8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, its salts, solvates or hydrates and its use for the treatment of CNS disorderes

t/eecnpiion

Fleld of the Inventlon [0001] The present ínventlon relates to compounds whlch act as modulators of SHTg. receptors, compositions in-dudlng the compounde, and methods of ueing the compounds.

Bækgreund of the Inventlon [0002] Obeeky is a life-threataning dlsorder ln which there Is an increased rtsk ol morbidlty and mortality arising from concomitant diseases such aa type II diabetes, hypertenslon, strake, canoer and gallbladder dlsease.

[0003] Obesity is now a major hsalthcare Issue in tha Westam Worid and increaslngly in some third world oountriaa. The Increase in numbars oF obese people Is due largely to the incraasing prafarenca for high fat contant foods but also, and this can be a more important factor, tha decraasa ln activity In most people's lives. In tha last 10 years there haa been a 30% increase in the Incldence of obeslty In the USA and that about 30% of the population of the USA is now conslderad obese.

[0004] Whether somaone is classlfied aa ovarwalght or obasa Is ganerally datanmlnad on tha basis oF thalr body mass index (BMI) whlch Is calculated by dlvidlng body waight (kg) by haight squared (m²). Thus, the units of BMI are kg/m² and It Is posslbletocalculatethe BMI rangeaeaoclated wlth mlnlmum mortallty In each decadeof llfe. Ovarweight Is deflned as a BMI In tha range 25-30 kgAn⁸, and obasity as a BMI greatar than 30 kgAn® (see TABLE below).

<img file="IS2134B_D0001.tif" /> [0005] As tha BMI Increases there is an Increased risk oF death from a varlety oF causes that is Independent of other rtek factora. The rnost oommon disaasas with obeslty ara cardiovascular dlsaase (particularty hypertansion), diabetae (obasity aggravatea tha development oF dlabetes), gall bladder dfeease (partlcularly cancer) and diseases oF repra-ductlon. Rasaarch haa ahown that evan a modest reduction In body weight can eorrespond to a signiflcant reduction In the rlsk oF developlng eoronary haart diseasa.

[0006] There are problarr» howevarwith the BMI deflnFtJon fn that it dœs nottake Into accounttha proportion o( body mass that Is muacle ln relatlon to fat (adlpoea tissua). To account For ttils, obeslty can alao ba dafined on the basls of body Fat contant: greater than 25% in malas and 30% in femalas, [0000 Obeelty conslderabty incraases tha rtek oF devaloplng cardlovaacular dlseases as wall. Coranary Insufficlency, atheromatous dlsease, and cardlac Insufficlency are at the forefront oF the cardiovaacular cornplication induced by obaeity. It is eetlmatad that IF tha entlre population had an Idaal walght, tha risk of coronary Insufflclancy would decreaae by 25% and the rlak oF cardlac IneulFldency and oF carabral vascular acddenta by 35%. Tha incldence oF coronaiy (ϋβθΒβββ is doubled in subjacts leas than 50 yaare of aga who ara 30% overwaight. Tha dlabetae patient faces a 30% reduead HFeepan. After aga 45, paopla with dlabates am about three timee more nkely than paople wlthout dlabetes to have slgnificant heart dlsease and up to flva tlmas more Ikaly to hava a atroka. These findlngs emphasize the fnter-relatlons bstwaen rlsks factore For NIDDM and coranaiy heart disaasa and the potantlal valua oF an Intagrated approach to the prevantlon oF ttiese conditlons baaed on the preventlon oF obesity (Parry, I. J„ at al„ SftW310,560-564 (1995)). [0008] Dlabetes has also baan Impllcatad in the davelopmant oF kidnay disaase, eye dlseases and narvous-systam problems. Kldney dlaease, also called nephropathy, oocure wtian the ΙάΟηβ/Β "fllter machanlsm" Is damaged and pratein leaks Into urina In exceeelve amourrts and eventually the kldney fails. Dlabetes is also a leading cause of damageto ttie retlna atthe back oF tha vp and Incraases riskof cataracts and glaucoma. Finally, dlabetas Is asaoclated wlth nerve damage, eapacfally In tha legs and faet, whlch Intarferee wtth the ability to senss pain and contributes to saríouB infectlons. Taken togsther, dlabetee compllcatlons are one of the nation's leadlng causes oF death.

[0009] The First line ot treatment is to offerdiet and llfe style advlcB to patients such as redueing the fat content of

<img file="IS2134B_D0002.tif" />

thelr dlat and incraasing thair physlcal actlvity. Howavarmany patíents flnd thls difflcult and naed additional help from drug therapy to malntain results from thesa efforts.

[0010] Most eurrently markated products have baen unsuœeaaful as treatmants for obeslty owlng to a lack of efOeacy or unacceptable aide-effect profiles. The most succasslul drug so far was the Indirectly acting 5-hydroxytryptamlne (5-HT) agoniat d-lenfluramlne (Redux™) but reports ot cardiac valve defects in up to ona third of patients (ed to its withdrawal by the FDA In 1998.

[0011] ln addltton, two drugs have recently been launched In ttie USA and Europe: Orlistat (Xanlcal™), a drug that prevante abeorptlon of fat by tha inhibition of pancreatfc lipase, and Slbutramlne (Raductil™), a 5-HT/noradrenaline re-uptake mhibitor. However, slde aflacts assodated with these produets may limit their long-term utility. Treatment with Xenleal™ Is reported to induee gastrolntastlnal dlstrese In some patlenta, whlle Stoutramine has bean assoclated with raised blood pressure In some patiente.

[0012] Serotonin (5-HT) naurotransmisslon plays an Important role in numerous physiological processee both in health and In peyehlatric dteordars. 5-HT has baan implicatad In the regulatlon of feedlng behaviorfor sometlma. 5-HT appears to work by Induolng a feellng of fullness or satlety so eatíng stops earller and fewar calories ara consumed. It hae been shown that a sthnulatoiy actlon of S-HT on tha 5HT_æ recaptor plays an Important rola ln the control of eatlng and In the antl-obaalty effect of d-fanfluramlne. As tha 5-HT_ac receptor Isexpressed in high density in tha brain (notably in tha llmbic structuras, extrapyramidal pathways, thalamus and hypothalamus l.e. PVN and DMH, and pre-domlnantly in the chorold plexus) and Is expresaad In low denaity or Is abaent In peripharal tlssues, a selectiva 5-HT^ reoaptor agonlst can be a more effective and safe anti-obaslty agant. Alao, δ-ΗΤχ knockout mlce ara overwelght with cognltlve impairment and susceptibllrty to seizure.

[0013] It is baliavad that SHTæ may play a rola in obsesalve compulslve dlsordar, soma forms of daptession, and epllepsy. Accoidlngly, agonlsts can hava antl-panlc propertiea, and propartlæ useful for the treatmenl of sexual dys-functlon.

[0014] In sum, tha 5ΗΤ_Κ receptor ls a validated and well-ecceptad receptor targat for the treatment of obesity and paychlatrlc dlsordera, and It can be sean that there Is a nead for eelective 5HTjc agonists whlch safaly decrease food Intake and body walght. The present Inventlon Is dlracted to thesa, as wall aa othar, Important encte.

[0015] US 3,852,543 (Hoagarie) descrlbes methods for tha preparatian of certain 1,2,4,5-tetrahydro-3-azepines whlch are allegedly useful as chemlcal fntaimedlatas. Sbc banzazaplne compounds appear In the table at column 8, llnes 25-35 (on tfia rlght hand skte) thereln. 7-chtora-1,2,4,5-tetrahydro-3-banzazeplne hydrochloride lacks an R_z group as requlred by tha clalmed invention (thls compound has -H as R^. 2-methyl-1,2,4,5-tetrahydro-3-benzazepine lacks Rj and R3 groupa as requlred by theclalmed Inventlon (thls compound has -H as R₂, and -H as Rj). 1 -phenyl-1,2,4,5-tet-rahydro-3-banzazaplne lacka and Rg greupa ae requlred by the elalmed Invention (this compound has -Ph as Ra, and -H as Rj). 1 ^,3,4,48,8,7,11 b-QCtahydro-5H-dlbenz[d_&gt;b]azepine doas not have tha same oore etructure as requlrad by the cblmed invention. 4-mattiyl-12,4,5-tetrahydrD-3-benzazeplne lacks R₂ and R₃ groups as required by the claimad Invention (thls compound hae -H as R₂, and -H aa Rg). 5-mathyl-8-l8opropyl-1,2,4,5-tetrahydro-3-benzazepine lacks Rg and R&lt; groups aa required by tha dalmed inventlon (thls compound has -H as Rj, and Isopropyl as R^.

[0016] US 4,111,957 (Holdart at al.) dascrbaa cartain 7,B-dlhydra)(y-2,3,4,5-tetrahydra-1H-3-benzazeplne8, which ara allegad to have dopamlnerglc actlvlty. A slngla banzazeplne compound (used aa a chamlcal Intermedlate) is shown at oolumn 8, llnea 28-27 theretn. 1 -hydrexy-7,8-dlmethoxy-2,3,4,5-tetrahydro-1 Η-3-benzazepine lacks an (¾ group as requlred by tha dalmad Irwentlon (thle compound hae -OCH₃ as RJ.

[0017] US 4,988,690 (Effland etal.) describea certain 1 -aryloxy-2_l3,4,5-tetrahydro-3-benzazepinee whlch are allagad to hava antldepre88ant, antJiypsrtenslve, and analgaslc propertles. All of these compounda lack R_a and R^ graupa ae raqulrad by tha clalmad invantlon (thesa compounda have aiyloxy aa R₂ and R^J. A slngle benzazepine compound (uaed aa achemlcal Intermedlate) te ehown atoolumn 12, Hnas 31-32therein. 1-hydroxy-2,3,43-teilrahydiO-1H-3-ben-zazeplna lacte an greup as requirad by the daimad invantion (thls compound has -H as fý.

[Ο01Β] US 6,015,639 (Bargar at al) daecrlbea certain 1-eubstibted-2,3,4,5-tetrahydro-1H-banzazepines whlch ara alleged to be usaful ln tha traatmant of paychoals, achizaphrenla, depresslan, paln, and anxlety. A generlc dsflnltlon of a larga n umber of benzazeplne compounds Is provlded at columna 1 and 2 therein. Each of thase compounds lacks an Rs group aa raqulred by the clalmed Invantion. In eaeh casa, tha redted group R® (correspondlng to tha group R₃herein) |a -OR¹⁰, -Ν^, or-OCJR^jOCOR’³.

[0019] GB1268243(Wallaca4'nemanlnc,)deBcribescartain 1,2,4,5-tstarhyrD-3H-bBnzazBplnaBWhlchareallegad to be useful as analgetlcs (In the traatmant of paln) and as antagonlats of nareotlcs (In tha treatmant of drug addtotion) and to hava antí hbtamlnlc and anticholinergie actívlíy. Twelve banzazaplne compounde are shown in the table on paga 23 theraln. The firat alx campounds lack an Rj group as required by the clalmed Invantlon (thaae compounds hava -OH or -OCH₃ aa Rj). Tha laat aix oompounde lack R, and R3 groups as requlred by tha clalmed invantlon (thase compounds hava varlous aryl-alkyl groupa as R_1t and -OH or-OCM₃ as R3).

Summary trl the Inventton [0020] Tha prasant Inventlon, In ona aepact, relataa to compounds reprasantad by Formula (I):

<img file="IS2134B_D0003.tif" /> wherein:

R-ι Is: -H or C₁₄alkyl;

1¾ is: C,.galkyl, -CH₂O-C₁₄alkyl, -C(=O)-O-C_Malkyl, -C(=O)-NH-C_Halkyl, -OH, or -CH₂OH;

Rjgls:-H;

or R2 and Rja togetherform -CH₂-CH₂-;

Rj is: halogen; pertialoalkyl; or a 5-mambered hetaroaryl ring havlng up lo two hateroatoms selected from Ο, N andS;

R₄ Is -H, halogan, perhaloalkyl, -CN, -OR_Sl -SR_s, -NHRj, -N(R₅)₂, -OH, aiyl, or heteroaryl, wherein aaid aryl can ba optlonally siJsstituted wlth up to two substituants aalectad frem C₁₄alkyl, halogan, perhaloalkyl, and altoxy, and sald heteroaryl can be optlonally aubstituted wtth up to two substltuents aalected from halogen and C^alkyl; or Rj and R₄ togathar wlth tha atoma lo whlch thay ara attached form a 5- or 6-membar hetarocydlc ríng having onaOatom;

aach Rj la independantly C₁₄alkyl, C₁₄alkenyl, aryl, hateroaryl, arylalkyl, hetaraaiylalkyl or parhaloalkyl, or allyl; and

Rgls-HorC^kyl;

and pharmaceutically acceptabte salts, solvates and hydrates thereoF; provlded that: íf Rg fa otharthan -H, then R₄ cannot be -H; and

If R₁ and R₂ aremethyl, and R₊ls -H, than Rj cannotbe Imldazole, substltuted imidazola, or an imldazole darlvaöve.

(0021] In eoma ambodlmanta of the compounda ol Formula (I), R, Is K. In some ambodlmants of tha compounds of Formula (I), R, te C_M alkyl. In aome ambodlmants of ttia compounds of Formula [I], R₁ is methyl. In some ambodiments of the compounda of Foimula (I), R^ Is n-propyl.

[0022] In eoma embodlments ol tha compounds ol Formula (I), Rj Is C₁₄ alkyl. In some ambodimants of tha compounds of Formula (I), R₂ ls methyl. In some ambodlments of the compounds of Formula (I), Rj Is ethyl. In some ambodlmants of tha compaunds of Formula (I), R₂ Is Isopropyl. In soma ambodimants of tha compounds of Formula (I), R₂ and R^ togetherform -CHgOHjr.

[0023] In 8ΟΓΠ8 embodlments of the compounds of Foimula (I), R3 is halogen. In some embodknente of tha com-pounde of Formuia (I), Rg is chlorina. In eome ambodimants of the compounds of Formula (I), R3 is bromine. In some embodlmants of tha compounds of Formula (I), Rj is lodlna. In awna embodimants of tha compounds of Formula (I), Rg Is perhaloalkyl. In some embodlmante of tha compounde of Formula (I), R₃ Is CF₃. In soma ambodimants of tha compounde of Formula (I), R₃ te a 5-membered heteraaiyl ring having up to two heteroatoms selected from Ο, N and S. In soma embodlmants, Rj Ib a radfcal darived fram thiophenyl, furanyf, pyrrolyl, pyrazolyl or Imldazolyl.

[0024] in some ambodlments of tha eompounds of Formula (I), R₄ ia perhaloalkyl. In some embodiments of tha compounds tít Formula (I), R₄ Is CF_a. In eoma ambodlmentB of the compounda of Formula (I), R₄ Is -OR₅. In some ambodlments Rj is mathyl, athyl, n-prapyl, leopropyl or allyl. In some embodlmants of tha compounds of Formula (I), Rg la methyl or allyl. In aoma ambodiments oí thecompounds of Formula (I), R₄ Is a 5-mambered hatatoaiyl ring havlng up to two heteroatoms selecíad from Ο, N and S, and up to two eubstltuants selected from halogen and C₁₄ alkyl. In eome ambodlrnants, r₄ Is a radical derlved from thiophenyl, furanyl, pyrrolyl, pyrazolyl or Imidazolyl, whlch can optionally be mono- or di-eubetftuted eelected from halogan or mathyl. In soma ambodimante of the compounds ol Formula (I), is phenyl optionally aubstituted with up to two substltuerrts selected f rom C₁₄ alkyl, halogen, and alkoxy. In some embodiments of the compounds of Formula (I), Rg and R₄ taken together form -O-CH=C(CH₃)-.

<img file="IS2134B_D0004.tif" />

[0025] Ιπ some embodiments of the compounds of Formula 0), Rj is halogan and R4 ls

-OR_S wharaln Rj Is C₁₄ alkyl. In soma embodimenta of the compounds of Formula (I), R3 Is ehlorine and R₄ is -OR_Swhereln R₅ Is alkyl. In aoma ambodlmants of the compounde of Formula (I), R3 Is bromlna and R₄ Is -OR₅ whereln

R_s Is alkyl. In some ambodlmente of the compounds of Formula (I), Rj Is lodlne and R₄ Is -OR_S wherein Rg b C₁₄alkyl. In some embodlmants of tha compounds of Formula (I), R₃ is halogen and R₄ Is methoxy. In one embodimant, R₃ Is chlorlna or bromlne and R₄ ls mathoxy. In soma ambodlments of Ihe compounds of Formula (I), R3 is halogen and Is allyloxy.

[0026] In soma ambodlments of tha compounds of Formula (I):

Rj Is methyl, athyl, Isaprapyl, or CHjOH; or Rj and R^ taken togethar torm -CHj-CHj-;

Rj Is halogen. or a 5-membared hetercaryl ring havlng up to two hetaroatoms selacted from Ο, N and S, and up to two aubstltuents aelactad from halogen and C₁₄ alkyl;

R₄ is H, alkoxy, a 5-memberad heteroaryl ring having up to two hateroatoms salectad from Ο, N and S and up to two aubstítuants selected from halogen and C₁₄ alkyl, or phanyl optionally substitutad with up to two subsötuents ealectad from C₁₄ alkyl, halogan, and alkoxy;

or R3 and R₄taken togetherfoim -O-CHsCJCHj)-; and

Rg ιβ H or mathyl; or a phamaceuttaally acceptable salt, solvate or hydrate theraof.

[0027] InsomeembodlmentsofthecompoundBd Formula(l):

Rg Is mattiyl, etfiyl, Isopropyl, or CHjOH; or R₂ and R_2a taken togathar form -ΟΗ^ΟΗ^;

1¾ Is chlorine, bromlne, or lodlne;

R₄tealkoxy;and

Rg ιβ H or mathyl; or a pharmacautlcally acceptable salt, solvala or hydrata thereof.

[0028] InBomaambodltnanteofthecompoundsof Fonralafl):

R,leH;

Rg Is methyl;

R3 Is H, chlorine, bromine, orthlophene;

R₄ Is alkoxy, pyrrazoly-3-yl or phenyl whereln sald pyrrazole optlonally has up to two substituents selected from halogen and C_1-3 alkyl, and sald phenyl optionally has a singla halogen substitutent; and Rg Ιβ H; or a pharmaceutlcally acceptable salt, solvata or hydrate thereof.

[0029] ln eome ambodlmante of the compounds of Formula (I), the eompound Is a metnber of the group eonalsting of: 8-Bromo-7-hydroxy-1-m0thyl-2_l3,4,5-tetrahydro-1H-3-benzazepine; 7-Allyloxy-8-bramo-1-methyl-2,3,4,5-tetrahy-dro-1H-3-benzazaplne; 7-Benzyloxy-8-brDmo-1-niethyl-2_l3_l4,5-tatrahydR&gt;-1H3-benzazeplne; 8-Bromo-7-ethoxy-1-methyl-2,3,4,5-tetraliydro-1H-3-benzazaplne; 8-Bramo-7-l8opropoxy-1-inethyl-2,3_l4_l5-tetrahydra-1H^-bBn-ZBZaplne; N-Propyl-8-bromo-7-methoxy-1-niethyl-2^_l45-1etrahydrD-1H-3-banzazepína; 7-Hydroxy-8-iodo-1-mettiyl2,3,45-tatrahydro-1AF3-benzazeplne; 7-AHyloxy-8-lodo-1-mathyF2_l3_l4.5-latrahydro-17+3-banzazaplna; 7-Allyloxy8-chloro-1-mathyl-25,4_I5-tatrahydro-1 Η-3-banzazeplne; 7-Mathoxy-1 -methyl-8-(2-thlenyl)-2,3,4,5-tetrahydro-1 H3-benzazeplne; 8-bromo-1-cydoprapyl-7-fnathoxy-2,3,4,5-tetrahydro-1H-3-benzazeplne; 8-bromo-1-hydroxymathyl7-methoxy-2,3,4,5-tetrahydro-1 HB-benzazeplne; 8-Bromo-1 -iaoprapyl-7-fnethoxy-2_l3,4,5-tetrahydro-1 Η-3-benzazeplne; 8-Bromo-7-hydroxy-14eopiDpyl-29_l4_l5-tBtrahydrD-1 Η-3-benzazaplna; 7-Allyloxy-B-bromo-1 -Isopropyl2,3,4,5-tetrahydro-l ftS-benzazaplne; 8-Bromo-7-mathoxy-1 ^-dlmathyl^.S^^-tetrahydra-l H-3-banzazapine; 7-AI-lyloxy-e-bromo-1 .A-dlmethyl-a.S.Áí-tetrahydro-l Η-3-benzazeplne; B-Chloro-1-hydroxy-2,3,4_l5-tetrahydra-1 Η-3-ban-zazepine; β-Bromo-l -&lt;nethyl-2,3_l45-tetrahydro-1 Η-3-banzazaplne; 8-Fluoro-1 -methyl-2,3,4,5-tatrahydro-1 Η-3-ban-zazeplna; 7_l8-Dtehtoro-1-methyl-2_l3,4,54etrahydro-1H-3benzazeplne,· N-Methyl-8-chloro-1-methyl-2,3,4,5-tetrehy-dro-1 /M-benzazaplna; 8-lodo-1 -πιβΒινΙ^-ϋΒΙυοΓΟΓηβΙΙιοχν-Σ,ΒΛ,Β-ΙβΟΒίινΟΓΟ-Ι Η-3-banzazaplna; N-Prapyl-B-lado7-mathoxy-1-methyl-2,3_l4,5-tetrahydro-1íM-banzazeplna; 1-Ethyl-8-iodo-7-methoxy-2,3,4,5-tetrahydro-1H-3-ban-zazeplna; 7-(2-fluorophanyl)-8-chtoro-1-methyl-2_l3,45-tetrahydro-1H-34)BnzBzeplna; and 8-bramo-1-methoxyme-thyt-7-mathoxy-2,3,4,5-tBtrahydro-1 W-3-benzazaplne; ora pharmaeeutlcally acceptable salt, aoivate or hydrate thereof.

[0030] in Boma embodlments of the compounde of Formula (I), the compound Is a mamber of the group consistlng of 8-Bramo-7-mettioxy-1 -mattTyl-2,3,4,64etrahydro-1 KS-banzazeplne; 8-Chloro-7-methoxy-1 -mathyl^^^.S-tetraíiy-dro-1/+3-banzazapina; 8-lodo-7-meftoxy-1-nwthyl-2,3_l4_l54atfitydro-1tt'3-banzazeplnB; N-Mathyl-8-bromo-7-methoxy-1 -mathyl-2,3_l4,5-tetrahydro-1 Η-3-benzazeplne; 8-Bromo-1 -611171-7^0010X^2,3,4,5-18^1170/0-1 H3-ben-zazeplne; 8-Chloro-1-ethyl-7-meithoxy-2,3,4,5-tetrahydio-1 Η-3-banzazapine; 8-lodo-1 -Bthyl-7-mathoxy-2,3,4,5-tatrahydro-1H-3-banzazeplna; 7-Mathoxy-1-mathyl-8-trifluoromathyl-2,3,45-tatrahydro-1H-3-banzazepina, and 7-Math-oxy-l-mathyl-e-pantafluoroethyl-Z.a^.S-tatrahydro-l f+3-benzazeplna; or a pharmaceutlcally acceptable salt, solvate or hydrata tharaof.

