AU2017200704A1 - Modulation of chemosensory receptors and ligands associated therewith - Google Patents

Abstract

The present invention includes methods for identifying modifiers of chemosensory receptors and their ligands, e.g., by determining whether a test entity is suitable to interact with one or more interacting sites within the Venus flytrap domains of the chemosensory receptors, and modifiers 5 capable of modulating chemosensory receptors and their ligands. The present invention also includes modifiers of chemosensory receptors and their ligands having Formula (1), its subgenus, and specific compounds. Furthermore, the present invention includes ingestible compositions comprising the modifiers of chemosensory receptors and their ligands and methods of using the modifiers of chemosensory receptors and their ligands to enhance the 0 sweet taste of an ingestible composition or treat a condition associated with a chemosensory receptor. In addition, the present invention include processes for preparing the modifiers of chemosensory receptors and their ligands.

Description

L1GAND$ ASSOCIATED THEREWITH

.CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Patent Application Serial No. 11760.592, entitled ''Moduiallon of Chemosensory Receptors and Ligaruls Associated Therewith''. tiled June Ik 200~; U.S. Patent Application Serial No. I 1756,074, entitled "Modulation of Chemosensory Receptors and Ligands Associated Therewith'', Hied August »S, 2007; and U.S. Patent Application Send No. 61/027,41.9, entitled '‘Modulation of Cheinmcnsory Receptors and Ligands Associated Therewith*, filed February S, 2098 The content of these applications are herein incorporated by reference in their entirety' for all purposes,

BACKGROUND OF TOE INVENTION

The taste system provides sensory information shout the chemical, composition of the external world, Tas-c iramducbon is one of -he most sophisticated forms of chemical-triggered sensation in animals. Signaling of taste is found throughout the: animal kingdom, from simple metazoans to the most complex of vertebrates. Sensations associated with taste arc thought to involve distinct signaling pathways mediated by receptors, he,, metabotropic or. ionotropic red'epRns, Cells which exp?css taste receptors, when exposedto certain chemical stimuli, elicit taste sensation by depoiariziag to generate an action potential, which is believed to trigger the sensation, litis· event is believed' to trigger the release of neurotranstni tiers at gustatory afferent neuron synapses, thereby initiating signaling· along neuronal pathways that mediate taste perception.

As such, taste receptors specifically recognize molecules that elicit specific taste sensation. These molecules are also referred to herein as “tsstantsA Matty taste: receptors belong to the 7-transntemhrane receptor superfomily, which are: also known as G protein-coupled receptors (GPCifo). Other tastes are believed to be mediated by channel proteins, G protein-coupled receptors control many physiological functions, such as endocrine function, exocrine function, heart rare, hpolysls, carbohydrate metabolism, and transmembrane signaling. F&r example, family C of G-protein coupled receptors (GPCRs) from humans comprises eight metabotropic glutamate fmGUg 1 -K}} receptor,·two;feetopoilimerie ganmiauuthnobiayne add{B) {GABAfB}} receptors, a ealcium-seming receptor (CaR), three uwte {T1R) receptors, & promiscuous L-al.plrs-areiuo acid receptor (GFRG6A}, and five orphan, receptors. The family € GPGRs arc characterised by a large ammodernfoial domain, which binds the endogenous orfoosteric agonists. Additionally, allosteric modulators which hind to the seven traosmembtatse domains of the receptors have also been reported.

In general,, upon ligand binding to a GPCR, the rcceptw presumably undergoes a conformational change leading to activation of a G protein, G proteins are comprised of three subunits: a gaanyl nucleotide binding msubunit, a β-sisbimit, and a y^abamt G proteins cycle between two: forms, depending on whether GDP or GTP is hound to the «-subunit. When .GDP is bound, the G protein exists as a heterotrime?: the Gyp·, com plea. When GTP is bound, the n-subaiitt dissociates front the heterotrimer, leaving a (¾ eomplex, When a Gy^ complex operatively associates with aa activated O proteitneoupled receptor ia a cell menforaae, the rate of exchange of GTP for bound GDP is increased and the rate of dissociation of the bound G* shbunst hoarthe Gain complex Increases, The hoe Gy subunit and G^, complex are thus capable oftrausfoitting a .Signal to downstream, elements of a variety of signal transduction pathways. These: events form the basis for a rualtiplicliy of difforeiit cell signaling phenomena, iaefuding for example the signaling phenomena that are Mead fled as neurological sensory perceptions siteh as taste andtor smell,

Mammals are believed to have five basic taste modalities: sweet, bitter, soar, salty, and umanu (foe taste of monosodiam glutamate), Numerous physiological studies ia animals have shown that taste receptor ceils may selectively respond to different Chemical stimuli-, in mammals, taste receptor cells are assembled into taste buds that are distributed Into different papillae in the tongue epithelium. Circumvaliatc papillae, found at the very back of the tongue, contain hundreds to thousands of taste buds. By contrast, foliate papillae, localized to the posterior lateral edge of the tongue, contain dozens to hundreds of taste: buds. Further, feugiform papillae, located at the front of the tongue, contain only a single or a few taste buds.

Each taste had,, depending on the species, contains 50-150 cells, including precursor cells, support cells, and taste receptor cells, Receptor cells are innervated a: their base by afferent nerve endings that transmit Information to the taste centers of the cortex through. synapses in the brain stern avid thalamus. Elucidating the median isms of taste cell signaling and information processing is important'to mtdcrst&admg'the function, regulation, and perception of th e sense of taste.

The gustatory system has been selected during evolution to detect nutritive and beneficial compounds as well as harmful or toxic substances. Outside the tongue, expression of has also been localized to gastric and pancreatic cells, suggesting that a taste-sensing •mechanism may also exist in the gastrointestinal (GIs tract. Expression of taste rccqptois has also been found in the lining of stomach, and intestine, suggesting that taste receptors may play a tote in. molecular sensing, of therapeutic' entities and toxinr.

Complete or partial sequences of numerous -human and. other eukaryotic ehemosensoiy receptors are currently known. Within the last several years, a number of groups including the present assignee Sencmyx, Inc. have reported the identification and cloning of genes from two GPCR families that are involved in taste modulation and have obtained experimental results related to the understanding of taste biology. These results indicate that bitter, sweet and amino acid taste, also referred as imiami. taste, are triggered by activation, of two types of specific receptors located at the surface of taste record-r cells (TRCs) on the tongue few T2Rs. ami TlRs. Bis eprtehtly believed that at least 26 to S3 genes encode fimctlonal receptors fT2Rs) for bitter tasting substances· in human and rodent respectively.

By contrast there arc only 3 TlRs, T1RI, TJR2 and T]R3, which are Involved in nnrami and sweet taste. Structurally, the TlR and T2R receptors possess the hallmark of G protoin-coupled receptors (GPGRs), /.0., 7 transmernhrane domains Banked by small extracellular and iateaeeliolar amino- and. carboxyi~teonini respeetlvely. T2.Rs have been cloned from .different mammals· including rate, mice .and humans, T.IRs comprise a novel family of human and rodent G protein-coupled receptor* that arc expressed in subsets oi taste receptor ceils of the tongue and palate epitheiia Those taste receptors are organized in clusters in taste cells ami are genetically linked to loci that influence bitter taste. The .fact, that T2Rs modulate bitter taste has been .demonstrated in cell-hased assays. For example, mT2R-3, hT2R-4 and. rnT2R~8 have been shown to be activated by bitter molecules in in vitro guslducin assays, providing cxper.i.rnoma! proof that T2Rs function as hitter taste receptors. See also T2Rs disclosed in 1.1.S. Patent No. 7,105,050, T.I R family members in general include TI R..1, TIR2, and Ti R3, rag., rTIRd, mil R3, hTl R3, rTl R2, mi l R2, hT!R2, and rTlR.1, mil RI and h'Tl R1. It Is known that tie three T1R gene members T1R1, T1R2 and TI R3 ibrrn. fimetional heterod briers that specifically recognize sweeteners and amine acids. It is generally believed that TI R2TIR3 combination recognizes natural and artificial sweeteners while the TIRi/Ti R3 combination recognizes several L-amino acids and monosodium glutamate (MSG), respectis'dy. For example, eo-exprcsslon of Ti R I and HR 3 m recombinant host ceils results in a hetero-oligomeric taste receptor that responds to annum taste stimuli. Umami taste stimuli include by way ot example monosodium glutamate and other molecules that elicit a "savory'" taste sensation. By contrast, co-expression ofTIE2 and TIR.o in recombinant host cells results la abetero-oligomcrfe sweet taste receptor that responds to both naturally occurring and artificial sweeteners.

There is a need in the art to develop various vvays of identifying compounds or other entities suitable for modifying receptors and their ligands associated with ehemosensory or eoomosonsory related sensation or reaction, in addition, there- is a need in the art for compounds or·other entities with such characteristics

BRIER SUMMARY OF THE INVENTION

The present invention is based, at least in pan, · <n the discovery·' that an ex tra-eel Inlar domain, e.g., the V enus fly trap domain of a ehemosensory receptor, especially one or «tore interacting sites within the Venus flytrap domain, is a suitable target dor compounds or other entities to modulate the elmmosensory receptor and/or its ligands. Accordingly, the present invention provides screening methods for identifying modifiers of ehemosensory receptors and: their ligands as well as modifiers capable of modulating ehemosensory receptors and their ligands.

In one em.hodim.eni, the present invention, provides a method of screening lor a candida te of a ehemosensory receptor ligand modifier. The method comprises determini ng whether a test. entity Is suitable to interact with a ehemosensory receptor vm an interacting site svithin the Venus flytrap domain of the ehemosensory receptor.

In another embodiment, the present invention provides a method, of screening for a candidate of a ehemosensory receptor l igand modi fier, The me thod comprises determining: whether a test entity is suitable to interact with a ehemosensory receptor via a first interacting so·.: widen the Venus ilvtrap domain of the dKinosensory receptor. wherein the first interacting siic is identified in light of a second interacting site identified based on the interaction between a chemosensory receptor hgand and the chemdsei^ory· receptor, in yet another embodiment, the present invention provider a method of screening for a candidate of a chemosensory receptor modifies - The method comprises determining whether a test entity is suitable to interact with a chemosensory receptor via an interacting site within the Venus flytrap domain of the chemosensory receptor, wherein the interacting she includes an interacting residue selected from the group consisting of NI43. SI 44.1167. S40, SI44, SI65. Y103, DI42. P277, K65. R383, 0307. E302. D278, P1s5. Ti Rf T326, E302. V384, A305.1325.006, D307, E382,1279. 467, V66, ¥309,83,03,1242, F103, Q328, and Si68 of "Π R2 and a combination thereof wheioin a test entity suitable to interact with the interacting site of t he chemosensory receptor is indicative o f a. candidate of a chefttoseasory recepto r modifier . in yet. another embodiment, the present invention provides a method of modulating the activity of a chemosensory receptor ligand. The method comprises contacting a chemosensory receptor ligand modifier with a cell containing T1R2 Venus flytrap domain in the. presence of a chemosensory receptor ligand, wherein the chemosensory receptor ligand moodier interacts: with an interacting site oftho-chopipsensory reeepts c

In still another embodiment, the present invention provides a chemosensory receptor ligand modifier, wherein in the presence of a chemosensory receptor ligand: it interacts with T1R.2 Venus flytrap domain via at least three interacting residues seiacted from the: group consisting ofN143, Si44,1167, S40, 81:44, S,l657YT03,1)14.2, P277. Key R333, 0307, Γ302,. D27R PI85, TI $4,.1326,6302, V384, A305,1325, 006, E382,1270. 167, V66, V309, S303, 1242, F103, Q328, and Si68 of TIR2.

In «tiil another embodiment, the present invention, provides a chemosensory receptor ligand modifier having a structure of For nod a Π):

or a tautomer, salt, solvate, and/or ester thereof wherein; G forms a single bond with either Dor E and a double bond with tit© other of Dor E; R! is hydrogen, alkyl, substituted alkvk aryi, substituted ary], arylalkyl, substituted arylalkyl. acyl, substituted acyl, heteroalkyL substituted heieroalkyl, hcteroaryl, substituted hcicroaryL hcteroarvlalkyl, substituted heieroarylalkyl, -CN, -NO.·, -OR’. -S(0)..R \ ~NR-R\ -OONR’R4, -CO-R \ -NR'COdkk -NR-'CONRV, -NINCSNR’rA -NR'C(===NH}NR4Rsi SO.-N'R· RR -NR^SO.-R L -N'R'SO>NR'fR L -BtOR'KORN, -P{OhOR-}(OR4} or-P(0#R;KOR*fc R· is hydrogen, alkyl, substituted alkyl, aryl substituted aryl, ary Lb by l substituted arylalkyl, acyl, substituted acyl, heteroulkyk substituted hetcroaikyl, beteroaryk substituted beteroaryk hercroarylalkyl. substituted hetcroarylalky], -ON, -NO.;, -OR"» -0(0)-,R", NR'R L -CONR'R L -CO;-Rk -NRTOrRk -NRVONlORk -NR'rSKR Rk -NR'Y( NIuNINRk -SO?N R;R6, -NR-SOiRk -NR'SO>NR:'R \ - B(OR; H ORO, - Pi 0)(011^( OR''), or -P(0){RJ StOR'l; or alternatively, R* and R“, together with the atoms to which they are bonded, form an aryl, substituted aryl, heteroaryl, substituted beteroaryk eycloaikyl. substituted cseloalkyi. cyclobctcroalkyJ or substituted cycloheterculkyl ring wherein she ring is optionally fused to another aryl, substituted aryl., beteroaryk substituted beteroaryk cyeloalkvl, stibsibuted cyeloalkyi, eyclohetsroalkyl or .substituted eyctoheieroalky! ring; with the proviso that R! and Rb* are not both hydrogen; A is hydrogen,h|kyl,-substituted alkyl, aryl, substituted aryl, ay lalkyl, substituted arylalkyl, aeyl, substituted acyl. heteroaiky], substituted hetero&amp;lkyk heteroaryl, substituted heteroaryi, heieroarylalkyl, substituted ..heteroaryl alkyl, halo, -ON. -NO-,. -OR:', -SlObA5, -NR^CORr0, -Nd-fOR^, -NR"RKi, -NOR5, -CONR:>RKi, -C02R!\ -NR\Xk.RuL -NR9CONR,uR!!, -NR OSNR 50R:h, -HR9C(^H)NR;iyRsk ~B(ORi0)(ORJs), -PiOiCOR^KOR1*) or -R(OltRi0}(OR55); B Is -N~ or ~C(R u‘)«; R " is hydrogen, alkvk substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, hetcroalkyl, substituted heteroalkyl, beteroaryk, substituted beteroaryk heieroarylalkyl,.substituted heteroarvialkyi, -NR ! 'R-CN, -OR: -SCO)#13, ~C02Rr< or -;CQNR! T<! b is -C- or -SijLhfog provided that when G is -S(0)2-, then ¢3 forms a single bond with E; when the h««nd between D and G is a single bond, then D is hydrogen, alkyl, stfosiitnted alkyl, aryl, substituted aryl, aryhilkyl, substituted arylalkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heicroalkyl, beteroaryi, substituted helcroaryl, hetcroarylalkyl, substituted bcreroarylaikyl, -OR5'. -ΜΜ.>Κί:1 -SiO),R:i. -NRlV\ “Nil-NIIR l -CCKR!\ or -conigV6 when G forms a double bond with IX'theft D is :::Os ::::S , :::N~OR!y or :::MNHR*”; o is 0 when G is -SiOl·-, and n is I when G is ·€·; E is-NR5'-. -N~or -OfR1’)·; provided that E Is -NR* onh when O forms a single bond with E; R* is hydrogen, alk> I, substiiuted alkyl. a;yb substituted uryL ars blkyl, substituted arylalkyl, acyl substituted acyl hcrernnikvL substituted heteroalsyk beteroaryi, substituted beteroaryi, heteroaryiaikyl. substlmted hereroarylalksi or -COvR'*':

Ris is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arykdkyi, substituted arylalkyl. acyl, substituted acyl, heteroalky], substituted bcteroalkyk beteroaryi, substituted heteroaryl, hetoroaryialkyl substituted hetcroarylalkyl. -NR/GX:, -CN. -OR"’”, -SCOkR". -CO/R;:i or -CONR;f’R/X a, b, c, d, e and fare independently 0. 1 or 2; and R h R4, R5, R\R7>RS} R*\ R!a, Kdi EX R;\ R}\ R'X R1sy R^an^.R2·5 are independently hydrogen, alkyl, substituted alkyl, aryl .substituted' aryl, aryfaikyl substituted aryl&amp;lkyl, acyl substituted acyl, betexoaikyl substituted hetcroalkyl beteroaryi, substituted heterouryl heteroarylalkyi or substitutedhetemarykiky 1; or alternatively, R' and R'l R'’ and E~, R:!i and R.'» IX an d R\ R.<y and R.5'1, R5<‘ and Ru, R! * and. R:!l R1* and R!<J, or R'VI and R*1, together with the-atoms to which they are bonded, form a eycbheteroalkyl or Substituted eyelohetoroalkyl ring, in one embodiment of Formula (I), the compound of the present invention has structural Formula (11): wherein:

Y forms a single bout! with either W or Z and a durable bond with tbe otberof W or Z; W is -C{Rri)% -S-. -N-, -NCRViH ur-O-j Y is -OtR'V or -N-; Z Is ~0,R'rK -S-, -N-. or -Os R''4 is hydrogen, a]kyl*$ttl^tuted'aIkyl.aQfi, substituted aryl, aryialkyl, substituted aryialkyl aeyl, substituted acyl, heteroalkyi subsihute&amp;hetero&amp;Ikyl, heteroaryl, substituted heteroaryl, heteroaryteikyl substituted heteroarylalkyi -CM, *·'Νθ>, -OR*\ “StOh»R"’iV* ‘NRz1i!w. CONROE30, -COiE39, -SQ>NR**Rΐ!ί -NR’9SO,R-°, -BCOR'^QR^}, "P(0)(ORVi'm - Pi O S( R')(0 R' R/1' is hydrogen, alkyl substituted alkyl aryl substituted aryl, aryialkyl substituted aryialkyl acyl substituted acyl hetctoaikyl substituted heteroalkyi. heteroaryl substituted heteroaryl, hetcroarylalkyl substituted heteroarslatkyl halo. -ON, -NO>, -0R':, 0C0R;S -NRmR \ -CONR SR\ -CO..RM, -SONRVi -NR,lSO;Rv, -BtOR^KOR^}, P(OMORn hOR,;) or P{0}fRM)iOR3··}; R;··' is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl aryialky!. substituted aryialkyl acyl, substituted aeyl heteroalkyi, substituted, beteroalkyl heteroaryl, substituted heteroaryl, het.etoarylalkyl, substituted heteroarylalkyl, halo, -CN, -110¾ -OR·**.-S(OXR'u, -OCOR:'·', -NR;:R!4, -CONR-R^.-COR'k ~C02Rx\-SOoNR^R34, -NR^SO?R?4, -8(OR:':?)COr4), #(O}(OR'0r:>Rn} or -PIOXR-'KOR44)or&amp;lternudvely R'5 andor tPand R4' together with the atoms to which they are bonded form a eycloalkyi, substituted eyebalkyl oyelobeteroalkyl or substituted cycloheteroaik\1 ring: g, h and i are independen tly 0 or 5 ; R*5 and K.** are independently hydrogen, alkyl substituted alkyl aryl, substituted aryl aryialkyl substituted aryialkyl, aeyl, substituted aeyl heteroalkyi, substituted heteroalkyi, heteroaryl, substituted heteroaryl. beteroarylalkyi or substituted heteroarylalkyl and

Rp R'l R'l R'\ R. and R:i are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryialkyl substituted aryialkyl, acyl, substituted acyl, heteroalkyi, substituted heteroalkyi heteroaryl substituted heteroaryl. beteroarylalkyi or substituted heteroaryJalky1; or alternatively R“:> and R'fo RjS and RJ“ or R:KVaud R:v+together with the atoms to which they are bonded form a eyelobeteroalkyl or substituted eyeloheteroalkyl dug: and with die folio whig provisos; RO when. Wis -0- or -S- or -NRp then 2. is -C(R :'l or -N-; and (hi nlietiZ is -0-or-S- or -NR“S, then W is -C(R':<) or -N-, structural Formula (01):

In one embodiment of Fonnula (1), the compound of the present invention has

wherein: H is -C(H "}- or ~N~; 1 is ~C(R30) or -N~; 1 is -OR' )- or -N~: K. is C(R')- or -M-; R*5 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryh aryhdkyl, substituted arylaikyi, acyl substituted acyl, halo» beteroalfcyl, substituted: hetermdkyt hetcroaryi, substituted heteroaryl, heteroarylalkyl, substituted heteroaryialkyi, -GN, -NO?, -00 0 -S{0JjR^»-OCOR -NR 'V,-CGNR.’V* -C03R*\ -SO^rV, ~NR:^0?R.4<\ -B(0R3S)(0R:,!S), -P(O)(0R3;JKOR'!<t) or -P(C>>{ R. :>(()R: R:'<? is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylaikyi,, substituted arylalkyl, aevl, substituted-.adyl, halo, heteroalkyL substituted heteroalkyl, heteroaryl, substituted hetcroaryi, heteroarylaj Ikyi substituted heteroarylalkyl. -CN, -N0>, -OR4'. -StO^R*1* ~0C0R4is -NRaR4". -CONR4;R42, -CO.iR4i, -SO.-:NR4iR4\ -NRiSSO>Ri3, -BlOR^XOR4'}, -Ft 0 )(0R4i }(OR40 or ~P(0XR4i >(0R'j 0; R3/ is hydrogen,, alky.ls substituted alkyl, aryl, suhstitntedaryL arylalkyl, substituted arylalkyl, aeyl, substituted acyl, halo, heieroalkvl, substituted heteroalkyL beteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl ,~CN, -NO?, -OR47, -S(0)iR4G -OCOR5'', -NR" V, -CONR4?R'u, -C02R:?\ «S02NR4*R4\ -NR :r<S02R‘H, -BiOR4'!}CQR44), ^(G)£0R43MOR·'4} « >R(OKR‘i4KORu); R54 is hydrogen, alkyl, substituted alkyl, aryl, substituted ;uyi, arylalkyl, substituted arylalkyl, aeyh substitutedaeyl, halo, heteroalkyj. substituted heteroalky], beteroaryl, substituted hetcroaryi, heteroarylalkyl., substituted bctcroarylalky !, -CN, -N0>, -OR4'. -S{0).,,R4:. -OCOR ir. -NK44R4fl -CONR45R4<5, -COR43, C02R"\ -SOiNR^R* -NRIsSCMl"6, -B(OR45)tOR46), -F(0)(()R'f;KOR4f') or -F(0)(R43)(OR'4fi): or alternatively i# and R*7 or R*7 and taken together with the atom to which they are bonded, form a eyeloalkyl, substituted eyeloalkyl, cvclohctcroalky i, or substituted cyclohcteroaikyl ring; j, k, 1 and m arc independently 0, ; or 2; and R'% R* E*1, R4fi R-, -R"”, R*5, arid R',v are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl. acyl, substituted acyl. hetcroaikyl, substituted heteroalkyl, heteroaryl. substituted heteroaryl, beteroaryudkyl or substituted heteroarylalkyl or alternatively R' ’ and R'*’1. R':! and R'::, }V' and R':': or R4' and R7" together with the. atoms to which they are: bonded form a eyciofieteroslkyl. or .substituted cyclohcteroaikyi ring; with the proviso that at most, two ofii, I. J sad K are -N-,

In one embodiment, the present invention pov-Mcs an kgesttble composition comprising- a ehemosensoty recent·:* ligand mod-tier, wherein in the presence of a ehemosensory receptor ligand it interacts with II R2 YehuSt flytrap domain cm at least three .iriteracfing residues selected from the group consisting ι»ΡΝ143, 8144, U67, 840, SI44, 8165, Y103, DI42, P277, K65, R383, D307. £302, 0.7 78, PJ85. T184. T326.17303, Y384. Λ305, 1325.1306. R382. OPf 167, ¥66, ¥304, 8303. T242,. FI 03,0328, and SI 68 of a -human' T1R2, in one embodiment, the ehemosensory receptor ligand modifier is a-'cbmpourwi having' structural Formula (I), (Ο), or (111), or a tautomer. salt, solvate, and/or ester thereof,. In another embodiment· the mgestible composition further-comprises one or more sweeteners ,

In one embodiment, the present invention provides a method of enhancing the sweet taste of an digestible composition -comprising contacting the iogeshblo composition -or precursors thereof with a clmnmsensoiry receptor ligand modifier to form a modified mgesiihle composition, In one embodiment, die efiemosensory receptor I igand modifier is- a. compound, having structural Formula (1), (II), or (HI), or a tautomer» salt, solvate, and/or ester thereof in one embodiment the present invention provides a method of treating a condition associated with a chemosensory receptor comprising administering to a subject in need of such treatment an effective amount of an entity selected from the group consisting of a eheaioscnsory receptor ns'dOHir. chcm.osensory receptor Iigan4imodtfier.ymd'-aoomhmsrib» thereof wherein the entity interacts with, an interacting site of the ehemoseasory receptor, in one embodiment,, tile ehemdsensory receptor ligand modifier is a compound having structural Formula (I), (II), or (HI), or a tautomer, salt, solvate, and/or ester thereof BRIEF HESCRIPriON OF THE FIGURES Figure 1. contains exemplary human. XfR.l polymorphic variations.

Figure 2 contains exemplary human Π R2 polymorphic '> analious Figure 3 show? the dendrograms for the sequence alignments ol'Ti RL Figure 4 shows the dendrograms lor the sequence alignments of TJR2.

Figure-5 shows exemplary interacting spaces for suerafose and one of the compound of the present invention. Proteinis representor! as a ribbon diagram.

Figure 6 shows exemplary interacting spaces and residues for sucralose and one of the compounds of foe present invention. Protein Is represented as a ribbon diagram.

Figure 7 shows exemplary interacting spaces and * endues associated with the binge region for sneraiose and one of the compounds of the present invention.

Figure 8 shows exemplary partial interacting surfaces snd interacting residues proximal to the hinge region for sucrose and sneraiose.

Figure 4 shows exemplary interacting spaces and residues associated w sth the lobes tbrsucralose and one of the compounds of the present invention.

Figure 10 shows exemplary interacting spaces and residues associated with an interacting site for sucraiose and one o f the compounds of foe present invention.

Figure 11 shows .exemplary results for mapping -studies·using human-rat chimeric receptors.

Figure 12 shows results for exemplary mutagenesis results. DETAILED' DESCRIPTION OF THE INVENTION Prior to specifically describing the invention,: foe following definitions are provided.

The term !ΤΙΙΓ family includes polymotphic variants, a holes, mutants, and homologs that: {I} have about 30-40% amino acid sequence identity, more Specifically about 40, SO, (>0, 70, 75, 80,85,90, 95, 96, 97,98. or 99% amino acid sequence identity to the TTRs known or disclosed, e.y,, in patent application 17.5 Sena! No. 10/179.373- filed on lime 26, 2.002, SerialNo, 09/799,629 filed on April .5, 2001 andlfS:. Serial No. 10/035,045 filed on dan nary 3, 2002, over a, window of about 25 artdno acids,. Optimally 50-100 am mb- acids; (2} specifically bind to antibodies raised against an immunogen comprising an amino aeid sequence selected from the group consisting of the T IR sequences disclosed infra, end conservatively modified variants thereof; (3) specifically hybridize (with a size of at least about 100, optionally at least about 500-1000 nucleotides) under strnigcut hybridization conditions -o a sequence \clccicd iron? the group consisting of the Tl R. DMA .sequences disclosed infra, and cojisen-utbcly modified variants thereof; (4) comprise a sequence at least .about 40% identical to an amino acid sequence selected from the group consisting of the TlR amino acid sequences disclosed infra or (5) are amplified by primers that specifically hybridize under stringent 'hybridisation conditions to the described TlR sequences.

In particular, these 'ΊI Rs' include taste receptor GPCRs referred to ns hi IRI, hTIR2, hTIR3, rTI Rl, rl IR2, rT 1R3. rul'i R1, mil Re, and ηΙΠ R5 having the nucleic acid sequences and amino acid sequences known or disclosed, ν.,χο, in I hS. Serial No. 10. i ?9,373 filed on June 26, 2002, U’,S. Serial No. 04.799,624 filed on April 5, 2001 and f'.S, Serial No. 10/035,045 Sled on January 3, 2002, and variants, alleles, mutants, orthologs and chimeras thereof which specifically bind and/or respond to sweet, nmarni, or any other chcmosensory related ligands including aetivatoss. inhibitors and enhancers. Also Tl Rs include taste receptor GPCRs expressed in humans or other marasmus, e.o., coils associated with taste anchor part of gastrointestinal system itu iudittg without, any Umittdon, esophagus, stomach.,- intestine (small and,large), colon,.liver,/biliary tract;,pancreas, gallbladder, etc. Also., TlR polypeptides include eBimeriC: sequences derived from portions of a particular TlR polypeptide sued as TlRl, T1R2 or T1R3 of different species or by combining portions of different f lRs wherein such .chimeric Tl R sequences are combined to produce a functional sweet or umami taste receptor. For example chimeric TI Rs may comprise the 'extracellular region of one T! R, i,e„ Tl R1 or T1R2 and the transmembrane region of another Til:, either 'f 1R1 or T.1R2,

Topologically, certain cbemosensqry GPCRs base an "C-terminal dominii;* “extcacclluliai -doutaiusr aAransmembrane domaer comprising seven rransmetnhrane regions, and eo:Ti;spending cytoplasmic and extracellular loops, ''cytoplasmic regions," and aAC-terrmnai region' (see, e,g., Boon at at, Ceil 96:541-51 (1994): Bucketat.. Ceil 65:175-87 (199.1)). These regions can be structurally identified using methods -known to those of skill in the art; such as sequence analysis programs that identify· hydrophobic and hydrophilic domains (see, Ago, Stryer, Biochemistry, {3rd ed. 1988); see also any of a number ofMternel based sequence analysis programs,.such as those found at d0timgembem.tmc.ede). These regions are useful tor making chimeric proteins and for in vitro assays of the invention, eg., ligand binding assays. "Extracellular domains” therefore refers to the domains of chcrnoscnsory receptors, eg., TIR polypeptides that protrude from the cellular membrane and arc exposed to the extracellular taco of the cel L Such regions' would include the *‘N4etminai domain” fealis exposed to the extracellular face of the cell, as well as the extracellular loops of the transmembrane domain that are exposed to the extracellular face of the celt, or?,, the extracellular loops between transmembrane regions 2 and 3, traasmembrane regions 4 and. 5, and transmembrane regions (> and 7, TheMKrteimhxal domain”' starts at the N--termmus and extends to a iegion dose to the shu t of the transmembrane region. These extracellular regions we useful for in vitro ligand binding assays, both soluble and solid phase. In addition, transtnemhrane regions, described below, can also he involved In ligand binding, either In combination with the extracellular region or alone, and are therefore also useful for ;« vitro ligand binding assays. "1: iansntenthrane domain,”' which comprises the severs transmembrane "‘regions,” refers to the domains of ehemosenaory receptors, e.y , TIR polypeptides that lie within the plasma membrane, and may also include the corresponding cytoplasmic (intracellular) smd extracellular loops, also referred to as transmembrane “regionsf5 The seven transmembrane regions and extracellular and cytoplasmic loops can be identified using standard methods, as described in Kyrc w m., I Mb/, Biol 157:105*32 ¢1982)), or in Stryer, sdpm, "Cytopbsmic· domains” refers to the domains of cbemosensory receptors, tye, TIR proteins that face the inside of the cell, ego the. 'TMermina] domain” and the iniraoeltolar loops of the transmembrane domain, a.g,, the intraeeilniar loops between tmnsmenibrane regions 1 and 2, transrnembrane regions 3 and 4, and transmembrane' regions 5 and 6,. ''Cdenfepal domain” refers to the reg ion feat spans from fee end of the last transniemfemne region to the C-termlnus of fee protein, and which Is normally located .within fee cytoplasm..

The term/'7--transmembrane receptor” means a polypeptide belonging to a superiamily of transmembrane proteins that, have seven regions that span the plasma membrane seven times (thus, the seven regions are called ^transmembrane” or ”Tfefw domains TM I to TM VH>.

The phrase ‘Tbnclional effects” or ‘'activity ” in the contex t of the disclosed assays for testing compounds that modulate a ehemosensory receptor, e.g,, enhance TIR. family member mediated signal transduction such as sweet or umumi receptor functional effects or activity includes the determination, of any parameter that is indirectly or directly under tire influence of: the particular chcmoscnsory receptor, e.g.. functional, physical and chemical effects. It includes, without any limitation, ligand binding, changes in ion flux, mernlirane potential, current flow, transcription, G protein binding, GPCR phosphorylation or dephosphorytoion, signal transduction, reccptor-ligand interactions, second messenger concentrations (o.g.. cAMF, cOMP, 1P3, or intracellular Chr'}, in -vitro* in vivo, and m; i /tv> and also includes other physiologic effects such increases or decreases of neurotraasmitfororfeomione release..

The term ‘•determining the functional effect"5 m receptor "aetiv lew means assays for a compound that Increases or decreases a parameter that Is. indirectly or directly under the influence of a chensosensory receptor, e,g., junctional, physical and. chemical effects. Such functional effects can be measured by any means known to those skilled, in the art, u.g., changes in spectroscopic characteristics {e.g.. fluorescence, absorbance, refractive index), hydrodynamic tv.g., shape), chromatographic, or solubility properties, patch clamping, voltage-sensitive dyes, whole cell currents, radioisotope efflux, inducible ’markers, oocyte ehcmosensorv receptor, t-.g,, Tl R gene expression; tissue culture cell ehemoscnsorv receptor, e.y., TIR expression; transcriptional -activation of ehemosensory receptor, c.g;, TIR genes; ligand binding assays; voltage, membrane potential and conductance changes; ion flux assays; changes in intracellular second messengers such as cAMP. eGlVlP, and inositol triphosphate (IPop changes in intracellular calcium levels; neuro transmitter release, and the like, "Inhibitors,” ikactivators,,J and ‘hBodidem5 of ehemosensory receptor, o.y., TIR. proteins aro used interchangeably to refer to inhibitory, activating, or modulating molecules identified «king m .vfcf^.«ndS. M vivo assays for ehemosensory signal transduction, e;g>, ligands, agonists, antagonists, and their hornofogs and. nthneiiesi Inhibitors are compounds that, e,g., hind, to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize. or down regulate taste 1 ransduedon, e,g., antagonists. Activators are compounds that, e.g-v bind to, stimulate, increase, open, activate, facilitate, enhance activation, sensitize, or up regulate chcmesensory signal transduction, c,g., agonists. Modifiers include compounds that, e.g,, alter, directly or indirectly, die activity of a receptor or the interaction of a receptor with its ligands, e.g., receptor ligands and optionally hind to or interact-with activators or inhibitors; G Froteins; kinases (e.g., bornologs of rhodopsin kinase and beta adrenergic receptor kinases that arc involved in deactivation ami desensitization of a receptor); ami arrestins, which also deactivate and desensitize receptors. Modifiers Include genetically modified versions of chomosensorv receptees, v.g.. T1 R family members, e,e.. svhh shored achv by. as well as naturally occurring and synthetic ligands, anuguonists, agonists. small chemical molecules and the like. The term "ehetnosensory rccepiot hgurnl modified' as used berem includes ehernosenson receptor ligand enhancer. In the 'present invention dus includes, w idiom auy limitation, sweet ligands (agonise; or antagonists), urnarni ligands (agonists and antagonists), sweet enhancers and urnami enhancers and sweet tao e or a nr sou taste inhibitors. ''Enhancer” herein refers to a compound that nuuhdar.es {increases) the activation of a pa; ticular reccptm. p; eferably rhe chcmosensory, .-,1: .. ΐ I R2.-T I R3 : eecptnr or ϊ IR1 .-T I R3 rceept-sj but which h> itself does not result in substantial activation of the particular receptor. Herein such enhances will enhance the activation of a. chentosensoryreceptor by its ligand. Typically the *e»banc«f5< will he specific to· a particular ligand, te., it will not enhance the activation of a cheinosensoty receptor by chcmosensos '.ig:t.»d' enbe* than the particular eheotosensory ligand or ligands closely related thereto. ''Putative enhancer*5 herein refers to a compound identified* &amp;g,, in silico or not, as a potential enhancer using assays which are dosed bed herein hot which enhancer activity has not yet been confirmed in vim, e.g,, in suitable taste tests.

The terms “pbiypqrtitjed’ “peptide5'' and “‘protein’5 are nsec! interchangeably .herein to refer to a polymer of amines acid, .residues. The terms apply to amino acid poly mors in which one or more amino acid .residue Is an artificial chemical mimetic of a corresponding naturally occurring amino acid,: as well as to naturally occurring amino acid polymers and .n.on-natural.ly occurring amino acid polymer.

The ‘‘extra-cellular domain55 and ehemosensory receptor, <xg., HR receptor regions or compositions described herein also include “analogs,55 or “‘conservative wiants55 and "Unimodes" {"peptidomlmefics'*) with structures and -activity that substantially correspond to the exemplary sequences. Thus, the terms “conservative variant5' or “analog55 or ‘‘minretie55 refer to a polypeptide which has a modified amino acid sequence, such, that the change(s) do: net substantially alter the polypeptide's (the conservative variant’s) structure and/or activity, as defined herein. These include eonservafively modified variations of an amino acid sequence, 1.0,, amino acid substitutions, additions or deletions of those residues that are not critical for prole in activiry,i>r subtUifuliou of amino acids with, residues having similar properties (e,g.:. acidic, basic, positively or negatively charged, polar os' rinri-poiar, tic.) such that the substitutions of even critical atnino acids docs riot substantially alter struciuiv andor activity.

More partietdarfy, “cohscrvalively modified vaidants,! applies to both amino acid and nucleic acid sapiences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the liueldc acid does not encode art amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of hmetiomnly identical nucleic adds encode any given protein.

For instance, the codecs GCA, GCC, GCG; aad GCU all encode the amino acid alanine. Thus, at every position where an alanine is specified, by a codon, the codon can be altered to any of the eomsponding codons described without altering the encoded jxdypepttde.

Such nucleic acid variations are "silent * a; laiinns." whieh are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of die nucleic acid. One of skill will recognize that each codon in a nucleic acid .(except AGO, which is ordinarily the only codon for methionine.» ami TOG, which is ordinarily the only codon, for tryptophan) can be modified to yield a fonctionally identical molecule. Accordingly, each silent variation of a nucleic acid, which encodes a polypeptide is implicit in each described sequence.

Conservative substitution tables providing fimotlouuity similar amino acids arc well known in the art, For example, one exemplary guide! ine to select conservative substitutions Includes (original residue followed by exemplary substitution)' aiargly or set; argdys; asn/gln or his; asp/gln; eys/ser; girGaso: gly/asp; giy/ala or pro; Ihs/asn or gin; iie/leu or val; leu/Iie or val; iys/arg or gin or glut toet/ien or iyr or ile; phe/met or leu or tyr; ser/dir; for/ser; trp/fyr; tyr/trp Of phe; val/ile or leu. An alternative exemplary guideline uses the following sis groups, each containing amino acids that are conservative substitutions lor one another: 1} Alanine (A), Serine iSh Threonine (T); 2} Aspartic acid (D), Glutamic acid (k); 3) Asparagine(N), Glutamine (Q); 4} Arginine (R), Lysine (1); 5} Isoleueine (1),: Leucine (L), Mctbionmc (M), Valine (V); and 6} Phenylalanine (F), Tyrosine (Y), Tryptophan (W); (see also, eg:, Creighton, Proteins, W. H. Freehian and Company (1984); Schultz and Schimer, Principles of Pro tein Structure, Springer-Verlag (1979)), One of skill in, the art will appreciate that the above-identified substitutions are not tbe only possible conservative substitutions. For example, for some purples, one may regard ail charged amino acid\ as» eonsci votive substitutions for each other whether they are positive or negative, in addition, individual .substitutions, deletions or additions that alter, add or delete a single amino: acid ora small percentage of amino acids in an. encoded se(|uenee can also be eonsidcred ''conservatively modified variations.'-

The terms ‘'mimetic5' and '‘pepiidomimeiic'" refer to a .synthetic chemical compound that has substantially the same structural and or functional characteristics of the polypeptides, η.ιρ, exira-ceikdar domain or any region therewith of Ti R2 or Tl RI. The mimetic can be cither entirely composed of synthetic, non·· natural analogs of amino acids, or may he a chimeric molecule of partly natural peptide amino acids and partly non-natural analogs of amino acids. The mimetic can also incorporate any amount of natural amino acid conservative substitutions long as such substitutions also do not substantially alter'the. mimetic's structure and >·: acin -f\,

As with polypeptides of the invention which arc conservative variants,, routine experimentation will determine whether a mimetic is within the scope of the invention, I a., that its structure and/or function is not substantially altered Polypeptide mimetic compositions e&amp;« contain any combination of non-natural structural components, which are typically from three structural groups: a) residue: linkage groups other than the natural amide bond (’/peptide: bond”) linkages; b) non-natural. residues in place of naturally occurring: anti no acid residues; ore) residues which Induce secondary structural mimicry /V.. to Induce or stabilize a scoond&amp;ry slrttCffe,:b.|t?.ηfebtaturn, gamma-tum, Udu shoot, alpha helix conformation, and the like. A polypeptide can be elwacterbed as a mimetic when all. or some; of tfe residues are joined by chemical means other thart natural peptide bonds. Individual peptidomimetie residues can be joined: by peptide bonds, ether chemical bonds or coupling means, such as e.g, giuramiuehydo, N-hydroxysuccinimide· esters, bi functional, maleimides, N.N'-dicyclohexylcarbcdHmide (DCC) or bi/Nf-diisopropyloarbodiimide (D1C), Linking groups that. can. be an alternative to the traditional amid© bond-("peptide bond”) linkages include, cygv, kefomethyleoe (e.jp, -€(0)^CHr fbr~C(0)-NM-}, amiuomcthyicuc ethylene, obfin -CH=CH«, ether 'CH.jQ-vthiostber -Cbb$-, tcir&amp;zole (CM*). thiacole, refroumide, iMoamtde or ester (sue, e.g. t Spatola, Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, .Vo1.,. 7, 267-357, Mameti Bekksr, Peptide Backbone Moditleations, NY (1983)). A polypeptide can also be characterised as a mimetic by containing all or some non-natural residue;' in place of naturally occurring nnurm acid residues, non-natural residues are well described in the scientific and patent literature. “AlkylT by uself or as part-of mrofeer-substituoat,. refers ία a saturated or unsaUaated. branched, straight-chain or cyclic mono valent hydrocarbon radical derived by the removal of one hydrogen atom from a. single carbon atom of a parent alkane, aif eno or aikyne. The term ‘‘alkyl5' includes <,cycl«*ulk>r as defined herembdow. Typical alkyl groups include,, but arc not limited to, methyl, ethyls such as ethanyl, ethenyi. cthynvl; propyls such as propan· i-yl propan-2-yl, cyclopropan-1··>·!, prop-l-cn-t-yl, prop-l-en-2-yi, prop-2-en- 1-yl (ally 1 >, cycloprop·I -en-l-yl. cydoprop-2-cn-l -y't. prop-1 ·νη· 1-yl prop-2-yn-i-yL e/r.. butyls such as biitan-l -yl. butun-2-vi, 2-mcthyl-propan-1 -yl 2 · methyl - propan-2 ·> 1, eye lobutao·· 1-yl, but-l-en-l-yk but -1 -en-2-yl, 2--mclh> 1-prop·· l-en-l-yl, hut-2-en-1 - yl but-2--cn--2--yl, buta-1.3-dien-l-yl. bnta-l3-dien--2--yl, cyclohut· i-en-1 -yt. cyclobut-1 -cn--d-yl, eyelobutu-1,3-dien-1 -y), but-byn-1-yl. but-1 -yo-a-yi. but-3-yn-l -yl. eic ; and the like. The term ‘'ulkyr is specifically intended to include groups having any degree or level of saturation. Im, groups having exclusively single, carbon-carbon bonds, groups haying one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, doable and triple: carbon-carbon bonds. Where a specific:- level of saturation is intended,, the expressions WlkanylT “alkenyl” and “alkynyf5 are «sect In some; embodiments, no alkyl group comprises from 1 to 20 carbon atoms (Cj-C^o alkyl). In other embodiments, an alkyl group comprises from 1 to 1(1 carbon, atoms {CrCu> alkyl k Instil! other embodiments, an alkyl group comprises from ! to 6 carbon.: atoms (Ci-Cg alkyl:}, ft is noted; that when an alkyl, .group is further connected to another atom, it becomes an “alkyleoe' group, In other words, the term Wlkyiene” refers -ο a divalent alkyl For example, -CH;CH: Is an ethyl while -CH;C'H;r is an ethylene. That is, “Alkylene,51 by itself or as part of another substituent, refers to a saturated or linsnmrated, branched, straight-chain or cyclic divalent hydrocarbon radical derived by the removal, of two hydrogen atoms from a single carbon atom or two different carbon atoms o f a parent alkane, alkene or aikyne. The {erm/^dkytend* includes Wyefoalkylene'5 as defined: herelnhelow. The term “alkylene” is specifically intended to include groups having any degree or level of saturation, /.e,, groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-earbon bonds, groups having one or more triple carbon-carbon bonds and -groups .havlugmixiurejs of single, double and triple carbon-carbon bonds. Where a specific level o ("‘saturation :s intended, the expression;' 'ktlkaoylcne," ‘‘ailenylcne." and “alkxtA lone" are used. In some embodiments, an a iky lone group comprises horn 1 to 20 casbon atoms {(VO v alkyteue). in other embodiments. an alkyiene group'comprises from. I to 10 carbon atoms tCrCro alky lend. In still other ©mbodimems,. on alkylene group .comprises from 1 to 6 carbon atoms (CvQ alkylenc). VVikaoylp b> itself or a^ pan of auothet sobstitueak s cfl-rs to a saturated branched, straight· chain or cyclic alkyl radical derived by the removal of one hydrogen atom front a single carbon atom of a parent alkane. The term “ai&amp;any!” Includes "cycloukanyf' as defined herehibciow, Typical alkauyl groups mcludc. but ate not limited to, tncihanyi; ethanyl; j>ropanyls such as propan·· b-> k pn»|Vfli-2-> I (isopropv Π. csclopropan-1 -yl. etc.: butanyls such as hunm- 1 - yL butan-2-y! (sve-nuty: ?, 2-medn i-prop.m· 1 \ O'S-benyl), 2-methyl·propaa»'2»yi (/butyl), cyclobutaiv-l-yl, c.v., and the hkc. “Alkenyl," by itself .-t as p,c t -Λ another substituent, refers to an unsaiurated branched, straight-chain or cyclic alkyl radical haying at least one carbon-carbon double bond derived by the removal of o ne hydrogen atom from a single carbon atom of a parent aifcene. The term Vlkenyf' includes ^ycio&amp;lkenyP as defined hereinbeloyv. The group may be in either the ds or tmm poafoppation about the double bondfs). Typical alkenyl groups include, but are not limited to, ethenyi: propenyls such as prop-l -en-i-yi, prop-I-en-2-yi, prop-l-en-l-yl C&amp;llyl), prop~2~en~2~yh cycloprop-l-en-t~yl; eydoprop-d-en- l~yl; bmenyls such, as hwt-I -en-i-yf but~i-en~2~yf 2~methyl-prof>l~en~1~yl, but-2-en-i-yl . bui-2-en-l-yi, bui~2~en-2~y!., buta-l 3~dien-l-yb buia~13~dieo~2~yb eyclobuN -en-1 -yl eyeiobut-l -cu-S-yl eyelohuta-ij-dien-l-yl, etc; and the like, VAIkynyly by itself or as part of another substituent: refers to an asisaiurated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent allryne. Typical alkyny! groups include, but are not. limited, fo, ethynyl; propynyis such as prop~i~yn-l-yl, prop~2yyo-!~yi. «&amp;?,; bnlynyls such as btri-l-yu-l -yb butc|-yn-3-yb butV~yn~I-yL c/c„; and the like. *Alkosy," by itself or as part of another substituent, refers to aradieaiof die formula -0-RiW, where R1'1 is alkyl or substituted alkyl as defined herein. '\AevT' by itself or as» pari of another substituent refem to a radical -CtOjR"W where is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylaikyl, substituted arylalkyl, bctcroalkyl. substituted heteroalkyl, hcteroa/ylaikyl or substituted hetejoarylaikyl as do lined herein. Representative examples include, but arc not limited to tormyl, acetyl, eyelohexyIcarbony l. cyclohexylmcthylcarbonyl, benzoyl, bcnzykatbottyl and the Eke, '‘Aryl,'-by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system, as defined herein. Typical aryl "groups··.include, but are not limited to, groups derived from uceanthrylene, acenaphthylene, abcph.e»a»fhfyte»e, anthracene, azulene, benzene, chrysene, cmvmene, fluoranthene, tliuuene, hexaccae, hesapbeae, faexalcpe. nsondacene, s-indaecne. inuane, indcnc, naphthalene, oetacene, oetapbene, oetaleue, ovaleue, pcnta-2,4-diene, pentaeene, pcnialene. pentaphene, pervlcne, phcnalene, ohenaniln enc, pmene, pieiadene. pyrene., pyranthrcoc, rubiccoe, triphonylenc·. trinaphthalene and the- like in some embodiments. an aryl group comprises iron) o to 20 carbon atoms {€<>-€ 2» and). In other embodiments, an and. group comprises from 6 to 15 carbon atoms (CVCis aryl). In still other embodiments, an aryl group comprises from. 6 to 15 carbon atoms {€<>*€a> and.). :'k<Aryk.lky|.r by itself or ns part of ancstbetsubstituent, refers to an acyclic alkyl group In which one of the hydrogen atoms: bonded to a carbon atom,, typically a terminal or sg' carbon atom, is replaced with an aryl group as. as defined.herein. Typical arylalkyl groups, include, but:are not limited to, benzyl, 2-phenvlethan-feyl, 2'pbeny1et.hen~l~yl, naphtbylmethyl. 2~naphtby:letban-i -yi, d-naphibyietben-! wi, oapbthofeenzyt, 2-:napbil)oph.enyied)an~l ~yl and the like. Where specific alkyl moieties are intended, the nomenclature ajyMkapyl,. ajylalkenyl and/or arylalkynyl is used,: In sotn® OPtb.odimept$,,:an·arylalkyl group is arylalkyl, u„e; the atkany), alkenyl or alkynyl moiety of the arylalkyl group Is tO;-O<d alkyl and the aryl moiety 1$ {Ο,-ρΝρ ary!, In other embodiments, an arylalkyl group is tCVO.sd arylalkyl, e.g , the alkenyl, alkenyl or alkynyl moiety of the arylalkyl group is (€>€*) alkyl, and the aryl moiety Is (Cs-Cu?) aryl. In. still other embodiments, m arylalkyl group is (CmCis) arylaiky!, eg., the alkanyl, alkeny l, or alkynyl moiety of the arylaikyl -group is (CfrCs) alkyl and the aryl moiety is (Cs-Cnt) aryl.

Wweloalkyiy5 by itself or its part of another substituent, refers to a saturated or unsatarated cyclic alkyl radical, as defined herein. Similarly, "'C'ycloalkyiene,"' by itself or as part of another substituent, refers -o a saluruted or onsatwated cyclic alkylene radical, as defined herein. Where a specific level of saturation is intended. the nomenclature ‘‘cydoalkanyr. “cycloalkenvl''. or '‘cycloalkynyr is used, Typical cycloalkyl groups include, bus are not hunted to, groups derived from cyclopropane, cydobufcaae, eyelopeMaue, cyclohexane, and the like, in some enfe-'di meats, the eycioulkyl group comprises fmm 3 to 10 ring atoms tCVCT, eycfeulkyl t. In other embodiments, fee cycloalkyl gr-mp composes front 3 to ? nng atoms ttVC- cydoalkyl). The evcloalkyl may b·.,- further substituted by-one or more heteroatoms including, 'but not limited, to, N, P. O, S, ami Si. which attach to the carbon· atoms oftlic cycloalkyl via monovalent or multivalent bond. '‘Ήοίβϊοβ^/’^ΉοίΟΓΟδΕ^ψΙ',·’ 'ideteroalkmyf' and wHeterpalky»y!f5 by themselves or as part of o ther substitnents* refer to alky l , alkanyl, alkenyl and aikynyl groups, respectively; in which one or more of the carbonattorns (and optionally any associated hydrogen, atoms), arc each, independently of one another., replaced with the same or different heferoatoms or heteroatonne groups. Similarly·. “Hcteroalkylcno." "Heteroalkany Ivnc/’ wHcf crouIkc-ov lone" and ‘Tl.eteroalkynyletiek by themselves or as part of other substituents, refer to afkylene, alkanylene, alkenyleue and olkyuyenel groups, respectively, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms), are each, indepeodeutly of one another, replaced with the same or different heteroatoms or heteroatomic groups. Typical heteroatoms: or heteroMomie groups which can replace the carbon atoms s * lode, but are not limited to, -0-, -3-, -N~, ~St~, -131:1-, -3(0)-, -8(0};-, -8(0)01-1-, -S(0);NH~ and the like and .combinations thereof The heteroatoms or heteroa tom So groups may he placed at any interior position of the alkyl, alkenyl or alkynyl groups. Typical heteroatomic groups:which can he included in these groups include, but are not limited to, -0-, -3-, -0-0-, -8-3-, -0-8-, -NR^R"5"-, ~N-N~V -18-18-, -N-N-NR2%"°\ -PR-->5-. -FtO)r, -POR**-. -0-^(0)=-, -80-. -SO:-.. -SnR.::rR2<::;- and fee like, nhore ίΐ"’5, R‘‘\ R^'y. R">+, ί0<κ\ R**' and R.V“N are independently hydrogen, alkyl, substituted..alkyl., aryl, substituted, aryl, arylalkyl, substituted arykdkyi, cycloalkyl, substituted cycloalkyl, eycloheieroalkyl, suhstituied.cycloheteroaikyl, heteroalkyl, suhstitnted heieroalkyl, hetsroaryl, substituted heteroaryl, heteroarylalkyi or substituted heieroarylalkyl, ^Cyeloheteroalkylfe or ‘feietsrocydylfeby itself or as part of another substituent, refers to a saturated or uusaiunued cyclic alkyl radical iu which one or more carbon atoms tand optionally any associated hydrogen atoms) are independently replaced with the same or different. hctcroatom. Similarly, ''Cycioheicroalkylcnc.'' by itself or a? pari of another substituent, relere to a saturated or nnsaturalcd cyclic alkvlene radical in which one or /«ore carbon atoms (avid 'optionally 'any'-associated hydrogen atoms) arc independently replaced with the same or different hcicroaiotn. The cyciohcleroalkyl may be funhex substituted by one or more heteroatoms including, bin not limited to. N. I\ O. S, and Si, which attach to the carbon atoms of the cydoheteroalkyi via monovalent or multivalent bond. Typical heteroatoms to replace the carbon atom(s) include, but arc not limited to. N, P, 0, S. Si. etc. Where a specific level of saturation is intended, the nomenclature ‘'cyclohetcroalkanyl5' or "eyeioheteroaikeny 1 ’’ is used. Typical eyclohcteroalkyi groups include, but arc not limited to, groups derived from epoxides, azMnes, tldiranes, imidazolidinc, morpholine, piperazine, piperidine, pyrazoildiae, pyjrohdone, tpinuelidine, and the 'like. In some embodiments. the cydoheteroaikyi group comprises from 3 to i 0 ring atoms (3-10 membered eyclohctcroulk} i) In other embodiments, the cycioalky 1 group comprise from d to 7 ring atoms (3-7 membered cyclehevcroalkyl). A eyclohcteroulkyi group may bo substituted at a heteroatom., for example, a m'trogen atom, with a (CyC(,) alkyl group. As specifAut^xanipl'esfN-niethyl-imidazoiidtnyh N-tnethyi-merphelinyhN-methyhpiperazinyh N-medwl-pipertdlnyi, N-methyl-pyrazelidiuyl and N-niefhyi-pyrrolidinyl are included within the definition of^eycloheteroaikvlf' A cyeloheieroalkyi group may be attached to the remainder of the .molecule via a ring carbon atom or a ring heteroatom.

''Compounds'' refers to compounds encompassed by structural formulae disclosed herein and includes any specific comp6uadS'Wit.Minth@se'forniute whose structure is disclosed, herein; Compounds may be identified either by their chemical structure and/or chemical name. Whop the ebemical strueture aed ehemical name conflict, the chemical structure Is deierminafive of the identity of the compound . The compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (/.a., geometric Isomers), enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers; and stereoisomers of the illustrated compounds including the siereoisommcally pure foroi(e.g,ygeometriea!Iy pure, enantiomerically pure or dmstereomerieally pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and: stereoisomerie mixtures can be'· resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known-the skilled artisan. The compounds may also exist in several tautomeric forms including the enoI form, the keio tom's and mixtures thereof. Accordingly, the chemical structures depicted herein encompass ah possible tautomeric tonus of the illustrated compounds. The compounds described also: melade isotopiealiy labeled compounds where one or mote, atoms have m atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to, H,' B, l'C\ ;>C, :'N. Y), ’Ό, WV'. Compounds may exist in onsoive.tcd forms as well as solvated forms, inducting hydrated forms and as Nmxides, In general, compounds may be hydrated solvated or Nroxides. Certain compounds may exist in multiple crystalline or amorphous forms. In general, all physical forms arc equivalent tor the uses contemplated herein and are Intended to he within the scope of the present invention. Further, it should he understood, when partial structures of the compounds are illustrated, that: brackets indicate the point of attachment of the partial structure to the rest of the molecule. The term '‘tautomer’' as used herein refers to isomers that change into one another with great ease so that they cart exist together in equilibrium. For example, the following compounds A and B are tautomers of each other:

"Halo," by itself or as part of another substituent refers to a radical -ft, -Cl, ~Br or

Yieteroaryl,' ’ by itself or as part of another substituen t, refers to a monovalent heteroaromatie radical derived by the removal of one hydrogen atom, from a single atom of a parent heieroaromatic ring systems, as defined herein. Typical hcteroaryl groups include, but are not limited to, groups derived from acridine, fhcarboline, dxrornane, ekremeoe, einnoliue, fitran, imidazole, iudazoie, indole, iudolme, indoltzine, isobenzofirau, isoehromone, isoindoio, Isoindoime, IsoquinoBne, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazoSo, peiimldiue, phenauthridifte, phetmnthrolhte, pheuazme, phtbalazme, ptericlsue, -purine, pyran, pyrazme, pyrazpte, pyridame, pyridine pyrimidine, pyrrole, pyrfohzine,qumazoline, quinoline, qumolizine, quinoxaline, tetrazole, ihiadiazole, thiazole, thiophene, triazoie, xanthene, and the like, hf some embodiments, the hcteroaryl group comprises from 5 to 20 ring atoms (5-20 membered heteroaryl), in other embodiments, the hcteroaryl. group comprises from 5 to 10 ring afoin,\ {5-10 membered hetcroary!). Exemplary heteroarvl groups include those derived frout furan, thiophene, pyrrole, benzoiluophenc, benzofuvart, benzimidazole, indole, pvridme, pymzole, quinoline, imidazole, oxazole, isoxazole and pyrazine. '*HetcroarylalkyΓ' by itself or as pari of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon anno, typically a terminal or v/f carbon atom, is replaced with a beteroaryl group. Where specific alkyl mso'eties are intended, the nomenclature betcroaiylaikanyk hetercarybkcnyl and or hercroaiylaikynyl is used. In some embodiments, the heteroaryhlkyl group is a 6-21 membered hctcioarylalky 1, rag., the alkanyl, alkenyl or alkyoyl moiety of the heieroarylalkyl is (CVQs) alkyl and the hetcroary! moiety is a. 545-metnhered heteroaryl, in. other embodiments,, the hetcroary lallyt is a o-13 membered heteroarylalkyl, e,g,, the alkanyl, alkenyl or aifcynyi moiety is (CpCf) alkyl and the heteroary! moiety is a 5-10 membered heteroatyl "Parent Aromatic Ring System" refers to an urssaiaraied cyclic or polycyclic .ring system having a conjugated n electron system, -Specifically, included within the definition of “parent: aromatic ring system® are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsat orated, such as, for example,, fiuorene, indane,indorse, phenaieue,,m<.\ Typical parent aromabc sing systems include, but are not limited to, acesnthrylene, acenaphthylene, accpbcnamhrylenc, anthracene, azulene, benzene, chrysene, coroncoe, fluoranthene, fluorcue. bcxaccnc, hexaphene, hcxaicnc, u.s-ira.iaeene, sondaeene, indorse, hidene, naphthalene, octaeerse, oeiaphene, octalene, ovalene, penia-d,4-diene, pentaeene, penlalene, peutaphenc, perykne, phenaleno, phenanthrone, pleene, pleiadene, pyrene, pynaitShrene, rubieene, ftiphettylene, trinaphlhalone and the like:, ^Parent Hcteroaromatic Ring System® refers to a parent aromatic ring system in which one or more carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with the same or different hefematom. Typical hetcroatoms to replace the carbon atoms include, but are hot limited to, hi, F, 0, S, Si, ate. Specifically included within the definition of “parent hetefoaromatie ring system® are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or uasatiwated, such as, for example,benzodloxan, benzofitran, ebromane, ebromene, Indole, indohne, xanthene, etc·. Typical parent betXToaromatie ring systems include, but are not limited to, arsindole, carbazole, p-carboline, chromane, chromcuc, cinnoiine, furan, imidazole, indazole, indole, istdoHne, indoliziuc, jsobcnzofurun, isoehromertc, isoindoic, isomdoline, isoqumoline, isodnazole, isoxazoie, naphthyridiue, oxadiazolc, oxaxolc, pcnmidinc, phcnanthridine. pbcnanthroiinc, phensxine, phthalazme. pteridme, puri.nc. pyran, pyrazmc, pyrazole, pyridazme, pyridine, pyrimidine, pyrrole, pyrvolizinc, qtfinazoime, quinoline, quinolizmCj. qoinoxaline, iclrazoky Ihiadiazole. thwzole. thiophene. triaznie, xamhene and the like, "Pat ienfi5 includes humans. The terms ' human’' and “patieat” are used interchangeably herein. " Pharmaceutically acceptable” refers to being suitable lor me in contact with the tissues of humans and animals without undue- fdxieity, irritation, allergic response, and the like, commensurate with a reasonable heneiitMsk ratio, and effective for their intended use within the scope of sound medical judgment. "Preventing” or ''prevention” refers to a reduction in risk of acquiring a disease or disorder Ike.., causing at least one of the clinical symptoms of the- disease not So develop in a patient that may bo exposed to or predisposed to the disease but docs not yet expert cnee or display symptoms of the disease). "Protecting group"' refers to &amp; grouping of atoms feat when attached, to a reactive functional group in a molecule masks, reduces, or prevents reactivity of the functional group. Examples of protecting groups can he found in Green eiaU “iteoteetsveGmups in Organic Chemistry'*, (Wiley, 2“a ed. 1991) and Harrison etaL, “CohtpddciiumOf Sjmiherio'Qrgafttq Methods”, Vote l~K {John Wiley and Sons, 197.1-1990). Representative amino protecting groups include, hut are not limited to, formyl, acetyl triflaoroacetyi, .benzyl, benzyloxyearhohyi C'CB2”y isyi-buioxycarhonyi ("Bor'), teitoethyisily! ("TMS”), 2-triinethylsslyi-efhanestilfe»yl. (''$E$”), trityl and substituted trkvl groups, aliyloxycarhonyl, 9-duorenylmet.hylox;yc&amp;t'boiiyl. {"FMOC"), nuro-veratrylosyearbonyl (kiN VOC") and the like. Representative hydroxy protecting groups include, but arc not limited to, those where the hydroxy group is either acyiated or alkylated such as benzyl, and trityl ethers as well as alky! ethers, tetrahydtopyratiyl ethers, trialkylsiM ethers and ally! ethers. "Saccharide ring” is also kno wn, as sugar ring and includes monosacehride, disaccharide, and polysaccharide ring. Preferably, the saccharide ring is a rnonosacharride ring. Examples of monosaccharides include glucose {dextrose}, .fructose, galactose, xylose and ribose. By ''derivative of saccharide ring”, it is meant the non-natural or artificial saccharide ring wherein the stereochemistry comers arc partially or completely different from (hose in' the natural saechartele ring. :WSalf; refers to a salt of a compound, winch possesses the .desired phannacolog&amp;al activity of foe parent compound. Such salts include: {1) acid addition sails, formed wuh inorganic acids such as hydrochloric acid, hvUrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the hkc; or formed w ith organic acids such as acetic acid, propionic acid, hexanote acid, cyclopcntanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, tumarie acid, tartaric acid, citric acid, benzoic acid, 3“(4«hydroxyhe«zoyi) benzoic acid, cinnamic acid, mandelic acid,methanesuifoaie acid, eihsnssitlfonic acid, 1 ^“Cfhape-dkttltonk acid, S-hydroxyethaacsuffooilc acid, .beazenesulfont'c acid. 4-chlorohcnzcriC»ulfonic acid, 2-nuphthak'nesuifomc acid, d-toluenesuifoaie acid, canyohorsulionic aetd. 4-methy 1 bicyel*>{2.2,21-oct-C-enc·· I - carboxylic acid, duceheptomc acid, 3-pheny) propionic acid, rimcthylaccde acid., tertiary butyfaeetic acid, Uutryf sulfuric aetd. gluconic acid, glutamic acid,, hydroxynaphthok acid, salicylic acid. stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound is 'replaced, by. a metal ion. ί·.χ.. an at kali metal ion, an alkaline earth, ion, or an aluminum-loti; or coordinates with an organic base such as.cfhanolaminc, dletltanoiamine, tric#aitohtminc, N'-methyigiueamine and the like, lvSolvafeff means a eompotmd formed by solvation {the combination of solvent molecules with molecules or ions of the solute}, or an: aggregate that consists of a solute ion or Pro bottle, be,, a compound of the present invention, with one or more solvent molecules, When water is the solvent the corresponding solvate: is '"hydrate:'’, ‘"N-oxidefo also known as amine oxide or annne-lfooxide, meansa compound that derives from a compound of the present invention via oxidation of an amine group of the compound of the present invention. An N-oxide typically contains the functional group &amp;j.bT-0" {sometimes written as R sN-O or R*N-?0). ’'Substituted,” when used to modify a specified group or radical, moans that one or more hydrogen atoms of the specified: group or radical are each, independently of one another, replaced with the same or different subsfituent(s). Substituent groups useful for substituting, saturated carbon atoms in the specified group or radical include, hut are not limited to -R". halo, -O', -O, -ORi!, ~8Ri!, -S', ™S, -NRCRC, NR". ===N-ORb, Irihaloniethyi -CFi, -CK, -()(IN, -S( ,N: -NO, -NO;. ===N.», -Ns. -SiOi;Rb. -StOcNR'’, -S<0)vO. -SiOfcOR\ -OStOhRC -0S(0>:0. *OS((»;ORb, -HOKO'.b. -P{0h0Rv')(0 ), -O0)(0R ;({>κΟ, -C(0)Rfi. -Cl SIRA -ONROR1'. -0(())0 , 'CiOsORR -CiSiOR", -C(OsNRrR\ -C(NR,;)NR°R\ -0C<0>Rh. -OC(S)Rh. -00(0)0) ~0€(0)0R:>, -OGSsORS -NRfoHOiRA -N)0C(S)R ( -NRb0(O}0 , -NRbC(0)0Rb. NR^OSiOR1', NRi'C(0)NKcR\ ~NRbC{NRb)Rb and -NRbC(NR*‘)NR‘'R\ where R* is selected from the group consisting of alkyl, cydoalkyl, heteroalkyl, cycloheteroulkyl. aryl, arylalkyl. hetetoaryl and heteroaryadkyi; each R1’ is independently hydrogen or R :; and each Re is independently R" or alternatively, the· two Rfo may be taken together with die nitrogen stem to which they are bonded form a 4~ , 5-, 6- or 7-merabered eycdoheteroalkyl which may optionally include horn l to 4 of the same or different .additional heterosioms selected from the group consisting of 0, N. and S. As specific examples, -NEilO is meant to include - -NH;g -NH-alhyl, N-pyrrolidios 1 and N-mm pholinvl. As another specific example, a substituted alkyl is meant to include 'mlkyleoo-O-alkyl, -alkyierte-hoteroary!. -.dkAdene-tycloheteroalkyi. -alkylcne-C(0)0Rs', -8ikyieoe-(i'fk))NRi'Ri'. and OHrd'C-Ci0)-(ΉThe one-or more substituent groups, taken together with the atoms to which they are bonded, .may form a cyclic ring' including 'cycJdalkyl and eycioheteroa.i kyl.

Similarly, substituent groups useful for substituting unsaturated carbon atoms in the specified group or radical include, but am not limited to, -R'!, halo. -O'. -0Rl>, -SR*1. -S , ~N>0R'. trihaiomethyl, -Cfo, -ON, -0("N. -SCN, -NO, -NO;, -Ns, -SiO);Rb, ~$(OpO , -SiOfORf -OSiOpR1) -0$(0)>0 : -0S{0};0Rb. -PiO}(0 -PiO)tORb)iO I, -PiO){OR")iORb}, ~0(θρ!), -€(S)Rb. -C{NRb)Rb, -0(0)0( -0(0)01¾^ -C::fS)ORf -C (0}NRRe, ~C(NRh)NRιΈ( -0C(0)ftb,;-0C(S)Rh, -00(0)0 , -0O0)0Rf( -OC(S)ORb, -NR!iaO)Rl\ -NRbC(S)Rb, ~NR-0(0)0( -NRhC(OR>Rb. -NRbC(S)ORb, -NR^C(0)McR*f -NRtTNRl,)Rb and -NET(NR 1>)NR“R°. where R( R’‘ and R" are as previously defined.

Substituent groups useful for substituting nitrogen atoms in heteroalkyl and eyeioheierealkyi. groups;· include, but are not limited to, -R'\ -O'. -OR", -SR.", -S'. -NR(:RC; idhalome th y I, - OF 3. -CIS, -NO, -N0>, -S(0);Rb, -8{0)·>0( -S(ObORl\-OS(0);R^ -08(0)4), -OSCOhOR'h -P(0)(0')3s ~P(0)(()Ri;)l0 ), ~P(<^(ORb>(QRb}, -00)8* -C{S)Rs( -€CNR5,}R!( ~.C(0)0Rb, ~C('S}ORb, ~C(OjNR£Re, -C{NR.^iN ReRe, -OC(0)Rn, -OC(S)R\ -00(0}0Rb, -0C(S)0Rh. -NRhC(0)Rb, -MRbC(S)Rb, ~KRbC{0>0Rb, -NRbQS)ORb, -NRbC<G)NRcRc, -N.RbC(NRb)Rb and -KR,,€(NRb)NRv'R\ where Rs. R" and PA are as previously defined.

Substituent groups from the above lists useful for substituting odser specified groups or aton is will be apparent to those of skill in the art.

The substituents used to substitute a specified group can be ferdier substituted, typically with one or mote of the same or different groups selected from the various groups specified above. "Treating" or "treatment'' of any disease or disorder refers, in some embodiments, to smcb-'nnmg the disease or disorder ii.e,. arresting or reducing die development of the disease or at. least one of the clinical symptoms thereof), (n other embodiments ''treating'' or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the patient In yet other embodiments. "treating" or "treatment" refers to Inhibiting the disease or disorder, either physically, tV.g,. stabilization of a discernible symptom), physiologically, (o,g,:, stabilization of a physical parameter) or both. In yet other embodiments, fereating" or "treatment" refers to delaying the onset of ihc disease or disorder. "Therapeutically effective amount” moans the amount of a compound that, when administered to a patient for iteming a disease, is sufficient to effect such treatment for the disease. The * therapeutically effective amount'5 will vary depending on the compound, fee disease and its: severity and .fee age, weight,, etc., o f the patient to be treated. "Vehicle55 refers to a diluent, adjuvant excipient or carrier with which « compound is administered.,

The present invention is based, at. least in part, on. die discovery that an: extracellular domain, e.g„ the Venus flytrap domain of a ehemosensory receptor, espeoinliy one or more: interacting sites within the Venus flytrap domain, is a suitable target for compounds or other entities to modulate the ehemosensory receptor and/or its ligands, Accordingly, the present invention provides screening methods for identifying ehemosensory receptor modifiers as well as ehemosensory receptor ligand modifiers. In. addition, the present invention provides compounds and compositions capable of modulating ehemosensory receptors as well as ehemosensory reeeptor ligands, A ccording to on© aspect of the present invention, it pro vides methods of screening-for ehemosensory receptor modifiers by determining: whether a test entity is sui table to interact with a ehemosensory receptor vis one or more interaciing sites within the exUamellular dornum of the ehemosensory receptor, o.ge, the Venus flytrap domain of the ehemosensory receptor.

According to (mother aspect of the present invention, it pro v ides methods of .screening for ehemosensory receptor ligand modi fieri- b\ dotettnining whether it test entity is sui table to interact with a chemosensory receptor, and optionally its ligand via one or .more interacting, si tes within the extra-cellular domain, e,g., the Venus flytrap domain of die ehemosensory recqjtor, optionally m the presence of a. chemoseosory receptor ligand.

In genco-d, the extra-eel luiar domain of a chcmosensory receptor refers tr= the estra-cellular ammo-terminus of a chemosensory receptor and usually includes a. ligand-binding domain and a cysteme-rieh linker domain, which connects the ligand-binding domain and the rest of the prutem. In Class € GPC'Rs, the hgand binding domain is generally referred to as a Venus flytrap domain, the struc ture of which has been elucidated, wg., using.X-ray erystalksgrapfey. A Venus flytrap domain typically eonsisrs-oftwo relatively rigid lobes connected by three strands forming a flexible “hinge" region. In the absence of a ligand, the Venus flytrap domain tends to adopt open cos-formations with well-separated lobes as well as closed, eonfermalions with lobes closer together. In one example, the Venus flytrap domain includes a region from, amino acid 36 to amino acid $0$ of human T1R1, ammo acid 31: to amino acid 507 of human TIR2, and/or amino acid 35 ro amino acid 511 of human 11R3,

The Venus flytrap domain of the present invention includes· any ligand binding domain or ligand interacting domain within the extra-eeilulur domain ofa ehemosensory receptor. In one embodiment, the Mums flytrap domain, of the present in venfton includes any ligand binding domain of a member of the TIE family. In another embodiment, the Venus flytrap domain, of the present invention inelod.es any extra-cellular domainof a ehemosensory receptor with a structure comprising ?wo; lobes connected, by a hinge region, in yet another embodiment, the Venus flytrap domain of the present iownrmn in J udes any doniain corresponding to the structure and/or function of a region including amino sold 36 to amino acid 509 of human. T.1 R1, amino acid 3:1 to: amino acid 507 of human T i R2, and/or amino sold 35 to amino acid 511 of human. Ti R3. In still another embodiment, the Venus flytrap domain of the present invention includes any ligand binding domain of TIR .1, TI R2, and/or T1R3 as well as any polymorphic variation, allele, or.mutation thereof Exemplary· illustrations of polymorphic variations for TIRf anti TI.R2 are shown in Figures 1-4.

According to the present invention. a ehemoscnsory receptor con be any receptor associated with ehemoscnsory sensation or ehemosoisory ligand 'triggered signal transduction, e.g„ via taste receptors or taste related receptors expressed in taste bud. gastrointestinal tract, etc, in one embodiment. a ehemoscnsory receptor is a receptor that belongs to the 7*transmembrsae receptor supcrfamiiy or O protein-coupled receptors {GPCRs). In another embodiment, a chemosensory receptor is a receptor carrying out signal transduction via one or more G proteins. In yet another embodiment, a ehemoscnsory receptor is a receptor that belongs to family C or class 0 of GPCRs. In vet another embodiment, a ehemoscnsory recent* =r is a receptor that belongs to the TiR family. In yet another embodiment, a ehemoscnsory receptor is a receptor of IIRl, TIR2, If R3, or their equivalency or variances or a .combination thereof. In still another embodiment, a chemoscnsoty receptor Is a hetero-dimer of T1R2 and T1R3, or their equivalences or variances.

According to the present invention., an nucraedog site within the Venus flytrap domain of a ehemoseoaory receptor can be one or more interacting residues· or a threedimensional interacting space or a. combination thereof. In otto embodiment, the interacting site of the present invention is within the Venus- flytrap domai not"HR2, in another embodi ment, the intemeting site of the present invention is within the Venus flytrap domain of Tl R3, in yet: another embodiment, the interacting site of the present' invention is within the Venus flytrap domain of both T1R.2 and T1R3 .

Usually such an interacting' she can fee determined by any suitable means known or later discovered in the art. For example, such interacting site can be determined based on computer' modeling.. e.gv, using software such as Homology: or Modeller (by Aeeelrys Corporation) to construct three dimensional homology models of a ohentosensory receptor Yates flytrap domain., e . the 'HR2 an.d'or Π R.3 Venus flytrap domains based on crystal' structures of homologous Venus flytrap domains.

Such an interacting site can also be determined, -based cm X-ray crystallography and the three dimensipna! stmeinre of a ebsolosenxosy receptor determined fherslrom, ag., the T1E2, Tl R3, or TIR2/T.1R3 beterodirrser,. Alternatively, for example, such an interacting site can be determined based on niolectslar mechanical techniques, normal mode analysis, loop generation techniques, Monte Carlo and/or molecular dynamics. simulations ιο explore morions and nltemiUiye. conformations of the Venus flytrap domains, docking simulations to Jock candidate receptor ligands and candidate receptor ligand modifiers into these models or into experimental !v determined structures of ehemosensory receptors, e.g., TI.R1 and 1112,

In addition, for example, such an interacting site can be determined baaed on mutagenesis,, e.g. „ · stfe-dircetcd. .muiagen&amp;sis or a eombmation of two or more suitable methods known or later discovered, e.g., methods described herein, hi one example, such an iiiteraeting site is located in part of a ehemosensory receptor, e,g., TIR2 and can be determined in the presence or absence of the other part of the ehemosensory receptor, e.g,. ΐ 113, In. another example, such an interacting site can be determined in the presence or absence of a ehemosensory receptor modifier and/or ebemosensory receptor ligand modifier, in one embed: mono the interacting site within the Venus flytrap domain of a ehemosensory receptor includes one or more interacting residues of the Venus tlvirap domain of a idicmoscnsory receptor. According to the present invention, the interacting residue of the Venus flytrap domain of a ehemosensory receptor is a fesidneassociated with any direct or indirect interaction between, a chentoseosory receptor and a cbemosensory receptor modifier or a ehemosensory receptor ligand modifier or both.

In one exampkythe: interacting residue of the present invention includes any resid ue of a ehemosensory receptor associated with an mteraetioo between a ehemosensory receptor modifier and at ohemosensory receptor. in another example, the intemeting residue of the present inwmtioo includes any residue of a ehemosensory receptor associated: with.-an. interaction. between, a ehemosensory receptor ligand modifier: and a ehemosensory receptor. In, yet another example, the interacting residue of the present invention includes any residue of a ehemosensory receptor associated with ah inieraction between a ehemosensory receptor, a ehemosensory receptor modifier and a ehemosensory rceeptor: ligand modifier,.

In stifl another example, the inieraeiing residue of the present invention includes any residue of a ohemoseusory receptor associated: with an. interaction, between a ebemosensory receptor and a sweet, flavor entity, e.g. any natural, or synthesized sweet flavor compound including, without any limitation, non-caloric sweet .flavor compounds, reduced calorie sweet flavor compounds, non-targetcaloric sweet flavor compounds, afe. Exemplary' sweet flavor compounds include, without any limitation, eyelamic acid, mogroside, tagaiose, maltose, galactose, mannose, sucrose, fructose, lactose. aspartame, ncotamc and other aspartame derivatives, saccharin, sueraiose, aecsuUamc 1C, glucose, eryihntol, D-frypiophan, glycine, mannitol, sorbitol, maltitol, iaetitol, isomaii, hydrogaaeted glucose syrup fllGS), hydrogenated "taidi hulroh/uie iHSH), sicvioslde, rebau-dioside A and other ssveet SteWo-based glycosides, ahiatne, caffobme and other guanidine-based sweeteners, tagatose, xviitoh high fructose com WHip. Γΰ.

In still another example, the interacting residue of the present insention include* any residue of a chcmnsensoiy recent·. >r associated with an interaction between a ehemosensory receptor and a sweet flavor entity enhancer, in sidhanotherexample, the mieraefiag residue of the -present invention iodudes any residue of a ehemosensory receptor associated with an interaction between a ehemosensory receptor, a sweet Savor entity, and a, sweet flavor entity enhancer, 1st another instance, the interacting residue of the present invention is a residue within the Venus flytrap domain, of a ehemosensory receptor, wherein any mutation of which could, result in a change of the activity of the ehemosensory receptor or the impact of a ehemosensory receptor ligand to the ehemosensory receptor or both.. For example, the interacting residue: of the present invention can include any residue: wiildnihe Venus flytrap domain of a ehentosensory receptor, wherein the mutation of which results in a detectable, change, eg,, qualitative or quantitative change of the activity of the ehemosensory receptor in response to a chemosensbry receptor modi tier and/or ehemosensory receptor ligand modifier.

In yet another instance, the tnteraeitng residue of the present invention is a residue within the Venus flytrap domain of a phemosensory roceptof that or forme productive intoraetion{s), van der Wads, burial of hydrophobic atoms or ,atomic groups, hydrogen bonds.. ring stacking interactions, or salt-bridging elcdttofctatie-mtoracftOm-'wldt afohetoosensoiy receptor modifier or chemoscnsorx receptor ligand modifier, or both:.

In still another instance, the interacting residue of the Venus flytrap domain of a ehemosensory receptor ean.be any residue constituting one or more interacting structural. components of the Venus flytrap domain,, -which.ait.a&amp;itooiaied*.direotly or indirectly, with the interaction between a eh.emosenso.ry receptor and a ehemosensory receptor modifier or a ehemosensory receptor ligand modifier or both. For example, the Venus .flytrap domain structure of a ehemosensory receptor generally includes two lobes j oint by a hinge region.

Residues eonsumUng an micracdue structural component of die Venus Iht-ap dwnam cuu bo, e.y.. see:dnee cim-ulm-mg the hinge region, die inner side of each lobe, or residues on each lobe that are brought into elo.se proximity daring activation or conformational change of the Venus: flytrap domain, inc luding without any limitation, residues 6«. the inner surfaces of the lobes pointing towards each other or mi the tips of the lobes where the residues are partially exposed to solvent but Vdl close to residues on the opposite lobe,

Exemplary interacting residues of the Venus flytrap domain, of a chemoseusory receptor include any one or more residues oi !} NI43, SI44, and 116? of a human 11112,2) S40, S144, S I 65, Y103, P142. and P277 of a human TIR2, 3} K65, R383, 0307. E302, and D2?8 of a human T1R2,4| U67. PI 85. ΊΊ84, T326, E302, V384, Λ 305,1325,1306. R3.S3, D3Q7, E382, D2~8, 079, In?, Y6(u V309, DI42, SI65, S40, S303. T242, FI03, Q32V and Si68 ofa human TIR2. 5} N143, S144. 1167, R65, R3S3. D307,13303, 027,3. p 183,11 84,1326, E302, V384, ,4303,1335, 150<\ 03() -1 E382. Ϊ279. PS7, V66. V309, 0142. Si65, $40. S305, Γ343, FI03. Q328 and SIo8 ofa human Π R2. and 6} N143.1167, K65. R3S3. 0307, 12502, .0278, PI 85. 11*4, 13.:0, V384. A305, 13.23.. 1306. ίΧΡ'Π, E385, 1270, 102, Y66. V309. D145, S165. S40, S505 1242, FI03.Q328.and SI 68 of a human TIR2.

Exemplary interacting residues of the Venus flytrap domain of a ehemoseasory receptor with respect to a ohemosensory receptor modifier include one or more residues of 1} N.M3, S144, and ..1167 ofa human T1R2, 2) $40, Si 44, SI 65. Y103, 01-12. and P27? ofa human TIR.2, 3) 1167, Pi85, T!J4,T326, 1330.2, V384, A305,1325, i30o R3s5. 1)307,15382, 0278. 1279,167, V66, ¥309,0142, Si 65, S40, S303, T242, FI 03, Q328, apdSIVS of a human T1E2, 4} N143 and! US? of a human T.1 R2V S)'S40, S165, Y103, D.14'2, and 0277 of a human T1R.2, and 6} 1167, PI85, '1184,1326, V384, A305.1325,1306, R.383, 0307,1382, D278,1279,167, V66, Y309,Dt42, SI.65, S40, $303, T242, FI 03» 0328, and Si 68 of a-human T1R2.

Exemplary interacting residues of the Venus flytrap domain of a chemoseusory receptor with respect to a sweet, flavor entity such as sucrose and suoralose include one or more residues ofS40, S144, YX03, 0142, P277 ofa human T1R2, Exemplary interacting ..residues of the Venus fly trap domain of a ehemosenxorx receptor with respect to a sweet flavor entity such as saccharin or aeesuflatne if include one or more residues -6.fR.65» 11:383, 0307., E302, and D278 of a human Π R2

Exemplary interacting residue!? of ?he Venus fiytrap domain of a chcmosensoiv receptor with respect to a chemosensorv receptor ligand modi Her, 0..0.; chcmoscnsory receptor ligand enhancer include one or more residues of 1) K63».R383;5 D3fi7, E302, and 0278 of a human ΙΊ R2, 25 S40. S144. S )65. Y103. Di 42, and PIT? of a human TIE 2, and 3} 1167, PIES, T 184,T32A, B02, V3S4. 1325,1306. R383. 0307, E382, D278, 1279, {67, ¥66, V309, 0142. S105, S40. $303, T242, F103. 0328, and S16s of a human ΠΕ2.

In the context of the present invention. any reference ro a particular interacting residue. η.»·., NI43 of a human T1R2 sccepto;, includes ail of its corresponding residues, e..g,, 15 any residue of a human or non-human Tl R2 that corresponds to the same position in any method of sequence alignment 2} any residue of a human or non-human T1R2 that corresponds to the same position in any method of computer'modeling in the: presence or absence of a ligand or ligand modifier 35 any residue of a. human or non-human TIR2 that corresponds to the structural or functional role of the particular interacting residue. 4) any residue of a human or non-human ΤIR2 that is a polymorphic variation, alleles, mutation* etc. of the particular residue,. 5) any residue of a human or non-human T1R2 that is a. conservative substitution or conservatively modified variant of the particular residue, and 6} any corresponding residue of a human or non-human T1R2 in tis modified form, e.g:, artificial chemical mimetic of the particular interacting residue or ua-modified. form, e.g„ naturally occurring: farm. in another embodiment, the interacting $iib Vithlb the Venus flytrap domain of a ebemosensory receptor is a three dimensional interaeting space within the Venus flytrap domain outlined or defined, partially or entirely, by interaeting residues or one or shore interfaces, egy, interacting points, lines or surfaces between a ehemosensory receptor and one or mote eherooseusotw receptor modifiers or eheniosensory receptor ligand modifiers or a combination thereof. According to the present Invention, a residue outlining or lining a space includes any residue having one or more backbones and/or side-chain atoms that are positioned so that they can potentially interact with atoms of a ebemosensory receptor ligand or chernoseosory receptor ligand modifier or both.

For example, fire interacting space of the present invention can be. any partial or whole apace within the Venus flytrap domain that is usually occupied by one or more ebemosensory receptor modifiers or ehemoseusory receptor ligand modifiers when they interact with a ebemosensory receptor individually or together. In one example, the interacting space of the present invention is a space within the Venus flytrap domain usually occupied by a ehemosensory receptor modifier, g.g.^, sweet flavor· entity, in another example, the.'interacting space of the present invention is a space within the Venus flytrap domain usually occupied by a ehemosensory receptor ligand modifier, r.y., sweet flavor enhancer in the presence of a ehemosensory receptor ligand, in yet another example. the interacting space of the present Invention Isa.space within the Vernas flytrap domain usually occupied by a ehemosensory receptor modifier, e..g.. sweet flavor entity and a ehemosensory receptor ligand modifier, e.g., sweet flavor entity enhancer, in still another example, the interacting space of the present invention is a space within the Venus flytrap domain that is defined, shaped, or transformed into based on an interaction between a ehemosensory receptor and its ligand or its ligand modifier occurred partially or entirely outside of foe space.

According to the present invention, She Venus flytrap domain of a cbens sensory receptor can be generally viewed as two lobes joined by a hinge region. 1: xemplary mu reefing space within the Venue flytrap· domain of a ehemosensory receptor metudvS any spa-„c «wsoeiated with the hinge region., the i oner side of one or two lobes, the: tip of one or two lobes or a combination thereo f of a ehemosensory receptor.

Exemplary interaetfog,space within the Venus flytrap domain of a ehemosensory receptor w ith respect to a ehemosensory receptor modifier includes any space within the Venus flytrap domain outlined or at least partially defined by the hinge region. According to the present invention, the hinge region usoally comp rises residues that are close f·» the three strands connecting the two lobes i In. one example, the hinge region comprises residues that are •homologous to residues observed coordinating agonists and antagonists in crystal structures of one or more Venus flytrap domains such as that of the mGtuR receptor.. In. another' example, the hinge region of T1R2 includes residues ΝΠ43, Si44, and Π67 ofTfRl,

Exemplary interacting sites within the Venus fly-trap domain of a ehemosensory receptor with respect fo a ehemosensory receptor ligand modifier include any space outlined or si least partially defined by foe barer .'side--ofone or two lobes away from the hinge region,: as well as residues on the tips of the lobes that are brought into close proximity to residues on the other lobe. in yet another embodiment, the interacting site within the Venus flytrap, domain, of a ehemosensory receptor is a combination, of one or more interacting residues with an interacting space of the ehemosensory receptor. For example, the interacting site of a ehemosensory receptor can be interacting residues associated with one interacting structural component of a ehemosensory receptor in combination with a three dimensional space·.adjacent, not less than 1 Angstrom and not wore than .10 Angstroms. to that interacting: structural component. Another example of the inret acting site of a ehemosensory receptor includes interacting residues associated, wit h one interacting structural component of a ehemosensory receptor in combination with a three dimensional- space: apart irons the interacting structural component. in general die screcningntethods provided by the present invention can be carried out by an> suitable means known or later discovered., in one^.embodiment, the screening methods provided by the present invention are carried out«? &amp;jihc0*-&amp;g., via "Virtue screening” using any suitable computer modeling system or v>u specific or rational design of a compound using any suitable computer design system. in another embodiment, the screening methods pr-.»viucd by the present invention, arc carried out.vin biological assays. <?.«„ high throughpufscreening of interactions between compounds and a ehemoseusory receptor or its fragments,. &amp;g.t .genetically modified ehemosensory receptors: or fragment^, thereof such as mtUated Venus flytrap domai ns of eheraosenspry receptors.. In yet another embodiment, the screening methods provided by the present invention are earned out via a combination of biological assay(s) and computer modeling and/or design.. For example, the screening methods- provided by the present invention can be a combination of high-ihroughput screening of interactions between comppter designed or pre-screened compounds: and mutated Venus flytrap domains of ehemosensory receptors,

In one example, the screening method provided by the present invention Aar ehemosensory receptor modifiers includes determining art interacting site using a known ehemosensory receptor modi tier, e.g., structurally similar to a ehemosensory receptor modifier of interest and then determining whether a test entity is suitable to ihtcra«st>vithtb.e;cbem<>i»cnsory receptor ukrthe interacting site so determined,

In another example, the screening method provided by the present invention for chsmoxenxory receptor modifiers includes determining whether a. test entity is suitable to interact with a ehemosensory receptor via a predetermined interacting site, e,g., an:interacting site-selected or determined prior to screening, including wuhout any limitation, selected or determined based on know,n chcmosensorv rccepior modifiers or desired characteristics of a ehemosensory receptor modifiers.

In yet another exianpie,. the screening method provided: by the present invention for chento.scn.sory receptor iigartd modifiers includes determining a docking site for a ehemosensory receptor ligand and subsequently determining whether a test entity is suitable.to interact with the chcmosenscrv receptor ligand via an interacting site selected 1st light of the docking of the ehemosensory receptor ligand. According to the present invention, docking process cun include any known or later discovered methods. For Instance, docking can. be a process in which the center of mass, orientations, and internal degrees of freedom of a molecule are modified to fit them into a. predetermined space in a structural model, in one example, docking ears be a process which includes translating and rotating a chemosensory receptor ligand relative to the ehemosensory receptor structural model v.g., the Venus flytrap domain of a chemosensory receptor model while simultaneously adjusting internal torsional angles of the chcmosenscrv receptor ligand 10 fit it into the interacting site of the ehemosensory receptor, An example of a widely used docking program, is QLIDF from Sehroedmger, Inc.

In yet another example, the screening method provided by the present invention for ehemosensory receptor ligand modifiers includes determining :a·diking;site &amp;r a ehemosensory receptor ligand and..subsequently determining an interacting site using a known modi fier of the chemosensory receptor ligand and then determining whether a test entity is suitable to Interact with the chemosensory receptor ligand via the interacting site so determined.

In yet another .example,, the screening method provided by the present invention for chemosensory receptor ligand modifiers includes determining whether sliest entity is suitable to. interact with a ehemosensory receptor vm a predetermined interacting site for ehemosensory receptor ligand, modi Iters. hi still another example, the screening method provided by the present invention for ehemosensory receptor ligand modifiers includes determining whether a test entity is suitable to interact with a chemosensory receptor by deteonming, wp., concurrently whether a chemosensory receptor ligand and the test entity are suitable to interact with the ehemosensory receptor in. a predetermined interacting site oft.be chemosensory receptor or an interacting: site determined using known ehern.oscii.sor>' receptor ligand and its modifier of interest,

In still another example, the screening method provided by the present invention for cheteosensory receptor Ugurul modi He is includes determining whether a tea* entity is suitable feV interact with a chcrooscnsory receptor na an interacting site, either predetermined Or not, as well-as-whether a test entity is .suitable to interact with a chcmoseasory receptor ligand.

In still soother example, the screening method provided by the present invention for -eheaicsensory receptor ligand modifiers includes determining whether a test entity is suitable to interact with a chcmosensory receptor via an interacting site, either prc-ilctermincd or not. as well as whether such interaction can stabilize a conformation, e.g.. a scmi-cioscd or closed conformation within the Venus fivtrap domain formed by (fee Interaction between a chemosensory. receptor ligand and a chemosensory receptor. 0..¾.. by forming productive additional interactions within the hinge region, lobes of the Venus flytrap domain, or tips of the flytrap domain via van der Weals, burial of hydrophobic atoms or atomic groups, hydrogen bonds, ring stacking interactions, or salt-bridging electrostatic interactions, vtc.

In general any suitable moans known or later discovered can bo used to determine whether a test entity is suitable to interact with an interacting site of the present invention. For example, one could determine the suitability of a test entity based on whether pad or all of a test entity fits into a particular space entailed by m interacting site, teg,, whether a test entity fits into a particular space entailed by an interacting site substantia! ly the same way a.: known chemosensory receptor modifier or ehemosonsorv receptor ligand modifier does.

Alternatively one could determine the suitability of a test entity with respect to an interacting site based on: whether it forms inte;mctions with a ebesnosensory reeeptor similar to the interactions formed by a: known eheurosensory receptor modi Her or chemosensory receptor ligand modifier when, they interact with the interacting site.

In addition, one could determine the suitability of a test entity based on whether it forms productive interactions with an Interacting site, e,y., van der Weals, burial of hydrophobic atoms or atomic groups, hydrogen bonds, ring stacking iercraefious, or salt-bridging electrostatic interactions. eta hi one embodiment* one could, determine the suitabili ty of a: test en tity being a eb.enioscnsory reeoptor ligand modifier based on'whether it forms productive interaetions with an interacting site without forming van der Wauls overlapping with one or more atoms of a chemosensory receptor or the chemosensory receptor ligands. e.g,, in. the context of one or more conformations of the Venus flytrap domain in light of the possible flexibility of ihc Venus flytrap domain.

According to the present invention, a-test entity suitable to interact with one or more interacting sites within the Venus flytrap domain of a ehernoscrisoiy receptor Is indicative of a candidate for a chemosensory receptor modi tier or c homo sensory receptor ligand, .modifier. In one embodiment, a test entity suitable to interact nidi one or more interacting sites within the Vemis flytrap domain of TIR2 is indicative of a candidate for a TIR2 receptor modifier or TIR2 receptor ligand modifier, in another embodiment, a test entity suitable to interact, with one or more interacting sites within the Verms flytrap domain of TfR2 is Indicative of a candidate for a I'lR receptor mpdifteror HR receptor ligand modifier. In yet soother embodiment, a test entity suitable to interact with one or more .interacting sites within the Venus flytrap domain of TIR2 Is indicative of a candidate for a receptor modifier or receptor ligand modifier for a receptor of GPOR superfamily. In still another embodiment, a test entity suitable to interact with one or more interaction si tea within the Venus flytrap domain of a chemosensory receptor is Indicative of a candidate for a receptor modifier or receptor ligand modifier of a receptor that corresponds to the chemosensory receptor or belongs to: the same fondly or class as of the chemosensory receptor.

According to the present invention, a test entity suitable to interact with one or more interacting sites within the Venus flytrap donrain of a eheniosensory receptor Is indicative of a candidate for a chemosensory reoepfor nioddur or chemosensory receptor ligand modifier.

In one cnihodimont, a test entity suitable to interact with one or nfofo interacting sites within the Venns flytrap domain of IiR-2 Is indteativo of a candidate for a T1R.2 receptor modifier or TIR2 receptor ligand modifier,

In one example, a test entity suitable to interact with one or more interacting sites containing one or more interacting residues of K.6S, D278,1,279,19307, R383, and V'3b'4 of human TJR2 is indicative of a candidate: for a TIR2 receptor ligand enhancer..

In attatfegr-ex&amp;niple,.a testentity suitable to interact with one or mere interacting sites eontalniug one or more interacting residues of S40, S144, YI03, Dl42, ami P.277 of human T.1R2 is indicative, of a caudidateibra T.I R'2'.roecptor ligand enhancer with respect to sucrose or soeralose or any hgaud: with a structure similar to sucrose or suerafose or any ligand interacting with Tf R2 in a wav similar ?o that of sucrose or sucruiosc, e.g., via ono or m»*rc interacting spaces and/or residues used by sucrose or snetalose.

In tile context of the present application, any reference to a modifier, e.g. enhancer or inhibitor of a T1R2 receptor or T1R.2 receptor ligand, includes a modifier for any Ti R receptor, any receptor oiGPCR super-family, orany receptor corresponding to TIR.2 receptor, e.g„ any receptor with a structure, function, or expression pattern overlapping.or similar to that of TIR2. In the present invention* a test entity can he any compound or molecule, e.g,, any compound or empt that potentially could. be a source fer a desired. ehemosensory receptor modifier or chemosensory receptor ligand modifier. For example, a test entity can he a member of a combinatorial library, a. member of a natural compound library, a “specifically designed”compound that fr designed based on various desirable features or rationales, eh.

In general, a chemosensory receptor modi Her or ligand includes any compound or entity capable of interne-ting with, e.,g:., binding to a chemosensory receptor or modulating the structure or (unction of a chemosensory receptor, mg,, aeriv.ue. deactivate, increase, or decrease the signal transduction activity of a chemosensory receptor, especially via G-protein signal transdaerion pathway.

In ope embodiment, a chemosensory receptor modifier or ligand is a compound or entity w ith sweet flavor «winding without any limitation any natural or synthesized sweet Savor compound, non-caloric sweet flavor comps \m«K, reduced calorie sweet flavor compounds, non-target calorie sweet Savor compounds, ek. Γ xempUfy sweei i!a\ or compounds ineludev without any limitation, eyefanric acid, mpgroside, tagatose, maltose, galactose, mannose,: sucrose, fructose, lactose, aspartame, neotame and other aspartame derivatives, saccharin, sncralose, acesul&amp;me K, glucose, etythfltol, D-tryptophan, glycine, mannitol, sorbitol, maitltol, laetitol, isomalt, hydroganeted glucose syrup (MGS), hydrogenated starch hydrolyeate (HSH), stevioside, rebandioside A and other sweet Stev/o-hased glycosides, alitame, earwlame and other guanidine-based sweeteners, tagatose, xylkol, high frucrose corn syrup, etc.

Ik auoillcr embodiment, a; chemoseusory receptor modifier or ligand (used interchangeably in the present invention) is a compound or entity capable of aetivating a chcaimxensory receptor, e.g., activating fee G-proiein signal tranaduetlen pathway associated with die chemosensory receptor, Ik yet another embodiment, a chemosensory receptor modifier or ligand is a compound or cKtity capable of blocking or decreasing the activation of a ehemosensory receptor. In still another embodiment, a ehemosensory receptor modifier or ligand is a compound Of entity capable of modulating the acti vity of a elwmnseasory receptor and inducing a therapeutically desirable reaction or signal transduction, la still another embodiment, a ehemosensory receptor modifier or. ligand is a ehemosensory receptor ligand modi fiei.

According to the present invention, a ehemasensery reeepmr ligand modifier Includes any compound or entity capable of interacting or modulating the activity of a ehemosensory receptor modifier or the activity of a chetnoscnsory receptor in the presence of a ehemoseaspry receptor modifier. In one embodiment, a cbemosensory receptor ligand modifier is an enhancer of a cbemosensory receptor modifier. In another embodiment, a cbemosensory receptor ligand modifier is an antagonist of a cbemosensory receptor modifier, in yet another embodiment, a ehemoscnsory receptor ligand modifier is an enhancer of a cbemosensory receptor modifier without having substantial activity of the ehemoscnsory receptor modifier. In. still another embodiment, a ehemoscnsory receptor ligand modifier is an enhancer of a sweet flavored -compound withorn having substantial sweet, flavor fey itself, mg., as judged by animals or humans such as majority of a panel of at least eight human taste festers, via procedures commonly known in the field, in still yet another embodiment a cbemosensory receptor ligand modifier is an enhancer or inhibitor of a cbemosensory receptor modifier and capable of inducing a desirable therapeutic reaction or signal transduction.

According to another aspect, of the present- invention, it provides cbemosensory receptor ligand modifiers. In one embodiment, i f provides ehemosensory receptor ligand modifiers identified by die screen methods of the present invention. In another embodiment, it pro vides ehemosensory receptor ligand modifiers: capable of interacting with a ehemosensory receptor via an Interacting site of the present invention, in yet another embodiment, it provides ehemosensory receptor ligand modifiers capable of interacting with a ehemosensory receptor via one or more interacting residues of die ehemosensory receptor in still another embodiment, it. provides: cheniosensory receptor Kgand modifi ers ca pabi e of interacting with: a ehemosensory receptor v&amp;rafc interacting space within the Venus flytrap domain that, is outlined, defined, or shaped, partially or entirely, by interacting residues of the ehemosensory receptor. In still yet another embodiment it provides ehemosensory receptor ligand modifiers excluding, natural or synthesised sweet enhancers kno wn, prior to the presen t in vention.

In the context of the present invention. * capable of interacting with" or “interacting with'’ means.that a compound or molecule binds to oi forms one or more molecular interactions, e.g., productive iftteractiimis with another Rmfecule, teR., a cliemosensory receptor; Exemplary mckcular 'interactions, e.g., productive interactions include van der WaaLs, burial of hydrophobic atoms or atomic groups, hydrogen bonds, ring stacking interactions, sait-bridgmg electrostatic interactions, or a combination thereof. 1st one embodiment, the present invention provides ehemosensory receptor ligand modifiers capable of intciacting with a chemoseusory receptor vni a group of interacting residues or a. space within the Venus flytrap domain that is outlined, shaped, or defined, partially or entirely by the group or any subgroup of interacting residues, optionally in the presence of a. cheinosensory receptor ligand, e.g., 1 s $40, SI 44, Slop, Y103, 0142, F27? of a ktmmu TfR2, 2) K65. R383, D30?, E302, and D278 of a human Ή R2, 3} lie?, PI 85, Π84. T326, B302, V3$4, .A305, 1325., 1300., R383.. D307, 15342, 0278.. 1279.167. Von.. ¥30«. 0: 42.. Si 65, S40. $303, T24 2. f : 03, Q324. and S16$ of a human T1 R2. 4) $40, S144, S1 6>, Y 103. D142.., P277. Key, R383. 0307,1:7302, and 027g of'a human P1R2, 5s S40, $:4-4. S:65, Y103, DI42.0277, 1:67, PI 45.. 1:84, 132,0. £.30.2, V3$4. A305. 1325.. 1306. R383, 0307, 17382, 0278, 1270,167, V66. V309, S303,1242, FI03. Q328, and S168 of a human 1112,.$) K;$S, K383,0307, E302, D278, 1167, PI 85.1184,1326, E302, ¥384, A505,1325,130$, £382,1279,167, V66, ¥309, D142, $165, S40„ $303,114 7, 1103. Q324, and $168 of a human H R 2, 7} S40, $144, $165., Yl 03, D142. F277, Kite. R.3g3. 0307. 12302,12)278, 1:67, Ps'85.. TI84, :'32o. F302, ¥384, Λ305, 1325. 1306, E382,1279,167, V66, V309, $303, T242, FI.03, Q328, and $168 of a human T1R2, 8} N143. S144, and 1167 of a human T1R2. or 9} 01-13. $40, $144. SIRS, Y 103., 0142, F277.,'K$5, R383. 0307., E30.?, 0278,1167, PI 85, Π 84,, T326,12302, V384.. A.305,1325,1306,12382,1279, 167, ¥66, V309, $303, T242, F103,Q328, and S I 68 of a human T1R2.

Ira· another embodiment'the present invention provides chemnssusory receptor ligand enhancers capable oHnierjeung with a chemosensory receptor in. the: presence of a chetnoscnsory receptor ligand via oue or more interacting residues of R.65, 0278,. 1.,279, D307, «383, $538-1 of a hutuan Ti 12:2. M yet another embodiment, the present invention provides sucrose arsecralose .enhancers capable of interacting with ochenioserssoiy receptor in the presence of sucrose or sucralcse via one or more· interacting residues of S40, 3144, Y103. DI42, R277 of a hunum Ti R2.

In still another embodiment, the present inventioft pro\ ides ehemoseasory: receptor ligand modifiers capable of interacting with a chemosensory receptor,· optionally in the pma-'cnce -»f a chemosensory receptor ligand via at least 1,2, 3, 4, 5, 6. 7. K. 9, or 1.0 Interacting residues selected from the group of N143. S40, SI 44. SiPO, VI03. 0142, P277, KA5, R3-S3. D307, If302, D2?S, 1167. PIS5, Ti84, '026, E302. V384, A30A (323, I30(\ 0*0,12?A 16 ~ V66. V309, S3 03, T242. F' 103, Q32S. and 8163 of a human ΊΊ R2.

In still another embodiment, the present invention provides chemosensory receptor ligand modifiers capable ofinteraeting with a chemosensory receptor to stabilize a conformation, rsy., scmi-closcd or closed conformation formed by the interaction between a chemosensory receptor and a chemosensory receptor ligand

In still yet another embodiment., the present invention provides chemosensory receptor ligand modi tiers, e.e . saccharin, saccharin analogues, acesuUaroc K, ucostilfame K analogues, or any oompemnd capable of interacting with a chemosensory receptor via&amp;n interacting site that is similar to or overlaps with an interacting site used by saeeltarin or aeesulhtme K, hi otto example, the present invention provides chemosensory receptor ligand enhancers, saccharin, saeofearia analogues,· acstsuffatpe.'K, or seesnlfanie K analogues that interact with a chemosensory receptor via an interacting site including one or more interacting residues of K.6S, R3K3, D307, E302 and D27K of a human ΊΠ..82.

According to yet another aspect of the present immudon, it provides chemosensory receptor modifiers. In one embodiment, it provides chemosensory receptor modifiers identified by the screen methods of the present invention,· In anotber embodiment, it provides chemosensory receptor modifiers capable of interacting with a cbem.bseosory receptor via an interacting site of the present invention. In yet another embodiment, it provides chemosensory receptor modifiers capable of interacting with a ohen -oseosory receptor via one or more interacting residues of the ehemosensory reeepior. In. sill another embodiment,: it provides eheniosensor}' reeepior modifiers capable of interaeting with a chemosensory receptor ve? an. interacting space within the Venus flytrap domain that is outlined, defined, or shaped, partially or entirely, by interacting residues of the chemosensory receptor. In still yet another embodiment, it provides chcrnosensory receptor modifiers excluding,, e,g.t natural or synthesized sweet Havcf entities known prior to tire present invention.

In one embodiment, .the present invention. provides chemosensory:receptor modifiers capable of interacting vvith a chemosensory recepior via a group of interacting residues or a space within the Venus flytrap domain that is outlined, shaped, or defined, partially or entirely by the group or any subgroup --1 interacting residues, e.g.. I $ $40, Si44, Slop. Vi03, D!42, P277 of a human T1R2, 2} K65, P363, 0307. E302. and D278 of a human TiR2, 3} 1!67, PI 85. T184, Γ326, 15302, V'384, A305, 1325. 1306, R383, D307. E382, 0278,1279, 167, V66. V309, D142. S165. S40. S303, T242, f 103. 0336, and S166 of a human Ή R2, 4) $40, Si44, S165. Y 1 03. 0142, F277, K66, R383, D307, E302, and D27.8 of a human T1 R2. 5 i S40, $144,

Si65, Y103. D142, P277. I! 67, P185. ΤΊ84, T326, 15302, V3S4. A305,1325.1306. R3s3, D30?, (5362, 0278, 1279,167, V66, V309, S303. Γ242, Pi 03, Q328, and Si 68 of a human T1R2, 6} K65, R383., D307. E302. D2 /8.1167, P185. ΤΊ84. 7326.1::302. V364, A30--. B25,1306. F3$3. 1279,167., V66. V309, 0142. SI65. $40. S303. 1242., H0'3. Q328. and Si68 of a human T1R2, 7} S40. S144, SI66. Y 163., 014 3. P277, K65. E363, D307.. 002, 0276. 1167, Pi65. ΊΊ84. 7326. E302. V384, A305.1325,130o, 15363,1379.. 167., V66. Y309, $303, T242. F103. Q336, and SI 66 of a Imman TIM, 8) M43, S.144, and 1167 of a human T1R2, or 9) NI93, S40, SI 44, SI65. Y103. 0142, P277. K65, R3$3. D307 E302, 0278. lie", Plsf. Π84, T326. E362, V384, A 305, 1335,!30o. E382, 1279. 167.. Y66, V'309. $303, Π 13,1 10¾ Q53Y and $166 of a human T1R.2. hi still another embodiment, the present invention provides e.hemoseosory receptor modiftet^re-apa-bk;of mtomc&amp;g with a chcmosensory receptor via at least 1.. 2.. 3. 4,5, 6,7, $, 9, or 10 interacting residues selected.·from the. group of N143, S40. $144, Si 65. Y103, 0142, P277, K.65, R3$3, 0307, E302, 0278, 1! 67, PI85, T184, T326, E302, V384, A305,1325, 1306.17382. 1279. 167, V66, V30T $303, 7242. FI 03, Q328. and Si 68 of a human 74 R2

According to still another aspect of the present inwntion. It provides methods for modulating a chemosensoiy receptor and/or its ligand by modulating one or mom interaeting sites oF the chemosensery receptor. For example, one can .-modulate a chcnrosensory receptor by contactings in vivo or m vitro, a ehemoserjsory receptor modifier or cbemosenvnn receptor ligand modifier or both, (e.p-„ optionally excluding natural sweet Huso; ente\ m. sweet enhancers known prior to the present invention) with, ceils eomaming the chemosensory receptor, wherein. the chcrnosensory receptor modifier or chemoscusory receptor ligand rs capable of interacting with or targeting one or more interacting sites of the chernosensory receptor.

In one embodiment, the method of modulating a chcrnosensory receptor arui-'or its ligand; is by modulating one or more interacting residues-or interacting spaces or a combination thereof. In another embodiment, the method -of modulating. a chentoscnsory receptor and/or its ligand is by interact?ng w oh one or mote Interacting residues in the. presence of a chernosensory receptor ligand. In yet another embodiment the method - of modulating' a. ehesnosensory receptor or its ligand includes modulating the impact, of a chcrnosensory receptor ligand on the chcrnosensory receptor by mtemctmg with the chcrnosensory receptor via one or more interacting residues in the presence of the chcrnosensory receptor ligand. I n yet another embodimen t, the method of mod ulating a;. chcrnosensory receptor and/or its ligand is by interacting with the chcrnosensory receptor via a group of interacting residues or a space outlined, shaped, or defined, partially or entirely, by the group or subgroup of interacting residues, optionally in the presence of a ehemoscosorv receptor ligand, e.g .. 1} $40, $144. Side.. YsOiK 1)142. P27? ofa human T1R2, 2) K65.R383, D$07, F302, and D2?8 ofa human Ti R2, 3} 1167. FI 85, Ή84, T326. 55302. V384, A305,1335,1306, R383, D307,13382, D278,1279,16?, V66, V3«9, 0142, Si 65, $40, S303.1242,1Ί03, Q32$, and $16,8 ofa human XIR2, 4) $40, S144, $ 165, ΥΊ03, 0142. P277, k'65. R383. 0307, E302, and D.27K ofa human hr:., 5| $40, $144, $165.. Y103, DM2. P277,1167, PI85, Π64 /0 26.1/302. V384, Λ305. 1335,13On, R383.. 030?, 0363, D278. 1270.167, V66, V309. $303, T342, FI 03, Q328, and $168 ofa human T1R3 ¢/ K65, R383.. 0307, F303, 0278. 1167. PI 85. TI84, Γ326, F302, V384, A305, 1325.1301). /382. 1279, 167, V66. Y309, DM2. $165, $40. $30.3, T242, FI03. Q32$. and $168 ofa human T1R2, 7) $40, $144, $165.. 3'103, DM2. P377, K65. R383, 0.307. 1/302,1)278, 1167, Pigs. 1184.. 7326, F.302, V384, A305, 1325. 1306. ϊ/3κ2, 1279, 167, V66, Y30‘), $303,, 1242, F! 0 3, Q328, and $168 ofa human 7 1R2. 8) NI43. $M4, and 1167 ofa human I/R2,or0) N143, $40, $144,. Si65, V 103. DI42, P277.1//5, R385. D307,1535)2, 0278 1167. P{8$ H$4, T326, E302, V5384, A305,1325,1306, E382,1279,167. V<>6. ¥309, $303, T242/F103, Q328, and $168 of a human TfR2. in yet another embodiment, the method of modulating a ehemosensory receptor and/or its ligand is by interacting with the chcrnosensory receptor via one or more interacting residues ofNX 43, $144, and 116? ofa human Ti R2,

In yet another embodiment, Use method of modulating a chemosensory receptor and/or Us ligand is by interacting with the ehetnoMasory receptor,, optionally in,the presence of a chemosensory receptor ligand via one 0-r.mote, interacting residues of 1965,. 0278,079, D367. mm, V384 of a human T1R2, in still another embodiment, the method of modulating a chemosensory receptor and or its ligand is by interacting with the chemosensory receptor, optionally in the presence of sucrose or sucralosc via one or snore interacting residues of S40, SI 40, γ j 03, 0142, P377 of a human T1R2, I n sti ll another embodim ent, the method, of enhancing a chemosensory receptor and/or Its ligand is by interacting with the chemosensory receptor, optionally in the presence of a chemosensory receptor ligand via one or more interacting residues of K65, D278, 'L279, D307, mm. V3S4, $40, SI44, Y103, DI42, P277 of a human T1R2,

In still another embodiment, the method of modulating a chemosensory receptor and/or its ligand is by interacting with the chemosensory receptor, optionally in the presence of a chemosensory receptor ligand via at least. 1.2.. 3.4. 5. 6.7. 8, 0, or 10 interacting residues selected.fromihe group of N143, S40. Si44, S165. Y103, DJ42. P277, £(>$, £383,0307, E302, D278,/1167, FI 85,1184, T326, £302, V384, A3«5,1325,1305, E382,1279,167, V66, Y309, S303, T242, FI 03, Q328, and $168 of a hums» T1R2,

In still another embodiment, .the: method ..ofmodulating: a chemosensory receptor and/or its ligand is fey Mieraeting with the chemosensory receptor, optionally in the presence of a chemosensory receptor ligand via at least 1, 223, 4, 5, 6, 7,/8, 9, or 10 interacting residues selected from the group of N143, S40, $144,13165, Y103,0142, P277. K65,R383. D307, E302, .0278,1107, 0185, T! 84,1326, B302, V384, A205,1325,1306, E382,1279,167,. V66. V309, $303.. T242, FI03, Q328.. and $168 of a human TIR2.

According to the present : own* ton, a nurihoJ ol modulating a. cnemosensory receptor and/or its ligaud includes/modulating the activity, structure, function, expression, and/or modification. of a chemosensory receptor as well, as modulating, treating, or taking prophylactic measure of a condition, e.g,, physiological or pathological condition, associated with a chemosensory receptor, in general, a physiological or pathological condition associated with a chemoseusory receptor includes a condition associated wi th a taste, wg;, sweet, uffianfi, hi tter, sour, salty, or a combination thereof or u condition associated ^vith, e.g.., gastrointestinal system, metabolic disorder;', functional gastrointestinal disorders, etc.

In one embodiment, the method of the present invention. e.g.. modulating a chernosemory receptor and/or its ligand includes modulating* increasing or decreasing it sweet or nmarni taste or a subpretk reaction, physiological or otherwise,, to a sweet or umarni taste, in. another embodiment, the. method of the present-invention, e.g·,, modulating a chemosemoty receptor and/or its ligand includes enhancing u sweet or umami taste or a subject’s reaction, physiological or otherwise, to a sweet or umami taste.

In yet another embodmient, the method' of the present; hweniion, e,g,, modulating a chemoscttsory receptor and/or its ligand includes modulation, treatment, and/or prophylactic measure of a condition associated with gastrointestinal system Including without any limitation conditions associated with esophageal motility U'.g., cricopharyngeal achalasia, globus hystericus, achalasia., diffuse esophageal spasm and related motor disorders, scleroderma involving the esophagus, ete.l. inflammatory disorders (e.g., gastroesophageal reflux and esophagitis, infectious esophagitis, e/c,l peptic ulcer, duodenal ulcer, gastric ulcer, gastrinoma, stress ulcers and erosions, drug-associated ulcers and erosions, gastritis, esophageal cancer, tumors of the stomach, disorders of absorption uyg.. absorption of specific nutrients such its carbohydrate, protein, ami.no acid, fet cholesterol and .fat-soluble vitamins, water and sodium, calcium, iron, water-soluble vitaniins, uted, disorders of malabsorption, defects in mucosal function (e,g.„ inflammatory et infitetw'udisbrders. biochemical or genetic abnormalities, endocrine and metabolic disorders, protein-losing enteropathy, eia% autolrnmmic diseases of the; digestive tract (e.g., celiac disease, Crohn's disease, ulcerative colitis, etc.}, irritable bowel syndrome, inflammatory bowel disease, gomplieatios>s of ihflajnnratery bowel disease, extraintestinal mani festaiions of inflantmatefy bowel disease, disorders of intestinal motility, vascular disorders of the intestine., anorectic! disorders {e.g, hemorrhoids, anal inflammation., t-jfr.l. colorectal cancer, tumors of the small intestine, cancers of the anus, derangements of hepatic metabolism, hyperbilimltinemia, hepatitis, aleoholio li ver disease anti cirrhosis, biliary cirrhosis, neoplasms of the liver, intiitrative and metabolic diseases affecting the liver (teg., lady liver, reyxfs syndrome, diabetic glycogenosis, glycogen storage disease, Wilsonfs disease, hemochromatosis}, diseases of the gallbladder and bile duets, disorders of the pancreas (e,,g.. pancreatitis. pancreatic exocrine insufficiency, pancreatic cancer, eu. K endocrine turners of she gastrointestinal tract and paeeieas,wi£.

In still another embodhirent, dte. .method of the present invention, ·?«., modulating · a chcmoscnsory receptor and/or its hgartd includes moduisiloti, treatment,· and/or prophylactic measure of a condition associated with metabolic disorders, e,g., appetite, body weighs, food or liquid intake or a subject's reaction to food or liquid intake, or state of satiety or a subject's perception of a state of satiety, nutrition intake and regulation, (e.g., prote in-energy 'makmtrititop, physiologic impariements associated with pudeia-energy Bislmttrition, Wd), obesity, secondary· obsesity te.y., hypothyroidism, Cushing's disease, iosullinoma, hypothalamic disorders, etC;% eating disorders (r-.g., anorexia, nervosa, bulimia, etc. 1, vitamin deficiency and excess, insulin metabolism, diabetes ttype 1 and typo 11} arid complications thereof fe.g., circulatory abnormalities, retinopathy, diabetic Bephropathy, diabetic neuropathy, diabetic· foot ulcers, eic.h glucose metabolism, far metabolism, hypoglycemia, hyperglycermia, hyptsrHpoprotememtas, efc.

In sn'll yet another embodiment, the method of the present' invention, eg., modulating a chemosensory receptor and/or its ligand includes,modulation, treatment, and/or prophylactic measure of a condition associated with functional gastrointestioal disorders, n«., in the absence of any particular patbological condition such as peptic ulcer «id cancer, a subject has abdominal dyspepsia, mg. , fooling of abdominal distention, nausea, vomiting, abdominal pain, anorexia, reflux of gastric acid., or abnormal bowel movement (constipation, diarrhea and the like}, optionally based oh the retention, of contents in gastrointestinal tract, especially in stomach.. In one example, functional gastrointestinal disorders in elude a condition without any organic disease of the gastrointestinal tract, but with one or more reproducible gastrointestinal symptoms that affect the quality of life of a subject, i?,.g. , hunnux

Exemplary functional gastrointestinal disorders include,without, any limitation, functional dyspepsia, gastroesophageal reflux condemn, diabetic gastroparesis, reflux esophagitis, postoperative gastrointestinal dysfunction and the like, nausea, vomiting, sickly feeling, heartburn, feeling of abdominal distention, heavy stomach, belching, chest writhing, chest pain, gastric discomfort, anorexia, dysphagia, reflux of gastric acid, abdominal pain, constipation, diarrhea, breathlessness, feeling of smothering,· low incentive or energy level, pharyngeal obstruction, feeling of foreign substance, easy fatigability, stiff neck, myotonia, month dryness (dry mouth, thirst, etc·.) tachypnea, burning sensation in. the gastrieintestina! tract. cold serration oioxUcrniiies, difficulty in concern* at ion. impatience. .sleep divider, headache. general malaise, palpitation, night sweat;, anxiety, dizziness, vertigo,, hot flash, excess sweating, depress loti, .etc.

In still yet another embodiment, die method of the present invention, e.g., modulating a chemosensory receptor and/or its ligand includes increasing or promoting digestion, absorption, blood nutrient level, and/or motility of gastrointestinal ‘tract in a subject, e.g.. promotion of gastric emptying fe.g.. clearance of stomach contents), reduction, of abdominal distention in the early postprandial period, improvement of anorexia, etc. In general, such i>rom--‘tioft can be ach ieved either directly or via increasing the secretion of a regulatory entity, teg., hormones, etc. lit still yet another embodiment, the method of the present invention, e.gf, modulating a chemosensory receptor and/or its ligand includes Increasing; one or more gastrointestinal functions of a subject., e.g.. to improve the quality of life or healthy state of a subject.

In still yet. another embodiment., the method of fhepresonf invention, eg,, modulating a ehemosensory receptor and/or its ligand includes modulating the activity of 11R (n,gt. Till, T1R2, of T1R3} expressing cells, e.g.. liver cells ie.g., hepatocytes, endothelial ceils, Knpffer ceils, Stellate cells, epithelial colls of bile duct, etc.}, heart cells (e.g*. endothelial, cardiac, and smooth .muscle cells, eteg, pancreatic cells (e.g., alpha cell, beta cell, delta cell, neurosecretory FP ceil, D.1 cell, etc.), cells in the nipple (e.g:gductal epithelial cells, etc:}, stomach cells (wg., mucous cells, parietal cells,: chief cells, cells, P/Dl cells), Intestinal ceils C&amp;g., enieroendoerinc cells, brush cells,e/e.), salivary gland ceils (wg.s Seromucotis celts, mucous cells, myoepit.he.Mai ceils, intercalated duet cell,:·striated·duct.·cell, <%·.}, I. ceils (e.g.. expressing GLIM, etc.}, enterochromaffin cells ie.q,, expressing serotonin), enteroehromafim-like cells, G cells ft.·,;.'., expressing gastrin), D ceils (delta ceils, e.expressing somatostatin), I ceils {e.g.. expressing cholescystokmin (CCK), K ceils {e.g , expressing gastric Inhibitory polypeptide), F/Dl cells (e,g.. expressing ghrelin), chief celis ief., expressing pepsin), and S ceils ie.g.. expressing secretin). In one example, the method of the present invention includes increasing the. expression level of T.l R in T1R expressing cells. In. another example, the method »>f the present invention includes increasing the secretion level of TI.R expressing cells.

In still vet another embodiment, the method of-be present invention, e.g., modulating a chcmosenNory receptor and or its ligand includes.-modulating 1'ne expression, secretion, and or functional level of HR expressing cells associated with hormone, peptide, enzyme producing, in one example, the method of the present invention includes modulating 'die level of glucose, e.g., inhibitors of a chemosensory receptor such as TIRd can be used to decrease glucose level Co.g., glucose absorption? in a subject. In another example, the method of the present invention includes modulating the level of ineteiins, e.g,, agonist of a ch.emosenso.ry receptor such as TIR2 can be used to increase glucagons-like pcotide I I GUM) and thus increase the production of insulin. In yet another example, the method of the -present invention includes modulating the expression, secretion, and/or activity level of hormones or peptides produced by TIE,expressing ceils or gastrointestinal hormone producing cells, e.g, ligandsfor 5ΒΓ tecepUns {*·..'„>. set otonin), incretms {e.g., CLP-1 and glucose-dependent ntsulinotropte polypeptide <01 P>>. gastrin., secretin, pepsin, cholecystokinin. amylase, ghrelin. leptin. somatostatin, a<e. In still, another example, the method of the present invention includes modulating the pathways associated with hormones, peptides, and/or enxymes secreted by TIE. expressing cells.

Exemplary chemosensory receptor ligand modifiers provided by the present invention and/or suitable to be used for methods of the present invention include· compounds of the following formulae.

In one embodiment of the present Invention:, the ebemosensory receptor ligand modifier is -a compound having a. structural Formula (I): iMnww&amp;v-R1 ΐ ] !

