HCV NS5B inhibitors

专利摘要:

公开号:AU2007211988A1
申请号:U2007211988
申请日:2007-02-07
公开日:2007-08-16
发明作者:Carl P. Bergstrom；Thomas W. Hudyma；Scott W. Martin
申请人:Bristol Myers Squibb Co；
IPC主号:C07D487-04

专利说明:
WO 2007/092888 PCT/US2007/061768 HCV NS5B INHIBITORS CROSS REFERENCE TO RELATED APPLICATIONS 5 This application claims the benefit of U.S. Provisional Application Serial Number 60/771391 filed February 8, 2006. BACKGROUND OF THE INVENTION 10 Hepatitis C virus (HCV) is a major human pathogen, infecting an estimated 170 million persons worldwide - roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma (Lauer, G. M.; Walker, B. D. N. Engl. J. Med. 2001, 345, 15 41-52). HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5'-untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All 20 members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame. Considerable heterogeneity is found within the nucleotide and encoded amino 25 acid sequence throughout the HCV genome. At least six major genotypes have been characterized, and more than 50 subtypes have been described. The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy. 30 The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple 1 WO 2007/092888 PCT/US2007/061768 sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the 5 second one is a serine protease contained within the N-terminal region of NS3 (also referred to as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in 10 the membrane localization of NS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the 15 replication of HCV. The HCV NS5B protein is described in "Structural Analysis of the Hepatitis C Virus RNA Polymerase in Complex with Ribonucleotides (Bressanelli; S. et al., Journal of Virology 2002, 3482-3492; and Defrancesco and Rice, Clinics in Liver Disease 2003, 7, 211-242. 20 Currently, the most effective HCV therapy employs a combination of alpha interferon and ribavirin, leading to sustained efficacy in 40% of patients (Poynard, T. et al. Lancet 1998, 352, 1426-1432). Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy (Zeuzem, S. et al. N. Engl..1. Med. 2000, 343, 1666-1672). However, even with 25 experimental therapeutic regimens involving combinations of pegylated alpha interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. Thus, there is a clear and important need to develop effective therapeutics for treatment of HCV infection. 30 DESCRIPTION OF THE INVENTION The invention encompasses compounds and pharmaceutically acceptable salts of formula I, and compositions and methods of treatment using these compounds. 2 WO 2007/092888 PCT/US2007/061768 One aspect of the invention is a compound of formula I R2 a b R1 N R3 R4 5 I wherein:
R
1 is CO 2
R
5 or CONR 6
R
7 ; 10 R 2 is furanyl, pyrrolyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, or tetrazolyl, and is substituted with 0-2 substituents selected from oxo, amino, alkylamino, dialkylamino, alkyl, (cycloalkyl)alkyl, hydroxyalkyl, (tetrahydrofuranyl)alkyl, (tetrahydropyranyl)alkyl, (CO 2 R)alkyl, (CON(R) 2 )alkyl, (COR)alkyl, (alkylsulfonyl)alkyl, and ((R)alkyl)CON(Rs); 15
R
3 is C 5 7 cycloalkyl;
R
4 is hydrogen, halo, hydroxy, alkyl, or alkoxy; 20 R 5 is hydrogen, alkyl, or cycloalkyl; Ri is hydrogen, alkyl, cycloalkyl, alkoxy, or SO 2
R
8 ; R7 is hydrogen, alkyl, or cycloalkyl; 25 or NR 6
R
7 taken together is pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, hornomorpholinyl, homopiperidinyl, morpholinyl, or thiomorpholinyl; R is alkyl, haloalkyl, cycloalkyl, amino, alkylamino, dialkylamino, or phenyl; 30 3 WO 2007/092888 PCT/US2007/061768 or R8 is pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, homomorpholinyl, homopiperidinyl, morpholinyl, or thiomorpholinyl;
R
9 is pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl, homomorpholinyl, 5 homopiperidinyl, morpholinyl, or thiomorpholinyl; and (a) is a single bond or a double bond, (b) is a single bond or a double bond, provided that at least one of (a) and (b) is a single bond; 10 or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a compound of formula I selected from the group consisting of R2 R2 15 R a R R3 RR, and R2 RI Another aspect of the invention is a compound of formula I where R is CONRR'; 20 R' is SO2R; and R 7 is hydrogen. Another aspect of the invention is a compound of formula I where R is cyclohexyl. Another aspect of the invention is a compound of formula I where R 4 is hydrogen. 25 Another aspect of the invention is a compound of formula I where R is methoxy. 4 WO 2007/092888 PCT/US2007/061768 For a compound of Formula I, any scope of R', R , R', R, Rs, R6, R , Rs, R , (a), and (b) can be used independently with the scope of any other variable. 5 Unless specified otherwise, these terms have the following meanings. "Alkyl" means a straight or branched alkyl group composed of 1 to 6 carbons. "Alkenyl" means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. "Cycloalkyl" means a monocyclic ring system composed of 3 to 7 carbons. "Hydroxyalkyl," "alkoxy" and other terms with a substituted alkyl 10 moiety include straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety. "Haloalkyl" and "haloalkoxy" include all halogcnated isomers from monohalo substituted alkyl to perhalo substituted alkyl. "Aryl" includes carbocyclic and heterocyclic aromatic substituents. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For 15 example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R. The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do 20 not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, 25 iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, mcgluminc, 4-phenylcyclohexylamine, pipecrazine, potassium, sodium, tromethamine, and zinc. 30 Some of the compounds of the invention possess asymmetric carbon atoms (for example, the structures below). The invention includes all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereoisomers such as 5 WO 2007/092888 PCT/US2007/061768 racemates. Some stereoisomers can be made using methods known in the art. Stereoisomeric mixtures of the compounds and related intermediates can be separated into individual isomers according to methods known in the art.
R
2 R2 RN R N 5 R 3 R Ra R 4 Synthetic Methods 10 Formula I compounds may be made by methods known in the art including those described below. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. The variables (e.g. numbered "R" substituents) used to describe the synthesis of formula I compounds are intended only to illustrate how to make and 15 are not to be confused with variables used in the claims or in other sections of the specification. Abbreviations used within the schemes generally follow conventions used in the art. Abbreviations used within the schemes generally follow conventions used in 20 the art. Some examples are as follows: THF means tetrahydrofuran; DMF means N,N-dimethylformnamide; RCM means ring-closing methasis; Boc means tert butoxycarbonyl; TFA means trifluoracetic acid; DMA means N,N dimethylacetamide; PPh 3 means triphonylphosphino; OAc means acetate; Mc means methyl; COD (or cod) means 1,5-cyclooctadiene; dtbpy means 4,4'-di-tert-butyl-2,2' 25 bipyridine; dba means dibenzylideneacetone; Xantphos means 4,5 bis(diphenylphosphino)-9,9-dimethylxanthine; aq means aqueous; EtOH means ethanol; MeOH means methanol; TBTU means 2-(1H-benzotriazole- 1-yl)-1,1,3,3 tetramethyluronium tetrafluroborate; DMSO means dimethylsulfoxide; HATU means O-(7-azabenzotriazol- I -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; 30 EEDQ means 2 -ethoxy-l-ethoxycarbonyl-1l,2-dihydroquinoline; WSC means 1-[3 6 WO 2007/092888 PCT/US2007/061768 (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride; DMAP means 4 dimethylaminopyridine; n-Bu means n-butyl; BEMP means 2-tert-butylimino-2 diethylamino- 1,3-dirnethylperhydro- 1,3,2-diazaphosphorine, polymer-bound; DIPEA means diisopropylethylamine; and TEA means triethylamine. 5 Scheme 1. 0 0 0 H H H HO N Cyclohexanone HO N H/Pd/C; MeO N NaOMe / MeOH / SOCI 2 MeOH / O HO HO H CHO MeO N Pyridinium MeO N Pd(PPh 3
)
4 Meo N / Tribromide / ArB(OH) 2 R1 O OH O H CHOO MeO N Dimethoxyphosphoryl Acrylate; MeO N /(Bu) 4 NOH// Rs R 7 WO 2007/092888 PCT/US2007/061768 Scheme 2. O OH O NH 2 O 0 MeO - N TBTU, DIPEA, DMF; MeO N
NH
3 , Dioxane R'J~ R' Burgess Reagent,
CH
2
CI
2 NeN N.NH CN O 0 MeO N Bu 3 SnN 3 , Tol, 150 OC MeO - N R' R' 1) RX, Cs 2
CO
3 , DMF 2) 1M NaOH, MeOH N-N R N-N R o o0 HO N HO / N ' + ~
.
/ XR' XR'
(CICO)
2 , Sulfamide N-N R IN I 9 0 0,. N e-N , N R' 8 WO 2007/092888 PCT/US2007/061768 Scheme 3. O OH O NH 2 0 0 MeO - N TBTU, DIPEA, DMF; MeO / N I, NH 3 , Dioxane Burgess Reagent,
CH
2
CI
2 N N N. NH CN 0 0 MeO N Bu 3 SnN 3 , Tol, 150 C MeO 1 N 1) RX, Cs 2
CO
3 , DMF 2) 1M NaOH, MeOH N-N R NerN R 0 0 HO-"- N HO / N - + / R' * R'
(CICO)
2 , Sulfamide N-N R N' N - N 9R' 9 WO 2007/092888 PCT/US2007/061768 Scheme 4. O 0-10O
NH
2 0NH I+OU4'O 1) WSC, DMF " R:ZT 2) N 2
H
4 , THF 5 Scheme 5. 00
NH
2 H-fH a NH I,. NI. 0 DIEA, CDI 0 . AcOH, 48% HBr 0 ITHE 114NHO N 10 Schemc 6. 0 BrN 0&0 0 ____ AcOH, 48% HBr O N CS 2
CO
3 , Nal 00 N THF, 60C -1- N HO3-4 I9 I Scheme 7. R O OH 0cI R N, 0, N Y OH o0-. (CO) 2 C1 2 0 NH 2 0 0 ~N CHCI 2 , DIEA, THF ~ DMF (ca) -uWave, 150C 15 Scheme 8. NLii, Py 1) (CO) 2 G1 2 0 0 0, 10 WO 2007/092888 PCT/US2007/061768 Scheme 9. /0, 0 N.1) CDI, THF, RTto reflux 6 N HO 0 N 0 0 0 N N NH 2 BUN N N / J H Scheme 10.
<NH
2
NNH
2 NH, N 0 N 0 00N hydrolysis 0 00 ~NNBrCN. NaHCO 3 "I N. N HOI-N.N 1,4-IDioxane, RT 5 Scheme 11.
N-<NH
2 N B N . N~r B r 0 N 0 py, THF A N 0Oto RT (H Nal RT HN N 0N N 0( 0 - 0 NN0 0 KOTMS HO N. N THF, RT N.NN WO 2007/092888 PCT/US2007/061768 Scheme 12. 0 c HC f H0 Cl HNfl 0. 0N 0 0 0 0 0O I N Pyridine, DCM O I N IT oluee, reflux N 0 Nl. 0 1) Bu 4
N'OH
THF, MEOH N., 0 A N 2) Oxalyl Chloride 0 CM. DMF t N 3) MorphollneI I K-OTMS THF, RT 00 1) CDI, THF, RT to refluxN 0 0 0. o,, 0 0 HOX 4..N 3-0 N" N 2/ N'PNH2 DBU H Scheme 13.
NH
2 N NH N.0 0 I~,PA, DIEA 0 NNNH IHI5-14 0 HN-N HOROH N 5 6NN 12 WO 2007/092888 PCT/US2007/061768 Scheme 14. NHN NN O NaH, Mel, DMF 0 0 ON 051 N K+-OTMS THF, RT 0 -C II N O 1) (CO)2Ct2 dI O " N N 2) ON-sNH2 HO N H ,o I BEMP Scheme 15. 0 O H NaH, Br / furan-3 0 N O N - boronic acid I/ / I0 / / Br Grubb's OO catalyst O O HO O N IM NaOH eO 5 Biological Methods 10 13 WO 2007/092888 PCT/US2007/061768 The compounds demonstrated activity against HCV NS5B as determined in the following HCV RdRp assays. HCVNS5B RdRp cloning, expression, and purification. The cDNA encoding 5 the NS5B protein of HCV, genotype lb, was cloned into the pET21a expression vector. The protein was expressed with an 18 amino acid C-terminal truncation to enhance the solubility. The E. coli competent cell line BL21(DE3) was used for expression of the protein. Cultures were grown at 37 oC for - 4 hours until the cultures reached an optical density of 2.0 at 600 nm. The cultures were cooled to 20 10 oC and induced with 1 mM IPTG. Fresh ampicillin was added to a final concentration of 50 ptg/ml and the cells were grown overnight at 20 'C. Cell pellets (3L) were lysed for purification to yield 15-24 mgs of purified NS5B. The lysis buffer consisted of 20 mM Tris-HC1, pH 7.4, 500 mM NaC1, 0.5% 15 triton X-100, 1 mM DTT, 1mM EDTA, 20% glycerol, 0.5 mg/mnl lysozyme, 10 mM MgCl2, 15 ug/mI deoxyribonuclease I, and Complete TM protease inhibitor tablets (Roche). After addition of the lysis buffer, frozen cell pellets were rcsuspended using a tissue homogenizer. To reduce the viscosity of the sample, aliquots of the lysate were sonicated on ice using a microtip attached to a Branson sonicator. The 20 sonicated lysate was centrifuged at 100,000 x g for lhr at 4 'C and filtered through a 0.2 p.m filter unit (Coming). The protein was purified using three sequential chromatography steps: Heparin sepharose CL-6B, polyU sepharose 4B, and Hitrap SP sepharose 25 (Pharmacia). The chromatography buffers were identical to the lysis buffer but contained no lysozyme, deoxyribonuclease I, MgCI2 or protease inhibitor and the NaC1 concentration of the buffer was adjusted according to the requirements for charging the protein onto the column. Each column was eluted with a NaCI gradient which varied in length from 5-50 column volumes depending on the column type. 30 After the final chromatography step, the resulting purity of the enzyme is >90% based on SDS-PAGE analysis. The enzyme was aliquoted and stored at -80 oC. Standard HCVNS5B RdRp enzyme assay. HCV RdRp genotype lb assays were run in a final volume of 60 tl in 96 well plates (Costar 3912). The assay buffer 14 WO 2007/092888 PCT/US2007/061768 is composed of 20 mM Hepes, pH 7.5, 2.5 mM KC1, 2.5 mM MgC12, 1 mM DTT, 1.6 U RNAse inhibitor (Promega N2515), 0.1 mg/ml BSA (Promega R3961), and 2 % glycerol. All compounds were serially diluted (3-fold) in DMSO and diluted further in water such that the final concentration of DMSO in the assay was 2%. 5 HCV RdRp genotype lb enzyme was used at a final concentration of 28 nM. A polyA template was used at 6 nM, and a biotinylated oligo-dT12 primer was used at 180 nM final concentration. Template was obtained commercially (Amersham 27 4110). Biotinylated primer was prepared by Sigma Genosys. 3H-UTP was used at 0.6 giCi (0.29 gM total UTP). Reactions were initiated by the addition of enzyme, 10 incubated at 30 oC for 60 min, and stopped by adding 25 pl of 50 mM EDTA containing SPA beads (4 tg/p l, Amersham RPNQ 0007). Plates were read on a Packard Top Count NXT after >lhr incubation at room temperature. Modified HCVNS5B RdRp enzyme assay. A modified enzyme assay was 15 performed essentially as described for the standard enzyme assay except for the following: The biotinylated oligo dT12 primer was precaptured on streptavidin coated SPA beads by mixing primer and beads in assay buffer and incubating at room temperature for one hour. Unbound primer was removed after centrifugation. The primer-bound beads were resuspended in 20 mM Hepes buffer, pH 7.5 and used in 20 the assay at final concentrations of 20 nM primer and 0.67 Ag/pl beads. Order of addition in the assay: enzyme (14 nM) was added to diluted compound followed by the addition of a mixture of template (0.2 nM) , 3H-UTP (0.6 pCi, 0.29 jiM), and primer-bound beads, to initiate the reaction; concentrations given are final. Reactions were allowed to proceed for 4 hours at 300 C. 25
IC
5 0 values for compounds were determined using seven different [I]. ICso values were calculated from the inhibition using the formula y = A+((B A)/(1 +((C/x)^D))). 30 FRETAssay Preparation. To perform the HCV FRET screening assay, 96 well cell culture plates were used. The FRET peptide (Anaspec, Inc.) (Taliani et al., Anal. Biochem. 1996, 240, 60-67) contains a fluorescence donor, EDANS, near one end of the peptide and an acceptor, DABCYL, near the other end. The fluorescence 15 WO 2007/092888 PCT/US2007/061768 of the peptide is quenched by intermolecular resonance energy transfer (RET) between the donor and the acceptor, but as the NS3 protease cleaves the peptide the products are released from RET quenching and the fluorescence of the donor becomes apparent. The assay reagent was made as follows: 5X cell Luciferase cell 5 culture lysis reagent from Promega (#E153A) diluted to IX with dH 2 0, NaCl added to 150 mM final, the FRET peptide diluted to 20 pM final from a 2 mM stock. To prepare plates, HCV replicon cells, with or without a Renilla luciferase reporter gene, were trypsinized and placed into each well of a 96-well plate with 10 titrated test compounds added in columns 3 through 12; columns 1 and 2 contained a control compound (HCV protease inhibitor), and the bottom row contained cells without compound. The plates were then placed in a CO 2 incubator at 37 'C. Assays. Subsequent to addition of the test compounds described above 15 (FRET Assay Preparation), at various times the plate was removed and Alamar blue solution (Trek Diagnostics, #00-100) was added per well as a measure of cellular toxicity. After reading in a Cytoflour 4000 instrument (PE Biosystems), plates were rinsed with PBS and then used for FRET assay by the addition of 30 ul of the FRET peptide assay reagent described above (FRET Assay Preparation) per well. The plate 20 was then placed into the Cytoflour 4000 instrument which had been set to 340 excite/490 emission, automatic mode for 20 cycles and the plate read in a kinetic mode. Typically, the signal to noise using an endpoint analysis after the reads was at least three-fold. Alternatively, after Alamar blue reading, plates were rinsed with PBS, 50 ul of DMEM (high glucose) without phenol red was added and plates were 25 then used for luciferase assay using the Promega Dual-Glo Luciferase Assay System. Compound analysis was determined by quantification of the relative HCV replicon inhibition and the relative cytotoxicity values. To calculate cytoxicity values, the average Alamar Blue fluorescence signals from the control wells were set 30 as 100% non-toxic. The individual signals in each of the compound test wells were then divided by the average control signal and multiplied by 100% to determine percent cytotoxicity. To calculate the HCV replicon inhibition values, an average background value was obtained from the two wells containing the highest amount of 16 WO 2007/092888 PCT/US2007/061768 HCV protease inhibitor at the end of the assay period. These numbers were similar to those obtained from naive Huh-7 cells. The background numbers were then subtracted from the average signal 5 obtained from the control wells and this number was used as 100% activity. The individual signals in each of the compound test wells were then divided by the averaged control values after background subtraction and multiplied by 100% to determine percent activity. EC5 0 values for a protease inhibitor titration were calculated as the concentration which caused a 50% reduction in FRET or luciferase 10 activity. The two numbers generated for the compound plate, percent cytoxicity and percent activity were used to determine compounds of interest for further analysis. Representative data for Formula I compounds are reported in Table 1. 15 Table 1. Example ICso ECso 1 A A 2 B A 3 B A 4 B A 5 A A 6 A A 7 A A 8 B A 9 A A 10 B A 11 B A 12 A A 13 B A 14 A A 15 B A 16 B A 17 B B 18 19 B A 20 21 B A 22 B A 23 A A 24 B A 25 B B 17 WO 2007/092888 PCT/US2007/061768 Example IC 50 so ECso 26 A A 27 B A 28 B A 29 30 A A 31 32 33 B A 34 35 A A 36 B A 37 B B 38 B B 39 A A 40 A A 41 A A 42 A A 43 B A 44 B A 45 B A 46 A A 47 B A 48 A A 49 A 50 B B 51 B A 52 B B 53 B B 54 B B 55 A 56 B A 57 B B 58 B B A>0.5 gM; B 0.001 gM - 0.5 gM; C <0.02 pM but an exact value was not determined; IC 5 0 values were determined using the preincubation protocol. EC50 values were determined using the FRET assay. 