AU2012200805B2

AU2012200805B2 - Benzazepine derivatives useful for the treatment of 5HT2C receptor associated diseases

Info

Publication number: AU2012200805B2
Application number: AU2012200805A
Authority: AU
Inventors: Shelley Aytes; Beverly W. Burbaum; Scott A. Estrada; Charles A. Gilson Iii; Max Rey; Dipanjan Sengupta; Brian Smith; Ulrich Weigl
Original assignee: Arena Pharmaceuticals Inc
Current assignee: Arena Pharmaceuticals Inc
Priority date: 2003-06-17
Filing date: 2012-02-10
Publication date: 2015-01-22
Anticipated expiration: 2024-06-16
Also published as: AU2012200805A1

Abstract

The present invention provides processes and intermediates for the preparation of 3 benzazepines and salts thereof which can be useful as serotonin (5-HT) receptor agonists for the treatment of, for example, central nervous system disorders such as obesity.

Description

AU.STRA LIA. Patents Act 1990 ARENA PHARMACEUTICALS, INC. CONI P LETE SPECIFiCA TION STANDARD PATENT Tide: Benzazepine deriativesusefid jr the tretment of 5- T2C receptor associated dis eases The following statement is a full description of this invention including the best method of performing it known to us- BENZA7PINE DERIVATIVES USEFULOR THE TREATMENT OFH-T2C RECEPTOR ASSOCIATED DISEASES REFERFEGNCTO RELATED APLIATIONS Tisaplicatin i a divisionalpplication dr S 9 ofthePatentslAt1990 of Atral Parent Appiatn No. 2004267016 wh corresponds to rnemationl appliation N PCIVUS2o00/19279 iled e 16, 2004 which lam priority nted States application No 6047980 fled June 7 2003 and Unied States application No, 60/512 967 led October 21,2003 the hAll cntens o5f eah of whic isicroaeWy eeec een FIELD OF THE INVENTION The present invention generally relates to processes and intermediates for the preparation of 3 henzepines ansalts theof which can be useul as stunni (54T) receptor agonis for the tratmenr of, br eampl, cenral nervous slytem disorders suc as obesit. BA CKGROUND OF THE INVENTION Serotonin (5-lHT) neurotransmission plays an important role in numerous physiological processes both in health and in psychiatric disorders. For example. 5-HT has been implicated in the regulation of feeding behavior, 5-4T is believed to work by inducing a feeling of fullness or satiety so eating stops 0 earlier and fewer calories are consumed, it has been shown that a stirmulatory action of 3-IT on the 5HN' 2 receptor plays an important role in the control of eating and in the anti-obesity effect of d fenfluramnine, As the 5-Hbc receptor is expressed in high density in the brain (notably in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus i.e. PVN and DMH and predominantly in the choroid plexus) and is expressed in low density or is absent in peripheral tissues, a selective 5-H Tc IS receptor agonist can be a more effective and safe anti-obesity agent. Also, 5-HiTie knockout mice are overweight cognitive impairmnt and susceptibilityo zure u, . 5HT1c receptor is recognized as a well-accepted receptor target for the treatment of obesity, psychiatric, and other disorders, 3-Benzazepines have been found to be agonists of the 5HT e receptor and show effectiveness at reducing obesity in animal models (s ., U.S.Ser. No. 60/479280 and U.S. Ser. No. 10/410,991, each of which is incorporated herein by reference in its entirety), Numerous synthetic routes to 3 benzazepines have been reported and typically involve a phenyl-containing starting material upon which is buil an amine- or amide-containing chain that is capable of cyclizing to form the fused 7-member ring of the benzazepine core. Syntheses of 3-benzazepines and intermediates thereof are reported in U.S. Ser. No. 60/479,280 and U.S. Set. No, 10/410,991 as well as Nair e a. Indian 1. Che., 1967. 5, 169; Oito 5 et al, Tetrahedron, 1980.3, 1 017; Wu et .at, Organic Process Reearch and Development, 1997, /. 359; Draper et al, Organic Process Research and Developmvent, 1998, 2, 175; Draper at a!., Orgcmte Process Research and Developm ent. 1998, 2, 1 86; Kuen burg at a., Organic Process Research and Development, 1999, 3, 425: Baindur et :k, J Med Chem.,1992, 35(1), 67; Neurneyerct al i MAed Chm, 1990, 33, 521; Clark cr ai.,j Med. Chen. 1990, 33, 633; Pfeiffer e at,.! Mcd, Chem, 1982, 25 352: Weinstock e 1, J Med Chem, 198(1 23(9), 973: Weinstock et at..! Med Chem, 1980, 23(9), 975: Chumpradit et al, I Med. Che., 1989. 32. 1431; Heys et at, Org. Chem, 1989. 54, 4702; Bremner et al .Progress in heterocyclic Chemisy, 2001. 13. 340: Hasan et atl Indian . (Them. 1971, 9(9) 1022; Nagle et a!., Tetrahedron Letters, 2000, 41, 301 1; Robert, e1 a, 1 Org CheW. 1987, .52 5594); and Deady et aL, Chem Soc. Perkin Trans. 1, 1973, 782. Other routes to 3-benzazepines and related compounds are reported in Ladd et al, Med. CheMo. 1986, 29, 1904; EP 204349; EP 285 919; CH1 500194; Tetrahedron Letterr, 1986, 27, 2023; Ger. Offen., 3418270, 21 Nov. 1985;. Org, Chem, 1985, 50, 743; U.S. Pat. Nos, 4,957,914 and 5,015,639: Synthetic Cown, 1988. 8, 671; Tetrahedron, 1985. 41, 2557: Hokkaido Daigaku Kogakubu Kenkyu HUkoku, 1979, .96 4 4 Chemical & Pharmaceutical Bulletin. 1975, 23, 2584; 1 Am Chem. Sac, 1970, 92, 5686: . Am. Chem. Soc, 1968, 90, 6522; 1 Atm, Chew. Soc, 1968, 90, 776; 1 Am Chem. Soc, 1967, 1039; and Chang et aL Bioorg, Med, Chem, Letters, 1992, 2, 399 iin view of the crowing demand for compounds for the treatment of disorders related to the 5 Ty receptor, new and more efficient routes to 3-benzazepines are needed. The processes and compounds described herein help meet these and other needs. Any discussion of documents acts, materials. devices, articles or the like which has been included in the present specifcation is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the Kid relevant to the presem disclosure as it existed before the priority date of each claim of this application. SUMMARY OF THE NVENTION Throughout this specification the word "comprise", or variations such as "comprises" or comprisingg", wil be understood to imply the inclusion of a stated element. integer or step, or group of elements inlegers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. The processes and itermediaes of the present invenion are useful in the preparation of therapeutic agents for the treatment or prophylaxis of 5-HT mediated disorders such as obesity and other central nervous system diseases, According to a first aspect, the present invention provides a process for preparing a hydrochloride acid salt of a compound of Formula Va or Vb: R4RIR

NR

1 NR) R R W, Vb comprising resovng a mniture of cotnds of ForMla a and b t yeld a compound of Formula Ma or a 5 compoundoFrmula Mb or a salt thereofnd combining sad compound of Formda Ma or b with PH to produce a hyad ride aid sa of a compound of Fornula Ma or Vb, x; herein: P s MeI s R f i "C Is R H i iH R" is i and R s Acoding to a second aspect, the present invention provides a hydrochloride acid salt obtained by the process of thefirst aspect. 5 According to another aspect. the present invention provides a composition comprising at least one hydrochloride acid salt according to the second aspect, According to a further aspect, the present invention provides the hydrochloride acid salt according to first aspect or a composition according to the second aspect when used in the treatment of the human or animal body. 20 A according to another aspect, the present invention provides the hydrochloride acid salt according to th rst aspect or a composition according to the second aspect when used in treatment of a -T mediated isorer induing satiety reding food intake; controling eating; or reatmeat of obesity. According to yet anolr aspect, the present invention provides use of the hydrochdde acid salt accodng to the frist aspect or the compositon according to the second asepecti the manfatue o a medicament. 3A According t a further aspect. the present inentionprovides use of he hydrochloride acidsalt according to theist aspect or the composion according io e second aspect in the ma facte of a Inedicamnt for N treatment of a 5H T mediated disorder; inducing satiety: reducing food inake; controlling eating; or treatment of obesity. 0 According to another aspect, the present invention provides a method of treatment of a human or animal body, comprising administering a therapeuticaly acceptable amount of the hydrochloride acid salt according to claim 4 or the composition according to claim 5 to the human or animal body to: treat a 5-T mediated disorder; induce satiety; S reduce food intake: control eating; or treat obesity. The present disclosure also provides, inter aia, a process for preparing a compound of Formula 1: R3R2 R4 L

NR

1 Re R 0a R or salt form theof wherein; R is ph R2 is C N alkyl, -CH1O(C 2 alkyl), C(O)O-(C 1 -C alky) -CO)NH-(C C alkyl), CC 4 25 haloalkyl, or CHOH: 3113 R, Rand R ar each, independently, H, halo, CEX alkyL CrCS alkeny I, CrS aikynyL CC cycloalky 1 4 haloalkyl, hydroxy, mercapo, OR'. SR a ikoxyalky C(O)-a lky, C(OO-alkyl C(O)NH-alkyl hvdroxyaikyl, NRR , CN, NO, heterocycloalkyl, aryL, or heteroaryl, wherein said aryi and heteroaryl can be substituted with one or more substituents selected from CLCs alkyl. halo, C-Cs haioalkyl, and alkoxy; or R 4 and R together with the atoms to which they are attached form a 5- or 6 member heteoehe n havng one atom R and R are each, independently. R halo! C-s alky, Cr-CRalkenyL CQC alkyny QC cycloalkyl, C-Cs haloalkyl, aikoxyalkyl, hydroxy, C(O)-alky L (O)O-alky C(O)NH-alkyl or hydroxyalkyl, or R and R together with the carbon atom to which they are attached form a CrC k and R are each, independently, H, halo, C'ICs alkyl C-Cs alkeny. C r2- alkynyt C cycloalky Cr-Cs haloalkyl, alkoxyalkyt hydroxy, C(O)-alkyl C(0)O-alky C(O)H-alkyt or hydroxyalkyL or R and R" together with the carbon atom to which they arc attached form a C-C, Scycloalkyl group; It H, c alkyl c alkenylkvnyy, CCco l C aakyt arakyl aryL heteroaryL heteroarylalkyl, or ally];

R

10 and R" are each, independently, H, Cr-Cs alkyl, Cr-Q alkenyl, Cr-Q alkynylC-C 7 cycloalkyL C-C 5 haloalky. aralkyt aryL heteroaryl heteroarylalkyl. or ally, or R O and R' together with I the N atom to which they arc attached form a heterocyclic ng; comprising reacting a compound of Formula II: 2

NR

1 R4) R 7 R 11 "wh a during agen oponall n te presence of a ewis acid for me and undef conditions suiae for terming said compoud of ornula 1 or sal Onbrthereofi e presentdsoure further provides a process Or preparing a compound of Fornua l or salt form thereof, w Terein R 3 is HorC 1 -Cs alkyl; RC is Cr-Cs alkyl, -CltrO-(Cr-Cs alkyly C(OO-C 5 alkyl), -C(0)NH(C 1 Cs alkyl), OHI C

C

4 haloalkyt, or CH 2

OH;

R. R R and R are each, independently, H, halo, 0Cv! alkyl CrCs alkeny Q-L C alkyny, Cv-C 3 cycloalkyl, Ci- 0 s haloalkyl. hyd roxy> mercapto, OR', SRX alkoxyalkyi, C(0)-alkyl. C(O)-alkyl, C(O)NH-alkyl, hydroxyalkyl, NRLRIR", CN, NO 2 , heterocycloalkyl, aryl, or heteroaryl. wherein said aryd and heteroaryl can be substituted with one or more substituents selected from C-C alkyl, halo, CECs 5 haloalky l and alkoxy: or R 4 and R together with the atoms to which they are attached form a 5- or 6 member heterocyclic ring having one o atom; Ra aid R - are each, in dependent, -, halo, C1-0 alkyl, C2-C aikenyl, C -C alkynyl C-C cycloalky L C haloalkyl, a Ikoxy alky I hydroxy, C(O)-alky, (0)-al kyl, C()NH-alky , or hydroxyalkyl, or R 2 N and R' 5 together with the carbon atom to which they are attached form a CKC e loa kyl group R and R are each, independently, H, halo, C aC alkyl CS alkenyl C, alkynyt CA cycloalkyi LQC> haloalkyl. alkoxyalky. hydroxy, CO)-alkyI, C(0)-alkyl, C(0 1)-alky L, or hydroxyalkyl. or R" and R" together with the carbon atom to which they are attached form a CC, cycloalkyl group; R" is F, CO alkyl. CCS alkenyl, C1-Cs alkynyl, CrC0 cycloalkyl, Cs haloalkyl, aralkyl, ary, heteroary L heteroar lalkyL or allyl; R "' and R " are each, independently, H. C-Cs alkyl, Ce-s alkenyi C1-0 alkynyi, C-7 eyeoaIkyk Cl-Cs haloalkyL aralkyL aryl, hetroaryiL heteroarytalky, or allyL or R 0 and R" together with the N atom to which they are attached form a heterocyclic ring; C) comprising reacting a compound of Formula Ill: R3 Rib R 7 N Re R~ R 8 8 or saltiorm thereof wherein: 5 L ishalo hydroxv, d 7Q aikoxy, C thioalkoxy, C -Cz acyloxy. -0SQR0 or t is 01-Cs alkyl, aryl or heteoaryl each opionaly substed by one or monre han cyano, nir 0C0 alkyL C 01 hlalkyl. C0. akoxy or C77 haloalkoxy; Rt is 0 Ca lkyl; 30 wh a ecliing reagent for a me and umder coditon suiablefor forming said compound of Formula Ior salt formn thereof.

The present disclosure further provides a process fr preparing a compound of Formula I or salt form thereof. whewein RI is igor Cgg aky R2 is C-Cs alkyt -CH-O-(C-C 2 alkyl, C(O)O-(Cr-C 8 alkyl). -C(O)NHi-(C 1 alkyl), OH, C C haloalkyt or CH 12ON1; R'R, R', and R M are each. independently. H, halo. CrCy alkyl C C alkenyl, CrQ alkynyl. CrC, cycloalkyl. C-C 2 haloalkyl hydroxy, mercapto. OR, SR alkoxyalkyL C(O)-alky L C(O)O-alkyl, C( O)NH--al kyt, hydroxyalkyl, NRNR 11 , CN, NO 2 , heterocycloalkyl, aryl. or heteroaryl, wherein said aryi S and heteroaryl can be substituted with one or more substiuents selected from CCa alkyl, halo, C 1 C haloalkyl, and alkoxy; or P and R together with the atoms to which they are attached form a 5- or 6 member heterocyclic ring having one ( atom;

R

t a and R ' are each, independently, W, halo. C-Cs alkyl, C-Cs alkenyI CrC, alkynytl CC, cycloalkyt I C 2 haloalkyl, alkoxyalkyl, hydroxy. C(O yalky, C(O)O-alkyl C(0NH-alkyl. or hydroxyalkyl or RS' and R7 together with the carbon atom to which they are attached form a CrCC cycloalkyl group; R*" and R* are each, independently, H, halo. C-C 2 alky C 2 alkeny C-Cs alkynyi CrC, cycloaiky L, C 1

C

8 halboal Ky] L lkoxya lky i hydroxy, C(O)-alkyl. C(O)O-alkyl C(O)Nl-H-alIkyl, or hydroxyalkyl, or R

(

u and R&1 together with the carbon atom to which they are attached form a C 2 -0 (I cycloalkyl group; R is H-I C 8 ~ alkyl. C~ alkenyl. Cr-Cs alkyny. CC cycboalkyi, C 1

-C

2 haloalkyl, aralkyl, aryl, heteroary] heteroarylalkyl or allyl; and R and R( are each, independently. H, C-Cs alkyl. 0C alkenyl, C-Cs alkyny L CrC cycloalkyl C-C 8 haloalkyl, aralkyt aryL heteroary, heteroarylalkyl, or ally, or Rn and R" together with O ihe N atom to which they are attached form a heterocyclic ring; comprising: () reacting a compound of F-ormula lii Rib R 7 0 R R

