiments, R⁶ is 2-pyridyl substituted with halo or haloalkoxy.

In certain embodiments, R⁶ is independently 2-pyridyl substituted with fluoro, chloro, or trifluoromethoxy. In certain embodiments, R⁶ is 2-pyridyl substituted with halo. In certain embodiments, R⁶ is independently 2-pyridyl substituted with fluoro or chloro. In certain embodiments, R⁶ is independently 2-pyridyl substituted with fluoro. In certain embodiments, R⁶ is independently 2-pyridyl substituted with chloro. In certain embodiments, R⁶ is 2- pyridyl substituted with trifluorom ethoxy.

[00170] In certain embodiments, R⁶ is independently unsubstituted2-pyridyl.

[00171] In certain embodiments, R⁶ is aryloxy substituted with halo, haloalkoxy, or haloalkyl.

[00172] In certain embodiments, R⁶ is unsubstituted aryl. In certain embodiments, R⁶ is unsubstituted heteroaryl. In certain embodiments, R⁶ is unsubstituted aryloxy.

[00173] In certain embodiments, R⁶ is phenoxy.

[00174] In certain embodiments, R⁶ is independently halo or aryloxy, wherein aryloxy is optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R⁶ is independently halo or aryl, wherein the aryl is optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R⁶ is independently halo or unsubstituted aryloxy. In certain embodiments, R⁶ is independently halo or unsubstituted aryl.

[00175] In certain embodiments, R⁶ is independently halo or phenyl, wherein the phenyl is optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R⁶ is independently fluoro, chloro or phenyl.

[00176] In certain embodiments, R⁶ is independently halo or phenoxy, wherein phenoxy is optionally substituted with halo, haloalkoxy, or haloalkyl. In certain

embodiments, R⁶ is independently fluoro, chloro or phenoxy.

[00177] In certain embodiments, ring B is piperazinyl, then R² is not furanyl or thiophenyl. In certain embodiments, R² is not furanyl or thiophenyl. In certain embodiments, R² is not furanyl. In certain embodiments, R² is not thiophenyl.

[00178] In certain embodiments, when ring B is piperidinyl or pyrrolidinyl, then R² is not imidazolyl. In certain embodiments, when ring B is piperidinyl, then R² is not imidazolyl. In certain embodiments, when ring B is pyrrolidinyl, then R² is not imidazolyl.

In certain embodiments, R² is not imidazolyl.

[00179] In certain embodiments, R² is not amino-substituted imidazolyl. In certain embodiments, when ring B is piperidinyl then R² is not amino-substituted imidazolyl. In certain embodiments, when ring B is pyrrolidinyl then R² is not amino-substituted imidazolyl. [00180] In certain embodiments, when R¹ is methoxy substituted phenyl, then R² is not unsubstituted phenyl. In certain embodiments, R¹ is not methoxy substituted phenyl. In certain embodiments, R² is not unsubstituted phenyl.

[00181] In certain embodiments, when R¹ is cyano substituted phenyl, then R² is not unsubstituted phenyl. In certain embodiments, R¹ is not cyano substituted phenyl.

[00182] In certain embodiments, R¹ is not substituted heteroaryl. In certain

embodiments, R¹ is not unsubstituted heteroaryl.

[00183] In certain embodiments, the compound of Formula (II) is wherein ring A is not pyrrolidinyl. In certain embodiments, the compound of Formula (II) is wherein ring A is not pyrrolidinyl.

[00184] In certain embodiments, the compound of Formula (II) is wherein R¹ is not substituted heteroaryl. In certain embodiments, the compound of Formula (II) is wherein R¹ is not un substituted heteroaryl.

[00185] In certain embodiments, the compound of Formula (II) is not A -[ l -[[(2L',4/ί)- l-[(3,4-dimethoxyphenyl)sulfonyl]-4-[(3-methoxyphenyl)methoxy]-2-pyrrolidinyl]carbonyl]- 3-pyrrolidinyl]-acetamide or trifluoroacetate salt thereof. In certain embodiments, the compound of Formula (II) is that wherein R¹ is not unsubstituted heteroaryl. In certain embodiments, the compound of Formula (II) is not/V-[l-[[-l-[(3,4- dimethoxyphenyl)sulfonyl]-4-[(3-methoxyphenyl)methoxy]-2-pyrrolidinyl]carbonyl]-3- pyrrolidinyl]-acetamide or trifluoroacetate salt thereof.

[00186] In certain embodiments, the compound of Formula (I) is that according to one of the following formulas:

Formula (Id); Formula (Ig); or Formula (Ih);

where all groups are as defined in the Summary or as defined in any of the embodiments described herein, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally

optionally a pharmaceutically acceptable salt thereof.

[00187] In certain embodiments, the compound of Formula (I) is that according to one of the following formulas:

Formula (Ie); Formula (Ii); or Formula (Ij);

optionally a pharmaceutically acceptable salt thereof.

[00188] In certain embodiments, the compound of Formula (I) is that according to one of the following formulas:

Formula (If); Formula (Ik); or Formula (II);

[00189] In certain embodiments, the compound of Formula (I) is that according to one of the following formulas:

Formula (Im), Formula (In), Formula (Io), or Formula (Ip); wherein for formulas (Im), (Io) and (Ip), m is 1, 2, or 3, and for formula (In), m is 0, 1, 2, or 3, where all other groups are as defined in the Summary or as defined in any of the embodiments described herein or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. [00190] In certain embodiments, the compound of Formula (I) is that according to one of the following formulas:

Formula (Iq), Formula (Ir), Formula (Is), or Formula (It); wherein for formulas (Iq), (Is), and (It), m is 1, 2, or 3, and for formula (Ir), m is 0, 1, 2, or 3, where all other groups are as defined in the Summary or as defined in any of the

embodiments described herein, or optionally a single stereoisomer or mixture of

stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[00191] In certain embodiments, the compound of Formula (I) is that according to one of the following formulas:

Formula (Iu), Formula (Iv), Formula (Iw), or Formula (lx); wherein m is 0, 1, 2, or 3, where all other groups are as defined in the Summary or as defined in any of the embodiments described herein, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[00192] In certain embodiments, the compound of Formula (I) is that according to one of the following formulas:

Formula (Iy), Formula (Iz), or Formula (Iaa); where all groups are as defined in the Summary or as defined in any of the embodiments described herein, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[00193] In certain embodiments, the compound of Formula (I) is that according to one of the following formulas:

Formula (lab), Formula (lac), or Formula (lad);

[00194] In certain embodiments, the compound of Formula (I) is that according to one of the following formulas:

Formula (Iae), or Formula (Iaf);

[00195] In certain embodiments, the compound of Formula (II) is that according to one of the following formulas:

Formula (He), Formula (lid), Formula (He), Formula (Ilf), or Formula (Ilg); wherein for formulas (lie), (He), (Ilf), and (Ilg), m is 1, 2, or 3, and for formula (lid), m is 0, 1, 2, or 3, where all other groups are as defined in the Summary or as defined in any of the embodiments described herein, or optionally a single stereoisomer or mixture of

[00196] In certain embodiments, the compound of Formula (II) is that according to one of the following formulas:

Formula (Ilh) or Formula (Hi);

wherein m is 1, 2, or 3, where all other groups are as defined in the Summary or as defined in any of the embodiments described herein, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[00197] In certain embodiments, the compound of Formula (II) is that according to one of the following formulas:

Formula (Ilj), or Formula (Ilk);

[00198] In another aspect, provided herein is a compound of Formula (III):

Formula (III), wherein:

ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms and is optionally substituted with 1, 2, or 3 R³ groups;

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

alkylcarbonylamino, or alkoxycarbonylamino;

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, or

alkoxycarbonylamino;

R⁷ is hydrogen or alkyl;

optionally a pharmaceutically acceptable salt thereof.

[00199] In certain embodiments, the compound of Formula (III) is that wherein ring B is piperidinyl or pyrrolidinyl. In certain embodiments, the compound of Formula (III) is that wherein ring B is piperidinyl. In certain embodiments, the compound of Formula (III) is that wherein ring B is pyrrolidinyl.

[00200] In certain embodiments, the compound of Formula (III) is according to Formula (Ilia):

Formula (Ilia),

wherein:

cycloalkyloxy, or (cycloalkyl)alkoxy; each R³ is independently halo or amino; and each R⁶ is independently haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein each aryl or heteroaryl is each optionally substituted with halo, haloalkoxy, or haloalkyl; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

[00201] In certain embodiments, the compound of Formula (III) is according to Formula (Ilia) that wherein:

ring A is a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with an amino; R¹ is aryl optionally substituted with cycloalkyloxy; and R² is aryl optionally substituted with 1 or 2 halo; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof. [00202] In certain embodiments, the compound or pharmaceutically acceptable salt of Formula (Ilia) is that wherein ring A is 8-azabicyclo[3.2.l]octanyl or (lR,5S)-3- azabicyclo[3.2.l] octanyl, each of which is substituted with an amino group; R¹ is phenyl or naphthyl, each R¹ independendtly substituted by cyclopentyloxy or cyclohexylmethoxy; and R² is phenyl substituted with a group selected from fluoro, chloro, and bromo.

[00203] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (lx), (Iy), (Iz), (Iaa), (lab), (lac), (lad), (Iae), or (Iaf), or a single stereoisomer or mixture of stereoisomers thereof, as defined herein.

[00204] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (II), (Ha), (lib), (He), (lid), (He), (Ilf), (Ilg), (Ilh), (Hi), (Ilj), or (Ilk), or a single stereoisomer or mixture of stereoisomers thereof, as defined herein.

[00205] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound of Formula (III) or (Ilia), or a single stereoisomer or mixture of stereoisomers thereof, as defined herein.

[00206] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound from Table 1. In certain embodiments, the compound or or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 1-1,

1-2, 2, 2-1, 2-2, 3, 3-1, 3-2, 4, 4-1, 4-2, 5, 5-1, 5-2, 6, 6-1, 6-2, 7, 7-1, 8, 8-1, 8-2, 9, 9-1, 9-2

10, 10-1, 10-2, 11, 11B, 11-1 , 11-2, 11-3, 11-4, 12, 12-1, 12-2, 13-1, 13-2, 14-1, 14-2, 15-1, 15-2, 16, 17, 18, 18-1, 18-2, 19, 19-1, 19-2, 20, 21, 22, 23, 24, 25, 26-1, 26-2, 27, 28, 29, 30,

31, 31-1, 31-2, 32-1, 32-2, 33, 34, 35, 36, 37, 38, 39, 39-1, 39-2, 39-3, 39-4, 40, 41, 41-1, 41-

2, 41-3, 42, 43, 44, 44-1, 44-2, 44-3, 45, 46, 46-1, 46-2, 47, 48, 49, 50, 51-1, 51-2, 52, 53, 53-

1, 53-2, 54, 54-1, 54-2, 55-1, 55-2, 56, 57, 58, 59-1, 59-2, 60-1, 60-2, 61-1, 61-2, 62-1, 62-2

63-1, 63-2, 64-1, 64-2, 65, 66-1, 66-2, 67-1, 67-2, 69-1, 69-2, 69-3, 70, 71, 72-1, 72-2, 72-3,

73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,

98, 99, 100, 101, 101-1, 101-2, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113

114, 115, 116, 117, 118, 118-1, 118-2, 119, 120, 120-1, 120-2, 121, 121-1, and 121-2, or a single stereoisomer or mixture of stereoisomers thereof.

[00207] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 1-2, 2, 3, 2-2, 3-2, 4, 4-2, 5, 6, 7, 5-2,

7-1, 6-2, 8, 8-2, 10-2, 11-1, 11-2, 9-2, 12-2, 13-2, 10-1, 9-1, 12-1, 14-2, 1-1, 2-1, 3-1, 4-1, 5- 1, 6-1, 8-1, 15-2, 13-1, 16, 14-1, 15-1, 17, 11-3, 11-4, 18-1, 18-2, 19-1, 19-2, 20, 21, 22, 23, 24, 25, 26-1, 26-2, 27, 28, 29, 30, 31-1, 31-2, 32-1, 32-2, 33, 34, 35, 36, 37, 38, 39-3, 39-4,

40, 41-2, 41-1, 42, 43, 39-1, 39-2, 44-2, 44-1, 41-3, 45, 46-1, 46-2, 44-3, 47, 48, 49, 50, 51-1,

51-2, 52, 53-1, 53-2, 54-1, 54-2, 55-1, 55-2, 56, 57, 58, 59-1, 59-2, 60-1, 60-2, 61-1, 62-1,

61-2, 62-2, 63-2, 63-1, 64-1, 64-2, 65, 66-1, 66-2, 67-1, 67-2, 70, 69-1, 71, 72-1, 69-2, 69-3,

72-2, 72-3, 73, 74, 75, 76, 77, 78, 80, 79, 81, 82, 83, 84, 89, 85, 86, 87, 88, 91, 90, 92, 93, 94,

95, 96, 97, 98, 99, 100, 101-1, 101-2, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118-1, 118-2, 119, 120-1, 120-2, 121-1, and 121-2, or a single stereoisomer or mixture of stereoisomers thereof.

[00208] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 1-2, 2, 3, 2-2, 3-2, 4, 4-2, 5-2, 7-1, 12- 2, 14-2, 15-2, 16, 17, 11-4, 19-1, 19-2, 20, 22, 23, 25, 27, 26-2, 27, 28, 29, 32-1, 33, 36, 37,

38, 40, 41-1, 42, 43, 44-1, 45, 46-2, 47, 48, 49, 51-1, 51-2, 52, 54-2, 56, 57, 58, 64-2, 70, 69-

1, 72-1, 69-2, 75, 76, 80, 79, 82, 83, 84, 96, 102, and 118-1, or a single stereoisomer or mixture of stereoisomers thereof.

[00209] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 1-2, 2, 3, 2-2, 3-2, 4, 4-2, 5, 6, 7, 5-2,

7-1, 6-2, 8, 8-2, 10-2, 11-1, 11-2, 9-2, 12-2, 13-2, 10-1, 9-1, 12-1, 14-2, 1-1, 2-1, 3-1, 4-1, 5- 1, 6-1, 8-1, 15-2, 13-1, 16, 14-1, 15-1, 17, 11-3, 11-4, 18-1, 18-2, 19-1, 19-2, 20, 21, 22, 23,

24, 25, 26-1, 26-2, 27, 28, 29, 30, 31-1, 31-2, 32-1, 32-2, 33, 34, 35, 36, 37, 38, 39-3, 39-4,

40, 41-2, 41-1, 42, 43, 39-1, 39-2, 44-2, 44-1, 41-3, 45, 46-1, 46-2, 44-3, 47, 48, 49, 50, 51-1, 51-2, 52, 53-1, 53-2, 54-1, 54-2, 55-1, 55-2, 56, 57, and 58, or a single stereoisomer or mixture of stereoisomers thereof.

[00210] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 1, 1-2, 2, 3, 2-2, 3-2, 4, 4-2, 5-2, 7-1, 12-

2, 14-2, 15-2, 16, 17, 11-4, 19-1, 19-2, 20, 22, 23, 25, 26-2, 27, 28, 29, 32-1, 33, 36, 37, 38,

40, 41-1, 42, 43, 44-1, 45, 46-2, 47, 48, 49, 51-1, 51-2, 52, 54-2, 56, 57, and 58, or a single stereoisomer or mixture of stereoisomers thereof.

[00211] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 70, 69-1, 71, 72-1, 69-2, 69-3, 72-2, 72-

3, 73, 74, 75, 76, 77, 78, 80, 79, 81, 82, 83, 84, 89, 85, 86, 87, 88, 91, 90, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101-1, 101-2, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,

114, 115, 116, 117, 118-1, 118-2, 119, 120-1, 120-2, 121-1, and 121-2, or a single stereoisomer or mixture of stereoisomers thereof. [00212] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 70, 69-1, 72-1, 69-2, 75, 76, 80, 79, 82, 83, 84, 96, 102, and 118-1, or a single stereoisomer or mixture of stereoisomers thereof.

[00213] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 59-1, 59-2, 60-1, 60-2, 61-1, 62-1, 61-2, 62-2, 63-2, 63-1, 64-1, 64-2, 65, 66-1, 66-2, 67-1, and 67-2, or a single stereoisomer or mixture of stereoisomers thereof.

[00214] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 64-2, 59-1, 60-1, 62-1, 63-1, 65, and 66- 2, or a single stereoisomer or mixture of stereoisomers thereof.

[00215] In certain embodiments, the compound or pharmaceutically acceptable salt thereof is a compound selected from the compounds 68, 68-1, and 68-2, or a single stereoisomer or mixture of stereoisomers thereof.

Pharmaceutical Compositions

[00216] In certain embodiments, optionally in combination with any or all of the above various embodiments, provided herein is a pharmaceutical composition comprising of a compound disclosed herein, for example, a compound of Formula (I), (la), (lb), (Ic), (Id),

(Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (lx), (Iy), (Iz), (Iaa), (lab), (lac), (lad), (Iae), (Iaf), (II), (Ila), (lib), (lie), (lid), (He), (Ilf),

(Ilg), (Ilh), (Hi), (Ilj), or (Ilk), or a compound of Table 1, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[00217] In certain embodiments, the pharmaceutical composition comprises a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im),

(In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (lx), (Iy), (Iz), (Iaa), (lab), (lac), (lad), (Iae), (Iaf), (II), (Ha), (lib), (He), (lid), (He), (Ilf), (Ilg), (Ilh), (Hi), (Ilj), or (Ilk), or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition comprises a compound of Table 1, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[00218] In certain embodiments, optionally in combination with any or all of the above various embodiments, provided herein is a pharmaceutical composition comprising of a compound disclosed herein, for example, a compound of Formula (III) or (Ilia), or a compound selected from of the compounds 68, 68-1, and 68-2, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[00219] Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.

[00220] Suitable excipients are well known to those skilled in the art. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form.

Formulation and Administration

[00221] All the compounds and pharmaceutical compositions provided herein can be used in all the methods provided herein. For example, the compounds and pharmaceutical compositions provided herein can be used in all the methods for treatment of all diseases, disorders or conditions provided herein. Thus, the compounds and pharmaceutical compositions provided herein are for use as a medicament. The compounds and

pharmaceutical compositions provided herein are for use in a method for the treatment of a disease or disorder that is mediated by the enzyme CGT. The compounds and

pharmaceutical compositions provided herein are for use in a method for the treatment of a disease or disorder in which inhibition of the enzyme CGT ameliorates or treats the disease or disorder. For example, a compound provided herein is a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (lx), (Iy), (Iz), (Iaa), (lab), (lac), (lad), (Iae), (Iaf), (II), (Ila), (lib), (lie), (lid), (He), (Ilf), (Ilg), (Ilh), (Hi), (Ilj), or (Ilk), or a compound of Table 1, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof. In certain embodiments, provided is a method for treating any of the diseases or disorders described herein comprising administering to a subject in need of treatment thereof a compound according to any of the various embodiments described herein or a pharmaceutical composition according to any of the various embodiments described herein. The compounds and pharmaceutical compositions provided herein are for use in a method for the treatment of a disease or disorder that is mediated by the enzyme CGT, or in which inhibition of the enzyme CGT ameliorates or treats the disease or disorder. In certain embodiments, the compounds and pharmaceutical compositions provided herein are used in the preparation or manufacture of medicaments for the treatment of a disease or disorder that is mediated by the enzyme CGT or in which inhibition of the enzyme CGT ameliorates or treats the disease or disorder.

[00222] In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (lx), (Iy), (Iz), (Iaa), (lab), (lac), (lad), (Iae), (Iaf), (II), (Ila), (lib), (lie), (lid), (He), (Ilf), (Ilg), (Ilh), (Hi), (Ilj), or (Ilk), or a compound of Table 1, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Table 1, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof.

[00223] In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (III) or (Ilia), or a compound selected from of the compounds 68, 68-1, and 68-2, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof.

[00224] In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound Formula (I), (la), (lb), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (II), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It), (Iu), (Iv), (Iw), (lx), (Iy), (Iz), (Iaa), (lab), (lac), (lad), (Iae), (Iaf), (II), (Ila), (lib), (lie), (lid), (He), (Ilf), (Ilg), (Ilh), (Hi), (Ilj), or (Ilk), or a compound of Table 1, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Table 1, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[00225] In certain embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound or pharmaceutical composition comprising a compound of Formula (III) or (Ilia), or a compound selected from of the compounds 68, 68-1, and 68-2, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. [00226] In certain embodiments, the disease or disorder is a lysosomal storage disease. In certain embodiments, the lysosomal storage disease or disorder is a defect in sphigolipid metabolism, Krabbe disease or Metachromatic Leukodystrophy (MLD). In certain

embodiments, the lysosomal storage disease or disorder is Krabbe disease or Metachromatic Leukodystrophy (MLD). In certain embodiments, the disease or disorder is Krabbe disease.

In certain embodiments, the disease or disorder is MLD. In certain embodiments, the disease or disorder is Parkinson’s disease.

[00227] The compounds or compositions disclosed herein can be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent. The compounds are typically administered as pharmaceutical compositions by any route which makes the compound bioavailable. In certain embodiments, the composition is a solid formulation adapted for oral administration. In certain embodiments, the composition is a tablet, powder, or capsule; or the composition is a tablet. In certain embodiments, the composition is a liquid formulation adapted for oral administration. In certain embodiments, the composition is a liquid formulation adapted for parenteral administration. In certain embodiments, the composition is a solution, suspension, or emulsion; or the composition is a solution. In certain embodiments, solid form compositions can be converted, shortly before use, to liquid form compositions for either oral or parenteral administration. These particular solid form compositions are provided in unit dose form and as such are used to provide a single liquid dosage unit. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (See, Remington: The Science and Practice of Pharmacy, supra;

Modified-Release Drug Delivery Technology , 2nd ed.; Rathbone et al. , Eds.; Marcel Dekker, Inc.: New York, NY, 2008).

[00228] The dosages may be varied depending on the requirement of the patient, the severity of the disease or disorder being treating and the particular compound and/or composition being employed. Determination of the proper dosage can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery. In certain

embodiments, the compounds are administered to a subject at a daily dosage of between 0.01 to about 50 mg/kg of body weight. In other embodiments, the dose is from 1 to 1000 mg/day. In certain embodiments, the daily dose is from 1 to 750 mg/day; or from 10 to 500 mg/day.

[00229] In certain embodiments, the pharmaceutical composition is in unit dosage form. The composition can be subdivided into unit doses containing appropriate quantities of the active component(s). The unit dosage form can be a tablet, capsule, or powder in a vial or ampule, or it may be the appropriate number of any of these in a packaged form. The unit dosage form can be a packaged form, the package containing discrete quantities of composition such as packeted tablets, capsules, or powders in vials or ampules. The quantity of active compound(s) in a unit dose of the composition may be varied or adjusted from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or from about 1 mg to about 25 mg.

[00230] The compounds or pharmaceutical compositions disclosed herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.

PREPARATION OF COMPOUNDS

[00231] The following are illustrative schemes and examples of how the compounds described herein can be prepared and tested. Although the examples can represent only some embodiments, it should be understood that the following examples are illustrative and not limiting. All substituents, unless otherwise specified, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare the compounds described herein.

General Scheme 1

[00232]

[00233] A Compound of Formula (I) can be prepared according to General Scheme 1. An intermediate of formula 1-3 can be prepared from an intermediate amine I-l and a sulfonyl chloride 1-2 using standard sulfonamide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the compounds of formulas I-l and 1-2, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with a base, either organic or inorganic base, such as DIPEA, Et₃N, or K2CO3, in a solvent, such as dichloromethane, DMF, or THF, at ambient temperature or up to 90 °C, to yield the intermediate of formula 1-3.

[00234] An intermediate of formula 1-5 can be prepared from the intermediate 1-3 using standard amide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-3 can be treated with an amine intermediate 1-4, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, in the presence of an amide coupling reagents, such as HATU or EDC, in a solvent, such as CH2CI2 or DMF, optionally with or without a base, such as DIPEA or Et₃N, at ambient temperature or up to 50 °C, to yield the intermediate of formula 1-5.

[00235] The protecting group (Pg) on the nitrogen of the intermediate of formula 1-5 can be removed using the corresponding deprotection conditions, which are depended on the nature of the protecting groups. More specifically, the intermediate of formula 1-5 with an Fmoc (fluorenylmethyloxycarbonyl) protecting group, which can be deprotected using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with a base, such as Et₂NH or piperidine in as solvent such as dichloromethane or THF, at ambient temperature or up to 50 °C, to yield an intermediate of formula 1-6.

[00236] The compounds of Formula (I) can be prepared using standard amine alkylation or acylation conditions, which are disclosed herein or are known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-6 can be treated with an intermediate of formula 1-7 (where X is halogen or a leaving group or C(=0)Cl or C(=0)Br) in the presence of a base, such as NaFlCCb, Na2C0₃, K2CO3, DIPEA, pyridine, or Et₃N, optionally with or without Nal, in a solvent such as EtOH, DMF, NMP, or THF, at ambient temperature or up to 120 °C, to afford the Compound of Formula (I).

[00237] The compounds of Formula (I) can also be prepared using standard reductive amination conditions, which are disclosed herein or are known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-6 can be treated with an intermediate of formula 1-7 (where X is CH(=0)) in the presence of a reducing reagent, such as NaBH(AcO)₃ or NaBH₃CN, optionally with or without an acid or a Lewis acid such as AcOH or KH2PO4 or Ti(/PrO)4, herein without an acid, in a solvent such as EtOH, MeOH, l,2-dichloroethane, or THF, at ambient temperature or up to 70 °C, to afford the Compound of Formula (I).

Generanl Scheme 2

[00238]

1-11 Formula (I)

[00239] A compound of Formula (I) or according to any of the embodiments disclosed herein, can also be prepared according to General Scheme 2. [00240] An intermediate of formula 1-9 can be prepared from an intermediate amine of formula 1-8 and the intermediate of formula 1-7 (where X is halogen or a leaving group or C(=0)Cl or C(=0)Br) using standard amine alkylation or acylation conditions, which are disclosed herein or are known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-8 can be treated with the intermediate of formula 1-7 (where X is halogen or a leaving group or C(=0)Cl or C(=0)Br) in the presence of a base, such as NaHCCb, Na2CCb, K2CO3, DIPEA, pyridine, or Et₃N, optionally with or without Nal, in a solvent such as EtOH, DMF, NMP, or THF, at ambient temperature or up to 120 °C, to afford the intermediate of formula 1-9.

[00241] The intermediate of formula 1-9 (where all other groups are as defined in the Summary of the Invention for a compound of Formula (I) or according to any of the embodiments disclosed herein) can also be prepared using standard reductive amination conditions, which are disclosed herein or are known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-8 can be treated with the intermediate of formula I- 7 (where X is CH(=0)) in the presence of a reducing reagent, such as NaBH(AcO)3 or NaBEECN, optionally with or without an acid or a Lewis acid such as AcOH or KH2PO4 or Ti(/PrO)4, herein without an acid, in a solvent such as EtOH, MeOH, l,2-dichloroethane, or THF, at ambient temperature or up to 70 °C, to afford the intermediate of formula 1-9.

[00242] The protecting group (Pg) on the nitrogen of the intermediate of formula 1-9 can be removed using the corresponding deprotection conditions, which are depended on the nature of the protecting groups (Pg). More specifically, the intermediate of formula 1-9 that has a Boc (tert-butyloxycarbonyl) protecting group, which can be de-protected using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with an acid, such as HC1 or trifluoroacetic acid in as solvent such as dichloromethane or THF, at ambient temperature or up to 50 °C, to yield an intermediate of formula 1-10.

[00243] An intermediate of formula 1-11 can be prepared from the intermediate 1-10 and sulfonyl chloride 1-2 using standard sulfonamide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-10 and 1-2, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with a base, either organic or inorganic base, such as DIPEA, Et₃N, or K2CO₃, in a suitable solvent, such as dichloromethane, DMF, or THF, at ambient temperature or up to 90 °C, to yield the intermediate of formula 1-11. [00244] The compounds of Formula (I) can be prepared from the intermediates 1-11 using standard amide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-11 can be treated with the amine intermediate of formula 1-4, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, in the presence of an amide coupling reagents, such as ITATEG or EDC, in a solvent, such as CH2CI2 or DMF, optionally with or without a base, such as DIPEA or EtxN, at ambient temperature or up to 50 °C, to afford the Compound of Formula (I).

General Scheme 3

[00245]

[00246] The intermediate of formula 1-11 can also be prepared according to General Scheme 3.

[00247] An intermediate of formula 1-13 (where R is a C i-Cx alkyl group) can be prepared from an intermediate amine 1-12 and the intermediate of formula 1-7 (where X is halogen or a leaving group or C(=0)Cl) using standard amine alkylation or acylation conditions, which are disclosed herein or are known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-12 can be treated with the intermediate of formula 1-7 (where X is halogen or a leaving group or C(=0)Cl or C(=0)Br) in the presence of a base, such as NaHCCb, Na2CCb, K2CO3, DIPEA, pyridine, or Et₃N, optionally with or without Nal, in a solvent such as EtOH, DMF, NMP, or THF, at ambient temperature or up to 120 °C, to afford the intermediate of formula 1-13.

[00248] The intermediate of formula 1-13 (where R is a Ci-Cx alkyl group) can also be prepared using standard reductive amination conditions, which are disclosed herein or are known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-12 can be treated with the intermediate of formula 1-7 (where X is CH(=0)) in the presence of a reducing reagent, such as NaBH(AcO)3 or NaBHiCN, optionally with or without an acid or a Lewis acid such as AcOH or KH2PO4 or Ti(/PrO)4, herein without an acid, in a solvent such as EtOH, MeOH, l,2-dichloroethane, or THF, at ambient temperature or up to 70 °C, to afford the intermediate of formula 1-13.

[00249] The protecting group (Pg) on the nitrogen of the intermediate of formula 1-13 can be removed using the corresponding deprotection conditions, which are depended on the nature of the protecting groups (Pg). More specifically, the intermediate of formula 1-13 that has a Boc (tert-butyloxycarbonyl) protecting group, which can be deprotected using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with an acid, such as HC1 or trifluoroacetic acid in as solvent such as dichloromethane or THF, at ambient temperature or up to 50 °C, to yield an intermediate of formula 1-14.

[00250] An intermediate of formula 1-15 (where R is a Ci-Cs alkyl group) can be prepared from the intermediate of formula 1-14 and sulfonyl chloride 1-2 using standard sulfonamide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-14 and 1-2, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with a base, either organic or inorganic base, such as DIPEA, Et₃N, or K2CO3, in a suitable solvent, such as

dichloromethane, DMF, or THF, at ambient temperature or up to 90 °C, to yield the intermediate of formula 1-15.

[00251] The intermediate of formula 1-11 can be prepared from the intermediate 1-15 (where R is an alkyl group, Ci-Cs) using standard ester hydrolysis conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediates of formula 1-15 can be treated with a base, such as LiOH, or with a lithium salt, such as LiCl or LiBr, in a solvent with water, such as THF/water, MeOH/water, or dioxane/water, at ambient temperature or up to 100 °C, to yield the intermediate of formula 1-11. General Scheme 4

[00252]

[00253] The intermediate of formula 1-13 (where L is -C(R⁴R⁵)-) can also be prepared according to General Scheme 4.

[00254] An intermediate of formula 1-17 (R is a Ci-Cx-alkyl group) can be formed from an intermediate amine of formula 1-12 and an intermediate aldehyde or ketone of formula 1-16 using benzotriazole mediated aminoalkylation conditions, which are disclosed herein or are known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-12 can be treated with the intermediate of formula 1-16, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, and lH-benzo[d][l,2,3]triazole, optionally in the presence of an acid in catalytic amount, such as p-toluenesulfonic acid, pyridinium p-toluenesulfonate, or methanesulfonic acid, or without an acid, herein without an acid, in a solvent such as benzene or toluene, with azeotropic removal of water, at boiling point temperature, to afford the intermediate of formula 1-17.

[00255] The intermediate of formula 1-13 (where R is a Ci-Cs alkyl group,) can be prepared from the intermediate of formula 1-17 using standard Grignard addition conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediates of formula 1-17 can be treated with a Grignard reagent (R⁵-MgX), which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, in a solvent, such as THF, dichloromethane, or l,4-dioxane, at temperature of -50 °C or up to ambient temperature, to yield the intermediate of formula 1-13. General Scheme 5

[00256]

Formula (II) 1-21

[00257] The intermediate of formula 1-20 and the compound of Formula (II) can also be prepared according to General Scheme 5.

[00258] An intermediate of formula 1-19 can be prepared from an intermediate amine 1-18 (where R is a C i-Cx alkyl group) and sulfonyl chloride 1-2 using standard sulfonamide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-18 and 1-2, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, can be treated with a base, either organic or inorganic base, such as DIPEA, Et₃N, or K2CO3, in a solvent, such as dichloromethane, DMF, or THF, at ambient temperature or up to 90 °C, to yield the intermediate of formula 1-19.

[00259] The intermediate of formula 1-20 and the compound of Formula (II) can also be prepared using standard Mitsunobu reaction conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediates of formula 1-19 can be reacted with an compound R²-OH in the presence of a phosphine reagent, such as triphenylphosphine, and an azodicarboxylate, such as as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), in a suitable solvent such as THF, toluene, acetonitrile or diethyl ether, at -20 °C or up to 80 °C, to yield the intermediate of formula 1-20.

[00260] The intermediate of formula 1-21 can be prepared from the intermediate of formula 1-20 (where R is a C i-Cx alkyl group) using standard ester hydrolysis conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediates of formula 1-20 can be treated with a base, such as LiOH, or with a lithium salt, such as LiCl or LiBr, in a solvent with water, such as

THF/water, MeOH/water, or dioxane/water, at ambient temperature or up to 100 °C, to yield the intermediate of formula 1-21.

[00261] The Compound of Formula (II) can be prepared from the intermediates 1-21 using standard amide formation conditions, which can include procedures disclosed herein or those known to one of ordinary skill in the art. More specifically, the intermediate of formula 1-21 can be treated with the amine intermediate of formula 1-4, which can be commercial available or prepared using procedures disclosed herein or are known to one of ordinary skill in the art, in the presence of an amide coupling reagents, such as HATU or EDC, in a solvent, such as CH2CI2 or DMF, optionally with or without a base, such as DIPEA or Et₃N, at ambient temperature or up to 50 °C, to afford the Compound of Formula (II).

SYNTHETIC EXAMPLES

[00262] Compound Al: Synthesis of 6-(cyclopentyloxy)naphthalene-2-sulfonyl

chloride

[00263] To a solution of sodium methanolate (1.6 g, 30 mmol) in ethanol (120 mL) was added sodium 6-hydroxynaphthalene-2-sulfonate Al-1 (5 g, 20 mmol) and was stirred at room temperature for 2 hours. The reaction mixture was filtered and washed with methanol to give intermediate Al-2.

[00264] To a solution of intermediate Al-2 (22 g, 82 mmol) in DMSO (50 mL) was added bromocyclopentane (36.7 g, 246 mmol). The mixture was stirred at 40 °C for 48 hours, cooled to room temperature, and diluted with acetone (300 mL), which was filtered to afford intermediate Al-3: LC-MS (ESI) m/z: 291 [M-Na]⁺; Ή-NMR (DMSO-Y 400 MHz): d (ppm) 1.59-1.63 (m, 2H), 1.69-1.78 (m, 4H), 1.95-2.03 (m, 2H), 4.93-4.97 (m, 1H), 7.10-7.13 (m, 1H), 7.27 (s, 1H), 7.64 (d, j= 8.4 Hz, 1H), 7.73 (d, j= 8.4 Hz, 1H), 7.85 (d, j= 8.8 Hz, 1H), 8.05 (s, 1H).

[00265] To an ice-cooled suspension of intermediate Al-3 (14 g, 44 mmol) in DMF (10 mL) was added thionyl chloride (13.2 g, 133 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into crushed ice with continuous stirring and extracted with ethyl acetate (500 mL). The organic layer was washed with water (100 mL x 3) and brine (100 mL), dried over anhydrous sodium sulfate, filtered,

concentrated, and purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to give compound Al: LC-MS (ESI) m/z: 311

[M+H]⁺; 1H-NMR (CDCb, 400 MHz): d (ppm) 1.50-1.70 (m, 6H), 1.88-2.00 (m, 2H), 4.89- 4.93 (m, 1H), 6.92-7.03 (m, 1H), 7.22 (s, 1H), 7.60 (d, J= 8.4 Hz, 1H), 7.69 (d, J= 8.4 Hz, 1H), 7.75 (d, j= 8.8 Hz, 1H), 8.00 (s, 1H).

[00266] Compound A2: Synthesis of 4-(cyclohexylmethoxy)benzenesulfonyl chloride

[00267] A mixture of compounds A2-1 (1.7 g, 10 mmol), (bromomethyl)cyclohexane (1.7 g, 10 mmol), and NaOH (0.8 g, 20 mmol) in water (10 mL) and ethanol (20 mL) was stirred at 100 °C overnight. The mixture was cooled with ice-water bath and a precipitate was formed. After filtration, the cake was washed with a little ethanol and dried to give intermediate A2-2: LC-MS (ESI) m/z: 269 [M-Na]⁺; 'H-NMR (DMSO-r/e, 400 MHz): d (ppm) 0.98-1.30 (m, 5H), 1.63-1.81 (m, 6H), 3.76 (d, J= 6.4 Hz, 2H), 6.83 (d, J= 8.4 Hz, 2H), 7.49 (d, J= 8.4 Hz, 2H).

[00268] Compound A2 was synthesized by employing the procedure described for compound A1 using intermediate A2-2 in lieu of intermediate Al-3: 'H-NMR (CDCb, 400 MHz): d (ppm) 1.05-1.33 (m, 5H), 1.72-1.88 (m, 6H), 3.85 (d, J= 6.0 Hz, 2H), 7.01 (m, 2H), 7.95 (m, 2H). [00269] Compound Bl:

[00270] To a solution of BnCl (20.2 g, 160 mmol) in dry THF (400 mL) was added 8- azabicyclo[3.2. l]octan-3-one Bl-1 (25.85 g, 160 mmol) and triethylamine (55.2 mL, 400 mmol). The solution was heated at 70 °C overnight. The mixture was treated with water (200 mL) and extracted with dichloromethane (700 mL x 2). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography on silica gel (ethyl acetate in petrol ether, from 10% to 15% v/v) to give intermediate Bl-2: LC-MS (ESI) m/z: 216

[M+H]⁺.

[00271] A mixture of hydroxylamine hydrochloride (12.9 g, 181 mmol) in methanol (60 mL) at 0 °C was treated with Na2CCh (13.4 g, 123 mmol) and stirred for 5 minutes. To the mixture was added a solution of intermediate Bl-2 (32 g, 145 mmol) in methanol (420 mL) and stirred under nitrogen at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was treated with brine (200 mL) and extracted with dichloromethane (700 mL x 2). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and washed with ethyl acetate to afford intermediate Bl-3: LC-MS (ESI) m/z: 231 [M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 1.49-1.64 (m, 2H), 1.96-1.98 (m, 2H), 2.11-2.15 (m, 1H), 2.21-2.26 (m, 1H), 2.57-2.62 (m, 1H), 2.96-3.00 (m, 1H), 3.33-3.36 (m, 2H), 3.61-3.69 (s, 2H), 7.23-7.27 (m, 1H), 7.30-7.34 (m, 2H), 7.35- 7.41 (m, 2H), 9.26 (s, 1H).

[00272] A solution of intermediate Bl-3 (23 g, 100 mmol) in absolute butan-l-ol (500 mL) was heated at 120 °C. To the solution was added sodium metal (28 g, 1.2 mol) in several small pieces over 2.5 hours. The reaction mixture was heated at 120 ⁰ C for 4 hours. It was cooled, treated with water (500 mL) carefully, and extracted with ether (300 mL ^c 3). The organic extracts were combined, washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to furnish intermediate Bl-4: LC-MS (ESI) m/z: 217

[M+H]⁺

[00273] To a solution of intermediate Bl-4 (4.95 g, 22.9 mmol) in dry

dichloromethane (70 mL) was added B0C2O (5.55 g, 25.2 mmol) and triethylamine (3.8 mL, 27.5 mmol). The solution was heated at reflux overnight, diluted with dichloromethane (150 mL), and washed with 5% sodium bicarbonate (70 mL) and brine (70 mL). The organic layer was, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified with flash column chromatography on silica gel (ethyl acetate in petrol ether, from 30% to 50% v/v) to furnish intermediate Bl-5: LC-MS (ESI) m/z: 317 [M+H]⁺; ¾-NMR (CDCh, 400 MHz): d (ppm) 1.43 (s, 9H), 1.44-1.53 (m, 2H), 1.67-1.70 (m, 2H), 1.78-1.82 (m, 2H), 2.00-2.03 (m, 2H), 3.19-3.21 (m, 2H), 3.51 (s, 2H), 3.82 (s, 1H), 4.35 (s, 1H), 7.23-7.37 (m, 5H).

[00274] To a solution of intermediate Bl-5 (8.4 g, 26.6 mmol) and glacial acetic acid (1 eq.) in ethanol (350 mL) was added 10% Pd/C (1 g) at 22 °C. The solution was stirred under H2 (4.5 atm) at 22 °C for 24 hours. The solution was filtered and concentrated to give intermediate Bl-6: LC-MS (ESI) m/z: 227 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 1.44 (s, 9H), 1.73-1.77 (m, 2H), 1.99-2.13 (m, 6H), 3.81-3.95 (m, 1H), 4.03 (s, 2H), 4.97 (m, 2H), 5.12-5.13 (m, 1H), 6.41-6.43 (m, 1H), 7.14-7.29 (m, 2H).