5 Additionally, compounds disclosed in US Patent application 11/181639, filed July 14, 2005 wcre shown to have activity in these assays (see Table 2). Table 2. Structure 18 WO 2007/092888 PCT/US2007/061768 Structure O OH 0 01-()-N 00 H0 N 0 HO N Ho N 0 HO 0~N 0 NO H 0N> o0 CyNS N 0 0 0 0 N 19 WO 2007/092888 PCT/US2007/061768 Structure 00 N N oP0 N N 0 / N -~ N crH 0 N. H 200 WO 2007/092888 PCT/US2007/061768 Structure olo 0N O,,O r~o 00 H oo o0 HN NN 00 4" N 'N N o0 0 N 00 o- r So N N oo rO 0 0 HN N oy0 0 0 2 OHO ON 00 O 0 O N 2N1 21H WO 2007/092888 PCT/US2007/061768 Structure 0 O N O N 0 oN r 000 0 N0 0 N O OO hN Pharmaceutical Compositions and Methods of Treatment 5 The compounds demonstrate activity against HCV NS5B and can be useful in treating HCV and HCV infection. Therefore, another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 10 Another aspect of the invention is a composition further comprising a compound having anti-HCV activity. Another aspect of the invention is a composition where the compound having anti-HCV activity is an interferon. Another aspect of the invention is where the 15 interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau. 22 WO 2007/092888 PCT/US2007/061768 Another aspect of the invention is a composition where the compound having anti-HCV activity is a cyclosporin. Another aspect of the invention is where the cyclosporin is cyclosporin A. 5 Another aspect of the invention is a composition where the compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5' 10 monophospate dehydrogenase inhibitor, amantadine, and rimantadine. Another aspect of the invention is a composition where the compound having anti-HCV activity is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B 15 protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection. Another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, an 20 interferon and ribavirin. Another aspect of the invention is a method of inhibiting the function of the HCV replicon comprising contacting the HCV replicon with a compound of formula I or a pharmaceutically acceptable salt thereof. 25 Another aspect of the invention is a method of inhibiting the function of the HCV NS5B protein comprising contacting the HCV NS5B protein with a compound of formula I or a pharmaceutically acceptable salt thereof. 30 Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof. Another aspect of the invention is a method of inhibiting the function of the HCV replicon. Another aspect of the invention is a method of inhibiting the function of the HCV NS5B protein. 35 23 WO 2007/092888 PCT/US2007/061768 Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in conjunction with (prior to, after, or concurrently) another compound having anti-HCV activity. 5 Another aspect of the invention is the method where the other compound having anti-HCV activity is an interferon. Another aspect of the invention is the method where the interferon is selected 10 from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastoid interferon tau. Another aspect of the invention is the method where the other compound having anti-HCV activity is a cyclosporin. 15 Another aspect of the invention is the method where the cyclosporin is cyclosporin A. Another aspect of the invention is the method where the other compound 20 having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine. 25 Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an 30 HCV infcction. Another aspect of the invention is the method where the other compound having anti-HICV activity is effective to inhibit the function of target in the HCV life cycle other than the HCV NS5B protein. 35 24 WO 2007/092888 PCT/US2007/061768 "Therapeutically effective" means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of hepatitis and HCV infection. 5 "Patient" means a person infected with the HCV virus and suitable for therapy as understood by practitioners in the field of hepatitis and HCV infection. "Treatment," "therapy," "regimen," "HCV infection," and related terms are used as understood by practitioners in the field of hepatitis and HCV infection. 10 The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. A therapeutically effective amount is that which is 15 needed to provide a meaningful patient benefit. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including capsules, tablets, losenges, and powders as well as liquid suspensions, syrups, elixers, and solutions. Compositions are made using common formulation techniques, and 20 conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. 25 Some examples of dosages are 1 rmg, 10 rmg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit. Liquid compositions are usually in dosage unit ranges. Generally, the liquid 30 composition will be in a unit dosage range of 1-100 mg/mL. Some examples of dosages arc 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mnL, and 100 mg/mL. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 1-100 mg/mL. 25 WO 2007/092888 PCT/US2007/061768 The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. 5 The specific dosing regime, however, will be determined by a physician using sound medical judgment. The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but 10 separately from, other agents useful in treating hepatitis and HCV infection. In these combination methods, the compound will generally be given in a daily dose of 1-100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regime, however, will bc determined by a physician using sound medical judgement. 15 Some examples of compounds suitable for compositions and methods are listed in Table 2. Table 2. Brand Name Type of Inhibitor or Source Company Bran Na e TagetSource Company Target Omega IFN IFN-co Intarcia Therapcutics Boehringer Ingelheim BILN-2061 serine protease inhibitor Pharma KG, Ingelheim, Germany Endo Pharmaceuticals Summetrel antiviral Holdings Inc., Chadds Ford, PA Roferon A IFN-a2a F. Hoffmann-La Roche LTD, Basel, Switzerland F. Hoffmann-La Rochc Pegasys PEGylated IFN-cx2a L al Si e LTD, Basel, Switzerland Pegasys and Ribavirin PEGylated IFN- F. Hoffmann-La Roche c2a/ribavirin LTD, Basel, Switzerland CellCept HCV IgG F. Hoffmann-La Roche CelCiept mmunosupprcssant LTD, Basel, Switzerland Wellferon lymphoblastoid IFN- GlaxoSmithKline plc, anl Uxbridge, UK 26 WO 2007/092888 PCT/US2007/061768 Brand Name Type of Inhibitor or Source Company Target Human Genome Albuferon - cx albumin IFN-a2b Sciences Inc., Rockville, MD Levovirin ribavirin ICN Pharmaceuticals, Costa Mesa, CA IDN-6556 caspase inhibitor Idun Pharmaceuticals Inc., San Diego, CA IP-501 antifibrotic Indevus Pharmaceuticals Inc., Lexington, MA Actimmune INF-y InterMune Inc., Brisbane, CA InterMune Infergen A IFN alfacon-1 Pharmaceuticals Inc., Brisbane, CA ISIS Pharmaceuticals ISIS 14803 antisense Inc, Carlsbad, CA/Elan Phamaceuticals Inc., New York, NY JTK-003 RdRp inhibitor Japan Tobacco Inc., Tokyo, Japan Pegasys and Ceplene PEGylated IFN-cL2a/ Maxim Pharmaceuticals immune modulator Inc., San Diego, CA Ceplene immune modulator Maxim Pharmaceuticals Inc., San Diego, CA Civacir HCV IgG Nabi immunosuppressant Biopharmaceuticals Inc., Boca Raton, FL RegeneRx Biopharmiceuticals Inc., Intron A and Zadaxin IFN-a2b/al-thymosin Bethesda, MD/ SciClone Pharmaceuticals Inc, San Mateo, CA Levovirin IMPDH inhibitor Ribapharm Inc., Costa Mesa, CA Viramidine Ribavirin Prodrug Ribapharm Inc., Costa Mesa, CA Ribozyme Heptazyme ribozyme Pharmaceuticals Inc., Boulder, CO Schering-Plough Intron A IFN-a2b Corporation, Kenilworth, NJ Schering-Plough PEG-Intron PEGylated IFN-x2b Corporation, Kenilworth, NJ 27 WO 2007/092888 PCT/US2007/061768 Brand Name Type of Inhibitor or Source Company Bran Na e TagetSource Company Target Schering-Plough Rebetron IFN-c2b/ribavirin Corporation, Kenilworth, NJ Schering-Plough Ribavirin ribavirin Corporation, Kenilworth, NJ PEGylated IFN- Schering-Plough PEG-Intron / Ribavirin /ribavirin Corporation, ct2b/ribavirin .ejwrlN Kenilworth, NJ SciClone Zadazim Immune modulator Pharmaceuticals Inc., San Mateo, CA Rebif IFN-P1 la Serono, Geneva, Switzerland Transition Therapeutics IFN-P and EMZ701 IFN-3 and EMZ701 Transition Therapeutics Inc., Ontario, Canada Tularik Inc., South San Batabulin (T67) P-tubulin inhibitor Tularik Inc., South San Francisco, CA Merimepodib IMPDH inhibitor Vertex Pharmaceuticals (VX-497) Inc., Cambridge, MA Vertex Pharmaceuticals Telaprevir NS3 serine protease Inc., Cambridge, MA/ (VX-950, LY-570310) inhibitor Eli Lilly and Co. Inc., Indianapolis, IN Omrniferon natural IFN-a Viragen Inc., Plantation, FL XTL XTL-6865 (XTL-002) monoclonal antibody Biopharmaceuticals Ltd., Rehovot, Isreal HCV-796 NS5B Replicase Wyeth Viropharma HCV-796 ____Inhibitor NM-283 NS5B Replicase Idenix / Novartis Inhibitor GL-59728 NS5B Replicase Gene Labs / Novartis Inhibitor GL-60667 NS5B Replicase Gene Labs / Novartis Inhibitor 2'C MeA NS5B Replicase Gilead Inhibitor PSI 6130 NS5B Rcplicasc Roche Inhibitor R1626 NS5B Replicase Roche Inhibitor SCH 503034 serine protease inhibitor Schering Plough NIM811 Cyclophilin Inhibitor Novartis Suvus Methylene blue Bioenvision 28 WO 2007/092888 PCT/US2007/061768 Brand Name Type of Inhibitor or Source Company Target Multiferon Long lasting IFN Viragen/Valentis Actilon (CPG10101) TLR9 agonist Coley Interferon-3 Interferon-3-l1 a Serono Zadaxin Immunomodulator Sciclone Pyrazolopyrimidine compounds and salts HCV Inhibitors From WO HCV Inhibitors Arrow Therapeutics Ltd. 2005047288 2'C Methyl adenosine NS5B Replicase Merck Inhibitor Merck GS-9132 (ACH-806) HCV Inhibitor Achillion / Gilead DESCRIPTION OF SPECIFIC EMBODIMENTS 5 Analytical HPLC and LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nM and Waters Micromass. NMR spectra were collected by using Bucker DPX-300 MHz or DRX-500 MHz instruments. 10 Intermediate 1
NH
2 MeO 2 C N 6-(aminocarbonyl)-13-cyclohexyl- 7H-indolo[2, l-a][2]benzazepine-10 15 carboxylic acid, methyl ester. To a solution of 7H-indolo[2,1-a][2]benzazepine-6,10 dicarboxylic acid, 13-cyclohexyl-, 10-methyl ester (1.10 g, 2.65 mmol) in DMF (7.0 mL) and DTPEA (1.85 mL, 10.6 mmol) was added TBTU (1.28 g, 3.97 mmol). The resulting solution was stirred at 22 oC for 15 min. Ammonia (0.5M in dioxane, 21.2 mL, 10.6 mmol) was added and this solution was stirred at 22 oC for 18 hr. 1M HCI 20 (50 mL) was added and the aqueous layer was extracted with CHC1 3 (2 x 50 mL). The 29 WO 2007/092888 PCT/US2007/061768 organic phase was dried over Na 2
SO
4 , filtered, and concentrated under reduced pressure. Silica gel chromatography (4:1 EtOAc:hexanes) of the concentrate afforded the title compound (900 mg, 82%) as a yellow oil. MS m/z 415 (MH+), 1 H NMR (300 MHz, CDC1 3 ) 8 ppm 1.17-1.69 (m, 5H), 1.79 (mn, 2H), 1.87-2.16 (m, 3H), 2.86 (m, 1 H), 5 3.94 (s, 3H), 4.14 (broad m, 1 H), 5.72 (broad m, 1 H), 7.38 (s, 1 H), 7.46 (mn, 2 H), 7.53 (dd, J=7.6, 8.4 Hz ,1 H), 7.61 (d, J=7.6 Hz, 1 H), 7.74 (d, J=8.4 Hz, 1 H), 7.87 (d, J=8.4 Hz, 1 H), 8.29 (s, 1 H). Intermediate 2 10 CN MeO 2 C N 6-cyano-13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, methyl ester. To a solution of 7H-indolo[2,1-a][2]bcnzazcpinc-10-carboxylic acid, 6 15 (aminocarbonyl)-13-cyclohexyl-, methyl ester (220 mg, 0.531 immol) in dichloromethane (5.1 mL) was added Burgess Reagent (506 mg, 2.12 mmol). The resulting solution was stirred at 22 oC for 6 hr. 1M HC1 (50 mL) was added and the aqueous layer was extracted with CHC1 3 (2 x 30 mL). The organic phase was dried over Na 2
SO
4 , filtered, and concentrated under reduced pressure to afford the title compound (200 20 mg, 95%) as a yellow oil. MS m/z 397 (MH+), 1H NMR (300 MHz, CDCI 3 ) 6 ppm 1.21-1.72 (m, 5H), 1.79 (m, 2H), 1.82-2.14 (m, 3H), 2.81 (mn, 1 H), 3.96 (s, 3H), 4.47 (broad m, 1 H), 5.08 (broad m, 1 H), 7.42 (d, J=8.4 Hz,1 IH), 7.49-7.59 (m, 4 H), 7.78 (d, J=8.4 Hz, 1 H), 7.88 (d, J=8.4 Hz, 1 H), 8.19 (s, 1 H). 30 WO 2007/092888 PCT/US2007/061768 Intermediate 3 0 OH 0 OVN 1 5 13-cyclohexyl-7H-indolo[2,1-aj[2]benzazepine-6,10-dicarboxylic acid, 10 methyl ester. Dissolve 7H-indolo[2,1 -a] [2]benzazepine-6,10-dicarboxylic acid, 13 cyclohexyl-, dimethyl ester (98mg, 0.23 mMol) in 1.5ml of THF, add 0.24 mL of 1.0M tetrabutylammonium hydroxide in methanol. The reaction was stirred at room temperature for 16 hrs then partitioned between ethyl acetate and 1N hydrochloric 10 acid. The organic layer was washed with 1N hydrochloric acid, water, then brine and dried over magnesium sulfate to yield 93mg (98%) of mono-acid product. 1H NMR (500 MHz, CHLOROFORM-D) 5 ppm 8.29 (s, 1 H) 8.00 (s, 1 H) 7.88 (d, J=8.55 Hz, 1 H) 7.74 (d, J=8.55 Hz, 1 H) 7.58 - 7.65 (m, 1 H) 7.45 - 7.59 (m, 3 H) 5.67 (s, 1 H) 4.21 (s, 1 H) 2.84 (t, J=12.05 Hz, 1 H) 1.99 - 2.18 (mn, 3 H) 1.92 (d, 3 H) 1.77 (d, 15 J=7.63 Hz, 2 H) 1.40 (d,J=12.51 Hz, 2 H) 1.17 - 1.31 (m, 6 H, trace Bu4NOH). MS m/z 416(MH'). Intermediate 4 O CI O 0 20 6-(chlorocarbonyl)-13-cyclohexyl-7H-indolo[2,1-a] [2]Jbenzazepine-10 carboxylic acid, methyl ester. 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylic 31 WO 2007/092888 PCT/US2007/061768 acid, 13-cyclohexyl-, 10-methyl ester (1.50g, 3.61 mMol) was suspended in 30ml of anhydrous dichloromethane. A solution of oxalyl chloride in dichloromethane (4.0ml, 2.0M, 8.0mMol) was added to the reaction. A catalytic amount of DMF (3drops) was added. The reaction briefly was brought to reflux under nitrogen and 5 allow to cool and stir under nitrogen for 2.5 hours. The reaction volatiles were removed in vacuuo. Residual oxalyl chloride was removed by azeotrop with a mixture of benzene/ dichloromethane to yield 1.59g of a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.25 (s, 1 H) 8.22 (s, 1 H) 7.89 (d, J=8.54 Hz, 1 H) 7.75 - 7.80 (m, 1 H) 7.61 - 7.66 (m, 2 H) 7.57 - 7.61 (mn, 1 H) 7.54 (dd, J=5.95, 1.98 10 Hz, 1 H) 5.62 - 5.75 (mn, .J=14.65 Hz, 2 H) 4.23 (s, 1 H) 3.96 (s, 3 H) 2.79 - 2.88 (m, 1 H) 1.99 - 2.17 (m, 3 H) 1.87 - 1.99 (m, 2 H) 1.77 (d, J=7.63 Hz, 2 H) 1.31 - 1.68 (m, 3 H) 1.13 - 1.30 (m, 1 H). Intermediate 5 15 NH NH *HCI OEt 0 Ethyl 2-(tetrahydro-2H-pyran-4-yl)acetirnidate hydrochloride. In a 3 neck round bottom flask equipped with a pipet gas inlet tube connected to an anhydrous 20 hydrogen chloride lecture bottle and a gas out let adapter to an bubbler containing ethanol was charged 4-cyanomethyltetrahydropyran (970mg, 775mMol) and approximately 15ml of anhydrous ethanol. The reaction was cooled with an ice bath and hydrogen chloride bubbled into the reaction for lhr. The reaction was then capped with a rubber septa and placed in a freezer for 3 days. The reaction removed 25 from the freezer, warmed to room temperature and volatiles removed in vacuuo from the reaction mixture, to obtain 1.657g of an amber oil. The oil was placed under nitrogen and placed in a frczcr to crystallize overnight to a off white solid. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 12.41 (s, 1 H) 11.52 (s, 1 H) 4.62 (q, J=7.12 Hz, 2 H) 3.92 (dd, J=l 1.44, 3.51 Hz, 2 H) 3.29 - 3.44 (m, 2 H) 2.65 (d, J=7.32 Hz, 2 30 H) 2.04 - 2.18 (m, 1 H) 1.54 - 1.63 (m, 2 H) 1.43 - 1.51 (m, 4 H) 1.38 - 1.43 (m, 1 H). 32 WO 2007/092888 PCT/US2007/061768 Intermediate 6 NH2 O0 NH 5 13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylic acid, 10 methyl ester, 6-hydrazide. The acid 7H-indolo[2,1-a][2]benzazepine-6,10 dicarboxylic acid, 13-cyclohexyl-, 10-methyl ester, (2.527g, 6.08 mMol) was dissolved in 45 ml of DMF with hydroxybenzotriazole (HOBt) (1.27g, 9.4 mMol). 10 The coupling agent 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.752g, 9.14 mMol) was added to the reaction mixture. A bright yellow precipitate was formed within 1 hour with stirring at room temperature and 50mL of THF added to dissolve the precipitate. The reaction was cannula transferred to a stirred flask containing 2ml of hydrazine (63.7 mMol) in 25 mL of THF and stirred for 3 hours at 15 room temperature. The reaction was transferred to a 1L Erlenmeyer flask and 500 ml of water added with rapid stirring. A yellow precipitate was filtered off, rinsed with water and dried in vacuuo over phosphorus pentoxide. To yield 2.618g (100%) of a pale yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.25 (s, 1 H) 7.85 (d,.I=8.54 Hz, 1 H) 7.73 (d, J.1=8.55 Hz, 1 H) 7.57 (d, .=7.63 Hz, 1 H) 7.48 20 7.54 (m, 1 H) 7.40 - 7.48 (m, 2 H) 7.30 (s, 1 H) 5.57 (s, 1 H) 4.17 (s, 1 H) 3.92 (s, 3 H) 3.21 (s, 2 H) 2.76 - 2.90 (m, 1 H) 1.87 - 2.23 (m, 4 H) 1.47 - 1.82 (m, 3 H) 1.07 1.47 (m, 4 H); MS m/z 430(MH +). Intermediate 7 25 33 WO 2007/092888 PCT/US2007/061768 00 Om O y-N, ' ' OMe 7H-Indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3 methoxy-6-(phenyllsulfonyl,)-, tert-butyl ester. To a solution of methyl 3-cyclohexyl 5 2-(2-formyl-4-methoxyphenyl)-lH-indole-6-carboxylate (6.00 g, 13.8 rmmol) in dioxane (28.0 mL) and BEMP (7.97 mL, 27.6 mmol) was addcd phenyl vinyl sulfone (27.6 g, 2.21 mmol). The resulting mixture was stirred in a sealed tube in a microwave at 120 'C for 15 min. The resulting solution was concentrated under reduced pressure. Silica gel chromatography (CH 2
C