A d) or a tautomer, salt, solvate, and/or ester thereof, wherein; G forms a single bond with either D or ,E and a double bond with the other of D or E; RJ is hydrogen, allcyl, substitoted alkyl, aryl,.substituted aryl, arylalkyl, substituted arylalkyl:, acyl,. substituted acyl, heteroalkyl, substituted heteroalkyk heteroaryl, substituted heteroaryl, heteroarylafk.y!, substituted heteroaryialkyi, -CM, -NO?, -OR'', -S(0}aR\ -NR^RE -CONElO. -COdT/ -NRTCwR*, -NR'COINRV, -NRTSNR^R', -NR C{ :NH.)NRdl'\ -$0;NR'R4, -NR4SO;R -NR-SOgNR*!*', dROR'kORO, - ^CR-OR'KOR!) or-PiOKR hORR; R' is hydrogen, alkyl. substituted alkyl, aryl, substituted arvl. arylalkyi, substituted arykdkvi, acyl, substituted acyl, heteroalkyl substituted heteioaikyh hetero.nyl suhstiimed hctcroaryl, hctcroarylalkyl. substituted helcroarylalkyi, -CN, -NIK -OR'', ~S(0)sR", NR,'R'J -€0'NR6Rl -CO.dli •NR'C'OdN, ~:\RTONRrR\ -NRVSNR'RR~ΚΤΓΟ Ml y\ Rill SO;.NR/R:\ -NR-'Sk).vR'\ -NR"SO>NR:'Rl dR(ORKOR\ Ik0)(011 BiOR' }, or -·Ρ(0)(R;;)(OR6); 05 alternatively, Rf and R". together with the atoms ίο which they are bended, torn· an aryl, substituted is;vk heteroaryl, substituted bcteroarvl eye Sou Iky i. substituted cyeloalkyL ovelohetcroaikyi or substituted eycioheteo-uiU i fine wherein the ring is optionally Bused to another aryl substituted: aryl, heteroaryl, substituted, heteroaryl, cyeloalkyl substituted eydoaikyS, cyebheteroaifcyl or substituted eyeloheteroalky! ring,; with the proviso that R1 and R"; are-not.both'hydrogen;. A is hydrogen, alkyl, substituted alkyl, aryl, substituted ary!., arylalkyi. substituted arylalkyi, acyl, substituted acyl heteroalkyl, substituted, heteroalkyb heteroaryl substituted heteroaryl, heteroarylaskyl, substituted Ireteroarylalkyi. halo, -CN. -NO;·. -OR.', -S(0}.R -NRVORK;, -NHOR'\ -NKV'\ -InOR'I -CONRVI -CO;R'. -NR.VOdll -NkVONIK;R; l -HR%$KR:%U? --NR%(-NB)NR;<:'R!5. 8(0RV,}{0R"), ·ΡίΟχΟϊ-Ιi :}(C>RJ 1) or rtO)fRl‘'»iORn>, B ss -N- or -€(RS"V.

Ru is hydrogen, alkyl, substituted alkyl, aryl, substituted asyl, arylalkyi, substituted aryfelkyi, acyl, substituted acyl, heteroalkyl. subkdiuted heteroalkyl,.heteroaryl, substituted heter0atyl,.betepoaryla1.kyi, substituted heterearylalkyl -N.R.1'>Ei‘i! -CN>.-OR,1** »S{0}aR'b., -CQsR'5' or -CON R.5 ' R: ’: G is ~C~ or -S{0)r; provided that when G is -8(01--. then G forms a single bond with E; when the bond between D and G is a single Bond, than, 0 Is hydrogen, alkyl, substituted alky!, aryl, suhstituted myh arvlalkyl substituted arvlaikyL acyl, substituted acyl, halo, heteroalkyl, substituted hsteroaikyl, heteroaryl, substituted heteroaryl heteroarylaikyL substituted heferoaryiaikyl -OR.*5, -NB-QR55, -RiO},R: l -NEi5ESii ~NB~NBR?5, -ΟΙΝΕ55, or -CONRi:'Ru’; when G forms a double bond wilkD, then ID is ::0, :::S , :::N-OR*or M8-NH R!': n is Ο άhen G is -$iO>.r· and η is 1 when G is -C-; {; is -NR r:··. -N- <u -Oir'k provided duil F k -NR' - only w hen G forms a.·single bond with E; R!' is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalks I, acyl, substituted acyl, Iwteroaikyl, substituted hetcroalkyi, heteroaryL substituted hetcroaryl hetcroasybikyl. substituted hetcroarylalkyl or -CCbR'l R!' is hydrogen, alkyl, substituted alkyl, aryl substituted aryl arylalkyl, substituted an lalkyl, acyl substituted acyl heteroalkyl substituted heteroalkyl, hetcroaryl, substituted heteroaryl helerourylalkyl, substituted heteroarylaikyl -NRYRY -CM -OR "', SCQifR"'I •(Od<;0or -CONR^R 'l a, b, c, U, e and fare Independently 11 1 or 2: ansi

Rl R*. R'l Rl Rl Rl Rl Rw, R", R'l R;l R:l Rll R*\ lYl and R”j are independently hydrogen, alkvf, substituted alkyl aryl, substituted aryl, arylalkyl, substituted arylalkyl. aeyi, substituted aeyi, heteroalkyl substituted heteroalkyl, hetcroaryl, substituted heteroaryk heteroarylalkyl or substituted heteroarylaikyl; or alternatively, R' and R4S 'R* and Rl R6 am! Rl R? and Rl R.:> and RK', and Ru, Rr< and Rfl R1J and Rw, or R;Si and R l together with the atoms to which they are bonded, form a eye io heteroalkyl or substituted eycloheteroalkyl ring.

In one embodimentof formula (I), IT and Ri together with the atoms to which they are 'bonded., form an aryl, substituted aryl heteroaryl, substituted heteroaryl cycloalkyl, substituted eycioalkyl, cycloheteroalky! or substituted cYcfoheteroaikyl ringwhere the ring is optionally feed to another aryl substituted aryl hetcroaryl substituted heteroaryl eycioalkyl., substituted ,cyc!0.«alfeyl. eydaheteroaikyfor substituted cyoloheleroaikyl ring.

In one embodimentof Forntula CI}, the ehemosensory receptor ligand modifier is a compoundhaving a structural Formula ill),

wherein: Y forms a single bom! with.either W or Z and a double bond with the other of W or Z; Wis -C(Rr<)% -S-. -N-, -NCRViH.br-0-; Y is -0( ICO- or-N-; Z Is ~(.YR'rK -N-. or -Os R''4 is hydrogen, alky!s.'^ntetttuted'd:kyh.aiyis substituted aryl, atvlalkyl, substituted aryialkyl, acyl, substituted acyl, hetaroalkyi, substituted heteroalky k heierouryi, substituted hetcroaryk heleroarylalkyl or substituted hetcroaryialkyi -ON'. -NO·.. -OR ', -S(0)PR'\ -CONIOV4,-('(OR'S -S<'CNR :;,R NR'-'SO^ROB(OR'"'hOR!\ ·Ρ{Ο}((^0ν){ΟΚ::ί} .r P(Ο .)(R')(0 R ;>; Β.:Λί is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryialkyl, substituted aryialkyl, acyl, substitutedacyl hcteroalkyl, substituted hefcfoaihyl. hctervaryL substituted heurromy 1, hctcroarylalkyl or substituted het&amp;oaryhlkyl -CN, -NO>, -OR'', -NR;s:R.!k OOSR:iK \ -COdCk -OCOR b SCYNR^R's -NR^SOdi S - B(OR-;){OR Ί, -Pi0)(0R.n hOR'o- or -P(OMR'<5)(OR··): R'" is hydrogen. alky), suhsthuted alky), aryl, substituted ary), aryiaikyl. substituted aryialkyl. acvL substituted acyl, boteroalky), substituted heteroulkyl. hetcroaryi, substitute^! hereroary), he ten.· aryl alky I or substituted hcterourylalky! -CN. -NO;. -OR.' .. -S(0),R!!, -NR"R'\ -€ONR"R/;\ -COR'·. -CO>R". -OCOR'', -$0>NR--R-4. -NR^SOdk \ -B(OR-'KOR:*|. -PCOikOR'OCOR’·4) or -FiO)(R:?)(OR34); or alternatively R34 and R36 or R3S and R37 together with the atoms to which they are hooded form a eyeloalkyl, substituted eyeloalkyl, eyelobeieroalkyl or substituted eyciohcteroolkx 1 ring: g, h and i are independently 0 or 1; and Ri4 are independently hydrogen, alkyl, substituted. alkyl, aryl, substituted aryl, aryialkyl, substituted aryialkyl, acyl, substituted acyl, heteroa&amp;yl, substituted hetex>a|kyl feeteroaryi, substitutes! heteroaryi. heteroarylalkyi or substituted, heieroaryadkyl; and R“n Rj'!, Rd1, R·'·. R.'·', and R3i are independently hydrogen, alkyl, substituted alkyl., aryl, substituted aryl, aryialkyl, substituted aryialkyl, acyl, substituted acyl, heteroalkyl. substituted heteroalkyl, heteroaryh substituted heteroaryi. heteroaryiaikyl or substituted heteroarylalkyl; or alternatively R"4 and RJ'4, RjS and RJ“, or R33 and R4' together with the atoms to which, they are bonded IPrra a eyeioheteroalhyl or substituted eyeloheieroalkyl ring: and with die following provisos: (;0 Allen. WIs -O- or -S- or -NRiv, then 2. is ~C(R:') or -Nk and (Id ohen.Z is -0- 00-8- or -NR"s,iheu W is -C(R‘;i}or -N-.

In one embodiment of Fonnula (Π), (D)»-G is

In oik embodiment of Foi mu!a (11), the compound. of the present invention has structural formula (lla):

with the following provisos: (a) when W is -0- or -S~ or ~NR/"\ then 2 is ) or ~N~; (b) when Z is -0- or -S- or -NRfy then W is -GCRY) or -My and (e) when B is -N~, men A is not halo.

In one embodiment of Formula (1¾ the compound of the present invention has structural formula (1 lbs:

wherein, W is -GCR22}- or ~N~; Y Is -C(R^}~ or -N-; and Z isor -0-.-

In one embodiment of Formula {I.Ib),,:W is -C<R24)-, and Y is -C(R2o)-,

In one embodiment of Formula (Mb), W is -QR**)-; Y is -CtR''>; R'“ is hydrogen, .alkyl, substituted alkyl, acyl, substituted aeyl, hcteroalkyh substituted hetcroalkyl·, ~CN, -N0&amp; -0R2%.-SiOJgR28, -OCOR^ ~NR:%?0, -€ONR2%2e ot -CO^R^; and R^ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, -hcteroalkyh substituted heieroalkyl, ~CN, -NO* -0R:n, -OCQiGb -SfO)i.Rn' -NR3*R", -CONR2 \R:?for -COcRn, i.u.a preferred embodiment, R*1, is hydrogen, -GIG. alkyl or substituted alkyl; and R:26 is hydrogen, -Cfo, alkyl or substituted alkyl

In one embodiment of Fonnula (Ilh), W is and Y is -C(R":f>)-; A is hydrogen,· alkyl, substituted alkyl aryl, substituted aryl, -CN, -NO;?, -8(0)..111 -NR1?RU), -CONR/R’l -CO.'R' or N!<i; R' is hydrogen, alkyl, substituted alkyl, arylalkyl. or substituted arylalkyl. R"4 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, hoieroalkyl, substituted hcteroalkyl -CN, -NfO». -SlOyR'9, -OCOR'i!, -NR^R.* -CONlC'dV0 or ~CO.:R'v; and R'“ a- hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, hcteroalky I, substituted heteroalkyl -CM, -J\CA, -OR!i ~S<O>sR:5\ -CXiOR^-KrWl *CDNRiVor

In one embodiment of Formula (1 lb). W Is -C(R"4}·; and Y is -C{R^'}·; Λ is -NR9COR10, -NHOR-, -NR:V -NOR \ -( XNR:>R K;, -CO>R\ -NR CO.-R, -OR", -NR'\'(>NRi:tRu, -NR^CnNR^R5* nr -NR\V:NFf)NRi;Rn; Rr is hydrogen, alkyl, substituted; alkyl, arylaikyL or substituted arylalkyl; R‘4 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, hcteroalky I, substituted heteroalkyl, -ON. -NO.;. -OR'-StORRl -DOOR."**, -NR‘VR'‘', -CONR 'R'' or -COyR'4; arid R*"' is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted hcteroalky I, -CN. -NO;·. -OR'1. -S(0)hR -OCOR'1 -NR:iR;'. -CONR^R- 'or -COdCl In a preferred embodiment, A is -OH. -NH;;: -NH(ill:, •NtCHd,. -NHOCHϊ, -NOCI-b. -NH('(0K:H;. -NlK'iOKX'lb. ~NHC{0)NiN. -NHC(S}NH-=. -NHC{NH}NH.. -CN, -OR OH. -ΟΙΗΝΗ;,. -CH >NHCH*. -CH?N(CH.:}j, -COd l. -CONIC, -CONHCiC or-GHyNK(;(0}CH;T; Ri7 is hydrogen, methyl, ethyl, props!. sro-propyl tr-butyf, «•o-b\ityls:^>bui>d,:^bdtyl.pfecttyl or benzyl; and RK is hydrogen, -CX, methyl ethyl, propyl, hro-propyl &amp;-b«tyt,·s<?i>b«tyl or /-butyl; and R^1 is hydrogen, -CIO, methyl, ethyl, propyl, Co-propyl, .u-hutyl, &amp;o~butyl soe-hutyl or i-buiyt In a: more preferred embodiment, A. is -NH;, R* ' Is hydrogen or methyl R** is hydrogen, -CIO, methyl or ethyl, and WJ> is hydrogen, -CFs, methyl or e thyl

In some embodiments of Formula 0.1b}, E~s is hydrogen, alkyl or arylalkyl.

In some embodiments of Formula (lib·,. R‘x is hydrogen, methyl or benzyl hi some specific embodiments of Formula (11b), the compounds have structural formula selected from the group consisting of:

or a tautomer, salt, solvate, and o? ester thereof. In some preferred embodiments, the salt of these.campotauls is hydrochloride or triiluoroacetate salt.

In one embodiment of Formula tlla), the compound of the present invention has structural Formula f He):

wherein, W is --S·, -NiiY'V, or -0-: Y is --OUYO·· or -N-; and Z is --QR" )· or -N-. In a preiened embodiment, Y i,s -C(R ! }-, and Z is -C{R':

In one embodiment of Formula (Has, W is -S~, -NCR*3)-» or -0-; Y fe-C(R^).- or -N-; Z is -€(R2')~ or -N-; K5'' is hydrogen, alkvl. substituted alkyl», aoyt, -substituted acyl, hetcroalkyl, substituted hoteroalkyl, -ON, -NO* -OR'e -$(0)JtM, -OCOR33, -NR:%K, •-CONR‘vRH or "CO-;R·'·': and R* is hydrogen, alkyl, substituted alkyl acyl, substituted acyl, heteroafkyl, substituted hetcroalkyl, -ON, -NQ2, -OR3*' -SiORR5*' -QCOR3’' -NR^R'1', »OONR:MRa or -CChR's

In one embodiment of Fornmk (ΙΟΥ W Is -N(R~:>, or -0-: Y Is -Ct ΗΛ>· or -N-: 2>.fe. -C(R2> or -N-; R26 and R2i together with the atom to whiehihey are bonded form a cyetoaikyl, substituted cycloslkyi, cyeloheteroalkyl or substituted cvdoheteroaikyl ring.

In one embodiment of Formula (Ila). \V is -S-, “fsiR '’V. or-0-: Y t\ -0(Ror -N-; Z is -C(R5'}- or-N~; A is hydrogen, alkyl, substituted alkyl, aryl, substituted ary!,, -NRv'CORK', -NHOR9 -NOR", -OR5, -NR^CONR^R’h -NRvCSNR,ftRu or ~N R Y Y:: N r i j N R;' !R5 5, -CN, -NOy, -$iO},R:', -?sR9Rii:. -Ci0;NR5R9l, -CO;R* or ~NR5CQ2Rii!:; a?td RSi is hydrogen, alkyl, substituted alkyl, aryklkyl, or substituted atyMkyl. in one embodiment of Formula. (Hay, W is ~N(R^K or -0-: Y Is -CCR"9)- or -N-; 7, is -€(R"}~ or -N-; A ts;hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, ~NR9€OKi!\ ~NHOR'\ -NOR’5, -OR9, -NR'tONR K’R u. -NR9CSNR,aRu or -NE'V'i:::NHiNR!"R55. -CN. -MO;, -$(0},Ri ~NR9Ri!\ -NR‘'QO}Ri0, -OCnXRK^ ~CO;;R9 or -NRXX'i.-R*"; R’ t.\ hydrogen. alkyl, .substituted alkyl, arylalkyi, or substituted arylalks-1; R" is hydrogen,..alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyi* substituted heteroaikyl, -CN. -NIK -OR-y -SK))iRK -OCOR'I -NR--R·4, -C(OiNR!iRi; or -CO.;R\ and R;<:i is hydrogen, alkyl, .substituted alkyl, acyl, substituted acyl, heteroalkyl substituted heteroalkyl. CN. -NO;. -OR'5, -S(0}::R· k -00(0 }RV\ -NR^R"', -C(0}NR· ;R-:cr -COdCk or alternatively R'6 and R' together with the atornts) to which they arc bonded form a eycloalkyl substituted cycloalkyl, eyclohetcroaJkvl or substituted cycloheteroalkyl ring. In a more preferred embodiment. A Is -NH.s Rf: is hydrogens, methyl, ethyl propyl, ho-propyl, «-butyl /.vo-hutyl, λ-λ··butyl, /-butyl phenyl or benzyl R *' and R " arc independently hydrogen, ahkanyl. substituted alkanyl ulkoxy, carboxylic acid, carboxylic acid amide, or carboxylic acid ester; or alternatively, R"': and R*' together with tire atomts) to which they are bonded form a cycloalkyl, substituted cycloalkyl. cyclobetcrualkyl or substituted eycioheteroaikyl ring.

In some specific embodiments of Formula Ola), the compounds have structural formula selected, from the group consisting oft

©r a tautomer, salt, solvate, ami/orester thereof I© some,preferred ernbodi meats*. the salt of these compounds is hydroeMotide or trill uoroaectaie salt;. 1« one embodiment of Formula (II). -ho compound of the present invention has structural Formula (lie):

wherein, G forms a single bond with E and a double bond with I); B is -N-; E is -NR'D is ::: S , :::N-OR: \ or ===N-NHRi?; W is -S-, -N· Rv:!~ or-Os Y is -C(R -f,)s end Z is -0( R‘V.

In one euibodinieut dfFormula ¢11), the compound of the present invention hah: structural Formula. (Hf): wherein, G forms a doable bond with E and a single bond with D: B is -Ns E. is -N-,

Dis -OR’·’, -NIi-OR'5, ~NH-NHR!s -SlOpR^. or -NRj:iRj^ W is -is·. -N(R· ')- or -©e Yds -C{R · ’)-, and Z is -Ci.R·' 1-.

In one embodiment of Formula (He) or (Hf), A is hydrogen, alkyl, substituted alkyl aryl, substituted aryl, -OR\ -SR", -OR -NR.'R.5”, -CONRvRu\ -CQ..R” -NR'XXhR1'*. -NR'CONRK>Ru, -NR9CSNRh;RiS or -NR’V:{-NH»NR{!!Rn. More preterabiy, Rr is hsdrogen, alkyl, substituted alkyl aryfalkyl or substituted arykdlcyk R" and R:' are independently hydrogen, alkatryi, substituted, alkanyl afkoxy; or alternatively, R* and R^' together with the: aiom(s) to which they are bonded form a cycloalkyi, substituted oyclOatkyl, cyeloheteroaikyl or substituted eyeloheteroaikyl ring.

In some specific embodintents of Formula (He} or (Ilf), the compound of the present invention has Structural formula selected from. the group consisting of

ora tautomer, salt, solvate, and/or ester thereof. In some preferred embodiments, the salt of these compounds is hydrochloride or triilooroacetate salt

In a embodiment of formula (11), the eomponnci of the present invention has structural' Formula f, I id); diii) with the following provisos: (a) when. W Is -0- or -S- or then 2 is --CfE"’) or -N-; anti (h| when Z is -0- or-S- or -HR"®, then W Is -0(100 or -N-.

In a embodiment of Formula (ltd), W is -S-, NR"'1, -G-; Y is -CFO6-: Z is -C(R")~; and W an d ¥ forms a single bond and Y and Z. forms a double bond.

In a gmhpdimefti.OfFprn»ik:(H(iJt,,:W is -ΟΠΥ'>: Y is -Cfo®-; Z is -S-, -HR;®-, -O-; and W and Y forms a double bend and Y and Z forms a single bond;

In a embodiment of Formula (lid), W is -S-. MR') -0-: Y is -N~; Z is -(/fR"')-: and W an d Y forms a single bond and Y and Z forms a double bond.

In a embodiment of Formula Hid}, W is - Nlfo) Y is -M-; and Z is -C(R'and Y forms a single bond with each: of W and. a double bond wife Z.

In some enfoodlmerds of Formula (lid), A is hydrogen, alkyl, substituted, alkyl, aryl substituted aryl, -OR9, -SR5) -€H, -HR^R®, -COHR^R * ·, -CO>Ry, -NRYiO^R®, -NR"CONRi0Rn,-NRyCSNRK5Rn or -NR9C'C:::HH)NRi?)R!!, Preferably, R,T is hydrogen. Adore preferably. R"° and R" arc independently hydrogen. alkanyl, substituted alkanyl, alkoxy, carboxylic acid, carboxylic acid osier; or alternatively, R:' and R'" together with the atonUs) to which they are bonded tone a cycloalky I os substituted eycloalks: ring.

In some specific ernbodi incuts· of Formula (lid), the compound of the present invention bos .structural formula selected from the group consisting of;

or a tautomer, salt, solvate, and/or ester thereof. In. some preferred embodiments, fee salt of these/compounds is hydrochloride salt or inflooroaeetate salt.

In one embodimeniof Formula fit, the chemoscnsory receptor ligand modifier is a compound Inning a structural Formula (illy

wherein:

R'·' is hydrogen, ajfcyl,aryl, substituted aryl, arylalkvi. mtbshrated arylalfcyi acyl, substituted acyl, hake heteroalkyl, substituted heteroaikyl, heteroaryl, substituted· heteroaryl bctcroary (alkyl or substituted heieroarylalkyl, -CM -NO?, -OR'"', -SCOijR'l. -NR’V'R40, -€O'NR44R4'\ 'CO.rR;y, -SO»NR*R*\ -NR wSO>R * -B(OR44)(OR40), -PiO){C)R'9}(ORi0i or -Pf OH R/?*>(Ori;>; R1, is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryiaikyl substituted atylalkyl acyl substituted acyl halo, heteroalkyl .substituted hetemalkyl, feeteroaryt, substituted heteroaiyLheteroarylalkyi or substituted hcteroaryhlkyl -ON, -NO·.., -S(OhR4:·. NR'aR'!\ ··< ONR ::R-00,R';\ -OCOR45, -SOfNR^R^, ..NR4!SO,R4'\ -Bi0R'!i(0R40, •RiOliORhOR4'} or -00 HlOllOR'd; R' hydrogen, alkyl, substituted alkyl aryl substituted aryl arytalkyl substituted atylalkyl, acyl, substituted acyl, kale, heteroalkyl substituted heieroalkyi, heteroaryl, substituted heteroaryl heteroarylalkyl or substituted heteroarylalkyl ,-CK -Nf0.u -OR4', -SiO);R’'\ -NR4;R44, -CONR4!R44, -CO^R*·, -OCORi:, -SO^R-R44, .NR^O^” -B^R^MOR”). -FtGMOR4' KOR11) or -PiOKR^XOR'”); or alternatively R36 and R37. taken togertber with the atom to which they are bonded, form a cyeloaikyl. substituted, cyclo^lkyi, cyeloheteroalky'l, or subst? ru te d cy c I o h e te ro a Iky I ring;

Rs is hydrogen,, alkyl, substituted'alkyl, aryl, substituted aryl, aryiaikyl, substituted aryiaikyl acyl substituted acyl, halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, hoteroarylalkyi or substituted heteroaryl alkyl -CN, -NO?, -OR4'', -SCON-ji^l -NR^R*', -CONR4 :Rki, -COR4', -CO.;R4R -OCOR*. -SOjNR‘,?R4\ -NR^CNR* -B{OR4i)(OR4\ -R(0)(0R 44}(OR4S or -P(0}( R4 biOR44}; j. k. 1 aud m are independently Cl, I; or 2; and R \ R*’. R>:. R4". R4iy;R*\ R4",«id R’*6':ate Independently hydrogen:, alkyl, substituted’ alkyl, aryl, substituted aryl, aryiaikyl, substituted aryiaikyl acyl, substituted acyl, heteroalkyl substituted heteroalkyl heteroaryl substituted heteroaryl, heteroarylalkyl or substituted heteroarsialkyl or alternatively R"*and Ri!i, R*! aud R*l R‘:o and R+<. or R4' and R‘° together with the atoms to which: they are bonded, form· isyeycloheteroalkyl ..orsubstituted cyclobeteroalkyi ring; with the proviso that at most:, two of H, 1,1 and K are -N-. By "'at most two of Η. I, I and K nrC'-Nrsl it is meant that there are zero nitrogen: atom:, one nitrogen atom, or two uitrogn. atoms among B,!, 1 and K. hi one embodiment of Formula (ill}, 02).,-(1 is

In one embodiment of Formula (III), the compound of the present invention has structural Formula .(.1.11a);

in one embodiment of Formula t Ilia), A is hydrogen, alkyl, substituted alkyl, ary!, substituted aryl, urylalkH. substituted aryfaNyk aevi. substituted acyl, hetcroaiky), .substituted hetcroaiky k hetcroaryi, substituted heferoaryl. hete/oarylalkvl, substituted heicroaryialkyl. *CN, -OR’. -NO, SiQhK*. -N110RC -NlCCOR’C -NR^R'C -CONR9R;!\ -CO;Rv. -NRYOyR1* -NR^CONR^’rA -NR\’SNRi;R;5. or -NR';Op==NH >NR!':R;!. Preferably. λ is -OH. -Nil·. -NHCR*, -N{CH,)., -NHOCTR. -NOC1L, .NHC(0)CHk -NHC(0)0CH.. -NRC(0}NB3, -NHCIStN'Il·, -NHCiNHlNH ·. -CM. -CH>OH, -OH>NH.., -ClhNHOIR, -0Ι;Ν(0!.>», C03B. CONΗ;, -CONHCFR or -CH^NHCiO)CH =.

In one embodiment of Formula (Ilia), R] / is hydrogen, alkyl, substituted alkyl, aryialkyi, or substituted uryialkyl. Prc tenthly, R," Is hydrogen, methyl, ethyl, propyl, /.vopropyi «-butyl, Ao-huiyk «ue-butyl /-butyl, phenyl or benzyl, .In otic embodiment of Formula (Ilia), H is ~C(R',5>}~; 1 Is -C(R'·6); I Is -€(R''and

K is -C(R'SK

In one embodiment of Formula (111a), A is hychogep, alkyl, substituted alkyl, aryl, substituted aryl -ON. -OR9, -NO;?, -SfOyi*. -NHOR9, -NR^COR59, -NRffRitt, -GONRV'V -CO’R *’ or “NR9€X>?RU!; and R1' is: hydrogen, alky!, substituted alkyl, aryialkyi, or substituted aryialkyi

In one embodiment of Formula (Ilia), A is -OH, -NHa, -NHCH;?, -:N(CH ?)/, -NHOCFR, -NOCH ·, -NHCCOjCH?, ·ΝΗΟ(0)ΟΟΗ·. -NHGOsNH.?, -NHC(S)NH2|, -NHCYNHfNFl·, -CN. -CFFOFL -CH.;NH.?. -('H.-NHCIF, -CH NiC'Hds ·0();;Η,-CONIR, -CONHCH·? or -OH;?NFICiO)CFIg and R‘ is hydrogen, methyl, ethyl, propyl, Ae-prepyl, a-butyl, Ao-butyl, m>-butyi, ί-butyl, phenyl or benzyl.

In ovte embodiment ot'Fonuula. HHa), R '" is hydrogen. alkyl, stibstiiutcd alkyl, halo, hctetoaikyL substituted heteroalky!, -CN, -NO.;, -ORv\ Ο{()),10\ -ΟΟΟΙΓ! -NR*5COR'\ -CONKER45, -CO#®, NR^R40, -SO^NR^R4* or-NR^SOsR^; Rk; k hydrogen, alkyl substituted alkyl halo, heteroalkyl, substituted heteroalkyi, -ON, «HI»,;, -OR"! ~S(0)>R4! -OCOR4! NR'UR4\ -NR4iCOR4N -CONR^R’i -0€ΜΓ! -SO.NR^R” oi-NR45SOdOy R:: t.s hydrogen, alkyl, sobNituted alkyl, halo, heteroalkyl, substituted heterouikyh -ON, -NO·.., -OR4 , -SiO.S.R'y -OCOR'! ΜΓΊ01 -NR4'COR'! -OONR'i :R", -COdC! -SO/NR'-R44. or “NR’SO.dV’, or alternatively R v and R·'! together with the atoms to which -.hey are bonded, harm a cycloheteroalkvl or substituted eyclohcteroalkyi ring, and R's is hydrogen, alkyl, substituted alkyl, halo, heferoaihyl substituted heteroalkyi, -ON, -NO.;. -OR" , -810),114 , -oroRs! nic fry -nr45cor!! -conr’^r*6, -eo.dc , .-sq-;Nr4Jr* -nr^sOjR·*. u r preferable that R'N is hydrogen, alknnyl, substituted aikunyU alkenyl substituted alkenyl, eye loaikany;, substituted eycloalkanyl. eyeloaikenyi. substituted oydcoalkenyl, Stale. he tma.tk.yl, substi tided heteroalkyi,, ~CN, -N0>, -OR45, ~SCO)|R45, -OCOR45, HR^R46,. -NR'O'Ok^ ~CONR45R45, -CO^R4! ~$0>NR45R4! -NR4 ;$0.d<4! It is ate.preferable that A is -NHa, Ri:' is hydrogen, methyl, eihvLbr bcftsyU and Rf"! It*0, RVi and RjS are irOepeodeRtly hydrogen, fluorcs, chloro, bromo, methyl. trifltuOffiethylleiltyl, isopropyl, cyclop-ropy!, propenyl, methy Ipropeayi, buienyl, methylbutenyI, substituted propexvyl, substituted methylpropeayl, substituted buienyl, substituted methylbuteuyl, -NH-alkanyb -NH-{substituted alkunyi), -OH, -OCHi, -O-eyeloalkanyi -O-benzyi, -CO^.H,

In some specific emhodimeuts of Formula (fila), the coimpotmd hgs sttucturitl formula selected fem the group eonsistiug of

or a tautomer, salt, soiy&amp;te, and/or ester theme-f. In some preferredembodiments, the salt of these eoiBpounds is^j^ehiqride^oftriiluoroacetiue salt.

In one embodiment of Formula (Ilia), the compound of the pmseuHnyeniiQn has Structural Formula {JJhU:

wherein, A Is hydrogen, alkyl, .substituted alkyl, aryl, substituted aryl., nrylaikyl, substituted aryialkyi. acyl, substituted acyl, hetcroalkyl, substituted hetcroalkyl. hctcroaryl, substituted hctcroaryl, heteroarylalkyl, substituted bcicrouryialkyi. -CN, -OR’'. -NO;. -SlOh-R* -NOR°. -NHORy -NR’'COR!-'!. -NR',R,i'i -CONR'fRK\ -CO:E’; or -KRTObr': R' is hydrogen, alkyl substituted alkyl, aryluil.yl or substituted aryialkyi;

Xf is -01:-, -Ο-, -NR.'-. -S-, -~SiO>-, or-StOp-: X* is- alkylene, substituted alkyfcnc. hctcroalkyicne, or substituted hetexo^lkyiene; hi is 0 or 1; Y{ is cycloheteroalkyi substituted cyebhetefoaikyL or

X' and X" are independently a covalent bond, or -NR'-; X4 is 0, NRl N-ORl or S: R' is halo·, -NO.·;, -ON, -OH. -NH\ alkyl substituted alkyl aryl, substituted aryl aryialkyi. substituted aryialkyi, hereroalkyl. substituted hereto,*iky!, bcteroaryi. substituted heteroaryi, hetero aryialkyi or au bsf i rated h cteroary I all y i; n is 0.. 1., 2, or 3; R'v is hydrogen, alkyl, substituted alkyl aryl substituted aryl aryialkyi. substituted aryialkyi. .heteroalkyl substituted hcteroalkyl, heteroaryi substituted beteroaryl. heturoaryklkyi or substituted beieroarylalkyl -NRl’lsy'"*; and eaeh Ry and E5'* is independently hydrogen, alkyl substituted alkyl aryl, substituted aryl aryialkyi substituted: aryialkyi, heteroalkyi,.substltuted beteroalkyl heteroaryl substituted heteroaryi heteroaryklkyl or substituted heteroaryiaikyl; with the proviso that when X is -0- or -5-. and rn is zero; then X' is not -0-,

In one embodlmeu· ,.>fFormula tiilai). X1 is ~CHr; and Y* is

In one embodiment olFormuiu {lllal), X' is -0-, -NR'5-, or-S-tro Is 0 or l, and Y! is eydoheterotdkyj or substituted cvcIobeterdaikyL

In one embodiment of Formula; (Hkd)v.X! : is --()-, - -NR'--, or --S-; m is I, and Y!

In sonic embodiments of Formula (Illal), X' methylene, ethylene, propylene, ditncihylcthylcnc, methyicyciopropylene, or eyel0propylmai:h.>lene.

In some embodiments of Formula (II hi 1), Λ is hydrogen, alkyl,. Substituted .alkyl, -CN, -OR*. -NO?, ~S(0),R9, -NOR9, -NHOR9, ~N.R9C0RK}? ~NR9R*9 -C0NR9Rift, -CO#9 or -NRY'0:Rhi. 1« some embodiments of formula (Illal}, Rs is hydrogen, alkyl, s«fesiita.ted alkyl

In some embodiments of Formula (illal), Ύ’ is eyelokeieroalkyi or substituted eycloheteroalkyi. It is preferable thatT1 is piperidinyl*substitutedpiperldinyi, i©tfahydrofum»yk substituted tcfrahydroftiranyl ietrahydmpyranyi, substituted tctmhydropyranyl, dihydrofuranyl substituted dih\ dudumuyh pyrrohdim), ‘u-hstituied pyrrolidinyI, oxetanvl, or.substituted oxctanyl. ii is aha; prcfomble dan hie substituted eycloheteroalkyi comprises sine or more substituent sdccrcJ Rom the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylaikyk substituted aryialkyi, acyl, substituted, acyl, hetereuikyk substituted beteroalkyl, hetero-aryl, substituted heteroaryk heteroaryialkyl, substituted heteroarylalkyk.-CN, -OR9. -NO;. -SIOkRi -NOR9,-NHOR9. -NR‘'(ORs‘5, ~NRV, -C^NR9RKV-C0Maud.:«NR'’C'02RMl

In some embodiments of Formula ( IIIsa 1), X4 is O.

In some embodiments· of Formula t Wail -X -0(\4)-Χ - ts ~€(0K -C(0)-NH-, -NI1-00)-,.-NH-CtOVNH-, -0(0)-0-, -0-0(0)-, -0-0(0)-0-, -HB-C{0)-0~, -0-€(0)~NH~, -C(HH)-, -0(ΝΗ)-ΝΒ-, -NH-C(NH)-, -NH-C'(NH)~HH~, ~0(Ν)ί}~0-, -O-C(NH)-, -0-0(^)1)-0-, -NE~C(N)I)~0-, -0~0(NB)-NH-,; -C(N-OII)~, or -C(S)~.

In some embodiments of Formula Cilia!), A is hydrogen, alkyl, substituted alkyl, or-NROO') Rr is h ydrogeu' and Y5 is piperidinyl, substituted pioendmyi, tetrahydtOfuram.1, subsiritured rotrahydrofurany!. tetmhydmpyranyl subsithufeJ tetrahydropyranyl, dihydroturariyi. substituted dihydrofuranyl pyrrolidinyl, substituted pyrrolklinyl oxetanyi, or substituted oxctanyl.

In some embodiments of Formula (Ilia! ), A. is hydrogen:, alky l, substituted alkyl, or :E:i? Is hydrogen; Y! is -X3-€(X4)-:XO; and -X3-C(X3>X5- Is ~C(Q)~, -C(0)-M:1- , -NH-OOk -Xtt-C(0)-NB~, -0(0)-0-, -0-0(0}-, -0-C{0VCK -NM-C(Q:)-0-, -O-C{0)-MFl~, - CCNI-Ικ -CtNHi-NIK -NH-CTNHK -NH-i i'NIis-NH-. -C(NH><K -0-C(NI-lK -O-CiNil·ίμκ ~ Ni t*C(NH ϊ-Ο-, -QN-OHK or -OS}-.

In some specific embodiments oi formula {HIM), the compoimd lias structural ionimla selected from the group consisting of

or a tautomer, salt, solvate. and or ester thereof' In some preferable .embodiments, tire salt of these compounds is hydrochloride or trifiuoroaeetaie salt

In one embodiment of Formula (III), the compound of the present invention has structural Formula (illbk

In one embodiment of Formula (llib), A Is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, -CN, -NO', -OR*, -S{(»,-R!\ -NR9COR,B. -NFIOR9, -NR9R l'°, -NOR*, ••CONR'dlY -CO-R\ - NR°CO.rRs'\ -NR°CONR!°R‘'. -NR*C$NRlwRn, 0* -N R'fC(::: N H)NR.i<>R5 5.

In one embodiment of Formula ¢1111)), R1' is hydrogen, alkyl, or substituted alkyl.

In one embodiment of Form ula (Illb), A is hydro gen, alky I, substituted alkyl, aryl, substituted aryl, -ORA ~$R\ -€;N, -NR^R Y -CONKER v\ -CO?R* -NtfCCARY -NR-'CONR^R**, -NRYSARKiR!i or ~NRY(^Fi}NR!0E{5; and lY' Is hydrogen, alkyl, or substituted alkyl.

In one embodiment of Formula flllb), Ή is -C{R'‘N)“ or -H-; .1 is ·»ϋ(&amp;'Υκ:·Ι is -CCr7}-; and K is -CCR'Y or ~N··.

In one embodiment of Formula flllb), H is «C(R''>; 1 is -C(R·*)-; J is 'C(Rii}-: and K is -C(R;Y.

In one embodiment of Formula (Illb), RSi is hydrogen, alkyl, substituted alkyL aryi, substituted aryl arylalkyh substituted aryialkyl, acyl, .substituted acyl, halo, beteroulkyl. substituted hcieroalkyl hcteroaryl substituted heieroaryl, imtcroaryialkyl or substituted hetcroaiylaikyl -CM -NO.s -OR’0, -SiOjjR", -GCOR'k -NR !9RW, -CONR’^R41', -COM -SOjNR'^R*^ -Nlh^SOdk4'4; RM> is. hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryblkyl, substituted arylalkyi, acyl substituted acyl halo, hc*eroalkyl, substituted hetcroalkyl, hctcroaryl, substituted hetcnuuyl hctercaryhlky! or substituted hetcroaryblkyl, -CM -NO·., -OR*5. -SiC >;·;.!<45, -OCOR4l -NR'aIC\ ~CONR4;R4l -OCMC1, -SO.NR^R4 '. -NR MOuM: R'~ is hydrogen, alkyl substituted alkyl aryl substituted arsl aryialkyl substituted aryl alky l acyl substituted acyl, halo, heieroaikyk substituted heteroalky], heieroaryl. substiuaed hctcroaryl heteroarylalkyl or substituted heierourykbkyi .-CM -V > . -ORM -StOlIM, ~Oi OR !\ -NR4'R44, CONIC’fC4, -COiR4·, -SCENICIC'l -NR^SiMR : R's * u>drogen. alkyl substituted alkyl, aryl, substituted aryl aryldkyk substituted aryblkyl, acyl substituted acyl halo, heteroalkyl substituted heteroalky!, hdciourvl, substituted hcteroaryl, heteroarslulkyl or substituted hereroarylalkyl, -CM -Nik. -OR'* \ -${G}n!R<J. -OCOR*\ -NR4· R;i -CONR4' R4*, -COR45, -CG.R4;\ -bO-NRMCl -NR45SO;R46

In one embodiment of Formula sjUh), A Is -MFb, K:' is hydrogen, methyl, ethyl or benzyl: «and R\ R;'.. R'’ and R'' are iindependently hydrogen, flttoro, eldoro, brom% -CM alkaayl substituted alkanyl alkenyl, substitued alkenyl alkyayi, substituted. alkynyl, cyeioalkaoyl substituted oycloulkanyl, eydoaikeny 1, subshtued eyeloalienyl beteroaikanyi, substituted heteroalkaoyt, cydoheteroalkyl, substlniredleyelohcteroalkyl -Q-alkanyi, -0-(substituted alkenyl). -O-aikenyi, -0-<substhuied alkenyl), -NH-alkanyl, -HFHsehstltuied alkanyl), -NH-alkenyl, -NH “(substituted alkenyl), -S~a|kany!, -S~(s«bstSoied alkanyl), alkenyl or ~S-(s»bsittuted alkenyl).

In some sfsecihe embodiments of Formula (ITib), the ’compound has structural fofntula selected from the group consisting of:

or a tautomer, salt, solvate, and/or ester thereof. In some preferred orabodimeets, the salt of these compounds is hydrochloride or tritlooroacetaie salt, hi one cmbodhnem of Formula (lllb). die compound of die present indention has structural Formula (I lib I):

whereiti, A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arvlaikvl. substituted •ayyW'kyij'^cy!,. substituted aeyl, heieroalkyL substituted hetero&amp;Ikyi, heteroarvL svfesiitufeil hetsroaryi, hotcroarylalkyl, substituted heteroaryialkyl, -CM, ~OR‘', -NO>. -Sk >},R -NR'CQRiC5, -INRV'. XONR-’R99 ~0>R° or -NR'XXFR10; R!; is hydrogen, alkyl,.substituted alkyl, arylalkyl, or substituted arylalkyl;

Xs is (ΓΗ;···, -Ο-, -NR9-, or X": is alkyleoe, substituted alkylene, hetcroalkylene, or substituted heteroalky I ene; rn is 0 or 1; Y! is heterosryl, substituted heteroaryl, cyeloheteroalkyl, substituted cyciohetcroalkvL, or

X ’ and X5 are independently a covalent bond, -O™ or-NR9-;

Xs k 0, NR9 H--OR9, or S: E* is halo, -NCk, X1N,-Old, -ΝΐΗχ, alkyl, substituted alkyl, aryl, substituted: aryl, arylalkyl, substituted arylalkyl beteroalkyl, substituted heteroalkyS, heteroaryl, substituted 'heteroarvl, bcterourylalkyi or substituted heteroaryialkyl;. n is 0. L 2, or d; R" is hydrogen, alkyl, substituted alkyl, aryl, substituted a/yk arykdkyi, substituted arylalkyi. heicroalkyl, substituted heteto&amp;ISfeyl, betexoaryl, substituted hetetoaryk. heicmatylalkyl dr substituted heterouryialkyi, >NRVR>'>; and each ,κ ' and Rk’ is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aiylalkyl, substituted arylalkyi, heicroalkyb substituted heteroalkyl, heteroaryl. substituted hetefoaty i, heieroaryiaikyl or substituted hcteroarylalkyi; v-ifh the pun-iso that u hers X1 is -O- or S , and m is zero; then X is not -O . lu one eutbodiment of Formula (IDM), X' is ~€%p; and Y'! is

In one embodi men! of Formula (11 lb I y X5 is ~0~, -KR5"”» or m is 0 or I, and

Yl is eyololieteroalkyi or substituted eyeiohoicroalkyl.

In one erobediment of Formula i 11 lb 1 ) \ a -Q~, -MR1'-» or m is 1, and YJ

In some embodiments of Formula 111 li>l), X" is alkanyleoe, substituted alhanytene, heteroal'kaiiylene,: substituted beieroalkanyiene, alkenyleue, NuKrirated alkenylene, hetemaikenyieoe, or substituted heieroaikenyiene.

In some embodiments' of bonnirfa (IlihlX X2 is methylene, ethylene., propylene, tso-propylene, butylene,, Χο-butylene, sembutyleue. penryiene, hexylene, hepiyleoe, dimetbylethyiepey.mefbylcyc!bpropylenevcyetopropyl'metbyten'e.>'0theayiene.« propenylene,, or butenyianc.

In one embodiment of Forniula ClObl}.. A is hydrogen* alkyl, substituted alkyl, ~CN, ·ΝΟ;>. -OR* -StOkR5, -MRi;CORi:;, -M:IOR\ -NRVV-NOR*, YX)NR^°, -€C)al9y -NRi?CO.'>Ri!‘, -NR'iek:)NRf,:>RiV~NR9C'$KR'i0R.:i':iJ. -NRYY:::Ni-t)KR^H.

In one embodiment of Fomiu]a (IIIb:i), R: is .hydrbgbn, alkyl or substituted tilky i.

In one embodlmcrn ofFormula (IIIbS}, Y: is eyoloheicroalkanvl. substituted cy cioheteroal kanyl, cyclohetcroidkenyl, or substituted cyc I ohctcroaikcny 1. Il is preferable that Y * is plpexkiinyl, substituted piperidinyl, terrahydrofuraoyf, substituted tetrahydrofura»vi, tctrahydropyranyl, substituted ttfrahydropyranyl, d< hydro hminy), substituted Jihydrohpanyl, pyrrolidins·t, substituted pyrrolidinvl. oxetanyb substituted oxetanyl, suechahde ring or its derivative, substituted saccharide ring or its derivative.

In one embodiment ofForiaola (IMbl), Y! is heferoaryl or'substituted heferoaryt ft is preferable that Yl is pyridinyk substitutedpyrsdiayi, pyrrolyl, substituted pyrrolyl, furanyi, substituted furanyf, pyrazoivl. substituted pyrazelyl, Isoxazoiyt substituted isoxazolyl, oxazolyL and substituted oxazolyj. It is also preferable that the substituted eydohetensaikauyl or the substituted eyefoheteroalkenyl comprises one or more substituents selected bom the group consisting of alkyl, substituted alkyl, aryl, substituted and, arylalkyl. substituted aryiaikvl, acyl, substituted acyl, hetoroaikyl. substituted hetctoaikvk hetoroaryL substituted hoteroaryl., hoterc&amp;rylaikyh substituted hctoroaryluikyl. -CN, -OR''.. -NO;·, -SiOs. R\ -NOR.', -NHUR\ -NR'V'OR*0. -NR -'R.;i:. -CONR.d<li;„ -COdO. and -NR';CO>R:ii.

In one embodiment of Formula Hllbl), Y is

itis preferable that X'4 isO,

In one efebodinidni of Fbriuida )., ~XY€(5rVX''- is -0(0)-, -CI0J-1YB-, - ΝΙΚϊΟκ -ΝΗ-0ίϋ)-ΝΗ-, -D0)0-, -O-CiOK -0-00)-0-, -NH-CiOi-O-. -0-C(0)~NH-,-Cf NR)-, -CINHi-NH-, -NiH-C(.NH}·, -NH-CTNHVNH-. -C<\R)-0-, -O-C(NH)-, -O-CfNHbO-, -ΝΗ-αΝΠ)-0-, -Ο-0(ΝΗ)-ΝΗ-, -C<N«OHV. or -€($)-.

In one embodiment ox Fo:rsnuln (IIIbl), A Is hydrogen, alkyl, substituted alkyl, or -NE%Ki:ES7 Is hydrogen; and. Ί I5 is piperidmyi, substituted piperidmyl, letrahydrofuranyl, kahsititutedtetrahydtofuranyt tetrahydropyranyl, sobsitftu.ted teuafeydropyraayt dihydrofomnyl, substituted dihydrofuranyl, pyrrolidinyf, substituted pyrroiidinyb oxetanyl, substituted oxetanyl, monosaccharide ring, substituted monosaccharide ring, pyridinyf. substituted pvridinyl, pyrrolyl, substituted jo rreiyL furanyi, substituted -orato I. pyrazolyL substituted pyrazolyL tsoxezoiyi, substituted isoxaxeiyl, oxaxolyl, or substituted oxazoiyl.

In one embodiment oiTonuuh (111b 1), Λ is hvdrogco, alkvK substituted alkyl, or -NRV'RK); Η5' is hydrogen; Yf is -X'-€(KNOT-; and -Χ'-0(Χ4ΚΧ’- is C{0)-, -GOh-ΝΒ-, -NH-QOK -NB-C(0)-NH~, -0(0)-0-, -0-0(0)-, -0-0(0)-0-, -NH-C(0)-Q-,.-Q-C(0)-NH-, -ONH)-, -C(N)I)-NK-, -NH-C(NH)-, -NH-C(NH)-NH-. -CCNH )-0-. -O-ttNHk -0-0(N»)-O-, -NB--C{NH)-0-, ·0··ΠΝΗ}··ΝΗ·, -8(0).-. -NK-SiO);,·-. -SfOb-NVi-, -O-S(O)·.·. -00.,-0-, ·ΠΝΟΗ}·, or --0(8)-.

In some specific embodiments of Formula (lllhlk the compound has structural formula selected from the group consisting of

or a tautomer, salt, solvate, and/or ester thereof In some preferred embodiments, the salt of these compounds is a hydrochloride or trifluoroaeetate salt.

In one embodiment of Formula ..00), the compound of the present invention has siructurai formal a (Me)

therein D is haio,-OEiS5 -NH*ORI\«hfH-NBR;,5s -S{0)#is, or

In one embodiment of Formula (life), RE'\ and are independently hydrogen, alkyl, or substituted alkyl. It is preferable that E is -Cpfc1*)-; I is -C(R% J Is -CfR'"')*; and K is -G Ry\i·'.

In some specific embodiment?, <:-l hmrtmia {Hie}, the compound lias strucutitrui formula selected from the group consisting of

of a tautomer, salt, solvate, and/or ester thereof, in some preferred embodiments, the salt of these compounds is hydrochloride or tnfiuoroaeetate salt.

In one cmbodaneot of Formula (lit), the ..compound of the present invention has-straeiurai Formula (XI): wherein,

R:' is hydrogen, -OH, fed!, -CNt -CH,()i! or XX) d); D is -OH or -SH, and A is -OH, -NH?I -NHCH.i, --N<€FHfe "NHC(0)CFH, -NHC(0)0CH*, -NHC<0}N%, "NeC(S)NH2, -HHONHjNiK -CN, -OH.-OH, XIBiNFR, -CHjNHCd H, ~CH;N(CH >.L· XX)]NH·., -CONHCH?. of Xdi feHC(()}CHo provided that when Ru is hydrogen, then R:fe R'X RJ\ and Rv are not hydrogen.

In one embodiment oid'ormnla (ΧΠ. R:' is -OH, -SH. -ON, Χ.Ή.>ΟΗ or ΧΧΑΗ; and A is -NIB, --NHC1F. -N(CHd> -N HOOK'HU -NHC(0)0CH·. -ΝΗΓ(0)ΝΗ>, -NHC{S)NH?, "NHC(NHlNH.\ -ON, ΧΓΗ.ΌΗ. -CffiNife, XXljlSHCH =, -OH feiOihp, --00¾ -ΟΟΝΉ-, -CONHCH.>, or ΧΉ-ΝΗΟΟίΟΗ:. in some embodiments of Formula (Xi), when R'X R'h ft'· and RX5 are hydrogen, D is -OB, and A is -CO.XI; then R.1"’ is not -CO2H or -OH; when R' . R'\ R?is and R';i are hydrogen:, D is -OH, and A is -ΝΉ·;; then Rl'! is not XXKH or CN; when R:^, RJ* and SO* are hydrogen, R'v is -OMe, D is -011, and Ais -CHeOf!; then R*~ is not -OfeOH; and

tthcn R °. Rjnd R ' arc hvdrogen, R' i? hydrogen or methyl, f> is -OH. arid A Is ··· COER then PC; 0 not -SR

In erne ©mlvodiruent οΠ“οπ»«1.&amp; ¢111), tile compound of the present invention has straemral Fornitda (XII): wherein

Ri3 is hydrogeo. -OR -SB, -CN, -CH OH.or-COdi; D is -SH or -OH: A is -OH, -NIK -NHid-R -NCCRo, -NHCiOKiR, -NHUOiOCH*, -NHCIOINIK -NHQSjNR, -ΝΗΠΝΗΙΝΗ;. -ON, -OROR -CRNIK -CH NHCR. RRNiCHR, -CO. R -CONH,:. -CONHCH... or-C RNHC AnCR: ** is hydrogen,.-OCR, -OC>R, -ORR, -CIO. -QR-. -Ci-NCRR -CROR ~CRO< I-l·. -CN, -CiO)NK*!Rw. -CO.dC\ -SORR^VC -NR^SOdr', -B(OR-ROR^}, -R(0){0R^h0R"1;i} or -ROHR ; and R': is hydrogen, -OCR, -OCRR -OC.dK -Ok -(CH.:. -C’H{CH:):, -CROR -CROCR, -CN, -CiO)MR i::R ::, -CQ;-R4'\ -SORR :' R 0 -NR'"SOR" -BiOR^nOR44). ~P:(Q}(OR"!'KORR or -PfO)(Rii3)(OR.").

In one embodiment ofForrftula: (XII), R f i is -OR -SH, -OR -CHyOH or -COyR In one embodiment of Formula (III), the eornpound of the present indention lias structural Formula fXlll):

wherein; D is :::0 or A is -OR ΝΗ-ϊ, -NHOH. -X(CBR:, -NBCiO}CR, -Β:Ηϋ(0)0θΊ?, -NBCCO)N% -ΝΗΟ{$)ΝΗ;;, ·ΝΗ€(Ν!ΠΜΊ.% -i'N, -CICOII, -CHCAk -CH,NKCH·. -ClRNa'Iho, -CO.di -CONIk -CONHCi h, or -CH.^NHCiOiCH=; R' is hydrogen, alkyl, aryl, urylaSkyi,

In one embodiment of Formula (XIII), when A is —NH^, and R", R: y IC; and .R."· are 'hydrogen; then R" is not methyl, ethyl or phenyl

In some specific embodiments of Form ula (XIII), the compound has stractopi fotmiila selected from the group consisting of

or a tautomer, salt. solvate, and/or ester thereof, in some preferred embodiments, the suit of those compounds is hydroc hloride or trifluoroacetatc salt •In one embodiment of Formula (ill)* the compound of the present invention has structural Formula (XIV;:

wherein Λ X -OH.. 'Nil··, -NHOH-N(CH do -NHC(0)CHU, -NBC(D)OCH^ -NBC(0)NHa. -NHC(S}NH·. -NHC(NH)NH>. -CN. ~CH>OH, ·€Η?ΝΗ;, -Cl-bNHCfh, -CFbXiCHdn -CChH, -CONi-F, -CONHCH.o or -CH»NHCYO)CH.; and Rr is alky!, aryl., or aryklkyb

In one embodiment of Formula (1),. tfee-ehem.08eftso.iry receptor ligand modifier is a:compound having a structural Formula (IV):

wliescnr t is >cmm~, -NR4) -Q- or -S-; M is CHR.·1-, -NR4*, -0- or -Sk E is CHR6\ -Q- or -S-.; T is ~£:HR*:\ ~NR;5(i, -0« or-Ss o and p are independently th L or 2)

Rw is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arykdkyh substituted arylalkyl, acyl substituted acyl, heteroaikyl, substituted heteroaikyl, heteroaryl, substituted heteroaryl, hcteroaryhlkyl or substituted heteroaryl alky l ,-CN, -NIK OR''4, «S((>KR°\ -OCOR64, -NR^COR65. -NR^Vi -CONR*R*\ -CO #C -SO # Ri4R6;l -NR^SO-R*. -BtOR^XOR*'}, -R(O}tOR0' KOR*) or -R(O}tRI>!HOR0'); R!ii k hydrogen, alkyl. substituted alkyl, aryl substituted aryl, arykillyL substituted arylalkyl, acyl, substituted acyl heteroalkyl substituted beteroalkyl heteroarvl substituted heteroaryl heteroarylaikyl or substituted heteroarylalkyl ,-CN, -NCR, OR' l -StOkR"1', -OCOR66, -NR^COR67, -NR60R6l -CONR66R6l -CO#66, -SCRNR^R67, -NR^SOjR*7, #(OR'v'}(OE/'\ ·Ρ<ΟΚΟΚν;ΚΟΚΜ) or -ΡίΟχΚ^ΚΟί^Ί;

Rw<r is hydrogen, alkyl substituted alkyl, aryl, substituted aryl, ajyklky *, substituted arylalkyl, acyl substituted acyl heteroalkyl, substituted heteroaikyl, heteroaryl substituted heteroaryl hcteroarylalkyl or substituted hetcroarylalkyl ,-CN, -Nib, -OR'"', -0(0),.11 ", -OCOR68. -NR^COR6*. -NR^R6*1, -CONR^R6*, -C0#f!\ -SO#R&amp;:R6l -NR^SO#", '•B(OR:VRORi:’), --P(O){OR;'0lORi;') or ~P(O}(llt6:){0R’°); R1'·' is hydrogen, alkyl, substituted alkyl, aryl, substituted aryi, aryklkvI. substituted arylalkyl acyl substituted acyl heteroaikyl substituted .heteroaikyl heteroaryl, substituted hetCKwyl hcteroarylalkyl or substituted heteroarylalkyl ,-CN, . -OR70, -SiOlR7'', -OCOR* “NR75)C0R7\ -NR?fiRJi, -CONR7f)R5l CO#70, -SO.>NRx’Rn, -NR’°SO#?1, ~B(OR :°)(0R -PiOXORvo)(OR4) or -P{OXR?0(ORv;l or alternatively Rii0 and R6’, i# and. R'4, or .R6" and R0' together with the atoms to which they are bonded form anarryi, substituted aryl .heteroaryl substituted heteroaryl eycloalkyl; substituted cydoalkyl cycloheietoalkyl or substituted eyclobeteroalkyl: dog;

Vo, v and K are independently 0, 1 or R'4 to R'‘ are indenendcotiy hydrogen, alkyl substituted alkyl. aryl substituted ary l arylalkyl substituted arylalkyl heteroaikyl substituted heteroaikyl heteroaryl, substituted hetcroaryl.heienQaryklkyl or substituted hcteroarylalkyl or alternatively Rm and R'l Rf':' and Ri>;, R66 and R^Vor R'° and R'! together with the atoms to ivhtcktkey are bonded tbnn a eyelohoteroalkyl. or substituted eyeloheteroalkyi. ring; and R'!: to R": arc independently hydrogen, alkyl, substituted alkyl, aryl substituted aryl, arylalkyl substituted arylalkyl, acyl, substituted acyl, heteroaikyl substituted heteroaikyl.

UetcroaryL substituted heteroaryl hctemaryhlkyi or substituted heteroaryhikyk \s ifh the prey Go that a? most only one of L, VI, R and Ί" is a heteroafom.

In one embodiment of Formula. (IV), E is -N-, and E is -NR'"* or -N~. It is preferable that G is ··('-.

In one embodiment of Formula (IV), the compoundoffhe present invent ion 'has structural Formula (XV).

wherein. D is -SB or -OH; and A is -OH. -Nil·, -NHOfe -NfCifok ~NBC(0}eH:,s ~KHC(0)CK'H-i. -NHC(0)NH7. -NKGSVNffo -NHCiNHINH;. ~CH, XJH2OH, "CH;NHCH ·. -(:Η.·Ν|(.:Η;ϊ>. -CO-jH, -CONN;.. -GORHOR. or -CH;NHCiO}CH*. in some specific embodiments of Formula (XV i.. the compound has structural formula selected from the group consisting of

or a tautomer, salt, solvate, and/or ester thereof. In. some preferred embodiments, the salt of these· compounds is hydrochloride or foil noma cerate, salt,. hi one embodiment of Formula (IV). B is.-N~; E is -HR..*·'-· or -N-· A is: hydrogen, alkyl, substituted alkyl aryl, substituted aryl -Olfi -SR9, -CM -ΝΕ:^ίδ, A){):NR9RW, X/CRR9, ^R9CX).di9l-NR9(X)NRiaR1^ -NRsC:SNRs^1hor-NR%:i:^B)MRi- R11; and D is -€), -S , ::::N-OR: \

In one embodiment of Formula (IV), the compound of the present invention has structural Formula (I¥b):

wherein L is M is ~CHI#< R is -CHR62-; T is -CRR^-.

In some specific embodiments of Formula {IV), the compound has si- uctuiai formula selected from the group consisting of:

or a tautomer, sah, solvate, and/or eater thereof In some preferred embodiment^, the salt of •those compounds is hydrochloride or trifluoroaectate salt.

In one embodiment of Formula {IV), -he compound of the present invention has structural Formula (iVa);

In one embodiment of Formula (IVa). L is M is -CHR6*»; R ^ -CEfiR1*·»; and T is -CHRs. If is preferable that A is hydrogen:,, alkyl, substituted alky i, arv), substituted aryl, -OR9, ~SR9, -CM, ~NR%!i), -CONR%i0,-CO3Rv, -NRgCOgRw, -MR'tONR^R -NRsCSNR 'ftR'5 or ~NR9G(-Ne>N:RiciRn,

In some specific embodiments of Formula (IVa), the-compound has stsuctural formula selected from, the group consisung ofr

of a tautomer, salt, solvate, and/or ester thereof. In some preferred embodiments, the salt of these compounds is hydrochloride or trifluoroacetate salt.

In one embodiment of Formula (11), me compound of the present hweniio&amp;has Structural Fonmila (V'a):

wherein D ishvUrogen, alkyl, aryl, halo, -ΟΙ!, --'Nil.. -SRi:. -Oil·. -OAH ον ~OONJ-jy. Λ is -NH.a -NHCVh, -N(CH.ifc. -NHaOsOll·, -NHC(Q>OCib, -NHC<0)NI-l>. -NHClSiNIR, -Kiiammis ~cr -oh.»oh. -a-RNil·, -ch>niicii^ -cibwi-hh. -co.-if -com% -ΓΟΝΙΚΉ o or -0H/NHC{0}0H<; and R.: is hydrogen, alkyl, substituted alkyl, arvialkyi.

In one embodiment of Formula (vat. Y forms a. single bond with W and a double bond with Z; W is ~C(R'':4}“ or-N~; Y is -CiR'A- or ---Nr and Z is -S-, -NCRY'1)., or-O··, in one embodiment of Formula (Vat. Y forms a double bond w jth W and a single bond with Z: W is --S··, -NfR"'}, or -0-: Y is -<'(R"’')· or Ν--, and Z is -OR"’}·

In some embodiments of Formula (Va), wherein B is ~-€(R 1« one embodiment of Formula iVa), the compound, of the present invention lias structural Formula (V):

wherein:

R'k> is hydrogen, alkyl, halo, ~CO-£K'\ CONR^R", -$02NR:1R'\ -NR^SO#55, ~R(O854)(0R“ n -Pi 0}(pRM){0RS'S') or -P(0){R54X0R: A R': is hydrogen, alkoxy, alkyl, substimt.ed,alkyl.. halo. -CN, <;{0)NR'i,R-:'\ '-COaR."’0». -NRi6SCFR;i\ -B(OR'i:){OR·’n ~P{OKOR'-°){OR'?> or -P{0>{R*'X0R;;vk or alternatively R·'* and Rx’ together with the atoms to which they am bonded form a eyclo-be-teroalky 1 or substituted ey eloheiemalky! ring and R'\ R'\. 106. and R'1' are mdependeniiy hydrogen, alkyl, substituted alkyl aryl,, substituted aryl, aryialkyh substituted arylalkyi, acyb substituted aeyl, heteroalkyl, substituted heteroalkyl, heterouryl, substituted beteroary!. heteroaryhdkyl or substituted hereroaryialkyl; or alternatively R'* and R'' or Rx' ami Rv together with the atoms to which they are bonded form, a eyeloheteroaiky! or substituted oydoheteroatkyl ring: provided that when. R^ and R2' are hydrogen, and D is -0¾ then A. Is -Nila In one embo diment of Formula: C V}„ when. D is. .methyl.* - A - is -dimethylammbv and E.^ is .hydrogen; then Rf* is not methyl, ethyl or carboxyl; when D Is methyl, A is dbnethylamlno, and R” Is methyl; then R:5* is not methyl. . . . . . , m. % _ . i J , · , ΐ·ν t when D is «SCHU, A is dimethyl amino, and K' in hydrogen; then R'“ is not carhocthoxy; when I) is hydrogen, A is dimelhyianuno, sodR:5' is hydrogea; then is ivot carboxyl Or earboeShoxy; when D is hydrogen, A is duneihyhtrmno and R" is methyl; then is not methyl; whoa D is h> thosen, A is methylsmiao a»d Rai is hydrogen: then Rs'’' is not .methyl, ethyl

Of carhocthoxy; when D is hydrogen. A is methyiamino and R; w methyl, then R5" is not methyl or carboethoxy; when D is hydrogen, A is methylamiao and B.a* is -CBeNMe; then R**. is not methyl or carboethoxy; when D is phenyl. Λ is methyiamino and R " is hydrogen then R" is not methyl; and whet) D is phenyl, A is -N Hi €0)01* and R is methyl then R is notcarbomerhoxy. in one embodiment of Formula €v}. the compound of the present invention has structural formula. (VI);

Where!» E> in hydrogen, -CBA «G2B5., phenyl or benzyl.

In 6ne'emfeodimfe»t of Formula (V)v the compound of th&amp; prmmtim&amp;tiiion has sit yetitraI formula (VII)'

wherein A is hydrogen, -(11, -1.)41,-., phenyl or benzyl .In one embodiment of Formula. (V), the compound of the present invention has siraotural formula (VIH); wherein

R1' and R'" arc independently hydrogen, -OH?, «0·,·Η<, phenyl or benzyl; and provided then both RJ andlR!<> arc not Hydrogen,

In one embodiment ok Formula (V), the compound of the ptesentinvOntion lias straemrai formula (.IX);

wherein R5? is alkyl. substituted alkyl. -CN, -Ctp)NR::'!R';-CO jR^'k -SO5NR SR -Ni^SOal55, ~B{ORJ ; i{OR5Sk -FiOHOR':}{OR55}. or -PiOX R :* i(OR"); R';: is alky]. CO>R'° or -CONR'kiR;;. -SifoNR'V \ -NR ;tCi>R % ~B(ORK)COR5?>, dd(J}(()kf: i or ~FfOHR56KORJ vi; and R'4 to RO arc independently hydrogen., alkyi. substituted alkyl, atyl, substituted aryl, aryialkyh substituted arylaikyj. acyl, substituted acyl, beteroalkyl, substituted hvtcroalky], he ternary], substituted hetcroaryl, teeroaryiaikyi. or substituted hetsroarylaikyl:; or alternatively Rx> and Rs" together with the atoms to which they are bonded form: a·eydobeieroalkyl or substituted cyelohetemalkyl ring.

In one embodiment of Formula (V), the compound of the present invention has Structural, formula (X):

wherein, D is -()1-1, -SB' or ,'NH# R··· is alkyl, substituted alk>k aikoxw -CN, -CfOJNR'Vk --CO >Rm -SOyMR^R55, -NR/"SO.?Rfo -B{ORw)<OR-·), -PH>kORw)<OR?\ -P(OJ(R?,KORw),

Rm and R" are independently hydrogen, alkyl, substituted alkyl, aryl,, substituted sryk aryi&amp;lkyl, substituted ary (alkyl, acyl» 'substituted aeyls heietoalkyl, substituted heteroslkyl, detcvwsyl, substituted heteroaryl, heteroars-Jaikyi or substituted heteroaryjalkyl; or alternatively· R'-’ and R ' together with the atoms to which they arc bonded form a cyclohctcxoaikyi or substituted cyclohetcroalky I ring. in some .specific embodiments of Formula CVa), die compound has structural, formula selected from the group consisting of

wherein, R;~ U OH, -SH. «ΟΝ, -(Ή;;ΟΗ. or CXhH: and RSJ Is CH% -Ce2CH3> benzyl or or a tautomer, salt, solvate, and/or ester thereof. Ift some preferred embodiments, tire salt of hose con-pounds is hydrochloride or trilluoroaceta-o salt

In another embodimen t of the present Invention,, the chemosensory receptor ligand modifier is a compound having a structure Formula (XVI):

or a tautomer, salt, solvate, and/or ester t hereof wherein: o is L 2 or 3; each G is imjependenily ~C(R''''}(R;^v~C(0K -NR.”--or -$(0}r; provided that, when ® is greater than one then only one 0: is -C(OK ~C(S), -SCOfe- or -NR7'7-; Y is -0(0 K -CIS) or -31(0)-.: R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyi, substituted atybikyh acyl, substituted acyl, heteroalkyi, substituted heieroalkyl, heteroarvl, substituted Keteioaryl, heteroarylalkyl, substituted heteroarylalkyl, -CN. -NO,-, -OR'-303)31'\ -NR :R \ -CONR’V\ -CO>R7··, -NRk'CO:R7N -Nn":CONR''RC -NiR'-CS.NR^R^ or -NR7;:i3(-NH)NR7'Vi -SO.;NR ' 'R· 3 -NR “SOyR '. ~NR7-'$0,:NR7'R7 \ -B(OR72)(OR7\ ~FiO)(OR MOR ''} or -PCO)(R s; a and b are independently Ο, I or 2; .R/': is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyi, substituted arylalkyi, acyl, substituted aeyh heieroalkyl, substituted lietsroalkyl? heteroarvl, substituted heteroarvl, hete?oaryla.ikyt, substituted heteroarylalkyl, -CN, -KH'N, -O.RN -SCORR/C -NRi:'R;i, -CONRv‘{R" \ -OOaR74/ '-NR‘;<fC02R' \ -NR‘nCONRv--R'^ .NR'-5C5NRv:R^'or-NRwC{-NB)NR'^R7s -SQ2NR7iR7N -NR^SCNR77, -NRnSO>NR7V6, -BfOR^KOR77), -P(0)i0R’4}(0R"·). -P(0)tR'"){0R '} or alternatively, R ' and R'7 together with the atoms to which they are bonded form an aryl, substituted uryl. heteroarvl. substituted hsrteroan l, eycloaikyk substituted cycloalkyi, eyclohetcroalkyi or substituted cyciohcteroaikyl ring where the ring is optionally fused to another aryl, substituted aryl,, heteroarvl, substituted heteroarvl, eydoaIky 1, substituted' cycloalkyl, eyefoheteroalkyi or substituted eye lohetsroalkyI ting; R3' to R.:>i are independently hydrogen, alkyl, substituted alkyl, and, substituted aryl, arylalkyi, substituted arylalkyi, acyl, substituted acyl, heieroalkyl, substituted heieroalkyl, heteroarvl, substituted heteroaryi, heteroarylalkyl or substituted heteroarylalkyl or alternatively, R'7 and. R'O R:' and R':+, R”* and R'75 and R'5 and R,fl together with the atoms to which they arc bonded form a eyclohetcroalkyi or substituted eyeloheteroalkyl.ri.ng; and R fo R arc independently hydrogen, alkyl, subsutuied alkyl, aryl. Mibstuuted aryl, arylaiky;, substituted arylalkyi, acyl, substituted acyl, heteroalkyl, snbsmutcd heferoallyyl, heteroaryj, substituted he ternary L heieroatylalkyi or substituted heteroaryfalkyl or after.natively, R''' arid R together with ti sc atoms to which they are bonded- form a cycioalkyi, substituted: evcloalkyl, cycloheteroalks 1 or substituted eyeloheteroaikyl ring. in some embodiments of Formula (XVI), when G is -0(0)- and R'h is.hydrogen, R’1 and R'" do not form, a phenyl ring. In other embodiments, R '' and R: ‘ together w ith the atoms to which they are bonded form an aryl, substituted aryl,, heteroaryl, substituted hctcroaryl, evcloalkyl, substituted cycioalkyi, eyolohetofoalkyl or substituted cyelofecteroalkyiring where the ring is optionally fused to another aryl, substituted aryl, hctcroaryl, substituted heieroaryL evcloalkyl, substituted cycloalkyh-cycloheteroatkyl or substituted eyeloheteroaikyl ring, in still other embodiments of Formula (XVR, a enmpi-und of structural formula (XVUK (XVtill, (XlXi or (XX} is provided: whew o Is 1 or 2,

«Λ *?·> . · ,

In some embodiments, R'' and R1 * together with the atoms to which they aw bonded form, an aryl,substituted aryl, hetematyk-:sub$fituted'.he.mraaryl,cy6!.oaIhyi, substituted cycioalkyi, cyelobeteroalky! or substituted eyei.oheieroal.kyl ring where the ring is optionally .fused to another aryl, substituted aryl, heteroaryl, substituted ftctemaryl, cycioalkyi, substituted cycioalkyi, eyeloheteroaikyl or substituted eyeloheteroaikyl ring.

In another embo diment of Fo nnula (X VI). tho chem.oseasory receptor ligand modifier Is a: compound having a struetnre Formula (XXI): wherein;

X. is 0 or S; H is -N- m -CRKi-, I jc -Nr or -CR-·'·: i is -N--o? K. is -N- or OR"'-.; with the proviso that so marc than 2 of Η, I ,.) or K. arc -N-;

Rss is hydrogen, alkoxy. -001., -0C1R, -OCdl·, aikyS. -0¾ -0,¾ -C HiC'H.} ,. •Π00Η, halo, chlorOs fiuoro, -CHlX'Hm-ON, -OiO}NRsiO;\ ~00.RS\ -SOXR'OO6. •NRv’SO;;Rv’, -BiOR':S(ORv·}, ~Ρ(0}10Ri:h(ORvd or --P(0}U0p0R-();

Rw is hydrogen, alkoxy, -00¾ -00..¾ -00.¾ alkyl. --0¾ -¾¾ -CH(CHjfc, -01¾¾ halo., cMoro.&amp;oro, -CiN, -0(0}^B:V\ -Cii2R8seSDrMRS6R^? -NRa8Si)2Rsk .B(OR.^QR^]i.-P{OKOR.^OR^>hr.-P(OXR^)(OR^);

Rh-' is hydrogen, alkoxy, -OCH:., -0(2¾¾ -0(0¾ alkyl, -0¾ -0¾¾ -CHl'Oi.?)?, -CH.OH, halo, chloru, fiuoro, --0000¾ -ON, ~CtO}NRv0O\ -CO..R"\ -SO.NR'OOy -NfkXiSOvR*\ -B{OR^){OR®}, -P(OXOR^)(ORv') or -!>{OHR'*XOR*5); R-4 is hydrogen, alkoxy, -00¾ -00¾¾ -0(0¾ alkyl, -0¾ -0¾¾ -CH(CH.O.t, -CH?.QH, halo, chloro, fluoro, -CH.?OC.H., -ON, -0(0}^¾¾^. -CO;R* -S0iNR'>2R:>l, -JsR'-SOdl- h -8i0R ';;}i0R;i!), -0O}(<)R'';;)iOR95} or -PCOKR0')<0R’’S K ;md

Rh> to R')f are independently hydrogen, alkyl, substituted: alkyl, aryl, substituted aryi, aryialkyl, substituted aryialkyl, acyl substituted aeyl hetoraalkyk substituted heteroalkyl,: heteroaryi, substituted heteroutyl, hoteroarylalkyi or substituted heteroaryUdkyl or alternatively 1¾ and Pa !' and R5* and R*°, or 1Λι and R9a together with the atems to which they are bonded form a oyeioalkyk substituted cyeloalkyi e¥cioheferoa!.kyi or substituted ey cioheteroalky 1 ring; provided that' K*1; R.h\ 1*'' and RM are not all hydrogen.

In some embodiment of Formula (ΧΧΪΪ), RSl, RV;, Rs' avid Rs+ arc independently hydrogen, alkoxy, -OCTh, -OC..H5, -OCdk alkyl, -Oil·, -Obi,, -CH(CH*h, halo,

ehloro. flisoro, ~CH;i()CH,. -ON. -CiOiNHMe. -00VH, -OOvClh -SOvNiCihR. -Ns BCOOfh, ~BfOB)2 or -PiOisOHO I--5 Mill other embodiments ofFormiila (XXil^-compoands havinglhg structisres beiowsre provided:

In another embodiment of the presold invention,, the chemosesisory receptor ligand'modifier &amp;.·« compotihd: having a sfeaciuie honnula (XIX!!):

or a taoiomer, salt, solvate, and/or ester .thsrehf, wherein; each G Is mdepemlesitly -NR9*- or -SCOfey ts. is.’ 1 ,:2 or 3; provided that w hen is i s greater than one then only one: G is >€{<))-, -S(0) >- or-NR;'4-;'· Y is ~CtOK *C(S)- or -S(()}.>-; L is -a R]tA)i Rw>, -CK Of -NE.iM~; R'" is hydrogen, alkyl, sisbstituted alkyl, aryl, sohsttasted asyl, arylalkyl, ssahstithted arylalkyl, acyl, sohsliioied acyl, heteroalkyi, snbsdtnted heteroalkyi, heteraaryl, substituted heteroaryk hctcroarylalkyL substituted keioroasylaikyk -CN, -NCn, -OR*', -StOh-R*, *NR ^R/h -CONR^R"', -CO;;R9\ -Kik'yCO..R" -NR-!*CONR^Rs00, -NR'YSNR’V* or -NR'^Ci === NB iNRwR50 X -SO,N! RVSR*\ -NR^SOvR"-’, -NR^SO.;NR*'R;0-Bt0R';0(0R''\ -FiOiiOR'^mC)R: ') or -idO){R:'s}K>R*!i: R*' is hydrogen, alkyl. substituted alkyl aryl- substituted unk arylulkyL substituted arvkilkyl, acyl substituted acyl, heteroalkyk substituted bctcroulkjh heteroaryk substituted heteroaryk heterouryiaikyi, substituted heterooryUilkyl. -CN, -NO>, -OR·!5<0}/ΒΜ. -NR!9!RfM, -CONR,0,R,e% -CO>RKii, -NRli!{<XhRSl", -NR;;\X>NRHJR!!'', ..\Rii'i«"’SNR or - NRii:iC(:::NH}NRki'Ri0k -SOvXR^R50', -NRii:iSO->RK''- -NRs,jSSO»NRKVRs'y •B(OR,0,KORlii:'k -Ρ(0}ί0Κη!!χ0Ρϊί:Ί, ~Ρ(0}ίΡ!ί:: κOR11'·} or alternatively, R% andR% together with the atoms to which they are bonded form an atyi, substituted aryl, heteroaryk substituted heteroary I. eycioaikyk.substituted cseloalkyk c>clohercroalkyl or substituted cycloheteroalkyl ring where the ring is optionally fused to another aryl, substituted ury!. hetemaryl, substituted heteroaryk cycloalkyl, substituted eyeloalkyk cycloheteroalkyl or substituted eyeloheteroalkyl ring; y and z are independently 0, 1 or 2; R':h to Ri0S are independently hydrogen, alkyl, substhuted alkyl, aryi, substituted aryl, arylaikyl, substituted aryialkyi, acyl,.substituted acyl, heteroalkyi, substituted heieroslkyS, heteroaryk substituted heteroaryl, heieroarylalkyl or'Sul^tift3.!ted.:hCteiCi«rylalk.yi or alternatively, R^ and R/'iy, Rvv and RKK':, R^J and or RJ'U and RM' together with the atoms to which they are bonded fonsh. a eyeloalkyk substituted eyeloalkyk cycloheieroslkyl or substituted eyek>heteroalk\ I ring; K:M to Rv> are independently hydrogen, alkyl, substituted: alkyl, aryl, substituted aryk arylaikyl,. substituted Stylalkyk acyl, substituted acyl, heteroalkyi, substituted heteroalkyi, heteroaryk substituted heteroaryk hcteroarylaibyl or substituted Heieroarylalkyl or alternatively, R' '' and R ' 2 together with the atoms to which they are bonded form a eyeloalkyk substituted eyeloalkyk eycloheteroalkyi or sitbstitnied cyeioheteroalkyl ring; R^ is hydrogen, alkyl, substituted alkyl, aryl, substituted :aryl, arylaikyl, substituted arylaikyl, acyl, substituted acyl, heteroalkyi, substituted heteroalkyi, heteroaryk substituted heteroaryk beteroarylalkyl or substituted hetcroatytalkyl: and R1<!i to R;I!' arc independently hydrogen, alkyl, substituted alkyl, aryl substituted aryl. arvialkyi, substituted arvhdkvl, acyl, substituted acyl, hcteroaikyk substituted hotcroaikyk hctcroaryi, substituted hcteroaryh hotcroarylaikyl or substituted hetoroasyialkyi or alternatively, Rh!* and together with the atoms to which they are hooded fcmnt cycloaikyh subsiituted eycfoalkyl, eycioheteroaikyl or substituted cycloheteroalky 1 ring.

In score embodiments, when L is 0, R!,s is hydrogen, R:,’A is methyl and the bond, connecting the carbon atoms bonded to. R;<": and RA' is a double bond then R;i> is not hydrogen, •in some embodiments Of Formula: (XXII), a compound. of structural formula {XXIII} is provided:

where when R" is -CM > toon R" is rmt hydrogen and that both R' 'v and R' are not ! tydrogou. in some embodiments of Formula {XXII k R*' and R”' are independently are independently hydrogen, -ΟΠ-k -0( ' Jh, -0( dk alkyl, -Cli·, -Cdk -CH(CHr)>, -CH>08, hate, chloro, linoro, -GHaCKilHa, ~€N, *SCH<, -C(0)!kH!Vle, ΧΧ),·Η, ~CO.jCbh. -SO;?N(CjH;yb>, -NHSOXRR, -E(OM);> or -P(p}(0H):2, In other embodiments*and R* together with the atoms to which they are attached forma eycioaikyh eycioheteroaikyl, aryl or heteroaryl ring.

In other embodiments Of Formula (XXII), compounds haring the structures below ate pro\ tded.

The definitions and substituents for various genus and subgenus of die presen? compounds have been described above in detail. U should be understood bv one skilled in the art that any combination of the definufous and subsituents described above should not result in a Inoperable species or eompetund, By "Inoperable species or compound^ it is meant a compound structure that violates the relevant scientific principle (such as, for example, a carbon atom connecting to -note than four covalent bonds) or is so unstable that separation of dtc compound bom a roucuon is impossible (such as, for example, more than three cat bony l groups connecting to each other continuously).

In one embodiment, the present invention, provides a process of preparing a compound having structural. Formula f a):

comprising· reacting a compound having stmeturai Formula (h)

with a base, 'λherein D is oxygen or sulfur; A is -Nil; or OR1’; R' is hydrogen. alkyl substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted arylalkyl; R‘" and R" arc independently hydrogen. alkyl, substituted alkyl, and, .substituted arvL arylalkyl substituted arylalkyi, acyl, substituted, acyl heteroalkyl, substituted hetaroslltyl, heteroaryl substituted hetcroar/1 heteroarylalkyl, substituted heteroarylalkyj, -CM *NO.s-ORM, ~8(0)ι,11'1 -NR^'R'i -CONRClVl -CO#S!, -S02NR?,R*2 or -NR2iS02R2 ·; or alternatively R2* andEM together with the atoms to which they arc bonded, ibrnt a eveloalkyl, substituted cyeloalkvl, heterocydoalkyl or substituted heterocycloalkyl ring; Ar is aryl or substituted aryl; and Ra is -CN, -0(0)1?*·, ~0{0)0R*l -QOiNiR* !.;; each. Rf' Is independently hydrogen, alkyl, substituted alkyl aryl, substituted aryl arylalkyl, substituted arylalkyl. acyl, substituted acyl, heioroalfcyi, substituted heteroalkyl, heieroaryl, substituted heteroaryl, heteroaryialkyt or substituted hetematyialkyl; h is 0,1 or 2; and R5i and R‘*' are independently hydrogen, alkyl, substituted alkyl aryl substituted aryl, arylalkyl substituted arylalkyl acyl substituted'acyl hetemalkyt, substituted heteroalkyl, heteroaryl substituted heteroaryl hcteroaryktlkyl or substirtued heleroarylalkyl; or alternatively R'* and R'u, together with the atoms to which they are bonded, form a eycioheteroalkyl or substituted: eyclpheteroalfcyl ring. It is preferable thatthe base is an inorganic base, such as N aOH,

In one embodiment, the compound having structural Formula (b) is prepared by reacting a compound having structural Formula <c):

, with.: a compound having structural Formula (d):

Preferably, the above Ar group Is phenyl or substituted phenyl in another embodiment, the present invention prot ides a process of preparing a compound having structural Formula (e);

comprising reacting u compound having. structural Formula (1)

with a base. wherein A is -NH; or -OR'’; R! is hydrogen, alkyl. substituted alkyl, aryl, substituted aryl, arylalkyi. or substituted arylalkyi; R'\ R"\ R' . and R * are each independently hydrogen, alkyl, athstitufed alkyl, aryl, substituted aryl, arylalkyi, substituted arylalkyi. acyl, substituted aeyl, halo, heteroaikyl, -substituted betemlkyl, heteroaryl, substituted heieroaryl, hereroarylalkyi or substituted hcteroaryblkvi, -CN. -NO;·. -OR"*, -S(OkR"*, -NjR+‘R4", -CONR.'uR"\ -CO<Rr\ -SO;NR.'i5R'c, and -NR.J,$0?R.Ji; or alternatively, R’? and Rv, R* and R-' . or R' and R ", together' with the atones to which they are bonded, torn· a cyck-alkyl, substituted.cyclopikyl,.heterpcycksdkyi. or substituted heterocydonikyi ring; R8 is is -CN, -C(0)Es, -C|0)OR^ -C(0)N(Eb}y; each Rb is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl aiylalkyl, substituted arylalkyi, acyl, substituted acyl, heteroaikyl, substituted heteroaikyl. heteroaryl, substituted heieroaryl, heteroarylalkyl. or substituted Uctcroaryiulky}'. and R*' and R*8 are independently hydrogen, alky), substituted alkyl, aryl, substituted aryl arylalkyi, substituted arylalkyi, acyl,.substituted acyl, heteroaikyl, substituted heteroalkyl, heforoaryl: substituted hetsroary 1, heteroarylalkyl or substituted heteroarylalkyl; or alternatively' R45 and R48, together with, the atoms to-which they are hooded, form a cyeloheteroalkyl or substituted cycloheieroalkyi ring. It is preferable that the bass is an inorganic base, such as NaOH.

In another embodiment, foe present Invention provides a process of preparing a compound baying structural Formula ter

comprising rending a compound having structural Formula (g*

with NH,>S(Of,?NH,? or Cl-SfOVNHl· in the presence of a base to provide directly a compound having structural Formula (c); or alternatively to provide the compound having structural formula (t) of claim 22.1 which is further reacted with a base to provide a compound having structural Formula· (a). It is preferable that the base is an organic base, such as DBU,

In general,· die compounds of the present invention, e<g,, compounds with the formulae .described herein can be synthesized according to the processes described above and the following exemplary procedures and 'or schemes.

As d i scussed hereinabove,: a: salt of the compound o f the present invention generally tan be formed by reacting the compound, with an acid or base, in one embodiment* the prcseM invention fiuther pavides a. sy nthede method for. preparing a sal t of the compound having any of the above-mentioned structural, .formula at a large scale. The synthetic: method enables preparation of a large quaufitiy of a salt of the present compound quickly and economical ly, The synthetic rncdiod can be applied in either a laboratory setting or an industrial setting:. One example of the synthetic method is described in·details as-Example 163' iarrembeiow.

In general, the compounds of the present Invention, e.compounds: with the formulae described herein can he synthesized according to the following exemplary procedures and/or schemes.

Pyrimidines B including fused pynmidme derivatives such as quinazolines ana •py«ido[2.3“dji>yrimidmes arc synthesized from 2-amino nitriles, 2-am|no ketones, or 2-amino: carboxyl derivatives A by reaction with the corresponding carboxyl derivatives as illustrated in Scheme 1 (Rad-Moghadam eiut^J. <if ifyerocycik: Chem, 2IKK?. 4% 913; Roy ei al., A Qrg;

Ckem. 2006, ?./, 382; Jung ei ah.,/. A feu. Chew. 2006. 49, 055; IChabnadidch ei ah. Bioorg. Med. Chem. 2005, /5, 2637), The amino group in the starting material A can be further functionalized by alkylation (Browne/ Med. Chew. 1900, /5, 1771) or reductive armaati0»-(Uehling ei ai., J. Med. Chem. 2000, 49. 2758, etc.) to provide the CQrivs|X»nd.mg'&amp;/mxonosubsututtxi 2-ammo nitnlcs, 2-umino ketone;-' or 2-amino carboxyl derivatives C. The coupling reaction of A or C with boOhicricyanaus such us, for example, benzoyl isottitio}c vanates and subsequent eyelization by treatment with NaOH provides the pyrimldin-2i lH)--tthi)onc derivatives E including, but not limited to, fused pyrimidin· 2{!HHthijones such as qumazolin-2(l Hi-ithijone and pyndo[2,8--d]pyrlrmbm--2(l H)-f thism-c derivatives (Eh-Shethetiy eial, Med. Chem. Rme 2000, Μ 122 and jcfcrenee* cited, therein; Ε&amp;άύγ ei al, Swdheiic CammmL· 1086, IS, 525; Wilson, Org. Let*. 2001. A 5s5, and references cited therein). Direct eyclization of A or C with iihi>})roeus m the presence of NaOH a bo results in the formation of pyrlnndin-2UBHtbi)one derivatives E (Scheme 1} (Naganuxva ei ai. Bioorg. Med Chem. 2006, //., 7121 and reference* cited therein).

Scheme 1

Pyrimidines B and pyrinndin-2(1H)-(thi)ones E can also be prepared froth, corresponding L3-dicarbonyl derivatives and α,β-imsaturated carbonyl derivatives by condensation with guamdinea, auiidines, or (thio)urea derivauves as shown in Scheme 2 {Shartna el®}.·, Eur,. .1 Med. Chem.. 2006,41, $3, and references cited therein; Bellur ei el, Teimkedirm 2086, 62, 5426 and .references cited, therein; Banset dial, J, Org. Ckem . 1053, iA, 588),

Scheme 2

Various pyrimidines and pynmidin-2i i f-f)-(thi}ooes as well as their fused UNTiinidme'aud pyriniidiu'2i IHH^Oone derivatives such as qulnazolines and qid«azolm~2f iBlmnes can he synthesizedikan pyti.uddinedL4{i B,3H)~dieue derivatives as well as.the fused pyriroidine-2yl(li3,3:I-i)"diones such as quinazolinfisS^IHiSH^ione and pyrido[2.3>d]pyrimidine>2.>4(1.H3Ji]Wionddefivatiy'es (Scheme 3);. Reaction.: of pynmidmes24fl.H3H)^didiE>e derivatives with .phosgene or POO3 provides the. corresponding 2,4-diehl0repyrlmidincs (Lee ei ai., Synieit. 2006, 65 and references cited therein). Subsequent dtspliseqm^nt&amp;.dithd two chlorides with various nucleophiles resulted in the formation of pyrimidines and pyrimid:iiv-2(l H'hCthiloues as well as 'fused pyrimidine and pyri.rnldm-2(l B)-(tiri)ohe derivatives (Kan.uma d? n/,, Bio&amp;rg, S Med, Chem. Led 2ll§5, /5, 3853 and references cited therein; Liu eial., Bimfgi &amp; Mail Ghem. .Lett 28117, /7, 668; Wilson elal, Bioorg. ά Med Chem. 2007, ./5,77; Boariand S al, J, Chem. Sac. 1051, 1218).

Scheme 3

'Similarly., |l,2i61ihiadiaziue-2,2~dioxides and fusedf 1 J,6lihiadiazine~23-ciloxide derivatives such as, for example, lH-benzo{c][i·,2,6]thiadiazine-2,2-dioxides are also synthesized from 2-amino nitriles, 2-annno ketones, or 2-anurto earboxvi derivatives A or C (Scheme 4), by reaction: with NBhSOyCl, (hhrayama. ei ai, Bmprg. &amp;. Med. €Mem. 2002, 10,. .1500; ICanhe et al., Bhxtrg, &amp; Med. Chem. Lett. 2006,15, 4000 and references cited therein) or NH.-SOyNHy (Maryanorr or u/.,,/. Med, Chew. 2006, 49, 3406, cod references cited therein:) and followed by cyclization In the presence ofNaOH {Goya etui, Heterocvdes, 1086, 24, 3451; Albrecht -v tii..d. Org. Chem, 1079, 44, 4101; Goya et a!.. Arch. pharm. (ii'Ceheim) 1904, 5/2, 777 i, i'he condensation of the corresponding 1,3-dicarbonyi derivatives, u.b-imsaturated carbonyl dcsivarKes with sulfamidc derivatives {Scheme 4) also results in the formation of 11,2,6jd'!iodiazine-2,2·dioxide derivatives iWright, J, Org. Chem, 1964,29,1905),

Scheme 4

Methods ibr the synthesis of t hi coo 12,3 -d jpy mn id esc derivatives arc described in Scheme 5, 2-Amino thiophene derivatives 303 arc synthesized via the Gewak! reaction (Chen, et al,, Sgmkette Qmmmimtkin 2004, 34, 38.01 and references cited therein; Ehnegeed ei ai„ Eur. J. Med. Chem, 2005, 41¾ 1283 and references cited therein). Compound 303 can, he eyelized with the coti espondmg earboxvi derivatives; to give the thle.no[2,3-d]pyrimidine derivatives 304 (Rad-Moghsdam,,/. Heienmdic Chem, 2006, 43, 913; Sedas ei ei.. Tetrahedron Lett, 20%.41., 2215, and references cited therein; Jdng et«L J. Med. Chem. 2006, 49, 955,).

Schemes

2-Affijflo thiophene derivatives 303 can be further alkylated bv either treatment with R^Br/KgCOx-or wi&amp;RCHO/NaBHiGAc}.·» to give the iWafkytated 2-amkio thiophene derivatives 305 (Brown ei «1, J. Med. Ckem, 1.090, 31,1771; Uchhng «t&amp;fi, X M&amp;£ Chem, 2000, 49, 2758 arid references eifed. therein), which are then reacted, for example, with hen;ioyiiso{thio)cyitnaie io give the corresponding benzoyl iihlognea derivatives 300, Compounds 300 may he cyehzed by treatment with NaOH to provide thlenoi2,3-djpyrirai:dlne derivatives 7 (El-Shcrhcny etui, Med. Chem. Rev. 2000, 10. 122, and references cited therein; Reddy ei aL*.SyMh&amp;ifc 'Chmmun: 1.988. /3, 525; Wilson, Org. Leif. 2001,3, 585 ant! /eferenees cited therein). When. E':::: B, eompournis 307 may be reacted with R-Br/NaOH to give the alkylated products 8 (Hirota at at... Bi<x>r%. Med. Own. 2063, //. 2715.). When R* ::: NH >, the amino group can be further functionalized io give the produce 300,

Si miiarly, quiruizolin-2{ \ H)*onc and q uinazoli η~2ί l H)-rhi one derivatives- 402 were synthesized from various 2<aminobcn?.o<c acid derivatives, 2mnurmbenznoIfriIe derivatives, 2-anunoaeetophen*>ne derivatives and 2-aminobenzamidc derivatives 400 as shown in Scheme b. Coupling reaction of compounds 400 with benzoyl isoitlno ley ancles lead to the formation, of corresponding benzoyl (thio)urea derivatives 401. Their cychzafion in the presence of NaOH provides the qumazolm--2i I HV(thi)one derivatives 402 tB-Sherbcny, Med. Own. Rev. 2000, lih 122 and references cited therein; Reddy et a/,, Synthetic Commuti. .1988, id, 525; Wilson, Org. Led. 2001,3, 585 and references cited therein).

Scheme i

1 B-l>enz0[e]( 1,2/;)thiadinzme--2,2 -dioxide derivatives 404 are synthesized from the same starting materials 400 (Scheme. 7} via their reactions with suit’amide or sulfamoyi chloride, followed by cydization with NaOH. Direct reaction of compounds 400 with sul&amp;mide in the presence of DSli at: the elevated temperature iitse resulted in the formation of lH-henzo[e][l!2s6)finadisz:tne~2,2-d!oxide derivatives 404 (Maryanoffpi m/., J. Med. Ckem. 2006,49, .3406, and. references cited therein}.

Scheme?

Quinazoline derivatives arc also synthesized from quimt/:oljric-2,4(!H3H)-ilionc> (Scheme 8), Reaction ofqinnazoiinc-2,4i i H.iHi-diones sviih ROCS, presided the corresponding dkhkuoqumazohries (Zonszain ei al. Bioorg, S: Med. Chem. 2005, 13,3681 and references cited therein.}, Subsequent displacements of the two chlorides with various nucleophiles resulted la formation of quinazolme derivatives (Scheme 8) (Katmraa etal, Btmrg, &amp; Med, Chem, Led. 2005, /5, 3853 and references cited the;dm Blackburn, inkBq, λ 3/··;/, Ctn-m. Let!. 2006, id, 2621).

Schemed

4"Aminofe,6,7 jAetrahydroquinazo!in~2( I H)~(thi)one derivatives and 4saramodd>,7,8uetrahydtoriB~benzo[e][ 1,2,6]rhiadia2inefe,2-dioxide derivatives, as well as struetutah analogs with different ring sizes, as shown in Scheme 9, are generally synthesized according to the methods described therein, Thorpe-Zlegler cyeltzation of dinitriles in the presence of base provides: d-amino-fep-unsamrafed nitrile derivatives (Winkler at of, 7<.'!!'{{!:,\i<2065, 61,4249; Yoshizawa et«/,. Green Chem. 200:2, 4, 68, am! references cited therein; Rodriguez-Hahn ef ai., Synthetic Commun· 1984,14,967, and references cited therein;

Francis ei oL./ Med. Chtm. 1991, 3A 2899). The $~amino-a$-unsaturated nitriles may he reacted, toy example, with benzoyHso(thto)eyauate and subsequently cyehzed by treatment with. NaOH to provide 4*attiinoriS,6J%8>fcHrahydn>qttinazGlin>2( 1II MthOone derivatives (EhSherheeiy e/ aLsMed, Ckem. cfer. 2000. /9, 122, arid references died therein; Reddy m aL, Synthetic Commim. 1988, IS, 525} us well as their structural analogs with different ring sizes (Scheme 9). Similarly reaction of jyamino-«sp-unsatufatfd nitrile derivatives with suifemoyl chloride, followed by treatment with NaOH provides 4-amino-5,6,7,8-tctiah vdro··I H-bcrszo(ej[i ,2sbjthiadiazinc-2,2-dioxide derivatives, as v-eU us structural analogs with different ring size (Scheme 9} (Hitayama et at , Bioorg. A M ed. Ckem. 2002, HK 1509: Kanbc ei ai„ Biooi^, A Med. Chem. leit. 2006, /6, 4090 and references cited therein).

Scheme 9

Acesuifeoie and fused aeestilfeme derivatives C such ad: benzo|e](l ,2?3]oxEdhiazih*4(3H}~one-2,2"dto?i.ides can be synthesized via the reaction of 1,3-diearhonyl derivatives A or 2-hydroxy carboxyl derivatives 8 aod,I> with SO? or ClSOsNHs, as described in Scheme 101 Li aides eta!, Syttiimh 1990,405 and references ch'ed therem; Ahmed dadi 6½. Chew. 1988. 53. 4112, Ahmed et oL /fefevmrfes 1989.29, 1391).

Scheme 1«

Aeeselfene derivatives €’ can also be synthesized via eyelixatlon of ailQ/fses or ends with FSO.tNCO iGlauss ei .<?/., Tetrahedron Lett. 1976, 7, 119} or OlSOvNOO (Rasmussen et ai, J. Org. Chem. .1973, 38, 21 14; lifer et at.,J. Org. Chew. .1986, 5./, 5405; Tripathi et o;., Indian ,/. Chem. Seel. 8 1.987, 26B, 1082.) as shown in Scheme 11. : Scheme Π

Saccharin derivatives may be synthesized by direct: oxidative eyelixadon of N-alkyi-o-soediyi-arenesollhnamides as shown in Scheme 12 (Xu et ah. Tetrahedron 2006, 6.:, /902 and references cited therein: Pal et u!, Let ten in Drag Design &amp; Discovery 2005. 2. 329}. Cyclization of o-carboxyi-arenesolfonyl chloride derivatives with primary amines can also provide saccharin derivatives (Robinson et at.,Ear:,/ Org. Chem. 2006, /9, 4483 and references died therein; Yam.ada etaL,J, Med. CMem. 2005, 48, 7457 and references cited therein; Da Seitmio et ah, J. Med. Chem. 2005, 48, 6897). Other hetefoaroffiatie feed isothiazol-3(2ii)-0ne~l,J -dioxide derivatives may he synthesized similarly.

Scheme 12

According to the present invenuon, chonipsemoty receptor Modifiers or ehemosensury receptor ligand modifiers of the present invention can be used for one or more methods of the present invention, e.y.. m< ululating a chemosensorv receptor and/or its ligands, in general, chennosensorv receptor modi nets and chemosensory receptor ligand modifiers of the present' invention are provided in a composition, such as, wg., an iugestihle composition. As used herein, an ‘ii-tgcstible conipoaitiotv5 includes any substance intended For oral consumption cither alone or together with another substance. The mgestiblo composition: includes both· “food or beverage products" and “non-edible products". By "Food or beverage products'', it is meant any edible product intended lor consumption by humans or animals., including solids, semisolids, or liquids (e.g>, beverages). The tcmi^non-ediblo products’"or “noncomestible eomposrtioh“ incl udes supplements, nutraeeutieais, functional. foodprtfouets fe.g., any fresh or processed food claimed to have a healih-pmtPoting and/or disease-preventing properties beyond, the basic nutritional: .function· of supplying nutrients}, pharmaoeutieal and over the counter medications, oral care products snob as dentifrices and mouthwashes, cosmetic products such as sweetened lip balms and other personal eare products that use suersiose and or other sweeteners.

The ingestihle composition also includes pharp3a0e»»^l.,.tpedicin»l or eomestihle composition, or alternatively in a formulation, e.y:., a pharmaceutical or medicinal formulation or a food or beverage product or formulation.

In one embodiment, the chcmosensory rCecptor modifiers or ehomosensory receptor ligand .modifiers provided by the present invention can be used at very low concentrations on the order of a few parts per million, in combination with one or moredenown sweeteners, natural or artificial, so as to reduce the concentration of the known sweetener required to prepare an ingestible: eoteposition having the desired degree of s weetness.

Commonly used known or artificial, sweeteners for use in such eonibiuatfons of sweeteners include but are not limited to the common saccharide sweeteners. egg., sucrose. fructose, glucose. and sweetener compositions comprising natural sugars, such as corn syrup (including high fructose conn syrup? or other syrups or sweetener concentrates· -derived from natural fin ή and vegetable sources, semi-synthetic "sugar alcohol" sweeteners such: as erythritoL isomalt, laciitol, mannitol. sorbitol, xylitol, tnaltodcxtrio, and the like, and tirtifkial. sweeteners such os aspartame, saccharin, acesulfame-K, cyclamate. sucralosc, and aliiame. Sweeteners also include eyelamic acid, mogroside, tagoiose, maltose, galactose, mannose, sucrose, fructose, lactose, neotame and other aspartame derivatives, glucose, D·tryptophan, glycine, maltitol, laetitol, isomalt, hydrogenated glucose syrup (NOS), hydrogenated starch hydroiyzatc (BSE), stevioside, rebauuioside A and other sweet Skmin· based glycosides, carrelame and other guanidine-based sweeteners, etc. The term, "sweeteners*' also Includes combinations of sweeteners as disclosed herein,

Chemosensmy receptor modifiers and chemosensory receptor ligand modifiers of the present invention can also he provided, individually or in combination, with any ingestlbic composition known or later discovered. for example, the ingest;bio composition can be a comestible cornpostion or noncomeshble composition. By "comestible composition", itis meant any composition that can be consumed as food by humans or animals, including solids, gel, paste, foamy material, semi-solids, lic|uids,or mixtures thereof. By 'btemeomeslible composition5*, it is meant any composition that is intended to be consumed or usecl by humans or animals not as food, including solids, gel, paste, foamy material, semi-solids, liquids,or mixtures shereof. The·noncbmeSiMe'composition includs, but is not limited to medical composition, which: refers to a noncomestihle composition intended to be used by humans or animals for tberapeutie purposes. By "animaT5, it includes any nun-freman animal, such as, for example, farm: animals and pots.

In one embodiment, the cbemosensory receptor modifiers and cheroosensory receptor ligand modifiers are added to a noneomesbble composition or non-edible product, such ns supplements, nutraeeutieals, functional food products (c.g,, any fresh or processed food claimed to have a bealth-promoring and/or disease-preventing: properb.es beyond the basic nutritional function of supplying: nutrients/, pharmaceuticaland over the counter medications, oral, care products such as dentifrices and mouthwashes, cosmetic products such as sweetened lip balms and other personal care products that use sucralosc and or other sweeteners.

In general, over (he counter (OTC) product and o/al hygiene product generally refer to product tor household anU.'or personal use widen may be sold without a prescription arid or without a visit to a medical professional l samples of the OTC products include, but are not I united to Vitamins and dietary supplements; Topical analgesics andor anaesthetic; Cough, cold and allergy remedies; Antihistamines and/or allergy remedies; and combinations thereof. Vitamins and dietary supplements include, but are not limited to vitamins, dietary supplements, tonics/boided nutritive drinks, child-specific vitamins, dietary supplements, any other products of or relating to or providing nutrition, and combinations thereof. Topical analgesics and/or anaesthetic include any topical creamfeointments/gels. used fo alleviate superficial or deep-seated aches and pains, e.g. muscle pain; tcethmg gel. patches with analgesic ingredient; and combinations thereof. Cough, cold and allergy' remedies include, but are not limited to decongestants, cough remedies, pharyngeal preparations, medicated confectionery, antihistamines and ehikbsnee.iiic cough, cold and allergy remedies; and combination pi'duets. Antihistamines and/or allergy remedies include, but arc not limited to any systemic treatments for bay fever, nasal allergies. Insect bites and stings. Examples of oral hygiene product.' include, but arc not limited to mouth cleaning strips, toothpaste, toothbrushes, ntoufewashes/dental rinses, denture care, mouth, fresheners ai-home teeth whiteness and dental floss.

In another embodiment, the chcmusensory receptor modifiers and ehemosensory receptor ligand modifiers arc added to food or beverage products or formulations, Examples of food and beverage products or formulations include, but are not limited to sweet coatings, frostings, or glares for comestible products or any entity included its the Soupcategory, the Dried Processed Food category, the Beverage category, the Ready Meal category,, the Canned or Preserved Food category, the Frozen. Processed Food category, the Chilled Processed Pood category, the Snack Food category, the Baked Goods category, the Confectionary category, the Dairy Product category, the Ice Cream category, the Meal Replacement category, the Pasta and Noodle category, and the Sauces, Dressings, Condiments category, the Baby Food category, and/or the Spreads category.

In general, tire Soup category refers to eatmed/preserved, dehydrated, instant, chilled, 11111' and frozen soup. For the purpose of this definition soup(s) means a food prepared ironimeat, poultry, fish, vegetables, grains, fruit and other ingredients, cooked in a liquid which may include visible pieces: of some or all of these ingredients, it may be clear (as a broth) or thick tas a chowder}, smooth.. purecd or chunky, ready-to-serve, semi-condensed or condensed and .maybe served hoi or cold, as a first course or as the mam course of a meal or as a between meal snack -(sipped like a beverage). Soup may he used as au ingredient for preparing other meal components and. may range front broths {consomme) to sauces (cream or eheesedsased soups). ^Dehydrated and Culinary Food Category"' usually means: ti) Cooking aid products such as: powders, granules, pastes, concentrated liquid products, including concentrated bouillon, bouillon and bouillon like products in pressed cubes, tablets or powder or granulated form, which are sold separately as a finished product or as an ingredient, within a product, sauces and recipe mixes (regardless of technology); til) Meal solutions products such as: dehydrated and freeze dried soups, including dehydrated soup mixes, dehydrated instant soups, dehydrated ready-’io-cook soups, dehydrated or ambient preparations of ready-made dishes, meals and single serve entrees including pasta, potato and rice dishes: and (hi) Meal embellishment products such as: condiments, marinades, salad dressings, salad toppings, dips, breading, leaner mixes, shelf stable spreads, barbecue sauces, liquid: recipe mixes, concentrates, sauces or sauce mixes, Including recipe mixes for salad, sold as a finished product, or as art ingredient within a product., whether dehydrated, liquid or frozen.

The Beverage category usually means, bev emgcw beverage mixes and eonc-entrates, ineindiag but not limited to, carbonated and non-esrbonated beverages, alcoholic· and non-aleobolie beverages, ready to drink beverages, liquid concentrate:-formulations for -propsring beverages such as sodas, and dry powdered beverage precursor mixes. The Beverage category also include the alcoholic drinks, the soft, drinks. Sports drinks. Isotonic beverages, and hot drinks.. The:alcoholic drinks Include, but are not limited to beer, oider/perry:, FABs, wine, antispirits. The soli drinks include, hut are not limited to carbonates, sucha as colas and. nom .colacarbonates: fhm juice, such as juice, nectars, juice drinks and fruit flavoured drinks; bottled water, which includes sparkling water, spring water and purifieduabie water; functional drinks, which can be carbonated or still and include sport., energy or elixir drinks; concentrates, such as liquid and powder concentrates in ready to drink measure. The bet drinks include, but are not limited to coffee, such as fresh, instant, and combined coffee; tea, such as black,, green, white, oolong, and flavored tea; and: other hot drinks, io.eh.sdmg flavour-, malt- or plant-based powders, .granules, blocks or tablets mixed with milk or water.

The Snack Food category generally reion' to any (bod that cars bo a light informal meal including, but not limited to Sweet and satoury stacks and snack bar:'. Examples of snackc food include, but are net limited to ixidt snacks, eirips/crisps, extruded snacks* iertilla/cem cliips, popcorn, pretzels, mbs and other sweet and save cry snacks. Examples of snack bars include, but are not Hunted ip granola/muesii bars, breakfast bars, energy bars, fruit bats and other snack bats.

The Baked Goods category generally refers to any edible product the process of preparing which involves exposure to heat or excessive sunlight. Examples of baked goods include, but me not limited to bread, buns, cookies, muffins, cereal, toaster pastries, pastries, waffles, kuthhs, biscuits, pies, bagels, tarts, quiches, cake, any baked foods, and. any combination thereof.

The lee lb coin category generally refers to frozen dessert containing cream and sugar and flavoring. Examples of ice cream ioelnde. but are not limited to; impulse see cream; take-home ice cream: frozen-yoghurt and artisanal ice cream; soy, oaf bean (e.g„ red bear, and' •taxing bean), and rice-based, ice creams.

The Confectionary category generally refers to edible product that is sweet to the taste. Examples dfconfep«paary.i»eh|^:.^ are bot limited to candies, gelatins, chocolate confectionery, sugar confectionery, gum, and the likes and any combination products.

The Meal Replacement gategroy generally refers to any food intended tit replace the normal meals, particularly for people having health or fitness Concerns. Examples of meal replaernent include, but are not limited to slimming products and convalescence products,

The Ready Meal category generally refers to any food that can be served as meal without extensive preparation or processing. The read meal include products that have had recipe ''skills1' added to them by the manufacturer, resulting in a high degree of readiness, completion ami convenience. Examples of ready meal include, but are not limited to eannedfpreserved, frozen, dried, chilled ready meals; dinner mixes: frozen pizza; chilled pizza; and prepared salads.

The Pasta and/Noodie eategroy includes any pastas and/or noodles indudhig, but not limited to canned, dried: and. ehilied/fi'esh pasta; and plain, Instant, chilled, frozen and snaek noodles.

The Canncd/Prcscrved Food category includes, but is not limited to can»ed*preservcd meat and meat pukiu..i\. fish sea food, vegetables, tomatoes, beans, fruit, ready meals, soup, pasta, and other canned ptoses s ed foods.

The Frozen P.roc cswd Food category includes, but is not limited to frozen processed red meat, processed poultix, processed ftsh/seafoou, processed vegetables, meat substitutes, processed potatoes, bakery products, desserts, ready meals, pizza., soup, noodles, and other frozen food.

The Dried Processed Food category includes, but is not limited to rice, dessert mixes, dried ready meals, dehydrated soup, instant soup, dried pasta, plain noodles, and· instant' noodles.

The Civil] Processed Food categroy includes, but is not limited to chilled, processed meats, processed fish, seafood products, lunch kits, fresh cut fruits, ready meals, pizza, prepared salads soup, fresh pasta and noodles.

The Sauces, Dressings and. Condiments .eatpfory includes, but is not limited to tomato pastes and purees, bouliloo/stoek cubes, herbs and spices, monosodium glutamate (MSG), table sauces, soy based sauces, pasta sauces, wef/coohiug sauces, dre sauces/powder mixes, ketchup, mayonnaise, mustard, salad dressings, vinaigrettes,: dips, pickled products, and other sauces, dressings and condiments.

The Baby Food oategroy includes:, hut is note Iimred to milk- or soybean-based, formula; and prepared,, dried and. other Baby: food.

The Spreads category Includes, but Is not limited to jams and preserves, honey, chocolate spreads, nut based spreads, and yeast Based spreads.

The Dairy Product category generally refers to edihh. product produced from mummers milk. Examples of dariy product include, but are not limited to drinking milk products, cheese, yoghurt and sour milk drinks, and other dairy products-

Additional examples for comestible composition, particularly food;and beverage products: or formulations, are provided as follows. Exemplary comestible compositions include one or more confectioneries, chocolate confectionery, tablets:, couniiines,. bagged sclilincsSoltliues, boxed assortments, standard Boxed assortments, twist wrapped miniatures, seasonal chocolate, .chocolate with toys, aifejores, other chocolate confectionery, mints, standard mints, power minis, boiled sweets, pastilles, gums,.tellies and chews, toffees, caramels and nougat, medicated confectionery. lollipops, liquorice, other sugar confectionery, guru, chewing gitm, sugarized gum. sugar-free gum. functional gum. bubble gum. bread, packaged ''industrial bread, uopackaged-’arnsanal broad, pastries, cakes, packa:ged.dndastrial cakes, uirpackagcd/artisanal cukes, cookies, chocolate coated biscuits, sandwich biscuits, ill led biscuits, savory biscuits and crackers, bread substitutes, breakfast cereals, rte cereals, family breakfast, cereals, flakes, muesli, other cereals, children's breakfast, cereals, hot. cereals, ice cream, Impulse ice cream, single portion dairy Ice cream, single portion water tee cream, multi-pack dairy ice cream, multi-pack water ice cream, take -home iec cream, take-home dairy ice cream, tec cream desserts, bulk ice cream, take-borne water Iec cream, frozen yoghurt, artisanal ice cream, dairy-products, milk, Iresh.pa.steurtzed milk, full fat fresh, pasteurized milk, semi skimmed fresh, pasteurized milk, long-life/uht milk. full fat king Itfe unl milk, semi skimmed long life/uht milk, fat-free long life/uht milk, goat: milk, eoiidensedmvapo.mted .milk, plain eondensedrevaporated milk, flavored, functional and other condensed milk, flavored milk drinks, dairy only flavored milk drinks, flavored milk drinks with fruit juice, soy milk, sour milk drinks, fomented dairy drinks, coffee whiteners, powder milk, flavored powder milk drinks, cream, cheese, processed cheese, spreadable processed cheese, nmproadafele processed, cheese, unprocessed' cheese, spreadable unprocessed cheese, hare! cheese, packaged hard cheese, ufipackaged hard cheese, yoghurt, plaifonaitu-al yoghurt, flavored yoghurt, fruited- yoghurt,, probiotic yoghurt, drinking yoghurt, regular drinking yoghurt, probiotic drinking yoghurt, chilled and shelf-stable desserts, dairy-based desserts, soy-based desserts, chilled snacks, frontage frais and quark, plain ffomage frais and quark, flavored ffomage frais and quark, savory frontage fens and quark, sweet and savory snacks, irultsnaeks, ehips/orisps, extruded snacks., tortilla/eorn chips, popcorn, pretzels, nuts, other sweet and savory snacks, snack fears, granola bars, breakfast fears, energy bars, fruit bars, other snack fears, meal, replacement products, slimming products, convalescence drinks, ready meals, canned ready meals, frozen ready meals, dried ready meals, chilled ready meals, dinner mixes, frozen pizza, chilled pizza, soup, canned soup, dehydrated soup, instant soup, chilled soup, hot soup, frozen soup, pasta, canned pasta, dried, pasta, ekilled/fossh pasta, noodles, plain nooili.es, instant noodles, cups/bowl instant noodles, pouch, insiant noodles, chilled noodles, snack noodles, canned food, canned nieai and meat prod nets, canned fish/seafood, canned vegetables, canned tomatoes, canned beaus, canned fruit, canned ready meals, canned soup, canned.pasta, other canned foods, frozen food, frozen processed red meat, frozen processed poultry, frozen 'processed fbh/scafood, frozen processed vegetables, frozen meat substitutes, frozen potatoes, overs baked potato chips, other overs baked potato pfoditets,.non-oven frozen potatoes, frozen hL·ess moducts, frozen desserts, frozen ready meals, frozen pizza, bw.cn soup, frozen noodles, ofocn home food, dried food, dosseri mixes, dried ready meals, dehydrated soup, instant soup, dried pasta, plain noodles, instant noodles,, eops/bowl instant noodles, pouch instant noodles, chilled food, chilled processed, meats, chilled fish/seafood products, chilled processed fish, chilled coated fish,...chilled, smoked fish, chilled lunch kit, chilled ready meals, chilled pizza, chined soup, chilied/lVesh pasta, chilled noodles, oils and fats, olive oil, vegetable and seed oil, cooking fats, butter, margarine, spreadable oils and fats, functional spreadable oils and fats, sauces, dressings and condiments, tomato pastes and purees, houlllon/stoek cubes, stock cubes, gravy granules, liquid stocks and fends, herbs and spices, fermented sauces, soy based sauces, pasta sauces, wet sauces, dry sauces-povzder mixes, ketchup, mayonnaise, regular mayonnaise, mustard, salad dressings, regular salad dressings, low fat salad dressings, vinaigrettes, dips, pickled products, other sauces, dressings and condiments, baby food, milk formula, standard: milk formula, follow-on milk formula, toddler milk formula, hypoallergenic milk formula, prepared, baby food, dried baby food, other baby food, spreads, jams and preserves,, honey, chocolate spreads, nub based spreads, and yeast-based spreads. Exemplary comestible compositions also include .'confectioneries, bakery products, ice creams, dairy products, sweet and. savory·· snacks, snack bars., meal, replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fiats, baby foods, or spreads or a mixture thereof Exemplary comestible compositions also include breakfast cereals, sweet beverages or solid or liquid, concentrate compositions for preparing beverages, ideally so as to enable foe reduction in concentration, of previously known saccharide sweeteners, or artificial, sweeteners.

Typically at least a chemosensory receptor modulating amount, a chemosensory receptor ligand modulating amount, a sweet flavor modulating amount, a sweet .flavoring- agent amount or a sweet flavor enhancing amount of one or more of the cbemosensory receptor modifiers Or chemosensory receptor ligand modi fiers of the present invention w ill be added to the comestible or medicinal prod uct, optionally in the presence of known sweeteners, e.g. f so that foe sweet flavor modified comestible or medicinal produet has an increased, sweet taste as compared to the comestible or medicinal product prepared without the modifiers of the present invention. as judged by human beings or animals in general, or in the ease of ibnnulalions testing, us judged by a majority of a panel of at least eight human taste testers, v»u 'procedures commonly known in the field.

The eobeentration of.wvcel flavoring agent needed to modulate or improve the flavor of the comestible or medicinal product or composition tv ill of course depend on many variables, including the specific type of comestible composition and its various ether ingredients, especially the presence of other known sweet flavoring agents and the boncentfafions thereof the natural genetic variability and indiv tuual preferences and health conditions-of varioushuman beings tasti ng the compositions, and the subjective effect of the .particular compound on the taste of such cheniosensory compounds.

One application of the ehemoseasory receptor modifiers and/or ebemosensory receptor ligand modifiers is for modulating (inducing·, enhancing or inhibiting) the sweet taste or other laste properties of other natural or synthetic sweet iastants. and comestible compositions made therefrom. A broad but also low range of eoncenirations of the compounds or entities of the present invention.would 'typically be required, ufo from about 0.001 ppm to 100 ppm, or narrower alternative ranges from, about 0,1 ppm to about 10 ppm, from about 0.01 ppm to about 30 ppm, from about 0,05 ppm to about 10 ppm, from about 0,03 ppm to about 5 ppm, or from about 0,02 ppm to about 2 ppm, or from about 0.01 ppm to about 1 ppm.

In yet. another embodiment, the chemoseusery receptor modifier and. ehemosensory receptor ligand modifier of the present invention eaft be provided in pharmaceutical c ompositions co n taming a therapeutically effective amo unt of one or more compounds of dm present invention, preferably in purified form, together with axuiishle amount of a pharmaceuticaliy acceptable vehicle, so. as to provide the form for proper administration to a patient..

When administered to a patient, the compounds of the present invention and pharmaceutically acceptable vehicles are preferably sterile. Water is a preferred vehicle when a compound of the present invention is administered, intravenously. Sal im? solutions and aqueous dextrose and glycerol solutions can. also be employed, as liquid vehicles, particularly for Injectable solutions. Suitable, jfoMmacetrtieal. vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk., silica gel, sodium stearate, glycerol mottosteanue, talc, sodium chloride, dried skim milk, glycerol.» propylene, glycol, water, ethanol aru) the like. The present pharmaceutical compositions, if desired, can also contain nunoi arnotmts of wetting m emulsifying agents, or pH buffering agents, hi addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.

Pharmaceutical compositions comprising a compound of the present indention may be manufactured by means of conventional mixing, dissoh tog. granulating. dragee-making, levigating, emulsifying, encapsulating, entrapping or hcphilizing processes. Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate processing o! compounds of the prevent indention into preparations which can be used pharmaecuhcolly, Proper formulation .is dependent upon the route of administration chosen.

The present pharmaceutical compositions ean take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, ponders, sustained-release formulations. suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use In some embodiments, the pharmaceutically acceptable vehicle is a capsule (see e.g>, Grosswaid et al, Gnited. States Patent No. 5,698,155). Other examples of suitable pharmaceutical vehicles have been; described in the art: (see Remington: The Science and Practice o f Pharm acy,, Philadelphia College of Pharmacy and Science, 2(f' Edition, 2060)..

For topical administration a compound of the present invention may be formulated as solutions, gels, ointments, creams, suspensions, etc, as is, well-known, in the art.

Systemic formulations' ineludethose designed for administration by injection., subcutaneous, intravenous, Imramnscular, intrathecal or miraperitoueal infection, as well as those designed for fransdermal, hransmneosai, oral or pulmonary administration, Systemic fbfmniaiions may be made in combination with a further active agent that improves mucociliary clearance of airway mucus or reduces mucous viscosity. These active agents include, but are nett, limited to, sodium channel blockers., antibiotics, N-ucety! cysteine, homocysteine and phospholipids. in some embodiments, the eomponnds ofthe present; invention: are ihrmidaied la: accordance with routine· procedures as a; pharmaceutical composition adapted lor intravenous administration to human beings. Typically, compounds of the present invention for intravenous administration are solutions in. sterile ssofonie aijneous buffer. For injection, a compound of the present invention, may be formulated in aqueoos solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. The solution may contain fotnabatovy agents such as suspending, stabilizing an Tor dispersing agents. When necessary, the pharmacbadcal compositions may also include a solubilizing agent.

Pharmaceutical compositions for intravenous administration may optionally include a local anesthetic such as lignocaine- to ease pain at the she of rhe injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachctte indicating the quantity of active agent. When the compound of the present invention is administered by infusion, it can he dispensed, for example, w ith an infusion. bottle containing sterile pharmaceutical grade water or. saline,. When the-compound of the present, invention is admiutstered by injection, an ampoule of sterile water for iniccdon or saline can be provided so ;h,n the ingredients may be mixed prior to administration. for transmueosal administration, penetrants appropriate to the barrier to he permeated are used in the formulation. Sited penetrants are generally known ip the art.

Pharmaceutical compos!horn for oral delivery may be i.p the form of tablets, lozenges, aqueous or oily suspensions, gramsl.es, powders, emulsiops, eapsiil.es, syrups, or elixirs, for example. Orally administered pharmaceutical compositions may contain one or more optionally agents, for example, sweetening agents stsch as;·fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wfotergreen, or cherry coloring agents and preserving agents* to provide a pharrnaeuufiealiy palatable preparation.

Moreover, where in tablet or pill form, the phannaeeiStical compositions may be coated, to delay disintegration and absorption In foe gastrointestinal irntfo Thereby providing a. sustained action over an extended period Of time. Selectively permeable mesnhranes surrounding aft osrnotically active driving compound are also suitable for orally administered compounds of the present invention in these later platforms, fluid from the environment surrounding the capsule is imbibed by the driving-compound» which swells to displace the agent or agent •composition, through an aperture. These delivery platforms can provide an esseiitially xe.ro order delivery profile as opposed io the spiked profiles of immediate release formulations, A time delay material sueh as glycerol, monosiearate or glycerol stearate may also be used. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine. cellulose, magnesium cashonatc. vU . Such vehicles arc preferably of pharmaceu ii e a I gt ade.

For oral liquidp&amp;p&amp;rationsMdt as, for example, suspensions, elixirs and solutions, suitable carrier's, excipients, or diluents include water, saline, alkyleueglycols (eg., propylene glycol), polyulkykne glycols (o.”·,, polyethylene glycol) oils, alcohols, slightly acidic buffers between pH 4 and pH ii (eg., acetate, citrate, ascorbate at between about 5.0 mM to about 50.0 mM) etc. Additionally, flavoring agents, preservatives, coloring agents, bile salts, acyiearnitines and the like may be added. for buccal administration, the pharmaceutical compositions may take the form of tablets, lozenges, me. formulated in conventional manner.

Liquid drug formulations suitable for use with nebulizers and liquid spray devices and EBD aerosol devices will typically include a compound of the present invention with a pharmaceutically acceptable vehicle. Preferably, the pharmaceutically acceptable vehicle is a liquid such as alcohol, water, polyethylene glycol or a pertlnoroearbon. Optionally, .mother material may be added, to alter the aerosol properties of the solution or suspension of compounds of the invention. Preferably, this material is liquid such as an alcohol, glycol.-polyglycoi ora fatty acid. Other methods offbmrulating liquid drug solutions or suspension suitable tor use in aerosol devices are known to those of «kill in the art (sec. e.v., Btesalski. United States Patent No. 5,112.598; Biesalski. United States Patent No. 5,55b ol I) A: compourrd of the present invention may also be fofmttlated in tecta! or vaginal pharmaceutical compositions such as suppositories or retention enemas, eg.,containing conventional suppository bases such as cocoa fender or other glycerides, in addition to the formulations descri bed previously , a compound of the present: invention may also be formulated as, a depot preparation. Such long acting formulations may fee administered by in-plantation (lor example subcutaneously or intramuscularly) or fey intramuscular injection. Thus, for example, a compound of the present invention may be formulated:: with suitable poly merle or hydro phobic materials (for example, as an emulsion in an acceptable oil) Or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

When a compound of the present invention is acidic, if -nay be included in any of the above-described formulations as the free acid, a pharrn.aeeuticaliy acceptable salt, a solvate or hydrate. Pharmaceutically acceptable salts substantially retain the activity of the free acid, rnay be prepared by reaction with bases -arid tend to be more soluble in aqueous and other pro tic solvents than the cor responding free acid form. A compound of the present invention, and/or* pMttBaceu&amp;eal coippo&amp;itiaa thereof, will generally be used in an amount effective to achieve the intended purpose for use to treat or prevent diseases or disorders the compounds of the present invention and/or pharmaceutical eompbsitiods thereof, are administered or applied in a therapeutically effective amount.

The amount of a: compound of the present invention that will be effective in the trea tm en t of a particular disorder or condition disclosed herein w ill depend on the nature of the disorder or condition and can be determined by. standard ellnleal techniques known in the art. Inaddition, in vitro or in vivo assays may optionally he employed to help identity optimal dosage ranges. The amount of a compound of the present invention administered will, of course, be dependent on, among other factors, the subject being treated, the weight of the subject, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.

