Title of Invention

SUBSTITUTED AZEPINE DERIVATIVES AS SEROTONIN RECEPTOR MODULATORS

Abstract

The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents More specifically, compounds of the present invention are hexahydroazepinoindole and octahydroazepinomdole compounds These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. anxiety, depression and obesity).

Full Text

WO 2006/004931 PCT/US2005/0 23282 SUBSTITUTED AZEPINE DERIVATIVES AS SEROTONIN RECEPTOR MODULATORS FIELD OF THE INVENTION The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents More specifically, compounds of the present invention are hexahydrothienoazepine and octahydi othienoazepme compounds. These compounds are serotonin receptoi (5-HT) Hgands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. addiction, anxiety, depression and obesity) BACKGROUND OF THE INVENTION Serotonin has been implicated in a number of diseases, disorders, and conditions that originate in the central nervous system, including diseases, disorders, and conditions related to, for example, sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, addiction and schizophienia Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of conti actile, secietory, and electrophysiologic effects Because of the broad distribution of serotonin within the body, there is a need for drugs that affect serotonergic systems In particular, agonists, partial agonists, and antagonists of serotonergic systems aie of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disordeis, schizophrenia, autism, neurodegenerative disorders (e g, Alzheimer's disease, Parkmsonism, and Huntington's chorea), and chemothei apy-induced vomiting. The major classes of serotonin receptors (5-HTi_7) contain one to seven separate receptors that have been formally classified See Glennon, et al., Neuroscience and Behavioral Reviews, 1990,14, 35, and D Hoyer, et al. Pharmacol Rev 1994,46, 157-203. For example, the 5-HT2 family of leceptors contains 5-HT2a, 5-HT2b, and 5-HT2c subtypes, which have been grouped together on the basis of primary structure, secondary messenger system, and operational profile All three 5-HT2 subtypes are G-protein coupled, activate phospholipase C as a principal transduction mechanism, and contain a seven- WO 2006/004931 PCT/US2005/023282 transmembrane domain structure. There are distinct differences in the distribution of the three 5-HT2 subtypes in a mammal The 5-HT2b and 5-HT2a receptors are widely distributed in the peripheral nervous system, with 5-HT2a also found in the brain. The 5-HT2c receptor has been found only in the central nervous system, being highly expressed in many regions of the human brain See G Baxter, et at. Trends in Pharmacol Sci 1995,16, 105-110. Subtype 5-HT23 has been associated with effects including vasoconstriction, platelet aggregation, and bronchoconstnction, as well as certain CNS effects, while subtype 5-HT2C has been associated with diseases that include depression, anxiety, obsessive compulsive disorder, addiction, panic disorders, phobias, psychiatric syndromes, and obesity. Very little is known about the pharmocologic role of the 5-HT2b receptor. See F Jenck, et al., Exp Opm Invest Drugs, 1998, 7, 1587-1599; M Bos, etal, J Med. Client, 1997, 40, 2762-2769; J.R Martin, et al, Hie Journal of Pharmacology and Experimental Therapeutics, 1998, 286, 913-924; S M Bromidge, et al, \.Med Chem, 1998,41,1598-1612, GA Kennett, Drugs, 1998,1, 4,456-470; and A Dekeyne, et al, Neurophannacology,1999, 38, 415-423. WO 93/13105 discloses thiophene derivatives; U.S. Patent No. 4414225 discloses thiophene, furan and pyrrole derivatives and WO 96/12201 discloses furan derivatives SUMMARY OF THE INVENTION The present invention is directed to compounds of the formula: where X is S, O or NR5; R1 and R2 are independently selected from the group consisting of H, halogen, C1-8 alkyl, C1-8 alkylaryl, Ci-s alkyl heteroaryl, C1-8 alkenyl, perhalo alkyl, CN, OR5, SR5, N(R5)2, CON(R5)2, NR5COR5j NR5CO2R5, SO2N(R5)2, NRSSO2R5, aryl and heteroaryl, wherein said aryl or heteroaryl can be optionally substituted with up to three substituents selected from alky], halogen and alkoxy or R1 and R2 taken together form a 5- or 6-member ring, 2 WO 2006/004931 PCT7US2005/023282 R3 is selected from the group consisting of H, Cu alkyl, Ci_s alkylaryl, Ci-g alkylheteroaryl, OR5, -CHZ-O-CLS alkyl, -CH2OH, -COO-CL6 alkyl, -CON(R5)2) and aryl; R3a is H or R3 and R3a taken together are -CH2CH2- or R2 and R3 form a 5- or 6-member ring, R4 is selected from the group consisting of H, C].8 alkyl, Cj_8 alkylaryl, Ci.g alkylheteroaryl, OR5, -CH2-O-C1-S alkyl, -CH2OH, -COO-Ci_8 alkyl, -CON(R5)2 and aryl; R4a is H or R3 and R3a taken together are -CH2CH2-; and R5 is selected from the group consisting of H, C1-8 alkyl, Cj_a alkylaryl, Ci-s alkylheteroaryl, aryl, heteroaryl, and perhaloalkyl or together with the atom to which it is attached, R5 forms a heteroaryl ring Another embodiment of the present invention provides a pharmaceutical composition comprismg a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Still another embodiment of the present invention provides a method of treating a disease, disorder and/or condition in a mammal (e g.s animal or human), wherein a 5-HT2c receptor is implicated and modulation of a 5-HT2C function is desired The method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the mammal Yet another embodiment of the present invention comprises a method of modulating 5-HT receptor function with an effective amount of compound of Formula (I), or a pharmaceutically acceptable salt thereof A further embodiment of the present invention provides a method of treating or preventing diseases, disordeis, and/or conditions of the central nervous system. The method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the mammal. Specific diseases, disorders and/or conditions for which compounds of the Formula (I) may have activity include obesity, depression, schizophrenia, anxiety, obsessive compulusive disorder, addiction, panic disorders, sleep disordeis, migraine, Type II diabetes, epilepsy, phobias and phychiatnc syndromes 3 WO 2006/004931 PCT/US2005/023282 DETAILED DESCRIPTION OF THE INVENTION The following definitions are used, unless otherwise described. As used herein, the term "alky]" includes straight chained and branched hydrocarbon groups containing the indicated number of carbon atoms, typically methyl, ethyl, and straight chain and branched propyl and butyl groups. The term "alkyl" also encompasses cycloalkyl, i.e., a cyclic C3-C8 hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl Reference to an individual group or moiety, such as "propyl," embraces only the straight chain group or moiety A branched chain isomer, such as "isopropyl," is specifically referred to The term "alkenyl" as used herein, alone or in combination, refers to a substituted or unsubstituted straight-chain or substituted or unsubstituted branched-chain alkenyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl and the like. The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term "alkyl" is as defined above Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like. The term "halo" is defined heiein to include fluoro, chloro, bromo, or iodo. Similarly, the term "halogen" is defined herein to include fluorine, chlorine, bromine, and iodine. The term "amino", alone or in combination, includes the group -NH2 or -NRaRb wherein Ra and R* are independently hydrogen, alkyl, alkylaryl, or aryl The term "aryl," alone or in combination, is defined herein as a monocychc or bicyclic aromatic group (e g., phenyl or naphthyl) that can be unsubstituted or substituted, for example, with one or more, and in particular one to three of the following substituents selected from the group consisting of H, halo; CN, NO2, CF3, N3, C^aHcyl, OH, NRaRb, OC1-6 alkyl, ORa, C(=O)NRflRb, C(=S)NRaRb, tetrazoyl, triazoyl, amidinyl, guamdinyl, thioguanidinyl, cyanoguanadinyl, and aryl. Generally, "aryl" denotes a phenyl group, or an ortho-fused bicyclic carbocyclic group having nine to ten ring atoms in which at least one ring is aromatic (e g. naphthyl or tetrahydronaphthyl). The term "aryl" also is abbreviated in the various chemical structures as "Ar " The term "heteroaryl" is defined herein as a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, 4 WO 2006/004931 PCT/US2005/023282 oxygen, or sulfur atom in an aromatic ring, and which can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, like halo, alkyl, hydroxy, h3'droxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, mtro, ammo, alkylammo, acylamino, alkylthio, alkylsulfonyl, and alkylsulfonyl. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-mdoIyl, 4H-quinohzmyl, 4nH-carbazolyl, acridinyl, benzo[b]thienyl, benzothiazolyl, 13-carbohnyl, carbazolyl, chromenyl, cinnaohnyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, mdazolyl, indolisiny], indolyl, isobenzofuranyl, isoindoly], isoquinolyl, isothiazolyl, isoxazolyl, naphthyndinyl, naptho[2,3-b], oxazolyl, perimidinyl, phenanthndinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazmyl, phenoxatminyl, phenoxazinyl, phthalazinyl, pteridmyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyndyl, pyrimidmyl, pynmidinyl, pyrrolyl, quinazolmyl, qumolyl, quinoxahnyl, thiadiazolyl, thianthienyl, thiazolyl, thienyl, triazolyl, and xanthenyl In one embodiment the term "heteroaryl" denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of non-pei oxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, 0, C;_4alkyl, phenyl or benzyl. In another embodiment heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-denvative or one derived by fusing a propylene, or tetramethylene diradical thereto. The term "Het" generally represents a heterocyclic gioup, saturated or partially unsaturated, containing at least one heteroatom selected from the gioup consisting of oxygen, nitrogen, and sulfur, and optionally substituted with C1-6alkyl or C(=O)ORtf Typically "Het" is a monocyclic, bicyclic, or tiicyclic group containing one or more heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur A "Het" group also can contain an oxo group (=0) attached to the ring Nonlimlting examples of Het groups include 1?3-dihydrobenzofuran, 1,3-dioxolane,11,4-dioxane, 1,4-dithiane, 2H-pyran, 2-pyrazohne, 4H-pyran, chromanyl, imidazolidinyl, lmidazohnyl, indohnyl, isochromanyl, isoindolinyl, morphohne, piperazinyl, pipendine, piperidyl, pyrazolidine, pyrazohdmyl, pyrazolinyl, pynolidine, pyrroline, quinuchdme, and thiomorphohne. Preferred embodiments of the present invention include Embodiment 1: 5 WO 2006/004931 PCT/US2005/023282 where R1 and R2 are independently selected from the group consisting of H, halogen, C1-8 alkyl, C1-8 alkylaryl, Ci_s alkylheteroaryl, C1-8 alkenyl, perhalo alkyl, CN, OR5, SR5, N(R5)2, CON(R5)2, NR5COR5) NR5CO2R5, SO2N(R5)2, NR5SO2R5, aryl and heteroaryl, wherein said aryl or heteroaryl can be optionally substituted with up to three substituents selected from alkyl, halogen and alkoxy or R1 and R2 taken together form a 5- or 6-member ring, R3 is selected from the group consisting of H, C1-8 alkyl, OR5, -CH2-O-C1-8 alkyl, -CH2OH, -COO-C1-8 alkyl, -CON(R5)2, and aryl; R3a is H or R3 and R3a taken together are -CH2CH2- or R2 and R3 form a 5- or 6-member ring; R4 is selected from the group consisting of H, C1-8 alkyl, C1-8 alkylaryl, C1-8alkylheteroaryl, OR5, -CH2-O-C1-8 alkyl, -CH2OH, -COO-Cug alkyl, -CON(R5)2 and aryl, R4a is H or R3 and R3a taken together are -CH2CH2-; and R5 is selected from the group consisting of H, C1-8 alkyl, C1-8 alkylaryl, C1-8 alkylhetroaryl, heteroaryl, and perhaloalkyl or together with the atom to which it is attached, R5 forms a heteroaryl ring. Embodiment 2 where R1 and R2are independently selected from the group consisting of H, halogen, C1-8 alkyl, C1.8 alkylaryl, C,.8 alkyl heteroaryl, C,.8 alkenyl, perhalo alkyl, CN, OR5, SR5, N(R5)2, CON(R5)2, NR5COR5, NRSCO2R55 SO2N(RS)2, NR5SO2R5s atyl and heteroaryl, wherein said 6 WO 2006/004931 PCT/US2005/023282 aryl or heteroaryl can be optionally substituted with up to three substituents selected from alkyl, halogen and alkoxy or R1 and R2 taken together form a 5- or 6-member ring, R3 is selected from the group consisting of H, C1-8 alkyl, C1-8 alkylaryl, C1-8 alkylheteroaryl, OR5, -CH2-O-C,.8 alkyl, -CH2OH, -COOd.8 alkyl, -CON(R5)2, and aryl, R3a is H or R3 and R3a taken together are -CH2CH2- or R2 and R3 form a 5- or 6-member ring; R4 is selected from the group consisting of H, C1-8 alkyl, Ci-« alkylaryl, C1-8 alkylheteroaryl, OR5, -CH2-O-C1-8 alkyl, -CH2OH, -COO-C1.8 alkyl, -CON(R5)2 and aryl; R4a is H or R3 and R3a taken together aie -CH2CH2-; and R5 is selected from the group consisting of H, C1-8 alkyl, C1-8 alkylaryl, aryl, C1-8 alkylhetroaryl, heteroaryl, and perhaloalkyl or together with the atom to which it is attached, R5 forms a heteroaryl ring Embodiment 3 wheie R] and R2 are independently selected from the group consisting of H, halogen, C1-8 alkyl, C1-8 alkylaryl, C1-8 alkylheteroaryl, Ci s alkenyl, perhalo alkyl, CN, OR5, SR5, N(R5)2, CON(R5)2, NR5COR5, NR5CO2R5, SO2N(R;)2, NR5SO2R5, aryl and heteroaryl, wherein said aryl or heteroaryl can be optionally substituted with up to three substituents selected fiom alkyl, halogen and alkoxy or Rj and R? taken together form a 5- or 6-member ring, R3 is selected from the group consisting of H, C1-8 alkyl, C1-8 alkylaryl, C1-8 alkylheteroaryl, OR5, -CH2-O-C1-8 alkyl, -CH2OH, -COO-C1-8 alkyl, -CON(R5)2, and aryl, R3a is H or R3 and R3a taken together are -CH2CH2- or 7 WO 2006/004931 PCT/TJS2005/023282 R2 and R3 form a 5- or 6-member ring; R4 is selected from the group consisting of H, C1-8 alkyl, C1-8 alkylaryl, CI_B alkyl heteroaryl, OR5, -CH2-O-C1-8 alkyl, -CH2OH, -COO-C1-8 alkyl, -CON(R5)2 and aryl; R4a is H or R3 and R3a taken together are -CH2CHr-; and R5 is selected from the group consisting of H, C1-8 alkyl, C1-8 alkylheteroaryl, C1-8 alkylaryl, aryl, heteroaryl, and perhaloalkyl or together with the atom to which it is attached, R5 forms a heteroaryl ring Preferably X is S, Ri is selected from the group consisting of halogen, C1-8 alkyl, OR5, SO2N(Rs)2 and perhaloalkyl; R2 is selected from the group consisting of hydrogen, halogen, C1-8 alkyl and OR5, or together with R3 forms a 5-membered ring; R3 is hydrogen or C1-8 alkyl; R3 is hydrogen; R4 is hydrogen or C1-8 alkyl, R4 is hydrogen; and Rs is hydrogen or C1-8 alkyl or, together with the atom to which it is attached form a heteroaryl ring. Presently preferred compounds include 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine, 2-Bromo-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine; 2-Chloro-5,6)7,8-tetrahydro-4H-thieno[2,3-d]azepine; 2)3-Dibromo-5)6,7,8-tetrahydro-4H-thieno[2 3-d]azepine; 2,3-Dichloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine; 2-Bromo-3-chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine, (R,S)5,6,7J8-Tetrahydio-4H-thieno[2,3-d]az,epin-4-oI; 2-Chloro-4-methoxy-5,6s738-tetrahydro-4H-thieno[23-d]azepine; 2-Chloro-4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3~d]azepme; 2,3-Dichloro-4-methyl-5,6,7,8-tetrahydro-thieno[2,3-d]azepme; 2-(4-Trifluoromethoxy-phenyl)-5s6,7,S-tetrahydro-4H-thieno[2,3-d]a2epine; 