R

6 Rab Rsaa L where: LI s halo, hydroxy, (Cs aikoxy. CQ thioalkoxy, C "C acyloxy, -NSO 2 R. or -OS i(R'; t is Cr-0 aikyL aryl or heteroaryl each optionally substituted by one or more halo, cyano, niro, C-C4 alkyl, CC4 haloalkyl, C alkoxy, or C1C4 haloalkoxy; and S R' is CpO alkyh; with a cyclizing reagent for a time and under conditions suitable for forming a compound of Formula Hi or salt form thercot; and b) reactng said compound oFormua i oslfm therofwih arducing agent optionally ineth: presence of a Lewis anid for a time and under conditions suitab fbr forming said 0 compound of formula I or salt form thereo Theesent diclr further provides a process for preparig a compound of Fornla I or sa form thereof whercin: R is Ht or OCg~ alkyl: 5 R is C-Cs alkyl, -CHO-(C; -~ alky), C(O)O-(C'- alkyl) ~C(O)NH-(C-C 8 alkyl), OF, C C0 haloalkyl, or CH 2 fH R RK and R are each, independently, H. halo, Ci-Q alkyl, Crs alkenyl, 0r4 alkynyl, C- cyc loal ky 1, C -C haloalkyl, hyd roxy, mercapto, OR t SR a lkoxyalky L 0(O)-alky I C(O)O-alkyt C(O)NH-alkyil hydroxyalkyl. NRg: 1 !, ON, NO, heterocycloalkyl, ary or heteroaryl wherein said ary! and heteroaryl can be substituted with one or more substituents selected from C-Cs alkyl, halo, C-C, haloalkyL and alkoxy; or R 4 and R' together with the atoms to which they are attached form a 5- or 6 member heterocyclic ring having one O atom; R and IIR are each, independently, H, halo, C4s alkyt, C2~O alkenyt C> alkynyl, CrCC> cycloalkyl, C+0s haloalkyl, alkoxyalkyL hydroxy, 0(O)-alkyl, C(0)-alkyl C(O)NH-alkyL or S hvdroxvalkyl, or Ro and R together with the carbon atom to which they are attached form a Cr-C cycloalkyl group; Rt and R" are each. independently, H. halo, Cr4% alkyl C70s alkeny, CjrC alkynyl, C-C, cycloalky, L0C0~ haloalkyl, alkoxyalkyl, hy droxy, C'(O)-alky, C(O)0- alkyl, C(O)N H-alkyl. or hydroxyalkyl or R and RY" together with the carbon atom to which they are attached forn a Q&C 50O cycloalkyl group; R" is , C> alkyl, C-s alkenyl Cr-C alkynyl, C-07 cycloalkyl, Cr- haloalkyL aralkyi, aryI heteroaryl heteroarylaliyl or atlyl; and RV and R" are each, independently, H, C alkyl, C-( alkenyl, C-C alkynyl CC cvcloaikv. CCheaoalk aray garyl eteroary hteroaylalk or a or " and '' together th iS the N aon to Wihhey ae attached forma heterocycic ring; comprising: (a) reaching a compound of Formula IV: PIV R'2 Rzb RNa R5 NH-R 1 Re R 8

R

8 a L 0 whv erein: L is halo hydroxy. C 1 Qe alkoxy, C-? thioalkoxy, CCs acyloxy, -OSO 2 R, or -OSi( R')t; P is C-0 ~aW . w, Wheteroarylea-h optionally substituted by one or more halo. yano. nitro. CW iakxh C Hhaloalky akoxyor C haloalkox W) P CQ Q alkvi: and 0 is Jaxing group. Or a Wne and tinder condition suhable tfornnag a compound of Formua. I or sal form their o ng said compound of Fomlda l or sal formthereO Sr ent fr ni and under conditions suta f ig a compound of Formula I. or t fo thereof; and (c) reacting said compound of Formula II with a reducing agent optionally in the presence of a Lewis acid for a time and under conditions suite for forming said compound of Formula I or salt A'rm thereof. f te prest disclosure further proids a process or reparing compound of Formu I or alt form thereofW wherin 1' is H or C l Aaikyl 2 iCHalky, -CHA-O-(CCsagyl C(O0-KC Ha lkyl), -C()NR-(Csalkyix H. :5 ~ alalky or 01H H1;

R

3 , R , and RI are each, independently. H, halo, CA 0 s aIkyl, Q-Cs alkenyl 02CCs alkynyl, ClC cyclokyl, C-Cs halo'alkyi hydroxy. mercapto. OR SR alkoxyalkyl C(O)-alkyl, C()-aky C()Nh~-alkyl. hydroxyalkyl N, NO 2 heterocycloalkyl aryl or heteroaryl wherein said aryl and heteroaryl can h substituted with one or more substitutes selected from C-Cs alkyl halo, C-H

S

haloa ky. and alloxy; or R 4 and R5 together with e atoms t which they are attached fom a 5o 6 membe he-Ion die ring having one C atom; R and R'P are ach, ind pendently - halo, C-Q alkyl, C-C aIkeny'l CCs alkyny C-Q cycioaikyl CrCs haloalkyl, aikoxyalkyt hydroxy, C(O)-alkyI C(O)0-alkyl C(O)NH-akyt or S hydroxyaLky, or R" and R" together with the carbon atom to which they arc attached frm a 03-C; cycloalkyl group; R* and R*~ are each, independently, H, halo. C 3

-C

5 alkyl, Cr-05 alkenyl, CrCa alkynyi, C-,-0 eyeloalkyl. C,-Ca haloalkyt. alkoxyalky L. hydroxy, C(O)-alkyit ()0-alkyIL C(O)NH-alkyl, or hydroxyalkyl, or Rt' and Rn together with the carbon atom to which they are attached form a C0C< .3 cyloalkyl goup; RI is H, CAC alkyL CR> alkeny 0C>ql alkynyL Cr-C cycloalkyt, Cr haloalkyl aralkyl, ary1 heteroaL, heeroarylalkvLr ai.; and R" and R are each, independently, I CrC aikyl. C-C! alkeniL C-C alkvny Cec, eye loalkyl 0,-C> haoalkyl a ralkl L aryl,t heroabeteroar Llkv L or allyL or R" and R together wth 5 the N atom to which they are attached form a heterocycbc ring; comprising reacting a compound of Fornula M11a: R, R R' R R' NR EQ LiHa wherein: L: is halo. hydroxy, C-a alkoxy C,-C thioaikoxv, C,-s acyloxy, -OSO.R, or R is C-C> alkyl ary, or heteroaryl each optionally substituted by one or more halo, cyano, nitr, C1-04 alkyl. C,-C haloalkyLI Cj-C4 alkoxy, or C,-C4 haloalkoxy; and R' is C2,Cs alkyl: withh a cy'clizing reagent for a time and under conditions suitable fo rforming said compound of Formula L. The present disclosure further provides a process for preparing a compound of Formula lila or whr in:reo R isHort C1<alkyl; 0 R 2 i C,-C alyl,-H-b--(0-C alky) 0{0)040,-C alkyl), G(O)NH-0:Cs alkyi) CM. 0, Ct haloalky lor CI- 2

H;

R R, Ro, and Rt are each, independently. H, halo, C alkyl, CrCs alkenyl, C-Cs alkynvi, C 3C' cycioalIky 1, C ~s haloal ky , hy~droxy, mrercapto, ORK. SR i. alkoxyalkyt C(O)-al1ky!, C(0)0-alky I, C(O)NH-aikyl, hvdroxyalkyl. NR 0 R' CN, NO 2 , heterocycloalkyl, airyl, or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from CrC ailkyl, halo, C-C S haloalk, and alkoxy; or R' and R together with the atoms to vhich they are attached form a 5- or 6 member heterocyclic ring having one 0 atom; Rd and R' are each, independently, H hi ale, C -OG alky L C-Cs alkenyi L$0C alkynyl, C3-C, cvcloal1ky L C --C, haloalkyl alkoxyalk;Ly hy droy C(0alkyl, 1(0)-alkyl, C(O)NH-alkv, or hy droxyalkyl or Rn and RV together w ith the cabon atom to which they are attacherd fm a CQ 3 cycloalkyl group; R SHand R*' are each, independently, H , halo. CEC> aikyl, CrCs alkeny, C-Ca alkynyl, CrC> eyeloalky, C>-C> h aloalkyl. alkoxyalky. hydroxy, C(O)-alkyl C(0)O-akyl, C(O)NH-alky!, or hydroxyalky!, or R" and R" together with the carbon atom to which they are attached form a CrC cycloalkyl group; Ris H alk LaQeQASn C Cy alkyl Clkyl haloalkl, aralkyl, ary hteroary heteroaaraky or at

R

1 3and R are each, independently, H, ClCa alkyl C-C alkenyl, C-Cs alkynyl CrC2 cycboalky. C>-C> haloalky aralkyl aryL heteroaryl, heteroarylalkyl, or ally!L or RI and R" together with the N atom to which they are attached form a heterocyclic ring L ishodo, C akoxy C> thioalkoy Cr acyloxv. -OSO 2 R.or -OS(R' R is C>-C alkyl, ary, or heteroaryl each optionally substituted by one or more halo, eyano, nitro, CI-C> alky l, Ce-C haloalkvy, Ce-Cg alkoxy, or Ct-C> haloalkoxy; and R' i C-C4 a1kyl; S comprising retn anopound of ormula ll R R R hdungagent qaponall inO prossee ofaaewk adfor a tionan und et ce~onAssukable ForNoniingAd impound of Ernna ina, l-'-e prevent chscluurW er proddes a grocusfQpreparing a orpound of FmnnulaIi alt fotherof wwtir 10 .

R is 1i or C 1 Caky R is CC alkyl -CTrO-(CvCs all), C(O)O-(C 1 Cs alkyix -C(O)NH-(C 1

C

8 alkyl) OH, C

C

4 haloaikyL or CIOlH; R R R and R are each. independently, H, halo, C-Cs alkyL C14 alkenyt C-C alkyny . 5 CC, cycloalkyl, CC haloalky, hydroxy inercapto, ORO. St alkoxyalkyl, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl hydroxyalkyL N.MR R CN. NO, heterocycloalkyt aryl or heteroaryl, wherein said aryl and heteroaryl can be substituted with one or more subslituents selected from C-Cs alkyl, halo, C 1

-C

8 haloalky L and alkoxy; or Ri and RS together with the atoms to which they are attached fo a 5- or 6 mcmbcr hetercychc ring hang one 0 atom; R and R are each. independently, H, halo, CC 8 alkyaL CW-C- alkenyl CnC 8 alkynyl C-C 7 cycloalky L C-Cs haloaIkyL, alkoxyalky L hydroxv, C(O)-alkyl, (O)O-aikyl, C(O)NHIalkyI, or hydroxyalkyl or R' and R t together with the carbon atom to which they are attached form a C-C cycloalIkyl group; R lan R are each, independently, H, halo, CrC alkyl, Cr-C alkenyi CrCs alkynL cycloalkylt C-C haloalkyk alkoxyalkyl, hydroxy, C(O)-alky, C(O)Oal kyl C(O)NH-alky, or hydroxyalkyl, or R' and RW together with the carbon atom to which they are attached form a C-C 2 eveloalikyl group; R is H, C-C 5 alkyl, C-CV alkenyl, CC akyl , cycloalkyL C-C? haloalkyt aralkyl arl heteroaryL hetrary K or ay; R ' and R, reach, independently, R C-C 5 alkyL C-C 8 alkenyl, Cr-C alkynyl CrC cycloalkyl C-C 5 haloalky, aralkyl, aryl heteroaryL harakl, or ally, or R' and R' together with the N atom to which they are attached form a heterocyclic ring; comprising a) ectn a compound of Formnula llf ) wherein; L is halo, hydroxy, C-C alkoxy, C-C 8 thioalkoxy, C-C 5 acyloxy, -OSO 2 R, or -OS i(R '; R isC-C 5 alkyl aryl or heteroaryi each optionally substituted by one or more halo, cyano, nitro.

C

1

-C

4 alkyt. C 1 -C haloalkyl, C-C4 alkoxy, or C 1

-C

4 haloalkoxy; and U R' is CrCR alkyl; wih a reducing agent oponally the p n of a ewis acid for a time and tudr conditins soItable ormig a. ompoundofFrmua l and b) reacting said conmound of Formula Illa with a cyclizing reagent tbr a time and under 5 conditions suitable for forming said compound of Formula 1. The present disclosure further provides a process for preparing a compound of Formula I or salt Monathereof, whvlerein: R is u Or Cv-C alkyl; RO is C;-Cg alkyl, -CH 2 O-(CQ- alkyl), C(O)O4C-C> alkyl), -C(O)NH-(C 1 Cs alkyl) OH, C C> haloalkyL, or CH 2 OH; RC R RA, and R are each, idependently. H, halo, C-C> alky C -C alken C -C alkynyt 5 Cv-C7 cycloalkyl C C>~ haloalikyt, hydroxy, mercapto, ORG, SR'. alkoxyalkyl, C(O)-alkylt C(O)O-alkyl. C(O)N.H-alkyl hydroxyalkyl NRmR", CN. NO, heteroccloalkyl aryl or heteroaryl wherein said aryl and heteroaryl can be substituted with one or more substituents selected from QC 5 aikyl halo, C-C> haboalkyl, and alkoxy; or R4 and RA together with the atoms to which they are attached form a 5- or 6 member heterocychi ring having one ( atom; 3 ~ Ra and R 4 are each, independently, H, halo, C>~ alkyl LC>~ alkenyl, Ce-Cs alkynyl Cr-C7 cycloalkyl, KCCs haboalky i alkoxyalkyl, hydroxy, C(0-alky C(0)-alkyl C(O)NH-alkyl or hydroxyalkyl, or Ra and " together with the carbon atom to which they are attached form a C 7C cycloalkyl group; R" and R4 are each, independently, 1H, halo, C-Cs alkyl, KC alkenyl CrC8 alkynyl CAC7 cycioalky, CrC> haoalkyt alkoxyalkyL hydroxy, 0(O)-alkyl, C(0)0-alkyh C(O)NI-avly or hydroxyalkyl, or R and Rt together with the carbon atom to which they are attached form a CrC7 cycioalIkyl group; R is H, CC alkyL C'-C alkeny, -C> alkynytl CC, cycloalkyl, C ;-a haloalkyl aralkyl, aryiL heteroaryl, heteroarylalkyt. or allyl; R' and R" are each, independently, H. C-C> alky l Cl-C> alkenyl ClC> aikynyt ClCT cycloalkyl, C-C> haloalkyl, aralkyl aryl heteroaryl, heteroarylalkyl, or alyl, or Rm and R together with the N atom to which they are attached form a heterocyclic ring; cornpri sing: a :eacting a compound of Formula f' or salthrm theref, ith a. coIound of Form uda: wherein: . i halo hydroy C- alkoxyy KC Tho oxv. C 1 -, acyxy -QOftR, or -OSi(RgI IR is Cr akyL a i orheteroaryl each optionaly substuted by one or me halo gyao n . C a a L Q& hbalk CLC alkoxy or C, 4 haloalkoxv ' is C -C alkyl; and Qa isa leavig group, fra. tie and undekndtions suitable for forming a compound aonomula 11 orsalt fbrmtereof; (b) reacing said compound of Frmuda w4h aducg agent optonalnay in dhe presence of a Lw acid for a tie and andr conditions stable for fomng a compomd of Frmula l and (C reacting said compound of Formula lia with a cyclzing reaget for a tie and und cndiions suilee formningsaid compound 01: Formula m . S The present disclosure father provides a mehod f resolng a miue of o ounds of Formulas aand 1 RR

P

5 NP NT 1 RR R RR NRR R b pa R R S P& w herein: R is H or CrC0 alkyl

R

2 is C10 alkyl, -CH-0(0C-Cs alkyl, C(Oi0-(CQ-C, alkyk -C(0)MIL( 1 0 ailkyh OH, C 04 haloalkyL or C112014 I I and R" are each, independently, , halo. CC8 alkyl. Cr- alkenyl 0r< alkynyt, 5 C--s cycloalkyl, QC haloalkyl, hydroxy, merc apto, OR SR alkoxyalky L C(O)-alkyl, C(0)O-akyl, C(O)NH-alkyl, hydroxyaky L NR"R" CN, NO_ heterocycioaky , aryL or heteroaryL wherein said aryl and heteroaryl can be substituted with one or more substituents selected fron C- alkyl, halo, C>-C haloalky L and al koxy; or R! and R' together with the atoms to which they are attached form a 5- or 6 member heterocyclic ring having one 0 atom; 20 R and R are each, independently, H, halo, Cr-0 alkyl, C-0- alkenyl, 2-0 alkyny, 0-0 cycloalkyl, -C s haloalkyl, alkoxyalky L hydroxy, C(O)-alky , C(O)O-alkyl C(O)NH-alkyL or hydroxyalkyL or R and R" together with the carbon atom to which they are attached form a OCXC cycloalklI group; Rt and R" are each, independently, H, halo. Cp-s alkyl C-0s alkenyl, Crs alkyny, C;C, 25 cycloalkyl, C-0 haloalkyl. alkoxyakyL hydroxy, C(O)-aky. C(O)O-alkyl, C(O)NH-alkyi, or hydroxyalky, or R' and R's together with the carbon atom to which they are attached form a CC0 cycloalkyl group;

R

9 is H, CQ-Q alkyl. C-C alken , C -0 alkynyl, C03 cycloalkyl, CC haloalkyl, aralkyl, aryl heteroaryk heiteroaryial L or ally1; 30 R 1 U and R' 1 are each, independently, H, C ;-0 alkyL C-0s alkeny. 1-8 alkynyl, Cr3C7 cycloalkyl C-C haloalkyl, aralkyk aryL heteroaryl, heeroarylalky, or allyl or KR and R" together with the N atom to which they are attached form a heterocyclic ring; 1 3 cornp rising: contacting said mixture of compounds with a chiral resolving acid to form chiral resolving acid sals of said compounds, wherein said chiral resolving acid comprises substantially out sterenisomer; and precipiating said chiral resolving acid sats of said compounds, wherein the resuming precipitate i enr in de cial resolving acd sAlt of one ofSaid compounds of formula Ia or A The present disclosure futhr provids a compound of rFormula If or ll or Sal on Mheef wheren: R: is H or C KC4 alkyl; (} ~ R2 is Cv Cs alkyl, -CHr-(jCrC 5 alkyl), C{O)O-C 8 ~ alkyl), -C(O)N H-C 5 ~ alkyl), OH, Ce