[0031] In some embodlmants of tha compounds of Formula (I), the compound Is a mamber of tha group consfeting of: B-Chloro-1 -mathyl-2,3_l4_l5-tetrahydro-1 ft3-benzazeplna; B-Bromo-1 -mathyl-2,3_l4,5-tatrahydro-1 Η-3-banzazeplna; 8-Iodo-1 -mathyl-2,3,4,5-tetrahydro-1 Hð-benzazaplne; B-Trtfluoromathyl-1 &lt;nathyl-2,3,4_l5‘tetrahydro-1 H3-benzazapine; B-Trifluoromethyl-1 -ethyl-2,3,4,5-tatrahydro-l tt-3-benzazepine; 8-Chloro-1 -ethyF2₁3,4,5-tatrahydrQ-1 Η-3-benzazaplne; e-Bromo-1 -athyl-25_l4,5-tetrahydro-1 /M-benzazaplna; a-lodo-1 -athyl-2,3_l4,5-tetrahydro-1 H3-benzazepine; 7,B-Dichloro-1-methyl-2_l3,4,5-t0tralTydrt&gt;-1fW-benza2epine; 7,B-Dlchloro-1-ethyl-2_l3,4_l5-tetrahydro-1H-3-banzazapine; 8-Chlora-7-fluora-1-mBthyl-2_l3,4,5-tatrahydro-1H-3-benzazaplne; and 8-Chlora-7-fluoro-1-ethyl2,3,4.5-tetrahydro-l H3-benzazepina; or a pharmaceutlcally acceptable salt, solvate or hydrate thereof.

[0032] Tha presant invantion alao providas composltlona comprislng ona or mora compounds of tha invention, and ona or fnora pharmaceutlcally acceptable caniere.

[0033] Descríbed hereln are mathods of modulating a δΗΤ^ receptor comprlslng contacting said recaptor with a pharmaceutlcally affectlvB amount of a compound or composttlon of the Invantion. Preferably, aald compound Is an agonist of said receptor.

[0034] Also dascribed hereln are methods of prophylaxls or treatment of disordere of obesity.

[0035] Also described hereln are methods of decreasing food intake of a mammal comprising administering to said mammal a pharmaceutlcally effectfva amount of a compound or compositlon of the inventlon.

[0036] Also dascrbed herain are methods of indudng satiety in a mammal comprising administering to said mammal a pharmaceutically effactiva amount of a compound or eompositlon of tha invention.

[0037] Also describad harein ara mathods of controlllng weight galn of a mammal comprlsing administaring to sald mammal a pharmeceutfcally effectlve amount of a compound or compositlon of the invenOon.

[00381 Ateo daecribad hereln are methods of traating obeslty comprising admlnlstaring to a patient In nead of such traatment a phannaceutically effactiva amount of a compound or compositíon of The invention.

[0039] ln aoma ambodlmente, soma of the foregolng mathods turthercomprlse the step of IdantHýing a subjact, said subjact baing in need of decreaalng food intake, contralling welght gain, or treating obesity, wherein sald identifying stap Is performed prior to admlnlstarlng lo sald subjact sald pharmacautlcally effactlva amount of sald compound or composltion of The invention.

[0040] One aapect of tha present Invention pertains to a compound of Formula (I) for uee in a method of treatment of the human or anltnal body by tharapy.

[0041] One aapact of the present invertöon pertains to a compound of Formula (I) for usa in a method of prophylaxis or traatment of abealty.

[0042] One aspect of the present Invantton pertains to a compound of Formula (I) for the manufacture of a medlca-mant for usa in tha propylaxla or treatmant of obaslty.

[0043] Also descrlbed hareln are methods for allevlatlon ol a aymptom of any of ttia dlsaases, conditions or disorders mentionad hereln.

[0044] Appllcante reserve the right to axclude any one or more of the compounds from any of the ambodimants of The invention. Appllcanl addltlonally reservas the right to exclude any disorder frem any of tha embodiments of tha ΙπνβηΟοπ·

Brtaf Deaerlptlon of tha Flguna [0045]

Figures 1A-1G lllustrata tha affacts of savan differant eompounds of the Inventlon on food Intaka in food-deprivad rate.

Detailad DaaerlpUon of the InvenUon [0048] The prasant Invantlon relataa to 5HT_æ recaptor agonlet eompounds, whieh ara useful in mathods of modu-latfng 5ΗΤ_Κ recaptora by contactlng tha raceptors wlth one or more compounds of the invantion, and in mathods of decreaalng food htake, controlllng walght galn, or treating obeslty, uslng compounds of the Invantion.

[0047] The tarm 'antagonlat" Is Intanded to maan moletlea that competltlvöly blnd to tha recaptor at the same slte as agontete (for example, the endoganous llgand), but whlch do not activate tha intracellular response initiatad by the actíve fárm oT the raceptor, and can thareby Inhiblt the intracedular rasponeee by agonists or partf al agonlets. Antag-onista do notdimlnteh tha baeaDna Intracellularreeponse Intheabaence of an agonist or partial agonist. As used hereln, tha term "agonlsf Is intandad to maan moletlea that actlvate the Intracallular raeponse when thay blnd to the recaptor, or anhance GTP blndng to rnembranes. In the «ntaxt ot the present kwenttan, a pharmaceutical composition com-prialng a δΗΤ^ receptor agonlst of the inventtan can be utillzed for modulatlng the actlvlty of the SHTjc receptor, dacreasing food intaka, induclng satlatlon (i.a., the fealing of fullness), controlllng welght galn, treating obeaity, decreasing body welght and/or affectlng metaboltem such that the raclpiant loses waight and/or maintaina weight. Such pharmaceutical compositlone can be used in the context of diaorders and/or disaaaes where waight gain is a component of tha disBaae and/or dlaorder such as, f or axampla, obeslty.

[0048] As used hereb, theterm "contact' or"contactlng* ahall mean bringlng the indicated moietias togather, whether In an In vltro system or an In vivo system. Thus, "contactlng” an SHTjc receptor wfth a compound of tha inventlon includas tha admlniatration of a compound of ttia Invention to an animal having an 5KT_2C recaptor, as well as, for axampla, introdudng a compound of the invantlon Into a sampla contalning a cellular or more purffled preparallon containing an SHTæ recaptor.

[0049] Compounds of the invantkxi Indude thoaa havlng tha Formula (I), shown above.

[0050] In one embodlment, if Is 0¾. than 1¾ eannot be alkyl.

[0051] In aoma ambodlmenta, If b OR₅, then R₂ cannot be cyclopantyl, -CHg-cyclohaxyl, 3,3-dimethyl-2-aHyl,

3,3-dlmethyl-2-fnathytallyl, 2-mathylallyl, 2-butanyl, cydopropylmethyl, cyclohexyl, or allyl.

[0052] lt will be appreclated that compounds of Formula (I) may hava one or more chiral centars, and exlat as enan-tlomarB or dlastareomars. The InvenBon ia to ba understood to axtend to all euch enantlomsra, dlastereomare and mlxtures thareof, Includlng racematea. Formula (I) and tha formulaa haralnaftar ara intendad to rapresant all indivldual laomere and mbttures thereof, unlesa atated or shown otherwlse.

[0053] As uaed hareln, tha tarm “alkyT Is Intendad to danote tiydrocarbon groupe Including etraight chaln, branched and cycllc hydrocarbona, Indudlng for axampla but not llmited to methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sac-butyl, tert-butyl, cydobutyl, cydopropylmethyl, n-pentyl, Isopentyl. tart-pentyl, cyclopantyl, cyclopentylmathyl, n-hexyl, cyclohexyl, and the llke. Threughout thla spaciffcattan, It should be underatood that the term alkyl Is Intended to encompasa both non-cyclb hydrocarbon groupa and cycllc hydrocarbon groups. In aome ambodlmants ol the com-pouncfe of the Inventíon, alkyl groups ara non-cyclfc. In further embodimenta, alkyl groups are cyclc, and In furthar embodlmants, alkyl groupa ara both cyclb and nonoycllo. Whare no praferanca la speeifled, the term ’alkyl* Is Intended to danote groups thal ara both cydb and non-cyclic.

[0054] As usad haraln, thé term 'aHœnyl* b Intendad to danota hydroearbon compounds Indudlng stralght ehaln, branehed and cycllc hydrocarbons that contain at least one doubla bond, Indudlng for axample allyl, 2-methyl-allyl,

4- but-3-enyl, 4-hex-5-enyl, 3-mathyl-but-2-anyl, cydohax-2-enyl and the llke.

[0055] As usad hereln, tha taim "halogan* has Its normal meanlng of perlod seven elamants, Indudlng F, Cl, Br and I. [0056] Tha term ‘alkoxy* la Intended to denote subatltuente of the formula -O-alkyl, indudlng -O-allyl. The term 'lower¹' when usad In connacöon wlth subetltuants such as alkyl Indlcatas 8 carbone or lasa.

ροβη Tha tarm "arytalkyi" or 'aralkyT Is Intanded to danote an alkyl graup that bears an aryl substituant, fbr example a banzyl group. Tha tarm 'alkylaryr or 'alkaryT Is intended to danota an aryl graup that baars an alky I substítuent, for example a 4-mathylphanyl group.

[0058] As usad hareln, tha taim 'aryl" Is Intandad to maan monocydlc and polycydlc aramatb groups. Although aryl groupa can Indude asfaw as 3 carbon atoma, prafarred aryl groupa have 6 to about 14 carbon atoms, more preferably 8 to about 10 carbon atorrn. Examples of aiyl graups Includa phanyl, naphthyl, anthracyl, phenanthryl and pyrenyl. [0059] Tha term 'hetaraaiyr b Intendad to danota an aryl group thal eontabs at least one, and preferably from one to four ring "hetara’ (l.e., non-carbon, e.g., Ο, N or S) atom. Examptee of "heteroaryr groupa are radbals darived from

5- and 6-membar aryl rlng eompounde having from one to four nltrogen, sulfur and/or oxygen atoms, for example pyrrola, pyrazole, Imldazola, triazola, tetrazda, pyridina, pyrimldlne, furan, pyran, thlophene, benzlmldazola, qulnollne, iaoquinolina, oxazole, thlazole, and thiadlazola.

[0060] Aa used hardn theterm hetaroarylalkyl means an alkyl group that beara a heterearyl substituent, for exampte a greup havfng tha atructure -CH^rrole-2-yl.

ΡΚ»1] Thaterm ‘substltutadthlazola* maana a radlcal darivadfrom thlazole that bears at laaat ona aubstltuentgroup. Tha tarm thlazole derivatlve* means a fuaad ring aystam In whbh one of tha fusad rings is thbzole.

[0052] Tha tarm *8ubstltutad Imidazole" maane a radbal darivad from Imldazola that baara at laast ona subatltuant group. Tha tarm "imldazole derivatfve* maans a fuaed ríng system In whlch one of the fused rlngs Is imidazole. [0063] In aoma ambodimante of tha Invantlon, R4 Is OR₅. In soma auch embodlmanta, Rj eannot be cycbpantyl, -CHj-cyclohexyl, 3,3-dlmethyt-2-aHyl, s.S-dlmethyl-Z-methylallyl, 2-methylallyl, 2-butanyl, cydopropylmethyl, cy-dohaxyl, or allyl. In furthar auch embodinianta, 1¾ cannot ba alkyl.

Ρ064] In eorna embodlmente of tha compounde of Formula (I), Rg b halogen and R₄ is

-OR₅. in 8oma ambodiments of the compounda of Formula (I), R_s Is allyl, 2-mathyl-allyl, 4-but-3-anyl, 4-hex-5-enyl, 3-mathyt-but-2-anyl or cyclohex-2-enyl, In aoma ambodlmenta of the compounda of Formula (I), R_s Is mathyl, athyl, n-propyl, isopropyl or allyl. In some ambodlments of the compounds of Formula (I), is mathyl or allyl.

[0065] Cartaln aubaótuente of tha compounda dbdoasd haraln can optlonally basubetltutad, i.e., they can optionally bear further substltuent greups. Some preferred eubsttajent graups Indude halogen, lower alkyl (Includlng methyl, ethyl, Isopropyl, cydopropyl, tart-butyl, and methylcydopropyl), alkoxy, mono-, dl- or tríhaloalkoxy (a.g., -0-0X3 where

X fe halogen), -(ΟΗ^ΝΗ* -(CH^NHBoc, phenyl, methoxyphenyl and naphthyl.

[0086] At various placas In the present spaclflcatlon substituants of compounds of the Invantlon are disdosed In groups or In rangas. It Is spaclflcally Intandad that the Invantíon Include each and every Indlvldual subcomblnatlon of the members of such groups and ranges. For example, the tarm *C₁₄ alkyl* Is speciflcally intended to indivldually dlsclose methyl, ethyl, ¢3 alkyl, C&lt; ölkyl, C_s alkyl, Cg alkyl, Cj alkyl and C₈ alkyl.

[0067] ln a preferred ambodiment, the compounds of Formula (I) ara satected fram;

8-Bn&gt;mo-7-hydroxy-1 -methyl-2,34,5-tetrahydro-1 W3-benzazeplne; 7-Allyloxy-8-bramo-1 -methyl-2,3 A&amp;tet-rahydro-1H-3-banzazaplna; 7-Banzyloxy-8-bromo-1-n,athyl-2,3_l4,5-tetrahydro-1H-3-benzazepine; 8-Bromo-7-athoxy-1 -mathyl-2,3,4,5-tatrahydro-1 Η-3-benzazeplna; 8-Bromo-7-laopropoxy-1 -mathyl^.SAS-tetrahydro-l H3-benzazepine; N-Propyl-8-bromo-7-mathoxy-1 -methyl-29 A.5-tetrahydro-1 Η-3-banzazeplne; 7-Hydroxy-8-iodo-1 -mathyl^.S^.S+etrahydra-l Η-3-benzazepina: 7-Allyloxy-8-lodo-1-malhyl-2A4,5-tatrahydra-1 H-3-benzazapina; 7-Allyloxy-8-chloro-1 -mettiyl-2,3,4,5-tatrahydro-1 Η-3-benzazapine; 7-Methoxy-1 -mathyl-8-(2-tfiianyt)-2,3,4,5-tetrahy-dra-1 Η-3-benzazeplne; B-bromo-1 -cydopropyt-7-mathoxy-2,3,45-tatrahydro-1 Η-3-benzazaplne; 8-bromo-1 -hy-draxynathyl-7-mattioxy-2,3,4,5-tatrahydro-1 Η-3-benzazepine; 8-Bromo-1 -l8opropyl-7-mettioxy-2,3,4,5-tetrahydru-1 /W-benzazapina; 8-Bramo-7-liydroxy-1 -lsopropyf-2,3,4,5-tetrahydro-l H3-benzazeplne; 7-Allyloxy-8-bromo-1 -Iso-propyl-2,3,4,5-tatrahydro-1 Η-3-banzazaplna; 8-Bromo-7-mathoxy-1 Adimethyl-a.SAe-tetrBhydro-l Η-3-ban-zazaplne; 7-AHyldxy-8-bromo-1,4-dlmethyl-2,3,45-tetrahydro-1H3-benzazeplne; B-Chloro-1-hydroxy-2,3,4,5-ta{-rahydro-1 Η-3-banzazepine; 8-Bromo-1-methyl-2_l3,4_l5-tetrahydro-1 Η-3-benzazeplne; B-Fluoro-1 -rnethyl-23,4,5-tet-rahydro-1 Η-3-benzazaplna; 7,8-Dichloro-1 -methyl-2,3,4,5-tatrahydro-1 Η-3-benzazeplna; N-Methyl-8-chloro-1 -ma-thyl-2,3,4,5-tetrahydro-1 Η-3-benzazapine; B-lodo-1 -methyl-7-trifluoromathoxy-2,3,4,5-tetrahydro-1 Η-3-benzazapine; N-Propyl-8-lodo-7-mattioxy-1 -methyl-2,3,4,5-tetrahydro-1 /H-benzazeplne; 1 -Ethyl-B-lodo-7-methoxy-2,3,4,5-tst-rahydre-IA+3-banzazaplne; 7-(2-fluorophenyl)-8-chloro-1-methyl-2,3,4_l5-tetrahydro-1H-3-benzazepina; and 8-bro-mo-1 -mathoxymethyl-7-mathoxy-2,3,4,5-talrBhydro-1 Η-3-benzazeplna; or a pharmaceutlcally acceptabla salt, solvate orhydratathareof.

[0068] ln a preferrad ambodlment, the compounda of Formula (I) are salectad from:

N-methyl-B-Brorno-7-methoxy-1 -methyl-2,3,4,5-tetrahydro-1 tf-3-benzazeplne; N-methyl-8-Chloro-7-methoxy-1 -methyl-2,3,4,5-tetrahydra-1 Η-3-benzazeplna; N-methyl-8-lodo-7-mathoxy-1 -mathyl-2,3,4,5-taatrtiydro-1 W-3-ben-zazaplna; N-Mathyl-8-bromo-7-methoxy-1 -methyl-2,3,4,5-tetrahydro-1 W-3-banzazaplna; N-methyl-8-Bromo-1 -elhyl-7-mathoxy-2,3,4,5-tetrahydro-1 Η-3-benzazepine; N-mathyl-8-Chloro-1 -athyF7-methoxy-2,3,4,5-tetrahydra-1 H3-banzazeplne; N-mathyl-e-lodo-l-ethyl-y-methoxye.s^^-tetrahydro-IH^-benzazeplna; N-mathyl-7-Mathoxy-1-mathyl-8-trtfluoromethyl-2,3,4,5-tetrahydro-1H-3-banzazaplne; and N-methyl-7-Methoxy-1-methyl-8-pentafluorae-thyl-2_l3_l45-tatrahydro-'l tf3-benzazeplne; or a pharmacautlcally accaptabla salt, solvate or hydrate ttiareof.

[0069] ln a prafarred embodinent, tha compounda of Formula (I) are salected from:

N-mathyl-8-Chloro-1 -methyl-23,4,5-tatrahydro-1 /+3-banzazeplna; N-mathyl-8-Bromo-1 -methylí.SAS-tet-rahydra-17+3-banzazeplna,· N-metttylS-lodo-l-metiiyl-Q^^^^etrBhydrO-IH-S-bemazeplne; N-methyl-8-Trifluor-omathyl-1 -rnalhyl-2,3_l4,5-tetrahydro-1 Η-3-benzazeplna; N-mathyl-8-Trffluoromathyl-1 -ethyl-2,34,5-tatrahydro-1 H-3-banzazaplna; Ν-ΓΐϊθϋιγΚ8-ΟΙιΙαΓθ-1-βΐΗνΙ-2,3,4,5-Ιθϋ'β}ψάΐΌ-'Ι/+34ίβηζ3ΖΒρΙπβ; N-fnathyl-8-Bromo-1-athyl2,3,45-tetrahydro-1H-3-benzazaplne; Ν-ηηβΟιν^-Ι(χ1ο-1-βΟψΡ2,3,4,6-ΙβίΓΒΐιγ6πι-1//·3-6θπζβζβρίηθ; N-methyl·

7,8-Dlchloro-14ηββι^2,3,4,6-ΐΒ(ηΙ)76ιο-1 Ha-benzazaplne; N-msthyl-7,B-Dlehlore-1 -athyl-2^,4,5-tatrahydra-1 H-3-banzezeplna; N-methyl-B-Chloro-7-fluoro-1 -mathyF2,3,4_l5-tatrahydro-1 W-3-benzazepina; and N-mathyl-8-Chloro-7-fluoro-1-ethyl-2_I3_l45-tatrahydra-1 FM-banzazaplna; or a pharmaceuUcally acceptable salt, solvate or hydrata thara-of.

[0070] in a prafarrad embodiment, tha compounds of Formula (I) ara salactad from:

6-Bromo-7-methoxy-1 -methyt-2,3,4,5-tatraliydra-1 H&amp;benzazepine; e-Chtoro-7-fnethoxy-1 -mettiyl-2,3,4,5-t0t-rahydro-1/+3-benzazeplne; 8-lodo-7-methoxy-1-mathyl-2_l3_l4_l5-taetrtiydiO-irF3-benzazaplne; N-Methyl-6-bromo7-mettioxy-1 -rmthyt-2,3,4,fi-tetrahydra-1 H-S-banzazeplna; a-Bromo-1 -ethyl-7-mathoxy-2,3,45-tatrahydro-1 Η-3-ban-zazeplne; B-Qiloro-l-ettiyl-y-niethoxy^.SAS-tetrahydro-IH-S-benzazeplrie; B-lodo-1 -ethyl-7-methoxy-2,3,4,5-tet-rahydro-1 AF3-benzazeplne; 7-Mathoxy-1 -melbyl-8-ti1fluoroinethyl-2_l3 A5-tetrahydro-1 fM-benzazeplne; and 7-Math- .

oxy-1-mathyl-8-pentafluoraethyl-2,3,4,5-tetrBhytíro-1 W-3-benzazaplna; or a pharmaceutksHy aoceplabb satt, sotvate orhydratethereof.

p»71] In a preterred ambodlment, tha compounds of Formula (I) are selacted from:

8-Chlora-1 -methyF2,3,4,5-tatrahydro-1 Η-3-benzazaplna; B-Bromo-1 -methyt-2,3,4,5-tatrahydro-1 Η-3-benzazeplne; S-lodo-1 -mathyl-2,3,4,5-tatrahydra-1 tfð-banzazeplna; B-Trifluoromathyt-1 -mathyl-2,3,4,5-tetrahydro-1 H-3-benzazepina; 8-Trifluoromethyl-1 -ett^.aAS-tetrahydro-l Η-3-benzazeplna; 8-Chloro-1 -athyl-2,3,4,S-tetrahydra-1H-3-bafizazeplne; B-Bromo-1-athyl-2^,4,5-tatrahydro-1H-3-benzazaplna; B-lodo-1-athy 1-2,3,4,5-tetrahydro-IW3-benzazaplna; 7,8-Dichloro-1 -methyl-2,3,4,5-telrahydro-1 Η-3-benzazeplne; 7,8-Dfchlora-1 -ethyl-2,3,4,5-tetrahydro-1/+3-benzazeplne; 8-Chloro-7-fluoro-1-methyl-2,3_l4_l5-tetrBhydro-1/+3-benzazepine; and 8-Chloro-7-fluoro-1-ethyl·

2,3,45-tatrahydro-1/F3-benzazapbie; or a pharmaceutlcally acceptable salt, solvate or hydrata thereof.

[0072] The compounds of the invantion may oontaln one or mora asymmatric catbon atoms, so that the compounds can sxist in different Btaraoisomeric forme. The compounds can ba, for axample, racemates or optically active forms. The optlcally actlva forms can ba obtalnad by resolution of tha racematas or by asymmetric synthesis. In some am-bodlments, compounds of Formula (I) are flenanttomera. In some embodiments, compounds of Formula (I) are S anantiomars. In some ambodlmente, compounde of Formula (I) are varylng mbrtures of snandomers.

[0073] Accortiing ta a further aspect of the invantion, compounds of Formula (I) are provided for use in therapy. The compounda of Formula (I) can ba ueed In tha praphylaxis or treatment of obaslty.

[0074] Accordlng to a further aspact of The invention, there Is provldad uee of a oompound of Fomnula (I) in the manufacture of a medteament far tha prophylaxis or traatment of the dieofdars disclosed herein. In a preferred am-bodiment, thera Is provldad a uee of a compound of Formula (I) in tha manufacture of a medfcament fortfia praphylaxis ortreatmentof obeelty.

[0075] Tha compounda accordlng to the Invantlon may optíonally exist as pharmaceutlcally acceptable salts indudlng pharmaceuÐ'eally accaptable acld addition salts prepared fram pharmaceutlcally acceptable non-toxic adds indudlng Inwganlc and organlc aclds. Such acids Include acetfc, benzartasulfonlc, benzolc, camphorsulfonic, cltrte, athanasul-fonlc, dlchloroacatlc, foimlo, fumaric, gluoonlc, glutamie, hippuric, hydrobromlc, hydrachlorlc, isethlonic, lactic, maleie, mallc, mandallc, msthaneaulfönle, muelc, nltrte, oxallc, pamolc, pantothenlc, phosphorlc, succlnic, sulfirlc, tartaric, oxal· ic, p-toluanesulfonic and tha like, such as the pharmacautlcaliy acceptabla salte listad ln Journal of Pharmacautlcal Sdence, 66,2 (1977).