2-(3-TrifluoromethyI-phenyl)-5,6,7s8-tetrahydro-4H-thieno[2,3-d]azepine; 2-(2-Trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine; 2-(4-FIuoro-phenyl)-5,6)7s8-tetrahydro-4Hthieno[2,3-d]a2epine; 2-(2J5-Difluoro-phenyl)-5)6,7,8-tetrahydro-4H-thieno[2,3-d]azepine, 8 WO 2006/004931 PCT/US2005/0 23282 i 2-(3-Chloro-4-fIuoro-phenyl)-5,6,7,8-tetia]iydro-4H-thieno[2s3-d]azepme, 2-(2,5-Dichloro-phenyl)-5,6,7s8-tetrahydro-4H-thieno[2,3-d]azepine; 2-(5-Fluoro-2-methoxy-phenyI)-5,6,7,8-tetrahydro-4H-thieno[2)3-d]a2epine) 2-(3)4)5-Trimethoxy-phenyl)-5,6s7]8-tetrahydro4H-thieno[2s3-d]azepines 2-(4-EtIioxy-phenyl)-5,6s7)8-tetrahydro-4H-thieao[2,3-d]azepine) 2-(4-EthyI-phenyI)-5s6,7a8-tetrahydio-4H-thieno[2,3-d]a2epine, 2-(3-Methoxy-phenyl)-5,6,7s8-tetrahydio-4H-thieno[2,3-d]azepme; 2-Phenyl-5,637,8-te1xahydro-4H-thieno[2,3-d]azepine, 2-(3-Fluoro-biphenyl-4-yl)-5)6J7,8-tetrahydro-4H-thieno[2)3-d]azepine, 2-(2-Fluoro-biphenyl-4-yI)-5)6,7,8-tetrahydro-4H-lhieno[2)3-d]azepine, 2~Bromo-3-methyl-5,6,7,8-tetrahydro-4H-thieno[233-d]azepine) 2-Bromo-3-methoxy-5)6,758-tetrahydro-4H-thieno[2,3-d]azepine, 2-Bromo-4-methyl-5,6,7,8-tetrahydro-4H4hienot2,3-d]azepine; 2-Bromo-S-methyl-5s6,7s8-tetiahydro-4H-thieno[233-d]azepine, 2-(PyiToIidme-l-sulfonyI)-5J657,8-tetrahydio-4H-thieno[2,3-d]azepine, 5,6,7,8-Tetrahydro-4H-tliieno[2,3-d]azepine-2-sutfomcaciddimethylamide, 3-Methyl-5,6J7>8-tetrahydro-4H-thieno[2s3-d]azepine-2-sulfonicacid dimethylamide, 2-Bromo-4)4aJ5)6,7,8-hexadydro-3H-l-thia-6-aza-cyclopenta[cd]azulene, 2-Methyl-4s4a,5,657,8-hexahydro-3H-l-thia-6-aza~cyclopenta[cd]azuIene) Trifluoromethyl-5,6,7,8,-tetraliydro-4H-thieno^^-dJazepine; 3-Bromo-2-tnfluoromethyl-5J6,7>8-tetrahydro-4H-thieno[2)3-d]azepine; 2-tert-ButyI-3-methoxy-5,6,7,8-tetrahydro-4H-thieno[2,3]d]azepine; 2-Naphthalene-l-yl-5>6,7,8-tetrahydro-4H-thienof2!3-d]azepine, 2-Naphthalene-2-yl-5,6s7)8-tetrahydro-4H-thieno[2,3-d]azepine, 2-(2,6-Difluoro-phenyI)-5s6,7,8-tetrahydio-4H-thieno[2,3-d]azepme; 3-(256-Difluoro-phenyl)-5J6,7JS-tetrahydio-4H-thieno[2,3-d]azepine, 2-(2-Chloro-6-fluoro-benzyI)-5)6J7s8-tetrahydro-4H-tIneno[2,3-d]azepine; 3-Bromo-2-(2-chloro-6-fluoro-benzyI)-5,6,7,8-tetrahydro-4H-thieno[2s3'd]azepines 2-Amino-5,6,7,8-tetrahydro-4H-thieno[253-d]azepine-3-carboxylic acid ethyl ester, 2-Ammo-5)617)8-tetrahydro-4H-thieno[2s3-c]azepine-3-carboxylic acid ethyl ester, 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine-3-carboxylic acid ethyl ester; and 5,6,7,8-Tetrahydro-4H-thieno[2,3-c]azepine-3-carboxylic acid ethyl ester Particularly preferred compounds include. 5,6,7,S-Tetrahydro-4H-thieno[2,3-d]azepines 9 WO 2006/004931 PCT/US2005/023282 2,3-Dichloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d)azepine, 2-Bromo-3-chloro-5,6J7J8-tetrahydro-4H-thieno[2,3-d]azepme; 2-Bromo-3-methyl-5s6,7,8-tetrahydro-4H-thieno[2,3-d]azepine; 2-Bromo-3-methoxy-5,657,8-tetrahydro-4H-thieno[2,3-d]azepine; 2-Bromo-4-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine5 2-Bromo-S-methyI-5s6s7J8-tetrahydro-4H-thieno[2s3-d]azepines 2-(Pyrrolidine-l-sulfonyl)-5,6,7s8-tetrahydro-4H-thieno[2,3-d]azepme, 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine-2-sulfomcacid dimethylamide, 3-Methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]a:;epine-2-suIfoiiicacid dimethylamide; 2-Biomo-4,4a)5)6J758-hexadydro-3H-l-tliia-6-aza-cyclopenta[cd]azulene; 2-MethyI-4,4a,5)65718-hexahydro-3H-l-thia-6-aza-cyclopenta[cd]azulene, Trifluoromethyl-5)6,7,8-tetrahydro-4H-thieno[2,3-d]azepine; , 3-Bromo-2-trifluoromethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepuie;and 2-tert-Butyl-3-methoxy-5,6)7,8-tetrahydro-4H-thieno[2s3]d]azepine. Certain compounds of the. invention may exist in different isomenc (e g enantiorners and distereoisomers) forms. The invention contemplates all such isomers both in pure form and in admixture, including racemic mixtures. Enol forms are also included The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, e.g., hemi-hydiate In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol, and the like are equivalent to the unsolvated forms for the purposes of the invention. Certain compounds of the invention also form pharmaceutically acceptable salts, e g., acid addition salts. For example, the nitrogen atoms may form salts with acids. Examples of suitable acids for salt formation are hydrochloric, sulfunc, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, furmanc, succinic, ascorbic, maleic, methanesulfonic and other mineral carboxylic acids well known to those in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The fiee base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous hydroxide potassium carbonate, ammonia, and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid salts are equivalent to their respective free base forms for purposes of the invention (See, for example S M Berge, et al., "Pharmaceutical Salts,"J Pharm Set, 66:1-19 (1977) which is incorporated herein by refeience. 10 WO 2006/004931 PCT/US2005/023282 As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, dnectly or indirectly, from a combination of the specified ingiedients in the specified amounts The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids The phrase "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgement, suitable foi use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensuiate with a reasonable benefit/risk ratio Pharmaceutically acceptable salts are well-known in the art For example, S. M. Berge et al describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences. 1977. 66' I etseq The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid Representative acid addition salts include, but aie not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), Iactate, maleate, methanesulfonate, ntcotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenyIpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate Also, the basic nitrogen-containing groups can be quatermzed with such agents as lower alkyl hahdes such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, mynstyl and stearyl chlorides, bromides and iodides; arylalkyl hahdes like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succmic acid and citric acid. Basic addition salts can be prepaied in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydi oxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amme. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali 11 WO 2006/004931 PCT/US2005/023282 metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammomum, dimethyl ammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others. Other representative organic amines useful for the formation of base addition salts include ethylenediarnine, ethanolamine, diethanolamine, pipendine, piperazine and the like Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated However, it is within i the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention can be employed in pure fonn or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily i usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder, activity of the specific compound employed, the specific composition employed; the age, body weight, 12 WO 2006/004931 PCT/US2005/023282 general health, sex and diet of the patient, the time of administration, route of administration, and rate of excretion of the specific compound employed, the duration of the treatment, drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved The total daily dose of the compounds of this invention administered to a human or lower animal may lange from about 0 0001 to about 1000 mg/kg/day. For purposes of oral administration, more preferable doses can be in the range of from about 0 001 to about 5 mg/kg/day If deshed, the effective daily dose can be divided into multiple doses for purposes of administration, consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. i The present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or moie non-toxic pharmaceutically acceptable carriers The pharmaceutical compositions can be specially formulated for oral administiation in solid or liquid form, for parenteial injection or for rectal administration The pharmaceutical compositions of this invention can be administered to 1 i humans and other mammals orally, rectally, parenterally, mtracisternally, intravaginally, i intrapentoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes of administration which include intravenous, inhamuscular, intraperitoiieal, intrasternal, subcutaneous and mtraarticular injection and infusion In another aspect, the present invention provides a pharmaceutical composition comprising a component of the present invention and a physiologically tolerable i diluent The present invention includes one or more compounds as described above formulated into compositions together with one or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for intianasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, among others. The compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary stent (a tubular device composed of a fine wiie mesh), oi via a biodegradable polymer. The compounds may also be complexed to ligands. such as antibodies, for targeted delivery 13 WO 2006/004931 PCT/US2005/023282 Compositions suitable for parenteral injection may comprise physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof. These compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also he desirable to include isotonic agents, for example sugars, sodium chloride and the like Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin,1 Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, macrocrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as pblylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile 14 WO 2006/004931 PCT/US 2005/023282 solid compositions which can be dissolved or dispersed in sterile water or other sterile mjectable medium just prior to use. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, suciose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enleiic coatings and other coatings well-known in the pharmaceutical formulating art They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or pieferentially, in a certain part of the intestinal tract, optionally, in a delayed manner Examples of embedding compositions which can be used include polymeric substances and waxes The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients i Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydiofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof. 15 WO 2006/004931 PCT/US2005/023282 Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfumingagents. Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds' of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound Compounds of the present invention can also be administered in the form of Hposomes As is known in the art, hposomes are generally derived fiom phospholipids or other lipid substances Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed m an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizes, preservatives, excipients,and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology.Volume XIV, Academic Press, New York, N Y. (1976), p. 33 etseq The term "pharmaceutically acceptable prodrugs" as used herein represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use m contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention Prodrugs of the present invention may be rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems.V. 14 of the A C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design.American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference. The compounds of the present invention may be prepared by the procedures set forth in Schemes. The general analytical conditions set forth were utililized in all examples. 16 WO 2006/004931 PCT/US2005/023282 General Analytical Conditions: HPLC analysis and purification was performed using a Waters 2525 binary gradient pump, Waters 2767 sample manager, Waters 2487 UV .detector (220 and 254 nM), and Waters Micromass ZQ electrospiay mass spec detector The Micromass ZQ was set for both positive and negative lomzation (cone voltage = 25 and 50, lespectively). Analytical HPLC analysis was performed as follows: Waters XTerra MS C18 50 x 4 6 mm 3 5um column Mobile Phase 1 OmM Ammonium Acetate buffer at pH 5 75 and Acetonitrile Acetomtrile 10 to 75% at 3.5 mmutes, 75 to 99% at 3 9 minutes, 99% hold to 4 2 minutes, 99 to 10% at 4.5 minutes, re-equilibrate Preparative HPLC was performed as follows Waters XTena Prep MS CIS 50 x 19 mm 5 urn column Mobile Phase: lOmM Ammonium Acetate buffer at pH 5 75 and Acetonitrile Acetonitiile: 10 to 99% at 8 minutes, 99% hold to 9 minutes, 99 to 10% at 9 5 mmutes, re- equilibrate NMR analysis was performed using a Biukei BioSpin UltiaShield NMR (300MHz) 17 i WO 2006/004931 PCT7US 2005/023 282 Scheme la: Synthesis of trifluoromethyl and monohalogenated thienylazepines. Scheme lb: Synthesis of dihalogenated and13-bromo-2-trifluoromethyl-thienyIazepines. 18 WO 2006/004931 PCT/US2005/023282 — i. Scheme 2: Synthesis of biaryl thienylazepines. Scheme 3: Synthesis of alkyl and benzyl ffaienylazapines analogs 19 WO 2006/004931 PCT/US2005/0 23282 Scheme 4. Synthesis of 2-bromo-3-methyl thienylazepine and 2,3-dichlorothienylazepine and related analogs. 20 WO 2006/004931 PCT7US2005/0 23282 I Scheme 5. Synthesis of 3-Methoxy thienylazepines 21 WO 2006/004931 PCT/US2005/0 23282 Scheme 6. Synthesis of halogenated 4-methyI-thienyIazcpines and related compounds * denotes that enantiomerically pure material was isolated ' i i i ' 22 WO 2006/004931 PCT/US2005/023282 Scheme 7. Synthesis of halogenated 8-inethyl-thienylazepines and related compounds * denotes that enantiomerically pure material was isolated Scheme 8. Synthesis of 2-sulfonamido- and 2-amido-thienyIazepines 23 WO 2006/004931 PCT/US2005/023282 Scheme 9: Synthesis of 3-alkyI thienylazapines and related analogs * denotes that enantiomencally pure material was isolated Scheme 10: Synthesis of tricyclic thiophene azepine derivatives * denotes that enantiornerically pure material was isolated 24 WO 2006/004931 PCT/US2005/023282 Scheme 11: Synthesis of furanylazepines 25 WO 2006/004931 PCT/US2005/023282 Example 1. 