MXPA06009671A

MXPA06009671A - 6-substituted 2,3,4,5-tetrahydro-1h-benzo[d]azepines as 5-ht2c receptor agonists

Info

Publication number: MXPA06009671A
Application number: MXPA/A/2006/009671A
Authority: MX
Inventors: Zhang Deyi; John Rodriguez Michael; Philip Cohen Michael; Victor Frantz; Gordon Allen John; Briner Karin; Stanley Galka Christopher; Lynne Hellman Sarah; Angeles Martinezgrau Maria; Robert Reinhard Matthew; Ryan Rothhaar Roger; Wade Tidwell Michael; Caerwyn Williams Andrew; Armen Boyd Steven; Gerard Conway Richard; S Deo Arundhati; Lee Waiman; Stephen Siedem Christopher; Singh Ajay; Philip Mazanetz Michael
Original assignee: Gordon Allen John; Armen Boyd Steven; Briner Karin; Philip Cohen Michael; Gerard Conway Richard; S Deo Arundhati; Eli Lilly And Company; Stanley Galka Christopher; Lynne Hellman Sarah; Lee Waiman; Angeles Martinezgrau Maria; Robert Reinhard Matthew; John Rodriguez Michael; Ryan Rothhaar Roger; Stephen Siedem Christopher; Singh Ajay; Wade Tidwell Michael; Victor Frantz; Caerwyn Williams Andrew; Zhang Deyi
Priority date: 2004-02-25
Filing date: 2006-08-24
Publication date: 2007-04-20

Abstract

The present invention provides 6-substituted 2,3,4,5-tetrahydro-1H-benzo[d]azepines of Formula I as selective 5-HT2C receptor agonists for the treatment of 5-HT2C associated disorders including obesity, obsessive/compulsive disorder, depression, and anxiety:I where:R6 is -C=C-R10, -O-R12, -S-R14, or -NR24R25;and other substituents are as defined in the specification.

Description

2,3,4, 5-TETRAHIDRO-lH-BENZO [D] AZEPINAS 6-SUBSTITUTED AS AGENTS OF THE 5-HT2c RECEPTOR The serotonin neurotransmitter (5-hydroxytryptamine, 5-HT) has a rich pharmacology resulting from a heterogeneous population of at least seven receptor classes. Serotonin class 5-HT2c is further subdivided into at least three subtypes, designated 5-HT2A, 5-HT2B, and 5-HT2c. The 5-HT2c receptor has been isolated and characterized (Julius, et al., US Patent No. 4,985,352), and it has been reported that transgenic mice lacking the 5-HT2c receptor show attacks and an eating disorder resulting in increasing consumption of food (Julius et al., US Patent No. 5,698,766). The 5-HT2c receptor has also been linked to several other neurological disorders including obesity (Vickers et al., Psychopharmacology, 167: 274-280 (2003)), hyperphagia (Tecott et al., Nature, 374: 542-546 (1995)), obsessive-compulsive disorder (Martin et al., Pharmacol.

Biochem. Beba., 71: 615 (2002); Chou-Green et al., Physiology & Behavior, 78: 641-649 (2003)), depression (Leysen, Kelder, Trends in Drug Research II, 29: 49-61 (1998)), anxiety (Curr Opin, Invest Drugs 2 (4), p.317 (1993)), substance abuse, sleeping disorders (Frank et al., Neuropsychopharmacology 27: 869-873 (2002)), hot flushes (EP 1213017 A2), epilepsy (Upton et al., Eur. J. Pharmacol., 359: 33 (1998); Fitzgerald, Ennis, Annual Reports in Medicinal Chemistry, 37 : 21-30 (2002)), and hypogonadism (Curr Opin, Invest Drugs 2 (4), p.317 (1993)). Certain substituted 2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine compounds have been described as useful therapeutics such as for example: U.S. Pat. No. 4,265,890 discloses certain substituted 2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine compounds as dopamine receptor antagonists for use as antipsychotics and antiemetics, among others.

EP 0 285 287 describes certain substituted 2,3,4,5-tetrahydro-lH-benzo [d] azepine compounds for use as agents for treating gastrointestinal motility disorders, among others. WO 93/03015 and WO 93/04686 disclose certain substituted 2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine compounds as alpha-adrenergic receptor agonists for use as agents for treating hypertension and cardiovascular diseases in which changes in vascular resistance are desirable, among others. WO 02/074746 A1 discloses certain substituted 2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine compounds as 5-HT2c agonists for the treatment of hypogonadism, obesity, hyperphagia, anxiety, depression, disorders of the sleep, among others.

WO 03/006466 A1 discloses certain substituted tricyclic hexahydroazepinoindole and indoline compounds as 5-HT ligands and consequently their utility to treat diseases where modulation of 5-HT activity is desired. High affinity 5-HT2c receptor agonists will provide useful therapeutics for the treatment of the disorders associated with the above-mentioned 5-HT2 receptor including obesity, hyperphagia, obsessive / compulsive disorder, depression, anxiety, substance abuse, sleep disorder , hot flashes, and hypogonadism. High affinity 5-HT2c receptor antagonists that are also selective for the 5-HT2c receptor will provide such therapeutic benefit without the undesirable adverse events associated with current therapies. The selectivity achieved by the 5-HT2c receptor, particularly as against the 5-HT2ñ and 5-HT2B receptors, provides a difficulty in the design of 5-HTc agonists. The 5-HT2 receptor agonists have been associated with problematic hallucinogenic adverse events. (Nelson et al., Naunyn-Schmiedeberg's Arch. Pharm., 359: 1-6 (1999)). 5-HT2B receptor agonists have been associated with cardiovascular related adverse events, such as valvular disease. (Setola et al., Mol.Pharmacology, 63: 1223-1229 (2003), and references cited therein).

Previous references for substituted 2,3,4,5-tetrahydro-lH-benzo [d] azepine compounds as potential therapeutics have predominantly mentioned their uses as alpha adrenergic and / or dopaminergic modulators. Adrenergic modulators are frequently associated with the treatment of cardiovascular diseases (Frishman, Kotob, Journal of Clinical Pharmacology, 39: 7-16 (1999)). Dopamine receptors are primary targets in the treatment of schizophrenia and Parkinson's disease (Seeman, Van Tol, Trends in Pharmacological Sciences, 15: 264-270 (1994)). It will be appreciated by those skilled in the art that selectivity, as against these and other physiologically important receptors, will generally also be preferred characteristics for therapeutics for the specific treatment of disorders associated with 5-HT 2c as described above. The present invention provides selective 5-HT2c agonist compounds of Formula I: I where: R1 is hydrogen, fluoro, or alkyl (C? -C3); R2, R3, and R4 are each independently hydrogen, methyl, or ethyl; R5 is hydrogen, fluoro, methyl, or ethyl; R6 is -C = C-R10, -0-R12, -S-R14, or -NR24R25; R7 is hydrogen, halo, cyano, (C? -C6) alkyl optionally substituted with 1 to 6 fluoro substituents, (C2-C6) alkenyl optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl, alkoxy ( C? -C6) optionally substituted with 1 to 6 fluoro substituents, alkylthio (C? -C6) optionally substituted with 1 to 6 fluoro substituents, Ph1-alkyl (C0-C3), Ph1-alkyl (C0-C3) - O-, or P ^ -alkyl (C0-C3) -S-; R8 is hydrogen, halo, cyano, or -SCF3; R9 is hydrogen, halo, cyano, -CF3, -SCF3, or (C? -C3) alkoxy optionally substituted with 1 to 6 fluoro substituents; R10 is -CF3, ethyl substituted with 1 to 5 fluoro substituents, (C3-C6) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, Arx-alkyl (C0-) C3), Ph1-(C0-C3) alkyl, or 3-alkyl (C? -C4) -2-oxo-imidazolidin-1-yl-(C1-C3) alkyl; R12 is Ph2-alkyl (Ca-C3), Ar2-alkyl (C? -C3), alkyl (C-C6) -S- (C2-C6) alkyl, (C3-C7) -S- (C2-C6) alkyl, phenyl-S- (C2-C6) alkyl, Ph2-S- (C2-) alkyl C6), phenylcarbonyl-alkyl (C? -C3), Ph2-C (0) -alkyl (C? -C3), alkoxycarbonyl (C? -Ce) alkyl (C3-C6), cycloalkyl (C3-C7) -OC (0) -alkyl (C3-Cd), phenyloxycarbonyl-(C3-C6) alkyl, Ph2-0C (0) -alkyl (C3-C6), Ar2-0C (0) -alkyl (C3-C6), cycloalkyl ( C3-C7) -NH-C (0) -alkyl (C2-C4) -, Phx-NH-C (0) -alkyl (C2-C) -, Ar2-NH-C (0) -alkyl (C2- C4) -, or R13-C (0) NH- (C2-C4) alkyl; R13 is (C3-C7) cycloalkyl (C0-C3) alkyl, Ph1, Ar2, or (C? -C3) alkoxy optionally substituted with 1 to 6 fluoro substituents, P ^ -NH- or Het1 linked to N; R14 is Ar2 which is not linked to N to the sulfur atom, Ph2, R15-L-, tetrahydrofuranyl, tetrahydropyranyl, or substituted phenylmethyl in the methyl portion with a substituent selected from the group consisting of (C? -C3) alkyl- n-substituted with hydroxy, alkyl (C? -C3) -O-alkyl (C? -C2) -n-, alkyl (C? -C3) -C (0) -alkyl (C0-C2) -n-, and (C? -C3) -0-C (0) -alkyl (C0-C2) -n- alkyl, wherein when R14 is Ph2 or Ar2, where Ar2 is pyridyl, then R14 can also, optionally, be substituted with phenyl -CH = CH- or phenyl-C = C-, phenyl-CH = CH- or phenyl-C = C- are further optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, alkyl (C? -C6) optionally further substituted with 1 to 6 fluoro substituents, and (Cx-Ce) alkoxy optionally further substituted with 1 to 6 fluoro substituents, and wherein when Ar2 is pyridyl, the pyridyl may alternatively, optionally replace with R2 8R29N-C (0) -, and optionally further substituted with a methyl, -CF3, cyano, or substituent -SCF3, or with 1 to 2 halo substituents, and wherein tetrahydrofuranyl and tetrahydropyranyl may optionally be substituted with an oxo substituent, or with one or 2 groups independently selected from methyl and -CF3; R15 is -OR16, cyano, -SCF3, Ph2, Ar2, quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, phthalimido, benzothiophenyl, optionally substituted in the 2-position with phenyl or benzyl, benzothiazolyl optionally substituted in the 2-position with phenyl or benzyl, benzothiadiazolyl optionally substituted with phenyl or benzyl, 2-oxo-dihydroindol-1-yl optionally substituted at the 3-position with dimethyl gem or alkyl (Ci-Cß) optionally further substituted with 1 to 6 fluoro substituents, 2-oxo-dihydroindole-5- ilo optionally substituted in the 3-position with gem dimethyl or (C? -C6) alkyl optionally further substituted with 1 to 6 fluoro substituents, 2-oxo-imidazolidin-1-yl optionally substituted in the 3-position with dimethyl gem or alkyl ( Cx-Cß), optionally further substituted with 1 to 6 fluoro substituents, 2-oxo-tetrahydropyrimidinyl optionally substituted in the 3 or 4 position with dimethyl gem or alkyl (Ci-Cß) optionally further substituted with 1 to 6 fluoro substituents, 2-oxo-tetrahydroquinolin-1-yl optionally substituted at 3-position with gem dimethyl or (C 1 -C 6) alkyl optionally further substituted with 1 to 6 fluoro, 2-oxo substituents -dihydrobenzimidazol-1-yl optionally substituted in the 3-position with dimethyl gem or alkyl (Ci-Cß) optionally further substituted with 1 to 6 fluoro substituents, -NR17R18, -C (0) R22, or a saturated heterocycle selected from the group which consists of pyrrolidinyl, piperidinyl, morpholinyl, and thiomorpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, wherein Ph 2 and Ar 2 when Ar 2 is pyridyl, can also be optionally substituted with phenyl-CH = CH- or phenyl-C = C-, phenyl-CH = CH- and phenyl-C = C- are further optionally substituted on the phenyl portion with 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, (C? -C6) alkyl optionally further substituted with 1 to 6 subs Fluoro substituents, and (Ci-Cβ) alkoxy optionally further substituted with 1 to 6 fluoro substituents, and wherein Ar2 may alternatively, optionally be substituted with a substituent selected from the group consisting of (C3-C) cycloalkyl (C0) alkyl -C3), Het1-alkyl (C0-C3), pyridyl-C0-C3 alkyl, and phenyl-C0-C3 alkyl, and optionally further substituted with a methyl substituent, -CF3, cyano, or -SCF3, or with 1 to 2 halo substituents, the pyridyl (C0-C3) alkyl and phenyl (C0-C3) alkyl optionally are further substituted with 1-3 substituents independently selected from halo, -CH3, -OCH3, -CF3, - OCF3, -CN, and -SCF3, and wherein when Ar2 is pyridyl, the pyridyl may alternatively, optionally be substituted with R28R29N-C (0) -, or alkyl (C-Ce) -C (0) - optionally substituted with 1 up to 6 fluoro substituents, and may optionally be further substituted with a methyl substituent, -CF3, cyano, or -SCF3, or with 1 to 2 halo substituents, and wherein when Ar2 is thiazolyl, the thiazolyl may alternatively, optionally be substituted with (C3-C7) cycloalkyl (C0-C3) -NH- alkyl, and wherein the pyrrolidinyl, piperidinyl, morpholinyl, and thiomorpholinyl is substituted with oxo- on a carbon atom adjacent to the nitrogen atom in the ring, or is N-substituted with a substituent selected from the group consisting of alkylcarbonyl (C? -C6), alkylsulfonyl (Ci-Cß), cycloalkyl (C3-) C7) alkyl (C0-C3) -C (O) -, cycloalkyl (C3-C7) (C0-C3) alkyl -S (O) 2-, Ph ^ (C0-C3) -C (0) - alkyl, and Ph1-(C0-C3) alkyl -S (0) 2- , and may optionally be further substituted with 1 or 2 methyl substituents or -CF3, and when substituted oxo, may optionally further be N substituted with a substituent selected from the group consisting of (C? -C6) alkyl optionally further substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, and Ph1- (C0-C3) alkyl, and wherein tetrahydrofuranyl and tetrahydropyranyl can optionally be substituted with an oxo substituent, and / or with one or 2 groups independently selected from methyl and -CF3; L is branched or unbranched alkylene (Ci-Cß), except when R15 is -NR17R18 or Ar2-N-linked to L, in which case L is branched or unbranched (C2-Ce) alkylene, and when L is methylene or ethylene, L can optionally be substituted with ethane gem or with 1 to 2 fluoro substituents, and when R15 is Ph2, Ar2, or a saturated heterocycle, L can alternatively, optionally be substituted with a substituent selected from the group consisting of hydroxy cyano, - SCF3, (C? -C6) alkoxy optionally further substituted with 1 to 6 fluoro substituents, alkoxycarbonyl (C? -C6) optionally further substituted with 1 to 6 fluoro substituents, alkylcarbonyloxy (C-C?) Optionally further substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) -O-, (C3-C7) cycloalkyl-(C0-C3) alkyl -OC (O) -, and (C3-C7) cycloalkyl- alkyl (C0-C3) -C (0) -0-; R16 is hydrogen, (C1-C3) alkyl optionally substituted with 1 to 6 fluoro substituents, alkylcarbonyl (C6-6), cycloalkyl (C3-C7) alkyl (C0-C3), cycloalkyl (C3-C7) alkyl (C0) -C3) -C (0) -, Phx-alkyl (C0-C3), P ^ -alkyl (C0-C3) -C (0) -, Ar2-alkyl (C0-C3), or Ar2-alkyl (C0) -C3) -C (O) -, R17 is (C? -C4) alkyl optionally substituted with 1 to 6 fluoro, t-butylsulfonyl, cycloalkyl (C3-C7) alkyl (C0 ~ C3) -C (0) substituents -, cycloalkyl (C3-C7) (C0-C3) alkyl-sulfonyl, PtT (C0-C3) alkyl, Ph1- (C0-C3) alkyl-C (0) -, Ph ^ -alkylsulfonyl (C0-C3), Ar2-alkyl (C0-C3), Ar2- (C0-C3) alkyl-C (0) -, Ar2-alkylsulfonyl (C0-C3), R190C (0) -, or R20R21NC (O) -; R18 is hydrogen or (C? -C) alkyl optionally substituted with 1 to 6 fluoro substituents, or R17 and R18, taken together with the nitrogen atom to which they bind form Het1 where Het1 is substituted with oxo- on a carbon atom adjacent to the nitrogen atom in the ring, or R17 and R18, taken together with the nitrogen atom to which they bind, form an aromatic heterocycle selected from the group consisting of pyrolyl, pyrazolyl, imidazolyl, 1, 2, 3-triazolyl, and 1, 2,4-triazolyl, the aromatic heterocycle optionally is substituted with 1 to 2 halo substituents, or substituted with 1 to 2 (C? -C4) alkyl substituents optionally further substituted with 1 to 3 fluoro substituents, or mono-substituted with fluoro, nitro, cyano, -SCF3, or (C? -C4) alkoxy optionally further substituted with 1 to 3 fluoro substituents, and optionally further substituted with an alkyl substituent (C? -C) optionally further substituted with 1 to 3 fluoro substituents; R19 is (C-Cß) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, Ar2- (C0-C3) alkyl, or PhTalkyl (C0-C3), R20 is alkyl (C? -C6) optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, Ar2- (C0-C3) alkyl, or Pt ^ -alkyl (C0-C3), R21 is hydrogen or (C? -C) alkyl optionally substituted with 1 to 6 fluoro substituents, or R20 and R21, taken together with the nitrogen atom to which they are linked, form Het1; R22 is alkyl (Ci-Ce) optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, R23-0-, Ph1- (C0-C3) alkyl, Ar2-alkyl (C0) -C3), or R32R33N-; R23 is (C? -C6) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, Ph ^ (C0-C3) alkyl, or Ar2-alkyl (C0-C3); R24 is (C? -C6) alkoxy (C2-C5) alkyl optionally substituted with 1 to 6 fluoro substituents, alkylthio (C? -C6) (C2-C5) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C?) Alkyl-O-alkyl (C? -C5), cycloalkyl (C3-) C7) alkyl (C0-C?) -S-alkyl (C-C5), phenyl-n (C-C3) alkyl, Ph2-n (C? -C3) alkyl, Ar2-n (C0-C3) alkyl, phenylalkyl ( C0-C?) - O-alkyl (C? -C5), phenylalkyl (C0-C?) -S-alkyl (C? -C5), Ph1-alkyl (C0-C?) -C (0) NH- alkyl (C2-C), Pha-alkyl (C0-C?) -NH-C (0) NH-alkyl (C2-C), pyridyl-alkyl (C0-C?) -C (O) NH-alkyl (C2-C4), pyridyl-alkyl (C0-C?) -NH-C (0) NH-alkyl (C2-C4), or Ar3alkyl (C? -C2), where Ar3 is a bicyclic portion selected from a group consisting of indanyl, indolyl, dihydrobenzofuranyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzo [1,3] dioxolyl, naphthyl, dihydrobenzopyranyl, quinolinyl, isoquinolinyl , and benzo [1,2,3] thiadiazolyl, the Ar3 optionally is substituted with optionally further substituted alkyl (C? -C6) with 1 to 6 fluoro substituents, phenylalkyl (C0-C?) optionally further substituted with 1 to 6 fluoro substituents, or substituted with (C3-C7) cycloalkyl (C0-C3) alkyl, or substituted with 1-3 substituents independently selected from the group consisting of halo, oxo, methyl, and -CF3, the phenyl n-alkyl ( C? -C3), Ph2- n-alkyl (C-C3), or Ar2 n-alkyl (Co ~ C3) are optionally substituted on the n-alkyl portion when presented with (C? -C3) alkyl, dimethyl, ethane gem, 1 to 2 fluoro substituents, or alkyl (Ci-Cß) -C (0) -, the Ar2 n-alkyl (C0-) C3) is alternatively optionally substituted with a substituent selected from the group consisting of (C3-C7) cycloalkyl (C0-C3) alkyl, He ^ -alkyl (C0-C3), pyridyl-(C0-C3) alkyl, phenylalkyl ( C0-C3), pyridyl-(C0-C3) -NH- alkyl, phenyl-alkyl (Co-C3) -NH-, alkyl (C? -Ce) -S-, and (C3-C7) -alkyl-cycloalkyl ( Co ~ C3) -S-, and optionally further substituted with a methyl substituent, -CF3, cyano, or -SCF3, or with 1 to 2 halo substituents, pyridyl (C0-C3) alkyl and phenyl-alkyl (C0-) C3) are optionally further substituted with 1-3 substituents independently selected from halo, -CH3, -OCH3, -CF3, -OCF3, -CN, and -SCF3, and the Ph2-n-alkyl (C? -C3) and Ar2 n (C0-C3) alkyl wherein Ar2 is pyridyl, optionally also substituted on the phenyl or Ar2 portion, respectively, with phenyl-CH = CH- or phenyl-C = C-, phenyl-CH = CH- or phenyl -C = C- are also optionally substituted with 1 to 3 substituents independently selected from the group with halo, cyano, -SCF3, (C? -C6) alkyl optionally further substituted with 1 to 6 fluoro substituents, and (C? -Cd) alkoxy optionally further substituted with 1 to 6 fluoro substituents, and Ar2 n -alkyl (C0-C3) where Ar2 is pyridyl, alternatively, optionally is substituted with alkyl (C? -C6) -C (0) - or R28R29N-C (0) -, and optionally further substituted with a methyl substituent, - CF3, cyano, or -SCF3, or with 1 to 2 halo substituents, the phenylalkyl (C0-C?) -O-alkyl (C? -Cs), or phenylalkyl (C0-C?) -S-alkyl (C? -C5) are optionally substituted in the phenyl portion with (C? -C2) -S (O) 2-, or with 1 to 5 independently selected from halo substituents, or with 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, alkyl (C? -Cg) optionally further substituted with 1 to 6 fluoro substituents, and (C-Ce) alkoxy optionally further substituted with 1 to 6 fluoro substituents, and the pyridyl-alkyl (C0-C?) -C (O) NH- (C2-C4) alkyl and pyridyl-alkyl (C0-C?) -NH-C (O) NH-alkyl ( C2-C) are optionally substituted in the pyridyl moiety with methyl, -CF3, or 1 to 3 halo substituents; R25 is hydrogen, (C? -C3) alkyl optionally substituted with 1 to 6 fluoro substituents, or allyl; R26 is hydrogen, (C? -Ce) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl; R27 is hydrogen or (C? -C4) alkyl optionally substituted with 1 to 6 fluoro substituents, or R26 and R27, taken together with the nitrogen atom to which they are attached, form Het1; R28 is (C? -C8) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C8) alkylcycloalkyl (C0-C3), tetrahydropyran-3-yl (C0-C3) alkyl, tetrahydropyran-4-yl (C0-C3) alkyl, tetrahydrofuranyl (C0-C3) alkyl, Ph1- n-alkyl (C0-C2), or Ar2-n-alkyl (C0 ~ C2), the Pl ^ -n-alkyl (C0-C2) and Ar2-n-alkyl (C0-C2) are optionally substituted on the alkyl portion when presented with (C1-C3) alkyl, dimethyl, or gem-ethane; R29 is hydrogen or alkyl (C? -C3); R30 is hydrogen, (C? -C6) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, Phx-(C0-C3) alkyl, or Ar2alkyl (C0-C3) , R31 is hydrogen or (C? -C5) alkyl optionally substituted with 1 to 6 fluoro substituents, or R30 and R31, taken together with the nitrogen atom to which they bind, form Het1, Het1 optionally is also substituted with phenyl optionally further substituted with 1 to 3 halo substituents; R32 and R33 are each independently hydrogen or (Ci-Cß) alkyl optionally substituted with 1 to 6 fluoro substituents, or R32 and R33, taken together with the nitrogen atom to which they are linked, form Het1, or R32 is Ph1alkyl (C0-C?) With the proviso that R33 is hydrogen; Ar 1 is an aromatic heterocycle substituent selected from the group consisting of furanyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, and pyridazinyl, any of which can optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halo, alkyl ( C? -C3), (C? -C3) alkoxy, -CF3, -0-CF3, nitro, cyano, and trifluoromethylthio; Ar 2 is an aromatic heterocycle substituent selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2-triazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2 , 4-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,3-thiadiazolyl, pyridyl, pyridazinyl, and benzimidazolyl, any of which can optionally be substituted with 1 up to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, (C? -C6) alkyl optionally further substituted with 1 to 6 fluoro substituents, and (C? -C6) alkoxy optionally further substituted with 1 to 6 fluoro substituents, and wherein pyridyl and pyridazinyl may also optionally be substituted with alkylamino (C? -C6) optionally further substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, 0 (C3-C7) cycloalkyl (C0-C3) -amino; Het1 is a heterocycle substituent containing saturated nitrogen selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, and homothiomorpholinyl, any of which may optionally be substituted with alkyl (Cx-Ce) or with 2 substituents methyl; Het2 is a heterocycle substituent containing saturated oxygen, selected from the group consisting of tetrahydrofuranyl and tetrahydropyranyl, any of which may optionally be substituted with alkyl (Cx-Cß) or with 2 methyl substituents; Ph1 is phenyl optionally substituted with 1 to 5 independently selected from halo substituents, or 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, (C? -C6) alkyl optionally further substituted with 1 to 6 fluoro substituents, and (C-C?) Alkoxy optionally further substituted with 1 to 6 fluoro substituents; Ph2 is phenyl substituted with: a) 1 to 5 independently selected from halo substituents; or b) 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF 3, nitro, hydroxy, alkyl (C-Ce) optionally further substituted with 1 to 6 fluoro substituents, and (Ci-Cβ) alkoxy optionally further substituted with 1 to 6 fluoro substituents; or c) 0, 1, or 2 substituents independently selected from the group consisting of halo, cyano, -SCF3, methyl, -CF3, methoxy, -OCF3, nitro, and hydroxy together with a substituent selected from the group consisting of i) alkyl (C? -C? o) optionally further substituted with 1 to 6 substituents of fluoro or mono-substituted with hydroxy, (C? -C6) alkoxy, (C3-C7) cycloalkyl (C0-C3) alkyloxy, Het2- (C0-C3) alkyloxy, Ph1-C0-C3 alkyloxy, ii) alkoxy (C? -C10) -alkyl (C0-C3) optionally further substituted with 1 to 6 fluoro substituents, and optionally further substituted with hydroxy, iii) alkyl (C? -C6) -C (O) -alkyl (C0-) C5) optionally further substituted with 1 to 6 fluoro substituents, iv) carboxy, v) alkoxycarbonyl (C? -C6) optionally further substituted with 1 to 6 fluoro substituents, vi) alkyl (C? -C6) -C (O ) - (C0-C3) -O- optionally further substituted with 1 to 6 fluoro substituents, vii) alkylthio (C? -C6) -alkyl (Co-C5) optionally further substituted with 1 to 6 fluoro substituents, viii) rent sulfinyl (C? -Ce) -alkyl (C0-C5) optionally further substituted with 1 to 6 fluoro substituents, ix) alkylsulfonyl (C? -C6) -alkyl (C0-C5) optionally further substituted with 1 to 6 substituents of fluoro, x) alkylsulfonyl (C? -C6) -alkyl (C0-C3) -0- optionally further substituted with 1 to 6 fluoro substituents, xi) (C3-C7) cycloalkyl (C0-C3) alkyl, optionally further substituted in the cycloalkyl with 1 to 4 substituents selected from methyl and fluoro, xii) (C3-C7) cycloalkyl (C0-C3) alkyl-O-, optionally further substituted in the cycloalkyl with 1 to 4 substituents selected from methyl and fluoro, xiii ) (C3-C7) cycloalkyl (C0-C3) -C (O) -, xiv) cycloalkyl (C3-C7) alkyl (C0-C3) -OC (O) -, xv) cycloalkyl (C3-C7) alkyl (C0-C3) -S-, xvi) cycloalkyl (C3-C7) alkyl (C0-C3) -S (0) -, xvii) cycloalkyl (C3-C7) alkyl (C0-C3) -S (0) 2 -, xviii) Pl ^ -alkyl (C0 ~ C3), optionally substituted in the portion a alkyl with 1 to 2 fluoro substituents, xix) Pl ^ -alkyl (C0-C3) -O-, optionally substituted on the alkyl portion with 1 to 2 fluoro substituents xx) Pl ^ -alkyl (C0-C3) -C (0) -, xxi) Pl ^ -alkyl (C0-C3) -0-C (O) -, xxii) Pl ^ -alkyl (C0-C3) -C (0) -alkyl (C0-C3) -O -, xxiii) Ph1-alkylthio (C0-C3), xxiv) Ph1-alkylsulfinyl (C0-C3), xxv) Ph1-alkylsulfonyl (C0-C3), xxvi) Ar2 alkyl (C0-C3), xxvii) Ar2 alkyl ( C0-C3) -O-xxviii) Ar2 (C0-C3) alkyl -S-, xxix) Ar2 (C0-C3) alkyl -C (0) -, xxx) Ar2 (C0-C3) -C (S) alkyl ) -, xxxi) Ar2-alkylsulfinyl (C0-C3), xxxii) Ar2- (C0-C3) alkylsulfonyl, xxxiii) Het1 (C0-C3) -C (0) alkyl - optionally substituted in the Het1 portion with Ph1, xxxiv ) Het1 (C0-C3) alkyl-C (S) - optionally substituted in the portion Het1 with Ph1, xxxv) Het1-C (0) -alkyl (C0-C3) -0- linked to N, xxxvi) Het2-alkyloxy (C0-C3), xxxvii) R26R27N-, xxxviii) R28R29-N-alkoxy (C-C3), xxxix) R28R29N-C (0) -, xl) R28R29N-C (0) -alkyl (C? - C3) -0-, xli) R28R29N-C (S) -, xlii) R30R31N-S (O) 2-, xliii) H0N = C (CH3) -, and xliv) HON = C (Ph1) -, or a The pharmaceutically acceptable salt thereof is subjected to the following conditions: a) not more than 2 of R1, R2, R3, R4, and R5 may be different from hydrogen; b) when R2 is methyl, then R1, R3, R4, and R5 are each hydrogen; c) when R3 is methyl, then R2 and R4 are each hydrogen; d) when R3 is methyl, R7 and R8 are each -OH, and R1, R2, R4, R5, and R9 are each hydrogen, then R6 is different from cyclohexylthio, furanylthio, or phenylthio; and e) when R12 is Ar-alkyl (C? -C3), then R7 is different from hydrogen or R9 is different from chlorine. This invention also provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient. In another aspect of the present invention, there is provided a method for increasing activation of the 5-HT2c receptor in a mammal comprising administering to a mammal in need of such activation an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt. of the same. The present invention also provides a method for treating obesity in mammals which comprises administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The present invention also provides a method for treating obsessive / compulsive disorder in mammals which comprises administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. Additionally, the present invention provides a method of treating depression in mammals which comprises administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

Additionally, the present invention provides a method of treating anxiety in mammals which comprises administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In preferred embodiments of the above methods for treatment using a compound of the Formula, or a pharmaceutically acceptable salt thereof, the mammal is a human. In another aspect of the present invention, there is provided a compound of Formula I for use in selectively to increase activation of the 5-HT2c receptor and / or for use in the treatment of a variety of disorders associated with reduced activation of 5-HT2c receptors Preferred embodiments of this aspect of the invention include a compound of Formula I for use in the treatment of obesity, hyperphagia, obsessive / compulsive disorder, depression, anxiety, substance abuse, sleeping disorder, hot flashes , and / or hypogonadism. Particularly preferred modalities of this aspect of the invention include the treatment of obesity, obsessive / compulsive disorder, depression, and / or anxiety. In another aspect of the present invention, there is provided the use of one or more compounds of Formula I in the manufacture of a medicament for the activation of 5-HT2c receptors in a mammal. In preferred embodiments of this aspect of the invention, there is provided the use of one or more compounds of Formula I in the manufacture of a medicament for the treatment of obesity, hyperphagia, obsessive / compulsive disorder, depression, anxiety, substance abuse, sleep disorder, hot flashes, and / or hypogonadism. Particularly preferred embodiments of this aspect of the invention include the use of one or more compounds of Formula I in the manufacture of medicaments for the treatment of obesity, obsessive / compulsive disorder, depression, and / or anxiety. Additionally, the present invention provides a pharmaceutical formulation adapted for the treatment of obesity, or for the treatment of obsessive / compulsive disorder, or for the treatment of depression, or for the treatment of anxiety, each of which comprises a compound of the Formula I in association with a pharmaceutically acceptable carrier, diluent or excipient. In those cases where disorders that can be treated by 5-HT2c agonists are known by established and accepted classifications, their classifications can be found in various sources. For example, at present, the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV ™) (Diagnostic and Statistical Manual of Mental Disorders) (1994, American Psychiatric Association, Washington, DC), provides a diagnostic tool to identify many of the disorders described herein. Also, the International Classification of Diseases, tenth revision (ICD-10), provides classifications for many of the disorders described herein. The experienced technician will recognize that they are nomenclatures, nosologies and classification systems for disorders described herein, including those as described in the DSM-IV and ICD-10, and that the terminology and classification systems are developed with medical scientific developments. The general chemical terms used throughout have their usual meanings. For example, the term "alkyl" refers to a saturated branched or unbranched hydrocarbon group. The term "n-alkyl" refers to an unbranched alkyl group. By way of illustration, but without limitation, the term "(C? -C2) alkyl" refers to methyl and ethyl. The term "n-alkyl (C? -C3)" refers to methyl, ethyl, and propyl. The term "(C? -C3) alkyl" refers to methyl, ethyl, propyl, and isopropyl. The term "n-alkyl (C? -C4)" refers to methyl, ethyl, n-propyl, and n-butyl.

The term "(C? -C) alkyl" refers to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The term "(C? -C5) alkyl" refers to all branched and unbranched groups having from one to 6 carbon atoms. The term "(C3-Ce) alkyl" refers to all branched and unbranched alkyl groups having from 3 to 6 carbon atoms. The term "(C2-Cd) alkyl" refers to all branched and unbranched alkyl groups having from 2 to 6 carbon atoms. Alkyl (Cx-Cy) can also be used in conjunction with other substituents to indicate a saturated branched or unbranched hydrocarbon binder for the substituent, where x and y indicate the range of carbon atoms allowed in the binder portion. By way of illustration, but without limitation, -alkyl (C0-C?) Refers to a single bond or a methylene linker moiety; -alkyl (C0-C2) refers to a single bond, methylene binder portion, methylene-1, or ethylene; alkyl - (C0-C3) further includes trimethylene, alpha- or beta-methyl ethylene, or ethyl methylene. -alkyl (C? -C2), -alkyl (C? -C3), -alkyl (C? -C), and -alkyl (C? -C6) refers to branched or unbranched alkylene binders ranging from 1 to 2, 3, 4, or 6 carbons, respectively.

The term "alkenyl" refers to an unsaturated branched or unbranched hydrocarbon group. By way of illustration, but without limitation, the term "(C2-C6) alkenyl" refers to a branched or unbranched hydrocarbon group having from 2 to 6 carbon atoms and 1 or more carbon-carbon double bonds. Ally means a propyl-2-en-l-yl moiety (CH2 = CH-CH2-). The term "(C3-C) cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkylalkyl refers to a cycloalkyl moiety linked through a branched or unbranched alkylene linker, such as, but not limited to, -CH2-, -CH2CH2-, -CH (CH3) -, -CH2CH2CH2-, CH2CH (CH3) -, -CH (CH3) CH2-, -CH (CH2CH3) -, and the like. Cycloalkyl (C3-C7) alkyl (Co-C ?, 2 0 3), refers to cycloalkyl linkers through a single bond (that is, C0- alkyl) or an alkylene binder. Each alkyl, cycloalkyl, and cycloalkylalkyl group may be optionally substituted as provided herein. The terms "alkoxy", "phenyloxy", "sulfonyloxy", and "carbonyloxy" refers to an alkyl group, phenyl group, sulfonyl group, or carbonyl group, respectively, this is linked through an oxygen atom. The terms "alkylthio", "trifluoromethylthio", "cycloalkylthio" ("cyclohexylthio"), "phenylthio", and "furanylthio" refer to an alkyl group, trifluoromethyl group, cycloalkyl group (cyclohexyl), phenyl group, or furanyl group, respectively, this is linked through a sulfur atom. The terms "alkylcarbonyl", "alkoxycarbonyl", "phenylcarbonyl", and "phenyloxycarbonyl", refers to an alkyl, alkoxy, phenyl, or phenyloxy group linked through a carbonyl moiety. The term "alkylcarbonyloxy" refers to an alkylcarbonyl group linked through an oxygen atom. The terms "alkylsulfinyl (C? -C6)", "P? ^ -alkylsulfinyl (C0-C3)", and "Ar2-alkylsulfinyl (C0-C3)", refers to an alkyl, Ph1-alkyl (C0-C3) ), or Ar2-alkyl (Co ~ C3), respectively, a group linked through a sulfinyl moiety (-SO-). The terms "alkylsulfonyl" (t-butylsulfonyl), "cycloalkylsulfonyl (C3-C7)", "phenylsulfonyl", "Pl ^ -alkylsulfonyl (C0-C3)", and "Ar2-alkylsulfonyl (C0-C3)", refers to to an alkyl (t-butyl), (C3-C7) cycloalkyl, phenyl, Ph ^ (C0-C3) alkyl, or Ar2-(C0-C3) alkyl linked through a sulfonyl moiety (-S02-). The term "phenylamino" refers to a phenyl group linked through a nitrogen atom. The term "linked to N" means that the referred portion is linked through its nitrogen atom, by way of illustration, but without limitation, Het1 linked to N means the portion Het1 is linked through a nitrogen atom in the ring of the Het1 portion, and Ar2 bound to N means the Ar2 portion is ligated through a nitrogen atom in the ring of the Ar2 portion. The term "halo" refers to fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro, chloro, and bromine. The most preferred halo groups are fluoro and chloro. The term "heterocycle" is taken to mean a saturated or unsaturated 4- to 7-membered ring containing from 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, the ring optionally being benzofused. Exemplary saturated heterocycles, for the purposes of the present invention, include azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like. Exemplary unsaturated heterocycles include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, , 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, and Similar. Exemplary benzofused heterocyclic rings include, but are not limited to, indolyl, dihydroindolyl, indazolyl, benzisoxazolyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzoxazolyl, benzo [1,3] dioxolyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, benzopyranyl, dihydrobenzopyranyl, cinolinyl. , quinazolinyl and the like, all of which may be optionally substituted as provided herein, which also optionally includes substituted on the benzene ring when the heterocycle is benzofused. In one embodiment, preferred heterocycles include pyrrolidinyl, piperidinyl, homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, isoxazolyl, 1,2,4-oxadiazolyl, thiophenyl, thiazolyl, 1,2,3-thiadiazolyl, pyridyl, pyridazinyl, indolyl, dihydroindolyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, benzoxazolyl, benzo [1,3] dioxolyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, and benzopyranyl, all of which may be optionally substituted as provided herein. In yet another embodiment, preferred heterocycles include pyridyl, pyridazinyl, and thiophenyl. The terms "gem", "geminal", or "geminate" refers to 2 identical substituents linked to a common carbon atom, such as, but not limited to, methyl gem, means 2 methyl groups linked to a common carbon atom , as for each case in a 3,3-dimethyltetrahydrobenzofuranyl group. For the purposes of this application, ethane gem means an ethylene substituent wherein both carbons are bonded to the carbon atom of the substituted group to form a cyclopropyl moiety, such as, but not limited to, the substituent ethane in the 2-phenyl group. (1, 1-ethane) ethylamino then: It will be understood that when a basic definition of a group lists optionally permitted substituents, and in another place that said group is also optionally substituted with other mentioned substituents, then it is intended that those other substituents mentioned be added to the list of optionally permitted substituents. listed in the basic definition of the group. Conversely, if in another place it is said that that group will be to be alternatively, optionally substituted with other mentioned substituents, then those other substituy mentioned is intended to replace the list of optionally-permitted substituents mentioned in the basic definition of the substituent. For example, but not limited to, Ar2 has a basic definition that mentions that any of the listed heteroaromatic groups can "optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, alkyl (C? -Cd optionally further substituted with 1 to 6 fluoro substituents, and (C? -C6) alkoxy optionally further substituted with 1 to 6 fluoro substituents, and wherein pyridyl and pyridazinyl may also optionally be substituted with (C-C) alkylamino optionally further substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, or (C3-C7) cycloalkyl (C0-C3) -amino alkyl. " This will be understood to mean that any of the listed heteroaromatic groups can optionally be substituted with [1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, (C? -C6) alkyl optionally further substituted with 1 to 6 substituents of fluoro, and (C? -C6) alkoxy optionally further substituted with 1 to 6 fluoro substituents, and that when Ar2 is selected to be pyridyl or pyridazinyl, the list of substituents are selected for the 1 to 3 substituents are also expanded to include [alkylamino (C? -C6) optionally further substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, and (C3-C7) cycloalkyl (C0-C3) -amino] alkyl. Similarly, in the definition of R, the terminology "where ... Ar2, where Ar2 is pyridyl, where R14 can also, optionally, be substituted with phenyl-CH = CH- or phenyl-C = C-. it will be understood that it means that the list of substituents are selected for the 1 to 3 substituents optionally allowed on Ar2 = pyridyl again also expanded to include [phenyl-CH = CH- or phenyl-C = C-. . .]. Conversely, later in the definition of R14, the terminology "wherein when Ar2 is pyridyl, the pyridyl may alternatively, optionally be substituted with R28R29N-C (O) - and optionally further substituted with a methyl substituent, -CF3, cyano, or - SCF3, or with 1 to 2 halo substituents, will be understood to mean that when R14 is selected to be Ar2 = pyridyl, then the list of 1 to 3 independently selected substituents optionally allowed in the basic definition of Ar2 can be replaced by " R28R29N-C (0) - and optionally further substituted with a methyl substituent, -CF3, cyano, or -SCF3, or with 1 to 2 halo substituents. " The term "amino protecting group" as used in this specification refers to a substituent commonly employed to block or protect the amino functionality while reacting with other functional groups in the compound. Examples of such amino protecting groups include the formyl group, the trityl group, the acetyl group, the trichloroacetyl group, the trifluoroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, carbamoyl type blocking groups such as benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (" FMOC "), t-butoxycarbonyl (t-BOC), and similar amino protecting groups. The amino protecting group species employed are not critical so that as the derivatized amino group is stable to the conditions of subsequent reactions in other positions of the molecule and can be removed at the appropriate point without disruption of the rest of the molecule. The selection and use (addition and subsequent removal) of amino protecting groups is well known within ordinary skill in the art. Additional examples of groups referred by the terms described by T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis" (Protecting groups in organic synthesis), 3rd edition, John Wiley and Sons, New York, NY, 1999, chapter 7, hereinafter referred to as "Greene". The term "pharmaceutical" or "pharmaceutically acceptable" when used herein as an adjective means substantially non-toxic and substantially non-deleterious to the recipient. By "pharmaceutical composition" it further means that the carrier, solvent, excipients and / or salts must be compatible with the active ingredient of the composition (e.g., a compound of Formula I). It will be understood by those of ordinary skill in this art that the terms "pharmaceutical formulation" and "pharmaceutical composition" are generally interchangeable, and that they are used for the purposes of this application. The term "effective amount" means an amount of a compound of Formula I which is capable of activating 5-HT2c and / or external receptors gives a pharmacological effect. The term "suitable solvent" refers to any solvent, or mixture of solvents, inert to the following reaction that sufficiently solubilizes the reagents to provide a medium within which to effect the desired reaction. It will be understood that the compounds of the present invention can exist as stereoisomers. As such, all enantiomers, diastereomers, and mixtures thereof, are included within the scope of the present invention. Where the specific stereochemistries are identified in this application, the Cahn-Prelog-Ingold designations of (R) - and (S) - and the cis and trans designation of relative stereochemistry are used to refer to specific isomers and relative stereochemistry. Known optical rotations are designated by (+) and (-) for dextrorotatory and levorotatory, respectively. Where a chemical compound is resolved in its isomers, but with absolute configurations or optical rotations that are not determined, the isomers are arbitrarily designated as isomer 1, isomer 2, etc. While all enantiomers, diastereomers, and mixtures thereof, are contemplated within the present invention, preferred embodiments are simple enenatiomers and simple diastereomers. It will generally be understood by those of experience in this art, that the compounds intended for use in pharmaceutical compositions are routinely, but not necessarily, converted to a salt form in efforts to optimize such characteristics as handling properties, stability, pharmacokinetics, and / or bioavailability, etc. Methods for converting a compound to a given salt form are well known in the art (see, for example, Berge, SM, Bighiey, LD, and Monkhouse, DC, J. Pharm, Sci., 66: 1, (1977) ). In that the compounds of the present invention are amines and therefore based on the natural, they readily react with a wide variety of pharmaceutically acceptable organic and inorganic acids to form pharmaceutically acceptable acid addition salts therewith. Such salts are also embodiments of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and the like. Salts derived from organic acids, such as mono- and dicarboxylic aliphatic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic and hydroxyalkanedioic acids, aromatic acids, aliphatic acids and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include chloride, bromide, iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate, phenylbutyrate, α-hydroxybutyrate, butino- 1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, hippurate, lactate, malate, maleate, hydroximelate, malonate, mandelate, nicotinate, isonicotinate, oxalate, phthalate, terephthalate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, benzenesulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethyl sulfonate, methylsulfonate (mesylate), naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene -1,5-sulfonate, p-toluenesulfonate, xylene sulphonate, tartrate, and the like. It is well known that such compounds can form salts at various molar ratios with the acid to provide, for example, the salt of the hemi-acid, mono-acid, di-acid, etc. Where the process of salt formation, the acid is added in a specific stoichiometric ratio, unless otherwise analyzed to confirm, the salt is presumed, but not known, to form its molar ratio. Terms such as "(acid) / 'will be understood to mean that the molar ratio of the salt formed is not known and can not be presumed, as for example, but without limitation, (HC1) X and (methanesulfonic acid) x. Abbreviations used herein are defined as follows: "2B-3 ethanol" means ethanol denatured with toluene "AIBN" means 2, 2'-azobisisobutyronitrile "Calculated" or "Anal. Caled "means calculated elemental analysis" APCl "means chemical ionization of atmospheric pressure" pe "means boiling point" BINAP "means rac-2, 2 '-bis (diphenylphosphino) -1, l'binaftilo." Boc " or "t-Boc" means tert-butoxycarbonyl, "brine" means a solution of saturated sodium chloride.

"CV" means calorific value of oxygen. "DBU" means 1,8-diazabicyclo [5.4.0] undec-7-ene. "DCE" means 1,2-dichloroethane. "DCM" means dichloromethane (this is methylene chloride, CH2C12). "DIBAL-H" means diisobutylaluminum hydride. "DIEA" means N, N-diisopropylethylamine. "DMAP" means 4- (dimethylamino) pyridine. "DME" means 1,2-dimethoxyethane. "DMEA" means N, N-dimethylethylamine. "DMF" means N, N-dimethylformamide. "DMSO" means dimethylsulfoxide. "DOI" means (+) -1- (2,5-dimethoxy-4- [125I] -iodophenyl) -2-aminopropane. "EDC" means 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride. "EDTA" means ethylenediaminetetraacetic acid. "EE" means energy dispatch. "EtOAc" means ethyl acetate. "GC-MS" means mass spectrometry by gas chromatography. "GDP" means guanosine diphosphate. "GTP" means guanosine triphosphate. "GTP? [35S]" means guanosine triphosphate having the phosphate terminal substituted with 35S instead of an oxygen. "HATU" means 0- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate. "HMPA" means hexamethylphosphoramide. "HOBT" means 1-hydroxybenzotriazole hydrate. "CLAR" means high pressure liquid chromatography. "EMAR" means high resolution mass spectrometry. "ISPA" means proximity assay of scintillation by immunoadsorption. "m-CPBA" means meta-chloroperoxybenzoic acid. "pf" means melting point. "Ms" in a chemical structure that means the methanesulfonyl moiety (-S02CH3). "EM (ES +)" means mass spectroscopy using electro-ionization ionization. "MTBE" means methyl t-butyl ether. "NBS" means N-bromosuccinimide. "NMP" means l-methyl-2-pyrrolidinone. "NMR" means nuclear magnetic resonance. "Pd / C" means palladium on activated carbon. "RQ" means respiratory ratio. "SCX chromatography" means chromatography on an SCX column or cartridge. "SCX column" or "SCX cartridge", as used herein, refers to a strong cation exchange resin column based on Varian Bond Elute® silica or disposable cartridge or equivalent. "Sudan III" means 1- [(4-phenylazo) phenylazo] -2-naphthalenol. "Tf" in a chemical structure means the trifluoromethanesulfonyl portion (-S02CF3). "TFA" means trifluoroacetic acid. "THF" means tetrahydrofuran. "CCD" means thin layer chromatography. Although all compounds of the present invention are useful as 5-HT2c agonists, certain classes are preferred, such as, for example, compounds having any of the following enumerated selections of substituents: compounds wherein 1) R7 is halo; 2) R7 is chlorine; 3) R7 is (Cx-Cß) alkyl optionally substituted with 1 to 6 fluoro substituents; 4) R7 is (C? -C3) alkyl optionally substituted with 1 to 6 fluoro substituents; 5) R7 is -CF3; 6) R7 is (C3-C6) alkenyl optionally substituted with 1 to 6 fluoro substituents; 7) R7 is (C3-C6) alkenyl; 8) R7 is cyano; 9) R-5 ° are each hydrogen; R 4 is methyl or ethyl; 11 R4 is methyl; 12 R is methyl; 13 R is hydrogen; R9 is alkoxy (C? -C3); R9 is methoxy; 16 R is halo; 17 R9 is chlorine; R6 is -C = C-R10; R10 is Pl ^ -alkyl (C0-C3); R10 is PtTalkyl (C? -C2); R10 is Phenyl (C0-C3) alkyl; R10 is (C3-C7) cycloalkyl (C0-C3) alkyl; R10 is cycloalkylmethyl (C3-C7); R10 is (C4-C6) alkyl; R10 is branched (C-C6) alkyl; R10 is (C6C6) alkyl substituted with 2-6 fluoro substituents; 27 R10 is A ^ -alkyl (C0-C3); R10 is Ara-alkyl (C? -C2); R6 is -O-R12; R12 is Ph2-alkyl (C0-C3); R12 is Ph2-alkyl (C -C2); 32) R12 is Ph2-alkyl (C? -C2) and Ph2 is substituted with 1-3 halo substituents; 33) R12 is Ph2-alkyl (C? -C2) and Ph2 is substituted with 1-3 fluoro substituents; 34) R12 is Ph2-alkyl (C? -C2) and Ph2 is substituted with cyano; ) R12 is Ph2-alkyl (C? -C2) and Ph2 is substituted with R30R31N-S (0) 2-; 36) R12 is Ph2-alkyl (C? -C2), Ph2 is substituted with R30R31N-S (0) 2-, R30 is alkyl (C? -C3) optionally further substituted with 1-3 fluoro substituents and R31 is hydrogen; 37) R12 is Ar2-(C0-C3) alkyl; 38) R12 is Ar2-alkyl (C? -C2); 39) R12 is Ar2-alkyl (C? -C2) and Ar2 is pyridyl, thiazolyl, oxazolyl, or pyrazolyl, each optionally substituted with methyl; 40) R12 is benzazolyl-alkyl (C-C3); 41) R12 is Ph2-C (O) -alkyl (C? -C3), 42) R12 is Ph2-C (O) -alkyl (C? -C3) and Ph2 is substituted with 1 to 3 halo substituents; 43) R12 is Ph2-C (O) -alkyl (C? -C3) and Ph2 is substituted with 1 to 3 haloofluoro substituents; 44) R12 is Phx-S (0) 2-; 45) R12 is alkyl (C? -C6) -O-C (O) -alkyl (C3-C6); 46) R12 is alkyl (C? -C3) -O-C (O) -alkyl (C3-C6); 47) R12 is R13-C (O) NH- (C2-C4) alkyl; 48) R12 is R13-C (O) NH-alkyl (C2-C4) and R13 is Ph1; 49) R12 is R13-C (O) NH-C2-C4 alkyl, R13 is Ph1; substituted with 1 to 3 halo substituents; 50) R12 is R13-C (O) NH- (C2-C4) alkyl and R13 is (C3-C7) cycloalkyl; 51) R12 is R13-C (O) NH- (C2-C4) alkyl and R13 is pyridyl; 52) R12 is R13-C (O) NH- (C2-C4) alkyl and R13 is (C? -C3) alkoxy; 53) R12 is R13-C (O) NH- (C2-C4) alkyl and R13 is (C3-C7) cycloalkyl; 54) R6 is -S-R14; 55) R6 is -S-R14 and R14 is Ph2; 56) R6 is -S-R14, R14 is Ph2 substituted with 1 to 3 halo substituents; 57) R6 is -S-R14, R14 is Ph2 substituted with cyano; 58) R6 is -S-R14, R14 is Ph2; substituted with cyano and 1 to 2 halo substituents; 59) R6 is -S-R14 and R14 is Ar2; 60) R6 is -S-R14, R14 is Ar2, and Ar2 is optionally substituted pyridyl or pyridazinyl; 61) R6 is -S-R14, R14 is Ar2, and Ar2 is thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl optionally substituted; 62) R6 is -S-R14 and R14 is tetrahydrofuranyl or tetrahydropyranyl; 63) R6 is -S-R14 and R14 is tetrahydrofuranyl or tetrahydropyranyl and the tetrahydrofuranyl or tetrahydropyranyl is substituted with oxo at a carbon adjacent to the oxygen ring; 64) R6 is -S-R14 and R14 is R15-L-; 5 65) L is alkylene (C? -C2); 66) L is branched (C2-C3) alkylene; 67) L is methyl-methylene; 68) L is di-methyl-methylene; 69) L is methyl-ethylene; 10 70) L is gem-di-methyl-ethylene; 71) L is gem-ethane-ethylene; 72) R1S is Ph2; 73) R15 is Ph2 substituted with 1 to 3 halo substituents; 74) R15 is Ph2 substituted with cyano; 15 75) R15 is Ph2 substituted with alkoxy (C? -C6); 76) R15 is Ph2 substituted with (C? -C6) alkoxy optionally further substituted with 1 to 3 fluoro substituents; 77) R15 is Ph2 substituted with (C? -C6) alkoxy alkyl (C? -C?); 78) R15 is Ph2 substituted with (C? -C6) alkoxy (C? -C?) Alkyl further substituted with 1 to 3 fluoro substituents; 79) R15 is Ph2 substituted with alkylthio (C? -Cd); 80) R15 is Ph2 substituted with alkylthio (Cx-Cß) optionally further substituted with 1 to 3 fluoro substituents; 81) R15 is Ph2 substituted with alkylthio (C-C6) alkyl (Cx-25 Cx); 82) R15 is Ph2 substituted with alkylthio (C? -C6) alkyl (C? -Cx) further substituted with 1 to 3 fluoro substituents; 83) R15 is Ph2 substituted with cycloalkyl (C3-C7) alkyl (Co-Ci); 84) R15 is Ph2 substituted with alkylsulfonyl (Ci-Cβ) (C0-C?) Alkyl optionally further substituted with 1 to 3 fluoro substituents; 85) R15 is Ph2 substituted with alkylsulfinyl (C? -C6) (C0-C?) Alkyl optionally further substituted with 1 to 3 fluoro substituents; 86) R15 is Ph2 substituted with Ph 1 -alkyl (C0-C?) -sulfonyl; 87) R15 is Ph2 substituted with P? ^ - (C0-C?) Alkyl; 88) R15 is Ph2 substituted with R26R27N-; 89) R15 is Ph2 substituted with Het1; 90) R15 is Ph2 substituted with (C? -C6) -C (O) alkyl optionally further substituted with 1 to 3 fluoro substituents; 91) R15 is Ph2 substituted with (C? -C6) -0-C (O) alkyl optionally further substituted with 1 to 3 fluoro substituents; 92) R15 is Ph2 substituted with Ph1; 93) R15 is Ph2 substituted with Ph1 (C0-C3) -O- alkyl; 94) R15 is Ph2 substituted with Ph1 alkyl (C0-C3) -C (O) -; 95) R15 is Ph2 substituted with Ph1 alkyl (C0-C3) -C (O) -; 96) R15 is Ph2 substituted with Ar2 (C0-C3) alkyl-C (O) -; 97) R15 is Ph2 substituted with Ar2 (C0-C3) -C (0) - alkyl and Ar2 is optionally substituted pyrazolyl as provided for Ar2; 98) R15 is Ph2 substituted with R28R29N-C (0) -; 99) R15 is Ph2 substituted with R28R29N-C (0) - and R28 is alkyl (C? -C6); 100) R15 is Ph2 substituted with R28R29N-C (0) - and R28 is (C3-C7) cycloalkyl (C0-C3) alkyl; 101) R15 is Ph2 substituted with R28R29N-C (0) - and R28 is Phx-n-alkyl (Co ~ C2) optionally substituted on the alkyl portion when presented with (C? -C3) alkyl, dimethyl, or -ethane gem; 102) R15 is Ph2 substituted with R28R29N-C (O) - and R28 is Ar2-alkyl (Co ~ C2) -n- optionally substituted on the alkyl portion when presented with (C? -C3) alkyl, dimethyl, or - ethane gem; 103) R15 is Ph2 substituted with Hetx-C (0) -; 104) R15 is Ph2 substituted with Het1-C (0) - further substituted with Ph1; 105) R15 is Ar2; 106) R15 is Ar2 further substituted with methyl; 107) R15 is Ar2 further substituted with (C3-C7) cycloalkyl (Co ~ C2) alkyl, Het1, pyridyl, or phenyl optionally further substituted with methyl, -CF3, cyano, -SCF3, or with 1 to 3 halo substituents; 108) R15 is pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1, 3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, or 1,3,4-thiadiazolyl, any of which can optionally be substituted with 1 to 3 substituents selected from the group consisting of halo, cyano , -SCF3, (C? -C6) alkyl optionally further substituted with 1 to 6 fluoro, and (C? -Cg) alkoxy optionally further substituted with 1 to 6 fluoro. 109) R15 is optionally further substituted pyridyl as provided for Ar2; 110) R15 is tetrahydrofuranyl or tetrahydropyranyl, either optionally substituted with an oxo substituent, or with one or 2 groups independently selected from methyl and -CF3; 111) R15 is tetrahydrofuranyl or tetrahydropyranyl, are substituted with an oxo substituent, and optionally are further substituted with one or 2 groups independently selected from methyl and -CF3; 112) R15-L- is pyrid-2-ylmethyl; 113) R15-L- is pyrid-3-yl-methyl; 114) R15-L- is pyrid-2-yl-CH (CH3) -; 115) R15-L- is pyrid-3-yl-CH (CH3) -; 116) R15 is pyridazinyl optionally further substituted as provided for Ar2; 117) R -L- is pyridazin-2-yl-methyl; 118) R15-L- is pyridazin-3-yl-methyl; 119) R15-L- is pyridazin-2-yl-CH (CH3) -; 120) R15-L- is pyridazin-3-yl-CH (CH3) -; 121) R15 is pyridyl further substituted with (C3-C) cycloalkyl (C0-C2) alkyl, Het1, pyridyl, or phenyl optionally further substituted with methyl, -CF3, cyano, -SCF3, or with 1 to 3 halo substituents; 122) R15 is pyridazinyl further substituted with (C3-C7) cycloalkyl (C0-C2) alkyl, Het1, pyridyl, or phenyl optionally further substituted with methyl, -CF3, cyano, -SCF3, or with 1 to 3 halo substituents; 123) R15 is R22-C (0) -; 124) R15 is R22-C (0) - and R22 is (C? -C6) alkyl optionally substituted with 1 to 6 fluoro substituents; 125) R15 is R22-C (0) - and R22 is (C? -C6) alkoxy optionally substituted with 1 to 6 fluoro substituents; 126) R15 is R22-C (0) - and R22 is (C3-C7) cycloalkyl (C0-C3) alkyl; 127) R15 is R22-C (0) - and R22 is (C3-C7) cycloalkyl (C0-C3) -0- alkyl; 128) R15 is R22-C (0) - and R22 is Pl ^ -alkyl (C0-C3); 129) R15 is R22-C (0) - and R22 is Ph1-(C0-C3) -O- alkyl; 130) R15 is R22-C (0) - and R22 is Ar2-(C0-C3) alkyl; 131) R15 is R22-C (0) - and R22 is Ar2-(C0-C3) alkyl-O-; 132) R15 is R2-C (0) - and R22 is R32R33N-; 133) R15 is phthalimido; 134) R15 is R17R18N-; 135) R15 is R17R18N- and R17 is (C-C3) -C (0) - alkoxy; 136) R15 is R17R18N- and R17 is (C3-C7) cycloalkyl (C0-C2) -C (0) -; 137) R15 is R17R18N- and R17 is Ph1- (C0-C2) -C (0) -; 138) R15 is R17R18N- and R17 is Ar2- (C0-C2) -C (0) -; 139) R15 is R160-; 140) R15 is R160- and R16 is oalkyl (C? -C6) -C (0) -; 141) R15 is R160- and R16 is (C3-C7) cycloalkyl (C0-C2) -C (0) -; 142) R6 is R2 R25N- and R24 is (C6-6) alkoxy (C2-C5) alkyl optionally substituted with 1 to 6 fluoro substituents; 143) R6 is R24R25N- and R24 is alkylthio (C? -C6) (C2-C5) alkyl optionally substituted with 1 to 6 fluoro substituents; 144) R6 is R24R25N- and R24 is (C3-C7) cycloalkyl (C0-Cx) -O-alkyl (C? -C5); 145) R6 is R24R25N- and R24 is (C3-C7) cycloalkyl (Co-Ci) -S-alkyl (C? -C5); 146) R6 is R24R25N- and R24 is phenyl n-alkyl (C? -C3) optionally substituted on the n-alkyl portion when presented with (C? -C3) alkyl, dimethyl, or gem ethane; 147) R6 is R2 R25N- and R24 is Ph2-n-alkyl (C? -C3) optionally substituted on the n-alkyl portion when presented with (C? -C3) alkyl, dimethyl, or gem ethane; 148) R6 is R24R25N- and R24 is Ar2 n-C0-C3 alkyl optionally substituted on the n-alkyl portion when presented with (C? -C3) alkyl, dimethyl, or gem ethane; 149) R6 is R2R25N- and R24 is Ar2 n-C0-C3 alkyl optionally substituted on the n-alkyl portion when presented with alkyl (C? -C3), dimethyl, or gem ethane, wherein Ar2 contains an atom of nitrogen, and Ar2 is substituted; 150) R6 is R24R25N- and R24 is Ar2 n-(C0-C3) alkyl optionally substituted on the n-alkyl portion when presented with (C? -C3) alkyl, dimethyl, or gem ethane, where Ar2 contains an atom of nitrogen, and Ar2 is substituted with (Cx-Cβ) alkoxy optionally further substituted with 1 to 6 fluoro, alkylamino (Ci-Ce) optionally further substituted with 1 to 6 fluoro, or (C3-C7) cycloalkyl (C0-C2) alkyl optionally also substituted with 1 to 6 fluoro; 151) R6 is R24R25N- and R24 is Ar2 n-(C0-C3) alkyl optionally substituted on the n-alkyl portion when presented with alkyl (C? -C3), dimethyl, or gem ethane, and wherein Ar2 is pyridyl or pyridazinyl and is substituted with optionally further substituted alkoxy (Cx-Ce) with 1 to 6 fluoro, alkylamino (C? -Ce) optionally further substituted with 1 to 6 fluoro, or (C3-C7) cycloalkyl (C0-C2) alkyl optionally further substituted with 1 to 6 fluoro; 152) R6 is R24R25N- and R24 is Ar2 n-C0-C3 alkyl optionally substituted on the n-alkyl portion when presented with (C1-C3) alkyl, dimethyl, or gem-ethane, and wherein Ar2 is substituted pyridyl with R28R29N-C (0) - and R28 is (C3-O7) cycloalkyl (C0-C2) alkyl or Ph1 and R29 is hydrogen; 153) R6 is R2 R25N- and R24 is Ar2 n-(C0-C3) alkyl, wherein Ar2 is pyridyl substituted with R28R29N-C (0) - and R28 is (C3-C7) cycloalkyl or phenyl optionally substituted with 1 to 3 halo, preferably fluoro, and R29 is hydrogen; 154) Rd is R24R25N- and R24 is PiT-alkyl (C0-C?) -O-alkyl (C? -C5); 155) R6 is R2 R25N- and R24 is Phx-alkyl (C0-C?) -S-alkyl (C1-C5) / 156) R6 is R24R25N- and R24 is Ph ^ alkyl (C0-C?) -C (0) NH-alkyl (C2-C4); 157) R6 is R2 R25N- and R24 is Ph ^ (C0-C?) -NH-C (0) NHalkyl (C2-C4) alkyl; 158) R6 is R24R25N- and R24 is pyridyl (C0-C?) Alkyl-C (0) NHalkyl (C2-C4) optionally substituted in the pyridyl moiety with methyl, -CF3, or 1 to 3 halo substituents; 159) R6 is R24R25N- and R24 is pyridyl-alkyl (C0-C?) -NH-C (0) NHalkyl (C2-C4) optionally substituted in the pyridyl moiety with methyl, -CF3, or 1 to 3 halo substituents; 160) R6 is R24R25N- and R24 is Ar3-alkyl (C? -C2); 161) R6 is R2 R25N- and R24 is Ar3-methyl; It will be understood that the above classes can be combined to form additional preferred classes. Exemplary combinations include, but are not limited to: 162) Any of preferred embodiments 19) to 161) (the preferred sections for R6), combined with any of preferred embodiments 1) through 9) (the preferred sections for R7); 163) Any of preferred embodiments 19) to 161) (the preferred sections for R6), wherein R7 is halogen; 164) Any of the preferred embodiments 19) to 161) (the preferred sections for R6), wherein R7 is chloro; 165) A preferred combination according to 162), 163), or 164), wherein R1-5, and R8 are each hydrogen; 166) A preferred combination according to 162), 163), or 164), wherein R1-5, R8 and R9, are each hydrogen. 167) Any of the preferred embodiments 37), 38), or 39), wherein R7 is different from hydrogen; 168) Any of the preferred embodiments 37), 38), or 39), wherein R9 is hydrogen; 169) Any of preferred embodiments 37), 38), or 39), wherein R7 is different from hydrogen and R9 is hydrogen; 170) Any of the preferred embodiments 37), 38), or 39), wherein R7 is chloro and R9 is hydrogen; 171) The compounds of the formula (I) wherein Rd is -C = C-R10 and wherein R10 is selected from defined values in any of the embodiments 19) to 28); 172) The compounds of the Formula (I) wherein R6 is -0-R12 and wherein R12 is selected from defined values in any of the embodiments 30) to 53); 173) The compounds of the Formula (I) wherein R6 is -S-R14 and wherein R14 is selected from the defined values in any of the embodiments 55) to 63) or 64) wherein L is selected from the values of 65) to 71) and R15 is selected from the values defined in any of the modes 72) to 141); 174) The compounds of the formula (I) wherein R6 is R2R25N- and wherein R24 is selected from the defined values in any of the embodiments 142) to 161); 175) The compounds according to embodiment 172) wherein R12 is selected from the values defined in any of the modalities 37), 38) or 39); 176) The compounds of the formula (I) wherein R7 is different from hydrogen; 177) The compounds according to any of embodiments 171) or 174) wherein R7 is different from hydrogen; 178) The compounds according to any of embodiments 171) or 174) wherein R7 is chloro; 179) The compounds according to any of embodiments 171) or 174) wherein R9 is hydrogenous) Compounds according to any of embodiments 171) or 174) wherein R9 is (C1-C3) alkoxy; 181) The compounds according to any of embodiments 171) or 174) wherein R9 is methoxy; 182) Compounds according to any of embodiments 171) or 174) wherein R7 is chloro and R9 is hydrogenated) Compounds according to any of embodiments 171) or 174) wherein R7 is chloro and R9 is alkoxy ( C? -C3); 184) The compounds according to any of embodiments 171) or 174) wherein R7 is chloro and R9 is methoxy; 185) The compounds according to any of embodiments 171) or 185) wherein R9 is hydrogen; 186) The compounds according to any of embodiments 171) or 185) wherein R9 is (C? -C3) alkoxy; 187) The compounds according to any of embodiments 171) or 185) wherein R9 is methoxy; 188) Compounds according to any of embodiments 171) or 187) wherein R1"5 are each hydrogen; Generally, when R6 is -S-R14, then R15-L- is more preferred R14.When R14 or R15 is substituted Ar2, para-substitution is preferred When L is present, particularly methylene, and methyl-methylene are particularly preferred R15-L- is when R15 is Ph2 and L is methylene Also particularly preferred is when R15 is Ph2 and L is methyl-methylene Also particularly preferred is when R15 is Ar2 and L is methylene Also particularly preferred is when R15 is Ar2 and L is methyl-methylene Also generally, when Rd is -NR2R25, then Ph2-n-alkyl (C? -C3) is particularly preferred on phenyl n-alkyl (C? -C3) Preferred compounds of Formula (I) are those wherein R6 is -C = C-R10 and wherein R10 is selected from the values defined in any of the modes 19) to 28), or R6 is -O-R12 and in wherein R12 is selected from the values defined in any of the embodiments 30) to 53); or R6 is -S-R14 and wherein R14 is selected from the values defined in any of the modes 55) to 63) or mode 64) wherein L is selected from the defined values in any of the modes 65) to 71) and R15 is selected from the values defined in any of the modes 72) to 111) and 121 to 141), or R15-L- is selected from the values defined in any of the embodiments 112) to 120); or R6 is R24R25N- and wherein R24 is selected from the defined values in any of modalities 143) to 161). Particularly preferred compounds of Formula (I) are those wherein R6 is -O-R12 and wherein R12 is selected from the defined values in any of embodiments 37), 38) or 39).

In addition, the preferred compounds of the formula (I) are those in which R7 is different from hydrogen. In particular, R7 is preferably selected from the values defined in any of the embodiments 1) to 8). More preferably, R7 is selected from halo (especially chloro), (C? -C3) alkyl optionally substituted with 1 to 6 fluoro substituents (especially methyl, ethyl, n-propyl or CF3), and cyano. Particularly preferred compounds of the formula (I) are those wherein R7 is halogen, and in particular wherein R7 is chloro. Preferred compounds of the formula (I) are those in which R9 is (C? -C3) alkoxy, preferably methoxy, or halo, preferably chloro. Also preferred are those compounds of the formula (I) wherein R9 is hydrogen. Particularly preferred compounds of formula (I) are those wherein R7 is different from hydrogen and R9 is hydrogen, and more especially wherein R7 is chloro and R9 is hydrogen. In addition, the preferred compounds of the formula (I) are those wherein R 1 is hydrogen. Also preferred are those compounds of the formula (I) wherein R2 is hydrogen. Also preferred are compounds of the formula (I) wherein R3 is hydrogen or methyl, and especially wherein R3 is hydrogen. Other preferred classes of compounds of formula (I) is that wherein R 4 is hydrogen, methyl or ethyl, particularly wherein R 4 is hydrogen or methyl, and especially wherein R 4 is hydrogen. Furthermore, those compounds of the formula wherein R5 is hydrogen are preferred. Also preferred are those compounds of the formula (I) wherein R8 is hydrogen. A preferred group of the compounds of the present invention is that represented by the formula (la), and pharmaceutically acceptable salts thereof: wherein R7a is halogen, and especially chloro; R9a is hydrogen, halogen or (C? -C3) alkoxy, particularly hydrogen, chlorine or methoxy, and especially hydrogen; and R6 as defined in relation to formula (I). Preferred specific compounds of the present invention are those described in the Examples herein, including the free bases and the pharmaceutically acceptable salts thereof. It will be appreciated that the preferred definitions of the various substituents mentioned herein may be taken alone or in combination and, unless otherwise stated, applied to the generic formula (I) for compounds of the present invention, as well as to the preferred classes of the compounds represented by the formula (la). The compounds of the invention can be prepared according to the following synthetic schemes by methods well known and appreciated in the art. Suitable reaction conditions for the steps of these schemes are well known in the art and appropriate substitutions of solvents and co-reactants are within the skill in the art. Similarly, it will be appreciated by those skilled in the art that synthetic intermediary schemes can be isolated and / or purified by various techniques well known as necessary or desired, and that frequently, it will be possible for use of several intermediates directly in subsequent synthetic steps with little or no without purification. Additionally, the experienced technician will appreciate that in some circumstances, the order in which the portions are introduced is not critical. The particular order of the steps required to produce the compounds of the formula I depends on the particular compound being synthesized, the starting compound, and the relative reliability of the substituted portions as is well appreciated by those of ordinary skill in the art. All substituents, unless otherwise indicated, as previously defined, and all reagents are well known and appreciated in the art. The compounds of the formula I wherein R6 is a substituent linked to acetylene can be prepared as illustrated in the reaction scheme I where Pg is a suitable protecting group for a secondary amine such as, but not limited to, 2, 2, 2 -trifluoroacetyl or tert-butoxycarbonyl, and variables R1, R2, R4, R5, R7, R8, R9 and R10 as previously defined.

Reaction scheme I (a) ® (la) The 6-triflate mixture of 2, 3, 4, 5-tetrahydro-lH-benzo [d] azepines (a) with an appropriately substituted acetylene, a suitable palladium / copper catalyst mixed in A solvent, typically DMF, uses triethylamine as a base, and is heated to provide the desired compound (b). The deprotection reaction and standard chromatographic and extractive techniques provide the desired compound (la). The appropriate 6-triflate of 2, 3, 4, 5-tetrahydro-lH-benzo [d] azepines (a) can be prepared as described in Reaction Scheme II. The compound (a) can be prepared from 1-naphthol. 1-Naphthol can be converted to 5-hydroxy-l, 4-dihydronaphthalene (c) by Birch reduction using ammonia and lithium metal at lower temperature. Methylation of the 6-hydroxy group provides the compound (d). Ozonolysis of (d) and subsequent reduction with sodium borohydride provides the diol (e). After the 2 hydroxyl groups are converted into 2 good starting groups, for example methanesulfonates, the compound (f) is cyclized to the 6-methoxy-2,3,4,5-tetrahydro-lH-benzo [d] azepines (g) with aqueous ammonia under pressure. The nitrogen in the ring is protected with a variety of alkyl halides, chloro acids or anhydrides such as trifluoroacetic anhydride to give the compound (h). Subsequently methyl ether (h) is converted to phenol (i) with BBr3 in dichloromethane or other methods well known in the literature [see for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and sons, Chapter III, New York (1999)]. The functionalization of the aromatic ring to introduce the substituents R7, R8 and R9 is well known in the art and very dependent on the desired substitution. The subsequent trifluoromethanesulfonylation of 6-hydroxy (j) gives the desired 2, 3, 4, 5-tetrahydro-lH-benzo [d] azepines (a) Reaction Scheme II Ce) (eO e) 0) Ca) Alternatively, compound (g) can be prepared from 1,2-bis (cyanomethyl) -3-methoxybenzene (1), previously described in the literature (J. Med. Chem. 1984, 27, 918-921), as shown in Reaction Scheme III below.

Reaction scheme III The compounds of the formula I wherein R6 is an oxygen-linked substituent can be prepared as illustrated in Reaction Scheme IV where Pg is a suitable protecting group for secondary amine, such as 2,2,2-trifluoroacetyl or tert-butoxycarbonyl, and variables R7, R9 and R12 are as previously defined.

Reaction Scheme IV Ü) Cm) (Ib) Compound (m) can be prepared by treating 6-hydroxy-2, 3, 4, 5-tetrahydro-lH-benzo [d] azepines (j) with an appropriate alkylation reagent, such as a alkyl halide or sulfonate, and a base in a suitable solvent, typically acetone, ethanol or acetonitrile, followed by standard chromatographic and extractive techniques. Deprotection of the nitrogen ring gives the compound (Ib).

Alternatively, the compound (m) can be obtained by Mitsunobu reaction with an appropriate alcohol, a phosphine reagent such as triphenylphosphine, and diethyl azodicarboxylate (DEAD) or 1, 1 '- (azodicarbonyl) -dipiperidine in an anhydrous solvent, for example THF . Compounds of the formula LE where R6 is a nitrogen-linked substituent can be prepared as illustrated in Reaction Scheme V. The 2, 3,, 5-tetrahydro-IH-benzo [d] azepines protected by 6-triflate (a ) can be converted to the compounds (n), under Buchwaid conditions, by treatment with an appropriate amine (q) in the presence of an effective palladium catalyst, and a base in a suitable solvent, typically toluene or 1,4-dioxane under a inert atmosphere. The introduction of a second substituent R25, if necessary, can be carried out. Standard chromatographic and working techniques followed by deprotection give the compound (le). Alternatively the 6-amino-2, 3, 4, 5-tetrahydro-lH-benzo [d] azepines (p) can be transformed to the desired compound (n) by reaction with an appropriate bromide (r), and an appropriate base in a suitable solvent. The bromides (r) are either commercially available or can be prepared by methods well known to one of skill in the art. The amines (q) are either commercially available or can be prepared by methods well known to the skilled artisan.

Reaction Scheme V The compounds of formula I wherein R is a sulfur-linked substituent can be prepared as illustrated in Reaction Scheme VI.

Reaction Scheme VI (Id) The 3- (tert-butoxycarbonyl-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepines appropriately substituted with an appropriate base in a suitable solvent, such as methanol, is heated. , to obtain the thiol intermediate (t) The thiol intermediate (t) is isolated, if required, and treated with an appropriate electrophile (alkyl halide or sulfonate) The compound (u) is isolated by chromatographic and extractive techniques standards and is deprotected to provide the desired compound (Id.) The required halides and alkyl sulfonates are either commercially available or can be prepared by methods well known to the skilled artisan.The skilled artisan will also appreciate that not all substituents in the compounds of Formula I will tolerate certain reaction conditions used to synthesize the compounds.These portions can be introduced at a convenient point in the synthesis, or they can be protected and then deprotegers e as necessary or desired, as is well known in the art. The skilled artisan will appreciate that the protecting groups can be removed at any convenient point in the synthesis of the compounds of the present invention. The methods for introducing and removing the protecting groups used in this invention are well known in the art; see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and sons, New York (1999). The following preparations and examples are illustrative of methods useful for the synthesis of the compounds of the present invention. The exemplified compounds are also particularly preferred compounds of the present invention.

General procedure 1-1 Dissolve. 3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine appropriately substituted in ammonia / methanol solution (1.0-7.0 M). Stir for 1-16 h at room temperature unless otherwise specified. The volatiles are removed in vacuo. Purify by chromatography on silica gel by levigating with 1-20% 2M ammonia / methanol in DCM, or by SCX chromatography levigating with 1.0-7.0 M ammonia in methanol.

General Procedure 1-2 3- (2,2,2-Trifluoroacetyl) -2, 3, 4, 5-tetrahydro-1H-benzo [d] azepine is appropriately substituted (1.0 equiv.) In methanol. A 0.5 M aqueous solution of potassium carbonate (4.0 equiv.) Is added and stirred at room temperature for 6 h. Concentrate in vacuo and partition the residue between water and DCM. The aqueous phase is extracted twice with DCM. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. If necessary, they are purified by chromatography on silica gel by levigating with 1-20% 2M ammonia / methanol in DCM, or by SCX chromatography levigating with 1.0-7.0 M ammonia in methanol.

General procedure 1-3 Properly substituted 3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine is dissolved (1.0 equiv.) In methanol or ethanol (solution 0.1 to 2M) and 10-50% by volume of a 1.0-5.0 N aqueous solution of sodium hydroxide or lithium hydroxide is added. The reaction mixture is stirred at room temperature for 0.25-16 h and concentrated in vacuo. The residue is partitioned between EtOAc or DCM and water. The organic fraction is dried and dried over Na 2 SO 4, filtered, and concentrated in vacuo. Purify by SCX chromatography, followed by chromatography on silica gel by levigating with 1-20% 2M ammonia / methanol in DCM or reversed phase HPLC.

General Procedure 1-4 Appropriately substituted 3-tert-butoxycarbonyl-2,3,4,5-tetrahydro-1H-benzo [d] azepine is dissolved in 4M hydrogen chloride in dioxane or 1M hydrogen chloride in ethyl ether and stir the mixture for 2-16 h at room temperature unless otherwise specified. The solvent is removed in vacuo. If a solid is obtained, wash the solid with ether and filter under vacuum to provide the desired hydrochloride salt. If an oil is obtained, dissolve the oil in a minimum volume of DCM, methanol or EtOAc and add ether to precipitate the solid. The solvent is removed in vacuo, the solid is washed with ether and filtered. The solid is dried in vacuo or under a stream of nitrogen.

General Procedure 1-5 Properly substituted 3-tert-butoxycarbonyl-2,3,4,5-tetrahydro-1H-benzo [d] azepine is dissolved in a mixture of trifluoroacetic acid / DCM (from 1: 0 to 1:10 ratio) and the reaction is stirred for 1-16 h at room temperature. Concentrate in vacuo and either the residue is subjected to SCX chromatography or the residue is partitioned between saturated aqueous NaHCO3 and DCM or EtOAc. Dry the organic layer over Na2SO4 and concentrate in vacuo. It is purified either by chromatography on silica gel (levigating with 1-20% ammonia / 2M methanol in DCM) or reversed phase HPLC.

General procedure 1-6 Acetyl chloride (40 equiv.) Is added to cold methanol (0 ° C) and stirred for 5 min. Then a solution of appropriately substituted 7-chloro-3- (tert-butoxycarbonyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (1 equiv.) In methanol is added. The reaction is stirred at room temperature for 12 h. The solvent is removed in vacuo, basified with saturated aqueous NaHCO 3 and extracted 3 times with DCM. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel, levigating with 1-20% 2M ammonia / methanol in DCM.

General procedure 2-1 The purified free base (1 equiv.) Is dissolved in acetone, ether or methanol and a solution of succinic acid (1 equiv.) In a minimum volume of acetone or methanol is added. Stir for 1 h at room temperature. Concentrate to an oil, add a minimum volume of DCM and ethyl ether to precipitate the salt. Alternatively, to precipitate the salt, the reaction mixture is allowed to stand 1-16 h at room temperature, 4 ° C or -10 ° C and ether or hexane is added. Filter and wash the solid with ether or hexane to obtain the succinate salt. Alternatively, the solvent is evaporated in vacuo, the solid is washed with ether and the solvent is filtered or decanted to obtain the succinate as a solid. The solid is dried in vacuo or under a stream of nitrogen.

General procedure 2-2 The purified free base (1 equiv.) Is dissolved in a minimum volume of acetone, dioxane, methanol or DCM and an excess of 4M hydrogen chloride in dioxane or a 1M solution of hydrogen chloride in ether is added. ethyl. Stir for 1 h and evaporate the solvent to obtain the salt as a solid. Alternatively, the reaction mixture is allowed to stand for 1 to 16 h at room temperature and ether or hexane is added to precipitate the salt. Filter and wash the solid with ether or hexane to obtain the salt as a solid. Alternatively, the solvent is evaporated in vacuo, the solid is washed with ether, the solvent is filtered or decanted to obtain the hydrochloride salt as a solid. The solid is dried in vacuo or under a stream of nitrogen.

General Procedure 2-3 The purified free base is dissolved in methanol, a solution of ammonium chloride (1 equiv.) In methanol is added and it is stirred for 1 h. Slowly the volatiles are removed in vacuo. The residue is dissolved in methanol and more of the solvent is removed in vacuo. Anhydrous ethyl ether or EtOAc is added to precipitate the hydrochloride salt. The solid is collected, the solid is washed with ether and then the solid is dried in vacuo or under a stream of nitrogen.

General procedure 2-4 The purified free base (1.0 equiv.) Is dissolved in methanol. A 0.5 M solution of methanesulfonic acid in methanol (2.0 equiv) is added. Mix well, stir for 1 h, then remove the solvent in vacuo. The residue is dissolved in a minimum volume of DCM. Ethyl ether is added to precipitate the solid. The solvent is removed in vacuo to form a foam. Dry in vacuo or under a stream of nitrogen to obtain the methanesulfonic acid salt.

General procedure 2-5 The purified free base (1 equiv.) Is dissolved in a minimum volume of acetone and a solution of oxalic acid (1 equiv.) In a minimum volume of acetone is added, the mixture is allowed to stand for 10 min. 16 at room temperature to -10 ° C, and / or ether or hexane is added to precipitate the solid. Filter and wash the solid with ether or hexane to obtain the oxalic acid salt as a solid. The solid is dried in vacuo or under a stream of nitrogen.

General Procedure 2-6 The purified free base (1 equiv.) Is dissolved in a minimum volume of cyclohexane, isohexane, chloroform, dichloromethane, methanol or a mixture thereof and a solution of (L) -tartaric acid in isopropanol is added or methanol. If a precipitated solid is filtered and the solid is washed with ether, cyclohexane, isohexane or EtOAc. If the formation of the non-solid is observed, all volatiles were removed in vacuo to form a foam. Dry in vacuo or under a stream of nitrogen to obtain the tartaric acid salt.

General Procedure 3 Suitable 3-substituted 3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine or 7-chloro-3- (2,2,2-trifluoroacetyl) is dissolved ) -6-trifluoromethanesulfonyloxy- 2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (1 equiv.), PdCl2 (PPh3) 2 (0.1 equiv.), Tetrabutyl ammonium iodide (3 equiv.), and copper iodide (I) (0.3 equiv.) in triethylamine / DMF (1: 5). The mixture is stirred for 5 min at room temperature, the suitably substituted acetylene (2 equiv.) Is added and heated at 70 ° C for 2-16 h in a sealed tube. The reaction mixture is cooled to room temperature, diluted with EtOAc / hexane (1: 1) and washed with water. The organic fraction is dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc mixtures.

Preparation 1 7-Chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine -Methoxy-1, 4-dihydronane aleno: Powdered potassium carbonate (193.1 g, 1397 mol) is added to a solution of 5-hydroxy-1,4-dihydronaphthalene [68.08 g, 90% potency based on 1H -RMN / 0.4657 mol, from Societa Italiana Medicinala Scandicci, srl, Reggello (Florence), Italy] in ethanol (700 mL). The solution is cooled to 0 ° C with ice / water and dimethyl sulfate (88.1 g, 66.1 mL, 0.699 mol) is added dropwise, maintaining the temperature between 5 ° C and 10 ° C. The reaction mixture is then heated to 40 ° C until the CCD (10: 1 hexane / EtOAc) shows the absence of starting material (about 2 h). The solids are completely filtered by vacuum filtration and the solvent is removed in vacuo. The residual brown oil is diluted with diethyl ether (500 mL), washed with 10% aqueous NH 4 OH (500 mL), water (500 mL), brine (500 mL), the organic layer is dried over Na 2 SO 4, filtered and Concentrate in vacuo to give the crude product as a brown oil (73 g). The crude product is purified by a short path distillation under vacuum (bp 120-13 ° C / 5 Torr) to give the desired intermediate as a clear oil (69.0 g, 92.5% correct potency) (contains some 1, 2, 3,4-tetrahydro-5-methoxynaphthalene as an impurity). 1 H NMR (300 MHz, CDC13), d 7.15 (t, ÍH, J = 7.9), 6.72 (dd, 2H, J = 15.7, 7.9), 5.93-5.88 (m, 2H), 3.83 (s, 3H), 3.42-3.39 (m, 2H), 3.30-3.28 (m, 2 H); Rf = 0.58 levigating with 10: 1 hexane / EtOAc. 2, 3-Bis- (2-hydroxyethyl) -1-methoxybenzene: Change a 5-L 4-necked flask equipped with a mechanical top-head stirrer, reflux condenser, thermocouple, and gas dispersion apparatus with 5- methoxy-1-dihydronaphthalene (264.54 g, 89.5% strength based on XH-NMR, 1478 mol) in DCM (1.3 L) and 2B-3 ethanol (1 L). Sudan III (10 mg) is added to give a faint red color. The solution is cooled to -65 ° C or lower, then 03 is passed through the solution until the solution becomes light yellow and the CCD (10: 1 hexane / EtOAc, KMn0 'dyed) shows the absence of the material starting (around 30 h). The solution is transferred by means of a cannula into a paste of NaBH 4 (97.8 g, 2.59 mol) in 2B-3 ethanol (500 mL) and cooled in ice / water. It is important that the temperature is maintained at or above 0 ° C, such as between 0 ° C and 10 ° C, throughout the transfer to ensure that the ozonide is completely reduced to the diol. After the transfer is complete, heat the solution to room temperature and stir for about 30 min. The thick solution is cooled to 0 ° C with ice / water then acetone (540 mL, 7.4 mol) is slowly added to remove excess NaBH4. After all the solids dissolve, the solvent is removed in vacuo. The yellow solid is dissolved in DCM (1 L) and water (1 L), the layers are separated and the aqueous layer is extracted with DCM (750 mL). The combined organic layers are washed with brine (1.5 L), toluene (750 mL) is added and the solvent is removed in vacuo. Dissolve the solid in DCM (500 mL) with heating, then add toluene (750 mL) and concentrate the solution in vacuo to give the desired intermediate as a light yellow solid (283.7 g, 89% correct power, mp 82 -83 ° C) (contains 1, 2, 3, 4-tetrahydro-5-methoxynaphthalene as an impurity (8.6%)). The product is further purified by vacuum drying overnight at 75 ° C, 5 Torr, to remove all but a trace amount of the 1, 2, 3, 4-tetrahydro-5-methoxynaphthalene impurity. 1 H NMR (300 MHz, CDC13), d 7.16 (dd, ÍH, J = 8.2, 7.6), 6.83 (s, 1H, J = 7.0), 6.76 (s, 1H, J = 8.2), 3.85-3.77 (m , 7H), 3.01-2.91 (m, 4H), 2.35 (s, 2H); 13 C NMR (300 MHz, DMSO-d 6), d 157.5, 138.9, 126.5, 125.2, 122.0, 108.4, 62.1, 60.5, 55.3, 36.1, 29.6; IR (KBr): 3006, 2960, 2886, 2829, 1583, 1461, 1440, 1264, 1091, 1041 c "1; MS (ES +) m / z 178 (M + H) +; Analysis calculated for C? H1603 : C, 67.32; H, 8.22; N, 0. Found: C, 67.26, H, 8.10, N, 0.21, Rf = 0.23 levigating with 95: 5 DCM / methanol. 2, 3-Bis- (2-me-ansulfonyloxyethyl) -1-methoxybenzene: To a paste of 2,3-bis- (2-hydroxyethyl) -1-methoxybenzene (50.6 g, 0.258 mol, 1 equiv.) And triethylamine ( 78.3 g, 0.774 mol, 3 equiv.) In DCM (500 mL) at 0 ° C, a solution of methanesulfonyl chloride (65.0 g, 0.567 mol, 2.2 equiv.) In DCM (100 mL) is added dropwise during 45 min. The addition is exothermic and methanesulfonyl chloride is added in a ratio to keep the temperature below 10 ° C. After the addition is complete, the reaction is heated to room temperature. The solution is washed with water (2 x 500 mL), and then brine (750 L). Dry the organic layer over Na 2 SO 4, filter and concentrate in vacuo to obtain the desired intermediate as a dark yellow oil (87.4 g, 96.2%), which is used in the next reaction without further purification. An analytical sample is obtained by flash column chromatography by levigating with 100% diethyl ether. 1H NMR (300 MHz, CDC13), d 7.20 (t, ÍH, J = 7.9), 6.82 (s, 1H, J = 7. 2), 6.80 (s, ÍH, J = 8.2), 4.41-4.34 (m, 4H), 3.83 (s, 3H), 3. 16-3.09 (m, 4H), 2.91 (s, 3H), 2.87 (s, 3H); 13C NMR (300 MHz, CDC13), d 158.07, 136.55, 128.26, 123.34, 122.39, 109.24, 69.88, 69.08, 55.55, 37.35, 37.14, 32.57, 26.47; 13 C NMR (300 MHz, DMSO-d 6), d 157.58, 136.79, 127.81, 122.91, 122.00, 109.33, 70.19, 68.88, 55.55, 36.49, 36.47, 31.56, 25.72; IR (KBr): 1586.8, 1469.4, 1358.51, 1267.3, 1173.9, 1105.4, 972.4, 954.6, 914.3 cm "1; MS (ES +) m / z 257 (M + H) +; Analysis calculated for C 13 H 20 O 7 S 2: C, 44.31; H, 5.72; N, 0. Found: C, 44.22, H, 5.68, N, 0.13, Rf = 0.72 levigating with 95: 5 DCM / methanol. 6-Methoxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: 2,3-bis- (2-methanesulfonyloxyethyl) -1-methoxybenzene (474.4 g, 1346 mol) is dissolved in acetonitrile (7). L) and the mixture was divided into 2 equal lots. In 2 separate runs, concentrated aqueous NHOH (3.5 L) is added and the solution is changed to a pressure vessel (PARR apparatus). The solution is heated in a closed reactor to 100 ° C for 20 min (internal pressure is reached around 100 psi (7.03 kg / cm2)), and maintained at 100 ° C until the reaction is complete (about 1 hr. , monitored with CLAR). The reaction mixture is cooled to room temperature. The 2 batches are combined and the solvent is removed in vacuo. The residue is dissolved in MTBE (3.5 L) and water (3.5 L). The pH is adjusted to 6.5 using 2M aqueous NaOH or 1M aqueous HCl as appropriate (typically the pH is around pH = 5.1 and the adjustment requires about 50 mL 2M aqueous NaOH). The organic layer is discarded, the aqueous layer is adjusted to pH = 13 using 50% NaOH (about 150 mL). Extract with MTBE (2 x 3.5 L), wash the combined organic layers with brine (3.5 L), dry over NaS04, filter and concentrate in vacuo to give the title compound as a crude yellow oil which solidifies during rest (179.3 g). The material is used for the next step without further purification. An analytical sample is prepared by purification by 2 Kugelrohr distillations to give a clear oil that solidifies upon standing, mp 44.3-45.0 ° C. 13 C NMR (300 MHz, DMSO-d 6) d 156.1, 144.4, 130.3, 126.2, 121.5, 108.9, 55.5, 48.2, 47.9, 39.9, 29.1; MS (ES +) m / z 163 (M + H) +; Analysis calculated for C H H15NO: C, 74.54; H, 8.53; N, 7.90. Found: C, 74.28, H, 8.62, N, 7.86. 6-Ethoxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride: 6-methoxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine crude (35.1) is dissolved g, 0.198 mol) in 2B-3 ethanol (250 mL), the solution is heated to reflux and 2M HCl in ethanol (108.9 mL, 0.218 mol, 1.1 equiv.) is added. Slowly add heptane (700 mL) for 10 min, then remove the heating layer and cool the solution to room temperature, and finally continue cooling with an ice / water mixture. The resulting solid is collected by vacuum filtration and washed with ethanol: cold heptane (1: 2) (3 x 100 mL), dried with air for 15 min under vacuum, then the product is also dried in a vacuum oven at 60 ° C for 1 h to give the desired intermediate as a white granular solid (35.53 g, 63%): mp 246.6-246.9 ° C; X H NMR (300 MHz, DMSO-d 6), d 9.82 (broad s, ÍH), 7.12 (dd, ÍH, J = 7.6, 7.9), 6.88 (d, 1H J = 8.2), 6.78 (d, 1H, J = 7.3), 3.75 (s, 3H), 3.20-3.00 (m, 8H); 13 C NMR (300 MHz, DMSO-d 6), d 156.2, 141.3, 127.4, 127.2, 121.6, 109.7, 55.7, 44.9, 44.7, 31.6, 21.7; MS (ES +) m / z 178 (M + H) +; Analysis calculated for CuH15ClNO: C, 62.12; H, 7.11; N, 6.59. Found: C, 61.95, H, 7.64, N, 6.58. 6- ethoxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: To a paste of 6-methoxy-2, 3, 4 hydrochloride, 5-tetrahydro-lH-benzo [d] azepine (35.3 g, 0.165 mol, 1 equiv.) And triethylamine (69.1 mL, 0.496 mol, 3 equiv.) In DCM (300 mL) is cooled to 0 ° C with ice / water, a solution of trifluoroacetic anhydride (25.7 mL, 0.182 mol, 1.1 equiv.) in DCM (40 mL) is added dropwise during 30 min, but at a ratio that keeps the temperature below 10 ° C. After the addition is complete, the reaction mixture is warmed to room temperature and stirred until the reaction is complete (check by CCD using 9: 1 CH2C12: methanol, about 2 h.). The solution is washed with water (2 x 350 mL), and then brine (350 mL), the organic layer is dried over Na 2 SO 4, filtered and concentrated in vacuo to give the desired intermediate as a yellow oil which solidifies during the rest (44.9 g, 96%). The material is used without further purification in the next step. An analytical sample is prepared by chromatography on silica gel by levigating with 40% diethyl ether in hexane, mp 74-76 ° C. XE NMR (300 MHz, CDC13), d 7.16-7.11 (m, 1H), 6.81-6.74 (m, 2H), 3.81 (s, 3H), 3.79-3.64 (m, 4H), 3.11-3.07 (m, 2H), 2.99-2.95 (m, 2H); X H NMR (300 MHz, DMSO-d 6), d 7.13 (dd, ÍH, J = 1.5, 7.0), 7.08 (d, ÍH, J = 1.5), 6.88-6.74 (m, 1H), 3.75 (s, 3H ), 3.67-3.61 (m, 4H), 3.04-2.92 (, 4H); 13 C NMR (300 MHz, DMSO-de), d 156.43. 156.38, 155.06, 155.00, 154.60, 154.54, 154.14, 154.08, 141.31, 141.04, 127.44, 127.18, 127.05, 127.01, 122.27, 121.94, 121.90, 118.46, 114.64, 110.80, 109.52, 109.41, 55.63, 55.61, 47.11, 47.07, 46.67, 46.63, 45.61, 45.16, 35.90, 34.65, 26.18, 24.91; Analysis calculated for C 13 H 14 F 3 N 0 2: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.17, H, 5.27, N, 5.08. 6-Hydroxy-3- (2, 2, 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine: To a 1M solution of BBr3 (1.1 L, 1.6 equiv.), cool to 0 ° C with an ice-water bath, add 6-methoxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-benzofd] azepine (187 g, 0.684 mol) in DCM (200 mL) for 1 h., While maintaining the temperature between 0 ° C and 10 ° C. The reaction mixture is warmed to room temperature and stirred until the HPLC indicates the completion of the reaction (about 2 hours). The solution is cooled to 0 ° C and transferred by means of a cannula into an ice / water solution (1.2 L), thereby precipitating the product as a white solid. EtOAc (2 L) is added to dissolve more of the precipitate, the layers are separated and the organic layer is concentrated in vacuo. The aqueous layer was extracted 3 times with EtOAc (2 x 2 L, 1 x 1 L). Wash the combined organic layers with water (2 L), then brine (2 L), dry over Na 2 SO 4, filter and concentrate in vacuo to give the desired intermediate as a light yellow solid (166.3 g, 94%). . The product is used for the next step without further purification. An analytical sample is prepared by chromatography on silica gel by levigating with 40% diethyl ether in hexane: m.p. 183.0-185.2 ° C. aH NMR (300 MHz, DMS0-d6), d 9. 39 (s, ÍH), 6.94-6.88 (m, 1H), 6.72-6.68 (m, ÍH), 6.61-6.57 (m, ÍH), 3.67-3.32 (m, 4H), 2.99-2.86 (m, 4H); 13C NMR (300 MHz, DMSO-d6), d 154.50, 141.47, 141.18, 126.77, 126.64, 125. 77, 125.33, 120.38, 120.32, 118.49, 114.67, 113.64, 113.47, 47.31, 47.27, 47.00, 46.96, 45.83, 45.49, 36.17, 34.93, 26.46, 25.18, 20.66, 14.00; MS (ES +) m / z 260 (M + H) +; Analysis calculated for C12H12F3N02: C, 55.60; H, 4.67; N, 5.40. Found: C, 55.51, H, 4.71, N, 5.29. 7-Chloro-6-hydroxy-3- (2, 2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: A mixture of 6-hydroxy-3- is heated (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (120 g, 0.4629 mol) and toluene (14.4 L) up to 70 ° C for 45 min until more of the starting material dissolves. Diisobutylamine (1197 g, 1.62 mL, 9.26 mmol) is added followed by the addition of sulfuryl chloride (62.48 g, 37.19 L, 0.463 mol) in toluene (360 mL) for 20 min. The reaction mixture is stirred for 50 min and then additional sulfuryl chloride (4.536 g, 2.70 mL, 0.0336 mol) is added and the reaction mixture is stirred for 15 min at 70 ° C. The reaction mixture is cooled to 24 ° C during min and then INN hydrochloric acid (2.00 L) is added. Separate, wash the organic layer with saturated aqueous NaHCO3 (2.00 L), brine (2.00 L) and then dried over Na2S04. Filter and remove the solvent with a rotary evaporator at 70 ° C until about 672.5 g remaining using the minimum effective vacuum in order to maintain a sufficient vapor phase to prevent drying above the solvent line and self-drying, in this way crystallization is prevented under these conditions. When using hot toluene at 70 ° C, transfer the light yellow solution to a pre-heated 3-neck flask (70 ° C) equipped with a mechanical stirrer. The temperature is reduced to 58 ° C for 1 h. If available, the solution is seeded with crystals of 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine from a previous synthesis to increase crystallization. After 30 min, the additional temperature is reduced to 55 ° C and the initiation of the crystallization process is observed. The temperature is maintained at 55 ° C for 2 h. then for 4 h. at 45 ° C, then the heat is turned off to allow the mixture to slowly reach 24 ° C (room temperature). After stirring for 8 h. With the heat off, the mixture is cooled to 0 ° C for 2 h. then for 2 h. at -10 ° C. The resulting dense, white and granular crystals were collected by vacuum filtration at -10 ° C. The crystals are rinsed twice with cold toluene (-10 ° C) and dried under vacuum at 50 ° C, 5 Torr, for 12 h., To obtain the desired intermediate as a white solid (120.7 g, 99.5% purity). , 88.8%): mp 133-134 ° C. MS (ES +) m / z 294 (M + H) +. Analysis calculated for C? 2HuClF3N02: C, 49.08; H, 3.78; N, 4.77; Cl, 12.07. Found: C, 49.01; H, 3.63; N, 4.72; Cl, 12.32. 7-Chloro-3- (2,2,2-trifluoroacetyl) -6-tri-fluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: A solution of 7-chloro-6 is cooled hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (60 g, 0.204 mol), triethylamine (62.6 mL, 0.448 mol, 2.2 equiv. ), and DCM (590 mL) in an ice bath and trifluoromethanesulfonic anhydride (43.5 mL, 0.258 mol, 1.26 equiv.) was added dropwise over 70 min. The ice bath is removed and the reaction mixture is stirred for 2 h. The reaction mixture is washed sequentially with water (500 mL), 1N aqueous HCl (500 L), water (500 mL), and brine (500 mL). Dry the organic layer over Na2SO4 and concentrate in vacuo to give the crude product as a brown solid (90 g). The solid is dissolved in hot toluene (200 mL). It is further purified by plug filtration chromatography on silica gel (500 g) by sequentially levigating with hexane (1 L), hexane / EtOAc (9: 1, 1 L), hexane / EtOAc (4: 1, 1 L), and hexane. EtOAc (7: 3, 9L). The levigantes are pooled and the solvent is evaporated to obtain the product as a yellowish brown solid (86.3 g). The solid is dissolved in hot EtOAc (86 mL) and then hexane (700 mL) is added. If available, the solution is seeded with crystals of 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanolsulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine from a previous synthesis to increase crystallization. The mixture is allowed to stand at room temperature for 30 min. The mixture is cooled to -10 ° C for 2 h, filtered, the crystals rinsed with cold hexane / EtOAc (-10 ° C), and air dried on the filter under vacuum to obtain the title as a first crop of crystals (73.54 g). The mother liquor is concentrated to obtain a solid (12.7 g). The solid was recrystallized from a mixture of EtOAc / hexane (15 mL: 121 L) to obtain the additional title compound (7.65 g, total yield: 81.19 g, 93%).

Preparation 2 3- (2,2,2-Trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine A solution of 6-hydroxy-3- (2,2,2-trifluoroacetyl) -2 is cooled, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (2 g, 7.72 mmol), triethylamine (1.4 mL, 10.1 mmol) and DCM (50 mL) in a cryogenic bath is fixed at -30 ° C and trifluoromethanesulfonic anhydride (1.7 mL, 10.1 mmol) is added dropwise over 20 min. Stir at -30 ° C for 2 h and then warm to room temperature overnight. The reaction mixture is washed sequentially with water (100 mL), IN aqueous HCl (100 mL), water (200 mL), and brine (200 mL). Dry the organic layer over Na2SO4 and concentrate in vacuo to give the title compound as a colorless to light yellow oil (2.7 g, 89%) which is used without purification. An analytical sample is obtained by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the title compound as a completely white waxy solid. GC-MS m / z: 391 (M +).

Preparation 3 3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine 6-Hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5,5-tetrahydro-1H-benzo [d] azepine (5-g, 19.3 mmol) is dissolved in 7N ammonia in methanol (50%). mL) and stirred at room temperature for 16 h. The reaction mixture is concentrated to an oil and used without further purification. The residue is dissolved in a solvent mixture consisting of methanol (20 mL), DCM (10 L) and water (100 L), and potassium carbonate (5 g) and di-tert-butyl-dicarbonate (5.05) are added. g, 23.2 mmol). The reaction mixture is stirred at room temperature for 16 h and concentrated in vacuo. The aqueous phase is extracted with DCM, dried over Na 2 SO 4, filtered and concentrated. The residue is used without further purification. Dissolve the material in a mixture of DCM (300 mL) and pyridine (30 mL) and cool in an ice bath. It is added dropwise to the stirred solution of trifluoromethanesulfonic anhydride (5.84 L, 34.7 mmol) and the reaction mixture is stirred for 2 h at room temperature. The reaction mixture is diluted with DCM (400 mL) and washed with 2.5N aqueous HCl. The organic fraction is dried over NaSO, filtered and concentrated to give the title compound as a yellow solid (6.1 g, 80%). MS (ES +) m / z: 396 (M + H) +.

Preparation 4 7-Fluoro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine 2-Sulfonate of N-fluoro-4,6-bis (trifluoromethyl) -pyridinium (3.02 g, 9.6 mmol) is added to a stirred mixture of 6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (2.5 g, 9.6 mmol) and hexafluoro-2-propanol (10 mL) in DCM (150 mL). Stir at room temperature for 16 h. The reaction mixture is concentrated and the residue is partitioned between EtOAc and IN aqueous HCl. The organic fraction is washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated. Purify by chromatography on silica gel by levigating with hexane / EtOAc (20: 1, 10: 1, 6: 1, 5: 1 and 3: 1) to give 7-fluoro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4, 5 -tetrahydro-lH-benzo [d] azepine as a white solid (1.8 g, 68%). 7-Fluoro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepine (1.5 g, 5.41 mmol) is dissolved in a mixture of DCM (20 mL) and pyridine (2 mL) and cooled in an ice bath. A mixture of trifluoromethanesulfonic anhydride (1.64 mL, 9.74 mmol) in DCM is added dropwise to the stirred solution and the reaction is stirred for 1.5 h at room temperature. The reaction is diluted with DCM (300 mL) and washed with 2.5N aqueous HCl. The organic fraction is dried over Na 2 SO 4, filtered and concentrated to give the title product as a white solid (2.2 g, 99%). MS (ES +) m / z: 410 (M + H) +.

Preparation 5 3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine Dissolve 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (3 g, 10.2 mmol) in 7 N ammonia in methanol (50 mL) and stirred at room temperature for 16 h. The reaction mixture is concentrated to an oil and used without further purification. The residue is dissolved in a solvent mixture consisting of DCM (25 mL) and saturated aqueous potassium carbonate solution (25 mL) and di-tert-butyl-dicarbonate (2.2 g, 10.2 mmol) is added. The reaction mixture is stirred at room temperature for 4 h, concentrated in vacuo and the aqueous residue extracted with DCM. The organic fraction is dried over Na 2 SO, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 5) to give the title compound as a white solid (2.3 g, 76%). MS (ES-) m / z: 296 (M-H). " Example 1 6- (3-Phenyl-prop-1-ynyl) -2, 3, 4, 5-tetrahydro-l-benzo [d] azepine hydrochloride A method similar to General Procedure 3 is used to couple 3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (0.6 g, 1.5 mmol) with 3-phenyl-1-propine (0.38 mL, 3 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 40: 1 and 20: 1) to give 3-tert-butoxycarbonyl-6- (3-phenyl-prop-1-ynyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as an aanaranjadodo oil (400 mg, 74%). A method similar to General Procedure 1-5 is used to deprotect 3-tert-butoxycarbonyl-6- (3-phenyl-prop-1-ynyl) -2, 3, 4, 5-tetrahydro-1H-benzo [d] azepine (68 mg, 0.19 mmol). Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (1: 0, 20: 1 and 10: 1) to obtain the free base of the title compound. A method similar to General Procedure 2-2 is used to give the title compound as a brown solid (48 mg, 85%). MS (ES +) m / z: 262 (M + H) +. Examples 2-4 can be prepared essentially as described in Example 1 by using 3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine and the appropriate alkene. The general performance and EM (ES +) data are shown in the Table below.

Example 5 Succinate of 6- (3, 3-Dimethyl-but-l-ynyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 3 is used to couple 3-tert-butoxycarbonyl-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (0.5 g, 1.3 mmol) with 3, 3- dimethyl-l-butyne (0.311 mL, 2.5 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (10: 1) to give 3-tert-butoxycarbonyl-6- (3, 3-dimethyl-but-l-ynyl) -2, 3, 4,5- tetrahydro-lH-benzo [d] azepine as a yellow oil (304 mg, 74%).

A method similar to General Procedure 1-5 is used to deprotect 3-tert-butoxycarbonyl-6- (3, 3-dimethyl-but-l-ynyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d ] azepine. Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (1: 0, 50: 1, 20: 1, 15: 1 and 10: 1) to obtain the free base of the title compound. A method similar to General Procedure 2-1 is used to give the title compound as a brown solid (171 mg, 53%). MS (ES +) m / z: 228 (M + H) +.