2 ) of the concentrate afforded 10 the title compound (5.64g, 70%) as a yellow oil. MS m/z 584 (MIH). 1H NMR (500 MHz, CHLOROFORM-co) 8 ppm 1.18-1.33 (1 H, m), 1.34-1.45 (2 H, min), 1.49-57 (1 H, m), 1.64 (9 H, s.), 1.74-1.82 (2 H, m), 1.90-2.09 (4 H, m), 2.73 (1 H, m,), 3.93 (3 H, s), 4.38 (1 H, broad d), 5.08 (1 H, br. d), 7.09 (1 H, d, J=2.75 Hz), 7.12-7.18 (3 H, mn), 7.22 (1 H, d, J=7.45 Hz), 7.30 (1 H, s), 7.48 (1 H, d, J=8.85 Hz), 15 7.54 (1 H, dd, J=8.55, 1.22 Hz), 7.61 (2 H, m), 7.67 (1 H, d, J=8.55), 8.01 (1 H, s). Intermediate 8 Sn(n-Bu)3 0 O 20 7H-indolo[2,1-aJ][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-3 methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester. 1,1-dimethylethyl 13 cyclohexyl-3-(methyloxy)-6-(tributylstannanyl)-7H-indolo[ 2 ,1-a][2]benzazepine-10 34 WO 2007/092888 PCT/US2007/061768 carboxylate. Dissolve 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13 cyclohexyl-3-methoxy-6-(phenylsulfonyl)-, 1,1-dimethylethyl ester (1.00g, 1.71 mMol) in 26mL of benzene along with bis(tributyltin) (2.8mL, 5.54 mMol), tributyltin hydride (136uL, 0.513 mMol) and triethylamine (1.05mL, 7.5 mMol). 5 The solution was sparged for approximately for 10 minutes with nitrogen then 2,2' bisazoisobutyronitrile (AIBN) (96mg, 0.58mMol) added to the reaction. The reaction was heated to reflux under nitrogen for 2hr. The reaction was followed by LC-MS using the following HPLC conditions: Shimadzu Analytical HPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, 10mmol Ammonium Acetate %B= 10 95% acetonitrile, 5% water, 10mmol Ammonium Acetate; Initial %B= 0; Final % B=100; Gradient= 3 min; Runtimce= 10 min; Flow ratc= 5 ml/min; Wavelength= 220nm; Column= Waters Xterra, 3mm x 50mm, S7. To the reaction was added tributyltin hydride (0.45mL, 1.7mMol) and AIBN(95mg, 0.58mMol), the reaction heated to reflux for 2hrs, and analyzed for progress. AIBN (99mg, 0.60mMol) added 15 to the reaction and the reaction heated to reflux under for an additional 6hrs using a timer. The reaction was analyzed by LC-MS for progress then tributyltin hydride(1.0ml, 3.8mMol) and AIBN (97mg, 0.59mMol) was added and the reaction heated to reflux for 2hrs 20min. The reaction was analyzed by LC-MS and AIBN (97mg, 0.59mMol) added to the reaction. The reaction was heated for lhr under 20 nitrogen at reflux and the cooled and analyzed by LC-MS. Volatiles were removed in vacuuo from the reaction and the reaction was purified by column chromatography using a C 18 i packing of 190g of YMC GEL ODS-A, 120A spherical 75 uM. The reaction residue (6.67g of yellow oil) was dissolved in a minimum of dichloromethane and the solution applied onto the reverse phase column packed in 25 10% dichloromethane in acetonitrile. Initial elution was done using 10% dichloromethane in acetonitrile followed by elution with 15% dichloromethane in acetonitrile. The chromatography was monitored by TLC using Whatman MKC18F reverse phase 1 "x3" 200uM thickness TLC plates cluting using 15% dichloromethane in acetonitrile. Compound observation was accomplished by UV 30 lamp at 254nm and iodine staining of TLC plates. Product fractions were collected and volatiles removed in vacuuo to yield 647mg (52%) as a pale yellow foam. 1H NMR (500 MHz, CHLOROFORM-D) 6 ppm 0.71 - 0.83 (m, 9 H) 0.85 - 0.96 (mn, 3 H) 0.95 - 1.08 (m, 6 H) 1.15 - 1.27 (m, 7 H) 1.27 - 1.49 (m, 11 H) 1.53 (s, 5 H) 1.60 35 WO 2007/092888 PCT/US2007/061768 1.67 (m, 9 H) 1.68 - 1.82 (m, 2 H) 1.84 - 1.96 (m, 1 H) 1.96 - 2.16 (m, 3 H) 2.74 2.91 (m, 1 H) 3.90 (s, 3 H) 4.16 - 4.40 (m, 1 H) 4.82 - 5.03 (m, 1 H) 6.72 - 6.90 (m, 2 H) 6.96 (dd, J=8.55, 2.44 Hz, 1 H) 7.43 (d, J=8.55 Hz, 1 H) 7.66 (dd, J=8.39, 1.37 Hz, 1 H) 7.81 (d, J=8.55 Hz, 1 H) 8.04 (s, 1 H). LC-MS: Shimadzu Analytical 5 HPLC using Discovery VP software: %A= 5% acetonitrile, 95% water, 10mmol Ammonium Acetate; %B= 95% acetonitrile, 5% water, 10mmol Ammonium Acetate; Initial %B= 0; Final % B=100; Gradient= 3 min; Runtime= 10 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column=-- Waters Xterra, 3mm x 50mm, S7. Retention Time= 4.2min, MS m/z 734(MH+). 10 Intermediate 9 o~ o0 O N
O
O 0N S0O 15 Methyl 1 3 -cyclohexyl-3-(methyloxy)-6-(((5-(methyloxy)-2,5 dioxopentyl)amino)carbonyl)-7H-indolo[2, 1-a][2]benzazepine-1 0-carboxylate. 13 cyclohexyl-3-(methyloxy)-10-((methyloxy)carbonyl)-7H-indolo[2,1 a][2]benzazepine-6-carboxylic acid (1.00g, 2.24mMol) was dissolved in 20ml of DMF along with 1-hydroxy-7-azabenzotriazole (483mg, 3.5mMol). The reaction 20 was placed under nitrogen and 1-[3-(dimcthylamino)propyl]-3-cthylcarbodiimide hydrochloride (663mg, 3.5mMol) was added and the reaction stirred for lhr at room temperature. 5-aminolevleunic acid hydrochloride (608mg, 3.35mMol) was added to the reaction followed by diisopropylethyl amine (0.44mL, 2.5mMol). The reaction was stirred overnight under nitrogen at room temperature. Volatiles were removed 25 in vacuuo and the residue was partitioned between ethyl acetate and 0.1 N hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the organic phases combined, washed with brine and dried over magnesium sulfate. Volatiles were removed in vacuuo to yield 1.47g of crude product which was 36 WO 2007/092888 PCT/US2007/061768 combined with 698mg of a previous experiment. The crude product was purified by silica gel chromatography eluting with a gradient of 10% ethyl acetate/ dichloromethane to 25% ethyl acetate / dichloromethane to yield 1.64g (84%) of product as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) E ppm 1.12 5 1.30 (m, 1 H) 1.32 - 1.50 (m, 2 H) 1.77 (d, J=9.16 Hz, 2 H) 1.89 - 1.99 (m, 1 H) 1.99 - 2.18 (m, 3 H) 2.67 (t, J=6.10 Hz, 2 H) 2.72 - 2.87 (m, 3 H) 3.67 (s, 3 H) 3.91 (s, 3 H) 3.94 (s, 3 H) 4.15 (d, J=19.23 Hz, 1 H) 4.31 (d, J=34.79 Hz, 2 H) 5.62 (d, J=12.82 Hz, 1 H) 6.70 (t, J=4.12 Hz, 1 H) 6.96 (d, J=2.44 Hz, 1 H) 7.08 (dd, J=8.55, 2.75 Hz, 1 H) 7.33 (s, 1 H) 7.51 (d, J=8.55 Hz, 1 H) 7.73 (d, J=8.24 Hz, 1 H) 7.84 (d, J=8.24 10 Hz, 1 H) 8.26 (s, 1 H); MS m/z 573(MHW); MS m/z 571(M-H)-. Intermediate 10 0 O 00 N 15 13-cyclohexyl-3-(methyloxy)-10-((methyloxy)carbonyl)-7H-indolo[2,1 a][2]bcnzazcpine-6-carboxylic acid (1.50g, 3.37mMol) was dissolved in 32ml of DMF along with 1-hydroxy-7-azabenzotriazole (697mg, 5.1mMol). The reaction was placed under nitrogen and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide 20 hydrochloride (967mg,5.04mMol) was added and the reaction stirred for 1.5hr at room temperature. Aminoacetaldehyde dimethylacetal (0.44mL, 4. lmMol) was added to the reaction and the reaction stirred at room temperature under nitrogen for 16hrs. Volatiles were removed in vacuuo and the residue was partitioned between ethyl acetate and 0.1 N hydrochloric acid. The aqueous phase was extracted with 25 ethyl acetate and the organic phases combined, washed with 0.1N hydrochloric acid then brine and dried over magnesium sulfate. Volatiles were removed in vacuuo to yield 1.98g of crude product which was used in the next reaction without purification. 37 WO 2007/092888 PCT/US2007/061768 The crude acetal (1.4g, 2.7mMol) was dissolved in 30mL of acetone and 2M hydrochloric acid (1.6mL, 3.2mMol) and briefly heated to reflux then allow to stir for 2.5hrs before being briefly heated to reflux again and allowed to stir an additional 1.5hrs. 1N hydrochloric acid (200mL) was added to the reaction and a precipitate 5 filtered off and rinsed with water and dried in vacuuo, to yield 1.14g (87%) of crude product. The product was purified by silica gel chromatography eluting with a gradient of 15% ethyl acetate in hexanes to 25% ethyl acetate in hexanes to yield 0.81 g (62%) of product as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) 6 ppm 1.25 (t, J=7.17 Hz, 1 H) 1.31 - 1.48 (m, 2 H) 1.48 - 1.63 (m, 3 H) 1.77 (d, 10 .1=9.46 Hz, 2 H) 1.86 - 1.98 (mn, 1 H) 1.98 - 2.16 (m, 3 H) 2.77 - 2.89 (m, 1 H) 3.91 (s, 3 H) 3.94 (s, 3 H) 4.18 (d, J=14.04 Hz, 1 H) 4.32 (d, .J=34.79 Hz, 2 H) 5.62 (d, J=1 1.29 Hz, 1 H) 6.65 (s, 1 H) 6.97 (d, J=2.75 Hz, 1 H) 7.09 (dd, J=8.55, 2.75 Hz, 1 H) 7.35 (s, 1 H) 7.52 (d, J=8.85 Hz, 1 H) 7.73 (d, J=8.55 Hz, 1 H) 7.84 (d, J=8.54 Hz, 1 H) 8.26 (s, 1 H) 9.71 (s, 1 H). Shimadzu LC-MS discovery software; %A= 15 10% methanol, 90% water, 0.1% TFA; %B= 90% methanol, 10% water, 0.1% TFA Initial %B= 50; Final % B=100; Gradient - 5min; Runtime=6min; Flow rate= 5ml/min; UV@ 220nm; Column= Phenomenex Luna C18, 10Ou, 3.0 mm x 50 mm Product Rctention time = 4.2min. MS m/z 487(MH+). 20 Intermediate 11 H 0 ON 0 0 13-cyclohexyl-6-[[(5-methoxy-2,5-dioxopentyl)aminoJcarbonyl]- 7H 25 indolof2, I-aj[2jbenzazepine-1 0-carboxylic acid, methyl ester. 7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid, 6-(chlorocarbonyl)-13-cyclohexyl-, methyl ester (499mg, 1.15mMol) was dissolved in 1Oml of anhydrous dichloromethane and 38 WO 2007/092888 PCT/US2007/061768 methyl 5-aminolevulinate hydrochloride (244mg, 1.34mMol) was added to the reaction mixture followed by 0.5ml of pyridine (6.2mMol). The reaction was stirred under nitrogen at room temperature for 40 hours. Volatiles were removed in vacuuo and the residue was partitioned between ethyl acetate and 0.1 N hydrochloric acid. 5 The organic phase was washed with brine, dried over magnesium sulfate to yield 603mg of crude product. The product was combined with 433mg of a previous reaction run under the same conditions. The mixture was purified by silica column chromatography eluting with a gradient of 20% ethyl acetate in dichloromethane to 20% ethyl acetate in dichloromethane to yield 0.56g (45%) of product. 1H NMR (500 10 MHz, CHLOROFORM-D) 5 ppm 8.28 (s, 1 H) 7.87 (d, J=8.55 Hz, 1 H) 7.74 (dd, .J=8.55, 1.22 Hz, 1 H) 7.59 (d, J=7.93 Hz, 1 H) 7.43 - 7.56 (m, 3 H) 7.38 (s, 1 H) 6.71 (t, J=4.12 Hz, 1 H) 5.65 (d, J=10.99 Hz, 1 H) 4.31 (d, J=27.16 Hz, 2 H) 4.14 - 4.23 (m, 1 H) 3.94 (s, 3 H) 3.67 (s, 3 H) 2.80 - 2.91 (m, 1 H) 2.01 - 2.16 (m, 3 H) 1.70 2.00 (m, 3 H) 1.29 - 1.70 (m, 6 H) 1.14 - 1.31 (m, 2 H); MS m/z 543(MH 4 ), 15 560(MNH4+). Intermediate 12 HINO 0 HN 0 0 HO N 20 13-cyclohexyl-, 6-[2-[2-(tetrahydro-2H-pyran-4-yl)acetylJhydrazide]-7H indolo[2,1-a][2]benzazepine-6,10-dicarboxylic acid. 7H-indolo[2,1 a][2]benzazepine-6,10-dicarboxylic acid, 13-cyclohexyl-, 6-[2-[2-(tetrahydro-2H pyran-4-yl)acetyl]hydrazide] was isolated as a by-product from the hydrolysis of 25 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[5 39 WO 2007/092888 PCT/US2007/061768 [(tetrahydro-2H-pyran-4-yl)methyl]-1,3,4-oxadiazol-2-yl]-, methyl ester using the above HPLC conditions. Retention time was 6.9 minutes. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 11.64 (s, 1 H) 9.68 (d, J=5.80 Hz, 1 H) 8.56 (s, 1 H) 7.92 (d, J=8.54 Hz, 1 H) 7.78 (d, J=8.24 Hz, 1 H) 7.65 (d, J=7.63 Hz, 1 H) 7.46 - 7.61 (m, 5 4 H) 5.84 (d, J=14.95 Hz, 1 H) 4.18 (d, J=14.34 Hz, 1 H) 3.93 (d, J=10.99 Hz, 2 H) 3.37 (t, J=1 1.44 Hz, 2 H) 2.79 - 2.91 (m, 1 H) 2.44 (d, J=6.71 Hz, 2 H) 1.92 - 2.25 (m, 7 H) 1.76 (t, J=l 1.29 Hz, 3 H) 1.67 (t, J=9.92 Hz, 3 H) 1.53 (d, J=10.99 Hz, 2 H) 1.32 - 1.50 (m, 5 H) 1.15 - 1.28 (mn, 1 H); MS m/z 542(MH). 10 Example 1 N-- N N.. NH MeO 2 C N 13-cyclohexyl-6-(IH-tetrazol-5-yl)-7H-indolo[2, 1-a][2]benzazepine-I 0 15 carboxylic acid, methyl ester. To a solution of 7H-indolo[2,1-a][2]benzazepine-10 carboxylic acid, 6-cyano-13-cyclohexyl-, methyl ester (200 mg, 0.504 rmmol) in toluene (2.0 mrL) was added tributyltin azide (502 mg, 1.51 mmol). The resulting solution was stirred in a sealed tube in a microwave at 150 oC for 30 min. 1M HC1 (15 mL) was added and the aqueous layer was extracted with CHC1 3 (2 x 30 mL). The 20 organic phase was dried over Na 2
SO
4 , filtered, and concentrated under reduced pressure. Silica gel chromatography (9:1 EtOAc:methanol) of the concentrate afforded the title compound (191 mg, 86%) as a yellow oil. MS m/z 440 (MH+), 'H NMR (300 MHz,
CD
3 OD) 6 ppm 1.18-1.69 (mi, 5H), 1.79 (m, 2H), 1.86-2.15 (m, 3H), 2.87 (mn, 1 H), 3.94 (s, 3H), 4.52 (broad m, 1 H), 5.97 (broad m, 1 H), 7.49-7.54 (m, 3 H), 7.62 (d, 25 .J=7.6 Hz, 1 H), 7.68 (d, .J=8.4 Hz, 1 H), 7.75 (s, 1 H), 7.86 (d, .J=8.4 Hz, 1 H), 8.38 (s, I H). 40 WO 2007/092888 PCT/US2007/061768 Examples 2 and 3 N-NN-.. NN N N
HO
2 C N
HO
2 C N NNi 5 13-cyclohexyl-6- (2-ethyl-2H-tetrazol-5-yl)-5H-indolo[2, 1-a][2]benzazepine 1 0-carboxylic acid and 13-cyclohexyl-6-(2-ethyl-2H-tetrazol-5-yl)- 7H-indolo[2, I a][2]benzazepine-10-carboxylic acid. To a solution of 7H-indolo[2,1 a][2]benzazepine-10-earboxylic acid, 13-cyclohexyl-6-(1H-tetrazol-5-yl)-, methyl ester (40 mg, 0.09 mmol) in DMF (1.0 mL) and cesium carbonate (60 mg, 0.18 10 mmol) was added iodoethane (28 mg, 0.18 mmnol). The resulting mixture was heated at 60 'C for 18 hr. Water (1 mL) was added and the mixture was heated at 60 0 C for an additional 8 hr. 1M HC1 (15 mL) was added and the aqueous layer was extracted with CHC1 3 (2 x 30 mE). The organic phase was dried over Na 2
SO
4 , filtered, and concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to 15 afford the title compounds. 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13 cyclohexyl-6-(2-ethyl-2H-tetrazol-5-yl)-: 20mg, 49% yield. MS m/z 454 (MH*), 1 H NMR (300 MHz, CD 3 OD) 8 ppm 1.17-1.66 (m, 5H), 1.68 (t, 3 H), 1.79 (mn, 2H), 1.86-2.15 (mn, 3H), 2.88 (m, 1 H), 4.49 (broad m, 1 H), 4.70 (q, 2 H), 5.97 (broad m, 1 H), 7.47-7.58 (m, 3 H), 7.62 (d, J=7.6 Hz, 1 H), 7.71 (d, J=8.4 Hz, 1 H), 7.86 (d, 20 J=8.4 Hz, 1 H), 7.90 (s, 1 H), 8.41 (s, 1 H). 5H-indolo[2,1-a][2]benzazepine-10 carboxylic acid, 13-cyclohexyl-6-(2-ethyl-2H-tetrazol-5-yl)-: 11mg, 27% yield. MS m/z 454 (MH ), 1 H NMR (300 MHz, CD 3 OD) 8 ppm 1.16-1.64 (m, 5H), 1.68 (t, 3 H), 1.79 (m, 2H), 1.86-2.15 (m, 3H), 3.05 (m, 1 H), 3.68 (broad m, 1 H), 4.13 (broad m, 1 H), 4.67 (q, 2 H), 7.31-7.39 (m, 2 H), 7.41-7.48 (m, 2 H), 7.96 (t, J=8.4, 8.4 Hz, 25 2 H), 8.20 (s, 1 H), 8.38 (s, 1 H). 41 WO 2007/092888 PCT/US2007/061768 Example 4 N-N 0.90 o N , N -- N I H N 5 13-cyclohexyl-N-[(dimnethylamino)sulfonylU-6-[2-ethyl]-2H-tetrazol-5-yl]-7H indolo[2, I-a][2]benzazepine-1 0-carboxamnide. To a solution of 7H-indolo[2, I a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-(2-ethyl-2H-tetrazol-5-yl)- (87 mg, 0.19 nmmol) in CH 2 C1 2 (1.0 mL) was added 2M oxalyl chloride (0.48 mL, 0.96 mmol). This solution was stirred at 22 oC for 3 hr and then concentrated under 10 reduced pressure. BEMP (0.22 mL, 0.76 mmol), CH 2
C
2 (1.0 mL) and N,N dimethylsulfamide (120 mg, 0.96 rmmol) was added to the resulting oil. The resulting mixture was stirred for 6 hr at 22 0 C. 1M HCI (15 mL) was added and the aqueous layer was extracted with CHCl 3 (2 x 30 mL). The organic phase was dried over NazSO 4 , filtered, and concentrated under reduced pressure. This oil was purified by reverse-phase 15 prep HPLC to afford the title compound (56 mg, 52%) as a yellow paste. MS m/z 561 (MH'), 1 HNMR (300 MHz, CD 3 OD) 8 ppm 1.16-1.64 (m, 5H), 1.68 (t, 3 H), 1.80 (mn, 2H), 1.86-2.16 (m, 3H), 2.89 (m, 1 H), 3.09 (s, 6H), 4.52 (broad m, 1 H), 4.71 (q, 2 H), 5.97 (broad m, 1 H), 7.45-7.56 (m, 3 H), 7.61 (d, J=7.6 Hz, 1 H), 7.69 (d, J=8.4 Hz, 1 H), 7.83 (d, J=8.4 Hz, 1 H), 7.87 (s, 1 H), 8.40 (s, 1 H), 8.69 (broad s, 1H). 20 Example 5 N. N/ OH N N ON
HO
2 C N 42 WO 2007/092888 PCT/US2007/061768 13-cyclohexyl-6-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]- 7H-indolo[2, 1 aJ[2]benzazepine-10-carboxylic acid. To a solution of 7H-indolo[2,1 a][2]benzazepine-1 0-carboxylic acid, 13-cyclohexyl-6-(1 H-tetrazol-5-yl)-, methyl ester (40 mg, 0.09 mmol) in DMF (1.0 mL) and cesium carbonate (60 mg, 0.18 5 mmol) was added 2-chloroethanol (15 mg, 0.18 mmol). The resulting mixture was heated at 60 oC for 18 hr. Water (1 mL) was added and the mixture was heated at 60 oC for an additional 8 hr. IM HCI (15 mL) was added and the aqueous layer was extracted with CHCl 3 (2 x 30 mL). The organic phase was dried over Na 2
SO
4 , filtered, and concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to 10 afford the title compound (21mg, 49% yield) as a yellow paste. MS m/z 470 (MH+), 1 H NMR (300 MHz, CD30D) 8 ppm 1.18-1.69 (m, 5H), 1.79 (m, 2H), 1.86-2.15 (m, 3H), 2.89 (m, 1 H), 4.20 (broad m, 1 H), 4.32-4.56 (broad m, 2H), 4.68-4.92 (broad m, 2H), 5.92 (broad m, 1 H), 7.48-7.58 (m, 3 H), 7.61 (d, J=7.6 Hz, 1 H), 7.66 (d, J=8.4 Hz, 1 H), 7.75 (d, J=8.4 Hz, 1 H), 7.90 (s, 1 H), 8.39 (s, 1 H). 15 Examples 6 and 7 N 1,NVN - NJ:-V HOC HO2C N N 20 13-cyclohexyl-6-[2-(cyclopropylmethyl)-2H-tetrazol-5-yl]- 7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid and 13-cyclohexyl-6-[2-(cyclopropylmnethyl) 2H-tetrazol-5-yl]-5H-indolo[2,1-a][2]benzazepine- lO-carboxylic acid. To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-(1H 25 tetrazol-5-yl)-, methyl ester (40 mg, 0.09 mmol) in DMF (1.0 mL) and cesium carbonate (60 mg, 0.18 mmol) was added (bromomethyl)cyclopropane (24 mg, 0.18 mmol). The resulting mixture was heated at 60 oC for 18 hr. Water (1 mL) was added and the mixture was heated at 60 oC for an additional 8 hr. IM HCI (15 mL) was 43 WO 2007/092888 PCT/US2007/061768 added and the aqueous layer was extracted with CHC1 3 (2 x 30 mL). The organic phase was dried over Na 2
SO
4 , filtered, and concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compounds. 7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[2-(cyclopropylmethyl)-2H 5 tetrazol-5-yl]- : 22mg, 50% yield. MS m/z 480 (MH'), '1H NMR (300 MHz, CD 3 OD) 8 ppm 0.58 (m, 2 H), 0.70 (m, 2 H), 1.17-1.67 (m, 6H), 1.80 (m, 2H), 1.85-2.15 (m, 3H), 2.90 (m, 1 H), 4.42-4.58 (broad m, 3 H), 5.94 (broad m, 1 H), 7.49-7.54 (m, 3 H), 7.62 (d, J=7.6 Hz, 1 H), 7.72 (d, J=8.4 Hz, 1 H), 7.86 (d, J=8.4 Hz, 1 H), 7.91 (s, 1 H), 8.49 (s, 1 H). 5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13 10 cyclohexyl-6-[2-(cyclopropylmethyt)-2H-tetrazol-5-yl]- : 11mg, 25% yield. MS m/z 480 (M-H'), 1H NMR (300 MHz, CD 3 OD) 8 ppm 0.50 (m, 2 H), 0.59 (mn, 2 H), 1.19 1.69 (m, 6H), 1.81 (m, 2H), 1.85-2.15 (m, 3H), 3.10 (m, 1 H), 3.71 (broad m, 1 H), 4.18 (broad m, 1H), 4.49 (d, 2H), 7.31-7.39 (m, 2 H), 7.42-7.49 (m, 2 H), 7.96 (t, J=8.4, 8.4 Hz, 2 H), 8.20 (s, 1 H), 8.37 (s, 1 H). 15 Examples 8, 9, and 10 NNN-N N--N 0
HO
2 C N HO 2 C N "O 2 C 20 13-cyclohexyl-6-[2-[(tetrahydro-2-furanyl)methylU-2H-tetrazol-5-yl]-5H indolo[2, 1-a][2]benzazepine-10 -carboxylic acid and 13-cyclohexyl-6-f[2 [(tetrahydro-2-jitranyl)methyl]-2H-tetrazol-5-yl]-7H-indolo[2,1-aj [2]benzazepine 1 0-carboxylic acid and13-cyclohexyl-6-[1-[(tetrahydro-2-furanyl)methyl]-1H 25 tetrazol-5-yl]- 7H-indolo[2,1-a][2]benzazepine-1 0-carboxylic acid. To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-(1H-tetrazol-5 yl)-, methyl ester (40 mng, 0.09 mmol) in DMF (1.0 mL) and cesium carbonate (60 mg, 0.18 mmol) was added 2-(bromomethyl)-tetrahydrofuran (30 mng, 0.18 mmol). 44 WO 2007/092888 PCT/US2007/061768 The resulting mixture was heated at 60 oC for 18 hr. Water (1 mL) was added and the mixture was heated at 60 oC for an additional 8 hr. IM HC1 (15 mL) was added and the aqueous layer was extracted with CHCI 3 (2 x 30 mL). The organic phase was dried over Na 2
SO
4 , filtered, and concentrated under reduced pressure. This oil was purified by 5 reverse-phase prep HPLC to afford the title compounds. 7H-indolo[2,1 -a][2]benzazepine 10-carboxylic acid, 13-cyclohexyl-6-[2-[(tetrahydro-2-furanyl)methyl]-2H-tetrazol-5 yl]-: 22mg, 48% yield. MS m/z 510 (MH), 'H NMR (300 MHz, CD 3 OD) 6 ppm 1.18-1.69 (m, 5H), 1.79 (m, 2H), 1.86-2.27 (m, 7H), 2.92 (m, 1 H), 3.78 (m, 1H), 3.93 (m, 1H), 4.52 (broad m, 1 H), 4.54-4.87 (m, 3H), 5.98 (broad m, 1 H), 7.49-7.54 10 (m, 3 H), 7.64 (d, J=7.6 Hz, 1 H), 7.78 (d, J=8.4 Hz, 1 H), 7.91 (d, J=8.4 Hz, 1 H), 7.95 (s, 1 H), 8.49 (s, 1 H). 5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13 cyclohexyl-6-[2-[(tetrahydro-2-furanyl)methyl]-2H-tetrazol-5-yl]- : 10mrng, 22% yield. MS m/z 510 (MH*), 1H NMR (300 MHz, CD 3 OD) 8 ppm 1.19-1.69 (m, 5H), 1.81 (m, 2H), 1.83-2.25 (mn, 7H), 3.12 (mn, 1 H), 3.71 (broad m, 1 H), 3.83 (m, 1H), 3.92 15 (m, 1H), 4.15 (broad m, 1H), 4.51 (m, 1H), 4.62 (m, 1H), 4.73 (m, 1H), 7.32-7.38 (m, 2 H), 7.42-7.49 (m, 2 H), 7.98 (t, J=8.4, 8.4 Hz, 2 H), 8.20 (s, 1 H), 8.38 (s, 1 H). 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[1-[(tetrahydro 2-furanyl)methyl]-1H-tetrazol-5-yl]- : 8 mg, 17% yield. MS m/z 510 (MH), 1H NMR (300 MHz, CD 3 OD) 8 ppm 1.19-1.70 (m, 5H), 1.78 (m, 2H), 1.84-2.26 (m, 20 7H), 2.92 (m, 1 H), 3.80 (m, 1H), 3.92 (m, 1H), 4.50 (broad m, 1 H), 4.55-4.87 (m, 3H), 5.97 (broad m, 1 H), 7.49-7.54 (m, 3 H), 7.65 (d, J=7.6 Hz, 1 H), 7.78 (d, J=8.4 Hz, 1 H), 7.90 (d, J=8.4 Hz, 1 H), 7.94 (s, 1 H), 8.48 (s, 1 H). 25 Examples 11, 12, 13, and 14