C

4 haloalkyl or CHOH : R'. R R.1 and it arc each. independently H, halo, C 1 -C, alkyl C 2 C alkenyl, CC 8 aikynvl, C-C cycloalkyl, C -Q haloalkyv hvdroxy. mercapto. OR', SR alkoxyalky C0)~a4t C(M )-alkyL C(O)NIH-alkyt hdroxyalkyl. NR'R 2 , CN, NO. .heterocycioalky aryl or heteroary wherein said aryl 5 and heteroaryl can be substituted with one or more substituents selected from C-C alkyl, halo, CrCs haloalkyl, and alkoxy: or R' and R 5 together with the atoms to which they are attached form a 5- or 6 member heterocyclic ring having one O aton; R' and R are each. independently, 11, halo, CC alkyl CrCs alkenyl, CrC 5 alkynyl C-C 7 eveclo alky I. Cr C 8 haloal kyl, alkoxyalkyl, hydroxy, C(O)-alky 1, C(O)O-alkyl, C(O)NH-alkyl, or (d hvd roxyalkyl or R" and Rh together with the carbon atom to which they are attached form a CrC 7 cyclo0alkvl group; Ru and It are each, independently, H, halo, C-Cs aikyl, C-Cs alkenyi. CrC, aikynyL CrC cyclo alkyl, C 1 C haloalkyl, alkoxyakyl. hydroxy, C(0)-alkyl. 0(0)0-alkyl, C(O)NH-alkyl, or hydroxyalkyi or R and R together with the carbon atom to which they arc attached form a 5cycloalkyl group; R" is H, C-C alkyl C 1 Cs alkenyl, C-Cs alkyny, C-C 7 cycloalkyl, C-Cs haloalkyl, aralky aryl, heteroaryi, heteroarylalkyit or allyl; R." anid R" are each, independently, H, CrCs aikyl, C,-Cs alkenylt C,-Cs alkynylt Cr-C 2 cycloalkyl, C-C 8 haloalkyl arkyarl heteroary heteroarylalky, or allyl or R and Ri togetherwth the N atom to which they are attached fort a heterocyclic ring; L is halo hydroxy. C,-C 5 alkoxy, C-Cs thioalkoxy, CCs acyloxy, -0SO R, or -OS i(R' s. ia s C aikyl arl or hetearyn each optionally su bstrtedi by one or ranre halocyannro, C, a ( C hAoakY C-C alkoxy orC hakx a The present discosure further poides a chial reson acd sat oa compound fForndua a or hb wherein: 14 is H orCa- alkl; R is CCa alall, (CH: CI& ak ()CCakyl -C(O)NH-(C 1 Cj alkyl), OH, C C> haloalkyl, or CItOH; R R R 5 and R are each, independently. H. halo, C 1

C

5 alkyl, C 5 alkeny, CrC> alkynyi, CrC cycloalkyl C Cs haloalkyl, hydroxy, mercapto. OK SR" alkoxyalkyl. C(O)-alkyl C(O)O-alky. C(O)NH-alkyt hydroxyalky1 NRR ", CN, NO" heterocycloalkyi, aryl or heteroary, wherein said aryl and heteroaryl can he substituted with one or more substituents selected from C 1 4 alkyl, halo, CC 8 haloalky and at koxy; or R 4 and R 5 together with the atoms to which they are attached form a 5- or 6 member heterocyclic ring having one O atom; 0 R 7 and RT are each, independently. H, halo, C-Cs alkyl, Cr-s alkenyl, C-Cs alkynyi, C-0 cycloalkyl, CrC haloalkyl, alkoxyalkyl, hydroxy, C(O)-alkv L C(O)-alky I C(O)NH-alkyl, or hydroxyakyL or R' and R 2 ogether with the carbon atom to which they are attached form a CWC cycl oalkyi group; R{8a and R" are each, independently, H, halo, C1-s alkyL C-Cgalkeny L C> aikynyl, CC cycoalkyl C C> hoaoalkyL, alkoxyalky I hyvdroxy, C(O)-alkyl 0(O)-aIkyl, C(O)NH-alkylt or hydroxyalk, or R 8 : and Rn together with the carbon atom to which they are attached form a CA cycloalkyl group; R4 is H, C alkyl, C 1 -0 alkenyL CC alkynyl Cr-C cycloalky IC 8 & haloalky, araiky , aryl 1 heteroaryl, heteroarylaikyl, or allyl; anrd o R"' and R 7 are each, independently, H, Cr10 alkyl, C-Cs alkenyt, Crl alkynl, C-C cycloalkyL, CCs haoalky, aralkyl, aryl, heteroaryl, heteroarylalkyl or allyl, or R t Q and R"together with the N atom to which they are attached form a heterocyclic ring, The present disclosure further provides a process for preparing a compound of Formula V:

ER

4 NR R, ReN R ' or satthereol wherein: IT' is H or Cl-Cq alkl R s Cr-Cs alkyL -CltO-(CC> alkyl), C(O)O-(C -C> alkyl), -C(O)NH-C-C alkyl) or C -C 30haloalkyl; R R R> and Rc are each, independently H halo, CCC alkyl C-C5 aikenyl, Cr-0 alkynyL CrC 7 cycloalkyl, CCs haloalkl, hydroxy, OR. alkoxyalkyl, 0(O)-alkyl C(0)-alky, C(O)NH-alkyl, 15 hydroxyaikyvl NRICRtI, CN,.NO> heterocycloalkylt aryl, or heteroaryL. wherein said aryl and heteroaryl can he substituted with one or more substituents selected from C C alkyl, halo. C-C haloalky. and alkoxy; or R 4 and R 2 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom: R& and RM are each, independently 1. halo. CrC, alkyl LK alkenyt CL alkynyL CC-C ey cloalkyl C-C haloalky, alkoxyalkvl hydroxv C(Ohalk) l. Cq0)0-alkyl. C(OYN -alkvl. or h droxalkv L, or R 8 Q and R" together wKith the eabon atom to which they are attached form a CC cycloalkyl group R" is YL C-C 5 alky C,-Q alkenyl, Cr- alkynyi. CrC, cycloalkyl, CrC haioalkyl aralkyl, 0 anL heteroaryl, heteroarylaikyt or allyl; and R and R are eachide, de pende Ctly ayL CL CC alkeny CA; Q aikyL C-lC kynyl CC cycloalkyl. CL C haioalkyl, aralkyt aryl, heterarl heteroaryialkyiL or allyl, or R and R" together with the N atom to which they are attached form a heterocyclic ring; comprigreactingacompoud of Noua TXu : R R5

NR

1 IX or salt thereof, wherein X is halo or SO R" and R" is C 1 -Q alkyf, aTy i, or heteroaryl each optionally substituted by one or more halo, cyano. nitro. C -C, alkyl C-C 4 haloalkyl. C-Ca alkoxy, r CC: haloalkoxy, with a ccizing reaent fOr a and under conditions suitable for forming said compound 20 of Formula V. The present disclosure further provides a process for preparing a compound of Formula X: R3 t 2 NR or salthereof R' is IH or C.-C alk) 1: R2 is C-Kk alkyl -CH-O-(C 3 -Q aLkvl) C(0)O-CeC 8 aikYlk -C(Y)NHKC- alkyl), or C 1

C

4 haoaiky

R

1 R R 5 and R'' are each, independently, H-, halo, C:&g alkyl, C-Cs alkenyl. C 2 -Cs aikynyl,

C

3 C cycloalkyl, CC 5 haloalkyl hydroxy, OR". alkoxyalkyL C(0)-alkyl. C(O)O-alkyi C(O)N-alkyl hydroxyakyl NR R ", CN, NO> heterocycloalkyt arl, or heteroary wherein said aryl and heteroaryl can be substituted with one or more substitnents selected from CQ alkyl, halo. CAC haloalkyl, and 5 alkoxy; or R' and R) together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom: RE and R are each, independently, H, halo. CA> alkyl. C-C alkenyl, C-Q alkynyl CrCy eyeoalkyl. C -C 2 haioalkyt alkoxyalkyl. hydroxy, C(O)-aIkyl, C(O)O-alkyl, C(O)NH-alky, or hydroxyalky, or It and R together with the carbon atom to which they are attached form a CC7 0 vebo alkyl eroup. R" is H, CyCs alkyl, C C aikenyl, C-C 2 alkynyl C 3 C cycloalky, CIA> haloalkyl, aralkyl, aryL heteroaryl heteroarylaikyl, or allyl; and R and R" are eaeh, independently. H. CrC alkyl, C-C alkenyl, C-C alkvnyl, CrC cycloalky l C:Cs haloalkyl, aralky Larl, heteroaryL heteroarylalkyl, or allt or R 0 and R" together with the N atom to whieh they are attached form a heterocyclic ring; comuprisang reatin a cm d of Formula XI: R' Rb R Xl whrn >2is a leaving group. I) wt a compound of ormula OH for a time and under conditions suitable for forming said compound of Formula X. The present disclosure further provides a process for preparing a compound of Formula V or salt 5 thereot wherein: I i~s H or C:42s alkyl; R) is Cr4> alkyl, -C HrO-(C rC 2 alkyl), C(O)O-(C 1

-C

2 alkyl), -C(O)NH-(C 1

-C

8 alkyl), or CeC 4 haloalkyl; 17 R R o and RP are each, independently, H, halo, C C 8 alkyL C 8 alkenyl, CrCg alkynyl, Q-C cycloalkyL C-C 8 haloalkyt hydroxy, OR", alkoxyalkyL C(O)-alkyl. C(O)O-alkyl C(O)NH-aikyl, hydroxyaikyl NR RR, CN, NO> heterocycloalkyl ary or heteroaryl wherein said aryl and heteroarvl can be substituted with one or more substituents selected from C-C 9 alkyl, halo. C-Cs haloalkyt and S alkoxy; or R, and Rt together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one 0 atom; R and R' are each, independently, H. halo, CCs alky C-C alkenyit, C-Cs alkyny, CrC cv cloaik l. CC haloalky l alkoxvalkyl hydgroxy. CO)-alky, CiO)O,-aikvl LC(O)NIT-alkyt or hydroxyalky1, or R" and R together uwithe carbon atom to which they are adached tAnn a CC; 0 eveloakyl group; R' is H C00 alkl CC alkeny CC alkynylCC cyckolkyl C haloalk, arakyl, al heteroaryl heteroariay or AL and Rm and 1 ale each, independently. H, C-Cc alkL C alken' L C-C4 alkynL CrC cc cloalkylL C -C, haloalky L aralkv L aryl heteroarvi. heteroarvlalkyl or ally L or R' and R" together Wth 5 the N atm to which they are attached form a heterocychc ring: comprising: a) reacting a compound of Formula X or salt thereof; with a halogenating/sulfonating reagent for a time and under conditions suitable for forming a compound of Formula IX or sah thereof; wherein X 2 is halo or SOR' and R" is C-C alkyl, aryi or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C,-C 4 alkyvL Cr-C 4 haloalkyl, C 1 -4 alkoxy, or C-C 4 haloalkoxy; and b) reacting said compound of Formula QX with a cyclizing reagent for a time and under conditions suitable for forming "aid compound of Formula V. The present disclosure further provides a process for preparing a compound of Formula V or salt thereon R' is 1- or C,-C 8 alkyl; R- is C 8 0 alky4. -CHrO-(CrCS alkyl), C(O)O-(C-C 8 alkyi), -C(O)NH-(CrC 8 alkyl), or C-C 4 hakoalkvl: R0 RW R , and Rt are each, independently, H, halo, C-C 8 alky, C-C alkeny, C-C 8 alkynyl,

C-C

7 cycloalkyl C rC 8 haloalky hydroxy, OR< alikoyakyL C(O)-alk-yL C(O)O-alkyl C(O)NH-alky L hydroxyalkyl NR<R", CN, NO> heterocycloalkyl, ary. or heteroary, wherein said aryl and heteroaryl can be substituted with one or more substituents selected from Cr.- alkyl. halo, CC haloalkyl, and alkoxy; or R t and R" together with the atoms to which they are attached form a 5- or 6-member 3 heterocyclic ring having one 0 atom: K> and H ae eac, indepen dent ,a alkl C ak C-CKylC cylolkl.CI-C 8 n haloalkyl, aikoxyall hyvdr-ox. COllk C"(O")-alkvl C()Lakl or hydroxyalkyL or R' and R" together with the carbon atom to which they are attached form a Cr-C, cycloalkyl group; R4 is HE CrCs alkyl. QC~ alkenyi, C 1 Cs alkynyl, CrC< cycloalkyl, CrC 3 haloalkyl, aralkyt, aryl, hete roaryl. heteroarylalkylt or allyl; and

R

0 and R " are each, independently, H, 0C 5 aikyl C-Ce alkenyl, CPC alkynyl, CrC alky[ Ly aralkyl. aryL heteroaryl, heeroarylalkyl r ally or R and R" together vth the N atom to which they are attached form a heterocyclic ring comprisng: a) reacting a compound of Formula XI: R"

R

4 R wherein X, is a leaving group, with a compound of Formula; orl heofor a time anunde condiion s sutabe for coming a compound of Formula X orsaltthrorf; h) reacting said compound of Formula X with a halogenating/sulfonating reagent for a time and under conditions suitable tor forming a compound of Formula IX or salt thereof: 20 wherein X is halo or SOR" and R" is C-C 8 alkyL aryl or heteroaryl each optionally substituted by one or mote halo, cyano, nitro, C-C 4 alkyl C-C 4 haloalkyl. C-C 4 alkoxy, or CrC 4 haloalkoxy; and C reacting said compound of Formula IX with a cyclizing reagent for a time and under conditions suitable for forming said co mpound of Formula V, The present disclosure further provides a process for preparing a compound of Formula V or sal 'wherein: R. is H or C 1

-C

8 alkyl;

R

2 is C C alkyl, -ClrO-(C 1 -C alkyi\ C(O)O-(C-C 8 alkyl) -C(O)NH~(C 1 Cs alkyl), or C-C 4 haloalkyl; R R and R are eaCh, independently, HI halo, C 8 s alkyl. C - aiLenyl CrCs alkny CC,- ycloalkyI CrC> haloalkyl hydroxy, OR?, alkoxyalkl, C(O)-alky L (0)-alky. C(O)NH-alkyt hydroxyalky, NR"R 1 , CN NO> heterocycloalky, aryi or heteroary, wherein said ary and heteroaryl can he substituted with one or more substituents selected from C 1 C% alkyL halo, CC 8 haloalkyl, and S alkoxy; or R' and R 5 together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having oue O atom: Ra and RN' are each, independently, H, halo, C1-s alkyl C 2 C alkenyl CrCs alkynyl C-C 7 cycloalkyl, CQ haloalkyl, alkoxyalky. hydroxy, C(O)-alkyt C(O)O-alkyl, C(O)NI-alkyl, or hydroxyalkyL or IR and R" together with the carbon atom to which they are attached form a C3C7 cycloalkyl group; R" is H CC> alky b CC alkenyi& C1C alkynyl. Cr-C cycloalkyl, C-C haloalkyl, aralky t aryl heteroaryL heteroarylalkyl or ally; and R and R" are each, independent. H. C -0 alkyl Cr-C 8 aikenyl, CC> alkyny, CrC c yC alkytI C-C, haloalkyt, aralkyL ary> heteroaryl heteroarylalkyL or ally or R 1 and R together with 5 the N atom to which they are attached form a heterocyclic ring comprising: a) reacting a compound of Formula XII:

R

4 RR OH Rb R 8 b' R 8 a XlI 0 with a halogenating/sufonating reagent for a time and under conditions suitable for orming a compound of Formula Xl wherein X9 is a leaving group; b) reacting saiompound of Formula X1 wih a compouind ofForul: OH 25 or salt thereof, for a time and under conditions suitable for forming a compound of Formula X or salt thereol? c) reacting said compound of Formula X with a further halogentig/sulnaig reagent for a time and under conditions suitable for forming a compound of Formula ,X or salt thereof wherein X: is halo or SOR" and R is CC8 alkyL aryl, or heteroaryl each optionally substituted by one or more halo, cyano, nitro, C Ca alkyl, C-C4 haloalkyl CrC 4 alkoxy, or CC 4 haloalkoxy; and d) reacting said compound of Formula IX with a cyclizing reagent for a time and under conditions suitable for frrming said compound of Formula V. The present invention further providves a compound of Formula IX or X or salt orm tereof. 5 wherin: R is H or C 1 -C alkyl;