2-Bromo-5,6,7,8-tetrahvdro-4H-thieno[2.3-d1azepiDe (Scheme la) a)IEthoxvcarbonvI-(2-thioplien-2-vl'ethvlVamino"l-acetic acid ethvl ester: 2-Thiophen-2-yl-ethylamine (21g5165 mmol) was stirred in 1 liter of DC1-8 Ethyl giyoxylate (165 mmol, 50% in toluene) was added followed by 50 µL HOAc. The reaction was stirred for 10 minutes after which time NaBH(OAc)3 (214 mmol, 45g) was added slowly. After 15 minutes HOAc was added (214 mmol) and the reaction was stirred for 20 minutes. The reaction was concentrated and the crude material was dissolved in 500 mL each of THF and water. NaHCO3 (42g, 500 mmol) was acided followed by ethyl chloroformate (21 mL, 214 mmol). Saturated NaHCO3 was added slowly to the reaction until the gas evolution was minimal. After stirring overnight, the reactipn was diluted with EtOAc (400 mL) The product was extracted 2x into EtOAc, dried over MgSO4 and concentrated to give the subtitle product as a dark oil that was used without further purification b 1 rEthoxvcarbonvl-(2-thiophen-2-vl-eth\iVamino1-acetic acid The crude material from step a) (-165 mmol) was dissolved in EtOH (700 mL) and treated with 600 mL of 1M NaOH After stirring overnight, the reaction was acidified with concentrated HC1 to pH~l The crude reaction was diluted with EtOAc (400 mL) and washed with water. The water was back-extracted with EtOAc. The combined organic extracts were washed with water (2x) and dried over MgSO4. Concentration and evaporation from toluene (2x) gave the subtitle product as a solid, which was used without further purification c )4-Qxo-4,5,7.8-tetrahvdro-thieno[213-d|[azepine:6-carboxvlic acid ethyl ester The product of step b) (-165 mmol) was dissolved in 1L of DC1-8. DMF (100 wL) was added followed slowly by oxalyl chloride (21.7 mL, 247 mmol). After 1 hour the reaction was concentrated to dryness and the crude material was re-dissolved in DCE (1L) A1CI3 (55g, 410 mmol) was carefully added and the reaction was stirred at room temperature for 1/2 hour The crude reaction was quenched with ice, diluted with EtOH (300 mL), washed with water (3x), and dried over MgSO4- The title product was purified by silica gel chiomatography 26 WO 2006/004931 PCT/US2005/023282 (30% EtOAc in Hexanes) to give 10.5g of the subtitle compound as an off-white solid. MS ESI (positive) 240 (M+H) d 1 4.5,7.8-Tetrahvdro-thieiior2.3-d1azepine-6-carboxvlic acid ethyl ester A1C13 (3 95g, 29.7 mmol) was added to 50 raL DC1-8 at 0" C Borane-t-butyl amine complex (5.2g, 59.5 mmol) was added followed by the product of step c) (2 37g, 9.9 mmol) dissolved in DC1-8 (50 mL) The reaction was stirred for 2 hours at room temperature after which time another 3 95g (29 7 mmol) of AICI3 was added After stirring 10 minutes, the reaction was quenched carefully with 0 1 M HC1 (-50 mL). After concentration of the organic solvent, the crude reaction mixture was partitioned between 1M HC1 and EtOAc (70 mL each). The aqueous layer was back extracted lx EtOAc The combined organic layers were dried over MgSO4 and concentrated. The subtitle product (1.45g) was obtained after purification by silica gel chromatogiaphy (EtOAc/Hexanesigradient) 'HNMR (300 MHz, CDC13) 6 96 (d, J= 5 Hz, 1 H), 6 76 (d, Jh 5 Hz, 1 H), 4 18 (q, J= 7 Hz, 2 H), 3 52-3 78 (m, 4 H), 2 78- 3 08 (m, 4 H), 1 28 (t, J= 7 Hz, 3 H) MS" ESI (positive) 226 (M+H). e 1 5.6.7.8-Tetrahvdro-4H-thienor2.3-d1azepine- The product of step d) (200 mg, 0 89 mmol) was dissolved m 15 mL CHCI3 and treated with TMSI (4 5 mmol, 600 uL) After heating fo 70° C overnight, the reaction was carefully quenched with MeOH (10 mL) and ] M NaOH (20 mL) The subtitle compound was extracted into DC1-8 (3 x 20 mL). The extracts were dried over MgSO4 and concentrated to give 178 mg of the subtitle compound !H NMR (300 MHz, DMSO) 7 20 (d, J= 5 Hz, 1 H), 6 85 (d, J= 5 Hz, 1 H), 3 42-3 61 (m, 4 H), 2 71-3 03 (m, 4 H) MS- ESI (positive) 154 (M+H). f.1 4,5.7,8-Tetrahvdro-thieno[2.3-dlazepirie-6-carboxvhc acid tert-butvl ester: The product of step e) (296 mg, 1 93 mmol) dissolved m a 50:50 mixtuie of acetone/water (8 mL) was tieated with NaHCO3 (340 5 mg, 4.03 mmo!) at 0 °C, and stirred for 30 minutes To the lesulting solution was added di-tert-butyl dicarbonate (463 mg, 2 12 mmol). The reaction mixture was stirred at ambient temperature foi 14 hours. The reaction mixture was poured into water (50 ml) and extracted with EtOAc (3 x 50 ml) The combined organic phases were washed with brine (75 ml), dried (MgSO4), and concentrated m vacuo to give the crude product as an oil Purification by silica gel chromatography (EtOAc/Hexane-gradient) gave the subtitled compound as a clear oil, yield (93 %). JH NMR (300 MHz, CDCI3) 5 6.96 (d, J= 27 WO 2006/004931 PCT/US2005/023282 5 Hz, I H), 6 76 (d, /- 5 Hz, 1 H), 3.44-3.68 (m, 4 H), 2 76-3.06 (m, 4 H), 1.50 (s, 9 H). MS: ESI (positive) 254 (M+H). g.) 2-Bromo-4.5.7.8'tetrahvdro-thienof2,3-d]azeDine-6-carboxvIic acid tert-butvl ester. The product of step i) (10 mg, 0.039 mmol) dissolved in a S0"50 mixture of chloroform/acetic acid (1 ml) was treated with N-bromosuccinimide (7 mg, 0.041 mmol) The reaction mixture was stirred for 30 minutes at ambient temperature The reaction mixture was poured into water (5 ml) and extracted with CHCI3 (3 x 5 ml). The combined organic phases were washed with 10% KOH solution (5 mi), brine (5 ml), dried (MgSO4), and concentrated to give the crude product as an oil Purification by HPLC gave the subtitle compound as an oil. MS: ESI (positive): 332, 334 (M+H). h.~)2-Bromo-_5.6.7.8-tetrahydro-4H-thienor2J3-d1azepine The product of step g) (0 39 mmol) dissolved in ether (] ml) was treated with 4 M HCl/d/oxane (1 ml). The reaction mixture was stirred for 18 hours at ambient temperature The resulting precipitate was filtered and washed with anhydrous diethyl ether to give the title compound as its HC1 salt. 1H NMR (300 MHz, PMSO) 5 9 40 (s, 2 H), 7 05 (s, 1 H), 3.14-3.33 (m, 4 H), 2.94-3.23 (m, 2 H), 2.76-3.06 (m, 2 H) MS: ESI (positive). 232, 234 (M+H). Example 2. 2-_Chloro'5,6,7,8-tetrafavdro-4H-thieno[_23-d]azepipe (Scheme la) a) 2-ChIor '.7,8-tetrahvdro-thienor2.3"d]azepirie-6-carboxvlic acid tert-butvl ester. The produ Example 1, step f) (10 mg, 0,039 mmol, Example 1) in CHC13 (1 ml) and HOAc (I A'as treated with N-chlorsuccinimide (6 mg, 0.041 mmol) The reaction mixf stirred for 12 hours at ambient temperature. The reaction mixture was poured into water (5 ml) and extracted with CHCU (3x5 ml) The combined organic phases were washed with 10% KOH solution (5 ml), brine (5 ml), dried (MgSO4), and concentrated to 28 WO 2006/004931 PCT/US2005/023282 give the crude product as an oil Purification by HPLC gave the subtitled compound as a clear oil MS. ESI (positive)- 288 (M+H) b 1 2-Chloro-5.6.7.8-tetrahvdro-4H-thjenor2.3-d1azemne The title compound was prepared by the method of Example 1 step h), using the product of step a) ]H NMR (300 MHz, DMSO) '6 6 72 (s, 2 H)5 2 78-2 85 (m, 2 H), 2 72-2 79 (m, 4 H), 2 51-2 70 (m, 2 H). MS: ESI (positive) 188 (M+H). Example 3 23-Dibromo-5,6,7,8-tetrahvdro-4H thieno[23-dl azepine (Scheme lb) a) 2,3-Dibromo-4.5,7,8-tetrahydro-thieno[2,3-dlazepine-6-carboxvhc acid ethyl ester. The product of Example 1, step d) (95 ing, 0.42 mmol) was dissolved in CHCI3 (1 ml) and 1 HOAc (1 mL) and treated with NBS (661 mg, 0 42 mmol) The reaction mixture was stirred for 20 minutes at ambient temperature. To this mixture was added sodium acetate (138 mg, 1.68 mmol) and additional NBS (133 4 mg, 0 84 mmol). The reaction mixture was stirred at 60 °C until the leaction was complete as detei mined by LC/MS The leaction mixture was i cooled to ambient temperature, diluted with saturated sodium bicarbonate (2 ml), and extracted with CHCI3 (3x2 ml). The combined organic phases were washed with brine (10 ml), dried (MgSO4), and concentrated m vacuo to give the product as a crude oil. Purification by flash chromatography (EtOAc/Hexane-gradient) provided the subtitled compound as an oil MS ESI (positive) 384 (M+H). b.)2,3-Dibiomo-5,6.7,8-tetiahydro-4H-thienor2,3-dlazepine The product of step b) (0 42 mmol) was dissolved in DC1-8 (2 ml) and treated with lodotrimethylsilane (0 46 mmol). The reaction mixture was stirred at reflux for 24 hours. The reaction mixture was poured into saturated sodium bicarbonate (10 ml) and extracted with dichloromethane (3x5 ml) The combined organic phases were washed with brine (10 ml), dried (MgSO4), and concentrated in vacuo to give an oil Purification by preparative HPLC provided the title compound ]H NMR (300 MHz, CDC13) 5 2.94-3 05 (m, 4 H), 2 85-2.92 (m, 4 H), 1 92 (s, 1 H) MS ESI (positive)- 312 (M+H) 29 WO 2006/004931 PCT/US2005/023282 Example 4. 2,3-Dichloro-5,6,7,8-tetrhydro-4H-thieno[2,3-d1azepine (Scheme 4) a.) (4,5-Dichloro-thiophen-2"VlVoxo-acetic_acid ethvl ester- At 5-10 °C3 Chloro-oxo-acetic acid ethyl ester (5.43 ml, 48.7 mrnol) was added to 2,3-Dichlorothiophene (5 g, 32 6 mmol). A solution of AlCb (6.49 g, 48.7 mmol) dissolved in mtromethane (13 ml) was added dropwise such that the internal reaction temperature did not rise above 10 °C. After 1 hour, the reaction mixture was poured into ice water and extracted with CH2CI2 (2x100 ml) The organic layei was washed with 10% NaHCO3 (2x50 ml), water (1x50 ml) and brine (1x50 ml). Drying (NaiSO4) and concentration provided a light orange solid that was purified by silica gel chromatography (EtOAc/hexane-gradient) providing 6 8 g (82%) of the subtitle compound. b.1 (4,5-Dichloro-thiophen-2-vl)-hydroxv-acetic acid ethvl ester. A solution of the product from step a) (23 0 g, 90.9 mmol) in THF (500 ml) was treated with NaBH(OAc)3 (23 1 g, 109 mmol) and AcOH (250 ul) at 60 °C for 1 hour. The reaction was quenched with AcOH (8 ml) and concentiated to -250 ml The contents were diluted with H2O (400 ml) and extracted with CH2C12 (lx 400 ml; lx 100 ml). The organic layer was dried (MgSO4) and concentrated providing 23 g of the subtitle compound. lH NMR (300 MHz, CDCI3) d 6.91 (s, 1 H), 5.25 (dd, Jff 6 Hz, J2= 1 Hz, 1 H), 4 22-4.40 (m, 2 H); 3.52-3.60 (br m51 H), 1.33 (t, J= 7 Hz, 3 H). c) (4,5-Dichloro-3-methoxvcarbonvlmetnvl-thiophen-2-vlVacetic acid ethvl ester A solution of the product from step b) (12.2 ga 48 0 mmol) in decahn (145 ml) was treated with tnmethylorthoacetate (24 5 ml, 192 mmol) and hexanoic acid (0 61 ml). The flask was equipped with a vigreux column and heated to 180 °C. Additional hexanoic acid (3ml) was periodically added over 6 hours and the reaction was heated overnight. The reaction was concentrated on the rotavap and the residue was extracted with MeOH(1OO ml x2). The MeOH extracts were concentrated and purified by silica gel1 chromatography (EtOAc/Hexane-gradient) providing 4.56 g (29%) of the subtitle compound MS. ESI (positive). 311, 313 (M+H). 30 WO 2006/004931 PCT/US2005/0 23282 d 1 [3-Carboxvmethvl-4.5-dichloro-thiophcn-2-vlVacetic acid" A solution of the product from step c) (1.14gJ 3.66 mmol) in MeOH (7 ml) at 0 °C was treated dropwise with 2M NaOH (3 8 ml) The reaction was wanned to 22 °C and stirred overnight. The solvent was evaporated and the residue was dissolved in 2 M NaOH (50 ml) and extracted with ether (2x50 ml). The basic layer was cooled to 0 °C and acidified to pH 1 with 6 M HCl The acidic layer was back extracted EtOAc (4x100 ml) and the organic layer was dried (MgSO4) and concentrated. The crude solid was triturated with hexanes and filtered providing 2.75 g (73%) of the subtitle compound MS ESI (negative)- 267, 269 (M-H). e 12-r4.5-Dichloro-3-C2-hvdioxv-ethvl')-thiophen-2-vl1-ethanol: A solution of the product from step d) (2 5 g, 9.33 mmol) in THF (85 ml) was cooled to 0 °C and a 1M solution of BH3-THF (46 6 ml, A6.6 mmol) was added dropwise over 10 minutes and stined for an additional 20 minutes after the addition was complete The reaction was warmed to 22 °C and stirred for 2 hours The reaction was poured into ice cold sat NaHCO3 (150 ml) and extracted with EtOAc The ci'ude was passed through a plug of silica gel washing with EtOAc. Concentration of the eluent provided 1.99 g (88%) of the subtitle compound f) Methanesulfonic acid 2-r4.5-dichloro-2-f2-methanesulfonvloxv-ethvlVthiophen-3-vl"i-ethyl ester A solution of the product from step e) (1 99 g, 8 25 mmol) m CH2CI2 (41 ml) was cooled to 0 °C and treated with tnethylamine (3 4 nil, 24 7 mmol) followed by dropwise addition of methanesulfonyl chloride (1 4 ml, 18 1 mmol) over 10 minutes. After 45 minutes the crude reaction was diluted with CH2C12 (100 ml) and washed with ice water (25 ml), 10% citric acid (2x25 ml), sat NaHCO3 (2x25 ml) and brine (1x25 ml). The organic layei was dried (MgSO4), concentrated to 20 ml and diluted with anhydrous dioxane (76 ml). This mixture was concentrated to remove remaining CH2CI2 and the resulting dioxane solution was carried forward to the next reaction g)6-Benzvl-2,3-dichloro-5.6.7.8-tetrahvdro-4H-thienor2 The bismesylate dioxane solution generated in step f) was transferred to a 3-neck reaction flask equipped with a dropping funnel and condenser. Anhydrous potassium caibonate (4 93 31 WO 2006/004931 PCT/US2005/023282 g, 35.7 mmol) was added and the contents were heated to reflux. Next, a solution of benzylamme (2 71g, 25 3 mmol) in anhydrous^loxane (27 ml) was added dropwise over 45 minutes and heating was continued for 16 hours The salts were filtered off and the solvent was concentrated. The crude was purified by silica gel chromatography (EtOAc/Hexane-gradient) providing 1 43 g (62%) of the subtitle compound. 1H NMR (300 MHz, CDC13) 8 7.20-7.40 (m, 5 H); 3.73 (s, 2 H), 2 68-2 89 (m, 8 H); MS" ESI (positive)' 312, 314 (M+H). h^2.3-Dichloro-5.6.7.8-tetrahvdro-4H-thierLof2,3-d]azepineHvdrochloride-A solution of the product from step g) (727 m'g, 2 33 mmol) m anhydrous dichloroethane (116 ml) was cooled to 0 °C, treated with 1-Chloroethyl chloroformate (1.27 ml, 11 65 mmol) and the reaction was warmed to 22 °C for 1 hour. The reaction diluted with CH2CI2 (50 ml) and washed with sat NaHCO3 (25 nil). The sat NaHCO3 was back extracted with CH2CI2 and the combined organic layers were washed with brine (25 ml), dried (MgSCU) and concentrated providing an oily residue, which was taken up in anhydrous MeOH (75 ml) and refluxed for 1 hour. The MeOH was evaporated and the crude residue was triturated with ether and filtered providing 323 mg (54%) of the subtitle compound. !H NMR (300 MHz, DMSO) 5 9.60 (br s, 2 H); 3.14-3 28 (m, 6 H), 2 97-3.50 (m, 2 H); MS* ESI (positive). 222, 224 (M+H). Example 5 2-Bromo-3-chloro-5,6 a) 2-Bromo-3-chloro-4.5.7.8-tetrahvdro-thienor2.3-d]azepine-6-carboxvlic acid tert-butvl ester: The product of Example 1, step f) (54 mg, 0.21 mmol) was dissolved in CHCI3 (1 ml) and HOAc (1 mL) and treated with hydroquinone (2 mg, 0.02 mmol) and N-bromosuccinimide (38 mg, 0 21 mmol). After stirring at ambient temperature for 20 minutes, N-chlorosuccinimide (28 mg, 0.21 mmol) was added and stirring was continued at ambient temperature for 48 hours The reaction mixture was poured into saturated sodium bicarbonate (10 ml) and extracted with chloroform (3x5 ml). The combined organic phases 32 WO 2006/004931 PCT/US2005/023282 were washed with brine (10 ml), dried (MgSO4) and concentrated providing a crude oil, which was used without further purification b)-Bromo-3-chloro-5,6,7,8-tetrahvdro-4H-thienora.[2,3,d]-diazepineHvdrochloride. The title compound was prepared by the method of Example 1 step h), using the product of step a). ]H NMR (300 MHz, DMSO) 5 9 12 (bs, 2H), 3.22-3.31 (m, 4H)S 3.13-3.20 (m, 2H); 2.98-3.05 (m, 2H) MS ESI (positive): 266,268 (M+H) Example 6. 2-(4-TrifluorQmetho\T-phenYlV5,6,7,8-tetrahvdro-4H-tfaienor2,3-dlazepine (Scheme 2) a')2-('4'Trifluoromethoxv-phenvl)-4.5,7.8-tetrahvdio-thienor2.3-d1azepine-6-carboxvlic_acid tert-butvl ester: The product of Example 1, step g) (20 mg, 0 06 mmol) was dissolved in DME (5 mL) and treated with palladium acetate (1 mg, 0 004, mmol), triphenylphosphine (4 7 mg, 0 018 mmol) and 1 M sodium carbonate (Na2COj, 0 45 mL). The mixture was stirred at ambient temperature for 5 minutes and then treated with 4-trifluoromethoxy phenylboronic acid (28.4 mg, 0 138 mmol) After heating for 5 houis at 85 °C, additional 4-trifluoromethoxy phenylboronic acid (6.2 mg, 0 03 mmol) was added and stirring continued for 12 hours The reaction mixture was cooled to ambient temperature, passed through a pad of dry celtte and filtered through a silica plug eluting with PC1-8 (5 ml) and EtOAc (5 mL) The filtrate was evaporated to give the subtitle compound as a crude oil, which was used without further purification b.)2-(4-Trifluoromemoxy-phenvl')-5.6,7.8-tetrahvdro-4H-thienor2.3-dlazepine The title compound was prepared by the method of Example 1 step h), using the product of step a) The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the title compound. JH NMR (300 MHz, DMSO) 5 7 76 (d, J= 8 Hz, 2 H), 7.48 (d, /= 8 Hz, 2 H), 7.36 (s, 1 H), 2.77-3.06 (m, 8 H),'2 0 (s, 1 H) ) MS ESI (positive) 314 (M+H). 