USOO7749992B2

(12) United States Patent (10) Patent No.: US 7,749,992 B2 Cao et al. (45) Date of Patent: Jul. 6, 2010

(54) COMPOUNDS AND METHODS FOR 5,602,122 A 2/1997 Flynn et al. TREATING DSLPIDEMA 5,622,947 A 4/1997 Ogawa et al. 6,090,824 A 7/2000 Bernstein et al. (75) Inventors: Guoqing Cao, Carmel, IN (US); Ana 6,096,735 A 8 2000 Ogawa et al. Maria Escribano, Alcobendas-Madrid 6,140,343 A 10/2000 DeNinno et al. (ES); Maria Carmen Fernandez, 6,147,089 A 11/2000 DeNinno et al. Alcobendas-Madrid (ES); Todd Fields, 6,147,090 A 11, 2000 DeNinno et al. Indianapolis, IN (US); Douglas Linn 6, 197,786 B1 3/2001 DeNinno et al. Gernert, Indianapolis, IN (US); R R 58: N et al - K - aO a shortly to Troy, NY 6,586.448 B1 7/2003 DeNinno et al. s s 6,689,897 B2 2/2004 Damon et al. NAGA S. (US Nath: Bryan 6,962.931 B2 11/2005 Gumkowski et al. antlo, Brownsburg, N (US); Eva 2002/00725 14 A1 6/2002 Brendel et al. Maria Martin De La Nava, 2002/0103225 A1 8/2002 Curatolo et al. Alcobendas-Madrid (ES); Ana Isabel 2003/0198674 A1 10, 2003 Curatolo et al. Mateo Herranz, Algobendas-Madrid 2004/0082609 A1 4/2004 Ghosh et al. (ES); paniel Ray Mayhugh, Carmel, IN 2004/0204450 A1 10, 2004 Bechle et al. (US); Xiaodong Wang, Carmel, IN (US) 2005/0059810 A1 3, 2005 Maeda et al. (73) Assignee: Eli Lilly and Company, Indianapolis, 2005/0234212 A1 10/2005 Depuydt et al. IN (US) 2006/010O239 A1 5/2006 Nagasaki et al. (*) Notice: Subject to any disclaimer, the term of this 2007/0173526 A1 7, 2007 Bell et al. patent is extended or adjusted under 35 2007/0208003 A1 9, 2007 Bell et al. U.S.C. 154(b) by 994 days 2007/0244095 A1 10, 2007 Chen et al. M YW- 2008/0269284 A1 10, 2008 Escribano et al. (21) Appl. No.: 10/574,649 (22) PCT Filed: Oct. 7, 2004 (86). PCT No.: PCT/US2004/030907 FOREIGN PATENT DOCUMENTS EP 1125929 11, 2000 S371 (c)(1), JP 1997 2214746 A 8, 1997 (2), (4) Date: Mar. 30, 2006 WO WOO1/4019.0 A1 6, 2001 (87) PCT Pub. No.: WO2005/037796 WO WO 2005/033O82 A2 4/2005 WO WO 2005/033O82 A3 4/2005 PCT Pub. Date: Apr. 28, 2005 (65) Prior Publication Data OTHER PUBLICATIONS US 2007/O254869 A1 Nov. 1, 2007 Related U.S. ApplicationO O Data Bisgaier et al. J of Lipid Res. 1993, 34, 1625-1634. Primary Examiner Brenda L. Coleman (60) Eyinal application No. 60/509,736, filed on Oct. (74) Attorney, Agent, or Firm—James B. Myers; Francis O. s Ginah (51) Int. Cl. A6IP3/06 (2006.01) (57) ABSTRACT A6IP 9/10 (2006.01) A6 IK3I/55 (2006.01) CO7D 22.3/4 (2006.01) Compounds of formula I CO7D 22.3/6 (2006.01) CO7D 223/32 (2006.01) 4 CO7D 225/06 (2006.01) R R3 CO7D 403/04 (2006.01) CO7D 403/2 (2006.01) 1N CO7D 405/06 (2006.01) (R)- (CH2) CO7D 405/2 (2006.01) 4NuS (R2) CO7D 413/04 (2006.01) N CO7D 49/04 (2006.01) (CHR) R1 (52) U.S. Cl...... 514/213.01:54.0/593 N1 (58) Field of Classification Search ...... 514/213.01; S lication file f 1 hhi 540,593 whereinn, m, p, q, y, R. R. R. R. R. and Rare as defined ee application file for complete search history. herein and their pharmaceutical compositions and methods of (56) References Cited use are disclosed as useful for treating artherosclerosis and its sequelae. U.S. PATENT DOCUMENTS 5,484,783 A 1/1996 Flynn et al. 14 Claims, No Drawings US 7,749,992 B2 1. 2 COMPOUNDS AND METHODS FOR have relatively low HDL cholesterol, whereas mice and rats TREATING DSLIPIDEMA do not express CETP and carry nearly all their cholesterol in HDL. Further more, transgenic expression of CETP in mice REFERENCE TO RELATED APPLICATIONS results in significantly reduced HDL cholesterol levels and developed severe atherosclerosis compared to control mice This application is submitted as a United States national (K. R. Marotti et al., (1993) Severe atherosclerosis in trans phase entry, pursuant to 35 U.S.C S371, of PCT/US2004/ genic mice expressing simian cholesteryl ester transfer pro 030907, filed on Oct. 7, 2004, which claims the benefit of U.S. tein. Nature: 364, 73-75). Expression of human CETP in provisional patent application Ser. No. 60/509,736, filed Oct. Dahl salt-sensitive hypertensive rats led to spontaneous com 8, 2003, which is incorporated by reference herein. 