[0076] The acld addltlon salta can be obtained as tha dlrect preduete of compound synthesis. In Ihe altemaöve, the free base can be diaeolved in a aultable solvent contalnlng the appropriate add, and the salt isolated by evaporatlng tha solvant or ottierwise saparatlng the salt and aolvent. Tha compounds of this Invention may form solvates wlth standard low molacular weight solvents using methods known to the skiiled artisan.

[0077] CompoeWona of tha inventlon may convenlantiy ba admlnlstarad in unlt dosage form and can be prepared by any ol tha methods wall known In the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sdencoa (Mack Pub. Co., Easton, PA, 1980).

[0078] Tha compounds of the Inventlon can ba employad as the sole actlve agent in a pharmaceutlcal or can be uaed in comblnation wlth other actlve Ingredients which eould fadlltate the therapeutic affect of the compound.

[0079] Compounds of tha present inventlon or a solvate or physlologlcally functional derivative thereof can be used as actlve Ingrediente In pharmaceutical compoaltlons, spedflcally as 5HTjc receptor agonists. Bf the term ‘active Ingradient" la daflned In the contaxt of a ‘pharmaeautical eompoaltlon* and shall mean a component of a pharmaceutlcal composltion that providaa the primary pharmaceutical beneflt, as opposed to an 'inactive Ingredient" which would ganarally be racognlzed aa providlng no pharmacautlcal benafit. The tarm "pharmacautical composlflon" shall mean a composltlon comprlslng at laast one active Ingredtent and at least one ingredlent that Is not an acttva ingradlent (for example and not Mtatlon, a flllar, dye, or a mechanlsm tor slow ralease), wheraby lhe compositlon Is amenable to uaa for a specifled, effleadous outcoma In a mammal (lor example, a human).

[0080] "Πιβ data developed hereln eupporta the concluaion that the preaently dladosed SHTjq receptor agonists are ol un for Iha treatment or prephylaxls of dlnleal obaalty or ovaiwalght dteordars In mammals, Induding humans. Compounda of the preaent Inventlon can ba adminleterad by oral, subllngual, parenteral, rectal, toplcal adminlstration or by a tranadannal patch. Tranedarmal patches dlspeme a drug at a controlled rate by presentlng the drug for ab-eorptlon In an effldant manner wlth a mlnlmum of degradatlon ttt the drug. Typlcally, transdermal patehes comprlse an Impermeabte baddng layar, a slngle preeaure eeneltlve adheslva and a removable protectfve layer w#h a release llner. One of ordlnaiy skll I In tha art wlll underatand and appredata the technlquea appropriate for manufacturing a desired efficadoue tranadermal patch based upon the naeda of ttie artlaan.

[0081] ln addttlon to the neutral torma of compounds of ttie present Invention, by approprlate addltion ol an lonlzable aubsfltuent, which doaa not alter tha receptor epaclflcity of the compound, phyelologlcally æceptable salts of the com-pounda may also ba formed and used as therapeutlc agants, Dlfferent amounts of the compounds of the present Inventlon wlll be requlred to achleve the deslrad blologlcal effect. The amount willdepend on factora eueh as the specifte compound, tha use far whlch It le Intended, the mearw ot admlnlatratlon, and the condltlon of the treated Indivldual · all of then dodng paramatara are wfthin the leval of one ol ordlnary akill ln the medlcinal arts. A typlcal doae can be expacted to fall In tha ranga of 0.001 to 200 mg par Wlogram of body weight of the mammal. Unlt doses may contaln from 1 to 200 mg of tha compounds of tha present invention and can be adminlatered one or more tlmes a day, Indl-viduallyorln multþlm.

[0082] Pharmaceutlcal compoaltlona, for axample, pharmaceutlcal composltions eomprislng at leaet ona compound ofthe prasant Inventlon and/or an accaptable salt or solvata thereof (e.g., a pharmaceutically acceptable salt or solvate) as an actlve lngredlent comblned wlth at least one carriar or exdpient {o.g., pharmacautical carriar or sxdpient) can ba usad In the traatmant of clinical conditiona for whlch a 5ΗΤ_Κ receptor agonist Is indicatad. At least one compound of the prasent invantion oan be comblned with the cam'er In aithar solid or liquid form in a unit dose formulation. The pharmacautlcal carriar muat ba compatlbla wlth the other Ingredients in the composltion and must ba tolerated by the indMdual reclplent. Other physiologieally acthre ingredienta can be incorporatad into the phaimaceutical composition of the Inventlon If dasirad, and if auch ingradlents are compatibla with the othar ingrediants in the composition. For-mulatlona can ba preparad by any sultable method, typieally by unltormly mbdng the active compound(s) wHh llqulds or flnely divldsd solld carriers, or both, in the raqulred proportions, and than, If neceeaary, forming the reaulting mixture Into a deslred shape.

[0083] Conventional excipiants, such as blndlng agenta, fillers, acceptable wetting agents, tabletting lubricants, and dlsintegranta can be used In tablets and capsules for oral adminlstration. Liquid preparatians for oral admlnlstratton can be In the fortn ot solutions, amulsiorts, aqueoua or oily suspanslons, and syiups. Altematively, the oral preparations can be In tha form of diy powdar that can be raconstitutad with water or another sultable llquld vehicle before use. Addítlonal addRlves such as suspendlng or emulslfylng agants, non-aqueous vehicles (Includlng edible oils), preserv-atlvee, and flavoringa and cotorants can be added to tha liquid preparations. Parantaral dosage forms can ba prepared by dissoMng tha compound of the Invantlon in a sultebla llquld vahlcla and flker starMzing the solutlon bafore filling and seallng an appropriate vlal or ampoule. Theae are juat a few examples of the many appropriate methods well knownlntheartforpraparingdo8agefonns.

[0084] It ls noted that whan the SHTæ receptor agonists are utillzed as acthn Ingradlants in a pharmaceutical com-posltlon, theae ara not intendad for use only In humana, but In othar non-human mammals as well. Indeed, racent advancas in the area of animal haalth-care mandate that conslderetlon ba given forthe use of 5HT_æ receptor agonlsis for tha traatment of obeslty ln domestlc anlmals (e.g., cats and doge), and δΗΤ^ racaptor agonlata in other domestic anknals where no disease ordlsorder la evidant (e.gr., food-oriented anlmals such as cowa, chlckens, flsh, etc.).Thoae of ordlnary akill ln the art ara readlly credlted wlth understanding the utllity of such cotnpounds In sucti eettings. [0085] Tha compounds 01 the preaent Inventlon can ba readlly prepared aceordlng to a variety of aynthetie manipu-latfons, all of whteh would be famlllar to ona skllled In the art A rapresentatlve general ayntheels is set forth below In Scbanal:

Schemel

GENERAL REACTION SCHEME <img file="IS2134B_D0005.tif" /> [0086] niose of sklll In the art will appreclata that a wlda variety of compounds of tha Inventlon can be prepared accordlng to Schame I. For axample, by starting with an appropriately substltuted 2-phenyl athylarnino eompound A havlng any of a wlda varlaty of subsBtuents and Rj, tha corresponding 7- and/or 8-subetltuted 1 -methyl-2,3,4,5-tet-rahydro-1 Η-3-benzazapine (compound H) can be prepared. N-alkylatlon can be accompllehed by, for example, treat-mentwlth excesa paraformaldehyde (formathylatton) ora hlgharorderaldehyde, followed by reduction wilh NaBHgCN

<img file="IS2134B_D0006.tif" />

according to tha genaral procedura of synthatic axamples 9 and 10, Infra. In addltion, by starting with an apprapriately substltuted 1-alkyl-2-phanyl ethylamlno compound A having any of a wlde variety of substituents and R_z, the oor-respondlng 7- and/or 8-substltutad 2,5-dialkly-2_l3,4_l5-tetrahydro-1H-3-benzazapine compound can ba prapared. [0087] ln the syntheais of many compounds of tha Invantlon, protacting groupe can be raquired to protect various functtonality or functionalities during the synttiasis. Represantativa protacting groups suitable for a wlde variaty of aynthetlc tranefomnatlons are diaclosad in Greena and Wute, Ptotedive Gmups in Organk Synthesis, 2d ad, John Wley &amp; Sons, New York, 1891.

[0088] As wðl be recognlzed, thaateps of tha mathods dascrlbed hereln need not be parformed any partlcular number of tlmes or In any particular sequence. Addltlonal objacta, advantages, and features of The invention will become apparent to those skilled In the art upon examination of the followlng examples thareof.

Examplea

Synthatlc Exampte»

Example 1: (R,S) 8-Bronio-7-methoxy-1-methyl-23,4^-tetrahydro-1H-3-benzazeplna [0089] .

<img file="IS2134B_D0007.tif" />

N-Trffluoroa&lt;^-3^ðfftaQpbeíMfhytem/he [0090] Aeolution of S-mathoxyphenathylamlne (10.0 g, 84.0 mmol) in dichtoromathane (150 mL), was cooled to 0*C, and treated with pyrídlne (63 mL, 83.5 mmol) followed by tha dropwlse addhlon of trtf luo racatlc anhydride (17.9 g, 83.5 mmol) and the resultlng mixture stirred lor 3 hours while warming to 20^aC. The praduct mixture was dlluted wtth EtOAc (500 mL), washadsequentlally wlth 10% aqueous HCI (100 mL), water(100 mL), brine (100 mL), drlad with NajSO₄and cortcentrated to glve 15.8 g of a yallow oil. 1H NMR (400 MHz, CDCI3) d 7.26 (dd, J=8,8 Hz, IΗ], 6.81 (d, J=8 Hz, 1 H), 6.77 (d, J=8 Hz, IH), 6.72 (a, 1 K), 6.30 (bs, 1 Η), 3.B0 (s. 3 H), 3.62 (dd, J=7,7 Hz, 2 Η). 2.B6 (dd, J=7,7 Hz, 2 H). MS cateulated fbr C₁₁H₁₈F₃NO_ítH: 248, observed: 248.

N-Ttífluomacefyl-2-iodo-S-methoxyphenethylamlne [0091] A solution of N-trilluoraacetyl-3-methoxyphanathylamlne (15.8 g, 64 mmol) !n methanol (325 mL) was cooled to -78"C, and treated wtth CaCO₃ (14.7 g, 145 mmol), followed by a solutlon of ICI (29 g, 181 rnmol) ln methanol (40 mL). The reaction was allowed to waim to 20“C whlle stirring ovemight and than filterad, concentratad, dlsaolved In EtOAc (200 mL), waahad twice with 5% aqueouesodlum bisuffite (100 mL), once wlth bríne (100 tnL), dried w#h NajS0₄and eoneantratad to ghra 23.8 g of a whlta solld powdar. 1H NMR (400 MHz, CDCI3) d 7.6B (d, J=9 Hz, 1 H), 6.76 (s, 1 H), 6.57 (d, J=9 Hz, 1 H), 6.42 (bs, 1 H), 3.77 (a, 3 H), 3.61 (dd, J=7,7 Hz, 2 H), 2.99 (dd, J=7, 7 Hz, 2 H). MS calculatad for CflH^INO^H: 374, obsarvad: 374.

N-ARyl, Ν-ΜϋυοΓθβεβί^2-ιοόο·5-ίπβϋιοχγρ&gt;ιβπΒθΐγΙβπιίπβ [0092] A eolutton of N-trifluoroacetyt-2-lodo-5-methoxyphenathylamina (23.8 g, 63.8 mmol) In toluene (425 mL) was sequentially treatad with KjCO₃ (12.4 g, 89.8 mmol), KOH (11.6 g, 207 mmol), n-Bu₄NBr (22 g, 6.9 mmol) and allyl bromlde (10.7 g, 89.8 mmol). The mlxture was etirred at 80’Cfor 3.5 hours, coolad to 20° C, acidifiad wrth 10% aqueous HCI, separatad and the aquaous phaae extracted wlth ether (500 mL). The combined organlc phaaes were washed with brine (200 mL), dried wlth NagSO₄ and concentrated to giva 20.5 g of a brown oll. 1H NMR (400 MMz, CDCy, mlxture ofratamare d 7.67 (m, 1 Η), 6.B0 (m, 1 H), 6.57 (m, 1 H), 5.9-5.6 (bm, 1 H), 5.27 (m, 2 K), 4.11 (d, J=6 Hz, 0.5 H), 3.85 (d, J=6 Hz, 0.5 H), 3.77 (m, 3 H), 3.55 (m, 2 H), 3.00 (m, 2 H). MS calculated for C₁₄H₁₅F₃INO2+H: 414, obseived: 414.

<img file="IS2134B_D0008.tif" />

Ν-ΤήΙΙυοΓθ8θβΙγΙ·7-πΐθΚ)θχγ·1-πΐθ^^Ιβηβ-2,3,4,5-ΙβύΒ^γ(1ια·1Η-3·0βηίβ2βρΙπβ [0093] Α soluflon οί N-altyl, N-trffluoreacetyl-2-iodo-5-mettioxyphenethylamine (20.5 g, 50 mmol) In dimethylfoima-mlda (250 mL) Is treated with KOAc (14.6 g, 14Θ mmol), n-Bu₄NBr (16.0 g, 50 mrnol), PPh₃ (1.3 g, 5.0 mniol), Pd (OAcJj (0.56 g, 2.5 mmol) and stlrred ovemlght at 90*C. Tba product mlxture was cooled to 20' C, flltared, dlluted witti water (500 mL) and axtractad wfth athar (3 x 500 mL). The combinad organic phasee wera washed wlth water (100 mL), brtns (100 mL), drfed with NajSC^ and œncentrated. Flash chromatography (10% EtOAc ln hexane, slllca) re-eutted In 6.6 g of a yallow oll. 1H NMR (400 MNz, CDCy d 7.26 (d, J=B Hz, 1 H), 6.77 (d, 4=8 Hz, 1 H), 8.66 (s, 1 H), 5.34-5.19 (m, 2 H), 4.40 (m, 2 H), 3.83 (m, 2 H), 3.80 (s, 3 H), 3.00 (m, 2 H). MS calculatad for C₁₄H₁₄F₃NC&gt;2+H: 285, obsarved: 2B5.

N-TrUhMoecet^7-metheKy-1-melh^2,3,4,5-tBtr^bo-1H&amp;benza2epim [0094] A aolutlon of N-trifluoroacatyFZ-methoxy-l-wathylena^.aA.S-trihydro-l H3-benzazepine (6.6 g, 23.2 mmol) In ethanol (100 mL), was treated wlth 10% Pd/C (0.75 g, 2.3 mmol) and stlrred ovemlght under an atmosphere of hydragen. Tha product mbctura was flltared through a pad of cellte and slllca and the solvent removed to glve 6.27 g of awhltesolld.1 HNMR (400 MHz, CDCIj.mixlureof ratamere)d 7.10 (m, 1 H), 6.74 (m, 1 H),6.6B(m, 1 H), 4.1-3.8 (bm, 2 H), 3.8 (s, 3H), 3.5 (m, 15 H), 3.4 (m, 0.6 Η), 3.2-2.Θ (bm, 4 H), 1.32 (m, 3 H). MS caloulatadforC₁₄H₁₆F₃NO2+H: 28B, otaerved: 288.

N-Trifluoroacetyl-&amp;Proina-7-rnethoxy-1-rnethyl-2_l3_l4,S-tebatiy(1m-1H-3^}eraezeplne [0095] A solutlon of N-trifluoroacatyl-7-niathoxy-1 -methyl-2,3,4,5-tetrahydro-1 H-3-benzazaplna (125 g, 4.35 mmol) In a»tonltrfle (40 mL) was treatad wtth N-bromosuednknide (0.852 g, 4.79 mmol) and stirred ovemight at 20°C. The product mixture was diluted with EtOAc (200 mL), washed with eaturatad aquaous sodlum bisutfltB (100 mL) and brina (100 mL), drled wlth N^SO₄ and concantratad. Flaah chromatography (15% EtOAc in haxana, alllca) rasultad In 1.55 g of a ctear oH. 1H NMR (400 MHz, CDCIg, mbðure ol rotamers) d 7.34 (s, 1 H), 625 (m, 1 H), 3.87 (s, 3 H), 3.81 (m, 1 H), 325 (m, 12 H), 3.37 (m, 0.7 H), 3.2-2.9 (bm, 4 H), 1.30 (m, 3 H). MS calculatad for C₁₄H₁₅BrF₃NO2&lt;-H: 366, ΟΟΒΘΓνθΟ. oOO.

8-&amp;vmo-7-me»heKy-1-metí^A4,S-tetitíiydm-1H-3i)enza2eplm [0096] A aolutlon of N-trNluoraacetyl-&amp;-bromo-7-methoxy-1-methyl-2,3,4_l5-tatrahydro-1H2-benzazepine (0.95 g, 2.59mmol) In mathanol (20 mL) was traatad wtth 15% aqueous NaOH (25 mL), and stirred ovemight at 20'C. Tha product mlxture was dllutad wlth water (100 mL), axtractad twlca wlth EtOAc (100 mL), tha comblnad organic phases wera waahed wlth brina (100 mL), drled with NajSO₄ and concentrated to give 0287 g of a daar oll. 1H NMR (400 MHz.CDCy d 7.92 (a, 1 H), 6.34 (s, 1 H), 3.87 (s, 3 H), 3.1-2.9 (m, 6 H), 2.75 (m, 1 H), 2.60 (bs, 1 H), 1.31 (d, J=7 «, mw daleulBUd ftr C^S^NO+H: 270, obsetved: 270.

, 2: (R.8) 8-Chloro-7-methoxy-1-rrwthy1-22,4,5-tetrahydrD-1 Η-3-benzazaplne « ; ' i ' ", Ϊ ié-i · „ :

N-T)ieuoroecetyl-8-tí&gt;lorc&gt;-7-methoxy~1-fnetbyl-2,3,4,5-tetrattydro-1H-3-benzvepine ðF N-trffluoR»oetyl-7-methoxy-1-mathyl-22,4,5-tetiBhydro-1H-3-banzBzepine (0.900 g, 227 * Ιβ4όηφΜ (3Ö mL) waa treatad whh N-chlorosucclnlmlda (0.357 g, 2.67 mmol) and stlnred ovamight at 70’C. ^M^d!|nixture waa dflutdd wlth water (100 mL), axtracted twlce wlth EtOAc (100 mL), the combined organlc ABm'i^8|||d wt® brine (100 mL), drled wlth NaaSO₄ and concentrated. Flaah chromatography (20% EtOAo in Klja,4ilicjresuitad In 0.399 g of a daaroll. 1H NMR (400 MHz, CDCIa, mlxtura of rotamera) d 7.17 (a, 1 H), 6.68 (m, 1 H), 3.88 (s, 3 H), 3.78 (m, 1 H), 3.6-3.3 (m, 2 H), 3.2-2.9 (m, 4 H), 1.34 (m, 3 H). MS calculated for

WWsW-H: 322, otaervad: 322.

' ·

<img file="IS2134B_D0009.tif" />

8-Chloro-7-methaxy'1-rnethyl-2,3,4,S-tetrahydro-1H-3-bemaiaplne [0099] A solutlon of N-trlfluoraacetyl-B-chloro7-niethoxy-1-methyl-2_l3_l4,5-tetfahydro-1/+3-benzazeplne (0.389 g, 1.24 mmol) In methanol (20 mL) was treated with 15% aqueous NaOH (20 mL), and atirred ovemlght at 20*C. The product mixture waa dlluted wlth water (100 mL), extracted twlca wlth ElOAc (100 mL), tha combined organic phases were washed wlth brina (100 mL), driad with Na₂SO₄ and ooncantrated to glva 0.306 g of a yellow solid. 1H NMR (400 MHz, CDCIj) d 7.05 (s, 1 H), 6.59 (s, 1 H). 3.80 (s, 3 Η), 3.0-2.B (m, 6 H), 2.62 (m, 1 H), 2.16 (bs, 1 H), 124 (d, J=7 Hz, 3 H). MS calculated for C₁₂H_leCINO+H; 226, observed; 226.

Example 3: (R,S) &amp;-lodo-7-meithoxy-1-methiyl-2,3_l43-taetrhydro-1/A3-benzazeplne [0100] <img file="IS2134B_D0010.tif" />

N-Trifíuoroacetyl-8-iodo-7-methaxy-1-methyl-2,3,4,5-tetmhydro-1H-3-benzazepine [0101 ] A solutlon of N-trffluoroacetyl-7-nriethoxy-1 -methy 1-2,3,4,5-tetrahydro-l AF3-benzazepine (1.50 g, 5.22 mmol) In methanol (70 mL) was treated with CaCO₃ (1.06 g, 10.44 mmol) followed by a solution of ICI (1.70 g, 10.44 mmol) In methanol (10 mL), and stlrrad ovamlght at 20’C. The praduct mlxtura was filtarad, concantratad, dlssoh/ed in EtOAc (200 mL), extractad twlce with 5% aqueous aodium bteulflte (100 mL), once with brina (100 mL), dried with Nb₂SO₄and concentrated. Flash chromatography (15% EIOAc in hexana, slllca) resutted In 1.54 g ofa whtte solid. 1H NMR (400 MHz, CDCIj, mixture of rotamera) d 7.55 (m, 1 H), 6.57 (m, 1 Η), 3.B6 (a, 3 H), 3.80 (m, 1 K), 3.60-3.30 (m, 2 H), 3.20-2.80 (m, 4 H), 1.30 (m, 3 H). MS ealeulated for G^H^FglNOji-H: 414, observed: 414.

84oá&gt;-7^^K»iy-1-me^2,3,4^-tetia7vdm-1H-34)enza2Bplne [0102] A solution of N-trif luoroacetyl-8-iodo7-methoxy-1 -methyl-2,3,4,5-tetrahydro-1 W-3-benzazaplne (0.600 g, 1.45 mmol) In methanol (20 mL) was treatad wlth 15% aquaoua NaOH (20 mL), and atlrrad for 3 hours at 50*C. Tha product mixture waa diluted with water (100 mL), extractad twice with EtOAc (100 mL), the comblned organlc phasas wara waahad wRh brina (100 mL), drtad wlth NagSC^ and concantratad to glva 0.425 g of a yallow solld. 1M NMR (400 MHz, CDClg) d 7.52 (8,1 H), 6.57 (8,1 H), 3.86 (s. 3 H), 3.12-3.06 (m, 4 Η), 2.B5 (m, 2 H), 2.75 (m, 1 H), 2.43 (bs, 1 H). 1.33 (d, J=B Hz, 3 H). MS calculatad for C_1ZH₁₆INO+H: 318, observed: 31B.

Example4: (R,S) B-Bromo-7-hydioxy-1-iiwthyl-2^4^trtrehydre-1fM-l9enzazeplne [0103] <img file="IS2134B_D0011.tif" />

N-Trifíuomaatyl-84m&gt;ni&amp;-74íydmK^1-me^2,3,4^4eOa7vdm-1H-34)en2a2eplne

Ρ104] A solution of N-trlfluoroacatyl-8-b«XTK&gt;7-methoxy-1-methyl-2,3_l4_l5-tetrahydro-1H3-benzazeplne (1.50 g, 4.10 mmol) in dlctiloromathane (80 mL) was treated dropwlse wlth BBr₃ (9.4 mL of a 1,0M soliitlon in CH₂CI₂, 9.4 rnmol), and the mlxtura stiired ovemlght while warmlng to 20°C. Tha axcese BBr₃ was quanchad wlth the dropwiae additlon of water, the mlxture dlluted wlth athar (200 mL), washed wlth Na₂CO₃ (100 mL) and brine (100 mL), dried wlth Na2SO₄ and concantrated. Flash chromatography (15% EtOAc in hexane, aiHca) reeulted In 125 g of a white aolid foam. 1H NMR (400 MHz, CDC^, mixture ofrotamars) d 7.25 (s, 1 H), 6.79 (m, 1 H), 3.79 (m, 1 H), 3.7-3.3 (m, 2 H), 32-2.8 (m, 4 H), 1.32 (m, 3 H).