33 WO 2006/004931 PCT/US2005/023282 Example 7. 2-(2-Trifluorometfavl-phenYl)-5,6,7.8-tetrahvdro-4H-thienor2,3-d1azepine (Scheme 2) a)2-(2-TrifluorQmethylrphenyl),5.7.S-tetrahvdrQ-thieno[2.3-d1azepine-6-carboxylic acid tert-butvl ester: The subtitle compound was prepared by the method of Example 6 step a), using 2- trifluoromethyl-phenyl boronic acid b")2-(2-Trifluoromethyl-phenvl)5.6,7.8-tetrahvdio-4H-thienor2.3-dlazepme: The title compound was prepared by the method of Example 1 step h), using the product of step a) The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the title compound. MS- ESI (positive): 298 (M+H). Example 8. 2-(4-Fluoro-phenvO-5,6,7,8-tetrahvdro-4H-thieno[2,3-d1azepine (Scheme 2) a) 2-(4-Fluoro-phenvl)-4,5,7.8-tetrahvdro-thienor2,3-d1azepine-6"Carboxvlic acid tert-butvl ester: The subtitle compound was prepared by the method of Example 6 step a), using 4-fluorophenyl boronic acid. b.')2>(4-Fluoro-phenvn-5,6J,8-tetrAhvdro-4H-thienor2.3-dla2epine: The title compound was prepared by the method of Example 1 step h), using the product of step a). The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the title compound. MS. ESI (positive). 248 (M+H) 34 WO 2006/004931 PCT/US2005/023282 Example 9. 2-(3-Chloro-4-fluoro-nhenyl)-5,6,7,8-tetrabydro-4H-thienof2.3-d1azepine (Scheme 2) a ) 2-(3-Chloro-4-fluoro-phenvl)4,5.7.8-tetrahydro-thieno[2.3-dla2epine-6-carboxvlic acid tert-butvl ester: The subtitle compound was piepared by the method of Example 6 step a), using 3-chloro-4- fluorophenyl boronic acid b)2-[3-Chloro-4-fluoro-phenvI)-5,6.7.8-tet]-ahydro-4H-thienor2.3-d1a2epine: The title compound was prepared by the method of Example 1 step h), using the product of step a) The reaction mixture was concentrated m vacuo and puufied by preparative HPLC to give the title compound. MS ESI (positive) 282 (M+H). Example 10 2-(2,5-Dichloro-phenyI)-5,6J,8-tetrahvdro-4H-thienof2,3-d]azepine (Scheme 2) a) 2-a,5-dichloro-phenyl)-4.5.7.8-tetrahvdro-thienor2,3-d1azepine-6-carboxvlic acid tert-butvl ester The subtitle compound was prepared by the method of Example 6 step a), using 2,4-dichlorophenyl boronic acid b>2-(2,5-Dichloio-DhenvlV5.6.7.8-tetrahydro-4H-thienof2,3-d]azepine. The title compound was prepared by the method of Example 1 step h), using the product of step a). The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the title compound MS. ESI (positive). 298 (M+H). 35 WO 2006/004931 PCTAJS2005/023282 Example 11_ 2-(4-Ethvl-pheayl)5,6,7,8-tetrahydro-4H-thieno[23-dlazepine (Scheme 2) ai 2-(4-Ethvl-phenvn-4,5,7,8-tetrahvdro-thienor2.3-d1azepine-6-carboxvlic acid t&rt-butyl ester. The subtitle compound was prepared by the method of Example 6 step a), using 4- ethylphenyl boronic acid b) 2-C4-Ethvl-phenvlV5,6.7.8-tetrahydro-4H-thieno[2.3-d]azepine- The title compound was prepared by the method of Example 1 step h), using the product of step a) except the reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the title compound. MS: ESI (positive): 258 (M+H). Example 12. i 2-(3-Methoxv-pbenvl)-5,6,7,8-tetrahvdro-4H-thienof23-dlazepine (Scheme 2) a) 2-('3-Methoxv-phenvl')-4,5,7,8-tetrahvdro-thienor2,3-d')azepine-6-carboxvlic acid tert-butyl ester. The subtitle compound was prepared by the method of Example 6 step a), using 3-methoxyphenyl boronic acid. b.~)2-(3-Methoxv-phenvlV5.6.7.8-tetrahvdio-4H-thienor2.3-d1azepine-The title compound was piepared by the method of Example 1 step h), using the product of step a) except the reaction mixture was concentrated in vacuo and purified by preparative HPLC to give the title compound MS ESr (positive): 260 (M+H). 36 WO 2006/004931 PCT/US2005/0 23282 Example 13. 2-PhenYl-5,6,7,8-tetrahvdro-4H-thienor2,3-dkzepine (Scheme 2) a) 2-PhenvI-5.6.7.8-tetrahydro--4H-thienor2,3-dlazepme-6-carboxvlic acid tert-butvl ester The subtitle compound was prepared by the method of Example 6 step a), using phenyl boronic acid b) 2-Phenvl-5.6.7.8-tetrahvdro-4H-thienor[2,3-d1azepine The title compound was prepared by the method of Example 1 step h), using the pioduct of i step a) except the leaction mixture was concentrated in vacuo and purified by preparative HPLC to give the title compound MS. ESI (positive). 230 (M+H) Example 14 2-(2-Chloro-6-fluoro-benzvlV5,6,7,8-tetrdhydro-4H-thienoF2,3-d1azepine (Scheme 3) i a) 2-Bromo-4,5,7,8-tetrahvdro-mienor2.3-d1azepine-6-caiboxvlic acid ethyl ester The product of Example 1, step d) (300 mg, 1 33 mmol) was dissolved in chloroform (3ml) and acetic acid (3ml) and treated with N-bromosuccinimide (248 mg, 1 40 mmol) and stirred at ambient temperature for 30 minutes The reaction mixture was carefully quenched by dilution with saturated sodium bicarbonate|(20 ml) and extracted with chloroform (3 x 20 ml). The combined organic phases were washed with brine (50 ml), dried (MgSO4), and evaporated in vacuo to give a crude oil Purification by preparative TLC (hexane/ethyl acetate) provided the subtitle compound as1 an oil MS. ESI (negative) 302 (M-H) b) 2-(2-ChIoro-6-fluoro-benzyl')-4.3.7.8-tetrahvdro-thienor2,3-d1azepine-6-carboxvIic acid ethyl ester" 37 WO 2006/004931 PCT/US2005/023282 The product of step a) (144 mg, 0 48 minol) m 2 ml dry diethyl ether was tteated with NiCl2(dppp) (3-5 mol %) followed by dropwise addition of 2-chIoro-6-fluorobenzyl magnesiumbromide (0 25 M solution, 1 2 mmol, 4.8 ml) over 30 minutes at ambient temperature The reaction mixture was heated to reflux for 12 hours. The reaction mixture was cooled to ambient temperature, quenched with 1M HC1 (10 ml) and extracted with diethyl ether (3 x 10 ml). The combined etheriextiacts were washed with water (30 ml), dried (MgSO4), and evaporated providing a crude oil. Purification by HPLC provided the subtitle compound. MS calculated for C]SH]9C1FNO2S4-H 369, observed 369. c.)2-a-Chloro-6-fluoro-benzvtV5.6,7.8-tetrahvdro-4H-thienor2.3-d]azep_ine. The title compound was prepared by the method of Example 3 step b), using the product of step b) !H NMR (300 MHz, C6D6) 6 6.94 (d, J= 8 Hz, 1 H), 6 52-6 70 (m, 2 H), 6.49 (s, 1 H), 4.17(s, 2 H), 2.47-2.78 (m, 8 H), 2.03 (s, 1 H) MS- ESI (positive): 296 (M+H) Example 15. 3-Bromo-2-(2-chloro-6-fluoro-beDgvlV5.6.7,8-tetrahvdro-4H-thienof2,3-dlazepine (Scheme 3) a.)3-Bromo-2-(2-chloro-6-fluoro-benzvlV4.5.7,8-tetrahydro-thienor2,3-dlazepine-6-carboxvlic acid ethyl ester: The product of Example 14, step b) (49 mg, 0 13 mmol) was dissolved in a 1:1 mixture of CHCl3/HOAc (1 mL) and treated with sodium acetate (43 mg, 0 52 mmol) and N-bromosuccinimide (27 mg, 0 15 mmol). The reaction mixture was heated at 60 °C and stirred for 30 minutes. The reaction mixture was' cooled to ambient temperature, diluted with water (5 ml), and extracted with chloroform (3x5 ml). The combined organic extracts were washed with 10 % K.OH, dried (MgSO4),jand evaporated in vacuo to give the subtitle compound as an oil, which was used without furthei purification 38 WO 2006/004931 PCT/US2005/023282 b.}3-Bromo-2-(2-chloro-6-fluoro-benzvlV5.6.718-tetrahvdro-4H-thienor2.3-dlazepme: The title compound was prepared by the method of Example 3 step b), using the product of step a) ]H NMR. (300 MHz, C6D6) 6 6.33-6 78 (m, 3 H), 4.09 (s, 2H),2 18-3.20 (m, 8 H), 1.62 (s, 1 H). MS calculated for C15H14BrClFNS+H 374, observed 374. Example 16 2-Bromo-3-methvl-5,6,7,8-tetrahvdro-4H-thienor2.3-d1azepine (Scheme 4) a ) (5-Bromo-4-methvl-thiophen-2-vl')-hvdrt3xv-acetic acid ethyl ester 2-Bromo-3-methyI thiophene (13 2 mL, 113 inmol) was stirred in 1 liter of DC1-8 at 0° C Ethylchloro oxalate (13.9 mL, 124 mmol) was added followed by A1C13 (16 5g, 124 mmol) After stirring for 10 minutes, the reaction was carefully poured over ice (—500 mL) and EtOH (~300 mL). Upon warming to room temperature, the product was extracted into DC1-8 (2x) and dried over MgSO4. Concentration gave 37 5g of an orange solid which was dissolved in THF (1 liter) and-treated with NaBH(OAc)3 (36g, 170 mmol) After heating to 60° C for 1 hour, the reaction was cooled and quenched with HO Ac (13 6 mL, 226 mmol) The leaction was concentrated and the residue was partitioned between DC1-8/EtOH (5.1) and water The aqueous layer was extracted lx with DC1-8 and the combined organic extracts were dried over MgSO4 and concentrated to give the subtitle compound (35g), which was used without further purification b.1 (5-Bromo-3-ethoxycarbonvlmethvl-4-methvl-thiophen-2-vlVacetic acid ethyl ester The product of step a) (-113 mmol) was treated with 300 mLdecahn, 103mLof triethylorthoacetate (565 mmol), and hexanoic acid (6 2 mL, 50 mmol). The reaction was heated to 180" C for 10 minutes after which time another 50 mmol of hexanoic acid was added After heating 10 minutes, additional hexanoic acid was added (50 mmol) and the reaction was again heated for 10 minutes The reaction was cooled and concentrated under vacuum with heat to give the sub-title compound as an oil that was used without further purification 39 WO 2006/004931 PCT/US2005/023282 c) l-[5-Bromo-S-Q-hydroxv-ethyl)-methvl-thiophen-l-vll-ethanol The product of step b) (-113 mmol) was dissolved in EtOH (1 liter) and cooled to 0° C then treated with 170 mL of 2M NaOH. After stirring for 24 hours, the resulting precipitate was filtered and washed with ethanol to give 15g of the disodium salt A portion of this material (3g, 8.9 mmol) was dissolved in 90 mL THF and treated with 4M HC1 in dioxane (4 mL, 16 mmol) After stirring vigorously for Vi hour, BH3-THF (44.4 mL of 1M) was added and the solution was stirred at room temperature for 2 hours. The reaction was quenched cautiously with saturated NaHCC>3 and concentrated The crude residue was partitioned between EtOAc and water (150 mL each) The organic layer was dried over MgSO4 and concentrated to give 1.94g of the sub-title compound 1 d.) 6-Benzvl-2-bromo-3-methvl-5,6J.8-tetrahvdro-4H-thienor2.3-d1azepine: The product of step c)(l 94g, 7 3 mmol) was dissolved in 75 mL of DC1-8, cooled to 0" C and treated with Et3N (29 3 mmol, 4 1 mL) followed by MsCl (22 mmol, 1 71 mL) After 1 hour, additional Et3N and MsCl were added (2eq and 1 5eq, respectively) and the reaction was stirred an additional hour The crude reaction was poured over 5% citric acid, extracted into DC1-8, and washed with saturated NaHCO3 After drying the organic solution over MgSO4 and concentration, the crude product was dissolved in dioxane (200 mL) and tieated with K2CO3 (36.6 mmol, 5 Og). After heating to reflux, BnNH2 (22 mmol, 2.4 mL) was added and the reaction was refluxed overnight. The reaction was cooled, filtered, and concentrated. The sub-title compound was purified by silica gel chromatography (10% EtOAc in hexanes) to give 419 mg of the subtitle compound e~)2-Bromo-3-methvl-5.6.7.8-tetrahvdro-4H-thienof2.3"d1azepine. The product of step d) (80 mg, 0 24 mmol) was dissolved in 2 mL DCE. 2-ChloroethyI chloroformate (103 uL, 0 95 mmol) was added and the reaction was stirred at room temperature for 15 minutes. The reaction was quenched with 3 mL MeOH and the crude mixture was briefly heated to reflux and then concentrated to dryness. The crude residue was dissolved in lA mL of MeOH and triturated with ether to give 47 mg of the title compound as a white solid JH NMR (CD3OD) 5 3 36-3.30 (m, 4H), 3.12 (t, J= 5 2 Hz, 2H), 3 00 (t, J= 5 1 Hz, 2H), 2 11 (s, 3H); MS ESI (positive) 246,248 (M+H). 1 40 WO 2006/004931 PCT/US2005/023282 Example 17 3-Methoxv-2-methvl-5,6,7,3-tetrahYdro-4H-thieno[2,3-d1azepine (Scheme 5) a") 5-Oxo-azepane-1.4-dicarboxvhc acid diethvl ester: 4-Oxo-piperidme-l-carboxyhc acid ethyl ester (20g, 117 mmol) was dissolved in 120 mL Et2O and cooled to -30*C BF3-OEt2 (14 8 mL) and ethyl diazoacetate (16 mL, 152 mmol) were added simultaneously (each in 15 mL Et20) over the couise of 30 minutes, maintaining an internal tempeiatuie of approximately —20° C. The leaction was warmed to room temperature and stirred for 3 hours after which time the leaction was quenched carefully with 30% K2CO3 (60 mL). The organic layer was dried over K2CO3 and concentrated to give 30 4 g of the subtitle compound. b) 3-Hvdroxv-4.5.7,8-tetrahydro-thienor2.3-dlazepine-2.6-dicarboxvlic acid diethvl ester The product of step a) (20g, 77.8 mmol) was dissolved in 300 mL EtOH The solution was cooled to 0° C and HC1 gas was bubbled into the reaction for 10 minutes. Ethyl thioglycolate (7 8 mL, 77.8 mmol) was added and HC1 gas was again bubbled into the solution for 3 minutes. After stirring for 4 days at room temperature, the reaction was concentrated, neutralized with saturated NaHCO3, and extracted into ether (200 mL). After drying the extracts over MgSO4 and concentration, the residue was dissolved m EtOH (100 mL) and treated with NaOEt (100 mL of 21% NaOEt in EtOH). After stirring overnight, the reaction was diluted with 500 mL water and washed with 300 mL DC1-8. The DC1-8 was extracted with 150 mL water and then lepeatedly extracted with 5% KOH (~10x 75 mL). The combined aqueous extracts were acidified with concentrated HC1 and extracted into DC1-8 (4x200 mL). The DC1-8 extracts were dried over MgSO4 and concentrated to give 7.5g of the subtitle compound as an oil. c.) 3-Methoxv-4,5.7.8-tetrahydro-thienor2.3-dlazepine-2.6-dicaiboxvlic acid diethvl ester The product of step b) (2.3g, 7.3 mmol) was dissolved in 60 mL of 1 1 MeOH THF Diisopropylethylamine (1 9 mL, 10 9 mmol) was added followed by TMSCHN2 (10 9 mL of 2M) The reaction was stirred overnight at room temperature then quenched carefully with 41 WO 2006/004931 PCT/US200 5/023 282 0.4 mL HO Ac. After stirring Va hour, the reaction was partitioned between DC1-8 and 1M HC1 (100 mL each) The organic layer was dried over MgSO4 and concentrated to give 2 75g of the subtitle compound d ) 2-Hydroxvmethyl-3-methoxv-4,5,7,8--tetrahvdro-thieno[23-dlazepine-6-carboxvlic acid ethyl ester The product of step c) (2 5g, 7 8 mmol) was dissolved in 125 mL dry THF and treated with LiCI (0 65 g, 15.3 mmol) followed by LiBH4 (15 3 mL of 2M). After stirring for 1 hour, the reaction was quenched caiefully with EtOH and HOAc till no gas evolution was observed The crude reaction mixture was partitioned between water and DC1-8. The organic extract was dried over MgSC>4 and concentrated to give 2.3g of a clear oil which was purified by silica chromatogiaphy (30% EtOAc/Hex) to give 1 03g of the subtitle compound e.")3-Methoxv-2-methvl--5,6.7.8-tetrahvdro-4H-thienol2,3-d]azepine: The product of step d) (70 mg, 0.25 mmol) was dissolved in 10 mL EtOAc and treated with 35mg of 10% Pd/C (wet, Degussa type E10 L) and stirred rapidly under an atmosphere of H2 for 3 hour The leaction was filtered and concentrated. The crude residue was dissolved in I mL EtOH and treated with 1 mL 40% aqueous KOH. After heating to 80° C overnight, the reaction was diluted with water and the product was extracted 2x into DC1-8 The title compound was obtained upon purification by preparative HPLC-MS. *H NMR (CDCI3) 8 1 3 69 (s, 3H), 3.21-3.14 (m, 4H), 3 00 (t; /« 5 2 Hz, 2H), 2.88 (t, /= 5.1 Hz, 2H), 2.29 (s, 3H), MS. ESI (positive). 