HO
2 C 2C C N 45 WO 2007/092888 PCT/US2007/061768
HO
2 C N HO 2 C N 13-cyclohexyl-6-[2-[(tetrahydro-2H-pyran-4-yl)methyl]-2H-tetrazol-5-yl] 7H-indolo[2,1-a] [2] benzazepine-1 0-carboxylic acid and 13-cyclohexyl-6-[2 5 [(tetrahydro-2H-pyran-4-yl)methyl]-2H-tetrazol-5-yl]-5SH-indolo[2,1 a][2]benzazepine-10-carboxylic acid and 13-cyclohexyl-6-[f1-[(tetrahydro-2H-pyran 4-yl)methyl]-JH-tetrazol-5-yl]-7H-indolo[2,1-aJ [2]benzazepine-10-carboxylic acid and 13-cyclohexyl-6-[1-[(tetrahydro-2H-pyran-4-yl)mnethyl]-1H-tetrazol-5-ylJ-5H indolo[2,1-a][2]benzazepine-10-carboxylic acid. To a solution of 7H-indolo [2,1 10 a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-(1H-tetrazol-5-yl)-, methyl ester (40 nmg, 0.09 mmol) in DMF (1.0 mL) and cesium carbonate (60 mg, 0.18 mmol) was added 4-(bromomethyl)-tetrahydro-2H-pyran (31 mg, 0.18 mmol). The resulting mixture was heated at 60 oC for 18 hr. Water (1 mL) was added and the mixture was heated at 60 oC for an additional 8 hr. IM HCI (15 mL) was added and 15 the aqueous layer was extracted with CHC1 3 (2 x 30 mL). The organic phase was dried over Na 2
SO
4 , filtered, and concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compounds. 7H-indolo[2,1-a][2]benzazepine 10-carboxylic acid, 13-cyclohexyl-6-[2-[(tetrahydro-2H-pyran-4-yl)methyl]-2H tetrazol-5-yl]-: 21mg, 44% yield. MS m/z 524 (MH+), 1 H NMR (300 MHz, CD 3 OD) 20 8 ppm 1.18-1.69 (m, 6H1), 1.79 (m, 2H), 1.86-2.20 (m, 7H), 2.91 (m, 1 H), 3.39 (m, 2H), 3.96 (m, 2H), 4.52 (broad m, 3 H), 5.97 (broad m, 1 H), 7.48-7.54 (mn, 3 H), 7.62 (d, J=7.6 Hz, 1 H), 7.71 (d, J=8.4 Hz, 1 H), 7.87 (d, J=8.4 Hz, 1 H), 7.95 (s, 1 H), 8.39 (s, 1 H). 5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6 [2-[(tetrahydro-2H-pyran-4-yl)methyl]-2H-tetrazol-5-yl]- : 9mg, 19% yield. MS m/z 25 524 (MH+), 1H NMR (300 MHz, CD 3 OD) 8 ppm 1.19-1.69 (mn, 6H), 1.81 (m, 2H), 1.83-2.21 (m, 7H), 3.10 (m, 1 H), 3.42 (m, 2H), 3.71 (broad m, 1 H), 3.98 (m, 2H), 4.12 (broad m, 1H), 4.51 (m, 2H), 7.32-7.38 (mn, 2 H), 7.42-7.49 (m, 2 H), 7.98 (t, J=8.4, 8.4 Hz, 2 H), 8.20 (s, 1 H), 8.38 (s, 1 H). 7H-indolo[2,1-a][2]benzazepine-10 46 WO 2007/092888 PCT/US2007/061768 carboxylic acid, 13-cyclohexyl-6-[1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-tetrazol 5-yl]-: 6mg, 13% yield. MS m/z 524 (MH'), 1 H NMR (300 MHz, CD 3 OD) 6 ppm 1.18-1.69 (m, 6H), 1.79 (m, 2H), 1.86-2.20 (m, 7H), 2.90 (m, 1 H), 3.59 (m, 2H), 3.89 (m, 2H), 4.52 (broad m, 1 H), 4.69 (m, 2H), 5.97 (broad m, 1 H), 7.48-7.54 (m, 5 3 H), 7.62 (d, J=7.6 Hz, 1 H), 7.71 (d, J=8.4 Hz, 1 H), 7.87 (d, J=8.4 Hz, 1 H), 7.94 (s, 1 H), 8.40 (s, 1 H). 5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13 cyclohexyl-6-[1-[(tetrahydro-2H-pyran-4-yl)methyl]-l1H-tetrazol-5-yl]- : 3mg, 6% yield. MS m/z 524 (MH ), 1 HNMR (300 MHz, CD30D) 8 ppm 1.18-1.70 (m, 6H), 1.79 (m, 2H), 1.84-2.21 (m, 7H), 3.11 (m, 1 H), 3.41 (m, 2H), 3.70 (broad m, 1 H), 10 4.01 (m, 2H), 4.12 (broadm, 1H), 4.52 (m, 2H), 7.32-7.38 (m, 2 H), 7.43-7.48 (m, 2 H), 7.99 (t, J=8.4, 8.4 Hz, 2 H), 8.21 (s, 1 H), 8.36 (s, 1 H). Example 15 NN 0 00S..,,' N NN/ H 15 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[2-[(tetrahydro-2H-pyran-4 yl)methylf-2H-tetrazol-5-yl- 7H-indolo[2,1-aj[2]benzazepine-10-carboxamide. To a solution of 7H-indolo [2,1-a] [2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6- [2 20 [(tctrahydro-2H-pyran-4-yl)mcthyl]-2H-tctrazol-5-yl]- (100 mg, 0.19 mmol) in
CH
2
C
2 (1.0 mL) was added 2M oxalyl chloride (0.48 mL, 0.96 mmol). This solution was stirred at 22 oC for 3 hr and then concentrated under reduced pressure. BEMP (0.22 mL, 0.76 mmol), CH 2 C1 2 (1.0 mL) and N,N-dimethylsulfamide (120 mg, 0.96 mmol) was added to the resulting oil. The resulting mixture was stirred for 6 hr at 22 25 oC. 1 M HCI (15 mL) was added and the aqueous layer was extracted with CHC1 3 (2 x 30 mL). The organic phase was dried over Na 2
SO
4 , filtered, and concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (41 mg, 34%) as a yellow paste. MS m/z 631 (MH+), 'H NMR (300 MHz, CD 3 OD) 6 ppm 1.17-1.71 (m, 6H), 1.78 (m, 2H), 1.86-2.20 (m, 7H), 2.89 (m, 1 47 WO 2007/092888 PCT/US2007/061768 H), 3.11 (s, 6H), 3.40 (m, 2H), 3.97 (m, 2H), 4.52 (broad m, 3 H), 5.99 (broad m, 1 H), 7.49-7.55 (m, 3 H), 7.62 (d, J=7.6 Hz, 1 H), 7.69 (d, J=8.4 Hz, 1 H), 7.85 (d, J=8.4 Hz, 1 H), 7.92 (s, 1 H), 8.38 (s, 1 H), 8.71 (broad s, 1 H). 5 Example 16 N-N O N.,N 0 HO- N - OMe 1 3 -cyclohexyl-3-methoxy-6-[2-[(tetrahydro-2H-pyran-4-yl)methyl]-2H 10 tetrazol-5-yl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid. 7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid, 1 3 -cyclohexyl-3-methoxy-6-[2-[(tetrahydro 2H-pyran-4-yl)methyl]-2H-tetrazol-5-yl]- was made in an analogous fashion to 7H indolo[2,1 -a][2]benzazepine- 10-carboxylic acid, 13-cyclohexyl-6-[2-[(tetrahydro-2H pyran-4-yl)methyl]-2H-tetrazol-5-yl]- (see above) to yield 110 ming (90% yield final 15 step) of a yellow solid. MS m/z 555 (MH+), 1 H NMR (300 MHz, CD 3 OD) 8 ppm 1.18-1.69 (m, 6H), 1.81 (m, 2H), 1.92-2.38 (m, 7H), 2.89 (m, 1 H), 3.46 (m, 2H), 3.95 (s, 3H), 3.99 (m, 2H), 4.52 (broad min, 1H), 4.56 (m, 2 H), 5.89 (broad m, 1 H), 7.05 (s, 1 H), 7.11 (d, J=8.4 Hz, 1 H), 7.58 (d, J=8.4 Hz, 1 H), 7.79 (d, .J=7.8 Hz, 1 H), 7.88 (d, J=7.8 Hz, 1 H), 7.94 (s, 1 H), 8.44 (s, 1 H). 20 Example 17 'N" rN N v 0 o 4H 0 48 WO 2007/092888 PCT/US2007/061768 13-cyclohexyl-N-[(dimethylamnino)sulfonyl]-3-methoxy-6-[2-[(tetrahydro-2H pyran-4-yl)methyl]-2H-tetrazol-5-ylj- 7H-indolo[2, I-a][2]benzazepine-J 0 carboxamnide. To a solution of 7H-indolo[2,1 -a][2]benzazepine- 10-carboxylic acid, 13-cyclohexyl-3-methoxy-6-[2-[(tetrahydro-2H-pyran-4-yl)methyl]-2H-tetrazol-5 5 yl]- (110 mg, 0.20 mmol) in CH2C1 2 (1.0 mL) was added 2M oxalyl chloride (0.50 mL, 1.00 mmol). This solution was stirred at 22 oC for 3 hr and then concentrated under reduced pressure. BEMP (0.23 mL, 0.80 mmol), CH 2
CI
2 (1.0 mL) and N,N dimethylsulfamide (124 mg, 1.00 mmol) was added to the resulting oil. The resulting mixture was stirred for 6 hr at 22 oC. IM HCI (15 mL) was added and the aqueous 10 layer was extracted with CHC1 3 (2 x 30 mL). The organic phase was dried over Na 2
SO
4 , filtered, and concentrated under reduced pressure. This oil was purified by reverse-phase prep HPLC to afford the title compound (84 mg, 64%) as a yellow paste. MS m/z 661 (MH+), 'H NMR (300 MHz, CD 3 OD) 8 ppm 1.18-1.69 (m, 6H), 1.79 (m, 2H), 1.93 2.40 (mn, 7H), 2.89 (m, 1 H), 3.09 (s, 6H), 3.42 (m, 2H), 3.93 (s, 3H), 3.96 (m, 2H), 15 4.52 (broad m, 1H), 4.56 (m, 2 H), 5.92 (broad m, 1 H), 7.05 (s, 1 H), 7.09 (d, J=8.4 Hz, 1 H), 7.58 (d, .J=8.4 Hz, 1 H), 7.78 (d, .J=7.8 Hz, 1 H), 7.86 (d, J=7.8 Hz, 1 H), 7.90 (s, 1 H), 8.47 (s, 1 H), 8.69 (broad s, 1 H). Example 18 20 HN O 0 NN o N 13-cyclohexyl-6-(4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl)-7H-indolof2,1 aj[2jbenzazepine-1O-carboxylic acid, methyl ester. The hydrazide (771mg, 1.80 25 mMol) 7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylic acid, 13-cyclohexyl-, 10 methyl ester, 6-hydrazide was partially dissolved in 18ml of THF and diisopropylethyl amine (DIEA) (0.34mL, 1.95 mMol) added and stirred for 5 min 49 WO 2007/092888 PCT/US2007/061768 then 1,1 '-carbonyldiimnidazole(CDI) (316mg, 1.95 mMol) was added and the reaction stirred overnight under nitrogen at room temperature. An additional 100mg of CDI and 0.1ml of DIEA was added to drive the reaction to completion. The reaction was partitioned between ethyl acetate and 0.1 N hydrochloric acid. The organic phase 5 washed with 0.1 N hydrochloric acid, brine, and dried over magnesium sulfate to yield 0.82g of product. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 9.43 (s, 1 H) 8.20 (s, 1 H) 7.79 (d, J=8.54 Hz, 1 H) 7.67 (d, J=8.54 Hz, 1 H) 7.61 (d, J=7.63 Hz, 1 H) 7.54 (t, J=7.32 Hz, 1 H) 7.43 - 7.51 (min, 2 H) 7.41 (s, 1 H) 5.44 (d, J=13.43 Hz, 1 H) 4.00 (d, J=15.87 Hz, 1 H) 3.90 (s, 3 H) 2.80 (t, J=15.87 Hz, 1 H) 2.00 - 2.17 10 (m, 2 H) 1.89 (d,.J=41.20 Hz, 2 H) 1.51 - 1.80 (m, 3 H) 1.28 - 1.53 (mi, 4 H) 1.11 1.22 (m, 1 H); MS m/z 456(MH), MS m/z 454(M-H)-. Example 19 N0 HO HO N 15 13-cyclohexyl-6-(4,5-dihydro-5-oxo-1,3, 4-oxadiazol-2-yl)- 7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid. 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 1 3 -cyclohexyl-6-(4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl)-, methyl ester ( 20 91mg, 0.20 mMol) was suspended in 5ml of acetic acid and 2.5ml of 48% aqueous hydrobromic acid added. The reaction was heated to 111 C for 4 hours. The reaction cooled and a yellow precipitate filtered off and rinsed with a small amount of acetic acid, then water. The product was dried in vacuuo at room temperature to yield 75mg of product.1H NMR (500 MHz, CHLOROFORM-D, MeOD) 8 ppm 8.17 (s, 1 25 H) 7.75 (d, J=8.54 Hz, 1 H) 7.61 (d, J=8.55 Hz, 1 H) 7.48 (d, J=7.32 Hz, 1 H) 7.35 7.44 (m, 3 H) 7.30 (s, 1 H) 5.52 (d, J=12.82 Hz, 1 H) 4.18 (d, J=8.85 Hz, 1 H) 2.65 50 WO 2007/092888 PCT/US2007/061768 2.78 (mn, 1 H) 1.89 - 2.04 (mn, 2 H) 1.71 - 1.85 (m, 1 H) 1.63 (d, J=10.99 Hz, 2 H) 1.16 - 1.49 (m, 3 H) 1.11 (s, 2 H); MS m/z 442(MH ). Example 20 5 N0 0 o ° 13-cyclohexyl-6-[4,5-dihydro-5-oxo-4-[(tetrahydro-2H-pyran-4-yl)methyl] 1,3,4-oxadiazol-2-yl- 7H-indolo[2, 1-a][2]benzazepine-10-carboxylic acid, methyl 10 ester. 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-(4,5 dihydro-5-oxo-1,3,4-oxadiazol-2-yl)-, methyl ester (203mg, 0.45mnMol) was dissolved in a mixture of 2ml DMF and lml THF with heating. To the reaction was added 4-(bromomethyl)tctrahydropyran (115mg, 0.64mMol), cesium carbonate (201mg, 0.62mMol) and sodium iodide (90mg, 0.6mMol) was added. The reaction 15 was capped and heated to 60C overnight. The reaction contents were transferred to a 25ml Erlenmeyer flask and water added with rapid stirring. A bright yellow precipitate was filtered off and rinsed with water and air dried to yield 236mg of material (95%). 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.32 (s, 1 H) 7.88 (d, J=8.55 Hz, 1 H) 7.74 (dd, J=8.55, 1.22 Hz, 1 H) 7.62 (d, J=7.02 Hz, 1 H) 7.48 20 7.56 (m, 3 H) 7.43 (s, I H) 5.64 (d,J=13.12 Hz, I H) 4.31 (d,J=14.95 Hz, I H) 3.88 - 4.02 (in, 5 H) 3.67 (s, 2 H) 3.25 - 3.44 (m, 2 H) 2.77 - 2.87 (mn, 1 H) 1.88 - 2.21 (in, 5 H) 1.70 - 1.82 (m, 2 H) 1.50 - 1.70 (m, 4 H) 1.11 - 1.50 (m, 6 H); MS m/z 554(MH ). 51 WO 2007/092888 PCT/US2007/061768 Example 21 0 N O 00 O HO '~N 5 13-cyclohexyl-6-[4,5-dihydro-5-oxo-4-[(tetrahydro-2H-pyran-4-yl)methyl] 1,3,4-oxadiazol-2-yl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid. 7H indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[4,5-dihydro-5 oxo-4-[(tetrahydro-2H-pyran-4-yl)methyl]-1,3,4-oxadiazol-2-yl]-, methyl ester (225mg, 0.41mMol) was suspended in 5ml of acetic acid and 2.5ml of 48% aqueous 10 hydrobromic acid was added. The reaction was heated to 100 C for 2hrs and then to 120C for 1.5hrs and finally to 130C for an additional 3 hours then allow to cool overnight. Filter off yellow solid from reaction mixture (55mg) whose major component by HPLC analysis was starting material. The filtrate was diluted with 50ml of water and extracted with ethyl acetate. The organic phase was washed with 15 water, then brine and dried over magnesium sulfate. The crude product residue was isolated by removal of volatiles in vacuuo. The crude product was dissolved in an acetonitrile DMF mixture and purified by reverse phase HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% TFA; %B= 90% methanol, 10% water, 0.1% TFA 20 Initial %B= 35; Final % B=100; Gradient= 30min; Runtime=40min Flow rate = 20ml/min; Wavelength= 220nm; Column= YMC Pro Pack 20mm x 150mm S5. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.40 (s, 1 H) 7.92 (d, J=8.54 Hz, 1 H) 7.82 (d, J=8.55 Hz, 1 H) 7.63 (d, J=7.63 Hz, 1 H) 7.47 - 7.58 (mn, 3 H) 7.44 (s, 1 H) 5.66 (d, J=14.95 Hz, 1 H) 4.33 (d, J=14.65 Hz, 4 H) 3.87 - 4.13 (in, 25 2 H) 3.72 (dd, J=29.76, 5.95 Hz, 2 H) 3.26 - 3.52 (m, 2 H) 2.78 - 2.93 (m, 1 H) 2.14 52 WO 2007/092888 PCT/US2007/061768 2.26 (min, 1 H) 1.86 - 2.12 (mn, 4 H) 1.31 - 1.84 (m, 9 H) 1.12 - 1.32 (min, 1 H); MS m/z 538(M-H)-. Example 22 5 HN O N N 0 HO 1 N 13-cyclohexyl-6-[3-[(tetrahydro-2H-pyran-4-yl)methyl]-lH-1,2, 4-triazol-5 yl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid. The synthesis 7H 10 indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[3-[(tetrahydro 2H-pyran-4-yl)methyl]-1H-1,2,4-triazol-5-yl]- was preformed using the literature procedure: Kap-Sun Yeung, Michelle E. Farkas, John F. Kadow and Nicholas A. Meanwell; Tetrahedron Letters, 46 (2005) 3429-3432. In a 2ml microwave reaction tube the following reagents were combined in 0.47ml of n-butanol: 7H-indolo[2,1 15 a][2]benzazepine-6,10-dicarboxylic acid, 13-cyclohexyl-, 10-methyl ester, 6 hydrazide (100mg, 0.23 mMol), 4-cyanomethyltetrahydropyran (88.3mg, 0.71 mMol), potassium carbonate (16.6mg, 0.12 mMol). The reaction was heated in a microwave at 150 C for 7 hours. The intermediate n-butyl ester was identified by LC/MS m/z 579(MH
+
) Volatiles from the reaction were removed in vacuuo and 20 crude reaction mixture subject to hydrolysis conditions of 10ml acetic acid, 5ml 48% aqueous hydrobromic acid at 80 to 100 C for 4 hours to yield the final product. Volatiles from the reaction mixture were removed in vacuuo and the residue dissolved in DMF/methanol for isolation by preparative HPLC using the following conditions: two 2ml injections on: Shimadzu prep. HPLC using Discovery VP 25 software: %A= 10% methanol, 90% water, 0.1% TFA; %B= 90% methanol, 10% water, 0.1% TFA; Initial %B= 35; Final % B=100; Gradient-- 30min; 53 WO 2007/092888 PCT/US2007/061768 Runtime=40min; Flow rate= 20ml/min; Column=-- YMC Pro Pack 20mm x 150mm S5. Product peaks identified by LC/MS- MS m/z 442(MH) and combined to yield 25.2mg. 1H NMR (500 MHz, CHLOROFORM-D, MeOD) 8 ppm 8.35 (s, 1 H) 7.78 (d, J=8.55 Hz, 3 H) 7.59 - 7.67 (min, 2 H) 7.53 (dd, J=5.65, 3.51 Hz, 1 H) 7.44 - 7.49 5 (m, 1 H) 7.35 - 7.43 (m, 2 H) 5.89 (d, J=15.26 Hz, 1 H) 4.29 (d, J=14.34 Hz, 1 H) 3.84 (dd, J=l 1.90, 3.05 Hz, 2 H) 2.80 (t, J=l 1.44 Hz, 1 H) 2.63 (d, J=7.32 Hz, 2 H) 1.60 - 2.18 (m, 8 H) 1.48 - 1.60 (min, 2 H) 1.08 - 1.41 (m, 6 H). Example 23 10 N-O 0IN O~ 0 O N I I 13-cyclohexyl-6-(3-methyl-i,2, 4-oxadiazol-5-yl)-7H-indolo[2, 1 a][2Jbenzazepine-1O-carboxylic acid, methyl ester. The 1,2,4-oxadiazole ring 15 structure can be synthesized according to the literature procedure of Ying Wang and Regan L. Miller et. al. Organic Letters 7 (5) 2005 p. 925-928. 7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid, 6-(chlorocarbonyl)-13-cyclohexyl-, methyl ester 250mg, 0.58mMol) was taken dissolved in 4.4ml of anhydrous THF. Acetamrnide oxime (48mg, 0.65mMol) and Diisopropylethyl Amine (0.2mL, 20 1.15mMol) was added to the reaction in a 5ml microwave reactor tube. The reaction was capped under nitrogen and heated in a microwave at 150C for 15minutes. Additional Acetamide oxime (12.8mg, 0.17mMol) was added to the reaction and heated at 150 C for 10 minutes. The reaction was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic phase was then washed with 1N 25 hydrochloric acid, brine and dried over magnesium sulfate to yield 244mg of crude product. Pure product (105mg, 40%) was isolated from silica gel chromatography eluting with dichlormethane. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.36 54 WO 2007/092888 PCT/US2007/061768 (s, 1 H) 7.92 (s, 1 H) 7.88 (d, J=8.24 Hz, 1 H) 7.75 (d, J=8.55 Hz, 1 H) 7.60 - 7.66 (m, 1 H) 7.47 - 7.59 (m, 3 H) 5.85 (s, 1 H) 4.48 (s, 1 H) 3.96 (s, 3 H) 2.85 (t, J=11.75 Hz, 1 H) 2.44 (s, 3 H) 1.84 - 2.21 (m, 4 H) 1.77 (d, J=7.93 Hz, 2 H) 1.31 - 1.48 (m, 3 H) 1.15 - 1.29 (m, 1 H); MS mn/z 454(MH+). 5 Example 24 O ,N OO 0 HO N 10 13-cyclohexyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid. 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-, methyl ester (97mg, 0.2 1mMol) was dissolved in 2.5ml of pyridine along with lithium iodide (91mg, 0.68mMol). The reaction was heated to 180 C for 2hrs in a microwave. Reaction 15 volatiles were then removed in vacuuo and the residue partitioned between ethyl acetate and 1 N hydrochloric acid. The organic phase was washed with IN hydrochloric acid, Brine and dried over magnesium sulfate. Pure product (42mg, 45%) was isolated by silica gel chromatography by elution with 5% methanol in dichloromethane. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.46 (s, 1 H) 7.88 20 - 8.02 (mn, 2 H) 7.83 (d, J=7.32 Hz, 1 H) 7.61 - 7.70 (m, 1 H) 7.48 - 7.61 (m, 3 H) 5.89 (s, 1 H) 4.49 (s, 1 H) 2.86 (t, J=l 1.44 Hz, 1 H) 2.47 (s, 3 H) 1.86 - 2.29 (m, 4 H) 1.78 (d, J=7.63 Hz, 2 H) 1.31 - 1.51 (m, 2 H) 1.13 - 1.32 (m, 2 H); MS m/z 440(MH+); MS m/z 438(M-H)-. 55 WO 2007/092888 PCT/US2007/061768 Example 25 N 0 -,N 0 0 N N * N I H 5 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-(3-methyl-1,2,4-oxadiazol-5 yl)-7H-indolo[2, 1-a][2]benzazepine-10-carboxamide. 7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-(3-methyl-1,2,4-oxadiazol-5 yl)- (38mg, 0.086mMol) was placed in a 25ml round bottom flask and 2ml of 2.0M oxalyl chloride in dichloromethane added, followed by 1 drop of DMF. The reaction 10 was briefly heated to reflux then stirred at room temperature for 2hrs. Volatiles were removed in vacuuo and the residue acid chloride was dissolved in Iml of anhydrous THF and added dropwise over 7 minutes to the preformed anion of N,N dimethylsulfamide prepared as follows: N,N-dimethylsulfamide (35.9mg, 0.289mMol) was dissolved in 0.4ml of anhydrous THF and 2-tert-butylimino-2 15 diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (62uL, 0.214mMol) was added and the reaction stirred for 10 Ominutes at room temperature under nitrogen. The reaction was allow to proceed at room temperature under inert atmosphere for hour. The reaction mixture was partitioned between 0. IN hydrochloric acid and 30mL of ethyl acetate. The organic phase washed with 0.1N hydrochloric acid, brine 20 and dried over magnesium sulfate. Volatiles removed in vacuuo and the residue dissolved in acetonitrile and purified by preparative HPLC using the following conditions to yield 26.8mg (57%) of pure product as a yellow solid. Shimadzu prep. HPLC using Discovery VP software: %A= 10% acetonitrile, 90% water, 0.1% TFA %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 30; Final % B=100; 25 Gradient= 15 min; Runtime= 25 min; Flow rate= 25 ml/min; Wavelength= 220nm; Column= Phenonenex Luna 21.2mm x 100mm slO0. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.60 (s, 1 H) 8.19 (s, 1 H) 7.89 - 7.95 (m, 2 H) 7.61 56 WO 2007/092888 PCT/US2007/061768 7.66 (m, 1 H) 7.50 - 7.61 (m, 3 H) 7.47 (dd, J=8.55, 1.53 Hz, 1 H) 5.81 (s, 1 H) 4.50 (s, 1 H) 3.08 (s, 6 H) 2.80 - 2.91 (m, 1 H) 2.45 (s, 3 H) 1.84 - 2.18 (m, 4 H) 1.77 (d, J=10.68 Hz, 2 H) 1.10- 1.62 (m, 5 H); MS m/z 546(MH). 5 Example 26 / O N O 0 13-cyclohexyl-6-[3-[(methylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl]-7H 10 indolo[2,1-a]j[2]benzazepine-10-carboxylic acid, methyl ester. 7H-indolo[2, 1 a][2]benzazepine-10-carboxylic acid, 6-(chlorocarbonyl)-13-cyclohexyl-, methyl ester (776mg, 1.79mMol) was dissolved in 13ml of anhydrous THF in a 20ml microwave vessel. N-hydroxy-2-(methylsulfonyl)ethanimidamide (308mg, 2.02mMol) was added to the reaction along with diisopropylethyl amine (0.64ml, 15 3.67mMol). The reaction was stirred for 5minutes at room temperature then heated in the microwave at 150 C for 15minutes. The reaction was partitioned between 0.1 N hydrochloric acid and ethyl acetate, washed with brine and dried over magnesium sulfate. The residue was chromatographed on silica gel and the product eluted with 2% ethyl acetate in dichloromethane to yield 287mg (30%). 1H NMR 20 (500 MHz, CHLOROFORM-D) 3 ppm 1.13 - 1.23 (m, 1 H) 1.29 - 1.64 (in, 5 H) 1.77 (d, J=9.77 Hz, 2 H) 1.87 - 2.00 (m, 1 H) 2.04 - 2.17 (m, 2 H) 2.79 - 2.90 (mn, 1 H) 3.23 (s, 3 H) 3.94 (s, 3 H) 4.47 (s, 2 H) 4.51 (d, J=14.04 Hz, 1 H) 5.84 (d, J=1 1.29 Hz, 1 H) 7.51 - 7.62 (m, 3 H) 7.62 - 7.67 (mn, 1 H) 7.70 - 7.78 (m, 1 H) 7.88 (d, J=8.24 Hz, 1 H) 7.99 (s, 1 H) 8.30 (s, 1 H); MS m/z 532(MH+). 25 57 WO 2007/092888 PCT/US2007/061768 Example 27 ,0 o-' N- O O ,N 0 HO 5 13-cyclohexyl-6-[3-[(mnethylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl]-7H indolo[2,1-a][2]benzazepine-10-carboxylic acid. 7H-indolo[2,1-a][2]benzazepine 10-carboxylic acid, 13-cyclohexyl-6-[3-[(methylsulfonyl)methyl]-1,2,4-oxadiazol-5 yl]-, methyl ester (193mg, 0.36mMol) was dissolved in 3.6ml of pyridine in microwave tube. Lithium iodide(166mg, 1.24mMol) was added and the reaction was 10 placed under nitrogen and heated to 180C in a microwave for 1hr. The reaction was partitioned between ethyl acetate and 0.1 N hydrochloric acid and brine was added to aid in phase separation. The organic layer was washed with 0.1N hydrochloric acid/ brine mixture, dried over magnesium sulfate and volatiles removed in vacuuo to yield 180mg of a brown solid. The crude reaction product was combined with 73mg of 15 crude reaction product from a previous trial experiment and purified by silica gel chromatography eluting with 5% methanol in dichloromethane to yield 75mg (29%) of product. A separate less pure fraction (13.6mg) was further purified by Prep HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software: %A= 10% acetonitrile, 90% water, 0.1% TFA; %B= 90% acetonitrile, 20 10% water, 0.1% TFA; Initial %B= 30; Final % B=100; Gradient- 15 min Runtime= 20 min; Flow rate= 25 ml/min; Wavelength= 220nm; Column= Phenonenex Luna 21.2mm x 100mm sl 0. Product retention time= 13.0min, 5.9mg product recovered. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 1.13 - 1.52 (inm, 4 H) 1.53 - 1.85 (m, 3 H) 1.86 - 2.23 (m, 4 H) 2.82 - 2.91 (m, 1 H) 3.29 (s, 3 H) 4.44 25 - 4.65 (m, 3 H) 5.89 (d, J=12.21 Hz, 1 H) 7.52 - 7.65 (m, 3 H) 7.64 - 7.70 (m, 1 H) 58 WO 2007/092888 PCT/US2007/061768 7.83 (d, J=8.55 Hz, 1 H) 7.94 (d, J=8.55 Hz, 1 H) 8.00 (s, 1 H) 8.39 (s, 1 H); MS m/z 518(MH+). Example 28 5 o,.s
N
0 ,IN 0 0 N N - N I H I 13-cyclohexyl-N-[(dimethylamino)sulfonylj-6-[3-[(methylsulfonyl)methyl] 1,2, 4-oxadiazol-5-yl]-7H-indolo[2,1-a][2]benzazepine-10-carboxamide. 7H 10 indolo[2,1-a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[3 [(methylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl]- (75mg, 0.13mMol) was dissolved in 1.5ml of THF, and carbonyldiimidazole (27.7mg, 0.17mMol) was added. The reaction was stirred for 40minutes at room temperature under a nitrogen atmosphere then heated to reflux for 40minutes. The reaction was cooled to room temperature 15 under nitrogen and N,N-dimethylsulfamide (84mg, 0.68mMol) added along with 22uL (0.15mMol) of DBU. The reaction was stirred overnight (-16hr) at room temperature, then partitioned between ethyl acetate and 0.1N hydrochloric acid, washed with 0.1N hydrochloric acid, brine, and dried over magnesium sulfate. Volatiles were removed in vacuuo and the residue purified by Prep. HPLC under the 20 following conditions: Shimadzu prep. HPLC using Discovery VP software: %A= 10% acctonitrilc, 90% water, 0.1% TFA; %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial /oB= 30; Final % B=100; Gradient-- 15 min; Runtime= 20 min Flow rate= 40 ml/min; Wavelength= 220nm; Column= Waters Sunfire 30mm x 100mm S5. Product retention time= 13.3min, 45.3mg (51%) product recovered. 1H 25 NMR (500 MHz, CHLOROFORM-D) 6 ppm 1.10 - 1.50 (m, 3 H) 1.50 - 1.65 (mn, 1 59 WO 2007/092888 PCT/US2007/061768 H) 1.
6 9 - 1.
8 3 (m, 2 H) 1.85 - 2.16 (m, 7 H) 2.79 - 2.92 (m, 1 H) 3.07 (s, 6 H) 3.2 2 (s 3 H) 4.51 (s, 3 H) 5.84 (d, J=l 1.60 Hz, 1 H) 7.47 (d, J=8.24 Hz, 1 H) 7.52 - 7.64 (m, 3 H) 7.63 - 7.69 (m, 1 H) 7.91 (d, J=8.55 Hz, 1 H) 7.95 (s, 1 H) 8.13 (s, 1 H) 8.83 (s, 1 H); MS m/z 624(MH+). 5 Example 29 N H 2 N 0 0 O 10 6-(5-amino-1,3, 4 -oxadiazol-2-yl)-13-cyclohexyl-7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid, methyl ester. To a suspension of 7H indolo[ 2 ,1-a][2]benzazepine-6,10-dicarboxylic acid, 13-cyclohexyl-, 10-methyl ester, 6-hydrazide (1.01g, 2.35mMol) in 20ml of 1,4-dioxane was added sodium bicarbonate (203mg, 2,42mMol) in 5.3ml of water. The reaction was stirred for 20 15 minutes at room temperature then cyanogen bromide (256mg, 2.42mMol) added to the reaction. The reaction was capped and stirred for 18hrs at room temperature after which cyanogen bromide (35mg, 0.33mMol) was added. The reaction was stirred for an additional 6 hours at room temperature. The reaction was filtered and rinsed with water and the precipitate dried in vacuuo to yield 8 80mg (82%) of product. 1H 20 NMR (500 MHz, DMSO-D6) 8 ppm 8.21 (s, 1 H) 7.93 (d, J=8.55 Hz, 1 H) 7.63 7.69 (m, 2 H) 7.53 - 7.62 (m, 3 H) 5.74 (d, J=13.43 Hz, 1 H) 4.39 (d, J=14.95 Hz, 1 H) 3.89 (s, 3 H) 2.73 - 2.87 (mn, 1 H) 1.94 - 2.12 (m, 3 H) 1.84 - 1.94 (m, 1 H) 1.70 (d, J=6.71 Hz, 2 H) 1.32 - 1.48 (m, 3 H) 1.06 - 1.18 (m, 1 H); MS m/z 455(MH+), MS m/z 453(M-H)-. 25 60 WO 2007/092888 PCT/US2007/061768 Example 30
NH
2 SN 0 0 HOI :)N 5 6- (5-amino-1,3,4-oxadiazol- 2 -yl)- 13-cyclohexyl- 7H-indolof2,1 af][2]benzazepine-10 O-carboxylic acid. 7H-indolo[2,1-a][2]bcnzazcpinc-10-carboxylic acid, 6-(5-amino- 1,3,4-oxadiazol-2-yl)- 13-cyclohexyl-, methyl ester (27.7mg, 0.061mMol) was suspended in 0.6ml of THF, and 0.2ml of 1.0M tetrabutylammonium hydroxide in methanol was added to the reaction. Upon 10 addition of the tetrabutylammonium hydroxide solution the reaction became homogenous. The reaction was stirred at room temperature for 16 hours resulting on only partial conversion to product. The reaction was heated to 60 C for 2 hours then cooled and 1N hydrochloric acid and DMF added. The solution was injected on a prep HPLC to isolate 7.4mg of product using the following conditions: Shimadzu 15 prep. HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% TFA; %B= 90% methanol, 10% water, 0.1% TFA; Initial %B= 35; Final % B=1 00; Gradient- 30min; Runtime=50min; Flow rate= 20ml/min; Column= YMC Pro Pack 20mm x 150mm S5. 1H NMR (500 MHz, DMF) 8 ppm 12.90 (s, 1 H) 8.38 - 8.41 (m, 1 H) 7.70 - 7.78 (m, 3 H) 7.63 - 7.69 (m, 1 H) 7.59 - 7.63 (m, 1 H) 7.45 (s, 2 H) 7.40 20 (s, 1 H) 5.91 (d, J=17.09 Hz, 1 H) 4.51 (d, J=12.82 Hz, 1 H) 2.03 - 2.22 (m, 3 H) 1.92 (t, J=10.68 Hz, 1 H) 1.73 (d, J=7.02 Hz, 2 H) 1.39 - 1.52 (m, 3 H) 1.18 (d, .J=12.82 Hz, 1 H) 0.84 - 0.91 (m, 1 H). 61 WO 2007/092888 PCT/US2007/061768 Example 31 Br HN NO O 0N N 0 0 4 ~N 5 6-[5-[(bromoacetvl) amino]-1,3,4-oxadiazol-2-yl]-13-cyclohexyl- 7H indolof2, 1-a] [2jbenzazepine-1 0-carboxylic acid, methyl ester. 7H-indolo[2, 1 a][2]benzazepine-10-carboxylic acid, 6-(5-amino-1,3,4-oxadiazol-2-yl)-13 cyclohexyl-, methyl ester (50.7mg, 0.125mMol) was suspended in 1.0ml of THF, and pyridine (12uL, 0.148mMol) added. The reaction was cooled to 0 C under nitrogen 10 then bromoacetyl bromide (13uL, 0.15mMol) added. The reaction was stirred at OC for Ihr and warmed to room temperature over 30 minutes. The reaction was partitioned between water and organic consisting of ethyl acetate , THF and dichloromethane. The organic phase was washed with 0.1N hydrochloric acid, brine and dried over magnesium sulfate to yield 65mg (90%) of product. 1H NMR (500 15 MHz, DMSO-D6) 8 ppm 12.28 (s, 1 H) 8.25 (s, 1 H) 7.94 (d, J=8.55 Hz, 1 H) 7.74 (d, J=7.63 Hz, 1 H) 7.57 - 7.70 (m, 5 H) 5.80 (d, J=14.04 Hz, 1 H) 4.49 (d, J=11.90 Hz, 1 H) 4.17 (s, 2 H) 3.90 (s, 3 H) 2.74 - 2.86 (m, 1 H) 1.94 - 2.12 (m, 3 H) 1.82 1.95 (m, 1 H) 1.70 (d, J=7.32 Hz, 2 H) 1.36 - 1.50 (m, 3 H) 1.08 - 1.20 (m, 1 H); MS m/z 575(MH+); MS nm/z 573(M-H)-. 20 62 WO 2007/092888 PCT/US2007/061768 Example 32 HNN O 00 N O 0 N -,0 5 13-cyclohexyl-6-[5-[(4-morpholinyvlacetyl)aminol-1,3,4-oxadiazol-2-ylJ- 7H indolo[2,1 -aj[2]benzazepine-10-carboxylic acid, methyl ester. 7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid, 6-[5-[(bromoacetyl)amino]-1,3,4-oxadiazol-2 yl]-1 3-cyclohexyl-, methyl ester (62mg, 0.1 lmMol) was stirred in Iml of DMF and morpholine (28uL, 0.32mMol) added to the reaction. A small pea of sodium iodide 10 was added to the reaction and the reaction capped, stirred at room temperature for 16 hrs. The reaction was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer dried over magnesium sulfate and volatiles removed to yield 67mg of product. 1 H NMR (500 MHz, CHLOROFORM-D) 6 ppm 8.35 (s, 1 H) 7.86 (d, J=8.55 Hz, 1 H) 7.74 (d, J=8.54 Hz, 1 H) 7.58 - 7.66 (rn, 2 H) 15 7.44 - 7.56 (m, 3 H) 5.81 - 5.98 (m, 1 H) 4.37 - 4.53 (m, 1 H) 3.94 (s, 3 H) 3.83 (s, 4 H) 2.69 - 2.87 (mn, 5 H) 1.85 - 2.20 (m, 6 H) 1.34 - 1.86 (mn, 14 H) 1.12 - 1.37 (m, 17 H) 0.74 - 0.94 (mn, 9 H) Aliphatic region of NMR contains hydrocarbon (grease) contaminates not observed by HPLC; MS m/z 582(MH); MS m/z 580(M-H)-. 63 WO 2007/092888 PCT/US2007/061768 Example 33 HN N O
HN-
N, O 0 HO HO I N 5 13-cyclohexyl-6-[5-[(4-morpholinylacetyl)amino]-1,3,4-oxadiazol-2-yl]-7H indolo[2,1-aj[2]benzazepine-10-carboxylic acid. 7H-indolo[2,1-a][2]benzazepine 10-carboxylic acid, 13-cyclohexyl-6-[5-[(4-morpholinylacetyl)amino]-1,3,4 oxadiazol-2-yl]-, methyl ester (60mg, 0.10mMol) was dissolved in lml of anhydrous THF and potassium trimethylsilanoate (78mg, 0.61mMol) added. The reaction was 10 capped and stirred at room temperature for 2.5 hours. Hydrochloric acid (6ml of 0.1M) was added to the reaction and the product extracted into ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The residue was triturated with hot diethyl ether to yield 18.7mg (32%) of product as a yellow solid. 1H NMR (500 MHz, DMSO-D6) 8 ppm 12.64 (s, 1 H) 11.55 (s, 1 H) 8.23 (s, 1 15 H) 7.91 (d,.J=8.55 Hz, 1 H) 7.72 (d, J=7.63 Hz, 1 H) 7.51 - 7.69 (mn, 5 H) 5.79 (d, J=13.12 Hz, 1 H) 4.48 (d, J=12.21 Hz, 1 H) 3.55 (s, 4 H) 2.72 - 2.91 (m, 1 H) 1.80 2.17 (m, 4 H) 1.61 - 1.81 (m, 2 H) 1.29 - 1.56 (m, 3 H) 1.03 - 1.22 (m, 1 H); MS m/z 568(MH+); MS m/z 566 (M-H)-. 64 WO 2007/092888 PCT/US2007/061768 Example 34 0 0 N O 0 5 1 3 -cyclohexyl-6-[5-(3-methoxy-3-oxopropyl)-2-oxazolyl] 7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid, methyl ester. 7H-indolo[2,1-a][2]benzazepine 10-carboxylic acid, 13-cyclohexyl-6-[[(5-methoxy-2,5-dioxopentyl)amino]carbonyl] , methyl ester, (0.25g, 0.46mMol) was dissolved in 4.6ml of toluene and 93 uL phosphorous oxychloride added. The reaction was heated at reflux for approximately 10 1.5 hours. The reaction was cooled and poured into an ice cold solution of saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to yield 221mg (92%) of product. 1H NMR (500 MHz, CHLOROFORM-D) 6 ppm 8.38 (s, 1 H) 7.86 (d, J=8.55 Hz, 1 H) 7.73 (d, J=8.55 Hz, 1 H) 7.56 - 7.62 (m, 2 H) 7.42 - 7.54 (m, 3 H) 15 6.90 (s, 1 H) 5.93 (d, J=12.51 Hz, 1 H) 4.36 (d, J=11.29 Hz, 1 H) 3.95 (s, 3 H) 3.69 (s, 3 H) 3.03 (t, J=7.48 Hz, 2 H) 2.82 - 2.92 (m, 1 H) 2.69 (t, J=7.48 Hz, 2 H) 1.68 2.19 (m, 8 H) 1.49- 1.61 (m, 1 H) 1.31 - 1.49 (m, 2 H) 1.14- 1.31 (m, 2 H); MS m/z 525(MH). 65 WO 2007/092888 PCT/US2007/061768 Example 35 N
-
0N 5 13-cyclohexyl-6-[5-[3-(4-morpholinyl)-3-oxopropyl-2-oxazolylj- 7H indolo[2, 1-aJ[2]benzazepine-10-carboxylic acid, methyl ester. 7H-indolo[2, 1 a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[5-(3-methoxy-3-oxopropyl) 2-oxazolyl]-, methyl ester (281mg, 0.53 mMol) was dissolved in 3.5ml of THF and 0.Sml of 1.0M tetrabutylammonium hydroxide in methanol was added to thc 10 reaction. The reaction was stirred at room temperature for 3.5 hours and quenched by partitioning between 0.1N hydrochloric acid and ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate. Volatiles were removed and the sample dried in vacuuo to yield 232mg (86%) of a yellow solid which was carried on without further purification. The yellow solid was suspended in 3 ml of 15 dichloromethane and 2ml of 2.0M oxalyl chloride in dichloromethane added to the reaction followed by 1 drop of DMF. The reaction was stirred at room temperature under nitrogen for 3 hrs 20min. Volatiles from the reaction were removed in vacuuo and the sample dried in vacuuo at room temperature for 2hr 45min then dissolved in 5ml of dichloromethane and 0.15ml (1.72mMol) ofmorpholine added. The reaction 20 was stirred under a nitrogen atmosphere at room temperature for 2days. The reaction was partitioned between ethyl acetate and 0.1 N hydrochloric acid, washed with brine, dried over magnesium sulfate to yield 282mg of residue. The reaction product was purified by silica column chromatography using a gradient elution of 5% ethyl acetate/ dichloromethane to 30% ethyl acetate/ dichloromethane to yield 157mg 25 (60%) of a yellow amorphous solid. 1H NMR (500 MHz, CHLOROFORM-D) 66 WO 2007/092888 PCT/US2007/061768 ppm 8.38 (s, 1 H) 7.86 (d, J=8.55 Hz, 1 H) 7.73 (d, J=8.55 Hz, 1 H) 7.57 - 7.63 (m, 2 H) 7.45 - 7.53 (min, 3 H) 6.92 (s, 1 H) 5.92 (d, J=13.43 Hz, 1 H) 4.37 (d, J=14.04 Hz, 1 H) 3.95 (s, 3 H) 3.47 - 3.76 (m, 6 H) 3.38 (d, J=4.27 Hz, 2 H) 3.07 (t, J=7.48 Hz, 2 H) 2.80 - 2.92 (mn, 1 H) 2.65 (t, J=7.48 Hz, 2 H) 1.87 - 2.19 (min, 5 H) 1.66 - 1.86 (m, 4 5 H) 1.50 - 1.66 (m, 2 H) 1.15 -1.50 (mn, 5 H); MS m/z 580(MH+). Example 36 N N0 0 HO 0N 10 13-cyclohexyl-6-[5-[3-(4-morpholinyl)-3-oxopropyl]-2-oxazolyl]-7H indolof2,1-a][2]benzazepine-10-carboxylic acid. 7H-indolo[2,1-a] [2]benzazepine 10-carboxylic acid, 13-cyclohexyl-6-[5-[3-(4-morpholinyl)-3-oxopropyl]-2 oxazolyl]-, methyl ester (22.4mg, 0.039mMol) and potassium trimethyl silanolate 15 (75mg, 0.19mMol) was placed in a 1 dram vial with a magnetic stir bar and 0.4ml of anhydrous THF added. The reaction was capped under nitrogen and stirred at room temperature for 22 hours. The reaction was acidified by the addition of acetic acid, diluted with acetonitrile and purified by PREP HPLC using the following conditions to yield 12.7mg (57%) of product: %A= 10% acetonitrile, 90% water, 0.1% TFA; 20 %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 30; Final % B=100; Gradient - 15min; Runtime=20min; Flow rate= 25ml/min; Column= Phenomenex Luna 21.2mm x 100mm slO0; 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.52 (s, 1 H) 7.90 (d, J=8.55 Hz, 1 H) 7.80 (dd, J=8.55, 1.22 Hz, 1 H) 7.65 (s, 1 H) 7.59 7.64 (m, 1 H) 7.44 -7.56 (m, 3 H) 7.01 (s, 1 H) 5.88 (d, J=13.43 Hz, 1 H) 5.46 (s, 4 25 H, H 2 0/H'peak) 4.40 (d, J=13.12 Hz, 1 H) 3.51 - 3.69 (m, 6 H) 3.34- 3.45 (mn, 2 H) 67 WO 2007/092888 PCT/US2007/061768 3.10 (t, J=7.32 Hz, 2 H) 2.82 - 2.91 (m, 1 H) 2.66 - 2.73 (m, 2 H) 1.98 - 2.19 (m, 3 H) 1.87 - 1.99 (m, 1 H) 1.70 - 1.85 (m, 2 H) 1.34 - 1.65 (mn, 3 H) 1.15 - 1.34 (mn, 3 H); MS m/z 566(MH ). 5 Example 37 0 N 0 N 0 0, 0 0, 'N 'N '-. N I H 13-cycIohexyl-N-[(dimethylamino)sulfonyl]-6-[5-[3-(4-morpholiny)-3-oxopropyl]-2 10 oxazolyl- 7H-indolof2,1-aJ[2]benzazepine-10-carboxamide. 7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[5-[3-(4-morpholinyl)-3 oxopropyl]-2-oxazolyl]- (75mg, 0.13mMol) was dissolved in 1.5ml of THF. Carbonyldiimidazole (28mg, 0.17mMol) was added to the reaction and the reaction was stirred under nitrogen at room temperature for 40 minutes then heated to reflux 15 for 40 minutes. The reaction was cooled under nitrogen and N,N-dimethylsulfamide (84mg, 0.68mMol) added to the reaction followed by DBU (22uL, 0.15mMol). The reaction was stirred overnight at room temperature. The reaction was partitioned be 0.1N hydrochloric acid and ethyl acetate. The organic phase was washed with 0.1N hydrochloric acid, brine and dried over magnesium sulfate. Volatiles were removed 20 in vacuuo and the residue was purified by Prep HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software:; %A= 10% acetonitrile, 90% water, 0.1% TFA; %B= 90% acetonitrile, 10% water, 0.1% TFA; Initial %B= 30; Final % B=100; Gradient= 12min; Runtime=22min; Flow rate= 25ml/min; Column=-- Waters Sunfire 19 x 100mm S5; Collected 49.6mg (55%) of 25 product as an orange solid with retention time = 10.6min; 1H NMR (500 MHz, 68 WO 2007/092888 PCT/US2007/061768 CHLOROFORM-D) 8 ppm 1.09 - 1.32 (m, 1 H) 1.32 - 1.61 (m, 3 H) 1.68 - 1.87 (m, 2 H) 1.91 - 2.18 (m, 4 H) 2.69 - 2.79 (m, 2 H) 2.82 - 2.93 (m, 1 H) 3.05 (s, 6 H) 3.07 - 3.11 (m, 1 H) 3.14 (s, 1 H) 3.44 (d, J=4.58 Hz, 2 H) 3.53 - 3.75 (m, 6 H) 4.40 (d, J=9.16 Hz, 1 H) 5.76 (d, J=14.04 Hz, 1 H) 6.97 (s, 1 H) 7.49 - 7.57 (m, 3 H) 7.62 (d, 5 J=7.32 Hz, 1 H) 7.68 (d, J=8.55 Hz, 1 H) 7.71 (s, 1 H) 7.92 (d, J=8.55 Hz, 1 H) 8.49 (s, 1 H) 9.99 (s, 1 H); MS m/z 672(MH'); MS m/z 670(M-H)-. Example 38 010 N 0 I H 10 1 3 -cyclohexyl-N-[(dimnethylamino)sulfonyl]-6, 7-dihydro-6-[5-[3-(4 morpholinyl)-3-oxopropyl]-2-oxazolylj-5H-indolo[2,1-a][2]Jbenzazepine-10 carboxamide. 