For example, the dosage may he delivered in a pharmaeeufieal composition by a single administoitiou, by multiple applications, or controlled release. In some embodiment, the compounds of the present invention are delivered by oral sustained release, administration. Dosing may be repeated intermittently, may be provided alone or in eotuhination with other drugs ahd may continue as long as required for effective treatment of the disease state or disorder,

Suitable dosage ranges lor oral, administration depend; on potency, but are generally between, about 0,001 mg to about 200 mg.'of a compound of the ."present invention, per kilogram body weight. Dosage mnges niay he readily determined by methods known to the artisan of ordinary skill the art

Suitable dosage ranges for intravenoitSi fl.v,} administration are about 0,01 mg to about 1.00 mg per kilogram, body weight. Suitable dosage ranges for intraoasai administration: are generally about 0.01 nig/kg body weight to about .1. mg/kg body weight. Si^positoties generally contain about 0,01 milligram to-about 50 .milligrams of a compound of the present invonii.au per kilogram body weight and comprise acti ve ingredient in the range of about 0.5% to about 10% by weight, Reeamruended dosages tor iutradermah intramuscular, inirape.riioueal, subcurancous. epidural, sublingual or intracerebral administration are in the range of about 0.001 mg to about 200 nig per kilogram of body weight. Inactive doses may be extrapolated from dose-response curves derived from in vitro or animal, model test systems. Such animal models and systems arc well-known in the art.

Preferably, i* therapeuticaHy effective dose of a compound of the present invention described herein will provide therapeutic benefit without censing substantial toxicity. Toxicity of compounds of the present invention may be determined: using standard pharmaceutical procedures and. may be readily ascertained by the skilled artisan. The dose ratio between tox ic and therapeutie effect is the therapeutic· index, A compound of the present invention u id prcferabls exhibit .particularly high therapeutic indices in treating disease ansi disorder. The dosage of a compound of the present itnemmu dose; died herein w ill pjeferahly be within a range ofeaoulaong e>:-neenu.ifion\ die- include an effect is e dove w -rh lirbc nr uo toxicity.

In certain embodiments of the present invenbou. the compounds of the present inventi'ort'and/orpharrnaceatical compositions thereof ean.be used in combination therapy with at least one other agent. The compound of the present inven tion and/or pharmaceutical, composition thereof and the other agent can act addibvely or. more preferably, synefgistically, in some embodiments, a compound of the presentinvention and/or pharmaceutical composition thereof is administered concurrently with the admins stmt ten of another' agent, which may be part of the same plnwmaceotieat Ροηφοχΐίίοη as the compound of die present invention or a different pbarmacenfical composition. In. other embodiments, a pbarmaceutieal composition o f the presen t Invention is adminisieredfrier or subsequent to administration of another agent. in still another embodiment, the ehemosensory receptor modifiers, and ehemosensory receptor ligand modifiers of the present invention and/or pharmaceutical compositions thereof may he advantageously used in human medicine.

When used to treat and/or prevent diseases or disorders, the compounds described herein, and/or phannaoeutieal compositions ussy be administered or applied singly, or in combination with other agents. Tile compounds and/or pharmaceutical compositions thereof may also be administered or applied singly, in combination with, other active agents.

Methods of treatment and prophylaxis by administration to a patient of a therapeutically electi ve amount of a compound described heroin and/or pharmaceutical composition thereof are provided herein. The patient may be an animal move preferably, a mammal and most preferably, a human.

In one example, the compounds described herein and/or pbariBaceutleal compositions (hereof, are administered orally, lire compounds of the present invention and/or pharmaceutic»! compositions thereof may also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutsueons linings (e.g., oral mucosa, rectal, and intestinal mucosa, etc,). Administration can be systemic or local. Various delivery systems are known, (e.g., encapsulation in liposomes, microparticles, micvoeapsules, capsules, «*·.) that can be used to administer a compound described herein and/or pharmaceutical composition thereof Methods.of adnunistratipn-include, bur are not limited, to, latradermai, intramuscular, intrapbritoaeat intravenous, subcutaneous, imranasal, epidural oral, sublingual intranasal, intracerebral mtravaginal, transdermal. rectally, by inhaiation, or topically, particularly to the ears, nose. eyes, or skin. The preferred mode of administration is left to the discretion of the practitioner and will depend in-part upon the site of the medical: eo.ftdii.tott. In most. instances, administration will result in the release of the compounds and/or pharmaceutical compositions thereof into the bloodstream.

In another example, it may be desirable to administer one or more: compounds of the present invention and/or pharmaceutical composition thereof locally to the amain need of •treatment1.. This may be achieved, for example, and not by way of limitation, by local ioftssfon during surgery, topical application, In conjunction with a wound dressing after surgery. by injection* by means of a catheter, by means of a snpposlfory, or by means of an implant, said implant being of a porous, nomporous, or gelatinous material, including membranes, such as sialastic membranes, or fibers. In one embodiment, administration can be by direct Injection .at the site (or former site) of the condition. in yef another example, it maybe desire.hie to introduce one or more compounds (dfihe present Invention md/ot pharmaceutical compositions thereof into the central, neswous system by any suitable route, including intraventricular, intrathecal and epidural injection. Intraventricular Injection may be fkeil stated, by an intraventricular eaiheter, for example, attached to a reservoir, such as an Ommaya reservoir , A eompouud of the present invention and/or pharmaceutical composition thereof may also he administered directly to the lung, by inhalation, For administration by inhalation, a. compound of the present invention and/or pharmaceutical composition thereof tnav be conveniently delivered to the long by a number of different device;'. Pot example, a Metered Dose Inhale? DMDF·), which utilizes canisters that contain a,suitable low boiling propellant, d ichlorodifluororncthanc, triehIoroiluoromcfbane, dichloio'tetraftuoroetl'janev^hnn dioxide or any other suitable gas) may be used to deliv er compounds of the present invention and/or pharmaceutical compositions thereof directly to. the lung.

Alternatively, a Dry Powder Inhale? r'DPP’i device may be used to administer a compound of the invention and/or pharmaceutical eoruposition thereof to the lung. DPI dev sees typically use a mechanism such as a burnt of gas to create a cloud of dry pow dor inside a container, which may then be inhaled by the patient, DPI devices are also well known in the art:, A popular variation is the multiple dose DPI f'MDDPP) system, which allows for the delivery of nt-'ae than one therapeutic dose. For example, capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the present invention and a suitable powder base such as lactose or starch for these systems.

Another type of device that may be used to deliver a compound of the present invention end/or pharmaoeistica! composition thereof to the lung.is a liquid spray device supplied, for example, by Aradigm Corporation, Hayward, €A, Liquid spray systems use extremely small nozzle holes to aerosolize liquid drug formulations that may then be elirectiy Inhaled Into the lung,

In yet another' example, a nebulizer is used to deliver a compound of ;he present invention and/or pharmaoeutleakcomposition thereof to the luug- Nebubzers create aerosols from liquid dreg formulations: by using, lor example, ultrasonic· energy to form fine particles that may be readily inhaled (see e.g., Ttersehoyle ei el, British. A Cmc&amp;\ 099, 80, Suppi 2S 96), Fxanipl.es of tebu; izers include devices supplied by Sheffield Pharmaceuticals, Inc (See, /Inner &amp;t ah* United States Patent No. 5,954,047; van der Linden ml, United States Patent No, 5.050Λ19; van der Linden m a/,, United Scares Patent No. 5,9/0,9741. and Bafelle Pulmonary Therapeutics, Columbus, OH.

In yet another example,, an electrohydrodynumie pEBD’’) aerosol device is used to deliver-a: eomfiouud of tire present invention and/or pharmaceutical composition thereof to the lung, BHD aerosol devices use electrical energy to aerosolize liquid drug, solutions or suspensions (see e.g,, Noakes et ml. United States Patent No, 4,795,559). The elech'ochemieai. properties of the forumbdou may be important paraniefeis to optimize when delivering a compound of the present invention and/or pharmaceutical composition thereofto the lung with an FHD aerosol device and such optimization is routinely performed by one of skill in the ail FJID -aerosol devices may mote efficiently deliver compounds to the lung than other pulmonary defect\ technologies. in yet another example, the compounds of the p event im enmni and /a pharmaceutical compositions thereof can be delivered in a vesicle, in particular a liposome (Langer, 19911, Science 249; 1527-1.533; Treat et al, in 'Tiposomes in the Therapy of infectious Disease ami Cancer/' Lopez-Berestelo and Fidler (eds,), Liss, New York, pp, 353-355 (19X9); see generally “Liposomes in the Therapy of Infectious Disease: and Cancer,- Lo;iez-Berestein and Fidler (eds.), Li'-,". New York, pp.353-3o5 (19X9)). in yet another example, the compounds of the present, invention and/or pharmaceutical compositions thereof can be delivered via sustained release systems, preferably oral sustained release systems, in one embodiment, a pump may be used I See, Langer, supra, Scftoa* 1987, CMC Cfit. Me/, BmmedEng, 14:261; SaudefcM al, 1989, 'v Engl JMed. 32.1:574).

In yet another exampl e, polymeric material* mm be used (see “Medical Applications of Controlled Release/" Langer and Wise (eds.), CRC Pres,, Boca Staton, Florida (1.9741: ‘'Controlled Drug Bioavailability," Drug Product. Design and Performance, Smoleo and Ball (eds.K Wiloy, New York (1984); Lunger ef ol. 1983.3 Mtscrouml Sci, Rev, Macmmol Chaw, 23:61; see ak&amp; Levy et ¢)/.,1985, Science 228; 190; During et al, 1989, Amy '-Nmml 25/351Howard et el, 1989, ,7. 'Nmmsurg, 71; 105),

In still other embodiments, polymeric materials are used lor oral sustained, release delivery. Preferred polymers include sodium enrboxymethy ice! In lose. hydroxypropylceUnlese, hydroxypropylmethylcelluiose and bydrOxyethyleelUdose (most preferred, hydroxypropyl. rnediyleellulose). Other preferred cellulose ethers hats.' been described (Alderman, 1«/.,/

Mhwm. fee/. &amp; Prod. ML, 1.984. 5(3) 1-9). Factors affecting drug release are ;well,known to the skilled artisan and have been described in the art fBamha .et aL· Im.,/. Phurm„ 1979,2, 307), M yet another example, enteric-coated preparations can be used for oral sustained release administration. Preferred coating materials include polymers with a pH-dependent solubility (he., pH.-eon.troIbd release), polymers with a slow or pil-depcndent rate of swelling. dissolution or erosion {/.e., tone-controlled release), polymer?· that a/c degraded by e a? vines ihe., enzyvnowomrolled release) and polymers that fotmilrm layers that are destroyed by an increase in pressure (lev, pressore-eontrolled release».

In still another example, osmotic delivers systems are used for oral sustained release administration (Verma el at., Drag Dev, fait. Phann., 2tH)tf 26:695-708). In yet other embodiments. OROS:"' osmotic devices, are used formal sustained release delivery devices flhecuues 0/ at., United States Patent No, 3,845,770; Theeuwes el £?/., United States Patent No. 3,916.899).

In still aaotbet example, a ccsutrolled-rdease system can be placed In proximity of the target of the compounds and/or pharmaceutical composition of the invention, thus requiring only a .fraction of the systemic· dose (See, e>g., Goodxon, .in “Medieai Applications of Controlled Released' supra, vol. 2, pp. 1 15-138 $ 19S4). Other controlled-releas. sv'tons discussed in hanger. 1990. SJetuv .:49,1577-1033 may also be used.

Having now generally described the invention, the same will be more readily understood: by reference to the following examples, which are provided by warn of illustration and. are not intended as limiting. It is 'understood that various mod.rficatious and. changes can be made to the herein disclosed exemplary embodiments without departing from the spirit and scope of the invention. examples EXPERIMENT 1: Modeling mk! Meftlfleatlott··bfIPatefttiai Chemesensory Meceptor ligand Enhancer

The geneml procedures for identifying .a potential ehemosensory receptor ligand enhancer is summarized :»s the tclldwittg. 1. Constructing a model of the structure of the Venus flytrap 11R2 domain 2 Docking a ehemosensory receptor ligand, <ng., a sweetener into the active site of the striioture ofthe Venus flytrap domain of T|R2, with or without T1R3 present 3.. Docking a ehemosensory receptor ligand enhancer, e,g,, a sweet enhancer into the active site in the presence of the ehemosensory receptor ligand, e,g., the sweetener 4, Selecting a ehemosensory receptor ligand enhancer, sweet enhancer •candidate, based:on.·two criteria: a) it fits the active site in the morlel, and b) if forms productive interactions with she Venus flytrap domain of TlR.2 and wtth die diernosensory receptor ligand, the sweetener, interactions can be van dcr Waals, burial of hydrophobic atoms or atomic groups, hydrogen bonds, ring stacking interactions, ot sail-bridging electrostatic interdetions. Key residues for such interactions include the hinge residues, the near active site, the pincer residues, e.g., interacting residues described in the present inyeatioa. Candidates are not restricted to fitting completely within the active site, us it is open and ehemoscn.so.ry receptor ligand enhancer candidates may extend beyond the active site as long as they partially extend into it,

MaMMiteteSdEg A model of the structure of the Venus Flytrap T1R2 domain may come from crystal structures of T1R2 or of TIR2 complexed with ΊΊ R.V The domains may be in open or in closed form, and may or may not be APO or contain a ligand. Aifemathciy a model of the structure of the Venus Flytrap T1R.1 domain may be built using standard homology modeling methods using crystal structures of available Venus flytrap domains such as the mOluR receptor Venus flytrap domains as templates-to.construct the model.

An example of a procedure .for building such a model is to use the commercial software Homology or Modeller from the Aecclrys Corporation'that is well documented in the literature and available eoarmercially. Alternative eoufbrmations of tire model may further be exploreditslng addtdonal molecular mechanical techniques that may Include but are not limited to normal mode analysis to explore rdarbe movement *>f the lobes of the model, loop generation techniques to generate alternative con formations of loops in the model, or Monte Carlo and/or molecular dynamics simulations,

BssMss A: ohemosehsory receptor ligand, e.g., sweetener was first docked into the active site of T1R2. Its modeled pose in the active site was selected by its ability to form productive van. der Weals, ring stacking, hydrogen bonding, and/or salt bridging interactions with interacting residues within, the active site of the Venus flytrap domain of ΤΙΙΪ.2. A. candidate tor a ehemosensory receptor ligand modifier, e.g,:, sweet:enhancer was then dor-fed into tire .active site in the presence of the ligand, e,,g., the sweetener 'described in the previous paragraph, its active pose and its candidacy as a potential ehentosensory receptor ligand, modifier, tog., sweet enhancer was based on sis ability to form productive interactions in the form of \an dor Waals, rim’ stacking, hydrogen bonding, and oi sail bridging interactions with interacting resumes described in the present invention, with additional residues of die T1 R.2 domain, arid optionally with the eheriioseasoiy receptor ligand. «eg., tlm sweetener placed ?«the active site as described above. A molecule was considered a candidate if it can he docked into the active site in the presence of a cheraosensory receptor ligand, e.g., sweetener, forming productive interactions with interacting residues described in the present invention. We defined.fvvo spaces within the active site: a first space occupied by a chomosensory receptor ligand, e.g,, sweetener, and a second space occupied by a chentosensory receptor ligand modifier, egg,, enhancer. Modeling and mutagenesis results established key residues that were considered to be likely to line these spaces for the chcmosensory receptor ligand, e.g., sweeteners and chentosensory iCvCpt»·» ligand modifier, egg , sweet enhancers. In the context e-four study, ''residue lining the space" meant th.it the residue had backbone and/or side-chain atoms that were positioned so that they can potentially interact with atoms of ihe.ehemosenso.ry. receptor ligand, e.g., sweetener (space #-!) and/or eheniosonsdry receptor ligand modifier, e.g., sweet enhancer (space #2), While the eBemosensory receptor ligand, e.g., sweetener and che.mosensd.ry receptor ligand modifier, c.y., sweet enhancer themselves eannoi occupy the same space, their corresponding spaces may overlap due to the ability of residues to contact both the ofiemoxensory receptor ligand, e.g;, sweetener and the chemoscnsory receptor ligand modifier, e.g-, sweet enhancer, due to protein: flexibility, due to ligand flexibility, and due to the potential, for: multiple binding modes for a chemosensoty receptor ligand,: wg., sweetener or ehemesensory receptor ligand modifier, e.g., sweet enhancer. Information on important residues lining space #1 and space#2 came from modeling and docking and from site directed mutagenesis.

The hinge residues are considered to he associated with the first space (space hi). We have discovered that one of the spaces occupied by a ehemosensory receptor ligand, eg.,. sweetener is partially lined by residues herein, called. hinge residues. Marry Venus flytrap domains have been .crystallized with agonists includingmGluRI, mGl.uRd, and mfoluRB that, show agonists .forming interactions with homologous residues to those identified herein for TIR2. Many ehemosensory receptor ligands, e.g,, sweeteners docked to the.model 0.fTllS:2 can be docked to this region. Our site directed mutagenesis also provides strong evidence to support the finding Thai hinge residues or residues spatially adjacent lo it me key residues to the activation of a ehemosensory receptor, e.g., Ti R2 related receptor. Since ehemosensory receptor ligands, e.g., sweeteners vary in size, there are additional residues lining first space for larger residues where the list of these additional residues is dependent, .partially on the' size of the ehemosensory receptor ligand, e.g.* sweetener.

Pincer residues are considered'fa be associated with ike second space (space #2). 'Venus flytrap domains are known to transition from an ‘'‘open” state to a “closedf state on agonist binding. 7 he flytrap domain is comprised of two lobes commonly referred ίο m the literature as the upper lobe and lower lobe. In the “open* state the lobes are further apart, while in the dosed state the lobes undergo a relative motto» that brings the upper and lower lobe closer together. In addition to direct stabilization ofthe closed state of T1R' by rhe agonist, our modeling study has demonstrated that there is additional stabilization of the closed state through interactions of residues on the upper lobe with corresponding residues on the lon er lobe that are herein called the ‘"pmcer residues” We have discovered, that an interacting site, &amp;g.t interacting space for a ehemosensory -receptor ligand ..modifier, e.g... sweet enhancer is the space that is partially lined by these pincer residues, since additional interactions m this region can further stabilize the closed, agonized form of the Veuus: flytrap domain. Our site directed mutagenesis study also provides evidence to support the finding that piueer residues and residues spatially adjacent to them, are key residues associated1 with modulation of ehemoseusory receptor hgands t g.. enhancement activity of the ligand.

The first space and se&amp;mi spam can be swapped. In the above discussion the chemosensoiy receptor modifier, e.g\„ sweetener binds to the binge while the ehemosensory receptor ligand modifier, egy, sweet enhancer binds to the pincer region. This is just one example and should not be construed restrioti vely. For example, our modeling and docking study has also demonstrated that a likely binding mode tor saccharine as an agonist, (sweetener) involves binding to the pincer region. Such result was further supported by our site-directed mutagenesis. With a ehemosensory receptor modifier, reg., sweetener bound,to the pincer region, there is opportunity for .further stabilization of the closed form of the Venus flytrap domain through binding of a ehemosensory receptor ligand modifier, cap, sweet enhancer to the hinge region. L Docking.

Dodd tig. id gen era! iy eon s i dered m the process of it an a iating an d rot a u \ i g die candidate mo locate relative to a chevnoscosory receptor, e.g., !"! R2 structural model while, simultaneously adjusting internal torsional angles of the candidate molecule to fit the candidate molecule into the arose site of the chemosensory receptor, e.g·., T1 R2 structural model Poses of the candidate molecule 1positions, relative orientations, and internal torsions} are selected based on whether the molecule Ilfs the active site, and whether the molecule can form productive van der Wauls interactions, hydrogen bonds, ring stacking interactions, and salt bridge interactions with residues of the active site and with the che.niose.nsor> receptor ligand, e.g,, sweetener. Key residues can be identified. Λ candidate is considered more likely if it interacts with sets of residues in the active site as the hinge region, the near active site, the pincer residues, and the totality of the active site. It is also considered more likely if it forms direct interactions w ith a chemosensory receptor ligand, wg., a sweetener, 2, Homology Modeling

Homology modeling is generally considered as the process of constructing a model of the Venus dytrap domain of a ehemosemery receptor, e,g., T1R2 from its ammo acid sequence and iksn the three dimensional coordinates of one or more homologous Venus flytrap domain proteins. Homology modeling may be performed using standard methods weil-desenhed in the literature and available in commercial software such as the Homology program or Modeler from the Aeeelrys Corporation. Models based on eatperinrsefflally determined structures of open and closed forms, as 'well as animation of models using normal mode analysis,, were used to define the pincer residues discussed above, ffoempimxjihfafra^ F igures 5 to 10 illustrate ioveracting spaces and residues .tsv stated w ith one of our molecular modeling studies. EAP!"RrMENT 2: Mutagenesis Study for Ideiitlieatlou of Cfeefoosensory Eecepior ligand Muddler: Enhancer M our previous patent applications {Iniernational. Publication No. W007047988: and International Publication No WOO/OI04709), we described a method using human-rat chimeric sweehuruami chimeric, receptors to map the binding sites of sweet and umatni instants.

Our data dcnumauated dun a number of sweeteners, including sucrose, fructose, arspariamc, neotamc, D-Uypiophar: iD-Vrp), Acestdfhnie K, saccharin and duieim all Interact with the T1R2

Venus flytrap domain (VFT». while the uniami tastants, including L-glutamate, iTiosinc-5*'-fnortophospbale (IM P), and guanosioe-5-monophosphate. (GMP), all interact with the ΊΊ R1 Venus flytrap domain.

Under the guidance of molecular modeling, we performed site-directed mutagenesis on human IIR2 VFT. The mutagenesis was done using the routine PGR-based method, lluma»T! Rl mutants were transiently transfected into HEK293 eel! together with the human TTR3 wild type eDNA, and the transfected cells w ere characterized using an automated FLIPR machine or a calcium imaging system as described in our previous patent applications,. In order to control for plasma membrane expression, protein folding and other tailors that might contribute to changes in receptor activity, we used 2 sweeteners which interact with other domains of the human sweet receptor as positive controls. The 2 control sweeteners were evclamate and compound X (Senomv-x), It is known from our previous data that cyelamate interacts with the human 1183 transmembrane- domain, whiieoompoimd X internets with the human TIR 2 trausmembrane domain.

The mutagenesis data for a number of sweeteners arc summarised » the following tables. Based on the data, we concluded that 6 residues {$40, Si44, SI 65, ¥ 103,. D!42, P27?) are critical for inieraetlon with those sweeteners.

Mutagenesis data ©» FOFR

Mu Agenesis data on eatdusn imaging

Addittoual mutations on R3S3

The sweet eiihancer, compound A. is selective for the hum»» sweet receptor, and inactive onithe rat sweet receptor, Using the previously described human-rat chimeric receptors, we mapped the binding site of compound A u? h‘HR2 VFT. As shown in Figure IL compound A enhanced the sueralose activity on human sweet recepi©r(h2^3): but: not rat sweet receptor (r2/r3). When we replaced the rat receptor HR2 VFT with its human counterpart (Ii2-r2 r8). rho receptor can. be enhanced, by compound A. On the other hand, when we replaced the human receptor T1R2 VFT with its rat counterpart (rd-MdiS), the receptor can. no longer be enhanced by compound A. We .conclude that compound A interacts with, human. TI R2 VFT. Due to the diferent sensitivity ofhuman· and rat receptors: to sttcratosevtidTerent. suemtose concentrations were used to achieve hEC20 of the dii'ierent receptors.

Following cptnpmmd A, 8 more analogues have been identified to enhance the sueralose -activity of human sweet receptor. The same mapping experiments were carried, opt on these 8 analogues, and: we observed: the same activity pattern as compound A as sumniarked in the following table. We conclude that all. 8 compound .A analogues interact with human T1R2 VFT. .After mapping .the enhancers to human T.1R2 YFT, we performed mutagenesis analysis to further define the interaction site. As summarised, hi the following table,, six residues (KA5. D27&amp;, 1..270, D307. R3>G, V384d wore identified as critical for the aeiiviiies of compound A and analogous. These compounds, namely, compounds A and Λ1 m Λ8, are representative compounds of the present invention including compounds of structural Formula i 1} and its subgencric formulas. Interestingly, V5<s4 Is also important for the activities of .1 structurally related sweeteners las shown in Figure LI), saccharin and acesulfame K (AccK). mdivathig that these sweeteners might occupy similar space in the human TIES VFT. The eoticchtratmns lot the sweeteners are Aspartame f 15 mM), D-Trp (20 mM),.Sucrose 1200 niM). Sucralose (3,2 mM), AeeK (8 mM)».'Saccharin (3,2 mM), Cydamatc (80 mM h S3sAs (25 μΜ),

'* '027$ H a critical residue tor the esboaoeao because all eahaneers: iil the above table show agomsi activity oa D278A mutant,. i,e., they activate the mutant receptor in the absence of sucraiese:. EX PERI Μ ΕΝ Γ 3: Chesmcul 8s n thesis of (he Compounds of the Present Invention Example 1; 4“Atm»o-5,6-dimethytthteft»}'2,3-rijp> rimidine-2{ I H)-thio«e

A solution of Nu3-cvano"4.5-aUmethylthiophen43-yicarbamcihioyi)beozanhde {example 13} (1.90 3, 6.00 mm»l) and NaOH (2 IN. 8.3 ml) in EtOH (25 nits was stirred at 100 ¢( under nitrogen for half an hour. After cooling to room temperature, the clear reaction solution was filtered and the filtrate was care full v neutralized with 10 % AcOK with vigorous stirring at 0 °C. Tire resultant precipitate whs collected by filtration, washed with warm wafer and then 20 '3 EiOH in water to give rhe final product 4-a.mmo~55.6-dio:ieihylthienop J-d|pyr;im5dine-2{1 hi)~tl0one (1,.1.1 g, 87 %) as an ofiAvMie solid, M p.· > 200 'C. Ή NMR (400 MHz. DMSCM3 0 2 25 (s. 3H).. 2.26 (s. 31:1) MS 212 iMH >.

Examine la: N"{3-Csuno-4.5-dimeih>Uhiofmen-2-y!curbamot.hioyl}benz;xinide

To a solution of 2~ammo:4,S'dimefhyMtiopheae'-3-carbomlriie (1.52 g, I'0.0 mtftot) in 1.4-dt'Qxtme (20 niL) was added benzoyhsothiocyaoate (1.63 g, 10.0 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitation seas collected by filtration, washed with EiOAe/Hexanes i l :4), and dried under vaeitum overnight to give N->(3-Cyano-4,SwiinKahylthiopbenAhylead^anuofhioyIlben2,mwidc as a White solid: lH NMR (400 MHz, CDCb) 3 2,23 (s. 3H). 231 (s, 3Hb 738-734 (m, :2H), 7,68-7.66 (m. IH). 7.94 pj.J ===7.2 Hx: 2H), 9.S3 (b.\ IH). MS 316 i MW*);

Example 2: 4~AmlnoquIssazoiine-2(lfi)»thm«e

Prepared as in example I feta K5-(2“eya.n:Opheityksrba.mothioyl)benzamide: (Example 2a). !B NMR (400 MHz, DMSO-4>3 7.25 (dt,,/- 1.0, 8.2 Hz, 1H), 735 id, ,/- 8.2 11/, IB),7.65 (dl,/- 1.0,8.2 Hz, 111), 8.05 (dd,/- 1.0, 8,1 Bz, 1H), 8.30 (s, Hi). 8.35 (s, 111), 1234 (s. IB). MS 178 (MB ).

Example 3a: N~{2-Cyanophenv learbamottooyllbcnzamide:

Prepared as? in Example la from 2~amirmbcnz6mtrileandfee»zoyU$6d«0eyaft&amp;ie as a pale-yellow solid. lH N MR (400 MHz. DMSO-</>) 0 735-7.5* (m. 3B), 7.67 (t, 1M), 7.75-7,76 {&amp; J ----- 5.2 Hz. 2H), 7.89-7.91 (d. J - 7.2 Hz. 2H). 7.98-8.0! {dd. ./1- 1.6 Hz ./7 8.2 Hz, 2B), ILOOls. IB), 12.54 (s, I Ids. MS 282 (MB).

Example 3: 4 - Ami m>-5- is s et in Ip n 1 n a ι. ο I in e- 2 {ill)-! 8 krae

Prepared as la example 1 from N-{2-cyan0-3-methylphen>4carbamotM0yl)beaZa«iidc {Example 3a) as an off-white solid. M.p.: > 250 *€. !H NMR (400 MHz, DMSO-/P 6 2.68 (s, 3B), 7.03 (d../ - 6,8 Hz. 1 Hi. 7.13 (b. i B), 7.22 (d;/- 6.8 Hz, 1H), 7.48 (%/- 6,8 Hz, 1 H), 8,50 (6, IB), 12,26 (s, 1H), *'C NMR, fDMSO-/;) 0 23.26, 109,86, 11437. 1:27.16,13431, .136,97,143,57,160.58,179.67; MS 192 (MH ).

Example 3a: l9-(2-Cvmmpb:ea>4:earbamotl6oyllbepzaml(le

Prepared: as in example 1 a fern and: benzoyl

Isoth.ioeyaftate as a pale-yellow solid, {HI8MR. (400MHz, DMSO-/·/* 6 7.40 (ni, I B), 7.52-7.69 (m, SB), 7.98-8.01 (m, 2B), 11.99 (% 111), 12.54(s. IB). MS 296 (MB ).

Example 4 : 4-ami uo-5/-dimethyl thiene 12 3~djpyrimkit n-2(i B}~mw

A solution of 61/3-oya«o-4,5“dir?K9hy|(ide]i|-ere-2-ylearlxano>!;h>e«zamide (example 4a) (44.35 g, 148,1 mmol) and NaOH (2 N, 204 mil m EiOH (400 raL) wax stirred at 100 °G under nitrogen for four hours. The clear reaction solution was filtered and the filtrate was cooling So room lent pot untre, and then wifi carefully neutralized with 10 % AcOH f- 1.20 mLi w-th \ igmoux Muring an 0 C. After Mirring overnight horn 0 °C to rooift ienfperature* the resultant, precipitate was collected by filtration, washed with warm water (60-70 37. i5§ ml s 4) and 20 % EtOB in water (200mL x 2), and then dried at 50 *67 «rider vacuum overnight to give the final product 4“airurio-5.6-dime{hylrhicno(2,3-d)pynrnidin-2{1H)-onc (27.7 g, % %) as a white solid. *H NM R (400 MHz, DMSO-foq a 7.96 (bi.x, I Hi, 2.24 (w 3H>, 2.19 is, 3H4. MS i % (MH }.

Example 4a; Nf-{3-eyano"4s5·dimesh> Uftiophcn 2 y!curbatn«ndlbenzamide I'o a. solution of 2--amina--45--diinethy|thiophcne-3-carhr'nin'de {example 4b) (25 g, 164.5 mmol) in l.4-dio.xanc (600 rnt) was added benzov 1 isocyanate {24.2 g. 164,5 mmol), llie reaction mixture was then stirred at room temperature under nitrogen overnight The: precipitate was collected by filtration, washed wub 1,4-Uioxanc t20 ml x 3p and dded under vacuum at 40 °C for 3 hours to give N-Co-eyano^ J~dimethyithiophen-2~ylearbamoyl)bvUzau«d:e (4435 g, 9036) as a. white solid. *H NMR (400 Mi 1/. DMSCMk) S 2.10 (s. 3HL 2.24 (s. 3H)S. 7.52-7.56 (m, 2H), 7.64-7,69 (m? I H)s 8.01 -8.03 (m, 2H), 1.1.57 (bm41H), 12.05 (brs, 1Ι-Ϊ). MS 3001 Ml i d.

Example 4k 2-aml«o-4,S-dlmelhvithiophsne-3-carbaultriIe

To a solution of hutimorte (162.0 mL,1 .8 mol;), sidfur (57.99 g. 1.8 mol), and ;maiono.o.ii?ile (119.49 g, 1.8 mol) iu anhydrous Ethanol (1.2 L) was added at O'-'C iriediylaraiue (251.4 ml, l.S mol), The reaction was stirred at 032 fot 15 minutes then heated &amp;i SifC for 70 minutes. After cooling to mom temperature, ethanol (920 .nt'L) wan removed reduced pressure and aqueous Nad (30°1 75(1 niL) was added. The resulting mixture teas stirred: for 10 minutes, and cxitacicd w ith diethyl ether (I Lh fisc aqueous layer was further extracted with diethyl ether (500 mLi and the insoluble solids were removed by filtration after which the organic layer was separated and combined with the first diethyl ether extract. The combined organic ex tract, was dried over MgSOq filtered: and concentrated under reduced pressure. The residue was stirredfbr 2 hours in diehloronicfhane (300 mL) and a. solid wax collected., More solid was isolated from the diehloromethane solution cooled: to ‘78'C. I he combined solid product was refluxed in dichloromethane (600 mL) for 10 minutes then stirred at room temperature for 30 minutes and cooled to -7MG. The resultant precipitate was collected by filtration to give the: crude product. (115 g). The filtrate was concentrated and the residue was chromatographed on silica gel (duenC. dk'hloi'Oii'K'Oianc; to pro'. Ido a .sola! that was combined aid the prc\ ions crude product. The resulting residue was pariiscd by flash chromatogsuphy on silica gel (did'iiorornediane) ίο yield ^-ajtmtta^S-dt'methyithiopiiene-S-i&amp;ai'bciaitrile (105 g, M%) as an off white solid. sH NMR ¢400 Mils. DMSOO*} d 1,93 (0,/-1.2 Hz. 311), 2,07 id.,/- L2 Hz. 3H), 3.33 is, 2H). MS 153 (MHO.

Example St 4"AHdEO~S;6"bttt>1eiteth!e«oi2,3“d]pyrimlilMe~2{ll !}nhso«e

Prepared as is Example I front 14-{3-eyano~4,5>d,?-teiTahydmbenxo|b]thiopheiv2~ylcarbaoiofbieyI)ben2e5Bido (Example $a). !H NMR (400..MHz, DMSO-40 7 1.75 (m, 4H), 2,62 (m. 2H), 2.74 (nt, 2H), MS 238 (MH } N-(3~Cy-ano-4j5,627"tehabydrobenzo[bltfiophea"2"yleerbanYofhicw4-)^en2a:niide,

Prepared as. in example la from 2~amino-4y5,6,7-tetrah.ydiObenzo[b]fbioplteae~3~carbdsfiOile (example 5b) .raid benzoyltsoiMocyanate as a pale-yellow solid, MS 342 (MH ),

Example 5b; 2~AnntK>4.52n7-te:pahydre<benzo(b|ihiopbene”3“ea.rbooilrile A solution of cyclohexanone (i ,96 g, 20.0 nuneif ntalononitrile (1.32 g, 20.0 mmoi}, sulfur (640 mg, 20 0 mmol), end triethylamine (2.(H. g, 20 nunol) in EtOH (50 ml,) was refluxed for 6 h under nitrogen The solvent was remm on under reduced pressure and the residue partitioned between 140Ac and water. The organlo layer was separated, washed with brine, and dried over Ka^SOt, Ailer evaporation oftbe solvent, the residue was purified by ebromatograplty oh siliea gel eluting with EtOAc/Bexanes (2:3) to give the title product as a yellow solid, SH NMR (400 MHz, CDCIj) 0 1,79 (m, 4B), 2.50 (nt,4H), 4,59 is, 2H), MS 179 (MH ).

Example 6: 4"Amio0'-S'-»ierhyk|utea20li8«2{lH]he»e.

Prepared as in example 1 flora N-(2-cyaae~3~ffieihylpheByicarbaaioy!)beazaffiide (example Pa}· 5I INMR (400 MHz, DMSO-/p 0 3.04 (s, 3H), 7.43 (d, / - 1.2 Hz, 1.1:1), 7.51 (d,,/ - 1.2 11/., Hi), 1.91 (0,/- 7.2 11/, 111). MS 176(ME).

Example 6a: N-{2-Cy cmo-3«methylpheuy kx» binno\ Rbenzarolde

Prepared as in example la. from 2«aroiao~P~mctbyIbenzonitrile and benzoyl isocyanate as an eff-white solid, 5 El NMR (400 MHz, DMSO-al) 4 7.49 (d, I:::: 7,6 Hz, I.H), 1,52-1.68 (m, 5¾ 8.02-8.08 (m, 2H), 1.1,32 (s, Hi), 1L46 (s, I.H). MS 280 (MH ).

Example 7ί. 4-Am«m~6~etfeyl~S~i»etl0y lthle?m|2 J"dlpyemtdu5--2i 1111-one

Prepared as In Example .1 from N-(3-eyano-5-'eihyl-4-meO>yUhiop6eo-2-ylea,rbamoyl)li)e:aza.mide. (Example 7a). ;1ΗΝΜΕ (400 MHz, DMSOo/;} 4 1.11 (6/-1.6 Hz, 3H), 2,26 (s, 3¾ 2,60-2.6? (q, / - 1.6 Hz, 2H). MS 210 (MB/

Example 7a; N-(3-Cyajm-5'ei0yl-4-ffieiliiyl{hiopliee-2-yl:eaf6a:moyI)benzamide Prepared as,in example la from 2-ainincv-5-eilvyi-H-methyifbiopbet5e-3--earbooitrilc (example 7b) and benzoyl isocyanate as a pale-yellow solid. MS 314 (MET).

Example 7b:: 2- Amino-S-eilwIHmaethyllfeiopheoe -3 -car boaftri ie

Prepared as in example: 5b from 2-pefita«one, malonoBitrile, sndsoifar as a yellow solid. MS 1.67 (Mff),

Example 8: ltfaUmo[2,3-d]py«midlii-2(.lH>'0»e

Prepared a-'· in Example 1 from N~(3~eyarK.>-5-mcih> ltbiophc»-2*> u-arbaMoy]}bon?art5idc t Cv.impie oa) !H NMR {-1 «>0 \1H;\ DM$0-4)J 2.M (s. 3H), <1.97 (s. IH), 7.50 (s, IH). MS 1.82(ΜΗΗ,

Example 8a: N-{3"C);aiio~5':mstliyithIaphesi-2-ylcarbamoyl}be«xamIde

Prepared, as in .Example .la from S-amieO'S-mothyltlYiephene-B'earbonitrlle and benzoyl isocyanate as a white solid. Ή NMB. (400 MHz, BMSG-<i<§) <12,36 (d,·./ ~ 1.2 Hz, 311),. o 80 id. J \ .2 H;:\ 1H). 7.55 U\ J » 8.0 H;p 211), 7.00 (J. J - 7.2 He, 1H). 8.03-8 01 (m, 2H). 11 .00 (brs. IΗ κ 12.08 i bs. i H). MS 286 (MH.)

Example 7' 4-AmiBe“b"(bydr0xymetlyO~S-metbyMika0j2,3~d|pynmiiliae~2(l H)~thioa«'

Prepared as in Example I. bom N-0“-cyai)O':5-<bydroxymeihyl)"4-me.(hyithiopimn“,2-ylearbat»bth.byl)fec.H^aimide.'(Exampie..ta|.. 5H NMR (400 MHz, DMSO-d) $ 2.30 (.% 314), 4,54-4.55 (¾ ./ - 5,:2 Hz,. 2H), 5.54 (t, 1B), MS 228 (MH'),

Example 9a; N--(3--C4ia«o--5--{hydi<.rsv?vreihyI)-4--ivreths-l'd-siophep^2-ylea.rbapiotlitoyl)~be?:tza.n.ttde Prepared as in example la from 2~amioo--5--(liYdrox>meihyH“4-meihyltbiophenc-3-carbonitrile (Examine 91») and hmfo> 1 isp.thiocyanate ay a yellow solid MS 332 (MET),

Example 0b: 2-A.mlpo-5-(hx,droxymetby!V4--metbylthiopheoo-':3--carbomtrile

Prepared ax in example Sb from 4-bydr0xybnian-2-ooe, malonoOitfile, and sulfur as a yellow solid ’H MM R (400 MHz, DMSO-d) 11.91 (s. BHr 4.30-4.31 (d,,/- 5,6 Hz, 2M), 5.10(1, 1H), 7.00(4, 2¾

Example .16: 4-Ami»n-5.6,7 .8-tetraIn droqmansoiste»2{ IB)AMo«e

Prepared, as in Example I from N~(2~eyaaocyelohes-i -e.n^!earbm«oihioyl)benxamide .(Example -10¾) as a white solid. * H NMR (400 MHz, DMSCM,} 0 1.60-1.6.5 (rn. HI). 2 13 iai, 2H). 23* ho. 2fii. 6,93'(s, 111) 7.56.(s, IH). ! 1.54 is, ! H). MS 182 (MB).

Example 10a: N-(2-Cyanocydohex-1 -mylearbamo.thk>yt)ben2amid.e

Prepared as hi Example la from 2-aroinoc>dohex~l.~encca{lxsniirile (Example 10b) arid benzoyl ssethiocyanafe as a white solid. MS 286 (Mlf).

Example ) 0b: 2-Amioocyciohex-1 -enecarbooUrile A stirred mixture of I ./-heptanod untrue (24.44 g. 0.2 mol) and t-BuOK (22,44 g, 0.2 mol) was heated at 80 "€ for 3 h. trader nitrogen. The mixture was theft cooled down to room temperature and stored at that temperature overnight. The residue was treated with water, and extracted with ether (2X). The combined orgarde layers were washed. with brine, dried over NajSQi, filtered and cprsoeniraied. The residue was purified by rcerysfaliLtafion from. MeOIl to give the title com pound as-a, White solid (18.2 g. 75 %}. Ή NME (400 ΜΗχ. CDCb) § 1,58-.1,71 (m, 4B). 2.1.2-2,-20 (% 4H)S 4.23 (bs. 2.H). MS 123 (MH: %

Example 11: 4- Aftdnrr-h-oH'tiiy itΙίΕο?ο|2,3-·ίΙ]py rbmdm- 2(I I D-one

Prepared as in Example I from K->;(3.-cyanothiophen-2-ylcarbamoyl)ben2amiite (Example 11 a). *H NMR («00 MHz. DMSO-d&amp;d 6.97 (s. ./ - 5.2 Hz, IH>. 731 (J.. ./ - 6 0 Hz. 1H),:7-.60 is. 2H). 11.38 ibs. IH). MS I6S(MH'>.

Example I la: N-(3~CyapofhiopBeti-2-ylearhatppyt)beozamide

Prepared as in Example la from 2«aminothii=phcne-3-carhonitrile and benzoyl isocyanate as a >vhuc so lid. Ή NMR (400 MHz, DMSO-ώ) 0 7.23~~.W {no 2H). 7.55 (t,./ -= x.O ΓΙ/, 20). /.70-7,60 (m, 111). 8.04-8,02 (m, 20), 11 .62 <bs, III}. 12.18 (bs,: 0 0. MS 272 (Mil ), Example 1.2: 4»A«si«i>i|»iaaKOllE~2(10)»i5Ae

'Prepared os in Example I from N{ 2-cya.nophcm lenrbaac -y: }b·.,·ε/ζϊϊϊε·??0c «Example 12a.) an a white solid (156 mg, 41%). Ή NMR {400 MHz, DMSO-m·,} 0 7. = 2-7 20 (m, 2H), 7.54-7.63 (m. 10), 8.08-8.10 (d, IH). 8.60 (b. 20 ). 11.2 (b. 10). "C NMR (DMSO-<E) 5 108.72. 11 5.98. 122.32, 125.51, 135.38, 142.%. 154,96, =63.51. MS 1C i.VIH ).

Example 12a; N-C2"Cyaooohetwlcai%amoyl)benzamide

Prepared as in Example la from S-smiftobeazonitrEe and benzoyl isocyanate as a white powder (66 > mp. 54 %>. lH NMR {400 MHz. OMSO-m.) o 7.27-7,29 (% 10), 7.52-7.56 (t. 1 Hi, 7.64-7.74 (m, 2H>, 7.82-7.85 (dd, 10). 8.02-8,04 i,m,. 20K 8.22-8.24 Id, Oil. MS 266 (MH t.

Example 13: 4-Amino-b-nietkexy-S-metfevltblesinf 2 J-i | jjyrimi cii n-2 (I Hpone

Prepared as in Example I. .from N-( 3-cyano-5~methoxy>*l«rnoihylfhiophcn-2-ylcarbarnoyDbenza{r!kle (Example 13a). !O NMR. (400 MHz, DMSCW*} S 2.19 N, 3H). 3.78 (s. 30). 2.74 {s, 2M). MS 212 (MO }.

Example 13a: N-{3 -Cyano-5-mcthoxy-N-methyIthior4ie«-2-yjcarbamoyl)benzanudk\ Prepared as in Example la from l-ammo-S-meihoxy-d-metbyltlimpbene-S-carbonidIfe (example 13b) and benzoyl isocyanate m an off-white solid, ;fi NMR (400 MOx, DMSO-C) 3 2,03 (iy 3H), 3.86 (s, 30). 7.54 (t.,/ - 7,2

Hz, :'2H), 7.6'7 (t> / - IS Hz, IH), 8.01-8.03 (d, J === 8,41¾ 21:1), 11.60 (s, IB), 12.03 is, IB). MS 316 (Mil ).

Example Ob: 2-Amin0-5-msth.0xV"4-m:ethviihlophe«g-3-caAoBltrl je

Prepared as ia .Example 5b from 1 -medmxypropa»~2~o»e, pialoaomtrile, and suhur as a browa solid. MS 16*? (MH').

Example 1.4: 4"AmMO»lks«eih>.lqainaz0ia“2(li;l}»p.rie

Prepared as is Example 1 from Ν^2 wvauo-4-rneths Ipjicnx icarbamoy Ubcnzamide (Example 14a} a.\ a while solid (250 nig. 57 %.i Tl NMR (400 MHz, DMSO-2·,} d 2.29 is, 3H), 6.99-7.05 (to. IH), 7.35-7.37 id, IHh 7.72 (b. 2H), ?.7<Hs, IBs 10.55 (bs. IH). MS 176 iMH'}.

Example 14a; N-^-Cyano-i-raethylphfnylearhumoybbenzaiai'de

Prepared as in Example la from 2-ammm-5"Oiedwlbenzoniirde (Example EU·} as a white powder (724 mg, 46 %). MS 2-s0 (Mil').

Example 14b. 2-Aouno-3--mc!hy!bcnzonio lie 5-Me&amp;yi-2-?dtrobepxointrile (1,92 g, 11.84 mmol) was added m portions to a stirred solution of SnCb (11.22 g, 59,2 mmol) in cone. HC1 (12 mL) ant! EiOfI (12 mL). The reaction temperature was maintained at 20-30 A3 using an ice bath. The reaction mixture was then stirred at room temperature for 1 h and poured; into an ice cold aqueous sohtti on of NaQB. (6.N, app. 30 mL) to neutralize· to pH 7. The product was extracted into ItOAe, washed with brine, dried over MgSO* and concentrated to provide the title product (1.56 g, 99 %) as a. yellow-brown solid. SB NMR (400 MHz, DMSOuL) 32.21 (s, 3H), 5,79 (bs, 2H), 6.68-6.71 (d, IH), 7.10-7,13 (dd, IB), 7.15 (s, IB).5'C NMR (DMSO-ds! 6 20.13,93.99, 116,12, 118194, 125.38, 13232,135.76, 150.21. MS 1 33 (MH:).

Example 15: 4-Amiao-8-methykj

Prepared as iu Example I from N-{2«cyano-6-meihyjphenyic3rbajnoy! focnzamide (Example I 5a) as a white solid (60 mg. 56 %). Si "NMR (400 MHz, DM $()-</*} 0 2.29 {a.. 3H.h 6.96-7.00 it., I Η), 7.37-7.38 td, 1H). 7./0-7.72 (h, 2Eh, 7.80-7.82 (d. Hi), 9 <57 ihs, 1H) MS 176 (MR '}.

Example 15a: N-(2-(i(yaBO-6-meiltyIpheiiylearbam.oy1}beo'xamtde

Prepared, as in Example .1 a from 2-amino-3-rncihy!bc.nzo«itHte (Example 1.5b) ami benzoyl isocyanate as a white powder (186 mg* 67 %). MS 280 (MR ).

Example 15b. 2-Ammo-3-tneih> 1 bcuzonitr He

To a solution of 2-bromo-o-nK'fhv icmiIine t J 2o pi.. I mmol} in dry NMP (3 rnl.) W® added CaCN (197 mg, 2.2 mmol). The mixn.se was irradiated in a microwave at 220 "0 tor 40 mmutos. cooled to room, temperature and poured into a Mixture of ammonia (50 % w/v, .10 ;mL) and ice. The mixture was stirred for 30 min arid, the product was extracted with diehlorpniethane (3 x:20 ml.·). The organic layers were combined, washed with water and brine, dried over MgSG* and eon.centraied. The crude material was purified o.n silica gel (50 % EtOAe/hexanes) to yield a brown oil that crystallized on standlng (128 mg, 96 %). *1:1. MMR (400 MHz, DMSO-fod <> 2.08 (s. 3R), 5.68 (bs, 2HJ, 6.:51--6.55 (h 1H), 7.17-7,19 (¾ IB), 7.22-7.24 tdd. 1H). MS 133 (MHf),

Example 16: 4-Andm)pyrlnddoH,5--djpynimi.lhr-2(lli>-one

Prepared. as in Example 1 Swm. N-(2~cyano-4,.5~dimethyifnrari-3-ylearbamoyl)benxan'nde (Example 16¾). lM NM.E. (400MHz, DMSO-t/.-9 0 8.91 (s. IH), 8.92 (s. 1H), 9,23 (s: 2H), 11.50 (fo IB). MS 164 (MET),

Example Ida: N-{2-Cyano-42'*duneih>ifurnn-3-y!carb«movl)btw.ai*Hde;

Prepared a? in Example 1a from 4-jn'iino]prrinudinc-5-ccirboMii'iie and benzoyl isocyanate m an off-white powder. MS 268 (MB").

Example 17: 4~ A mine- 7- metIsyh\airia/.ohne-2( 1H)-4hsοne

Prepared as hi Example 1 front N"(2“cyano--5--rnethylphcn> lcarbaotQ&amp;ioyl)benzamide (Example 17a). *Η 'NMR (400 MHz,. DMSO-id.) 6 2.3? (s. 3H>, 7.08 (A J = 8 0 Hz. j B).. 7.1 3 sv i HI 7 A; yd,./ = 8.0 Hz, 1H). 8.21 B, 1 Hi. 8.24 (a, 1 H). 12.26 {$.. 1H). MS 192 (Mii )

Example Γ/a: N-(2-Cyano-5-mcthylphcnyleafbam0fhipyl)benzam.k!e

Prepared as m Example la from 2-ammo~4~mc4hytbonzcpitrile and benzoyl isothiocyanate as a pale-yellow powder. ΛΗ NMR (400 MHz, DM$€M$) $ 7.32.(4 I8.0 Hz, IH), 7' 51--258 (m, 3H), 7.67 (t, j= 7J Hz. 1H), 7.78 pi J - «.0 Hz, 1 H), 7.98-8.01 im .:11), 13.88 (s, H I), 12.49 (s, ; Hi. MS 2M'dMH 1

Exsmplf 18; 4-Amkio^f6~dimeifeylfprol2,3-d|pyidmiclia-2(lE|~0ne

Prepared as in Example 1. hont N-(2-cyan:o-4,S-dimethYlmr;av-3-y1carh;anoyUbc!i2at«ide (Example 18a). lH NMR (400 MHz, BMS0-ift) d 2.11 {s, 3H). 2.20 pp 3H). MS 180 (ΜΕΓ).

Example 1 SB; N ·{ 2 ·Cyaoe-4,5-01 nrcthyIfardsi~3«ylcarliaiil0yi)tetzafiii:de Prepared in a similar manner ίο Example la from 2-amiito-4J-d.imetlrv1fi.n';.ui";v->.'a.rboinirilc and benzoyl isocyanate as an off-white solid. MS 284. (MB ).

Example 1 0; 4-Λ m ia o 7 m ti hv Ip u s is a xo Si a- 2( 1H )-0¾¾ e

'Prepared as in Example 3 from N*(2*cyano»5“mcth\-|phcny]e»rbamoyl}bei',zamide «Example i9a}. }H BMR (400 MHz, DMSO-dB 0 2,59 (s, 31¾ 7,3? (s, IH). 7,49 (d, J --- 72 Hz, IB). 8.21 (d,7.2 BjUH}. MS 176.(MB'-).

Example HE: N42 Cyano 5 mcthvlphcny(carbamoylH^cnzamide

Prepared as tn Example la. from 2-amino-4·mcthylbenzonitnle and benzoyl isocyanate as a white solid, Ή MMft(400 MHz, DMSO-xhi) # 7.10-7.13 (ra, 1H}« 7,54 (t, j ™ 7,8 Hz, 2B), 7.66 (t, 3 - 7.8 Hz, IB). 7,71 (31, J - 3.0 Hz, 1H>, 8,02-8.04 (m, 2B), 8,07 (s, I B), 11,32 Ο,. 1H), 11.44 (¾ !H). MS 280 (MET).

Example 20: 4“Aminiol-beazvE5,b-ilimetbyhi8ienop,3~d|pyrhnn1:ine--2( rH}~ttdone

Prepared as in Example 3. from N-CEenzyl(3-cyaBO-4,5-dimPt:hyidtiophen-2-yi)earb:amotbioyl3benzamide (Example 20a). MS 302 (MB').

Example 20a: K-(Benzyl{3Kyani?^5.5'^i:me:tlbyHhi<>phen.-2--'yi)eart>smx>thioy?)>ben2aimide, Prepared as in Example 4a fem: 24baizylamino}“455~dimethyUhiophene~3-earbi!nltri3e (Example 20b) and benzoyl isatldoeyanate. MS 406 (MET),

Example 20b: 2-(Benzy!a.miin>)-4,5-dlmed.ryitliiopiKnte-3-earlxxonrile

To a solution oi2-anuno-4,5~dimethylthiophene3xwarborhiriie (151 mg, 1,0 mmol) and benztddebyde (106 mg, I mmol) in 15 mL of 4 7<; acetic acid in diebloroetbanc was added silica supported cyanoborobydride (3.0 g. 2.0 mrnoi). The reaction w as placed in a microwave reactor for 5 nannies at 135 *€. Silica, supported eyanobotobydride wax removed by

filiation, and the product purified by prep HPLC using acetorntriJc/watcr as solvent. MS 24? (MH ).

Example 21: 4“Asiiin»*l»eiliyi“S,b“diftiethylt:hleu0j2!3M|pyris»idln“2(il:I)"e:si.e

Prepared as in Example I from N^(3~eyan€^4s5~dimetbylihioplK'ev2-v|)(eihy!)earbaaK>yl;}benxan:iide {Exaoiple 21 a), MS 224 (ΜΗ"),

Example 21a: N-{{3-€yano43'dun£ihybhiopbcn*.2*yl»(cthyl)carbaoK>yl ibcnzantfde. Prepared in a similar manner to Example la front 2-(etlwhimino)-4,5-dirneihyIthiophcue-Mcaibenttrilc (Example 21b) and benzoyI isocyanate. MS 328 (MH),

Example 21b: 2-{Etiwlamino|-4.:$-djoteih:v1tbiopligno~3~earboaiMk

To a mixture of 2~(benay)amirip)-4,5~dinieibyItbiopIieoe~3^earbonilTi]e (302 mg, 2.0 mmol), potassium carbonate (276 mg, 2.0 mmol), and a catalytic arnom-st of potassium iodide in acetonitrile (I mL) in a 20 mL microwave: vial was added ethyl iodide {3 HI mg, 2,9 morel), The reaction vial was placed in a microwave reactor for 15 minutes at 165 °C. The reaction mixture was dissolved in ethyl acetate tmd washed with water and brine. The ethyl, acetate portion was dried over sodium sulfate and solvent was evaporated noder reduced pressure, and the product was purified by prep BFLC using acetonitrile-water as solvent. MS 181 (Mbf ). Example 22: 4*.A«il»o-l ,5,6~tri»* fctb>1lbiea<>j2.3“d |j>yri*«idi&amp;“2(lll>«aiise

Prepared as in Example I from

Nhi 3-cyano>4^«4HneihyIthiophcm-2*YlKrncthyliembamox I}lvn/aundc «Example 22a). MS 210 (MH }.

Example 22a: N-{(34;\ya/m*4,5«dinKHhyjihKiphcn-'2*-y|.Xmethiyl)eari3amoyi)~ben^M»Me. Prepared as in Example la from 4,5~dimethy 1-2-: methy !amiRQ)^JO|>hene*3<^1JOiiitrtl.p (Example 22b) and beuxoyi isocyanate, MS 3)4{MH ).

Example 22b; 4;5“Di»Ktlwl-2-(melEylamlao)liriopheiie-3-carbotEtriie

Prepared a.s in Example 21 h from 2-amino-4,5 ·dimctbyltyephene-S-c^bemtrile and methyl iodide.

Example 23: III-Ben/ojejj1,2,6Hldadiaxs»-d-amlne-2,.2-di(>xKle

A stirred niix-tpre of 2-eyanoaniline i236 mg, 2,0 mmol), sulfamide (192 sag» 2.0 miftot) and DBU (304 mg, 2,0 mmol) was beated at IPO under nitrogen for 3 days. After cooling to room temperamre, the reaction mixture was diluted with water and extracted three times with EtOAe, The agueous layer was removed under vacuum and the residue was purified by chromatography: on siliea gel eluting with f #&amp; MeOE in dichloromethane to give the tide compound m a pale yellow solid. i.B AIMR (400 MHz, DMSO-ίΑ) d 7,03 (dd, J - 0.8, ,3,0 Hz, 1 Id), 7.12 (dt, J - 0.8, 8.0 Hz, IH), 7.56 i.dt, J - 0.8, 8.0 Hz, 1 H)v 7 85 (dd, J = 0.8, 8.0 Hz, i IT). MS 198 (MH )

Example 24: 5~Me0ryI~i;H~henzo|e)[t,2,6)ihkdtaz!n~4~am|»e~3 J~dfoxiile

A solution of N-:2-eyano-3mwkylphenyilsulfannde (Example 24a) (211 mg, 1.0 urmoi) in EiOH was treated with NaOH (2.(1 M, 1.Omit* 2.0 tittabfy MdThe i^ltatooktipn heated ίο 100 <:'C and stirred at that temperature for 0.5 h. After cooling to room temperature, the eiear reaction solution was filtered and the filtration was carefully neutralized with 10 °o AeOH while with, vigorous sfirifing at 0 °C. The resultant precipitate was collected by filtration, washed with warm water and 20 % BtOB in water to give the title product >Mediyl-l 11-000201011 i.2.0jthiadiazin-4-arnme-2,2-dioxide as an off*white solid. Ή N.MR (400 MHz. DMSO-ds) S 2.50 is.. 3B). 6.85-6 8? (d. J - <14 Hz, 1 H>« 6.92*0.94 (d.. J » 7.2 lie, 1B), 7.24 (s, ΙΜί. 7.37 (p ,/- 7.6 Hz, Hite S.24 (s, iH>, 10.76 (s, 114). MS 212 (MB'),

Example 39a: N-{2-€yano-3-rn.ethyl.phenyl)sulfonftde A sottttion.of2-atniao«6-m.c4hylhen20:fi.itri'le (1.32 g, 10 mmol) and sul&amp;tnide -(431 g, 50 mmols in dry 1.,4-dioxafte (50 mL) was'-mfktxdd-under nitrogen For 3 days. After the reaction mixture was cooled down to room temperature, the precipitate was filtered and washed \v;th dioxaue. The filtrate is as concentrated unde? reduced pressure, and the residue was pns died by chromatography on silica gel churns with HtOAc. hewmes {3.7) to give the title compound as a pale-white solid. 44 NMR (400 MHz, DMSO-</*> ό 2.44 (s, 311S. 7.19-7.21 ten. 314), 7.39-7.4! (d, J:::: 8.4 life, 1 Id), 7.53 (t </::: 8.0¾ 113),.9,41 (s, Bd).

Example :25: S,6-Bii»etlni"2"(Methy1thte)thieno|23"dfpyrlmidta~4~aiitiae

To a suspension of

INy3-e>asM-4,S~dtmethyli!-d0phen~2~ylearbamoth5oy|)-henzasmde (Example la) {1.33 g, 4.22 mmol) m ethanol (25 mL) was added NaOH (2.0 N. 53 mL) at room tempera tuse under .nitrogen. After stirring at 1 (10 i!C under nitrogen for 0.5 h, the reaction mixture was cooled in an ice bath and Met (0.4 mL) was added drbpwise. After stirring ftft another 0,5 h, the resulting precipitate was collected by filtration,,rinsed with, water. 20 % EtOB/BsO, and dried under vacuum to give the tide compound (840 mg. :89-¾). ^MR (900 Mfilz, DMSO-sid 62.32 (% 314), 2.34 (s, 31¾ 2.42 (s, 3H),-0.93 (bs. 2H). MS 226 (MB'),

Example 26: 2-Methoxy-5,6-dsmethylthkm0|2.3»4}p>rimidlit“4sami«e

prepared in s similar manner to Example 25 from N·O·c>an*>-4.5"dimcthyHhiophen-2-vlcarhumoy 1ibenzamide {Example 4a} and methyl iodide in 86 % yield. lH NMR <400 MHz. COO.,} <) 2.35 (a, 3H). 2.36 N, 3H). 3.53 (s,3H), 40 (fes, 2H). MS 210 (MH }.

Example 27; 5J~l>imetfeyl~2~(methyllid olid re\2,3-djpyritiiidis-d-amiae

Prepared as in Example 2.5 from N-(2-eyano^,5“diffiethylturan-3-ylcarb;niKrd:rioyl}btn:5Zarnide (Example 27a), !H NMR. (400 MHz, EMSO-,/,) 3 2.16 (x. 3H)52.23 (s, Ml), 2.41 (s, 3H), 6.92 (s. 2H). MS 210 (MB/),. Example 27a: NK2R7yanoM,5-dimethyl furan-3-ylcaroaniothtoyl)henzamide

Prepared ax in Example la from 2~amino«4>$«dimcthyifurar!-3-earbonilriie and :hetm>yl. ii^ihi.ooyanafee .MS 300 (Mil ).

Example 28: 7~M’eth:y!~2H:meilly!tl6oR|ni»z0lm*4~amine

Prepared as in Example 25 from !N^2H^yario-5»mcihylphenylcarhian.'!oU»oyi}bcr!Z.amide (Example 1.7a).. (400 MHz, DMStJ-rE) 3 2,40 (s. 314), 2.45 (s, 314.), 7.17 (dd,./- 24X 8 8 14z, IB), 7.32.(s, 114), 7.71 (bs 214), 8.01 id, ·/ === 8.414z. 114). MS 206 (M145).

Example 29: 5~Methyl~2~(»ierhylthioKj|»laa%on»r4*aiiilpe

Prcp-ifed as in Example 25 from 'N-{2-cy»m>~3~nsefhylpbettyiead>amoth.iovl)ben2;a.mide {Example 3a), lB NMR. (400 MHz, DMSOfoo <> 2.46 Mil 235 3, Mil 7Λ i id. J - 7.2 Hz.. 1 Vi), 7.33 td. 7 = 7 2 He. IW K 7.51. (dd../ = OX, 7 .: He. I Hi. MS 206 (MH j.

Example 30:

A iiiixture of 2-aii?mo«4,5>diiPctbyi{ruophene-3-oarboaiUil.e (500 mg, 3.29 mmol.},· cyanoguumdine (276.6mg„ 3.29 mmol) and HC! (2 N, 1.5 nil..) in water{10 mL) was refluxed under nitrogen for 2 b. The reaction mixture was cooled to room temperature, and hasified with dilated NaOH aqueous solution to PH 7-x, After evaporation of stater, the residue was purified by preparative. HPLC eluting with acetonitrile and w ater to give the title compound (33 rug, 5 %). lE NMR (40O MHz. DMEO-iA) 9 2.22 (s, 3% 2:27 (s, 3H), 5.55 (bs, 2E), 6.29 (bs, 2H). MS 195 (MH ).

Example 31: 2..5.CbTriroefhyIthieito[2,3 -d|p> rimitli n-4-ajotne

A iihxfors of 2-amiho-455“dimethy{tfn:oplieue~3~eafb0hiid!.e (2CM)mg, 132 mmol), anmionia acetate (204 mg, 2.64 mmol), and trietbyl ortboaeetate (2,0 mL) was stirred in a sealed tube at 120 Λ0 overnight. After the reaction mixture: was cooling down to room temperature, the; precipitate was:collected by filtration, rinsed with EtGAc and dried in the air to give title compound (52 mg, 60 %) as a yellow solid. !H NMR (400 MHz, CPCl.d 0 2.41 Uy 511). 2.45 (s. 3H>, 2.56 (s. 3B), 5.28 {bs, 2H). MS 194 (MH:}.

Example 32: 5,6"Dinsefhylthie.mi[23“ii||>M'toIcll»*4«attii«e

Prepared as in Example 31 fro.ml-amlBo4.3^wt%tt1jiophme~3~earboaitfile andtn'elhyl ordmibrniate. lH NMR (400 MHz, DMSO-4) d 2.38 (ss. 3B).(-2.3.9 (ss. 6.85 (bs, 2H), 8.14 <s. IH). MS 180 (MH').

Example 33: 2-Edyyl~5,6-dimt4lsyi).idenid2.,3"il|p>simidia~4-amine

'Prepared as is- Example 31 from 2-ammo-4,5-dimt4hyUhjophcnd-3-eurbofoi&amp;tI« and triethyl orthopropunak. !H NMR (400 MHz, D.MSO-aS) δ 1,19 ft, J ~ 7.6 Hz, 3H), 2.33is,3H), 2.36 (s. 3HK 2,61 (q, J - 7.6 Hz, 2H), 6,74 (bs, 2H). MS 208 (MH|

Example 34ySJ~PtwthyH2spPenylfliieBOp,3-dipyrimiclte~4~a»3iae

A mixture of 2mminoM,5-diuieihyMiiophe«e-3-carhomtriie (1,52 nig, 1.0 nimol},. ammonia acetate (308,3 mg, 4.0 mmol) and irieihyl orihobeuzoaie (2,0 ml.) in a sealed tube was put in amicrowave at 200 '33 ler 20 min. After the reaction. mixture was cooled to room temperature, it was diluted with EtO Ac, washed with saturated NaHCO? and HjO, The solvent was removed by vacuum and the residue-was purified by preparativeHOLC eluting with acetonitrile and water- to give the title compound (80 mg. 31 %),· Ή NMR (400 MHz, ΠΧΊ 9 δ 2,45 (s, 3H2.48 (s, 311.), 5.34 (bs, 2H), 7,46-7.43 (m, 5H). 8,4-8.38 (m, 2H). MS 256 Alii ).

Example 35: 5.6»Dim£?hyi~2-prdptHi;kmc{X3-d]p>rlmiditt-4-ae5U5C

Prepared as hi Example 34 from 3-amino-4,5-dimcth> h hiophcne-3-curbonit rile andtricthvl ojthoburanate. !H NMR <,400 MHz, DMSCKA) «>' 0.87 i\. J - 7.(, Hz, 3H)« i .72-1 .{>7 (m, 2H). 2.33(s. 3HV2.36 (s, 3H)S 2,57 (t, j~ 7,2 Hay2ii), 6.73 (bA2H), MS 222 (MH1, Example36: 5,6~l>smediyi~2*(mediy!8iditHsj1)ii«eao|2.5-d|p>TsmiiMii~4~ami?3.e

To u Muperaion of 5,6-dioietbyl*2*(methyUhio}tbleno[2,3-d]pyrimi-Jm-4-amj?ic·' «I simple I) (200 mg, 0.,K0 mmol) in DCM (25 ml.,} w,*s added /«Oh)oroperoxybenzoic acid (767 51¾ 4.44 .mmol), After stirring at room temperature overnight, the feaeiioo mixture was 'diluted-with EtOAe, -washed with water and brine;, dried over NaaSCh, Shored ahd evaporated. The residue was porifiedhy preparative HFLC eluting with acetonitrile and water ta: give the title compound (45 mg,20 %). JH NMR (400 MHz, DMSOMs) S 2.42 (s, 6E1), 3,27 (s,3Ei). MS 258

Example 37: Ethyl o^tllsuetliyl-l-tMo.io-i J~tilhydrothlean|2,iAd|pysdm!dla~4~ylea?'baaiaie

Το, a suspension of 4mnftno“5,6~duneihv Uhieno|2s3-d}pyHraidioe^2( 1 HHbiooe (211. mg, 1 mmol) in DMF{5 ml.) was added Ft?Ν (0.21 ml, 1.5 mmol) and ethyl chJoroform.ate (0.143 mi.,, 1.5 mmol); I he reaction mixture "was stirred at room temperature overnight, then diluted with EtOAe, washed with water and brine, dried over Na^SO*, Hlferod and evaporated

The residue was puritied on Btoiage Sf'-i eluting. with EtOAc/hexane to give the title compound (i 54 mg. 54 %). 41 NMR (400 MHz. DMSO-to) ΰ t .22 (t, J === /.2 Hz, 3H r 2.38 is, 3H>, 2.39 (s, 3H). 4.25 U|, ·/- 7.2 Hz, 2H>, 7.25-7.21 top 2H). MS 284 {Mi I t Example 38: :2»€'lilot-oq|ui»az0li8-4*a*ni»e

To a solution of 2,4-=iUcWofoqumazolme (2,0 g, 10 mmol) mTHF (10ml.), was added ammonia (28-30 % in water, 18 mL), The reaction mixture was stirred at room temperature .overnight. The reaction mixture was diluted with EtOAc, washedwith saturated. NaHCCo, water and brine., dried over htoSO.;, filtered and evaporated. The resulting solid was washed with EtOAc to give the title compound {1 .3 g. 72 93). Ή NMR. (400 MHz. DMSO-«/>) 0 7.52-7.48 (in, 1H), 7.6-7.58 (nt, IH). 7,8-476 (m.. t H). 8.22-8 20 (m, I H). 8.32 tbs.. 2H). Example 3$: S-CdilortwM-methykpdsnszoIa-d-amiae

Prepared as in Example 38 from 2 ,4-diehloroqtHnazolinc arid orrthylamine, Ή NMR (400 MHz, DMSOto) h 2.98 UL ,/=== 4,1 Hz. 3H). 7.53-7 <1-9 (nr. I.H). 7.61-7.58 to, 111}, 7.79-7.75 to, III), 88.19-8.1? (m, 111),.78 tbs, III).

Example 40: l-Chlora-NrlS'-iisiiettryltiuinazollfi-d-amliie

Prepared as in Example 38 from d.d-dichterogumuzolme and dlmethyiamioe, !H NMR (400 MHz, CHCl.d 3 3.43 (s, 6ii), 7.43-7.39 (nr Hit,' Η-' Φ (m, IM),.7,79-7.77 (m, Hi), 8 03-8.0: (m. III) MS 308 (Ml! ).

Example 41: N2,N2,N4,N4~T^rs«i«thylqutaavt:0litte*<2,4>diantl»#

Prepared as m Example 38 firom..2,4-djchlorpq«ma2oiiac and dimethylamlne. !H NMR (400 MHz, CDChj 6 3.27-3.23 (m. 1 2Hs, 7 01-6.97 (m, 11¾ 7,51-7.47 (m, 2H), 7,80-7.78 {-ο. 1H). MS 217 (MH }.

Ex a ropic 4 2: 2~ Hy ti raxiGylci i5lmxelG~4~a.miae

A «Oxime oF2-ebloroquiRaxo!m-4-amine (Example 38) (100 m.g. 0.76 mmol) amt hydrazine (0.09 mL, 2.79 mmol) in ethanol (5 mi,) was heated in a sealed tube at 80*0 overnight Aftet the reaction mixture was cooled down, the resulting precipitate was collected by nitration, rinsed with ethanol and dried in the air to gise the Erie compound (84 mg.. 86 *··;>}. ‘H NMR (400 MHz, DMSO-c/B <) 4 2 (bs, ,?H). -1.6 (bs, 2Hi. 7.0 (0 J - 7.2 Hz, l H). 7.27 (d.../ - 8.0 Hz, 1H), 7.43 (4, 1II), 7.61 (s, IB), 7.S7 (d,: J- 7.6 Hz, IB).

Example 43; 2~(llydroxyamino)t|ainnzolin-4~amkse

Prepared as in Example 42 from 2-chlordqmnazo!ln-4-:amine (Exanip!e 38) and hyd?x>xylamiim \H NMR (400 MHz, DMSOo/V) 0 7.44-7.35 (m5 .-28), 7.78-7.74 (m, 2H), 8.24-8.22 (ju, IE\ 8.95-8.76 |m5 2B). MS 177 (MB").

Example 44: 2-{M£ih0x;vamio0}(|UHm/.0ii»-4-afM&amp;e

Prepared as in Example 42 front 2<ddGroqmria2Q.lin-4-amirie (Example 310 and oicthoxylaminc. Ή NMR (400 MHz. OhiSO-ώ,} o 3.70 (s, 3Hh 7.48-7.44 !rn, i Hp, 7.86-7.80 (»i,M)»S.27(<isJ===-8;0 Hz. 1H), 8.99 is. 1H), 0.16 (¾ Hi). 12.3902.06 (m, 1H). MS 19| (ΜΗ')·

Example 45: N!-(4-Arafat>{|uPrazx>li«-2-vl)aeeioiiydrazi(le

Prepared as in Example.42 from 2-chforoquina?oiitt-4-aroine (Example 38} and methoxylaminc. *H NMR (400 MHz, DMSO-rO;} d 1M (s, 3H), 7.09 (t, J * 7.2 Ηζ,Ι K), 7.2? id. J === 8.4 Ηζ,ΙΗ), 7.54-7,44 (m, 3H), 8.04-7.99 (m. 2H). 0.63 is. IH). MS 218 ;MH' s.

Example 46:4"(Methylamm0)i|pmazeii»e"2(lHHfe^»E«

A 'mixture of 2-cfeloro~N-meihylqamazolim4~a:m5Be (Example 39) (100 mg.. 0,57 nttnoi), ftsiourea (47,5 mg, 0.62 mmol) and .formic acid (0=.0,2 mt, 0.52 nunol) in ethane»! (5 mt.) was refluxed for 1,5 h. After cooling to roonrteo^eimiorerfee toaedo»..mixture was;ftemruiized wi&amp;diluted NaOH aqueous solotkm.· The solvent was removed under vacuum and the residue was plained by preparative HPI..C eluting with acetonitrile and water to give the title compound (18 mg5 18 %). Ol NMR (400 MHz.. DMSO-d*} 6 2.99 (d,./ == 4.8 Bzs 3M), 7.25 (t J- 7.6 Hz, 111). 7.35 (d../ 8.0 Hz. 1 H).. 7.65-7.61 (m. Ill), 8,0 (d, ,/=== 8.0Hz, ill}, 8,70 (d, J ==== 4.4 Hz, 111), 1232 (s, 111). MS 192 (MHO.

Example 47: 4-{I)*i«et!n lamieo'Hptraa/oliiie ·2< IItHhione

Prepared as m Example 46 from 2^Moro-^N-dsme&amp;yIq«inazoi.m*4-^Bimo. (Example 40) and thiourea, JR NMR (400 MHz, DMS0-/<) 0 331 (s, 6H), 7,24-7.19 (m, 1 % 7.40-7,38 im.. 1H), 7.65-7.61 (op 1H), 8.00 (6,/- 8.0 Hz, IH), 1235(s, 1H). MS 206 (MB:). Example 48: 5.6.,7.8~Tetralpvdro^dnazolme~2.4( 1H.3H .H.Ooae

Λ solution of z-oxocyele-hoxanociirbonitriio (6i 5 mg, 3.0 mmol) and urea {6061 mg, 10,0 mmol) in 1.25 N HC! in EtOH (20 ml,) was reiluxed over night. After it was cooled down to CMC, the precipitation -was collected by Okratton, washed with EtOH/lHO, and' dried under vacuum overnight to give the product as. a white solid, J.H HME. ¢400 Mlfe, GDjQC)) § I. 67-1.80 (m„ 4H), 3.25-2.29 (π:ν2Η), 2.38-2.42 (m,2H). MS 167 (MHz),

Example 49: 5.?-f>ihyd«bifeie»o||>4Kljpyrimtdine«2>4(iHs3H)>4li&amp;»p

Prepared as in Example 48 from 4~oxotetrahydrothiopl3eue~3~carfeonitriie as a white solid, % NMR (400 MHz, DMSO-iC) 9 3,74 ((, / - 3,6 Hz. 2H), 3,96 (i,./ 3,6 Hz, 2H}, II. 06/, HI), 11,21 (a, HI). MS 171 (54111.

Example S8; 5,ό“0^εί&amp;νΙ-2-ΐΙ«οχο-2,3-#ί*γ<ΪΓβίϊ^ίϊο(2.3-d jpynmklm~4t HHfi-one

To a suspension of ethyl 4.5-din icthy 1-2 -thiourcidori ti ophcnoo-carboxy late (Example 50a) (3:7 tog, 0.1 7 mmol) In dry EtOH (10 ML) was added sodium hydroxide (21 Mg, 0.52 mmol). The nsaeiion mixture was then stirred: at room temperature for 5 minutes and refinxed tor 10 Minutes. The reaction mixture was cooled to room temperature, neutralized with 10% AcOH and then eooecvsraic-j to dryness. The residue was purr tied by chromatography on silica gel (Gradient 0-50 % EtOAc in Hexanes) to give the title compound to mg) in 24 % yield. lH NMR (4()1):Mffe, DMSO-fo) p :.25 is. 6H), 12.24 $s, IH), 13.27 (s. I Hi. MS 202 (ME'').

Example 50a: Ethyl djS-dimethy'hSstyourddotMppheae-S-eattexyiate

To a solution of ethyl 2-dsothioeyanato -4,3“0imsthyithiophene^3-earbox'y.late (Example 50b) (1.21 g, 5.27 mmol) io dielfioromefoane (10 ml) was added ammonia .(7 M in MeQH. 1.12 mL, 7.91 mmol) at 0 °G. The reaction mixture was then .stilted' at room temperature; for 3 h. quenched with w*t$r and extracted with diehloromethang (3 ;X), lire combined organic layers were washed with brine, dried over MgSOg, filtered and concentrated, The dark orange residue was purified, by chromatography on silica·gel (Gradient 0-501¾ EtQAe in Hexanes) to give the tide compound 07.1. mg, 3 ¾). 3Ti NMR (400 MHfoOMS0-i4) S 1.32 (t, 3il,/- 7,.1 Hz), 2.18 (s, old), 2.19 (s, 3H), 4.30 0, 211,,7- 7,1 He), 8.43 is, 2H), 11.38 (s, IB). MS 259 IMH ).

Example 50b: Ethyl S-isothioeyanato-d.S-dimefhylthiophcne-d-cin-hoNslaie

To a mixture of thiopliosgene (5.10 mL, 7,64 mmol) and calcium earhoaate (i ,05 g, 10,54 mmol) hi CBClyhlzD (1/2 by volume, 6 mL) was added dropwise a solution of ethyl 2-amino-4y50im.erhyHbiophene~3~carbpxyiafo:(l,O5 g, 5,27 mmol) In CH€h(? ml.) at 0 °C over a period of 1 h. The reaeiion mixture was the stilted for 2,5 h m 0 %'. washed with water (3 X). The organic layer was dried over MgSO*> filtered and concentrated to give the tide compound (1.21 g, 100 %) SH NMR (400 MHz, DMSO-fo) 3.1,32 (t, 3H, /- 7.1 Hz), 2.19 (s, 3H)V 2,30 (s, 3B)S428.(q, 2B,./-=7,1 Hz).

Example 51: 4-Ethy!-5,<MltmethvHlHe«o£2.3-d)pyrimidi«*-2f 1H)-one

To a solution of i-(4,5-dimssihy{-3-propionyltiijpphen-2~yi)ufea (Example 51a) (15 .4 rug, 0.068 mmol) in dry EtOH (10 ml..} was added sou asm. hydroxide ί K .-5- sag. 0.5.0 mmol}. The reaction mixture was then stirred at RT for 30 minutes under nitrogen. The reaction mixture was neutralized with 10 % AeOH and then concentrated to dryness. The residue was purified by chromatography on silica got (Gradient 0Ί0 % MeUH in elieblorosnetha.ne; to give the title compound (5.7 mg, 10 °<d. Ή NMR (400 MHz, COCK) <> 1.43 it. J 7.0 Hz. 314.), 5.31 (s. 3H), 2.33 is, 3H), 7.0ό tq.../ - /.6 Hz, 5H>. MS 509 <MH').

Example .5ia: l*(4.5-Di}nethyi-3-piopionylthio]'herv-2-yl)urea

To a solution of tnpbo^gtnc (68 mg, 0.224 mmol) in dry dichioronscthane (2 ml.,) was added dropwise a mixture of .1 “(2»ammo-4,5>*d5:m8thyl.thipphsn“3“yi)propa.n~l~o.ne (Example 51 bs {111 mg. 0.605 mmol) and D1EA 0).54 ml... 1.344· mmol) iss dry dtchloromethane (3.5 ml.) over a period of 30 minutes. After the reaction mixtisre was stirred for 5 mi miles, a mixture of ammonia (7 M th M'eOH, 0,086 ml, 0.605 msnol} and. DIEA (9,24 ml.., 1.344 mmol) in dry diehloyomethane (2mL) was added In one portion, The reaction mixture was then stirred at room temperature for I. h/under nitrogen. The reaction mix hire was concentrated to dry ness. The residue teas dissolved in EtOAe (SO mL) and then washed With 10 % NaHSO.s, 5 f-f NaHCOi. and brine. The organic layer was dried over MgSCTj, filtered and concentrated. The yellow residue was purified by chroiuafography on silica gel (Gradient 0-5() % EtOAe in. I4exanea}to give the title: compound (15.4 mg, 30 %), It NMR (400 iVtlhg CDCH) S 1.1¾ (UB../ - 7.2 Hz). 2.25 (s, 314)52.30 (s, 314), 2.87 (q,2R,/ 7.2 Hz), 4.77 (s,2H),lL99 (s. IB),. MS227 (MB').

Example 21 b: 1 -(2-Amhio-4,5-dimcthyIthionhcn-3-y!}propan~i~bne·

To a solution of 3-oxopentancnitril.c (971 mg, 10 tnrnol) in dry EtOlf (.100 tnL) was added sulfur ¢2,57 g, 10 mmol), btuauoae (C191 mL, lO tnmol) and morpholine' (0.¾¾ mL, 10 mmol) at room temperature under nitrogen. The reaction, mixture was thee '.refluxed at 90 X for fob, and then stirred overnight at; room temperafnre under nitrogeo. The orange brown reaction: mixture was concentrated. The residue was diluted with water,, and extracted with EtOAe (2 X).

The combined organic hvcrx were washed with brine, dried over MgSOj, filtered sod concentrated. The residue *as punfied twice: first by chromatography on silica gel {Gradient 0-25 Λό EtOAc in hexanes), and then by Prep I iPLC (0-90'h, acetonitrile in water) to give the title com poor id < 123 mg, 7 Tp. Ή N.MR (400 MH?. C'DCl·) 0 i .1 7 i t, 3H, J - 7.2 Hz), 2,17 (s. 31¾ 2.24 (s, 3H). 2,"8 fq. 2R J - 7.2 He). 0.81 K 2H). MS 184 (MH ).

Example 52: 4-Eihyl-5,&amp;-dtmethyitiiietiu{2,3-djp>nmidhi~2(lH)-»me

To a solution of ntethyinuignesium bromide (3.0 M in ether.. 4 0 mi... 12.0 mmol) in dry ether (5 mi,} was added dropwiso a solution of 2-aniinohenz.oniiri!e ( 723 mg, 0.0 mmol) in dry .ether (5 mt) at RX under .nitrogen. After it was refluxed for 2 h under nitrogen, the reaction mixture was cooled down ίο 0 °C and methyl ehloroformate {0.7 rnL 7.0 mmol) was added drop* isc. Dry THE (5 tnL) was added to dissolve the resultant precipitate. The reaction mixture was then refluxed overnight tinder nitrogen. The .reaction mixture was acidified with I N 1:K. j and then neutralized with 5% NaHCOy aqueous solution. The water mixture was washed with EtOAe and the water layer was concentrated. The residue was purified by Prep H PI.C ((0-90 % acetonitrile in water) to give the title compound {15.2 mg). *H NMR (490 Affix. CDiODl <> 2.79 is, 3H), 7.33 id,,/- 7.1. Hz, 1H), 7.34 (t.,/ 7.1 Hz, I H). 7/c< Ud. /- 1.2, 7.8 Hz, fid). 8,03 i do. ./ 1.2 8.4 Hz. Hi}. MS 161 (MH }.

Example S3: 4>amittopyridoP,l“/|pyrimidih:“2(lM}~h«e

A solution 0fAJ-0-cyahqpyridin-2-ylcarbamoyl)ben2innide f example Seal (580 nig, 1.35 mmol) and Na()H;(2N, LdSniL) in EtOH (SniL) was' stirred at 100 /2 under nitrogen for half an. hour. After cooling ίο room temperature, the clear reaction, solution was filtered and the filtrate was carefully neutralized with. 10 % AeOH with vigorous stirring at 0 /7. The res alia; n precipitate was collected by filtration, and washed wnb warni 20 % EiOH in water to give the final product 4«afirinopyrido[2,3«u}pyrinridiri-2(i K)-onc (120otg, 55 %} os a while solid. -5H NMR (400 MHz, DMSO~%)ri 7.22 (dd,.,/====4.4 Hz, 4.8 Hz, 111),.7.29 (dd,./ === 41 Hz, 11 lb 8.24 {dd, J === 2 1¾ 1.6 Hz, IH),8.59 (dd, J ==== 2 Hz, 1,6Hz, 1H), 8.06-8.71 (In,2H),8.70(d, 1 1.2 Η/. 1H) MS 162 (MH ’}.

Example 53a: ΛΜ3 -eyanopyridtn-2-yfearbamoyDbenz^ntde

To a solution ofS-amino-S-cyuoopyridinc (300 mg. 2.5 mmol) in l ,4-dioxane (5 ml.) was added benzoyl isocyanate (370 mg. 2.5 mmol), Tbe reaction mixture was then stirred at room temperature tinder nitrogen. overnight The precipitation was collected by hltraiio», washed with EtGAe/Hexanes ί l :4), and dried under vaeuumto -give'N~('3-cyanopyrtdia-2-yIearbamoyl}be»zsmide as a white solid (360:ntg, 54%), MS 266 (MH'),

Example 54: 5J~dioseihy|gumuzoiHU'--2;4(l//.3/:/i~dlo»e

Prepared as in Example 53 from iV~(2-cyano~3,4-dimcthyipbcstylcarhamoyObcnzamidc (Example 54a) as a white solid (POmy, 66%). !H HMR (400 .MHz. DMSOmV) d 2.24 (s, 3H), 2.54 (s. 3H), 6.87 (d. I === 8.4 Hz, IK), 7,32 id. i === 8,4 Hz, I I f ), 10:5.1 (s, \ I f). MS 189 (MB:).

Example 54a: 56-(2 -ey an 0-3,4-dimeihy !pheny1ciahamoyi)benzamtde:

Prepared as in Example: 53a from C^sntihO'2,|*dihte6iyifeejizo'aiirile and benzoyl isocyanate as ao#white solid (2IOmg, 72%). *B NMR (400 MHz, DMSQ-A) 32,27 (s, 3ff), 2,43 (s. 3H>, 7.48 (d, J - 6 4 Hz, 2Hh 7.53 (t, 1 - 8 Hz, 7.6 Hz, 2H), 7.65 (t, J = 7.2 Hz,·· 1H), 7.94 (dJ - 8 Hz, 1H), 8.03 HU - 7.6 Hz.2H), 11.29 (s, I.Pi), 11.37 (s, IHK MS 293 (MIT). Example 55: 4~aminO“7“Stw4htrxytpriiiazobtt~2(13/)''Oae

Prepared as in example 53 from AM 2~eyano«S« metboxyphcnylcarbamoyl ibenzamide (Example 5Saf as a whiie .solid (24mg, 37%). -Η NME (400 MHz, DMSO-xfri 3 3-79 (s, 31¾ 6,63 (d, J ==== 4 Hz. 1H), 0.67 (¾ J - 2.4 Hz, 2,8 Hz. 11¾ 7.67 (hr, 2H4, z8v(dJ === 8.8 Hz, 11¾ 10.61 (s, iH>. MS 191 {MHO.

Exam ok. 55a; ;Y- f 2 -e> ano-S-methoxypbeny lewbamoy ] }be«zaro idc:

Prepared as in Example 53a from 2-amhio-4«melhoxybeozortitnie und benzoyl Isocyanate as white solid <99mg> 45%). Ή NMR {400 MHz, DM SO· ¢4) r> 3.·5-ο ο;, 3H), 6.8" (dd, J == 2.5 Hz, 2.4 Hz, 1H), 7.54 it, j === 8 Hz, 2H), 7.66 {=, j === 1.2 Hz, IHf, 7.77 (d. j-= "2 Hz,

IH), 7.89 id, I == 8,4 Hz, 1H), 8.03 id, .1 === 2.8 Hz, 2H). 11.35 is, IK), I i .52 is, 1H). MS 295 iMH

Example 56: 4~amhm»5-iBetiosyqi;i!aaZ0lia~2{ 1 //>-one

Prepared as in example 53 from &amp;^2~eysn&amp;-3- methoxyphenykarb.mioyf)bcnzaroide {Example· 56a) as a light yellow solid ;35mg, 51%), *H NMR (400 MHz.. DM$0-<4} * 5.93 is. 3H), 6.67 (¾ J == 7.6 Hz, 8.4 Hz. 21¾ 7,45 (U- 8 Hz, iff), 7.75 is. Iff), 7.93-7.9? (br, 1H), 10 69 (s, IH). MS 191 (MB')·

Example 56a: .•V-^-cy.ano-S-medioxyphenyicarbamoylibenzamldd:

Prepared as in Example 53a. from 2=4m!»nO“6-mefc apd:he&amp;«oy1 isocyanate as fight orange solid (1 18nig, 41,J>} 'f1 NMR (400 MHz.. DMSO-rfr) 3 3.94 (s, 3B), 6,98 (d, J - 8 Hz, =1¾ 7,5=1 n, J '= 8 hz, 2ff), 7.64 { J - 8.4 Hz, 2H;„ 7J8 (d, 1 - 8,4 Hz, IB), 8.0-1 6.1, j - 5.6 Hz, 2H). I 1.35 (s, ! Η), 11.51 is, f ff). MS 295 i MH ).

Example 57; 4~amino~S-<fcy4mxf^»i«i»«olitt~2( I W)~o»e

Prepared as in example 53 from /v-i 2-eyiirio-3- :%dit3!xypheiwicarbainoyi)beii2ami<le''(Exairipfe 57a) as a green solid (SOmg, 53%). *0 N.MR ¢400 Mila, DMSO-4-d S 6.66 id, J === 8,4 11/, 1D), 6,73 id. J === 7.6 1¾ 1 1¾ 7,57 (t, i ==== S J Bzt 1H), 9.47 (x, Hi}, 9.oK (s. I H r 11.84 (s, I H1. MS 17" (Mi l ). =v· t -l -cv an* )-3-hv droxypheny learbanw> I jbenzamidc.

Prepared as in Example 53a from 2s*mhm-6-hydrox>bcn«>nitnje urul bcnzovl Isocyanate as an ofi-Msae solid 1 looms. 46°«}. Ή NMR 140(1 MHz, DMSO ·»/<.) 6 6,76 (d, J -= 8.4 Hz, ΙΉΙ 7,46 (g j - S Hz, I Hi, 7.54 a. j - 6 Hz, 2Hi. 7,60-7.73 (m, 2Hi. 0.04-8.00 (d. j === t Hz, 2B), 11,24 (s, HI), :1.50 (s, Hi}, 11.42 (s, 1H), MS 28! (ΜίΓ).

Example 5&amp; 4>apilE»“7”Kydrexyq»lRa2oIla-2(I

Prepared as in example 53 from t\;-(2-cyaoo~5·* hydtmyphenylearbaraoy I ihenzamkle (Example 58a) as a light grey solid (104rag„ 41 %). ΊΊ NMR (400 MHz, DMSO-ifr) <> 6,51 is, 2H), 6.52 Id, J === 2.4 Hz. 1 H}„ 7.69-7.72 (br, 1H), 7.82 (d, .1 ==== f .2 Hz, 2B)? 10.57 (Or, 1H). MS 177 (MH"}.

Example 55a: .MCl-evaoo-S-bvdroxvolienylcarbameYiibenzamide:

Prepared as iu Example 53a.? but refluxed l?xacetone instead of 1,4~dioxwe, from 2~aminO”4”hydroxyh©nzoniirsle and benzoyl isocyanate as a;yellow solid (399mg, 94%), MS 251 mir 1.

Example 59: 4 -am 1 no-8-metboxygmmuoIm-2( 1 H)~mw

Prepared as in example 53 from 56-(2-cya.no-6-^ meihoxyphsnyl.carbamoyl)benzamide (Example 5%) as a dark, white solid (75mgs. 3932)- 5H. NMR ¢40() ΜΗ/., DM&amp;.hy d 8.86 {>, 3K), 7.02 ((. j === 8.4 Hz, 1B), 7.17 (d, .!' - 7.2 Hz, 1H), 7.50 ui. J === 46 Hz. IR), 7.85 (br, 20), 9.?3<s. IH). MS 191 * MB').

Exam pic 59a; Afodmyatmfomieihoxyphmiyicarbanioylfoeozarmde:

Prepared as in Example 53a from J^asttifto-e^aiethoxybeMoftifrilbaiif.d: benzoyl isocyanate us a. light orange solid (,2S0mg, 95%). Ή NMR (400 MHz. DMSO-fr;) A 3.89 (s, 3H), 7.42 U,) === 3.2 Hz, :H>. 7.46 (d, j === 8.6 Hz, I Hi 7.54 (t, j - 8 Hz. 2H), 7.66 p, 1 == 7.6 Hz, i H), 8.05 (d, J == 8.6 Hz, 2H.K =0.55 (s, !H). 11.32 (s, IH>. MS 295 (MH }.

Example 60: (framino-(1,3|d foxo k>\4,5--.4quimazeIsafo(57/Hme

Prepared as in example 53 from /V~(6~cyanobeiizo[i?rj[l 3J$exoi-5-y1carbamoyl)benzaj«ide (Example 60a) as a light yellow solid (80mg, 77%). ‘14 NMR (400 'MHz, DMSG-cfr) 3 6,24 (s, 2H), 6.74 (s, 10),7.75(8, III), 9.36 (dJ>=l0.4Hz, HI), 9,80 (4 i === 7.2 Hz, I O). I2.01(s, =H). MS 205 {MR*}.

Example 60a: frfrhmyanohenzoii/): 1,3jdio\olfo-ykurbamo\d)benzSmide:

Prepared as in. Example- 53a..from 6a=nmnobenxo(4l| 13]0ioxole*5marbonitri.le and benzoyl isocyanate as a yellow solid (1. 57mg, 82%), lH"NMR (400= MHz., DMSO-yfr) 9 6,19 (s, 20}, 7,42 (s, 10)., 7.54 0, j === 8 11./, 2H}„ 7 .66 (t, J = 7.6 0/., IB), 7.74 ($, 01), 8.03 (d, 3 = 9.2 Hz. 211), 1 U2 fo.J = 12.8 0¾ 20). MS 309 (MO").

Example 61: 4~{Meihoxyamino)<|amazoSin-2(I H'hme

To a suspension of 2.4--dich!otoqulnaxo!i«c (995 mg, 5.0 mmol)In dry EtOH (100 nC), were added metboxyamine hydrochloride (569 mg, $.5 mmol) aod 'NaOlf (227 mg, 5.5 mmol) in one portion at 0 “C. The reaction mixture was stirred: at 0 °C for 1 homy then placed in a refrigerator at. 4 °C for 72 h. Upon completion, the reaction was concentrated, and the residue ms dissolved in litOAc and washed with saturated NaHC'O» (lx» and brine Ux>. The organic phase was dried over MgSOa. filtered and concentrated. The crude product was punned by preparative RPLC {10-90 % CM»ON in Η;·0) ίο provide 4-imethoxyarnino)qujriazolin-2{ l/fhone (556 mg, 56%) as an off-white solid. *H KK! R (400 MHz, DMSO-rR) 3 5.68 (sffiff 7.02 (s.../ === 7.4 Hz. 1H), 7.55 {J. J === 7.9 Hz.. 1 Hi. 7.52 (ddd, J === 8.1, 7.0, i .5 Hz, 1H), 7.77 tdd, J ==== 7.8,1.4 Hz, I Η?, 10.15 Hip 10.89 (hr s, IB). MS 192.2 (MM ).

Example 62; 4-I:dimxYqm«szoii«~2i l//)~onc

Puritkabmi by preparative HPLC ( = 0-90 % CH ;€R in HyO) of the crude reaction of example 61 also mot idee! 4-ethosyqt liouzol in -2« I liy one (90 mg, 9/¾) as an. offwhiie solid,

Ί:1 NMR (400 MHz, DMSG-ffd 6 .! .35 (t,./==== 7.6 Hz, 3H). 4.44 (q, ,/==== 7,0 Hz, 2Hj, 7.34 (ddd, J ===8.1, 7,0,1.2 li.z. IH), 7.46 (dd,,/=== 8,2, 1.,0 Hz, IH), 7.71 (ddd, J ==== 8J, 7.0, 1,2 Hz, 11·% 8.,01 (dd,4== 8,2, 1.5 Hz, 1 H}: 12.25 (hr s, ,1H), MS 101 ..1

Example add

To a solution of ferwbistyl 4-miaind«5-die%'i»2*oxo4,2<4i%dr6thieh0[23> i?lpyTimidii=tC“6-cerrbQxyh-ite (example 64«) (10,7 g, 38.03 romot) m CH^Cl; (25 ml,), was added trifluoiroacetie-meld (25 mL, 324.5 mmol). The reaction mixture was stirred ut rt overnight The precipitated solid was collected by filtration, and washed with CH;Ci> to yield -l-Amino-S-methylff-oxo-l , Adihydroih:cnof2,3~djpynnudme-e-carbcxynr acid (6.98 g, 82 %) as a light brown solid, Ή NMR (400 MHz, DMSO-ff;} d 2 78 {s, 3H). MS 336.0 (Mlf).

Example 64ΐ ferf-Bxstyi 4~amiHO~S~meil5xl~2~pxml J-dll^drothfenoliJ-^pEtimldlue-O-earhoxylafe

To a suspension of/urz-bufyi 5-{3-ben2oylw?ido)-4-cyano*3*mcfhyUhiophenc«2* carhoxylate (example 64a} (18 g, 60.52 mmol) in EtOH (200 niL} was added NaOH (75 ntL, 2N>. The suspension became clear. and the mixture was heated to reflux for 30 min. Λ tier cooling to it, (He react ion was filtered, and the filtrate was cooled to Cl °C in an iee/water bath.. The solution was neutralized with 10 % acetic acid. The precipitated solid was collected by filtration., and heated in BOH at 80 *0 .under N; for 20 min After cooling to ri., the product was 'collected by filtration and washed with. .10-%-EtOB i.hJEO to yield terf-Bntyl. 4-amino~5~methyl~ 2~oxo~i .2-diltydrothionop.3“</|nyrtmidi«e-6“Carboxylate (10.73 g, 63 %) as a brown solid. *H N.MR (400 MHz, DMSO-ώ; 0 1.51 (s. 'hi), 2.73 (s. 3Hy 3. i 8 (s. 2Hj. MS 262.2 tMH }.

Example 64a: toW-hup. 1 5*(3rbcnc.oyiurcido}-4*cy«ino~.1“rncthylthiophette“2-carboxylate To a solution of sowbutyl 5-aroinQ'4>cyarioomwOiy]tmophcnc-2-carboxyl&amp;te' (example 640} (lb g, 67.1.4 mm.pl) in dsosane. (200 ml,}, was added benzoyl isocyanate, (10 g, 67.14 mm.pl). The fea.et.ion mixture eras stirred ai rt oveoright, and upon completion, was diluted with BiCIAe, washed with MaHCOj, water, brine, dried over MgSQs, .filtered and concentrated to yield /«-/-butyl 5»(3-bcnzoylnrcido)^~cyano-a-m8&amp;yl.tbiophe«e^2-carbb'xykte (21,78 g, 84 %) as-a brown .solid. Hi hi MR (400 M.Hx, DMSCtoE) 3 1.54 is, 9R), 3.58 (s. 3.H), ?.5H (UJ == 7.5 He, 20)(7.71 <!·,./=== 7.5 Hz. I.H), 7.88 (d../=== 7.5 Hz. 1H>. 8.05 (d. J == 7.5 Hz, 2H), 12.25 ibrs. 1H).

Example 64b: tew-hutvl 5-amhre-4--cyano-3~ruethvlthlopheue--2~eafhoxviate

To a solution of tod-butyl 3-oxobntanoate (30 inL, 183,94 mmol) in dry EtOH (360 nil,), wore added e:lemental sulfer (5.90 g, 183,94 mmol),, maionomfilie (12Λ6 g, 183,94: mmol) and dicihyiamiue (25.6 ml.., 1 *3.94 mmol). The reaction. mixture was heated to 80 'Tl and stirred for 2 h. After cooling to rt. the mixture was concentrated under reduced pressure.

The resulting residue wa* dis.-Olved m ElOAc. washed with SaHCOy*. Water, brine, dried over MgSOe, filtered and concentrated. The crude residue· was purified by Sash chromatography on sdica: gel (10 % ItOAein hexane} to yield. /erEbutyf 5-amioo»4”eyanc«3»mcthylthiopheue“2-earbexylate (31,2 g, 73 36) as a brown solid.

Example 65: 4-Λmίaoquinoli«-2ΐ 1H Bone

4-Ami»4“®?* I .I-diliydroquiooliiie-S-earboxylie acid (Example. 64)-(0,030 g, 0.15 mmol) was beared neat at MAC for 10 nwnues, then cooled to roan temperature fo give 4--aminoquinolin-2{ 1 H)«onc {0.023 g, 99%) as a light voiles solid. M,p.; ; 250 Ό. Ή NMR (400 MHz. DMSO-teq d 5.-42 is. IH), 6.55 (S. 2H}. .07 fg ·’ =' 7.6 Hz, IH). 7.19 Ut J = -S 0 Hz. IB), 7 42 it../ 7..: Hz. I R), 7 80 id.../ - 7.0 Hz, 1H>.. I0J! (s, 1H> MS 161 (MH)

Example 66: «i-Amlao^'-oxo-l^-dlhydreqalaoliae-'S^arfeaxylic acid

Benzyl d-annuo-e-oxo-1:2-dihydroqumoline-3-car6oxylatc {Example 66a) (0.6 g, 2.04 mmol) was dissolved in DMF (8 ml..) and heated at 70a€'under a hydrogen balloon in the presence of i0%.'Pd/'C (OJSg) for 1 hour. The Bd/€ was filtered out and washed with dlelibromeiliane and die solvents were removed under vacuum.. The residue was dlssolved/suspended In NaQfd (2M, 40 :mL), stirred at room temperature lb/ 30 minutes, and the solution washed with discMoroffieijaane. The aqueous layer was cooled to 0°€ and acidified to pf! I with 2M I H'l The resultant precipitate was collected and washed with dicli1orq.uiet.hane to give 4-amrao-2-Gwo- 1,f2-di%droqumo1ine-3^e'afboxy.ilc acid (0.050 g, 12%) as a light yellow solid. M.p.: >250X7 NMR (400 MHz. DMSCM,) d 7,32 (m, 1 ®% 7.39 (d, J- 7,6 Hz,. iff), 7.69 (m, IB) 8,27 (¾./- 8.4 Hz. IH), 3.86 (s. IH}.. 9.87 (s. ! By ] ] J5 (s, IB) MS 205 (MEf).

Edemiple 66a: Benzyl 4-aioinn-2~oxo~i .2-dihydroquirso!ir!C-3~Carbbxyiate

Benzyl 4-chloro-2-oxo* I./.“dihydroqyino'nne-d-carhoxylaie iExample 66b) ({).55 g, 1.75 mmol) was dissolved hi DMF (8 ml,} and 4-tnefhpxybeuzylmtuue: |0,5§;^Ε·* 4.31. mmol) was added.. The reaction was heated at .1,15*0 fbr 30 minutes, then cooled to room temperature and poured into ice water. The resultant pfeeipitat© was dissolved in: lO.mL.TFA and stirred at romn temperature For )5 minutes, then the mixture was poured into* ice water. The rovultaW precipitate was» collected. dissolved in dichlorotnethane. dried over MgSOj. filtered and evaporated to give the crude benzyl. 4-aau»o~2~oxt>t>2~dihydroQ'UiUollue’«3'~c«j''box>-late (600 .mg) which was used as this-without further purifieut ion. 5 Id 245 <MH ).

Example 66b: Benzyl 4-chloro-2-exo· i ,2-d iftydr>-quiuol iac-3-catbo\> Une

Dibenzyfmalonate (7,75 mL. 31.6 mmoli was added slow h to j suspension, of 60% sodium hydride in mineral oil (1.41 g, 35.3 mmol) in imhydious DMP 5100 mL) at -20"C under nitrogen. Aliev stirring at room temperature for 30 .minutes, isatolc anhydride (5.0 g, 30.7 mmol): was added, aud the reaction was heated at 120 V f«w I hour, 'foe reaction was then cooled to -50'·' C and o scaly I chloride «10.7 mL, 123 mmol.) was slowly added. The reaction mixture was stirred at room temperature for 2 hours then poured into aqueous NaCl (10%, 750 mL) at 0°C. and the resultant precipitate was filtered out. The precipitate was dissolved in dlelikxro.rnetiisoe, dried over MgSiV. filtered and evaporated under reduced pressure. Diethyl ether was added to the .residue, and the resultant solid was collected to give benzyl 4-di!oro~2~ oxo-l ,2'dihydToqutno!tnc-3'Carbo\yjate (5.50 g, 37% yield) which, was used-Without fiirthef pay ideation, MS 314( Ml I i.

Example 67: Ethyl d~hydroxy-2-pxm:l,2-dihydror|Minoi.ne-3-ea.td>ox.ylate

Dietbylniaionsfe (11,4 mL, 75.1 mmol) was added slowly to a. suspension of 60% sodium hydride in mineml.--oi.l.-(3.0 g, 77.3 mmol) in anhydrous DMF (100 mL) si-IlfCunder nitrogen. After stirring at room temperature for 30 minutes, isaloie anhydride (12.0 g„ 73.6 mmol) was added, and die reaction was heated at 115°C for 2.5 hours. The reaction was cooled to room temperature, then poured into ice water (1.4 L) and acidified to pH 4 with 2M BCL The resultant precipitate was collected, then dissolv'od'sn.spended in diehioroinethane (450 ml,). The d!#Jdronwibane solution was filtered out then evaporated to provide a residue that was vigorously triturated with diethyl ether (150 ml,} for 1 hour. The solid was collected to give ethyl 4-hydroxy~2“Oxo-1 !2-dihydt0qutnohne-3-carbox.ylaic (3.63 g, .21%) as a white solid. M.px 190 C. NMR (400 MHz, DMSO-4* (> 131 U.J- 7.2 Hz, 3)1),4.35 ;q,J ~ : If/. 2H), 7.21 (ra, IH)S 7,27 (d, / - 8,0 1¾ 1B), 7-63 (m,. 1.1¾ 7.93 (dd, J - 0,8, 8.4Hz,. .1B), i i ,51 (s,1.1¾ 13.40 (s, .1B). MS 234 (MB ').

Example 68:

Methyl 4-^midhoxyhen/yi.numcd"2wxoB AMihydroqimiohueTv-earboxyiaie (Example 68a) (0.841 g, 2.49 mmol) was dissolved in TEA. (5 oil,}: and stirred at room temperature for 30 minutes. The TFA was removed under reduced pressure, and the residue was dissolved in dichloromcthtmc. then precipitated cut b> adding excess diethyl ether. The resultant sislid was collected by filtration, suspended indkMoromefhane, and washed with concentrated sodium bicarbonate. The solid was collected to give methyl 4ramino-2-Oxolf2-di'hydroquino'ime“3*cati>oxylate. (0.3 30 y. 42%) as a white solid. M .p.: 286'%;, !H NMR (400 MHz, DMSCA^)J:3.73 (s, 3H). 7.12 {S../-8.0Hz, 11¾ 7,17 (d../- 8.0 Hz, !H), 7.52 (0,/-8.0 Hz, IB), 8,08 (d, J- 8.0 Bz, IB), 8.38 (be, 2B), 10.88 (bs, IB). MS 219 (Μ1Γ).

Example 68a: methyl 4r(4«h5eth0%>bertzyi.amino}~2~oxo-1.2-dihydroqumoline-3>' earboxylate

Methyl 4-chtom-2r0^o>l^dihydrQqoiueimie~3.~eartioxy1iate (Example 69} (0.928 g, 3.91 .mmol) was dissolved in DMP (6 niL)s hud 4-m.ethois.ytetzylamme :(1.14 ml,,. 8,:78 mmol) was added. The reaction was heated at 90“€ for 30 qprmies, then cooled to.room temperature and poured into a stirred mixture of SO .thL hexanes and 100 oft iee water. The resultant, precipitate was collected by filtration and further chromatographed on silica gel (0% to 20% MeGH in dichlorontetimne} m give methyl 4-{4-methoxybenz.Ylatnino)-2-oxo-l ,3-:dihy4^ui»oUne~3~e^03tyl8te as- aw off whit® .solid (0.84] g, 04%y MS 339 (MB).

Example 69: Methyl 4~dslor«~2-0X0~l J-dihydroqaiaolue-3-enrboxyfete

Dimethyinuiiooate (2.2 mi,, 19.2 mmol) was added slowly to a suspension. of 60% sodium hydride hi mineral oil {0.81 g, 20.3 mmol) in anhydrous D.MF ίΙΟΟ niL) to -10°C under nitrogen. A tier stirring ai room temperature for 30 .minutes, isatoie anhydride (3.0 g, 184 mmol) was added, and the reaction mixture was heated at 115°C for 2.5 hours. The reaction was then cooled to -40°C and oxaJyl chloride .(6 xnL, 68.8 mtftol) was slowly added. The reaction was stirred at room temperature for 20 minutes, and. was then poured into 1200 mt of 10% NaGi si 0' C. The resultant precipitate was collected by filtration to give crude methyl d-cnloiofoOxo-L2'dihydroqoinojioc*3~e<Arix>XYlaie (I 40 g. 32%), which was used without further purification, foi NMR M00 MHz. DMSO-dd 0 3 87 is, 3H>. 7.39 (m.2H). 7.70 {m. 1H>.. 7 92 fd. ,/== 8.4 Hz, 1H), 12.49 fs, 1H). MS 238 {Mil ).

Example 7fh Meihy 14-hydroxy~2~o.xo~l .2-dihydroq»inoHae-3-earbaxyiaie

Dim.efhylmaiouate (2.2 mL, 19,2 mmol.) was added slowly to a suspension of 50% sodium hydride in. mineral, oil (0,81 g, 20.3 mmol) m anhydrous DMF (50 ml.) si -1CFC under •nitrogen. After stirring at room temperature for 30 minutes» isalolc anhydride (3,0 g, 18 .9 mmol) was added» and the reaction was heated :u I i 5¾ for 2.5 hours. The reaction was cooled to room, temperature, then 'poured into ice water (500 mi. i .cui acidified to pH 2 ά it!· 2M Ho'I. The resultant precipitate was collected by filtration to give erode methyl 4-bydm?ty-2-oxo-1 »2-dlfofofoquiuolroe-S-earboxylate (2.89 g, 72%),. which wasused without further purification.. !H NMR (400 MHz, OMSO-p) r) 3.86 (s, 31%. 7.23 inn 2H). 7.63 (m. 1H), 7.94 (dd. /= 0.8. 8.0 Hr, 1 FI). 11.55 (s, 1 FI), 13,33: (s, 1%). MS 220 (ΜΗΓ),

Example 71 rd-Amino^-oxcn-l^-dlhydroqninolbteM-carriesdi rile

4-ch!oro~2~ox.o~i »2~ilihydm^ainoliW3~csrbo«5trile (example 7.?.} i 0 .< i g, 3.23 mmol)'was suspended. in DMP (7 mL), aad·4Hmeihox>dtenzy!amine (0.94 ml, 7 30 .mmol) was added. !%© reaction was heated at 100°C for .1 hour and the DMF was removed under vacuum.. The residue was dissolved in IT A (0 niL) and stirred at 'room temperature for 3(5 minutes and dichloromethane (10 ml,} was added. The solid product, that formed wu;- collected, suspended in water and the solution stirred overnight. The solid was collected by hUratimi to give 4-ominn-2·· Pxo-I.J*dih^idroq«iao!ine-3^e;arbottitftk (0.150 g. 25%} as a white solid. M.p.: > 2$0°C. ΛΒ NMR (400 Μ11..-:, DMSO~49 S ?J9 (m, 2H), 7.57 (tm 111), 7.88 (bs, 20), 8.12 ;d. ,/- 7.5 1.1,·% H i). 11,23 (is, 1 hi). MS 186 (MIT),

Example 72; 4<*ch.iaFO-2-oxo-i,2-di&amp;ydrnqwlHCiKae-3-carlip«itrile

2,4-dichloroquin0iine-3-carboiiitrile (Example 72a) (0.9$ g, 4.20 mmol) and ammoniuni acetate (036 g, 4.67 rum.oi) were heated in acetic acid: (20 ml.) at 14(6(1 for 4 hours, then cooled, to room temperature. The reaction was poured into tec water (400 ml,·), and the resultant precipitate was collected by filtration, to give 4~ehioro-2-*QXG-1,2-dihydroqdmo1ine~3~ earberatrile (0.668 g. 71%) as a light yellow solid. M,p,: > 250CC. Ti NMR. (400 MHz*· DMSO-(4).fS 7,42 (m, 214), 7.79 (m, 111), 7,9b Cd,/==- 8.4 Be.. 1H'h 12.72 (s, I B). IMS 205 i.MH }.

Example 72a: 2,4Michloroqtunolinev3warbonitri!e 'N-cyclohexyl-4~hydroxy”2“OxO"L2-dihydroqutnolinc-3-cafbox'&amp;mide (Example 73) (US g, 4,12 mmol) was dissolved in phosphorus oxychloride {15 niL) and tnethylasttine (1.72: mL, 12.4 mmol) wsssiowly added, The reaction was heated or 12fi°0 for 7 hours, then cooled to room temperature and poured carefully into-ice'water (300 mL). The resultant precipitate was collected bv filtration -o give 2.4-dichio/QqujrK»linc«3-carbonilrile ίϋ.848 g, *>2ft«}, which was used without further purification. MS 223 {MH ).

Example 73: Nw\vch'!lK-xylMdrvdrexv2'0s0'-i J-dshydroqiPiHdiae^Vcafbaxamide

Methyl 44jydrox.y-2-ox.o- 1 ^-dlhydroouluoline-S-earhoxylate. (Example 70) (2,70 g, 12,3 mmol) was .suspended in toluene (27 mL), and eyetohexylamme (1,40 g, 1.4.1 mmol.) was added. The reaction was heated at 1iSAIlbr 5 hours, then cooled to room temperature. Diethyl ether (50 mL) - was added, and the resultant precipitate was collected by filtration to give 1ST eyclohcxyl*4-hydroxy-2-oxo· 1,2-dihvdrocjumo!me-3-carboxamide (1.22 g, 357(.} us an off white solid. M.p.; 221°C. ;H NMR. «'400 Mil?. DMSO-/>) a ] .3? (m. ill}. I 55 tm. 1H}, 1 />8 (m, 2Hh 1.88 {τη. 2H), 3.86 (nt, 1 HI, 7.28 (t, J 3.0 Hz, 1H). 7.3b {d, 7:::: 8.0 Hz, 1 Hi. 7.68 {?. J ::: 7.6 hie. I B), 7.95 .(4/ = 8.0 Hz, IB), 10.35 (d../=== 7,.6 Bz, 1 Η), 11.83 (bs, 1H). MS 287 (MH.:). Example 74: 4~andsrm2-«x«-! J~dihydr0t|Mmoiiae~3~ca:rboxaa«ile

A/ /v-bis(4-methQxybert2yi)-4 -{4-roeuhoxyhcnzyiamioo}~2-oxo-1,2* dihydroquinohne-dwarfeoxauUde ((Example 74 a) (2.0 g, 3.55 mmol) was dissolved an TFA (IS mL)' and. the solution was stirred at room temperature for 6 hoars. The TEA was removed under vacuum, and the resultant solid was stirred in water overnight, then collected by filtration to give 1.8 grams of crude final product, JH NMR (400 MHz. DMSO-44 S 7.18 (m, 2H), 7.25 id, /== 7.2 Hz, 1H), 7,56 (t,,/ === 8.0 Hz, ! H), 8.09 (d, J === 7.6 Hz, 2HL 9,83 (d, /=== 4,8 Hz, i H), ! 0..85 (bs, 1H ·, 11.12 (s. 1 H r MS 204 ί ΜH'}.

Example ?4a: ΜΑϊ:4>1χΐ14”ΠκηΗοχν0οηζν1)~4Τ4^ιοίόοχν:6€ηζ54,οίη1ηο)-2~οχΟ-! ,2-di by droquinol ine-3-carboxantide 4-chlovo-A;.A''-bis{4-mclhoxvbenze!)- 2-oxο-I,2>dihvdjoqiunolinc-3-carboxamide (Example ?4b) (4.25 g, 9.15 mmol) was dissolved in DMF {20 mL). and 4*mcthcxybcn£>larninc (2,68 mL, 20,6 mmol) was added. The reaction was heated at; 1.00*0 for 1,5 hours, then cooled to room temperature and poured into ice water (30(1 m.L). The msultani precipilate was collected by Miration and further chromatographed on silica gel (05¾ to 20%. MeOH in bichloromeihane} to give crude .V. Y-bis(4-meihoxybc3r?.yI)-4-{4-methoxy benxy InrnmoK'-oxo- i ,2-

dihy thxxiumoiinc-3-carboxamide i3.05g, 71%), which was used without further purification. MS 504%11-n.

Example ?4b: 4H5hi.o.ro-A(iV4>is(4r.ntethoxybei)2>d)-2.«oxo~l,2--dihydmq«inoh»e--3~ carboxanlidc

Trictbyiamine (5.73 ml... 41.2 mmol) was added to phosphorus oxychloride (60 mi.}, followed by 4-hydtvxy-M/v,-bis.(4-inctboxybenzyl}-2'-oxO’'1,2-dibyilroc{uinoline--3·· carboxamide (Example 74c) (6.11 g, 13.7 mmol). The reaction was heated at 65%’ for 4 hours, then cooled to room tempcratuic and carefully poured info ice water (1200 niL). The solution was extracted dichloromothauc (2x200 ml.. The organic layers were combined and washed with, water, dried over MgSCb, Okercd and evaporated. The residue was dissolved in dici-loromed-anc (18 mi) and poured Inio 200 mi of 30% hexanes in diethyl ether. The resultant precipitate was collected by filtration to give crude 4~chloro-%(V~his(4~ methoxybenzyl}~.2~o.xo-1,2-dihydroquinoline-3>e«rbpx:an3ide (4.25 g. 6?%} which was used withoid finfher purification. MS 463 (ΜΙΓ).

Example 74c: 4-Hydroxy~%i%bisi4-methoxyben2yl)~2~oxo-'i,,2-'dihydroqiiinol.inC''3-carboxamide

Ilhyi4'-hydro,xy%.~o>a>~i,,2'-dihydroquinoiine-'3'-earboxykne (Example 67) (3.58 g, 1.5,4 mmol) aHd;bi$(4-metlioxybeuxyl)amine.(4.54 g, 17.6 rnmol} were suspended in toluene (36 mL) and heated at 115°€ for 5 hoursvthen cooled to room temperature, Diethyl ether was added (50 ml,.), and the resultant precipitate was collected by fifiraflon to give crude 4-hvdroxy-;V,:<V~ :bis(4~.m;iUjtoxyben/s 1)-2-0^0-l ,3“dthydroqulnoline"3^ea.rbosanilde (6.46 g, 959V) which was used. Without further yuri Heirdom,

Example 75: 1 H~cjelqpeBtiaP)p^^

A solution of N*C2*eyap0eydope»f-· 1 -eaylcarbamoyi) benxamlde (example 75a) (500 mg, 1.90 a»!) and.NaOH (2 N* 2,7 mL) In.BlOH .(20. ntL) was stiffed at 100 Ai under nitrogen for 2 hours. After cooling to room temperature, the clear reaction solution was filtered and the iihraic was carefully neutralized with 10 % AcOH with s igorous siirriog at 0 ' C, The resultant, precipitate was collected by filtration, washed with: wans, water and then 2(1 % EiOTl in water to give the final prodnet 4~atntno~6s?-dihydro-1 H~oyelope»tu[d]pyTimidin-2(5H)'-one (200 mg, 68·%) as a white solid. ;H NMR (400 MHz.. DMSO-ίΑ} S 10.57 sbrs, 1 H), (>.93 (brs, S.H), 6,65 (brs, !H), 2.56 (0 ./ == 7,2 Hz, 2H), 2,43 (0/== 7,6 Hz, 2H) L96-1J9 (m, 2H), MS 152 .Example 75a: .N-fd-cyanocyelopent-l-euylcarhamoyilbenzamiile

To a solution oi2~ammoeyelopeui~l~eneeafbon.ihi!e (400 mg, 3.7 mmol)inr lA-dioxane (20 mL) was added benzoyl isocyanate (545 g, 3,7 mmol), The reaction mixture was then siin'ed. at r mm temperature under-.nitrogen overnight. The freeipitaie was collected fey iiltration. washed with 1A-dioxaoe, and dried to give N-{2-eyanocyclopem-! -cnylcarbamoyl) benzamide (720 mg, 76 %) as.a while solid. *H NMR (400 MHz, CDCl.d 4 11.33 (s, 1H), 11.22 (brs, 1H).. 7 99-7.97 (m, 2H).. 767-7.6} (m, IHi. 7.54-7 51 (m, 2H), 3.04-3 0 (in, 2H), 2/1-2 4‘? (m. 2H) 1.95-1 AO (m, 2H). MS 256 (MH A

Example 76s 4~amloo-6,7,8,9~ietrahyilro~ll:lreyetohepia|fllpyrlmiiSa~:2(5l:l)^oU:e

Prepared as in example 75 from- (2)-N-(2=oy8noeyclohepf-l -enylearbameyl) benzamide (Example 76a). 11 NMR (400 MHz, OMSC-Ad 5 10.29 (brs, 1H), 6.72 (brs, 2ΙΊ), 2.49-2,46 (m, 2B), 2.3S- 2 on i m 2H) 1.72-1Μ (M, 2% 1.52-1,48 (m, 2H) 1.41-1,36 (m, 2H), MS 1.80 (MH )

Example 76a: (Zj-N-t 2-cyarKjcydohepi- l-enyfcarbamoyi toenzamide:

Prepared a? in Example ?5a lions tZ}-2-aminocyclohepi-1 -crscearbonesilc and iaenzoyl isocyanate as a while solid. MS 284 (MHV).

Example 77: 6~FIuoro~1.H-l>ett*<>ic|[1,2 J|tldadlam^amlae-2,2-tl»xiie

A solution of N-(2-cyuno-4-fluorophenyl)sultamide (Example ??a) (211 mg. 1.0 mmol) in.EtOH {I mU was treated with N»OH (2.0 N, 1,0 ml. 2.0 mmol), and the icsultant solution was healed to 100 l'C for 0.5 h After it was cooled down to room temperate re the solution was neutralized. With 10 % AcOH. The resultant precipitate was collected by filtration, washed with water to give 6-fiaoro-l H'bonzo[c1[!>2,61:iMadiazis--4--aoiiito4"2s2~d!oxide as an off-white solid. *H NMR (400 MHz. DMSO-mO 0 7..01-7 05 Ud,.,/ = 8.81¾ 5 2Hz, 1H). 7.45-7.5 (ffi, 1H), 7.80-7.83 (dd../-9.6Hz. 2.4Hz, ?H), 8.24 (s, !Hf 11.03 (s. 1 H>.

Example 77a: N-t 2-Cyano-4~f!uoro|?heAyl)sUlfsmide A solution, of 2-aniin0-5-fluomhco^nittile (136 mg. 1 mitmi) and sidfetrtoyl chloride 014 mg, 3 mmol) in DMA (2 ml..) vm,- stirred at runm temperatero for 2 hours. The reaction was purified' by Vartan HPLC (10% Acetonitrile/Water) to give N-(2-CyanoM-fluoroplheayl)sulfiimide as a. pale-white solid. Tf N'MR (400 MHz. DMSO-iij) 7.18 (ro, 2H), 7.56-7.60 fdd ./=== 8.8 Hz., 2.8Hz ,?H) 9 44 A, 1 B)„

Example 78.; .6-Cfeioro-lH-heH2o[cj [l,2,6lthtadrazInM-aMt«e»2,2-dIoxicle

Prepared as in Example 77 from N-(3-cyauo~4~Phloropbeny!)sulfamlde (Example 78a), !H NMR (400 MHz, OMSO-d*} S 7,00-7.03 (d5 J- 8.8Bz, .1B), 7.59-7 62 fdd. J ==== 8.8Bz, 4Bz, IK), 8.05-8 06 (d,./=== 2.4Bzs 1H), 8.27-8.33 (d, ,/==== 25 Bz,111), 11,.1¾ (s. 1H),

Example 78a: N-{2-cyano*4»chl&amp;r&amp;phcny!)su!famii]e

Prepared as in Example 7?a irons 2~a{ni«0'-5'-cbiorobenxo»itfi.te.'a«d suifamoyl. cliionde, lH.NMR (400 MHz, DMSO-4) 7.3 (S,.2H), 7.54-7.56 (d 9.2 Hz, 10), 7.74-7.?? (ddJ - 8,4Hz, 2 Hz. 1 B), 9.67 (s, ills.

Example ?f; .5-(n‘dfn'O' l!-I'-benzo!cj| ! ,2,6|i:|0adiazie'-4-amine~2,2"diOziile

Prepared a;, in Example 77 from 5-chiorO"<2"<'yuoO"3-ehlorophcnyMsolfamide (Example 7¾). Hi NMR (400 MHz, DMSO-r/o) d 7.00-7:.03 (πι,ΐΗ), 7.20-7,23 (dd, J- 8.4Hz, 1.2Hz, 1H), 7.48-7.52 (m. I.H), 7.75 (sJH): 8.61 (sJH), 11,22 (s, IHi Example 79s: H-(2-Oyano-3-ch!oropbcoylpul faroide

Prepared as m Example 77a from x-andno-O-cMDroteizosdirile and sidfe«oyi chloride,

Example 3(0 S-Fluoro-l H-beozoiej 11 -2,6] ilria(liazlft'4~apdni'-2,2-diexk!e

Prepared as in Example ·?? from N*C2rCy«p-3-f!ilPfopbenyl)sidfamide (Example 80a). lH NMR {400 MiH... DMSO-ife) 4 6.84-6,97 (as 2H), 7.53-7.57 (m, IB), 7.59 {x 111). 8.42 (s.i Η). 11.20 (β. IH).

Example 80a: N-{2-Cyano-3-0uoropbenylsseOiaaide

Prepared as in Example 77a. from 2~amwo-6-fluorcben?.<.miJ.rile and sulmmoyl ehlerlde

Example 81: 6,7 -Oimelboxy-lll-beazeielj 1,2,6)UH»d»8£in~4~amlm>2,2-tlbmde

Prepared as in Example 77 ffomN^2“C^Mo-4,-5-di«ie&amp;oxypheayI)siiife«J:jd.e (Example 8la}.sHNMR (400 MHz, DMSO-A) 4 3.75-3.70 (d../ S4A 6«},. 6.48 (s, IH), 7.38 is. ' H x 7.89 (MM), 8,04 (bJH), 0.64 .(&amp;* IH).