10 bined hyperlipidemia, coronary heart disease and decreased survival (V. L. M. Herrera et al., (1999) Spontaneous com FIELD OF THE INVENTION bined hyperlipidemia, coronary heart disease and decreased Survival in Dahl salt-sensitive hypertensive rats transgenic for The current invention relates to the fields of medicinal human cholesteryl ester transfer protein. Nature Medicine: 5, organic chemistry, pharmacology, and medicine. Further, the 15 current invention relates to a group of compounds that dem 1383-1389). onstrate utility for treating pathological states due to dyslipi Antibodies either directly injected into the plasma or gen demia erated through vaccine injection can effectively inhibit CETP activity in hamsters and rabbits resulting in elevated HDL BACKGROUND OF THE INVENTION cholesterol (C. W. Rittershaus, (1999) Vaccine-induced anti bodies inhibit CETP activity in vivo and reduce aorticlesions Coronary heart disease (CHD) is one of the major causes of in a rabbit model of atherosclerosis. Furthermore, antibody morbidity and mortality worldwide. Despite attempts to neutralization of CETP in rabbits has been shown to be anti modify risk factors such as obesity, Smoking, lack of exercise, atherogenic (Arterio. Thromb. Vasc, Biol. 20, 2106-2112: G. and treatment of dyslipidemia with dietary modification or 25 F. Evans et. al., (1994) Inhibition of cholesteryl ester transfer drug therapy, CHD remains the most common cause of death protein in normocholesterolemic and hypercholesterolemic in the U.S. Over 50% of all CHD deaths are due to underlying hamsters: effects on HDL Subspecies, quantity, and apolipo atherosclerotic coronary heart disease. protein distribution.J. Lipid Research. 35, 1634-1645). How Dyslipidemia is a major risk factor for CHD. Low plasma ever, antibody and/or vaccine therapy is not currently a viable levels of high density lipoprotein (HDL) cholesterol with 30 option for the treatment of large populations of patients in either normal or elevated levels of low density (LDL) choles need of treatment for dyslipidemia and resultant or associated terol is a significant risk factor for developing atherosclerosis disease state manifestations. and associated coronary artery disease in humans. Indeed, Benzazepines have been reported as useful for certain several studies on lipoprotein profiles of CHD patients have therapeutic purposes. For example, Kondo et all teaches the shown that about 50% of the CHD patients have cholesterol 35 use of certain benzazepines derivatives as potent orally active levels that are considered to be in the normal range (<200 non-peptide arginine vasopressin V2 receptor antagonists, mg/dl). Furthermore, these studies found low HDL choles see Kondo et al., 7-chloro-5-hydroxy-1-2-methylbenzoy terol in about 40% of the normo-cholesterolemic CHD lamino)benzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine patients as compared to the general population reported in the (OPC-41061): A potent, Orally Active Vasopressin Non-pep National Health and Nutrition Examination Survey. Since 40 tide Arginine Vasopressin V2 Receptor Antagonist, Bioor low levels of HDL cholesterol increase the risk of atheroscle ganic and Medicinal Chemistry 7 (1999) 1743-1754. rosis, methods for elevating plasma HDL cholesterol would There have also been several reports of small molecule be therapeutically beneficial for the treatment of cardiovas CETP inhibitors. Barrret et al. (J. Am. Chem. Soc., 188, cular disease including, but not limited to, atherosclerosis, 7863, (1996)) and Kuo et al. (J. Am. Chem. Soc., 117, 10629, CHD, stroke, and peripheral vascular disease. 