R

2 is C-CR alkyl. -C M-O~(C 1

C

5 aikyl) C(0C0-(C7C 8 alkyl) -C(0)NH-(C alkyl), or CMC haloalky I: R,. R and 10 kre each, ndependemly. H. halo, CC, alkylL 0C1n alkeny C-Cs alkyni o Ct-C 7 Nycloalkyl, C 1 .C haloalkyt hydroxy, OR alkoxyalkyl C(O-alkyl C(O)O-alkyl C(O)NH-a kyt hydroxyalkyl, NRtR" Cx, NO heterocycioalkyl aryl or heteroaryl wherein said ard and heteroaryl can be substituted with one or more substituents selected from CC aklkl halo. CC haloalkyl, and alkoxy; or Rf and R together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one O atom; $ R and Rt are each, independently, R, halo, CEC 8 alkyl, C -Cgalkenyl, CrC 8 alkynyl C-C cycloalkyl CIC haloalkyl. alkoxyalkyi hydroxy, C(OhalkyL C(O)O-alkyl C(O)NH-alkyt or hydroxvakyi. or R" and R" together with the carbon atom to which they are attached form a CC 7 cycloalkyl group; R" is H, C-C 5 alkyl, C-C 8 alkenyl, C-C alkynyt CQCs cycloalkyl, CrC haloalkyt, aralkyl o aryL heteroaryi, heteroaryl alkyi or allyl; REU and R'' are each, independently, H, CrCS alkyl C-Cs alkenyl CEC alkynyt C 1 CT cycloalkys C-C 8 haalky L aralkyI aryL, heteroaryt heteroarylalky n or allyl. or .RN' and R" together with the N atom to which they are attahed form a heterocyclic ring; and X is halo or SO 2 R"; and R" is C 1 C alkyl, aryl, or heteroaryi each optionaly substituted by one or more halo, cyano, nitro, CC alkyl, C-C 4 haIoalkyl, CEC. alkoxv, or' CC 4 haloalkoxy. ihe p resent disclosure further provides a method of resolving a mixture of compounds of Formula Va and Vb: NR R" R' is H Mr CQW alkl; W 21,

R

4 is Ce- 0 s aikyl.t -C~b-O-(C -Cs alkyl}, C(O)O-(C-Cs alkyl), -C(O)NH10C-Cs alkyl), OH, Cr ( " haloalkyl, or CH OHKI R R " and Iare eack independently HK halo, C(:43 aNyl CQ&alken Q& aikynyl CG cycloalky Cs haloalkyl hydroxy OR alkoxyakl, 0(O)alky 1 C(O)alkvl C(ONH-alkyl 5 hydroxyaIkyl, NRR K CN NO 2 heterocycloalkyl aryl or heteroaryl, wherein said aryl and heteroaryi can be substituted with one or more substituents selected from C-CI aikyl halo, C-CR haloaiky, and alkoxy; or R and R together with the atoms to which they are attached torm a 5- or 6-member heterocyclic rinA having one 0 atom: R and R are each, independently. 11, halo, C,- alkyl C-Cs alkenyl, C3Q alkynyl, CC o cycloalkyl C-Cs haloalkylt alkoxyalkyl, hydroxy. C(O)-alkyl. C(O)Oalkyl C(O}NH-alkyl, or hydroxyalkyl or R 0 and R together with the carbon atom io which they are attached form a CQ cyci oalky1 group; RI is H, C1-Cs alkylt-r5 alkenylt C,-Q alkynyl. C3rC cy'cloalkyi, Cr- 0 s haloalkyl, aralkyl. aryl, hetemary L heterarvlalkyL or alM: and RC and ' arc each, independently, H, ClCs alkyl, C s alkenyl, CCs aikynyl, C3CC cyc lo(alkyl, C-Cs haloalkyl araiky aryl, heteroaryl, heteroarylalky or alY! or R" and R" together with N atom to which they are attached form a heterocyclic ring: comprising cntacting said ne of compodds wAth a hal resong acd to fornchirale n acid salts of aid compntds wherein said chiral resoing acd comprisesubstantially oneseoisom and precipating said ciral resoving acid salt said cmponsds erein the rsutingpecipiate is enriched in he chral rson acisalt ofone osad compounds of Form Va w O, The present diclsure furher pIovides a chiral resolving acid sat of a compuAnd of Formula Va or Vb .5 wherein

R

1 is H or ( C alkyl RI s C -CV ail C117-07NC al kyl), C(O)O-(r( , alk Iky -C(O)NH-(C1 -2 aikyl)) OH. Q C4 haloalkyl- or CH1OH: R'. it R' and R arc each, i independently, I halo, Cl-C alkylL C-C alkeny CC alkyny, 30 (-C cyctoalkyl C14 haloalkyt hydroxy, 01R alkoxyalkyl, C(0)-alkyL C()O-alkyl, C(0)NH-alkyl, hydroxyalkyl NRR CON. NO 2 heterocycloalkyl aryl or heteroaryL wherein said aryl and heteroaryl can be substituted with one or more subst ituems selected from Ct-Os alkyl, halo, C-C haloalkyl. and alkoxy; or R" and IR together with the atoms to which they are anached form a 5- or 6-member heterocyclic ring having one 0 atom; 35 Rt an d Rt are each, independently, , halo, CCs alkyl C2-0 alkenyl C-Cs alkynyl C3KC cyclo alkyt, C e-Q haloalkyl, aiknxyalkyt. hydroxy, C(O')~alkyl 0 (0)O-alkyl. C(O)NH--alkyt, or hydroxyaikyl, or R" and R" together with the carbon atom to which they are attached form a Cr-Q cyc oalkyl group; R is H, C 1 -C alkyl, QC 8 alkenyl, CC 8 alkynyl, Cr-C 7 cycloalkyl, C-C, haloalkyl, araikyl, aryl, b.eteroary, heteroaryl alkyl, or ally1; and R' and R" are each, independently, H, CC, alkyl, CCa alkenyl. CC alkynyiC 3 -& cycloakyL C!-C haloalkyl. aralkyl, aryl, heteroaryl, heteroarylalkyl, or allyl, or RV and R together with the N atom to which they are attached fbrm a heterocyclic ring.

DETAIED DESCRIPTION OF EMBODIMENTS OF THE INVENTION The processes and inrermedates of the present invention are useful in the praparation D therapeutic agents or the treatment or prophylaxis ofA 5-T mediated disorders such as obesity and oter central nervous system diseases. Example processes and intermediates of the present disclosure are provided below in Scheme I, wherein constituent members for the compounds depicted therein are defined hereinbelow. The symbol * " designates optionally chiral centers that can he substantiallv retained or inverted over the course of the depicted reactions. Sdem RT7 y 7 R'2 R< / cyclizat on ini reductioncytti0 it 2t isQ ly -P- T kyyC U 1 1 ) C lila R20 cyclization R 3 rdcion The present disclosure provides processes. such as are exemplified by Scheme L. that involve compounds of Fornmulas 1, Ia, lb, IL ill, illa, and IV. or salt forms thereof, wherein: 15 ~ R' is Hi or Ce-Ca alkyl; R is CeCs alkyi, -CH 2 rO-(C 1

-C

8 alkyl), C(O)0-4C 1 Cs aikyl), -C(O)NH-(C--Cs alkyl). OH, C C4 haloalky L, or CH2tOH; RR N and R 6 are each, independently. H, halo, C~ alkyiL Ca-Ct alkenyl, Cr-Cs alkynyl, Cr-C2 cycloalkyl, C 1 -Q halualkyl, hydroxy, mercapto, OR 9 , SR, aikoxyalkyl, C(O)-alkyl, C(O)-alky L C(O)NHaky hL bydroxyaIky, NR'R CN., NO heterocycloalkyl, ayl, or heteroaryl wherein said aryl and heteroaryl can be substituted with one or more substitucnts selected from C-Cs alkyl halo, Cj-Q haloalkyl, and alkoxy; or R 4 and W together with the atoms to which they are attached form a 5- or 6 member heterocyclic ring having one 0 atom; R arnd R* are each, independently, H, halo, CCAA alkyl Cg aikenyl, Cr-C alkynyl. Cr-C cyckoyaIKy C 1 -Q hakna ikyl, alkoxyalkyl, hydroxy, C(O)-alky I C(O)O-alkyl, C(O)NH-~alkyl, or hydroxyalkyl, or R" and R' together with the carbon atom to which they are attached form a C-C, cycloalkyl group; R and R " are eachl, independently, H. halo, C Cs alkyl, CirC alkenyl CCs alkyn,& CrC cy'cloalkyl C-Cs haloalkyl alkoxyakyl, hydroxy, C(O)-alkyl, C(O)O-alkyl, C(O)NH-alkyl, or hydroxyalkyl, or R" and R$ together w uh the carbon atom to which they are attached form a CI-s cycloalkyl group: RW is H, Cr-s alkyl, ClCs alkeny, C-Cs alkyny, C 3

C

7 cycloalkyl, (C 8 haloalkyl, aralky, ary , heteroaryL heteroarylalkyl or allyl; R n and R" are each, independently, H, CCa C alkenyl, C-Cs alkynyl L ClC cvcloaikyl, C-5 haloalkyL aralkyL aryl heteroaryl heteroarialkyt or allt or R 0 and RK together with the N atom to which they are attached form a heterocyclic ring; L is halo, hydroxy. C-Ch alkoxy. C 1 -Cj thialkoxy, C-Ch acyloxy, -OSO 2 R, or -OSi(R'b R is Ct alkyL arl o heterua ach otional subsnted by one or mre hao eanonitro,

C-C

4 ail C-4 haloalky. C- akoxy, or C- haloalkoxy; and In sonmembodiment it' is C7-C alkyl-H-O(d ak C(O)O-( alkyni N 1

-C

5 alkylV OH. or R8 and Re are each II and are eac independently halo. CC haloalkyl, hydroxe, O1t SR 9 aikoxvalkv NHRC NR 0 R arvl or etoary, rein said ary can besubstitued with p to to sbstituents i selected from C-Cs alkyl, halo, CrC haloalkyl. and alkoxy, and said heteroaryl can he optionally substituted with up to two substituents selected from halogen and C-C 5 alkyl; or R 4 and R together with the atoms to which they are attached fbmn a 5- or 6-member heterocyclic ring having one 0 atom; R' isi; R(U is H- or Cl-Cs alkl; R and Ru are each H; and IU and R " are each, independently, C-Cs alky i C lC alkenyl, Cl-Cs haloaIk L, ary, hereroa.i araikyl, heteroarylalkyl, or alyl.

In some embodiments, (A) if R, is methyl and R4 is 41, then R is not thiazole, substituted thiazole or a thiazole derivative; i sonme embodiments, (B) if R is H and Rb is other than H, then neither R nor R' can be H; In some embodiments, (C) if R and R 2 are nwthyt, and R' is H then R' is not NHR'm or NR'"tR In some embodiments, (D) if R and R2 are methyl and R 5 is H, then R4 is not imidazolyl. substituted imidazoly , or an imidazole derivative; In some embodiments. (E) if R, is 1 or CNh and Rl is Cl-4 or OH, then R R RA and R" cannot all be H. In some embodiments(F) if R is H and R is isopropyl or 01, then it and R 5 cannot both be OC~ieor OH. in some bdinntsif' is Cl- and R 2 i propyl then R cannbeOH. R' cannotC and R and V cannot both h l in further embodiments, R' is . In further embodiments, R' is Ce-C 8 alkyl in further embod iments, R2 is methyl ethl, n-propyl, or isopropytL In further embodiments, R is methyl In further embodiments. I4 is Cl, Br, haloalkylt CO. thiophenyvL furanyt. pyrrolyl, pyrazolyl, or imidazoly L in further embodiments, R' is CL. In further embodiments, R is methoxy. ethoxy, n-propoxy. isopropoxy, allyloxy, thiopheny1, furanyl, pyrrolyl, pyrazolyl, hnidazolyL or phenyl, wherein said imnidazoly is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituents selected from CC alkyl, C-C haloalkyl halo, and alkoxy. I further embodiments, HR is H. In some emibodimnts: is C1117 C alkyl, -C1 -O(- alkyl), CV haloalky, or CHM : R", R1, and Hare each, idependently, Hhalo, ak alk CC ha ndll, hydroxy , 30 CN. or NQ 2 and Ra H 2 R and R" each H. In some embodime when R s Malky 4 #C 1 alky), or CHOH thend I and R are rot both I; and 35In some embodiments. () when I is ClH then R R and R are each I and R is not R or isopropyi. In further emnbodimems. R is H 26 In further erbodiments, R is C-Cs alkyl In further embod iments, JRL is C-Ca alkyi or C -C 4 haloalky L In further embodiments, Rt is methyl ethyl, isopropyl, n-hutyL or CF, In further embodimens,R R . and R" are each, independently, H, methyl, N-, CN halo, CV. NO). or OH, In further embodiments, FR JR tR and 1R are each H, in further ehodiments, R 3 and R 6 are each H. In further embodiments, R 5 R and R 6 are each H. In further erbodiniems., lR o is halo. In further embodiments, R' is CL In further em odiments, R is CC 4 alkyl In further embodiments, Rt is methyl in further embodiments, R is H, in further embodiments, R 1 is H or CC4 alkyl, R 2 is C 1

-C

4 askyl, R 3 is H, R 4 is halo, R is H, JR is H, R'M is H. JR' is H, Rt is H, and Rit is 1-1 In further embodiments, JR 1 is H-, Rt is Me, JR 1 is H-, JR 4 is Cl, JRd is H, JRd is H, JRN is H-, JR' is & R II s I, and I ist Infurter enmbodiments L ishalo. In further embodimens.Is is hydroxy. In further embodiments. -I is CL In uher embodi mern C is Br. Ifurther embndiments. . isO -0 2 R such as suifonates (egmesylate, rifate. methy sui mbate)i S ln frther embodiments, V.is-Oi(R} such as tniethyiviy. in furter embodients, th compng d ofl Formua I hasan S confiuration at th carbonlbearing Ifuther embodiments, he compound of Formuan Ihas an R? cofiguration at the carbon bearing The present disclosure provides a process fur preparing a compound of Formula I: R3 \, R4I

-N,

or salt form hereof comprising reacting a compound of Formua a : R2 RR RR

R

6 Raa H with a reducing agent optional in the presence of a Lewis acid for a time and under conditions suitable for forming the compound of Formula I or salt form thereof. In some embodiments, the reducing agent comprises a borane such as BIT In further embodiments, the reducing agent comprises a metal hydride such as a borohydride or aluminum hydride. In some embodiments., the reducing agent is BH;THF. Other reducing agents are suitable and can be selected by one skilled in the art. Example suitable reducing agents are compounds that selectively reduce the amide moiety of the compound of Formula IIl in further embodiments, a Lewis acid can be present in the reaction in an amount sufficient to increase reaction rate. Suitable Lewis acids include boron-containing Lewis acids such as BF, and adducts thereof including BFjTBME (t-butyl methyl ether); BF O t; BF 3

:O(CH

2 CH2CH 2 CIt: BF:T.HF; and the like. Suitable amounts include fromo.e about 0N eq t about I eq relative to amount of compound of Formula II. Due to potential sensitity of the rducing aen to air, the reaction can be conducted under an ~nert atmosphere. Reacting an be cared out in any inrt sovent such as a dialkyether or cycli ether e.g TH 0 at anysuitabletnperaite sc as rom temperature The duraon ofthe reduto a b rdou for mout me determinedb one skiled in the art In some embodimens he reacton duration i sumiient to allow the reacton to go substantalto c neion. For ample action durations canl range from about 10 minutes to about 8 hos. soma bodmens he raion duration s about 12 hours, Reain completion can be monitored f example by LQMS, 25 The amount of reducing agent provided is typicaly sufficent to provide at kast enough reducing equaivalens to reduce the compound of Formula I to e desired product Forexampl an excess of reducng agent can be provided suh as about , abom 5x about R, on about 2x recng equivakt excess. For boranes and eleod reducing agents, the molar rato of redcing agent to e compound tf Formula [[ can be, for example abott 2:1, about 3 about 21 or about 0:1In some emnbodiIent, the ;P molar ratio is about 3:1. some embodiments, te yed for the rduction reaction based on amount oopound of Formula B) i greater than about 50, about 60%, about70%, about 80%. or about 90%.