Example Si a; N-(3 -Cyano-4,5 -41 met{v>xyphewl}suifamide

Prepared as in Example 77a from 2 amino·4,5-dimethoxybenzornlr i ie and si'!fiiv«»vl chi-'-rkle. *H NrMR (400 MHz, DMSO../0 4 3.77-3.80 id,./- 14.8, OH). 7.05 R I HE 7.00 i H), 7,29 RIB), 9.15 A IB).

Example 82-5 7'-TnOrn)rpmeOrvi-lH'-Eenxi.4idrk2ddOiiadiaxhs-'4--ipnine-'2,2-'dioxide

Prepared as in Example 77 from N-(2-CyanO“5“tnfluoromcthylphcny!)swifaini'd^ (Example 82a), '*&amp;. NMR (400 MHz, DMSCM*) 4 7.28 (s, 1H), 7.43-7.45 (dd, J - 8.8¾ 1.6Hz, 1 Η) N 14-8.1.6 (dv./“ 7.6Hz, ;H).8.4j-8 53(b:2H), ] ] .40 (s, l.H.i.

Example «82a· N-(2-Cyano-5-mduoromed:ymhenyi}suimmide

Prepared as in Example 77a from z-ammo-d-irifujororaetfeylbenzonitrik-^ad solfirmoyi: eMoride/B NMR (400 MHz, DMSO-A) 4 7.53{s, !H), 7:74-7.76 (4,,/- 8,4¾ 1 If), 8.01-8.03(44/- 8.4Hz. 1.6Hz, 1.11.),8.23 (sJH). 104 6 (b, 1H;.

Example 83: 6-Phenyl-1 H~l}enxo}c|il72/0Odads8zin~4~amiae~2,2-dbixl?le

Prepared as in Example 77 from N-i2~Cyaixa-4-phenyl.pl3e.n.yl)sulfamide (Example 83a)- ' H NMR (400 MHz, HMSO-A) 4 6.72-6.70(8,,/::: 8HziH), 6,97-7.0 (m. 1H)S. 7.08-7.1: irmdHi, 7.34-7.30 0-0,:10/7.50-7.53 <dd, ,/=== 8.4Hz, j Mi/... ill). 7.83 ib. 1H),7.87#, I Hi. 8.0?<h. 1Hi) 10.75 (st, IB).

Example 83a; B-|2«CyMo^-phe»y1pteiyl)s&amp;ifamide

In a 2rnL microwave vial, phenyl boronic acid (75 mg. 0.6 mmol), N~(2~eya»o«4« bromophtmyljsuffamide (Example S3b) $ 157 mg. 0.5 mmol). and pota.N0.jun; carbonate (400 mg. 1.5 mmol s were dissolved in DMEAVater mixture (1.5 mL. DM E··'Water 4; I . The so!«tie» was degassed by bubbling bD ga.~. into the reaction solution for 5 minutes and Palladium terrakis inphenylphospine (25 mg, 0.025 mmol.) vvas added. The jeaetion was placed ni a mlcrowase reactor for 5 mtbutes at 150¾. The crude .reaction, w dissolved in water, and Washed with ethyl acetate. The aqueous-solution wots evaporated.under vacuum: to give N-(2-Cyan.o-4“ phenyiphen} 1 >su!feaxide.

Example 83b. N··<2-eyano~4 bi-omolphenyl)sulfamide

Prepared as. in Example ??a iron'! 2-amino-5-bromobenxonitrik’ and sulfamoy! chloride.'H NMR (400 MHz. DMSO-m},) 7.3Us. 2H), /.48-7.50 (d.,./ === 8 Hz, id s, 7.85-7.88 (dd, ,/ -9.3 Hz, ! 2 He. 114),8.05-8,06 (d..E 2.4Hz. IH}, 9.67 (s, IH}.

Example 84; 6-(EEpr«p-1-ettyl-ll;i~l>eiixo[c||l4,6Ithiadta«ia~4~atniue~2,2~di»xiiIe

Prepared as in Example 77 from N-{2“eyano~4~(E)-prop~I-enyIpheny !}sulfamide-(Example 84a). JH NMR (45)0 MHz, DMSCM«)$ I 83-1.82(0,,/-== 5.6Hz 3H), 6.29-0..:.5 (m, IH). 0 585.-6.87 (d, J === 8.411/.. ; H). 7.5-7 53 {dd, <7 = 8.4Hz. 1 .Ml/.. 1 HT 7.80 (s, 1 H), 7.90 (b, 2H), 10.95(6., 1H).

Example 84a: N >{ 2-CVano'^(B)~prdp«iHshylphettyl^itlfantid^

Prepared as In Example ??a from N“(2-dyano~4~bmmolpbenyl:)grd.femide (Example 83b) and (.6)-pax>p-i-mxylb0.ro.aie: acid.

Example 85: 6“{2~metbyIpra^i.~«»yl>‘lB”b«B«o|eI {! ,2.6|ihtadisi3dl.»-4~a'«il«e~2^!~dlnxlde:·

Prepared as in Example 77 from N · {2 · Cvano -1-(1- methyl prop- I -cay!) phenyl}sul famkle (Example 8¾} fH NMR (400 MHz, D\iS^-.-Vi 0 1,8-Ϊ .85{dd, J-:22.4ίΙζ, 1.2 Hz, 6H), 4 IK (s, I Η), 6.84-6.86 <4 J------ 8.4Hz, lid), 731-733 £4/- 8,41¾ IH), 7.66 {*, 1 H>. 7.78(4 2B3. 10.7 i ib, 111)

Example 83a: N/2-Cyaoo-4-{2-rnethy Iprep-1 -coy!) phenyl}suifamide

Prepared as in Example 7 7a iron'! N-{2-cyano~4 -brcmolphertvl Bui fann-Je (Example 83b) and 2-roethy Inrop-1 -enylfcoromc acid.

Example 86; 6~Tw0w«romethyl· 11 Ebeszoie] [l,2^1thiadia2l»r4.>a«il«e~2^Hiloxide

Prepared, as in Example· 7? from H-(2*cyuno~4~lrlfti0fPptoy|)^ilf^nide (Example 86a). VH NMR (406 MHz, DMSO-/0 $ 7.14-7.16 (d,/= 8.8Bz, ΙΗ}, 7 JS-7.88 (del, / « 8,8Hz, 1,6Hz, IHh 8.37-8.36 id.../ - 6 6Hz, 1H). 8.52 (lx ?.H). 11 5*> K 111)

Bxaospic 86a: N/ 2-Cy a«o~«-truhroromcihvlphcnyI}sulfamide

Prepared as in Example 77a from 2~3mlno«5-(Triflu<.'‘romefhyl)hen^o.aUrite (Example Mb) andsuliamnyl chloride. *Η NMR (400 MBzs DM$CH/«> $ 7.S3fs, 211), 7,74-7.76 (d,./ 8.4 Hz, IH>, 8.01 -8.03 (dd? /- 8,4Βζ, Ε6Ηζ, IH), 8:33-8,233 (d,./ 13Hz, IB),: 10.16 (b. IB).

Example 86b; 2^:mitt^Mtnfimwm^yd)b$nzohiM'ki:

In a 20mL microwave xial, 2-bmm.o-4-(tnfIimmnxihyliiadli-ie (238 mg, j mmol) and copper eyamde (90 mg, 1 rrnnol) were dissolved m^-iPethyipyrrolidonc (HMF) {10 ml,). The reaction was planed in a mlerowaxe reactor for 5 minutes at 200/3 The crude was dissolved In ethyl. acetate and the precipitate was removed by filtration. The clear solution was washed wiib. water. The organic layer was collected,, dried over sodium sulfate, and evaporated under vacuum. The residue was purified by Yana HPLC (10% acetonitrile/water} 10 give the title compound.

Example §7: 6-1 sopropyl-1 Ii-f>en/,o jc j Γ1,2,6] Us ladle Asr-d-ansks e-2,2-di«xkle

Prepared as in Example 77 from N«T2'<e/am>-4-\isopropy!pfeeayl)siillamide /Example 87a). XH NMR <4Q0 MHz, DMSO-d.·.} ri U 8-1.2(4/- 6,¾6H), 2,85 (m, IH),

6 <>1-6.93 (d, ,/ = 6.8Hz, 1 H). 7.42-7 45 idd. J = 8.8Hz. ?Mz \ H). 7.768-7 773 (d.J = 2Hz, 11¾ 8.13(0, 2E). :0.8 fs, ; HO

Example 87a: N^2-Cy.8no-4~isopropyl:phenyi)s:al&amp;tiiid.e

Prepared as in Example 77a from 2~Amino-^usopropylbenzdnitrile (Example 87b) and sid&amp;moyi chloride.

Example 87b; d-AmiRo-S-isopropylbeiizetutrile

Prepared iasrift Example 86b from e-bromo-d-isopropylasdiine.

Example 88y6-Iy0bsiiyEtlI~benz0|ei|i,256)tbladia2l®~4-amMe“2,2-dloxicle

Prepared as in Example ?? fipm ^-C2~eyaeo-4-isobrrtylpheuyI)so:|fimilde (Example 88a). 5HMMR: (400 MOzs DMSO-^) 6 1.27¾ 911), 6.92-6.94 (d, 7-8.41¾ iH). 7,58-7.61 (dd../ 8,8Hz, 2 4Hz 11:1), 7.84-7.85 (¢1,,./- 2.4Hz. 1H), 8.06 (h, iH), 8.33 (b, IB), 10.8 (s, IH).

Example 88a: N-(2-C;yai:io-4-isobuiyiphenyI)sul{amide

Prepared as in Example 77a::tlx>m. 2-A.ay'no-5-iaobiriylbenzonitriIe (Example 8,8b) and sul&amp;moyi chloride,

Example 66b: S-Aruino-S-isebatylbeftxomirile

Prepared as in Example 86b from 24>romo44>*'butyluniUnc.

Example 89; 6-MeibyMIMranzoj c|| .1^.2 ]thla^[axia~4*srati»€~2^2iHd[ioidde

Prepared as m Example 77 from 'M^-eyaiio-^BietfeylphienyOsirifamMe (Example 89a). MS 212 {MH ·.

Example 89it; N-(2-cyano-4~jncthvlpheny!)sHifami<ie

Prepared «< in Example 77a sn-m 2~amioe-$-rnethylbcn;zonbrik· (Example 14b)' ami suHamoyl chloride.

Example 90; N'usoprupyl-l H-beassojej j 1 Jv6HI«adia«iie43“dia»ime~2v2~iJi0xale

A solution of 2~amlno-6-(kop»pylapxino)bencsopitrik sislfarnide (Example 90a) ¢0.14 g, 0,54 mmol) and NaOM (2 N> 0.54 mt) in EtOB (3 mE) was stirred at 90 °C under mifogep. for 0.5 hour. The reaction mixture was cooled to room temperature, and concentrated under vacuum. 1EO (i mL.) was added and the reaction mixture was neutralized to pH -- 3 with 10% AeOH. The resultant precipitate--was extracted with EtGAc. and after evaporation of Solvents the residue was'purified by preparative thin lager chromatography using a DCM/EtGAc (4:1) solution as eluant, to give NMsopropyl-d H~henxo|ejll.2,6)tInadi.aAne-4 J'-dia;rdne-2!2~ dioxide (0.02 g). SH HMR (400 MIfe, I5MSCM4) ft 1.11 (d,,/ === 0.4 Hz, 61:1.), 1.84 (bs. IH>, 5,:24 (hs, NB). 6.22-6.19 (np 2B,]ftH), 7.09 (p i - 8.0 Hz, 1B), 7.48 (hs, 2B). MS 255 (MB").

Example 90a: 2~amino-6~(isopropyiaminolbermomtrile sulftuntde

To a solution ot'2-ami«0'6-(kopropylamino)bcnr.onitrilc (Example 90b) (0,09 g, 0.54 mmoi) in DMA {3 mL) was added suftamoyl chloride (0.19 g„ 1.62 mmol). The reaction mixture: was stirred at mom. temperature under nitrogen for 2 hours, diluted: with BgO (5 i«L) and extracted witir EtQAe. Solvents of the combined organic phases were evaporated and: the residue ms purified by preparative thin layer chromatography u^ing a Hexane i\t<) 3c {3.2) solution as eluant, to give 2^mino-Misoptopylaminojbeuzoniirlie sulfanuue (0.14 g). MS 255 fMH }, Example OQb: 2-ainiuO“6>Tisopropylanuno}bcnzomtriIe

To a solution of 2«{i?op{xspylarnino)«6-nitrober!zonitrjie < Example-90c} (0.21 g, 1.02 mmol) in MeOH <9 ml.) won added concentrated HC1 (2 ml). Then he (0,1? g, .ΤΟ” «imp!) was added portionwise, and. the reaction mixture was refluxed atOffC for 15 minutes. After cooling to room temperature, dilution with EHO (50 ml.) and extraction with I >C\1 (3\ 5*1 ml), the combined organic phases were washed with brine, dried over MgSvE and the -<Φ woie evaporated to give 2-anhnc>--fr-{tsopropybmhi>frbenzonmilc {0, | Q g, 100 %) as a brown oil which was used In the next step without any further purification. MS 170 (MH }.

Example 90c: 2-i -sopronylaminor-b-nhrobenzoniiriie

To a solution of em-dinitrohenxonitrdc (0.5S g, 3.00 mmol) in DMF (6 ml) was added isoprofryiamme (0 71 g. 12.00 mmol) and the reaction mixture was stirred, at 50 ' C tinder nitrogen for ten minutes. After cooling to room tempet aturct dilution with lEO and extraction with EtOAc, solvents of the combined organic phases were evaporated and the residue was purified, by flash chromatography (Biotage system,. 80 gsilleagel coliaaa) using a Hexanc/BOAc (3:2} solution as eluant, to give 2'“Ci^pmpylamihh)-6-.nt:bloben^0.nt^!le;(i}.,22-'g, 35 %)3H NIMR f400 MHz. DMSO-d,} 0 1.20 id.J - 6.4 He, 6H1 3,85-3,80 (m, lift 5.94 id, ,/-* 8.0 Hz. mi 7,26 (d. ,/::: 9.0 Hz, IH). 7,42 (&amp;./=== 9.0 Hz, IB), 7.60 (r,./=== 8.8 Hz, IH), Example 91; 6-“meihyEII:Mhienop,2»c]Il,2^|fltiadiazin”4"antine”2,2"Clipxide

A sole lion of3>amino-5-mcthyHhiophcne-2-c-arf>oniidlc 1250 mg, 1,0 eq,, 1.81. mmol) and stdfamoyl chloride. (2.71. mmol, 1.5 eq., 314 mg) in .DMA (5 ml) was stirred at mom temperature overnight. Water (30 ml.) sod MaOH (13 eel,» 10 N, 2.71 mmol, 271 p.L) were added and the mixture was frozen, in a dry iee/aeelone bath and the volatiles were removed on, the lyophilizer. The resetting solid was w ashed with water and then suspended in EtOH (25 niL, 200 proof). To this -suspension was added NaOH fl M, 2,5 eq:,, 4.52 mmol, 4.52 mL) and. the mixture heated to reilux lot 45 minuter. The reaction fixture was cooled to room temperature and quenched with HCl {I N, 2.5 eq.. 4.52 mmol, 4.52 mL}. The· pH was adjusted to ·- i-2 with 1 N HCl and the volatiles removed on a rotary evaporator. The resulting solid was suspended in water (10 rnL). stirred, filtered off, and washed with water. The crude product was dried m a vacuum .oven to give (>·methyl· I H-?hieno!3.2--c ji 1,2.6jth sadiaziu-4-amine·2,2 -dioxide 1257 mg) asmoff-white powder !H NMR (400 MHz. DM-SO-c/*) 62.46 (d. J ------ 0.,S Ha, 3H>. 6,53 (q,</::: 0.8 He. IH), 7.75 (hr. a, 2ti). ! 1.34 (s. HR. Hi NMR (400 MHz. CD>OD) <72.52 id. 7- 0.3 Hz, 3Hi. 6.55 {·:.]. 7- 0 3 Hr:. 1 Hi. MS 218 (MR').

Example 92: 5wwcl«prop>l~111-1)00,rojcΠ L27»Rhiadiazin~4~amine~2,2'dinxiik>

A solution of2~ajpr:nor6«eyc|opropy:^nzomtrtte (Example 92a) (1.0 eq., 626 prnoL 99 mg} and sidiamoyl chloride (3.5 eq,s 939 Llmel, .109 mg) in DMA (1 rnL) was stirred in a seintillatiott vial at room temperature:. Ate2: hours, NaOIf (1,5 eq„ 939 pmol IN, 939 μι,} and water {18 mU were added and the resulting precipitated 'product stirred overnight at room temperature. The precipitate was filtered offend washed with water to X 5 rn I.-).. The wet precipitate wax dissolved in EtOH (5 mL, 200 proof) and NaOfl (2.5 eq., 1565 pmol, IN, ! 565 uL) was added. The reaction was heated to 80 ° C with stirring overnight, The reaction mixture was cooled to room temperature and HCl (3..5 eq., 1565 psu-.d, 1NV 1565 pL; was added to the reaction vial. The ethanol and most of the water was removed on the rotors evaporator. The resulting precipitate was suspended hi water (5 mL), stirred, filtered off, and washed with water (20 mL). The produce was dried in a vacuum oven to gi ve 5-eyelopropy LlH~ benzo[e]( L2,6]thiadiaztn--9--amme'-2?2~dioxide (4.1. rng, 28%) as an off-wltite solid, ΛΗ NMR. (400 MHz, DMSOufs) ¢70.71 (m, 2H), 1.04 (m, 2H): 2.403 im, IS), 6,8$ (cl, 7 - S 1¾ 2H), 7.37 (i t- hr. s, .1 8 Hz, 2H), 8.40 (hr. s, 1H), 10,80 (s, 3 H). *H NMR. (400 MHz, CIMOD) 30.89 (m. 2H), 1J5 (m,2H), 236 (m, |H), 6.90 (d, 7=8 Hz, 1 id), 6.97 (d, 3 = 8 Hz, 1% 7.41 (t, J~ 8 Bz, HI). MS 238 (Mil ).

Exeauplg 92a: S'mnino-'d'-cyclopropylfeenzoB.iirifc Λ 2-5 rnL microwave v kt! containing d-aynino-b-broumbenzimilrde (! .0 on.. i .0 mmol, 1.9? mg), cycbpropylboronk: acid (1.5 cq.. 1.3 mnu>), l 12 nig), and KsPOj (3-5 eq., 3.5 mmol, 743 nig) was Hushed v%iih nitrogen. To this vial was added toluene (4 ml., Sure-Scal i, water (200 ,uL), iricyclohexylphosphia© (0.018 eq., 18,1 praol 88% pure. 20% in hexanes, 32 p.L), -and palladium (FI) acetate (0.05 eq, wPd»*? irimer, 0,916?-mmol, 12 mg), all under iiift'ogen. The reaction via! was flushed with nitrogen, sapped with a crimp-top septum, and microwaved for 30'minutes at 130 ° C, The reaction mixture was cooled to room temperature, partitioned between EtOAc (3 mL) and water (1 ml,), The layers were separated, the water layer extracted EtOAc (2 X 3 mL), the combined organic layers dried over sodium sulfate. The EtOAc was filtered through a 0.45 pm PTFE ml to remove finely divided solids and concentrated on a rotary-evaporator. The crude product was purified on silica gel fSiliaPrep 80g cartridge, gradient elution from j 0/3 EtOAc/hc.xancs to 49% EtOAc· hexanes, loaded in solution in 1:1 hcxanesdX'M), The fractions containing product were concentrated on a rotary evaporator to give 2-'and.no-'6*cycloprojrvlberuronitrilc 199 mg. 62,7%) as a waxy yellow solid. !ΗΝΜΕ. (400 MHz, DMSOwM r.> 0.668 (m, 2H). 0.979 fm. ,'H s, 1.978 (m, 1H). 5.882 (fir. s, 2B),C>.12g (d, 3** 8Flz, 111),6.546 id../- 8 Hz, !Η). 7.129 (t../ - 8 Hz, IH).

Example 93: 5^6-14^5 ~dihydronaphtfio( I ld-thieno[23-e][1,2,6|du2Kliaziru4-':an«:ne-'2,2- di oxide

A solution of 2--sidfarnoylan-dno-4,5“di.hydionaphtho( I,2-bjthiopheuc-3-earfiomtffte (Example 93a) (336 mg, 1J1 mmol)·in EtQH (5 mL) was treated with NaOH (2.0 N,

1,1 roL, 2,22 .mmol), andthe resultant solution was 'healed to 100 "€ and stirred at that temperature for 1,5 ft. After it was cooled down to room temperature, the clear solution was filtered, and the fifirate was: carefully neutralized with 10 % AeOB while; it Was vigorously stirred ttt 0 %% The resultant precipitate was: collected by filtration, washed with warm water, and' 20 %>:Ei€)IT in water to give ;105 mg of the title product as an off-white solid in 31 % yield. T:I NMR ¢400 MHz, DMSOM&amp;) 3 2.48 (m,4B), 5.70 (§, 2B), 6.87-6.89 (ci J- 7.6 Hz, IB), 6.96 (t I Hi. 7.06-7. j 0 On, 5H). MS 306 (MH ).

Exam pic 93 a: 2-sulfaiuoy].atttift0-4^5~dihyck'©i1iS|)iHhoj'!,2“b)fhiophcnc-3'-cadx>t«iriIe To a solution of2-affiioo~4,5"diiiydronap68n>r i .2-b]thiophenc-.koarbo.aitriIe (Example 43b) {550 roc, I. Π mmoB in diroethylacetamidc <5 ink) was added sitlfamoyl chloride (385 ms. 3.33 mtnoi). The reaction mixture was stirred at room temperature under nitrogen for about ! hr, then it was diluted with water and extracted with EtOAc, the organic layer was washed w oh brute, dried f*verNu\SOi„ filtered aud evaporated trs give the etude product wbidi was cart led on for next step.

Example 93h. 2-amfno»4,5-dihyuronaphtho{ 1.2 ·bjf hi«spheric*3-catbpnitrik A solution of 3,4-dihydronapbthalcft-2f I Hi-one (2.2 s, 15.05 mmol?, maiononitfiic (994 mg, 15.05 mmol}. suO\u ( 485 mg. 15.05 mmol}, and tnethylamme i 1.52 g, 15.<35 mmol) in Ιϊ.ί,ΟΗ (100 roU was refluxed for 2 hr under nitrogen. The solvent was rhon removed under reduce;.! pressure and the residue was crystallised from EtOAc/Hexanea to give 2,91 g of the title product ay a brown solid in 86% yield. % NMR (400 MHz, DMSO-fA) <12,59 It, 2H}, 2.86 (t, 2(1), 6.94 (4,1H)S 7,03 (t, ! H), 7.1 l~7J6 (ms 2H), 7.48 (y 2H).

Example 94; 5d6(dihydro-476l"cycb.:'P£'rita·· I'H)rbtenc‘|23-ell'1,2,6]thiadiazro-4mrame-2,2” dioxide

prepared as in Example 93 fiPrak-sul&amp;moylaminp^S.d^diiiydro-dH-eyelopen:ta[b]tldopheno~3~carboniM|e (Exampi’e 94a). lB NMR (400 MHz, BMSO-fA) 9 2.15 (m, 2H). 2,53 2.68 (m, 2B). 5,39 is, 214), MS 244 (VIH).

Example 94a: 2-^it:ifeth0ytoJn0->5s6-dihydro-4H->cydopema[bjthtophesie-3-.eatti®nftrik Prepared as (n Example 93a. from 2~amlno-5.6~dihydro~4.H” cyelope3ifa[b]ihiopiie».e~3~earbonitrib'(.Example 94b), Ή NMR (400 MHz, CDCE) 3 2.41 (m, 2H), 2.82 On, 2H), 2.89 (mf 2B), 5.46 1H).

Example 94b : 2-aniino~5,6-dlhydro-4B~eyt4:op:e.nla(b)thiophe«e-3-carboai:6'i.ie

Prepared as in Example 03b from cvclopentanonc. '*1-1 NMR (400 MHz, DbASO-dr,} 0 2.23 {rn, 23-1 k 2.53 (τη, 2H), 2.63 {m, 231k 7.00 (s, 2Hk

Example 05: S-eltoMS-methy I~1 !Mlmmoj23-cf,2-dtoxide

Prepared as in Example 93 from 2~su!fomoy!am}RO-4-cthyl-5-mcihyUhiopbooe-3-earbonitriie (Example 05a). *H NMR (400 MHz, DMSO-l) 0 1.0) (t. 3R), 2.06 (s, 3H). 2.53 iq. 2R), 150 2H) MS 246 (MR }.

Example 05¾: 2-^ujfamx>ytoiao-4<ihy1r5rmethy1ttiio|jhcn^3-carlfdoMie

Prepared as in. Example 93a from 2"amino~4~etliyl~5-methyMil6phen;e~3~· earbomtriie (Example 95b). !H Ν'MR (400 MHz. CDCE) 0 1.17 0, 3Hk 2 3! (s. 3H'k 2 59 (q. 2H), r 45{n, 3H?

Example 95b: 2--annm>-4-etby l- 5- methylfhi ophene- 3 - carheftitrite

Prepared ax in Example 93b from peaian~3-one. fH HMR (400 MHz, DMSO-foj) r> 1.01 (t, 30), 2.06 (5, 31-1), 2.33 (q.. 215),614 (s: 2Π). MS 167 (MR ),

Example 96r 5,6-dimtuhylMli“thleiB:r|2J"C||i>2,6Itfeladia:el»^a:ml,ae^2,2~i.®xscle

Prepared ax in Example 93 from 2 -su!ta$noylaminO“4,5-dioicthyHhiopheac-3* carbonifdle (Example 96a). *3-1 NMR (400 MHz, DMSO-</;d > 2.04 ts, 3H), 2.10 (s, 3H), 5.4P (·>, 211). MS 232 ΓΜΗ ).

Example 96a; 2'-5idErrn.oylamin.O”4,5"dimeflwltbiophepe'-3--earboniirile 'Γρ asolttfion saf 2--amiPCr-4,5--dii»eiliyltlN6]:4lene'13r<xartKniiirrile (ExaBipie 4b) (1.-0 g, 6,57 mmol) in l,4foioxane (50 ml.) was added sulfasmde (3,47 g, 40,30 mmol). The reaction mixture was .heated to reflux for 24 br, after cooled to room temperature, the solvent was removed under reduced pressure and the residue was purified by duomsiographv on silica gel eluting with EtOAc.'Tfcxanes (2:3s to give 300 mg of product as a dark red oil. Ή N.V1R (400 MHz, DMSO-Ad d 2.09 (3, 3H), 2.2ft (s, 3H;), 732 (x, 2Kh 10.17 <s> IH).

Example 97: (E'}“S“(3-^;IetlH>v>psa>p“.l“e?syI)«iIl“l>eiiK»|eff 13?6|iltta#a^iM“4“aiBine*2,2" dioxide

A'solution of(£)»2-sull^mo.ylamino-6-{3^mothox.ypro|>-l"00yi)bo'U20i«iri1e 1 Example 97¾} (139 mg. 0.5 mmol.) in EtOH was treated with NaOH (3 .0 N, 0..5 mL 1,0 mmol}, and tiro resultant solution was hosted to 100 0 and stirred at that temperature lor 4 h, After it was cooled down to room temperatores the clear reaction solution was filtered, and the filtrate was carefully neutralized with 10 % AeOH while it was vigorously stirred at 0 °C. The resultant precipitate was collected by Sitraiiou, washed with warm, water, and. 20 % EtOfi is water to give the title product :(A)"3^(3'-MethoxYprop~i."ehyl)~llHf ~heszo[e][! ,2:,6]ftiiadi:azm-4mmiBeA,2-· dmxuie i 108 tug.. 78 %> as a white solid, 'll NMR (40*0 Mi le. lAMSO-u.·,) 0 3,29 (s, 3 hi), 4,06 (dd..,/ - 4.3, 1.2 Hz. 211), 6,2ft (dt,./ - ! 6.2, 5.0 Hz, 1H), 6.3] -ft.95 im, 2H1, ft.37 (bs. 111),7.1 ft (d, J- 7.2 Hz, IKK 7,4ft (t,,/- 8.0 Βζ, IH), 5.31 (s. i Hh 10,93 (s. Hi). i?C NMR (DMSOM.) d 58/4:772,5, 111,6,117.0, 122..4,129.0, 132.5, 134.0, 138.1. 143.7. 162.9. MS 268 (Mlf). Example 97a: i7Vn.7sidiaou>\k®t!no-6A30Oethoxyp'rep-t! wNu>dibes20iiitrile

To at v.;dutton of {£)-3-'imino-6-(3-mefhozyprop"l"eayl)fce«z0ttimie (Example 97b) (188 mg, 1.0 mmol) in DMA w as added NH^SO>CI (347 mg, 3 .0 mmol) at 0 A3 under nitrogen. The reaction mixture was then stirred at room temperature' for 6 hrs, diluted with EtOAc, washed with brine (SX), and dried over Na-.'SO,·,. The'.solvent was evaporated under reduced pressure to give (£'VOswlfmipyiamino-^<3rmethpxyi«x?p*t-enyl)'boitzonitriie.a,s,a pate-yellow solid, which was used in the nextstep without further purification.

Example 97E; (A)-2~amino~6A3-methoxyprop-1-enyi)beBzopitrile

To a solution of 2m,mlno-6-hromobenzo:uitri!e f 1.0 g, 5.C) mmol), (.(71-2-(3-mctfenxyprppenyi)«4,4,5,3~tetramethyl*(lv3,2)“dioxab$)manc ί 1.2 gv 6 0 mmol), and 16/70¾ (1 -38 g, 10.0 mmol) in DMEd-l/) (4H, 20 rnL> was added Pdi PPh <).< (289 nig) at room temperature underrutrogen. The reaction .mixture was wanned to 85 Aland stirred at that temperature under nitrogen overnight Afterit was cooled down to room teniperainre, the reaction solution was: diluted with EtOAc, washed with brine (2Xt and dried over Ν&amp;2$0«. After removal of die solvent, the residue was .purified by chromatography on silica gel eluting with 30 % EtOAc in hexanes to give the title compound as a pale-yellow solid. Ή NMR {400 MHz, Ο.ΧΊ?} 0 3.40 is, 3H), 4.12 idd. J - 6.0, I ,H Hz. 2H). 4.42 {s. 2H). 0.42 ult, </::: 16.0A.8 Hz, HE. 6.63(0,./ 8.0 Hz, I H), 6.85 (d,d ::: 16.0 Hz, 1H), 6.93 (d,3- 8.0 Hz. 1H), 7.26 it,./=== 8.0 Hz, Hi). {'C NMR (CDCIi) d 58.2, ?2.7, 65.4, 11 3.6. ] 15.0, 116.6, I 28.5. 130.9, 133.4, 140.3, 150,1. MS 180 iMH }.

Example 98: 5H3Aleilreli)utAww2wl>1l:{drenzo|c|H,:A6ityadiazft5Mwminc-2,2wiioxlde

Prepared as in Ehafttple 97 from d-arnino-ddd'tncthxibut-d-eswS-yEbenzcnitrile (Example 98 a) as a white solid, *Η NMR. (400 MHz, CDCh) di.53 ($, 3hl), 1.80 (s, 3M), 1,86 (3, 31-1). 6.70 (dd,./- 7.2, 1J Hz, 1H), 6.82 (a, ΪΗ), 6.93(dd, J-= 7,2,1.0 Hz, 1H), 7.46 (t J-7.2 Ηζ,.ΙΗ), 8,28 is, 1H), 10,98 (s, IB). nC NMR CDMSQ-dft 0 20,8,21.42:2.6, 109,4, 116.8, 124,4, 1.29.7, 132.0, 134.3,144.1,144,0. HO I. MS 266(MHz}.

Example 98a: 2-Amino-6ft3-mcth.vIbtu-2 -en-2-yl)bcnzo»itrile

Prepared as in Example l a from l-ammoA-ftromofteazonitrile and 3-Methyft2“ buieh-2-ylbOrOmc acid as an orange oil. MS 187 (MHf).

Example 99tS”BroMo-!e-beitzo|ci 11,2,61 tMuftkziE-4-amiiie-2,2-dloxide

Prepared as in Example 97 from.l-asruno^d-hromobesizonitrile as a white solid, ft:nx%iR.(400:Mhf2,D:MS6M6,wi 7.03-7.0? (m, 114),7.37-7.42 tin, 2Hi, 7.65 (s. IH). 8.60 (s, mi 11.19 (sj B}. tsC NMR (BMSCAiA).4 1 0,3,.118J, HI .0, 09.0,135.0, 145.5,1613. MS 2/507? (M.H :).

Example Mil: 4tt-Naphthdi2a<|[Witfciadla^tt-l^i»i««^2^^fes(|-de

Prepared as in Example 97 Eon: 2-amino-1 -nuphthonitriie as a white solid !H NMR <400 MHz.. DMSO-Js) if 7. I 7 (d, ./ = 8 0 Hz. j Hi, 7.48 <di, J = i ..2. 3.0 Hz, 1 H). 7 .*3 idt.J = 1 2, 8.0 Hz, 1H). 7.90 la, : H). 7.93 (dd,./ = 1 2, 8.0 Hz, 1H). 8.24 o' Π H 8.3« id, ·/:: 8.0 Hz. IH), : I 42 (s, IH}. '*€ NMR (DMSO-Aj 0 106.3. 118.2. 124.9, 125 4, 129.2. 129.8. 130.0,

130.2., :35,9, 143.7. 163.2, MS 248 (MB

Example 101: 54>7,8“'14'trn0>'dr0“!ilMeaze|ciii,2,6|tfeiatMaziH~4~aBiiae~2,2~<ll0XMle

Prepared as in Example 97 from 2-ami5aocye:lQhex-f-eaecarl>oniiril.e (Example 10b) as a pale yellow solid. !H NMR. (400 MHz, DMSO-m) 0 1.544,62 (m, 41:1), 2.08 (t,./- 5,4 Hz. 2H), 2.20 (t,,/- 5.4- Hz, 2H), 6.94 (s, IH), 7.41 (s, l.H), 10,53 (s, IH). !3C^MjR^DMSO^} 6 21.6, 22.5.28.3. 97.6, 150.3. 163.4. MS 202 (MB').

Example !J2i 11iEpyrsi|o|2,3~e| (i,2,6|thiadiazi«~4~amine^2i2-itoxMe

A stirred mixture of 2mminoniee4hmnirnte (238 th£, 4.0 mmol), sulfinmdc: (192 mg, 2,0 mmol), and 1 mL of DBlfwas heated at 160 X under nitrogen overnight, After it.was cooled down to room temperature, the reaction: mixture was diluted with water, and extracted three times with EtOAc. Tire aqueous layer wad dried down under vacuum.. and the residue was purified by d'lKuuamgruphv on silica gel eSudng with 15 % McOH in dichfoiOmeThane to give the title compound as a yellow so I id. ’ Η N M R (400 M Hz, D MSO-d,,) 0 6.5? n. J=== 5 .6 Hz, 1H), 7.95 (brs, 2H), 8.22 (d, /=== 5,2 Hz, 1H), 8.39-5.3“ (m* IB), 12.58 (bis, 1B). MS 199 (MB''). Example H13; 6“Brorno“tl;I4.ienzo|c]H,2,6|tbiadh:«iaH -amiiK·

Prepared as in Example 97 from 2“ammo-5“bfomobeazo.mtrUe. SB NMR (400 MHz, DMSO-/3 d 6.95 (d, J === 8.8 Hz, 1 HI. 7.78-:,70 (on 1 Η). N. I 7 id,7 1.0 Hz, IB), 8,28 f'ors, 2H), 11.9 is. f H). MS 275. 277 tMhf j.

Example 194: 5~{MethyIihto)-1 H~be«/.o|e|| R2,6)thtadmBs-4~amisse~2,2-di0xlde

Prepared as in Example 97 from 2~sulfamoylaniin()-6-(nreth>lTbK>)benze«iitriie .(Example !<Ma> fH NMR (400 MHz, DMSO-/0 0 2.39 (s, 3H), 6,38-6,36 (Op 111), 6.47-6,45 (m, IH), 6,59 (brs, 7H), 6 97-6,94 (m, 1H) MS 344 (MH ).

Example 104«*): 2-sai famoylamino-6-(meiby1th}o)benzbmtHk

Prepared as in Example 1. from 2-amino-6-(meibylthio)beozoniirile (Example 8b) and suifamoyi chloride, NMR (400 MHz, DMSO-/·,) 6 2.56 (a, 311), 7.18 (d,/=== 8,4 Hz. 1 H), 7.26 (s, 2H), 7.33 (d,/ == 8 0 Hz, IH), 7.59 (t,../ ==- 8 40 Hz, 1H), 9.51 is. IH).

Example 106b: 2-andno-6~(metbyfihio)benzonltrile

To a solution of 2~(ffiath>4thio)-6-mtrob:euxoniiriie (Example 104c) (1.5 g, 7.73 mmol) in EtOH (150 ml)/THF (50 ml REtOAc (50 ml) was added 200 mg of 10 % Pd/€. The reaction mixture was hydrogenated on part shaker overnight. After the filtration, the filtered solution was dried down under vacuum, and the residue was purified by chromatography on silica gel. ©luting: with EtOAe/Hexane to give the title compound (79 °c). Ή NMR (406MBx, CDCb) 6 2,51 ($, 3H). 4.47 (/214), 6.53-6,51 (m, IB), 6.58 (d, 7==== 8,CTBz, IH), 7.27-7.21 fm. HI).

Example 104c; 2'{nicthy Uhio)-6~aitrobenzonitrite

To a suspension of 2,6-uinilrobcnzonilriic <5.0 g, 25.89 mmol) in 100 ml. of anhydrous MeOE was added NaSMe (2.0 g in. 100 ml, of MeOH) dropwlse:through: addition funnel under m'trege» ht 0 “€. Λ tier the completion of addition, the reaction roixuirc was sliced at 0 "C for 3. hr. Then 250 mL o f water was added to. the reaction mix ture, the resultant precipitate was collected by filtration and dried in the air to give the title product as a yellow solid m %). 'H NMR (400 MHz, ΠΧΊ ,-i o' lo4 ts, 3H), 7.60-7.5? tin. I Hi. 770 (t, ./ - 8.4 Ex, I Hi, 5.01-7.90 (m, Hi?

Example 105:: SJ-ilhSyohd'-tetrahydro-dtJ'-etinlefmdioxIde-besreol-llI-thienolZ^-e] [ 14,61 f lshadlaxhi~4“?ti«isse"24”dioxide

Prepared as in Example 97 from 2->ami»o~S,?-djh>>dro-4H~ spued benzoib]thiophene--6,2!-[ I J}dioxoiancj-.>~carboni$rile (.Example .105a). ‘M NMR. (400 MHz, DM SO-<4) 4 1.80 (LJ - 6.0 fix, 2H), 2.65 (s, 2D), 2,79 ft,./ - 6,0 Hz, 2B), 3.94-3.91 (m, 4H),5.99 (nrs. 2D). MS 316 (ME).

Example 105a: 2-ammo-5,7-dlhydro-4li-sDlrofbenzoihlthiouhene-6.2,-i i .31 dioxolane]- 3- carboninilc A solution of l,4-dioxaspim[4.5]deean-8~one (5.0 g, 32.,0 mmol), malonoUiMle (2.1:1 g, 32.01 mmol), nnlfur (1,03g, 33.0 mjnol), and tnethybjtdne (4,.5 rnL, 32.0 mmol) in EtOE (100 mL) was stirred at mom. temperature for I. h under nitrogen. The solvent was then, removed under reduced pressure and the residue was treated with EtOAe. The resultant: precipitate was collected by Miration and dried lit the air to glee the title product.as a light green solid (44 %). Ti NMR (400 MHz, DMSO-M) $ 1.7? (t,,/ - 6.8 Hz, 2H), 2,43 ((1 6.4 Hz, 214), 2,57 (s, 2H), 3.88 (s, 4H), 6.99 (a, 2B). MS 237 (MH\).

Example IMi 5#<1 %2M514Meirahyd^ 11,24] IMadlazm- 4- ami«e-2,2-uhoxkle

Λ. slitK'i! rnature > η I :.2\ Rd'-teijdiydm-2',2'-cthylcncdio.xidc-bcnzo)-·i H- ;hierkt[2,3-cjj S .2,0| 0wudi.c5u--4.-;muue~2,2'd:o=dde «Example HH) (130 mg, 0.41 mmol), 5 ml.. <4 ϊ H bund 1 mi of 2 \ !uwas red-wed under nmvgen t'>>? 2 h/v Λ iter it mas cook'd do wo m room .temperature,, the resultant precipitate was collected by filtration and dried in the air to give the title product as a pink >olid. * H NMR (400 MHz, DMSCMA) 0 2.5? (%J ==== 6,8 01¾. 21¾ 3.10 (t,,/ === 6.4 Hz, .2H i, 3,50 (s, 2M)? 6.91 ibrs. 111), 7.83 (hrs, 1H). 11,81 (bra, 1 Ϊ1) . MS 272 (MB1'). Example 107; 1,5,0,7-tetrahydrocydopeatajel(1duijtidadiaxm~4-ami»e-2,2-dίο side

A solution: of2-sul.f^mcylonimocyc.lopent-1 -enecarhonitrile (Example 107 a)(108 'mg, 0.57.mmol) in EtOH was treated vvitb NaOIi (2,0 N, 0.5 m.L), and the resultant solution was heated to 100 X'. ami stirred at that temperature for 4 h. After it was cooled down to room temperature, the reaction solution was carefully neutralized.with 2N HQ while it was vigorously stirred at 0 *€. The reaction solution was dried down under vacuum, and the residue·Was purified by chromatography on silica gel dating with 10 % MoOf-l in riichloronjcihrinc n> give the utle compound. ;H NMR (400 MHz, DMSO-A) 4 1,69-1.63 <m. 211). 2.2 U. / 7.6 Hz, 2H). 2.3 it,J ----- 6.8 Hz. 2H), 5..: 2 (s. 2H}. MS 188 (MH:).

Example 107a: 2-suifarnoyl.ami:uoc.ye.Iopeai~l~enecarhonitriie

To a solution of 2-ami:noeyciopont-l-e.n.eearbonitrl!.e .(440.mg, 4.07 mmol) m 10 rnL of DMA wus added sUliutnoyl chloride (941,3 ptgg8J5mmol.)5 and the resultant mixture, was stirred at room temperature under nitrogen tor 2 h. Then it teas diluted with EtOAe, the organic layer was washed with brine and dried down under vacuum, and the residue was purified by chromatography on silica gel eluting with HtOAc 'Hexane to give the title compound. Ή NMR (469 MHz, CDCf) 6 2.04-1,97 (m, 211), 2.61 -2,57{m, 2H). 2R-2.80 (m. 2H)? 5.66 (s, 2H)? 8.04 is, 1H).

Example 108; S-iPhenvUhio)-1 H-benzoCejj I <2,d)

Prepared a? in Example 97 from 2-!mlfamoyiarnino>6-’(phcnyUhi0)bcnzofurrilc (Example 108a) *H NMR {400 MHz. DMS<W,) «> 6.47-6.40 On, 1E), 6.64-6.62 (m, IH), 6.75 (brs. 2PI), 7.01-6.97 (in, IH), 7.22-7.15 (m, 8H), 7.3-W26 isr 2H). MS 306 {ΜΡΓ )

Example iQKa: 2*suifamoyl^iimo~6»(phcnyiihio>bcnzoni03:le

Prepared as? in Example 104a from 2-amn:n-0-{pheny!thk0beftzemtriie(Example 10-Sbi. :E NMR (400 MHz, DMSO-<E) 6 6.85-6.62 (m, IH), 7.32 (s, 2B), 7.47-7.42 («, 6PI), 7.53 it,./ - 8.0 Hz, IH). 0.68 (3, IH).

Example 106b: 2-ammo-6-(phcnyIthio ibenzonHriie

Prepared as m Example 104b from 2~omw6“tphenyIthio)feenzomirue (Example lOS'c). 5H NMR (400 MHz. DMSO-ib;) 0 6.20 (brs, 2H). 6.82-6,30 (m, ill), 6.69-6.67 (m, IH), 7,19 i t, J::: 8:,0 Hz, M), 7.4-7,34 (m, SH),

Example i 08c: 2~altro-6-(phcoy! thiolbenzonittile

To a mixture of 2.6-dimtP0fee«z0iutriIc (2.0 g, 10,36 .mmol) and KjCCfi (1.43 g, 10.36mmol) in5.mLofanhydtous DMF was added PhSH(LI4 ml in 5 mL of DMF) dropwise under nitrogen at 0 <;C. After ike completion of addition, the reaction mixture was stirred at 0 :'C for 0.5 hr. Then the reaction mixture was poured into 50 mL of water, the resultant precipitation was collected by filtration, washed with water and dried in the air to give the title produet. Example 109; S^MetfeylsHlfiaylEIH-benxojclllii^lthladiaxin-d-amme-l^-dioxide

Prepared as in Example 107 Ovm 2-sulfamoyiamino-6·· (methylsuliinyi)benzointrik (Example i0'>a) Ή 'Si MR (400 MHz. DMSO-<.(·.) 0 .:.56 {.\. 3H), 6.51 ibrs. 2H), 6.7S-6.76 i-n. 1(1),6.94-68)2 (ro. I H), /.23-7.19 On, IH). MS 360 (Mill

Example 10%: 2 »su! famoy iamirK»-6-(racth\ kulfinvi )ben;v»n itrile

The mixture or2-sulfamoylaraino^-imtfhyhhin)benwmtri!e«Example. 104a) (48 rag, 0.2 rmmdi ami MCPBA (69 mg, 0.4:mftiol) in dleliioreffieiha.ne (16 mL) was heated reilttxed overnight. Alter cooling down, the precipitation was colieeied by i Oration, rinsed with dichbromethane. dried in the air to give the tide compound. rH.NMR (400 MHz, DMSO-idd d :.Kd is. mi (br.s :h), 7.7:-6.69 <m, :hi, ?.>>: o,./ ao hz, ihi,9mi tbm, ih).

Example Π0:5'>(Metfeyisalfo»yl)4H**be»z»(c| i 1 x2«b|lbradisudiu‘4'*aniiae>2^di0xide

Prepared as in Example 107 from a-sulhunoylanurm-d-(metbylsulfbnyl)berizomtelk (Example 1.1¾). NMR{4O0 MHz, DMSG-cfc) d 3.30 (8, 3H), 6.95-6.93 (m, 1B>, 7.01 (bs, Zfd), 7,17-7.17 (ra, lid), 7.24-7.: 1 (m. 276 (MB')

Example 110a; S-stdiamoyiamieo-b-lmcthvisnifoavilbcnzomtdte

Prepared as in Exahlpk 107a from 2-araino-6”(mcthyb^fonyl)benzoniidie (Example 1090) lH NMR *400 MHz, DMSCMO} d 3.37 is, 3H|. 7.46 (S, 2B), 7.85-7.83 (m, 1B), 7.93-7.91 (m, 2H), 9.92 (s. Hi).

Example 110b; S-amlee-b-lmetbyisulfenvilbenzoHitrde

Prepared as m Example 107b Spm2-(meibyisu!b>nyi)-6-ni:trebeiizenitri1e (Example 110c). *H NMR (400 MBz, DMSD-iA) 9 3.26 ts< 3H), 6.63 :(brs, 2B>, 7.15-7)09 (m, 2H), 7.5.1 -7,47 (ay H i).

Example 110c: 2-(me%Wfpnyl)-6-nit^ben^nsh;ile

Prepared as in Example 109a irpm .drli^etliylthib^-^-mtt'O'benzPnifi'ile' (Example. 104e) ?H NMR (400 MBx, DMSCMi) d 3,48 (s, 3H), 8,21 (d,/- 7.6 Hz,: lid), 8,49-8.47 (m, HI), 8.66-8,64 (ay 111).

Example 1 1 i 1d-Araino-S-Cpropy toxy> 1 J2~feenz« f e| {1,2.6 |ihiadiazme-2,2-illoxIde

To a suspension of2-$tt!famoyl.^»ift0«6~|)i5opoxybe«2.onit«le·(Example.'Ilia) -(4:73 g, IE,S3 mmol) m ethanol (65. mL)s was added aqueous NaOB (2151, 18,.6 nil, 37.06 mrool). The resulting dear solution was refluxed for 3 hours under nitrogen. Λ (for cooling to room temperature, the resulting solution wa.- filtered, the filtrate was eooied to 0 "C and neutralized with 10% acetic acid. The resulting precipitate was collected by filtration., suspended or 50 nil of ethanoi-wvater (1:1) and warmed to 40 "(' for 30 nun. The solid was collected b> filtration to 'provide 4“Ammo-S“(propyloxYf /i-bcnxo[<.')( 152.6}thiadiazme-2,2-dk)xidc (4 g, 85%i as a pale yellow powder, M.p.. 229-230 "U. Tl NMR {400 MHz. DMSCMs) d 05>Mi« J === 7.3 I Iz, 3K), I 81 (sext.,/- 7.3 Hz, 2H>, 4 10(1.,./- 6 7 Hz. 2H*, ¢--.60(0.,/- 8,6 Hz. 1H), ft 73 (d.,/- 8.ft Hz.. 1H j, ? 44 ({,./-6.6 Hz, 1H), 7,81 (hr a. 1 H>, 8.35 (brs, HI). 10.93 (brs. 1H). r:C NMR (400 MHz, DMSOwpb 0 I 1.07,. 22,18, 71.41, 100.93.. 105 64, 110.21. 135.53. 195.16. 1.58.47., 161 !(). MS 256 (MET). .Example 11 1 a: 2-SoI&amp;p:myJamiim~6~prdpoxybe^

Tp: a solution of 2-ammo-6-frpppxybenzo:triirile {Example 11 lb) (4.23 g, 24.01 mmol) iu dfmeihylaceiamide (20 mL) under ME was added sulhunoyl chloride (5..56 g, 48,02 thitidl). The reaction mixture was then stirred at mo sb tempera lure under nitrogen for 4 hours. Upon completion,, the reaction was quenched by addition of iecAvater (250 ml,), The rssdMog precipitate was collected by filtration, rinsed with water apt! dried to yield 2wulhmi0ylamlnO“6-propoxybonzoJtitrile {4.73 g ’’7%) us a pale yellow solid. !H .NMR (400 MHz, DMSOu/riri 1.01 (tb./- 7.2 Hz, 3.H), 1.76 (sext,../ - 7.2 Hz, 2H), 4,08 (t,,/- 6.8 Hz, 2H), 6.96 (d, J - 8.5 Hz, IT!), 7.15 ({,,/ - 8.5 Hz. 1 Hi, 7.28 (hr a, 2H), 7.57 (d, J - 8.5 Hz, Hip 9.46 (s, 1 H), MS 256 (MTU), Example 111b: 2 - A? n i no~6~ pro ( >ox y be rszon itrile 2-?4itro-6-prppo'xybenzoui(rlie (Example 1.1 lei(4,95 g, 2-4.01 omrol) was dissolved In BiOH (50 ml,)-and THE {! 5 ml..), 10% fid,C (255 mg, 2,4 mmol) was added, and the reaction was hydrogenated using a Parr apparatus for '12 hours at 40 psi. Upon completion, the reaction was filtered, through cel fie ami the filtrate concentrated to provide 2-nitro~6-propoxybcvizonmiie {4-.3 g. 100%) as a ligin brown gel. Ή NMR ¢400 Ml 1/. CDCU) 3' 1.05 (d,../ - /.4 Hz, 311). 1.83 (soxl, J - 7.0 Hz, 211), 5.% (t, J - 7.0 Hz, 2H). 4.38 (br s, 2 H), 6.20 (d,./ - 8.5 Hz, ; H), 0.2 s (t, J - 8.5 Hz. 1H), 7.14 id,./- 8.5 Hz, 1 H>.

Example Π ic: 2 N s Oo - 6·· pr opo x > b enz ο n h π! e

To a. solution of xtoMIrbtroheozonitrdc (6 g, 31.07 mmol) in·dry DMF (45 mL) at 0 /2, was added a solution of sodium (815 mg, 35,42 mmol) tan-propanol (23,5 ml,) dropwise over 30 minutes·. After compete addition, tire reaction mixture: was warmed to room temperature and stirred for 2,5 hours. The reaction: was poured into an ice/water mixture (250 ml,), and the precipitate was collected by filtration and dried to yield 2 · η itos-6-propoxybenzoaittiic (4.45 g, 77%) as a light brown solid. ΊΊ NMR (400 MHz. CDCI:·) did) (d, J == 7.5 Hz, 3H), 1.93 Next, J 7.5 Hz, 2H), 4.14 (t,/== 7.0 Hz. 211),7.31 (4/:== s.p Hz, IH), 7.69 (t, J == 8.6 Hz, SH), 7.82 (d, /=- 8.6 Hz. IH).

Example 112: 4~Am3«o~54peHtoxyM/Mmuoh j ij ,2 /> j t h iadjazin e - 2,2-d ioxsde

Prepared ax in Example 111, from 2~$ρ1.βρη<«vlamim>4wpentoxyben:zonMl©· (Example Π/a) to provide d-asminoonpeuloxyhl/frbePZvioji 1,2.6)U-iiadiazine"2,2Mi0xido (59 mg, 43%), }H NMR (406 MHz, DMSO-to) A 0.88 (t,/= 7.3 Hz, 3H). ! .35 (m, 411), 1J0 (quint, / = 6.8 Hz. 2H>, 4,14 (;, / == 6 1 Hz. 2H), 4,59 id, / === 8.2 Hz, ! Hi, 6.73 (d. / == 8.56 Hz, IHE 7,44 (t, / === 8.5 Hz, 1H). 7.8; (br s; i H), 8.33 (br s, !H), 10.92 (br s, IH). MS 284 (Mil:).

Example 112<r. 2'SuifainoyIamino~6~pentDxybomronil:ri!:e

Prepared as in Example I.a: .fi'o:m. 2"amin0''6~pe»toxyben:zonifri.k to provide: 2-sidEsmoybmiuo-'O-penibx^'henzoni.trile:,

Example 112b: 2-Anrlno-6-(penivloxv)besizonlfrilc

Prepared as in Example j 116 fem.'2-hi:feo.~64(pentyloxy)l^ni!:pnitri.|e to provide 2-A-Pti.nO'b'-fpentyloxylbeOMnitri!e. MS 205 (MIT),

Example 1I2c: 2-N1 t re -6 -( j >c toy; 0x3=) bonze π i η H e

Prepared as in Example 111c from 2,6-dinittobenzorsifrile: and pentanol to provide 2mitro~6-(pemyloxy3benzomtrilo,

Example 113; 4~Aaiitto-5-(pbeooxy)-l//^enzojd (1,2.6 jtluadia/.iae-2.2-di<m<le

Prepared as m Example 111 from 2~su!dmioylsmirio~6"phersoxybeii^osiiirile (Example 11 3a) to provide 4-Ammo-5-^henoxy}- i/:/-benzo[<'][ 1 ..7Alrhiudiazine-lJ:-dioxide (29 mg. 60«·»)· }H NMR (400 MHz.. MeOD) S 6.3v tdd../ = M3, 0 8 Hz. 1 H), 6.75 (dd,./ = M2, 1. i Hz. Ill), ".IS (m, .:.1()., " .30 an, flip /,40 0. J ~ 8.5 He, IH), 7.48 no. 2Rs. MS 290 (MH ). Example I i 3a: 2-Sulfimioylarnino-6-phenoxybe«2'.o«itnle'

Prepared m in Example .111 a from 2-amino-6“phenoxytkszonitHie (Example 113b} to provide c-suHlenoylamino-b-ptenoxybenzonitrile (250 rag, 100%). S!:F NMR (400 MHz, MeOD) 0 6.o0 0.1,7 - 8,6 Ife, IH), 7,11 (4, J - 8.0 Hz, IH), 7,26 (1,./- 7,5 Ffe, IH), 7.39 0.1./ ::: 8 3 Hz, I FI h /,45 {so, 2 HI. 7 50 (v,,/::: 8 <\ Hz. i H). MS 2‘40 (.MH ) pxanpbe 113b: 2w\nur,M>yfocrxco. beuzoniuiie

Tp a solution of 2-n.Hm-6-(pheooxy}beozoasirite (Example 14 $¢).(1.04 .g., 8.08 mmol) in MeOH (164 mL) was slowly added concentrated HQ (7,23 mL) followed by Iron powder (1.58 g, 28.3 mmol), The' reaction was refluxed for 30 min and bonceutraled m vacuo. The residue was dissolved in EtOAe and washed with 1N NaOFi, water and brine. The organic layer was dried over MgSifo, filtered, concentrated arid purified by flash chromatography 1:1 FlexanerEli/Ae to yield 2-amino-0~pheiKjxybenzoniin.le (384 mg, 22.6%). !H NMR (400 MHz, MeOf>)d 5.97 (d,J-8.3 Ffe. IH), 6.50 (d, J --- 8..6 Hz, I H>, 7.06 (m, 2H), 7.18 (m. 2H), 7.40 (m, 2Hi. MS 210 (MB').

Example 113c: 2-Niiro-'6-pbenOxybenxO:nirrile A solution of 2,6-dinitrobeBZ0nitrile (2,0 g, 10,5 mmel), phenol (1,42 g, 15.1 mmol) and K?CO? (1.45 g, 10.5 ramol) in DMb 120 mL) was stirred at rt under N > tor 4,5 hours. Upon completion, the reaction was diluted with EtOAe (100 ml..), washed with H;iO, dried over MgSCH, filtered and concentrated, The residue was reerysralhzcd from Hexane/IrtOAe. to provide Iraitro-O^thermxybmzonilrile (1.94 g, 77%). 'FI AMR (400 MHz. McOD) ό 7.20 ian 2H), 7,28 (dd,../ === 8.6,-1Λ Hz, I Η), 7.34 mi. 1Η), 7.51 (m, 2Η), ?.7χ (1,./=== 8.7 Ha, I Id), 8.0$ sdd.,/ === 8.2, 0.8 Hz. ; H).

Example .114:4“A.mltto-5-(4-aietlmxybfeizylox>d“WM>eMm|e]jli2?ilitla4ismme“2,2»ii0xM«

Prepared as so Example H i 'front 2~xulfusnoylammonH4~msdk>xybenzyl.oxy) benzouifrilc (Example 114a> io provide 4-amtno-5-(4-ntefhoxy bestzy1oxy)%/:/-bcnzojy]j'! ,2.<4thi3dnrzine“2,2-dio.xtde t12 mg, Η>%». Ή NMR. (400 MHz. IlMSCMiO 4 3,76 (s, 3Hk 6.72 {<!,./=== 8.4, 1H).<>.80 {J,,/ == H.i. jΗ»,6.95 (m,2H),7.48 (0: 3Hi, 10,89 (hrs, .114), i 1.0 (br i. HI). MS 334 tMH 1.

Example ΐ 14a; 2'$ulfjniOYhniino-6-{4-niethox>ben;'.Yloxy) heo.'.omtnle

To a ^oh.uion oiehlorostdibsiy; isocyanate {212 mg, 1.50 mmol) Ιο i TH€b (0.55 ml,) at. 0 V<C, was added .formic acid (0.S7S ml,) mider N?, The reaction was stirsrsd tor 30 min, and -a-.solution of 2-umin0'”644rxnpt^/fiy^s^yfey) beoxorutrlle (Example-1146).(19.1, mg, 0.7$ mmol) in CHvCia (4 ml.) was added aiO H7,.followed by Ei?N (0.627 mL, 4.,5-0-mmol). After 30 rnisi, the reaction was eoneeotratad. hi vaeao and diluted with water. The pH was adjusted to 7 with cones'·itrawd HCi, and purified by reverse phase HPI..C (j0-00% acetonitrile in water) to provide 2"Sidhanoyknmno~6~(4-rnedioxybcnzy!oxy) benzonirrile (130 srsg. 52%). Ή NMR (400 MHz. MeOD) ft3.80 (%3H), 5.1.5 (s, 2M), 6 J8 (d,./ - t,I Hz 1H), 6.94 (m. 2H), 7,40 (m, 2H), 7.48 (t. ,/====.8.7 Hz, I Hi, 7.75 (dd, ,/==== 8,6,0.8 Hz, i H).

Example 114b. 2 -A.mit=m-6"(4mi£thoxybeozy!.oxy) benzonittile

Prepared as in Example 113b (tom 2-nitro-6-(4 -metho.xy bemrv loxy) benzottitrtle. (Example 114c) to provide 2 -amino-M4~meti toxy benzylo.xy) bcrszosuirile (451 mg, 22%», Ή NMR (400 MHz. McOD) Λ 3.80 H. 3H). 5M is, 2HL 6.33 (dd, J == 8.3. 0.x Hz, t HI 6.38 un. 1H>, o <’3 {m, 2H), 7.19 {%/- 8,2 Hz, 1(1),7.38 (m, 214).

Example 114c; 2-Niiro-6-(4-methoxy:beazyioxy) benzomtrils

Prepared as in Example 112c from 2,6-,) Inirrobenzoniiriie and 4-rnelhoxybenzyl alcohol to provide 2mitro-6k4-rne{hoxybcrizyloxy) benzomtrilo {2.40 g. 81%). Ή NMR <4<K* Mil/, CDCR) S 3.82 fa, 3H). 5.26 (s: 2B), 6,93 (ro, 211), 7.35 (dd,7- 8,6,. 0.7 Hz, IH), 7.38 (m, 211·. 7.65 0. 7-5.611/, IHi. 7.83 (dd,7- 8.2,0.8 Hz, 10).

Example ίIS; 4-Amino-5-oxyaeeiIe add-1 /M>e*ue[cj[ 1.2,3j (ldadia/.i?ie-2,2-cisp.sMe

Prepared hvadmtlarmanner as Example 11! from ethyl 2*<2-cysjKKU (sulfamoytomno)phcnoxy)aeelurc {Example 115a) to pro\ sde 4-Ammo-5roxyaeeiie aeid-1//-· benzene j[1 ,2,3]ihi&amp;dia2ine~2,2-dioxide {74.9 mg. 15°«} as a. white solid. *H NMR (400 MHz, DMSO-rO) S 4.88 (s, 2H), 6,65 kid. 7 = 8.3. 0.8 Hz. 1 H>, 6.69 (dd. J - 8.5. 0.7 Hz, IH), 7.46 st, 7 - 8.3 Hz, IH), 8.42 (hr s, IH), 8.58 <br s, 1 H> 11.02 (hr v i H 6 13.49 (hr s, IHs. MS 272 (MH j. Ex ample 113a: Ethyl2-(2-e yano-Msu j famuylum inolphenoxylacefaie

Prepared in a sbmlar manner as Example' 131a from: ethyl 2-(3-amino-2-cyanophenoxy)acetute (Example 5b) to provide ethyl 2-(2-ey8»o-3- (suU2tmoylamioo)pbeaoxy)aeeiate (567 mg, 79%) as a light yellow solid.. lH NMR C400 MHz, DMSO-ί/Π <> 1.22 (t, 7 -7.0 Hz, 3H), 4.19 (q. 7 - 7.0 Hz, 2B), 5,01 (s, 2.H), 6,87 id, 7- 8.6 Hz, IH), 7.20 Id, 7- 8.3 Hz, 1H), 7.32 (s, 2H), 7,56 (r. 7- 8.6 Hz, 3H), 9.53 ibr s, IH),

Example 115b: Ethyl 2-(3-am:ino-2--eyanophepoxyi8eetaie:

Prepared. in :a similar manner as Example: 11 !h from, ethyl 2-(3-amino~2~ oikophenoxylacetate (Example 115e) to provide ethyl 2~(3~antirroU-cyanophenoxyjacetaie (539 mg, 56%) as an ctT-whire solid. :H NMR (400 MHz. DM$0-7») 5 i .21 it. J - 7.6 11/ 311), 4.17 tq,7 7.6 Hz, 211), 4.85 k,2H}, 6.06 (hr s, 21. U: 6. i0(0,7 8.0 Hz, IH), 6.38 (dd, 7- 8.6, 0,8 Hz, 1H);7.17 R,7- 8,4 Hz, IH).

Example 115c: Ethyl S-lS-amino-E-nItropbesmxylacetaie

To a solution of 2~hydroxy~6~ihlrobestzQnttrik (Example 115(1) (61 <3 mg, 4:33 mmol) and (718 mg, 5.20 mmol) in acetone; (8 ml.,}, was added ethyl hromeaeetate (0.576 ml... 5.20 nano!) The reaction was refluxed imder Nb for 4.5 hoars. Upon completion, the reaction was filtered, and the filtrate was concentrated and dried lo yield e4yl 2-(5-urnino-2-nitrophenoxy i. JH NMR (400 MHz, RMSO-/,) 4 1.23 R ,/ ===7.0 Hz, 3H), 4.20 tep./=== ?.! Hz. 2H}. 5.19 ts. 2H). 7.69 ukl J == *.4 0.* Hz, UR 7.89 u, J === 8.4 11/, IK), 7.9? idd../=== 8.5, 0.8 11/. IHj. iMllfiLiiM;. '2-Hy droxy 6-η i tro benzon itri h

To a solution of 2,6-dinitrobenzonitrile t10.0 g, 52.3 mmol) in MeOH (215 mt). m added, a solution of Na (1.52 g, 57.5 mmol) in MeOH (23.5 ml. t. The reaction was refluxed under N3 for 2.5 hours, cooled to ιt ansi the precipitate was collected by filtration. The ws-ulting residue was combined with pyridine hydrochloride (15.1 g, 130 mmol), and the solids were melted at 200 "C tor I 8 hours. 'Upon completion, the reaction was cooled to rt, '.cashed with 'brute ij x 300 rnt) and extracted with EtOAc R x 500 mth The organic layers were combined*· dried over MgSO.;. filtered and concentrated to provide 2·hydro\y-6-nitrobcnzonitn 1c (0.70 g. 87%). !H NME (400 MHz, MeOD) 4 7.35 (dd, J” 8J, 0.8 Hz, 11¾ 7 J? (f /= 8.2 Hz, 11¾ 7,77 (¢14/ 5.2 id Hz. I R).

Example 116:4~Aftri«0~5/j<mpropoxyH//l}e«zojd f l.?24t|tbiadiazi«e~2?2"diosicle

Prepared In a similar maimer as Example 111 from, 2~suI&amp;noylamino4~ isoprepoxybenzonitnle (Example 1. ].6a) to provide 4-amino~5~(ixopropox:y)“l H~ bersZoRJ[.1,2/)ibiadiazinc-2,2-dioxide (50 mg, 17 04). Ή NMR. (400 MHz, DMSCMfr) &amp; .1.38 (d,./ 5.8 Hz, OH), 4.84 (sept,./ 5.9 Hz, 1H), 6 59 (¢1,/- 8.7 Hz, 1H), 6:77 (d,,/ = 8,7 Hz,

Hi). 7-45 (¢1,/-8.7 Hz, 111), 7,81 (hr s. 111), 8.32 (hr s, H R 10.94 (br a, I B),MS 266 (Μ1Γ).

Example 116a: d-Snl&amp;Boylamino-O/sopropoxybenzonitrife

Prepared in a similar manner' as Example 111a from 2-ambm-6-kopropoxybenzonitrik (Example 6b) to provide l-aislihmipdmntrKj-b-LsopropoxytePzorrifrile (2.1 mg, 8%). JH NMR (400 MHz, MeOD) 4 1.37 (d,./ 5.6 Hz. 6R), 4,67 (sept, /- 6,0 Hz. ill), 6,29 (d,,/ 8.2 Hz, 1H), 6,36 (dd,/- 8.1, 0/ Hz, 111), 7 0“ (>.,/ 8.2 Hz, HI).

Exam|>kjl^:2^mtnO”6rkoprdpoxybenzo.nitnie·

Prepared in a .similar mariner as Example 113b from 2-nitro-6~ isopropoxybepzonitrik {Example I I6e) to provide 2-aroino-6-isopropoxyben;romtrilc <201 mg,. 76%) as a yellow oil. *H'NMR(400 Ml iz, MeOD} 4 1..34 (0,/==== 6,0 Bz, 6E}, 4,64 feqit,/=== 64 Hz, 1H), 6.25 (d, / === 8.1 Hz, 1H), 6.34 (dd,../ === 8.2. 0.8 El, 10), 7.18 (t, J ==== 8.3 Hz, .1H). feaiiakllM 2-Mi tro 6 i sopropoxy benzo η i trite

Prepared in a similar manner as Example 115c from 2-hydroxy-6-mtrobdnznnitrilc (Example 115d) and isopropyl bromide to provide 2--nitro-6-isopropoxy tenzonitrile (324 mg, 64%), {H NMff (400 MHz, MeOD} $ 1,43 id, /==== 6.2 Hz, 6H), 4,89 (sept, J 6.2 Hz, 111),7.6] (del./ === 8.0,1.0 Hz, tH), 7.80(),/==== 8.2 Hz, IE), 7.85 tdd,./ 8.2, 1.2 Hz. ill).

Example Π 7:4”AmisKK6~(l>ettzyln\y >-1 S^beazOjel11,2,6|ibl»diazifte"2,2~diox!de

Prepared as in Example 111 from 2->eHllambykttnno*6/benzyloxy)benzonitriie (Example 117a)to provide 4mmiim~5--(be62yfoxy}"3i/-benz0[e)[l,2,6]ihiadiazme~2>2-dioxiiie (42 mg, 61%). 11 NMK (400 MHz. MeOD) d 5.32 (s, 2H), 6,65 (dd, J === 8.3. 1.2 Hz, IΗj, 6.85 (dd, J » 8.6. 1.0 Hz, 1H). 7.30-7 57 (m, oH). MS 304 (ME!).

Example 1 Γ/a: 2-Snlf;ioioy:lamiR0~6~(ixmzybxy)beozorriirile

Prepared as in-Example· 11 la frDro. 2-aminio~6~(benzybxy)be:i'szonlirile (Example 1 17b) to provide 2-sult>.ntoYlamino-6-{benzyloxy)benzonitrile (74 mg, 30%), B NMR (400 MHz, MeOD) 4 5.22 (x, 2H}, 6,98- (0..J === 8.5 Hz, 1H). 7 26 (d: J === 8/ Hz, 111), 7,32 (m, IB), 7.38 (t, /== 7.2 Hz, 2HK 7.47 (d, J - 7.4 Hz, 2H), 7 51 (f / == 8.2 Hz, IB).

Example 11 ?b- 2-Amino-6-(benzyJoxy)benzonitrile

Prepared as in Example 113b from 3-mtrO“6'(benzyJoxY)bcniZonitnle (Example .117c) to provide 2-amm0--6>(fc>e;nzyloxy)b6P.zoatfeile (2.15 mg, 63%). !H MMR (400 MHz, MeOD) 4 5.16 (s, 2H), 6.32 (0, /== 8.2 Hz, 1H), 6,39 (d, / ==== 8.2 Hz, 1H). 7.20 (), / ==== 8.4 Hz, 111), 7.38 (),,/ === 7,6 Hz, 2H), 7.46 (0,/=== 7,4 Hz, 2H>. MS225:(MB*),

Example 117c: 2 -N i so-im henry! oxy)benzosutrile Ίο a solution of zdwdeoxy-o-miTobenzorsio sic {Example 115} (1.0 g, 6.09 mmol) and Cs-aCQ* (2..16 g, 6.64 mm»!).in acetone (14 rat) was added benzyl komide (06 g, 6.76 mmol). Tiie reaction was refluxed nodes· N,· Tor 1.5 hours, then fskered arid die filtrate concentrated. The residue was purified by flash ekomsuography 3:2 HexnneEiOAe m provide 2·mtro-6-(bcnzy f oxv )bcnzonitrilc (300 rng, 32% h Ή NMR (400 MHz. MeOD) d 5.40 (s, 2Hk 7.34-7,45 Oil, 3H). 7.53 Tm, 2H), 7,69 MOO 8.6, Ox Hz. 1H), 7.52 in J 3.4 Hz, IN), 7.91 (i. ./=== K.2,0.3 Hz, I Hi.

Example i 18:: 4- Amim>5-(efln:m)-! /7-henmin}[1 «2,6);thladia*iae“2^"dtoxMe

Prepared as in Example 111 from 2«snl^moyiaKtino-6*eth6xyheftzoniirik (Example 118a) to provide 4-amino-5-efhoxy· i //-beswojej! 1.2,6 jthiadiazinc-2,2 ·dioxide f 120 rng, 50%), 5B NMR (400 MHz,DMS0-i/y):0 1.37 (1,/==== 6,9 Hz, 3H), 4.18 (q,./ === 6.9 Ez, 2H), 6.96 (d, J ==== 8.8 Hz, IB), 7.16 (4/=== 8.8 Hz, i B), 7.27 (km 2H|, 7,57(1,4==== 8,4 Bz,. I H). 9.44 (br s, IB). MS 242 (Mil ).

Example 1 i 8a; 2-SuiEunovbnisno-0-crhoxybc;Tzonstriie

Prepared in a similar manner as Example Ilia Eom/mmino-O efhoxybenzontirile (Example 8b} to provide 2-suifamoylamin.p»#^tbexyben2oniffi|e (161 mg, 67%). MS 242. (ΜΤΓ).

Example 118 b: 2-Am irio-6 -ethoxybenzon&amp;rile

Prepared in a similar manner as Example 111b from 2-nitro--6»eihoxybenzomtri1e (Example 8c) to provide S-ammo/mthoxybcnzonilnle (162 mg, 1003«)- MS 163 (MB'). Example 118c: 2 N i rro-6-et hi * x vbenzomtf i:le

Prepared m a similar manner as Example 1 i 5c from 2-hydroxy>.6'·' nitroheazonifTile (Example I I5d) and ethyl bromide to provide 2-nitro~6-ctboxyben20ftiiJile (192 mg, 50%).

Example 119: 4Mmm0-S4b«texy)-lJEbe«zof tfj {1,2,6 ptadlazf «eM^ioxlde

Prepared te a similar manner as Example M l from 2~su!izmoyiamme>-6" biitoxybenzoniirile (Example 119a) ίο provide 4-aroinor5~baioxy-1.H-benzo|cJ| 1,2,6|thiadiazme- 2,2-dioxide (67 mg, 50%). *H NMR (400 MHz, DMSOted 4 0.95 (t, 7.4 Hz, 3H), 1,44 (sext, ./- 7.4 Hz, 2H). 1.81 (quint-./= 7.9 Hz, 2 Hi 4 1 7 (i. /=6.7 Hz. .:Hi.,o6l (d./=8.2 Hz, 1H). 6 76 id. / = 6.2 Hz, \ H). 7.46 (i, /= 6.2 Hz. IH), 7 Hz (br s. 1 Η), 835 (br x, 1H). 10.06 (br s. 1H) MS 270 (ΜΗ ),

Example 119a: /-Sullkmovlamlno-d-bmoxvbeuzdteirile

Prepared in a similar manner as Example 11 la from 2~amino-6-butoxyhenzonifrile (Example 9b) to provide 2-suI&amp;moy!am.mo~6~biiioxybeozomirile. MS z 70 fMH).

Example 119b: 2-Λnuno-r.-btu«.>x> kuzoniirile

Prepared in a smriiar manner as Example ! 1 l b from 2-nifr0^buioxyhenzonitrile (Example 9c) ίο provide 2-aminp~6~buioxybenzoniiriie (190 mg, 71%), MS 191 (Μ1Γ),

Example 11,9c: 2-nilro-6"buipx.ybepzonilrile

Prepared br a similar manner as Example I. ilk from. 2-bydroxy~6~ rdirebebzordtrile (Example i I5d) and butyl, bromide to provide 2-nitro-6dmioxybenzoniiriIe. Example 120:ϊ-oieihj 1-///~pymzoIb[C) |!,2teJtfeiadiazjue~2,2"dioxide

Prepared in a similar manner as Example 111 .from. S-snlfemoylamino-l-ineibyb iifrpyrazoleM-earboniirile (Example 120a) to provide 4~AnbnoMv«eihyl~ //% pyraxnio[ej[] ,2te|diiadiazioe''2,2~dloxide (100 mg, 50%), Ί1ΝΜΕ (400 MHz, DMSO-4>) 4 3.76 (s, 3H), 7.4 3 (s, 2H), ? 9H (x, 1H). 9 H4 fr, 111)

Example 120a: 5-stdEmv.>yiambrO“l-m.erhyi“/:.H-pynizole-4~oasi>on!irile

Prepared in a similar manner as £ sample 11 la from 5-amino- l-metU\ 1-///-pyragoie-d-carbonitriie io.provdde'5~sul:f^npyiainipOT.1~«iethyi~i/?<'pyi^zc!te~4~earbo»'itrilp. Example 121: 4-Andni.>-2H~pynmoleis;j p.,2#|tyadiaasine-2t2-ciioxUle

Prepared in. a sindiar, manner as Example 111 irom 3-snifomoylammo-i/-/-•pyrazde-4-eattiomtr?ic (Example \ la) to ptx>vide4»amiiio«2/ji*pyrazolpi[tv][I^><)'}tosciiaz.a>e-242-dioxide (90 me, 48%). *H NMR (400 MHz, DMSO-,/,} t> p.97 (Ss 2H), 8.47 is. IH), 9.71 <s. IH), 13.36 (s, IH).

Example 121a; 3“Sui'fen>oyknime-/i?*pyi3Zole4*eaitpnMb

Prepared in a similar manner as Example 11 la from 3-amino-iE(»pyfazoIe>4» carbonltrik to provide 3*sn{famoylMmno*M^>yi,82s>ie»4''car'bonitdie;

Example 122:4~ A mi « o-7- m et ho xy ~ / .//- be n xo j e j I1,2,6|tliiadlaxt?te-2,2~dioxMe

Prepared in a similar manner as Example: II I,firo.pi-2“«ul&amp;mdylaPiino>4~ meilK.rxyben20.ni(rile (Example 122a) tdprovide4«Μ^.ίθο·τ7'”η3όίώΡΧ>νIH-benxo[c][I .2i>jthiadiaaine~2;2'-tli.oxide. (49 mg, 65%). Ή NMR (400 MBx, DMSO-<4) S 3.81 (a, 3B), 6,58(0,4-2.3 Hx, 1B). 6.75 (dd,,/- 9,1,2.7Ifa.Jll), 7.82 (0, J-;8J Hz, 111),10.85¾ s, ill), 1.0,99 (hr s, HI). MS 228 (MH ).

Example 122a: 2-SnlPmio\lamin0-4-me(hoxybenxO:nl(ri.le

Prepared in a similar manner as Example 114a fiom '2-aniino~4~ methoxybenzoniinle (Example 122b> ie· provide 2-&amp;idfumoy1aroino~4-mcihoxybcnzoni!;rilc as while eryxials (11.1. mg, 44%). Of NMR (400 MHz, MeODl 0 3.88 b, 8H). 6.78 idd,,/ - 9.0. 2.8 Hz. IB}. 7.54 <d, J- 9.0 Bz, IB), 7.84 (d,../- 2,4 Hz, IH). MS 228 (MB').

Example 1220: 2~Ammb-4-theiboxybenxonitrlie

Prepared in a similar mariner as Ex ample 111b from 2-nitro-4- meihoxybenzonitrile to provide 2«aimfto~4>itteih.oxyben2onstrtl.e (910 mg, 78%). H MMR (400 MHz, CDCb)6 3.79 («,30), 4.73 (hr s. 2H), 6.20 (m. III). 6.31 (m, IH), 7.30(d,,/- 8.7 iw. 1H).

Example 123; Ethyl 4-ami.»o-5«i«ei h> 1- Toxo·· 1,2-d dnd r o thieηoj e j11,3,6j1 his d6sxi ae-2,2-dio\idO“P-enrl>osylate

Prepared in a similar manner as Example· 111 from ethyl 5-sult>.moylamino-4-eyaoo-3-3-oeihylrhiopheiV-2-eafboxyl;iro {Example 123a) to provide ethyl 4-amino-5-met.hy!»2-oxo-l ,2-dihydrethienofiji 1.3,6|fhiadiaxine~2..:.-dioxide-d~earboxyiat·.- {' 23 g. 72?·«}· lM NMR. {400 MHx. DMSO-iUo = .26 (r:. .7 6 9 Hz. 3H), 2.73 (s. 3H>, 4.17 (q5:j- 7.0Hz, 2H). MS 290 (MB').

Example 123a: Ethyl 5~sulfamoylainsno-4-cya?Kv3-metliylthiopheiic 2-carboxylate Prepared in a similar manner as Example ! 14a from ethyl 5~an>ino~4~cyarto-3-nietliyiiliiopheBe-S-oarbaxylate (Example !23h} to provide ethyl 5-sulfash.oylamino-4-cyano-3“· metbyUhipphene-2-earboxyiaie (1.73 g, 80¾¾}. 7l HMR (400 Mile, DMSO-rM 6 1.28 (t../- 7 0 ife, 3fl), 2.36 (s. 3H,p 4.24 (q, ./- 7,1 fix, 2B).

Example 123b- Ethyl 5~ani:iBO~4-oyano-3-n:iethyItixiopheoe-2-'Oarlx>xy!ate

To o. solution of ethyl 3-oxobutano;.ue (3.0 ml.,. 23.5 mmol), malonermrile (! 55 g, 33.5 mmol} aod sulmr Π53 mg, 23 5 mmol) ίο EtOH (39 ml..), eas added Εί,Ν (3.28 ml.., 23 5 mmol), The reaefion was refinxed; under Nj for 3 horns* then dlreefiy purified, by flash 'Chromatography (99; .1 GfECbiEiCMc) to provide ethyl S-amino-d-eyano-a-meihyhhiophene-d-earboxyiaie (2,18 g, 44%), S.H NMR. (400 MHz, DMSO-40 S-1.21. (t, J 7.0 Hz, 311), 2.36 (s, 3e},4JS (q, J-7.2 ex, 211),

Example 124: 4~And?m-7-ntethy 1-1 H-iieazo j ej j 1,2,6 j1irindiaxisse-2,2~diOxide

Prepared in a ^nilar manner a.* Example 11 i from 2-.sulfann\yiarnino-4~ methv Ibenzoni tri ie {Example 124a> to provide 4-amm<>7-meihyW//-benzoi'i'jj l,2,hjthiadiazme~ 2,2-dioxide (50 mg, 50%)- NMR (400 MHz, MeOD)' 4 2.40 (s, 3B), 6.92 (s, 1Ή), 7.03 op. I Hi. 7.70 (d, J 8.2 Hz, 111). MS 212 (MH).

Example 124a: 2~Snlfenoyiainind«4~.T«.eiiiylbe.ii2onitHle

Prepared in a similar manner as Example I I 4a from 2-umino-4-meihvlbenzonurik (Example 14h) ίο provide 2"Sulfamoylamni<'-4-methyibenz:'>niti'ife (205 mg. 82%). Ή NMR (400 MHz. ( 001) 9' 2.35 K 3H). 0.88 (rn. 1 Hi 7.38 <d../ - 7.? Hz, IHk 7 "2 (br s, HI), 7.97 is. ! H), 9.37 (s, 1H},. MS 212 (MH ).

Example 124b: 2-Amm0~44nethy!benzo.nrtrite A solution of 2-brom».>-4-meth>ibenzomtrile (2.0 g, 10.7 mmol) and CuCN (1.92 g,.2.1,4 .mmol) in NMP (10 raL) was reacted in a microwave lor 20 min at 200 °C. Upon completion fee reaction was cooled to 0 !C, and 15% aqueous NH^OH (215 roL) was slowly added,. The-: mixture was stirred 'at it for 30 minyfeeti extracted with CH;?C1:;, The organic layer was washed wife PUD, brine, dried over tyig$04, filtered and coeeenixated. The residue was. purified by Sash chromatography (3:1 HoxanciEtDAe) to provide 2pmtino-4-dneth>3benzonitriie (1.24 g, 88%). 1H mm CDCfe) $ 145 (s, 3H), 5.70 (m, W% 5.84 (m, 113), 6.41 fd,/ ::: 8.0 Hz, 1 Hi.

Example 125:

Prepared in a similar pmitner as Example 111 from d-suifemoylamino-e-metbylbenzonitrile(Example 125a) to prexdde4mtmne4"metbyi»/iy-benzo|e][!,2fe]ihtadia2ine* 2.::-dioxide (0 rng, 8%>. Ή NMR (400 MHz, MeOD} 0 2.37 (s, 3K), 7.09 it. ,/ ==· 7,~ I b. ί H), 7.45 uK ./ === 7.3 Hz, : Hr 8.04 id.,/- 7.7 Hz. Hi). MS 212 (ΜΗ'}.

Example j 25a: 2*Su!fanioylao»uo-3-/ncihylbenzonitriic

Prepared in a similar manner as Example I I 4a from 2-amino~3~ meih> lbcnzonitrilc (Example 15b) to provide 2-salfamoylam:no-3-methylbenzomis do ί 115 mg. 46¾}. ;H NMR 1400 MHz, MeOD) ,·> 2,34 is. 3H), 7,31 (f, J 7.5 Hz, 1H). 7 57 (01, 2H}. MS 212 <, MH: i.

Example 126; iMadiazme~2,2”diaxide

Prepared in· a similar manner as Example 1,14a from 2-amiootcre^htEalonitrife-(Example 12.6a) to preside 4mmiim~?~eyanoH/Hbenzo[e}[l,2,6)t!iiadiaxMe-2,2~di0xide(40 m.g, .16%). :H NMR (400 MHz, DM$0-<E) 0 7.37 (d, / - 1.5 Hz, IH), 7.57 (dd, / ==== 8.2. 1.6 11/, 1U). a 12 id, Ϊ === 8,5 Hz, IH), 8.51 (hr s, 2H), 11.51 (x 1 K>. MS 223 (Mff ),

Example 126a: 2 - A n i no tc roph il 1 a! 0 n i ο 11 e

Prepared in a similar maimer as Example 124b from 2,$-dibromoatdlme to provide d-arninoierephibaiooitrile (1.14 g, 100%); Ή NMR (400 MHz, MeOD) δ 6.9! (dd, J -8.2, 1.6 Hz, 1H), 7.1.2 (d,J ™ 1.6 Hz, HI), 7.51 (d,J - 8.0 HxJ 0),

Example 127: 4x\ndm>-8~methoxyn//-!KmzoSef|lt2,6}lliladiazi.ae~2,2-dloxlde

Prepared in. a similar maimer as Example 1.1.1 from 2~su!iimioyl.aminp-3-meihoxybenzoniirile f'Exampl.e 127a) io; provide 4-amino>ftHRK:th0XY*7£&amp; benzo[c}[ i,2,6]tbiadiazine-2,2-dloxide (11 mg, 1553). !HNMR (400 MHz, MeOD) 6 3.07 (x 3H), 7,14 (1,/=== 7.9 Hz, iH), 7.22 (dd,/- 7.8,1,2 Hz, IH), 7.72 (d,/- 8.2, 1.2 Hz, IH). MS 228 (MM").

Example 127a; 2*SithanioyianMno-3-mcihoxybenzoniiriIc

Prepared in a skniiar manner as Example II4a from. 2-ami:iK>~3~ niethoxybettZonMie (Example 127b) to.pfovi<ie.2>s«I^mvoylaa'«fttv3‘>j»eth0xyte.n2©iiitrfie (1.13 mg, 45¾). *H NMR (400 MHz. DM$ϋ~,4) Λ 3.H5 is. 3H), 737 (in, IH), 7.30 (dd. J === 7.7, 1.7 Hz. IH), 735 (0,1 J === 7.9, = ,7 Hz, 1H}, 8.87 is. IH), 9.09 (hr s, IH), MS 328 (MH )..

Example 127b: 2 Am mo -3 mcthoxybcnzonitrile

Prepared in a similar manner as Example 1110 from 3-mmho\v-3· mtrobenzonitrlle to provide 2-amin<xvmethoxybenzonitrilc (346 mg, 60%). Ή NMR(400 MHz, MeOD) P 3.87 is, 3H), P.05 (t J === ?J Hz,. IH), 6.95:(dd, /=== 7.7,1,2 Hz, IH), 7.00(d.d,/ 8.2,.) >2 Elz. IH). MS 149 (MH ).

Ex a mple 128:4-AiMsiO" 7 » by droxy- j e| (1,2,6j iM«diaxtiie~2dHdiimiIe

Prepared in a similar manner as Example ΓΙ1 from. 2~s«ifam6ylanjiao-4-hydroxybenzonitrile (Example 128a) to provide 44ammO”?-hydroxy-//4. benzo[c][S ,2,6]thiadiazittm2,2--dioxidc (7 mg, 14¾.). {H NMR (400 MHz, MeQD) S 630 id, ,/==== 2.0 Hz, IH), 6.65 (dd,,/=- 9.0,2.4 Hz, 114), 7.82 (d. J = 8.8 Hz, 111). MS 214 (MET).

Example 128a: S-SisilbmQykmino-Hdtydroxybenzommie

Prepared in a similar manner as Example 114a. Irom 2«amino«4» hydraxybenzemirne (Example 18b) to pres ide 2“8ulfamoyfammo.-4*hydroxybenzoniirslc 151 rag, 22%). Ή NMR (400 MHz. M =.-00) 0 0 56 {dd, J = 8.6,2.4 Hz, I Hi, 7,43 (d, J = 8.6 Hz, 1H). 7 68 (d, J === 2..: Hz, IH). MS 214 (MH ).

ExampU: 128b' 2-A:ttfti6o~4-bydfPiybbbz6aMb·

Prepared in. a similar manner as Example 11.lb from 4~byd.roxy'2-nilrobenzonitrlle (Example 128c) to provide 2“AminO'4-hydrcrxybe«z.o.ni:bdle (286 mg, 100%), !H NMR (400 MHz, MeOD) 0' 6.15 (dd,,/= 8,5, 23 Hz, IB), 6,20 (d, «/== 1.9 Hz, HI), 7.18 (cl, J === 8.6 Hz, HI),

Example 128c: 4-Hydroxy~2~nHfobcezoouri!c Λ mixture of 4-mcthox y-2-m uobcnzoni in I c (820 nig, 4.6 mmol) and pyridine hydrochloride {755 mg. 4.6 mmolf was heated at: 200 ‘'Guilder hb for .18 hoars. Upon, completion;, the -reaction, was cooled to room tempmtate, washed with brine- and extracted with. ElOAc (2 x 100 mL), The organic layers were combined, dried over MgSEfi. filtered and concentrated. The residue .was purified by flash chromatography (1:1 Hexane:EiOAe) te provide 4-hydroxy"2-Tnitiebenzonin'iie (200 mg, 26%), Ή NMR (400 MHz, McUDi 0 ".24 (dd. J 8.6, 2.4 Hz. 1 H), 7.70 (d,./ - 2.4 Hz. iHk 7.83 (d../ === 8.6 Hz, IH).

Example 124: 4--8 mi a 0-8-( 2 ret Is y i ρ rop-! · e my 1} -! H-hen/ojcj 11,2,31 tltiadiaxine»2,2wlii)xide

To a stirred solution of 2-sulfomoyiatniuo-6“{2«moihylprorw 1 -coyI)bonzonitriie (Example 120.;·! (i .60 g, 6,73 mmol) in EtOli (29.0 ml..), under a nitrogen atmosphere, an aqueous solution ofNaOH (2.0M, 6.73 ntL, I 3.45 mmol) was added at room temperature. The obtained mixture was heated at reflux, for 4 h, cooled: to room temperature and neutralized with 1.0% AcOH (pH - 6), The neutralized mixture rvas kept in an ice bath, for 30 min. The obtained precipitate was filtered, washed with cold water and dried, to give I -49 g (888¾) of the title eompoimd as a white solid. The product was purified by crystallization flpm. ethanol.. m..p,: > 260 -¾. !H-NME (400 MHz;DMSC3-i&amp;) #10,91 (broad s, !lh, 8.30 (broads, 111),..7:46&amp;.3 -8,09 Hz, H i). 6.96 (broads, 111),6.92 (d, j - 8/-1 Hz, H i), 6.83 id,) - 7,2 Hz. HI). 6.46 (broad s, 1 Η), 1,89-1.87 (m, 3H V ! .65-1,63 (m, 311). 1 'C-NMR (10OMf-fe, DMSO-A,} fi 162.1. 143,1, 138,8, 137.6,132.9, 124,4, 123.3, 115,7,. 110,7, 25.8 and 19,2, MS 252 (MH7),

ExanipiejT^: 2-S:uiSm:oyiaminO"6"(2"metiiy Iprop-1-enyflbeftzomtrile A solution oi^nuft^'Cl^tt^thyipt-op-i -Cayl)bCn20.nMb (Example') 2-9$) (1,-24 g; 7.23 -mnvoi) in 'N,Nwltntethyiaeetamide (DMA) (20.0 nit-), under a nitrogen atmosphere, was treated with sulfatnoy! chloride 11.67 g; 14,45 mmol) at room temperature. The obtained mixture was stirred at: room tomiperaiwe for 2 h and (he reaction was quenched with water ( 40 mL). The mixture was extracted with ItOAc (4 x 80 mL), the combined extract was: washed with water (2 x 20 mL) and bride, and. dried w- ith MgSOy The filtrate Was evaporated and:the residue was purified fey ehromatogfophy on silica gel using gradient (llexanes/EtOAe 1:0 fo 1:1.),M give 1.69 g (43%) of the tiilc compound as a while solid. 'H-NMR (400 MHz. DMSO-<4) <*>9.42 (broad s, IH), 7.61 (0 i - 8.0 Hz. I Hi. 7.44 (d. j - $.0 Hz.. I H). 7.24 (broad s. 2Hk 7.19 (d, j - 8 0 Hz. Hi), 6.35 (broad s. 1 Η).. 1.42-1.95 (m, 30), 1.76-1.79

Example 129b: 2'AnvLao--6-{3-mshhyiprop-l-e.oy1}beBzonitr.ife

Concentrated HCI (65.5 mL) was added slowly io a solution of 2-miro-6-(2- m.cthy!.prop-,l-e.ny!)bcnzonf triic(Example i29c> (2.00 g; 9.89 mmol) in EtOH Π.:.0.2 ml.,} at oo.n temperature. Then, ihc obtained mixture was treated with iron powder (5.52 g, 98.91 mmol), added in small. portions at the same temperature. The mixture teas stirred at room temperature for IS min, and then heated at reflux for 30 min. The mixture was cooled to room temperature, EtOH was evaporated and the pH was adjusted to pH·-' 10 with aqueous NaOH (2.0M). The basuied mixture was extracted with IhOAc (4x100 ml..) and die combined extract was dried whh anhydrous MgSOi. The filtrate was evaporated and die residue was purified by chromatography on silica gel using, gradient hexanes to hexanes.lOOAe (8:2), to afford 1.32 g (77%) of the tide compound us yellow oil. 5H-NMR {400 MHz. DM $<>··</<·.) #7.19-7.25 (np IHL 6.62 (d, J - 8.-1 Hz., IH1, 6.46 {d, j - 7,2 Hz, 1H), 6.23 (broad s, 1H), 5.91 (broad s, 213), 1.861 88 (m. 3H). 1,72-1.74 (m. 711). 1ϊ\0.9)ΠΑ^ϋ.2.9.ο: 2-Ni:rv-6-(2~methylprop~ 1 -enyi }bersxesnin 1e A suspension of 2-eyano-3-nIt ropbenyl trirluoromethanesulfonate {Esample 129d) (8.80 g; (6.21 mmol), .2~methy-1-propeiiylboromo acid. (2,43 g; 24.32 mmol),. tetiirkis(6phenylphosphiiTe)palladium(Cl) (1,87 gy 1,62 mmol), sodium carbonate (1.89 g; ( 7.83 mmol) and water (33.0 mL) in dlnicthoxyetfiane (DME) (132.0 ml.) was heated at reflux tor 4 h, under a nitrogen atmosphere. The reaction mixture was cooled to room' temperature and diluted with water (100 ml:) and EtOAc (250 mL). The organic phase was separated and the aqueous phase was extracted with ElOAc (3 x 100 mL),Tfie combined extract was washed with brine and dried with anhydrous MgSO.:, The Silraie was evaporated and the'residue was purified by chromatography mi .silica gel using gradient hexanes to hexanes/EtOAe (7:3), to give 2.01 g (61%) of the title compound as a yellow solid. (400 MHz:, DMSO-ifc) #8.19-8,23 (m, 11:1)37.83-7.93 (m, 2H), 6.45 (broads, 1 Η), 1.95-1 .98 (m, 311), 1.75-1.79 {ro, 3H).

Example 129d: 2-Cyano-3-nitroplienyl trifi.uorom.erhanesullbn.are

To a solution of 2diydroxy-6-nitrobenzonitrile (Example 129e) (2.90 g, 17,67 mniol) in CH?Ch; (90.0 ml.,), at. 0°C and under a nitrogen atmosphere, triethylamine (3.58 g, 4.93 nil... 3534 mmol) was added, followed by drop wise additim i of *ri floor on icthm torn] f« mk anhydride (7.48 g. 4.46 ml... 26.51 mmol). The reaction mixture λ as stirred at 0 ‘Ό tor 30 min anddie reaction was quenched with saturated aqueous N&amp;jCOj soΙοΐΐοή (IfKlmL). The organic layer was separated and the aqueous phase was -extracted with -GHbCfe (3 x 100 mL). The combined extract was dried with anhydrous MgSO** filtered and evaporated. The residue seas purified by chromatography on silica gel using gradient hexanes to Iiexanes/EtOAe (6:41. to afford 5,23 g 000%) of the title compound as a. brown solid. Ίΐ-NMR (400 MHz, DM SO 4,3 3' 8.40-8.53 {m, 1 Hi. 8.23-8.27 fvn, 1.14)58.13-8.19 (ni, IB),

Example 129c: 2-Hydruxy-6-ultTxibenzouitrile 2~Medtoxy~6~n.itfofcieri20mtfi.ie'{Exa»'tpie 1254T) (10,73 g. 60.2 rmnob and pyridine hydrochloride (16.0 g, 1 38 mmol) were mixed together a;' solids under nitrogen, aval then heated in a preheated oil bath at 200VC for 40 min. After cooling to room temperature* water «200 ml..) and ClbCl· (206 ml.) were added and stfncd vfgmoosly for 1 bom. Then, the precipitated product was eolieoied by .filtration and reetysfal&amp;ed. from 'water,. to give 8,2 g5. (83%) of 2-hydrox.y~6«nitobenzomtrile as a brown solid, Tl-NMR. (400 Mila* DMSO-ife) #12,13 (broad ss 1H), 7 68-7.79 (m, 2H).. 7.39-7.44 (in, 1H).

Example I2i:fo 2-Methoxy-6-nitroben2fmitrile A solution of sodium raethoxide, obtained by adding sodium (i .68 g, 73,1 mmol) to anhydrous MeOH (73 mL), was added to 2,6"dmhrobcti&amp;osifeile.;(l3.20 g, 68.4 mmol) in dry MeOB (289 mL) under nitrogen at room! temperature over 10 min. The reaction was refluxed for 1 hour, and then MeOH was removed under vacuum, Diehl oromefoaue ; 460 mL) was added, and the insoluble solids were .filtered out. The organic layer was washed with brine (100 mL), dried with MgSCfo and removed under 'vacuumto give 11.45 g (94%) of 2~methcxy-6-mtrobenzomtrik, which was used without further purification Ti-’NMR. (400 MB&amp;, DMSO-foj $ 7.87-7.94 (m, 2B), 7.68-7.75 (m, I B), 4,01 (fo 3B),

Example 13814“AmitirK5"((B)~peop”i~miyi)"114“bestzo(e)ll,2^]fbladiamne-2,2"Clmxide

To a stirred solus ion ο Γ E) - 2 - s u 1 tIst s so s 1 α n uv 10 - e gp j, - j v i or Urdu (Example 1303} (0.32 g, .1.45 mmol} hi EtOH (15.0 mL), unde: -t ntoogen .itomsphcic aqueous solution of MaOH (2.9 M, 3.45 tuL, 6.90 mmol) was added at room temperature. The obtained mixture was heated at reflux for 4 ft Hie mix tom was cooled to room temperatofs arid neutralized {pH’ --6} with ] 0% AcO’H. The neutralized mix tore was kept lit an ice hath for 30 min. The obtained precipitate was filtered, washed with water and dried to afford 0,7(1 § (86%) of the title compound. The product was purified by -Crystallization front ethanol. m,p.: > 260 Τ'. !H-NMR (400 MHz. DMSOwfc) £10.90 (broad s, 18), 8.32 (broad, s, IB), 7.45 (t, I === 7.6 Hz, ΓΗ-, '7.11 (d,i ==== 7.6 Hz, 1 Hi. 6.95 (broads. ill), 6.91 hi, J === 7.2 Hz, 1H),6.75 <dd, J ==== 15.6 Hz, J ==== 1.2: Hz. 1H), 6.23 (dq, J === 15.6 Ex, j ==== 6,8 11/, 1H), 1,88 (dd. J === 6.8 Ex, J ==== 1.6 Hx, 3B>, ‘•’C-NMIUlOOMHz. DMSO-4) 6(62.2, 142.9, 138.3. 133.2, 131.2, 128.8, 121.7. 115.8, 11(1.4, and 18.7. MS 238 (MH ).

Example 130a: (E}-2-SuffarnoyI amioo-6-{ prop-1 -cnyI }henz.omfrile Λ solution of (£>2-amino-6~<prop-i -enyDbenzonitrllo (Example 130b) (0.60 g, 3.82 mmol) in N.N-dimerhyiaeetamldc (DMA) (15.5 mL). under a nitrogen atmosphere, was treated with stdiamoyl chloride (0.88 g, 7.63 mmol) at room temperature. The obtained.’mixture was stirred at room temperature for 2 h and the reaction was quenched with water (30 ml. }. The mixture was extracted with EtOAc (4 x SO mL). the combined extract was washed with water (2 x 20 ml) and brine, and dried with Mg$0<. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient hexanes to Imxanes/BiOAe (1; 1 jto give 0:.83 g (92%) of the title compound as a white· solid, Ή-NMR. (400= MHz, DMSO-4;} £9,39' (broad s, 1H), 7,48-7.00 tug 2H), 7.38-7,43 0», IE), 7.21 (broad s, 2Ή), 6.51-6,65 (m, 2H), 1,88! 94 (m, 3H).

FxampU: 130b~ t.67n2-A.n:firu^~6~(prOp-!-euyi)benxonilri:le

Concentrated HO (34.5 ml.) was added slowly to a solution of (E)~2~nhro-6-(prop-J-euyfibenzonitrik; (Example 2e} (0,98 g, 5.21 mmol) in EtOH (63.5 ml..) at room, temperature. Then, the obtained mixture xvas treated: with nxm powder (2,91 g, 52.08 mmol), added in small portions at the same temperature. The mixture was stirred at room temperature for 13 min. and then heated at reflux for 30 min. The mixture was cooled to room, temperature,

EtOH was evaporated and the pH was adjusted to pH-40 with aqueous solution of NaOE (2.0M). The basified mixture was extracted with EtOAc (4x100 ml..} and the comhiued extract \νίΐ^ dried wdh anhydrous MgSO.i. The Ultra ie was evaporated arid die residue was purified by chromatography or; silica gel using gradient hexanes to hexanes.'KtOAe (8:2), to afford 0.67 g (81%) of die tule compound as a white solid. !M~NME (400 MHz, DMSCNfo) 37,16-7,23 (¾ 1H), 6.78 (d, I - 7.2 Hz. 1H):. 6,59-6.64 (up 10), 635-6,53 (m, 2Id). 5.92 (broad s, 21E 1.83-I N*-> i m 3H).

Example 130c: {£)-2-Nhro-6-{prop-1 -eiiyifbenzonitrile A suspension of 2-iodo-6-nitfobertzonit{ile ί Example !30di ί 1.52 g, 5.53 mmol), tetiaKi$(dphe«yiphos|>hi»e;)paik4ttM'»(0) ¢9.64 g, 0.55 mrnol), tram A -propee-l -ylborotnc acid i035 g, ; ; .06 mmol), sodium carbonate {0.65 g, 6.98 rnmoi) and water (10,9 mL) in dimethoxy ethane (DME) (40,9 .mL) was heated at reflux for 15 h, under a ..nitrogen atronsphere, The reaction mixture was cooled to room temperature and diluted with ware;' (20 ml,) and BtOAc (100 ml..), t he organic phase was separated and the aqueous phase was extracted with 1:1(),4e {3 >1 50 ml,t.The combined extract was washed wnh brine and dried with anhydrous MgSCfo The 0 it rate was evaporated and the residue was "purified by chromatography on silica gel using gradient hexanes to hexanes/BtOAe (7:3), to give 9.98 g (94%) of the title compound as a white solid. JB-NMR (400 MHz,i)MSO·^) 48.16-8.24 <m, 2H), 733-7.89 (m, IE), 6,7)-6.84 (m, 2H). 1,90-2.02 (nr, 3H),

Example I30d: 2-l0do-6~nitrobenzomtri.ie 2-AmipO“6~bitrpbe«za»itrj.le (Example 130e) (432 g, 26 5 motpI).was added i n small, portions to a suspension. of sodium. nitrile (2,10 g. 31.7 mmol) in concentrated hESCAi (43 mL) and acetic acid (43 mL) at 4533. The reaction was heated at 45°C for 1 h arid then added in small portions: to a solution of potassium iodide (7.47 gy 45,() mmol) in FLSCE 0 M, 43imL}* After stirring at room, temperature for 1.5 h, iced, water was added to the reaction and the precipitated product Was collected by filtration. The product was purified by chromatography on silica gel eluting wltbCHyCI?. to give 2~iodo-6-mtrebetwonitrile (336 g. 53%) as a yellow solid. ^1-NM.R :(490 MHz, DM$0-%) $8.46-8.52 (re,. IB), 8.34-8.38 (m, IH)V 7.66-7.7): (op IH), Example 139c: 2-Ammo-6-mtrobenzomtrile

Concentrated HCI (39 ml,) was added to a solution of 23»dinitrobenzonitrile (13.3g, 58,5 mmol) in MeOH (235 mL) and 1,4-dioxane (145 ml,) at 70''G, External heating was removed, and iron, powder (11.44 g,. 295 mmol) was added slowly in portions at a rate which maintained a temperature of 70%). Afe the addition of iron was complete, the reaction was heated at reflux for a further 50 mux (hers cooled to room temperature and poured into EtOAc (400 mL) and water (400 mL). The solids were filtered out and extracted twice with boding EtOAc (300 mL). The combined organic extract seas dried with MgSO;p filtered and evaporated to give e-arnmn-b-nitrohonzonitrile (6,5 g, 663¾} as a red solid, which was used without further purification, ]e~NME (400 MBA DMSCnL) SIM-7M (m, ΙΉ), 7,41-7.45' (m, Ilf), 7.18-7.22 (m. Hi), 6.74 (broad s, 2H). EAampfe 131: 4-Attiino-5-((Z}-prop~l-eny i)~lH-henzo{c) 11,2,3{thiadiartBe-l^-dioxide

Prepared as in Example 129 Ortm^^ul'famoylaimao-iS^prop-!-cnyl}bett2onitnk· (Example 13 i a) to provide 4-Atnino-5"((Z)-pix>p··l -00)4)-1H--benzofejf 1,.7.3 jthiad hrine-2,2 -dioxale (28..:. mg. 91¾} as a white solid. lH N.YtR (400 MHz, DMSCW:p 6 10.92 (broad s, l H}.8 30 (broad s, 1H). 7.44-7.51 (m. IH), 6.90-7.00 im. 2H), 6.83-6.89 (m. IH), 6.65-6.73 fire i H), 5.88-5.99 fire ! Hi, 1,60-1.66 fire 3H).

Example 131a: (Zl-d-Sulfemoylanono-b-Cprop- i -enyllbenzonitnle

Prepared as in Example 129a from (A«2«armnO”6"{prep~1 -enyl)benzouitriie (Example 3b) id amount of 32 J mg (92%) as a white solid, Ή NMR (400 MHz, DMSO-dVi A 9.45 (broad s, 1H), 7,:59-7.65 (m, ΙΗ), 7.47 (d, J - 7.6 Hz, IB), 7.18-7.28 (m, 3H), 6,50-6.57 (m, 111). 5.99-6.09 (m. I PI). 1.74-! .79 im, 3H).

Example 131 b~ (Z)-2-Amino-6-{prop-1 -eny 1 }benx6mhile

Concemratcvl HO (1.54 ml.) was added to &amp; $»8pb»idb.ft -of - etryllbeuxoniMIe (Example:3e) ¢035 g, 1,86 mmol) in MeOH (30mL) add LA-dioxune (15ml) at memtempemture,..followed by portion wise: addition of itohpowder (0,73 g, 13.0 mmol). The obtained mixture was heated at refluxed for 2:5 b, cooled to (FL and the pB was adjusted to pH-10 with aqueous 50% solution of HaOH, The mixture was extracted with EtOAc (3 x 50 ffiL), the combined extract was dried with MgSG*, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with gradient 0% to 100% DCM nr hexanes, to give 0:24 g (80%) of4Z)-2-aminO'-6-(pmp-! -enyi)benzonitrsle as a yellow oil *H'NMR (400 MHz, OmQ-ώ,) ο 7.24-7.30 fm, 1 Η), 6.68 (d, 1 === <8.4 Hz. !H>. 6.55 (d, J ·=== 7.2 Hz, IHi. 6,426.48 um IB), 5.98 (broad s, 2H). 5.89-5.97 (m. IH), ! .74-1.78 (m, 3H). MS 159 (MET).

Example 131e: (Zp2-NsTro~6-fprop- 1 -onyj)bcnzonitriie

Prepared a? in Example 129c from 2-eyano-3mmOphenyl hdflaoromethanestdfonate Example (I29ds and as-1 -propen··I -v Iboronic add. The crude product was purified by chromatography on silica gel eluting with solvent gradient 0% to 100°'··? DCM :n hexanes, to give 0.80 g (97%) of tZ)-2-nitro-64prop-1 -enyObcnzoninile (97%s as a yellow solid. XU NMR (400 MHz. DMSO-dB ό 8.25-S.30 (m. IH), 7.90-7.9X an, 2B), o.25-6.70 (m, IH), 6.17-6,28 (m, 1 Hi. 1.78-1.82 (m, 3H).

Example 132: 4,S-i>tamltM>"l H»be**zeici(1,2,3|tfeiadiaztEe~2?2“i!®s;ye

Prepared as in Example 129 from 2-auifam0yiamino-6-aminoberiZonitril£; (Example 132a) in amount 0695.2¾ mg (8482} as a brown solid. lH NMR (400 MHz, DMSCK-4) $ 10.55 (broad s, IH), 7.80 (broad s, 2HK 7.09-7.16 (t, J - 8.0Hz, IH), 6.42 (<j,i = 8.4 Hz, !H), 6.22 (d, I === 8.4 Hz, 1 HE 5.79 (broad s, 2H).

Example 132a: 2-Sitl&amp;ft-tO¥lamino-6-:.iniiiiobenz;OBitr}le

Prepared as: in Example 129a from 2,6-diamioobeazonii ri Ie (Example 132b) in amount of 129.4 mg (6086) as a brown solid, !H NMR (400 MHz, DMSO-d-,) S 9.00 (broad s,

1H)„ 7 18 (i, j ~ 8.0 Hz, III), 7.08 (broad s, 2H), 6.62-6.67 (m, ! H), 6.49-6.54 (m,} H), 5.95 (broad s, 3.HE

Example 132b 2,6-Dlam.onobenxoaltrije

Coneepirated HO (44,3 mL) was added to a solution ef 2,6~diniimbenzoni:trile (12.9 g, 67.1 mmol) in MeOH. (269 ml.) and l,4-dioxa;Pe (1.66 ml.) at 70¾.External heating was removed, and iron powder (13,1 g, 235 mmol) was·added slowly in portions aia rate which maintained a temperature of 70:€, After the addition of iron was complete, the reaction was I tested at reflux for a further 30 nun, then cooled to room temperature and poured into EiOAc (400 mL) and water (400 mL), The solids were filtered out and extracted twice with boiling EtOAc (300 mL):, The organic layers were 'combined, dried with MgSCL, filtered and concentrated. The crude product was purified by reverse phase chromatography (0-)00% CB.'CN in H.>0) to give the title compound (1.0 g, 1.1%), which was used without further, purification. MS 134 (MBf).

Example 133; 4-Am*n<>-5-viHy1MIi-f>e«/o)c|f f,2,3]Ui»adia/J««-2,2-diexi<Ie

Prepared as in Example 129 from 2-sulfamoylannno-6-vinylberczoniirife (Example 133 a) in .amount of 3611 mg (4H%) as a white solid. Ή N.V1R (400 Ml·!?.. DM SO-J.·,* <> 10.95 (broad $, IB), 3.33 (broad s, IH), 7.43 (t, .1 - 3.0 Hz, Hi). 7.13 (d, J - 7.6 Hz,. Hi), 7.09 (dd, i - 17.6. 10.3 Hz. I H>. 6.90-6.99 (m, 2H). 5.73 (dd. j - 17.6, 1 6 Hz, PH), 5.17 (dd. j == 11.2:, L2 Hz, III).

Example 133a: 2 'Sul fan toy lanurio-6-viftyll>enzonitrile

Prepared as in Example 129a from e-amino-b-vinylbenzonifnle (Example 133b) in amount of 63.0 mg (31%), as a white solid. !PI NMR (400 MHz, DMSG-i/.p 3 9.46 (broad s, IBP 7.59-7.67 (m, 2H), 7.46-7.52 (in. i H). 7.23 (broad a, 2H). 6.93 (dd. J - j 7.2. 10.3 Hz. IR), 6.08 pP ===== 17.2 Hz, 11I). 5.59(0,.) Π.2 Hz, HI).

Example 133 b: S-Ammo-O-vInxlhenzonltrile

Prepared as in. Example 129b from 2~niiro-6-vmylhenzo»ltrile (Example 133e) in. amount of 123.9 mg (7.1 %), as a white solid ’Η NMR: (400 MHz, OMSCMR <! 7,25 (i, I==== 3.0 H,\ Hi). 6,37 {d, J ::: 7.2 Hz, 1H), 6.30 (dd, J === 17.2,11,6 Hz. I Hi, <409 (d,.! === 3,4 Hz, IHh 6,00 shroud s, 2H), 5.92 (d, J === 17.2 Hz, Hi), 5.44 (d, j === HIS Hz, IB),

Example 133c: 2-Niho -6- vmylbenzonlirile

Prepared as in Example 129c from 2-eyand-3~hitr0j5he:nyl tridoemmeihanesidPnute Example (I29d) in amount of 0.61 g (8634) as a yellow solid, 'H NMR (400 MHz, DMSO-dd 0 n.26-8.34 (m, 211), 7,90-7,98 (m, IH), 7.09 (dd, J === .17.6,11.2 Hz, I Hi.. 6.26 (d, i - 17.6 Hz. 1Η I, 5.S0 (d. J == 11,6 Hz, IH).

Example 134: d-Aridnmb-fluormS-CS-methylprop-I-eaiyl)-III-heuzn{e](1,2,3)ttiiaiiazme-2,2MtaMe

Predated as in Example 129 from 3-iIooro·2 d 2-mcdiy Iprop-i -coy I) -6· sulfamovluminobenzoni trile (Example I34uj in amount of i 25.0 mi; («6%) us a white solid. in.p.:>25(t'C. !H NMR (400 MHz. DMSO-rL) S 1,51 (s, 311), 1,90 (s,311), 6,2? (a, 1H), 7.00 Cm, IH). 7.10 (broad s, I.H), 7.45'(m? 1H), 8.35 ibroad.% IE). 10.95 (broad s, IB),.MS 270 (MBf), Example 1 34a: 3T>5K>TO~2-{2*methylprop· I -enylhh-sulfamoylammobenzonitrile Prepared as in Example 129a from 6-iimjno-3-flaoro-2-i2-nicihyiprop-i-eivyl)berizoiii;rile (Example 134b) m amount of 156.0 mg i 88%). as a white solid. MS 270 (ME").

Example 134b. 6M:mmdM-fiimiw2dy-ffiethy]prop4 wuy i)be.nzonitrlIe

Prepared as in Example 129b from 3-fluoro-2«(2>mcthyIprop-1 -enyl)-6-nitrobenzomtrilc (Example 134c) in amount of 0.38 g, (84%) as a white solid MS 191 (MH ), Example 134c: 3 F luori>-2-(2*jnethylprop- 1 -enyD-b-nitrobenzonitri ie '2-Bromb-3^flboror6-iiiu‘obeTuo->nitdle (Example 134d) (0.62 g, 2,53 mmol). 2-faethylprop-i -enyiboropie acid (0.50 g, 5,05 mmol), .palladium®) acetate (0,023 g, 0,102 mmol), IMPO^Cl-Oi g, 7,58 mmol), and dieyeiohexyi(2^6!-dimetbpix>%ipheoy|“2^yi)phosphme: ¢0,083 g, 0,202 mmol) were suspended'm ah'bydrous TEF (16 mL) trader nitrogen and heated at 70°C for 4,5 h. Solvent was removed under vacuum, and the produetwas purified by chromatography on silica gel eluting with gradient 0% ίο 100% ethyl acetate ίο hexanes, to gi ve 3-iluoro-2-('2"nietlryl.prop~l-enyl:)d>miirobeuz:onitrlle 0.44 g (785¾) a$ a yellow solid. MS 221

Example 134d:, 2~BronmM-fiuoro~6~ni trobenxeuitrile

Triethylarnine (2.53 mL, 1.8,2 .mmol) was added to a suspension, of l-hromo-S-tlubrb.-6-mtroteuanudc (Example 6c) (1.60 g. 6.08 mmol) in POC! t (32 mL), and the mixture: was heated at 75°C tor 1.5 h. The mixture was carefully poured into a mixture of Ice and water (400 ml.) and extracted twice with ChECL The combined extract was dried MgS'CL. filtered and eoneeotrated under vacuum. The residue was purified by chromatography rm silica gel eluting with solvent gradient 0% to 100% KrOAc in hexanes, to give 2-bron»o-3-f!uoro-6-nitrobenzonitrile 0.95 g, (64%) as a yellow solid.

Example 134e: 2-Bionto-3*fiuoro-O*nitrobenza&amp;iide

2-Bronw>3-fluoro-6-nitrolKw.oie soul (Example 1345; (24.83 g, 94.0) romol, (mixture of two regknsomcrs} was dissolved in anhydrous THE (200 rot.} under a nitrogen atmosphere at room temperature. Anhydrous DMF id.75 ml) was added and the obtained mixture was cooled to 0:C. Oxaiyl chloride (12.3 mL, 141 «nmol) was slowly added and the reaction mixture was stirred at 0°C for Hi min, and at room.temperature for a further 2 h. The reaction was evaporated to dryness, suspended in anhydrous frit·' i too mL) arid added slowly to concentrated ammonium hydroxide (350 ml-·)·«*' 0°C. Alter stirring for 45 minutes at D°C the mixtare was extracted with 0¾¾ (5 x 100 mL), and. the organic extractions were then discarded. At this point the desired regiotsomer existed as an Insoluble precipitate in the ugueou.' layer, which was collected'by filtration to give 10,3 g (423¾) of 2-bromo-3-fincro-A·· mtrohenzarnide which was used, without further purification.. *14 NMR (4CK) MHz, DMSO-Hg) S 8.27 (dd, 1 =- 8,8,4.4 Ha 1H), 8.10 (broad s, 1H), 735 (broad s, 1H), 7.56 (dd, J -= 9.6,7,6 Hz. 1H)

Example 13411 2-Brboto-3*fluom-64Pti^behzoic aci d

In a TL, three necked flask fitted with a dropping funnel and a thermometer were charged.E-bromo-a-fluorobenzok acid (Example 13%) (28.23 g, 0,13 mol) and Concentrated H2SO4 (200 nil,). After cooling to 0 T, HNO* (7034,16.0 mL) was added dropwise over 30 min, keeping the temperature-between 0 to 10 *C. After I h, the reaction mixture was poured Into the: •crashed tec keeping-the temperature below 20 °C. The mixture was extracted with EtOAo (2 x 200mL). the combined extract was washed with brine and dried with MgSO+. The filtrate was evaporated to give 27 .? 7 g (7734) of a mixture of 2-fcroiV:0~3-iluoro-6-nim4.vnzoie acid ;md 2~ hromo-S-fioorQ-Smitrobeozoie acid (1:0.4) as a brown solid, Ή NMR (400 MHz, DMSCW.fl d 833 (dd, I-9.6,4,8 Hz, 1H). 7 21 (dd;i - 10.0,8.0Hz, IH),

Example 134g 2 - B ro mo- 3 -fl oorobenzoie acid

In a 1L, three necked flask fitted, with a dropping fiumel and thermometer, were charged 2-amino~3~tluorobcnzoic acid (20.0 g. 0.15 mol) and acetonitrile (100 ml.}. After cooling to 0 "C, T-JSr (47%, 160 ml.) was added drop wise over 10 min. To the resulting solution, a solution of MaMO,: (10.0 g, 0.14 me!) In water (20.0 ml,) was added drop wise over I fv After addition, the reaction mixture was stored at 0V>C for 5 nun, and cupper(l) bromide (22.0 g, 0.15 mol; was added poriionxvise over 30 nnn. Stirring was continued at 70 "C ina an oil bath for i h. After cooling to 0 -"C,. 700 .ml,ofwater was added and the precipitate was .filtered, washed With cold water and dried under Vacuiun to give 2d.23 g (100%) of the tide compound as a-white solid. The crude product was used in the nest step without purification.

Example f 35: 4-Ammo-5-i cj dopaiten-i -v H-i li-bcn/oj c I {f,2,3jt!dadsa/iae-:2,2«ilio:siile

Prepared as in Example 1.20 from 2-xuinimoyiammo~6-(oyclopemen-!-yllbenzonltrik (Example 135a) in antouni of 3d 0 tug {33%» as a white solid. Ή IN MR. i40b MHz, DMSOwfr) 0 1.07 <rn. 2H), 2,43 <;m. 2B).. 2 53 im„ 2VI), 5.04 On, Ifi), 0.83 (broad s; 6.92 <»n. 2H). 7.46 sm, IHl, 8.2.5 (broad s. j Η), ! i 02 «broad s, ! H). MS 264 (MH ).

Example 133a: d-SulfarnoxIarrsino-n-teveloponteu-l-yljhetwcnUriie

Erepered as in Example 129a from 2~am.mo~6~(eyelopenien-i-yl)benxomfriIe (Example 1.35 b} irs amount of 156.0 mg (88%), as a white solid.

Example 135b: 2-Amino-6-{cyclo}tenfen-1 -y! Ibenzon itrile

Prepared as in Example 129b front 2-{cyc;opeuion-1 -yfi-d-nttrobcnzonitrile (Example IS.vi hi amount of 0.44 g, (84%) as a white solid. MS 185 (MH ).

Example 13So: 2-(Cyclopenten-1 -y!}~6~ni frohenzoni Pile

Erepared as in Example 129e from. 2-cyaoo-3-nitro;pheoyl trifruoromethanesuliOnale (Example .129d) in amount of 0.62 g (84%) as a white solid.

Example 136:

Erepared as in Example 129 from 3~su1|hm0yl9mip0-4~^pr6pyIl^tx?oaHp.le (Example 1.36a) In amount of 1443 mg (66%):ax a white solid, *H NMR (400 MHz,'DMSQ-d^j ύ 10.73 (broad s, I F!), 8.14 (broad s, IH),. 7,44 (broad s, 1:B);,.738 (t I - 8.0 Hz, )H), 6.47 (d, i === 6.8 Hz, ; K), 6.86 (d. j - <7.0 Hz. ! IH, 2.9? (», J === 7-6 Hz, 2H), i ,51 (box.) === %0 Hz. 2H3. 0.8) (t J=== 7,6 Hz. 30).

Example 136a: 2-Sul famovlasmno-tw?-propyjbenxonitnle

Prepared ax hi Example 17¾ fours 2-emwo--6--v--prrtpyibenzeafo'de (Example ! 36b) in amount of 238.4 mg (4]¾). as a white solid, Ή NMR i 400 MHz, DMSO-fo) 4 9.57 (broad s, Πί), 7.55 a. j - S.4 Hz, IHt 7.39- 7.44 (m, 1H). 7.17-7.23 (m, 3H). 2.7| it, j === 8.0Hz, 2H). 1.60 (hex. J ~ 7.6 Hz. 2H), 0.90 a. .1 =- 7.6 Hz. 3H).

Bxmrmk 1366: 2--Amirss>-6-/i--pr>>ps foenzonunie (Z)^2-Ammo“(KpiOp-=l'-ettyi)bcnzp«firite:'(Example 13 l b) (0,45 g, 232 mmol) and 10% PdC (0,17 g) were stirred in EiQH (15 mL) under a hydrogen atmosphere for 4 h, The catalyst was filtered out, and the organic layer was omeesmuted under vacuum to give 0,45 g (96%) of 2-8miao-6-«-ptopyibe.nzonitrile· as yellow oil, which was used without further nun-leaf ion. MS )61 (MH )

Example 137; 4~ Amim.K5-inethoxy~1Fl-foesuo jefolH,3 ftfoadfoxme--2,2wtiovIde

Prepared as in Example 129 from: 2-suifenmylammo--6-me!h0xybenzdnitnle (Example 137a) in amount of 134,9 mg (93%) as a white solid, *H NMR (400 MHz, DMSO-nV) d 10.09 (broad s, )H), 8.28 (broad s, IH), 8.03 (broads, IH), 7,44 (t, J === 8.0 Hz, Hi), 6,70 (d, J == 8,4 Hz, 1H), 6.58 (d, 3 =- 8,0 Hz, IH), 3.89 is, 3H).

Example =87;.;; 2-Sul&amp;movla;niao-6-mefboxyhenzonitrilo

Prepared as in Example 129a front 2mnii,uo--6--meiboxyben2o:niirile (Example. I 37h) In amount of 175.9 mg (8=1%), ax a white solid, *Η AMR (400 MHz, OMSCfoPd d 9;44 (broad s, 1.H), 7,56 (t J = 8.4 Hz. IH), 7,25 (broad s, 214), 7,14 (d, 4 =3.0 Hz, 1H)S 6,93 (d,4 = 8.8 Hz, 1H). 3.87 3H). .Example r37h: 2-Amlnu-b-modKiXyhenxooiinle A solution of d-nrethoxy-h-nurobenzonurile (1. ,01 g, 5,69 mniol), cyelohexoue (2,84 g. 3,51 ml,,, 34,58 mmol) and 10% PdC (0.58 g) is- EtOH (25 mL) 'was refluxed:for 1,5 h.

The mixture was cooled to room temperature, filtered and evaporated, to afford the title compound 0.8.3 g (98%). The crude product was used hi the .next step without luthier purification. {H NMR(400 MHz, DMSOMAd 7.17(61-8.0 f!z, IB), 631- 6.35 (m, 10), 6,476.21 frit, 1H.K 5.9:7 (broad s, 2B)S 3.76 (s, 3B),

Example 138: 4-Amlm>-5-(pr0p-1<uu-2.-yi}-1ii4>en?:o|ei[U2,31tyadiazIiK>-2,:2-di»xiiie

Prepared as. in Example 129 faun 2-atdfamoylaroino-6-f prop-1-en~2-.y!)benzonii.rije (Example 136a) in amount of 63 8 tug (62%} as a whin: solid. H \Y1R (-400 MHz. DMSO-^i Λ 11.05 tbroad s. 1 Η), 8.32 {broad s. IH). 7 44- 7.52 (to. IW), <>.94.00 mi. IH), 6.64-0.89 (m, 1H). 6.82 {broad s. 1 H), 5.)6-5.19 fm. ) H), 5.31-5.35 (m, i f-i). 2 tit) κ. 3B), Example 138a: 2-SoIikmoyknrino~6~(prop~1 -en~2~y!}benxomtnle

Prepared ax in Example 129a from 2-arnino-6-(prop-i -cn-2-yl}benzomtril.e (Example 138b) in amount, ef 80.5 mg (10057}.. ax a yellow solid, Ή NMR (400 MHz, DVISO-<6) 09,40 (bread χ. 1H) ' 58-7.64 (m, l R), 7 48-7,53 (m, 1H). 7.7.5 (broad s. 2H), 7.1^7.24 {m. IB), 5,34-5,40 (ms IB), 5.1.0-5.14(m. IB), 2,i0 (x: 3H).