45 (1995)) describe cyclopropan-containing CETP inhibitors. Cholesterol ester transfer protein (CETP) is a 74KD gly Pietzonka et al. (Biorg. Med. Chem. Lett. 6, 1951 (1996)) coprotein that facilitates the exchange of cholesterol esters in describe phosphanate-containing analogs as CETP inhibi HDL for triglycerides in triglyceride-rich lipoproteins (A. R. tors. Coval et al. (Bioorg. Med. Chem. Lett. 5, 605, (1995)) Tallet. al., (1999) 1999 George Lyman Duss Memorial Lec describe Wiedendiol-A and -B related sesquiterpines as ture: Lipid transfer proteins, HDL metabolism and athero 50 CETP inhibitors. Japanese Patent Application No. genesis. Arterio. Thromb. Vasc. Biol. 20:1185-1188.). The net 10287662-A describes polycyclic, non-amine containing, result of CETP activity is a lowering of HDL cholesterol and polyhydroxylic natural compounds possessing CETP inhibi an increase in LDL cholesterol. This effect on lipoprotein tion properties. Lee et al. (J. Antibiotics, 49, 693-96 (1996)) profile is believed to be proatherogenic, especially in Subjects describe CETP inhibitors derived from an insect fungus. whose lipid profile constitutes an increased risk for CHD. 55 Buschet al. (Lipids, 25, 216-220 (1990)) describe cholesteryl Niacin can significantly increase HDL, but has serious tol acetyl bromide as a CETP inhibitor. Morton and Zilversmit eration issues that reduce compliance. Currently marketed (J. Lipid Res., 35,836-47 (1982)) describe that p-chloromer fibrates and HMG CoA reductase inhibitors raise HDL cho curiphenyl sulfonate, p-hydroxymercuribenzoate and ethyl lesterol only modestly (~10-12%). As a result, there is a mercurithiosalicylate inhibit CETP. Connolly et al. (Bio significant unmet medical need for a well-tolerated agent 60 chem. Biophys. Res. Comm. 223, 42-47 (1996)) describe which can significantly elevate plasma HDL levels, thereby other cysteine modification reagents as CETP inhibitors. Xia reversing or slowing the progression of atherosclerosis. et al. Describe 1,3,5-triazines as CETP inhibitors (Bioorg. CETP is expressed in multiple tissues and secreted into Med. Chem. Lett., 6,919-22 (1996)). Bisgaier et al. (Lipids, plasma, where it associates with HDL (X. C. Jiang et. al., 29, 811-8 (1994) describe 4-phenyl-5-tridecyl-4H-1,2,4-tria (1991) Mammalian adipose tissue and muscle are major 65 Zole-thiol as a CETP inhibitor. Oomura et al. Disclose non sources of lipid transfer protein mRNA. J. Biol. Chem. 266: peptidic tetracyclic and hexacyclic phenols as CETP inhibi 4631-4639). Humans and monkeys, which express CETP. tors in Japanese Patent Application No. 10287662. US 7,749,992 B2 3 4 U.S. Pat. No. 6,586,448 B1 describes 4-caboxamino-2- The above disclosures notwithstanding, a great need substituted-1,2,3,4-tetrahydroquinolines of formula I remains for effective compounds useful to treat and/or pre vent conditions caused by, associated with or exacerbated by dyslipidemia. O 5 SUMMARY OF THE INVENTION R5 R3YN lsOR The present invention provides a compound of formula I 10 R4 R3 1N 15 (R'), H. A B CHz) and prodrugs thereof, and pharmaceutically acceptable salts 4N JS(R) of said compounds and said prodrugs; wherein R. R. R. R. R. R. RandR areas defined therein. Similarly, PCT patent chel N1 RI applications WO 03/063868A1, WO 0017164, No. 0017165, and WO 0017166, discloses variously, formulations, methods of preparation and methods of use of compounds tetrahydro wherein quinoline compounds generally related to that of U.S. Pat. No. 6,586,448 B1 form which it derives or is a divisional n is 0, 1, 2, or 3: m is 0, 1, 2, or 3: application thereof. 