The present closure further rovids a process preparing a conpoundof Formula 1i or form thereof, comprising reacting a compound of omula Il P11 C

P

5 NP or salt form thereof, with a cyclizing reagent for a time and under conditions suitable for forming the compound of Formula I or salt form thereof. In some embodiments, L of the compound of Formula itI is halo. In further embodiments. L of the compound of Formula III is Cl, In som erembodiments, the living reagent includes a wis acid, such as Or example a C-Qs alkyl aluminum halide (e.g., methyl aluminum chloride, ethyl aluminum chloride, etc.), a C 1 , dialkyl aluminum halide (eg. d imethyl aluminum chloride, diethyl aluminum chloride, et.) trialkylaluminum,

AICI

3 or AlBr 3 In some embodiments, the cyclizing reagent is AICI. Other suitable cyclizing reagents include acids such as sulfuric acid. Cclization can be carried out in the absence of solvent or in the presence of solvent. Suitable solvents include non-polar or weakly polar solvents such as decahydronaphthalene or 1,2 dichlorobenzene, Other suitable solvents inl ude haloalkanes and other halogenated amomatics such as I dichlorobenzene and I4-dichlorobenzene. The cyclizing reanent can be provided in an amount suitable for maximizing the yield of the () cyclized product. In some embodiments, the cyclizing reagent can be pros ided in molar excess relative to the amount of compound of Formula lit Example molar ratios of cyclizing reagent to compound of Formula Ill include about 2:1 about 3:1. about 5:1, or about 10:1 In some embodhnents, the molar ratio is abom 3:1 In further embodiments, cyclization is carried out at elevated temperature such as at about 80 to 23 about 160 *C. in some embodiments, eyclization is carried out at about I50 CC. The cyclization reaction can be monitored by LC/MS. Duration to substantial completion can be about 10 minutes to about 24 hou, in some embodiments reaction duration is from about 3 hours to about 15 hours, income embodiment the yiel r the eiion reaction (based on amount of compound of Formula lilt is greater thanmabout4%, about 50%, about60% about 0%. about 80% or about 90%. Th present disclosure further provides preparng a compound oFomua ll comprising rating compoundformna PV RN R R Rs

R

8 ' R 8 PV or salt orm thereof, wih a compound of F ormu a: 0 wherein Q is a leaning group, for a time and under conditions suitable for forming the compound of Formula III or salt form thereof. According to sonic embodiments. Q is hydroxy, alloxy. halo, or O(CORX wherein R is CC alkyl, CJC? cycloaikyt aryl, heteroaryl, or heterocycloalkylt in some embodiments, Q is halo such as Cl. In other embodiments, Q is hydroxy, In yet other embodiments, Q is alkoxy, such as methoxy, ethoxy, or t-butoxv. Atide formation can be optionally carried out in the presence of base such as an amine (eg NMe, N~b, nm"orpholine. pyridine, iisopropyiethyiamine, piperidine, N,N-dimethylaminopiperidine, and the like). Other suitable bases include inorgaui bases such as NaOH, KOlH CsOH, and the like. Relative amounts of reagents suitable for carrying out the reaction include about molar 5 equivalents of each. For exampk, the m formation reaction can be carried out w ith a molar ratio of compound of Formula TV to compound of Formula: C L of aboul in father embodiments an qAvaent amount of ban ian Aso be lded| olar ratio of about 1:e1:1 In vt further ombodincn base can bedded excess relative to the amount of ?0 compound of Formula !V. In further embodiment the anide formaton reaction ca be carded out in solvent suca polar soent Anample oa polr vent is aconile Renart temperature can vary om bout -10 to about 30 N , In som embodents, tie reaction can start a emperatum below room nempratire sich as about 0 "C and fr the reaction diation rise o about rooI temperatue Reaction progress can be 25 mniored foexmp b and time to completion can be fom Aot 10 nutesto about 5 hours. depending on, for example sca I of the acton.

ln some embodimenms. the yield for the amide formation reaction (based on amount of compound of Formula 1), is greater than about 40%. about 50%. about 60%. about 70%, about 80% or about 90% IU an aieriate route to compounds of Formula i the prescnt invention provides a process for preparing a compound of Formula I: NRR RD or salt fbrm there, Or reac in r a compound of Formula Ll a: P3 R~ R 7 N

R

6 P~ RS NR with a cyclizing reagent for a time and under conditions suitable for forming the compound of Formula F in some embodiments, L of the compound of Formula lla is halo. In further embodiments. L of the compound of Formula ia is Br or CL In some embodiments, the cyclizing reagent includes a Lewis acid, such as, for example, a Cj&, .5 alkyl aluminum halide (e.g, methyl aluminum chloride, ethyl aluminum chloride, etc.), a C 2 CS dialkyl aluminum halide (e.g, dimethyl aluminum chloride, diethyl aluminum chloride, etc.). trialkylaluninum,

ACI

3 l or AlBr;. Other suitable cyclizing reagents include acids such as sulfuric acid. Cyclization can be carried out in ihe absence of solvent or in the presence of solvent. Suitable solvents include ion-polar or weakly polar solvents such as decahydronaphthalene or 12 20 dichlorobenzene. Other suitable solvents include haloalkanes and other halogenated aromatic such as I1,3-dichiorobenzene and 14-dichlorobenzene, The cyclizing reagent can be provided in an amount suitable for maximizing the yield of the cycl ized product. in some embodiments, the cyctizing reagenit cant be provided in molar excess relative to the amount of compound of Formula lila. Example molar ratios of cyclizing reagent to compound of 25 Formula Tlla include about 2:1, about 3:1, about 5:1 . or about : i, in some embodiments, the molar ratio is about 1 In further embodiments, cyclzation is carried our at elevated temperature such as at about 80 to about 160 NC in some embodiments, eyclization is carried out at about I 40 C. The cyclization reaction can he monitored by LC/MS, Duration to completion can be about 10 minutes to about 24 hours. In some embodiments. reaction duration is from about 3 hours to about 15 hours. In some embodimens the field for the cyclization reaction (based on amount of compound of Formula lla}. i greater than at 40% about 50%, about 60% about 70%. about 80, or about 90% The present disclosure further provides a process for preparing a compound of Formula lila. or sah form thereof. comprising reacting a compound of Formula ii: Rb R with a reducing agent optionally in the presence of a Lewis acid for a time and under conditions suitable for forming said compound of Formula Illa. in some embodiments, the reduction of IIT can be carried out so that the stereochemistry of one or more chiral centers present i the compound of Formula I is substantially retained in the reduced product (Formula ITla). In further embodiments, the reduction of lila can be carried out using a substantially pure stercoisomer of lILa, In yet further embodiments, the reduction of 'ia can be carried out using a substantially pure stercoisomer of ila and resul in a substantially lure stereoisomer of ilt For example, a compound of Formula il having ee of greater than about 8O, about 90, or about 95 % can ) reduced to form a compound of Formula Hia having a similar ee. In some embodiments, the reducing agent comprises a borane such as Bis In further embodiments, the reducing agent comprises a metal hydride such as a borubydeide or aluminum hydride. In some enbodiments, the reducing agent is BS-:THF, Other reducing agents are suitable and can be selected by one skilled in the art Example suitable reducing agents are co pounds that selectively reduce the amide moiety of the compound of Formula HL In further embodiments, a Lewis acid can be present in the reaction in an amount sufficient to increase reaction rate. Suitable Lewis acids include boron-contaming Lewis acids such as BF 3 and adducts thereof including BF:BME (b-butyI methyl ether); B 3 :OETi BE: O(CH 2

CH

2

CHCH

3 h:;

BF

3 :THF; and the like, Suitable amounts include from about 0.01 eq to about 1 eq relative to amount of compound of Formula 11. Due to potential sensitivity of the reducing agent to air, the reaction can be conducted under an inert atmosphere.

The eduion reaction can be caned out in iet solvent such as adiakether or cyclic ether e, IF) at an sutiae temperate, snh asroo temperate. Te duration f thereducton can be cariedout for any amount of mCe In some enibodients the reaction duration is sufient to allow be reaction to go substaay o completion For example reaction duration can range front about 0 minutes to about 72 h s In some embodiments the reaciaduration isbou ho eacon completion can bee nmonitored, for example. by it/MS. The amount reducing agent provided is tyiall suicien o provide at ast gouged ng equialets t reucetecmon of Formul U to Te desred podct For example, ;a excess o~f reducing Dagen can be provided such as about 1 Ox, $x, X or &x reducng equivalent excess. For boranes an eated reduing ages the molar rato freducng agent to the compound of Fomula 11 can be. forn example. 2:1, 3:1. 5:. or 101 in sone embodients, the moar rao is 3:1. Isome embodimenthe ielid for the reduction eati (based on amount of compound of Frnma I) is greater han about50%, bout 60%, about 70%, about HW or about 90% The present disclosure further provides processes provided below in Schemes Ta, lb and Ic, wherein constituent members of the structures depicted therein are defined above. Scheme a R3 R reduction yclzaon RR Rl' cy CtZation Rl \ edl 2 0 NP

RS

5 R R Scheme lb P0 p8a R~

R

4 ~ A A 4 NR~ NM - ~ y 'N Ii coupling N ~~AA T 'N<A 'N A pS ~?S - 'N ,A

R

1 HN' 7$ P0 R'~ pEt / reduction { cyclization

P

2 pBS C / / / / P0 ~AA NY 'N 'NM 'N~z>A NN\A ML ;NP~ P0 N'Nx~X R'~ P' 0 P' R 8~ \ Re cyciization P0 reduction P" N / NNX&AN~., / P0" NRBS Pb Scheme Ic

P

3 RB R 2 pEe pEt / pA ANHP N A 'N. reductive P 4

NP

1 L N amination o A II - A Rb H~ 2 pEt Rb 1~ 2) reducing agent, (eg~. NaBH 4 ) // cycft~ation I

P

2 RB

P

4 A 7 NP A / j I K pb pIES 34 -the embixm ets, Ie pst d sclostre prdes a method o rsvg a i of compounds of Frmus la and 1b: 2 2 RR Nb by onactngthe mue of compomunds wi a chira resolving acid enriched in one stroisomer (eg., ee grete tan about 50%, about 75%, about 90% cor about 95%) to ter Mhra resolving acid salts ofth compounds of the miture, and thn precipiatig the cAM resovng acid salsZTh resultig precipiat is typically enriched in the chiral1 rsving acid salt of." one of- the cm un o Formula:s la or Tb(eg. ee > 50%), In some ernbodiments, the precipiate is enriched in the chira resolving aci sat form of th compound of Forula aIn someembodimernts, thepcptatew i's enriched in hechni reolin cid sat fOrmn of the compound of Formula Tb. in further emoie ts, te ciral resolving acid is a stereosome o tloyl tartic acdampic c acid, ketogulonic aci,or tartaric acidJ. In further embdiens, hechralreoling ac id is a trosmrof tarta-ric acid suc h as: L()traiacd. Contacting of compounds with a chiral resolving acid can be carried out in soluin Sutable sovnssupport dissolutobn of both the chira resolvig acid and the comou d 1oFrmulas la and Ib', Some examnple sovents include polar solvent or wtrmsiesovnssuch-, a ac 4ool (e InethanouL ethanol. isopropatial, t-butanot and the like, ispoplctae ater, and mixtures thereof In further embMOdmns the solvent conains a Mixtur of t-butanol a-nd water. Soe xamnpe imixtuiresinud about 5-25 %1 water and about 75-95%v -butanot. In some embodiments, tesolve..nt contains abo -ut 8 I2 ae and about 88-92 of t-buawnt Frciitteco.natainig thechrareolvn ac itfom can be fome by precipitan from any, sutalesovet hchdisove tes-ahssus the ovn in wihcmcigwscridot Preciptatin can be induced by any method known in te art suc as by heating a solutin containig the rmxue of salt followd by coolng. Peitateca be separad frm the sovetbyor eape filtratn Enchment of the jyprecpiat in one Mhra vsal over the othr can be chaaried by an enantiomeric excess (ee) of getertan about 50%, about 60%. about 70% abou 80%,. abou 90%, about' 95%, about 984%, or about 99%, in soMmodimets ee, is grae tal but8%iPeiiato a be repeaed one or more times to inease the prooton of a chirllt in the rcptt y edsovn The presen dislosr further, provides a chra resolving acid sait of a compound of Faol La or ib cR i INH11: n Ofo R RI Ia lb wheein cnten t emesae defined hereabove Compositions of the present invention can contain oneoror both the sa fom of a compound of Formnla Ia and the at frm of a compoundm cd Fmula lb. soeembodment the a for o the compound of rmula la is present in the compositin in an amountgreater than the sal form of a compound of Formua lb. In other embodimendtsthe sa form oi te compound of Fornula 1 i psent i K co osion an amount grater than he s for of compound of Formula Ia, Further example processes and intermediates of the present disclosure are provided below in Scheme A1 where constituent members of compounds depicted therein are defined hereinbelow, The symbol * designates optionally chiral centers that can be substantially retained or inverted over the course of the depicted reactions. Scheme H haC nation INNNHR? cauplng Rhalogenation PP F 3 R FX2 ar sulfonat n HO NR? 4R? cycliata Kio 7 The present disclosure also provides processe, such as are exemplified by Scheme IM that involve compounds of Formulas V, Va. Vb IX, XL and XIL or sah forms thereof wherein: R < is HI or Ct-Ce aikyl;

R

2 is C Cs alky, -CHrO-(C 1 Cs alkyl), C(0)O-(C Cs alkyl) -C(O)NH-(Q-Cs alkyl), Ol, Cr

C

4 haloalkyl, or CHJ 5 OH; RU Ri R, and Ra are each, independently, H1, halo. Cs alkyk. C-Csaikenyl CrCs alkynyl CC1 cycloalkyl, CjC haloalkyl hydroxv, OR , aikoxyalkyl, C(O)-alvky. C()-alky. C(O)NH-alkyl, hydroxyalkyl, NRR", CN, NC> heterocycloalkyl, aryl, or heteroaryl. wherein said arl and heteroaryl can be substituted with one or more substituents selected from Cr-C alkyl, halo, Cr-Cg haloalkyl, and alkoxy or R! and R together with the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one 0 atone: R and Rb are each, independently, H, halo, C"C al Cr-Cs alkeny L CCs aikynyl, CC cycioal1kyl, C-C 8 ha]oaiky I a lkoxya Ikyl, hyd roxy, C(O)-alkLyl 0(0)0-alkL, C(O)N HI-alkylt or hydroxyalkyl, or R 8 " and R together with the carbon atom to which they are attached form a CrC, 5 yloalkyl group; RW is H, CCe alkyL Cr-C alkenyl CQ aikynyl, C-Cy cycloalky1, C-C haloalkyl, aralkyl, aryl, heteroary. heteroarylalkyl, or allyl; and R' and R"' are each, independentlyI H, ClCs alkyl, CrCs alkenyL C-Cs alkynyt C cycloalkyl, Cr-Cs haloalkyl, aralkyl. aryl heteroarylk heteroarylalkyl. or ally]. or R" 0 and R' together with the N atom to which they are attached form a heterocyclic ring X is a leaving group; X is halo or SO 7 R"; and R" is ClCs alkyl, arl, or heteroary each optionally substituted by one or more halo, cyano, nitro, C1C4 alky. CC4 haloalkyl, C-C alkoxy, or CC4 haloalkoxy. In some embodiments: R is CrC alkyl, -CH 2 -O-(C-C, alky]), C(0C-Cs alyly), -C(O)NH-(Ce alLy), OH, or 30R andP tCare each z RU and R 8 are each, independently, H, halo, Cr- 0 s haloalkyl, hydroxy, OR?, SR 9 alkoxyalky I NH R NRNR" aryL or heteroaryL wherein said aryl can be substituted with up to two substituents selected from C-Cg alkyl. halo, CQ&s haloalkyl, and xand said heteroaryl can be optionally substituted with up to two substituents selected from halogen and C-Ca aikyl; or R 4 and R 5 together wih the atoms to which they are attached form a 5- or 6-member heterocyclic ring having one 0 atom; 35H is Kt a is H or Ci-Cs alkyl:

R

5 ' and R* 5 are each H; and

RI

0 and R C are each, independently, CCs alkyL C 3 Cs alkenyL C 1 C haloalkyl, ary L heteroary L aalkl L heternay lalky L or ally in some embodiment (A) if R2 is methyl and R is H, then R is not ihiazole, substituted rhiazole or a thiazoie derivative. in some embodiments, (B) if RN is R' is other than IH, then neither R 4 nor R5 can he -1. In some embodiments, (C) if R and R 2 are methyl, and R 3 is H then R 4 is nor NHR R or NR nR". In some embodiments.. (D) if R and R2 are methyl and R is H, then R is not imidazolyl, substituted iidazolyl. or an imidazole derivative, in some embodimenms, () if R is H or CIt and R' is CHt or OH, then R:. R, R' and R cannot A he H . In some embodiments (F) if R i H and I' is isopropyl or OIL then R' and Rf cannot both be

OCH-

3 or OH, n some emhodiments, (G) if R is -' and is n-propyL, then R 4 cannot be 01-1, R cannot C, and R and R: cannot both be H In further embodiments, R is H. in further embodiments, R' is C;C alkyL. in further embodiments, R 2 is methyL ethyL n-propy L or isopropyl In further embodiments. Ri is methyl. In further embodimens, R' is CL Br, haloalkyl, Cv thiophenx L furanyl pyrrolyl, pyrazolyl, or imidazolyl. In further embodiments, R 4 is CL In further embodiments, R is methoxy, ethoxy, n-propoxy, isopropoxy, allyloxy, thiophenyl, S furanyl, pyrrol pyrazolyl, imidazolyi or phenyL wherein said imidazolyl is optionally substituted by one or more halo or methyl and said phenyl is optionally substituted with up to two substituenis selected from CvCs alkyl, CiC haloalkyt halo, and alkoxy. In further embodiments, RC is i-, 30 In some embodiments: C i C. y ay -CH OK-C aIkyC). , C ,haloa kl. or CHOI P" V R, and R" re each dependent, , halo. (77C, A)ky, C-C haloalkyL hydoxyNh CN, or NO 2 ; and R R 7 . R. and Rh are each H. in some embodiments. (H) when R3is C C alkyl, -CH104C,C alkyt or CH{>H, then R' and R' are not both H.