Example 1366: 2-Anrmp~6-(prop-1 -ers.-2-y !}he«xoniirite

Prepared: as in ..Example 129b from 2«mtro.«6-(prop-X4ep,'-2i'yl|benzbpitdk: (Example ,13Be) In ambimt of 303,4 mg (83%), as a yellow solid, !H NMK (400 MHz, OM’SO-(.U) 0' 7,18-7.25 (m, 11:1), 6,67-6,72 (m, 114). 6.47-6,51 (m, IB), 5.97 (broads, 2H), 5.24-5.27 (rn. 1H), 5.07-5.10 (m, 1H), 2.03-2.06 (m, 31!)

Example 138o: 2-Nitro-6-(pro|^T-du-2^1.)henz0nitriIb. A suspension of S-eyano-S-oilrdphsmd. inOaorometlnmesulidnate (Example 129d) (0.93 g, 3,15 mmol), potassium trifii)Oro(prop~l-ert-2-yI)borate (0.70 g, 4.73 mmol), dtchloro l,Γ-bix(diphenylpliasphbm)iaToeene pailMiumO 1) (0.26 g, 0,32 mmol), cesium carbonate (3,08 g, 9.45 mmol) and water (5,6 niL) in THE (56 mt) was heated at reflux, for 25 min, under a nitrogen atmosphere,. Tire reaction mixture was cooled to room temperature and diluted w ith water (100 m.L) and BtOAc (KMt niL). The'organic phase was separated and the aqueous phase was extracted with -EtOAe (3x 100 mlQ.Ihe combined extract was washed with dilute»! HC! (I.5M). bnne am! dried with anhvdrous MgSO*. The filtrate was evaporated and the residue was purified by chromatography on shica gel using gradient hexanes to hexancs/BOAc {/.at, to give 0.30 g {493») of the tide cornpotmd a.* a yellow solid. !H NMR{400 MHz, DMSG-,4! 0 8.24-8.29 (m, I B), 2.86-7.95 (m, 2B), 5.47-5.52 <m* IH), 5.20-5.23 (m, l.M), 2.12-2.15 :(m, 3H).

Example 139: 4-sVmiiH>“S“ethy!“IIM>enzo|e|i I JJ](hi:Hliaimv2,2-dteide

Prepared as in Example 1.79 fro os 2-suUlwwykmnno4)~vinyibe;wonmhe d 'ample 139a} in amount, of84.2 mg (808«) as a white solid. lH NMR (400 MHz. DMSO-fA) 3 10.74 (broad s, HI), 8.16 (broad s, 1B)S 7.24- 7.52 (m, 2fl), 6.99 (d, 1 = 7,2 Bz, 1H), 6.84-6.88 (m. ! H8.00 (0.. J = 7.6 Ez; 2H), 1.12 (t. .1 - 7.0 Hz. 5H).

Example i 39a: 2-Sollkmoykmino-6-vissylbestzon:itrile

Prepared as to Example T29a from 2-aoibno-6~et.byfbenzcmitfUe (Example 139b) in amount of 280.3 mg (9876), as a white solid, *Ή NMR (400 MHz, DMSO-r4) 6 9,86 (broad s, 1.H), 7.52-7,60 (t, J " 8.4 Hz, IB), 738-7.43 (m, IH), 7 19 7.24 7,19 (broad s, 2H),2.73 (q, 1 - 8.0, 2H). 1,18 (t. J - 7.6 Hz, 3H),

Example 139b: 2~Am:Hm-6-etbylbenxonlrrlle

Prepared as in Example J29b iron· 3-efhyl-6-nii.mbenzonif.rile (Example 139c) In amount of 0.46 g (748¾}. as a orange solid. *H NMR (400 MHz, DMSO-f/s) 6 7.18 (l, j ~ 8.0 Hz, IH), 6.59 id, I :: 8.0 Hz, 1H). 6.4? id, I - 7.2 Hz, IH). 5.89 (broad s, 2H), 2.60 (u, j - 7.6 Hz, IHl I 15 if, J - 7.6 Hz, 3H}.

Example 139c: 2-Efhvl-6-nifrobenzonlfrile A suspension of 2 ef.lwl-6-pitroaniline (Example I39d} (1,96 g, 11,80 mmol) In a .solution o.fHCI (3.064, 24,5 ml,) was stirred at room, temperature far 20 min., After eOolIng to 05 ”C, a solution of NaNC);< (.1.63 g, 23,6 mmol) hi water (12.25 mL) was added over a period of 10 min. The obtained: mixture was .stirred ai 0-5 *€ for 30 min, and the obtained homogeneous selulion was transferred to a solution of CuCN (2.63 g, 29.5 mmol) and K.GN (5.06 g, 77,8 mmol) hi water (60 ml,} and EiOB (31.0 mL). The resulting mixture was stirred x igorousiy at romn tempctuntrc Mr 30 min, and then heated at 70 '% for another 30 min to complete the feactlo». The cold mixture was filtered: end extracted with EtCMc (3 x Γ00 mL). The combined extract was washed with NaOH f 0.5M> anti banc. and dried with anhydrous MgSO*. The filtrate was evaporated and the residue was purified by ehrontslography oft silica, gel eluting with 30% EtOAc m hexanes. t»> afford 0.66 g 133%) of the title compound as an orange solid. Ή NMR 1400 MHz. DM SO-.-Λ,) 0 8,18-8.34 (rn, 1H), 7.85-7.0? fm. 2H), 3.93 Up 1 - 7,2 Hz, 2H), 1.24 (it j == 7.:: Hz,3H).

Example J 390 2 Eihyl-6-nitroamiioe A solution 0fiN.-(2-€diyl”6-ftttrophenyl)act8mMe (Example 139e) (0.62 g, 2198 .mmol) in EtQH (21 mL) aud concentrated. HC1 (13 mL) was refluxed for 24 h. EtOH was evaporated, the residue w as diluted with water 110 ml) ami the pH was adjusted to pH-8 with NuOH (2.0M aqueous solution). The neutralized solution was extracted n u.h EtOAc (3 x 50 nits, the combined extract was washed with water and brine, and dried with anhydrous MgSO.·.. The filtrate was evaporated and. ike residue was purified on FiPLC to give 0.32 g (64%) of 2-eihyi-6-nitroaniline as an orange solid. !H NME.(400 MHz, DMSO-A) ri 7.82-7 87 On, IH). 7.27-7.32 (m,:lH),;7.l6 (broad s, 2ft). 6.55-0 62 (m, 1 H). 2.55 (eg) = 7.2 Hz, 2H). J .13 it. .1 = 7 2 Hr. 3Ht.

Example 139c: %“(2-edryh6-Jiiiropheayi)aeetamide A solution of nitric acid (4.2 mL) in glacial acetic acid (5.2 mL)) was added drop wise to solution ofT8“(2-ethylphenyi)ae4temi:de (Example 1391){LOO g, 6.13 mmol}·in AeOH 132 mL) and acetic anhydride (18 m.L) at 07'C. The reaetioo was stirred af 0°C for i h, diluted with water (50 ml.) and neutral (zed. with 'N^COs (pEMI)- The neutralked mixture was extracted; with. EtOAc -(3 x 50 mL), the combined extrac t was washed: with water and brine, and dried with anhydrous MgSO.:, The filtrate was evaporated and the residue was purified on HPLC t.o give 0.62 g (48%) of the title compound, as a white solid. lH NMR (400 MHz, DMSCKA) S 9.81 (broads, 111),7.68-7.73 (m, 10),7.57-7,62 (tn, 111),7.39 <t, J - 8.0 Hz, 111),2,64 (q,j - 8.00¾ IH l 2 00 (s, 3H)„ I 10 (t, J = 8.0 Hz. 3H).

Example 13vf: N~(2-ethvlDben.vi)aeetum.tde 2-Ethylaniline (9 .70 g, 80.0 nnn.o!) was added te a mixture: of glacial AcOH (30 mL) and actio anhydride (20 tnL), and foe resulting· mMure was refluxed at 1201% fordb. The reaction mixture was then c< at led to room temperature and poured into a boiling mixture of water and EtOH (20 mL each) The mixture was stirred at rt for 1 h and: then coaled (0-5 PC) overnight.

EtOH was evaporated and the remainder of the mixture diluted with water (100 bjL). Tile obtained mixture was neutralized with Na:CO* and extracted with EiOAc..The combined.extract was washed with brine, .dried-with aidrydrous MgSO*, filtered and evaporated. The residue was purified by chromatography on silica gc! eluting with 5** MeOH in CIECE to afford 5.50 g (42%) of the title compound as a pmk solid. *H NMR t400 MHz. DMSO-iA) «>' 0.25 (broad s, 1 Hi. 7.05-7,40 (to, 4Hn 2.55 fq. 1 = 7.6 Hz. 2H), 2.02 (s, 3H). 1.00 (t, j -= ?.e Hz. 3H).

Example 140:4> A miao-5-hydrox> >1 H-be»zo{e) 11{tfetadi.asd[ag~2,2”di»id'cle

Prepared as M-Example 1.29 from 2~sulfam0ylammo^6“hydroxybe»zob5tri).e (Example 140a) in .amount of 50,6 mg. (20%) as a brown .solid, lH NMR (400: Mill?, DMSO-*^) 3 11.00 (broad s, 1H), 9.24 (broad s, HE. 737 (t. J === g.OHz, 1H), 7.18 (broad s,2M), 637 (d, J ==== 8.4 Hz. lH). 6.71 id..) === 8.4 Hz. ! H ?.

Example .1.40a: 2«Sulfainoylaminofvdn droxybestzonitil!e

Prepared as in Example 123a from 2~amiuo«MtydT‘>xyhettzouitri!e (Example 140b) in- amount of 0.25 g (99%), as a.brown solid. *111 NMR. (400 MHz, DMSO-ifi) 3-.1.1.01. (broad a, IH), 9.25 (broads, 1H), 737 (1, J 8.0 Hz, 114),7.18 (broads, 211), 6.95-639 (op 11:1), 6.69-6.74 (rn, 112).

Example 140b: 2-A.onno%3rydroxvbonzonitriIc A .solution of2“methoxy-6-nitrobcnzonifrile «Example 1290 (Ell g. (>.7u rnmol) in EtOH (120 mt) was hydrogenated over a catalytic, amount of 10% Pd/C (0,15 g) at room, temperature under hydrogen (1 atm). Aifter 2 h, the mixture was filtered and the catalyst was washed with EtQAe (150 roL). The combined extractwm-evaporated, to give l.i 1 g: (1005¾) Of the tide compound as a brown solid. The crude productwas used in the next step without further purification. SB NMR(400 MHz, DMSO-sfi)9 1039 (broads, 1H), 7.00 (t,I ==== 8,0 Hz, IHi, 6,12-6.17 cm. | Hj. 6.01-,4.05 (m. 1H), 5.77 (broad s, 2H).

Example 141: 4-AminmS~phenyt«l li-Mazoje] [1,2Jftbiadlazine-SjS-’Clioxtde

Prepared asin Example 129 from 2~xullamoyIammo^S-pheayl.ben:Z:C.a.utrile (Example i 4 i a) in amount of 114.7 mg (90%) as a white solid, Hi NMR (400 MHz, t>MSO~i£s> 4 1.U2 (broad e, 1H). 8.04 (broad s, 0¾ 7,52-7.58 (m, 1H), 7,39-7.50 (m, 31¾ 7.32-7.38 (m, 2H), 7.02-7.07 (m, 1H), 6.97-7.01 (m, 1H), 5.61 (broad s5 1H).

Example 141a: 2 - S η I fa moy I a n * 1 uo-6-ρ j ten y henzordtrde

Prepared as in Example 129a from 3-ammobiphenyl-2-earbomir.ile (Example 14! b» in amount of :42.3 mg 19438), as a white solid. !H N.MH (400 MHz., DMSO-i/s) 4 9.44 ibi-oad ,N 1H), 7.68-7.74 (m, I Eh, 7.58-7.62 im, 111), 7.44-7.53 {ra, 5Η», 7.30-7.34 (m, IK), 7.29 (broad x, 211).

Example 141 b: 3~Annno-blpheny 1-2 -carbomfrlie.

Prepared as in Example 129l> from 3~mfrobipheoy!~2~eafbonifri:I.e (Example-141.c) m amount of) 17.0 mg (805ip, as a white solid. MS 195 (MH }.

Example idle: 3-NitroNnhcnyl~2~carbonit«|$

Prepared a- in Exam-pie 129e from 2:-cyapo-3-mirophepyi trifroQiomeihaaesidfonate 1 Example 129d)and pbenilboronie acid .

Example !42i d-Aatirro-S-ssopropyl-IH-feenwIo]|I,2,3}thiadiaz5ao~2,2:-dioxi:de

Prepared as in Example 129 from 2-$m0m)oy!aroino-6-isopropylbenzooifnie (Example 142 a) in .amount of 53.7 mg (49%) as a white solid. *H NMR (400 MHz, DM$0-t/.,) 4 10.74 (broad % XH), S 19 (broad s, 1H), 7 42 (t, J - 8:013¾ 1H),.7.15 (broad s, IHk 7,07-7.13 (m, 11:1), 6,83-6.88 (m, 1H), 3.71 (hep,.! ::: 6,4 Hz, IE), 1.1:8 (d, J :::: 6.8 Hz, 611).

Example 142a: 2-Su: bunovla·mno-b-tsonronylhenxonifrlle

Prepared ax in Example 129a from, 2-ami no~6~ i sopro(»y!benzoivitrile (Example 1.42b) in amount of 112.0 mg.(97%), ax awhile solid. Ή NMR (400 MHz, DM.SQ-ii?) 4 9,35 (broad s, i H), 7.60 (L j - HA Hz, 1H h 7.4! sd j - 6.0 Hz, IΠ), 7.27 <J, J - 7.6 Hz. 1H), 7.20 (broad 2H), 3.20 (hep, j - 6.6 Hz. 1 Η). 1.23 id,.) - 6.x Hz. 6Hi. E .sample 1.42b~. '2-An sino-ftHsopropy 1 henzonitnlc

Prepared a? in Example 136b from 2-Am«in-6-(pjop-1 -cm-2-vl)ber*^PitH.le {Example 13Kb) in amount of 112.0 nis (9?%>. at- a whin.;· solid.. :H N'MR (400 MHz.DMSO </,>} ο 7.21 U, i -= 8.0 Hz, I Hi. 6.60 (d 3 - x.4 Hz, IH h 6.52 (d J - 7.2 Hz. IH6 5.67 (broad s, 2H), 3.03 (hep,.) - 6.6 Hz. I Hr US (d. J -= 6.3 Hz. 6Hi.

Example 143: 4~Ai.mno-S-iSohssHi-1 H-beo/.o|c| j 1,2,3 jthladimd»ο-22Μ1οΜΐΙο

Prepared as so Example 129 from 2-suifamoYlamino-6-Hobui\dbonzottiinie (Example 143a) in amount of 32.5 mg {63%} as a white solid 'H NMR (400 MHz. DMSO-d:} d 10.70 (broad s, 1H), 8.08 (broad s. 1 H>. 7.55 (broad s. His, 7 36 (i, j » 8.0 Hz. I Hi. 6.89-6.94 (m, 1H), 6.84-6.88 (m, IH). 2.8? (d. J - 6.8 Hz. 2K), 1.69-1,81 (m, 1H), 0.72 (d. 1 -= 6.8 Hz. 6H), Example 143a: 2-SdfamovkBiino-6-isobutvIbe»zomtrile

Prepared as in Example' 129a ff0m.2>an«»e>6*isok}^lbenzo.hitriie:.(Exaiapl.e 143b) in amount of 52,0 mg (91 %), as a white solid fH NMR (400 MHz, DMSO-dO 9 9.36 (broad s, 1H>, 7.55 (t J 8.0 Hz, IH), 7.4! (0, J - 8.0 Hz, 111),7.21 (broad s, 2H), 7.16 (d, f - 6.8 Hz, !H), 2.62 (d, J - 7.6 Hz, 2H>, 1.82-1.96 (m, 1H). 0.88 (<J, J -= 6.4 Hz, 6H),

Example 143b: 2-Am!no-6-lsc!btdY)bstszenit:riie

Prepared as in Example l36b from 2-Amino-6-(2-mei.hy1prop^i«epyl)'benzPm(fiIe (Example 12'4>) m amount PF76.-.4 mg (98%), as a yellow o it 5H KME (400 MHz, DM50”iE) r> ?. 17 (t J - 8 0 Hz. 1H), 6,60 (d J -= 8,4 Hz, 1 H), 6,42 (d j- 7,6Bz, IB), 5,88 (bread s, 2H), 2. 47 (d; i - 7 o Hz, 2H), 1,78-1,92 (m, 1H>, 0 86 (d, j -= 6.4 Hz, 6H),

Example 144: 4-A nsisso~8~isiilnoromet.by 1-1H -beuzo je j (1,2,311 hiaddziue-2,2-diozide

Prepared as ip Example 129 from 2-s«lfamoylamm.O:'6'· tri(iuoromethy IbenzonUr ile {Example 14.4a) in amount of l 14.8 vne (90%) as a white, solid. Ή NMR {400 M Hz. DMSO-40 S '11.41 (broad.% 1H), 7.64-7.12 (m, 1.1:1), 7.50 (if, 1 - 7,2 Hz, IH), 7.38-7.68 {broad s, 1.H), 7.31 (d, J - 8.4 Hz, IH).Λ10-3,60 (broad s, ill).

Example 144a: 2-Sullarnoy I arni η o -6 -1 r f lhiaronietbyibe«20Bitrile

Prepared as in Example 123a from 2'aminoO-irifl.\i.ofomerhY]ben?.onitriIe {Example 1.44b) ip an so: «η of 138.5 mg (82%). as a while solid. Ή NMR «400 MHz, 03-130-%) 4 7.9; {'broad s, IH), 7.84-7.92 iro. 2H). 7.09-7.76im. IH). 7.42 (broad s, 2H).

Example 144b; 2-Amino-6-- pifluorobenzoaitrilc 2-{4-Methoxybeb2sylaii»a0)-6*{tfiflu0romcthyl)bcnzdnMk (Example 144c) (3.49 g. 11.4 mmol) was treated with trlfluoroacetic add (TEA) (35 mpat 0'C. and then stirred at room tempera.! arc lor 20 min. The. TFA. waateptoved under vacuum, and the residue was dissolved in €H*'€J> {, 150 ml) and washed with 1M NaOH, The organic· layer was dried with MgSO.i, filtered and removed under vacuum., The crude product was perilled by eliromatography on silica gel eluting with CfBCb to give 2J2 g (9973) 2-4minp.^(trifl.aorpmetby!)lx:n20atirile. as a white solid. Hi NMR (400 MHz, DMSCMh) 3 7.45 (m, 1B), 7.07 (m, IH), 6.96 (m, IB), 6:60 (hr s, 2B).

Example 144c: 2-t4-Methoxvbcnzvlamino)-6-Urifluommotl;vObcnzonitfiic 2-FIuoro-6-(trifiuoromethyl)benzonitrile (2.44 g, 12.9 m.mol) and 4--methoxy be.nr.v ianunc (7.09 g, 51.7 mmol) were suspended .'in 1,4-dioxane {10: mL) and heated in a: microwave at 1'80®C for 30 min. The 1,4~dioxaPe was removed under vacuum, and die crude material was purifiedby chromatography on silica gel eluting with CHxCBto give 3,71 g of2~(4-ineihoxybejwyl.ao:hiic(i-0-(tritluoronKS,byl)heuzonifr.i.Ie (94%) as an: off white solid. Ή NMR. (400 MIL·., DMSO-d,,} 4 3.71 N, 3B). A.42 (d, J --- 5.6 Bz. 2.H), 6.89 (m, 2H), 6,.97 (m, 2H). 7.29 pm, 3B). 7.48 (vn. 1 Hi.

Example P45: 4-Ami.?u>-h-hydroxyMH4>osw:oic|jL2J|{Idadiazino-2.2-di0xidc

Prepared as la E&amp;dmpk 129 from 2»suUamoS'lamioO"3-hydroKytenEohitfile (Example I 45a) in amount of 53.9 mg i6o"«} as a white solid JH N'MR (400 MHz. DMSO-iT;} d 10.14 (breads..: H) x <4 (broad s. 2HT “31- '-39 $m, 1M) 0.97-7.03 (m, 1H>: 6.88 if. J - 7.6 Hz. Hi). ];;3.a.0iOb:..J.::L“:9;. .7 - S n i fatnoy 1 am ί η o ~ 3 ~h y d ro x y b e η zo η4τ d z

Prestarcd as in Example 129a from 2-an^soo-3-hydroxybeazoeiiri1e (Example 145b) in amount of 83.5 mg (393-.), as a white solid. !H NMR 1400 MHz, DMSO~ds} d 10.23 (broad a, IB), 8.60 (broad s, 1H), 7.14-7.27 (m, 3H), 6,71 (broad s, 21!). 17.77).7017.67...1:37:.0.'. 2-Annno~3~hydro\ybetszonhriio

To a solution of 2-nmim'--3-methoxybenzonlirile (Example 127b) (0.98 g, 6 59 mmol) in CH;;€b (25.0 ml..), a solution ot'BBr-, in OHCh O.OM, 19.8 mi... 19.7? mmol) was added drop wise at ~78 under a nitrogen, atmosphere, The obtained mixture was stirred at -78 °€ lor 30 Pirn, and then at room temperature overnight. The reaction was quenched with wafer* basifled with saturated aqueous NaHCCh (pH-8) a.nd extracted with €%€%. The combined extract was dried with MgSO.;. filtered and e\ operated. The title compound was obtained In amount, of 0.80 g (9172) as orange Si.nid and was used in ib·.· near step without further purification, *B NMR (400 MHz. DMSO-.4..) ύ 9 80 (broad ·», I.H). 632-6.87 (m. 2H), 6.46 0.. J ™ 8.0 Hz, i H), 534 (broad s, 2H),

Example 146?. d-AmliiiwS^iShT'-dihydim-d’H-p’^'-elpyt'fUtulfttenopJ-di-pvrspliiae- 2(111)-0150

Λ solution of N4 3-eyano--8,7-dihydro-4 H -vhi one[2,3-c jp wan-2-ylcarbamoy)) beuxamMe (Example 146a I (500 mg, 1.53 turned) and NaO'H (2 N, 2.1 mL) in ElOM ί-Ηf mL) was stirred at 100 °C under nitrogen overnight. After cooling to .room temperature, the clear reaction solution was filtered, and the Choate w a- eaiefully neutralised widt 10% AeOHwhh \igorons stirring at 0 Ό. T’he resultant precipitate was collected bv ffluation, washed with water and then 20 % EtOH in waver to give the final product (280 mg., Kg ‘\>) as an e-IT-white solid., which was dried under vacuum overnight. M.p.: 260"%'. :H NMH (400 MHz. OMSC-ft,.} 0 2.S3 it, J 5 M fo, 2H), 3.86 (t, J - 5.6 Bz, 2H), 4,58 (% 2M)< 7,23 (brs, 2H), 11.56 (bm, IB). MS 224 (MU !

Example 146a; N-(3>cyano-5,?-dthyd{t>>4H'!tbicno[2»3-c}py.ran-2-y!cai!5amoyl) bemranride

To a solution of 2-amino· 5»?"dihydrO"4H-thicno{2,3-Cjpyran-3-carbontirile (Example 146b) (400 mg, 2.22 mmol) in 1.4-dioxanc (30 mL) was added benzoyl isocyanate {327 mg, 2.22 mmol). The reaction mixture was then stirred-at room temperature under nitrogen overnight. The precipitate was collected by filtration, washed with-1 .^dioxafte,· and'dried: in the· air to give the title compound (5?? mg. 80 %> as a light, yellow solid. lH NMR (400 MHz,: DMSO-aft) 6 2.62 it,J - 5.2 Hz, 2H), 3.87 it, J - 5.2 Hz. 2H), 4.62 (s. 2H), 7.56 -7.53 (m, 2Efft 7.67-7.65 (m. !H), 8.04-8.0) (m, 2H>, U.60(brs, IH), 12,13 (bos. IHt.

Example 146b: 2-amino-g,7~dlh:vdro~4H-thteaoj,2.3-clDvran'-3'-earb&amp;nitrlIc

To a mixture of dihydro--2H--pyraP--4(3Hftone (820 mg, 8J9 msiml),:BiaSoao«itriS:e (541 mg, 8.T9 mmol:) and sulfur (263: nig, 8.19 mmol) in Ethanol (50.mL) was added triethyiamine (1.14.mL, 839 mmol), The reaction snixiure was then refluxed under nitrogen overnight. After cooling to room temperate©* the precipitate was collected by filtration,. washed with ethanol, and dried in the air to give the title competed (1.1.5 g, 78 %} as a light brown solid, ft-f NMR (400 MHz, DMSOaft) 0 2 43-2,40 (m, 211), 3,80 (ft J - 5.6 Hz, 2H), 4.40 (ft 3- 2,0 Hz, 711}, 7,09 (s, 2H), MS 18! (MU ).

Example 147: (E)~4~nmm0~$-0~m eih oxyprop-J -coy tjQnmazolin~2( 1. Ttftone

Prepared as in Example 146 from (iri-2-amino~6~(3-n^ethoxyprop·'!-enyJ}benzomtrile (Example 97a} as a white solid. !H NMR MOO MHz.. DMSOi.6) &amp; 3.28 h, 3H). 4.02 (dd,./ = 6 0, 1.2 Hz, 2H). 6.13 (dr.,/- lo.O. 3.8 Hz., \H). 7 06 fd../ === 8.0 Hz, 1H). 7 .:3 id.,/ = 8 0 Hz. I H,K 7.52 (¢., J = 8,0 Hz IH). 7.S0 id../ = 16 0 Hz. 1 Hi, : 1.07 is. ! Vi s, Π, 13 (s, 1 Hi, LV; NMR iDMSCMN) 0 58.0, ?2.v. 111,4, i 13.5, 121 6\ 1.:9.0. 131.2. 134.7, 140.2. 14.:.7. 1:64,1.

Example 148;: 4~AmlnO"5i6-(2h37dihydro~l^"€yclopeni8[b])~ihieoeI2,3~d]pvrimidin~2(lH}" one»2,2-dioxi<k

Prepared as in Example 4 from N^3:my4»0>5*6-dihydf©*4ii!·· eyeippe#ta{j5lthtephp»-2-yic®bmapyl)hep.zami<le i Exapiple 148a). Ή NME (400 MHz, DMSO-di$2.M (m, 2H), 2,76 % 2Η),2Μ (t,2H), 7.51 (brm, 21%. ί! .50 (br% 1H},MS 2.08 (MH :).

Example 148a : M-.(3*eyaivo»5,6Mihydre-4Ef•cyciopenUtjh]ihiophes'i*2« yk-arbamoyi)benzamide

Prepared a* in Example 4afrom,2“amiaos5,Mikydro^4H«' CYclopema[b]th(ophene~3->ca:bo:4frile / Example 148b). Ή NME (400 MHz, DMSO-%} 6 2.34 im. 2H i, 2.72 (¢., 2H). 2.82 U 2H), 7.M α, 2H), ‘ 05 <t, S H), 8.01 id, 2H).. 11.56 Μ, 1H3. ! 2.06 is, III)

Example 148b : 2-am.m0~S,bMibydm-'4H~eyelopenta[b]tliiephen;;”5“earboa itrile

Prepared as if- Example 5b from cyeiopentafione. Ή .NMR (400 MHz. DMSOmN) S 2,23 (m, 2H). .2.53 im. 2H), 2.63 pn, 2H). 7.00 (>;, 2H):H NME (400 MHz. DMSOM,,} d 2.23 i,m, 2H). 2.53 (ί. 2H), 2.62 (i, 2H), 7.00 (a, 2H).

Example 149: 4-itrninoo.M I b2\.V.4Meirahyd/obcti/o(b) Mhicrtoj 2.3-d)pyriουαΐη-2{ ί H)-one- 2,2-dioxide

Prepared a* in Example 4 from N~(3 wyarmM,5..VMen'ahydmbenzo[bJtkiopbeo-2-y!carbamey!)benzamide {Example 149a}. lH N.MR (400 MHz, UMSCK/?)# 1.73 (m. 4H). 2 5? (ί.. 2H), 2.72 {t. 2B). MS 222 (MM )

Example 149a: N-{3-cyam:M_5,6.?4.ctrahYdroben/ofb}tinopivn-3- ylearhamoyObenzamide

Prepared as la Example 4a from: 2~aarinoM33^i?“Wrahydrobea2o[b}thiopheae”3~ earbonitriie (Example 5b). *H NME (400 MHz, BMSO-xi:;) ΰ 1,75 (m, 4H), 2.51 (t* 2M), 2,60 (t, 2H), 7.54 (t, 2I-I), 7.66 (t. ί H), 8.02 (d, 2H), 11.57 (s. Hi), 12.06 (s. Ill),

Example 150:4“Armm>5*(2~methylpro8>-l-eu>4)ifakumdin-2{ I //(-one

A suspension of A^2-cyano~3~(2~meiindprop~l.~enyU phenyl carbamoyl) benzamide (Example ISOa) (0,133 g, 0.416 mmol) In EtOli (3 m!..) wax treated with a, solatlop of NaOH {2 M. 0.416 ml.,, 0.832 mmol.) at room temperature. The obtained mixture was boated at 90*C for 30 rnm, cooled to room temperature and neutralized with 10% AcOff. The precipitated product was collected by filtration to give 09,0 mg (773«) ef 4-a m ino-5-(2-methy Iprop-I-enyl)qid.naz:olio~2( I /7)-one as a white solid. ' H NMR (400 MHz. DMSO-ii;;} S 1.60 (d, J'~ i ,2 11/,311), 1.93 (d. ,7-1.2 Hz, 311), 6.58 (4,1H), 6.67 (broad s. Hi), 6.73 (m, 1H), 7,05 (m, ili), 7,48 (mS:!B), 7.93 (broad s. Hi),.10.72 (broad xs IB). MS: 216 (MB1).

Example 150a: A;-{2~eyattp-3~(-2~r»ethylprop« 1 -eny !)pheh>deafb$moy| ibeM/amufe

Benzoyl isocyan.Uo (85 I mg.: 0.60 mmol) was added to-a solution of2-affimo~6~ (2-m:eihyipropB-euyl.}hen/«nitr)Ie (Example 129b) (75,2 mg, 0.44 mmol) in asdtydrons 1,4- dio\anc under nitrogen. and \su;> birred ai room temperature lor 12 h. The mixture was concentrated under vacuum, and put hied by chromatography on silica gel eluting with solvent gradient 0% to 1 5% McOH in CIECE. to give 125,0 mg ί865-ot of ;V-(2-cyano-3~i2-rnethylprop-1 -ens 1 sphersylearbarnoyllbenzamide as* a white solid, !B NM R.{400MHz, DMSO-e/s) 4 .1.80 (d, J - 1.2 Hz, 3B), 1.95 (4 J 1.2 Hz, 311), 0.40 (s. ! 1:1), 7.19 (m, 111).7.55 (m, 211). 7,67 (50,21¾ 8.03 (m. 211), S. 13 (oi. 111). 11.33 is. 111), 11.48 (s, 111).

Example 151:4*Ajmi*Ms-5-vi «> fcj auia^oIia*2<i//)«oae

Prepared as iu Example 150 from N-t2-cyano~3-viny lphcny learbamoyl)bcnzamidc (Example .151 a) in amount of 20.0 mg ¢3330), as a while solid. JH NMR(400 MHz, DMSO«f/o) 4 5.53 (m, 1§3), 5.64 (m5.IB), 6.50 (broad s. 113), 6.98.(m, !B). I'M (m, 1H), 7.37 (m, 11:1), 7 50 (m, 1B), 8.0 (broad s, IM) J0.75 (broad s, 11f). MS 188 (MH'}.

Example 151a: Nd2-cyanos)Mnyipheriy!enrbmnoy0beuzamido

Prepared as in Example 150a from 2-amino«6-Yinylbenzonhrde (Example 133b) in amount of 99,3 mg (83%), as a white solid.

Example 152: d-Arndm-S-Cprop-l-e«-2-yl)qahrazobn-2(Ii7>one

Prepared as in Example 150 from A'~(2diyano'3-(prop~l''en~2~ yl.)]>heiryloarbamoyl)benzarnide {'Example 152a) in amount of 30.0.mg (47%), as a white solid, lH NMR (400 MHz, DMSO-nb) 6 2.07 (s, 3H), 5,14 (πρ 1..H), 5.43 (ni, IH), 6.67 (broad s. IH), 6.80 (m, I i l>. 7 1! (nr. IB), 7.50 (re, IH), 7,.99 (broad s, .1.11), 10.81. (broad s. IH). MS 202 (MH).

Exam pie 152a: Ndd-Cyano-a-Cprup--1 ~e«-2--yl)pbenylca.rbamoyi)benzami de

Prepared as in Example I50a from 2 -aminotM prop-1 -cn-2-vi}ben/.oidla]e (Example 138bl in amount of 96.0 mg (72¾)}. as a while solid. ;H N.Y1R (400 MHz, DMSOM,) 7 2.) 5 (s, 3H i 5.23 (m, I H), 5,43 (aa, M), 7.25 (m, IH), 7.55 (*, 2HK 7.68 (m, 2H)S. 8,04 (m, 2H K 8. i 9 (m. I Η), 1.1.35 is, .1Π). 11.54 (s, 1H),

Example 153: 4-Ar.(0no-5-e>elo|>eel:e.(?> iqiss«a/.0i?n~2(l//}“O(ie

Prepared as in Example 150 from N-iCyaoc-3-oyelepemenyiphenylcarbamoyl)bersxamkle (Example 153a) in amount of 60.0 mg (75%), as a white, solid. ; H NMR {400 MHz. DMSM) 5 2.01 {m. 7H}„ 2 55 (m, 7H). 3.01 i'm. 2K}, 5.** I (s, )1-1), 6.49 (broad s. IH), 6.81 <m, 1ΡΠ. 7,08 {m, ihi).. 7 48 ?np )H), 7,88 (broads, 11:)), 16,76 (s, IH), MS 228 (MIf).

Example 153a: iN^CCvano-J-'oydopontgnylphgnvlcarbamoyDbengamido prepared ax in Example 150a from 2-amioo~6~(eyelopeivien.” 1 -yI)benzonitriie (Example 05b) in amount of 1 Γ7.0 mg (9382), as a while solid. df KM'E (400 MHz, OMSC-cb;} S 1.99 (m, 211), 2,5? (m, 2H), 2,78 (m, 2H), 6.45 (m, IH), 7,26 (m, .1¾ 7,5? (ms2H), 7.68 (ms 211),8.06 (rn,am 8,15 (nr, I i I), sUdibrs, HI},. 11.51 (x, IH).

Example 154: (1()-4-Anmm-5~(pr0pM~esiyI)ipma:rf

Prepared ax in .Example 150 from (''VPldlnblvano-S-Cprop-l-enyllplionylearbanioydlbenzamide (Example 154a) in aenomd of 13,0 mg (8%), as a 'white solid, !ll NMR (400 MHz, DMSO-d*) 0 1.91 im,3H}, 6.09(m, 1¾ 6.40 (broad s, 1 H;., 491 (m. 21!I. 7,03 (m, HI), 7.45 (ms iH), 7,9 (broad s,: ill), 10.70Is, IH). MS 202 (ΜΕΓ).

Example ? 34a: ifl-NMS-CvaGO-S^ro-'p-l-enyDpfeeoxdeaifeaimoylllxinzamids·

Prepared as in Example 150a from {£)-2-anuno-6-{prop-1 -enybbenzooitri le (Example 130bi in amount of 0.22 g (88%). ess a white solid. !H NMR {400 MHz, DMSO-<&amp;) *5 1 1.50 (broad s, I H), I j .34 abroad s, I Hi. 8. 13 (d j ==== 8.4 Η?., 1H i, 8.02-8.05 (up 2H). 7.04-/.70 (op 2H), 7.52-7.59 (ftp 21¾ 7.20 (d, J ==== 8.0 id:·-., IB), 5.50-5.18 (ftp. 211), 3.55-3,59 Βτρ 3M). Example 155; 4o?miru>-5-e;vcloprnpYk|5iis5azoiin.....2(U:i s-oae

A .'solution of l-amino-b-cyelopropylbenzonitrile (Example 92a) (1.0 eq„ J 0 mmol, 158 rng) aadbenzoyl isocya-oate (90% pure, 1.0 eq,, 1.0 mmol, LI 71 g/nit, l40.pL)-w* dioxane (15 mL) was stirred at room temperature. After 2 'hours,· the volatiles were removed .on a rotary evaporator, fire resulting crude N-benzoy! urea was suspended in L'tOH Π0 .ml., .:00 proof) and :9:4311 (2.5 0:.5.. 3.5 mmoi, 1N. 2.50 oft..; was added. The reaction was heated to 75 ' C with stirring for 7 hours. The solvent wore.'evapbrateci and: the residue diluted with water (10 mL). The reaction mixture was acidified with 10% citric acid/waiet solution and carefully titrated to pH 7-8 with saturated NaBCO? solution. TBe preeipitated p-roduOt was collected by vacuum filtration, washing with wafer,. The residue was..suspended in BOH (3 mL, 200 proof) and BCi was added (12.1N, 3 mL), The mMure was heated to 90 0 C for 1 hour. The reaction mixture was cooled to room, temperature and diluwd wuh water (20 mL), filtered (0.45 pm PTFE frit), and the filtrate concentrated on. a rotary evaporator. The residue was further purified by preparative TLC (10001.1m, 1CV90 McOB/DCM) and trituration with methanol at room temperature. The reaction gives 25 mg (1:2.4%) of the title compound as an oft-whhe solid. SII .'NMR (400MHz, DMSCK%) 33).802 (m, 2H), 1.086 (m, 2M), 2.345 (m, =H). 6.922 (d, ,/===== 8 I:fe, 111)27.000 (d, J - 8 Hz, 1 H>, 7,253 (hr. s,: I IT), 7397 (t, J = 8 fix, IB), 8:02:2 (hr, s, 1H), 10,844 ($,111). MS 202 1MH ).

Example 156: N5~iuethyl~i B-henzojcj 11,2Aft tidedbmine-4,5~dmmim~2,2-dIoxMe

Prepared ax in Example 90 from 2-annno-0-imethylandoo)benzonitrdc xiddimide (Example I56a> to give Nmethyl·· I H-benzo[c)[ 1 .2,61 ?hia<iiazme-4-,5-diamine-2.d-dioxide (27.7 mg, 45 %) *H NMR (400MHz.. DM SOM.·- ; 4 .7..67 id, I *= .7 Hz. 3H j, 5 «1 son, NH). 6.21-6.1 7 (m, 2H), 7.17 0. } = 8 Hz. s Hi. 7.51 {bs, 2H), 10.6 ibs. NH) MS 227 iMH }

Example 156a: 2-umino-64metbyianuoo}bcnzonitrik· sulfamide

Prepared a-; in Example 90a from 2 · ,an i η o - 0 -·{ ι tK d vy- i a οι i ι a‘ > s i. η zoo i s ri !e (Example 156b) to give 2-ammo--6~(mefhyiamino}benxoniirUe sulfamkie (65 mg, 30 *0,1. ;H NMR (400MHzf CDCU) ·? 2,88 (d.J = 5.2 Hz.. 3H). 4.23 (bx. NH). 4.66 ibs, NH).4.87 (bs, 2H)S €<44 id. J = 8 Hz. S H). 6.90 (d. J = 8 Hz. !H|. 7.39 (·. j = 8 Hz. 1H ;. MS 227 (MH )

Example 156b: 2-amino-6-(oieihyUmino)bcnzomirilc

Prepared ax in Example 90b from 2-methyiamino-6miirobcnzooiir i !e (example 1.56b) t.o give 2-amino4S>iroedrytenuno)txmzonirri1e (0.30 g. 85%) ax a brown oil which wax used in the next Hep without any further purification. NMR {400MHz, CDCU) 6 3..87 (d, 1 ~ 5.2 Hz. 3H). 4,25 (bs, 2H), 4.47 (bs, NH), 5.96 id, J = 8.8 Hz, 1H), 6.02 (d, i - 8.4 Hz, 1 H)s 7.13 (t I =S Hz, III). Ms 148 (MR ).

Example 156c; O-metbxdaniino-O-nitrobenzoniMje

Prepared as in Example 90c from 2,6Mimtrobenzomtrile and methylatmne to give 2~meftylamino~6~oitTofeenzonitTile (0,42 g, 79%), 41 NMR (400MBz, DMSO-i/rt) S 2.85 (d, J ::: 5.2 Hz, 311), 6.75 id, S --- 4.8 Hz, NH), 7.16 (d, J - 8.4 Hz, 111), 7.45 (d, J - 7.6 Hz, IH). 7.64 it i 8.4 Hz, ill).

Example 157: 4-a0EiKv5"(putfhylamsBo)riwiMazolia~2(III)-iMse

Λ solution of N-ί 2-cyarm-J^uethylamtnoipheny Scat barneyI Jbenzamidc (Example I 5 7 a) (0.05 g, 0. I 7 mmol) and NaOH (2N, 0. 1 7 mL) in IrJOM (6 mL) was stirred at 90 "C under nitrogen for half an hour. The reaction mixture was cooled down to room temperature, and concentrated under vacuum. 1I:0 11 ml > was added and the reaction: mixture was neutralized. to pH ~-4 u irh 10"AcOH, I lie tcsuUanr precipitation was filtered and dried under vacuum. The crude product was purified b\ picparauvc thin layer chromatography using a DCM/MeOH (9; I} solution a.' eluant, to giv e 4-umm«-MMCthylumino)quinuz»iin-2{iH)--0ne (18.2 mg. 56 %}. Ή NMR {400MHz, DMV)-,6.10 2.7ο (v 3H o 6.10 td..1 - 7.6 Hz, I Hx 6.12 (d. j - S Hz, IK), 7.0 5 Hz. It'h, 7.25 ths.NHi. Aon ib-y Nil) 10.] 3 (hs, 2H>. MS 191 IME;).

Example 137a: N -12 ey an,.· -3 auk-thy hmm<fipheris lea^ banmvl)henzamiue

To a solution of 2-aminn-6-(melh>lannno)bcnzonii r ue {example I56h> (0.14 g, 0.97 mmol) m 1,4-dmxane (3mL) was added benzoyl isocyanate (0.17 g, 1.17 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight. The obtained precipitate was filtered and dried under vacuum to give N-(2-cyano-3-(metlwlamino)phenyiearbamoyl)benzamide (57 mg, 207¾). !H NMR (400MHz* DMSO-<4) S 2.75 (d, 1 = 4.4 Hz, 3H)S 6.26 (d, I - 4.8. Hz, MB), 6.43 (d, I - 9.6 Hz, IB), 7.40-7,43 (m, 2H), 7.51-7.55 (m, 21¾ 7.63-7.65 (m. LH), 8,1)1 (ύ, i - 8.4 Hz, 2Η), 11,23 (s. NH), 11.36Cm NH). MS 295 (Mlf),

Example I§8; Ns-prupyi- IB»Wazo|cj {1,2,6jshiadmziee^J^iamlnehS^-cImxicle

Prepared as in Example 90 from 2”a:m!!m-6-{pfop>4aniino)benzonitriie sulfamide (Example 158a) to give NNpmpyl-lH~benzq(e][l,2.,6jth:Mi^zi'n:^4,S-vcliaminc-2,2«<lioxide (183 mg, 74 %). lH NMR,(400MHz, DMSCN/*} 60.91 (t, 1 = 7,2 Hz,31¾ 1,57-1 .63 (m, 2H). 2.48 (q, J - 7.2, 2H); 5.85-5.88 (m, NH), 6.27 (d, i - 8 Hz, 1H), 6.37 (d, J - 8.4 Hz, 1H), 7 24 ({, j - 8 Hz. IH), 7.87 (bs. 2H), 10,65 (bs. NH). MS 255 (MIT).

Example 158a: 2-amino-4-'Cpropylamiuo^benztmftrUe sulfamide

Prepared, as in Example 90a from S-amisio-ii'CpropylaiBlnctlbenzonitrile {Example. 158b>io ;give.2-anun<.(-6-(|x,opydamino)beazonitrilexuIfem!de(254 mg*.43 %), !H NMR (400MHz, CDCI.0 <>’ 0.87 (i, j =· 72 Hz, 3H), 1.48- i .57 « m. 2Hs, 3.10 (q, J ==== 6, j === 5.6.214), 5.86-5.89 (m., NHi. 6.49 (d, J ==== 8.4 H.% 1H), 6.69 (d, J ==== 7.6 Hz, 1H), 7.13 {.«, 2H>. 7.29 {t, j === 8 11/, 10). 9.06 (s, NH). MS 255 (MU').

Example· 156bl 2-amlao~6-CpK)nvlaminolbeazo?iiirile iheparcd os hi Example 90=> from 2 -p r o p> J a πί j rjo-i>- η j ΐ = o b cs n s U sic («ample 158c} to give 2~am.irK>6*(pfopyl.ami.uo)be»zonIttiie(0:,4I g, 91%) as .a· brown oil which was used in the next step widieutmy'^itlter pufiScatio». MS 175 (MET).

Example 15Sc: 2-p? <mybmisss-0-nitrobenzonimlc 15cnoroo ot.s m Example 90c fv.-ni em-dmimrnenzooipiie and pmpybmmo 2-propyianiino-6--nilroberiZoni1riic =,0.53 g, 8i=->%>, Ή NMR (400MHz. DMSO··/·.· .·> 0.,\,x (t, j = 7.2 Hz, 3H), 1.51 1.57 nr, 2H), 3.22 %. J =-= 5.6. P - 6.4, 2H). 6.60-6. b3 (m. NH), 7.22 (d. .1 - 8.8 Hz. IH), 7.40 (d. J ” 7,<s Hz. ! H), 7.58 % I = 8.4 Hz, UN.

Example 159: 5-(pirroHdio-l-yll-l 1-M>enzo{ci|l,2,6ithjadiazitt-4-a«noe-2,2-i.1ioxide

Prepared ax h i Example 90 from 2-a.minO“6-(pyrrohdm-l-yi}benzooltrile sulHrmde (example 159a) to give 5-(pyrr0hdin-l-yi)-lH4>e?.izo[e](lv2,6]tbiadkj2hi-9-aml5'.ie-2,2-diojd.de (14.2 mg, 11 %}, lH NMR (400 MHz, DMSQ-ds) 0 1.88-1,86 (m, 4H), 3.16-3,10 (#, hr, 4H)2 6.45 (d, / === 7,6 Hz, 114), 6,64 (d,/=== 8.4 Hz, Hi), 7,30 (6/=== 8.0 Hz, 1H), 7,83 (s, IH, 19142), 8.14 (s, IH, NB2), 10.79 (x, 1NH), MS 267 (Mil ).

Example 159a: 2-aro:00-6 (pyrrol«Jin-1 -vi)benzonitrilc xu:fam:de

Prepared ax in Example 90a. from 2-amino-6-{ pyrrol id in-1 -yl )hcRZOfiiltrile (Example 159b) to give 2“ammp-6-(pyifpfi#v 1 -yllheazoaittile sulfsmide (0,34 g, 100%). *H 18MR (400 MHz, DMSO-/N <> 1.94-1.91 (m, 4¾ 3,48-3.45 <m, 4H), 6,55 (d,/- 7.6 Hz, I B), 6.81 (d,./- 8.0 HZ, 1B), 7.15 (s, 2B, NH·.?)* 732 (t, J- 8.0 Hz, 1H). 8.9 (s,.iNH), MS 267 (MH i.

Example 159b; 2-animp”{>"(pyrre:IIdin-l-yl)be5®omtrile

Prepared as in Example 90b from 2-niiro-6-{pyrrol idin-1 -ySSbenzormnie (example i 59c) ίο give 2»arninO'b'(pytTolidin>I -yiJbenzomtriSe (0.48 g, 85 %) as a brown oil which was used in the next step without any further purification. Ή NMR (400 MHz, DMSO'-f/'j d 1.911.88 un. 41-1). 8,43-3.40 (m, 4Hr 8.61 (s. 211, Nib). 5.86 (d, J === 8.8 Hz, Ills, 6.06 (4,./=== 8.0 Hz. IH)* 6.99 it. J === 8.0 Hz, IH). MS 188 (ΜH ).

Example 159c: 2-nitro· 6·ipyrrolidin-1·> 1 }benzomtrilc

Prepared as in Example 90c from 2;,6“di»ittobe»zoiiiinle and pyrrolidin ίο give 2-oiijij-O-ipy rrolklin- I -yilbenzomime which was used in the next step'withoutahy fortlier purification, 5K NMR (400 MHz, DMSO-7>} P i .97- i .94 (in, 414), 3,60-3.57 On. 411), 7,22 (d, J - 8.0Hz, IS 11 7.41 (d, J 6.8 Hz, IH), 7.58 (t, ,/=-= 8.0 Hz, IH), MS 218 (ΜII:),

Example i60: 4-ikiMftOrS”fe0b»t0^/?3f-be»2P[<| 11/dH^i&amp;d*az»i<:-2,2~diox5de

Prepared in the same manner as example ! 1! 2-sriiFanioy!anii:ne-6-Isobutexybenzoniidle (example 160a) to provide 4-mnmo-$-l$obutexy-i/:l~ benzp[e]i1,2,6JthiMiazine-2,2~dioxide (65 nig,· 50%), 'El NMR (400 MHz, DMSO--4;) 4 1.01 (d, ,/ === 6.7 Hz, bH), 2.06 (sepb,/ === 6.6 Hz, IH),3,90 (4/==== 6.2 Hz, 2Hs, 6,96 (4, ,/ ==== 8.3 Hz, 11 1). 7.15 (d, J. ==== 8.0 Hz, 1 Hi, 7.27 (fits, 2H), 7,56 (t,,/ === 8,7 Hz, = Hi, R46 (s, iH). MS 270 1:: x a mole 160a: 2-$uifctrnoy!aroino-6-tsobutoxyhc.nzonitnle

Prepared in a similar manner a? example Ilia from 2-amino-6-feobute^ybertzonifrite: (sample 160b) to provide: d-sul&amp;moylaniirso-ft-isobutoxybenzonitrile (BO mg, 50%). MS 191 (MH VNHySOzl

Example 160b: 2-Ainmo-6-Isobal6xvbenzo:nibile

Prepared in a similar maimer as example 111 b from d-isofeuioxy-O"' nitrofieszeniinSe (example (60c) to provide 2-amiHoMfisobutaxybcnxonitrile. MS 191 (MB'). Example 160c: O-lxoPittoxy-O-nitrebeazgnlmle

Prepared in a similar manner as example 160c frornS^-dioitrobenzonltnle and iso.bufanol to provide 2 irobuioxy/bnitrobenzonitrile, lH NMR (400 MHz, DMSOroM t% 1.05 Cd, ./ - 6.4 Hz. 6Η>, 2.11 {scpL J - 6.6 Hz, 1Hi 4.0? (d. J ~ 6 * Hz, 2H>, uld../ - 8.0,1.9 Hz. mi 7.91 O.j - 8.2 Hz. \ Hl /.94 ukl,./- 8.2, i .9 H III).

Example 161:: 4-Andsso-5--see-baioxy- ///--0enzojd {1,2,6|ihiadiaxi oe- 2,2-¢1 k«ifie

Prepared ba similar raamier as example 111 from 2-sujnm-oylamirm~6^a:> btfroxybeoxomfrile (example 161a) to pmykie 4«aml»o«3-W“b«toxy.-///-be«zo|i:"][1,2,6] ihiad iazbe-2,2-diexkle (57 mg, 44%). 14 NMR (400 MHz, DMSO-4) 8 0,95 % J 7.9 Hz. 3H>, 1 28 (d. J - .8.9 Hz, 301), 1.6? irm,/- 7.4 Hz, 2H), 4.57 (sext 7- 5.9 Hz, IB), 6.98 (d, 7- 8.7 Hz, IHp 7.13 (d5,/« 8/3 Hz, 1H), 7.27 (br s, 2H), 7,55 (t, J- S.3 I4z, 114), 9,41 (s. IH). MS-270 (MM ).

Example 161a: 2-Sulfamoy 1 anlim^-O-xee-butoxybenzoidtrile

Prepared in a similar manner as example la from 2-am.bo~6~.vee-· bidoxybenzonlirile (example 20b) to. provide 2~s«l:fbmoyi.mpIpo-6-aep-bptoxyberszonftrile. MS 191 {MH-NH,S()2}.

Example 1.61 b: 2~ Appno~6~,?gckmoxybeazoaltr0:e

Prepared in a similar manner as example 11 lb limn 2-s&amp;‘~bmoxy-6-mtrobeezovbirOo (example lf»lc) ιο provide 2-aourK>-6-.vet'-butoxybe«zO0it!File. MS 1,91, (Mil ».

Example· ;l6ie> 2-xee-Biiioxy-bmitrBbeazoBitrile

Prepared b 'a similar raarraer as example 161c from 2!6”dici5:robepzosiitei!.e: m'sd xee-boamol to provide l^r-batoxy-^bifmlktiSomtffte.^E NMR. (400 M14z, DMSO-cfr) 0 9.98 (t,7- 7.5 Hz, 3H), 1.33 {J .7 -5.9 Hz. Mil 1.73 {m, 214), 4,70 (so. L ./- 5.9 Hz, IH), 778 (d4 7 -0.8,2.8 Hz, ; H). 7,90 (m, 2H>,

Example 162: 4^A.«d8Kf-cyelol>»toxy-7/Mie«zo|c|fl,2i6|ilfradia'zte~2,2~iisoxide

Prepared in a similar mariner as example 111 from 2-soifariK\yksrnino-6-cyclobutoxybenzonitrilc (example I 62a> to provide 4-am ino-cveiobuιοχ v* ///- benzo[c][l ,2d>]lirisdiazine-2,2~d:io>ride (19.4 i«g, 10%) as a while solid. ! H NMR, (400 MHz,. UMSO-r/a) 3 1.65 («ι, 1 H), 1,79 (ftp 1.M), 2.19 (m, 2B), 2,43 (mS: 2H), 4M2 (m, IH), 6,52 (4 J::;: 7.9 Hz, IH), 6.58 (4../=== 8.2 Hz, 114),7.40(0/===8.1 1¾ IB)......6 U« a, IH), 8.31 (brs. IB), 10.92 ibrv). MS 26X{MH3.

Example 163a: d-SnjfnmoyHmino-b-eyciobutoxybcnzomtriie .Prepared in s similar manner as example Ilia from 2-aminc/>» cyctobatoxybenzonih lie texample 162b) to provide 2"Su!famoylamiao>C>> cyciolmtoxylxmzotdtrik· (231 mg,..100%) as a while solid. S:B NMR (400 MHz, BMSO-i/s) <4 I..6? (m, 1H), 1.82 irn, IB). 2.08 (m. 2H), 2.4? (m. 2H b 4.83 (pent, /=== 7.2 Hz. 1H), 6.79 (d,../ === 8.2 Hz, 1H), 7,!5(d,,/ = a.2 Hz, I Hi. 7.38 (br s, IH), 7,54 (t,/ === 8.2 0¾ B4), 9.46 ; hr s, 1H), MS 268 (MH )

Example 162b;. 2~Affllno%wyclebt4ox¥benzon4nk

Prewired in a similar manner as example 111b from. 2~eye!obufoxv~6~ nitrobenzonilrdo {example 162e) to provide /-amino-h-eyciohniexybeezonilrile (174 mg, 70%) as white needles, !KNMR (400 MHz, DMSD-/;) 3 1.65 (m. !H), 1 ..81 HP, !H), 2.06 (m. 2H), 2.44 (m. 214.), 4.72 (pent, /- 7.3 Hz, ! H). 6.00 (br s, 2H0 6.97 (d, /- 7.8 Hz, 1H>, 6,34 (dif,/ -n 3,0.8 Hz, 111),7.17 (0/- 8.1 Hz, 1H).MS 189{MH‘)>

Example 162c: 2~Cycibfeutoxy-6~nitroben»>nitrile

Prepared in a similar manner ax example 1 I le from .:.,6 JimVohemiominle and eyciohirtapo! ie provide 2-aroino-6-cyelobuioxybenzoniiriie (298 mg. 34%) ax a white solid. H NMR (400 MHz, DMSO/d 3 1.69 (m, I Η), 1.85 (m, ! H), 2 14 (m, 2H), 2.52 (m, 2H), 4.98 (pent,/-= 7.3 Hz, 1H0 7.55 (dd, J = 8 2, U Hz, 1)-1),7.87(1./ - 8.2 Hz, IHj, 7.92 (dd, J == 8.4, I 3 Hz. !H).

Exanspk 163: 4”.=\ndnn~S^cyel6bMioxyi|nipazolpi~2( ///{-one

Prepared in a similar mariner as example 111 from ;V"{2-eyanO”3·' cyck>b»k>xyphenyicarbainoyi)benzamide (example 163a) to provide 4~st«mo«5« 'cydobtttoxyq«i«a2:oUft-2{ ///)-one (19,4 mg, 76%) as an solid. Ή NMi (400 MHz, DMSCKdi) 3 1.68 {sxk \ Η). 1.84 im, I H;-. 2.20 (m, 2H), 3.40 <m. 2H l 4.87 (pent, J * 7.2 1¾ IH),7.52 id,./' = 8.2 Hz, IH), 6.7] (d,./ -= 8.2 Hz, IH). 7.92 0../ =- 8.2 Hz, IHk 7.48 (brs, IH), 7.88 (or s. lib. 10.65 (br s. ]Η >. MS 232 -:MH ).

Example 163a: -V-i2-rvano-3-e>ckdaifoxyphcn viearbam*»y 1 ibenzamide

To a solution of 2-amino-6·cyclobutoxybenzonitrile (example 162b) (.30 mg, 0.16 mmol) in 1,4-dioxane (2 ml) \Viis added benzoyl isocyanate (23 mg, 0.16 mmol). The reaction was stirred at-it under N.> for 19 hours. Upon completion* the reaction was diluted with EtOAc, washed with saturated NaHCO.> (2x>. water, brine, dried c'vcr MpSCy, filtered uhdconcentrated to provide ,·ν..{2··ον^ηο··3··ο>ο1·:Φ«ΐί>χνρΗοηνίο^6ΐλΐηο>1)Ικηζ3ηΊ)4η 5.38 mg, 71%). lH KMK (400 MHz, DMSO-c/ιίi 0 1.64 (m, ! Η), 1.8I (m. 3H), 2 0.8 (m, IH). 2.42 (m: 2H), 4.71 (pom, J -=== 7.1 Hz, 1H). 6.05 id.,./ = 8.2 Hz. IH), 6 33 <d,./ === 8.3 Hz. 1Hs, 7. j 5 it,./ === 8 5 Hz. IH), 7.45 pm 1H),7.56 Cm, 2H)S 7J? (m, IH), 8.05 Cm, if!]. 11,35 (s, IH)

Example 164: 4-Ami»0“5~(3~i«eth>4b»t^2'^a“2~>fl)^ut»aizo!ia”2(1 lli-oae

Prepared in a similar manner to example 146 from 1 .N-(2--eyano -3 -(3 n-ethylbat'-2r-en--2->'l}pheoylcs.diamoyi)bemiamide (example I;64ai as a white solid. JH NMR (400 MHz, CDCl.o 0 t.44 (a, 3H), t.83 (s, 3H), 1.89 (s,3H), 6.63 (ckl,,/=== 7.2,1.01¾ 1H), 6,60 tbs, 2H), 7.04 (dd, J = 7.2,3.0 Hz, IH), 7.48 (f, ,/= 7.2 Hz, I H), 10.74 (s, IH). MS 230 (ΜΗ i

Example 164¾ H42-cva:n0-3~i3~m.edtYibut-2-en--2--yf) phenyl carbamoyl) benzaroide Prepared, in a similar manner to example 146a from 2-ammo-6-(3~mcthyibiU-2-en-2-yl}henzonitnIe (Example 98a) as a while solid. *H N.MR (400 MHz, DMSCW;,} 6 1.47 (s„ 3H), I.M (S, 3H), 1.02 (s, 3H), 7.01-7¾ (m, IH), 7,51-7.56 (nr, IH), 7,62-7:69 (in, 3H)/8>01- 8.04 |m. 3H), 8 12-8.15 Cm, IH), 1132 (s, IH), 11.49 (s, HI), MS 334 (Mlf),

Example i 65: ft»i>roveil. synthesis of pyrlmidin:e~2(11rl)~oue hydrochloride

Thk example describee an improved method for preparing the MCI salt of compound 1, Specifically, the improved: method involves a. particular washing protocol and formation of the HCi salt as the final step. When compared io the general method for preparing HCI salt, this method provides significantly more pure material with improved solubility and ease of handling.

To a solution of 4~amioo-5,6-di.msiliyi:thieno{23~djpyrimidine:~2(ll:i)-one (Example ibSa) (1082 g, 5,54 moles) in water (8.1 IT) was added, an ethanolic solution of HQ (I 25 N is? 200 proof ethanol). The resulting slurry was heated to reflux tor 15 minutes to afford a clear solution. < in some eases additional 1:1 Η„<0: i .25 N HCI in ethanol must be added to obtain a clear solution). The solution was .filtered while hot and the filtrate cooled to 0 °€ while stirring. The resulting precipitate wax collected by filtration. and washed with acetone sv3 x 5 4 L) and heptane (2 x 5.4 L), The solids were placed. In drying trays and dried under vacuum overnight to give 4~amino~$,h»dimethyiddenol23”d]pyrimidine-2(l Hrione hydroehioricleos an off white powder (1176 g. 92% yield), > 9954 pnre as determined by HPLC. M.p,: > 26 ft c'€,. *H NMR (400 MHz· DM.SO-dft S 2.30 is, 6H), 8.56 (bs, IH), 9.54 ft*. 114), 12.92 (b&amp;, 2H), !3C NiVsR. (400 MHx. DMSO-d/.) 0 12.2, 13.3, 106,5, 125.5, 125.7, 146.1, 154.9, 155.3. MS 1.96.2 (MH ). Purity as deicrorincd by HPLC, 99.645'».

Example 165a: 4~amiho-5,6-dimefhyhlnesmp3“d|pyriniidIne-2(iH)~one,

Ethanol was added to a SO L three neek flask (3:0,8 L) and stirring was Initiated, Nri3wyano-4,5~diniethylihiophen-2-ylearbamoyi)benxan«de (Example 165b}' (933 g, 3,12 mol) was added followed by the addition of NaOH i 2. N, 4.5 L) The reaction mixture was heated to reSux Q77 *€) tan! stirred under nitrogen for 2.5 hours, The solution wssthen cooled to 65 °C and treated with charcoal (233 g). After stirring for 30 minutes the hot solution was filtered and the filtrate was slowly cooled to room, temperature. The filtrate was carefully neutraiteed with 4 NI4C! with vigorous stirring, then further cooled to -5 °€ to 5 °C, The resulting precipitate was .collected by filtration, washed, with water (3 x 14 1 pH Vi 1' ί I: x I § .7 L), acetone (3 x 14 L) and. water (3 x 14 L). The solids were placed in drying trays and dried. under vacuum overnight to give 4~amirkw5,6'd;melhyhmeno[2,3-d)pyrinudme~2i 1 Hs-drone (573 g. 87 il·.) as an otY-whiie soiid. M.p.: > 260 °€. Ti MMR (400 MHz, DMhO-A) 4 7,05 (he, I H), 2,25 Is, 3H), 2,16 (s, 3H). MS ; ). Purhy as determined by HPLC, 94.643,;

Example 165b: N-O<Yano-4.5-dirneiiiYithiv|0ten-2-ylcarham.oyI.)benzamide

To a solution of 2-andrm-i,5~dhHcthyldaophene-3~carbo»iuiie {168:} g. ) j .04 mol; in 1.4>dioxune (42 I.) was added benzoy Itsocvaj sate i 1624 g, 11,04 mol). The react son mixture was then stirred a? room temperature under nitrogen overnight. The resulting precipitate was collected by nitration, washed with 1.4-dioxanc (3 x 1.7 i) and heptane (3 x 1.7 L), and dried under vacuum overt sight to give N43-Oyano-4.5«dimethylthiQplre«4^ytea&amp;Mtoyl}beazamid:e'a.x a white solid (2800 g. 84.70¾ yield), jH NMR (400 MHz, DMSO-m.) ,02.10 (s, 31-1.), 2.24 (s, 31-1), 7.52-7.56 (m, 211), 7.64-7.69 (m, lid),. 8.01-8,03 (m, 2H), 1157 (brs, i H), 12.05 (bre, 1H). MS 300 (Mi i s.

Example 166: 4-42-(4-Amur0-///-bett/.ojr( \ 124>jil0:i«iiir/.ine-22-di(>xide-5-ylQxy)eihyl)plperMi»i«m chloride

txtr'6-14pty4*442-(4-’Ami.oo:w2H-beiizo|e][H2,6]fhtadiazi.oe-2d0<lio>ade-5·-yloxy )cthyi)p'iperidtBe*l·warhoxyiaie (Example 166a) (20 mg, 0,047 mmol) wax dissolved, in a. solution ofHCl in BiQH (1. ml,, 1,:25 M), The reaction was stirred at reflux under Ns; Opoa completkm, the precipitate was collected by vacuum, nitration to provide the desired product (17 mg, 100%) as a white solid. NME (400MHz, DM:$0-<4} <>' § .38 (m, 2H), 1.73 (m. 111). 1.81 (m, 2H), 1.87 (m, 211). 2.84 im, 2B), 3,24 (m, 20), 4,21 (t, J * 6.4 Hz, 2H>. 6.64 (d. ./-8.1 Hz, IB), 6.78 Id,./-83 Hz, Hi), 7,47 (U- 8.3 Hz, IH), 7.81 (br a, 1H), 8,35 (hr s, IB), 8,59 (m, 1 Hi 8 85 (m, 1 H), 10.99 (br s, IH). MS 325 (MH' 1.

Example 166a: re/7*Bpiyl.4-(2^(4«8mthb~W^ri20|dJ[144jthiadi4zme^2«2“dtp.xi4^5“ yi.om>,)oihyl)piperidiae-1 'Cu.rbpx.ykt8

Prepared as in Example I1 i from /e?r/-bu*yj 4-(2-(2-ovano-3-(suihimoy};ottmomhcr!GXY}ethyl}pipehdt?tc-Ucarboxykae {Example !66% in 15% vicld css a white solid. *HNMR (400 MHz, 08)50-/0 ό 1.07 (qd,../ === i 2.5. 4.6 Hz. 2H), =.40 (s. 91 h. l.60 (m, :1 Η), 1 /70 C®, :21:1), 1,79 (q, 7 === 6.7 Hz, 211), 2 70 (up 2M), 3.93 (m, 20), 4,21 (t, 7 === 6,7 Hz. 2H), 6.62 id, ,/= 8.1 Hz, 1H), 6.78 (d, 7==== 83 Hz, IB), 7.46 (t,,/ = == 83 Hz, IB), 7.82 (br s, 1H), 8.24 (br s, I H). 10,96 tbr s, i H p

Example 166b: Mt~Biityl%42~ (2”Cyano3"(suIfam»y laoii nolphenexy) ethyl) piperidine-1 -ear boxy late

Prepared as in Example 11 la from /wt-bitty! 4“{2*(3"ami:ao“2· cyanophenoxy>ethyl.)pipendjt»c*-l-earboxylate (Example 166c) in72% yield as a clear syrup. NMR (400 MHz, DMSO--/·-} d 1,08 (m. 2H), 1.40 (s. 9H), 1.71 (np 5Hp 2.70 (m, 2H}, 3.93 (m, 2H ·, 4.17 (t, J ==== 6,3 Hz, 2H), 6,98 (4 7 x.ft Hz, IH). 7.16 (d, J 8.3 Hz, i H), 7,28 (br s, 2H), 7 57 ({.,J = 8.3 Hz. I Hi, 9.45 (br a. IH).

Example 166c: fert-Butyl 4-(2-(3-amino^2-cyanopHen;oxy)eihyilpiperidi»e"l-e«rhoxyIale,' Prepared ax in Example .1 l i b from ten-butyl -1-(2-( 2-eyano-3* ni{TO|)henoxyietbyi)|>iperidine-l -earboxykte (Example 166d) in 3653 ax a white foam, 14 NMR (40() MHz, CDCI0 (V 1.06 irw, 2H), 1.40 (s, 9H), 1.68 (m, 5H), 2,70 sm. 2H), 3.93 (m, 2Hp 4,05 (i, 7 = 6.0 Hz, 2H), 5.98 (br s, 2H), 6.23 (d, 7 - 8,4 Hz, EH), 634 (d, / = 8.4 Hz. 1 HI. 7,18 (t, 7 = 8 2 Hz. :H). Ελample 166d; mn-Bntvl-44 242-eyane~3~Bltronheaoxv)ethyl)niperidine*i*carboxylate: Tip a suspension of 7er?~^p^1~4H(2*hydrc)xyethyl)piperidino-! -carboxyl*,te {769 μΐ,, 330 atmel) mi.NaH (118 mg, 330 mmol,:60% dispersion in. mineral oil) ir, dry DMF (5: mL) at 0 UC„ was added a solution of 2,6-d initfobenzonitr* 1c (6.19 mg, 3.18 mmol) in dry DMF (4 mL). The reaction was stirred under N;>„ warming to it. Upon completion, the reaction was quenched with HbO (50 mL), «mi the precipitate was collected by vacuum filtration to provide 4rrp»butyl-3-(2-(2-cy8.sKs-3-nitropbe'iKxxy9ethyl)piperidioe-"l -oarboxy1a.te (955 mg, 80581 as a tan solid ?H NMR (400 MHz, UDCU) 4 1.09 (ι% 2B), 1.40 (s, 9H), 1.73 (m, 5H), 2.70 (m, 2Hf 3,94 (m; 2((),4.32 0,7 === 6.8 Hz,214)(7/75 (m, IB),7.92(np 2H).

Example 16714-t2-{9-Ainiao*2“Cixti-l,2~(liliydroi|iri!nw:olsn“5“yloxy) ethyl) ptpemhtmsm chloride

Prepared as in Example 166 from /<=rM>uiyi -4-¾ 2~<-aittln0-2«0XO-! ,2-dihydrofjninazoHn-5-yloxyjethyI}pipcridino* i -carboxy late (Example I6?a) in 92% yield as a white solid, SB. NMR (400 MHz, DMSOwN) 6 1,36 (m5:2M), 1.70 (m, M% 1,83 (¢1, /=- 0.5 Hz, 2H), i .88 im, 2Hh 2.84 (m, 2H), 3.20 <m« 2H6 4.30 (t. /==== 0.4 Hz, 2H). 6.86 id. / === 8.3 Hz,. !B). 6.99 ¢¢1, /==== 8.3 Hz, IH), 7.76 it./=== 8.8 Hz. Hi). 8.50 ibrs, IH), 8.74 (brs, IH). 8.98 (hr s, IH), 9.46 (br s, Hi). 11.99 (hr s, IH). MS 289 (MM ).

Example 107a; m·?· Butyl 4·{2··{4-amino-2-oxo·· 1,2-dihydroquinaznl in ·5-yloxy ieihy Hplpendirie·· I -carboxylate

Prepared as in Example 1 II from tertJmtyl 4H2^3-(3-benz©y!«reido>2-eyaaophenoxy)ethyI)pipcridme· I -carboxylate (Example. 167b) in 31% yield Ή NMR (400 MHz, DMSO-<4) 3 1.08 (qd, /==== 12,8,4.6 Hz. 2H), 1.40 (s, 9H), \ .60 im, IH), .1.70 (m, 2H), '1.79'(q, /=== 6,4 Hz, 2Hy 2.69 (try 2B), 3.93 tm, 21%, 4.23 {¢, / === 6.9 Hz, 2H), 0.73 (m, 2H), 7.47 (U J === 8,2 Hz, 1H), 7,57 (bra, 1H), 7,93 (br s, .IH), 1.0,71%br x, IH),

Example i67b: /rt-Butyl 4-C2-(3“(3-benz©yIuieido)-2-cyan6pbcnoxy)ethyl) piperidine-1-car boxy tafe

Prepared as In Example 140a from l/t-bidyl 4-(2-(3-amlao=-2-cyanophencmy)etbyl)piperidine-I-eaxbD>;:yIate (Example 167e.i In 100% yield as awhlte solid, Ή NMR (400 MHz, DMSO-/) 9 ! .09 (m, 2H):, 1.40 (s, 9H), 1.60 (m.,: IH), 1.71 (m, 5H), 2771 (m, 2H), 3.94 (m, 2H), 4,21 (t,/- 6.5 Hz, 2H), 7.01 (//- 8.5 Hz, !H), 7.56 (t,/- 7.4 Hz, 2(|), 7.47 (t,,/ - 8.2 biz, IH), 7.64 (t,,/- 8.5 Hz, IH), 7.68 5% J - 7.3,1,5 Hz, IH), 7,87 (d, /- 8.31 Hz. 1H }. 8.05 tm. 2H). i 1.35 (br s, IH), 11.49 (hr s, HI)..

Example 168t 4~AmiH0-S-(eyclohexyi0xyHl/6I)eaz»|e||I ,2,0)ihmdiazine-2,2”dtCixlile

Prepared as in example 111 from; SAul&amp;moylamffio-'OJrexyloxybenzomtrile (Example Ι6Χ=0 in 63% yield :k a white crystalline solid. M.p.r I >2 Id "C. :H. NMR ¢400 MHz, DMSO-cA) d 130-1.71 un. xH>, I .99 inn 2H). 4.o3 Ini. I H), 0.(4) <dd,./-=== S3. O.S Hz, I HI, o32 id, / ·· 8.: Hi. IH), 7.45 it. J 83 Η.?, IH), 733 ibr d. ./ =- 10 Hz, I Hi. S.40 (br d,./ 2.4 Hz,

IHi. 10.05 (br s, I Hi MS »o (MH

Exampk H=Sa: 2-Su]famoylamino-i>-cyd->he\Yioxybe=izon!rrill.-:

Prepared as In Example 11 la from /mmiso^myclohexyloxybonzoniirile (Example 168b) in 91¾ yield as a white solid. 'B NMR (400 MHz, DMSO-ifr) d i 37 (m, 3B), 1.51 (m, 3H), 1.70 (m. 2H), L8S (m, 2H), 4.55 (m, IH)S 6,98 (d,,/ - 8.1 Hz, lHfc 7 JO (d, /- 8.5 Hz, IH). 7.24 (br s. 2H), 7.51 (e./ - H 5 Hz. IH), 9.39 j Hy Example 168b: 2-Ar«i«o~ft~cyclohexyloxybe0Zonitrife:

Prepared as in Example 1I I b from 2»Nifro%wye!ohoxyioxybenzonltriIe ίο provide 2--amino-7>--c:yel6he,xykexybenzcnhinle (420 mg, 27%) as a green syrup, !H NMR (400 MHz, CDC1.J O 1.37 (In, 3H), 1,50 (ni, 3B), 1,71 (m, 2H}: 135 (m, 211),433 (m, 1 H), 5,94 (br s, 2HK 0.26 (d./- 8.0 Hz, IB), 0.3! (0, /- 8.1 Be, HI), 74646,/-8,1 BzJB}, MS 215 (MH ).

Example 168c·: 2-Niiro-6-cyclonesyIoxybenz-aniiriIe:

Prepared as: in Example I00d from 2-okro~6-cyciohexyloxyben2onttrile and eyetohexano! in 100% yield as a light tan solid, \H NMR (40() MHz, CDCH) S 1.45 (m, 4H), 1.60 (m, 2B), 1,74 (m, 2H), 1.90 (m, 2B), 4,76 (to, IB), 7J9(hMHX 7.89^213^

Example 169: 4Mkm«»~5/eyoIope«ioxyHI%henx«|eift,2^^

Prepared as in Example ! i I from 2-su!famoylammo-6«pcntoxybi:ivonjtrile· (Example 169a) in 38% yield as off-white needles M.p.: -'-260 %\ !H MMR (400 MHz, DMSO 4) «5 1.67 (m, 4B}, ] .85 (m, 2U), 138 (ms 211), 5.05 (m, tH), 6,61 (d,/- 7.8 1¾ 1H),6,76 (d, J - 7.8 Hz, 10). 7.46 ft,./- 7.8 Hz. 10), 7.72 (hr s, IH), 8,35 (hr s, .1.1:1), 10.06 (bra, .10),. MS 212 (MO).

Example 169a: 2-Sulfamoyl3ntino-6-cyclopmtoxybchzonMfer

Prepared as in Example Ilia from 2-mniuo-6-cydotxmioxy bcozo nitrile (Example 169b) in 100% yield as a light brown svrup. ‘H NMR ΐ4ϊ>0 MBz, DMSO-4) 6 1.61 (4, 20), 1,74 (kl 4.0). 1.93 (m. 20).4.98 im, 1Π). 6,96 (d,,/ - 9.0 ΙΟ IH), 7.14 |d,/- 8.2 Bz. IH), 7.28 (br s, 20), 7.55 (t, J - 8.2 Hz, 10), 9.43: (s, 10).

Example 169b. 2-Λ rn me 4 -eve I open toxy bcnxors i MS e.

Prepared as In Example 1116 from 2-NiiroMrevciopenioxybcnzoniirjle (Example 169c) in 84/. yield as a green svrup. Ή NMR<400 MHz, €DCh>6 1,58 (rn, 20), i ml un, 4Hs, 1 ;89 (?n. 20). 4.84 inp I H), 5.94 Mr s. 20). 6.20 <d, J - 8.0 Hz, 10), 6.31 (d, J - 8.5 0/, 10)s. 7.17(6,/- 8.5 11./, :0).

Example iS9e; l-Miteo-6-cvclc>i»enioxvbcnzo.attrUe;

Prepared m m Example 106U from. 2,6”dinitr0benzonltrile and eyclppenianol in 78% yield as a light tan solid. *14 NMR (400 MHz, CDCfr) 9 1,64 (m5 20), 1.77 Cm, 40),1.97 (np 20), 5.14 (m. 10), 7.73 (m. 10), 7,88 tm, 20).

Example 179:: 4-42-44% mi no·· 1 //-benzxdcj (1,2,61tldadlazine”2,2"dioxide“5·-·

Prepared as in Example 166 from: fort-btityl 4-(244~Mmm-U3 benzol c][S ,2,6]th.iadia2i,ncv-2,2-<li%xide-5-yloxy)metbyl):psperid:ke”l -earboxylate (Example 170s) in 8978 yield as a white solid.10 NMR (400 MOz, DMSO-%) 6 1.49 (m, 2H)> 1,90 (d, J- 13.1 Hz, 2H), 2.23 (re, 10)., 2.89 (cp J - 11 .:6 Oz, 20). 3 JO (d,/- : 2,3 Hz, 2B}, 4.09 (br% / - 6.6

Ox, 20), 6.65 (d, J - 5 2 Hz, 10), 6.82 id, J - 8.2 Ozf 1.H), 7.48 (t J ------ 8.2 Hz, IH), 7.74 (br IH ·, 8.33 (b? s, 1 0), 8 6* my 04), 8.92 (m, 10), i i .01 is, 10}. MS 272 (MO ).

Example 17(0-; 4«(2>(4«ami»o-1 H-benzolelΓ1,2.6]thiadaizine-z.z-dioxidc-5- yIozy)methyI)piperidIyje-1 "Carboxylate 'Prepared as hi Example 11 i from «V/t-biuyl 4~{{2<yaim^3-isuifamovlummcjphenoxv>meih> 1 ipiperidme-1-earboxylate {Example 170b) m 91% as·a white solid. MS 355 (MO C(CH.>}.>}.

Example 170b; /<? /-Butyl 4-((2xeyaae“3-{«»lfamoykauno)\phe»oxy)i&amp;ethyl)piperMi8e” I-earboxylaie

Prepared as in Example Il ia from ww-butyl 4-{{3-arnino-2-e\-anophenoxy)merhyi)piperidine-l"CarbDx>,late (Example 170c) in 56(4, yield as a white solid. lH NMR (400 MH?„ DMSO-4) <> lH NMR (400 MHz. DMSO-fr,} >> 1.20 (m. 7Hi. 1.41 (s, 9HE I /6 (d../ = 13.2 Hz, 2H). 1.97 (m 20}, 4.00 (m, 40). 6.96 id, 7 = 8.6 Hx: j H] 16 id../ = 8,3 Hz, 1H). 7.28 K ZH). 7.57 ((.../ = 8.3 Hz.. 10).9.47 is. 1.0).

Example Hftc: Μ7-ΒμυΙ 4-((3~anv;no-2-oyan;^>b:enoxy)nie(%I)pi:peridine"I"Carboxylate Prepared as m Example 11 lb from tmwboiyt 4-((2-eyarK}~3-mWophetmxy}methyl)pipendmed-carboxylme (Example 17Qd) in 7418, yield as a white: solid, *0 NMR (400 MHz, DMSCK4) 4 i.lkiqd.J- 12.6,3.8 Hz, 2Hy 1.41 (s,9H), ),.74(4/=- 12,6 Hz. 20), 1.93 (ny 3H).. 2. /5 (m, 2.H), 3,88 (d,./ === 6.6 Hz, 20}.. 3.99 (br d, ./ = 13,1 Hz. 20}, 6.00 (br s, 20), 6,21 (d;J = 8,2 Hz, 1H), 6.34 (d„ J ==== 8.3 Hz, 1H}, 7. i.8 ((, J = 8.2 Hz, 1H).

Example 170d: mn~Btftyl 4-((2 -cyano~3 -nitrophe nox ylmetby frpiperidi ne~ 1 -carbpxy 1 ace Prepared as in Example Π Ic from 2,6-dimtrobenzonhnle and orr-butyl 4-(hyd roxymetbyhpiperidine- l-carboxylae; ίο 730¾ as a ran solid. Ή NMR (400 MHz., MeOJD) P 1.24 (ijd, J ------ 12,S: 1.4 Hz, 3Hr, 1,4( (s, 9H), 1 78 (br d,./ === S 2 1 Hz. 2H}, 2,07 (m, 210, .1,77 (m. 3.H). 3.00 fbr d. J === 13.1 Hz.. 2Π}, 4.1 5 (4 J === 6.3 Hz.. 2H). 7.74 (dd, J === /.5, ! 5 Hr, 1H),

7.91 (m.lHK

Example 171;: 4~AmiBm5^(eyeIob5:!ylMeib®xy)~1i4-fee«z0[e||l J,6|fyad!a25tte-2/~dlex!de

Prepared as in Example 111 from 2··Άϊ1&amp;ιηυ> lammo-O” cycidbutylmcthoxybenzomtrilc (Example 171 a > in 21 % yield .as a yellow solid. ?H NMR. (400 MHz, DMSO-md d 1.88 (m. 4H), 2.OS <m, 2H>, 2J6 (sept../- 7.9 Bz, IB). 4.16 (d, J-63 Hz, 2H>, 6.62 (<ki, J ----- 8.2. 1.2 Hz, I B.I, 6.77 (dm./ - 8.6. 0.7 Hz. IB), 7.47 (t ? -- 8.2 Hz, IH), 7.76 (hrs. IH), 8.39 <hr s, IH). 10.98 (brs, IH*. MS 282 (MB').

Example 171 it: 2-3mfamoy1amino--6·· cyclobutylmethoxybeazonitrile

Prepared as in Example 11 la from 2-aniinO"0"Cycicdiut.ylmeihoxybenzopiirile (Example 17 I bp in 94% yield as a light yellow solid. Ί4 NMR (400 MHz, DMSO-4) $ 1:94 (m,. 4H), 2.12 (an 2H). 2.86 (sept,./ - 7.5 Hz, IB), 4.13 (d,/ = 6.3 Hz. 2H), 7.00 (d, J~ <14 Hz, 1H), 7J9 (d:,/ - 8.2 Hz, 1H), 731, (br % 2H), 7.60 (t,</- 8.4 Hz, 1H), 9.48 (br s, iff).

Example 17ik 2-Amino--6-eyclobalylmethoxytozonttrile

Prepared asift Example 111b from S-fritro^v-eyclobutyimedidxytejzoitimie' (Example 171c) in 41% yield as a yellow oil MS 203 (MM ' )

Example 171e: 2'-Nitro-6-eyc.lp^atyh»ethoxybenzooitrile

Prepared as in Example 166d from 2,6'Mmlbwbenzooitnle and eyciobinylmethanol in 68% as a iansolid, SH NMR (400 MHz, DMSO~iij) δ 1.93 (m, 41:1)., 2.10 (m, 2H). 2.79 (m, IH), 4,25 (d,,/- 63 Hz, 2H), 7.74 (dd, 3-8,5,: 2.2 Hz, 1% 7-91 (m. 2H). Example 172: 4-Aodm>~5~(teirAydro~2//-pyranM-yltoxyE1 | j 1*2,61 tbiadiazisse- 2,2-die:sMe

Prepared as in Example 111 Horn. S'-suISipioylamino-ddteirabydrci-dH'pyrap-A"' yloxyibcngonlfrile (Example 172a) in 69% yield as a white solid. If NMR (400 MHz, DMSO dft) δ 1.77 (m, 2H), 2 05 ιηι 21 1 $, 3.5 i {hi J === 1! .6, 11 Hz, 2H). 3.85 (dt, J == 11.4, 3.¾ Hz, 20), 4.83 vsept J ===4,; Hz. iΗί, 6.62 (d,./ === 8.0 Hz, Eh. 6.88 (d,./ === 3.4 Hz, lHj. %46 μ.../ === 8.2 Hz, .1 H)f 7.7S ibr s, I lh. 4.37 (br s, HI), 10.% (bv s. Hi). MS 298 iMH"). 15xa?rtiilo 172a: 2-Sulfamoylamino~o4leoumdro-2//-p>ηιπ-4-ν]οχγ)hcnzonitviie Prepared as in Example i I la bom 2umnno/Mrenxrhydn>-C//--p>r;.in-4·· yloxv/benzonltrue {Example i 72b) in 5x"·*· as a light orange solid, SH NMR 1400 MHz, DMSO-/3 δ 1.64 (m. 2)1). 1.99 im. 2Hs, 3.53 (ddd../ - ! 1.6. 8.3, 3. i Hz. 2H), 3.85 (m, 2H), 4.80 (sept, /-4.0 Hz, 1HL 7.07 ul, ·/ : xj Hz. 1H), 7.16 ?d, J ~ 8.1 Hz. i H ), /.28 (hr s, 2H). 7.50 (t./- 8.5 Hz, HI), 9.4':' (hi s, 1H).

Example 172b: 2-Amin<>6“(tett'ahy<iro-2/f-pymi:-4-yl0xy)kiazonltj.'ik

Prepared as in Example 1 1 lb from 2-nilro-6-{letrahydrol-E-pytm^ ylox>}beruonitn}e (Example I 72e> in 49"« as an orange syrup. MS 219 (ME ).

Example P2c: 7-Nivro-b-i'ks.r;ih)\iro-.'.bb''o>yrari-9-yio.\>\ibe;r;'on;U'ile

Prepared as in Example 166d. from 2.,(>~dmitrobenzopitriie and. fetrahydrch2£f~ pynm-4-e-i in 100% yield ;»s a van solid. AHNMR(400 MHz, 0MS0~/<s} S 1,69 (m, 2H), 2,03 (m, 2H), 3 5b (m, 2H). 3 J? (m, 2H), 4.98 kept,,/- 3.8 Hz, 111)/7.90%¾ 3H)«

Example 173; 4-Ami »0*5%cyclopea tyloxy)qnina«»li »*2(1 //)-0 ne

Prepared as in Example 111 from M(2'>cya00r3* (cyclopcrityloxyjpbcnylcarbamoyllbcnzarnidc (Example j 73a) in 45% yield as a wkitc solid,, !H NMR (400 MHz, DMSO-A) 0 1.68 (m, 4H), 1.84 (m, 211), 1.49 (m. 2H), 5.06 {rn, IH). 6.70 id../ === 8.3 Hz, 2H). 7.43 (s. IH), 7.45 (1,,/ === 8/2 Hz. I.H), 7.85 (br a.. = Hi. 10.65 fbr s. IH)

Example 173a; ;V»(2-(3yano-3»(cyclopeniyloxy)phe.nyk:arbamoyl'}bs«z^«ide'

Prepared as in Example 1.46a from 2-am.inO‘^K;yelo'pen|p)iybenzomdil.e'{Ex.«-£8pk. 173b) m70% yield a* a yellow solid. *H NMR (400MHz, DMSCN&amp;)/ 1.63 (m, 2H), 1,77 (m, 41::1), L98 fe, 2H), 5.03 {m,· IH), 6.98 (4/==== 8.6 Hz, IE), 7.55 (t,/ === 7.6 Hz, 2H), 7.62 (t/==== 8. o Hz. 1Η), {ft J ------ 7.4, ! .2 Hz, ; B), ?.K? (d. J ----- 8.0 Hz, i IB, 8.06 (m, 2E% l i 37 ibr s, I Hi, i 1.54 {hi s. ! H).

Example 1 "4: 4~ Amia^S-CtetrafeydrafaraB^flexyH^^e^l^HA^^l iMadia«&amp;e»2,2“ dioxide

Prepared as in Example 111 from 2>etsifiniioyIamino4)~(tetraliydrotbran-3~ yloxy)be«2onitrile {Example 174a) in 33% yield ax a white .solid. Ή iVvlR (-400 MHz. DMSO-d*} $ 2,07 (m, IH), 2.26 (m, iH)s 3,74 (Id, J- 8,4,4.7 Hz, IH), 3.84 (m, 2H), 355 (d, ,/-16.4 Hz, IHj. /35 Ire 111),6.61 id../ S I Hz. !E). 0.73 (u../- 8.4 Hz. I Hi. 7 48 {:. ./ 8.1 Hz. IH), 7.64 (brs, IH), 833 (brs, IH), 10,97 (brs, 1.H). MS 284 (MH:>,

Example 174a: 2-Sal.famoyl.ammo-6^totmhydrofiirafl.-3-yl.oxy')bonzonitriie Prepared as-in Example. 11 la from 2~amino-{Htetehydre1«ran-3-yloxylbenzomirile (Example 174b) in 48% yield as as off-white solid. !fi NMR (400 MHz, DM$C%/,:.)6 15>9(m, IH).. 2.38 (m, Hi), 3.77 Ud,/-83. 4.7 Hz, HI), 3 83 (m, IH), 3.8"'(d. /

- 7.3 Hz, IH). 35)2 Hid,/ 10.2, 4.4 Hz, HI), .5.19 (m. 111),65)6 (d../- 8 3 Hz. IH), ” IS {d J - 8 3 Hz. 1H), 7.29 {s, 2H), 7.58 (t,./ - 8,3 Hz.. 1H), 9,.)-:) (br -,. ] H).

Ex.)snple 1746; 2-5rn-i.ino~6~(ietrafeydro:6tran~3~yIoxy)henzos)M!e

Prepared as in:Example 11 lb fipm.2~niiirp^6^t8tmbyd4bfti«“3“ yloxy/benzonilnle (Example 174c) in 97% yield asa light %own syrup. MS 205 (ΜΙΓ), Example)74c: 2-Niiro-6-(tetTahydroftiran-3-yi:Oxy)ben:zo.nitrile

Prepared as m-Exampk 1.66(.1 from 2,6-dimtrohen2on«ri!e andt.eimhyiIrofuran-3-ol in 50% yield as a light yellow -Mid. 31 NMR (400 MHz, l/MSO-/,} P 2.04 fm, 1 H}, 2.32 (m, IH). 3.81 ud.,/ 8,3, 4.6 Hz.. IHk 3%) 00,21¾ 3,98 (64 J- 10.8,4,5 Hz,IH), 5.36 (m, 1H), 7,75 (d4/-8.)., 1,5Hz, IH), 7.91 (1,/- 8.2 Hz, IH), 7.95(04,/ - 8,2, t.6 Hz, IH).

Example 175: 4~Ami«0~§~(Msc^r^yi^ipeMdl»Hi^yto^|;)~.1.0~beBzo|£,|11?2.v6|fhlsidi82iB«4»2r dioxide

Prepared, m in Example 1.11 from 2-suIiamoykmBno~6A!Msopropylpiperidm~4-y f oxy>benz.onirrllc (Example l?5b! in 12% yield as a while solid. ΉΝΜΚ {400 MHz. DMSO-.**) i> i .24 Uk ·/=== 0.7 Hz, OH), 2.11 {m, 2Hp 2.28 (m. 211). 3.B (rn, 411). 4.8? (m, 111). 0.07 pi„/ - 8.0 Hz, 1H}, 6.87 {d, J ==== 8.6 Hz, 1I h, 7.40 (t,./ - 8.3 Hz, IH), 7.67 {bf s, HI). 8^.1« h .s. Π1). 10.79 {brs, 1 Hi. MS 130 {MM ).

Example 175m 2~Sdli^»0yl.^t»iao~6~(Misppi'Of|>ylpipendm~4'«yloxy)beazoniftii©

Prepared as In Example 11.1 a from 2~ammo-6-(1 4sopr0pylpiper.idip-4-vinxylbenzomifile (Example 175b). The product was carried onto tile next step without Further puruicaiion.

Example 175b: 2-·Αηηηο··6··{ i4s^ropylpipenuin-4"y]oxy}ben2onmilc

Preparedas in Example 11 lb from 2-niiro-tw 1 -isopropyJpiperidity4-yloxy)benzoni?rbe (Example 175c) in 80% y=dd as a brown syrup. MS 260 (MB' ),

Example .17Se; 2 A9ltro-·/1 -tsoptopylpiperldi.n<4-y!dxy)-6“benx0:nitri1e Prepared as in Example 166d Ex>ni:2?6~dkitfobe«zOiiitf0e and. T~ lsopropylpiperidm-4-ol in 90% yield as a tan. solid. *8 NMR (400 MHz, DMSC.W).) 0 0.94 (d. J -= 6.8 Hz, 6H), 1.72 (m, 2H), .1,95 (m, 2H), 2.4! fm, 2H), 2.71 (m, 3H), 4,80 (m, !Mh 7.81 (dd../ ===8.2,1.3 Hz. VH). 7.89 (m, 2B).

Example 176: (R)“4-AatlttO“5“((.l4iufyry!pyrrelidlp«2“yl)?nethox> p II/» bmuo|<i 11,2,6 f Madiazine-l J“dioxMe

To a solution oftR}-2'atrrino-6-{{ 1 -bmyrvlpyrrohdin-2->1)mcthoxy)bcn?o nitrile (84 mg, 0.29 mmol) {Example 1 76a I in acetonitrile (9 roL), was added sult'amoyi chloride (70 mg, 0.60 rnmol). The reaction was stirre-,1 a* rt for 20 h, and upon cornpleiion was concentrated fo vacua·. The resulting residue was dissolved m BOH (1 mi..), and 2N aqueous NaOH (4 mL) was added. The mixture was refluxed for 2 h, and upon completion was cooled to rt. neutral seed with IN HC! and stirred at 0 !>C. The resulting precipitate was collected by vacuum tl if ration to provide the desired product (38 mg, 3$%} as a white solid. !H NMR (400 MHz, DMSO-</.-.) 0 0.89 it,./ === 7.3 Hz, 3H), 1 .54 fsext,,/ === 7.3 Hz, 21B, 1 .94 (m, 4H), 2.20 (t,,/- 7.3 Hz. 211). 3.49 (m, 2H), 4.10 (m, IH), 4.25 (m, IH), 4.43 (m, 1El), 6.62 (d, %- 8.2 Hz, IH), 6.90 (d, i - 8.2 Hz, IH), 7.45 (t, ,/ ==== 8.2 Hz, 1H), 8,08 (hr s, 1H), 8,34 (hr s, EH), .10,93 (br s, Iff I. MS 367 (MET).

Example I 76a: (/%-2~ Amino-6-{( 1 -butv /> Ipyrrolidm-2 -y!>rneihoxy)berizoniinle

Prepared as in Example f f f b from (/()-2-0 }-butyryipy rrohd in-2-y l)mcthoxyWj-nitiobertzoniti de (Example 176b) in 77% yield. MS 2^4 (MH ». EMmakI26k i -Butyrylpyrrolidin-2'yl)rncihoxv)-6-mirohenzoniirile

To a suspension Off R)~2-i< 2-cy ano-.Lnrtropheooxy frnethvi Ipyrroi id mium chloride (140 mg, 0.49 mmol) (Example 176c) m THE (3 mL) were added EoN (143 pL, 1.03 mmol} and b-.rt.yryl chloride (56 μ.Ι.., 0,54 mmol). The reaction was stirred for 72 h at rt: under Ny, -Upon completion, the reaction was filtered. and the filtrate was concentrated, to pfpv 16^(//)-2-({1 -butysyipytToUdio-S-yiimcthoxyl-b-nitiobenzonitrije (127 mg, 82%) as a. yellow syrup. MS 318 (MBl. .Example·! 76e; (/t^d^l^^yano^iitrephcnois^methyl^yTtoiidihiuiti chloride.

Prepared ax in Example 166 from (EMeW-fmEd 2--((2-cyaoo-3-nitmphenoxy imethyIipyrtolidinc-1 -carboxv late (Example 176d) in 71% yield as an off-white solid. *H NMR (-1015 MHz. DMSO-effid f.'E? (m. 2H). 2.14 (m. 2H;„ 3.28 (m, 2H). 3.0/ (m. 2H), 4.50 (dd, J =710 6, 6/4 Efz, 1H), 4.57 (dd,J- 10.9, 3.5 Hz, I Ef), 7.7? (d,,/- 8:0 Hz, f H)> 7.98 (m, 2H). 9.30 (hr s. 1 HE 9 7-1 (br s. IH).

Example l.?6d;. (/?}~imt~Bmyf 2.^P-eya«o-3^uttfpphcpo«>O-mefhyI)p>Tt0!idi-nc>l-earboxyEue

Prepared as in. Example 1,66d from 2,6Mimtrdbeozon:iiriSe and (/?Her?~huiyl. 2~ (lryxirO:xy:nHrdiyl)p)uax>lidhie'-I'-carboxylate in 87% yield as a tan solid. l.H NMR (400 MHz, DMSO-4) d 139 (s, 90), 1.82 to, 1H), 2.02 (m, 3¾ 332 Cm, 2H), 4.08 (m, 1II), 4.32 (m, 2H), 7.79 Ul ,/- 8.0 11/., 1B), 7.91 (ffi, 2M).

Example 177: A-pr»|)yIpyrr0lMitte» 1 “CarfodxaiaMe

Prepared as in Example 176 from (^S-CCS-amino^-eyanopfeenoxyjmethyl^iV*. propylpv rrot ϋ inc·! - carboxamide (Example 177a) in 57% yield as a white solid, Ή NMR (400 MHz, DMSO-i/ft) «) 0.83 (e J -- 7.6 Ha, 3HL 1.42 (sext,J- 7.3 H2,2H), L90 (m, 4¾ 3.00 (m, 2H). 3 2«{m, 1 H>. 3,43 (ro. 3 Hi. 4 01 (m, 1H|. 3.1 elm. iHi., 4.33 (ay 1)1),6.27 in. 111),6.61 id ./ » 8.4 Hz, | R). 6 89 id. J » 8.3 Hz, 1H). 7.45 (?.../ - 8.2 Hz. ill). H 19 (br s, ! H ?, 837 (br s, 1H), 10.91 (s, 1H). MS 382 (MH ).

EmsiMsjlM i/?)-24(3-Am:nio3-cyanophenoxy:)melhyl)-A9pfCigylpyfroiiSne-l-earhoxamlde

Prepared as in Example 11 lb from (i?)-2-({2“Cyano-3-«itropheGOxy)mothy'{)-Ar-propySpyrrolidine-1 'carboxamide (Example l??h) in 14%« yield. MS 303 (MH ).

Example 177b: (//)-2--((2-CyaGO-3-niirophenoxy)meihyl)-/V-propylpyrrolidiae-1 -carboxamide

Prepared.as in Example .176b from (R}~2-ii2«cyanos3-niEophenoxylnyyhyljpyrroHdii'iiun-i chloride (Example 1 ?6c) and propyl isooyaaaie in 100% yield, as a. light yeiiow solid MS 333 (Mlf),

Example. 178( (ii)-2-((4~Anino«-iW~be»/.o|i'Hl,2»6|ihiadi*ayine->2J-^li0xl«I^S“y|texy)mettiy|)~

Pkctliylpyrrplditte-l-earboxamiile

Prepared a.s hi Example 176 from iR)-2-ii}·-am I oo-C-cyanQphenoxy)m«thyl) - .V· .^thylpyrmHUme-I-carboxamide (Example 178a) in 60% >idd as a white solid. (H NMR (-400 MHz, DMSO-Mb d 1.02 (t, J - 6.8 Hz, 3Hb 1.90 (m, -H), 3.OS squirm./ -- 6.8 Hz, 2Hh 3.30 (m, 2H), 4 01 (m, 1H>, 4.16 (m, 1B), 4.33 (m, IH), 6.27 imj H), 6.63 (d../ - ,v4 Hz, I Hh 6.89 {<(../ - 8,4 Hz, IH)f 7..46.(n,/ = 8.4 Hz, IH). 8.20 (hr s, 11¾ 8.27 (br s, Iff), 10,91 (s> 1H). MS 368 ΓΜΗ ).

Example 178a: (/i)-2-((3-Amioo-.'-c>att^phe»oxy}mcthylHA;-ethylpyrro!i(iine'rl~ carboxamide

Prepared as in 'Example 11 lb from {^)'2-ii2-cyariO*3*oitroph&amp;r»oxy}meib>il)-i^-.gihylpyrroK&amp;TO-ί-carboxamide (Example 178b) m 621¾ yield, MS 289 (ΜΗ.'),

Example 178b: i /2)-2··((2-(ly;am-3-iinrophes®xy>aieibyl)-/V--etbylpyn'oliiliBe-! -carboxamide

Prepared as in Example 1 Mb from {/?)-3-fr2'cyar:0-3~ niiropbenpxyimethyllpyrroHdIoiusn chloride (Example 176.«).andeihyHsocyanafe in 059¾ yield as a light yellow solid. M$ 319 (MH ).

Example 179: (i?)^-Ai«ioo-5^(i“is'eb»^iry^y;rr0lidl»»2“yl)meth^>liir* hcnzo[e|[l,2,6|0Madfazi«e~2j2»dmMie

Prepared as hi Example 176 from (^)-2~am:iho~6“^J“iSol>utyry-lpyrt;olidiP«'2«' yl)niothoxy)benzpniirile (Example: 17fb) in 10096 yield as a wind; solid, ]H MM.E (400; MHz, DMS0-<4> <> 1.02 id, ./=== 0.3 Hz, OH). ) .04 <ro. 4H), 2.70 (in. ! H), 3.55 inn 2H), 4.12 (m. I B\ 4.24 tm, 114).4.43 (m, IH). 6.62 id. ,/=== 7.0 Hz, 1HK6.91 id, ../====84 Hz, 1H), 7:47(4,/=== 8.1 Hz, .1Π), 8,04 (hr 8,- 1H>, 8.34 (br $, IH). 10.03 (br s. 1H). MS 367 t>1 H ">.

Example 179a: (//)-2-A?rHee~64(ibsoEutyrylpynO!idm-2-xi} meliioxy) benzohitrile

Prepared as in Example 11 ib from (6)-2-(( I -isobutyfylp>rrolidin-%yl)medmxy}·· 6mitrobenzooi(rile (Example 179b) in 8030 yield ax a. clear .syrup. MS 288 (ΜΗ' I.

Example 170b: {R}-24( I -fsobutyry Ipyrrol idm-2-yl jmethexy}·6·n itrobcnzonitrile Prepared as in Example 176b fmm (/()-2 -((2cyano-.i·· iaiiropbenoxy)-neih> Opyrroiidiniiun chloride and isohutyryl chloride in 100% yield as a yellow solid. ;H NMR <400 MHz, DMSO-%) P 0.96 ukl J - 6.6, 3.5 H:> ME 1.93 On, 4H), 2.1 4 (m, IH),2,66(sept,J == 6.6 Hz, IH).3.55 (m, iH),4.28 (m, 3H),7.79(dd,,/-7J, 1.8 Hz, IH), 7,89 irn. 2H).

Exa mple 180: (ii)~4~Aiuluo--5--(( I -phaloy ipy rrolidin -2 -vl)»i ei b oxv)- I/O hen/ojej i 1,2-,6 |ibradiazl«e-2,2-d ioxkte

Prepared ax in Example 1% bom. <R)-2-0¾nino-6-<(1 -pivaloy IpyrroItdin-2- yilmeihoxyibcnzoniinle (Example 180a) in 64% yield as a white solid. !H NMR (400 MHz, DMSO«/«)** id8 ($, 9.8), 1.92 (m,4H), 3.55 (m, IH), 3;73 (m, 1)4),4,13 (m, 18),4.27 <m, IH), 4.48 (m, 84),6,62 (d,</ - 8.2 Hz> 84), 6.92 (6,/== 8.214z,: IH), 7.47 (1,-/-8.2 Hz, IH), 7.95(br s, IH), 8,37 (br s, 18), 10.95 (br s, 84), MS 381 (MH).

Example 180a: (8/-2-Ami αο-6-U l-pivaloylpyrroHdin*2-yl)mcthoxy)b^nzonttri:ie

Prepared as in Example 11 lb from (6)-2-0 1 -pivaloyIpyrro1idift*2-yl)methoxy)-6-iiitfobenzoiiltfile (Example l86feW) in9i% yield as a clear syrup. MS 302 (Mff ):.

Example 180b: ((/)-2-((11 -Fivaloylpyrroli dim -2 -yl)nietboxy)-6-nitrobenz6nilrlle Prepared as in Example I 76b from. (E)-2 -((2-ey;mo-3-pltroplienox) )n^ethyl)pyit0lidmiwn'-eHiorl:ile'.aRd pivalovI chloride in 999». ?H NMR (400 MHz, DMSO-4) Ο ί.ί6 (8,90), 1.91 (m,m% 2.13(m, 1H), 3,70 Cm, 2H), 4.35 (m, 3H), 7.81 .(dd,,/-7.5, 2.1 Hz, sHi, 7.92 (r.n, 2H).

Example 181:: (/7i'-2-{i4-A«iiriO“1//-4K>5U.i4z:HL2i6|tl4a0ia/.iHe“2,2'(lioxlde'5-yloxv)rsH>lli\l)-A“lso|)rop> lpyrro)idiM»l“C5yi>oxaa«de

Prepared as in Example 1.76 from (i?)-2-(()Lamlno-2-cyapophenoxy)oiedryI)-M· hopropy IpyrroUdine-i -curboxamidc «Example 181a) in 23% yield ax an off-while solid, !H NMR (400 MHz. OhiSO~d·,} 0 1.05 (d, J 6.4 Hz, 6H), 1.87 (fry 4H). 3.] ? On. 1 Hy 3.79 (m, IH>, 3.98 On. IH), 4.15 (ny !H>. 4.3! (m. IH), 5 88 id,./ === 7.4 Hz, 113),6.59(0.7- 8.2 Hz.. 1H). 0.X6 (d,./ - 8.5 Hz, Hi), 7.43 (?,,/ - 8.2 Hz, 1H), 8.18 (br e, 1H), 8.23 ibr s, lHI), 10 88 κ, 1H) MS 382 (MET).

Example 1.81a: (R}-2~({3~A:miO0~2~eyanQph€«O:Xy}rne^^^ -I.- carboxamide

Prepared as in. Example 1.1 lb from (i?}-2~((2~eyano-3-rvitrp|>liepoxy)mefhyl)~A~ isop:rop\dpyrrolidi.n.e.~l~carboxamide (Example 1.81b) in 86% yield as a clear syrap, SH NMR (400 MHz, DMSO-dH 4 1,07 (d,,/- 5,9 Hz, 6H), 1.89 (m, 3H)S 2,10 (m, 111), 3,1.6 (m. III), 3,45 (m, HI), 3.78 Cm. Hi), 3.91 (m, ί H), 4.06 (m, IH), 4.12 (Ρΐ,ΙΗ), 5,85 (d,J-7.7 Hz, 1.11),6.00 (hr s, 213), 6.31 (0. J - 8.4 Hz, .111), 6.34 (d,,/- 8.4 Hz, IH}. 7.18 ft J - 8.4 Hz, 1H).

Example 16 f b: (/?l-2-((2-()¥anO"3-Bitr6ebepoxv)metbyl)-17-ison:ropy iiwiT6lidme~l -carboxamide

Prepared as In Example 176b from (^)-2“((2-cyapp~3“ mteopbmwxy)m®fhyl)pyttolidinium chloride (Example 176c) and isopropyl isocyanate Ip 100% yield as a yellow solid. lE NMR ¢400 MHz, DMSO-xA) 0 .1.07 (el,,/ - 6,5: Hz, 6M), 1,91 (m, 3H), 2.13 (m, 11:1),3.17 (m, IH), 3.79 (pi .IH), 4.19 (m, 2H), 4.32 (d,,/ - 8,8 Hz, IH), 5.91 (d, J - 8.1 Hz, IH), 7,89 (pi, 3H).

Example ί82: ($)-24f4~Ami.a»-i/i*ite«Z0}r j {1,2,6)1 iua^ia^i.ae-2,,2-dioxide·-$-> km pneih> 1 s-A-6>r^bui¥lpyi'i'oi«H5ie-l»carl>«xamlde

Prepared as in Example 176 from ^-Z-CO-smfeo^S-cymiopheooxy^ethyf^A-a-rt~ butyl pyrrol id me- .l-carhox amido (Example 182«) In §6% yield as an oil-white solid. H NMR (400 MHz, DMSO~%) 6 S .27 <«, OH), f M (m, 411), 3.2i (m, 1H). 4,02 (m. ! H), 4.19 (m, IH), 4.34 (m, Iff), 5.3:5 {». i H), 6.62 (m, l H). 6.86 (m, i 11), 7.46 On. 1H), 8 23 «hr s. Ilf). 8.2? (hr js, ill). 10.91 (S, j H). MS 5% (MH 4.

Example 182a: ($)-2-((3-4mlno-2-cyanophcnoxy}motfiylP.Y-reit-hpiylpyrrofidin-,1-earboxamiite

Prepared as in Example 1.1. Ih froai .($)-2-((2<yn«0-3-nitmi>he60xy)mei%i)-Ar-ipyrrolids:ne~l:~earboxamlde (Example 182 b) in 96% yield asp -'white solid, MS 317 (MH ). ESlSlik-lliZb; ($)-2-((2-Cy ano-3-T6.impherioxy).mt4:hyl )-;y~&amp;?r/4nnx1py.nxrld.Iine~l -carboxamide

Prepared as· in Example 176b from ($)-2-((2-cyano~,3~ rdiropheivoxylmethyllpyrrolidimun-i chloride (Example 1 76c) and fr-tf-butyl isocyanate in 10038 yield as art. off-white solid. SH NMF. (400 MHz. DMSO-n.',) A i .s? (s. 9H), 1.86 (m, I.H), .1.95 (m, 21:1), 2J2 (m,. IB), 3.18 (τη. IH).3.37(m, IH). 4.20 On. JH « 4.23 (dd. J --- 10.0,:6.31-12,111), 4.31 (dd,,/-9.7.2.7 Hz, IH), 5.36 is, IH). 7.84 idd,,/=== 7.4.0,9 Hz, IH)< 7.91 (m, 2H1. Example .183* 4~Α.«ήηο-.4-((.κ?η6ηί-3->1ο.χν)~1ίί~1>£'ηζο)<'Π1,2,6 j f Wadia**»*-^,2-d kmde

Prepared as in Example I1I from 2-suifantoy )apijru>-6-(pcrxran-3-y lox v) tenaoratrilc (Example I $3a) hi 48.7% yield. :0 NMR i400 MHz, DMSO*ii>) d 0.9 l (i, J - 7.6 11/, 60). 1.73 {m. 411s, 4.54 (a, JO), 6.59 (M J- 8.4,1.2 Hz, 113),. 6.79 (d,/- 8.0 0/. 10), 7.45 it J 8.4 Hz, 10)., 7,84 (b= d ,.J - 2.8 Hz, Hit. 838 (for 4 J - 1.6 liz, ! Η), 10.96 (s, 1M). MS 2S4 {Μ?Π.

Example s83a; 2-Sulfanioyianmso·Edpeman/bsIo\y)benzo.nuriic;

Prepared a'i in Example I I ia frum 2-aniino-Mpeman-d-yipxy ibenzomn He: i Example 188b) in 68.1 % yield. MS 284 i MH').

Example 183b: 2-v\minP~6-dpentan-4?~yioKyJbeazonMb:

Prepared as in Example 111 b from 2-nitix>^Hpe»t««“3-ylo.Hy)bcnzonitrile (Example I83c> m 100% yield. MS 205 (MH'}.

Example 185c: 2"NnriS"6«(pentan-5-vioxy)benzoniirile:

Prepared as in Example 111c from penum-a-oi end 2,6~djnirrobeozonit.n!e in 86.5% yield. lH NME {400 MHz. DMSO-/,} 6 0.9-1 (t.,/- 7.6 Hz. r-H). j .70 nm 404.62 (ra, 10), 7.78 {dd, J- 73,2.4 Hz. !H), 7.88 (m, 2H).

Example 184; ixV)~4~Amiaci-'5-'(.vei'--bisl:(>xy)-'lff--6enz(>d.'|j;l,2,i>|ihiad?azine--2,2-'dioxide

Preparedas in Example 111 Eom33)-3--sullanioy}a»Hao--6--ifei'”bidoxybenzs?nti:ile (Example 184a) in 43,236 yield.!H NMR (400 MHz, 0MSO-<%) 0.94 (t, J - 7.6 Hz, :3H), 1,29 (d,/- 6.4 Hz, 30), 1.69 (m, 2H>, 4..72 (m, 10), 6,59 (dd,/- 8,4, 1.2 Hz, HI), 6.79 (4/- 8.0 0zj 0), 7.45 It, / - 8.4 Hz, 10), 7.84 (br d, /- 2.8 Hz, iH), 838 (br d,,/- 1,6 Hz, 1H), 10.96 (a, 10), MS 270{MH3,

Example i 89a: (/33-Sulikiioylammo·· 6*xee»lmioxy benzoniirile:

Prepared as in Example 111 a from {/)3--am:ino-"6“xembuioxy;beazonilriIe (Example i 84b) in 69.1 % yield. MS 270 }MH }.

Example I84b~ (5)-2-Aniino/'Xer-butexybenzonitdle;

Prepared as in Example 11 lb frotri <S)-2~se<‘«buioxy-6-nitrobenzonitrile < Example 184c) in 100% yield. MS 1 % (MIT).

Example lS4e: (S)~2-.svc-Bo:oxy-6~iutr0b£P2:<>miriIe:

Prepared a? in Example 111c from <Sl-butandbol and 2,6-dinitrobcns.onitrile in *5.2*4 yield. ’HNMR (400 MBz, DMSO# d 0.94 (t.7-7.6 .¾ 38),.1.29 (d, J- 0.4 Hz, \ H). 1.69 (m, 2H), 4.72 im, 1 HK 2.74 (dd,./ - 6.6. 2.4 Hz, 1H), 7.80 (ra, i H (

Example 185: {5)'4*Amiao»5»(metiioxypr6pox> M/M>en?.<>je|j 1,2,6) lhiadiairme-2.2-iii8xid«

Prepared as in Example I 1 I from 2-sidPnnoylanHne-6"(5-tacshoxypmpoxyjbenzoniirile /Example 185a.) in 69.3% yield. :H MIR «400 Mil?, DMSC-,/>) 0 2.03 im. 261), 3.23 (s, 3H), 3.50 (:../- 5.4 Hz, 2H), 4.18 u, J - 5.e Hz. 2H), 6 5s (dd, ./ M, 0.6 Hz, ; H), 6.70 {(id,./::: 8.4. 0.8 Hz, HU 7.43 U.- 8.0 Hz. I Hi 7a 23 (% s IH),8 M (hr <. IB), 10.90 (y IB). MS 286 (MB"').

Example 185a: 2-S:al&amp;m.0vlamino»6"(3~meOrexxfareaexy)l>em0nitrile;

Prepared as in Example 11 la frem 2 ammoUHS-nreilmxypfepoxylbenzonitrile (Example lS5b) in 69.794 yield. MS 280 (MH).

Example 1856: S-AmmoU-O-niethoxvoiPeoxvlbcnxoffltrlle;

Prepared as in Example 11) b troro 2 (.vnrv;vlK3xyprop6xy3-4>-nifrobenxonltrile (Example iS5e)ip 100% yield. IMS 207 (MB').

Example 183c::2n3~MellmxvnrepexvV6~nllT6benzoeltrlle: .Prepared.as in Example 11 le from 3~methoxyprf>p;m-!-ol and 2,6-di nkmbenzom iriie in 63.6% yield, *HN.ME (400 MH?., CDC13) 0 2.10 (m, 2H), 3.36 (s. 3H), 3.63 (:, ,/ - 5.6 Hz. 3H)„ 4.29 (:., J - 0 4 Hz. 2H), 735 (dd, ,/ - 8.8, 0.8 Η?, IH), 7.69 (i, ,./- 8.8 Hz, 111). {dd../ - 8,-1.. 0,8 Hz. j H), dioxide

Prepared as m Example 11J ίκ-m 2-sulfanioylaniirio-f'-(cyckipropyirncUioxs^benxoniirile (Example I86:0 In 49.4% yield. M.P : 246*247 SH NMR (400 MHz. DMSO-i//;) ·! 0.39 (m, 2H). i .60 (m. 214), I .36 (m, I HP 4.02 (d.,/ - 7.2 Hz, 2H1. 6.60 idd,./ - 8,4, 0.8 Hz, l H), 6.73 id. J === 8,4 Hz., ] HI. 7.43 {t.,/ - 8.8 Hz, 1H). 7,99 (br i ,7=== l .6 Hz. IH), 8,41 (br d.,/ - 1.6 Hz. HO. i 0.96 (hr s, i H) MS 268 (MH i.

Example 186a: 2-SiOd6envjamino-6-(cydoor6pylmei:hoxv)benzoiiitrile;

Prepared <k in Example I Ha from 2-amieo~6-{v.yelopropy!methoxy}benzor;iir;le (Example 186b} in 87.5% vicki ‘H NMR {'400 MHz, DMSO-mO 0 0 18 (m. 2H). 0.41 (ro. 2H), I 07 im, IH). 3.80 (d,./ -= 7 2 Hz. 214), 6.76 (d,,/ === 8.0 Hz. Hi;, o 96 id. J === 7.6 Hz, {HI 7.09 ibr s, 2H), 7 37 ά, 8 0 Hz. IH). MS 268 (MH ).

Example I86h: 2.“Air!!ju>“6-(cyc1o{)ir«pylm!etb0^y)beB'2diiilirild;

Prepared as in Example i lib from 2-(eye lopropyl metboxy }>6~beezopitrile' (Example 186c) in 100% yield. 5H NMR (400 MHz, DMOO-/4) 0 0.33 Cm. 2H), 0.S8 (m, 2H), 1.23 (m, lH), 8 86 (d. ,/ === 7.6 Hz, 2H}„ 5.98 (br \ 2H), 6.20(d.../ === 8.0 Hz, !H), 6 27. (dd: ,/ === 8.x 0 8 Hz. IH), 7.1 7 (i, 8.8 Hz, ! H) MS 189 i MH ).

Exampig !86e: 2-iCvclonronvlipgdiexvE6*benz0oltrilc;

Prepared as in Example I.! I c .from 2,6~d®iirobenzoriiPi|.e and eyetopropvIin.ethaa.ol in 90%. Ή NMR: (400 MHz, DMSO-<£s) $ 0.40 (m, 2Β% 0.62 {«p 214), 1,29 (m, 1.14),4.14 (d,./::: 7.2 Hz, 214), 7.71 (dd, ./=== 71, 1.214^114),7.9(^, 2H),

Example 187: 4”,4i«iBi>~5-(rne0ioxyie1rahydrii"2i/"pyrai~4~yll~i®~ Ι'Ηΐηζο|ί'|{1 J ,61 Hi iasiiaziss£~2,2-dioxide

Prepared as in Example I 1 I from 2~sul.&amp;mo>4amiab-6-(tcnuhYdro-2//*pyrars~4~ yObenzondrile (Example 187a} in 92'/« yield ax a cream colored solid. Ή NMR (-100 MHi. DMSO-/0 d 131 (m, 4H). 1.63 (br m, 4H). 3.31 (br m, 2H), 3.36 (br m, 2H>. 4.01 id,./ - 6.8 Hz. 2H). 6.57 (d,/ - 3.4 Hz. His., 6.71 (d../ - 8.0 Hz, l Eh 7.4:.1 (I, J = 8,01¾ IB), 7,68 (br, .1H), 8/24 (s, .1B), 10.90 (by 1H). MS 312 (ΜΗ/),

Example I8?a: 2-SuIiamoyiavnmo~6~(ietrahydro~2i-Rpymrml-yl}hoimomirile

Prepared as m Example IΊ la from 2-armmv6-(<tYirahydro~2//“pymn“4“ yl)incUioxy)bcnzonitrib (Example 187b) In 51¾ yield as an orange solid. Ή NMR s-HKl MHz. DMSO-/0 /> 1 35 Cm, 211). 1.66 (br.. 2H), 2 01 (br. 1.H). 3.32 (br, 2H), 3.37 {br nr, 2Hi. 3.96 (d. J === 6-4 Hz, 2H), 6,92 (d, J * 8.4 1¾ 1 Id), 7..12 (d, J - 8.4 Hz, IH), 7.19 (br s, 2:13)., 7,52 (t, / - 8,4 Hz. 111),9 44 (br s. il l.}:.

Example 187b: 2-AmmO''6-((tg:trabvdro-27/-ovran-4-vl3mgfbQxv)benze«itrife Prepared as in. Example 111b frQni/Hmtro/^tcbahydro^/i-pyran^ yl)methoxy)benz.onitj-iie (Example .18' 7c) in 80% yield as a yellow solid. *H NMR (40{)MIIz, DMSG-/3 6 I 32 (m, 2H), i .64 ( m, 2H), 1.97 (br, HU), 331 (m, 2H), 3.86 (m, 4H), .5.97 (s, 2H). 6.19(0, 7- 8.4¾. 1H j. <·3 = (d, HI), 7.15 (ΐ,/-8.4 Hz, III).

Example 187c:· 2-Nilro-6-iimtr3iydr0-2H~pyran~4-yI)me(bexy}berwomMle:

To a solution of tedMiydfopyram4-oiethanol. (782 mg, 6.73 mmol) I» THE (25 ml), was added slowly 1,38M rsBuL-i (4.13 m.L, 5.70mmo!) In bexane at-78 !>C under nitrogen. At one hour a solution of 2,6~dinjtrobenzcmitriie (1.00 g, 5.18 mmol) in THE (25 niL) was: added. The reaction was stirred mxter Ny overnight atrt/then was guenched with water (iOOmL), Tire precipitate was collected by filiration to prrwd.de 2-mtro-6-((te4rabyxbx>-2ii-pyran-4-yi)Hietiioxy)benzomttile (1,13g, 8376) as a: light brown solid. lH NMR (400MBZ, 0M8O-iA) 3 I As ym. 2H), 2.06 (hr, ί H). 333 (m, 2H), 3.88 (m, 2H), 4,11 ¢4./==== 6,0 Hz, 2H), 7.72 (d, /- 6,0 Hz, . 1H), 7.89-7,85 (m, 2H).

Example 188; 4~Aa*laf»-5-{mefhox> utfrahydrofa {1,2,6 j rlifadiasase- 2,2-ilioxide

Prepared as in Example 11 1 from 2-s«lfemoylaroino-6-(nK4hoxyteirahydrofuran*· 3-yhbcnzonitrilc (Example 188a) in 26% yield as a while solid. :H. NMR (400 MHz, DMSO-4>) ;> 1.64 (rn, Hi), 1.99 (m, I H). 2.73 (m. 1 H), 3.56 (m, 2H>. 3.67 {t«, 1H), 3.7.5 (m, .1H), 4.04 (m„ 2H}< 6 51 id. J 8.4 Hz, 1H), 6.62 (d. ./!!! 8.4 Hz, 1H), 7.34 (t. j - 8.0 Hz, .1H), 7.70 (br s, Hi), 8 09 (hr s. i H,h 10.92 (br s, ! HP M$ 298 -IΜ H }

Example 188a: S-SuIfamoylarnino^-lntethoxyteirahyckoforan-^-yDhenzomtrUe' Prepared as? in Example Ilia from 2-amiru>-6-({teirahydrofuran-3-yl)raehtoxy)bcnzonitrilc iExample 188b) m 1483 yield as a white solid. Ή NMR ¢400 Ml!/, DMSO-t/,) 0 1.62 pm IB), 1.96 <m, 1M), 2 .43 (m. 111),2,61 (m, 111),3.48 (m, 111),3,60 (m, III), 3,71 (m, 211). 3.99 (m. 311), 6.90 (d../ 8.8 Bx, IB), 7.09 (d, J- 8.0 Hz, IB), 7.19 (s, 1H). 7,49 (t,./- 8,4.Hz, 111), 9,42 (s, IB).

Example 1.88h: 2-Arni.no-6-((te?.rahydrofuran-3-yl)mehtoxylbenzonitrile;

Prepared as in Example 1.1 ..1 b from. y!.3Hietb.oxy)beazooittt.le (Exa?:nple 188c) in 99% yield as a golden brown oil. MS 219 (MIT ), Example 168ε: :2"Nltro--6-i(teirt4redreldi4«r-3-vI)methoxv )beozO:nllrfle;:

Prepared as Irt Example 166d from 2,6~dimtrobe»zoiitlrde and. 3.-hyd^xymethyltetmhydrolbran in 48% yield as art onatvec-rcd solid, Ή NMR (400 MHz,. DMSCTmO S-1.68 (m, IB),2,00 (m, IB), 2.70 (m, IH), 3.54 (ra. IB), 3.66 (m, ?H), 3.76 (m, 211). 4.03 (ra, IB), 4,19 Pm, IE), 7.73 (d,,/ - 7.6 Hz. 1H), 7.90-7.95 (m, 211).

Exan sple 189; 4« Ami sto»S"((ietmlty drpfii ra8~2-yl)mel b ox> )<j m«azelin»2( J ITl-mte

'Prepared,^ in Example 111 from ^'S^yaao-S-C^eti'^ydro^iran^-yt)mcthoxy)phcnylorbaowyi ibenzamidc {Example 1 89 a) in 39% -yield. *B NMR (400 MHz, /· DMSO} d 1.65 (hr m, 1 Η), 1 .85 (hr m, 2H), i .99 {hr m. 1H), 3.71 Cm. 2H>, 3:78 (t% IB), 3.98 fm, !Hi, 6.70-6.67 cm, 3H|, 7.42(4,./-- 8.0 He. IH}, 7.62 (s. iBp 7.88 (s, IBs. 10.63 (s, IBs.