25 PCT international application WO 2004/020393 A1 dis p is 1 or 2; closes selective and potent CETP activity inhibiting dibenzy q is 0, 1, 2, or 3; lamine compounds represented by the general formula 1 Y is a bond, C=O, or S(O), whereint is 0, 1, or 2: R" is selected from a group consisting of hydroxy, C-C, 30 alkyl, aryl, C-C alkenyl, C-C haloalkyl, C-C alkyl heterocyclic, C-C cycloalkyl, C-C alkylcycloalkyl: C-C alkylaryl, heterocyclyl, C-C alkylalcohol, C-C, alkoxy, aryloxy, —OC-C alkenyl, —OC-Chaloalkyl, —OC-C alkylheterocyclic, —OCs-Cs cycloalkyl, 35 —OC-C alkylcycloalkyl, - NR'R'' and—OC-C alky N laryl, -O-heterocyclic, and —OC-C alkylheterocyclic; provided that R' is not hydroxy when Y is S(O), CO or whennandy are both Zero; and wherein each of cycloalkyl, aryland heterocyclic group is optionally Substituted with 1 40 to 3-groups independently selected from oxo, hydroxy, halo, C-C alkyl, C-C alkene, C-C alkynyl, C-C, alkoxy, C-Chaloalkyl, C-C alkylalcohol, CONR'R'', NR''SOR, NR''COR2, C-C, alkylNR'R'', C-C, alkylCOR'', Co-Co alkylCOOR'', cyano, C-C alkylcy 45 cloalkyl, phenyl, —OC-C alkylcycloalkyl, —OC-C, Wherein R' and Reach is optionally halogenated Calkyl, alkylaryl, —OC-C alkylheterocyclic, and C-C alky etc.; and R. R. and Reach is a hydrogen, halogeno, etc., laryl; provided that R and R may form an optionally substituted R is bound only to carbon atoms and is a group indepen homocycle or heterocycle in cooperation with the carbon dently selected from hydrogen, hydroxy, halo, C-C alkyl, atoms bonded thereto; A is N(R)(R), etc.; ring B is arylor 50 C-C alkene, C-C alkynyl, C-C alkoxy, C-C, a heterocyclic residue; R is hydrogen, halogeno, nitro, C. haloalkyl, CONR'R'', NRSOR, NR''COR'?, C-C, alkyl, etc.; and n is an integer of 1 to 3); a prodrug of the alkylNR'R'', C-C alkylCOR'', C-C alkylCOOR'', compound; or a pharmaceutically acceptable salt of either. cyano, nitro, Co-C alkylcycloalkyl, phenyl, and Co-C European Patent Application No. 818448 by Schmidt et al. alkylaryl heterocyclyl, C-C cycloalkyl, and C-C, describes tetrahydroquinoline derivatives as cholesteryl ester 55 haloalkyl: transfer protein inhibitors. European Patent Application No. 818197, Schmek et al. describe pyridines with fused hetero R is hydrogen; cycles as cholesteryl ester transfer protein inhibitors. Brandes R" is a group represented by the formula—NR'R'': et al. in German Patent Application No. 19627430 describe R is selected from a group consisting of hydrogen, hydroxy, bicyclic condensed pyridine derivatives as cholesteryl ester 60 halogen, C-C haloalkyl, C-C cycloalkyl, C-C alky transfer protein inhibitors. In U.S. Pat. No. 6,207,671 laryl, C-C alkylheterocyclic, aryl, heterocyclic, cyano, Schmidt et al. describe substituted pyridine compounds as nitro, C-C alkyl, C-C alkenyl C-C alkoxy, aryloxy, CETP inhibitors. In WO Patent Application No. 09839299, —OC-C alkenyl, - OC-C haloalkyl, -Co-C and WO Patent application No. 03028727 by Muller-gli alkylNR'R''. Co-CalkylCOR7, C-C alkylCOR7, Co-C emann et al. and Erfinder/Anmelder respectively, describe 65 alkylCONR7R, CONR'SOR', NR'SOR, NR7COR, quinoline derivatives as cholesteryl ester transfer protein N–CR7R, OCONR7R, S(O).R7, SONR7R, C-C, inhibitors. alkylalcohol, US 7,749,992 B2 5 6 —OC-C alkylheterocyclic, and —OC-C alkylaryl oms selected from oxygen, nitrogen or Sulfur and is option wherein each of the alkyl, cycloalkyl, aryland heterocyclic ally substituted with oxo, C-C alkyl, COR', and SOR: groups is optionally Substituted by oxo, alkyloxy, aryloxy; or a pharmaceutically acceptable salt, Solvate, enantiomer, and wherein any two R groups may combine to form an racemate, diastereomer or mixture of diastereomers thereof. optionally substituted 5-7 member carbocyclic or hetero The present invention also provides a method for modulat cyclic, Saturated or unsaturated ring fused with the A-ring ing CETP activity comprising the use of a compound of to which they are attached; formula I or a pharmaceutically acceptable salt, Solvate, enan R is independently selected from a group consisting of tiomer, racemate, diastereomer or mixture of diastereomers hydrogen, C-C alkyl, C-C alkenyl, hydroxy, COR". thereof, for the treatment, prevention or amelioration of C-C alkoxy, aryloxy, —OC-C alkenyl, —OC-C, 10 CETP mediated diseases. haloalkyl, C-C alkylNR'R'', C.