In some embodiments, (I) when i-h, then R Rt and R^ ae each H and R is not H or isopropyl. In further embodiments, R 1 is H, In further embodiments. R' is CrCa aikyl. In further embodiments k 2 is Cr-C> alkyL -CIO-(CC, alkyl), C(O)O)-(CC alkyl), C(O)NH-(C 1 C alkyl), or C,- haloalkyl; In further embodiments, R2 is C 1 C> aikyl or Ce-C4 haloalkyl. In further embodiments, R2 is methyl, ethyl, isopropyl, n-butyit or Cr> in further embodiments, RU R RU and R 4 are each, independently, H, methyl, NHl 7 , CN. halo. CFT, NO , or OH. In further embodiments, PR Rt R and R 55 are each H. In further embodiments, R and R are each -. In further embodiments, R RK and R" are teh H. in further embodiments, R 4 is halo, In further embodiments, R 4 is CL. In further embodiments, R s C,-C 4 alkyL In further enmbodimns R is. methyl In further embodimn is H-!. In further embodiments, X is halo. In further embodiment, X is Br. hn further enbodimelnts, X is Cli In further embodiments, X 2 is halo, In further embodiments, X 2 is Br. In further embodiments. XI is CL. In further embodiments, R 1 is H or C,-C alkyl, R 2 is Cr-Ca alkyl LP 3 is H, Rt is halo, R 4 is H. pR is H, Rp" is H, R"' is H, R" is H, and it is H, In further mbodinments, R is H. R is Me, R, is H, R is CL R5 is .H. R is H, R" is H, RN is H, JRt is H. and R is . Infurther embodimentsthecompound of Formila V has an S configuraton at the carbon bearing In further embodiments, the compound of Formula V has an R configuration at the carbon bearing Po The present disclosure provides a processafor preparing a compound ofnFormula #'

-

4 R RS RNii R6 R 8 Ra or salt thereof. by acting a compound of Formula IX: RR, RNR' or salt thereof, wth a cyclizing reagen fo a me and under conditions suitable fr forming the compound of Formula V, In some embodiments, the cyc ling reagent includes a Lewis acid, sh as, for example, a Cr7 alkyl aluminum hai de (e g., methyl aluminum chloride, ethyl aluminum chloride, etc.), a C 2 C dialkyl aluminum halide (eg., dimethyl aluminum chloride, diethyl aluminum chloride, etc.), trialkylaluminum, ACIl 3 or A (IIr 3 Other suitable cyclizing reagents include acids such as sulfuric acid. The cycizig reagent can be provided in an amount suitAbe for maximizing the yield of the cyclized product. In some embodiments, the cyclizing reagent can be provided in molar excess relative to the amount of compound of Formula IX, Example molar ratios of cyclizing reagent to compound of 5 Formula. IX include about 5:1, about 2:1. about 3:1, about :1 or about 10:1 in some embodiments, the lnar ratio is about 1 5:I Reacting can be carried out in the presence of an' suitable solvent (or in the absence of solvnt) uch as a non-polar or weakly-polar solvent or a high boiling solvent (boiling point greater than for water). In some embodiments, acting can be carried out in the presence of I ,2-dichlorobenzene. In 10 further embodiments, reacting can be carried out in the presence of decalin. Reaction temperature can be any suitable temperature such as temperatures that do not readily degrade the reactants vet maximize reaction efficiency and/or minimize reaction time. In some embodiments, reaction is carried out at elevated temperature such as, for example, between about 80 and about 170 "C. In some embodiments, elevated temperature is from about 100 to about 150 about 120 )5 to abut 530.or about140 N The eveliatn.eaction can b monitored by iMS Duratiin to completion carn be about 10 nutes: to about24hors In s om-e embodit, reactio duration is, 'from aot3hours t~oaot1 hours In rher enbodiments, reaction duration is abo 2 to j hours. Ssome embodimns, the yield for the g nation reaco (based on amount of compound ot is greater than aut 40%. about 50 about 60 about n % abou80%. or abou 90% The present disclosure further provides a process for preparing a compound of Formula IX: R3 R Ri or salt thereof by acting a compound of Formula X

R

4 HO~ RN or sal thereof with a haiogenatng/sulfnating reagent for a time and under conditions suitable for foing the compound of nornmula X. Suiable halogenatingsufonatin reagents are capale of placing the O)I moinet i the compound of Formula X with a halogen aom or sulfonate moiety I some embodiments, the h aklge nating/sulfonating reagent i SCBr 2 or SOC. The baiogenatingifontingreagent can be provided in an amant sufficient t toreically lvoduce m mm yid Suitable tmoh ratios of halogenatingsufonating reagent compound of X ormula Xinclude he ratios of about 1(4: =Mbo . abu 31, about 2:1, or aOu 1.51. In some embdimentshe molar ratio is about 1 0: ito about 1,4:1. Reacting can be carried out in any suitable solvent o in the absence of solvent, such as solvents capable of dissoing at ast one of the compound of omua X or the agenatig fo grectant. in some ehodiments, the so'ent contains DMF menthy rmamide in further embodment the 25 s ent conts ou ce In vet rather enmodimens. the solvent contains dick omethane. In some emodiments, the solvent contains dimathlformnaide and toluene, audinfeeremboiment, te solvent contins d iueths Iformaide and d ioromeanc 411 Any reaction temperature that does not substantialy decompose Te sang materis sent, or prodcts i suiable n some embodimeeactine is arred ot t temperatures such as from about -4 to aboutd0 . about i0 abou0 or abou"0 as toaut temperature In some embodients the compound of FunuaXl i ioated such as by recrytalzaton fro a s ont Yid e grea tha bout greateran about 3% greater than abou 40%, or greater than about 50%. In some embodiments. yied is greater tha aboutn(1%. The present disclosure also provides a process fOr preparing a compound formulaa X:

R

3

R

2 RHO RNRN

R

6

R

8 Re or salt therof. omprsia g reacrng a compound of Formula X I: RS

R

4 Xi S wgith a compound of Forniula: foaime and under conditions suable fbr fbrmng the compound ofFormula X The reactng can he carried out for example, ateated temperature such as frim abot 80 to S about 110 0 C or 90 to about 100 bQ in some mbodants, radg i earned on at about 95 OC' Anysuitable inert solent can he used, and in some embodmeents, reacting carried ou the absence of sent. A sufficient amount of compound of Formula: can be provided in the reatint obtain a theorica Or mialaxi id E e amnts can range from a east about molar equialen to any amoum that would be in molar xcess (eg, ab IO or I Sx) relive to the amount of compound or Formula X. Anelxanple react duatin can be from abot3 to about hours The present disclosure rather process of eparing a compoud of Formul X1 by reactng a cornpound oormula X: Rl 3

R

4 Re 6 Rb Rsa XII natig/sulfonaing reagen for a time and under conditions sitabl for forming the compound formula X. The haiogenating/sulfbnating reagent can be any suitable reagent capable of replacing the hydroxy moiety of the compound of Formula Xi1 with a sutiable leaving group such as a halogen atom or suonac noiety. In some embodiments, the halogenating/sulfonating reagent is, for example, PBr or PCT. Any suitable solvent can be used or the rating can be n ied out in the absence of solvent. eato temperatue canbe redilyseleed by heart dskiled. i some enbodiments reacig s carried out at loweredtemeratures such as from about -20 to abot 15 T% about -10 to about il "C, or S about 0 C. In some embodentsthereaction temperature is below bout0 C alogenating/sufonating reagent can be provided in amnt efficient to produce manimumi theoretical yield, For example the molar ratin o genating fonng gen compound of orlan I canrange ronm about t 21 to abouh 21. In some embodiments halogenating/ onatig reagent proved in Aght excess such as in a raio of abou . or about A, Ra In eld can be greater than au 7u greater than about r about greater than abot 95. or greaterhan about 9S%. In aome embodiments. yield is from nabout9 to about 100% in itrther mbodiments the present disclosure provides a method of resolving mixure of 3( compounds of Formuls Va and Vb: 43 R2 R2

R

3

F

2 R NR NR 1 RRRt R , RRR Va Yb by contacting the mixture of compounds with a chiral resolving acid enriched in one stereoisomer (e.g.. e greater than about 50%, about 75%, about 90% or about 95%) to form chiral resolving acid salts of the compounds of the mixture, and then precipitating the chiral resolving acid salts. The resuming precipitate is typically enriched in the chiral resolving acid salt of one of the compounds of Formulas Va or b (e g., c 50% In some embodimetshe precipitate is enriched in thie ral revng acid sat form of te c pod of F ula a In some mbodinttthe preipta is enriched ih th reso lvng acid salt frm of the compound of Formua ib In further embodied the chiral resoving id is a ster!ser of toluoyl tararic acid. camphoric acid. katoguionic acid. or tatric acd in further mbodimentshe chira reso g acid is tarta acid such as L44tartari acid, Conacting f compounds of Formnas a and b with a chiral resoAving ac an be carded out in on, Suitable solents support dissolution of boh the chira solving ac and he compounds of Formulas \a andl b. Some example solvents include polar soents or water-ascible solvents such as alcohols je, inethanol, ethand, isopropanol, tunol I-butara and the Rke) isopropyletate, rahyd ofra, acetone, methyl isobutyl ketone, water and mixtures thereof n some embodiments. the solent contains mixture of alcohol and ater In further embodients, the solent contais a mixture biofuano and waxr. Somme eampe fixtures icde about 525 % water and about 595% hutano In some embodimens sosolvent counts about 12 water and about 892% o butanoI somne enmbodimns, he slent contains a mixture otaceneand water Preiptat cntanig he cJiral eovn;cdsl forms can be formed by precipitton from any suitables which dissolves the sals such as th solvent hi conactnwa i Precipitation can be induced by any method known in the art such as by heating a solution containing the mixture of salts followed by cooling. Precipitate can be separated from the solvent by. for example, filtration. Enrichment of the precipitate in one chiral salt over the other can be characterized by an enantiomeric excess (ee) of greater than about 50%, about 60%, about 70%, about 80%, about 90%. about 95%, about 98%, or about 99%. in some embodiments, ce is greater than about 80%. Precipitation can 3 e repeated one or mor ties to cease the proportn ofa chira sl in the precipitate by re-disolving and re-precptatig previously obtaied precipitate 44 The present disclosure further provides a chiral resolng acid sal of a compound of Formula Va R R R\ N R R5R R6 b 6 R va Vih herein cnstiuentmembes are defid hereino. Compositions of the peent ivendon can conan one or or both h alt form of a compond of Formula Va and the sail m of a compound of Fomulk SInsomeembodment e sa rmon e compound of Formula an is in h cit an amnt greater than the sa form of a compound of Formula b. In other embodiments he sat forn of the compound of Frmula Vb is present in the compositin i an amount create tan the sat fA of a compound of Formula Va. The resentdosur further p desa hy ch Eaid at ofa cmpod of oma Va or 'b and compositions thereof is appreteat etai features of the invention, wich are, for rtydecried ihe exoseparate embodine may so le provided in combination in a single embodiment. Conversely various features of the invention which are. "for bevit desired te contexof a sigle emm entay al be poided sepatey o hi any suia subeombination. As used herein, e term yalk IS meant to refer to a saturated hydrocbn which is straighthaind or branded Example All groups include meathl (Me), ethyl (Ely Propy! (eAI. n propli and isro butyl ( ut sobuty tutl penyl g. n-pnt iopentineopenty), and the like. An alkyl group can contain fom to abou 20 frn 2 to about 20 from I to about 10, from 1 to about from to about ,om to about orfrom 1 to about 3cabn atoms As used herein lkenyl refers to an alk group having one or more double arbon-carbon bonds Exanle alkenl groups inde thenl prpednyl c lohexenvi and the ke, As used heein alynyrefers to an alkygroup having one or moele carboncabon bonds. Example alkynyl groups include ethynyl, propynyl, and the like. As used herein, "haloalkyl" refers to an alkyl group having one or more halogen substituents. Example haloalkyl groups include CF, C 2

F

5

CHF

2 CCI> CHiCi> C 2 CI. and the like. An alkyl group in which all of the hydrogen atoms are replaced with halogen atoms can be referred to as "perhaloalkyl." W5 As used herein, "aryl" refers to monocyclic or polycyclic aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to about 20 carbon atoms. As used herein, "cycloalkyl" refers to non-aromatic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groups can include mono-, bi- or poly-cyclic ring systems as well as double and triple bonds. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of pentane, hexane, and the like. As used herein, "heteroaryl" groups are monocyclic and polycyclic aromatic hydrocarbons that have at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-S-oxide, 2,3-dihydrobenzothienyl-S-dioxide, benzoxazolin-2-on-yl, indolinyl, benzodioxolanyl, benzodioxane, and the like. In some embodiments, heteroaryl groups can have from I to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms. In some embodiments, heteroaryl groups have I to about 4, 1 to about 3, or I to 2 heteroatoms. As used herein, "heterocycloalkyl" refers to a cycloalkyl group wherein one or more of the ring forming carbon atoms is replaced by a heteroatom such as an 0, S, N, or P atom. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the nonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl pyromellitic diimidyl, phthalanyl, and benzo derivatives of saturated heterocycles such as indolene and isoindolene groups. As used herein, "halo" or "halogen" includes fluoro, chloro, bromo, and iodo. As used herein, "alkoxy" refers to an -0-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. As used herein, "thioalkoxy" refers to an alkoxy group in which the 0 atom is replaced by an S atom. As used herein, "aryloxy" refers to an -0-aryl group. An example aryloxy group is phenoxy. As used herein, "thioaryloxy" refers to an aryloxy group in which the 0 atom is replaced by an S atom. As used herein, "aralkyl" refers to an alkyl moiety substituted by an aryl group. Example aralkyl groups include benzyl, phenethyl, and naphthylmethyl groups. In some embodiments, arylalkyl groups have from 7 to 20 or 7 to I I carbon atoms. As used herein, "hydroxyalkyl" refers to an alkyl group substituted by hydroxy. 46 As used herein, "alkoxyalkyl" refers to an alkyl group substituted by an alkoxy group. As used herein, the term "reacting" is used as known in the art and generally refers to the bringing together of chemical reagents in such a manner so as to allow their interaction at the molecular level to achieve a chemical or physical transformation. As used herein, the term "substituted" refers to the replacement of a hydrogen moiety with a non 5 hydrogen moiety in a molecule or group. As used herein, the term "thiazole derivative" refers to a moiety containing a thiazolyl group. As used herein, the term "imidazole derivative" refers to a moiety containing a imidazolyl group. As used herein, the term "contacting" refers to the bringing together of substances so that they can interact at the molecular level. 10 As used herein, the term "reducing agent" is used as known in the art and refers to any chemical reagent that carries out the reduction of another chemical reagent. In some embodiments, a reduction carried out by a reducing agent involves lowering the number of bonds of an atom (e.g., a C atom) to oxygen or sulfur. For example, a reducing agent can convert (or reduce) a ketone to an alcohol. In some embodiments, the reducing agent converts an amide to an amine. Numerous reducing agents are known 15 in the art and can be identified by comparing redox potentials of the reducing agent and the substance to be reduced. Typically, a reducing agent has a lower reducing potential than the substance to be reduced! Methods for measuring redox potentials are well known in the art. In other embodiments, the reducing agent can be an oxo acceptor. Example reducing agents include metal hydrides such as borohydrides (e.g., NaBH 4 , LiBH 4 , NaBH 3 CN) and aluminum hydrides (e.g., LiAIH 4 ) including, for example, C-C 8 20 alkyl aluminum hydrides, C 2

-C

16 dialkyl aluminum hydrides, alkoxy aluminum hydrides (e.g., mono-, di-, and trialkoxy aluminum hydrides). Other suitable reducing agents include boranes such as BH 3 or B 2

H

6 and adducts thereof. Example borane adducts include, for example, dialkylsulfide boranes (e.g.,

BH

3

:CH

3

SCH

3 ), amine boranes (e.g., BH 3 :triethylamine), dialkyl ether boranes (e.g., BH 3 :diethyl ether), cyclic ether boranes (e.g., BH 3 :tetrahydrofuran), C 1

-C

8 alkyl boranes, C 2

-C

16 dialkyl boranes, C 3

-C

24 25 trialkyl boranes (e.g., 9-borabicyclo[3.3.l]nonane), cyclic boranes (e.g., borolanes), and the like. Further example reducing agents include Red-Al and H 2 optionally in the presence of catalyst such as Pd/C. As used herein, the term "cyclizing reagent" refers to any chemical reagent that can be used in a reaction to cyclize a linear or branched molecule or portion of a molecule. In some embodiments according to the present invention, cyclization of a linear or branched moiety attached to an aryl 30 compound can be carried out using, for example, a Lewis acid. As is known in the art, a Lewis acid includes a molecule that can accept a lone pair of electrons. Example Lewis acids include hydrogen ion (a proton), boron derivatives such as BH 3 and BF 3 , and aluminum derivatives such as AICl 3 . Some example Lewis acids include C-C 8 alkyl aluminum halide (e.g., methyl aluminum chloride, ethyl aluminum chloride, etc.), a C 2

-C

16 dialkyl aluminum halide (e.g., dimethyl aluminum chloride, diethyl 35 aluminum chloride, etc.), and trialkylaluminum. In some embodiments, cyclizing can be carried out according to Friedel-Crafts alkylation chemistry which is known to follow the general transformation: ArH + RCH 2 CI - ArCH 2 R (Ar is aryl 47 and R is, for example, any alkyl, amino, or other group) in the presence of a reagent such as a Lewis acid. Friedel-Crafts reactions are typically carried out in the presence of AiC1 3 and optionally at elevated temperatures. Suitable Lewis acids include boron-containing reagents and aluminum containing reagents. Example boron-containing reagents include BH 3 , BF 3 and adducts thereof (e.g., BF 3 :TBME and 5 BF 3 :OEt 2 ). Example aluminum-containing reagents include alkyl aluminum halides, dialkyl aluminum halides, trialkyl aluminum, and aluminum halides (e.g., AIC1 3 and AIBr 3 ). Other suitable cyclizing reagents include, for example, acids such as sulfuric acid, sulfonic acids (e.g., CF 3