Example 18%; S'~{2·( \an*>3-({tenthstiiofuran-2-yi}mcthoxs> phenyl carbamoyObenaamide

Prepared ax in Example 140a from 2-aBiiaO"6"((teteihydr0iisraii--2^ yi)metboxy}benzDPit.rik' (Example 189 b) in 43% yield as a white solid, 13 NMR ¢400 MHz,¢7-DMSO) <> l .98-1,74 (m, 4H), 3.54 (m, 1H% 3.69 (m, 1.H), 4.20-43)? (ms 3B>, 6.97 (<J, J =* M Wk 1 H j, 7 67-7.51 (ffl,4H),

Example 1896: 2-Aailno-6-((t:CtraIiydrofara«-3.-yl)mefhoxy'jbeneosv4nle Prepared as rft 'Example Π lb from 2-mitro-b-d’iclrabydu'iurun-C·* yIJh^tfedxy)betepniMk:Xl|xample 189e> in 92% yield as a light bine clear oil *13 ΗΜ1ί{400 MHz, MeDD) /1 .974 .68 (m, 4H), 3.73-3.64: (m, 1H), 3.80-3,73 (m. 1H). 3.98-3.90 (m, 21!), 4,13-4.12 (m, I if), 5.96 (s, 111),6.18 (¢1/- 8.014¾ IH), 6.31 (0,/- 8:014¾ 1%.7.14%J-8.4 Hz, m). .Example I89e: 2-Bltro-6-Utcn'a1miroH;.ra.n-3-y1):nethoxyIbeneonilnle:

Prepared as in Example ! 66d from 2.6-dinitrehenzonitrile and s.etrafurfuryl alcohol in 68% yield. *H NMR (400 MHz, MeOD) 9 3.10-1 70 (m, 7H), 3.68-3.66 (m, 1 H}, 3.80-3.78 (ηr, 1H), 4.29-4 .20 (m: 3H), 7.72 (dsJ - 6.0 Hz, 1H)S 7.90-7.84 (m, 2Hi Example 190:4~Amf«»-5^(2~iBellmxybenzyl0xy)~17/~beHze|elllJ,6|lhtadiazli5e~2,2-ilioxiile

Prepared as in E&amp;aimpk III from 2»suUamoy!afnino^-<4*me^o^>'benzyloxy) berrzomtrile (Example 190 a) in SS% yield, 4l XMR (400 MHz, DMSCmE) δ 3.-81 Π. 3H), 525 is, 2HL6.59( 8.4 Hz. 1 Η), 6.86 -: d, J == S.O Hz. IH), v)6 = 7.2 Hz. IB), MM id, J = 8 0 Hz. IH), 7.37 (t,./ - 8 o Hz, Hi), 7.46-7.42 iv.i. 2H>, ”.9! (s. !H), 8.31 (s. IH), ]0 % (s. IH). MS 334 (MB'}..

Example ! 90a: 2-Suli%noyiamino-M2-med!Oxybenzyloxy) benxondrile Prepared as in Example Mia from 2-umirso~6~(( leirah s dr ol uran~2~ ylpne)hexy}benzonimle (Example 190b) in 23% yield. }H NMR μΟΟ MHz rf.DMSO) 3 3.80 (s, 3Hi, 6 2b <d:,/- 8,4 Hz, IH).6.88 (d,,./=- 8.1 Hz IH}, 6.96 se ./ - " *' Hz. IH), ".06 pi../ - x.O Hz, 2H), 7.1.6 id, J === 8.4 Hz, IH), 7.39-733 (as, 5M), 7,45 (d../ == “.2 1 6-, 1 Η), 11.20 lx. ] H). Example )90b: 2-AnHn0-6-(2-mcthoxy.beazyk,xy) benzendrilc

Prepared ax in Example Π lb from 2-n)trO“6~{2-mgt1ioxybcnzykxy} benzonIt.riIe (example i90c> in 56% yield. *H NMR (400 MHz, M'eOD) 3 3.79 (s, 3H), 5.04 (s, 21-1), 6.306 26 (m, 2 H )/7.06-6,94 (m, 3H), 7.33-7,28 (rn, :3H}, 7.54 (s, IH).

Example 190c: 2-Ni;rvi-0-(2-n'ieibo.xybenzyl.ox¥) benzpnitril.e

Prepared, as in Example .1.1.1 e fem 2-,6-i!initrobenzonitrile and 2-meihoxybenzyl aleobol in .58% yield. !H NMR (400 MHz, DMSO) 6 3.82 (s, 3H), 534 (s, 2H), 6.99 (1,,/- 7.6 He, Hi), ?.08(d,,/=8.4 Hz, IH), 7.37 (t,,/- 8,4 Hz, 1(1),7,46 (d, ,/==6.0 Hz, IH), 7,81 (ds ,/= 7.6 Hz, 111), 7.93-737 (ny 2H).

Example 01;: 4~Amiam5-(meihbxyteO'a&amp;ydrofsra«-2-y!)-17/-benzp|i?| (i,2,6|tbiaillazl«e~ 2,2~dfex!de

Prepared as irt Example 111 from S-suldimDyiainiao-d-Cfflettexyicftafedro&amp;raa·· 2-yl)benxonariie (Example 191a} in 100% weld as a while sola! Ή NMR (400 MHz, DMSO-1 .65 (;η, IHk 1.86 (m, IHE 1.98 un. IH), 3.es> {m, I HE l?Min, i Η), 3.98 ρη, IK) 4.25 {m, 1 HE 6.6I id,/ === 7.2 Ha 1H), {>.74 ul > NO Hz. IH).

Example 191a: 2-S«lfamoylam}no-6-<mediuxyictrahydm&amp;ifaft-2~yl)beazoPari'k Prepared as in Example 11 la frofti:2-ai«ifio-6~((teirahydroii5raa-2-.y!)mrthoxy}beozooif.rik> (Example 1 89b) in 79% yield as a light yellow solid *H NMR (400 MHz, DMSO-aM 0 2.02-1 M (m, 2B), 3.66 (m, IH), 3.81-3,76 (m* IH), 4.20-4.03 (m, 3HK 6.93 (d,./ = 8.4 Hz, 1.H), 7.12-,1 J = = 6 4 Hz. IH}. 7.23 {>. I H}. 7 53 (!..../ === 8 4 Hz. IHk 9.34 (bra, IH).

Example I92i4-Amipo-5~ClMraii~3-yl?»eilioxy>li^l)eMzo|;c|fli2J|ililaiIiazine-2,2»dioxiiIe

Prepared as in Example i 11. Rom 2-su]taMoy)arni«c-6-{Eira?n3-yhucUioxy)benzonitrile (Example 192a) in 45% yield as an off white solid. !H NMR (400 MHz, PMS©~//d 5.1 ..1 (s, 2H). P.54 (d,,/ ==== 0,4 Hz, 1 PI), 6,56 ($, IH), 6.80 (0,/==== 8.8 Hz, IH), 7.39 (6 / === 8.4 Hz, IH), 7.64 IH), 7.74 (s, HI), 7.81 is, HI}, 8.23 (s, I H), 10.90 (s, I B), MS 294 (MH ).

Example 192a: 2-S:ol&amp;movlamlno-6-(furan-3-x Unethoxy )benzomtnle

Prepared as in Example i lia front 2~ammo-6-ifuraii-3“yImethoxy}beflzonitni.e·· (Example 192b) in 5774 yield as an off white solid Ή NMR (400 MHz, d-DMSO) 4 5.04 fs. 2H), 6.62 is. ί Η), 6.88 id,,/- 83 Hz, 1E), 7.15 i±J - 8.1,03 Hz. ! H), 7.35 (d, J - 8.5 Hz, I Hi, 7.39-732 irn, 2H), 7.67 (s, i Hi, 7.79 (s, 1 Hi, 7.86 (s. HI), 7.93 is. 1H), 10.91 is., IE), Example: 192b: 2-Ami;m-6-{fm3i>3-ylnicthoxy}benzQniirile Prepared as iir.Example 11 lb from (Example |9‘>e? m 213« yield as a jfohi yellow oil :H NMR (400 MHz, d-DMSOl 0 4/12 s\, 2Hi. 631-6.26 (m..2H), 6..59 is, IE), 6.99 0,./==: 8.4 Hz, El). 7.27 (s, 31),34%... IHK 7.66 {s. IHh 7.76 (x, 1H),

Example 192e: 2--Niiro--6-(l\iran--3--ylmethoxy foenzooitriIc

Prepared ax in Example 1 i 1 c ftom'2,6-diartrobenzonitrile agd; 3--&amp;raame:tSianol in 100% yield, lH NMR i4O0 MHz, d-DMSO) 4 5,2? Is. 2H), 6.59 <s, IB), 7,69 is, IE), 7,91-7,84 (m, 4H).

Example 193; 4-Ami«0“5~(3~methexybe»2a''lPxy)“1,£f-be»xo|ci \ 1,23|ildadiazOm-'2,2~d4oxide

Prepared as m Example 11-1 from: 2-s«lSpm>ylapim6-6-(3-n se tho x y benzy i o xy} be η xo n u η 1 e {E χ ;o n jf e i 1*3 si in 34% yield. Ή NMR. (400 MHz. ,/43 MSI)} 7 3.74 is.. 3H), 5.27 (:> 2Ei, 0./4 (-1,,/ - 8.0 Hz, i 11}, t».79 (d.../ - 8.0 Hz, ! Hi, 6 9(} (d,./ - 8.0 Hz, 11¾ 7.04 id,./ - 7.2 Hz, Hi), ".08 :(s, lH), 731 (t,,/- 8,4 Hz, 1¾ 7.42 (I,,/- 8.0 1¾ 11¾ ?.# (br s> 1H), 8 32 (br s. HI), 10.96 (br% 1H). MS 334 (ΜH'). :Bxaoiptel93a: 2-Sid.femoylai?:ilntV'6“{3-'nxahv<\ybenzylex> )benzooitrife

Prepared asin. Example Ilia from l-amino-b-CS-meihexybe^loxy^pzombriie (Example 193b) ml7%yield asawhiie solid. MS 334<MH‘),

Example 193b: 2-Apdoo-6--B--melhoxvbejizy!oxv)tepzomidl.g

To a mixture of 2mitro~6-(3"m.eihoxybe«zyl0xy)beozoaftrik (Example 193c) (480mg,l .69 mmol) k >: 1 aeodme-waier (9 mid was added zinc (S$2mg, 8,44 mmol) and •ammonium chloride (9! I mg, 16.9 mmol). The reaction was stirred at, room iemperato.ro for 30 minutes, then filtered and conemiraied. The residue was purified by flash elirdmamgrqfoy (55.-^5 A".tO:"\C" ϊ'ΐΟΧϋΗΟ-) · 0 pi'O Vicic 2 'νΠΎΟ ΠΟ"0"1 OCi' Z Y K>.vY )beffizomirile 133? mg, 78%). SB NMR (400 Μ11/, i/-DMSO) d 3.73 (s, 3H), 5.04 (s, l H), m2? i d.,7 === 8.0 Hz. 1 Η). 6.31 id. J === 8.4 Hz, .1H), 7.00-0.07 (m,3B), 7.27 itJ === 8.0 Hz. Ill), 7.3- m. 1H). 7.55 is. HI).

El^Bljkl23c: 2-(3-Mcd: .oxybe.fizyio'xyJ-O^itfObei'jzoiMtrile

Prepared as in Example Hie fmm 2.6-umiuobenzoniirilc and 3-roetboxytaylaicohol in 83% yield. *H NMR-(400 MHz, d-DMSO) 3 3.75 is, 3B), 538 is, 2H), 6.01 (d, J === 8.0 Hz. IH), 7.04 (d, J === 7.6 Hz. I Η), 7-.07 is, | H). ":35 (r. J -8.0 Hz, I H *. 7.78 ul, J === 8.8 Hz, 4H), 7.93-7.87 (m, 2H).

Example 194; 4--{2-i4-Annno- ///-henzoie||1,2,60ldiHliazHie-2,2'-di(>xide'5'-yloxy)roeOiyl)p>rroUdmium cMwiile

Prepared as in Example 166 from mrr-B«i>d3H{.3{4-amino»/i7-bexiz0[c]fi-,2f6]thia4iazine-2;2-dioxide»5'yiDxy)metliyl)pyrf0lidme-l-cafboxyiaie (Example 194a) in 23% yield as a white solid. Ί1 NMR (400 MHz. DMSO-J,) ·? 1.72 (m, HH 2 0" On 1H), 2 52 (m, 1H), 2.64 (m,} H), 2.94-2.74 (m, 3H>, 3.79 (m, 2H), 6.26 (d J === 8 0 S1/. 1 Hi 6 3" (d. J === 8.8 Hz, 1 Hi,. 7 09 ¢6 J === 8.0 Hx: I H), 7,31 (br s.. HI), 7.96 (hr s, 1 Hi 9 03 tbr v =H)

Example s 94a: mw-Bmyl 3-(2-(4-ammo-//7-benzofr'ji 1 %2.6]thiar a/me-’ ,2-diox«U"5-yloxyimethyl)pyn'c4i4iOe-l-oart^xyWd

Prepared as in Example 111 from ;m';-buiyE5~{(2'0yaoi>3~ (sulfomoJ$methy!)pheno.xy}me!hy!) pyrrolidine-1 -carboxylate (Example 194b) in 94% yield as a white solid. *H NMR (==00 MHz, OMSC-dO δ !.37 (s, 9H), S 66 (br m, 1 Hi, I 97 ibr m, 1 Hi. 2.78 (br m, 1 Hi, 3.48-3.20 (br m. 4Hx 4.12 (br. m 2H). 6.60 id../ === 8.0 Hz, 1 H)„ 6.74 (d. J === 8.4Hz, IH), 7.44 (t, ,/ === 8.4 Hz, IH), 7.70 (a, i Ηχ 8.33 (>, j Hy 10.95 (s, = H).

Example 194b; /eri-Bitiyl 3-(i2-cya:»o-3*(snlEmmy iammo}phenoxy)n'ieibyi.) pyrrolidine -1 -carboxy late

Prepared as in Example I I la from /m-buty I 3-{{3«aoHuu-2« 'CyaaophenoxY trocthy 1 ipyrrolidinc-1 -carboxy lam (Example 194c) m 4yicid as a white solid. ’l l NMR (400 MHz, DMSO-</«) <> 13? (a, 9M), 1.70 (br, 1 H), 1,97 (hr, IH), 2.63 (br, Hi). 3.472.93 tbr m, 4H). 4.03 tbr m. 2H). 6.94 id. 7 - A8 Hz, !H), 7.14 (d, J-3.4 Bz, 1¾ 7.24 (x, IH), 7.48 (s, iH), 7.54 {(../ - 3.0. I HE 9.4* ib? ^ i H).

Ex am pie ; 94 c; h'ri - 8td> 1 3 0' 3"amin^3"Cyaftopheno.\y)methy})pyrroUUi ne I caroxylate Prepared as in Ex ample I i lb from /m x-b-nyl (C-cyann.s. aiiorphenoxylmeOpylipyrrolidloe-d-earboxylase (Example 1940) m 1003. yield as a cleat oil. lH NMR (400MHz, DMSO-i) ,·> 1 37 is. 4H>, 1.69: ( br, IH). 1 ** (bs. ! H). 2.5'* (b,. I HE 3.07 (br. IH). 3.23 (br, 1H). 335 (br, IH). 3.40 (br, IB), 3.96 (m, 2H), 5.98 (s, 2H>, 6.20 (d,,/- 8.0 Hz, i HE 6.32 id. ./- 3.0 Hz. IH). 7 J 5 if,./ - 8,4 Hz. 1H).

Example 194d: Pcr-Butyl --$52-cyano-3-mtmphermxy )meihyl(pyrrolidine·· 1-carboxylate Prepared as in Example 166d from 3,6-dinitrobcP£onitrile and ?<?/?-buty! 3-IhydroxymciEylijryrroiidipc-1 -carboxylate in 093( yield as a yd low .solid. MS 347 (MB ). Example 195: {/H^-Astis0~5~((l~acety!pyrrolidl»“2«y1)iMetboxy)<-ll/“ benzo jej f1,2,611 h lad i a zi ne -2,2~d b> x I de

Prepared as in Example 176 fern (ft)· 2· asnlscHHCi -^tee^yffo!idib*2-;yi)xnetbe.x.y)btnnrotnn-ik' (Example I95ar la 333 yield a.% a white solid. !HNMR(400 MHz, DMSO-tp.) 6 1.90 Cm. 4H>. 2.00 {.s. 3H). 3,19 (m. 2H). -109 idd„ J - 9 ?% ή.] Η?.. 1 H), 4.24 (dd, J - 9,3..5.7 Hz. ; Hr. 4,41 pm 1HE 6.o2 id.../ - 8.3 Hz, 111). 6.37 (a.../ - 3.5 Hz. IH), 7.46U, ./ - 3.3 Hz.. I Hr 8.! ? (br s, IH), 8.33 Cbr s, IH), 10.93 (br s, IM). MS 339 (MHy

Example !93a: (&amp;)-2r&amp;mmpH>((Ji-seetylpyrrolidm-2-yi)mottey)benzon.itrlle .Prepared, as in Example 1 i 1 b from: {#)-2-((1 «‘acerylpyrroKdia*2>;yl)iaethox.y.>6~ rdixobenzonilrile (Example 195b) in 77% yield as a clear syrup. MS 260 (MB').

Example l4Sh: (.8)-5-(( 1 “Acety1psrroHain-2~y1)methoxy)-6-nitroben/enitrUe

Prepared as in Example 170b bom ιβ)-2*π2·ί>αητ»ο-nitropheno\y)rncdn. hpynv>!idinhun chloride and acetyl chloride in 100% s icld as a. yellow syrup. MS 290 (Mil).

Example 196; 4~Ami«f>»SHmeth«xy“3-pyrell4Men~pr«pto«ylEl/l-Iren m j c} 1J,2d>jthia4i a/J»e-2,2~6io\i de

Prepared as in Example 1 .1.1 Irom 2-suIiam0yladiiB0~6-i{ l-pfOpl0«yipyrr0iidi.n-3-yi)raetlioxylaerrzonitrile (Example 196a) in 29% yield as an ofF-white solid. Ή NIvsR (400 MHz. DMSCKd.,) $ 0.95 (u ./ - 7.6 Hz, 311). 1.06 (m, Ill), 1.77 (m, IH), 1.97 (rn. Illy 2415 |m, 111). 2.21 (¾./ - %.0 Hz, 2!i), 2.74 (m, 111}, 2.50 {m, 1H). 2.62-3.2.1 (rn. 4 HI 4.13 (ra, 2H), 6.60 (d, J - 8.0 Hz, IH), 6.75 (d, J === 8,4 Hz, ΐ H), 7.44- i i../ === 8.0 Hz. 1 H), 7.72 (s, ills. 9 H-8.32 (nr, 1H), 10.94 fs. 1H).

Example 196a; z-Sullaumylamino-Oyi) -propionylpyrrolidin-3-y!) nrethoxybenxoniMle Prepared ay in Example 1.1.1 a from 2-:.irniriO~6~(('l~prepionylpyrrolldl:ir-3-yl)mei:lK>:xy}benzoniirlle (Example 196b) in 27% yield as a while solid. MS 353|Μί.Γ)<

Exarrmle 196b: 2-Arnlno-6'-((:l'-preplQnylp:yn’ol!diin3-yl)nieilaxxy)benzonltrlle:·,

Prepared as Id Exadiple .11 ib from 2-aitro~6-ii 1 -propiOBylpyrnUidio-S-yi)rnetiiOX> Hxmzonin sic Ur .sample 196c) in 1001·} yield as a clear oil. MS 274 ΜΗ 1 Example 196c: 2'Nm0-tV({i-propionylpyfroHdia-3-yi)mcthoxy)hen20nitnic;

Prepared as in Example 176b bom 2-nitm-6-{pyrroliilin-3-yln\ci50Xy)ben)somtrite hydrochloride (Example 1.964)and proplonyl cMonde in. 51 % as a yellow solid. MS 304 '(MET). Example I96d: 2-Niiro-6-(pyrrolidin”3-ylmeibpxy)bepzoditriie IrydfoeMoHde;:

Prepared as in Example 166 tc^-buiyi-Ue-cyiuvQ-J’ nitoipbenoxy)0)ethyl)pyrrplidlne-l -earboxylaie (Example 1944) in 100% yield as a yellow solid. MS 24S (MET).

Example 1f 7; 4~Amino-5 {mt-?hox s -3~p>rolMme-i ~t>utysy 1)-1nzoie) 11,2,0)ihiadiaisne~ 2,2-dioxide

Prepared as? in Example 111 from 2-sullamoyiamino-tw; i -biffx'rx ipx !Tolid0i~,V ydlmethoxybenzonitriie (Example 197a) in ~3% yield as a wink' solid. JH W1R (400 MHc. DMSO-%) <> 0.06 (1.,/=== 7.6 Hz, 3Hi, 1.48 (q,,/- 7.6 Hz. 21b. 1 o? (m. Hi). l.7Mm. lib, 1.0? (ro, IK), 2.05 {m, IE), 2.17 (k,/=== 72 Hx, 2H), 2.74(m, IHk2x5 (m. Hi). 3.10 <m. Hb,5.P4~ 3,23 im. 41-b. 4.12 (m, IB),.6.60 (6,/==== 8.0 Hi, 10),6.75 (d, /==== 8.3 Bzf HI). 7.44 (t:,./==== 3.4 1¾ .1ΓΙ). 7.71 is. 1H), 3.35-8.32 (as, 1 E), 10.04 (s,. HI).

Example 197a: 2-Su!famoy lamino-6-{{ 1 -butyryipyrroi idιη-3-yl)m.eihoxvbcnzoniiriIc: Prepared as in Example Ilia from 2-avrnnO'0~0 i -buty ry Ipyirolidi o~3-yl)meihexyIbenzonitrik (Example I °7b) in 19% yield as. a while solid, *E NMR:(4Q0 MHz. BMSC%6) 6 0.85 if./=== 7.6 Ik, 3H.L ! .43 (q,,/ - 7.6 Hz, 2B), 2,)3-1.64 (m, 2BV2J7 irm 2H), 2.75-2.53 (m, 2B), 3,65-3 J 3 (m, 4H), 4.09 (m, 2H), 6,94 (m, IB), 7.13 (ro, 1H), 7.25 fs, IH), 7.54 (m, 1H), 9.45 inp Hi).

Example 197b. 2-Amino-6-ii I -butyrylpyrroiidin-3-yi )metboxy jbenzonitrifc:

Prepared as in Example 11 lb Eom 2-nltro-Mi E/mvrylpYnobdm/-yl)metboxy)benzonitrde (Example 197c) in 10074 yield as &amp; brown, oil. MS 283 (ΜΡΓ),

Example 197c: 2~Nltrn~6-C(I-bulyrvlpyrrolidin-3-yi):methoxy}bermondrlle:

Prepared a$: in Example 176b from 2-Pib-o>6^pyrVoIidin-3*yl»ifeihoxyjbeii20itiMIe· hydrochionde '(Example I96d) and bmyryl eMoride in 100% yield as an orange solid. MS 316 (MET),

Example If Si (E)-4-Amino-5-{l -(prOpylearbamoylicyelopropylmetboxy )-111-feeiizo | ej 11,24>|ihladlazine-2,2~dloxkle

Prepared as ip Example 111 from l-((2*cyano-3-(sulfarnoylaroino)pbeno\y)Q)cfhyl)»Nqpr&amp;pylcycI&amp;propanccarboxiHnidc {Example I ‘hr.fi' 3. 948... yield as a white solid. ‘I-i-NMR {400 MHz, DMSO-ώ.) S 10.95 (broad s. I PI). 8.55 (broad s, i l l}.. 7 95 (broad a, 1H}. 7.76 (t. ) - 5.2 Hz, 1H), 7.45 (6 j -= 8.0 Hz., jHi, 6.69 {d, j - 8.8 Hz, 1H), 0.61 (d„ .1-7.6 Hz., ; Hi. 4.22 (a, 2H). 3.01 (q,J« 0.4 Hz, 21Π. 1.40 (hex. J - 6.8 Hz. 211),1,12-LIB (op21-1), 0.88-0.95 (m, 2H>, 0.80 (?.)-- 7,6 Hz, 3H), MS 353 (MIL).

Exam ple 198a : 1-(( 2-Cy an o- 3 ~{su itamoy lam bio }pheuoxy }me thyl )-19 -propylcyclopropanecsrboxannde

Prepared as m Example '1. Γ! a from l-((3-3Truoo-2-cyanophen0xy)methyI}-N~ propyleyclopmpaneesrboxamide (Example 198b) atid stilfeaioyl chloride 0)-78% yield as a white, solid. 5B.-NMR. (400 MHz, DMSO-d's} #9.45 (broad s, 111),7.51-7,61 (m, 20), 7.26 (broad s, 2H), 7.16 (d, X- 8.(1 Hz, 11% 6.91 (i I- 8.4 Hz, 1H), 4.24 (s, 2H), 3.04 (% X - 6.4 Hz,2H), 1.43 (hex,J - 7.6 Hz, 2H), 1.08-1.14 (m, 21% 0.83-0.88 (m, 2Hh 0.82 (t, I - 7.2 Hz, 3H).

Example 198 b: 1 -((3-Are inc · 2 -cyanophenoxy )methyl)-N-propyk'yeloprepanecaiboxannde A solgfi-OH. -of .Hhyd«itryn)eihyl)id^>p.repyleycfepre|^aiarb(Oxa)«tde (Example 198c) (0.671,4.25 mmel) in aahydmds'THF (.1-0 «%) 'w^.;teated::-with NaH (0.17 g, 4.25 mmol* 60% suspension in niinem! oil) at 0 under a nitrogen atmosphere. The obtained mixture was stirred at 0 “C for 1 ft min and at rt over 30' min. Then, a solution of 2~an:dno~6~0uorobenxonhrile (0.53 g, 3.86 mmol) in THE (5 0 ml.,) was added and the obtained mixture was heated at reflux overnight, The cold mixture was epenehed with saturated aqmmus.solution«f NH<C1 (20 mi.,} and extracted With EtOAc (3x50 ml,). The combined extract was washed with brine, dried, over anhydrous MgSOw filtered and evaporated. The residue was purified bv chromatography on silica gel using gradient hexsues hcxaoes/EtOAc (4:6), to give 0.75: g (71%) of the title compound. as a yellow solid. Ή-KMR 6-100 MHz. .DMSO-da) #7.5! it. .1-= 6,:0 Hz. i H}, 7.17 (t, .1 === 8.0 Hz. I Η}, 6.34 (d. J === 8.4 Hz. 1H), 6.19 id, I === 8.4 Hz, 1H), 5.97 <broad s. 2 Eh, 4.13 (s, 2H}. .3.04 up J === 6.4 Hz, 2H), 1.43 (hex, J === 6.8 Hz, 2Hi. 1.05-U 1 (m, 2H), 0.78-0.86 (up 5H).

Example I96e: 1*{Hydroxymethyl hN*pmpyl<^dopropanccarboxamiJc

To a solution of ethyl l-(propyIea/barooyi)cvciopropanecavboxylate (Example 19Sd) (1.65 g, 8.37 mmol) in EtOH (70 mL) wus added NaBH.; {{697 g, 25.64 mmol) at rt. The obtained mixture was stirred at rt over 2 days, quenched with 1.5M HCI and concentrated under reduced pressure. The concentrated mixture was extracted with EtOAc (4x70 ml..}, the combined extract was washed with saturated NaHCO.* and brine, and was dried over MgSCV The filtrate was evaporated and the i'esidue was purified by chromatography on silica gel using the solvent gradient hexanes —> hexanes.'EtOAc (1:9), to furnish 1.14 g (88%) of the product as a white solid. lH-NMR {-100 MHz. DMSQ-4.} /)7.49 (broad a. 1H), 5.09 (broad s. 1H), 5 49 (s, 2HI 3.05 (q, i ==== 6.4 Hz, 2H). 1.41 (hexj === 7.6 Hz, 2H), 0.86-0.91 (m, 2B), 0,83 (t, j === 7.2 Hz, 3H), ().55-0.60 (m, 2H).

Example 196d: Ethyl 1 -i propvlcarbamoyl tcydopropanccarixxxylate

To a solution of 1 -(etlioxVcih'bonyllcyddpircpancca/'bcxylie acid (Wheeler, T. H.; Ray, J, A, Synthetic· Cvmmunkattom 1988,18(2), 141} (1.52 g, 9,62 mmol)-and-«-propylamine (0.63 g, 10,58 mmol) in anhydrous DMF (65 tnL) at rt, were added NaHCO^ (4.04 g, 48.,.11 mmol), N~(3"diniethylaniinopropy|)~NWihyiearbodihoide hydrochloride (2.21 g, 11.34 mmol) and l-hydroxyberrzotrlazole hydrate (.1,77 g, 11,54 mmol) under a nitrogen atmosphere, After being stirred at rt overnight, the mixture was partitioned between watoj (100 tuL) and EtOAc· (300 mL). The organic phase was separated, washed with water and brine, and was dried over anhydrous MgSGf. The filtrate was evaporated to give 1,65 g (86%) of the crude: product which wax used in the .next step without purification; Ή-NMR (400 MHz, DMSO-ns) J8.33 s broad s, 1 H}> 4.08 (q, I ==== 6.8 Hz, 2B), 3,07 (q, j ==== 6.4 Hz, 211), 1.43 (hex, j === 6.4 Hz, 2H). 1,31 (s, 4H). .1.17 (t, i === 6.4 Hz. 3H), 0.85 (t, I - 7,:2 Hz, 3H).

Example !99t (IfiM-A0dno~5~(9“motl«>xyl>at~2-enylo.xy3~lfi~l>ea^o{c.||l,2,6fthiaiIiaz.iae~2,2-dioxide

Prepared as in Kxuropic 1 11 from 2-suifamoy lammo-**«(4*nicthoxybut-2- envloxy sbcnzonitrilc (Example 199a) in 01°¾ yield as a white solid. ‘0--NMR (400 MHz. DMSO"i/fi) <?i 0.94 (broad a, 1 Ef), 834 (broad &amp; 1H)? 7.90 (broad a, 1E}, 7AS (t, 1 - 8.4 Hz, 1H), '6.75 (d, I - 7.6 Ho, 1.0), 6.61 (d, J - 8.0 Hz.. .1H), 5.88-6,02 (m, 211), 4.75-4 8! (m5.20), 3,883.93 (n\ 20). 3.22 (,s. 30). MS 208 {MO').

Example 199a: 2-Su!tamoy l3ntino«6-{4-methoxybut-2-e?ty loxy)ben?.onitrile Prepared as in Example !! la front (EV2-amino-6-{4-roethoxvbut-2-coyloxyjhenzonitrtle (Example 100b) in 93'?·» yield as a white solid. Ή-NMR (400 MHz., DMSO-i4) <>'9.46 !broad s, Hi), 7.56 (t. j -8,4 Hz, IH), 7.26 {broad s.2H). 7.15 (d. j - 8,01Hz, Hi), 6.06 (d,.! 8.8 Hz, 1.0), 5:84-6.00 (m, 20), 4.68-4,76 (ny 20), 3,80-3 35 (m, 20), 3,23 (s. 3H).

Example 199b: {£>2-Amino-6-(4-methoxybirf-'2-eiiiy1oxy)bea^obifeile

To a-solution of (£>2-(4-methoxybu^2<«iyioxy)-6-nitrbbo»zonltriie (Example 199e) (0,25 g, 1.00 ramoli in a mixture of Ac-OH, EtOH and,water (33 rnE, 1 ;1:1;) was added iron, powder (0.56 g> 10.00 purtol) at Λ The obtained mixture was stirred at rt for 20 min., then was heated to 50 Tl fer a fisriher 15 min, and allowed to cool. The sosperedon was concentrated under reduced pressure; the residue was treated with water (50 tuL) and extracted with EtOAe (4x50 uiL):> The combined, extract was washed with saturated aqueous NaHC'O* and brine, and wits dried over anhydrous MgSOy The filtrate: was evaporated. and the residue was purified by silica gel flash efiromategraphy using gradient hexanes —>· hexanes/fiiOAc (1:1), to give 0.19 g (86%) of the title compound as a white solid. s li-OMR (400 MHz, DMSO-fie) 7..17 (t, 1 - 8.4 Hz, 10), 6.34 (d, I - 8,8: Hz, 10), 6.22 (d, J - 8.4 Hz, 1H), 6.00 (breads. 20), 5.82-536 (at. 20), 4.56-4.62 fm, 2H), 3.88-3.93 (rn. 2H), 3.23 (s. 3H).

Examnlc 199c: (£)-2-(4^McthoxybtAt-2-enyloxy)-6«nli:p5benz0n.ht:ite·

To a solution of (.e)-2-(4~hydroxybut~2-euyloxy)-6~uitrebenzouitrd:e (Example 1.994) (0,50 g, 2.13 tumol) and 2,6-dt-tert~butyl-4-meihyipyridiue (2.18 §, 10.65 mmol) in CHjC!:· (15.0 rnL) at si. was added (nrnethvloxorsisisn teiratluoroboraic (1.55 g, 10.65 mmols under s nitrogen atmosphere. Alter 1 h at si, the reaction wax quenched with water (50 ml) and extracted with EtOAc (4x50 mL). The combined extract was washed with water. 1.581 HCL saturated aqueous NaHCQj and btirie. and wax dried over anhydrous MgSOj. The filtrate was evaporated and the residue was pursued by chromatography on silica gei using the solvent gradient hexanes ---+ hcxaness/EtOAc (3::7), to give 0.25 g (72%) of the title componnd as-a yellow solid. Ti-AMR (400 MHz, DMSO-A.) #7.84-7.92 (six 2K), 7.68-7.73 (m, I H), 5.82-6.03 (rn. 2H), 4.82-4.88 (m. 2E), 3.87-3.93 (ssu 2H), 3.21 is. 3H).

Example ivvd. (£)-2-(4-Hydroxybut-2-enslaK>)-6-mtrobcozomtrilc

Prepared as in Example- 166d front .(£}~but:-2-e.ne~:l ,4-dlol (Miller, A. E. Gy Biss,. .1. W.; Sehwarizrnan. 1.., H../. (9?.g. Chem. 1959, 54, 027 us 30%yield as a yellow solid. Ή-NMR (400 MHz. PMSCKA) #7.83-7.94 (m. 211). 7.07-7.74 (m, 1H}, 5.97-6.07 ins, iH). 5.780.89¾us. 1H). 4.80-89 (m, 3Η», 3.0-1-4.02 Cm. 2H>.

Example 200:4~AMtno~5“(2~(hydr0xymetMyI)allyioxy)-iH-feen2efe)il,2,6ithladlaziite-2,2~ dioxide

Prepared as lit Example 111 .from. 2-((2~cya.no'r3-(sulfasttoylarsiino)pBenoxy)i»ethyl)aliyl acetate (Example 200a): in 44% yield as a white solid. slfiNMR (400 MHz, PMSO-%) S 10.95 (broad s, IE), 8,34 (broad s,J H), 8.01 (broad s, IH), 7.45 it, J - 8.0 1¼ 11) i. A76 <d, I == 8.4 Hz, 1H), 6.61 (d, .1 === 8.0 Hz, 1H). 5.26 is, 1H). 5.20 (s, 11:1)., 5.14 it, J === 5.2 Hz, IB). 4.78 {.s. 2H), 4.03 (d, J === 5.2 Hz. 2B). MS 284 (MIT).

Example 200a: .2-((2-Gyasto-3:-(su:lfesiroyknnPo)phenoxy)methy1)a;llyl acetate

Prepared as is: Example 1.1 lafrom.2~(X3-a.misiQ-2-cyanophe:no:xy)meihyl);a!|yl acetate (Example 20()h) ht 87% yield as a whits solid. (400MHz, DM $0-14) #9,50 (broad s, 1H), 7.5? (tj - 8 4 Hz. IH), 7,28 (broad s, 2H). 7.1 7 (d, J - 8.0 Hz, IH), 6.97 (d, J 8.4 Hz, IH), 5.39 (broads, IH), > 33 (broads, 111),.4.74 (s, 211).4.63 (s, 2H). 2.05 is, 3H), Example 300b: 2-{{3-Ajtnno-t2*€^8«op'henoXy;)n»et'h.yl)«iilyl acetate

Prepared as in Example 100b from 2-u2~c>ano-3-mtropiicnoxvimcthyDally I acetate (Example 200e) in 76¾ yield as a yellow oil Ή-NMR (400 MHz, DM SO· ,4? <>'7.la it, J - 8,4 Hz, INK 6.35 {d, 1- SJ Hz, 114), 6.23 (dsJ - 8.0 11¾ 1H)S 6.03 (broads. 214), 5,34-5.38 (m, illi s 28-0 'j (m, 1H), 4 61 (s, <JH), 2.05 is, 3H),

Example 200ez2“ff2-Cyaa.o-3-nitropheno:xs3metlwl)al!vi acetate

To a solution or2-{2-{,hydroxymedryi,>aliyIoxyHwntrobenz«>:UtriIc (Example 200d) (0.40 g, 1.73 mmol). 4-dimcthy landnopy riUinc (0.21 g, 1.73 mmols and pyridine (0.68 g, 8.64 mmol) in CH<T· S 10.0 rnL) at 0 ”C\ was added Ac/) (0.53 g, 5.10 -mmol) 'under a nitrogen atmosphere. After being stirred as 0 "C for 10 min, the mixture was stirred at rt ovemigSit. The reaction mixture was diluted with. BtOAe (100 mL), washed with 1,5M HQ, saturated aqueous NaHCX); and brine, and was dried over MgSOj. The filtrate was evaporated and the residue was purified by chromatography on silica gel using die solvent gradient hexanes hexcsries/EtOAc (3:7), to furnish 0.40 g (841¾) of the tjtie. compound as a yellow solid. Έ>ΝΜΕ (400 MHz, DMSO-mp 47.95 (dd, J - 8,4 Hz, I - 1.2 Hz, 1H), 7,91 (t, 3 - 8.4 Hz, I B), 7.74 (dd, 3 - 8,4 Hz, .1 - .1.2 Hz, 111), 5,43-5.46 (m, 1 Hi. 5.36-5 40 (m, = if). 4.9-0(s9.2B}54,h6(s,.2H)52.05(s,314). Example 200d: 2-(2-{Hydroxymeihyl)allyloxy)-6-rtifrobenzonftd&amp;

Prepared as in Example 166d from 2.6-dimtfPtehz6'attril@ ap<l 2-rnet!iylcnepsopane-l ,2~diol in 55% yield as a white solid. ‘H-NMR (100 MHz. DMSO-uy A7.93 (dd, 3 - 8.4 Hz, 3 - 0,8 Hz, 1H), 7.89 (t, J> 8.0 liz, IH), 7,73 (dd, J - 7.6 Hz, j - 0.8 Hz, 1¾ 5,23-5,29 (m, 2B), 5,03 (t, J - 5.6 Hz, Hi), 4,85 (s, 2H), 4,06 fd, J - 5.2 Hz,

If 4) jllatAMBOOS A1 jZZM ΠΙΑΓ]

Example 2il t 4^A.ml8Wi-5-(4s5-dlhydrdfarasi~2~y!)~l,l:l~i>€tMO|e)fl72it61thfailiazinfc2),2-imxiile

Prepared.as in. Example H i .fro*» 2-su!la.moylautiiio-6-(4,5-dlhydroferan-2~ yl)benzq«imie (Example 201 a) in 3)·%: yield as a white solid, *14 NMR (400 MBz, DMSO-iA) S 2.75-2.81 (m, 214), 4,43 (t. J 9,2 Hz, 2H), 5.35-5,36 Cm, 1H),7,0? {dd,</- 1,2, 8,0 Hz,IH), 7.12 (dd, J::: 1.2. 7.2H?, 11 n. 7,50-7.54 (m, IH), 8.2-8.4(broads, 10011.09 (s, ffi). MS 206 IMII).

Exam pic 201a; 2~S:u!feaoyia06n0-6-(455-dihydmfiiran~2~yi)benKoal!ti!e

Prepared as fa Example 1.1,1a from 2-amira3-6-(4!5-dfhyd.miiira0~2-yI}beis«0aito!e (Example 20! b) in 14% yield as a while solid. SH NMR 1400 MHz. DMSO-4) 0 2/2-238 (m, 2Hi. 4.45 (t, J ::: 9.6 Hz, 20), 5.80 (t, ,/- /.2 Hz. ! H), 7.2^ Is. 2H). 7.47 ul../ - 7.2 Hz, i Hi 7 56 (4./ :- 7.6 Hz, 1H;·. 7.67 (t../ ::: 8.0 Hz, j Hs. 9.42 (s. IB). MS 266 (MH j.

Example 20; h: 2-amino-6-(4,5-d{hsd:o1u{an-2-yiihcnzonitnlc S-xA.aaao^brp.mobenzoniirile (0.75 g. 5.81 mmol), i4,5 -d thy drot uran-2·· yl)trimethyteiatn>anc (Menez, P,; Fargcaw V., Poisson. J.. Ardixson. J.: Laltcroand.

Pancmzi, ,\. Tetnftiedmn Letters 1904,5.4426 7767) (] .(>2 g. 4,38 mmo!}, and palladium tenaUsU; iphcnvipbosphine) (0.33 g, 0.28 nunH) a ere reflused in toluene 510.0 uiL) under nitrogen Mr t.5 h. Saturated asomonirmt chloride (:2 rnLi and aoeytmtiitm Ityuroxi-Je (4 ml.,} were added, and the mixture vva.s extracted with EtOAc The orgastic layer was concentrated under vacuum and the restdtse was purified by cltfumalogruphy on. silica uxirtg 35% EtOAe/hexanes to give 0.48 g (688«) of the title compound ax yellow oil. Ή NMR. (400 MHz, Acetone-/*} d 2.78-2J3 (me 2B), 4.40 (t, J - 9.2 Hz, 21105,76 (t,,/ - 3.2 Hz, Hi), 6,04 0, 2H), 6.77-6 JO (in, 2H), 7.28 (t/- 8.0Ηζ, IH). MS 18? (ΜΗΓ).

Example 202; 4~ A0iiito-S-(teira0ycIr0faraa“2“yl)'4ll~Oerwolc] 11.2,6] tldadisszlae~2,2-iii»xiie

Prepared as in Example 1H frarn 2~Su:l:famo24aniiiio-6-(t.etrahyd!x:ditran-2-yl)feenzonuriIe (Example 202¾) in 52% yield as a white --,..416 !H NMR 1400 MHz, DMSCK/J 0 1.94-2.05 (m. 3H), 3.21-2,28 (ny 10), 3,81-3.87 (ny !H):, 3.92-3.97 (m, IH), 5 23-5.27 (m, 1H):, 7.02 ¢0,,/:==:8.0 Hz, 01),730(4/::::7.6 Hz, IB),"Jl. (i ,/== 7.6 Hz, 0-1). 7.9-8.5 (broad, 20), 10.04 (s, IH). MS 268 (MB:>

Example 202a: 3-Suiiamoyia0di:to-6/tstnt:bydrofl;ran-2-yi ibenzorsim !e 2-Araino*(H4,S^ihydrofutan.-2-yl ibenzomtriio (Example 202b) (0.24 g, 1.28 mmol), 10% Pd'C (0.24 g). and antrnouiurn formate (2.40 g. 38.1 rmnoi) acre refluxed in McOH (25 mh) under ni5rogc?i for 1,5 h. The insoluble solids were filtered oui ami discarded, and the solvent was removal unde? vacuum. The resultant residue was dissolved in F.rO.Ae, washed with saturated Na>CCo and brine, dried ov er MgSO.·. and concentrated unde?'vacuum. The residue was dissolved In anhydrous DMA 52,0 ml) and was treated with suifamoyl chloride (0.1! g. 0,9? mmol'*. The reaction mixture w as stirred under nitrogen for 30 minutes, quenched with water ¢ 5.0 ml,} and extracted with EtOAc 5 3x50 niL). The combined extract was dried over MgSO^ ΠHeard and concentrated under vacuum, t he crude product was nitrified oy silica gelpep-TLC using 65”·’· EtOAc hexanes to give -+5,0 mg {] 3N) of the title compm-nd as a white solid, Ti NMR 5400 MHz, Aectone-u',,) d 1.71-1.78 (m, 1 Hi. 2.02-2,07 5m, 2H>. 2.45-2.52 on, IN), 3,90 3.95 (nr 1 Hi, 4.10-4.15 im, 1H). 5.08 (t, J === 6.8 Hz, 1 H), fi.b-b.S thread, 2Hi. 7.30-7.3? 5m, IH). 7,62-7.03 5m.. 2H), 8.22 {broad s. 1H) MS 268 (MH ).

Example 203; 4-A^i»o^3“(p>^#»”2-yl)prcspoxyVII-i-beaM^e)|! *2,6j f hi«di8zis&amp;e~2*2~ dioxide

Prepared as in Example 111. from 2~sulfam«‘ybmi*t«>-t'>-(3-(pxruU»»2- yllpropoxylhenzonitrile (Example 203a) in 58% yield, as a white solid, ’ll NMR (400 MHz, DMSO-bM 6237 (quint,./ === 6.8 Hz. 2H), 2.89 {% ,/===== 7.2 Bz, 2H), 4.19 (t,/ ==- 0.0 Hz. 2Hh 6.60 (d, / ==== 8.4 Hz. I H>, 6,73 (¾ J ==== 8.8 Hz.. 1H), 7.19-7.22 im, ! H), 7.29 (¢1, .7 ==== 8,0 Hz, 1H). 7.44 (i, ,/==== 8,4 Hz, 1H), 7.08-7.72 $m. 1H), 7.92 (s. 11-1),8.36: (χ,ΙΗ), 8.49 (4, /=== 4.0 Hz. IH), 10.94 (broad s, IB), MS 333 >; MH').

Example 208a: 2-8u!:famcwhm.tin0-6--(3-(-pvi.ldin-2-vl)DtOnoxv?benzenltrile Prepared as in Example 11 l a from 2-amino-6-(3-(pyrklin-2-:yl)prt'?j-.x->xy)henzonifnic (Example 203b) in 97% yield as a while solid. Ή NMR (900 MHz, DMSO-sfo) <> 2,15 (quint. J ==== 0.4 Hz.. 2H>, 2.92 (f, / === 7.6 Hz, 2H), 4.15 (i, </- 6.0 Hz, 2H), 6,93 (d../ - x.4 Hz, IH}. 7.14 (d,,/ - *.4 Hz, 1 H), 7.20-7.29 (rn. 4K), 7 55 : u J === 8.4 Hz, 1Hi, 7.887.72 un. IB), 8.48 (d, J === 4.8 Hz, 1 Hi, 9.49 (broad s, IH}. MS 232 (Μ1Γ). |6sam|de2C^^ 2-Amiik^-6-(3-{pyHduv~2~yI)p'Opdxy)tei2oMti'iic Prepared a- in Example 199b from 2-mlro-6-(3-1 p\ riditi'2~ .yl)pmpoxy)beR20Mitile (Example'203c) in 85% yield as a white solid, lH NMR (4(10 MHz, DMSO-%) d 2,12 (quint, ./=== 6.8 Hz. 2H), 2,90 (t, ./=== 7.2 Hz. 2H), 4.02 (T. ./-= 6.4 Hz, 2H), 5.99 (s, 2H i, 6.18 (d../ === X.O Ηζ» I Hi. 6.23 id../ === 8.8 Hz, i H). 7.14-7.22 (m, 2H). %26 id, M 8.0 Hz. HR, 7.67-7.7! on, IH). 8.49 id, J === 3.6 Hz, IH). MS 254 (MH:).

Example 203c; 2 Nitre -6·(3pyridin-2 >I>propox>Ibenzonitriie 'Prepared as in Example 187c from 3--{pyr idin·2·y Opropan-1 -ol 2,6-diftitrebePzoftitriife in 867·;, yield as a while .solid. SH NMR 0400 MHz, DMSO-i/p S 2,21 {quint, J -= 6.4 Hz, 2Hi, 2.95 (i. J === 7.2 Hz» 2Hs, 4.3! (t. J === 6.4 Hz, 2H.!, 7.19-7.22 im, I Hi. 7.38 (d, J === 7 h Hz. IΗ κ -267-7.74 {ro. 2H), 7,86-7.92 (m. 28)» 8 48 fd. J === 4.8 Hz, IH) MS 284 (MH ). £xample 204: 4kA»*i»«~5-(2-(pyiMM-I-yt)ethexy)-1H»be**5S0|cj [1,2,6 \tMadlazme-i^ dioxule

Prepared as in Example 11I from :2->siiifi-mdy4attiino-6-(2-(pyi'idin“2-yI)etliiOxy]benzoinn-i!e (Example 204a) id 2286 yield as a white solid,\H NMR (400 MHz, DMSO-4) 6 3.29 U, </ =,5.6 Hz, 2B), 4.46 ,(t, J = 5.6 Hz, 28), 6.59 (&amp; J === 8.0 Hz. IH), 6.75 id, J == 8.8 Hz. IHl 7.28-7.31 (m, IH), 7,40-7,46 {m, 2H), 7.75-7.80 (m, 111),8,33-8.52 (m, 3H). 10,91 (4, Hi) MS 319 (MH 1.

Example 204a; 2~$u!!amaylamino-6-i2-(pyridin-2-y!)edioxy}benzomtriie Prepared as in Example 11la Irom 2-apjino^-(Z“(pyridi»-B:-.y-I)eihexy)henzon!lriie (Example 204 b) in 6?'% yield, as a white solid, *H NMR (400 MHz, DM50MR 6 3.22 (1,,/-6.4 Hz, 2H). 4,48 it, J - 6.4 Hz, 28), 7.00 {(!,,/= 8.8 Hz, IH), 7.1.4 id,,/ == 8.4 Hz, 1H), 7.23-7.26 (m» 38). 7.39 (d,./ = 7.6 Hz, IH}, 7,45 (1,./== 8.4 Hz,. HI), 7.73 (t ,/ = 7 2 Hz. :11),8.5: (d,./= 4.4 Hz, I.H)., 9.42 (s, 18). MS 319 (MH )

Example 204b: 2-Anjino-6-{2-: pyridin-2-yl)c*hoxy iberszon itriIc

Prepared as in Example 2b from 2-slitco-M 2-{ pyridin «2 ·yi)pj opo.xv)bcw.oiritrile (Example 221c) hi 60% yield us a white solid. il 'NMR (400 MHz, DM 80--%) 3 3.18 (1,,/====63 Hz. 2H ?, 4.36 (t. / === 6.8 Hz., 2Hh 5.97 (.v 2Hh 6.25 (d J === 8.4 Hz. Hi), 632 (d J === 8.4 Hz, IH), 7.17 (u / === 8.0 Hz, I Hi, 7.22-7.26 ini, IH), 7 37 (0../ 8.0 Hz, IH),7.70-7.75 (m, 1H), 8.51 (d, ,/ === 4.4 Hz, IH). MS 240 (ΜΗ }.

Example 204c: 2-Nit ro · 6 · (2 · spy rid=rv-2 · y I lethoxy )bcnzonTtri1e prepared as in Example 187c from 2--{pyriclin-2-y Oethanoi and 2.6-dlnilTobenzoiiitrile ία 82% yield as a yellow solid, S.R Ή ME. (400 MHz, DMSO<-/y d 3.27 (t,J~ 6.4 Hz, 2H), 4.64 (t,./ === 6.4 Hz, 2H). 7.23-7.27 (ro, IH). 7.41 (d,/ === 8.0 Hz, ιH), 7.71-7.70 (ra, 2H), 7.86-7.91 (m. 2H), 8.50-8.52 (m. IH). MS 270 (MH%

Example 205: 4-ASt»i«o-'5-((5-i«ethyiisoxazok1-'yl)metho\jiI l-benzo jc| 113,61 rhiadtaiae-2,2 -dioxide

Prepared as lit Example 1Π from 2"Sullamoylai«liio--6-((5mtethyIisoxszoE3~ yl)meihoxy)henz0oitrlle (Example 205a) in 83% yield as a white solid. lH-NMR (400 MPfz, PMS©~%) 32.42 (s, 3H),..5.40 ts, 2H), 6.36 is, ! H), 6.65 (d,./ === 8,4 Hz, 111),631 (d J === 8.4 Hz, 114)/7,48 (1,,/ - 8.4 Hz, IHh 8.06 (n IHk 8.40 (s. IH). 11.02 (s. IH). MS 309 (Mli+), Example 205a: 2-S«ifamoykaw.a0-6-((5- methylisoxazol-3 -yl)meth oxy )be.ozomtrile Prepared ah in Example 1 i l a from 2--amino-6'((5-methyiisoxazol-3-ylimcthoxy/beiJzoniinle iExaittple 2226) in 85% yield as. a white solid. ^tt NMR (400 MHz, 'DMSO-<&amp;):<f2,42 (s,·3¾ 5.32 (s, 2H), 6,34 (s, IH), 7.07 (d,/- 8,0 ffz, IH), 7.19 Id,./- 8.0 Hz, 1H), 7.30 (s, 2H), 7.59 (t,,/- 8.8 Hz, 1H), 9.53 (s, 1H). MS 309 (Mif ).

Example 208 b: 2 A mi no -6-((5- methyl isoxazo I -3-y l)mefnoxy }he nzon 0 ri le

Prepared ax in Example 199b from 2-ff5-mcthyjisoxmzol--3-yl}meihoxy)--6·· niizobeBzeoorde (I sample 205c) in 52% yield as a yellow solid. *H N.MR {400 MHz... 08.1.80-¾½) 42.42 ($, 3H). 5.19 % 2H). 6.07 (s/2H), 6.3146,33 (m, 2B), 6.37 (d J - 8,4 Hz, IH), 7.20 (¢,/- 8.4 Hz, IH), MS 230 (Mil ).

Example 205c; 2a(5-MethyUsioxa2:oi-3«yl}{rieihoxy)-6-nUroberizonnrlie

Prepared as in Example IK7c from <5-nmthy!isoxazQ]-3-y!knctiianoi and 2.6-dimlmbeaxomtrile In 86% yield as a yellow solid 5II MMR:(40O MHz, DMSO-*) 42.43 id J -0.8 Hz, 3H k 5.50 is, 2H), 6,35 (d,,/- 0.4 He, 11¾ 7.83 (dd,,/- 1.2,8.4 Hz, llif), 7 .91-7.98 (m, 2H), MS 260 i.MH'}.

Example 206: 4-Ammo-fM S-eycloptopyfetho.vy ) I I:W>e»z6|ef 11,2,i|tldadiazme-2,2-atioxiile

Prepared as In Example 11 I from 2>snlfarnoy(amioo~6~< 2> .qy.ciopfOpyiefhoxy)beni:onitrilc (Example 206a) In 94% viok! a;' a white solid. !H ΝΜΙί (400 MHz, DMSO-d) d 0.1 1-0.15 (no 2E), 0.43-0.48 (m. 2H), 0.^-0.81 «m, IH), 1.73 (q, J.- 6.8 Hz, 2PI),4.21 (i,./=== 6.8 Hz, 2H), 6.61 id../- .8.0 Hz. IH),6.77 id,,/-8.4 Hz, 111), 7.46 (t, J-8.4 Hz, IH), 7.87 (s, 11-1), 8,39 (s, I Id), 10,96 (w IB), MS 282 (Mif).

Example 206a: 2-Sulfanioyianrkio-6-(2-eye!iJpropyletlip.xy}be:azoniirile

Prepared as in Example ,1.1 la from 2-amm0-6-(2-cyclopr0pyiethoxy)banxomtriIe (Example 206b) in 80% yield as a wliiie solid. NMK (400 MHz, DMSO-d>) δ 0.13-02 7 (rm 2H ;·, 0.41-1646 (rn, 211), 0.82-0.87 On, IH>, 1.64 (qf./ - 6.4 Hz, 2H), 4.16 ;(tt ./ - 6.4 Hz, 2H), 6.96 (d,./- 8.0 Hz. 1H>, 7,14 (6,J::: 8.8 Hz, 1Ή), 7.27 (», 2HI, 7.56 (1,./ - 8,8 Hz, 1H),:9.44 (s, IH). MS 282 (MH t.

Example 2066: 2"Amlae-6-(2-cvolop?Off%etlmxy)benxorntrIk

Prepared as m Example .199b from 2-(2-cyclQpropyletimxy)-6-rnirobeaxmdtnle (Example 206c) In 90% yield as a. yellow oil, lH' NMR (400 Mile, DMSO-ds) 0 0.13-0.16 (m, mu 0.40-0.41 (m,2H), 0.81-0.85 (m, I H), i .61 (q, ,/-6,8 Hz, 2H), 4,04 a,,/- 624 Hz, 2H), 5.97 (s, 2H), 6 .21 (d,,/ - 8,0 Hz, 1H), 6,32 (d J - 8.8 Hz, IH), 7,17 (/, ,/ - 8.4 Hz, 1H). MS 203 iMH ).

Example 206c: 2-( 2-Cyclopropvletboxy H>-«itrobeftzo»itrile

Prepared as in Example 187c from 2-eyeloprppyletbaaol and 2,6-diniifobenzottilTiie in $5% yield as a yellow oil. *H NMli (400 MHz, DMSO-dz) 6 0.15-0,20 (m, 2H), 0.434).4/ (m. 2H), 0.84-0.89 On, 1 H), 1 .04 {op./- 0.8 Hz, 2H ), 4.3) (t, ,1---- 6.4 Hz, 2H). 7.73-7,76 (m, 1H), /.86-7.93 (m, 2H). MS 233 ι VIΠ 5.

Example 207:4~Aiaia»*S^{fey4r©xymelhyi)-lH-be«20|cHi^,6]<:yaclia2i»P-2»2*iliosl.'d[e

Prepared as in Example 111 from 2-e>^ino-3-(suUumoytiai«!no)bor!Zj'l acetate (Example 207a) in 53% yield as a white solid. :H NMR (400 MHz: D.MSO-sW 0 4,60 (s, 2Hh 6.62-6.63 lm. 111),7.04 (d,./ = 8 0 Ho. )H)., 7.00 (d../=== 7.2 Ho. IH). 7 51 (0./=== 7.6.Hz, i.H)s H 33 (broad s, 1 H). 8.86 (broad s. IH). lO^is, IH). MS 328 (MH } .17.2-4)/.).2 OJ.V..02'/..:. 2 - C ya no-3-(su ί fa m oy I a /:/i η o }bc n xy I acetate

Prepared as in Example 111a from 3-amino-.Vcyanobenzy! acetate (Example 207b) in <->0% yield as a white solid. 'H NMR (400 MKx, Acetone-;/,) 6 2.09 (s, 3H). 5.24 fa, 2H). 6.76 {broad s. 2H>, 7 38 (dd. J === 0.8.7 2 Hm IH), 7.66-7.75 (m: 2H), 8 40 (broad a, 1H). MS 270 (MIC).

Example 2070: 3-A m I jw-I-cyanobcnzyi acetate

Prepared as in Example 199b from 2-eyarto-3-r»trobenzvl acetate (Example 207c) in 84% yield as yellow oil. ! H NOvlR (400 .MHz. Methanol-*/,) 4 2.10 (x, 341),.5.11 (x, 2B), 6.70 (ti 4====7.2 Hz. 11-1),6.78(4,./===8 81-17. IH), 7.28 (1,./===8,4 Hz, IH). MS 191 (MB ).

Example 207c: 2-Gyan.o~3mitrobenzy! aceta.fr

Acetic anhydride (0.84 rnL, 8.87 motel) was added to a solution ,pf..2-(hydrQXy:m.ethylV67tiitTObetKiottitrilo (Example. 2074) (0.81 g, 1.77 mrnnl), pyridine (0,86 ml.,. .10.6 nirnol),, and DMAP f 0.22 g, 1.77 mmol) in CH/20- f 10 ml.), and stared for 24 h. attl The mixture was washed once with AeOIl (1 M, 20 ml,), dried with MgSCfr, concentrated, and purified by chromatography on silica using CihCfr, to give the tide compound in amount of 0.86 g (92%) as a yellow solid. ‘H NMR (400 MHz, DMSO~<G} 9 2.12 fr, 8H), 5,35 G, 2H), 7.99 ft../ ==== 8.0dfeje>, 8,0€(dd,,/-0,8, 8.0¾ 111),8.87 (dxi,/ == 0.8, 8.0 Hz. IH).

Example- 2=074:. 2-( Hydroxy methy fEb-ai trohenxoni trite

Sodium borohydridc (92.0 mg, 2.43 mmol) was added to a solution of 2-ferny 1--6-nitrobenzomtrilc (Example 20?e) (0.86 g, 4.88 mmo!) in McOH {38 mL) and THF (38 mL) at - 8 €. and was stirred at fhat temperature for no more than 30 mk Tire reaction was- quenched with BC1 (ί> M, 4.88 mL), followed by addition of water (SO ml..), and brine (50 mL). The mixture was extracted with BtOAc, the comhinod extract was dried over MgSCfo filtered: and concentrated. The crude product was purified by chromatography on silica. using the solvent gradient CTLC ly-OluilyMeOH (8:2) to give the tide compound in amount of 0.3 2 g, (57%}, Which wa$ 'used inunedtatdy' in the.next step. !B NMR (400 MHz, OMSOwL) 44.77 (d, 1~- 3.6 Hz, 2H!. 5.8? (t, J 5.6 Hz. i Hi. ?/>? (?../- x.O Hz. 1H), 8.07 (dd,,/ - 0.4, 8.0 Hz, IH), 8,28 (dd, J '' 0.8,8.011/, U!>.

Example 207e: 2-Form>!-6-nitTObenz.omU-de 1 ,l-Di3neihoxy-:V,A-dirncthy}methanan'iine (18.56 mL. i 02 mrnoi) was added to a s.>lution of2-iuethyl-6-nitrobenz.onitrilc (1 3.0 g. 02.8 mmol) in anhydrous DMF (60 mbs under nitrogen and was heated at 130°C for 15 h. Ice water (300 rot.) was added, and the result ant dark precipitate was col (acted'by filtration and dried under vacuum. Phosphate buffer (pH 7, 350 mL) and then TsalO-t (40 g„ 1.87 mmol) were added to a solution of the dark precipitate in THF (350 ml,} and stirred at rt for 3 h. The mixture was extracted with EtOAe, the combined extract was svashed with brine and dried with MgSO.; The fdtrate w as concentrated and the residue was purified by chromatography on silica using the sol ven gradient hexan.es^EtCTO.e. to give 3.07 g (19%) of the title compound as a yellow solid. SH MMR (400 MHz, DMSO-fo) S 8.15 (f, J -- 8,4 Hz, 1H). 8,41 (dd, J - 1.2. 7.6 Bz, 1H), 8.62 (dd. J - 1.2, 8,4 Hz. lift 10,25 (s, IB),

Example W$t (J7)M~Ai«lB0~5~(4~oxoM-(propylaBifanibfo-S-cayfoxy)»!Η» berno'dc|fi,2,8|fhiadiazine»2,2~dio\ide

Prepared as in Example 111 from {.6h-4-(2-cyano~3dsul:ftetoylamino)phorjoxy)» .N~propy.(bBfs'2»mamide (Example 208a) in .19% yield as a white.solid.· ?H 19MR (400 MBx, Acelone-fo) &amp; 0.8? ((,./- 7,2 Hz, 31ft, 1.47 (hex,./ 7,6 Hz, 2H), 3.1 i-7.17 On,4H), 535 (q,./ - 7.2 Hz, IH), 6.70 (d.../==== 6.0 Hz, iH L 6.7? (d,,/=== 8.0 Hz. i H), 6.87 (d,./ - 8.0 Hz. I K), 7.2 7.5 (broad s, 211).7.51 (i, ,/=-8.0 Hz, HI). 8.10 {broads, IH}, 9.5-10.5 (broad s, IH). MS 339 (Mil ").

Example 206a: //1)-4-¾ 2-€yano-3-{sulfanroylannno)phenoxy)-N-propyIbin-2-enamide Prepared as in Example Ilia from {£')-4-(3-ami»o·2-cyanophenoxy)-N-propylbut-2-cnamide (Example 20$b) In 87% yield as a white solid. ‘Η NMR (400 MHz, DMSO-%) .·> 0.84 {t J == 7.2 Hz. 8H), 1.45 (hex, J === 6.8 Hz, 2H% 3.06 (q,,/ === 6.8 Hz. 2Hu 4.00. h.L ? 2.x Hz/2H), 6.15 (d, ,/==== 15:6.¾ IH), 6.70-6.77. (m, !M), 6.91 (i J 8 J Hz, H I). 7.,17 (d, ./ 8.4 Hz, iK), 7.27 (broad s, 2H), 7.57 (6./=== 8.8 Hz, IH). 8.13-8.16 (m, IH), 9.52 (breads, IMP MS 339 (MET),

Example 208b: (£)-4-(3-Amino-2"Cyanophenoxy)~N-propylbut-2-enamide

Prepared as in Example 199b fmm (£)..4..(2-cyano-3-niOophcnoxyV-N-propylbut· 2~en=umde (Example 208c) in 7376 yield as yellow solid. :H NMR. (400 MHz. DMSO-i/d 0 0 84 it. J === 7.2 Hz, 3He S .42 ibex../ === 7.2 Hz, 3H), 3.06 (q. J === 6.8 Hz. 2H). 4.77-4 74 (m. 2H). 6.04 (s, 214=., 6.11-6.20 (m. 2H>. 6 35 id. J === 8,4 Hz, \ H). 6.67-6.74 (m, = H): 7. = 8 it../ === 8.0 Hz, '= H). 8.1 1-8. = 4 Ur, I H). MS 260 (MH }.

Example 206e; (£)-4-(2•Cyano-S-RitrophenexyD-N-mopvlbist-/-eaamide (AI-l-Bromo-N-propylbut-i-enamide (Elliott, M.; Eaeoham, A. W.; Janes, N, F,; johUsoa, D. Me Fulmars, D. A, P&amp;sik'hie Science 1987 /67-/.} 229) (044 g, 0.70 mmol), 2=-lwdrox>=-6-nf!robenzonit.i'iki (0,14 g, 0.88 mmol), potassium carbonate (0 39 g, 2.81 mmol), and 18~erown~6 (0,1 i g, 0,42 mmol) were refluxed In acetone (6 rnL) Jbr 2 h, and. then poured Into ice water (45 oil.,), The .resultant precipitate was.collected by nitration to give 0 16 g (79=.80- of the tide compound as an off white solid. *H NMR (400 MHz, DM$0-<A) 0 0.84 (?.,,./ == 7.2 Hz, 3H).. I 43 (hex.../ === 7.2 Hz. 3H), 2.06 (q. J == 6.8 Hz, 3H), 5 0? id, J == 2.x Hz, 2H). 6.16 (0,,/== 1.6=,0 Hz, Hi), 6,71-6.78 (m. IH), 7.69 (d, ./= 8,0 Hz, 1H), 7,88-7,96 (m, 2H), 8,11-8J4 (m, IH), Example 209: (,V}~4~ % mi no-5-(( I -neety I j tyr.raHdle-^yllme^.osyH#*' beuzn[e|[l,2,6iiliiadtazine“2,2-dinxtile

Prepared as in Example 176 from idT-c-amino-O-fi 1 -acetyIpyrroiuljn>2-.yi)iaeili0xy}beirz-o»itrjk· (Example 209«) in 10% yield as a while solid. *H NMR (400 MHz, DM8Q-4) $ 1.93.(m, 411). 2.00(s. 3Hr 3.50 (ne 2H). 100 idd,./- 10.0. 6.2 K/.. 1H),424 (¾ ./- 10.0, 5.6 Hz, I Hi, 4.41 (m, 1H). 6.62 id, J-8.2 Hz, IH), 647 id,./- 4.5 Hz, Ills, 7.46 <t>/ - 8.5 Hz, IH), 8.12 (hr s, 1H). 8.33 ibr s. Hi). 10.03 (br s, HI). MS 350 i MH i.

Example 209a. S.S)-2- \mi«*>6-((| -acety i pyrrol idiu-2-yt}joedtoxyibcnzonio iie

To a su'-ivo'iscm «r(5i-2"U2“C\'aoo-3-niiroj)hcno.vy):ncrh> 1 jpyrfotiduuofb. chloride (130 mg, 0.46 mmol). (Example 209b) in THE (5 ml.) were added EfiN(l35 g.L, 0.97 rnrnoh and acetyl chloride (36 μ!., 0.50 mnwsl). The reaction was stirred at .ft fist 18 h,. filleted and diluted with Er.UH (20 ml..}. The resulting solution was hydrogenated (20 Bars using 10% Pd/O as the catalyst. l:p-m completion, the reaction raix.true was concentrated.to provide (fee title compound (61 rag, M%t as a clear syrup. MS 260 (ME"),

Example 209by(,S)-2-((2“CyanO-3-nifiopbonOxy)merbvi)pvrroIldinlum chloride Prepared as in Example 166 ftosn (S^-w-buty!(2-cYano-i3-n5tophenoxy)nw(hyl)pyriO!i:dine-l:~cas4oaylate (Example 209c) in 81 % yield as an. oiPwJnte solid. MS 258 (MH -HO).

Example 209c: (.SWer/-Butyl 2-((2 -c yano-3-nitrophenoxv }methy I }pyrroI id 1 ne-1 - carboxyl ate

Prepared as in Example 1664 from 2.(v-dinifeofee«»>nitrite and {.S>/ew-butyl 2-:(hyd.toxyaTxu.hy!)pyrrolidi:ne-l-earboxy!afc in 89% yield ag a tan solid. *H NMR (400 MHz, DMSO-ib) S 1.40 is, 9H), 1.81 fin, III), 2.03 (m, 3H>„ 8.52 Cm. 211). 4.08 (m, 1H)? 4.33 (τη, 2H), 7.7° id. J - 2.8 Hz, 1H). 7.9.3 (m, 2H).

Example 21 (N (^~4ud»e-5~((l-pro^tn«ylj|yrroSdi»''i“yI)metfe«xy>'l:ii'' beaxe [of [1,2,6] iliiadtaEne-lJ-iliexlde

Prepared as iu Example P6 from rS)*2-anunO“M(i~propioriy')|>yrm!.idin“2~ yl)med:Oxy)henzonitnic (Example 2! Oa) in !5% yield us an off-white solid. *B NMB. (40() MHz, DMS< )-ώ,} 4' 1.01 0. ·/ - λ;·: Hz, 3H). i.05 (m. -Hi), 2.31 in?, 2(-1). 3.48 (m, 2H), 4,11 (dd, J 10.0, ¢-. 4 Hz. IH), 1.27 (dd, / - 9.8, 5.0 Hz, iH), 4.43 (m. i H), 6 64 id. /- 7.9 ft?., 10), 6.92 (a,,/ - 8.4 Hz., i Hi, /,48 {?../ - 8.2 Hz, ; H), 8.09 (br x, \ H), 8.34 <br s, i H), .10.95 (hr s,. !H). MS .353 (MH ).

Example 2 j Oa: (S)~2~AiiiiTK)~6~((I -'propipny:lpyrroIidin“2“y1}meflx>xy)!-je.nzxxdtriIe Prepared as in Example 20% n'on6(63-2-((2-cyarso~.3~ «2&amp;X>pbenoxy}nieti)y{}pynxdidini«m chloride (Example 21.0b). and propl/myl ehiaridd» 9()% yield as a clear syrup. MS 274 (MB').

Example 211: (5y4~Amia«“5H(i ~b«iyryipyrrolidi2.s~2~yl)52ud.ho\y)~ 1//- heu»o[e] 11..2,6] ihisdfaKiise-ljl-dioxtde

Prepared as in Example 176 fjp&amp;m. C$|r25ami»OrC>-((ί-hutyrylpyrroOditv-l-yl)meihexy)be«zoniitile (Example' 21 la) in 789¾ yield as an nff-wbite solid. *H KMK (400 MH% DMSO-43 9 0.88 (t, J * 7.5 Hz, 3B), 1.54 (q, /- 75 Hz), 1.94 (m, 4H), 2.26 Ct J - 75 Hz, 2B), 3.48 (m, 2Hi 4.10 (m, 1H), 4.25 (m, 1H), 4.43 (m, I Hi 6.62 (d, /-8.1 Hz, Hi). 6.89 (d,/- 8.6 Hz, 1 Hi7.47(1,/-83 Hz, IH),8.08 (bra, IHk 8.32(brs, IB), 10.93 (bra, 1H),MS 367 (MB').

Example 211 a; (6)"2-Ammo-6-f(1 -b:a;6wl6vrrglidm-2Al)meibozy3beftzc?nitnie

Prepared as in Example 209a from (S)-2-(12-cvano-3-nitrophenoxy ;rrsethyUpyrrosidmhirn chloride (Example 209b) and butyryl onloikle to m 90% yield as a white solid. MS 288 (MH ).

Example'21.2ί (^>2H{4-Ami8si^i/:/dKirr/.oiiir^24Uldad.ia/a«ca-2<2-<li0\kle-5-yloxy)0U'thyl)·· S-mcihyIpyrro Msmv I ^carboxamide

Prepared as in Example I ?6 from (,SV2%{.Earniim42-cyanophcnoxy)rncih>4)-:V-> •nielhylpyvrolidine-1 -carboxandde (Example 212a) in 30% yield as art off-white solid. *H NMR (400 MHz, DMSO-4) $ 1.8$ 2.60 (4,/- 3,9 Hz. 3Hh 3.2(¾ (m. 2H), 4.01 (¾ Hi), 4.16 (ra, 1H), 4.32 (m, IB), 6.23 (m, IH), 6.62 (d, J - 8.2 Hz, 1H). 6.x9 i,U ----- 8.8 Hz, Hi), 7.46 (t, / - 8.2 Hz, 04), 8,19 (br s, IH), 8.27(br s, 1 Η), 10.92 is, 10}. MS 854 i,MH'),

Example 212a: (M-2-{(3-Amino--2-evanophenoxv?mcrhv)i-.V-meihvlnvrfoIldine-H carboxamide

Freparedas in Example 209a O'0m|3l-2-4i2-cyan0--3-nitfopfeerto:xy)mffffeyi)pyrroiidinlitra chloride ^Exampl e 209b) and methyl Eecyanaie in 33% yield as a white, solid, MS. 275 (MHf).

Example 213!: <S>2K(^AmiaP“lf/”M«20|p]|;ijtMadia2l»e4»2-eloMd€'$*> %~et h y 3py r r o 11 d urn-1 -ea r bos ami de

Prepared as in Example 276 ftaa (5)-2-ii3-amirm~2~eyaimphenoxy)omilwl)-i% ethylpyrrolidine-l -earbexamide (Example 213a) is 68% yield as an ofEwbite solid. Ή NMR (400 MHz, BMS€)-4d 4 l .CB (i:.J 6.9 Bz, 6H), 1.90 (m, 40), 3,08 (paint,/- 6.6 Hz. 2H), 3:20 (rn, IK), 3-31 (m. IH), 3.00 (dd. J === 9.7. 6.7 Hz. 1H). 4.17 (d-d,./- 9.7. 6.0 Hz. 1H), 4.33 <m, 1HK 6.77 (d,./ === 5.7 Hz, IH1, 6.62 (d../ === 8.2 Hz, lH), 6.89 ul, ./=== 8.3 Hz, 11::1), 7.46 it./ === 8.2 Hz, 1H), 8.20(brs, U B, Χ.26 ib-m Π Π, 10.01 (s. 1M>. .MS 368 (Mi l ).

Example 213a: (5)-2-((3-Ammo-2-eyaBOpIienoxy)ffie&amp;y I)~i9-ei6yIpyfro 1.1 dine-1 -carboxamide

Prepared as In Example 209a from (51-2-((2••eyano-S” mtropbenoxy)metbyl)py«Oliiiiaium chloride (Example 209bW) and ethyl Isocyanate in 100% .yield as a white solid. MS 2*9 $MH s.

Example 214:: (53-2-(i9-An08U>-l//d>enzoScI[l,2,6]tbhtdiaz0Ki-2,2-dioxide-5-yloxy)mi'ShyI)-/V-propylpyrmUdiae-l'-carfeoxaniide·

Prepared as In Esample 2/6 from (5y2-({3-arnino-2-cyariophci'iox>-irneihvl}-A·-prr>py}pyrroiid!pe-1 -carboxamide (Example 214a) in 37% yield as an off-white solid. Ή NMR (400 MHz. DMSO-%) ΰ 0.84 (t, J === 7.6 Hz, 6H>, 1.43 (soxt, J === 7.4 Hz, 2H), i.92 (m. <111). 3.0:1 (m, 2H), 3,21 (ra,: 111),3.33 (m, HI), 4.02 (dd,,/- 9.7, 6.4 Hz, !H). 4.18 (dd,./- 9,7, 5.9 Hz, I Hi, 434 (m. 1H), 6.27 (d,,/ 5.6 Hz, IB), 6.62 id,,/- 8.4 Hz, IB), 639 (d, ./- 8,6 Hz, IB), 7.46 (6 >/ ·==· 83 Hz, 1B), 8.20 (bf s, IH), 8.27 (br s. 1H), 10.91 (s, 111). MS 382 (ΜH.:).

Example 2I4a:(5)-2-((3-AmmQ-2-cva60Dhenoxy)nvofevl)-jV-DrooviDvrrobdke-l-earboxamide

Prepared as in Example 209a .fk>nvi54-2-((2-cyano-3-i:.«trophenoxy)mefhyl)pyrrolidinium chloride (Example 209b) and, propyl Isocyanate in 1110% yield as: a, white solid, MS 303 (MB '/,

Example 213: N-propylprepaHamicIe

To u stirred solution o.f5~(3-sultaroo>damioo-.%cyunophenoxy)~272-dimerhy!-N-propylpropamunide (S 8.52 g. 53.55 mmol)( Example .: 1 5 a) !n l:.sQH (! 50 nil) was added NaOH solution (2,0 N, 523'mL) at room temperature. The reaetltm mixture was then refluxed for 2 fers until the reaetiost was complete by TLC. The solution was cooled to 0 *€ and neutralized care.ftt.Ily with 10% acetic acid and die precipitate was collected by filtration and washed with water. The product was further purified by recrystaliizution from EtOH/HhO (1:4). dried under vacuum to give the title .compound as a white solid (13.5 g„ 73%). M.p.; 225-226 ®C. Ή NMR (400 MHz, DMSO-n',} d 0.75 u, j - 7.4 Hz, 3H), 1.22 (a, OH). = .38 fin. 2Ri, 5.01 (o. j - 6 5 Hz, 211), 4.07 is, 211), 6.59 (d ,.1 === 8,0 Hz, 1 B), 0.7! id, I - 8.0 Hz, ill), 7,44 0,1 ==== 8.0 Be, III), 7.82 (t,.1==== 5.0 Π,-, ill), 7.92 (s, 1M}, 8,33 (s, 111 h 10.93 (s, 1! 14. MS 355 (ΜΗ5). tomie215a;3d3 *stilfk«oyiajt#inO~2>cyaiioph.eooxy)~2>2sdtatieihyHH-=|>irO'pyl-propan amide

To a solution of '.H5~amirio-2-cyanophenoxy}~2,2-dimeth>4-'N-propyipropanamide (16,5 g, 59.92 mmol) (Example 215b) in DMA (50 mL) was added sul.fhtrio.yl chloride (13.85 g, 11=0.84 mmol)·at 0 4>C under nitrogen. The teactlen mixture xvas then stirred at room temperature under nitrogen for3 hrs then diluted with f.tOAc. washed successively with NaRCO·;. brine., dried ever N;wSO.;, filtered and evaporated to give the title compound as a off white solid 118.52 g,87%). *H NMR (400 .MHz, DMSO-ίό;) <> 0 79 (i, j - '7.6 Hz. .01}.. 1.20 (s. 6H}, 1 38 pu, 2M). 5.()1 (q, j - 6.5 Hz, 2H), 4 05 (s, 7R), 6.92 (if 1 - 8.4 Hr, HI), 7.15 (d. J === 8.4 Hz, !H), 7.24 (s, 2H), 7.53 (ts I ===== 8,4 Bz, 1H), 7.55 (t5J ^ 5.6 flz, 1H:)5 9,42 (s. HI) MS 355 (MB }.

Example 215b: 3-:(3-amluO”2-cyanophenoxy)^2,2-dlmei:hyl-:N-propyIpropanamide •Method A: To a solution of 5-{2-cyan.o-3-aitrophenoxy)~2.2-dimsthyl~N-propylpropanami.de (305 mg, 1,0 mmol) (Example 2,15c) in EtOAc (20.0 ml..} was= added 109¾ VAsC {50 mg). The suspension was stirred under an atmosphere of H> at room tstnperalure overnight. The Pd/C was filtered off. and washed, with EtCMc, The filtrate was concentrated under reduced pressure and die residue was purified by chromatography on silica gel eluting with 50% EtOAe in hexanes to give the title coni pound (267 mg, 91%) as a white solid. MS 27b (MH i.

Method B: To a solution of 3-hydroxy -2,2-dirnethy I-N-propy Ipropanatni Je (20.2 g„ 0.127 mol) (Example 2! 5d) in dry THF (500 rnLi was carefully added NaH (60% in mineral oil. 7.04 g, 0.]··)] mol) in small portions at 0 ':C under·nitrogen. The reaction mixture was then warmed to room temperature end stirred under nitrogen lor I hr, ίο this solution was slowly added at room temperature 2-antir;o-h-fiuorobcnzc>nitfi.le (17.3 g, 0.127 mol) in THF (1.00 ®L) and the reaction mixture refluxed overriighr under nitrogen then cooled down to room tempefatttrev.quenched with brine, and extracted with EtOAe t?Xt. The combined organic layers were washed wnh brine, dried over NseSOi, evaporated and the residue was crystallised from FiuAc Hexune to give the compound as a white solid (10.5 g, 48%). Ms 276 ;MH S.

Example 2!3c:·3-(2-cvaoo-3-nitrophcrioxy |-2.2-ϋΙπ*οΐηνΙ·Ν-ρ®ρνίρΓοραο3η·ι1ϋο

To a solution of 3-hydroxy-2,2-dimethybN-propylpropanamide i 1.50 g. 10.0 mmol) (Example 215d) in dry THF (30· mL) wds carefidJy added NaH (60% in. mineral, oil, 400 mg, 10,0 mmol) in small portions at 0 °C under nitrogen. The reaction mixture was stirred sift "C under nitrogen for 2 hrs, To this solution was added 2,6~d®itrobenzoniirite (1.93, 10.0 mmol), and the reaction solution was· stirred: at 0 °C ~ ϋΐ imdernstirageii overnight The reaction mixture xvas quenched with brine, and extracted with EtOAc (3X). The combined organic layers were washed with brine, dried over Na-.SO.i. After evaporation of the solvent, theresidue was purified by chromatography on silica gel eluting with 60% FiOA.e in hexanes to give the title: compound as a pale yellow solid (2,21 g, 72%), MS 306 (MB '),

Example 213d. Sdtydroxy-2,2-dimeihy!-N'propyipiopariarnide

Method,A: A solution of methyl 3 -hydroxy-2,2 -dimethylpt opanoate (2.64 g, 20 mmol) and d-propylamme (1,61 g, 30 mmol) was heated at 190 TC under microwave for 10 hm. The excessive amine was removed under vacuum to give the title compound as colorless oil (3.18 g, 100%); MS 160 (ΜΒΊ,

Method B; To a solution of 3-hydroxy-2,2-dimethydprop;jnoic. acid (20,0 g, 0,169 mol), propylamine (15.3 ml.,, 0,186 mol), and B.OBl (25,1 g, 0.186 mol) in dry dieMorrmiethane (500 m.L) was added EDO (35.6 g, 0.186 mmol) at room, temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen overnight. The rede-lion quenched with brine, and extracted EiOAc ($X). The combined organic layers were washed w>th saiurawd NaHCO.* solution, ado;c MCI, brine, and dried over NipSOi. Evaporation of die solvent under reduced pressure gave the title compound as colorless oil (19,2 g, 71%). MS 1.60 (MIT). Example 21 6; N-(5 -(4-amim>-2,2-dmside - i ϊ I jfl .2,61ihiadin/irs -5-y hm )-2 ' - mefhylpr»past*.2--yl)be««amlde

Prepared as in Example 255 from N-(l-(?'SujfanK.'yhmiiiio-2-cy;mophoiio\y)-2-mcthvipropan'2'> ; ibermamide 5 Example 2Hui) m 93% yield as a while solid. M.p.: 235-235 °C. lH NMK (400 MHz, OMSCk/·,} n 1,47 (a. OH), 4.35 (:-, EH).. 0.61 (d. ,5 == 8.4 Hz. ! H). 6.77 (J, j =. NO Hz. 151), v, 39--551 nrs.dHs, 7.75 {U, J === 7.6 Hz, 3.H). 7.90 is, ι H). N.i 7 H·, ιΗ).8.4?Π, ! H). 10.97 {*. S H). MS 389 (ΜΗ .).

Example 216a; Ν-(ΐ 43-sulfamoytomme-2-ovabophenoxv)~2-methy%ro:r»tt-2- :yi)beuzamlde

Prepared as in Example 215a from N~C i -{3-amiP0*2-cy»hophenoxy)-2-incthylpropan-2-yl)bcnea:Mide (Example 216b) in 98% yield as a white solid. MS 389 (MIT). Example 216p: N-(l>0-amin&amp;“2-gyanop5-ienoxv)-2~metbvlprop3n~2--vl)benzami:de

Prepared as in Example 215b (Method A) from. N-(.I-(2-eyano”3“niirophenoxy>>2~ PiethylpfPpan^-y'^be.R^.mtdiei (Example 256c) in 96% yields a white solid. MS 310 (MH‘). Example 250c: N>( I 47'Cyano~3-rHnophenoxY)“2-nwdiyipropan-2~Yi)benxairdde

Prepared as in Example 215c from N-{ 5-hydroxy-7>inetby1proparu2w.l)benxamide (Boyd, R.N.; Hansen, R.H. J. 4;«. Chen). S<n\ 5953, 5896) and 2,6-'dimuwbenxondn:e in 91 % yield as a pale yellow solid. MS 340 (MIT),

Example 21.7r5"(neope?viylbxy)~I1i~beEZO[c|[l,2,61ihiadtaziSi~4~amlue^,2-dloxidle

Prepared as in Example 215 from 2-sulfan ιονlammo»6« (»copcntyloxy)bcnzonjfrile (Example 2 i ?a> in 73% yield as a while .solid. Ή NME (400 MHz, DM SO-(.4} <> 1.01 (% 9El'ZMiif2E), 6-61 (4 J - 8.0 Hz, 10), 6-77 (d,i - 8,0 Hz, I 1¾ 7,45 (L J - 8.0 Hz, IH), 7.66 (s, I Hh 0.49 (s. IH), 10.99 is, IH). MS 284 (MH1).

Example 217a: 2 snifanioybmino“6^»e0peatyloxy)benzpateile

Prepared as in Example 215a fteaaw-amitto-O-MeopemylexylbertzomO'ile (Example 217b) in 92% yield. MS 204 (MB >.

Example 21 ?b: 2-amino· neojxjntyioxvjbenzonitrilc

Prepared as in Example 215b (Method A) from 2"(rseope«iyloxy)“6“ mtrohenxomtrlie t Example 217c> In 96% yield. MS 205 (MH }.

Example 217c: 2·{rseopentyloxy}-6-niiroben2omirsle

Prepared as in. Example 215c from 2.2-dimcrh>lpropan~l-ol and 2,6“ diniirobcmmnirnle in N0% yield. MS 255 (MB ).

Example 218: 3-(4~mnino~2 j-diemde-I H»bepx0|ei|i4«6|ibiadiazI»"5"ytef}”N"O -'(beszyiexylefhj 1 *~2 \2 “--dimeiliylptOpaEamMe

Prepared as in Example 215 from 3-(3-sulfapioyliimino-2*cyynophepoxy)-N-(2*· (benzyloxv}ethyl)-2,2~dimethylpropanarnide (Example 2i8a) in 92% yield as a white solid, SH mm. (400 MHz, DMSO-4) 6 1.22 (s, 6H), 3.26 (ip j - 5.8¾ 2H), 3.41 (t, J =- 5.8 Hz, 20), 4.07 (s, 2H), 4,36 (s, 2H), 6.60 (4 J - 7.6 Hz, 1 El), 6.71 (d, i:> 7.6 Hz, III), 7.19-7.28 (m, 4H), 7.43 (t, I - 8.0 Hz, 211), 7.9! (4 111),7.97 4 J - 5,8 Hz, Hi). 834 (s, I Hi. 10.93 (s, IH). MS 447 (MH'),

Example 218a; 3d3-'iulfai»<)yi«mino-2-cyanophenoxy)-N-(2-(ben^yloxy)ethyi}-2,2- dlmeth yfpropanam ide

Prepared as in Example 215a fro hi 3-(3 -amino-a-eyanophehoxy)- N -(2-(benzy!oxy)ethy|)-23"dimetbyipropa»amide (Example 2:18b) In 10038 yield. MS 447 (MET).

Exam|4e218k 3-(3-amino-2-eyanopbenoxy)-N-(24ben2y1ox.y)e:tiiyi}-2,2--dinieibyi-propanaroicle

Prepared as in Example 21 5b (Method B) from. N-(2-(bcnzy lo.xy)cthyi)-3- hydrosy~2,2Mmmlhylpropansmide (Example 2 i be) and 2^ηώίθ~6~β^ϊ?θ&amp;αϊ20»ίΜΙδ'ίη. 82% yield. MS 368 (ΜΙΓ).

Example 218c: N'(2-(bcmzyloxy)cihy!)-3-hydroxy«2,2-dirnrthyij^pana«ucte

To a ^Ιιιίΐρίΐ.οΤ.^^άτοχγ'Ζ^'^ΐίΒβΐί^Ι-ρτορδηοίδ acid(236 g,.20 mmol), 2-(benzy !r*xyiethanaminc 0.02 g, 20 mmol), and HOBt. (2.7! g. 20 mmob In thy dtehloromethane. (100 ml.) was added EDO (3:.82 g, 20 mmol) at room temperature under nitrogen. lire: reaction mixture was then stirred at rood!temperature under nitrogen overnight. The reaction was Quenched with brine, and extracted with EtOAc (3X). The combined organic layers were washed with saturated NaBCO-f solution, dilute HCt, brine, and dried over Na^SCA. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 40% EtOAd in hexanes to give the title compound as colorless oil (4.84 g) m 97% yield. MS 252 iMH ). Example 21*1: 3~{4~immio-2,2~dioxide~tH"bejuo|c}j I.2,6H!riadiium-S~>loxy i-N-U'’-hyd roxyet hvb-2 42 Miametfeytpropanamtde

To a solution of3-{4-aroina~lH“bc«zo[cH1,2,63thiadtazttw5-yloxy)-2,2-dioxide->· N-(2'dlvn;i:yloxy)ethylh2\2'-dimethylpropanamide(Examplc 218, 112 ma, 0,25 mmol) m EtOAc EtOH/THF (1:1:1, 20,0 ml..) was added 10 % Pd/C (51* mg). And the suspension was stirred under an atmosphere of Hi.:? at room .temperature for 2 hrs. The Pd/C was filtered off, and washed with MeOH, The filtration was concentrated under reduced pressure, add the residue was purified by rcervsiailization from EtOH to give the title compound as a while solid (81 mg) in 9033 yield. lH NMR (400 MHz, DMSO-ifr) fr l .22(s, 6B), 3.11 (q,i = 6.0 Hz, 2H). 3.35 iq, i -6,() Hz, 211), 4.05 (s, 2H), 4.(,] (t, I === 6.0 Hz, 1H), 6.59 id, 1 - 8.0 Hz. i Η).. ό.ΑΊ (J, J === s.O Hz, 1H), 7.43 (t, J - 8.0 Hz, > H), 7.78 it, 1 === 6.0 Hz, Hip 7.03 (s. i H). 8 29 % IRg 10.93 (s, IR>. MS 357 (MH ).

Example 220:3-(4-» mln»-2,2-dipxide-i B»frenz» |e| f Ϊ ^^lifeiadiazIn-S-yloxy)^^ * r~ methoxybenzyfr-afrZ^dtoefhylprupanamicle

Prepared, as in .Example 215 from 3-{3:"Se]fam»y1ami.no~2-cyanophe«oxy)-N~{4-m.eihoxybenxyl)“2,2-dimetfeylp.mpanamide-.(Exampb 220a) k 92% yield as a white solid, ’ll NMR (400 MHz, D.MSOwy) d i .25 K OH), 3.00 w, 5H), -i.12 is, 2Hi. -1.21 id, .1 - 5.6 Hz, 2H). 0.61 (d, .1 - 6.1 Hz, I Hi. 6.71 (d. j - 8,1 Hz, 1H). 6.73 Id, j - 8.0 Hz, 2H). 7.00 id. .1 - 6.0 Hz, 2Hi, 7.44 (t. J - 8.4 Hz. IH). 7.87 is, IH), 8.31 -is, 1H), 8.55 U..) - 5.0 Hz. 1Hr 10.95 (s, LH). MS 433 {MH"}.

Example 220ar3W3wuikmovtotkne~2wyancphenox¥t--Nd9--nwtliox¥benzyl)-2,2-dirn ethyl propanamide

Prepared as in Example 215a deni 3-4 3--amiuO“2-cyanophenoxy}-'N-(4-rncthoxybcnzylV2,2--dmxdhylpropanamiile (Example 220b) in 100% yield. MS 4.)3 (MH ).

Example 220b. 3-(3>arnino-2~cyanophcmox>hN><4>mctboxybenzyl)-2<2“Jimcthyl- propanarpide

To a solution o.f 3~(:2<yaaO”3“idirofdieiiQxy)-N-(4--m.etlKixybeazyl)-:2,2--d;S:rnetliyl.-· propanamide (LI 5 g, 3.0 mmol) (Example 220e) m diglyme (30 rnL) Was added dmpwise a solution o£ Sn€!r2H.?0 -:2.03 g, 0.0 mmol) in eoncemrated MCI (15 ml..) at 0 The reaction rnixmre was then stirred at 0 ®C for another I hr. The reaction solution was neutralized with 2 N Ns0H at 0 *C, and extracted with EtOAe (2%). The combined organic layers were washed with brine, dried over NasSCfr. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 50% EtOAe k hexanes to give the title compound as a white solid (0.91 g) in 8638 yield. MS 354 (MEfr).

Example 220c: 3-(2“Cyano-3-ni(roph^uoxy)-N-(4-meth:0^y|fenzyl)-2,2-dimeihyl'-propauamide

Prepared axin' Example 215e from 3-fry droxy-N d4--i«cthoxyhen2yl)-2,2-dfkethylpropwwmide (Example 220¾) and 2%-diffltrobeazominlc k 9$% yield as a pale yellow solid. MS 384 iMff).

Example 220d: 3-hy dmxv-N44-mc*ho\y ben? >l)-2,2-,11nrcthy Ipropanamidc Prepared as hi Example 4c horn 34rydro\y~2.2'dhneihylpTopauoic acid and 4-5oethoxs baizv landne hr 97% yield as a white solid. MS 238 (MM ).

Example 221; 3-(4-amimi-2,2-d?oxide-l B-benxo jcl { 1,2,6| thiadiaxhr--5-yl(m )-N,2 22-trim et h >1 p rop a 5¾ a m kl e

Prepared as la Example 215 from 3-(3~aulllMsoyla.Hun0-2-cymrop:he.nox.y)~N52.2-irimethyipropanamide (Example 221a) in 6234 yield as a while solid. Ή NMR (400 MHz.. DMSOmy) <> 1.21 is, 6H)„ 2.58 id.) - 1. .2 Hz. 3H)„ 4 05 (&amp;, 2B), 6.60 (d J - 8.0 11:1),6.72 (d, 1 - 8.0 Hz, HI), 7.44- ((, J =- 8.0 Hz, IH). 7.80 irp J === L2 Hz, IB), 7.96 <>, IB), 8.33 (s, 1 E)s 10.93 (s. i ll). MS 327 (Mil i.

Example 221a: 3-(3-xulfamoylandno-2~cyc5nophcnox>t-N,2,2~lrinvcihy]p?opamimide' Prepared ax in. Example 215a from. 3-(3-arnino-2~eyanophcrioxy)>N.2,2- iriawiliylpropar!.ami:de (Example 221b) m.69% yiehl MS 327 (ΜΙΓ),

Example 221b; 3-:(3-amino-2"eyaaopEenoxy)~N?2,24rimeiliylpsx>panamide

Prepared as in Example. 2.15b ( Method A) Horn 3-(2-cyano~3miirophenoxy)-N22.2~irirnelip/!propanamide (Example 221,c) in 95% yield as a white solid. MS 248 {MB' }. iMIMkJllc; 3--(2--eya.nO"3-m0eph©noxyj-N.2,2-trimethsipropanamidc

Prepar'd as in Example 215e fern 3d5ydroxy4M2;,24rimethyipropaoamide (Example 231 el) and 2,6-dmitrobehxerMrile 1» 77% yield ax a pale yellow xolid, MS 378 (Mil4-Example 221 dy 3-hy droxy-N J,2-mlmeihylpropaaamlde

Prepared as in Example 2I5d item methyl 3-hydmxy"2,2“dimeth:y lprppa.poaie and meihylamino hr 51% yield. MS 132 ί ΜB I.

Example 222; 3>C4“amln0“2:“Oxo«E2“dilsydr0q«tnaKOl:itt“5“yloxy)"2»2"di:mel:byl“N“

A solMiofi cvfN-('2-cysiio~3:A'2;J^diniei!ivl-3“Oxo-5-{prvp>'larninv)pj:opoxy)'· pkcoyicurbanmylibcnzantidc (example 222a) (141. mg, 0.2 mmol) and NaOH. (.2 N. 0.3 ml.» in EtOH ¢5 mL) was stirred at 1 00 ''C under nitrogen for 2 hrs. After cooling to room temperature, the dear reaction solution waft filtered., and tiro filtrate was carefully notundized with 10 %

AcOH with vigorous stirring at 0 °C. The resultant precipitate was collected by filtration, washed with water and. that 20 % EtOH in * ater to give the fmal product ¢81 mg) In 76:% yield as an ofEwhhe solid. *H NMR (400MBz, DMNfodd 0 0.73 (t, J- 7.4 Hz, 3H), Ϊ.2! (s, 6B), 1.33-1,41 (m, 2H), 3.01 (q, J - 7.4 Hz. 2H), 4.08 (s, 2H), 6.64 (d, I “ 8.0 Hz. IH), 6.69 Cd, I - 8.0 Hz. 1H). 7.42 (t. 1 - 8.0 Hz. 1H), 7.47 (s, IH), 7.79 (t 3 - 7,4 Hz, I If), 7.84 % IΗ h ! 0.60 (s, I Hi MS 3 % i ΜΗ j.

Example 223a; N"t2"cyaoo--3422i~dtmethyl~3"0.v«5"3“(pfopyltad«o)propoxy)pheijyl·» earhanfoyl)b©«zamide

Prepared.as in Example 146a f«m 3-(3:":amino-2~cyanophenoxy)-2,2-di0tethy|-N-propyS·pcopanamidc tfxample 2.1:50, Method A) stfo benzoyl isocyanate in 85% yield as a white sohd. MS 423 (MH )

Example 223; 4-amm0-5"(steopeatyfoxy)qti.ioazoMft~2(l H)~&amp;m

Prepared as in Example 222 from N-(2~cyauo>3~ (ncopemyloxy)phcuylca#bsrnoyl}bcnzan»uc (Example 22.1a) in 90% yield: as a White: solid. fH NMR (400 MHz, DMSO-%) S 1.03 (s, 9H). 3.90 is, 2H). 5.96 is, 20), 6.15 (d, 3 -7.6 Hz, 1H), 6.30 (d, 3 === 7.6 Hz, 10), 7.14 (t. .1 === 7.6 Hz, IH), 11.22 (s, IH). MS 246 (MHO.

Example 223a: N42-€¥anO"34h©o0cnMex¥tehemdcarbame¥l)b©Hxaml:de

Prepared as in Example 146a from 2-arnino-6-ίneopenty loxyl-beozonPrile (Example 2l?b) aad benzoyl Isocyanate in 96% yield as a whim solid. MS 882 {MH').

Example 224: 5-(3-met itoxy-S-metlnllmmay}» 1 t;I-henzo|e||l,2.6 jtfbadiazin“4-amiae-2,2-dioxide

Prepared as in Example 213 from 2--s«iiamoyiainiao“6"C3--meihoxy~3~ mcihylh«n>\ydx-nzonuriictExample 224a) in 32% yield as a white solid. Ή NMR (4(K) MHz, DMS< UM d U‘S is, *SH), {.98 (t, J = m2 Hz. 2B), 3.09 m 3H>, 4Js u, i -- m2 Hz. 2HE S.57 (d. J -= S.O Hz. IH). 6.73 id. i === 8.0 Hz, IH). 7.48 tv. J 6.0 Hz. IH). 6.25 (s. !H>. 6.80 (s, ΙΗ». 10.69 m. | H). MS 314 IMH ).

Example 224a: 2-auIfamoyEmine~6-(3-methoxy-3-methyibutoxy )benzomP'ile Prepared as m Example 215a from 2-imwnPs6~(3-:meihcxy-3-methylbutoxylbenzoBitriie (Example 224b) in 95% yield, MS 314 (MIT).

Example 224b; 2-amino-6”t3“met’hoxy-3-methylburoxyibenz.o«ltrile

Prepared as in Example 215b (Method A) from 2-(3- t«.ethoxy*3-m4thylbamx> )-6-iiitfobenzoiiitrile (Example 224c) in 62% yield. MS 235 (MR ).

Example 224o: P-fS-ntetboxy-S-methvlbatoxvI-d-nitrobeazoaitfile

Prepared as in Example 21Sc frQm:3“metboxy--3--meihylbnian-i-o1 and 2,6-dlmimhebzomirUe in 52% yield, MS 265 (MB'),

Example 225: 3-(4-aodn0~2.,2-dibxide-iIf»beftzd|e)|l,2,6|thiadlszi.n-5-yIoxy)-N-(2,'!-methoxy e th yj}~3 ,2 Mb so et hy ipropa tm mide

Prepared as in Example 215 from 393-s=i]ianK)vlarn;rK.>-2'Cyanoplmimxy S-N'(2~ medK>xyetfeyl}«2,2~dimethylpropauamidc (Example 225a) in 12% yield as a while solid. Ή NMR (400 MBz, DMSO-;/,) 5 1.21 (s, 6H), 5.13 (s, 3E), 5.17-3.22 (rn. 2H), .).25 *L j === 6.0 Hz, 21%. 4.07 (s, 211!. 6.59 (cl j ==== 6.0 Hz, Hh. 6./1 (¾ j ==== 8.0 Hz, HO. 7.43 (t. I === 8.0 Hz:. 11:1), 7.87 (s, 1 Ηk 7.9) (u 1 === 5.6 Hz. IB), 8.83 6=. 1 Η), 10.92 <s. IE),MS 371 (ΜίΓ).

Example 225a; 3“(3“Sui:fempyI.am.m©-2-cyanophei)ioxyf)*'^*('2-metIioxyethyl)«242-uirnediylpropimamidc

Prepared as in Example 215a from 3-(3"amino-2-cyanophenoxy)-N"(2·· Riethoxyelhyl)-2,2-diraethy!propanainide (Example 225b) in 41% yield. MS 37! (MB’).

Example 225b: .3-(3»amitio-2>cyapopbenoxvI N (2-me^i0XvethYl^2.2>dimcthyI»

i ) 6·' pill 1,'λΟ) IOC

Prepared as in Example 215b { Method A) from 3-(2"CyanO"3-niifopheRoxy)-N«' (2~methoxysthyI)-2,2-dimcthylpropanamide (Example 225c) in 91 % yield. MS 292 (MH }. Example 225c: 3-(2~oyuno-3-mtfophenoxy}~N-{2-roodu>xyeihyi}~2.2-dimcdivl- propanamide

Prepared as in. Example 215c from. S-hydroxy-N-CS-mciiiexyetiiyll-S.S-dimoilwipropanamide (Example 225d) and d.O-diiHtrobenzooitrile in: 55% yield. MS 322 (MB'). Example 223d, 34wdroxv--56(2 -methoxyethyI )-2.2-dlmetbvlpropammide

Prepared ax in Example 21 Sd (Method A) from rricihyl 3-hydroxY-2,2~ dimethylpropadbato and 2-methoxyethanamme hi 100% yield MS 176 (MH ).

Example 3;2&amp;: %-C3-(4-a«Htto-)~2,2-di0xide-iB~bettZ0i0l|l,2,6lfiiadiazia"5-ytoxy-2'2i-

Prepared as in. Example 2! 5a from H*(3“(3.~M»mb>.2~cyahophenoxy)i-2.i2-dimethylp-topyl)propio'namide (Example 226a) and sulfamoy.1 chloride in 17% yield as a white mild. !H NME (400 MHz. DMSO-%) ό 0.93-0.96 (η·. 9H), 2.06-2 11 <m 211K 3.07 (0,/-6,0

Hz, 2H), 3.74 {», 2H), 6.58 it,,/ - 8.4 Hz. !H). 6.60 ul, ·/-· 8.8 Hz. 1H), 7.4i it./ - 8.4 Hz, 1 E% 7.93-7.98 (m, 2H), 8.55 (brs, 1H), 10.9! (brs, 1H). MS 355 (Ml! E

Example: 236a: N*{3^3~amim>-2-cyajjoj>be«oxy)-:2,2-djmetbyipit>|iy]}p«>pioaa»'«iiie

Prepared a? in Example 215b t Method A} from N-i ?-«2-cyano-3-»;iti'0phem>xy)r' dJ-dimethylprepyOpropionamide (Example 226b) m 10059 yield. MS 276 (ΜΗΓ).

Example 226b: N-·(3-(2-eya.no -3-nitrophenoxv)-2,2.-dimethylpropyDpropionamide Prepared as in Example 2 ! 5c from N--t 3-hvdroxy--2,2-djraethyiprdpyOpropionanndc (Example 226c) and 2<6-Uiniirobe.02onitrile m 68% yield. MS 306 (MH1. iEMRPk.22.6e;. N (3 · hydroxy-2,2 · d imet by ipropy 1 ipropinaamide

Prepared according to the literature (Boyd. R.N.; Hansen. R H ./. .On. O' tM. son. 1953, 7.5, 5896} from 2--amino-2·mcthylpropan-1-ol and benzoyl chlmIde ns M‘S. >;eld as u white solid. MS 160 (MH ),

Example 227: l-(3-(4“amiitp*2,2-dioxide-XH-ibeiiz«i.«|{t,2,6!ihi3dtazi»-5-yloxy)-2*,2''-dimetbyIpropyl)~3’-etbylMt'ea

Prepared as in Example 215 'from l -(:3-(3-suliBmoyl8ml5m”2<ey8noplieftoxy)-2,2» dimethylpropyi)-3-ethy!urea (Example 227a) in 55/4 yield as a white solid. fH NMli (400 MHz, OMSO-t/j) 0 0.88-0.96 (m. 9.H), 2.90-2.97 (m, 2E), 3.01 (d. ./- 6.4 Hz, 2H). 3 ?2 (s. 214),5.75 it.,/- 5.6Hz, 1M), 6,07 s l ./ 6.4 Hz, 1H >, 6.56 (d J - 8.4 Hz, IK), 6.67 (d../- 8.8 Hz, I HR 7.39 (t,,/- 8,4 Hz, jH), 8 05 (brs, IHp 8,25 (brs, 1 HE 10,89 (s, IKE MS 370 (MH%

Example 227a: 1 -(5-(3 mlfamoyiamino-2-cya«ophepoxy)-2,2-dimethy!propy!)-3-· eiby lure;.;

Prepared as in -Example 215a from- ί -.(3-(3“δ®56χΕ·2·-4ί^Μρ%11ηοΧ>/|μ2,2-0ίη^^γΙρΓορ>4)-3-Λγ1ηΓε8 (Example 227b) in 10051» Yield. M'S 370 (ΜΤΓ),

Example 2276' 1 ~(343-a.tnin»o-2-eyanophc.noxy}~2.2-dimcthv)propyl)-3^tbylpre-a.

Prepared as in Example 21 5b ( Method A) from I n/^-cyano-.wnrrophenoxv)-· 2.2- d:jmetKylpropyl)“3-e(hyhirea S Example 227cl m 90% yield. MS 291 (MM ).

Example 22?c: 1 -( 3-f 2-<:yano/5-nitrophenoxy)-2J! -dirncihs hm.-py 1 l-B-ethylnrea

Prepared ap in Example 215c from i -edm-3--(3-hydmxy~2 ,2-dimetfiyiprogyl}mtja (Example 227d) and 2,6-dmitrobenzoeitrile in 472« yield. MS 321 iMH }.

Example 22 ?d: I ctby 1-3-13- by dr·.; x y --2.2. -dim eth yIpropyi)orea

To a solution of3”amino-2,2-dimethytpropan-1 -ol i 1.03 g, 10 mmol) in dry 1.4-dioxane (20 mL) was added dropwise ethyl isocyanate (0.71 g, 10 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen overnight. The solvent was removed imdcr reduced .pressure -to give the title compound as colorless oil (1.74 g, 100".)}. MS 175 (MH }.

Example 228: 3-(4~ammo-2,2"di0xide” 1 Tl-hes zojcΗ1,2,6]tMadiazIn-S-yloxv}-N4miy!-2%2 dimeUtylpropauarntde

Prepared as in Example 215 and l a from .Mi-amino-2 -cy at tophenoxy >-N -buty i- 2.2- dimetliYipropsnaPiiife (Example 228a)' and snlffenoyl chloride in 145¾ yield as a white solid, *E NMR (400 MHz, DMS0-/1 4 0.?#(!, /.= 7,2 Hz, 3H.I, 1.14-1,22 (ffi? 8H), 1.33- 1,37 (m, 2ME 3.02-3.07 (m, 2H), 4,07 (s, 2H), 6.60¾ / - 8.0 Hz, 1H), 6.71 (d, /- 8,8 Hz, 1 HI 7.44 ft, / - 8,4 Hz, IE), 7,80 (t,/- 5.6 Hz, 1H), 7.91 Cs, 1H).8.33 is, IH), 10.92 (a, IH). MS 367 (MET).

Example 228a:-3-(3-amino-2-cvanephenoxy1-N-butvi-2,2-dimethvipropanamide., Prepared as m Example 215b ( Method A) from N-bttty I ·3··(2-cyano-3· nitfophencj:xy)-2:2 dim.ethvdpropcmanude (Example 228b; in 89% s ieki. MS 290 (MH ).

Example 2?8b N-iruty!-3-(2-eya:no-3-oiiro:pheHcexy,r-2,2-diniei1y\4propanamide

Prepared ah in Example 215e from N-4)iMyl-3-liydroxy-2/.-d5methylp:re:pasamid:e (Example 22Sc) and 2,6'(rl?nna>benzQnit.rile in 66% yield, MS 320 (Mill.

Example 228c: N-butvI-S-^dfoxy^.^-dimethylprepananstde

Prepared as in Example 215d (Method A) from methyl 3-hydroxv-2,2-dimeihyipropunoate and m-butyl am mem 100% yield. MS 174 iMH ).

Example 22frN~CM4~amM0^2~dtaideHlI»ta^^ inrOyvIproparv^’Hlli.ratyraridde

Prepared as .'in Example 2 Ϊ 5 from N-t 1 -t3-sulfaraoy larmim-l-ey anephemxy)-2~ oicthylpmpari'2'yl)butyramidc 1 Example 229a) and .sodium hydroxide in 54% yield as a white solid. !B NMR {400 MM2, DMSO-cA»j ό 0.78 (t, J- 7.2 Hr... SB), 1.32 (s, eH), 1.43* 1.44 (m. 211 >, 2.00 {?../- 7.2 Hz, 2B1, 4.24 (s. 21! i. 0.00 (d, J - 8.0 Hz. Ill), 0.73 (d, J - 8.4 }¾ 111), 7.44 (t. J==== SB Hz, 1H ),7.77 (s, 11! s, 7.82 (s, I Hi. 8.42 {s. IHS. 10.97 (s. I H>. MS 355 (Mil ).

Example 229a: 84 -(1 *(3 ~sui famoy lammo-2 -cyaoopheno' \ 1-2-methyi propan *2-vl)> butyramide

Prepared m in Example 21.% from N-( 1 -{S-amino-l-pyspophenoxy )-2-meihyipr0pan”2-yl)liuiyfarrdde (Example 229fa.) and sulfarnoyl chloride hi 100% yield. MS 355 (MB').

Example 229h: N--(l -(3-arpifio-2-cyanopheuoxy)-2“methylpiopan“2-yl)b«tyrairutle

Prepared as in Example 215b ί Method A) from 84-( 1 -(2-cyano-3-nitropbenexy)-.2-mtifeylpfppan-2-Y 1 Ibufyrami-ic (Example 229c) m 1003« yield, MS 276 t MH ).

Example 229c: N (= *{2^aft04«ftitrpphe»i0ety)*2rmeibylpi^paii»2*yl)bdt^-n.iidb Prepared as in Exaft^pl.p'215ofrdipi''N^Cl-hydroxy-2-rftip{feytji>fppaa?2* yllbaryramide (Example 2290) and 2,6-dimtrohenzonitrile in 72% yield, MS 31)0 (MH").. Example 229d: NH:ld)\%oxv-~2--metlwlnrdpari--2--yi3ha%ramlde

Prepared according to the literature (Boyd. R.N.: Hansen. R..H. J. Am. Chvm. 5<.v. 1953. 7/, 58%) from 2·amino-2-mcthy I propun-1 -ol and buryryl chloride in 3278 yield. MS 160 IMH ).

Example 230; %(%(4-amln«-2,2*dloxIde~llEfeeaxo{o)|l,2,6}iiiaitia»a-5~ytoxy)-2-metfaylpropan~2 ?-yI}-3 MOlnluroa

Prepared as in Example 215 from l-(l-(3'SidiamoyiannriO'-2'-oyanophenoxy}'2~ Metfeylpfopan~2-yI}-3~eihyhirea {Example 230a} m 37¾ yield as a white solid. !H NME (400 MHz, DMSO-<4> i) 0.92 if ./ === 7.2 Hz. 3H), 1.27 is, OH), 2.90-2.93 (m, 2H), 4.21 is. 2B), 5.63 (f J==== 5 J Hz, Π-1.Κ 53)5 (&amp;, I Hi. 6.59 (d,,/ === <9.0 Hz, Hi), 6.72 (d,./ === 8.4 Hz, i H), 7.42 if ,/ === 8,4 Hz, 04), 7.94 (s, I Hu 8.34 (s, IH), 10.94 is, \H). MS 356 (MH ).

Example 33{H: H(i-(3^s&amp;l.famoyiam:in<>-2-cya.aO;phe»oxy)-2-'Rt.ethylpro.0a5i=-2-y!)«3» ethyiurea

Prepared a.s in Example 215a from I -(i ··{3-ainino-2-cyanophcnox>)-2- mmhylpropam.2-yiV-3-ethylarea (Example 23(16} arid sulfamoyl chloride in 10078 yield. MS 356 (MB f

Example 230b: t“{l“{3'-amiii0-2-:cyappfphano.xy)-2-mei5ylproj>aP"2->U"3-cfhy1iii'€^

Prepared as in Example 215b ( Method A) from .1.-(H'2-evano-3-nitrophenoxy)-2-nie?hy|pmpam2-yl!--3--cThylnrea (Example 230c) in 86% yield. MS 277 (MH ).

Example 230c: 1 -(M2-cyano*3“nitrophcaoxy)-2-n>cihylprppasi-2-yl)-3-cthyiure-a.

Prepared as in Example 215c from t-cthyi-3-(l -hydmxy--2-methyl propari-2-yl)urea (Example 23.94) a»di 2,6Mi?«trobeazohitrile in 65% yield, MS 307 (MfE).

Example 230d: 1 -cthylM-p “hydroxy-2-aite&amp;ylpfapa»-2--yl)prea.

Prepared as in Example 22?d frem 2m:min:0-2-m.ethylprop3n4-b1 and ethyl Hoeyanate in 94% yield, MS 161 (MBS,

Example 230 4^4-aituB0-2^-dioxMe'.iH-^.e»zo[c|j;lt2,6j'tfemdlaziii*<5~yIoxyf~2>»

Prepared as in Example 215 irons 4-(2-c >ano*.i-{suifcunovianiino)phcnoxy )-2-;nefhy[biitan-2-yi acetate tExample 251:.0 in 20°;» yield as a while solid. lH NMR (4<}i) MHz, DMSO-tfe) $ 1.15 (s, m\ 1J9 ft,/=== 6.4 Hz, IE), 4.22.ft/- 6.4 Hz, 2H), 4,62 is,!H}, 6.5? (d, /=== 8.0 Hz, IH), 6.73 (d, J === 8.4 Hz, 10), 7.4.1 ft ,/ =-8.4 Hz, 1H), 8.22 is. ] Π). 8.50 is, Η I), 10.87 (s, 1H). MS 300 (Mil 6

Ex am pie 25 la: 4--( 2-cvano-3-{ suifamoylam inolphenoxx )-2- methy ibutan--3--vi acetate

Prepared as in Example 215a from 4-(3-umifm-C--e>anophenoxv}-2-nierhylbatan-2-yl acetate (Example 231b) and sulfa,moyi chloride in 100% yield. MS 542 (MH').

Example 231b: 4--{3--umino--2-cyutmphes50xy}--2--mcth>lb»taii-2->i acetate

Prepared as in Example 215b ( Method A) from d.-td-eyanoMohiiopheuoxyftE mcihylbuiaaO-y'i acetate (Example 231c). MS 263 (MH }.

Example 251c: 4--(2-eyano· 3-nil; opherioxy}-2 methyibuiun-2-vl aecone

To solution of2-t3-hydfoxy~3-methysbutoxy)~6*nitrobenrooitrite (Example .731 dt (250 mg, 1 trietbylatnioe (3 eqpiv.), and DMA? (0.1 eqthv } 1st dry dichloromethane (20 mL) wag added drapwsse acetyl chloride (1.5 equiv.)·at 0 °C under nitrogen. Tbc reaction mixture was then stirred at 0 Hi; - room temperature overnight. The reaction was diluted wish Es.OAc, washed with brine, and dried over Na>SO-i. After evaporation of the solvent* the residue was pari Hud by chromatography on silica gel eluting with 20% EtOAc in;hexanes to give the title compound (I 3" mg. 47%), MS 293 (MTT),

Example 23 I d: 2-(3- hydroxy~3-mcfhv!huvoxy)~6~nitrohenzoJiiiriIs

Prepared as in Example 21 4c from 3-metbyIbutan.e-l ,3“diol and 2,6-dinifrobenzonitrik m 81% yield, MS 251 (MB),

Example 232: 2^((4~a8BkH>~2.2HUoxide-ri:I-l>erszo[ejil/.o)ihmdinziM“5-ytoxy)nteihyl)~2·" eihylbuian~i-~ol

Prepared as isi Exaspplo 215 from 2~ethyl~2>((2^methYl'3> (sulfamof;laiRi:in:o)phe»oXy}in.ethyl}hwf34 acetate (Example 232a) in 2084 yield as a white .solid. !H NMR (400 MHz, DMSO-7,) <5 0.734).40 tm. 014). 1.21-1.37 (ra. 4H), 3.31-3.33 (rn. 2H), 3-39 is, 2H), 4.92 (brs, 1H}„ 0.56 id, ./- 8.0 Hz, 1H). 0.73 (d,,/ === 4.4 Hz, 1H), 7.40 (t,./- 3.4 Hz, 1H). 0.16 thrs. 2H), 10.91 {brs, HI). M3 324iMH0.

Example 232a: 2-((2-cyano-3-{suifatnoylammotphcnoxy)medwb-2-cthy lb«t>-I acciatc Prepared as in Example 215a from 2 ·{( 3 · amino-2-cyonophenox>}methy 1)-2 · ethy Hurry! acetate (Example 232b) and MUfamoyi chloride in 90% yield. ‘H NMR (400 MHz. DMSO-d,-.) Ο 0.30 (t,7 === 7.6 Hz, 6H), 1.37-1.43 (m, 4H), 1.94 <=>. 3H), 3.47 {a, 2H), 3.06 (a. 2B), 0.94 id, ./=== 3.3 Hz, 1H), 7.1 3 id, J === 4.4 Hz, i H), 7,25 (,y 2B), 7.54 (t, ./===· 3.4 Hz. IH), 9.46 (a. IH).

Example 232b:' 2 · CO · amino-2-c yanophenoxv )mcthvl)-2-cth vlbutv 1 acetate Prepared ax in Example 215b (Method A) from 2··{(2··ον;.!ηο··3-nitrophenoxy)methy 1 )-2-ethylbutyI acetate (Example 232c) in 9|%yield. Ή NMR (400 MHz, DMSO-f/s) A 0.79 (t, J - 7.6 Hz, 6H). 1.34-1.41 (m, 4H), 1.97 (s>. 3H), 3.76 (,ν 2H), 3.94 (s, 2H), 5.97 (a. 2.H}, 0..21 (d, J = 4 0 Hz. IH), 6.3 j (e../ = 4.4 Ηz. 1H)., 7,15 (t, J = 3 0 Hz: 1H), MS 291 (MB ).

Example 232c: 2-< {2-cvano-3-nltropltenoxv)p^th.yO-2-ethy1.EutyI acetate

Prepared as in Example 23 Ic from 2-(2-«hyl4Hbydroxyraethyi)batoxy)46r nliTobesizotiitrile (Example 232-3.) and acetyl chloride in 82% yield. MS 321 (MR ).

Example 2323: 2-(2-ethy!~2-*<hydroxymeUiYl)butoxyMEnitrobenzcnitri!e

Prepared as in. Example 21 3c from 2,2-dierhy}propmi.eB3Ali<)i: and 2,6-dinitrobenzenitrile in %6% yield. SB NMB (400 MHz. DMSOuB) 0 0J0 (U~ 7,6 Hz. 6H), 1,34 (q,./ 7.6 Hz, 4H), 3.33 id, ,/-:5,0 Hz, 2B},3,96 s>, 2H), 4.S7 (o J-5.3 Hz, IB),7,74-7.76 Cm, IB), 7.44-7.90 (n>, 2B).

Example 233: 3-(4-nmifKy~2,2-d5oxide-B:i4u>8ze|elil,2,0|iidadmzin--5--yioxy)-'222<'~

Prepared as in Example 215 from 3-( 2-cyano-.Hsulfomoyi-ami no Iphcooxy )-2.2-diracthylpropyl acetate (Example 255¾) m 30% yield as a v-hite solid. Ί1 NMR (400 Ml 1/., DMS()-«5) ,> 0.94 is, 611)(3.29-3,31 (m5 2B)V 3.88 (s, 2H), 5.01 (t, ,/==== 4,4 Bz, .1B)> 6.S8 (4,/==== 8.4¾ 114),6./1 (d,./=== 8.41:¾ IB), 7.42 ((,./=== 8.0¾ 10), 8,14(8, IS), 8.3:2 (s, IB), 10.92 (s, 1H). MS300(MB'). 6 \ am pic 238:.0 3··(2··οναηο··3··ι saiiOmo > lam inoiphenoxy) 2,2-Ui methylpropyl acetate Pi spared as in Example 215a from 3-|3-amino· 2· e> aoophenoxy )-2,2-dimethylpropyl acetate (Example 233b) and sulfitmovi chloric m o0% =- sold. lH NMR (4))5} MHz, DMSO-PV! 0 0.99 (v PH). 1.98 {>,, 3HX 3.85 Is. 2H). 3.91 (s, 2H). 6.91 (d. 7 === 8.4 Hz, IB), 7.12 (d, ,/==== 8.0 Hz, ί B), 7.23 (g, 211), 7.52 (t,../- 8.0 Hz, IB), 9.45 (s, IB).

Example 333b: 3--{3--aimno-2-cyam^lumoxy}--2,2-di?neth>lpropyi act-tatc

Prepared as in Example 215b (Method A) from 3·(2·cyano-3-nitrophenoxy )--2,2· dimeihyipropyi accede (Example 333c} in 773« yield Ή NMR (500 MHz, DMSOm/O 0 0.98 (s, 6H), 2 00 (s, 3H). 3 75 is, 3.H). 3.90 (s, 2H). 5.99 (s. 2H). 6.17 (d, 3 == 8.4 Hz. 1 H). 6.31 id, J === 8 4 Hz. iB), 7..:5 (ί,./== 8.0 Hz.. IB).

Example 233c: 3-(2-cvan(>-3-«ltfopltenoxy)-2<2-dtmethylprdpyl acetate

Prepared as in Example 23ie fmm 2-(3·hydroxy-2,2-d imethyIpropoxy )-6-nitroivn, ooitrde) 1- xamplc 233d) and acetyl chloride in 66% yield. Ή NMR (4()0 MHz, DMSO-,<4) 0 * 91 nil) 7 90 {v 311) 3.95 (s, 2.H). 4.02 O, 2H). 7.70-7 72. (m„ I H), 7.85-7 92 (m. 2B}. f-cnnpU 273d 24 Vh\dr6xy-2,2-di met hylpropoxy R6-ni tr-..^erizoni trile

Prepared as in Example 2.15c from 2.2-diree:hy!pn>pa!ie~l;3-diol aiid dzS-dimlrobenzoniirile in 73% yield. Ή NMR (400 MHz., OM.SCW·,} »> 0.94 (s,,6B), 3.29-3,31 (m, 7H). 3.95 (s.. 2H), 4.69 (:., J 5,6 Hz, IH), 7.69-7 71 (m, SB), ?.*4-7,90(av2B}.

Example 234: N~(4~(4~amiimM/Z-dioxideSH-henzolcjl I,2,61thi5rdPazi«~^yRixy)Eidyi)” acetamide

Prepared a.» in Example 215 fmra N-(4-(2-cya,no^3-:(salSmoyIamiao)pliv.nr>x>0h!5/}l}aeeranr)de (Examp!e 234a) in 30% yield. SII NMR (400 MBz, DMSQ~<k)$ 1.48-1 .51 (m, 2H), 1.77-1.51 (m, 5H), 3.03-3,08 (m, 21¾ 4,14 (1,.,/ - 6,0 Hz, 211), 6,59 (d. ,/-= 8.0 11/, Ϊ 0), 6.73 (d, ./-8.4 Hz, 1 In, 7.43 (4.,/- 8.4 14/, 1 if}. 7.78 (s,111). 7.84 { bvs. 1Μ ), 8.32 ¢:,.111), 10.93 /, f H). MS 327 (MH ).

Example 234a: N-(4,(2<yyarKj-3-(xulfarnoylaminolphenoxy }buJyl)acetarnide 'Prepared as in Example 2.15a finm N-(4-( 3··;η7ύηο··2· eyanophenoxy)bmyI}aectamide (Example 234h) and snlRirnoy 1 ehlonUe in 1007¾ yield. :H NMR (400 MHz, DMSO-ώ;) o 1.51-1.54 On. 2Ηί, 1.70-1.73 On. 2H>, 1/7 (s, 3H). 3.04-3.09 ρη, 2H), 4.09 (0/- 6.4 Hz, 2H), 6.93 id,,/- 8,4 Hz, 1H), 743 id,./- >Y0 Hz, 11¾ 7.25 (a, 21¾ 7.54 (t,,/ =- 8.0 Hz, Hi), 7,s5 (brs, 1H), 9.42 is, 1H).

Example 2346; N-(4-( 3~umin«“2“cy8iiopheapxy)bptyI)aeetamide

Prepared as in Example 215b (Method A) from N-i4-(2-e>ano-3-isitrophenoxyIbuiyljacetanmie (Example 234c) in 85% yield. Ή NMR (400 MHz, DMSO·/*) d I 49-1.5=1 (m, 2H> f .66-1,70 (m, 2H1. f .77 is., 3H). 3.03-3 08 (m, 2H). 3.97 (t. J === 6.8 Hz, 2H). 5.95 (a 214),6.18 (4,/=-8 0 ,Hz. 114)/..31 (d../=== 7.6 Hz. IHs, 7,15 ((, / === 8 4 Hz, 114),7.83 (b'N.l 14).