-Cs cycloalkyl, hetero The present invention provides a method for treating or cyclic, aryl, and C-C alkylcycloalkyl: preventing dyslipidemia comprising administering a com each R" is independently selected from a group consisting of pound of formula I, pharmaceutically acceptable salt, Solvate, hydrogen, C-C alkyl, C-C alkenyl, C-C alkynyl, enantiomer, racemate, diastereomer, mixture of diastere —OC-C alkyl, C-C haloalkyl, —O-aryl, —OC-Cs 15 omers, or prodrug thereof, to a patient in need thereof. cycloalkyl, -O-heterocyclic, NR'R''. —C-C alky The present invention provides a method for treating or lcycloalkyl, —OC-C alkylcycloalkyl, —OC-C alkyl preventing Cardiovascular Disease including CHD and the heterocyclic, C-C alkylheterocyclic. —O C-C alky sequela thereof, comprising administering a compound of laryl, C-C cycloalkyl, heterocyclic, aryl, and C-C, formula I, pharmaceutically acceptable salt, Solvate, enanti alkylaryl, wherein each alkyl, cycloalkyl, heterocyclic or omer, racemate, diastereomer, mixture of diastereomers, or aryl group is optionally Substituted with 1-3 groups inde prodrug thereof, to a patient in need thereof. pendently selected from hydroxy, halogen, oxo, C-C, alkyl, C-C alkoxy, SOR', SO2NR11R12, C-C, The present invention provides a method for treating and/ alkylSONR'R'', COOR'', C-C haloalkyl, and or preventing artherosclerosis comprising administering a 25 compound of formula I, pharmaceutically acceptable salt, NR'R'', or R'' and R' combine to form a nitrogen con Solvate, enantiomer, racemate diastereomer, mixture of dias taining heterocyclic ring having 0, 1, or 2 additional het tereomers, or prodrug thereof, to a patient in need thereof. eroatoms selected from oxygen, nitrogen and Sulfur and The present invention provides a method for treating and/ wherein the nitrogen-containing heterocycle is optionally or preventing diseases related to abnormal CETP activity substituted with oxo, or C-C alkyl: 30 comprising administering a compound of formula I, pharma each R is independently selected from a group consisting of ceutically acceptable salt, Solvate, enantiomer, racemate dias hydrogen, C-C alkyl, C-C alkenyl, C-C alkynyl, —O tereomer, mixture of diastereomers, or prodrug thereof, to a C-C alkyl, C-C haloalkyl, -O-aryl, —OC-Cs patient in need thereof. cycloalkyl, -O-heterocyclic, NR'R''. —C-C alky The present invention provides a methodofraising the ratio lcycloalkyl, —OC-C alkylcycloalkyl, —OC-C alkyl 35 of plasma HDL-cholesterol to plasma LDL-cholesterol in a heterocyclic, C-C alkylheterocyclic. —O C-C alky mammal comprising administering a therapeutically effec laryl, C-C cycloalkyl, heterocyclic, aryl, and C-C, tive dose of a compound of formula I, pharmaceutically alkylaryl, wherein each alkyl, cycloalkyl, heterocyclic or acceptable salt, Solvate, enantiomer, racemate, diastereomer, aryl group is optionally Substituted with 1-3 groups inde mixture of diastereomers, or prodrug thereof, to a patient in pendently selected from hydroxy, halogen, C-C alkyl, 40 need thereof. C-C alkoxy, C-C haloalkyl, and NR'R'', or R'' and The present invention provides a method of raising the R" combine to form a nitrogen containing heterocyclic level of plasma HDL-cholesterol in a mammal comprising ring having 0, 1, or 2 additional