7H-indolo[2,1-a][2]benzazepine-10-carboxamide, 13-cyclohexyl-N 15 [(dimethylamino)sulfonyl]-6-[5-[3-( 4 -morpholinyl)-3-oxopropyl]-2-oxazolyl] (18mg, 0.027mMol) was dissolved in a mixture 1.0ml of THF, 0.5ml of methanol and 10% palladium on carbon (7mg) was added. The reaction was placed under hydrogen (balloon atmosphere) and stirred at room temperature for 22 hours. The reaction was filtered through a celite plug, and the celite rinsed with methanol and 20 THF. Volatiles from the filtrate were removed in vacuuo and the residue was dissolved in methanol and purified by Prep HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software:; %A= 10% methanol, 90% water, 0.1% TFA; %B = 90% methanol, 10% water, 0.1% TFA; Initial %B= 35; Final % B=100; Gradient= 30min; Runtime=50min; Flow rate= 20ml/min; Column= 25 YMC Pro Pack 20mm x 150mrm SS; Product Retention time= 29.4min.; 1H NMR 69 WO 2007/092888 PCT/US2007/061768 (500 MHz, CHLOROFORM-D) 8 ppm 1.19 - 1.32 (m, 1 H) 1.31 - 1.53 (mn, 2 H) 1.68 (d, J=12.21 Hz, 1 H) 1.78 (d, J=9.46 Hz, 2 H) 1.93 (d, J= 1.90 Hz, 1 H) 1.97 - 2.11 (m, 3 H) 2.55 - 2.75 (m, 2 H) 2.80 - 2.89 (m, 1 H) 2.89 - 3.14 (m, 10 H) 3.16 - 3.24 (m, 1 H) 3.33 - 3.61 (m, 3 H) 3.62 - 3.74 (mn, 5 H) 3.84 (dd, 1 H) 4.06 (dd, J=1l5.11, 5 5.95 Hz, 1 H) 4.80 (d, J=15.26 Hz, 1 H) 6.89 - 6.95 (mn, 1 H) 7.45 (d, J=5.19 Hz, 4 H) 7.62 (d, J=7.63 Hz, 1 H) 7.90 (d, J=8.54 Hz, 1 H) 8.05 (s, 1 H) 9.68 (s, 1 H); MS m/z 674(MH+). Example 39 10 N-CC NNO 0 o 13-cyclohexyl-6-[5-[(tetrahydro-2H-pyran-4-yl)methyl]-, 3,4-oxadiazol-2 ylj-7H-indolo[2,1-a][2Jbenzazepine-10-carboxylic acid, methyl ester. 7H-indolo[2,1 15 a][2]benzazepine-6,10-dicarboxylic acid, 13-cyclohexyl-, 10-methyl ester, 6 hydrazide (720mg, 1.68mMol) and Ethyl 2-(tetrahydro-2H-pyran-4-yl)acetimidate hydrochloride (422mg, 2.05mMol) was suspended in 5.2 mL of isopropanol and diisopropylethyl amine (DIEA) (4.4ml, 25.3mMol) added to the reaction. The reaction was stirred for 10minutes and heated to approximately 70C under nitrogen 20 for 2 hours before increasing the reaction temperature to 80C. After 21 hours of heating, HPLC analysis of the reaction showed approximately 27% conversion to cyclized triazole with approximately 72% as uncyclized intermediate. The reaction was transferred to a 20mL microwave vessel and an additional 5mL of isopropanol added to the reaction. The reaction was heated in a microwave to 150C for 1 hour. 25 Reaction volatiles were removed in vacuuo and the residue shaken in a separatory funnel with ethyl acetate and 1 N hydrochloric acid. The reaction residue failed to 70 WO 2007/092888 PCT/US2007/061768 adequately dissolve in the organic phase, therefore most of the aqueous phase was drained off and dichloromethane added. The pH of the organic phase was raised by washing with saturated sodium bicarbonate. This step appeared to aid in solids dissolution. The organic phases were washed with brine and dried over magnesium 5 sulfate to yield 905mg of a yellow-orange solid. The oxadiazole product (Rr= 0.55 in 25% ethyl acetate in dichloromethane) was isolated using silica gel column chromatography eluting with a gradient of 10% ethyl acetate in dichloromethane to 30% ethyl acetate in dichloromethane. Weight of product =182mg as a yellow solid. An analytically pure sample (164.6mg) was obtained by trituration with hot methanol 10 (2mnil) and rinsing with 2ml of methanol at room temperature. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 7.88 (d, J=8.24 Hz, 1 H) 7.63 (t, J=3.36 Hz, 2 H) 7.46 7.58 (m, 3 H) 5.94 (d, J=7.32 Hz, 1 H) 4.46 (d, J=1 1.29 Hz, 1 H) 3.86 -4.01 (m, 5 H) 3.38 (t, J=l 1.60 Hz, 2 H) 2.75 - 2.95 (m, 3 H) 2.00 - 2.23 (mn, 4 H) 1.88 - 2.00 (m, 1 H) 1.66 -1.85 (m, 5 H) 1.51 -1.66 (m, 2 H) 1.33 -1.50 (m, 4H) 1.13 -1.31 (m, 1 H); 15 MS rn/z 538(MH+). Example 40 HN O N N 0 O 20 13-cyclohexyl-6-[5-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-1,2,4-triazol-3 yl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, methyl ester. From the reaction mixture describing the preparation of 7H-indolo[2,1 -a][2]benzazepine-1 0 carboxylic acid, 13-cyclohexyl-6-[5-[(tetrahydro-2H-pyran-4-yl)methyl]-1,3,4 25 oxadiazol-2-yl]-, methyl ester, the titled compound was isolated (Rf=0.17 in 25% ethyl acetate in dichloromethane) from the above silica gel column chromatography 71 WO 2007/092888 PCT/US2007/061768 to yield 476mg (53%) as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.38 (s, 1 H) 7.75 - 7.90 (m, 2 H) 7.68 (d, J=8.24 Hz, 1 H) 7.56 - 7.63 (mn, 1 H) 7.50 - 7.56 (m, 1 H) 7.41 - 7.50 (mn, 2 H) 5.91 (d, J=12.21 Hz, 1 H) 4.26 (d, J=l 1.90 Hz, 1 H) 3.87 - 4.02 (m, 5 H) 3.33 (t, J=1 1.29 Hz, 2 H) 2.87 (s, 1 H) 2.76 (s, 2 H) 5 1.
8 4
-
2
.
1 7 (m, 6 H) 1.68 - 1.82 (m, 2 H) 1.30 - 1.66 (m, 8 H) 1.13 - 1.29 (m, 2 H); MS m/z 537(MH'). Example 41
°
0 NN O NI 10 1 3 -cyclohexyl-6-[1-mtnethyl-5-[(tetrahydro-2H-pyran-4-yl)methyl]lH-1, 2, 4 triazol-3-yl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, methyl ester. 7H indolo[2,1-a][2]bcnzazcpinc-10-carboxylic acid, 13-cyclohcxyl-6-[5-[(tctrahydro 15 2H-pyran-4-yl)methyl]-1H-1,2,4-triazol-3-yl]-, methyl ester (167mg, 0.3 1mMol) was dissolved in 3ml of DMF. Iodomethane (39uL, 0.62mMol) was added to the reaction followed by sodium hydride (60% in mineral oil, 0.47mMol). The reaction was capped under nitrogen and stirred at room temperature for 16hrs. Volatiles were removed in vacuuo and the reaction partitioned between ethyl acetate and saturated 20 aqueous ammonium chloride. Extract aqueous with ethyl acetate. Combine organic fractions and wash with saturated ammonium chloride, brine, dry over magnesium sulfate to obtain 174mg of a yellow-brown solid. Chromatograph residue on silica gel using 10% ethyl acetate in dichloromethane to obtain 100mrg (58%) of product. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.47 (s, 1 H) 7.85 (d, J=8.55 Hz, 1 25 H) 7.67 - 7.76 (m, 2 H) 7.60 (dd, J=5.19, 3.66 Hz, 1 H) 7.49 - 7.56 (mn, 1 H) 7.41 7.49 (m, 2 H) 5.97 (d, J=13.12 Hz, 1 H) 4.35 (d, J=14.04 Hz, 1 H) 3.90 - 3.98 (m, 5 72 WO 2007/092888 PCT/US2007/061768 H) 3.87 (s, 3 H) 3.37 (t, J=11.44 Hz, 2 H) 2.84 - 2.93 (m, 1 H) 2.68 (d, J=7.02 Hz, 4 H) 2.68 (d, J=7.02 Hz, 2 H) 1.89 -2.18 (m, 6 H) 1.67 - 1.83 (mn, 2 H) 1.64 (d, J=12.82 Hz, 2 H) 1.49- 1.61 (m, 3 H) 1.32 - 1.48 (mn, 5 H) 1.14- 1.31 (m, 3 H) 5 Example 42 NN N N 0 HO 1 3 -cyclohexyl- 6- [1-methyl-5-[(tetrahydro-2H-pyran-4-yl)methyl] H- 1, 2,4 10 triazol-3-yl -7H-indolo[2,1-aj[2Jbenzazepine-10-carboxylic acid. 7H-indolo[2, 1 a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[ 1 -methyl-5-[(tetrahydro-2H pyran-4-yl)methyl]- 1 H- 1,2,4-triazol-3-yl]-, methyl ester (94mg, 0.17mMol) was dissolved in 1.7ml of anhydrous THF and potassium trimethylsilanolate (104mg, 0.81mMol) added to the reaction. The reaction was capped under nitrogen and 15 stirred at room temperature for 22 hrs. The reaction was quenched with 1 N hydrochloric acid and the product extracted into ethyl acetate., washed with brine and dried over magnesium sulfate. Volatiles were removed in vacuuo to yield 89mg of crude product. The product was purified by trituration with diethyl ether to yield 59mg (64%). 1H NMR (500 MHz, CHLOROFORM-D) 6 ppm 8.55 (s, 1 H) 7.89 (d, 20 J=8.55 Hz, 1 H) 7.78 (d, J=8.55 Hz, 2 H) 7.61 (dd, J=5.34, 3.51 Hz, 1 H) 7.51 - 7.58 (in, 1 H) 7.46 (dd, J=5.49, 3.36 Hz, 2 H) 5.97 (d, J=14.04 Hz, 1 H) 4.36 (d, J=13.43 Hz, 1 H) 3.94 (dd, J=11.44, 3.51 Hz, 2 H) 3.88 (s, 3 H) 3.38 (t, J= 1.29 Hz, 2 H) 2.83 - 2.96 (m, 1 H) 2.71 (d, J=6.41 Hz, 2 H) 1.88 - 2.25 (m, 6 H) 1.76 (d, J=1 1.60 Hz, 2 H) 1.65 (d, J=11.90 Hz, 2 H) 1.30 - 1.59 (m, 6 H) 1.16 - 1.27 (min, 2 H); MS m/z 25 537(MH+). 73 WO 2007/092888 PCT/US2007/061768 Example 43 c 0 N N N N I H 5 1 3 -cyclohexyl-N-[(dimethylamnino)sulfo'nyl]-6-[1-mnethyl-5-[(tetrahydro -2H-pyran-4 yl)mnethylJ-lH-1,2,4-triazol-3-yl]-7H-indolo[2,1-a][2Jbenzazepine-10-carboxamnide. 7H-indolo[2,1-a][2]bcnzazcpinc-10-carboxylic acid, 13-cyclohexyl-6-[1-mcthyl-5 [(tetrahydro-2H-pyran-4-yl)methyl]-1H-1,2,4-triazol-3-yl]- (58mg, 0.1 ImMol) was dissolved in 2ml of dichloromethane containing 2.0 M of oxalyl chloride. One drop 10 of DMF was added to the reaction mixture and the reaction was stirred for 2.5hrs under nitrogen. The volatiles were removed in vacuuo and the acid chloride stored under nitrogen until needed. N,N-dimethylsulfamide (45.7mg, 0.37mMol) was dissolved in 0.5ml of THF and 2-tert-butylimino-2-diethylamino-1,3 dimethylperhydro-1,3,2-diazaphosphorine (68.8uL, 0.238mMol) added. The 15 reaction was stirred at room temperature for approximately 15 minutes then the above acid chloride dissolved in lml of THF was added dropwise via syringe. The reaction was capped under nitrogen and stirred for 2 hours at room temperature after which the reaction progress was monitored by HPLC. Additional N,N dimethylsulfamide (20mg, 0.16mMol) and 2-tert-butylimino-2-diethylamino- 1,3 20 dimethylperhydro-1,3,2-diazaphosphorine (46ul, Mmol) in 0.3mL of THF was added to the reaction. The reaction was stirred for an additional 15.5hrs under nitrogen. The reaction was partitioned between ethyl acetate and 0.1 M citric acid, washed with 0.1M citric acid. The organic phase was washed with brine, dried over magnesium sulfate and the volatiles removed in vacuuo to yield 125mg of a brown 25 oil. The product (4.3mg, 6%) was isolated by Prep HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software:; %A= 10% 74 WO 2007/092888 PCT/US2007/061768 methanol, 90% water, 0.1% TFA; %B = 90% methanol, 10% water, 0.1% TFA; Initial %B = 35; Final % B=100; Gradient - 30min; Runtime=50min; Flow rate = 20ml/min; Wavelength = 220nm; Column= YMC Pro Pack 20mm x 150mm S5. I H NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.73 (s, 1 H) 8.27 (s, 1 H) 7.91 (d, 5 J=8.55 Hz, 1 H) 7.77 - 7.88 (m, 2 H) 7.58 - 7.65 (m, 1 H) 7.44 - 7.57 (m, 5 H) 5.81 (d, J=14.34 Hz, 1 H) 4.41 (d, J=1 3.12 Hz, 1 H) 3.91 - 4.04 (m, 7 H) 3.32 - 3.44 (m, 2 H) 3.13 - 3.23 (m, 1 H) 3.07 (s, 6 H) 2.81 - 2.95 (m, 4 H) 1.85 - 2.16 (m, 7 H) 1.67 1.83 (m, 3 H) 1.50 - 1.65 (m, 4 H) 1.15 - 1.51 (m, 8 H); MS m/z 643(MH+). 10 Example 44 N O O HO N 13-cyclohexyl-6-[5-[(tetrahydro-2H-pyran-4-yl)methyl]-l, 3,4-oxadiazol-2 15 yl]-7H-indolo[2,1-aj[2]benzazepine-10-carboxylic acid. 7H-indolo [2,1 a][2]benzazepine-10-carboxylic acid, 13-cyclohexyl-6-[5-[(tetrahydro-2H-pyran-4 yl)methyl]-1,3,4-oxadiazol-2-yl]-, methyl ester (156mg, 0.29mMol) was dissolved in anhydrous THF and potassium trimethylsilanolate (198mg, 1.54mMol) was added to the reaction. The reaction was capped under nitrogen and stirred at room temperature 20 for 19 hours. The reaction was partitioned between ethyl acetate and 0.1N hydrochloric acid. The reaction was extracted with ethyl acetate and the organic phases combined and washed with brine, dried over magnesium sulfate and volatiles removed in vacuuo to yield 166mg of crude material. Approximate 87mg of the crude reaction was dissolved in a mixture of methanol/acetonitrile/DMF and 25 subjected to HPLC purification using the following conditions: %A= 10% acetonitrile, 90% water, 0.1% TFA; /oB= 90% acetonitrile, 10% water, 0.1% TFA; 75 WO 2007/092888 PCT/US2007/061768 Initial %B= 30; Final % B=100; Gradient= 10min; Runtime=15min; Flow rate= 25ml/min; Column= Phenomenex Luna 21.2mm x 100mm s10; Retention Time of 7H-indolo[2,1 -a][2]benzazepine- 10-carboxylic acid, 13-cyclohexyl-6-[5 [(tetrahydro-2H-pyran-4-yl)methyl]-1,3,4-oxadiazol-2-yl]- was 9.9 minutes. 1H 5 NMR (500 MHz, CHLOROFORM-D) 8 ppm 8.48 (s, 1 H) 7.91 (d, J=8.55 Hz, 1 H) 7.80 (dd, J=8.55, 1.53 Hz, 1 H) 7.61 - 7.68 (rn, 2 H) 7.49 - 7.58 (m, 3 H) 5.96 (d, J=13.12 Hz, 1 H) 4.48 (d, J=8.24 Hz, 1 H) 3.96 (dd, J=1 1.44, 3.20 Hz, 2 H) 3.33 3.44 (mn, 3 H) 2.81 - 2.92 (m, 3 H) 2.01 - 2.20 (m, 4 H) 1.90 -2.01 (m, 1 H) 1.65 1.84 (mn, 4 H) 1.51 - 1.62 (m, 1 H) 1.32 -1.52 (m, 5 H) 1.16 -1.29 (m, 1 H); MS m/z 10 524(MH+); MS m/z 522 (M-H)-. Example 45 ~0 HO N N 15 13-Cyclohexyl-6-(furan-3-yl)- 7H-indolo{2,1 -a][2]benzazepine-10-carboxylic Acid. Step 1: Sodium hydride (44 mg of 95 %, 1.74 mmol) was added to an ice cold solution of methyl 3-cyclohexyl-2-(2-vinylphenyl) 1H-indole-6-carboxylate (0.500 mg, 1.34 mmol) in THF (6 mL). When the evolution of hydrogen subsided, 2,3 20 dibromoprop-1-ene (402 mg, 2.01 mmol) was added in a single portion. Stirring was continued at 0 0 C for 2 hr and then at 22 0 C for 24 hr. The solution was concentrated and the residue chromatographed on SiO2 with petroleum ether-ethyl acetate (10:1) using the flash technique to afford methyl 1-( 2 -bromoallyl)-3-cyclohexyl-2-(2 vinylphenyl)-1H-indole-6-carboxylate (285 mg, 44.5 %) as a gummy solid. MS m/z 25 479 (MH+). Step 2: Tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.033 mmol) was added to a stirred and degassed mixture of methyl 1-(2-bromoallyl)-3 cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate (157 mg, 0.33 mmol), 3 furylboronic acid (54.5 mg, 0.49 mmol), LiCl (55 mg, 0.66 mmol) in ethanol (2 mL) and toluene (2mL) containing IM aqueous sodium carbonate (0.82 mL, 0.82 mmol). 76 WO 2007/092888 PCT/US2007/061768 The mixture was heated under reflux for 1 hr, cooled and partitioned between ethyl acetate and water. The organic layer was washed (water, brine), dried over sopdium sulfate and concentrated. The crude product was purified on a silicic acid thick layer plate. The plate was eluted with hexanes-ethyl acetate (10:1) to provide methyl 3 5 cyclohexyl-l-(furan-3-yl)-2-(2-vinylphenyl)-l1H-indole-6-carboxylate as a gum (57 mg, 37 %). MS m/z 466 (MH 4 ); 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 1.15 - 1.89 (m, 10 H) 2.42 - 2.53 (mn, 1 H) 3.91 (s, 3 H) 4.25 (s, 1 H) 4.48 (d, J=17.40 Hz, 1 H) 4.82 (d, J=17.40 Hz, 1 H) 4.82 (d, J=17.40 Hz, 1 H). 5.09 - 5.17 (m, 2 H) 5.69 (d, J=17.70 Hz, 1 H) 6.34 - 6.47 (m, 2 H) 7.18 - 7.23 (m, 2 H) 7.28 (t, J=7.93 10 Hz, 1 H) 7.32 (t, .1=1.68 Hz, 1 H) 7.42 (t, .J=7.63 Hz, 1 H) 7.69 (d, .J=7.63 Hz, 1 H) 7.79 - 7.85 (mn, 2 H) 8.00 (s, 1 H). Step 3: Grubb's second generation catalyst (10 mg) was added to a solution of methyl 3-cyclohexyl- 1-(furan-3-yl)-2-(2-vinylphenyl)- 1H indole-6-carboxylate (47 mg) in methylene chloride (8 mL). The solution was stirred under reflux for 18 hr and concentrated to dryness The residue was purified on a 15 silicic acid preparative plate. The plate was eluted with hexanes-ethyl acetate (10:1). The product containing band was extracted and the extract was concentrated. Purification on a second thick layer plate afforded 13-cyclohexyl-6-(furan-3-yl)-7H indolo {2,1-a][2]bcnzazcpine-10-carboxylate as a golden solid (17 mg, 39 %). MS m/z 438 (MH+); 1H NMR (300 MHz, CHLOROFORM-D) 8 ppm 1.11 - 2.16 (mn, 10 20 H) 2.78 - 2.95 (m, 1 H) 3.94 (s, 3 H) 4.34 - 4.49 (m, 1 H) 5.00 - 5.15 (m, 1 H) 6.60 (s, 1 H) 6.93 (s, 1 H) 7.38 - 7.45 (m, 4 H) 7.55 (d, .1=8.42 Hz, 1 HI) 7.70 (dd, .1=8.42, 1.46 Hz, 1 H) 7.81 - 7.88 (m, 2 H) 8.17 (s, 1 H). Step 4: A mixture of the preceding ester (17 mg) in THF (250 gL), methanol (250 gL), and 1.0 N NaOH (200 gL) was heated at 100 0 C on a microwave apparatus for 15 min. The resulting solution was 25 cooled and acidified with dilute HC1 to precipitate the titled acid as a golden solid. MS m/z 424 (MH+). Example 46 77 WO 2007/092888 PCT/US2007/061768 NO 0/ 0 Jf Methyl 13-cyclohexyl-3-methoxy-6-(5-(3-methoxy-3-oxopropyl)-1,3-oxazol-2 yl)-7H-indolo[2,1-aj [2]benzazepine-10-carboxylate. Methyl 13-cyclohexyl-3 5 (methyloxy)-6-(((5-(methyloxy)-2,5-dioxopentyl)amino)carbonyl)-7H-indolo[2,1 a][2]benzazepine-10-carboxylate (1.60g, 2.79mMol) was suspended in 38ml of toluene along with phosphorus oxychloride (0.58mL, 6.34mMol). The mixture was heated to reflux under nitrogen for 3hrs, cooled and poured into a sepratory funnel containing ice and saturated aqueous sodium bicarbonate solution. The aqueous 10 mixture was extracted with ethyl acetate. The organic layer was washed sequentially with aqueous saturated bicarbonate, brine and dried over magnesium sulfate. Removal of volatiles and drying in vacuuo produced the title product in quantitative yield (1.55g). 1HNMR (500 MHz, CHLOROFORM-d) 5 ppm 1.27 (1 H, br. s.),1.36 - 1.45 (2 H, m), 1.59 (2 H, br. s.), 1.78 (2 H, d, J=9.77 Hz), 1.96 (1 H, br. s.), 2.06 (2 15 H, br. s.), 2.71 (2 H, t, J=7.48 Hz), 2.81 - 2.90 (1 H, m), 3.04 (2 H, t, J=7.32 Hz), 3.70 (3 H, s), 3.95 (3 H, s), 3.98 (3 H, s), 4.37 (1 H, d, J=11.60 Hz), 5.93 (1 H, d, J=12.51 Hz), 6.91 (1 H, s), 7.02 (1 H, d, J=2.75 Hz),7.07 (1 H, dd, J=8.70, 2.59 Hz), 7.53 (2 H, s), 7.74 (1 H, d, J=8.55 Hz), 7.85 (1 H, d, J=8.55 Hz), 8.38 (1 H, s). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: %A = 10% 20 methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=100; Gradient= 5 min; Runtime= 6 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm SO10; Retention Time= 4.48 min, purity 96%. Flow injection Mass Spectrometry: MS m/z 555(MH). 25 78 WO 2007/092888 PCT/US2007/061768 Example 47 0 OH NO 5 3-(2-(13-Cyclohexyl-3-methoxy-1O-(methoxycarbonyl)- 7H-indolof2,1 a]f[2]benzazepin-6-yl)-1,3-oxazol-5-yl)propanoic acid. Methyl 13-cyclohcxyl-3 methoxy-6-(5-(3-methoxy-3-oxopropyl)-l1,3-oxazol-2-yl)-7H-indolo[2,1 a][2]benzazepine-10-carboxylate (1.53g, 2.92mMol) was dissolved in 20mL of THF and 5.8mL of 1.0M solution of tetrabutylammonium hydroxide in methanol was 10 added. The reaction was stirred under nitrogen atmosphere for 2hrs to completion. The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The ethyl acetate layer was washed with 1N hydrochloric acid then the aqueous layers combined and back extracted with ethyl acetate. The organic layers were combined, and washed sequentially with IN hydrochloric acid, brine and dried over 15 magnesium sulfate. Volatiles were removed in vacuuo to yield a amorphous yellow solid/foam (1.54g). 1H NMR (500 MHz, CHLOROFORM-d) 8 ppm 1.21 - 1.31 (2 H, m), 1.32 - 1.50 (2 H, mn), 1.56 (1 H, br. s.), 1.72 - 1.82 (2 H, mn), 2.01 (1 H, br. s.), 2.03 - 2.13 (3 H, m), 2.76 (2 H, d, J=6.41 Hz), 2.80 - 2.89 (1 H, in), 3.13 (2 H, t, J=6.26 Hz), 3.92 (3 H, s), 4.00 (3 H, s), 4.40 (1 H, d, J=12.82 Hz), 5.81 (1 H, d, 20 J=16.17 Hz), 6.92 (1 H, s), 7.01 - 7.09 (0 H, m), 7.03 (1 H, d), 7.07 (1 H, dd), 7.53 (1 H, d, J=8.55 Hz), 7.73 (2 H, s), 7.86 (1 H, d, J=8.55 Hz), 8.40 (1 H, s). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=100; Gradient= 5 min; 25 Runtime= 6 min; Flow rate= 5 ml/min; Wavelength = 220nm; Column= Phenomenex 79 WO 2007/092888 PCT/US2007/061768 Luna 3.0mm x 50mm S10. Retention Time= 4.11min, purity 97%. Flow injection Mass Spectrometry: MS m/z 541(MH*), m/z 539(MH-). Example 48 5 N O o N 00 o 0 No Methyl 13-cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3 oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate. 3-(2-(13-Cyclohexyl 10 3-methoxy- 10-(methoxycarbonyl)-7Hf-indolo[2,1-a][2]benzazepin-6-yl)-1,3-oxazol 5-yl)propanoic acid (1.522g, 2.82mMol) was dissolved in 28mL of THF and carbonyldiimidazole (548mg, 3.38mMol) added to the reaction. The reaction was stirred for lhr at room temperature under nitrogen then heated to reflux under nitrogen for lhr. The reaction was cooled and morpholine (0.3mL, 3.44mMol) 15 added, the reaction was stirred under nitrogen for 2hrs. Volatiles from the reaction were removed in vacuuo and the residue partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The aqueous was extracted with ethyl acetate and the organic layers combined and washed sequentially with 1N hydrochloric acid and brine, dried over magnesium sulfate to yield 1.62g of crude product. The title 20 compound was purified by silica gel chromatography eluting with a gradient of 50% ethyl acetate in dichloromethane to 65% ethyl acetate in dichloromethane to yield 1.28g (74%) of product as a amorphous yellow solid. 1H NMR (500 MHz, CHLOROFORAM-d) 8 ppm 1.27 (2 H, t, J=7.17 Hz), 1.40 (1 H, t, J=7.63 Hz), 1.53 1.62 (2 H, m), 1.78 (2 H, d, J=10.99 Hz), 1.95 (1 H, br. s.), 2.05 (2 H, br. s.), 2.66 (2 25 H, t, J=7.48 Hz), 2.86 (1 H, td, J=11.83, 3.51 Hz), 3.09 (2 H, t, J=7.48 Hz), 3.36 80 WO 2007/092888 PCT/US2007/061768 3.44 (2 H, mn), 3.56 (2 H, d, J=4.27 Hz), 3.62 (2 H, br. s.), 3.64 (2 H, d, J=2.75 Hz), 3.93 (3 H, s), 3.96 (3 H, s), 4.38 (1 H, d, J=12.21 Hz), 5.92 (1 H, d, J=14.65 Hz), 6.92 (1 H, s), 7.02 (1 H, d, J=2.75 Hz), 7.07 (1 H, dd, J=8.85, 2.75 Hz), 7.55 (2 H, t, J=4.27 Hz), 7.73 (1 H, d, .J=8.55 Hz), 7.85 (1 H, d, J=8.24 Hz), 8.38 (1 H, s). LC 5 MS: Shimadzu Analytical HPLC using Discovery VP software: %A = 10% methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 0; Final % B=100; Gradient - 2 min; Runtime = 4 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm S10. Retention Time= 2.93 min, MS m/z 610(MH+). 10 Example 49 0 N O 0 N 15 Methyl 13-cyclohexyl-3-mnethoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3 oxazol-2-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate. Methyl 13-cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol-2-yl) 7H-indolo[2,1-a][2]benzazepine-10-carboxylate (610mg, 1.00mMol)) was dissolved in 15ml of THF and 5ml of methanol. To this reaction was added 83mg of 10% 20 palladium on carbon. The reaction was placed under hydrogen atmosphere (latin, balloon pressure) and stirred at room temperature for 22 hrs. The reaction was filtered through a celite plug and rinsed with THF. Volatiles were removed from the filtrate in vacuuo to yield 569mg (93%) of the title compound as a yellow solid. LC MS: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% 25 methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 81 WO 2007/092888 PCT/US2007/061768 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=100; Gradient= 3 min; Runtime= 4 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm S10. Retention Time= 2.55 min, MS m/z 612(MH*). 5 Example 50 oO 0 N ,O HO N 13-Cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-, 3-oxazol 10 2-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid. Methyl 13 cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol- 2 -yl)-6,7 dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (560mg, 0.92mMol) was dissolved in THF and potassium trimethylsilanolate (585mg, 4.56mMol) added. The reaction was stirred under nitrogen atmosphere at room temperature for 20hrs. 1N 15 aqueous hydrochloric acid was added to the reaction. The reaction was extracted with ethyl acetate. The organic phase washed with brine, dried over magnesium sulfate and volatiles removed in vacuuo to yield 585mg of a yellow amorphous foam. LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A = 10% methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 20 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=100; Gradient-- 5 min; Runtime= 6 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm S10. Retention Time= 4.05 min, MS m/z 598(MH), 1195 (2M+H) . 82 WO 2007/092888 PCT/US2007/061768 Chiral Resolution of 13-cyclohexyl-3-methoxy-6-(5-(3-(4-rnorpholinyl)-3 oxopropyl)-1,3-oxazol-2-yl)-6,7-dihydro-5H-indolo[2, 1 -a][2]benzazepine-1 0 carboxylic acid. Conditions: Chiralpak AD-H analytical column, 4.6mm x 250mm, 5um; Mobile phase: 35% (0.1%TFA) methanol in carbon dioxide; Temperature= 35 5 'C; Flow rate= 2.0ml/min for 16min.; UV monitored @ 213nm; Injection: 5uL of approximately lmg/mL solution in ethanol. Retention time of Isomer A: 5.96min; Retention time of Isomer B: 11.65min. Prep. Chiral separation: ChiralPak AD-H, 30mm x 250mm, 5um; Mobile phase: 65% carbon dioxide, 35% methanol with 0.1% trifluoroacetic acid; Temperature: 35 oC; Pressure: 150 bar; Flow rate: 70ml/min; 10 UV: 213nm; Peak 1 Isomer A: 7.20 min to 9.20min; Peak 2 Isomer B: 12.4min to 16.6 min. From 498mg of racemate, 216mg of Isomer A and 231mng of Isomer B were obtained. Example 51 15 0 No * Chiral Isomer A HO N 13-Cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol 2-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid. (Peakl 20 Chiral Isomer A). 1H NMR (500 MHz, CHLOROFORM-D) 3 ppm 1.20 - 1.52 (m, 3.3 H) 1.68 (t, J=12.97 Hz, 1.1 H) 1.79 (d, J=8.55 Hz, 2 H) 1.88 - 2.12 (m, 4 H) 2.46 (t, J=7.32 Hz, 1.4 H) 2.71 (t, J=7.63 Hz, 0.5 H) 2.79 - 2.88 (m, 1 H) 2.88 - 3.11 (m, 3.5 H) 3.15 (dd, J=12.97, 5.95 Hz, 0.8 H) 3.19 - 3.31 (m, 1.4 H) 3.45 - 3.75 (m, 6.3 H) 3.84 (s, 0.7 H) 3.87 - 3.95 (m, 3 H) 3.94 - 4.03 (mn, 0.5 H) 4.07 (dd, J=15.11, 5.34 25 Hz, 0.8 H) 4.81 (d, J=14.95 Hz, 0.9 H) 6.82 - 6.97 (m, 1.4 H) 6.97 - 7.04 (mn, 1.5 H) 83 WO 2007/092888 PCT/US2007/061768 7.38 (t, J=7.63 Hz, 1 H) 7.72 - 7.84 (m, 1 H) 7.85 - 7.93 (m, 1 H) 7.98 - 8.08 (m, 0.7 H) 8.22 (s, 0.2 H). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: %A = 10% methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=100; 5 Gradient= 5 min; Runtime= 6 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm S10; Retention Time= 3.16 min, purity 98%. Flow injection Mass Spectrometry: MS m/z 598(MH), m/z 596(MHt). Example 52 10 N O 0* Chiral Isomer B HO NN 13-Cyclohexyl-3-mnethoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-l,3-oxazol 2-yl)-6,7-dihydro-5H-indolo[2,1-aj[2]benzazepine-10-carboxylic acid (Peak2 15 Chirall somer B). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: %A = 10% methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B = 50; Final % B=100; Gradient= 5 min; Runtime= 6 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm S10. Retention Time = 3.18 min, 20 purity 99%. Flow injection Mass Spectrometry: MS m/z 598(MH+), m/z 596(MH-). Example 53 84 WO 2007/092888 PCT/US2007/061768 0 N 0 N 0 N N N Isomer B 1 3 -Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(5-(3-(4 minorpholinyl)-3-oxopropyl)-1,3-oxazol-2-yl)-6, 7-dihydro-5H-indolo[2, I 5 a][2]benzazepine-10-carboxamnide (Isomer B).13-Cyclohexyl-3-methoxy-6-(5-(3-(4 morpholinyl)-3-oxopropyl)-1,3-oxazol-2-yl)-6,7-dihydro-5H-indolo[2,1 a][2]benzazepine-10-carboxylic acid (Peak2- Chiral Isomer B) (100mg, 0.17mMol) was dissolved in 1.9m1 of anhydrous THF and carbonyldiimidazole (37.1mg, 0.23mMol) added. The reaction was stirred under a nitrogen atmosphere at room 10 temperature for lhr and heated at reflux for 1 hr under nitrogen. The reaction was cooled under nitrogen and dimethyl sulfamide (145mg, 1.17mMol) and DBU (27.5uL, 0.18mMol) added to the reaction. The reaction was heated to 50C under a nitrogen atmosphere for 4hrs, then cooled to room temperature and analyzed by HPLC for progress. The reaction was heated for an additional 2.5hrs at 50C and 15 again monitored by HPLC. Dimethyl sulfamide (100mg) and DBU (27uL) were added to the reaction and the reaction heated to reflux for 3hrs under nitrogen. Heat was removed and the reaction cooled to room temperature and stirred overnight. The reaction was partitioned between ethyl acetate and IN aqueous hydrochloric acid and the aqueous phase extracted with ethyl acetate. The organic phases were combined 20 and washed sequentially with IN aqueous hydrochloric acid, brine then dried over magnesium sulfate. Removal of volatiles in vacuuo left 209mg of crude product which was purified by reverse phase HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% TFA; %B= 90% methanol, 10% water, 0.1% TFA; Initial %B= 50; 25 Final % B=100; Gradient - 15min; Runtime=15min; Flow rate= 45ml/min; Column= 85 WO 2007/092888 PCT/US2007/061768 Waters Sunfire 30mm x 100mm; Peak collection 8.2min to 9.1min.; The title compound was isolated as a colorless solid, 71.2mg (60%). 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 1.25 (q, J=12.82 Hz, 1.2 H) 1.31 - 1.53 (m, 2.1 H) 1.58 1.85 (m, 3.2 H) 1.86 - 2.12 (m, 4.2 H) 2.54 - 2.76 (m, 2.1 H) 2.81 - 2.99 (m, 3.3 H) 5 2 .99 -3.12 (m, 7.3 H) 3.14 -3.24 (m, 1 H) 3.34 - 3.61 (m, 3.1 H) 3.60 -3.73 (m, 5.3 H) 3.72 - 3.82 (m, 0.9 H) 3.84 (s, 0.6 H) 3.90 (s, 2.5 H) 4.02 (dd, J=14.95, 6.10 Hz, 0.9 H) 4.77 - 4.92 (mn, 1.3 H) 6.78 - 6.87 (m, 1 H) 6.88 - 7.05 (m, 2 H) 7.30 - 7.51 (in, 1.2 H) 7.64 (dd, J=8.39, 1.37 Hz, 0.8 H) 7.81 - 7.95 (m, 1.0 H) 8.01 - 8.21 (m, 1 H) 8.67 (s, 0.2 H) 9.86 (s, 0.8 H). HPLC analysis: Shimadzu Analytical HPLC using 10 Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=100; Gradient= 5 min; Runtime= 6 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm S10. Retention Time= 3.03 min, purity 99%. Flow injection Mass Spectrometry: MS m/z 704(MH+), 15 726(M+Na)
+
, m/z 702(M-H)-. Chiral Purity: Column: Chiralacel OJ-H analytical column 4.6mm x 250mm; Mobile Phase: 12% methanol in carbon dioxide; Temp: 35 oC; Flow rate: 2.0ml/min for 40min; UV monitoring= 213nm; Injection: 5uL of approximately 1mg/mL solution in ethanol; Retention time: 32.5min, purity= 100% EE=99.9%. 20 Example 54 0 N 0 or N~ 0 N NN H O1 86 WO 2007/092888 PCT/US2007/061768 13-cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(5-(3-(4 morpholinyl)-3-oxopropyl)-1, 3-oxazol-2-yl)-6,7-dihydro-5H-indolo[2,1 a][2Jbenzazepine-10-carboxamnide (Isomer A). Same procedure used for preparation of above enantiomer except 13-cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3 5 oxopropyl)-1,3-oxazol-2-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10 carboxylic acid (Peakl- Chiral Isomer A) was used as starting material. HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid; %B = 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B = 50; Final % B=100; Gradient-- 5 min; 10 Runtime= 6 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column = Phenomenex Luna 3.0mm x 50mm SO10. Retention Timc = 3.03 min, purity 99%; Flow injection Mass Spectrometry: MS m/z 704(MH+), 726(M+Na)
+
, m/z 702(M-H)-. Chiral Purity: Column: Chiralacel OJ-H analytical column 4.6mm x 250mm; Mobile Phase: 12% methanol in carbon dioxide; Temp: 35 oC; Flow rate: 2.0ml/min for 40min; UV 15 monitoring= 213nm; Injection: 5uL of approximately lmg/mL solution in ethanol. Retention time: 27.1min, purity= 100% EE>99.9%. Example 55 N I / 20 Methyl 13-cyclohexyl-3-methoxy-6-(1,3-oxazol-2-yl)- 7H-indolof2,1 a][2]benzazepine-10-carboxylate. Methyl 13-cyclohexyl-3-(methyloxy)-6-(((2 oxoethyl)amino)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (410mg, 25 0.84mnMol) is dissolved in 10mL of THF in a microwave reactor tube with stirbar. Burgess Reagent, (602mg, 2.53mMol) (methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt was added to 87 WO 2007/092888 PCT/US2007/061768 the reaction vessel. The reaction was placed under nitrogen atmosphere and heated in a microwave for 1 minute at 100 watts. The reaction was monitored by HPLC and additional Burgess Reagent (200mg, 0.84mMol) was added to the reaction. The reaction was further heated for Iminute at 100 watts power. The reaction was 5 partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The organic phases were combined and washed sequentially with 1N aqueous hydrochloric acid and brine, dried over magnesium sulfate and volatiles removed in vacuuo to obtain 0.71g of crude product. The title compound was purified by silica gel chromatography eluting with a gradient 10 of 0% ethyl acetate in dichloromethane to 15% ethyl acetate in dichloromethane to give 150mg (38%) as a yellow solid. 1H NMR (500 MHz, CHLOROFORM-d) 8 ppm 1.27 (1 H, br. s.), 1.32 - 1.50 (2 H, m), 1.57 (1 H, br. s.), 1.78 (2 H, d, J=9.77 Hz), 1.95 (1 H, br. s.), 2.07 (3 H, br. s.), 2.71 - 2.98 (1 H, mn), 3.94 (3 H, s), 3.97 (3 H, s), 4.43 (1 H, br. s.), 5.92 (1 H, br. s.), 7.03 (1 H, d, J=2.44 Hz), 7.09 (1 H, dd, J=8.70, 15 2.59 Hz), 7.29 (1 H, s), 7.55 (1 H, d, J=8.55 Hz), 7.68 (2 H, d, J=10.99 Hz), 7.74 (1 H, dd, J=8.55, 1.22 Hz), 7.86 (1 H, d, J=8.55 Hz), 8.38 (1 H, s). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacctic acid; %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=100; Gradient - 5 min; Runtime= 6 20 min; Flow rate= 5 ml/min; Wavelength = 220nm; Column= Phenomenex Luna 3.0mm x 50mm S10. Retention Time= 4.43 min, purity 97%.; Flow injection Mass Spectrometry: MS m/z 469(MH). Example 56 25 8 N8 0 NO HO 88 WO 2007/092888 PCT/US2007/061768 13-Cyclohexyl-3-methoxy-6-(1,3-oxazol-2-yl)- 7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid. Methyl 13-cyclohexyl-3-methoxy-6-(1,3 oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate (75.4mg, 0.16mMol) was dissolved in 2mL of THF and potassium trimethylsilanolate (103mg, 0.80mMol) 5 added to the reaction. The reaction was stirred at room temperature under a nitrogen atmosphere for 19hrs. The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The organic phase was washed sequentially with IN aqueous hydrochloric acid and brine, dried over magnesium sulfate and volatiles removed in vacuuo to yield 68mg (93%) of the title product as a yellow solid. 1H 10 NMR (500 MHz, CHLOROFORM-d) 8 ppm 1.18 - 1.33 (1 H, m), 1.36 - 1.45 (2 H, m), 1.58 (1 H, br. s.), 1.79 (2 H, d, J=10.07 Hz), 1.96 (1 H, br. s.), 2.08 (3 H, br. s.), 2.88 (1 H, t, J=12.05 Hz), 3.94 (3 H, s), 4.44 (1 H, br. s.), 6.00 (1 H, br. s.), 7.04 (1 H, d, J=2.75 Hz), 7.09 (1 H, dd, J=8.70, 2.59 Hz), 7.31 (1 H, s), 7.56 (1 H, d, J=8.85 Hz), 7.65 (1 H, s), 7.68 (1 H, s), 7.82 (1 H, dd, J=8.55, 1.22 Hz), 7.90 (1 H, d, J=8.55 15 Hz), 8.54 (1 H, s). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=100; Gradient - 5 min; Runtimc= 6 min; Flow ratc= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm S10. Retention Time= 3.83 min, purity 20 96%.; Flow injection Mass Spectrometry: MS m/z 455(MH+), m/z 453(M-H)-. Example 57 N O0 N N H / N/ O 25 13-Cyclohexyl-N-((dimnethylamino)sulfonyl)-3-methoxy-6-(1,3-oxazol-2-yl) 7H-indolo[2,1-a][2]benzazepine-10-carboxamide. 13-Cyclohexyl-3-methoxy-6-(1,3 89 WO 2007/092888 PCT/US2007/061768 oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (63mg,0.14mMol) was dissolved in 1.7mL of THF and carbonyldiimidazole (3 1mg, 0.19mMol) added. The reaction was stirred under a nitrogen atmosphere at room temperature for 1 hr then heated to reflux for lhr. The reaction was cooled under nitrogen atmosphere 5 and dimethylsulfamide (91mg, 0.73mMol) added followed by DBU (23uL, 0.15mMol). The reaction was heated to 50C under a nitrogen atmosphere for 4hrs, cooled under nitrogen and stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and 1N aqueous hydrochloric acid. The organic phase washed with brine, dried over magnesium sulfate and volatiles removed in 10 vacuuo to yield 103mg of a crude product as an amorphous yellow film. The crude product was dissolved in methanol and purified by prep HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software:; %A= 10% methanol, 90% water, 0.1% TFA; %B= 90% methanol, 10% water, 0.1% TFA; Initial %B= 50; Final % B=100; Gradient - 15min; Runtime=25min; Flow rate= 15 25ml/min; Column= Waters Sunfire 19mm x 100mm; Peak collection= 12.16min to 12.96min. 1H NMR (500 MHz, CHLOROFORAM-d) 8 ppm 1.23 (1 H, br. s.), 1.36 1.45 (2 H, m), 1.56 (1 H, br. s.), 1.78 (2 H, d, J=10.07 Hz), 2.00 (2 H, br. s.), 2.07 (2 H, br. s.), 2.78 - 2.91 (1 H, m), 3.09 (6 H, s), 3.94 (3 H, s), 4.43 (1 H, br. s.), 5.91 (1 H, br. s.), 7.03 (1 H, d, .J=2.44 Hz), 7.10 (1 H, dd, .J=8.55, 2.75 Hz), 7.50 (1 H, d, 20 .J=1.53 Hz), 7.55 (1 H, d, J=8.55 Hz), 7.65 (1 H, s), 7.69 (1 H, s), 7.89 (1 H, d, J=8.55 Hz), 8.24 (1 H, s), 8.81 (1 H, br. s.). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=100; Gradient - 5 min; Runtime= 6 min; Flow rate= 5 25 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm S10. Retention Time= 3.65min, purity 93%; Flow injection Mass Spectrometry: MS m/z 561(MH'), m/z 559(M-H)-. Example 58 30 90 WO 2007/092888 PCT/US2007/061768 N O0 N-S N N H / I 13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(1,3-oxazol-2-yl) 6,7-dihydro-5H-indolo[2, 1-a][2]benzazepine- 10-carboxamide. 13-Cyclohexyl-N 5 ((dimethylamnino)sulfonyl)-3-methoxy-6-(1,3-oxazol-2-yl)-7H-indolo [2,1 a][2]benzazepine-10-carboxamide (45mg, 0.08mMol) was dissolved in 3.8mL of THF and 0.9mL of methanol added. 10% palladium on carbon (13mg) was added and the reaction placed under l atm (balloon) of hydrogen atmosphere and stirred at room temperature for 18hrs. The reaction was filtered through a plug of celite and 10 the celite rinsed using dichloromethane. Removal of volatiles from the filtrate in vacuuo yield 47mg of material which was purified by prep. HPLC under the following conditions: Shimadzu prep. HPLC using Discovery VP software:; %A= 10% methanol, 90% water, 0.1% TFA; %B= 90% methanol, 10% water, 0.1% TFA; Initial %B= 50; Final % B=100; Gradient= 15min; Runtime=20min; Flow rate= 15 25ml/min; Column= Waters Sunfire 19mm x 100mm; Peak collection= 10.09min to 10.88min. Obtained 33.7mg (75%) of the title compound as a colorless solid. 1H NMR (500 MHz, CHLOROFORM-D) 8 ppm 1.20 - 1.31 (mn, 1.1 H) 1.31 - 1.52 (inm, 2.1 H) 1.66 (d, J=13.12 Hz, 1.1 H) 1.78 (d, J=9.16 Hz, 2.0 H) 1.93 (d, J=13.12 Hz, 1.1 H) 1.96 - 2.09 (mn, 2.9 H) 2.82 - 2.98 (mn, 2.2 H) 3.03 - 3.08 (mn, 6.0 H) 3.11 - 3.19 20 (min, 1.0 H) 3.73 - 3.81 (mn, 1.0 H) 3.84 (s, 1.3 H) 3.90 (s, 1.8 H) 3.97 - 4.02 (in, 0.9 H) 4.05 (dd, J=14.95, 5.80 Hz, 0.7 H) 4.75 - 4.85 (m, 0.4 H) 4.90 (d, J=14.95 Hz, 0.6 H) 6.84 (d, J=2.44 Hz, 0.4 H) 6.94 (dd, J=8.55, 2.44 Hz, 0.5 H) 6.97 - 7.01 (mn, 1.2 H) 7.09 - 7.17 (mn, 1.0 H) 7.32 - 7.49 (mn, 2.0 H) 7.64 (s, 0.6 H) 7.69 (s, 0.4 H) 7.78 7.87 (in, 1.2 H) 7.90 (d, J=8.55 Hz, 0.4 H) 8.02 (s, 0.4 H) 8.42 (s, 0.5 H) 8.59 (s, 0.4 25 H). HPLC analysis: Shimadzu Analytical HPLC using Discovery VP software: %A= 10% methanol, 90% water, 0.1% trifluoroacetic acid; %B= 90% methanol, 10% water, 0.1% trifluoroacetic acid; Initial %B= 50; Final % B=100; Gradient- 5 91 WO 2007/092888 PCT/US2007/061768 min; Runtime= 6 min; Flow rate= 5 ml/min; Wavelength= 220nm; Column= Phenomenex Luna 3.0mm x 50mm S10. Retention Time= 3.02min, purity 99%; Flow injection Mass Spectrometry: MS m/z 563(MH ), m/z 561 (M-H)-. 5 92