198 (M+H). Example 18. 2"Bromo-3-methoxv-5,6,7,8-tetrahvdro-4H-thieno[2,3-d1azepine (Scheme 5) a.) 3-Metlioxv-4,5.7.8>tetrahydro-thienor2,3-dlazepine-2,6-dicarboxvlic acid 6-ethvl ester: The product from Example 17, step c) (1.0,ga 3.19 mmol) was stirred in ethanol (20 mL) with 1 lMNaOH (6.38 mL, 6.38 mmol) at 80° C overnight. The reaction was cooled to ambient temperature, acidified with a 10% HC1 solution, and extracted with 5% EtOH in DC1-8 (x2) 42 WO 2006/004931 PCT/US2005/023282 The organic extracts were combined and washed with water. The organic layer was dried over NaSCU, filtered, and concentrated to give 912 mg of the subtitled compound that was used without further purification MS ESI (positive). 300 (M+H). b) 2-tert-Butoxvcarbonvlamino-3-methoxv-4.5,7.8-tetrahvdro-thienor2,3-d1azepine-6-carboxvhc acid ethyl ester. A solution of the product from step a) (790 mg, 3.01 mmol) was stirred with diphenylphosphoryl azide (647 uL, 3 01 mmol) and triethylamme (41S uL, 3 01 mmol) m tert-butano\ (20 mL) at 80° C overnight. The|reaction was cooled to room temperature and i pouied into a saturated aqueous solution of NaHCC>3. The resultant mixture was extracted with ethyl acetate The oiganic extract was dried over MgSCU and purified by silica gel chromatography (EtOAc/Hex-gradient) to give 852 mg of the subtitle compound MS. ESI (positive). 370 (M+H) c 1 3-Methoxv-4.5.7t8-tetrahvdro-thienof2,3-d1azepine-6-carboxvhc acid ethvl ester. The product from step b) (256 mg, 0 69 mmol) was stirred in TFA (2 mL) for 30 minutes The reaction was concentrated and dissolved m EtOH (5 mL) Isoamyl nitrite (140 uL, 1 04 mmol) and Cu(OAc)2 (188 mg, 1.04 mmol) were added to the solution and the reaction was stirred at room temperature overnight The leaction was filtered through a silica plug and purified by silica gel chromatography (EtOAc/Hex-gradient) to give 17 mg of the subtitle compound MS* ESI (positive) 271 (M+H). d 1 2-Bromo-3-methoxy-4.5,7 ester: The product of step c) (17 mg, 0.067 mmol) was dissolved in 1 mL 1:1 acetic acid CHCI3 and treated with 7V-bromosuccinimide (12 mg, 0 068 mmol). After 30 minutes, the reaction solution was added diopwise to a solution of saturated sodium bicarbonate and extracted with ethyl acetate. The organic extracts weie concentrated to give the subtitle compound, which was used without further purification e > 2-Bromo-3-methoxv-5.6.7.8-tetrahydro-4H-thienor2.3-d1azepine A 40% KOH solution in water (1 mL) was added to the product of step d) (-0 067 mmol) in 1 mL ethanol. After heating to 80° C overnight, the reaction mixture was cooled to ambient temperature and partitioned between water and DC1-8. The organic extract was concentrated 43 WO 2006/004931 PCT/US2005/023282 and purified by preparative LC1-8S to give the title compound. ]H NMR (CD3OD) 5 3 83 (s, 3H), 3.22-3.28 (m, 4H), 3.05 (t, J= 5 1 Hz, 2H), 2 93 (t, J= 5.1 Hz, 2H); MS: ESI (positive) 262 (M+H). Example 19. 2-Chloro-3-methoxV"516,7,8-tetrahYdro-4H-thienoF2.3-d1azepine (Scheme 5) a > 2-Chloro-3-methoxv-4,5,7,8-tetrahydro-thienor2.3-d1azepine-6-carboxvUc acid ethyl ester The sub-title compound was prepared by the method of Example 18, step d) using the product from Example 18, step c) and AT-chlorosuccLnimide b.t2-Chloro-3-methoxy"5.6,7,8-tetrahvdro-4H-thienor2,3-d]azepine: The title compound was prepared by 1lie method described in Example 18, step e) using the product from step a) 'HNMR (CD3OD) 5 3 86 (s, 3H)5 3.19-3.26 (m, 4H), 3.01 (t, J= 5 4 Hz, 2H), 2 88 (t, J- 5 4 Hzs 2H). MS ESI (positive): 218 (M+H) Example 20 2-Isopropenvl-3-methoxv-5,6t7,8-tetrahydro-4H-thieno[2,3-dlazepine (Scheme 5) 1 a) 2-l5opropenvl-3-methoxv-4.5.7.8-tetrahvdro-tiiienof2.3-d]azepine-6-carboxvlic acid ethyl ester: The product of Example 17, step c) (59 mg, 0 19 mmol) was dissolved in 5 mL THF and cooled to 0" C. MeMgBr (0.54 mL of 1.4M) was added and the reaction was stirred at room temperature for 1 hour The reaction was quenched with water and HOAc (-3 mL of 10.1) 44 WO 2006/004931 PCT/US2005/023282 and extracted into DC1-8 (2x 5mL) The organic extracts weie concentrated to give the subtitle compound as an oil, which was used without further purification. b)2-Isopiopenyl-3-methoxv-5.6.7.8-tetrahvdro-4H-thienor2,3-d1azepine-The product of step a) (-0.19 mmol) was treated with 2 mL each of EtOH and 40% aqueous KOH After heating to 100" C for 16 hours, the reaction was diluted with water and the product was extracted into DC1-8 (2x 4 mL). The organic extracts were concentrated and the title compound was purified by preparative HPLC-MS ]H NMR (CD3OD) d 5.41 (s5 1H), 5 02 (t, J= 1 6 Hz, 1H), 3.14-3.08 (m, 4H), 2 96 (t, J= 5 1 Hz, 2H), 2 82 (t, J= 5 1 Hz, 2H), 2 09 (s, 3H), MS ESI (positive) 224 (M+H). Example 21 2-tert-Butyl-3-methvI-5,6,7,8-tetrah^'dro-4H-thienor2,3-dlazepine (Scheme 9) a) 3-Methvl-4.5,7.8-tetrahvdro-thienor2.3-d1azepme-6-carboxvlic acid ethyl ester The product of Example 16, stepe) (475 mg,'l.68 mmol) was dissolved in 50 mL DC1-8 and treated with Et3N (585 wL, 4 2 mmol) and einyl chloroformate (210 wL, 2.18 mmol) After stnring for 3 days at room temperature, the reaction was concentrated onto silica gel and pmified by silica gel chromatography (EtOAc/Hex-gradient) to give 380 mg of the ethyl carbamate. The ethyl carbamate (60 mg, 0.19 mmol) was dissolved in 4 mL EtOH and treated with -10 mg of 10% Pd/C (wet, Degussa grade E101) and stirred under an atmosphere of hydrogen for 12 hours Filtration and concentration gave the sub-title compound b) 2-tert-Butyl-3-methvl-4,5,7,8-tetrahydro-thienor2.3-dlazepine-6-carboxvlic acid ethyl ester: The product of step a) (37mg, 0 16 mmol) was stirred in 1 5 mL DCE t-Butanol (19 wL, 0 20 mmol) was added followed by BF3-OEt2 (20 uL, 0 16 mmol). The leaction was heated to 60° C for 1 hour Concentration gave the subtitle compound, which was used without further purification. 45 WO 2006/004931 PCT/US2005/023282 c) 2-tert-Butyl-3-methvl-5.6 J,8-tetrahydro-4H-thieno[2.3-d1azepine: The product of step b) was tieated with 2 mL each of EtOH and 40% aqueous KOH. After heating to 100° C for 12 hours, the reaction was cooled, diluted with water, and extracted 2x into DC1-8 The title product was purified by preparative HPLC-MS. MS. ESI (positive). 224 (M+H) Example 22 2-Isopropvl-3-methoxv-5,6,7,8-tetrahydro-4H-thienoT2,3-d1azepme (Scheme 5) a) 2-Isopropyl-3-methoxv-4,5,7,8-tetrahvdro-thienof2,3-dlazepine-6-carboxvHc acid ethyl ester. The product of Example 20, step a) (35 mg, 0 13 mmol) was dissolved in 2 mL of EtOH and treated with 50 mg of 10% Pd/C (wet, Degussa grade E101). After stirring 3 hours at room temperature under an atmosphere of hydrogen, the reaction was filtered and concentrated to give the subtitle compound as an oil. b.")2-Isopropvl-3-methoxv-5,6.7,8-tetrahydro-4H-thieno[2.3-d1azepine: The product of step a) was deprotected according to the procedure described for Example 20, step b). Purification by preparative HPLC-MS gave the title compound. JH NMR. (CD3OD) d 3.69 (s, 3H), 3.29-3.21 (m, 5H), 3 03 (t, J = 5.2 Hz, 2H), 2.88 (t, /- 5.4 Hz, 2H), 1.24 (d, J = 6 9 Hz, 6H); MS: ESI (positive)- 226 (M+H). Example 23. 2-Bromo-4-metbvl-5,6,7,8-tetrahydrO"4H-thienot2.,3-d1azepine (Scheme 6) a.') 4-Methvlene-4,5.7,8-tetrahydro-thienor2,3-d1azepine-6-carboxylic acid ethyl ester: 46 WO 2006/004931 PCT/US2005/023282 Methyl tnphenylphosphonium bromide (6.3 g, 17 6 mmol) was dissolved in 150 mL THF and cooled to 0" C KHMDS (3 2g, 16 2 mmol) was added portionwise and the reaction was stirred for !/2 hour The product of Example 1, step c) (3 Og, 12 5 mmol) was added as a solution in 25 mL THF The reaction was warmed to room temperature and stirred for 1 hour The mixture was concentrated and the title product was purified by silica gel chromatography (EtOAc/Hexanes-gradient) to give 2.6g of the subtitle compound b 14-Methvl-4.5.7,8-tetrahydro-thienor2,3-d1azepme-6-carboxvlic acid ethyl ester The product of step a) (2 6g, lO.Smmol) was dissolved in 100 mLEtOH and tieated with 0 5g of 10% Pd/C (wet, Degussa type E101) Aftei stirring rapidly for 14 hours under an atmosphere of hydrogen, the reaction was filtered through celite and concentrated to give 2 3g of the subtitle compound as a clear oil MS- ESI (positive): 240 (M+H) c) 2.3-Dibromo-4-methvl-4.5.7.8-tetrahvdro-thienor2.3-dlazepme-6-carboxvhc acid ethvl ester The product of step b) (5 6g, 23 4 mmol) was dissolved in 250 mL cyclohexane and treated with NaHCO3 (11 8g, 140 mmol). Bromine (3.6 mL, 70 3 mmol) was added slowly and the reaction was stirred for XA hour at room temperature after which time it was quenched with Na2S03 (180 mL of 5% aqueous) After stirring rapidly for 15 minutes, EtOAc was added (-100 mL) and the organic layer was removed and dried over MgSO4 to give 9 lg of the subtitle compound The racemic material was separated using a Chiralpak® AD-RH® 20 x 250 mm column from Chiral Technologies (10 mL/min MeOH mobile phase) to give enantiomer 1 (rt = 9 8 minutes) and enantiomer 2 (rt = 11.4 minutes) of the subtitle compound. d) 4-Methvl-4,5,7,8"tetiahydro-thienor2,3-d1azepine-6-carboxvlic acid ethvl ester The product of step c) (800 mg, 2.0 mmol) was dissolved in 150mLEtOH and tieated with 800 mg of 10% Pd/C (wet, Degussa grade E101) After stirring overnight, another 300 mg of Pd was added and stirring was continued 3 hours The reaction was filtered through cehte, diluted with DC1-8 (300 mL), and washed with water (1x300 mL). The organic layer was dried over MgSCU and concentrated to give 475mg of the subtitle compound e) 2-Bromo-4-methyl-4.5.7.8-tetiahydro-thieno[2.3-d1azepine-6-carboxvlic acid ethvl ester' The product of step d) (80 mg, 0 35 mmol) was dissolved m 2 mL of 1 • 1 CHCl3/HOAc N- Bromo-succinimide (62 mg, 0.35 mmol) was added and the reaction was stined for 15 47 WO 2006/004931 PCT/US2005/023282 minutes. Concentration and purification by silica gel chromatogiaphy gave the subtitle compound as a yellow oil. f~)2-Bromo-4-methvl-5.6.7.8-tetrahvdro-4H-thieno[2.3-dlazepme The product of step e) was deprotected accoidmgto the procedure described for Example 20, step b) to provide the title compound. 'H NMR (CD3OD) d 6 97 (s, 1H), 3 46-3.11 (m5 7H), 1.39 (d, ./= 7 2 Hz, 3H); MS* ESI (positive) 246,248 (M+H) Example 24, 2-BromQ-8-methvl-5,6,7,8-tetrahvdro-4H-thieno[23-d1azepine (Scheme 7) a ^ 2-Thiophen-3-vl-ethvlamroe Thiophen-3-yl-acetonitnle (5.0g, 40.6 mmol) was dissolved in 50 mL THF. BH3-THF (61 mL, 1M in THF) was added slowly The reaction was heated to 60° C overnight then quenched carefully with 4% aqueous HC1 until no effervescence was observed. The crude reaction mixture was then partitioned between EtOAc and water (300 mL each) The aqueous layer was acidified with 30% NaOH to pH -12 and the product was extracted into DC1-8/EtOH (4:1, 3x). The organic extracts were dried over MgSCU and concentrated to give 2.9g of the subtitle compound as an oil. b 1 fEthoxvcarbonvl-(2-thiophen-3-vl-emyl1-amino]-acetic acid ethyl ester: 1 The subtitle compound was prepared from the pioduct of step a) using the procedure described in Example 1, step a). c > rEthoxvcarbonvl-(2-thiophen-3-vl-ethv1Vamino"1-acetic acid" The subtitle compound was prepared from the product of step b) using the procedure described for Example 1, step b) 48 WO 2006/004931 PCT/US2005/023282 d) 8-Oxo-4.5.7,8-tetrahvdro-thienor2,3-d1azepme-6-carboxvhc acid ethyl ester-The subtitle compound was prepared fiom the product of step c) using the procedure described for Example 1, step c) e) 8-Methvlene-4.5,7.8-tetiahvdio-thieno[2.3-d1a2epme-6-carboxvlic acid ethyl ester MePPh3Br (785 mg, 2 2 mmol) was dissolved in 7 mL THP and treated with KHMDS (408 mg, 2 04 mmol) After stnring for 30 minutes, the product of step d) (350 mg, 1 5 mmol) was added as a solution in 3 mL THF After stirring for 1 hour, the reaction was diluted with EtOAc and washed with water The organic layer was concentrated and the product was purified by silica gel chromatography (EtOAc/Hex-gradient) to give 188 mg of the subtitle compound. f) 8-MethvI-4.5.7.8-tetrahydro-thieno["2.3-d'jazepine-6-carboxvlic acid ethyl ester. The product of step a) (59 mg, 0 25 mmol) was dissolved in 5 mL EtOH and treated with 75 mg of 10% Pd/C (wet, Degussa grade El01) After stirring for 1 hour under an atmosphere of hydrogen, the reaction was filtered and concentiated to give the subtitle compound that was used without further purification g)2-Biomo-8-methvl-5,6,7,8-tetrahvdro-4H-thienor2,3-dla2epine-The product of step f) was dissolved in 2 mL of 1 1 CHCU/HOAc and treated with NBS (62mg, 0 35 mmol) After stirring for 10 minutes, the reaction was concentrated to dryness and filtered through a pad of silica gel, eluting with EtOAc. The eluent was concentrated and the residue was treated with 2 mL each EtOH and 40% aqueous KOH. After heating for 14 hours at 100° C, the reaction was diluted with water and extracted 2x into DC1-8 The title compound was purified by preparative HPLC-MS. The two enantiomers were separated using a Chiralpak® AD-RH® 20 x 250 mm column from Chiral Technologies (10 mL/min MeOH mobile phase) to give enantiomer 1 (rt = 11 6 minutes) and enantiomer 2 (rt = 13 6 minutes) of the title compound. 1H NMR (CD3OD) 8 6 92 (s, 1H), 3 48-3.34 (m, 3H), 3.17-2 99 (m, 4H), 1 44 (d, J= 7.2 Hz, 3H), MS.lESI (positive). 246, 248 (M+H). Example 25 2-Bromo-S-spirocYcloproDvl-5,6,7,8-tetrahvdro-4H-thienor2,3-d1azepine (Scheme 7) ! 49 WO 2006/004931 PCT/US 2005/023282 a.) 8-Spirocvclopropyl-4 5.7.8-tetrahvdro-thienor2.3-d]azepme-6-carboxvlic acid ethvl ester. A solution of ZnCl2 (2 49 rnL, 1M in hexane) and CH2I2 (100 uL, 1.24 mmol) were stirred at 0° C in DC1-8 for 30 minutes The product from Example 24, step e) (59 mg, 0 25 mmol) was added as a solution in DC1-8 (lmL) and the reaction was stirred at ambient temperature for 48 hours. The reaction was diluted with water and extracted into DC1-8. The organic layer was washed with saturated NH^Cl, water, and brine. Concentration of the organic layer gave the sub-title compound, which was used without further purification. MS: ESI (positive). 252 (M+H). b ) 2-Bromo-8-spirocvclopropvl-4.5.7,8-tetrahvdro-thienor2,3-d1azepine-6-carboxyhc acid ethvl ester. The subtitle compound was prepared by the method described in Example 18, step d) using the product from step a) and was used in crude form without purification. MS: ESI (positive) 330 (M+H). c)2-Bromo-8-spirocvclopropvl-5.6.7.8-tetrahydro-4H-thienof2.3-d]azepine: The title compound was prepared by the method described in Example 18, step e) using the product from step b). !H NMR (CD3OD) d 6.84 (s, 1H), 3.20 ft J~ 5 1 Hz, 2H), 3.02 ft J» 5.1 Hz, 2H), 3.06 (s, 2H), 1.08 (d, J= 9.6 Hz, 2H), 1.05 (d, J= 9 6 Hz, 2H). MS ESI (positive)* 258 (M+H). Example 26. 