[00275] To a solution of intermediate Bl-6 (5 g, 17.5 mmol) in dichloromethane (150 mL) was added 10% NaOH (20 mL) at 10 °C. The solution was stirred at 22 °C for 0.5 hour and extracted with dichloromethane (100 mL ^c 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound Bl: LC-MS (ESI) m/z: 227 [M+H]⁺; ¾-NMR (CDCh, 400 MHz): d (ppm) 1.44 (s, 9H), 1.74-1.80 (m, 5H), 1.90-1.95 (m, 2H), 3.55 (s, 2H), 3.81-3.85 (brs, 1H), 4.36-4.40 (m, 1H).

[00276] Compound B2

c

Cbz Cbz

B2-7 B2-8 B2

[00277] A solution of /er/-butyl 3,3-difluoro-4-oxopiperidine-l-carboxylate B2-1

(2.00 g, 8.51 mmol) and l-phenylmethanamine (1.82 g, 17.02 mmol) in dichloromethane (20 mL) was stirred at room temperature for 3 hours. To the solution was added NaBH(OAc)3

(3.61 g, 17.02 mmol) and stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (160 mL), washed with water (120 mL x 3) and brine (100 mL). The

organic layer was separated and dried over anhydrous sodium sulfate, filtered, and

concentrated under reduced pressure. The residue was purified with flash column

chromatography on silica gel (methanol in dichloromethane, from 0% to 6% v/v) to yield intermediate B2-2: LC-MS (ESI) m/z: 327 [M+H]⁺.

[00278] A mixture of intermediate B2-2 (2.00 g, 6.13 mmol) and 10% Pd/C (1.00 g) in methanol (30 mL) was stirred under hydrogen (1 atmosphere) at 20 °C for 16 hours. The mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give intermediate B2-3: LC-MS (ESI) m/z: 259 [M+Na]⁺; ¾-NMR (CDCb, 400 MHz): d

(ppm) 1.49 (s, 9H), 1.77-1.94 (m, 2H), 2.91-3.08 (m, 1H), 3.45-3.73 (m, 2H), 3.94-4.17 (m, 2H).

[00279] To a solution of intermediate B2-3 (2.30 g, 9.74 mmol) and NaHCCh (1.64 g, 19.48 mmol) in l,4-dioxane (10 mL) and H2O (2 mL) was added FmocCl (3.03 g, 11.69

mmol) in several small portions at 0 °C. The mixture was stirred at room temperature for 3 hours and diluted with ethyl acetate (160 mL). The organic layer was washed with water (120 mL x 3) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (methanol in dichloromethane, from 0% to 6% v/v) to yield intermediate B2-4: LC-MS

(ESI) m/z: 459 [M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 1.47 (s, 9H), 1.64-1.96 (m,

2H), 2.84-3.07 (m, 1H), 3.45-3.73 (m, 2H), 3.93-4.08 (m, 1H), 4.19-4.27 (m, 1H), 4.38-4.48 (m, 2H), 5.03 (s, 1H), 7.30-7.43 (m, 4H), 7.58 (d, J= 7.2 Hz, 2H), 7.77 (d, J= 7.6 Hz, 2H). [00280] A mixture of intermediate B2-4 (2.30 g, 5.02 mmol), HC1 solution in 1,4- dioxane (4 M, 3 mL), and dichloromethane (10 mL) was stirred at 20 °C for 16 hours. The mixture was filtered. The filter cake was washed with diethyl ether (20 mL) and all organic layers were combined and dried under vacuum to afford intermediate B2-5: LC-MS (ESI) m/z: 359 [M+H]⁺; ¹H-NMR (DMSO-r/e, 400 MHz): d (ppm) 1.88-2.02 (m, 2H), 3.09-3.22 (m, 1H), 3.51-3.74 (m, 3H), 4.24-4.40 (m, 3H), 7.32 (t, J= 7.2 Hz, 2H), 7.43 (t, J= 7.2 Hz, 2H),

7.71-7.75 (m, 2H), 7.90 (d, J= 7.2 Hz, 3H), 9.33 (s, 2H).

[00281] To a mixture of intermediate B2-5 (2.00 g, 5.08 mmol) and NaHCCh (1.28 g, 15.24 mmol) in THF (30 mL) and H2O (10 mL) was added CbzCl (954 mg, 5.58 mmol) in several small portions at 0 °C. The mixture was stirred at room temperature for 3 hours and diluted with ethyl acetate (160 mL). The organic layer was washed with water (120 mL x 3) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to provide residue, which was purified with flash column chromatography on silica gel

(methanol in dichloromethane, from 0% to 6% v/v) to yield intermediate B2-6: 'H-NMR (DMSO-r/e, 400 MHz): d (ppm) 1.61-1.86 (m, 2H), 3.05-3.67 (m, 4H), 3.82-4.16 (m, 4H), 5.10 (d, = 3.6 Hz, 2H), 7.31-7.44 (m, 9H), 7.71-7.90 (m, 4H).

[00282] A mixture of intermediate B2-6 (2.20 g, 4.47 mmol) and piperidine (5 mL) in dichloromethane (20 mL) was stirred at 20 °C for 16 hours. The mixture was diluted with ethyl acetate (160 mL), washed with water (120 mL x 3) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (methanol in dichloromethane, from 0% to 7% v/v) to yield intermediate B2-7: LC-MS (ESI) m/z: 271 [M+H]⁺; Ή-NMR (CDCh, 400 MHz): d (ppm) 1.33-1.59 (m, 1H), 1.92-2.01 (m, 1H), 2.99-3.27 (m, 3H), 4.00-4.13 (m, 2H), 5.16 (s, 2H), 7.31-7.39 (m, 5H).

[00283] To a solution of intermediate B2-7 (600 mg, 2.22 mmol) and K2CO3 (307 mg, 4.44 mmol) in l,4-dioxane (10 mL) and H2O (3 mL) was added (Boc)20 (968 mg, 4.44 mmol) at room temperature. The mixture was stirred at room temperature for 16 hours and diluted with ethyl acetate (160 mL). The organic layer was washed with water (120 mL x 3) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (methanol in dichloromethane, from 0% to 6% v/v) to yield intermediate B2-8: LC-MS (ESI) m/z: 371 [M+H]⁺; ¾-NMR (DMSO-r/e, 400 MHz): d (ppm) 1.39 (s, 9H), 1.52-1.61 (m, 1H),

1.72-1.77 (m, 1H), 3.02-3.20 (m, 1H), 3.37-3.54 (m, 1H), 3.88-4.16 (m, 3H), 5.09 (s, 2H), 7.23 (d, J= 9.2 Hz, 1H), 7.31-7.39 (m, 5H). [00284] A mixture of intermediate B2-8 (700 mg, 1.89 mmol) and 10% Pd/C (300 mg) in methanol (20 mL) was stirred under hydrogen (1 atm) at 20 °C for 16 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to yield compound B2: LC-MS (ESI) m/z: 237 [M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 1.46 (s, 9H), 1.49-1.56 (m, 2H), 2.00-2.04 (m, 1H), 2.63-2.87 (m, 2H), 3.05-3.08 (m, 1H), 3.21- 3.28 (m, 1H), 3.95-4.05 (m, 1H), 4.76-4.87 (m, 1H).

[00285] Compound B3

[00286] To an ice-cooled solution of fV)- l -(/c/7-butoxycarbonyl)piperazine-2- carboxylic acid (2.20 g, 9.6 mmol) and DIPEA (4.2 mL, 23.9 mmol) in water (14 mL) was dropped a solution of 9-fluorenylmethyl chloroformate B3-1 (2.72 g, 10.5 mmol) in 1,4- dioxane, and stirred at room temperature for 6 hours. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (30 mL x 4). The combined organic extracts were washed with saturated sodium bicarbonate solution (30 mL) and water (30 mL) and 1N HC1 solution (30 mL) and water (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give intermediate B3-2: LC-MS (ESI) m/z: 475 [M+Na]⁺.

[00287] To a solution of intermediate B3-2 (4.0 g, 8.85 mmol) in dichloromethane (100 mL) was added a solution of HC1 in l,4-dioxane (4 M, 40 mL). The mixture was stirred at room temperature overnight and evaporated to provide a residue furnish Compound B3-3: LC-MS (ESI) m/z: 353[M +H]⁺.

[00288] A mixture of intermediate B3-3 (1.64 g, 4.65 mmol), compound A2 (1.34 g, 4.65 mmol), and DIPEA (8 mL) in dichloromethane (250 mL) was stirred at room

temperature overnight. The mixture was diluted with water (250 mL) and extracted with dichloromethane (250 mL x 2). The combined organic extracts were washed with water (250 mL x 2) and brine (250 mL), dried over sodium sulfate, filtered, and concentrated under the reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to yield intermediate B3-4: LC-MS (ESI) m/z:

605[M+H]⁺.

[00289] A mixture of intermediate B3-4 (3.0 g, 4.97 mmol), /tvV-butyl piperidin-4- ylcarbamate (1.0 g, 5.0 mmol), and E1ATU (2.7 g, 7.1 mmol) in dichloromethane (250 mL) was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane (250 mL), washed with water (250 mL x 3) and brine ((250 mL), dried over sodium sulfate, filtered, and concentrated to yield intermediate B3-5: LC-MS (ESI) m/z: 809[M+Na]⁺.

[00290] To a solution of intermediate B3-5 (3.3 g, 4.2 mmol) in dichloromethane (200 mL) was added diethylamine (10 mL). The mixture was stirred at room temperature

overnight and concentrated to provide a residue, which was purified with flash column chromatography on silica gel (methanol in dichloromethane, 10% v/v) to afford compound B3: LC-MS (ESI) m/z: 565[M+H]⁺.

[00291] Compound B4

NHBoc NHBoc

B4-1 B4

[00292] Compounds B4-1 and B4 were synthesized by employing the procedures described for compounds B3-5 and B3 using /er/-butyl (3,3-difluoropiperidin-4-yl)carbamate (B2) and Compound B4-1 in lieu of /er/-butyl piperidin-4-ylcarbamate and Compound B3-5. Compound B4-1: LC-MS (ESI) m/z: 767[M+H-56]⁺. Compound B4: LC-MS (ESI) m/z:

60l[M+H]⁺.

[00293] Example 1

[00294] Synthesis of (4-aminopiperidin-l-yl)(4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (1)

[00295] A mixture of Compound 1A (5.13 g, 33 mmol), (4-chlorophenyl)boronic acid (5.52 g, 30 mmol), tetrabutylammonium bromide (9.66 g, 30 mmol), K2CO3 (8.28 g, 60 mmol), and Pd(PPh3)Cl2 (420 mg, 0.66 mmol) in water (240 mL) was stirred at 25 °C overnight. The mixture was extracted with dichloromethane (200 mL x 2). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 2% v/v) to yield Compound IB: LC-MS (ESI) m/z: 217 [M+H]⁺. ¾-NMR (CDCh, 400 MHz): d (ppm) 7.45 (d, J= 8.4 Hz, 2H), 7.56 (d, J= 8.4 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 7.95 (d, J= 8.4 Hz, 2H), 10.06 (s, 1H).

[00296] To a solution of Compound IB (5.4 g, 1 mmol) in EtOH (40 mL) was added NaBH₄ (0.95 g, 25 mmol) at 0 °C. The mixture was stirred room temperature for 2 hours, quenched with 1 N HC1 solution (40 mL), and extracted with dichloromethane (30 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 1C: LC-MS (ESI) m/z: 201 [M-OH]⁺.

[00297] To a solution of Compound 1C (2.18 g, 10 mmol) in dichloromethane (20 mL) was added SOCI2 (1.09 mL, 15 mmol) at 0 °C. The mixture was stirred at 50 °C for 15 hours and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 3% v/v) to yield Compound ID: 'H-NMR (CDCh, 400 MHz): d (ppm) 4.64 (s, 2H), 7.40-7.56 (m, 8H). [00298] To a solution of Compound ID (320 mg, 1.35 mmol) in EtOH (10 mL) was added l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (311 mg, 1.35 mmol), Nal (125 mg, 0.675 mmol), and Na2CCb (574 mg, 5.42 mmol). The mixture was stirred at 78 °C for 15 hours and concentrated under reduced pressure. The resulting solid was dissolved in methanol and dichloromethane (50 ml, v/v 5/100), filtered, and concentrated to furnish Compound IE: LC-MS (ESI) m/z: 431 [M+H]⁺.

[00299] To a solution of Compound IE (400 mg, 0.5 mmol) in dichloromethane (2 mL) was added a solution of HC1 in l,4-dioxane (4.0 N , 6 mL), stirred at room temperature for 2 hours, and concentrated under reduced pressure. The residue was purified with preparative HPLC to furnish Compound IF: LC-MS (ESI) m/z: 331 [M+H]⁺.

[00300] To a solution of Compound IF (73 mg, 0.2 mmol) in dichloromethane (10 mL) was added Compound A2 (58 mg, 0.2 mmol) and /V,/V-diisopropylethylamine (0.16 mL, 1 mmol) at 0 °C under N2. After the mixture was stirred at 0 °C for 0.5 hour, to it was added tert-butyl piperidin-4-ylcarbamate (60 mg, 0.3 mmol) and HATU (137 mg, 0.26 mmol). The reaction mixture was stirred at room temperature for 2 hours, washed with water (10 mL x 3) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated to furnish Compound 1G: LC-MS (ESI) m/z: 765 [M+H]⁺.

[00301] To a solution of Compound 1G (200 mg, 0.2 mmol) in dichloromethane (2 mL) was added a solution of HC1 in l,4-dioxane (4.0 N , 2 mL) and was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was purified with preparative HPLC to furnish Compound 1: LC-MS (ESI) m/z: 665 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.92-1.05 (m, 2H), 1.20-1.77 (m, 12H), 2.05-2.12 (m, 2H), 2.49-2.87 (m, 3H), 3.13-3.23 (m, 1H), 3.37-3.76 (m, 5H), 3.95-4.17 (m, 2H), 4.31-4.49 (m, 2H), 4.54-4.67 (m, 1H), 5.47 (s, 1H), 6.98-7.03 (m, 2H), 7.44-7.52 (m, 4H), 7.67-7.72 (m, 4H), 7.80 (d, J= 8.8 Hz, 2H).

[00302] Synthesis of (R)-(4-aminopiperidin-l-yl)(4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (1-1)

[00303] Compounds IE-1, 1F-1, 1G-1, and 1-1 were synthesized by employing the procedures described for Compounds IE, IF, 1G, and 1 using ( R)-\-{tert - butoxycarbonyl)piperazine-2-carboxylic acid, Compounds IE-1, 1F-1, and 1G-1 in lieu of 1- (tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds IE, IF, and 1G. Compound IE-1: LC-MS (ESI) m/z: 43 l[M+H]⁺. Compound 1F-1: LC-MS (ESI) m/z: 331 [M+H]⁺. Compound 1G-1: LC-MS (ESI) m/z: 765 [M+H]⁺. Compound 1-1: LC-MS (ESI) m/z: 665 [M+H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 0.92-1.15 (m, 4H), 1.22-1.35 (m, 6H), 1.70- 1.89 (m, 10H), 2.10-2.14 (m, 1H), 2.45-3.18 (m, 2H), 3.40-3.78 (m, 3H), 3.80 (d, J= 6.8 Hz, 2H), 4.06-4.13 (m, 1H), 4.58-5.52 (m, 2H), 6.92-7.52 (m, 6H), 7.65-7.81 (m, 6H).

[00304] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (1-2)

[00305] Compounds IE-2, 1F-2, 1G-2, and 1-2 were synthesized by employing the procedures described for Compounds IE, IF, 1G, and 1 using {S)-\-{tert- butoxycarbonyl)piperazine-2-carboxylic acid, Compounds IE-2, 1F-2, and 1G-2 in lieu of 1- (tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds IE, IF, and 1G. Compound IE-2: LC-MS (ESI) m/z: 431 [M+H]⁺. Compound 1F-2: LC-MS (ESI) m/z: 331 [M+H]⁺. Compound 1G-2: LC-MS (ESI) m/z: 765 [M+H]⁺. Compound 1-2: LC-MS (ESI) m/z: 665 [M+H]⁺; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.96-1.05 (m, 2H), 1.19-1.77 (m, 12H), 2.04-2.14 (m, 2H), 2.48-2.89 (m, 3H), 3.14-3.24 (m, 1H), 3.39-3.76 (m, 5H), 3.95-4.17 (m, 2H), 4.31-4.68 (m, 3H), 5.46 (s, 1H), 6.98-7.03 (m, 2H), 7.44-7.52(m, 4H), 7.67-7.72 (m, 4H), 7.80 (d, J= 8.8 Hz, 2H).

[00306] Example 2

[00307] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)(4-((4'-chloro-[l,l'- biphenyl]-4-yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (2)

[00308] Compounds 2A and 2 were synthesized by employing the procedures described for Compounds 1G and 1 using Compounds Al, Bl, and 2A in lieu of Compound A2, tert-butyl piperidin-4-ylcarbamate and Compound 1G. Compound 2A: LC-MS (ESI) m/z: 813 [M+H]⁺. Compound 2: LC-MS (ESI) m/z: 713 [M+H]⁺; 'H-NMR (CD₃OD, 400 MHz): d (ppm) 1.70-2.07 (m, 17 H), 2.27-2.83 (m, 2H), 3.24-3.31 (m, 1H), 3.41-3.96 (m, 3H), 4.11-4.36 (m, 2H), 4.53-4.79 (m, 2H), 4.96 (s, 1H), 5.44 (s, 1H), 6.94-7.34 (m, 4H), 7.42-7.63 (m, 5H), 7.71-7.91 (m, 4H), 8.25-8.40 (m, 1H).

[00309] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((R)-4-((4'-chloro-[l,l'- biphenyl]-4-yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (2-1)

[00310] Compounds 2A-1 and 2-1 were synthesized by employing the procedures described for Compounds 1G and 1 using Compounds Al, Bl, 1F-1, and 2A-1 in lieu of Compound A2, tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 1G. Compound 2A- 1: LC-MS (ESI) m/z: 813 [M+H]⁺. Compound 2-1: LC-MS (ESI) m/z: 713 [M+H]⁺; ¾- NMR (CD3OD, 400 MHz): d (ppm) 1.70-2.07 (m, 17 H), 2.27-2.83 (m, 2H), 3.24-3.31 (m, 1H), 3.41-3.96 (m, 3H), 4.11-4.36 (m, 2H), 4.53-4.79 (m, 2H), 4.96 (s, 1H), 5.44 (s, 1H), 6.94-7.34 (m, 4H), 7.42-7.63 (m, 5H), 7.71-7.91 (m, 4H), 8.25-8.40 (m, 1H).

[00311] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((S)-4-((4'-chloro-[l,l'- biphenyl]-4-yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (2-2)

[00312] Compounds 2A-2 and 2-2 were synthesized by employing the procedures described for Compounds 1G and 1 using Compounds Al, Bl, 1F-2, and 2A-2 in lieu of Compound A2, tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 1G. Compounds 2A- 2: LC-MS (ESI) m/z: 813 [M+H]⁺. Compounds 2-2: LC-MS (ESI) m/z: 713 [M+H]⁺; ¾- NMR (CD3OD, 400 MHz): d (ppm) 1.69-2.10 (m, 17 H), 2.31-2.83 (m, 2H), 3.24-3.27 (m, 1H), 3.45-4.00 (m, 3H), 4.08-4.37 (m, 2H), 4.51-4.82 (m, 2H), 4.97 (s, 1H), 5.42-5.46 (m, 1H), 6.91-7.23 (m, 2H), 7.25-7.71 (m, 8H), 7.81-7.91 (m, 3H), 8.25-8.40 (m, 1H).

[00313] Example 3

[00314] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)(4-((4'-chloro-[l,T- biphenyl]-4-yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (3)

[00315] Compounds 3A was synthesized by employing the procedure described for Compound 1G using Compound B1 in lieu of tert-butyl piperidin-4-ylcarbamate: LC-MS (ESI) m/z: 791 [M+H]⁺.

[00316] To a solution of Compound 3A (200 mg, 0.2 mmol) in dichloromethane (20 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was purified with preparative HPLC to afford Compound 3: LC-MS (ESI) m/z: 691 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 0.94-1.32 (m, 6H), 1.70-2.10 (m, 14H), 2.40-2.87 (m, 2H), 3.35-3.80 (m, 5H), 4.09-4.20 (m, 2H), 4.42-4.45 (m, 1H), 4.80-4.84 (m, 2H), 5.32-5.38 (m, 1H), 6.91-7.03 (m, 2H), 7.42-7.82 (m, 10H). [00317] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((R)-4-((4'-chloro-[l,l'- biphenyl]-4-yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone

(3-1)

[00318] Compounds 3A-1 and 3-1 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Bl, 1F-1, and 3A-1 in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds IF, and 3A. Compound 3A-1: LC-MS (ESI) m/z: 691 [M+H]⁺. Compound 3: LC-MS (ESI) m/z: 691 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 0.94-1.32 (m, 6H), 1.70-2.10 (m, 14H), 2.40-2.87 (m, 2H), 3.35-3.80 (m, 5H), 4.09- 4.20 (m, 2H), 4.42-4.45 (m, 1H), 4.80-4.84 (m, 2H), 5.32-5.38 (m, 1H), 6.91-7.03 (m, 2H), 7.42-7.82 (m, 10H).

[00319] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((S)-4-((4'-chloro-[l,l'- biphenyl]-4-yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (3-2)

[00320] Compounds 3A-2 and 3-2 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Bl, 1F-2, and 3A-2 in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds IF, and 3A. Compound 3A-2: LC-MS (ESI) m/z: 791 [M+H]⁺. Compound 3-2: LC-MS (ESI) m/z: 691 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 0.94-1.34 (m, 6H), 1.73-2.10 (m, 14H), 2.40-2.87 (m, 2H), 3.35-3.80 (m, 5H), 4.09-4.20 (m, 2H), 4.41-4.45 (m, 1H), 4.78-4.81 (m, 2H), 5.32-5.38 (m, 1H), 6.91-7.03 (m, 2H), 7.42-7.82 (m, 10H).

[00321] Example 4

[00322] Synthesis of (4-aminopiperidin-l-yl)(4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (4)

[00323] Compounds 4A and 4 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds A1 and 4A in lieu of Compounds A2 and 3A. Compound 4A: LC-MS (ESI) m/z: 787 [M+H]⁺. Compound 4: LC-MS (ESI) m/z: 687 [M+H]⁺; 1H-NMR (CD₃OD, 400 MHz): d (ppm) 1.87-2.09 (m, 14H), 2.12-3.11 (m, 4H), 3.32-3.96 (m, 2H), 3.97-3.77 (m, 5H), 4.97-5.55 (m, 2H), 6.98-7.37 (m, 4H), 7.47-7.92 (m, 9H), 8.25-8.41 (m, 1H).

[00324] Synthesis of (f?)-(4-aminopiperidin-l-yl)(4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (4-1)

[00325] Compounds 4A-1 and 4-1 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Al, 1F-1, and 4A-1 in lieu of Compounds A2, IF, and 3A. Compound 4A-1: LC-MS (ESI) m/z: 787 [M+H]⁺. Compound 4-1: LC-MS (ESI) m/z: 687 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.87-2.09 (m, 13H), 2.12-3.11 (m, 4H), 3.32-3.96 (m, 2H), 3.97-3.77 (m, 6H), 4.97-5.55 (m, 1H), 6.98-7.37 (m, 4H), 7.47-7.92 (m, 9H), 8.25-8.41 (m, 2H).

[00326] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (4-2)

[00327] Compounds 4A-2 and 4-2 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Al, 1F-2, and 4A-2 in lieu of Compounds A2, IF, and 3A. Compound 4A-2: LC-MS (ESI) m/z: 787 [M+H]⁺. Compound 4-2: LC-MS (ESI) m/z: 687 [M+H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 1.37-2.13 (m, 17H), 2.26-3.04 (m, 2H), 3.21-3.32 (m, 1H), 3.37-3.76 (m, 2H), 3.97-4.67 (m, 3H), 4.97-5.53 (m, 2H), 6.98-7.37 (m, 4H), 7.47-7.92 (m, 9H), 8.25-8.41 (m, 1H).

[00328] Example 5

[00329] Synthesis of ((R)-3-aminopyrrolidin-l-yl)(4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (5)

[00330] Compounds 5A and 5 were synthesized by employing the procedures described for Compounds 1G and 3 using (R)-tert- butyl pyrrolidin-3-ylcarbamate and Compound 5A in lieu of tert-butyl piperidin-4-ylcarbamate and Compound 3A. Compound 5A: LC-MS (ESI) m/z: 751 [M+H]⁺. Compound 5: LC-MS (ESI) m/z: 651 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 0.97-1.1.77 (m, 11H), 2.04-2.77 (m, 4H), 3.36-4.19 (m, 12H), 4.45-4.48 (m, 1H), 5.23-5.25 (m, 1H), 6.97-7.00 (m, 2H), 7.44-7.51 (m, 4H), 7.66-7.68 (m, 4H), 7.76-7.80 (m, 2H).

[00331] Synthesis of ((R)-3-aminopyrrolidin-l-yl)((R)-4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (5-1)

[00332] Compounds 5A-1 and 5-1 were synthesized by employing the procedures described for Compounds 1G and 3 using (R)-tert-butyl pyrrolidin-3-ylcarbamate,

Compounds 1F-1, and 5A-1 in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds IF, and Compound 3A. Compound 5A-1: LC-MS (ESI) m/z: 773 [M+Na]⁺. Compound 5-1: LC- MS (ESI) m/z: 651 [M +H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.89-1.32 (m, 8H), 1.47-1.57 (m, 1H), 1.71-1.89 (m, 8H), 2.54-2.72 (m, 2H), 3.46-4.l3(m, 9H), 4.37-5.23 (m, 1H), 6.91-7.01 (m, 3H), 7.44-7.52 (m, 3H), 7.66-7.81 (m, 6H).

[00333] Synthesis of ((R)-3-aminopyrrolidin-l-yl)((S)-4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (5-2)

[00334] Compounds 5A-2 and 5-2 were synthesized by employing the procedures described for Compounds 1G and 3 using (R)-tert-butyl pyrrolidin-3-ylcarbamate,

Compounds 1F-2, and 5A-2 in lieu of (R)-tert-butyl pyrrolidin-3-ylcarbamate, Compounds IF, and 3A. Compound 5A-2: LC-MS (ESI) m/z: 751 [M+H]⁺. Compound 5-2: LC-MS (ESI) m/z: 651 [M+H]⁺; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.95-1.37 (m, 5H), 1.50-1.60 (m, 1H), 1.70-1.93 (m, 5H), 2.01-2.18 (m, 1H), 2.33-2.85 (m, 3H), 3.33-3.39 (m, 1H), 3.49-3.75 (m, 6H), 3.83-4.16 (m, 5H), 4.41-4.46 (m, 1H), 5.18-5.22 (m, 1H), 6.98-7.17 (m, 2H), 7.44- 7.51 (m, 4H), 7.66-7.70 (m, 4H), 7.76-7.81 (m, 2H).

[00335] Example 6

[00336] Synthesis of (4-((4'-chloro-[l,l'-biphenyl]-4-yl)methyl)-l-((4-

(cyclohexylmethoxy)phenyl) sulfonyl)piperazin-2-yl)(piperazin- 1 -yl)methanone 2,2,2- trifluoroacetate (6)

[00337] Compounds 6A and 6 were synthesized by employing the procedures described for Compounds 1G and 3 using tert-butyl piperazine- l-carboxylate and Compound 6A in lieu of tert-butyl piperidin-4-ylcarbamate and Compound 3A. Compound 6A: LC-MS (ESI) m/z: 751 [M+H]⁺. Compound 6: LC-MS (ESI) m/z: 651 [M+H]⁺; Ή-NMR (CD3OD, 400 MHz): d (ppm) 0.85-1.1.82 (m, 13H), 2.55-2.85 (m, 2H), 3.30-3.42 (m, 3H), 3.50-3.72 (m, 4H), 3.74-4.22 (m, 6H), 4.45-4.51 (m, 1H), 5.44-5.52 (m, 1H), 6.94-7.01 (m, 2H), 7.44- 7.51 (m, 4H), 7.63-7.68 (m, 4H), 7.77-7.82 (m, 2H).

[00338] Synthesis of (R)-(4-((4'-chloro-[l,r-biphenyl]-4-yl)methyl)-l-((4- (cyclohexylmethoxy) phenyl)sulfonyl)piperazin-2-yl)(piperazin- 1 -yl)methanone 2,2,2- trifluoroacetate (6-1)

[00339] Compounds 6A-1 and 6-1 were synthesized by employing the procedures described for Compounds 1G and 3 using tert-butyl piperazine- l-carboxylate, Compounds 1F-1, and 6A-1 in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 3A. Compound 6A-1: LC-MS (ESI) m/z: 751 [M+H]⁺. Compound 6-1: LC-MS (ESI) m/z: 651 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.85-1.1.82 (m, 12H), 2.55-2.85 (m, 2H), 3.30-3.42 (m, 3H), 3.50-3.72 (m, 4H), 3.74-4.22 (m, 6H), 4.45-4.51 (m, 1H), 5.44-5.52 (m, 1H), 6.94-7.01 (m, 2H), 7.44-7.51 (m, 4H), 7.63-7.68 (m, 4H), 7.77-7.82 (m, 2H).

[00340] Synthesis of (S)-(4-((4'-chloro-[l,r-biphenyl]-4-yl)methyl)-l-((4- (cyclohexylmethoxy) phenyl)sulfonyl)piperazin-2-yl)(piperazin- 1 -yl)methanone (6-2)

[00341] Compounds 6A-2 and 6-2 were synthesized by employing the procedures described for Compounds 1G and 3 using tert-butyl piperazine- l-carboxylate, Compounds 1F-2, and 6A-2 in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 3A.

Compound 6A-2: LC-MS (ESI) m/z: 751 [M+H]⁺. Compound 6-2: LC-MS (ESI) m/z: 651 [M+H]⁺; 1H-NMR (CD₃OD, 400 MHz): d (ppm) 1.01-1.28 (m, 8H), 1.63-1.82 (m, 6H), 2.13- 2.20 (m, 2H), 2.30-2.50 (m, 2H), 2.59-2.61 (m, 2H), 2.76-2.79 (m, 2H), 3.24-3.31 (m, 2H), 3.45-3.48 (m, 1H), 3.61-3.64 (m, 1H), 3.76-3.78 (m, 2H), 3.87-3.88 (m, 1H), 4.72-4.73 (m, 1H), 6.93-6.96 (m, 2H), 7.24-7.26 (m, 2H), 7.33-7.36 (m, 2H), 7.46-7.53 (m, 4H), 7.60-7.62 (m, 2H).

[00342] Example 7

[00343] Synthesis of (4-aminopiperidin-l-yl)(4-(4'-chloro-[l,r-biphenyl]-4-carbonyl)- l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (7)

[00344] To a mixture of Compound 7 A and a drop of DMF (200 mg, 0.86 mmol) in THF (10 mL) was added oxalyl chloride (0.08 mL, 1.03 mmol) at room temperature. The mixture was stirred at room temperature for 30 minutes, heated to reflux for 30 minutes, and concentrated under reduced pressure. The residue was dissolved in THF (10 mL) and concentrated under reduce pressure to give Compound 7B, which was used directly in the next step without further purification.

[00345] To a mixture of l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (200 mg, 0.86 mmol) and DIPEA (333 mg, 2.58 mmol) in THF (8 mL) and DMF (0.5 mL) was dropped a solution of Compound 7B (216 mg, 0.86 mmol) in THF (8 mL) at 0 °C. The reaction mixture was stirred at room temperature under nitrogen overnight and concentrated under reduced pressure. The residue was purified with reverse phase chromatography eluting with 25%-50% methanol in water (0.1% MLOH) to give Compound 7C: LC-MS (ESI) m/z: 445 [M+H]⁺.

[00346] Compounds 7D, 7E, and 7 were synthesized by employing the procedures described for Compounds IF, 1G, and 3 using Compounds 7C, 7D, and 7E in lieu of Compounds IE, IF, and 3A. Compound 7D, which was used directly in the next step without further purification. LC-MS (ESI) m/z: 345 [M+H]⁺. Compound 7E: LC-MS (ESI) m/z: 779 [M+H]⁺. Compound 7: LC-MS: (ESI) m/z: 679 [M+H]⁺. Ή-NMR (CD3OD, 400 MHz): d (ppm) 1.39-1.08 (m, 7H), 2.19-1.69 (m, 9H), 3.58-3.36 (m, 3H), 4.01-3.80 (m, 6H), 4.41-4.21 (m, 2H), 4.85-4.67 (m, 1H), 5.13-5.06 (m, 1H), 7.07-7.00 (m, 2H), 7.48-7.46 (m, 4H), 7.79- 7.61 (m, 6H).

[00347] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-(4'-chloro-[l,r-biphenyl]-4- carbonyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (7-1)

[00348] Compounds 7C-1, 7D-1, 7E-1, and 7-1 were synthesized by employing the procedures described for Compounds 7C, IF, 1G, and 3 using (S)-l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid, Compounds 7C-1, 7D-1, and 7E-1 in lieu of (R)-l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds IE, IF, and 3A.

Compound 7C-1: LC-MS (ESI) m/z: 445 [M+H]⁺. Compound 7D-1, which was used directly in the next step without further purification. LC-MS (ESI) m/z: 345 [M+H]⁺. Compound 7E- 1, which was used directly in the next step without further purification. LC-MS (ESI) m/z: 779 [M+H]⁺. Compound 7-1: LC-MS: (ESI) m/z: 679 [M+H]⁺. 'H-NMR (CD3OD, 400 MHz): d (ppm) 1.08-1.36 (m, 7H), 1.69-1.94 (m, 9H), 2.58-2.72 (m, 1H), 3.32-3.40(m, 2H), 3.80-4.07 (m, 6H), 4.23-4.41 (m, 2H), 4.70-4.83 (m, 1H), 5.13-5.15 (m, 1H), 7.02-7.04 (m, 2H), 7.36-7.48 (m, 4H), 7.64-7.73 (m, 6H).

[00349] Example 8

[00350] Synthesis of (4-aminopiperidin-l-yl)(4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)- 1 -((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (8)

[00351] Compounds 8A and 8 were synthesized by employing the procedures described for Compounds 1G and 3 using 4-(trifluoromethoxy)benzene-l-sulfonyl chloride and Compound 8A in lieu of Compounds A2 and 3A. Compound 8A: LC-MS (ESI) m/z: 737 [M+H]⁺. Compound 8: LC-MS (ESI) m/z: 637 [M+H]⁺; 'H-NMR (CD₃OD, 400 MHz): d (ppm) 1.47-1.61 (m, 2H), 2.01-2.08 (m, 2H), 2.70-3.14 (m, 4H), 3.33-3.41 (m, 3H), 3.60-4.60 (m, 6H), 5.40-5.41 (m, 1H), 7.32-7.49 (m, 6H), 7.66-7.93 (m, 4H), 8.02-8.04 (m, 2H).

[00352] Synthesis of (R)-(4-aminopiperidin-l-yl)(4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)-l-((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone (8-1)

[00353] Compounds 8A-1 and 8-1 were synthesized by employing the procedures described for Compounds 1G and 3 using 4-(trifluoromethoxy)benzene-l-sulfonyl chloride, Compounds 1F-1, and 8A-1 in lieu of A2, Compounds IF, and 3A. Compound 8A-1: LC- MS (ESI) m/z: 737 [M+H]⁺. Compound 8-1: LC-MS (ESI) m/z: 637 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 0.92-1.69 (m, 6H), 2.23-2.32 (m, 2H), 2.72-2.94 (m, 5H), 3.66- 3.71 (m, 3H), 3.95-3.99 (m, 1H), 4.15-4.17 (br, 1H), 7.37-7.45 (m, 6H), 7.55-7.62 (m, 4H), 7.88-7.90 (m, 2H).

[00354] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)- 1 -((4-(trifluoromethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (8-2)

[00355] Compounds 8A-2 and 8-2 were synthesized by employing the procedures described for Compounds 1G and 3 using 4-(trifluoromethoxy)benzene-l-sulfonyl chloride, Compounds 1F-2, and 8A-2 in lieu of Compounds A2, IF, and 3A. Compound 8A-2: LC-MS (ESI) m/z: 737 [M+H]⁺. Compound 8-2: LC-MS (ESI) m/z: 637 [M+H]⁺; 'H-NMR (CD₃OD, 400 MHz): d (ppm) 1.49-1.65 (m, 2H), 2.03-2.11 (m, 2H), 2.67-3.31 (m, 4H), 3.35-3.75 (m, 4H), 4.10-4.63 (m, 5H), 5.51-5.55 (m, 1H), 7.48-7.59 (m, 6H), 7.66-7.75 (m, 4H), 8.04-8.08 (m, 2H).

[00356] Example 9

[00357] Synthesis of (4-aminopiperidin-l-yl)(l-((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)-4-(4-(trifluoromethyl)benzyl)piperazin-2-yl)methanone (9) and (R)-(4- aminopiperidin-l-yl)(l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)-4-(4- (trifluoromethyl)benzyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (9-1)

[00358] Compounds 9B, 9C, 9D, and 9 were synthesized by employing the procedures described for Compounds IE, IF, 1G, and 3 using Compounds 9A, 9B, 9C, Al, and 9 in lieu of Compounds ID, IE, IF, A2, and 3A. Compound 9B: LC-MS (ESI) m/z: 387 [M-H] . Compound 9C: LC-MS (ESI) m/z: 287 [M-H] . Compound 9D: LC-MS (ESI) m/z: 745

[M+H]⁺. Compound 9 was separated with chiral HPLC to give Compound 9-1: LC-MS (ESI) m/z: 645 [M+H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 1.47-2.10 (m, 13H), 2.71-3.30 (m, 5H), 3.37-3.75 (m, 2H), 3.97-4.60 (m, 5H), 5.03-5.06 (m, 1H), 5.42 (s, 1H), 7.28-7.35 (m, 2H), 7.58-7.81 (m, 5H), 7.94-7.99 (m, 2H), 8.45 (s, 1H). Chiral separation condition: n- Hexane/EtOH contained 0. l%DEA (50/50); Cellulose-4 (4.6 x 250 mm, 5 pm); retention time: 11.84 minute.

[00359] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)-4-(4-(trifluoromethyl)benzyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (9- 2)

[00360] Compounds 9B-2, 9C-2, 9D-2, and 9-2 were synthesized by employing the procedures described for Compounds IE, IF, 1G, and 3 using (S)-l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid, Compounds 9A, 9B-2, 9C-2, and 9D-2 in lieu of l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds ID, IE, IF, and 3A. Compounds 9B-2: LC-MS (ESI) m/z: 389 [M+H]⁺. Compounds 9C-2: LC-MS (ESI) m/z:

289 [M+H]⁺. Compound 9D-2 was used directly in the next step without purification. LC-MS (ESI) m/z: 745 [M+H]⁺. Compound 9-2: LC-MS (ESI) m/z: 645 [M+H]⁺; Ή-NMR (CD₃OD, 400 MHz): d (ppm) 1.47-2.10 (m, 13H), 2.71-3.30 (m, 5H), 3.37-3.75 (m, 2H), 3.97-4.60 (m, 5H), 5.03-5.06 (m, 1H), 5.42 (s, 1H), 7.28-7.35 (m, 2H), 7.58-7.81 (m, 5H), 7.94-7.99 (m, 2H), 8.45 (s, 1H).

[00361] Example 10

[00362] Synthesis of (4-aminopiperidin-l-yl)(l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(4-(trifluoromethyl)benzyl)piperazin-2- yl)methanone (10) and (R)-(4-aminopiperidin-l-yl)(l-((4- (cyclohexylmethoxy)phenyl)sulfonyl)-4-(4-(trifluoromethyl)benzyl)piperazin-2- yl)methanone (10-1)

[00363] Compounds 10A and 10 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds 9C and 10A in lieu of Compounds IF and 3A. Compound 10A: LC-MS (ESI) m/z: 723 [M+H]⁺. Compound 10 was separated with chiral HPLC to give Compound 10-1: LC-MS (ESI) m/z: 623 [M+H]⁺; 'H-NMR (CD₃OD, 400 MHz): d (ppm) 1.03-1.29 (m, 9H), 1.61-1.80 (m, 7H), 2.06-2.73 (m, 6H), 2.99-3.21 (m, 1H), 3.32-3.55 (m, 3H), 3.75-3.79 (m, 3H), 4.26-4.28 (m, 1H), 6.92-6.95 (m, 2H), 7.33-7.61 (m, 6H). Chiral separation condition: n-Hexane/EtOH contained 0. l%DEA (50/50);

Cellulose-4 (4.6 x 250 mm, 5 pm); retention time: 13.94 minute.

[00364] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(4-(trifluoromethyl)benzyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (10-2)

[00365] Compounds 10A-2 and 10-2 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds 9C-2 and 10A-2 in lieu of Compounds IF and 3A. Compounds 10A-2: LC-MS (ESI) m/z: 723 [M+H]⁺. Compounds 10-2: LC-MS (ESI) m/z: 623 [M+H]⁺; 1H-NMR (CD₃OD, 400 MHz): d (ppm) 1.09-1.58 (m, 7H), 1.73-2.08

(m, 8H), 2.72-3.11 (m, 4H), 3.32-3.42 (m, 4H), 3.90-4.42 (m, 7H), 5.37-5.38 (m, 1H), 7.11- 7.13 (m, 2H), 7.66-7.86 (m, 6H).