<img file="IS2134B_D0012.tif" />

<img file="IS2134B_D0013.tif" />

B-Bromo-T-hydroxy-l-meth^-S^^^tetrahydro-IH-S-beraazeplne [0105] A aolution of Ν-Ιι·1ίΙιιθΓθΗ£»Ι^8-0Γοη·ιο-7-Ιιν&lt;ΐΓθχγ-1-σιβΙ^2₁3,4,5-ΙθΐΓίΛνάΓθ-1ίΛ3-Ρθηζ3Ζβρίηβ (0.655 g, 1 .B9 mmol) in mathanol (20 mL) wae treated wlth 15% aqueous NaOH (20 mL), and stlrred ovemlght at 20%. TTie product mixture was diluted with water (100 mL), axtractad twk» with EtOAc. (100 mL), the combined organic phases were washed wlth brine (100 mL), dried wRh NajSC^ and concentrated to glve 0.460 g of a dear oll. 1H NMR (400 MHz. DMSO-dj) d 7.11 (s, 1 H), 6.65 (s, 1 H), 2.90 (m, 1 H), 2.73 (m, 5 H), 2.55 (m, 1 H),1.19 (d, J=7 Hz, 3 H). MS calculated fdr C^H^rNO+H: 256, obsatved: 256.

Exampla 5; (R,S) 7-Allyloxy-8-bronio-1-niethyl-2,3,4,5-tetrahydro-1H-3-benzazeplne [0106] <img file="IS2134B_D0014.tif" />

N-TrllluorOecetyl-7-aIlyloxy-3-bromo-1-mettiyl-2,3,4,5-tetrahydro-1H-3-beni:eíepine [0107] A solutlon oí N-trffluoraacetyl-a-bromo-7-hydroxy-1-methyl-2,3_l4_l5-tGtrahydro-1W-3-benzazeplne (0.160 g, 0.426 mmol) In dichloromethane (5 mL) was treated wfth allyl bromlde (0.155 g, 1.28 rrvnol) and DBU (0.195 g, 1.28 mmd) and then stlrred 2 houre at 20%. "Πιβ product mixture was dlluted wlth EtOAc (50 mL), washed wlth 5% aqueous HCI (20 mL), brine (20 mL), dried with NegSO* and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted In 0.149 g of a dear oll. 1H NMR (400 MHz, CDCIg, mixture of rotamere) d 7.34 (s, 1 H), 6.65 (m, 1 H), 6.04 (m, 1 H), 5.47 (d, J=17 Hz, 1 H), 5.30 (d, J=9 Hz, 1 H), 4.59 (s, 2 H), 3.80 (m, 1 H), 3.6-3.3 (m, 3 H), 3.2-2.8 (m, 4 H), 1.31 (m, 3 H). MS calculated for C_1sH₁₇BrF₃NO₂+H 392, observed: 392.

7^lytoxy^4)fomo-1-nHdiytí,3,4,61dmfvdf^ ΙΗ-9-benzazeplne [0108] A solutlon of N-trffluorDacetyl-7-allyloxy-6-bromo-1-methyl-2,3,4_l5-tetrahydro-1/+3-benzazeplne (1.16 g, 3.00 mmol) ln mathanol (35 mL) was treated wtth 15% aquaous NaOH (35 mL), and stlrred ovemight at 20%. The praduct mlxtura was dlluted wlth water (200 mL), extracted twlce wlth EtOAo (200 mL), tha combined organic phasea were waahad wtth brlne (100 mL), drlad wlth NajSO₄ and concentrated to glve 0.680 g of a dear oll. 1H NMR (400 MHz, CDCI3) d 7.29 (s, 1 H), 6.63 («, 1 H). 6.04 (m, 1 H), 5.47 (d, J-17 Hz, 1 H), 5.29 (d. J-11 Hz. 1 H), 4.58 (s, 2 H), 3.01 (m, 3 H), 2.89 (m, 3 H), 2.75 (m, 1 Η), 1.31 (d, J=7 Hz, 3 H). MS caleulatadfDrC₁₄H₁₈BrNO+H: 296, obsarved: 296. Enmple 6: (R,S) 7-BenzyloxyMrBino-1-iiiethyl-29A!MitrahydR&gt;-1 f+3-benzazeplne [0109] <img file="IS2134B_D0015.tif" />

N-THfíuoroacetyt-7-beruyloxy-e-bromo-1-methyl-2,3,4,5-tetrahydro-1H-3-beraazepine [0110] A solutlon of N-trtfluoraacety^8-bΓomo-7-hyclraxy-1-πlθthy^2,3,4,5-tetrahydra-1H-3-bθπzazθpinθ (0.075 g, 0.213 mmol) In dichloromethane (5 mt) was treated wfth benzyl bramlde (0.072 g, 0.64 mmol), DBU (0.100 g, 0.64 mmol), and stirred 2 hours at 20%. The product mlxture wae dlluted wlth EtOAo (50 mL), washed wlth 5% aqueous HCI (20 mL), brlne (20 mL). dried wlth NagSO+and concentrated. Flaeh chrematography (15% EtOAc In hexane, elllca) rmulted ln 0.081 g of a dear oll. MS calculatad for C₂₀H₁₉BrF₃NO₂+H: 442, obseived: 442.

<img file="IS2134B_D0016.tif" />

<img file="IS2134B_D0017.tif" />

T-Benzyloxy-B-bromo-l-methylS.S^.S-tBlmhydm-IH-S-benzaœplne [0111] Α aolution of N-trlfluomacetyl-7-benzylQxy-8-bramo-1-methyl-2,3_l4,5-tetrahydro-1/+3-benzazepln0 (0.81 g, 1 B3 mmol) In mathanol (20 mL) was treated wlth 15% aqueous NaOH (20 rnL), and stirred ovamight at 20°C. The product mixture waa diluted with water (200 mL), extracted twl» with EtOAc (200 mL), the combined organic phasas wara washed wtth brine (100 mL), drlad wlth NagSO₄ and concantratad to glve 0.412 g of a claar oil. 1H NMR (400 MHz, CDCIjj) d 738 (d, J=B Hz, 2 H), 7.30 (dd, J=7,8 Hz, 2 H), 7.23 (m, 2 H), 6.61 (s, 1 H), 5.03 (8,2 H), 2.94 (m, 3 H), 2.81 (m, 3 H), 222 (m, 1 H),2.30(b8,1 H),1.24(d,J=7Hz,3H).MScalculatödforC₁₈H₂₀BrNO+H:346,observad: 348.

Example 7: (R,S) 8-Βιχκηο-7-β1ήοχγ-1-ιτ«ΙΙιγΡ2,3,4,5-ΙβΐΓ8ΚγΡΓθ-1 Η-3-benzazeplne [0112] <img file="IS2134B_D0018.tif" />

Ν-ΤπΙΙυοτοβ&lt;χ(γ1ϋ-ύη)τπο·7-βΟ}αφ·1'ΤηΒ^γΙ·2_ι3_ι4_ι5-(βΜγύη&gt;· IH-S-beraaiepme [0113] A solution of N-trifluoroecetyF8-bromo-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1fF3-benzazepine (0.015 g, 0.043 mmol) In dtahtoromethane (1 mL) was traatad wtth ethyl lodlda (0.018 g, 0.102 mmol), DBU (0.016 g, 0.102 mmol) and stlrred 2 hours at 20°C. The praduct mixture was diluted with EtOAc (10 mL), washed wlth 5% aqueous HCI (5 mL), brlne (5 mL), drled with Nb2SO₄ and concentrated. Flash chromatography (15% EtOAc in hexane, sillca) resulted in 0.010 g of a clear oil.

8-Bromo-7-ethoxy-1-methyl-2,3,4,5-tetmhydm· 1H-3-benzazeptne [0114] A solutlon of N-trifluoroacetyl-B-bromo-Z-ethQxy-l-melhyl^.S^.B-tatrahydro-IH-S-benzazeplna (0.010 g, 0.026 mmol) In methanol (1 mL) was traated wlth 15% aqueous NaOH (1 mL), and stirred ovemight at 20°C. The product mlxlure was dlluted wlth water (3 mL), axtractad twlca wlth EtOAc (5 mL), the comblnad organfc phasas ware washed with brina (3 mL), dried wlth Na2SO₄ and concentrated to give 0.007g of a dear oil. 1H NMR (400 MHz, CDCIj) d 729 (s, 1 H), 6.63 (a, 1 H), 4.07 (q, J=6 Hz, 2 H), 3.03 (m, 3 H), 2.91 (m, 3 H), 2.73 (m, 1 H), 2.26 (bs, 1 H), 1.46 (t, J=6 Hz, 3 H), 1.32 (d, J=7 Hz, 3 H). MS cabulated for C_1sH₁₇BrF₃NO2+H: 380, obaervad: 380.

Exarnple 8: (R,8) 8-Brorno-7-lsoprDpoxy-1-niethyl-2,3,4,5-tetrBhydro-1H-3-benzBzepiiie [0115] <img file="IS2134B_D0019.tif" />

N-Trtlluoroacetý^mmoJ48opmpcKy-1-mBthyl-2_l3_l4_l5-tBtiahydro-1H-&amp;benzazBplnB [0116] A soluöon of N-trlfluoroacetyl-8-bromo-7-hydroxy-1-methyl-2_l3_l4_l5-tetrahydro-1H-3-benzazepine (0.035 g, 0.099 mmol) In dlchloromethana (1 mL) was traatad wlth Isopropyl bromlda (0.037 g, 0297 mmoQ, DBU (0.048 g, 0.205 mmol) andstfired2 houreat20°C. Theproductmlxtura was dlluted with EtOAc (10mL), washed with 5% aqueous HCI (5 mL), brlne (5 mL), drlsd wlth NagSO₄ and concentrated. Flash chromatography (15% EtOAc In hexane, slllca) resultad fn 0.014 g of a ciaar oil. MS calculated tor C^^^NOj+H: 394, obaerved: 394.

<img file="IS2134B_D0020.tif" />

<img file="IS2134B_D0021.tif" />

8-Bromo-7-isapropaíy-1-mettiyl-2.3,4,5-tatmlTydKb1H-34&gt;enzazeplne [0117] A solutlon of N-trtfluoroacetyl-e-bramo^-leopropoxy-l-methyl^íAB-tetrahydra-lW3-benzazapine (0.014 g, 0.035 mmol) In methanol (1 mL) waa treated with 15% aqueous NaOH (1 mL), and stlrred ovemight at 20°C. The product mlxtura was dlluted wlth water (3 mL), extractad twlca with EtOAc (5 mL), tha comblned organlc phases were washad wlth brfne (3 mL), dríed wlth NbjSO^ and eoncentrated to glve 0.008 g of a dear oll. 1H NMR (400 MHz, COCy d 7.24 (s, 1 H), 6.64 (s, 1 H), 4.48 (m, 1 H), 2.98 (m, 3 H), 2.87 (m, 3 H), 1.36 (m, 6 H), 1.30 (d, J=7 Hz, 3 K). MS calculatad for C^H^BrNO+H: 298, observed: 298.

Example 9: (R,S) N-MeMiyP8-bromo-7-meöioxy-1-methyl-2,3,4,5-tefrahydre-1 W-3-benzazeplne [0118] <img file="IS2134B_D0022.tif" /> [0119] A solution of 8-Bromo-7-methoxy-1 -methylí^^.S-tetrahydra-l Η-3-benzazepine (6 mg, .022 mmol) in methanol (1 mL) was traatad with axcass paraformaldahydB, 1.0 M HCI in ether (0.004 mL, 0.004 mrnol), NaBH₃CN (1.0 mg, 0.013 mmol), and atirred ovemtght at 20°C. The praduct mlxture was dlluted wlth 5% aqueous NaOH (5 mL), axtracted 3 timas wlth CH₂CI₂ (5 mL each), the combined organic phases ware drled with NagSO^ and concentrated. Flash ehromatography (10% MaOH in CH₂CI₂, slllea) resulted In 5 mg of a clear oll. 1H NMR (400 MHz, CDCy d 7.31 (8,1 H), 8.88 (8,1 H), 3.87 (s, 3 H), 3.28 (bm, 2 H), 3.01 (bs, 1 H), 2.85 (m, 2 H), 2.45 (s, 3 H), 2.45-2.25 (in, 2 H), 1.36 (d, J=7 Hz, 3 H). MS cafculated for C₁₃H₁₈BrNOtH: 284, obeerved: 284.

Example 10: (R,S) N-Propyl-8-bromo-7-met)ioxy-1-methyl-2,3,4,5-tetrahydro-1 W-3-benzazepine [0120] <img file="IS2134B_D0023.tif" /> [0121] AsoluUon of8-Bromo-7-methoxy-1 -methyl-1,2,4,5-tetrahydro-3H-3-benzazeplne (β mg, 0.022 mmol) in methanol (1 mL) was treated wlth proplonaldehyde (5.0 mg, 0.067 mmol), 1.0 M HCI in ether (0.004 mL, 0.004 mmol), NaBHjCN (1.0 mg, 0.013 mmol), and sflrred ovemlght at 20’C. The product mixtura was diluted wlth 5% aqueous NaOH (5 mL), extradad 3 tlmes wlth CHjCIj (5 mL each), the comblned organlc phases ware driad wlth NbjSQ^ and concentrated. Flaeh chromatography (10% MaOH ln CHjCIj, s llica) resutted In 4 mg of a dear oll. 1H NMR (400 MHz, CDgOD) d 7.33 (8,1 H), 6.87 (8,1 H), 3.84 (8,3 H), 3.25 (m, 2 H), 3.11 (m, 2 H), 2.97 (m, 1 H),2.78 (bm, 2 H), 2.83 (bm, 2 H), 1.67 (m, 2 H), 1.38 (d, J=7 Hz, 3 H), 0.96 (t, J=7 Hz, 3 H). MS calculatedfor CuHæBrNO+H: 312, obsarved; 312.

Example 11: (R,S) 7-Hydroxy-8-lodo-1-niethyl-2,3_l4_&gt;5-tetrahydro-1H'3-benzazeplne [0122] <img file="IS2134B_D0024.tif" />

<img file="IS2134B_D0025.tif" />

<img file="IS2134B_D0026.tif" />

<img file="IS2134B_D0027.tif" />

N-Trifíuoroacetyl-7-hydraxy-s-iodo-1-methyl-2_l3.4,5-tetrahydro-1H-3-benzazepine [0123] A βοΙιΛοη of N-trffluoroaeetyl-8-todo-7-methoxy-1 -methyl-2,3,4,5-tetrahydro-1 Wa-benzazepine (80 mg, 0.19 mmol) in dichloramathana (3 mL) was treatad wtth BBr₃ (0.40 mL of a 1.0M solution in CHgCl^ 0.40 mmol) and stírred ovemlght at 20%. Tha axcess BBr₃ was quenched wlth water and tha product mixture was dilutad with ether (20 mL), washed wlth NajCO₃ (10 mL) and brlna (10 mL), dried wtth Na^O* and concantratad. Flash chromatography (15% EtDAc in hexane, silica) raeulted in 74 mg of a whíta solld. MS calculated for C₁₃H₁₃F₃INO₂+H: 400, observed: 400. 7-Hydroxy-8-iodo-1-medtyl-2,3,4_l5-totrahy&lt;lro-1H-3’benzaiepine [0124] Asolutlon of N-trif1uoroacatyl-7-hydroxy-8-iodo-1 -mathyl-2_l3_l45-tetrahydro-1 W-3-benzazepine (25 mg, 0.063 mmol) in methanol (2 mL) was treated wlth 15% aquaous NaOH (2 mL), and stlrred ovamlght at 20%. Tha product mixture waa diluted with water (5 mL), axlracted twica with EtOAc (5 mL), the comblned organic phases ware washed with brine (5 mL), dríad wlth Na^O^. and concentratad to give 13 mg of a white solid. 1H NMR (400 MHz, CD₃OD) d 7.46 (s, 1 H), 6.64 (s, 1 H), 3.16 (m, 3 H), 2.84 (m, 3 H), 2.81 (m, 1 H), 1.35 (d, J=7 Hz, 3 H). MS calculatad for Ο^Η-μΙΝΟ+Η: 304, obsenréd: 304.

Example 12: (R,S) 7-Allylwcy-8-lodo-1 -methy1-2,3,4,5-tetrahydro-1 f+3-benzazeplne [0125] <img file="IS2134B_D0028.tif" />

N-TrHluoroacetyl-7-aByloxy-&amp;-lodo-1-mettiyt-2,3,4,5-tetrAiydrO-1H-34}en2iazepine [0126] Asolution of N-trifluoroac^yl-7-hydroxy-B-lodo-1-fnetliyl-2,3_l4_l5-tetrBhydro-1 Η-3-benzazepine (30mg, 0.075 mmol) In dichloromethana (2 mL) was traated wtth allyl bromlde (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stlrred 2 hours at 20%, The product mixture was diluted wíth EtOAc (10 mL), washed wlth 5% aqueous HCI (5 mL), brine (5 mL), dried wlth Na^O^ and concantrated. Flash chromátography (15% EtOAc in haxana, sillca) resulted In 23 mg of a clear oil. MS calculated for C₁₆H₁₇F₃INO₂+H: 440, observed: 440.

TAfíytoxy-B-Mo- 1wethyl-2,3,4,5-tetmhydro-1H-3-benzazepine [0127] A solutlon of N-trif1uoroacetyl-7-allyloxy-8-lodo-1-methy1-2,3,4Æ-t0trahydro-1 HS-benzazepina (23 mg, 0.058 mmol) In mathanol (2 mL) waa treatad wlth 5% aqueous NaOH (2 mL), and stlrred ovemlght at 20%. The product mixtura was dllutad wlth water (5 mL), axtracted twlca wlth EtOAc (5 mL), tha comblnad organic phasas were washed wlth btlna (5 mL), drlad wlth Ne^SO₄ and concentrated to glve 18 mg of a whlte solid. MS calculated for C_UH₁₈INO+H: 344, observed; 344.

Exampla 13: (R,S) 39-Dlnwthyl-6,7A9'Mnihydro-5H-1-&lt;ixa-7-aza- cyclolwptalndene [0128] <img file="IS2134B_D0029.tif" />

N-trifíuoroaaetyl-3,5-&lt;emeth^-6,7,8,9-{Btrahydro-SH-1-oiiB-7-aza-cycloheptalndenB [0129] A eolutton of N-írlfluoroacatyl-7-allyloxy-8-lodo-1-methyl-2,3,4,5-tarrahydro-1H-3-benzazaplne (158 mg, 0.360 mmol) In dlmathylformamlda (4 mL) wae treated wlth KOAc (106 mg, 1.08 mmol), n-Bu₄NBr (116 mg, 0.360 mmol), PPhs (13 mg, 0.036 mmol), PdfOAc^ (4 mg, 0.01 B mmol) and stirred ovemight at 100%. The product mixture

<img file="IS2134B_D0030.tif" />

<img file="IS2134B_D0031.tif" />

was filtered, water (10 mL) added and than axtractad twlce wlth EtOAc (10 mL). The combined organlc phasas were washed with brine (10 mL), dried wlth Na₂SO₄ and concentrated. Flash chromatography (5% EtOAc in hexane, sillca) resulted In 15 mg of a clear oll. MS calculated for C_ieH₁₆F₃NO2+H: 312, obseived; 312.

3,5-DimethyMSJ,B,9-tetohydro-5H-1wa-7-aza-cyMeptain(tene [0130] A solution of N-trffluoroacetyl-3,5-dimathyl-6,7,B,8-tatrahydro-5H-1-oxa-7-aza-cycloheptalndena (15 mg, 0.048 mrnol) in methanol (2 mL) was traatad wlth 15% aqueous NaOH (2 mL), and stlrrad ovemight at 2Q°C. Tha product mixture was diluted with water (5 mL), extracted twira wRh EtOAc (5 ml), the combined organic phases were washed wtth brine (5 mL), drfed with Nb₂SO₄ and concentratad to glve 10 mg of a whlta soUd. 1H NMR (400 MHz, CDCI_a) d 725 (a, 1 H), 7.12 (s, 1 H), 7.09 (s, 1 H), 3.12 (m, 1 H), 2.97 (m, 4 H), 2.85 (m, 1 K), 2.84 (bm, 1 H), 2.15 (s, 3 H), 1.34 (d, J=8 Hz, 3 H). MS calculalad for C₁₄H₁₇NO+H: 216, observed: 216.

Example 14: (R,S) 7-ΑΙΙ/Ιαηι-8-οΗΙοια-1-πκΗφΙ-2,3,4Λ-Μπι&gt;ηΜη-1/Μ4&gt;βπζΒζβρΙπΒ [0131] <img file="IS2134B_D0032.tif" />

Ν·ΤτηυθΓθβοθΙ^-8-αΜθΓθ·7-^Γαν-1-πκύι^2,3,4,5·ΙβΙΤ37ν0ιο·1Η-3-0βηί8ίβρΙπβ [0132] A solution of N-trtfluaroacetyl-8-chloro-7-rnethoxy-1-methyF2,3_l4,5-tetrahydro-1H-3-benzazepina (48 mg, 0.15 mmol) In dichloromethane (2 mL) was treated wlth BBr₃ (0.30 mL of a 1.0M solutlon in CH^, 0.30 mmol) and stlrrad ovamlght at 20°C. Tha excase BBr₃ was quanchad wtth watar and tha rasultlng mlxture dlluted with ether (20 mL), washad with NbjCC^ (10 mL) and brine (10 mL), dried wlth NajSO₄ and eoneentrated. Flash chromatography (15% EtOAc In hexane, silica) raaulted in 24 mg ot a whlta solld. MS calculatad for C₁₃H₁₃CIF₃NO₂+H: 308, observed: 308.

N-Trífíuoroacetyf-7-altytoxy-e-chlom-1-inethyl-2,3_l4,5-teWahy(lro-1H-3-benzazeplne [0133] A solutlon of N-trtfluorbacelyl-B-chloro-7-hydroxy-1-methyl-2,3,4,5-tatrahydFo-1H3-benzazepine (24 mg, 0.078 mmol) In dtehloromethane (2 mL) was treated wtth allyl bromlde (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred 2 houra at 20"C. Tha praduet mfxture was dlluted wlth EtOAc (10 mL), washed wlth 5% aqueous HCI (5 mL), brtne (5 mL), drlad wlth Na₂SO₄ and concentrated. Flash chromatography (15% EtOAc ln hexane, slllca) resulted In 23 mg of a whlte solld. MS calculated for C_laH₁₇CIF₃NO2+H: 348, observed: 34B.

7ΑΜ&lt;φ-8-ΰΜχο-1-Μβ^2_ι3Α,5-(βΐΓΒ%ύΐΌ-1Η-3-ί)βηζΒζβρΙηβ [0134] A solutlon of N-trlfluorDacetyl-7-allytoxy-8-chlora-1-niethyF2_l3,4,5-tatrahydra-1H-3-benzazepina (23 mg, 0.068 mmol) In msHianol (2 mL) was treated with 15% aqueoue NaOH (2 mL), and stirred ovemight at 20’C. The product mbðure was dllutad wlth watar (6 mL), extracted twlca wlth EtOAc (6 mL), tha comblned organic phases were washed with brine (5 mL), dried wlth Na^j end concentratad to glve 19 mg oí a whrte solid. 1H NMR (400 MHz, CDgOD) d7.12 (8,1 H), 6.81 (s, 1 H), 6.03 (m, 1 H), 5.43 (d, J»17 Hz, 1 H), 5.24 (d, J=10 Hz, 1 H), 4.57 (d, J=5 Hz, 2 H), 3.1-2.9 (m, 5 Η), 2.B1 (m, 1 H), 2.63 (m, 1 H), 1.30 (d, J=7 Hz, 3 H).