Example 6 Succinate of 6- (3,3-dimethyl-but-l-ynyl) -7-fluoro-2,3,3,5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 3 is used to couple 7-fluoro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (1 g, 2.4 mmol) with 3,3-dimethyl-l-butyne (0.599 mL, 4.9 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (10: 1) to give 6- (3,3-dlmethyl-but-1-ynyl) -7-fluoro-3- (2,2,2-trifluoroacetyl) ) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a yellow oil (700 mg, 84%). A method similar to General Procedure 1-3 is used to deprotect 6- (3, 3-dimethyl-but-l-ynyl) -7-fluoro-3- (2,2,2-trifluoroacetyl) -2,3,4 , 5-tetrahydro-lH-benzo [d] azepine. Purify by SCX chromatography followed by chromatography on silica gel levigating with DCM / ammonia 2M in methanol (1: 0, 50: 1, 20: 1, 15: 1 and 10: 1) to obtain the free base of the title compound. A method similar to General Procedure 2-1 is used to give the title compound as a white solid (589 mg, 83%). MS (ES +) m / z: 246 (M + H) +.

General Procedure 4-1 7-Chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-1H-benzo [d] azepine (1 equiv.) Is added, the appropriate alkylating agent (1.2 equiv.), ground K2C03 (3 equiv.) and Kl (0.1 equiv.) for a suitable solvent (acetone, ethanol or acetonitrile) and heated to reflux for 6 to 16 h unless otherwise specified. The reaction mixture is cooled to room temperature, quenched with IN aqueous HCl and the aqueous layer extracted 3 times with EtOAc. The organic fractions are combined, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc mixtures.

General procedure 4-2 7-Chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-1H-benzo [d] azepine (1 equiv.) Is added, the appropriate alcohol (1.1 equiv.), triphenylphosphine (1.2 equiv.) and diethyl azodicarboxylate (1.1 equiv.) sequentially for anhydrous THF. The mixture is stirred at room temperature under nitrogen. Add triphenylphosphine (1.2 equiv.) And diethyl azodicarboxylate (1.1 equiv.) If the reaction has not been completed (monitored by CCD). The mixture is diluted with EtOAc, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc mixtures.

General Procedure 4-3 7-Chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-1H-benzo [d] azepine (1 equiv.) Is added, the appropriate alcohol (1.2-1.5 equiv.) and triphenylphosphine (1.5 equiv.) sequentially for anhydrous THF. The mixture is stirred at 0 ° C under nitrogen for 10 min. 1,1 '- (Azodicarbonyl) dipiperidine (1.5 equiv.) Is added and the mixture is left to warm at room temperature for 16 h. It is diluted with ether, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc mixtures.

Preparation 6 7-Chloro-9-fluoro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine l-Fluoro-4-methoxy-2- (2-nitro-vinyl) -benzene: Warm 2-fluoro-5-methoxybenzaldehyde (15 g, 97.4 mmol) with nitromethane (32 mL, 584 mmol) and ammonium acetate ( 30 g, 390 mmol) in acetic acid (136 L) under reflux for 30 min. The solvent is evaporated and the residue is dissolved in ether. The organic fraction is washed with water, saturated aqueous NaHCO3 and evaporated to give the desired intermediate (18.7 g, 97%). GC-MS m / z: 197 (M) +. 2- (2-Fluoro-5-methoxyphenyl) -ethylamine; Carefully add sulfuric acid (14.7 mL, 265 mmol) dropwise at 0 ° C for lithium aluminum hydride (1M solution in THF, 565 mL) with efficient stirring. The mixture is heated at room temperature for 20 min and then cooled back to 0 ° C. A solution of l-fluoro-4-methoxy-2- (2-nitro-vinyl) -benzene (18.7 g, 95 mmol) in THF is added (150 mL) through a cannula and stir 2.5 h at room temperature. The mixture is cooled to 0 ° C, water is carefully added (4.6 L) followed by 2N aqueous NaOH (4.6 mL) and water (6.5 mL). The precipitate is removed by filtration and the filtrate is evaporated to give the desired intermediate (16 g, 100%). EM (ES +) m / z: 170 (M + H) +.

N- (2, 2-Dime oxy-ethyl) -2, 2, 2-trifluoro-N- [2- (2-fluoro-5-methoxy-phenyl) -ethyl] -acetamide: Dissolves 2- (2- fluoro-5-methoxyphenyl) -ethylamine (16 g, 95 mmol) and dimethoxy acetaldehyde (60% aqueous, 21.5 mL, 142 mmol) in methanol (500 L). After 1.5 h, carefully add sodium borohydride (5.39 g, 142 mmol) at 0 ° C and then stir at room temperature for 3 h. Acetone is added and the mixture is evaporated. The residue was dissolved in DCM (250 mL), cooled to 0 ° C and triethylamine (26.5 mL, 190 mmol) and trifluoroacetic anhydride (20.1 L, 142 mmol) were added.

After 30 min, wash the mixture with IN aqueous HCl (4 x 100 L), brine and saturated aqueous NaHCO 3. Dry the organic layer over Na 2 SO and concentrate in vacuo. Purify by chromatography on silica gel to give the desired intermediate (19.7 g, 59%). MS (ES +) m / z: 322 (M-OMe) +. 9-Fluoro-6-methoxy-3- (2, 2, 2-trifluoroacetyl) -2, 3-dihydro-lH-benzo [d] azepine: N- (2,2-dimethoxy-ethyl) -2 is dissolved, 2, 2-trifluoro-N- [2- (2-fluoro-5-methoxy-phenyl) -ethyl] -acetamide (5 g, 14.2 mmol) in chlorobenzene (100 mL). Polyphosphoric acid (5 g) and P205 (2.5 g) are added and heated at 80 ° C for 2 h. Water is added to the hot mixture, cooled to room temperature and extracted with DCM. Dry the organic extracts over Na2SO4 and concentrate in vacuo to obtain the desired intermediate (3.0 g, 73%). MS (ES +) m / z: 290 (M + H) +. 9-Fluoro-6-methoxy-3- (, 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 9-fluoro-6-methoxy-3- ( 2,2, 2-trifluoroacetyl) -2, 3-dihydro-lH-benzo [d] azepine (9.4 g, 32.4 mmol) with 10% Pd / C (the dry base, Degussa type, 1.4 g, 0.65 mmol) in EtOAc / ethanol (1: 1, 200 mL) and stirred at room temperature under a balloon of hydrogen for 4.5 h. The mixture is filtered through a pad of silica gel and the filtrate is evaporated to obtain the desired intermediate (8.6 g, 91%). MS (ES +) m / z: 292 (M + H) +. 9-Fluoro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 9-fluoro-6-methoxy-3- is dissolved (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (8.1 g, 27.7 mmol) in DCM (250 mL), cooled to 0 ° C and added Boron tribromide (5.24 mL, 55.5 mmol). Stir at room temperature for 1.5 h, wash the mixture with brine, dry the organic layer over Na 2 SO 4 and concentrate in vacuo to obtain the desired intermediate (7.6 g, 99%). MS (ES +) m / z: 278 (M + H) +. 7-Chloro-9-fluoro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 9-fluoro-6 is dissolved hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.0 g, 3.6 mmol) in toluene (36 L) with diisopropylamine (41 μL, 0.29 mmol). It is heated to 60 ° C and a solution of sulfuryl chloride (0.32 mL, 3.97 mmol) in toluene (10 mL) is added dropwise. After 2 h, the mixture is washed with brine, the organic layer is dried over Na 2 SO 4 and evaporated on silica gel. Purify by chromatography on silica gel by levigating with EtOAc / hexane (0: 1 to 1: 0) to obtain the desired intermediate (1.0 g, 92%). MS (ES +) m / z: 312 (M + H) +. 7-Chloro-9-fluoro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: A 7-chloro solution is cooled -9-fluoro-6-hydroxy-3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (2.5 g, 8.0 mmol), pyridine (3.25 mL) , 40.2 mmol) and DCM (80 mL) at 0 ° C and trifluoromethanesulfonic anhydride (2.43 mL, 14.5 mmol) was added dropwise over 20 min. Stir at room temperature for 1 h. The reaction mixture is washed sequentially with IN aqueous HCl, saturated NaHCO 3 solution and brine. The organic fraction is dried over Na2SO4 and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (gradient from 19: 1 to 1: 1) to obtain the title compound (3.1 g, 87%).

Preparation 7 4-Bromomethyl-N-methyl-benzenesulfonamide 4- (Bromomethyl) -enzylsulfonyl chloride (2.7 g, 10 mmol), anhydrous potassium carbonate (1.4 g, 10 mmol) are added and Anhydrous THF (60 mL) under nitrogen. The mixture is cooled in an ice bath, a 2M solution of methylamine in THF is added dropwise, and it is stirred at this temperature for 30 min. The ice bath is removed and stirred at room temperature for 16 h. Dilute with EtOAc then wash with IN aqueous HCl. The organic layer is separated, dried over Na 2 SO and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 4: 1, 7: 3 and 13: 7) to obtain the title compound (1.5 g, 71%). MS (ES +) m / z: 266 (M + H) +. The compounds of preparations 8-9 can be prepared essentially as described in Preparation 7 by using 4- (bromomethyl) benzenesulfonyl chloride and the appropriate amine. The performance data and EM (ES +) are shown in the Table below.

R Preparation 10 Thiazol-2-yl-methanol 2-thiazolecarboxaldehyde (1.1 g, 10 mmol) and ethanol (30 L) are mixed under nitrogen. Sodium borohydride (416 mg, 11 mmol) is added at 0 ° C. The mixture is stirred and heated slowly at room temperature for 12 h. Quench with saturated aqueous ammonium chloride and concentrate in vacuo. The residue is diluted with EtOAc and washed with brine. Dry the organic fraction over Na2SO4 and concentrate in vacuo to obtain the title compound as an oil (1.0 g, 87%). MS (ES +) m / z: 116 (M + H) +.

Preparation 11 (l-Methyl-lH-pyrazol-3-yl) -methanol Dissolve 3-dimethoxymethyl-1-methylpyrazole (1562 g, 10 mmol) in acetone (100 mL), add p-toluenesulfonic acid (190 mg, 1.0 mmol) and stirred at room temperature for 12 h. Volatiles are removed in vacuo, the residue is dissolved in EtOAc, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo to provide an oil. The oil is dissolved in methanol (15 mL), sodium borohydride (567 mg, 15 mmol) is added and the reaction mixture is stirred at room temperature for 12 h. Volatiles are removed in vacuo, the residue is dissolved in EtOAc, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with EtOAc / hexane (6: 1) to give the title compound as an oil (530 mg, 47%).

Preparation 12 6- (2-Amino-ethoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine 6- (2-tert-butoxycarbonylamino-ethoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: A method is used similar to General Procedure 4-3, when using 7-chloro-6-hydroxy-3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (277 mg , 0.94 mmol) and N- (tert-butoxycarbonyl) ethanolamine (244 mg, 1.51 mmol) to give, after chromatography on silica gel, levigating with hexane / EtOAc (1: 0 and 3: 1), the desired intermediate ( 392 mg, 95%). MS (ES +) m / z: 337 (M + H-Boc) +. 6- (2-Amino-ethoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Dissolves 6- (2 -ter-butoxycarbonylamino-ethoxy) -7-chloro-3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (997 mg, 2.28 mmol) in 4M hydrogen chloride in dioxane (15 mL) and stirred at room temperature for 30 min. Concentrate to obtain the hydrochloride salt. The salt is dissolved in DCM and washed with saturated aqueous NaHCO3. The basic aqueous layer is extracted with DCM. Dry the combined organic extracts over MgSO4, and concentrate in vacuo to provide the title compound (731 mg, 95%). MS (ES +) m / z: 337 (M + H) +.

The compounds of the preparations 13-14 can be prepared essentially as described in Preparation 12 by using 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro- lH-benzo [d] azepine and the appropriate alcohol. The general performance and EM (ES +) data are shown in the Table below.

Example 7 7-Chloro-6- (4-fluorobenzyloxy) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Succinate A paste of sodium hydride (60% in mineral oil, 99 mg, 2.5 mmol) is prepared in DMF (4 mL) and heated to 65 ° C. A solution of 3-tert-butoxycarbonyl-7-chloro is added. 6-hydroxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (250 mg, 0.84 mmol) in DMF (5 mL) dropwise and stir for 1 h. A solution of 4-fluorobenzyl bromide (191 mg, 1.0 mmol) in DMF (1 mL) is added, stirred at 65 ° C for 1.5 h and cooled to room temperature. Water (1 mL) is added and the mixture is concentrated to an oily residue. The residue is partitioned between EtOAc / hexane (1: 1) and water. Dry the organic layer over Na 2 SO 4, filter and concentrate in vacuo. The residue is dissolved in DCM, washed with 2N aqueous NaOH, the organic layer is dried over Na 2 SO, filtered, and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (20: 1, 10: 1 and 7: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (4-fluorobenzyloxy) -2.3, 4,5-tetrahydro-lH-benzo [d] azepine as an oil. A method similar to General Procedure 1-5 is used to deprotect 3-tert-butoxycarbonyl-7-chloro-6- (4-fluorobenzyloxy) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine. Purify by SCX chromatography followed by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (1: 0, 50: 1, 20: 1, 15: 1 and 10: 1) to give the free base of the title compound . A method similar to General Procedure 2-1 is used to give the title compound as a white solid (178 mg, 50%). MS (ES +) m / z: 306 (M + H) +.

Example S 7-Chloro-6- (4-cyanobenzyloxy) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride H Hl 3-tert-Butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (200 mg, 0.67 mmol), potassium carbonate (111 mg, 0.8 mmol), and 4-cyanobenzyl bromide (263 mg, 1.34 mmol) in DMSO (5 L) and the stirred mixture is heated at 100 ° C for 24 h. It is cooled to room temperature and the mixture is partitioned between water and EtOAc / hexane (1: 1). The organic layer is washed with brine and dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (5: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (4-cyanobenzyloxy) -2, 3, 4, 5-tetrahydro-lH- benzo [d] azepine as an oil. A method similar to General Procedure 1-5 is used to deprotect 3-tert-butoxycarbonyl-7-chloro-6- (4-cyanobenzyloxy) -2, 3, 4, 5-tetrahydro-1H-benzo [d] azepine. Purify by SCX chromatography to give the free base of the title compound. A method similar to General Procedure 2-2 is used to give the title compound as a completely white solid (66 mg, 27%). MS (ES +) m / z: 313 (M + H) +.

Example 9 7-Chloro-6- [2- (4-fluorophenyl) -2-oxo-ethoxy)] - 2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 4-1 is used, using 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3,, 5-tetrahydro-lH-benzo [d] azepine (294 mg, 1.0 mmol) and 2-bromo-4'-fluoroacetophenone (260 mg, 1.2 mmol) to give, after purification by chromatography on silica gel levigating with hexane / EtOAc (7: 1), 7-chloro -6- [2- (4-fluorophenyl) -2-oxo-ethoxy)] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a solid (402 mg, 93%). MS (ES +) m / z: 430 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- [2- (4-fluorophenyl) -2-oxo-ethoxy)] -3- (2,2,2-trifluoroacetyl) -2, 3,4,5-tetrahydro-lH-benzo [d] azepine (402 mg, 0.93 mmol). Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (96: 4) to give the free base of the title compound (278 mg, 89%). MS (ES +) m / z: 334 (M + H) +. A method similar to General Procedure 2-3 is used to give the title compound.

Example 10 7-Chloro-6- (4-methylsulfamoyl-benzyloxy) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride 7-Chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 5-tetrahydro-1H-benzo [d] azepine (200 mg, 0.68 mmol) is dissolved in acetone ( 30 mL). Anhydrous potassium carbonate powder (276 mg, 2.0 mmol) and powdered potassium iodide (11.3 mg, 0.068 mmol) is added followed by 4-bromomethyl-N-methyl-benzenesulfonamide (528 mg, 2.0 mmol). The reaction mixture is stirred at room temperature for 12 h. Concentrate in vacuo, dilute with EtOAc and wash 2 times with IN aqueous HCl. The organic layer is separated, dried over Na 2 SO 4 and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 4: 1) to obtain 7-chloro-6- (4-methylsulfamoyl-benzyloxy) -3- (2,2,2-trifluoroacetyl) - 2,3,4,5-tetrahydro-lH-benzo [d] azepine (201 mg, 60%). A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- (4-methylsulfamoyl-benzyloxy) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H -benzo [d] azepine (196 mg, 0.41 mmol). Purify by SCX column to give the free base of the title compound (110 mg, 70%). MS (ES +) m / z: 381 (M + H) +. A method similar to General Procedure 2-2 is used to obtain the title compound. Examples 11-12 can be prepared essentially as described in Example 10 by using 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-1H-benzo [ d] azepine and the appropriate bromide. The EM (ES +) data are shown in the Table below.

Example 13 Alien 1 7-Chloro-9-fluoro-6- (4-fluorobenzyloxy) -3- 2, 2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] hydrochloride azepine Dissolve 7-chloro-9-fluoro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (0.25 g, 0.8 mmol) in DMF (8 mL), potassium carbonate is added (0.56 g, 4.0 mmol) and 4-fluorobenzyl bromide (0.46 mL, 2. 4 mmol). After 14 h at 90 ° C, it is diluted with ether and washed with brine. Dry the organic layer over Na2SO4 and evaporate on silica gel. Purify by chromatography on silica gel by levigating with EtOAc / hexane (0: 1 to 1: 0) to obtain 7-chloro-9-fluoro-6- (4-fluorobenzyloxy) -3- (2,2,2-trifluoroacetyl) ) -2, 3,4, 5-tetrahydro-lH-benzo [d] azepine. A method similar to General Procedure 1-1 is used, using 7-chloro-9-fluoro-6- (4-fluorobenzyloxy) -3- (2, 2,2-trifluoroacetyl) -2, 3, 4, 5- tetrahydro-lH-benzo [d] azepine, to give the free base of the title compound. A method similar to General Procedure 2-2 is used to obtain the title compound (275 mg, 95%). HRMS calculated for C? 7H? 7NOF2Cl 324. 0902, found 324. 0957 Example 14 7-Chloro-6- (pyridin-2-ylmethoxy) -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A paste of sodium hydride is prepared. { 60% in mineral oil, 168 mg, 4.2 mmol) in DMF (4 mL) and heated to 65 ° C. A solution of 3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2 is added dropwise, 3,4,5-tetrahydro-lH-benzo [d] azepine (250 mg, 0.84 mmol) in DMF (5 mL) and stir for 1 h. A solution of 2- (bromomethyl) -pyridine hydrobromide (256 mg, 1 mmol) in DMF (1 mL) is added, stirred at 65 ° C for 0.5 h and cooled to room temperature. Water (1 mL) is added and the reaction mixture is concentrated to an oily residue. The residue is partitioned between EtOAc / hexane (1: 1) and water. Dry the organic layer over Na 2 SO 4, filter and concentrate. Purify by chromatography on silica gel by levigating with hexane / EtOAc (10: 1, 5: 1 and 3: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (pyridin-2-ylmethoxy) -2, 3,4,5-tetrahydro-lH-benzo [d] azepine as an oil.

A method similar to General Procedure 1-5 is used to deprotect 3-tert-butoxycarbonyl-7-chloro-6- (pyridin-2-ylmethoxy) -2,3,4,5-tetrahydro-1H-benzo [d] azepine . Purify by SCX chromatography to give the free base of the title compound. A method similar to General Procedure 2-1 is used to give the title compound as a white solid (228 mg, 67%). MS (ES +) m / z: 289 (M + H) +.

Example 15 7-Chloro-6- (pyridin-3-ylmethoxy) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine diuccinate A method similar to Example 14 is used, using 3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (250 mg, 0.84 mmol) and 3- (bromomethyl) -pyridine hydrobromide (256 mg, 1 mmol) to give the free base of the title compound. A method similar to General Procedure 2-1 is used with 2 equivalents of succinic acid to give the title compound as a white solid (354 mg, 80%). MS (ES +) m / z: 289 (M + H) +.

Example 16 7-Chloro-6- (thiazol-2-ylmethoxy) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 4-2 is used, using 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine and thiazol-2-yl-methanol (86.2 mg, 0. 75 mmol) to give, after chromatography on silica gel, levigating with hexane / EtOAc (9: 1 and 7: 3), 7-chloro-6- (thiazol-2-ylmethoxy) -3- (2.2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (163 mg, 61%). MS (ES +) m / z 391 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- (thiazol-2-ylmethoxy) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H -benzo [d] azepine. Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (94: 6) to obtain the free base of the title compound (99 mg, 81%). MS (ES +) m / z: 295 (M + H) +. A method similar to General Procedure 2-2 is used to give the title compound.

Example 17 7-Chloro-6- (thiazol-5-ylmethoxy) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride CN 'YV? NH HCl A method similar to General Procedure 4-2 is used, using 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (294 mg, 1.0 mmol) and 5-hydroxymethylthiazole (127 mg, 1.1 mmol) to give, after chromatography on silica gel, levigating with EtOAc / hexane (1: 3), 7-chloro-6- (thiazole). 5-ylmethoxy) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil (350 mg, 89%). MS (ES +) m / z: 391 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- (thiazol-5-ylmethoxy) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H -benzo [d] azepine (350 mg, 0.90 mmol). Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (95: 5) to give the free base of the title compound (203 mg, 76%). MS (ES +) m / z: 295 (M + H) +. A method similar to General Procedure 2-2 is used to give the title compound. Examples 18-19 can be prepared essentially as described in Example 17 by using 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepine and the appropriate alcohol. The general performance data and EM (ES +) data are shown in the Table below.

Example 20 7-Chloro-6- (3-methylthio-propoxy) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 4-2 is used, using 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine and 3- (methylthio) -1-propanol (191 mg, 1.8 mmol) to give, after chromatography on silica gel, levigating with EtOAc / hexane (1: 8), 7-chloro-6- (3-methylthio) -propoxy) -3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil (65 mg, 14%). A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- (3-methylthio-propoxy) -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-1H -benzo [d] azepine (65 mg, 0.17 mmol). Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (94: 6) to give the free base of the title compound (25 mg, 51%). MS (ES +) m / z: 286 (M + 1) +. A method similar to General Procedure 2-1 is used to give the title compound.

Example 21 7-Chloro-6- (4-methylthio-butoxy) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to Example 20 is used, using 7-chloro- 6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine and 4- (methylthio) -1-butanol to give the title compound. MS (ES +) m / z: 300 (M + 1) +.

Example 22 7-Chloro-6- (3-pyridin-2-yl-propoxy) -2, 3,, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 4-3 is used, using 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (50 mg, 0.17 mmol) and 3- (2-pyridyl) -1-propanol (35 mg, 0.255 mmol) to give, after the reversed phase HPLC (10-95% of solvent B in 12.8 min, 25 mL / min; solvent A: water, 0.1% trifluoroacetic acid, solvent B: acetonitrile, 0.1% trifluoroacetic acid; column: YMC SH-341-5, S-5Dm, 12 nm, 100 x 20 mm), 7-chloro-6 - (3-pyridin-2-yl-propoxy) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine.

A method similar to General Procedure 1-1 is used, using 7-chloro-6- (3-pyridin-2-yl-propoxy) -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine to give the free base of the title compound. A method similar to General Procedure 2-2 is used to give the title compound as a solid (26 mg, 39%). MS (ES +) m / z: 317 (M + H) +. Examples 23-26 can be prepared essentially as described in Example 22 by using 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepine and the appropriate alcohol. The general performance and EM (ES +) data are shown in the Table below.

Example 27 6- (2-Benzoylamino-ethoxy) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride Benzoyl chloride (19.3 mg, 0.137 mmol), PS- morpholine (109 mg, 0.272 mmol), 6- (2-amino-ethoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d ] azepine (46 mg, 0.137 mmol) in DCM (1.5 mL) and stirred at room temperature for 16 h. The resin is filtered, washed with DCM and concentrated in vacuo. It is purified by reverse phase HPLC (10-95% of solvent B in 12.8 min, 25 mL / min, solvent A: water, 0.1% trifluoroacetic acid, solvent B: acetonitrile, 0.1% trifluoroacetic acid, column: YMC SH-341- 5, S-5 μm, 12 nm, 100 x 20 mm) to give 6- (2-benzoylamino-ethoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2.3.4, 5 -tetrahydro-lH-benzo [d] azepine. A method similar to General Procedure 1-1 is used, using 6- (2-benzoylamino-ethoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro- lH-benzo [d] azepine to give the free base of the title compound. A method similar to General Procedure 2-2 is used to give the title compound as a solid (51 mg, 98%). MS (ES +) m / z: 345 (M + H) +. Examples 28-40 can be prepared essentially as described in Example 27, by using 6- (2-amino-ethoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine or 6- (3-amino-propoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH- benzo [d] azepine or 6- (4-amino-butoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate acyl chloride. The general performance and EM (ES +) data are shown in the Table below.

Example 41 7-Chloro-6- [2- (2-fluorobenzoylamino) -ethoxy] 2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride Dissolve 6- (2-amino-ethoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (100 mg, 0.297 mmol) in DCM (5 mL). Add 2-fluorobenzoyl chloride (39 μL, 0.326 mmol), triethylamine (62 μL, 0.445 mmol) and stir at room temperature for 72 h under nitrogen atmosphere. Dilute with DCM, add 1M aqueous HCl and extract the aqueous phase with DCM. The combined organic extracts are dried over MgSO4 and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (7: 3 and 2: 1) to give 7-chloro-6- [2- (2-fluorobenzoylamino) -ethoxy] -3- (2.2, 2). -trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (111 mg, 82%). A method similar to General Procedure 1-1 is used, using 7-chloro-6- [2- (2-fluorobenzoylamino) -ethoxy] -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine to give the free base of the title compound. A method similar to General Procedure 2-2 is used to give the title compound as a solid (112 mg, 95%). MS (ES +) m / z: 363 (M + H) +.

Example 42 7-Chloro-6-chlorohydrate. { 2- [(pyridine-2-carbonyl) -amino] ethoxy} -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Picolinic acid (40 mg, 0.327 mmol), EDC (57 mg, 0.297 mmol) and HOBT (40 mg, 0.297 mmol) in DCM (3 mL) are combined. Stir for 10 min at room temperature. 6- (2-Amino-ethoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (100 mg, 0.297 is added mmol). Stir for 16 h at room temperature. Dilute with DCM, add water and extract the aqueous layer with DCM. Wash the combined organic extracts with 1M aqueous NaOH and brine. Dry the organic layer over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (3: 2) to give 7-chloro-6-. { 2- [(pyridine-2-carbonyl) -amino] -ethoxy} -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (94 mg, 74%). A method similar to General Procedure 1-1 is used, when using 7-chloro-6-. { 2- [(pyridine-2-carbonyl) -amino] -ethoxy} -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine to give the free base of the title compound. A method similar to General Procedure 2-2 is used to give the title compound as a solid (81 mg, 72%). MS (ES +) m / z: 346 (M + H) +.

Example 43 7-Chloro-6-chlorohydrate. { 2- [(pyridine-3-carbonyl) -amino] -ethoxy} -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine A method is used in Example 42, when using nicotinic acid (40 mg, 0.327 mmol) and 6- (2-amino-ethoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (100 mg, 0.297 mmol) to give the title compound as a solid (105 mg, 93%). MS (ES +) m / z: 346 (M + H) +.

Example 44 7-Chloro-6- [2- (3-phenyl-ureido) -ethoxy] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride Phenyl isocyanate (16.3 mg, 0.137 mmol), 6- (2-amino-ethoxy) -7-chloro-3- (2,2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH is combined -benzo [d] azepine (46 mg, 0.137 mmol) in DCM (1.5 mL) and stirred at room temperature for 16 h. Concentrate in vacuo. It is purified by reverse phase HPLC (10-95% of solvent B in 12.8 min, 25 mL / min, solvent A: water, 0.1% trifluoroacetic acid, solvent B: acetonitrile, 0.1% trifluoroacetic acid, column: YMC SH-341- 5, S-5μm, 12nm, 100x20mm) to give 7-chloro-6- [2- (3-phenyl-ureido) -ethoxy] -3- (2,2,2-trifluoroacetyl) -2, 3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to General Procedure 1-1 is used, using 7-chloro-6- [2- (3-phenyl-ureido) -ethoxy] -3- (2,2,2-trifluoroacetyl) -2,3, 4,5-tetrahydro-lH-benzo [d] azepine to give the free base of the title compound. A method similar to General Procedure 2-2 is used to give the title compound as a solid (8 mg, 15%). MS (ES +) m / z: 360 (M + H) +. Examples 45-46 can be prepared essentially as described in Example 44 by using phenyl isocyanate and 6- (3-amino-propoxy) -7-chloro-3- (2,2,2-trifluoroacetyl) -2, 3 , 4, 5-tetrahydro-1H-benzo [d] azepine or 6- (4-amino-butoxy) -7-chloro-3- (2, 2, 2-trifluoroacetyl) -2,3,4,5- tetrahydro-lH-benzo [d] azepine. The general performance and EM (ES +) data are shown in the Table below. R HCl Example 48 7-Chloro-6- (3-methoxycarbonyl-propyloxy) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Succinate Methyl 4-bromobutyrate (1.9 mL, 10.4 mmol) is added to a mixture of 3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-benzo [d] azepine (310 mg , 1.0 mmol), DBU (0.23 mL, 1.6 mmol) and DMF (10 L) at room temperature under nitrogen. The reaction mixture is stirred for 16 h. Dilute with hexane / EtOAc (1: 1, 60 mL), wash the mixture with 10% aqueous NaCl (4 x 25 mL), dry the organic layer over Na 2 SO and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 2: 3) to obtain 3-tert-butoxycarbonyl-7-chloro-6- (3-methoxycarbonyl-propyloxy) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (303 mg, 73%). MS (ES +) m / z: 398 (M + H) +. A method similar to General Procedure 1-5 is used to deprotect 3-tert-butoxycarbonyl-7-chloro-6- (3-methoxycarbonyl-propyloxy) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (295 mg, 0.74 mmol). Purify by SCX chromatography followed by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (99: 1 to 90:10) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to give the title compound (160 mg, 52%). MS (ES +) m / z: 298 (M + H) +.

General procedure 5-1 Properly substituted 3- (2, 2, 2-trifluoroacetyl) -6-trifluoromethane-sulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine is dissolved (1 equiv.) , palladium (II) acetate (0.1-0.4 equiv.), BINAP (0.2-0.8 equiv., ratio of BINAP / catalyst 2: 1) and cesium carbonate (1.4-3.0 equiv.) in toluene (0.2- solution) 0.05 M). The amine (1-3 equiv.) Is added, the mixture is degassed with vacuum / nitrogen or argon purge and heated at 80-110 ° C for 4-16 h. The mixture is cooled to room temperature, diluted with EtOAc, filtered through a pad of silica gel or through Celite® washed with EtOAc or ether, and the solvent is evaporated to obtain the crude mixture. Alternatively, the reaction mixture is partitioned between brine or saturated aqueous NaHCO3 and EtOAc, ether or DCM, the organic layer is dried over Na2SO4, and concentrated to obtain the crude mixture. The crude mixture is purified by chromatography on silica gel by levigating with hexane / EtOAc mixtures and further SCX chromatography if necessary.

General Procedure 5-2 Properly substituted 3- (2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine is dissolved (1 equiv.), Tris (dibenzylidene ketone) ipalladium (0) (0.1-0.5 equiv.), BINAP (0.2-1.0 equiv., ratio BINAP / catalyst 2: 1) and cesium carbonate (1.4 equiv.) in toluene (0.05-0.5 M solution). It is degassed under vacuum and refilled 3 times with nitrogen. The appropriately substituted amine (1.0-5.0 equiv.) Is added and the mixture is heated at 80-100 ° C for 2-16 h in a sealed flask under a nitrogen atmosphere. The reaction flask is cooled to room temperature, the mixture is diluted with EtOAc or DCM, filtered through Celite® and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc mixtures and further SCX chromatography if necessary.

General Procedure 5-3 Properly substituted 3- (2, 2, 2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (1 equiv.), appropriate amine (1.2-3.0 equiv.), palladium (II) acetate (0.2-0.4 equiv.), tris (dibenzylidenacetone) dipalladium (0) (0.1-0.2 equiv.), BINAP (0.6-1.2 equiv.) BINAP / catalyst 2: 1), cesium carbonate (2-2.5 equiv.) And toluene or 1,4-dioxane (0.05-0.2 M solution) to a flask, degassed and refilled 3 times with nitrogen. The mixture is heated at 80-100 ° C for 10-16 h. The mixture is diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo to give the crude mixture. Alternatively the volatiles are removed from the reaction mixture to directly give the crude mixture, or the reaction mixture is filtered through Celite® and concentrated in vacuo. It is purified by chromatography on silica gel by levigating hexane / EtOAc and also SCX chromatography if necessary.

General Procedure 5-4 Combine 6-amino-7-chloro-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine, the appropriate bromide (1.0 -2.0 equiv.), Cesium or potassium carbonate (1.0-2.0 equiv.) And toluene, DMF or acetonitrile in a sealed tube and heated at 50-150 ° C for 3-72 h. It is cooled to room temperature and the solvent is evaporated in vacuo to obtain the crude mixture. Alternatively, the reaction mixture is partitioned between diethyl ether / brine (1: 1), the organic layer is dried over anhydrous Na 2 SO and concentrated to obtain the crude mixture. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1, 4: 1, 7: 3 and 3: 2).

General Procedure 6-1 4- (tert-Butoxycarbonylamino-methyl) -benzoic acid (1 equiv.), HATU (1 equiv.), DIEA (2 equiv.) And the appropriately substituted amine (1 equiv.) In DCM are dissolved. or DCM / DMF and stirred at room temperature for 4-16 h. Concentrate in vacuo, dissolve the residue in DCM and wash successively with saturated aqueous NaHCO3, IN aqueous HCl, water, brine, and dry over Na2SO4. The solution is filtered and concentrated and the material is used without further purification. The residue is deprotected using General Procedure 1-5 and purified by SCX chromatography.

General Procedure 6-2 4- (tert-Butoxycarbonylamino-methyl) -benzoic acid or lithium salt of 5- (tert-butoxycarbonylamino-methyl) -pyridine-2-carboxylic acid (1 equiv.), HATU (1 equiv. .), DIEA (2 equiv.) And the appropriately substituted amine (1 equiv.) In DCM or DCM / DMF and is stirred at room temperature for 4-16 h. Concentrate in vacuo, dissolve the residue in DCM and wash successively with saturated aqueous NaHCO3, water, brine, and dry over Na2SO4. The solution is filtered and concentrated and the material is used without further purification. The residue is deprotected using General Procedure 1-5 and purified by SCX chromatography.

General Procedure 6-3 Appropriately substituted acetophenone is dissolved (1.0-1.2 equiv.) In THF, titanium ethoxide (IV) is added (33-35% Ti02, 2.0 equiv.) And the corresponding (R) -2-methyl-2-propansulfinamide or (S) -2-methyl-2-propansulfinamide (1.0 equiv.). The mixture is heated at 40-60 ° C for 2-16 h under a nitrogen atmosphere. The reaction is cooled to -78 ° C, then the cold mixture is added over 3-10 min to a THF / NaBH4 (2-4 M) slurry at -78 ° C. The mixture is allowed to warm up to room temperature for 2-16 h. The mixture is poured into brine, the resulting paste is filtered through Celite® and washed completely with EtOAc. Concentrate in vacuo. The oil is diluted with EtOAc, washed with brine and the aqueous phase is extracted with EtOAc. Dry the combined organic extracts over Na2SO4 and concentrate in vacuo. The crude sulfinamide is purified on silica gel by levigating with hexane / EtOAc mixtures to obtain the higher diastereomer. The larger diastereomer is dissolved in excess 4M hydrogen chloride in dioxane, the mixture is stirred for 1 h and concentrated in vacuo to a solid. A paste of the solid is made in diethyl ether, then filtered in vacuo to obtain the desired hydrochloride salt of the amine. The free base of the amine is prepared either by means of SCX chromatography or by basic extraction.

General Procedure 6-4 Appropriately substituted benzonitrile is added in portions to a flask containing a paste of lithium aluminum hydride (3.0-6.0 equiv.) In diethyl ether (solution 0. 1-0.3 M) under a nitrogen atmosphere. The mixture is stirred for 1 h and quenched slowly with water (0.5-2.0 mL), followed by 5N aqueous NaOH (0.5-2.0 mL). The paste is filtered through Celite® and the cake is washed with diethyl ether. Concentrate in vacuo to obtain the desired amine. If additional purification is needed, the amine is dissolved in ether and an excess of 2M hydrogen chloride in ether is added. It is filtered to obtain the desired amine as the hydrochloride salt. The free base is prepared by using SCX Chromatography or by dissolving the hydrochloride salt in an aqueous solution of cesium carbonate (1.0-5.0 equiv.) Or saturated aqueous NaHCO3 (1.0-5.0 equiv.). The mixture is extracted with DCM or toluene, dried over Na2SO4 and concentrated in vacuo to obtain the amine.

General Procedure 6-5 BH3-THF complex (1-3 equiv., 1M solution in THF) is added dropwise to an appropriately substituted benzonitrile solution in anhydrous THF at room temperature then stirred overnight. Alternatively the reaction may be heated to reflux overnight. Add either methanol or aqueous HCl (3 equiv.) Carefully at room temperature and stir vigorously until gas evolution stops. Concentrate in vacuo, basify and then extract into EtOAc. The organic phase is washed with brine, dried over MgSO 4 and concentrated in vacuo. Purify by SCX chromatography by levigating with methanol followed by a solution of ammonia in methanol (3-7 M) to give the desired benzylamine.

Preparation 15 7-Cyano-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine 7-Bromo-6-hydroxy- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Dissolves 6-hydroxy-3- (2,2, 2 -trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine (18 g, 69.4 mmol) and DIEA (0.98 mL) in DCM (1.4 L). A solution of NBS is added dropwise (12.4 g, 69. 4 mmol) in DCM (500 mL) for 75 min. The reaction mixture is stirred at room temperature for 1 h, poured into water (500 mL) and the mixture extracted with DCM. The organic fraction is washed with brine, dried over Na2SO, filter and concentrate. Purify by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to give the desired intermediate as a white solid (20.9 g, 89%). MS (ES-) m / z: 337 (M-H). " 7-Cyano-6-hydroxy-3- (2, 2, 2-tri-luoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Copper nitrile (2.6 g, 28 mmol) is added ) to a solution of 7-bromo-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-1H-benzo [d] azepine (2.4 g, 7.0 mmol) in Anhydrous NMP (45 mL) is degassed and purged with nitrogen and heated at 150 ° C for 18 h. Allow the reaction mixture to cool to room temperature and then dilute with EtOAc / heptane (2: 1) and filter through a pad of silica. The filtrate is diluted with water, and the aqueous phase is extracted twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with EtOAc / heptane (1: 4 to 1: 1) to obtain the desired intermediate as an orange oil (1.7 g, 86%). MS (ES-) m / z: 283 (M-H). " 7-Cyano-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: Dry pyridine (3 mL) is added to 7-cyano 6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.1 g, 3.9 mmol) in anhydrous DCM (45 L) and cool to 0 ° C. Trifluoromethanesulfonic anhydride (1.3 mL, 7.7 mmol) is added slowly, the reaction mixture is allowed to warm to room temperature and is stirred for 3 h. Dilute with DCM and wash with 2N aqueous HCl. Dry the organic layer over MgSO4, filter and concentrate in vacuo to obtain the title compound as an orange / brown oil (1.6 g, 100%) which is used without purification. MS (ES-) m / z: 415 (M-H) A Preparation 16 3- (2,2,2-Trifluoroacetyl) -6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo [d] azepine 6-Hydroxy-7-iodo-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 6-hydroxy-3- (2, 2) is added , 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (1.037 g, 4.0 mmol) and diisopropylamine (60.7 mg, 0.6 mmol) to anhydrous DCM (350 mL) and stirred at 10-20 ° C. A solution of N-iodosuccinimide (1035 g, 4.6 mmol) in DCM (100 mL) is added slowly over a period of 3 h. The reaction mixture is stirred overnight and gradually warmed to room temperature. The reaction is quenched with saturated aqueous NaHCO3, the organic layer is separated, the organic layer is washed with 0.1 N aqueous HCl, brine, dried over Na2SO4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1:20 to 1:10) to give the desired intermediate as a white solid (1.0 g, 65%). MS (ES +) m / z: 386 (M + H) +. 7-iodo-3- (2, 2, 2-trifluoroacetyl) -6- tri luoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine: Triethylamine (496 mg, 4.90 mmol) is added to a solution of 6-hydroxy-7-iodo-3- (2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (945 mg, 2.45 mmol) in DCM (30 mL) at 0 ° C. Trifluoromethanesulfonic anhydride (1244 g, 4.41 mmol) is added dropwise and stirred at 0 ° C for 1 h. Heat at room temperature overnight. The mixture is diluted with DCM, washed with water, saturated aqueous NaHCO3 and brine. It dries on Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 6) to give the desired intermediate as a white solid (1246 g, 98%). MS (ES +) m / z: 518 (M + H) +. 3- (2, 2,2-Trifluoroacetyl) -6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: Cul (367 mg, 1.93 mmol), 2,2-difluoro-2- (fluorosulfonyl) methyl acetate (1852 g, 9.64 mmol) are added and HMPA (1728 g, 9.64 mmol) was added to a solution of 7-iodo-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine ( 1.246 g, 2.41 mmol) in DMF (8 mL) and the mixture is heated at 70 ° C for 1.5 h. The same amount of Cul, 2,2-difluoro-2- (fluorosulfonyl) methyl acetate, and HMPA are added and further stirred for 4 h. The mixture is cooled to room temperature, quenched with saturated aqueous ammonium chloride, the organic layer is separated, and the aqueous layer is extracted with EtOAc three times. Combine the organic layers, wash with saturated aqueous NaHCO3, brine, dry over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1:20 to 1:10) to give the title compound as a white solid (321 mg, 29%) and to recover the starting material (741 mg, 59%). MS (ES +) m / z: 460 (M + H) +.

Preparation 17 7-Ethyl-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine 9-Bromo-6-hydroxy-3- ( 2, 2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Bromine (10.8 mL, 0.21 mol) in acetonitrile (260 L) is added dropwise to a slurry. 6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (51.8 g, 0.2 mol) in acetonitrile (400 mL) at 0 ° C It is cooled with ice water to maintain the temperature between 2-5 ° C. The reaction is warmed to room temperature and stirred for 30 min. The mixture is poured into water cooled with (2 L) to obtain a white precipitate. The solid is collected by vacuum filtration, washed with water and dried under vacuum at 105 ° C. The crude material is recrystallized from toluene / heptane and the mixture is cooled in an ice bath. Collect the solid by vacuum filtration, wash with heptane and dry under vacuum at 105 ° C to obtain the desired intermediate as a white solid (54.63 g, 81%). MS (ES +) m / z: 338 (M + H) +. 6-Acetoxy-9-bromo-3- (2, 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Under a nitrogen atmosphere, 9-bromo-6 is mixed -hydroxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (6 g, 17.8 mmol), anhydrous pyridine (0.06 mL, 0.72 mmol), DMAP (222 mg, 1.8 mmol) and acetic anhydride (30 mL). The mixture is heated at reflux for 8 h and then stirred at room temperature for another 8 h. Concentrate in vacuo, dilute the residue in EtOAc, wash with IN aqueous HCl, and then with saturated aqueous NaHCO 3. Dry the organic layer over Na 2 SO 4, filter, and concentrate in vacuo to obtain the desired intermediate (5.64 g, 84%) which is used without further purification. MS (ES +) m / z: 380 (M + H) +. 7-Acetyl-9-bromo-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Under a nitrogen atmosphere, mix 6 -acetoxy-9-bromo-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (2.8 g, 7.4 mmol) and nitrobenzene (5 mL). Anhydrous aluminum chloride (980 mg, 7.4 mmol) is added. Heat at 180 ° C for 2 h. The mixture is cooled to room temperature. Concentrated HCl (10 mL) is added dropwise. The mixture is stirred for 30 min. Aqueous 1N HCl is added then extracted with EtOAc. Dry the organic layer over Na 2 SO 4, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with EtOAc / hexane (0: 1 to 1: 4) to provide the desired intermediate (833 mg, 30%). MS (ES-) m / z: 378 (M-H). " 7-Acetyl-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 7-acetyl-9-bromo-6- is mixed hydroxy-3- (2,2, 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine (833 mg, 2.2 mmol), tetrakis (triphenylphosphine) palladium (0) (150 mg , 0.13 mmol) and sodium formate (224 mg, 3.3 mmol) in anhydrous DMF (15 L). It is degassed 2 times then discharged with argon. The flask is maintained under argon and the reaction is heated at 95 ° C for 16 h. Dilute with EtOAc then wash with IN aqueous HCl. The organic layer is separated, dried over Na 2 SO, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with EtOAc / hexane (0: 1, 1: 9 and 1: 4) to give the desired intermediate (448 mg, 68%). MS (ES +) m / z: 302 (M + H) +. 7-Ethyl-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 7-acetyl-6-hydroxy is dissolved under nitrogen 3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.0 g, 3.32 mmol) in anhydrous THF (100 mL). The solution is cooled to 0 ° C, boron trifluoride diethyl etherate (3.4 mL, 26.6 mmol) and sodium cyanoborohydride (836 mg, 13.3 mmol) are added. The ice bath is removed and stirred for 5 h at room temperature.

Dilute with EtOAc and wash with 0.1N aqueous HCl. The organic layer is separated, dried over Na 2 SO, filtered and concentrated in vacuo. MS (ES-) m / z: 302 (MH). "The residue was mixed with trifluoroacetic acid (40 mL) and anhydrous DCM (50 mL) under nitrogen, cooled to 0 ° C in an ice bath and dried. triethyl silane (3.5 mL, 21.9 mmol) is added, after 15 min, the ice bath is stirred and stirred at room temperature for 16 h, concentrated in vacuo and purified by chromatography on silica gel with levigating with EtOAc / hexane (1: 9) to obtain the desired intermediate (698 mg, 73%). EM (ES-) m / z: 286 (M-H) ". 7-Ethyl-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine: 7-ethyl-6-hydroxy is mixed under nitrogen 3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (698 mg, 2.4 mmol), triethylamine (0.67 L, 4.8 mmol) and anhydrous DCM (25 L). The mixture is cooled in an ice bath, trifluoromethanesulfonic anhydride (0.81 mL, 4.8 mmol) is added dropwise and stirred at room temperature for 3 h. It is quenched with water and extracted 3 times with DCM. The organic extracts are washed with aqueous HCl 0. IN and brine. Dry over Na 2 SO 4, filter and concentrate to obtain the title compound (1.0 g, 100%). MS (ES +) m / z: 420 (M + H) +.

Preparation 18 7-Propyl-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine 6-Allyloxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Dissolves 6-hydroxy-3- (2,2,2-trifluoroacetyl) ) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (1 g, 3.9 mmol) in acetone (5 mL) and powdered potassium carbonate (2.8 g, 20 mmol) is added. A solution of allyl bromide (1.04 L, 12 mmol) in acetone (3 mL) is added dropwise over 10 min and stirred at room temperature overnight. The solids are filtered, washed with acetone and concentrated in vacuo to give the desired intermediate as a completely white solid (1.15 g, 98%). GC-MS m / z: 299 (M +). 7-Allyl-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-te rahydro-lH-benzo [d] azepine: Dissolves 6-allyloxy-3- (2, 2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.1 g, 3.7 mmol) in DCM (15 mL) and cooled to -15 ° C. Add 1M boron trichloride in DCM (15 mL, 15 mmol) and heat to room temperature. It is stirred for 30 min at room temperature. Water (50 mL) is added and the aqueous layer extracted 3 times with DCM. Wash the combined organic extracts with water (100 mL), brine (100 mL), dry over MgSO, filter, and concentrate in vacuo to give the desired intermediate (980 mg, 89%) as a light yellow oil. which solidifies to a completely white solid during rest at room temperature. MS (ES +) m / z: 300 (M + H) +. 6-Hydroxy-7-propyl-3- (2, 2, -trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 7-allyl-6-hydroxy-3- ( 2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (1.5 g, 5 mmol) in EtOAc (50 mL) containing 10% Pd / C (1.3 g) . Stir at room temperature at 1 atm with H2 (balloon) for 30 min. The catalyst is filtered and washed with water (100 mL). The resulting filtrate is extracted 3 times with EtOAc, the combined organic extracts are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the desired intermediate as a white solid (1.45 g, 97%). MS (ES +) m / z: 302 (M + H) +. 7-Propyl-3- (2, 2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: A solution of 6-hydroxy-7-Propyl is cooled -3- (2,2, 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine (500 mg, 1.9 mmol), triethylamine (390 μL, 2.3 mmol) and DCM (20 mL) in a cryogenic bath is fixed at -35 ° C and trifluoromethanesulfonic anhydride (325 μL, 2.3 mmol) is added dropwise over 20 min. It is stirred at this temperature overnight. The reaction mixture is washed sequentially with water, 1N aqueous HCl, water, and brine. Dry the organic layer over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to obtain the title compound as a completely white waxy solid (550 mg, 75%). MS (ES +) m / z: 434 (M + H) +.

Preparation 19 6-Amino-7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepine 7-Chloro-6- (4-methoxybenzylamino) -3- (2, 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Attaches 7-chloro-3- (2, 2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (15 g, 35.3 mmol), with 4-methoxybenzylamine (13.7 mL, 106 mmol) when using tris (dibenzylideneacetone) -dipaladium (0) (1.62 g, 1.76 mmol), BINAP (4.40 g, 3.5 mmol) and cesium carbonate (16.1 g, 49.4 mmol) at 80 ° C for 17 h. The mixture is filtered through a pad of Celite® and the filtrate is evaporated. The residue is dissolved in DCM and filtered through a pad of silica gel. The filtrate is evaporated and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 to 2: 3) to give the desired intermediate as a white solid (12.4 g, 86%). MS (ES +) m / z: 412 (M + H) +. 6-Amino-7-chloro-3- (2, 2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: It is 7-chloro-6- (4-methoxybenzylamine) ) -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (5.41 g, 13.1 mmol) with 2,3-dichloro-5,6-dicyano -1,4-benzoquinone (3.59 g, 15.8 mmol) in toluene (66 mL) at room temperature for 2 h. The mixture is diluted with EtOAc and washed with saturated aqueous NaHCO3 (5 x 100 mL). The aqueous layer was extracted with ether, the organic extracts were combined and evaporated to a volume of 300 mL. The organic phase is extracted with IN aqueous HCl (5 x 100 mL), and then the combined aqueous layers are washed with ether (4 x 75 mL). The aqueous phase is cooled to 0 ° C, neutralized with 5N aqueous NaOH (100 mL), and extracted with DCM (5 x 200 mL). The combined organic extracts are washed with brine, dried over Na 2 SO 4 and evaporated to obtain the title compound as a white solid (3.6 g, 94%). MS (ES +) m / z: 293 (M + H) +.

Preparation 20 6- (2-Amino-ethylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine 6- (2-tert-butoxycarbonylamino-ethylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: A method is used similar to General Procedure 5-1, when using 7-chloro-3- (2,2, 2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (150 mg , 0.352 mmol), palladium (II) acetate (8 mg, 0.0352 mmol), BINAP (22 mg, 0.0352 mmol), cesium carbonate (163 mg, 0.5 mmol), t-butyl N- (2-aminoethyl) - carbamate (254 mg, 1.59 mmol) and toluene (6 mL) to give, then chromatography on silica gel by levigating with hexane / EtOAc (4: 1), the desired intermediate (136 mg, 89%). 6- (2-Amino-ethylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Dissolves 6- (2 -ter-butoxycarbonylamino-ethylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (136 mg, 0.31 mmol) in chloride of 4M hydrogen in dioxane (20 mL) and stirred at room temperature for 25 min. Concentrate to provide the hydrochloride salt. The salt is dissolved in DCM and washed with saturated aqueous NaHCO3.

The basic aqueous layer is extracted with DCM, the organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (64 mg, 62%). MS (ES +) m / z: 336 (M + H) +.

Preparation 21 6- (3-Amino-propylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine A typical method 20 Preparation 20 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine ( 600 mg, 1.41 mmol) and tert-butyl N- (3-aminopropyl) -carbamate (1.11 g, 6.34 mmol) to give the title compound (34% overall).

Preparation 22 7-Chloro-6- (4-hydroxybenzylamino) -3- (2,2,2-trifluoroacetyl) 2,3,4,5-tetrahydro-lH-benzo [d] azepine 7-Chloro-6- (4-methoxybenzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepine (1,667 g) is dissolved in DCM ( 40 mL). A 1M solution of boron tribromide in DCM (10 mL) is added at 0 ° C. The reaction is stirred for 12 h and gradually rises to room temperature. Quench the reaction with saturated aqueous NaHCO3 and extract with DCM 3 times. The organic extracts are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 3) to give the title compound as an oil (888 mg). MS (ES +) m / z: 399 (M + 1) +.

Preparation 23 7-Chloro-6- (3-chloro-4-hydroxybenzylamino) -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine 7-Chloro -6- (3-Chloro-4-methoxybenzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: A method similar to the procedure is used. general 5-3, when using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (1277 g, 3.0 mmol ) and 3-chloro-4-methoxy-benzylamine (669 mg, 3.9 mmol) to give the desired intermediate as a light yellow yellow oil (1554 g, 100%). 7-Chloro-6- (3-chloro-4-hydroxybenzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: A method is used similar to Preparation 22, when using 7-chloro-6- (3-chloro-4-methoxybenzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [ d] azepine (1.36 g, 3.0 mmol) to give the title compound as a completely white solid (876 mg, 67% yield). MS (ES +) m / z: 433 (M + H) +. MS (ES-) m / z: 431 (M-H). " Preparation 24 3- (tert-butoxycarbonyl) -6- (4-carboxy-benzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine Combine 7-chloro-6- (4-methoxycarbonyl-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.4 g, 0.82) mmol), potassium carbonate (4 g, 28.9 mmol), methanol (3 mL), water (3 mL) and heated at 50 ° C for 2 h. The reaction mixture is cooled to room temperature, saturated aqueous Na 2 CO 3 is added and diluted with DCM (10 mL). Di-tert-butyl-dicarbonate (2.4 g, 10.9 mmol) is added in portions. The organic layer is separated and the aqueous layer extracted with DCM (3 x 10 mL). The organic extracts are combined, dried over anhydrous Na2SO4, the solvent is evaporated and purified by chromatography on silica gel by levigating with DCM and DCM / methanol (9: 1) to give the title compound as a white solid (0.3 g. , 80%). MS (ES +) m / z: 331 (M + H-Boc) +.

Preparation 25 2-Benzyloxyethylamine (2-Benzyloxyethyl) -carbamic acid tert-butyl ester: tert-Butyl-N- (2-hydroxyethyl) -carbamate is dissolved (10 mL, 64.5 mmol) in anhydrous THF (500 mL) at 0 ° C. Sodium hydride (60% in mineral oil, 3.1 g, 77.4 mmol) is added and stirred for 30 min at 0 ° C. Benzyl bromide is added (9.2 mL, 77 mmol) followed by tetrabutylammonium iodide (3.7 g, 10 mmol) and stirred at room temperature overnight. It is quenched with water (500 mL), extracted with diethyl ether (3 x 100 mL), the combined organic extracts are washed with brine, dried over MgSO, filtered, and evaporated to give the desired intermediate (15 g), which is used without further purification. 2-Benzyloxyethylamine: (2-benzyloxyethyl) -carbamic acid tert-butyl ester (15 g) is dissolved in DCM (50 mL), trifluoroacetic acid (20 L) is added and the mixture is stirred at 0 ° C for 3 h. The residue is concentrated and dissolved in a minimum amount of DCM. Purify by chromatography on silica gel by sequentially levigating with hexane / EtOAc (4: 1 and 1: 1), EtOAc and 2M ammonia in methanol to give the title compound (8.3 g, 85%).

Preparation 26 (R) -2-Benzyloxy-1-methyl-ethylamine (R) -3-Benzyloxy-2- (tert-butoxycarbonylamino) -propane: (R) - (+) - 2- (tert-butoxycarbonylamino) is dissolved -1-propanol (875 mg, 5 mmol) in anhydrous THF (50 mL). Sodium hydride (60% in mineral oil, 210 mg, 5.2 mmol) is added and stirred at 0 ° C for 30 min. Benzyl bromide (620 μL, 5.2 mmol) is added followed by tetrabutylammonium iodide (20 mg, 0.05 mmol) and stirred for 3 h at room temperature. The mixture is poured into water (200 mL), extracted with DCM (3 x 50 mL), washed with brine, dried over MgSO4, filtered and concentrated. Purify by chromatography on silica gel by levigating with hexane / EtOAc (19: 1) to give the desired intermediate as a colorless oil (800 mg, 60%).

(R) -2-Benzyloxy-1-methyl-ethylamine: (R) -3-benzyloxy-2- (tert-butoxycarbonylamino) -propane (800 mg, 3 mmol) is dissolved in DCM (10 L), acid is added trifluoroacetic (5 mL), and stirred at 0 ° C for 20 min. Evaporate and purify by SCX chromatography to give the title compound as a colorless oil (440 mg, 89%). MS (ES +) m / z: 166 (M + H) +.

Preparation 27 (R) -2- (4-Fluorobenzyloxy) -1-methyl-ethylamine (R) -2- (tert-butoxycarbonylamino) -3- (4-fluorobenzyloxy) -propane: Dissolve (R) - (+) -2- (tert-butoxycarbonylamino) -1-propanol (1.75 mg, 10.5 mmol) in anhydrous THF (50 mL). Sodium hydride (60% in mineral oil, 480 mg, 12 mmol) is added and stirred at 0 ° C for 30 min. Add benzyl 4-fluorobromide (1.5 mL, 12 mmol) followed by tetrabutylammonium iodide (370 mg, 0.1 mmol) and stir for 72 h at room temperature. The mixture is poured into water (500 mL), extracted with DCM (3 x 150 mL), washed with brine, dried over MgSO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the desired intermediate as a yellow oil (2.18 g, 77%).

(R) -2- (4-Fluorobenzyloxy) -1-methyl-ethylamine: (R) -2- (tert-butoxycarbonylamino) -3- (4-fluorobenzyloxy) -propane is dissolved (2.18 g, 7.7 mmol) in DCM (50 mL), trifluoroacetic acid (25 mL) is added, and it is stirred at 0 ° C for 20 min. Evaporate and purify by SCX chromatography to give the title compound as a colorless oil (1.2 g, 85%). MS (ES +) m / z: 184 (M + H) +.

Preparation 28 (R) -l-Methyl-2-phenoxy-ethylamine (R) -2- (tert-butoxycarbonylamino) -3-phenoxy-propane: Dissolve (R) - (+) -2- (tert-butoxycarbonylamino) -1-propanol (1.75 g, 10 mmol) and phenol (0.95) g, 10 mmol) in anhydrous THF (75 mL). Cool to 0 ° C, add triphenylphosphine (4.0 g, 15 mmol) and diisopropylazodicarboxylate dropwise and stir at room temperature for 18 h. The mixture is poured into water (300 mL), basified to pH 10 with 5N aqueous NaOH, and extracted with ethyl ether (3 x 100 mL). The organic phase is washed with brine, dried over MgSO 4, filtered and concentrated. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the desired intermediate as a completely white solid (340 mg, 14%).

(R) -l-Methyl-2-phenoxy-ethylamine: (R) -2- (tert-butoxycarbonylamino) -3-phenoxy-propane (340 mg, 1.35 mmol) is dissolved in DCM (80 mL), acid is added trifluoroacetic acid (35 mL), and stirred at 0 ° C for 2 h. Evaporate and purify by SCX chromatography to give the title compound as a colorless oil (186 mg, 91%). MS (ES +) m / z: 151 (M + H) +.

Preparation 29 4- (Aminomethyl) -2-methyl-thiazole 4- (Azidomethyl) -2-methyl-thiazole: 4- (Chloromethyl) -2-methyl-thiazole (350 mg, 2.37 mmol) and azidotrimethylsilane (315 μL, 2.37 mmol) are dissolved in anhydrous THF (1 mL) under nitrogen . A 1M solution of tetrabutylammonium fluoride (3.6 mL, 3.56 mmol) in THF is added and stirred at room temperature overnight. The reaction mixture is poured into water (10 mL), extracted with ethyl ether (3 mL), the organic extracts are washed with brine, dried over MgSO4, filtered, and evaporated. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the desired intermediate as a colorless oil (165 mg, 45%). 4- (Aminomethyl) -2-methyl-thiazole: 4- (Azidomethyl) -2-methyl-thiazole (165 mg, 1.07 mmol) is added to a methanol paste containing 10% Pd / C (75 mg) and stir vigorously under 1 atm of H2 for 1 h. Filter, evaporate the solvent, and purify by SCX chromatography to give the title compound (55 mg, 40%).

Preparation 30 2-Fluoro-4-phenoxy-benzylamine Ter-butyl ester of (4-Bromo-2-fluorobenzyl) -carbamic acid: 4-bromo-2-fluorobenzylamine hydrochloride (7.2 g, 30 mmol), di-tert-butyl-dicarbonate (9.8 g) is mixed under nitrogen , 45 mmol), and potassium carbonate (12.4 g, 90 mmol) in anhydrous THF (200 L). Stir at room temperature for 16 h. Filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to obtain the desired intermediate (6.4 g, 70%). GC-MS m / z: 247 [(M-C4H9) +]. (2-Fluoro-4-phenoxy-benzyl) -carbamic acid tert-butyl ester: (4-bromo-2-fluorobenzyl) -carbamic acid (2.12 g, 7.0 mmol) is mixed under an argon atmosphere. , phenol (1.32 g, 14 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (129 mg, 0.7 mmol), and cesium carbonate (4.56 g, 14 mmol) in anhydrous NMP (15 mL ). The flask is degassed, filled with argon and copper (I) chloride (346 mg, 3.5 mmol) is added rapidly. The flask is degassed then filled with argon and heated at 120 ° C for 5 h. Cool to room temperature, dilute with EtOAc and filter. The mixture is washed sequentially with 0.5N aqueous HCl, 0.5N aqueous NaOH and brine. The organic layer is separated, dried over Na 2 SO 4 and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1 and 3: 1) to obtain the desired intermediate (1.28 g, 58%). GC-MS m / z: 260 f (M-C4H9) +]. 2-Fluoro-4-phenoxy-benzylamine: (2-Fluoro-4-phenoxy-benzyl) -carbamic acid tert-butyl ester (2.44 g, 7.72 mmol) is dissolved in DCM (200 L). Trifluoroacetic acid (50 mL) is added, then it is stirred at room temperature for 16 h. The solvent is evaporated, the residue is dissolved in DCM and washed with IN aqueous NaOH. Dry over Na2SO and concentrate in vacuo. Purify by SCX chromatography to obtain the title compound (557 mg, 33%). MS (ES +) m / z: 201 (M + H-NH 3) +.

Preparation 31 2-Fluoro-4- (3 '-fluorophenoxy) -benzylamine H " A method similar to Preparation 30 is used, using (4-bromo-2-fluorobenzyl) -carbamic acid tert-butyl ester (2.12 g, 7.0 mmol) and m-fluorophenol (1.57 g, 14 mmol) to give the title compound (468 mg, 47% in general).

Preparation 32 4- (2 * -Fluorophenoxy) -benzylamine 4- (2 * -Fluorophenoxy) -benzonitr Mixed under argon atmosphere 4-bromobenzonitr(2.0 g, 11.3 mmol), 2-fluorophenol (2.5 g, 22.6 mmol), 2, 2, 6, 6-tetramethylheptane-3 , 5-dione (203 mg, 1.1 mmol), and cesium carbonate (7.4 g, 22.6 mmol) in anhydrous NMP (19 mL). The flask is degassed, filled with argon and copper chloride is added (I) (554 mg, 5.6 mmol) rapidly. The flask is degassed then filled with argon and heated at 120 ° C for 3 h. Cool to room temperature, dilute with EtOAc, filter and wash the filtrate sequentially with 2M aqueous HCl, 0.3M aqueous HCl, 2M aqueous NaOH and brine. The organic layer is separated, dried over Na 2 SO 4 and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain the desired intermediate (1.6 g, 66%). MS (ES +) m / z: 231 (M + NH4) +. 4- (2 * -Fluorophenoxy) -benzylamine: Add 4- (2'-fluorophenoxy) -benzonitr(1.5 g, 7.0 mmol) and Raney® nickel activated wet with ethanol (0.4 g) to a Parr pressure vessel. Immediately add a 7N solution of ammonia in methanol (170 mL) and seal the container. The reaction vessel is purged with nitrogen, the reaction mixture is pressurized with hydrogen (3400 KPa), the vessel is sealed, the reaction is stirred and heated to 60 ° C. The reaction is continued for 18 h, in turn completely heated and the reaction mixture is allowed to cool to room temperature. Excess hydrogen is vented from the vessel and the vessel is purged with nitrogen. The reaction mixture is filtered to remove the Raney® nickel. Concentrate in vacuo and purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (9: 1) to obtain the title compound (1.2 g, 79%). MS (ES +) m / z: 201 (M + H-NH 3) +. The compound of Preparation 33 can be prepared essentially as described in Preparation 32 by using 4-bromobenzonitrand 3-fluorophenol. The general performance and EM (ES +) data are shown in the Table below.

Preparation 34 4- (3'-Isopropylphenoxy) -benzylamine A method similar to Preparation 32 (Step 1) is used, using 4-bromobenzonitr(2.0 g, 11.3 mmol) and 3-isopropylphenol (3.08 g, 22.6 mmol) to give 4- (3'-isopropylphenoxy) -benzonitr( 885 mg, 33%). MS (ES +) m / z: 255 (M + NH4) +. A method similar to the reduction procedure described in Preparation 45 (Step 2) is used, using 4- (3'-isopropylphenoxy) -benzonitr(875 mg, 3.7 mmol) to give the title compound (703 mg, 79% ). MS (ES +) m / z: 225 (M + H-NH 3) +. The compounds of the 35-39 preparations can be prepared essentially as described in Preparation 34 by using 4-bromobenzonitrand the appropriate phenol. The general performance and EM (ES +) data are shown in the Table below.

Preparation 40 2- (4-Aminomethyl-phenoxy) -benzonitrile (4-Hydroxybenzyl) -carbamic acid tert-butyl ester: 2, 2, 2-trifluoro-N- (4-hydroxybenzyl) -acetamide (8.8 g, 40 mmol), and 5N aqueous NaOH (20 mL) in methanol (100 mL). Stir at room temperature for 4 h. The pH is adjusted to about 8 with aqueous HCl. Solid sodium bicarbonate (4.4 g, 52 mmol), di-tert-butyl-dicarbonate (9.3 g, 40 mmol) and DCM are added. Stir at room temperature for 16 h. Dilute with DCM, wash with 1N aqueous HCl and purify by silica gel chromatography by levigating with hexane / EtOAc (9: 1 to 5: 5) to obtain the desired intermediate (7.8 g, 87%). MS (ES-) m / z: 222 (M-H). " 2- (4-Aminomethyl-phenoxy) -benzonitrile: (4-hydroxybenzyl) -carbamic acid tert-butyl ester (1.5 g, 6.7 mmol), 2-bromobenzonitrile (813 mg, 4.5 mmol), is mixed under argon. , 2, 6,6-tetramethylheptane-3,5-dione (83 mg, 0.45 mmol), and cesium carbonate (2.2 g, 6.7 mmol) in anhydrous NMP (8.5 mL). The flask is degassed and filled with argon. Copper (I) chloride (223 mg, 2.25 mmol) is added rapidly. The flask is degassed, filled with argon and heated at 120 ° C for 3 h. It is cooled to room temperature, diluted with EtOAc, filtered and concentrated in vacuo. Purify by chromatohy on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1 and 3: 1). The solvent is evaporated and the residue is dissolved in DCM (100 mL). Trifluoroacetic acid (20 mL) is added and stirred at room temperature for 16 h. Concentrate in vacuo, dissolve the residue in EtOAc and wash with NaOH Acuso IN. Dry over Na2SO4 and concentrate in vacuo. Purify by SCX chromatohy to obtain the title compound (385 mg, 38%). MS (ES +) m / z: 225 (M + H) +. The compounds of preparations 41-43 can be prepared essentially as described in Preparation 40 by using (4-hydroxybenzyl) -carbamic acid tert-butyl ester (1.5 g, 6.7 mmol) and the appropriate bromide. The general performance and EM (ES +) data are shown in the Table below.

Preparation 44 3- (4-Aminomethyl-f-enoxy) -benzonitrile A method similar to Preparation 40 (Step 2) is used, using 2, 2, 2-trifluoro-N- (4-hydroxybenzyl) -acetamide (1.0 g, 5.5 mmol) and 3-bromobenzonitrile (673 mg, 3.7 mmol ). Purify by chromatohy on silica gel by levigating with hexane / EtOAc (1: 0 and 3: 1). Concentrate in vacuo. The residue (287 mg, 0.89 mmol) is dissolved in methanol (25 mL) and 5N NaOH (7 mL) is added. Stir at room temperature for 4 h. It is diluted with DCM and solid sodium chloride is added to the mixture. The aqueous layer was extracted 3 times with DCM. Combine the organic extracts, dry over Na2SO4 and concentrate in vacuo. Purify by chromatohy on silica gel by levigating with DCM / 2M ammonia in methanol (94: 6) to obtain the title compound (124 mg, 62%). MS (ES +) m / z: 500 (M + H) +.

Preparation 45 4- (3, 3-Dimetlbutoxy) -benzylamine 4- (3, 3-Dimethylbutoxy) -benzonitrile:. 4-cyanophenol is mixed (1.2 g, 10 mmol), l-bromo-3, 3-dimethylbutane (5.3 g, 32 mmol), potassium carbonate powder (4.14 g, 30 mmol), and potassium iodide powder (166 mg, 1 mmol) ) in acetone (60 mL). It is stirred under an inert atmosphere and heated to reflux for 48 h. The reaction mixture is cooled to room temperature. It is diluted with acetone, filtered and evaporated. Purify by chromatohy on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain the desired intermediate (1.8 g, 89%). MS (ES +) m / z: 221 (M + NH 4) +. 4- (3, 3-Dimethylbutoxy) -benzylamine: Lithium aluminum hydride (1.0 g, 26.6 mmol) and anhydrous ethyl ether (70 mL) are mixed under nitrogen atmosphere. Stir and cool to 0 ° C in an ice bath. A solution of 4- (3,3-dimethylbutoxy) -benzonitrile (1.8 g, 8.87 mmol) in anhydrous ethyl ether (20 L) is added dropwise. Stir for 2 h at 0 ° C, remove the ice bath and stir at room temperature for 18 h. The reaction flask is cooled in an ice bath and water (1 mL), 2N aqueous NaOH (1 mL), and water (2 mL) are carefully added dropwise and sequentially. Stir for 30 min, filter, separate the organic layer, dry over Na2SO4 and concentrate in vacuo to obtain the title compound (1.62 g, 88%). MS (ES +) m / z: 191 (M + H-NH 3) +. The compounds of the preparations 46-48 can be prepared essentially as described in Preparation 45 by using 4-cyanophenol and the appropriate bromide. The general performance and EM (ES +) data are shown in the Table below.

Preparation 49 4-Benzyloxy-benzylamine 4-Benzyloxy-benzonitrile: 4-cyanophenol (1191 g) is added, 10 mmol), benzyl bromide (1881 g, 11 mmol), potassium carbonate (3.455 g, 25 mmol) and potassium iodide (166 mg, 1 mmol) for acetonitrile (80 L) and refluxed for 12 hours. h. It is cooled, partitioned between EtOAc and water, the organic layer is separated, and the aqueous layer is extracted with EtOAc. Combine the organic extracts, wash with brine, dry over Na 2 SO, filter and concentrate. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 6) to give the desired intermediate as a white solid (2.098 g, 100%). MS (ES +) m / z: 227 (M + NH4) +. 4-Benzyloxy-benzylamine: A method similar to Preparation 58 is used, using 4-benzyloxy-benzonitrile (2.098 g, 10 mmol), to give the title compound as a white solid (2.021 g, 94%). MS (ES +) m / z: 197 (M + H-NH 3) +.

Preparation 50 (+) -4- (1-Phenylethoxy) -benzylamine (±) -4- (1-Phenylethoxy) -benzonitrile: Triphenylphosphine (7.869 g, 30 mmol) is added to a solution of sec-phenylethyl alcohol (1467 g, 12 mmol), 4-cyanophenol (1191 g, 10 mmol). and diethyl azodicarboxylate (4.528 g, 26 mmol) in anhydrous THF (50 mL) at 0 ° C. The reaction is stirred at room temperature for 12 h. Dilute with EtOAc, wash with brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 8) to give (±) -4- (1-phenylethoxy) -benzonitrile with a small amount of triphenylphosphine (2.49 g total). (±) -4- (1-Phenylethoxy) -benzylamine: A method similar to Preparation 58 is used, when using (±) -4- (1-phenylethoxy) -benzonitrile curd, to give the title compound as a - colorless oil (1.6 g, 70% two stages). MS (ES +) m / z: 211 (M + H-NH 3) +, 455.3 (2M + H) +.

Preparation 51 4- (3, 3-dimethyl-2-oxo-butoxy) -benzylamine 2,2,2-Trifluoro-N- (4-methoxybenzyl) -acetamide: 4-methoxybenzylamine (13.7 g, 100 mmol) and N-methylmorpholine in anhydrous THF (300 mL) are mixed under nitrogen. It is cooled to 0 ° C in an ice bath. A solution of trifluoroacetic anhydride (15.6 mL, 110 mmol) in anhydrous THF is added dropwise. (25 mL). Warm to room temperature slowly and stir for 16 h. Concentrate in vacuo. It dissolves in EtOAc and washed successively with aqueous NaOH IN, aqueous HCl 1N, and brine. The organic layer is separated, dried over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 and 4: 1) to obtain the desired intermediate (19 g, 81%). MS (ES-) m / z: 232 (M-H). " 2,2,2-Trifluoro-N- (4-hydroxy-benzyl) -acetamide: 2,2,2-trifluoro-N- (4-methoxybenzyl) -acetamide (11.6 g, 50 mmol) is dissolved under nitrogen. in DCM (250 mL). It is cooled to 0 ° C in an ice bath. 1M Boron tribromide in DCM (100 mL, 100 mmol) is added dropwise and stirred for 20 min after the addition. Warm to room temperature and stir for 16 h. The reaction mixture is cooled in an ice bath and quenched very carefully with saturated aqueous NaHCO3. The organic layer is separated. The aqueous layer was extracted 2 times with chloroform. Dry the combined organic extracts over Na 2 SO and concentrate in vacuo to obtain the desired intermediate (8.8 g, 40 mmol). MS (ES-) m / z: 218 (M-H). " N- [4- (3,3-dimethyl-2-oxo-butoxy) -benzyl] -2,, 2-trifluoroacetamide: 2, 2, 2-trifluoro-N- (4-hydroxy-benzyl) -acetamide is mixed (438 mg, 2.0 mmol), 1-bromopinacolone (430 mg, 2.4 mmol), anhydrous potassium carbonate (829 mg, 6.0 mmol) and potassium iodide (33 mg, 0.1 mmol) with acetone. Heat under reflux for 12 h. It is acidified with IN aqueous HCl and extracted with EtOAc 3 times. The organic extracts are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 3) to give the desired intermediate as a colorless oil. MS (ES +) m / z: 335 (M + NH 4) +. MS (ES-) m / z: 316 (M-H). " 4- (3,3-dimethyl-2-oxo-butoxy) -benzylamine: Aqueous 5N NaOH (15 mL) is added to a solution of N- [4- (3, 3-dimethyl-2-oxo-butoxy) - benzyl] -2, 2, 2-trifluoroacetamide (552 mg, 1.74 mmol) in methanol (10 mL) and stirred for 2 h at room temperature. The mixture is extracted with DCM 3 times. The combined organic extracts are dried over Na 2 SO, filtered and concentrated. Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (92: 8) to give the title compound as a colorless oil (337 mg, 87%). MS (ES +) m / z: 205 (M + H-NH 3) +.

Preparation 52 N- (2-Chloro-acetyl) -piperidine Chloroacetyl chloride (1242 g, 11.0 mmol) is added to a mixture of potassium carbonate (2.073 g, 15 mmol) and piperidine (852 mg, 10 mmol) in THF (50 mL) at 0 ° C. The reaction is stirred for 12 h and gradually rises to room temperature. Dilute with water, extract with EtOAc 3 times. The organic extracts are combined and washed sequentially with saturated aqueous NaHCO3, 0.1 N aqueous HCl and brine. Dry over NaSO 4, filter and concentrate to give the title compound (1.65 g, 100%).

Preparation 53 4-Benzylthio-benzylamine 4-Benzylthio-benzonitrile: 4-Fluorobenzonitrile (1.21 g, 10 mmol), benzyl mercaptan (1.86 g, 15 mmol), and cesium carbonate (6.5 g, 20 mmol) in anhydrous NMP are mixed under argon atmosphere. mL). The flask is degassed and filled with argon. Heat at 120 ° C for 3 h. Cool to room temperature, dilute with EtOAc, filter and wash with IN aqueous HCl. The organic layer is separated, dried over Na 2 SO and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain the desired intermediate (689 mg, 31%). GC-MS m / z: 225 (M +). 4-Benzylthio-benzylamine: The reduction procedure described in Preparation 45 (Step 2) is used, using 4-Benzylthio-benzonitrile (689 mg, 3.1 mmol) to give, after SCX chromatography, the title compound ( 464 mg, 64%). MS (ES +) m / z: 213 (M + H-NH 3) +.

Preparation 54 4- (2, 2, 3, 3, 3-Pentafluoropropoxy) -benzylamine 4- (2, 2, 3, 3,3-Pentafluoropropoxy) -benzonitrile: A mixture of potassium fluoride complex of 4-hydroxy-benzonitrile (3.0 g, 16.9 mmol) and 1, 1, 2, is heated. 2-pentafluoro-3-iodo-propane (10.8 g, 37.2 mmol) in DMSO (80 mL) at 130 ° C for 20 h. The mixture is cooled to room temperature, diluted with hexane / EtOAc (1: 1, 200 mL) and washed with 10% aqueous NaCl (3 x 50 mL). The organic layer is dried, concentrated in vacuo and purified by chromatography on silica gel by levigating with hexane / EtOAc (10: 1, 10: 2 and 10: 3) to obtain the desired intermediate (1.1 g, 26%). GC-MS m / z: 251 (M +). 4- (2, 2, 3,3, 3-Pentafluoropropoxy) -benzylamine: A method similar to General Procedure 6-4 is used, using 4- (2, 2, 3, 3, 3-pentafluoropropoxy) -benzonitrile ( 1.1 g, 4.1 mmol), to obtain the title compound (1.1 g, 99%). GC-MS m / z: 254 (M + -H).

Preparation 55 4- (2, 2, 3, 3-Tetrafluoropropoxy) -benzylamine A method similar to Preparation 54 is used, using the potassium fluoride complex of 4-hydroxy-benzonitrile (4.2 g, 23.7 mmol) and 1,2, 2-tetrafluoro-3-iodo-propane (10 g, 41. 3 mmol), to give the title compound (38% in general). GC-MS m / z: 236 (M + -H).

Preparation 56 4- (2, 2, 2-Trifluoro-l, 1-dimethyl-ethoxy) -benzylamine 4- (2,2,2-Trifluoro-l, l-dimethyl-ethoxy) -benzonitrile: It is added 2-trifluoromethyl-2-propanol (3.4 g, 27 mmol) was slowly added to a paste of sodium hydride (0.6 g, 60% in mineral oil, washed with hexane) in HMPA (5 mL) under nitrogen. The paste is stirred for 15 min and a solution of 4-nitrobenzonitrile (2.0 g, 13.5 mmol) in HMPA (10 mL) is added. The resulting purple paste is stirred at room temperature for 16 h, diluted with diethyl ether (100 mL) and washed with 5% aqueous HCl (30 mL). Separate the layers and extract the aqueous layer with diethyl ether (2 x 50 mL). The organic extracts are combined and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1) to obtain the desired intermediate (780 mg, 25%). GC-MS m / z: 229 (M +). 4- (2, 2, 2-Trifluoro-1, 1-dimethyl-ethoxy) -benzylamine: A method similar to General Procedure 6-4 is used to reduce 4- (2,2,2-trifluoro-1, 1- dimethyl-ethoxy) -benzonitrile (780 mg, 3.4 mmol). Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (40: 1, 20: 1 and 10: 1) to obtain the title compound (780 mg, 98%). GC-MS m / z: 232 (M + -H).

Preparation 57 (±) -4- (2, 2, 2-Trifluoro-l-methyl-ethoxy) -benzylamine (±) -4- (2, 2, 2-Trifluoro-1-methyl-ethoxy) -benzonitrile: 1,1-Trifluoro-2-propanol (3.8 g, 66 mmol) is added slowly to a hydride paste. Sodium (730 mg, 60% in mineral oil, washed with hexane) in HMPA (5 mL) under nitrogen. The paste is stirred for 15 min and 4-fluorobenzonitrile (2 g, 16.5 mmol) is added. The paste is heated in a sealed flask at 90 ° C for 16 h. The mixture is cooled to room temperature and the mixture is poured into a flask containing 5% aqueous HCl. (20 mL). The mixture is extracted with diethyl ether (3 x 50 mL), and washed with 5% aqueous HCl (25 mL). Dry the organic layer over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to obtain the desired intermediate (2.5 g, 70%). GC-MS m / z: 215 (M +). (±) -4- (2, 2, 2-Trifluoro-l-methyl-ethoxy) -benzylamine: A method similar to General Procedure 6-4 is used, when using (±) -4- (2, 2, 2 -trifluoro-1-methyl-ethoxy) -benzonitrile (1.0 g, 4.6 mmol), to obtain the title compound (1.1 g, 95%). GC-MS m / z: 218 (M + -H).

Preparation 58 3-Methoxybenzylamine Lithium aluminum hydride (3.795 g, 100 mmol) is added in portions to a solution of 3-methoxybenzonitrile (5326 g, 40 mmol) in anhydrous ethyl ether (200 mL) at 0 ° C. Stir for 1 h, heat to room temperature and continue stirring for 12 h. The reaction is quenched with 0.1N aqueous NaOH, the solid is filtered, the filtrate is dried over Na2SO4 and concentrated to give the title compound as a colorless oil (5.107 g, 93%). MS (ES +) m / z: 138 (M + H) +.

Preparation 59 3- (tert-butyl) benzylamine Dissolve 3-tert-butyltoluene (0.5 mL, 2.9 mmol) in carbon tetrachloride (20 mL). NBS (530 mg, 3 mmol) is added and the reaction mixture is irradiated with a 250 watt lamp with simultaneous heating to reflux for 1 h. It is cooled to room temperature, filtered, and the filtrate is concentrated to dry to give crude 1-bromomethyl-3-tert-butylbenzene. Crude l-bromomethyl-3-tert-butylbenzene (600 mg) is dissolved in anhydrous DMF. Sodium azide (260 mg, 4 mmol) is added in portions and stirred at room temperature for 2 h. The mixture is poured into water (250 mL), extracted with EtOAc (3x50 mL), the combined organic extracts are washed with brine, dried over MgSO4, filtered and the solvent evaporated to give 1-azidomethyl-3-ter- crude butylbenzene, which is used without further purification. Dissolve crude l-azidomethyl-3-tert-butylbenzene in methanol containing 10% Pd / C (75 mg) at 5 ° C, and stir the resulting paste under 1 atm of H2 for 1 h. Filter, concentrate in vacuo and purify by chromatography on silica gel by sequentially levigating with hexane / EtOAc (4: 1 and 1: 1), EtOAc, methanol and 2M ammonia in methanol to give the title compound (255 mg, 53% in general). MS (ES +) m / z: 164 (M + H) +.

Preparation 60 (3-Pyrrolidin-1-yl) benzylamine A mixture of tert-butyl ester of (3-bromobenzyl) -carbamic acid (600 mg, 2.1 mmol, U.S. Patent Application Publication US 2003134885), pyrrolidine (450 mL, 5.2 mmol), tris (dibenzylidenacetone) is made thick. ) dipalladium (0) (200 mg, 0.21 mmol), BINAP (400 mg, 0.63 mmol) and cesium carbonate (960 mg, 2.94 mmol) in anhydrous toluene (10 mL). It is degassed under vacuum, the system is filled with nitrogen and heated in a sealed flask at 90 ° C for 18 h. Cool to room temperature, dilute with diethyl ether, filter, and concentrate in vacuo. The resulting residue is dissolved in DCM (10 mL) and trifluoroacetic acid (5 mL) is added. It is stirred at room temperature for 1 h and concentrated in vacuo. Purify by chromatography on silica gel by sequentially levigating with hexane / EtOAc (1: 1), EtOAc and 2M ammonia in methanol. Purify again by SCX chromatography to give the title compound as a brown oil (300 mg, 85% in general). MS (ES +) m / z: 178 (M + H) +.

Preparation 61 (±) -C- (3-Methyl-2,3-dihydro-benzofuran-5-yl) -methylamine 4-Allyloxy-3-bromo-benzonitrile: 3-Bromo-4-hydroxy-benzonitrile (1520 g, 8.0 mmol), allyl bromide (1161 g, 9.6 mmol), potassium carbonate (3.317 g, 24 mmol) are mixed. and potassium iodide (133 mg, 0.1 mmol) in acetone (80 mL). The mixture is heated to reflux for 12 h. It is cooled to room temperature, EtOAc is added, the organic layer is washed with water, and the aqueous layer is extracted 2 times with. EtOAc. The combined organic extracts are dried over Na2SO4, filtered and concentrated. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 8) to obtain the desired intermediate. (±) -3-Methyl-2, 3-dihydro-benzofuran-5-carbonitrile: Tri-n-butyltin hydride (5.821 g, 20 mmol) and AIBN (411 mg, 2.5 mmol) are added to a solution of 4 g. -aliloxy-3-bromo-benzonitrile (595 mg, 2.5 mmol). The reaction is heated to reflux for 20 h. It is diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc 3 times. The organic extracts are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 8) to give the desired intermediate as a white solid (474 mg, 100% with a trace amount of the tributyltin derivative).

(±) -C- (3-Methyl-2, 3-dihydro-benzofuran-5-yl) -methylamine: A method similar to Preparation 58 is used, when using (+) - 3-methyl-2, 3- dihydro-benzofuran-5-carbonitrile (474 mg, 2.98 mmol) to give the title compound as a colorless oil (410 mg, 84%). The compounds of the preparations 62-64 can be prepared essentially as described in Preparation 61 by using 3-bromo-4-hydroxy-benzonitrile or 4-bromo-3-hydroxy-benzonitrile and the appropriately substituted allyl bromide. MS data (ES +) are shown in the Table below.

ND = Not determined Preparation 65 C- (2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-5-yl) -methylamine N- (2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran- 5-ylmethyl) -2,2,2-trifluoroacetamide: 2-bromoisobutyryl bromide is added (1.724 g, 7.5 mmol) to a solution of 2,2,2-trifluoro-N- (4-methoxy-benzyl) -acetamide (1166 g, 5.0 mmol) in 1,2-dichloroethane (8 mL) at 15 °. C, then anhydrous iron (III) chloride powder (973 mg, 6.0 mmol) is added. The reaction is stirred at 15 ° C for 3 h and at room temperature for 8 days. Saturated aqueous sodium potassium tartrate is added dropwise, then water and EtOAc, and stirred for 1 h. The solid is filtered completely, the organic layer is separated, and the aqueous layer is extracted 3 times with EtOAc. Combine the organic extracts, wash with brine, dry over Na 2 SO 4, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 3) to give the desired intermediate (253 mg, 17%).

C- (2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-5-yl) -methylamine: N- (2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran) is dissolved -5-ylmethyl) -2, 2, 2-trifluoroacetamide (253 mg, 0.88 mmol) in 7M ammonia in methanol and stirred at room temperature for 5 days. Volatiles are removed in vacuo, purified by chromatography on silica gel, levigating with DCM / 2M ammonia in methanol (92: 8) to give the title compound (44 mg, 26%). MS (ES +) m / z: 175 (M + H-NH 3) +.

Preparation 66 C- (2,2-dimethyl-3-oxo-2,3-dihydro-benzofuran-6-yl) -methylamine 2, 2, 2-Trifluoro-N- (3-methoxy-benzyl) -acetamide: Trifluoroacetic anhydride (6.3 g, 30 mmol) is added to a solution of 3-methoxybenzylamine (3.43 g, 25 mmol) and N-methyl- morpholine (3.793 g, 37.5 mmol) in THF (80 mL) at 0 ° C and stirred at this temperature for 4 h. Warm to room temperature and stir for 12 h. Dilute with EtOAc, wash sequentially with water, IN aqueous HCl, saturated aqueous NaHCO3, and brine. The organic layer is dried over Na 2 SO, filtered and concentrated. Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 3) to give the desired intermediate (5.344 g, 91%).

C- (2, 2-dxmetxl-3-oxo-2, 3-dxhydro-benzo uran-6-yl) -methylamine: A method similar to Preparation 65 is used, using 2,2,2-trifluoro-N- (3-methoxy-benzyl) -acetamide (1166 g, 5 mmol), to give the title compound (220 mg, 23 mg). % 2 stages). MS (ES +) m / z: 192 (M + H) +.

Preparation 67 6-Aminomethyl-2,2-dimethyl-2H-chromene 2, 2-Dimethyl-2H-chromene-6-carbonitrile (1.5 g, 8.1 mmol) and wet Raney® activated nickel with ethanol (0.4 g) are added to a Parr pressure vessel. Immediately add 7N ammonia in methanol (170 mL) and seal the container. The reaction vessel is purged with nitrogen, the reaction mixture is pressurized with hydrogen (3400 KPa), the vessel is sealed, the reaction is stirred and heated at 60 ° C for 20 h. In turn, it is completely heated and the reaction mixture is allowed to cool to room temperature. Excess hydrogen is vented from the vessel and the vessel is purged with nitrogen. The reaction mixture is filtered to remove the Raney® nickel. Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (9: 1) to obtain the title compound (1.5 g, 97%). MS (ES +) m / z: 175 (M + H-NH 3) +.

Preparation 68 4- (2-Methylthiazol-4-yl) -benzylamine 4- (2-Methyltxazol-4-yl) -benzonitrol: 4-Cyanophenacyl chloride (515 mg, 2.23 mmol) is suspended in ethanol (15 mL). Thioacetamide (171 mg, 2.23 mmol) and sodium bicarbonate (187 mg, 2.23 mmol) are added and the mixture is heated under reflux for 2 h. Concentrate in vacuo and dissolve the residue in DCM. The organic fraction is washed with water, dried over Na 2 SO 4, filtered and concentrated to give a solid. The solid was suspended in ether / hexane and filtered under vacuum and washed with hexane to obtain the desired intermediate as a white solid (415 mg, 93%). GC-MS m / z: 200 (M +). 4- (2-Methyltxazol-4-yl) -benzylamine: 4- (2-Methylthiazol-4-yl) -benzonitrile (305 mg, 1.52 mmol) is dissolved in anhydrous THF (50 mL). A 1M solution of lithium aluminum hydride in THF (3.05 mL, 3.05 mmol) is added. The mixture is heated overnight under reflux. The reaction mixture is cooled with ice / water and worked sequentially with EtOAc and water. The mixture is filtered over Celite®. The organic phase is separated, and the aqueous phase is extracted with chloroform. The combined organic extracts are dried over Na2SO4, filtered and concentrated to obtain the title compound as an oil (120 mg) which is used without further purification. GC-MS m / z: 204 (M +).

Preparation 69 4- (Pyridin-4-yl) -benzylamine N ~ (tert-butoxycarbonyl) -4-bromo-benzylamine: Di-tert-butyl-dicarbonate (1173 g, 5.375 mmol) and triethylamine (1.087 g, 1.0 mL, 10.75 mmol) are added to a stirred solution of 4-bromobenzylamine (1.0 g, 5.375 mmol) in anhydrous DCM (15 mL). It is stirred overnight at room temperature, diluted with DCM and washed with water. The organic phase is separated, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 19: 1 and 9: 1) to obtain the desired intermediate as a solid (1.24 g, 81%).

N- (tert-butoxycarbonyl) -4- (pyridin-4-xl) -benzylamine: N- (tert-butoxycarbonyl) -4-bromo-benzylamine (0.8 g, 2.807 mmol) is dissolved in anhydrous DME (12 mL) under nitrogen. Tetrakis (triphenylphosphine) palladium (0) (0.162 g, 0.14 mmol), pyridine-4-boronic acid (0.513 g, 4.211 mmol), and a 2M aqueous Na2CO3 solution (2.8 mL, 5.614 mmol) are added. The reaction is heated overnight at 70 ° C. The mixture is cooled to room temperature, diluted with EtOAc, and filtered over Celite®. The organic fraction is washed with water, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 4: 1 and 1: 1) to give the title compound as an oil (0.295 g, 37%). GC-MS m / z: 284 (M +). 4- (Pirxdin-4-xl) -benzylamine: N- (tert-butoxycarbonyl) -4- (4-pyridyl) -benzylamine is dissolved (363 mg, 1.276 mmol) in anhydrous DCM (10 mL). 4N hydrogen chloride in dioxane (10 mL) is added and stirred overnight at room temperature. Concentrate in vacuo to obtain the hydrochloride salt in pure form as a solid. The solid is dissolved in saturated aqueous NaHCO3 and extracted 3 times with DCM and 3 times more with EtOAc. Combine the organic extracts, dry over Na 2 SO, filter and concentrate to obtain the title compound as a solid (166 mg, 71%). CG-MS m / z: 184 (M +) Preparation 70 4- (Pyridin-2-yl) -benzylamine 4- (2-Pyridyl) -benzaldehyde oxime: Hydroxylamine hydrochloride (0.379 g, 5.458 mmol) and a solution of NaOH are added (0.327 g, 8.187 mmol) in water (2 mL) was added to a solution of 4- (2-pyridyl) -benzaldehyde (0.5 g, 2.729 mmol) in ethanol (10 mL).

The mixture is heated at 80 ° C for 2 h. It is cooled to room temperature and the solvent is removed in vacuo. The residue is partitioned between EtOAc and water. The organic phase is separated and dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 4: 1) to obtain the desired intermediate (311 mg, 58%). GC-MS m / z: 198 (M +). 4- (Pyridin-2-yl) -benzylamine: Pd / C (10%, 50 mg) and concentrated HCl (2 mL) are added to a solution of 4- (2-pyridyl) -benzaldehyde oxime (0.29 g, 1.46 g. mmol) in absolute ethanol (20 mL). The mixture is hydrogenated at 50 psi (3.515 kg / cm2) for 2 h. Filter over Celite®, wash with ethanol and concentrate in vacuo to obtain the hydrochloride salt in pure form as a solid. The solid is dissolved in saturated aqueous NaHCO3, the aqueous solution extracted 3 times with DCM and 3 times more with EtOAc. Combine the organic extracts, dry over Na2SO, filter and concentrate in vacuo to obtain the title compound as a solid (130 mg, 48%). GC-MS m / z: 184 (M +).

Preparation 71 4- (l-Methyl-lH-imidazol-2-yl) -benzylamine [4- (l-Methyl-lH-imxdazol-2-yl) -benzyl] -carbamic acid tert-butyl ester: 4- (N-tert-butoxycarbonyl-aminomethyl) phenylboronic acid (1.9 g, 7.4 mmol) is added ), 2-bromo-1-methyl-1H-imidazole (800 mg, 5.0 mmol), tetrakis (triphenylphosphine) -palladium (0) (287 mg, 0.25 mmol) and potassium carbonate (860 mg, 6.2 mmol) flask containing toluene (10 mL). The mixture is heated in a sealed flask at 90 ° C for 16 h. The mixture is cooled, diluted with EtOAc (50 mL), filtered through Celite®, and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc / methanol (49: 50: 1) to obtain the desired intermediate (1.2 g, 83%). GC-MS m / z: 287 (M +). 4- (l-Methyl-lH-xmidazol-2-yl) -benzylamine: tert-butyl ester of the acid is dissolved [4- (l-methyl-lH-imidazol-2-yl) -benzyl] -carbamic acid (500 mg, 1.7 mmol) in DCM (20 mL) and trifluoroacetic acid (5 mL). The mixture is stirred for 1 h at room temperature. Concentrate in vacuo and purify by SCX chromatography to obtain the title compound (240 mg, 74%). MS (ES +) m / z: 188 (M + H) +.

Preparation 72 4-Etanesulfonyl-benzylamine 4-ethylthio-benzonitrile: Combine 4-mercapto-benzonitrile (0.4 g, 2.96 mmol), bromoethane (1.4 mL, 8.88 mmol) and potassium carbonate (3.3 g, 23.7 mmol) in anhydrous DMF (7 mL) and heat at 60 ° C for 17 h. The reaction mixture is cooled to room temperature and partitioned between brine (20 mL) and EtOAc (20 mL). The organic layer is separated, dried over anhydrous Na 2 SO and concentrated. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1 and 4: 1) to obtain the desired intermediate as a colorless oil (0.4 g, 83%). 4-Ethanesulfonyl-benzonitrile: 4-ethylthio-benzonitrile (0.4 g, 2.4 mmol) is dissolved in TFA (10 mL) and hydrogen peroxide (30 p%, 10 mL) is slowly added at 5 ° C. The reaction mixture is stirred at room temperature for 2 h and divided between brine (20 L) and DCM (20 mL). The organic layer is separated, dried over anhydrous Na 2 SO and concentrated to obtain the desired intermediate as a white solid (0.5 g, 100%). GC-MS m / z: 195 (M +). 4-Ethanesulfonyl-benzylamine: Combined 4-ethanesulfonyl-benzonitrile (0.7 g, 3.5 mmol), Raney® 3201 Nickel (paste in water, 0.1 g), 2N ammonia in methanol (20 mL) and hydrogenated at 50 psi ( 3.515 kg / cm2) for 17 h. The reaction mixture is filtered through a pad of Celite® and concentrated in vacuo. Purify by SCX chromatography to obtain the title compound as a yellow oil (0.3 g, 43%).

Preparation 73 4- (2-Propanesulfonyl) -benzylamine A method similar to Preparation 72 is used, using 4-mercapto-benzonitrile (0.5 g, 3.7 mmol) and 2-bromopropane (1.4 g, 11.38 mmol), to obtain the title compound as a yellow oil (0.3 g, 39% in general).

Preparation 74 4-Aminomethyl-N-tert-butyl-benzamide N-tert-butyl-4-cxano-benzamide: Combine 4-cyanobenzoic acid (30 mg, 2.07 mmol), tert-butylamine (0.5 mL, 4.13 mmol), triethylamine (0.4 mL, 2.89 mmol), and HATU (1.1 g, 2.89 mmol) in anhydrous DMF (7 mL). Stir at room temperature for 17 h. The reaction mixture is partitioned between brine (15 mL) and diethyl ether (15 mL), the organic layer is separated, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. Purify by chromatography on silica gel by levigating with DCM to obtain the desired intermediate as a white solid (0.4 g, 89%). MS (ES +) m / z: 203 (M + H) +. 4-Aminometxl-N-tert-butyl-benzamide: N-tert-butyl-4-cyano-benzamide (0.4 g, 1.78 mmol), Raney® 3201 nickel (paste in water, 0.03 g), 2N ammonia in methanol (20 mL) and hydrogenated at 50 psi (3.515 kg / cm2) for 1 h. Filter the reaction mixture through a pad of Celite®, remove the solvent and purify by SCX chromatography to obtain the title compound as a colorless oil (0.4 g, 95%). MS (ES +) m / z: 207 (M + H) +.

Preparation 75 4-Aminomethyl-2-fluoro-N-tert-butyl-benzamide 4-Bromo-N-tert-butyl-2-fluoro-benzamide: Combine 4-bromo-2-fluoro-benzoic acid (5.0 g, 22.83 mmol), thionyl chloride (10 mL, 0.137 mol) in toluene (10 g. mL) and refluxed for 2 h. The reaction mixture is evaporated to obtain 4-bromo-2-fluoro-benzoyl chloride (5.0 g, 93%) and used for the next step without further purification. Dissolve tert-butylamine (0.8 mL, 5.12 mmol) and triethylamine (0.8 mL, 6.32 mmol) in anhydrous DCM (20 mL), cool to 0 ° C and add a solution of 4-bromo-2-fluorobenzoyl chloride. (1.0 g, 4.22 mmol) in anhydrous DCM (10 mL). The reaction mixture is stirred at 0 ° C for 10 min, warmed to room temperature and continued for stirring for 30 min. The reaction mixture is washed with brine (2 x 10 mL), the organic extracts are dried over anhydrous Na 2 SO 4, the solvent is evaporated and purified by chromatography on silica gel by levigating with DCM to obtain the desired intermediate as a white solid ( 1.0 g, 87%). MS (ES +) m / z: 275 (M + H) +.

N-tert-butyl-4-cxano-2-fluoro-benzamide: Combined 4-bromo-N-tert-butyl-2-fluoro-benzaptide (1.0 g, 3.65 mmol) and copper cyanide (I) (0.7 g , 7.29 mmol) in anhydrous DMF (10 mL) and refluxed for 17 h. The reaction mixture is cooled to room temperature and treated with 50% (w / w) aqueous ethylenediamine (20 mL). The reaction mixture is extracted with diethyl ether (3 x 10 mL), the organic extracts are combined, washed with brine (2 x 10 mL) and the organic layer is dried over Na2SO4. The solvent is evaporated and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1, 4: 1, 7: 3 and 3: 2) to obtain the desired intermediate as a white solid (0.6 g, 77%). MS (ES +) m / z: 221 (M + H) +. 4-Aminomethyl-2-fluoro-N-tert-butyl-benzamide: N-tert-butyl-4-cyano-2-fluoro-benzamide (0.6 g, 1.78 mmol), Raney® 3201 nickel (paste in water) is combined , 30 mg), 2N ammonia in methanol (30 mL) and hydrogenated at 50 psi (3.515 kg / cm2) for 1 h. Filter the reaction mixture through a pad of Celite®, concentrate in vacuo and purify by SCX chromatography to obtain the title compound as a colorless oil (0.6 g, 96%).

Preparation 76 4-Aminomethyl-2-fluoro-N-methyl-N-propyl-benzamide A method similar to Preparation 75 is used, using 4-bromo-2-fluoro-benzoic acid (1.0 g, 4.56 mmol) and N-methyl-propylamine (0.5 mL, 5.05 mmol), to give the title compound as a colorless oil (0.5 g, 49%). GC-MS m / z: 224 (M +).

Preparation 77 4-Aminomethyl-N- (2,2,2-trifluoro-ethyl) -benzamide General Procedure 6-1 is used, using 2,2,2-trifluoroethylamine (197 mg, 2 mmol) and 4- (tert-butoxycarbonylamino-methyl) -benzoic acid, to give the title compound as a clear oil ( 440 mg, 94%). MS (ES +) m / z: 233 (M + H) +. The compounds of Preparations 78-93 can be prepared essentially as described in Preparation 77 by using 4- (tert-butoxycarbonylamino-methyl) -benzoic acid and the appropriate amine. General performance data and EM (ES) are shown in the Table below.

Preparation 94 4- (Piperidin-1-ylcarbonyl) -benzylamine General Procedure 6-1 is used, using piperidine (373 mg, 4.4 mmol) and 4- (tert-butoxycarbonylamino-methyl) -benzoic acid to give the title compound as a white solid (1.03 g, 100%). MS (ES +) m / z: 219 (M + H) +.

Preparation 95 4-Aminomethyl-N-cyclohexyl-2-fluoro-benzamide 4-Bromo-N-cyclohexyl-2-fluoro-benzamide: 4-Bromo-2-fluoro-benzoyl chloride (1 g, 4.21 mmol) is dissolved in DCM and the solution is cooled in an ice bath. Triethylamine (0.87 mL, 6.32 mmol) and cyclohexylamine (502 mg, 5.1 mmol) are added and the mixture is stirred at room temperature for 2 h. Divide the reaction mixture between brine and DCM. Dry the organic layer over Na 2 SO 4, filter and concentrate in vacuo to give the desired intermediate as a white solid (1.24 g, 98%). 4-Cyano-N-cyclohexyl-2-fluoro-benzamide: A mixture of 4-bromo-N-cyclohexyl-2-fluoro-benzamide (1.24 g, 4.13 mmol) and copper cyanide (740 mg, 8.26 mmol) is heated DMF (20 mL) was refluxed for 16 h. The mixture is cooled to room temperature, ethylenediamine is added and the mixture is stirred for 30 min. The mixture is extracted with hexane / EtOAc (1: 1), the organic layer is dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (5: 1) to give the desired intermediate as a white solid (620 mg, 61%). MS (ES-) m / z: 245 (M-H). " 4-Aminomethyl-N-cxclohexxl-2-fluoro-benzamide: 4-cyano-N-cyclohexyl-2-fluoro-benzamide (620 mg, 2.5 mmol) is dissolved in 7N ammonia in methanol (150 mL) and hydrogenated at 500 psi (35.15 kg / cm2) pressure in the presence of Raney® nickel (500 mg) for 16 h at 60 ° C. The mixture is filtered and concentrated in vacuo. Purify by SCX chromatography to give the title compound as a white solid (600 mg, 94%). MS (ES-) m / z: 251 (M-H). " Preparation 96 5- (Aminomethyl) -pyridine-2-carboxylic acid cyclohexylamide - (Tert-butoxycarbonylamino-methyl) -pyridine-2-carboxylic acid lithium: 5-aminomethyl-2-chloro-pyridine (2 g, 14 mmol) and di-tert-butyl-dicarbonate (3.37 g, 15.4 mmol) are dissolved. ) in DCM (30 mL) and stirred at room temperature for 2 h. The reaction mixture is concentrated and purified by chromatography on silica gel by levigating with hexane / EtOAc (10: 1 and 5: 1) to give 5- (tert-butoxycarbonylamino-methyl) -2-chloro-pyridine as a yellow solid. (3.6 g, 100%). MS (ES +) m / z: 243 (M + H) +. Dissolve 5- (tert-butoxycarbonylamino-methyl) -2-chloro-pyridine (1 g, 4.12 mmol) in a mixture of ethanol (15 mL) and DMF (5 mL), and add potassium carbonate (427 mg, 3.09 mmol), palladium (II) acetate (92 mg, 0.4 mmol) and diphenylphosphinoferrocene (240 mg, 0.44 mmol). The mixture is pressurized at 15 psi (1.0545 kg / cm2) with carbon monoxide gas and the reaction mixture is heated at 90 ° C for 16 h. The reaction mixture is filtered, the filtrate is concentrated, and the residue is partitioned between water and hexane / EtOAc (1: 1). Dry the organic layer over Na 2 SO, filter, and concentrate in vacuo. The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (3: 2) to give 5- (tert-butoxycarbonylamino-methyl) -pyridine-2-carboxylic acid ethyl ester as a brown oil (920 mg, 80%). MS (ES +) m / z: 281 (M + H) +. Dissolve 5- (tert-butoxycarbonylamino-methyl) -pyridine-2-carboxylic acid ethyl ester (920 mg, 3.28 mmol) in a water / THF mixture (1: 2, 15 mL) and add lithium hydroxide. (87 mg, 3.61 mmol). The mixture is stirred at room temperature for 4 h and concentrated to a solid. The material is dried by azeotroping with toluene to give the desired intermediate as a brown solid (1 g, 100%). MS (ES +) m / z: 253 (M + H) +.

- (Aminomethyl) -pyrxidine-2-carboxylic acid cyclohexylamide: General Procedure 6-2 is used, using cyclohexylamine (1 mL), 5- (tert-butoxycarbonylamino-methyl) -pyridine-2-carboxylic acid lithium ( 1 g, 3.96 mmol) and DIEA (5 mL) as a cosolvent, to give the title compound as a white solid (200 mg, 22%). MS (ES +) m / z: 234 (M + H) +.

Preparation 97 5- (Aminomethyl) -pyridine-2-carboxylic acid 4-fluoro-benzylamide General Procedure 6-2 is used, using 4-fluoro-benzylamine (551 mg, 4.4 mmol), 5- (tert-butoxycarbonylamino-methyl) -pyridine-2-carboxylic acid lithium (740 mg, 2.93 mmol) and DIEA (2.6 mL) as a cosolvent, to give the title compound as a white solid (200 mg, 26%). MS (ES +) m / z: 260 (M + H) +.

Preparation 98 2-Aminomethyl-5- (2,2,2-trifluoroethoxy) -pyridine 2-Me il-5- (2,2,2-trifluoroethoxy) -pyridine: Add 5-hydroxy-2-methyl-pyridine (3.3 g, 30.6 mmol), potassium carbonate (17 g, 122.4 mmol) and 2 -bromo-l, 1,1-trifluoroethane (10 g, 61.2 mmol) to a flask containing DMF (60 mL) and heated at 95 ° C for 20 h. The mixture is cooled, diluted with 10% aqueous NaCl (20 mL) and extracted with hexane / EtOAc 1: 1, 100 mL). The bi-phasic mixture is filtered through Celite® is separated and the organic layer is washed with 10% aqueous NaCl (3 x 50 mL) and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1) to obtain the desired intermediate (4.1 g, 70%). 2-bromine xl-5- (2,2,2-trifluoroethoxy) -pyridine: 2-methyl-5- (2,2,2-trifluoroethoxy) -pyridine (2.5 g, 13.1 mmol) is added, NBS (2.3 g, 13.1 mmol) and benzoyl peroxide (50 mg) to a flask containing carbon tetrachloride (30 mL). The mixture is heated at 80 ° C in a sealed flask for 16 h. The flask is cooled, NBS (1.1 g, 6.5 mmol) and benzoyl peroxide (100 mg) are added, then heating is continued at 80 ° C for an additional 5 h. The mixture is cooled, diluted with DCM, then washed with saturated sodium bisulfite (10 mL). The organic layer is collected and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to obtain the desired intermediate (460 mg, 13%). 2-Ammonomethyl-5- (2,2,2-trifluoroethoxy) -pyridine: Sodium azide (270 mg, 4.0 mmol) is dissolved in DMF (30 mL). The solution is cooled to 0 ° C, then 2-bromomethyl-5- (2,2,2-trifluoroethoxy) -pyridine (440 mg, 1.6 mmol) is added at 0 ° C. Slowly heat the mixture from 0 ° C to 80 ° C for 30 min. The reaction is cooled, diluted with EtOAc (100 mL) and washed with 10% aqueous NaCl (3 x 25 mL). The organic layer is collected and concentrated in vacuo for a volume of 50 mL. The solution is transferred to a pressure vessel. 10% Pd / C (type Degussa ElOl, 50% water by weight, 500 mg) is added and the vessel is pressurized under hydrogen (10 psi (0.703 kg / cm2)) for 1 h with agitation. The mixture is filtered through Celite® and the filter cake is washed with hot methanol followed by DCM. Concentrate in vacuo, then purify by chromatography on silica gel, levigating with DCM / 2M ammonia in methanol (20: 1) to obtain the title compound (180 mg, 54%). MS (ES +) m / z: 207 (M + H) +.