2- a ) 2-Chlorosulfonvl-4.5.7.8-tetrahvdro-thieno[2,3-d1azepme-6-carboxvlic acid ethvl ester 50 WO 2006/004931 PCT/US2005/O23282 The product of Example 1, step d) (400 mg, 1.8 mmol) was dissolved in 10 mL CHC13 and treated with chlorosulfonic acid (355 wL, 1 8 mmol). After 5 minutes, the reaction was quenched over ice and immediately extracted into DC1-8 (2x10 mL) The organic extracts were dried over MgSO4 and concentrated to give 200 mg of the subtitle compound as a solid, which was used without further purification b)2-fPvrroiidine-l-sulfonvl)5,6,7,8-tetTahvdro-4H-thienor2.3-dlazepme-The product of step a) (45 mg, 0 14 mmol) was stirred in 2 mL CHCI3 and treated with pyrrohdine (46 iiL, 0.55 mmol) After stirnhg for 5 minutes, the reaction was concentrated to dryness and the residue was dissolved in 2 mL each of EtOH and 40% aqueous KOH. The reaction was heated in a sealed vessel to 100'C overnight Upon cooling, the reaction was diluted with water and the pioduct was extracted into DC1-8 (4x 3 mL) The organic extracts were concentrated and the title compound was purified by prepaiative HPLC-MS ]H NMR (CD3OD) 5 7 42 (s, 1H), 3 43-3 34 (m, 4H), 3 31-3.24 (m, 6H), 3.13 (t, J= 5.2 Hz, 2H), 1 81-1 76 (m, 4H); MS ESI (positive) 287 (M+H) Example 27. 5,6,7,8-Tetrahydro-4H-thienof2,3-d1azeipine-2-sulfonicacid dimethylamide (Scheme 8) i The title compound was prepared according to the procedure outlined in Example 26, step b) using dimethyl amine hydrochloride and Et3N 1H NMR (CD3OD) d 7.38 (s, 1H), 3.44-3.27 (m, 4H), 3.32-3.26 (m, 2H), 3 17-3 14 (m, 2H), 2.72 (s, 6H); MS- ESI (positive)- 261 (M+H) Example 28 3-Methyl-5,6/7,8-tetrahydro-4H-thienoT2,3-dlazemne-2-suIfonic acid dimethylamide (Scheme 8) 51 WO 2006/004931 PCTYUS2005/023282 a ) 2-Chlorosulfonyl-3-methyl-4,5,7,8-tetrabydro-thieno[2,3-d]azepme-6-carboxylic acid ethyl ester The subtitled compound was prepared according to the procedure outlined in Example 26, step a) using the intermediate from Example 21, step a). The product was used without further purification b ) 3-Methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine-2-sulfonic acid dimethylamide. The title compound was prepared according to the procedure outlined for Example 26, step b) using the product from step a) and dimethyl amme hydrochlonde and Et3N ]H NMR (CD3OD) d 3 41-3 35 (m, 4H), 3 24 (dd, J = 5.1,6 6 Hz, 2H), 3 04 (t, J= 5.2 Hz, 2H), 2 75 (s, 6H), 2 41 (s, 3H); MS: ESI (positive): 275 (M+H) Example 29. 5,6,7,8-Tetrahvdro-4H~thienof2.3-d1azepine-2-carboxvIic acid cyclppentvlamide (Scheme 8) a ) 2-Cvclopentvlcarbamovl-4.5,7,8-tetrahvdro-thienor2,3-d]azepine-6-carboxylic acid ethyl ester* The product from Example 1, step d) (50 mg, 0.222 mmol) was stirred with isocyanato-cyclopentane (25 uL, 0 222 mmol) and A1C13 (35 mg, 0.266 mmol) in dichloroethane (2 mL) at ambient temperatuie for 4 hours. Additional isocyanato-cyclopentane (25 pLt 0.222 mmol) and AICI3 (35 mg, 0.266 mmol) were added and the reaction was stirred overnight. The reaction was partitioned between water and DC1-8. The organic layer was washed with water and concentrated to give the sub-title compound, which was used without further purification. MS* ESI (positive)- 337 (M+H). b) 5.6.7 The product from step b) (37 mg, 0.111 mmol) was treated with TMSI (50 uL, 0 333 mmol) in DC1-8 (2 mL) and stirred at 50° C overnight. The reaction was then treated with methanol 52 WO 2006/004931 PCT/US2005/023282 (1 mL), concentrated to dryness, and purified by preparative LC-MS to give the title compound MS: ESI (positive). 265 (M+H) Example 30 5,6.7.8-Tetrahvdro-4H-thienof2,3-dlazei]ihe-2-carboxvIic acid dimethvlamide (Scheme 8) a 12-Dimethvlcarbamovl-4.5.7.8-tetrahvdro-thienor2.3-d1azepine-6-caiboxvIic acid ethyl ester" The product from Example 1, step d) (50 mg, 0 22 mmol) was stirred in dichloroethane with phosgene lminium chloride (84 mg, 0 518 mmol) and AICI3 (35 mg, 0.266 mmol) at 75° C overnight. The reaction was cooled to ambient temperature, quenched with water (2 mL) and extracted into DC1-8 The organic layer was then passed through a pad of celite and concentrated to give the subtitle compound that was used without further purification. MS. ESI (positive): 297 (M+H). b) 5,6.7,8-Tetrahvdro-4H-thienor2.3-d1a2eDine-2-carboxylic acid dimethytamide The title compound was prepared by the method described in Example 29, step b) using the pioduct from step a) MS: ESI (positive) 225 (M+H) Example 31 (R,SV2-ChIoro-8-methYl-5,6,7,3-tetrahvdro-4H-thienof2,3-dlazepine (Scheme 7) ( The title compound was prepared from the intermediate described m Example 24, step f) and N-chloro succinimide using the procedure from Example 24, step g) MS" ESI (positive) 202, 204 (M+H) 53 WO 2006/004931 PCT/US2005/023282 Example 32 i 23-Pibromo-4-methvl-5,6,7,8-tetrahydro-4H-thienor23-d1azepine (Scheme 6) i The product of Example 23, step c) was deprotected by the procedure described in Example 20, step b) to provide the title compound, !H NMR (CD3OD) d 3 60-3 52 (m, 3H), 3.35-3 11 (m, 4H), 1.33 (d, J~ 6 9 Hz, 3H), MS. ESI (positive)- 324, 326, 328 (M+H) Example 33. (R,SV2-Bromo-4-methoxv-5.,6J,8-tetrahvd]ro-4H-thienof2,3-d1azepine (Scheme 6) I a.1 (R,S1-4-Hvdroxy-4,5,7.8-tetrahvdro-thienof2.3-dlazepine-6-carboxylic acid ethyl ester Sodium borohydride (154 mg, 4.18 mmol) was added to a solution of the product from Example 1, step c) (200 mg, 0.837 mmol) in ethanol (2 mL) and stirred at ambient temperature for 30 minutes. The reaction was quenched with acetic acid and partitioned between DC1-8 and water. The organic layer was washed with water and concentrated to give the subtitle compound, which was used without further purification. MS: ESI (positive)- 264 (M+Na). b.) (R.S)-4-Methoxv-4,5,7,8-tetrahvdro-thienor2.3-d')azepine-6-carboxvlic acid ethyl ester' The product from step a) (160 mg, 0.664 mmol) in anhydrous THF (2.0 mL) was cooled to -78° C A solution of 1M LHMDS m THF (800 uL, 0.797 mmol) was added to the solution and the reaction was warmed to room temperature Mel (63 |iL, 0 996 mmol) was added to the reaction and stirred at ambient temperature for 72 hours The reaction was partitioned between ethyl acetate and water and the organic layer was concentrated to give the subtitle 54 WO 2006/004931 PCT/US2005/023282 compound that was purified by silica gel chromatography (EtOAc/Hex-gradient) prior to use in subsequent steps MS ESI (positive)- 278 (M+Na) c) (R.SV2-Bromo-4-methoxv-4,5,7.8-tetrahvdro-thieno|"2.3-d1azepine-6-carboxvlic acid ethyl ester The subtitle compound was piepared by the method of Example 18, step d) using the product fiom step b) d~)fR,SV2-Bromo-4-methoxv-5.6.7.84etrahvdro-4H-thienor2,3-d1azepine The title compound was prepared by the method described in Example 18, step e) using the product from step c) MS- ESI (positive) 262 (M+H) Example 34 2-Bromo-8,8-dimethYl-5,6,7,8-tetrahvdroL4H-thienor2.3-d1azepine (Scheme 7) ai 8.8-Dimethvl-4.5.7.8-tetiahydro-thienor2.3-d1azepine-6-carboxvlic acid ethyl ester DC1-8 (5 mL) was cooled to -78° C and treated with T1CI4 (274 wL, 2 5 mmol) followed by Me2Zn(1.3 mL of 2M solution in toluene). After stirring the daik red solution at-78° Cfor 15 mmutes, the product of Example 24, step d) (100 mg, 0.42 mmol) was added slowly as a solution in 5 mL DC1-8 The reaction was warmed to 0° C and stured for 2 hours The leaction was quenched over ice and the product was extracted into DC1-8 (2x). The organic extracts were dried over MgSO4 and concentrated to give the subtitle compound, which was used without furtheripurification b')2-Bromo-S,8-dimethvl-5,6.7,8-tetrahvdro-4H-thienor2.3-d1azepine The product of step a) (45 mg, 0 18 mmol) was dissolved in 4 mL of 1 1 HOAc/CHCl3 and treated with NBS (44mg, 0 25 mmol) After stirring for Vz hour, the reaction was concentrated to dryness and treated with 2 mL each of EtOH and 40% aqueous KOH. The mixture was heated to 100" C overnight, cooled, and diluted with water. The product was extracted 2x into DC1-8 (2x4mL), concentrated, and purified by preparative HPLC-MS. 1H 55 WO 2006/004931 PCT/US2005/023282 NMR (CD3OD) d 7.19 (s, 1H), 3 40-3 34 (m, 2H), 3 28 (s, 2H), 3 21-3.17 (m, 2H), 1 41 (s, 6H), MS ESI (positive) 260, 262 (M+H) Example 35 (R,SV2-Bromo-4-etbvl-5%6 a ) (E.Z>-4-Ethvhdene-4,5.7.8-tetrahvdro-thierior2,3-d1azepine-6-carboxvlic acid ethyl ester. KHMDS (233 mg, 1 17mmol) was added to a solution of (Ethyl)tnphenylphosphonium bromide (466 mg, 1.26 mmol) in THF (5 mL) cooled to 0° C and the resultant solution was stirred for 20 minutes. The product from Example I, step c) (200 mg, 0 837 mmol) in THF (5mL) was added to the reaction and the reaction was warmed to ambient temperature over 1 hour. The reaction was quenched with water and partitioned between ethyl acetate and water. The organic layer was concentrated and the jciude product was purified by silica gel chromatography (EtOAc/Hex-gradient) to give 151 mg of the subtitle compound as a mixture of the E and Z iosmers MS: ESI (positive). 252 (M+H). b.) (R,S)-4-Ethvl-4,5.7.8-tetrahvdro-thienor2.3-d1azepine-6-carboxvlic acid ethyl ester The product of step a) (151 mg, 0.602 mmol) was stirred with 10% Pd/C (50 mg) in ethanol (3 mL) under H2 (latm) for overnight. The reaction was filtered over celite and concentrated to dryness to give the 131 mg of the subtitle compound as a purple oil that was used without further purification. MS- ESI (positive): 254 (M+H) c.) fR The subtitle compound was prepared by tine method of Example 18, step d) using the product 1 from step b) and was used in crude form without purification. d)(R,SV2-Bromo-4-ethvl-5.6.7.8-tetrahvdro-4H-thienor2.3-d'|azepine- 56 WO 2006/004931 PCT/US2005/023282 The title compound was prepared by the method described in Example 18, step e) using the product from example step c) !HNMR (CD3OD) d 6.88 (s, 1H), 3.19-3 28 (in, 3H), 2 92-3.15 (m, 4H), 1 61-1 84 (m, 2H), 0 98 (t, J= 7 3 Hz, 3H) MS ESI (positive)- 260 (M+H) Example 36 2-Bromo-3,4-dimethvI-5,6,7,8-tetrahvdro-4H-thieno[2,3-d1azepine (Scheme 9) a) 3-Bromo-4-methvl-4.5.7.8-tetrahvdro-thienor2.3-dla2epme-6-carbo>:vlic acid ethyl ester The product of Example 23, step c) (enantiomer 2, 0 75g, 1 9 mmol) and Zn (0.25g, 3 8 mmol) were heated to leflux m 20 mL each water and HO Ac After Vz hour, the reaction was cooled, diluted with EtOAc, and washed 2x with water. The organic layer was dried over MgSO4 and concentrated to give 490 mg of the subtitle compound as an oil, which was used without further purification. b 13.4-Dimethvl-4.5.7>8-tetrahvdro-thienor2,3-d1azepine-6-carboxylic acid ethyl ester 1 1 The product of step a) (150 mg, 0.47 mmol) was dissolved in 3 mL dioxane and treated with 1 Me2Zn (0 47 mL of 2M in toluene) and Pd(ddf)2Cl2 (11 mg, 0 014 mmol) After heating to 100" C for 3 hours, the reaction was quenched with water and filtered. The filtrate was partitioned between EtOAc and water (7 mL each) The organic layer was dried over MgSO4 and concentrated to give 92 mg of the subtitle compound, which was used without further purification c) 2-Bromo-3.4-dimethvl-4,5.7.8-tetrahvdro-thienor2.3-d1azepine-6-carboxvlic acid ethyl ester The product of step b) (92 mg, 0 36 mmol) was dissolved in 4 mL of 1 1 HOAc/CHCl3 and treated with NBS (67 mg, 0 38 mmol). After stirring for 1/2 hour, the reaction was diluted with EtOAc (70 mL), washed with water (3x30 mL), and 1M NaOH (2x30 mL). The organic solution was dried over MgSO4 and concenti ated The crude pi oduct was purified by silica gel chromatography (EtOAc/Hex-gradient) to give 90 mg of the subtitle compound. 57 WO 2006/004931 PCT/US2005/023282 d ~) 2-Bromo-3.4-dimethvl-5.6.7,8-tetrahvdro-4H-thienor2.3-d]a2epinc The product of step c) was deprotected as described for Example 20, step b) The title compound was obtained after purification by preparative HPLC-MS. 1H NMR (CD3OD) 6 3.59-3 08 (m, 7H), 2.13 (s, 3H), 1 31 (d, J= 7.2 Hz, 3H), MS. ESI (positive). 260, 262 (M+H). *Enantiomer 1 can be piepared in a similar fashion Example 37 2-Bromo-4,4a,5^6,7,8-hexahvdro-3H-l-thia-6-aza-cyclopentafcdlazulene (Scheme 10) a) (E,Z1-4-Ethoxvcarbonvlmethvlene'4,5,7,8-tetrahvdro'-thienor2,3-d1azepine-6-carboxvUc acid ethyl ester: To a solution of triethyl phosphonoacetate (4 mL, 16 74 mmol) in anhydrous THF (100 mL) was added a 1.6M LHMDS solution m THF (15 mL) The mixture was stirred at for 15 minutes followed by the addition of product from Example 1, step c) (2.0 g, 8 37 mmol). The reaction was stirred overnight then treated with additional LHMDS solution (3.2 mL of 1.6 M) and triethylphosphonoacetate (800 u,L, 3.3 mmol). After stirring 3 hours, the reaction was quenched with water and diluted with DC1-8. The organic layer was dried over MgSO4 and concentrated to give the subtitle compound, which was used without further purification MS- ESI (positive): 310 (M+H). b ) (R.S)-4-Ethoxvcarbonylmethvl-4,5.7,8-tetrahydro-thienof2.3-d]azepine-6-carboxvlic acid ethyl ester- The product of step a) (2.47 g, 8 mmol) was stirred with 2 Og of 10% Pd/C (wet, Degussa grade E101) m methanol (8 mL) under H2 (latm) for 72 hours. The reaction was filtered over celite and concentrated to dryness to give the subtitle compound as an oil, which was used without further purification. MS: ESI (positive)* 312 (M+H). 58 WO 2006/004931 PCT/US2005/023282 c.) (R.S)-4-Carboxymethvl-4,5 J,8-tetrahvdro-thienor2.3-d]azepine-6-carboxylic acid ethyl ester. The product of step b) (2 47 g, 8 mmol) was stirred m ethanol (60 mL) with 1M NaOH (30 mL) at ambient temperature overnight The reaction was acidified with 1M HCI and partitioned between DC1-8 and water The organic layer was washed with water, dried over i MgSO4, and concentrated to dryness to give the 2 13g of the subtitle compound as a yellow oil, which was used without further purification. MS* ESI (positive). 284 (M+H) d) (R,S)3-Oxo-3,4,4a,5,7,8-hexahvdro-l-thia-6-aza-cvcIoDentarcd]a2ulene-6-carboxvlic acid ethyl ester ' Oxalyl chloride (3mL, 37 7 mmol) and a catalytic amount of DMF were added to a solution of the product from step c) (2.13 g, 7 54 mmol) in DC1-8 (40 mL) and the reaction was stirred at ambient temperature foi 1 hour The reaction was concent ated to dryness and redissolved in dichloroethane (100 mL) AICI3 (2 0 g, 15.1 mmol) was added to the solution and the reaction was stirred at ambient temperature overnight. The reaction was quenched with ice and partitioned between DC1-8 and water The organic layer was concentrated to give the subtitle compound, which was purified by silica gel chromatography (EtOAc/Hex-gradient, isolated 1.02g) prior to use in subsequent steps MS ESI (positive) 266 (M+H). e 1 (R,S)-3,4,4a,5,7,8-Hexahvdro-l-thia-6-aza-cvclopentarcd1azuIene-6-carboxylic acid ethyl ester AICI3 (627 mg, 4.72 mmol) was added to BH^BuNH2 (492 mg, 5.66 mmol) in DC1-8 (2mL) at 0° C The solution was stirred for 10 minutes then treated with the product from step d) (250 mg, 0 943 mmol) as a solution in DC1-8 (1 mL). After warming to rt, the reaction was quenched with 0.1M HCI dropwise and concentrated to dryness. The reaction was diluted in 1M HCI and extracted into EtOAc The organic layer was concentrated to give the sub-title compound, which was purified by silica gel chromatography (EtOAc/Hex-gradient) prior to use in subsequent steps MS ESI (positive): 252 (M+H) f) CR.SV2-Bromo-3.4.4a.5.7.8-hexahydio-l-1hia-6-aza-cvclopentarcd1azulene-6-carboxylic acid ethyl ester The sub-title compound was prepared by the method of Example 18, step d) using the product from step e) and was used in crude form without purification. 