Example 15: (R,S) 7-Methoxy-1-methyFB-p-ttilenyl)-2,3,4,5-tBtrahydro-1/F3-benzazepine [0135] <img file="IS2134B_D0033.tif" />

<img file="IS2134B_D0034.tif" />

<img file="IS2134B_D0035.tif" />

N-Tri^luoroacβtyl7-rπettιoκy-1-methyl·B·(2-thlenyl)2,3,4,5-^Btrstιydro^1H^3^b6nzazeplnβ [0136] A solution of N-trifluoromethylacetyl-8-bramo-7-methoxy-1-metíiyl-1,2,4,5-tatreihydro-3H-3-banzazepina (51 mg, 0.14 mrnol) in 1,4-dloxane (2 mL) was treated with thtophene-2-boronic add (36 mg, 0.28 mmol), I^COj (58 mg, 0.42 mmolj, water (0.1 mL), Pd(PPh₃)₄ (16 mg, 0.014 mmol) and stlrrad overnlght at 10O’C. Tha product mixture was dllutad wlth EtOAc, fittered, absorbed on sillca and purifled by flash chromatograghy (10% EtOAc in hexane, silica) resuttíng In 28 mg of a yallow aolld. MS calculated for C₁gH_1gF₃NO₂S+H: 370, observed: 370.

7-ΜεΙ^χτ1-πιβ[^8-(2-ΜΒηγΙ)-2,3,4,5-ΙβΙί8ψ0η&gt;1Η-3-ύετχΒΖβρίηβ [0137] A solution af N-trifluoraacetyl-7-mathoxy-1-methyl-B-(2-thlenyl)-2,3,4,5-tetrahydro-1H-3-b6nzazeplne (28 mg, 0.076 mmol) in methanol (2 mL) was traatad wlth 15% aqueous NaOH (2 ml), and stirred 0.5 houre at 50‘C. Hia product mixture was diluted with watar (5 mL), extracted twlca with EtOAc (5 mL), the combined organlc phases were washed with brine (5 mL), dried wlth NaaSO₄ and concentratad to give 18 mg of a yallow oil. 1H NMR (400 MHz, CDCIjj) d 7.45 (d, 4=4 Hz, 1 H), 7.89 (s, 1 H), 7.27 (d, J=6 Hz, 1 H), 7.07 (dd, J=4,6 Hz, 1 H), 6.71 (a, 1 H), 3.90 (s, 3 H), 3.1-2.9 (m, 6 H), 2.80 (m, 1 H), 2.22 (bs, 1 H), 1.38 (d, J=7 Hz, 3 H). MS calculated for C₁₃K_ieNOStH: 274, obMrvad: 274.

(Comparatlve) Example 16: (R2) &amp;-CyBno-7-mettioxy-1-methyl-2,3,4,5-tetrahydro-1 Η-3-benrazeplne [0138] <img file="IS2134B_D0036.tif" />

N-rdffuoroacefy(-8-cy8no-7-matficwy-1-metfiy/-2,3,4,5-íeffahydro-1H-3-benzazep/ne [0139] A aoluUon of N-trtfluoroacetyl-8-bromo-7-mettioxy-1-methyl-2_l3,4,5-tetrahydro-1W-3-benzazepine (18 mg, 0.05 mmol) In dlmethylformamida (1 mL) was treated with CuCN (20 mg, 0.24 mmol) and the mlxture was mlcrowaved at 200*0 for 02 houre. Tha product mlxture was dllutad with watar (5 mL), extractad twlca with EtOAc (5 mL), tha comblnad organlc phases ware washed wlth brine (6 mL), driad witti NagSO₄ and concantrated. Flash chromatography (35% EtOAc in haxane, slllca) reaultad In 10 mg of a claar oil. MS calculatad for C^H^FgNjO^H: 313, observed: 313. ð-Cyano-7-maftoxy-/-mstfjyf-2,3,4,5-ÉBlrahyd«&gt;-íf^3-tonzazBp/ne [0140] A aolutbn of N-trifluoroacetyt-B-cyano-7-fnettioxy-1-mathyt-2,3,4,5-tetrahydro-1H2-benzazeplne (10 mg, 0.032 mmol) In methanol (2 mL) was treatad wtth 15% aqueous NaOH (2 mL), and atlrred 1 hour at 50’C. The product mixturewaa dlluted with watar (5 mL), axtractadtwk» wlth EtOAc (5 mL), tha combined organie phases were washed wlth brina (5 mL), drled wlth Νβ2&amp;0₄ and concantiatad to glva 6.0 mg of a whita solld. 1H NMR (400 MHz, CD₃OD) d 7.33 (s, 1 H), 6.93 (s, 1 H), 3.91 (a, 3 Η), 3.18-2.97 (m, 5 Η), 220 (m, 1 H), 220 (m, 1 H), 1.33 (d, J=8 Hz, 3 H). MS calculatad for CuHjgNaO+H: 217, obseivad: 217.

Exampto 17: (R.8) 8-bromo-1-cyctopropyF7-methoxy-2,3_l4,5-tatrahydro-1 M-benzaxeplne

Ρ141]<img file="IS2134B_D0037.tif" />

N-Trtfíuoroece(yl-1-cyclopmpyl-7-meltKxy-2,3,4,5-tetraf&gt;ydTO-1H-3-benzazeplne [0142] A aolution of dlathyl zlnc (1 mL, 1 M In haxanea) In dlchloromethane (1 mL) at 0’C was traatad wlth trifluor-

<img file="IS2134B_D0038.tif" />

<img file="IS2134B_D0039.tif" />

oacotic acid In dichloromathane (0.5 mL) and tha mixture stirred fbr 15 min. Diiodomathana (0.280 g, 1.0 mmol) in didiloromathane (0.5 mL) was then added and stirred for 15 mlnutes. N-Trífluoraacetyl-7-methoxy-1-methylene2,3,4,5-tatrahydro-1H-3-banzazapine (0.075 g, 026 mmol) in dichloromattiana (1 mL) was added and tha mlxture stlrred for 30 mlnutes at 0°C and then fár 2 hours at 20%. The product mixtute was quanched with aqueous salurated NH₄CI (5 mL), axtraded twice wlth CHjCIj (20 mL), washad wltti saturatad aqueous NaHCO₃ (10 mL), washed with H_ZO (10 mL), and concantralad. Rash diromatography (7% EtOAe in hexanas, slllca) resulted in 0.050 g of a white soltd. MS calcuiated for C^H^FjNO^H: 300, obseived: 300.

N-r/flíuora8cefy/-e+jramo-í-cydopropy/-7-meftaxy-2,3,4,5-te(raft)«ífO'íH-3-benzazep/ne [0143] A solutlon of N-tr1fluoroacetyl-1-cydopropyl-7-methoxy-2,3,4,5-tatrahydrD-1 W-3-benzazepine (0.025 g, 0.08 mmol) in acetonitrile (1 mL) was traatad wtth N-bromosuœlnlmlda (0.032 g, 0.18 mmol) and stirred for2 hre. at 50’ C. "Πιβ praduct mbcture was concantraled and than purffied by flash chromatography (10% EtOAc in hexanes, ailíca) raeulting in 0.014 g of a whlte aolid. MS calculated for 0_1$Η₁₅ΒγΡ₃Ν02&lt;-Η: 378, obsarvad; 378.

8-bromo-1-cydopropyl-7-methoxy-2,3,4,5-tetralTydrO-1H-3-benzazeplne [0144] Asolution of N-tiífluoroacetyl-e-bromo-l cydopropyl-7-methoxy-2,34_l5-telrahydro-1 Η-3-benzazepine (0.014 g, 0.037 mmd) In methanol (1 mL) was treated wlth 15% aquaoue NaOH (1 mL), and stlrrad for2 hours at 50%. The productmixturewasdHutedwlthbrina(10mL),exlractedlwlcewith EtOAc(IOmL), driedwrtti MgS0_4landconcentrated to give 0.008 g of a clear oil. 1H NMR (400 MHz, CD₃OD) d 7.26 (s, 1 H), 6,78 (s, 1 H), 3.83 (s, 3 H). 3.02 (m, 2 H).

2.82 (m, 2 H), 2.67 (s, 2 H), 0.91 (m, 2 H), 0.85 (m, 2 H). MS calculatad for Ο^Η^ΒγΝΟ+Η: 282, observed: 262. Example 18: (R,S) 8-bremo-1-hydreKymethyl-7-nietlioxy-23A5-lBtnihyclra-1 tf-3-benzazeplne [0145] <img file="IS2134B_D0040.tif" />

N-TrifluoiOacetyl-1-hydmxymethy(-7-mett&gt;axy-2,3,4,5-tetrahy(lm-1H-3-ben2a2eplne [0148] A aolutlon of N-trifluoroacetyF7-mathoxy-1-methylene-2,3,4,5-tBtrahydro-1H-3-banzazeplna (0.100 g, 0.35 mmol) In tetrahydrofuran (1 mL) was treated wlth BHyTHF complex (0.36 mL, 1 M In THF), and stirrad for 30 mln. at 20%. Water (0.5 mL), saturated aqueous NaHCQa (0.5 mL), and 30% HjOg (0.2 mL) were added aaquentíally and tha reacUon stlrred for 30 mln. at 20%. The product mixture was dlluted wlth EtOAc (10 mL), washad wlth brína (10 mL), and concentrated. Flash chramatography (33% EtOAc In haxane, slllca) resultad in 0.035 g of a claar oll. MS calculated fbr (^Η^ΝΟ^Η: 304, obe«ved: 304.

N-Tflfíuoroecetyf-64mrno-1-hydm)iymettyl-7-melhaxy-2_l3,4,S-tetratiydro-1H-3-ben2a2eplne [0147] A solutton of N-trffluoromethylacetyl-1-hydiOxymathyl-7-methoxy-2,3,4,5-t0trahydro-1H-3-bBnzazepine (0.036 g, 0.12 mmol) ln acetonitrile (1 mL) wbb treated wtth N-bromosuccinlmlde (0.025 g, 0.14 mmol), and stirrad for 30 mln. at 20%. The product mlxtura waa concentrated and then puriflad by flash chromatography (33% EtOAc In haxana, slllca) rasultlng In 0.019 g dearoll. MS calculated for C^jBrFgNOj+H: 382, obsarvad: 382. 8-bnmo-1-hytlmKyrnethyl-7-fnBthaíy-2,3/í,5-tgtratydro-1H-3-bema2ep/ne [0148] A solutton of N-trtfluoroacatyl-8-hromo-1-hydroxymethyl-7-nnathoxy-2,3,4,5-tetrahydro-1H-3-benzazepina (0.009 g, 0.024 mmol) in mathanol (1 mL)wastreatedwlth 15% aquaous NaOH (1 mL),andstlrredfor1 hourat50%. Tha product mlxture was dllutad wlth brlna (5 mL), extracted twlce wlth EtOAc (5 mL), drfed wlth MgSO₄, and concentrated to glve 0.006 g daar oll. 1H NMR (400 MHz, C0₃OD) d 7.28 (e, 1 H), 6.79 (s, 1 H), 3.84 (m. 2 H), 3.0-2.8 (m, 7 H). MS calculatedforC₁₂H_ieBrNO2+H; 286, observed: 286.

<img file="IS2134B_D0041.tif" />

Example 19: (R,S) β-Βηπο-Ι-β^γΡΤ-ιηβΏοχγΐ,βΛΒ-ΙβΙιιΙινάιυ-ΙΗΰ-ΡβηζΒΖβρΙηβ [0149] <img file="IS2134B_D0042.tif" />

N-Cmtyl, N-tΓlΠυoroacBtyl·2-kx^o5-mβthaίyphβnethylarπiπβ [0150] A solutlon of N-trifluoroacatyl-2-todo-5-methoxyphenethylamlne (0.68 g, 17.9 mmol) in toluene (100 mL) was treated wlth I^COg (322 g, 23.3 mmol), KOH (3.01 g, 53.7 mmol), n-Bu^NBr (0.580 g, 1.60 mmol) and crotyl bromide (3.15 g, 23.3 mmol). The mlxture was stirred at 75"C for 16 houra, cooled to 20* C, diluted wlth Et₂O (500 mL), washed wlth 10% aqueous HCI (500 mL) and concentrated. Flash chromatography (10% EtOAc in hexane, slllca) resultad in 522 g of a claar oll. MS calculated for C₁₅H₁₇F₃INO₂+H: 428, obaarved: 42B.

N-Trifíuoroacetyl-1-e1lTylene-7-methoxy-2,3,4,5-tetratiydro-1H-3-benzazepine [0151] A solution tíl N-crotyl, N-trifluoroacatyF2-iodo-5-mathoxyphBnathylamlna (5.20 g, 12.2 mmol) in dlmethylfor-marnlda (80 mL) wastreatadwKh KOAo (3.59 g, 30.6 mmol), n-Bu₄NBr (3.93 g, .122 mmol), PPh₃ (0.320g, 1.22 mmol), Pd(OAc^ (0.137 g, 0.61 mmol) and stlrrad ovamight at 90*C. Ήιβ product mixture was cooled to 20’C, diluted with water (200 mL), axtractad twlce wlth ather (500 mL), tha comblnad organlc phaaea washed twlce with brlne (200 mL), and concentrated. Flash chromatography (10% EtOAc in haxane, slllca) resulted In 2.29 g of a clear oil, which conslsts of a mixture of oleflnic laomers. MS cafculated for C_1sH_ieF₃NO₂tH: 300, obsarvad: 300.

N-THfíuoroecetyl-1-ethyl-7-methoxy-2A4_l54etrahydro-1H-34^nzazeplne [0152] A solution of N-trifluoroacetyl-1-ethylena-7-methoxy-2,3,4_l5-tetrahydro-1H-3-benzazepine (2.29 g, 7.65 mmol) In methanol (100 mL) was treatad wlth 10% Pd/C (4.0 g, 0.77 mmol)) and sttrred ovemlght under an atmosphere of hydrogan. Tbe product mixlure was filtarad through a pad of cslite and siBca, and the solvent removed to give 2.14 g of a etear oil. MS cafculated for C_1SH_1BF₃NO₂+H: 302, obsarved: 302.

Ν-ΤΓΐίΙυοΓθβΒβΙγΙ^Γοπο-1^^ί7-Μβί^χγ-2,3,4,5-Ιβ{ΓβϊιγύΓΐ&gt;-1Η-3-Ι)βηζ8ζβρίηβ [0153] Asolutlon of N-trtfluorolacatyl-1-ethyl-7-methoxy-2,3_l4_l5-tetrahydra-1 Μ-3-benzazeplna (0.710 g, 2.36 irvnol) In acetonltrlle (20 mL) was treated wlth N-bromosuccinlmlde (0.504 g, 2.83 mmol), and stfrred ovemlght at 20°C. The produd mixture was concentrated, diluted with EtOAc (100 mL), waehed wlth watar (50 mL) and brina (50 mL), drled wtth Na₂SO₄ and eoncentratad. Flash chromatography (10% EtOAc In haxanas, sillca) rasultad in 0.561 g of a clear oll. MS calculated for C₁₅H₁₇BrF₃NO2+H: 380, obseived: 380.

8-Bronrn-1-etl^7Hnethoxy^3,4,S-telrahyiíiO‘1H-3-benzBæplne [0154] A aoludon ot N-trffluoroecetyl-8-bramo-1-ethyl-7-mettioxy-2_l3_l4_&gt;5-tetratiydro-1W3-benzazepine (0.561 g, 1.48 mmol) in methanol (30 mL) wes ireatad wlth 15% aqueoua NaOH (30 mL), and stirred ovemight at 20’C. The product mlxture was dllutad wlth brina (100 mL), axtracted twlca wlth EtOAc (200 mL), driad wlth MgSO₄, and concentrated to glve 0.412 g of a dear oll. 1H NMR (400 MHz, CD₃OD) d 7.24 (s, 1 H), 6.76 (e, 1 H), 3.83 (b, 3 H), 3.02 (m, 3 H), 2.91 (8,1 H), 2.85-2.76 (m, 3 H), 2.63 (m, 1 H), 1.78 (m, 1 H), 1.72 (m, 1 H), 0.94 (dd, J=8, 8 Hz, 3 H). MS calculated tor C₁₃H₇₃BrNO+H: 284, observed: 284.

<img file="IS2134B_D0043.tif" />

Example 20: (R,S) 8-Chloro-1-rthyF7-mathoxy-23/1^-tetrahydro-1H-3-benzazeplne [0155] <img file="IS2134B_D0044.tif" />

Ν-ΤπηυοηβοβΙγ1-&amp;^)τ&amp;-1^γί7-πεΜθ)(γ-2_ι3,4,5-&lt;β(ΤΒψθΓθ-1Η-3-ί)θηζβζβρΙηΒ [0156] A solutlon of N-trifluarolacetyl-1 -ethyl-7-mathoxy-2,3,4,5-tetrahydro-1 Η-3-benzazaplne (0.600 g, 1.99 mmol) in acatonltrlle (20 mL) was treatad wlth N-chlorosucdnlmlda (0.057 g, 0.32 mmol), and stlrrad ovamlght at 60°C. The product mbrture was concentrated, dilutsd wfth EtOAc (100 mL), washed wíth water (50 mL) and bríne (50 mL), dried with Na2SO₄ and concantratad. Flash chramatography (10% EtOAc in hexanes, sllica) resulted in 0.421 g of a clear ail. MS calculatad for C₁₅H₁₇CIF₃NO2t-H: 336, obseived: 336.

8-^lom-1-elti^-7-me8Kay-2,3,4,B4et/ahyáo-1H-3-benia2epine [0157] A aolutlon of N-trifluoroacatyl-8-chloro-1-athyl-7-rnethoxy-2,3,4,5-tetrahydro-1H-3-banzazeplne (0.421 g,

1.25 mmol) in methanol (30 mL) waa traated wlth 15% aqueous NaOH (30 mL), and stirred ovemlght at 20“C. Tha product mlxture was dilutad with brine (100 mL), «ctracted twlce wlth EtOAc (200 mL), dried with MgSO₄, and concen -traled to giva 0.241 g of a clear oll. 1H NMR (400 MHz, CD₃OD) d 7.05 (s, 1 H), 6.79 (s, 1 H), 3.84 (s, 3 H), 3.03 (m, 3 H), 2.91 (s, 1 H), 2.86-2.76 (m, 3 H), 2.64 (m, 1 Η), 1.B1 (m, 1 H), 1.72 (m, 1 H), 0.93 (dd, J=B, B Hz, 3 H). US calculated for C^gdNO+H: 240, observed: 240.

Example 21: (R,S) 8-Bromo-1-laopropyl-7-fnettioxy-2,3,42-tetrahydro-1 Η-3-tenzazeplne [0158] <img file="IS2134B_D0045.tif" />

N-(3-methytbut-2-enyt), N-trt8uamae^24odo-S-nnhoxyphenettylairtnB [0159] A solutbn of N-trifluoroacetyl-2-todo-5-methoxyphenerthylaminB (0.700 g, 1,8B mmol) In toluana (25 mL) was treated with KjGOj (0240 g, 2.4 mmol), KOH (0210 g, 3.76 mmol), n-Bu₄NHr (0.060 g, 0.19 mmol) and 4-bromo-2-methyl-2-butane (0.364 g, 2.44 mmol). Tha mlxtura was stlrred at BO’C for 3 hours, cooled to 20^sC, dlluted wlth ather (100 mL), waahad wlth 10% HCI (50 mL) and concentratad. Flash ehromatography (10% EtOAc In hexane, alliœ) resultad In 0.272 g of a clear oll. 1H NMR (400 MHz, CDCI₃, mixtuie of rotamars) d 7.65 (m, 1 H), 6.75 (m, 1 H), 6.54 (m, 1 H), 6.20 (m, .4 H). 6.0 (m, .6 H), 4.10 (m, 1 H), 3.82 (m, 1 H), 3.76 (d, 2H), 3.50 (m, 2 H), 3.02 (m, 2H), 1.76 (m, 3H), 126(m, 3H).

N-TrtOuoroecetyl-l^aopropylene-Z-methcixy^MS-tetrattydro-IH-a^jenzazepine [0160] Aaolution of N-(3-methytbut-2-enyl), N-trifluoroacetyl-2-iodo-5-mathoxyphenethylamine (.0272 g, 0.62 mmol) in dimethylformamlda (12 mL) was treatad with KOAc (0.183 g, 1.86 mmol), n-Bu₄NBr (0200 g, .062 mmol), PPh₃(0.016g, 0.062 mmol), PdfOAejg (0.183 g, 1.86 mmol) and stlrred ovamlgbt at 90“C. The product mixture was eoolad to 20’C, dlutad wlth water (50 mL), axbactad twlce with ethar (50 mL), ttie combined organic phases ware washad wltb brina (50 mL), and oonœntrated. Flaah chromatography (10% EtOAc In haxane, alllea) rasulted in 0.096 g of a dear oll. MS calculated for C_ieH₁₃F₃NO^H·. 314, observed: 314.

<img file="IS2134B_D0046.tif" />

<img file="IS2134B_D0047.tif" />

N-Trffluomacetyl~1-lsoprapyl-7-methaiy-2,3_l4,5-tetrahydro-1H-3-bena2eplne [0161 ] A solutlon of N-trtfluoroacatyH -isoprapylane-7-matliDxy-2,3,4,5-tatrahydro-1 Η-3-benzazepine (0.096 g, 0.31 mmol) in ethanol (2 mL) was treatad with 10% Pd/C (0.033 g, .031 mmol)) and stirred ovemight under an atmosphere of hydragan. The product mixtura was filtered through a pad of calite and silica, and the solvant removad to give 0.091 g of a dear oil. MS calculatad for C₁₆H₂₀F₃NO₂+H: 316, observed: 316.

W-Triffuo«»cafyf-3iromo-í-teopropy/-7-metf)oxy-2₁3,4₁5-felra/iydro-/H-3^)enzazBp(ne [0162] A solutlan of N-trifluorolacetyl-1-[Bopropyl-7-methoxy-2_l3,4_l5-tBtrehydra-1H.3-benzazeplne (0.091 g, 0.29 mmol) in acetonitrlla (3 mL) was treated with N-bromosuccinimide (0.057 g, 0.32 mmol), and stirred overnight at 20°C. Aftar removing the solvent, flash chromatography (10% EtOAc in hexanes, silica) resultad in 0.056 g of a daar oil. MS calculated idr C_1eH₁₉BrF₃NO2+H: 394, obsarved: 394.

e-Bmmo-l-lsopropyl-T-melhoxy-ZSA.S^etrahydro-IH-S-bemazeplne {0163] A solutlon of N-trifluoroacetyl-8-bromo-1-isopropyl-7-msthoxy-2,3,4,5-tetrahydro-1H-3-banzazaplne (0.013 g, 0.03 mmol) methanol (0.5 mL) was treated wtth 15% aqueous NaOH (0.6 mL), and stirrad ovemlght at 20’C. Tba produd mlxture was dllutad wtth brfne (5 mL), extractad twk» wlth EtOAc (5 mL), driad wlth MgSO₄, and concentrated to glve 0.10 g of a daar oil. 1H NMR (400 MHz, CD₃OD) d 7.08 (s, 1 H), 6.64 (s, IΗ), 3.72 (s, 3 H), 3.2-3.10 (m, 3 H), 2.7-2.5 (m, 3 H), 23-2.1 (m, 2 H), 0.96 (d, 3 H), 0.63 (d, 3 H). MS cateulatad for C-^N^BrNOH: 296, observad: 298. Example 22: (R,S) 8-Bronx&gt;-7-hydroxy-1-lsopropyl-2,3,4,5-tetrahydro-1H-3-benzazeplne [0164] <img file="IS2134B_D0048.tif" />

N-TrtfhjQroaeetyl-B-biOMrfJiydroxy-IJsopropfá.SASJetrahydrQ-IH-S-benzazeplne [9168] A solutlon of N-trilluoroacetyl-8-bromo-1-bopropyl-7-methoxy-2^,4_l5-tdrahydro-1/+3-benzazeplnB (0.041 g, 0.10 mmol) In dlehloremethana (1 mL) was treatsd wlth BBr₃ (0.32 ml, 1.0 M solutlon ln CH^y and stlrrad overnlght at 20’C. The excass BBr₃ Is quenched wtth watar and tha resultlng mlxtura diluted wlth ethar (50 mL), washed twice with eaturatad aqueoua NajCC^ (20 mL) and concentrated. Flash chromatography (20% EtOAc In hexanas, slllca) resulted in 0.037 g dear oll. MS calculated for C_lsH₁₇BrF₃NO₂+H: 380, obseived: 380.