Preparation 99 2-Aminomethyl-5- (2,2,2-trifluoro-1,1-dimethyl-ethoxy) -pyridine -Chloro-pyridine-2-carbonitrile: Add 2,5-dichloropyridine (6.0 g, 40.5 mmol), zinc cyanide (2.9 g, 24.7 mmol), zinc powder (116 mg, 1.8 mmol) and 1.1 '- [bis (diphenylphosphino) ferrocene] dichloropalladium (II) (20 mg, 0.98 mmol) to a flask containing DMF (40 mL). The mixture is heated under reflux for 5 h, then cooled to room temperature. The mixture is diluted with EtOAc (300 mL) and washed with 10% aqueous NaCl (3x75 mL). The organic layer is collected, concentrated in vacuo and purified by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1) to obtain the desired intermediate (2.6 g, 46%).

-Fluoro-pyridine-2-carbonitrile: 5-Chloro-pyridine-2-carbonitrile (3.0 g) is added, 21.7 mmol) and potassium fluoride (3.9 g, 67.1 mmol) were added to a flask containing NMP (75 mL). The mixture is heated at reflux for 16 h. Additional potassium fluoride (1.0 g, 17.2 mmol) and NMP (10 5 mL) are added, then heating at reflux for 3 h. The mixture is cooled, diluted with EtOAc, then washed with saturated NaCl (3 x 50 mL). The organic layer is collected, concentrated in vacuo and purified by chromatography on silica gel by levigating with hexane / EtOAc (20: 1) to obtain the desired intermediate (1.5 g, 53%). - (2,2, 2-Trifluoro-l, l-dimethyl-ethoxy) -pyridine-2-carbonitrile: 2-trifluoromethyl-2-propanol (1.1 g, 8.3 mmol) is slowly added to a paste of sodium hydride (202 • 15 mg, 60% mineral oil, washed with hexane) in HMPA (3 mL) under nitrogen. The paste is stirred for 15 min, then 5-fluoro-pyridine-2-carbonitrile (510 mg, 4.2 mmol) is added. The paste is stirred for 16 h at room temperature. The mixture is adjusted to pH 9 with sodium carbonate then extracted with diethyl ether (3 x 50 mL). The organic layer is collected, dried over Na 2 SO 4 and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (95/5 to 80/20) to obtain the desired intermediate (768 mg, 79%). GC-MS m / z: 230 (M +). 2-Aminomethyl-5- (2,2,2-trifluoro-1,1-dime-il-ethoxy) -pyridxane: 5- (2,2,2-trifluoro-1,1-dimethyl-ethoxy) - pyridine-2-carbonitrile (580 mg, 2.5 mmol), 10% Pd / C (type Degussa ElOl, 50% water by weight, 400 mg) and trifluoroacetic acid (2 mL) in ethanol (20 mL) to a container Pressure. The vessel is pressurized to 50 psi (3.515 kg / cm2) with hydrogen for 1 h. The mixture is filtered through Celite® and the cake is washed with hot ethanol followed by DCM under a nitrogen atmosphere. Concentrate in vacuo to obtain the crude product. as the trifluoroacetic acid salt. The free base is prepared with SCX Chromatography, then purified by using chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (20: 1) to obtain the title compound (261 mg, 45%). MS (ES +) m / z: 235 (M + H) +.

Preparation 100 (±) -2-Aminomethyl-5- (2,2, 2-trifluoro-1-methyl-ethoxy) -pyridine (±) -5- (2, 2, 2-Trifluoro-1-methyl-ethoxy) -pyrxdine-2-carbonxtrile: 1,1-Trifluoro-2-propanol (971 mg, 8.5 mmol) is added slowly to a paste of sodium hydride (205 mg, 60% mineral oil, washed with hexane) in HMPA (8 mL) under nitrogen at 0 ° C. The pulp is allowed to warm to room temperature and is stirred for 5 min. 5-Chloro-pyridine-2-carbonitrile (590 mg, 4.2 mmol) is added, then the mixture is heated at 90 ° C for 4 h. The mixture is adjusted to pH 9 with sodium carbonate, then extracted with diethyl ether (2 x 50 mL). Dry the combined organic extracts over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (95/5 to 80/20) to obtain the desired intermediate (818 mg, 89%). GC-MS m / z: 216 (M +). (±) -2-Aminometxl-5- (2, 2, 2-trxfluoro-1-methyl-etoxx) -pyrxdine: Add (±) -5- (2,2,2-trifluoro-1-methyl-ethoxy) -pyridine-2-carbonitrile (810 mg, 3.7 mmol), 10% Pd / C (Degussa ElOl type, 50% water by weight, 300 mg), and trifluoroacetic acid (4 mL) in methanol (50 mL) in a pressure vessel. The vessel is pressurized to 40 psi (2812 kg / cm2) with hydrogen for 0.25 h. The mixture is filtered through Celite® and the cake is washed with hot ethanol followed by DCM under a nitrogen atmosphere. Concentrate in vacuo to obtain the crude product as a trifluoroacetic acid salt. The free base is prepared with SCX ion chromatography, then purified by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (20: 1) to obtain the title compound (676 mg, 82%). GC-MS m / z: 220 (M +).

Preparation 101 2-Aminomethyl-5-fluoro-pyridine 2-Bromo-5-fluoro-pyridine: Hydrobromic acid 48% (44 mL, 4.4 equiv.) Is cooled in an ice / acetone bath at -5 ° C, then 2-amino-5-fluoropyridine (10.0 g) is added. , 89.2 mmol, 1.0 equiv.) In portions for 10 min and the temperature is maintained below 5 ° C throughout the addition. Bromine (14 mL, 3 equiv.) Is added at 0 ° C for 2 h and the temperature is maintained at 0 ° C throughout the addition. The mixture is stirred for 30 min, then a solution of sodium nitrite (15.4 g) in water (30 mL) is added by means of the addition funnel for 2 h and the temperature is maintained below 0 ° C throughout the addition. The mixture is stirred for 30 min, then a solution of NaOH (34 g) in water (34 mL) is added over 1 h and the temperature is kept below 10 ° C. The mixture is stirred for 3 min. it is extracted with diethyl ether (5 x 250 mL), the combined organic extracts are dried over Na2SO4 and concentrated in vacuo to give the desired intermediate (12.1 g, 77%). (5-Fluoro-pyridin-2-yl) -methanol: At -78 ° C under nitrogen, n-butyllithium (2.5 M in hexane, 16.4 mL, 40.9 mmol) is added via syringe to a solution of 2- bromo-5-fluoro-pyridine (6.0 g, 34.1 mmol) in toluene (220 mL), while maintaining the reaction temperature below -60 ° C. The mixture is stirred at -78 ° C and then DMF (3.4 mL, 44.3 mmol) is added and stirred for 1 h at this temperature. Warm to -10 ° C and quench with methanol (10 mL). The mixture is concentrated for half the volume in vacuo. Dilute with methanol (150 mL), cool the mixture to -78 ° C and add sodium borohydride (3.2 g, 85.2 mmol) in portions over 5 min. The mixture is warmed to room temperature and stirred for 2 h. Quench with water (10 mL) and remove the organic solvent in vacuo to obtain an oil / water mixture. Extract with diethyl ether (3 x 100 mL), dry the combined organic extracts, wash with brine, dry and concentrate in vacuo to obtain the desired intermediate as an oil (3.9 g, 91%). (5-Fluoro-pyridin-2-yl) methyl ester of methanesulfonic acid: Methanesulfonyl chloride (1.8 mL, 23. 5 mmol) was added to a solution of (5-fluoro-pyridin-2-yl) -methanol (2.5 g, 19.7 mmol) and triethylamine (8.2 mL, 59.0 mmol) in DCM (150 mL) at 0 ° C under nitrogen. The mixture is stirred for 30 min and concentrated in vacuo. Dilute with water (20 mL) and extract the mixture with EtOAc (3 x 50 mL). The organic extracts are combined and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc to obtain the desired intermediate (2.2 g, 54%). 2-Aminomethyl-5-fluoro-pyridine: Methanesulfonic acid (5-fluoro-pyridin-2-yl) -methyl ester (1.5 g, 7.3 mmol) is dissolved in DMF (5 mL) and sodium azide (950) is added. mg, 14.6 mmol). The mixture is stirred for 30 min, then diluted with hexane / EtOAc (1: 1, 50 mL). The mixture is washed with 10% aqueous NaCl (3 x 10 mL). Dry the combined organic extracts over Na2SO4 and remove half of the solvent in vacuo. EtOAc (20 mL) and a suspension of 10% Pd / C (200 mg) in EtOAc (2 mL) are added. The mixture is stirred for 1 h at room temperature in a pressurized vessel under 50 psi (3.515 kg / cm2) of hydrogen. The paste is filtered through Celite® and concentrated in vacuo to obtain 2-aminomethyl-5-fluoro-pyridine (613 mg, 60% yield, 80% purity by GC / MS). GC-MS m / z: 126 (M +).

Preparation 102 3-Aminomethyl-5-fluoro-pyridine In a Parr bottle is added 2,6-dichloro-3-cyano-5-fluoropyridine (20 g, 0.105 mol), ethanol (336 mL), triethylamine (24 mL), and 5% Pd / C (4 g). It is placed in a Parr agitation apparatus under 60 psi (4.218 kg / cm2) for 1 h at room temperature. The reaction mixture is filtered and ammonia gas is bubbled on a filter for 10 min. Raney® nickel (5.2 g) is added and placed in a Parr shaker under 500 psi (35.15 kg / cm2) of hydrogen for 18 h at 60-70 ° C. The reaction mixture is filtered and concentrated in vacuo. Dissolve in methanol and add 1 N hydrogen chloride in ether until a precipitate forms. Cool in an ice bath, completely filter the precipitate, wash the solid several times with ether, and dry to give the title compound as the hydrochloride salt (12 g, 70%). MS (ES +) m / z: 127 (M + H) +. The hydrochloride salt is dissolved in water, aqueous 0.1 N NaOH is added to adjust to pH 10, extracted with DCM, the organic layer is dried over Na 2 SO, filtered and concentrated to give the title compound.

Preparation 103 3-Aminomethyl-4-trifluoromethyl-pyridine 4-Trifluoromethyl-nicotinonitrile (1.0 g, 5.8 mmol) and wet Raney® activated nickel with ethanol (0.2 g) are added to a Parr pressure vessel. Immediately add, at room temperature, 2B-ethanol (25 mL) previously saturated with ammonia gas and seal the container. The reaction vessel is purged with nitrogen, the reaction mixture is pressurized with hydrogen (400 KPa), the vessel is sealed, the reaction is stirred and heated to 40 ° C. The reaction is continued for 20 h then in turn completely heated and the reaction mixture is allowed to cool to room temperature. Excess hydrogen is vented from the vessel and the vessel is purged with nitrogen. The reaction mixture is filtered to remove the Raney® nickel, washed with ethanol and concentrated in vacuo. Purify by SCX chromatography to give the title compound (560 mg, 55%). MS (ES +) m / z: 177 (M + H) +.

Preparation 104 2-aminomethyl-6-fluoropyridine dichlorohydrate 3-Fluoropyridine-N-oxide: 3-fluoropyridine (2.5 g, 25,749 mmol) is dissolved in anhydrous DCM (75 L). M-CPBA (70% suspension, 12.696 g, 51.499 mmol) is added and stirred at room temperature overnight. The reaction mixture is washed with saturated aqueous NaHCO3, the organic phase is dried over Na2SO4, filtered, and concentrated in vacuo. Purify by chromatography on silica gel by levigating with DCM and DCM / methanol (97: 3) to obtain the desired intermediate as a solid (1.413 g, 49%). MS (ES +) m / z: 115 (M + H) +. 2-Cyano-3-fluoropyridine: 3-fluoropyridine-N-oxide (1.0 g, 8.687 mmol) is dissolved in anhydrous acetonitrile (100 mL). Triethylamine (1319 g, 1.82 mL, 13.031 mmol), trimethylsilylcyanide (3.447 g, 4.63 mL, 34.749 mmol) is added and the mixture is heated under reflux overnight. It is cooled to room temperature and concentrated in vacuo. The residue is dissolved in EtOAc and washed with saturated aqueous NaHCO3. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 17: 3) to give the desired intermediate as a solid (746 mg, 70%). GC-MS m / z: 122 (M +). 2-Aminomethyl-3-fluoropdridine dichlorohydrate: 2-Cyano-3-fluoropyridine (300 mg, 2.457 mmol) is dissolved in absolute ethanol (12 mL). 10% Pd / C (93 mg) and concentrated HCl (0.614 mL, 7.37 mmol) are added. Hydrogenate at 40 psi (28.12 kg / cm2) overnight. Filter through Celite® and concentrate in vacuo to give the title compound as a solid (440 mg, 90%). MS (ES +) m / z: 127 (M + H) +.

Preparation 105 2-aminomethyl-6-fluoropyridine 2 HCl dichlorohydrate 2-Cyano-6-fluoropyridine: Dissolve 2,6-difluoropyridine (12 g, 104.2 mmol) in anhydrous DMSO (5 mL). A solution of sodium cyanide (1.3 g, 26.53 mmol) in DMSO (60 mL) is added over 12 hr using a syringe pump. The mixture is heated at 100 ° C overnight. Cool to room temperature, dilute with EtOAc (500 mL), and wash with brine. The organic phase is dried over Na 2 SO 4, filtered, and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 4: 1) to give the desired intermediate as a solid (723 mg, 22%). GC-MS m / z: 122 (M +). 2-Aminomethyl-6-fluoropyridine dichlorohydrate: 2-Cyano-6-fluoropyridine (300 mg, 2.46 mmol) is dissolved in absolute ethanol (12 mL). 10% Pd / C (93 mg) and concentrated HCl (0.614 mL, 7.37 mmol) are added. Hydrogenate at 40 psi (28.12 kg / cm2) overnight. Filter through Celite® and concentrate to give the title compound as a solid (356 mg, 73%). MS (ES +) m / z: 127 (M + H) +.

Preparation 106 4-Aminomethyl-N- (pyridin-2-yl-methyl) -benzamide General Procedure 6-2 is used, using 2- (aminomethyl) pyridine (181 mg, 0.172 mL, 1.67 mmol) and 4- (tert-butoxycarbonylamino-methyl) -benzoic acid (420 mg, 1.67 mmol) to give the compound of the title as a solid (427 mg, 100 %). MS (ES +) m / z: 242 (M + H) +. The compounds of preparations 107-117 can be prepared essentially as described in Preparation 106 when using 4- (tert-butoxycarbonylamino-methyl) -benzoic acid and the appropriate amine. The general performance and EM data (ES +) are shown in the Table below.

Preparation 118 (±) -1- (3-Fluorophenyl) ethylamine Sodium cyanoborohydride (452 mg, 7.2 mmol) is added to a solution of 3-fluoroacetophenone (500 mg, 3.6 mmol) and ammonium acetate (2.8 g, 36 mmol). ) in methanol (11 mL). The mixture is stirred for 96 h at room temperature under a nitrogen atmosphere. Adjust to pH 2 with 2M hydrogen chloride in diethyl ether. The paste is concentrated in vacuo, the residue is diluted with DCM and washed with 5N aqueous NaOH followed by saturated aqueous NaHCO3. Dry the organic layer, concentrate in vacuo for half the volume, and load the solution onto an SCX column (one column is pre-washed with methanol followed by DCM., then eluted with 2M ammonia in methanol). The fractions are concentrated for half the volume to remove the ammonia, excess 2M hydrogen chloride is added in diethyl ether and concentrated to obtain the hydrochloride salt (70:30 mixture of the title compound and dimer). Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (20: 1) to obtain the title compound (323 mg, 51%). MS (ES +) m / z: 140 (M + H) +.

Preparation 119 1- (3-Fluorophenyl) ethylamine, isomer 2 The flask equipped with condenser, mechanical stirrer and addition funnel is prepared. 3-Fluoroacetophenone (25 g, 0.18 mol) and formic acid (4.2 g, 0.09 mol) are added via the addition funnel to a flask containing formamide (32.6 g, 0.72 mol) at 140 ° C for 15 min, and then the mixture is heated to 160 ° C. Formic acid is added successively (4.2 g, 0.5 equiv.) By means of an addition funnel to the flask every hour for 4 h while maintaining the reaction temperature at 160 ° C. The reaction mixture is cooled, extracted with toluene (3 x 100 mL), and the organic layer is concentrated in vacuo. Aqueous HCl (37%, 40 mL) is added to the residue and heated to reflux for 2 h. It is cooled to room temperature and the aqueous mixture is washed with toluene (2 x 100 mL), then the aqueous mixture is basified with 5N aqueous NaOH (120 mL). The basic mixture is extracted with EtOAc (3 x 100 mL), the combined organic extracts are dried over Na2SO and filtered. The filtrate is acidified with 2M hydrogen chloride in diethyl ether to pH 2 and concentrated in vacuo to a solid. The solid was suspended in diethyl ether, filtered and washed with diethyl ether. Dry the solid in a vacuum oven at 50 ° C to obtain (±) -l- (3-fluorophenyl) ethylamine hydrochloride (21.5 g, 68%). MS (ES +) m / z: 140 (M + H) +. Dissolve (+) - l- (3-fluorophenyl) ethylamine hydrochloride (42.5 g, 0.24 mol) in THF (520 mL) and saturated aqueous NaHCO3 (430 mL). Di-tert-butyl-dicarbonate (69 g, 0.31 mol) is added and stirred for 16 h at room temperature. The organic layer is separated, diluted with EtOAc (300 mL) and washed with 2N aqueous NaOH (1 x 400 mL) and water (2 x 200 mL). The organic layer is concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to obtain (±) -N- [1- (3-fluorophenyl) ethyl] -carbamic acid tert-butyl ester (56 g, 97 %). GC-MS m / z: 183 [(M-C4H9) j. The racemic mixture of tert-butyl ester of (±) -N- [1- (3-fluorophenyl) ethyl] -carbamic acid is separated by a normal phase chiral chromatography (Chiralcel OD 8 x 34 cm, eluted with 95 ml). : 5, heptane / isopropanol). By using General Procedure 1-4, which deprotects the desired isomer [20.7 g, > 95% ee (Chiralcel OD, 4.6 x 250 mm, elute: 95: 5 heptane / isopropanol with 0.2% DMEA, 1.0 mL / min)] to obtain the title compound (9.4 g, 78%). MS (ES +) m / z: 140 (M + H) +.

Preparation 120 (±) -1- (2-Fluorophenyl) ethylamine Sodium cyanoborohydride (1.8 g, 29 mmol) is added to a solution of 2-fluoro-acetophenone (2.0 g, 14.5 mmol) and ammonium acetate (11.2 g, 145 mmol) in methanol (45 mL). The mixture is stirred for 20 h at room temperature under a nitrogen atmosphere. The mixture is adjusted to pH 1 with 2M hydrogen chloride in diethyl ether. The paste is concentrated in vacuo, the residue is diluted with DCM and washed with 5N aqueous NaOH. The organic layer is dried, carefully concentrated, as the amine is volatile, under reduced pressure to one third of the volume, and the material is loaded onto an SCX column (column pre-washed with methanol, followed by DCM, eluted with 2M ammonia in methanol). The fraction is concentrated to half the volume to remove the ammonia, then 2M hydrogen chloride in diethyl ether is added and concentrated to obtain the hydrochloride salt. Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (20: 1) to obtain the title compound (280 mg, 13%). MS (ES +) m / z: 140 (M + H) +.

Preparation 121 1- (2-Fluorophenyl) ethylamine, Isomer 1 A method similar to General Procedure 6-3 is used, using 2-fluoroacetophenone (1.4 g, 9.9 mmol) and (R) - (+) - 2-methyl- 2-propanesulfinamide (1.0 g, 8.2 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc / 2M ammonia in methanol (90: 9: 1 to 50: 45: 5). 4M hydrogen chloride in dioxane is added to obtain the title compound as the hydrochloride (600 mg, 35%). MS (ES +) m / z: 140 (M + H) +. The hydrochloride is dissolved in an aqueous solution of cesium carbonate (1.5 equiv.) And extracted with toluene to obtain the free base. The compounds of preparations 122-141 can be prepared essentially as described in Preparation 121 by using (R) - (+) - 2-methyl-2-propanesulfinamide or (S) - (-) - 2-methyl-2- propansulfinamide and the appropriate acetophenone. General performance data and mass spectrum are shown in the Table below.

ND = Not determined Preparation 144 (±) -1- (2, 5-Difluorophenyl) ethylamine A paste of 2 ', 5' -difluoroacetophenone (0.9 g, . 76 mmol), ammonium acetate (4.44 g, 57.5 mmol) and sodium cyanoborohydride (755 mg, 12 mmol) in anhydrous methanol (25 mL) and stirred for 18 h at room temperature. Acidify with 5N aqueous HCl (5 mL), dilute, extract with ethyl ether (3 x 150 mL), basify the aqueous layer with 5N aqueous NaOH, extract with DCM (3 x 75 mL), wash the organic layer with brine, dried over MgSO4, filtered and concentrated in vacuo. Purify by SCX chromatography to give a mixture of (+) - l- (2,5-difluorophenyl) ethylamine and bis- [1- (±) -2,5-difluorophenyl) ethyl] -amine (total 400 mg, weight raw). MS (ES +) m / z: 158 (M + H) + and m / z: 298 (M + H) +.

Preparation 145 (±) -1- (3,5-Difluoro-4-methoxyphenyl) ethylamine The paste is made of 3 ', 5' -difluoro-4 '-methoxyacetophenone (1.0 g, 5.0 mmol), ammonium acetate (4.14 g, 50 mmol) and sodium cyanoborohydride (630 mg, 20 mmol) in anhydrous methanol ( 35 mL) and stirred for 18 h at room temperature. Acidify with IN aqueous HCl (5 mL), dilute, extract with ethyl ether (3 x 150 mL), basify aqueous with IN aqueous NaOH, extract with DCM (3 x 50 mL), wash the organic extracts with brine, dried over MgSO, filtered and concentrated in vacuo. Purify by SCX chromatography to give the crude title compound as a yellow oil (380 mg).

Preparations 146 and 147 1- (4-Phenoxyphenyl) -ethylamine, Isomer 1 and Isomer 2 4-Phenoxyacetophenone (5.3 g, 25 mmol), ammonium acetate (14.5 g, 187.5 mmol) and sodium cyanoborohydride (3.2 g, 50 mmol) are mixed in anhydrous methanol (200 mL). Stir for 18 h at room temperature. It is acidified with IN aqueous HCl (10 mL), diluted, extracted with ethyl ether (3 x 150 mL), dried over MgSO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by sequentially levigating with hexane / EtOAc (4: 1, 1: 1 and 0: 1) and EtOAc / methanol (1: 1) to give (±) -1- (4-phenoxyphenyl) - ethylamine (1.6 g, 30%). The racemate (1.1 g, 5.2 mmol) is dissolved in DCM (100 mL), triethylamine (l.dmL, 11.4 mmol) is added followed by di-tert-butyl-dicarbonate (1.7 g, 7.8 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give (±) -a-methyl- (4'-phenoxy) -benzylamino] carbamic acid tert-butyl ester as a completely white solid. (1.3 mg, 81%). It is separated by means of chiral chromatography (heptane / isopropanol / DMEA 95: 5: 0.2, 4.6 x 250 mm Chiralpak AD, 1 mL / min, UV detector at 260 nm) to give [α-methyl- (4'-phenoxy) benzylamino] carbamic acid tert-butyl ester, isomer 1 (315 mg, chiral HPLC: tR = 7.35 min; 99.1 % ee) and tert-butyl ester of [α-methyl- (4'-phenoxy) benzyl-aminocarbamic acid, isomer 2 (400 mg, chiral HPLC: tR = 8.7 min, 97.2% ee). Tert-butyl ester of [a-methyl- (4'-phenoxy) benzylamino] carbamic isomer 1 or isomer 2 is dissolved in DCM / trifluoroacetic acid (1: 1, 20 mL) to give, then the solvent for evaporation and chromatography on SCX column, 1- (4-phenoxyphenyl) -ethylamine, isomer 1 (Preparation 146) and l- (4-phenoxyphenyl) -ethylamine, isomer 2 (Preparation 147). MS (ES +) m / z: 214 (M + H) +.

Preparation 148 (5-Fluoro-indan-1-yl) amine, Isomer 1 A method similar to General Procedure 6-3 is used to react 5-fluoro-indan-1-one (1.5 g, 9.9 mmol) and (R) - (+) -2-methyl-2-propanesulfinamide (1.0 g, 8.3 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (5: 2). 4M hydrogen chloride in dioxane is added to obtain the title compound as the hydrochloride (254 mg, 16%). MS (ES +) m / z: 152 (M + H) +. The hydrochloride is dissolved in an aqueous solution of cesium carbonate (1.5 equiv.) And extracted with toluene to obtain the free base.

Preparation 149 1-Phenyl-cyclopropylamine 1-Phenyl-cyclopropanecarboxylic acid (2.5 g, .4 mmol) in a mixture of sulfuric acid (12.5 mL) and DCM (25 mL). Sodium azide (2.3 g, 35.4 mmol) is added in small portions at room temperature. The reaction mixture is heated at 50 ° C for 8 h, cooled to 0 ° C and 2M aqueous NaOH is slowly added until pH 11. The reaction mixture is extracted with DCM (3 x 100 mL), the extracts are combined organic and dried over anhydrous Na2SO4. The solvent is evaporated and purified by chromatography on silica gel by levigating with DCM and DCM / 2M ammonia in methanol (9: 1) to obtain the title compound as a brown oil (1.1 g, 54%). MS (ES +) m / z: 134 (M + H) +.

Preparation 150 1- (2,4-Dichlorophenyl) -cyclopropylamine A method similar to Preparation 149 is used, using 1- (2,4-dichlorophenyl) -cyclopropanecarboxylic acid (3.5 g, 15.4 mmol), to obtain the title compound as a yellow oil (1.0 g, 32%). MS (ES +) m / z: 203 (M + H) +.

Preparation 151 4-Methylamino-benzo [1,3] dioxol c "" Oo-eOoH-cCol-cNoH2 Benzo [1, 3] dioxol-4-yl-methanol: Benzo [1, 3] dioxol-4-carbaldehyde (2.0 g, 13.3 mmol) is dissolved in anhydrous THF (30 mL) and treated with sodium borohydride (0.5 g, 13.3 mmol) at 0 ° C. The reaction mixture is stirred for 30 min at room temperature and quenched with water (30 mL). The reaction mixture is extracted with DCM (3 x 10 mL), the organic extracts are combined and dried over Na 2 SO 4 amhydro. The solvent is removed to obtain the desired intermediate as a colorless oil (1.9 g, 94%). 4-Chloromethyl-benzo [1,3] dioxole: Benzo [1,3] dioxol-4-yl-methanol (1.9 g, 12.5 mmol) is dissolved in thionyl chloride (3 mL, 41.1 mmol) and placed a. reflux the reaction mixture for 1 h. Concentrate in vacuo to obtain the desired intermediate as a yellow oil (1.9 g, 91%) which is used without further purification. GC-MS m / z: 170 (M +). 4-Methylamino-benzo [1,3] dioxole: Dissolve 4-chloromethyl-benzo [1, 3] dioxol (1.9 g, 11.1 mmol) in methanol (5 mL), cool the solution to 0 ° C and saturate with anhydrous ammonia for 15 min. The reaction mixture is maintained at 0 ° C for 18 h. The solvent is evaporated and purified by SCX chromatography to obtain the title compound as a yellow oil (0.6 g, 36%). GC-MS m / z: 151 (M +).

Preparation 152 6-Bromomethyl-benzothiazole Methyl ester of the benzothiazole-6-sarboxxyliside: L-methyl-3-nitro-l-nitrosoguanidine (5.0 g, 33.9 mmol) is added to a mixture of diethyl ether (20 mL) and 1N aqueous NaOH (20 mL) at room temperature. Separate the organic layer and add slowly to a solution of benzothiazole-6-carboxylic acid (1.0 g, 5.58 mmol) in THF (50 mL) at 0 ° C. The solvent is evaporated to obtain the desired intermediate as a yellow solid (1.1 g, 100%). MS (ES +) m / z: 194 (M + H) +.

Benzotxazol-6-yl-methanol: A solution of benzothiazole-6-carboxylic acid methyl ester (0.5 g, 2.59 mmol) in anhydrous THF (10 mL) is added slowly to a suspension of lithium aluminum hydride (0.1 g) , 2.85 mmol) in anhydrous THF (20 mL) at -10 ° C and stirred for 20 min at -10 ° C. The reaction mixture is treated with 2N aqueous NaOH until the granular starting precipitate is formed and filtered through a pad of Celite®. The solvent is evaporated and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1, 4: 1, 7: 3, 3: 2 and 1: 1) to obtain the desired intermediate as a yellow oil (0.4 g, 99%). MS (ES +) m / z: 166 (M + H) +. 6-Bromomethyl-benzothiazole: Dissolve benzothiazol-6-yl-methanol (0.4 g, 2.55 mmol) in diethyl ether (10 mL) and slowly add a solution of phosphorus tribromide (0.7 g, 2.55 mmol) in diethyl ether ( 5 mL). The reaction mixture is stirred for 2 h at room temperature, washed with brine, the organic phase is dried over anhydrous Na 2 SO 4, the solvent is evaporated and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9). : 1 and 4: 1) to obtain the title compound as a white solid (0.5 g, 86%). MS (ES +) m / z: 229 (M + H) +.

Preparation 153 6-Bromomethyl-2-cyclohexyl-benzothiazole Br JCO-O Ethyl ester of the acid sislohexanosarboxxmidiso, slorohydrate: Cyclohexanecarbonitrile (1.0 g, 9.20 mmol), ethanol (0.4 g, 9.20 mmol) and 4N hydrogen chloride in dioxane (8 mL) are combined and the reaction mixture is stirred for 17 h at room temperature. The solvent is evaporated and the residue triturated with diethyl ether to obtain the desired intermediate as a white solid (1.4 g, 80%). 2-Cislohexyl-6-methyl-benzothiazole: Zinc salt of 2-amino-5-methyl-benzenethiol (1.0 g, 2.91 mmol, prepared as in Synth, Commun. 1980, 10, 167-173), hydrochloride ethyl ester of cyclohexanecarboximide (1.1 g, 5.82 mmol), methanol (20 mL) and the reaction mixture was refluxed for 17 h. The solvent is evaporated and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain the desired intermediate as a white solid (1.15 g, 85%). 6-Bromomethyl-2-sislohexyl-benzothiazole: Combined 2-benzyl-6-methyl-benzothiazole (0.6 g, 2.42 mmol), NBS (0.5 g, 2.54 mmol), AIBN (40 mg, 0.24 mmol), carbon tetrachloride (10 mL) and refluxed for 3 h. The reaction mixture is cooled to room temperature, diluted with chloroform and washed with water. The organic extracts are dried over anhydrous Na2SO4, concentrated in vacuo and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain the title compound as a white solid (0.4 g, 53%). MS (ES +) m / z: 311 (M + H) +.

Preparation 154 6-Bromomethyl-2-phenyl-benzothiazole 6-Methyl-2-phenyl-benzothiazole: Zinc salt of 2-amino-5-methyl-benzenethiol (1.0 g, 2.91 mmol, is prepared as described in Synth, Commun. 1980, 10, 167-173) , ethyl benzimidate hydrochloride (1.1 g, 5.82 mmol), methanol (20 mL), and the reaction mixture was refluxed for 17 h. The solvent is evaporated and purified by chromatography on silica gel by levigating with hexane / EtOAc. (1: 0 and 9: 1) to obtain the desired intermediate as a white solid (1.1 g, 85%). MS (ES +) m / z: 226 (M + H) +. 6-Bromomethyl-2-phenyl-benzothiazole: Combined 6-methyl-2-phenyl-benzothiazole (0.2 g, 0.98 mmol), NBS (0.2 g, 1.02 mmol), AIBN (20 mg, 0.10 mmol), carbon tetrachloride (5 mL) and refluxed for 3 h. The reaction mixture is cooled to room temperature, diluted with chloroform and washed with water. The organic extracts are dried over anhydrous Na2SO4, concentrated and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1, 8: 2 and 7: 3) to obtain the title compound as a white solid (0.2 g, 69%).

Preparation 155 2-Benzyl-6-bromomethyl-benzothiazole C c "- - (XxoHa - - CO- _ -N Br. XX Ethyl ester of the acid 2-Phenyl-asetimidiso, slorohydrate: Benzyl cyanide (1.0 g, 8.50 mmol), ethanol (0.4 g, 8.50 mmol) and 4N hydrogen chloride in dioxane (8 mL) are combined and the reaction mixture is stirred at room temperature for 17 h. The solvent is evaporated and the residue triturated with diethyl ether to obtain the desired intermediate as a white solid (1.7 g, 100%). 2-Benzyl-6-methyl-benzothiazole: Zinc salt of 2-amino-5-methyl-benzenethiol (1.0 g, 2.91 mmol, is prepared as described in Synth, Commun. 1980, 10, 167-173) , 2-phenyl-acetylimic acid ethyl ester chlorohydrate (1.16 g, 5.82 mmol), methanol (20 mL) and the reaction mixture was refluxed for 17 h. The solvent is evaporated and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain the desired intermediate as a white solid (1.0 g, 72%). MS (ES +) m / z: 240 (M + H) +. 2-Bensyl-6-bromomethyl-benzothiazole: Combined 2-benzyl-6-methyl-benzothiazole (0.6 g, 2.51 mmol), NBS (0.5 g, 2.63 mmol), AIBN (40 mg, 0.25 mmol), carbon tetrachloride (10 mL) and refluxed for 3 h. The reaction mixture is cooled to room temperature, diluted with chloroform and washed with water. The combined organic extracts are dried over anhydrous Na2SO4, the solvent is evaporated and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain the title compound as a white solid (0.2 g). , 69%). MS (ES +) m / z: 319 (M + H) +.

Preparation 156 5-Bromomethyl-benzoxazole -Methyl-benzoxazole: Combined 2-amino-4-methyl-phenol (1.0 g, 8.12 mmol), [(dimethylaminomethylene-aminomethylene) dimethylammonium chloride (Gold reagent) (1.6 g, 9.91 mmol), 1.4 anhydrous dioxane (25 mL) and refluxed for 17 h. The reaction mixture is cooled to room temperature, the solvent is evaporated and purified by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to obtain the desired intermediate as a yellow oil (0.7 g, 65%).

-Bromomethyl-benzoxazole: 5-methyl-benzoxazole (0.5 g, 3.75 mmol), NBS (0.7 g, 3.93 mmol), AIBN (60 mg, 0.37 mmol), chloroform (10 mL) were combined and refluxed for 1 hour. The reaction mixture is cooled to room temperature, diluted with chloroform and washed with water. Dry the organic extracts over anhydrous Na 2 SO 4, evaporate the solvent and purify by chromatography on silica gel levigating with hexane / EtOAc (1: 0, 9: 1, 4: 1 and 7: 3) to obtain the title compound as a white solid (0.1 g, 13%).

Preparation 157 5-Methylamino-2-phenyl-benzoxazole x ^ xH 2-Trimethylsilanyl-Ethyl Ester of 2- (Phenyl-benzoxazol-5-ylmethyl) -sarbamate acid: (2-Phenyl-benzoxazol-5-yl) -acetic acid (1.0 g, 3.95 mmol) is combined, triethylamine (0.5 g, 4.34 mmol), and anhydrous toluene (20 mL), is heated to reflux and diphenylphosphoryl azide (1.2 g, 4.15 mmol) in anhydrous toluene (8 L) is slowly added. The mixture is refluxed for 3 h, cooled to room temperature, 2-trimethylsilylethanol (0.9 g, 7.89 mmol) is added to the reaction mixture and the mixture is refluxed for 3 h. The solvent is evaporated and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1, 4: 1 and 7: 3) to obtain the desired intermediate as a yellow solid (0.4 g, 26% ).

-Methylamino-2-phenyl-benzoxazole: 2-Trimethylsilanyl-ethyl ester of (2-phenyl-benzoxazol-5-yl-methyl) -carbamic acid (0.4, 0.99 mmol) is dissolved in anhydrous THF (5 mL) and it is treated with 1M tetrabutylammonium fluoride in THF (1.5 mL, 1.54 mmol). The mixture is heated under reflux for 30 min, the solvent is evaporated and purified by SCX chromatography to obtain the title compound as a yellow oil (0.1 g, 27%).

Preparation 158 4-Aminomethyl-1-methylindole l-Methylindol-4-sarbonitrile: A solution of indole-4-carbonitrile (1.0 g, 7.04 mmol) in anhydrous DMF (5 mL) is slowly added to a suspension of sodium hydride (60% dispersion in mineral oil, 0.6 g , 8.64 mmol) in anhydrous DMF (2 mL) at 0 ° C and the reaction mixture is warmed to room temperature. Iodomethane (0.7 mL, 10.6 mmol) is added and the reaction is stirred for 1 h at room temperature. The reaction mixture is diluted with 1M aqueous NH 4 OH (30 mL) and extracted with diethyl ether (3 x 10 mL). The organic extracts are combined, dried over anhydrous Na2SO4, concentrated in vacuo and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1, 4: 1 and 7: 3) to obtain the intermediate desired as a yellow oil (1.0 g, 87%). GC-MS m / z: 156 (M +). 4-Aminomethyl-l-methylindol: Dissolve l-methylindol-4-carbonitrile (1.0 g, 6.18 mmol) in anhydrous THF (10 mL) and slowly add to 1M lithium aluminum hydride in THF (12.4 mL, 12.37 mmol) at room temperature. The reaction mixture is heated at 50 ° C for 17 h and cooled to room temperature. The reaction mixture is quenched with water until a granular starting precipitate is formed and filtered through a pad of Celite®. The solvent is evaporated and purified by SCX chromatography to obtain the title compound as a yellow oil (0.9 g, 91%). GC-MS m / z: 160 (M +).

Preparation 159 6-Aminomethyl-l-methylindole l-Methylindole-6-carbonitrile: A solution of indole-6-carbonitrile (1.0 g, 7.04 mmol) in anhydrous DMF (5 mL) is slowly added to a suspension of sodium hydride (60% dispersion in mineral oil, 0.6 g , 14.1 mmol) in anhydrous DMF (2 mL) at 0 ° C and the reaction mixture is warmed to room temperature. Iodomethane (0.7 mL) is added, 1.06 mmol) and the reaction mixture is stirred for 1 h at room temperature. The reaction mixture is diluted with 1M aqueous NHOH (30 mL) and extracted with diethyl ether (3 x 10 mL). The organic layers are combined, dried over anhydrous Na 2 SO 4, the solvent is removed and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1, 4: 1 and 7: 3) to obtain the intermediate desired as a yellow oil (1.0 g, 87%). MS (ES +) m / z: 156 (M + H) +. 6-Aminomethyl-l-methylindol: Dissolve l-methylindol-6-carbonitrile (0.97 g, 6.18 mmol) in anhydrous THF (10 mL) and slowly add to 1M lithium aluminum hydride in THF (1.24 mL, 1.24 ptmol) at room temperature. The reaction mixture is heated at 50 ° C for 17 h and cooled to room temperature. The reaction mixture is quenched with water until a granular starting precipitate is formed and filtered through a pad of Celite®. The solvent is evaporated and purified by SCX chromatography to obtain the title compound as a yellow oil (0.9 g, 91%).

GC-MS m / z: 160 (M +).

Preparation 160 6-Aminomethyl-benzofuran Dissolve benzofuran-6-carbonitrile (0.5 g, 3.28 mmol) in anhydrous THF (10 mL) and slowly add to 1M lithium aluminum hydride in THF (6.56 mL, 6.56 mmol) at room temperature. The reaction mixture is heated at 50 ° C for 17 h and cooled to room temperature. The reaction mixture is quenched with water until a granular starting precipitate is formed and filtered through a pad of Celite®. The solvent is evaporated and purified by SCX chromatography to obtain the title compound as a yellow oil (0.4 g, 79%).

Preparation 161 4-Aminomethyl-benzofuran Benzofuran-4-sarbonitrile: 4-bromo-benzofuran is combined (1.0 g, 5.07 mmol), copper cyanide (I) (0.9 g, 10.2 mmol), anhydrous DMF (16 mL) and refluxed for 17 h. The reaction mixture is cooled to room temperature, treated with 50% (w / w) aqueous ethylenediamine (25 mL). The reaction mixture is extracted with diethyl ether (3 x 15 mL), the organic extracts are combined, washed with brine (15 mL) and dried over anhydrous Na2SO4. The solvent is evaporated and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1 and 4: 1) to obtain the desired intermediate as a colorless oil (0.3 g, 39%). 4-Aminomethyl-benzofuran: Dissolve benzofuran-4-carbonitrile (0.3 g, 1.96 mmol) in anhydrous THF (5 mL) and slowly add to 1M lithium aluminum hydride in THF (3.91 mL, 3.91 mmol) at room temperature . The reaction mixture is heated at 50 ° C for 5 h and cooled to room temperature. The reaction mixture is quenched with water until a granular starting precipitate is formed and filtered through a pad of Celite®. The solvent is evaporated and purified by SCX chromatography to obtain the title compound as a brown oil (0.4 g, 79%). GC-MS m / z: 147 (M +).

Preparation 162 4-Aminomethyl-benzo [b] thiophene Lithium aluminum hydride (1M solution in THF, 7.5 mL) is added to benzo [b] thiophene-4-carbonitrile (prepared as described in WO 0168653) (0.6 g, 3.8 mmol) at 0 ° C in THF ( 38 mL). After 17 h at room temperature, it is cooled to 0 ° C and water (1.89 mL), 2N aqueous NaOH is added sequentially. (1.89 mL) and water (2.69 mL). The solids are filtered and the filtrate is evaporated to obtain the crude amine. It is purified by SCX chromatography. The column is rinsed with methanol, a solution of the crude amine in methanol is added, the column is washed with methanol and then eluted with IN ammonia in methanol. Concentrate to give the title compound (0.57 g, 93%). GC-MS m / z: 163 (M +).

Preparation 163 6-Aminomethyl-benzo [b] thiophene Benzo [b] iof n-6-carbonitrile: Heat copper (I) cyanide (0.84 g, 9.4 mmol) and 6-bromobenzo [b] thiophene (prepared as described in WO 01/23381) (1.0 g, 4.7 mmol) at 160 ° C for 13 h. The mixture is cooled to 0 ° C, 33% aqueous ethylenediamine (20 mL) is added and diluted with ether. The organic mixture is washed with brine, dried over Na 2 SO 4 and evaporated. Purify by chromatography on silica gel by levigating with EtOAc / hexane (0: 1 to 1: 3) to give the desired intermediate (0.58 g, 78%). GC-MS m / z: 159 (M +). 6-Aminomethyl-benzo [b] iofen: Add 1M lithium aluminum hydride in THF (7.3 mL) to benzo [b] thiophene-6-carbonitrile (0.6 g, 3.6 mmol) at 0 ° C in THF (36 mL) ). After 15 h at room temperature, it is cooled to 0 ° C and water (1.82 mL), 2N aqueous NaOH (1.82 mL) and water (2.60 mL) are added sequentially. The solid is filtered and the filtrate is evaporated to obtain the crude amine. It is purified by SCX chromatography. The column is rinsed with methanol, a solution of the crude amine in methanol is added, the column is washed with methanol and then eluted with IN ammonia in methanol. Concentrate in vacuo to give the title compound (0.55 g, 92%).

Preparation 164 8-Bromomethyl-quinoline Combine 8-methyl-quinoline (1.0 g, 6.99 mmol), NBS (1.3 g, 7.13 mmol), benzoyl peroxide (6.0 mg, 0.03 mmol), carbon tetrachloride (30 mL) and reflux for 17 h . The reaction mixture is cooled to room temperature and the solvent is evaporated. The residue is dissolved in chloroform (30 mL), the organic solution is washed with saturated aqueous NaHCO3 (2 x 10 mL), brine (10 mL) and dried over anhydrous Na2SO4. The solvent is evaporated and purified by chromatography on silica gel by levigating with DCM to obtain the title compound as a white solid (1.3 g, 83%). MS (ES +) m / z: 223 (M + H) +.

Preparation 165 2-Aminomethyl-quinoline Quinoline-2-carbonitrile (0.2 g, 1.29 mmol), Raney® 3201 nickel (paste in water, 0.05 g), 2N ammonia in methanol (10 mL) are combined and hydrogenated at 50 psi (3.515 kg / cm2) for 15 min. Filter the reaction mixture through a pad of Celite®, remove the solvent and purify by SCX chromatography to obtain the title compound as a yellow oil (0.2 g, 98%). MS (ES +) m / z: 159 (M + H) +.

Preparation 166 3-aminomethyl-quinoline dichlorohydrate Combine quinoline-3-carbonitrile (1.0 g, 6.49 mmol), 10% Pd / C (0.2 g), 5% TFA in methanol (100 mL) and hydrogenate at 30 psi (2.1409 kg / cm2) for 2 h. The reaction mixture is filtered through a pad of Celite® and the solvent is evaporated. The residue was dissolved in ethanol (10 mL), treated with IN hydrogen chloride in diethyl ether (5 mL) and the mixture allowed to stand at 5 ° C for 18 h. The precipitate is filtered, washed with ethanol and dried under vacuum to obtain the title compound as a white solid (0.6 g, 53%).

Preparation 167 2-aminomethyl-isoquinoline dichlorohydrate Isoquinoline-3-carbonitrile (1.0 g, 6.49 mmol), 10% Pd / C (0.2 g), 5% TFA in methanol (95 mL) is combined and hydrogenated at 30 psi (2,109 kg / cm2) for 17 h. The reaction mixture is filtered through a pad of Celite® and the solvent is evaporated. The residue is dissolved in ethanol (10 mL), treated with IN hydrogen chloride in diethyl ether (5 mL) and allowed to stand at 5 ° C for 18 h. The precipitate is filtered, washed with ethanol and dried under vacuum to obtain the title compound as a white solid (0.6 g, 55%). Preparation 168 6-Aminomethyl-quinoline 6- uinolinosarboxamide: Combine 6-quinolinecarboxylic acid (2.0 g, 11.6 mmol), 1,1-carbonyldiimidazole (3.8 g, 23.45 mmol) in DCM (50 mL) and stir at room temperature for 1 h. The reaction mixture is saturated with anhydrous ammonia and is continued for stirring for 1 h. The reaction mixture is quenched with water (100 mL) and extracted with chloroform (3 x 50 mL). Combine the organic extracts, dry over anhydrous Na 2 SO 4 and evaporate the solvent to obtain the desired intermediate as a white solid (1.6 g, 78%). 6-Quinolinsarbonitrile: 6-quinolinecarboxamide (1.5 g, 8.95 mmol) is dissolved in DCM (50 mL), triethylamine (2.7 g, 26.8 mmol) is added and the reaction mixture is cooled to 0 ° C. Trifluoroacetic acid anhydride (2.4 g, 11.16 mmol) is added to the reaction mixture and stirred for 10 min at 0 ° C. The reaction mixture is quenched with water (20 mL) and the organic layer is separated. The aqueous layer is extracted with DCM (2 x 15 mL). The organic extracts are combined and dried over anhydrous Na2SO4. The solvent is evaporated to obtain the desired intermediate as a white solid (1.0 g, 73%). GC-MS m / z: 154 (M +). 6-Aminomethyl-quinoline: Combined 6-quinolinecarbonitrile (1.0 g, 6.49 mmol), Raney® 3201 nickel (paste in water, 0.2 g), 2N ammonia in methanol (20 mL) and hydrogenated at 50 psi (3.515 kg) / cm2) for 1 h. Filter the reaction mixture through a pad of Celite®, remove the solvent and purify by SCX chromatography to obtain the title compound as a yellow oil (0.8 g, 78%).

Preparation 169 (+) -2- (1-Aminoethyl) -5-methylthiophene (±) -2- (1-Hydroxyethyl) -5-yl-iiophen: Sodium borohydride (270 mg, 7.13 mmol) is added to a solution of 2-acetyl-5-methylthiophene (1.0 g, 7.13 mmol) in methanol (40 mL). The mixture is stirred for 1 h at room temperature. The solvent is removed in vacuo and the residue divided between water and DCM. The organic phase is separated, dried over Na 2 SO 4, filtered and concentrated to obtain the desired intermediate as an oil (0.995 g, 98%) which is used without further purification.

GC-MS m / z 142 (M +). (±) -2- (1-Azidoethyl) -5-me iliophen: DBU (1.228 g, 1. 2 mL, 8.07 mmol) was added to a solution of (±) -2- (1-hydroxyethyl) -5-methylthiophene (0.955 g, 6.72 mmol) and diphenylphosphoryl azide. (2.22 g, 1.74 mL, 8.07 mmol) in anhydrous toluene. Stir at room temperature for 18 h. The mixture is diluted with EtOAc and washed with water and 0.5N aqueous HCl. The organic phase is dried over Na 2 SO 4, filtered and concentrated. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 19: 1) to obtain the desired intermediate as an oil (0.875 g, 78%). GC-MS m / z 167 (M +). (±) -2- (-Amxnoethyl) -5-methylthioen: Lithium aluminum hydride (29 mg, 0.72 mmol) is added to a solution of (+) -2- (1-azidoethyl) -5-methylthiophene ( 100 mg, 0.59 mmol) in anhydrous THF (5 mL). Stir at room temperature overnight. Work the mixture with EtOAc and water. The mixture is filtered over Celite®. The organic phase is separated and washed with brine. Dry over Na 2 SO 4, filter and concentrate in vacuo. It is purified by SCX chromatography. Rinse with DCM / methanol (1: 1), charge the crude mixture in methanol and elute sequentially with methanol and IN ammonia in methanol to obtain the title compound as an oil (80 mg, 95%). GC-MS m / z 141 (M +).

Preparations 170 and 171 1- (5-Phenyl-thiophen-2-yl) ethylamine, Isomers 1 and 2 N- [(5-Phenylthiophen-2-yl) -methylene] -2-methylpropanesulfinamide: To a solution of 5-phenyl-2-thiophenecarboxaldehyde (1.25 g, 6.64 mmol) in anhydrous THF (50 L), ethoxide is added titanium (IV) (3.03 g, 2.78 mL, 13.28 mmol) and (R) - (+) -2-methyl-2-propanesulfinamide (0.965 g, 7.968 mmol) under nitrogen. The reaction is heated at 80 ° C overnight. The mixture is cooled to room temperature and diluted with EtOAc. Water is added and the resulting precipitate is filtered over Celite®. The organic phase is separated and dried over Na 2 SO 4, filtered and concentrated in vacuo to obtain the desired intermediate as a yellow solid (1.93 g, 100% yield) which is used without purification.

N- [1- (5-Phenylthiophen-2-yl) ethyl] -2-mepropropanesulfinamide (Isomer 1) ^ N- [1- (5-phenylthio-2-yl) ethyl] -2-methylpropanesulfinamide (Isomer 2): Methyllithium (8.1 mL, 12.92 mmol, 1.6M ether solution) is added slowly to a solution of N- [(5-phenylthiophen-2-yl) -methylene] -2-methylpropanesulfinamide (1883 g, 6.46 mmol) in anhydrous THF (50 mL) at -40 ° C. The reaction is warmed to -20 ° C and stirred for 2 h. Heat to 0 ° C and stir for an additional 2 hours. Saturated aqueous NHC1 is added and extracted with EtOAc. The organic phase is dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (7: 3 and 1: 1) to obtain N- [1- (5-phenylthiophen-2-yl) ethyl] -2-methylpropanesulfinamide (Isomer 1) (575 mg, 30% yield) and N- [1- (5-phenylthiophen-2-yl) ethyl] -2-methylpropanesulfinamide (Isomer 2) (847 mg, 44% yield). 1- (5-Phenyl-thiophen-2-yl) ethylamine (Isomer 1, Preparation 170) 4N hydrogen chloride in dioxane (0.837 L, 3.349 mmol) is added to a stirred solution of N- [1- (5-phenylthiophene) -2-yl) ethyl] -2-methylpropanesulfinamide (Isomer 1) (515 mg, 1675 mmol) in methanol (8 mL) at room temperature. It is stirred for 2 h and the solvent is removed in vacuo to obtain a solid which is washed with ethyl ether. The solid is dissolved in DCM and washed with saturated aqueous NaHCO3. Dry the organic phase over Na 2 SO 4, filter and concentrate in vacuo to obtain the desired intermediate (236 mg, 69% yield). 1- (5-Phenyl-thiophen-2-yl) ethylamine (Isomer 2, Preparations 171) 4N Hydrogen chloride in dioxane (1112 mL, 4.449 mmol) is added to a stirred solution of N- [1- (5-phenylthiophen-2-yl) ethyl] -2-methylpropanesulfinamide (Isomer 2) (684 mg, 2225 mmol ) in methanol (10 mL) at room temperature. It is stirred for 2 h and the solvent is removed in vacuo to obtain a solid which is washed with ethyl ether. The solid is dissolved in DCM and washed with saturated aqueous NaHCO3. Dry the organic phase over Na 2 SO 4, filter and concentrate in vacuo to obtain the desired intermediate (347 mg, 77% yield).

Example 49 6- (2-Benzoylamino-ethylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride Dissolve 6- (2-amino-ethylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (70 mg, 0.208 g. mmol) in DCM (4 mL). Benzoyl chloride is added (24 μL, 0.208 mmol), and triethylamine (44 μL, 0.312 mmol) and stirred at room temperature for 24 h under nitrogen atmosphere. Dilute with DCM and add 1M aqueous HCl. The aqueous layer was extracted with DCM. Dry the organic layer over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 7: 3 and 1: 1) to obtain 6- (2-benzoylamino-ethylamino) -7-chloro-3- (2, 2, 2 -trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to General Procedure 1-1 is used, using 6- (2-benzoylamino-ethylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro- lH-benzo [d] azepine, to give the free base of the title compound. A method similar to General Procedure 2-2 is used to give the title compound (77 mg, 90% in general). HPLC: tR = 2.64 min (20-80% solvent B in 7.5 min Solvent A: water, 0.1% TFA Solvent B: acetonitrile, 0.1% TFA Column: C18 Metachem, 5 micron, 4.6x50). Examples 50-52 can be prepared essentially as described in Example 49 by using 6- (2-amino-ethylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4, 5- tetrahydro-lH-benzo [d] azepine or 6- (3-amino-propylamino) ~ 7-chloro-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [ d] azepine and the appropriate benzoyl chloride. The general performance and EM (ES +) data are shown in the Table below.

Example 53 7-Chloro-6-chlorohydrate. { 2- [(pyridine-3-carbonyl) -amino] -ethylamino} -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Nicotinic acid (28.2 mg, 0.23 mmol) is dissolved in DCM (3 mL). EDC (40 mg, 0.208 mmol), HOBT (28.1 mg, 0. 2081mmol) and stirred at room temperature for 10 min. 6- (2-Amino-ethylamino) -7-chloro-3- (2, 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (70 mg, 0.208) is added mmol) and stirred at room temperature for 10 hr. Dilute with DCM, add water and extract the aqueous layer 3 times with DCM. The combined organic extracts are washed with 1N aqueous NaOH, and brine. Dry the organic layer over MgSO4, concentrate in vacuo and purify by chromatography on silica gel, levigating with hexane / EtOAc (1: 0, 1: 1, 3: 7 and 1: 9) to obtain 7-chloro-6. -. { 2- [(pyridine-3-carbonyl) -amino] -ethylamino} -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to General Procedure 1-1 is used, when using 7-chloro-6-. { 2- [(pyridine-3-carbonyl) -amino] -ethylamino} -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine to give the free base of the title compound. A method similar to General Procedure 2-2 is used to give the title compound as a solid (92 mg, 98%). CLAR: tR = 1.38 min (20-80% Solvent B in 7.5 min Solvent A: water, 0.1% TFA Solvent B: acetonitrile, 0.1% TFA Column: C18 Metachem, 5 micron, 4.6x50).

Example 54 7-Chloro-6- [3- (3-phenyl-ureido) -propylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride Phenyl isocyanate is combined (15 μL, 0.137 mmol) and 6- (3-amino-propylamino) -7-chloro-3- (2, 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (48 mg, 0.137 mmol) in DCM and stirred for 16 h. Concentrate, add DCM, filter and collect the solid to obtain 7-chloro-6- [3- (3-phenyl-ureido) -propylamino] -3- (2,2,2-trifluoroacetyl) -2, 3,4,5-tetrahydro-lH-benzo [d] azepine (18 mg, 28%). A method similar to General Procedure 1-1 is used, using 7-chloro-6- [3- (3-phenyl-ureido) -propylamino] -3- (2,2,2-trifluoroacetyl) -2,3, 4,5-tetrahydro-lH-benzo [d] azepine, to give the free base of the title compound. A method similar to General Procedure 2-2 is used to give the title compound (14 mg, 23%). MS (ES +) m / z: 373 (M + H) +.

Example 55 6- (2-Phenoxy-ethylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 5-1 is used, using 3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (100 mg , 0.23 mmol) and phenoxyethylamine (63 mg, 0.4 mmol) - to give, then chromatography on silica gel levigating with hexane / EtOAc (85:15) followed by SCX chromatography, 6- (2-phenoxy-ethylamino) -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a yellow oil. MS (ES +) m / z: 379 (M + H) +. A method similar to General Procedure 1-1 is used to deprote 6- (2-phenoxy-ethylamino) -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-1H-benzo [d] ] azepine (75 mg, 0.19 mmol). Purify by SCX chromatography to give the free base of the title compound. A method similar to General Procedure 2-2 is used to give the title compound as a white solid. MS (ES +) m / z: 283 (M + H) +. Examples 56-61 can be prepared essentially as described in Example 55 by using 7-chloro-3- (2, 2, 2- 'trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The performance data for Stage 1 (General Procedure 5-1) and EM (ES +) are shown in the Table below.

ND Not determined Example 62 7-Chloro-6- [(2-ethoxyethyl) amino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 5-1 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (200 mg, 0.47 mmol) and 2-ethoxyethyl amine (105 μL, 1.0 mmol) to give, then chromatography on silica gel levigating with hexane / EtOAc (95: 5) and additional SCX chromatography, 7-chloro-6 - [(2-Ethoxyethyl) amino] -3- (2,2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (32 mg, 19%). MS (ES +) m / z: 365 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- [(2-ethoxyethyl) amino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro- lH-benzo [d] azepine (30 mg, 0.08 mmol). Purify by SCX chromatography to give the free base of the title compound. A method similar to General Procedure 2-1 is used to give the title compound as an oil (23.8 mg, 75% over 2 steps). MS (ES +) m / z: 269 (M + H) +. Examples 63-68 can be prepared essentially as described in Example 62 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [ d] azepine and the appropriate amine. The performance data during Stage 1 (General Procedure 5-1), optical rotations and EM (ES +) are shown in the Table below.

D Not determined Example 69 6- (2-Fluorobenzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 5-1 is used, using 3- (2,2,2-trifluoroacetyl) -6-trifluoromethylsulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (100 mg , 0.26 mmol) and 2-fluorobenzylamine (88 μL, 0.77 mmol) to give, then chromatography on silica gel, levigating with hexane / EtOAc (9: 1), 6- (2-fluorobenzylamino) -3- (2, 2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a yellow oil (45 mg, 48%). MS (ES +) m / z: 367 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 6- (2-fluorobenzylamino) -3- (2, 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (40 mg, 0.11 mmol). Purify by SCX chromatography to give the free base of the title compound as a yellow oil (28 mg, 94%). A method similar to General Procedure 2-2 is used to give the title compound as a completely white solid (29 mg, 95%). MS (ES +) m / z: 271 (M + H) +. Example 70 can be prepared essentially as described in Example 69 by using 3- (2,2,2-trifluoroacetyl) -6-trifluoromethylsulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and , 6-difluorobenzylamine. Performance data during Stage 1 (General Procedure 5-1) and EM (ES +) are shown in the Table below.

Example 71 7-Chloro-6- (2-fluorobenzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 5-1 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine and 2-fluorobenzyl amine. Purby chromatography on silica gel by levigating with hexane / EtOAc (9: 1 and 4: 1) to give 7-chloro-6- (2-fluorobenzylamino) -3- (2,2,2-trifluoroacetyl) -2, 3,4,5-tetrahydro-lH-benzo [d] azepine as a yellow solid. MS (ES +) m / z: 401 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- (2-fluorobenzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzole [d] azepine. Purby SCX chromatography to give the free base of the title compound as a yellow oil. A method similar to General Procedure 2-2 is used to give the title compound as a light yellow solid. MS (ES +) m / z: 305 (M + H) +. Examples 72-80 can be prepared essentially as described in Example 71 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [ d] azepine and the appropriate amine. EM (ES +) data are shown in the Table below.

(HCI) x Example 81 Succinate of 6- (4-tert-butylbenzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-1 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (300 mg, 0.7 mmol) with 4- (tert-butyl) benzyl amine (375 μL, 2.1 mmol). Purby chromatography on silica gel by levigating with hexane / EtOAc (95: 5) followed by 'SCX chromatography to give 6- (4-tert-butylbenzylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) ) - 2,3,4,5-tetrahydro-lH-benzo [d] azepine as a colorless oil (240 mg, 78%). MS (ES +) m / z: 439 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 6- (4-tert-butylbenzylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH -benzo [d] azepine (235 mg, 0.54 mmol). Purby SCX chromatography to give the free base of the title compound (161 mg, 87%). A method similar to General Procedure 2-1 is used to give the title compound as a completely white gum (190 mg, 88%). MS (ES +) m / z: 343 (M + H) +. Examples 82-88 can be prepared essentially as described in Example 81 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [ d] azepine and the appropriate amine. EM (ES +) data are shown in the Table below.

Example 89 7-Chloro-6- (4-cyanobenzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 5-1 is used by reacting 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (504 mg, 1.2 mmol), 4-cyanobenzylamine (476 mg, 3.6 mmol), palladium (II) acetate (29 mg, 0.1 mmol), BINAP (148 mg, 0.2 mmol) and cesium carbonate (540 mg, 1.7 mmol) in toluene (5 L). Purby chromatography on silica gel by levigating with isohexane / EtOAc (1: 0 to 1: 1) to give 7-chloro-6- (4-cyanobenzylamino) -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a white gum (108 mg, 22%). MS (ES +) m / z: 408 (M + H) +. A method similar to General Procedure 1-2 is used to deprotect 7-chloro-6- (4-cyanobenzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzole [d] azepine (98 mg, 0.2 mmol). Purification by preparative liquid chromatography eluted with a water / acetonitrile gradient (19: 1 to 1:19) to give the free base of the title compound (31 mg, 42%). MS (ES +) m / z: 312 (M + H) +. A method similar to General Procedure 2-1 is used, using 7-chloro-6- (4-cyanobenzylamino) -2,3,4,5-tetrahydro-1H-benzo [d] azepine (31 mg, 0.1 mmol) to give the title compound as a beige solid (41 mg, 95%). MS (ES +) m / z: 312 (M + H) +.

Example 90 Succinate of 7-Chloro-6- (3-phenyl-benzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (0.3 g, 0.706 mmol) with 3-phenyl-benzylamine (0.388 g, 2.117 mmol) when using palladium (II) acetate (32 mg, 0.141 mmol), tris (dibenzylidene ketone) dipalladium (0) (65 mg, 0.070 mmol ), BINAP (264 mg, 0.424 mmol) and cesium carbonate (460 mg, 1412 mmol) in toluene (12 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 19: 1) to give 7-chloro-6- (3-phenyl-benzylamino) -3- (2,2,2-trifluoroacetyl) - 2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil (0.257 g, 79%). MS (ES +) m / z: 459 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- (3-phenyl-benzylamino) -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro- lH-benzo [d] azepine (237 mg, 0.516 mmol), to give the free base of the title compound as an oil (188 mg, 100%) which is used without further purification. A method similar to General Procedure 2-1 is used, using 7-chloro-6- (3-phenyl-benzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (188 mg, 0.518) mmol) to give the title compound as a white solid (191 mg, 77%). MS (ES +) m / z: 363 (M + H) +.

Example 91 Succinate of 7-Chloro-6- (4-chlorobenzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (700 mg, 1.6 mmol) with 4-chlorobenzylamine (354 mg, 2.5 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) and then SCX chromatography to give 7-chloro-6- (4-chlorobenzylamino) -3- (2,2,2-trifluoroacetyl) ) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine (459 mg, 69%). MS (ES +) m / z: 417 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- [1- (4-chlorobenzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro- lH-benzo [d] azepine. Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (95: 5) to give the free base of the title compound. MS (ES +) m / z: 321 (M + H) +. A method similar to General Procedure 2-1 is used to obtain the title compound.

Examples 92-98 can be prepared essentially as described in Example 91 by using 7-chloro-3- (2, 2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and the appropriate amine. The yields for stage 1 (General procedure 5-3) and EM data (ES +) are shown in the Table below.

Examples 99-106 can be prepared essentially as described in Example 91 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The yields for stage 1 (General procedure 5-3) and The EM (ES +) data are shown in the table below.

Example 106 7-Chloro-6- (2-fluoro-4-phenoxy-benzylamino) 2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate By using a method similar to general procedure 5-3, 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] is coupled azepine (1.1 g, 2.5 mmol) with 2-fluoro-4-phenoxy-benzylamine (550 mg, 2.5 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) and then SCX chromatography to obtain 7-chloro-6- (2-fluoro-4-phenoxy-benzylamino) -3- (2.2, 2). -trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine. MS (ES +) m / z: 493 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- (2-fluoro-4-phenoxy-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5 -tetrahydro-lH-benzo [d] azepine. Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (95: 5) to give the free base of the title compound (468 mg, 47% in general). MS (ES +) m / z: 397 (M + H) +. A method similar to general procedure 2-1 is used to obtain the title compound.

Example 107 7-Chloro-6- [2-fluoro-4- (3'-fluoro-phenoxy) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to Example 106 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (426) mg, 1.0 mmol) and 2-fluoro-4- (3 '-fluorophenoxy) -benzylamine (340 mg, 1.4 mmol) to give the free base of the title compound (162 mg, 39%). MS (ES +) m / z: 415 (M + H) +. A method similar to General Procedure 2-1 is used to obtain the title compound. Examples 108-121 can be prepared essentially as described in Example 107 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The yields for stage 1 (General procedure 5-3) and EM data (ES +) are shown in the Table below.

Example 122 7-Chloro-6- [4- (3'-cyanobenzyloxy) -benzylamino] 2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate 7-Chloro-6- (4-hydroxy-benzylamino) -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (150 mg, 0.38) is mixed mmol), 3-cyanobenzyl bromide (90 mg, 0.46 mmol), potassium carbonate powder (105 mg, 0.76 mmol), potassium iodide powder (6.6 mg, 0.04 mmol) and acetone (30 mL). Stir and heat to reflux under nitrogen for 16 hr. It is diluted with acetone, filtered, concentrated in vacuo and purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 4: 1) to obtain 7-chloro-6- [4- (3 '- cyanobenzyloxy) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (72.4 mg, 37%). MS (ES +) m / z 514 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- [4- (3'-cyanobenzyloxy) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine. Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (95: 5) to give the free base of the title compound (42 mg, 71%). MS (ES +) m / z: 418 (M + H) +. A method similar to General Procedure 2-1 is used to obtain the title compound. Examples 123-126 can be prepared essentially as described in Example 122 by using 7-chloro-6- (4-hydroxy-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5 -tetrahydro-lH-benzo [d] azepine and the appropriate bromide. The general performance data and EM (ES +) are shown in the Table below.

Example 127 7-Chloro-6- [3-chloro-4- (3, 3-dimethyl-2-oxo-butoxy) benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 4-1 is used by reacting 7-chloro-6- (3-chloro-4-hydroxy-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine (438 mg, 1.01 mmol) and 1-bromopinacolone (217 mg, 1.21 mmol). Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 4) to give 7-chloro-6- [3-chloro-4- (3, 3-dimethyl-2-oxo-butoxy) -benzylamino] - 3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a colorless oil (441 mg, 82%). MS (ES +) m / z: 531 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- [3-chloro-4- (3, 3-dimethyl-2-oxo-butoxy) -benzylamino] -3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (441 mg, 0.83 mmol). Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (93: 7) to give the free base of the title compound (278 mg, 95%). MS (ES +) m / z: 435 (M + H) +. A method similar to General Procedure 2-1 is used to give the title compound.

Example 128 7-Chloro-6- (3-chloro-4-benzyloxy-benzylamino) 2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate H 02C (CH 2) 2C 02H The title compound can be prepared essentially as described in Example 127, by using 7-chloro-6- (3-chloro-4-hydroxy-benzylamino) -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine and benzyl bromide (64%). MS (ES +) m / z: 427 (M + H) +.

Example 129 Succinate of (±) -7-Chloro-6- [4- (1-phenyl-ethoxy) -benzylamino] 2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (851 mg, 2.0 mmol) and (±) -4- (1-phenyl-ethoxy) -benzylamine (721 mg, 2.6 mmol). Purify by chromatography on silica gel by levigating with EtOAc / hexane (1: 8) to give (+) - 7-chloro-6- [4- (1-phenyl-ethoxy) -benzylamino] -3- (2.2 , 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine (702 mg, 69%). MS (ES +) m / z: 503 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect (+) - 7-chloro-6- [4- (1-phenyl-ethoxy) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2 , 3,4, 5-tetrahydro-lH-benzo [d] azepine (702 mg, 1.40 ptmol). Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (92: 8) to give the free base of the title compound (368 mg, 65%). MS (ES +) m / z: 407 (M + H) +. A method similar to General Procedure 2-1 is used to obtain the title compound.

Examples 130 and 131 Succinate of (-) - 7-Chloro-6- [4- (1-phenyl-ethoxy) -benzylamino] -2,3,4,5-tetrahydro-1H-benzo [d] azepine and succinate of (+) - 7- Chloro-6- [4- (1-phenyl-ethoxy) -benzylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine The two enantiomers of Example 129 are separated by Chiral HPLC [Chiralcel OJ-H column, acetonitrile / methanol (20:80) with 0.2% DMEA; flow ratio 1 mL / min; Isomer 1: tR = 5.0 min, Isomer 2: tR = 6.5 min]. A method similar to General Procedure 2-1 is used to prepare the succinate of each enantiomer: Succinate of (-) -7-chloro-6- [4- (1-phenyl-ethoxy) -benzylamino] -2, 3,4,5-tetrahydro-lH-benzo [d] azepine, [a] 20D -17.4 ° ( c 0.5, CH3OH), and Succinate of (+) - 7-chloro-6- [4- (1-phenyl-ethoxy) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine, [a] 20D +18.2 ° (c 0.5, CH30H).

Example 132 7-Chloro-6- [4- (3, 3-dimethylbutoxy) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine mesylate (CH3SO3H). A method similar to General Procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (426 mg, 1.0 mmol) and 4- (3,3-dimethylbutoxy) -benzylamine (325 mg, 1.5 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) and then SCX chromatography to obtain 7-chloro-6- [4- (3, 3-dimethylbutoxy) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine. MS (ES +) m / z: 483 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- [4- (3, 3-dimethylbutoxy) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4 , 5-tetrahydro-lH-benzo [d] azepine. Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (95: 5) to give the free base of the title compound (161 mg, 42% in general). MS (ES +) m / z: 387 (M + H) +. A method similar to General Procedure 2-4 is used to obtain the title compound.

Example 133 7-Chloro-6- (4-cyclohexylmethoxy-benzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine mesylate (CH3S03H) x The title compound can be prepared essentially as described in US Pat. Example 132, by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine and 4-cyclohexylmethoxy-benzylamine ( 27% yield, MS (ES +) m / z 399 (M + H) +).

Example 134 7-Chloro-6- (3-pyrrolidinyl-benzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 5-1 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (300 mg, 0.7 mmol) and 3- (pyrrolidin-1-yl) benzylamine (300 mg, 1.7 mmol) to give, after chromatography on silica gel levigating with hexane / EtOAc (19: 1, 9: 1, 4: 1 and 3: 2), 7-chloro-6- (3-pyrrolidinyl-benzylamino) -3- (2, 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a yellow oil (195 mg, 62%). MS (ES +) m / z: 452 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- (3-pyrrolidinyl-benzylamino) -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro- lH-benzo [d] azepine (195 mg, 0.43 mmol). Purify by SCX chromatography to give the free base of the title compound (136 mg, 89%). A method similar to General Procedure 2-1 is used, using 7-chloro-6- (3-pyrrolidinyl-benzylamino) -2,3,4,5-tetrahydro-1H-benzo [d] azepine (130 mg, 0.37 mmol), to give the title compound as an opaque white gum (111 mg, 61%). MS (ES +) m / z: 356 (M + H) +.

Example 135 6- (4-Methoxybenzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to general procedure 1-1, using 6- ( 4-methoxybenzylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.1 g, 0.24 mmol) to give the free base of the title compound. A method similar to general procedure 2-2 is used to give the title compound (75 mg, 80%). HRMS calculated for C? 8H21ClN20 317.1421, found 317.1410.

Example 136 7-Chloro-6- [4- (2, 2, 3, 3-tetrafluoropropoxy) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (500 mg, 1.2 mmol) with 4- (2, 2, 3, 3-tetrafluoropropoxy) -benzylamine (835 mg, 3.5 mmol) in toluene (10 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (10: 1, 5: 1 and 3: 1) followed by SCX chromatography [the column is pre-washed with methanol followed by DCM, the dissolved material is loaded into DCM, then eluted with DCM / 2M ammonia in methanol (1: 1) and concentrated in vacuo] to obtain 7-chloro-6- [4- (2,2,3,3-tetrafluoropropoxy) -3- (2,2,2-trifluoroacetyl) -2, 3, 4,5-tetrahydro-lH-benzo [d] azepine (600 mg, 99%). A method similar to general procedure 1-3 is used to deprotect 7-chloro-6- [4- (2,2,3,3-tetrafluoropropoxy) -3- (2,2,2-trifluoroacetyl) -2,3, 4, 5-tetrahydro-lH-benzo [d] azepine (600 mg, 1.2 mmol). Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (99: 1 to 90:10) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to give the title compound (390 mg, 62%). MS (ES +) m / z: 417 (M + H) +.

Examples 137-138 can be prepared essentially as described in Example 136 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine and the appropriate amine. The general performance and EM (ES +) data are shown in the Table below.

Examples 139 and 140 Succinate of (-) - 7-Chloro-6- [4- (2, 2, 2-trifluoro-1-methyl-ethoxy) -benzylamino] -2,3,4, 5-tetrahydro-lH- benzo [d] azepine and Succinate of (+) - 7-Chloro-6- [4- (2, 2, 2-trifluoro-l-methyl-ethoxy) -benzylamino] -2,3,4, 5-tetrahydro- lH-benzo [d] azepine A method similar to general procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (500 mg, 1.2 mmol) with (±) -4- (2,2,2-trifluoro-1-methyl-ethoxy) -benzylamine (515 mg, 2.3 mmol) in toluene (10 mL). Chromatography is purified on silica gel by levigating with hexane / EtOAc (10: 1, 5: 1 and 3: 1) followed by SCX chromatography [the column is pre-washed with methanol followed by DCM, dissolved material is loaded into DCM, then elute with DCM / 2M ammonia in methanol (1: 1) and concentrate in vacuo] to give (±) -7-chloro-6- [4- (2, 2, 2-trifluoro-l-methyl-ethoxy) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (530 mg, 90%). GC-MS m / z: 494 (M +). A method similar to General Procedure 1-3 is used to deprotect (±) -7-chloro-6- [4- (2, 2, 2-trifluoro-1-methyl-ethoxy) -benzylamino] -3- (2, 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (520 mg, 1.1 mmol). Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (99: 1 to 90:10) to give (±) -7-chloro-6- [4- (2,2,2-trifluoro-1 -methyl-ethoxy) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to general procedure 2-1 is used to obtain (±) -7-chloro-6- [4- (2,2,2-trifluoro-1-methyl-ethoxy) -benzylamino] -2,3 succinate] , 4,5-tetrahydro-lH-benzo [d] azepine. The two enantiomers of (+) - 7-chloro-6- [4- (2, 2, 2-trifluoro-1-methyl-ethoxy) -benzylamino] -2- 3 succinate are separated., 4, 5-tetrahydro-lH-benzo [d] azepine by normal phase chiral chromatography (Chiralpak AD 8x30 cm, elute with 85:15 heptane / 3A ethanol with 0.2% DMEA). A method similar to General Procedure 2-1 is used to obtain (-) - 7-chloro-6- [4- (2, 2, 2-trifluoro-1-methyl-ethoxy) -benzylamino] -2,3 Succinate] , 4,5-tetrahydro-lH-benzo [d] azepine [137 mg, 71% recovery, 98% ee (Chiralpak AD, 4.6x150 mm, levigant: 85:15 heptane / isopropanol with 0.2% DMEA, 0.6 mL / min )]. MS (ES +) m / z: 399 (M + H) \ [a] 20D -7.9 ° (c 0.5, MeOH). A method similar to General Procedure 2-1 is used to obtain (+) - 7-chloro-6- [4- (2,2,2-trifluoro-1-methyl-ethoxy) -benzylamino] -2,3 Succinate] , 4,5-tetrahydro-lH-benzo [d] azepine [133 mg, 69% recovery, 97% ee (Chiralpak AD, 4.6x150 mm, levigant: 85:15 heptane / isopropanol with 0.2% DMEA, 0.6 mL / min )]. MS (ES +) m / z: 399 (M + H) +. [a] 20D + 9.2 ° (c 0.5, MeOH).

Example 141 Succinate of 6- (4-acetyl-benzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (200 mg, 0.47 mmol) with 4- (2-methyl- [1, 3] dioxolan-2-yl) -benzylamine (prepared by following the procedure described in J. Med. Chem. 1978, 21, 507) (182 mg, 0.94 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 19: 1 and 9: 1) to give 6-. { 4- (2-methyl- [1, 3] dioxolan-2-yl) benzylamino} -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil (150 mg, 68%). GC-MS m / z 468 (M +). Dissolves 6-. { 4- (2-methyl- [1, 3] dioxolan-2-yl) benzylamino} -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (150 mg, 0.32 mmol) in methanol (5 mL) and added 1N aqueous HCl (1 mL). The solution is stirred at room temperature for 2 h. The solvent is removed, the residue is dissolved in DCM and washed with saturated aqueous NaHCO3. The organic phase is dried over Na 2 SO, filtered and concentrated. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1, 17: 3 and 4: 1) to obtain 6- (4-acetyl-benzylamino) -7-chloro-3- (2 , 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil (107 mg, 79%). GC-MS m / z 424 (M +). A method similar to General Procedure 1-2 is used, using 6- (4-acetyl-benzylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro- lH-benzo [d] azepine (100 mg, 0.23 mmol), to give the free base of the title compound as an oil (76 mg, 99%) which is used without further purification. A method similar to General Procedure 2-1 is used, using 6- (4-acetyl-benzylamino) -7-chloro-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (76 mg, 0.23). mmol), to give the title compound as a white solid (102 mg, 97%). MS (ES +) m / z: 329 (M + H) +.

Example 142 6- (3-Acetylbenzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to Example 141 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 3- (2-methyl- [1, 3] dioxolan-2-yl) -benzylamine (prepared by following the procedure described in J. Med. Chem. 2000, 43, 3315), to give the title compound as a solid. MS (ES +) m / z: 329 (M + H) +.

Example 143 7-Chloro-6- [4- (1-hydroxyiminoethyl) -benzylamino] 2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate Hydroxylamine hydrochloride (19 mg, 0.27 mmol) and pyridine (0.04 mL, 0.54 mmol) are added to a solution of 6- (4-acetylbenzylamino) -7-chloro-3- (2,2, 2-trifluoroacetyl) -2 , 3,4,5-tetrahydro-lH-benzo [d] azepine (115 mg, 0.27 mmol) in ethanol (10 mL). The reflux mixture is heated for 2 h. The solvent is removed in vacuo and the residue partitioned between DCM and 0.1N aqueous HCl. The organic phase is dried over Na 2 SO, filtered and concentrated. The oil is dissolved in the minimum amount of ether and hexane is added to the solid precipitate. Filter to obtain 7-chloro-6- [4- (1-hydroxyiminoethyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a solid (112 mg, 94%) that is used without further purification. MS (ES +) m / z: 440 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- [4- (1-hydroxyiminoethyl) -benzylamino] -3- (2,2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (100 mg, 0.23 mmol), to give 7-chloro-6- [4- (1-hydroxyiminoethyl) -benzylamino] -2, 3, 4, 5-tetrahydro-lH -benzo [d] azepine as an oil (61 mg, 78%) that is used without further purification. A method similar to General Procedure 2-1 is used, by using 7-chloro-6- [4- (1-hydroxyiminoethyl) benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine (58 mg, 0.17 mmol) to give the title compound as a white solid (68 mg, 87%). MS (ES +) m / z: 344 (M + H) +.

Example 144 6- (4-Benzoyl-benzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 5-3 is used to couple 7-chloro-3 ~ (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (272 mg, 0.64 mmol) with 4- (aminomethyl) benzophenone (prepared by following the procedure described in J. Biol. Chem. 1993, 268 (19), 14230) (270 mg, 1.3 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1, 17: 3 and 4: 1) to give 6- (4-benzoyl-benzylamino) -7-chloro-3- (2 , 2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as an oil (300 mg, 96%). A method similar to General Procedure 1-2 is used, using 6- (4-benzoyl-benzylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro- lH-benzo [d] azepine (80 mg, 0.16 mmol), to give 6- (4-benzoyl-benzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine as a oil (47 mg, 73%) that is used without further purification. A method similar to General Procedure 2-1 is used, when using (4-benzoyl-benzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (45 mg, 0.11 mmol) , to give the title compound as a white solid (37 mg, 63%). MS (ES +) m / z: 391 (M + H) +.

Example 145 7-Chloro-6- [4- (1-hydroxyiminobenzyl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate H02CCH2CH2C02H Hydroxylamine hydrochloride (52 mg, 0.75 mmol) and pyridine (0.1 mL) are added to a solution of 6- (4-benzoyl-benzylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2, 3,4,5-tetrahydro-lH-benzo [d] azepine (91 mg, 0.19 mmol) in ethanol (10 mL). The mixture is heated under reflux overnight. The solvent is removed in vacuo and the residue partitioned between DCM and 0.1N aqueous HCl. The organic phase is dried over Na 2 SO 4, filtered and concentrated. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 4: 1 and 3: 1) to give 7-chloro-6- [4- (1-hydroxyiminobenzyl) -benzylamino] -3- (2 , 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a mixture of E / Z isomers (93 mg, 99%). A method similar to General Procedure 1-2 is used, using 7-chloro-6- [4- (1-hydroxyiminobenzyl) benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5 -tetrahydro-lH-benzo [d] azepine (97 mg, 0.19 mmol), to give 7-chloro-6- [4- (1-hydroxyiminobenzyl) -benzylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as an oil (68 mg, 87%) that is used without further purification. A method similar to General Procedure 2-1 is used, using 7-chloro-6- [4- (1-hydroxyiminobenzyl) benzylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (65 mg, 0.16 mmol), to give the title compound as a white solid (67 mg, 80%). MS (ES +) m / z: 406 (M + H) +.

Example 146 7-Chloro-6- [4- (pyridin-4-yl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 5-3 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (178 mg, 0.426 mmol) and a solution of 4- (pyridin-4-yl) -benzylamine (116 mg, 0.63 mmol) in THF / toluene (1: 1, 8 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 7: 3 and 1: 1) to give 7-chloro-6- [4- (4-pyridin-4-yl) -benzylamino] - 3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil (120 mg, 63%). MS (ES +) m / z: 460 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- [4- (pyridin-4-yl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4,5-tetrahydro-lH-benzo [d] azepine (153 mg, 0.33 mmol), to give 7-chloro-6- [4- (pyridin-4-yl) -benzylamino] -2, 3, 4, 5 -tetrahydro-lH-benzo [d] azepine as an oil (110 mg, 91%) that is used without further purification. A method similar to General Procedure 2-1 is used, using 7-chloro-6- [4- (pyridin-4-yl) -benzylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (105 mg, 0.289 mmol) to give the title compound as a white solid (123 mg, 88%). MS (ES +) m / z: 364 (M + H) +. Examples 147-149 can be prepared essentially as described in Example 146 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and the appropriate amine. The general performance data and EM (ES +) are shown in the Table below.

EXAMPLE 150 (-) - 7-Chloro-6- [4- (4-phenyl-4,5-dihydro-lH-imidazol-2-yl) -benzylamino] -2,3,4,5-tetrahydroxychlorohydrate lH- benzo [d] azepine 7-Chloro-6- (4-cyanobenzylamino) -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine is mixed (200 mg, 0.49 mmol, 1.0 equiv.), 1- (R) -phenyl-ethane-1,2-diamine (600 mg, 4.4 mmol, prepared as described in J. Org.

Chem. 1997, 62, 3586) and p-toluenesulfonic acid monohydrate (102 mg, 0.53 mmol) in a sealed tube equipped with a magnetic stirrer. The mixture is heated at 200 ° C for 16 h. The mixture is cooled to room temperature. Dilute with DCM (50 mL) and wash with saturated aqueous NaHCO3 (10 mL). The organic fraction is collected and concentrated in vacuo. Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (98: 2 to 80:20). A method similar to General Procedure 2-3 is used to give the title compound as the hydrochloride. Reversed phase HPLC is used [Column: C18 symmetry, 10x300 mm, flow = 25 mL / min, water with 0.1% TFA / Acetonitrile (9: 1 to 2: 3)] followed by SCX chromatography to obtain the free base of the compound of the title. A method similar to General Procedure 2-3 is used to obtain the title compound (38 mg, 16%). MS (ES +) m / z: 431 (M + H) +. [a] 20D -20 ° (c 0.5, MeOH).

Example 151 7-Chloro-6- [4- (l-methyl-lH-imidazol-2-yl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (455 mg, 1.1 mmol) with 4- (1-methyl-lH-imidazol-2-yl) -benzylamine (240 mg, 1.3 mmol) in toluene (8 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (10: 1, 5: 1 and 3: 1) followed by SCX chromatography [the column is pre-washed with methanol followed by DCM, dissolved material is loaded in DCM, then it is eluted with DCM / 2M ammonia in methanol (1: 1) and concentrated in vacuo] to obtain 7-chloro-6- [4- (l-methyl-lH-imidazol-2-yl) -benzylamino] -3 - (2,2, 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzofd] azepine (429 mg, 93%). MS (ES +) m / z: 463 (M + H) +. A method similar to General Procedure 1-3 is used to deprotect 7-chloro-6- [4- (1-methyl-1H-imidazol-2-yl) -benzylamino] -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine. Purify by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (99: 1 to 90:10) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to give the title compound (350 mg, 73%). MS (ES +) m / z: 367 (M + H) +.

Example 152 7-Chloro-6- (4-ethanesulfonyl-benzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 5-2 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (0.2 g, 0.35 mmol) and 4-ethanesulfonyl-benzylamine (0.2 g, 1.06 mmol) to give 7-chloro-6- (4-ethanesulfonyl-benzylamino) -3- (2,2, 2-trifluoroacetyl) -2 , 3,4,5-tetrahydro-lH-benzo [d] azepine as a colorless oil. A method similar to General Procedure 1-1 is used to obtain the free base of the title compound as a yellow oil. A method similar to General Procedure 2-2 is used to form the hydrochloride salt. It is purified by reverse phase preparative HPLC (Zorbax SB-Phenyl 21.2x250 mm, 5 micron, 22 mL / min 0.1% HCl in water / acetonitrile (9: 1 to 1: 1) for 30 min, detector at 230 nm) to obtain the title compound as a white solid (57 mg, 36%). MS (ES +) m / z: 379 (M + H) +.

Example 153 7-Chloro-6- [4- (2-propanesulfonyl) -benzylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride The title compound can be prepared essentially as described in Example 152, by using 7-chloro-3- (2, 2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and 4- (2-propanesulfonyl) -benzylamine (11% yield, MS (ES +) m / z 393 (M + H) +).

Example 154 7-Chloro-6- (4-methoxycarbonyl-benzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate 4-Aminomethyl-benzoic acid methyl ester hydrochloride (0.2 g, 0.71 mmol) is treated with K2CO3 (1.0 g, 0.71 mmol) in a toluene / water mixture (1: 1, 2 mL). The organic layer is separated, dried over anhydrous Na2SO4 and used as a toluene solution for the next step. A method similar to General Procedure 5-2 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (0.1 g, 0.24 mmol) and 4-aminomethyl-benzoic acid methyl ester (0.2 g, 0.71 mmol) to give 7-chloro-6- (4-methoxycarbonyl-benzylamino) -3- (2, 2, 2 -trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a colorless oil. A method similar to General Procedure 1-1 is used to obtain the free base of the title compound as a yellow oil. A method similar to General Procedure 2-1 is used to obtain the title compound as a white solid (20 mg, 18%). MS (ES +) m / z: 345 (M + H) +.

Example 155 6- (4-Carboxy-benzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride 7-Chloro-6- (4-methoxycarbonyl-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine is combined (70 mg, 0.16 mmol), potassium carbonate (0.87 g, 6.3 mmol), methanol (2 mL), water (2 L) and heated at 50 ° C for 3 h.

Purify by SCX chromatography to obtain 6- (4-Carboxy-benzylamino) -7-chloro-2,3,4,5-tetrahydro-1H-benzo [d] azepine as a yellow oil. A method similar to General Procedure 2-2 is used to form the hydrochloride salt. It is purified by reverse phase preparative HPLC [Zorbax SB-Phenyl 21.2x250 mm, 5 micron, 22 mL / min 0.1% HCl in water / acetonitrile (9: 1 to 1: 1) for 30 min, detector at 230 nm] to obtain the title compound as a white solid (30 mg, 46%). MS (ES +) m / z: 331 (M + H) +.

Example 156 7-Chloro-6- (4-methylcarbamoyl-benzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride 3- (tert-butoxycarbonyl) -6- (4-Carboxy-benzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine is combined (0.1 g, 0.3 mmol), methylamine hydrochloride (31 mg, 0.46 mmol), triethylamine (0.1 g, 0.9 mmol), HATU (0.2 g, 0.5 mmol), anhydrous DMF (3 mL) and stirred at room temperature 17 h. The reaction mixture is partitioned between brine (5 mL) and diethyl ether (5 mL), the organic layer is separated and dried over anhydrous Na2SO4. The solvent is evaporated to obtain 3- (tert-butoxycarbonyl) -7-chloro-6- (4-methylcarbamoyl-benzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a yellow oil ( 0.1 g, 93%). MS (ES +) m / z: 344 (M + H-Boc) +. A method similar to General Procedure 1-5 is used and the residue is purified by SCX chromatography to obtain the free base of the title compound as a yellow oil. A method similar to General Procedure 2-2 is used to form the hydrochloride salt. It is purified by reverse phase preparative HPLC [Zorbax SB-Phenyl 21.2x250 mm, 5 micron, 22 mL / min 0.1% HCl in water / acetonitrile (9: 1 to 1: 1) for 30 min, detector at 230 nm] to obtain the title compound as a white solid (0.9 g, 65%). MS (ES +) m / z: 344 (M + H) +. Examples 157-158 can be prepared essentially as described in Example 156 by using 3- (tert-butoxycarbonyl) -6- (4-Carboxy-benzylamino) -7-chloro-2, 3,4,5-tetrahydro-lH -benzo [d] azepine and the appropriate amine. The general performance and EM (ES +) data are shown in the Table below.

Example 159 6- (4-tert-Butylcarbamoyl-benzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 5-2 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.2 g, 0.35 mmol) and 4-aminomethyl-N-tert-butyl-benzamide (0.2 g, 1.06 mmol), to give 6- (4-tert-butylcarbamoyl-benzylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5,5-tetrahydro-1H-benzo [d] azepine as a colorless oil. A method similar to General Procedure 1-1 is used to obtain the free base of the title compound as a yellow oil. A method similar to General Procedure 2-2 is used to form the hydrochloride salt and purified by reverse phase preparative HPLC [Zorbax SB-Phenyl 21.2 × 250 mm, 5 micron, 22 mL / min 0.1% HCl in water / acetonitrile (9: 1 to 1: 1) for 30 min, detector at 230 nm] to obtain the title compound as a white solid (65 mg, 41%). MS (ES +) m / z: 386 (M + H) +. Examples 160-161 can be prepared essentially as described in Example 159 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and the appropriate amine. The general performance and EM (ES +) data are shown in the Table below.

Example 162 7-Chloro-6- [4- (cyclohexylaminocarbonyl-) 3-fluoro-benzylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 5-2 is used by reacting 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (500 mg, 1.17 mmol) with 4-aminomethyl-N-cyclohexyl-2-fluoro-benzamide (441 mg, 1.76 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (20: 1, 10: 1, 7: 1 and 5: 1) to give 7-chloro-6- [4- (cyclohexylaminocarbonyl-) 3-fluoro-benzylamino ] -3- (2, 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil. A method similar to General Procedure 1-3 is used and purified by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (1: 0, 20: 1, 10: 1 and 7: 1) followed by phase HPLC. semi-preparative inverse [SymmetryPrep column C18, 7 Dm, 19x300 mm eluted with acetonitrile / O .1% trifluoroacetic acid in water (1: 9 to 8: 2) at 20 mL / min] and SCX chromatography to give the free base of the composed of the title. A method similar to General Procedure 2-1 is used to give the title compound as a yellow solid (97 mg, 15%). MS (ES +) m / z: 430 (M + H) +.

Example 163 7-Chloro-6- [4- (2, 2, 2-trifluoroethylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (250 mg, 0.59 mmol) with 4-aminomethyl-N- (2,2,2-trifluoroethyl) -benzamide (273 mg, 1.17 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (20: 1, 10: 1, 7: 1 and 5: 1) to give 7-chloro-3- (2,2,2-trifluoroacetyl) -6- [4- (2, 2, 2-trifluoroethyl-aminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil. A method similar to General Procedure 1-3 is used and purified by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (1: 0, 20: 1, 10: 1 and 7: 1) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to give the title compound as a white solid (191 mg, 61%). MS (ES +) m / z: 412 (M + H) \ Examples 164-177 can be prepared essentially as described in Example 163 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6- trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and the appropriate amine. The general performance and EM (ES +) data are shown in the Table below.

Examples 178 and 179 Succinate of (-) - 7-Chloro-6- [4- (2, 2, 2-trifluoro-1-methyl-ethylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH - benzo [d] azepine and Succinate of (+) - 7-Chloro-6- [4- (2, 2, 2-trifluoro-1-methyl-ethylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro -lH-benzo [d] azepine Dissolve (±) -7-chloro-6- [4- (2, 2, 2-trifluoro-1-methyl-ethylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine (472 mg, 1.11 mmol) in DCM (50 mL) and add di-tert-butyl-dicarbonate (300 mg, 1.34 mmol) and a solution of sodium carbonate (2 g) in water (50 mL). The reaction is stirred at room temperature for 2 h then it is diluted with DCM, washed with water, dried over Na 2 SO, filtered and concentrated. Purify by chromatography on silica gel by levigating with hexane / EtOAc (10: 1, 5: 1 and 3: 1) to give (±) -3-tert-butoxycarbonyl-7-chloro-6- [4- (2, 2,2-trifluoro-l-methyl-ethylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-benzo [d] azepine (330 mg, 57%). The two enantiomers are separated by chiral HPLC [Chiralpak AD column, 8x30 cm, eluted with 0.2% DMEA in heptane / isopropanol (9: 1)]. A method similar to General Procedure 1-5 is used to deprotect the first levigating compound and purified by SCX chromatography to give (-) - 7-chloro-6- [4- (2,2,2-trifluoro-1-methyl -ethylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to General Procedure 2-1 is used to give succinate of (-) - 7-chloro-6- [4- (2, 2, 2-trifluoro-1-methyl-ethylaminocarbonyl) -benzylamino] -2, 3 , 4,5-tetrahydro-lH-benzo [d] azepine as a white solid (50 mg, 15%). MS (ES +) m / z: 426 (M + H) +; [a] 20D -3.3 ° (c 0.5, CH30H).

A method similar to General Procedure 1-5 is used to deprotect the second levigating compound and purified by SCX chromatography to give (+) - 7-chloro-6- [4- (2,2,2-trifluoro-1-methyl) -ethylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to General Procedure 2-1 is used to give (+) - 7-chloro-6- [4- (2, 2, 2-trifluoro-1-methyl-ethylaminocarbonyl) -benzylamino] -2- 3 succinate. , 4,5-tetrahydro-lH-benzo [d] azepine as a white solid (55 mg, 16%). MS (ES +) m / z: 426 (M + H) +; [a] 20D + 4.4 ° (c 0.5, CH 3 OH).

Examples 180 and 181 Succinate of (+) - 7-Chloro-6- [4- (l-methyl-3,3,3-trifluoropropylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH- benzo [d] azepine and (-) -7-Chloro-6- [4- (1-methyl-3,3,3-trifluoro-propylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro- succinate lH-benzo [d] azepine Dissolve (±) -7-chloro-3- (2,2,2-trifluoroacetyl) -6- [4- (l-methyl-3,3,3-trifluoro-propylaminocarbonyl) -benzylamino] -2, 3, 4,5-tetrahydro-lH-benzo [d] azepine (985 mg, 2.24 mmol) in DCM (50 mL) and di-tert-butyl-dicarbonate (605 mg, 3. 36 mmol) and a solution of sodium carbonate (2 g) in water (50 mL). The mixture is stirred at room temperature for 1 h then diluted with DCM, washed with water, dried over Na2SO, filter and concentrate. Purify by chromatography on silica gel by levigating with hexane / EtOAc (10: 1, 5: 1 and 3: 1) to give (±) -3-tert-butoxycarbonyl-7-chloro-6- [4- (l-methyl-3,3,3-trifluoro-propylaminocarbonyl) - benzylamino] -2,3,4,5-tetrahydro-benzo [d] azepine. The two enantiomers are separated by chiral HPLC [Chiralpak AD column, 8x30 cm, levigating with heptane / isopropanol / 0.2% DMEA in methanol (90: 5: 5)]. A method similar to General Procedure 1-5 is used to deprotect the first levigating compound and purified by SCX chromatography to give (+) - 7-chloro-6- [4- (1-methyl-3, 3, 3-trifluoro -propylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to General Procedure 2-1 is used to give (+) - 7-chloro-6- [4- (1-methyl-3, 3, 3-trifluoro-propylaminocarbonyl) -benzylamino] -2- 3 succinate. , 4,5-tetrahydro-lH-benzo [d] azepine as a white solid (186 mg, 15%). MS (ES +) m / z: 440 (M + H) +; [] 20D + 6.5 ° (c 0.5, CH3OH). A method similar to General Procedure 1-5 is used to deprotect the second levigating compound and purified by SCX chromatography to give (-) - 7-chloro-6- [4- (1-methyl-3, 3, 3-trifluoro -propylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to General Procedure 2-1 is used to give succinate of (-) - 7-chloro-6- [4- (l-methyl-3,3,3-trifluoro-propylaminocarbonyl) -benzylamino] -2, 3 , 4,5-tetrahydro-lH-benzo [d] azepine as a white solid (191 mg, 15%). MS (ES +) m / z: 440 (M + H) +; [a] 20D -5.2 ° (c 0.5, CH 3 OH).

EXAMPLE 182 Succinate of (R) - (+) - 7-Chloro-6- [4- (1-phenyl-ethylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (250 mg, 0.59 mmol) with (R) -4-aminomethyl-N- (1-phenyl-ethyl) -benzamide (298 mg, 1.17 mmol) in toluene (15 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (20: 1, 10: 1, 7: 1 and 5: 1) to give (R) - (+) - 7-chloro-6- [4- ( 1-phenyl-ethylcaminocarbonyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil. A method similar to General Procedure 1-3 is used and purified by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (1: 0, 20: 1, 10: 1 and 7: 1) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to give the title compound as a yellow solid (158 mg, 49%). MS (ES +) m / z: 434 (M + H) +; [a] 20D + 18.7 ° (c 0.5, CH 3 OH).

Example 183 (S) - (-) - 7-Chloro-6- [4- (1-phenyl-ethylaminocarbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to Example 182 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (250 mg, 0.59 mmol) and (S) -4-aminomethyl-N- (1-phenyl-ethyl) -benzamide (298 mg, 1.17 mmol) to give the title compound as a white solid (95 mg, 29%). MS (ES +) m / z: 434 (M + H) +; [a] 20D -20.1 ° (c 0.5, CH 3 OH).

Example 184 7-Chloro-6- Succinate. { 4- [(2-thiophen-2-yl-ethyl) -carbamoyl] -benzylamino} -2, 3,4, 5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-3 is used to react 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d ] azepine (250 mg, 0.588 mmol) with 4-aminomethyl-N- (2-thiophen-2-yl-ethyl) -benzamide (306 mg, 1176 mmol) when using palladium (II) acetate (26 mg, 0.118 mmol ), tris (dibenzylideneacetone) dipalladium (0) (53 mg, 0.059 mmol), BINAP (220 mg, 0.353 mmol) and cesium carbonate (383 mg, 1176 mmol) in dioxane (6 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 7: 3 and 1: 1) to give 7-chloro-6-. { 4- [(2-thiophen-2-yl-ethyl) -carbamoyl] -benzylamino} -3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil (233 mg, 91%). MS (ES +) m / z: 535 (M + H) +. A method similar to General Procedure 1-2 is used, when using 7-chloro-6-. { 4- [(2-thiophen-2-yl-ethyl) -carbamoyl] -benzylamino} -3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (223 mg, 0.416 mmol), to give 7-chloro-6-. { 4- [(2-thiophen-2-yl-ethyl) -carbamoyl] -benzylamino} -2, 3,4,5-tetrahydro-lH-benzo [d] azepine as an oil (145 mg, 79%) which is used without further purification. A method similar to General Procedure 2-1 is used, when using 7-chloro-6-. { 4- [(2-thiophen-2-yl-ethyl) -carbamoyl] -benzylamino} -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (145 mg, 0.330 mmol), to give the title compound as a solid (123 mg, 67%). MS (ES +) m / z: 440 (M + H) +. Examples 185-194 can be prepared essentially as described in Example 184 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine and the appropriate amine. The general performance and EM (ES +) data are shown in the Table below.

Example 195 7-Chloro-6- [4- (2-pyridin-2-yl-ethylcarbamoyl) benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 5-3 is used by reacting 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (200 mg, 0.471 mmol) and 4-aminomethyl-N- (2-pyridin-2-yl-ethyl) -benzamide (241 mg, 0.942 mmol) when using palladium (II) acetate (21 mg, 0.094 mmol) , tris (dibenzylidene ketone) dipalladium (0) (43 mg, 0.047 mmol), BINAP (176 mg, 0.283 mmol) and cesium carbonate (307 mg, 0.942 mmol) in dioxane (5 mL). Purify by chromatography on silica gel by levigating with hexane and hexane / EtOAc / DCM / methanol (7: 1: 1: 1) to give 7-chloro-6- [4- (2-pyridin-2-yl-ethylcarbamoyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil (107 mg, 43%). MS (ES +) m / z: 531 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6 ~ [4- (2-pyridin-2-yl-ethylcarbamoyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) - 2,3,4,5-tetrahydro-lH-benzo [d] azepine (107 mg, 0.202 mmol), to give 7-chloro-6- [4- (2-pyridin-2-yl-ethylcarbamoyl) -benzylamino] -2,3,4, 5-tetrahydro-lH-benzo [d] azepine as an oil (85 mg, 97%) which is used without further purification. A method similar to General Procedure 2-2 is used, using 7-chloro-6- [4- (2-pyridin-2-yl-ethylcarbamoyl) -benzylamino] -2,3,4, 5-tetrahydro-lH- benzo [d] azepine (85 mg, 0.195 mmol), to give the title compound as a solid (103 mg, 97%). MS (ES +) m / z: 435 (M + H) +.

Example 196 Succinate of 7-Chloro-6- [4- (piperidine-1-carbonyl) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine By using a method similar to general procedure 5-2, to react 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d ] azepine (500 mg, 1.17 mmol) with 4- (piperidin-1-ylcarbonyl) -benzylamine (308 mg, 1.41 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (20: 1, 10: 1, 7: 1 and 5: 1) to give 7-chloro-6- [4- (piperidine-1-carbonyl) -benzylamino ] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil. A method similar to General Procedure 1-3 is used and purified by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (1: 0, 20: 1, 10: 1 and 7: 1) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to give the title compound as a yellow solid (284 mg, 47%). MS (ES +) m / z: 398 (M + H) +.

Example 197 7-Chloro-6- [2- (cyclohexylaminocarbonyl-pyridin-5-ylmethyl) -amino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (348 mg, 0.82 mmol) with 5-aminomethyl-pyridine-2-carboxylic acid cyclohexylamide (200 mg, 0.86 mmol). Purify by chromatography on silica gel by levigating with hexane / EtOAc (20: 1, 10: 1, 7: 1 and 5: 1) to give 7-chloro-6- [2- (cyclohexylaminocarbonyl-pyridin-5-ylmethyl) -amino] -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as oil. A method similar to General Procedure 1-3 is used and purified by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (1: 0, 20: 1. : 1 and 7: 1) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to give the title compound as a yellow solid (147 mg, 34%). MS (ES +) m / z: 413 (M + H) +.

Example 198 7-Chloro-6- [2- (4-fluoro-benzylaminocarbonyl) -pyridin-5-ylmethyl] -amino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate The title compound can be prepared essentially as described in Example 197, by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 5-aminomethyl-pyridine-2-carboxylic acid 4-fluoro-benzylamide (28% yield, MS (ES +) m / z 439).

Example 199 7-Chloro-6- (4-tert-butylthiocarbamoyl-benzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride It is combined 6- (4-tert-butylcarbamoyl-benzylamino) -7-chloro-2,3,4,5-tetrahydro-lH-benzo- [d] azepine (0.3 g, 0.67 mmol), 2,4-bis ( 4-methoxyphenyl) -1,3-dithia-2,4-diphosphtane-2, 4-disulfide (Lawesson's reagent) (0.3 g, 0.67 mmol) and anhydrous 1,4-dioxane (10 mL) in a sealed tube and it is heated at 100 ° C for 5 h. The reaction mixture is cooled to room temperature, the solvent is evaporated and the residue is purified by SCX.

Example 200 Succinate of (S) - (-) - 7-Chloro-6- [1- (4-fluorophenyl) -ethylamino] 2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (7.0g, 16.4mmol) with (S) -l- (4-fluorophenyl) ethylamine (6.9 g, 49.3 mmol) in toluene (175 mL). Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1) followed by SCX chromatography [pre-washed column with methanol followed by DCM, loaded with material dissolved in DCM, then levigating with DCM / ammonia 2M in methanol (1: 1) and concentrated in vacuo] to give 7-chloro-6- [1- (S) - (4-fluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2 3,4,5-tetrahydro-lH-benzo [d] azepine (3.96 g, 58%). GC-MS m / z: 414 (M +). A method similar to general procedure 1-3 is used to deprotect 7-chloro-6- [1- (S) - (4-fluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2.3 , 4,5-tetrahydro-lH-benzo [d] azepine (3.92 g, 9.5 mmol) and purification by chromatography on silica gel levigating with DCM / 2M ammonia in methanol (99: 1 to 80:20) to give the base Free of the title compound. A method similar to general procedure 2-1 is used and the solid is crystallized from ethanol and methyl t-butyl ether. Filter and dry the solid in a vacuum oven at 60 ° C overnight to obtain the title compound (3.4 g, 83%). MS (ES +) m / z: 319 (M + H) +; [a] 20D -102.8 ° (c 0.5, MeOH). Examples 201-209 can be prepared essentially as described in example 200 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The performances for stage 1 (General procedure 5-2), optical rotation and EM data (ES +) are shown in the table below.

H02C (CH2) 2C02H ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine 205 2,3- Ar14 diF elare-e- [1- (2, 3-difluorophenyl) -ethylamino] -2,3 Succinate] , 4,5- tetrahydro-lH-benzo [d] azepine 206 2,3- Succinate of. { -) -! - 80 -107.9 ° 337 diF Chloro-6- [l- (2,3- (c 0.5, (M + H) difluorophenyl) - MeOH) ethylamino] -2,3,4,5- tetrahydro- lH- benzo [d] azepine 207 2,4- Succinate of (+) - 7- 94 + 101.4 ° 337 diF Chloro-6- [l- (2,4- (c 0.5, (M + H) difluorophenyl) - MeOH) ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine 08 2,4- (-) - 7- 96 diF Chloro-e- [1- (2,4-difluorophenyl) succinate ) - ethylamino] -2, 3,4,5- EXAMPLE 210 (+) - 7-Chloro-6- [(2-trifluoromethoxy-phenyl) -ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine oxalate A method similar to general procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (0.15 g, 0.35 mmol) with l- (2-trifluoromethoxyphenyl) -ethylamine Isomer 2 at 90 ° C for 15 h. A method similar to general procedure 1-2 is used and purified by reverse phase preparative HPLC to give the free base of the title compound. A method similar to general procedure 2-5 is used to give the title compound (27 mg, 16%). HPLC tR = 4.2 min (Chiralpak AD 4.6x150 mm, 3 micron column, 1.0 mL / min 94.8 / 5 / 0.2 heptane / ethanol / isocratic dimethyethylamine, detector is at 225 nm); HRMS calculated for Ci 9 H 20 ClF 3 N 2 O 385.1294, found 385.1285; [a] 20D + 95.4 ° (c 0.5, MeOH).