59 WO 2006/004931 PCT/US2005/023282 g) 2-Bromo-4,4a.S.6,7,8-hexahvdro-3H-l-thia 6-aza-cvcIopentafcdiazulene: The title compound was prepared by the method described in Example 18, step e) using the product from step f) and purified by preparative HPLC-MS The two enantiomers were separated using a Chiralpak® AD-RH® 20 x 250 mm column from Chiral Technologies (10 mL/mm MeOH mobile phase) to give enanf lomer 1 (rt = 8.6 minutes) and enantiomer 2 (rt = 10 8 minutes) of the title compound. "HNMR (CD3OD) d 3 45-3 56 (m, 2H), 2 89-3 08 (m, 3H), 2 45-2.65 (m, 4H), 1 99-2 04 (m, 2H) MS" ESI (positive)- 260 (M+H). Example 38. (R,S)-2-Methvi-4,4a,S,6J,8-hexahvdro-3H-l-thia-6-aza-cvclopentafcdla2uIene: (Scheme 10) a~)(R.S)-2-Methvl-3.4.4a,5.7.8-hexahvdro-l"thia-6-aza-cvclopenta|"cd1azulene-6-carboxyhc acid ethyl ester: A solution of 2M IvfoZn in toluene (1 5mL) was added to the product from Example 37, step f) (50 mgs 0 150 mmol) and Pd(dppf)2Cl2"(4 mg, 0.0045 mmol) in dioxane (1 mL). After ~ i heating to 100° C for 3 hours, the reactionjwas quenched with water and extracted into ethyl acetate. The organic layers were combined and concentrated to give the subtitle compound that was used in crude form without purification. MS: ESI (positive)- 266 (M+H) b.>(R.SV2-MethvI-4,4a,5,6.7,8-hexahvdro-3H-l-thia-6-aza-cvclopentarcd1azulene: The title compound was prepared by the method described in Example 18, step e) using the product from step a) and purified by preparative HPLC-MS 1H NMR (CD3OD) d 3 52-3 64 (m, 2H), 3.25- 3.30 (m, 1H), 2 86-3 10 (m, 4H), 2.46-2 73 (m, 4H), 2.23 (s, 3H) MS: ESI (positive): 194 (M+H). Example 39. 2-tert-Butyl-4,4a,5,6,7,8-hexahvdro-3H-l-thia-6-aza-cyclopeptaTcd1azulene: (Scheme 10) 60 WO 2006/004931 PCT/US2005/023282 a)(R,S)-2-tert-Butvl-3,4,4a.5,7,8-hexahydro-l-thia-6-aza-cvclopentarcdla2;ulene-6-carboxylic acid ethvl ester- The product from Example 37, step e) (100 mg, 0.398 mmol), BF3 OEt (50 µL, 0 398 mmol), and tert-butanol (56 µL, 0 597 mmol) were heated to 75° C for 2 hours in dichloroethane (1 mL). The reaction was quenched with water and extiacted into DC1-8. The organic layers were combined and concentrated overnight to give the subtitle compound that was used in crude form without purification MS ESI (positive) 308 (M+H). b) 2-tert-Butvl-4.4a.5.6,7,8-hexahvdio-3H-l-thia-6-aza-cyclopentarcdlazulene The title compound was prepared by the method described in Example 18, step e) using the product from step a). The two enantiomers were separated using a Chiralpak® AD-RH® 20 x 250 mm column from Chiral Technologies (10 mL/min MeOH mobile phase) to give enantiomer I (rt = 7.7 minutes) and enantiomer 2 (rt = 10 2 minutes) of the title compound. ]HNMR (CD3OD) 5 3.20-3.34 (m, 2H)5 2.91-3 01 (m, 1H), 2.56-2 91 (m, 5H), 2 27-2 3-9 (m, 2H), 1.74-1 88 (m, 1H), 1.30 (s, 9H) MS ESI (positive) 236 (M+H) Example 40 2-TrifluoromethYl-5.6,7,S-tetrahvdro-4K-thienol2,3-d1azepine (Scheme la) a) 2-Iodo-4.5.7.8-tetrahvdro-thienor2t3-d1azepine-6-carboxvlic acid ethvl ester A solution of the product from Example 1, step d) (470 mg, 2.09 mmol) in CHC13 (5 ml) and AcOH (5 ml) was treated with A^-iodosuccinimide (493 mg, 2.19 mmol) at 22 °C. After 1 hour, the reaction was diluted with CH2CI2 (20 ml) and poured into sat. NaHCO3 (20 ml) The organic layer was washed with brine (1x20 ml), dried (MgSO4) and concentrated providing the crude subtitle compound as a yellow oil, which was used without further purification. 61 WO 2006/004931 PCT/US2005/023282 b 12-Tnfluoromethvl-4.5.7.8-tetrahvdro-thienor2.3-d1azepin_e-6-carboxvlic acid ethyl ester. A solution of the product from step a.) (75 nig, 0 21 mmol) in DMF (0 5 ml) and NMP (0 5 ml) was treated with bipyridyi (43 mg, 0 27 mmol), Cul (44 mg, 0 23 mmoi), KF (13 mg, 0.23 mmol) and trimethylsilyltrifluoromethaLne (2.1 ml, 1.05 mmol). The reaction mixture was heated to 80 °C for 3 days. The reaction was cooled and filtered through celite washing with EtOAc (20 ml). The eluent was washed with brine (2x3 ml) and dried (MgSO4) i providing the subtitle compound as a brown oil that was used without further purification. c.')2-Trifluoromethvl-5.6,7.8-tetrahvdro-4H-thienor2.3-dlazepme' A solution of the crude product from step b ) (26 mg, 0.089 mmol) in CH2C12 (0 5 ml) was treated with lodotnmethylsilane (19 ul, 0.134 mmol) at 50 °C for 12 hours. The reaction was quenched by the addition of MeOH and the solvent was evaporated The residue was purified by preparative LC/MS providing the title compound NMR (300 MHz, CDC13) 6 7 18 (s, 1 H); 3.42-3 56 (m, 6H), 3 31-3.39 (m, 2 H), 2 09 (s, 1 H), MS: ESI (positive): 222 (M+H). Example 41. 3-Chloro-2-trifluoromethvl"5 a) 2.3-Dichloro-4,5 J.8-tetrahvdro-thienof23-d1azepine-6-carboxvIic acid ethyl ester: A solution of the product from Example f, step H) (323 mg, 1.25 mmol) in CH2C12 (6.25 ml) was cooled to 0 °C and triethylamine (522 µl, 3 75 mmol) was added followed by ethylchloroformate (144 ul, 1.5 mmol) After 1.5 hours the reaction was poured into water (25 ml) and diluted with EtOAc (50 ml). The organic layer was dried (MgSO4) and concentrated providing 341 mg (93%) of the subtitle compound that was used without further purification. MS: ESI (positive)- 294,296 (M+H) b 1 3-Chtoro-2-iodo-4.5.7.8-tetrahvdro-thie_nor2.3-dlazepine-6-carboxvlic acid ethyl ester: A solution of the product from step a) (129 mg, 0.44 mmol) in anhydrous THF (2.2 ml) was cooled to -78 °C and treated with 1.5 equiv of n-BuLi (412 ul, 0.66 mmol) After lh, the 62 WO 2006/004931 PCT/US2005/023282 reaction was quenched with a THF solution of I2 (167 mg, 0 66 mmol). The reaction was warmed to 22 °C and diluted with EtOAc (15 ml). The organic layer was washed with sat NaSO3 (5 ml), brine (5 ml) and dried (MgSO4) providing 98 mg (58%) of the crude subtitled compound that was used without further purification MS' ESI (positive)- 386 (M+H) c) 3-Chloro-2-trifluoromethvl-4.5.7.8-tetrahvdro-thieno("2.3-dlazepine-6-carboxvIic acid ethyl ester: A solution of the product from step b) (140 mg, 0 363 mmol) in NMP (0 9 ml) and DMF (0 9 ml) was treated with Cul (76 mg, 0.39 mmol), KF (46.4 mg, 0 79 mmol), bipyridyl (74 mg, 0 472 mmol) and TMSCF3 (267 µl, 1 81 mmol) The mixture was heated to 80 °C for 12 hours The crude reaction mixture was diluted with EtOAc and filtered through celite The organic phase was washed with H2O (2x1 ml), brine (lxl ml), dried (MgSCU) and concentrated The crude pi oduct was pur] fied by preparative TLC using 10 1 hexanes/EtOAc providing 14.4 mg (12 1%) of the subtitle compound d) 3-ChIoro-2-tnfluoromethvl-5.6.7.8-tetrahvdro-4H-thienor2.3-d1azepine A solution of the product from step c) (14 4 mg, 0.044 mmol) in CH2C12 (220 jx!) was treated with iodotrimethylsilane (19 u,l, 0 13 mmol) at 60 °C for 12 hours The reaction was quenched by the addition of MeOH and the solvent was evaporated. The residue was purified by preparative LC/MS providing 2 3 mg (18%) of the title compound. MS1 ESI (positive): 256 (M+H). Example 42 3-Bromo-2-trifluoromethvl-5,6,7,8-tetrahvdro-4H-tbienof2,3-d1azepine (Scheme lb) I a) 3-Bromo-4,5,7,8-tetrahvdro-thienor2,3-d1azepine-6-carboxvlic acid ethyl ester A solution of the product from example 3, step a) (148 mg, 0.39 mmol) in AcOH (80 pi,) and H2O (1.92 ml) was treated with Zn (76 mg, L 17 mmol) at 105 °C for 4 5 hours Next, the contents were cooled to 22 °C, pouied into sat NaHCO3 (25 ml) and extracted with EtOAc 63 Wp 2006/004931 PCT/US2005/023282 (2x25 ml). The organic layer was dried (MgSO4) and concentrated providing 80 mg (68%) of the subtitle compound, which was used withoui further purification b ) 3-Bromo-2-iodo-4,5,7,8-tetrahvdro-thienof2,3-d1azepine-6-carboxvlic acid ethyl ester A solution of the product from step a) (124 mg, 0 41 mmol) in CHC13 (1 0 ml) and AcOH (1 0 ml) was treated with AModosuccinimide (97 mg, 0.43 mmol) for 30 minutes. Next, the crude reaction was poured into sat. NaHCO3 (5 ml) and extracted with CH2CI2 (2x4 ml) The organic layer was washed with sat NaHCOi (3 ml), dried (extrelut column), concentrated and purified by preparative TLC (80% hexanes 20% EtOAc) providing 134 mg (76%) of the subtitle compound c.) 3-Bromo-2-trifluoroniethvl-4.5.7.8-tetrahvdro-thienor2,3-d]azepine-6-carboxylicacid ethyl ester: A solution of the product from step b) (134 mg, 0 31 mmol) in NMP (1 ml) and DMF (1 ml) was treated with KF (20 mg, 0 34 mmol), dul (65 mg, 0.34 mmol) and bipyndyl (62 mg, 0 4 mmol) at 50 °C for 15 minutes. Next, a 0 5 M solution of trimethylsilyltrifluoro-methane (3.1 ml, 1.55 mmol) was added and the reaction mixture was stirred 16 hours at 80 °C. The reaction mixture was cooled to 22 °C, diluted with CH2CI2 (5 ml) and washed with brine (10 ml). The'aqueous"layer was extracted with CH2Cl2"(3x5 ml) and the combined organic layers were dried (extrelut column), passed through a plug of silica gel, concentrated and purified by 1 preparative LC/MS providing 26 mg (23%) of the subtitle compound. d)3-Bromo-2-trifluoromethyl-5.6t7.8-tetrahvdro-4H-thienor2,3-d1azepine. A solution of the product from step c) (51 mg, 0.137 mmol) in CH2CI2 (685 uj) was treated with iodotrimethylsilane (59 ul) at 50 °C for 16 hours. The reaction was quenched by the addition of MeOH and the solvent was evaporated. The residue was purified by preparative LC/MS providing 16 mg (39%) of the title compound. NMR (300 MHz, CDCI3) 5 4.10-4.40 (br s, 1 H); 2 90-3 60 (m, 8 H). MS: ESI (positive): 300, 302 (M+H). Example 43 3-MethyI-5,6,7,8-tetrahYdro-4H-thienQf23-d1azepine (Scheme 3) 1 64 WO 2006/004931 PCT/US2005/0 23282 a) 3-Methvl-4.5.7,8-tetrahydro-thicnor2,3 -diazepine-6-carboxylic acid ethyl ester. A solution of the product from Example 42, step a) (122 mg, 0 40 mmol) in dry THF (2 ml) was treated with NiCh(dppp) (2-3 mg, 0 004 mmol) followed by dropwise addition of a 1.4 M solution of methylmagnesium bromide (0.71 ml, 1 mmol) at 22 °C and then the reaction was refluxed for 16 hours The reaction mixture was cooled to 22 °C, diluted with ether (5 ml), and quenched with IN HC1 (2 ml) The aqueous layer was back extracted with ether (3x5 ml) The combined organic extracts were washed with water (10 ml) and dried (MgSO4) The solvent was evaporated giving the crude subtitle compound as a tan oil, which was used without further purification b) 3-Methvl-5.6.7.8-tetrahvdro-4H-thieno[23-d1azepine A solution of the product from step a) in CH2CI2 (1 ml) was treated with iodotnmethylsilane at 50 °C for 16 hours The reaction was quenched by the addition of MeOH and the solvent was evaporated The residue was purified by preparative LC/MS providing 1 6 mg of the title compound NMR (300 MHz, CDCI3) 5 6 69 (d, J= 1 Hz, 1 H); 4.8-5 2 (br s, 1 H), 3 20-3 40 (m, 6 H), 3 00-3 1 (m, 2 H); 2 14 (d, ./= 1 Hz, 3 H), MS ESI (positive) 168 (M+H) Example 44. 2-tert-But^1-3-methoxv-5 a ) 2-tert-Butvl-3-methvl-4.5.7.8-tetrahvdro-thienor2.3-d]azepine-6-carboxyhG acid ethyl ester- To a stirred solution of the product of Example 18, step a) (20 mg, 0 078 mmol) in 0 5 mL DCE was added t-ButanoI (25 wL, 0 26 mmol) followed by BF3-OEt2 (10 uL, 0.078 mmol) The reaction was heated to 75° C for 2 hours The reaction was allowed to cool to room WO 2006/004931 PCT/US2005/023282 temperature, concentrated to dryness, and the residue used without further purification. MS ESI (positive): 312 (M+H) b) 2-tert-Butvl-3-methvI-5.6.7.8-tetrahvdro-4H-thienor2,3-d1azepine: The product of step a) was treated with 0.5 mL each of EtOH and 40% aqueous KOH After heating to 100" C for 18 hours, the reaction was cooled, diluted with water, and extracted into DC1-8 (2x10 ml) The organic layer was concentrated to dryness and the residue purified by preparative HPLC-MS to give the title compound lK NMR (300 MHz, CD3OD) 5 3 78 (s, 3H); 3.30-3 38 (m, 4 H); 3 06-3.15 (m, 2 H); 2 94-3 03 (m, 2 H), 1.45 (s, 9 H). MS: ESI (positive)'240 (M+H) Example 45 2-tert-Butyl-5,6,7,8-tetrahYdro-4H-thienof23-dlazepine (Scheme 9) To a stirred solution of the pioduct from Example 1, step d) (66 mg, 0.29 mmol) in 2.5 mL of DCE was added t-Butanol (36 wL, 0.38 mmol) and BF3-OEt2 (36 uL, 0.29 mmol). The reaction was heated to 60° C for 2 hours. rChe reaction was concentrated to dvyness and treated with 2 mL each of EtOH and 40% aqueous KOH. The mixture was heated to 100" C overnight, cooled, and diluted with water. The product was extracted into DC1-8 (2x1 OmL), concentrated, and purified by preparative HPLC-MS to give the title compound. MS" ESI (positive)-210 (M+H). Example 46 2-tert-Butvl-3-chloro-S,6,7,3-tetrahydro~4H-thieno[23-d1a2eDine (Scheme 4) Example 47 3-ChIoro-2-(iq,33-tetramethvl-butvn-5,6,7.8-tetrahydro-4H-thienor2,3-d1azepine (Scheme 4) Example 48. 3-Chloro-5,6,7,8-tetrahYdro-4H-thiencf2,3-d1azepine (Scheme 4) 66 WO 2006/004931 PCTAJS 2005/0 23282 a) 3-Chloio-4.5.7.8-tetrahvdro-thienor2.3-dlazepine-6-carbox^iic acid ethyl ester* A solution of the pioduct from Example 41 step a ) (382 mgs 1 3 mmol) in THF (6 5 ml) was cooled to -78 °C and treated with a 1 6 M solution of n-BuLi (2 26 ml, 1 36 mmol) After 1 hour, the reaction was quenched with water and extracted with EtOAc (2x30 ml) The organic layer was washed with bnne (1x15 ml), dried (MgSO4) and concentrated The crude yellow oil was punfied by silica gel chiomatogiaphy (EtOAc/Hexane-giadient) providing 156 mg (46%) of the subtitle compound ]H NMR (300 MHz, CDC13) 8 6 88 (s, 1 H), 4 19 (q, /= 7 Hz, 2 H); 3 57-3 72 (m, 4 H), 2 92-3 03 b) 2-tert-Butvl-3-chloro-4.5.7.84etrahvdro-thienor2,3-d1azepine-6-carboxylic acid ethyl ester A solution of the product from step a.) (156 mg, 0.6 mmol) in dichloroethane (3 ml) was treatedwith/-BuOH(172ul, 1 8 mmol) and BF3-OEt2(113 ul, 0 9 mmol). The reaction mixture was heated at 85 °C for 6 hours followed by evaporation of the solvent pioviding the crude subtitle compound. c) 2-tert-Butvl-3-chloio-5.6.7.8-tetrahvdro-4H-thienoF2,3-d1azepine, Example 44. 