8-Bmmo-7-hydroxy-1-lsopropyt-2,3,4,5-tetrahydro-1H-3benzazepine [0166] AeolutionofN-trlfluoraacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetraliydro-1H-3-benzazepina(0.Q18g, 0.047 mmd) In mathanol (1 mL) was treated wlth 15% aquaous NaOH (1 mL), and stlrrad for 3 houra at 50’C. The product mlxbjra was brought to pH 7-8 with 10% aqueouB HCI, extraded three tlmas wlth EtOAc (60 mL), driad with MgSO₄, and concentratad to give 0.013 g of a white solld. 1H NMR (400MHz, CD₃OD) d 7.10 (s, 1 H), 6.60 (s, 1 H), 3.30 (m, 1H), 3.2-3.0 (m, 2 H), 2.76 (m, 1H), 2.7-23 (m, 2H), 23-2.1 (m, 2 H), 1.05 (d, 3 H), 0.73 (d, 3 H). MS cateulated for C₁₃H_1eBrNO+H: 284, observBd: 284.

<img file="IS2134B_D0049.tif" />

Exampls 23: (R,S) 7-AHyloxy-8-bromo-1-l8opropyl-2,3,4_l5-tetrahydro-1M-3-benzazeplne [0167] <img file="IS2134B_D0050.tif" />

N-Triftooroecetyl-7-allybxy-8-bmiTio-149opmpyl-2,3,4,546tr8hydro-1H-3-benzazepine [0166] A solution of N-trifluoroacelyl-8-bromo-7-hydroxy-1 -isoprapyl-2,3,4,5-tetrahydro-1 H3-benzazapine (0.017 g, 0.045 mmol) In dlchlorwnethane (1 mL) was traatad with N"'-tBrt-butyl-N, N, Ν', Ν', N", N’-haxamathylphosphorimldlc trlamlda (0.016 g, 0.068 mmol), allyl bramide (0.011 g, 0.09 mmol) and stirred for 3 hours at 20°C. Tha product mixture was dlluted wffli 10% aqueous HCI, extracted twfca wlth dtehloromethane (20 mL), and concentrated. Flash chromatography (10% EtOAc In hexanas, sllica) resultad in 0.011 g ot aclear oil. MS calcutatad for C^^BrFjNOg+H: 420, obsen/ed: 420.

7-Alfyloxy^-bromo-1-ísopropyl-2,3,4,5-tetrahydrO-1H-34}efae2epine

10169] A sdutton of N-trifluoroacetyl-7-aHyloxy-8-bromo-1 -isoprapyl-2,3,4,5-tetrahydro-1 Η-3-benzazaplna (0.011 g, 0.026 mmol) ln methanol (0.5 mL) wastreated with of 15% aqueous NaOH (0.5 mL), and sörred for 3 houis at 50°C. The product mixture was dilutad wtth brina (5 ml), extiactad twice wlth EtOAc (5 mL), dried with MgSO₄, and concentrated to glve 0.010 g of a dear oll. 1H NMR (400 MHz, CDsOD) d 7.09 (s, 1 H), 6.62 (s, 1 H), 5.94 (m, 1 H), 5.32 (dd, 1H), 5.12 (dd, 1H), 4.46 (d, 2H), 3.19 (m, IH), 3.05 (m, 2 H), 2.66 (m, 1 H), 25 (bm, 2 H), 2.3-2.1 (m, 2 H), 0.95 (d, 3 H), 0.63 (d, 3 H). MS calculated tor C^HæBrNO+H: 324, observed: 324.

Example 24: B-Bremo-7-methoxy-1_l4-dlmethyl-25_l4_l54etrahydro-1/A3-benzazeplne [0170] <img file="IS2134B_D0051.tif" />

N-TrHluoroacetyl-1-(3-methoxyphenyí)-2-propylamlne [0171] A solutlon of 1-(3-mathoxyphenyl)-2-prapylamine (3.59 g, 21.7 mmol) In dlchloromethane (75 mL) at 0’G, WB8 trealad wlth pyridlne (2.1 mL, 2B.2 mmol), WfHioracetlc anhydrlde (5.9 g, 28.2 mmol), and then stirred for 3 hours whlle warmlng to 20’C. The product mixture was dlluted wlth EtOAc (300 mL), washed sequentlally with 10% aqueous MCI (100 mL), water (100 niL), brine (100 mL), dried with NagSC^ and concentratad. Flash chromatography (20% EIOAc In hexana, slllca) rasultad In 4.29 g of a yellow solld. 1H NMR (400 MHz, CD₃OD) d 7.17 (dd, J=8, B Hz, 1 H), 0.70 (m, 3 H), 4.19 (m, 1 H), 3.77 (a, 3 Η), 2.7B (m, 2 H), 1.21 (d, J=7 Hz, 2 H).

NJffluoroacety1^2-kxb-S-rne4hoxyphenyl)-2yropytambB [0172] A solutlon of N-trt(luoroacetyl-1-(3-íTiethoxyphanyl)’2-propylamine (429 g, 15.7 mmol) in mathanol (100 mL) was cooled to -7B’C and treated with CaCO₃ (3.17 g, 31.4 mmol), followed by a solution of ICI (6.37 g, 39.3 mmol) in methanol (50 mL). The reactlon was allowed to warm to 20°C whlle stlnlng ovemlght. The produet mlxture was filtered, concantratad, dlsaolved In EtOAc (200 mL), washed twk» wlth 5% aqueoua sodium bteulfrte (100 mL), once wlth brlne (100 mL), driad wlth NagSO₄ and concantratad to glve 6.72 g ot a whlte solld powdar. MS calculated fbr C₁₂H₁₃F₃INO2í+I: 388, observed: 388.

<img file="IS2134B_D0052.tif" />

<img file="IS2134B_D0053.tif" />

N-Aíyi, N^uam8(Xtyl-1-(2-lodo-5-methoxyphenyl)-2yropylamlne [0173] A solutlon of N-trifluoroacetyl-1-(2-lodo-5-methoxyphanyl)-2-prapylamlna (6.09 g, 15.7 mmol) In toluene (450 mL) was trealed wlth K2CO3 (2.82 g, 20.4 mmol), KOH (2.45 g, 47.1 mmol), n-Bu₄NBr (0.506 g, 1.57 mtnol) and allyl bromlde (2.47 g, 20.4 mmol), and stirred ovemlght at 80°C. The product mixture was acidlf ied with 10% aqueous HCI, saparated, the aqueoua phase extractad wlth ether (500 mL), tha comblnad organlc phasea wsre washed with brlna (200 mL), dried wlth NagS0₄ and ooncentrated to glve 4.45 g of a brown oil.

N-TrifíuorOacetyl-7-fneth&lt;«y-4-methyl-1-metttylene-2,3,4,5-tetrafiyí1ro-1H-3-bemBzep/ne [0174] A solutlon of N-allyl, N-trtfluoraacetyl-1-(2-todo-5-methoxyphanyl)-2-prapylainine (4.45 g, 10.8 mmol) in dfmethylformamida (120 mL) was treated with KOAc (3.17 g, 32.3 mmol}, n-Bu₄NBr (3.47 g, 10.8 mmoQ, PPh₃ (0.283 g, 1.08 mmol), Pd(OAc)j(0.242g, 1.08mmol)andstlrredovemlghtat80’C.Theproductniixturawascooledto20’C, flltared, dilutsd wlth watar (200 mL), extractad wlth ethar (3 x 200 mL), tha combined organic phaaas washed with water (100 mL), brine (100 mL), dried with Na2SO₄ and concentrated. Flaah chromatography (10% EtOAc in hexane, slllca) reaulted In 1.39 g of a yellow olL

N-Trilhioroecetyl-1,4-dimetfiyl-7-methaxy.2,3,4,5-telrahydro-1H-3-ben2azeplne

0175] A solutton of N-trtfluoroacetyl-7-mBthoxy-4-methyl-1 -methylana-2,3,4,5-tetrahydro-1 Η-3-benzazepine (1.39 g, 4.64 mmol) in athanol (40 mL) was treated with 10% Pd/C (0.49 g, 0.46 mmol) and atlrred ovemlght undar an atrnoaphere of hydragen. The product mlxture was filtered through a pad of cellta and slllca and than concentrated. Aaeh chromatography (20% EtOAc In hexane, slllca) resutted In 0.77 g of a clear oll. 1H NMR (400 MHz, CDCI₃, mbtture of rotamera) d 7.06 (m, 1 H), 6.71 (m, 1 H), 6.63 (m, 1 H), 4.38 (bm, 1 H), 3.8 (a, 3H), 3.6 (m, 1 H), 3.25 (m, 1 H), 3.1 B (bm, 2 H), 2.72 (m, 1 H), 1.34 (m, 3 H) 122 (m, 3 H).

N-Trilluoroecetyl-8-bmma-1,^ctím&amp;hyl-7-melhoxy-2,3_l4,&amp;-tBtrBhydro-1H-3bemazepine

0175] A solutton N-trifluoroacetyl-1,4-dlmethyl-7-methoxy-2,3,4,5-tetrahydrQ-1H-3-benzazapine (0.452 g, 1.50 mmol) in acetonitrlle (20 mL) was treated wtth N-bromosucclnlmlde (0.294 g, 1.65 mmol) and stirred ovemlght at 20°C. The preduct mlxture waa dlluted wlth EtOAc (100 mL), washed wlth aodlum bisulftta (50 mL) and brina (50 mL), dried wlth NajSO₄ and concentratad. Flaah chromatography (20% EtOAc in haxana, sllica) resulted in a clear oil. 1Η NM R (400 MHz, CDCI_3l mlxture of rotamere) d 7.32 (s, 1 H), 6.82 (m, 1 H), 4.37 (m, 1 H), 3.87 (a, 3 Η), 3.B1 (m, 1 H), 3.28-3.10 (m, 3 H), 2.73 (m. 1 H), 1.31 (m, 3 H), 1.25 (m, 3 H).

8-Bromo-1,4-dlmettyl-7-methoxy-2.3,4,5-tetratiydro-1H-34iema2epine

01771 A aolution of N-tr1fluoroacatyl-8-bromo-1 ^-dlmethyl^-methoxy-Z.S,4,5-tetrahydro-1H-3-benzazeplne (21 mg, 0.056 mmol) in mathanol (2 ml) was treatad wlth 15% aqueous NaOH (2 mL), and stlrred ovemlght at 20^aC The praduct mlxtura waa dtlutad with watar (6 mL), axtracted twks wtth EtOAc (10 mL), the combinad organlc phasas ware washadwithbrine (10mL), dried withNa2S0₄andconcentratedtoglve 11 mg of aclearoil. 1H NMR (400 MHz, CDCI₃) d 729 (s, 1 H), 6.64 (a, 1 H), 3.88 (a, 3 H), 3.02 (m, 2 H), 2.89 (dd, J=9,14 Hz, 1 Η), 2.B0 (m, 1 H), 2.67 (d, J=14 Hz, 1 H), 2.53 (dd, J=10,13,1 H) 1.30 (d, J=7 Hz, 3 H), 1.19 (d, J»6 Hz, 3 H). MS calculated for C₁₃H₁₈BrNCM-H: 284, obaerved: 284.

Exampla 25:7-Allytoxy-8-bromo-1,4-dlmethy1-2,3,4,5-tetrBhydro-1 Η-3-benzazeplne [0178] <img file="IS2134B_D0054.tif" />

N-TrlfíuaroaoBtyl-84iromo-1_l4-dlmethyt-7-hydraxy-2,3,4,B-tBtrahydra-1H-3-bemaÍeplne

0179] A solutlon of N-trlfluoroacatyl-84)roiTio-1,4-dlmethyl-7-methoxy-2,3_l4_l5-tetrahydro-1 Η-3-banzazaplne (0.383

<img file="IS2134B_D0055.tif" />

g, 1.01 mmol) In dlchloromethane (30 mL) was treatad with BBr₃ (2.35 mL of a 1.0M solution In CHjCIj, 2.35 nvnol) and stirred overnight while warmlng to 20%. Tha excess BBr₃ is quenched with water, and the resultlng mixtura was diluted with ether (100 mL), washed wlth saturated aqueous NagCO₃ (50 mL) and brine (50 mL), driad with NajS0₄and concentrated. Flash chromatography (15% EtOAc In hexane, siliea) resulted in 0.302 g of a whlte solid. 1H NMR (400 MHz, CDCIj, mixture ofrotairiera) d 7.22 (m, 1 M), 6.77 (m, 1 H), 5.34 (s, 1 H), 4.35 (m, 1 H), 3.62 (m, 1 H), 3.24 (m, 1 H), 3.13 (m, 2 H), 2.69 (m, 1 Η], 1.31 (m, 3 H). 1.22 (m, 3 H).

N-Tiifluomacetyl-7-allyk)xy-8-brOmo-1,4-dlinethyl-2,3,4,5-{etrahydiO-1H-3-ben2azeplne [0180] A solutlon N-trlfluoraacetyl-B-bromo-1,4-dhiethyl-7-hydroxy-2,3,43-tatrahydro-1 Η-3-benzazeplne (0.030 g, 0.082 mmol) In dichloromatliana (2 mL) was treatad wrth allyl bromide (0.030 g, 0.246 mtnol), DBU (0.037 g, 0.246 mmol) and stirred 2 houra at 20%. "Πιβ product mixture was dlluted wlth EtOAc (10 mL), washed with 5% aqueous HCI (2 mL), brine (5 mL), drfed with NajSO* and concentrated. Flash chramatography (15% EtOAc in hexane, silica) fesulted in 0.028 g of a dear oll. 1H NMR (400 MHz, CDCI₃, mixture of rotamers) d 732 (s, 1 H), 6.62 (m, 1 H), 6.02 (m, 1 H), 5.45 (d, J=17 Hz, 1 H), 5.30 (d, J=11 Hz, 1 H), 438 (s, 2 H), 4.36 (m, 1 H), 3.62 (m, 1 H), 3.23 (m, 1 H), 3.11 (m, 1 Η), 2.B1 (d, J=10Hz, 1 Η), 2.Z0 (m, 1 H), 1.34 (m,3 H), 1.21 (m,3H).

7-AIfylaxy-8-brom&gt;-1,4-tilmethyl-2,3,4,S-tetrahydK&gt;-1H-3bema2epine [0181] A solutlon of N-trifluoroacetyl-7-allyloxy-8-bromo-1,4-dimathyl-2,3,4,5-tetrahydro-1 H3-benzazepina (0.028 g, 0.069 mrnal) ln methanol (2 mL) was treated wkh 15% aqueous NaOH (2 mL), and stirred for 3 houra al 20%. Tha product mbcture was dlluted wtth water (10 mL), axtracted twica wlth EtOAc (10 mL), the combined organlc phasas wara waahed wlth brine (10 mL), driad with NajSO₄ and concentrated to glve 0.020 g of a clear oil. 1Η NM R (400 MHz, GDCIj) d 730 (β, 1 H), 6.64 (b, 1 H), 6.06 (m. 1 H), 5.47 (d, J-17 Hz, 1 H), 5.30 (d, d=11 Hz, 1 Η), 4.56 (s, 2 H), 3.03 (m, 2 H), 2.90 (dd, J»9,14 Hz, 1 H), 2.80 (m, 1 H), 2.05 (d, J=14 Hz, 1 H), 235 (dd, J=10,14 Hz, 1 Η), 1.77 (bs, 1 H), 1.30 (d, J=7 Hz, 3 H), 1.20 (d, J=6 Hz, 3 H).

Example 26: (R,S) 8-Chlon-1-mBthyl-ð,3,4^-tetrahydre-1fF3-benzaaplne [0182] <img file="IS2134B_D0056.tif" />

N-TrHluoroacetyl-4~chlon^)henethylamlne [0183] A solutlon &lt;rf 4-chlorophenethylamlne (1.0 g, 6.4 mmol) In dtehloromathane (20 mL) was cooled to 0%, treated wlth pyridlna (1.0 mL, 123 mmol), trifluoracetic anhydrlde (1.6 g, 7.7 mmol) and then stlrred for I hour whlla warmlng to 20 C. The praduct mixture was diluted with EtOAc (100 mL), washed saquentially wlth 10% aquaous HCI (50 mL), watar (50 mL), brlne (50 mL), drled wlth N^SO₄ and oonoantrated to glva 1.6 g of a white solld.

Ν·ΤίΙΙΙυοΓθδοβ(^2-Ιούο-4~οΗΙοη^βηβ(^βπιϊηβ [0184] A eoluOon of N-trtfluoroacatyl-4-chlorophenethylaiTilne (1.6 g, 6.4 mmol) In dfctiloramathene (20 mL) waa traatad wfth bb(pyrldlne)lodonlum(l)tatrafluoroborate (2.6 g, 7.0 mmol), CF₃SO₃H (2.1 g, 14.1 mmol) and stirred overnight at 20 C. The product mlxture was concantrated, dlssolved in EtOAc (100 ml). washed twica with 5% aquaous sodium bleulflta (50 mL), twlca wlth saturated aquBous NaHCO₃, (50 mL) once with brtne (50 mL), drled wlth NajSO₄and concantrated to giva 0.94 g of a claar oil. MS calculated for C₁₀H₈CIF₃INO+H·. 37B, obsarvad: 378.

W-Affy( N-trlfluorOBcetyl-2-io(M-chlorophenethylarnlne [0185] A solutlon of N-trffluoroacatyl-2-lodo-4-chlorophenBthylamlne (0.94 g, 2.4 mmol) In toluene (25 ml) was treat-ad wlth KjCOa (0.43 g, 3.12 mmol), KOH (0.40 g, 72 mmol), n-Bu^Br (0.077 g, 0.24 mmol) and allyl bromlda (0.43 g, 3.6 mmol) eequentlally. "Πιβ mlxture was stlrred at 8O%for33 houre, cooled to 20% and acidlfled wlth 10% aquaous HCI. Tha phasas wara saparatad, tha aqueous phase extracted with ather (100 mL), tha combined organic phases were washsd wtth brina (50 mL), dried wlth NagSQi and concentrated to glve 0.76 g of a clear oil. MS calculated for

<img file="IS2134B_D0057.tif" />

C₁₃H₁₂CIF₃INO+H: 418, observed: 418.

N-TfHluoroacetyl-8^loro-1-methylena-2,3,4,5-tetTatiydm-1H-3-bema2epíne [0186] A 8olution of N-allyl, N-trifluoroacalyl-2-iodo-4&lt;htorophanathylaminB (0.76 g, 1.8 mmol) ln dimethyfforrnamlde (20 mL) waetreated wth KOAc (0.53 g, 5.4 mmol), n-Bu₄NBr(058 g, 1.8 mmol), PPh₃ (0.047 g, 0.18 mmol), Pd(OAc)_a(0.041 g, 0.18 mmol) and atlrred ovamlght at 105’C. Ήιβ produet mlxture was cooled to 20*0, flltered, dlluted wlth water (100 mL), axtracted wlth ether (3 x 100 mL), tha combinad organfc phases washed wlth water (100 mL), brlne (100 mL), dried with Nb₂SO₄ and concentraled. Flash ctiromatography (10% EtOAc In hexane, sílica) resulted in 0.228 g of a clear oll. 1H NMR (400 MHz, CDCIj) d 7.29 (s, 1 H), 7.18 (m, 1 H), 7.04 (m, 1 H), 5.38 (m, 2 H), 5.40 (d, J=16 Hz, 2 H), 3.80 (m, 2 H), 3.00 (m, 2 H). MS cabulated for ά,^,Ο^ΝΟ+Η: 290, observed: 290.

N-Trinuoroacetyt-8-chlaro-1-rnethyl-2,3,4,5-tetrahydro-1H-3-bemsíief&gt;ine [0187] ΑεοΙιΛαπ of N-trffluoroacstyl-8-chloro-1-maÖiylenB-2,3,4,6-trihydro-1/+3-benzazapina (0.16 g, 0.55 mmol) In mattianol (10 mL) was treated wlth 10% Pd/C (0.02 g) and stirred 30 mlnutes under an atmosphere of hydrogen. Ήιβ product mixtura wea filtered, eoncentrated and purffled by flash chromatography (5% EtOAc In haxane, sllica) reaultlng In 0.057 g of a white solid. MS calculated for C₁₃H₁₃CIF₃NOH: 292, observed: 292.

8-Chbro-1-methyl-2&amp;4,S-tetmhydro-1H&amp;benzazepine [0188] A solutlon of N-trifluoroacetyl-8-chloiO-1-methyl-2,3,4,5-tetrahydra-1 Η-3-banzazeplna (65 mg, 0.22 mmol) In methanol (2 mL) was treated with 15% aquaous NaOH (2 mL), and stirred for 3.5 hours at 60*C. The product mlxture was concentratad, extracted 3 tlmas with CH₂C^ (5 mL), drfed wlth Na₂SO₄ and concantratad to glva 35 rng of a clear oil. 1H NMR (400 MHz, CDCIa) d 7.11 (s, 1 H), 7.05 (d, J=B Hz, 1 Η), B.98 (d, J=8 Hz, 1 H), 3.1-2.9 (m, β H), 2.71 (m, 1 H), 2.68 (bs, 1 H), 1.32 (d, J=8 Hz, 3 H). MScateulatadforC^^^CIN+H: 196, observad: 196.

(Comparatíva) Example27: (R,S) 7-{2-Methyl-2H-pyrBZOI-3-yl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazaplne [0169] <img file="IS2134B_D0058.tif" />

N-Trifíuomacetyí-7-hydmxy-1-methyl-2.3,4_l5-tetrahydm-1H-3rbemazeplne [0190] A solution of N-trHluoroacetyl-7-methoxy-1-methyl-25,4,5-tetrahydro-1H3-benzazepine (0.508 g, 1.76 rranol) In dfchloromathana (20 mL) waa traatad wfth BBr₃ (4.1 mL of a 1.0M aolirtlon In CHjCIj, 4.1 mtnol) and atirrad ovamlght whila warming to 20*C. The excess BBr₃ was quanched wlth water, and ttie resulting mixture was diluted wtth athar (200 mL), waehad wlth NagCO₃ (100 mL) and brina (100 mL), drlad with Na^SOt and concenbated. Flash chromatography (15% EtOAo in haxana, sllka) reauttad In 0.460 g of a whita solid foam. MS calculated for C₁₃H₁₄F₃NO^H: 274, observed: 274.