Example 211 Succinate of (±) -7-Chloro-6- [1- (3-fluorophenyl) -ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Palladium (II) acetate (27 mg, 0.12 mmol), BINAP (146 mg, 0.24 mmol), cesium carbonate (270 mg, 0.8 mmol) and (±) -1- (3-fluorophenyl) -ethylamine ( 230 mg, 1.6 mmol) to a solution of 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (250 mg , 0.6 mmol) in toluene (9 L). The thick mixture is degassed and filled with nitrogen. The mixture is heated at 95 ° C for 16 h. Additional palladium (II) acetate (0.1 equiv.) And BINAP (0.2 equiv.) Are added and the reaction is continued heating for an additional 24 hours. The cold mixture is diluted with EtOAc (50 mL) then filtered through Celite®. The filtrate is concentrated and purified by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1) followed by SCX chromatography to obtain (±) -7-chloro-6- [1- (3-fluorophenyl) ) -ethylamino] -3- (2, 2, 2-trifluoroacetyl) -2, 3,, 5-tetrahydro-lH-benzo [d] azepine (138 mg, 56%). GC-MS m / z: 414 (M +). A method similar to general procedure 1-3 is used to deprotect (±) -7-chloro-6- [1- (3-fluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2, 3 , 4,5-tetrahydro-lH-benzo [d] azepine (132 mg, 0.3 mmol) and purification by chromatography on silica gel levigating with DCM / 2M ammonia in methanol (99: 1 to 90:10) to give the base Free of the title compound. A method similar to general procedure 2-1 is used to give the title compound (98 mg, 70%). MS (ES +) m / z: 319 (M + H) +.

Example 212 Succinate of (+) - 7-Chloro-6- [1- (3-fluorophenyl) -ethylamino] 2,3,4,5-tetrahydro-lH-benzo [d] azepine The two enantiomers of (+) - 7-chloro-6- [1- (3-fluorophenyl) -ethylamino] -2,3,4,5,5-tetrahydro-lH-benzo [d] azepine succinate were separated by normal phase (Chiralpak AD 2x25 cm, eluted with 95: 5 heptane / isopropanol with 0.2% DMEA). A method similar to general procedure 2-1 is used to obtain the title compound [23 mg, 30% recovery, 99% ee (Chiralpak AD, 4.6x250 mm, levigant: 95: 5 heptane / isopropanol, with 0.2% DMEA, 1.0 mL / min)]. EM (ES +) m / z: 319 (M + H) +; [a] 20D + 64 ° (c 0.5, MeOH).

Example 213 Succinate of (-) - 7-Chloro-6- [1- (3-fluorophenyl) -ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Add tris (dibenzylidenacetone) dipalladium (0) (3.4 g, 3.8 mmol), BINAP (4.7 g, 7.5 mmol), cesium carbonate (8.6 g, 26.3 mmol) and 1- (3-fluorophenyl) -ethylamine Isomer 2 ( 5.8 g, 41.3 mmol) was added to a solution of 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (8.0 g , 18.8 mmol) in toluene (225 mL). The thickened mixture is degassed and filled with nitrogen. The mixture is heated at 95 ° C for 8 h. Additional tris (dibenzylidene ketone) dipalladium (0) is added (0.1 equiv.), And BINAP (0.2 equiv.). The reaction is continued heating for an additional 16 hours. The cold mixture is diluted with EtOAc (200 mL) then filtered through Celite®. Concentrate in vacuo and purify by chromatography on silica gel levigating with hexane / EtOAc (9: 1) followed by SCX chromatography to obtain 7-chloro-6 ~ [1- (3-fluorophenyl) -ethylamino] -3- ( 2, 2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (6.0 g, 78%). GC-MS m / z: 414 (M +). A method similar to general procedure 1-3 is used to deprotect 7-chloro-6- [1- (3-fluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5 -tetrahydro-lH-benzo [d] azepine (6.0 g, 14.4 mmol). Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (99: 1 to 90:10) to give the free base of the title compound. A method similar to general procedure 2-1 is used and the solid is crystallized from ethanol and methyl t-butyl ether. Filter and dry the solid under vacuum at 60 ° C overnight to obtain the title compound [5.3 g, 84% yield, 99% ee (Chiralpak AD, 4.6x250 mm, levigant: 95: 5 heptane / EtOH, with 0.2% DMEA, 1.0 mL / min)]. MS (ES +) m / z: 319 (M + H) +; [a] 20D -90.6 ° (c 0.5, MeOH).

Example 214 Succinate of (±) -7-Chloro-6- [1- (2-fluorophenyl) -ethylamino] 2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-1 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (250 mg, 0.6 mmol) with (±) -1- (2-fluorophenyl) -ethylamine (206 mg, 1.5 mmol) in toluene (5 L). The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1) followed by SCX chromatography [pre-washed column with methanol followed by DCM, loaded with material dissolved in DCM, then levigating with DCM / 2M ammonia in methanol (1: 1) and concentrated in vacuo] to obtain (±) -7-chloro-6- [1- (2-fluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) ) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (86 mg, 35%). GC-MS m / z: 414 (M +). A method similar to general procedure 1-3 is used to deprotect (±) -7-chloro-6- [1- (2-fluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2.3 , 4,5-tetrahydro-lH-benzo [d] azepine (85 mg, 0.2 mmol) and purification by chromatography on silica gel levigating with DCM / 2M ammonia in methanol (99: 1 to 90:10) to give the base Free of the title compound. A method similar to general procedure 2-1 is used to give the title compound (70 mg, 80%). MS (ES +) m / z: 319 (M + H) +. Examples 215-216 can be prepared essentially as described in Example 214 by using 7-chloro-3- (2,2, 2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and the appropriate amine. The yields for stage 1 (General procedure 5-1), optical rotation and EM data (ES +) are shown in the table below.

Example 217 Succinate of (S) - (-) - 7-Chloro-6- (1-phenyl-ethylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Palladium (II) acetate (396 mg, 1.8 mmol), BINAP (2.2 g, 3.5 mmol), cesium carbonate (8.0 g, 24.6 mmol), and 1S- (-) -methylbenzylamine (6.4 g, 52.9 mmol) are added. ) to a solution of 7-chloro-6-trifluoromethanesulfonyloxy-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-1H-benzo [d] azepine (7.5 g, 17.6 mmol) in toluene (173 ml). The thick mixture is degassed and filled with nitrogen. The mixture is heated at 95 ° C for 16 h. GC / MS showed some starting materials that were still present after 16 h, additional palladium (II) acetate (0.1 equiv.), BINAP, and 1S- (-) -methylbenzylamine (1.0 equiv.) Were also added. The reaction is continued heating for an additional 24 hours. The cold mixture is diluted with EtOAc (250 ml) then filtered through Celite®. Concentrate in vacuo and purify by silica gel chromatography by levigating with hexane / EtOAc / methanol (84: 15: 1) followed by SCX chromatography to give (S) -7-chloro-6- (1-phenyl-ethylamino) -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (4.38 g, 63%). GC-MS m / z: 396 (M +). A method similar to general procedure 1-1 is used to deprotect (S) -7-chloro-6- (1-phenyl-ethylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5 -tetrahydro-lH-benzo [d] azepine (4.3 g, 10.8 mmol). Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (99/1 to 80/20) to give the free base of the title compound. A method similar to general procedure 2-1 is used and the solid is crystallized from ethanol and methyl t-butyl ether. Filter and dry the solid in a vacuum oven at 70 ° C overnight to obtain the title compound (3.6 g, 80%). MS (ES +) m / z: 301 (M + H) +. [a] 20D -95.6 ° (c 0.5, MeOH). Examples 218-227 can be prepared essentially as described in example 217 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The yields for stage 1, optical rotation or enantiomeric excess (determined by chiral CLAR) and EM data (ES +) are shown in the table below.

D = Not determined Example 228 Succinate of (-) - 7-Chloro-6- [1- (3-chloro-4-fluoro-phenyl) ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (426 mg, 1.0 mmol) with 1- (3-chloro-4-fluorophenyl) -ethylamine Isomer 1 (226 mg, 1.3 mmol). Purification by chromatography on silica gel by levigating with EtOAc / hexane (1: 7) to give 7-chloro-6- [1- (3-chloro-4-fluoro-phenyl) -ethylamino] -3- (2, 2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a yellow oil (293 mg, 65%). A method similar to general procedure 1-1 is used to deprotect 7-chloro-6- [1- (3-chloro-4-fluoro-phenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2 , 3,4, 5-tetrahydro-lH-benzo [d] azepine Isomer 1 (293 mg, 0.65 mmol). Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (94: 6) to give the free base of the title compound as an oil (157 mg, 68%). MS (ES +) m / z: 353 (M + H) 0. A similar method is used for preparation E-1 to convert the free base to the title compound. [a] 20D-115.9 ° (c 0.5, MeOH). Examples 229-235 can be prepared essentially as described in example 228 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The performances for stage 1 (General procedure 5-3), optical rotation and EM data (ES +) are shown in the table below.

Example 236 Succinate of (±) -7-Chloro-6- [1- (4-chlorophenyl) -ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (852 mg, 2.0 mmol) and (+) -4-chloro- (α-methyl) benzylamine (622 mg, 4.0 mmol). Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain (±) -7-chloro-6- [1- (4-chlorophenyl) -ethylamino] -3- (2,2, 2-trifluoroacetyl) -2,3,4 , 5-tetrahydro-lH-benzo [d] azepine (326 mg, 38%). MS (ES +) m / z: 431 (M + H) +. A method similar to general procedure 1-1 is used to deprotect (±) -7-chloro-6- [1- (4-chlorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2, 3 , 4,5-tetrahydro-lH-benzo [d] azepine. Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (95: 5) to give the free base of the title compound (61 mg, 100%). EM (ES +) m / z: 335 (M + H) 0. A method similar to general procedure 2-1 is used to obtain the title compound.

Examples 237 and 238 Succinate of (-) - 7-Chloro-6- [1- (4-chlorophenyl) -ethylamino] -2,3,5,5-tetrahydro-lH-benzo [d] azepine and Succinate of (+ ) -7- Chloro-6- [1- (4-chlorophenyl) -ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine It was remitted (±) -7-chloro-6- [1- (4-chlorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [ d] azepine (326 mg, 0.76 mmol) to chiral chromatography (Chiralpak AD, 4.6x150 mm, levigating with heptane / ethanol (9: 1) with 0.2% DMEA, lmL / min) to provide the two enantiomers: 7-chloro 6- [1- (4-chlorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Isomer 1 (102 mg, tR = 5.25 min) and 7-chloro-6- [1- (4-chlorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d ] azepine Isomer 2 (110 mg, t R = 6.40 min). A method similar to general procedure 1-1 is used to deprotect 7-chloro-6- [1- (4-chlorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5 -tetrahydro-lH-benzo [d] azepine Isomer 1. Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (95: 5) to give 7-chloro-6- [1- (4-chlorophenyl) - ethylamino] -2,3,4, 5-tetrahydro-lH-benzo [d] azepine Isomer 1 (Example 237, 82 mg, 100%). MS (ES +) m / z: 335 (M + H) +. A method similar to general procedure 2-1 is used to obtain the title compound. [a] 20D-127.7 ° (c 0.5, CH30H). A method similar to general procedure 1-1 is used to deprotect 7-chloro-6- [1- (4-chlorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5 -tetrahydro-lH-benzo [d] azepineIsomer 2. Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (95: 5) to give 7-chloro-6- [1- (4-chlorophenyl) -ethylamino] -2.3.4, 5 -tetrahydro-lH-benzo [d] azepine Isomer 2 (Example 238, 68 mg, 78%). MS (ES +) m / z: 335 (M + H) +. A method similar to general procedure 2-1 is used to obtain the title compound. [] 20D + 133.6 ° (c 0.5, CH30H).

Examples 239 and 240 7-Chloro-6- [1- (2,5-difluorophenyl) -ethylamino] -2,3,5,5-tetrahydro-1H-benzo [d] azepine Isomer 1 Succinate and Succinate 7 -chloro-6- [1- (2, 5-difluorophenyl) -ethylamino] -2, 3, 4,5-tetrahydro-lH-benzo [d] azepine Isomer 2 A method similar to general procedure 5-1 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (550 mg, 1.27 mmol) and crude (+) -a-methyl- (2 ', 5' -difluoro) benzylamine (400 mg). The two enantiomers were separated by chiral chromatography (levigant: 75: 20: 5 heptane / isopropanol / methanol, 4.6x250 mm Chiralpak AD, 1 mL / min, uv 260 nm) to obtain 7-chloro-6- [1- (2 , 5-difluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine Isomer 1 [150 mg, 29%; Chiral HPLC: tR = 4.5 min; MS (ES +) m / z: 433 (M + H) +] and 7-chloro-6- [1- (2,5-difluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2 , 3,4, 5-tetrahydro-lH-benzo [d] azepine Isomer 2 [130 mg, 25%; Chiral HPLC: tR = 5.5 min; MS (ES +) m / z: 433 (M + H) +], both as opaque oils which solidified during standing to opaque white waxy solids. A method similar to general procedure 1-1 is used to deprotect 7-chloro-6- [1- (2, 5-difluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4 , 5-tetrahydro-lH-benzo [d] azepine Isomer 1 (140, mg, 0.32 mmol). Purify by SCX chromatography to give 7-chloro-6- [1- (2, 5-difluorophenyl) -ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Isomer 1 (102 mg, 95%) as a yellow oil. A method similar to general procedure 2-1 is used to obtain Isomer 1 of the title compound (130 mg, 95%) as an opaque white solid. MS (ES +) m / z: 337 (M + H) +. A method similar to general procedure 1-1 is used to deprotect 7-chloro-6- [1- (2, 5-difluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4 , 5-tetrahydro-lH-benzo [d] azepine Isomer 2 (125 mg, 0.29 mmol). Purify by SCX chromatography to give 7-chloro-6- [1- (2, 5-difluorophenyl) -ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Isomer 2 (87.7 mg, 90%) as a yellow oil. A method similar to general procedure 2-1 is used to obtain isomer 2 of the title compound (117 mg, 99%) as an opaque white solid. MS (ES +) m / z: 337 (M + H) +.

Example 241 Succinate of (-) - 7-Chloro-6- [1- (3,5-difluoro-4-methoxy-phenyl) -ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-1 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (300 mg, 0.7 mmol) and crude a-methyl- (3 ', 5' -difluoro-4 '-methoxy) benzylamine (380 mg). Purification by chromatography on silica gel levigating with hexane / EtOAc (95: 5) followed by chiral chromatography [heptane / isopropanol / dimethylethylamine (90: 10: 0.2), 4.6x250 mm Chiralpak AD, 1 mL / min, uv 250 nm] to give 7-chloro-6- [1- (3, 5-difluoro-4-methoxy-phenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro- lH-benzo [d] azepine Isomer 1 [59 mg, 18% yield, 99% ee, chiral HPLC: tR = 6.0 min; MS (ES-) m / z: 461 (MH) "] and 7-chloro-6- [1- (3, 5-difluoro-4-methoxy-phenyl) -ethylamino] -3- (2.2.2 -trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine Isomer 2 [50 mg, 15% yield, 99% ee, chiral HPLC: tR = 7.7 min; MS (ES-) m / z: 461 (MH) "]. A method similar to general procedure 1-1 is used to deprotect 7-chloro-6- [1- (3,5-difluoro-4-methoxy-phenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2,3, 4, 5-tetrahydro-lH-benzo [d] azepine Isomer 2 (50 mg, 0.14 mmol). Purify by SCX chromatography to give 7-chloro-6- [1- (3, 5-difluoro-4-methoxy-phenyl) -ethylamino] -2,3,4,5-tetrahydro-1H-benzo [d] azepine Isomer 2 (35 mg, 70%) as a yellow oil. A method similar to general procedure 2-1 is used, using 7-chloro-6- [1- (3, 5-difluoro-4-methoxy-phenyl) -ethylamino] -2, 3, 4, 5-tetrahydro-IH -benzo [d] azepine Isomer 2 (35 mg, 0.10 mmol), to give the title compound (44 mg, 97%) as an opaque white powder. MS (ES +) m / z: 367 (M + H) +; [a] 20D -107.0 ° (c 0.5, CH30H).

Example 242 (+) - 7-Chloro-6- [(2-methylphenyl) -ethylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine oxalate A method similar to general procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.15 g, 0.35 mmol) with (R) -1- (2-methyl) -ethylamine (162 mg, 1.2 mmol) at 90 ° C for 17 h. The deprotection according to the general procedure 1-2. Purify by reverse phase preparative HPLC and form the oxalate salt according to general procedure 2-5 to give the title compound (72 mg, 51%). CLAR tR = 4.0 min (Chiralpak AD 4.6x150 mm, column 3 microns, 1.0 mL / min 89.8: 10: 0.2 heptane / isopropanol / DMEA, isocratic, detectors at 225 nm); HRMS calculated for C? 9H23ClN2 315.1628, found 315.1623. [a] 20D + 67.2 ° (c 0.5, CH 3 OH).

Example 243 Succinate of (+) - 7-Chloro-6- (indan-1-ylamino) -2, 3,, 5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-1 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (200 mg, 0.5 mmol) with (R) -1-aminoindan (188 mg, 1.4 mmol) in toluene (5 mL). Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1) followed by SCX chromatography [pre-washed column with methanol followed by DCM, loaded with material dissolved in DCM, then levigating with DCM / ammonia 2M in methanol (1: 1) and concentrated in vacuo] to give 7-chloro-6- (indan-1-ylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro -lH-benzo [d] azepine (129 mg, 67%). GC-MS m / z: 408 (M +). A method similar to general procedure 1-1 is used to deprotect 7-chloro-6- (indan-1-ylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH -benzo [d] azepine (125 mg, 0.3 mmol) and purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (99: 1 to 80:20) to give the free base of the title compound. A method similar to general procedure 2-1 is used to give the title compound (104 mg, 78%). MS (ES +) m / z: 313 (M + H) +. [a] 20D + 73.9 ° (c 0.5, MeOH).

Example 244 Succinate of (+) - 7-Chloro-6- (5-fluoro-indan-1-ylamino) -2,3,4,5-tetrahydro-1H-benzo [d] azepine A method similar to general procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (210 mg, 0.5 mmol) with 5-fluoro-indan-ylamine Isomer 1 (161 mg, 1.1 mmol) in toluene (10 mL). Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1) followed by SCX chromatography to obtain 7-chloro-6- [1- (3,5-bis-trifluoromethyl-phenyl) -ethylamino] 3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine Isomer 1 (616 mg, 99%). A method similar to general procedure 1-3 is used to deprotect 7-chloro-6- (5-fluoro-indan-ylamine) -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro -lH-benzo [d] azepine Isomer 1 (200 mg, 0.5 mmol). Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (99/1 to 90/10) to give the free base of the title compound. The preparation E-1 is used to give the title compound (140 mg, 66%). MS (ES +) m / z: 331 (M + H) +. [a] 20D + 80. 0 ° (C, 0.5, MeOH).

Example 245 Succinate of (±) -7-Chloro-6- (2,3-dihydro-benzofuran-3-ylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.15 g, 0.35 mmol) with 2,3-dihydro-benzofuran-3-ylamine (prepared as described in WO 0069816) (0.14 g, 1.1 mmol) at 90 ° C for 18 h. A method similar to general procedure 1-2 is used and purified by preparative reverse phase HPLC [Zorbax SB-Phenyl 4.6x150 mm, 5 micron column, 1 mL / min 0.1% TFA in water / ACN (9: 1 up to 1: 9) for 30 min, detector at 230 and 254 nm]. A method similar to general procedure 2-1 is used to give the title compound (4.3 mg, 3%). HRMS calculated for C? 8H19ClN20 315.1264, found 315.1256.

Example 246 Succinate of 7-Chloro-6- (indan-2-yl-amino) -2, 3, 4, 5-tetrahydro-IH-benzo [d] azepine A method similar to general procedure 5-3 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (426 mg, .1.0 mmol) and 2-aminoindan (400 mg, 3.0 mmol), to give 7-chloro-6- (indan-2-yl-amino) -3- (2,2, 2-trifluoroacetyl) - 2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a slightly yellow oil (354 mg, 86%). MS (ES +) m / z: 409 (M + H) +. A method similar to general procedure 1-1 is used, deprotecting 7-chloro-6- (indan-2-yl-amino) -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro -lH-benzo [d] azepine '(354 mg, 0.87 mmol) to obtain 7-chloro-6- (indan-2-yl-amino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a pale yellow oil (166 mg, 61%). MS (ES +) m / z: 313 (M + H) +. A method similar to general procedure 2-1 is used to give the title compound.

Example 247 Succinate of (-) - 7-Chloro-6- [(N-methyl) -1-phenylethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine (-) - 7-Chloro-6- (1-phenyl-ethylamine) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine ( 192 mg) in DCE (5 mL) and acetic acid (0.33 mL, 5.8 mmol), formaldehyde (37% solution, 0.5 mL) and sodium triacetoxyborohydride (570 mg, 2.7 mol) are added and the reaction is stirred at room temperature. for 16 h. The reaction is diluted with DCM and washed with aqueous IN NaOH. The organic Na2SO layers are dried, filtered and concentrated. Purification by chromatography on silica gel by levigating with hexane / EtOAc (20: 1, 10: 1 and 5: 1) to give (-) - 7-chloro-6- (methyl-1-phenylethylamino) -3- (2, 2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil. A method similar to general procedure 1-3 is used to deprotect (-) - 7-chloro-6- (methyl-1-phenylethylamino) -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5 -tetrahydro-lH-benzo [d] azepine and purified by SCX chromatography to give the free base of the title compound. A method similar to general procedure 2-1 is used to give the title compound as a white solid (176 mg, 85%). MS (ES +) m / z: 315 (M + H) +. [a] 20D -5.4 ° (c 0.5, CH 3 OH).

Example 248 7-Chloro-6- [(N-methyl) -benzylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Succinate Dissolve 6-benzylamino-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (330 mg, 0.86 mmol) in DCM (3 mL) and add triethylamine (250 DL, 1.8 mmol ) followed by di-tert-butyl-bicarbonate (260 mg, 1.2 mmol). Stir at room temperature for 1 h. The mixture was poured into water (250 mL), extracted with DCM (3x25 mL) and concentrated in vacuo to give, after chromatography on silica gel, levigating with hexane / EtOAc (9: 1), 6-benzylamino-3 -ter-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine as a colorless oil (260 mg, 78%). Dissolve 6-benzylamino-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (50 mg, 0.11 mmol) in acetonitrile (3 mL) and add one formaldehyde solution in water (37%, 85 μL, 0.97 mmol) followed by sodium cyanoborohydride (16.5 mg, 0.26 mmol). The solution is heated at reflux for 1 h, cooled to room temperature, glacial acetic acid (0.25 mL) is added and the mixture is stirred for 72 h. The mixture was poured into water (100 mL) containing methanol (1 mL), extracted with DCM (3x20 mL), the organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is dissolved in DCM (5 mL), and trifluoroacetic acid (2 mL) is added. It is stirred for 2 h at room temperature and the solvent is evaporated. It is purified by SCX chromatography. A method similar to general procedure 2-1 is used to give the title compound (45 mg, 95%). MS (ES +) m / z: 301 (M + H) +.

Example 249 Succinate of 7-Chloro-6- [(N-methyl) -3-fluorobenzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine HO2C- (CH2) 2 -CO2H The compound of The title can be prepared essentially as described in example 248 by using 7-chloro-6- (3-fluorobenzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (85% yield and MS (ES + ) m / z 319 (M + H) +).

Example 250 7-Chloro-6- (1-phenyl-cyclopropylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to general procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.2 g, 0.47 mmol) with 1-phenyl-cyclopropylamine (0.2 g, 1.41 mmol) using tris (dibenzylideneacetone) dipalladium (0) (43.0 mg, 0.05 mmol), BINAP (0.1 g, 0.15 mmol) and cesium carbonate ( 0.3 g, 0.97 mmol) at 90 ° C for 17 h to obtain 7-chloro-6- (1-phenyl-cyclopropylamino) -3- (2,2,2-trifluoroacetyl) -2, 3,4,5-tetrahydro -lH-benzo [d] azepine as a colorless oil. A method similar to general procedure 1-1 is used to obtain the free base of the title compound as a yellow oil. A method similar to general procedure 2-1 is used to obtain the title compound as a white solid (85 mg, 33%). Example 251 can be prepared essentially as described in example 250 by using 7-chloro-3- (2, 2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d ] azepine and 1- (2,4-dichlorophenyl) -cyclopropylamine. The overall performance (3 stages) is shown in the table below.

Example 252 Succinate of (+) - 7-Chloro-6- (2,3-dihydro-benzofuran-3-yl-methylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-2 is used to couple 2,3-dihydro-benzofuran-3-yl-methylamine (prepared as described in WO 0069816) (0.14 g, 1.1 mmol) with 7-chloro-3- ( 2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (0.15 g, 0.35 mmol) at 90 ° C for 18 h. A method similar to general procedure 1-2 is used to deprotect 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine . Purify by preparative reverse phase HPLC [5-micron Zorbax SB-Phenyl column 4.6x150 mm, 1 mL / min of 1% TFA in water / ACN (9: 1 to 1: 9) for 30 min, detector at 230 and 254 nm]. A method similar to general procedure 2-1 is used to give the title compound (4.3 mg, 3%).

Example 253 Succinate of 7-Chloro-6- [(2,3-dihydrobenzo [b] furan-5-yl) -methylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine H02C (CH2) 2C02H The commercially available 2,3-dihydrobenzo [b] furan-5-yl-methylamine hydrochloride (1.0 g, 5.4 mmol) was suspended in DCM (100 mL). Aqueous IN NaOH (15 mL) is added and stirred until all solids are dissolved. Two spatulas of NaCl were added. The mixture is stirred and extracted twice with DCM. The combined organic layers were dried over Na2SO4, and concentrated in vacuo to obtain 2,3-dihydrobenzo [b] furan-5-yl-methylamine (650 mg, 81%). MS (ES +) m / z: 133 (M + H-NH 3) +. A method similar to general procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (426 mg, 1.0 mmol) with 5-aminomethyl-2,3-dihydrobenzo [b] furan (223 mg, 1.5 mmol). Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain 7-chloro-6- [(2,3-dihydrobenzo [b] furan-5-yl) -methylamino] -3- (2,2,2-trifluoroacetyl) -2 , 3,4, 5-tetrahydro-lH-benzo [d] azepine (244 mg, 58%). MS (ES +) m / z: 425 (M + H) +.

A method similar to general procedure 1-1 is used to deprotect 7-chloro-6- [(2,3-dihydrobenzo [b] furan-5-yl) -methylamino] -3- (2,2,2-trifluoroacetyl) -2, 3,, 5-tetrahydro-lH-benzo [d] azepine. Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (95: 5) to give the free base of the title compound (105 mg, 32%). MS (ES +) m / z: 329 (M + H) +. A method similar to general procedure 2-1 is used to obtain the title compound. Examples 254-260 can be prepared essentially as described in Example 253 by using 7-chloro-3- (2, 2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The yields for stage 1 (General procedure 5-3) and MS data (ES +) are shown in the table below.

Example 261 7-Chloro-6- (naphthalen-2-yl-methylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to general procedure 5-2 is used to couple 2-aminomethylnaphthalene (prepared as described in WO 9509159) (0.17 g, 1.1 mmol) with 7-chloro-3- (2,2,2-trifluoroacetyl) -6. -trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (0.15 g, 0.35 mmol) at 90 ° C for 18 h. A method similar to general procedure 1-2 is used to give the free base of the title compound. HRMS calculated for C2XH2? ClN2 337.1471, found 337.1461. A method similar to general procedure 2-1 is used to give the title compound (104 mg, 66% general).

Example 262 7-Chloro-6- [(quinolin-6-yl-methyl) -amino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to general procedure 5-2 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.2 g, 0.35 mmol) and 6-aminomethyl-quinoline (0.2 g, 1.06 mmol) with tris (dibenzylidene ketone) dipalladium (0) (32.0 mg, 0.04 mmol), BINAP (44.0 mg, 0.07 mmol) and cesium carbonate (0.2 g, 0.71 mmol) at 90 ° C for 17 h , to obtain 7-chloro-6- [(quinolin-6-yl-methyl) -amino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d ] azepine as a colorless oil. A method similar to general procedure 1-1 is used to obtain the free base of the title compound as a yellow oil. A method similar to general procedure 2-2 is used to form the hydrochloride salt and purified by reverse phase preparative HPLC [Zorbax SB-Phenyl 21.2 × 250 mm, 5 micron column, 22 mL / min 0.1% HCl in water / acetonitrile (9: 1 to 1: 1) for 30 min, detector at 230 nm) to obtain the title compound as a white solid (50 mg, 56% general). MS (ES +) m / z: 338 (M + H) +. Examples 263-266 can be prepared essentially as described in Example 262 by using 7-chloro-3- (2, 2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The general performances and EM data (ES +) are shown in the table below.

Example 267 Succinate of 6- [(Benzofuran-6-ylmethyl) -amino] -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-2 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (0.2 g, 0.35 mmol) and 6-aminomethyl-benzofuran (0.2 g, 1.06 mmol) with tris (dibenzylideneacetone) dipalladium (0) (32.0 mg, 0.04 mmol), BINAP (88.0 mg, 0.11 mmol) and cesium carbonate ( 0.2 g, 0.71 mmol) at 90 ° C for 17 h, to obtain 6- [(benzofuran-6-yl-methyl) -amino] -7-chloro-3- (2,2,2-trifluoroacetyl) -2, 3,4,5-tetrahydro-lH-benzo [d] azepine as a colorless oil. A method similar to general procedure 1-1 is used to obtain the free base of the title compound as a yellow oil. A method similar to general procedure 2-1 is used to obtain the title compound as a white solid (72 mg, 46% general). MS (ES +) m / z: 327 (M + H) +.

Examples 268-271 can be prepared essentially as described in example 267 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The general performances and EM data (ES +) are shown in the table below.

Example 272 6- [(Benzothiazol-6-yl-methyl) -amino] -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine oxalate A method similar to General Procedure 5-4 is used, which combines 6-amino-7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.1 g, 0.35 mmol), 6-bromomethyl-benzothiazole (80 mg, 0.35 mmol), and potassium carbonate (47.0 mg, 0.35 mmol) in anhydrous DMF (1 mL) in a sealed tube. Heat at 150 ° C for 3 h to obtain 6- [(Benzothiazol-6-yl-methyl) -amino] -7-chloro-3- (2,2,2-trifluoroacetyl) -2.3.4, 5 -tetrahydro-lH-benzo [d] azepine as a colorless oil. A method similar to general procedure 1-1 is used to obtain the free base of the title compound as a yellow oil. A method similar to general procedure 2-5 is used to obtain the title compound as a white solid (25 mg, 16% general). MS (ES +) m / z: 344 (M + H) +.

Example 273 7-Chloro-6- [(quinolin-8-yl-methyl) -amino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 5-4 is used, which combines 6-amino-7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.1 g, 0.35 mmol), 8-bromomethyl-quinoline (83.6 mg, 0.038 mmol), cesium carbonate (0.2 g, 0.68 mmol) and anhydrous acetonitrile (1 mL) in a sealed tube and heated to 50 ° C. for 12 h to obtain 7-chloro-6- [(quinolin-8-yl-methyl) -amino) -amino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro- lH-benzo [d] azepine as a colorless oil. A method similar to general procedure 1-1 is used to obtain the free base of the title compound as a yellow oil. A method similar to general procedure 2-2 is used to form the hydrochloride salt and purified by reverse phase preparative HPLC [Zorbax SB-Phenyl 21.2x250 mm, 5 micron column, 22 mL / min 0.1% HCl in water / acetonitrile (9: 1 to 1: 1) for 30 min, detector at 230 nm) to obtain the title compound as a white solid (13 mg, 8% overall). MS (ES +) m / z: 338 (M + H) +.

Example 274 Succinate of 7-Chloro-6- [(2-cyclohexyl-benzothiazol-6-ylmethyl) -amino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-4 is used, which combines 6-amino-7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (60 mg, 0.21 mmol), 6-bromomethyl-2-cyclohexyl-benzothiazole (0.1 g, 0.31 mmol), potassium carbonate (58 mg, 0.42 mmol) and anhydrous toluene (2 mL) in a sealed tube and heated at 100 ° C for 72 h to obtain 7-chloro-6- [(2-cyclohexyl-benzothiazol-6-yl-methyl) -amino] -3- (2,2,2-trifluoroacetyl) -2,3,4 , 5-tetrahydro-lH-benzo [d] azepine as a colorless oil. A method similar to general procedure 1-1 is used to obtain the free base of the title compound as a yellow oil. A method similar to general procedure 2-1 is used to obtain the title compound as a white solid (40 mg, 35% general). EM (ES +) m / z: 427 (M + H) X Examples 275-277 can be prepared essentially as described in example 274 by using 6-amino-7- 'chloro-3- (2,2,2-trifluoroacetyl) ) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine and the appropriate bromide. The general performances and MS Data (ES +) are shown in the table below.

Example 278 7-Chloro-6- [(1-methyl-indol-4-yl-methyl) -amino] 2,3,4,5-tetrahydro-1H-benzo [d] azepine Succinate A method similar to General Procedure 5-1 is used, which couples 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [ d] azepine (0.1 g, 0.24 mmol) with 4-aminomethyl-l-methylindole (0.1 g, 0.71 mmol) to obtain 7-chloro-6- [(1-methyl-indol-4-yl-methyl) -amino] -3- (2,2, 2-trifluoroacetyl) -2, 3,, 5-tetrahydro-lH-benzo [d] azepine as a colorless oil. A method similar to general procedure 1-1 is used to obtain the free base of the title compound as a yellow oil. A method similar to general procedure 2-1 is used to obtain the title compound as a white solid (0.1 g, 91% general). MS (ES +) m / z: 340 (M + H) +. Examples 279-280 can be prepared essentially as described in Example 278 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine with the appropriate amine. The general performances and EM data (ES +) are shown in the table below.

Example 281 7-Chloro-6- (pyridin-2-ylmethylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to general procedure 5-1 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (500 mg, 1.17 mmol) with pyridin-2-ylmethylamine (254 mg, 2 equiv.) Using palladium acetate (0.1 equiv.), BINAP (0.3 equiv.) And cesium carbonate (1.4 equiv.) In toluene (5 equiv.). mL). The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (10: 1)., 5: 1, 3: 1, and 1: 1) to give 7-chloro-6- (pyridin-2-ylmethylamino) -3- (2,2, 2-trifluoroacetyl) -2,3,4, 5- tetrahydro-lH-benzo [d] azepine as an oil. A method similar to general procedure 1-3 is used to deprotect 7-chloro-6- (pyridin-2-ylmethylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH -benzo [d] azepine. Purify by SCX chromatography followed by silica gel chromatography by levigating with DCM / 2M ammonia in methanol (1: 0, 40: 1, 20: 1 and 10: 1) to give the free base of the title compound. A method similar to general procedure 2-2 is used to give the title compound as an opaque white solid (207 mg, 55% general). MS (ES +) m / z: 288 (M + H) +.

Example 282 7-Chloro-6- (pyridin-4-ylmethylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride It can be prepared essentially as described in example 281 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and pyridin-4-iimethylamine (28% yield, and MS (ES +) 288 (M + H) +).

Example 283 (±) -7-Chloro-6- [(1-pyridin-4-yl-ethyl) -amino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to general procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (400 mg, 0.94 mmol) and (±) -l-pyridin-4-yl-ethylamine (prepared as described in Bull. Kor. Chem. Soc. 1998, 19 (8), 891-893) (172 mg, 1.41 mmol). Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 4: 1 and 1: 1) to give (+) - 7-chloro-6- [(1-pyridin-4-yl-ethyl) - amino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to general procedure 1-1 is used to give the free base of the title compound (73 mg, 26%). A method similar to general procedure 2-1 is used, using (+) - 7-chloro-6- [(l-pyridin-4-yl-ethyl) -amino] -2,3,4,5-tetrahydro-IH -benzo [d] azepine (73 mg, 0.243 mmol), to give the title compound (31 mg, 31%). MS (ES +) m / z: 302 (M + H) +. Examples 284-287 can be prepared essentially as described in Example 283 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The yields for stage 1 (General procedure 5-3) and MS data (ES +) are shown in the table below.

HO2C (CH2) 2CO2H Example 288 Succinate of 7-Chloro-6- [(5-fluoro-pyridin-2-ylmethyl) -amino] 2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-1 is used to couple 2-aminomethyl-5-fluoro-pyridine (230 mg, 1.8 mmol) and a solution of 7-chloro-3- (2,2,2-trifluoroacetyl) -6. -trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (500 mg, 1.2 mmol) in toluene (4 mL). Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1) followed by SCX chromatography to give 7-chloro-6- [(5-fluoro-pyridin-2-ylmethyl) -amino] -3 - (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (302 mg, 64%). GC-MS m / z: 402 (M +). Dissolve 7-chloro-6- [(5-fluoro-pyridin-2-ylmethyl) -amino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [ d] azepine (297 mg, 0.74 mmol) in ethanol (5 mL). Aqueous 5N NaOH (10 equiv.) Is added and stirred for 1 h at room temperature. Concentrate in vacuo and purify by SCX chromatography followed by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (99: 1 to 9: 1) to obtain the free base of the title compound. A method similar to general procedure 2-1 is used and the solid is crystallized from methanol and diethyl ether. The solid was dried in a vacuum oven at 60 ° C overnight to obtain the title compound (181 mg, 58%). MS (ES +) m / z: 306 (M + H) +.

Example 289 Succinate of 7-Chloro-6-. { [5- (2, 2, 2-trifluoro-ethoxy) -pyridin-2-ylmethyl] -amino} -2, 3,4, 5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-2 is used to couple 7-chloro-6-trifluoromethanesulfonyloxy-3- (2, 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepine (370 mg, 0.9 mmol) with 2-aminomethyl-5- (2,2,2-trifluoroethoxy) -pyridine (180 mg, 0.9 mmol) in toluene (8 mL). Purification by chromatography on silica gel by levigating with hexane / EtOAc (10: 1, 5: 1 and 3: 1) followed by SCX chromatography [pre-washed column with methanol followed by DCM, loaded with material dissolved in DCM, then levigating with DCM / 2M ammonia in methanol (1: 1) and concentrated in vacuo] to obtain 7-chloro-6-. { [5- (2, 2, 2-trifluoro-ethoxy) -pyridin-2-ylmethyl] -amino} -3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to general procedure 1-3 is used to deprotect 7-chloro-6-. { [5- (2, 2, 2-trifluoro-ethoxy) -pyridin-2-ylmethyl] -amino} -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine. Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (99/1 to 90/10) to obtain the free base of the title compound. A method similar to general procedure 2-1 is used to give the title compound (184 mg, 42%). MS (ES +) m / z: 386 (M + H) +. Examples 290-291 can be prepared essentially as described in Example 289 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and the appropriate amine. The general performances and MS Data (ES +) are shown in the table below.

Examples 292 and 293 Succinate of (-) - 7-Chloro-6-. { [5- (2, 2, 2-trifluoro-1-methyl-ethoxy) -pyridin-2-ylmethyl] -amino} -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine and Succinate of (+) - 7-Chloro-6-. { [5- (2, 2, 2-trifluoro-1-methyl-ethoxy) -pyridin-2-ylmethyl] -amino} -2, 3,4,5- tetrahydro-lH-benzo [d] azepine The two enantiomers of (+) - 7-chloro-6- succinate were separated. { [5- (2, 2, 2-trifluoro-1-methyl-ethoxy) -pyridin-2-ylmethyl] -amino} -2, 3,4, 5-tetrahydro-lH-benzo [d] azepine by normal phase chiral HPLC (Chiralcel OD 8x35 cm, levigating with 4: 1 heptane / 3A-ethanol with 0.2% DMEA). Each enantiomer is purified by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (20: 1). A method similar to general procedure 2-1 is used to obtain the title compounds: (-) - 7-Chloro-6- succinate. { [5- (2, 2, 2-trifluoro-1-methyl-ethoxy) -pyridin-2-ylmethyl] -amino} -2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (Example 292, 75 mg, 38%), 95% ee [Chiralpak AD, 4.6x150 mm, levigant: 85/15 heptane / 3A ethanol with 0.2% DMEA, 0. 6 mL / min)]; MS (ES +) m / z: 400 (M + H) +. [a] 20D -12.1 ° (c 0.5, MeOH). Succinate of (+) - 7-Chloro-6-. { [5- (2, 2, 2-trifluoro-1-methyl-ethoxy) -pyridin-2-ylmethyl] -amino} -2, 3,4, 5-tetrahydro-IH-benzo [d] azepine (Example 293, 72 mg, 37%), 93% ee [Chiralpak AD, 4.6x150 mm, levigant: 85/15 heptane / 3A ethanol with 0.2% DMEA, 0.6 mL / min)]. MS (ES +) m / z: 400 (M + H) X [] 20D + 7.4 ° (c 0.5, MeOH).

Example 294 Succinate of (±) -7-Chloro-6- [(1-thiophen-2-yl-ethyl) -amino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (200 mg, 0.47 mmol) with (±) -1-thiophen-2-yl-ethylamine (prepared as described in J. Amer, Chem. Soc. 1942, 64, 477-479) (200 mg, 1.57 mmol) Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1 and 4: 1) to give (±) -7-chloro-6- [(1-thiophen-2-yl-ethyl) -amino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (126 mg, 67%). A method similar to general procedure 1-1 is used, using (±) -7-chloro-6- [(1-thiophen-2-yl-ethyl) -amino] -3- (2,2,2-trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine (126 mg, 0.313 mmol), to give the free base of the title compound (73 mg, 77%). A method similar to general procedure 2-1 is used, using (±) -7-chloro-6- [(1-thiophen-2-yl-ethyl) -amino] -2,3,4,5-tetrahydro-1H -benzo [d] azepine (73 mg, 0.241 mmol) to give the title compound (100 mg, 50% general). MS (ES +) m / z: 307 (M + H) +.

Example 295 Succinate of (+) - 7-Chloro-6- [(1-thiophen-2-yl-ethyl) -amino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine, Isomer 1 The two enantiomers of (+) - 7-chloro-6- [(1-thiophen-2-yl-ethyl) -amino] -3- (2,2,2-trifluoroacetyl) -2,3,4 were separated. 5-tetrahydro-lH-benzo [d] azepine by chiral preparative HPLC (Chiralpak AD, 8x30 cm, levigant: 9: 1 heptane / isopropanol with 0.2% DMEA, flow: 350 mL / min at 240 nm (UV), -650 mg charge] to obtain 7-chloro-6- [(l-thiophen-2-yl-ethyl) -amino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH -benzo [d] azepine Isomer 1, ee = 100% [Analytical column: Chiralpak AD, 4.6x250mm, levigant: 9: 1 heptane / isopropanol with 0.2% DMEA, flow: 1 mL / min at 250nm (UV). a method similar to general procedure 1-1, using 7-chloro-6- [(l-thiophen-2-yl-ethyl) -amino] -3- (2,2,2-trifluoroacetyl) -2,3,4 , 5-tetrahydro-lH-benzo [d] azepine Isomer 1, to give 7-chloro-6- [(1-thiophen-2-yl-ethyl) -amino] -2, 3, 4, 5-tetrahydro-lH -benzo [d] azepine Isomer 1. A method similar to general procedure 2-1 is used, using 7-chloro-6- [(1-thiophen-2-yl-ethyl) -amino] -2, 3, 4, 5-tetrahi dro-lH-benzo [d] azepine Isomer 1 (73 mg, 0.241 mmol) to give the title compound (100 mg, 98%). MS (ES +) m / z: 307 (M + H) +. [a] 20D + 115.0 ° (c 0.5, MeOH).

Example 296 Succinate of (+) - 7-Chloro-6- [1- (5-methylthiophen-2-yl) ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method is used similar to general procedure 5-1 for coupling 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (96 mg, 0.227 mmol) with (±) -2- (1-aminoethyl) -5-methylthiophene (48 mg, 0.34 mmol) using palladium acetate(II) (10 mg, 0.0454 mmol), BINAP (60 mg, 0.0908 mmol) and cesium carbonate (148 mg, 0.454 mmol) in toluene (10 mL).

Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 19: 1) to give (±) -7-chloro-6- [1- (5-methylthiophen-2-yl) ethylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5,5-tetrahydro-lH-benzo [d] azepine as an oil (47 mg, 50%). GC-MS m / z 416 (M +). A method similar to general procedure 1-2 is used, using (±) -7-chloro-6- [1- (5-methylthiophen-2-yl) ethylamino] -3- (2,2,2-trifluoroacetyl) - 2,3,4,5-tetrahydro-lH-benzo [d] azepine (47 mg, 0.113 mmol) to give (±) -7-chloro-6- [1- (5-methylthiophen-2-yl) ethylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as an oil (30 mg, 83%) that is used without further purification. A method similar to general procedure 2-1 is used to give the title compound as a white solid (36 mg, 88%).

MS (ES +) m / z: 321 (M + H) +.

Example 297 Succinate of (+) - 7-Chloro-6- [1- (5-phenyl-thiophen-2-yl) ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.328 g, 0.773 mmol) with l- (5-phenyl-thiophen-2-yl) ethylamine Isomer 1 (0.236 g, 1.16 mmol) using palladium (II) acetate (69 mg, 0.309 mmol), tris (dibenzylideneacetone) -dipaladium (0) (142 mg, 0.155 mmol), BINAP (578 mg, 0.928 mmol) and cesium carbonate (504 mg, 1546 mmol) in toluene (10 mL). Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 19: 1) to give 7-chloro-6- [1- (5-phenyl-thiophen-2-yl) -ethylamino] -3- ( 2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine Isomer 1 (89 mg, 34%).

A method similar to general procedure 1-2 is used, using 7-chloro-6- [1- (5-phenyl-thiophen-2-yl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2 , 3, 4, 5-tetrahydro-lH-benzo [d] azepine Isomer 1 (89 mg, 0.186 mmol) to give 7-chloro-6- [1- (5-phenyl-thiophen-2-yl) -ethylamino] -2, 3,4,5-tetrahydro-lH-benzo [d] azepine Isomer 1 (65 mg, 92%) as an oil that is used without further purification. A method similar to general procedure 2-1 is used, using 7-chloro-6- [1- (5-phenyl-thiophen-2-yl) -ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Isomer 1 (65 mg, 0.17 mmol), to give the title compound as a white solid (58 mg, 68%). MS (ES +) m / z: 383 (M + H) +; [] 20D + 159.0 ° (c 0.5, MeOH).

EXAMPLE 298 Succinate of (-) - 7-Chloro-6- [1- (5-phenyl-thiophen-2-yl) -ethylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (0.484 g, 1138 mmol) with 1- (5-phenyl-thiophen-2-yl) ethylamine Isomer 2 (0.347 g, 1.71 mmol) using palladium (II) acetate (102 mg, 0.45 mmol), tris (dibenzylidenacetone) -dipaladium (0) (209 mg, 0.228 mmol), BINAP (851 mg, 1366 mmol) and cesium carbonate (741 mg, 2.276 mmol) in toluene (12 mL). Purification by chromatography on silica gel by levigating with hexane: EtOAc (1: 0 and 19: 1) to give 7-chloro-6- [1- (5-phenyl-thiophen-2-yl) -ethylamino] -3- ( 2, 2, 2-trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine Isomer 2 (247 mg, 63%). A method similar to general procedure 1-2 is used, using 7-chloro-6- [1- (5-phenyl-thiophen-2-yl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2 , 3,4, 5-tetrahydro-lH-benzo [d] azepine Isomer 2 (247 mg, 0.516 mmol) to give 7-chloro-6- [1- (5-phenyl-thiophen-2-yl) -ethylamino] -2,3,4, 5-tetrahydro-lH-benzo [d] azepine Isomer 2 (184 mg, 93%) as an oil that is used without further purification. A method similar to general procedure 2-1 is used, using 7-chloro-6- [1- (5-phenyl-thiophen-2-yl) -ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Isomer 2 (184 mg, 0.48 mmol) to give the title compound as a white solid (200 mg, 83%). MS (ES +) m / z: 383 (M + H) +; [a] 20D -196.5 ° (c 0.5, MeOH).

Example 299 Succinate of (+) - 7-Chloro-6- [(1-thiophen-3-yl-ethyl) -amino] -2,3,4,5-tetrahydro-1H-benzo [d] azepine A method similar to general procedure 5-3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (200 mg, 0.47 mmol) with (+) - 1-thiophen-3-yl-ethylamine (prepared as described in J. Heterocycl, Chem. 1988, 25, 1571-1581) (90 mg, 0.70 mmol). Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1 and 4: 1) to give (±) -7-chloro-6- (l-thiophen-3-yl-ethylamino) -3 - (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (100 mg, 53%). A method similar to general procedure 1-1 is used, using (+) - 7-chloro-6- (1-thiophen-3-yl-ethylamino) -3- (2,2,2-trifluoroacetyl) -2,3 , 4,5-tetrahydro-lH-benzo [d] azepine (100 mg, 0.248 mmol), to give the free base of the title compound (74 mg, 98%). A method similar to general procedure 2-1 is used, using (+) - 7-chloro-6- (l-thiophen-3-yl-ethylamino) -2,3,4,5-tetrahydro-lH-benzo [d ] azepine (74 mg, 0.242 mmol) to give the title compound (108 mg, 54% general). MS (ES +) m / z: 307 (M + H) +.

EXAMPLE 300 7-Chloro-6- [(5-methyl-furan-2-ylmethyl) -amino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride 7-Chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo [d] azepine (100 mg, 0.24 mmol), 2- ( di-tert-butylphosphino) -biphenyl (6.8 mg, 0.023 mmol), tris (dibenzylideneacetone) dipalladium (11 mg, 0.012 mmol) and potassium phosphate (70 mg, 0.33 mmol) in a pressurized tube and degassed. The mixture is dissolved in dry toluene (2 mL) and degassed. A solution of 5-methylfurfurylamine (30 mg, 0.27 mmol) in toluene (1 mL) is added and degassed. Stir at 90 ° C for 24 h. It is cooled to room temperature, diluted with ethyl ether and filtered through Celite®. Concentrate and purify by chromatography on silica gel by levigating with hexane / EtOAc (20: 1) The solvent was removed and 7M ammonia in methanol (4 mL) was added. It is stirred at room temperature for 24 h.

Concentrate and purify by SCX chromatography to give the free base of the title compound. A method similar to general procedure 2-2 is used to obtain the title compound as a solid (56 mg, 66%) ..EM (ES +) m / z: 291 (M + H) +.

Examples 301-302 can be prepared essentially as described in Example 300 by using 7-chloro-3- (2, 2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The general performances and EM data (ES +) are shown in the table below.

Example 303 7-Chloro-6- (thiazol-5-ylmethyl-amino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride Thiazole-5-sarbaldehxdo: DEMO is added slowly to a solution of oxalyl chloride (1.6 g, 13 mmol) in anhydrous DCM (30 mL) under nitrogen at -78 ° C and stirred for 10 min. A solution of 5-hydroxymethylthiazole (1.15 g, 10 mmol) in DCM (10 mL) is added dropwise and the mixture is stirred for 40 min. Triethylamine is added and stirred for 5 min and then the reaction was quenched with water. The mixture was extracted three times with ether, the organic extracts were combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purification by chromatography on silica gel by levigating with EtOAc / hexane (2: 5) to give thiazole-5-carbaldehyde (337 mg, 29%). 3- (tert-butoxyarbonyl) -7-sloro-6- (thiazol-5-ylmethyleneamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Dissolves 6-amino-7-chloro- 3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (285 mg, 0.97 mmol) in methanol (10 mL). 7N ammonia in methanol (10 mL) is added and stirred overnight at room temperature. Concentrate in vacuo and dissolve the residue in THF (10 mL). Saturated aqueous NaHCO3 (5 mL) and di-tert-butyl-bicarbonate (254 mg, 1.16 mmol) are added. The reaction mixture is stirred at room temperature for 4 h. The mixture is diluted with water, extracted three times with EtOAc, the organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo to give the crude material. Thiazole-5-carbaldehyde (165 mg, 1.45 mmol) is mixed with the crude residue above (0.97 mmol, assuming 100% conversion), acetic acid (87 mg, 1.45 mmol) and 1,2-dichloroethane (10 mL). Stir at room temperature for 20 min. - Sodium triacetoxyborohydride is added and stirred under nitrogen overnight. The reaction is quenched with saturated aqueous NaHCO3, the organic layer is separated and the aqueous layer extracted three times with DCM. Combine the organic extracts, dry over Na2SO4, filter and concentrate in vacuo. Purification by chromatography on silica gel by levigating with EtOAc / hexane (1: 3) to provide the desired intermediate as a yellow oil (228 mg, 60% three steps). MS (ES +) m / z: 392 (M + H) +. 3- (t-Bu oxisarbonyl) -7-sloro-6- (thiazol-5-ylmethyl-amino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Dissolves 3- (t-) butoxycarbonyl) -7-chloro-6- (thiazol-5-ylmethyleneamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (228 mg, 0.58 mmol) in methanol (10 mL), added Sodium borohydride (263 mg, 7 mmol) and reflux for 28 h. Cool to room temperature, dilute with EtOAc and slowly add water. The organic layer is separated, the aqueous layer is extracted three times with EtOAc. The organic extracts are combined, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purification by chromatography on silica gel by levigating with EtOAc / hexane (1: 3) to give the desired intermediate as a colorless oil (134 mg, 58%). MS (ES +) m / z: 394 (M + H) +. 7-Chloro-6- (thiazol-5-ylmethyl-amino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride: A method similar to general procedure 1-6 is used to deprotect 3 - (tert-butoxycarbonyl) -7-chloro-6- (thiazol-5-ylmethyl-amino) -2,4,5,5-tetrahydro-lH-benzo [d] azepine (134 mg, 0.34 mmol). Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (94: 6) to give 7-chloro-6- (thiazol-5-ylmethylamino) -2, 3, 4, 5-tetrahydro-1H- benzo [d] azepine as an oil (90 mg, 90%). MS (ES +) m / z: 294 (M + H) +. A method similar to general procedure 2-2 is used to obtain the title compound.

Example 304 7-Chloro-6- [(3-pyridyl) amino] -2,3,4,5,5-tetrahydro-l-benzo [d] azepine Succinate A method similar to general procedure 5-1 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (300 mg, 0.7 mmol) with 3-aminopyridine (75 mg, 0.85 mmol). Purification by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to give 7-chloro-6- [(3-pyridyl) amino] -3- (2,2,2-trifluoroacetyl) -2,3, 4,5-tetrahydro-lH-benzo [d] azepine as a white opaque solid (20 mg, 8%). MS (ES +) m / z: 370 (M + H) X A method similar to general procedure 1-1 is used to deprotect 7-chloro-6- [(3-pyridyl) amino] -3- (2, 2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (20 mg, 0.05 mmol). Purify by SCX chromatography to give 7-chloro-6- [(3-pyridyl) amino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a yellow oil (15 mg, 99%) . A method similar to general procedure 2-1 is used, using 7-chloro-6- [(3-pyridyl) amino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine (15.1 mg, 0.05 mmol), to give the title compound as a light yellow solid (20 mg, 97%). MS (ES +) m / z: 319 (M + H) +.

Example 305 7,9-Dichloro-6- (3,4-difluorobenzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride Dissolve 7-dichloro-6- (3,4-difluorobenzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (150 mg, 0.36 mmol) in anhydrous toluene (20 mL). Add N-chlorosuccinimide (140 mg, 1 mmol) and heat at 60 ° C for 4 h. It is cooled to room temperature, the reaction mixture is poured into water (250 mL) and extracted with EtOAc (3x50 mL). The organic extracts are washed with water, brine, dried over Na 2 SO 4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to give 7,9-dichloro-6- (3,4-difluorobenzylamino) -3- (2,2,2-trifluoroacetyl) -2, 3 , 4,5-tetrahydro-lH-benzo [d] azepine (110 mg, 67%). MS (ES +) m / z: 453 (M + H) +. A method similar to general procedure 1-1 is used to deprotect 7,9-dichloro-6- (3,4-difluorobenzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro -lH-benzo [d] azepine (120 mg, 0.26 mmol). Purify by SCX chromatography to give 7,9-dichloro-6- (3,4-difluorobenzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a yellow oil (81 mg, 88%). A method similar to general procedure 2-2 is used, using 7,9-dichloro-6- (3,4-difluorobenzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (75 mg, 0.21 mmol), to give the title compound as a yellow gum (80 mg, 96%). EM (ES +) m / z: 357 (M + H) +.

Example 306 Succinate of 7-Chloro-9-fluoro-6- (3-fluorobenzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-1 is used to couple 7-chloro-9-fluoro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (130 mg, 0.3 mmol) with 3-fluorobenzylamine (100 DL, 0.89 mmol). Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 and 4: 1) followed by SCX chromatography to give 7-chloro-9-fluoro-6- (3-fluorobenzylamino) -3- (2.2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a yellow oil (35 mg, 28%). MS (ES +) m / z: 401 (M + H) +. A method similar to general procedure 1-1 is used to deprotect 7-chloro-9-fluoro-6- (3-fluorobenzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro -lH-benzo [d] azepine (32 mg, 0.08 mmol). Purify by SCX chromatography to give 7-chloro-9-fluoro-6- (3-fluorobenzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a yellow oil (10 mg, 45% ). A method similar to general procedure 2-1 is used, using 7-chloro-9-fluoro-6- (3-fluorobenzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (10 mg, 0.033 mmol), to give the title compound as a light yellow solid (14 mg, 97%). MS (ES +) m / z: 323 (M + H) +.

Example 307 Succinate of 7-Fluoro-6- (4-fluorobenzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-1 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (250 mg, 0.61 mmol) with 4-fluorobenzylamine (92 mg, 1.2 equiv.) Using palladium (II) acetate (0.1 equiv.), BINAP (0.3 equiv.) And cesium carbonate (1.4 equiv.) In toluene ( 5 mL). Purification by chromatography on silica gel by levigating with hexane / EtOAc (10: 1, 5: 1, 3: 1 and 1: 1) to give 7-fluoro-6- (4-fluorobenzylamino) -3- (2.2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil. A method similar to general procedure 1-3 is used to deprotect 7-fluoro-6- (4-fluorobenzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzole [d] azepine. Purify by SCX chromatography to give the free base of the title compound. A method similar to general procedure 2-1 is used to give the title compound as an opaque white solid (14 mg, 6%). MS (ES +) m / z: 289 (M + H) +.

Example 308 Succinate of 6-Benzylamino-7-cyano-2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-1 is used to couple 7-cyano-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (125 mg, 0.3 mmol) with benzylamine (0.1 mL, 0.9 mmol) using palladium (II) acetate (7 mg, 0.03 mmol), BINAP (37 mg, 0.06 mmol) and cesium carbonate (137 mg, 0.4 mmol) in toluene (3 mL). Purification by chromatography on silica gel by levigating with heptane / EtOAc (4: 1 to 1: 1) to give 6-benzylamino-7-cyano-3- (2,2,2-trifluoroacetyl) -2,3,4,5 -tetrahydro-lH-benzo [d] azepine as a clear oil (60 mg, 54%). MS (ES +) m / z: 374 (M + H) X A method similar to general procedure 1-2 is used, using 6-benzylamino-7-cyano-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (56 mg, 0.15 mmol), to give 6-benzylamino-7-cyano-2,3,4,5-tetrahydro-lH-benzo [d] azepine as a clear oil (38 mg, 93%). MS (ES +) m / z: 278 (M + H) +. A method similar to general procedure 2-1 is used to give the title compound as a white powder (39 mg, 71%). MS (ES +) m / z: 278 (M + H) +. Examples 309-310 can be prepared essentially as described in Example 308 by using 7-cyano-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the appropriate amine. The general performances and MS Data (ES +) are shown in the table below.

Example 311 Succinate of 6- (3-Fluorobenzylamino) -7-trifluoromethyl-2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-1 is used to couple 3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (110 mg, 0.24 mmol) and 3-fluorobenzyl amine (90 μL, 0.7 mmol). Purification by chromatography on silica gel by levigating with hexane / EtOAc (95: 5) followed by SCX chromatography to give 6- (3-fluorobenzylamino) -3- (2,2,2-trifluoroacetyl) -7-trifluoromethyl-2, 3 , 4,5-tetrahydro-lH-benzo [d] azepine as a yellow oil (55 mg, 53%). MS (ES +) m / z: 435 (M + H) X A method similar to general procedure 1-1 is used to deprotect 6- (3-fluorobenzylamino) -3- (2,2,2-trifluoroacetyl) -7- trifluoromethyl-2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (55 mg, 0.13 mmol). Purify by SCX chromatography to give 6- (3-fluorobenzylamino) -7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo [d] azepine as a yellow oil (34 mg, 81%). A method similar to general procedure 2-1 is used to give the title compound as an opaque white solid (33 mg, 72%). MS (ES +) m / z: 339 (M + H) +.

Example 312 Succinate of (S) - (-) -6- [1- (4-Fluorophenyl) -ethylamino] -7-trifluoromethyl-2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-3 is used to couple 3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (430 mg, 0.94 mmol) with (S) -l- (4-fluorophenyl) ethylamine (195 mg, 1.40 mmol). Purification by chromatography on silica gel by levigating with EtOAc / hexane (1: 8) to give (S) -6- [1- (4-fluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -7 -trifluoromethyl-2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (279 mg, 66%). MS (ES +) m / z: 449 (M + H) X A method similar to general procedure 1-1 is used to deprotect (S) -6- [1- (4-fluorophenyl) -ethylamino] -3- (2 , 2,2-trifluoroacetyl) -7-trifluoromethyl-2, 3,4,5-tetrahydro-iH-benzo [d] azepine (279 mg, 0.62 mmol). Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (94: 6) to obtain (S) -6- [1- (4-fluorophenyl) -ethylamino] -7-trifluoromethyl-2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a colorless oil (190 mg, 87%). MS (ES +) m / z: 353 (M + H) +. A method similar to general procedure 2-1 is used to give the title compound. [a] 20D-96.7 ° (c 0.5, MeOH).

Example 313 Succinate of (S) -7-Ethyl-6- [1- (4-fluorophenyl) -ethylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 5-3 is used to couple 7-ethyl-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine (335 mg, 0.8 mmol) and (S) -l- (4-fluorophenol) ethyl amine (557 mg, 4.0 mmol). Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 9: 1 and 17: 3) to give (S) -7-ethyl-6- [1- (4-fluorophenyl) -ethylamino] -3 - (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (127 mg, 39%). MS (ES +) m / z: 409 (M + H) +. A method similar to general procedure 1-1 is used to deprotect (S) -7-ethyl-6- [1- (4-fluorophenyl) -ethylamino] -3- (2,2,2-trifluoroacetyl) -2,3 , 4,5-tetrahydro-IH-benzo [d] azepine. Purification by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (93: 7) to give (S) -7-ethyl-6- [1- (4-fluorophenyl) -ethylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (70 mg, 72%). MS (ES +) m / z: 313 (M + H) +. A method similar to general procedure 2-1 is used to obtain the title compound.

Example 314 7-Propyl-6- [(2-thienyl) methylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride (HCl) X A method similar to general procedure 5-1 is used to couple 7-propyl-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 2- (aminomethyl) -thiophene. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 and 4: 1) to give 7-propyl-6- [(2-thienyl) methylamino] -3- (2,2,2-trifluoroacetyl) - 2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a yellow solid. MS (ES +) m / z: 397 (M + H) +. A method similar to general procedure 1-1 is used to deprotect 7-propyl-6- [(2-thienyl) methylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro- lH-benzo [d] azepine. Purify by SCX chromatography to give the free base of the title compound as a yellow oil. A method similar to general procedure 2-2 is used to give the title compound as a light yellow solid. MS (ES +) m / z: 301 (M + H) X General Procurement 7 The appropriate substituted 3-tert-butoxycarbonyl-6-dimethylcarbamoyl-thio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (1.0 equiv) in methanol (0.1-0.2 M solution) is dissolved. . Potassium hydroxide (32 equiv.) Is added and the mixture is heated at 50 ° C for 2-8 h. The reaction is cooled to room temperature and the appropriate halide (1.0-5.0 equiv.) Is added. The mixture is stirred at room temperature for 0.5-16 h. The solvent was removed in vacuo and the residue was partitioned between DCM and water. The aqueous phase is extracted with DCM, the organic extracts are combined, dried over Na 2 SO 4, filtered and concentrated. Purify by chromatography on silica gel by levigating with hexane / EtOAc mixture to obtain the desired compound.

Preparation 172 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine 7-Chloro-6-dimethylthiosarbamoyloxy-3- (2,2,2-trifluoro-la-yl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 7-chloro-6-hydroxy-3 is placed - (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (64.3 g, 219 mmol) in acetone (450 mL) and water (200 mL) with K2C03 (91.8 g, 664 mmol) and dimethylthiocarbamoyl chloride (31.5 g, 255 mmol). Stir at room temperature for 1.25 h. Additional dimethylthiocarbamoyl chloride (3 g, 24 mmol) is added and stirred for an additional 1.75 hours at room temperature. Add more dimethylthiocarbamoyl chloride (0.7 g, 5.7 mmol) and water (150 mL) to the mixture and stir for 0.5 h at room temperature. Water (500 mL) is slowly added to the reaction for 2 h to promote crystallization and the resulting thick mixture is stirred at room temperature for 1.5 h. The solid is collected by filtration to give the desired intermediate (76 g, 91%). 3-tert-butoxysarbonyl-7-sloro-6-dimethylsarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine: Dissolves 7-chloro-6-dimethylthiocarbamoyloxy-3- (2,2, -trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (155 g, 407 mmol) in diphenyl ether (1500 mL) and heated at 250 ° C for 2.5 h. The reaction is cooled and diluted with methanol (308 mL). Aqueous IN NaOH (616 mL) is added and stirred at 60 ° C for 4 h. The reaction is cooled to room temperature and extracted between DCM (3 x 500 mL) and water (500 mL). The organic extracts are combined and added to aqueous IN HCl (1 L). The reaction is stirred at room temperature for 0.25 h then washed with hexane (5 x 400 mL). The pH of the aqueous layer is adjusted to 7.0 with aqueous 5N NaOH and the aqueous solution is mixed with DCM (2.5 L). The mixture is cooled in an ice bath and K2CO3 (169 g, 1221 mmol) and di-t-butyl bicarbonate (67.5 g, 390 mmol) are added and the reaction is stirred at room temperature for 0.5 h. Add di-t-butyl bicarbonate (16.35 g, 75 mmol) and stir for 0.3 h at room temperature. Di-t-butyl bicarbonate is added (0.1 g, 0.46 mmol) and stirred for 0.25 h at room temperature. The mixture is concentrated in vacuo to remove the volatiles and heated to 45 ° C. The mixture was seeded with a small amount of the title compound and stirred for 1 h at 45 ° C. The reaction is cooled in an ice bath and stirred for an additional 2 hours. The resulting solid is collected by filtration and rinsed with cold hexane (100 mL). The filtrate is concentrated in vacuo, recrystallized from DCM / heptane, and the solids are isolated by filtration. The solids are combined and dried in vacuo to give the title compound as a white crystalline solid. (142 g, 91%). MS (ES +) m / z 385 (M + H) +.

Preparation 173 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio- 2, 3,4, 5-tetrahydro-lH-benzo [d] azepine 7-Chloro-6-hydroxy-3- (2, 2, 2-trifluoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine and 7,9-dialoro-6-hydroxy-3- (2, 2, 2-trifluoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: To a solution of 6-hydroxy-3- (2, 2,2-trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine (0.961 g, 3.71 mmol) in toluene (30 mL) at 70 ° C, Diisobutylamine (52 μL, 0.30 mmol) followed by slow addition of pure sulfuryl chloride (343 μL, 4.27 mmol). Stir for 1 h at 70 ° C and concentrate in vacuo. The residue is diluted with water, extracted three times with EtOAc, dried over anhydrous Na 2 SO and concentrated in vacuo to provide a 4: 1 mixture of 7-chloro-6-hydroxy-3- (2,2,2-trifluoroacetyl). ) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine and 7,9-dichloro-6-hydroxy-3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5- tetrahydro-lH-benzo [d] azepine as a white solid (1.07 -g, 98%). 7-Chloro-6-dimethylthiosarbamoyloxy-3- (2,2,2-trifluoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine and 7,9-disloro-6-dimethylthiosarbamoyloxy-3- (2,2, 2-tri luoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: To a mixture of 4: 1 7-chloro-6-hydroxy-3- (2, 2 , 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine and 7,9-dichloro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3, 4,5-Tetrahydro-lH-benzo [d] azepine (0.513 g, 1.75 mmol) in anhydrous dioxane (10 mL) under nitrogen, add dimethyl thiocarbamoyl chloride (0.432 g, 3.50 mmol), 4-dimethylaminopyridine (21 mg) , 0.18 mmol) and triethylamine (731 μL, 5.24 mmol) and heated under reflux overnight. The reaction mixture is cooled to room temperature and diluted with water, extracted three times with EtOAc, dried over anhydrous Na 2 SO and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (17: 1) to give a mixture of 4: 1 7-chloro-6-dimethylthiocarbamoyloxy-3- (2,2,2-trifluoroacetyl) -2,3,4 , 5-tetrahydro-lH-benzo [d] azepine and 7,9-dichloro-6-dimethylthiocarbamoyloxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d ] azepine as a yellow oil (0.64 g, 95%) 7-Chloro-6-dimethylsarbamoylthio-3- (2,2,2-trifluoroasethyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine and 7, 9-disloro-6-dimethylsarbamoylthio-3- (2, 2, 2-tri luoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: The mixture is heated to 4: 1. 7-Chloro-6-dimethylthiocarbamoyloxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine and 7,9-dichloro-6-dimethylthiocarbamoyloxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.630 g, 1.66 mmol) in diphenyl ether (4.5 mL) at 250 ° C for 4 h under nitrogen . It is cooled to room temperature. Purification by chromatography on silica gel by levigating with hexane / EtOAc (7: 3) to give a mixture of 4: 1 7-chloro-6-dimethylcarbamoylthio-3- (2,2,2-trifluoroacetyl) -2, 3, 4 , 5-tetrahydro-lH-benzo [d] azepine and 7,9-dichloro-6-dimethylcarbamoylthio-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d ] azepine as a yellow oil (0.54 g, 85%). 3-tert-butoxysarbonyl-7-sloro-6-dime-lyssarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 3-tert-butoxy-arbonyl-7,9-disloro-6-dimethylsarbamoylthio-2 , 3,4,5-tetrahydro-lH-benzo [d] azepine: To the 4: 1 mixture of 7-chloro-6-dimethylcarbamoylthio-3- (2,2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine and 7,9-dichloro-6-dimethylcarbamoylthio-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.536 g, 1.47 mmol) in methanol (7 mL), aqueous potassium carbonate (0.812 g, 5.88 mmol in 1.5 mL of water) is added. Stir for 5 h at room temperature, add di-tert-butyl bicarbonate (418 mg, 1.91 mmol) and stir for an additional 30 minutes. It is diluted with EtOAc and water. The layers were separated and the aqueous layer extracted three times with EtOAc. Dry over anhydrous Na2SO4, and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (7: 3) to give a mixture of 4: 1 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1H -benzo [d] azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine as a white solid (0.52 g, 96% ).

Preparation 174 7-Bromo-3-tert-butoxycarbonyl-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine A similar method is used for preparation 172, using 7-bromo-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine to give the title compound.

Preparation 175 3-tert-butoxycarbonyl-6-dimethylcarbamoylthio-7-methyl-2, 3,4,5-tetrahydro-lH-benzo [d] azepine 7-Bromo-6-methoxy-3- (2, 2, 2-trifluoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: potassium carbonate is added (10,214 g, 73.9 mmol) to a solution of 7-bromo-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (5.0 g, 14.8 mmol) in acetone (50 'mL) and stirred for 10 min. Methyl iodide (4.2 g, 1.5 mL, 29.6 mmol) is added and the mixture is stirred overnight at room temperature.

The solvent was removed in vacuo and the residue partitioned between water and DCM. The aqueous phase is extracted twice with DCM. Combine the organic extracts, dry over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a solid (5.15 g, 99%). MS (ES +) m / z: 352 (M + H) +. 6-Methoxy-7-methyl-3- (2, 2, 2-trifluoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Potassium carbonate (5.65 g, 40.91 mmol) is added , tetrakis (triphenylphosphine) palladium (1.576 g, 1.363 mmol) and trimethylboroxin (2.053 g, 2.3 mL, 16. 35 mmol) was added to a solution of 7-bromo-6-methoxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepine (4.8 g, 13.63 mmol ) in dimethylformamide (40 mL) under nitrogen. The mixture is heated at 115 ° C for 6 h. Water is added and the aqueous phase is extracted twice with EtOAc. The organic extracts are combined, dried over Na 2 SO 4, filtered and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 19: 1) to obtain the desired intermediate as a solid (3.23 g, 83%). GC-MS m / z 287 (M +). 6-Hxdroxy-7-methyl-3- (2, 2, 2-trifluoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Boron tribromide (21.6 mL, 1.0 M solution is added in DCM) to a solution of 6-methoxy-7-methyl-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepine (3.1 g, 10.8 mmol ) in DCM (200 mL) at 0 ° C under nitrogen. It is warmed to room temperature and stirred overnight. It is diluted with DCM and washed with water. The organic layer is dried over Na 2 SO 4, filtered and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain the desired intermediate as a solid (2.74 g, 93%). MS (ES +) m / z: 274 (M + H) +. 6-Dxmethythasarbamoyloxy-7-methyl-3- (2, 2, 2-trifluoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Dissolves 6-hydroxy-7-methyl-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.0 g, 3.66 mmol) in acetone (50 mL). Potassium carbonate (1517 g, 10.98 mmol) and dimethylthiocarbamoyl chloride (0.904 g, 7.32 mmol) are added. The mixture is heated under reflux overnight. The solvent was removed in vacuo and the residue partitioned between water and DCM. The organic phase is dried over Na 2 SO, filtered and concentrated. Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain the desired intermediate as a solid (1.18 g, 90%). MS (ES +) m / z: 361 (M + H) +. 6-Dxmethylsarbamoylthio-7-methyl-3- (2,2,2-trifluoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Dissolves 6-dimethylthiocarbamoyloxy-7-methyl-3- (2,2,2-trifluoroacetyl) -2,4,4,5-tetrahydro-lH-benzo [d] azepine (1.15 g, 3.19 mmol) in diphenyl ether (20 mL) and heated at 265 ° C for 3 hours. h in a sealed tube. The reaction is cooled to room temperature. Purification by chromatography on silica gel by levigating with hexane / EtOAc (4: 1 and 7: 3) to obtain the desired intermediate as a solid (1.10 g, 96%). MS (ES +) m / z: 361 (M + H) +. 3-tert-butoxyarbonyl-6-dimethylsarbamoylthio-7-methyl-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: Dissolves 6-dimethylcarbamoylthio-7-methyl-3- (2,2, -trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (1.048 g, 2.9 mmol) in methanol (40 mL). A solution of potassium carbonate (1.6 g, 11.6 mmol) in water (10 mL) is added. Stir at room temperature overnight. The solvent was removed and the residue divided between water and DCM. The aqueous phase is extracted twice with DCM. The organic extracts are combined, dried over Na 2 SO 4, filtered and concentrated. The residue is dissolved (0.756 g, 2.86 mmol) in DCM (50 L). Add triethylamine (0.579 g, 0.8 mL, 2.0 equiv) and di-tert-butyl bicarbonate (0.624 g, 2.86 mmol) and stir at room temperature overnight. It is diluted with DCM and washed with water. The organic phase is dried over Na2SO4, filtered and concentrated to obtain the title compound as a foam (1.038 g, 99%). MS (ES +) m / z: 264 (M + H-Boc) +.

Preparation 176 3-tert-butoxycarbonyl-7-cyano-6-dimethylcarbamoylsulfanyl-2,3,4,5-tetrahydro-lH-benzo [d] azepine 7-Cyano-6-dimethylthiosarbamoyloxy-3- (2,2,2-trifluoroasethyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepine: Dimethylthiocarbamoyl chloride (197 mg, 1.58 mmol) is added to a stirred solution of 7-cyano-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,5,5-tetrahydro-1H-benzo [d] azepine (150 mg, 0.53 mmol), DMAP (6 mg, 0.05 mmol) and dry triethylamine (300 μL) in dry 1,4-dioxane (5 mL) under a nitrogen atmosphere and heated at 120 ° C for 6 h. It is cooled and it is continued stirring during 2 days at room temperature. Dilute with EtOAc, wash with IN aqueous HCl, water, saturated aqueous Na 2 CO 3 and brine. Dry over MgSO4 then concentrate in vacuo. Purification by chromatography on silica gel by levigating with EtOAc: heptane (0: 1 to 3:10) to give the desired intermediate as a white solid (158 mg, 81%). 7-Cyano-6-dimethylsarbamoylsulfanyl-3- (2, 2, 2-tri luoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: A round bottom flask containing a solution is heated of 7-cyano-6-dimethylthiocarbamoyloxy-3- (2,2,2-trifluoroacetyl) -2,4,4,5-tetrahydro-lH-benzo [d] azepine (786 mg, 2.12 mmol) in diphenyl ether ( mL) in a preheated oil bath at 230 ° C for 2 h. Cool and purify by chromatography on silica gel by levigating with EtOAc: heptane (0: 1 to 1: 1) to give the desired intermediate as a yellow foam (740 mg, 94%). aH NMR (300 MHz, CDC13) d 7.60-7.56 (d, ÍH), 7.36-7.30 (d, ÍH), 3.88-3.68 (m, 4H), 3.34-3.03 (m, 10H). 3-tert-butoxysarbonyl-7-aiane-6-dimethylarybamoylsulfanyl-2,3,4,5-tetrahydro-lH-benzo [d] azepine: Potassium carbonate (4.13 g, 30 mmol) is added to a stirred solution of sodium hydroxide. -cyano-6-dimethylcarbamoylsulfanyl-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (740 mg, 2.0 mmol) in methanol (40 mL) / water (15 mL) and stir for 1.5 h. Add DCM (10 mL), di-tert-butyl bicarbonate (480 mg, 2.2 mmol) and stir at room temperature for 3 days. Concentrate in vacuo and dilute with DCM, wash with water and extract with DCM. The organic layers are combined, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica gel by levigating with EtOAc: heptane (0: 1 to 1: 1) to give the title compound as a colorless foam (370 mg, 50%). 1H NMR (300 MHz, CDC13) d 7.52 (d, J 8 Hz, ÍH), 7.29 (d, J 8 Hz, ÍH), 3.69-3.48 (m, 4H), 3.26-3.02 (m, 10H), 1.45 (s, 9H).

Preparation 177 (S) -3-tert-butoxycarbonyl-7-chloro-6- (5-oxo-tetrahydro-furan-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine To a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo [d] azepine (137 mg, 0.356 mmol) in methanol (2 mL) is added hydroxide. pelletized potassium (640 mg, 11.4 mmol) and heated for 3 h at 50 ° C. Cool to room temperature, add saturated aqueous NH4C1, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Dissolve the crude thiophenol thus obtained in dry DMF (2 mL), and add with stirred sodium hydride (18 mg, 0.713 mmol, 95% dispersion), followed by (S) - (+) - dihydro-5- ( p-toluylsulfonyloxymethyl) -2- (3H) -furanone (144 mg, 0.533 mmol). Stirring is continued overnight at room temperature, then carefully diluted with EtOAc and cooled with saturated aqueous NH4C1. Extract three times with EtOAc, dry over anhydrous Na 2 SO, and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (7: 3) to give the title compound as a colorless oil.

Preparation 178 5-Chloromethyl-3-methyl- [1,2,4] oxadiazole Hydroxylamine (50% in water, 25.0 mL, 0.380 mol) is added with stirring to a solution of acetonitrile (5.0 mL, 95.0 mmol) and ethanol (500 mL). It is heated at 70 ° C for 18 h. concentrate in vacuo to give crude N-hydroxyacetamidine (7.0 g, 100%). It is slowly added with stirred vinyl chloroacetate (2.1 mL) to N-hydroxyacetamidine (J. Org. Chem. 1971, 36, 1306-1307) (1.00 g, 13.5 mmol) and heated at 90 ° C for 5 h. Cool to room temperature, dilute with DCM, wash with saturated aqueous 1N NaOH, dry over anhydrous Na2SO4 and concentrate in vacuo to give the title compound (904 mg, 50%). The compounds of Preparation 179-182 were prepared essentially as described in Preparation 178.

Preparation 183 2-Bromomethyl-6-chloropyridine A mixture of 2-chloro-6-methylpyridine (5.46 g, 42.8 mmol), NBS (8.38 g, 47.08 mmol), and benzoyl peroxide (500 mg, 2.06 mmol) in carbon tetrachloride (80 mL) is heated for 20 minutes. it has 85 ° C. Cool to room temperature, filter, and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / toluene (4: 3) to give the title compound as a white solid (3.64 g, 41%).

Preparation 184 3-Bromo-2-bromomethyl-pyridine A mixture of 3-bromo-2-methylpyridine (J. Med. Chem. 1987, 30, 871-880) (2.7 g, 15.8 mmol), NBS is heated. (3.10 g, 17.42 mmol), and benzoyl peroxide (190 mg, 0. 78 mmol) in carbon tetrachloride (50 mL) overnight, at 85 ° C. Cool to room temperature, filter, and concentrate in vacuo. Purification by chromatography on silica gel by levigating with toluene to give the title compound as a white solid (1.81 g, 45%).

PREPARATION 185 2-Bromo-6-bromomethyl-pyridine A similar method is used for preparation 184, using 2-bromo-6-methylpyridine, to give the title compound.

Preparation 186 5-Bromo-2-bromomethylpyridine 2-Hydroxymethyl-5-bromopyridine: Dissolve 2,5-dibromopyridine (10 g, 42 mmol) in toluene (500 mL) and cool to -78 ° C. 2.5M n-butylithium in hexane (20.3 mL, 50.6 mmol) is added and the mixture is stirred for 7 h at the same temperature. DMF (4.2 mL, 54.87 mmol) is added and stirred for 1 h. The solution is warmed to 0 ° C and sodium borohydride (3.2 g, 84.42 mmol) is added. The mixture is stirred at room temperature for 3 h. Dilute with EtOAc and saturated aqueous NH 4 Cl. The layers were separated and the aqueous layer extracted three times with EtOAc. Dry over anhydrous Na2SO4, filter and concentrate in vacuo. Recrystallization of hexane / EtOAc (9: 1) gives the desired intermediate as a white solid (5.3 g, 66%).

-Bromo-2-bromome-pyridine: Dissolve 2-hydroxymethyl-5-bromopyridine (5.21 g, 27.7 mmol) in 48% aqueous hydrobromic acid (20 mL). The mixture is heated at 150 ° C for 2 h. Cool to room temperature and remove excess hydrobromic acid under vacuum. Dilute with water, carefully add NaHCO 3 and extract three times with EtOAc. Dry over anhydrous Na2SO4, filter and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the title compound as a pink oil (6.0 g, 87%) which was crystallized in the freezer.

Preparation 187 2-Chloromethyl-3-methylpyridine hydrochloride 2-Hydroxymethyl-3-methylpyridine: A mixture of 3-methylpicolinic acid (1.0 g, 7.3 mmol), potassium carbonate (4.1 g, 29.7 mmol), and iodomethane (4.4 g, 31.0 mmol) in acetone (35 mL) is heated. ) overnight under reflux. Filter, wash the residue with EtOAc, and concentrate in vacuo. Pass through a short plug of silica gel by levigating with hexane / EtOAc (1: 1) to provide 2-methoxycarbonyl-3-methylpyridine as a pale yellow liquid (630 mg, 57%). To a solution of 2-methoxycarbonyl-3-methylpyridine in anhydrous THF (10 mL) at 0 ° C is added with a stirred solution of 1M lithium aluminum hydride in THF (5 mL, 5 mmol), and stirring is continued for 30 min at 0 ° C. Allow the mixture to warm to room temperature and quench carefully with 0.5M aqueous NaOH. The mixture is heated at 60 ° C for 40 min, cooled to room temperature, extracted with EtOAc, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (4: 3) to give the desired intermediate (90 mg, 18%). 2-Chloromethyl-3-methylpyridine hydrochloride: A 2-hydroxymethyl-3-methylpyridine (90 mg, 0.73 mmol) in dry DCM (10 mL) at room temperature is added with stirred thionyl chloride (0.53 mL, 7.3 mmol) . The mixture is stirred overnight, concentrated in vacuo, and azeotroped three times with chloroform. The residue is triturated with dry ether, filtered, and dried under vacuum to obtain the title compound as a beige solid (130 mg, 100%).

Preparation 188 2-Chloromethyl-6-methylpyridine It is added with a stirred solution of thionyl chloride (0.77 mL, 10.6 mmol) in dry DCM (20 mL) to 2-hydroxymethyl-6-methylpyridine (1.0 g, 8.12 mmol) in DCM. dry (20 mL) at 0 ° C. Stirring is continued at 0 ° C for 1. 25 h. Quench with isopropanol and concentrate in vacuo.

The residue is dissolved in DCM, washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound. EM (ES +) m / z 142 (M + H) +.

Preparation 189 5-Butyl-2-chloromethylpyridine hydrochloride A similar method is used for preparation 187, using fusaric acid, to give the title compound. MS (APCI +) m / z 184 (M + H) +.

PREPARATION 190 6-Bromomethylnilotinonitrile A similar method is used for preparation 184, using 5-cyano-2-methylpyridine, to give the title compound.

Preparation 191 5-Bromomethyl-pyridine-2-carbonitrile A similar method is used for preparation 184, using 5-methyl-picolinonitrile (J. Chem. Soc. 1962, 2637-2658), to give the title compound.

Preparation 192 2-Chloromethyl-3-trifluoromethylpyridine hydrochloride The chlorination method described in Preparation 187 is used, using 2-hydroxymethyl-3-trifluoromethylpyridine, to give the title compound. MS (APCI +) m / z 196 (M + H) 0 Preparation 193 2-Chloromethyl-3-methoxypyridine 2-Hydroxymethyl-3-methoxypyridine: A mixture of 3-hydroxypicolinic acid (5.3 g, 38 mmol), potassium carbonate (15.8 g, 114 mmol), and iodomethane (9.6 mL, 153 mmol) in acetone (100 mL) is heated. ) and DMF (10 mL) overnight at 60 ° C. The reaction mixture is cooled to room temperature, it is drained in brine, extracted three times with ethyl ether, dried over anhydrous MgSO 4 and concentrated in vacuo. Pass through a short plug of silica gel levigating with ether to provide 3-methoxy-2-methoxycarbonylpyridine as a pale yellow liquid (6.3 g, 100%). To a solution of 3-methoxy-2-methoxycarbonyl-pyridine (2.34 g, 14.0 mmol) in dry THF (25 L) is added slowly with a stirred solution of 1M lithium aluminum hydride in THF (10 mL, 10 mmol) and stirring is continued overnight at room temperature. It is carefully quenched with sodium sulphate decahydrate, filtered under suction and the solids are rinsed with additional THF. Concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (3: 1) to provide the desired intermediate as a white solid (350 mg, 18%). 2-Chloromethyl-3-methoxypyridine: A similar method is used for preparation 188, using 2-hydroxymethyl-3-methoxypyridine, to give the title compound. MS (APCI +) m / z 158 (M + H) +.

Preparation 194 2-Chloromethyl-6-methoxypyridine hydrochloride 2-Hydroxymethyl-6-methoxypyridine: To 6-methoxy-pyridine-2-carbaldehyde (J. Org. Chem. 1990, 55, 69-73) (11.0 g, 80.3 mmol) in moist THF (200 mL) is added in portions with stirring sodium borohydride (3.0 g, 79mmol) and stirring is continued for 1 h at room temperature. Brine is added, the reaction mixture is extracted twice with EtOAc, the organic layer is dried over anhydrous Na 2 SO and concentrated in vacuo. Pass the residue through a small plug of silica gel by levigating with hexane / EtOAc (3: 1) to provide the desired intermediate as a clear liquid (9.0 g, 81%). 2-Chloromethyl-6-methoxypyridine hydrochloride: The chlorination method described in Preparation 187 is used, using 2-hydroxymethyl-6-methoxypyridine, to give the title compound as a pale yellow solid. MS (APCI +) m / z 158 (M + H) +.

Preparation 195 3-Bromomethyl-6-chloro-pyridazine A similar method is used for preparation 184, using 3-chloro-6-methylpyridazine, to give the title compound as a red-orange liquid that darkens upon standing.

Preparations 196 (+) -2- (1-Chloroethyl) -3-cyanothiophene 2-Asethyl-3-sianothiophene: A stirred solution of 2-acetyl-3-bromothiophene (1.49 g, 7.29 mmol) (Chem. Pharm. Bull. 2000, 48, 1558-1566) in dry NMP (72 mL) is heated. for 10 h at 150 ° C in the presence of copper cyanide (3.26 g, 36.5 mmol). The mixture is diluted with water, extracted three times with diethyl ether, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (10: 1) to give the desired intermediate as a dark oil (1.1 g, 99%). (±) -2- (1-Hydroxyethyl) -3-sianothiophene: A method similar to the reduction procedure described in Preparation 194 is used, using 2-acetyl-3-cyanothiophene, to give the desired intermediate as a dark oil. (±) -2- (1-Chloroethyl) -3-sianothiophene: A similar method is used for preparation 188, using (±) -2- (1-hydroxyethyl) -3-cyanothiophene, to give the title compound as a dark oil. The crude material is used without further purification.

Preparation 197 (+) -2- (1-Bromoethyl) -pyridine At (±) -2- (1-hydroxyethyl) -pyridine (Bull. Chem. Soc.

Jpn. 1990, 63, 461-465) (10.0 g, 81.3 mmol) in DCM (120 mL) a 0 ° C, triphenylphosphine (22.39 g, 85.365 mmol) is added with stirring followed by NBS (15.2 g, 85.4 mmol) in portions. The reaction mixture is heated to room temperature and stirring is continued for 3 h. Concentrate in vacuo and purify by chromatography on silica gel by levigating with hexane / EtOAc (19: 1) to give the title compound.

Preparation 198 (±) -2- (1-Chloroethyl) -6-methylpyridine hydrochloride (±) -2- (1-Hydroxyethyl) -6-methylpyridine: To 6-methylpyridine-2-carboxaldehyde (2.0 g, 16.5 mmol) in dry THF (55 mL) at 0 ° C under nitrogen, a solution of 3M Methyl magnesium bromide in ether (6.0 mL, 18.0 mmol) dropwise with stirring. After 1 h at 0 ° C, quench with saturated aqueous NH 4 Cl, extract three times with EtOAc, dry over anhydrous Na 2 SO 4 and concentrate in vacuo to give the desired intermediate (crude, 2.3 g). (±) -2- (1-Chloroethyl) -6-methylpyridine hydrochloride: A crude 2- (1-hydroxyethyl) -6-methylpyridine (1.6 g, 11.7 mmol) in dry DCM (15 mL) is added with stirring Thionyl chloride (2.0 mL, 27 mmol) and continue stirring overnight. Concentrate in vacuo, azeotrope three times with dry chloroform and dry under high vacuum to give the title compound as a brown solid (1.9 g, 85%). MS (APCI +) m / z 156 (M + H) +.

Preparation 199 Ester of (R) -Metanesulfonic acid 1- (6-methyl-pyridin-2-yl) -ethyl ester (±) -1- (6-Me-pyridin-2-yl) -ethanol: A similar method is used for preparation 198 (Step 1), using 6-methyl-2-pyridinecarboxaldehyde and methylmagnesium bromide, to give the desired intermediary.

(R) -1- (6-Methyl-pyridin-2-yl) -ethanol: A mixture of 1- (6-methyl-pyridin-2-yl) -ethanol (2.9 g, 21 mmol), dry powder is stirred. 4A molecular sieve (3 g), vinyl acetate (6 mL) and lipase acrylic resin from Candida Antartica (0.87 g) in i-Pr20 (40 mL) at room temperature overnight (J. Org. Chem. 1998, 63, 2481-2487; Synlett 1999, 41-44). The solid residue is removed by filtration. The volatiles were evaporated and purified by chromatography by levigating with hexane / EtOAc (7: 3 to 1: 1) to give the quick levigating ester of 1- (6-methyl-pyridin-2-yl) -ethyl acid ester (R ) -acetic (1.9 g, 50%), and the (S) -alcohol is eluted slower as a light yellow oil (1.258 g, 43%). The ester of (R) -acetic acid 1- (6-methyl-pyridin-2-yl) -ethyl ester (1.72 g, 9.62 mmol) is dissolved in methanol (50 mL) and potassium carbonate (5.3 g, 38.5 mmol) in water (10 mL). The mixture is stirred at room temperature for 4 h. Dilute with brine, extract three times with EtOAc, dry over anhydrous Na2SO4, filter through a short pad of silica gel and concentrate in vacuo to give the desired intermediate as a colorless oil (1.17 g, 89% ). 1- (6-Methyl-pyridin-2-yl) -ethyl ester of the (R) -Metansulfoniso ester: To a stirred solution of (R) -1- (6-methyl-pyridin-2-yl) -ethanol ( 175 mg, 1.28 mmol) and triethylamine (355 μL, 2.56 mmol) in DCM (5 mL) at 0 ° C was added methanesulfonyl chloride (148 μL, 1.92 mmol). It is stirred at 0 ° C for 30 minutes and the reaction mixture is quenched with saturated aqueous NaHCO 3 at the same temperature. The mixture is extracted three times with EtOAc, dried over anhydrous Na 2 SO and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (8: 2) to give the title compound as a colorless oil (274 mg, 100%).

Preparations 200 (±) -2- (1-Bromoethyl) -3-methyl-pyridine (±) -1- (3-Methyl-pyridin-2-yl) -ethanol: N, N-dimethylethanolamine (70.45 mmol) is dissolved in hexane (90 mL) at 0 ° C, 2.5M n-butyl lithium is added. in hexane (140.9 mmol,) and stirred for 30 minutes at this temperature. A solution of 3-picoline (35.23 mmol) in hexane is added (10 mL) and continue stirring at 0 ° C for 1 h. The resulting mixture is cooled to -78 ° C, acetaldehyde (70.45 mmol) is added and stirring is continued at -78 ° C for 1 h. It is diluted with water, warmed to room temperature, extracted three times with EtOAc, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. Purify by chromatography by levigating with hexane / EtOAc (85:15) to give the desired intermediate as a light yellow oil. (±) -2- (1-Bromoethyl) -3-methyl-pyridine: A similar method is used for preparation 197, using 1- (3-fluoro-pyridin-2-yl) -ethanol, to give the compound of Title.

Preparation 201 (±) -2- [1-Methanesulfonyloxy- (2, 2, 2-trifluoroethyl)] pyridine (±) -2- [1-Hydroxy- (2, 2,2-trifluoro-yl)] -pyridine: To a stirred solution of 2-pyridine carboxaldehyde (2.09 g, 19.5 mmol) and (trifluoromethyl) tri-ethylsilane (3.33 g , 23.4 mmol) in THF (30 mL) at 0 ° C is added 1M tetrabutylammonium fluoride in THF (956 μL, 0.956 mmol). Stirring is continued for 30 min at 0 ° C and then at room temperature for 2 h. Aqueous 1M HCl (20 mL) is added and the mixture is stirred at room temperature for 2 h. Dilute with 1M aqueous NaOH to pH 8, extract the mixture three times with EtOAc, dry over anhydrous Na 2 SO 4, and concentrate in vacuo. Purify by chromatography by levigating with hexane / EtOAc (8: 2) to give the desired intermediate as a yellow oil (3.22 g, 93%). (±) -2- [1-Methanesulfonyloxy- (2,2,2-trifluoroethyl)] pyridine: A similar method is used for preparation 199 (Step 3), using (±) -2- [1-hydroxy- ( 2, 2, 2-trifluoroethyl)] pyridine, to give the title compound.

Preparation 202 (+) -2- (1-Bromopropyl) pyridine (±) -l-Pyridin-2-yl-propan-l-ol: To a stirred solution of 2-pyridine carboxaldehyde (4.0 g, 37.34 mmol) in THF (50 L) at 0 ° C, ethyl bromide is added 3M magnesium in ether (18.7 mL, 56.0 mmol), stirring is continued for 30 min at 0 ° C and then at room temperature for 2 h. Water (200 mL) is added, extracted three times with EtOAc, dried over anhydrous Na2SO4, filtered through a short pad of silica gel and concentrated in vacuo to give the desired intermediate as a yellow oil (3.39 g. , 66%). (±) -2- (1-Bromopropyl) pyridine: A similar method is used for preparation 197, using l-pyridin-2-yl-propan-1-ol, to give the title compound.

Preparations 203 (±) -l-Pyridazin-3-yl-ethanol 3- (1-Ethoxyvinyl) pyridazine: Pyridazine-3 chloride (WO 0107416) (2 g, 17.5 mmol) is heated with tributyl- (1-ethoxyvinyl) tin (7.1 mL, 21.1 mmol) and dichlorobis (triphenylphosphine) palladium ( II) (1.1 g, 1.6 mmol) in DMF (18 mL) at 110 ° C for 13 h. The mixture is cooled, diluted with ether (175 mL) and a solution of potassium fluoride (5.43 g, 94 mmol) in water (10 mL) is added. After 1 h, the mixture is filtered through Celite®, and the filtrate is washed with brine. The combined organic extracts are dried over Na 2 SO and evaporated. Purification by chromatography on silica gel by levigating with EtOAc: hexane (0: 1 to 6: 4) to obtain the desired intermediate (1.7 g, 65%). CLAR tR = 3.7 min (Zorbax Eclipse XBD-C8 4.6 x 150 mm, 5 micron column, 1.5 mL / min from 90/10 to 10/90 0.1% TFA in water / acetonitrile for 10 min. Detector is at 230 and 254 nm.). l-Pyridazin-3-yl-ethanone: 3- (1-Ethoxyvinyl) pyridazine (1.7 g, 11.3 mmol) is stirred in acetone (6.3 mL) and 2.5 N aqueous HCl (3.1 mL) for 2 h at room temperature and evaporated. . The residue is dissolved in DCM and the organic layer is washed with saturated aqueous NaHCO3, the organic layer is dried over Na2SO4 and evaporated to obtain the desired intermediate (1.4 g, 99%). CLAR tR = 1.9 min (Zorbax Eclipse XBD-C8 4.6 x 150 mm, 5 micron column, 1.5 mL / min 90/10 to 10/90 0.1% TFA in water / acetonitrile for 10 min. The detectors at 230 and 254 nm.). (±) -l-Pyridazin-3-yl-ethanol: To l-Pyridazin-3-yl-ethanone (1.4 g, 11.2 mmol) in methanol (112 mL) is added sodium borohydride (0.85 g, 22.5 mmol) at 0 ° C and stirred for 1 h at room temperature. The mixture is evaporated and purified by chromatography on silica gel by levigating with EtOAc: hexane (1: 1 to 1: 0) and methanol: EtOAc (0: 1 to 1: 9) to obtain the title compound (1.3 g, 93%).

Preparation 204 Methanesulfonate ester of (R) - (-) -1- (2-pyridinyl) ethanol (R) -1- (Pyridin-2-yl) -ethanol: A mixture of (±) -l- (pyridin-2-yl) -ethanol (21.2 mmol), molecular sieve powder 4A (3 g) is stirred. , vinyl acetate (6 mL) and Candida Antartica lipase acrylic resin (0.87 g) in i-Pr20 (40 mL) at room temperature overnight (J. Org. Chem. 1998, 63, 2481-2487; Synlett 1999 , 41-44). The solid residue is removed by filtration. The volatiles were evaporated and purified by chromatography by levigating with hexane / EtOAc (7: 3 to 1: 1) to give the quick levigant ester of (R) -acetic acid 1- (pyridin-2-yl) -ethyl ester as colorless oil (50%) and eluting slower (S) -alcohol as a light yellow oil (43%). Ester of 1- (pyridin-2-yl) -ethyl acid of (R) -acetic acid (9.620 mmol) is dissolved in methanol (50 mL) and potassium carbonate (38.48 mmol) in water (10 mL) is added. The mixture is stirred at room temperature for 4 h. It is diluted with brine, extracted three times with EtOAc, dried over anhydrous Na2SO, filtered through a short pad of silica gel and concentrated in vacuo to give the desired intermediate as a colorless oil (89%).

Methanesulfonate ester of (R) - (-) -1- (2-Pyridinyl) ethanol: To a stirred solution of (R) -1- (pyridin-2-yl) -ethanol (1.28 mmol) and triethylamine (2.56 mmol) ) in methanesulfonyl chloride (1.92 mmol) in DCM (5 mL) at 0 ° C. It is stirred at 0 ° C for 30 minutes and the reaction mixture is quenched with saturated aqueous NaHCO 3 at the same temperature. Extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to give the title compound as a colorless oil (100%). MS (APCI +) m / z 202 (M + H) +; [a] D25 = -73.5 ° (c 1, CHC13).

Preparation 205 (±) -1- (4-Fluorophenyl) ethyl bromide Method A: Carbon tetrabromide (646 mg, 1.95 mmol) is added to a solution of triphenylphosphine (511 mg, 1.95 mmol) and (+) -4-fluoro-a-methylbenzyl alcohol (260 mg, 1.86 mol) in dry DMF. (20 mL) at 0 ° C under nitrogen. The reaction is stirred for 2 h to give the title compound. No additional purification is required.

Method B: HBr (460 μL of 48% v / v in water, 4.28 mmol) is added to a solution of (+) -4-fluoro-a-methylbenzyl alcohol (300 mg, 2.14 mmol) in dry DCM (10 mL) at room temperature under a nitrogen atmosphere. It is stirred during 2. 5 h. The volume is reduced in vacuo to give the title compound. It is diluted with DCM (1 mL) and used without further purification.

Preparation 206 (+) -2- (1-Bromoethyl) benzonitrile A similar method is used for preparation 184, using 2-ethylbenzonitrile, to give the title compound as a clear liquid.

Preparation 207 1- (4-Bromomethylphenyl) -3,3-dimethylbutan-1-one (±) -3, 3-Dimethyl-lp-toluylbutan-l-ol: To a stirred solution of 4-methylbenzaldehyde (1.51 g, 12.6 mmol) in THF (30 mL) at 0 ° C, neopentyl magnesium chloride is added (33.0 mL, 16.34 mmol, 0.5-1M in ether) and continue stirring at 0 ° C for 1 h. Dilute with saturated aqueous NHC1, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (95: 5) to give the desired intermediate as a colorless oil (2.15 g, 89%). 3, 3-Dimethyl-l-p-toluyl-butan-l-one: To a stirred solution of (±) -3,3-dimethyl-lp-toluyl-butan-l-ol (2.15 g, 11.3 mmol) in hexane (30 mL) is added manganese dioxide (2.94 g, 33.8 mmol) and the mixture is heated during the night at 65 ° C. Cool to room temperature, filter the manganese salts, and concentrate in vacuo to give the desired intermediate as a colorless oil (2.2 g, 100%). 1- (4-Bromomethylphenyl) -3,3-dimethylbutan-1-one: A similar method is used for preparation 184, using 3, 3-dimethyl-1-p-toluylbutan-1-one, to give the title compound.

Preparation 208 1- (4-Bromomethylphenoxy) -3,3-dimethylbutan-2-one 1- (4-Hydroxymethylphenoxy) -3,3-dimethylbutan-2-one: Mix potassium carbonate (2764 g, 20 mmol), 4-hydroxy-benzyl alcohol (1.49 g, 12 mmol) in absolute ethanol (100 mL). ), 1-bromopinacolone (1791 g, 10 mmol) is added dropwise. The mixture is heated under reflux for 12 h. Water is added to dissolve the solid, and further stir the ethanol in vacuo. The mixture is extracted with EtOAc three times. The combined organic layers are washed with brine, dried over Na 2 SO 4, filtered and concentrated. The residue is purified by chromatography on silica gel by levigating with EtOAc: hexane (1: 2) to provide the desired intermediate as a colorless oil (1.08 g, 48%). MS (ES +) m / z: 205 (M + H-H20) +. 1- (4-bromome-1-phenoxy) -3,3-dimethylbutan-2-one: Phosphorus tribromide (1.45 g, 5.34 mmol) is added slowly to a solution of 1- (4-hydroxymethyl-phenoxy) -3, 3- dimethylbutan-2-one (1.08 g, 4.85 mmol) in anhydrous THF under nitrogen at 0 ° C. It is stirred at 0 ° C for 1 h and then rinsed at room temperature. It is stirred overnight. Dilute with EtOAc, wash with saturated aqueous NaHCO3, brine, dry over Na2SO4, filter and concentrate. The residue was purified by chromatography on silica gel by levigating with EtOAc: hexane (1: 6) to give the title compound (1152 g, 83%). MS (ES +) m / z: 205 (M-Br) +.

Preparation 209 1- (4-Bromomethyl-3-chlorophenoxy) -3,3-dimethylbutan-2-one Alsohol 3 ~ Chloro-4-hydroxybenzylx: A solution of DIBAL-H in toluene (1.0 M, 35 mL) to a solution of methyl 3-chloro-4-hydroxybenzoate (1.9 g, 10 mmol) at 0 ° C under nitrogen. The reaction is stirred at 0 ° C and gradually warmed to room temperature overnight. The reaction is quenched with slow addition of 0. HCl aqueous. More acid is added to break the gel-like solid into two clear layers. The organic layer was separated, and the aqueous layer was extracted with EtOAc three times. The organic layers are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated to give a white solid. MS (ES-) m / z 157 (M-H). " 1- (4-Bromomethyl-3-slorophenoxy) -3,3-dimethyl-butan-2-one: A similar method is used for preparation 208 to convert 3-chloro-4-hydroxy-benzyl alcohol to the title compound ( 1,144 g, 64% two stages). MS (ES +) m / z 319.0 (M + H) +.

Preparation 210 l-Bromomethyl-4- (2,2-dimethyl-propoxy) -benzene 1- (2, 2-Dimethyl-propoxy) -4-methyl-bensen: To a solution of p-cresol (526 mg, 4.87 mmol) in THF (50 mL), diisopropyl azodicarboxylate (2.16 mL, 10.7 g) is added with stirring. mmol) followed by triphenylphosphine (306 mg, 11.7 mmol) and neopentyl alcohol (5.15 g, 58.4 mmol). Heat at 60 ° C for 3 h, cool to room temperature and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc to give the desired intermediate as a colorless oil. l-Bromomethyl-4- (2, 2-dxmethyl-propoxy) -bensen: A similar method is used for preparation 184, using l- (2,2-dimethyl-propoxy) -4-methylbenzene, to give the compound of Title. Preparation 211 l-Bromomethyl-2-methanesulfonylbenzene (2-Methanesulfonylphenyl) methanol: To a stirred solution of 2-methanesulfonyl-benzoic acid (2.7 g, 13.5 mmol) in dry THF (60 mL) at 0 ° C, add a solution of borane in THF (27.0 mL, 0.5 M, 13.5 mmol). The mixture is allowed to warm to room temperature and stirring is continued for 2 days.

The excess borane is quenched by the slow addition of methanol, brine is added, extracted three times with EtOAc, dried over anhydrous Na 2 SO 4 and concentrated in vacuo to provide the desired crude intermediate as a clear, thick oil (2.4 g, 97%). l-Bromomethyl-2-methanesulfonylbensen: To a stirred solution of (2-methanesulfonyl-phenyl) methanol (735 mg, 3.99 mmol) in dry DCM (2 mL) at 0 ° C, a solution of 1M phosphorus tribromide in DCM (6.0 mL, 6.0 mmol) is added and stirring is continued for 1 h. Dilute with saturated aqueous NaHCO3, extract three times with ethyl ether, dry over anhydrous MgSO4 and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (12: 1) to give the title compound as a white solid (950 mg, 97%).

Preparation 212 l-Bromomethyl-4- (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio) benzene 3,3,3-Trifluoro-2-methyl-2-trifluoromethyl-propyl ester of methanesulfoniso acid: Al 2, 2-bis (trifluoromethyl) propanol (4.34 g, 22.1 mmol) in DCM (100 mL) at 0 ° C is added with stirred triethylamine (6.2 mL, 44 mmol) followed by methanesulfonyl chloride (2.6 mL, 33 mmol) . After 15 min at 0 ° C it is diluted with water and extracted three times with EtOAc. Dry over anhydrous Na2SO and concentrate in vacuo to give the crude desired intermediate as a yellow oil (6.16 g, 100%). l-Methyl-4- (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio) bensen: In a sealed tube, 4-methylbenzenethiol (4.13 g, 33.2 mmol) is dissolved in DMF (20 mL) at room temperature. . It is added in portions with stirred sodium hydride (899 mg, 37.5 mmol) followed by tetrabutylammonium iodide (82 mg, 0.22 mmol) and a solution of 3,3,3-trifluoro-2-methyl-2-trifluoromethyl-propyl methanesulfonic acid (6.16 g, 22.5 mmol) in DMF (10 mL). Stir at 150 ° C overnight, mix cold at room temperature and dilute carefully with water. Extract three times with EtOAc, dry over anhydrous Na 2 SO, and concentrate in vacuo.

Purification by chromatography on silica gel by levigating with hexane to give the desired intermediate as a yellow oil (4.5 g, 62%). l-Bromomethyl-4- (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio) bensen: A similar method is used for preparation 184, using l-methyl-4- (3, 3, 3-trifluoro) -2-methyl-2-trifluoromethylpropylthio) benzene, to give the title compound.

Preparation 213 l-Bromomethyl-4- (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl) -benzene l-Methyl-4- (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl) -bensen: Al 1-methyl-4- (3, 3, 3-trifluoro-2-methyl- 2-trifluoromethylpropylthio) benzene (4.5 g, 14.9 mmol) in acetic acid (15 mL) at room temperature, stirring with aqueous hydrogen peroxide (15 mL, 30% in water) and stirring for 1 h. The reaction is diluted with water, extracted three times with EtOAc, dried over anhydrous Na 2 SO 4, and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the desired intermediate as a colorless oil (4.125 g, 88%). l-Bromomethyl-4- (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl) -bensen: at 1-methyl-4- (3,3,3-trifluoro-2-methyl) 2-trifluoromethylpropane-1-sulfinyl) -benzene (4.13 g, 13.0 mmol) in carbon tetrachloride (50 mL) is added NBS (2.31 g, 13.0 mmol), benzoyl peroxide (314 mg, 1.30 mmol) and stirred for the night at reflux. It is cooled to room temperature, diluted with water and extracted three times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the title compound as a colorless oil (2.3 g, 55%).

Preparation 214 l-Bromomethyl-4- (2,2-dimethylpropane-l-sulfonyl) -enol 1- (2, 2-Dimethyl-propane-l-sulfonyl) -4-me-il-bensen: In a sealed tube, sodium salt of p-toluensulfinic acid (5.71 g, 32.1 mmol) is dissolved in DMF (20 L ) and water (10 mL). Neo-pentyl bromide (6.3 mL, 48 mmol) and tetrabutylammonium iodide (592 mg, 1.60 mmol) are added and the mixture is heated at 145 ° C overnight. The reaction is cooled to room temperature, diluted with water and extracted 3 times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the desired intermediate as a colorless oil (3.3 g, 45 g. %) l-Bromomethyl-4- (2,2-dimethylpropane-1-sulfonyl) bensen: A similar method is used for preparation 213 (Step 2), using 1- (2,2-dimethylpropane-1-sulfonyl) -4- methyl benzene, to give the title compound.