权利要求:
Claims (5)
[1] 2. A compound of claim 1 where R 1 is CONRR 7 ; Ri is S0 2 R 8 ; and R 7 is hydrogen. 20 3. A compound of claim 1 where R 3 is cyclohexyl.
[2] 4. A compound of claim 1 where R 4 is hydrogen.
[3] 5. A compound of claim 1 where R 4 is methoxy. 25
[4] 6. A compound of claim 1 selected from the group consisting of
[5] 13-cyclohcxyl-6-(1 H-tctrazol-5-yl)-7H-indolo[2,1-a][2]bcnzazcpinc-10-carboxylic acid, methyl ester; 30 13-cyclohexyl-6-(2-ethyl-2H-tetrazol-5-yl)-5H-indolo[2,1-a][2]benzazepine-10 carboxylic acid; 94 WO 2007/092888 PCT/US2007/061768 13-cyclohexyl-6-(2-ethyl-2H-tetrazol-5-yl)-7H-indolo[2,1-a] [2]benzazepine- 10 carboxylic acid; 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[2-ethyl]-2H-tetrazol-5-yl]-7H 5 indolo [2,1-a] [2]benzazepine- 10-carboxamide; 13-cyclohexyl-6-[2-(2-hydroxyethyl)-2H-tetrazol-5-yl]-7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid; 10 13-cyclohexyl-6-[2-(cyclopropylmethyl)-2H-tetrazol-5-yl]-7H-indolo[2,1 a][2]bcnzazcpinc-10-carboxylic acid; and 13-cyclohexyl-6-[2-(cyclopropylmethyl)-2H-tetrazol-5-yl]-5H-indolo[2,1 a][2]benzazepine-10-carboxylic acid; 15 13-cyclob exyl-6-[2-[(tetrahydro-2-furanyl)methyl]-2H-tetrazol-5-yl]-5H-indolo[2,1 a][2]benzazepine-10-carboxylic acid; 13-cyclohexyl-6-[2-[(tetrahydro-2-furanyl)methyl]-2H-tetrazol-5-yl]-7H-indolo[2,1 20 a][2]benzazepine-10-carboxylic acid; 13-cyclohexyl-6-[1-[(tetrahydro-2-furanyl)methyl]- 1H-tetrazol-5-yl]-7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid; 25 13-cyclohexyl-6-[2-[(tetrahydro-2H-pyran-4-yl)methyl]-2H-tetrazol-5-yl]-7H indolo [2,1-a] [2]benzazepine- 10-carboxylic acid; 13-cyclohcxyl-6-[2-[(tctrahydro-2H-pyran-4-yl)mcthyl]-2H-tctrazol-5-yl]-5H indolo[2,1-a][2]benzazepine-10-carboxylic acid; 30 13-cyclohexyl-6-[1-[(tetrahydro-2H-pyran-4-yl)methyl]-l1H-tetrazol-5-yl]-7H indolo [2,1-a] [2]benzazepine- 10-carboxylic acid; 95 WO 2007/092888 PCT/US2007/061768 13-cyclohexyl-6-[ 1-[(tetrahydro-2H-pyran-4-yl)methyl]- 1H-tetrazol-5-yl]-5H indolo[2,1-a][2]benzazepine-10-carboxylic acid; 1 3 -cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[2-[(tetrahydro-2H-pyran-4 5 yl)methyl]-2H-tetrazol-5-yl]-7H-indolo[2,1-a][2]benzazepine-10-carboxamide; 13-cyclohexyl-3-methoxy-6-[2-[(tetrahydro-2H-pyran-4-yl)methyl]-2H-tetrazol-5 yl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid; 10 1 3 -cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[2-[(tetrahydro-2H-pyran 4-yl)mcthyl]-2H-tctrazol-5-yl]-7H-indolo[2,1-a][2]bcnzazcpine-10-carboxamide; 13-cyclohexyl-6-(4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl)-7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid, methyl ester; 15 13-cycloh exyl-6-(4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl)-7H-indolo[2, 1 a][2]benzazepine-10-carboxylic acid; 13-cyclohexyl-6-[4,5-dihydro-5-oxo-4-[(tetrahydro-2H-pyran-4-yl)methyl]-1,3,4 20 oxadiazol-2-yl]-7H-indolo[2,1 -a][2]benzazepine-I 0-carboxylic acid, methyl ester; 13-cyclohexyl-6-[4,5-dihydro-5-oxo-4-[(tetrahydro-2H-pyran-4-yl)methyl]-1,3,4 oxadiazol-2-yl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid; 25 13-cyclohexyl-6-[3-[(tetrahydro-2H-pyran-4-yl)methyl]- 1H-1,2,4-triazol-5-yl]-7H indolo[2,1-a][2]benzazepine-10-carboxylic acid; 1 3-cyclohcxyl-6-(3-methyl-1,2 ,4-oxadiazol-5-yl)-7H-indolo[2, 1-a][2]bcnzazepinc 10-carboxylic acid, methyl ester; 30 13-cyclohexyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-7H-indolo[2,1-a][2]benzazepine 10-carboxylic acid; 96 WO 2007/092888 PCT/US2007/061768 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-(3-methyl-1,2,4-oxadiazol-5-yl)-7H indolo [2,1-a] [2]benzazepine- 10-carboxamide; 13-cyclohexyl-6-[3-[(methylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl]-7H-indolo[2,1 5 a][2]benzazepine-10-carboxylic acid, methyl ester; 1 3-cyclohexyl-6-[3-[(methylsulfonyl)methyl]-1 ,2,4-oxadiazol-5-yl]-7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid; 10 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[3-[(methylsulfonyl)methyl]-1,2,4 oxadiazol-5-yl]-7H-indolo[2,1-a][2]bcnzazcpinc-10-carboxamidc; 6-(5-amino- 1,3,4-oxadiazol-2-yl)-13-cyclohexyl-7H-indolo[2,1 -a] [2]benzazepine- 10 carboxylic acid, methyl ester; 15 6-(5-amino-1,3,4-oxadiazol-2-yl)-1 3-cyclohexyl-7H-indolo[2,1 -a][2]benzazepine- 10 carboxylic acid; 6-[5-[(bromoacetyl)amino]-1,3,4-oxadiazol-2-yl]-13-cyclohexyl-7H-indolo[2,1 20 a][2]benzazepine-1 0-carboxylic acid, methyl ester; 13-cyclohexyl-6-[5-[(4-morpholinylacetyl)amino]-1,3,4-oxadiazol-2-yl]-7H indolo[2,1-a][2]benzazepine-10-carboxylic acid, methyl ester; 25 13-cyclohexyl-6-[5-[(4-morpholinylacetyl)amino]-1,3,4-oxadiazol-2-yl]-7H indolo [2,1-a] [2]benzazepine- 10-carboxylic acid; 13-cyclohcxyl-6-[5-(3-methoxy-3-oxopropyl)-2-oxazolyl]-7H-indolo[2, 1 a][2]benzazepine-10-carboxylic acid, methyl ester; 30 13-cyclohexyl-6-[5-[3-(4-morpholinyl)-3-oxopropyl]-2-oxazolyl]-7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid, methyl ester; 97 WO 2007/092888 PCT/US2007/061768 13-cyclohexyl-6-[5-[3-(4-morpholinyl)-3-oxopropyl]-2-oxazolyl]-7H-indolo[2,1 a][2]benzazepine-10-carboxylic acid; 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[5-[3-(4-morpholinyl)-3-oxopropyl] 5 2-oxazolyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxamide; 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6,7-dihydro-6-[5-[3-(4-morpholinyl)-3 oxopropyl]-2-oxazolyl]-5H-indolo[2,1-a][2]benzazepine-10-carboxamide; 10 13-cyclohexyl-6-[5-[(tetrahydro-2H-pyran-4-yl)methyl]-1,3,4-oxadiazol-2-yl]-7H indolo [2,1-a] [2]bcnzazcpinc- 10-carboxylic acid, methyl estcr; 1 3-cyclohexyl-6-[5-[(tetrahydro-2H-pyran-4-yl)methyl]-IH- 1,2,4-triazol-3-yi]-7H indolo [2,1-a] [2]benzazepine- 10-carboxylic acid, methyl ester; 15 13-cyclohexyl-6-[1 -methyl-5-[(tetrahydro-2H-pyran-4-yl)methyl]- 1 H-1,2,4-triazol-3 yl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid, methyl ester; 1 3-cyclohexyl-6-[l-methyl-5-[(tetrahydro-2H-pyran-4-yl)methyl]- 1H-i ,2,4-triazol-3 20 yl]-7H-indolo[2,1 -a] [2]benzazepine-10-carboxylic acid; 13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[ 1-methyl-5-[(tetrahydro-2H-pyran-4 yl)methyl]-IH-i ,2,4-triazol-3-yl]-7H-indolo[2,1-a][2]benzazepine- 10-carboxamide; 25 13-cyclohexyl-6-[5-[(tetrahydro-2H-pyran-4-yl)methyl]-1,3,4-oxadiazol-2-yl]-7H indolo[2,1-a][2]benzazepine-10-carboxylic acid; 13-Cyclohcxyl-6-(furan-3-yl)-7H-indolo {2,1-a][2]bcnzazepine-10-carboxylic Acid; 30 Methyl 13-cyclohexyl-3-methoxy-6-(5-(3-methoxy-3-oxopropyl)-1,3-oxazol-2-yl) 7H-indolo[2,1-a][2]benzazepine-10-carboxylate; 98 WO 2007/092888 PCT/US2007/061768 3-(2-(13-Cyclohexyl-3-methoxy-10-(methoxycarbonyl)-7H-indolo[2,1 a][2]benzazepin-6-yl)-1,3-oxazol-5-yl)propanoic acid; Methyl 13-cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol 5 2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate; Methyl 13-cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol 2-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate; 10 1 3 -Cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)- 1,3-oxazol-2-yl) 6,7-dihydro-5H-indolo[2,1-a][2]bcnzazcpinc-10-carboxylic acid; 13-Cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol-2-yl) 6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid. (Peakl- Chiral 15 Isomer A); 13-Cyclohexyl-3-methoxy-6-(5-(3-(4-morpholinyl)-3-oxopropyl)-1,3-oxazol-2-yl) 6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (Peak2- Chiral Isomer B); 20 13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(5-(3-(4-morpholinyl)-3 oxopropyl)-1,3-oxazol-2-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10 carboxamide (Isomer B); 25 1 3 -cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(5-(3-(4-morpholinyl)-3 oxopropyl)-1,3-oxazol-2-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10 carboxamide (Isomer A); Methyl 13-cyclohexyl-3-methoxy-6-(1,3-oxazol-2-yl)-7H-indolo[2,1 30 a] [2]benzazepine- 10-carboxylate; 13-Cyclohexyl-3-methoxy-6-(1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10 carboxylic acid; 99 WO 2007/092888 PCT/US2007/061768 13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(1,3-oxazol-2-yl)-7H indolo[2,1-a][2]benzazepine-10-carboxamide; and 5 13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(1,3-oxazol-2-yl)-6,7 dihydro-5H-indolo[2,1 -a][2]benzazepine- 10-carboxamide; or a pharmaceutically acceptable salt thereof. 10 7. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 8. The composition of claim 7 further comprising at least one additional compound having therapeutic benefits for HCV wherein the compound is selected 15 from the group consisting of interferons, cyclosporins, interleukins, HCV metalloprotease inhibitors, HCV serine protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, HCV NS4B protein inhibitors, HCV entry inhibitors, HCV assembly inhibitors, HCV egress inhibitors, HCV NS5A protein inhibitors, HCV NS5B protein inhibitors, and HCV replicon inhibitors. 20 9. A method of treating hepatitis C infection comprising administering a therapeutically effective amount of a compound of claim 1 to a patient. 10. The method of claim 9 further comprising administering at least one 25 additional compound having therapeutic benefits for HCV wherein the compound is selected from the group consisting of interferons, cyclosporins, interleukins, HCV metalloprotease inhibitors, HCV serine protease inhibitors, HCV polymerase inhibitors, HCV helicase inhibitors, HCV NS4B protein inhibitors, HCV entry inhibitors, HCV assembly inhibitors, HCV egress inhibitors, HCV NS5A protein 30 inhibitors, HCV NS5B protein inhibitors, and HCV replicon inhibitors. 100

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同族专利:

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公开号 | 公开日

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WO2007092888A2|2007-08-16|

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DK1987038T3|2011-01-31|

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PL1987038T3|2011-03-31|

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AU2007211988B2|2012-02-02|

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US20070185083A1|2007-08-09|

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JP5147731B2|2013-02-20|

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AT483712T|2010-10-15|

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CN101379066A|2009-03-04|

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KR20080102161A|2008-11-24|

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EP1987038B1|2010-10-06|

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CY1111423T1|2015-08-05|

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DE602007009646D1|2010-11-18|

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US7456165B2|2008-11-25|

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EP1987038A2|2008-11-05|

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PT1987038E|2010-12-09|

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JP2009526081A|2009-07-16|

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CN101379066B|2011-08-03|

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NO20083513L|2008-10-14|

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WO2007092888A3|2007-10-11|

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SI1987038T1|2011-02-28|

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HRP20100672T1|2011-01-31|

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ES2352574T3|2011-02-21|

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法律状态:
2012-05-31| FGA| Letters patent sealed or granted (standard patent)|

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2016-09-01| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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US77139106P| true| 2006-02-08|2006-02-08||

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US60/771,391||2006-02-08||

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