[00366] Example 11

[00367] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)(4-((4'-chloro-[l,r- biphenyl]-4-yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone (11), ((R)-4-amino-3,3-difluoropiperidin-l-yl)((R)-4-((4'-chloro-[l,r-biphenyl]-4-yl)methyl)- l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone (11-1), and ((S)-4- amino-3 ,3 -difluoropiperidin- 1 -yl)((R)-4-((4'-chloro-[ 1 , 1 '-biphenyl]-4-yl)methyl)- 1 -((4- (cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone (11-2)

[00368] Compounds 11A and 11 were synthesized by employing the procedures described for Compounds 1G and 1 using Compounds B2 and 11A in lieu of tert-butyl piperidin-4-ylcarbamate and Compound 1G.

[00369] Compound 11 A: LC-MS (ESI) m/z: 801 [M+H]⁺.

[00370] Compound 11 was purified with preparative chiral -HPLC to furnish

Compound 11-1 and Compound 11-2, as well as Compound 11-3 and Compound 11-4.

Compound 11-1: LC-MS (ESI) m/z: 701 [M+H]⁺; Ή-NMR (CD₃OD, 400 MHz): d (ppm) 0.89-1.36 (m, 15H), 2.17-2.31 (m, 2H), 2.84-3.22 (m, 5H), 3.56-4.32 (m, 7H), 7.01 (d, 7= 8.8 Hz, 2H), 7.31-7.32 (m, 2H), 7.43 (d, J= 8.4 Hz, 2H), 7.54-7.62 (m, 4H), 7.67 (d, J= 8.8 Hz, 2H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50:50); S,S-Whelk- 01 (4.6 x 250 mm, 5 pm); retention time: 12.55 minute. Compound 11-2: LC-MS (ESI) m/z: 701 [M+H]⁺; 1H-NMR (CD₃OD, 400 MHz): d (ppm) 0.79-1.77 (m, 15H), 2.02-3.03 (m, 7H), 3.42-4.21 (m, 7H), 6.89 (d, J= 8.8 Hz, 2H), 7.19 (d, J= 8.4 Hz, 2H), 7.31 (d, J= 8.4 Hz,

2H), 7.42 (d, J= 7.6 Hz, 2H), 7.48 (d, J= 8.4 Hz, 2H), 7.55 (d, J= 9.2 Hz, 2H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50:50); S,S-Whelk-Ol (4.6 x 250 mm, 5 pm); retention time: 13.64 minute.

[00371] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)((S)-4-((4'-chloro-[l,r- biphenyl]-4-yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone ( 11B), ((R)-4-amino-3 ,3 -difluoropiperidin- 1 -yl)((S)-4-((4'-chloro-[ 1 , 1 '-biphenyl]-4- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (11-3), and ((S)-4-amino-3,3-difluoropiperidin-l-yl)((S)-4-((4'-chloro-[l,r- biphenyl]-4-yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (11-4)

[00372] Compounds 11A-2 and 11B were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds B2, 1F-2, and 11A-2 in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds IF, and 3A. Compound 11A-2: LC-MS ESI (m/z): 801 [M+H]⁺. Compound 11B was separated with preparative chiral -HPLC to give Compound 11-3 and Compound 11-4. Compound 11-3: LC-MS (ESI) m/z: 701 [M+H]⁺; ¾- NMR (CD3OD, 400 MHz): d (ppm) 0.91-0.99 (m, 2H), 1.16-1.48 (m, 4H), 1.67-1.77 (m, 6H), 1.96-2.01 (m, 1H), 2.18-2.22 (m, 1H), 2.37-2.47 (m, 1H), 2.64-2.67 (m, 1H), 3.25-3.31 (m, 2H), 3.44-3.55 (m, 2H), 3.66-3.72 (m, 2H), 3.95-4.18 (m, 3H), 4.43-4.47 (m, 1H), 4.60-4.63 (m, 1H), 4.96-5.05 (m, 1H), 5.49-5.59 (m, 1H), 6.96 (d, J= 8.8 Hz, 2H), 7.44-7.53 (m, 4H), 7.67-7.70 (m, 4H), 7.79 (d, J= 8.4 Hz, 2H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50:50); S,S-Whelk-Ol (4.6 x 250 mm, 5 pm); retention time: 16.13 minute. Compound 11-4: LC-MS (ESI) m/z: 701 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 0.95-1.03 (m, 2H), 1.22-1.36 (m, 4H), 1.67-1.79 (m, 6H), 2.21-2.25 (m, 1H), 2.52-2.91 (m, 2H), 3.19-3.26 (m, 2H), 3.32-3.39 (m, 3H), 3.62-3.72 (m, 2H), 3.91-4.69 (m, 5H), 4.78- 4.87 (m, 1H), 5.36-5.56 (m, 1H), 7.00 (d, J= 8.8 Hz, 2H), 7.41-7.52 (m, 4H), 7.67-7.69 (m, 4H), 7.78 (d, J= 8.4 Hz, 2H). Chiral separation n-Hexane contained 0.1% DEA/EtOH contained 0.1% DEA (50:50); S,S-Whelk-Ol (4.6 x 250 mm, 5 pm); retention time: 18.39 minute.

[00373] Example 12

[00374] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)(l-((6-

(cyclopentyloxy)naphthalen-2-yl)sulfonyl)-4-(4-(trifluoromethyl)benzyl)piperazin-2- yl)methanone (12) (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((R)-l-((6- (cyclopentyloxy)naphthalen-2-yl)sulfonyl)-4-(4-(trifluoromethyl)benzyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (12-1)

[00375] Compounds 12A and 12 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Al, Bl, 9C, and 12A in lieu of Compound A2, tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 3A. Compound 12A: LC-MS (ESI) m/z: 771 [M+H]⁺. Compound 12 was separated with chiral HPLC to give Compound 12-1: LC-MS (ESI) m/z: 671 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 1.63-2.01 (m, 16H), 2.36-2.48 (m, 1H), 2.94-3.17 (m, 2H), 3.30-3.59 (m, 2H), 3.69-4.18 (m, 4H), 4.55-4.61 (m, 2H), 4.94-4.95 (m, 1H), 5.21 (s, 1H), 7.18-7.25 (m, 2H), 7.44-7.74 (m, 5H), 7.84-7.89 (m, 2H), 8.36 (s, 1H). Chiral separation condition: n-Hexane/EtOH contained 0.l%DEA (50/50); IC (4.6 x 250 mm, 5 pm); retention time: 11.49 minute.

[00376] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((S)-l-((6- (cyclopentyloxy)naphthalen-2-yl)sulfonyl)-4-(4-(trifluoromethyl)benzyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (12-2)

[00377] Compounds 12A-2 and 12-2 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Al, Bl, 9C-2, and 12A-2 in lieu of Compound A2, tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 3A. Compound 12A- 2 was used directly in the next step without purification. LC-MS (ESI) m/z: 771 [M+H]⁺. Compound 12-2: LC-MS (ESI) m/z: 671 [M+H]⁺; Ή-NMR (CD3OD, 400 MHz): d (ppm) 1.63-2.01 (m, 16H), 2.36-2.48 (m, 1H), 2.94-3.17 (m, 2H), 3.30-3.59 (m, 2H), 3.69-4.18 (m, 4H), 4.55-4.61 (m, 2H), 4.94-4.95 (m, 1H), 5.21 (s, 1H), 7.18-7.25 (m, 2H), 7.44-7.74 (m, 5H), 7.84-7.89 (m, 2H), 8.36 (s, 1H).

[00378] Example 13

[00379] Synthesis of (R)-(4-aminopiperidin-l-yl)(4-benzhydryl-l-((4-

(cyclohexylmethoxy)phenyl) sulfonyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (13-1)

[00380] A mixture of Compound 13A (605 mg, 2.46 mmol), l-(/er/-butyl) 2-methyl (f?)-piperazine-l,2-dicarboxylate (500 mg, 2.05 mmol), and K2CO3 (424 mg, 3.07 mmol) in DMF (10 mL) was stirred at 60 °C for 4 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% v/v) to yield Compound 13B-1: LC-MS (ESI) m/z: 411 [M+H]⁺.

[00381] Compound 13C-1 was synthesized by employing the procedure described for Compound IF using Compound 13B-1 in lieu of Compound IE: LC-MS (ESI) m/z: 311 [M+H]⁺.

[00382] A mixture of Compound 13C-1 (150 mg, 0.48 mmol), Compound A2 (139 mg, 0.48 mmol), and DIPEA (187 mg, 1.45 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight. The mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic extracts were washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to yield Compound 13D-1: LC-MS (ESI) m/z: 563 [M+H]⁺.

[00383] To a solution of Compound 13D-1 (150 mg, 0.27 mmol) in DMSO (5 mL) was added LiCl (112 mg, 2.7 mmol). The mixture was stirred at 145 °C for 12 hours. The mixture was diluted with water (50 mL), adjusted its pH to about 5 with diluted HC1 solution, and extracted with EtOAc (50 mL x 2). The combined organic extracts were washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield Compound 13E-1: LC-MS (ESI) m/z: 549 [M +H]⁺.

[00384] A mixture of Compound 13E-1 (80 mg, 0.15 mmol), tert-butyl piperidin-4- ylcarbamate (30 mg, 0.15 mmol), HATU (83 mg, 0.22 mmol), and DIPEA (56 mg,

0.44mmol) in dichloromethane (10 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (50 mL x 3) and brine ((50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield Compound 13F-1: LC-MS (ESI) m/z: 731 [M+H]⁺.

[00385] Compounds 13-1 was synthesized by employing the procedure described for Compound 3 using Compound 13F-1 in lieu of Compound 3A: LC-MS (ESI) m/z: 631

[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.12-2.12 (m, 16H), 2.48-2.93 (m, 4H), 3.21 (s, 2H), 3.37-3.40 (m, 1H), 3.67-4.06 (m, 5H), 4.63-4.67 (m, 1H), 5.11 (s, 1H), 7.04 (d, J =

8.0 Hz, 2H), 7.31-7.41 (m, 10H), 7.74 (d, J = 8.8 Hz, 2H).

[00386] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-benzhydryl-l-((4- (cyclohexylmethoxy)phenyl) sulfonyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (13-2)

[00387] Compounds 13B-2, 13C-2, 13D-2, 13E-2, 13F-2, and 13-2 were synthesized by employing the procedures described for Compounds 13B-1, IF, 13D-1, 13E-1, 13F-1, and 3 using l-(tert-butyl) 2-methyl (S)-piperazine-l,2-dicarboxylate, Compounds 13B-2, 13C-2, 13D-2, 13E-2, and 13F-2 in lieu of l-(tert-butyl) 2-methyl (R)-piperazine-l,2-dicarboxylate, Compounds IE, 13C-1, 13D-1, 13E-1, and 3A. Compound 13B-2: LC-MS (ESI) m/z: 411 [M+H]⁺. Compound 13C-2: LC-MS (ESI) m/z: 311 [M+H]⁺. Compound 13D-2: LC-MS (ESI) m/z: 563[M+H]⁺. Compound 13E-2: LC-MS (ESI) m/z: 547[M-H] . Compound 13F-2: LC-MS (ESI) m/z: 73 l[M+H]⁺. Compound 13-2: LC-MS (ESI) m/z: 631 [M +H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 1.14-1.65 (m, 7H), 1.66-3.31 (m, 14H), 3.33-3.34 (m, 2H), 3.51-4.45 (m, 5H), 4.60-5.35 (m, 2H), 7.04 (d, J = 8.4 Hz, 2H), 7.35-7.42 (m, 10H), 7.75 (d, J = 8.4 Hz, 2H).

[00388] Example 14

[00389] Synthesis of (R)-(4-aminopiperidin-l-yl)(l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(4-(l- (trifluoromethyl)cyclopropyl)benzyl)piperazin-2-yl)methanone (14-1)

[00390] A mixture of Compound 14A (3.8 g, 21.1 mmol), 2-bromo-3,3,3- trifluoroprop-l-ene (4.4 g, 25.2 mmol), Pd(PPh3)2Cl2 (2.96 g, 4.22 mmol), and Na2CCb (4.43 g, 21.11 mmol) in toluene (20 mL), EtOH (10 mL) and H2O (2 mL) was stirred at 80 °C for 8 hours. The mixture was cooled down to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to afford Compound 14B: LC-MS (ESI) m/z: 231

[M+H]⁺. ¾-NMR (CDCh, 400 MHz): d (ppm) 3.93 (s, 3H), 5.86-5.87 (m, 1H), 6.05-6.06 (m, 1H), 7.53-7.55 (m, 2H), 8.05-8.07 (m, 2H).

[00391] To a solution of potassium hydroxide (12.8 g) in water (50 mL) and diethyl ether (50 mL) in an ice bath was added A-nitroso-A'-methylurea (5.07g, 49 mmol) in several small portions. The mixture was stirred at 0 °C for 10 minutes. The organic layer was separated and dried over potassium hydroxide to give a solution of diazomethane in diethyl ether. To a solution of Compound 14B (2 g, 8.65 mmol) in diethyl ether (50 mL) was added the solution of diazomethane in diethyl ether (50 mL). The reaction mixture was stirred at 0 °C for 1 hour and concentrated to give a crude Compound 14C, which was used directly in next step without further purification. LC-MS (ESI) m/z: 273 [M+H]⁺.

[00392] A mixture of Compound 14C (1.3 g, 4.78 mmol) in xylene (20 ml) was stirred at 140 °C for 8 hours and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to afford Compound 14D: LC-MS (ESI) m/z: 245 [M+H]⁺; 'H-NMR (CDCh, 400 MHz): d (ppm) 1.05-1.06 (m, 2H), l.38-l.4l(m, 2H), 3.93 (s, 3H), 7.52-7.54 (m, 2H), 8.00-8.02 (m, 2H).

[00393] To a solution of Compound 14D (260 mg, 1.06 mmol) in THF (5 mL) was added DIBAL-H (1.1 mL, 1.6 mmol) at 0 °C. The mixture was stirred at room temperature for 3 hours, diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 33% v/v) to afford Compound 14E: LC-MS (ESI) m/z: 199 [M-OH]⁺; 'H-NMR (DMSO-rL, 400 MHz): d (ppm) 1.09-1.10 (m, 2H), 1.30-1.33 (m, 2H), 4.48-4.50 (m, 2H), 5.22-5.24 (m, 1H), 7.31-7.33 (m, 2H), 7.40-7.42 (m, 2H).

[00394] Compounds 14F, 14G-1, 14H-1, 141-1, and 14-1 were synthesized by employing the procedures described for Compounds ID, IE, IF, 1G, and 3 using

Compounds 14E, 14F, (R)-l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, 14G-1, 14H-1, and 141-1 in lieu of Compounds 1C, ID, l-(tert-butoxycarbonyl)piperazine-2- carboxylic acid, IE, IF, and 3A. Compound 14F: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 14G-1: LC-MS (ESI) m/z: 429[M+H]⁺. Compound 14H-1: LC-MS (ESI) m/z: 329 [M+H]⁺. Compound 141-1: LC-MS (ESI) m/z:

763 [M+H]⁺. Compound 14-1: LC-MS (ESI) m/z: 332 [M/2+H]⁺; Ή-NMR (CD₃OD, 400 MHz): d (ppm) 0.94-1.32 (m, 12H), 1.63-1.82 (m, 8H), 2.07-2.86 (m, 7H), 3.43-3.86 (m, 6H), 4.11-4.22 (m, 1H), 4.75-4.78 (m, 1H), 6.95-6.97 (m, 2H), 7.15-7.16 (m, 2H), 7.30-7.32 (m, 2H), 7.60-7.62 (m, 2H).

[00395] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(4-(l-

(trifluoromethyl)cyclopropyl)benzyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (14-2)

[00396] Compounds 14G-2, 14H-2, 141-2, and 14-2 were synthesized by employing the procedures described for Compounds IE, IF, 1G, and 3 using (S)-l-(tert-butoxycarbonyl) piperazine-2-carboxylic acid, Compounds 14F, 14G-2, 14H-2, and 141-2 in lieu of l-(tert- butoxycarbonyl) piperazine-2-carboxylic acid, Compounds ID, IE, IF, and 3A. Compound 14G-2: LC-MS (ESI) m/z: 429 [M+H]⁺. Compound 14H-2: LC-MS (ESI) m/z: 329 [M+H]⁺. Compound 141-2: LC-MS (ESI) m/z: 763 [M+H]⁺. Compound 14-2: LC-MS (ESI) m/z: 663 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.10-1.62 (m, 11H), 1.73-2.09 (m, 8H), 2.65-3.16 (m, 4H), 3.33-3.63 (m, 4H), 3.87-4.61 (m, 7H), 5.41-5.43 (m, 1H), 7.02-7.21 (m, 2H), 7.42-7.62 (m, 4H), 7.81-7.90 (m, 2H).

[00397] Example 15

[00398] Synthesis of (R)-(4-aminopiperidin-l-yl)(l-((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)-4-(4-(l-(trifluoromethyl)cyclopropyl)benzyl)piperazin-2-yl)methanone (15-1)

[00399] Compounds 15A-1 and 15-1 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Al, 14H-1, and 15A-1 in lieu of Compounds A2, IF, and 3A. Compound 15A-1: LC-MS (ESI) m/z: 785 [M+H]⁺. Compound 15-1: LC-MS (ESI) m/z: 343 [M/2+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.00-1.32

(m, 7H), 1.63-2.29 (m, 13H), 2.45-2.88 (m, 5H), 3.60-3.93 (m, 3H), 3.94-4.13 (m, 2H), 4.99- 5.01 (m, 1H), 7.17-7.38 (m, 6H), 7.69-7.71 (m, 1H), 7.88-7.94 (m, 2H), 8.25-8.26 (brs, 1H).

[00400] (S)-(4-aminopiperidin-l-yl)(l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)- 4-(4-(l-(trifluoromethyl)cyclopropyl)benzyl)piperazin-2-yl)methanone (15-2)

[00401] Compounds 15A-2 and 15-2 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Al, 14B-2, and 15A-2 in lieu of Compounds A2, IF, and 3A. Compound 15A-2: LC-MS (ESI) m/z: 785 [M+H]⁺. Compound 15-2: LC-MS (ESI) m/z: 685 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 0.96-1.47 (m, 8H), 1.63-2.31 (m, 12H), 2.41-2.89 (m, 5H), 3.53-4.57 (m, 5H), 5.01-5.03 (m, 1H), 7.21-7.38 (m, 6H), 7.70-7.72 (m, 1H), 7.88-7.94 (m, 2H), 8.25-8.26 (m, 1H).

[00402] Example 16

[00403] Synthesis of ((S)-3-aminopyrrolidin-l-yl)((S)-l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(4-(l- (trifluoromethyl)cyclopropyl)benzyl)piperazin-2-yl)methanone (16)

[00404] Compounds 16A and 16 were synthesized by employing the procedures described for Compounds 1G and 3 using tert-butyl (S)-pyrrolidin-3-ylcarbamate,

Compounds 14B-2, and 16A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 3A. Compound 16A: LC-MS (ESI) m/z: 749 [M+H]⁺. Compound 16: LC-MS (ESI) m/z: 649 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.02-1.38 (m, 10H), 1.76-2.38 (m, 10H), 2.45-3.01 (m, 2H), 3.37-4.04 (m, 10H), 4.42-4.63 (m, 1H), 7.07-7.09 (m, 2H), 7.26- 7.28 (m, 2H), 7.40-7.42 (m, 2H), 7.75-7.77 (m, 2H).

[00405] Example 17

[00406] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((S)-l-((4-

(cyclohexylmethoxy) phenyl)sulfonyl)-4-(4-(l- (trifluoromethyl)cyclopropyl)benzyl)piperazin-2-yl)methanone (17)

[00407] Compounds 17A and 17 were synthesized by employing the procedures described for Compounds 1G and 3 using tert-butyl (8-azabicyclo[3.2. l]octan-3- yl)carbamate, Compounds 14B-2, and 17A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds IF, and 3A. Compound 17A: LC-MS (ESI) m/z: 789 [M+H]⁺. Compound 17: LC-MS (ESI) m/z: 689 [M+H]⁺; 1H-NMR (CD₃OD, 400 MHz): d (ppm) 0.91-1.32 (m, 8H), 1.36-1.96 (m, 15H), 2.15-2.24 (m, 2H), 2.67-2.94 (m, 2H), 3.10-3.17 (m, 2H), 3.59-3.76 (m, 2H), 3.86-4.00 (m, 4H), 4.35-4.36 (m, 1H), 4.74-4.75 (m, 1H), 7.04-7.06 (m, 2H), 7.23-7.25 (m, 2H), 7.38-7.40 (m, 2H), 7.73-7.75 (m, 2H).

[00408] Example 18

[00409] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)( 4-((4'-chloro-[l,l'- biphenyl]-4-yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2- yl)methanone (18), ((R)-4-amino-3,3-difluoropiperidin-l-yl)((R)-4-((4'-chloro-[l,r- biphenyl]-4-yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2- yl)methanone (18-1), and ((S)-4-amino-3,3-difluoropiperidin-l-yl)((R)-4-((4'-chloro-[l,r- biphenyl]-4-yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2- yl)methanone (18-2)

[00410] Compounds 18A and 18 were synthesized by employing the procedures described for Compounds 1G and 1 using Compounds B2, Al, and 18A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds A2, and 1G.

[00411] Compound 18A: LC-MS (ESI) m/z: 823 [M+H]⁺.

[00412] Compound 18 was separated with chiral HPLC to furnish Compound 18-1 and Compound 18-2. Compound 18-1: LC-MS (ESI) m/z: 723 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.28-3.29 (m, 17H), 3.49-4.64 (m, 5H), 4.99-5.03 (m, 2H), 5.61 (s, 1H), 6.92- 7.91 (m, 13H), 8.39 (s, 1H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50/50); S,S-WHELK-Ol (4.6 x 250 mm, 5 pm); retention time: 17.19 minute.

Compound 18-2: LC-MS (ESI) m/z: 723 [M+H]⁺; Ή-NMR (CD3OD, 400 MHz): d (ppm) 1.69-1.96 (m, 10H), 2.21-2.92 (m, 4H), 3.42-4.68 (m, 10H), 5.52-5.66 (m, 1H), 6.70-7.93 (m, 13H), 8.41 (s, 1H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50/50); S,S-WHELK-Ol (4.6 x 250 mm, 5 pm); retention time: 15.77 minute. [00413] Example 19

[00414] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)((S)-4-((4'-chloro-[l,r- biphenyl]-4-yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2- yl)methanone ( 19), ((R)-4-amino-3 ,3 -difluoropiperidin- 1 -yl)((S)-4-((4'-chloro-[ 1 , 1 '- biphenyl]-4-yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (19-1), and ((S)-4-amino-3,3-difluoropiperidin-l-yl)((S)- 4-((4'-chloro-[l,r-biphenyl]-4-yl)methyl)-l-((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (19-2)

[00415] Compounds 19A and 19 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds B2, Al, 1F-2, and 19A in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds A2, IF, and 3A.

[00416] Compound 19A: LC-MS ESI (m/z): 845 [M+Na]⁺.

[00417] Compound 19 was separated by chiral HPLC to give Compound 19-1 and Compound 19-2. Compound 19-1: LC-MS (ESI) m/z: 723 [M+H]⁺; ¾-NMR (CD₃OD, 400 MHz): d (ppm) 1.70-2.83 (m, 12H), 3.14-3.31 (m, 2H), 3.37-3.58 (m, 3H), 4.03-4.72 (m, 6H), 4.96-5.07 (m, 1H), 5.59-5.67 (m, 1H), 6.91-6.95 (m, 1H), 7.18-7.35 (m, 3H), 7.44-7.57 (m, 4H), 7.67-7.71 (m, 4H), 7.90 (d, J= 9.2 Hz, 1H), 8.41 (s, 1H). Chiral separation condition: n- Hexane/EtOH contained 0.1% DEA (50:50); S,S-Whelk-Ol (4.6 x 250 mm, 5 pm); retention time: 22.91 minute. Compound 19-2: LC-MS (ESI) m/z: 723 [M+H]⁺; ¾-NMR (CD3OD,

400 MHz): d (ppm) 1.69-2.99 (m, 12H), 3.14-3.31 (m, 2H), 3.40-3.67 (m, 3H), 3.93-4.72 (m, 6H), 4.96-5.05 (m, 1H), 5.52-5.67 (m, 1H), 6.97-7.00 (m, 1H), 7.20-7.37 (m, 3H), 7.51-7.56 (m, 4H), 7.67-7.75 (m, 4H), 7.91 (d, j= 9.2 Hz, 1H), 8.42 (s, 1H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50:50); S,S-Whelk-Ol (4.6 x 250 mm, 5 pm); retention time: 24.02 minute.

[00418] Example 20

[00419] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)-4-(4-(trifluoromethoxy)benzoyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (20)

[00420] Compounds 20B, 20C, 20D, and 20 were synthesized by employing the procedures described for Compounds 7C, IF, 1G, and 3 using (S)-l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid, Compounds 20A, 20B, 20C, Al, and 20D in lieu of l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds 7B, IE, IF, Compounds A2, and Compound 3A. Compound 20B: LC-MS (ESI) m/z: 441 [M+Na]⁺. Compound 20C was used directly in the next step without purification. LC-MS (ESI) m/z: 319 [M+H]⁺. Compound 20D: LC-MS (ESI) m/z: 775 [M+H]+. Compound 20: LC-MS: (ESI) m/z: 675 [M+H]⁺. ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.27-1.41 (m, 2H), 1.69- 2. l6(m, 12H), 2.44-3.23 (m, 1H), 3.31-3.32 (m, 2H), 3.38-4.77 (m, 5H), 5.02-5.27 (m, 3H), 7.22-7.48 (m, 6H), 7.65-7.75 (m, 1H), 7.87-7.92 (m, 2H), 8.22-8.32 (m, 1H). [00421] Example 21

[00422] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(4-(trifluoromethoxy)benzoyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (21)

[00423] Compounds 21A and 21 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds 20C and 21A in lieu of Compounds IF and 3A. Compound 21 A: LC-MS (ESI) m/z: 775 [M+Na]⁺. Compound 21: LC-MS: (ESI) m/z: 653[M+H]⁺. ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.03-1.45 (m, 6H), l.72-2.2l(m, 10H), 2.54-2.74 (m, 1H), 3.38-3.94 (m, 7H), 4.22-4.32 (m, 4H), 4.77-4.81 (m, 1H), 7.01-7.07 (m, 2H), 7.35-7.52 (m, 4H), 7.64-7.66 (m, 1H), 7.74-7.75 (m, 1H).

[00424] Example 22

[00425] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((S)-l-((6-

(cyclopentyloxy)naphthalen-2-yl)sulfonyl)-4-(4-(l- (trifluoromethyl)cyclopropyl)benzyl)piperazin-2-yl)methanone (22)

[00426] Compounds 22A and 22 were synthesized by employing the procedures described for Compounds 1G and 3 using Bl, Compound Al, 14B-2, and 22A in lieu of 1- (tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compound A2, IF, and 3A. Compound 22 A: LC-MS (ESI) m/z: 811 [M+H]⁺. Compound 22: LC-MS (ESI) m/z: 711 [M+H]⁺; ¾- NMR (CD3OD, 400 MHz): d (ppm) 0.96-1.37 (m, 6H), 1.47-2.23 (m, 16H), 2.67-3.11 (m, 4H), 3.71-4.27 (m, 5H), 4.73-4.74 (m, 1H), 4.99-5.03 (m, 1H), 7.20-7.37 (m, 6H), 7.74-7.76 (m, 1H), 7.90-7.95 (m, 2H), 8.31-8.32 (m, 1H).

[00427] Example 23

[00428] Synthesis of ((S)-3-aminopyrrolidin-l-yl)((S)-l-((6-

(cyclopentyloxy)naphthalen-2-yl)sulfonyl)-4-(4-(l- (trifluoromethyl)cyclopropyl)benzyl)piperazin-2-yl)methanone (23)

[00429] Compounds 23A and 23 were synthesized by employing the procedures described for Compounds 1G and 3 using tert-butyl (S)-pyrrolidin-3-ylcarbamate,

Compounds Al, 14B-2, and 23A in lieu of l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds A2, IF, and 3A. Compound 23A: LC-MS (ESI) m/z: 771 [M+H]⁺.

Compound 23: LC-MS (ESI) m/z: 671 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.82- 1.21 (m, 5H), 1.56-2.27 (m, 12H), 2.67-2.98 (m, 4H), 3.20-3.88 (m, 6H), 4.53-4.59 (m, 1H), 4.89-4.92 (m, 1H), 7.10-7.26 (m, 6H), 7.57-7.62 (m, 1H), 7.77-7.84 (m, 2H), 8.14-8.17 (m, 1H).

[00430] Example 24

[00431] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)-4-(4-(trifluoromethyl)benzoyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (24)

[00432] Compounds 24B, 24C, 24D, and 24 were synthesized by employing the procedures described for Compounds 7C, IF, 1G, and 3 using (S)-l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid, Compounds 24A using Et₃N as base, 24B, 24C, Al, and 23A in lieu of l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid,

Compounds 7B using DIPEA as base, IE, IF, A2, and 3A. Compound 24B: LC-MS (ESI) m/z: 401 [M-H] . Compound 24C: LC-MS (ESI) m/z: 303 [M+H]⁺. Compound 24D: LC-MS (ESI) m/z: 759 [M+H]⁺. Compound 24: LC-MS (ESI) m/z: 659 [M+H]⁺; 'H-NMR (CD₃OD, 400 MHz): d (ppm) 1.36-2.15 (m, 12H), 2.69-3.19 (m, 2H), 3.35-3.49 (m, 4H), 3.64-4.14 (m, 3H), 4.27-4.49 (m, 1H), 4.70-4.82 (m, 1H), 5.02-5.28 (m, 2H), 7.13-7.32 (m, 2H), 7.47-7.97 (m, 7H), 8.23-8.37 (m, 1H). [00433] Example 25

[00434] Synthesis of ((R)-3-aminopyrrolidin-l-yl)((S)-4-(4'-chloro-[l,r-biphenyl]-4- carbonyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (25)

[00435] Compounds 25A and 25 were synthesized by employing the procedures described for Compounds 1G and 3 using tert-butyl (R)-pyrrolidin-3-ylcarbamate,

Compounds 7D-1, and 25A in lieu of l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds IF, and 3A. Compound 25A: LC-MS (ESI) m/z: 765 [M+H]⁺. Compound 25: LC-MS (ESI) m/z: 665 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 1.03-2.61 (m, 13H),

3.14-3.20 (m, 1H), 3.34-4.15 (m, 12H), 4.51-4.90 (m, 1H), 7.05-7.07 (m, 2H), 7.47-7.49 (d, J = 8.4 Hz, 4H), 7.63-7.72 (m, 6H).

[00436] Example 26

[00437] Synthesis of (4-aminopiperidin-l-yl)((S)-4-((S)-l-(4'-chloro-[l,r-biphenyl]-4- yl)ethyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone (26-1) and (4- aminopiperidin- 1 -yl)((S)-4-((R)- 1 -(4'-chloro-[ 1 , 1 '-biphenyl]-4-yl)ethyl)- 1 -((4- (cyclohexylmethoxy)phenyl) sulfonyl)piperazin-2-yl)methanone (26-2)

[00438] To a solution of Compound IB (1.08 g, 5.0 mmol) in dry THF (30 mL) was added a solution of methylmagnesium bromide in THF (3 M, 2.0 mL, 6.0 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 2 hours, quenched with saturated aqueous MLCl solution (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 10% to 30% v/v) to yield Compound 26A: LC-MS (ESI) m/z: 215 [M-OH]⁺.

[00439] Compounds 26B, 26C-1, and 26C-2 were synthesized by employing the procedures described for Compounds ID and IE using Compounds 26A, 26B, and l-(tert- butyl) 2-methyl (S)-piperazine-l,2-dicarboxylate in lieu of Compounds 1C, ID, and l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid. Compound 26B: LC-MS (ESI) m/z: non- ionizable compound under routine conditions used. The mixture of 26C-1 and 26C2 were separated with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 40% v/v). Compound 26C-1: LC-MS (ESI) m/z: 459 [M+H]⁺; HPLC retention time: 1.66 minute (214 nm). Compound 26C-2: LC-MS (ESI) m/z: 459 [M+H]⁺; HPLC retention time: 1.65 minute (214 nm).

[00440] Compounds 26D-1, 26E-1, 26F-1, 26G-1, and 26-1 were synthesized by employing the procedures described for Compounds IF, 13D-1, 13E-1, 13F-1, and 3 using Compounds 26C-1, 26D-1, 26E-1, 26F-1, and 26G-1 in lieu of Compounds IE, 13C-1, 13D- 1, 13E-1, and 3A. Compound 26D-1: LC-MS (ESI) m/z: 359 [M+H]⁺. Compound 26E-1: LC-MS (ESI) m/z: 611 [M+H]⁺. Compound 26F-1: LC-MS (ESI) m/z: 597 [M+H]⁺.

Compound 26G-1: LC-MS (ESI) m/z: 779 [M+H]⁺. Compound 26-1: LC-MS (ESI) m/z: 679 [M +H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 0.93-1.06 (m, 3H), 1.12-1.28 (m, 9H), 1.60- 1.80 (m, 8H), 2.16-2.38 (m, 2H), 2.60-2.80 (m, 3H), 3.28-3.58 (m, 3H), 3.68-3.80 (m, 3H), 4.13 (brs, 1H), 4.65 (brs, 1H), 6.91 (d, J= 8.8 Hz, 2H), 7.22-7.36 (m, 4H), 7.40-7.62 (m, 6H).

[00441] Compounds 26D-2, 26E-2, 26F-2, 26G-2, and 26-2 were synthesized by employing the procedures described for Compounds IF, 13D-1, 13E-1, 13F-1, and 3 using Compounds 26C-2, 26D-2, 26E-2, 26F-2, and 26G-2 in lieu of Compounds IE, 13C-1, 13D- 1, 13E-1, and 3A. Compound 26D-2: LC-MS (ESI) m/z: 359 [M+H]⁺. Compound 26E-2: LC-MS (ESI) m/z: 611 [M+H]⁺. Compound 26F-2: LC-MS (ESI) m/z: 597 [M+H]⁺.

Compound 26G-2: LC-MS (ESI) m/z: 779 [M+H]⁺. Compound 26-2: LC-MS (ESI) m/z: 679 [M +H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.94-1.07 (m, 3H), 1.12-1.28 (m, 9H), 1.60- 1.80 (m, 8H), 2.16-2.38 (m, 2H), 2.60-2.80 (m, 3H), 2.96-3.05 (m, 1H), 3.28-3.58 (m, 2H), 3.68-3.80 (m, 3H), 4.13 (brs, 1H), 4.67 (brs, 1H), 6.91 (d, J= 8.8 Hz, 2H), 7.22-7.36 (m, 4H), 7.40-7.62 (m, 6H).

[00442] Example 27

[00443] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-(4'-chloro-[l,r-biphenyl]-4- carbonyl)- 1 -((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (27)

[00444] Compounds 27A and 27 were synthesized by employing the procedures described for Compounds 1G and 3 using Compounds Al, 7D-1, and 27A in lieu of

Compounds A2, IF, and 3A. Compound 27A: LC-MS (ESI) m/z: 801 [M+H]⁺. Compound 27: LC-MS (ESI) m/z: 701 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.07-2.20 (m, 11H), 2.44-2.53 (m, 1H), 2.68-3.24 (m, 1H), 3.31-3.59 (m, 3H), 3.65-4.53 (m, 6H), 4.65-4.83 (m, 1H), 5.01-5.29 (m, 2H), 7.22-7.24 (m, 1H), 7.31-7.37 (m, 2H), 7.42-7.44 (m, 3H), 7.62- 7/76 (m, 5H), 7.90-7.92 (m, 2H), 8.23-8.33 (m, 1H).

[00445] Example 28

[00446] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-(bis(4-

(trifluoromethyl)phenyl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (28)

[00447] To a solution of l-bromo-4-(trifluoromethyl)benzene (2.25 g, 10 mmol) in dry THF (10 mL) was dropped a solution of n-BuLi in THF (2.5 M, 4.8 mL, 12 mmol) at -78 °C. After the mixture was stirred at -78 °C for 30 minutes, to it was dropped Compound 28A (1.74 g, 10 mmol). The reaction mixture was stirred at -78 °C for 10 minutes, quenched with saturated ammonium chloride solution (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to afford Compound 28B: LC-MS (ESI) m/z: 303 [M-OH]⁺; Ή-NMR (CDCb, 400 MHz): d (ppm)5.82 (s, 1H), 7.43-7.54 (m, 8H).

[00448] Compounds 28C, 28D, 28E, 28F, 28G, 28H, and 28 were synthesized by employing the procedures described for Compounds ID, 13B-1, IF, 13D-1, 13E-1, 13F-1, and 3 using Compounds 28B, 28C, l-(tert-butyl) 2-methyl (S)-piperazine-l,2-dicarboxylate, 28D, 28E, 28F, 28G, and 28H in lieu of Compounds 1C, 13A, l-(tert-butyl) 2-methyl (R)- piperazine-l,2-dicarboxylate, IE, 13C-1, 13D-1, 13E-1, and 3A. Compound 28C was used directly in the next step without further purification. LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 28D: LC-MS (ESI) m/z: 547[M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 1.46-1.49 (m, 9H), 1.98-2.36 (m, 5H), 3.35-3.38 (m, 5H), 4.85-4.87 (s, 1H), 7.42-7.62 (m, 8H). Compound 28E: LC-MS (ESI) m/z: 447 [M+H]⁺. Compound 28F: LC-MS (ESI) m/z: 699 [M+H]⁺. Compound 28G: LC-MS (ESI) m/z: 685 [M+H]⁺. Compound 28H was used directly in the next step without further purification. LC- MS (ESI) m/z: 867 [M+H]⁺. Compound 28: LC-MS (ESI) m/z: 767 [M+H]⁺; 'H-NMR

(CD3OD, 400 MHz): d (ppm) 1.16-1.63 (m, 8H), 1.64-2.13 (m, 9H), 2.35-2.39 (m, 1H), 2.61- 2.79 (m, 3H), 2.90-2.96 (m, 1H), 3.47-3.49 (m, 1H), 3.48-3.95 (m, 4H), 4.54-4.63 (m, 2H), 4.93-4.96 (m, 1H), 7.04-7.06 (m, 2H), 7.52-7.63 (m, 8H), 7.70-7.74 (m, 2H).

[00449] Example 29

[00450] Synthesis of (4-aminopiperidin-l-yl)((2S)-l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(phenyl(4-(trifluoromethyl)phenyl)methyl)piperazin- 2-yl)methanone 2,2,2-trifluoroacetate (29)

[00451] Compounds 29A, 29B, 29C, 29D, 29E, 29F, 29G, and 29 were synthesized by employing the procedures described for Compounds 26A, ID, IE, IF, 13D-1, 13E-1, 13F-1, and 3 using phenylmagnesium bromide, Compounds 28A, 29A, 29B, 29C, l-(tert-butyl) 2- methyl (S)-piperazine-l,2-dicarboxylate, 29D, 29E, 29F, and 29G in lieu of

methylmagnesium bromide, Compounds IB, 1C, ID, l-(tert-butoxycarbonyl)piperazine-2- carboxylic acid, IE, 13C-1, 13D-1, 13E-1, and 3A. Compound 29A: LC-MS (ESI) m/z: 235 [M-OH]⁺. Compound 29B: 1H-NMR (CDCh, 400 MHz): d (ppm) 6.14 (s, 1H), 7.31-7.40 (m, 5H), 7.53 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H). Compound 29C: LC-MS (ESI) m/z: 479 [M+H]⁺. Compound 29D: LC-MS (ESI) m/z: 379 [M +H]⁺. Compound 29E: LC-MS (ESI) m/z: 631 [M+H]⁺. Compound 29F: LC-MS (ESI) m/z: 617 [M +H]⁺. Compound 29G: LC-MS (ESI) m/z: 799 [M+H]⁺. Compound 29: LC-MS (ESI) m/z: 699 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 1.09-1.56 (m, 7H), 1.73-2.08 (m, 9H), 2.34-2.39 (m, 1H), 2.68- 2.80 (m, 3H), 2.98-3.12 (m, 2H), 3.49 (s, 1H), 3.88-3.89 (m, 4H), 4.48-4.62 (m, 2H), 4.98 (s, 1H), 7.03-7.06 (m, 2H), 7.22-7.38 (m, 5H), 7.53-7.61 (m, 4H), 7.71-7.74 (m, 2H).

[00452] Example 30

[00453] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)-4-(4-(trifluoromethyl)phenethyl)piperazin-2-yl)methanone (30)

[00454] To a solution of Compound 30A (5.00 g, 24.51 mmol) in THF (80 mL) at 0 °C was added L1AIH4 (1.21 g, 31.86 mmol) in several small portions and stirred at 25 °C for 3 hours. The reaction mixture was cooled down to 0 °C and quenched with water (1.2 mL),

15% aqueous NaOH solution (1.2 mL), and water (3.6 mL). The resulting mixture was stirred at 25 °C for 30 minutes and filtered through Celite. The filtrate was concentrated and the residue was purified with flash column chromatography on silica gel (methanol in

dichloromethane, from 0% to 6% v/v) to yield Compound 30B: LC-MS (ESI) m/z: 173 [M- OH]⁺; 1H-NMR (CDCh, 400 MHz): d (ppm) 1.42 (t, J= 5.6 Hz, 1H), 2.93 (t, J= 6.4 Hz, 2H), 3.87-3.92 (m, 2H), 7.36 (d, J= 8.0 Hz, 2H), 7.57 (d, J= 8.0 Hz, 2H).