Preparation 215 l-Bromomethyl-4- (3, 3, 3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfonyl) -benzene l-Methyl-4- (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfonyl) bensen: Al 1-methyl-4- (3, 3, 3-trifluoro-2-methyl-2) -trifluoromethylpropylthio) benzene (3.47 g, 11.49 mmol) in trifluoroacetic acid (15 mL) at room temperature is added with stirred aqueous hydrogen peroxide (15 L, 30% in water) and stirred for 1 h. After removing the trifluoroacetic acid in vacuo, it is diluted with saturated aqueous NaHC03. Extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the desired intermediate as a colorless oil (2.8 g, 74%). l-Bromomethyl-4- (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfonyl) -bensen: A similar method is used for preparation 213 (Step 2), using l-methyl-4 - (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfonyl) benzene to give the title compound.

Preparation 216 l-Bromomethyl-4- (4'-trifluoromethyl) -phenylsulfonylbenzene l-Methyl-4- (4-trifluoromethyl) -phenylthio-bensen: A mixture of 4-methylbenzenethiol (7.67 g, 61.8 mmol), 1-bromo-4-trifluoromethyl-benzene (4.63 g, 20.6 mmol), is heated. , 2,6,6-tetramethyl-3,5-heptanedione (379 mg, 2.06 mmol), cesium carbonate (20.1 g, 61.8 mmol) and CuCl (102 mg, 1.03 mmol) in NMP (30 mL) at 150 ° C for 3 h. The mixture is cooled to room temperature, diluted with water, extracted three times with EtOAc, the organic layer is dried over anhydrous Na2SO4, and concentrated in vacuo. The residue is recrystallized from hexane / EtOAc to give the desired intermediate as a white solid (3.87 g, 70%). l-Bromomethyl-4- (4-trifluoromethyl) -phenylsulfonyl-bensen: A similar method is used for preparation 215, using 1-methyl-4- (4-trifluoromethyl) -phenylthiobenzene, to give the title compound.

Preparation 217 1- (4-Bromomethylbenzenesulfonylmethyl) -2,4-difluorobenzene A similar method is used for preparation 214, using 2,4-difluorobenzyl bromide, to give the title compound.

Preparation 218 l-Bromomethyl-4-cyclohexylmethanesulfonyl-benzene A similar method is used for preparation 214, using cyclohexylmethyl bromide, to give the title compound.

Preparation 219 methyl 4-bromomethyl-2-fluorobenzoate Methyl 2-fluoro-4-methyl-benzoate: L-bromo-2-fluoro-4-methylbenzene (15 g, 79.4 mmol), palladium acetate (712 mg, 3.17 mmol), 1,3-bis ( diphenylphosphino) -propane (2.94 g, 7.14 mmol), triethylamine (16.1 g, 159 mmol) in methanol (150 mL) and DMF (100 mL). The mixture is degassed under vacuum and pressurized to 65 psi with carbon monoxide. The reaction is stirred at 110 ° C for 2 days. The methanol is removed in vacuo, the mixture is diluted with water, and extracted three times with EtOAc. Dry over anhydrous Na 2 SO and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the desired intermediate as a white solid (7.40 g, 55%).

Methyl 4-bromomethyl-2-fluoro-benzoate: A similar method is used for preparation 184, using methyl 2-fluoro-4-methylbenzoate, to give the title compound as a white solid.

Preparation 220 4-Chloromethyl-N-cyclohexylbenzamide To 4-chloromethylbenzoyl chloride (1.03 g, 5.47 mmol) in DCM (20 mL) at 0 ° C, is added with stirred triethylamine (0.839 mL, 6.02 mmol) followed by cyclohexylamine (0.688 mL, 6. 02 mmol), and stirring is continued for 15 min. The reaction mixture is diluted with aqueous 1M hydrochloric acid, extracted three times with EtOAc, washed with water and saturated aqueous NaHCO3. The combined organic extracts are dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as a white solid (1.31 g, 95%). The compounds of the preparations 221-235 can be prepared essentially as described in Preparation 220 by using 4-chloromethylbenzoyl chloride and the appropriate amine.

Preparation 236 2- (2-iodoethoxy) propane 2-isopropoxyethyl ester of the methanesulfonyl ester: To a stirred solution of 2-isopropoxyethanol (2.0 mL, 17.37 mmol) in DCM (100 mL) at room temperature is added methanesulfonyl chloride (1.48 mL, 18.08 mmol). Triethylamine (2.70 L, 19.37 mmol) is added slowly followed by DMAP (catalytic). The mixture is stirred overnight and concentrated in vacuo. Diethyl ether is added and filtered. The filtrate is washed with aqueous IN HCl, brine, and saturated aqueous NaHCO 3. Dry over anhydrous MgSO 4 and concentrate in vacuo to give the desired intermediate (2.97 g, 94%). 2- (2-iodoethoxy) propane: To a stirred solution of 2-isopropoxy-ethyl ester of methanesulfonic acid (2.95 g, 16.2 mmol) in acetone (200 mL) at room temperature is added sodium iodide (7.28 g, 19.4 g). mmol) and continue stirring overnight. Concentrate in vacuo, add diethyl ether and filter, and concentrate in vacuo to give the title compound as a pale yellow liquid (3.12 g, 90%).

Preparation 237 Tetrahydrofuran-3-yl ester of (R) -Toluene-4- sulfonic acid Al (R) -tetrahydro-furan-3-ol (2.0 g, 22.7 mmol), triethylamine (3.8 mL, 27.3 mmol), DMAP (277 mg, 2.26 mmol), and silver oxide (5.26 g, 22.7 mmol) in Dry DCM (30 mL) at 0 ° C under nitrogen is added in portions with stirred p-toluenesulfonyl chloride (4.76 g, 25.0 mmol). It is warmed to room temperature overnight, filtered from silver salts, and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (7: 1) to give the title compound as a clear liquid (4.7 g, 85%).

Preparation 238 Tetrahydrofuran-3-yl ester of (S) -Toluene-4- sulfonic acid A similar method is used for preparation 237, using (S) -tetrahydro-furan-3-ol, to give the title compound as a clear liquid.

PREPARATION 239 2- (2-Bromoethyl) -pyridine HBr Bromohydrate A method similar to the bromination procedure described in Preparation 186 (Step 2) is used, using 2-pyridineethanol, to give the title compound. It is recrystallized from 2-propanol to give a light brown solid.

Preparation 240 5- (3-Bromopropyl) -3-tert-butyl- [1,2,4] oxadiazole Vinyl ester of the acid 4-Bromobutyrate: To the 4-bromobutyric acid (1.0 g, 6.0 mmol) in vinyl acetate (54 mL) is added with stirred palladium (II) acetate (188 mg, 0.84 mmol) and is continued stirring overnight at room temperature. Filter and concentrate in vacuo to provide the desired crude intermediate. - (3-Bromopropyl) -3-tert-butyl- [1,2,4] oxadiazole: A similar method is used for preparation 178, using 4-bromobutyric acid vinyl ester, to give the title compound.

Preparation 241 l-Bromomethyl-2-fluoro-4-phenoxybenzene 2- (4-Bromo-2-fluoro-bensyloxy) -tetrahydro-pyran: 4-bromo-2-fluorobenzyl alcohol (4.1 g, 20 mmol), dihydropyran (2 g, 24 mmol) is mixed under a nitrogen atmosphere, p-Toluenesulfonic acid monohydrate (100 mg, 0.52 mmol), and anhydrous DCM (70 mL). Stir for 16 h at room temperature. Dilute with DCM, wash sequentially with saturated aqueous NaHC03 then brine. The organic layer is separated, dried over Na 2 SO 4 and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 9: 1) to obtain the desired intermediate as a clear oil (4.36 g, 75%). MS (ES +) m / z: 312 (M + Na) +. 2- (2-Fluoro-4-phenoxy-bensyloxy) -tetrahydro-pyran: is mixed under an atmosphere of argon 2- (4-bromo-2-fluorobenzyloxy) -tetrahydropyran (2.9 g, 10 mmol), phenol (1.9 g) , 20 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (184.3 mg, 1.0 mmol), cesium carbonate (6.5 g, 20 mmol) and anhydrous NMP (20 mL). The flask is degassed and filled with argon. Copper (I) chloride (495 mg, 5 mmol) is added rapidly. The flask is degassed three times then filled with argon. Heat at 120 ° C for 3 h. It is cooled to room temperature. Dilute with EtOAc and filter. Concentrate in vacuo and purify by chromatography on silica gel to obtain the desired intermediate (2.05 g, 68%). MS (ES +) m / z: 325 (M + Na) +. (2-Fluoro-4-phenoxy-phenyl) -methanol: 2- (2-Fluoro-4-phenoxy-benzyloxy) -tetrahydro-pyran (2.05 g, 6.8 mmol), methanol (60 mL) is mixed under nitrogen. and p-toluenesulfonic acid monohydrate (260 mg, 1.35 mmol). Stir at room temperature for 16 h. Dilute with EtOAc. Wash with saturated aqueous NaHCO3. The organic layer is separated, dried over Na 2 SO 4 and concentrated in vacuo to give the desired intermediate (1.41 g, 95%). MS (ES +) m / z: 201 (M-0H) +. l-Bromomethyl-2-fluoro-4-phenoxy-bensen: It is dissolved under a nitrogen atmosphere (2-fluoro-4-phenoxyphenyl) -methanol (1.41 g, 6.5 mmol) in anhydrous THF (60 mL). It is cooled to 0 ° C in an ice bath. Phosphorus tribromide (2.11 g, 7.8 mmol) is added. The mixture is stirred cold for 1 h, then the ice bath is removed and stirred at room temperature for 16 h. The reaction is quenched with saturated aqueous NaHCO3. The aqueous phase is extracted three times with EtOAc. The organic fractions are combined, washed with brine, dried over Na 2 SO and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1). The solvent is evaporated to obtain the title compound (1.31 g, 72%).

Preparation 242 3-tert-butoxycarbonyl-7-chloro-6- (4-hydroxymethyl-benzylthio) 2,3,4,5-tetrahydro-lH-benzo [d] azepine 3-ter-butoxxsarbonil-6- (4-sarboxi-bensxltio) -7-sloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: To a solution of 3-tert-butoxycarbonyl-7- Chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (1.0 g, 2.6 mmol) in methanol (15 mL) under nitrogen, is added with stirred potassium hydroxide (4.5 g, 80.3 mmol) at room temperature. Heat at 55-60 ° C for 2 h, cool to room temperature, and add methyl 4-bromomethylbenzoate (1.2 g, 5.2 mmol). CCD after 20 minutes showed the formation of the product; however, after 4 hours at room temperature both CCD and LC / MS indicated that hydrolysis of the ester and the carbamate is complete. Dilute with saturated aqueous NH4C1, extract three times with EtOAc, dry over anhydrous MgSO4, and concentrate in vacuo. The crude material is dissolved in THF (10 mL), treated with di-tert-butyl-bicarbonate (2 equiv) and saturated aqueous NaHCO 3 (10 mL), and stirred overnight. Extract three times with EtOAc, dry over anhydrous MgSO 4 and concentrate in vacuo to give the desired intermediate as an oil that was used without further purification [2.32 g, 50% purity with (Boc) 20]. EM (ES +) m / z 348 (M + H-Boc) 0. 3-tert-butoxysarbonyl-7-sloro-6- (4-hydroxymethyl-bentylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: To a solution of 3-tert-butoxycarbonyl-6- (4-carboxybenzylthio) -7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (1.85 g, 50% purity, 2.06 mmol) in anhydrous THF (40 mL) under nitrogen, added with borane 1M stirred in THF (4.2 mL) at 0 ° C. Warm to room temperature and stir 2-3 h. It is quenched by the careful addition of water (3 mL), diluted with saturated aqueous NaHCO3, extracted three times with ethyl ether, dried over anhydrous MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (5: 1) to give the title compound as a white solid (485 mg, 54%).

Preparation 243 3-tert-butoxycarbonyl-7-chloro-6- (4-methanesulfonylmethylbenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine 3-tert-butoxysarbonyl-7-sloro-6- (4-me ansulfonyloxyme-bensylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: To a stirred solution of 3-tert-butoxycarbonyl -7-chloro-6- (4-hydroxymethyl-benzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (170 mg, 0.391 mmol) in anhydrous DCM under nitrogen, methanesulfonyl chloride is added (33 μL, 0.426 mmol) and triethylamine (61 μL, 0.44 mmol) and stirring is continued for 2 h. It is diluted with water (5 mL) and extracted three times with DCM. The combined organic extracts are washed with brine, dried over anhydrous Na 2 SO, and concentrated in vacuo to obtain the desired intermediate that was used without further purification. 3-tert-butoxyarbonyl-6- (4-bromomethyl-bensylthio) -7-sloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine: 3-tert-butoxycarbonyl-7-chloro is dissolved -6- (4-methanesulfonyloxymethyl-benzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine crude in anhydrous acetone (3 mL), treated with anhydrous lithium bromide (335 mg, 3.89 mmol ) and continue stirring overnight. Water is added, the reaction mixture is extracted three times with ethyl ether, washed with brine, dried over anhydrous MgSO, and concentrated in vacuo to obtain the desired intermediate which was used without further purification. 3-tert-butoxysarbonyl-7-sloro-6- (4-me ansulfonylmethyl-bensylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: A 3-tert-butoxycarbonyl-6- ( 4-bromomethyl-benzylthio) -7-chloro-2, 3,4,5-tetrahydro-1H-benzo [d] azepine crude in anhydrous DMF (1 mL) under nitrogen, sodium metane sulphinate (400 mg, 3.9 mmol), and stirring is continued for 30 minutes at room temperature followed by 2 h at 40 ° C. Water is added, extracted three times with EtOAc, washed with brine, dried over anhydrous MgSO 4, and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (3: 1) to give a clear oil which solidifies on standing to a white solid (118 mg, 61%).

Preparation 244 6- (4-Bromo-3-fluorobenzylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine l-Bromo-4-bromomethyl-2-fluorobensen: A similar method is used for preparation 184, using 4-bromo-3-fluorotoluene, to give the desired intermediate as a white solid. 6- (4-Bromo-3-fluoro-benzylthio) -3-tert-butoxy-aryl-7-sloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine: A similar method is used for preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and l-bromo-4-bromomethyl-2-fluorobenzene to give the title as a white solid.

Preparations 245 (±) -3-tert-butoxycarbonyl-7-chloro-6- (1-methoxycarbonyl-1-phenyl-methylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine (±) -3-tert-butoxyarbonyl-6- (1-sarboxy-l-phenyl-methylthio) -7-sloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: To a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.23 g, 3.2 mmol) in methanol (20 mL) under nitrogen is added with stirred potassium hydroxide (5.36 g, 95.5 mmol) at room temperature. Heat at 55-60 ° C for 2 h, cool to room temperature, and add methyl-bromophenylacetate (600 μL, 3.81 mmol). After 30 min, dilute with saturated aqueous NHC1, extract three times with EtOAc, dry over anhydrous MgSO, and concentrate in vacuo. The crude material is dissolved in THF (10 mL), treated with di-tert-butyl-bicarbonate (2 equiv) and saturated aqueous NaHCO 3 (10 L), and stirred overnight. Extract three times with EtOAc, dry over anhydrous MgSO 4 and concentrate in vacuo to give the desired intermediate as an oil that was used without purification (1.1 g, 77%). (±) -3-tert-butoxyarbonyl-6- (1-methoxysarbonyl-l-phenyl-methylthio) -7-sloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: A solution is treated of 3-tert-butoxycarbonyl-6- (1-carboxy-l-phenyl-methylthio) -7-chloro-2, 3,4,5-tetrahydrobenzo [d] azepine (200 mg, 0.447 mmol) in anhydrous DMF (2 mL) with methyl iodide (317 mg, 2.237 mmol) and potassium carbonate (310 mg, 2.237 mmol) for 1.5 h at room temperature. Water is added and the aqueous phase is extracted three times with EtOAc. The organic phase is dried over MgSO4 and concentrated to obtain the title compound which was used without further purification.

Preparation 246 6- (3-Bromo-4-chloro-benzylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine 2-Bromo-4-bromomethyl-1-sloro-bensen: A similar method is used for preparation 184, using 3-bromo-4-chlorotoluene, to give the desired intermediate. 6- (3-Bromo-4-sloro-bensylthio) -3-tert-butoxyarbonyl-7-sloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine: A similar method is used for the preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylsulfanyl-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and 2-bromo-4-bromomethyl-1-chloro-benzene, give the title compound.

Preparation 247 3-tert-butoxycarbonyl-6- (5-carboxy-pyridin-2-ylmethylthio) -7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine 3-tert-butoxysarbonyl-7-sloro-6- (5-me-oxisarbonyl-pyridin-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 3-tert-butoxycarbonyl is dissolved -6- (5-Bromopyridin-2-ylmethylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (2.13 g, 4.40 mmol), palladium acetate (35 mg, 0.156) mmol), 1,1'-bis (diphenylphosphino) ferrocene (150 mg, 0.271 mmol) and triethylamine (1.30 mL) in methanol (10 mL) and DMF (5 mL). It is degassed and then heated under a balloon filled with carbon monoxide at 75 ° C for 10 h. The methanol is removed in vacuo, and the mixture is diluted with water. Extract three times with EtOAc, dry over anhydrous Na 2 SO, and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (7: 1) to give the desired intermediate as a clear oil (1.86 g, 91%). MS (APCI +) m / z 463 (M + H) +, 363 (M + H-Boc) +. 3-tert-butoxyarbonyl-6- (5-sarboxy-pyridin-2-ylmethylthio) -7-sloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: 3-tert-butoxycarbonyl- is dissolved 7-Chloro-6- (5-methoxycarbonyl-pyridin-2-ylmethylthio) -chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.86 g, 4.03 mmol) in methanol (25 mL). 1M aqueous lithium hydroxide (12 mL) is added and stirred at room temperature overnight. Methanol is removed in vacuo, and the mixture is diluted with cold aqueous 0.5M HCl to pH 4. Brine is added and extracted three times with EtOAc. Dry over anhydrous Na2SO, and concentrate in vacuo to give the title compound as an opaque white solid (1.78 g, 95%). -EM (APCI +) m / z 449 (M + H) +, 349 (M + H-Boc) +.

Preparation 248 6- (4-Bromo-thiophen-2-ylmethylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine 3-Bromo-5-bromomethyl -thiophene: The bromination procedure described in Preparation 211 (Step 2) is used, using (3-bromothiophen-2-yl) methanol (Synthesis 1983, 1, 73-75), to give the desired intermediate as a brown liquid. Clear. 6- (4-Bromo-thiophen-2-ylmethylthio) -3-tert-butoxyarbonyl-7-sloro-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine: A similar method is used for the preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 3-bromo-5-bromomethyl-thiophene, to give the title as a rubber.

Example 315 7-Chloro-6- (2-isopropoxyethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride To a 4: 1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 3-tert-butoxycarbonyl-7,9-dichloro -6-dimethylcarbamoylthio-2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (200 mg, 0.52 mmol) in methanol (5 mL) under nitrogen, add potassium hydroxide (0.9 g, 16.1 mmol) at room temperature. When the mixture became homogeneous, it was heated at 55-60 ° C for 2-3 h, until the CCD showed the disappearance of the starting material. It is cooled to room temperature, saturated aqueous ammonium chloride is added, it is extracted three times with diethyl ether, dried over anhydrous MgSO, and concentrated in vacuo. The crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-lH-benzo [d] azepine is dissolved in anhydrous THF (5 mL) under nitrogen and added with t- 1.0 M potassium butoxide stirred in THF (1.0 mL) at room temperature. After 10 min, 2- (2-iodoethoxy) propane (223 mg, 1.04 mmol) is added, and the reaction is allowed to continue overnight. Dilute with saturated aqueous ammonium chloride, extract the mixture three times with diethyl ether, dry over anhydrous MgSO 4, and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (12: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (2-isopropoxy-ethylthio) -2, 3,, 5-tetrahydro-1H- benzo [d] azepine as a clear oil (127 mg, 63%). A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (ES +) m / z: 300 (M + H) +.

Example 316 (+) - 7-Chloro-6- (l-pyridin-2-yl-ethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to general procedure 7 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and (±) -2- ( l-bromoethyl) -pyridine to give, after deprotection by a method similar to general procedure 1-4, the title compound as a white solid. MS (APCI +) m / z: 319 (M + H) +.

Example 317 Succinate of (-) - 7-Chloro-6- (l-pyridin-2-yl-ethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine The enantiomers were separated. of (±) -7-chloro-6- (1-pyridin-2-yl-ethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine by chiral normal phase chromatography (Chiralpak column AD 8x30 cm, levigating with 0.2% DMEA in methanol). The second isomer is taken by levigating and purified by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (100: 1 to 80:20). The general procedure 2-1 is used to give the title compound as a white solid (4.27 g, 33%). MS (ES +) m / z: 319 (M + H) +; ee = 99.4%; [a] 20D -179 ° (c 0.5, CH 3 OH).

Example 318 (-) - 7-Chloro-6- (l-pyridin-2-yl-ethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to general procedure 7 is used, except that the alkylation is carried out at 0 ° C, to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro- lH-benzo [d] azepine with (R) - (-) -1- (2-pyridinyl) ethanol methanesulfonate ester. A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (APCI +) m / z: 319 (M + H) +; ee = 98.6% [Chiral HPLC: Chiralpak AD-H column 0.46x15 cm, levigating with 15:85 ethanol / heptane].

Example 319 (±) -7-Chloro-6- [1- (6-methylpyridin-2-yl) -ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 315 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and (±) -2- hydrochloride (l-chloroethyl) -6-methylpyridine to give, after deprotection by a method similar to general procedure 1-4, the title compound as a brown solid. MS (ES +) m / z: 333 (M + H) +.

EXAMPLE 320 7-Chloro-6- [1- (6-methylpyridin-2-yl) -ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride, Isomer 1 A similar method is used for preparation 177, except that the alkylation is carried out at 0 ° C, to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3, 4, 5-tetrahydro- lH-benzo [d] azepine with (R) -metanesulfonic acid 1- (6-methyl-pyridin-2-yl) -ethyl ester. A method similar to general procedure 1-5, basic preparation, and a method similar to general procedure 2-2 is used to give the title compound as a white solid. MS (APCI +) m / z: 333 (M + H) +; ee > 97%, tR = 6.53 min. (Chiral HPLC: Chiralpak OJ 120A 4.6x250 mm, 45 ° C, levigant: 20% isopropanol with 0.05% triethylamine in CFS, flow ratio 2 mL / min, UV detector at 234 nm).

Example 321 (±) -7-Chloro-6- [1- (3-methylpyridin-2-yl) -ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A similar method is used for preparation 177 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine with (±) -2- (1-bromoethyl) -3-methyl-pyridine. A method similar to general procedure 1-5, basic preparation, and a method similar to general procedure 2-2 is used to give the title compound as a white solid. MS (APCI +) m / z: 333 (M + H) +.

Example 322 (-) - 7-Chloro-6- [1- (3-methylpyridin-2-yl) ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride The enantiomers of (±) -7-chloro- [1- (3-methyl-pyridin-2-yl) -ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine were separated by chromatography of normal chiral phase (Chiralpak AD column 8x30 cm, levigating with 85:15 heptane: 0.2% DMEA in ethanol). The second levigating isomer is taken and purified by SCX column chromatography. General procedure 2-2 was used to give the title compound as a white solid (60 mg, 43%). MS (ES +) m / z: 333 (M + H) +; [a] 20D -232 ° (c 0.5, CH 3 OH).

Example 323 (+) - 7-Chloro-6- (2, 2, 2-trifluoro-l-pyridin-2-yl-ethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] hydrochloride azepine A similar method is used for preparation 177 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine with (+) -2- [1-methanesulfonyloxy- (2, 2, 2-trifluoroethyl)] -pyridine. A method similar to general procedure 1-5, basic preparation, and a method similar to general procedure 2-2 is used to give the title compound as a white solid. MS (APCI +) m / z: 373 (M + H) +.

Example 324 (±) -7-Chloro-6- (l-pyridin-2-yl-propylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Preparation 177 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine with (+) -2- (1-bromopropyl) pyridine. A method similar to general procedure 1-5, basic preparation, and a method similar to general procedure 2-2 is used to give the title compound as a white solid. MS (APCI +) m / z: 333 (M + H) +.

Example 325 (±) -7-Chloro-6- [1- (pyridazin-3-yl) -ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine oxalate Dissolve (±) -l-Pyridazin-3-yl-ethanol (38 mg, 0.31 mmol) in thionyl chloride (0.14 mL) at 0 ° C and stir for 1 h at room temperature. The mixture is evaporated, toluene is added and evaporated again. This residue is treated with the thiolate prepared from tert-butyl ester of 7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine-3-carboxylic acid (0.1 g) , 0.25 mmol) according to general procedure 7 in the presence of potassium carbonate (0.3 g, 2.25 mmol) in DMF (3 mL) at 80 ° C for 16 h. A method similar to general procedure 1-5, basic preparation, and a method similar to general procedure 2-5 is used to give the title compound (38 mg, 37%). HRMS calculated for C 16 H 19 C 1 N 3 S 320.0988, found 320.0970.

Example 326 (+) - 7-Chloro-6- [1- (pyridazin-3-yl) -ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine oxalate Dissolve (±) -l-Pyridazin-3-yl-ethanol (0.29 g, 2.35 mmol) in thionyl chloride (1.0 mL) at 0 ° C and stir for 1 h at room temperature. The mixture is evaporated, toluene is added and evaporated again. This residue is treated with the thiolate prepared from 7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine-3-carboxylic acid tertbutyl ether (0.72 g, 1.88 g. mmol) according to general procedure 7 in the presence of potassium carbonate (2.60 g, 18.8 mmol) and tetrabutylammonium iodide (7 mg, 0.02 mmol) in DMF (20 mL) at 80 ° C for 28 h. The enantiomers were separated by preparative HPLC (Waters Symmetry C18 4.6 x 150 mm, 3.5 micron column, 1 mL / min 90:10 to 50:50: 0.1% TFA in water: ACN for 25 min. Detector is at 254 nm ) to obtain 3-tert-butoxycarbonyl-7-chloro-6- [1- (pyridazin-3-yl) -ethylthio] -2,4,4,5-tetrahydro-1H-benzo [d] azepine, isomer 1. A method similar to general procedure 1-5, basic preparation, and a method similar to general procedure 2-5 is used to give the title compound (56 mg, 7%). HPLC tR = 3.0 min (Chiralpak AD-H 4.6x150 mm, 3 micron column, 1.0 mL / min 99.8: 0.2 methanol / isocratic dimethyethylamine, detector at 225 nm); HRMS calculated for C? 6H? 9ClN3S 320.0988, found 320.1001. [a] 20D + 160 ° (c 0.5, CH 3 OH).

Example 327 7-Chloro-6- (pyridazin-3-ylmethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride 3-Chloromethyl-pyridazine (prepared as described in WO 99/54333, WO 98/49166) (1.8 g, 11.0 mmol) is reacted with 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3, 4,5-tetrahydro-lH-benzo [d] azepine (2.2 g, 5.7 mmol) according to general procedure 7 in the presence of tetrabutylammonium iodide (0.1 g, 0.27 mmol) at room temperature for 3 h. A method similar to general procedure 1-4 is used to give the title compound as a brown powder (1.9 g, 98%): HRMS calculated for C? 5H? 6ClN3S 306.0832, found 306.0829.

Example 328 7-Chloro-6- (6-chloro-pyridazin-3-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A similar method is used for preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 3-bromomethyl-6-chloropyridazine to give 3-tert-butoxycarbonyl-7-chloro-6- (6-chloro-pyridazin-3-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to general procedure 1-4 is used to give the title compound as an opaque white powder. MS (APCI +) m / z: 340 (M + H) +.

Example 329 7-Chloro-6- [6- (2, 2-dimethylpropoxy) -Pyridazin-3-ylmethylthio] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride To a stirred solution of neopentyl alcohol (105 mg, 1.19 mmol) in THF (5 mL) at room temperature is added sodium hydride (31 mg, 95%, 1.19 mmol) and stirring is continued for 3 h at room temperature. A solution of 3-tert-butoxycarbonyl-7-chloro-6- (6-chloro-pyridazin-3-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (315 mg, 0.59 mmol) in THF (1 mL) and stirring is continued overnight at room temperature and then at 60 ° C for 1 h. Dilute with water, extract the reaction mixture three times with EtOAc, dry over anhydrous Na 2 SO 4, and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (6: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- [6- (2, 2-dimethyl-propoxy) -Pyridazin-3-ylmethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a clear oil (81 mg, 28%). MS (APCI +) m / z: 492 (M + H) +, 392 (M + H-Boc). A method similar to general procedure 1-4 is used to give the title compound as a white powder. MS (APCI +) m / z: 392 (M + H) +, m / z: 322 (M + H-C5Hu) +.

Example 330 7-Chloro-6- (thiophen-2-ylmethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride To a 4: 1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo [d] azepine (108 mg, 0.281 mmol) in methanol (3 ml), potassium hydroxide is added pelletized (504 mg, 9.0 mmol) and the mixture is heated 2 h at 50 ° C. The reaction is cooled to room temperature, 2-chloromethylthiophene (186 μL, 1,406 mmol) is added and stirring is continued for 30 min. It is diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted three times with EtOAc, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (19: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (thiophen-2-ylmethylthio) -2,3,4,5-tetrahydro-benzo [d] azepine as a colorless oil (36 mg, 31%). A method similar to general procedure 1-5 is used, using 3-tert-butoxycarbonyl-7-chloro-6- (thiophen-2-ylmethylthio) -2,3,4,5-tetrahydro-benzo [d] azepine to give , after basic preparation and a method similar to general procedure 2-2, the title compound as a white solid. MS (ES +) m / z: 310 (M + H) +.

Example 331 (+) - 7-Chloro-6- (3-cyanothiophen-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine trifluoroacetate A similar method is used for preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and (±) -2- ( 1-chloroethyl) -3-cyanothiophene to give, after deprotection using a method similar to General Procedure 1-5, the title compound as a white solid. MS (APCI +) m / z: 349 (M + H) +.

Example 332 7-Chloro-6- (5-methyl isoxazol-3-ylmethylthio) 2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride To a 4: 1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 3-tert-butoxycarbonyl-7,9-dichloro -6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine (200 mg, 0.521 mmol) in methanol (3.3 mL) under nitrogen add potassium hydroxide (0.9 g, 16.1 mmol) to room temperature. When the mixture became homogeneous, it is heated at 55-60 ° C for 2-3 h, until the CCD showed the disappearance of the starting material. It is cooled to room temperature, 3- (chloromethyl) -5-methylisoxazole (82 mg, 0.62 mmol) is added and stirring is continued for 30 min. Aqueous saturated ammonium chloride is added, the mixture is extracted three times with diethyl ether, dried over anhydrous MgSO, and concentrated in vacuo. Treat a solution of the crude material obtained in DCM (2 mL) with 2M hydrogen chloride in ether (excess) and continue stirring until the CCD showed the consumption of the starting material. Concentrate in vacuo, purify by preparative CCD by levigating with 19: 1 DCM / ammonium saturated in methanol, and converted to the hydrochloride by following a method similar to general procedure 2-2 to give the title compound as a white solid. MS (APCI +) m / z: 309 (M + H) +.

Example 333 7,9-Dichloro-6- (5-methylisoxazol-3-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride The free base of the title compound is obtained as a minor product of Example 332, after preparative CCD by levigating with 19: 1 DCM / ammonium saturated in methanol. A method similar to general procedure 2-2 is used to give the title compound as a white solid. MS (APCI +) m / z: 343 (M + H) +.

Example 334 7-Chloro-6- (2-methylthiazol-4-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 332 is used, using 3-ter -butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 4-chloromethyl-2-methylthiazole hydrochloride to give, after deprotection by general procedure 1 -4, the title compound as a white solid. MS (APCI +) m / z: 325 (M + H) +.

Example 335 6- (4-Bromothiophen-2-ylmethylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to general procedure 1-4 is used, using 6- (4-bromothiophen-2-ylmethylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d ] azepine to give the title compound as a white solid. MS (APCI +) m / z: 390 (M + H) +.

Example 336 7-Chloro-6- (4-cyanothiophen-2-ylmethylthio) 2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A stirred solution of 6- (4-bromothiophen-2-ylmethylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (183 mg, 0.37) is degassed. mmol), zinc cyanide (50 mg, 0.42 mmol) and tetrakistriphenylphosphine palladium (0) (30 mg, 0.026 mmol) in dry DMF. It is purged with dry nitrogen, and heated at 120 ° C for 6 h. Dilute with water, extract three times with EtOAc, dry over anhydrous MgSO 4 and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (10: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (4-cyanothiophen-2-ylmethylthio) -2, 3, 4, 5-tetrahydro -lH-benzo [d] azepine as an oil (85 mg, 52%). MS (APCI +) m / z: 335 (M + H-Boc) +. A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (APCI +) m / z: 335 (M + H) +.

Example 337 7-Chloro-6- ([1, 2, 4] -oxadiazol-3-ylmethylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine hydrochloride A similar method is used for the Preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo [d] azepine and 3-chloromethyl-1,2,4-oxadiazole to give, after deprotection using a method similar to General Procedure 1-4, the title compound as a white solid. MS (ES +) m / z 296 (M + H) +. Examples 338-343 can be prepared essentially as described in example 337 using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 5- appropriately substituted chloromethyl-1,2,4-oxadiazole or 4-chloromethyl-thiazole. The data EM (ES +) are included in the following table.

Example 344 7-Chloro-6 - '(pyridin-2-ylmethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 7 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylaminocarbonylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (8 g, 20.8 mmol) with 2-picolyl chloride hydrochloride (3.41 g, 20.8 mmol). The reaction mixture is diluted with diethyl ether and the precipitate is filtered. The filtrate is concentrated in vacuo, the residue is dissolved in diethyl ether (100 mL) and aqueous IN HCl (100 mL) is added. The mixture is stirred for 16 h at room temperature. Separate, wash the aqueous layer with diethyl ether, adjust the pH of the aqueous layer to 12 with sodium hydroxide and extract with diethyl ether. Dry over Na2SO4 and concentrate in vacuo to give the free base of the title compound. The general procedure 2-2 is used to give the title compound as a white solid (4.91 g, 78%). MS (ES +) m / z: 305 (M + H) +.

Example 345 7-Chloro-6- (pyridin-2-ylmethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Succinate Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine (1 equiv.) In methanol (0.1-0.4 M) and add hydroxide of potassium (8-20 equiv.). Stir at 60 ° C for 4-24 h. The reaction mixture is cooled in an ice bath, picolyl chloride hydrochloride (1-3 equiv.) Is added and the mixture is stirred at room temperature for 16-24 h. A volume of toluene approximately equal to the volume of the reaction mixture is added and the resulting mixture is concentrated to approximately the total resulting volume and this process was repeated once more. Water is added until the solids dissolve and the layers are separated. The organic layer is dried over Na2SO4 and filtered. The solution (containing about 0.25-0.40 M of the free base of the title compound) is heated to 50-75 ° C and then optionally seeded with pre-formed crystals of the title compound. Succinic acid (1-1.3 equivalents) in isopropyl alcohol (0.25-0.40M solution) is added to the solution for 5-45 min. The solution is cooled to 20-25 ° C for 1-3 h and filtered, rinsed with a solution of toluene / isopropyl alcohol (1: 1). The resulting solid is dried under vacuum at 50-70 ° C / 5 Torr to give the title compound as a white solid, m.p. 159-160 ° C. Analysis calculated for C 20 H 23 ClN 2 O 4 S: C, 56.80; H, 5.48; N, 6.62. Found: C, 56.56; H, 5.41; N, 6.57.

Example 346 7,9-Dichloro-6- (pyridin-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride It is obtained as a minor product of the reaction of the 4: 1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 3-ter -butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo [d] azepine with 2-bromomethylpyridine bromohydrate, a method similar to General Procedure 7 is used. the crude mixture in DCM with 4M hydrogen chloride in dioxane (excess) overnight. Concentrate in vacuo and purify by preparative CCD by levigating with 19: 1 DCM / ammonium saturated in methanol. A method similar to general procedure 2-2 is used to give the title compound as an opaque white solid. MS (APCI +) m / z: 339 (M + H) +.

Example 347 7-Chloro-6- (2-fluorobenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride To a mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6- dimethylcarbamoylthio-2,3,6-tetrahydro-benzo [d] azepine (102 mg, 0.267 mmol) in methanol (2 ml), pelletized potassium hydroxide (450 mg, 8.02 mmol) is added and the mixture is heated has 60 ° C. Cool to room temperature, add saturated aqueous ammonium chloride solution, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. The crude thiophenol thus obtained is dissolved in dry DCM (2 mL) under nitrogen, and DBU (80 DL, 0.54 mmol) and 2-fluorobenzyl bromide (65 DL, 0.54 mmol) are added with stirring. It is stirred overnight at room temperature, diluted with water, extracted three times with EtOAc, dried over anhydrous Na 2 SO 4, and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (2-fluorobenzylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine as a yellow oil (31 mg, 25%). A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (ES +) m / z: 322 (M + H) +.

Example 348 7-Chloro-6- (pyridin-3-ylmethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 347 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 3- (bromomethyl) pyridine bromohydrate. to give, after deprotection by a method similar to general procedure 1-4, the title compound as a white solid. MS (ES +) m / z: 305 (M + H) +.

Example 349 Succinate of 7-Chloro-6- (5-fluoropyridin-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine (527 mg, 1.4 mmol) and potassium hydroxide (1.1 g, 20.5 mmol ) in methanol (10 mL) and heated. reflux solution for 2 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue is mixed with EtOAc (50 mL), and the thick mixture is washed with saturated NH 4 Cl. It is collected and the organic phase is dried over Na 2 SO, the solvent is removed under reduced pressure to obtain the thiophenol intermediate as an oil. Dissolve the oil in DMSO (10 mL), add triethylamine (1.1 mL, 8.2 mmol) and 5-fluoro-pyridin-2-ylmethyl ester of methanesulfonic acid (500 mg, 2.4 mmol). The reaction mixture is heated at 60 ° C for 1 h. The reaction was monitored by CLAR and CCD. The reaction is cooled to room temperature, 1: 1 hexane / EtOAc (80 ml) is added and the organic layer is washed with 5% NaCl (3 X 30 ml). The organic layer is collected, concentrated, and purified by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1) to obtain 3-tert-butoxycarbonyl-7-chloro-6- (5-fluoro). -pyridin-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (519 mg, 89%). MS (ES +) m / z: 423 (M + H) +. The general procedure 1-4 is used to deprotect 3-tert-butoxycarbonyl-7-chloro-6- (5-fluoro-pyridin-2-ylmethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (510 mg, 1.2 mmol). Purify by SCX chromatography followed by chromatography on silica gel by levigating with DCM / 2M ammonia in methanol (99: 1 to 90:10). The general procedure 2-1 is used to give the title compound (370 mg, 70%). MS (ES +) m / z: 323 (M + H) +.

Example 350 7-Chloro-6- (6-chloropyridin-2-ylmethylthio) 2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A similar method is used for preparation 177, using 3-ter -butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 2-bromomethyl-6-chloropyridine hydrochloride to give, after deprotection by a method similar to the procedure General 1-4, the title compound as an opaque white solid. MS (APCI +) m / z: 339 (M + H) +. Examples 351-360 can be prepared essentially as described in example 350 by using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and chloromethylpyridine approximately substituted, bromomethylpyridine or chloromethylquinoline. The EM (ES +) data are included in the following table.

Example 361 7-Chloro-6- (3-methoxypyridin-2-ylmethylthio) 2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 315 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 2-chloromethyl-3-methoxypyridine for to give, after deprotection by a method similar to general procedure 1-4, the title compound as a white solid (71 mg). MS (APCI +) m / z: 335 (M + H) +.

Example 362 7-Chloro-6- (6-methoxypyridin-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to example 330 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 2-chloromethyl-6-chlorohydrate. methoxypyridine to give, after deprotection by a method similar to general procedure 1-4, the title compound as a white solid (120 mg). MS (APCI +) m / z: 335 (M + H) +.

Example 363 6- (5-Butylpyridin-2-ylmethylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 315 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 5-butyl-2-chlorohydrate chloromethylpyridine to give the title compound as a white solid. MS (APCl0 m / z: 330 (M + H) +.

Example 364 7-Chloro-6- [5- (3-methylbutyl) -pyridin-2-ylmethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A 6- (5-Bromo-pyridin-2-ylmethylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (219 mg, 0.452 mmol) and Dichloro [1, 1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (18 mg, 0.022 mmol) under dry nitrogen is added with stirring a solution of 3-methylbutylzinc bromide 0.5M in THF (4.6 mL , 2.3 mmol). It is degassed, purged with dry nitrogen, and stirred overnight at room temperature. Dilute with EtOAc, wash with water, dry over anhydrous MgSO 4 and concentrate in vacuo. Purification by silica gel chromatography by levigating-with hexane / EtOAc (5: 1) gives 3-tert-butoxycarbonyl-7-chloro-6- [5- (3-methyl-butyl) -pyridin-2-ylmethylthio] -2 , 3, 4, 5-tetrahydro-lH-benzo [d] azepine as an oil (160 mg, 75%). MS (APCI +) m / z: 475 (M + H) +. A method similar to general procedure 1-4 is used to give the title compound as a brown solid. MS (APCI +) m / z: 375 (M + H) 0.

Example 365 7-Chloro-6- [5- (2, 2-dimethylpropyl) -pyridin-2-ylmethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride To a stirred solution of 1.0 M neopentyl magnesium chloride in diethyl ether (50 mL, 50 mmol) at -78 ° C under nitrogen, a solution of 0.5 M zinc chloride in THF (100 mL, 50 mmol). Warm gradually to room temperature and transfer by means of a syringe of this solution (25 mL, ~ 8.33 mmol) to a stirred solution of 3-tert-butoxycarbonyl-6- (5-bromo-pyridin-2-ylmethylthio) - 7-Chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (300 mg, 0.62 mmol) in THF (2 mL) at room temperature. A dichloro [1, 1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (50 mg, 0.061 mmol) is added and heated at 65 ° C for 6 h. Cool to room temperature, dilute with EtOAc, wash with water, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (6: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- [5- (2, 2-dimethyl-propyl) -pyridin-2-ylmethylthio ] -2,3,4, 5-tetrahydro-lH-benzo [d] azepine as an oil (69 mg, 24%). MS (APCI +) m / z: 501 (M + H) +. A method similar to general procedure 1-4 is used to give the title compound as a white powder. MS (APCI +) m / z: 375 (M + H) +.

Example 366 7-Chloro-6- (5-cyclohexylpyridin-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride To a mixture of 6- (5-bromopyridin-2-ylmethylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (146 mg, 0.30 mmol) and a dichloro [1, 1 '-bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (12 mg, 0. 015 mmol) under dry nitrogen is added with a stirred solution of 0.5 M cyclohexyl zinc bromide in THF (3.0 mL, 1.5 mmol). It is degassed, purged with dry nitrogen, and stirred overnight at 60 ° C. Cool to room temperature, dilute with EtOAc, wash with water, dry over anhydrous MgSO4 and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (5: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (5-cyclohexyl-pyridin-2-ylmethylthio) -2.3.4, 5 -tetrahydro-lH-benzo [d] azepine as an oil (46 mg, 32%). MS (APCI +) m / z: 487 (M + H) +. A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (APCI +) m / z: 387 (M + H) +.

Example 367 7-Chloro-6- (5-cyclopentylpyridin-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to example 366 is used to react 6- (5-bromo-pyridin-2-ylmethylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d ] azepine with a solution of cyclopentyl zinc bromide in THF. A method similar to general procedure 1-4, basic preparation, and a method similar to general procedure 2-1 is used to give the title compound as a brown solid. MS (APCI +) m / z: 373 (M + H) +.

Example 368 7-Chloro-6- (5-cyclohexylmethylpyridin-2-ylmethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to example 366 is used to react 6- (5-bromo-pyridin-2-ylmethylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d ] azepine with cyclohexylmethylzinc bromide. A method similar to general procedure 1-5, basic preparation, and a method similar to general procedure 2-2 is used to give the title compound as a white solid. MS (APCI +) m / z: 401 (M + H) +.

Example 369 7-Chloro-6- (3, 4, 5, 6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-methylmethylthio) -2,4,4,5-tetrahydro-1H-benzohydrochloride [d] azepine In a sealed tube, add tris (dibenzylidene ketone) dipalladium (0) (3.44 mg, 0.00376 mmol) and 2, 2'-bis (diphenylphosphino) -1,1-phenylphthalate (4.98 mg, 0.00752 mmol) to a mixture of 6- (5-Bromopyridin-2-ylmethylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (242 mg, 0.501 mmol), tert-butoxide sodium (96 mg, 1.0 mmol), 18-crown-6 (13 mg, 0.050 mmol) and piperidine (496 μL, 5.01 mmol) in toluene (3 mL). The mixture is cleaned with nitrogen and heated overnight. It is cooled to room temperature, diluted with water and extracted three times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6 '-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a yellow oil (179 mg, 73%). A method similar to general procedure 1-5 is used, using 3-tert-butoxycarbonyl-7-chloro-6- (3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-6'-methylmeththio ) -2,3, 4, 5-tetrahydro-lH-benzo [d] azepine to give, after basic preparation and a method similar to general procedure 2-2, the title compound as a yellow solid. MS (ES +) m / z: 388 (M + H) +.

Example 370 7-Chloro-6- (5-pyrrolidin-1-yl-pyridin-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to example 369 is used, using 6- (5-bromopyridin-2-ylmethylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine and pyrrolidine to give the title compound as a pale yellow solid. MS (ES +) m / z: 374 (M + H) +.

Example 371 6- (5-Azepan-1-yl-pyridin-2-ylmethylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride H (HCl) X A method similar to example 369 is used, using 6- (5-bromopyridin-2-ylmethylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine and homopiperidine to give the title compound as a yellow solid. MS (ES +) m / z 402 (M + H) +.

Example 372 7-Chloro-6- ('3, 4, 5, 6-tetrahydro-2H- [1,2'] bipyridinyl-5'-methylmethylthio) -2,3,4,5-tetrahydro-lH- hydrochloride benzo [d] azepine A method similar to example 369 is used, using 3-tert-butoxycarbonyl-7-chloro-6- (6-chloropyridin-3-ylmethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine and piperidine, to give the title compound as a white solid. MS (ES +) m / z: 388 (M + H) +.

Example 373 7-Chloro-6- [5- (4-fluorophenylethynyl) -pyridin-2-ylmethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride Dissolve 3-tert-butoxycarbonyl-6- (5-bromopyridin-2-ylmethylthio) -7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (1.0 g, 2.07 mmol), tetrakistriphenylphosphine palladium (O) (120 mg, 0.104 mmol), copper iodide (20 mg, 0.105 mmol), triethylamine (2.60 mL) and l-ethynyl-4-fluorobenzene (500 mg, 4.16 mmol) in DMF (8 mL). The mixture is degassed, purged with nitrogen, and heated at 65 ° C for 3 days. The mixture is diluted with water, extracted three times with EtOAc, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (50: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- [5- (4-fluorophenylethynyl) -pyridin-2-ylmethylthio] -2.3 , 4, 5-tetrahydro-lH-benzo [d] azepine as a brown foam (1.02 g, 95%). MS (APCI +) m / z: 523 (M + H) +, 423 (M + H-Boc) +. A method similar to general procedure 1-4 is used to give the title compound as a brown powder. MS (APCI +) m / z: 423 (M + H) +.

Example 374 (Z) -7-Chloro-6-hydrochloride. { 5- [2- (4-fluorophenyl) vinyl] -pyridin-2-ylmethylthio} -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine Dissolve 3-tert-butoxycarbonyl-7-chloro-6- [5- (4-fluorophenylethynyl) -pyridin-2-ylmethylthio] -2,3,4,5-tetrahydro-1H-benzo [d] azepine (1.0 g , 1.9 mmol), Lindlar catalyst (240 mg), and quinoline (0.8 mL) in methanol (30 mL). It is degassed, purged with nitrogen, and stirred under a hydrogen balloon for 36 h. The mixture is filtered and the catalyst is washed with additional methanol. The filtrate is concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (8: 1) to give (Z) -3-tert-butoxycarbonyl-7-chloro-6-. { 5- [2- (4-Fluoro-phenyl) -vinyl] -pyridin-2-ylmethylthio} -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a clear oil (630 mg, 63%). MS (APCI +) m / z: 525 (M + H) +, 425 (M + H-Boc) +. A method similar to general procedure 1-4 is used to give the title compound as a pale yellow solid. MS (APCI +) m / z: 425 (M + H) +.

Example 375 Succinate of 7-chloro-6- [5- (2-fluoro-4-trifluoromethylbenzylcarbamoyl) -pyridin-2-ylmethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Dissolve 3-tert-butoxycarbonyl-6- (5-carboxypyridin-2-ylmethylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (300 mg, 0.67 mmol) in DMF (5.0 L). It is treated sequentially with HATU (305 mg, 0.802 mmol), N, N-diisopropylethylamine (140 μL, 0.804 mmol) and 2-fluoro-4- (trifluoromethyl) benzylamine (260 mg, 1.34 mmol). It is stirred overnight at 40 ° C. The mixture is diluted with water, extracted three times with EtOAc, dried over anhydrous Na 2 SO and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (3: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- [5- (2-fluoro-4-trifluoromethyl-benzylcarbamoyl) -pyridin-2- ilmethylthio] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a foam (409 g, 98%). A method similar to general procedure 1-4 is used to give, after basic preparation and a method similar to general procedure 2-1, the title compound as an opaque white solid. MS (APCI +) m / z: 524 (M + H) +.

Example 376 Succinate of 7-Chloro-6- [5- (2, 2-dimethylpropylcarbamoyl) -pyridin-2-ylmethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to Example 375 is used, using 3-tert-butoxycarbonyl-6- (5-carboxy-pyridin-2-ylmethylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine and neopentylamine, to give the title compound as an opaque white solid. MS (APCI +) m / z: 418 (M + H) +. Example 377 7-Chloro-6- [5- (4-fluoro-benzylcarbamoyl) -pyridin-2-ylmethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to Example 375 is used, using 3-tert-butoxycarbonyl-6- (5-carboxy-pyridin-2-ylmethylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 4-fluorobenzylamine, to give the title compound as an opaque white solid. MS (APCI +) m / z: 456 (M + H) +.

Example 378 7-Chloro-6- [5- (cyclohexylmethylcarbamoyl) -pyridin-2-ylmethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 375 is used, using 3-tert-butoxycarbonyl-6- (5-carboxy-pyridin-2-ylmethylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine and aminomethylcyclohexane to give, after deprotection by General Procedure 1-4, the title compound as a white solid. MS (APCI +) m / z: 444 (M + H) +.

Example 379 6- (5-tert-Butylcarbamoyl-pyridin-2-ylmethylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 375 is used, using 3-tert-butoxycarbonyl-6- (5-carboxy-pyridin-2-ylmethylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine and tert-butylamine to give, after deprotection by General Procedure 1-4, the title compound as an opaque white solid. MS (APCI +) m / z: 404 (M + H) +.

Example 380 7-Chloro-6- (4-trifluoromethoxybenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride To a 4: 1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 3-tert-butoxycarbonyl-7,9-dichloro -6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine (102 mg, 0.27 mmol) in methanol (1.7 mL) under nitrogen, add potassium hydroxide (0.9 g, 16.1 mmol) at room temperature. When the mixture became homogeneous, it was heated at 55-60 ° C for 2-3 h, until the CCD showed the disappearance of the starting material. It is cooled to room temperature, a saturated aqueous amino chloride solution is added, it is extracted three times with diethyl ether, dried over anhydrous MgSO 4 and concentrated in vacuo. The crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-lH-benzo [d] azepine is dissolved in anhydrous DCM (2 mL) under nitrogen. DBU (80 μL, 0.532 mmol) and 4- (trifluoromethoxy) benzyl bromide (77 μL, 0.53 mmol) are added with stirring at room temperature and the reaction is allowed to continue overnight. Dilute with a saturated aqueous amino chloride solution, extract three times with diethyl ether, dry over anhydrous MgSO and concentrate in vacuo. Treat a solution of crude 3-tert-butoxycarbonyl-7-chloro-6- (4-trifluoromethoxy-benzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine in DCM (2 mL) with 2M hydrogen chloride in ether (excess) and stirring is continued until the CCD shows the consumption of the starting material. Concentrate in vacuo and triturate the solid obtained with ether / pentane (10:90). Purify by preparative CCD by levigating with 19: 1 DCM / ammonium saturated in methanol and converted to the hydrochloride following a method similar to general procedure 2-2 to give the title compound as a white solid (48 mg, 43%). MS (APCI +) m / z: 388 (M + H) +. Examples 381-383 can be prepared essentially as described in Example 380 by using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and the properly substituted benzyl bromide. Example 382 can be purified after deprotection by reverse phase preparative HPLC [Column: YMC ODS-AQ 120A 20x250mm [S10-20μm], levigant: gradient from 95: 5 to 5:95 A / B, flow ratio: 15 mL / min; solvent A: water, 0.1% TFA, 1% isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol]. The EM (ES +) data are included in the following table.

Example 384 7-Chloro-6- (4-fluoro-benzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine trifluoroacetate A method similar to example 380 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1H-benzo [d] -azepine with 4-fluorobenzyl bromide. Purify by preparative reverse phase HPLC [Column: YMC ODS-AQ 120A 20 x 250mm [S10-20μm], levigant: gradient from 95: 5 to 5:95 A / B, flow ratio: 15 mL / min; solvent A: water, 0.1% TFA, 1% isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol] to give the title compound as a white solid. MS (ES +) m / z: 322 (M + H) +. Examples 385-386 can be prepared essentially as described in example 384 by using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and bromide of properly substituted benzyl. The EM (ES +) data are included in the following table.

Example 387 7-Chloro-6- (3,4-dichlorobenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine trifluoroacetate To a 4: 1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 3-tert-butoxycarbonyl-7,9-dichloro -6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine (200 mg, 0.521 mmol) in methanol (3.3 L) under nitrogen add potassium hydroxide (0.9 g, 16.07 mmol) to room temperature. When the mixture became homogeneous, it was heated at 55-60 ° C for 2-3 h, until the CCD showed the disappearance of the starting material. It cools at room temperaturea solution of saturated aqueous ammonium chloride is added, extracted three times with diethyl ether, dried over anhydrous MgSO 4 and concentrated in vacuo. The crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2, 3,4,5-tetrahydro-lH-benzo [d] azepine is dissolved in anhydrous DCM (5 mL) under nitrogen. PS-DIEA (Argonaut, 3.83 mmol / g, 410 mg, 1.57 mmol) and 3,4-dichlorobenzyl bromide (100 μL, 0.586 mmol) are added at room temperature and the reaction is allowed to continue overnight. Filter the reaction mixture to give the resin and rinse with DCM (2 mL), methanol (2 mL), DCM (2 mL), and methanol (2 mL). Concentrate in vacuo. A solution of crude 3-tert-butoxycarbonyl-7-chloro-6- (3,4-dichloro-benzylthio) -2, 3,4,5-tetrahydro-lH-benzo [d] azepine in DCM (2 mL) with 2M hydrogen chloride in ether (excess) and stirring is continued until the CCD shows the consumption of the starting material. Concentrate in vacuo and triturate the solid obtained with ether: pentane (10:90). It is purified by reverse phase preparative HPLC (Column: Xterra Prep RP18 19x250mm; Solvent A: 10 mM aqueous ammonium carbonate, Solvent B: acetonitrile; 30-100% B for 20 minutes; flow ratio 25 mL / min) to give the title compound as a white solid (97 mg, 38%). MS (APCI +) m / z: 374 (M + H) +. Examples 388-393 can be prepared essentially as described in example 387 by using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and bromide of properly substituted benzyl. The EM (ES +) data are included in the following table.

Example 394 7,9-Dichloro-6- (3-fluorobenzylthio) 2,3,4,5-tetrahydro-lH-benzo [d] azepine trifluoroacetate The product of the reaction of the mixture is 4: 1 of 3. -ter-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2, 3 , 4,5-tetrahydro-benzo [d] azepine with 3-fluorobenzyl bromide, a method similar to Example 387 is used. The title compound is deprotected and the title compound is isolated as a white solid after preparative reverse phase HPLC. MS (ES +) m / z: 356 (M + H) +.

Example 395 7,9-Dichloro-6- (3,4,5-trifluorobenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine trifluoroacetate It is obtained as a minor product of the reaction of the 4: 1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 3-ter -butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo [d] azepine with 3,4,5-trifluorobenzyl bromide, a method similar to Example 387 is used. and the title compound is isolated as a white solid after preparative reverse phase HPLC. MS (APCI +) m / z: 392 (M + H) +.

Example 396 7-Chloro-6- (2-nitro-benzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 387 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1H-benzo [d] -azepine and 2-nitrobenzyl bromide to give , after chromatography by levigating with hexane / EtOAc (10: 1) and deprotection by general procedure 1-4, the title compound as an opaque white powder. MS (APCI +) m / z: 349 (M + H) +. Examples 397-399 can be prepared essentially as described in example 396 by using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and bromide of properly substituted benzyl. The EM (ES +) data are included in the following table.

Example 400 7,9-Dichloro-6- (3,5-bis-trifluoromethylbenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride (2148393) It is obtained as a minor product of the reaction of the 4: 1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 3-ter -butoxycarbonyl-7, 9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo [d] azepine with 3, 5-bis-trifluoromethylbenzyl bromide, a method similar to Example 396 is used. It is deprotected the crude mixture and purified by preparative reverse phase HPLC (Column: Xterra Prep RP18 19x250mm, solvent A: 10 mM aqueous ammonium carbonate, solvent B: acetonitrile, 30-100% B for 20 minutes, flow ratio 25 mL / min). A method similar to general procedure 2-2 is used to give the title compound as a white solid. MS (APCI +) m / z: 474 (M + H) +.

Example 401 7-Chloro-6- (2,6-difluorobenzylthio-) 2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to example 330 is used, using 3-tert-butoxycarbonyl-1-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo [d] azepine and 2,6-difluorobenzyl bromide for to give, after deprotection by General Procedure 1-4, the title compound.

Example 402 7-Chloro-6- (2-trifluoromethylbenzylthio) 2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 347 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo [d] azepine with 2-trifluoromethylbenzyl bromide. A method similar to general procedure 1-4 is used to give the title compound as a waxy brown solid. MS (APCI +) m / z: 372 (M + H) +.

Example 403 7-Chloro-6- (4-methoxycarbonylbenzylthio) -2,3,4,5-tetrahydro-benzo [d] azepine hydrochloride A similar method is used for preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoythio-2,3,4,5-tetrahydro-1H-benzo [d] azepine and 4- (bromomethyl) benzoate of methyl to give, after deprotection by general procedure 1-4, the title compound as a white solid. MS (ES +) m / z: 362 (M + H) +.

Example 404 7-Chloro-6- (3-methoxycarbonylbenzylthio) 2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 347 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine with methyl 3- (bromomethyl) benzoate . A method similar to general procedure 1-5, basic preparation, and a method similar to general procedure 2-2 is used to give the title compound. MS (APCI +) m / z: 362 (M + H) +.

Example 405 7-Chloro-6- (2-methoxycarbonylbenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 347 is used, using the 4: 1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 3-tert-butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo [d] azepine with methyl 2- (bromomethyl) benzoate. A method similar to the general procedure is used 1-4 and purified by preparative reverse phase CLAR (Column: Xterra Prep RP18 19x250mm, solvent A: 10 mM aqueous ammonium carbonate, solvent B: acetonitrile, 30-100% B for 20 minutes, flow ratio 25 mL / min). A method similar to general procedure 2-2 is used to give the title compound as a white solid. MS (ES +) m / z: 362 (M + H) +.

Example 406 7,9-Dichloro-6- (2-methoxycarbonylbenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride The free base of the title compound is obtained as a minor product of example 405, after preparative reverse phase HPLC (Column: Xterra Prep RP18 19x250mm, solvent A: 10mM aqueous ammonium carbonate, solvent B: acetonitrile, 30-100 % B for 20 minutes, flow ratio 25 mL / min). A method similar to general procedure 2-2 is used to give the title compound as a white solid. MS (ES +) m / z: 396 (M + H) +.

Example 407 6- (4-Benzoylbenzylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 380 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo [d] azepine with 4- (bromomethyl) benzophenone. It is purified by reverse phase preparative HPLC (Column: Xterra Prep RP18 19x250mm, Solvent A: 10mM aqueous ammonium carbonate, Solvent B: acetonitrile, 30-100% B for 20 minutes, flow ratio 25mL / min). A method similar to general procedure 2-2 is used to give the title compound as a white solid.

MS (ES +) m / z: 408 (M + H) +. Example 408 Succinate of 7-Chloro-6- [4- (3, 3-dimethyl-2-oxo-butoxy) benzylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to general procedure 7 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine (577 mg, 1.5 mmol) and 1- (4-bromomethylphenoxy) -3,3-dimethylbutan-2-one (556 mg, 1.95 mmol) to give, after chromatography on silica gel, levigating with EtOAc / hexane (1: 5), 3-tert-butoxycarbonyl -7-chloro-6- [4- (3, 3-dimethyl-2-oxo-butoxy) -benzylthio] -2, 3,4,5-tetrahydro-lH-benzo [d] azepine as a colorless oil (669 mg, 86%). MS (ES +) m / z: 518 (M + H) +. A method similar to general procedure 1-5 is used to deprotect 3-tert-butoxycarbonyl-7-chloro-6- [4- (3, 3-dimethyl-2-oxo-butoxy) -benzylthio] -2, 3, 4 , 5-tetrahydro-lH-benzo [d] azepine (669 mg, 1.29 mmol). Purification by chromatography on silica gel by levigating with DCM / 2M ammonium in methanol (92: 8) to give the free base of the title compound as a colorless oil (349 mg, 64%). MS (ES +) m / z: 418 (M + H) +. A method similar to general procedure 2-1 is used to give the title compound.

Example 409 Succinate of 7-Chloro-6- [3-chloro-4- (3, 3-dimethyl-2-oxo-butoxy) -benzylthio] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine A method similar to Example 408 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 1- (4-bromomethyl-3 chlorophenoxy) -3,3-dimethylbutan-2-one to give the title compound. MS (ES +) m / z: 452 (M + H) +.

Example 410 7-Chloro-6- (4-methanesulfonylmethyl-benzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to general procedure 1-4 is used, using 3-tert-butoxycarbonyl-7-chloro-6- (4-methanesulfonylmethyl-benzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine to give the title compound as a white solid. MS (ES +) m / z: 396 (M + H) +.

Example 411 7-Chloro-6- (5-chloro-thiophen-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 387 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 2-chloro-5- (chloromethyl) ) thiophene to give, after the formation of chlorohydrate by general procedure 2-2, the title compound as a brown solid. MS (APCI +) m / z: 344 (M + H) +.

Example 412 7-Chloro-6- (pyridin-4-ylmethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 387 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 4-bromomethylpyridine bromohydrate to give, after the formation of chlorohydrate by general procedure 2-2, the title compound as a white solid. MS (APCI +) m / z: 305 (M + H) +.

Example 413 7-Chloro-6- (6-methyl-pyridin-2-iimethylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine hydrochloride A method similar to example 387 is used, using 3 -ter-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 2-chloromethyl-6-methylpriidine to give, after chromatography on silica gel, levigating with hexane / EtOAc (4: 1) and deprotection by the general procedure 1-4, the title compound as a white solid. MS (ES +) m / z: 319 (M + H) +.

Example 414 7-Chloro-6- [3-f luoro-4- (3-methylbutyl) -benzylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride To 6- (4-bromo-3-fluorobenzylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (0.210 mg, 0.42 mmol) and a dichloro [1, 1 '-bis (diphenylphosphino) -ferrocene] palladium (II) dichloromethane adduct (17 mg, 0.021 mmol) is added 0.5 M 3-methylbutylzinc bromide in THF (4.2 mL, 2. 10 mmol). It is degassed, purged with dry nitrogen, and stirred overnight at 80 ° C. It is cooled to room temperature, diluted with EtOAc, washed with water, dried over anhydrous MgSO 4 and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- [3-fluoro-4- (3-methylbutyl) -benzylthio] -2,3,4,5-tetrahydro-lH-benzo [d ] azepine as a yellow oil (85 mg, 42%). A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (ES +) m / z: 392 (M + H) +.

Example 415 7-Chloro-6- (4-cyclohexylmethyl-3-fluorobenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to Example 414 is used to react 6- (4-bromo-3-fluorobenzylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine with (cyclohexyl) methylzinc bromide. A method similar to general procedure 1-4, basic preparation, and a method similar to general procedure 2-1, is used to give the title compound as a white solid. MS (ES +) m / z: 418 (M + H) +.

Example 416 7-Chloro-6- (4-cyclohexyl-3-fluorobenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 414 is used, using 6- (4-bromo-3-fluorobenzylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine and exilzinc cycle bromide. A method similar to general procedure 1-4, basic preparation, and a method similar to general procedure 2-1, is used to give the title compound as a white solid. MS (ES +) m / z: 404 (M + H) +.

Example 417 7-Chloro-6- (2, 5'-difluoro-2'-methoxybiphenyl-4-ylmethylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine hydrochloride A stirred mixture is degassed of 6- (4-bromo-3-fluorobenzylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (212 mg, 0.424 mmol), 5-fluoro-2-methoxybenzene boronic acid (108 mg, 0.636 mmol), potassium carbonate (292 mg, 2.12 mmol) ), triphenylphosphine (11 mg, 0.0424 mmol) and bis (triphenylphosphine) -palladium (II) chloride (15 mg, 0.0212 mmol) in dioxane (3 mL) and water (1 mL). It is purged with dry nitrogen and heated at 100 ° C for 5 h. It is cooled to room temperature, water is added, it is extracted three times with EtOAc, dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (2, 5'-difluoro-2'-methoxy-biphenyl-4-ylmethylthio) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine as a yellow oil (216 mg, 93%). A method similar to general procedure 1-4 is used to give the title compound as a yellow foam. MS (ES +) m / z: 446 (M + H) +.

Example 418 7-Chloro-6- (2'-chloro-2-fluorobiphenyl-4-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 417 is used, using 2-chlorophenylboronic acid to give, after deprotection by General Procedure 1-4, the title compound as a white solid. MS (ES +) m / z: 432 (M + H) +.

Example 419 7-Chloro-6- (3-fluoro-4-piperidin-1-yl-benzylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine hydrochloride In a sealed tube, add tris (dibenzylideneacetone) dipalladium (13 mg, 0.014 mmol) and 2,2 '-bis (diphenylphosphino) -1,1 * -bubfethyl (19 mg, 0.029 mmol) to a mixture of 6- ( 4-bromo-3-fluorobenzylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (957 mg, 1.91 mmol), sodium tert-butoxide (367 mg, 3.83 mmol), 18-crown-6 (50 mg, 0.191 mmol) and piperidine (944 μl, 9. 57 mmol) in toluene (10 mL). The mixture is flushed with nitrogen and heated overnight. It is cooled to room temperature, diluted with water and extracted three times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (3-fluoro-4-piperidin-1-yl-benzylthio) -2, 3 , 4,5-tetrahydro-lH-benzo [d] azepine as a yellow oil (511 mg, 33%). A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (ES +) m / z: 405 (M + H) +.

EXAMPLE 420 7-Chloro-6- (3-fluoro-4-pyrrolidin-1-yl-benzylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine hydrochloride A method similar to that of Example 419 is used to react 6- (4-bromo-3-fluorobenzylthio) -3-tert-butoxycarboni-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine with pyrrolidine. A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (ES +) m / z: 391 (M + H) +.

Example 421 Hydrochloride 6- (4-Azepan-1-yl-3-fluorobenzylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to Example 419 is used to react 6- (4-bromo-3-fluorobenzylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine with homopiperidine. A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (ES +) m / z: 419 (M + H) +.

Example 422 7-Chloro-6- (4-chloro-3-pyrrolidin-1-yl-benzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 419 is used, using 6- (3-bromo-4-chloro-benzylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine and pyrrolidine to give, after deprotection using a method similar to General Procedure 1-4, the title compound as a white solid. MS (ES +) m / z: 407 (M + H) +.

Example 423 7-Chloro-6- (4-cyclohexylmethoxybenzylthio) -3-tert-butoxycarbonyl-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A similar method is used for preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 4- (chloromethyl) acetate. phenyl to give 6- (4-acetoxybenzylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-1H-benzo [d] azepine as a white solid. To 6- (4-acetoxybenzylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (532 mg, 1.15 mmol) in methanol (8 mL) at room temperature is added with a stirred solution of potassium carbonate (796 mg, 5.77 mmol) in water (4 mL) and the mixture is stirred for 2 h. Dilute with water, extract three times with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo. A portion of the crude phenol thus obtained (204 mg, 0.487 mmol) in THF (5 mL) is added with stirred diisopropyl azodicarboxylate (216 μL, 1.71 mmol) followed by triphenylphosphine (306 mg, 1.17 mmol) and cyclohexylmethanol (619 mg). 5.42 mmol). Heat at 60 ° C for 3 h, cool to room temperature and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (4-cyclohexylmethoxy-benzylthio) -2,3,4,5-tetrahydro-1H -benzo [d] azepine as a colorless oil (176 mg, 70%). A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (ES +) m / z: 416 (M + H) +.

Example 424 7-Chloro-6- (4-cycloheptyloxybenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 423 is used to react 6- (4-acetoxybenzylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo [d] azepine with cycloheptanol. A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (ES +) m / z: 416 (M + H) +.

Example 425 7-Chloro-6- [4- (2, 2-dimethylpropoxy) -benzylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A similar method is used for preparation 177 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and l-bromomethyl-4- (2,2-dimethylpropoxy) -benzene. A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (ES +) m / z: 390 (M + H) +.

Example 426 7-Chloro-6- (2-methanesulfonylbenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A similar method is used for preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and l-bromomethyl-2-methanesulfonyl -benzene to give, after deprotection by General Procedure 1-4, the title compound and as a white solid. MS (APCI +) m / z: 382 (M + H) +.

Example 427 7-Chloro-6- (4-methanesulfonylbenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to example 380 is used, using 3-tert-butoxycarbonyl-7 -chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 4-methylsulfonylbenzyl bromide to give, after the formation of chlorohydrate by general procedure 2-2, the compound of title as a white solid. MS (ES +) m / z: 382 (M + H) +.

Example 428 7-Chloro-6- [4- (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropane-1-sulfinyl) -benzylthio] -2,3,4,5-tetrahydro-1H- hydrochloride benzo [d] azepine To the 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine (723 mg, 1.88 mmol) in methanol (10 mL) is added hydroxide. pelletized potassium (3.34 g, 60.2 mmol) and the mixture is stirred at 50 ° C for 2 h.

Cool to room temperature, add saturated aqueous ammonium chloride, extract three times with EtOAc, dry over anhydrous Na 2 SO 4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine crude. The compound is dissolved in DMF (5 mL), cesium carbonate (920 mg, 2.82 mmol) and 1-bromomethyl-4- (3,3,3-trifluoro-2-methyl-2-trifluoromethyl-propane-1) are added. -sulfinyl) -benzene (824 mg, 2071 mmol) and stir 2 h at room temperature. Dilute with water, extract three times with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- [4- (3,3,3-trifluoro-2-methyl-2-trifluoromethyl) -propane-1-sulfinyl) -benzylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a yellow oil (986 mg, 83%). A method similar to general procedure 1-4 is used to give the title compound as a white foam. MS (ES +) m / z: 530 (M + H) +. Examples 429-432 can be prepared essentially as described in example 428 by using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine with bromide of properly substituted benzyl. The EM (ES +) data are included in the following table.

Example 433 Succinate of 7-Chloro-6- [4- (2, -difluoro-phenylmethanesulfonyl) benzylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to Example 428 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo [d] azepine with 1- (4-bromomethyl) benzenesulfonylmethyl) -2,4-difluoro-benzene. A method similar to general procedure 1-4, basic preparation, and a method similar to general procedure 2-1, is used to give the title compound as a white solid. MS (ES +) m / z: 494 (M + H) +.

Example 434 Succinate of 7-Chloro-6- [4- (3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio) -benzylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to Example 428 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo [d] azepine with l-bromomethyl-4- ( 3,3, 3-trifluoro-2-methyl-2-trifluoromethylpropylthio) -benzene. A method similar to general procedure 1-5, basic preparation, and a method similar to general procedure 2-1, is used to give the title compound as a white solid. MS (APCI +) m / z: 514 (M + H) +.

Example 435 7-Chloro-6- [4- (3, 3-dimethylbutyryl) -benzylthio] -1,2,4,5-tetrahydro-benzo [d] azepine hydrochloride A method similar to Example 428 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo [d] azepine with 1- (4-bromomethylphenyl) -3, 3-dimethylbutan-1-one. A method similar to general procedure 1-4, basic preparation, and a method similar to general procedure 2-2 is used to give the title compound as a white solid. MS (APCI +) m / z: 402 (M + H) +.

Example 436 (±) -7-Chloro-6- [1- (2-cyanophenyl) -ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A similar method is used for preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and (±) -2- ( l-bromoethyl) benzonitrile to give, after deprotection by general procedure 1-4, the title compound as a white solid. MS (APCI +) m / z: 343 (M + H) +.

Example 437 (-) - 7-Chloro-6- [1- (2-cyanophenyl) -ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride Succinate of (+) - 7-chloro-6- [1- (2-cyanophenyl) -ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine (326 mg, 1.0 mmol) is dissolved in DCM (5 mL) and pyridine (0.4 mL, 5 mmol). Di-tert-butyl-dicarbonate (270 mg, 1.2 mmol) is added and the mixture is stirred for 16 h at room temperature. The mixture is washed with aqueous 5N NaOH and saturated aqueous NaHCO3 successively. The organic layer is collected and concentrated in vacuo. The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 1) to obtain (±) -3-tert-butoxycarbonyl-7-chloro-6- [1- (2-cyanophenyl) -ethylthio] - 2,3,4,5-tetrahydro-lH-benzo [d] azepine (393 mg, 93%). The enantiomers of (±) 3-tert-butoxycarbonyl-7-chloro-6- [1- (2-cyanophenyl) -ethylthio] -2,3,4,5,5-tetrahydro-lH-benzo [d] azepine were separated by chiral normal phase chromatography (Chiralpak AD column 8x30 cm, levigating with heptane / isopropylamine, 95: 5). The second levigating isomer is taken and deprotected using general procedure 1-5. Purify with SCX chromatography. A method similar to general procedure 2-2 is used to obtain the title compound (125 mg, 37%). MS (ES +) m / z: 343 (M + H) +. [α] 20D -112 ° (c 0.5, CH 3 OH).

Examples 438 and 439 6- [4- (2-Butyl-2H-pyrazol-3-yl) -benzylthio] -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride and Hydrochloride 6- [4- (l-Butyl-lH-pyrazol-3-yl) -benzylthio] -7-chloro-2,3,3,5-tetrahydro-lH-benzo [d] azepine 4-Asethylbenzyl Bromide: A similar method is used for preparation 184, using 4-methylacetophenone, to give the desired intermediate as a white solid. 6- (4-Acetylbensylthio) -3-tert-butoxy-aryl-7-sloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: A method similar to Example 380 is used, using 3-ter butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 4-acetylbenzyl bromide to give, after chromatography, levigating with hexane / EtOAc (15: 1) , the desired intermediate as a white solid. MS (APCI +) m / z 346 (M + H-Boc) +. 3-tert-butoxysarbonyl-7-sloro-6- [4- (3-dimethylamino-acryloyl) -bensylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine: A solution of 6- ( 4-acetylbenzylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.0 g, 2.2 mmol) in toluene (10 mL) at 110 ° C during overnight in the presence of tert-butoxy-bis (dimethylamino) -methane (1.0 mL, 4.84 mmol). Concentrate in vacuo to provide the desired intermediate as a dark oil (1.2 g, 100%). MS (APCI +) m / z 401 (M + H-Boc) +. 6- [4- (l-Butyl-lH-pyrazol-3-yl) -bensylthio] -7-sloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride: To a stirred mixture of 3-tert-butoxycarbonyl-7-chloro-6- [4- (3-dimethylaminoacryloyl) -benzylthio] -2, 3,, 5-tetrahydro-lH-benzo [d] azepine (240 mg, 0.475 mmol), oxalate Butylhydrazine (102 mg, 0.574 mmol), sodium carbonate (55 mg, 0.444 mmol) in water (8 mL) and methanol (10 mL) add acetic acid (ca. 3-6 drops) to pH 5. Warm overnight at 70 ° C. Concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (10: 1) to give a mixture of the desired intermediate, 3-tert-butoxycarbonyl-6- [4- (2-butyl-2H-pyrazol-3-yl) -benzylthio] -7-chloro-2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (65 mg, 32%), MS (APCI +) m / z: 426 (M + H-Boc) + and 3-tert-butoxycarbonyl-6- [4- (1-butyl-lH-pyrazol-3-yl) -benzylthio] -7-chloro-2 , 3,4, 5-tetrahydro-lH-benzo [d] azepine (100 mg, 50%), MS (APCI +) m / z: 426 (M + H-Boc) +. A method similar to general procedure 1-4 is used, using 3-tert-butoxycarbonyl-6- [4- (2-butyl-2H-pyrazol-3-yl) -benzylthio] -7-chloro-2, 3, 4 , 5-tetrahydro-lH-benzo [d] azepine, to give 6- [4- (2-butyl-2H-pyrazol-3-yl) -benzylthio] -7-chloro-2,3,4,5-tetrahydro -lH-benzo [d] azepine (Example 438) as a white solid. MS (APCI +) m / z: 426 (M + H) +. A method similar to general procedure 1-4 is used, using 3-tert-butoxycarbonyl-6- [4- (l-butyl-lH-pyrazol-3-yl) -benzylthio] -7-chloro-2, 3, 4 , 5-tetrahydro-lH-benzo [d] azepine, to give 6- [4- (l-butyl-lH-pyrazol-3-yl) -benzylthio] -7-chloro-2,3,4,5-tetrahydro -lH-benzo [d] azepine (Example 439) as a white solid. MS (APCI +) m / z: 426 (M + H) +.

Example 440 6- (4-tert-Butylcarbamoyl-3-fluorobenzylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride 3-tert-butoxyarbonyl-7-sloro-6- (3-fluoro-4-methoxysarbonylbensylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine: A method similar to example 428 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and methyl 4-bromomethyl-2-fluorobenzoate, to give the desired intermediate as a solid White. 3-tert-butoxyarbonyl-6- (4-sarboxi-3-fluoro-benshylthio) -7-sloro-2,3,4,5-tetrahydro-1H-benzo [d] azepine: A stirred solution of 3-tert. butoxycarbonyl-7-chloro-6- (3-fluoro-4-methoxycarbonylbenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (3.56 g, 7.44 mmol) in THF (50 L) and water (40 mL) overnight at 65 ° C in the presence of potassium hydroxide (8.30 g, 148.77 mmol). The mixture is cooled to 0 ° C, an IN hydrochloric acid solution is added slowly to pH 5. It is extracted three times with EtOAc, dried over anhydrous Na2SO4 and concentrated in vacuo to provide the desired intermediate as a white solid (3.5 g, 99%). 6- (4-tert-Butylsarbamoyl-3-fluorobensylthio) -7-sloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride: To a solution of 3-tert-butoxycarbonyl-6- (4-carboxy-3-fluoro-benzylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.1 g, 2.36 mmol) in DMF (7 mL) was added. -butylamine (12.05 g, 165.2 mmol), EDC (1.81 g, 9.44 mmol) and HOBt (1.44 g, 10.62 mmol) and stirred in a sealed tube at 70 ° C overnight. Dilute with EtOAc, wash with water, dry over anhydrous MgSO 4 and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give 3-tert-butoxycarbonyl-6- (4-tert-butylcarbamoyl-3-fluorobenzylthio) -7-chloro-2, 3, 4, 5 -tetrahydro-lH-benzo [d] azepine as a clear oil. MS (APCI +) m / z: 421 (M + H) +. A method similar to general procedure 1-4 is used to give the title compound as a white powder. MS (APCI +) m / z: 421 (M + H) +.

Examples 441-447 can be prepared essentially as described in example 440 to react 3-tert-butoxycarbonyl-6- (4-carboxy-3-fluorobenzylthio) -7-chloro-2,3,4,5-tetrahydro- lH-benzo [d] azepine with the appropriate amine. The EM (ES +) data are included in the following table.

Example 448 (S) - (+) - 6 - (4-sec-Butylcarbamoyl-3-fluorobenzylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine 3-ter hydrochloride -butoxyarbonyl-7-sloro-6- (4-slorosarbonyl-3-fluorobensylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: To a solution of 3-tert-butoxycarbonyl-6- ( 4-carboxy-3-fluorobenzylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.95 g, 4.21 mmol) in DCM (20 mL) at 0 ° C under nitrogen, three drops of DMF and oxalyl chloride (1.06 g, 8.41 mmol) are added. Stir for 2 h and concentrate in vacuo to provide the desired intermediate as a yellow oil (1.93 g, 95%).

(S) -3-tert-butoxyarbonyl-6- (4-ses-butylsarbamoyl-3-fluoro-benzylthio) -7-sloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine: To a solution of 3-tert-butoxycarbonyl-7-chloro-6- (4-chlorocarbonyl-3-fluoro-benzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (415 mg, 0.860 mmol) in DCM (10 mL), add (S) - (+) - sec-butylamine (1.0 g, 13.7 mmol) and stir at room temperature for 30 min. Concentrate in vacuo and purify by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to give the desired intermediate as a pale oil (352 mg, 79%). MS (APCI +) m / z: 421 (M + H-Boc) +.

(S) - (+) - 6 - (4-ses-Butylsarbamoyl-3-fluorobensylthio) -7-sloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride: A method is used similar to general procedure 1-4, using (+) - 3-tert-butoxycarbonyl-6- (4-sec-butylcarbamoyl-3-fluoro-benzylthio) -7-chloro-2, 3,4,5-tetrahydro-lH -benzo [d] azepine, to give the title compound as a pale solid. MS (APCI +) m / z: 421 (M + H) +. [a] 20D + 8.7 ° (c 0.5, CH30H). Examples 449-454 can be prepared essentially as described in Example 448 to react 3-tert-butoxycarbonyl-6- (4-carboxy-3-fluoro-benzylthio) -7-chloro-2, 3, 4, 5- tetrahydro-lH-benzo [d] azepine with the appropriate amine. Optical rotation and EM data (ES +) are included in the following table.

Example 455 7-Chloro-6- (3-fluoro-4-isobutylcarbamoylbenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A method similar to Example 448 is used to react 3-tert-butoxycarbonyl-6- (4-carboxy-3-fluorobenzylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine with isobutylamine. A method similar to general procedure 1-4, basic preparation, and a method similar to general procedure 2-1 is used to give the title compound as a white solid. MS (ES +) m / z: 403 (M + H) +.

Example 456 7-Chloro-6- (4-cyclohexylcarbamoylbenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate A similar method is used for preparation 177 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo [d] azepine with 4-chloromethyl-N- cyclohexylbenzamide. A method similar to general procedure 1-5, basic preparation, and a method similar to general procedure 2-1 is used to give the title compound as a white solid. MS (ES +) m / z: 429 (M + H) +. Examples 457-465 can be prepared essentially as described in example 456 by using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and chloride of properly substituted benzyl. Optical rotation and EM data (ES +) are included in the following table.

Example 466 7-Chloro-6- [4- (2, 2-dimethyl-propylcarbamoyl) benzylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to example 456 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and 4-chloromethyl-N- (2 , 2-dimethyl-propyl) -benzamide to give, after deprotection by a method similar to general procedure 1-4, the title compound as a white solid. MS (ES +) m / z: 417 (M + H) +. Examples 467-471 can be prepared essentially as described in example 466 by using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and chloride of properly substituted benzyl. The EM (ES +) data are included in the following table.

Example 472 (±) -7-Chloro-6- (1-methoxycarbonyl-1-phenylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to general procedure 1-4 is used, using (+) - 3-tert-butoxycarbonyl-7-chloro-6- (1-methoxycarbonyl-1-phenyl-methylthio) -2,3,4,5-tetrahydro -lH-benzo [d] azepine, to give the title compound as a white solid. MS (ES +) m / z 362 (M + H) +.

Example 473 (+) - 7-Chloro-6- (2-hydroxy-l-phenyl-ethylthio) 2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride To a stirred solution of (±) -3-tert-butoxycarbonyl-6- (1-carboxy-1-phenyl-methylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (220 mg, 0.447 mmol) in THF (10 mL) at 0 ° C, a 1M solution of borane in THF (1.4 mL, 1.4 mmol) is added.

Stirring is continued for 2 h at 0 ° C and then overnight at room temperature. Quench by slow addition of methanol, stir 1 h at room temperature and concentrate in vacuo. Aqueous saturated ammonium chloride is added, extracted three times with EtOAc, dried over anhydrous MgSO 4 and concentrated in vacuo. Purification by chromatography on silica gel levigating with 19: 1 DCM / ammonium saturated in methanol. A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (ES +) m / z: 334 (M + H) +. Example 474 7,9-Dichloro-6-methoxycarbonylmethylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride It is obtained as a minor product of the reaction of the 4: 1 mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 3-ter -butoxycarbonyl-7,9-dichloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-benzo [d] azepine with methyl bromoacetate, a method similar to Example 347 is used. A method similar to the general procedure is used. 1-4 to give the title compound as a white solid. MS (ES +) m / z: 320 (M + H) +.

Example 475 6- (4-Benzyloxybenzylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine Succinate Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (706 mg, 1.84 mmol) in methanol (20 mL). Potassium hydroxide (3.5 g, 55 mmol) is added and the mixture is heated at reflux for 3 h. It is cooled to room temperature. The reaction is poured into saturated aqueous NHC1 solution. It is extracted three times with EtOAc. The organic extracts are combined, dried over Na2SO4 and concentrated in vacuo to obtain crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4-tetrahydro-lH-benzo [d] azepine ( 602 mg, 100%). Dissolve 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-lH-benzo [d] azepine (282 mg, 0.9 mmol) in acetone (30 mL). Add 4-benzyloxybenzyl chloride (251 mg, 1.08 mmol), potassium carbonate (powder) (373 mg, 2.7 mmol) and potassium iodide (powder) (15 mg, 0.1 mmol) and reflux for 16 h. The reaction is cooled to room temperature, diluted with acetone, filtered and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 17: 3) to give 6- (4-benzyloxybenzylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (309 mg, 67%). MS (ES +) m / z: 510 (M + H) +. A method similar to general procedure 1-4 is used and purified by chromatography on silica gel by levigating with DCM / 2M ammonium in methanol (95: 5) to obtain the free base of the title compound (230 mg, 92%). MS (ES +) m / z: 410 (M + H) +. A method similar to general procedure 2-1 is used to obtain the title compound.

Example 476 Succinate of 7-Chloro-6- [(2-fluoro-4-f-enoxy) -benzylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to example 475 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and l-bromomethyl-2-fluoro -4-phenoxybenzene to provide, after chromatography on silica gel, levigating with hexane / EtOAc (85:15), 3-tert-butoxycarbonyl-7-chloro-6- [(2-fluoro-4-phenoxy) -benzylthio] 2,3,4,5-tetrahydro-lH-benzo [d] azepine (384 mg, 83%). MS (ES +) m / z: 414 (M-Boc + 2H) +. A method similar to general procedure 1-4 is used and purified by chromatography on silica gel by levigating with DCM / 2M ammonium in methanol (95: 5) to obtain the free base of the title compound (203 mg, 65%). MS (ES +) m / z: 414 (M + H) +. A method similar to general procedure 2-1 is used to obtain the title compound.

Example 477 7-Chloro-6- [2- (4-fluorophenyl) -2-oxo-ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 475 is used, using crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 2-bromo-4 '- fluoroacetophenone (239 mg, 1.1 mmol) to provide, after being stirred at room temperature for 16 h and purified by chromatography on silica gel by levigating with hexane / EtOAc (4: 1), 3-tert-butoxycarbonyl-7-chloro-6 - [2- (4-fluorophenyl) -2-oxo-ethylthio] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (38 mg, 9%). A method similar to general procedure 1-5 is used and purified by chromatography on silica gel by levigating with DCM / 2M ammonium in methanol (95: 5) to obtain the free base of the title compound (23 mg, 78%). MS (ES +) m / z: 350 (M + H) +. A method similar to general procedure 2-2 is used to obtain the title compound.

Example 478 7-Chloro-6- (2-hydroxyethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 347 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and methyl bromoacetate to give 3-ter -butoxycarbonyl-7-chloro-6-methoxycarbonylmethylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine.

To a solution of 3-tert-butoxycarbonyl-7-chloro-6-methoxycarbonylmethylthio-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (750 mg, 1.94 mmol) in THF (25 mL) at -78 ° C under nitrogen, add 1M DIBAL in toluene (5.0 mL, 5.0 mmol) dropwise with stirring. Heat at -30 ° C for 1 h and carefully turn off with water. Extract with EtOAc, dry over MgSO 4 anhydrous and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (2-hydroxy-ethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (651 mg, 94% ).

A method similar to general procedure 1-4 is used, using 3-tert-butoxycarbonyl-7-chloro-6- (2-hydroxyethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (190 mg, 0.531 mmol) to give the title compound as a white solid (105 mg, 67%). MS (ES +) m / z: 258 (M + H) +.

Example 479 7-Chloro-6- (3-methoxycarbonylpropylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 347 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and methyl 4-bromobutyrate to give, after deprotection by General Procedure 1-4, the title compound as a white solid. MS (ES +) m / z: 314 (M + H) +.

Example 480 7-Chloro-6- (4-methoxycarbonyl-butylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 387 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo [d] azepine with methyl-5-bromovalerate. Purify by preparative CCD by levigating with 19: 1 DCM / ammonium saturated in methanol. A method similar to general procedure 2-2 is used to give the title compound as a white solid. MS (APCI +) m / z: 328 (M + H) +.

Example 481 7,9-Dichloro-6- (4-methoxycarbonylbutylthio) -2,3,5,5-tetrahydro-lH-benzo [d] azepine hydrochloride The free base of the title compound is obtained as a minor product of the example 480, after preparative CCD levigating with 19: 1 DCM / ammonium saturated in methanol. A method similar to general procedure 2-2 is used to obtain the title compound as a pale yellow solid. MS (APCI +) m / z: 362 (M + H) +.

Example 482 7-Chloro-6-cyanomethylthio-2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine trifluoroacetate A method similar to Example 387 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1H-benzo [d] azepine with bromoacetonitrile. It is purified by reverse phase preparative HPLC (Column: Xterra Prep RP18 19x250mm, Solvent A: 10 mM aqueous ammonium carbonate, Solvent B: acetonitrile, 30-100% B for 20 minutes, flow ratio 25 mL / min) to give the title compound as a white solid. MS (APCI +) m / z: 253 (M + H) +.

Example 483 6-Cyanomethylthio-7,9-dichloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine trifluoroacetate The title compound is obtained as a minor product of example 482, after preparative reverse phase HPLC (Column: Xterra Prep RP18 19x250mm, solvent A: 10mM aqueous ammonium carbonate, solvent B: acetonitrile, 30-100% B during 20 minutes, flow ratio 25 mL / min). EM (APCI +) m / z: 287 (M + H) +.

Example 484 (±) -7-Chloro-6- (1-cyanoethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A similar method is used for preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 2-bromopropionitrile to give, then of deprotection using a method similar to general procedure 1-4, the title compound as a white solid. MS (ES +) m / z: 267 (M + H) +.

Example 485 (+) - 7-Chloro-6- (1-cyanopropylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride To a stirred solution of 1.5M lithium diisopropylamide in cyclohexane (1.37 mL, 2.05 mmol) in dry THF (5 mL) at -78 ° C under dry nitrogen, a solution of 3-tert-butoxycarbonyl-7-chloro- 6-cyanomethylthio-2,3,4,5-tetrahydro-lH-benzo [d] -azepine (600 mg, 1.70 mmol) in THF (5 mL) and stirring is continued for 2 h. Rapidly transfer the above solution by means of a cannula to a solution of ethyl iodide (13.2 g, 84.9 mmol) in THF (5 mL) and stirring is continued for 1 h. Quench with a saturated aqueous amino chloride solution, extract three times with EtOAc, dry over anhydrous Na 2 SO 4 and concentrate in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give (+) - 3-tert-butoxycarbonyl-7-chloro-6- (1-cyanopropylthio) -2,3,4,5-tetrahydro -lH-benzo [d] azepine as a pale oil (350 mg, 68%). A method similar to general procedure 1-4 is used to give the title compound as an opaque white solid. MS (ES +) m / z: 281 (M + H) +.

Example 486 7-Chloro-6- (1-cyano-l-methylethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride To a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6-cyanomethylthio-2, 3,, 5-tetrahydro-lH-benzo [d] -azepine (300 mg, 0.85 mmol) in THF (5 mL) a 0 ° C, potassium tert-butoxide (480 mg, 4.26 mmol) is added at room temperature. After 15 min, methyl iodide (3.02 g, 21.31 mmol) is added and stirring is continued overnight at room temperature. Concentrate in vacuo and purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (1-cyano-1-methyl-ethylthio) -2 3,4,5-tetrahydro-lH-benzo [d] azepine (177 mg, 55%). MS (ES +) m / z: 282 (M + H-Boc) +. A method similar to general procedure 1-4 is used to give the title compound as an opaque white solid. MS (ES +) m / z: 282 (M + H) +.

Example 487 7-Chloro-6- (4-cyanobutylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 387 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo [d] azepine with 5-bromovaleronitrile. It is purified by reverse phase preparative HPLC (Column: Xterra Prep RP18 19x250mm, Solvent A: 10mM aqueous ammonium carbonate, Solvent B: acetonitrile, 30-100% B for 20 minutes, flow ratio 25mL / min). A method similar to general procedure 2-2 is used to give the title compound as an opaque white solid. MS (APCI +) m / z: 295 (M + H) +.

Example 488 7,9-Dichloro-6- (4-cyanobutylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride The free base of the title compound is obtained as a minor product of example 487, after preparative reverse phase HPLC (Column: Xterra Prep RP18 19x250mm; Solvent A: 10mM aqueous ammonium carbonate, Solvent B: acetonitrile; 30-100 % B for 20 minutes, flow ratio 25 mL / min). A method similar to general procedure 2-2 is used to obtain the title compound as a brown solid. MS (ES +) m / z: 329 (M + H) +.

Example 489 7-Chloro-6- (2-pyridin-2-yl-ethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A similar method is used for preparation 177, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 2- (2-bromoethyl) -pyridine bromohydrate to give, after deprotection using a method similar to General Procedure 1-4, the title compound. MS (ES +) m / z 319 (M + H) +.

Example 490 6- [3- (3-tert-Butyl- [1, 2, 4] oxadiazol-5-yl) -propylthio] -7-chloro-2,3,4,5-tetrahydro-lH-benzohydrochloride [d] azepine A method similar to Example 387 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine and 5- (3-bromopropyl) - 3-tert-butyl- [1,2,4] oxadiazole to give, after deprotection using a method similar to General Procedure 1-4, the title compound as a white solid. MS (APCI +) m / z 380 (M + H) +.

Example 491 (-) -7-Chloro-6- (tetrahydrofuran-3-ylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 332 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and tetrahydrofuran-3-yl ester of the (S) -toluene-4-sulfonic acid to give, after deprotection using a method similar to General Procedure 1-4, the title compound as an opaque white solid. MS (APCI +) m / z: 284 (M + H) +; [a] 20D -28.0 ° (c 0.5, CH 3 OH). ee = 97.8% [CLAR chiral: Column: YMC ODS-AQ 120Á 4.6x50 mm [S-3μm]; levigante: gradient from 95: 5 to 5:95 A / B; solvent A: water, 0.01% HFBA, 1% isopropanol; solvent B: acetonitrile, 0.01% HFBA, 1% isopropanol; flow ratio 2 mL / min].

Example 492 (+) - 7-Chloro-6- (tetrahydrofuran-3-ylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 332 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and tetrahydrofuran-3-ester. ilo of (R) -toluene-4-sulfonic acid to give, after deprotection using a method similar to General Procedure 1-4, the title compound as an opaque white solid. MS (APCI +) m / z: 284 (M + H); [a] 20D + 32.5 ° (c 0.5, CH 3 OH); ee = 95.7% [chiral HPLC: Column: YMC ODS-AQ 120A 4.6x50 mm [S-3μm]; levigante: gradient from 95: 5 to 5:95 A / B; solvent A: water, 0.01% HFBA, 1% isopropanol; solvent B: acetonitrile, 0.01% HFBA, 1% isopropanol; flow ratio 2 mL / min].

Example 493 (±) -7-Chloro-6- (tetrahydrofuran-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to example 330 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 2- (bromomethyl) tetrahydrofuran to give , after deprotection by General Procedure 1-4, the title compound as white crystals. MS (APCI +) m / z: 298 (M + H) +. Example 494 (±) -7-Chloro-6- (tetrahydropyran-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to example 330 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 2- (bromomethyl) tetrahydropyran to give , after deprotection by General Procedure 1-4, the title compound as a white solid. MS (APCI +) m / z: 312 (M + H) +.

Example 495 (S) - (+) - 7-Chloro-6- (5-oxo-tetrahydrofuran-2-ylmethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to general procedure 1-4 is used, using (S) -3-tert-butoxycarbonyl-7-chloro-6- (5-oxo-tetrahydrofuran-2-ylmethylthio) -2,3,4,5-tetrahydro -lH-benzo [d] azepine to give the title compound as a white solid. MS (ES +) m / z: 312 (M + H) +. [a] 20D + 78 ° * (c 0.5, CH3OH) Example 496 7-Chloro-6- (3-dimethylcarbamoylpropylthio) 2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride Treat a solution of 3-tert-butoxycarbonyl-7-chloro-6- (3-methoxycarbonyl-propylthio) -2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (385 mg, 0.90 mmol) in dioxane / water (1: 1, 3.5 mL) with lithium hydroxide (43.0 mg, 1.01 mmol) at 80 ° C for 1.5 h. It is cooled to room temperature, saturated aqueous ammonium chloride and brine are added, extracted three times with ethyl ether, dried over anhydrous MgSO and concentrated in vacuo. The residue was dissolved in DCM (3.5 mL) and EDC (162 mg, 0.84 mmol), 1-hydroxybenzotriazole (91.0 mg, 0.67 mmol), triethylamine (0.20 mL, 1.35 mmol), and dimethylamine (0.700 mL, 1.35 mmol) were added. ). It is stirred overnight at room temperature. It is diluted with water, extracted with ethyl ether, dried over anhydrous MgSO 4 and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc / methanol 60: 40: 1 to give 3-tert-butoxycarbonyl-7-chloro-6- (3-dimethylcarbamoyl-propylthio) -2,3,4,5-tetrahydro -lH-benzo [d] azepine. 3-tert-Butoxycarbonyl-7-chloro-6- (3-dimethylcarbamoyl-propylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine is dissolved in DCM (1 mL) at room temperature and add 4M hydrogen chloride in dioxane (200 μL, 0.8 mmol). Stirring is continued until the CCD shows the consumption of the starting material. Concentrate in vacuo, the solid obtained is triturated with dry diethyl ether and dried at 50 ° C under high vacuum overnight to give the title compound as a hygroscopic white solid (45.0 mg, 57%). MS (ES +) m / z: 327 (M + H) +.

Example 497 7-Chloro-6- [3- (1,3-dioxo-l, 3-dihydroisoindol-2-yl) -propylthio] -2,3,4,5-tetrahydro-lH-benzo [d] trifluoroacetate azepine Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (2.0 g, 5.20 mmol) in methanol (58 mL) and potassium hydroxide (9.36 g, 167 mmol) is added. It is heated at 50 ° C for 2 h. Cool to room temperature, add saturated aqueous ammonium chloride and water, extract three times with EtOAc, dry over anhydrous Na 2 SO 4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2. , 3, 4, 5-tetrahydro-lH-benzo [d] azepine (1.62 g, 5.20 mmol). The crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.40 g, 4.46 mmol) is dissolved in dry DMF (49.8 L) and DBU (0.80 mL, 5.35 mmol) and 3-bromopropyl phthalimide (1.55 g, 5.80 mmol) are added. Stir at room temperature for 3 h. Aqueous saturated ammonium chloride and water are added. It is extracted twice with EtOAc, dried over anhydrous Na 2 SO and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (6: 1) to give the free base of the title compound (1.64 g, 74%). A method similar to general procedure 1-5 is used to deprotect 3-tert-butoxycarbonyl-7-chloro-6- [3- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -propylthio ] -2,3,4,5-tetrahydro-lH-benzo [d] azepine and purified by reverse phase preparative HPLC to give the title compound. MS (APCI +) m / z 401 (M + H) +.

Example 498 6- (3-Benzoylaminopropylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine trifluoroacetate 3-tert-butoxycarbonyl-7-chloro-6- [3- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -propylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine (1.20 g, 2.39 mmol) in ethanol (53.2 mL ), hydrazine (0.150 mL, 4.78 mmol) is added and heated at 65 ° C for 2 h. Cool to room temperature, filter from the precipitate and concentrate in vacuo to give 6- (3-aminopropylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-1H- benzo [d] azepine (861 mg, 97%). MS (APCI +) m / z: 371 (M + H) +. To a solution of 6- (3-aminopropylthio) -3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine (46.7 mg, 0.126 mmol) in dry DCM ( 0.5 mL) at room temperature under nitrogen, add triethylamine (19.3 μL, 0.139 mmol) and benzoyl chloride (16.1 μL, 0.139 mmol). Stir at room temperature for 2.5 h. Aqueous saturated ammonium chloride and water are added, extracted three times with EtOAc, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was dissolved in DCM (0.16 L), trifluoroacetic acid (44.6 μL, 0.58 mmol) was added and it was stirred for 18 h at room temperature. Concentrate in vacuo and purify by preparative HPLC [Column: YMC ODS-AQ 120A 20x250mm [S10-20μm]; levigante: 95: 5 to 5:95 A / B; solvent A: water, 0.1% TFA, 1% isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol; flow ratio 20 mL / min] to give the title compound (7.0 mg, 12%). MS (APCI +) m / z 375 (M + H) +.

Example 499 6- [3- (3-Phenylureido) -propylthio] -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine trifluoroacetate A method similar to Example 498 is used, using phenyl isocyanate, to give the title compound. MS (APCI +) m / z 390 (M + H) +.

Example 500 7-Chloro-6- [3- (4-trifluoromethylbenzoylamino) -propylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine trifluoroacetate To a stirred solution of 4-trifluoromethylbenzoic acid (60.0 mg, 0.316 mmol) in anhydrous DMF (1.2 mL) at room temperature under nitrogen, add EDC (63.6 mg, 0.332 mmol), 1-hydroxybenzotriazole (44.8 mg, 0.332 mmol) , 4-dimethylaminopyridine (40.5 mg, 0.332 mmol) and a solution of 6- (3-aminopropylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (123 mg, 0.332 mmol) in DCM (2 mL). Stir for 18 h at room temperature. Water is added, extracted twice with EtOAc, dried over anhydrous Na2SO4 and concentrated in vacuo. Treat the residue with trifluoroacetic acid (0.272 mL, 0.640 mmol) in DCM (0.451 mL) at room temperature for 18 h. Concentrate in vacuo and purify by preparative reverse phase HPLC [Column: YMC ODS-AQ 120A 20x250mm [S10-20μm]; levigante: 95: 5 to 5:95 A / B; solvent A: water, 0.1% TFA, 1% isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol; flow ratio 20 mL / min] to give the title compound as a white solid (31.0 mg, 18%). MS (APCI +) m / z 443 (M + H) +.

Example 501 7-Chloro-6- [3- (4-tert-butylbenzoylamino) propylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine trifluoroacetate A method similar to example 500 is used, using 6- (3-aminopropylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 4-ter acid. -butyl benzoic to give the title compound as a white solid. MS (APCI +) m / z 431 (M + H) +.

Example 502 7-Chloro-6- (2-ethoxycarbonylamino-ethylthio) 2,3,4,5-tetrahydro-lH-benzo [d] azepine trifluoroacetate A method similar to Example 497 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 3-bromoethyl phthalimide to give 6- (3-aminoethylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine. MS (ES +) m / z 357 (M + H) +. A method similar to Example 498 is used, using 6- (3-aminoethylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and ethyl chloroformate to give , after deprotection using a method similar to General Procedure 1-5, the title compound as a white solid. MS (APCI +) m / z: 329 (M + H) +.

Example 503 7-Chloro-6- trifluoroacetate. { 2- [(pyridine-4-carbonyl) amino] -ethylthio} -2, 3,4, 5-tetrahydro-lH-benzo [d] azepine A method similar to example 500 is used, using 6- (3-aminoethylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and isonicotinic acid to give the title compound. MS (ES +) m / z: 362 (M + H) +.

Example 504 7-Chloro-6- [2- (cyclopropanecarbonylamino) -ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine trifluoroacetate A method similar to Example 498 is used, using 6- ( 3-aminoethylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-1H-benzo [d] azepine and cyclopropanecarbonyl chloride to give, after deprotection using a method similar to the general procedure 1-5, the title compound. MS (ES +) m / z: 325 (M + H) +.

Example 505 6- (2-Benzenesulfonylamino-ethylthio) -7-chloro-2,3,4,5-tetrahydro-lH-benzo [d] azepine trifluoroacetate A method similar to Example 498 is used, using 6- (3-amino-ethylthio) -3-tert-butoxycarbonyl-7-chloro-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and benzenesulfonyl to give, after protection, a method similar to General Procedure 1-5, the title compound is used as a white solid. MS (APCI +) m / z: 397 (M + H) +.

Example 506 7-Chloro-6- (3-pyrrol-1-yl-propylthio) 2,3,4,5-tetrahydro-1H-benzo [d] azepine trifluoroacetate A method similar to Example 497 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and N- (3-bromopropyl) pyrrole to give, after deprotection using a method similar to General Procedure 1-5, the title compound as a white solid. MS (ES +) m / z: 321 (M + H) +.

Example 507 7-Chloro-6- [2- (2, 2-dimethylpropionyloxy) -ethylthio] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride To a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6- (2-hydroxyethylthio) -2,3,4,5-tetrahydrobenzo [d] azepine (85 mg, 0.238 mmol) in DCM (3 ml) a 0 ° C, triethylamine (331 μl, 2.381 mmol) is added followed by trimethylacetyl chloride (147 μl, 1190 mmol). The mixture is stirred for 15 min, diluted with water, extracted three times with EtOAc, dried over anhydrous Na 2 SO 4 and concentrated in vacuo. Deprotection by general procedure 1-5, basic preparation, and by general procedure 2-2, gives the title compound. MS (ES +) m / z 342 (M + H).

Example 508 7-Chloro-6- (2-cyclohexanecarbonyloxy-ethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 507 is used, using cyclohexanecarbonyl chloride, to give the title compound. MS (ES +) m / z 368 (M + H).

Example 509 7-Chloro-6- (3-hydroxymethylbenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A similar method is used for preparation 242, using 3-tert-butoxycarbonyl- 7-chloro-6- (3-hydroxymethylbenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine to give, after deprotection by General Procedure 1-4, the title compound as a solid white. MS (ES +) m / z: 334 (M + H) +.

Example 510 7-Chloro-6- (2-hydroxymethylbenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A similar method is used for preparation 242, using 3-tert-butoxycarbonyl-7-chloro-6- (2-hydroxymethylbenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine to give, then of deprotection by General Procedure 1-4, the title compound as a white solid. MS (ES +) m / z: 334 (M + H) +.

Example 511 7-Chloro-6- (4-hydroxymethylbenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to general procedure 1-4 is used, using 3-tert-butoxycarbonyl-7-chloro-6- (4-hydroxymethylbenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine, for give the title compound as a white solid. MS (ES +) m / z: 334 (M + H) +.

Example 512 7-Chloro-6- (4-methoxymethylbenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride To a stirred solution of 3-tert-butoxycarbonyl-7-chloro-6- (4-hydroxymethyl-benzylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine (133 mg, 0.306 mmol) in Anhydrous DMF (2 mL) under nitrogen, sodium hydride (60% dispersion, 13-15 mg, 0.375 mmol) is added at room temperature and stirring is continued for 30 min. Methyl iodide (80 μL, 1.28 mmol) is added. After 15 min, it is diluted with water, extracted three times with EtOAc, dried over anhydrous MgSO 4 and concentrated in vacuo. Purification by chromatography on silica gel by levigating with hexane / EtOAc (15: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- (4-methoxymethyl-benzylthio) -2,3,4,5-tetrahydro-1H -benzo [d] azepine as a clear oil, which crystallizes on standing to a white solid (87 mg, 63%), together with recovered starting material (22 mg, 17%). A method similar to general procedure 1-4 is used to give the title compound as a white solid. MS (ES +) m / z: 348 (M + H-Boc) +.

Example 513 7-Chloro-6- (3-methoxymethylbenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to example 512 is used, using 3-tert-butoxycarbonyl-7-chloro-6- (3-hydroxymethylbenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine to give the title as a white solid. MS (ES +) m / z: 348 (M + H).

Example 514 7-Chloro-6- (2-methoxymethylbenzylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to example 512 is used, using 3-tert-butoxycarbonyl-7-chloro-6- (2-hydroxymethylbenzylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine to give the title as a white solid. MS (ES +) m / z: 348 (M + H).

Example 515 7-Chloro-6- (2-methoxyethylthio) -2, 3,, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to example 512 is used, using 3-tert-butoxycarbonyl-7-chloro-6- (2-hydroxy-ethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine, to give the title compound as a white solid. MS (ES +) m / z: 272 (M + H).