heteroatoms selected from administering a therapeutically effective dose of a compound oxygen, nitrogen and Sulfur and wherein the nitrogen of formula I, pharmaceutically acceptable salt, Solvate, enan containing heterocycle is optionally Substituted with oXo, 45 tiomer, racemate, diastereomer, mixture of diastereomers, or or C-C alkyl; prodrug thereof, to a patient in need thereof. R is COR7 or S(O).R7 wherein R is as defined above: The present invention provides a method of lowering the R" is selected from the group consisting of aryl, C-C alky level of plasma LDL-cholesterol in a mammal comprising laryl, C-C alkenylaryl, C-C alkynylaryl, C-C alkyl administering a therapeutically effective dose of a compound heterocyclic, C-C alkenylheterocyclic, C-C alkylcy 50 of formula I, pharmaceutically acceptable salt, Solvate, enan cloalkyl, C-C alkyl-O-C-C alkylaryl, and wherein tiomer, racemate, diastereomer, mixture of diastereomers, or each cycloalkyl, aryl, or heterocyclic group is optionally prodrug thereof, to a patient in need thereof. substituted with 1-3 groups independently selected from The present invention also provides a pharmaceutical com the group consisting of hydroxy, Oxo, —SC-C alkyl, position comprising a compound of formula I or a pharma C-C alkyl, C-C alkenyl, C-C alkynyl, C-C, 55 ceutically acceptable salt, Solvate, enantiomer, racemate, haloalkyl, halogen, C-C alkoxy, aryloxy, C-C alkeny diastereomer or mixture of diastereomers thereof, and a car loxy, C-C haloalkoxyalkyl, Co-C alkylNR'R'', rier. —OC-C alkylaryl, nitro, cyano, C-C haloalkylalcohol, The present invention also provides a method of treating and C-C alkylalcohol; and/or preventing the pathological sequelae due to low levels R'' and R'' are independently selected from a group consist 60 of plasma HDL and/or high levels of LDL-cholesterol in a ing of hydrogen, C-C alkyl, C-C alkenyl, C-Cs mammal comprising administering an effective dose of a cycloalkyl, heterocyclic, aryl, C-C alkylaryl, wherein compound of formula I, pharmaceutically acceptable salt, each aryl cycloalkyl and heterocyclic group is optionally Solvate, enantiomer, racemate, diastereomer, or mixture of substituted with 1-3 groups independently selected from diastereomers, thereof, to a patient in need thereof. halogen, C-C alkylheterocyclic, and C-C haloalkyl, or 65 The present invention also relates to the use of a compound R'' and R' combine to form a nitrogen containing hetero of formula I for the manufacture of a medicament for treating cyclic ring which may have 0, 1, or 2 additional heteroat and/or preventing atherosclerosis in a mammal comprising US 7,749,992 B2 7 8 administering an effective dose of a compound of formula I, present, and the remaining groups attach directly to the Sub pharmaceutically acceptable salt, Solvate, enantiomer, race strate. The present invention also contemplates that the term mate, diastereomer, mixture of diastereomers, or prodrug C-C alkyl or C-C alkenyl or similar terms also encompass thereof, to a patient in need thereof. the specified alkyl or alkenyl or similar group, which may be The present invention also provides a combination therapy 5 chiral, regio or steroisomeric. Such chiral or regio or stereoi involving a compound of formula I and one or more other Someric groups are also objects of the present invention. cardio protective agents such as for example, statins, leptin, The term alkylaryl refers to an alkyl group substituted by and/or other LXR, CETP, ABC A1 or lipid regulating agents an aryl group. For example, C-C alkylaryl indicates that a useful for the treatment and/or prevention of atherosclerosis. C-C alkyl group is attached to the aryl group, and that the 10 resulting C-C alkylaryl is attached to the nucleus via the DETAILED DESCRIPTION OF THE