[00455] To a solution of Compound 30B (1.30 g, 6.84 mmol) in Et₂0 (30 mL) was dropped PBn (1.85 g, 6.84 mmol) at 0 °C. The mixture was stirred at 15 °C for 3 hours, quenched with ice water (30 mL), and diluted with ethyl acetate (160 mL). The organic layer was washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 3% v/v) to give Compound 30C: ¹H-NMR (CDCb, 400 MHz): d (ppm) 3.23 (t, J= 7.2 Hz, 2H), 3.59 (t, J = 7.2 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H), 7.58 (d, J= 8.0 Hz, 2H).

[00456] A mixture of Compound 30C (300 mg, 1.19 mmol), l-(tert-butyl) 2-methyl (S)-piperazine-l,2-dicarboxylate (348 mg, 2.38 mmol), and NaHCCb (200 mg, 2.38 mmol) in NMP (3 mL) was stirred at 80 °C for 48 hours. The mixture was purified with Combi-flash using eluent (methanol in water (containing ammonia 0.05%), from 0% to 100% v/v) to yield Compound 30D: LC-MS (ESI) m/z: 417 [M+H]⁺; ¾-NMR (CDCb, 400 MHz): d (ppm)

1.44, 1.48 (s, 9H), 2.07-2.31 (m, 2H), 2.55-2.85 (m, 5H), 3.09-3.26 (m, 1H), 3.38-3.46 (m, 1H), 3.68,3.70 (s, 3H), 3.76-3.88 (m, 1H), 4.58, 4.75 (s, 1H), 7.29 (d, J= 8.4 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H).

[00457] Compounds 30E and 30F were synthesized by employing the procedures described for Compounds IF and 13D-1 using Compounds 30D, 30E, and A1 in lieu of Compounds IE, 13C-1, and A2. Compound 30E: LC-MS (ESI) m/z: 317 [M+H]⁺.

Compound 30F: LC-MS (ESI) m/z: 591 [M+H]⁺; 1H-NMR (CDCb, 400 MHz): d (ppm) 1.62-1.83 (m, 2H), 1.96-2.22 (m, 6H), 2.15-2.22 (m, 1H), 2.32-2.37 (m, 1H), 2.50-2.63 (m, 2H), 2.72-2.78 (m, 3H), 3.35-3.46 (m, 5H), 3.70-3.74 (m, 1H), 4.71 (s, 1H), 4.89-4.94 (m, 1H), 7.14 (s, 1H), 7.18-7.24 (m, 3H), 7.47 (d, J= 8.4 Hz, 2H), 7.67-7.70 (m, 1H), 7.77-7.82 (m, 2H), 8.25 (s, 1H).

[00458] A mixture of Compound 30F (260 mg, 0.44 mmol) and LiOH H₂0 (55 mg, 1.32 mmol) in THF (5 mL) and water (1 mL) was stirred at 25 °C for 3 hours. The mixture was evaporated and the residue was purified with reverse phase chromatography using eluents (methanol in water, from 0% to 100% v/v containing ammonia 0.05%) to yield Compound 30G: LC-MS (ESI) m/z: 577 [M+H]⁺; 1H-NMR (CDCb, 400 MHz): d (ppm) 1.81-2.04 (m, 8H), 2.46-2.61 (m, 3H), 2.72-2.76 (m, 2H), 3.49-3.74 (m, 3H), 3.97-4.05 (m, 1H), 4.18-4.31 (m, 1H), 4.72 (s, 1H), 4.90-4.94 (m, 1H), 7.14 (s, 1H), 7.19-7.25 (m, 3H), 7.47 (d, J= 8.0 Hz, 2H), 7.69-7.71 (m, 1H), 7.77-7.81 (m, 2H), 8.25 (s, 1H).

[00459] Compounds 30H and 30 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compounds 30G and 30H in lieu of

Compounds 13E-1 and 1G. Compound 30H: LC-MS (ESI) m/z: 759 [M+H]⁺. Compound 30: LC-MS (ESI) m/z: 659 [M+H]⁺; ¹H-NMR (DMSO-i/e, 400 MHz): d (ppm) 0.88-1.23 (m, 2H), 1.56-2.04 (m, 12H), 2.21-2.46 (m, 4H), 2.68-2.79 (m, 4H), 2.95-2.99 (m, 1H), 3.49-3.52 (m, 1H), 3.77-3.90 (m, 3H), 4.90 (s, 1H), 4.99-5.02 (m, 1H), 7.22-7.26 (m, 1H), 7.35-7.41 (m, 3H), 7.54 (d, J= 8.0 Hz, 2H), 7.67 (d, J= 8.8 Hz, 1H), 7.93 (d, J= 8.8 Hz, 1H), 8.02 (d, J= 8.8 Hz, 1H), 8.27 (s, 1H).

[00460] Example 31

[00461] Synthesis of (4-aminopiperidin-l-yl)((2S)-l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(5-(trifluoromethyl)-2,3-dihydro-lH-inden-l- yl)piperazin-2-yl)methanone (31), (4-aminopiperidin-l-yl)((S)-l-((4- (cyclohexylmethoxy)phenyl)sulfonyl)-4-((S)-5-(trifluoromethyl)-2,3-dihydro-lH-inden-l- yl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (31-1), and (4-aminopiperidin-l-yl)((S)-l- ((4-(cyclohexylmethoxy)phenyl)sulfonyl)-4-((R)-5-(trifluoromethyl)-2,3-dihydro-lH-inden- l-yl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (31-2)

[00462] To a solution of Compound 31A (4.5 g, 30.6 mmol) in aqueous hydrochloric acid solution (4 N, 35 mL) was dropped a solution of sodium nitrite (2.5 g, 36.7 mmol) in water (12 mL), wherein the internal temperature of the reaction mixture was below 5 °C. The resulting mixture was stirred at 0 °C for 5 minutes and then a solution of potassium iodide (6.1 g, 36.7 mmol) in water (25 mL) was dropped at 5 °C. The mixture was heated at 60 °C for 20 minutes. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with a saturated sodium thiosulphate solution (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to give Compound 31B: LC-MS (ESI) m/z: 259 [M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 2.65-2.68 (m, 2H), 3.11 (t, 7= 6.0 Hz, 2H), 7.46 (d, J= 8.0 Hz, 1H), 7.72 (d, J= 8.0 Hz, 1H), 7.91 (s, 1H).

[00463] To a mixture of Compound 31B (3.84 g, 14.9 mmol), copper(I) iodide (7.08 g, 37.2 mmol), and hexamethylphosphoramide (5.33 g, 29.8 mmol) in DMF (60 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (11.4 g, 59.6 mmol). The mixture was stirred at 85 °C under nitrogen for 16 hours. The mixture was cooled down to room temperature and filtered through Celite. The filtrate was diluted with ethyl acetate (200 mL), washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and evaporated to give a crude product, which was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to afford Compound 31C: LC-MS (ESI) m/z: 201 [M+H]⁺; 1H-NMR (CDCb, 400 MHz): d (ppm) 2.77-2.80 (m, 2H), 3.22 (t, J= 6.0 Hz, 2H), 7.63 (d, J= 8.0 Hz, 1H), 7.77 (s, 1H), 7.86 (d, J= 8.0 Hz, 1H).

[00464] Compounds 31D, 31E, 31F, 31G, 31H, 311, 31J, and 31 were synthesized by employing the procedures described for Compounds 1C, ID, IE, IF, 13D-1, 30G, 13F-1, and 3 using Compounds 31C, 31D, 31E, l-(tert-butyl) 2-methyl (S)-piperazine-l,2- di carboxyl ate, 31F, 31G, 31H, 311, and 31 J in lieu of Compounds IB, 1C, ID, l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid, IE, 13C-1, 30F, 13E-1, and 3A. Compound 31D: LC-MS (ESI) m/z: 185 [M-OH]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 1.94-2.01 (m, 1H), 2.52-2.60 (m, 1H), 2.83-2.91 (m, 1H), 3.06-3.13 (m, 1H), 5.26 (t, J= 6.4 Hz, 1H), 7.51 (s, 3H). Compound 31E was used directly in next step without further purification. LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used. Compound 31F: LC-MS (ESI) m/z: 429 [M+H]⁺. Compound 31G: LC-MS (ESI) m/z: 329 [M+H]⁺. Compound 31H: LC-MS (ESI) m/z: 581 [M+H]⁺. Compound 311: LC-MS (ESI) m/z: 567 [M+H]⁺. Compound 31 J: LC-MS (ESI) m/z: 749 [M+H]⁺. Compound 31 was separated with chiral HPLC to give Compound 31-1 and Compound 31-2. Compound 31-1: LC-MS (ESI) m/z: 649 [M+H]⁺; ¾- NMR (CD₃OD, 400 MHz): d (ppm) 1.11-1.61 (m, 7H), 1.74-2.42 (m, 11H), 2.65-3.16 (m, 7H), 3.41-3.63 (m, 2H), 3.94 (d, J= 6.0 Hz, 2H), 4.01-4.66 (m, 3H), 4.99-5.00 (m, 1H), 5.37- 5.43 (m, 1H), 7.21 (d, J= 8.4 Hz, 2H), 7.62-7.86 (m, 3H), 7.93-7.96 (m, 2H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (90/10); AS-H (4.6 x 250 mm, 5 mhi); retention time: 11.56 minute. Compound 31-2: LC-MS (ESI) m/z: 649 [M+H]⁺; ¾- NMR (CD3OD, 400 MHz): d (ppm) 1.14-1.54 (m, 6H), 1.65-2.11 (m, 12H), 2.64-3.24 (m, 8H), 3.32-3.45 (m, 1H), 3.93-4.20 (m, 3H), 4.53-4.88 (m, 3H), 5.35 (s, 1H), 7.03 (d, J= 8.8 Hz, 2H), 7.12-7.23 (m, 1H), 7.46-7.48 (m, 1H), 7.7l(s, 1H), 7.78-7.80 (m, 2H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (90/10); AS-H (4.6 x 250 mm, 5 pm); retention time: 21.21 minute.

[00465] Example 32

[00466] Synthesis of (4-aminopiperidin-l-yl)((S)-l-((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)-4-((S)-5-(trifluoromethyl)-2,3-dihydro-lH-inden-l-yl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (32-1) and (4-aminopiperidin-l-yl)((S)-l-((6-

(cyclopentyloxy)naphthalen-2-yl)sulfonyl)-4-((R)-5-(trifluoromethyl)-2,3-dihydro-lH-inden- l-yl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (32-2)

[00467] Compounds 32A, 32B, and 32C were synthesized by employing the procedures described for Compounds 13D-1, 30G, and 13F-1 using Compounds Al, 31G, 32A, and 32B in lieu of Compounds A2, 13C-1, 30F, and 13E-1. Compound 32A: LC-MS (ESI) m/z: 603 [M+H]⁺. Compound 32B: LC-MS (ESI) m/z: 589 [M+H]⁺. Compound 32C was purified by preparative TLC (ethyl acetate in petroleum ether, 33% v/v) to give

Compound 32C-1 and Compound 32C-2. Compound 32C-1: LC-MS (ESI) m/z: 771

[M+H]⁺. Compound 32C-2: LC-MS (ESI) m/z: 771 [M+H]⁺.

[00468] Compound 32-1 was synthesized by employing the procedure described for Compound 3 using Compound 32C-1 in lieu of Compound 3A: LC-MS (ESI) m/z: 671 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.45-2.12 (m, 14H), 2.50-3.22 (m, 8H), 3.38-3.66 (m, 2H), 4.13-4.66 (m, 3H), 4.84-4.87 (m, 1H), 5.04-5.09 (m, 1H), 5.45-5.50 (m, 1H), 7.34 (dd, J= 8.4, 2.0 Hz, 1H), 7.43 (s, 1H), 7.54-7.78 (m, 3H), 7.89-7.94 (m, 1H) 8.02- 8.10 (m, 2H), 8.56 (s, 1H). Chiral separation condition: MeOH contained 0.2% Methanol Ammonia; S,S-Whelk-Ol (4.6 x 100 mm, 5 pm); retention time: 3.6 minute.

[00469] Compound 32-2 was synthesized by employing the procedure described for Compound 3 using Compound 32C-2 in lieu of Compound 3A: LC-MS (ESI) m/z: 671 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.52-2.13 (m, 14H), 2.59-3.25 (m, 8H), 3.43-3.70 (m, 2H), 4.34-4.77 (m, 4H), 5.07-5.11 (m, 1H), 5.45 (s, 1H), 6.68-6.76 (m, 2H), 7.32 (d, j= 9.2 Hz, 1H), 7.41 (s, 1H), 7.59 (s, 1H), 7.77 (d, j= 8.4 Hz, 1H), 7.87 (t, j= 10.0 Hz, 2H), 8.40 (s, 1H). Chiral separation condition: MeOH contained 0.2% Methanol Ammonia; S,S-Whelk-Ol (4.6 x 100 mm, 5 pm); retention time: 4.16 minute.

[00470] Example 33

[00471] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-((4'-(trifluoromethyl)-[l,r-biphenyl]-4- yl)methyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (33)

[00472] A mixture of Compound 33A (450 mg, 2.0 mmol), 4- (hydroxymethyl)phenylboronic acid (334 mg, 2.2 mmol), CS2CO3 (1.30 g, 4.0 mmol), and Pd(PPh₃)Cl2 (140 mg, 0.2 mmol) in DMF/THF (10 mL, 1 : 1 in volume) was heated at 90 °C under nitrogen for 1 hour. The mixture was cooled down to room temperature, diluted with diethyl ether (50 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified with column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 33B: LC-MS (ESI) m/z: 235 [M-OH]⁺.

[00473] Compounds 33C, 33D, and 33 were synthesized by employing the procedures described for Compounds ID, IE, and 3 using Compounds 33B, 33C, B3, and 33D in lieu of Compounds 1C, ID, l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, and 3A.

Compound 33C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 33D: LC-MS (ESI) m/z: 799 [M+H] ⁺. Compound 33: LC-MS (ESI) m/z: 699 [M+H]⁺. ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.84-1.18 (m, 5H), 1.32-2.04 (m, 10H), 2.40-3.14 (m, 4H), 3.26-3.70 (m, 6H), 3.80-4.60 (m, 5H), 5.33-5.41 (m, 1H), 6.86-6.98 (m, 2H), 7.36-7.49 (m, 2H), 7.63-7.81 (m, 8H).

[00474] Example 34

[00475] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-((2-(4-chlorophenyl)thiazol-5- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (34)

[00476] A mixture of 4-chlorobenzothioamide, 34A, (1.55 g, 10.0 mmol) and 2- bromomalonaldehyde (1.5 g, 5.0 mmol) in ethanol (75 mL) was stirred at 70 °C for 16 hours. The mixture was concentrated under the reduced pressure and the residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to afford Compound 34B: LC-MS (ESI) m/z: 223[M+H]⁺; ¾-NMR (DMSO-r^, 400 MHz): d (ppm) 7.64 (d, J=8.4 Hz, 2H), 8.09 (d, =8.4 Hz, 2H), 7.79 (s, 1H), 10.09 (s, 1H).

[00477] To a mixture of Compound B3 (112.8 mg, 0.2 mmol) and Compound 34B (53.5 mg, 0.24 mmol) in l,2-dichloroethane (20 mL) was added sodium triacetoxy

borohydride (127.2 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated under the reduced pressure. The residue was purified with preparative HPLC to afford Compound 34C: LC-MS (ESI) m/z: 772 [M+H] ⁺.

[00478] Compound 34 was synthesized by employing the procedure described for Compound 1 using Compound 34C in lieu of Compound 1G: LC-MS (ESI) m/z: 672

[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.01-1.07 (m, 2H), 1.22-1.35 (m, 3H), 1.61- 1.83 (m, 8H), 2.06-2.08 (m, 2H), 2.50-2.80 (m, 3H), 2.24-2.32 (m, 2H), 3.36-4.18 (m, 6H), 4.37-4.59 (m, 4H), 5.42 (s, 1H), 7.04 (d, =4.0 Hz, 2H), 7.55 (d, =8.8 Hz, 2H), 7.81-7.85 (m, 3H), 7.96 (d, =8.4 Hz, 2H). [00479] Example 35

[00480] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-((5-(4-chlorophenyl)-l,3,4- thiadiazol-2-yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (35)

35D 35

[00481] To a mixture of 4-chlorobenzohydrazide, 35A, (1 g, 5.86 mmol) and K2CO3 (0.97 g, 7.03 mmol) in acetonitrile (30 mL) was dropped 2-chloroacetyl chloride (0.68 g, 6.08 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting solid was collected by filtration, washed with H2O and ether, and dried in vacuum to afford a crude Compound 35B, which was used directly in the next step without further purification. LC-MS (ESI) m/z: 247 [M+H]⁺.

[00482] The mixture of Compound 35B (300 mg, 1.2 mmol), Lawesson reagent (490 mg, 1.2 mmol) and toluene (10 mL) under N2 atmosphere was heated to reflux for 2 hours. The mixture was diluted with water (10 mL) and extracted with EtOAc (30 mL x 3). The combined extracts was dried over Na2S0₄, filtered, and concentrated to give a crude product, which was purified by flash chromatography (silica gel (12 g), ethyl acetate in petroleum ether = 1/5, UV=254 nm) to afford Compound 35C: LC-MS (ESI) m/z: 245 [M+H]⁺.

[00483] Compounds 35D and 35 were synthesized by employing the procedures described for Compounds IE and 3 using Compounds 35C, B3, and 35D in lieu of

Compounds ID, l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, and 3A. Compound 35D: LC-MS (ESI) m/z: 773 [M+H]⁺. Compound 35: LC-MS (ESI) m/z: 673 [M+H]⁺. ¾-

NMR (CD3OD, 400 MHz): ό (ppm) 1.05-1.42 (m, 5H), 1.49-1.64 (m, 2H), 1.65-1.80 (m, 6H), 2.00-2.10 (m, 2H), 2.36-2.85 (m, 3H), 2.95-3.14 (m, 3H), 3.27-3.37 (m, 1H), 3.58-3.60 (m, 1H), 3.84-3.90 (m, 3H), 4.08-4.23 (m, 3H), 4.50-4.53 (m, 1H), 5.05-5.10 (m, 1H), 7.05 (d, J = 9.2 Hz, 2H), 7.56 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 8.8 Hz, 2H), 7.95 (d, J= 8.4 Hz, 2H).

[00484] Example 36

[00485] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-((4'-(trifluoromethoxy)-[l,r-biphenyl]-4- yl)methyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (36)

36D 36

[00486] Compounds 36B, 36C, 36D, and 36 were synthesized by employing the procedures described for Compounds 14B, ID, IE, and 3 using (4-

(hydroxymethyl)phenyl)boronic acid, Compounds 36A, 36B, 36C, B3, and 36D in lieu of 2- bromo-3,3,3-trifluoroprop-l-ene, Compounds 14A, 1C, ID, l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid, and 3A. Compound 36B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. ¾-NMK (400 MHz, CDCb): S (ppm) 1.74 (t, J= 4.8 Hz, 1H), 4.76 (d, J= 4.0 Hz, 2H), 7.28-7.30 (m, 2H), 7.45 (d, J= 8.0 Hz, 2H), 7.55-7.61 (m, 4H). Compound 36C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 36D: LC-MS (ESI) m/z: 815 [M+H]⁺. Compound 36: LC-MS (ESI) m/z: 715 [M+H]⁺. ¹H-NMR (400 MHz, CDCb): d (ppm) 0.82-0.94(m, 3H),

1.09-1.26 (m, 3H), 1.51-1.77 (m, 8H), 2.03-2.21 (m, 2H), 2.46-2.76 (m, 2H), 2.97-3.19 (m, 1H), 3.36-3.47 (m, 2H), 3.57-3.88 (m, 4H), 4.05-4.52 (m, 4H), 5.11-5.32 (m, 2H), 6.78-6.82 (m, 2H), 7.24-7.33 (m, 4H), 7.48-7.64 (m, 6H), 8.26-8.41 (m, 3H).

[00487] Example 37

[00488] Synthesis of (S)-(4-aminopiperi din- l-yl)(4-((6-(4-chlorophenyl)pyri din-3 - yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (37)

[00489] Compounds 37B, 37C, and 37 were synthesized by employing the procedures described for Compounds 14B, 34C, and 1 using (4-chlorophenyl)boronic acid, Compounds 37A, 37B, and 37C in lieu of Compounds 14A, 2-bromo-3,3,3-trifluoroprop-l-ene, 34B, and 1G. Compound 37B: LC-MS (ESI) m/z: 218 [M+H]⁺. Compound 37C: LC-MS (ESI) m/z: 766 [M+H]⁺. Compound 37: LC-MS (ESI) m/z: 666 [M+H]⁺; 'H-NMR (CD₃OD, 400 MHz): d (ppm) 1.01-1.79 (m, 14H), 2.04-2.10 (m, 2H), 2.50-3.17 (m, 4H), 3.37-3.76 (m, 5H), 4.01- 4.64 (m, 5H), 5.41 (s, 1H), 7.02 (d, J= 8.4 Hz, 2H), 7.54 (d, J= 8.4 Hz, 2H), 7.81 (d, J= 8.4 Hz, 2H), 7.90-7.96 (m, 2H), 8.05 (d, J= 8.4 Hz, 2H), 8.63-8.69 (m, 1H). Five active hydrogens were not shown.

[00490] Example 38

[00491] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-((5-(4-chlorophenyl)pyridin-2- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (38)

[00492] Compounds 38B, 38C, and 38 were synthesized by employing the procedures described for Compounds 14B, 34C, and 1 using (4-chlorophenyl)boronic acid, Compounds 38A, 38B, and 38C in lieu of Compounds 14A,2-bromo-3,3,3-trifluoroprop-l-ene, 34B, and 1G. Compound 38B: LC-MS (ESI) m/z: 218. ¾-NMR (CDCh, 400 MHz): d (ppm) 7.50- 7.60 (m, 4H), 8.04-8.05 (m, 2H), 8.99 (s, 1H), 10.13 (s, 1H). Compound 38C: LC-MS (ESI) m/z: 766 [M+H]⁺. Compound 38: LC-MS (ESI) m/z: 666 [M+H]⁺; 'H-NMR (CDCh, 400 MHz): d (ppm) 0.96-1.30 (m, 5H), 1.96-1.81 (m, 3H), 2.00-3.44 (m, 8H), 3.65-3.72 (m, 4H), 4.19-4.49 (m, 10H), 5.06-5.21 (m, 1H), 6.90-6.92 (m, 2H), 7.44-7.69 (m, 7H), 7.95-7.97 (m, 1H), 8.44 (brs, 3H), 8.74 (s, 1H).

[00493] Example 39

[00494] Synthesis of (4-aminopiperidin- l-yl)(l -((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(cyclopentyl(4-

(trifluoromethyl)phenyl)methyl)piperazin-2-yl)methanone (39) (4-aminopiperidin- l-yl)((R)- l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)-4-((R)-cyclopentyl(4- (trifluoromethyl)phenyl)methyl)piperazin-2-yl)methanone (39-1), (4-aminopiperidin- 1 - yl)((R)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)-4-((S)-cyclopentyl(4- (trifluoromethyl)phenyl)methyl)piperazin-2-yl)methanone(39-2), (4-aminopiperidin- 1- yl)((S)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)-4-((S)-cyclopentyl(4- (trifluoromethyl)phenyl)methyl)piperazin-2-yl)methanone(39-3), and (4-aminopiperidin-l- yl)((S)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)-4-((R)-cyclopentyl(4- (trifluoromethyl)phenyl)methyl)piperazin-2-yl)methanone (39-4)

[00495] The mixture of l-(tert-butyl) 2-methyl (S)-piperazine-l,2-dicarboxylate (2.4 g, 10 mmol), 4-(trifluoromethyl)benzaldehyde, 28A, (1.7 g,l0 mmol), and 1 H- benzo[d][l,2,3]triazole, 39A, (1.2 g, 10 mmol) in toluene (100 mL) was heated at 110 °C for 16 hours, with azeotropic removal of water. The mixture was concentrated to give a crude Compound 39B: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used.

[00496] To a solution of Compound 39B (1.5 g, 2.9 mmol) in THF (10 mL) was added a solution of cyclopentylmagnesium bromide in THF (1.0 M, 14.5 mL, 14.5 mmol) at 0 °C under nitrogen. The mixture was stirred at 0 °C for 2 hours, quenched with water (0.5 mL), and concentrated to give a crude product, which was purified with flash column

chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 10% v/v) to furnish Compound 39C: LC-MS (ESI) m/z: 471 [M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 0.85-0.89 (m, 5H), 1.42-1.47 (m, 9H), 1.47-1.50 (m, 4H), 1.70-2.20 (m, 3H), 3.21-3.27 (m, 3H), 3.67-3.76 (m, 4H), 4.50-4.67 (m, 1H), 7.21-7.24 (m, 2H), 7.56-7.58 (m, 2H). [00497] Compounds 39D, 39E, 39F, 39G, and 39 were synthesized by employing the procedures described for Compounds IF, 13D-1, 30G, 13F-1, and 1 using Compounds 39C, 39D, 39E, 39F, and 39G in lieu of Compounds IE, 13C-1, 30F, 13E-1, and 1G. Compound 39D: LC-MS (ESI) m/z: 371 [M+H]⁺. Compound 39E: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; ¾-NMK (CDCb, 400 MHz): d (ppm) 0.85-1.55 (m, 12H), 1.70-2.80 (m, 11H), 3.16-3.59 (m, 7H), 3.77-3.78 (m, 2H), 4.59 (s, 1H), 6.87-6.90 (m, 2H), 7.16-7.20 (m, 2H), 7.55-7.65 (m, 4H). Compound 39F: LC-MS (ESI) m/z: 609 [M+H]⁺. Compound 39G: LC-MS (ESI) m/z: 791 [M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 0.85-1.45 (m, 25H), 1.56-2.0 (m, 9H), 2. l-3.4(m, 7H), 3.60-3.80 (m, 5H), 4.10-4.59 (m, 3H), 6.87-6.90 (m, 2H), 7.18-7.20 (m, 2H), 7.54-7.64 (m, 4H). Compound 39 was separated with chiral HPLC to furnish Compound 39-1, Compound 39-2, Compound 39-3, and Compound 39-4. Compound 39-1: LC-MS (ESI) m/z: 691 [M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 0.85-1.45 (m, 16H), 1.56-2.10 (m, 10H), 2.40-3.40 (m, 7H), 3.76-4.40 (m, 5H), 4.60 (s, 1H), 6.87-6.90 (m, 2H), 7.18-7.20 (m, 2H), 7.54-7.64 (m, 4H). Chiral separation condition: MeOH contained 0.2% methanol ammonia; (//,//)-Whelk-01 (4.6 x 250 mm, 5 pm); retention time: 7.61 minute. Compound 39-2: LC-MS (ESI) m/z: 691 [M+H]⁺; 1H-NMR (CDCb, 400 MHz): d (ppm) 0.85-1.45 (m, 17H), 1.56-1.90 (m, 8H), 2.20-3.45(m, 10H), 3.60-4.35 (m, 5H), 4.621-4.65 (m, 1H), 6.87-6.89 (m, 2H), 7.19-7.21 (m, 2H), 7.54- 7.64 (m, 4H), Chiral separation condition: MeOH contained 0.2% methanol ammonia; (R,R)~ Whelk-Ol (4.6 x 250 mm, 5 pm); retention time: 6.6 minute. Compound 39-3: LC-MS (ESI) m/z: 691 [M+H]⁺; 1H-NMR (CDCb, 400 MHz): d (ppm) 0.85-1.45 (m, 14H), 1.56-2.10 (m, 11H), 2.20-3.40(m, 10H), 3.76-4.65(m, 6H), 6.87-7.20 (m, 4H), 7.50-7.66 (m, 4H), Chiral separation condition: MeOH contained 0.2% methanol ammonia; (i?,i?)-Whelk-Ol (4.6 x 250 mm, 5 pm); retention time: 5.58 minute. Compound 39-4: LC-MS (ESI) m/z: 691 [M+H]⁺; 1H-NMR (CDCb, 400 MHz): d (ppm) 0.85-1.45 (m, 13H), 1.56-1.90 (m, 11H), 2.20-3.45(m, 11H), 3.60-4.60 (m, 6H), 6.90-7.21 (m, 4H), 7.51-7.65 (m, 4H), Chiral separation condition: MeOH contained 0.2% methanol ammonia; (//,//)-Whelk-01 (4.6 x 250 mm, 5 pm); retention time: 5.75 minute.

[00498] Example 40

[00499] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-((4'-fluoro-[l,r-biphenyl]-4-yl)methyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (40)

[00500] A mixture of (4-bromophenyl)methanol 40A (4.0 g, 21.5 mmol), 4- fluorophenylboronic acid (3.0 g, 21.5 mmol), Pd(dppf)Ch (1.57 g, 2.15 mmol), and K2CO3 (8.9 g, 64.5 mmol) in l,4-dioxane (160 mL) and H2O (40 mL) was heated at 90 °C under nitrogen overnight. The reaction mikxture was cooled down to room temperature and was concentrated under the reduced pressure. The residue was diluted with ethyl acetate (50 mL x 3), washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to furnish

Compound 40B: LC-MS (ESI) m/z: 185 [M-OH]⁺; ¾-NMR (CDCh, 400 MHz): d (ppm)

1.71 (t, J= 5.6 Hz, 1H), 4.76 (d, J= 5.6 Hz, 2H), 7.14 (t, J= 8.4 Hz, 2H), 7.45 (d, J= 8.0 Hz, 2H), 7.54-7.57 (m, 4H).

[00501] Compounds 40C, 40D, and 40 were synthesized by employing the procedures described for Compounds ID, 13B-1, and 3 using Compounds 40B, B3, 40C using acetonitrile as solvent at 70 °C, and 40D in lieu of Compound 1C, l-(tert-butyl) 2-methyl (R)-piperazine-l,2-dicarboxylate, Compounds 13A using DMF as solvent at 60 °C, and 3A. Compound 40C: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used; ¾-NMR (CDCh, 400 MHz): d (ppm) 4.65 (s, 2H), 7.14 (t, J= 8.4 Hz, 2H), 7.47 (d, J= 8.4 Hz, 2H), 7.53-7.57 (m, 4H). Compound 40D: LC-MS (ESI) m/z: 749 [M+H]⁺. Compound 40: LC-MS (ESI) m/z: 649 [M+H]⁺; 1H-NMR (CD₃OD, 400 MHz): d (ppm) 0.99-1.05 (m, 2H), 1.23-1.33 (m, 3H), 1.62-1.79 (m, 8H), 2.04-2.08 (m, 2H), 2.51-2.82 (m, 3H), 3.15-3.79 (m, 7H), 3.90-4.66 (m, 5H), 5.46 (s, 1H), 7.00-7.05 (m, 2H), 7.21-7.26 (m, 2H), 7.44-7.53 (m, 2H), 7.56-7.73 (m, 4H), 7.81 (d, J= 9.2 Hz, 2H). [00502] Example 41

[00503] Synthesis of (4-aminopiperidin-l-yl)(4-(cyclohexyl(4-

(trifluoromethyl)phenyl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2- yl)methanone (41), (4-aminopiperidin-l-yl)((S)-4-((R)-cyclohexyl(4- (trifluoromethyl)phenyl)m ethyl)- 1 -((4-(cyclohexylmethoxy) phenyl)sulfonyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (41-1), (4-aminopiperidin-l-yl)((S)-4-((S)-cyclohexyl(4- (trifluoromethyl)phenyl)m ethyl)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl) piperazin-2- yl)methanone 2,2,2-trifluoroacetate (41-2), and (4-aminopiperidin-l-yl)((2R)-4- (cyclohexyl(4-(trifluoromethyl)phenyl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl) piperazin-2-yl)methanone 2,2,2-trifluoroacetate (41-3)

[00504] Compounds 41A, 41B, 41C, 41D, 41E, and 41 were synthesized by employing the procedures described for Compounds 39C, IF, 13D-1, 30G, 13F-1, and 3 using cyclohexylmagnesium bromide, Compounds 41A, 41B, 41C, 41D, and 41E in lieu of cyclopentylmagnesium bromide, Compounds IE, 13C-1, 30F, 13E-1, and 3A. Compound 41A: LC-MS (ESI) m/z: 485 [M+H]⁺. Compound 41B: LC-MS (ESI) m/z: 385 [M+H]⁺. Compound 41C: LC-MS (ESI) m/z: 637 [M+H]⁺. Compound 41D: LC-MS (ESI) m/z: 623 [M+H]⁺. Compound 41E: LC-MS (ESI) m/z: 805 [M+H]⁺. Compound 41 was separated with chiral HPLC to afford Compound 41-1, Compound 41-2, and Compound 41-3. Compound 41-1: LC-MS (ESI) m/z: 705 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 0.79-2.37 (m,

3 OH), 2.40-3.22 (m, 4H), 3.42-3.49 (m, 1H), 3.71-3.87 (m, 3H), 4.41-4.65 (m, 2H), 5.30-5.48 (m, 1H), 6.90-6.92 (m, 2H), 7.44-7.47 (m, 2H), 7.69-7.71 (m, 4H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50/50); S,S-WHELK-Ol (4.6 x 250mm, 5um); retention time: 10.50 minute. Compound 41-2: LC-MS (ESI) m/z: 705 [M+H]⁺; 'H- NMR (CD3OD, 400 MHz): d (ppm) 0.80-3.25 (m, 34H), 3.44-3.74 (m, 2H), 3.87-3.96 (m, 2H), 3.97-4.87 (m, 2H), 3.30-5.47 (m, 1H), 6.88-6.92 (m, 2H), 7.38-7.49 (m, 2H), 6.67-7.76 (m, 4H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50/50); S,S- WHELK-Ol (4.6 x 250mm, 5um); retention time: 13.28 minute. Compound 41-3: LC-MS (ESI) m/z: 705 [M+H]⁺; ¾-NMR (CD₃OD, 400 MHz): d (ppm) ) 0.77-0.79 (m, 1H), 1.10- 1.35 (m, 11H), 1.62-1.89 (m, 12H), 2.10-3.18 (m, 10H), 3.43-3.83 (m, 2H), 3.85-3.87 (m, 2H), 4.39-4.68 (m, 2H), 5.01-5.30 (m, 1H), 6.89-6.93 (m, 2H), 7.38-7.43 (m, 2H), 7.67-7.75 (m, 4H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50/50); S,S- WHELK-Ol (4.6 x 250mm, 5um); retention time: 27.87 and 33.06 minute.

[00505] Example 42

[00506] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-(4-(5-chloropyridin-2-yl)benzyl)- l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (42)

[00507] Compounds 42B, 42C, and 42 were synthesized by employing the procedures described for Compounds 14B, 34C, and 3 using 4-formylphenylboronic acid, Compounds 42A, 42B, and 42C in lieu of Compounds 14A, 2-bromo-3,3,3-trifluoroprop-l-ene, 34B, and 3A. Compound 42B: LC-MS (ESI) m/z: 218; 1H-NMR (CDCb, 400 MHz): d (ppm) 7.77- 7.78 (m, 2H), 8.00 (d, J= 8.8 Hz, 2H), 8.14 (d, J= 8.8 Hz, 2H), 8.68 (s, 1H), 10.09 (s, 1H). Compound 42C: LC-MS (ESI) m/z: 766 [M+H]⁺. Compound 42: LC-MS (ESI) m/z: 666 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 0.96-2.13 (m, 15H), 2.55-2.89 (m, 3H), 3.15-3.28 (m, 2H), 3.42-3.95 (m, 5H), 4.08-4.3 (m, 2H), 4.45-4.68 (m, 3H), 5.47-5.49 (m, 1H), 6.98-7.01 (m, 2H), 7.44-7.56 (m, 2H), 7.79-7.82 (m, 2H), 7.97 (s, 2H), 8.06-8.08 (m, 2H), 8.68 (s, 1H).

[00508] Example 43

[00509] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-((2-(4-chlorophenyl)thiazol-4- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (43)

[00510] A mixture of Compound 34A (1.0 g, 5.85 mmol) and l,3-dibromopropan-2- one (1.37 g, 6.3 mmol) in ethanol (20 mL) was stirred at 70 °C for 16 hours. The mixture was concentrated and the residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to afford Compound 43A: LC-MS (ESI) m/z: 288 [M +H]⁺.

[00511] Compounds 43B and 43 were synthesized by employing the procedures described for Compounds 13B-1 and 1 using Compounds B3, 43 A, and 43B in lieu of l-(tert- butyl) 2-methyl (R)-piperazine-l,2-dicarboxylate, Compounds 13B and 1G. Compound 43B: LC-MS (ESI) m/z: 772 [M+H]⁺. Compound 43: LC-MS (ESI) m/z: 672 [M+H]⁺; Ή-NMR (CD3OD, 400 MHz): d (ppm) 1.06-1.09 (m, 2H), 1.24-1.38 (m, 3H), 1.49-1.87 (m, 8H), 2.06- 2.10 (m, 2H), 2.53-3.08 (m, 3H), 3.16-3.28 (m, 1H), 3.36-3.72 (m, 6H), 4.01-4.19 (m, 1H), 4.32-4.72 (m, 4H), 5.53 (s, 1H), 6.89-6.93 (m, 2H), 7.56 (d, =8.4 Hz, 2H), 7.74-7.82 (m,

3H), 7.97-8.01 (m, 2H).

[00512] Example 44

[00513] Synthesis of (4-aminopiperidin- l-yl)(l -((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(cyclopropyl(4-

(trifluoromethyl)phenyl)methyl)piperazin-2-yl)methanone (44), (4-aminopiperidin- 1 -yl)((S)- l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)-4-((R)-cyclopropyl(4-

(trifluoromethyl)phenyl)methyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (44-1), (4- aminopiperidin- 1 -yl)((S)- 1 -((4-(cyclohexylmethoxy)phenyl) sulfonyl)-4-((S)-cyclopropyl(4- (trifluoromethyl)phenyl)methyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (44-2), and (4-aminopiperidin- 1 -yl)((2R)- 1 -((4-(cyclohexylmethoxy) phenyl)sulfonyl)-4-(cyclopropyl(4- (trifluoromethyl)phenyl)methyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (44-3)

[00514] Compounds 44A, 44B, 44C, 44D, 44E, and 44 were synthesized by employing the procedures described for Compounds 39C, IF, 13D-1, 30G, 13F-1, and 3 using cyclopropylmagnesium bromide, Compounds 44A, 44B, 44C, 44D, and 44E in lieu of cyclopentylmagnesium bromide, Compounds IE, 13C-1, 30F, 13E-1, and 3A. Compound 44 A: LC-MS (ESI) m/z: 443 [M+H]⁺. Compound 44B: LC-MS (ESI) m/z: 343 [M+H]⁺. Compound 44C: LC-MS (ESI) m/z: 595 [M+H]⁺; ¾-NMR (CDCb, 400 MHz): d (ppm) 0.52-0.61 (m, 2H), 0.73-0.85 (m, 2H), 1.04-1.87 (m, 12H), 2.23-2.50 (m, 4H), 3.29-3.85 (m, 8H), 4.59-4.78 (m, 1H), 6.91-6.94 (m, 2H), 7.31-7.36 (m, 2H), 7.49-7.57 (m, 2H), 7.63-7.71 (m, 2H). Compound 44D: LC-MS (ESI) m/z: 581 [M+H]⁺. Compound 44E: LC-MS (ESI) m/z: 763 [M+H]⁺. Compound 44 was separated with chiral HPLC to furnish Compound 44-1, Compound 44-2, and Compound 44-3. Compound 44-1: LC-MS (ESI) m/z: 663 [M+H]⁺; ¾- NMR (CD₃OD, 400 MHz): d (ppm) 0.23-0.31 (m, 1H), 0.55-2.10 (m, 19H), 2.41-3.11 (m, 4H), 3.32-3.71 (m, 5H), 3.89-4.05 (m, 3H), 4.27-4.66 (m, 2H), 5.32-5.43 (m, 1H), 7.04-7.07 (m, 2H), 7.59-7.82 (m, 6H). Chiral separation condition: MeOH contained 0.2% methanol ammonia; IC (4.6 x 100 mm, 5 pm); retention time: 3.03 minute. Compound 44-2: LC-MS (ESI) m/z: 663 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) -0.05-0.01 (m, 1H), 0.36- 0.53 (m, 3H), 091-1.71 (m, 14H), 1.86-1.89 (m, 2H), 2.50-2.99 (m, 5H), 3.11-3.51 (m, 4H),

3.70-3.85 (m, 3H), 4.14-4.42 (m, 2H), 5.19 (s, 1H), 6.95 (d, J= 8.8 Hz, 2H), 7.56 (s, 4H),

7.70-7.72 (m, 2H). Chiral separation condition: MeOH contained 0.2% methanol ammonia;

IC (4.6 x 100 mm, 5 pm); retention time: 3.39 minute. Compound 44-3: LC-MS (ESI) m/z: 663 [M+H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) -0.05-0.01 (m, 1H), 0.42-1.70 (m, 17H), 1.86-1.97 (m, 2H), 2.20-3.02 (m, 5H), 3.l6-3.54(m, 4H), 3.68-3.71 (m, 3H), 4.04-4.47 (m, 2H), 5.13-5.21 (m, 1H), 6.87-6.97 (m, 2H), 7.40-7.72 (m, 6H). Chiral separation condition: n- Hexane/EtOH contained 0.1% DEA (90/10); OD-H (4.6 x 250 mm, 5 pm); retention time: 13.33 minute (34.08%), 18.37 minute (65.92%).