Example 516 7-Chloro-6- (4-methoxybutylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 478 is used, using 3-tert-butoxycarbonyl-7-chloro-β- (3-methoxycarbonyl-propylthio) -2,3,4,5-tetrahydro-1H-benzo [d] zepine to give 3 -ter-butoxycarbonyl-7-chloro-6- (4-hydroxybutylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine. A method similar to Example 512 is used, using 3-tert-butoxycarbonyl-7-chloro-6- (4-hydroxybutylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine to give the title as a white solid. MS (ES +) m / z: 300 (M + H) +.

Example 517 (+) - 7-Chloro-6- (2-methoxy-1-phenylethylthio) -2,3,4,5-tetrahydro-1H-benzo [d] azepine hydrochloride A method similar to Example 512 is used, using (±) -3-tert-jutoxycarbonyl-7-chloro-6- (2-hydroxy-1-phenylethylthio) -2, 3, 4, 5-tetrahydro-1J-benzo [] azepine to give, after deprotection by a method similar to General Procedure 1-4, the title compound as an opaque white solid. MS (ER +) m / z: 348 (M + H) +.

EXAMPLE 518 (-) - 7-Chloro-6- (2-methoxy-1-phenylethylthio) -2,3,4,5-tetrahydro-li? -benzo [d] azepine hydrochloride The enantiomers of (±) -7-chloro-6- (2-methoxy-1-phenyl-ethylthio) -2, 3, 4, 5-tetrahydro-li7-benzo [] azepine are separated by chiral normal phase chromatography ( Chiralcel column OJ 8x33 cm, levigating with DMEA 0.2% in ethanol / heptane, 40:60). The second levigation isomer is collected and General Procedure 2-2 is used to give the title compound as a white solid (76 mg, 29%). MS (ER +) m / z: 349 (M + H) +. [a] 20D -176 ° (c 0.5, CH 3 OH).

Example 519 6- (4-Fluorobenzylthio) -7-methyl-2,3,4,5-tetrahydro-l-benzo [d] azepine hydrochloride A method similar to General Procedure 7 is used, using 3-tert.-utoxycarbonyl-6-dimethylcarbamoylthio-7-methyl-2,3,4,5-tetrahydro-lH-benzo [d] azepine (75 mg, 0.206 mmol) and 4-fluorobenzylbromide (195 mg, 1.03 mmol) to give, after chromatography on silica gel, levigating with hexane / EtOAc (1: 0, 9: 1 and 4: 1), 3-ter- £ > utoxycarbonyl-6- (4-fluorobenzylthio) -7-methyl-2,3,4,5-tetrahydro-l-benzo [d] azepine as an oil (59 mg, 71%). MS (ER +) m / z: 302 (M + H-Boc) +. A method similar to General Procedure 1-4 is used, using 3-ter-1'-ethoxycarbonyl-6- (4-fluoro-benzylthio) -7-methyl-2,3,4,5-tetrahydro-li? -benzo [ d] azepine (55 mg, 0.137 mmol) to give the title compound as a white solid (42 mg, 91%). MS (ER +) m / z: 285 (M + H) +.

Example 520 7-Cyano-6- (4-fluorobenzylthio) -2, 3, 4, 5-tetrahydro-1-benzo [d] azepine Succinate A method similar to General Procedure 7 is used, using 3-tert-jutoxycarbonyl-7-cyano-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1-benzo [d] azepine (123 mg, 0.33 mmol) and 4-fluorobenzyl bromide (204 mg, 1.64 mmol), to give 3-tert-Jutoxycarbonyl-7-cyano-6- (4-fluoro-benzylthio) -2,3,4,5-tetrahydro-lif-benzo [d ] azepine as a colorless oil (118 mg, 87%). A method similar to General Procedure 1-4 is used, using 3-tert-butoxycarbonyl-7-cyano-6- (4-fluoro-benzylthio) -2,3,4,5-tetrahydro-1-p-benzo [d ] azepine (118 mg, 0.286 mmol) to give, after basic work, the free base of the title compound (89 mg, 100%). MS (ER +) ml z 313 (M + H) +. A method similar to General Procedure 2-1 is used to give the title compound (123 mg, 100%). MS (ER +) ml z 313 (M + H) +.

Example 521 Succinate of (+) - 7-Cyano-6- [1- (4-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro-l-1-benzo [d] azepine A method similar to the General Procedure is used 7, using 3-tert.-utoxycarbonyl-7-cyano-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine (171 mg, 0.46 mmol) and bromide (+) -1- ( 4-fluorophenyl) ethyl (377 mg, 1.85 mmol) to give, after purification by chromatography on silica gel, (±) -3-tert-jutoxycarbonyl-7-cyano-6- [1- (4-fluorophenyl) -ethylthio] -2,3,4,5-tetrahydro-1-benzo [d] azepine as a colorless oil (10.3 mg, 5.3%). MS (ER +) m / z 449 (M + Na) +, 465 (M + K) +. A method similar to General Procedure 1-5 is used, using (+) - 3-tert-J-butoxycarbonyl-7-cyano-6- [1- (4-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro- li? -benzo [d] azepine (10.3 mg, 0.024 mmol) to give, after basic work, the free base of the title compound (6.8 mg, 87%). MS (ER +) m / z 327 (M + H) +. A method similar to General Procedure 2-1 is used to give the title compound as a white solid (9.3 mg, 87%). MS (ER +) m / z 327 (M + H) +.

Example 522 Succinate of 7-Cyano-6- [1- (4-fluorophenyl) ethylthio] -2,4,4,5-tetrahydro-li? -benzo [d] azepine, Isomer 1 The two enantiomers of (+) - 7-cyano-6- [1- (4-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro-lff-benzo [d] azepine are separated by chiral HPLC (Chiralpak column AD-H 15cm x 4.6mm with a packing size of 5 μm Levigating with heptane / ethanol (95: 5) containing 0.2% DEA at 0.5 mL / min with an injection volume of 10.00 μL). The first levigation isomer (tR = 17.2 min, ee> 99%) is subjected to General Procedure 2-1 to provide the title compound as a white solid. MS (ER +) m / z 327 (M + H) +.

Example 523 7-Bromo-6- (3-ethoxycarbonylpropylthio) -2, 3, 4, 5-tetrahydro-li-benzo [d] azepine hydrochloride A method similar to Preparation 177 is used, using 3-tert-jutoxycarbonyl-7-bromo-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-li? -benzo [d] azepine and ethyl 4-bromobutyrate for giving, after deprotection by a method similar to General Procedure 1-4, the title compound. MS (ER +) m / z: 374 (M + H) +.

Example 524 7-Bromo-6- (3-dimethylcarbamoylpropylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to Example 523 is used, using 7-bromo-3-tert-jutoxycarbonyl-6- (3-ethoxycarbonylpropylthio) -2,3,4,5-tetrahydro-L-t-benzo [d] azepine, to give the compound of the title as a white solid. MS (ER +) m / z: 373 (M + H) +.

Example 525 7-Bromo-6- (4-oxo-4-pyrrolidin-1-yl-butylthio) -2,3,4,5-tetrahydro-li? -benzo [d] azepine hydrochloride A method similar to Example 523 is used, using 7-bromo-3-er-butoxycarbonyl-6- (3-ethoxycarbonylpropylthio) -2,3,4,5-tetrahydro-li? -benzo [d] azepine and pyrrolidine to give the title compound. MS (ER +) m / z: 397 (M + H) +.

Example 526 7-Bromo-6- [3- (1,3-dioxo-1,3-dihydroisoindol-2-yl) -propylthio] -2,3,4,5-tetrahydro-lif-benzo [d] hydrochloride azepine A method similar to Example 497 is used to react 7-bromo-3-tert-uxycarbonyl-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-li? -benzo [d] azepine with 3-bromopropyl phthalimide. A method similar to General Procedure 1-4 is used to give the title compound as a white solid. MS (ER +) m / z 445 (M + H) +.

Example 527 6- [2- (2, 2-Dimethylpropionyloxy) -ethylthio] -7-trifluoromethyl-2,3,4,5-tetrahydro-li? -benzo [d] azepine hydrochloride 3-tert.-butoxyarbonyl-6-dimethylsarbamoylthio-7-trifluoromethyl-2,3,4,5-te-trahydro-benzo [d] azepine: To a stirred solution of 7-bromo-6-dimethylcarbamoylthio-3- (2 , 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-li? -benzo [djazepine (1383 g, 3.254 mmol), in NMP (40 ml) add trifluoromethyl acetate (3.54 g, 26.03 mmol ), copper iodide (I) (2.47 g, 13.0 mmol) and the mixture is heated at 180 ° C for 4 h. It is cooled to room temperature. It is diluted with EtOAc, water and the solid copper residue is removed by filtration. The filtrate layers are separated and the aqueous layer extracted three times with EtOAc. Dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (6: 1) to give the desired intermediate as a yellow oil (882 mg, 74%). 3-fcer-butoxyarbonyl-6- [2- (tezr-Jbuyl-dimethylsilanyloxy) ethylthio] -7-trifluoromethyl-2, 3,4,5-tetrahydro-lff-benzo [d] azepine: A method similar to Preparation 177, using 3-tert -butoxycarbonyl-6-dimethylcarbamoylthio-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo [d] azepine and (2-bromoethoxy) -tert -tyldimethylsilane to give the desired intermediate. 3-tert-butylated aryl-6- (2-hydroxyethylthio) -7-trifluoromethyl-2,3,4,5-tetrahydro-lH-benzo [d] azepine: 6- [2- (tert-butyl-dimethyl- silanyloxy) -ethylthio] -7-trifluoromethyl-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (153 mg, 0.303 mmol) in THF (3 mL). 1.0 M tetrabutylammonium fluoride in THF (600 μL, 0.606 mmol) is added and stirred overnight. Dilute with water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (85:15) to give the desired intermediate. 6- [2- (2, 2-Dxmethylpropionyloxy) -ethylthio] -7-trifluoromethyl-2, 3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride: A method similar to Example 507 is used, using 3-tert-butoxycarbonyl-6- (2-hydroxyethylthio) -7-trifluoromethyl-2,3,4,5-tetrahydro-l-benzo [d] azepine to give, after deprotection using a method similar to General Procedure 1 -4, the title compound as a white solid. MS (ER +) m / z 376 (M + H) +.

General Procurement 8 Dissolve the appropriate bromide (2 equiv.) In isopropylamine (300-400 equiv.) At room temperature, under nitrogen, then add palladium (II) bis (benzonitrile) dichloride (0.2 equiv.), Triphenylphosphine (0.4 equiv.) and copper iodide (I) (0.2 equiv.). The solution is degassed and purged with nitrogen, then the appropriate alkyne (1.0 equiv.) Is added. The reaction vessel is sealed, stirred at room temperature for 30 min, then at 75 ° C for 3-4 h. Remove most of the solvent in vacuo, add diethyl ether and 2M aqueous HCl. Dry the organic layer over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with isohexane / EtOAc or hexane / EtOAc mixtures.

Preparation 249 2-Ethynyl-thiophene Trimethyl-thiophene-2-ylethynylsilane: A method similar to General Procedure 8 is used to couple 2-bromo-thiophene (0.97 mL, 10 mmol) with ethynyltrimethylsilane (2.82 mL, 20 mmol). Purify by chromatography on silica gel by levigating with isohexane to give the desired intermediate (1.46 g, 81%). GC-MS m / z 180 (M +). 2-Ethynyl-thiophene: A saturated solution of potassium carbonate in methanol (7.5 mL) is added to trimethyl-thiophene-2-ylethynylsilane (540 mg, 3 mmol) in deoxygenated methanol (100 mL) at room temperature under nitrogen . The reaction is quenched for 3.5 h, then diluted with dichloromethane (100 mL) and washed with water (3 x 100 mL). The organic layer is removed, dried using an ISCO® phase separator and then concentrated in vacuo to give the title compound (302 mg, 93%).

Preparation 250 3-tert-butoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-li? -benzo [d] azepine 7-sloro-3- (2, 2, 2-rifluoroasethyl) -6-trimethylsilanylethynyl-2,3,4,5-tetrahydro-1H-benzo [d] azepine: A method similar to General Procedure 3 is used to couple 7 -chloro-3- (2,2, 2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (425 mg, 1 mmol) with 2-trimethylsilylacetylene (0.28) mL, 2 mmol). Purify by chromatography on silica gel by levigating with isohexane / EtOAc (100: 0 to 85:15 gradient for 40 min) to give the desired intermediate (247 mg, 81%). MS (ER +) m / z 306 (M + H) +. 3- tert-Jbutoxisarbonyl-7-sloro-6-ethynyl-2,3,4,5-tetrahydro-lff-benzo [d] azepine: A solution of potassium carbonate (999 mg, 7.2 mmol) in water is added ( 5 mL) to 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trimethylsilanylethynyl-2, 3,4,5-tetrahydro-l-p-benzo [d] azepine (180 mg, 0.48 mmol) in methanol (10 mL) and stirred at room temperature, under nitrogen for 1.5 h. Di-tert-Butyl-dicarbonate (115 mg, 0.53 mmol) in dichloromethane (8 L) is added and stirred for 3 days. Another solution of di-tert-butyl-dicarbonate (115 mg, 0.53 mmol) in dichloromethane (5 mL) is added and stirred for 2 h. Water (10 mL) and dichloromethane (10 mL) are added and the organic layer is separated. The aqueous layer is extracted with dichloromethane (3 x 10 mL) and the organic layers are combined. Dry using an ISCO® phase separator and concentrate. Purify by chromatography on silica gel by levigating with isohexane / EtOAc (gradient 1: 0 to 4: 1 for 30 min) to give the title compound as a solid (150 mg, 100%). MS (ER +) m / z: 328 (M + Na) +.

Preparations 251 2-chloro-pyridazine 3 is added. { 2H) -pyridazinone (2 g, 22 mmol) to pure phosphorus oxychloride (4 mL) in a sealed tube and the mixture is heated at 80 ° C with stirring for 2 h. Water (10 mL), saturated aqueous NaHCO3 (50 mL) and solid Na2CO3 are added carefully until pH = 9. The mixture is extracted with dichloromethane (4 x 50 mL). Dry the organic layer over Na 2 SO 4, filter and concentrate in vacuo to give the title compound as brown oil (2 g, 84%).

Preparation 252 l-tert-Jbutyl-3-prop-2-ynyl-imidazolidin-2-one L-ter-util-imidazolidin-2-one (2 g, 14 mmol) is dissolved in anhydrous THF (60 mL) and cooled to -78 ° C. N-Butyllithium (6.8 mL, 17 mmol, 2.5 M solution in hexanes) is slowly added. The solution is stirred for 30 min. Propargyl bromide (3.2 mL, 28.2 mmol, 80% solution in toluene) is added rapidly. The solution is warmed to room temperature while stirring overnight. The reaction mixture is concentrated in vacuo and the residue is filtered on a pad of silica gel by levigating with dichloromethane / diethyl ether (1: 1) to give the title compound as a yellow oil which solidifies on standing (1.77 g). , 70%). GC-MS m / z (%) 180 (M +, 7), 165 (100), 123 (12), 84 (17).

Example 528 Succinate of 7-chloro-6-pyridin-2-ylethynyl-2,3,4,5-tetrahydro-J? -benzo [d] azepine A method similar to General Procedure 3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li? -benzo [d] azepine ( 425 mg, 1 mmol) with 2-ethynyl-pyridine (0.20 mL, 2 mmol). Purify by chromatography on silica gel by levigating with isohexane / EtOAc (gradient 1: 0 to 1: 1 for 40 min) to give 7-chloro-6-pyridin-2-ylethynyl-3- (2,2,2-trifluoroacetyl) ) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (342 mg, 90%). MS (ER +) m / z: 379 (M + H) +. A method similar to General Procedure 1-2 is used to deprotect 7-chloro-6-pyridin-2-ylethynyl-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lf-benzo [d] azepine (60 mg, 0.159 mmol). Purify by SCX chromatography to give the free base of the title compound (33 mg, 73%). MS (ER +) m / z: 283 (M + H) +. A method similar to General Procedure 2-1 is used to give the title compound as a light brown solid (45 mg, 95%). MS (ER +) m / z: 283 (M + H) +.

Examples 529-531 Examples 529-531 can be prepared essentially as described in Example 528 by using 7-chloro-3- (2, 2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3, 4, 5- tetrahydro-li? -benzo [d] azepine and the appropriate alkyne. The general performances and EM data (ER +) are shown in the Table below.

Example 532 7-Chloro-6-thiazole-2-ylethynyl-2,3,4,5-tetrahydro-1H-benzo [d] azepine Succinate 3-tert.-utoxysarbonyl-7-sloro-6- (thiazol-2-ylethynyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: A method similar to General Procedure 8 is used for couple 2-bromo-thiazole (0.09 mL, 0.96 mmol) with 3-tert-jutoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-t-benzo [d] azepine (148 mg, 0.48 mmol). Purify by chromatography on silica gel by levigating with isohexane / EtOAc (gradient 1: 0 to 4: 1 for 30 min) to give the desired intermediate (165 mg, 89%). MS (ER +) m / z: 389 (M + H) +.

Sussinate 7-sloro-6- (thiazol-2-ylethynyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: A method similar to General Procedure 1-5 is used to deprotect 3-ter - Utoxycarbonyl-7-chloro-6- (thiazol-2-ylethynyl) -2,3,4,5-tetrahydro-l, -benzo [d] azepine (140 mg, 0.36 mmol). Elute through SCX column to give the free base of the title compound (89 mg, 86%). MS (ER +) m / z: 289 (M + H) +. A method similar to General Procedure 2-1 is used to give the title compound as a light yellow solid (125 mg, 86%). MS (ER +) m / z: 289 (M + H) +. Example 533 { L) 7-Chloro-6-pyridazin-3-ylethynyl-2, 3, 4, 5-tetrahydro-l, -benzo [d] azepine tertate 3- fcer-Jbutoxisarbonyl-7-sloro-6-pyridazin-3-ylethynyl-2,3,4,5-tetrahydro-lff-benzo [d] azepine: A method similar to General Procedure 8 is used to couple 2-chloro pyridazine (98 mg, 0.86 mmol) with 3-tert-utoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-l-p-benzo [d] azepine (104 mg, 0.34 mmol). Purify by chromatography on silica gel by levigating with isohexane / EtOAc (gradient 1: 0 to 4: 1 for 30 min) to give 3-tert-jtoxycarbonyl-7-chloro-6-pyridazin-2-ylethynyl-2,3. , 4,5-tetrahydro-li-benzo [d] azepine (26 mg, 10%). MS (ER +) m / z: 384 (M + H) +.

(L) -7-Sloro-6-pyridazin-3-ylethynyl-3,4,5-te rahydro-l-p-benzo [d] azepine tartrate: A method similar to General Procedure 1-5 is used to check out 3-tert.-utoxycarbonyl-7-chloro-6-pyridazin-2-ylethynyl-2, 3,4,5-tetrahydro-li? -benzo [d] azepine. A method similar to General Procedure 2-6 is used to give the title compound as a solid (15 mg, 51%). MS (ER +) m / z: 284 (M + H) +.

Example 534 (i) 7-Chloro-6- (3-fluoro-phenylethynyl) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine A method similar to General Procedure 3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-lff-benzo [d] azepine (425) mg, 1 mmol) with (3-fluorophenyl) -ethyl (241 mg, 2 mmol). Purify by chromatography on silica gel by levigating with isohexane / EtOAc (gradient 1: 0 to 1: 1 for 40 min) to give 7-chloro-6- (3-fluoro-phenylethynyl) -3- (2, 2, 2 -trifluoroacetyl) -2,3,4, 5-tetrahydro-li? -benzo [d] azepine (247 mg, 64%). MS (ER +) m / z: 396 (M + H) +. A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- (3-fluoro-phenylethynyl) -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH -benzo [d] azepine (68 mg, 0.18 mmol). Purify by SCX chromatography to give the free base of the title compound (46 mg, 85%). MS (ER +) m / z: 300 (M + H) +. A method similar to General Procedure 2-6 is used to give the title compound as a white solid (61 mg, 94%). MS (ER +) m / z: 300 (M + H) +.

Example 535 Succinate of 7-chloro-6- (2-fluoro-phenylethynyl) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine A method similar to General Procedure 3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine ( 425 mg, 1 mmol) with (2-fluorophenyl) -etinyl (241 mg, 2 mmol). Purify by chromatography on silica gel by levigating with isohexane / EtOAc (gradient 1: 0 to 1: 1 for 40 min) to give 7-chloro-6- (2-fluoro-phenylethynyl) -3- (2.2, 2). -trifluoroacetyl) -2,3,4, 5-tetrahydro-li? -benzo [d] azepine (262 mg, 68%). MS (ER +) m / z: 396 (M + H) +. Methods similar to General Procedures 1-1 and 2-1 are used to give the title compound as a white solid (93%). MS (ER +) m / z: 300 (M + H) +.

Example 536 (L) -T- [3- (3-tert-butyl-2-oxo-imidazolidin-1-yl) -prop-1-ynyl] -7-chloro-2, 3, 4, 5-tertrate tetrahydro-li? -benzo [d] azepine A method similar to General Procedure 3 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li? -benzo [d] azepine ( 425 mg, 1 mmol) with l-tert-butyl-3-prop-2-ynyl-imidazolidin-2-one (360 mg, 2 mmol). Purify by chromatography on silica gel by levigating with isohexane / EtOAc (19: 1 to 3: 2 gradient) to give 6- [3- (3-tert-butyl-2-oxo-imidazolidin-1-yl) -prop-1-ynyl] -7-chloro-3- (2) , 2,2-trifluoroacetyl) -2,3,4, 5-tetrahydro-li? -benzo [d] azepine (380 mg, 83%) as a yellow oil. LC-MS (ER +) m / z: 478 (M + Na) +, 456 (M + H) +, t R = 4.43 min. A method similar to General Procedure 1-1 is used, but adding water (10 mL) to the ammonia / methanol solution (20 mL, 7N solution), to deprotect 6- [3- (3-tert-butyl-2- oxo-imidazolidin-1-yl) -prop-1-ynyl] -7-chloro-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine (329 mg, 0.72 mmol) and give the free base of the title compound (217 mg, 84%). A method similar to General Procedure 2-6 is used to give the title compound as a solid (211 mg, 58% overall yield). LC-MS (ER +) m / z: 360 (M + H) +, t R = 4.54 min.

Preparation 253 2, 2-Difluoro-2-phenyl-ethylamine 2, 2-Difluoro-2-phenyl-ethanol: Lithium aluminum hydride (5.18 mL, 5.18 mmol, 1M solution in THF) is added to a solution of methyl difluorophenylethanoate (0.964 g, 5.18 mmol, prepared by following the procedure described in J. Org. Chem. 1995, 60, 5174-5179) in anhydrous THF (10 L) at 0 ° C. The mixture is stirred at room temperature for 45 min. Cool to 0 ° C and quench with EtOAc and then water. The organic phase is separated and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are dried over Na2SO4, filtered and concentrated in vacuo to provide the desired intermediate (0.8 g, 98%) which was used without any further purification. 2, 2-Difluoro-2-phenyl-ethyl trifluoromethanesulfonate: Triflic anhydride (1.28 mL, 2.14 g) is added dropwise to a stirred solution of 2,2-difluoro-2-phenyl-ethanol (0.8 g, 5.06 mmol). ) and 2,6-di-tert-util-4-methylpyridine (1556 g, 7.59 mmol) in anhydrous dichloromethane (25 mL) at -78 ° C. The reaction is stirred overnight while the temperature warms. The mixture is diluted with pentane and the precipitate is filtered over Celite®. The filtrate was concentrated in vacuo and the crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (95: 5) to give the title compound (946 mg, 64%). (2-Azido-l, 1-difluoro-ethyl) -bensen: A solution of 2,2-difluoro-2-phenylethyl trifluoromethanesulfonate (759 mg, 2.617 mmol) and sodium azide (357 mg) is heated at 60 ° C. , 5.496 mmol) in anhydrous DMF (10 mL) under nitrogen for 3 h. The reaction mixture is cooled to room temperature. It is diluted with water and the aqueous phase is extracted twice with diethyl ether. The combined organic extracts are washed twice with ice cold water, dried over Na 2 SO 4, filtered and concentrated in vacuo to provide the desired intermediate as an oil (475 mg, 99%) which was used without any further purification. 2, 2-Difluoro-2-phenyl-ethylamine: Dissolve (2-azido-1,1-difluoro-ethyl) -benzene (475 mg, 2.59 mmol) in EtOAc (30 mL). 10% Pd / C is added and the mixture is exposed to hydrogenation under atmospheric pressure (balloon) for 1 h. The catalyst is filtered through Celite® and the filtrate is concentrated in vacuo to provide the title compound as an oil (400 mg, 98%) which was used without any further purification.

Preparation 254 2-Bromo-benzothiazole-6-carbonitrile 2-OXO-2,3-dihydro-benzothiazole-6-sarbonitrile: Combined 6-bromobenzothiazolinone (2 g, 8.69 mmol), copper cyanide (1.3 g, 1.48 mmol), anhydrous DMF (5 mL) and heated to reflux for 15 h. Water (20 mL) and sodium cyanide (1.4 g, 27.7 mmol) are added at 100 ° C. The reaction mixture is cooled to room temperature and stirred for 2 h. The reaction mixture is extracted with EtOAc (5 x 30 mL) at 70 ° C. The organic layers are combined, washed with water (3 x 40 mL) and dried over anhydrous Na2SO4. Concentrate in vacuo to obtain the desired intermediate as a yellow solid (2 g, 87%). GC-MS m / z: 176 (M +). 2-Bromo-benzothiazole-6-sarbonitrile: Combine 2-oxo-2,3-dihydro-benzothiazole-6-carbonitrile (1.1 g, 6.24 mmol), tetrabutylammonium bromide (3 g, 9.36 mmol), phosphorus pentoxide ( 2.7 g, 18.7 mmol), anhydrous toluene (40 mL) and refluxed for 2.5 h. The reaction mixture is cooled to room temperature. The toluene layer is decanted and washed with saturated aqueous NaHCO3 (3 x 10 mL). The organic phase is concentrated in vacuo and the residue purified by chromatography on silica gel by levigating with hexane / EtOAc (gradient 1: 0 to 4: 1) to obtain the title compound as a colorless oil (0.9 g, 61%). . GC-MS m / z: 239 (M +).

Preparation 255 6-Aminomethyl-2-cyclohexylmethyl-benzothiazole 2-Cislohexylmethyl-benzothiazole-6-sarbonitrile: Place 2-bromo-benzothiazole-6-carbonitrile (0.2 g, 0.96 mmol), anhydrous THF (3 L), 1-methyl-2-pyrrolidinone (3 mL), iodide tetrabutylammonium (1.1 g, 2.89 mmol), tris (dibenzylideneacetone) dipalladium (0) (18 mg, 0.09 mmol) and [1,1 '-bis (diphenylphosphine) ferrocyne] dichloropalladium (II) (11 mg, 0.09 mmol) in a flask. 0.5M cyclohexylmethylzinc bromide in THF (3.8 mL, 1.92 mmol) is added to the mixture, degassed 3 times upon partial evacuation of the atmosphere and flushed with nitrogen and the reaction mixture is stirred at 80 ° C for 2 h. The reaction mixture is cooled to room temperature, diluted with EtOAc (10 mL) and washed with brine (10 mL). The organic layer is dried over anhydrous Na 2 SO, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel by sequentially levigating with hexane / EtOAc (gradient 1: 0 to 4: 1) to obtain the desired intermediate as a yellow solid (140 mg, 57%). GC-MS m / z: 256 (M +). 6-Aminomethyl-2-sislohexylmethyl-benzothiazole: Dissolve 2-cyclohexylmethyl-benzothiazole-6-carbonitrile (0.2 g, 0.55 mmol) in anhydrous THF (2 mL) and slowly add 1M lithium aluminum hydride in THF (0.82 mL, 0.82 mmol) at room temperature. The reaction mixture is stirred at room temperature for 0.5 h. The reaction mixture is quenched with water until a granular precipitate begins to form and is filtered through a pad of Celite®. The solvent is evaporated and the residue purified by SCX chromatography to obtain the title compound as a yellow oil (0.1 g, 92%). MS (ER +) m / z: 260 (M + H) +.

Preparation 256 6-Aminomethyl-2-phenyl-benzothiazole 6-Methyl-2-phenyl-benzothiazole: A mixture of 2-amino-5-methyl-benzenethiol zinc salt (13.5 g, 24.9 mmol, prepared following the procedure described in Helv.

Chim. Acta 1974, 57, 2664) and ethyl benzimidate hydrochloride (9.23 g, 49.7 mmol) in methanol (240 mL) for 9 h. The mixture is filtered, the filtrate is evaporated and the residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (100: 0 to 85:15 gradient) to obtain the desired intermediate (5.7 g, 51%). MS (El) m / z: 225 (M +). 6-Bromomethyl-2-phenyl-benzothiazole: Warm 5-methyl-2-phenyl-benzothiazole (5.7 g, 25.3 mmol) and NBS (4.73 g, 26.6 mmol) in carbon tetrachloride (140 mL) at 80 ° C during 3 h. The mixture is cooled, the double volume is dichloromethane, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 to 7: 3 gradient) to obtain the desired intermediate (3.1 g, 40%). MS (El) m / z: 303, 305 (M +). 6-Aminomethyl-2-phenyl-benzothiazole: 6-Bromomethyl-2-phenyl-benzothiazole (2 g, 6.57 mmol) is added as a suspension in methanol (100 mL) to 7M ammonia in methanol (400 mL) at 0 ° C. for 10 min and then stirred for 3 h at room temperature. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel by levigating with dichloromethane / methanol (1: 0 to 3: 1) to obtain the title compound (1.2 g, 76%). MS (ER +) m / z: 241 (M + H +).

Preparation 257 5-Aminomethyl-2-isobutyl-benzothiazole 2-0x0-2, 3-dihydro-benzothiazole-5-aarbonitrile: A mixture of 5-chloro-3'T-benzothiazol-2-one (9. 3 g, 50 mmol), nickel (II) bromide (10) is heated. 9 g, 50 mmol) and sodium cyanide (4.91 g, 100 mmol) in 1-methyl-pyrrolidinone (100 mL) in a microwave reactor at 200 ° C for 15 min. And held for 1 h. The cooled mixture is filtered through a sintered glass, diethyl ether and brine are added and filtered again. The organic phase is washed with brine three times and concentrated in vacuo. The residue was passed through a plug of silica gel by levigating with hexane / EtOAc (2: 1) and then dichloromethane / methanol (9: 1) to obtain the desired intermediate (3.2 g, 36%). MS (ER +) m / z: 177 (M + H) +. 2-Bromo-benzothiazole-5-sarbonitrile: Heat 2-oxo-2,3-dihydro-benzothiazole-5-carbonitrile (3.2 g, 18.2 mmol) in toluene (120 mL) with tetrabutylammonium bromide (8.78 g, 27.2 mmol. ) and phosphorus pentoxide (7.73 g, 54.5 mmol) for 3 h at reflux. The mixture is cooled, the solution of the reaction residue is decanted and partitioned between diethyl ether and brine. Water and dichloromethane are added to the reaction residue and refluxed for 20 min. The dichloromethane layer is washed with saturated aqueous NaHCO3 and brine, and combined with the washed ether. The organic mixture is dried over Na2SO4 and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 to 3: 7 gradient) to give the desired intermediary (0.85 g, 20%). MS (El) m / z: 238, 240 (M +). 2-Isobutyl-benzothiazole-5-sarbonitrile: Heat 2-bromo-benzothiazole-5-carbonitrile (0.3 g, 1.26 mmol) in 1-methyl-pyrrolidinone (4.2 mL) with 2-methylpropylzinc bromide (5 mL, 2.5 mmol). , 0.5M solution in THF), N-methylimidazole (0.15 g, 1.88 mmol) and complex of [1, 1'-bis (diphenylphosphine) ferrocene] dichloropalladium (II) with dichloromethane (1: 1) (20.5 mg, 0.025 mmol) at 80 ° C for 3 h. The mixture is cooled and partitioned between diethyl ether and brine. Dry the organic layer over Na2SO4 and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (gradient 1: 0 to 1: 1) to give the desired intermediate (113 mg, 42%). MS (El) m / z: 216 (M +). 5-Aminomethyl-2-isobutyl-benzothiazole: Lithium aluminum hydride (0.78 mL, 0.78 mmol, 1M solution in THF) is added to 2-isobuty-benzothiazole-5-carbonitrile (113 mg, 0.52 mmol) in THF (5 mL ) and stirred for 4 h at room temperature. Water (0.27 mL), 2N sodium hydroxide (0.27 mL) and water (0.37 mL) are added. The precipitate is filtered and the filtrate is washed with brine. Dry over Na2SO4 and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 1) and then 1M ammonia in methanol / dichloromethane (1: 9). The polar fraction is purified by SCX chromatography to give the title compound (63 mg, 55%). MS (ER +) m / z: 221 (M + H +).Preparation 258 6-Aminomethyl-benzo [1,2,3] thiadiazole 6-Hydroxymethyl-benzo [1,2,3] thiadiazole: Sodium borohydride (1.35 g, 36 mmol) is added in five portions over 4 h to a solution of methyl ester of benzo [1,2,3] thiadiazole- 6-carboxylic acid (0.35 g, 1.8 mmol, prepared by following the procedure described in J. Heterocyclic Chem. 1972, 1149) in methanol (18 mL) at 0 ° C. Acetone is added to quench and evaporate the mixture on silica gel. The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 to 2: 3 gradient) to give the desired intermediate (133 mg, 45%). MS (GCMS) m / z: 166 M +. 6-Aminomethyl-benzo [1,2,3] thiadiazole: 6-Hydroxymethyl-benzo [1,2,3] thiadiazole (133 mg, 0.8 mmol) in thionyl chloride (5 mL) is stirred for 3 h at room temperature. The mixture is evaporated then 7M ammonia in methanol (10 mL) is added and stirred at room temperature in a sealed tube for 48 h. The mixture is evaporated and the residue purified by SCX chromatography to give the title compound (115 mg, 87%). MS (ER +) m / z: 166 (M + H) +.

Preparations 259 6-Aminomethyl-3-phenyl-benzothiophene 2- (3-Bromo-phenylthio) -1-phenyl-ethanone: Potassium hydroxide (4.89 g, 87.3 mmol) and 2-bromoacetophenone (15.8 g, 79.3 mmol) are added to a solution of 3-bromobenzenethiol (15 g, 79.3 mmol) in ethanol (200 mL, 70% in water) at 0 ° C. After stirring 16 h, water is added to precipitate a yellow solid. It is filtered to obtain the desired intermediate (24.6 g, 100%). 6-Bromo-3-phenylbenzothiophene: 2- (3-bromo-phenylthio) -1-phenyl-ethanone (4 g, 13 mmol) in polyphosphoric acid (4 g) is heated at 80 ° C for 4 h. EtOAc and water are added to the mixture and washed with saturated aqueous NaHCO3 and brine. Dry the organic layer over Na 2 SO 4, filter and concentrate in vacuo. The residue is made in hexane and purified by chromatography on silica gel by levigating with hexane to give the desired intermediate which is used without further purification (2.7 g, 72%). MS (GCMS) m / z: 289 M +. 6-Cyano-3-phenylbenzothiophene: Combine 6-bromo-3-phenylbenzothiophene (0.5 g, 1.73 mmol) and copper cyanide (0.56 g, 6.23 mmol) and reflux for 3 h in l-methyl-2-pyrrolidinone (1.73 mL). Ferric chloride (2.11 g, 7.79 mmol) in concentrated HCl (1.73 mL) is added and the mixture is stirred 1.5 h. The mixture is cooled and partitioned between diethyl ether and brine. Dry the organic layer over Na2SO4, filter and evaporate on silica gel. The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 to 3: 2 gradient) to give the desired intermediate which is used without further purification (0.27 g, 67%). MS (GCMS) m / z: 235 M +. 6-Aminomethyl-3-phenyl-benzothiophene: Dissolve 6-cyano-3-phenylbenzothiophene (0.27 g, 1.16 mmol) in anhydrous THF (6 mL) and add lithium aluminum hydride (3.45 mL, 1M solution in THF) to 0 ° C. After 2 h, water (0.86 mL), 2N aqueous NaOH (0.86 mL) and water (1.24 mL) are added. The solids are completely filtered and the residue evaporated. Purify by preparative HPLC (Zorbax SB-Phenyl column 21.2 x 250 mm, 5% up to 50% acetonitrile in 0.1% TFA-water solution) and free base is obtained by SCX chromatography to give the title compound which is used without purification additional (187 mg, 68%). MS (ER +) m / z: 223 (M-NH2) +.

Preparation 260 4- (Difluoro-phenyl-methyl) -benzylamine 4- (Difluoro-phenyl-methyl) -toluene (0.29 g, 1.35 mmol, prepared following the procedure described in Tetrahedron 1996, 52, 9), NBS (0.26 g, 1.48 mmol), and AIBN (6 mg, 0.03 mmol) in carbon tetrachloride (8 mL) and heated at 80 ° C for 16 h. The mixture is evaporated and the residue is passed through a pad of silica gel washed with hexane and the filtrate is evaporated. The residue is dissolved in methanol and added dropwise to 7M ammonia in methanol (100 mL) at 0 ° C. After 4.5 h, the mixture is evaporated and the amine is isolated by SCX chromatography (0.1 g, 32%). MS (ER +) m / z: 234 (M + H) +.

Preparation 261 4- (3, 3-Dimethyl-butyryl) -benzylamine 3,3,4'-Trimethylbutyrophenone: Tert-butylacetyl chloride (2 g, 14,858 mmol) is added slowly to an ice-cooled stirred solution of aluminum trichloride (2,972 g, 22.28 mmol) in anhydrous toluene (40 mL). The reaction mixture is stirred at room temperature overnight. Water cooled on ice is added slowly and the mixture is extracted twice with EtOAc. The combined organic extracts are dried over Na2SO4, filtered and concentrated in vacuo to give the desired intermediate (2.82 g, 100%) which was used without any further purification. GC-MS m / z: 190 (M +). 4- (3, 3-Dimethyl-butyryl) -bensyl bromide: A mixture of 3, 3, 4 '-trimethylbutyrophenone (2 g, 10.52 mmol), NBS is heated (2.061 g, 11.57 mmol), and AIBN (43 mg, 0.263 mmol) in carbon tetrachloride (60 mL) for 14 h at reflux. The reaction mixture is cooled to room temperature and washed sequentially with water, 1M aqueous HCl, 5% aqueous NaHCO3 and brine. The organic layer is concentrated in vacuo to provide the desired intermediate as oil (2.54 g, 90%) which was used without any further purification. 2- [4- (3,3-Dimethyl-butyryl) -bensyl] -isoindole-l, 3-dione: 4- (3,3-dimethyl-butyryl) -benzyl bromide (1 g, 3731 mmol) is added to a stirred suspension of potassium phthalimide (0.705 g, 3.805 mmol) in anhydrous DMF (20 mL). The mixture is stirred overnight at room temperature. It is diluted with EtOAc and washed twice with ice-cold water. Dry the organic layer over Na 2 SO, filter and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel by sequentially levigating with hexane and hexane / EtOAc (19: 1, 4: 1) to provide the desired intermediate as oil (1.24 g, 100%). 4- (3, 3-Dimethyl-butyryl) -bensilamine: Hydrazine hydrate (0.189 mL, 3.913 mmol) is added to a stirred suspension of 2- [4- (3, 3-dichlor-butyryl) -benzyl] -isoindole -1, 3-dione (875 mg, 2,609 mmol) in methanol (15 mL). The mixture is heated under reflux overnight. The mixture is cooled to room temperature and concentrated in vacuo. The residue is partitioned between EtOAc and 5N aqueous HCl and the acidic aqueous phase is washed again with 5N aqueous HCl. Basify with 5N aqueous NaOH to pH 12. Extract the basic aqueous solution three times with chloroform. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the title compound as a yellow oil (411 mg, 77%) which was used without any further purification.

Preparation 262 4- (3, 3-Dimethyl-butyryl) -3-fluoro-benzylamine 4-Azidomethyl-1-bromo-2-fluoro-bensen: Sodium azide (2,912 g, 44.8 mmol) is added to a bromide solution of 4-bromo-3-fluorobenzyl (6 g, 22.4 mmol) in anhydrous DMF (127 mL) at room temperature under nitrogen. The mixture is heated at 90 ° C for 1 h. Concentrate in vacuo and partition the residue between water and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic extracts are washed with water and ice. Dry the organic layer over Na 2 SO, filter and concentrate in vacuo to obtain the desired intermediate as a solid (4.92 g, 96%). 4-Brom.o -.y- (fcer-Jbutoxyarbonyl) -3-fluoro-bensylamine: Pd / C 10% (492 mg) and di-ter- £ g are added. Util-dicarbonate (4.668 g, 21.4 mmol) was added to a solution of 4-azidomethyl-1-bromo-2-fluorobenzene (4.92 g, 21.4 mmol) in ethanol (90 mL) and the mixture was exposed to hydrogenation at atmospheric pressure during the night. The reaction mixture is filtered over Celite® and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (85:15) to obtain the desired intermediate as a solid (1.55 g, 25%).

N- (fcezr-butoxisarbonyl) -3-fluoro-4- (l-hydroxy-3,3-dimethyl-buyl) -bensylamine: Butyl lithium (7.3 mL, 11.7 mmol) is added to a solution of 4-bromo- N- (tert-butoxycarbonyl) -3-fluoro-benzylamine (1.55 g, 5.1 mmol) in diethyl ether (54 mL) at -78 ° C under nitrogen and stirred for 30 min. 3 is added, 3-dimethylbutyraldehyde (562 mg, 0.7 mL, 5.6 mmol), stirred for 30 min at -78 ° C and then warmed to room temperature. Water is added and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (85:15) to obtain the desired intermediate as a yellow oil (394 mg, 24%). iV- (fcer-Jutoxisarbonyl) -4- (3,3-dimethyl-butyryl) -3-fluoro-benzylamine: Manganese dioxide (1132 g, 13 mmol) is added to a solution of N- (tert-> > utoxycarbonyl) -3-fluoro-4- (1-hydroxy-3, 3-dimethyl-butyl) -benzylamine (283 mg, 0.87 mmol) in anhydrous 1,4-dioxane (11.5 mL) at room temperature. The reaction mixture is heated at 70 ° C overnight. The reaction mixture is filtered over Celite® and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to obtain the desired intermediate as an oil (216 mg, 77%). 4- (3,3-Dimyl-butyryl) -3-luoro-bensylamine: 4N hydrogen chloride in dioxane (2.7 mL, 10.8 mmol) is added to a solution of N- (tert-butoxycarbonyl) -4- (3 , 3-dimethyl-butyryl) -3-fluoro-benzylamine (296 mg, 0.92 mmol) in dichloromethane (11 mL) and stirred for 4 h. Concentrate in vacuo and wash the obtained solid with diethyl ether. The solid is suspended in saturated aqueous NaHCO3 and stirred for 30 min. It is extracted twice with dichloromethane. Dry the combined organic extracts over Na 2 SO 4, filter and concentrate in vacuo to obtain the title compound as an oil. (175 mg, 82%).

Preparation 263 4- (3, 3-Dimethyl-butyryl) -2-fluoro-benzylamine 4-Bromo-JV- (tez- J utoxisarbonil) -2-f luoro-bensilamina: Triethylamine (6. 334 g, 8. 8 mL, 52.6 mmol) and di-ter-util-dicarbonate (4. 54 g, 20. 8 mmol) was added to a solution of 4-bromo-2-f luoro-benzylamine hydrochloride (5 g, 20.8 mmol) in dichloromethane (254 mL) and stirred overnight. The organic layer is washed with water and then the aqueous phase is extracted again with dichloromethane. Dry the combined organic extracts over Na 2 SO 4, filter and concentrate in vacuo to obtain the desired intermediate as a white solid (6.11 g, 97%). ÍV- (er-Jbutoxisarbonyl) -2-fluoro-4- (l-hydroxy-3, 3-dxmethyl-buyl) -bensylamine: Butyl lithium (14.2 mL, 22.7 mmol) is added to a solution of 4-bromo- N- (tert-butoxycarbonyl) -2-fluoro-benzylamine (3 g, 9.9 mmol) in diethyl ether (105 mL) at -78 ° C under nitrogen and stirred for 30 min. 3, 3-Dimethylbutyraldehyde (1.086 g, 1.4 mL, 10.8 mmol) is added, stirred for 30 min at -78 ° C and then warmed to room temperature. Water is added and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (85:15) to obtain the desired intermediate as a yellow oil (1179 g, 37%).

N- (tert-Jutoxyarbonyl) -4- (3,3-dimethyl-butyryl) -2-fluoro-bensylamine: Manganese dioxide (4.4 g, 50.6 mmol) is added to a solution of N-. { er-Jutoxycarbonyl) -2-fluoro-4- (1-hydroxy-3, 3-dimethyl-butyl) -benzylamine (1.1 g, 3.38 mmol) in anhydrous 1,4-dioxane (45 mL) at room temperature. The reaction mixture is heated at 70 ° C overnight. The reaction mixture is filtered over Celite® and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to obtain the desired intermediate as an oil (980 mg, 90%). 4- (3, 3-Dimethyl-butyryl) -2-fluoro-bensylamine: 4N hydrogen chloride in dioxane (5.5 mL, 22 mmol) is added to a solution of N- (tert-butoxycarbonyl) -4- (3, 3-dimethyl-butyryl) -2-fluoro-benzylamine (600 mg, 1.85 mmol) in dichloromethane (22 mL) and stirred for 6.5 h. Concentrate in vacuo and wash the obtained solid with diethyl ether. The solid is suspended in saturated aqueous NaHCO3 and stirred for 30 min. The aqueous phase is extracted twice with EtOAc. Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo to obtain the title compound as an oil (420 mg, 99%).

Preparation 264 3-chloro-4- (3, 3-dimethyl-butyryl) -benzylamine 4-Bromo-3-sloro-bensyl bromide: NBS (5.266 g, 23.9 mmol) and benzoyl peroxide (49 mg, 0.2 mmol) are added to a solution of 4-bromo-3-chlorotoluene (4.925 g, 23.9 mmol). ) in carbon tetrachloride (49 mL) and heated overnight at 90 ° C. It is cooled to 0 ° C and the mixture is filtered. The filtrate is concentrated in vacuo to obtain the desired intermediate as a yellow oil (5.807 g, 85%). 4-Bromo-3-sloro-N'- (di-tert-Jbutoxisarbonyl) -bensylamine: Sodium hydride (382 mg, 15.9 mmol) is added to a solution of di-tert-butyl-iminodicarboxylate (2.533 g, 11.7 mmol ) in anhydrous DMF (15 mL) at room temperature under nitrogen and stirred for 15 min. Then a solution of 4-bromo-3-chloro-benzyl bromide (3 g, 10.6 mmol) in anhydrous DMF (5 mL) is added and stirred for 1 h. Water is added and the aqueous phase extracted twice with EtOAc. The combined organic extracts are washed with ice water. Dry the organic layer over Na 2 SO, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to obtain the desired intermediate (2783 g, 62%). 4-Bromo-3-sloro- N- (tert-Jutoxiaarbonyl) -bensylamine: A solution of sodium hydroxide (264 mg, 6.6 mmol) in methanol (23.5 mL) is added to a solution of 4-bromo-3-chloro -N- (di-tert-J-butoxycarbonyl) -benzylamine (2783 g, 6.6 mmol) in THF (11.7 L) and stirring overnight. Concentrate in vacuo. Water is added and the formed precipitate is filtered to obtain the desired intermediate as a white solid (1.823 g, 86%).

N- (tert-Jbutoxyarbonyl) -3-sloro-4- (l-hydroxy-3,3-dxmethyl-butyl) -bensylamine: Butyl lithium (8.2 mL, 13.1 mmol) is added to a solution of 4-bromo-3. -chloro-N- (tert-butoxycarbonyl) -benzylamine (1823 g, 5.7 mmol) in diethyl ether (46 mL) at -78 ° C under nitrogen and stirred for 30 min. 3,3-Dimethylbutyraldehyde (1427 g, 1.7 mL, 14.3 mmol) is added, stirred for 30 min at -78 ° C and then warmed to room temperature. Water is added and the aqueous phase is extracted twice with EtOAc. Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to obtain the desired intermediate as a yellow oil (274 mg, 14%).

N- (tert-butoxioarbonyl) -3-sloro-4- (3,3-dimethyl-butyryl) -bensylamine: Manganese dioxide (1.096 g, 12.6 mmol) is added to a solution of N-. { tert-butoxycarbonyl) -3-chloro-4- (1-hydroxy-3, 3-dimethyl-butyl) -benzylamine (274 mg, 0.8 mmol) in anhydrous 1,4-dioxane (11.5 L) at room temperature. The mixture is heated at 70 ° C overnight. The reaction mixture is filtered over Celite® and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to obtain the desired intermediate as a yellow oil (175 mg, 64%). 3-sloro-4- (3,3-dimethyl-butyryl) -bensylamine: 4N hydrogen chloride in dioxane (0.9 mL, 3.6 mmol) is added to a solution of N- (er-butoxycarbonyl) -3-chloro-4 - (3,3-dimethyl-butyryl) -benzylamine (100 mg, 0.3 mmol) in dichloromethane (6 mL) and stirred overnight. Concentrate in vacuo and wash the obtained solid with diethyl ether. The solid is suspended in saturated aqueous NaHCO3 and stirred for 30 min. It is extracted twice with dichoromethane. Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo to obtain the title compound as a yellow oil (66 mg, 92%).

Preparation 265 2-chloro-4- (3, 3-dimethyl-butyryl) -benzylamine 4-Bromo-2-sloro-bensyl bromide: NBS (13.171 g, 74 mmol) and benzoyl peroxide (152 mg, 0.63 mmol) are added to a solution of 4-bromo-2-chlorotoluene (15.2 g, 74 mmol) ) in carbon tetrachloride (152 mL) and stirred for 6 days at 90 ° C. It is cooled to 0 ° C, the mixture is filtered and the filtrate is concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (99: 1) to obtain the desired intermediate as a yellow oil (12.7 g, 61%). 4-Bromo-2-sloro-N-di- (tert-Jutoxysarbonyl) -bensylamine: Sodium hydride (382 mg, 15.9 mmol) is added to a solution of di-tert-butyl iminodicarboxylate (2.533 g, 11.7 mmol) in anhydrous DMF (15 mL) at room temperature under nitrogen and stirred for 15 min. Then a solution of 4-bromo-2-chloro-benzyl bromide (3 g, 10.6 mmol) in anhydrous DMF (5 mL) is added and stirred for 1 h. Water is added and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are washed with ice water. Dry the organic layer over Na 2 SO 4, filter and concentrate in vacuo.

Purify by chromatography on silica gel by sequentially levigating with hexane and hexane / EtOAc (4: 1) to obtain the desired intermediate (4.2 g, 94%). 4-Bromo-y- (tert.-butoxyarbonyl) -2-sloro-bensylamine: A solution of sodium hydroxide (399 mg, 9.98 mmol) in methanol (35.5 mL) is added to a solution of 4-bromo-2-. Chloro-N-di- (tert-J-butoxycarbonyl) -benzylamine (4.2 g, 9.98 mmol) in THF (17.7 mL) and stirred overnight. Concentrate in vacuo and partition the residue between water and EtOAc. The aqueous phase is extracted twice with EtOAc. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to obtain the desired intermediate (2.625 g, 82%).

N- (er-butoxysarbonyl) -2-sloro-4- (l-hydroxy-3, 3-dxmet.-butyl) -bensylamine: Butyl lithium (11.7 mL, 18.65 mmol) is added to a solution of 4-bromo -N- (er-butoxycarbonyl) -2-chloro-benzylamine (2601 g, 8.11 mmol) in diethyl ether (86 mL) at -78 ° C under nitrogen and stir for 2 h. 3,3-Dimethylbutyraldehyde (1868 g, 2.3 mL, 18.65 mmol) is added, stirred for 30 min at -78 ° C and then warmed to room temperature. Water is added and the aqueous phase is extracted twice with EtOAc. Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating hexane / EtOAc (85:15) to obtain the desired intermediate as a yellow oil (1825 mg, 66%).

N- (tert-Jbutoxisarbonyl) -2-sloro-4- (3,3-dimethyl-butyryl) -bensylamine: Manganese dioxide (7.276 g, 83.7 mmol) is added to a solution of N-. { tert-butoxycarbonyl) -2-chloro-4- (1-hydroxy-3, 3-dimethyl-butyl) -benzylamine (1819 g, 5.3 mmol) in anhydrous 1,4-dioxane (75 mL) at room temperature. The mixture is heated at 70 ° C overnight. The reaction mixture is filtered over Celite® and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (85:15) to obtain the desired intermediate as a yellow oil (1362 g, 76%). 2-sloro-4- (3, 3-dimethyl-butyryl) -bensylamine: 4N hydrogen chloride in dioxane (6 mL, 24 mmol) is added to a solution of N-. { tert-jutoxycarbonyl) -2-chloro-4- (3, 3-dimethyl-butyryl) -benzylamine (700 mg, 2.06 mmol) in dichloromethane (25 mL) and stirred overnight. Concentrate in vacuo and wash the obtained solid with diethyl ether. The solid is suspended in saturated aqueous NaHCO3 and stirred for 30 min. It is extracted twice with dichloromethane. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound as a yellow oil (477 mg, 97%).

Preparation 266 4- [2- (3, 3-Dimethyl-butyl) - [1,3] dioxolan-2-yl] -benzylamine 4- (4,4-Dimethyl-pentanoyl) -benzonitrile: Mg moldings (402 mg, 15,251 mmol) are maintained in vacuo in a two-necked round bottom flask for 2 h. The flask is purged with nitrogen / vacuum several times. Some crystals of iodine, anhydrous THF (60 mL) and 3,3-dimethyl-bromobutane (0.8 mL, 5.59 mmol) are added slowly (exothermic reaction observed). The remaining 3, 3-dimethyl-bromobutane (1.6 mL, 11.18 mmol) is added dropwise and the mixture is refluxed overnight. Some additional 3, 3-dimethyl-bromobutane is added (0.24 mL, 1.67 mmol) and reflux for 30 min. The mixture is cooled to -10 ° C and a solution of 4-cyanobenzaldehyde (4 g, 30,502 mmol) in anhydrous THF (40 mL) is added. Warm the flask gradually at room temperature overnight. The mixture is quenched with aqueous HCl O.lM (100 mL) and extracted twice with EtOAc. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1) to give the desired intermediate as an oil (0.752 g, 23%). 4- [2- (3,3-Dimethyl-butyl) - [1, 3] dioxolan-2-yl] -benzonitrile: 4- (4,4-dimethyl-pentanoyl) -benzonitrile (275 mg, 1.28 mmol) is dissolved in toluene (10 mL). Ethylene glycol (0.35 mL, 6.4 mmol) and p-toluenesulfonic acid monohydrate (24 mg, 0.128 mmol) are added. The mixture is heated at 135 ° C in a Dean-Stark for 2 h and then at 120 ° C overnight. The mixture is cooled to room temperature, diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The crude mixture is purified by chromatography on basic alumina by levigating with hexane and hexane / EtOAc (19: 1) to give the desired intermediate as an oil (0.272 g, 82%). 4- [2- (3, 3-Dimethyl-butyl) - [1,3] dioxolan-2-yl] -bensilamine: 4- [2- (3, 3-dimethyl-butyl) - [1,3 ] dioxolan-2-yl] -benzonitrile (271 mg, 1046 mmol) in anhydrous THF (10 mL). Lithium aluminum hydride 1M in THF (2.1 mL, 2.1 mmol) is added under nitrogen at 0 ° C and the mixture is stirred at room temperature for 2 h. Cool to 0 ° C, add water and extract the aqueous phase twice with EtOAc. The combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo to obtain the desired intermediate as an oil (0.263 mg) which was used without any further purification.

Preparation 267 4-Cyclohexanecarbonyl-benzylamine Cislohexyl-p-toluyl-methanone: Cyclohexanecarbonyl chloride (2 g, 13.6 mmol) is dissolved in anhydrous toluene (30 mL). The solution is cooled to 0 ° C, aluminum trichloride (2.72 g, 20.46 mmol) is added in three portions and the reaction mixture is stirred at room temperature overnight. Cool to 0 ° C, add water slowly and extract the mixture with EtOAc. Dry the organic layer over Na 2 SO, filter and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (19: 1) to give the desired intermediate (2.75 g, 100%). 4- (Cislohexanesarbonyl) -bensyl bromide: A mixture of cyclohexyl-p-toluyl-methanone (1 g, 4943 mmol), NBS is heated (1.232 g, 6.92 mmol), and AIBN (41 mg, 0.247 mmol) in carbon tetrachloride (80 mL) for 14 h at reflux. Additional NBS (264 mg) and AIBN (19 mg) are added and the mixture is refluxed for 4 h. The reaction mixture is cooled to room temperature and filtered. The filtrate is concentrated in vacuo to provide the desired intermediate as oil (1132 g, 81%) which was used without any further purification. (4-Azidomethyl-phenyl) -islohexyl-methanone: Sodium azide (441 mg, 6.785 mmol) is added to a stirred solution of 4- (cyclohexanecarbonyl) -benzyl bromide (954 mg, 3.393 mmol) in anhydrous DMF (20 mg). mL) and the mixture is heated at 90 ° C for 2 h. The mixture is cooled to room temperature, water is added and the aqueous solution is extracted with diethyl ether. Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (19: 1) to give the desired intermediate as oil (310 mg, 38%).

N- (tert-Jutoxyarbonyl) -4-sialohexanecarbonyl-benaylamine: 10% Pd / C (100 mg) is added to a solution of (4-azidomethyl-phenyl) -cyclohexyl-methanone (310 mg, 1.274 mmol) and di- tert-butyl-dicarbonate (278 mg, 1274 mmol) in ethanol (5 mL). The mixture is subjected to hydrogenation under atmospheric pressure (balloon) for 1 h. The catalyst is filtered through Celite® and the filtrate is concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (92: 8) to provide the desired intermediate as a white solid (197 mg, 49%). 4-Cialohexanoaarbonyl-bensilamina: 4N hydrogen chloride in dioxane (1 mL) is added to a stirred solution of N- (er-jutoxycarbonyl) -4-cyclohexanecarbonyl-benzylamine (197 mg, 0.621 mmol) in anhydrous dichloromethane (4 mL) and the mixture is stirred at room temperature for 16 h. Concentrate in vacuo and partition the residue between dichloromethane and saturated aqueous NaHCO3. The aqueous phase is extracted twice with dichloromethane. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the title compound (125 mg, 93%) that was used without any further purification. MS (ER +) m / z: 218 (M + H) +.

Preparation 268 4- (2-Cyclopentyl-acetyl) -benzylamine 2-Cislopentyl-lp-toluyl-ethanone: Aluminum trichloride (2.719 g, 20.4 mmol) is added in three portions to a solution of cyclopentylacetyl chloride (2 g, 13.6 mmol) in anhydrous toluene (30 mL) at 0 ° C. . The solution is stirred at room temperature overnight. Cool to 0 ° C, add water and extract the aqueous phase with EtOAc. The organic phase is dried over MgSO, filtered and concentrated in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (19: 1) to give the desired intermediate as an oil (2.5 g, 91%). 1- (4-Bromomethyl-phenyl) -2-sislopen-y-ethanone: NBS is added (523 mg, 2.94 mmol) and AIBN (44 mg, 0.267 mmol) were added to a solution of 2-cyclopentyl-lp-toluyl-ethanone (540 mg, 2.67 mmol) in carbon tetrachloride (80 mL) and heated overnight at 85 ° C. Water is added and the aqueous phase is extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (98: 2, 95: 5) to obtain the desired intermediate as an oil (479 mg, 64%). iV-Di- (tert-b-oxisarbonyl) -4- (2-sislopentyl-asethyl) -bensylamine: Sodium hydride (42 mg, 1.65 mmol) is added to a solution of di-tert-butyl iminodicarboxylate (262 mg, 1.21 mmol) in anhydrous DMF (5 mL) at room temperature under nitrogen and stirred for 5 min. Then a solution of 1- (4-bromomethyl-phenyl) -2-cyclopentyl-ethanone (310 mg, 1.1 mmol) in anhydrous DMF (15 mL) is added and stirred for 1 h. Water is added and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are washed with ice water. Dry the organic layer over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (19: 1) to obtain the desired intermediate (360 mg, 78%). 4- (2-Cislopen-il-asethyl) -bensilamine: 4N hydrogen chloride in dioxane (15 mL) is added to a solution of N-di- (tert-butoxycarbonyl) -4- (2-cyclopentyl-acetyl) -benzylamine (300 mg, 0.72 mmol) in EtOAc (20 mL) and stirred overnight. Concentrate in vacuo, suspend the obtained solid in diethyl ether and add hexane. Filter and wash the solid with hexane. The solid is suspended in dichloromethane, saturated aqueous NaHCO3 is added and the mixture is stirred until both phases are cleaned (15 min). The aqueous phase is extracted with dichloromethane and EtOAc. The combined organic extracts are dried over MgSO, filtered and concentrated in vacuo to obtain the title compound as an oil which was used without any further purification.

Preparation 268 The compound of Preparation 269 can be prepared essentially as described in Preparation 268 by using cyclohexylacetyl chloride. Overall performance and EM data (ER +) are shown in the Table below.

Preparation 270 5-Aminomethyl-2- (3-methyl-butyryl) -pyridine -Azidomethyl-2- (3-methyl-butyryl) -pyridine: DBU (240 mg, 1.55 mmol) is added to a solution of 5-hydroxymethyl-2- (3-methyl-butyryl) -pyridine (250 mg, 1.29 mmol). mmol) and diphenylphosphorylazide (430 mg, 1.55 mmol) in anhydrous toluene (10 mL) at 0 ° C. Stir at 0 ° C for 30 min, warm to room temperature and stir for 4 h. it is diluted with EtOAc and water. The aqueous phase is extracted twice with EtOAc. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (9: 1) to provide the desired intermediate (300 mg, 99%). MS (ER +) m / z: 219 (M + H) +.

-Aminomethyl-2- (l-hydroxy-3-methyl-butyl) -pyridine hydrochloride: 10% Pd / C (20 mg) is added to a solution of 5-azidomethyl-2- (3-methyl-butyryl) pyridine (80 mg, 0.367 mmol) in ethanol (10 mL) containing concentrated HCl (1 mL). The mixture is subjected to hydrogenation at atmospheric pressure for 2 h. Filter the reaction mixture over Celite® and concentrate in vacuo to provide the desired intermediate (95 mg, 98%). MS (ER +) / z: 195 (M + H) +. -tert-Jbutoxisarbonilaminomethyl-2- (l-hydroxy-3-methyl-butyl) -pyridine: Di-ter-util-dicarbonate (78 mg, 0.356 mmol) and triethylamine (0.149 mL, 1.068 mmol) are added to a solution of 5-aminomethyl-2- (l-hydroxy-3-methyl-butyl) -pyridine hydrochloride (95 mg, 0.356 mmol) in anhydrous dichloromethane (5 mL). The solution is stirred at room temperature for 3 h., The reaction mixture is diluted with dichloromethane and washed with water. The aqueous phase is extracted with dichloromethane. Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to provide the desired intermediate (60 mg, 59%). -tert-Jbutoxisarbonilaminomethyl-2- (3-methyl-butyryl) -pyridine: Manganese dioxide (240 mg) is added to a solution of 5-tert-3-methoxycarbonylaminomethyl-2- (1-hydroxy-3-methyl-butyl) -pyridine (60 mg, 0.2 mmol) in anhydrous 1,4-dioxane (1 mL) at room temperature. The reaction mixture is heated at 70 ° C for 2 h. Filter the reaction mixture over Celite® and concentrate in vacuo to provide the desired intermediate (60 mg, 99%).

-Aminomethyl-2- (3-methyl-butyryl) -pyridine: 4N hydrogen chloride in dioxane (0.5 mL) is added to a solution of 5-terthoxycarbonylaminomethyl-2- (3-methyl-butyryl) -pyridine ( 60 mg, 0.2 mmol) in anhydrous dichloromethane (2 mL) and the solution is stirred overnight. Concentrate in vacuo and partition the residue between saturated aqueous NaHCO3 and dichloromethane. The aqueous phase is extracted with dichloromethane (2 x 15 mL) and EtOAc (2 x 15 mL). Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo to obtain the title compound (37 mg, 95%) which was used without any further purification.

Preparation 271 2-Bromo-5-tert-jutoxycarbonylaminomethyl-pyridine 2-Bromo-pyridine-5-sarbaldehyde oxime: Hydroxylamine hydrochloride (1494 g, 21,504 mmol) and a solution of NaHCO 3 (2.71 g, 32,256 mmol) in water (15 mL) are added to a solution of 2-bromo- 5-formyl-pyridine (2 g, 10 752 mmol, prepared by following the procedure described in J. Org Chem. 2004, 69, 250-262) in absolute ethanol (100 mL). The mixture is stirred at room temperature for 2 h. Concentrate in vacuo and partition the residue between EtOAc and water. The aqueous phase is extracted with EtOAc. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (9: 1, 4: 1) to provide the desired intermediate as a solid (1362 g, 63%).

-Aminomethyl-2-bromo-pyridine: A solution of 2-bromo-pyridine-5-carbaldehyde oxime (0.5 g, 2.487 mmol) in DME (10 mL) is added dropwise to a solution of titanium chloride ( IV) (0.573 mL, 5.223 mmol) and sodium borohydride (395 mg, 10.445 mmol) in DME (20 mL) at 0 ° C. The mixture is allowed to warm to room temperature and is stirred for 3 h. Water is added and the solvent is removed in vacuo. Basify the mixture at pH 12 with IN aqueous NaOH and extract with dichloromethane. Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo to provide the desired intermediate (340 mg, 73%) that was used without further purification. 2-Bromo-5-ter-Ju-oxisarbonylaminomethyl-pyridine: Di-tert-butyl-dicarbonate (397 mg, 1818 mmol) and triethylamine are added. (0.507 mL, 3636 mmol) was added to a solution of 5-aminomethyl-2-bromo-pyridine (340 mg, 1818 mmol) in anhydrous dichloromethane. (15 L). The solution is stirred overnight at room temperature. The reaction mixture is diluted with dichloromethane and washed with water. The aqueous phase is extracted with dichloromethane.

The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (4: 1) to give the title compound as a solid (322 mg, 62%).

Preparation 272 5-Aminomethyl-2- (3, 3-dimethyl-butyryl) -pyridine -tert-utoxy-arylaminomethyl-2- (l-hydroxy-3,3-dimethyl-bu-yl) -pyridine: Butyl lithium (1.088 mL, 1.741 mmol, 1.6M solution in hexane) is added slowly to a solution of 2- Bromo-5-terthoxycarbonylaminomethyl-pyridine (200 mg, 0.696 mmol) in anhydrous THF (10 mL) at -78 ° C. The mixture is stirred at this temperature for 35 min. 3,3-Dimethylbutyraldehyde (0.219 mL, 1741 mmol) is added and the mixture is stirred at -78 ° C for 3 h. The reaction mixture is quenched at -78 ° C with brine. The aqueous phase is extracted with EtOAc (3 x 15 mL). Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (3: 2) to provide the desired intermediate as a colorless oil (118 mg, 55%). MS (ER +) m / z 309 (M + H) +. -tert-Jbutoxisarbonilaminomethyl-2- (3, 3-dimethyl-butyryl) -pyridine: Manganese dioxide (472 mg, 5.429 mmol) is added to a solution of 5-tert.-utoxycarbonylaminomethyl-2- (1-hydroxy-3) , 3-dimethyl-butyl) -pyridine (118 mg, 0.383 mmol) in anhydrous 1,4-dioxane (5 mL) at room temperature. The reaction mixture is heated at 70 ° C overnight. Filter the reaction mixture over Celite® and concentrate in vacuo to obtain the desired intermediate (104 mg, 89%).

-Aminomethyl-2- (3,3-dimethyl-butyryl) -pyridine: 4N hydrogen chloride in dioxane (1 mL) is added to a solution of 5-tert-3-chloro-4-methoxycarbonyl-3-dimethyl-butyryl. ) -pyridine (104 mg, 0.339 mmol) in anhydrous dichloromethane (4 mL) and the solution is stirred overnight. Concentrate in vacuo and partition the residue between saturated aqueous NaHCO3 and dichloromethane. The aqueous phase is extracted with dichloromethane (2 x 15 mL) and EtOAc (2 x 15 mL). Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo to obtain the title compound as an oil (62 mg, 88%) which was used without any further purification. MS (ER +) m / z: 207 (M + H) +.

Preparation 273 4-Bromo-2-fluoro-benzoate methyl: 4-bromo-2-fluoro-benzoic acid (15 g, 68.5 mmol) is dissolved in methanol (70 mL). Concentrated sulfuric acid (500 μl) is added to the solution and the mixture is heated at reflux for 20 h under a nitrogen atmosphere. The mixture is cooled to room temperature and concentrated in vacuo. The residue is dissolved in EtOAc (200 mL) and washed successively with saturated aqueous NaHCO 3 (50 mL) and water (2 x 50 mL). Dry the organic layer over Na 2 SO 4, filter and concentrate in vacuo to obtain the desired intermediate (15.4 g, 96%). GC-MS m / z: 232 (M +).

Methyl 4-cyano-2-fluoro-benzoate: Methyl 4-bromo-2-fluoro-benzoate (5 g, 21.5 mmol) and copper (I) cyanide (3.8 g, 42.9 mmol) in DMF are made in paste. anhydrous (90 mL). The mixture is heated under reflux for 20 h under a nitrogen atmosphere. The mixture is cooled to room temperature, diluted with hexane / EtOAc (1: 1, 300 mL) and water (150 mL). Filter the mixture through Celite® by washing with hexane / EtOAc (1: 1) to reduce the emulsion layer. The organic layer is separated and the aqueous layer extracted with hexane / EtOAc (1: 1, 2 x 200 mL). The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1 gradient) to obtain the desired intermediate (2.9 g, 76%). GC-MS m / z: 179 (M +).

Asido 4-Cyano-2-fluoro-benzoiso: Methyl 4-cyano-2-fluoro-benzoate (2.9 g, 16.2 mmol) is dissolved in absolute ethanol (100 mL). Potassium hydroxide (4.5 g, 80.2 mmol) is added and the milky white mixture is stirred for 1.5 h. The mixture is diluted with water (125 mL) and washed with diethyl ether (50 mL). The aqueous layer is collected and concentrated in vacuo until the solids begin to appear in the flask, then the mixture is adjusted to pH 1 with concentrated HCl. The aqueous mixture is extracted with diethyl ether (3 x 500 mL). Combine the organic extracts and concentrate in vacuo to obtain the desired intermediate as a white solid (2.2 g, 83%). 4-Cyano-iV-sisloheptyl-2-fluoro-benzamide: 4-Cyano-2-fluoro-benzoic acid (1 g, 6.1 mmol) is dissolved in anhydrous toluene (25 mL) and thionyl chloride (15 mL). The mixture is stirred for 1 h at 90 ° C under a nitrogen atmosphere (the aliquots are quenched with methanol and evaluated by HPLC to determine if the starting material has been consumed). The reaction is cooled to room temperature and concentrated in vacuo to obtain the acid chloride as a yellow oil. (1.25 g). Dissolve the acid chloride (1.25 g) in diethyl ether (75 mL), add triethylamine (0.85 mL, 6.1 mmol) and cycloheptylamine (0.78 mL, 6.1 mmol). The mixture is stirred at room temperature for 16 h under a nitrogen atmosphere. The reaction is quenched with saturated aqueous Na 2 CO 3 (20 mL). The mixture is extracted with EtOAc (30 mL). Dry the organic layer over Na 2 SO 4, filter and concentrate in vacuo to obtain the desired intermediate (1.45 g, 91%). GC-MS m / z: 260 (M +). 4-Aminomethyl-iV-sisloheptyl-2-fluoro-benzamide: Add 4-cyano-N-cycloheptyl-2-fluoro-benzamide (1.4 g, 5.4 mmol), Pd / C 10% (Degussa type ElOl, 415 mg) , ethanol (40 mL), water (15 mL) and acetic acid (1.8 mL) to a pressure vessel. The vessel is pressurized to 55 psi (3.8665 kg / cm2) with hydrogen, and the mixture is stirred for 0.5 h (the reaction is monitored by CCD). The mixture is filtered through Celite® and the cake is washed with hot ethanol followed by dichloromethane under a nitrogen atmosphere. The filtrate is concentrated in vacuo to obtain the product as the acetic acid salt. SCX chromatography is used to obtain the title compound (1.36 g, 95%). GC-MS m / z: 264 (M +).

Preparations 274 4-Aminomethyl-N-cycloheptyl-3-fluoro-benzamide 4-Cyano-IV-sisloheptyl-3-fluoro-benzamide: 4-Cyano-3-fluoro-benzoic acid (1 g, 6.1 mmol) is dissolved in anhydrous toluene (20 mL) and thionyl chloride (10 mL). The mixture is stirred for 1.5 h at 90 ° C under a nitrogen atmosphere (the aliquots are quenched with methanol and evaluated by HPLC to determine if the starting material has been consumed). The reaction is cooled to room temperature and concentrated in vacuo to obtain the acid chloride as a yellow oil. The yellow oil is dissolved in diethyl ether (50 mL), triethylamine (0.86 mL, 6.1 mmol) and cycloheptylamine (0.79 mL, 6.1 mmol) are added. The mixture is stirred at room temperature for 16 h under a nitrogen atmosphere. The reaction is quenched with saturated aqueous Na 2 CO 3 (20 mL). The mixture is extracted with EtOAc (2 x 50 mL). Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo to obtain the desired intermediate (1.24 g, 77%). MS (ES-) m / z: 259.2 (M-H) +. 4-Aminomethyl-jV-sisloheptyl-3-fluoro-benzamide: Add 4-cyano-N-cycloheptyl-3-fluoro-benzamide (0.86 g, 3.3 mmol), Pd / C 10% (Degussa type ElOl, 250 mg) , ethanol (25 mL), water (9 mL) and acetic acid (1 mL) to a pressure vessel under a nitrogen atmosphere. The vessel is pressurized to 50 psi (3.515 kg / cm2) with hydrogen, and the mixture is stirred for 0.5 h. The mixture is filtered through Celite® and the cake is washed with hot ethanol followed by dichloromethane under a nitrogen atmosphere. The filtrate is concentrated in vacuo to obtain the title compound as the acetic acid salt. SCX chromatography is used to obtain the title compound (805 mg, 92%). MS (ER +) m / z: 265.3 (M + H) +.

Preparations 275 4-Aminomethyl-2-chloro-N-cycloheptyl-benzamide 2-sloro-4-sia-iV-sisloheptyl-benzamide: 2-Chloro-4-cyano-benzoic acid (1.1 g, 6 mmol) is dissolved in anhydrous toluene (20 mL) and thionyl chloride (15 mL). The mixture is stirred 1 h at 90 ° C under a nitrogen atmosphere (the aliquots are quenched with methanol and evaluated by HPLC to determine if the starting material has been consumed). The reaction is cooled to room temperature and concentrated in vacuo to obtain the acid chloride as an oil. The oil is dissolved in diethyl ether (40 mL), triethylamine is added (0.84 mL, 6 mmol) and cycloheptylamine (0.77 L, 6 mmol). The mixture is stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction is quenched with saturated aqueous Na 2 CO 3 (20 mL). The mixture is extracted with EtOAc (100 mL). Dry the organic layer over Na 2 SO, filter and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with dichloromethane to obtain the desired intermediate (1.1 g, 66%). MS (ER +) m / z: 277.2 (M + H) +. 4-tert-butoxy-arylaminomethyl-2-sloro-iV-sisloheptyl-benzamide: 2-Chloro-4-cyano-N-cycloheptyl-benzamide (460 mg, 1.7 mmol) is dissolved in methanol (15 mL). The solution is cooled to 0 ° C under a nitrogen atmosphere and di-tert-jutyl dicarbonate (726 mg, 3.3 mmol) and nickel (II) chloride hexahydrate (40 mg, 0.17 mmol) are added. Sodium borohydride (360 mg, 9.5 mmol) is then added in portions over 30 min. Stir at 0 ° C for 1 h then concentrate the mixture in vacuo. The residue is diluted with EtOAc (100 mL), washed with saturated aqueous NaHCO3 (40 mL). The aqueous layer is extracted with EtOAc (3 x 40 mL). The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with EtOAc to obtain the desired intermediate (627 mg, 99%). MS (ER +) m / z: 381.3 (M + H) +. 4-Aminomethyl-2-sloro-iV-sisloheptyl-benzamide: 4-tert-J-Ethoxycarbonylaminomethyl-2-chloro-N-cycloheptyl-benzamide (624 mg, 1.6 mmol) is dissolved in dichloromethane (30 mL) then trifluoroacetic acid is added (2 mL). The solution is stirred at room temperature under a nitrogen atmosphere for 1 h. The mixture is concentrated in vacuo. The crude mixture is purified by SCX chromatography to obtain the desired intermediate (395 mg, 85%). MS (ER +) m / z: 281.2 (M + H) +.

Preparation 276 4-Aminomet il-N-cycloheptyl-2-methyl-benzamide 4-Cyano- "ff-sisloheptyl-2-yl-benzamide: Cycloheptylamine (0.83 mL, 6.5 mmol), HOBT (838 mg, 6.2 mmol), EDC (1.2 g, 6.2 mmol) and diisopropylethylamine (3.2 mL, 18. 6 mmol) to a solution of 4-cyano-2-methyl-benzoic acid (1 g, 6.2 mmol) in dichloromethane (20 mL) at room temperature under a nitrogen atmosphere. The mixture is stirred for 16 h at room temperature. The mixture is washed with water (20 mL), separated and the organic layer is concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 3: 2 gradient) to obtain the desired intermediate (830 mg, 52%). MS (ER +) m / z: 257.3 (M + H) +. 4-Aminomethyl-JV-sisloheptyl-2-methyl-benzamide: Add 4-cyano-N-cycloheptyl-2-methyl-benzamide (0.82 g, 3.2 mmol), ethanol (23 mL), water (8 mL) and acid acetic acid (1 mL) to a pressure vessel. The vessel is heated to 50 ° C until all the solids are dissolved. 10% Pd / C (type Degussa ElOl, 250 mg) is added under a nitrogen atmosphere, then the vessel is pressurized to 55 psi (3.8665 kg / cm2) with hydrogen at room temperature. The mixture is stirred for 40 min. The mixture is filtered through Celite® and the cake is washed with hot ethanol (50 mL) followed by dichloromethane (100 mL) under a nitrogen atmosphere. The filtrate is concentrated in vacuo to obtain the title compound as the acetic acid salt. SCX chromatography is used to obtain the title compound (820 mg, 98%). MS (ER +) m / z: 261.3 (M + H) +.

Preparation 277. { R) -4-Aminomethyl-2-fluoro-N- (2,2, 2-trifluoro-1-methyl-ethyl) -benzamide (R) -4-Cyano-2-fluoro-iV- (2,2,2-trifluoro-1-methyl-ethyl) -benzamide: It is added. { R) - (2,2,2-trifluoro-1-methyl) -ethylamine (0.909 g, 6.08 mmol), HOBT (0.82 g, 6.1 mmol), diisopropylethylamine (2.1 mL, 12 mmol) and EDC (1.17 g, 6.08 mmol) was added to a mixture of 4-cyano-2-fluorobenzoic acid (1,004 g, 6.08 mmol) in anhydrous THF (40 mL) at room temperature. Stir overnight and divide the mixture between EtOAc (250 L) and saturated aqueous NaHCO 3 (100 mL). Dry the organic extract over Na 2 SO, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with dichloromethane / hexane (1: 1 to 1: 0 gradient for 71 min; 50 mL / min) to provide the desired intermediate as a white solid (0.985 g, 62%).

(.R) -4-Aminomethyl-2-fluoro-iV- (2,2,2-trifluoro-1-methyl-ethyl) -benzamide: A solution of. { R) -4-cyano-2-f luoro-N- (2, 2, 2-trifluoro-1-methyl-ethyl) -benzamide (0.904 g, 3.475 mmol) in absolute ethanol (26 mL), water (9.7 mL) ) and glacial acetic acid (1.2 mL) with 10% Pd / C (type Degussa ElOl, 0.27 g, 0.13 mmol) under nitrogen. The mixture is purged with nitrogen and then with hydrogen. The paste is stirred at room temperature under hydrogen at 55 psi (3.8665 kg / cm2) for 30 min. The reaction mixture is purged with nitrogen and then the paste is filtered over Celite®. The filter cake is washed with ethanol (100 mL) and THF (100 mL). The filtrate is concentrated and purified by SCX chromatography by levigating with dichloromethane / methanol (1: 1) to remove impurities and then with dichloromethane / 2M ammonia in methanol (1: 1) to elute the product. Concentrate to provide the title compound as a colorless oil (0.86 g, 94%).

Preparation 278 3-tert-butoxycarbonyl-6- (4-carboxy-3-fluoro-benzylamino) -7-chloro-2,3,4,5-tetrahydro-li? -benzo [d] azepine 4-Aminomethyl-2-fluoro-benzoate methyl: A solution of methyl 4-cyano-2-fluoro-benzoate (1 g) is combined, 5.58 mmol) in absolute ethanol (42 mL) and acetic acid (1.9 mL) with a 10% Pd / C mixture (Degussa ElOl type, 0.17 g, 0.078 mmol) in water (15.6 L) at room temperature under nitrogen. It is purged with nitrogen and then with hydrogen at 55 psi (3.8665 kg / cm2) and stirred for 1 h. The reaction is purged with nitrogen, filtered through Celite® and the filter cake is washed with ethanol (100 mL), THF (100 mL) and isopropanol (100 L). Concentrate in vacuo and purify by SCX chromatography and then silica gel chromatography (40 g RediSep® column) by levigating with dichloromethane / 2M ammonia in methanol (99: 1 to 9: 1 gradient for 30 min.; 35 mL / min) to provide the desired intermediate as a white solid (0.602 g, 59%). 7-Sloro-6- (3-fluoro-4-methoxysarbonyl-benzylamino) -3- (2,2,2-trifluoroasethyl) -2,3,4, 5-te rahydro-lH-benzo [d] azepine: use a method similar to General Procedure 5-2 to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine ( 1.24 g, 2.91 mmol) with methyl 4-aminomethyl-2-fluorobenzoate (1.065 g, 5.821 mmol) when using tris (dibenzylideneacetone) dipalladium (0) (0.533 g, 0.582 mmol), BINAP (0.725 g, 1.16 mmol ) and cesium carbonate (3.32 g, 10.2 mmol) under nitrogen in anhydrous toluene (20 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (gradient 19: 1 to 1: 1 for 71 min; 50 mL / min) to provide the desired intermediate as a yellow oil (1.3 g, 100%). 7-Sloro-6- (3-fluoro-4-methoxysarbonyl-benzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 1M aqueous NaOH (2.8 mL, 2.8 mmol) is added to a solution of 7-chloro-6- (3-fluoro-4-methoxycarbonyl-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lif-benzo [d] azepine ( 1.31 g, 2.86 mmol) in 1,4-dioxane (13.3 mL) and water (2.6 mL) at 11 ° C. The mixture is allowed to warm to room temperature and is stirred for 1 h. Concentrate in vacuo and partition the residue between dichloromethane (250 mL) and saturated aqueous NaHCO3 (100 mL). The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to provide the desired intermediate that was used without further purification. 3-tert-Jutoxyarbonyl-6- (4-sarboxi-3-fluoro-bensilamino) -7-sloro-2,3,4,5-tetrahydro-lff-benzo [d] azepine: 1M aqueous NaOH (5.7 mL) is added , 5.7 mmol) to a mixture of 7-chloro-6- (3-fluoro-4-methoxycarbonyl-benzylamino) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine (1.04 g, 2.86 mmol ) in 1,4-dioxane (13.3 mL) and water (2.6 mL) at room temperature. The mixture is heated at 50 ° C for 2 h. The mixture is cooled to 0 ° C, a solution of di-ter-util-dicarbonate (0.62 g, 2.9 mmol) in 1,4-dioxane (2 mL) is added and it is stirred at 0 ° C for 2 h. Concentrate in vacuo, add EtOAc (50 mL), aqueous KHS0 1N (5.7 mL, . 7 mmol) and water (20 mL) at a pH = 1. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to give the title Compound as a yellow oil (1.25 g, 98%) which was used. without additional purification. MS (ER +) m / z: 449.1 (M + H) +.

PREPARATION 279 5-Aminomethyl-2-cyclohexylamino-pyridine 6-Cislohexylamino-niaotinonitrile: Cyclohexylamine (7.1 g, 72 mmol) is added to a mixture of 6-chloronicotinitrile (1 g, 7.2 mmol), potassium carbonate (3 g, 21.7 mmol) and anhydrous DMF (10 mL). The mixture is heated in a sealed flask at 120 ° C for 1.5 h. The reaction is cooled to room temperature, diluted with hexane / EtOAc (1: 1, 100 mL) and the mixture washed with 5% aqueous sodium chloride (3 x 30 mL). The organic layer is collected and concentrated in vacuo to obtain the desired intermediate (1.4 g, 97%). GC-MS m / z 201 (M +).

-Aminomethyl-2-sislohexylamino-pyridine: A solution of 6-cyclohexylamino-nicotinonitrile (1.4 g, 7.1 mmol) in methanol (70 mL) and trifluoroacetic acid (5 mL) is charged to a pressure vessel containing Pd / C 10% (type Degussa ElOl, 600 mg). The vessel is pressurized to 40 psi (2812 kg / cm2) with hydrogen and stirred for 2 h. The mixture is filtered through Celite®, washed with hot ethanol, and dichloromethane. The filtrate is concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (99: 1 to 90:10 gradient) to obtain the title compound (920 mg, 54%). MS (ER +) m / z: 206.1 (M + H) +.

Preparation 280 The compound of Preparation 280 can be prepared essentially as described in Preparation 279 using 6-chloronicotinonitrile and cyclohexylmethylamine. Overall performance and EM data (ER +) are shown in the Table below.

Preparation 281 6-Benzylamino-pyridin-3-ylmethylamine 6-Bensylamino-nisotinonitrile: Heat 6-chloroniconitrile (0.58 g, 4.2 mmol) and benzylamine (4.6 mL, 42 mmol) in anhydrous DMF (3 mL) at 120 ° C for 4.5 h. It is cooled to room temperature. It is diluted with water and extracted with EtOAc. The organic phase is washed with brine, dried over MgSO 4, filtered, and concentrated in vacuo. Purify by chromatography on silica gel by sequentially levigating with hexane / EtOAc (4: 1, 2: 1, 1: 2) to give the desired intermediate as a white solid (840 mg, 96%). MS (ER +) m / z: 210 (M + H) +. 6-Bensylamino-pyridin-3-ylmethylamine: 6-Benzylamino-nicotinonitrile (680 mg, 3.3 mmol) and 10% Pd / C (type Degussa ElOl) are vigorously stirred in absolute ethanol (80 mL) under hydrogen at 25 psi ( 1.7575 kg / cm2) for 1 h. The solution is filtered through Celite® and concentrated in vacuo. Purify by chromatography on silica gel by sequentially levigating with 2M ammonia in methanol / dichloromethane (4:96, 9:91) to give the title compound as a white solid (320 mg, 45%). MS (ER +) m / z: 214 (M + H) +.

Preparations 282 (±) -4- [1- (1, 1, 2, 2, 2-Pentafluoroethyl) -ethoxy] -benzylamine (±) -4- [1- (1, 1, 2, 2, 2-Pentafluoroe) -ethoxy] -benzonitrile: Potassium carbonate (27.4 g, 198 mmol) is added to a mixture of 4-fluorobenzonitrile (8 g, 66 mmol) and (±) -3,3,4,4,4,4-pentafluoro-2-butanol (17.2 g, 105 mmol) in anhydrous DMF (60 mL). The mixture is heated in a sealed flask for 4 h at 130 ° C. The reaction is cooled to room temperature, diluted with hexane / EtOAc (1: 1, 350 mL) and washed with 5% aqueous sodium chloride (3 x 100 mL). The organic layer is collected, dried over Na 2 SO, filtered and concentrated in vacuo to obtain the desired intermediate (17.1 g, 98%). GC-MS m / z: 432 (M +). (±) -4- [1- (1,1,2,2, 2-Pentafluoroethyl) -ethoxy] -bensylamine: Add (+) -4- [1- (1, 1, 2, 2, 2- pentafluoroethyl) -ethoxy] -benzonitrile (1 g, 3.8 mmol) to a paste of lithium aluminum hydride (400 mg, 10 mmol) in diethyl ether (30 mL) at 0 ° C under a nitrogen atmosphere. The mixture is stirred at room temperature for 2 h, and then the reaction is quenched sequentially with water (1 mL) and 5N sodium hydroxide (1 mL). The paste is filtered through Celite®, the filtrate is dried over Na 2 SO, filtered and concentrated in vacuo to obtain the title compound (990 mg, 98%). GC-MS m / z: 268 (+).

Preparation 283 4- [1- (1,1, 2,2, 2-Pentafluoroethyl) -ethoxy] -benzylamine Isomer 2 Chiral Chiral 4- [1- (1,1,2,2,2-Pentyl) -ethoxy ] -benzonitrile Isomer 2: (+) -4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -benzonitrile is separated by normal phase chiral chromatography (Chiralcel OJ, 8 x 33 cm, levigating with heptane / ethanol 3A 97: 3, flow ratio 375 mL / min). The 2nd levigation isomer is collected as the desired intermediate (11.3 g, 40% recovered, 98.6% ee (Chiralcel OJ, 4.6 x 250 mm, levigating with heptane / ethanol 3A 97: 3, 1 mL / min). MS m / z: 265 (M +). 4- [1- (1, 1, 2, 2, 2-Pen afluoroe il) -ethoxy] -bensylamine Isomer 2: 4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -benzonitrile isomer 2 (11.4 g, 43 mmol) is reduced using General Procedure 6-4 to obtain the title compound (11.38). g, 98%). GC-MS m / z: 268 (M +).

Preparation 284 4- [1- (1, 1, 2,2, 2-Pentafluoroethyl) -ethoxy] -benzylamine Isomer 1 4- [1- (1,1,2,2,2-Pen-afluoroethyl) -ethoxy] -benzonitrile Isomer 1: Separate (+) -4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -benzonitrile by normal phase chiral chromatography (Chiralcel OJ, 8 x 33 cm, levigating with heptane / 3A 97: 3 ethanol, flow ratio 375 mL / min). The 1st levigation isomer is collected as the desired intermediate (4.5 g, 33% recovered, 99.3% ee (Chiralcel OJ, 4.6 x 250 mm, levigating with heptane / 3A ethanol 97: 3, 1 mL / min). m / z: 265 (M +). 4- [1- (1, 1, 2, 2, 2-Pentafluoroethyl) -ethoxy] -bensylamine Isomer 1: Reduced 4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] - benzonitrile isomer 1 (4.5 g, 17 mmol) using General Procedure 6-4 to obtain the title compound (4.3 g, 94%). GC-MS m / z: 268 (M +).

Preparation 285 (+) -2-Aminomethyl-5- [1- (1,1,2,2,2-pentafluoroethyl) -ethoxy] -pyridine 5-sloro-pyridine-2-sarbonitrile: Paste is made 2,5- dichloropyridine (6 g, 40.5 mmol), zinc cyanide (2.9 g, 24.7 mmol), zinc (powder) (116 mg, 1.8 mmol) and complex of [1,1 '-bis (diphenylphosphine) ferrocene] dichloropalladium (II) with dichloromethane (720 mg, 0.98 mmol) in anhydrous DMF (40 mL). The mixture is heated under reflux under a nitrogen atmosphere for 4.5 h. The mixture is cooled to room temperature, diluted with EtOAc (300 mL), washed with 10% aqueous sodium chloride (3 x 75 mL). The organic layer is collected, dried over Na 2 SO, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 1: 1 gradient) to obtain the desired intermediate (2.6 g, 46%). GC-MS m / z: 138 (M +). (±) -4- [1- (1, 1, 2, 2, 2-Pen afluoroethyl) -ethoxy] -pyridine-2-sarbonitrol: Add (+) -3, 3, 4, 4, 4- pentafluoro-2-butanol (710 mg, 4.3 mmol) slowly to a sodium hydride paste (104 mg, 1.2 equiv, 60% mineral oil, washed with hexane) in hexamethylphosphoramide (2 mL) under nitrogen at 0 ° C. The pasta is allowed to warm to room temperature and is stirred for 5 min. 5-Chloro-pyridine-2-carbonitrile (300 mg, 2.2 mmol) is added, then the mixture is heated in a sealed flask at 130 ° C for 4 h (reaction monitored by GC / MS). The reaction is cooled to room temperature, the mixture is adjusted to pH 9 with saturated aqueous Na 2 CO 3, then extracted with diethyl ether (2 x 50 mL). The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 7: 3 gradient) to obtain the desired intermediate (380 mg, 66%). GC-MS m / z: 266 (M +). (±) -2-Aminomethyl-5- [1- (1,1,2,2,2-pen-fluoro-yl) -ethoxy] -pyridine: Add (+) -4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -pyridine-2-carbonitrile (280 mg, 1 mmol), Pd / C 10% (type Degussa ElOl, 100 mg), methanol (20 mL) and trifluoroacetic acid (3 mL ) to a pressure vessel. The vessel is pressurized to 40 psi (2812 kg / cm2) with hydrogen, and the mixture is stirred for 1 h (the reaction is monitored by CCD). The mixture is filtered through Celite® and the cake is washed with hot ethanol followed by dichloromethane under a nitrogen atmosphere. The filtrate is concentrated in vacuo to obtain the crude product as a trifluoroacetic acid salt. The free base is prepared using SCX chromatography, then purified by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (20: 1) to obtain the title compound (172 mg, 61%). GC-MS m / z: 270 (M +).

Preparation 286 4- (1-Methyl-cyclohexylmethoxy) -benzylamine hydrochloride 4- (1-Methyl-sislohexylmethoxy) -benzamide: One drop of anhydrous DMF is added to a mixture of 4- (1-methyl-cyclohexylmethoxy) -benzoic acid (prepared by following the procedure described in Chem. Pharm. Bull. , 30, 3601-3616) (1 g, 4.03 mmol) and thionyl chloride (3.5 mL) at room temperature. The mixture is stirred for 1.5 h and then the excess of thionyl chloride is removed in vacuo. The crude acid chloride is taken in anhydrous THF (10 mL) and the resulting solution is added to cool concentrated NHOH (50 mL). Stir for 2.5 h at room temperature and concentrate in vacuo. The solid formed is collected by filtration medium and dried in vacuo to obtain the desired intermediate (0.94 g, 94%). MS (ER +) m / z: 248 (M + H) +. 4- (1-Methyl-sislohexylmethoxy) -bensylamine hydrochloride: A solution of 4- (1-methyl-cyclohexylmethoxy) -benzamide (6.82 g, 27.6 mmol) in anhydrous THF (75 mL) is added dropwise over 45 min. to a paste of lithium aluminum hydride (1.57 g, 41.3 mmol) in diethyl ether (100 mL) at room temperature. After the addition is complete, the mixture is heated at reflux for 5.5 h. The reaction mixture is cooled with an ice bath and quenched sequentially with water (1.6 mL), 5N aqueous NaOH (1.6 mL) and water (4.8 mL). The resulting suspension is stirred for 1 h and the solids formed are removed by filtration through Celite® by levigating with THF. The filtrate is dried over Na 2 SO 4 and the solution is treated with an excess of hydrogen chloride in diethyl ether. The mixture is concentrated in vacuo to obtain the title compound (6.68 g, 90%). MS (ER +) m / z: 233 (M + H) +.

Preparation 287 4-Cyclopentyloxy-benzylamine 4-Cislopentyloxy-benzonitrile: Sodium hydride (336 mg, 2.8 mmol, 60% suspension in mineral oil) is suspended in anhydrous 1,4-dioxane (10 mL) under nitrogen atmosphere. Cyclopentanol (620 mg, 7.2 mmol) is added and the resulting solution is stirred for 30 min. The preformed solution (3.35 mL, 2.4 mmol) is added to pure 4-fluorobenzonitrile. (240 mg, 2 mmol) in a microwave tube and the sealed mixture is heated at 100 ° C for 30 min. It is cooled to room temperature and concentrated in vacuo. Purify by chromatography on silica gel by levigating with isohexane / EtOAc (95: 5 to 1: 1 gradient) to obtain the desired intermediate (300 mg, 80%). GC-MS m / z: 187 (M +). 4-Cislopentyloxy-bensylamine: A solution of 1M BH3-THF complex in THF (4.8 mL, 4.8 mmol) is added to pure 4-cyclopentyloxy-benzonitrile (300 mg, 1.6 mmol) and the mixture is stirred for 3 h at room temperature and then for 3 h reflux. It is cooled to room temperature, the reaction is poured into 2N aqueous HCl (10 mL) and the mixture is stirred for 1 h at room temperature then concentrated in vacuo. Dissolve the crude mixture in methanol and filter through SCX column by levigating with methanol followed by 3M ammonia in methanol to obtain the title compound (223 mg, 73%).

Preparations 288-292 The compounds of Preparations 288-292 can be prepared essentially as described in Preparation 287 using the appropriate alcohols. For Preparations 288, 290 and 291, sodium bis (trimethylsilyl) amide (1.2 equiv., 2M solution in THF) was used as a base in the first step. The total yields and EM (El) data are shown in the Table below.

Preparation 293 5-Aminomethyl-2- (3, 3-dimethyl-butoxy) -pyridine 6- (3,3-Dime-il-bu oxy) -nisotinonitrile: Sodium bis (trimethylsilyl) amide (3.95 mL, 7.9 mmol, 2M solution in THF) is added to a solution of 3,3-dimethyl-butan-1 -ol (960 DL, 7.9 mmol) in anhydrous THF (10 mL). Stir for 30 min at room temperature and then add a solution of 6-chloro-nicotinonitrile (1 g, 7.2 mmol) in anhydrous THF (5 mL). Stir at room temperature overnight and then quench the reaction mixture with saturated aqueous NaHCO3 (100 mL). The aqueous layer is extracted with dichloromethane (3 x 100 mL) and the organic layer is washed with brine (100 mL). Dry the combined organic extracts over MgSO4 and concentrate in vacuo to give the desired intermediate as a yellow solid (1.4 g, 94%). GC-MS m / z: 204 (M +).

-Aminomethyl-2- (3, 3-dimethyl-butoxy) -pyridine: 6- (3,3-Dimethyl-butoxy) -nicotinonitrile (1.4 g, 6.86 mmol) is dissolved in anhydrous THF (10 mL) under nitrogen and Complex BH3-THF 1M is added in THF (20.6 mL, 20.6 mmol). The mixture is stirred overnight under nitrogen and then the reaction is carefully poured into 5N aqueous HCl (20 mL). The resulting suspension is stirred for 6 h at room temperature. It is then basified by adding 2N aqueous NaOH (50 mL) and extracted with dichloromethane (3 x 100 mL). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. The resulting oil is taken up in methanol and this is filtered through a SCX column by levigating with methanol followed by 3M ammonia in methanol. Concentrate in vacuo to obtain the title compound (754 g, 50%). GC-MS m / z: 208 (M +).

Preparation 294 3, 3-Dimethylbutanethiol In four separate microwave tubes thiourea (630 mg, 8.3 mmol) is added to a solution of 1-chloro-3,3-dimethylbutane (0.5 g, 4.4 mmol) in ethanol (5 mL) and heated in a sealed tube in a microwave reactor at 150 W at 100 ° C for 4 h. It is cooled to room temperature then left for three days. The reactions are combined and concentrated in vacuo to give a white solid. 2M aqueous NaOH (50 mL) is added and the mixture is refluxed overnight. Cool to room temperature then acidify to pH 2 with 5M aqueous HCl (20 mL). Extract in diethyl ether (50 mL), wash with brine (30 mL) then dry over MgSO 4 and concentrate in vacuo to give the title compound as a clear oil (2 g, 100%).

Preparation 295 5-Aminomethyl-2-ter-jutylthio-pyridine 6- (tert-Jutylthio) nisotinonitrile: Sodium ethoxide (12 mL of 21% w / v in ethanol, 36 mmol) is added to a solution of 2-methyl-2-propanethiol (4.06 mL), 36 mmol) in anhydrous ethanol (90 mL) at 0 ° C under nitrogen atmosphere. The solution is stirred and allowed to warm to room temperature for 30 min. 6-Chloronicotinonitrile (5 g, 36 mmol) is added and then the reaction is heated to reflux overnight. Cool to room temperature, add saturated aqueous NaHC03 and concentrate in vacuo. Extract in EtOAc or dichloromethane and wash with brine. Dry over MgSO4 and concentrate in vacuo to give the desired intermediate as orange crystals (6.31 g, 91%). MS (ER +) m / z: 193 (M + H) +.

-Aminomethyl-2-tert-butylthio-pyridine: A method similar to General Procedure 6-5 is used to react 6- (tert-butylthio) nicotinonitrile (4.4 g, 22.7 mmol) in anhydrous THF (25 mL) with 1M BH3-THF complex in THF (25 mL, 25 mmol). Aqueous 5M HCl (10 mL) is added carefully and the mixture is stirred overnight at room temperature. Extract into EtOAc, wash with brine, dry over MgSO4 and concentrate in vacuo to give an orange solid. The crude mixture was dissolved in methanol and filtered through an SCX column by levigating with methanol followed by 3M ammonia in methanol to obtain the title compound (2.74 g, 61%). MS (ER +) m / z 197 (M + H) +.

Preparations 296-303 The compounds of Preparations 296-303 can be prepared essentially as described in Preparation 295 using the appropriate thiol and 6-chloronicotinonitrile (Preparations 296-298) or the appropriate aryl fluoride (Preparations 299-303). The total yields and EM data (ER +) are shown in the Table below.

Preparations 304 5-Aminomethyl-2-ethoxy-pyridine 6- (Ethoxy) nisotinonitrile: Sodium ethoxide (1.6 mL of 21% w / v in ethanol, 4.8 mmol) is added to a solution of 6-chloronicotinonitrile (612 mg, 4.41 mmol) in anhydrous ethanol (15 mL) and heat the reaction to reflux for 3 h. It is cooled to room temperature and stirred overnight under a nitrogen atmosphere. Concentrate in vacuo and dissolve the residue in dichloromethane. Wash with saturated aqueous NaHCO3, dry over MgSO4 and concentrate in vacuo to give the desired intermediate as an opaque white solid (545 mg, 83%).

-Aminomethyl-2-ethoxy-pyridine: A solution of 1M BH3-THF complex in THF (7 mL, 7 mmol) is added to a solution of 6- (ethoxy) nicotinonitrile (911 mg, 4.41 mmol) in anhydrous THF ( 7 mL) and the mixture is stirred overnight at reflux. A second aliquot of the 1M BH3-THF complex in THF (7 mL, 7 mmol) is added and the mixture is stirred overnight at reflux. Aqueous 5N HCl (10 mL) is added carefully and the mixture is stirred overnight at room temperature. Concentrate in vacuo then dissolve the crude mixture in methanol and filter through a SCX column by levigating with methanol followed by 3M ammonia in methanol to obtain the title compound (250 mg, 40%). MS (ER +) m / z: 153 (M + H) +.

Preparations 305 4-Ethoxy-3-chloro-benzylamine The compound of Preparation 305 can be prepared essentially as described in Preparation 304 using the appropriate aryl fluoride (38% yield, MS (ER +) m / z 169 (M + H-NH3) +). Preparation 306 4- (Tetrahydro-pyran-4-yloxymethyl) -benzylamine 4- (Tetrahydro-pyran-4-yloxymethyl) -benzonitrile: Sodium bis (trimethylsilyl) amide (2.8 mL, 5.61 mmol, 2M solution in THF) is added to a solution of tetrahydro-pyran-4-ol (572 mg, 5.61 mmol) in anhydrous THF (20 mL) and stirred for 30 min. A solution of 4-bromomethyl-benzonitrile (1 g, 5.1 mmol) in anhydrous THF (5 mL) is added and the resulting mixture is stirred overnight at room temperature. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel by levigating with cyclohexane / EtOAc (98: 2 to 1: 1 gradient) to obtain the desired intermediate as a white solid (845 mg, 76%). GC-MS m / z: 217 (M +). 4- (Tetrahydro-pyran-4-yloxymethyl) -bensylamine: A method similar to General Procedure 6-5 is used to reduce 4- (tetrahydro-pyran-4-yloxymethyl) -benzonitrile (845 mg, 4 mmol). Reflux overnight to obtain the title compound (812 mg, 91%). EM (ER +) m / z: 222.2 (M + H) +.

Preparations 307-309 The compounds of Preparations 307-309 can be prepared essentially as described in Preparation 306 using 4-bromomethyl-benzonitrile and the appropriate alcohol. The total yields and EM data (ER +) are shown in the Table below.

Preparation 310 4- (2,2-Dimethyl-propoxymethyl) -benzylamine - (2,2-Dimethyl-propoxymethyl) -benzonitrile: Sodium is (trimethylsilyl) amide (3 mL), 6 mmol, 2M solution in THF) to a solution of 2,2-dimethyl-1-propanol (528 mg, 6 mmol) in anhydrous 1,4-dioxane. Stir until the suspension becomes homogeneous. Then a solution of 4-cyanobenzyl bromide (980 mg, 5 mmol) in anhydrous 1,4-dioxane (3 mL) is added. The mixture is heated in a microwave oven at 100 ° C for 30 min. Cool to room temperature, add water (50 mL) and extract with EtOAc (3 x 50 mL). Dry the combined organic extracts over MgSO4, and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with isohexane / EtOAc (95: 5 to 1: 1 gradient) to obtain the desired intermediate (811 mg, 80%). 4- (2, 2-Dimethyl-propoxymethyl) -bensilamine: 1M BH3-THF complex in THF (16 mL, 16 mmol) is added to pure 4- (2,2-dimethyl-propoxymethyl) -benzonitrile (3.043 g, mmol) and the mixture is stirred overnight at room temperature. Methanol is added and stirred until the hydrogen evolution stops. The solution is concentrated in vacuo. Dissolve the crude mixture in methanol and filter through a SCX column by levigating with methanol followed by 3M ammonia in methanol. Concentrate in vacuo to obtain the title compound (3 g, 96%).

Preparations 311 4-Cycloheptyloxy-benzylamine 4-Cisloheptyloxy-benzonitrile: Under a nitrogen atmosphere, 4-hydroxybenzonitrile (4 g, 33.5 mmol), cycloheptanol (2.55 g, 22.3 mmol), tri-n-butylphosphine (8.25 mL, 33.5 mmol), and dipiperidine are added. azodicarboxylate (8.45 g, 33.5 mmol) to anhydrous THF (60 mL) at 0 ° C. The mixture is stirred at 0 ° C for 1 h and then at room temperature for 12 h. it is diluted with EtOAc (50 mL) and water (50 mL). The layers are separated and the aqueous phase is extracted with EtOAc (4 * 30 mL). The combined organic extracts are washed with water (30 mL) and brine (20 mL). Dry over NaSO 4, filter and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel (RediSep 120 g column) by levigating with hexane / EtOAc (gradient 1: 0 to 1: 1 for 1.25 h, 80 mL / min) to provide the desired intermediate as a colorless oil ( 2.77 g, 58%). MS (APCl) m / z: 216 (M + H) +. 4-Cyclohep-iloxy-bensylamine: 4-Cycloheptyloxy-benzonitrile (2 g, 9.29 mmol) is dissolved in anhydrous THF (20 mL) and cooled to 0 ° C. Borane dimethylsulfide complex (2.8 mL, 27.9 mmol, 10-12 M solution) is added, stirred at 0 ° C for 0.5 h and then heated to reflux for 1 h. The mixture is cooled to 0 ° C, methanol (5 mL) is added and it is stirred for 15 min. Aqueous 2M HCl (15 mL) is added and stirred for 30 min at room temperature. The mixture is concentrated in vacuo and the residue is purified by chromatography on silica gel (RediSep 45 g column) by levigating with a gradient of dichloromethane in chloroform / methanol / concentrated ammonium hydroxide (80: 18: 2) for 30 min. mL / min) to provide the title compound as a colorless oil (1.87 g, 97%). MS (APCl) m / z: 220 (M + H) +.

Preparation 312 4-Cycloheptylthio-benzylamine 4-Methyl cycloheptylthiobenzoate: Under a nitrogen atmosphere, methyl 4-mercaptobenzoate (2.5 g, 15 mmol), cycloheptanol (2.55 g, 22.3 mmol), tri-n-butylphosphine is added. (5.26 g, 26 mmol) and azodicarboxylate dipiperidine (6.56 g, 26 mmol) was added to anhydrous THF (50 mL) at 0 ° C. The mixture is stirred 0 ° C for 1 h and then at room temperature for 12 h. it is diluted with EtOAc (50 mL) and water (50 mL) and the aqueous phase is extracted with EtOAc (4 x 30 mL). The combined organic extracts are washed with water (30 mL) and brine (20 mL). The organic phase is dried over Na 2 SO, filtered and concentrated in vacuo. The crude mixture is purified by chromatography on silica gel (RediSep 120 g column) by levigating with hexane / EtOAc (gradient 1: 0 to 1: 1 for 1.25 h, 80 mL / min) to provide the desired intermediate as a colorless oil ( 1.12 g, 40%). MS (APCl) m / z: 265 (M + H) +.

Asido 4-sisloheptiltio-benzoiso:. Methyl 4-cycloheptylthio-benzoate (1.1 g, 4.16 mmol) and sodium hydroxide are added (500 mg, 12.5 mmol) to methanol (20 mL) and stirred overnight. Aqueous 2M HCl (20 mL) is added and the aqueous phase is extracted with dichloromethane. The combined organic extracts are washed with water (20 mL) and brine (20 mL). The organic solution is dried over Na2SO4, filtered and concentrated in vacuo to provide the desired intermediate as a white solid (984 mg, 94%). MS (APCl) m / z: 251 (M + H) +. 4-Cialoheptylthio-benzamide: Thionyl chloride is added (1.35 mL, 18.4 mmol) was added to a mixture of 4-cycloheptylthio-benzoic acid (984 mg, 3.93 mmol) in dichloromethane (15 mL) at 0 ° C.