SO

3 H, CH 3

SO

3 H, pTSA), phosphoric acids, polyphosphoric acids (e.g., H 3

PO

4

/P

2 0 5 ), and the like. Additional suitable Friedel-Crafts alkylation catalysts include FeC 3 , TiC 4 , ZrC 4 , and ZnCl 4 . 10 As used herein, the term "halogenating/sulfonating reagent" refers to any chemical reagent that can be used to replace hydrogen or a chemical substituent on a molecule with a leaving group such as a halogen moiety or sulfonate moiety (e.g., alkyl sulfonate, mesylate, tosylate, etc.). In some embodiments, the halogenating/sulfonating reagent replaces a hydroxyl with a halogen moiety or sulfonate moiety. Example halogenating/sulfonating reagents include phosphorous trihalides (e.g., PBr 3 ), phosphorous 15 pentahalides, phosphorous oxyhalides, thionyl halides (e.g., SOBr 2 ), and the like. Other halogenating/sulfonating reagents include N-bromosuccinimide (NBS), 1,3-dibromo-5,5 dimethylhydantoin, pyridinium tribromide (pyrHBr 3 ), diethylaminosulfur trifluoride (DAST), N 7 fluorobenzenesulfonimide, and the like. Further halogenating/sulfonating reagents include sulfonyl halides such as mesyl chloride, tosyl chloride, and the like. 20 As used herein, the term "leaving group" refers to a moiety that can be displaced by another moiety, such as by nucleophilic attack, during a chemical reaction. Leaving groups are well known in the art and include, for example, halogen, hydroxy, alkoxy, -O(CO)Ra,

-OSO

2 -Rb, and -OSi(R') 3 wherein R" can be C 1 -Cs alkyl, C 3 -C7 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, wherein Rb can be Ci-C 8 alkyl, aryl (optionally substituted by one or more halo, cyano; 25 nitro, CI-C 4 alkyl, CI-C 4 haloalkyl, CI-C 4 alkoxy, or Ci-C 4 haloalkoxy), or heteroaryl (optionally substituted by one or more halo, cyano, nitro, CI-C 4 alkyl, CI-C 4 haloalkyl, CI-C 4 alkoxy, or CI-C 4 haloalkoxy), and wherein Rc can be Cl-Cg alkyl. Example leaving groups include chloro, bromo, iodo, mesylate, tosylate, trimethylsilyl, and the like. As used herein, the terms "resolving" and "resolution" are used as known in the art and generally 30 refer to the separation of a mixture of isomers such as stereoisomers (e.g., optical isomers such as enantiomers or diastereomers). Resolving can include processes that can increase the proportion of one stereoisomer over another in a mixture of stereoisomers. A mixture of stereoisomers having a greater proportion of a first steroisomer over a further stereoisomer can be said to be "enriched" in the first stereoisomer. 35 As used herein, the term "precipitating" is used as known in the art and generally refers to the formation of solid (e.g., precipitate) from a solution in which the solid is dissolved. The solid can be amorphous, crystalline, or a mixture thereof. Methods of precipitation are well known in the art and include, for example, increasing the proportion of solvent in which a solute is insoluble, decreasing 48 temperature, chemically transforming the solute such that it becomes no longer soluble in its solvent, and the like. Precipitation can be used to increase the proportion of a stereoisomer in a mixture of stereoisomers. The processes described herein can be monitored according to any suitable method known in the 5 art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 1 3 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography. In some embodiments, preparation of compounds can involve the protection and deprotection of 10 various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Green and Wuts, et al., Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, 1999, which is incorporated herein by reference in its entirety. The reactions of the processes described herein can be carried out in suitable solvents which can 15 be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a 20 particular reaction step can be selected. In some embodiments, reactions can be carried out in the absence of solvent, such as when at least one of the reagents is a liquid or gas. Suitable solvents can include halogenated solvents such as carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,l,1 25 trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, ct,cc,a-trifluorotoluene, 1,2.

dichloroethane, 1,2-dibromoethane, hexafluorobenzene, 1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane, chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride, dichlorofluoromethane, chlorodifluoromethane, trifluoromethane, 1,2 dichlorotetrafluorethane and hexafluoroethane. 30 Suitable ether solvents include: dimethoxymethane, tetrahydrofuran, 1,3-dioxane, I,4-dioxane; furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, or t-butyl methyl ether. Suitable protic solvents can include, by way of example and without limitation, water, methanol; 35 ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol. 49 Suitable aprotic solvents can include, by way of example and without limitation, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(I H) pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl 5 formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide. Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene. 10 Supercritical carbon dioxide can also be used as a solvent. The reactions of the processes described herein can be carried out at appropriate temperatures which can be readily determined by the skilled artisan. Reaction temperatures will depend on, for example, the melting and boiling points of the reagents and solvent, if present; the thermodynamics of the reaction (e.g., vigorously exothermic reactions may need to be carried out at reduced temperatures); and 15 the kinetics of the reaction (e.g., a high activation energy barrier may need elevated temperatures): "Elevated temperature" refers to temperatures above room temperature (about 20 *C) and "reduced temperature" refers to temperatures below room temperature. The reactions of the processes described herein can be carried out in air or under an inert atomosphere. Typically, reactions containing reagents or products that are substantially reactive with air 20 can be carried out using air-sensitive synthetic techniques that are well known to the skilled artisan. In some embodiments, preparation of compounds can involve the addition of acids or bases to effect, for example, catalysis of a desired reaction or formation of salt forms such as acid addition salts. Example acids can be inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Organic acids include formic acid, 25 acetic acid, propionic acid, butanoic acid, methanesulfonic acid, p-toluene sulfonic acid, benzenesulfonic acid, trifluoroacetic acid, propiolic acid, butyric acid, 2-butynoic acid, vinyl acetic acid, pentanoic acid; hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid and decanoic acid. Example bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, and potassium carbonate. Some example strong bases include, but are not 30 limited to, hydroxide, alkoxides, metal amides, metal hydrides, metal dialkylamides and arylamines, wherein; alkoxides include lithium, sodium and potassium salts of methyl, ethyl and t-butyl oxides; metal amides include sodium amide, potassium amide and lithium amide; metal hydrides include sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides include sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted 35 amides. The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated 50 in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. The processes described herein can be stereoselective such that any given reaction starting with 5 one or more chiral reagents enriched in one stereoisomer forms a product that is also enriched in one stereoisomer. The reaction can be conducted such that the product of the reaction substantially retains one or more chiral centers present in the starting materials. The reaction can also be conducted such that the product of the reaction contains a chiral center that is substantially inverted relative to a corresponding chiral center present in the starting materials. 10 Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a "chiral resolving acid" which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various 15 optically active camphorsulfonic acids such as p-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of a-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, camphoric acid, c-methoxy-ca trifluoromethylphenylacetic acid (MTPA or Mosher's acid), pyrrolidone-5-carboxylic acid, di-O 20 isopropylene-keto-glutamic acid, di-toluoyl-tartaric acid, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art. Compounds of the invention can also include all isotopes of atoms occurring in the intermediates 25 or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Compounds of the invention can also include tautomeric forms, such as keto-enol tautomers' Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. The present invention also includes salt forms of the compounds described herein. Examples of 30 salts (or salt forms) include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Generally, the salt forms can be prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack 35 Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference in its entirety. 51 Upon carrying out preparation of compounds according to the processes described herein, the usual isolation and purification operations such as concentration, filtration, extraction, solid-phase extraction, recrystallization, chromatography, and the like may be used, to isolate the desired products. The invention will be described in greater detail by way of specific examples. The following 5 examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters which can be changed or modified to yield essentially the same results. EXAMPLES 10 Example 1 Preparation of 2-(4-chlorophenyl)ethyl-N-2-chloropropionamide CI H N

CH

3 0 To a 1-liter, 3-necked round bottom flask under argon balloon equipped with reflux condenser and addition funnel, were added sequentially 2-(4-chlorophenyl) ethylamine (30 g, 193 mmol), 400 mL 15 acetonitrile, triethylamine (19.5 g, 193 mmol) and 80 mL acetonitrile. The clear colorless solution was stirred and cooled to 0 OC. 2-Chloropropionyl chloride (24.5 g, 193 mmol, distilled) in 5 mL acetonitrile was slowly added over 20 minutes to evolution of white gas, formation of white precipitate, and color change of reaction mixture to slight yellow. An additional 10 mL of acetonitrile was used to rinse the addition funnel. The mixture was stirred at 0 C for 30 minutes and then warmed to room temperature 20 and stirred vigorously for an additional one hour. The yellow reaction mixture was concentrated on the rotary evaporator to a solid containing triethylamine hydrochloride (76.36 grams). This material was taken up in 100 mL ethylacetate and 200 mL water, and stirred vigorously. The layers were separated and the aqueous layer was extracted with an additional 100 mL ethylacetate. The combined organic layers were washed twice with 25 mL of saturated brine, dried over magnesium sulfate, filtered, and 25 concentrated to a light tan solid (41.6 grams, 88 %). TLC in ethylacetate-hexane, 8:2 showed a major spot two-thirds of the way up the plate and a small spot at the baseline. Baseline spot was removed as follows: This material was taken up in 40 mL of ethylacetate and hexane was added until the solution became cloudy. Cooling to 0 *C produced a white crystalline solid (40.2 grams, 85 % yield). The product is a known compound (Hasan et al., Indian J. Chem., 1971, 9(9), 1022) with CAS Registry No. 34164-14 30 2. LC/MS gave product 2.45 minute; 246.1 M++H*. 'H NMR (CDCI,): 8 7.2 (dd, 4H, Ar), 6.7 (br S, I H, NH), 4.38 (q, I H, CHCH 3 ), 3.5 (q, 2H; ArCH 2

CH

2 NH), 2.8 (t, 2H, ArCH 2 ), 1.7 (d, 3H, CH 3 ). 52 "C NMR (CDCI): 169 (IC, C=O), 136 (IC, Ar-Cl), 132 (1C, Ar), 130 (2C, Ar), 128 (2C, Ar), 56 (1C, CHCI), 40 (1 C, CHN), 34 (1C, CHAr), 22 (1C, CH 3 ). Example 2 5 Preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one NH CI H3C 2-(4-Chlorophenyl)ethyl-N-2-chloropropionamide (10 g, 40.6 mmol) of Example I and aluminum chloride (16 g, 119.9 mmol) were added to a clean dry 100 mL round bottom flask equipped with an argon balloon, stirring apparatus, and heating apparatus. The white solid melted to a tan oil with 10 bubbling at 91 0 C. (Note: if impure starting materials are used, a black tar can result but clean product can still be isolated). The mixture was heated and stirred at 150 *C for 12 hours. (Note: The time is dependent on the reaction scale and can easily be followed by LC/MS; higher temperatures can be used for shorter time periods. E.g., a I gram sample was complete in 5 hours.) The reaction can be followed by LC/MS with the starting material at 2.45 minutes (246.1 M*+H*), the product at 2.24 minutes (209.6 15 M'+H*) on a 5 minute reaction time from 5-95% w/0.0 l % TFA in water/MeCN(50:50). After cooling to room temperature, the reaction mixture was quenched with slow addition of 10 mL of MeOH followed by 5 mL of 5 % HCI in water and 5 mL of ethyl acetate. After separation of the resulting layers, the aqueous layer was extracted a second time with 10 mL of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to a tan solid (6.78 20 grams, 80 % yield). LC/MS showed one peak, at 2.2 min and 209.6 MI. This material was taken up in ethyl acetate, filtered through celite and Kieselgel 60 (0.5 inch plug on a 60 mL Buchner funnel) and the filtrate was recrystallized from hexane/ethyl acetate to give final product (4.61 grams, 54 % yield). 'H NMR (CDCl 3 ): 7.3-7.1 (m, 3H, Ar), 5.6 (br S, IH, NH), 4.23 (q, I H, CHCH 3 ), 3.8 (m, I H, ArCH 2 CHNH), 3.49 (m, 1H, ArCH 2 CH2NH), 3.48 (m, IH, ArCH2CH 2 NH), 3.05 (m, IH; 25 ArCH2CH 2 NH), 1.6 (d, 3H, CH 2 ). 13 C NMR (CDCl 3 ): 178 (I C, C=O), 139 (1 C, Ar), 135 (1 C, Ar), 130, 129 (2C, Ar), 126 (2C, Ar), 42 (I C, C), 40 (1 C, CHN), 33 (1C, CHAr), 14 (1C, CH 3 ). Example 3 30 Preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine 53 NH CI H3C Procedure A HPLC purified 8-chIoro- I -methyl-2,3,4,5-tetrahydro- I H-3-benzazapin-2-one (150 mg, 0.716 mmol) of Example 2 was added to a 50 mL round bottom flask with 2M borane-tetrahydrofuran solution 5 (2 mL, 2.15 mmol). The mixture was stirred 10 hours at room temperature under an argon balloon. LC/MS showed the desired product as the major peak with approximately 5 % of starting material still present. The reaction mixture was quenched with 5 mL methanol and the solvents were removed on the rotary evaporator. This procedure was repeated with methanol addition and evaporation. The mixture was evaporated on the rotary evaporator followed by 2 hours in vacuo to give the product as a white solid 10 (117 mg, 70 % yield). NMR, LC/MS and other analytical data are provided below. Procedure B Recrystallized 8-chIoro- I -methyl-2,3,4,5-tetrahydro- 1 H-3-benzazapin-2-one (137 mg, 0.653 15 mmol) was added to a 50 mL round bottom flask with stirring under nitrogen gas. To the flask was slowly added borane-tetrahydrofuran solution (I M, 10 mL) followed by boron trifluoride TBME solution (1 mL, 8.85 mmol) with vigorous gas evolution. The mixture was stirred 6 hours at room temperature under nitrogen gas. LC/MS showed the desired product. The reaction mixture was quenched with 5 mL methanol and 3 mL conc. HCl and the solvents were removed on the rotary evaporator. This procedure 20 was repeated with methanol and HCI addition and evaporation. The mixture was evaporated on the rotary evaporator followed by 2 hours on the pump to dryness to give 8-chloro-l-methyl-2,3,4,5-tetrahydro-1 H-3 benzazapine hydrochloride (106 mg, 70 % yield). 'H NMR (CDCI 3 ): 10.2 (br s, 1 H), 9.8 (br s, 1 H), 7.14 (dd, I H, J = 2, 8 Hz), 7.11 (d, I H, J = 2 Hz), 7.03 (d, I H, J = 8 Hz), 3.6 (m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3 H), 1.5 (d, 3H, J = 7 Hz). 25 LC/MS: 1.41 minute, 196.1 M + H' and 139 major fragment. No impurities were observed. Example 4 Preparation of L-(+)-tartaric acid salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3 benzazepine 54 H3C ( L-(+)-tartaric acid) NH 2 To a clean, dry 50 mL round bottom flask were added 11.5 g (0.06 mol) of 8-chloro-l-methyl 2,3,4,5-tetrahydro-IH-3-benzazepine from Example 3 to 2.23 g (0.015 mol) of L-(+)-tartaric acid. The suspension was diluted with 56 g of tert-butanol and 6.5 mL of H 2 0. The mixture was heated to reflux 5 (75-78 C) and stirred for 10 min to obtain a colorless solution. The solution was slowly cooled down to room temperature (during I h) and stirred for 3h at room temperature. The suspension was filtered and the residue was washed twice with acetone (10 mL). The product was dried under reduced pressure (50 mbar) at 60 *C to yield 6.3 g of the tartrate salt (ee = 80). This tartrate salt was added to 56 g of tert butanol and 6.5 mL of H 2 0. The resulting suspension was heated to reflux and I to 2g of H 2 0 was added 10 to obtain a colorless solution. The solution was slowly cooled down to room temperature (over the course of I h) and stirred for 3h at room temperature. The suspension was filtered and the residue was washed twice with acetone (10 mL). The product was dried under reduced pressure (50 mbar) at 60'C to produce 4.9 g (48 % yield) of product (ee >98.9). If the ee value of the product obtained is not satisfactory, an additional recrystallization can be 15 carried out as described. Either enantiomer can be synthesized in high ee utilizing this method. Example 5 Conversion of Salt Form to Free Amine The L-tartaric acid salt of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine (300 mg, 0.87 20 mmol) from Example 4 was added to a 25 mL round bottom flask with 50% sodium hydroxide solution (114 pL, 2.17 mmol) with an added 2 mL of water. The mixture was stirred 3 minutes at room temperature. The solution was extracted with methylene chloride (5 mL) twice. The combined organic extracts were washed with water (5 mL) and evaporated to dryness on the pump to get free amine (220 mg crude weight). LC/MS 196 (M + H). 25 Example 6 Preparation of 2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride

CH

3

OH

3 HCH3 CI N C1 cl 0 To a dry 100-milliliter, round bottom flask under nitrogen with stirring was added 2-(4 30 chlorophenyl) ethyl-N-2-chloropropionylamide ( 8.8 g, 35.8 mmol) followed by borane in THF (1.8 M, 55 70 mL, 140 mmol) over 10 minutes (gas evolution and solid becomes solubilized). After the addition was complete, boron trifluoride in tert-butyl methyl ether (8 mL, 70.8 mmol) was added over 10 minutes with more gas evolution. After 4 hours, LC/MS showed complete reaction. The reaction mixture was quenched with 20 mL of conc. HCL (37 %) with additional of gas evolution. The reaction mixture was 5 stirred at 40 "C for 2 hours, cooled to room temperature and evaporated. Then, the white slurry was taken up in 40 mL ethyl acetate and 20 mL of 2.5 M NaOH to make a yellow solution over a white slurry. The yellow organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give 12.2 grams of white to yellow solid. This solid was recrystallized from ethyl acetate/ hexane in two crops to give 6.7 grams of white solid product (80 % yield). 10 'H NMR (DMSO-d6): 9.0 (br s, 2 H, NH, HCI), 7.2 (d, 2H, J = 8 Hz), 7.05 (d, 2H, J = 8 Hz), 4.5 (m, I H), 3.2 (m, 2H), 3.1 (m, 2H), 3.0 (m, 2H), 1.5 (d, 3H, J = 7 Hz). LC/MS: 1.71 minute, 232.1 M + H* and 139 major fragment. Minor impurity observed at 2.46 min with 321 and 139 peaks. 15 Example 7 Preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