Example 234c: M/9-(2-cyano-3~mtrophen0x.V)h9tyl3acetamjde

To a solution of 2T4-an:dirolmtoxy)“6-rn;irobonz(>nj(Tilc (Example 234df i235 mgx 1.0 mmol), trieflpdamiGe (3 equiv,)» and DMAP (0,! eejinv.) in dry·' dichloromethanc {20 -mL> was added dropwlse acetyl chloride (1.5 equiv.} at 0 °C under nitrogen. Tire reaction mix tore' was then stirred at 0 °C - RT overnight The reaction was diluted with EtOAe, washed- with brine, and dried o ver Na^SOn After evaporation of the solvent, the residue was purified by chroniatography on silica gel eiuting with *<*% Ft< t-\c in hexanes to give the tide compound (158 mg, 578:.0. MS 278 (MH O,

Example 234d: 2-(4-avni:nohntoxy)~6~nitrphen.2on:itri:!e A soluisou of r.ert-bntyl,4-(2-eyan.o-3-rh(rophenoxs0hup4earhainnie (Example 234'# (671 nig, 2 mmol.} in DCM/TFA (1:1,20 nxL) was stirred at room' temperature for 2 hrs. The solvent was removed under vacuum to give the title cogtpound (698 mg, 10044). MS 236 (MHO,

Example 234e; tert-hutvl 4-i2-eyano-3:mitrophenoxy)butylearhamate

Prepared as in Example 215c front tett-hutyf 4-hy d-oxHnnylea; bamatc and 2,6-dinihobe-iZoniitile in 7% yield as a pale yellow solid. T! NMR (400 MHz. 1>MS0-;//.) 5 (,35 90), L52-.I,55 (m, 20), 1.72-1.76 (in, 20), 2.94-2.99 im, 2l\l 4.24 (t,./- 6.8 Ox, 20), 6.86 (brs, )0-. 7.69-7.72 im. 1!!>, 7.85-7.90Crm20}.

Example 235: 4“(4'are6K>-2.2'-djoxiile-vlII“bee/.o|e]rL2,6]t8iadra/.iH-'5“;vloxy)l>?dyi selfamaie

Prepared as in Example 215 fern. 4-{2-cysBo~3-{s'ulfemOYiarmne)phenexy}b«iyl sullarnaie (Example 235a) in 3 1% yield. Ή NMR (400 MHz, DMSO-<M <> i ”4-1.79 (ns. 2H>, OS-1.91 (m, 2B)? 4.07 (t, J - 6.4 Ha, 2H),-4J8 (t, J - .6.8 Ha, 2H), 6,56-6.60 (m, 1 B), 6.74 id, ,/ - 8.4 11/, 10), 7.42-7.46 (ns, 30). 7.79 0,01),8.32 (s, 10), 10.93 0,10). MS 365 (Ml I ). iMoml® 238a·. 4-(2-cyano-3-4sultansoylammo)j>henoxv)biUYl Miiuirnuie Prepared as in Example 215a from 2'aoxiiK>~6~l4-itert-bul'yldimcthylsilylox>-)buioxy)bcnzoniliHe (Example 238b) and suliamoyi chloride in 63% yield, MS 3x2 {M -+41.4-0.

Example 235k 2-andno-6~(4:-(tert-buiyidlmeihylallyloxy)botoxy)b&amp;naoaiMb Prepared ax in Example 215b (Mediod A) from 2-(4-(ierl-bidyidimelb>dailyloxy)bu:toxy)-6-iHtrobenaonitrilc (Example 235c) In 7679 yield. MS 321 (Mlfr). Bxapxple 235c: 2-14-(tert-bi4YldimeihyOijvloxy)buroxy)-6-nitrobcn20ndriie

Prepared as in Example 218c irons 4-(terl-batykla-vred5yl-;6iylox.y)b«ian-l-ol and 2,6-dinitrobeozonitrife In 25% yield as a pale yellow solid, 'll NMR (400 MRa. PMSQ-d)} 0 0.01 %, 60), 0,8:1-0.83 (m, 90), 1.61-] ,66 (m, 20), 1.76-1.81 (m, 20), 3.63 (t, 7 - 6.8 0/, 20), 4.26 (t,,/:::: 6.4 0¾ 20), 7.68-7,70 (m, 10), 7.84-7.89 ;(m, 20).

Example 236: 4-(4-rHriiae-2,2-dioxide-Ill-beaac(c||l,2,6|ii-d:rdiiYain-5-yk>xv)-bnmsY-r-ol

Prepared as in Example 215: fern 4“(2-cyaBe-3-(snl&amp;mO:ykm:inQ)phenoxy}bo ly 1 suliamme (Example 235a) in 2% yield, di NMR (400 MHz, CDeOD) § 1,69-Ε73 (βι, 20), 1.95- 1.90 (rn, 2Η), 3.63 ({, J === 6.4 Hz, 2Η), 4.24 H, J === 6.4 Hz, 2H), 6.61-αο.ΐ no, IH), 6.75-6.7? (rn, I Hi. 7.45 (m.,/ - 4.0 Hz, 1 Hi. MS 246 {MH ).

Example 237: 3-o;4'OraOK>--2,2Hisoxkle- lIH!>ee/.o|e|rL2,6]tlPadiaziH.'5--;vloxy)-24-mcOtyfpropan-r-ol

Prepared as in Example 245 from M2-cyano·3•{'adfamoy! aminotphenoxy)-2-rocdiylpropyl acetate (Example 237a> in 4153 yield as a white solid. *H N'MR (400 MHz:.. 05150-(/,.) .)0.94 ah./-:= 6.4 Hz. 3H), 2.09-2.13 (m, iHi, 3.36-3.42 <m, JH>, 3.46-3.50 (ro, \ H% 4.05 id,./ - ή 4 Hz. 2H), 4.5-:1 ./ = 5.0 Hz. 1 H). 6..57 (d, J - 7 6 Hz. i H), 6.70 id,,/- 8.4 Hz, IB). /42 it.,./- 8.4 Hz., 1H). 8.05 {brs, 1H). 8.24 <bi*. Hi), 10.91 (s. Hi) M\ 2 so (Mil i. Example 237n: 33-«2-eyuno-3-(;ad famoylumioo)phenoxyV2· merh> I propyl acetate

Prepared re; in Example 315a from 3 - (3 - a m: a o -.: - c y a a o p h e; a=x > p 7 ~ m et b \ ip ro p y 1 acetate (Example 237b) and sbliamoyl eMonde m 78% yield. *H NMK t400 MH?, 10150-:¾)% 1.02 (d,./ - 6.8 Hz. 3H), 2.01 (s. 3H), 2.23-2.27 (m. 10), 3,99-4.07 (at,-4H), 6.94 id. /- %8 Hz, 1H), 7.14 (d, J - 8.0 Hz. IH% 7.26 (s. 2H), 7.55 0,,/ - 8.0 Hz, H I). 9.47 (s, 1 H i.

Example 2376: 3-('3-^mtno-2-cyanophmoxy)-2-mcrhylpiOpyl acetate

Prepared as in Example 21,5b i Method A) from 3-r2-ey<ino-3-nitroptedo8:y}-2·-. idethylprepyl acetate.23?e) in 73%¾ yield, '‘JiMMR {400 MHz, DMSO-<4) δ0.(99-(0, J - 7.2 Hz, 3H). 2,00 (x, 310. 3,19-2,24 (m, 1H): 3,91 {d,i - 5 2 Hz. 2H), 3.97-4.06 (ms2B), 5,98 (s; 2H), 6,19 svd,,/“ 8.0 Hz,1¾ 6,32 (d, J - 8.4 Hz, 114), 7,16 id J - 8.0 Hz, 1H),

Example 237c: 3-{2-ey:mo-3-mtrophenoxy)-2mieihylpropyj acerere

Prepared ax in Example 331-: irom 2*{3-hyaroxy-.?.-melhylprapoxy)-6-nitobeBzorn'irile (Example 2374) and acetyl chloride in 41% yield. !H N.MR {400 MHz.. DMSO* .</00 ),04(d.7- 6.8 Hz, 3H). 2.00 (x, 3H'p 2.28-2,33 (m, 111). 4.05-4 08 (m„ 2H), 4.18 (0,7 = 6.0 Hz, 2H>. 7.71-7,73 (m, 1 H): 7.86-7 97 (m, 2H).

Example 237tl: 2-(3:-hvdr0xv~2-msth.vl6ropox:v)-6-ndrobenzoaiM)e

Prepared as in Example 215c from 2-mcthylpropanc-1.3-dio) and 2,6-dinitrobenzoniTnlc m 3 /0¾ yield. MS 23? (MH ).

Example 238: 3--(4-0mino-2,2-dioxide- I H-ben/.oje| jf,2,8]duadlaxm-5--yloxyipropan-1 ?-oi

Prepared as in Example 31 5 from 3-f 2-eyavio-.Msoifermyiaminojpbcnoxy ipropyl sulfamatc (Example 238s) in 6% yield. Ή NMR (400 MPlx, P\J$0*i/ft) <* 1.92-1.9? (rn, 2H), 3.55-359 im. 211), 4.20 (t,,/ - 6.4 Bz, 2B). 4./9 (f ./- 4.8 Bz, ill). 657-659 inn 111). 6.71-6.73.(»>, IB). 7.43 (t, ,/- 8.4 Bz, ill). 8.12 (brs, 111). 8.28 <brs, 1H), 10.90 (s. 1H). MS 2/2 (MB }.

Example 238a: 3-(2-cvano-3-(sniramoylannno)phenoxy)propyl ««Ifamate

Prepared as in Example 215a from 2- amino·<m3--hydmxypropox>}benzonii πlc if vmrplc _o5h and sulfamoyl chloride in 30;N yield. Ή NMR (400 MHz. DMSO-;6·} d 2.1I-· 2.14 (m, 24%4:J6-4.21 (nv4B), 6,96 CO, 2-8.0 Bz, JBV7J5 (¾./-7;6 Bz, 1H), 7.26 (s,2BK 7.49 (8, 20),-756 (t, ,/- 8,4 Hz, 1H), 9.46 Cs, 1B).

Example 236b: 2-amlno-6-{3-hydmxypropoxy)benzo?HfnIe

Prepared as in Example 215b (Method A) from 2-(3“hydroxypropoxy)-6-ratrobenzomirile (Example 2238c) in 100% yield. Ή NMR (400 MHz, DMSCM*}· $ l .79· 1.85 (m. 2H), 3.52-3.56 (ra, 2H), 4.04 (t../ - 6 4 Hz, 2Hk 4.54 (6,/- 5.2 Bz, IH), 5.93 {*, 2H), 6.19 pi./ - 8.0 Fix, 1B), 6.30 (cl, ,/-8.4 Bz,. 1B). 7.15 (t. ,/- 8,0 Bz, 1B).

Example 238e: 2-(3-hydroxvpropoxy3-6-mtrobe;ftzoaii;rife

Prepared as ί»Έχη«ψ!ο 215c fre-m propane-Medial and2,6-dlnitrobc»zoniirile in 61% yield as a pale yellow solid. '!H NMR (400 MHz, DMSOmb) 9 i.89-1.93 (m. 2H), 3.56-3.61 (m, 2H), 4.30 (t, J - 6.4 Bz, 21¾ 4.61 (i,/- 5.2 Bz,. IB), 7.71-7.74 (m, 1H), 7.85-7,9! (me 2H), Example 239: 5-(b«ty!thlo>iH-fre»zni(eii;i,2»6pfelsdM8^d?^»f~2^-ieie^e

Prepared a.s in Example 2 15 from 2--sulfam»?>ium ino /> -(buty ]th io)bcnzonitnlc (Example 23%} in I 2% yield a-; a while a raid. % N.MR {400 MHz., DVJSO-</>} d 0.-55 ft. J === 7.6 Hz. 3.H), i.3-5-i .4? (m. 2H), 1.49-1.56 {m. 2H|, 2>>” sy, ./ == 7 3 Hz. 2H), 0.57 pi../ === 5.4 Hz: 1 Hi 7.1 2 id, / === 7 0 Hz. IH), 7.41 (E 7 === 7.6 Hz. 1 H). 5.12 (hrs 2H), 11.02 (Era. IH). MS 256 (MH ) Example 239a: 2-suJfamoylummo-6“(buiylrhio}ben^njtrfl*

Prepared as in Example· 216a from .?.-:A!-oino*64bulylt.bio}beri2omtri)c -Example 2 %% in 765a yield. ’H MMR (400 MHz. DMSO-jU 5 0 55 *e ./ === 7.7 Hz. 3H), l .36-1.4.5 im. .'H)s I 54-1.61 (in, 7H). 3 07 ft../ === 7.o Hz. 2H). 7.25-7.27 (m. 3H), 7 33-7.26 (m, IH), 7.57 ft, J == 5 4 Hz. I H), 0.50 (a. I Hi.

Example 239b: 2-am'mo-6-(butyiihio}bcnz®nitri1e

Prepared as in .Example 215b (Method A) from. 2~n{tro-)5-(bi)iy!{:hio)beHzo.e)irile (Example 239c> in 57% yield, !H NMR (1400 MHz, CDCh) /0.93 (4, /=== 7,2 Hz, 314}, 1.43-1.52 (m. 214). 1.63-] 70 2H), 2.97 (t/ = 6.6 14z, 214), 4,43 (bps, 214), 6.52-6,54 (6¾ 1¾ 6.67-6.69 fm. IH i, 7.21 (e ·/ == 5,0 Hz: IH).

Example 239c: 2-niiro-6-(butyIthiojbenzooiMie

Prepared as in Example 215c from birEme~t~:hio? and 2,6-diohmbenx.onuri!e in 90% yield, Vl NMR (400 MHz, CDCb) 0 0.97 (1,/== 7.2 11/. 311),1.42-1 55{mv2H), 1.70-1.77 (m, 211),:3.09 (e / === 7,2 Hz, 2H); 7.63-7.69 (m. 2H), 7.99-:5.01 (m, III),

Example 248r 6~(4~ami«o-2,3~dt0xide~llri~feeaze4e] [l,2,6|tMail!azj«^~ylOxy)feexyl mlbdnate

Prepared as in Example 215 from 6-{2-cyano-3-(sttl&amp;moyla'mi»0)phei]oxy)hoxyi sulfamme (Example 240a) in 46% yield. SH NMR (400 MHz, DM50-/,) ,11 03-1 05 Cm, 414). 1.26 (np 2H), 1.45 (m, 2H), 3.64 (t, i - 6.4 Hz, 2HK 37?5 (t, 4 =- 6.41¾ 214), o/3 id, I -= 7.6 Hz, mi 037 uK j ==: 7.6 Hz, IH), %02 is, 2H), 7.07 (t, J === 7.6 Bz, IH), 7,44 (s, IH), 7.96 (s. tH), 10.56(-. Hi). MS 393 (Mil ).

Exam pic 24( (v^^^vaao^-^^ftoojl^snoiph^tioxy^exyl Mlfamate

Prepared a? in Example 215a ft%m.2-tom0-^-(6-ky^x>xy^exylox><)be«26.aiMie·' (Example 740b) and Mtifamoyi chloride in 20% yield. MS 393 (MEf).

Example 2906; 2-amino-6-{6-hydr0xyhexyioxy)benzonitriie

Prepared as in Example 2156 (Method A) from. 2"(6~bydmxybexyt&amp;xy)--6" nitrobcnzonitrilc (Example 24Qc) in 09% yield. MS 235 (ΜΗΓ),

Example 29(¾; 2·(6-hydroxy hexyloxy}·6-nifrcbenzomtrile 'Prepared as in Example 215c from hexsβe^I,6^to^aad^2,(^d.mίtrdbeί¾^o»iimie in 88% yield as a pale yellow solid. MS ,265 (MHO.

Example 241: 5-(4-8 miae-2,,2-dioxide-lM-benzo je) (l524*]iMadiazi n-5->1exy)peaty! sulfamate

Prepared as in Example 215: from S-(2-cyaBO”3-(sul&amp;mO:yiam)nQ)-phenoxy)p©niyS suliatnale (Example 241 a) m 44% \ smd, Ή NME (400 MHz, DMSO-ifr) S 1.09 (¾ 20), 1,33 (m. 2H), i ,47 (m, 2H), 3.66 ((, J «* 0 Bz, 2B), 3.79 (ΐ, 1 === 6.6 Bz, 2H), 6,22 (d, J === 8.0 Hz, 1B), 6.37 (d, J === 8.0 Hz, 1H), 7.03 % 2H), 7.07 (i, J === 8.0 Hz, IH), 7.43 (s, IB), 7.95 {s, IB), 10.57 6=, 1 H). MS 379 iMH ),

Example 291a; 5-|2“eyanO“3^(s6liafnoylams»o)phenoxy}p:®Piyi xtdiamaie Prepared as inExample 215a from 2-amm0-6-(S“(tert< buiyldimeilvvlNllyiox>9penwicmy)bciizomtnle (Example 2410) and sidfamoyl chloride in 2684 yield. MS 379 (MHO.

Example 241b: 2-am'ino-6-(5-{tert-butyldimcihy{silyloxy)pentytoxy)ben20»itriie'

Prepared axm Example 215b {Method A) from 2,-{5-(4:eff-:bi%(ldime(hyE silyloxy)pen(yloxy)"'6-nitrob«mzoBfrrile (Example 2-1 to) m 93% yield. MS 335 (MB').

Example 24le::2-(54tert~bmvldlpmtb¥friiv!exv)penlylex.v3-6-njtrebenxoplfr)le

Prepared as in Example 215c from 5 -{lerEbury iui methyl -si ly loxy )pcman -1 -ol and 2A-diniirobenzonitrsic as a pale yellow solid in 4<Vg, yield. MS 365 {MB }.

Example 242: 5-(4-:¾mim~2,2-d soxlde-I B-beaxeje|H ,2,6] t Idmfiazi n-5-;vloxy)pearan-1 '-ol

Prepared as in Example 215 from z-sulfarnoyliumno-b-lS-hydroxy-perHvioxy)beriz.orsiuilc (Example 242a) m 3251.-1 yield. !11 NMR {41)0 MHz. DMSO-e/ft) <> 1 39 1.49 tm, 4Hk 1.77-1 ..84 On. 211), 3.31-3.44 {up 2H?, 4.14 n. j === 6.4 Hz, 2H), 4..>5 irm 1 H), 6.59 (d, J =::= 8.0 Hz, 1H), 6.74 {d. j === 8,0 Hz, IB), 7.44 <isj>= 8.0 Hz, HI). 7.81 (s, ill), 8.34 (s. Ill), 10.93(8, IB). MS 300 ίMB ).

Example 242a: 2'Su!famoylamino-6-(5-hydrQxypcn?yloxy)ben;?.oniiriIe

Prepared as in Example 21 6a from 2-a.mirio-6-(5-(iert-buryldimeihyfeilyioxy).pentyloxy)benzoa?tnle (Example 24 lb) and sulilsmoyi chloride ia 4% yield, MS 300 (MB:)-

Example 243: 1:-i4~osBmo~2;2-dmxideMB^^^ trimethy lpeotmi-3 “-ol

Prepared as in Example 215 from. I -(2-oyauo-3.-(!Sttltaamy!am.mo)'-phe»OvXy|~ 2,2,4-trimeihy1pe?dan-3-yi acetate (Example 243a) in 35-1¾ yield ax a white solid.!El NMR (400 MHz, OMSGMs) S0.76-0.78 (d, 3H), 0.93 (χ, ΟΗ), 1.05 (s, 3H), 1.86-1.89 (m, IH), 8.18-3.19 (d, 1B), 3.73-3.75 (d, 1H), 3.99-4.02 (d, 1 HI 4.98-4.99 (d, IH). 6.57-659 (d„ f - g Hz, 1 H}? 6.70-6,72 (d, j - g Ηζ,ΙΗ), 7..43 - 8 Bz, !H|, 8.29 (s, 1H.|, 8,43 (s, 1H), 10,88 (s, IH). MS 342 {MB').

Example 243a; l-(2-eyanO"3d:stilfiimoylaiBino)phePtP<y)-2,2,4-fnmHliyl]mrtap--2v'yi acetate

Prepared us in Example 215.t ;V> >;η i aornymooM-eyaviopheimxy )-2,2,4-Ir imcthylpeniaTKl-y 1 acetate t Example 243 b) and suHamow chloride in 90% vie id. MS 384 (MM").

Example 243b. ; '(3'amino-2~eyanophcnnxy )-2.2,4-tritmxhyjpentan-3-yi acetate

Prepared as in Example 2i5b (Method A) from l-(2-cyuno-3-niUophcn‘)Xv)~ 22M-4rimelhylpentaa-3·>) acetate (Example 243c} in 83% yield. MS 805 t.MH'}.

Example 243c: I · 12·c>ann-3-nit rophenoxy )-2,2.4~trimcthy Ipcman·3·y! acetate

Prepared as in Example 281c from 2-{3--hsdfoxy--2.2,4-t: imeih\4pcsnyf;x\>6“ nitrebenaonatnle (Example 243d) and acetyl chloride in 50% yield, MS 335 (MB'').

Example 243d: 2-(3-hydroxy-2.2,4-triincthylpentyloxy)-6-nitix)benzdn:itfi!e

Prepared as in Example 215c from 2,2.4dnmethylpeniane- l ,3-diol and 2,6» (hnitrobenzomtrik m 5Κ*?«ΐ .yield. MS 293 iMH }.

Example 244: 5~(4~(meihy1it«o)b«ioxy)-1114>ena)je]j 1,2,{p t Id ad i axi a~4-amine-2.2-dioxiύe

Prepared as in Example 2.15 from 2-sulfamoyiamino>6«(4*· rinethyfthio)buioxy)bemv;onitri!e (Example 2.44a) in 7')*·.» yield *H NMR (400 Mliz, DMSO-f/s) d 1.63-1.67 (m, 21:1),, 1.86-1.90 (m. 2H), 2.02 (s. 311). 2.48-2 53 (n\ 2B), 4,16 (t, 2H), 6.5/-6.60 (d;. .1===8.4 Be., i H). 6.72-0.74 (d„ j === 8,4 Hz.l HE 7.45 u. J 8 Be, \ HI 7.80 is, 1H). 8.35 is, i B). 10.92 is, IN). MS 81d tMH ).

Example 244a: 2-snl!amovi.anii:sm-6-(4-(mcths irino)bntoxy4benmiiMl.e

Prepared as in Example 215a from 2-timi.im-6-(4-(melhyIiiiio)~batexy)benxonitrije (Example 244b) and sofldmoy! ddorMle m 66% yield. MS 316 (MET).

Example 244b: 2-;i;nlno-6~i4dsitethvUItiotbnroxvtbenxonitrile

Prepared as in Example 215b (Method A) from 2-(4-(m.ed:tylthio)baloxy)-6~ ni;trobenxonilrile (Example 244c) in 95% yield. MS 237 (MM ).

Example 244c; 2444mctbyhhio)bntoxyE6-nifrobcnzonifnie

Prepared as in Example 215e from 4-(m©ihyltM6)bwlan-l--bi and 2,6-dinitmbenzonitrile in 89% yield, MS 267 (ME! ').

Example 245; 5~(4-(fne(h> hulfse>1)batos>}-11I-beirM>|c|[ii2,6|tlil'siciiamM»amisje'"2,2·' dioxide

To a solution of 5-{3~{niethy!thiQ)buto.KyH H-benzo[cj( l.2.6}ihiadiaziri-4-arnine- 2,2-dioxide (Example 244) <79 mg, 0.25 mrool) in 1X7 M3€H4Od I {20:1,20 rnL) was added MC'PBA {1.0 cquiv.! m room temperature. The reaction mixture was then stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was ;p«rified fey chromatography on silica gel eluting with 15% MeOH In diehlofomeihatie to give the title compound {74 tug, 90%) as a white solid. 11 NMR (400 MHz. DM.SO-4) δ 1.-74--1 .,77-(m, 211), 1.88-1.95 (m. 2H>, 2.50 is, oil), 2.68-2.72 «m. liU, 2.77-2.%(niJih, 4.19 (ί, 2H). 6.586.60 {d, j - 8.4 Hz, IH), 6.73-6.75 (d, J -= 8.0 Hz. IH}, 7.44 (t, i - 8.0 Hz, IH), 7.79 is, IH), 8.33 is, IH), 10.92 (s, lHi. MS 332 (ΜΗ ).

Exampte 246i S-Cd-Cme&amp;ylsnlfony^buteyi-ill-benznleljiJJlibiadlaziP-d-amsniylJ-dioxide

Prepared as)in Example 245 front 5-{4-(methyithio)butoxy)“iH-benzofe]| 1.2,6ithiadiazin>4“<t.ntim-«2>2-dtoxide (Example 244) by the reaction with 3 equivalent ©f MCTBA. as a white solid ip'8|% yield. Ti NMR 01-00 MHz, DMSO-4) δ i .80-1.82 (m. 2H), 1 91-1.95 (m, 211), 2,93 (s, 311)3.18 (5,711), 4J8 (1,211), 6.58-6,60 (4 J ::: 8-4 Hz., 1H), 6 736.75 id.. I =* 8.0 Hz, IH), 7.44 (6 j - 8 0 Hz, 161), 7.79 (s, IH), 834 (s, IH j, 10 92 K 1H). MS 348 (Min.

Example 247: 5-i3-imer.hyh.bti0pro|>oxy)»IH~berszo|ci \ 1,2d>|thiiuIt3ziu"4-smlrie-2,2Htioxid:C

Prepared as in Example 215 from S^snifemoyianamo-^O-(nYeihylthio)propoxy)t>eazcrtiilTile (Example 247a) in *>9% yield. lH NMR {400 MHz, BM$Ou4$)" d 2.05 ts. 3H>. 2.0s tm. 2Hi. (U J = 7.2 Hz., 2H): 4 2! fu j = 6.4 Hz., 2H), 6.59-6.0! (d. j = 8.0 Hz. 1H>. 6T.Vo.75 {d, j = 8> HzJHp 7.44 (t, J = 8.0 Hz, IH), 7.79 R \H), 8.33 is., IK),

SO 03 is,, 1H> MS )U2(MH V

Example- 24"a: 2-viPEara^\7sardBO~6”{3-{ineilwitl^io)propo.%0beozvpfiltri!e Prepared as in. Example 215a from 2-aminO'fK3'(metby1ihio)propoxy)benzom'tri'b (Example 247b) and snlfamoy! chloride in 69*;ί» yield. MS 302 (MH } 1 sample 247b: 2-amino-6-(3-{methyUhio)proiX»xy}ben20mtrile

Prepared as In Example 215b (Method A) from 2“(3:-(methylthie)propoxy)~6“ mrrobenzonunle (Example 247c) in 90'?·, yield. MS 223 (ΜΙΓ).

Example 247c:v2-(3-im.gth.y:ltfejo)r>ror>oxy)~6-nitrob©nzooitrik

Prepared, as in Example 115c from and 2,6- dinitrobeuzonitrileOn 89% yield. MS 353 (MH!).

Example 348; 5-(3dmelhyfe^ifinyi)|m0|K>xy)~IB~benxoicI[li241thfedlsxi«~4~amisie~2.2" dioxide

Prepared: as in Example 245 from 5-{3-{Tncihyltino)prepoxy)-l H-be:nZo[c]|,!i2,6|rl:nadia;Hn-4~arulia>2,2-'dioxide (Example 24") by the reaction with 1.0 equivalent of MCPBA as a white solid in *0% yield. SH NMR (400 MHz, DMSQ-A) 4 2,18-2.22 (ms 2H), 2.54 R 3H r 2.75-2.78 (rn, S. 14), 2.89-2.93 (m. IH), 4.26 ({, 1 - 6.4Hz, 2H), 6.60-6,6! (d, J - 8.4 Hz, IHh 6,73-6.75 01, J - 8.0 ΡΙζ,ΙΗ), 7.44 (%. J - 8.0 Hz, I PI), 7.83 R1 PI), 8.30 R 18), 10.92 R !H;i7MS 318(MP!d).

Example 249; 5~(3-(fne(byhulfba;vi)pro|>oxy}"112“lies«i>|cJ|L2«6|tfeiaciiazm“4»stmis5e'-2^2·' dioxide

Prepared as hi Example 245 from 54 3-(mcthy ith io jpropoxy)· i H-benzoic]} 1 ,2.6]thiabiazm--4--amine--2s2-diox(Ue (Example 247} by the reaction with 3.0 equivalent of MCPBA m 8“% y-dd as a o-hde solid. Ί1 NMR (400 MHz, DMSO-dd n 2.24-2.27 urn 2H). 3.00 (s, 3B), 3.26 (t, J - 7.6 1¾2H),4,24 (t, j -6.4 Hz, 2% 6.60-6.62 (<£ 4 - 8.01¾ llli. E?2-‘>.74 i-X J «.0 Hz,lH),:7.45 (t I - 8.0 Hz, 1H), 7J9 Is, IB), 8.31 (s, IB), 10.93(s, IE), MS 334¾ MB }.

Example 250; 5-42-¾ 2-eOioxyc^lsiwylethoxyplil-heoso j e} j 1,2&amp;\t h lad sa ή «-4~a m l ne-2,2-diexide

'Prepared, as in Example 215 from 2~suliiniKyvlaim!K>64342-ei'hc^xyctlioxy)ethoxy)ben,zonitr.ile. (Example 250a) in 52% yield.51:1 NMR (400 ME'z, OMSO-ffe). 0 1.05 Co j - 7.2 Bz, 3B),: 3,37-3.43 (ny 21:1), 3 47 (t, 2H), 3.58 (y 2H), 3.81 (y 2H), 4.26 (t, 2B), 6.60-6.62 (d, J === 8.0 Hz, 1H), 673-6.75 id, J === 8.0 Hz, IB), 7.45 (0 I === 8.4 Hz, 1H), 7.99 (s, IB), 832(y IB), 10.9? ly HI). MS 330 (MB 3-

Example 250a: 2-sul!d:moyl.an=imia-6-C2-(2-el:hoxyethoxy)s6iO:Xy }bef}zonltiils Prepared as in Example 2,15a from 2-amino-6-(2-{2-edioxyelh0xy)eihoxy}benzo«rinie (Example 250b) and saffamoyl. cliloride in 69% yield. MS 330 (MHO-

Example 250b: 2-amisiO“6-C2-(2-etnoxveihoxy)et.hoxv )benzonitrlle

Prepared as in Examv?le 215b (Miethod .4) ffO5ft'2”(2~(2~et|joxyoti)oxy jeihoxy]H0” rbtrobetizanitrik (Example 2S0c| in 9833 yield. MS 251 (MB').

Example 25Pc: 2-(24 2-elhoxycfhoxvlethoxy)-6-nOrobenzonuri Ic

Prepared as» in Example 215c from 2-<2-eihoxy ethoxy }elhanoi and 2,6-dmilmbenzorntnie in 66% yield. MS 2nI {MH ).

Example 251; S-(3-methyk>x^peidylox>)- 1M-t>en/.ojcj11,2,^1 AiailiaMsi“4-asMae^2J-dioxide

Prepared as in Example 215 from 2-x«lfaraoylcurjinOr6~{3-Metfeyteyeippeji^doxy)be»2omM!.e (Example 25.1a) in.45% yield. Ή NM3R (400 MHz. DM5D-0.,),)0.97-1.04 Or·. 3H), 1.28-1 3? 1m. 2H), 1.75-2.03 (m,4H), 2.31-2.38 (m. 1H), 4.95-5.02 (m. IH), 6.56-6.58 (d. 1 - 7.6 HzJ H). 6.67-6.69 (d. i - H.4 Hz. I H).7.42 it, S - 8.4 Hz, IH), ~.69~ 7.72 (ra,IH). X.30-8.36 {m, IH). 10.92%. IH). MS296(MH ).

Example 25 la: 2-sulfam<>y 1 aniinn-6-(3 methyIcyclopen?>tey)te&amp;onitrik Prepared as in Example 2.15a from 2-ammO"6-(3-rnclhylcyclopcnty{oxy)benzouitnle. (Example 251b) and .sulfaraoyl chloride in 52% yield. MS 296 (MH ).

BxanmkMlh;. 2-amino-6-(3-methykydopenty1oxv)bciVzonimk.

Prepared as in Example 215b (Method A) from 2-|3.-nkthylcyel6peiviyU>xy)-6-mtroheazemtnle (Example 251 c) in 98% yield. MS 217 (MH ).

Example 251 e: 2-(3-meiiwlevdepentylexy)-6~ailrobenzoalb'lle

Prepared as. in Example 215e from 3-meilwleyclepeaianol and 2,6-dinlnoncnxoniinle in 7(1% ykj&amp; MS 247 (ΜΡΓ).

Example 252: dirae thy ipeopy i) - 3'-(4" - m e t h oxy be « xy I) u rea

Prepared as in Example '15 from I ··( 3··<3·*υ1fume vlamino O -cyanopheni >xv ί-2,2» dimethylpropy1)-3-(4--methoxybenzy!jurca (Example 252a) in 77V b yickl as a white solid. Ή NMR (400 MHz. DMSO-md 0 0.92 {s. 6«}, 3.06 (d. i - 6.4 Hz, 2Hh 3.3: (s, 2H). 3.6? (s 3H), 4.06 (d, J - 6.0 Hz. 2H), 6.29 (> j - 6.0 Hz, 2Hl, 6.6! (u. j - 6.0 Hz. IH). 6.71 (U. j - 8.0 Hz. IH}, 6.74 (d, J - 8.8 Hz. 2H). 7.06 id. j -= 8.8 Hz. 2H). 7.44 it, j - 6.0 Hz. IH), 8. id (x, I Hi, 8.34 is, IH), 10,90 is, IH). MS 462 (MB’).

Example 252a.; !-(3-y23''Sulfamo>3a«dnO"2-myanophcaK>x>0-'2,2HtdM4hylpropyi)*'3--(4~ meihoxybenzyl}ureiA

Prepared as in Example 315a from 1-(3-(3-ami no-.?.~cyaoophcooxy )-2.2-dimethylpropyl)-3-(4·methexybeozy l }urea {Example 252b) aridsalfamoyl chloride In 100% yield, MS 46.: (ΜΗ Ί.

Example 2526; l-:0>P'^fe9-2^yms.9pb$ooxy)~2s2'’dtm$thylpropyl)»3^:4» methox y benzyl )erea

Prepared as in Example 215b {Method B) from ί -(3-hydiOxy-2.2. diniefhylpropyi}-3“(4-niethoxybenzyi)yrea (Example 252c) and 2-ammo~6”fit?orobenzonitnIe in 60% yield. MS 383 (MH }.

Example 252c: 1 -{3-hydroxy-2,2-draeihyipropyl)~3r(4~pietbo'xybenzyI)nrca. Prepared as in -Example 22?d Eon) 8-am.iBO~2:!2-dim.ei:hyi:propan-:l -o! and 4~methoxyhenzyl isocyanate in 1:00¾ yield. MS 267 (MU ).

Example 253: 5”(pr9p^l~y«y!)”iBMjenzojclii,24>|ti.daelmzin”4"anipe”2,2~illoxlde

Prepared as in Example 2)5 from 2-sulfanicy lammo-6«(3*{lrimctbyIsily bprop-1 ~ yny i}benxonhrdc S Example 255a) m 10% yield. *H NMR {400 MHz. DMSO-f/O /> 1.25 (s,.2H)* 2.16 (x, 311!. 0.09-7.01 id. 3 - 8.4 Hz, 1H), 7.21 -7,23 (d, I - 7,8; Hz, IH), 7.45 (t. .1 - 7.8 Hz, 1H). MS 230 (MH }.

Example 253a; 2-suifamoyjamjno--6--(3--{trjmethylsily 1)pr op- i >nyl}bcnzonitrile A solution of 2-omsn·.s--6-(3-{trimctbyKiiv 1 }prop··1-yny 1 jbenzonitrlle {Example 258b) (55? ing. 2,0 0-01-..9} and NH-SOvNPl· (0.96 g, 10 mmol) in dry 1,4-d:oxane (50 ml,} was refluxed under nitrogen for 2 days. The solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with 70% EtOAc in hexanes to give the title compound {31 mg. 5%) as a white solid. MS 308 tMH").

Example 2530: 2-amino-6--(3"(tr i methy Isi ly 1 )prop · I -ynynbenzonitrile To a stirred solution 6ffrimofhyi(p.mp*2-ynyl)sikno (1,12 g, 10 muiol), S-aMino-h-feromotkaigonitrite (Klanbert. D. Hz Scllsaxh, J. Hz. Gninosso. C. J.; Capotola. E. Jz. Beil, S. C ./. Mai. Chan. 1981, .7-/., 742} {1.0 g.. 5 mmol). Cut (0.01 eqoiv.) in tricihylamme (50 ml.,} was added 00(103-.,}. (0.1 equiv .) at room, temperature under nitrogen. The .reaction mixture was then refluxed under nitrogen overnight, lire solvent was evaporated, and: tire residue was titrated with BtOAe/wafer, The organic; layer was separated, were washed with ferine, and dried over NkpSCfe. After evaporation of the solvent, the residue was purified fey ehroniatography on silica get eluting.-with 15% EtOAs in hexanes to give, the title, compound (1.43 g, 63%) as a as a liquid, MS 229 {MH}.

Example 254:5-((2 -.oiethyleyclopropyl)0toth0xyTifeM^n^»lc||1,2,fe|thla#azin-4-amiae-2,2-dioxide

Prepared as in Example ,11,1 fkmv 2-arnino-6--((2.-meihy)eyvh<prnpyl}met!'Kmy)benzonimle sulfauude (example 254a) in, 68 % yield, (mixture of diaste,reoisomers),!H NMR (400MHz, DMSO-d-d O 0.1,7-0.40 (rn, IH), 0,54-0.58 (rn, 1.H), 0,76-0.85 (ivu 1H), 0.99 -1.12 (m. 4)1),3.96-4.33 (m. 2H), 6.58-6.61 (m, !H). 0.67-6.77 (m, 1H), 7.417.4? urn I Hi. 7.97 (.v NH). 8.38 K NH), :0.97 (s. Nils. MS 282 (MH:).

Example 254a: 2-ann;w--6--u2~rnethykyelopr>>py] Snwiboxylheazonitfile sulfamide-Prepared as ip example 40a from 2-amino-6-| (2-methyleyclopropyl>roet hoxyIbenzonitriic iExample 254b) in 100% yield. Ή NMR (400 MHz, DMSO-u,:) 50.34-0.36 (m. I Ht. 0.51-0.53 (m. IH). 0.77--0.79 (m. 1H). 0.95-0.97 (m, IH). 1.04· 1.09 (m. 3H), 3.92-4.03 (m. 2H). 0.86--6.88 ibm. IN). ?.! I -M-S (bm, 3Hi. 7.48-7.52 (bm, 1 Hi. 9.58 (bs, NH). MS 2b2 (MH ).

Example 254lv. 2"^minO“6~((2-mcthylcyclopfO|Vvl)mcthoxy)benzonltdk A solution 0f24i(2”m€dhyk-yclopropyl).mp&amp;oxy}“i6-»»itiX3ibe»2!onk'Ik'{cK.aiiipic 254c) (0.29 g. 1.25 mmol) in EtOAe/EtOB 1:1 (30 ftiL) was hydrogenated in an hbcu.be: apparatus using 10%MC as catalyst. The solution was evaporated to give 2--anuno-6-((2.·-:methyk-yci'Qpropyi)methox.y)ix;nzonitnIe (0..20 g. '79 %) as a yellow oil. MS 203 (MH’).

Example 254c: 2-((2- methyleyclopropyi)metboxy)-6-nitrobenzonitrsle

Empared as in Example l6od from (3-meihyicydopropyi)m.e(banol and2*6-* dinhrctbenzonhrile in 81 54 yield. MS 233 (MET).

Example 255: H54^fe«tyl--Ili-beH^(c]|i-^6)tWddia^»e*^^^isSMIiie“2^-dioxide:

Prepared as in-Example· 1.11. from 2~a.oi5BO~(m(isolA0y1amino)feenzcfnitrii.e sulfamide (Example 2S5a) in 23 '!> yield.)H NMR (400 MHz. DMSO-de) d 0.9$ (d,) » 6.8 Hz, 6HK 1.88-1.95 (m, 1H), 2.84 (t, 3 « 6.8 Hz,. 2H), 5.87 (t, J - 6.4 H;\ Mi), 6.31 (dd. J - 0.8 Hz. J === 8.0 Hz, IH), 6.40 (d, J === 8.0 Hz, IH), 7.26 (t, i === 8.4 Hz, l id), “ 8S is, Nik), 10.70 (s, NH) MS 269 (MH ).

Example 2S3a: S-ammo-S-iisobuiviamlnoibeuzonltriis sulfamide

Prepared as in Example 90a from. 2-amino~6-(isoht'U:yIamino)benson5m!e (Example 255b) and used in the next step with.oat'any-forther.pBtif5ie-8tmn., .MS 269 (Midi).

Example 2Toy 2-araiao-6-(isobutybmmo)bbnzomtrile·'

Prepared as in Example 90b from 2-iisobuJylaraino)-('>-nitrobenzonitriIc (Example 255 ia 66% yield. MS 190 (MH ).

Example 255c: 2-1 isoburylammo)-6~mtr6bed2on4rile

Prepared as .fa Example 90c from 2,6-dmrtrobenz0nit:rile ami metbylamine fa 92%. yield. MS 220 (MH ).

Example 2S6: 5-({1 -meifeyicycl»f>r0pyl)i»eife<m V-? f I-bessxo jej 11.2,6|iWadi.a5d»!4~^i!»e~2,2- dioxide

Prepared as fa Example 111 from 2~amfad-6-((.l-· mcthyleyclopropyl)mcthoxy )benzo«itriJc suifemidc(Example 250a), in 30 % yield JH \MR 1400 MHz, DMSO-d*} d 0.44-0 40 (m, 2H). 0.59-0.02 in·.. 2H), 1.2 is. 3H), 3.96 ;s. 211), (-.59 (d, ,% 8.4 Hz. I H), 0.66 Id, J ~ 8.0 Hz, 1H), 7.-43 0, J 8.0 Hz, lily 7.133 (bs. NH), EP40 lbs, NHs, 0.45 Uxe NH}. MS 2x2 (MH ).

Examp 2-ai»ino~6--((l”meihyleyeiopropyitocthoxy)hesizonifrilc salfamide

Prepared as in example 90a frQm 2-amiBO-Cs-((l -nieihyieyelopropyi)methoxy)beH2C>nitrile (Example 256b) in 100% yield.. ‘H NME. (400 MHz, DMS0~4) 6 0.40-0.43 (m, 2H), 0.53-0.56 (m, 2H). 1.20 Is, 31-1), 3.09 (s, 2H), 6.85 id, J - 8.0 Hz, Hi), 7.11-:.23 lbs, NH.fr 7,1 2 (d, j = 8,0 Hz, i H), 7.51 (0 ) ~8.4 Hz, ΓΗ}, 9.45 (bs, NH), MS 282 1 MH ).

Example 2S6b; 2-am.mo~6~f 1 I -metbvlcYelopmpylimedmxyibenzonitrlle

Prepared as in Example 254b from 2-((1 -iftethyieyfel.opfapyl)methox^)-6- n.iiroben:zoob.ri!e (Example 256e) in 88% yield as a yellow oil, MS 203 {MH')..

Example 256c: 2-((l~meibykp,elop:ropy:l)mei.bp.xy)-6-niiroberr;iomiril.e

Prepared as m Example 1 OOd from. (I -meihyleyeIopropyi)m.elbanol and 2,6-dimirobenzomfrile in 05% yield. Ή NMR (400 MHz, DMSO-rl·.) δ 1).44-0.46 (m, 2H), 0.57-0.59 (m, 2H), 1,22(a, 31¾ 4.06 (s, 2H), 7.67 Old, .1 1.6 Hz, I - 8.0 Hz. 11¾ 7.85-7.92 (m5 2B).

Example 257; .1 -aimao-l t:I4h£mzojejj (1 j2,6jihiadiaa:ifi-5-ylox> )efchv|)py p*oft#a*2-o»e·· 2,2-dioxide

Prepared as m Example 111 Ikon 2-aroino-6·{2·* 2·oxopvrrol idin-1 ·· \l)ebmx>lbenz--mirde .--ud,mode iEx,nimic 25"a5 in 45 Ήmold. Ή NMR t'400 MHz, DMSO-d<4 ο I Λ>4 u], j ".2 H e 2R). 2.2*. a. J 7.* Ha, 2H i 5.43 R, j ".3 Hz, 2H), 3.<M a. j -= 4.4 Hz. 2H >, 4.25 u, J 4.4 Hz, 2’Hi. i.,59 id. I 7/> Hz. IHi. E70 (d. J x a Hm IB), 7,43 (U === 3.4 Hz, UR. 7,82 ib-.:, NH), 8.2; (b;-. Mb. 10.9* ibe KH). MS 525 (MH ).

Example 257a; 2-:nmno-6-i24 2-oxopyrndidm· 1 > 1 }emoxxIbcoZ'-nitrite solfamide Prepared a.·» in examine R0« from 3-ao5UJ·‘-M2 -».2-oxopv iroUdim-1-yneihox’v}bcnz--r:4nic {Example 257b) in 100'S, yield. \H NMR (400 MHz. DMSS5-d,.4 5 1.94 (q, ,1 - 3.4 Hz. 2H), 2.22 (1. j * x,4 He 2H>. 540-5.58 rm. 4H). 4.2i 0. .1 - -l.S Hz, 214), 0,94 (bs, 1H), 7,37:(ά, I = 7.6 Hz, 1H)? 7.24 (bs.NBR, 7.54 (t. I - 7.2 Hz, 1H), 9.4.9 (bs,‘NB}, MS 325 iMH }.

Example 357b: 2-aftii»oB>(2K'2-0xppyrrg!idlo· I ·> 1 >ethpxy)benzpnhriie Prepared as in example 254b Item 2=mbro--b4 2-{2-ox0pyfroHdi«-l -yI)edmxy)benzomtrite (Example 257ci using trilIue.roetlianol/hexaflueroisoprc>pani>l 0:1) as solvent in j 00% vk-id MS 24b (MH ).

Example 257e: 2-iiiirO'-6~(2~(2~oxo|>yrrohdin-4 -yEeftoxydbenzonitrile .Prepared an m Example i 66d Emu i -(2-hydm^yo^OpyrroHdm-^K)®© and 2,6-dinitrofenzoniiril'e in 74 % yield. MS 2?o (MH ).

Example 2S8: BS~(3~metliox.ypsmpyl)”IB"Eenz«|e)|!,2,b|fidadlazme"43~dlsailne~2,2"piexide

Prepared as io Example 90 from2“amiRO“^{3«me^oxypropyiamin>o)bc»20'ftitriy sulUmndc «Example :58:,) In 69 % yield. Id NMR (400 MHz. DMSO-rEs o i .79 - i.85 (m, 2H), 3.06 J == 0 8 Hz.....I === 6.8 Hz, 2HV. 3..1: K 311). 3.4.:. if...../ === 6,0 Hz, 2H }, 5.94 (t, ,/ ==== 5.0 Hz, NH|, 6.26 (d. ./ === XA Hz, \ H) 6 34 id. J === 8.0 Hz, \ H). 7.33 (t. ./=== S.O Hz, 1 1:1).7.88 is. NH.j, 10.64 (s. NH). MS 285 (MH )

Example 2$8a; J-ammo-d-CS-methoxyprepylammolbcnzonimic suHamlue

Prepared as in Example 90a from :-;'mbnO"6~(3-meihoxypropyiamioo)bcnzomiriie in 65% yield :H NMR 1400 MHz, DMSCM/J d 1 .74-] .74 (m, .?>]}. '3.19 i'q../ === 6.8 Hz, J === 7,2

Hz, :H). 3.22 (x, 3H). 3.39 it...../ === 6.2 Hz, 2H ), 5.96 it.J === 5.6 Hz, NH), 6.47 (,),./ === 8.8 Hz, IH), 6.70 (d,./ === 8 0 Hz, 1 Hi, 7.09 (s, NH;), 7.31 (f../ -== ,x.O Hz. 1H), 9 09 (χ, NH). MS 285 (MH').

Example 258b: 2-amipQ--6-(3-me0)oxypropy:l:amipo)be:si:zopifri:le

To a solid! on of 2^3.-.methoxvpropjteind)-6-oii^-beiri^iB'iir&amp;- (Example 258e) (0.58 g. 2.48 mmi.-ii in lliOH {20 rnL) was added cyclol-exene (1,26 mi... I 2.4 mmol). Then 10% Pu/C (1.32 g) was added, and. die reaction mixture was refluxed at. 10073 for 20 minutes, cooled to room temperature, filtered/trough Cellte which was washed with EtOH (3x.20 ml...), and ovaperatedto gl=tm 2~aniioo%43'iuetboxypropylaittioo)feenzaiiitri]e (0.43 g, 84 %) as a colorless oil. ’ll NMR (400 MHz, DM SO-*) 6 1 Jill J7 (m, 211),3.10 (q, 2- 6.8 Hz, J === 6.8 Hz, 211), 3.22 is, 3H), 3.37 (t, ,,/==== 3.2 Hz, 2H ), 5.55 It,,/ === 5.2 Hz, NH), 5.63 is, HIM), S.79 (2,.,/ == 7.6 Hz, 1H), $.93 (d,./ === 8,0 Hz. IH). 6.98 (i,,/ === 8.0 Hz, 1 H). MS 206 (.Mil'

Example 258c: 2-(3~met.hoxypropykmi.n.o)-6-nitrobe:nEO«jMie

Prepared as in Example 90c from 2.6-diuiftobcnzonitrile and 3” loetharxypropylamine :in 83 % yield. !HNMR (400 MHz, DMSO-i/.·;) <1 1.76-1.81 (m, 2R), 3.23 (s. 3H), 3,28-3.33 (m, 2B)? 3.40 (E./ 5.6 Hz.JH), 6,66 (I, J === 4.8 Hz. NH), 7.30 (d, ./ === 8.8 Hz. 11-1),. 7,42 (d,,/==== 8.0 Hz, IH). 7.60 (6./=== 8:0 Hz, 1H),

Example 259; N5-etIivMlI-besszo(cj (1,24>|iMadlaMi3e-4,5“dis«ilii«'-2,2~dioxsde

Prepared aw in Example 11 1 from 2-amuK>~e-teibylannno)benzoniinle Mdfamide (Example 25½} in 57N yield. :H NMR (<W0 MHz, DMSCW.0 b i.NMt. J - e.S Hz. >H 2 99 3.06 < m.. 2H). 5.87 (?. J ::: 5.2 Hz. NH K 6.30 (d, j ::: “.6 Hz, IH}. 6.58 {J. j::: 7.6 Hz, 1 HI “26 (t, J - 8.0 Hz, i H). 7.90 i% NH:}, Ol(>8 {,s. NH) MS 2-1 i (MB' ). l;;S3310k.250‘9 2-ands50-o~(eibyia;mno)benzoniinSe ruitarm do

Prepared as in Example 0(}a from 2-avnmo~6-iethY]amino}bc5rzonbnfc «Example. 250b) in 47%yield. :H NMR <400 MHz, DMSO-d..} b I 14 «I, J == f 2 Hz, 3Hi, 3.15-3.22 <m„ 2H), 5.84 (hs, NH), 6,48 (d, j == 8.6 Hz, 1 Mb 6.72 {d, j - 8.0 Hz, 1H). 7.02 {bs, NIB;, 7.31 (t, I -8.0 Hz, 114),9,14 (bs, NH). MS 241 iMHO.

Example 250b: 2-aiTvkit>6-(ediylsmi»p)be»ao«itrIk

Prepared: as in Example 2546 from 2-(etby]arnino)~6~nitmbe;Koniiri1e (Example 259c) nsing T34finordeibaeoI/Hsxafiaorois0pr0paeo:l (2:1) as solvent, in 81 % yield, *H .NMR. ¢,-400 MHz. DMSO-H,) 6 1.14(6 .1- 7.2 Hz. 3H), 2.15-3.22 «m. 2H). 5.4! (bt. J === 5.2 Βχ,ΝΒ), 5.64 (s, NH.). 5.82 (d, I === 8.0 Hz. I H). 5.96 id. j === 8.0 Hz. J H), 7.00 (b .1 === 8.4 Hz, !H). MS 162 (MH ).

Example 259c: 2 - {e r i; y i a n; ino )-6-.nitrobedxorn bile

Prepared as in Example 90e from S/i-dlssitfefeenzoniti'iie and a 2M etbylamlae seksfspn in THF id 18 ;N yield. }H NMR. (400 MHz, DMSO-4) 11J3 (t,J ==== 7.6 Hz, 3H), 3.26 3.33 (m, 2H), 6.59:(bt,) === 5.2 Hz, NH), 7,22 (d, J ==== 9.2 Hz, IB), 7.42 (d, J ====1.0 Hz, 1H), 7.60 (1,1===38,4 :1½. IB), MS 162 (M-Et).

Example 260fN5-(2-(benz> lo\;v)eibyl)-| ll-bes^ojcj M »7 dioxide

Prepared as in example 90 from 2~ami 00-6-(2-(ben/y !o\yjcihyiammoibenzoniiriic suifamide (Example 260a) in 68 % yield, ’ll NMR (400MHz, DMSO-i/:;} 43.25 (ip 1 - 5.2 Hz, 1 - 6.4 Hz, 2114, 3.64 (41 - 5.6 1¾ 211), 4,49 (a, 2H), 5.91 (% J - 5,2 Hz. NH), 6.28 (d, 3 - 8.4 Hz, HI}- 6.40 (J, j =- 8.4 Hz, 1H), 2.23 (t,1 ==== 8,0 Hz, iH), 7.25-7 Λ5 On. 5Hn 7.90 Is, Nil·}, 10.6k ΝΙΠ. MS 34? (Mil").

Example 260a; 2-anmio-6'(2'(lxmzy I oxyJclhvlamjno)benzonilrile salfemide Prepar'd as in Example 90a from 2-amino6-(2-Ibcnxy lo\y )cih>lam mo)bcnzcumriic (Example 260b* ΐη45'Μ. Ή NMR (400MHz, CDC10 b 3-56 iq. J =- 5.: Hz. j = 5.6 Hz, 2H), 3.57 p.. j === 5.6 Hz, 2H), 4.49 (s, 2H), 5.76 it j == 5.6 Hz. NH>. 6.55 Id, J 8.4 Hz, IH), 6.72 61, j === 8.0 Hz, IH). 7.12 (s. NH>). 7.25-7.32 (m, 6H). 9.12 Is, NH), MS 347 ( MH ).

Example 260b. 2-amino^42-<benz>IoxyK'thyUtmi«o)benzvsnitnIc

Prepared as in Example 9*36 6om 2-(2-( benzybxyiethy lamino)-6· ni:6z>:beBZ6ni:6ikv(ExarBple 260c) in lOO'M yield as a brown oil. !H NMR (400MHz, CDC’H) 3 3.27 (% 1==== 5.2 Hz, 1==== 6.0 Hz, 2H). 3.56 (t, I === 5.6 Hz, 20),4.49 (s, 2H)? 5,34 ((,1==== 5.6 Hz, NH), 5,67 (s, Nfl·}, 5.84 (d, ,1 ==== 8.0 Hz, 1H), 5.95 (d, 1=== 8.4 Hz, IH), 6,98 (t, 1==== 8.2 Hz, IH), 7.30-7.34 (m, 5H). Ms 268 (MH ).

Example 240c: 2--(2-(henzyloxy)eihyj3mirieo--6-nirrobvnz0nitriie

Prepared as,in Example 90c from 2-(benz5doxy)etbanap4ne and 2.6-dmaiobeozonitnle in 778¾ yield. *H NMR (400MHz, DMSO-ofi) 6 3.49 (q, )=-5.2 Hz, j - 5.6 Hz, 2H), 3.59 (t, i === 5.6 Hz, 2H), 4,49 (s,2H), 6,47 (0 J === 5.8 Hz, NH), 7.23-7.31 (m, 6H), 7,43 (d. j - 8.0 Hz, IH), 758.(t, J - 8,4 Hz, IH).

Example 261: 2-(4- amino-lII-OenzpIclilii^iltliiadiazln-S-ylamlnpIcilmnoi-lJ-dioMde

Λ sole ύοπ of Μ'42-tbenzy loxy )-eth>danmm)M.Brben2o{c3i 1,2,(\|{hiadiaziae~4,5·' diaminc»2,2-dioxidc {Example 260) (0.10 g, 0,21) mmofi in EiOH Hi) mt) was chargedwith 20 mg of 10% Pu/C and H.-.· balloon and stirred at room fcmperuiu· e for 24 hours The reaction mixture was filtered trough Celtic which w as w ashed with EiOH, the combined organic phases were evaporated, and the residue was purified by flash chromatography using a DCM/MeOH (9:1:) solution as eluant to give 2-{4.-ammo·· I H-betuojcjj l,2,6 jthiadhzin-5-y lumino)cthanol-'2,2-dioxide (64.x mg, 8? %). JHNMR (400MHz, DMSOwti ,> 3.11 (q, i === 5.6 Hz, j 5.6 Hz, 2H)5 3.58-2,59 (m.. 2H), 4.84 (bs, IH), 5.X4 (t, j === 5.2 Hz, NH}, <3.26 (d, J === 8.0 Hz. 1H). 6.27 id, j == 8.4 Hz. IH), '222 (t, j === 8.0 Hz, \HI. ?.x6 (s, NH.·-}. {0.65 (bs, NH). MS 257 (MH }.

Example 262; 3-((4~^«ittiO“IH”benixo{c| 11,2,61 thiadiMa^yiaXj^iBethylHN'" prnpylpiperidine-l-earboxasmde-iJ-dinxtde

Prepared as in Example 111 from 34d3-ammo*.2TcyanbphePdxy)methy.l)~Nr prbpylpipemiitie^l-carbo^linide suUauude (Example 262a) in 88.% yield. Ή NMR (400 MHz, OMSO-dg) § 0,81 (t I === 6,8 Hz, 3Hο 1.23-1,43: («ν4% 1,60-1.63 (bin, Iff), 1 ..81-1.84 (bm. 111 ·., 1.99-2.05 (but III), 2.67-2,75 (m, IH), 2.80-2.85 (ηι, 03),2.93-2.98 (m, 2H)3.7i (bd, I === 12.8, I H), 2.90 |bd, J ==· 10.8, 1H), 3.98-4.08 (m, 2B}? 6.44 (4 J ==== 6.0 Hz, NH), 6.62 (d, 3 ==== 8.0 Hz, 1H), 6.76 id, J == 8.4 Hz, IH.h 7.46 (t J === 8.4 Hz, M% 7JO Is, NH), 8.37 (&amp;. NH), 10.95 (s, NO). M3 296 (MH ).

Example 262a: 3-((3-aromQ-2-eyanoplie.nox.y):metliyi)-N-propyIpipertdlne-1 carboxamide subamide

Prepared as in Example 90a from 3-{{3-arnino-2-evarKjphcrioxy)methyl)-N-· propylpipcndinc* 1 -carboxamide (Example 262b) in 100% yield. Ή NMR (4()0 MHz, DMSO-d,·;) δ 0.81 (t, J ==== 7.2 Hz, 311), 1.31-1.44 ft 41-1), 1.61-1.64 Cbm, Iff), .1.85-1.87 (bm, 2B), 2.60-2.75 έ m, 2H), 2.04-2.98 i m, 2H ).5./8(bd, j - ! 2.8 H,% 1H), 3.9.)-3.97 i m, 1 H), 4.01-4.10( rn, 2 H). 6.38 (d. j - 6.0 Hz, NH). 6.96 (d. i - 8.8 Hz, IH). 7.16 (d. j - 8.4 Hz, I Hf 7.27 (s, NH), 7.41 (s, NH). ~.57 is. J -= 8.4 Hz, I H.), 9.48 (s. NH). MS 39o (MH ).

Example 2626: 3"H3-mnmo-2-cyanophe:mxY)medtyi)"N-piOp>Ipiperidine-i -carboxamide· Prepared as in Example 254b from 3-((2 cymmM-ndroplmnoxylmeihyO-N-· propylplocndsnc-! -carboxamide (Example 262c) in 94 % yield. Mb 317 MH ).

Example 262e: 3-((2-eyano-3-ni0ophenoxy(methyll-N-propylparxridine-l -eai'boxaniide To a solution of2-nilro-6-(plperidi«-3-y1methoxy)lxinzonitnkv hydrochloride (Example 2620) (0.10 g, ().34 mmol) in THE {6 mb) were added tricfhyiaroine (0.10 mL, 0.76 mmol) :md propyl isocyanate (0.05 ml.., 0.52 mmol) and the reaction mixture was stirred at r.t. under nitrogen for 3 hour (hen filtered and evaporated, to mve 8-lt3~e\uoo-3-nitrophenoxy)n)etliyl)-N-propylpiperidin€>l -carboxamide (0.13 g, 100 %}. :‘H NMR (400 MHz, DMSQ-4) 6 0.81 (t, J = 7,2 Hz, 3H), 134-1.41 (rm 4H),! .62-1.64 Cbm, Hi), 137-1.95 (bm, 20),2.64-2,7? (m, 2H), 2.93-2.98 (m, 2H). 3.77 (bd, 3 - 12,8 Hz, 3 0),3.98 (bd, J - 1:2.8 Hz, 1.H). 4,09-4.: 3 (m, 1H), 4.17-4.50 (m. 1H), 6.38 id,) - 5.6 Hz, NH), 7.74 (bdd, 1 - 1,6 Hz, I -8 0 Hz. Hi), 7.88-7.94 (m; 2H). MS 547 (MH i.

Example 262d~ 2-nitro^(pt^ertdin-3-yInfethoxy)b«a)^hitnte hydrochloride prepared as in example 366 from: tert-bdfyl 3-((2-cya.no-3-mtophenoxy (methyl}p!pt;ridine-l-carboxylate (Example 262e) m 98 % yield, MS 262 (ΜΙΓ), Example 262c: tert-buty! 3-{{2-cyano~3-sutropbenQxy)mothyl (piperidine- t-cafboxydaio Prepared as in Example 215c from tert-bntyl 3-(hydroxymerirx4)piperi:dine-l-earboxylatc and 2.6-dinitrebenzonitriie in 58 % yield. MS 263 IMHOBoel .

Example 263: Ter (-butyl 3~f(4-amino-1 H-benzojej (.1,2,6|?.6iadiazln-5- yl»sy)melhyl)pipesidioe”!-carbax.yl6io~2,2-dioxye

Prepared as in Example 111 from tert-butyl OHio-smlne-S-c>anophenoxy}mdh> 1 )p iperidimr- I -carbo.xylate sulfamide (Exumple 263a). keeping the pH above 3 upon acidification, to give tert-butyl 3-((4-amino· I H-beuzoiejM ,2,0jihiudia2in-5· yloxy)metiiyl)p^fi€line*l“e-ai%osiylaie^2,2-<i0?i:ide (33 mg, 23-%). 5H NMK (400 MHz, DMSO-d,;> ό 1.27-1.40 (bo, 11 Hi. I .62-1.66 <bm, IBk ) .78-! .33 (bm, \ H >. 2.05-2.! 2 (bm, i H), 2.872.94 im. 2R), 3 64-3.71 (ban ! H}„ 3.85-5.86 (hn\ IB), 4,04 sbd. j - 7.2 Hz, 5H). 6.62 (d. J= 8:0 Hz. ! H). 0.77 (d.. j - 8.-: Hz. ) 11}. 7.46 (r. I - 8.4 Hz. ! H), 7 m (0s, Nil). 8.37 (by NH). 10 95 (s, NH). MS 3!! [M+H-Boe]'.

Example 263a: tert-butyl 3-{{3-amin0-2-cy^io.pheaoxy)j«etbyl}pipefid?»ed-68rboiK:ykfe suifemide

Prepared as in Example: 90a. from te.rt.4mty! 3-0 8-ammo-2-cyanophenoxy)eipthyi)pi|K;rf<ii«e-'i-parbpxy.late::.(^xapiple 203b.k Upon extraction, NaOH !M (! .50 ml... ! .56 mmei) was added to the ice-eneled. reaction. medium triggering formation of a sticky orangy material. Water was poured away and tbe residue diluted in EtOAc. and extracted,, :.o give tert-butyl 340-amino-2-iyancpbenoxy)me?.byl}pipermsne-]-carboxviate suiia-nide (5).15 g, 84 5«}. :H NMR 1400 MBs, DMSO-dfo δ \.55-1 40 (bs, UH), L63-L66 (fen, 1¾ 1.79-1,83 (bm. ; Hi. : .88-1 93 (bms IH), 5.7X-2.85 (m. 2H), 3.74-3.78 Cbm, 1% 3.9:2-4,04 (m, 3Bf 6M id, J - 8.4 Hz, I Hf 7.15 (d, 4-8.4 Hz, ! H), 7 27 (s, NH;>}> 7.56 (l, 1 - 8.8 Hz, Π!),. 9,4? (s> Ml). MS 3U |M t-H-Boc] .

Example 263b· tort-butyl 3-((.>-arnino-2-oyauopiicnoxy)metliyl)piperidine-1 -carimKykue Prepared as in example 2S4b from tert-butyl. 3-((2-eyaao-3-rniro!>beifoxy)me1:b.y!}pIperid:lne-.!-earboxy:!ate (Example 262c) in i 00% yield as an oil. MS 232 [M+H-Bpe] 7

Example 264; 4~Amitto-54*f'efiS~2-mef hy im elope» t>lo.\v H//-benx«[c}j I *2,6}thiiKliazme- 2,2-dfo side

To a solution of 2sirmno»M//v/«v-2-rm:ihylcydopcntylox>·Jbenzoni tide (Example 264a) (150 mg, 0.694 vnmol) in dimeiliylacetaniide.(3 mL) under Nj wax added sulfonioyl chloride (3 eqtav.). The reaction mixture was stirred at room temperature under M2 for 2 hours, diluted with ethyl acetate {50 niL> and quenched with water (20 ffiL). The layers were separated. The organic extract was evaporated. Ethanol (3 ml..) and aqueous NaOH (2N, 2.5 eqim.j were consecutively added to the residue. The resulting mixture was heated at 00 v>€ for 16 hours. The workup was performed as in Example 11 i to provide the desired product {160 mg, 78%) as a white powder . :hl NMR (400 MHz, DMSKM*) d i .02 (d, J === 6.4 Hz. 3H), 1.26 irn, j Μ), 1.71 (hr s, 3H), 1.89 (m, ΙΒ),2,12(ηι, ill), 2.24 (m. IH), 4.55 {hr s, IH), 6.60 id, ./=== 8.0 He. 111),6.71 (d. ,/==== 8.0 Hz, H I). 7.45 (t.,/=== 8.0 He, IK), 7.73 (bts, IH), 8.35 (br s, Hi), 10.96 (brs; IE). MS 296 (.Mil ).

Example 264a: 2'Aminofofo/fmrw2wBethyleyd0pentyfoxy)benxonitTll.e:

Prepared as in Example 1 i ib from 2-(/maw2-methylcyclopentyi0xy)^6-nitrobenzonitrile (Example 2oib) to give thefide compound in quantitative yield as a colorless oil SH NMR (400 MHz, GDC!0 0 1.04 (d, 7==== 7.2 Hz, 3E), 1.23 (rn, Hi), 1,72 (m, IE), 1,81 Cm, 2 H),: 1,99;(m, 2H), 2.26 (m. 1H), 4.28 (m, !H)? 4.36 (br s, 2H), 6,18 (4,/ = 8.4 Hz, Hi), 6:1.8 (d, ,/== 8.4 Hz, 1H), 7. = 8 it. J = 8.4 Hz. 1H). MS 2% (Mli:)

Example 364b: 2-{/ra#?ci-2-Merhyleyelopentyloxy)"6"nittoben2onjttiic Prepared as in Example 11 1c; 7rom2,6 dinslfobeuzDaitfile ami methyleyelopeutanol in 65% as u yeifow solid, MS 247 (MH").

Example 266: 4-Amiti(w§~(((2i?,344fi)~3,4-dilsydri>xy“6-metltoxyiefrafeydruflrsm-S» yl)meiMxyHl H~b^mo\c\it ,2,6 j 1 h mdsaxi ne- 2,2~d ioxs <te

To a solution of4-Amin0-5-(((2IO&amp;4/?)-3,43Hnhydroxyt4trahydrofuran~2-.y!)meiho&amp;y)-.t £(~ben2o[<?j[ 1,2i>]tliladiazine~2,2-dioxido (Example 265 a) (7 mg, 0,020 mmol) in. dry methanol (l ml.) was added trifeoroaeetic acid 0,2 mL) and the mixture was refluxed overnigh t 'The resulting so toilers, was evaporated to dryness to provide the title compound, as a white powder (7,28 mg, .100%, mixture of diasiereomets ·- 4/1), *11 NMR (4(10 MHz, DMSO-dy); ό j.3 17 is, y.M)l 3.22 (a. 3H.}, 3.81 (d, J - 4.0 Hr. Hi), j'3 93 (m, : vH.il.. 4.12 (m, 3H). 4.39 fra, IH). 4.71 (s. IH), [4.85 (d . J 4.0 Hz, HI)], 5.44 (hr s, 211), 9.63 (d, J - 5 0 Hz. 1 Hi, 0.81 pi ,/ - 8.0 Hz, 111).7.48 if,./- 8.0 Hz. 1H), 7.45 is, 1H).8.4! K IH). 11.00.(8, 11¾ [1L01 (s;I 7ΐΗ)|, Example 265a: 4- A mi no- 5 -(((2 J?, 35,4i?)~3,4,5-trihydroxyfetrahydrof0rmi “2-yl)meffepxy}~ 1 /7*benzo[t-j( 1,2,6)thiadiazme>2,2:-‘dtoxtde

To a suspeasion o:f 4-An0.no-5-(((3a.4siA>,6-i7,(>a/i!-0orietho-xy~2.2-din-a-ith)4teirahydroflrro[3sH:^[i,3]dioxo:M-yl)msiho>;y)-i//-berox-)[c-j[1,2,6]themdiazine-2s2-dioxide (Example 265h) (.1 $ mg, 0.038 mmol) in water -(1. ml.) was added trlOuoroaectie aeid (0,2 niL) and the mixture was heated overnight at 80 "(1 The reaction. mixture was evaporated to dryness to furnish the title compound as a white solid in. piiantitadveyieid (mixture of diastereomers - 10/1). lE 24MR. (400 MHz, DMSO-dy): § 3,71 fm, 4B), 4,12 (nm 31:1), 4.35 (m, 1H), 5.02(s, IH), 9.63 (d,,/ === 8,0 Hz, IH), 6.79 (0,./- 8.01¾ IH), 7.47 (t,./- 8,01:¾ IH), 8.03 (hr s, IH), 8,31 (hr s, IH), 10.96 (hr a, IH), [11.00 (hr s, 0.111)].

Example 268b: 4~A.mlno-5-((ii3aj9;4R,6./f.6aR)~6~tnethoxy-2.2-· dimeihyh-etrahydrofltro[3,4~d][l,3jdloxoi.-4-yl.).meth.oxy)-l.//~lxmzo[o][l,2,6]thiadiazin:e~ 2,2-dioxide

Prepared as in Example 111 bom 2-su)famo> lam»i<>~b~{(Q^AR£R&amp;$R)-<w ntctboxy-2,2-dinK-.ihyltet?ahyf;o>iu:o|3,4--</]i 1,3 jdtoxol-4-sI)mcihoxy}benzauiuilc (Example. 265c) m ~8% sidd as a beige solid. Ή NMR (400 MHz, D\hSO-d<d 6 1.28 (s, 3H). 1.41 is, 311), 3. 1H vs, 3Η), 4.00 (L J === 9.2 Hz, iH ). 4.32 (dd,../ - 5.2, 10.0 Hz, 1H), 4.59 (dd. ,/ === 5.2, 8.8 Hz, IH1. 4.63 (d, J === 6.0 Hz, I.H), 4.82 (d,,/ === 6.0 Hz, ! H). 5.02 is. 1H), 6.64 i J,../ === 8A Hz. HI). 6.70 (d, J === 8,4 Hz, 1H), 7.48 (t, ,/==== 8.4 Hz, IB), 7M (hr s, 1H), 8.43 (hr s, 114), 11,02 (fer s,

Hi).

Exarnok 265c: 2 Sidfamoyh=.rnhiou5-(((3in0,4/d6.'i.dn.0)-6-mcrhoxy-2,2--di methyl tetmhy drot\HT>(31,3 )dio\ol· 4· y i}metlwxy Hxmzemtdk

Pseparcd ax in Example I I ia from 2-aodim--MU3o./v,4P,6A6afr}--6--mediuxy-2.2·· dimethyUeirahsdrofufo(3.4-{/){ 1.3 jdiexorAj,\ imeihoxy Ibenxom-xik {Example 263d) in 77% yield as ,: white solid. lH NMR =,400 MHz, OD(V> 6 1.34 A. 3H1. I .50 A, 3H8 3.38 (s, 8H% 4.08 irn. 2H S, 4.51 (dd../ == 8 A 7.6 Hz, IH), 4.65 id. J = 6.0 Hz. IH}, 4.79 {i\. J - 6.0 Hz, ! Hi. 5.01 (H IB), 5.25 (hr s, 2H), 6.70 (d, ,/==== 8.4 Hz, i Hi, 7,28 (hr s, 11¾ 7.30 (d, ,/==== 8,0 Hz, HI). 7.51 (t, ./ 8.4 Hz. }!!}.

Example 265d: 2-Atnino-6-(t(3a/?.4/?,6/l6a/?i-6-mc-thoxy~2.2- dimAhyl:retrahydrO;t\iro(3,4^i/|[I J]ifioxol.A"yi)methox.y}beiizonitr5:le

Prepared ax in Example 11 lb from 24H3a/?i4//,6R,6a//)A-meihoxy~2A-' dimefhyUetrabydr0fu;ro[3,4~d]fl,3]dioxofr4-A4Aiethoxy)-6-a5)robenzoai)nle (Example 252e) m 40% yield as colorless sticky material ^H NMR (400 MHz, C.DCH* 6 t.33 {.\ 3H), 1.49 (s, 3H}, 3.33 is, 3HK 4.05 Cm, 2H), 4,45 (br s, 2Ei). 4.56 (dd, J - 6.0, 8,0 Hz, IH). 4.65 (d, J - 6.0 Hz, 1H), 4.82 (hr d, J === 6.0 Hz, 1H), 5.00 (a, 1H), 6.21 (dd, ,/== 0.8, 8.4 Hz, 1H), 6.33 (dd,,/- 0¾ 8.4 Hz, 1H), 7.20 (i J - 8.4 Hz, \ H).

Example 265e: 2'(((3afr,4/?t6i?,6:a/?)“6-Melbaxy“2,2~dimeihylteNahYdmftro|;3,4-z/|[l,3|dsoxoh4~yl;)mefh€<xyO~6~aiire^enz.eHi:lrik=:

Prepared as in Example file from 2.,6 riiniirohenzcioifrile and (/3aA4A6i?,6al?)~ 6-roeihoxy-2,2»dimethyltetrahydrot\*ro[3 Azijj'! v3 idioxol-4'vlJinothmwi in /5)1% yield a>; white solid. !H NMR (400 MHz. CDCh} 8 1.33 is, 3H), 1.49 (s. ill). 3.32 (s. 31¾ 4.23 id,./ == 2.0 Hz, 1H), 4.24 (s, 1 H), 4 60 (br t, J= 6,0 Hz, 1H}:, 4.67 (d, ./== 6.0 Hz, i H), 4,86 (br d,./== 6,0 Hz, 111). 5.01 (s, IB), 7.35 (d,,/ 8.4 Hz, 11¾ 7.72 (1, ./ === 8.4 Hz. Ill), 7.87 (dd, ,/ = 0.8, 8.4 Hz, ill).

Example 266:4rA»»t»o~5“(((3.»#$a&amp;fiiai£8^ l.dsllH|dksxiit0|4J~6:4frS%/)pyrai5"5~yllme?.lK>xy)~i//-benzei[rji 122,6(1 hhHlIazme-IA-dtoxIde

prepared ax in Example 264 from 2-amino- 6·{{(3a/t5a52KuS,»Sb.S'} -2,2,7, ?·· tetraniethy]tctv»hydro-3a^/"bii?| 1 J}dioxo{o[4,5-/.4\6Vjpycan-5-yl)mcthoxy}benzonitnU: (Example 266:;.} in 73.’·. yield as a white a;4id. Ή NMR (400 MHz, DMSQ-/>) 6 i .29 K 3H), 131. (s:, 311). 138 (8, 3:14), 1,43 (s, 3H), 4.07 (m, 21:1}.. 4.10 (br d, /- 8.4 Hz, IH), 4.86 (dd, /-1.2, 8,0 Hz, IHl, 4,4 1 (0/./===2.4,5.2 Hz, IH}, 4.44 (ud../=== 2.4, 10.0 Hz, IB), 4.67 (dd, J-2.4, 4.0 Hz. ! H), 5.5! (,1,./=== 4.8 Hz, I Hi, 6.63 (d../=== 4.0 Hz, IH), 6.7? (/./~ 6.4 Hz, I H), 7.45(1, 4 === 8.4 Hz, 1H). 7.86 (hr s. IH}., 8.41 (M s. IH), 10.98 {br 8, 1H). MS 456 (MR ).

Example 266a: 2-ArmoO'64ii3a/E5aS.8;/',KbS}3.2,7,7~ieirameihylreimhydru~8;;i/-1:/413)dioxolo^4,53>:4\5,-rfjpyran-5-yl}j«o{hoxy)benz.onitrile

Prepared as i«- Example 11 lb ftOm-2*ilitrd-6-<{(3aRsS:gSJa/8b5>2,2JJ-teirainetin4letrah>a!ro-3aH/Ms|l,3]d:icfXolo|4,§/>:4,,5’-x7|pyTan-3-y!)«ieihoxyibeezonitfile (Example 26(ib) in gnantitative yield. {H NMR (400 MHz, OMSO-ds) 6 1.28 ;s. 3H}. 1.81 ;a. 3H), 1.37 (s, 3H), 1.39 (s, 3H), 4.05 (m, 2H), 4.16 (del, J - 4.0, 8,8 Hz, IH), 4.37 {m, 2Hs, 4.67 (dd,,/- 2.4, 8.0 Hz, IH), 5.47 (0,/-4.8Hz, IB), 6.01 (br$,2H), 6.23:(d,,/-8.0Hz, IB),635 (0,/====84 Hz. IH}, 7.17(1,../=== 8.4 Hz. IH).

Example 266b: 2-Ndr0/4i:i3a.d.5a3,6adJb/}-2,2,7,74etranTetlwtletrabvdro-3a// ¥4l.>3l<Ji-o^0lo[/5^:42SM^pyra.ns|^yI)r3e^.xy)^«zoBMi.^

Prepared ax in Ex:;.mple file from 2.,6 d i nitrohenzonh die ;md if 3;df.5;^.8a5(8b.S)-2.2,757-ieiramethyH.eiriiKydro-3://-bis[! 3jdioxolo[4,5/:475//]pyran-S~ y l)ineihanol b; 59 % yield as white sticky material. MS 408 (MH/ 424 (MIEO },

Example 267: 4-Amino54142-methoxyet.byl}~l //0,2.5-i.riazol4pvl)“l /?-hettxo|e] [ 1,2,6)ihiadiazine~2,2 'dioxide

Prepared aj> in Example .1 i I from 2-sultamov lamiηο··6··{ 1 ··{2-methoxy ethyl)· IH-I J3-ttiazo)-4-yf)benzonitrife (Example 26~a) in 78% yield. Ή NMR <4i"f0 MHz, DMSO··/,} P 3.27 (s, 3H>, 3.7-X = 5.2 Hz, 2H), 4.59 (i,J --- 5.2 Hz, 2H},6.90 (brs, iHi, 7.09 (dd,./ - 0.8. m Hz, IH), 7.20 (dd, J- '0.8, 7.6 Hz, IB), 7.58 (t, /- 7.6 Hz, IB), 8.15 (k g, iH), 8,32 (s, HI), 11.09 {br s, 1 Hi. MS 333 ί ΜΤΓ).

Example 267a: 2~Sid&amp;moylamino~6-~(I~(2~meihoxyethyI)-| HA ,2,3HnazoM~ y!}bcnzo· nitrile

Prepared ax· in'Example 11 la Bonv2umiino/4i/2m'ieihoxyethyl)H/Tl,2,3~ iriazoM-yObenxordmic ( example 267bi in 70 % yield. SH .NMR {400 MHz. DMSO~/;} Λ 8 28 (s, 371), 3,79 (6 /- 5.2 Hz. 2H),4.66 (t,/-5,2 Hz, 2B), 7.32 {brs, 2B). 7.80(dd,/- 1,2,8.0 Hz. 03)/7.76 (t, / - 8,0 Hz, IH), 7.82 (64/ - /2- 8.0 Hz, HI), 8:.64 (s, 1H), 9,52 (br s, IB). Example 267b· 2-Ammo--6--(l--(2Haej:hexverhvn"177--1.2,3/fiazc)l-4-vnbcnzomtriie To a solution of I ·bromo·2·merhoxycthane {5.00 g, 35.97 mmol) in DMF (25 nil), was added sodium azide (3 equiv.) and die mixture was heated at 50 /7 for -18 hours. The reaction mixture was diluted with water (75 mi.} and extracted w ith diethyl ether, rhe organic extract was dried over MgSCH and concentrated to .furnish 1-axido-knoeihoxyeihane as a yellow liquid. This azide (200 mg, 1.04: mmol) was added to a solution of 2~A.mino~6~ etlwnylfeehzenltrile (250 mg, 1,76 mmol) (Example 26.7c) in Η/Τοοζ-ΒηΟΗ -· 1 ;2 (1 5 ml) and the solution was treated eonsecudvely wftb, sodium ascorbate (0.264 mraol) and Cu$0.> (0.035 mmol). The reaction mixture 'was stirred at room temperature for 48 hours, dilrtted with water and extracted with ethyl acetate. The organic extract was dried over MgSCXf and purified oxer silica, gel (ethyl acetaie/hexanc 6:4) to furnish fte title compound as a whits solid in 88 % yield , lE NMR. (400 MHz. 0^0-^^^:26-^3^,,3-78^,^== >.2 Hz, 21:1:), 4.23 (t,/-5.2 Hz, 211), 6,.13 (br s, 2Hs, 6.8§ (dd../ )..2, 8.4 Hz, IB), 7.09 (dd,/ 1,2, 7.6 Hz, ! H), 7.36 (t, /-8.4 Hz, 1H), 8 52 (s, 1H) MS .244 (Midi,

Example 267c: 2Άrnino-6-ethyrtyIfcenzonit rile

To a solution of ewrumoW-oromobenzoniude (1.25 g, 6.34 mmol) and ethynyltriaie:hyisilane(2,42 g, 12.7 mniol) in dry-.BtjN (15 ntL) was added under 1¾ C’a(l) (60 trig), EiltPPhr}) (560 rug) and the mixture \vat< stirred at 80 "C for 20 hours. The reaction mixture was cooled down to room temperature, diluted with ethyl acetate and washed with brine. The organic layer was evaporated and the residue was dissolved in methanol (20 mi.), heated with 1M aqueous NaOH solution (1.05 etjuiv.) and stirred at room temperature for ] hour. Methanol was evaporated off and the aqueous residue was extracted with CH>Cl·, dried over MgSO.;. and purified over silica gel (ethyl acetate, hexanes 75 25} to furnish the desired product in 93% yield, as light yellow solid. Ί1 NMR (400 .MHz, DMSO-r/.,) 5 4.54 is, I fig 6. w (hr s. 2H), 6.76 (dd, ../ 0.8, ”6 I lx, 111),6.82 tdd.7 0.8,8.4 Hz. ills, 7,28 (dd,./ 7.6, 6.4 Hz, IH). MS 143 (MiO.

Example 268; 4-Amiao~5~(fttt^iKV.> IhI fiT4bei*z«j<,j 11,2.61 tlMadiadEe~252~dioxk!e

Prepared as: in Example 11.1 from 2*sulfamrAdam«iK.^-(furaii3-yl)ben2omtrilt; (Example 26i>s) in 47% yield as a beige, solid. 5id NMR (400 MHz, DMSOsls) (i 634 (hr a, 1H}„ 6.51 (dd,,/ = 0.8:, '2.0 Hz, IH), 7.03 (m, 2H|, 7.52 (dd, J = 7.6, 8.0 Hz, i H}, 7.79 (t, / = i .6 Hz, 1H), 7.93 (dd, J™ 0,8,1.6 Hz, IH), 8,23 (hr s. IH}, 11.09 (sJH). MS 264 (MBl Ex^pIe268a:-2^ut.femQ¥lamme^(fura.B.3'->vl')bats^oMfe:

Prepared as in Example 11 la (rent 2>ammoHWfyr<m3~)d}ben2smiinle (Example 2686)»* 63% yield as a white solid. *H NMR (400 MHz, DM$0~i/:;) d 6 9? (dd../ ~ 0.8.. 2 0 Hz, IH), 7.29 (hr s, 2H). 7.46 (dd,,/ == 0.8. 7.6 Hz. 1H). 7.54 (,y, j„ o.H. 8.0 Hz, I H), 7 69 ft,,/ === 8.0 Hz, H I), 7.85 (t, J ----- 1.6 Hz, I H), 8.2 i (dd,,/ === 0 8, 1.6 Hz. 1H). 9.48 fbr s. 1H)

Example 268b: 2~Amino~6-ffitt^^3~yl)be.ozonitriIs

Prepared as m Example 129c i'om Etmu-3w IboFoaie acid and 2«.&amp;Μβο*6« hromobehzont trite in 74% yield its a yellow solid. Ή NMR· (400 MHz, €.0(¾) d 4.51 (br s, 2H), 6.66 (dd, J I2 Mil/. HIK o 78 (dd,../ === 1.2, 2.0 Hz, 1H), p.82 (dd,./ === 1.2, 8.0 Hz, IH). 7.31 (·,,/=== 8.0 Hz, 1 H), 7.50 (t, ,/=== 1.6 Hz. IH). 7.95 tdd »/===· 1.2. 1.6 Hz, 111).

Example 269; 4wimhm-5-(iido|}lMm-3-y 1)-1 ,2,6|tMadiaziMe-2,2-dlexide

Prepared as in Example 111 from 2-sulfarnoy landno-6-( thiophcri-3-yllbeozomirik (Example 269a) io 52% yield as a beige solid. Ή NMR (400 MHz, DMSO-dV,) o 5.82 (br s, I0), 7.05 (m. 3H). 7.54 it. J === 8,0 Hz, 1H), 7.67 έai, 1Hi, 8. ] 5 (br s, 1 li\ 11 .,13. (sd H). MS 280 (ΜΗ).

Example 269a; 2-Sul&amp;m.oylamino-6“(ildophe5i-3~yl4beaxoalirile

Prepared as in Example 11 la from 2-aniioo-64tlnophe«"3-y!)k'nzooitri!e (Example 269b) in 605¾ yield as a white solid, Ή NMR (400 MHz, DMSO<./>) 0 7,3i (br s, 2K), 7.42 (dd, J === 1.2, 2.8 Hz, l H), 7.43 (d, J === 1.6 Hz. IH), 7.57 (dd, J -=- 0,8, 8.0 Hz, i Hi 7.70 (1, J === 8.0 Hz. 1 !i), 7.75 (dd, J 2,8, 4.8 Hz, IH), 7.88 {αα. J === 1.2,2.8 Hz, IB), 9.48 (br &amp; PH).

Example 269b· 2-A?ydPO-6-(tb.iophen--3-vl)beozonitrile

Prepared as Id Example !29e from tblopben-d-ylboronie acid and 2-a:mmQ-6-bromobenzosuirik In 94 % yield as a beige solid. ! Η "NMR (400 MHz. DMSO--d3) 3 6.08 (br s, 2H;·, 6. /0 (dd. J 1.2, 7.6 Hz, SH), 6./7 (dd,,/ - 1.2, 8,4 Hz, 161), 7.31 (dd.,/ === 7,6, 8,4 Hz, 10), 7.38 (dd, J == 1.2,4.8 Hz, 1 Hi, 7.66 (dd. ,/= 2.8,4.8 Hz. 1H), 7.78 idd,/= i .2,.2,.8 Hz, 1M), Example 27IE S“(2,2»dimet6ykyeiopropy!)“lII-fte»zrr|el( l,2,6|tfetadiazsa-4“a?ttl«-2,2“ d (oxide

A solution, of 2~ami.no~6-{2,2foimethyleyc!o:propyi)beuzorntri!e {381 μπτοΙ» 71 mg) (Example 270a) and sultkmoyl chloride (572 μπκ>1,66 mg) ί» DMA (1 mL) was stirred at room temperature. After i hour, the reaction mixture was diluted with NaOH (IN, 572 pmol, 572 pLi arid water { "50 ml,?. The precipitate was filtered off. washed with water (5 X 5 mL) then dissolved in EtOH (10 mL) and .NaOH {IN, 053 pi..) was added. The reaction was heated to AO ° C with stirrmg. .After completion the solvent were evaporated and the residue was partitioned -between water (20 mL) and ether (5 mL) ..The aqneus layer was extracted, with ether (2 X 5 mL), then acidified to pH --3 with IN HC1. The precipitate was collected, washed with water, dried in vacuo to give the desired prodoet (59 mg, 58%) as an off-white solid, !H HMR {400 MHz, DMSOmh} J0.610 <m. !H), 0.63 (s. 3H), 0,89 (op ί Η), 1.20 <$, 3H), 148 (m, IH), 6.88 (d, J ----- 8 He, IH >, 6,92 <j, J 8 Hz, IH), 7.2! (hr. s, 1H), 7.39 it. J - 8 Hz, 1H), 8.42 (hr. s, IH),10.74 (s, I Hi. MS 2o6 {ΜΗ I.

Examok 2"0a; 2 -mmno-6-cydopropylbenzorhtrlte

To a degazed solution of 2-anrino-6-m'onmbonzoniinle (851 μηιοί, 168 mg*. 2.2-dimcihylcyciopropyihoromc acid (1.106 ftmok 126 mg) i Example 270b), and (VOfo ;2.9~o mmol, 970 mg) in DME (3,4 mL) ami water {850 μ],.} was added

Wtra.kis(triphcnylphosphlno)pailadinm(0): (43 gmol, 50 mg) under nitrogen and the reaction: mixture microwaved tor 2 hours at: 1.60 0 C, The reaction mixture was cooled to mom. temperature and extracted with EtOAc 13 X 5 ml) The combined organic layers was washed once with brine (5 mL), dried over sodium snliato, filtered and evaporated The crude product eras perilled on silica ge! {EtOAc.hexanes j 0%-40%) to give the desired product {71 mg. 457?») as a waxy, yellow solid, *H NMfo(400 MHz, CDCki J0J2 (m, 1H). 0.82 (s, 31!), 0.85 {m. IH), 1,33(s, 3H), 1.92 (m, 111),4.36 (hr. s;2E), 6.47 (o,./ g ID. !H)S 6.56 id,,/™ 8 Hz, IH), 7,20 0,./ - HID. 1.1-1),

Example 2?0h- 2,2'dimethy1cyclopropylboronic acid

To a solution of l.~hromo~2.2-dim.ei:hyicyci.op5'0|iaiie (7,48 mmoL I d 15 g) (Example 270«) in anhydrous THE (20 mL) was added tBuLi (8 23 m.mol. 1.7 M in pentane, 4,85 mL) dropwise at -78 0 C under .nitrogen. After 1 hour at -78 0 G, irirnelhvlberafe (8.23 mmol, 920 μΐ,} was added and the reaction, mixture was stirred for 2 hours at -78 C, wanned to room temperature, stirred for 1 hour,, and quenched, with sat, NELCI solution (20 mL). The reaction mixture was diluted to a total volume of 100 ml, with DCM and Iseated with HCl if N in water, 22.45 mmol. 3.74 ml,). The layers were separated, the aqueous layer extracted w ah dieholrometane (2 X 50 mL), the combined organic layers were Washed With brine (25 mL), dried over sodium suilate, filtered and evaporated. The residue was diluted v\ itb acetone {50 niL). and a. few drops of water,, (hen carefully concentrated in vacuo to give 214 tug (25.1 %) of product as an »ηΪΛ\hue solid. Ill NMR (400 MHz, acetone-ife) .40,(4) (m. IH }. 0.13 on, I Hi. 0.755 id ofd, J ----- 4 Hz, 8 Hz, ill). 0.465 (d of d,./ - 4 Hz. 8 lie, .1 B% 134«. 5EI), 1.40 is, 3H>, 0.4 i (s, 2 I h.

Example 270c: 1. -bromo ~2,2-di.mcthykycl.opropaiie'

To a suspension Of Zinc (dust, 319.4 .mmol, .20,88 g) in EtOH (20 mL) was added HCl (12 N, 5 ml.! at 0 ° C, A solution of 1,1 »dibrorno-2.2-d{rnethylcyclopropane (18.2 g) (example 270d) in EtOH (20 mid was added to the ouxture over 5 minutes with stirring. The reaction mixture was allowed to warm slowly to soon! temperature overnight. The zinc salts were filtered off through a pad of Celite, the Celtic washed with EfOH (50 mL). and the resulting solution partitioned between water (200'tnL)-andpentane <200 niL), The aqueous layer was further extracted with pentane (2 X 100 mL), and the .combined organic extracts successively washed with water <4 X 75 ml.), brine (25 mL), dried over sodium sulfate, filtered, and evaporated to gives the product (1,115 g , 9,43¾) as a volatile, colorless liquid, Ή NMR (40(1 MHz. acetone-fL) £0.602 (d ofd, J------ 4 Hz, 6 Ha, ill), 1.025 (d of d,./ === 6 Hz, 8 Hz, lid), .1 did (s. 3H). L233 (s, 3)¾ 2.963 (d ofd,J === 4 Hz, 8 Hz, 1H).

Example 270d: .1., i -drbmmo~2,2-di.tttelhykyelopropane

To a solution of peutane (200 ml..) cooled to -5 0 C was added isohtsiyiene (457.7 ro.mot, 25.60 g) followed by potassium tort-bis toxide (549.2 mmol, 6i;.63;g).'Th.en.htpm6,f0nn (457,7 mmol, 40.0 ml.,) was added dropwise with vigorous stirring over about 1 hour sit ~5 * C. The reacts on mixture was allowed to wari» slowly to room temperature ant! then partitioned between pentane (100 ml.) and water{200 mL). The aqueous layer was extracted with pentane (2 X 50 mL) and the combined organic'layers washedwith water (4 :X 75 mL), brine (51) mL), uned over sodium: sulfate, filtered and evaporated. The orange residue was pushed through a. silks plug eluting with pentane. The'solvent was evaporated to give· the desired product to5.70 g, 57.3%) as a colorless oil. *H NMR (400 MHz, acetonewk) £1392 is, 6H), 1.505 ts. 2H).

Example 271; (-.U-irans-S-i 2-( me I Is ox v me t hy I) eye iopropyi s-11 l-benzo j e j j1,2,6] (hiadm/.m-4-amme-2,2-dIosMe

Prepared as jo Example '270. from (ife}-ir8«s~2-ai»j.aO"(H2-|met!jiox.ymeihylk'yelopropy!)benz0mtrae (example 271a) and. sulfamoy! chloride in 34% as an otV-whde solid *H NMR (400 MHz, DMSCWn £(1.976 (m. iHI. J .172 Cm. jHi.. 1,340 (m, IH)S 2.2*2 (nu 1H). 3.|7Sul ctu,./ = S Hz, 10 Hz. IH>. 3.252 (s, 31¾.3,576 (d-of d, A-S Hz, 1.0 Hz. 1H}.6.XG2 i'XJ -- S Hz, IH), 6.455 id, J --- 8 Hz, IHl, 7.376 (t,J - 4 Hz, I Hi. 4.396 (br. s, IH), 6.473 (br. s, IH). 10.423 is, IH). MS 262 (MH >.

Example 271a: (0-1 runs 2 amino-6--(2(n)efhexypie%l)cyelopmpyl)^«zoajtrjle

Prepared as in Example 270a from (.. >-u:aos-2- (rneclioxyniethyl)eyelopropylboronie add (example -2-71- b) and d-arnibo^bronrebenaonitrile in 64"-;, yield as a yellowish brown wax\ solid. *H NMR (400 MHz, DMSO-f//;) <30.932 (m. 2H), I 341 (m. ill >, 1.679{sn, 1 Hi. 2.324 K 3H)„ 3.351 (d.,/- 6 IK 2H}. 5.8% (br. s, 2H). 6 J 44 Cd. ,/ - 3 Hz. IH),. 6,550 (0,,/- 6 1¾ I H), 7.13(1 (1,,/- 8 Η/. 1Π1

Example 27 lb: (dr).-tons~2-(methoxym.d(by;l)eyeloprpp>4|»5rdmc;aaki:'

To a solution of (T)-p-ans-2-(me(:hoxYmeCbyl)eyclopropyl}~4ri4,5,5''ieipinelky!:·' l:,3,2”dio.xaborobsne (10.0 mmol, 2,121 g) (example- 27!e) dissolved in THE (64 ®L) was added NaIO,4 (30.0 mmol, 6.417 g) and water'(16 mL), The reaction mixture was stirred at room tempemture for 3 minutes then treated with aqueous Hi I (2N, 5.3? mL). The reaeuou mnfute was stirred for one hour at room temperature, partitioned with EtOAe-..(:100 mL), the aqueous layer extracted with E-tGAC (2 X 50 mL), tbe: combined organic layers wasbetl with brine (25 mL), dried ever sodium sulfate, filtered, and evaporated. The mixture was taken up In acetone, treated with a few drops of water, and carefully evaporated' to a viscous oil, which slowly solidified at room temperature to give the desited product in quanUPatn e > i^id, !H NMR (400 MHz, DM 80-4;} <$-0.46? (rn, (Hi. 0.324 (m, 1H"), 0.532 On. I!I), 1.055 (in, i H), 3.044 (d of d, J- ? Hz. 10 Hz, 111), 3.186 (d of d../- ? Hz.. '10 Hz, HI). '..20«, is, 3H). 7.344 (s,:2II).

Example 271c: (^“frans-S-CmothoxymeOiylicycIop^pyll-iH JsS'teiramedwE 1,3,2-dioxaboiOlans

To a solution of (E)-2-(3-methoxy prop-1 -enylM,4,5,5-tetramctby!-1.3,2-dioxaborofanc (32 2 mmol. 6.3710 g) in.anhydrous toluene (50 otL) under nitrogen xvae added diethyl zinc (0.59 M in hexanes. 32.2 nunoh 54.0 mi.}. followed by Old.; (45.08 mmol, 3.63 mL·). The flask was heated to 50° 6' under nitrogen. A tier 4 hours, another portion of diethyl ziac (54,6 mL) arid 0¾½ (3.63 mL) was added and heated overnight-under nuiegeo. The' reaction, mixture was eooied to room temperature and- quenched with saturated aqueous NH4O (50 mL>. The reaction nr;stare was partitioned with other (200 ml.}, the layers separated, the organic layer washed with brine (25 mL), dried ever sodium sulfate, fthered and evaporated.

The residue was purified on silica gel (FiOAc.hexanes 1% to i 5¾) to gwe the desired product (5.552 g , 81.3¾} as a light-yellow oil Ή NME (400 MHz. acetone) <>'0.0 (2 ρη, IH i. 0,804 (en, 1 id). :0.944 (or 1.14), 1.1.72 (m, 1H), 3.484 (dd. J - 6 .Hz. 1.0 Hz,. 1.1:1), 3,553 (dd,./ - 6 Hz, 10 Hz. !H). 3.570 (s, 3H).

Example 272:

To a solution of (E)-5-(4-(tetrahydro-2H-pyran-2-yioxy)but-l -enyis-1H-benzo[c)[l,2;6]thiadiazin-4~amiuc-2,2-dioxide (322 Ltmol,43 mg) (Example273) in,THE(860 pL} was added AcCtH (1.7 .mL) and water (430 pL) and the solution heated overnight at 45 0 C. The solution was cooled to room temperature and the- solvent evaporated. The residue was triturated with boiling water then, cooled to room- temperature. The resulting solid was collected and washed with water to give the desired product (69 mg, 80%) as a light yellow solid, ‘1:1 NMR (400 MHz, DMSO-ώ,} A2.365 (%/- 6 Hz, 2.H). 3.568 (q, J --- 6 Hz, 2B}:, 4.681 it,./- 6 Hz. IB), 6.186 (don. J- 7Hz, 16 Hz, 1H), 6.786 (d,/- 16 Hz, IM), 6.922 (d,l- 8 Hz, ίΙΤ), 7.022 (br. s, 1Hu 7.088 (d, I - 8 Πχ. 1H}, 7.40* {i, J === 8 Hz, 1H S, 8.388 (br. s. ! f-b, 10.935 m, 1 Hi. MS 268 (MIT).

Example 273: (E)^4<teti«liydr^2H^yraft-2-yIe3£y)bia^J benz«jcl[l,2i61fhtadta3Ef»(4*a'atlne^2t2-<lioxMe

Prepared as is- Example 270 from {E)O-an»n0“M4Hf *'4rahy drO“2H~pyran.~2~· yfoxy}but~1 -cm 1 )benviooiu ilo (example 273a) ami suitamoyl chloride in 01% yield a» an. off-white solid. SH NMR <400 Ml 1/.. DMSOM·.} 0Ί .450 On. 41b. I .M0 (m. 2H), 1.700 On. 21b. 2 470 (q, j “ 6 Hz. 2H). 5 438 (m. 1 H). 3.528 {:rs. I Hi. 3 765 (m. 2H). -=.579 On. IH), <· '300 (d of I..,./-7 Hz. \u Hz. IH). <« 833 fd../ === Ιό Hz !H ),0.867( hr. s. I Hi. ¢-.931 (0../-8 Hz. IH), 7 087 (d.,/ === 8 Hz. IH). ",-173 (¢. J =· 8 Hz. IH). 8 401 (br. s, 1H) 10.945 (s. 11H. Mb 3 ml (MH' i.

Example 273a: enyEhenzonitrile

Prepared as m Example 2?0a from (Eb4,4,5d-tetrsm:etl^b2-(4“(tetraliydro-2H~ pyr^-l-y loxy)but-I*eny 1)-13.2-d ioxaibo rolane (Example 273b) and 2-ammo-0-bromdbenzonitrile in 47% yield as a yellow gum. ‘H NMR (400 MHz, CDCU) S 1..570 (m, 4E), 1.727 (m, 2E), 1.837 <m, 2R). 2.565 <q, J === 6 Hz, 2H). 5.541 (m. 2H), 3,879 (m. 2H). 4.38'“ {hr s, 2H), 4.035 Cm, 1H>, 6.423 (doft, ,/=== 7 Hz, 16 Hz, IH), 6.586 (0,.,/== 8 Hz, IH), 6.710 (4,/ = 16 Hz, 111),6.905 (d,,/== 8 Hz, ill). 7.237 (i, 7- 8 Hz, Hi).

Example 278 b: (£)4,4,5,5 ~ieirasi5eihy b2-(4-(ie(ralwdf 6"2li-pyrap-2%!oxy)b0:E 1 - enyl)-1,3,2-dioxabocobm·

Neat. 2-(bot-3-yny!o Hclrahydro-2H-pycm (12.8 mmol. 2.0 mL) was treated with pinacolborane (19.1 mmol, 2.78 ml-) at 60 0 C umler mtmgeii. After 2 hoars, mother portion of pmacelhonme (12,8 mmol, 1.86 ml) was added:ailii eontiniied heating at 60 0 G.

After 8: hours, the reaction nhxinre was diluted with hexanes (30 mL) and; treated: dropwise; With water (:1 mE), stirring until gas exolutton ceased. The layers were separated, fee water layer extracted \siih hexanes (2 X 5 ml.}, the combined organic Liver:·- washed with brine (5 mi. s. dried orei' magnesium sulfate, filtered. and evaporated. The crude product wax purified on silica gel (FtOAc.'hexunes 10% to 30%} to give -he product ί 1.73 g, 48%yield) as an oil. Ή NMR (400 MHz, CDCh.s S\2i2 (s.3H). 1.531 (m, 2H). !.699iro, I Hi, 1.812 (m, IB), 2.469 (d of eg J-2 Hz. 7 Hz, 2H). 3.495 (nr, 1H), 3.832 (m, 2H), 4.593 (d ofd, i - 3 Hz,4 Bz, 11¾ 5.52.3 (d oft,,/ ::: 2 Hz. 18 Hz, Hh. 6.834 (d oft,,/ ::: ? Hz. 18 Hz. IH >.

Example 274: 8H4-aminO“2,2~tiio*o-I H-ben/ojcj| i,2,6jlliia<lia5d».”5-yloxy)ociait->lrOl

To a solution of >N(.>-arnino~2-cyanophcnoxyjocty 1 acetate (740 μ mol, 227 mg) in DMA .(3 mL) was added sttH'umpyl chloride (1,492 mmol, 172 mg) sad. pyridine (4.476 mmol, 362 pi,}. The reaction mixture was stirred at room, tempdr&amp;ture until completion, then -quenched with sat, HaHCOs (15 mL) and solid Na€l added.. The· prccipato was collected and washed with wrrter.; The wet precipitate was suspended in,EtOH (15 mL} and. treated, with NaOH (8.952 mmol, IN, 8,95 mL). 'The.lreaefitj»mixturew^strefluxed ««til completion then cooled to room temperature. Most of the EtOH and water were removal in vacuo, then the reaction mixture was dissolved in water (15 ml), extracted with ether (3 X 5mL), filtered, through a 0.45 pm PTFE friL then acidified with. .1054 citric aeid/water solution to pB 4-5. The precipitate was .filtered off washed with water and: dried: to give the desired product 1,46 rag (57.3%) as an off-white solid, lH NMR *400 Xlliz, DMSO-oL} <>'1.26(5 tm. 6H >, 1,38(1 |m, 4H). 1.785 ipeniet, ,/-7 Hz. 2H}, 3.348 (q,./ - 6 Hz, 2.H). 4.303 (r. J = 5 Hz. 2H), 6.5M1 (ds j- 8 Hz, 1HT 6.724 up ./8 Hz, 1H), 7,428 it,./ - 8 Hz, IB), 7,796 (hr, s, IH), 8,329 (hr, s, ]H)J 0,922 (sJH), MS 342 (mh:).

Exam ole 274a: ^(S-aptiao^dyanophdnc^yloetyl acetate A solution of 8~(2-cy;mo-3-nUropIicno\y)octyi. acetate (802110101, 268 mg) (Example 27¾) in EtOH 115 mL) was hydrogenated in an. B-cubeapparatus using 10% Pd/C as catalyst The solution was evaporated to give 8~(3“aniino-2-eysnophcnoxy)octyl acetate (244 nig, 244 mg). .MS 305 (MH )

Example 2?4b: n »(2»c yano-.Vn itrophenoxyloctvl acetate 248diYdroxyr;ci} loxy1 - 6 ·n< trnbenzonurile (n04 μ mol, .‘.’35 mg) (Example 274c) was dissolved in dry DCM ( : 0 ml.), cooled to 0 "-1 C, and treated suocewsh. ely with pyridine (3.216 romol, 260 fiLi and acetyl chloride (! .608 mmol, 114 uL). The reaction, mixture was stirred and-allowed to warm slowly to room temperature. When the reaction wax complete, the volatiles were removed in vacuo and the crude product purified on silica, gel (10%- to 50% EtOAc. in hexanes) to give the desired product 6.168 mg, 100%), MS 335 IMH }.

Example 279c; 2-(K~hydro>:>\nu>dos;y)-0oiiitrohonzonitrile Te a soknion of 1,8-octancdiol. (3.8? mmol. 566 mg) in THE (dry··, 10 ml,) was added 2.,6-diniuobenzooiiriie (1.29 mmol, 250 mg) and D8U (1.30 mmol, 194 pi..). The reaction mixture was stirred for 24 hours at room temperature-an esapmaicd. The oily residue was triturated with 10% citric aeid/water and solid NaCI added. The precipitate was collected , washed with water, dried In vacuo and purified on silica gel (40% to 100% EtOAc tit hexanes) to give die desired product ¢235 mg. 62.3°«) asa pinkish solid, MS 293 (MM ).

Example 275; ?^4-ami«U"2:,2»dlexe-l:M-biBitzo|cj{1 v2a>ffhtadiazi»-5”yloxy)hepian"l"Ol

Prepared as in Example 274 from 7~(3wmiino3myaiKmhent.ixy)hepiy! acetate fix ample 275a) and suifamoyl chloride in 79,4% yield. \H hi MR (400 MHz. DM$O-;i0 ό ! .320 On. 4H), 1.405 im, 411 ), i .8! I (peotet.,/ === 7 He, 2H), 3,378 so../ === 6 Hz, 2H i, 4.154 (t, J == 6 Hz, 2H), 4.331 0../ :: 5 Hz, iH), 6.605 id. J === 8 Hz. 1H). 6.752 (<i, J === 8 Hz, 1H). 7.454 ft../ === 8 Hz. IS}, 7.823 (hr. s, 111)3358 (hr, MR), 10.046 (s, IH). MS 328 (Μ1Γ).

Example 273a: 7~(3--aminO'-2"CyanopheitOxy)heptyl acetate

Prepared as in Exantplo27#.^dini7^<y^O'34nit^:pho»4xy)b#tyl acetate (Example 275b) in 8956 yield. MS 291 (Mill

Example 2756: 7 IS^e-yano-'o-nitrophenoxy)heptyi acetate

Prepared ax in Example 274b from 2--(7-diydroxy1iepi>d:cmy )”fl-utitrobettxonitr.iie (Example 275c) in 10036:yield. MS 321 (MM ).

Example 275c: 2-{7-hyd?oxyhqpry!oxy)^H»ilrobcnzonitri ie

Prepared as in Example 2?4c (except DBU was replaced with tCOi&amp;u } from 1,7-heptaeedio! in 65% yield, MS 279 (MIT ).

Example 276:9-(4-amiap“252^1i>xO“i li-bea»o{e| ( .1,2 ,6 j t h la d I ax i a-5-y loxy) a on asi- 1 ~ol

Prepared as in Example 274 from 9-(3-ami«o~2~eyanopberi0xy}noayl acetate (Example 276a) and suU'amoyi chloride in 62.3% yield. Ή NMR {460 MHz, DM$0-<4) S1.250 (m, SH), I 381 (m, 4H), ! .791 tpenict, J ------ 7 He. 2B}, 3.349 (m ./ - 6 Hz. 2H), 4.135 it. J ------ 6 Bz, 2Hi. 4.301 0. J = 5 Hz. IH)., 6.585 (d../ = 8 Hz, 1 H). 6.726 id, J = H Hz, 1 Hi. 7.4,34 it../ = 8 Hz, 1H).. 7 798 ihr. x, H I). 8.329 fbr. a, HI). 10.924 {a.. HI). MS 350 (MH ).

Example %:6a: 9*«,3*amioo-2-cyanophe;u»xymonyl acetate

Prepared as in Example 274a from 9-{2~cYano~3-mtf0phen»xy}0onyl acetate (Example 2766) in 99,3% yield. MS 319 (MET)

Example 2 /6b: 9-{2-cyatno-3"nitfopbeaoxytoowl acetate

Prepared as in Example 274b froin 2“(9“hydroxyponyloxy)-6-nitrpbenzonitriie (Example 276c) ml00% yield. MS 349 (MH ). .Example 276c; 2-(9~h¥droxyponylo2y)-6-pltrobenzoniirile

Prepared as: ip Example 274c (except DBU was-replaced with J ,1,3,3-ictramethylguanidine) fro.tR .1,9~no:0.anediol and 2,6-diniirebenxeniirile in. 30,73% yield, MS 307 iMH'}.

Example 277:N-(6~(4~amlm>-2,2~dioxo~iU~t)enro|c||i72o6]thiadlsrin~5~yUixx )hexy!)~2~ Iiydro\y~2~meHiylproparm.mkie

Prepared as in Example 274 from j 46-f3-aniino-2-cyanopbcno.xy)hexylammo)-2- methyI4mxopropsn-2~yl acetate (Example 277a) in 65.50¾ yield. Ή NMR (400 MHz, DMSO-4) $1.201 (s, 6B), i .260 (m, 2H), 099 (ro< 4B), I.790 (pentet, J- 7 Hz, 2H), 3.036 (q,/== 6 Hz, 2H). 4.130 (t,./- 6 Hz., 2HK 5.272 is, iH). 6.567 <d ./ - 6 Hz. 1H), 6/28 id,/ - 8 Hz. ifit. 7 434 (t,./ - 6 ( 1/ : B), 7.594 {br. t. 1 H)„ 7 804 i hr. s, 1H). 6.32¾ {hr. s, !H1. 10.924 {s. ! I f). K18 399<MH:).

Example 277a: 1 a o-( 3-an: ino«2-c\ anopbeno\> )hc x> him n i«»»-2-nicih> !-I-oxopropan-2 - s i acetaic

Prepared as in. Example 274a from i.«<^«(2~cy^ft~3~nitropheao35;y)he?iyIiaiiimo)«2« nietfeyl- 1 «oxopsojjan-2-yi acetate (Example 274b) hi 94.4% yield. MS 362 (MfE)

OaiEUklZIb- 1 - {6-( 2 -cyano-3-nilrophcnoxy tb.exy iami no}-2-methy I-1 -oxopropan-2-y I acetate

To a so! udon of ten*butyl 6-{2wyano-3-nitrophenoxy}hexy1carbamatc (553 pmol, 121 mg; (Example 277c) in dtxounc (2 ml.) was added con. HCI (1 mL), After 15 minutes, die solution wars concentrated in-vacuo and dried on high vacuum. The crude EfO salt was suspended in. DCM (dry, ICfarL) and treated with pyridine (2.464 mmol, 2,15 pL) and I-ehforo-2--mcdtyM>oxoprQpan-2--yi acefetic (1.332 mmol, 193 μΐ.). The reaches mixture was refluxed under a nitrogen atmosphere until, clear (6 h). then cooled to room temperature: aud the volatiles removed in vacuo. The residue was purified on. silica gel. (40% to 100% EtCMc in hexanes) to give the product (117 mg, 90%) as a light yellow heavy oil. MS 392 (MB '), hxamoie 27?c: terEbutyl 6-C2~cyano-3--nitrop'hqnoxy)fiuxylbarfi4t03te'

Prepared as in Example 215c from tert-butyl h-liydroxyltexylcarbamafe in 53.8% yield as light yellow wdid. MS 364 {MB:).

Example 278: Ei6d4“antldO“2/»dioxO“iBB>eaz«le|il,2/i]ihiaiiazin“S~yloxy)liexyi)uren

A solution of 1 -(6-{4-amino-2,2-di0xd-.! H-benzo[c}(i ,2,6jthiadiazm-5-yloxy)hcxy:l)'3*(4-mcthoxybeozyl)urea (122 pmoh 58 mg) (Example 279) In DCM (2,5 mL) was treated with ΤΡΛ (2.5 nri,s. The reaction mixture was stirred at room temperature for 4 li<»tuv then the volatiles were removed under a stream of nitrogen. The oily residue wu'· triturated null ether, the precipitate collected, washed with ether, then dissolved in. Me-OII and evaporated to glares the desired product (44 nig.100% yield). H NMR (400 MHz. DM SO-/.) $ 1,364 {in, 6B), I 8? 2 ipeniet,./- 7 Hz, 214), 24)-43 <br t. 2H), 4,154 <d 7“ 7 Hz, 2H}. 4.13: if../- ? Hz, 214), 5,749 (br, s. 2H.i, 5,89-1 (br s, 1 Bj„ o 60? id. J -== <5 Hz. Hi), 0..752 (d, J === X Hz. 1H). 7,456 it. J-8 Hz, IH), 7.524 {hr. s, jH{, 8.351 (br, s, 111». lO.sus is, ! Hi. MS 356 (MHf).

Example 279; l~(6~C4~aanno"2,2~diosO”ll:I~beHao|c| (l^hlihtadiaaa-S-yloxy^xy!^^ me:t:hoxyhen^i)urea

To a suspend on of 6~(4~iimi η o 2,2 d ioxo·· 1 H.-benzo|c]f. 1 ,2,6]tliiadiaidn-' 5 -γΐ··>χν>hc&amp;an»l-amitnthn chloride (166 ftmoi, 52 mg) (Example 281)) in dry DCM (6 mL) was successively added EoN (332 umol, 46 μΕ) and H:isocy»natomethyl)>4>’.methoxybenzene (153 pmoh 26 (tt). The reaction was stirred for 48 hours at momternperature then; concentrated in vacuo. The residue was washed with water, dried, then purified on sifea gel (20% to 100%-EtOAein hexanes) to give,rite desired product (64 mg, 81,024 yield), SH NMR (400 .MHz, DMSO-rri) Al,296 (m, 2H), 1.371 (up 4H),: 1,791 (peMet, J ------8 Hz, 2H), 2.980 (¾,/- 6 Hz, 2H), 3,695 (s, 3H), 4.080 (d.J 6 Hz, 20}, 4.131 (i,./ 6 Hz, 2B), 5.836 (hr. t,/- 5 Hz.. 114), 6,141 (br. t,./=== 6 Hz, 1H), 6.585 (d,J- 8 Hz, IB), 6.727 id,,/ 8 Hz. ill), 6,840 (ύ,.Ι 9 Hz, 2H), 7,137 (d, J----- 9 Hz, 214.}, 7.433 (1,,/-814¾.. Ill), 7 803 (hr. s, IH), 8.32! (hr: a. IB), 10.926 is. IH), MS 476 ehlnri.de

To a solution of tert-butyl (ι6{4-8ΜΪ«ο-2,2^οχ<ΕΐB-tatzo[c){'I,2,6}thiadiazin-5« y!oxy)hexylcarbam«te (118 mg, 286 nmol) (Example 281) iudiexaae (2 ml,) \*as added con, HCi (I rnL) and the solution aimed at room temperature for 15 minutes. The solvents were removed in vacuo and the residue triturated with hot ethanol. After cooling to room temperature, the precipitated was collected, washed with hot ethanol, and dried in vacuo* to give the desired product 56 mg (619%) as an oIT-white powder. lH NMR (400 MHz. DMSO-J,) p ] .367 (nr. 4H), 1.529 tpentet,./-7 Hz, 2H). 1.795 (pca^t,J- 7 Hz, 2H), 2.74.1 (br m, 2H), 4.144 it,./ - 7 Hz, 2H!. 6.596 (d,,/- 8 Ex, IE), 6.733 (d.,/ - 8 Hz, IH), 7,440 (f,,/- 8 Ex, 1If), 7.725 (k. a, 3H). 7.795 (br. s, IE). 8.350 (k. s, 1 Hi. 10.954 (s. 1 H>. MS 30 (Mbf),

Example 28Π iert-buty 1 (m4-amiao-2,2~d»Gx«‘*lHdbe»zojc)( 1,2,bfihkdiazIu-S-y Iftxy tltesy tear hamate

Prepared as in Example 274 from tert-tetyl d-fB-amirso-S-cyanophenoxy)Hexylcarbamate (Example 281a) and siilfemoyl chloridb in 39,5% yield, Ή NMR (400 MHz, DMSO~k) <51.274 (vn. 2H), 1.339 (s, 9H). 1.361 (m, 4H). 1.779 (peniet,/- 7 Hz. 2H), 2.878 (q,,/ === 6 Hz, 2E), 4. S 22 (t. ./=== 0 Hz. 2H), 6.580 id, J - 8 Hz, IH), 6.722 (4 ,/- 8 Hz, iH), 0.75 (k (,,/-6 Hz, IE), 7.428 (t, </ - 8 Ex, IT!), 7,798 (hr, x, 119)18,323 (br, s, lH>, 10.921 (s, IE). MS413CMH1.

Example 28 la: tert-butyl 6-(3-aminos2”Cyanophenoxy)hexylcafbamnte

Prepared as in Example 274a from-tert-butyl 6~(2~cyano-3-nirrophcaoxv/HexvIcarbamate (example 277c} in quantitative yield. MS 334 (Mid ),

Example 283 j 5-(2-( IR-py rrcrU-ylJelhoxy)-! H-bernm) c) 11,2,6) tMadlazlu-4-ami ue-3,2-dioxidc

Prepared as in Example 2~<1 front 2-ί 2-( \ H-pyrrol- i -y|)eihoxy}-6« antmobenizontiri!e {Example 282a) and suifnnot 1 chloride in 66.6%yiehJ. ’ll NMR (400 Mil?, DMSO-,4) #43*2 (rn, 4H), 5.992 it,/ - 2 H/„ 211). 6.595 id. J-8 Hz, ilh, 6.692 id,,/ - 8 Hz, 1H). 6.8160../= 2 1-17.21-1),7.428((,./ = 8 Hz, IH}. 7.482 (br. s, : H). 8.2« {br. :-,. ΗΠ, 10.930 (S, 1 H). MS 30? (MH'),

Example 283a: 2-(2-11 l-i-pvn-ol4-yi)e0ioxy)~;6-ammobenzomtrile

Prepared as in Example 274a from 2-(2-(1 H-pyrrol-l~yi)eihoxy)-6-mrrobenzonii.rile (Example 282b) in 85.2% yield, MS 228 (MH ).

Example 282¾-. 2-(2-(.1 H~ pyr.ro I-1.-yl jefchoxy)-6-nitrobenzorHfrife

Prepared as in. Example 1(-60 from 2-(1 li-pyrrol-l -yi)e(ljano) and 2,6-diaiirebenzoaiiri!e, in 42.5%yield MS 258 (ΜΗ-1

Example 283:5-(2-CIH~pyraiol~l~y!)eifeoxy)~lH~bettxo|el|ti2,#|thladiaxm~4-am!ne~2,2-

Prepared. as in Example 274 front 2K-M-lHi'P>ira2:ol4-yl)ethox>’;)-'6-' anboobertzoniinle (Example, 283a) and sulfanloyl chloride in 54.5% yield. 'lH blMR (400 MHz, DMSO-mO S4.406 (t. J 5 Hz. 2H). 4.630 (t../ - 5 Hz, 2H). 6.266 (t,/- 2 Hz, 1 E% 6.S93 (d, J - 8 Hz. 1 Hh 6,689 (d. /- 8 Bt. Ili), 7.445 (br s. 1H), 7.425 it. J - 8 Hz, !H), 7:805 (d,,/- 2 Hz, 1H). 8.224 (br. s, 1 Η). 8.301 (br. s„ I Η), 10.904 (s. J H). .VIS 30s (\#Γ|.

Example 263a: 2-(2-( 1 H-pvrazol-1 -yl)fcthoxy)-6»ammolx3)^>mt.nle

Prepared as: in Example 274a from. 2-(2-(1 H- pyrazol -1.-yl)eih£>xy)~6~ ndrobonzomtrikt (Example 283b) in 46.2% yield. MS 229 (MB ).

Example 2S3b~ 2-(3-( 1H- nyrazol -.1 -y Delhi>\ γ)-<«··ηItrobenZobitt-de

Prepared as· in Example 215c from 2-: iH-pyrazol-l -yflethanol and 2,6-dinitrobenzonifri Ic in 69.2% vidd. MS 259 <MH‘).

Example 284:5-(2*(3,5-dl«.iethyi-:1JI~|}yra*»i«I -y!}eIho xy)- 114-irenm|ej 11,2,6j thiadiaviE-4~ 3s« i a e-2,2-d in x i d e

Prepared as in Example 21A from 2-t 2-{3,>dirneths I-1 H-pyrazel.-i-yl)ethoxy M>-aminohenzonitrile (Example 284a) and sulfarnoyl chloride in 18.2'%· yield. fHNMR {400 MHz. DMS<>··*/*) ^2.066 {s, 3H). 2.215 is, 3H). 4.3 12 ii. J -- 4 Hz. 2H), 4.39/ (t,./- 4 Hz. 2H>. 5,801 (s IHi. />584 (d,.’::: 8 Hz, 1 H). (>./>45 id, ,./ 4 Hz. iHi, ? 4 18 u,./ ::: 8 Hz. 1H). .\..%5 {hr. s, 1.H), 8.677 (br. s. I Hi, 10,885 is. ill). MS 336 CMΙΓ).

Example 284a: 2-(2-(3,5-dintethyl* 1H-pyrazoI-1 -yOetfeqxy^d-^inobenzamtnle

Prepared as in Example 2?4a from 2-{ 2-(3,5-dimethyl-1 B~ pyrazol -l-y!)etboxy)~ O-olirohenzhnltriie {example 284b) in 69.3% yield. MS 257 (Mil ).

Example 284b: 2-(2-(3,5-41:530(654-1 H- pvrazol -i.-ylkxla>xy )-<)->illmhenzoMlnie

Prepared as h; Example 215o from 2-(3.$-riimeth\ 1-1 H-pYinzo!-l-yI)ethtmol and 2,6-iImi(robenzpriidrij:0 in. 90,73¾ yield, MS 287 (MM' ). EXPERIMENT 4: Biological Assay

An HEK29.1 eel! line dersvarive (Chandrushekar -M. ul. Ceii 100. 703-711,2000) winch stably expresses Gal5 and hTi R2.1ΠΊ R3 {Li rt a!,. Pros: Natl Arm; Sc i USA 99, 4692-4696, 2002) (see also, International PebiieaiiomNo, WG 03/001376) was used in biological assays in association with identifying compounds with sweet taste enhancing properties, Compounds were initially selected based on their activity on the :hTlR2/hlHIl3-HEE293~Ciri:i S cell line Li et a/., supra. Activity was determined using art automated: lluommetrie imaging assay on a FL.j.PR instrument (Fltioromctric Intensity Plats: Reader. Molecular Devices, Sunnyvale. CA) (designated FLIER assay) ('ells from onb clone .(designated clone 3-0) were seeded into 364-well plates (at apnn.'ximatcK 50,000 cells pet web) in a medium containing DM EM Low Glucose {inviirogcn, Carlsbad, CA), 10% dialyzed feud bovine serum { hrvftrogen, Carlsbad, CA), 100 Uoits/uii Beuleililn O, arid 100 ug/mi Streptomycin {Ιην-trogcn, Carlsbad, CA) (Li c* a!., 2002) {see also, International Publication No, WO 03/001876). S-9 cells were grown for'24 hours at 37 ®C, S-9 cells were then loaded with the calcs um dye Fluo-3AM (Molecular Probes, Eugene, OR). 4 μΜ in a phosphate buffered saline (D-PBS) tlnvitrcaen. Carlsbad, CA). for I hour at room temperature. After replacement with 25 μΙ D-PBS, sUmulation was performed In the FLIPR msn ument and at room temperature by the addition of 25 pi D-PBS supplemented with compounds at concentrations corresponding to three times the desired final level (Stimulation I),

Ceils were incubated with the compounds for 7.5 mirimes and then another stimulation was pedonrted in the FLIPR instrument by the addition of 25 pi of D-PBS supplemented with a sub-optimal concentration of sweeteners (producing about 5% to 20% receptor activity) {Stimulation 2).

Alternatively after replacement with 25 μΙ D-PBS per well, stimulation was performed in the FLIPR instrument at room temperature by addition of 25 μΐ D-PBS supplemented with different stimuli

Typical, sweeteners used include, but are not limited to D-Ohseose, D-Fruetose, Sucralose, Aspartame and Sue-rose. Receptor activity was then quantified by determining the maximal fluorescence increases (Using a 480 nm excitation and 533 nm emission) after normalization to basal fluorescence intensity measured before sfimnlafton. Compounds producing an increase In §weete»^-mcdiatcd receptor-activity were chosen fer further characterization and quanfiftnailoa of potential enhancement properties.