N-Trifluoroacety-74iydraxy-1-me1hyté,3,4,5-tetrahydm-1H-3-benzazeplne, O-trifluorcmetfianesuttonate [0191 ] Asolution of N-trffluoroacetyl-7-hydroxy-1 -mathyl-2,3,4,5-tetrahydro-1 Η-3-benzazepina (460 mg, 1.76 mmol) In dlchloromettiana (15 mL) was traatad wtth pyridlne (417 mg, 5.27 mmol), trifluoromethanesulfonic anhydrida (991 mg, 3.52 mmol) and atlrred 1.5 houre at 20*C. Ήιβ product mixtura wae dlluted with dichloramethane (100 mL), washad wlth watar (50 mL), 5% aquaous HCI (50 mL), saturatad aquaoua NaHCC^ (50 mL), brina (50 mL), driad with Ne₂SO₄and coneentrated. Flash chromatography (15% EtOAe In hexana, sillca) raeutted in 65B mg of a claar oll. MS calculatad for C₁₄H₁₃F₆NO₄S+H: 406, obsarvad; 406.

<img file="IS2134B_D0059.tif" />

N-TrífluorOacetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4,S-tBtrahydro-1H-3benza2eplne [0192] Το a solutlon of N-trifluoroaoelyl-7-hydn»(y-1-inBthyl-2,3,4,5-telrahydro-1/W-banzazapinB, O-trifluorometh-anesulfonate (100 mg, 0.25 mmol) In dimethylformamide (2 mL) was treated w'rth (2-methy Ρ2Η-ργΐΈ»Ζ£^3-γ l)-trl-n-butyk tin (138 mg, 0.37 mmol), LiCI (21 mg, 0.50 mmol), PdlPPh^Ólj (35 mg, 0.05 mmol) and stlrred at 100’C for4 houra. The product mlxture was dlluted wfth EtOAc (20 mL), washad twlca with water (10 mL), once wlth brine (10 m L), drled with Na2SO₄ and concentrated. Flash chromatography (30% EtOAc in haxane, silica) resulted in 80 mg of a clear oil. MS ealeulated for C₁₇H₁₈F₃N₃O+H: 338, observed: 338.

7-(2~Methyl-2H-pyraiol-3-yt)-1-me^yt-2,3,4,S-tetrahy(iro-1H-3-beraazepln9

0193] A solutlon of N-trifluoroaBetyl-7-(2-Methyl-2H-pyrazol-3-yl)-1-methyl-2_l3,45-t0trahydro-1H-3-bBnzazBpine (48 mg, 0.14 mrnol) In methanol (2 mL) was treated wlth 15% aqueoua NaOH (2 mL), and the solution stirred ovemight at 20* C. The product mlxture was concentrated, extracted 3 times with CH₂CI₂ (5 mL), drled wlth NajSC^ and the eolvent evaporated. Flaah chromatography (0-15% MaOH ln CH₂C^, sllica) raeulted in 30 mg of a clear oll. 1H NMR (400 MHz, CDCI3) d 7.48 (s, 1 H), 7.21 (m, 2 H), 7.13 (s, 1 H), 6.27 (s, 1 H), 3.69 (a, 3 H), 3.3-2.9 (m, 9 H), 2.79 (dd, J=7,14 Hz, 1 H), 1.40 (d, J=B Hz, 3 H). MS «dculatedforC₁₅H₁₈IV^H: 242, obsarved: 242.

(Cðmparatlve) Example28: (R,S)7-(4-Bronro-2-methyRfFpyrazol-3-yl)-1-methyl-2,3,4,54etrahydre-1H·

3-benzazeplno

0194] <img file="IS2134B_D0060.tif" />

N-Triflyomacetyl-7-(4-bmmo-2-Methyl-2H-pyrazol-3-yl)-1-methyl-2,3,4.5-tetmhydro-1H-3-benna2epine

0196] To aaolutíon of N-trifluoroacetyl-7-(2-Methyl-2Hf&gt;yrazol-3-yl)-1 -methyl-2,3,4,5-tBtrahydro-1 H-a-benzazBpine (30 mg, 0.082 mmol) In dichloromethane (1 mL) was treated with N-bromosuccinimlde (15.3 mg, 0.086 mmol) and stJmed ovemlght at 20*C. The product mfxture was abaorbed on slllca and purified by flash chromatography (2-5% MaOH In CF^CIj, slllca) resuttlng In 37 mg of a whfte crystalllne solid. MS calculated for C₁₇H₁₇BrF₃N₃O+H: 416, obsarved:416.

7-(4-Brom&amp;2-methy1-2H-pyra&amp;l-3-yl)-1-methyl-2,3,4,5-tetratiydiO-1H-3-ben[azepine

0196] A aolutlon of N-trHluoroacetyl-7-(4-bromo-2-MBthyl-2H-pyr8zol-3-yl)-1-methyl-2,3,4_l5-tetrahydro-1H-3-bBn-zazeplne (37 mg, 0.089 mmol) In methanol (2 mL) waa treated wtth of 15% aquaous NaOH (2 mL), and stirred ovemight at 20* C. The praduct mixture was concentrated, axtractad 3 timea wlth CHjCIj (5 mL), drled wlth NajSO₄ and the eolvent evaporated. flash chramatography (0-15% MbOH ln 0¾¾ alllca) reaulted In 2B mg of a clear oll. 1H NMR (400 MHz, CDCy d 7.50 (s. 1 H), 7.25 (d, J=8 Hz, 1 H), 7.17 (d, J=8 Hz, IH), 7.10 (a, 1 H), 3.83 (s, 3 H), 3.17 (m. 1 H), 3.1-2.9 (m, 3 H), 2.80 (dd, J=7,13 Hz, 1 Η], 2.48 (ba, 1 Η), 1.40 (d, J=8 Hz, 3 H). MS caleulated for C,₅H₁₈Brt^+H: 320, observed: 320.

<img file="IS2134B_D0061.tif" />

(Comparathre) Example 29: (R,S) 7-{3-Chlorophenyl)-1 -methyl-2,3,4,5-tetrahydre-1 W-3-benzazepine [0197] <img file="IS2134B_D0062.tif" /> [0198] A solutlon ol IWrifluoraacetyl-7-hydroxy-1-methyl-2_l3,4,5-tefrahydro-1W3-benzazepinB_l O-trffluorometh-anesulfonate (50 mg, 0.123 mmol) ln 1,4-draxana (1£ mL) was traatad with 2-chlorophenylboranlc acid (39 mg, 0243 mmol), CbF (56 mg, 037 mmol), water (50 mg, 2.78 mniol), Pd(PPhg)₄ (29 mg, 0.025 mmol) and stirred ovemlght at 75%. The preduct mixture was diluted with EtOAc (20 mL), washed wlth water (10 mL), bríne (10 mL), dried with Na2SO₄ and concentrated. Ftash chromatography (10-20% EtOAc In hexane, slllca) resulted In 45 mg of a clear oil. MS calculated for C_iaH₁₇CIF₃NO+H: 368, observed: 368. The product (27 mg, 0.073 mmol) was dissolved In methanol (2 mL) traated wlth 15% aqueouB NaOH (2 mL), and stlrrad ovemlght at 20%. "Πιβ product mlxture was concentrated, BXtrected 3 thnes with CHjCIj (5 mL), dried with N^SO₄ and tha solvent evaporated to glva 18 mg of a clear oil. 1H NMR (400 MHz, CDCI3) d7.54 (s, 1 H), 7.42 (d, J=6 Hz, 1 H), 7.35-721 (m, 5 H), 3.14 (m, 1 H), 3.1-2,9 (m, Β H), 2.80 (bm, 2 H), 1.38 (d, J=B Hz, 3 H). MS cateulated for C₁₇H₁₈CIN₃+H: 272, observed: 272.

(Comparatlve) Example 30: (R,S)7-(2-Chloropheny1)-1-mettiyl-2,3,4,5-tetrahydro-1H-3-benzazeplne [0199] <img file="IS2134B_D0063.tif" /> [0200] A solution of N-trifluoroac8tyl-7-hydnixy-1-inBthyl-2_l3,4,5-tetrBhydro-1Ff3-benzazaplna, Otrífluorometh-aneeulfonate (50 mg, 0.123 mmol) ln 1,4-dloxane (1.5 mL) was treated wlth 2-ehlorophenylboronic acld (39 mg, 0.243 mmol), CsF (56 mg, 037 mmol), water (50 mg, 2.78 mmol), Pd(PPh₃)₄ (29 mg, 0.025 mmol) and etirred ovamight at 75%. The product mixture was dlluted wlth EtOAc (20 mL), washed wlth water (10 mL), brine (10 mL), dried with Na^O. and concentrated. Flash chromatography (10-20% EtOAc In haxana, slllca) resultad In 36 mg of a clear oll. MS cateulatad for C₁₉H₁₇CIF₃NO+H: 368, observed: 368. The product (27 mg, 0.073 mmol) was dlssolved In methanol (2 mL) treated wlth 15% aqueous NaOH (2 mL), and stirred ovemlght at 20%. The product mlxture was concantratad, axtractad 3 timee with CHgC^ (5 tnL), driad wlth NajSO₄ and the solvent evaporated to glve 24 mg of a clear oil. 1H NMR (400 ΜΗΖ, CDCy d 7.44 (d, 4=8 Hz, 1 H), 7.35-722 (m, 5 H), 7.15 (s, 1 H), 3.14 (m, 1 H), 3.1-2.9 (m, 8 H), 2.60 (dd, J=13, Hz, 1 H), 231 (bs, 1 H), 138 (d, J=8 Hz, 3 H). MS calculated (or C₁₇N₁₈CINa+H: 272, obBerved: 272. Example 31: (R,S) e-Chtoro-l-hydroxy^S^.S-tetrBhydro-lfM-benzazeplne [0201] <img file="IS2134B_D0064.tif" />

<img file="IS2134B_D0065.tif" />

<img file="IS2134B_D0066.tif" />

<img file="IS2134B_D0067.tif" />

N-Trifluoroacefyl-M&gt;loro-1-oxo-,3,4,5-trthydiO-1H-3-benzaZBplne [0202] A solutlon of N-trlfluoroaeatyl-8-ehlora-l -mathylene-3,4,5-trihydro-1 Η-3-banzazaplna (0.23 g, 0.80 mmol) In 1:1 methanol/dichloromethane (45 mL) was cooled to -78*C, treated with ozone until the solution tumed blue (about 20 minutes), PPh₃ (0.21 g, 0.80 mmol) was addad and the resultlng aolutlon was stirred 90 mlnutss whlle warming to 20’C. Tha product mlxture was concentrated and purlfied by flash chromatography (30% EtOAc In haxane, sllica) rasulting in 0215 g of a whita solid. MS calculated for C^HgCIF^Oj+H: 292, observad: 292.

8-Chloro-1Jiydmxy-2,3,4,5-tetrahydm-1H-3-benzezepine [0203] A solutfon of N-trtfluoroacetyl-8-chloro-1 -oxo-3,4,5-trihydro-1 Η-3-benzazeplne (50 mg, 0.17 mmol) In mathanol (2 mL) was traatad wlth NaBH₄ and the reaulllng mlxtura was stirred 16 hours at 20°C. The white eolld product was collected by filtration, washed wlth water and dried, resulting in 30 mg of a whlte solrd. 1M NMR (400 MHz, CD_aOD) d 7.39 (s, 1 H), 7.12 (d, J-B Hz, 1 H), 7.06 (d, J=8 Hz, 1 H), 4.74 (d, J=8 Hz, 1 H), 3.1-2.7 (m, 6H). MS cateulatadforCnjHuCINO+H: 198, obaervad: 198. "

Example32: (R,S) B-Bromo-1-methyl-2^,4,5-tetrahydro-1 W-3-benzazeplne [0204] <img file="IS2134B_D0068.tif" /> [0205] By tha same general procedure as In exampla 26, (R,S) B-bromo-1-methyl-2,3,4,5-tetrahydro-1AW-ben-zazaplne was obtalnad from 4-bramophBnethylamlne aa a colortass oll. 1H NMR (400 MHz, CDCIj) d 7.27 (s, 1 H), 7.22 (d, J=8 Hz, 1 K), 6.94 (d, J=8 Hz, 1 H), 3.1-2.85 (m, 8 H), 2.72 (m, 1 K), 2.25 (bs, 1 H), 1.33 (d, J=7 Kz, 3 K). MS cabulated for CnH₁₄PrN+H: 240, otaarved: 240.

Exwnple 33: (R,S) B-F1uoro-1-mrthyP25,4,5-tetrahydro-1/F3-benzazeplne [0206] <img file="IS2134B_D0069.tif" /> [0207] By the sama general procedura aa ln example 28, (A,S) 8-fluoro- 1-methyl-2,3,4,5-tetratiydro-1/+3-ben-zazepina waa obtalned from 4-fluorophenethylamlne œ a colorlesa oll. 1H NMR (400 MHz, CDCy d 7.00 (dd, J=B, 10 Hz, 1 H), 6.86 (d, J=10 Hz, 1 H), 6.76 (d, J=8 Hz, 1 H), 3.08-2.56 (m, 7 H), 1.85 (bs, 1 H), 1.31 (d, J=7 Hz, 3 H). MScalculBlBdforC^Hf^+H: 180, observed: 180.

(Comparathre) Enmple34: (R.sp-nuoio-l-nwH^MS-tataliydrQ-lftt-benxazeplne [0208] <img file="IS2134B_D0070.tif" /> [0209] By the same general precedure as In example 26, (R,S) 7-fluoro-1-methyl-2,3,4,5-tetrahydro-1H-3-ben-zazeplne waa obtalnad from 3-fluorophenethylamlne as a colorless oll. 1H NMR (400 MHz, CDCI_a) d 7.09 (dd, J=6,8

<img file="IS2134B_D0071.tif" />

<img file="IS2134B_D0072.tif" />

<img file="IS2134B_D0073.tif" />

Ηζ, 1 Η), 6.85-6.78 (m, 2 Η), 3.10-2.89 (m, 6 Η), 2.71 (dd, J=7,13 Ηζ, 1 Η), 1.91 (bs, 1 Η), 1.33 (d, J=7 Ηζ, 3 Η). MS caloulatedforC₁₁H_uFN+H: 180, obeerved: 180.

(Comparatlve) Example35: (R,S)7-Chk&gt;ro-1-methyF2,3,4,5-tetrahydre-1/+3-benzazeplne [0210] <img file="IS2134B_D0074.tif" /> [0211] By ttie same general precedura aa In example 26, (R,S) 7-chloro-1-methyl-2,3,4,5-tstrahydro-1H-3-ben-zazepina was obtalnad from 3-chlorophenethylamlne as acolorteaa oil. 1H NMR (400 MHz, CDCIg) d 7.10 (d, J=8 Hz, 1 H), 7.06 (m, 2 H), 3.1-2.9 (m, 6 H), 2.70 (dd, J= 13,7 Hz, 1 H), 1.69 (ba, 1 H), 1.31 (d, J=7 Hz, 3 H). MS calculated forC^HuCIN-i-H: 196, observed: 196.

Example 36: (R£) 7,8-Dlchloro-1-mcthyl-2^,4,5-tetrahydro-1H-3-benzazeplne [0212] <img file="IS2134B_D0075.tif" />

0213] By the sama general pracadura as ln example 26, (R,S) 7,8-dlchloro-1 -mettiyl-2,3,4,5-tatrahydra-1 tf-3-ban-zazeplne waa obrtalned from 3,4-dlchlorophenethylamine as a colorlass oil. 1H NMR (400 MHz, CDCIj) d 7.20 (s, 1 H), 7.16 (s, 1 Η), 3.05-2.B6 (m, 6 H), 2.71 (dd, J=7,13 Hz, 1 H), 1.83 (bs, 1 H), 1.33 (d, J=7 Hz, 3 H). MS calculated forC^^jCljN+H: 230, otaeived: 230.

Example 37: (R,S) N-MettiyF8-chloro-1-methyF2,3,4,5-tetrahydro-1/F3-benzazepIne

0214] <img file="IS2134B_D0076.tif" />

0215] By the aame general procedure en In exampla 9, (R,S) N-methyl-e-chloro-1 -mathyl-2,3,4,5-tetrahydro-1 H-3-benzazeplne was obtalnad from (R,S) B-chlora-1 -methyl-2,3,4,5-tetrahydro-1 /+3-benzazeplne aa a colorless oll. MS calculated for C_iaH_1BCIN+H: 210, obeérvad: 210.

(Compareöve) Example 38: (R.S) 1-ΜβΙΗγΡ7-ΜίΙυοκ)πιβΗΜχγ-2,3,4,5-»ΐΓ8ΐιγίΐΓθ-1 Η-3-benzazepine

0216] <img file="IS2134B_D0077.tif" />

0217] By the same general procedure aa In example 26, (R,S) 1-methyl-7-trifluoromethoxy-2,3,4,5-tetrahydro-1/í 3-benzazaplne was obtainad from S-tiifluoromethoxyphanethylamlna as a coloriass oll. 1H NMR (400 MHz, CD₃OD)

<img file="IS2134B_D0078.tif" />

<img file="IS2134B_D0079.tif" />

<img file="IS2134B_D0080.tif" />

<img file="IS2134B_D0081.tif" />

7.39 (d, J=8 Hz, 1 H), 7.19 (m, 1 H), 3.46 (m, 2 H), 3.38 (d, J=13 Hz, 1 H), 3.29 (m, 1 H), 3.16 (m, 2 H), 3.05 (dd, J=13, 9 Hz, 1 H), 1.50 (d, J=B Hz, 3 H). MS calculated forC₁₂H_uF₃NCM-H: 246. observed: 246.

Example 39: (R,S) 6-lodo-1-methyl-7-trlfluorometho][y-2,3,4,5-tetrahydro-1 W-3-benzazepine [0218] <img file="IS2134B_D0082.tif" />

0219] By the same general procedure as in exampla 3, (R,S) B-lodo-1 -methyl-y-trifluoromethoxy^.a^.S-tetrahydro-1/M-benzazeplna was obtalned from N-trifluoroacetyl-1-methyl-7-trifluorornethoxy-2,3_l4,5-tetrahydrc&gt;'ltf-3-ben· zazeplne as acoloriese oll. 1H NMR (400 MHz, CD₃OD) d 7.79 (8,1 H), 725 (s, 1 H), 3.46-3.40 (m, 3 Η), 3.2B-3.12 (m, 3 H), 3.07 (dd, J=13,9 Hz, 1 H), 1.47 (d, J=7 Hz, 3 H). MS calculated for C₁₂H_UF₃INO+H: 372, observed: 372. Example 40: (R,S) N-Propyl-8-lodo-7-me1hoxy-1-nidhyF2,3,4_l5-tetrahydro-1H-3-benzazeplne

0220] <img file="IS2134B_D0083.tif" />

0221] By the eame general procedure as In axample 10, (R,S) N-PropyFB-todo-7-methoxy-1 -methyF2,3,4,5-tetrahy-dro-1 Η-3-benzazaplna was obtained from (R,S) 8-k)do-7-methoxy-1 -mathyl-1,2,4,5-tatrahydro-3H-3-benzazepine as a colorlaes oil. MS ealculated for Ο^Η^ΙΝΟ+Η: 360, observed: 360.

Exampla 41: (R,S) 1-Ethyl-8-lado-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazBplne

0222] <img file="IS2134B_D0084.tif" />

0223] By the eame general pracedure as In example 19, (R,S) 1-ethyl-8-iodo-7-niethoxy-2,3,4,5-tetrahydro-1H· 3-benzazeplne was obtained from Ν-ΙτΙΙΙιιοκίΐΒΜίγΙ-Ι-βίΚγΕΖ-τηΒΐΙιοχγ^,βΛ,δ-ίθίΓΒΐ^ΓΟ-ΙΗ-Β-άβηζΒΖβρΙηβ as a colorless Oil. 1H NMR (400 MHz, CDCIj) d 7.47 (8,1 H), 6.54 (s, 1 H), 3.86 (s, 3 H), 3.20-2.97 (m, 4 M), 2.93-2.75 (m, 3 H), 2.64 (m, 1 H), 1.78 (m, 2 H), 0.95 (dd, J=8,8 Hz, 3 H). MS calculatad for C,₃H₁₈INO+H: 332, observed: 332.

<img file="IS2134B_D0085.tif" />

<img file="IS2134B_D0086.tif" />

<img file="IS2134B_D0087.tif" />

(Comparatlve) Exampla 42: (R.S) 7-{3-Methoxyphenyl)-1-methyl-2_l3,4,5-ta1rahydro-1H-3-benzazeplne [0224] <img file="IS2134B_D0088.tif" /> [0228] By tha sama ganaral procadura as in axampla 29, (R,S) 7-(3-Mathoxyphenyl)-1-mathyF2,3,4,5-tatrahydro-ΙΗΰ-benzazepitie was obtained from N-trlfluoroacelyl-7-hydrexy-1-malhyl-23,4_l5-tatrahydro-1H3-benzazeplna_l O-trifluoromathanesulfonata as a colortess oil. 1H NMR (400 MHz, CDCIj) d 7.37 (dd, J=7,7 Hz, 1 H), 7.30 (m, 2 H), 7.21 (d, J=7 Hz, 1 H), 7,14 (d, J=7 Hz, 1 H), 7.09 (S, 1 Η), 6.88 (d, J=0 Hz, 1 Η), 3.B5 (s. 3 H), 3.2-2.9 (m, 6 Η), 2.80 (m, 1 H), 2.64 (bs, 1 H), 1.38 (d, J=7 Hz, 3 H). MS cateulated for ό,^ΝΟ+Η: 288, observad: 268.

(ComparaHve) Exampla 43: (R,S)7-(2,MifluorophenylH-mettiyl-2,3,4,S-tetrBhydro-1H-3-benzBzepine [0226] <img file="IS2134B_D0089.tif" /> [0227] By tha same ganeral procadure as In axample 29, (R,S) 7-(2,6-dlfluorophanyl)-1 -methyl-2,3,4,5-tetrahydro-1 Η-3-benzazeplna was obtalned from N-trifluoroeeetyl-7-hydroxy-1 -methyl-2,3,4,5-tetrahydro-1 Η-3-benzazepine, O-trtfluoromathaneeulfonale as a coloriaea oll. 1H NMR (400 MHz, CDCIj) d 7.35-7.10 (m, 5 H), 6.95 (dd, J=7,8 Hz, 1 H), 3.2-2.9 (m, 6 H), 2.79 (dd, J=8,13 Hz, 1 H), 2.70 (bs, 1 H), 1.38 (d, J=8 Hz, 3 H). MS calculated for C₁₇H₁₇F₂N+H: 274, obnrvad: 274.

Example 44: (R,S) 7-(2-fluorophenyl)-8-chloro-1-mBthyt-23,43-tBtrahydro-1 Η-3-banzazeplne [0228] <img file="IS2134B_D0090.tif" /> [0229] By the aama ganaral procedura aa In axampla 29, (R,S) 7-(2-fluorophanyl)-8-chloro-1 -mattiyl-2,3,4,5-tetrahy-dro-1 H3-benzazaplne was obtalned fram N-trtfluoroaca!yF8-chloro-7-hydroxy-1 -methyl-2,3,4,5-tetrahydro-1 Η-3-ben-zazaplne aa a colorlees oil. 1H NMR (400 MHz, CDCIj) d 7.35-723 (m, 3 H), 7.19-7.09 (m, 2 Η), 7.03 (s, 1 H), 3.15-2.88 (m, 7 H), 2.76 (dd, J=8,13 Hz, 1 H), 1.38 (d, J=8 Hz, 3 H). MS calculated for C₁₇H₁₇CIFN+H: 290, observed: 290.