The mixture is heated at reflux for 1 h. The mixture is cooled to room temperature and concentrated in vacuo. The residue is dissolved in dichloromethane (20 mL) and cooled to 0 ° C. Triethylamine (1.1 mL) is added, 7.86 mmol) and ammonia gas is bubbled through the solution. The mixture is warmed to room temperature and stirred for 1 h. Dilute with water (20 mL) and extract the aqueous phase with dichloromethane (3 x 20 L). The combined organic extracts are washed with saturated aqueous NaHCO3 (20 mL). The organic solution is dried over Na2SO4, filtered and concentrated in vacuo to provide the desired intermediate as an opaque white solid (976 mg, 99%). MS (APCl) m / z: 250 (M + H) +. 4-Cycloheptylthio-benzylamine: Under a nitrogen atmosphere, add 4-cycloheptylthio-benzamide (976 mg, 3.91 mmol) to a paste of lithium aluminum hydride (0.398 mg, 11.7 mmol) in anhydrous THF (25 mL) at 0 ° C. The mixture is heated for 1 h. The mixture is cooled to 0 ° C and diethyl ether (50 mL) is added. Carefully add water (0.4 mL), 3M aqueous NaOH (0.4 mL) and water (1.2 mL). The solid residue is filtered and the filtrate is concentrated in vacuo. The crude mixture was purified by chromatography on silica gel (RediSep 45 g column) by levigating with a gradient of dichloromethane in chloroform / methanol / concentrated ammonium hydroxide (80: 18: 2) for 45 min (80 mL / min) to give the title compound as a colorless oil (530 mg, 57%). MS (ER +) m / z: 236 (M + H) +.

Preparations 313 Chlorohydrate 4-cyclohexylmethyl-benzylamine 4- (Cislohexyl-hydroxy-methyl) -benzonitrile: 4-formyl-benzonitrile (5 g, 38.1 mmol) is dissolved in anhydrous toluene (50 mL). Chlorodicyclohexyl borane (39 mL, 39 mmol, 1M solution in hexane) and 2,6-lutidine (4.25 mL, 39 mmol) are added and the mixture is stirred overnight at room temperature. Cool to 0 ° C, add aqueous hydrogen peroxide (5.4 mL, 48 mmol, 30%) and 3M aqueous NaOH (16 mL, 48 mmol) and stir for 15 min. EtOAc is added and the aqueous phase is extracted with EtOAc. The combined organic extracts are washed with water and brine. Dry the organic solution over Na 2 SO, filter and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel (RediSep 45 g column) by levigating with hexane / EtOAc (gradient 1: 0 to 1: 1 for 60 min, 80 mL / min) to provide the desired intermediate as a clear oil ( 2.3 g, 23%). MS (APCl) m / z: 197 (M-H20) +. 4- (Cislohexyl-methanesulfonyloxy-methyl) -benzonitrile: 4- (Cyclohexyl-hydroxy-methyl) -benzonitrile (1 g, 4.66 mmol), and triethylamine (1.3 mL, 9.3 mmol) are dissolved in dichloromethane (20 mL). The mixture is cooled to 0 ° C, methanesulfonyl chloride (1.49 mL, 5.34 mmol) is added and the solution is stirred for 2 h at 0 ° C. Water (10 mL) and saturated aqueous NaHCO3 (10 mL) are added. The layers are separated and the aqueous phase is extracted again with dichloromethane (3 * 20 mL). Combine the organic layers, wash with water (20 mL), dry over Na 2 SO 4, filter and concentrate in vacuo to provide the desired intermediate as a yellow oil (1.29 g, 94%). MS (APCl) m / z: 294 (M + H) +. 4-Aislohexylmethyl-bensilamine hydrochloride: 4- (Cyclohexyl-methanesulfonyloxy-methyl) -benzonitrile (1.36 g, 4.64 mmol) is dissolved in diethyl ether (20 mL) and the solution is cooled to 0 ° C. Lithium aluminum hydride (528 mg, 13.9 mmol) is added and the mixture is stirred at 0 ° C for 2 h and then at room temperature for 3 h. The mixture is cooled to 0 ° C and carefully added water (0.5 mL), 3M aqueous NaOH (0.55 mL), and water (1.5 mL). The solid residue is filtered and the filtrate is concentrated in vacuo. The crude mixture is dissolved in diethyl ether and hydrogen chloride is bubbled to form a white precipitate. Filter and dry the solid in vacuo to give the title compound as a white solid (420 mg, 44%). MS (APCl) m / z: 204 (M + H) +.

Preparations 314 (2-Methyl-butyl) -benzylamine 4- (l-Hydroxy-2-methyl-bu il) -1-bromo-bensen: A solution of 2-bromo-butane (4.8 g, 35 mmol) in anhydrous THF (20 mL) is slowly added to a stirred mixture. of magnesium (980 mg, 37 mmol) and anhydrous THF (10 mL) under a nitrogen atmosphere. The mixture is heated at reflux for 30 min. The mixture is cooled to room temperature and 4-bromo-benzaldehyde (5.36 g, 29 mmol) is added. After stirring for 5 min, the mixture is cooled in an ice bath and acidified with 3N aqueous HCl (50 L). The mixture is diluted with water and extracted twice with diethyl ether. The combined organic extracts are washed with water and brine. The organic phase is dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0, 20: 1 and 1: 1) to provide the desired intermediate as a clear oil (2 g, 28%). MS (APCl) m / z 243 (M + H) +. 4- (1-Hydroxy-2-methyl-butyl) -benzonitrile: 4- (1-hydroxy-2-methyl-butyl) -1-bromo-benzene (1.9 g, 7.8 mmol), zinc cyanide (1.82 mmol) is added. g, 15.6 mmol), and tetrakistriphenylphosphine palladium (0) (260 mg, 0.22 mmol) to anhydrous DMF (40 mL) under a nitrogen atmosphere. The mixture is heated at 90 ° C for 12 h. The mixture is cooled to room temperature, diluted with water and the aqueous phase is extracted twice with dichloromethane. The combined organic extracts are washed with water and brine. Dry the organic solution over Na 2 SO 4, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 and 20: 1) to provide the desired intermediate (1.2 g, 75%). MS (APCl) m / z: 190 (M + H) +. 4- (L-Methanesulfonyloxy-2-methyl-butyl) -benzonitrile: Methanesulfonyl chloride (540 mg, 4.72 mmol) is added to a solution of 4- (l-hydroxy-2-methyl-butyl) -benzonitrile (800 mg , 4.23 mmol) and triethylamine (0.88 mL, 6.35 mmol) in dichloromethane (10 mL) at 0 ° C. The mixture is warmed to room temperature and stirred for 1 h. The mixture is diluted with water and dichloromethane. The aqueous layer is extracted with dichloromethane. The combined organic extracts are washed with water. Dry the organic solution over Na 2 SO 4, filter and concentrate in vacuo to provide the desired intermediate as a clear oil (1.38 g) which was used without further purification. MS (APCl) m / z: 268 (M + H) +. 4- (2-Methyl-butyl) -bensylamine: Under a nitrogen atmosphere, add a mixture of 4- (1-methanesulfonyloxy-2-methyl-butyl) -benzonitrile (1.3 g, 4.9 mmol) in diethyl ether ( 5 mL) was added to a paste of lithium aluminum hydride (820 mg, 19.5 mmol) in diethyl ether (25 mL) at 0 ° C. The mixture is heated under reflux for 1 h. The mixture is cooled in an ice bath and water (0.9 mL), aqueous NaOH 15% (0.9 mL) and water (2.8 mL) are added. The mixture is applied to a column of silica gel by levigating with dichloromethane and 5: 1 dichloromethane in chloroform / methanol / concentrated ammonium hydroxide (80: 18: 2) to give the title compound (450 mg, 52%). EM (ER +) m / z: 178 (M + H) +.

Preparation 315 4- (3, 3-Dimethyl-butyl) -benzylamine 4- (3, 3-Dimethyl-but-l-ynyl) -benzonitrile: 4-Bromobenzonitrile (3 g, 16.48 mmol) is dissolved in anhydrous DMF (30 mL) in a sealed tube. The solution is degassed, purged with nitrogen, and tris (dibenzylideneacetone) dipalladium (0) is added. (453 mg, 0.49 mmol), copper (I) iodide (188 mg, 0.99 mmol), triphenylphosphine (1.08 g, 4.12 mmol), triethylamine (10 mL) and 3,3-dimethylbutine (6.1 mL, 49.44 mmol). The mixture is heated at 90 ° C overnight. It is cooled to room temperature, water is added and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (19: 1, 9: 1) to give the desired intermediate as a solid (2.75 g, 92%).

N- (tert-Jutoxyarbonyl) -4- (3,3-dimethyl-butyl) -bensylamine: 4- (3,3-Dimethyl-but-l-ynyl) -benzonitrile (0.85 g, 4.64 mmol) is dissolved in methanol (50 mL). 10% Pd / C (type Degussa ElOl, 0.68 g) and di-tert-butyl-dicarbonate (1.21 g, 5.57 mmol) are added. The mixture is subjected to hydrogenation under atmospheric pressure (balloon) for 6 h. The catalyst is filtered through Celite® and the filtrate is concentrated in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (9: 1, 4: 1) to provide the desired intermediate as an oil (1.25 g, 93%). MS (ER +) m / z: 314 (M + Na) +. 4- (3, 3-Dxm-butyl) -bensylamine: 4N hydrogen chloride in dioxane (15 mL) is added to a stirred solution of N- (tert -butoxycarbonyl) -4- (3, 3-dimethylbutyl) ) -benzylamine (1.25 g, 4.29 mmol) in methanol (20 mL) and stirred at room temperature overnight. Concentrate in vacuo and wash the solid with diethyl ether. The solid is suspended in dichloromethane and saturated aqueous NaHCO3 and stirred until both phases are cleaned (15 min). The aqueous phase is extracted twice with dichloromethane. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to give the title compound as an oil (0.654 g, 80%) which was used without any further purification. MS (ER +) m / z: 192 (M + H) +.

Preparations 316 3-Aminomethyl-6- (3, 3-dimethyl-butyl) -pyridine The title compound can be prepared essentially as described in Preparation 315 by using 6-bromonicotinonitrile (45% yield, MS (ER +) m / z 193 (M + H) +).

Preparation 317 3-Aminomethyl-6-cyclohexylmethyl-pyridine 3-te-r-Jutoxyarbonilaminomethyl-6-sislohexylmethyl-pyridine: Dissolve 2-bromo-5-ter-rp? Toxicarbonylaminomethyl-pyridine (500 mg, 1.74 mmol) in anhydrous THF (5 mL) in a sealed tube. The solution is degassed, purged with nitrogen and 1,1'- [bis (diphenylphosphine) ferrocene] dichloropalladium (II) (127 mg, 0.174 mmol) and cyclohexylmethylzinc bromide 0.5M in THF are added. (10.4 mL, 5.22 mmol). The mixture is heated at 60 ° C overnight. Cool to room temperature and dilute the reaction mixture with EtOAc. Water is added and the precipitate is filtered over Celite®. The organic phase is dried over MgSO, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (4: 1, 3: 2) to give the desired intermediate as an oil (359 mg, 68%). MS (ER +) m / z: 305 (M + H) +. 3-Aminomethyl-6-sislohexylmethyl-pyridine: 4N hydrogen chloride in dioxane (10 mL) is added to a solution of 3-tert-butoxycarbonylaminomethyl-6-cyclohexylmethyl-pyridine (345 mg, 1.13 mmol) in EtOAc (10 mL). and it is stirred during the night. Concentrate in vacuo, suspend the obtained solid in diethyl ether and add hexane. Filter and wash the solid with hexane. The solid is suspended in dichloromethane, saturated aqueous NaHCO3 is added and the mixture is stirred until both phases are cleaned (15 min). The aqueous phase is extracted twice with dichoromethane. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the title compound as an oil (205 mg, 97%) which was used without any further purification. MS (ER +) m / z: 205 (M + H) +.

Preparations 318 2-Aminomethyl-5- (3, 3-dimethyl-butyl) -pyridine - (3, 3-Dimethyl-but-l-ynyl) -2-siane-pyridine: 5-Bromo-2-cyano-pyridine (316 mg, 1.72 mmol) is dissolved in anhydrous DMF (7 mL) in a tube sealed. The solution is degassed, purged with nitrogen, and tris (dibenzylideneacetone) dipalladium (0) (47 mg, 0.05 mmol), copper iodide (I) (20 mg, 0.1 mmol), triphenylphosphine (113 mg, 0.43 mmol) is added. , triethylamine (2 mL) and 3, 3-dimethylbutyne (0.64 mL, 5.16 mmol). The mixture is heated at 90 ° C overnight. It is cooled to room temperature, water is added and the aqueous phase is extracted twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (19: 1) to give the desired intermediate as a solid (310 mg, 97%). 2-Aminomethyl-5- (3,3-dimethyl-butyl) -pyridine: 5- (3,3-dimethyl-but-l-ynyl) -2-cyano-pyridine (255 mg, 1.5 mmol) is dissolved in methanol (15 mL). 10% Pd / C (type Degussa ElOl, 230 mg) is added and the mixture is exposed to hydrogenation under atmospheric pressure (balloon) overnight. The catalyst is filtered through Celite® and the filtrate is concentrated in vacuo to provide the title compound as a solid (231 mg, 87%) which was used without any further purification. MS (ER +) m / z: 193 (M + H) +.

Preparation 319 4- (1, 3, 3-Trimethyl-butyl) -benzylamine 4- (1-Hydroxy-1,3-trimethyl-butyl) -benzonitrile: 4-acetylbenzonitrile (1 g, 6.88 mmol) is dissolved in diethyl ether / THF (1: 1, 60 mL) and the solution is cooled to 0 ° C. 1M Nepentylmagnesium chloride in diethyl ether (8.3 mL, 8.3 mmol) is added under nitrogen and the mixture is stirred at room temperature overnight. Saturated aqueous NH4C1 is added and the mixture is extracted twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (19: 1, 9: 1) to give the desired intermediate (364 mg, 24%). 4- (3, 3-Dimethyl-l-methylene-butyl) -benzonitrile: p-Toluenesulfonic acid monohydrate (308 mg, 1.62 mmol) is added to a solution of 4- (1-hydroxy-1,3,3- trimethyl-butyl) -benzonitrile (352 mg, 1.62 mmol) in toluene (10 L). The solution is heated to 100 ° C for 30 min. The reaction mixture is cooled to room temperature, the reaction mixture is diluted with EtOAc and the organic phase is washed with saturated aqueous NaHCO3. The organic phase is dried over MgSO, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (98: 2, 19: 1) to give the desired intermediate as an oil (200 mg, 62%).

N- (tert -toxhoxycarbonyl) -4- (1,3,3-trimethyl-butyl) -bensylamine: Dissolve 4- (3,3-dimethyl-1-methylene-butyl) -benzonitrile (164 mg, 0.82 mmol) in methanol (15 mL). 10% Pd / C (type Degussa ElOl, 130 mg) and di-tert-butyl-dicarbonate (197 mg, 0.902 mmol) are added. The mixture is subjected to hydrogenation under atmospheric pressure (balloon) for 3 h. The catalyst is filtered through Celite® and the filtrate is concentrated in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (19: 1, 9: 1) to provide the desired intermediate as an oil (227 mg, 90%). MS (ER +) m / z: 328 (M + Na) +. 4- (1, 3, 3-Trimethyl-butyl) -bensylamine: 4N hydrogen chloride in dioxane (10 mL) is added to a stirred solution of N- (tert-butoxycarbonyl) -4- (1, 3, 3) trimethyl-butyl) -benzylamine (225 mg, 0.74 mmol) in EtOAc (15 mL) and the mixture is stirred at room temperature overnight. Concentrate in vacuo and wash the solid with diethyl ether. The solid is suspended in dichloromethane and saturated aqueous NaHCO3 and stirred until both phases are cleaned (15 min). The aqueous phase is extracted twice with dichloromethane. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to give the title compound as an oil (0.136 g, 90%) which was used without any further purification. MS (ER +) m / z: 206 (M + H) +.

Example 537 Succinate of 7-chloro-6- (2,4-difluorobenzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-1 is used to react 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-l, l-benzo [d] azepine (3 g, 7.06 mmol), palladium (II) acetate (0.16 g, 0.71 mmol), BINAP (0.88 g, 1.41 mmol), 2,4-difluorobenzylamine (3.03 g, 21.18 mmol) and cesium carbonate (3.22 g). 9.88 mmol) in degassed toluene (120 mL). The mixture is degassed with vacuum / nitrogen purge and heated at 100 ° C for 16 h. The mixture is cooled to room temperature, diluted with EtOAc, filtered through Celite® and concentrated in vacuo to give a brown oil. The crude mixture is purified by chromatography on silica gel by levigating with hexane and then hexane / THF (95: 5) to obtain 7-chloro-6- (2,4-difluorobenzylamino) -3- (2, 2, 2, trifluoroacetyl). ) -2,3,4, 5-tetrahydro-li-benzo [d] azepine as oil (2.25 g, 76%). MS (ER +) m / z: 419 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- (2,4-difluorobenzylamino) -3- (2, 2, 2, trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lf -benzo [d] azepine (2.2 g, 5.26 mmol), to give the free base of the title compound as an oil (1.66 g, 98%) which solidifies on standing at room temperature and was used without further purification. MS (ER +) m / z: 323 (M + H) +. A method similar to General Procedure 2-1 is used, using 7-chloro-6- (2,4-difluorobenzylamino) -2,3,4,5-tetrahydro-TL-benzo [d] azepine (1.66 g, 5.14 mmol ) to give the title compound as a white solid (2.03 g, 90%). MS (ER +) m / z: 323 (M + H) +.

Example 538 Succinate of 7-chloro-6- (2,5-difluorobenzylamino) -2, 3, 4, 5-tetrahydro-l-benzo [d] azepine Example 538 can be prepared essentially as described in Example 537 using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-l-p-benzo [d ] azepine and 2,5-difluorobenzylamine (68% yield, MS (ER +) m / z 323 (M + H) +).

Example 539 Succinate of 7-chloro-6- (2, 2-difluoro-2-phenyl-ethylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-3 is used to react 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1H-benzo [d] azepine (541 mg, 1.274 mmol), palladium (II) acetate (57 mg, 0.225 mmol), tris (dibenzylideneacetone) dipalladium (0) (117 mg, 0.127 mmol), BINAP (0.506 g, 0.764 mmol), 2,2-difluoro-2-phenyl-ethylamine (400 mg, 2.547 mmol) and cesium carbonate (830 mg, 2.548 mmol) in degassed toluene ( 35 mL). The mixture is degassed with vacuum / nitrogen purge and heated at 100 ° C for 16 h. The mixture is cooled to room temperature, diluted with EtOAc and filtered over Celite®. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (19: 1) to obtain 7-chloro-6- (2,2-difluoro-2-phenyl-ethylamino) -3- (2, 2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-li-benzo [d] azepine as an oil (335 mg, 61%). MS (ER +) m / z: 433 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- (2, 2-difluoro-2-phenyl-ethylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4 , 5-tetrahydro-lH-benzo [d] azepine (317 mg, 0.734 mmol), to give the free base of the title compound as an oil (215 mg, 87%) which was used without further purification. MS (ER +) m / z: 337 (M + H) +. A method similar to General Procedure 2-1 is used, using 7-chloro-6- (2, 2-difluoro-2-phenyl-ethylamino) -2,3,4,5-tetrahydro-l-p-benzo [d] azepine (215 mg, 0.64 mmol) to give the title compound as a white solid (220 mg, 76%). MS (ER +) m / z: 337 (M + H) +.

Example 540 Succinate of 7-chloro-6- (2, 2-difluoro-2-pyridin-2-yl-ethylamino) -2,3,4,5-tetrahydro-li? -benzo [d] azepine Example 540 can be prepared essentially as described in Example 539 using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [ d] azepine and 2,2-difluoro-2-pyridin-2-yl-ethylamine (prepared by following the procedure described in J. Med. Chem. 2003, 46, 461-473), (37% yield, MS (ER +) m / z 338 (M + H) +).

Examples 541-544 Examples 541-544 can be prepared essentially as described in Example 262 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3.4, 5-tetrahydro-l-l-benzo [d] azepine and the appropriate amine. The total yields and EM data (ER +) are shown in the Table below.

Example 545 7-Chloro-6- (3-phenyl-benzothiophen-6-ylmethylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride A method similar to General Procedure 5-2 is used, using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li? -benzo [d] azepine (0.28 g, 0.66 mmol) and 6-aminomethyl-3-phenyl-benzothiophene (0.19 g, 0.8 mmol) with tris (dibenzylidene acetone) dipalladium (0) (120 mg, 0.13 mmol), BINAP (165 mg, 0.26 mmol) and cesium carbonate (0.3 g, 0.93 mmol) at 90 ° C for 17 h, to obtain 7-chloro-6- (3-phenyl-benzothiophen-6-yl-methylamino) -3- (2,2, 2- trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine which is used without further purification (234 mg, 69%). MS (ER +) m / z 515 (M + H) +. A procedure similar to the General Procedure is used 1-1 to deprotect 7-chloro-6- (3-phenyl-benzothiophen-6-yl-methylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (234 mg, 0.45 mmol) in 7M ammonia in methanol (20 mL). It is purified by reverse phase HPLC (Vydac C18 5 x 25 cm, 30% up to 100% acetonitrile in 0.1% TFA-water solution). The free base is coated by SCX chromatography and forms the salt according to General Procedure 2-3 to obtain the title compound (38 mg, 17%). HRMS (ER +) m / z: 419.1340 (M + H) +.

Example 546 7-Chloro-6- [(difluoro-phenyl-methyl) -benzylamino] -2,3,4,5-tetrahydro-L-t-benzo [d] azepine Succinate A procedure similar to Example 262 is used using 1- chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1,1-benzo [d] azepine and 4- (difluoro-phenyl-methyl) -benzylamine, followed by deprotection in accordance with General Procedure 1-2 and salt formation in accordance with General Procedure 2-1 to obtain the title compound (175 mg, 77%). MS (ER +) m / z 413 (M + H) +.Example 547 Succinate of 7-chloro-β- [4- (3, 3-dimethyl-butyryl) -benzylamino] -2,3,4,5-tetrahydro-li? -benzo [d] azepine A method similar to General Procedure 5-3 is used to react 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (250 mg, 0.588 mmol), palladium (II) acetate (26 mg, 0.118 mmol), tris (dibenzylideneacetone) dipalladium (0) (53 mg, 0.059 mmol), BINAP (0.22 g, 0.353 mmol), 4- (3,3-dimethyl-butyryl) -benzylamine (241 mg, 1176 mmol) and cesium carbonate (383 mg, 1176 mmol) in degassed toluene (10 mL). The mixture is degassed with vacuum / nitrogen purge and heated to 100 ° C for 16 h. The mixture is cooled to room temperature, diluted with EtOAc and washed with saturated aqueous NaHCO3. Dry the organic layer over Na 2 SO, filter and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and then hexane / EtOAc (90:10, 85:15) to obtain 7-chloro-6- [4- (3, 3-dimethyl-butyryl) -benzylamine ] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-l-p-benzo [d] azepine as oil (185 mg, 65%). MS (ER +) m / z: 481 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- [4- (3, 3-dimethyl-butyryl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2.3 , 4, 5-tetrahydro-lH-benzo [d] azepine (165 mg, 0.343 mmol), to give the free base of the title compound as an oil (130 mg, 98%) which was used without further purification. MS (ER +) m / z: 385 (M + H) +. A method similar to General Procedure 2-1 is used, using 7-chloro-6- [4- (3, 3-dimethyl-butyryl) -benzylamino] -2,3,4, 5-tetrahydro-Iñ-benzo [d ] azepine (130 mg, 0.338 mmol) to give the title compound as a white solid (128 mg, 76%). MS (ER +) m / z: 385 (M + H) +.

Example 548 Succinate of 7-chloro-6- [4- (3, 3-dimethyl-butyryl) -3-fluoro-benzylamino] -2,4,4,5-tetrahydro-li? -benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (96 mg, 0.225 mmol) with 4- (3, 3-dimethyl-butyryl) -3-fluoro-benzylamine (105 mg, 0.45 mmol) when using tris (dibenzylideneacetone) dipalladium (0) (41 mg, 0.045 mmol) , BINAP (56 mg, 0.09 mmol) and cesium carbonate (103 mg, 0.315 mmol) in anhydrous toluene (15 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give 7-chloro-6- [4- (3, 3-dimethyl-butyryl) -3-fluoro-benzylamino] -3- (2 , 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1-benzo [d] azepine as a yellow oil (54 mg, 49%). MS (ER +) m / z: 499 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- [4- (3, 3-dimethyl-butyryl) -3-fluoro-benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4, 5-tetrahydro-l-benzo [d] azepine (53 mg, 0.11 mmol) to give the free base of the title compound as a yellow oil (42 mg, 96%) which was used without purification additional. A method similar to General Procedure 2-1 is used, using 7-chloro-6- [4- (3, 3-dimethyl-butyryl) -3-fluoro-benzylamino] -2, 3,4,5-tetrahydro-1H -benzo [d] azepine (42 mg, 0.105 mmol) to give the title compound as a white solid (30 mg, 60%). MS (ER +) m / z: 403 (M + H) +.

Example 549 Succinate of 7-chloro-6- [4- (3, 3-dimethyl-butyryl) -2-fluoro-benzylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (127 mg, 0.3 mmol) with 4- (3, 3-dimethyl-butyryl) -2-fluoro-benzylamine (120 mg, 0.54 mmol) when using tris (dibenzylideneacetone) dipalladium (0) (27 mg, 0.03 mmol) , BINAP (40 mg, 0. 06 mmol) and cesium carbonate (137 mg, 0.42 mmol) in anhydrous toluene (20 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 and 9: 1) followed by reverse phase CLAR [Zorbax Bonus RP, 5 DM 21.2 x 100 mm, levigating with water / acetonitrile (TFA 0. 05% in each) (35:65 to 15:85 gradient for 5 min), flow ratio 25 mL / min, UV detector (230 nm)] to give 7-chloro-6- [4- (3, 3 -dimethyl-butyryl) -2-fluoro-benzylamino] -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lff-benzo [d] azepine as an oil (72 mg, 49 %). EM (ER +) m / z: 499 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- [4- (3, 3-dimethyl-butyryl) -2-fluoro-benzylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-liY-benzo [d] azepine (26 mg, 0.052 mmol) to give the free base of the title compound as a yellow oil (19 mg, 91%) which was used without purification additional. A method similar to General Procedure 2-1 is used, using 7-chloro-6- [4- (3, 3-dimethyl-butyryl) -2-fluoro-benzylamino] -2, 3, 4, 5-tetrahydro-líT -benzo [d] azepine (18 mg, 0.045 mmol) to give the title compound as a white solid (20 mg, 86%). MS (ER +) m / z: 403 (M + H) +.

Example 550 Succinate of 7-chloro-6- [3-chloro-4- (3,3-dimethyl-butyryl) -benzylamino] -2,3,4,5-tetrahydro-li? -benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (90 mg, 0.212 mmol) with 3-chloro-4- (3, 3-dimethyl-butyryl) -benzylamine (102 mg, 0.43 mmol) when using tris (dibenzylideneacetone) dipalladium (0) (39 mg, 0.0424 mmol) , BINAP (53 mg, 0.0848 mmol) and cesium carbonate (97 mg, 0.297 mmol) in anhydrous toluene (10 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give 7-chloro-6- [3-chloro-4- (3, 3-dimethyl-butyryl) -benzylamino] -3- (2 , 2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine as an oil (72 mg, 49%). MS (ER +) m / z: 516 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- [3-chloro-4- (3, 3-dimethyl-butyryl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2.3, 4, 5-tetrahydro-li? -benzo [d] azepine (70 mg, 0.136 mmol) to give the free base of the title compound as a yellow oil (57 mg, 99%) which was used without additional purification. A method similar to General Procedure 2-1 is used, using 7-chloro-6- [3-chloro-4- (3, 3-dimethyl-butyryl) -benzylamino] -2,3,4, 5-tetrahydro-liZ -benzo [d] azepine (57 mg, 0.136 mmol) to give the title compound as a white solid (50 mg, 68%). MS (ER +) m / z 420 (M + H) +.

Example 551 Succinate of 7-chloro-6- [2-chloro-4- (3, 3-dimethyl-butyryl) -benzylamino] -2, 3, 4, 5-tetrahydro-l-benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,3,5-tetrahydro-1-benzo [d] azepine ( 300 mg, 0.71 mmol) with 1- (4-aminomethyl-3-chloro-phenyl) -3,3-dimethyl-butan-1-one (338 mg, 1.41 mmol) when using tris (dibenzylideneacetone) dipalladium (0) ( 130 mg, 0.142 mmol), BINAP (177 mg, 0.284 mmol) and cesium carbonate (324 mg, 0.994 mmol) in anhydrous toluene (31 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (92: 8) followed by reverse phase HPLC [Hichrom Kromasil C18, DM 21.2 x 100 mm, levigating with water / acetonitrile (TFA 0.05% in each) ( 1: 4 to 1:19 gradient for 5 min), flow ratio 25 mL / min, UV detector (230 nm)] to give 7-chloro-6- [2-chloro-4- (3, 3-dimethyl- butyryl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1-yl-benzo [d] azepine as an oil (77 mg, 21%). MS (ER +) m / z: 516 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- [2-chloro-4- (3, 3-dimethyl-butyryl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (77 mg, 0.15 mmol) to give the free base of the title compound as a yellow oil (93 mg, 99%) which was used without purification additional. A method similar to General Procedure 2-1 is used, using 7-chloro-6- [2-chloro-4- (3, 3-dimethyl-butyryl) -benzylamino] -2, 3,4,5-tetrahydro-1H -benzo [d] azepine (63 mg, 0.15 mmol) to give the title compound as a white solid (52 mg, 65%). MS (ER +) m / z: 420 (M + H) +.

Example 552 7-Chloro-6- [4- (4,4-dimethyl-pentanoyl) -benzylamino] -2,3,4,5-tetrahydro-l.H-benzo [d] azepine Succinate A method similar to General Procedure 5-2 is used to react 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (233 mg, 0.55 mmol), tris (dibenzylideneacetone) dipalladium (0) (50 mg, 0.055 mmol), BINAP (73 mg, 0.11 mmol), 4- [2- (3, 3-dimethyl-butyl) - [1, 3] dioxolan-2-yl] -benzylamine (263 mg, 1 mmol) and cesium carbonate (250 mg, 0.77 mmol) in degassed toluene (20 mL). The mixture is degassed with vacuum / nitrogen purge and heated at 100 ° C for 14 h. The mixture is cooled to room temperature, diluted with EtOAc and filtered through Celite®. The crude mixture was purified by chromatography on silica gel by levigating with hexane and then hexane / EtOAc (19: 1, 9: 1 and 4: 1) to obtain 7-chloro-6-. { 4- [2- (3, 3-dimethyl-butyl) - [1, 3] dioxolan-2-yl] -benzylamine} -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-li? -benzo [d] azepine as oil (185 mg, 63%). MS (ER +) m / z: 539 (M + H) +. Dissolve 7-chloro-6-. { 4- [2- (3, 3-dimethyl-butyl) - [1, 3] dioxolan-2-yl] -benzylamine} -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lE-benzo [d] azepine (185 mg, 0.34 mmol) in methanol (10 mL) and IN aqueous HCl is added ( 2 mL). The mixture is stirred for 2 h and concentrated in vacuo. The residue is dissolved in dichloromethane and washed with saturated aqueous NaHCO3. Dry the organic phase over MgSO, filter and concentrate in vacuo to obtain 7-chloro-6- [4- (4,4-dimethyl-pentanoyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-l, -benzo [d] azepine as an oil (150 mg, 89%). A method similar to General Procedure 1-2 is used, using 7-chloro-6- [4- (4,4-dimethyl-pentanoyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2, 3 , 4, 5-tetrahydro-l, -benzo [d] azepine (150 mg, 0.3 mmol), to give the free base of the title compound as an oil (100 mg, 83%) which was used without further purification. A method similar to General Procedure 2-1, using 7-chloro-6- [4- (4,4-dimethyl-pentanoyl) -benzylamino] -2,3,4,5-tetrahydro-l, -benzo [d] azepine (100 mg, 0.25 mmol) to give the title compound as a solid (100 mg, 78%). MS (ER +) m / z 399 (M + H) +.

Example 553 Succinate of 7-chloro-6- (4-cyclohexanecarbonyl-benzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-2 is used to react 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (150 mg, 0.353 mmol), tris (dibenzylideneacetone) dipalladium (0) (64 mg, 0.071 mmol), BINAP (88 mg, 0.141 mmol), 4-cyclohexanecarbonyl-benzylamine (125 mg, 0.576 mmol) and cesium carbonate (230 mg, 0.706 mmol) in degassed toluene (10 mL). The mixture is degassed with vacuum / nitrogen purge and heated at 100 ° C for 6 h. The mixture is cooled to room temperature, diluted with EtOAc and filtered through Celite®. The crude mixture was purified by chromatography on silica gel by levigating with hexane and then hexane / EtOAc (90:10 and 85:15) to obtain 7-chloro-6- (4-cyclohexanecarbonyl-benzylamino) -3- (2.2 , 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine as oil (130 mg, 75%). MS (ER +) m / z: 493 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- (4-cyclohexanecarbonyl-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1H -benzo [d] azepine (120 mg, 0.243 mmol), to give the free base of the title compound as an oil (86 mg, 89%) which was used without further purification. MS (ER +) m / z: 397 (M + H) +. A method similar to General Procedure 2-1 is used, using 7-chloro-6- (4-cyclohexanecarbonyl-benzylamino) -2,3,4,5-tetrahydro-L-t-benzo [d] azepine (86 mg, 0.217 mmol ) to give the title compound as a solid (85 mg, 77%). MS (ER +) m / z: 397 (M + H) +.

Examples 554-557 Examples 554-557 can be prepared essentially as described in Example 553 using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro -lH-benzo [d] azepine and the appropriate amine. The total yields and EM data (ER +) are shown in the Table below.

Example 558 Succinate of 7-chloro-6- (4-cycloheptylcarbamoyl-3-fluoro-benzylamino) -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li? -benzo [d] azepine (1.1 g, 2.5 mmol) with 4-aminomethyl-JW-cycloheptyl-2-fluoro-benzamide (1.35 g, 5.1 mmol) in anhydrous toluene (25 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (gradient 19: 1 to 1: 1) followed by SCX chromatography to obtain 7-chloro-6- [4-cycloheptylcarbamoyl-3-fluoro-benzylamino] -3- ( 2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine (720 mg, 53%). MS (ER +) m / z 540.2 (M + H) +. A method similar to General Procedure 1-2 is used to deprotect 7-chloro-6- [4-cycloheptylcarbamoyl-3-fluoro-benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5 -tetrahydro-lH-benzo [d] azepine. Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (99: 1 to 90:10 gradient) to obtain the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (665 mg, 89%). MS (ER +) m / z: 444.2 (M + H) +.

Example 559 (i) 7-Chloro-6- (4-cycloheptylcarbamoyl-2-fluorobenzylamino) -2,3,4,5-tetrahydro-1H-benzo [d] azepine-tertrate A method similar to General Procedure 5 is used -2 to couple 7-chloro-3- (2,2, 2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li? -benzo [d] azepine (640 mg, 1.5 mmol) with 4-aminomethyl-N-cycloheptyl-3-fluoro-benzamide (795 mg, 3 mmol) in anhydrous toluene (20 mL). The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 3: 2 gradient) to obtain 7-chloro-6- (4-cycloheptylcarbamoyl-2-fluoro-benzylamino) -3- (2). , 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lyf-benzo [d] azepine (568 mg, 70%). MS (ER +) m / z: 540.2 (M + H) +. A method similar to General Procedure 1-2 is used to deprotect 7-chloro-6- (4-cycloheptylcarbamoyl-2-fluorobenzylamino) -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro -lfí-benzo [d] azepine. Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (99/1 to 93/7 gradient) to give the free base of the title compound. The free base (400 mg, 0.9 mmol) and L-tartaric acid (135 mg, 0.9 mmol) are dissolved in methanol. Concentrate in vacuo to an oil. The oil is triturated with dichloromethane and the solvent removed in vacuo to obtain the title compound as a solid (460 mg, 74%). MS (ER +) m / z: 444.2 (M + H) +.

Example 560 (L) - 7-Chloro-6- (3-chloro-4-cycloheptylcarbamoyl-benzylamino) -2,3,4,5-tetrahydro-l-benzo [d] azepine Example 560 can be prepared essentially as described in Example 559 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine and 4-aminomethyl-2-chloro-N-cycloheptyl-benzamide (50% yield, MS (ER +) m / z 460.2 (M + H) +).

Example 561 7-Chloro-6- (4-cycloheptylcarbamoyl-3-methyl-benzylamino) -2,3,4,5-tetrahydro-li? -benzo [d] azepine Succinate A method similar to General Procedure 5- 2 to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (660 mg, 1.6 mmol) with 4 -aminomethyl-i \ 7-cycloheptyl-2-methyl-benzamide (810 mg, 3.1 mmol) in anhydrous toluene (18 mL). The crude mixture was purified by chromatography on silica gel by levigating with hexane / THF (19: 1 to 7: 3 gradient) to obtain 7-chloro-6- (4-cycloheptylcarbamoyl-3-methyl-benzylamino) -3- (2 , 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-l, l-benzo [d] azepine (690 mg, 83%). MS (ER +) m / z: 536.3 (M + H) +. A method similar to General Procedure 1-3 is used to deprotect 7-chloro-6- (4-cycloheptylcarbamoyl-3-methyl-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5 -tetrahydro-li? -benzo [d] azepine (680 mg, 1.3 mmol). Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (99: 1 to 97: 3 gradient) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (473 mg, 65%). MS (ER +) m / z: 440.3 (M + H) +.

Example 562 Succinate of (i?) -7-chloro-6- [3-fluoro-4- (2,2,2-trifluoro-1-methyl-ethylcarbamoyl) -benzylamino] -2,3,4,5-tetrahydro -lH- benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (0.561 g, 1319 mmol) with. { R) -4-aminomethyl-2-f luoro-N- (2, 2, 2-trifluoro-1-methyl-ethyl) -benzamide (0.698 g, 2. 642 mmol) when using tris (dibenzylideneacetone) dipalladium (0) (0.241 g, 0.264 mmol), BI? AP (0.33 g, 0.53 mmol) and cesium carbonate (1.51 g, 4.63 mmol) in anhydrous toluene (13 mL). Purify by chromatography on silica gel (RediSep® column 40 g) by levigating with hexane / EtOAc (gradient 19: 1 to 1: 1 for 30 min; 35 mL / min) and then by SCX chromatography to provide () -7- chloro-6- [3-fluoro-4- (2, 2, 2-trifluoro-1-methyl-ethylcarbamoyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5- tetrahydro-lH-benzo [d] azepine as a colorless oil (0.444 g, 62%). MS (ER +) m / z: 540.1 (M + H) +.

A method similar to General Procedure 1-3 is used to check out. { R) -7-chloro-6- [3-fluoro-4- (2,2,2-trifluoro-1-methyl-ethylcarbamoyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2.3 , 4,5-tetrahydro-1-yl-benzo [d] azepine (0.224 g, 0.415 mmol). Purify by chromatography on silica gel (RediSep® solvate 12 g) by levigating with dichloromethane / 2M ammonia in methanol (99: 1 to 90:10 gradient for 30 min, 35 mL / min) to provide the free base of the title compound as a white foam (0.142 g, 77%). A method similar to General Procedure 2-1 is used, using (J?) -7-chloro-6- [3-fluoro-4- (2,2,2-trifluoro-1-methyl-ethylcarbamoyl) -benzylamino] - 2,3,4,5-tetrahydro-l, -benzo [d] azepine (0.132 g, 0.299 mmol) to give the title compound as a white solid (0.135 g, 80%). MS (ER +) m / z: 444.2 (M + H) +.

Example 563 7-Chloro-6- (3-fluoro-4-isopropylcarbamoyl-benzylamino) -2,3,4,5-tetrahydro-L-benzo [d] azepine Succinate Isopropyl amine (0.15 mL, 1.8 mmol), HOBT (0.24 g, 1.8 mmol), diisopropylethylamine (0.63 L, 3.6 mmol) and EDC (0.34 g, 1.8 mmol) are added to a mixture of 3-tert.-utoxycarbonyl-6- ( 4-carboxy-3-fluoro-benzylamino) -7-chloro-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (0.403 g, 0.9 mmol) in anhydrous THF (11.8 mL) at room temperature . Stir overnight at room temperature and partition the mixture between EtOAc (250 mL) and saturated aqueous NaHCO 3 (100 L). The organic phase is dried over Na 2 SO, filtered and concentrated in vacuo. Purify by chromatography on silica gel (RediSep® column 40 g) by levigating with hexane / EtOAc (gradient 19: 1 to 1: 1 for 30 min; 50 mL / min) to provide 3-tert-jutoxycarbonyl-7-chloro- 6- (3-Fluoro-4-isopropylcarbamoyl-benzylamino) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine as a thick, colorless oil (0.439 g, 100%). MS (ER +) m / z: 490.2 (M + H) +. A method similar to General Procedure 1-4 is used to deprotect 3-ter- £ > Utoxycarbonyl-7-chloro-6- (3-fluoro-4-isopropylcarbamoyl-benzylamino) -2,3,4,5-tetrahydro-li? -benzo [d] azepine (0.406 g, 0.83 mmol) in 1.4- dioxane (12.8 mL). Purify by SCX chromatography by levigating with dichloromethane and dichloromethane / 2M ammonia in methanol (1: 1) followed by chromatography on silica gel (RediSep 40 g column) by levigating with dichloromethane / 2M ammonia in methanol (99: 1 to 90:10 30 min) and then dichloromethane / 2M ammonia in methanol (90:10 for 30 min; 35 mL / min) to provide 7-chloro-6- (3-fluoro-4-isopropylcarbamoyl-benzylamino) -2.3.4, 5-tetrahydro-li? -benzo [d] azepine as a colorless oil (0.3237 g). MS (ER +) m / z: 390.1 (M + H) +. A method similar to General Procedure 2-1 is used, using 7-chloro-6- (3-fluoro-4-isopropylcarbamoyl-benzylamino) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine ( 0.301 g, 0.772 mmol) to afford the title compound as a beige solid (0.328 g, 84%). MS (ER +) m / z: 390.1 (M + H) +.

Example 564 (L) - 7-Chloro-6- (3-f luoro-4-propylcarbamoyl-benzylamino) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine A solution of n-propylamine (6.3 mg, 0.11 mmol) in anhydrous THF (0.5 L), HOBT (14.5 mg, 0.11 mmol), a solution of diisopropylamine (27.7 mg, 0.21 mmol) in anhydrous THF (0.5 mL) is added. and EDC (20.5 mg, 0.11 mmol) to a mixture of 3-ter- £ > Utoxycarbonyl-6- (4-carboxy-3-fluoro-benzylamino) -7-chloro-2,3,4,5-tetrahydro-li? -benzo [d] azepine (48.1 mg, 0.11 mmol) in anhydrous THF (1.4 mL) at room temperature. Stir overnight at room temperature and partition the mixture between EtOAc (50 mL) and saturated aqueous NaHCO 3 (20 L).

The organic phase is dried over Na 2 SO 4, filtered and concentrated in vacuo. Purify by chromatography on silica gel (RediSep® column 12 g) by levigating with hexane / EtOAc (gradient 19: 1 to 1: 1 for 30 min; 35 mL / min) to provide 3-tert-jutoxycarbonyl-7-chloro- 6- (3-fluoro-4-propylcarbamoyl-benzylamino) -2, 3,4, 5-tetrahydro-lJ? -benzo [d] azepine as a thick, colorless oil (37.1 mg, 71%). MS (ER +) m / z: 490.2 (M + H) +. A method similar to General Procedure 1-4 is used to deprotect 3-tert-Jutoxycarbonyl-7-chloro-6- (3-fluoro-4-propylcarbamoyl-benzylamino) -2,3,4,5-tetrahydro-1H-benzo [d] azepine (33.1 mg, 0.83 mmol) in 1,4-dioxane (1 mL). Purify by SCX chromatography by levigating with dichloromethane and dichloromethane / 2M ammonia in methanol (1: 1) to provide 7-chloro-6- (3-fluoro-4-propylcarbamoyl-benzylamino) -2, 3, 4, 5-tetrahydro- li? -benzo [d] azepine as a colorless oil (25.2 mg, 96%). MS (ER +) m / z: 390.1 (M + H) +. A method similar to General Procedure 2-6 is used, using 7-chloro-6- (3-fluoro-4-propylcarbamoyl-benzylamino) -2,3,4,5-tetrahydro-li-benzo [d] azepine (25). mg, 0. 064 mmol) to provide the title compound as a white foam (31.4 mg, 91%). MS (ER +) m / z: 390.1 (M + H) +.

Example 565 (L) - 7-Chloro-6- [4- (cyclohexylmethylcarbamoyl) -3-fluoro-benzylamino] -2,3,4,5-tetrahydro-lüT-benzo [d] azepine Example 565 can be prepared essentially as described in Example 564 by using 3-tert-Jutoxycarbonyl-6- (4-carboxy-3-fluoro-benzylamino) -7-chloro-2, 3, 4, 5-tetrahydro- 1H-benzo [d] azepine and cyclohexylmethylamine (67% yield, MS (ER +) m / z 444 (M + H) +).

Example 566 7-Chloro-6- (6-cyclohexylamino-pyridin-3-ylmethylamino) -2,3,4,5-tetrahydro-1-benzo [d] azepine Succinate A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-l, t-benzo [d] azepine (800 mg, 1.9 mmol) with 5-aminomethyl-2-cyclohexylamino-pyridine (910 mg, 4.4 mmol) in anhydrous toluene (15 mL). The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 3: 2 gradient) to obtain 7-chloro-6- (6-cyclohexylamino-pyridin-3-ylmethylamino) -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine (520 mg, 58%). MS (ER +) m / z: 481.0 (M + H) +. A method similar to General Procedure 1-3 is used to deprotect 7-chloro-6- (6-cyclohexylamino-pyridin-3-ylmethylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5 -tetrahydro-lií-benzo [d] azepine. Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (99/1 to 85/15 gradient) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (360 mg, 66%). MS (ER +) m / z: 385.1 (M + H) +.

Example 567 7-Chloro-6- (6-cyclohexylmethylamino-pyridin-3-ylmethylamino) -2, 3, 4, 5-tetrahydro-lff-benzo [d] azepine Succinate The title compound can be prepared essentially as described in Example 566 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-l-benzo [d] azepine and 5-aminomethyl-2-cyclohexylmethylaminopyridine (22% yield, MS (ER +) m / z 399.1 (M + H) +).

Example 568 6- [6- (Benzylamino) -pyridin-3-ylmethylamino] -7-chloro-2,3,4,5-tetrahydro-lJ-benzo [d] azepine Succinate A method similar to General Procedure 5-2 is used to couple 6-benzylamino-pyridin-3-ylmethylamine and 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3, 4, 5 -tetrahydro-l, -benzo [d] azepine to give, after deprotection and salt formation by methods similar to General Procedures 1-3 and 2-1, the title compound as an opaque white solid (45% overall yield) ). HRMS (ER +) miz: 393.1836 (M + H) +.

Example 569 Succinate of (+) - 7-chloro-6-. { 4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -benzylamino} -2, 3,4, 5-tetrahydro-li? -benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6- trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (751 mg, 1.8 mol) with (±) -4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) - ethoxy] -benzylamine (950 mg, 3.5 mmol) in anhydrous toluene (20 mL). The crude mixture is purified by chromatography on silica gel by sequentially levigating with hexane / EtOAc (10: 1, 5: 1, 3: 1) to obtain (+) - 7-chloro-6-. { 4- [1- (1,1,2,2, 2-pentafluoroethyl) -ethoxy] -benzylamino} -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine (990 mg, 99%). A method similar to General Procedure 1-3 is used to deprotect (+) - 7-chloro-6-. { 4- [1- (1, 1, 2, 2,2-pentafluoroethyl) -ethoxy] -benzylamino} -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-l, t-benzo [d] azepine (980 mg, 1.8 mmol). Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (99: 1 to 90:10 gradient) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (650 mg, 64%). MS (ER +) m / z: 449.1 (M + H) +.

Example 570 Succinate of (-) - 7-chloro-6-. { 4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) ethoxy] -benzylamino} -2, 3,4, 5-tetrahydro-lf-benzo [d] azepine Chiral A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-l,? -benzo [d] azepine (9 g, 21.1 mmol) with 4- [1- (1, 1,2, 2,2-pentafluoroethyl) -ethoxy] -benzylamine isomer 2 (11.4 g, 42.3 mmol) in anhydrous toluene (270 mL). The crude mixture is purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 4: 1 gradient) to obtain 7-chloro-6-. { 4- [1- (1, 1,2,2, 2-pentafluoroethyl) -ethoxy] -benzylamino} -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine isomer 2 (9.5 g, 83%). A method similar to General Procedure 1-3 is used to deprotect 7-chloro-6-. { 4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -benzylamino} -3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-L-t-benzo [d] azepine isomer 2 (9.5 g, 17.4 mmol). Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (99: 1 to 90:10 gradient) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (5.9 g, 60%). MS (ER +) m / z: 449. 1 (M + H) +. [a] 20D -11.6 ° (c 0.5, MeOH).

Example 571 Succinate of (+) - 7-chloro-6-. { 4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -benzylamino} -2, 3,4, 5-tetrahydro-l, -benzo [d] azepine Chiral A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li-benzo [d] azepine (3.4 g, 8 mmol) with 4- [1- (1, 1,2, 2,2-pentafluoroethyl) -ethoxy] -benzylamine isomer 1 (4.3 g, 16 mmol) in anhydrous toluene (100 mL). The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 3: 1 gradient) to obtain 7-chloro-6-. { 4- [1- (1, 1,2,2,2-pentafluoroethyl) -ethoxy] -benzylamino} -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-l-p-benzo [d] azepine isomer 1 (3.7 g, 85%). A method similar to General Procedure 1-3 is used to deprotect 7-chloro-6-. { 4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -benzylamino} -3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-l, -benzo [d] azepine isomer 1 (3.7 g, 6.8 mmol). Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (99: 1 to 97: 3 gradient) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (2.8 g, 74%). MS (ER +) m / z: 449.1 (M + H) +. [a] 20D + 13.0 ° (c 0.5, MeOH).

Example 572 Succinate of (±) -7-chloro-6-. { 4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -pyridin-2-ylmethylamino} -2, 3, 4, 5-tetrahydro-l-benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-l, -benzo [d] azepine (268 mg, 0. 6 mmol) with (±) -2-aminomethyl-5- fi, 1,2,2, 2-pentafluoroethyl) -ethoxy] -pyridine (170 mg, 0.6 mmol) in anhydrous toluene (3 mL ). The crude mixture is purified by chromatography on silica gel by sequentially levigating with hexane / EtOAc (10: 1, 5: 1, 3: 1) to obtain (±) -7-chloro-6-. { 4- [1- (1,1,2, 2, 2-pentafluoroethyl) -ethoxy] -pyridin-2-ylmethylamino} -3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-l-benzo [d] azepine (270 mg, 79%). MS (ER +) m / z: 546.1 (M + H) +. A method similar to General Procedure 1-3 is used to deprotect (±) -7-chloro-6-. { 4- [1- (1, 1,2, 2,2-pentafluoroethyl) -ethoxy] -pyridin-2-ylmethylamino} -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-li? -benzo [d] azepine (265 mg, 0.5 mmol). Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (99: 1 to 90:10 gradient) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (172 mg, 63%). MS (ER +) m / z: 450.1 (M + H) +.

Example 573 Succinate of (-) - 7-chloro-6-. { 4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -pyridin-2-ylmethylamino} -2, 3,4, 5-tetrahydro-li? -benzo [d] azepine Chiral Succinate is removed from (±) -7-chloro-6-. { 4 ~ [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -pyridin-2-ylmethylamino} -2, 3,4,5-tetrahydro-lino-benzo [d] azepine (172 mg) by normal phase chiral chromatography (Chiralcel OD, 8 x 35 cm, levigating with heptane / isopropanol 4: 1 with DMEA 0.2%) . The 1st isomer is collected by levigating, then a method similar to General Procedure 2-1 is used to obtain the title compound [50 mg, 96.3% ee (Chiralcel OD-H, 4.6 x 150 mm, levigating with heptane / isopropanol 4: 1 with DMEA 0.2%, 0.6 mL / min)]. MS (ER +) m / z 450.1 (M + H) +. [a] 20D -10.5 ° (c 0.5, MeOH).

Example 574 Succinate of (+) - 7-chloro-6-. { 4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -pyridin-2-ylmethylamino} -2, 3,4, 5-tetrahydro-lZ-benzo [d] azepine Qulral Succinate is removed from (±) -7-chloro-6-. { 4- [1- (1, 1, 2, 2, 2-pentafluoroethyl) -ethoxy] -pyridin-2-ylmethylamino} -2, 3,4,5-tetrahydro-l, -benzo [d] azepine (172 mg) by normal phase chiral chromatography (Chiralcel OD, 8 x 35 cm, levigating with heptane / isopropanol 4: 1 with DMEA 0.2%) . The 2nd levigando isomer is collected, then a similar method is used.

General Procedure 2-1 to obtain the title compound [41 mg, 95.6% ee (Chiralcel OD-H, 4.6 x 150 mm, levigating with heptane / isopropanol 4: 1 with DMEA 0.2%, 0.6 mL / min)]. MS (ER +) m / z: 450.1 (M + H) +. [a] 20D + 13.1 ° (c 0.5, MeOH).

Example 575 (L) - 7-Chloro-6- [4- (1-methyl-cyclohexylmethoxy) -benzylamino] -2,3,4,5,5-tetrahydro-1-J-benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li? -benzo [d] azepine (200 mg, 0.47 mmol) with 4- (1-methyl-cyclohexylmethoxy) -benzylamine (120 mg, 0.51 mmol) in anhydrous 1,4-dioxane (7 mL). The crude mixture was purified by chromatography on silica gel by levigating with isohexane / EtOAc (19: 1 to 4: 1 gradient) to obtain 7-chloro-6- [4- (1-methyl-cyclohexylmethoxy) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lyf-benzo [d] azepine (101 mg, 39%). A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- [4- (1-methyl-cyclohexylmethoxy) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4 , 5-tetrahydro-l, -benzo [d] azepine (100 mg, 0.19 mmol). Purify by SCX chromatography by levigating with methanol and 3M ammonia in methanol. A method similar to General Procedure 2-6 is used to obtain the title compound (78 mg, 73%). MS (ER +) m / z: 413.2 (M + H) +.

Examples 576-580 Examples 576-580 can be prepared essentially as described in Example 575 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5- tetrahydro-1-benzo [d] azepine and the appropriate amine. The total yields and EM data (ER +) are shown in the Table below.

Example 581 (L) 7-Chloro-6- (4-cyclohexyloxy-benzylamino) 2,3,4,5-tetrahydro-1-benzo [d] azepine tertarate A method similar to General Procedure 5-1 is used for couple 7-chloro-3- (2, 2, 2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4, 5-tetrahydro-li? -benzo [d] azepine (100 mg, 0.43 mmol) with 4-cyclohexyloxy -benzylamine (58 mg, 0.285 mol) in anhydrous toluene (1 mL). the crude mixture by chromatography on silica gel with ciciohexano levigating / EtOAc (9: 1) purified to give 7-chloro-6- (4-cyclohexyloxy-benzylamino) -3- (2, 2, 2-trifluoroacetyl) -2 , 3, 4, 5-tetrahydro-li-benzofd] azepine (78 mg, 69%). A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- (4-cyclohexyloxy-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-li ? -benzo [d] azepine (237 mg, 0.49 mmol) to obtain the free base of the title compound. A method similar to the General Procedure is used 2-6 to obtain the title compound (208 mg, 80%). MS (ER +) m / z: 385.2 (M + H) +.

Example 582 (L) - 7-Chloro-6- [4- (tetrahydro-pyran-4-yloxy) -benzylamino] -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine -Tartrate Example 582 can be prepared essentially as described in Example 581 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-l-benzo [ d] azepine and 4- (tetrahydro-pyran-4-yloxy) -benzylamine (4% yield, MS (ER +) m / z 387 (M + H) +).

Example 583 Succinate of (+) - 7-chloro-6- [4- (3, 3-dimethyl-cyclohexyloxy) -benzylamino] -2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li? -benzo [d] azepine (387 mg, 0.91 mmol) with (±) -4- (3,3-dimethyl-cyclohexyloxy) -benzylamine (233 mg, 1 mmol) in anhydrous 1,4-dioxane (14 mL). The crude mixture was purified by chromatography on silica gel levigating with cyclohexane / EtOAc (gradient 19: 1 to 1: 1) to obtain (+) -7-chloro-6- [4- (3, 3-dimethyl-cyclohexyloxy) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lff-benzo [d] azepine (227 mg, 50%). A method similar to General Procedure 1-1 is used to deprotect (±) -7-chloro-6- [4- (3, 3-dimethyl-cyclohexyloxy) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine (220 mg, 0.43 mmol). Purify by SCX chromatography by levigating with methanol and 3M ammonia in methanol. The residue is further purified by preparative HPLC. A method similar to General Procedure 2-1 is used to obtain the title compound (65 mg, 13%). MS (ER +) m / z: 413.2 (M + H) +.

Example 584 Succinate of 7-chloro-6- (4-cyclohexylthio-pyridin-3-ylmethylamino) -2,3,4,5-tetrahydro-li? -benzo [d] azepine Cesium carbonate (2.04 g, 6.27 mmol), palladium acetate (II) (46 mg, 0.209 mmol) and BINAP (195.21 mg, 0.313 mmol) to a solution of 7-chloro-3- (2, 2 is added, 2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (1.79 g, 4.18 mmol) and 5-aminomethyl-2-cyclohexylthio-pyridine (1.11 g, 5.02 mmol ) in anhydrous toluene (30 mL). The resulting suspension is sonicated for 30 min then heated at 100 ° C for 18 h. The reaction is cooled to room temperature. The crude mixture was purified by chromatography on silica gel levigating with cyclohexane / EtOAc (98: 2 to 60:40 gradient) to give 7-chloro-6- (4-cyclohexylthio-pyridin-3-ylmethylamino) -3- (2 , 2,2-trifluoroacetyl) -2,3,4, 5-tetrahydro-L-t-benzo [d] azepine as an oil (1.1 g, 53%). A method similar to General Procedure 1-1 is used to deprotect 7-chloro-6- (4-cyclohexylthio-pyridin-3-yl-ethylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4 5-tetrahydro-li? -benzo [d] azepine (1.1 g, 2.21 mmol). Purify by SCX chromatography by levigating with methanol and 3M ammonia in methanol. A method similar to General Procedure 2-1 is used to obtain the title compound as a white solid (0.884 g, 77%). MS (ER +) m / z: 402 (M + H) +.

Example 585 (L) -tartrate of 6- (4-tert-butylthio-pyridin-3-ylmethylamino) -7-chloro-2,3,4,5-tetrahydro-lJ? -benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (990 mg, 2.32 mmol) with 5-aminomethyl-2-tert-butylthio-pyridine (500 mg, 2.55 mmol) in anhydrous toluene (15 mL). The crude mixture was purified by chromatography on silica gel by levigating with isohexane / EtOAc (1: 0 to 3: 1 gradient) to obtain 6- (4-ter-rp? Tiltio-pyridin-3-ylmethylamino) -7-chloro- 3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-li? -benzo [d] azepine (650 mg, 59%). MS (ER +) m / z: 472 (M + H) +. A method similar to General Procedure 1-2 is used to deprotect 6- (4-tert-butylthio-pyridin-3-ylmethylamino) -7-chloro-3- (2,2,2-trifluoroacetyl) -2,3,4 , 5-tetrahydro-li-benzo [d] azepine (650 mg, 1.37 mmol). Purify by SCX chromatography by levigating with methanol and 3M ammonia in methanol. A method similar to General Procedure 2-6 is used to obtain the title compound (362 mg, 50%). EM (ER +) m / z: 376 (M + H) +.

Examples 586-593 Examples 586-593 can be prepared essentially as described in Example 585 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5- tetrahydro-L-T-benzo [d] azepine and the appropriate amine. The total yields and EM data (ER +) are shown in the Table below.

Example 594 (L) - 7-Chloro-6- [4- (2, 2-dimethyl-propoxymethyl] benzylamino] -2,3,4,5-tetrahydro-l, t-benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (426 mg, 1 mmol) with 4- (2,2-dimethyl-propoxymethyl) -benzylamine (230 mg, 1.1 mmol) in anhydrous toluene (20 mL). The crude mixture is purified by chromatography on silica gel by levigating with isohexane / EtOAc (gradient 1: 0 to 4: 1) to obtain 7-chloro-6- [4- (2,2-dimethyl-propoxymethyl) -benzylamino] - 3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (380 mg, 79%). MS (ER +) m / z: 483 (M + H) +. A method similar to General Procedure 1-2 is used to deprotect 7-chloro-6- [4- (2, 2-dimethyl-propoxymethyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3 , 4,5-tetrahydro-1-yl-benzo [d] azepine (380 mg, 0.88 mmol). Purify by SCX chromatography by levigating with methanol and 3M ammonia in methanol. A method similar to General Procedure 2-6 is used to obtain the title compound (319.2 mg, 70%). MS (ER +) m / z: 387 (M + H) +.

Example 595 (L) - 7-Chloro-6- (4-cyclohexylthio-benzylamino) -2,3,4,5-tetrahydro-li? -benzo [d] azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1-benzo [d] azepine (167 mg, 0.392 mmol) with 4-cyclohexylthio-benzylamine (95.4 mg, 0.431 mmol) in anhydrous 1,4-dioxane (5 mL). The crude mixture was purified by chromatography on silica gel by levigating with isohexane / EtOAc (1: 0 to 13: 7 gradient) to obtain 7-chloro-6- (4-cyclohexylthio-benzylamino) -3- (2.2, 2). -trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine (155 mg, 79%). MS (ER +) m / z: 519 (M + Na) +. A method similar to General Procedure 1-2 is used to deprotect 7-chloro-6- (4-cyclohexylthio-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-li ? -benzo [d] azepine (155 mg, 0.312 mmol). Purify by SCX chromatography by levigating with methanol and 3M ammonia in methanol. A method similar to General Procedure 2-6 is used to obtain the title compound (95 mg, 75%). MS (ER +) m / z: 401 (M + H) +.

Examples 596-597 Examples 596-597 can be prepared essentially as described in Example 595 by using 7-chloro-3- (2, 2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5- tetrahydro-li? -benzo [d] azepine and the appropriate amine. The total yields and EM data (ER +) are shown in the Table below.

Example 598 (L) - 7-Chloro-6- (3-chloro-4-ethoxy-benzylamino) -2,3,4,5-tetrahydro-l, -benzo [d] azepine tertake A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (150 mg, 0.35 mmol) with 4-ethoxy-3-chloro-benzylamine (94.7 mg, 0.51 mmol) in anhydrous 1,4-dioxane (10 mL). The crude mixture was purified by chromatography on silica gel by levigating with isohexane / EtOAc (100: 0 to 77:23 gradient) to obtain 7-chloro-6- (3-chloro-4-ethoxy-benzylamino) -3- (2 , 2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-L-t-benzo [d] azepine (111.3 mg, 68%). MS (ER +) m / z: 483 (M + Na) +. A method similar to General Procedure 1-1 is used, but adding water (10 mL) to 7M ammonia in methanol solution (20 mL), to deprotect 7-chloro-6- (3-chloro-4-ethoxy-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-l-t-benzo [d] azepine (27 mg, 0.072 mmol) to give the free base of the title compound. A method similar to General Procedure 2-6 is used to give the title compound as a solid (29 mg, 78%). MS (ER +) m / z: 365 (M + H) +.

Example 599 7-Chloro-6- (4-cycloheptyloxy-benzylamino) -2,3,4,5-tetrahydro-1-benzo [d] azepine Succinate Under a nitrogen atmosphere, 4-cycloheptyloxy-benzylamine (451 mg, 2.06 mmol), 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro is added. -lü-benzo [d] azepine (500 mg, 1.17 mmol), palladium (II) acetate (26 mg, 0.117 mmol), BINAP (110 mg, 0.176 mmol), and cesium carbonate (1.15 g, 3.52 mmol) to toluene (20 mL). The mixture is heated at 90 ° C for 12 h. The mixture is cooled to room temperature and diluted with EtOAc (25 mL). The solids are filtered through cellulose (20 g) and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel (RediSep 45 g column) by levigating with hexane / EtOAc (gradient 1: 0 to 4: 1 for 1 h; 80 mL / min) to give 7-chloro-6- (4 -cycloheptyloxy-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine as a colorless oil (384 mg, 61%). MS (APCl) m / z: 495 (M + H) +. Dissolve 7-chloro-6- (4-cycloheptyloxy-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1-yl-benzo [d] azepine (370 mg, 0.747 mmol) and lithium hydroxide monohydrate (153 mg, 3.73 mmol) in methanol (5 mL) and stirred for 6 h. The mixture is concentrated in vacuo and the residue dissolved in water (20 mL). The mixture is extracted with EtOAc (3 * 20 mL). Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo. Purify the crude mixture by reverse phase HPLC [Phenomonex C18 (2) column, 5 * 25 cm, levigating with a water / acetonitrile gradient (0.1% TFA in each) (9: 1 through 1: 9 during 40 min), 118 mL / min] to provide the trifluoroacetate salt of the title compound. The residue is dissolved in methanol and eluted through an SCX column with ammonia saturated in methanol to give the free base of the title compound (197 mg, 65%). A method similar to General Procedure 2-1 is used to give the title compound as an opaque white solid (250 mg, 100%). MS (APCl) m / z: 399 (M + H) +.

Example 600 7-Chloro-6- (4-cycloheptylthio-benzylamino) -2,3,4,5-tetrahydro-L-benzo [d] azepine Succinate Example 600 can be prepared essentially as described in Example 599 by using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-lyf-benzo [ d] azepine and 4-cycloheptylthio-benzylamine (6% yield, MS (ER +) m / z 415 (M + H) +).

Example 601 Succinate of 7-chloro-6- (4-cyclohexylmethyl-benzylamino) 2,3,4,5-tetrahydro-li? -benzo [d] azepine Under a nitrogen atmosphere, 4-cyclohexylmethyl-benzylamine hydrochloride (352 mg, 1.47 mmol), 7-chloro-3- (2,2, 2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5 is added. -tetrahydro-líf-benzo [d] azepine (500 mg, 1.17 mmol), palladium (II) acetate (52.7 mg, 0.235 mmol), BINAP (293 mg, 0.47 mmol) and cesium carbonate (1.53 g, 4.7 mmol) in toluene (20 mL). The mixture is heated at 90 ° C for 12 h. The mixture is cooled to room temperature and diluted with EtOAc (25 mL). The solids are filtered through cellulose (20 g) and the filtrate is concentrated in vacuo. The crude mixture is purified by chromatography on silica gel (RediSep 45 g column) by levigating with hexane / EtOAc (gradient 1: 0 to 4: 1 for 1 h; 80 mL / min) to provide 7-chloro-6- (4-cyclohexylmethyl-benzylamino) -3- (2,2,2-trifluoroacetyl) -2, 3, 5-tetrahydro-l-benzo [d] azepine as a colorless oil (354 mg, 63%). MS (APCl) m / z: 479 (M + H) +. Dissolve 7-chloro-6- (4-cyclohexylmethyl-benzylamino) -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-li? -benzo [d] azepine (354 mg, 0.739 mmol) and lithium hydroxide monohydrate (100 mg, 2.43 mmol) in methanol (5 mL) and stirred overnight. The mixture is concentrated in vacuo and the residue dissolved in water (20 L). The mixture is extracted with EtOAc (3 x 20 mL). Dry the combined organic extracts over Na2SO4, filter, and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel (RediSep 40 g column) by levigating with a gradient of dichloromethane and chloroform / methanol / concentrated ammonium hydroxide (80: 18: 2) for 1 h (80 mL / min) followed by Reverse phase HPLC [Phenomonex C18 column (2) (5 * 25 cm), levigating with water / acetonitrile (0.1% TFA in each) (9: 1 to 1: 9 gradient for 40 min), 118 mL / min] to obtain the trifluoroacetate salt of the title compound. The residue is dissolved in methanol and eluted through SCX column with ammonia saturated in methanol to provide 7-chloro-6- (4-cyclohexylmethyl-benzylamino) -2,4,4,5-tetrahydro-lH-benzo [d ] azepine (184 mg, 64%). A method similar to General Procedure 2-1 is used to give the title compound as a white solid (240 mg, 100%). MS (ES) m / z: 383 (M + H) +.

Example 602 Succinate of 7-chloro-6- [4- (2-methyl-butyl) -benzylamino] -2,3,4,5-tetrahydro-li? -benzo [d] azepine Under a nitrogen atmosphere, 4- (2-methyl-butyl) -benzylamine (450 mg, 2.54 mmol), 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3 is added. , 4,5-tetrahydro-l-benzo [d] azepine (720 mg, 1.7 mmol), palladium (II) acetate (40 mg, 0.17 mmol), BINAP (222 mg, 0.34 mmol) and cesium carbonate (1.4 g, 4.3 mmol) to toluene (20 mL). The mixture is heated at 95 ° C for 12 h. The mixture is cooled to room temperature and the mixture is applied to a column of silica gel by levigating with hexane / EtOAc (10: 1) to provide 7-chloro-6- [4- (2-methyl-butyl) -benzylamino] -3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-127-benzo [d] azepine (450 mg, 59%). MS (ER +) m / z 453 (M + H) +. Dissolve 7-chloro-6- [4- (2-methyl-butyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-li? -benzo [d ] azepine (450 mg, 1 mmol) and concentrated ammonium hydroxide (5 mL) in methanol (10 mL) and stir overnight. The mixture is concentrated in vacuo. The crude mixture is purified by SCX chromatography by levigating with methanol and 3M ammonia in methanol. The product is concentrated in vacuo and the residue is purified by reverse phase HPLC [Phenomonex Luna C18 (2), 50 mm x 250 mm, levigating with acetonitrile / water with 0.1% TFA (2: 3)]. Concentrate in vacuo, basify with potassium carbonate and extract in dichloromethane. Dry the organic solution over Na 2 SO, filter and concentrate in vacuo to provide the free base of the title compound (205 mg, 57%). A method similar to General Procedure 2-1 is used to give the title compound as a white solid (280 mg, 59%). MS (APCl) m / z: 357 (M + H) +.

Example 603 Succinate of 7-chloro-6- [4- (3, 3-dimethyl-butyl) -benzylamino] -2,3,4,5-tetrahydro-t-benzo [d] azepine A method similar to General Procedure 5-1 is used to react 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-li? -benzo [d] azepine (623 mg, 1.46 mmol), palladium (II) acetate (33 mg, 0.146 mmol), BINAP (182 mg, 0.292 mmol), 4- (3, 3-dimethyl-butyl) -benzylamine (560 mg, 2.93 mmol) and cesium carbonate (666 mg, 2.04 mmol) in degassed toluene (40 mL). The mixture is degassed with vacuum / nitrogen purge and heated at 100 ° C for 16 h. The mixture is cooled to room temperature, diluted with EtOAc and washed with water. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane and then hexane / EtOAc (19: 1, 9: 1) to obtain 7-chloro-6- [4- (3, 3-dimethyl-butyl) -benzylamine. ] -3- (2, 2, 2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-lf-benzo [d] azepine as oil (622 mg, 91%). MS (ER +) m / z: 467 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- [4- (3, 3-dimethyl-butyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2.3 , 4, 5-tetrahydro-l, -benzo [d] azepine (448 mg, 0.96 mmol), to give the free base of the title compound as an oil (320 mg, 90%) which was used without further purification. MS (ER +) m / z: 371 (M + H) +. A method similar to General Procedure 2-1 is used, using 7-chloro-6- [4- (3, 3-dimethyl-butyl) -benzylamino] -2,3,4,5-tetrahydro-127-benzo [d ] azepine (315 mg, 0.85 mmol) to give the title compound as a white solid (340 mg, 82%). MS (ER +) m / z: 371 (M + H) +.

Example 604 Succinate of 7-chloro-6- [6- (3, 3-dimethyl-butyl) -pyridin-3-yl-methylamino] -2,3,4,5-tetrahydro-12β-benzo [d] azepine A method similar to General Procedure 5-2 is used to react 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li-benzo [d] azepine (166 mg, 0.39 mmol), tris (dibenzylideneacetone) dipalladium (0) (71 mg, 0.078 mmol), BINAP (103 mg, 0.156 mmol), 3-aminomethyl-6- (3, 3-dimethyl-butyl) -pyridine (150 mg, 0.78 mmol) and cesium carbonate (178 mg, 0.546 mmol) in degassed toluene (20 mL). The mixture is degassed with vacuum / nitrogen purge and heated at 100 ° C for 14 h. The mixture is cooled to room temperature, it is diluted with EtOAc and filtered through Celite®. The crude mixture was purified by chromatography on silica gel by levigating with hexane and then hexane / EtOAc (19: 1, 9: 1 and 4: 1) to obtain 7-chloro-6- [6- (3, 3-dimethyl- butyl) -pyridin-3-yl-methylamino] -3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-127-benzo [d] azepine as an oil (149 mg, 82%) . MS (ER +) m / z: 468 (M + H) +. A method similar to General Procedure 1-2 is used, using 7-chloro-6- [6- (3, 3-dimethyl-butyl) -pyridin-3-yl-methylamino] -3- (2, 2, 2- trifluoroacetyl) -2,3,4, 5-tetrahydro-lH-benzo [d] azepine (140 mg, 0.29 mmol), to give the free base of the title compound as an oil (96 mg, 86%) which was used without additional purification. MS (ER +) m / z: 372 (M + H) +. A method similar to General Procedure 2-1 is used, using 7-chloro-6- [6- (3, 3-dimethyl-butyl) -pyridin-3-yl-methylamino] -2,3,4,5-tetrahydro -l-f-benzo [d] azepine (96 mg, 0.258 mmol) to give the title compound as a solid (119 mg, 94%). MS (ER +) m / z: 372 (M + H) +.

Examples 605-607 Examples 605-607 can be prepared essentially as described in Example 604 using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro -127-benzo [d] azepine and the appropriate amine. The total yields and EM data (ER +) are shown in the Table below.

Preparation 320 2-Hydroxymethyl- [1, 3, 4] -thiadiazole-Vinyl- [1,3,4] -thiadiazole: Combined 2-bromo- [1, 3, 4] -iadiazole (3.5 g, 21.2 mmol) , tributylvinyltin (6.20 mL, 21.2 mmol) and tetrakis (triphenylphosphine) palladium (0) (735 mg, 0.6 mmol) in anhydrous toluene (141 mL). The mixture is heated at reflux for 18 h. Methanol and dichloromethane are added until the residue is dissolved and evaporated on silica gel. The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 to 1: 4 gradient) to give the desired intermediate (0.49 g, 21%). GC-MS m / z: 112 (M +). 2-Hydroxymethyl- [1,3,4] -thiadiazole: At -10 ° C, ozone is bubbled through a solution of 2-vinyl- [1, 3, 4] -thiadiazole (400 mg, 3. 57 mmol) in methanol (18 mL). After 20 min the starting material is consumed. Sodium borohydride is then added (37 mg, 0.98 mmol) and warmed to room temperature. The mixture is evaporated and the residue purified by passing through a pad of silica gel by levigating with methanol / dichloromethane (98: 2 to 96: 4 gradient) to give the title compound (0.24 g, 60%). MS (ER +) m / z: 117 (M + H) +.

Preparation 321 5-chloromethylthiazole Combine 5-methylthiazole (1.5 g, 15.1 mmol), N-chlorosuccinimide (2.6 g, 19.4 mmol) and AIBN (0.26 g, 1.6 mmol) in carbon tetrachloride (15 mL). Reflux under nitrogen for 3 h. The reaction mixture is cooled and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to give the title compound as a yellow oil (0.38 g, 19%).

Preparation 322 5-Bromomethyl-2-chlorothiazole -sloromethyl-2-slorothiazole: 5-methyl-2-chlorothiazole is combined (1.05 g, 7.5 mmol), NBS (1.7 g, 9.6 mmol) and AIBN (0.12 g, 0. 73 mmol) in carbon tetrachloride (10 mL). Reflux under nitrogen for 7 h. Cool and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the title compound as a yellow oil (0.82 g, 51%).

Preparations 323 (±) -l-Methanesulfonyloxy-l-thiazol-2-yl-ethyl (±) -l-thiazole-2-yl-ethanol: Sodium borohydride (357 mg, 9.4 mmol) is added in portions, over 5 min, to a solution of 2-acetylthiazole (1.0 g, 7.8 mmol) in methanol ( 25 mL) at 0 ° C under a nitrogen atmosphere. The mixture is stirred for 2 h at room temperature. The mixture is concentrated in vacuo, the residue is diluted with brine (30 mL) and the mixture is adjusted to pH 6 with 5N aqueous HCl (10 mL). The mixture is extracted with EtOAc (40 mL). Dry the organic layer over Na 2 SO, filter and concentrate in vacuo to obtain the desired intermediate (1.0 g, 99%). GC-MS m / z: 129 (M +). (±) -1-Methanesulfonyloxy-l-thiazol-2-yl-ethyl: 1-thiazol-2-yl-ethanol (1.0 g, 7.7 mmol) is dissolved in dichloromethane (30 mL) and triethylamine (1.2 mL, 8.5 mmol ). The solution is cooled to 0 ° C, then methanesulfonyl chloride (690 μl, 8.9 mmol) is added under a nitrogen atmosphere. The solution is stirred for 1.5 h at room temperature, then washed with saturated aqueous NaHCO3 (30 mL). Dry the organic layer over Na 2 SO 4, filter and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with dichloromethane / hexane / methanol (50: 45: 5) to obtain the title compound (1.3 g, 81%). GC-MS m / z: 207 (M +).

Preparation 324 (+) -1- (3-Fluorophenyl) ethyl bromide (+) -1- (3-fluorophenyl) ethanol (250 mg, 1786 mmol) is dissolved in carbon tetrachloride (10 mL). Phosphorus tribromide (0.1 mL, 1786 mmol) is added at 0 ° C and the solution is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane and washed with brine. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound (285 mg) which was used without any further purification.

Preparation 325 (S) -1- [4- (1-Hydroxyethyl) -phenyl] -3,3-dimethylbutan-1-one 1- [4- (Die oxymethyl) -phenyl] -3,3-dimethylbutan-1-ol: l-Bromo-4- (diethoxymethyl) -benzene (6.1 g, 23.55 mmol) is dissolved in anhydrous THF (150 mL) and the solution is cooled to -78 ° C. N-Butyl lithium (11.3 mL, 28.26 mmol, 2.5M solution in hexane) is added and the mixture is stirred for 30 min. 3,3-Dimethylbutyraldehyde (4.7 mL, 35.33 mmol) is added and the mixture is stirred for 1 h. Water and EtOAc are added. The solution is warmed to room temperature and the aqueous layer is extracted three times with EtOAc. Dry the combined organic extracts with Na 2 SO 4, filter and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (93: 7) to give the desired intermediate as a colorless oil (3.8 g, 58%). 1- [4- (Diethoxymethyl) -phenyl] -3,3-dimethylbutan-1-one: 1- [4- (diethoxymethyl) -phenyl] -3,3-dimethylbutan-1-ol is dissolved (3.8 g, 13.57 mmol) in hexane (50 mL). Manganese dioxide (3.5 g, 40.71 mmol) is added and the mixture is stirred at 60 ° C overnight. The solid is filtered and the filtrate is concentrated in vacuo to give the desired intermediate as a colorless oil (3.49 g, 93%). 4- (3,3-Dimethyl-butyryl) -benzaldehyde: l- [4- (diethoxymethyl) -phenyl] -3,3-dimethylbutan-1-one (3.49 g, 12.55 mmol) is dissolved in acetone (50 mL) . P-Toluenesulfonic acid monohydrate (238 mg, 1.256 mmol) is added. The mixture is heated under reflux for 3 h. Concentrate in vacuo and partition the residue between water and EtOAc. The aqueous phase is extracted three times with EtOAc. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (9: 1) to give the desired intermediate as a colorless oil (1.67 g, 65%). 1- [4- (1-Hydroxyethyl) -phenyl] -3,3-dimethylbutan-1-one: 4- (3,3-Dimethyl-butyryl) -benzaldehyde (1.67 g, 8.186 mmol) is dissolved in anhydrous THF ( 20 mL) and the solution is cooled to -10 ° C. Methyl magnesium bromide (2.7 mL, 8.186 mmol, 3M solution in diethyl ether) is added and the mixture is stirred for 30 min. Water is added at 0 ° C, diluted with EtOAc and the aqueous layer extracted three times with EtOAc. Dry the combined organic extracts over Na2SO4, filter through a short pad of silica gel and concentrate in vacuo to give the desired intermediate as a yellow oil (1.519 g, 84%).

(S) -1- [4- (1-hydroxyethyl) -phenyl] -3,3-dimethylbutan-1-one: 1- [4- (1-hydroxyethyl) -phenyl] -3,3-dimethylbutan- is dissolved. canvas (1.519 g, 6.905 mmol) in diisopropyl ether (20 mL). Molecular mesh powder 4Á (1.5 g), vinyl acetate (2 mL) and lipase acrylic resin Candida Antarctica are added (150 mg). The mixture is stirred at room temperature overnight. The solid residue is removed by filtration. The filtrate is concentrated in vacuo and the crude mixture is purified by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) to give (R) -1- (1-acetoxy-ethyl) -4- (3, 3). -dimethyl-butyryl) -benzene as a colorless oil (0.661 g, 36%) and (S) -l- [4- (1-hydroxyethyl) -phenyl] -3,3-dimethylbutan-l-one as a light yellow oil (0.737 g, 49%).

Preparation 326 4-Acetyl-benzyl bromide A mixture of 4 '-methylacetophenone (5 g, 37.26 mmol), NBS (6.964 g, 39.12 mmol), and AIBN (153 mg, 0.93 mmol) in carbon tetrachloride (120 mL) is heated for 14 h at reflux. It is cooled to room temperature and washed sequentially with water (100 mL), 1M aqueous HCl (100 mL), 5% aqueous NaHCO3 (100 mL) and brine (100 mL). The organic phase is dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by sequentially levigating with hexane and hexane / EtOAc (19: 1, 9: 1) to give the title compound as an oil (5.191 g, 65%). GC-MS m / z: 213 (M +).

Preparations 353-354 The compounds of Preparations 353-354 can be prepared essentially as described in Preparation 326 using 4'-methylpropiophenone (Preparation 353) and 4'-methylbutyrophenone (Preparation 354). The yields are shown in the Table below.

Preparation 329 4- (3-Methyl-butyryl) -benzyl bromide 3,4A -Dimethylbutyrophenone: Isovaleryl chloride (3.0 g, 24.88 mmol) is slowly added to an ice-cooled stirred solution of aluminum trichloride (4976 g, 37.32 mmol) in anhydrous toluene (60 mL). The reaction mixture is stirred at room temperature overnight. Water cooled on ice is added slowly and the mixture is extracted twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the desired intermediate (4.38 g, 100%) that was used without any further purification. GC-MS m / z: 176 (M +). 4- (3-Methyl-butyryl) -bensyl bromide: A mixture of 3,4 '-dimethylbutyrophenone (3 g, 17.02 mmol), NBS (3.787 g, 16.18 mmol), and AIBN (70 mg, 0.425 mmol) is heated. ) in carbon tetrachloride (80 mL) for 14 h at reflux. It is cooled to room temperature and the mixture is filtered. The filtrate is concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by sequentially levigating with hexane and hexane / EtOAc (9: 1) to give the title compound as an oil (2802 g, 65%). GC-MS m / z: 255 (M +).

Preparations 356-357 The compounds of Preparations 356-357 can be prepared essentially as described in Preparation 329 using the appropriate acyl chloride. The total yields and CG-MS data are shown in the Table below.

Preparation 332 4- (Pyridine-3-carbonyl) -benzyl methanesulfonate [4- (tert-Jbutyldxmethylsilyloxymethyl) -phenyl] -pyridin-3-yl-methanol: 4- (tert-butyldimethylsilyloxymethyl) bromobenzene (1 g, 3319 mmol, prepared following the procedure described in J. Am. Chem. Soc. 1995, 117, 704-714) in anhydrous THF (20 mL). The solution is cooled to -78 ° C, n-BuLi (4149 mL, 6.638 mmol, 1.6M solution in hexane) is added and stirred at this temperature for 1.5 h. Warm to -60 ° C, stir for an additional 30 min, and add carboxaldehyde 3-pyridine. The reaction mixture is allowed to warm gradually to room temperature and is stirred overnight. Brine is added and extracted with EtOAc. The organic phase is dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by sequentially levigating with hexane and EtOAc to give the desired intermediate (380 mg, 35%). MS (ER +) m / z: 330 (M + H) +. [4- (tert-Butyldxmethylsilyloxymethyl) -phenyl] -pyridin-3-yl-methanone: Manganese dioxide (1.44 g) is added to a stirred solution of [4- (tert-butyldimethylsilyloxymethyl) -phenyl] -pyridin-3. -l-methanol (360 mg, 0.303 mmol) in anhydrous 1,4-dioxane (25 mL). The mixture is heated at 70 ° C overnight. The reaction mixture is cooled to room temperature, filtered through Celite® and washed with EtOAc. The filtrate is concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by sequentially levigating with hexane and hexane / EtOAc (1: 1) to provide the desired intermediate (233 mg, 65%). GC-MS m / z: 327 (M +). Alsohol of 4- (pyridine-3-sarbonyl) -bensyl: Tetrabutylammonium fluoride (1.37 mL, 1.37 mmol, 1M solution in THF) is added to a solution of [4- (tert-butyldimethylsilyloxymethyl) -phenyl] -pyridin-3 -yl-methanone (225 mg, 0.687 mmol) in anhydrous THF (10 L) at 0 ° C and stirred at this temperature for 1 h. The solvent is concentrated in vacuo and the crude mixture purified by chromatography on silica gel by levigating with EtOAc to provide the desired intermediate (85 mg, 58%). MS (ER +) m / z: 214 (M + H) +. 4- (Pyridine-3-sarbonyl) -bensyl methanesulfonate: 4- (Pyridine-3-carbonyl) -benzyl alcohol (85 mg, 0.399 mmol) is dissolved in dichloromethane (5 mL). Cool to 0 ° C and add triethylamine (0.056 mL, 0.438 mmol) and methanesulfonyl chloride (0.033 mL, 0.438 mmol). The mixture is allowed to warm to room temperature and is stirred for 2 h. The reaction mixture is diluted with dichloromethane and washed with saturated aqueous NaHCO3. The organic phase is dried over Na 2 SO 4, filtered and concentrated in vacuo to give the title compound as an oil (115 mg, 100%). GC-MS m / z: 291 (M +).

Preparation 333 4- (Pyridine-4-carbonyl) -benzyl methansulfonate The compound of Preparation 333 can be prepared essentially as described in Preparation 332 using 4- (tert-butyldimethylsilyloxymethyl) bromobenzene and carboxaldehyde 4-pyridine (GC-MS m / z 291 (M) +).

Preparation 334 4- (4-Cyano-benzoyl) -benzyl bromide 4- (4-Methyl-benzoyl) -benzonitrile: 4-Cyanobenzoyl chloride (2.0 g, 12 mmol) is suspended in anhydrous toluene (30 mL). Aluminum trichloride (2.4 g, 18 mmol) is added in three portions and the reaction mixture is stirred at room temperature overnight. Cool to 0 ° C, carefully add water and extract the mixture twice with EtOAc. Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo to give a solid. The solid is suspended in diethyl ether and filtered to obtain the desired intermediate (1.30 g, 49%) which was used without any further purification. GC-MS m / z 221 (M +). 4- (4-Cyano-benzoyl) -bensyl bromide: A mixture of 4- (4-methyl-benzoyl) -benzonitrile (300 mg, 1356 mmol), NBS (386 mg, 2169 mmol), and AIBN ( 22 mg, 0.136 mmol) in carbon tetrachloride (10 mL) for 14 h at reflux. Additional NBS (121 mg) and AIBN (11 mg) are added and the mixture is refluxed for 3 h. The reaction mixture is cooled to room temperature and the mixture is filtered. The filtrate is concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by sequentially levigating with hexane and hexane / EtOAc (9: 1) to give the title compound as a solid (286 mg, 70%). GC-MS m / z: 300 (M +).

Preparation 335 4- (3-Cyano-benzoyl) -benzyl bromide The compound of Preparation 335 can be prepared essentially as described in Preparation 334 using 3-cyanobenzoyl chloride (GC-MS m / z 300 (M +)).

Preparation 336 2-Methanesulfonyloxymethyl-5- (3-methyl-butyryl) -pyridine 2- (tear-butyldimethylsilyloxymethyl) -5- (l-hydroxy-3-methyl-butyl) -pyridine: 5-bromo-2- (tert-butyldimethylsilyloxymethyl) -pyridine (0.5 -g, 1654 mmol, prepared as follows) is dissolved. the procedure described in J. Med. Chem. 1987, 30, 871-880) in anhydrous THF (12 mL). The solution is cooled to -78 ° C, n-BuLi (1.14 mL, 1819 mmol, 1.6M solution in hexane) is added and stirred at this temperature for 40 min. Isovaleryl aldehyde (0.284 mL, 2.646 mmol) is slowly added and the mixture is stirred for 5 h at -78 ° C. Additional isovaleryl aldehyde (0.089 mL, 0.827 mmol) is added and the mixture is stirred for 1.5 h at -78 ° C. Ammonium chloride is added at -78 ° C and the mixture is warmed to room temperature. EtOAc is added and the aqueous layer is extracted twice with EtOAc. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (4: 1) to give the desired intermediate as oil (330 mg, 64%). GC-MS m / z: 309 (M +). 2- (tert-Jbutyldimethylsilyloxymethyl) -5- (3-methyl-butyryl) -pyridine: Manganese dioxide (1.32 g) is added to a stirred solution of 2- (er-Jbutyldimethylsilyloxymethyl) -5- (1-hydroxy-3). -methyl-butyl) -pyridine (330 mg, 1066 mmol) in anhydrous 1,4-dioxane (30 mL). The mixture is heated at 70 ° C overnight. The reaction mixture is cooled to room temperature, filtered through Celite® and washed with EtOAc. The filtrate is concentrated in vacuo to provide the desired intermediate as oil (327 mg, 100%). GC-MS m / z: 307 (M +). 2-Hydroxymethyl-5- (3-methyl-butyryl) -pyridine: Tetrabutylammonium fluoride (2.13 mL, 2.13 mmol, 1M solution in THF) is added to a solution of 2- (tert-butyldimethylsilyloxymethyl) -5- (3- methyl-butyryl) -pyridine (330 mg, 1066 mmol) in anhydrous THF (20 mL) at 0 ° C and stirred at this temperature for 1 h. The solvent is concentrated in vacuo and the crude mixture is purified by chromatography on silica gel by levigating with EtOAc to provide the desired intermediate (327 mg, 100%). 2-Methanesulfonyloxymethyl-5- (3-methyl-butyryl) -pyridine: 2-hydroxymethyl-5- (3-methyl-butyryl) -pyridine (190 mg, 0.98 mmol) is dissolved in dichloromethane (10 mL). Cool to 0 ° C and add triethylamine (0.151 mL, 1.08 mmol) and methanesulfonyl chloride (0.083 mL, 1.08 mmol). The mixture is allowed to warm to room temperature and is stirred for 2 h. The reaction mixture is diluted with dichloromethane and washed with saturated aqueous NaHCO3. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as an oil (263 mg, 98%).

Preparation 337 5-Methanesulfonyloxymethyl-2- (3-methyl-butyryl) -pyridine - (tert-Butyldimethylsilyloxymethyl) -2- (3-methyl-butyryl) -pyridine: 2-Bromo-5- (tert-butyldimethylsilyloxyethyl) pyridine (1.99 g, 6.583 mmol, prepared following the procedure described in J) is dissolved. Org Chem. 2004, 69, 250-262) in anhydrous THF (20 mL). The solution is cooled to -78 ° C, n-BuLi (4.32 mL, 6.912 mmol, 1.6M solution in hexane) is added and stirred at this temperature for 40 min. A solution of N-methoxy-N-methyl-3-methyl-butyramide (0.955 g, 6.583 mmol) in anhydrous THF (5 mL) is slowly added. The mixture is stirred for 2 h at -78 ° C and then the mixture is allowed to warm to room temperature. Brine is added and the aqueous layer is extracted twice with EtOAc. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (19: 1) to give the desired intermediate as a yellow oil (890 mg, 44%). GC-MS m / z: 307 (M +).

-Hydroxymethyl-2- (3-methyl-butyryl) -pyridine: Tetrabutylammonium fluoride (5.853 mL, 5.853 mmol, 1M solution in THF) is added to a solution of 5- (tert-Jutyldimethylsilyloxymethyl) -2- (3- methyl-butyryl) -pyridine (900 mg, 2,927 mmol) in anhydrous THF (30 mL) at 0 ° C and stirred at this temperature for 2 h. The solvent is concentrated in vacuo and the crude mixture is purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (3: 2) to provide the desired intermediate (478 mg, 84%). MS (ER +) m / z: 194 (M + H) +.

-Methanesulfonyloxymethyl-2- (3-methyl-butyryl) -pyridine: 5-Hydroxymethyl-2- (3-methyl-butyryl) -pyridine (210 mg, 1086 mmol) is dissolved in dichloromethane (5 mL). Cool to 0 ° C and add triethylamine (0.167 mL, 1195 mmol) and methanesulfonyl chloride (0.093 mL, 1195 mmol). The mixture is allowed to warm to room temperature and is stirred for 2 h. The reaction mixture is diluted with dichloromethane and washed with saturated aqueous NaHCO3. The organic phase is dried over Na 2 SO 4, filtered and concentrated in vacuo to provide the title compound (256 mg, 87%). GC-MS m / z: 271 (M +).

Preparation 338 1- (3-chloro-propyl) -1, 3-dihydro-indol-2-one Reflux was carried out together with oxindole (2.66 g, 20.0 mmol), l-bromo-3-chloropropane (2.56 mL, 26.0 mmol) and potassium carbonate (5.52 g, 40.0 mmol) in acetonitrile (300 mL) under nitrogen for 16 h. h. The suspension is cooled to room temperature and the precipitate is completely filtered. The filtrate is concentrated in vacuo and the crude mixture is purified by chromatography on silica gel by levigating with isohexane / EtOAc (1: 0 to 3: 2 gradient for 40 min) to give the title compound as an orange oil (1.65 g, 39%). MS (ER +) m / z: 210 (M + H) +.

Preparation 339 1- (2-Chloro-ethyl) -pyrrolidin-2-one T CA. O rH-Cl Thionyl chloride (5 mL) is added to 1- (2-hydroxy-ethyl) -pyrrolidin-2-one (1.12 mL, 10.0 mmol) dropwise then stirred at room temperature for 10 min. Solvent is removed in vacuo to give the title compound as an orange oil. MS (ER +) m / z: 148 (M + H) +.

Preparation 340 1- (3-Bromo-propyl) -3-methyl-l, 3-dihydro-benzoimidazol-2-one 3-Methyl-l, 3-dihydro-benzoimidazol-2-one (400 mg, 27.0 mmol) is added in portions to a suspension of sodium hydride (1296 g, 32.4 mmol of 60% dispersion in oil) in anhydrous THF ( 200 mL) under nitrogen for 15 min., then continue until shaken for 30 min. 1,3-Dibromopropane (11.0 mL, 108 mmol) is added and stirred overnight. Then it is heated to reflux for 3 days. The suspension is cooled to room temperature, it is drained in brine (400 mL), extracted with diethyl ether (300 mL), dried over MgSO4 and concentrated in vacuo. Purify by chromatography on silica gel by levigating with isohexane / EtOAc (gradient 1: 0 to 1: 1 for 40 min) to give the title compound as a colorless oil (2.15 g, 30%).

Preparations 341-342 The Compound of Preparation 341 can be prepared essentially as described in Preparation 340 using 3-methyl-1,3-dihydro-benzoimidazol-2-one and 1,4-dibromobutane. The Compound of Preparation 342 can be prepared essentially as described in Preparation 340 using l-ter-util-imidazolidin-2-one and l-bromo-3-chloropropane. The yields are shown in the Table below.

Preparation 343 i- (3-Bromo-propyl) -3-isopropenyl-l, 3-dihydro-benzoimidazol-2-one Sodium hydride (600 mg, 16.5 mmol of 60% dispersion in oil) is added to a solution of 1-isopropenyl-1,3-dihydro-benzoimidazol-2-one (1.311 g, 7.53 mmol) in anhydrous DMF (10 mL ) under nitrogen at room temperature and stirred for 2 h. L-bromo-3-chloropropane (900 μL, 9.03 mmol) is added and stirred for 3 days. The suspension is poured into water (100 mL), extracted with diethyl ether (2 x 50 mL). The organic extract is washed with brine (100 mL), dried over MgSO4 and concentrated in vacuo to give the title compound without purifying with 1- (3-chloro-propyl) -3-isopropenyl-1,3-dihydroxy. benzoimidazol-2-one (2.03 g, 1: 1 mixture). MS (ER +) m / z: 251 (M + H) +, 293 (M + H) +.

Preparation 344 5- (3-Chloropropyl) -3,3-dimethyl-1,3-dihydro-indol-2-one - (3-sloropropionyl) -3,3-dimethyl-1,3-dihydro-indol-2-one: Under a nitrogen atmosphere, chloropropionyl chloride (1.54 mL, 16.13 mmol) is added to a mixture of 3.3 dimethyl-1,3-dihydro-indol-2-one (2.0 g, 12.41 mmol) and aluminum trichloride (10.26 g, 76.92 mmol) in carbon disulfide (70 mL). Heat under reflux for 3 h then allow to cool. The solvent is completely decanted and this is carefully replaced with ice / water (200 mL). The resulting suspension is allowed to stir for 20 min before completely filtering the product and washing with water (80 mL). Dry in vacuo to obtain the desired intermediate as a pale brown solid (3.08 g, 99%). - (3-sloropropyl) -3,3-dimethyl-1,3-dihydro-indol-2-one: Under a nitrogen atmosphere, 5- (3-chloropropyl) -3,3-dimethyl-1,3 is added. -dihydro-indole-2-one (3.08 g, 12.24 mmol) to trifluoroacetic acid (9.4 mL, 122.4 mmol). The resulting suspension is cooled to 0 ° C and then triethylsilane (4.5 mL, 28.2 mmol) is added dropwise over 2 min. Heat at 45 ° C for 30 min then stir at room temperature overnight. The reaction mixture is poured onto ice / water (100 mL) and extracted with EtOAc (2 x 100 mL). Dry the combined extracts over MgSO4, filter and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (gradient 1: 0 to 4: 1), to give the title compound as a yellow-orange solid (2.12 g, 73%).

Preparation 345 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-9-fluoro-2,3,4,5-tetrahydro-12Y-benzo [d] azepine 7-sloro-6- (O-dimethylthiosarbamoyl) -9-fluoro-3- (2,2,2-trifluoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Warm 7- chloro-9-fluoro-6-hydroxy-3- (2,2,2-trifluoroacetyl) -2,3,4,5-tetrahydro-1,2-benzo [d] azepine (0.56 g, 1.8 mmol) at reflux in Anhydrous 1,4-dioxane (18 mL) with triethylamine (1.01 mL, 7.2 mmol), 2V, 2V-dimethyl-4-aminopyridine (22 mg, 0.18 mmol) and dimethylthiocarbamoyl chloride (0.67 g, 5.4 mmol) for 16 h . The mixture is cooled and the mixture washed with IN aqueous HCl, saturated aqueous NaHCO3 and brine. Concentrate in vacuo is purified by chromatography on silica gel by levigating with hexane / EtOAc (1: 0 to 3: 2 gradient) to give the desired intermediate as a yellow oil which solidifies on standing (0.69 g, 96%). MS (ER +) m / z: 399 (M + H) +. 7-sloro-6-dimethylsarbamoylthio-9-fluoro-3- (2,2,2-trifluoroasethyl) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 7-chloro-6- is heated (O-dimethylthiocarbamoyl) -9-fluoro-3- (2,2,2-trifluoroacetyl) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine (0.69 g, 1.73 mmol) in ether from diphenyl (6 mL) at 245 ° C for 2.5 h. The mixture is cooled and loaded onto a column of silica gel. Diphenyl ether is washed off with hexane and levigated with hexane / EtOAc (1: 0 to 3: 2 gradient) to give the desired intermediate (0.44 g, 64%). MS (ER +) m / z: 399 (M + H) +. 3-tert-butoxyarbonyl-7-sloro-6-dimethylsarbamoylthio-9-fluoro-2,3,4,5-tetrahydro-lff-benzo [d] azepine: 7-chloro-6-dimethylcarbamoylthio-9-fluorocarbon is heated 3- (2,2, 2-trifluoroacetyl) -2,3,4,5-tetrahydro-lff-benzo [d] azepine (0.2 g, 0.5 mmol) in methanol (50 mL) with potassium carbonate (0.28 g, 2 mmol) at reflux for 5 h. The mixture is cooled, a solution of di-tert-butyl-dicarbonate (0.22 g, 1.0 mmol) in dichloromethane (20 mL) is added dropwise and the mixture is stirred for 17 h. The mixture is evaporated on silica gel and purified by chromatography by levigating with hexane / EtOAc (1: 0 to 3: 2 gradient) to give the title compound (0.12 g, 62%). MS (ER +) m / z: 303 (M + H-Boc) +.

Examples 608-611 Examples 608-611 can be prepared essentially as described in Example 350 by using 3-tert-Jutoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-127-benzo [ d] azepine and the appropriately substituted chloromethylheterocycle or bromomethylheterocycle. The EM (ER +) data are shown in the Table below.

Example 612 7-Chloro-6- ([1, 3, 4] thiadl-2-yl-methylthio) 2,3,4,5-tetrahydro-12β-benzo [d] azepine hydrochloride 2-Hydroxymethyl- [1, 3, 4] -thiadle (241 mg, 2.1 mmol) in thionyl chloride (15 mL) is stirred for 1 h and concentrated in vacuo. This residue is treated with the thiolate prepared from 3-tert-jutoxycarbonyl-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1,2-benzo [d] azepine (0.4 g, 1.04 mmol) and potassium hydroxide (1.37 g, 24.5 mmol) in methanol (3.5 mL) in accordance with General Procedure 7 to give 3-tert-jutoxycarbonyl-7-chloro-6- ([1, 3, 4] thiadl-2-yl-methylthio) -2 , 3, 4, 5-tetrahydro-127-benzo [d] azepine (0.3 g, 70%). An aliquot is treated with trifluoroacetic acid to obtain the mass spectrum. MS (ER +) m / z: 312 (M + H) +. A method similar to General Procedure 1-5 is used to deprotect 3-tert-jutoxycarbonyl-7-chloro-6- ([1, 3,4] thiadl-2-yl-methylthio) -2,3,4, 5- tetrahydro-lH-benzo [d] azepine (300 mg, 0.73 mmol). A method similar to General Procedure 2-2 is used to give the title compound (208 mg, 82%). MS (ER +) m / z: 312 (M + H) +.

Example 613 7-Chloro-6- (thl-5-ylmethylthio) -2, 3, 4, 5-tetrahydro-127-benzo [d] azepine Succinate A method similar to General Procedure 7 is used, using 3-tert-jutoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-12β-benzo [d] azepine and 5-chloromethylthle to give, after deprotection and salt formation by methods similar to General Procedures 1-5 and 2-1, the title compound as a white solid (700 mg, total 80%). HRMS (ER +) m / z: 311.0427 (M + H) +.

Example 614 7-Chloro-6- [2- (cyclohexylmethylamino) -thl-5-ylmethylthio] -2,3,4,5-tetrahydro-1,2-benzo [d] azepine Succinate A method similar to the General Procedure is used 7 using 3-tert.-ethoxycarbonyl-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and 5-bromomethyl-2-chlorothle to give 3-tert-jutoxycarbonyl-7-chloro-6 - (2-chlorothl-5-ylmethylthio) -2, 3, 4, 5-tetrahydro-12? -benzo [d] azepine as a yellow oil (0.9 g, 71%). Dissolve 3-tert-Jbutoxycarbonyl-7-chloro-6- (2-chlorothl-5-ylmethylthio) -2, 3, 4,5-tetrahydro-l-benzo [d] azepine (120 mg, 0.27 mmol) and cyclohexylmethylamine (1 mL, 7.7 mmol) in absolute ethanol (1 mL) in a thick-walled Pyrex tube. The reaction is heated in an oil bath at 82 ° C for 24 h. The reaction mixture is cooled and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (4: 1) Methods similar to General Methods 1-5 and 2-1 are used to deprotect and give the title compound as a yellow oil (19 mg, 26% total). MS (ER +) m / z: 422 (M + H) +.

Example 615 Succinate of (-) - 7-chloro-6- [1- (thl-2-yl) -ethylthio] -2,3,4,5-tetrahydro-1,2-benzo [d] azepine Potassium hydroxide (3.9 g, 70 mmol) is added to a solution of 3-tert-4-chloro-6-chloro-6-dimethylcarbamoylthio-2,4,4,5-tetrahydro-1-benzo [d] azepine (900 mg)., 2.3 mmol) in methanol (25 mL) under a nitrogen atmosphere. The mixture is heated at 80 ° C for 1.5 h. The mixture is cooled to room temperature, then concentrated in vacuo to an oil. Dissolve the oil in EtOAc (50 mL) and wash with saturated aqueous ammonium chloride (30 mL). The organic layer is separated and the aqueous layer is extracted with EtOAc (3 x 50 mL). The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo in an oil (735 mg). Dissolve the oil in anhydrous DMSO (20 mL), then add triethylamine (1.9 mL, 14 mmol) and (±) -l-methanesulfonyloxy-1-thiazol-2-yl-ethyl (1.3 g, 6.3 mmol) at room temperature. environment under nitrogen. The mixture is heated at 40 ° C for 1 h. The reaction is cooled to room temperature, then the mixture is diluted with hexane / EtOAc (1: 1, 50 mL) and washed with 5% aqueous sodium chloride (3 x 50 mL). The organic layer is separated and the aqueous layer is extracted again with EtOAc (3 x 50 mL). The organic extracts are combined and concentrated in vacuo. The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 7: 3 gradient) to obtain (+) - 3-tert-jutoxycarbonyl-7-chloro-6- [1- (thiazole-2 -yl) -ethylthio] -2,4,5,5-tetrahydro-lH-benzo [d] azepine (779 mg, 79%). MS (ER +) m / z: 425.0 (M + H) +. Separate (±) -3-tert -butoxycarbonyl-7-chloro-6- [1- (thiazol-2-yl) -ethylthio] -2,3,4,5,5-tetrahydro-1,2-benzo [d] azepine (770 mg, 1.8 mmol) by normal phase chiral chromatography [Chiralpak AD, 8 x 30 cm, levigating with heptane / ethanol 3A (9: 1)]. The 2nd levigation isomer of 3-tert-butoxycarbonyl-7-chloro-6- [1- (thiazol-2-yl) -ethylthio] -2,3,4,5-tetrahydro-lJ-benzo [ d] azepine. { 348 mg, 99% ee [Chiralpak AD-H, 4.6 x 150 mm, levigant heptane / ethanol 3A (9: 1)]} . A method similar to General Procedure 1-5 is used to deprotect 3-tert-jutoxycarbonyl-7-chloro-6- [1- (thiazol-2-yl) -ethylthio] -2,3,4,5-tetrahydro-12 β-benzo [d] azepine isomer 2. Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (98: 2 to 90:10 gradient) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (350 mg, 96%). MS (ER +) m / z: 325.0 (M + H) +. [a] 20D -160 ° (c 0.5, MeOH).

Example 616 Succinate of 7-chloro-3-methyl-6- (pyridin-2-ylmethylthio) -2,3,4,5-tetrahydro-12? -benzo [d] azepine 7-Chloro-6- (pyridin-2-ylmethylthio) -2,3,4,5-tetrahydro-1,2-benzo [d] azepine hydrochloride is suspended in saturated aqueous NaHCO 3 and extracted three times with EtOAc. Dry the combined organic extracts over MgSO4. Filter and concentrate in vacuo to give the free base as a yellow oil. Combine the free base (0.2 g, 0.66 mmol), sodium triacetoxyborohydride (0.78 g, 3.7 mmol), formaldehyde (37% solution in water, 0.2 mL, 2.7 mmol), and acetic acid (0.45 mL, 7.9 mmol), in 1,2-dichloroethane (5 mL). Stir at room temperature for 12 h. The crude reaction mixture is concentrated in vacuo and the residue partitioned between EtOAc / water. Separate the layers and extract the aqueous phase with EtOAc (3 x 30 mL). The combined organic extracts are washed with 1M aqueous NaOH. Dry over MgSO, filter and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with 2M ammonia in methanol / dichloromethane (4:96). A method similar to General Procedure 2-1 is used to give the title compound as a sticky crystal (140 mg, 48%). HRMS (ER +) m / z: 319.1029 (M + H) +.

Examples 617 and 618 7-Chloro-6- (2, 2, 2-trifluoro-l-pyridin-2-yl-ethylthio) -2,3,4,5-tetrahydro-12β-benzo [d] azepine hydrochloride Isomer 1 and 7-chloro-6- (2, 2, 2-trifluoro-l-pyridin-2-yl-ethylthio) -2, 3, 4, 5-tetrahydro-12? -benzo [d] azepine Isomer 2 The two enantiomers of (+) - 7-chloro-6- (2,2,2-trifluoro-l-pyridin-2-yl-ethylthio) -2,3,4,5-tetrahydro-12? -benzo [d] azepine by normal-phase chiral chromatography (Chiralpak AD, 2 x 25 cm, levigating with heptane / ethanol (85:15) with DMEA 0.2%). The first levigation isomer is subjected to General Procedure 1-4 to obtain 7-chloro-6- (2,2,2-trifluoro-l-pyridin-2-yl-ethylthio) hydrochloride) -2,3,4,5 -tetrahydro-127-benzo [d] azepine isomer 1 [99% ee (Chiralpak AD-H, 4.6 x 150 mm, levigating with heptane / ethanol (85:15) with DMEA 0.2%, flow ratio 0.6 mL / min) ] MS (ER +) m / z: 373.1 (M + H) +. The second levigation isomer is subjected to General Procedure 1-4 to obtain 7-chloro-6- (2,2,2-trifluoro-l-pyridin-2-yl-ethylthio) -hydrochloride) -2,3,4,5 -tetrahydro-lH-benzo [d] azepine isomer 2 [99% ee (Chiralpak AD-H, 4.6 x 150 mm, levigating with heptane / ethanol (85:15) with DMEA 0.2%, flow ratio 0.6 mL / min) ] MS (ER +) m / z 373.1 (M + H) +.