[00515] Example 45

[00516] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-((4-(4-chlorophenyl)thiazol-2- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (45)

45D 45

[00517] A mixture of Compound 45A (484 mg, 3.64 mmol) and 2-bromo-l-(4- chlorophenyl)ethanone (848 mg, 3.64 mmol) in ethanol (20 mL) was stirred at 70 °C for 16 hours. The mixture was concentrated and the residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to afford Compound 45B: LC-MS (ESI) m/z: 268 [M +H]⁺.

[00518] To a solution of Compound 45B (300 mg, 1.12 mmol) in dry dichloromethane (20 mL) was dropped a solution of DIBAL-H in toluene (1.5 M, 2.0 mL, 3.0 mmol) at -78 °C under nitrogen over 5 minutes and stirred at -78 °C for 1.5 hour. The reaction mixture was quenched with diluted HC1 solution (1 N, 40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude compound 45C, which was used directly in the next step without further purification. LC-MS (ESI) m/z: 224 [M +H]⁺.

[00519] Compounds 45D and 45 were synthesized by employing the procedures described for Compounds 34C and 1 using Compounds 45C and 45D in lieu of Compounds 34B and 1G. Compound 45D: LC-MS (ESI) m/z: 772 [M+H]⁺. Compound 45: LC-MS (ESI) m/z: 672 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.08-1.14 (m, 2H), 1.24-1.38 (m, 3H), 1.41-1.89 (m, 8H), 2.06-2.10 (m, 2H), 2.53-2.85 (m, 3H), 3.16-3.31 (m, 2H), 3.32-3.82 (m, 6H), 4.21-4.65 (m, 4H), 5.31 (s, 1H), 7.02 (d, J=8.4 Hz, 2H), 7.45 (d, =8.4 Hz, 2H), 7.80 (d, =8.0 Hz, 2H),7.94 (d, J=6.8 Hz, 3H).

[00520] Example 46

[00521] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)((S)-l-((4-

(cyclohexylmethoxy)phenyl) sulfonyl)-4-((4'-fluoro-[l,r-biphenyl]-4-yl)methyl)piperazin-2- yl)methanone (46), ((S)-4-amino-3,3-difluoropiperidin-l-yl)((S)-l-((4- (cyclohexylmethoxy)phenyl) sulfonyl)-4-((4'-fluoro-[l,r-biphenyl]-4-yl)methyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (46-1), and ((R)-4-amino-3,3-difluoropiperidin-l-yl)((S)- 1 -((4-(cyclohexylmethoxy)phenyl) sulfonyl)-4-((4'-fluoro-[ 1 , 1 '-biphenyl]-4- yl)methyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (46-2)

[00522] Compound 46A was synthesized by employing the procedure described for Compound IE using (S)-l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid and Compound 40C in lieu of l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid and Compound ID: LC- MS (ESI) m/z: 415 [M+H]⁺; ¾-NMR (CDCb, 400 MHz): d (ppm) 1.42 (s, 9H), 2.76-2.99 (m, 2H), 3.59-3.82 (m, 2H), 4.04-4.14 (m, 2H), 4.34-4.37 (m, 1H), 4.53-4.60 (m, 1H), 4.85- 5.06 (m, 2H), 7.13 (t, J= 8.4 Hz, 2H), 7.50-7.64 (m, 6H).

[00523] To a mixture of Compound 46A (1.2 g, 2.9 mmol) in methanol (50 mL) was added SOCh (1 mL) and heated at reflux overnight. The reaction mixture was concentrated to give Compound 46B: LC-MS (ESI) m/z: 329 [M+H]⁺.

[00524] Compounds 46C, 46D, 46E, and 46 were synthesized by employing the procedures described for Compounds 13D-1, 30G, 13F-1, and 1 using Compounds 46B, 46C, B2, 46D, and 46E in lieu of Compounds 13C-1, 30F, tert-butyl piperidin-4-ylcarbamate, 13E-1, and 1G. Compound 46C: LC-MS (ESI) m/z: 581 [M+H]⁺. Compound 46D: LC-MS (ESI) m/z: 567 [M+H]⁺; ¾-NMR (CDCb, 400 MHz): d (ppm) 0.84-0.91 (m, 2H), 0.99-1.09 (m, 3H), 1.22-1.34 (m, 5H), 1.74-1.98 (m, 10H), 3. 73 (d, J= 5.6 Hz, 2H), 6.85 (d, J= 8.4 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 7.12-7.18 (m, 2H), 7.15 (d, J= 8.0 Hz, 2H), 7.53-7.57 (m, 5H), 7.73 (d, J= 8.4 Hz, 1H). Compound 46E: LC-MS (ESI) m/z: 785 [M+H]⁺. Compound 46 was separated with chiral HPLC to furnish Compound 46-1 and Compound 46-2.

Compound 46-1: LC-MS (ESI) m/z: 685 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 0.96-1.00 (m, 2H), 1.19-1.34 (m, 3H), 1.51 (s, 1H), 1.70-1.77 (m, 5H), 1.91-2.00 (m, 1H), 2.20-2.23 (m, 1H), 2.46-2.51 (m, 1H), 2.67-2.71 (m, 1H), 3.22-3.71 (m, 3H), 3.47-3.54 (m, 2H), 3.68-3.75 (m, 2H), 3.95-4.15 (m, 3H), 4.43-4.46 (m, 1H), 4.54-4.58 (m, 1H), 4.98-5.02 (m, 1H), 5.47-5.55 (m, 1H), 6.99 (d, J= 8.8 Hz, 2H), 7.24 (t, J= 8.4 Hz, 2H), 7.44 (d, J= 8.0 Hz, 2H), 7.65 (d, J= 8.4 Hz, 2H), 7.69-7.73 (m, 2H), 7.81 (d, J= 8.4 Hz, 2H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50/50); Cellulose-SC (4.6 x 250 mm, 5 pm); retention time: 14.22 minute. Compound 46-2: LC-MS (ESI) m/z: 685 [M+H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 0.99-1.04 (m, 2H), 1.20-1.31 (m, 3H), 1.56 (s, 1H), 1.77-2.01 (m, 6H), 2.22-2.25 (m, 1H), 2.60-2.80 (m, 1H), 2.81-2.94 (m, 1H), 3.34-3.63 (m, 4H), 3.72-3.75 (m, 3H), 3.92-4.18 (m, 3H), 4.38-4.66 (m, 2H), 4.89-4.92 (m, 1H), 5.42-5.56 (m, 1H), 6.98-7.03 (m, 2H), 7.23 (t, J= 8.4 Hz, 2H), 7.44-7.50 (m, 2H), 7.64-7.72 (m, 4H), 7.80 (d, J= 8.8 Hz, 2H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50/50); Cellulose-SC (4.6 x 250 mm, 5 pm); retention time: 17.08 minute.

[00525] Example 47

[00526] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-((5-(4-chlorophenyl)thiazol-2- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (47)

[00527] A mixture of Compound 47A (380 mg, 1.84 mmol), triethylamine (1.15 mL, 8.28 mmol) and ethyl 2-chloro-2-oxoacetate (366 mg, 2.69 mmol) in dichloromethane (20 mL) was stirred at 25 °C for 6 hours. The mixture was concentrated under reduced pressure and the residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to afford Compound 47B: LC-MS (ESI) m/z: 270 [M+H]⁺.

[00528] A mixture of Compound 47B (330 mg, 1.23 mmol) and P2S5 (630 mg, 2.84 mmol) in dichlorom ethane (25 mL) was stirred at 60 °C for 16 hours. The mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 5% v/v) to afford Compound 47C: LC-MS (ESI) m/z: 268[M +H]⁺.

[00529] Compounds 47D, 47E, and 47 were synthesized by employing the procedures described for Compounds 45C, 34C, and 1 using Compounds 47C, 47D, and 47E in lieu of Compounds 45B, 34B, and 1G. Compound 47D was used directly in the next step without further purification. LC-MS (ESI) m/z: 224 [M +H]⁺. Compound 47E: LC-MS (ESI) m/z:

772 [M +H]⁺. Compound 47: LC-MS (ESI) m/z: 672 [M +H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.02-1.11 (m, 2H), 1.22-1.38 (m, 3H), 1.41-1.86 (m, 8H), 2.05-2.08 (m, 2H), 2.53-2.95 (m, 3H), 3.16-3.21 (m, 2H), 3.32-3.45 (m, 2H), 3.72-3.84 (m, 4H), 4.15-4.64 (m, 4H), 5.27 (s, 1H), 7.05 (d, J=8.8 Hz, 2H), 7.47 (d, =8.4 Hz, 2H), 7.64 (d, =8.4 Hz, 2H),7.80 (d, =8.8 Hz, 2H), 8.03 (s, 1H).

[00530] Example 48

[00531] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(4-(5-fluoropyridin-2-yl)benzyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (48)

[00532] Compounds 48B, 48C, and 48 were synthesized by employing the procedures described for Compounds 40B, 34C, and 1 using 4-formylphenylboronic acid, Compounds 48A, 48B, and 48C in lieu of (4-fluorophenyl)boronic acid, Compounds 40A, 34B, and 1G. Compound 48B: LC-MS (ESI) m/z: 202 [M+H]⁺; 1H-NMR (CDCb, 400 MHz): d (ppm) 7.50-7.55 (m, 1H), 7.82 (q, J= 4.8 Hz, 1H), 7.99 (d, J= 8.0 Hz, 2H), 8.13 (d, J= 8.0 Hz,

2H), 8.59 (d, J= 3.2 Hz, 1H), 10.08 (s, 1H). Compound 48C: LC-MS (ESI) m/z: 750

[M+H]⁺. Compound 48: LC-MS (ESI) m/z: 650 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 0.96-1.09 (m, 2H), 1.21-1.33 (m, 3H), 1.43-1.83 (m, 8H), 2.04-2.11 (m, 2H), 2.55-2.93 (m, 3H), 3.14-.25 (m, 1H), 3.35-3.64 (m, 4H), 3.72-3.80 (m, 2H), 3.95-4.19 (m, 2H), 4.28- 4.66 (m, 3H), 5.48 (d, J= 7.2 Hz, 1H ), 7.04 (q, J= 9.2 Hz, 2H), 7.54 (q, J= 8.0 Hz, 2H), 7.72-7.83 (m, 3H), 7.99-8.08 (m, 3H), 8.59 (d , , j= 2.4 Hz, 1H).

[00533] Example 49

[00534] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((4-

(cy cl ohexylmethoxy)phenyl)sulfonyl)-4-((6-(4-(trifluoromethyl)phenyl)pyri din-3- yl)methyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (49)

49D 49

[00535] A mixture of (6-chl oropyri din-3 -yl)m ethanol 49A (0.75 g, 5.26 mmol), 4-

(trifluoromethyl)phenylboronic acid (1 g, 5.26 mmol), K2CO3 (2.18 g, 15.78 mmol), and Pd(PPh₃)4 (607 mg, 0.526 mmol) in DME-H2O (24 mL, 5: 1 in volume) was heated at 90 °C under nitrogen overnight. The mixture was cooled down to room temperature, diluted with ethyl acetate (50 mL), washed with water (50 mL x 2) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified with column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50% v/v) to yield Compound 49B: LC-MS (ESI) m/z: 254 [M+H]⁺.

[00536] Compounds 49C, 49D, and 49 were synthesized by employing the procedures described for Compounds ID, IE, and 3 using Compounds 49B, 49C, B3, and 49D in lieu of Compounds 1C, ID, l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, and 3A.

Compound 49C: LC-MS (ESI) m/z: 272 [M+H]⁺. Compound 49D: LC-MS (ESI) m/z: 800 [M+H]⁺. Compound 49: LC-MS (ESI) m/z: 700 [M+H]⁺. 'H-NMR (CD3OD, 400 MHz): d (ppm) 1.01-1.06 (m, 5H), 1.23-1.78 (m, 8H), 2.03-2.07 (m, 2H), 2.75-2.98 (m, 4H), 3.35-3.50 (m, 6H), 4.40-4.49 (m, 5H), 5.45-5.46 (m, 1H), 7.04-7.06 (m, 2H), 7.84 (d, J= 8.4 Hz, 4H), 8.00-8.06 (m, 2H), 8.28 (d, J= 8.4 Hz, 2H), 8.72-8.74 (m, 1H).

[00537] Example 50

[00538] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((4-

(cy cl ohexylmethoxy)phenyl)sulfonyl)-4-((6-(4-(trifluoromethoxy)phenyl)pyri din-3- yl)methyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (50)

[00539] Compound 50B was synthesized by employing the procedure described for Compound 40B using (4-(trifluoromethoxy)phenyl)boronic acid and Compound 50A in lieu of (4-fluorophenyl)boronic acid and Compound 40A: LC-MS (ESI) m/z: 268 [M+H]⁺; ¾- NMR (DMSO-i¾, 400 MHz): d (ppm) 7.54 (d, J= 8.4 Hz, 2H), 8.25 (d, J= 8.4 Hz, 1H), 8.32-8.37 (m, 3H), 7.18 (d, J= 1.2 Hz, 1H), 10.16 (s, 1H).

[00540] A reaction mixture of Compound 50B (267 mg, 0.17 mmol) and Compound B3 (80 mg, 014 mmol) in 1, 2-dichloroethane (3 mL) was stirred at room temperature for 1 hour, then NaBH₃CN (18 mg, 0.28 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (acetate ethyl in petroleum ether, from 10% to 80% v/v) to furnish Compound 50C: LC-MS (ESI) m/z: 816 [M+H]⁺.

[00541] Compound 50 was synthesized by employing the procedure described for Compound 1 using Compound 50C in lieu of Compound 1G: LC-MS (ESI) m/z: 716

[M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.04-1.10 (m, 2H), 1.21-1.84 (m, 11H), 2.03-2.10 (m, 2H), 2.57-2.93 (m, 3H), 3.04-3.18 (m, 1H), 3.40-3.81 (m, 6H), 3.96-4.15 (m, 2H), 4.28-4.58 (m, 3H), 5.40 (s, 1H), 7.06 (d, J= 8.0 Hz, 2H), 7.44 (d, J= 8.8 Hz, 2H), 7.83 (d, J= 8.8 Hz, 2H), 7.79-8.00 (m, 2H), 8.17 (d, J= 8.0 Hz, 2H), 8.67-8.73 (m, 1H).

[00542] Example 51

[00543] Synthesis of ((S)-4-amino-3,3-difluoropiperidin-l-yl)((S)-4-(4-(5- chloropyridin-2-yl)benzyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (51-1), and ((R)-4-amino-3,3-difluoropiperidin-l-yl)((S)- 4-(4-(5-chloropyridin-2-yl)benzyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (51-2)

[00544] Compounds 51B, 51C, and 51D were synthesized by employing the procedures described for Compounds 49B, ID, and IE using 4-

(hydroxymethyl)phenylboronic acid, Compounds 51A, 51B, B4, and 51C using DIPEA as base and CEECN as solvent in lieu of (4-(trifluoromethyl)phenyl)boronic acid, Compounds 49A, 1C, l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, and ID using Na2CCb as base and EtOH as solvent. Compound 51B: LC-MS (ESI) m/z: 220 [M+H]⁺. Compound 51C: LC- MS (ESI) m/z: 238 [M+H]⁺. Compound 51D was separated with preparative HPLC to furnish Compound 51D-1 and Compound 51D-2. Compound 51D-1: LC-MS (ESI) m/z: 802 [M+H]⁺; retention time: 1.69 minute. Compound 51D-2: LC-MS (ESI) m/z: 802 [M+H]⁺; retention time: 1.74 minute.

[00545] Compound 51-1 was synthesized by employing the procedure described for Compound 3 using Compound 51D-1 in lieu of Compound 3A: LC-MS (ESI) m/z: 702

[M+H]⁺. ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.93-1.36 (m, 5H), 1.47-1.58 (m, 1H), 1.72- 1.83 (m, 6H), 1.91-2.67 (m, 4H), 3.40-3.73 (m, 7H), 3.89-4.59 (m, 5H), 5.40-5.53 (m, 1H), 7.00 (d, J= 8.4 Hz, 2H), 7.46-7.48 (m, 2H), 7.79 (d, J= 8.8 Hz, 2H), 7.97-7.98 (m, 2H), 8.04-8.06 (m, 2H), 8.68 (s, 1H).

[00546] Compound 51-2 was synthesized by employing the procedure described for Compound 3 using Compound 51D-2 in lieu of Compound 3A: LC-MS (ESI) m/z: 702

[M+H]⁺. ¾-NMR (CD3OD, 400 MHz): d (ppm) 0.97-1.37 (m, 5H), 1.54-1.93 (m, 7H), 2.18- 2.91 (m, 4H), 3.38-3.77 (m, 7H), 3.94-4.63 (m, 5H), 5.25-5.54 (m, 1H), 7.00-7.02 (m, 2H), 7.48-7.52 (m, 2H), 7.77-7.79 (m, 2H), 7.96-8.05 (m, 4H), 8.67 (s, 1H).

[00547] Example 52

[00548] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-((6-(4-fluorophenyl)pyridin-3-yl)methyl)piperazin- 2-yl)methanone (52)

[00549] Compounds 52B, 52C, 52D, 52E, and 52 were synthesized by employing the procedures described for Compounds 40B, 1C, ID, IE, and 3 using Compounds 52A, 52B, 52C, B3, 52D using DIPEA as base and CH₃CN as solvent, and 52E in lieu of Compounds 40A, IB, 1C, l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, ID using Na2CCh as base and EtOH as solvent, and 3A. Compound 52B: LC-MS (ESI) m/z: 202 [M+H]⁺. Compound 52C: LC-MS (ESI) m/z: 204 [M+H]⁺. Compound 52D was used directly in next step without further purification. Compound 52E: LC-MS (ESI) m/z: 750 [M+H]⁺. Compound 52: LC-MS (ESI) m/z: 650 [M+H]⁺; ¾-NMR (CD₃OD, 400 MHz): d (ppm) 1.03-1.90 (m, 16H), 2.20- 2.37 (m , 2H), 2.53-3.06 (m, 5H), 3.36-3.79 (m, 4H), 3.85 (d, J= 6.0 Hz, 2H), 3.95-4.23 (m, 2H), 7.02 (d, J= 8.4 Hz, 2H), 7.19 (t, J= 8.8 Hz, 2H), 7.69 (d, J= 8.4 Hz, 2H), 7.78-8.00 (m, 4H), 8.47-8. (m, 1H).

[00550] Example 53

[00551] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)((S)-l-((4-

(cyclohexylmethoxy)phenyl) sulfonyl)-4-((4'-(trifluoromethoxy)-[l,r-biphenyl]-4- yl)methyl)piperazin-2-yl)methanone (53), ((R)-4-amino-3 , 3 -difluoropiperidin- 1 -yl)((S)- 1 -((4- (cyclohexylmethoxy)phenyl) sulfonyl)-4-((4'-(trifluoromethoxy)-[l,r-biphenyl]-4- yl)methyl)piperazin-2-yl)methanone (53-1), and ((S)-4-amino-3,3-difluoropiperidin-l- yl)((S)-l-((4-(cyclohexylmethoxy)phenyl) sulfonyl)-4-((4'-(trifluoromethoxy)-[l,r- biphenyl]-4-yl)methyl)piperazin-2-yl)methanone (53-2)

[00552]

[00553] Compounds 53A and 53 were synthesized by employing the procedures described for Compounds IE and 3 using Compound B4, Compounds 36C using DIPEA as base and CEECN as solvent, and 53A in lieu of l-(tert-butoxycarbonyl)piperazine-2- carboxylic acid, Compounds ID using Na2CCb as base and EtOH as solvent, and 3A.

[00554] Compound 53A: LC-MS (ESI) m/z: 851 [M+H]⁺.

[00555] Compound 53 was separated with chiral HPLC to furnish Compound 53-1 and Compound 53-2. Compound 53-1: LC-MS (ESI) m/z: 751 [M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 1.25-1.29 (m, 10H), 1.37-1.46 (m, 7H), 1.76-1.87 (m, 6H), 3.01-3.04 (m, 4H), 3.78-3.40 (m, 2H), 6.91 (d, J= 8.8 Hz, 2H), 7.28-7.31 (m, 4H), 7.46-7.48 (m, 2H), 7.56-7.58 (m, 2H), 7.66 (d, J= 8.8 Hz, 2H). Chiral separation condition: n-hexane/EtOH contained 0.1% DEA (50/50); S,S-WHELK-Ol (100 x 4.6 mm, 5 pm); retention time: 14.70 minute. Compound 53-2: LC-MS (ESI) m/z: 751 [M+H]⁺; Ή-NMR (CDCb, 400 MHz): d (ppm) 1.25-1.29 (m, 11H), 1.76-1.87 (m, 6H), 2.34-2.48 (m, 2H), 2.82-3.01 (m, 4H), 3.38-3.41 (m, 1H), 3.62-3.65 (m, 1H), 3.78-3.80 (m, 3H), 4.73 (s, 1H), 6.91 (d, J= 8.4 Hz, 2H), 7.28-7.30 (m, 4H), 7.45 (d, J= 8.0 Hz, 2H), 7.55 (d, J= 8.8 Hz, 2H), 7.64 (d, J= 8.4 Hz, 2H). Chiral separation condition: n-hexane/EtOH contained 0.1% DEA (50/50); S,S-WHELK-Ol (100 x 4.6 mm, 5 pm); retention time: 12.87 minute.

[00556] Example 54

[00557] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)((S)-l-((4-

(cyclohexylmethoxy)phenyl) sulfonyl)-4-((4'-(trifluoromethyl)-[l,r-biphenyl]-4- yl)methyl)piperazin-2-yl)methanone (54), ((R)-4-amino-3,3-difluoropiperidin-l-yl)((S)-l-((4- (cyclohexylmethoxy) phenyl)sulfonyl)-4-((4'-(trifluoromethyl)-[l,r-biphenyl]-4- yl)methyl)piperazin-2-yl)methanone (54-1), and ((S)-4-amino-3,3-difluoropiperidin-l- yl)((S)-l-((4-(cyclohexylmethoxy) phenyl)sulfonyl)-4-((4'-(trifluoromethyl)-[l,r-biphenyl]- 4-yl)methyl)piperazin-2-yl)methanone (54-2)

[00558] Compounds 54A and 54 were synthesized by employing the procedures described for Compounds IE and 3 using CompoundsB4, 33C using DIPEA as base and CEECN as solvent, and 54A in lieu of l-(tert-butoxycarbonyl)piperazine-2-carboxylic acid, Compounds ID using Na2CCb as base and EtOH as solvent, and 3A. Compound 54A: LC- MS (ESI) m/z: 835 [M+H]⁺. Compound 54 was separated with chiral HPLC to furnish Compound 54-1 and Compound 54-2. Compound 54-1: LC-MS (ESI) m/z: 735 [M+H]⁺. ¾- NMR (CDCb, 400 MHz): d (ppm) 0.99-1.12 (m, 2H), 1.20-1.34 (m, 8H), 1.70-1.90 (m, 8H), 2.30-2.51 (m, 2H), 2.76-3.10 (m, 3H), 3.36-3.56 (m, 2H), 3.61-3.68 (m, 1H), 3.75-3.90 (m, 4H), 4.73 (s, 1H), 6.89-6.95 (m, 2H), 7.30-7.34 (m, 2H), 7.47-7.52 (m, 2H), 7.62-7.70 (m, 6H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (70/30); IC (4.6 x 250 mm, 5 pm); retention time: 12.40 minute. Compound 54-2: LC-MS (ESI) m/z: 735 [M+H]⁺. ¾-NMR (CDCb, 400 MHz): d (ppm) 0.99-1.12 (m, 2H), 1.20-1.34 (m, 8H), 1.70- 1.90 (m, 8H), 2.30-2.52 (m, 2H), 2.76-3.14 (m, 5H), 3.28-3.56 (m, 2H), 3.64-3.94 (m, 3H), 4.73 (s, 1H), 6.89-6.94 (m, 2H), 7.30-7.35 (m, 2H), 7.49-7.54 (m, 2H), 7.64-7.70 (m, 6H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (70/30); IC (4.6 x 250 mm, 5 pm); retention time: 15.96 minute.

[00559] Example 55

[00560] Synthesis of ((R)-4-amino-3,3-difluoropiperidin-l-yl)((S)-4-((6-(4- chlorophenyl)pyri din-3 -yl)m ethyl)- l-((4-(cy cl ohexylmethoxy )phenyl)sulfonyl)piperazin-2- yl)methanone 2,2,2-trifluoroacetate (55-1) and ((S)-4-amino-3,3-difluoropiperidin-l-yl)((S)- 4-((6-(4-chlorophenyl)pyridin-3-yl)methyl)-l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (55-2)

[00561] Compounds 55B, 55C, and 55D were synthesized by employing the procedures described for Compounds 49B, ID, and IE using (4-chlorophenyl)boronic acid, Compounds 55B, 55C, and B4 in lieu of (4-(trifluoromethyl)phenyl)boronic acid using DIPEA as base and CEECN as solvent, Compounds 1C, ID, and l-(tert- butoxycarbonyl)piperazine-2-carboxylic acid using Na2CCb as base and EtOH as solvent. Compound 55B: LC-MS (ESI) m/z: 220 [M+H]⁺. Compound 55C: LC-MS (ESI) m/z: 238 [M+H]⁺. Compound 55D was separated with preparative HPLC to furnish Compound 55A-1 and Compound 55A-2. Compound 55A-1: LC-MS (ESI) m/z: 802 [M+H]⁺; retention time: 1.85 minute. Compound 55A-2: LC-MS (ESI) m/z: 802 [M+H]⁺; retention time: 1.89 minute.

[00562] Compound 55-1 was synthesized by employing the procedure described for Compound 3 using Compound 55D-1 in lieu of Compound 3A: LC-MS (ESI) m/z: 702

[M+H]⁺. ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.98-1.76 (m, 12H), 1.76-2.22 (m, 2H),

2.47-2.71 (m, 2H), 3.20-3.32 (m, 2H), 3.48-4.16 (m, 8H), 4.38-4.61 (m, 2H), 5.51 (s, 1H), 7.01 (d, J= 9.2 Hz, 2H), 7.55 (d, J= 8.4 Hz, 2H), 7.82 (d, J= 8.8 Hz, 2H), 7.90-7.96 (m,

2H), 8.07 (d, J= 8.4 Hz, 2H), 8.63 (s, 1H). Chiral separation condition: MeOH contained 0.2% Methanol Ammonia; AS-H (4.6 x 1000 mm, 5 pm); retention time: 1.76 minute.

[00563] Compound 55-2 was synthesized by employing the procedure described for Compound 3 using Compound 55D-2 in lieu of Compound 3A: LC-MS (ESI) m/z: 702

[M+H]⁺. 1H-NMR (CD3OD, 400 MHz): d (ppm ) 1.01-1.07 (m, 2H), 1.24-1.31 (m, 3H), 1.56- 1.59 (m, 1H), 1.71-2.20 (m, 7H), 2.57-3.20 (m, 3H), 3.42-4.80 (m, 12H), 5.36-5.53 (m, 1H), 7.03 (d, J= 7.2 Hz, 2H), 7.55 (d, J= 8.4 Hz, 2H), 7.81 (d, J= 8.0 Hz, 2H), 7.97 (s, 2H), 8.06 (d, J= 7.6 Hz, 2H), 8.62-8.67 (m, 1H). Chiral separation condition: MeOH contained 0.2% Methanol Ammonia; AS-H (4.6 x 1000 mm, 5 pm); retention time: 1.84 minute.

[00564] Example 56

[00565] Synthesis of (S)-(4-aminopiperidin-l-yl)(l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(4-(5-(trifluoromethoxy)pyridin-2- yl)benzyl)piperazin-2-yl)methanone 2,2,2-trifluoroacetate (56)

[00566] Compounds 56B, 56C, 56D, 56E, and 56 were synthesized by employing the procedures described for Compounds 40B, 1C, ID, IE, and 3 using 4-formylphenylboronic acid, Compounds 56A, 56B, 56C, B3, 56D using acetone as solvent, and 56E in lieu of (4- fluorophenyl)boronic acid, Compounds 40A, IB, 1C, l-(tert-butoxycarbonyl)piperazine-2- carboxylic acid, ID using EtOH as solvent, and 3A. Compound 56B: LC-MS (ESI) m/z: 268 [M+H]⁺. Compound 56C: LC-MS (ESI) m/z: 270 [M+H]⁺. Compound 56D was used directly in next step without further purification. Compound 56E was used directly in next step without further purification. LC-MS (ESI) m/z: 816 [M+H]⁺. Compound 56: LC-MS (ESI) m/z: 716 [M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 0.93-1.01 (m, 2H), 1.12-1.28 (m, 3H), 1.69-1.78 (m, 8H), 2.09-2.11 (m, 2H), 2.61-2.78 (m, 1H), 3.39-3.69 (m, 10H), 4.00-4.48 (m, 4H), 5.14 (s, 1H), 6.87 (d, , J= 4.0 Hz, 2H), 7.43 (t , J= 7.2 Hz, 2H), 7.59-7.66 (m, 3H), 7.75 (t, J= 5.2 Hz, 1H), 7.93 (t , j= 7.2 Hz, 2H), 8.39 (s, 3H), 8.58 (d, J= 6.4 Hz, 1H).

[00567] Example 57

[00568] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-((4'-chloro-[l,r-biphenyl]-4- yl)methyl)-l-((5-(cyclohexylmethoxy)pyridin-2-yl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (57)

[00569] To a solution of 6-bromopyridin-3-ol 57A (4 g, 22.9 mmol) in DMF (10 ml) was added NaH (1.28 g, 32.1 mmol, 60% suspension in liquid paraffin). After the mixture was stirred at room temperature for 30 minutes, to it was added (bromomethyl)cyclohexane (8.1 g, 45.8 mmol) and stirred at room temperature for 3 days. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (200 mL x 2). The combined extracts was dried over MgS0₄, filtered, and concentrated to give a crude product, which was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 20% v/v) to furnish Compound 57B: LC-MS (ESI) m/z: 270 [M+H]⁺.

[00570] To a solution of Compound 57B (4 g, 14.8 mmol) in toluene (30 mL) was added phenylmethanethiol (1.8 g, 14.8 mmol), DIPEA (5.7 g, 44.4 mmol), tris

(dibenzylideneacetone)dipalladium (0) (541 mg, 0.6 mmol), and 4,5-bis

(diphenylphosphino)-9,9-dimethylxanthene (684 mg, 1.2 mmol) and heated at 80°C under nitrogen for 3 hours. After cooled down to room temperature, the mixture was filtered through Celite. The filtrate was concentrated to give a crude product, which was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 20% v/v) to furnish Compound 57C: LC-MS (ESI) m/z: 314 [M+H]⁺.

[00571] To a solution of Compound 57C (1.3 g, 4.15 mmol) in acetic acid (9 mL) and water (3 mL) was added N-chlorosuccinimide (2.2 g, 16.6 mmol). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with EtOAc (100 mL x 2). The combined extracts was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column

chromatography on silica gel (ethyl acetate in petroleum ether, 0% to 30% v/v) to furnish Compound 57D: LC-MS (ESI) m/z: 290 [M+H]⁺.

[00572] Compounds 57E, 57F, 57G, 57H, and 57 were synthesized by employing the procedures described for Compounds 13D-1, 13F-1, Compound B3, IE, and 3A using Compounds 57D, Compound B3-3, 57E, 57F, 57G using DIPEA as base and CEECN as solvent, and 57H in lieu of Compound A2, Compounds 13C-1, 13E-1, Compound B3-5, 1- (tert-butoxycarbonyl)piperazine-2-carboxylic acid using Na2CCh as base and EtOH as solvent, and 3A. Compound 57E: LC-MS (ESI) m/z: 606 [M+H]⁺. Compound 57F: LC-MS (ESI) m/z: 788 [M+H]⁺. Compound 57G: LC-MS (ESI) m/z: 566 [M+H]⁺. Compound 57H: LC-MS (ESI) m/z: 766 [M+H]⁺. Compound 57: LC-MS (ESI) m/z: 666 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 0.93-1.35 (m, 5H), 1.51-1.77 (m, 8H), 2.07-2.14 (m, 2H), 2.76- 2.90 (m, 2H), 3.13-3.25 (m, 2H), 3.36-3.81 (m, 6H), 4.05-4.71 (m, 5H), 5.48-5.51 (m, 1H), 7.48-7.58 (m, 5H), 7.70-7.77 (m, 4H), 7.93-7.01 (m, 2H).

[00573] Example 58

[00574] Synthesis of (S)-(4-aminopiperidin-l-yl)(4-((5'-chloro-[2,2'-bipyridin]-5- yl)methyl)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperazin-2-yl)methanone 2,2,2- trifluoroacetate (58)

[00575] Compounds 58A, 58B, 58C, and 58 were synthesized by employing the procedures described for Compounds 49B, ID, IE, and 3 using (5-chloropyridin-2-yl)boronic acid, Compounds 58A, B3, 58B using acetone as solvent, and 58C in lieu of (4- (trifluoromethyl)phenyl)boronic acid, Compounds 1C, l-(tert-butoxycarbonyl)piperazine-2- carboxylic acid, ID using EtOH as solvent, and 3A. Compound 58A: LC-MS (ESI) m/z: 221 [M+H]⁺. Compound 58B was used directly in the next step without further purification. LC- MS (ESI) m/z: 239 [M+H]⁺. Compound 58C was used directly in next step without further purification. LC-MS (ESI) m/z: 767 [M+H]⁺. Compound 58: LC-MS (ESI) m/z: 667 [M+H]⁺; ¹H-NMR (DMSO-i/e, 400 MHz): d (ppm) 0.88-1.33 (m, 7H), 1.56-1.85 (m, 8H), 2.08-2.42 (m, 1H), 2.49-3.17 (m, 5H), 3.57-4.20 (m, 9H), 5.00 (s, 1H), 6.96 (d, J= 9.2 Hz, 2H), 7.62 (d, j= 8.4 Hz, 2H), 7.74 (s, 1H), 7.88 (s, 3H), 8.01 (dd, j= 8.4, 2.4 Hz, 1H), 8.24 (d, j= 6.8 Hz, 1H), 8.31 (d , J= 8.8 Hz, 1H), 8.50 (s, 1H), 8.67 (d, J= 2.4 Hz, 1H).

[00576] Example 59

[00577] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4S)-4-(4- chlorophenoxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (59-1)

[00578] To a solution of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid 59A-1 (4.0 g, 30 mmol) in methanol (20 mL) was added sulfurous dichloride (4.7 g, 40 mmol) at 0 °C. The reaction mixture was stirred at 80 °C for 16 hours and concentrated to afford Compound 59B-1: LC-MS (ESI) m/z: 146 [M+H] ⁺. [00579] Compound 59C-1 was synthesized by employing the procedure described for Compound 13D-1 using Compounds A1 and 59B-1 in lieu of Compounds A2 and 13C-1: LC-MS (ESI) m/z: 420 [M+H]⁺.

[00580] A reaction mixture of Compound 59C-1 (1.7 g, 4.05 mmol), 4-chlorophenol (0.57 g, 4.46 mmol), and PPh₃ (1.17 g, 4.46 mmol) in dry THF (25 mL) was stirred at room temperature for 1 hour, then DIAD (0.9 mL, 4.46 mmol) was added to the mixture and stirred at 25 °C under nitrogen atmosphere overnight. The reaction mixture was quenched with water (50 mL) and extracted with dichloromethane (150 mL x 2). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20 % v/v) to yield Compound 59D-1: LC-MS (ESI) m/z: 530 [M+H]⁺.

[00581] Compounds 59E-1, 59F-1, and 59-1 were synthesized by employing the procedures described for Compounds 30G, 13F-1, and 1 using Compounds 59D-1, 59E-1,

Bl, and 59F-1 in lieu of Compounds 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 1G. Compound 59E-1: LC-MS (ESI) m/z: 516 [M+H]⁺. Compound 59F-1: LC-MS (ESI) m/z: 724[M+H]⁺. Compound 59-1: LC-MS (ESI) m/z: 624 [M+H]⁺; 'H-NMR (CD₃OD, 400 MHz): d (ppm) 1.68-1.98 (m, 11H), 2.01-2.19 (m, 6H), 2.5-2.70 (m, 1H), 3.58-3.78 (m, 3H), 4.52-5.07 (m, 5H), 6.76-6.82 (m, 2H), 7.18-7.28 (m, 3H), 7.34 (s, 1H), 7.61-7.90 (m, 1H), 7.96-7.99 (m, 2H), 8.39-8.44 (m, 1H).

[00582] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4R)-4-(4- chlorophenoxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (59-2)

[00583] Compounds 59B-2, 59C-2, 59D-2, 59E-2, 59F-2, and 59-2 were synthesized by employing the procedures described for Compounds 59B-1, 13D-1, 59D-1, 30G, 13F-1, and 1 using Compounds 59A-2, 59B-2, Al, 59C-2, 59D-2, 59E-2, Bl, and 59F-2 in lieu of Compounds 59A-1, 13C-1, A2, 59C-1, 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 1G. Compound 59B-2: LC-MS (ESI) m/z: 146 [M+H] ⁺. Compound 59C-2: LC-MS (ESI) m/z: 420 [M+H]⁺. Compound 59D-2: LC-MS (ESI) m/z: 530 [M+H]⁺. Compound 59E-2: LC-MS (ESI) m/z: 516 [M+H]⁺. Compound 59F-2: LC-MS (ESI) m/z: 724 [M+H]⁺.

Compound 59-2: LC-MS (ESI) m/z: 624 [M+H]⁺; Ή-NMR (CD₃OD, 400 MHz): d (ppm) 1.68-2.39 (m, 18H), 3.70-3.79 (m, 3H), 4.75-4.84 (m, 4H), 5.04 (s, 1H), 6.09 (s, 2H), 6.76- 6.79 (m, 2H), 7.20 (d, J= 8.8 Hz, 1H), 7.29 (s, 1H), 7.71-7.75 (m, 2H), 7.85 (d, J= 8.4 Hz, 1H), 8.17 (d, J= 6.4 Hz, 1H).

[00584] Example 60

[00585] Synthesis of (4-aminopiperidin-l-yl)((2S,4S)-4-(4-chlorophenoxy)-l-((6-

(cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (60-1)

[00586] Compounds 60A-1 and 60-1 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compound 59E-1 and 60A-1 in lieu of

Compounds 13E-1 and 1G. Compound 60A-1: LC-MS (ESI) m/z: 698 [M+H]⁺. Compound 60-1: LC-MS (ESI) m/z: 598 [M+H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 1.40-1.91 (m, 9H), 2.04-2.12 (m, 5H), 2.42-2.84 (m, 2H), 3.15-3.24 (m, 1H), 3.37-42 (m, 1H), 3.58-3.71 (m, 2H), 4.23-4.80 (m, 3H), 5.01 (s, 1H), 6.76-6.82 (m, 2H), 7.18-7.28 (m, 3H), 7.34 (s, 1H), 7.61-7.80 (m, 1H), 7.82-7.98 (m, 2H), 8.39-8.42 (m, 1H).

[00587] Synthesis of (4-aminopiperidin-l-yl)((2S,4R)-4-(4-chlorophenoxy)-l-((6- (cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate

(60-2)

[00588] Compounds 60A-2 and 60-2 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compound 59E-2 and 60A-2 in lieu of

Compounds 13E-1 and 1G. Compound 60A-2: LC-MS (ESI) m/z: 698 [M+H]⁺. Compound 60-2: LC-MS (ESI) m/z: 598 [M+H]⁺; ¾-NMR (CD₃OD, 400 MHz): d (ppm) 1.50-2.01 (m, 8H), 2.04-2.12 (m, 5H), 2.32-2.44 (m, 1H), 2.78-2.94 (m, 1H), 3.55-3.58 (m, 2H), 3.64-3.82 (m, 2H), 4.38-4.40 (m, 1H), 4.62-4.73 (m, 1H), 4.80-5.08 (m, 3H), 6.06-6.11 (m, 2H), 6.78 (d, J= 8.8 Hz, 2H), 7.20 (d, J= 8.8 Hz, 1H), 7.30 (s, 1H), 7.73 (d, J= 8.8 Hz, 2H), 7.80-7.88 (m, 1H), 8.16 (s, 1H).

[00589] Example 61

[00590] Synthesis of (4-aminopiperidin-l-yl)((2S,4S)-4-(4-chlorophenoxy)-l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (61-1)

[00591] Compounds 61A-1, 61B-1, 61C-1, 61D-1, and 61-1 were synthesized by employing the procedures described for Compounds 13D-1, 59D-1, 30G, 13F-1, and 1 using Compounds 59B-1, 61A-1, 61B-1, 61C-1, and 61D-1 in lieu of Compounds 13C-1, 59C-1, 30F, 13E-1, and 1G. Compound 61A-1: LC-MS (ESI) m/z: 398 [M+H]⁺. Compound 61B-1: LC-MS (ESI) m/z: 508 [M+H]⁺. Compound 61C-1: LC-MS (ESI) m/z: 492 [M-H] .