<img file="IS2134B_D0091.tif" />

<img file="IS2134B_D0092.tif" />

<img file="IS2134B_D0093.tif" />

(Comparatlve) Example 45: (R,8) T-fS-TNfluoremethylphenyiy-l-methyl-Z.SAS-tetrahydro-l/FS-benzazeplne [0230] <img file="IS2134B_D0094.tif" /> [0231] By the sama ganaral procadure as In example 29, (R,S) 7-(2-trifluoromethylphonyl)-1 -methyl-2,3,4₁5-tatrahy-dro-1 Η-3-banzazapina was obtainad from N-trlfluoraacatyl-7-hydroxy-1 -τπβΟιγΙ^,βΛ,Β-ΙθίΓβΙτγάΓο-Ι W-3-benzazepina, CHrifluorornethanasulfonata as a oolorieee oil. 1H NMR (400 MHz, CDClg) d 7.71 (d, J=8 Hz, 1 H), 7.52 (dd, J=7,8 Hz, 1 H), 7.42 (dd, J= 7,8 Hz, 1 H), 731 (d, J=7 Hz, 1 K), 7.17 (d, J=8 Hz, 1 H), 7.11 (d, J=8 Hz, 1 H), 3.15 (m, 1 H),

3.1-2.9 (m, 5 H), 2.78 (dd, J=B, 13 Hz, 1 H), 2.37 (bs, 1 H), 1.38 (d, J=B Hz, 3 H). MS cabulated for C₁₈H₁₈F₃N+H: 308, obsarvad: 308.

(Comparathre) Example46: (R,8) 7-(3-TrltIuoromethylphHiyl}-1-methyl-23_l4,5-tetrahydro-1/A3-benzazeplne [0232] <img file="IS2134B_D0095.tif" /> [0239] By the eama ganaral procadure as In exampla 29, (R,S) 7-(3-trifluoramathylphanyl)-1 -methyl-2,3,4,5-tatrahy-dro-1 Η-3-benzezeplna wa&amp; obtalned frem N-Oifluoroaeetyl-7-hydroxy-l -mathyl-2,3,4,5-tetrahydro-1 Η-3-benzazapine, O-trffluoramathanasuironata aa a colorteaa oil. 1H NMR (400 MHz, CDCy d 7.80 (s, 1 H), 7.73 (d, J=8 Hz, 1 H), 7.57-7.48 (m, 2 H), 7.38 (d, J-8 Hz, 1 H), 7.30 (s, 1 H), 7.24 (d, J=7 Hz, 1 H), 3.18 (m, 1 H), 3.1-2.9 (m, 6 H), 2.79 (dd, J=8,13 Hz, 1 H), 1.38 (d, J=8 Hz, 3 H). MS cabulatad for C₁₈H₁₈F₃N+H: 306, observed: 306.

(Comparatlve) Example47: (R,S)7-{4-'nifluoromBttiy1phenyl)-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazeplne [0234] <img file="IS2134B_D0096.tif" /> [0235] By the eama ganaral procedura as In axampta 29, (R,S) 7-(4-trffluoramethylphenyl)-1 -methyl-2,3,4,5-tetrahy-dro-1 W-3-benzazaplna was obtalnedfrom N-trtfluoraacetyl-7-hydroxy-1 -mBttiyi-2,3,4,5-tstrahydrO-1 tf-3-benzazeplne, Otrffluoromethanesulfonata as a colorbas oil. 1H NMR (400 MHz, CDCI₃) d 7.65 (s, 4 H), 7.38 (d, J=8 Hz, 1 H), 7.31 (s, 1 H), 7.24 (d, J=8 Hz, 1 H), 3.15 (m, 1 H), 3.1-2.9 (m, 5 H), 2.80 (dd, J-B, 13 Hz, 1 H). 2.48 (bs, 1 H), 1.38 (d. J=B Hz, 3 H). MS cateulated lor C₁₈H₁₈F₃N+R. 306, obeenrad: 306.

<img file="IS2134B_D0097.tif" />

<img file="IS2134B_D0098.tif" />

<img file="IS2134B_D0099.tif" />

(Comparatlve) Example 48: (R3) 8-(2-Chloraphenyl)-1 -methyl-2,3,4,5-tatrahydre-1 Η-3-benzazepine [0236] <img file="IS2134B_D0100.tif" /> [0237] A solution of N-trifluoraac0tyl-8-broma-1 -mettiyl-2,3,45-tetrahydiO-1 (+3-banzazaplne (84 mg, 0.229 mmol) In dlmethylfarmamlde (2.5 mL) was treated wlth 2-chloraphanylboronio add (43 mg, 0.275 mmol), CsF (52 mg, 0.34 mmol), watar (70 mg, 3.9 mmol), PdfPP^ (27 mg, 0.023 mmol) and stirred ovamight at 75°C. The product mixture wasdlluted wtth EtOAc(20mL), washedwlthwater{10mL), brine(IOmL), driedwlth Na^C^andconcantrated. Flash chromatography (10-20% EtOAc in hexane, siBca) resulted In 36 mg of a clear oil, MS calculated for C_igH₁₇CIF₃NO+H: 388, obsarvad: 368. "Πιβ product (39 mg, 0.106 mmol) was dlssolved ln methanol (2 mL) treated with 15% aqueous NaOH (2 mL), and stirred ovamight at 20’C. Ttie product mlxture was concantrated, extracted 3 times with CH₂CI₂ (5 mL), dried wlth Na₂SO₄ and the solvant avaporatad to glve 18 mg of a elaar oil. 1H NMR (400 MHz, CDCI₃) d 7.44 (d, J=8 Hz, 1 H), 7.35-7.17 (m, 5 H), 7,12 (d, J«=8 Hz, 1 H), 3.14 (m, 1 H), 3.1-2.9 (m, 5 H), 2.79 (dd, J-7,13 Hz, 1 H), 2.36 (bs, 1H), 1.36 (d, J=7 Hz, 3 H). MS calculatad for C₁₇H₁₈CIN3+H: 272, observed: 272.

Example 49: (R,S) 7-ΜβΛοχγ-1-ιτιβ0τγΙ-8-ΐΓΗ1ιΐ0Γ0ΠΐΒίΙιγΡ2,3,4,5-ΐβΐΓΒΐψΰι·ο-1Η-34&gt;βηζ8ΖβρΙΠΒ [0238] <img file="IS2134B_D0101.tif" /> [0239] A solutlon of N-trlfluorem0thylacetyl-8-lodo-7-methoxy-1 -mathyl-1,2,4,5-tBtrahydro-3H-3-banzazepine (135 mg, 0.327 mmol) in dimethylfomnamide (3 mL) and toluene (0.5 mL) was traaled wlth sodlum trlfluoraacetate (133 mg, 0.981 mmol), copper (I) lodlde (124 mg, 0.654 mmol) and the toluena dlstillad off to remove any resldual water. Tha reaction mlxture waa stirred at 155’C for 3.5 houre, dllutad wtth EtOAc, f litered, absorbed on sllica and purified by flash chramatography (10% EtOAc In hexane, slllca) resultlng In 26 mg of a colorlasa oil. MS calculated for C_1SH₁₅F₈NO₂+H: 356, obsoved: 356. The Irrtermadlata (26 mg, 0.073 mmol) ln mathanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stlrred 0.5 houre at 50’C. The product mlxture was dilutad with water (5 mL), extracted twk» wlth EtOAc (5 mL), the comblned organlc phases ware washed wtth brfne (5 mL), dried wfth Na₂SO₄ and eoneantrated to glve 14 mg ol a coloriess oll. 1H NMR (400 MHz, CDCy d 7.32 (s, 1H), 6.73 (s, 1 Η), 3.B9 (s, 3 H), 3.1-2.9 (bm. 6 H), 2.75 (bm, 1 H), 223 (bs, 1 H), 1.36 (d, J=B Hz, 3 H). MS ealculatad for C₁₃H_1BF₃NO+H: 260, observed: 260.

Example 50: (R,S) 7-Methoxy-1-methyl-8-pentafluoro«thyl-2,3,4,5-tetrahydro-1H-3-bBnzazeplne 0240] <img file="IS2134B_D0102.tif" />

0241] A solution of N-trlfluoiomethylacetyl-8-todo-7-mflthoxy-1-methyl-12,4,5-tetrahydro-3H-3-banzazepine (100 mg, 0.242 mmol) In dimethyltornianilde (3 mL) and toluena (1 mL) was treated with sodium pentaf luoropropionate (64 mg, 0.344 mmol), copper (I) lodlde (92 mg, 0.484 mmol) and tha toluana dlstlllad off 1» remova any rasldual water. Tha reactten mixture was atlrred et 16O°Cfor 3.5 hours, diluted wlth EtOAc, tllterad, absorbed on sillca and purified by flash chromatograptiy (10% EtOAc In hexane, slHca) raaultlng In 22 mg of a colorlass oll. MS calculated for C^H^FjNO^H:

<img file="IS2134B_D0103.tif" />

<img file="IS2134B_D0104.tif" />

<img file="IS2134B_D0105.tif" />

406, observed: 406. The inlermadlata (22 mg, 0.054 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and atlrred 0.5 hours at 50%. The preduct mlxture was diluted wlth water (5 mL), extracted twica with EtOAc (5 mL), the comblned organlc phasas ware washad wlth brína (5 mL), driad wlth NagSO₄ and concentratad to give 14 mg of a coloriass oil. 1H NMR (400 MHz, CDCy d 725 (s, 1 H), 6.74 (s, 1 Η), 3.B5 (s, 3 H), 3.1-2.9 (bm, 6 H), 2.76 (bm, 1 H), 2.37 (bs, 1 H), 1.35 (d, J=8 Hz, 3 H). MS calculatad for Ci₄H_ieF_aNQ«-H: 310, observed: 310.

Example 51: (R,S) 8-lHnuoromethyM-mrthyl-25A5-ttrahydre-1 Η-3-benzazeplne [0242] <img file="IS2134B_D0106.tif" /> [0243] By ttia aame ganaral pracedura as In exampb 26, (R,S) 8-trlfluoromethy 1-1 -mathy 1-2,3,4,5-tatrahydro-IH· 3-benzazepine was obtained from 4-trifluoromtíhylphenethylamine as a colorbas oil. 1H NMR (400 MHz, DMSO) d 7.55 (d, J=8 Hz, 1 H), 7.49 (s, 1 H), 7.43 (d, J=B Hz, 1 H), 355-3.50 (m, 1H) 3.43-3.23 (m, 7 H), 3.13 (dd, J=16,7 Hz, 1H), 3.0-2.91 (m, 2H)„ 1.36 (d, J=7 Hz, 3 H). MS calculatad tdr C₁₂H₁₄F₃N+H'. 230.19, observed: 230.4 Example 52: (R,S) 8-bromo-1-methoxymethy1-7-methoxy-2,3,4,5-tetrahydro-1 Η-3-benzazeplne [0244] <img file="IS2134B_D0107.tif" /> [0245] A solutlon of B-bromo-1-hydroxymethyl-7-mathoxy-2,3,4,5-tetrahydra-1H-3-banzazapina (0.075 g, 0.26 mmol) In dbhbromathana (2 mL) was trealad wfth BOCjO (0.062 g, 0.29 mmol), and stfrred ovemight at 20%. The product was absorbed on slllca and purtflad by flash chromatography (33% EtOAc In hexane, sillca) resultlng In 0.034 g of a cbar oll. MS calculatedfor C^H^BrNO^H: 388, obsarvad: 386. Tha BOC-protactad intarmediate was dlssolved ln dlmathyltormamida (1 mL), treated wtth axcass NAH and axcess todomethane aaquentially, and then stirred for 1 hour at 20%. The reactlon mlxture was quanchad wlth water (5 mL), axtractad twbe wltti EtOAc (5 mL), tha combined organic phasea were washed wlth brtne (5 mL), drbd wlth Na₂SO₄ and ooncentrated to give 0.019 g of a ctear oil. MS calculatad fbr C_iaH2gBrNO₄+H: 400, obaovad: 400. The N-BOC protectad mathylethar was then treatad wlth 4M HCI lndloxana(1 mL) andatirred2houreat20%. Evaporatlon resultad In 0.009 gofthedesiredproductasaclearoll. 1H NMR (400 MHz, CDgOD) d 7.30 (s, 1 H), 6.92 (s, 1 H), 3.67 (a„ 3H), 3.65 (s, 3H) 3.6-3.1 (m, 9 H). MS calculated for C^H^BrNO^H: 300, obseived: 300.

Example 53: (R,S) 8-Chloro-1-ethyF2,3,4,5-tetrahydro-1 W-3-benzazeplne [0246] <img file="IS2134B_D0108.tif" />

N-Crotyl, N-trilluoroacβtyl·24oclo^^c^ιlorophβnelhytemiπe [0247] A aoluflon of N-trifluoroacetyl-2-iodo-4-chtorophenethylanilne (82 g, 15.B mmol) in dimethylformamida (350 mL) was traated wtth KjCOg (15.8 g, 114 mmol) and crotyl bromida (8.0 g, 44 mmol) sequentlally, tha mlxture was

<img file="IS2134B_D0109.tif" />

<img file="IS2134B_D0110.tif" />

<img file="IS2134B_D0111.tif" />

sörred at 60’C for 16 hours and then cooled to 20°C. Tha mlxtura waa dilutad wlth EtOAc (360 mL), washed wlth water (3 x 300 mL), dried with N^SO₄ and concentrated. Flash chromatography (5-15% EtOAc In hexane) resulted In 25 g oí a clsar oll. MS calculated for C₁₄H₁₄CIF₃INO+H: 432, obsarved: 432.

N-Wfluoroaoaiyf-8-c/i/o/D-1-effy/-2,3,4,5-tefraftydfo-íH-3-benzaz0p/ne [0245] A solution of N-crotyl, N-trifluoroacatyl-2-lodo-4-dibrophanetliylamina (2.5 g, 5.8 mmol) in dimethylforma-mlde (250 mL) was treatad wfth KOAc (1.07 g, 10.9 mmol), n-Bn₂Et₂NBr (153 g, 5.84 mmol), Pd(OAc)₂ (0.063 g, 0.28 mmol) and stlrred ovamight at 77°C. The praduot mixture was coolad to 20°C, filtered, dilutad wlth water (100 mL), extracted wHh EtOAc (3 x 100 ml), tha comblnad organlc phases washed with watar (100 mL), brine (100 mL), drtad with Na₂SO₄ and concantrated. Flash chromatography (2-20% EtOAc In hexane, sillca) resulted In 0.339 g of a clear oil. Tha product, which waa assumed to be a mixture of double-bond isomers, was dissolved In methanol (50 mL) treated with E^N (0.2 mL), 10% Pd/C (0.10 g) and stirred 16 houre under 100 psl (0.69 MPa) of hydragan. The product mixtura was ffltared, concantratad and purffiad by flash chromatography (5% EtOAc In hexana, silica) resulting in 0.20 g of a whlte solld. MS calculatad for C₁₄H₁₅CIF₃NO+H: 306, observed: 306.

8-CMwo- 1-6thyl-2,3,4,5-tetrahydro-1 Η-3-benzazepíne [0249] A eolutlon ol N-trffluoroacetyl-8-chloro-1 -athyl-2,3,4,5-tetrahydro-1 W-3-banzazeplne (63 mg, 0.207 mmol) In matfianol (2 mL) was treated wlth 15% aqueous NaOH (2 mL), and stirred for 3.5 houra at 60’C. The product mlxture waa concantrated, axtractad 3 trnaa witti CHjCfe (5 mL), driad with Na2SO₄ and concantratad to giva 35 mg of a clear oll. 1H NMR (400 MHz, DMSO-dg) d 7.2 (m, 3 H), 3.3-3.0 (m, 7 Η), 1.9-1.6 (m, 2 H), 0.91 (t, J=7 Kz, 3 H). MS calculated forC₁₂H₁₆CIN+H: 210, obseived: 210.

Example 54: (R,S) 8-Chloro-7-fluoro-1-methyF2,3,4,5-tetrahydro-1/F3-benzazeplne [0260] <img file="IS2134B_D0112.tif" />

N-TrHhxiroacetyl-B-chloro-7-fhJoio-1-mettiyl-2,3,4_l5‘tetrahydro-1H‘34}en2azeplne [0251] A solution of N4rffluorDacatyl-8-chlQiQ-1-niethyl-2,3_l45-tatrahydro-1H3-benzazBpine (25 g, 85 mmol) In 1 ,2-dlchloroattiana (15 mL) was treatad wtth Salactfluor (3.9 g, 11 mmol), trifluoromathanaeuttonlc acld (8 mL, 90 mmol) and etlrred 60 houra at 75*C. The product mixture was pourad Into watar (200 mL), axtractad wlth EtOAc (200 mL), tha organlc phaaa waahad wlth saturated aquaoua NaHCOj (2 x 100 mL), brlne (100 mL), drled witti Na₂SO₄ and concentratad. Tha cnide product waa purifled by flash chromatography (6 % EtOAc in haxane, silica) rasulting In 1.6 g of a whtta solld. MS calculated for C₁₃H₁₂CIF₄NO+H: 310, obeeivad: 310.

8-Chlom-7-fluom-1-methyl-2,3,4_l5-tetrahy(lm-1H-3-benza2Bplne [0252] AaolufionofN-titfluoroacetyHJ-chtoro-7-fluoro-1-n»thyl-2,3,4_l5-tetrBhydro-1/M-berizazepine(ieOmg,0.22 mmol) In methanol (3 mL) was treated wlth 15% aquaoua NaOH (2 mL), and sOrrad tbr 35 hours at 25°C. The product mixtura waa concentrated, extracted 3 times wlth CH^ (5 mL), dried with NajSO₄ and concantrated to give 93 mg of a dear oll. 1H NMR (400 MHz, CDCIj) d 7.11 (m, 1 H), 6,85 (m, 1 H), 3.05-2.95 (m, 3 Η), 2.95-2.B0 (m, 3H), 2.68 (m, 1 H), 2.36 (bm, 1 H), 1.31 (m, 3 H). MS cateulatad for ^H^CIFNfH: 214, observed: 214.

Exampto 55 Saparatlon of enantlomera tor aatected eompounds ol the InvenUon [0253] Ήιβ followlng eompounde were aaparatad Into thalr raspectlva anantiomars uslng a Varian ProStar HPLC aystem with a 20 mm x 250 mm Chlraleel OD chlral column, aluting wlth 0.2 % dlethylamlne in various concantratlons of laopropanol (IPA) in haxanas, saeTable 1 balow. In eome caeas, tha aaparatlons wara parformad on tha Intarmediate trffluoroacatamida protected amines.

<img file="IS2134B_D0113.tif" />

<img file="IS2134B_D0114.tif" />¹ Tha eeparated trtfluoraacetamkje amntlenwr woa hydralyzad to glva EnanUenar 1 ef Compound 2B ² Tha aapanlad trffluoroaoatamlda anantlsmar waa tydralyzad to ghií Enantkmar 2 of Compound 28.

³ Tha aapanlad trfluoroaeatanikio ananUgmar waa hydralyzad and autaagquandy N-mellyMad to ghí» EnanUomer 1 of Compound 37.

⁴ Tha aapaialad trdluoroaeetaniWe anandoniar waa tydralyzad and nAaaquantly N-maHiytatad to glv· Enanttomer 2 or Canpound 37.

⁵ Tha aapanbd trffluoreacelarolde anantlaniar was hyiftolyzad to glva Emrtfemer 1 of Compound 51.

³ Ή» aqMraM MluanaGalamlda anaitianBr waa hydrolyzed to glve EianHamer 2 of Compourtd 51.

⁷ Tha aapdMad trfflueioacalmlda ananHamar waa hydrotyzad to gtv« Enanfamar 1 d Cwnpound 53 ³ The aaparatad triflinroBcatamlda anaitianiir waa hydrolyzad to gba Enanttoow 2 of Compound 53.

ExampleSC

Intracellular IP₃ Aeeumulatton Aiuy [0264] HEK293cell8weretran8fectedln 15cmster0edlshBswtthorwlthout(control) leugofhumanS-HTæraceptor cDNA uslng 25ul of llpofectamlne. Cella were then Incubated for 3-4 houra at 37*Cffi%CO₂ and then transfection media was removed and raplaeed wlth 10Oul of DMEM. Cells werathen plated onto 100cm aterile dlshes. The next day cells were platad Into 98 wall PDL microtltar platas at a denslty of 55K/0.2ml. Slx hours lattar, medla was exchanged wlth pH]lnoaltol (0.25 uCiZwsll) In inositol free DMEM and platas were incubated at 37°C/5%CO_Z ovemight. The next day, wells wera aaplratad and 200ul of DMEM corrtainlng test compound, 10uM pargyllne, and 10mM LICI was added to approprfate walls. Platee were then Incubated at 37*CÆ%CO₂ for three hours followed aspiratlon and by addltion of frssh k» cold stop eolutlon (1Μ KOH, 19mM Na-borate, 3.6 mM EDTA) to aach well. Plates wera kept on lce for 5-10 min and the wells were neutralized by addttion of 200ul offresh lce cold neutralzatlon solutlon (7.5% HCI). Plates ware then frozen until further processlng Is deslred. The lyeata was then transferrad into 1.5 ml Eppendorf tubes and 1 ml of chloraform/methanol (1:2) wae addedrtuba. "Πιβ solutlon was vortaxed for 15 seconds and the uppar phasa was applled to a Biorad AG1-X8™ anion exchange resin (100-200 mesh). Flrst, the resin was washed with water at 1:1.25 W/V and 0.9 ml of upper phase was loadsd onto the column. Tha column was then washad wtth 10 ml of 5 mM myo-Inosltol and 10 ml of 5 mM Na-borate/60mM Na-formate. The Inositol tris phosphates were eluted into scintil latlon vlals contalnlng 10 ml of sdntillation cocktall wlth 2 ml of 0.1 M formic acld/1 M ammonlum formata. The columns ware regenerated by washlng wlth 10 ml of 0.1 M formic acid/3M ammonlum formate and rinsed twice with dd HjO and stored at 4’C In water.

<img file="IS2134B_D0115.tif" />

[0255] The blological acOvitiee In the IP Accumulation Assay for several represantative compounds are shown in Table 2 below:

<img file="IS2134B_D0116.tif" /> • ItapoiM valun ar· avnagw gf at tant two IrUi.

[0256] The majorlty of the other compounds of the Examples were tested at least once, and thay showad actlvltlea in the IP Aceumulatlon Assay In the range between ~1.4 nM and - 5 μΜ.

Example57

Inhlbltlon of food Intate in tood-deprived nrta [0257] Male Sprague-Dawlay rata (250-350g) were deprivad of food ovemight prior to testlng. Prior to food depriva-tion, the anknate ware welghed and separated Into treatment graups in order to balance graups aocoiding to body walght. On tha test day, anlmals ware placad Into Indlvldual cagas (no beddlng) at 9:00am wlth free access to water. At 10:00am, animate ware injected with tastcompound (p.o., I.pors.c.) and then presented with apre-waighed amount of food ln a dbh elthar 60mln (p.o.) or 30min (l.p. and e.o.) aftar drug adminlatration. Food consumptlon over dWerent tlme polnte was tfran datermlned by weighlng ttia food cup at 1,2,4, and 6hr aftor tfia food was presented. Thus, lood consumptlon waa measurad at 2,3,5, and 7hr post-lnjectton in p.o. studles, and at 1.5,2.5,4.5, and 6.5hrpost-lnjection In l.p. and e.c. studlas.

[0258] Flgures 1A-G illuatrate tha effects of aeven dlfferent compounda on food Intake in food-deprived rats. All compounds Inhlblted food Intaka dose-dependenöy. Thls effect was conslatenlly most pranounced over the flrat 1 hr after food presentatlon. Some compounds (Flgures 1A, 1C, and 1E) malntalned an inhlbitory effect on food intake relaUve to vehlcle-treated controls at 6hr after food preeentatlon. Compounda wara also ahown to ba affectiva via all routes of adminlstratlon Induding p.o.

[0259] Each of the patents, applicationa, printed publteations, and other published documents mentioned or referred to ln thle speclficatlon are cltad in order to more fully describe the state of the art to which the Inventlon pertains.

<img file="IS2134B_D0117.tif" />