In this follow assay, a fixed concentration of oomponnds was added in duplicates to 10 consecutive columns (20 wells total) during stimulation 1, Typical compound concentrations tested were 300 μ.Μ, 100 μΜ, 50 tiM, 30 μΜ, 10 μ Μ, 3 μΜ and I uMf (5.3 μΜ, 0J μΜ, or 0.03 μΜ, After the 7,5 minute incubation period, increasing coocentrafions of sweetener (to generate a dose-response curve) was presented, in lbs same wells, in duplicates, during stimulation 2, The relative efficacy' of compounds at enhancing the receptor was determined by the calculating the magnitude of a shit) In the E€<o tor the sweetener. Enhancement was defined as a ratio (ECjoR) corresponding to the ECV> of sweeteners. determined in Use ab^cuco of the tes* compound. divided by the ! C-, of the sv\ ectoucr. •deterautted in the presence of the test compound. In some embodiments, compounds ha\c$p ECsoB· between, about 1 '(e.g., >1) and: about 1000. In other embodiments, compounds have an EC50R between about 1.25 and about 500. hi still other embodiments, compounds' have -an BCfoR between about 1.50 and about 100. la yet other embodiments, compounds have an ECaoR between about 1 fo,y„ >1} and about 50,

In still oilier embodiment, compounds at about 50 uM kne an 1:T-,.R between about 1 (mg,, I) and about i 000, between about 1,25 and about 500, between about t .50 and about 100, or between about 1 (e.g,. >1} and about 30, Assay results lot compmmds.are illustrated in Table A below.

In one illustrative example, the prenneobated sucralose EQ;.;R at 50 uM for one group of specific compounds of the present invention generally ranges from 0,73 to 5.20, while the co-stimulation suemiosc ECjoR at 50 μ\1 for the same group of compounds generally ranges from Of"? i<> 4.4ό, in number illustnuive example, the eo-stimulaten sucrose hCh.R at 50 μΜ for one group of specific compounds of the present invention generally ranges from 1.30 to 4 35, the eo wtimnlation sucralose BCsoR at 50 μΜ for the same group of compounds generally ranges from 1,73 to 24,09, and foe co-stimulation fructose EC&amp;R at 50 μΜ for the same group of compounds generally ranges from 0.81 to 4.40, In another illustratlve example, the eo~ stiniulated sucrose EChyR. at. 50 μΜ for one group-of specific' compounds of the present, invention generally ranges from 1.,05 to 2,44, the co-stimulation Sucralose ECfoR at 50 μΜ for the same group of compounds generally ranges from 1,57 to 11,63, and the co-stimulation ffuetose ECb# at 50 μΜ for the same group of compounds generally ranges from 6,99 to 1,78, hr another iilRStratiye example, the co-sbmulated sucrose ECjsR at 50 μΜ for one group of sped he compounds of the present invention generally ranges from 1,?? to 116:56, the Cv-fonmlatfon sucralose ECfoJR. at 50 μ.Μ for the same group of compounds generally ranges from 1.,48 to 157.63. and the co-stimulation fructose ECfoR at 50 u.M for the same group of compounds generally ranges from 0,68 to 9,56, In another illustrati ve example,: the eo-sdmnlated sucrose ECfoR. at 59 μΜ for one group of speefOe compounds of the present invention generally ranges Horn 0.88 to 86,66, the eo-stiniukdon sucralose EEfoR. at 50 μΜ for the same group of compounds generally ranges from 1,07 to 101.1.5, and the co-stimulation, fructose BChnR at 50 μΜ for the same group of compounds generally ranges from. 0.71 to 7,09, In another illustrati ve example, the co-stimulated sucrose EiCjeR at 50 μΜ for one group of specific compounds of the present invention generally ranges from 1.39 to 17.17, the co-stimulation sucralose EC?pR at 50 g.M for the saute group of ..compound's generally ranges from 3.80 to 49,89, and the co-stimuiaiion fructose EC%R at 50 uM tor the same group of compounds generally ranges from 0.93 to (>.07. in another illustrative example, the co-stimulated sucrose BC%R at 50 μΜ for one-group of specific compounds of the present invention generally ranges from 1.30 to 56,27, the co-stimulation sucralose EC*jR at 50 uM for the same group of compounds generally ranges from !.2i> to 304.98. and the co-stimulation fructose EOy>R at 50 μΜ for the same group of compounds generally ranges from 1.14 to 8.37. EXPERIMENT Si Sweet Flavor and Sweet Flavor E®ha«e«siie»i Measurement Using Human Panelists Conduct! sg a Sealing Test

Test samples containing experimental compounds were compared ro a dose-response curve for perceived .sweetness intensity of sweeteners fxucb as, for example, sucralose, sucrose, fructose and other aweetencts) eo.nce»trattom to determine equivalent sweetness intensity. A group of eight or more panelists tasted solutions including sweeteners at various concentrations, as well as the experimental coarpo tied bot h with and without added sweetener. irimelists then rated, sweetness intensity of all samples on a structured horizontal line Seale, anchored from 0 to 15, where 0 equals no sweetness and 15 equals equivalent sweetness to a 1 S% sucrose sample, Scores for sweetness intensity were averaged across panelists. Then using the average scores and/or equation of the line her the sweetener dose-response curve, equivalent sweetness concentrations were determined far·the· samples' containing, experimental, compounds.

Subjects had been previously familiarized with the key attribute taste and were trained to use the 0 to 15 point. line scale,. Subjects refrained from eating or drinking (except water) tor at least 1 hour prior to the test. Subjects ate a cracker and rinsed with water several, times to clean the month.

Sweetener solutions are provided at a wide range of concentrations such as 100 ppm, 200 ppm, 300 ppro, 400 ppm, and 500 ppm for sucralose, or between 0% and 12% for .sucrose or fructose, in order to create a dose-response curve. Samples containing experimental compound Άcrc prepared bods alone and m a. 100 ppm sucralose solution ora 6% sucrose or fructose solution, AIL samples were made up in low-sodium buffer pH 7,1. In order, to. aid dispersion, solutions can be made up in 0-1% etbano!,

The solutions· were'dispensed in 20 mi volumes into .1 ox. sample eups and served to the subjects at room temperature. All samples were presented in randomized counterbalanced order to reduce response Mas, Further, two sessions of testing may be used to cheek panel precision*

Subjects tasted each sample individually and rare sweetness intensity on the line scale prior to tasting the next sample. All samples were expectorated. Subjects may retaste'.the. samples but can only use the volume of sample given. Subjects must-rinse with water between samples. Eating ait unsalted cracker between samples may be: required depending onthe samples lasted.

The scores tor each sample were averaged across subjects and standard error was calculated- The dose-response curve was-plotted graphically, and. this may be used to ensure the. paueHs rating accurately; i.e„ increasing the concentration of sucralose should correspond, to increased average scores for sweetness, A 2-way AMOY A (factors being samples and panelists) and multiple comparison tests (such as TukeyM Honestly Significant Difference test) can be used to determine differences among samples and/or panelists. A 3-way AMOVA, with, sessions: as the third factor, can he used to determine if there Is any difference·in the ratings- between sessions.

The compounds tested in this Experiment, namely , compounds Cl to-.02-1 * are representative compounds of the present invention, including compounds of structural Formula (1) and. its subgenei k; formulas.

The results of human taste tests with a compound: Q are-found -below, Table 1 indieai.es that 10ft μΥ! compound C! in TOO ppm. sucralose has sweetness equivalent to 200 ppm sucralose- Table 1 indicates that 100 μ.Μ compound Cl. alone has. no sweetness, and therefore can he defined as a .true sweet enhancer ,

Table I. Average sweetness scores for various sucralose samples, including 100 ppm sucralose with j 00 μ.Μ compound Cl. n ::: 32 (lo Panelists x 2 replicates). Tukoyks value ::: 1.409 (a ::: 0:.051, ‘

^ ‘

Table 2, Average sweetness scores fo? 100 μΜ compound Cl and low sodium bailer, ή1 5 (15 Panelists x. 1 repj. Tukey’s value ::: 0,1(o

::: 0.05).

The results of human· taste tests with compound €2 are found below.. Table 3 indicates that 100 μΜ compound in 100 ppm sucralose has sweetness equivalent to about 600 ppm sucralose. Table 4 shows: a dose response curve of compound €2 with 100 ppm sucralose which shows ?hut the sweetness of sucralose is significantly enhanced by addition of increasing amounts of compound €2. Table 5 indicates that 100 μΜ compound CZ clone has little or no sweetness, and therefore can be defined as a true sweet enhancer, 'Table 3. Average so outness scores, n ~ 12 (12 Panelists x 1 rep). Tukey’s value 2.449 (a ~ 0 05 K 2.209: (a :::: 0.1.01.

Tabk· 4, Average sweetness scores, n ::: 26 (:4 Panelists x I rep; 12 panelists x 1 reps T«key’s value ::: I .5*4 ία ::: 0 05s, 1.452 ui. O.H'SS.

Tabic Average sweetness scorer·;, n ::: 12(12 Panelists x. 1 rep). Tuhev’s value ::: 0.809 (o.:::: Ο.ΟόΜΙ.ΤΧΜα - 020)....................................................................................................................'...........................................

The results of human taste rests with compound €3 are found below Table 0 Indicates that :00 μΜ compound sir 100 ppm sucralose has sweetness equivalent to about between 200 and '<00 ppm sueralo.se. Table 7 indicates that. 100 uM compound CXI alone has no sweetness, and theses'; e can be defined .as a true sweet enhancer.

Table 6. Average sweetness scores, o ~ 13 11 3 Panelists x 1 rep). 1'nkey's value - 2 333 (a -

Table 7, Average sweetness scores, n ::: 13 113 Panelists x I rep). Tukcy's value ::: {19()6 (« - 0.051 0.8 II («-0,10).

......' ...........

The results of husitan taste tests with, a eompo.u«d.€4 are Toand. below; Table: 8 indicates that 100 μΜ compoimd C4 in 6% sucrose has sweetness equivalent to 854 suerose. Table '1 indicates that 100 μΜ compound C4 alone has no sweetness, and therefore can he cHined as a true sweet enhancer.

Table 8. Average sweetness scores for various sucrose samples, including 6% sue/ose with 100 μΜ compound €4, n ::: 28 (14 Panelists x 2 replicates). Takes- "s value ::: 1.001 (a::: 0;05), 0.97b (a ::: 0,10).

Table 9. Avcraue sweetness scores, n ::: 14 {14 Panelists >; I rep). T«key's value ::: <0.876 ία ::: 0.05K 0./84 iu- 0.i0s. '

The results' of human taste tests with a compound .C5 are found below. Table 10 indicates that 100 uM eornpoitod €S in 6% sucrose has sweetness ©ttuivalent to 0% sucrose. Table 11 indicates that HK> μΜ compound CiS alone has no sweetness, and therefore can he defined as a true sweet enhancer.

Tabic 10. Average Sweetness. u ::: 24 (12 Panelists x2 reph TuiaVs value-::: 0.832 (¾ ::: 0.03), 0.744 (e - 0.10)7.................................................................................................'..................'.....................................................

Tabic 11. Average Sweetam, 14 (14 Panelists x 1 rep), Tokeyh value ::: (P98I 0.05), 0.877 (a ::: 0. 10».

The results of human: taste tests whh a compound €6 are found below. Table 12 indicates that 100 μΜ 'compound CO In 63» sucrose has sweetness equivalent to abont 10% sucrose, Table:..! 3 indicates that 100 nM. compound CO atone 1ms no sweetness, and:therefore can. he defined as· a. true sweet enhancer.

Table 12. Average Sweetness, n ::: 28 {1.4 Panelists x .2 rep), Tukcy's value ::: 0.818 (a ::: 0,05), 0.732 (a 0.10).' ' '

Table 13. Average Sweetness, n ::: H (14 Panelists x 1 reps. Tukcv’s value ::: 1.238 (a ::: 0.05). .1.10? («.-0.10)7

" " " ΊΙη: results of human taste tests wnh a compound C7 are found below, iablc 14 indicates that 50 μ.M compound C7 in 0% sucrose has sveeOsoss eqiusaient to about T\> sucrose.

Table 14. Average Sweetness, n 26.(O BandiMs x 2 rep). Tukey's value:::: 0.762 (a::: 0.05), _0.O82 {j;L;;; 0J 0).’....................................^........................................................_.................'................^............................................'

The results of human taste tests with a compound €8 are found below. Table 15 Indicates that TOO μΜ compound CM in 6% suerbse has sweetness opoivdebtio about 8% sucrose. Table 1.6 indicates that 100 μΜ compound O alone has no sweetness, and dwreforc can be defined as a true sweet: enhancer.

Table IS. .Average Sweetness, n - 28 (14 Panelists x 2 rep). Tukey's vslue ~ 0.859 (a ~ 0.05), ().768 (a :: 0.10).

Table Id. Λ\orajic Sweetness, a ::: 14 {14 Panelists x 1 rep). Tukev's value:::: 1.029 {a =- 0.05), 0.92! {« - OJO?'

'

The results of human taste tests with a expound C9 are found. below. Table 1? indicates that from about 40 to about 55 μ.Μ compound £9 in ! 00 ppm. sueralose has sweetness equivalent to about 400 ppm sue.raiose. Table .15 indicates that from about 40 to about 55 μΜ eontpOund. €9 alone has no sweetness, and therefore can be defined as a ime sweet enhancer.

Tabic 17. Average Sweetness. π ::: 26 (14 Panellcds x2 reph Tehey’s value-::: 1.304 (¾ ::: 0.05), 1.1/8 (a - 0.10)7 ...... ' '

Table 18. Aserago Swcomcss, n ::: 22 (11 Panelists x 2 rep). lukey's value ::: 0Λ93 (a ::: 0.05), 0.6.19 la ::: 0.10?.

The-ileSt#s'of:b«n5&amp;«tete'id5ts'wiTb'a eompound ClO are found helow, "Fable 19 indieat.es that 25 μΜ in 6% sucrose has sweetness equivalent to. about 8'% sucrose,

Table 15). Average Sweetness, a ~ 1)6 (14 Panelists >: 2 rep). T’ukeys value ~ 0.747’ (et·™ 0.05), 0.666 {a ::: 0.1 ()}

fable 20 indicates that 25 uM of compounds CIO alone· ha? no sweetness, and therefore can be defined as hue sweet enhancers.

Table 21b Average Sweetness, n :::: 14 (.14 Panelists x 1 .rep), Tnfcey’s value ::: 0,957(a::: 0.05), O.Sobta Ο.ΙΟίΓ

The results of human taste tests svith a compound Cll arc found below. Table 21 indicates that 50 μ.Μ compound CVt in 0% sucrose has sw eetness equivalent to about 8% sucrose.

Table,2.1, Average Sweetness,« ™ 1.5 O S Panelists x .1.: rep). TukeyS value0.905 (a := 0.05), 0..S S 0 (n - 0.10).

The results of human, taste: tests with a compound €12 are found, below. Table 22 indicates that 50 μΜ compound €12 in 0% sucrose has sweetness eguivaloMfo about 9% -10% sucrose.

Tabic 22. Average Sweetness. n ::: 26 (13 Panelists x 2 rep l. TulaVs value ::: 0.492 (o ::: 0.05), 0.440 (o - 0.10?’’

' '

The results of human taste tests with a eofttpouMOS are found below. Table 23 indicates that 25 u.M compound 03 in 6% sucrose has sweetness equivalent to about %% sucrose.

Tabic 23. Average Sweetness, n::: 26 (D Panelists x 2 rep). Tekey's value:::: 0.636 (a::: ().05), 0.50 {ft,::: 0, 10).

The results of human, taste tests with a compound € 14 are found below, Table 24 Indiesies that 50 μΜ compound 04 hr 6% sucrose has sweetness equivalent to about &amp;%~9% sucrose,

Tabic 24. Average Sweetness. u ::: 26 (12 Panelists x i rep; 14 Panelists \ 1 rep}. TukcvS value - 0./62 6; - 0.05).0.701 mOUOt..........................................................................................................................'

The results of human taste tests with a compound OS are found below. Table 25 indicates that 50 μ.Μ compound 05 in 6% sucrose has sweetness equivalent to about 924-10% sucrose.

Table 25. Average Sweetness, u ::: 25 (.1.1 Panelists x 1 rep; !4 Panelistsx 1 rep). Tukey's value :::: -0.688 _(«::: 1).051. 0,61 7 ia ::: 0.1 Or

The results of human taste tests with eontpound 06 are found below. Table 26 indigates that 25 μΜ conrpound 06 in u% sucrose has sweetness equivalent to about 1024-1 2°<> sucrose. Table 27 shows a dose response curve of compound 06 with. 6% sucrose which shows) that fire sweetness of suerose is significantly enhanced by addi tion of increasing amounts' of compound 06. Table 28 indicates that 1-4.1.1 μ.Μ compound 0,6 in. SO pprn: sueralpse has sweetness equivalent to -about 200 ppni-300 ppm sneralose, Table 29 indicates that 25 uM 'Compound 06 hi 6% fructose has sweetness equivalent between 624 and: 8% fructose. Table 29 indicates that 25 μ. M compound € 16 alone has liOle or no sweeWsess, arid Iherefore can be defined as a true swoes enhancer.

Table 26, Average Sweetness, n :::: 24 (12 Panelists x 2 .rep), Tukey’s value ::: 1.079 (a:::: 0.05), 0,974 ία ::: 0,10),

Table 27. Average Sweetness, n ~ 30 (.15 Panelists x 2 rep). TafceyS value ~ 1,133 (a::: 0,05), 1.043 (a - O.iO)...................................................................................................................................................................

Tabic 2¾. Average Sweetness. u ::: 28 (14 Panelists x 2 rep). Tukcy‘s value-::: 0.%9 (¾ ::: 0.05), 0:881 (a-0,10). .........

Table 20. Average Sweetness, n !!! 26 (13 Panelists x 2 rep). Tukey's value::: 0."14 (ft - 0,05), 0.639 (ft 0.10)

Table 30, Average Sweetness, a - 80t15 Panelists x 2 rep). TukevV value ::: 0.585 (a - 08)5), 0,479 (a ~ 0.10)., ^ ^ .....

............ ^

The results of huptan taste tests with cornpoumi O 7 are found'below. Table 31 indicates that 8 μΜ compound CI7 in sucrose lias sweetness equivalent to ahoht-0%~lQ%. sucrose. Tabic 32 indicates that X μΜ compound €.1? alone has little or no sweetness., arid therefore can he defined as n true sweet enhancer.

Table 31. Average Sweetness, n ::: 38 (14 Panelists x 3 rcpi. Tukey's value :: 0.657 (o.=== 0.05), 0.588 (a=== 0.10).

Table 32. Average Sweetness, n==== 28' (14 Panelists x 2 rep), Tukey’s value==== (),407 (a -= 0,05), 0.425 ta ::: 0.10.?.

EXPKRIMEN Γ 6: Sweet Flavor asset Sweet Flavor Enhancement Measurement Using Butman Panelists Conducting a Paired Comparison t est

Test samples containing experimental eompoarsis are presented in pairs to the panelist and they arc asked to determine w hich of the sample is sweeter. A group of 1(H6 or more panelists participated in each test. Subiects refrained' from eating·or drinking (except water) for at least 1 hour prior to the test Subjects rinsed with, water several times to clean the mouth.

All samples are prepared with ethanol to ensure dispersion of the compound in solution. This includes samples without compound; ali solutions are balanced for 0.1% ethanol.

Samples are also prepared with low sodium buffer (pH 7, I) in place of water. Buffer contains (1952 g of KCl, 5,444 g of Na;HPCp. and (1952 g of HATCH in 40 L of DIUF svau-r. Sample volumes are usually 20 ml.

In one paired .comparison test, the panelist is presented with two·-different samples, and asked to identify the son-piewhich is sweeter. The samples within a paired comparison test are presented in a. randomized, counterbalanced order, Panelists have up to a 1 minute: delay between taste: tests to clear the mouth of any tastes.

Binomial probability tables are used to determine the prbb&amp;bslify of the correct number of responses occurring: for each, rest at alpha -0.05 ,

The results of human taste tests with a compound Cl8 ore found· below, "fable 35 indicates that panelists perceived 6% Frueiose + 1:9# μΜ CIS as being significantly sweeter than a solution, of 6% Fructose (p<0,05)

Table 33. Sample selected as mom sweet by panelists: n ~ 36 (13 panelists x 2 reps).

The results of human taste tests with a compound Of are found belo w. Table 34 Indicates that panelists perceived 6% Fructose -r 100 μ,Μ €19 as being significantly sweeter than a 'solution of 6% .fructose· (p<0.0S)

Table 34. Sample selected as more sweet by panelists: π “24 (12 panelists x 2 rep),

The'i^uJtsbf:hun5U«iaste4dyts'wtt1S-a' compound 06 are found·below. "Fable 34 Indicates that panelists perceived. 6% Fructose < 1:00 μΜ CM as being sigBlfieautly sweeter than a solution o£ b% Fructose (f<0,05). Table 36 indicates that 100 μΜ ooiopount! €20 alone has little or no sweetness on its own tilperimeot 5).

Table 35. Sample selected as more sweet by panelists: n ::: ] 0 (19 panelists x 1 repp

Tabic 36. Average Sweetness, π ::: 13 (15 Panelists x i rep). Tt&amp;ey's Value ::: 0.753 0.05), 0.674 (o ο.κηΓ.................................................................................................'..................'.......................................

The results of human taste rests with a compound C21 arc found below. Table 3? indicates that panelists perceived 0% Fructose -t 25 μΜ C’2 l as being significantly sweeter· than a solution of (>% Fructose {p<0.05>. Table 3t< indicates * bat panelists perceived 6% Fructose 25 μΜ C2.t has the same sweetness intensity than a solution of 7% Fructose.

Table37. Sample selected as more sweet by panelists: n ::: 25 (25 panelists.:*: 1 rep):.

Table 351. Sample selected as more sweet by panelists; si::: 25 i25 panelists x I rep).

EXPERIMENT 7. Solubility Oetermin&amp;iron. of the Compounds of the. Present Iswention sttd Their ΐΚΊ Saits hi Propylene Oyeoi

The solubility of the present compounds and their MCI salts in propyleneglyeol was determined h ''-hake desk method'. Approximately 50 mg of the test oootpotmd wak weighed out and added to a 4-mL glass vial, and then 1 mi, of propylene glycol was -added to the vial. The vial was sonicated for 10 minutes and then shaken for 24 hrs on an orbital shaker set at 300 fpm. An aliquot of 200 μ.Ι, of fhe.-solution wa&amp;: transferred from the vial into a 1.5 mL centrifuge via! and centrifuged at. 12,500 rpm for 10 min. An aliquot of 50 μί- of the supernatant was diluted by 100 times with propylene glycol. Then 50 pL of this solution was further diluted 100 times with water and analyzed by liquid ehipmatogfaphy mass spectrometry (Cl8 column with, gradient elution with a How rate of-2.0mldnum 'water with 0.1% trifluotoacetie acid as mobile phase A and methanol with 0.1 % triOueraacetleacid as mobile phase B, mobile phase B. % rising from 5% to 95% in 0.6 min and then being held at. 95% for 1.4 min). The result of one exemplary solubility test is shown in Table A.

Table A, .Solubility of Compound C2 and .Its HQ Sal t

All publications and patent applications heroin arc incorporated by reference to· the same extent as if each individual publication· or patent application was specifically and individually indicated to he incoiponited by reference.

The foregoing detailed description has been given for dearness of understanding only and no unnecessary limitations should be understood therefrom as modifications will he obvious to those shilled in the art, ft Is not an admission that any of the information provided herein is prior art or relevant to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art.

Unless defined otherwise, all technical and scientific terms used herein'have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Embodiments of this invention are described herein, including rhe best, mode known to fire inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as 8|lpropfia.te, atid the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited· in the claims appended hereto ms permitted by applicable kw. Moreover, any combination of the. above^describvd eiem;mr.s in all pos-eble varianon\ thereof is encompassed by the iswentton unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims (165)

1. Wo claim: .1. A. method of screening for a candidate of a chetuosensory receptor ligand modifier comprising determining whether a lest entity is suitable to interact'a ids a chemoserw'tv receptor n\{ a first interacting. site within the Venus flytrap domain of the ehemosensciy receptor. •2. The method of claim I, wherein, the first interacting site of the Venus flytrap domain of the chemosensory receptor includes one-or more interacting residues of the Venus flytrap domain of the ehemosensory receptor,
2. 3, The method of claim 1. wherein the -first interacting site of the Venus flytrap domain of the ehemosensory receptor includes one or more interacting spaces of the Venus flytrap domain of the ehemosensory receptor,
3. 4, The method of claim L wherein the first interacting site of the Venus flytrap domain includes an interacting space identifiedbased on one or more interacting residues,
4. 5, The method of claim I .wherein the. first interacting site of the Venus riytrap domain of the ehemosensory receptor includes one or more interacting residues, which are identified based on mutagenesis analysis of the Venus flytrap domain, ft The method of claim I. wherein the. first interacting site of the Venus flytrap domain is identified based on computer modeling. X-ray crystallography, or a comMuafinii thereof. ?. The method of claim L wherein· .the first interacting site of the Venusfiytrap domain is ideutifled based:on. one or more known ehemosensory receptor ligands,
5. 8, The method of daini 1, wherein, the first interacting site of the Venus flytrap domain is identified based on one or more known ehemosensory receptor ligand modifiers.
6. 9, The method of claim 1. wherein the first interacting site of the Venus flytrap domain is identified based on a predetermined chemosensory receptor ligand.
7. 10, The .method .of claim I, wherein the first interacting site of the Venus flytrap domain. is predetermined,
8. 11, The method of claim 1, wherein the first interacting site of the Venus flytrap domain is in the Tf 1C Venus flytrap domain.
9. 12, The method of claim I, wherein the fn si interacting site of the Venus flytrap ..domain· is in the TIR2 Venus flytrap domain and Is idem!tied in the presence of ITRS Venus flytrap domain.
10. 13, The method of claim 1, wherein the determination is carried cm in s.dieo.
11. 14, A method of screening for a candidate of a chemosensory receptor ligand modifier comprising determining whether a rest entity is suitable to interact with a ehemosensory receptor wo a first interacting site within the Venus flytrap domain of the chemosensory receptor, wherein the first Interacting she is identified in light of a second interacting site identified based on the interaction between a chemosensory receptor ligand and the ch.emoseosory receptor. '15. Hie method, of claim 14, wherein the first and second interacting site are in: the T1R.2. Venus flytrap domain, 16> The method of claim 14, wherein the first and second interacting site are in the TI.R2 Venus flytrap domain and Identified in the presence of T.IR3 Venus flytrap domain,
12. 17. The method of claim I, wherein the first intemeting site Includes an interacting residue selected .from' the group consisting of aruino acid Nl 43, SI44, and. Oh7 of a human TI.R2 an d a: c ο n hi? \ ati ο n thereof 1The method of claim 1, wherein the first inietuedrig she includes an interfering residue selected from the group consisting of amino acid S40, S144, Si 65. YI03, Π i 42. and P27“ of a hitman T1R2 and. a .combination thereof.
13. 19, The method of claim 1, wherein the first interacting site includes an interacting te.Mduc selected from the group consisting of amino acid K.65, R383. D307, E302, and IX: 78 of a human'll R2 and a combination'thereof
14. 20, The method of claim 1, wherein the first interacting site includes an interacting residue selected from the group consisting -if amino acid 1167s PI 85, TI84, T326, 13302. Y384, AS05, 1325, IS06. R383, D307. E3R2. D278. 1279,167, Y66, V309, DI 42, SI05. $40, SSOS. T242, FI 03, Q328, and $16 8 of a human TIR2 and a combination thereof 2.1. The method of claim I.. wherein the first interacting site Includes un interacting :·.ό4οο selected front the group consisting of amino acid hi 143, S144,1167, 840, .$.144, S165. Y103, Dl42, P277, K65,.R383, D3Q7f B302, D278, Pi 85, TI84, T326, B302, V384,A305,1325, 1306. D307, E3§2,1279, Ιό", V66, ¥309,8303,. T242,F103, Q328, and 8168 of a human IIR2 und a combination thereof
15. 22. The method of claim 1,. wherein the .firsrinteracting site includes a group of interacting residues selected from the group consisting of I) ¥143. $144, and f 167 of a human TIR2, 2) S40,S144,8165, Y103, DI42, F2.77 or a.human ΠR2.3} K65,R383, D307, E302, and D278of a human TIR2.4) Ilf?, PI85, ΤΙ¥1; T326.1 402. Y38-1, A305.1325,1306, R383. D307, 0.382, 0278. 1279.167, Voo, Y309, 0142,$ 165, 840, $303, 1212, f 103, Q328, and $168 of a human TfR2, 5} 19143. $144,1147, $.p;f SI44, $165. Y103, DU2, 0277, K65, R383, D307.17302 P27S, PI85, TJ 84, T326, E302, ¥384, A305,1325,1306,17382,1279,167, V66, V309, S303, T242, Fi CB. Q32K, and S168 of a human T1R2, and 6} a combination' thereof 23 , "The method of claim 1, wherein, the first mtemPting site includes. an interacting residue selected fimtn. the group consisting of amino acid K65. D278,1,279, D307. R383 and V384 of a human T.1 R2 and a combination thereof and wherein :a test .· entity suitable to interact with the first interacting site of the chcmoscnsory receptor is indicative of a candidate of a cherooseosorv receptor ligand enhancer.
16. 24. The method of claim .1, wfeerem the first interacting site includes, an interacting residue selected from the group consisting of amino acid S40, SI44, Y 163. DI42, P277 of a human 11R2 and a combination tivteof wherein a test entity suitable to interact with the first interacting site of the chcmoscnsory receptor is indicative of a candidate of an enhancer for sucrose or sueralosc.
17. 25. The method of claim 1, wherein the test entity is a designed compound, structure.

    16. The method of claim L wherein the chemosensory receptor ligand is a sweet flavor entity selected front the group consisting of cyclaroie acid, mogrosiue. tngafose. maltose, galactose., mannose, sucrose, fructose., lactose, aspartame, aspartame derivatives, ncofamc. sacs'harin. sucralose, acesuliame K, glucose, crythritoL D-tryptophan, glycine, mauuitol, -sorbitol, maititoh lactitol, isomait, hydroganeted glucose syrup (HQS), hydrogenated starch hydrolyaaie (HSH), stevioside, cebaudioside A, sweet Stevakbased glycosides, albame, earrelame, guanidine-based sweeteners, tagatosc, xylitol, and high fructose com syrup.
18. 27. A method of screening For a: candidate of a cSseoioseosory receptor modifier comprising determining whether a test entity is suitable to Interact-with a chemosensory receptor vm an. interacting site within the Venus flytrap domain, of the ehentosensory receptor, wherein the interacting site includes an interacting residue selected from. the group .consisting of N143, SI 44,1167, S40, S144, Si65, Y103, DI42, F277, K65, R383, D307, E302, D178, J>}85. 1184, Γ326,1.:30.7, VA.s-i, A305,1325.. 1306. D307,13362,1.:79.. 167, V66,, V309, S303, T242, F103, Q328, and SI 68 of a human Tl.R2aad a combination thereof, wherein a test entity suitable ip interact with, the iotcraering site of the ehemosensory receptor is indicative ofa candidate of a chemosensory receptor modifier. 2$. The method of claim 27, wherein the interacting site includes an interacting residue selected front the group consisting of amino acid N145, S144, and II6“ of a human T1R2 and a 'combination thereoh
19. 29, The method of claim 27, wherein the interac ting site includes an interacting residue selected limn the: group consisting of amino addS40< S144, VI03. DI42, and P27? of a hnniati "Π R2 and a. combination thereof
20. 30, The method of claim 27, wherein the interacting site includes an interacting residue selected from the group consisting -d' II67, P1S5, TlH-k T326, E302, V3S4, Λ305,1325, 1300, R3S3, D307, E332, D27X. (279,167, Vtm, V300, 0142. S165, S40. S303, T242. f 103, Q328, and SI 68 of a Iranian T1R2 and a combination thereof. '31. The method of claim 27, wherein the interacting site is in the T1JR2 Venus flytrap domain,
21. 32. The method of claim 27,. wherein the interacting site is in the T1R2 Venus flytrap domain and. identified in the presence of Ϊ1R3. Venus flytrap domain.
22. 33. The method of claim 27, wherein the determination is carried out m silica,
23. 34. The method of claim 27, wherein the test entity is a: designed, eompoand structure..
24. 35. A eheniosensory receptor 1 igand modifier identified by the method: of claim i.
25. 36. A ehemosensory receptor modifier identified By the method of claim 27. 37. A. ehemosensory receptor ligand enhancer identified by the method of claim 1, and having.' structural Formula (1):

    or a tautomer, salt, solvate, and or ester thereof wherein: G forms a single bond. with, either D orB and a double bond with the other of D or E; •R- is hydrogen. alkyl, substituted alkyl, aryl, substituted aryl, arylaikyl, substituted arylaikyl, acyl, substituted acyl. heteroalkyl, substituted heietoalkyk heferoan j, substituted heisroaryi. heUtroaryialkyl.. substituted heteroarylalkyi, “CN».~NO.&amp; -OR*, -$<0)„Rk -nrV, -conr-V. -CO>R', -NR'CCER4, -NR’C0NR4R\ -NR'CSNR4R', -NR'C^N! I }NR!R\ -SGoNH'E k -NR*SO>Rk -NtfSO-.NR'Rk -ΒίΟΧχοΧ). --hObOR')(OR4 S or --foO.K R" Si OR4); R": is hydrogen, alkyl, substituted. alkyl, aryl, substituted aryl, arylaikyl, substituted arylaikyl. acyl, substituted acyl, heteroalkyl, substituted hetemalkyk beteroaryk substituted hoieroaryi, bederoaryialkyl, substituted beieroarylalkyi, -CN, ~N€fo -OR'k -Sfofo.Rh -NlfoR k -CONlGRk -C(). R ;, -NR6C().Rk -NR^CONR/Rk -NR/f'SNR' R\ -NR*C( NH)NR ?R :, -SifoNRVk ~NR' SONG’. -NRsSO:NR6IE, ~8{OR')(OR''}, -P{0)i0R''){0Ri'), or -P{0){R")(0Rv); or alternatively, R* ane R . together with the atoms to which they are bonded, form an aryl, substituted aryl, beteroaryk substituted beteroaryk eyeloalkyl, substituted cycloalfcvL eyeibheteroalkyl dr substituted cyeloheteroalkyl ring whtgref ftth$.ring· is:0|?jS0nh.lly fused to another aryl, substituted aryl, heteroaryl, substltutedheteroaryl, eyeloalkyl, substituted eyeloalkyk eycloh eteroalky 1 o r s u bsiltuted: e yel oheteroal kyl .ri ng;: with the proviso ih.at.Tl1 end R': are not bath hydrogen.; A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryi, a.rykdkyl, substituted aryMkyl, acyl, substituted acyl, hetemalkyk substituted lieieroalfeyl, beteroaryk substituted 'heteroaryl, heteroarylaikyl, substituted beieroarylalkyi, halo, -ON, ->NOy -OR0, -SCObR·1, -NlfoCOR50, -NHOR'k -NR%i0, -NORr -CONR-Rm\ -GOaiR/k • NR'tXfoR:r NiGCONIG!'R.!s, -NR"'CSNR:<>R11, -NRv'C(::NH)NR.;<'R; k -B(ORi<?){OR!i>, -INOhORXOR.11 1 or -PiίοhRSvl>fOR11); B is -N - or -C (R: ; Ru is hydrogen, alkyl substituted alksh aryl, substituted aryl, arvlaikvl, substituted' aryiaifcyl, acyl, substituted. acyl, heteroaikyi, substituted heteroaikyi, keteroaryb substituted: beteroaryl, heteroarylull;y 1, substituted hetemaryMkyi, -NR^R.^, -CN, -OR5', -8((¾¾1% -CCfeR13 or -CONR^R*4; G :s ·€ or -SfOb··; provided that when G is -8(01.:-, then G (firms a single bond with E: when the bond between 0 and Q is a single bond, then D is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryUdkyl. substitoted urylalksl, jcG, substituted acyl, hah.·, heteroaikyi, substituted heteroaikyi, hetcroaryL substituted heferosry], 'hetemurylalkyl, substituted heurroarylalkyL -OR'', -NH-OR'G -SiOoR'y -NR1 R,w, -NH-NHRJ% -COdG ;, or -ΓΟΝΤΓκ4; w hen G forms a double bond with D, then D is 0, :::8 , :::N~OR'% or :::N-NHRi>; o is 0 when G is -8(0¾. and n is 1 When G is -C-; E is -NR;:~. -N- or-C(R:''}-: provided that h is -NR5'- only when 0 forms a single bond with Εκ5 ' is hydrogen, alkyl, substituted alkyl, aryl,, substituted aryl, arylalfcyl, substituted arvlalkyl. acyl, substituted acyl, heteroaikyi, substituted heteroaikyi, beteroaryl, substituted hctcroaryl hetcroarylalkyL substituted heteroarylalkyl or -COvRiV; Rls is hydrogen, alkyl, substituted alkyl, aryl, «substituted aryl, arxlatkyl, substituted arylalkyk aeyl. substituted acyl, heteroaikyi, su.bstirut.ed.l>eteroalkyk, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted beteroarylalkyk, -ON. -OR41. -SiOifR'% -CO>R10 or -CONR'GGk a. b. e. d. e and fare independently 0. 1 or .% and R% R\ R\ R'\ H\ Rs, Rv, Rk*v Kff„ Rl\ R54, R*\ RUi, R,sy R2iy and.RJJ are independently hydrogen, alkvl, substituted alkyl, aryk substituted aryl, aryhlky 1, substituted, arylalkyl, acyl, substituted aeyl., heteroaikyi, substituted heteraalkyh beteroaryl, substituted: beteroaryl., heteroarylalkyl. or .substituted hetesoaryialkyl; or altematha!> JG aud R4, R4 arid:R5, R4 aud R% R7and:R4, R4 and R.® l.ift and R.1 \ l.u arid R44, R ' and Rki5 or !G4 and Rf !, together with the atoms to which they are bonded, firms a eveloltcferoaikyi or substituted cyclohctcroalkyl ring. 3-8. A method of modulating the activity of a chemosensory receptor ligand comprising contacting a chcrnoscnsory receptor ligand modifier with a coll containing T1R2 Venus flytrap, domain in the presence of a cheumsmsorv.receptor ligand, wherein the chemosensory receptor ligand modifier interacts with an Interacting alto of the ehemosensory receptor,
26. 39. The method of claim 39, wherein the interacting site of the chernoseosory receptor includes an interacting residue selected from the group consisting of amino· add NI43, SI 44, and 116? of a human. TIE? and a combination thereof,
27. 40. The method of claim 38, whereto the interacting she of the chcntoscmory receptor includes an Interacting residue selected from the group consisting of ammo acid $46, 8144, SI ο?. YI03, DI42, and P27? of a human TIR2 and a combination thereof.
28. 41. The method of claim 3$, wherein the interacting site of the eheniosensory receptor includes, an interacting residue selected from the group consisting of amino acid R63. F 383, D307, E302,and D.T78 of a human TlR2a;nd a combination thereof,
29. 42. The method of claim 38, wherein the interacting site of the ehemoseasory receptor includes an interacting residue selected "from the group consisting of amino acid .1167, FI 85, TIS4. T326. F.302. V384, A30Y 1325, 1508, R383, 0307, DM2, D278,1279, 167. ¥66, V309. 0142, SI 65-, 840, S303, T242, F103 ,0328. and 8168 of a human 'ΠΕ2 and a combination thereof
30. 43. The method of Claim 3-8. wherein the interacting site includes an interacting residue selected from the group consisting of amino acid N143, $ 144. 1167, $40, $ i 44, $ 16.1. Y i 03, DM2, F27/, K6.Y R383, D307, 0.302., 0278, 0183, H84, T336, 6302, V38 1. 4 305,1323, 1306. 0307, E3t? 1279,167, ¥66, ¥309, S3CB, T242.F103, Q328,and $16$ of altuman TIE? and a: combination thereof
31. 44. The method of claim 38, wherein the interacting she includes a group of interacting residues, of K65, D3 /8,1.,373, D307, R3R5, arid Y384 of a human T1R2 anil wherein the chemosensory receptor ligand modifier enhances' the activity of a ciiemosensory receptor ligand..
32. 45. The method of claim 38, wherein the interacting site includes a group of interacti»g residues of S40. SI 44, V HB, D143, and P377 of a human ΊΊ R3. and u herein the chemosensory receptor ligand is selected from the group consisting of sucrose and ‘wcralose,
33. 46. The method: of claim 38, wherein the chemosensory receptor ligand modifier' stabilizes a close conformation within TIR2 Venus .flytrap domain formed by the interaction between the chemosensory receptor ligand and the ebenic-serisory receptor.
34. 47. Tire method of claim 38, wherein the ebemosensory receptor ligand modifier is a chemosensory receptor ligand enhancer and has structural Formula (.1):

    or a tauiomew salt s»>i\,m , and/or ester thereof, wherein: '0 forms a single hood with either D or E and a double bond with the other of D or E; Rf is hydrogen, alkyl, substituted: alkyl, aryl, substituted, aryl, aryMkyi substituted aiyialkyl acyl, substituted acyl, heteroalkyi substituted heterorslkyl heteroaryl, substituted hetcroaryl. hcrcrotuylalkyl, substituted hcteroarylalky], -€N, ~MClb, -OR', -SmyoRl -NR*R'\ -CiONR' R\ -CO>R\ -NRYXIRR -NR CONR'IN. -NR V;SNR'!R\ -'NR?C(===NH)NRjR% -SO>NR'R1-NR'NCoRl -NR-!SO;NRjR\ -BiOR RlOR b, -R(OKOR!KORO or -3(0)( R5 HORN; E~ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryMIiyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl heteroaryl, substituted beteroaryl, heteroaryl.alkyl, substituted 1 wte ro aryl alkyl -CN, ~N€b, -OR*, -SiOkEi -NR<;R1 -(X>NflV, -CCRRl -NRTOdO, -NR*C0NR7R;\ -NR'CSNP.dll -NRlSC(-Ml}NR?Rl. -SOsNR'Rl -NR?$0,R6. -NRsSO.NRcRl -BiOR'KOR0}. -P{0)t0R5){0R\ or -!hO){R?)(Or>; or alternatively. R? and R\ together with -he atotn.s to which they arc bonded, form an aryl substituted'asyl hcicroarvl, substituted heteroaryl eyeloalfcyl substituted cydoalkyl, cycloheteroalkyl Or substituted cyclcheteroalkyi ring wherein the ring is optionally fused to another aryl substituted aryl -heteroaryj, substituted hclcmaryl cydoalkyl substituted cydoalkyl cyciobeteroalkyi or substituted cyclohcteroalkyl ring; with the proviso that R: and R" are not both hydrogen; A is hydrogen, ulkvl substituted alkyl aryl substituted aryl arylalkyl, substituted arylalkyl acyl, substituted acyl heteroalkyl substituted 'heteroalkyl heteroaryl. substituted heteroaryl heterourylaikyl substituted beteroaryMkyl, hales, *CM, -NO?, OR', -StO\.R* -NR 'COR^l -NHORl -NR VI -NOR*. -CONRVi <Χ>>βΛ -N R':C() ;R;<ί. -NR'CON R;i:'R!~NRXISNR ;i>R 3 3, -Nkid NH)NR:!iR: -B(OR 5,,K0R 11), -Pi OKOR ;<!KOR3 3) or -PtO hR'°)(OR 11); B is -'N- or -CIR 5>; Rl' is hydrogen, alkyl snhstituiei! alkyl aryl substituted. aryl, arylalkyl substituted arylaikyi, acyl substituted acyl hcteroalkyl, substituted heteroaikyi, heteroaryl substituted heteroaryl heteroarylalkyl, substitutedbeteroarylaikyl -NRbR*l -C'N, ~OR: \ -C01!; or ~CONR':Ri+· 0 h -0- or -S{0)s-; provided that when 0 ls: -S:(0)r? then G forms a single bond with B; when, the bond .between,0 and G is a single bond, then :D is hydrogen,, alkyl substituted atkyl aryl substituted, aryl, ary ialkyl, stibsritured aryl alkyl. acyl suhsuruted acyl halo, heteroalkyl substituted hetcroaikyl beicroaryl, substituted heteroaryl, beteroarylaikyl substituted heteroaryialkyl, -0R.l\ -Nhf-OR”1, -SfO'lV'l -NR'V*, ~NB~ M illl -C(NR:or -CONilVl when G .forms', a double bond with D, then 0 is -0, =:: 'S ^N-dR^or-M-NHR15; n is 0 when G is -S{G);~. undo is I when G is ~C~; Eis-NRsS„.N.or -C(RS>; . . . ϊ N . . . .... provided that E Ls -NR. ~ only when. G forms a single bond with E; R!' is hydrogen, alkyl substituted alkyl, aryl substituted aryl ary! alky I, substituted arylalkyl, acyl, substituted ucvl. hetcroalkyi, substituted hetcroalkyi. heicroaryl. substituted hctcfoaryk heteroaryialkyi. subsiituted beieroarylalkyi or ~CO;>Rf<''; Rl!>is hydrogen, alkyl, substituted alkyl, ary·!,, substituted ary!, arylalkyl, substheied aty ialkyl, acyl, substituted acyl, netoroatkyl, substitutedheierualkyl, hctcroaryl. substituted heieiouryl, hcteroaryndkyi, substituted hctcroaryialkyl, «NR^R.·41., CNl -OR'", ·Α(ίρ1<Λ\ or TX)NR^R\ a, b, c, d. e and f are independently 0. I »»r 1; and Ry R\ Ry RA R', R\ Rf R!A RH Rsy Ru, Rly R*\ R*\ Rsl, and Ru ate independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, styialkyl, substituted arylalkyl, acyl: substituted'acyl, heteroalkyl, substituted, hetero.alkyk hetcroaryl, substituted hderoaryl, beieroarylalkyi ax substituted hctercaryiuikyl: or alternatively, R‘ and R4, R4 and Ry Rf‘ and !<' R" and R\ R"' and R1”, RK’ uruiR11, Rn and R.! !, R!5 and R!°, or R'1 and R ' :, together noth the atoms to which they are bonded, form a cycloheteroalkyl or substituted cy do heteroa lky I ting;
35. 48. The method of claim 38, wherein the cell contains T1R2 Venus flytrap domain within a OPCR pathway,
36. 49. The method of claim 38, whereiatho ohomosensory receptor ligand modifier is provided in a comestible composition.
37. 50. Tiie method of claim 38. wherein the cheniosensory receptor ligand .modifier Is provided in a medicinal composition, 51. 11 e method of claim 38, wherein the elmmosensory receptor ligand modifier is provided hi a, food, or -beverage product, 52. A. ehemosensery receptor ligand modifier, wherein in' the presence of a ohemosemory receptor ligand it interacts with TIR:2 Venus flytrap domain via si least three interacting residues selected from the group consisting ofNI43, S144,1167, S40, Si 44, $16$. Y103, DJ42. P277. Χίο, R383. D307, Ε302, D278, P1XS, 'Π 84.. T326. E302, V384, A305, 025, 130o, E382,1279, (67, Υό6. V309, S303, T242. FI 03, Q32-S, and Si 68 of a human XIR2.
38. 53. The ehcmo?icnsory receptor ligand modifier of claim 52, wherein it interacts with Ti R2 Venus flytrap domain via a group of ammo acids selected tr«m the group consisting of i) N143, Si44. and H(>7 of a human Ή R2, 2) S40, Si 44. Si65, Y] 03. D142. P277 or a. human Ti R2, 3) Xo5, R383, D307, E302. and D27S of a human TIR2, 4) 1167, PI85.TI84, T326, E302, V384, A305. 1325, BOO. R383, D307, E3S2. D278,1279, 167, V00, V309. D! 42, Si65. S40, S303. T242, FI 03, Q32S. and SI 68 of a human T!R2. and 5} N i 4 3, Si 44. Π67, S40, SI 44, Si 65, V i03. Di42, P277, X65, R383, D307, £302, D27X, P185.1184, '1326, E302. V384, A305, B25. 1306, E38.2,1270,167, V66. Y309, S303, T242, F103, Q328. and Si 68 of a human TIR2.
39. 54. The cheroosenaory receptor ligand modifier of claim 52, wherein it Interacts will· T! R2 Venus flytrap domain via a group of amino acids K.65, D278. L279. D307, R383, and Y3-84 of a hitman TI R2 and wherein it enhances the activity of a ehemesensory receptor ligand. 55» The chemosepsery receptor ligand modifier of claim .52, wherein it interacts with TTR2 Venus flytrap domain vm a group of amino aeids of S40, Si 44, Y103, PI42, P277of a. human T1R2 in tire presence of sucrose or sucra lose and. wherein it enhances-the 'afeiifiiy of sucrose or sueralose.
40. 56, Tlie ehemosensory receptor ligand modifier of claim 52 is a compound having structural Formula (1):

    or a tautomer, salt, solvate, and/or ester thereof wherein: G forms a single bond wi th either O or E and a double hood with, the other ot' D or B; R* is hydrogen, alkyl, substituted alkyl aryl, substituted aryl, aryMkyl, substituted aryktlkyl acyl, substituted acyk hetcroalkvl, substituted hcteroalkyi. hctcroaryl, substituted hcvroaryl hetcroarylalkyi, substituted hclcroarylalkyl, -ON, -OR\ -S(0>JR\ -NR/R4, -conr’r4, -ccari -nr· co.dO. -NR' CONR4Rs, -NR· CS'NR4R\ -NR Xh-NiRNRlO, -sonr· ro -NRNSO:R\ -nrno3nr4r ·, 8(010 mOR4}. PiOHOR >:OR4} or Pi0)(84 }i OR* s. R" is hydrogen, alkyl. substituted alkyl. aryl substituted aryl, aryiaikyi substituted arylalkyl, acyl substituted acyl heteroalkyl, substituted heteroalkyi, heieroaryl substituted heteroaryl heteroavylalkyl, substituted heiernarylalkvl, -CN, -NO;?, OlO, ~S(OMO, -N'RXO. -CONRAN. -COrR:\ ~NR';00;;R*. -NRVONRlO, -NRTSNR'R\ -NR\BBH}NRvR\ -SO/NRsR0-NR'sOdr, -'NR?SO:NRlC, 8(0R 0(081, -PtOi(ORitOR"), or ••P{0}tRi(0RA); or alternatively. Rj and R2, together with the atoms to which they arc bonded, form an aryl, substituted aryl, hetcroaryt substituted hetoroaryk cyeioalkyl, substituted cyeioalkyl. eycloboteroalkyl or substituted eycloheteroalkyl ring wherein the ring is optionally fused r.o another aryl, substituted aryl, heteroaryl, substituted heieroaxyl, eyokmLkyh substituted cyeioalkyl, eyeloheieroalkyl or substituted cyelohetemalkyl ring; with the proviso that R* and R‘? axe not,both hydrogen; A is hydrogen, alky!:, substituted alkyl, axyl* substituted aryl, arylalkyl, substituted arylalkyl acyl, substituted acyl, heteroalkyi, substituted heteroalkyi heteroaryl, substituted heteroaryl heioroaxylalkyh substituted heteroaryialkyi, halo, -C v -N0>, -OR*, S(0)S!\ "NR9OORr\ -NH0R® -NR-R5! -NOR9,-CONRVy ~CO;R\ -NRACOdN~NH*€ONR '“R51, -NR^CSNR !0R”v «NR9€(~NH)NR K}R1 “B(ORs"rOR15'J, -PiOb.OR '"rOR ' ’) or ~P(0){R R is -N- dr-C(R *")·>; RK is hydrogen, alkyl, substiaited alkyl aryl substituted aryl arylalkyl, substituted arylalkyl. acvl stibslitaied aoyl, heteroalkyl substituted heteroalkyl, .hetnroatyl,,. substituted beteroaryl. hotoroaryMkyl, substituted heterosjykdkyL ~NRbR!y -CN, -ORO -S(O)dR'0 -(CAR: or -CONRwOR G is -C~ or ~S(C%~; provided that,when G Is -SfO)--. then G ibrnss a single bond with E; when the bond between D and G is a single band, then D is hydrogyui, alkyl.. substituted alkyl, aryl, substituted aryl, arylalkyl, substituted a/ylalkyl, acyl, substituted acyl, halo, heferoalkyl, substituted heleroalkyl, hctcioaryl. substituted beteroaryl, heteroatylaikv!, substituted hctcroarylalkyl, -OR'''', *NH-OR' \ -8(0)^’ , -NR!jR''', -NH-NiilT'. -CC.KRfo or -CONIV'R*; when G forms a double bond with D. then D is -----0, :::S , :::N-ORl , or 'N-NHIl5"; n is 0 when G is -8(0)--, and n is I when G is ··€··: E is -NR"-, --N- or -OR;s)-; j« . . . provided that E is -NR - oalywhoh G forms a single bond with E: Rxy Is hydrogen, alkyl substituted alkyl, aryl substituted ctrs l arylalkyl, substituted arylalkyl acyl, substituted acyl, heteroaikyl, substltuted. lieteroalkyl beteroaryl, substituted heteroaryl, hcteroarylalkyl substituted heteroaryialky 1 or -CXihE*7; R'"’ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl substituted .arylalkyl, acyl substituted acyl, heteroalkyl substituted heteroalkyl, hetcre-aryl, substitute·:.! heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, -NR^R’k ~CN, -OR·'", -${0)rR:-\ -I'OdP or -CONRa!R2i; a, b, c, d, e and f are independently 0, I or 2; and E\ R.4, R\ R°, R\ R% Rl, Rw? R11., Kn,;$Lu» R!5, Ri6, RiS? ra, ffldfa are: indepeadeatly hydrogen, alkyl, substituted alkyl aryl substituted aryl aryialkyS, substituted arylalkyl acyl substirnted acyl heteroaikyl, substituted heteroaikyl, heteroaryl., substituted heieroaryl, heteroaiylalkyl or substituted heferoaryialkyl; or alternatively, E3 and R4, R4 and R5. R* and R7, R7 and E4, E9 and. Esii, Rje: and Rn, E17 and R K, R.° and R,i6, orft^ and R'1, together with the atoms to whioh they are bonded, form a. etmloheteroaikyl or substitated eyetobeteroalkyI ring. •v. The compound ot'el.um ό whorom R ;:»! R tngethot v. sib the atoms :-..5 which they are bonded, form an aryl, substituted and, heteroun 1, substituted het-.maryk eyeloalkyl, oyeloalkyl., eyolohetsroalkyl or siibslituted oycloheieroaikyi ring where the ring Is optionally fused to another aryl substituted aryk beteroaryl substituted heteroaryl., eyefoalkyl, substituted cyeioaikyl, cycloheteroalkyl or substituted eyelobeteroalkyl ring,
41. 58. The compound of claim 56, having stmoinraf. Fojmnfof IR, wherein:

    Y tortus -a single bond wife either W or Z and a double bond with the other of W or /.: W is -C'iR'Vs -S'. -N-, ~MR:>. or -0-; Y is -C(R*V or -H-; Z is -C(R27}-, -S-, -N-, -N(R:>. or -Ο-: R24 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aylaikyl, substituted aryhdkyl. aryl. substituted acyl, hcteroalkyi. substituted hcter«»nikyl, heteroaryl, substituted hetoroarsi, heferoaryblksi, substituted heteroaryiaikvL -ON, -NO.', -OR" ’. ~S{0'i,,R 0 -NR''R 0 -CONR/'R"1, -CO. R \ -S0.;NR.:;iR'h. -NR'COdC-BtOR^KOR'O. -PtOttOR^KOR*") or ~ldO)sR'>Q)i.(>R."'}; R'w is hydrogen, alkyl, substituted alkyl, aryl, substituted aryk aryhdkyl, substituted aryhdkyl, .acyl, substituted acyl, hsteroalkyi, substituted hetcroalkyl, hctcroaryl, substituted lietemarxk hetcroaryMkyl,.substituted heteroarylalkyl, halo. -CN, -NO2, -OR"'\ ~SfO)t(R'\ -OCOR ~NR.;iR.u, -CONR’dCf, -COdf'h -SO.NR.'hR"2, -NROIOvR'n -8s0R'MX0R''}, -P(0)C0R;!: h.OR *0 or -R(0}(R h)(()Rr. FC1 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylaikyl, substituted aryhdkyl. acyl, substituted acyl, hetcroalkyl, substituted hetcroalkyl. hctcroaryl, substituted hctcroaryl, hetcroarylalkyl, substituted bcteroarylalkyl, halo, -CN. -NO,». -OR' , -S{0},R'‘y -OCOR”, -NR22R2\ -CONRAN'. -COR3-. -CG>R'\ -SO»NR!!R'^\ -NRCOdC’h ~B{GR'<KOR '*). -P{0}ipR }{OR '+) or -P{0}{R"){0R"<) or alternatively R"4 and R";' or R~'' and R‘“ together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, •eyclobctcroalkyl or substituted cyelohctcroalkyl ring: g, h and rare Independently 0 or 1; R” and R:'4 are Independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryl alky I, substituted aryhdkyl, acyl, substituted acyl, hetcroalkyl, substituted hetcroalkyl, heteroaryl, substituted hctcroaryl, betcroarylalkyl or substituted heicroarylalkyl; and R'"5, Ry'\ RRv', R"', tmd R'4 are independently hydrogen, alkyl, substituted alkyl, aryl. substituted aryl, aryialkyh substituted aryiaikyL aeyL subsdiuicd acyL heicroaikyh substituted hetcroalkyk hetcroaryi, subsUfutcu hefecoaryl, hctcroarylalkyl or substituted hcicroaryialkyl: or altcrrsaii'.’ciy Ry v andR'’0, R',J ami R'" or R"and R’" together with the. atoms to which they are bonded form a cydohetcroalkyl or substituted cyelohoteroaiky! ring; ami with the following provisos: a) when W is -O- or -S- or -NR "b thou Z is 0(R" 1 or -N-; and (b) when Z is -0- or -S- or NR'T then W is -0( R" ’ > or -N-.
42. 59. The compound of claim 58, wherein (DfoG is
43. 60. The compound of claim 56, having stmctorai Formula (Ha):

    -with the following provisos- (a) when W is -O- or -S- or -NR2'1, then Z is ™€(R2’) or -IN-; (b) when Z is -0- or-S- or then W is -Cfl-Ofo or -N~; ami (c) when R is -N-, dam A is not halo,
44. 61. The compound of claim 60, having structural. Fo.tmui.a f Ob); where :n:

    W is -CfR^)- or -N-; Y is-C(R;5S> or-N-; and 2 is -N{R 'S)- or-0-.
45. 62. The compound of el aim. 6 1, wherein W is -CYR; V- sod γ is ~cm-V 63. ) he compound of claim 62. wherein R'{ is hydrogen, alkyl substituted alkyl, acyl, substituted acyl, heteroalks I, substituted heteroiilkyl, -CN, -NO;, -OR;:% -S(OI,RX -OCOR39, -NR23R3a, -CONRBiR3ff or -CG;R'3; and RX Is hytbo^en. alkyl simstirmed ulkyl, acyl substituted acyl, heteroalksi, substituted heteroaikyL -CM, -NO;, ~0R5\ -OCOR,;, -SiOW1· -ΝΚΧΓγ ~rONI0!R ‘or -CO;Ri:.
46. 64. The compound of claim οι therein R'4 Is hydrogen,. -CiFjealkyl or substituted alkyl; and R-* is hydrogen, -€?<, .alkyl or substituted alkyl.
47. 65. The compound of claim 62. wherein A k hydrogen, alkyl, substituted alkyl, arylsubsfilisted aryl, -CN, -NO;, ^{0)^, ~\R 'R.O-CONR^R·0, -CO;R” or -NR'CChR54; R!' Is hydrogen, alkyl, substituted alkyl, arsblkyl, or Substituted arylalkvl; :R.*4' is hydrogen, alkyl, substituted, alkyl, acyl, substituted acyl, heteroalkvl, suhsdtuted heteroalky I, -CN,:-NCX -OR29, -${0)*ίΡ, -OCOR39, -NR^, -CONR2V<s or -COR37, and R"" is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroal.kyl, siibsdiufed heferoalkyl, -ON, -N0<s -OR31, -SCO}#3', -OCOR3', -NR:?Vn -0008¾¾ -CO#35.
48. 66. The eo.rnpoanJ of elOm 62, wherem A Is -NR&amp;COR ". -MiOR3, ~NR9R!0, -NOR9, -€QNR3RS3\ -COrf, -NR%XRli', -OR3, -NR^DNR%}}? ~KR 'csxR K'rS ’ or -NR’O-----NH}.NR! SR ‘1, R:: is hydrogen,, ulkyl, substituted alkyl, aryl alkyl, or substituted- arytelkyl; R"4 Is hydrogen, alkyl substituted alkyl, acyl, substituted acyl, hetcroalkyl, substituted, heiemalkvl, -ON, -NO;·, -OR37. -S(0},R37, -0C0R::7, -NR3-R30 ~CONR33R3· or ~CO>R3°; and R"<s is hydrogen. alkyl, substituted alkyl, acyl, substituted acyl, hclcroalkyl, substituted heteroaikyl, -ΟΝ. -NO,·, -OR \ -$(0};JT\ -OCOR-NR/!R-\ -OONR'!R'%r -CllR'i
49. 67. The compound. of claim 66, wherein' A is -OH, -NFk -NH'CH.c-K(Qhp, -N'HOCH.c -NOCTh, -ΝΉΠΟΚΧΙ, •N HO OtOOh, -NHG 0}N!F, -ΝΉΟίS)NIF, -NHCtNH }Nhb, -ON. -CH>QH, -ΟΠ.ΟΙΤ, -CHGHChh, -010(110 -(()71 -COOT, -CONHCI! or -ΓΗΟΗΟΟΚΧΟ R.:' is hydrogen, methyl, ethyl propyl /sp-propyl «-butyl,. όνΟιηνί. so -butt L /-butyl, phem i <u hemp. 1, R * -s h\di<>geu, -CF;j:, methyl,.e$tyl,-propyl,.«Kt-pro.pyl> «-butyl, /sp-butyl, see-butyl or t-butyl: and 11' is Ip. d:«).gen, -CF·.?, .methyl, ethyl, .propyl, ivo-propyS, «-butyl, /so-butyl, see-butyl or /-butyl.
50. 68. The compound, of claim 67, wherein A is -NFb, R:' is hydrogen or methyl, Rm is hydrogen, -CIF3, methyl or ethyl, and' is hydrogen, -CFo methyl or ethyl
51. 69. The compound of any of claims 62 to 68, wherein. Is hydrogen, alky! or arylalkyl 70. lire compound of any of claims 62 to 68, wherein. Rss is hydrogen, methy l or benzyl
52. 71. The compound of claim 61 huving struemra! formula selected from the group consisting of

    or a tautomer, salt, solvate, anchor ester thereof
53. 72. The compound of claim 71, wherein the salt is hydrochloride- or tri.fl uoroacct a re salt.
54. 73. The compound of claim 60. having structural Formula {Hot wherein*

    W is -S-, -NCR· 5)-, or -ΟΥ is -CiR'O- or -N-: and Z k>C{R'?)· or-N-.
55. 74. The eompoimd of claim 73, wherein Y &amp;-€(£*% mid Z ·> C(Rr)·.
56. 75. Th e compound of claim 74, wherein BY is hydrogen, alkyl, substituted alkyl, acyl, substituted· acyl, heteroaikyi, substituted, heteroaikyi, -CM, -NO., -OR" , -S(Q)iR"\ -OCOR", -MR5#·54. ~C0NR?'V4 or -CO#"; and R~fos hydrogen, alkyl, substituted alkyl, acyl, si&amp;stitutsdacyl, heteroaikyi,. substituted heteroaikyi, -CM, -NO,., -OR·1· -S(0)hR51; -OCOR'u -HR?1#,-CON# ιΙΥ~ or -CO#:'1,
57. 76. The compound of claim 74,, wherein R^ and' R“' together with the atom to which they are hooded, form. a cyeioatkyl, substituted cyel:oal.kyl,:cyelx>lK5.reroalkyl o.r -substituted eyelohoteroalkyi ring;. ??, The compo und of claw :74, wherein A. is· hydrogen, alkyl, substituted .alkyl, aryl, substituted·aryl, ~NRi>COR.’% -NilOR^, -NGRy -OR/''. -NRVONRV1. -NR-;C$NRk,Rn or -NR<VC(:::NliJNRlftR*-CN, -NCT, ~S(0).R\ -ΑΚΑΤο ·ΓίΟ;ΝΚ:>ί0\ -CCbR* or -NllT'CTR^; and R:; is hydrogen, alkyl, substituted alkyl, at dully l or 'mbstitutcd-arylalkyl 78; The compound of claim 74, wherein A is hydiogen, alkyl, substituted alkyl, aryl, substituted aryl, --ΝΤΙ’ΓΟΙΤΤ -MHOR*'', -NOR''. -OR', -NR'’CONRlVl.-NR9CSNR!i;Rff or-NR\>=NH)NRl'Vl, -ON. -NCR, -SiO.S. R. , -NR 'R:<. -NaVtOR10, -CiO)NRVi!, - CCKR7 or -NR\"X)dRl<’; R7 is hydrogen, alkyl, substituted alkyl, aryjalkyj, or substituted arylaikyl, R· is hydrogen, alkyl, substituted alkyl, acyl., substituted acyl, heteroalky!, substituted heteroalky!, -CN.-NO·:. -Of*"". ~$iOyR;;. -OCUR". -NR^Ra, -CXOINR/dV* or -COdT'k and R·” is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalky!. substituted heteroalkyl, -CN. -NO;. -OR". -StO^R'a -OQOiR'1. -CiO}NR :!R bar -CCTR3*, or alternatively R";> and R."' together with the atoffi(s) to which they are bonded form a eycloalkyi, substituted cyelealkvl cyelobeteroalfcyl or substituted cyeloheleroalkyl ring,
58. 79. The compound, of claim: 78, wherein A is --NHs; R: is hydrogen, methyl ethyl;, propyl Ampropyl «.-butyl, Ao-Bruyl, see-butyl, i-butyl phenyl or beneyl; R26 and R;; : are independently hydrogen, alkanyl, substituted alkanyl, al.koxy, carboxylic acid, carboxylic acid amide, or carboxylic acid ester; or alternatively, R7 ‘ ami R7 together with the atom(s) tv which, they are/bonded form a cyeioalkyl suhstRutedcyehsaikyh eycloheteroai.feyl or sisbsditucd cyeioheleroalkyi ring,
59. 80, The compound of claim 73, having structural formula selected from the group eonaisiihg of:

    or a tautomer, salt, solvate, and-'or ester thereof. 8 I, The compound of claim 80, whereia the sail is liydrocModde. or m&amp;oroaeeiate salt, 82, The compouftd of claim. $&amp;,. havi ag structural Formal a Ole);

    whereiu, G forms a single bo?id with E artel a double bond with D; Bis-N~; E is -NR! D is ~S , ~.N-OR®5, or ~N-NHR:k Wis -N(R25)·· or -O; Y is -CCR^}”; and Z ts -€(Rr)·.
60. 83. The compouftd of claim 83.. having .structural Formula. (llfh wherein,

    G forms a double bond with 1:. and a single* bond with D: B is -N-; r: is -N-. D is ~OR:y -NH~OEts', -NH-NHR15, -$(0%%*% or -NR'V; Wis -S-. ~N{ Rw)- or \ li> -v {R ϋϊϊϋ Z is - C'i R' }.
61. 84, The compound of chin- 82 or 83, wherein A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl -OR", -SRn -CR -NR'lC0, -CONR:>RS0, -CO>R9, .NRVOiR* -NR.·C()NR1:!R!-NR ΪGNRr'R!5 or MCO NH}NRi ;:R1 s.
62. 85, The compound of claim 84, wherein R! ' is hydrogen, alkyl, substituted alkyl, arylalkyl or substituted urylaikyl; B4° and Rw are independently hydrogen, alkanyl, substituted alkanyl, alfeoxy;: or alternatively, R*ft arsd R"1' together with the atonds) to which they are bonded form a ey cl balky!, substituted eycloaikyf, eyeloheteroalkyl or substituted eycloheioroallcy! ring.
63. 86, The compound of claim 82 or 83, having structural formula selected from the; group consisting of

    ora tautomer, salt solvate, astci/or ester thereof. §7, The compoimd of claim §6, whereift the salt is hydrochloride or trill uoreacetato pit
64. 88. The oompoumi of claim 5K, having structural Formula (lid):

    with the following provisos: (a) when W is -O- or ~S~ or ~NR.2'\ then Z is.-C(R2'') or ~N~; and (hi when Z is -0- or ~S~ or ~NR'\ then W is -OR''*) or-H~,
65. 89. The compound of claim 88, wherein. W is -S-, NR~\ -0-; Yis-CR2®-; Z is -(7 R :)-\ and W and Y forms a single bond and Y and Z ln®a double bond,
66. 90. The compound of clai m. 88, wherein, W is -O'R ' V. Yis-C'R-'T; Z LS -S% -NR··"-, -0-; and W ami Y forms a dooble bond and Y and Z forms a single bond,
67. 91, The compound. of claim 8¾ where!» W is -S-, NR"5, -ΟΥ is -N-; Z is -€{R" }-; and W and Y forms a single bond and Y and Z forms a doable bond, '92. The compound of claim 88, wherein W is - NR;'5; Y is -N··; and /.. is ~(_.{R· )-; and Y forms- a single bond with each of W and a doable bond with 2.
68. 95. The compound; of any of claims 88 lo 9.1 wherein A. is hydrogen, alkyl , suhsfi mted alkyl, aryl, substituted aryl -OR9, -SR9, -CM -NR9R5if, -CONR.V,.*NR*CO.;Rir’, -NR9CON R i0Rf -N R 'CSNR K:R55 or K R°C(:::N H >NRTiiR5\

    94. The compound of claim 93, wherein R1' is hydrogen,.

    95. The compound. of claim 94, wherein R"5 and R"’ are independently hydrogen, alfcanyl, substituted.alfchuyl, alfcoxy, carboxylic acid, carboxylic acid ester; or alternatively. Rw and R"J together with the atom(s) ro which they are bonded form a eyeiofilkyl or substituted cycloalkyl ring,
69. 96. The compound ofelaim. 88, having structural formula selected from tbe group consisting oh

    or a tautomer,, salt, solvate, and/or ester thereof. 9? . 'The compound of claim 56 having structural Formula <111);

    wherein: H is - OP ’ I- or -N-; I is -CCR1') or -N-; Its-Cm· > or-Ns K is -ccr*}- Of "Ns R'5 is hydrogeo» alkyl,.substituted alkyL aryl, substituted aryh aryhlkyl, substituted aryialkyl, acyl, substituted acyl, Hide, heteroalky!, substituted heteroalkyi, beteroaryl, substituted hetetoaryl heteroarylaikyl, substituted noteroarylalkyl, -CM -KO.% -OR·'*, -SiO>jR -OCOR'*s -NRr'!R40, -CONR^R40, -CO:R'!<\ -$0;KR'Vy -NR-59$Q>R*k -$(OR**XOR4e), -PiOHOR^KORw) or -ΡίΟκ^ΧΟϊΓ'); RK> is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, afylalkyi substituted aryialkyl acyl, substituted acyl halo, betctoalkyl substituted betetoalkyl, heteroaryl, substituted beteroaxyl.beteroarylalkyk substituted hetcroarylaikyl, -CN, -N03, -OR45, -$(0)kR4\ -0€OR4'\ -NR41R4,\ -CONR4iR4\ -COvR4*, -SO..NR4iR:5\ -NR4SSO>R4·. -BiOR” KplG;J, -PlOKORi: SlOR4"} or ”P{0)(R4i)iOR' ·}: R'' is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aiyiaikyl, substituted arylalkvl, acyl, substituted acyl, halo, hcicroalkyl, substituted hctcrcaikyi, heteroaryl, substituted hetcroaryl, hetensurylaikyl, substituted heteroeryhdkyl ,-CN, -Nf0>, -QR4\ -StOjiR4', -DOOR4'. -NR4’R44. -CONR^R44, -CilRG SO\!VR4',R44, •NR'SilRfl StOR4’ }iOR">. -PiOKOR^KOR^ior-PiOHR'-KOR44}; R ' is hydrogen, alkyl, substituted alkyl, aryl, substituted ary], arylalkyi, substituted arylalkyj, acyl substituted acyl, halo, heteroalkyl, substituted heteroulkyl. heteroaryl, substituted heteroasyl, hctcfoarylalkyl. substituted heteroarylalkyl, --CM -NO.·.-, -OR.'1 , -S{0}mR'<!, -OCOR45, NR4V\ .<ONR-'-R·16, ~COR4\ -CO.->Ri5. -SOvNR4'R';f, -NR^SO^R46, -B(OROR4*}, PtOMOR'i ;HOR-;i'} t}{ -p(0}tR‘:<){OR46}; or alternatively R?6 andR??Or R3? and Rs8 taken together with rite a torn to which they are bonded, form a eyoioalkyl, substituted eycloaikyl. cycioheforGalkyl, or substtiutoo cydoheferoaikyl ring; j, k. 1 and m are independently 0, ] Or 2: and R \ R^. R*!. R4··. R“\ R/l R’\ and R46 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryialkyl, substituted aryialkyl, acyl, substituted acyl heteroaihyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl heteroaryiaikyl or substituted: heieroarylalkyl or alternatively R "4 and R R4! and R4'\ R*'' and RT4 or R 4' and R* together with the atoms to which they are bonded tbrm a cyeloheteroalkyS or substituted eycioheteroallyl riitg; with the proviso that at most, two of Η, 1,1 and: K are -ihk 9S, The compound of claim :97y wherein is
70. 99. The compound of claim 97* having structural Formula (Ilia);
71. 100. The compound of chin- 00, wherein A is hydrogen, alkyl, substituted a sky I, awl, substiuned aryl mylaikyl, substituted mydaliyl, acyl,substituted acs I, hcteroalkyh substituted heteroalkyl, hete'oaryl, substituted heteroaryh hcteroaryiulkyk subsumed lietcroarylalkyl, -ON, OR1, -NO;, -StOk-RV-NHORw -NRYoR!\ -NR^R* -CONR'Y''. -{'O.dTT - NR;,CO-Rhy -NR9CONR!yR!!. -NR'TSNR,f,Rn. or -NRXh:::NH}NR{f!RA ICO. The compound of claim 100, wherein A is -OH. -NH?, --NHOH·., -N'CH·.};·, -NHOCH*, ••NOCB-n- -NHC(0)rHw -NHC(0)OCH., -NHC(0}NH.·, -NHC{S}N'H>, -ΝΗΠNHINIK -( N, ·Π1:ΟΗ, -OH;NH., -Π'ΗΝΗΠ'Κ -CH;N{CH;).*- ^ΌΤΙ ·<ΌΜΗ, -CONHCbl· or --CH-AHUOK'H·.
72. 102. The compound of claim 99, wherein Rx" is hydrogen, alkyl, shhsdtuiecl alkyl, arylalkyl, or substituted aryialkyL 103:. 'The compound of claim 102, wherein R':is- hydrogen, methy 1, ethyl, propyl, Ao -propyl, «-butyl, Ao-hniyl, wee-butyl, /-butyl, phenyl erbebzyl, 1:04, The compo umi of claim 99,, wherein Hi:S>C(R'V; I m o IR 'O; I is -C < R' >-; and K la -C(R O- 1.0S, The compound of claim 99, wherein A is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl. -CN. -OR?,"NQs, ~S(Q)cR?, -NR0R7. -NRYORY -NRYT -CONRV. -0>Ry or -NR\O;R:r>· and R' is hydrogen, alkyi, subsidised alkyl, aryutll.yi, or substituted arylalkyl
73. 106. The compound of el aim. 99, wherein A is -OH. -NH_\ -NHCH;, -NtOfUb, -MlOClh, -NO€Hs,-NM(\Ov:TR, -NBC(0}OCH·. -NHQONH,. -NH('(S)NH.>. ·ΝΗ(ΪΝ1 nNih. -CN,-CH;OH, -CHjNH.·. CHiNHCK., ·ί 'Η:Ν(ΓΗ.0.ο -00:91, -OON1K -CONHCih or-ΟΗ,ΝΗΟΟΚΊ h; and R: is hydrogen, methyl ethyl, propyl Aw-propyl n-butyb ho-huts 1, .wc--butyl /-butyl, phono or benzyl 1()7.. The compound of claim 99, wherein R'· is hydrogen, alkyl, substituted alkyl hulo. heteroalky!, substituted heteroatkyl -CN, -NO;, -OR/l-S10s;R l -ΟΓΟκ l -NRv*COR"-CONKER4*’, -CO.R^ ΝΕ^'ΙΓΙ -SO»NR®R* or~NR ; 'SO;R ;i; Rfc ty hydrogen, alkyl, substituted alkyl, halo, hetomalkyl, substituted heteroalkyl -CN, ~N0a, -OR41, -S(0)]R'n, -OCOiC5, NKi4R4-. -NR4iCQE.4y -CONE41!42, -CO#45, -SO#!4#42, or-NR^SO#4’', R'v is hydrogen:, alkyl, substituted alkyl, halo, heteroalky l substituted heteroalkyl, -CN, -NO;, -OR4·, -SlOMC'. -OCOR*\ NIC R"!i, -NR4'COR.4\ -CONRriC\ -OOdCl -S02NR*sR4\ or -NR^'SC##: oralternatively Rw and R'l together with ihc atoms to which they are bonded, form a cyeloheieroalkyi or substituted eydoheteroaikyl ring; and H:'* is hydrogen, alkyl, substituted alkyl, halo, heteroalkyl substituted heteroalkyl, -CM, -NO;, -OR45, -S(0)|R* -0COR4s\ NR45R4e, -NR^COR4*, -CONR<5R* -CO#'*5, -$0>NR45R^ ~NR';'SO;R4'. 1 OS, The compound of claim 107 , wherein ·%’? ..... R"" is hydrogen, aikanyl, substituted alkenyl, alkenyl, substituted alkenyl, eycioalkanyi, substituted eycioalkanyi, cycloalkenyl, ^ubstttttted.eyfl'ediilkeoyi, halo, heieroalkyi, substituted heteroalkyh -CN, -NO;, -OR"44, -SCO)#45, -OCQR45, NR4#46, -NR4sCOE#, -CONR4#4* ~CO#4C -SOsNR4#46, -NR43SO;R4S 1 ()9:, The compo and of claim 1.07, wherein A ί'Λ -Nils R: is hydrogen, methyl, ethyl or benzyl; amf R'5, R'v'V R:v 'and K'^ are independently hydsogen, flaoro, chloro, Imnno, methyl f MtM'onicthyl, ethyl, isopropyl, cyelopropyl, property!, nicthyipropcnyl, butenyl, mcthylbuienyl, substituted property!, substituted methylpropenyl, substituted butenyl. substituted nvethylbutenyl. -iNH-allcanyl,.~NR-(substituted alkenylκ -OH, -OCHy, “O^eyelpalkasyl,τθ-berasyl» -COfH,
74. 110, The compound of claim 99 having structurM fdOTula selected from the group consisting of

    or a tautomer, salt, .solvate» and/or ester thereof .11.1., The compound of claim. .1 lO/whercintfee salt is hydrochloride or trifiuoroaeetate salt.
75. 112. The compound of claim 99, 'having structural Formula filial); wherein,

    A is hydrogen, alkyl, substituted: alkyl,, aryl,.substituted:aryl, arylalfcyl, substituted aryfalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl. heteroaryl, substituted heterdaryl,. hetcr0arylalh>4, suhstituted hefemarylalkyl, «GR -OR\ -NOv, -SsOIcRVNGRo »NHORs, -NR°COR10, -NR%ift, COhlR^RMV-CO^or-NR>',CO-Rift; R!' is hydrogen, alkyl, substituted alkyl, arylalkyh or substituted arySalkyk X1 k -Ol.-. -0-, -NR·-, -$- -8-:0)- , or-SlOb-; X*' is alky iene, substituted aikyiene, heteroalkyleue, or substituted heteroalkylene; rn is 0 or 1; Ύ' is cyclobctcroalkyl substituted cycloheteroaikyl or

    X and X" arc independency a covalent bond, ~€k~ or -NR*-'·; XI is Ο,ΝΚΐ N-ORlorS: 8s is halo, -NO;?, -CN, -OH, -MHj, alkyl, substituted alkyl, aryl substituted aryl, aiylalkyl, substituted aryialkyl, helcroalkyl substituted hcteroaikyl, heiefoaryk substituted heteroaryj. hetermuylalkyi or substituted heteroarylalkyl n is 0, 1.2, or 1 R* is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryialkyl, substituted aryialkyl heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heterdaryl heteroaryklkyl or substituted heteroarylalkyl -NRaRw; and each if’ and Rl!> is independently hydrogen, alky), substituted alkyl, aryl substituted and, arylaikyi, substituted aryialkyl heicroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl heteroarylalkyl or substituted hcteroarylalkyl: with the proviso that when X* is~Q™ or ™S~, and ro is zero: then X' Is not.-0-,
76. 113. The compound of claim 112, wherein \' is ''ΙΤΙ-; and Y! is
77. 114.. The compound of claim I I2, wherein X! is 0 . NR" . m 3 : m Is 0 or .1, and Y* is eyeloheieroalkyl. or substituted eyeiohetsroalfcyL IIS. The compound of claim 112, wherein X.^is~,Q~,~N&amp;%or-4s m us 1, and Y1 is
78. 116, The compound of any one of claims 112,114, and 115,: wherein is methylene, ethylene, propylene, dimeibylcthyleae, methylcycloptopyienc, or eyelopfop> hnmhylene.
79. 117. Th e compound of any one of claims 112. to 116, wherein A is hydrogen, alkyl, substituted alkyl -CM. -OR‘\ - NO >, -Sip},R'. -NOR7. -NHOR.\ -NRyCOR* -NRyR;". -C0NR7Rl". -CXTR' or -NRyCO.>Ria.
80. 118, The compound of any one of claims 1 12 to 116, wherein R!' is hydrogen, alkyl, substituted alkyl.
81. 119. The compound of claim 112, wherein Yl is cyeioheteroalkyl or substituted eydohcteroalkyi.
82. 120, The compound of claim 119, wherein Y! is piperidlnyi, substituted piperidmyl, ietrahydrofuranyl, subsitiruted tetrahydrofurany I. tetrshydropyranyi. substituted tetrahydropyranyl, dibydrofuranyl, substituted dihydroftnanyi, pyrrolidinyS, substituted pyrruhdiny l oxctanvl or substituted oxetanyl
83. 121. The compound of claim 119 or 121), wherein the substituted eyeiobeteroaihyl comprises one or more substituents selected fern the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted aryUtlkvl, acyl, substituted acyl, heteroalkyi, substituted hcteroalbyl, heteroaryl, substituted heteroapyl, heteroarylalkyl substituted heteroarylaikyl, -CN, -OR9, ~NOm -S(0)CR9, -NOR:9, -NHOR9, -NR'tX)Rm, -NRXR.50, -CONRV, -CCNRX and ~NRvC02RS',
84. 122, Hie compound of claim 112, wherein X" k O, .123. The compound of claim 112, wherein .X'-0{X4)-X*- k -0(0)-, -C{0>-NH,, -NH-CCOh *NH*C(Ol-NH-, -0(0)-0-, -0-0(0}-, -0-0(0)-0-, -811-0(0)-0-, -0-0(0)-88-, -€{>10}-, -€'(NH;-NH-, -NH-CfNH}··, -NH-C{NH)-NH··. -0(88)-0-, -O-QNHk -0-C{N8K>-, -NH-CVN0)-0-, "0-C(NH)-NH-. -0(0-00)-, or -C(S}-,
85. 124, The compo imd of claim' 13 2, wherein. A k hyd*> igc.a, alkyl, substituted alkyl, or -KRvRhi; R! is h> Of men. and Y! ispiperidinyl, subi-tituied pincridunh tetrahsUmiorany], substituted tetrahydrofuronvh tebahyuropyra»\j, substituted tetrahydropyraoyl, dihydrohtranyl, substituted dihydrofuranyi, pyrrol id inyh substituted pyrrol id inyi, oxemmT or substituted oxer any!

    5. The compound of el aim 112, wherein A is hydrogen, alkyl, substituted alkyl, or -NR ;Rni: R: is hydrogen; Y; is ·Χ::·.0{Χ4).χΫ; and -X:-C(X4)-X:;- is --0(01-, -CYOl-NH-, -ΝΉ-ΟΟ)-. -NH-C(0)-NH-. -CYO)-CK -0-0(0)-, -0-0(0)-0-, -NH-C(OK)-, -0-0(0)-08-, -C'(NH)-, -CiOHl-NH-. -NH-C(N8k -NH-C{NH)-NH-, -€(NH}-0~, -0-0(88)-, -0~C(N8)-0-, -N8~C{MH)-0-, -0-0(88)-88-, -0(8-08)-, or -CCS)-.

    120. The compound of claim 112, hu\ ing structural formula selected from the group consisting of

    or a tautomer, ««alt, solvate, and/or ester thereof. 1,27. The compound of claim 122, wherein the: salt is hydrochloride or tdiluomacetafe salt, 128, The compound of claim 77, having structural: Formula (Hlb);

    12<>. The compound of claim Ϊ 28. wherein Λ is hydrogen. alkyl, substituted alkyl, aryl substituted aryl. -ΓΝ. -NO;, -OR'i -SiO},R' ~NR '(OR! \ -NROR'. -NR'k:\ -NOR'. -CONR’RK'? -COvR9. -NRgCO;-Rs". ~NR<?CONR]i;R!\ -NR'CSNR: V\ or ~\ThTT::NH)NR;V\
86. 130. The compound of claim 12k. wherein Ri- is hydrogen, alkyl, or substituted alkyl
87. 131. Th e compound of claim 128, wherein A is hydrogem alkyl, substituted alkyl, aryl,, substituted aryl -OR*,. -SR\ -CN,-NR'R5y, -CONRV, -C:0>Rn -NR'JCO;R1:0f -NRrCONRiftRu, -NR9CSNRHiRH or-NR9C{^NH}NR5f,Ru; and RJJ ishydrogen, alkyl, or substituted alkyl
88. 132. The compound of claim 12k, wherein H is>C(R' '> or-hi-; Ida -('{ITO-: J is ; and K is -C(R3S)- or -N-. OS. The compound of Claim 128, wherein. II is -Cffi:'5)-; f ia-CtR >; I is ? R )- ami. K is -C(R"S}-. 1:34. The compound of Claim 128, wherein R" is hydrogen, alkyi, substituted alkyl, aryl, substituted aryl, arsialkyi, substituted arvlalkyl, acyl, subsinufed aevl, halo, hcteroalkyl, .substituted hcteroalkyl, hctcroaiyl, substituted kctcroaryi, ikdcroarvialkyl or substituted heterotuyiaik vl, -CN, -NO\ -OR"', -S(O;I, -OCOR", -NR'V, -CONR'V, ACTRte -SOAR^R" -NR^SO.tR* Rv‘ is hydrogen, alkyl, substituted alkyl, aryl. substituted aryl. arylalkyL substituted arylafkyl, aeyi. substituted acyl, halo, heteroaikyL substituted hcteroalkyl, heteroatyl. substituted heietoaryl. hetcroaryiaikyl or substituted hcicroafylaik'yl, -(I N, -NOe, -OR4', -StOgR4', OOOR'i!, -NR4,R4',-CONR4iR4··, -CO.-ROb -SO;N'R4iR4\ NR.^SOdOy R' is hydrogen, alkyl, substituted alkyl, aryl substituted aryl, arylafkyl. substituted arylafkyl, aeyi. substituted acyl, halo, heteroaikyL substituted hcteroalkyl, heteroatyl. substituted hetetoaryk hetcroaryfalkyf or substituted hcteroarylafkyl ,-CN, -Ni>, -OR4', -8ίΟ);Κ’’\ -OCOR'te -NR4'!R44, -CONKER44, -0>Ri:, -SO;NR4iR44, -NiONCuR**: R 'x is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylafkyl. substituted aryialkvL aeyi, substituted acyl, halo, heteroaikyl, substituted hcicroulkyi, heteroaryl, substituted heteroaryi, beteroaryl.alkyi or substituted heteroarvlaikyL -CN, -NO.u -OR4'" -$(OWR4'\ -OCOR45, -NR45R46, -CONR^R^-eOR45, ~CO.>R4\ -SCANR4'RSA -NR4t‘SO?R4f‘.
89. 135. The compoundof pkim 128, wherein A is R 's hydrogen, methyl, ethyl or benzyl; and :Rt'\ R'V R;'!i' and R >s are independently hydrogen, fluoro, ebioro, bromo, -CN, alkenyl, stihsthuted alkany!, aikonyl. substitued alkenyl, alkvnyl substituted alkynyl, eyeloslkanyl, substituted eyeloalkanyl, cydoalkenxl.subsumedcycloai:kebyl>.ho'teroalfei3ny:k.§»b.sdtat0il heteroalkanyl, cyckobeteroal.kyi, substituted cycloheteroalkyi, -O-aikanyl, ~0-{subsiituted alkanyl), -O-alkeuyL -0-{substiluted alkenyl), -Mf-alkauyi. -NH-(substituted aikanyi} -NR-alkenyl, -NH-(substituted alkenyl), -S-alkunyl, -S~(sB-l>stittsted aikanyi), -S~alke;nyl, or -S~ (substituted alkenyl},
90. 136, A compound of Claim 128 having structural ibrrmda selected Rasn tlie group consisting of:

    or a tautomer. eah% solvate. and or ester thereof. 1.37. The compound of claim 136, wherein the salt: is hydrochloride or irifiooroaoetate salt.
91. 138, The compound of claim 123, having structural Formula (Illb l}:

    wherein, A is hydrogen, alkyl, substituted. alkyl, aryl, substituted aryl, arykukyh substituted arylalkyl, aeyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heieroaryh heteroerylaikyh substituted heteroarykdkyl, -GN, ~GF\ -NO?, -$(Q}CR:', -NOR9, “NhlOR9, -NR*CORi0, -NR9RK\ -CONR9Rw -C02R'j or -NR-5CO?RKi; R:: is hydrogen, alkyl substitoed alkyl arylalkyl or substituted arylalkyl;; Xy is--010--, --0--, -NR9--, -S-. -S(Ol-, or -StO). X"' is alkylene, substituted alkylene, heteroulkylcne, or substituted heleroslkylene; m is 0 or 1 j Y{ is betcroaryi substituted beteroaryk eyeloheieroalkyi, snbstirnted eyebheteroaikyi, or

    Χ·' andX* are independently a covalent bend, ~0~ or -MR4™; X4 is Q;n:C N-OR9, or S; R'4 is halo. -NO.·;, -ON, OH, -NH>. alkyl, substituted alkyl, aryl, substituted aryl, aiylaikyh sebsoiuied arykdkyi, hcicroalkyl, substituted hctcroaik.vl, heteroaryl, substituted heteroaryl, hetcroarylaiky! or substituted hcferoafyialkyl; n is 0. l. 2. <«' 3: R' i'; hydrogen. alkyl, substituted alkyl, aryl. .substituted aryl, aryialkyL substituted aryialkyL· heteroalky!, substituted heteroalkyl, hctcroaryl, substituted hcwtoaryl. octet oaryluikyi or substituted bctcroury'ialkyl, «NR'R’'\ and each R ! and R*!> Is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylaikyi, substituted aryialkyL heteroalkyi, substituted heteroalkyi, heteroaryl, substituted heteroaryh hetcroas yMkyl .or substituted heteroarylalkyl:; with the proviso that when X5 is -O- or and m is zero: then X' is not -<3-, 139 l ire compound of claim 13k. wherein X ‘ is -CH:?-; and Y! is
92. 140. The eorn|x>and of claim 13d, wherein Xr is -Or, -NR5*-, or m is 0 or 1, and Y1 Is cyclohet.ero.aS.kyi or sobstitufed cydoheteroalky 1
93. 141, The compound of claim 13¾ wherein X! is-O-, -AR'Y.or-S-; m is I. and •xti v Ύ m

    .142, The compound of any one of claims 138, 140, and 141, wherein X" is alkanylcne, substituted alkanylcne, heicroalkanyiene. subsmuteJ hctci'oalkanylene,. alkeayicne, substituted aikenylcmy beteroalkcnyiene, o; substituted heteroalkenyiene.
94. 143, The compound of any one of claims 138, 1411, and 141, wherein X" is methylene, ethylene, propylene, liw-prepyleue, butylene, lxo~ butylene, ,wrdxmdene, pentylene, hexylene, hepfyleoe, dlinethyleihykne, methylcycioptopylene, eyclopropyhnethyknc, eihenylcne, propenvlcnc, or butehykne,
95. 144, The compound of claim i 38, wherein A is hydrogen, alkyl, substituted alkyl, -CR -NOs, -OR ', Y(0),R 7 -NR<:COR;Y -NHOR’f -NR';R;,!5 -NOR9, -CONRyRl\ -CfTRX -NR T'OvR^, -Rk TONR!%u, -N R'CSNR u’R ! 5, -NRyC{:::NH}NR!ftR{5.
96. 145, The compound of claim 138, wherein R;' is hydrogen, alkyl, or substituted, alkyl,
97. 146, The compound of claim 138, wherein. Xs is eyelohekmalkanyl, substituted cydohemroaikanyi, cyeloheteroalkenyl, or substitoted cyeloheteroalkenyl
98. 147, The compound of claim 146, wherein Y! h piperidinyl substituted piperidiayl tbtr^ydtPfufanyt.stibsirinUdd.tett^tydfhfitmUyi tetrsbydropyranyl subsitituted tetmhydropyranyl, dihydrofuranyh substituted tiihydrofutanyl., pyrrolidinyi substituted pyrrohdinyi oxetanyl, substituted oxetany!,. saccharide ring or its. derivative, substituted saccharide ring or its derivative. 14S, The compound of claim 138, wherein Yf is heteroand or substituted hmeroaryf, 149:, The compound of claim 148, wherein Yj is pyfidinyl, substituted.pyjidiay h jsyrrolyh substituted pyrrolyl, furanyl, substituted furanyl, pymeolyl, substituted pystmolyl, isoxaxolyl, substituted feoxazolyl>:Oxa20lyl,.'iindysuWitutsd oxaxolyl.
99. 150. The compound of claim 14<S or 147, wherein the substituted cyclohcteroalkanyi or die substituted cyclobcteroaIkcnyI comprises one or more substituents selected from the group consisting of alkyl, 'substituted alkyl, aryl, substituted aryl, aryl alkyl, substituted asyislkyl, acyl, substituted acyl, heteroalkyl, substituted hetcroaikyi, heteroaryk substituted heieroarvl, heteroarylalkyl, substituted heierourylalkyl, -ON. -OR', -NO>, -StOhR/', -NOR·', -NHOR:', -NR4COR*0 -NR'3Ri0. -CONR9R:'l -CO.;R', and -NR\'O;RK’.
100. 151., The compound >u claim 138,w herein Y is
101. 152, The compound of claim 15L wherein X4 is 0> 1.33, The compound of claim 13b, wherein -X ’-C(X4)-XX is -43(0)-, -€(0)~NH-s -ΜΗ-€{0)-, -ΝΗ-ΟίΟ)-ΝΗ-, -0(0)-0-, -0-0(0)-, - 0 - C{ 0 )-0~, ~N H~C(0) -CK ~O-C(0)-MH-, -€(MH)-, -UNHi-NH··, -ΝΗ-ΟΝΗ}-, ·ΧΗ·(.ΪΝΗ)·ΝΗ·. -C(NH>-0·, -0-ONHh -0·0(ΝΗ}·0-, -NH-Ci"NH)-0-, -0-C(NHVNH·, ·0(Ν-ΟΗ)-, or -0(5-)-.
102. 154. The compound, of claim 138, wherein A is hydrogen, -alkyl»' substituted alkyl, or dNR^K1*'; .Rs is hydrogen; and Yl is pipcrrdtnyl, substituted piperidinyl, tetrahydro.furanyh subsithutcil tetrahydroiuranyh tetrahydropyninyi, substituted fetrahydropyraoyl, dihydrohimuyb substituted dihydtoloramd, pyrrolidinyl, substituted pyrroIidinyL oxetany!, substituted oxetanyl, monosaccharide ring, substituted monosaccharide ring, pyridinyL substituted pyridioyl, pyrruiyl, substituted pyrrolvl, furauyi, sttbshtsrted fbranyi pyruxolyi, substituted pyrazolyl, Isoxaxolyk substituted isoxazolyh oxazoM, or substituted oxaxofyl, .155. The compound of claim 130 ά hot On A is hydrogen, alkyl, substituted alkyl, :or -NR4RJ{!; R3 y is hydrogen; Y! is -Χ·-£Γ(Χ4)-Χ·'-; and -X' -0(Χ'4ϊ-Χ5·- is -0(0)-. -Q0)-N10, -N 0-0(0}-, -NO-CYOj-NI-!-, -0(0)-0-, -0-0(0)-, -0-0(0--0-. -011-1-0(0)-0-, -0-0(0 )-0 0». -0(00)-. -0(00:)-00-, -ΝΈ0ΠΝΗΚ -0100(011)-010, -0(01-0-0-. -0-0(010-. -0-0(00)-0-, -NH-ONΗ)-<>-. -()-0(00)-00-, -S(C)>3-5 -νη-SiO)-.-, 8(0):--.00-, -0-8(0):--, -8(0):--0-, -0(Ν··0Η}··, nr -( tS)-.
103. 156, The compound of claim 138, lumng structural formula selected from (ho group coosist-ng of

     or a tautomer, salt, solvate, and/or ester thereof
104. 157, The eomijound of claim 156, wherein the salt, is a hydrochloride or irifluoroacetate salt,
105. 158. The compound of claim 97, having srructural formula (llle) wherein:

     l>is halo, --NH--ORR -NH-NHR15, -$(OU-V\ or -NR/''R!6V
106. 159. The compound of claim 155, wherein R' 5 R*’, R'% and R:'s are independently hydrogen, alkyl, or Mfasihuied alkyl
107. 160. The compound of claim 159, where!» H is -OR>: 1 is ·Γ(1<Τ'}: J is t { [\ }·. ana K is ·<Υ1Τ>.
108. 161. The compound of claim 156, having stmeutm'd fe me la selected fro m the group consisting of

     or a tairfomer,. salt, solvate, and/or esier ihereoE ] 62. The eoropound oFefaioi .1 61, wherein the salt is hydroey odde or iriSyoroacetais salt i 63. The campo'ttnd ofelairsx 97, having sirueiitral Fomifita (XI):

     wherein, IIs k hydrogen, -OB, -SB, ~CN, -CBaOB or-CM -D is-OB or -SB; and A Is -Oil, -NH&amp; -NBCFE, -NiCH;)·, -NHC(<E>)CH3» -NHC(C)JOCIB?.-NH<S(0)NB2i -NHC(S)NH2, -NHC(NH)NH25 -CN, -CBjOB, "CHjNHCTh, -CHbNiCHBa, -C02K* •CONfK -CONHCH:,or-CBdSBaCdCBy provided that who» R’" is hydrogen, then R' "VR:,!i E'dary B7S ere not hydrogen.
109. 164. The compound of claim 163, wherein Rs? ;s -OR -SR -CN, or -COAT and Ak-NHy-NHCR, -N{CH^)2,-NHC{0)Ce^-NHC(0)0CHs>.-NHC(0)NH2, ~NHC(S}NTR ~NHC(NH)NH:>, -CN, -α·{>ΟΗ, -ΟΒ2ΝΒ2, -CRNBCR,-CB2NCCBR, ~CQRh -CONR, -CONBCR. or "CHhNHC(0}CR. 165. Ί ]5c compound of claim 164, wherein when R-'\ RA, R:i and R" arc hydrogen, D is -ORand Λ Η ·0(>.Ή: men Ri: is not •CO 41 or -OH; when E'4', 1" y iR and R*5 arc hydrogen, D is -OH, and A is ---NR; then Eu is not •CO 41 or CN; when E R ' and R are hydrogen. R'- is -OMe, D is (411 and A is -CH.>OH; then R is not and when R X R. 1 and R '' arc hydrogen, R;v: is hydrogen or methyl, P h -00, and A is -COAT then R1 ’ is not-SH.
110. 166. The compoimd of claim. 97, fund ng structural Forraui a 6X11); wlierein

     Ri2 is: hydrogen, -OH, -SR -CN, XifNOR or -CRH; D is -SH. or -OH; A.is -OB,.-NR, -NHCBi. -ROB A, -KHQO)('H?- ~NHC0}Q€BN.-MiC<O)M-R ~NeC(S)HB2, ~NBC(;NI:I}NI-B, -CN, ~CH -OH, -(41.NH . -CRNBCTF, -CBAXeBA, -COAT -CONR, -CON NCR, or A!:iRHCiO)CR; R:M is hydrogen, -OCR, -ORR, -ORH-, -CHy -RR, -CH(CH3)2, -CROR -CBXXAIy -CN, -C(O)NR4ll0% -CO>R4!, ~SORR3%4y -NR>#S02R*\ -BCQR^XOR40), -PCOMOR^KOR40} or -PCOKRwKOR40), and R?’ is hydrogen, -OCA, -OCAR N)RHy -Ok -CAR -CRCAk -CXhOH, -0Η20€Ην -Γ'Ν, -0(0}ΝΙΓ%4\ -C<>2R4\ ^QaNEtV4, -NR43502R44, -B|OR5')(OR44k -P{0)(0R i;HOR44) or -P{0)(R4-'){ORu). 16/. The ligand modifier of claim 166, wherein Rais -OH, -SB, -ON, -CB2OH or -0001. 1:68. The cempourid of claim 97, having struetaral Formula(Xtll): wherein:

     D is -Ο or ™:S; A η ΌΗ.. NH:, -NHCH-ί. -NiCKO;. -0110(0)(1-0,-0110(0)0011 ·. -NH0(0>NH2, ~NHO(S)NH;. -NHC(NH)NH >, -ON. -OH,>OH. -CH?NH;, -CBfNHOfk -OH =N{OH :)., -001:1. CONHl·, -OON HCH,?, or -CH>NHC(0)CH?; R! 0 hydrogen, alkyl, ary!. arylalkyl.
111. 169. The compound of claim 168, wherein when A is -0911). and .R:^ RR'' and R:r4 are hydrogen; then Rs; h not methyl., ethyl or phenyl 1.70, The compound of claim 168, having siraernml formula selected; from the group consisting of

     or a tautomer, p.U„ solvate, aad/or ester thereof,
112. 171. The compound of claim 170, whereto the pit is hydrochloride or trifluoroacetaiesalt
113. 172. The compound of claim 97, having structural Formula (X1Y); wherein Ι

     Α is -OH, -ΝΗ?. -NHOh. -Ν<ΟΙ»κ -NHttOCHi. -NHUOiOCVH, -MH€(G)NH2, -NHClSjNH», -NHCi NH)NH;·. -CN, -O\ OH, ~CH2HH2> -CH;NHOH<. -CRjNpik, -0¾¾ -CONH7. -CONHOi,. or -CH.NHQpR'H,, R; is alkyl, aryl, or atyialkyl,
114. 173. The eompo.und.Of claim 56, having structural Formula (IV):

     wherein: L is -CHR*-, -NR'57, -()- or -S-; M is -CHR.*5’-, -NR·*8, -0- Or -S~; Ris -CTIR6·-, -NR*\ -0- or -S~; I is -CHRfii-, -NR50, -0- or -S-; 0 and p are Independently 0, i, or 2; hydrogen, alkyl, auhstliuted alkyl, aryl, substituted aryl, arylalkyl, substituted arykdkyk acyl, substituted acyl, heicroalkyl, substituted hetetouikyk heteroaryl, substituted beteroaryL heteroarybikyl or substituted hete^oaryialkvl ,-CN. -NO:.·, -OR.'"’, -3(0),R)”, -OCOR6i, -NR^COR* -NR'-'-R"·', -C'CNR^R-5, -COdCN -S().iNRwRf>5. -NR^SO-R* »B(OR65 )(0R:ii5), -P(0)i OR6-}(ORiis) or -R(0)CR:-4)(0R6S}; R“ is hydrogen, alkyl, .substituted alkyl, aryl, substituted aryl aryfelky!, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted beteroalkyl, heteroary k substituted heteroaryl, before aryl alkyl of: substituted heteroarylalkyl ,-CN, -NG&amp;.-OR47', -StOkR06, -0C0R5* -NR^'C'OR4'·, -ΝΚ':Ίΐ° RX)NRtt:R<:\ -COall -SO.-NR^R6·. -NE^'SCEE^, -RtOR^KOR^k -PiOMOR^KOR''") or ~1>{0KR™}{0R*?); R^; is hydrogen, tdkyk'sutelituted alkyl aryl, substituted aryl, axylalkyb substituted aryblkyl, acyl, Mihsri rural acyl, heteroalky h substituted heteroalky k heteroaryk substituted heteroaryk heicrourvialkyi or substituted heteroarvlalkyi ,-CN, -NfO.% -OR'', ·$(0)νΚ*Ί -OCOR6\ --NR^COR vl -NR^R^, -CON'R''V;\ ·ΓΟ;;κ:ν. -ΧΟ:;ΝίΓ'4Γΐ -GR" sO.dd'l -B(OR'a)(ORw). ·P(0)(0R,aKORw) or -PlOXR^KOR*): R<;' is hydroyen, alkyl, substituted alkyl, aryl substituted ary], arylalkyl substituted arylaikyi, acyl, substituted acyl 'heteroalky!, substituted hcterodlkyl, heteroaryl, substituted hetetoaryb hetcroarytalkyl or substituted heteroarylalkyl ,-CN, -NO·.., -OR i;, -S(OkRΊ -OCOR:°, •NR';;'<'OR‘i, -NR i:R. !, ~CONR;i:Rvl -(ΧΗΓΙ -SO-NR'^R'5'. -NR^SQ.R71, • BtOR-'0KOR'''·},- P(OKORT°KORyi} or l>(OKR"i;}50Rri); or alternatively R6" and R6', R;a and R;'·. or R** and Rw together with the atoms to which they are bonded form an aryl, substituted aryl heteroaryk substituted hetoroaryi. eyefcalkyl, substituted cydoalkyl cyclohetcroalkyi or substi tu to d cy c 1 o h e te ro a iky 1 ring; t. u, v and x are independently 0. ] or 2: R‘a to R;i tbe.iftdop$hd?b#:hydro&amp;Kk-a&amp;yk.sal^tttuted alkyl aryl, substituted aryl,, arylalkyl, substituted arylalkyl heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl hetero arylalkyl of substituted heteroarylalkyl or alternatively Rm and RR'1· and R,: , R^' and Re\.bt.R.'8t«id'R.’;l together with the atoms to which they are bonded: form a eyolobewroalky: or substituted eyoiobeleroalkyl ting; and R4' to R"<! are independently hydrogen, alkyl substituted alkyl aryl substituted aryl, arylalkyl substituted arylalkyl asyk substituted1 acyl,, heforoalkyl substituted, heterualkyl heteroaryl substituted heteroaryl heioroarylalkyl or substituted heteroarylalkyl; with the-proviso that at most only one o.t L. M, R. and T is a heteroatom,
115. 174, Th e compo und of clai m 173, wherem .SB. is -N-, audEjs -141¾1 or -N~,
116. 175, The compound of claim 174, wherein G is
117. 176, The compound of claim 175, having struc rural Form u la (Xkr)-: wherein:

     D is -SH or-OH;-and Λ is -Oil -NH?, -NHCH·;. -NtOH-T. -NHCiOCH,.. -NHCtplOCH :. -NHC(Q)NHi. •NHC(S)NH:·. -NHC(NH|NH>, -CN.-CH.OH, -CH.NH . -CH,>NHCH?, -CHjNCOHOz. -CO»H* -CONH.v -CONHCH e or -CH.-NHCtO)CH =.
118. 177, The compound of claim 176, having siroetursl formula selected from the group consisting of

     or-a taotomer, salt, solvate, aud/Or ester thereof
119. 178. The compound ofelaim. .177, wherein, the salt, is hydrochloride or irifluoroaeetate salt.
120. 179. The compound of claim, 174, wherein A Is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, -01:6 -81¾9. -€N,-NR9Ri:i, -CQNfcV, -CCihR9, -NR^CGhk \ -NR9C0NRmRu? ~M!l'!CSNR!uRn or -NR9CO=NHlNK%n; and D is <>, ===S , ;::N-OR:
121. 180, The compound of claim 174, having structural Fm nula (!Yb); wherein.

     L is -CHR''*-; M is -CHR65-. R is -('HR:5'··. T is -CHR’ 18L The compound of daim. 180, having: structural formula selected from the group consisting of;

     or a tautomer,, salt, solvate, and/or ester thereof
122. 182. The compound of daim i 8.1,. wherein the salt is hydrochloride or trifluoroacetate salt.
123. 183. The compound of claim 173, having structural Formula (§Ya>:

     84. The compound of Claim .! 83, wherein L is -CHR·*-; M is -CHR—:. R is -CHIR^^-fand T Is -('HR'"-. ! 85. The compound of Claim 184, wherein A is hydrogen, aikyh substituted alkyl, aryl, substituted aryl, ~GR\ -SRu -CN, -NRV'f -CONRV*. --CCHR', -NR’"CO,R:i;,. -NR^XINR16!^-NR'CSNRi?iR!5 or -NR^Cf-NHlNR5'^11,
124. 186. Th e ccinpo und of claim 183, having structural formula selected from the group consisting ofi

     or a tautomer, salt, solvate, and/or ester thereof. 18'?. The compound of claim 186, wherein the salt: is hydrochloride or iriSuoroaeeiaie salt.
125. 188. The compound of claim 58* having structural Formula {Va); wherein:

     0 is.hydrogen, alkyl, ar>!, halo. -OH, -SR1", -OH'.. -CCTH or -CONH>: A is -NBw -KHOR. -N(CHig, -NfKdOKTiv -NHOO)OCB.n -NBC{0}NH.:;. ~NHC{S)NH.\ -ΝΗΠΝΗΙΝΗ··, -CN, -01/)11 -(Ή>ΝΗ;, YTlNHCfR, ·Π 10(010, -CCbB, -CONH =. -CUNHCH ·... or -€H;NHC(0}CHg ana R5j is hydrogen, alkyl, substituisd alkyl, arylalkyl
126. 189. The cm pound of claim 188, wherein Y terms a single bond with W and a double bond with Z; W is -CfRf V ©r~N»;. Y Is -0(Κλ>όγ “-In-; and: 2 Is 8-,. -Ni R‘\ · a —0-,
127. 190. The compound of e!aim 188, wherein Y forms a double bond.with'W and a single-bond. with. Z; W Is S-..-Nir:K or -ΟΥ Is “ C(R ^}- or -N-; and

     7. Is -0(11 1- or -hi*. .191. The compound of claim. 189 or .190, wherein B is -€(RU}-. .192. The compound of claim, 188, having structural F<>'"nula (V):

     wherein: R·'· is hydrogen, alkyl. halo, -COdT'A -COMR^R55, -SOa'NR^R55, -NR^SGiE55, •B<OR5: i(OR::'}, -PiOKOR^iCOR"·} or PlOltR^OR"): R'" is hydrogen, alkoxy. alkyl substituted alkyl, b,dos -ON. -{'iOiNR'"R , ·Γ0;;Ϊ<>{'.. -SOvNRGV; -NR^SO.R"·, .BiOR^KOR*7), -PIOMOR^XOR'"} or "P(OXR-*>iOR-1; or alternatively RJ“ and R5’ together with the atoms to which they are bonded form a cycioheteroalky] or substituted evciohctcroalkyi ring and R·4. R'\ R ;i:, and Rv are independently hydrogen, alkyl, substituted alky!., aryi. substituted aryl, aryl alkyl, substituted arylalkyl, acyl su^dnit^-sicylvhetero'alkyl, substituted he seres iky I. hcteroasyl. substituted heteroaryl, heterourylalkyl or substituted hcteroarylalkyi; or aiternatively R " and R '' or R/': ansi R' together with the atoms to which: they/ are bonded form a cyeloheteroaiky i or substituted cyeloheteroalkyl ring; provided that when R 'e' and R~: are hydrogen, and D is -SK; then A is ~Nlis,
128. 193. The compound of claim .192, wherein when D is methyl, A is dimethyl amino, and R>-' is hydrogen:; then R><! U not. methyl, ethyl or carboxyl; when D is methyl, A Is dimethylmnino, and R" is methyl; then R."1 is not'methyl; when I> is -SCH>, A. is dimethyl amino, anti R*" is hydrogen; then is not earboefhnxy; when D is hydrogen·, A Is diotethyiamhio, and R'v is hydrogen; then R/‘,<: is not carboxyl of earboethoxy; when D is .hydrogen, A is diinethyiandno and R"‘ is methyl; then R'' is not methyl; when D is hydrogen, A is rnethylamino and R.ro is hydrogen; then R'" is not methyl, ethyl or earboeihoxy;: , . ^ ¾ · -’5·'Τ when D is hydrogen,. A: is rnethylamino and BA is methyl;, then R"‘ ' is not methyl or earboeihoxy; when D is hydrogen, A is rnethylamino and ΒΛ> is -CH;NMc; then R'' is not methyl or carhoetboxy; when D is phenyl A is methyiamino and R" is hydrogen then R ' R not methyl; and when I> is phenyl. A is -NlhCOlCHi and R is methyl then R " is no! earbomeUtoxy.
129. 194. The ligand modifier of claim 192, ha ving structural formula ( VI);

     wherein D is hydrogen. -ΓΗ.?, -C/hl.e phenyl or benzyl.
130. 195. The compound of claim 192, having strucfnml formula (VII):

     wherein A Is hydrogen, -CH.?, -¾¾ phenyl or benzyl
131. 196. The compo nod of claim 192, having structural formula (VIII};

     wherein ifo and R50 are independently hydrogen, -011,1, -¾¾ phenyl or benzyl; and provided that both hfo and. R1:0 are not hydrogen.

     97, The compound of claim 192, having structural formula (IX): wherein

     R·· is alkyl, substituted alkyl, -ON', -CiOiNR':R''. -t'iVR- \ -yOfoR^R^, -NR^SOjR". ~B>;OR5!)(0R"), -f>(0)iOR/" i(ORor -Pi OKRM){OR " k R" is alkyl, 00.;R·'' or -CONfR?f,R5\ .SO;.NR*R5\-NRs%02RS7s. ~Β(0106)(()Κ5% -P{0)(0R:;<:H()Rr} or -R(())i!00iOR;;“), and R^to R5’ are independently hydrogen, alkyl, substituted alkyl, aryl Mthstituied aryl, arylafkyl, substituted uryiaikyl acylysubstituted acyl, hcteroaikyl substituted hcteroaikyl. heteroaryi, substituted heioroaryl. heteroarylalkyl or substituted heteroaryialkyk or altemameh R' : and R ' together vvith the atoms to which they are bonded form a eycioheteroutkyl or substituted cyclohcteroaikvf ring,
132. 198. The compound of claim, 192, having structural formula (X): wherein,

     D is ~0H, ~SH or -NHj, R ' is alkyls substituted alkyl, alkoxy, -C'N, -0(0)NRJ<R'', -CO,>R' ‘, -SO.-NR^R''*, -TiR^SCoR77, ~.B(OR' ;}iOR ···), -P(0)(0R "KOR55}. «P{0}(RM}i0Rr}, and l”4 arklR" are independently hydrogen, alkyl substituted alkyl aryl, substituted aryl, ayylaikyi, substiiofod arylalkyi, acyl, srihsbtuted acyl, heteroalkyl, substituted heieroalkyh heteroaryi, snhstilnted lieteroaryl, heteroarylalkyl or suhstTruted hetemafylalkyl; or alternatively R/4 and R ' together with the atoms to which they are bonded form a: eycloheteroalkyl or subhti to ted eye I oheteroalky 1 ring.
133. 199, The compound of claim 1 sh, having structural formula selected, from, the group consisting of

     wherein, R;~ U OH, -SH. «ΟΝ, -(Ή;;ΟΗ. or CXhH: and RSJ Is CH% -Ce2CH3> benzyl or or a tautomer. said solvate, and/or ester thereof.
134. 200. The compound of claim 109, wherein the: salt, is hydrochloride or irifuom&amp;cetate salt, 201., Α» mgesdbfe composition comprising the ehemosensory receptor bgaod modifier of claim 52.
135. 202. The ingestibie composition of claim 20.1, selected from the group consisting of a comestible composition, a medicinal composition, a .pharmaceutical composition, cot! eonibinaiions thereof 2:03. The ingcsiibk· composition of claim 201, selected from the group consisting of food or beverage product, non-edible product, and combinations, thereof
136. 204, The mgesiihle composition. of claim 203, wherein the food or beverage product is selected from the group consisting of the Soup category; the Dried. Processed. Food category; the Beverage category; the Ready Meal category", the Canned or Preserved Food category, the Frozen Processed Food category; the Chided Processed Food category: the Snack Food category; the Baked Goods category; the Confectionary category; the- Dairy Product category; due tcc Cream category; the Meal Replacement category; the Rasta and Noodle category-; the Sauces, Dressings, Condiments category; the Baby Food category:-; the Spreads category; sweet coalings, frostings, or glazes; and combinations thereof. 2()5. The iogestibie composition of claim 2(B, wherein the non-edible product is selected from the group consisting of nutritional products and dietary supplements, pharmaceuticals, over the .counter medications, ora! care products, and cosmetics,
137. 205. The ingestjfete; composition of claim 201. wherein the ehemosensory receptor ligand modifier is acompound having structural Formula (f) as described in claim 5fi, or a tautomer, salt, solvate, and/or ester thereof
138. 207. The higestihle composition of chum. 20 i. comprising at least about 0.0001 ppm of the ehemosensory receptor ligand modifier. 20h, The ingestibie composition of claim 20.1, comprising from about 0,0001 ppm. to about 10 ppm of the ehemosensory receptor ligand rnodifier.
139. 209. The digestible composition of claim 2(.0., comprising from about 0.(.0 ppm to about 100 ppm of the. chemosettsoty receptor ligand. modifier,
140. 210. The digestible composition of claim 201, comprising from about 1.0 ppm to about 100,000 ppm of the ehemoscnsms receptor ligand modi Her.
141. 211. The ingostible composition .of claim 201, further comprising one or more sweeteoers,
142. 212. The digestible composition of claim 211, wherein the sweetener is selected frout the group consisting of sucrose, fructose, glucose, galactose; mauaose, lactose, tagatose, maltose, corn syrup (including high fructose conn syrup), D-tryptophan, glycine, tryihntoi, isomalt, lactitof, mannitol sorbitol, xyiitoi, maitodextrin, rnaltitol, isomalt, hydrogenated glucose syrup (HGS). hydrogenated starch hydrolysate (HSH), stevioside, rebaudioside A, other sweet S term-based giyeosidss, carrei&amp;me, other guanidine-based sweeteners, saccharin, accsulfamc-K, cyclamafe, sueraiose. ahtam.e. mogroside, neotame, aspartame, other aspartanm derivatives, and co m bin at ions the reo f
143. 213. The digestible composition of claim 20b, wherein the obemoseasory recep tor ligand tnodiHer *s a comp.mud having structural Formula (111 as described in claim 58 or struiural Formula {111) as described, m claim 97, or a tardomer, salt, solvate, and/or ester thereof.
144. 214. The ingestible composition of claim 20b, wherein the chemosenspry receptor ligand modifier has structural Formula (lla) as described in claim 60, structural Formula (He) as described in claim 73, structural 'Formula·· (Illb) as deserihed in claim 124, or struetural. Formula (TTIb I) as described in claim; 133, or a tautomer, salt., solvate, and/or ester thereof
145. 215. The ingestible composition of claim. 202, wherem the phamiaceutioal composition comprises a compound having structural. Form ula (I) as described in claim 56, of a tautomer, salt, so \ ate, and/or ester thereof; and a pharmaceutically acceptable vehicle.
146. 216, A method of enhancing the sweet taste of an ingest*b!e composition comprising contacting the irigcshble composition or precursors thereof with a chcniosensorv receptor ligand, modifier to form, a modified: mgestlbie composition,
147. 217, The method of claim 216, wherein the in geshble composition is selected from the group consisting of a comestible composition, a .medicinal composition, a pharmaceutical composition, and ..compositions thereof.
148. 218, The method of claim 216, wherein the ingestlhle/composition is selected'from the group consisting of food, or beverage -prodact, non-edibleprod.net, and combinations thereof 2i‘T The method of claim 21b, wherein the m> «dined inccMiWe composition comprises at: least about 0 001 ppm of the ehemos«ens«ir>· receptor ligand modifier.
149. 220, The method of chum 216, wherein the modified ingestible "composition comprises from: about 0.001 ppm to shoot i 00,000 ppm of the chonioseusory receptor ligand modifier,
150. 221, The method of claim: 216, wherein the ehemosensory receptor ligand modifier is a compound having structural Formula (!) as: described in claim 56, ora tautomer, sab, solvate, and/or ester thereof
151. 222, The method of claim 216, wherein the ehemosesasory receptor ligand esichaneer Is a compound having structural Formula (IV) as: described In claim 58 orstruinrai Formula (111) as described in claim 9'K or a tautomer, sab., solveto, and/or ester thereof
152. 225. The method of claim 216. wherein the chcmosensory receptor ligand enehancer has structural formula (11a) as described: in claim. 60, structural Formula (He) as described in claim 73, structural· Formula (Iflb) as described in claim 128, or structural Formula (inbl) as described In claim 1:38, or a tautomer, salt, solvate, and/or ester thereof

     224. A method of Itcaimg a condition associated with a chemosensory receptor compiiMW» administering to a. subject ίο need of such treatment an effecti ve amount of an, entity selected from the group consisting of a ehemosensory reesspior .hiodifier,'CbmosemOfy' receptor ligand modiiier, and a combination thereof wherein the entity iatmefe. with an interacting site of the chemosensory receptor.

     225. The method of claim 224, where!» the condition associated with a eheaiosensory receptor is taste,
153. 226. The method of claim 224, wherein the-conditio» ^oocutcd w no a chemosensory receptor is a. condition associated with gastrointestinal system or metabolic disorders.
154. 227. The method of claim 224, wherein die condition associated with a chemosensory receptor is a condition associated with a functional gastrointestinal disorder.
155. 228. The method of claim 224, wherein the condition, associated with a ehemosensory receptor is a. condition associated with cells expressing allR.

     224. The method of claim 224, whesein the condition associated, with a chemosensory receptor is a condition associated with hormone-producing cells that express a: Ti ff ,
156. 230. Hie method of claim 224, wherein the entity is a chemosensory receptor ligand modifier.
157. 231. The method of claim 230, wherein the chemosensory receptor ligand modifier is a compound having structural Formula (1) as described in claim 56, or a tautomer, salt,, solvate, and/or ester thereof
158. 232. Tl re method of claim 230, wherein the chemosensory receptor ligand modifier is a compound has ing structural Formula (II) as described hi claim 58 or struinrafForrmila (III) as described in claim 47, or a tautomer* salt, solvate, and/or ester thereof.
159. 233. The method of claim 230, wherein the chemoscnsory receptor ligand modifies has structural Formula (lla) as described in claim <V), structural Formula (lie) as described in claim 73, structural Formula,.(illfc) as described in claim 12S, or structural. Formula (IBbl) as.dsscribed in claim 138, or a tautomes, salt, solvate, asid/or ester thereof.
160. 234. A process of preparing a compound ha\ am sirucmnd Formula (a);

     comprising reaodng a con mound having structural Formula ib} v\ dh a base,

     wherein: D is oxygon or'sulfur; A is -M:b or -ORhf R.!: is hydrogen, alkyl,· substitnted alkyl, aryl, substituted· aryl, arylaiky!, or substituted arylalkyk Rf: and R " arc independently hydrogen, alkyl, substituted •-cks 1. ay,k substituted aryl, arylalkyi. substituted arylalkyl, acyl, substituted acyl, heteroalky 1, substituted hctcroaik>L beteroaiyl, substituted hcteioaryl, heterearylaikyl, substituted heteroaryialkyl, -CN, -NOa, -OR:’5, "S{C)}hRrs, -CONKER ·\ -S07NR’-5R’-\ or -NR^SOjR/2; or alternativelyW6 and Rftogether with theorems to winch they are bonded, form a eycioalkyf, substituted. cxv-loalkyVheterobydfeaikyi, of sd&amp;$tuted bctcrocycloulkyl ring; Ar is aryl or substituted aryl; and E* is -CN, -iftOlRT ·μΟΚ)Ε\ -00)^(¾¾ each Rf is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryhikyl, substituted arylalkyl, acyl substituted acyl, hetcroalkyl, substituted hctcroaikyL hctcroaryk substituted hctcroarvl, hctcrearyblkyl. or substituted hciemarydalkyl; h is 0, l or 2; and R'· and R*- are independently hydmgen, alkyl, substituted alkyl, aryl substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl. substituted heterowyl. hctcroarylalkyl or substituted heteroaryialkyk or altemameh R'! and R':, together with the atoms to which they are bonded, form a eyclobcteroalkyl or substituted cycloheteroaiky I ring,
161. 235, The process of claim 234, where!» the base is an inorganic base, 236;, The process of claim .734, wherein the compound having structural Formula -b) is prepared by reacting a compound having structural Formula (eg

     ά nh a eoitipoabdhaying structural Fonmula fd}:
162. 237, The process of claim 334 or 236, wherein Ac is phenyl or substituted phenyl.
163. 238, A process of preparing a compound having structural Formula (e);

     comprising reacting » compound having structural Formula'll) with a base,

     wherein: A is -NH; or -OR*'; RJ ·' is hydrogen, alkyl, substituted alkyl, aryl substituted aryi, aryiaikyh or substifeted. arytaikvl·. R'Rfo', R;,i5 and R:><s are each independently hydrogen, aikyl, substituted.alkyi,. aryl, substituted aryl. ray.bilk). I. substituted arylaikyl, acyl, substituted acyl. haio. ) ale ro alkyl, substituted heteroaikyl, ho ternary!, substituted heteroaryl, heteroarylalkyl or substituted heteroarylaikyi,fodfo-NCb, -OR41, -${0}kR4\ -NR%43, -CONR'^R4". ~CO>Rn, -S02NR41R42, and -NR^'SQjR^' or alternatively) R'4 and R'T R ''' and R'b or R' ; and. R2*, together with the atoms to which they are bonded, form a cyeloalkyl, substituted eyeloa.ik.yk heferocycioalkyl, or substituted heterocycloalkyl ring; Re is is -CHf -0(0)¾13. -C(0)0R\ *C(0)N(Rn)v each R° is independently hydrogen, alkyl, substituted aikyl, aryl, substituted aryl, arylalkyl, substituted arylalkyi, acyl, substituted acyl, heteroaikyk substituted beterbaikyi, beteroaryl, substituted beteroaryl, beteroarylaikyl, or substituted heteroarylaikyi; and R*‘ and Ru are independently hydrogen, alkyl, stsbslituted alkyi, aryl, substituted aryl, arylalkyi, substituted arylalkyi, acyl, substituted acyl, beteroalkyl, substifeted. heteroalkyf, heteroaryl, substituted beteroaryl, heteroarylaikyi or substituted beteroaryiaikyi; or alternatively R4! and R4 together with the atoms to which they are bonded, form, a eyelobeteroalkyi or su bst tt \ tted eve I o heter oa I ky I ri n g,
164. 239. The process of c laim 23b, wherein .the base is an inorganic bass,
165. 240. Λ process of preparing a compound having structural Formula to.

     comprising rending a compound having structural Formula (gr

     with NH,>S(Of,?NH,? or Cl-SfOVNHl· in the presence of a base to provide directly a compound having structural Formula (c); or alternatively to provide the compound having structural formula (t) of claim 22.1 which is further reacted with a base to provide a compound having structural formula (cl. 24L The process of claim 240, therein the base is an organic base.