Compound 61D-1: LC-MS (ESI) m/z: 676 [M+H]⁺. Compound 61-1: LC-MS (ESI) m/z: 576 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.08-1.17 (m, 2H), 1.23-1.39 (m, 3H), 1.46- 1.75 (m, 3H), 1.78-1.90 (m, 5H), 2.04-2.11 (m, 3H), 2.53-2.83 (m, 2H), 3.16-3.26 (m, 1H), 3.32-3.66 (m, 3H), 3.88 (d, J= 6.4 Hz, 2H), 4.28-4.79 (m, 4H), 6.80-6.85 (m, 2H), 7.12 (d, J = 6.4 Hz, 2H), 7.22-7.26 (m, 2H), 7.82-7.87 (m, 2H).

[00592] Synthesis of (4-aminopiperidin-l-yl)((2S,4R)-4-(4-chlorophenoxy)-l-((4- (cyclohexylmethoxy)phenyl)sulfonyl)pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (61 -2)

[00593] Compounds 61A-2, 61B-2, 61C-2, 61D-2, and 61-2 were synthesized by employing the procedures described for Compounds 13D-1, 59D-1, 30G, 13F-1, and 1 using Compounds 59B-2, 61A-2, 61B-2, 61C-2, and 61D-2 in lieu of Compounds 13C-1, 59C-1, 30F, 13E-1, and 1G. Compound 61A-2: LC-MS (ESI) m/z: 398 [M+H]⁺. Compound 61B-2: LC-MS (ESI) m/z: 508 [M+H]⁺. Compound 61C-2: LC-MS (ESI) m/z: 492 [M-H] .

Compound 61D-2: LC-MS (ESI) m/z: 676 [M+H]⁺. Compound 61-2: LC-MS (ESI) m/z: 576 [M+H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 1.13-1.39 (m, 5H), 1.51-1.95 (m, 8H), 2.07- 2.23 (m, 3H), 2.34-2.42 (m, 1H), 2.74-2.88 (m, 1H), 3.35-3.49 (m, 1H), 3.59-3.63 (m, 1H), 3.72-3.82 (m, 3H), 4.36-4.39 (m, 1H), 4.64-4.97 (m, 4H), 6.44-6.49 (m, 2H), 6.93 (d, J= 6.4 Hz, 2H), 7.13 (d, J= 6.4 Hz, 2H), 7.68 (d, J= 12 Hz, 2H).

[00594] Example 62

[00595] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4S)-4-(4- chlorophenoxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)pyrrolidin-2-yl)methanone 2,2,2- trifluoroacetate (62-1)

[00596] Compounds 62A-1 and 62-1 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compounds Bl, 61C-1, and 62A-1 in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 62A-1: LC-MS (ESI) m/z: 702 [M+H]⁺. Compounds 62-1: LC-MS (ESI) m/z: 602 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 1.08-1.17 (m, 2H), 1.23-1.39 (m, 3H), 1.69-1.95 (m, 11H), 2.03-2.16 (m, 4H), 2.52-2.70 (m, 1H), 3.53-3.58 (m, 2H), 3.65-3.74 (m, 1H), 3.89 (d, J= 6.4 Hz, 2H), 4.40-5.01 (m, 4H), 6.81-6.86 (m, 2H), 7.12-7.15 (m, 2H), 7.23-7.27 (m, 2H), 7.82- 7.90 (m, 2H).

[00597] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4R)-4-(4- chlorophenoxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)pynOlidin-2-yl)methanone 2,2,2- trifluoroacetate (62-2)

[00598] Compounds 62A-2 and 62-2 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compounds Bl, 61C-2, and 62A-2 in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 62A-2: LC-MS (ESI) m/z: 702 [M+H]⁺. Compound 62-2: LC-MS (ESI) m/z: 602 [M+H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 1.10-1.42 (m, 5H), 1.67-2.30 (m, 15H), 2.37-2.42 (m, 1H), 3.58-3.84 (m, 5H), 4.63-4.86 (m, 4H), 6.47 (d, J= 8.8 Hz, 2H), 6.93 (d, J= 6.4 Hz, 2H), 7.11-7.14 (m, 2H), 7.67-7.72 (m, 2H).

[00599] Example 63

[00600] Synthesis of ((2S,4S)-4-([l,l'-biphenyl]-4-yloxy)-l-((6-

(cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2-yl)(3-amino-8- azabicyclo[3.2. l]octan-8-yl)methanone 2,2,2-trifluoroacetate (63-1)

[00601] Compounds 63A-1, 63B-1, 63C-1, and 63-1 were synthesized by employing the procedures described for Compounds 59D-1, 30G, 13F-1, and 1 using [l,l'-biphenyl]-4- ol, Compounds 59C-1, 63A-1, 63B-1, Bl, and 63C-1 in lieu of 4-chlorophenol, Compounds 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 1G. Compound 63A-1: LC-MS (ESI) m/z: 572 [M+H]⁺. Compound 63B-1: LC-MS (ESI) m/z: 558 [M+H]⁺. Compound 63C-1: LC-MS (ESI) m/z: 766 [M+H]⁺. Compound 63-1: LC-MS (ESI) m/z: 666 [M+H]⁺; 'H-NMR (DMSO-A 400 MHz): d (ppm) 1.56-2.12 (m, 18H), 3.36-3.62 (m, 2H), 3.68-3.94 (m, 1H), 4.47-4.55 (m, 1H), 4.58-4.75 (m, 3H), 4.98-5.05 (m, 1H), 6.82-6.92 (m, 2H), 7.28-7.34 (m, 2H), 7.39-7.60 (m, 7H), 7.70-7.96 (m, 4H), 8.01-8.13 (m, 2H), 8.42-8.50 (m, 1H).

[00602] Synthesis of ((2S,4R)-4-([l,l'-biphenyl]-4-yloxy)-l-((6- (cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2-yl)(3-amino-8- azabicyclo[3.2. l]octan-8-yl)methanone 2,2,2-trifluoroacetate (63-2)

[00603] Compounds 63A-2, 63B-2, 63C-2, and 63-2 were synthesized by employing the procedures described for Compounds 59D-1, 30G, 13F-1, and 1 using [l,l'-biphenyl]-4- ol, Compounds 59C-2, 63A-2, 63B-2, B2, and 63C-2 in lieu of 4-chlorophenol, Compounds 59C-1, 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 1G. Compound 63A-2: LC-MS (ESI) m/z: 572 [M+H]⁺. Compound 63B-2: LC-MS (ESI) m/z: 558 [M+H]⁺. Compound 63C- 2: LC-MS (ESI) m/z: 766 [M+H]⁺. Compound 63-2: LC-MS (ESI) m/z: 666 [M+H]⁺; Ή- NMR (DMSO-A 400 MHz): d (ppm) 1.56-2.36 (m, 18H), 3.55-3.76 (m, 3H), 4.52-4.62 (m, 1H), 4.68-4.78 (m, 1H), 4.78-4.88 (m, 1H), 4.93-5.08 (m, 2H), 6.28-6.38 (m, 2H), 7.14-7.26 (m, 2H), 7.27-7.34 (m, 1H), 7.38-7.50 (m, 6H), 7.72-8.00 (m, 6H), 8.23-8.31 (m, 1H).

[00604] Example 64

[00605] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4R)-4-(3-butoxy-4- chlorophenoxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (64-1)

[00606] A mixture of Compound 64A (2 g, 13.8 mmol), l-bromobutane (2.28 g, 16.6 mmol), and KF (l.6g, 27.6 mmol) in acetonitrile (20 mL) was stirred at 80 °C overnight. The mixture was filtered and concentrated to give a crude product, which was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 10% to 33% v/v) to furnish Compound 64B: LC-MS (ESI) m/z: 201 [M+H]⁺. Ή-NMR (DMSO-r/e, 400 MHz): d (ppm) 0.916 (t, J= 7.2 Hz, 3H), 1.42-1.48 (m, 2H), 1.66-1.71 (m, 2H), 3.94-3.97 (m, 2H), 6.33-6.36 (m, 1H), 6.50-6.51 (m, 1H), 7.13-7.15 (m, 1H), 9.64 (s, 1H).

[00607] Compounds 64C-1, 64D-1, 64E-1, and 64-1 were synthesized by employing the procedures described for Compounds 59D-2, 30G, 13F-1, and 3 using Compounds 64B, 59C-2, 64C-1, 64D-1, Bl, and 64E-1 in lieu of 4-chlorophenol, Compounds 59C-2, 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 3A. Compound 64C-1: LC-MS (ESI) m/z: 602 [M+H]⁺. Compound 64D-1: LC-MS (ESI) m/z: 586 [M-H] . Compound 64E-1: LC-MS (ESI) m/z: 796 [M+H]⁺. Compound 64-1: LC-MS (ESI) m/z: 696 [M+H]⁺; Ή-NMR (CD₃OD, 400 MHz): d (ppm) 0.99 (t, J= 7.2 Hz, 3H), 1.46-2.41 (m, 22H), 3.42-3.49 (m, 2H), 3.83-3.87 (m, 3H), 4.61-4.86 (m, 4H), 5.02-5.04 (m, 1H), 5.46-5.51 (m, 1H), 5.93-5.96 (m, 1H), 6.91-6.97 (m, 1H), 7.21-7.29 (m, 2H), 7.75-7.86 (m, 3H), 8.25 (s, 1H). [00608] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4S)-4-(3-butoxy-4- chlorophenoxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (64-2)

[00609] Compounds 64C-2, 64D-2, 64E-2, and 64-2 were synthesized by employing the procedures described for Compounds 59D-1, 30G, 13F-1, and 3 using Compounds 64B, 59C-1, 64C-2, 64D-2, Bl, and 64E-2 in lieu of 4-chlorophenol, Compounds 59C-1, 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 3A. Compound 64C-2: LC-MS (ESI) m/z: 602 [M+H]⁺. Compound 64D-2: LC-MS (ESI) m/z: 586 [M-H] . Compound 64E-2: LC-MS (ESI) m/z: 796 [M+H]⁺. Compound 64-2: LC-MS (ESI) m/z:696 [M+H]⁺; Ή-NMR (CD3OD, 400 MHz): d (ppm) 1.00 (t, J= 7.2 Hz, 3H), 1.49-2.15 (m, 21H), 2.49-2.64 (m, 1H), 3.61-3.73 (m, 3H), 3.90-3.94 (m, 2H), 4.51-4.86 (m, 4H), 5.01-5.04 (m, 1H), 6.32-6.52 (m, 2H), 7.14-7.35 (m, 3H), 7.84-7.99 (m, 3H), 8.40-8.45 (m, 1H).

[00610] Example 65

[00611] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4S)-l-((6-

(cyclopentyloxy)naphthalen-2-yl)sulfonyl)-4-phenoxypyrrolidin-2-yl)methanone 2,2,2- trifluoroacetate (65)

[00612] To a solution of Compound 59D-1 (100 mg, 0.19 mmol) in EtOH (20 mL) was added PtCh (20 mg) and stirred at 80 °C under Eh atmosphere (2 MPa) for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford a crude Compound 65A: LC-MS (ESI) m/z: 496 [M+H]⁺.

[00613] Compounds 65B, 65C, and 65 were synthesized by employing the procedures described for Compounds 30G, 13F-1, and 1 using Compounds 65A, 65B, Bl, and 65C in lieu of Compounds 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 1G. Compound 65B: LC-MS (ESI) m/z: 482 [M+H]⁺. Compound 65C: LC-MS (ESI) m/z: 690 [M+H]⁺.

Compound 65: LC-MS (ESI) m/z: 590 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.69- 1.92 (m, 11H), 2.04-2.15 (m, 6H), 2.52-2.70 (m, 1H), 3.59-377 (m, 3H), 4.51-5.08 (m, 5H), 6.78-6.83 (m, 2H), 6.90-6.96 (m, 1H), 7.19-7.28 (m, 3H), 7.35 (s, 1H), 7.82-7.9l(m, 1H),

7.99 (d, J= 8.8 Hz, 2H), 8.40-8.45 (m, 1H).

[00614] Example 66

[00615] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4R)-4-((6-chloro-

[1,1 '-biphenyl]-3 -yl)oxy)- 1 -((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2- yl)methanone 2,2,2-trifluoroacetate (66-1)

[00616] Compounds 66A-1, 66B-1, 66C-1, and 66-1 were synthesized by employing the procedures described for Compounds 59D-2, 49B, 13F-1, and 1 using 3-bromo-4- chlorophenol, Compounds 59C-2, 66A-1, phenylboronic acid, 66B-1, Bl, and 66C-1 in lieu of 4-chlorophenol, Compounds 59C-2, 49A, (4-(trifluoromethyl)phenyl)boronic acid, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 1G. Compound 66A-1: LC-MS (ESI) m/z:

608[M+H]⁺. Compound 66B-1: LC-MS (ESI) m/z: 590 [M-H] . Compound 66C-1: LC-MS (ESI) m/z: 800 [M+H]⁺. Compound 66-1: LC-MS (ESI) m/z: 700 [M+H]⁺; 'H-NMR

(CD3OD, 400 MHz): d (ppm) 1.68-2.44 (m, 19H), 3.71-3.84 (m, 3H), 4.67-4.88 (m, 4H), 6.12 (d , J= 2.8 Hz, 1H), 6.19-6.24 (m, 1H), 6.97 (t, J= 8.8 Hz, 1H), 7.16-7.22 (m, 4H), 7.36-7.44 (m, 3H), 7.74-7.86 (m, 3H), 8.27 (s, 1H).

[00617] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4S)-4-((6-chloro- [1,1 '-biphenyl]-3 -yl)oxy)- 1 -((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2- yl)methanone 2,2,2-trifluoroacetate (66-2)

[00618] Compounds 66A-2, 66B-2, 66C-2, and 66-2 were synthesized by employing the procedures described for Compounds 59D-1, 49B, 13F-1, and 1 using 3-bromo-4- chlorophenol, Compounds 59C-1, 66A-2, phenylboronic acid, 66B-2, 1, and 66C-2 in lieu of 4-chlorophenol, Compounds 59C-1, 49A, (4-(trifluoromethyl)phenyl)boronic acid, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 1G. Compound 66A-2: LC-MS (ESI) m/z: 608

[M+H]⁺. Compound 66B-2: LC-MS (ESI) m/z: 590 [M-H] . Compound 66C-2: LC-MS (ESI) m/z: 800 [M+H]⁺. Compound 66-2: LC-MS (ESI) m/z: 700 [M+H]⁺; Ή-NMR (CD3OD, 400 MHz): d (ppm) 1.67-2.17 (m, 18H), 2.50-2.67 (m, 1H), 3.60-3.75 (m, 3H), 4.52-4.81 (m, 3H), 5.01-5.04 (m, 1H), 6.76-6.86 (m, 2H), 7.25 (d, J= 8.8 Hz, 1H), 7.32-7.44 (m, 7H), 7.81-7.97 (m, 3H), 8.39-8.44 (m, 1H).

[00619] Example 67

[00620] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4R)-4-(4-chloro-3- phenoxyphenoxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2- yl)methanone 2,2,2-trifluoroacetate (67-1)

[00621] To a mixture of Compound 67A (l.OOg, 5.4mmol) in acetonitrile (40mL) and TFA (0.5mL) was added N-chlorosuccinimide (7l7mg, 5.4mmol) and stirred at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified with preparative HPLC to afford Compound 67B: LC-MS (m/z): 219 [M-H]-. ¹H-NMR (DMSO-£¾ 400 MHz): d (ppm) 6.40 (d, J= 2.8 Hz, 1H), 6.60 (dd, J= 8.8, 2.8Hz, 1H), 6.98 (d, J= 8.0 Hz, 2H), 7.15 (t, J= 7.2 Hz, 1H), 7.34 (d, J= 8.8 Hz, 1H), 7.40 (d, J= 8.0 Hz, 2H), 9.85 (s, 1H).

[00622] Compounds 67C-1, 67D-1, 67E-1, and 67-1 were synthesized by employing the procedures described for Compounds 59D-2, 30G, 13F-1, and 1 using Compounds 67B, 67C-1, 67D-1, Bl, and 67E-1 in lieu of 4-chlorophenol, Compounds 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 1G. Compound 67C-1: LC-MS (ESI) m/z: 622 [M+H]⁺.

Compound 67D-1 was used directly in the next step without further purification. LC-MS (ESI) m/z: 608 [M+H]⁺. Compound 67E-1 was used directly in the next step without further purification. LC-MS (ESI) m/z: 816 [M+H]⁺. Compound 67-1: LC-MS (ESI) m/z: 716

[M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.78-2.32 (m, 18H), 2.86-2.88 (m, 1H), 2.99-3.02 (m, 1H), 3.78-3.80 (m, 3H), 4.64-4.78 (m, 3H), 5.81-5.86 (m, 1H), 6.05-6.10 (m, 1H), 6.75-6.81 (m, 2H), 6.94-7.01 (m, 1H), 7.06-7.14 (m, 1H), 7.18-7.26 (m, 2H), 7.30-7.38 (m, 2H), 7.69-7.84 (m, 3H), 8.20-8.25 (m, 1H).

[00623] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4S)-4-(4-chloro-3- phenoxyphenoxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2- yl)methanone 2,2,2-trifluoroacetate (67-2)

[00624] Compounds 67C-2, 67D-2, 67E-2, and 67-2 were synthesized by employing the procedures described for Compounds 59D-1, 30G, 13F-1, and 1 using Compounds 67B, 59C-2, 67C-2, 67D-2, Compound Bl, and 67E-2 in lieu of 4-chlorophenol, Compounds 59C- 1, 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 1G. Compound 67C-2: LC-MS (ESI) m/z: 622 [M+H]⁺. Compound 67D-2 was used directly in the next step without further purification. LC-MS (ESI) m/z: 608 [M+H]⁺. Compound 67E-2 was used directly in the next step without further purification. LC-MS (ESI) m/z: 838 [M+Na]⁺. Compound 67-2: LC-MS (ESI) m/z: 716 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.38-2.26 (m, 18H), 2.62- 2.84 (m, 2H), 3.38-3.66 (m, 3H), 4.48-4.66 (m, 3H), 5.55-5.90 (m, 2H), 6.50-7.20 (m, 8H), 7.45-7.60 (m, 3H), 7.96-8.04 (m, 1H).

[00625] Example 68

Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S)-4-((4-chlorophenyl)amino)-l-((6- (cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2-yl)methanone (68), (3-amino-8- azabicyclo[3.2. l]octan-8-yl)((2S,4R)-4-((4-chlorophenyl)amino)-l-((6- (cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2-yl)methanone 2,2,2-trifluoroacetate (68-1), and (3-amino-8-azabicyclo[3.2. l]octan-8-yl)((2S,4S)-4-((4-chlorophenyl)amino)-l- ((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)pyrrolidin-2-yl)methanone 2,2,2- trifluoroacetate (68-2)

[00626] To a solution of Compound 59C-2 (2.3 g, 5.48 mol) in dichloromethane (50 mL) was added l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (Dess-Martin reagent; 2.79 g, 6.58 mmol) at 0 °C and stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (250 mL) and filtrated to remove the precipitate. The filtrate was washed with saturated NaHCCb solution (100 mL) and water (100 mL x 2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 33% v/v) to give Compound 68A: LC-MS (ESI) m/z: 418 [M+H]⁺.

[00627] To a mixture of Compound 68A (500 mg, 1.2 mmol) and 4-chloroaniline (229 mg, 1.8 mmol) in CHCh (10 mL) was added tetraisopropoxytitanium (682 mg, 2.4 mmol) and stirred at 60 °C overnight. To the mixture was added MeOH (10 mL) and NaBEE (456 mg, 12 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with dichlorom ethane (100 mL) and water (100 mL), stirred at room temperature for 30 minutes, and filtrated. The organic layer was washed with water (100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford Compound 68B, which was used directly in next step without further purification. LC-MS (ESI) m/z: 557 [M+H]⁺.

[00628] Compounds 68C, 68D, and 68 were synthesized by employing the procedures described for Compounds 30G, 13F-1, and 3 using Compounds 68B, 68C, Compound Bl, and 68D in lieu of Compounds 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 3A.

Compound 68C: LC-MS (ESI) m/z: 515 [M+H]⁺. Compound 68D: LC-MS (ESI) m/z: 723 [M+H]⁺. Compound 68 was separated with preparative HPLC to give Compound 68-1 and Compound 68-2. Compound 68- 1: LC-MS (ESI) m/z: 623 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.71-2.31 (m, 19H), 3.43-3.53 (m, 1H), 3.65-3.82 (m, 2H), 3.92-3.99 (m, 1H), 4.77-4.82 (m, 2H), 5.02-5.05 (m, 1H), 5.97-6.01 (m, 2H), 6.69-6.74 (m, 2H), 7.17-7.20 (m, 1H), 7.25 (s, 1H), 7.65-7.71 (m, 2H), 7.79-7.83 (m, 1H), 8.13-8.16 (m, 1H). Compound 68-2: LC-MS (ESI) m/z: 623 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.62-2.17 (m, 19H), 2.42-2.60 (m, 1H), 3.61-3.87 (m, 3H), 4.75-4.79 (m, 2H), 5.02-5.05 (m, 1H), 6.41-6.50 (m, 2H), 6.97-7.02 (m, 2H), 7.26-7.36 (m, 2H), 7.78-8.00 (m, 3H), 8.36-8.43 (m, 1H).

[00629] Example 69

[00630] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4S)-4-(4- chlorophenoxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (69-1)

[00631] Compounds 69B, 69C, 69D, and 69E were synthesized by employing the procedures described for Compounds 1C, 59B-1, 13D-1, and 59D-1 using Compounds 69A, 69B, 69C, Al, and 69D in lieu of Compounds IB, 59A-1, 13C-1, A2, and 59C-1. Compound 69B: LC-MS (ESI) m/z: 246 [M+H]⁺. Compound 69C: LC-MS (ESI) m/z: 160 [M+H]⁺. Compound 69D: LC-MS (ESI) m/z: 434 [M+H]⁺. Compound 69E was separated by preparative TLC (ethyl acetate in petroleum ether, 25% v/v) to yield Compound 69E-1 and Compound 69E-2. Compound 69E-1: LC-MS (ESI) m/z: 544 [M+H]⁺. Compound 69E-2: LC-MS (ESI) m/z: 544 [M+H]⁺.

[00632] Compounds 69F-1, 69G-1, and 69-1 were synthesized by employing the procedures described for Compounds 30G, 13F-1, and 1 using Compounds 69E-1, 69F-1,

Bl, and 69G-1 in lieu of Compounds 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 1G. Compound 69F-1: LC-MS (ESI) m/z: 530 [M+H]⁺. Compound 69G-1: LC-MS (ESI) m/z: 738 [M+H]⁺. Compound 69-1: LC-MS (ESI) m/z: 638 [M+H]⁺; Ή-NMR (CD3OD, 400 MHz): d (ppm) 1.01-1.50 (m, 2H), 1.62-2.26 (m, 19H), 3.57-3.78 (m, 2H), 3.96-4.00 (m, 1H), 4.53-4.80 (m, 1H), 4.93-5.03 (m, 2H), 5.19-5.34 (m, 1H), 6.75-6.84 (m, 2H), 7.14-7.36 (m, 4H), 7.75-7.99 (m, 3H), 8.34-8.44 (m, 1H).

[00633] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4R)-4-(4- chlorophenoxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (69-2)

[00634] Compounds 69F-2 and 69F-3 were synthesized by employing the procedure described for Compound 30G using Compound 69E-2 in lieu of Compounds 30F. Compound 69F-2: LC-MS (ESI) m/z: 530 [M+H]⁺. Compound 69F-3: LC-MS (ESI) m/z: 530 [M+H]⁺.

[00635] Compounds 69G-2 and 69-2 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compounds Bl, 69F-2, and 69G-2 in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 69G-2: LC-MS (ESI) m/z: 738 [M+H]⁺. Compound 69-2: LC-MS (ESI) m/z: 638 [M+H]⁺; ¾-NMR

(CD3OD, 400 MHz): d (ppm) 1.06 (s, 1H), 1.45-2.09 (m, 19H), 3.55-3.65 (m, 2H), 4.11-4.18 (m, 1H), 4.21 (s, 1H), 4.31 (s, 1H), 4.64 (s, 1H), 4.91-4.95 (m, 1H), 5.00-5.05 (m, 1H), 6.80 (d, J= 8.8 Hz, 2H), 7.20-7.33 (m, 4H), 7.81-7.84 (m, 1H), 7.93-7.96 (m, 2H), 8.04 (s, 1H).

[00636] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2R,4R)-4-(4- chlorophenoxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (69-3)

[00637] Compounds 69G-3 and 69-3 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compounds Bl, 69F-3, and 69G-3 in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 69G-3: LC-MS (ESI) m/z: 738 [M+H]⁺. Compound 69-3: LC-MS (ESI) m/z: 638 [M+H]⁺; 'H-NMR

(CD3OD, 400 MHz): d (ppm) 1.02-1.35 (m, 1H), 1.42-1.77 (m, 5H), 1.83-1.97 (m, 7H), 2.00- 2.25 (m, 7H), 3.56-3.77 (m, 2H), 3.97-4.00 (m, 1H), 4.54-4.85 (m, 2H), 5.05 (s, 1H), 5.19 (s, 1H), 5.35 (s, 1H), 6.75-6.84 (m, 2H), 7.14-7.29 (m, 3H), 7.34-7.36 (m, 1H), 7.75-8.00 (m, 3H), 8.34-8.45 (m, 1H).

[00638] Example 70

[00639] Synthesis of (4-aminopiperidin-l-yl)((2S,4S)-4-(4-chlorophenoxy)-l-((6-

(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate

(70)

[00640] Compounds 70A and 70 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compounds 69F-1 and 70A in lieu of

Compounds 13E-1 and 1G. Compounds 70A: LC-MS (ESI) m/z: 712 [M+H]⁺. Compounds 70: LC-MS (ESI) m/z: 612 [M+H]⁺; ¹H-NMR (CD3OD, 400 Hz): d (ppm) 1.13-1.59 (m, 3H), 1.70-2.20 (m, 13H), 2.59-2.79 (m, 1H), 3.14-3.24 (m, 1H), 3.38-3.64 (m, 2H), 3.88-3.96 (m, 1H), 4.33-4.59 (m, 2H), 4.77(s, 1H), 5.03 (s, 1H), 5.31-5.42 (m, 1H), 6.76-6.80 (m, 2H), 7.15-7.35 (m, 4H), 7.75-7.97 (m, 3H), 8.33-8.40 (m, 1H).

[00641] Example 71

[00642] Synthesis of (4-aminopiperidin-l-yl)((2S,4S)-4-(4-chlorophenoxy)-l-((4-

(cy cl ohexylmethoxy)phenyl)sulfonyl)piperi din-2 -yl)methanone 2,2,2-trifluoroacetate (71)

[00643] Compounds 71A and 71B were synthesized by employing the procedures described for Compounds 13D-1 and 59D-1 using Compounds 69C and 71A in lieu of Compounds 13C-1 and 59C-1.

[00644] Compound 71A: LC-MS (ESI) m/z: 412 [M+H]⁺.

[00645] Compound 71B was separated with preparative HPLC to yield Compound 71B-1 and Compound 71B-2. Compound 71B-1: LC-MS (ESI) m/z: 522 [M+H]⁺. Compound 71B-2: LC-MS (ESI) m/z: 522 [M+H]⁺.

[00646] Compounds 71C, 71D, and 71 were synthesized by employing the procedures described for Compounds 30G, 13F-1, and 1 using Compounds 71B-1, 71C, and 70D in lieu of Compounds 30F, 13E-1, and 1G. Compound 71C: LC-MS (ESI) m/z: 508 [M+H]⁺.

Compound 71D: LC-MS (ESI) m/z: 712 [M+Na]⁺. Compound 71: LC-MS (ESI) m/z: 590 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.12-1.40 (m, 7H), 1.48-1.58 (m, 2H), 1.73- 1.92 (m, 8H), 2.04-2.30 (m, 2H), 2.72-2.78 (m, 1H), 3.14-3.21 (m, 1H), 3.39-3.54 (m, 2H), 3.77-3.90 (m, 3H), 4.41-4.60 (m, 2H), 4.76-4.84 (m, 1H), 5.22-5.34 (m, 1H), 6.83-6.85 (m, 2H), 7.08-7.12 (m, 2H), 7.19-7.23 (m, 2H), 7.76-7.85 (m, 2H).

[00647] Example 72

[00648] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4S)-4-(4- chlorophenoxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2- trifluoroacetate (72-1)

[00649] Compounds 72A-1 and 72-1 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compounds Bl, Compounds 71C, and 72A-1 in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compounds 72A-1: LC-MS (ESI) m/z: 716 [M+H]⁺. Compounds 72-1: LC-MS (ESI) m/z: 616 [M+H]⁺; Ή-NMR (CD3OD, 400 MHz): d (ppm) 1.09-1.48 (m, 7H), 1.64-2.25 (m, 16H), 3.47-3.56 (m, 1H), 3.67-3.75 (m, 1H), 3.83-3.91 (m, 3H), 4.63-4.77 (m, 1H), 4.83-4.91 (m, 1H), 4.91-4.96 (m, 1H), 5.13-5.26 (m, 1H), 6.83-6.89 (m, 2H), 7.08-7.14 (m, 2H), 7.19-7.23 (m, 2H), 7.77-7.89 (m, 2H).

[00650] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4R)-4-(4- chlorophenoxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2- trifluoroacetate (72-2)

[00651] Compounds 72A-2 and 72A-3 were synthesized by employing the procedure described for Compound 30G using Compound 71B-2 in lieu of Compounds 30F. Compound 72A-2: LC-MS (ESI) m/z: 508 [M+H]⁺. Compound 72A-3: LC-MS (ESI) m/z: 508 [M+H]⁺.

[00652] Compounds 72B-2 and 72-2 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compounds Bl, 72A-2, and 72B-2 in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 72B-2: LC-MS (ESI) m/z: 716 [M+H]⁺. Compound 72-2: LC-MS (ESI) m/z: 616 [M+H]⁺; ¾-NMR

(CD3OD, 400 MHz): d (ppm) 1.04-1.91 (m, 20H), 2.02-2.06 (m, 2H), 2.31-2.35 (m, 1H), 3.50-3.58 (m, 2H), 3.88 (d, J= 6 Hz, 2H), 4.05-4.10 (m, 1H), 4.20 (s, 1H), 4.28 (s, 1H), 4.66 (m, 1H), 4.85-4.86 (s, 1H), 6.82 (d, j= 6 Hz, 2H), 7.07 (d, j= 6 Hz, 2H), 7.22 (d, j= 6 Hz, 2H), 7.83 (d, = 6 Hz, 2H).

[00653] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2R,4R)-4-(4- chlorophenoxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2- trifluoroacetate (72-3)

[00654] Compounds 72B-3 and 72-3 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compounds Bl, 72A-3, and 72B-3 in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 72B-3: LC-MS (ESI) m/z: 716 [M+H]⁺. Compound 72-3: LC-MS (ESI) m/z: 616 [M+H]⁺; ¾-NMR

(CD3OD, 400 MHz): d (ppm) 1.09-1.48 (m, 7H), 1.63-2.25 (m, 16H), 3.45-3.57 (m, 1H), 3.66-3.76 (m, 1H), 3.83-3.91 (m, 3H), 4.62-4.95 (m, 3H), 5.11-5.25 (m, 1H), 6.82-6.89 (m, 2H), 7.08-7.13 (m, 2H), 7.18-7.23 (m, 2H), 7.77-7.89 (m, 2H).

[00655] Example 73

[00656] Synthesis of (4-aminopiperidin-l-yl)((2S,4S)-4-((4'-chloro-[l,r-biphenyl]-4- yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2- trifluoroacetate (73)

[00657] To a solution of Compound 69A (243 mg, 1 mmol) in THF (10 mL) was added L-selectride (1.5 mL, 1.5 mmol) at 0 °C and stirred at 0 °C for 3 hours. The reaction mixture was quenched with 1 N HC1 (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give a crude Compound 73A: LC-MS (ESI) m/z: 268 [M+Na]⁺.

[00658] Compounds 73B, 73C, 73D, 73E, 73F, and 73 were synthesized by employing the procedures described for Compounds 59B-1, 13D-1, 59D-1, 30G, 13F-1, and 1 using Compounds 73A, 73B, 73C, 4'-chloro-[l,T-biphenyl]-4-ol, 73D, 73E, and 73F in lieu of Compounds 59A-1, 13C-1, 59C-1, 4-chlorophenol, 30F, 13E-1, and 1G. Compound 73B: LC-MS (ESI) m/z: 160 [M+H]⁺. Compound 73C: LC-MS (ESI) m/z: 412 [M+H]⁺.

Compound 73D: LC-MS (ESI) m/z: 598 [M+H]⁺. Compound 73E: LC-MS (ESI) m/z: 584 [M+H]⁺. Compound 73F as a colorless oil (50 mg, crude). LC-MS (ESI) m/z: 788 [M+Na]⁺. Compound 73: LC-MS (ESI) m/z: 666 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.09- 2.24 (m, 20H), 2.72-2.79 (m, 1H), 3.13-3.25 (m, 1H), 3.38-3.59 (m, 2H), 3.77-3.90 (m, 3H), 4.41-4.62 (m, 2H), 5.23-5.34 (m, 1H), 6.93 (d, J= 8.4 Hz, 2H), 7.08-7.12 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.48-7.54 (m, 4H), 7.76-7.85 (m, 2H). [00659] Example 74

[00660] Synthesis of ((S)-3-aminopyrrolidin-l-yl)((2S,4S)-4-((4'-chloro-[l,l'- biphenyl]-4-yl)oxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone

(74)

[00661]

[00662] Compounds 74A and 74 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using (S)-tert-butyl pyrrolidin-3-ylcarbamate, Compounds 73E, and 74A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 74A: LC-MS (ESI) m/z: 774 [M+Na]⁺. Compound 74: LC-MS (ESI) m/z: 652 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.09-1.41 (m, 7H), 1.58-2.50 (m, 11H), 3.45-4.18 (m, 9H), 5.04-5.11 (m, 1H), 6.95 (t , J= 9.6 Hz, 2H), 7.12 (d, J= 8.8 Hz, 2H), 7.39 (d, J= 8.8 Hz, 2H), 7.48-7.54 (m, 4H), 7.79-7.84 (m, 2H).

[00663] Example 75

[00664] Synthesis of ((R)-3-aminopyrrolidin-l-yl)((2S,4S)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone

(75)

[00665] Compounds 75A and 75 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using (R)-tert-butyl pyrrolidin-3-ylcarbamate, Compounds 73E, and 75A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 75A: LC-MS (ESI) m/z: 774 [M+Na]⁺. Compound 75: LC-MS (ESI) m/z: 652 [M+H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 1.08-1.42 (m, 7H), 1.54-2.55 (m, 11H), 3.49-4.19 (m, 9H), 5.06-5.07 (m, 1H), 6.95 (d, J= 8.4 Hz, 2H), 7.12 (t , J= 9.6 Hz, 2H), 7.39 (d, J= 8.4 Hz, 2H), 7.48-7.54 (m, 4H), 7.77-7.85 (m, 2H).

[00666] Example 76

[00667] Synthesis of ((lR,5S,8S)-8-amino-3-azabicyclo[3.2.l]octan-3-yl)((2S,4S)-4-

((4'-chloro-[ 1 , 1 '-biphenyl]-4-yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (76)

[00668] Compounds 76A and 76 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using tert-butyl ((lR,5S,8r)-3-azabicyclo[3.2. l]octan- 8-yl)carbamate, Compounds 73E, and 76A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 76A: LC-MS (ESI) m/z: 814 [M+Na]⁺. Compound 76: LC-MS (ESI) m/z: 692 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.14-1.37 (m, 7H), 1.58-1.94 (m, 11H), 2.10-2.39 (m, 3H), 2.95-3.03 (m, 1H), 3.30-4.14 (m, 8H), 4.78-4.82 (m, 1H), 5.29-5.31 (m, 1H), 6.89-6.96 (m, 4H), 7.38-7.40 (m, 2H), 7.47-7.53 (m, 4H), 7.81- 7.83 (m, 2H).

[00669] Example 77

[00670] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4S)-4-((4'-chloro-

[1,1 '-biphenyl]-4-yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (77)

[00671] Compounds 77A and 77 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using tert-butyl 8-azabicyclo[3.2. l]octan-3- ylcarbamate, Compounds 73E, and 77A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 77A: LC-MS (ESI) m/z: 814 [M+Na]⁺. Compound 77: LC-MS (ESI) m/z: 692 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.08-1.42 (m, 6H), 1.60-2.32 (m, 19H), 3.75-3.95 (m, 5H), 4.58-4.80 (m, 1H), 5.10-5.26 (m, 1H), 6.88-7.00 (m, 2H), 7.05-7.16 (m, 2H), 7.35-7.42 (m, 2H), 7.44-7.56 (m, 4H), 7.72-7.81 (m, 1H), 7.85- 7.90 (m, 1H).

[00672] Example 78

[00673] Synthesis of ((2S,4S)-4-((4'-chloro-[l,l'-biphenyl]-4-yl)oxy)-l-((4-

(cyclohexylmethoxy) phenyl)sulfonyl)piperidin-2-yl)(piperazin- 1 -yl)methanone 2,2,2- trifluoroacetate (78)

Boc

[00674] Compounds 78A and 78 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl piperazine- l-carboxylate, Compounds 73E, and 78A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 78A: LC-MS (ESI) m/z: 752 [M+H]⁺. Compound 78: LC-MS (ESI) m/z: 652 [M+H]⁺; 1H-NMR (CD₃OD, 400 MHz): d (ppm) 1.08-1.40 (m, 8H), 1.55-1.95 (m, 9H), 2.24- 2.27 (m, 1H), 3.19-3.26 (m, 1H), 3.47-3.54 (m, 1H), 3.66-3.98 (m, 6H), 4.20-4.26 (m, 1H), 4.91-4.95 (m, 1H), 5.24-5.25 (m, 1H), 6.93-6.95 (m, 2H), 7.11-7.13 (m, 2H), 7.37-7.40 (m, 2H), 7.48-7.53 (m, 4H), 7.83-7.85 (m, 2H).

[00675] Example 79

[00676] Synthesis of ((lR,5S,8S)-8-amino-3-azabicyclo[3.2.l]octan-3-yl)((2S,4S)-4-

((4'-chloro-[ 1 , 1 '-biphenyl]-4-yl)oxy)- 1 -((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (79)

[00677] Compounds 79A, 79B, 79C, 79D, and 79 were synthesized by employing the procedures described for Compounds 13D-1, 59D-1, 30G, 13F-1, and 3 using Compounds Al, Compounds 73B, 79A, 4'-chloro-[l,l'-biphenyl]-4-ol, 79B, 79C, tert-butyl ((lR,5S,8r)-3- azabicyclo[3.2. l]octan-8-yl)carbamate, and 79E in lieu of Compounds A2, 13C-1, 59C-1, 4- chlorophenol, 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 3A. Compound 79A: LC- MS (ESI) m/z: 434 [M+H]⁺. Compound 79B: LC-MS (ESI) m/z: 620 [M+H]⁺. Compound 79C: LC-MS (ESI) m/z: 606 [M+H]⁺. Compound 79: LC-MS (ESI) m/z: 714 [M+H]⁺; ¾- NMR (CD3OD, 400 MHz): d (ppm) 1.27-2.39 (m, 18H), 2.91-3.05 (m, 1H), 3.37-4.19 (m, 6H), 4.69-4.94 (m, 1H), 4.99 (s, 1H), 5.36-5.37 (m, 1H), 6.89 (d, J= 8.8 Hz, 2H), 7.24-7.52 (m, 8H), 7.79-7.83 (m, 1H), 7.93-7.97 (m, 2H), 8.38-8.39 (m, 1H).

[00678] Example 80

[00679] Synthesis of (4-aminopiperidin-l-yl)((2S,4S)-4-((4'-chloro-[l,r-biphenyl]-4- yl)oxy)- 1 -((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2-yl)methanone 2,2,2- trifluoroacetate (80)

[00680] Compounds 80A and 80 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compounds 79C and 80A in lieu of Compounds 13E-1 and 1G. Compound 80A: LC-MS (ESI) m/z: 732 [M-55]⁺. Compound 80: LC-MS (ESI) m/z: 688 [M+H]⁺; ¾-NMR (CD₃OD, 400 MHz): d (ppm) 1.21-2.21 (m, 16H), 2.60- 2.79 (m, 1H), 3.14-3.31 (m, 1H), 3.36-3.47 (m, 1H), 3.59-3.70 (m, 1H), 3.87-3.96 (m, 1H), 4.34-4.61 (m, 2H), 4.78-4.84 (m, 1H), 5.00-5.04 (m, 1H), 5.31-5.43 (m, 1H), 6.85-6.87 (m, 2H), 7.25-7.5 l(m, 8H), 7.75-8.10 (m, 3H), 8.33-8.41 (m, 1H).

[00681] Example 81

[00682] Synthesis of ((2S,4S)-4-((4'-chloro-[l,l'-biphenyl]-4-yl)oxy)-l-((6-

(cyclopentyloxy) naphthalen-2-yl)sulfonyl)piperi din-2 -yl)(piperazin- 1 -yl)methanone 2,2,2- trifluoroacetate (81)

Boc Boc

[00683] Compounds 81A and 81 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using tert-butyl piperazine- l-carboxylate, Compounds 79C, and 81A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 81A: LC-MS (ESI) m/z: 718 [M-55]⁺. Compound 81: LC-MS (ESI) m/z: 674 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.29-1.30 (m, 2H), 1.72-2.30 (m, 11H), 3.15-3.27 (m, 4H), 3.56-3.71 (m, 2H), 3.91-4.00 (m, 3H), 4.21-4.28 (m, 1H), 5.03-5.04 (m, 1H), 5.34-5.35 (m, 1H), 6.87 (d, J= 8.8 Hz, 2H), 7.26-7.51 (m, 8H), 7.82 (d, J= 6.8 Hz, 1H), 7.96 (m, 2H), 8.40 (s, 1H).