3-Chloro-2-n.l.3.3-tetramethvl-butyl)-5,6.7.8-tetrahydro-4H-thienor2.3-d1azepine. Example 45; 3-Chloro-5.6,7,S-tetrahydio-4H-thienor2.3-d1azepine, Example 46- A solution of the ciude product from step b) in EtOH (4 ml) and 40% aqueous KOH (4 ml) was treated with tetra-butylammomum bromide (20 mg) and heated to 95 °C for 2 days. Next, the reaction was cooled to 22 °C and extracted with CH2C12 (3x25 ml) The organic layer was washed with brine (1x10 ml), dried (MgSCU), and concentrated to dryness The residue was purified by preparative LC/MS providing the subtitle compounds (A) 'H NMR (300 MHz, CDCI3) d 6 50-6 80 (br s, 1 H), 3.05-3.14 (m, 4 H), 2.87-2 99 (m, 4 H), 1.43 (s, 9 H); MS: ESI (positive): 244 (M+H), (B) JH NMR (300 MHz, CDCh) 5 3 58-3 70 (br s, 1 H); 2 98-3 09 (m, 4 H), 2.88-2.94 (m, 2 H), 2.82-2.87 (m, 2 H); 1 91 (s, 2 H), 1.46 (s, 6 H); 0.81 WO 2006/004931 PCTAJS2005/023282 (s, 9H), MS: ESI (positive) 300 (M+H), (C) fH NMR (300 MHz, CDC13) d 6 75 (s, 1 H); 2.92-3 11 (m, 6 H), 2.85-2.90 (m, 2 H), 2 72-2.82 (br s, 1 H); MS. ESI (positive) 188 (M+H). Example 49 2-Bromo-5,6.7,8-tetrahvdro-4H-furof2,3-d1azepioe (Scheme 11) a.1 Furan-2-yl-oxo-acetic acid ethyl ester* i Furan-2-yl-oxo-acetic acid (15 g, 107 mmol), dissolved in CHC13 (420 ml), was treated with EtOH (9.6 ml, 165 mmol) and H2SO4 (1 ml) and heated to 63 °C for 12 hours. Next, the reaction mixture was transferred to a separatory funnel and washed with sat. NaHCO3 (100 ml). The organic layer was washed with brine (100 ml), dried (MgSO4) and concentrated providing 16.9 g (66%) of the above subtitle compound, which was carried forward without further purification. b.) Furan-2-vl-hvdroxy-acetic acid. A solution of the producffrom step a.) (25 g, 135 mmol) in EtOH (250 ml) was cooled to 0 DC and treated with a solution of NaBEU (2.5 g, 66 mmol) in H2O (27 ml) for 5 minutes. Next, the reaction mixtuie was quenched with AcOH (17 ml) and H2O (271 ml) and concentrated to dryness. The crude oil was dissolved in CH2CI2 (300 ml), washed with brine (2x100 ml), dried (MgSCU) and concentrated providing 17 5g (70%) of the above subtitle compound, which was carried forward wilhout further purification. a") (3-Carboxymethvl-furan-2-vD-acetic acid: A solution of the product from step b ) (10 9 g, 64 mmol) in decalin (193 ml) was treated with trimethylorthoacetate (48 2 ml, 384 mmol) and hexanoic acid (2.0 ml). Next, the reaction mixture was fitted with a Vigreaux column and heated to 180 °C for 18 hours. Additional hexanoic acid (3x1 5 ml) aliquots of hexanoic acid were added every 2 hours for the first 6 hours of reaction time. Next, the reaction was cooled to 22 °C and extracted with MeOH providing 27 g of a crude mixture of the diestei and decalin. This mixture was dissolved in MeOH (250 ml), cooled to 0 fC.'and treated with 2 MNaOH (150 ml). After 12 hours, the solvent was evaporated and the residue was taken up in 2 N NaOH (100 ml) and 68 WO 2006/004931 PCT/US 2005/023 28 2 washed with ether (2x150 ml). The basic layer was acidified with 4 M HC1 to pH 1 and back extracted with EtOAc (4x100 ml) The organic layer was washed with brine, dried (MgSO,*) and concentrated providing 6 4 g (54%) of the: above subtitle compound d) 2-r3-f2-Hvdioxv-ethavl)-furan-2-vn-ethanol- A solution of the product from step c) (6.4 g, 35 mmol) in dry THF (400 ml) was cooled to 0 °C and a 1 0 M solution of BH3 in THF (174 ml, 174 mmol) was added dropwise over 10 minutes After the addition was complete the mixture was stirred for an additional 20 minutes at 0 °C and then warmed to 22 °C foi 2 houis. Next, the mixture was poured into ice cold sat NaHCO3 (300 ml) and extracted with EtOAc (2x200 ml). The oiganic layer was dried (MgSO4) and concentrated providing 3 58 g (65%) of the subtitle compound. MS ESI (positive) 157 (M+H) e) Methanesulfomc acid 2-r3-f2-memanesulfonvloxv-ethvl):faran-2-yl]-ethvl ester: A solution of the product from step d.) (3 58 g, 22.9 mmol) in CH2CI2 (114 ml), was cooled to 0 °C, and treated with tnethylamine (9.56 ml, 68 7 mmol) followed by dropwise addition of methanesulfonyl chloride (3 88 ml, 50 4 mmol) over 10 minutes. After 1 hour, the reaction mixture was transferred to a separatory funnel and extracted with ice water (1x50 ml), 10% citric acid (2x50 ml), sat NaHCO3 (2x50 ml) and brine (1x50 ml). The organic layer was dried (MgSC1-8), concentrated to 20 ml, diluted with dry dioxane (42 ml) and further concentrated to remove remaining CH2CI2 The lesulting dioxane solution of the bismesylate was immediately carried into step f) 1 f)6-Benzvl-5.6,7.8-tetrahvdro-4H-furo[2,3-d1azepine The bismesylate dioxane solution, generated in step e), was diluted with dry dioxane (168 ml) and transferred to a 3-neck reaction flask equipped with a dropping funnel and condenser. Anhydrous K2CO3 (46 5g, 337 mmol) was added and the mixture was heated to 102 °C Next, a solution of benzylamme (7 5 g, 70 t mmol) in dioxane (74.4 ml) was added dropwise over 45 minutes and the reaction was refluxed for 18 hours The mixture was cooled to 22 °C, the salts were filteied off, and the solvent was evapoiated The crude oil was purified by silica gel chromatography (EtOAc/Hexane-gradient) providing 2 56 g (49%) (combined yield over steps e and f) of the subtitle compound MS. ESI (positive)- 228 (M+H). 69 WO 2006/004951 PCTAJS2005/023282 g) 5.6.7.8-Tetrahvdro-4H-furo[23-d]azepine Hvdrochloride A solution of the product from step f) (2 56 mg, 11.3 mmol) in anhydrous dichloroethane (56 ml) was cooled to 0 °C, treated with 1-chloroetlryl chloroformate (6 11 ml, 56.4 mmol) and the reaction was warmed to 22 °C for 1 hour, irhe reaction was diluted with CH2CI2 (100 ml) and washed with sat. NaHCO3 (50 ml) The sat. NaHCO3 was back extracted with CH2C12 and the combined organic layers were washed with brine (50 ml), dried (MgSO4) and concentrated providing an oily residue, which was taken up in anhydrous MeOH (150 ml) and refluxed for 1 hour. The MeOH was evaporated and the crude was triturated with ether and filtered providing 1 71g (87%) of the subtitle compound 1H NMR (300 MHz, DMSO) 5 9 56 (br s, 2 H), 7.43 (d, /== 2 Hz, 1 H), 6.34 (d, J= 2 Hz, 1 H); 3.18-3 30 (br m, 4 H); 3.03-3 10 (br m, 2 H), 2 74-2.82 (br m, 2 H); MS- ESI (positive): 138 (M+H) h) 4,5,7,8-Tetrahvdro-fiirof2,3-d]azepine-6-carboxyIic acid tert-butyl ester A solution of the product from step g) (500 mg, 2 88 mmol) in acetone (7.2 ml) and water (7.2 ml) was treated with NaHCO3 (484 mg, 5 76 mmol) and di-tert-butyl dicarbonate (691 mg, 3.17 mmol) under vigorous stirring for 1 hour The contents were diluted with H2O (10 ml) and extracted with EtOAc (2x50 ml) The organic layer was dried (MgSO4), concentrated and purified by chromatography (EtOAc/Hexane-gradient) providing 643 mg (94%) of the subtitle compound. MS: ESI (positive). 238 (M+H). i.)2-Bromo-5.6,7.8-tetrahydro-4H-furor2,3-d1azepine A solution of the product from step h) (50 mg, 0.21 mmol) in CHC13 (527 u.1) and AcOH (527 ul) was treated with N-bromosuccinimide (38.1 mg, 0 21 mmol) at 22 °C. After 1 hour, the contents were poured into sat. NaHCO3 and extracted with EtOAc (2x5 ml). The organic layer was washed with brine (1x5 ml), dried (MgSO-O and purified by preparative TLC (80% hexanes'20% EtOAc) providing 2-bromo-4,5,7,8-tetrahydro-furo[2,3-d]azepine-6-carboxylic acid tert-butyl ester which was directly treated with 4 M HC1 in dioxane (2 ml). The dioxane was evaporated and the residue was dissolved in MeOH and purified by preparative LC/MS providing 1.3 mgofthe title compound. 'HNMR(CDCl3) 6 08 (s. 1 H); 3.02-3.07 (m, 4H); 2 89-2.92 (m, 2 H); 2 57-2 70 (m, 3 H); MS: ESI (positive 1+H). 70 WO 2006/004931 PCT/US 2005/023282 The following procedure was utilized to evaluate representative compounds of the present invention as 5HT2c receptor agonists The results of this assay are set forth in Table 1. Cell culture VNV Isofornr HEK 293 EBNA expressing the human 5HT2c receptor (Burns et al, NATURE 387 30308, 1997) were grown in DMEM containing 10% dialysed FBS, 9 (ig/ml blasticidin at 37°C m 5% CO2 atmosphere Calcium mobilization HEK 293 EBNA cells expressing human 5HT2C receptor (2xlO4/well) were seeded in black 384-well collagen coated plates and incubated overnight at 37°C in a 5% CO2/95% atmosphere. After removing medium, cells were treated with HBSS buffer (137 mM NaCl, 5 4 mM KCI, 5.5 mM Glucose, 20 mM Hepes, pH 7 5,2.1 mM MgCl2,0 3 mM CaCt2,0.02mM MgSO4, 3 OmM NaHCO3s and 0 64mM KH2PO4) containing the Calcium3 dye (Molecular Device, CA), 2 5 mM probenecid and 0 08% pluronic acid for 60 minutes according to manufacture's instruction. Compounds were diluted in CsCl Ringers buffer (58 3 mM CsCl, 5 4 mM KCI, 5 5 mM Glucose, 20 mM Hepes, pH 7 5, 2 1 mM MgCI2,1 2 mM CaCl2). 5HT was utilized as a positive connol Ligand induced calcium release and consequent fluorescence was measured on a Fluorometric Imaging Plate Reader (FLIPR, Molecular Device, CA) Data analysis All data were analyzed by nonlinear least square curve fitting using Prism 4 0 software Agonist stimulation of calcium-induced fluorescence in FLIPR was fitted to sigmoidal dose response using equation Y=Bottom + (Top-Bottom)/(l+10A((LogEC50-X)))5 where X is the logarithm of concentration of compounds and Y is the fluorescent response. 71 72 WO 2006/004931 PCT/US2005/023282 73 WO 2006/004931 PCT/US2005/023282 74 WO2006/Q04931 PCT/US2005/023282 75 i WO 2006/004931 PCT/US2005/0 23282 76 PCTYUS2005/023282 WO 2006/004931 77 WO 2006/004931 PCT/US2005/023282 78 WO 2006/004931 PCT/US2005/023282 79 WO 2006/004931 PCT/US2005/023282 80 PCT/US2005/023282 WO 2006/004931 WO 2006/004931 PCT/US2005/023282 Claims 1 A compound of the formula where X is S, O or NR5, R1 and R2 are independently selected from the gioup consisting of H, halogen, C1-8 alkyl, CM1-8aikylaryl, C1-8 alkyl heteroaryl, C1-8 alkenyl, perhalo alkyl, CN, OR5) SR5, N(R5)2, CON(R5)2, NR5COR5j NR5CO2R5, SO2N(R5)2, NR5SO2R55 aryl and heteroaryl, wherein said aryl or heteioaryl can be optionally substriuted with up to three substituents selected from alkyl, halogen and alkoxy or R1 and R2 taken together form a 5- or 6-member ring; R3 is selected from the group consisting of H, C1-8 alkyl, Cj-s aikylaryl, C1-8 alkylheteroaryl, OR5, -CH2-O-CL8 alkyl, -CH2OH, -COO-C1-8 alkyl, -_CON(R5)2, and aryl; R3a is H or R3 and R3a taken together are -CH2CH2- or R2 and R3 form a 5- or 6-member ring; R4 is selected fiom the group consisting of H, C1-8 alkyl, C1-8 aikylaryl, Cj.s alkylheteroaryl, OR5) -CH2-O-C,.8 alkyl, -CH2OH, -COO-Cn alkyl, -CON(R5)2 and aryl, R4a is H or R3 and R3a taken together are -CH2CH2-, and R5 is selected from the group consisting of H, C1-8 alkyl, C1-8 aikylaryl, C1-8 alkylheteroaryl, aryl, heteroaryl, and perhaloalkyl or together with the atom to which it is attached, R5 forms a heteroaryl ring 2. A compound as in claim 1 where: XisS; Ri is selected from the group consisting of halogen, C1-8 alkyl, OR5, SO2N(Rs)2 and perhaloalkyl; R2 is selected from the group consisting of hydrogen, halogen, C1-8 alkyl and OR5, or together with R3 forms a 5-membered ring, 81 WO 2006/004931 PCT/US2005/023282 R3 is hydrogen or C1-8 alkyl, R3 is hydrogen; R4 is hydrogen or C1-8 alkyl; R4 is hydrogen; and R5 is hydrogen or Q4 alkyl or, together with the atom to which it is attached form a heteroaryl ring, 3. A compound as in claim 1 selected from the group consisting of 5,6,7,8 -Tetrahy dro-4H-thieno[2,3 -d]azepine, 2-Bromo-5,6J7,84etrahydro-4H-thieno[2,3-d]azepine; 2-Chloio-5>6,7,8-tetiahydro-4H-thieno[2}3-d]azepine; 2)3-Dibromo-5J6,7,8-tetrahydro-4H-thieno[2)3-d]azepine, 213-DichIoro-5,67,8-tetrahydro^H-thieno[2,3Ki]azepine, 2-Bromo-3-chloio-5J6s7,8-tetrahydro-4H-thieno[2,3-d]azepme; (R,S) 5,6,7,8-Tetraliydro-4H-thieno[233-d |azepin-4-oI; 2-Chloro-4-methoxy-5,6J7,8-teti-ahydro*4H-thieno[2,3-d]azepine; 2-Chloro-4-methyl-5,6,7,8-tetrahydro-4H thieno[2>3-d]azepine) 2,3-Dichloro-4-methyl-5,6J7,8-tetrahydro-thieno[2,3-d]azepine; 2-(4-Trifluoromethoxy»phenyl)-5,6,7,8-tetraliydro-4H-thieno[2J3-d]azepine; 2-(3-TnfIuoromethyI-phenyl)-5,6,7,8-tetrahj'dro-4H-thieno[2s3-d]azepine; 2-(2-Trifluoromethyl-phenyl)-556s7,8-tetrahydro-4H-thieno[253-d]azepine, 2-(4-Fluoro-phenyl)-5,6,7»8-tetrahydro-4H-thieno[2,3-d]azepine; 2-(2,5-Difluoro-phenyI)-5,6,7,8-tetrahydro-4H-thieno[2,3-d]a2epine; 2-(3-Chloro-4-fluoro-phenyl)-5,6,7?8-tetrahydro-4H-thieno[2)3-d]azepine; 2-(2,5-Dichloro-phenyl)-5J6)7,8-tetrahydro-4H-thieno[2,3-d]azepine, 2-(5-FIuoro-2-methoxy-phenyl)-5,6,7,8-tetrahydro-4H-thieno [2,3-d] azep ine; 2-(3,4,5-Trimethoxy-phenyl)-5,6,7J8-tetrahydro-4H-thieno[2>3-d]azepine; 2-(4-Etlioxy-phenyl)-5J6,7,8-tetrahydro-4H-thieno[2,3-d]azepine; 2-(4-Ethyl-phenyl)-5,6,7f8-tetrahydro-4H-thieno[2,3-d]azepineJ 2-(3-Methoxy-phenyl)-5,6,7)8-tetrahydro-4H-thieno[2,3-d]azepine, 2-Phenyl-5,6,7s8-tetrahydro-4H-thieno[2,3-d3azepine; 2-(3-Fluoro-biphenyl-4-yI)-536s7,8~tetrahydro-4H-thieno[2>3-d]azepine; 2-(2-Fluoro-biphenyl-4-yl)-5,6s7,8-tetrahydlro-4H-thieno[2,3-d]azepine, 82 WO 2006/004931 PCT/US 2005/023282 2-Naphthalene-l-yl-5,6,7,8-tetrahydro-4H}-thieno[2>3-d]azepine; 2-NaphthaIene-2-ylL5,6,7J8-tetrahydro-4HftIiieno[2s3-d]azepine> 2-(2,6-Difluoro-phenyl)-5J6s7sS-tetrahydro^H-thieno[2s3-d]azepine; 3-(2,6-Difluoro-phenyl)-5,6,7>8-tetiahydro-4H-thieno[2,3-d]azepine; 2-(2-Chloro-6-fluorp-benzyI)-5)6}7,8-tetrah>'dro-4H-thieno[2,3-d]azepine, 3-Bromo-2-(2-chloro-6-fluoro-benzyl)-5J6,7hS-tetrahydro-4H-thieno[2)3-d]azep!ne; 2-Amino-5,6,7,8-tetiahydro-4H^hieno[2,3LdJazepine-3-carboxyhc acid ethyl ester, i 2-Amiiio-5,6s7,8-tetrahydro-4H-thieno[2,5fc3azepine-3-carboxylic acid ethyl ester; S^^S-Tetiahydio^H-thienop[2,3-c]-djazepine-S-carboxyhc acid etliyl ester, 5,6,7,8-Tetrahydro-4H-thieno[2>3-c]azepme-3-carboxylic acid ethyl ester; 5,67,8-Tefrahydro-4H-thieno[2,3-dJazepme; 2,3-DichIoro-5,6,7)8-tetrahydro-4H-thieno[2,3-d]azepine, 2-Biomo-3~chIoro-5^6,7s8-tetiahydio-4H-1hieno[2,3-d]azepme; 2-Biomo-3-methyI-5,6?7,8-tetrahydro-4H-thieno[2)3-d]azepine; 2-Bromo-3-methoxy-5J6)7,8-tetrahydro-4H-thieno[2,3-d]azepme, 2-Bromo-4-methyI-5)6,7s8-tetiahydro-4H-thieno[2,3-d]azepine; 2-Bromo-8-metIiyl-5,6)758-tetrahydro-4H-(iiieno[233-d]azepme; 2-(Pyrrolidine-l-sulfonyl)-5,6,738-tetrahydro-4H-thieno[2}3-d]azepine, i j 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine-2-sulfonic acid dimethylamide, S-Methyl-5,6,7,8-tetrahydro^H-thienop[2,3-d]azepine-2-sulfonicaciddimethylaniide; 2-Bromo-4)4a35,6J7,8-hexadydro-3H l-thia76-aza-cyclopenta[cd]azulene, i 2-MethyI-4,4a,5J6,758-hexahydro-3H-l-thiar6-aza-cyclopenta[cd]azulene; Tnfluoromethyl-5,6,7,8--tetrahydio^H-thienop[2,3-d]azepine, 3-Bromo-2-trifluoromethyl-5,6J7,8-tetrahydro-4H-thieno[2,3-d]azepine, and 2-tert-ButyI-3-methoxy-5)6s7,8-tetrahydio-4H-thieno[2,3]d]azepine> 4 A compound as in claim 1 selected from the group consisting of i 5,6,7,8-Tetrahydro-4H-thieno[2,3-d]azepine, 2,3-Dichloio-5,6,7,8-tetrahydro-4H-thienot[2,3-d]azepine, 2-Bromo-3-chloro-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine; 2-BromO"3-methyl-5,6,7,8-tetrahydro-4H-thietio[2s3-d]azepine; 2-Bromo-3-methoxy-5,6,7,8-tetrahydro-4H-thitenop[,2,3-d]azepine, 2-Bromo-3-methoxy-5,6,7,8-tetrahydro-4H-thitenop[,2,3-d]azepine, 2-Bromo-8-rnethyI-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine; 2-(Pyrrohdine-l'Sulfonyl)-5)6)7J8-tetrahydro-4H-thieno[2J3-d]azepme, 83 i WO 2006/004931 PCT/US2005/023282 5,6>7,8-Tetrahydro-4H-thieno[2,3-d]azepine-2-sulfonicaciddimethylamide; 3-Methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d*|azepine-2-sulfonicaciddiraethylamide; 2-Bromo-4,4as5,6>7,8-hexadydro-3H-l-thia-6-a2a-cycIopenta[cd]azulene; 2-MethyI-4,4a,5,6,7,8-hexahydro-3H-l~thiia-6-a2a-cyclopenta[cd]azulene; Trifluoromethy!-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine; 3-Bromo-2-trifluoromethyI-5s6,7,8-tetrahydro-4H-thieno[2,3-d]azepine;and 2-tert-Butyl-3-methoxy-5s6Js8-tetrahydro-4H-thieno[2,3]d3azepine. 5. A pharmaceutical composition comprising at least one compound of claim 1 i and a pharmaceutically acceptable carrier. 6. A method of treating a disease, disorder and/or condition in a patient wherein modulation of a 5-HT2C function is desiredi comprising administering an effective amount of at least one compound of claim 1 to a patieni in need of such treatment. i 84 SUBSTITUTE SHEET (RULE 26) The present invention generally relates to a senes of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents More specifically, compounds of the present invention are hexahydroazepinoindole and octahydroazepinomdole compounds These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e g anxiety, depression and obesity)

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