CH

3 H N C H3 Small Scale 20 2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride (1 g, 4.3 mmol) of Example 6 was reacted with aluminum chloride (3 g, 22 mmol) in a dry 50 mL round bottom flask under nitrogen gas in an oil bath at 120 *C with stirring. Analysis by LC/MS showed complete reaction in two hours. After cooling the resulting black oil to room temperature, 20 mL ethyl acetate and 20 mL of pH 6 water were added. After 30 min of vigorous stirring the mixture was solubilized to a clear colorless upper organic layer and a 25 brown clear lower aqueous layer. After separation of the layers, the aqueous layer was extracted two additional times with 20 mL ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 0.55 grams (55 % yield) of a white to slightly yellow solid containing the HCI salt. This material was found to be very hygroscopic. The remaining aqueous layer (pH 6) was brought to pH 15 by addition of 5 grams of NaOH pellets. The aqueous layer became a thick 30 white emulsion. Three times 40 mL of ethyl acetate were added to the thick white emulsion and decanted off. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 0.3 g (36 %) of a brown oil containing free amine. The combined yield was 91 %. 56 H NMR (CDC 3 ): 7.2 (d, I H, J = 2.5 Hz), 7.15 (dd, I H, J = 2.5, 8 Hz), 7.05 (d, I H, J = 8 Hz), 3.6 (m, 2. H), 3.5 (m, 2H), 3.1 (m, 2 H), 2.9 (m, 2 H), 1.5 (d, 3H, J = 7 Hz). 1 3 C NMR (CDCl 3 ): 144, 136, 133, 131, 127 (2), 51, 45, 32, 30, 17. LC/MS: 1.41 minute, 196.1 M + H* and 139 major fragment. No impurities observed. 5 Large Scale 2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride (49.24 g,179.92 mmol) and aluminum trichloride (34.79 g, 260.89 mmol) were added to a flask under a nitrogen atmosphere. To this solid mixture, 1,2; dichlorobenzene (139.31 g) was added resulting in a suspension which was then heated to 120 *C which 10 was associated with evolution of hydrogen chloride gas, which was neutralized in a sodium hydroxide filled gas scrubber. The reaction mixture became a yellow to brown solution which was heated at 120*C for a total of 12 hours. At the end of this time HPLC analysis indicated that the ratio of product to starting material was greater than 99:1 The reaction solution was cooled to 20 to 30*C and added drop wise to a mixture of sodium hydroxide solution (176.0 g, 1320 mmol) approx. 30 %, water (79.5 g), and 15 cyclohexane (176 g), so that the internal temperature did not exceed 50'C. The layers were separated and the lower aqueous layer was extracted with cyclohexane (74 g). The combined organic layers were extracted with a solution of aq. hydrochloric acid (22.76 g, 231 mmol) 36/38 % and water (68.23 g). The organic layer was extracted with water (45.47 g). The combined aqueous layers were washed with cyclohexane (37 g). To the aqueous layer was added sodium hydroxide (40.08 g, 301 mmol) solution 20 approx. 30 % and cyclohexane (100 g). The aqueous layer was extracted with cyclohexane (100 g). The combined organic layers were concentrated at 40*C to 60'C and a final vacuum of 30 mbar to give 36.79 g, of a yellow oil. HPLC analysis indicated that the product had a purity of 85.45 %, thus giving a corrected yield of 89.29%. 25 Example 8 Preparation of 2-(4-chlorophenyl)ethylbromide | Br CI 2-(4-Chlorophenyl)ethylbromide was prepared according to Robert, et al., J. Org. Chem., 1987, 52, 5594). 30 Small Scale To a 100-mililiter, round bottom flask under nitrogen containing 2-(4-chlorophenyl)ethanol (10 g, 193 mmol) was added phosphorous tribromide (19g, 193 mmol) via syringe while cooling 0 *C. After the addition was complete, the ice bath was removed and the mixture was heated to 95 "C for two hours. The 35 reaction mixture was quenched with slow addition of water in an ice bath. The material was taken up in 57 30 mL of methylene chloride, the layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to obtain 13.8 grams of clear oil (98 % yield). LC/MS and proton NMR were as expected. 'H-NMR: 3.10 t, 3.51 t, 7.11 d, 7.26 d. 5 Large Scale To 171.05 g (1.092 mol) of 2-(4-chlorophenyl)ethanol was added dropwise 147.82 g (0.546 mol) of phosphorous tribromide over 3 hours and at a temperature of 0 'C. The mixture was stirred at 0 'C for 15 min, at room temperature for 2h, and then at 100 'C for 2h, cooled to 0 'C, hydrolized by dropwise addition of 400.0 g of water and diluted with 400.0 g of tert-butyl methyl ether. The organic layer was 10 separated and washed with 100.0 g of water. The solvent was distilled off under reduced pressure to yield a colorless liquid. Yield: 95 % (based on purity). Purity: 96 %. Volume yield (reaction): 100.0%. Volume yield (extraction): 18.0 %. 'H-NMR: 3.10 t, 3.51 t, 7.11 d, 7.26 d. Example 9 15 Preparation of 2-(4-chlorophenyl)-N-ethyl-N-2-propanol

CH

3 OH CI Small Scale To 2-(4-chlorophenyl)ethylbromide (0.5 g, 2.28 mmol, from Example 8) in a 25 mL round 20 bottom flask were added l-amino-2-propanol (1.7 g, 22.8 mmol) dropwise via syringe at 95 "C. The addition was carried out over one hour and the reaction mixture was stirred at 95 0 C for an additional two hours. Then, the reaction mixture was cooled to room temperature and 3 mL of water were added, 10 mL of ethylacetate were added, and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated to obtain 0.453 g of yellow solid (93 % yield). LC/MS and proton NMR were as 25 expected. Large Scale To 821.25 g (10.93 mol) of 1-amino-2-propanol was added dropwise 240.01 g (1.093 mol) of 2 (4-chlorophenyl)ethylbromide during 3 hours and a temperature of 90-100 *C. The mixture is stirred at 30 90-100 *C for further 1 h, cooled to room temperature, and diluted with 859.6 g of water. The water layer was extracted three times with 150.0 g of tert-butyl methyl ether. The combined organic phases were washed with 100.0 g of water, the solvent was distilled off at a temperature of 60 'C and reduced pressure to yield a colorless solid with a melting point of 68-70 *C. Yield: 87 % (based on purity). Purity: 99 %. 58 Volume yield (reaction): 21 %. Volume yield (extraction): 12 %. 1 H-NMR: 1.12 d, 2.42 dd, 2.5-2.9 m, 2.62 d, 2.82 t, 3.75 m, 7.11 d, 7.23 d. Example 10 5 Preparation of 2-(4-chlorophenyl)-N-ethyl-N-2-propylbromide

CH

3 Br C1 This preparation was based on Nagle et al., Tetrahedron Letters, 2000, 41, 3011. 10 Small Scale 2-(4-Chlorophenyl)-N-ethyl-N-2-propanol (453 mg, 2.12 mmol, see Example 9) was dissolved ii 1.5 mL methylene chloride and dimethyl formamide (0.77 mL) was added to the solution. The reaction mixture was cooled to at 0 0 C and thionyl bromide (0.23 mL, 3.0 mmol) was added dropwise. The reaction was then stirred at room temperature for two hours. The product precipitated. The mixture was 15 cooled to 0 "C and the precipitate was filtered and washed with cold methylene chloride to obtain 350 mg of white solid. A second crop was obtained by concentrating, retaking up in methylene chloride, and cooling to obtain an additional 72 mg of product (56 % yield). 'H NMR (DMSO-d 6 ): 8.7 (br s, I H), 8.6 (br s, I H), 7.2 (d, 2H, J = 8 Hz), 7.1 (d, 2 H, J = 8 Hz), 4.32 (m, I H), 3.51 (br m, I H), 3.28 (br m, I H), 3.03 (m, 2H), 2.82 (m, 2H), 1.5 (d, 3H, J = 7 Hz). 20 "C NMR (DMSO-d 6 ): 136, 131, 130 (2), 128 (2), 53, 47, 44, 30, 23. LC/MS: 1.56 min, 278 M + H 4 (-HBr) and 139 major fragment. Large Scale 194.0 g (0.91 mol) of 2-(4-chlorophenyl)-N-ethyl-N-2-propanol were dissolved in 1000.0 g of 25 CH 2

CI

2 . Then 31.17 g (0.46 mol) of NN-Dimethylformamide were added and the clear solution was cooled down to 0 *C. At this temperature, 264.3 g (1.4 mol) of thionyl bromide were added within I h. After complete addition, the reaction mixture was allowed to warm up to room temperature and stirred for further 12 h, while precipitation of the product occurred. The reaction mixture was cooled to 0 *C and the precipitate was filtered off and washed with 500.0 g of ice-cold CH 2 C1 2 , dried at 80 *C under reduced 30 pressure to obtain an off-white powder with a melting point of 194-197 *C. Yield: 63 % (based on purity). Purity: 97 %. Volume yield (reaction): 14 %. 'H-NMR: 1.80 d, 3.05 m, 3.15 m, 3.45 m, 4.59 m, 7.15 d, 7.40 d, 8.95 s. Example 11 59 Preparation of 2-(4-chlorophenyl)-N-ethyl-N-2-propylchloride

CH

3 CI C1 267 g (125 mmol) of 2-(4-chlorophenyl)-N-ethyl-N-2-propanol was diluted with 364 g of toluene 5 and warmed to 40*C. 19.30 g, 222 mmol dimethylacetamide were added and following this 111.83 g 940 mmol thionyl chloride was added dropwise so that the internal temperature was kept between 40 and 60"C. The resulting thick suspension was stirred for 2 to 3 hours at 60 to 65*C. The suspension was filtered and washed with 335 g of toluene via the reactor. The resulting 397.1 g of a brown crude product was suspended in 326 g of isopropanol and 35.2 g of water, and heated to approx. 80 to 85'C to reflux 10 forming a clear brown solution. The solution was then cooled over 3 to 12 h to 0 to 5oC and stirred for at least 1 hour at 0 to 5'C, before being centrifuged. The wet product was washed with 146 g of isopropanol in several parts via the reactor and with 100 g of isopropanol directly over the filter cake (when the material is still colored, the amount of isopropanol can be increased until colourless material is obtaind). About 790 g of mother liquid with pH = 0 was also formed. 157.93 g of a white to lightly beige wet 15 product was yielded, which was dried at 70*C in vacuum at 30 mbar. Yield: 113.42 g (99.53 percent by weight). Example 12 Preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine N H CI 20 H3C Small scale To 2-(4-chlorophenyl)-N-ethyl-N-2-propylbromide (0.343 g, 0.959 mmol, see Example 10) in a 50 mL round bottom flask was added aluminum chloride (0.192 g, 1.44 mmol). The two solids were heated at 140 *C for 4 hours and then cooled to 90 *C. Toluene (350 microliters) was added and the 25 reaction mixture was cooled to room temperature. Water (350 microliters) was added as well as I gram of ice. The mixture was stirred for 15 minutes then sodium hydroxide solution (350 microliters of a solution made up of 2 g of NaOH in 6 g water) was added. The reaction mixture was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give 218 mg of a dark yellow oil product (90% yield). 60 Attempted distillation of the oil product at 115-180 *C and 0,1 torr caused decomposition and dimerization. LC/MS and proton NMR are as expected. 5 Large Scale A 750 mL reaction vessel was charged with 2-(4-chlorophenyl)-N-ethyl-N-2-propylbromide (240 g, 0.67 mol) to which aluminum chloride (134 g, 1.01 mol) and 1,2-dichlorobenzene (480 g) were added. The resulting suspension was heated to 138-142 'C (yellow solution) and HBr-gas evolved (neutralized with sodium hydroxide solution). The reaaction was stirred for 8-12 hours (monitored by HPLC). The 10 reaction was cooled to 20-30 'C and transferred to a dropping funnel. Extraction mixture containing water (300 g), 30% sodium hydroxide solution (670 g), and cyclohexane (670 g) was added to the reaction vessel. The reaction solution was added portionwise to the extraction mixture while cooling keeping the temperature below 50 *C. The resulting layers were separated and the aqueous phase was extracted with cyclohexane (144 g). The organic layers were combined and extracted with a solution of 15 HCI (pH of the water layer was <2). The organic layer was extracted once more with water. The combined water layers were washed with cyclohexane. A 30% sodium hydroxide solution (100 g) was then added (pH of the water layer was >13). The water layer was first extracted with cyclohexane (720 g) and then with further cyclohexane (144 g). The combined organic layers were dried over sodium sulfate. The sodium sulfate was filtered out and the filtrate was evaporated under reduced pressure at a 20 temperature of 45-50 *C. Crude product was obtained as a glutinous oil (134.42 g). Example 13 Large Scale Preparation of L-(+)-tartaric acid salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H 3-benzazepine 25 Crude product (134.32 g) of the large scale synthesis of Example 12 was dissolved in tert-butanol (480 g). An aqueous solution of L-(+)-tartaric acid (21 g of acid in 30 g of water) and seed crystals were added. The solution was stirred at 15-25 'C overnight until crystals formed. The resulting suspension was filtered and the precipitate washed with acetone. EE was 68.1% (HPLC). The precipitate was then refluxed in additional tert-butanol (480 g) and water (10 g). Water (80 g) was added until the precipitate 30 dissolved completely and then the solution was cooled to 15-25 *C and stirred overnight. The resulting precipitate was filtered out and washed with acetone. EE was 96.8% (HPLC). The precipiate was again refluxed in additional tert-butanol (480 g) and stirred for 1 hour at reflux. The resulting suspension was cooled to 15-25 *C and stirred overnight. The resulting precipitate was filtered out and washed with acetone. EE was 98.7% (HPLC) and the product was dried under vacuum at 60 'C. Yield was 34.96 g. 35 Example 14 Preparation of Hydrochloric Acid Salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1Hbenzazepine 61 To a clean, dry 25 mL round bottom flask were added (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro I H-3-benzazepine free amine (220 mg), 3 mL methylene chloride, and 1.74 mL of I M HCI in ether. The mixture was stirred for 5 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid, the HCI salt. The salt was re-dissolved in methylene chloride (3 mL) and an 5 additional 1.74 mL of I M HCI was added and the solution was again stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure to give the desired HCI salt of 8-chloro-l methyl-2,3,4,5-tetrahydro-lH-3-benzazapine (190 mg crude weight, 95 % yield). NMR data was consistent with the desired product. ' H NMR (CDCl 3 ): 10.2 (br s, I H), 9.8 (br s, I H), 7.14 (dd, I H, J = 2, 8 Hz), 7.11 (d, I H, J = 2 Hz), 7.03 10 (d, I H, J = 8 Hz), 3.6 (m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3 H), 1.5 (d, 3 H, J = 7 Hz). Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application is incorporated herein by 15 reference in its entirety. Throughout this specification the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. 20 It is to be understood that any discussion of public documents, acts, materials, devices, articles or the like included herein is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters were common general knowledge in the field relevant to the present invention as it existed before the priority date of any claim of this application. 62

Claims

2. 1the process of ClaNm I wheein said hydrochloride acid salt is a hyd chloride acid ,s of a compound of frma.h b. 3 A process , comprising: combining a compound of Formula Vb, methylene chioridc, and 111 in ether to form a mixture; and removing solvent under reduced pressure to give a hydrochloride acid salt of a compound of Formula Vb in solid form,
4. A hydochloride acid s obtaNed by the press of claim I or 2. A composition comprising at least one hydrochloride aCid sal according to claim 4.
6. The hydrohoride acid ordig to cm 4 Or a composion accordng to AM 5 when sed in treaiment f the human or animba ody.
7. The hydrohlride acid salt according to claim 4 or a comipositon accordnig to clai 5 when used in: treatment of a 5-T mediateddiorder: inducing satiety; redig food J itake: controling eatig;o treatment obesiy S. use of the hydrochloride acid salt according to claim 4 or the composition according to claim 5 in the manufacture of a medicament.
9. Ue of the hydrochloride acid salt according to claim 4 or thecompositionacording to claia 5 in the manufacre o a medIcarent for: etment ofa 5-H ediated disorder; nducing ae reducing food intake counting eing r treatment of obesity. 10, A method of treatment of a human or animal body, comprising administering a therapeutically acceptable amount of the hydrochloride acid salt according to claim 4 or the composition according to claim I to the human or animal body to: eat a 5--T mediaed disorder; ndue sie reduce food ntake; cotoCating: or, treat obesity.
11. The process according to any one of claims 1, 2 or 3, the hydrochloric acid salt according to any one of claims 4, 6 or 7, the composition according to any one of claims 5, 6 or 7, the use according to claim 8 or 9, or the method according to claim 10 substantially as hereinbefore described. 64