[00684] Example 82

[00685] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4S)-4-((4'-chloro-

[1,1 '-biphenyl]-4-yl)oxy)- 1 -((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (82)

[00686] Compounds 82A and 82 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using Compounds Bl, 79C, and 82A in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 82A: LC-MS (ESI) m/z: 758 [M-55]⁺. Compound 82: LC-MS (ESI) m/z: 714 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.11-2.07 (m, 20H), 3.61-3.73 (m, 2H), 3.95-4.00 (m, 1H), 4.55-4.77 (m, 1H), 4.88-5.02 (m, 3H), 5.21-5.34 (m, 1H), 6.84-6.91 (m, 2H), 7.26-7.50 (m, 8H), 7.77-7.98 (m, 3H), 8.35-8.45 (m, 1H). [00687] Example 83

[00688] Synthesis of ((R)-3-aminopyrrolidin-l-yl)((2S,4S)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (83)

[00689] Compounds 83A and 83 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using (A’)-tert-butyl pyrrolidin-3-ylcarbamate, Compounds 79C, and 83A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 83A: LC-MS (ESI) m/z: 718 [M-55]⁺. Compound 83: LC-MS (ESI) m/z: 674 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.54-2.54 (m, 14H), 3.39-3.72 (m, 3H),

3.82-4.22 (m, 4H), 4.79-4.85 (m, 1H), 4.88-5.02 (m, 1H), 5.12-5.15 (m, 1H), 6.86 (t, J= 8.0 Hz, 2H), 7.26-7.51 (m, 8H), 7.76-7.84 (m, 1H), 7.94-7.99 (m, 2H), 8.35-8.40 (m, 1H).

[00690] Example 84

[00691] Synthesis of ((S)-3-aminopyrrolidin-l-yl)((2S,4S)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (84)

[00692] Compounds 84A and 84 were synthesized by employing the procedures described for Compounds 13F-1 and 1 using fV)-tert-butyl pyrrolidin-3-ylcarbamate, Compounds 79C, and 84A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 1G. Compound 84A: LC-MS (ESI) m/z: 718 [M-55]⁺. Compound 84: LC-MS (ESI) m/z: 674 [M+H]⁺; ¾-NMR (DMSO-i¾, 400 MHz): d (ppm) 1.06-1.49 (m, 2H), 1.62-1.76 (m,

7H), 1.89-2.31 (m, 6H), 3.02-3.23 (m, 1H), 3.52-3.96 (m, 5H), 4.65-4.75 (m, 1H), 4.93-5.12 (m, 2H), 6.87-6.92 (m, 2H), 7.08-7.26 (m, 1H), 7.43-7.59 (m, 7H), 7.70-8.09 (m, 6H), 8.38- 8.44 (m, 1H).

[00693] Example 85

[00694] Synthesis of ((S)-3-aminopyrrolidin-l-yl)((2R,4R)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (85)

[00695] To a solution of Compound 85A (10 g, 35 mmol) in dichloromethane (300 mL) at 0 °C was added EDC (8 g, 52 mmol), DMAP (6.3 g, 52 mmol), and 2, 2-dimethyl- 1,3- dioxane-4,6-dione (5 g, 35 mmol). The mixture was stirred at room temperature for 3 hours and washed with KHS0₄ solution (1 N, 200 mL x 2). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and heated to reflux for 5 hours. After cooled down to room temperature, the mixture was washed with 1 N KHSCri solution (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and evaporated to give a crude product, which was slurred in a mixture of ethyl acetate and petroleum ether (100 mL, 10% v/v) to yield

Compound 85B: LC-MS (ESI) m/z: 314 [M+H]⁺.

[00696] To a mixture of Compound 85B (4.66 g, 14.88 mmol) in dichloromethane (100 mL) and acetic acid (10 mL) at 0 °C was added NaBLL (1.69 g, 4.46 mmol) in several small portions and stirred at room temperature for 72 hours. To the mixture was added water (100 mL) and concentrated to remove dichloromethane. The residue was extracted with ethyl acetate (200 mL x 2). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated to give a crude product, which was slurred in petroleum ether (50 mL) to yield Compound 85C: LC-MS (ESI) m/z: 216 [M-Boc+H]⁺; 'H- NMR (DMSO-i¾ 400 MHz): d (ppm) 1.34-1.49 (m, 18H), 2.06-2.07 (m, 1H), 2.14-2.17 (m, 1H), 2.29-2.34 (m, 1H), 2.61-2.66 (m, 1H), 4.01-4.02 (m, 1H), 4.47-4.50 (m, 1H), 5.04 (d, J = 3.2 Hz, 1H).

[00697] To a solution of Compound 85C (2.7 g, 8.57 mmol) in THF (30 mL) at 0 °C was added BH₃ SMe2 (4.04 mL, 42.85 mmol) and stirred at room temperature overnight. The reaction mixture was cooled down to 0 °C, quenched with methanol (10 mL), stirred for 10 minutes, and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with saturated NaHCCh solution (100 mL) and 1 N KHSCri solution (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated to yield Compound 85D: LC-MS (ESI) m/z: 202 [M-Boc+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 1.46 (s, 18 H), 1.63-1.89 (m, 4H), 2.36-2.39 (m, 1H), 3.23-3.36 (m, 1H), 3.76-3.90 (m, 1H), 4.14 (s, 1H), 4.54-4.73 (m, 1H).

[00698] Compounds 85E, 85F, 85G, 85H, 851, 85J, and 85 were synthesized by employing the procedures described for Compounds IF, 59B-1, 13D-1, 59D-1, 30G, 13F-1, and 3 using Compounds 85D, 85E, 85F, 85G, 4'-chloro-[l,l'-biphenyl]-4-ol, 85H, 851, tert- butyl (S)-pyrrolidin-3-ylcarbamate, and 85J in lieu of Compounds IE, 59A-1, 13C-1, 59C-1, 4-chlorophenol, 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 3A. Compound 85E: LC-MS (ESI) m/z: 146 [M+H]⁺. Compound 85F: LC-MS (ESI) m/z: 160 [M+H]⁺.

Compound 85G: LC-MS (ESI) m/z: 412 [M +H]⁺. Compound 85H: LC-MS (ESI) m/z: 598 [M+H]⁺. Compound 851: LC-MS (ESI) m/z: 584 [M+H]⁺. Compound 85J: LC-MS (ESI) m/z: 752 [M+H]⁺. Compound 85: LC-MS (ESI) m/z: 652 [M+H]⁺; 'H-NMR (CD₃OD, 400 MHz): d (ppm) 1.09-1.39 (m, 7H), 1.72-2.52 (m, 11H), 3.48-3.69 (m, 3H), 3.83-4.16 (m, 6H), 5.07-5.08 (m, 1H), 6.94-6.96 (m, 2H), 7.09-7.13 (m, 2H), 7.38-7.40 (m, 2H), 7.48-7.54 (m, 4H), 7.77-7.86 (m, 2H).

[00699] Example 86

[00700] Synthesis of ((R)-3-aminopyrrolidin-l-yl)((2R,4R)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (86)

[00701] Compounds 86A and 86 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using (R)-tert-butyl pyrrolidin-3-ylcarbamate, Compounds 851, and 86A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 86A: LC-MS (ESI) m/z: 752 [M+H]⁺. Compound 86: LC-MS (ESI) m/z: 652 [M+H]⁺; 1H-NMR (CD₃OD, 400 MHz): d (ppm) 1.09-1.39 (m, 7H), 1.57-2.52 (m, 11H), 3.44-3.69 (m, 3H), 3.83-4.16 (m, 6H), 5.04-5.10 (m, 1H), 6.92-6.96 (m, 2H), 7.09-7.13 (m, 2H), 7.38-7.40 (m, 2H), 7.48-7.54 (m, 4H), 7.79-7.84 (m, 2H).

[00702] Example 87

[00703] Synthesis of (4-aminopiperidin-l-yl)((2R,4R)-4-((4'-chloro-[l,r-biphenyl]-4- yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2- trifluoroacetate (87)

[00704] Compounds 87A and 87 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using Compounds 851 and 87A in lieu of Compounds 13E-1 and 3A. Compound 87A: LC-MS (ESI) m/z: 788 [M+Na]⁺. Compound 87: LC-MS (ESI) m/z: 666 [M+H]⁺; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.09-1.17 (m, 2H), 1.24-1.37

(m, 4H), 1.40-1.62 (m, 2H), 1.70-1.96 (m, 8H), 2.03-2.11 (m, 3H), 2.16-2.24 (m, 1H), 2.76- 2.77 (m, 1H), 3.19-3.20 (m, 1H), 3.34-3.36 (m, 1H), 3.56-3.60 (m, 1H), 3.84-3.90 (m, 3H), 4.51-4.62 (m, 2H), 5.34-5.36 (m, 1H), 6.92-6.94 (m, 2H), 7.08-7.12 (m, 2H), 7.38-7.40 (m, 2H), 7.48-7.54 (m, 4H), 7.76-7.85 (m, 2H).

[00705] Example 88

[00706] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2R,4R)-4-((4'-chloro-

[1,1 '-biphenyl]-4-yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (88)

[00707] Compounds 88A and 88 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using Compounds Bl, 851, and 88A in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 88A: LC-MS (ESI) m/z: 814 [M+Na]⁺. Compound 88: LC-MS (ESI) m/z: 692 [M+H]⁺; 'H-NMR (CD₃OD, 400 MHz): d (ppm) 1.09-1.40 (m, 7H), 1.46-1.54 (m, 1H), 1.66-2.30 (m, 16H), 3.50-3.62 (m, 1H), 3.67-3.77 (m, 1H), 3.85-3.93 (m, 3H), 4.63-4.78 (m, 1H), 4.93-5.00 (m, 1H), 5.13-5.26 (m, 1H), 6.92-6.98 (m, 2H), 7.09-7.14 (m, 2H), 7.38-7.54 (m, 6H), 7.78-7.90 (m, 2H). [00708] Example 89

[00709] Synthesis of ((lR,5S,8R)-8-amino-3-azabicyclo[3.2.l]octan-3-yl)((2R,4R)-4-

((4'-chloro-[ 1 , 1 '-biphenyl]-4-yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (89)

[00710] Compounds 89A and 89 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl (lR,5S,8r)-3-azabicyclo[3.2. l]octan- 8-ylcarbamate, Compounds 851, and 89A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 89A: LC-MS (ESI) m/z: 814 [M+Na]⁺. Compound 89: LC-MS (ESI) m/z: 692 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.14-1.37 (m, 7H), 1.60-1.94 (m, 11H), 2.03-2.39 (m, 3H), 2.95-3.03 (m, 1H), 3.56-4.18 (m, 8H), 4.80-4.89 (m, 1H), 5.30-5.32 (m, 1H), 6.93-7.11 (m, 4H), 7.38-7.40 (m, 2H), 7.49-7.54 (m, 4H), 7.81- 7.83 (m, 2H).

[00711] Example 90

[00712] Synthesis of ((R)-3-aminopyrrolidin-l-yl)((2R,4R)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (90)

[00713] Compounds 90A, 90B, 90C, 90D, and 90 were synthesized by employing the procedures described for Compounds 13D-1, 59D-1, 30G, 13F-1, and 3 using Compound Al, Compounds 85F, 90A, 4'-chloro-[l,l'-biphenyl]-4-ol, 90B, 90C, tert-butyl (R)-pyrrolidin-3- ylcarbamate, and 90D in lieu of Compounds A2, 13C-1, 59C-1, 4-chlorophenol, 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 3A. Compound 90A: LC-MS (ESI) m/z: 434 [M +H]⁺. Compound 90B: LC-MS (ESI) m/z: 620 [M+H]⁺. Compound 90C: LC-MS (ESI) m/z: 604 [M-H]-. Compound 90D: LC-MS (ESI) m/z: 796 [M+Na]⁺. Compound 90: LC-MS (ESI) m/z: 674 [M +H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 1.25-2.58 (m, 15H), 3.43-3.68 (m, 2H), 3.81-4.22 (m, 4H), 4.79-4.84 (m, 1H), 5.01-5.21 (m, 2H), 6.85-6.91 (m, 2H), 7.25-7.28 (m, 1H), 7.34-7.38 (m, 3H), 7.43-7.51 (m, 4H), 7.79-7.84 (m, 1H), 7.96 (d, J= 8.4 Hz, 2H), 8.36-8.41 (m, 1H).

[00714] Example 91

[00715] Synthesis of (4-aminopiperidin-l-yl)((2R,4R)-4-((4'-chloro-[l,r-biphenyl]-4- yl)oxy)- 1 -((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2-yl)methanone 2,2,2- trifluoroacetate (91)

[00716] Compounds 91A and 91 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using Compounds 90C and 91A in lieu of Compounds 13E-1 and 3A. Compound 91A: LC-MS (ESI) m/z: 810 [M +Na]⁺. Compound 91: LC-MS (ESI) m/z: 688 [M+H]⁺; ¾-NMR (CD₃OD, 400 MHz): d (ppm) 1.20-1.40 (m, 1H), 1.40-1.60 (m, 2H), 1.70-1.97 (m, 8H), 2.01-2.25 (m, 5H), 2.61-2.81 (m, 1H), 3.21-3.31 (m, 1H), 3.38- 3.43 (m, 1H), 3.60-3.71 (m, 1H), 3.82-4.01 (m, 1H), 4.30-4.63 (m, 2H), 4.80-4.92 (m, 1H), 5.01-5.02 (m, 1H), 5.30-5.41 (m, 1H), 6.85-6.88 (m, 2H), 7.23-7.32 (m, 1H), 7.34-7.40 (m, 3H), 7.41-7.55 (m, 4H), 7.71-7.92 (m, 1H), 7.94-8.01 (m, 2H), 8.33-8.42 (m, 1H).

[00717] Example 92

[00718] Synthesis of ((S)-3-aminopyrrolidin-l-yl)((2R,4R)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (92)

[00719] Compounds 92A and 92 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl (S)-pyrrolidin-3-ylcarbamate, Compounds 90C, and 92A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 92A: LC-MS (ESI) m/z: 774 [M+H]⁺. Compound 92: LC-MS (ESI) m/z: 674 [M+H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 0.46-2.46 (m, 15H), 3.43-3.44 (m, 1H), 3.55-3.69 (m, 2H), 3.85-4.02 (m, 4H), 5.01-5.12 (m, 2H), 6.86-6.90 (m, 2H), 7.25-7.51 (m, 8H), 7.76-7.99 (m, 3H), 8.35-8.40 (m, 1H).

[00720] Example 93

[00721] Synthesis of (4-aminopiperidin-l-yl)((2S,4R)-4-((4'-chloro-[l,r-biphenyl]-4- yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2- trifluoroacetate (93)

[00722] A reaction mixture of Compound 93A (3 g, 10 mmol), 2-phenoxyacetic acid (2.27 g, 15 mmol), and PPI13 (3.9 g, 15 mmol) in THF (100 mL) was stirred at room temperature for 1 hours, and then DIAD (3 mL, 15 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ice-water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were washed with water (50 mL x 2) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 20% v/v) to yield Compound 93B: LC-MS (ESI) m/z: 458 [M+Na]⁺.

[00723] To a solution of Compound 93B (2 g, 4.6 mmol) in THF (10 mL) and water (10 mL) was dropped a 1 N NaOH solution until pH 10. The mixture was stirred at 35 °C overnight, cooled to room temperature, and extracted with ethyl acetate (50 mL x 2). The combined organic extracts were concentrated under reduced pressure. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, 50% v/v) to yield Compound 93C: LC-MS (ESI) m/z: 324 [M+Na]⁺; 'H-NMR (CDCb, 400 MHz): d (ppm) 1.44-1.46 (m, 18H), 1.54-1.62 (m, 1H), 1.68-1.72 (m, 2H), 1.87-1.95 (m, 1H), 2.40-2.47 (m, 1H), 2.92-3.06 (m, 1H), 3.62-3.69 (m, 1H), 3.97-4.07 (m, 1H), 4.67-4.88 (m, 1H).

[00724] Compounds 93D, 93E, 93F, 93G, 93H, 931, and 93 were synthesized by employing the procedures described for Compounds IF, 59B-1, 13D-1, 59D-1, 13E-1, 13F- 1, and 3 using Compounds 93C, 93D, 93E, 93F, 4'-chloro-[l,l'-biphenyl]-4-ol, 93G, 93H, and 931 in lieu of Compounds IE, 59A-1, 13C-1, 59C-1, 4-chlorophenol, 13D-1, 13E-1, and 3A. Compound 93D: LC-MS (ESI) m/z: 146 [M+H]⁺. Compound 93E: LC-MS (ESI) m/z: 160 [M+H]⁺. Compound 93F: LC-MS (ESI) m/z: 412 [M+H]⁺. Compound 93G: LC-MS (ESI) m/z: 598 [M+H]⁺. Compound 93H: LC-MS (ESI) m/z: 584 [M+H]⁺; Ή-NMR (DMSO- ck, 400 MHz): d (ppm) 1.01-1.30 (m, 5H), 1.44-1.54 (m, 1H), 1.63-1.89 (m, 8H), 2.42-2.45 (m, 1H), 3.51-3.52 (d, J= 8.0 Hz, 2H), 3.86 (d, J= 6.4 Hz, 2H), 4.50-4.52 (m, 1H), 4.74 (s, 1H), 6.91 (d, j= 8.8 Hz, 2H), 7.07 (d, j= 8.4 Hz, 2H), 7.46 (d, j= 8.4 Hz, 2H), 7.56 (d, j = 8.8 Hz, 2H), 7.62(d, J= 8.8 Hz, 2H), 7.74 (d, J= 8.8 Hz, 2H), 12.6 (s, 1H). Compound 931: LC-MS (ESI) m/z: 766 [M +H]⁺. Compound 93: LC-MS (ESI) m/z: 666 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 1.08-2.33 (m, 20H), 2.93 (s, 1H), 3.14 (s, 1H), 3.47-3.55 (m, 1H), 3.87-3.89 (m, 3H), 4.04-4.38 (m, 2H), 4.69 (s, 1H), 4.96 (s, 1H), 6.91 (d, J= 8.4 Hz, 2H), 7.06 (d, J= 8.8 Hz, 2H), 7.39 (d, J= 8.8 Hz, 2H), 7.50-7.55 (m, 4H), 7.78 (d, J= 9.2 Hz, 2H).

[00725] Example 94

[00726] Synthesis of ((R)-3-aminopyrrolidin-l-yl)((2S,4R)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (94)

[00727] Compounds 94A and 94 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl (R)-pyrrolidin-3-ylcarbamate, Compounds 93H, and 94A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 94A: LC-MS (ESI) m/z: 752 [M +H]⁺. Compound 94: LC-MS (ESI) m/z: 652 [M +H]⁺; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.09-1.40 (m, 5H), 1.73-2.46 (m, 12H), 3.42-4.02 (m, 9H), 4.64-4.68 (m, 2H), 6.94 (d, J= 8.8 Hz, 2H), 7.08 (d, J= 8.8 Hz, 2H), 7.40 (d, J= 8.4 Hz, 2H), 7.53-7.55 (m, 4H), 7.78-7.83 (m, 2H).

[00728] Example 95

[00729] Synthesis of ((S)-3-aminopyrrolidin-l-yl)((2S,4R)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (95)

[00730] Compounds 95A and 95 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl (S)-pyrrolidin-3-ylcarbamate,

Compounds 93H, and 95A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 95A: LC-MS (ESI) m/z: 752 [M +H]⁺. Compound 95: LC-MS (ESI) m/z: 652 [M +H]⁺; 1H-NMR (CD3OD, 400 MHz): d (ppm) 0.97-1.27 (m, 6H), 1.59-2.41 (m, 11H),

3.29-3.95 (m, 9H), 4.47-4.73 (m, 2H), 6.83 (d, J= 8.4 Hz, 2H), 6.95-6.98 (m, 2H), 7.28-7.31 (m, 2H), 7.42-7.45 (m, 4H), 7.69 (d, J= 8.4 Hz, 2H).

[00731] Example 96

[00732] Synthesis of (4-aminopiperidin-l-yl)((2S,4R)-4-((4'-chloro-[l,r-biphenyl]-4- yl)oxy)- 1 -((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2-yl)methanone 2,2,2- trifluoroacetate (96)

[00733] Compounds 96A, 96B, 96C, 96D, and 96 were synthesized by employing the procedures described for Compounds 13D-1, 59D-1, 13E-1, 13F-1, and 3 using Compounds Al, Compounds 93E, 96A, 4'-chloro-[l,l'-biphenyl]-4-ol, 96B, 96C, and 96D in lieu of Compounds A2, 13C-1, 59C-1, 4-chlorophenol, 13D-1, 13E-1, and 3A. Compound 96A: LC- MS (ESI) m/z: 434 [M+H]⁺. Compound 96B: LC-MS (ESI) m/z: 620 [M+H]⁺. Compound 96C: LC-MS (ESI) m/z: 606 [M+H]⁺; ¹H-NMR (DMSO-A 400 MHz): d (ppm) 1.45 (s, 1H), 1.63-1.79 (m, 8H), 2.01-2.04 (m, 2H), 2.34-2.44 (m, 1H), 3.59-3.70 (m, 2H), 4.53-4.77 (m, 2H), 5.01 (s, 1H), 6.89 (d, J= 8.4 Hz, 2H), 7.23-7.26 (m, 1H), 7.43-7.45 (m, 3H), 7.51 (d, J = 8.4 Hz, 2H), 7.59 (d, J= 8.4 Hz, 2H), 7.79-7.81 (m, 1H), 7.95-8.05 (m, 2H), 8.43 (s, 1H). Compound 96D: LC-MS (ESI) m/z: 788 [M+H]⁺. Compound 96: LC-MS (ESI) m/z: 688 [M+H]⁺; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.72-2.35 (m, 17H), 2.93 (s, 1H), 3.61 (s, 1H), 4.07-4.37 (m, 3H), 4.66 (s, 1H), 4.84 (s, 1H), 5.02 (s, 2H), 6.87 (d, J= 8.4 Hz, 2H), 7.23-7.26 (m, 1H), 7.33 (s, 1H), 7.38 (d, J= 8.8 Hz, 2H), 7.47-7.54 (m, 4H), 7.78-7.81 (m, 1H), 7.92-7.96 (m, 2H), 8.36 (s, 1H).

[00734] Example 97

[00735] Synthesis of ((R)-3-aminopyrrolidin-l-yl)((2S,4R)-4-((4'-chloro-[l, - biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (97)

[00736] Compounds 97A and 97 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl (R)-pyrrolidin-3-ylcarbamate, Compounds 96C, and 97A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 97A: LC-MS (ESI) m/z: 774 [M+H]⁺. Compound 97: LC-MS (ESI) m/z: 674 [M+H]⁺; ¾-NMR (CD3OD, 400 MHz): d (ppm) 1.69-2.51 (m, 14H), 3.39-4.10 (m, 7H), 4.61-4.65 (m, 1H), 4.73-4.76 (m, 1H), 5.01-5.04 (m, 1H), 6.89 (s, 2H), 7.24-7.27 (m, 1H), 7.34 (s, 1H), 7.38-7.40 (m, 2H), 7.46-7.53 (m, 4H), 7.80-7.82 (m, 1H), 7.93-7.97 (m, 2H), 8.36-8.39 (m, 1H).

[00737] Example 98

[00738] Synthesis of ((S)-3-aminopyrrolidin-l-yl)((2S,4R)-4-((4'-chloro-[l,l'- biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (98)

[00739] Compounds 98A and 98 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl (S)-pyrrolidin-3-ylcarbamate, Compounds 96C, and 98A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compounds 98A: LC-MS (ESI) m/z: 774 [M+H]⁺. Compound 98: LC-MS (ESI) m/z: 674 [M +H]⁺; ¾-NMR (CD₃OD, 400 MHz): d (ppm) 1.72-2.55 (m, 14H), 3.38-4.12 (m, 7H), 4.67-4.83 (m, 2H), 5.02 (s, 1H), 6.91 (d, J= 8.4 Hz, 2H), 7.24-7.26 (m, 1H), 7.33 (s, 1H), 7.39 (d, J= 8.4 Hz, 2H), 7.50-7.55 (m, 4H), 7.80-7.82 (m, 1H), 7.92-7.96 (m, 2H), 8.38 (s, 1H).

[00740] Example 99

[00741] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)((2S,4R)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (99)

[00742] Compounds 99A and 99 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using Compounds B2, Compounds 96C, and 99A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 99A: LC- MS (ESI) m/z: 824 [M+H]⁺. Compound 99: LC-MS (ESI) m/z: 724 [M+H]⁺; 'H-NMR

(CD3OD, 400 MHz): d (ppm) 1.29-2.42 (m, 15H), 2.67-3.01 (m, 1H), 3.62-4.35 (m, 4H), 4.68-4.82 (m, 2H), 5.02-5.10 (m, 2H), 6.85 (d, J= 8.8 Hz, 2H), 7.23-7.25 (m, 1H), 7.32 (s, 1H), 7.38 (d, J= 7.6 Hz, 2H), 7.48-7.54 (m, 4H), 7.75-7.78 (m, 1H), 7.89-7.96 (m, 2H), 8.32 (s, 1H).

[00743] Example 100

[00744] Synthesis of (4-aminopiperidin-l-yl)((2S,4S)-l-((4-

(cyclohexylmethoxy)phenyl)sulfonyl)-4-(4-(trifluoromethyl)phenoxy)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (100)

[00745] Compounds 100A, 100B, 100C, and 100 were synthesized by employing the procedures described for Compounds 59D-1, 30G, 13F-1, and 3 using 4- (trifluoromethyl)phenol, Compounds 73C, 100A, 100B, and 100C in lieu of 4-chlorophenol, Compounds 59C-1, 30F, 13E-1, and 3A. Compound 100A: LC-MS (ESI) m/z: 456 [M- Boc+H]⁺. Compound 100B: LC-MS (ESI) m/z: 542 [M+H]⁺. Compound 100C: LC-MS (ESI) m/z: 746 [M+Na]⁺. Compound 100: LC-MS (ESI) m/z: 624 [M+H]⁺; 'H-NMR

(CD3OD, 400 MHz): d (ppm) 1.07-1.58 (m, 8H), 1.68-2.03 (m, 8H), 1.98-2.23 (m, 3H), 2.72- 2.79 (m, 1H), 3. l4-3.22(m, 1H), 3.38-3.54 (m, 2H), 3.80-3.91 (m, 3H), 4.43-4.63 (m, 2H), 4.94-4.97 (m, 1H), 5.26-5.36 (m, 1H), 6.91-7.02 (m, 2H), 7.02-7.13 (m, 2H), 7.51-7.54 (m, 2H), 7.54-7.68 (m, 2H).

[00746] Example 101

Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)((2S,4S)-4-((4'-chloro-[l,r-biphenyl]-4- yl)oxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone (101), ((R)-4- amino-3 ,3 -difluoropiperi din- 1 -yl)((2S,4S)-4-((4'-chloro-[ 1 , 1 '-biphenyl]-4-yl)oxy)- 1 -((4- (cy cl ohexylmethoxy)phenyl)sulfonyl)piperi din-2 -yl)methanone (101-1), and ((S)-4-amino- 3,3-difluoropiperidin-l-yl)((2S,4S)-4-((4'-chloro-[l,r-biphenyl]-4-yl)oxy)-l-((4- (cy cl ohexylmethoxy)phenyl)sulfonyl)piperi din-2 -yl)methanone (101-2)

[00747] Compounds 101A, 101B, 101C, and 101 were synthesized by employing the procedures described for Compounds 59D-1, 30G, 13F-1, and 3 using 4'-chloro-[l,l'- biphenyl]-4-ol, Compounds 73C, 101A, 101B, B2, and 101C in lieu of 4-chlorophenol, Compounds 59C-1, 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 3A. Compound 101A: LC-MS (ESI) m/z: 598 [M+H]⁺. Compound 101B: LC-MS (ESI) m/z: 584 [M+H]⁺. Compound 101C: LC-MS (ESI) m/z: 824 [M+Na]⁺. Compound 101 was separated with chiral HPLC to afford Compound 101-1 and Compound 101-2. Compound 101-1: LC-MS (ESI) m/z: 702 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.75-0.81 (m, 4H), 0.97-1.06 (m, 3H), 1.40-1.51 (m, 4H), 1.68-1.71 (m, 6H), 1.77-1.81 (m, 2H), 2.10-2.15 (m, 1H), 3.15- 3.21 (m, 2H), 3.77-3.79 (m, 2H), 3.91-4.64 (m, 3H), 5.19-5.25 (m, 1H), 6.78-7.14 (m, 4H), 7.25-7.29 (m, 2H) 7.38-7.44 (m, 4H), 7.64 (d, J= 9.20 Hz, 2H). Chiral separation condition: EtOH contained 0.1% DEA; S,S-WHELK-Ol (4.6 x 250mm, 5um); retention time: 13.85 minute (97.6%), 12.44 minute (2.4%). Compound 101-2: LC-MS (ESI) m/z: 702 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.75-0.81 (m, 3H), 1.10-1.14 (m, 3H), 1.20-2.16 (m, 13H), 3.04-3.14 (m, 2H), 3.34-3.52 (m, 1H), 3.77-3.79 (m, 2H), 4.13-4.69 (m, 3H), 5.18-5.24 (m, 1H), 6.82-7.14 (m, 4H), 7.27-7.29 (m, 2H), 7.37-7.44 (m, 4H), 7.67-7.70 (m, 2H). Chiral separation condition: EtOH contained 0.1% DEA; S,S-WHELK-Ol (4.6 x 250mm, 5um); retention time: 11.49 minute (97.4%), 14.16 minute (2.6%).

[00748] Example 102

[00749] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4R)-4-((4'-chloro-

[1,1 '-biphenyl]-4-yl)oxy)- 1 -((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (102)

102

[00750] Compounds 102A and 102 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using Bl, Compounds 96C, and 102A in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 102A: LC-MS (ESI) m/z: 8l4[M+H]⁺. Compound 102: LC-MS (ESI) m/z: 714 [M+H]⁺; 'H-NMR (CD₃OD, 400 MHz): d (ppm) 0.99-2.09 (m, 19 H), 2.41-2.45 (m, 1H), 3.57-3.65 (m, 2H), 4.16-4.31 (m, 3H), 4.71 (s, 1H), 4.95-5.03 (m, 2H), 6.89 (d, J= 8.4 Hz, 2H), 7.24-7.27 (m, 1H), 7.34 (s, 1H), 7.38-7.41 (m, 2H), 7.48-7.53 (m, 4H), 7.83-7.85 (m, 1H), 7.94-7.97 (m, 2H), 8.42 (s, 1H).

[00751] Example 103

[00752] Synthesis of ((lR,5S,8S)-8-amino-3-azabicyclo[3.2.l]octan-3-yl)((2S,4R)-4-

((4'-chloro-[ 1 , 1 '-biphenyl]-4-yl)oxy)- 1 -((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)piperi din-2 -yl)methanone 2,2,2-trifluoroacetate (103)

103

[00753] Compounds 103A and 103 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl ((lR,5S,8r)-3-azabicyclo[3.2. l]octan- 8-yl)carbamate, Compounds 96C, and 103A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 103A: LC-MS (ESI) m/z: 8l4[M+H]⁺. Compound 103: LC-MS (ESI) m/z: 714 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.66-2.53 (m, 19 H), 2.76-2.99 (m, 1H), 3.26-4.24 (m, 5H), 4.73 (s, 1H), 5.02-5.19 (m, 2H), 6.86-6.94 (m, 2H), 7.21-7.26 (m, 1H), 7.33 (s, 1H), 7.38-7.40 (m, 2H), 7.46-7.53 (m, 4H), 7.77-7.79 (m, 1H), 7.90-7.96 (m, 2H), 8.33-8.37 (m, 1H).

[00754] Example 104

[00755] Synthesis of ((2S,4R)-4-((4'-chloro-[l,l'-biphenyl]-4-yl)oxy)-l-((6-

(cyclopentyloxy) naphthalen-2-yl)sulfonyl)piperi din-2 -yl)(piperazin- 1 -yl)methanone 2,2,2- trifluoroacetate (104)

104

[00756] Compounds 104A and 104 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl piperazine- l-carboxylate, Compounds 96C, and 104A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 104A: LC-MS (ESI) m/z: 774[M +H]⁺. Compound 104: LC-MS (ESI) m/z: 674 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.72-2.62 (m, 12H), 3.00-3.14 (m, 3H), 3.44-3.83 (m, 5H), 4.09-4.15 (m, 1H), 4.69 (s, 1H), 4.96-5.03 (m, 2H), 6.90 (d, J= 8.8 Hz, 2H), 7.24-7.27 (m, 1H), 7.33 (s, 1H), 7.38-7.41 (m, 2H), 7.52-7.56 (m, 4H), 7.79-7.81 (m, 1H), 7.92-7.96 (m, 2H), 8.36 (s, 1H).

[00757] Example 105

[00758] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2S,4R)-4-((4'-chloro-

[1,1 '-biphenyl]-4-yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (105)

105

[00759] Compounds 105A and 105 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using Compounds Bl, 93H, and 105A in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 105A: LC-MS (ESI) m/z: 792[M+H]⁺. Compound 105: LC-MS (ESI) m/z: 692 [M+H]⁺; 'H-NMR (CD3OD, 400 MHz): d (ppm) 0.97-2.43 (m, 23H), 2.38-2.43 (m, 1H), 3.51-3.57 (m, 2H), 3.88-3.89 (m, 2H), 4.10-4.29 (m, 3H), 4.74 (s, 1H), 6.91 (d, J= 8.4 Hz, 2H), 7.08 (d, J= 9.2 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.50-7.54 (m, 4H), 7.83 (d, J= 8.8 Hz, 2H).

[00760] Example 106

[00761] Synthesis of ((lR,5S,8S)-8-amino-3-azabicyclo[3.2.l]octan-3-yl)((2S,4R)-4-

((4'-chloro-[ 1 , 1 '-biphenyl]-4-yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (106)

106

[00762] Compounds 106A and 106 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl ((lR,5S,8r)-3-azabicyclo[3.2. l]octan- 8-yl)carbamate, Compounds 93H, and 106A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 106A: LC-MS (ESI) m/z: 792[M+H]⁺. Compound 106: LC-MS (ESI) m/z: 692 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 0.66-2.51 (m, 23H), 2.81-2.97 (m, 1H), 3.39-3.65 (m, 3H), 3.74-3.99 (m, 3H), 4.11-4.30 (m, 1H), 4.72-4.77 (m, 1H), 6.90-6.97 (m, 2H), 7.04-7.08 (m, 2H), 7.38-7.41 (m, 2H), 7.49-7.54 (m, 4H), 7.77- 7.80 (m, 2H).

[00763] Example 107

[00764] Synthesis of (4-aminopiperidin-l-yl)((2R,4S)-4-((4'-chloro-[l,r-biphenyl]-4- yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2- trifluoroacetate (107)

[00765] Compounds 107B, 85F, 85G, and 107C were synthesized by employing the procedures described for Compounds 73A, 59B-1, 13D-1, and 93B using Compounds 107A, 107B, 85F, and 85G in lieu of Compounds 69A, 59A-1, 13C-1, and 93A. Compound 107B: LC-MS (ESI) m/z: 146 [M-l00+H]⁺. Compound 85F: LC-MS (ESI) m/z: 160 [M+H]⁺.

Compound 85G: LC-MS (ESI) m/z: 412 [M+H]⁺; ¾-NMR (CDCh, 400 MHz): d (ppm) 1.04-1.11 (m, 2H), 1.26-1.32 (m, 2H), 1.69-1.88 (m, 9H), 1.94-2.00 (m, 1H), 2.36-2.40 (m, 1H), 3.52-3.63 (m, 5H), 3.80 (d, J= 6.4 Hz, 2H), 4.11-4.15 (m, 1H), 4.70 (d, J= 6.4 Hz, 1H), 6.92-6.95 (m, 2H), 7.72-7.75 (m, 2H). Compound 107C: LC-MS (ESI) m/z: 454 [M+H]⁺; ¾-NMR (CDCh, 400 MHz): d (ppm) 1.04-1.11 (m, 2H), 1.31-1.48 (m, 5H), 1.70-1.99 (m, 8H), 2.02 (s, 3H), 2.35-2.40 (m, 1H), 3.26-3.33 (m, 1H), 3.59 (s, 3H), 3.79-3.85 (m, 3H), 4.76 (d, j= 4.8 Hz, 1H), 6.95 (d, j= 8.4 Hz, 2H), 7.72 (d, j= 8.4 Hz, 2H).

[00766] To a solution of Compound 107C (850 mg, 1.9 mmol, crude) in methanol (5 mL) was added potassium carbonate (260 mL, 1.9 mmol). The reaction mixture was stirred at ambient temperature for 3 hours, diluted with DCM (50 mL), washed with water (50 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 50% v/v) to afford Compound 107D: LC-MS (ESI) m/z: 412 [M+H]⁺; ¾-NMR (CDCb, 400 MHz): d (ppm) 1.01-1.10 (m, 2H), 1.27-1.31 (m, 3H), 1.65-1.92 (m, 10H), 2.34-2.38 (m, 1H), 3.16-3.29 (m, 1H), 3.59 (s, 3H), 3.73-3.80 (m, 3H), 4.85-4.86 (m, 1H), 6.93 (d, J= 8.4 Hz, 2H), 7.72 (d, J= 8.4 Hz, 2H).

[00767] Compounds 107E, 107F, 107G, and 107 were synthesized by employing the procedures described for Compounds 59D-1, 13E-1, 13F-1, and 3 using 4'-chloro-[l,l'- biphenyl]-4-ol, Compounds 107D, 107E, 107F, and 107G in lieu of 4-chlorophenol, Compounds 59C-1, 13D-1, 13E-1, and 3A. Compound 107E: LC-MS (ESI) m/z: 598

[M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 1.02-1.10 (m, 2H), 1.26-1.35 (m, 4H), 1.70- 1.88 (m, 7H), 1.98-2.02 (m, 1H), 2.07-2.13 (m, 1H), 2.72-2.76 (m, 1H), 3.50 (s, 3H), 3.61- 3.64 (m, 1H), 3.79 (d, J= 6.0 Hz, 2H), 4.69-4.70 (m, 1H), 4.79-4.81 (m, 1H), 6.82 (d, J= 8.4 Hz, 2H), 6.94 (d, J= 8.4 Hz, 2H), 7.35-7.37 (m, 2H), 7.42-7.45 (m, 4H), 7.75 (d, J= 8.4 Hz, 2H). Compound 107F: LC-MS (ESI) m/z: 584 [M+H]⁺; 'H-NMR (CDCb, 400 MHz): d (ppm) 1.00-1.10 (m, 2H), 1.18-1.33 (m, 3H), 1.70-1.87 (m, 10H), 2.71-2.74 (m, 1H), 3.65- 3.66 (m, 2H), 3.78-3.79 (m, 2H), 4.82-4.83 (m, 1H), 6.81-6.84 (m, 2H), 6.92-6.95 (m, 2H), 7.32-7.45 (m, 6H), 7.74-7.75 (m, 2H). Compound 107G: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 107: LC-MS (ESI) m/z: 666 [M+H]⁺; 1H-NMR (CD3OD, 400 MHz): d (ppm) 1.08-1.60 (m, 8H), 1.72-2.03 (m, 10H), 2.19-2.41 (m, 2H), 2.83-2.97 (m, 1H), 3.18-3.27 (m, 1H), 3.45-3.55 (m, 1H), 3.87 (d, J= 6.4 Hz, 2H), 3.98- 4.07 (m, 2H), 4.30-4.43 (m, 1H), 4.68 (s, 1H), 4.92-5.00 (m, 1H), 6.90-6.92 (m, 2H), 7.05- 7.08 (m, 2H), 7.38-7.40 (m, 2H), 7.50-7.55 (m, 4H), 7.77-7.80 (m, 2H).

[00768] Example 108

[00769] Synthesis of ((S)-3-aminopyrrolidin-l-yl)((2R,4S)-4-((4'-chloro-[l,l'- biphenyl]-4-yl)oxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (108)

108

[00770] Compounds 108A and 108 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl (S)-pyrrolidin-3-ylcarbamate, Compounds 107F, and 108A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E- 1, and 3A. Compound 108A: LC-MS (ESI) m/z: 752 [M+H]⁺. Compound 108: LC-MS (ESI) m/z: 652 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.08-1.40 (m, 6H), 1.72-1.91 (m, 9H), 2.18-2.47 (m, 2H), 3.40-4.05 (m, 9H), 4.64-4.67 (m, 2H), 6.93-6.95 (m, 2H), 7.07-7.09 (m, 2H), 7.39-7.41 (m, 2H), 7.53-7.55 (m, 4H), 7.81-7.83 (m, 2H).