Example 619 (-) - 7-Chloro-6- (l-pyridin-2-yl-propylthio) -2,3,4,5-tetrahydro-12-benzo [d] azepine hydrochloride The two enantiomers of (±) -7-chloro-6- (l-pyridin-2-yl-propylthio) -2,3,4,5-tetrahydro-12β-benzo [d] azepine are dissociated by chromatography Normal phase chiral (Chiralcel OJ, '8 x 33 cm, levigating with heptane / methanol / ethanol 3A (85: 10: 5) with DMEA 0.2%). The second levigation isomer is subjected to General Procedure 1-4 to obtain the title compound [93% ee (Chiralcel OJ, 4.6 x 250 mm, levigating with heptane / methanol / ethanol 3A (90: 5: 5) with DMEA 0.2 %, flow ratio 0.6 mL / min)]. MS (ER +) m / z: 333.1 (M + H) +. [a] 20D -240.6 ° (c 0.5, MeOH).

EXAMPLE 620 (+) - 7-Chloro-6- [1- (4-fluorophenyl) ethylthio] 2,3,4,5-tetrahydro-127-benzo [d] azepine hydrochloride It dissolves 3-tert-Jbutoxicarbonil-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lJ? -benzo [d] azepine (415 mg, 1.08 mmol) in methanol (20 mL) and potassium hydroxide (1.938 g, 34.53 mmol) is added. It is heated at 60 ° C for 4 h. The reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride is added and concentrated in vacuo. The residue is partitioned between EtOAc and water. The organic phase is dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-12β-benzo [d] azepine (0.34 g) 1.086 mmol). The crude 3-tert-jutoxicarbonil-7-chloro-6-mercapto-2,3,4,5-tetrahydro-12Y-benzo [d] azepine (0.34 g, 1086 mmol) is dissolved in anhydrous DMF (10 mL), Sodium hydride (65 mg, 1.63 mmol, 60% in mineral oil) is added and the mixture is stirred for 5 min. A solution of (±) -l- (4-fluorophenyl) ethyl bromide (332 mg, 1.63 mmol) in anhydrous DMF (5 mL) is added and the solution is heated at 45 ° C overnight. It is cooled to room temperature, water is added and the aqueous phase is extracted twice with EtOAc. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (19: 1 and 9: 1) to give (+) - 3-tert-jutoxycarbonyl-7-chloro-6- [1- (4 -fluorophenyl) ethylthio] -2,3,4,5-tetrahydro-lf-benzo [d] azepine as oil (397 mg, 84%). MS (ER +) m / z: 336 (M + H-Boc) +. A method similar to General Procedure 1-4 is used to deprotect (±) -3-tert-jutoxycarbonyl-7-chloro-6- [1- (4-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro- 12-benzo [d] azepine (47 mg, 0.108 mmol) and give the title compound as a solid (39 mg, 99%). MS (ER +) m / z: 336 (M + H) +.

Examples 621-622 Examples 621-622 can be prepared essentially as described in Example 620 using 3-tert -butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1-yl-benzo [d ] azepine and the appropriate alkyl bromide. The total yields and EM data (ER +) are shown in the Table below.

Examples 623 and 624 Succinate of 7-chloro-6- [1- (4-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro-12β-benzo [d] azepine Isomer 1 and 7-chloro succinate 6- [1- (4-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro-12? -benzo [d] azepine Isomer 2 The two enantiomers of (±) -3-tert-Jutoxycarbonyl-7-chloro-6- [1- (4-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro-127-benzo [d] azepine are separated by chiral CLAR (column Chiralcel OJ-H 4.6 x 150 mm, levigating with methanol at 0.6 mL / min). Isomer 1 (tR = 7.3 min, ee> 99.9%) is subjected to General Procedure 2-1 to provide succinate of 7-chloro-6- [1- (4-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro-1H-benzo [d] azepine isomer 1 as a white solid. EM (ER +) m / z 336 (M + H) +. Isomer 2 (tR = 12.9 min, ee = 99.9%) is subjected to General Procedure 2-1 to provide succinate of 7-chloro-6- [1- (4-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro-li? -benzo [d] azepine isomer 2 as a white solid . EM (ER +) m / z 336 (M + H) +.

Examples 625 and 626 Succinate of 7-chloro-6- [1- (3-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro-127-benzo [d] azepine Isomer 1 and Succinate of 7-chloro-6 - [l- (3-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine Isomer 2 The two enantiomers of (±) -3-tert -butoxycarbonyl-7-chloro-6- [1- (3-fluorophenyl) ethylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine are separated by chiral HPLC (Chiralcel OJ-H 4.6 x 150 mm column, levigating with methanol at 0.6 mL / min). Isomer 1 (tR = 5.4 min, ee> 99.9%) is subjected to General Procedure 2-1 to provide 7-chloro-6- [1- (3-fluorophenyl) ethylthio] -2,3,4 succinate, 5-Tetrahydro-lino-benzo [d] azepine isomer 1 as a white solid. MS (ER +) m / z 336 (M + H) +. Isomer 2 (tR = 11.2 min, ee = 99.7%) is subjected to General Procedure 2-1 to provide 7-chloro-6- [1- (3-fluorophenyl) ethylthio] succinate] -2,3,4, 5 -tetrahydro-lH-benzo [d] azepine isomer 2 as a white solid. MS (ER +) m / z 336 (M + H) +.

Example 627 (S) -7-Chloro-6-hydrochloride. { 1- [4- (3, 3-dimethylbutyryl) -phenyl] -ethylthio} -2, 3, 4, 5-tetrahydro-lH-benzo [d] azepine The mixture of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (310 mg, 0.807 mmol) and potassium hydroxide (1.45 g) is heated. , 25.83 mmol) in methanol (5 mL) at 50 ° C for 3 h. The reaction mixture is cooled to room temperature and diluted with saturated aqueous NHC1 and EtOAc. Separate the layers and extract the aqueous layer three times with EtOAc. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-lH-benzo [d] azepine is dissolved in anhydrous DMF (2 L) and cooled to 0 ° C. Sodium hydride (21 mg, 0.888 mmol) and a solution of (R) -l- [4- (l-bromoethyl) -phenyl] -3,3-dimethylbutan-1-one are added. { is prepared by the mixture of (S) -1- [4- (1-hydroxyethyl) -phenyl] -3,3-dimethylbutan-1-one (213 mg, 0.969 mmol), triphenylphosphine (296 mg, 1130 mmol) and NBS (201 mg, 1.13 mmol) in anhydrous THF (5 mL) at 0 ° C and then room temperature} . The mixture is stirred at 0 ° C for 30 min and quenched with water. Dilute with EtOAc and extract the aqueous layer three times with EtOAc. The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (85:15) to give (S) -3-tert-butoxycarbonyl-7-chloro-6-. { 1- [4- (3,3-Dimethylbutyryl) -phenyl] -ethylthio} -2, 3,4, 5-tetrahydro-lH-benzo [d] azepine as yellow oil (197 mg, 47%). A method similar to General Procedure 1-4 is used, using (S) -3-tert-butoxycarbonyl-7-chloro-6-. { 1- [4- (3, 3-dimethylbutyryl) -phenyl] -ethylthio} -2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (197 mg, 0.382 mmol) to give the title compound as a white solid (161 mg, 93%). MS (ER +) m / z: 416 (M + H) +; ee = 92%, tR = 11.27 min (Chiralcel OJ, 4.6 x 250 mm, 45 ° C, levigant: 20% isopropanol with 0.05% triethylamine in CFS, flow ratio 2 mL / min, UV detector at 234 nm).

Example 628 (5) -7-Chloro-6- (1-phenyl-ethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine hydrochloride Example 628 can be prepared essentially as described in Example 627 using 3-tert-jutoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1-benzo [d] azepine y. { R) - (1-bromo-ethyl) -benzene (64% yield, MS (ER +) m / z 318 (M + H) +).

Example 629 6- (4-Acetyl-benzylthio) -7-chloro-2,3,4,5-tetrahydro-127-benzo [d] azepine hydrochloride A method similar to General Procedure 7 is used to react 3-ter- 7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1,2-benzo [d] azepine (200 mg, 0.521 mmol) with 4-acetylbenzyl bromide (555 mg, 2605 mmol). The crude mixture was purified by chromatography on silica gel by sequentially levigating with hexane and hexane / EtOAc (9: 1, 4: 1) to obtain 6- (4-acetyl-benzylthio) -3-tert-Jutoxycarbonyl-7-chloro- 2, 3, 4, 5-tetrahydro-127-benzo [d] azepine (190 mg, 82%). A method similar to General Procedure 1-4 is used to deprotect 6- (4-acetyl-benzylthio) -3-tert-jutoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-l-benzo [d] azepine (170 mg, 0.381 mmol) and give the title compound as a white solid (140 mg, 96%). MS (ER +) m / z: 346 (M + H) +.

Examples 630-634 Examples 630-634 can be prepared essentially as described in Example 629 using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-127-benzo [d ] azepine and the appropriate benzyl bromide. The total yields and EM data (ER +) are shown in the Table below.

EXAMPLE 635 7-Chloro-6- [4- (pyridine-3-carbonyl) benzylthio] -2,3,4,5-tetrahydro-lJ-benzo [d] azepine hydrochloride Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1-benzo [d] azepine (150 mg, 0.39 mmol) in methanol (10 mL) and add hydroxide of potassium (0.7 g, 12.47 mmol). It is heated at 60 ° C for 4 h. The reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride is added and concentrated in vacuo. The residue is partitioned between EtOAc and water. Dry the organic phase over anhydrous Na 2 SO 4 and concentrate in vacuo to give 3-tert-jutoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-127-benzo [d] azepine (0.12 g) . The crude 3-tert-3-chloro-6-chloro-6-mercapto-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (0.12 g, 5.2 mmol) is dissolved in anhydrous DEMO (6 mL) and triethylamine (0.325 L, 2.34 mmol) and 4- (pyridine-3-carbonyl) -benzyl methanesulfonate (114 mg, 0.39 mmol) are added. The solution is heated at 40 ° C overnight. Cool to room temperature, dilute the mixture with hexane / EtOAc (1: 1, 100 mL), and wash the organic solution sequentially with brine and ice water. Dry the organic layer over anhydrous Na 2 SO 4, filter and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (1: 1) to give 3-tert-butoxycarbonyl-7-chloro-6- [4- (pyridine-3-carbonyl) -benzylthio] -2, 3, 4, 5-tetrahydro-l2? -benzo [d] azepine as oil (123 mg, 64%). A method similar to General Procedure 1-4 is used to deprotect 3-ter- £ > Utoxycarbonyl-7-chloro-β- [4- (pyridine-3-carbonyl) -benzylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine (113 mg, 0.22 mmol) and give the compound of the title as a solid (105 mg, 99%). MS (ER +) m / z: 409 (M + H) +.

Examples 636-638 Examples 636-638 can be prepared essentially as described in Example 635 using 3-ter- £ > utoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1-benzo [d] azepine and the appropriate methanesulfonate. The total yields and EM data (ER +) are shown in the Table below.

Example 639 7-Chloro-6- [4- (3-cyanobenzoyl) -benzylthio] 2,3,4,5-tetrahydro-127-benzo [d] azepine hydrochloride Dissolve 3-tert-utoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-li? -benzo [d] azepine (200 mg, 0.52 mmol) in methanol (12 mL) and add potassium hydroxide (0.935 g, 16.66 mmol). It is heated at 60 ° C for 4 h. The reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride is added and concentrated in vacuo. The residue is partitioned between EtOAc and water. The organic phase is dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give 3-ter-> g. utoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-127-benzo [d] azepine (0.16 g, 5.2 mmol). The crude 3-tert-jutoxicarbonyl-7-chloro-6-mercapto-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (0.16 g, 0.52 mmol) is dissolved in anhydrous DMSO (5 mL) and triethylamine (0.435 mL, 3.12 mmol) and 4- (3-cyano-benzoyl) benzyl bromide (289 mg, 0.96 mmol) are added. The solution is heated at 40 ° C overnight. Cool to room temperature, dilute the mixture with hexane / EtOAc (1: 1, 100 mL), and wash the organic solution sequentially with brine and water cooled on ice. Dry the organic layer over anhydrous Na 2 SO 4, filter and concentrate in vacuo. The crude mixture is purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (9: 1, 4: 1) to give 3-ter- £ > utoxycarbonyl-7-chloro-6- [4- (3-cyanobenzoyl) -benzylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine as an oil (212 mg, 77%). A method similar to General Procedure 1-4 is used to deprotect 3-ter- £ > utoxycarbonyl-7-chloro-6- [4- (3-cyanobenzoyl) -benzylthio] -2,3,4,5-tetrahydro-1-benzo [d] azepine (200 mg, 0.37 mmol) and give the title compound as a solid (136 mg, 77%). MS (ER +) m / z: 433 (M + H) +.

Example 640 7-Chloro-6- [4- (4-cyanobenzoyl) -benzylthio] -2,3,4-ahydro-12β-b .CeNnz [d] • "azepine hydrochloride Example 640 can be prepared essentially as described in Example 639 using 3-tert-jutoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine and bromide 4 - (4-Cyano-benzoyl) benzyl (49% yield, MS (ER +) m / z 433 (M + H) +).

Example 641 7-Chloro-6- (4-ter-utiltiocarbamoyl-benzylthio) -2,3,4,5-tetrahydro-127-benzo [d] azepine hydrochloride 7-Chloro-6- (4-tert-butylcarbamoyl-benzylthio) -2,3,4,5-tetrahydro-127-benzo [d] azepine (53 mg, 0.13 mmol) is combined with 2,4-bis (4 -methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (53 mg, 0.13 mmol) in anhydrous 1,4-dioxane (1 mL) in a sealed tube and it is heated at 100 ° C for 2 h. The reaction mixture is cooled to room temperature, concentrated in vacuo and the residue is purified by SCX chromatography to obtain 7-chloro-6- (4-tert-butylthiocarbamoyl-benzylthio) -2,3,4,5-tetrahydro- 12? -benzo [d] azepine as a yellow oil. Purify by reverse phase preparative HPLC [Zorbax SB-Phenyl 21.2 x 250 mm, 5 microns, 22 mL / min 0.1% aqueous HCl / acetonitrile (9: 1 to 1: 9) for 30 min, detector at 230 nm] . A method similar to General Procedure 2-2 is used to obtain the title compound as a yellow solid (36 mg, 58%). MS (ER +) m / z 419 (M + H) +.

Example 642 Succinate of 7-chloro-6- [4- (4-fluorobenzylthiocarbamoyl) -benzylthio] -2,3,4,5-tetrahydro-l27-benzo [d] azepine 7-Chloro-6- [4- (4-fluorobenzylcarbamoyl) -benzylthio] -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine (23 mg, 0.05 mmol) is combined with 2, 4- bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphtane-2,4-disulfide (Lawesson's reagent) (23 mg, 0.05 mmol) in anhydrous 1,4-dioxane (1 mL) in a tube sealed and heated at 100 ° C for 2 h. The reaction mixture is cooled to room temperature, concentrated in vacuo and the residue purified by SCX chromatography to obtain 7-chloro-6- [4- (4-fluorobenzylthiocarbamoyl) -benzylthio] -2,3,4, 5- tetrahydro-li? -benzo [d] azepine as a yellow oil. A method similar to General Procedure 2-1 is used to obtain the title compound as a white solid (10 mg, 42%). MS (ER +) m / z: 471 (M + H) +.

Example 643 Succinate of 7-chloro-6- (6-cyclohexylamino-pyridin-3-ylmethylthio) -2,3,4,5-tetrahydro-l-benzo [d] azepine A method similar to General Procedure 7 is used, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-12β-benzo [d] azepine (2 g, 5.2 mmol) and 2-chloro-5- (chloromethyl) pyridine (843 mg, 5.2 mmol) to give 3-tert-jutoxycarbonyl-7-chloro-6- (6-chloro-pyridin-3-ylmethylthio) -2.3.4, 5-tetrahydro-li? -benzo [d] azepine (2.2 g, 95%). MS (ER +) m / z: 439.1 (M + H) +. Palladium (II) acetate paste (434 mg, 1.9 mmol), BINAP (1.2 g, 1.9 mmol), sodium tert-butoxide (644 mg, 6.7 mmol), cyclohexylamine (1.4 g, 14.4 mmol) and 3 are made. -ter-Jutoxycarbonyl-7-chloro-6- (6-chloro-pyridin-3-ylmethylthio) -2,3,4,5-tetrahydro-li? -benzo [d] azepine (2.1 g, 4.8 mmol) in toluene anhydrous (70 mL). The paste is degassed under vacuum housing, then nitrogen is bubbled. The mixture is heated at 95 ° C for 16 h under a nitrogen atmosphere. The mixture is cooled to room temperature, diluted with EtOAc (50 mL) and filtered through Celite®. The filtrate is concentrated to an oil and purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 13: 7 gradient) to obtain 3-tert-jutoxycarbonyl-7-chloro-6- (6-cyclohexylamino- pyridin-3-ylmethylthio) -2, 3, 4, 5-tetrahydro-l2? -benzo [d] azepine (800 mg, 33%). MS (ER +) m / z: 502.2 (M + H) +. A method similar to General Procedure 1-5 is used to deprotect 3-tert-Jutoxycarbonyl-7-chloro-6- (6-cyclohexylamino-pyridin-3-ylmethylthio) -2, 3, 4, 5-tetrahydro-lff-benzo [d] azepine (790 mg, 1.6 mmol). Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (gradient 99: 1 to 95: 5) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (670 mg, 82%). MS (ER +) m / z: 402.1 (M + H) +.

Example 644 Succinate of 7-chloro-6- (6-trifluoroethylamino-pyridin-3-ylmethylthio) -2,3,4,5-tetrahydro-1,2-benzo [d] azepine Example 644 can be prepared essentially as described in Example 643 by using 3-tert-butoxycarbonyl-7-chloro-6- (6-chloro-pyridin-3-ylmethylthio) -2, 3, 4, 5-tetrahydro- 12-benzo [d] azepine and 2,2,2-trifluoroethylamine (10% yield, MS (ER +) m / z 502.2 (M + H) +).

Example 645 7-Chloro-6- (6-cyclohexylmethylamino-pyridin-3-ylmethylthio) -2,3,4,5-tetrahydro-l27-benzo [d] azepine Succinate Cyclohexylmethylamine (3 mL) is added to a flask containing 3-tert-jutoxycarbonyl-7-chloro-6- (6-chloro-pyridin-3-ylmethylthio) -2, 3, 4, 5-tetrahydro-lH-benzo [ d] azepine (340 mg, 0.8 mmol) and ammonium chloride (50 mg, 0.92 mmol). The contents are heated in a sealed flask at 170 ° C for 7 h. The flask is cooled to room temperature, diluted with EtOAc (50 mL) and washed with water (20 mL). The organic layer is collected and concentrated in vacuo. The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 4: 1 gradient) to obtain 3-tert-butoxycarbonyl-7-chloro-6- (6-cyclohexylmethylamino-pyridin-3-ylmethylthio) -2.3, 4, 5-tetrahydro-lH-benzo [d] azepine (160 mg, 40%). A method similar to General Procedure 1-5 is used to deprotect 3-tert-jutoxycarbonyl-7-chloro-6- (6-cyclohexylmethylamino-pyridin-3-ylmethylthio) -2,3,4,5-tetrahydro-127-benzo [d] azepine. Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (99: 1, 98: 2, 96: 4 gradient) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (115 mg, 70%). MS (ER +) m / z: 416.0 (M + H) +.

Example 646 7-Chloro-6- (2, 2-difluoro-2-phenyl-ethylthio) -2,3,4,5-tetrahydro-12β-benzo [d] azepine hydrochloride 3-tert-J-Ethoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-12β-benzo [d] azepine (200 mg, 0.52 mmol) is dissolved in methanol (10 mL) and add potassium hydroxide (0.934 g, 16.64 mmol). It is heated at 60 ° C for 4 h. The reaction mixture is cooled to room temperature, saturated aqueous ammonium chloride is added and concentrated in vacuo. The residue is partitioned between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert.-utoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1,2-benzo [d] azepine (0.163 g. ). The crude 3-tert-Jutoxycarbonyl-7-chloro-6-mercapto-2, 3,4,5-tetrahydro-lE-benzo [d] azepine (0.163 g, 0.52 mmol) is dissolved in anhydrous DMSO (5 mL) and triethylamine (0.43 mL, 3.12 mmol) and 2,2-difluoro-2-phenylethyl trifluoromethanesulfonate (151 mg, 0.52 mmol) are added. The solution is heated at 40 ° C overnight. It is cooled to room temperature, water is added and the aqueous phase is extracted twice with EtOAc. Dry the combined organic extracts over anhydrous Na2SO4, filter and concentrate in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane and hexane / EtOAc (19: 1, 9: 1 and 4: 1) to give 3-tert -butoxycarbonyl-7-chloro-6- (2, 2- difluoro-2-phenyl-ethylthio) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine as oil (132 mg, 56%). A method similar to General Procedure 1-4 is used to deprotect 3-tert-fouxycarbonyl-7-chloro-6- (2, 2-difluoro-2-phenyl-ethylthio) -2,3,4,5-tetrahydro-1,2 ? -benzo [d] azepine (132 mg, 0.29 mmol) and give the title compound as a solid (111 mg, 98%). MS (ER +) m / z: 354 (M + H) +.

Example 647 7-Chloro-6-hydrochloride. { 2, 2-difluoro-2-pyridin-2-yl-ethylthio) -2,3,4,5-tetrahydro-l27-benzo [d] azepine Example 647 can be prepared essentially as described in Example 646 using 3-tert-7-chloro-6-dimethylcarbamoylthio-2,4,4-tetrahydro-12β-benzo [d] azepine and trifluoromethanesulfonate from 2, 2-difluoro-2-pyridin-2-yl-ethyl (prepared by following the procedure described in J. Med. Chem. 2003, 46, 461-473) (66% yield, MS (ER +) m / z 355 (M + H) +).

Example 648 Succinate of 7-chloro-6- [3- (2-oxo-2,3-dihydro-indol-1-yl) -propylthio] -2,3,4,5-tetrahydro-1H-benzo [d] azepine Potassium hydroxide (899 mg, 16.64 mmol) is added in one portion to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-lH-benzo [d] azepine (200 mg, 0.52 mmol) in methanol (10 mL). The reaction is heated at 50 ° C under nitrogen for 24 h, then cooled to room temperature and 1- (3-chloro-propyl) -1,3-dihydro-indol-2-one (217 mg, 1.04 mmol) is added. ). The reaction is stirred at room temperature for 4 days. The solvents are removed in vacuo, dichloromethane (20 mL) and water (20 mL) are added. The organic layer is removed and dried using an ISCO® phase separator then concentrated in vacuo to give 3-tert.-utoxycarbonyl-7-chloro-6-f3- (2-oxo-2,3-dihydro-indole-1). -yl) -propylthio] -2,3,4,5-tetrahydro-12? -benzo [d] azepine as an orange powder. MS (ER +) m / z: 509 (M + Na) +. Dissolve 3-ter-¿> Utoxycarbonyl-7-chloro-6- [3- (2-oxo-2,3-dihydro-indol-1-yl) -propylthio] -2,3,4,5-tetrahydro-1,2-benzo [d] azepine (0.52 mmol) in dichloromethane (10 mL), then add TFA (2 L) dropwise and stir for 2 h. The solvents are removed in vacuo, then the free base using an SCX column, levigating with 7M ammonia in methanol. Purify using UV-guided reverse phase HPLC [Supelco Discovery C18 column (21.2 x 100 mm, 5 μm packed), 20 mL / min flow ratio, levigate with water / acetonitrile / acetic acid gradient for 15 min, collection of activated fraction using UV detector (220 and 254 nm)] followed by SCX column, levigating with 7M ammonia in methanol, then mass-guided reverse phase CLAR [Supelco Discovery C18 column (21.2 x 100 mm, packed 5μm), flow ratio 25 mL / min, levigating with water / acetonitrile / acetic acid gradient for 12 min, collection of fraction driven by EM Electrorocium] and SCX column. Concentrate in vacuo, then use a method similar to General Procedure 2-1 and freeze dry to give the title compound as a light pink solid (51 mg, 19%). MS (ER +) m / z: 387 (M + H) +.

Examples 649-650 Examples 649-650 can be prepared essentially as described in Example 648 using 3-tert-jutoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-127-benzo [d ] azepine and the alkyl chloride appropriately substituted. The total yields and EM data (ER +) are shown in the Table below.

Example 651 Succinate of 7-chloro-6- [3- (3, 3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl) -propylthio] -2,3,4,5-tetrahydro- líT-benzo [d] azepine Potassium hydroxide (170 mg, 3.03 mmol) is added in one portion to a solution of 3-tert -butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-li? -benzo [d] azepine (187 mg, 0.49 mmol) in methanol (10 mL). The reaction is heated to reflux under nitrogen overnight. Then add additional portion of KOH (867 mg, 15.45 mmol) and heat to reflux for 3 h. Then it is cooled to room temperature and 1- (3-bromo-propyl) -1,3-dihydro-3, 3-dimethyl-indole-2-one (274 mg, 0.97 mmol, prepared following the procedure described in US Pat. Perkin 1 2000, 769-774). The reaction is stirred at room temperature overnight. The solvents are removed in vacuo, water is added and extracted with diethyl ether (2 x 50 mL). The organic extracts are combined, washed with water (2 x 50 mL) and brine (50 mL). Dry over MgSO 4 and concentrate in vacuo. Purify by chromatography on silica gel by levigating with isohexane / EtOAc (gradient 1: 0 to 1: 1 for 40 min) to give 3-tert-jutoxycarbonyl-7-chloro-6- [3- (3, 3-dimethyl- 2-oxo-2,3-dihydro-indol-1-yl) -propylthio] -2,3,4,5-tetrahydro-li? -benzo [d] azepine as a colorless oil (330 mg), contaminated 50% with l- (3-methoxypropyl) -1,3-dihydro-3, 3-dimethyl-indol-2-one. MS (ER +) m / z: 537 (M + Na) +. Dissolve 3-tert-butoxycarbonyl-7-chloro-6- [3- (3, 3-dimethyl-2-oxo-2, 3-dihydro-indol-l-yl) -propylthio] -2,3,4,5-tetrahydro-lH-benzo [d] azepine (240 mg, 0.52 mmol) in dichloromethane (10 mL), then TFA is added (1 mL) dropwise and stir at room temperature overnight. The solvents are removed in vacuo to give a straw colored oil (580 mg), then the free base using an SCX column, levigating with 7M ammonia in methanol. Concentrate in vacuo, then use a method similar to General Procedure 2-1 and dry by freezing to give the title compound as a solid (196 mg, 82%). MS (ER +) m / z: 415 (M + H) +.

Examples 652-654 Examples 652-654 can be prepared essentially as described in Example 651 using 3-tert-jutoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-1,2-benzo [ d] azepine and the appropriate alkyl bromide. Examples 655-657 can be prepared essentially as described in Example 651 using the appropriate alkyl chloride. The total yields and EM data (ER +) are shown in the Table below.

Example 658 Succinate of 7-chloro-6- [3- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylthio] -2,3,4,5-tetrahydro-127-benzo [d] azepine Potassium hydroxide (933 mg, 16.6 mmol) is added in one portion to a solution of 3-ter- £ > Utoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-12? -benzo [d] azepine (200 mg, 0.52 mmol) in methanol (10 mL). The reaction is heated to reflux under nitrogen for 4 h. Then it is cooled to room temperature and 1- (3-bromo-propyl) -3-isopropenyl-1,3-dihydro-benzoimidazol-2-one (142 mg, 0.52 mmol) is added. The reaction is stirred at room temperature overnight. The solvents are removed in vacuo, extracted into diethyl ether (2 x 50 mL), washed with water (2 x 50 mL) and brine (50 mL). Dry over MgSO 4, filter and concentrate in vacuo to give 3-tert-jutoxycarbonyl-7-chloro-6- [3- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylthio] - 2,3,4,5-tetrahydro-127-benzo [d] azepine as an oil (209 mg, 76%). MS (ER +) m / z: 550 (M + Na) +. Dissolve 3-tert-jutoxycarbonyl-7-chloro-6- [3- (2-oxo-2,3-dihydro-benzoimidazol-1-yl) -propylthio] -2, 3,4,5-tetrahydro-127- benzo [d] azepine (209 mg, 0.396 mmol) in dichloromethane (10 mL), then add TFA (0.5 mL) dropwise and stir at room temperature overnight. The solvents are removed in vacuo then the free base using an SCX column, levigating with 7M ammonia in methanol. Concentrate in vacuo, then use a method similar to General Procedure 2-1 and freeze dry to give the title compound as a solid (140 mg, 70%). MS (ER +) m / z: 388 (M + H) +.

Example 659 Succinate of 7-chloro-6- [3- (3,3-dimethyl-2-oxo-2,3-dihydro-litho-indol-5-yl) -propylthio] -2,3,4, 5- tetrahydro-li-benzo [d] azepine Under a nitrogen atmosphere, potassium hydroxide (138 mg, 2.46 mmol) is added to a stirred solution of 3-tert-jutoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lif-benzo [ d] azepine (375 mg, 0.97 mmol) in methanol (10 mL). Heat under reflux for 2 h then add additional potassium hydroxide (159 mg, 2.83 mmol) and continue heating under reflux for another 6 h. The reaction mixture is cooled and a solution of 5- (3-chloropropyl) -3,3-dimethyl-1,3-dihydro-indol-2-one (245 mg, 1.03 mmol) is added dropwise via cannula. ) in methanol (10 mL). It is stirred at room temperature overnight then heated at 50 ° C for 5 h. Potassium iodide (186 mg, 1.12 mmol) is added to the reaction mixture and then heated under reflux for 5 h. Concentrate in vacuo and partition the residue between water (100 mL) and EtOAc (50 mL). The aqueous phase is extracted with EtOAc (2 x 50 mL). The combined extracts are washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to obtain the crude mixture as a yellow oil. This oil is diluted with dichloromethane then reconcentrated in vacuo and repeated until a solid remains. The solid is dried in a vacuum oven to give 3-tert-jutoxycarbonyl-7-chloro-6- [3- (3, 3-dimethyl-2-oxo-2,3-dihydro-12-indol-5- il) -propylthio] -2,3,4,5-tetrahydro-127-benzo [d] azepine as a yellow solid (481 mg) which was used without further purification. MS (ER +) m / z: 537 (M + Na) +. Trifluoroacetic acid (0.2 mL, 2.6 mmol) is added to a solution of 3-tert- £ > Utoxycarbonyl-7-chloro-6- [3- (3, 3-dimethyl-2-oxo-2,3-dihydro-127-indol-5-yl) -propylthio] -2,3,4,5-tetrahydro- 127-Benzo [d] azepine (257 mg, 0.5 mmol) in dichloromethane (5 mL) was then stirred at room temperature over the weekend. Concentrate in vacuo. The residue is dissolved in methanol and loaded onto an SCX column.

Levigate with methanol followed by 7M ammonia in methanol. The basic fraction is collected and concentrated in vacuo. The residue was purified by preparative LCMS [Supelco Discovery C18 column (21.2 x 100 mm, 5 μm packed), 25 mL / min flow ratio, levigating with a water / acetonitrile gradient containing acetic acid as a modifier for 12 min, fraction collection activated by EM Elecorcio] to give 7-chloro-6- [3- (3, 3-dimethyl-2-oxo-2,3-dihydro-12? -indol-5-yl) -propylthio] -2, 3, 4,5-tetrahydro-127-benzo [d] azepine as a white solid (101 mg, 25% over 2 steps). MS (ER +) m / z: 415 (M + H) +. Dissolve 7-chloro-6- [3- (3, 3-dimethyl-2-oxo-2,3-dihydro-l2? -indol-5-yl) -propylthio] -2, 3, 4, 5-tetrahydro -127-benzo [d] azepine (101 mg, 0.24 mmol) in a mixture of diethyl ether (3 mL) and methanol (2 mL). Succinic acid is added (28.7 mg, 0.24 mmol) and the resulting suspension allowed to stir at room temperature for 2 h. Concentrate in vacuo and dry the residue in a vacuum oven to provide the title compound as a white solid. MS (ER +) m / z: 415 (M + H) +.

Example 660 7-Chloro-6- (N-phenylcarbamoyl-methylthio) -2, 3, 4, 5-tetrahydro-12T-benzo [d] azepine Succinate Potassium hydroxide (890 mg, 15 mmol) is added in one portion to a solution of 3-terthoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lH-benzo [d] azepine (180 mg, 0.47 mmol) in methanol (10 mL). The reaction is heated to reflux under nitrogen for 3 h. Then it is cooled to room temperature, 2-chloro-2V-phenyl-acetamide (79 mg, 0.47 mmol) is added and the mixture is stirred overnight. The solvents are removed in vacuo, extracted in diethyl ether (2 x 50 mL), washed with water (2 x 50 mL) and brine (50 mL). Dry over MgSO4, filter and concentrate in vacuo to give 3-tert.-utoxycarbonyl-7-chloro-6- (N-phenylcarbamoyl-methylthio) -2, 3, 4, 5-tetrahydro-1,2-benzo [d ] azepine as a clear oil (210 mg, 100%). MS (ER +) m / z 460 (M + Na) +. 3-tert-butoxycarbonyl-7-chloro-6 is dissolved. { N-Phenylcarbamoyl-methylthio) -2,3,4,5-tetrahydro-12? -benzo [d] azepine (210 mg, 0.47 mmol) in dichloromethane (10 mL) then add TFA (0.5 mL) dropwise and it is stirred at room temperature for 3 days. The solvents are removed in vacuo then the free base using an SCX column, levigating with 7M ammonia in methanol. Concentrate in vacuo, then use a method similar to General Procedure 2-1 and freeze dry to give the title compound as a solid (150 mg, 69%). MS (ER +) m / z: 347 (M + H) +.

Example 661 7-Chloro-6- (3-methylcarbamoyl-propylthio) -2, 3, 4, 5-tetrahydro-127-benzo [d] azepine Succinate 3-tert-butoxysarbonyl-7-sloro-6- (3-sarboxi-propylthio) -2,3,4,5-tetrahydro-lff-benzo [d] azepine: Potassium hydroxide (700 mg, 12.5 mmol ) in one portion to a solution of 3-tert.-utoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-li? -benzo [d] azepine (150 mg, 0.39 mmol) in methanol ( 10 mL). The reaction is heated to reflux under nitrogen for 4 h. Then it is cooled to room temperature, 4-bromo-butyric acid (65 mg, 0.39 mmol) is added and stirred for 3 days. The solvents are removed in vacuo, neutralized with ammonium chloride (200 mL) and extracted in EtOAc (2 x 50 mL). Dry over MgSO4, filter and concentrate in vacuo to give a clear oil (125 mg). Dissolve the oil in anhydrous DMF (10 mL) and add sodium hydride (30 mg, 0.78 mmol of 60% dispersion in oil) under nitrogen. Stir for 30 min. 4-Bromo-butyric acid (65 mg, 0.39 mmol) is added and stirred for 30 min. It is poured into water (50 mL) and extracted with diethyl ether (2 x 50 L). The combined organic extracts are washed with brine (50 mL) and dried over MgSO4. The filtrate is concentrated in vacuo to give the desired intermediate as a solid (146 mg, 94%). MS (ER +) m / z: 398 (M + H) +. 3-ter-.butoxyarbonyl-7-sloro-6- (3-methylsarbamoyl-propylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: 0-benzotrixol tetrafluoroborate is added -yl-N, N, N ', Nr-tetramethyluronium (123 mg, 0383 mmol) in portions to a solution of 3-tert-butoxycarbonyl-7-chloro-6- (3-carboxy-propylthio) -2, 3, 4,5-tetrahydro-127-benzo [d] azepine (146 mg, 0365 mmol) and methylamine (182 μL, 0.365 mmol) in anhydrous DMF (5 mL) under nitrogen at 0 ° C. It is stirred for 15 min then diisopropylethylamine (127 μL, 0.73 mmol) is added in anhydrous DMF (1 mL) and it is continued until it is stirred at 0 ° C for 1 h. Warm to room temperature and continue until shaken overnight. It is poured into water (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts are washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). Dry over MgSO4, filter and concentrate in vacuo to give a pale yellow oil (74 mg). MS (ER +) m / z: 398 (M + H) +. Purify using mass-guided reverse phase HPLC [Supelco Discovery C18 column (21.2 x 100 mm, packed 5μm), 25 mL / min flow ratio, levigating with water / acetonitrile / acetic acid gradient for 12 min, collection of activated fraction by EM Electrorocium]. Concentrate in vacuo to give the desired intermediate as a colorless oil (30 mg, 20%). MS (ER +) m / z 435 (M + Na) +.

Sussinate of 7-sloro-6- (3-methylsarbamoyl-propylthio) -2,3,4,5-tetrahydro-lff-benzo [d] azepine: 3-tert-butoxycarbonyl-7-chloro-6- (3) is dissolved -methylcarbamoyl-propylthio) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine (30 mg, 0.07 mmol) in dichloromethane (10 mL) then add TFA (0.5 mL) dropwise and Stir at room temperature for 3 days. The solvents are removed in vacuo then the free base using an SCX column, levigating with 7M ammonia in methanol. Concentrate in vacuo, then use a method similar to General Procedure 2-1 and dry by freezing to give the title compound as a solid (21 mg, 72%). MS (ER +) m / z: 313 (M + H) +.

Example 662 Succinate of 7-chloro-6- (1-cyano-l-methyl-ethylthio) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine 3-ter-l > utoxysarbonyl-7-aloro-6- (1-sianedithio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Potassium hydroxide (10.8 g, 192 mmol) is added to a solution of 3-tert.-utoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-l-t-benzo [d] azepine (3 g, 7.8 mmol) in degassed methanol (150 mL) under a nitrogen atmosphere . The mixture is heated at 80 ° C for 6 h. The mixture is cooled to room temperature, then concentrated in vacuo to an oil. The oil is dissolved in EtOAc (50 mL), washed with saturated aqueous ammonium chloride (30 mL). The organic layer is separated and the aqueous layer is extracted with EtOAc (3 x 50 mL). Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo to an oil (2.4 g). The oil is dissolved in anhydrous DMF (50 mL). Slowly add sodium hydride (470 mg, 11.7 mmol) in portions over 5 min followed by 2-bromopropionitrile (1 mL, 11.7 mmol). The mixture is stirred under nitrogen at room temperature for 16 h. The mixture is diluted slowly with EtOAc (100 mL) and washed with cold aqueous saturated ammonium chloride (50 mL). The organic layer is separated and the aqueous layer is extracted with EtOAc (3 x 50 mL). The organic extracts are combined and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 3: 1 gradient) to obtain the desired intermediate (2.5 g, 89%). MS (ER +) m / z: 267.2 (M-Boc) +. 3-tert-butoxyarbonyl-7-aloro-6- (1-sia-l-methyl-ethylthio) -2,3,4,5-tetrahydro-lH-benzo [d] azepine: Slowly add a solution of 3- tert-butoxycarbonyl-7-chloro-6- (1-cyano-ethylthio) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine (2.5 g, 6.8 mmol) in anhydrous THF (20 mL) to a paste of sodium hydride (1.4 g, 34 mmol) in anhydrous THF (50 mL) at 0 ° C under a nitrogen atmosphere. The paste is stirred for 5 min, then iodomethane (12.7 mL, 204 mmol) is added to the pulp while maintaining the temperature below 30 ° C. The mixture is stirred for 3 h at room temperature then quenched with methanol (10 mL) and concentrated in vacuo. The crude mixture was purified by chromatography on silica gel by levigating with hexane / EtOAc (19: 1 to 9: 1 gradient) to obtain the desired intermediate (2 g, 79%). MS (ER +) m / z: 281.2 (M + H-Boc). 7-Sloro-6- (1-sia-l-methyl-ethylthio) -2,3,4,5-tetrahydro-lff-benzo [d] azepine Sussinate: A method similar to General Procedure 1-5 is used for deprotect 3-tert-jutoxycarbonyl-7-chloro-6- (1-cyano-1-methyl-ethylthio) -2,3,4,5-tetrahydro-12β-benzo [d] azepine (1.4 g, 3.5 mmol) . Purify by chromatography on silica gel by levigating with dichloromethane / 2M ammonia in methanol (99: 1 to 90:10 gradient) to give the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (992 mg, 71%). MS (ER +) m / z: 281.2 (M + H) +.

Example 663 7-Chloro-6- (1-cyano-cyclopropylthio) -2, 3, 4, 5-tetrahydro-12β-benzo [d] azepine Succinate Potassium hydroxide (5.4 g, 96.2 mmol) is added to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2, 3,4,5-tetrahydro-lff-benzo [d] azepine. (1.5 g, 4.7 mmol) in degassed methanol (75 mL) under a nitrogen atmosphere. The mixture is heated at 80 ° C for 6 h. The mixture is cooled to room temperature, then concentrated in vacuo to an oil. Dissolve the oil in EtOAc (50 mL) and wash with saturated aqueous ammonium chloride (30 mL). The organic layer is separated and the aqueous layer is extracted with EtOAc (3 x 50 mL). The combined organic extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo to an oil (1.4 g). Dissolve the oil in anhydrous DMF (25 mL), then slowly add sodium hydride (282 mg, 7.1 mmol) and bromoacetonitrile (470 μL, 7.1 mmol). The mixture is stirred under nitrogen at room temperature for 16 h. The mixture is diluted slowly with EtOAc (100 mL) and washed with cold aqueous saturated ammonium chloride. { 40 mL). The organic layer is separated and the aqueous layer is extracted with EtOAc (3 x 50 mL). The organic extracts are combined and concentrated in vacuo. The residue is purified by chromatography on silica gel by levigating with hexane / EtOAc (9: 1 to 7: 3 gradient) to obtain 3-tert.-utoxycarbonyl-7-chloro-6- (1-cyano-methylthio) -2, 3 , 4,5-tetrahydro-1,2-benzo [d] azepine (1.34 g, 81%). MS (ER +) m / z: 253.2 (M-Boc) +. Sodium bis (trimethylsilyl) amide (5.4 mL, 5.4 mmol, 1M solution in THF) is added at room temperature under nitrogen to a solution of 3-tert- £ > utoxycarbonyl-7-chloro-6- (1-cyano-methylthio) -2, 3, 4, 5-tetrahydro-li? -benzo [d] azepine (380 mg, 1.1 mmol) in anhydrous toluene (4 mL). The solution is stirred for 10 min, then 1,2-dibromoethane is quickly added (2.8 mL, 32.4 mmol) followed by anhydrous DMF (4 mL). An exothermic reaction was observed and the reaction temperature increased to 38 ° C. The mixture is stirred for 15 min at room temperature, then quenched with methanol (2 L). Concentrate in vacuo and purify by silica gel chromatography by levigating with hexane / EtOAc (9: 1) to obtain 3-tert-jutoxycarbonyl-7-chloro-6- (1-cyano-cyclopropylthio) -2, 3.4 , 5-tetrahydro-li? -benzo [d] azepine (259 mg). A method similar to General Procedure 1-5 is used to deprotect 3-tert-utoxycarbonyl-7-chloro-6- (1-cyano-cyclopropylthio) -2,3,4,5-tetrahydro-li? -benzo [d] azepine. Purify by reverse phase chromatography [Column: Symmetry C18, 19 x 300 mm, flow ratio 30 mL / min, levigating with water with 0.1% TFA / acetonitrile (gradient 19: 1 to 1: 1)] followed by SCX chromatography to obtain the free base of the title compound. A method similar to General Procedure 2-1 is used to obtain the title compound (120 mg, 28% yield over 3 steps). MS (ER +) m / z: 279.2 (M + H) +.

Example 664 Succinate of 6- (4-ter-benzoyl-benzylthio) -7-chloro-9-fluoro-2,3,4,5-tetrahydro-1,2-benzo [d] azepine A method similar to Example 456 is used to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-9-fluoro-2,3,4,5-tetrahydro-12β-benzo [d] azepine with 4-chloromethyl -N- (tert-Jbutyl) -benzamide. Methods similar to General Methods 1-5 and 2-1 are used to give the title compound as a white solid. MS (ER +) m / z: 421 (M + H) +.

Example 665 Succinate of 7-chloro-6- [4- (3, 3-dimethylbutyryl) -benzylthio] -9-fluoro-2,3,4,5-tetrahydro-lH-benzo [d] azepine A method similar to Example 435 is used to react 3-tert-utoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-9-fluoro-2,3,4,5-tetrahydro-12β-benzo [d] azepine with l- ( 4-bromomethylphenyl) -3,3-dimethylbutan-1-one. Methods similar to General Procedures 1-5 and 2-2 are used to give the title compound as a white solid. MS (ER +) m / z: 420 (M + H) +.

Preparation 346 4- (2, 2-Dimethyl-propane-1-sulfonyl) -benzylamine 1- (2, 2-Dimethyl-propylthio) -4-methyl-bensen: 4-Methyl-benzenethiol (1.5 g, 12.08 mmol) is dissolved in anhydrous DMF (6 mL).

The solution is cooled to 0 ° C, sodium hydride (435 mg, 17.21 mmol, 95%) is added and the mixture is stirred under a nitrogen atmosphere for 15 min. L-iodo-2, 2-dimethylpropane is added (1.93 mL, 14.5 mmol), the mixture is stirred for 1 h at 0 ° C, warmed to room temperature and stirred overnight. Water is added and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are washed twice with ice water, dried over NaSO4, filtered and concentrated in vacuo to give the desired intermediate (1.476 g, 63% yield). 1- (2, 2-Dimethyl-propane-l-sulfonyl) -4-methyl-bensen: 1- (2,2-dimethyl-propylthio) -4-methyl-benzene (1476 g, 7. 6 mmol) in trifluoroacetic acid (9.5 mL). Hydrogen peroxide (9.9 mL, 30% in water) is added dropwise. The mixture is cooled to 0 ° C and stirred 15 min at this temperature and 45 min at room temperature. The mixture is concentrated in vacuo, diluted with saturated aqueous NaHCO3 and the aqueous phase extracted twice with EtOAc. Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo to give the desired intermediate (1548 g, 90%). l-Bromomethyl-4- (2, 2-dimethyl-propane-l-sulfonyl) -bensen: A method similar to Preparation 213 (Step 2) is used, using 1- (2,2-dimethyl-propane-l- sulfonyl) -4-methyl-benzene (560 mg, 2.47 mmol) to give the desired intermediate.

N- (di-tert-butoxycarbonyl) -4- (2,2-dimethyl-propane-l-sulfonyl) -benzylamine: Sodium hydride (60 mg, 2.39 mmol) is added to a solution of di-tert-butyl -iminodicarboxylate (519 mg, 2.39 mmol) in anhydrous DMF (2mL) at room temperature under nitrogen and stirred for 15 min. Then a solution of l-bromomethyl-4- (2,2-dimethyl-propane-l-sulfonyl) -benzene (731 mg, 2.39 mmol) in anhydrous DMF (3 mL) is added and stirred for 1.5 h. Water is added and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are washed with ice water. Dry the organic layer over Na 2 SO 4, filter and concentrate in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc (88:12) to obtain the desired intermediate (460 mg, 44% over 2 steps) 4- (2,2-Dimethyl-propane-1-sulfonyl) -bensylamine: 4N hydrogen chloride in dioxane (2 mL) is added to a solution of N- (di- e -butoxycarbonyl) -4- (2.2 -dimethyl-propane-1-sulfonyl) -benzylamine (460 mg, 1.04 mmol) in dichloromethane (20 mL) and stirred overnight. Concentrate in vacuo, suspend the solid obtained in EtOAc, add saturated aqueous NaHCO 3 and stir until both phases are cleaned. The aqueous phase is extracted three times with dichloromethane EtOAc. Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo to obtain the title compound as an oil that was used without any further purification (166 mg, 71% yield). MS (ER +) m / z: 242 (M + H) +. The compounds of Preparations 347-348 can be prepared essentially as described in Preparation 346 using l-iodo-3,3,3-trifluoropropane (Preparation 347) or 1,1-trifluoro-3-iodobutane (Preparation 348). ). EM data (ER +) are shown in the Table below.

Preparation 349 4- (2-Methyl-propane-2-sulfonylmethyl) -benzylamine 4-tert-Butylthio-ethyl-benzonitrile: Sodium hydride (359 mg) is added, 14.21 mmol) was added to a solution of 2-methyl-2-propanethiol (900 mg, 9.98 mmol) in anhydrous DMF (15 mL) under nitrogen. The mixture is stirred for 15 min, 4-bromomethyl-benzonitrile (2348 g, 11.97 mmol) is added and the resulting mixture is stirred overnight at room temperature. Water is added and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are washed twice with ice water, dried over Na 2 SO, filtered and concentrated in vacuo. Purify by chromatography on silica gel by levigating with hexane / EtOAc 92: 8 to give the desired intermediate (1.42 g, 69% yield). 4- (2-Methyl-propane-2-sulfonylmethyl) -benzonitrile: 4-tert-Butylthiomethyl-benzonitrile (1.42 g, 6.9 mmol) is dissolved in trifluoroacetic acid (9 mL). Hydrogen peroxide (9 mL, 30% in water) is added dropwise. The mixture is cooled to 0 ° C and stirred 15 min at this temperature and 45 min at room temperature. The mixture is concentrated in vacuo, diluted with saturated aqueous NaHCO3 and the aqueous phase extracted twice with EtOAc. Dry the combined organic extracts over Na 2 SO 4, filter and concentrate in vacuo to give the desired intermediate (1.46 g, 89%). 4- (2-Methyl-propane-2-sulfonylmethyl) -bensylamine: 4- (2-Methyl-propane-2-sulfonylmethyl) -benzonitrile (300 mg, 1.26 mmol) is dissolved in methanol (50 mL). Concentrated HCl (10 drops), 10% Pd / C (type Degussa ElOl, 60 mg) are added and the mixture is exposed to hydrogenation at atmospheric pressure for 1 h. Filter over Celite® and wash with methanol. The filtrate is concentrated in vacuo to give the hydrochloride salt of the title compound as a solid which was washed with diethyl ether (366 mg, 87%). The solid is partitioned between saturated NaHCO 3 and EtOAc and the aqueous phase is extracted twice with EtOAc. Dry the combined organic extracts over Na 2 SO, filter and concentrate in vacuo to give the title compound (195 mg, 74%). MS (ER +) m / z: 242 (M + H) +.

The Compound of Preparation 350 can be prepared essentially as described in Preparation 349 using 4- (2-bromo-ethyl) -benzonitrile. EM data (ER +) are shown in the Table below.

Preparation 351 3-Aminomethyl-6- (2-cyclohexyl-ethyl) -pyridine 6-Cislohexiletinil-nisotinonitrile: Cyclohexylacetylene (1.54 mL, 11.6 mmol), dichlorobis (triphenylphosphine) palladium (200 mg, 0.28 mmol), copper iodide (100 mg, 0.53 mmol), and triethylamine (2.0 mL, 14.3 mmol) are added. to a solution of 6-chloronicotinonitrile (1.38 g, 9.9 mmol) in DMF (4 mL). The mixture is heated in a sealed flask for 3 h at 100 ° C. The mixture is cooled to room temperature, diluted with 1: 1 hexane / EtOAc (100 mL) and washed with a 10% aqueous sodium chloride solution (3 x 30 mL). The organic layer is collected, concentrated in vacuo, and the residue purified by chromatography on silica gel (90 g silica, hexane / EtOAc 95/5 to 85/15 gradient) to obtain the desired intermediate (1.75 g, 83% ) 3-tert-Jbutoxisarbonyl-aminomethyl-6- (2-sislohexyl-ethyl) -pyridine: 6-Cyclohexylethynyl-nicotinonitrile (1.75 g, 8.3 mmol), 10% Pd / C (Degussa ElOl type, 50% water by weight) is added ) (1.0 g), methanol (100 mL), and di-t-butyl dicarbonate (2.3 g, 10.4 mmol) were added to a pressure vessel under a nitrogen atmosphere. The vessel is pressurized at 30 psi (2,109 kg / cm 2) with hydrogen, and the mixture is stirred for 3 h (reaction by CCD is observed). The vessel is purged with nitrogen, the mixture is filtered through Celite® and the cake is washed with dichloromethane under a nitrogen atmosphere.

The filtrate is concentrated in vacuo. The residue is purified by chromatography on silica gel (90 g silica, hexane / EtOAc, 95/5 to 50/50 gradient) to obtain the desired intermediate (1.05 mg, 40%). MS (ER +) m / z: 319.2 (M + H) +. 3-Aminomethyl-6- (2-sislohexyl-ethyl) -pyridine: Trifluoroacetic acid (2.0 mL) is added to a solution of 3-tert-butoxycarbonyl-aminomethyl-6- (2-cyclohexyl-ethyl) -pyridine. (1.05 g, 3.3 mmol) in methanol (20 mL). The solution is stirred for 1 h at room temperature under a nitrogen atmosphere. The solution is concentrated in vacuo and the residue is purified by means of SCX chromatography to obtain the desired intermediate (670 mg, 93%). EM (ER +) m / z: 219.2 (M + H) +.

Preparation 352 2-Aminomethyl-5- (2-cyclohexyl-ethyl) -pyridine The title compound can be prepared essentially as described in Preparation 351 by using 5-chloro-pyridine-2-carbonitrile (24% yield, MS (ES) m / z 219.2 (M + H) +.

Example 666 (i) - 7-Chloro-6- [4- (2, 2-dimethyl-propane-1-sulfonyl) -benzylamino] -2,3,4,5-tetrahydro-l-benzo [d] -Tartrate azepine A method similar to General Procedure 5-2 is used to couple 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-1-benzo [d] azepine (158 mg, 0.37 mmol) with 4- (2,2-dimethyl-propane-1-sulfonyl) -benzylamine (166 mg, 0.73 mmol) when using tris (dibenzylideneacetone) dipalladium (0) (68 mg, 0.074 mmol), BINAP (92 mg, 0.148 mmol) and cesium carbonate (169 mg, 0.518 mmol) in anhydrous toluene (15 mL). Purify by chromatography on silica gel by levigating with hexane / EtOAc (8: 2) and then by inverse HPLC [Zorbax Bonus RP, 5 DM 21.2 x 100 mm, levigating with water / acetonitrile (TFA 0.05% in each), detector UV (230 nm)] to give 7-chloro-6- [4- (2, 2-dimethyl-propane-1-sulfonyl) -benzylamino] -3- (2,2,2-trifluoroacetyl) -2.3, 4,5-tetrahydro-12? -benzo [d] azepine as an oil (153 mg, 80%). MS (ER +) m / z: 517 (M + H) +.

Methods similar to General Methods 1-2 and 2-6 are used to give the title compound as a white solid. MS (ER +) m / z: 421 (M + H) +. Examples 667-672 can be prepared essentially as described in Example 666 using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-li-benzo [d] azepine and the appropriate amine. Examples 673-674 can be prepared essentially as described in Example 666 using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-12? - benzo [d] azepine and the appropriate amine but the succinate salt was prepared as described in General Procedure 2-1. EM data (ER +) are shown in the Table below. 672 (L) -Tartrate of 7-403 (M + H) + chloro-6- [4- (t-butylthioethyl-benzylamino] -2,3,4,5-tetrahydro-li? -benzo [d] azepine 673 Succinate of 7-chloro-6-416 (M + H) + [(6-cycloheptylthio-pyridin-3-ylmethyl) -amino] -2,3,4,5-tetrahydro-l-benzo [d] azepine 674 Succinate of 7-chloro-6- 447 (M + H) + [4- (3,3,3-o? Ls F-trifluoropropane-1-sulfonyl) -benzylamino] - at UOH 2, 3, 4, 5- tetrahydro-lJÍ-benzo [d] azepine Examples 675-676 can be prepared essentially as described in Example 604 using 7-chloro-3- (2,2,2-trifluoroacetyl) -6-trifluoromethanesulfonyloxy-2, 3,4,5-tetrahydro-127-benzo [d] azepine and the appropriate amine but the (L) -tartrate salt was prepared as described in General Procedure 2-6. The EM (ER +) data are shown in the Table below.

Examples 677-684 can be prepared essentially as described in Example 563 by using 3-tert-butoxycarbonyl-6- (4-carboxy-3-fluoro-benzylamino) -7-chloro-2, 3, 4,5- tetrahydro-lH-benzo [d] azepine and the appropriate amine. Examples 685-689 can be prepared essentially as described in Example 563 by using 3-tert -butoxycarbonyl-6- (4-carboxy-benzylamino) -7-chloro-2,3,4,5-tetrahydro-yl- benzo [d] azepine and the appropriate amine. The EM (ER +) data are shown in the Table below. 3-fluoro-benzylamino] -2,3,4,5-tetrahydro-li? -Xo benzo [d] azepine 681 Succinate of 7-chloro-6- 418 [4- (3-pentylcarbamoyl) - (M + H) + 3-fluoro-benzylamino] -2,3,4,5-tetrahydro-li? -benzo [d] azepine 682 Succinate of 7-chloro-6- 432 [4- (4-methyl-2- (M + H. +. + Pentylcarbamoyl) -3-fluoro-benzylamino] -2,3,4,5-tetrahydro-li? - benzo [d] azepine 683 7-Chloro-6- 418 succinate [4- (3-methyl-2- (M + H) + butylcarbamoyl) -3-fluoro-benzylamino] - 2, 3, 4, 5- tetrahydro-lJ? -benzo [d] azepine 84 7-Chloro-6- 376 [4- (ethylcarbamoyl) -3- (M + H) + fluoro-benzylamino] -2,3,4,5-tetrahydro-succinate 12? - The compounds of the present invention are relatively selective for the 5-HT2c receptor. The compounds of the present invention are particularly selective for the 5-HT2c receptor compared to the other 5-HT receptor subtypes and specifically the 5-HT2a and 5-HT2B receptors. This selectivity is demonstrated in the following assays of agonist activity and receptor binding assays.

Assays of Agonist Astivity (G alpha q-GTP? [35S] Enlase assays) 5-HT2 receptors are functionally coupled to specific G proteins. The agonist activation of receptors coupled to the G protein 5-HT2 result in the ratio of GDP from the subunit to (G alpha q or G alpha i) of the G protein and the subsequent binding of GTP. The binding of the stable analog GTP? [35S] is an indicator of receptor activation (this is, agonist activity). The G-alpha q-GTP [35S] binding assay is used to determine the in vitro potency (EC5o) and maximum efficacy (Emax, normalized to the 5-HT response) of a test compound at the 5-HT2A receptors, 5-HT2B, and 5-HT2c. The area under the dose response curve (AUC) is also determined for each receptor subtype and is used to measure the selectivity of test compounds for the 5-HTc receptor on the 5-HT2a and 5-HT2B receptors, expressed as selectivity ratios (AUC 2C / 2A and AÜC 2C / 2B, respectively). The Selectivity relationships allow the evaluation of selectivity based on both power and efficiency. A measure of selectivity that incorporates both potency and efficacy at the 5-HT2c receptor, when compared to the 5-HT2a and 5-HT2B receptors, is considered important due to the adverse events associated with 5-HT2α agonist activity. and 5-HT2B (see introduction). Preparation of membranes; Stable AV12 cells transfected with the human 5-HT2a, 5-HT2B or 5-HT2c receptors are grown in suspension, harvested by centrifugation, the cell pellet is washed with phosphate buffered saline, pH 7.4, the cells are pelleted again, the supernatant is removed, the cell pelletization is frozen in dry ice and stored at -70 ° C. The pelletizing of reserve cells is thawed and resuspended in 50 mM Tris, pH 7.4, aliquots are formed in 1-2 mL volumes and refreezing at -70 ° C for subsequent tests. (As appreciated in the art, optimal amounts of the cell used per aliquot will vary with the individual transfected cell line used.) In one embodiment, the transfected 5-HT2a and 5-HT2c cells are typically used in about 6 x 108 cells per aliquot, while 5-HT2B cells are typically used in about 7.5 x 108 cells per aliquot). On the day of the assay, the membranes are thawed, the membranes are washed with assay buffer (50 mM Tris-HCl (pH 7.4), 10 mM MgCl2, 100 mM NaCl, and 0.2 mM EDTA), resuspended in solution buffer assay and incubate for 10 minutes at 37 ° C to hydrolyze any residual endogenous 5-HT. The membranes are again washed with assay buffer and resuspended in assay buffer at a concentration to provide aliquots of about 1-4x106 equivalent cells per well (typically about 1-2x106 equivalents of cells for assays with HT2a or 5-HT2c receptor assays and about 3-4x106 cell equivalents for assays with 5-HT2B receptor assays). The cells are homogenized with a tissue mill and the homogenate is used directly in the assay as described below. G-alpha q-GTP binding assays [35S]: The immunoadsorption scintillation proximity assay (ISPA) of the [35S] -GTP? S to G alpha binding is modified from published conditions (DeLapp et al, JPET 289 (1999) 946-955). The test compounds are dissolved in DMSO and diluted in assay buffer to provide a range of concentrations to generate a concentration response curve. In the wells of a 96-well microtiter plate, the diluted test compound, GDP (0.1 μM final concentration), and [35 S] -GTPγS (between 0.5 and 0.1 nM final concentration) are mixed. An aliquot of membrane is added to the incubation mixture and the plates are mixed to initiate stimulation of the nucleotide exchange agonist (final volume of 200 μl). The microtiter plates are incubated for 30 min. At room temperature. The incubation with IGEPAL® CA-630 detergent (0.27% final concentration) is switched off. The affinity-purified polyclonal rabbit anti-G alpha antibody (about 1-2 μg per well) is added, and the anti-rabbit Ig scintillation proximity test beads (Amersham, about 1.25 mg per well, 300 μl final volume). The plates are sealed and the mixture is incubated for 3 hours at room temperature. The microtiter plates are centrifuged briefly to palletize the beads. The binding of (GTP? [35S] is quantified by microtitre plate scintillation spectrometry ((Wallac Trilux MicroBeta ™ scintillation counter) Data Analysis: For each concentration response curve for a test compound to a receptor Given, the data is analyzed with the GraphPad Prism ™ software (v3.02; GraphPad Software, San Diego, CA) running on a personal computer with a Microsoft Windows OS®, by using a non-linear regression analysis curve that is adjusted to determine the EC5o and Emax (normalized to the 5-HT control curves) The area under the agonist concentration response curve (AUC) is determined with GraphPad Prism ™ by the trapezoidal method. Selectivity first, determine the AUC for the test compound for each subtype of the receptor as described above, Second, normalize the AUCs in each subtype of the receptor relative to the AUC determined for 5-HT in that The AUC normalized for a test compound to a given receptor is therefore expressed as a percentage of the AUC determined for 5-HT in that receptor. For example: Normalized AUC of 5HT2a = a = (AUC test compound in 5HT2 & amp; amp; X) 100% (AUC 5-HT in dHTa receptor) Normalized AUC of 5HT2B = a = (AUC test compound in 5E? 2B receptor) X 100% (AUC 5-HT in 5H? 2B receptor) AUC Normalized of 5HT2c = a = (AUC test compound in 5HT2C receptor) X 100 % (AUC 5-HT in 5HT2C receptor) Third, calculate the selectivity ratios for the test compound as follows: Selectivity ratio for the 5-HT2c receptor / 5-HT2a receptor (AUC2C / 2A) = c / a. Selectivity ratio for the 5-HT2c receptor / 5-HT2B receptor (AUC2C / 2B) = c / b. For reference purposes, the AUC 2C / 2A and AUC 2C / 2B for 5-HT are each 1.0. Similarly, the ratios for mCPP (meta-chlorophenylpiperazine) are tested and found to be 2.1 and 2.1 respectively. Representative compounds of the present invention are tested in the G alpha q-GTP? [35 S] assays for the 5-HT 2a, 5-HT 2B, and 5-HT 2c receptors essentially as described above and are found to be selective and highly selective agonists. potentiates of the 5-HT2C receptor with the EC50 typically less than or equal to 200 nM, and the ratios of AUC 2C / 2A and AUC 2C / 2B greater than 1.5. Preferred compounds are those with EC50 less than or equal to 100 nM, and AUC 2C / 2A and AUC 2C / 2B ratios greater than or equal to 2. 0. Those with EC50 less than or equal to 50nM, and ratios of AÜC 2C / 2A and AUC 2C / 2B greater than or equal to 3.0 are more preferred.

Ligand Enlase Assays The binding affinity of the ligand of the compounds of the present invention to the HT2C receptor subtype is measured essentially as described by Wainscott (Wainscott, et al., Journal of Pharmacology and Experimental Therapeutics, 276: 720- 727 (1996)). The data are analyzed by non-linear regression analysis in the response curves to the concentration using the four-parameter logistic equation described by DeLean (DeLean, et al., Molecular Pharmacology, 21, 5-16 (1982)). The IC 50 values are converted to the Ki values using the Cheng-Prusoff equation (Cheng, et al., Biochem. Pharmacol., 22, 3099-3108 (1973)). The representative compounds of the present invention are tested essentially as described above and are found to have an excellent affinity for the 5-HT 2C receptor with K 1. typically less than or equal to about 200 nM. Preferred compounds with those Ki less than or equal to about 100 nM. Those with Ki less than or equal to 50nM are more preferred. The affinities for other receptor subtypes can be easily determined by a light modification of the radioligand receptor binding assay described above using cells transfected with the desired receptor in place of cells transfected with the 5-HT2C receptor subtype and using a suitable radioligand. The binding affinities for the representative compounds of the present invention for a variety of receptors are determined in such assays and the compounds are found to have surprisingly higher affinity for the 5-HT2c receptor. The affinity for the 5-HT2c receptor is found to be significantly higher for other 5-HT receptor subtypes and markedly superior to the 5 HT2a and 5-HT2B receptor subtypes. Preferred compounds are those with an IC5o's equal to or greater than 300 nM for the alpha 1 and alpha2 adrenergic receptors and equal to or greater than 500 nM for the dopaminergic receptors Di and D2. The most preferred compounds are those with IC50 equal to or greater than 1000 nM for the adrenergic receptors alpha 1 and alpha 2 and the dopaminergic receptors Di and D2. Even more preferred are those compounds with IC50 's equal to or greater than 3000 nM for the alpha 1 and alpha 2 adrenergic receptors and the dopamine receptors Di and D2. For previous in vitro tests, the exemplified compounds are tested and found to have either an EC50 or a Ki value equal to or less than 50 nM and having AUC 2C / 2A and AUC 2C / 2B ratios greater than or equal to 2.0. The exemplified compounds are tested and found to have the ICso's of the alpha 1 and alpha 2 adrenergic receptor equal to or greater than 300 nM and the IC5o's of the dopaminergic receptor Da and D2 equal to or greater than 500 nM.

Rat Feeding Assays The ability of the compounds of the present invention to treat obesity is demonstrated by the test in feeding trials with acute and chronic rats. Animals: Long-Evans male rats (Harían Sprague-Dawley, Indianapolis, IN) are obtained that are approximately one hundred days old and have been kept on a high-calorie diet since weaning (fat calories; TD 95217, 40% Teklad , Madison, Wl). The rats are housed individually with a light cycle: 12 hr dark: 12 h (the lights are switched on from 10 p.m. to about 10 p.m.) and the rats are kept on the same diet (TD95217) with free access to water for about 1-2 weeks to acclimatize the rats to the environment. The rats are dosed orally with vehicle (10% acacia with 0.15% saccharin in water) once a day for at least 1 day (typically 1-2 days) to acclimate the rats to the procedures. The rats are randomly selected into groups so that each group has similar average body weights. Acute Calorimetric Feeding Test: At approximately 8:00 on the day of the test, each rat is weighed and transferred to the individual chambers of an open-circuit calorimetry system (Oxymax, Columbus Instruments International Corporation, Columbus, OH) with access free to feed (pre-weighed) and water and start measuring V02 and VC02. At approximately 10:00 h, the rats are dosed orally with the vehicle or test compound, returned to their calorimetry chambers and V02 and VC02 are continued to be measured at regular time intervals (approximately every hour). At approximately 8:00 a.m. the next day, the body weight of the rat and the remaining food are measured, assuming that the difference in weight of the food is equal to the mass of food consumed. The energy expenditure for 24 hours (EE) and the respiratory quotient (RQ) is calculated essentially as described in Chen, Y. and Hei an, M. L., Regulatory Peptide, 92: 113-119 (2000). The EE during the light photoperiod is indicative of the resting metabolic rate and RQ is indicative of the fuel source used by the animal (the pure carbohydrate metabolism gives an RQ of around 1.0, the pure fat metabolism gives an RQ of around 0.7 the metabolism of fat and mixed carbohydrates gives intermediate values for RQ). Calculate EE as the product of calorific value (CV) and V02 per body weight (kg); where CV = 3.815 + 1.232 * RQ, and RQ is the ratio of C02 produced (VC02) to 02 consumed (V02). The caloric intake is calculated as (mass of food intake in 24 hours in grams) x (value of the physiological fuel of the diet in kilocalories / g) per kg of body weight. Acute Feeding Test with a Selective 5-HT2C Receptor Antagonist: The previous acute calorimetric feeding assay is performed with the following modifications. Open circuit calorimetry systems are not used and only the periodic food intake is measured in 24 hours if the body weight. Three groups of rats are used with the first group receiving a subcutaneous dose of saline (0.5 mL) about 15 minutes prior to the oral dose of vehicle the second group receives a subcutaneous dose of saline (0.5mL) about 15 minutes prior to the oral dose of the test compound in the vehicle and the third group receives a subcutaneous injection of a selective receptor antagonist 5-HT2C, 6-chloro-5-methyl-N-. { 2- [(2-methylpyridin-3-yl-oxy) pyridin-5-yl] aminocarbonyl} -2, 3-dihydroindole (3 mg / Kg, in 35% cyclodextrin, 0.5 mL) about 15 minutes prior to the oral dose of the test compound in the vehicle. Chronic Feeding Trial: Between approximately 8:00 am and 10:00 am on day 1 of the trial, each rat is weighed and orally dosed with vehicle or test compound and the animal is returned to its home cage with free access to the food (pre-weighed) and water. For each of the days 2-15, between approximately 8:00 h and 10:00 h, the body weight of the rat and the weight of the food consumed in the last 24-hour period are measured and the oral dose of the test compound or vehicle is administered daily. On days 2 and 15 the total fat mass and the non-fat mass or nuclear magnetic resonance (NMR) are measured using a system at EchoMRI ™ (Echo Medical Systems, Houston Texas). See Frank C. Tinsley, Gersh Z. Taicher, and Mark L. Heiman, "Evaluation of a New Quantitative Magnetic Resonance (QMR) Method for Mouse Whole Body Composition Analysis", Evaluation of a New Quantitative Magnetic Resonance (QMR), Obesity Research, remitted on May 1, 2003). Representative compounds of the present invention are tested in acute and chronic feeding feeding assays essentially as described above. In acute trials, the compounds are found to significantly reduce food intake in 24 hours, whose effect is blocked by pre-administration of the 5-HT2c receptor antagonist. The compounds are also found to reduce the RQ dose dependent without significantly changing the energy expenditure during the light photoperiod. Thus, it is found that the compounds reduce caloric intake and increase the proportion of fuel derived from the use of fat, without significantly changing the metabolic rate at rest. In the chronic trial, the compounds are found to significantly decrease the cumulative dietary intake and the change in cumulative body weight in a dose-dependent manner compared to the control animals. The decrease in body weight is found to be due to the loss of adipose tissue while the non-fat body mass does not change. The ability of the 5-HT2c receptor agonists of the present invention to treat an obsessive / compulsive disorder is demonstrated by testing in a variety of in vivo assays as follows: Test of Canis Osultas (Marble Burying) The marbles hidden in mice have been used to model anxiety disorders that include obsessive compulsive disorders (OCD) due to the ethological study of behavior (for example, Gyertyan I. "Analysis of the marble burying response: Marbles serve to measure digging rather than evoke burying "(Analysis of the hiding response of marbles: Marbles are used to measure the excavation instead of causing concealment), Behavioral Pharmacology 6: 24-31, (1995)), and due to the pharmacological effects of clinical standards (cf, Njung'E K. Handley SL. "Evaluation of marble-burying behavior as a model of anxiety" (Evaluation of marbling concealment behavior as a model of anxiety), Pharmacology, Biochemistry &Behavior 38: 63-67, (1991)); Borsini F., Podhorna J., and Marazziti, D. "Do animal models of anxiety predict anxiolytic effects of antidepressants?" (Do animal models of anxiety predict the anxiolytic effects of antidepressants?) Psychopharmacology 163: 121-141, (2002)). Thus, drugs used in the treatment of generalized anxiety in humans (for example benzodiazepines) as well as the compounds used to treat OCD (for example, SSRIs such as fluoxetine) reduce concealment. NIH Swiss mice experimentally new laboratory mice (Harían Sprague-Dawley, Indianapolis, IN) weighing between 28-35 g in groups of 12, for at least three days prior to the test in a vivarium with 12 cycles of light and darkness. Experiments were performed during the light cycle in an experimental test room with dim light. The mice were dosed with vehicle or the test compound and after a specific pretreatment interval (generally 30 min), each mouse is individually placed in a rotorod (Ugo Basile 7650) operating at a speed of 6 revolutions per minute and watch the fall. After 2 minutes in the rotorod, the mice are placed individually in a high plastic tub of 17 x 28 x 12 cm with sawdust 5 mm on the floor that is covered with 20 blue marbles (1.5 cm diameter) placed in the middle. After 30 minutes, count the number of hidden marbles (covered in 2/3 with sawdust). The effect of the test compound on the hidden marbles is evaluated with Dunnett's test and the effect on rotorod performance by Fisher's exact test. The clinically effective standard compounds suppress the concealment of marbles at doses that are devoid of motor debilitating effects when measured in the rotor. The in vivo efficacy of the 5HT2C compounds at the 5HT2C receptor is confirmed by the prevention of effects of 5HT2c agonists in the occultation of marbles by the co-administration of the 5HT2C 6-chloro-5-methyl-N- receptor antagonist. { 2- [(2-methylpyridin-3-yl-oxy) pyridin-5-yl] aminocarbonyl} -2, 3-dihydroindole. The representative compounds of the present invention are tested in the marbling concealment assay essentially as described and surprisingly found to reduce the hiding behavior in the test mice. The reduction of the behavior to hide is found to be blocked by the co-administration of the 5HT2C antagonist. In contrast to the compounds of the present invention, the anxiolytic compound chlordiazepoxide and the antipsychotic compound chlorpromazine decrease the hiding of marbles only at doses that also alter the performance of the rotorod.

Shredded Nest (Nestlet Shredding) Mice will naturally build nests of available material in their living environment. Since this behavior is obsessive by nature, the OCD model has been used (Xia Li, Denise Morrow and Jeffrey M. Witkin, "Decreases in nestlet shredding of mice by serotonin uptake inhibitors: comparison with marble burying" of mice by serotonin uptake inhibitors: comparison with hiding marbles), Psychopharmacology, remitted on July 14, 2003). NIH Swiss mice experimentally laboratory new males (Harían Sprague-Dawley, Indianapolis, IN) weighing between 28-35 in groups of 12 for at least three days prior to testing in a vivarium with a 12-hour light / dark shekel . Experiments are carried out during the light cycle in an experimental room with fluorescent lighting in the upper normal part. The mice are dosed with vehicle or test compound and after a specific pre-treatment interval (generally 30 min.), The mice are placed individually in a high plastic tub of 17 x 28 x 12 cm with around fragments of 5 mm sawdust on the floor together with a pre-weighed multi-layer gauze pad (51 mm square). After 30 minutes, the weight of the remainder of the gauze pad is not removed by the mouse. The weight of the gauze used for the construction of the nest by subtraction is determined. The results for the mice treated with test compounds are compared with the results for the mice treated with the vehicle control with the Dunnett test. Standard compounds for the treatment of clinically effective OCD suppress trituration of the nest at doses that are devoid of motor debilitating effects when measured by the rotorod test. The in vivo efficacy of the 5HT2C compounds at the 5HT2C receptor is confirmed by the prevention of the effects of 5HT2C agonists in triturating the nest by the co-administration of the 5HT2C 6-chloro-5-methyl-N- receptor antagonist. { 2- [(2-methylpyridin-3-yl-oxy) pyridin-5-yl] aminocarbonyl} -2, 3-dihydroindole. The representative compounds of the present invention are tested essentially as described above and it is surprisingly found that they suppress trituration of the nest at doses that are devoid of motor debilitating effects when measured by the rotorod test. In contrast to the compounds of the present invention, the anxiolytic chlordiazepoxide and the psychomotor stimulant of d-amphetamine decrease the crushing of the nest only at doses that produce motor side effects (depression or stimulation, respectively).

Polydipsia Induced by Calendar Rats devoid of food exposed to intermittent feed presentations will drink quantities of water that are well in excess of their intake and normal area and in excess of their intake when they are given all their food at once (Falk JL. " Production of polydipsia in normal rats by an intermittent food schedule "(Production of polydipsia in normal rats through an intermittent feeding program), Science 133: 195-196, (1961)). This excessive behavior is persistent and has been used to model the OCD. Wistar rats are maintained on a restricted food diet (to maintain 85% free-feed weight) but with free access to water. The rats are trained in a behavioral test chamber to press a lever to receive a granule of feed under a schedule of fixed intervals so that the rats are rewarded with a 45 mg feed pellet the first time they press in. a lever after an interval of 120 seconds has elapsed. Then the fixed interval is restored to 120 seconds and the process is repeated. Thus during a 90-minute test session, rats can earn a maximum of 45 pellets. The behavior chamber is also occupied with a water bottle that is weighed before and after the session to determine the amount of water consumed. Test compounds are administered on Tuesdays and Fridays. The control day performances are determined on Thursdays. Compounds are administered either orally at 60 minutes before the start of a test session or subcutaneously at 20 minutes before the start of a testing session. The proportions of the lever that presses and the water consumption are compared for each performance of the animal during the sessions after the treatment with the test compound with that performance of the animal during the control sessions expressed as a percentage of the control relationship. The individual percentage of control ratios is averaged for each dose and the standard error of the mean is calculated. The standard compounds for treatment of clinically effective OCD (eg, clomipramine, fluoxetine) suppress calendar-induced polydipsia without producing noticeable changes in motor patterns, food intake or behavior the next day. The in vivo efficacy of the 5HT2c compounds at the 5HT2c receptor is confirmed by the prevention of the effects of 5HT2c agonists with excessive drinking by the co-administration of the 5HT2c receptor antagonist, 6-chloro-5-methyl-N-. { 2- [(2-methylpyridin-3-yl-oxy) pyridin-5-yl] aminocarbonyl} -2, 3-dihydroindole. Representative compounds of the present invention are tested in a calendar-induced polydipsia assay essentially as described above and surprisingly found to suppress calendar-induced polydipsia without producing noticeable changes in motor patterns, food intake and daily behavior. following. The suppression of behavior is blocked by the co-administration of the 5HT2c antagonist. In contrast to the compounds of the present invention, the psychomotor stimulant of d-amphetamine decreases excessive drinking only at doses that stimulate behavior and these effects are not avoided by the 5HT2c receptor antagonist. Although it is possible to administer the compounds employed in the methods of this invention directly without any formulation, the compounds are usually administered in the form of pharmaceutical compositions comprising a pharmaceutically acceptable excipient and at least one compound of formula I or a pharmaceutically acceptable salt thereof. These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. The compounds employed in the methods of this invention are effective both as injectable and oral compositions. Such compositions are prepared in a well-known form in the pharmaceutical art see for example, REMINGTON'S PHARMACEUTICAL SCIENCES (Pharmaceutical Sciences, Remington, (16th ed 1980) In the elaboration of the compositions employed in the present invention, the active ingredient is usually mixed with at least one excipient diluted by at least one excipient or enclosed within such a carrier which may be in the form of a capsule, sachet, paper, or other container.When the excipient serves as a diluent it may be a solid, semi-solid or liquid material which acts as a carrier vehicle or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, dragees, sachets, capsules, amylaceous capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols, (as a solid medium or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, hard and soft gelatin capsules, suppositories, sterile injectable solutions, and packaged powders is In the preparation of a formulation, it may be necessary to grind the compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it is ordinarily milled to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size is usually adjusted by grinding to provide a substantially uniform distribution in the formulation for example around 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water , syrup, and methyl cellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents, preservatives such as methyl and propylhydroxybenzoates; sweetening agents and flavoring agents. The compositions of the invention can be formulated so as to provide a sustained or delayed rapid release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions are preferably formulated in a unit dosage form each dose contains from about 0.05 about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient. The term "unit dose form" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. The compounds are generally effective over a wide dose range. For example, doses per day formally fall within the range of about 0.01 around 30 mg / kg. In the treatment of adult humans the range of about 0.1 around 15 mg / kg / day in single or divided doses is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician in light of the relevant circumstance, including the condition to be treated the chosen route of administration of the compound, current compounds administered the age, weight and response of the individual patient and the severity of the patient's symptoms and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some cases, dose levels below the lower limit of the previous range may be more than adequate while in other cases still higher doses may be employed. Another preferred formulation employed in the methods of the present invention employs transdermal delivery device ("patches"). Such transdermal patches can be used to provide a continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art see for example U.S. Patents 5,023,252, issued June 11, 1991, which is incorporated herein by reference. Such patches can be constructed for continuous delivery, pulsing or delivery at the request of pharmaceutical agents. Under some circumstances, it will be desirable or necessary to introduce the pharmaceutical composition to the brain either directly or indirectly. Direct techniques usually involve the placement of a catheter for delivery of the drug into the host's ventricular system to bypass the blood barrier to the brain. One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5,011,472 issued April 30, 1991, which is incorporated herein by reference. Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide drug latency by the conversion of hydrophilic drugs into lipid-soluble drugs or pro-drugs. Latency is generally achieved by blocking the primary amine, hydroxy, carbonyl and sulfate groups present in the drug to make the drug more soluble in lipids and akin to transport through the blood barrier to the brain. Alternatively, the supply of hydrophilic drugs can be enhanced by the intra-arterial infusion of hypertonic solutions which can transiently open the blood barrier to the brain. The type of formulation used for the administration of the compounds used in the methods of the present invention may be dictated by the compound employed in particular, the type of pharmacokinetic profile desired from the route of administration and the condition of the patient.

Claims

1. - A compound of Formula I:

I wherein: R1 is hydrogen, fluoro, or alkyl (C? ~ C3); R2, R3, and R4 are each independently hydrogen, methyl, or ethyl; R5 is hydrogen, fluoro, methyl, or ethyl; R6 is -C = C-R10, -O-R12, -S-R14, or -NR2R25; R7 is hydrogen, halo, cyano, (C? -C6) alkyl optionally substituted with 1 to 6 fluoro substituents, (C2-C6) alkenyl optionally substituted with 1 to 6 fluoro substituents, (C3-C) cycloalkyl, alkoxy ( C? -C6) optionally substituted with 1 to 6 fluoro substituents, alkylthio (C? -C6) optionally substituted with 1 to 6 fluoro substituents, Ph1-alkyl (C0-C3), Ph1-alkyl (C0-C3) - O-, or Pl ^ -alkyl (C0-C3) -S-; R8 is hydrogen, halo, cyano, or -SCF3; R9 is hydrogen; R10 is -CF3, ethyl substituted with 1 to 5 fluoro substituents, (C3-Cd) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, Ar1-alkyl (C0-) C3), Ph1-(C0-C3) alkyl, or 3-alkyl (C? ~ C4) -2-oxo-imidazolidin-1-yl-(C1-C3) alkyl; R12 is Ph2-alkyl (C? -C3), Ar2-alkyl (Cx-C3), alkyl (C? -C6) -S-alkyl (C2-C6), cycloalkyl (C3-C7) -S-alkyl (C2) -C6), phenyl-S-alkyl (C2-C6), Ph2-S-alkyl (C2-C6), phenylcarbonyl-alkyl (C? ~ C3), Ph2-C (0) -alkyl (Cx-C3), alkoxycarbonyl (Ci-Cg) alkyl (C3-C6), cycloalkyl (C3-C7) -OC (O) -alkyl (C3-C6), phenyloxycarbonyl-alkyl (C3-C6), Ph2- 0C (0) -alkyl ( C3-C6), Ar2-OC (0) -alkyl (C3-C6), cycloalkyl

(C3-C7) -NH-C (0) -alkyl (C2-C4) -, Phx-NH-C (0) -alkyl (C2-C4) -,

Ar2-NH-C (0) -alkyl (C2-C) -, or R13-C (0) NH-alkyl (C2-C4); R 13 is (C 3 -C 7) cycloalkyl (C 0 -C 3) alkyl, Ph 1, Ar 2, or (C 1 -C 3) alkoxy optionally substituted with 1 to 6 fluoro substituents, Ph 1 -NH- or N-linked Het 1; R14 is Ar2 which is not linked to N to the sulfur atom, Ph2, R15-L-, tetrahydrofuranyl, tetrahydropyranyl, or substituted phenyl-methyl in the methyl portion with a substituent selected from the group consisting of alkyl (C? ~ C3) ) -n-substituted with hydroxy, alkyl (C? -C3) -0-alkyl (C? -C2) -n-, alkyl (C? ~ C3) -C (0) -n-alkyl (C0-C2) , and alkyl (Ci ~ C3) -0-C (0) -n- (C0-C2) alkyl, wherein when R14 is Ph2 or Ar2, where Ar2 is pyridyl, then R14 can also, optionally, be substituted with phenyl- CH = CH- or phenyl-C = C-, phenyl-CH = CH- or phenyl-C = C- are further optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, alkyl (Ci-Ce) optionally further substituted with 1 to 6 fluoro substituents, and (C? -C6) alkoxy optionally further substituted with 1 to 6 fluoro substituents, and wherein when Ar2 is pyridyl, the pyridyl may alternatively, optionally be substituted with R28 R29N-C (O) -, and optionally further substituted with a methyl, -CF3, cyano, or substituent -SCF3, or with 1 to 2 halo substituents, and wherein tetrahydrofuranyl and tetrahydropyranyl may optionally be substituted with an oxo substituent, or with one or two groups independently selected from methyl and -CF3; R15 is -OR16, cyano, -SCF3, Ph2, Ar2, quinolinyl, isoquinolinyl, cinolinyl, quinazolinyl, phthalimido, benzothiophenyl, optionally substituted at the 2-position with phenyl or benzyl, benzothiazolyl optionally substituted at the 2-position with phenyl or benzyl, benzothiadiazolyl optionally substituted with phenyl or benzyl, 2-oxo-dihydroindol-1-yl optionally substituted at the 3-position with dimethyl gem or alkyl (Ci-Cß) optionally further substituted with 1 to 6 fluoro substituents, 2-oxo-dihydroindole-5- ilo optionally substituted in the 3-position with gem dimethyl or (C? -C6) alkyl optionally further substituted with 1 to 6 fluoro substituents, 2-oxo-imidazolidin-1-yl optionally substituted in the 3-position with dimethyl gem or alkyl ( C? -C6) optionally further substituted with 1 to 6 fluoro substituents, 2-oxo-tetrahydropyrimidinyl optionally substituted in the 3 or 4 position with dimethyl gem or alkyl (Ci-Cβ) optionally further substituted with 1 to 6 fluoro substituents, 2-oxo-tetrahydroquinolin-1-yl optionally substituted at the 3-position with dimethyl gem or alkyl (Ci-CQ) optionally further substituted with 1 to 6 fluoro substituents, 2-oxo-dihydrobenzimidazol-1-yl optionally substituted at the 3-position with dimethyl gem or alkyl (Ci-Ce) optionally further substituted with 1 to 6 fluoro substituents, -NR1R18, -C (0) R22, or a saturated heterocycle selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, and thiomorpholinyl, tetrahydrofuranyl, and tetrahydropyranyl, wherein Ph2 and Ar2 when Ar2 is pyridyl can also optionally be substituted with phenyl-CH = CH- or phenyl-C = C-, phenyl-CH = CH- and phenyl-C = C- are further optionally substituted in the phenyl portion with 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, (C? -C6) alkyl optionally further substituted with 1 to 6 fluoro substituents, and (Ci-C?) alkoxy optionally further substituted with 1 to 6 fluoro substituents, and wherein Ar2 may alternatively optionally be substituted with a substituent selected from the group consisting of (C3-C7) cycloalkyl (C0-C3) alkyl, Het1-(C0-C3) alkyl, pyridylalkyl (C0-C3), and phenyl (C0-C3) alkyl, and optionally further substituted with a methyl substituent, -CF3, cyano, or -SCF3, or with 1 to 2 halo substituents, pyridyl-alkyl (C0-C3) and phenyl-alkyl (C0) -C3) are optionally further substituted with 1-3 substituents independently selected from halo, -CH3, -OCH3, -CF3, -OCF3, -CN, and -SCF3, and wherein when Ar2 is pyridyl, the pyridyl may alternatively, optionally replace with R28R29N-C (O) -, or (C? -C6) alkyl-C (O) - optionally substituted with 1 to 6 substitute fluoro testosterone, and can optionally be further substituted with a methyl substituent, -CF3, cyano, or -SCF3, or with 1 to 2 halo substituents, and wherein when Ar2 is thiazolyl, the thiazolyl can alternatively, optionally be substituted with cycloalkyl ( C3-C7) -alkyl (C0-C3) -NH-, and wherein the pyrrolidinyl, piperidinyl, morpholinyl, and thiomorpholinyl is substituted with oxo- at a carbon atom adjacent to the nitrogen atom in the ring, or is N- substituted with a substituent selected from the group consisting of alkylcarbonyl (C? ~ C6), alkylsulfonyl (Ci-Cß), cycloalkyl (C3-C7) alkyl (C0-C3) -C (0) -, cycloalkyl (C3-C7) alkyl (C0-C3) -S (0) 2-, Pl ^ -alkyl (C0-C3) -C (0) -, and Ph1-alkyl (C0-C3) -S (0) 2-, and may optionally it is further substituted with 1 or 2 methyl substituents or -CF3, and when it is substituted with oxo, it may optionally further be N substituted with a substituent selected from the group consisting of alkyl (Ci-C) e) optionally further substituted with 1 to 6 fluoro, cycloalkyl (C3-C7) alkyl substituents

(C0-C3), and Pl ^ -alkyl (C0-C3), and wherein tetrahydrofuranyl and tetrahydropyranyl may optionally be substituted with an oxo substituent, and / or with one or two groups independently selected from methyl and -CF3; L is branched or unbranched alkylene (Ci-Cd), except when R15 is -NR17R18 or Ar2-N-linked to L, in which case L is branched or unbranched (C2-Cd) alkylene, and when L is methylene or ethylene, L can optionally be substituted with ethane gem or with 1 to 2 fluoro substituents, and when R15 is Ph2, Ar2, or a saturated heterocycle, L can alternatively, optionally be substituted with a substituent selected from the group consisting of hydroxy cyano, - SCF3, alkoxy (Ci-Ce) optionally further substituted with 1 to 6 fluoro substituents, alkoxycarbonyl (C? ~ Ce) optionally further substituted with 1 to 6 fluoro substituents, alkylcarbonyloxy (Ci-Cß) optionally further substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl-alkyl (Co-C3) -0-, cycloalkyl (C3-C7) -alkyl (C0-C3) -OC (0) -, and cycloalkyl (C3-C7) -alkyl (C0-C3) -C (0) -0-; R16 is hydrogen, (C1-C3) alkyl optionally substituted with 1 to 6 fluoro substituents, alkylcarbonyl (Ci-Cß), cycloalkyl (C3-C7) alkyl (C0-C3), cycloalkyl (C3-C7) alkyl (C0-) C3) -C (0) -, Phx-alkyl (C0-C3), Pl ^ -alkyl (C0-C3) -C (0) -, Ar2-alkyl (C0-C3), or Ar2-alkyl (C0-) C3) -C (O) -, R17 is (C? -C4) alkyl optionally substituted with 1 to 6 fluoro, t-butylsulfonyl, cycloalkyl (C3-C) alkyl (C0-C3) -C (0) - substituents , (C3-C) cycloalkyl (C0-C3) -sulfonyl, Pb ^ - (C0-C3) alkyl, Ph1- (C0-C3) alkyl- C (O) -, Pl ^ -alkylsulfonyl (C0-C3) , Ar 2 -alkyl (C 0 -C 3), Ar 2 -alkyl (C 0 -C 3) -C (0) -, Ar 2 -alkylsulfonyl (C 0 -C 3), R190C (0) -, or R 20 R 21 CN (0) -; R18 is hydrogen or (C? -C) alkyl optionally substituted with 1 to 6 fluoro substituents, or R17 and R18, taken together with the nitrogen atom to which they are bound form Het1 where Het1 is substituted with oxo at a carbon atom adjacent to the nitrogen atom in the ring, or R17 and R18, taken together with the nitrogen atom to which they are bonded, form an aromatic heterocycle selected from the group consisting of pyrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl, the aromatic heterocycle optionally is substituted with 1 to 2 halo substituents, or substituted with 1 to 2 alkyl substituents (C 1 -C 4) optionally further substituted with 1 to 3 fluoro, or mono-substituted substituents with fluoro, nitro, cyano, -SCF3, or (C? ~ C) alkoxy optionally further substituted with 1 to 3 fluoro substituents, and optionally further substituted with an alkyl substituent (C? ~ C4) optionally further substituted with 1 to 3 fluoro substituents; R19 is (C? -C6) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, Ar2-alkyl (C0-C3), or Phx-alkyl (C0-C3) , R20 is (C? -C6) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C) cycloalkyl (C0-C3) alkyl, Ar2- (C0-C3) alkyl, or Ph1-alkyl (C0-C3) ), R21 is hydrogen or (C? -C) alkyl optionally substituted with 1 to 6 fluoro substituents, or R20 and R21, taken together with the nitrogen atom to which they are linked, form Het1;

R 22 is alkyl (C 1 -C 6) optionally substituted with 1 to 6 fluoro substituents, (C 3 -C 7) cycloalkyl

(C0-C3), R23-0-, Pl ^ -alkyl (C0-C3), Ar2-alkyl (C0-C3), or

R32R33N_.

R23 is (C? -C6) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, P ^ -alkyl (C0-C3), or Ar2-alkyl (C0-C3) ); R24 is alkoxy (Ci-Ce) (C2-Cs) alkyl optionally substituted with 1 to 6 fluoro substituents, alkylthio (Ci-Cg) (C2-C5) alkyl optionally substituted with 1 to 6 fluoro substituents, cycloalkyl (C3-) C7) alkyl (C0-C?) -O-alkyl (C1-C5), (C3-C7) cycloalkyl (C0-C?) - S- (C1-C5) alkyl, phenyl n-C1-C3 alkyl, Ph2-n-alkyl (C? -C3), Ar2-n alkyl (C0-C3), phenyl (C0-C?) Alkyl-O-(C1-C5) alkyl, phenyl (C0-C?) -S- (C1-C5) alkyl, Pl ^ -alkyl (C0-C) !) - C (O) NH- (C2-C4) alkyl, P ^ -alkyl (C0-C?) -NH-C (O) NHalkyl (C2-C4), pyridyl-alkyl (C0-1) -C (O) NH- (C2-C4) alkyl, pyridyl-alkyl (Co-Ci) -NH-C (O) NH- (C2-C4) alkyl, or Ar3 alkyl (C? ~ C2), where Ar3 is a bicyclic portion selected from a group consisting of indanyl, indolyl, dihydrobenzofuranyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzo [1,3] dioxolyl, naphthyl, dihydrobenzopyranyl, quinolinyl, isoquinolinyl, and benzo [1,2, 3] thiadiazolyl, the Ar3 optionally is substituted with alkyl (Ci-Ce) optionally further substituted with 1 to 6 fluoro substituents, phenyl (C0-C?) alkyl optionally further substituted with 1 to 6 fluoro substituents, or substituted with cycloalkyl (C3-C7) (C0-C3) alkyl, or substituted with 1-3 substituents independently selected from the group consisting of halo, oxo, methyl, and -CF3, the phenyl alkyl (C? ~ C3) n-, Ph2 -n-alkyl (Cx-C3), or Ar2 n-(C0-C3) alkyl optionally is substituted on the n-alkyl portion when presented with alkyl (C? -C3), dimethyl, gem-ethane, 1 to 2 substituents fluoro, or alkyl (Q.-C6) -C (O) -, the Ar2 n-C0-C3 alkyl is alternatively optionally substituted with a substituent selected from the group consisting of (C3-C7) cycloalkyl-alkyl ( Co ~ C3), Het1-alkyl (C0-C3), pyridyl-alkyl (C0-C3), phenylalkyl (C0-C3), pyridyl-alkyl (C0-C3) -NH-, phenyl-alkyl (C0-C3) -NH-, alkyl (C? -C6) -S-, and cycloalkyl (C3-C7) -alkyl (Co ~ C3) -S-, and optionally further substituted with a methyl substituent, -CF3, cyano, or -SCF3 , or with 1 to 2 halo substituents, the pyridyl (C0-C3) alkyl and phenyl (C0-C3) alkyl optionally are further substituted with 1-3 substituents independently selected from halo, -CH3, -OCH3, -CF3, -OCF3, -CN, and -SCF3 , and the Ph2-alkyl (Cx-C3) n- and Ar2alkyl (C0-C3) n- where

Ar2 is pyridyl, optionally also substituted in the phenyl or Ar2 portion, respectively, with phenyl-CH = CH- or phenyl-C = C-, the phenyl-CH = CH- or phenyl-C = C- are further optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, alkyl (Ci-Cd) optionally further substituted with 1 to 6 fluoro substituents, and alkoxy (CI-CT) optionally further substituted with 1 to 6 fluoro substituents, and the Ar2 (C0-C3) alkyl n- where Ar2 is pyridyl, alternatively, optionally is substituted with alkyl (C? -C6) -C (0) - or R28R29N-C (0) -, and optionally further substituted with a methyl substituent, -CF3, cyano, or -SCF3, or with 1 to 2 halo substituents, the phenyl alkyl (C0-C?) -O-(C1-C5) alkyl, or phenyl alkyl (CO-QL) ) -S- (C1-C5) alkyl optionally are substituted on the phenyl portion with (C? ~ C2) -S (O) 2-, or with 1 to 5 independently selected from halo, oc substituents on 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, alkyl (Ci-Cß) optionally further substituted with 1 to 6 fluoro substituents, and (C? -C6) alkoxy optionally further substituted with 1 to 6 fluoro substituents, and pyridyl (C0-C?) -C (0) NH-alkyl (C2-C4) alkyl and pyridyl-alkyl (C0-C?) -NH-C (0) NH-alkyl ( C2-C) are optionally substituted in the pyridyl moiety with methyl, -CF3, or 1 to 3 halo substituents; R25 is hydrogen, (C1-C3) alkyl optionally substituted with 1 to 6 fluoro substituents, or allyl;

R26 is hydrogen, (C? -C6) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C) cycloalkyl (C0-C3) alkyl; R27 is hydrogen or (C? -C) alkyl optionally substituted with 1 to 6 fluoro substituents, or R26 and R27, taken together with the nitrogen atom to which they are linked, form Het1; R28 is (Ci-Cß) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C8) cycloalkyl (C0-C3) alkyl, tetrahydropyran-3-yl (C0-C3) alkyl, tetrahydropyran-4-yl alkyl ( C0-C3), tetrahydrofuranyl (C0-C3) alkyl, Phx-n-alkyl (C0-C2), or Ar2-n-alkyl (C0-C2), the Pl ^ -n-alkyl (C0-C2) and Ar2 -N-alkyl (C0-C2) are optionally substituted on the alkyl portion when presented with (C1-C3) alkyl, dimethyl, or gem-ethane; R29 is hydrogen or (C1-C3) alkyl; R30 is hydrogen, (C? -C6) alkyl optionally substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, Ph1-(C0-C3) alkyl, or Ar2 (C0-C3) alkyl ), R31 is hydrogen or (Ci-C) alkyl optionally substituted with 1 to 6 fluoro substituents, or R30 and R31, taken together with the nitrogen atom to which they are linked, form Het1, Het1 is optionally also substituted with phenyl optionally further substituted with 1 to 3 halo substituents; R32 and R33 are each independently hydrogen or (Ci-Cβ) alkyl optionally substituted with 1 to 6 fluoro substituents, or R32 and R33, taken together with the nitrogen atom to which they are linked, form Het1, or R32 is Phxalkyl ( C0-C?) With the proviso that R33 is hydrogen; Ar 1 is an aromatic heterocycle substituent selected from the group consisting of furanyl, thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, and pyridazinyl, any of which can optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halo, alkyl ( C? ~ C3), alkoxy (C? ~ C3), -CF3, -0-CF3, nitro, cyano, and trifluoromethylthio; Ar2 is an aromatic heterocycle substituent selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, thiophenyl, thiazolyl , isothiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyridazinyl, and benzimidazolyl, any of which may optionally be substituted with 1 to 3 substituents independently selected from the group consisting of halo, cyano, - SCF3, (Ci-Cd) alkyl optionally further substituted with 1 to 6 fluoro substituents, and (C 1 -C 6) alkoxy optionally further substituted with 1 to 6 fluoro substituents, and wherein pyridyl and pyridazinyl may also optionally be substituted with alkylamino (C? ~ Cß) optionally further substituted with 1 to 6 fluoro substituents, (C3-C7) cycloalkyl (C0-C3) alkyl, or (C3-C7) cycloalkyl (C0-C3) alkyl-amino; Het1 is a saturated nitrogen-containing heterocycle substituent selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, and homothiomorpholinyl, any of which may optionally be substituted with alkyl (Ci-Cß) or 2 methyl substituents; Het2 is a saturated oxygen-containing heterocycle substituent selected from the group consisting of tetrahydrofuranyl and tetrahydropyranyl, any of which may optionally be substituted with alkyl (Ci-Ce) or with 2 methyl substituents;

Ph1 is phenyl optionally substituted with 1 to 5 independently selected from halo substituents, or with 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF3, alkyl (Ci-Cß) optionally further substituted with 1 to 6 substituents of fluoro, and (Ci-Cβ) alkoxy optionally further substituted with 1 to 6 fluoro substituents; Ph2 is phenyl substituted with: a) 1 to 5 independently selected halo substituents; or b) 1 to 3 substituents independently selected from the group consisting of halo, cyano, -SCF 3, nitro, hydroxy, alkyl (Ci-Cg) optionally further substituted with 1 to 6 fluoro substituents, and (C 1 -C 6) alkoxy optionally further substituted with 1 to 6 fluoro substituents; or c) 0, 1, or 2 substituents independently selected from the group consisting of halo, cyano, -SCF3, methyl, -CF3, methoxy, -OCF3, nitro, and hydroxy, together with a substituent selected from the group consisting of i) (Ci-Cio) alkyl optionally further substituted with 1 to 6 fluoro or mono-substituted substituents with hydroxy, (C? -C6) alkoxy, (C3-C7) cycloalkyloxy (Co-C3), Het2-alkyloxy (CO-) C3), Ph1-(C0-C3) alkyloxy, ii) (C1-C10) alkoxy-(C0-C3) alkyl optionally further substituted with 1 to 6 fluoro substituents, and optionally further substituted with hydroxy, iii) alkyl (Ci) -Ce) -C (0) -alkyl (C0-C5) optionally further substituted with 1 to 6 fluoro substituents, iv) carboxy, v) (C? -C6) alkoxycarbonyl optionally further substituted with 1 to 6 fluoro substituents, vi) (C 1 -C 6) alkyl -C (O) - (C 0 -C 3) -0- optionally further substituted with 1 to 6 fluoro substituents, vii) alkylthio (Ci-Cβ) -alkyl (C0-C5) optionally further substituted with 1 to 6 fluoro substituents, viii) alkylsulfinyl (Ci-Ce) -alkyl (C0-C5) optionally further substituted with 1 to 6 fluoro substituents, ix) alkylsulfonyl (Ci-Cß) -alkyl (C0-C5) optionally further substituted with 1 to 6 fluoro substituents, x) alkylsulfonyl (Ci-Ce) -alkyl (Co ~ C3) -0- optionally further substituted with 1 to 6 fluoro substituents, xi) cycloalkyl (C3-C7) (C0-C3) alkyl, optionally further substituted in the cycloalkyl with 1 to 4 substituents selected from methyl and fluoro, xii) (C3-C) cycloalkyl (C0-C3) -O- alkyl, optionally further substituted in the cycloalkyl with 1 to 4 substituents selected from methyl and fluoro, xiii) (C3-C7) cycloalkyl (C0-C3) alkyl -C (0) -, xiv) (C3-C7) cycloalkyl (C0-C3) alkyl- OC (0) -, xv) (C3-C7) cycloalkyl (C0-C3) -S-, xvi) cycloalkyl (C3-C7) alkyl (C0-C3) -S (0) -, xvii) cycloalkyl (C3) -C7) alqu ilo (C0-C3) -S (0) 2-, xviii) Pl ^ -alkyl (C0-C3), optionally substituted in the alkyl portion with 1 to 2 fluoro substituents, xix) Ph1-alkyl (C0-C3) -0-, optionally substituted in the alkyl portion with 1 to 2 fluoro substituents xx) Pb ^ -alkyl (C0-C3) -C (0) -, xxi) Ph 1 -alkyl (C0-C3) -0-C ( 0) -, xxii) Ph 1 -alkyl (C0-C3) -C (0) -alkyl (C0-C3) -0-, xxiii) P ^ -alkylthio (C0-C3), xxiv) Ph1-alkylsulfinyl (C0-) C3), xxv) Ph1-alkylsulfonyl (C0-C3), xxvi) Ar2 alkyl (C0-C3), xxvii) Ar2 alkyl (C0-C3) -O-xxviii) Ar2-alkyl (C0-C3) -S-, xxix) Ar2 (C0-C3) alkyl -C (0) -, xxx) Ar2 (C0-C3) alkyl -C (S) -, xxxi) Ar2-alkylsulfinyl (Co ~ C3), xxxii) Ar2- (C0-) C3) alkylsulfonyl, xxxiii) Het1 (C0-C3) -C (0) alkyl-optionally substituted in the portion Het1 with Ph1, xxxiv) Het1 (C0-C3) -C (S) alkyl- optionally substituted in the Het1 portion with Ph1, xxxv) N linked to Het1-C (0) -alkyl (C0-C3) -O-, xxxvi) Het2-alkyloxy (C0-C3), xxxvii) R26R27N-, xxxviii) R28R29-N-alkoxy (C? ~ C3), xxxix) R28R29N-C (0) -, xl) R28R29N-C (0) -alkyl (C? -C3) -0-, xli) R28R29N -C (S) -, xlii) R30R31N-S (O) 2-, xliii) H0N = C (CH3) -, and xliv) H0N = C (Ph1) -, or a pharmaceutically acceptable salt thereof, subjected to the following conditions: a) no more than two of R1, R2, R3, R4, and R5 may be erent from hydrogen; b) when R2 is methyl, then R1, R3, R4, and R5 are each hydrogen; c) when R3 is methyl, then R2 and R4 are each hydrogen. 2. The compound according to claim 1 wherein R7 is selected from halo, -CN, and CF3. 3. The compound according to either claim 1 or claim 2 wherein R7 is chloro. 4. The compound according to one of any of claims 1 to 3 wherein R6 is -C = C-R10. 5. The compound according to one of any of claims 1 to 3 wherein R6 is -0-R12. 6. The compound according to one of any of claims 1 to 3 wherein R6 is -S-R14. 7. The compound according to claim 6 wherein R6 is -S-L-R15. 8. The compound according to claim 7 wherein R15 is Ph2 or Ar2. 9. The compound according to one of any of claims 1 to 3 wherein R6 is -NR24R25. 10. The compound according to claim 9 wherein R24 is Ph2-n-alkyl (C? ~ C3). 11. The compound according to claim 9 wherein R24 is Ar2-n-alkyl (C? ~ C3). 12. The compound according to one of any of claims 9 to 11, wherein R25 is hydrogen.

13. The compound according to one of any of claims 1 to 12, wherein R1, R2, R3, R4, R5, and R8 are each hydrogen.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 as an active ingredient in association with a pharmaceutically acceptable carrier, diluent or excipient.

15. The compound according to one of any of claims 1 to 13, for use in therapy.

16. A method for the treatment of obesity in mammals, comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1.

17. The method of claim 16, wherein the mammal He is a human.

18. A method for the treatment of obsessive-compulsive disorder in mammals, comprising administering to a mammal in need of such treatment, an effective amount of a compound according to claim 1.

19. The method of claim 18, where the mammal is a human.

20. A method for the treatment of depression in mammals, comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1.

21. - The method of claim 20, wherein the mammal is a human.

22. A method for the treatment of anxiety in mammals, comprising administering to a mammal in need of such treatment, an effective amount of a compound according to claim 1.

23. The method of claim 22, wherein the mammal is a human.

24. The compound according to one of any of claims 1 to 13, for use as a pharmacist.

25. The compound according to one of any of claims 1 to 13, for use in the treatment of obesity in mammals.

26. The compound according to one of any of claims 1 to 13, for use in the treatment of obsessive / compulsive disorder in mammals.

27. The compound according to one of any of claims 1 to 13, for use in the treatment of depression in mammals.

28. The compound according to one of any of claims 1 to 13 for use in the treatment of anxiety in mammals.

29. The compound according to one of any of claims 25-28, wherein the mammal is a human. The use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of a disorder selected from obesity, hyperphagia, obsessive / compulsive disorder, depression, anxiety, substance abuse , sleep disorder, hot flushes and / or hypogonadism. 31. The use of a compound according to one of any of claims 1 to 13 in the manufacture of a medicament for the treatment of a disorder selected from obesity, obsessive / compulsive disorders, anxiety, or depression. 32. A pharmaceutical composition adapted for the treatment of obesity, comprising a compound according to one of any of claims 1 to 13 in combination with one or more pharmaceutically acceptable excipients, carriers or diluents for the same. 33. A pharmaceutical composition adapted for the treatment of obsessive / compulsive disorders, comprising a compound according to one of any of claims 1 to 13 in combination with one or more pharmaceutically acceptable excipients, carriers or diluents for the same. 34. A pharmaceutical composition adapted for the treatment of depression comprising a compound according to one of any of claims 1 to 13, in combination with one or more excipients, carriers or pharmaceutically acceptable diluents for the same. 35.- A pharmaceutical composition adapted for the treatment of anxiety, comprising a compound according to one of any of claims 1 to 13, in combination with one or more pharmaceutically acceptable excipients, carriers or diluents for the same.