[00771] Example 109

[00772] Synthesis of ((2R,4S)-4-((4'-chloro-[l,l'-biphenyl]-4-yl)oxy)-l-((4-

(cyclohexylmethoxy) phenyl)sulfonyl)piperidin-2-yl)(piperazin- 1 -yl)methanone 2,2,2- trifluoroacetate (109)

109 [00773] Compounds 109A and 109 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl piperazine- l-carboxylate, Compounds 107F, and 109A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 109A: LC-MS (ESI) m/z: 752 [M+H]⁺. Compound 109: LC-MS (ESI) m/z: 652 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.08-1.40 (m, 7H), 1.72-1.91 (m, 8H), 2.10- 2.15 (m, 1H), 2.32-2.36 (m, 1H), 3.06 (brs, 2H), 3.46-3.67 (m, 4H), 3.87 (d, J= 6.0 Hz, 2H), 4.01-4.08 (m, 1H), 4.70-4.84 (m, 1H), 4.87-4.89 (m, 2H), 6.93-6.95 (m, 2H), 7.06-7.08 (m, 2H), 7.39-7.41 (m, 2H), 7.54-7.57 (m, 4H), 7.79-7.81 (m, 2H).

[00774] Example 110

[00775] Synthesis of ((R)-3-aminopyrrolidin-l-yl)((2R,4S)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (110)

110

[00776] Compounds 110A and 110 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl (R)-pyrrolidin-3-ylcarbamate, Compounds 107F, and 110A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E- 1, and 3A. Compound 110A: LC-MS (ESI) m/z: 752 [M+H]⁺. Compound 110: LC-MS (ESI) m/z: 652 [M+H]⁺; ¾-NMR (CD₃OD, 400 MHz): d (ppm) 1.07-1.40 (m, 6H), 1.72-2.29 (m, 11H), 3.35-4.06 (m, 9H), 4.54-4.72 (m, 2H), 6.93-6.95 (m, 2H), 7.05-7.08 (m, 2H), 7.39-7.41 (m, 2H), 7.52-7.56 (m, 4H), 7.79-7.81 (m, 2H). [00777] Example 111

[00778] Synthesis of ((2S,4R)-4-((4'-chloro-[l,l'-biphenyl]-4-yl)oxy)-l-((4-

(cyclohexylmethoxy) phenyl)sulfonyl)piperidin-2-yl)(piperazin- 1 -yl)methanone 2,2,2- trifluoroacetate (111)

111

[00779] Compounds 111A and 111 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl piperazine- l-carboxylate, Compounds 93H, and 111A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 111A: LC-MS (ESI) m/z: 752[M+H]⁺. Compound 111: LC-MS (ESI) m/z: 652 [M+H]⁺; ¹H-NMR (DMSO-^, 400 MHz): d (ppm) 1.02-1.10 (m, 2H), 1.64-2.10 (m, 13H), 2.92 (s, 2H), 3.02-3.06 (m, 1H), 3.10-3.15 (m, 2H), 3.55-3.64 (m, 3H), 3.87-3.88 (m, 3H), 4.01-4.23 (m, 1H), 4.66-4.76 (m, 2H), 6.88 (d, J= 8.4 Hz, 2H), 7.10 (d, J= 8.8 Hz, 2H), 7.46 (d, j= 8.8 Hz, 2H), 7.55 (d, j= 8.4 Hz, 2H), 7.62 (d, j= 8.8 Hz, 2H), 7.75 (d, j= 8.8 Hz, 2H), 9.04 (s, 2H).

[00780] Example 112

[00781] Synthesis of ((2R,4R)-4-((4'-chloro-[l,l'-biphenyl]-4-yl)oxy)-l-((6-

(cyclopentyloxy) naphthalen-2-yl)sulfonyl)piperi din-2 -yl)(piperazin- 1 -yl)methanone 2,2,2- trifluoroacetate (112)

[00782] Compounds 112 A, 112B, 112C, 112D, and 112 were synthesized by employing the procedures described for Compounds 13D-1, 59D-1, 30G, 13F-1, and 3 using Compounds Al, 85F, 4'-chloro-[l,l'-biphenyl]-4-ol, 112A, 112B, 112C, tert-butyl piperazine- l-carboxylate, and 112D in lieu of Compounds A2, 13C-1, 4-chlorophenol, 59C- 1, 30F, 13E-1, tert-butyl piperidin-4-ylcarbamate, and 3A. Compound 112A: LC-MS (ESI) m/z: 434 [M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 1.63-2.04 (m, 11H), 2.37-2.44 (m, 1H), 3.47 (s, 3H), 3.54-3.73 (m, 2H), 4.11-4.12 (m, 1H), 4.76-4.93 (m, 2H), 7.14-7.21 (m, 2H), 7.70-7.83 (m, 3H). 8.25 (s, 1H). Compound 112B: LC-MS (ESI) m/z: 620 [M+H]⁺; ¾- NMR (CDCb, 400 MHz): d (ppm) 1.57-2.14 (m, 11H), 2.35-2.50 (m, 1H), 3.53 (s, 3H), 3.57- 3.73 (m, 2H), 4.21-4.25 (m, 1H), 5.02-5.05(m, 1H), 5.39-5.41 (m, 1H), 6.88 (d, J= 8.8 Hz, 2H), 7.24-7.52 (m, 8H), 7.79-7.83 (m, 1H), 7.94-7.97 (m, 2H), 8.34-8.35 (m, 1H). Compound 112C: LC-MS (ESI) m/z: 606 [M+H]⁺. Compound 112D: LC-MS (ESI) m/z: non-ionizable compound under routine conditions used. Compound 112: LC-MS (ESI) m/z: 674 [M+H]⁺; 1H-NMR (DMSO- 400 MHz): d (ppm) 1.19-2.12 (m, 12H), 3.04-3.13 (m, 4H), 3.49-3.62 (m, 3H), 3.84-3.89 (m, 3H), 4.68-4.76 (m, 1H), 5.01-5.03 (m, 1H), 5.32-5.33 (m, 1H), 6.89 (d, J= 8.8 Hz, 2H), 7.27-7.30 (m, 1H), 7.44-7.61 (m, 7H), 7.80-7.82 (m, 1H), 8.01-8.10 (m, 2H), 8.43 (s, 1H), 8.91 (brs, 2H).

[00783] Example 113

[00784] Synthesis of ((lR,5S,8R)-8-amino-3-azabicyclo[3.2.l]octan-3-yl)((2R,4R)-4-

((4'-chloro-[ 1 , 1 '-biphenyl]-4-yl)oxy)- 1 -((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (113)

[00785] Compounds 113A and 113 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using tert-butyl ((lR,5S,8r)-3-azabicyclo[3.2. l]octan- 8-yl)carbamate, Compounds 112C, and 113A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 113A: LC-MS ESI (m/z): 814 [M+H]⁺. Compound 113: LC-MS (ESI) m/z: 714 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.37-2.06 (m, 15H), 2.18-2.40 (m, 3H), 2.91-3.05 (m, 1H), 3.32-3.79 (m, 3H), 3.90-4.23 (m, 3H), 4.73-4.85 (m, 1H), 5.02-5.05 (m, 1H), 5.39-5.41 (m, 1H), 6.89 (d, J= 8.8 Hz, 2H), 7.24-7.52(m, 8H). 7.79-7.83 (m, 1H), 7.94-7.97 (m, 2H), 8.38-8.39 (s, 1H),

[00786] Example 114

[00787] Synthesis of (4-aminopiperidin-l-yl)((2S,4R)-l-((4-

(cy cl ohexylmethoxy)phenyl)sulfonyl)-4-(4-(trifluoromethyl)phenoxy)piperi din-2- yl)methanone 2,2,2-trifluoroacetate (114)

[00788] Compounds 114A, 114B, 114C, and 114 were synthesized by employing the procedures described for Compounds 59D-1, 30G, 13F-1, and 3 using 4- (trifluoromethyl)phenol, Compounds 93F, 114A, 114B, and 114C in lieu of 4-chlorophenol, Compounds 59C-1, 30F, 13E-1, and 3A. Compound 114A: LC-MS (ESI) m/z: 556 [M+H]⁺. Compound 114B: LC-MS (ESI) m/z: 542 [M+H]⁺. Compound 114C: LC-MS (ESI) m/z: 724 [M+H]⁺. Compound 114: LC-MS (ESI) m/z: 624 [M+H]⁺; Ή-NMR (CD3OD, 400 MHz): d

(ppm) 1.09-1.40 (m, 8H), 1.73-2.29 (m, 13H), 2.92 (s, 1H), 3.52 (s, 1H), 3.86-4.00 (m, 4H), 4.36 (s, 1H), 4.75 (s, 1H), 4.96 (s, 1H), 6.97 (d, J= 8.0 Hz, 2H), 7.06 (d, J= 9.2 Hz, 2H), 7.54 (d, J= 8.4 Hz, 2H), 7.78 (d, J= 8.8 Hz, 2H).

[00789] Example 115

[00790] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)((2S,4R)-4-((4'-chloro-[l, - biphenyl]-4-yl)oxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (115)

115

[00791] Compounds 115A and 115 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using Compounds B2, 93H, and 115A in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 115A: LC-MS (ESI) m/z: 802[M+H]⁺. Compound 115: LC-MS (ESI) m/z: 702 [M+H]⁺; 'H-NMR (DMSO-^, 400 MHz): d (ppm) 0.96-1.30 (m, 7H), 1.62-2.29 (m, 12H), 3.41-4.21 (m, 6H), 4.61 (s, 1H), 4.88(s, 2H), 6.78 (d, J= 8.8 Hz, 2H), 6.92-6.96 (m, 2H), 7.28 (d, J= 8.4 Hz, 2H), 7.39-7.45 (m, 4H), 7.62-7.65 (m, 2H). [00792] Example 116

[00793] Synthesis of (3-amino-8-azabicyclo[3.2.l]octan-8-yl)((2R,4S)-4-((4'-chloro-

[1,1 '-biphenyl]-4-yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (116)

116

[00794] Compounds 116A and 116 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using Compounds Bl, 107F, and 116A in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 116A: LC-MS (ESI) m/z: 792 [M+H]⁺. Compound 116: LC-MS (ESI) m/z: 692 [M+H]⁺; 'H-NMR (CD₃OD, 400 MHz): d (ppm) 1.07-1.40 (m, 7H), 1.53-2.09 (m, 15H), 2.38-2.44 (m, 1H), 3.49-3.57 (m, 2H), 3.88 (d, J= 6.4 Hz, 2H), 4.10-4.28 (m, 3H), 4.72-4.76 (m, 1H), 4.85-4.89 (m, 1H), 6.92 (d, J = 8.8 Hz, 2H), 7.08 (d, J= 8.8 Hz, 2H), 7.39 (d, J= 8.4 Hz, 2H), 7.49-7.54 (m, 4H), 7.83 (d, J= 8.4 Hz, 2H).

[00795] Example 117

[00796] Synthesis of ((lR,5S,8R)-8-amino-3-azabicyclo[3.2.l]octan-3-yl)((2R,4S)-4-

((4'-chloro-[ 1 , 1 '-biphenyl]-4-yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (117)

117

[00797] Compounds 117A and 117 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using /er/-butyl (lR,5S,8r)-3-azabicyclo[3.2.l]octan- 8-ylcarbamate, Compounds 107F, and 117A in lieu of tert-butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 117A: LC-MS (ESI) m/z: 792 [M+H]⁺. Compound 117: LC-MS (ESI) m/z: 692 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.08-1.40 (m, 7H), 1.59-2.51 (m, 15H), 2.81-2.97 (m, 1H), 3.39-3.79 (m, 4H), 3.87 (d, J= 6.4 Hz, 2H), 3.92-4.17 (m, 1H), 4.71-4.76 (m, 1H), 4.92-5.12 (m, 1H), 6.90-6.97 (m, 2H), 7.04-7.08 (m, 2H), 7.39 (d, J= 8.4 Hz, 2H), 7.50-7.54 (m, 4H), 7.78 (J = 8.4 Hz, 2H).

[00798] Example 118

[00799] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)((2S,4S)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone (118), ((R)-4-amino-3,3-difluoropiperidin-l-yl)((2S,4S)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (118-1), and ((S)-4-amino-3,3-difluoropiperidin-l- yl)((2S,4S)-4-((4'-chloro-[l,r-biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)piperi din-2 -yl)methanone 2,2,2-trifluoroacetate (118-2)

[00800] Compounds 118A and 118 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using Compounds B2, 79C, and 118A in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 118A: LC-MS (ESI) m/z: 846 [M+Na]⁺. Compound 118 was separated with chiral HPLC to afford Compound 118-1 and Compound 118-2. Compound 118-1: LC-MS (ESI) m/z: 724 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.30-1.42 (m, 1H), 1.61-1.89 (m, 8H), 2.03-2.27 (m, 5H), 2.85- 3.11 (m, 1H), 3.42-3.71 (m, 2H), 3.91-3.99 (m, 2H), 4.52-4.81 (m, 3H), 5.01-5.02 (m, 1H), 5.34-5.40 (m, 1H), 6.84-6.87 (m, 2H), 7.24-7.52 (m, 8H), 7.76-7.81 (m, 1H) 7.93-7.97 (m, 2H), 8.35 (s, 1H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50/50); S,S-WHELK-Ol (4.6 x 250 mm, 5 pm); retention time: 25.05 minute (99.3%), 20.93 minute (0.6%). Compound 118-2: LC-MS (ESI) m/z: 724 [M +H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.10-1.94 (m, 16H), 3.16-3.24 (m, 1H), 3.31-3.39 (m, 1H), 3.94-4.01 (m, 2H), 4.76- 4.80 (m, 1H), 4.97-5.03 (m, 2H), 5.35-5.51 (m, 1H), 6.87-6.89 (m, 2H), 7.26-7.51 (m, 8H), 7.84-7.99 (m, 3H), 8.37-8.43 (m, 1H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (50/50); S,S-WHELK-Ol (4.6 x 250 mm, 5 pm); retention time: 20.93 minute (98.1%), 25.05 minute (1.6%). [00801] Example 119

[00802] Synthesis of (4-aminopiperidin-l-yl)((2R,4S)-l-((4-

(cy cl ohexylmethoxy)phenyl)sulfonyl)-4-(4-(trifluoromethyl)phenoxy)piperi din-2- yl)methanone 2,2,2-trifluoroacetate (119)

[00803] Compounds 119A, 119B, 119C, and 119 were synthesized by employing the procedures described for Compounds 59D-1, 13E-1, 13F-1, and 3 using 4- (trifluoromethyl)phenol, Compounds 107D, 119A, 119B, and 119C in lieu of 4- chlorophenol , Compounds 59C-1, 13D-1, 13E-1, and 3A. Compound 119A: LC-MS (ESI) m/z: 556 [M+H]⁺; ¹H-NMR (CDCb, 400 MHz): d (ppm) 1.01-1.11 (m, 2H), 1.19-1.35 (m, 4H), 1.76-1.98 (m, 7H), 2.08-2.13 (m, 1H), 2.71-2.74 (m, 1H), 3.45 (s, 3H), 3.54-3.70 (m, 2H), 3.79 (d, J= 6.4 Hz, 2H), 4.73-4.74 (m, 1H), 4.79-4.81 (m, 1H), 6.81-6.83 (m, 2H), 6.93-

6.95 (m, 2H), 7.49-7.51 (m, 2H), 7.73-7.75 (m, 2H). Compound 119B: LC-MS (ESI) m/z:

542 [M+H]⁺. Compound 119C: LC-MS (ESI) m/z: 724 [M+H]⁺. Compound 119: LC-MS (ESI) m/z: 624 [M+H]⁺; 1H-NMR (CD₃OD, 400 MHz): d (ppm) 1.08-2.31 (m, 21H), 2.71-

2.95 (m, 1H), 3.39-3.54 (m, 1H), 3.87 (d, J= 6.4 Hz, 2H), 3.954-4.43 (m, 3H), 4.75 (s, 1H), 4.92-4.96 (m, 1H), 6.96-6.98 (m, 2H), 7.05-7.08 (m, 2H), 7.53-7.56 (m, 2H), 7.77-7.79 (m, 2H).

[00804] Example 120

[00805] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)((2R,4R)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone (120), ((R)-4-amino-3,3-difluoropiperidin-l-yl)((2R,4R)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((6-(cyclopentyloxy)naphthalen-2-yl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (120-1), and ((S)-4-amino-3,3-difluoropiperidin-l- yl)((2R,4R)-4-((4'-chloro-[ 1 , 1 '-biphenyl]-4-yl)oxy)- 1 -((6-(cyclopentyloxy)naphthalen-2- yl)sulfonyl)piperidin-2-yl)methanone 2,2,2-trifluoroacetate (120-2)

[00806] Compounds 120A and 120 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using Compounds B2, 112C, and 120A in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 120A: LC-MS ESI (m/z): 846 [M+Na]⁺. Compound 120 was separated with chiral HPLC to give Compound 120-1 and Compound 120-2. Compound 120-1: LC-MS (ESI) m/z: 724 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.08-2.30 (m, 14H), 2.74-3.24 (m, 2H), 3.35-4.49 (m, 4H), 4.75-4.86 (m, 1H), 4.96-5.04 (m, 2H), 5.38-5.55 (m, 1H), 6.87-6.89 (m, 2H), 7.25-7.35 (m, 1H), 7.38-7.51 (m, 7H), 7.80-7.87 (m, 1H), 7.96-8.00 (m, 2H), 8.37-8.43 (m, 1H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (10/90); Cellulose-4 (4.6 x 250 mm, 5 pm); retention time: 7.67 minute. Compound 120-2: LC-MS (ESI) m/z: 724 [M+H]⁺; ¹H-NMR (CD3OD, 400 MHz): d (ppm) 1.31-1.73 (m, 14H), 2.91-3.15 (m, 1H), 3.39-3.73 (m, 2H), 3.91-3.95 (m, 2H), 4.51-4.81 (m, 3H), 5.01-5.04 (m, 1H), 5.38-5.41 (m, 1H), 6.85-6.87 (d, J= 9.2 Hz, 2H), 7.25-7.27 (d, J= 8.8 Hz, 1H), 7.35-7.39 (m, 3H), 7.45-7.53 (m, 4H), 7.76- 7.82 (m, 1H), 7.94-7.97 (m, 2H), 8.35 (m, 1H). Chiral separation condition: n-Hexane/EtOH contained 0.1% DEA (10/90); Cellulose-4 (4.6 x 250 mm, 5 pm); retention time: 9.44 minute. [00807] Example 121

[00808] Synthesis of (4-amino-3,3-difluoropiperidin-l-yl)((2R,4S)-4-((4'-chloro-[l,r- biphenyl]-4-yl)oxy)-l-((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone (121), ((R)-4-amino-3 ,3 -difluoropiperidin- 1 -yl)((2R,4S)-4-((4'-chloro-[ 1 , 1 '-biphenyl]-4- yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2-yl)methanone 2,2,2- trifluoroacetate (121-1), and ((S)-4-amino-3,3-difluoropiperidin-l-yl)((2R,4S)-4-((4'-chloro- [1,1 '-biphenyl]-4-yl)oxy)- 1 -((4-(cyclohexylmethoxy)phenyl)sulfonyl)piperidin-2- yl)methanone 2,2,2-trifluoroacetate (121-2)

[00809] Compounds 121A and 121 were synthesized by employing the procedures described for Compounds 13F-1 and 3 using Compounds B2, 107F, and 121A in lieu of tert- butyl piperidin-4-ylcarbamate, Compounds 13E-1, and 3A. Compound 121A: LC-MS (ESI) m/z: Non-ionizable compound under routine conditions used. Compound 121 was separated with chiral HPLC to give Compound 121-1 and Compound 121-2. Compound 121-1: LC-MS (ESI) m/z: 702 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.08-2.40 (m, 19H), 3.40- 4.41 (m, 7H), 4.67-4.76 (m, 1H), 4.99-5.11 (m, 1H), 6.88-6.90 (m, 2H), 7.04-7.07 (m, 2H), 7.38-7.40 (m, 2H), 7.49-7.55 (m, 4H), 7.74-7.76 (m, 2H). Chiral separation condition: MeOH contained 0.1% DEA; OZ-H (4.6 x 250 mm, 5 pm); retention time: 9.59 minute. Compound 121-2: LC-MS (ESI) m/z: 702 [M+H]⁺; ¹H-NMR (CD₃OD, 400 MHz): d (ppm) 1.08-2.40 (m, 19H), 2.96-3.08 (m, 1H), 3.49-4.15 (m, 6H), 4.71 (m, 1H), 4.99-5.00 (m, 1H), 6.88-6.90 (m, 2H), 7.03-7.05 (m, 2H), 7.38-7.41 (m, 2H), 7.51-7.55 (m, 4H), 7.73-7.76 (m, 2H). Chiral separation condition: MeOH contained 0.1% DEA; OZ-H (4.6 x 250 mm, 5 pm); retention time: 12.06 minute.

BIOLOGICAL EXAMPLES

[00810] The following describes ways in which the compounds described herein were tested to measure in vitro activity in enzymatic assays. A person of ordinary skill in the art would know that variations in the assay conditions could be used to determine the activity of the compounds.

CGT enzyme assay

[00811] Full-length human CGT cDNA was cloned into the BamHl/Xhol site of pcDNA3. l (+) mammalian expression vector (V90-20, Invitrogen, Carlsbad, CA) and the plasmid was transfected into Chinese hamster ovary (CHO) cells. Lysate was prepared using M-PER (Mammalian Protein Extraction Reagent, ThermoFisher Scientific, Grand Island,

NY) in the presence of a protease inhibitor cocktail (P8340, Sigma, Saint Louis, MO). Each 100 mm dish (100% confluent, approximately 1 X 10⁷ cells) was lysed with 250 pL of M- PER containing protease inhibitors. Protein concentration was determined using a Pierce BCA protein assay kit (ThermoFisher Scientific). Four micrograms of CHO/CGT lysate was incubated with various concentrations of a compound (0.001 pM - 50 pM) in 10 mM HEPES (pH 7.2) containing 35 pM dioleoylphosphatidylcholine, 5 mM MgCk, 5 mM MnCh,

1% BSA, 15 mM KC1, 1 mM EGTA, 8 mM CHAPS, 0.01% tween-80, 10 pM C6-NBD- dihydro-ceramide and 17.5 pM ETDP-galactose in a final reaction volume of 20 pL at 37 °C for 1 hour. The final concentration of DMSO was 0.5% in both compound-treated and mock- treated samples. Each individual reaction was diluted with 80 pL of methanol :acetronitrile (1 :3) containing 5 pM N-docdecanoyl-NBD-galactosylceramide (internal standard) to stop the reaction. 200 pL H20:acetonitile (1 : 1) was added to precipitate the protein. After sufficient mixing, the plates were centrifuged at 2469 g for 38 minutes, 200 pl of supernatant was transferred to a LC-MS 96-deep well plate and a second spin was performed at 2469 g for 10 minutes. The final supernatant was injected in triplicate for RapidFire/MS/MS analysis.

[00812] Quantitative analysis using the RapidFire/MS/MS method: The quantitative analysis of C6-NBD-dihydro-ceramide and C6-NBD-dihydro-galactosylceramide was performed on a Rapid Fire 360 high-throughput mass spectrometry system (Agilent

Technologies, Palo Alto, CA) coupled with a API4000⁺ triple quadrupole mass spectrometer (Applied Biosystems, Concord, Ontario, Canada). RapidFire software packages, including RapidFire Control panel, RapidFire UI and RapidFire Integrator (Agilent Technologies), were used to control the RapidFire instrument and to process data. Analyst 1.6.2 software packages (Applied Biosystems) were used to control the MS system and acquire MS data. 10 pL of sample was loaded on a micro-scale C4 solid-phase extraction (SPE) cartridge (Agilent Technologies) and salts were removed using water supplemented with 0.1% formic acid at the flow rate of 1.5 mL/min for 3 sec. C6-NBD-dihydro-ceramide and C6-NBD-dihydro- galactosylceramide were co-eluted into the mass spectrometer using acetonitrile containing 0.1% formic acid at the flow rate of 1.0 mL/min for 3 sec. The total cycle time of one injection was 8 secs. The MS/MS detection was performed in ESI negative mode. The mass transition of C6-NBD-dihydro-galactosylceramide was m/z 752.6®678.6 using a -40 V collision energy, the mass transition of C6-NBD-dihydro-ceramide was m/z 590.6— 1 15.8 using a -40 V collision energy and the mass transition of N-docdecanoyl-NBD- galactosylceramide was m/z 820.9®746.3 using a -45 V collision energy.

[00813] The C6-NBD-dihydro-galactosylceramide reading was normalized first by dividing the peak area of C6-NBD-dihydro-galactosylceramide by the peak area of the internal standard, N-docdecanoyl-NBD-galactosylceramide. ICso values (see Table 1, data ranges correspond to analysis using the RapidFire/MS/MS method with 0.01% Tween 80 added) were generated from sigmoidal dose-response curves (variable slope) with GraphPad Prism software (GraphPad Software, Inc., San Diego, CA) using the normalized peak areas of C6-NBD-dihydro-galactosylceramide or the percent inhibition of C6-NBD-dihydro- galactosylceramide accumulation relative to DMSO control.

[00814] An alternative RapidFire/MS/MS method can be used to generate ICso values. The method is identical to the one described above except that 0.01% tween is not used. [00815] An alternative LC-MS/MS based method can be used. For the LC-MS/MS readout, the CGT assay is identical to the one described above except for the following: 10 pg of CHO/CGT lysate can be used as the CGT enzyme source, Cl2:0 (2R-OH) ceramide can be used as the ceramide substrate and 0.3 mIUI C12 ceramide can be used as the internal standard. Tween 80 is not present in the reaction mixture. The final supernatant can be injected for LC-MS/MS analysis.

[00816] Quantitative analysis using the LC-MS/MS method: The quantitative analysis of 02:0 (2R-OH) ceramide and 02:0 (2R-OH) galactosylceramide by LC-MS/MS can be performed on a Shimadzu ultra-fast liquid chromatography (Shimadzu, Japan) coupled with API 4000 mass spectrometer (Applied Biosystems, Concord, Ontario, Canada). Analyst 1.5 software packages (Applied Biosystems) can be used to control the LC-MS/MS system, as well as for data acquisition and processing. 10 pL of sample can be loaded onto a Luna 08 column (50mmx2.0mm, I.D. 3pm, IOqA) (Phenomenex, USA) for chromatographic separation. Mobile phase A can consist of HPLC grade water with 0.1% formic acid (v/v) and mobile phase B can consist of acetonitrile supplemented with 0.1% formic acid (v/v).

The separation can be achieved using the following gradient program at a flow rate of 0.8 mL/min: the initial mobile phase can be 70% B, which can be increased in a linear fashion to 95% B in 1.50 min, and then maintained at 95% B until 3.50 min. The mobile phase can then be reset to 70% B within 0.01 min, and maintained until 4.50 min. The total run time can be 4.50 min. The MS/MS detection can be performed in ESI positive mode. The mass transition selected for quantification was can be m/z 498.5®264.3 for 02:0 (2R-OH) ceramide under the collision energy of 38.8 V, and the mass transition of 02:0 (2R-OH) galactosylceramide can be m/z 660.6®264.5 under the collision energy of 51 V. The mass transition of 02 ceramide used as internal standard can be m/z 482.4®264.3 under the collision energy of 33 V. Compound ICso values can be calculated using a protocol identical to the one described for the RapidFire method.

CGT cellular assay

[00817] A stable cell line overexpressing human full-length CGT was made by transfecting Chinese hamster ovary (CHO) cells with 10 pg hCGT-pcDNA3.l(+) DNA and 30 pL of X-tremeGENE HP DNA transfection reagent (6366236001, Roche, Indianapolis, IN), followed by 800 pg/mL G418 selection. CHO cells stably expressing human full-length CGT (B5 cells) were seeded onto a CytoOne 96-well TC plate (USA Scientific, CC7682- 7596) at 3xl0⁴ cells/well in F12K media containing 10% FBS and incubated overnight at 37°C, 5% CO2. The next day, the media was removed and replaced with 90 pL incubation media (F12K media containing 5% FBS and 1.1 mM eliglustat). In a separate 96-well tissue culture plate, the test compounds were serially diluted in DMSO (1 mM to 0.1 pM) followed by a lOO-fold dilution with F12K media containing 5% FBS. 10 pL of compound was added to the cells and incubated at 37°C, 5% CO2 for 2 hours. The final concentration of DMSO was 0.1% in both compound-treated and mock-treated cells. The C6-NBD-dihydro-ceramide substrate was diluted with F12K medium containing 5% FBS and 11% BSA to make a 110 pM substrate solution. 10 pL of substrate solution was added to the plate and incubated at 37°C, 5% CO2 for 1 hour. Following the reaction, the plate was washed two times with PBS followed by the addition of 120 pL of lipid extraction solvent (methanol with 0.5% acetic acid) containing 1 pM of N-dodecanoyl-NBD-galactosylceramide (internal standard). The sealed plate was placed on shaker for 2 hours (around 20 RPM) to extract product. After centrifugation at 2469 g for 30 mins, 80 pL of supernatant was transferred to a LC/MS 96- deep well plate containing 40 pL ddFhO. After mixing thoroughly, a second spin was performed at 2469 g for 20 mins. The final supernatant was injected for LC-MS/MS analysis.

[00818] The quantitative analysis of C6-NBD-dihydro-ceramide and C6-NBD- dihydro-galactosylceramide was performed on a Shimadzu ultra-fast liquid chromatography (Shimadzu, Japan) coupled with API 4000 mass spectrometer (Applied Biosystems, Concord, Ontario, Canada). Analyst 1.5 software packages (Applied Biosystems) were used to control the LC-MS/MS system, as well as for data acquisition and processing. 10 pL of sample was loaded onto a KinetexCl8 column (50mmx2.lmm, I.D.2.6pm, IOOA) (Phenomenex, USA) for chromatographic separation. Mobile phase A consisted of HPLC grade water with 0.1% formic acid (v/v), and mobile phase B consisted of acetonitrile supplemented with 0.1% formic acid (v/v). The separation was achieved using the following gradient program at a flow rate of 0.7 mL/min: the initial mobile phase was 35% B and was ramped in a linear fashion to 98% B in 2.40 min. From 2.40 to 3.00 min, the gradient was maintained at 98% B. Then, mobile phase was reset to 35% B in 0.01 min, and maintained until 3.50 min. The total run time was 3.50 mins. The MS/MS detection was performed in ESI negative mode. The mass transition of C6-NBD-dihydro-ceramide was m/z 590.4 516.4 under the collision energy of -34 V. The mass transition of C6-NBD-dihydro-galactosylceramide was m/z 752.4 678.5 under the collision energy of -46 V. The mass transition of N-Dodecanoyl- NBD-galactosylceramide which was used as internal standard was m/z 820.5 l 15.6 under the collision energy of -72V. Compound ICso values were calculated using a protocol identical to the ones described above for the CGT enzyme assay.

[00819] Using the above CGT enzyme and CGT cellular assays, the compounds of Table 1 were tested. In Table 1, biological data range of ICso values calculated from the enzymatic assays (using the RapidFire/MS/MS method with 0.01% Tween 80 added) are provided, where:

A is < 1 mM;

B is > 1 to 10 mM;

C is > 10 to 30 pM;

D is > 30 to 100 pM; and

NT is not tested.

Table 1

Twitcher Mouse Model

[00820] The twitcher is a naturally-occurring mouse mutant caused by an abnormality in the gene coded for galactosylceramidase (Kobayashi et al., Brain Res. 202: 479-483 (1980); Suzuki and Suzuki, Am. J. Path. 111 : 394-397 (1983)). It is therefore genetically equivalent to human globoid cell leukodystrophy (Krabbe disease). Affected mice develop clinical symptoms at the onset of the active myelination period and, if untreated, die by 35± days. The pathology is very similar to that in human disease. Toxicity of

galactosylsphingosine (psychosine) that accumulates abnormally in the nervous system is considered to be primarily responsible for the pathogenesis.

[00821] To evaluate the potential efficacy of different compounds described herein in Krabbe disease, the Twitcher mouse model was used. This model is as described in

Hawkins- Sal sbury et al., J. Neurosci. 35(16): 6495-6505 (2015), which is incorporated herein by reference in its entirety.

[00822] If tested compounds are found which have a marked effect on the

experimental endpoints ( e.g ., life span with improved motor function, GALC expression, psychosine levels, and neuroinflammation), an additional experiment is performed looking at effects on activity, inverted screen, and bar crossing tests, as well as average survival time, compared to vehicle-treated (control) mice.

[00823] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following description. It should be understood, however, that the description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the present description will become apparent from this detailed description.

[00824] All publications including patents, patent applications and published patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

WE CLAIM:

1. A compound of F ormul a (I) :

Formula (I),

wherein:

heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups; provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R³ groups;

L is a bond, C(O), or -[C(R⁴R⁵)]_P-;

p is 1 or 2;

R¹ is aryl or heteroaryl, each of which are optionally substituted with 1, 2, or 3 groups

independently selected from alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino,

alkoxycarbonylamino, cycloalkyloxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy and (cycloalkyl)alkoxy;

each R⁴ is independently H or alkyl;

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

alkylcarbonylamino, or alkoxycarbonylamino;

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, or

alkoxycarbonylamino;

provided when ring B is piped dinyl or pyrrolidinyl, then R² is not an amino-substituted

imidazolyl;

optionally a pharmaceutically acceptable salt thereof.

2. The compound or pharmaceutically acceptable salt thereof of claim 1, wherein ring B is piperazinyl, piperidinyl, or pyrrolidinyl.

3. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein the compound of Formula (I) is according to Formula (la):

Formula (la).

4. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 3, wherein L is -[C(R⁴R⁵)]_P- and p is 1 or 2; and each R⁴ is H and each R⁵ is independently H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl.

5. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to

3, wherein L is C(O) or a bond.

6. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to

4, wherein L is -[C(R⁴R⁵)]_P-, wherein p is 1 or 2; each R⁴ is H and each R⁵ is independently H, methyl, ethyl propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl, wherein the phenyl is optionally substituted with trifluoromethyl, difluorom ethyl, l,l,l-trifluoroethyl, or trichloromethyl.

7. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 4, or 6, wherein L is -[C(R⁴R⁵)]_P-, wherein p is 1 or 2; and each R⁴ and R⁵ are both H

8. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 4, or 6, wherein L is C(R⁴R⁵)-; and R⁴ is H and R⁵ is methyl, ethyl, propyl, butyl, pentyl or hexyl.

9. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 4, or 6, wherein L is C(R⁴R⁵)-; and R⁴ is H and R⁵ is phenyl, wherein the phenyl is substituted with trifluoromethyl, difluorom ethyl, l,l,l-trifluoroethyl, or

trichloromethyl.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to

9, wherein R¹ is aryl optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy.

11. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to

10, wherein R¹ is naphthyl substituted with cycloalkyloxy or R¹ is phenyl substituted with haloalkoxy or (cycloalkyl)alkoxy.

12. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 10, wherein R¹ is phenyl substituted with trifluoromethoxy, difluoromethoxy, 1,1,1- trifluoroethoxy, trichloromethoxy, cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy.

13. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 9, wherein R¹ is heteroaryl optionally substituted with (cycloalkyl)alkoxy.

14. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 9, or 13, wherein R¹ is 2-pyridyl or 3-pyridyl substituted with (cycloalkyl)alkoxy.

15. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to

14, wherein ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups, provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R³ groups.

16. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to

15, wherein ring A is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, or diazepanyl, each of which is substituted with 1, 2, or 3 R³ groups.

17. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to

16, wherein each R³ is independently halo or amino.

18. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 14, wherein ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups.

19. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 14, or 18, wherein ring A is 8-azabicyclo[3.2.l]octanyl or (lR,5S)-3-azabicyclo[3.2.l] octanyl, each of which is substituted with an R³ group.

20. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 14, or 18-19, wherein R³ is amino.

21. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to

20, wherein R² is aryl optionally substituted with 1 or 2 R⁶ groups.

22. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to

21, wherein R² is phenyl or indanyl, each of which is optionally substituted with 1 or 2 R⁶ groups.

23. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 20, wherein R² is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms, and is optionally substituted with 1 or 2 R⁶ groups.

24. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 20, or 23, wherein R² is 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, or 1,3,4- thiadiazolyl, each of which is substituted with 1 or 2 R⁶ groups.

25. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 24, wherein each R⁶ is independently haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with halo, haloalkoxy, or haloalkyl.

26. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 25 wherein each R⁶ is independently trifluoromethyl, difluoromethyl, 1,1,1- trifluoroethyl, trichlorom ethyl, trifluoromethoxy, difluoromethoxy, 1,1,1- trifluoroethoxy, trichlorom ethoxy, (trifluoromethyl)cyclopropyl, phenyl, 2-pyridyl, 3- pyridyl, or 4-pyridyl, wherein the phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl is each independently and optionally substituted with fluoro, chloro, trifluoromethyl, or trifluoromethoxy.

27. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 22, or 25, wherein R² is phenyl optionally substituted with an R⁶ group, wherein the R⁶ group is independently selected from haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, and heteroaryl, wherein each aryl or heteroaryl, is independently and optionally substituted with halo, haloalkoxy, or haloalkyl; or R² is indanyl is optionally substituted with haloalkyl.

28. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 20, or 23-24, wherein R² is 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, or 1,3,4- thiadiazolyl, each of which is optionally substituted with R⁶, wherein R⁶ is aryl or heteroaryl, each of which is substituted with halo, haloalkyl, or haloalkoxy.

29. A compound of Table 1; optionally as a single stereoisomer or mixture of

30. A compound of F ormul a (II) :

Formula (II),

wherein:

ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups; provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R³ groups;

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,

alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy,

alkylcarbonylamino, or alkoxycarbonylamino;

dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, alkoxycarbonylamino, (haloalkyl)cycloalkyl, cycloalkyl, cycloalkyloxy, heterocycloalkyl, heterocycloalkyloxy, aryl, aryloxy, or heteroaryl, wherein each aryl or heteroaryl is independently and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, haloalkyl, hydroxyalkyl, alkoxy,

dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, or

alkoxycarbonylamino;

optionally a pharmaceutically acceptable salt thereof.

31. The compound or pharmaceutically acceptable salt thereof of claim 30, wherein ring B is piperazinyl, piperidinyl, or pyrrolidinyl.

32. The compound or pharmaceutically acceptable salt thereof of claims 30 or 31,

wherein the compound of Formula (II) is according to Formula (Ila):

Formula (Ila).

33. The compound or pharmaceutically acceptable salt thereof of claims 30 or 31,

wherein the compound of Formula (II) is according to Formula (lib):

Formula (lib).

34. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to 33, wherein R¹ is aryl optionally substituted with cycloalkyloxy or

(cycloalkyl)alkoxy.

35. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to

34, wherein R¹ is naphthyl optionally substituted with cycloalkyloxy or R¹ is phenyl optionally substituted with (cycloalkyl)alkoxy.

36. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to

35, wherein ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups, provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R³ groups.

37. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to

36, wherein ring A is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, or diazepanyl, each of which is substituted with 1, 2, or 3 R³ groups.

38. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to

37, wherein each R³ is independently halo or amino.

39. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to 35, wherein ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R³ groups.

40. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to 35, or 39, wherein ring A is 8-azabicyclo[3.2.l]octanyl or (lR,5S)-3-azabicyclo[3.2.l] octanyl, each of which is substituted with an R³ group.

41. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to 35, or 39-40, wherein R³ is amino.

42. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to

41, wherein R² is aryl optionally substituted with 1 or 2 R⁶ groups.

43. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to

42, wherein R² is phenyl optionally substituted with 1 or 2 R⁶ groups.

44. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to

43, wherein each R⁶ is independently alkoxy, halo, haloalkyl, aryloxy, or aryl optionally substituted with halo.

45. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to 43 wherein each R⁶ is independently methoxy, ethoxy, propoxy, butoxy, chloro, fluoro, bromo, trifluoromethyl, difluoromethyl, l,l,l-trifluoroethyl, trichloromethyl, phenyl, or phenoxy, wherein the phenyl is optionally substituted with fluoro, chloro, or bromo.

46. The compound or pharmaceutically acceptable salt thereof of any one of claims 30 to 31, or 34 to 44, wherein R² is phenyl optionally substituted with an R⁶ group, wherein the R⁶ group is halo, haloalkyl, or aryl, wherein the aryl is optionally substituted with halo.

47. The compound or pharmaceutically acceptable salt thereof of any one of claims 30,

31, or 33 to 44, wherein R² is phenyl optionally substituted with 1 or 2 R⁶ groups, wherein each R⁶ group is independently selected from alkoxy, halo, aryl, and aryloxy.

48. A pharmaceutical composition comprising the compound of any one of claims 1 to 47, optionally as a single stereoisomer, or mixture of stereoisomers, and additionally optionally as a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

49. A method of treating a disease or disorder comprising administering to a subject having the disease or disorder the compound or salt of any one of claims 1 to 47, or the pharmaceutical composition of claim 48.

50. The method of claim 49, wherein the disease or disorder is mediated by the enzyme CGT.

51. The method of claims 49 or 50, wherein the disease or disorder is lysosomal storage disease.

52. The method of claim 51, wherein the lysosomal storage disease is Krabbe disease or Metachromatic Leukodystrophy.

53. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 47 or the pharmaceutical composition of claim 48 for use as a medicament.

54. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 47 or the pharmaceutical composition of claim 48, for use in a method of treating a lysosomal storage disease.

55. The compound or pharmaceutically acceptable salt thereof for use or the

pharmaceutical composition for use of claim 54, wherein the lysosomal storage disease is Krabbe disease or Metachromatic Leukodystrophy.