INVENTION alkyl group. A most preferred alkylaryl group is benzyl. The term “substituted phenyl' or “optionally substituted The current invention provides novel compounds of for phenyl refers to a phenyl group having one or more substitu mula I useful in modulating CETP activity. ents selected from the group consisting of C-C alkyl, C-C, The term "modulation' would include, but not be limited 15 alkoxy, hydroxy, COOR', Co-C alkylNR'R'', nitro, to, up-regulation, down-regulation, inhibition, agonism, chloro, fluoro, bromo, iodo, C-Chaloalkyl, C-C, antagonism of the CETP receptor as appropriate to achieve haloalkoxyalkyl, Co-C alkylheterocyclic. HDL raising, or LDL lowering and the resulting biological The term “optionally substituted as used herein unless sequelae from Such intervention. otherwise specified means that the Subject group may be The phrase “diseases” or “diseases related to CETP modu Substituted with one or more fragments or groups selected lation” or “diseases mediated by CETP activity” refers to from C-C alkyl, C-C alkoxy, hydroxy, COR. -COOR, pathological states where atherosclerosis and cardiovascular Co-CalkylNRR, nitro, oxo, chloro, fluoro, bromo, cyano, diseases are prone because of dyslipidemia and/or other risk C-C cycloalkyl, C-C alkylcycloalkyl, C-C haloalkyl, factors and are therefore beneficially affected by down-regu C-Chaloalkoxyalkyl, heterocyclic, and Co-Co alkylhetero lation (modulation) of CETP activity. The phrase “diseases” 25 cyclic. as used herein also include diseases caused by, exacerbated The term “aryl refers to a substituted or unsubstituted by, or otherwise related to CETP activity. These diseases aromatic or heteroaromatic carbocyclic or heterocyclic radi include but are not limited to hyperlipidemia and its sequelae cal selected from the group consisting of 2-furyl, 3-furyl, such as atherosclerosis, CHD, elevated blood pressure, CHF, 2-thienyl 3-thienyl, 1-pyrrolyl 2-pyrrolyl, 3-pyrrolyl, phe stroke, hypertension, hypertriglyceremia, diabetes, obesity, 30 nyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-naphthyl 2-naphthyl, inflammatory diseases including but not limited to dermatitis, 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl, arthritis, and pain, and diseases of the central nervous system 6-benzofuryl, 7-benzofuryl, 2-benzothieny, 3-benzothienyl, including but not limited to dementia, cognitive disorders 4-benzothienyl, 5-benzothienyl, 6-benzothienyl, 7-ben Such as Alzheimer's disease. Zothienyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-in The term “Cardiovascular Disease' and the sequelathereof 35 dolyl, 6-indolyl and 7-indolyl. As used herein the term aryl as used herein includes atherosclerosis, peripheral vascular also encompasses the benzyl group. disease, dyslipidemia, hyperlipoproteinemai (including The term "C-C cycloalkyl or similar terms refer to a alpha and beta), hypercholesterolemia, cardiovascular disor saturated carbocyclic ring having from 3 to 8 carbon atoms. ders, angina, ischemia, cardiac ischemia, stroke, myocardial The term “carbocycle' as used herein refers to a cyclic infarction, reperfusion injury, angioplastic restenosis, hyper 40 group having only carbon and an appropriate number of tension, vascular complications of diabetes, obesity or endot hydrogen atoms. The term encompasses groups such as oxemia. The use of CETP to treat Cardiovascular Diseases as cycloalkyl, cycloalkene, cycloalkylene, naphthyl, phenyland enumerated above is Supported by disclosures including U.S. the like. Pat. No. 6,140,343. The term “heterocycle”, “heterocyclyl”, or "heterocyclic” The term “treatment' bears its usual meaning which 45 refers to a 5, 6 or 7 member saturated, partially unsaturated, or includes prohibiting, inhibiting, ameliorating, halting, aromatic mono-cyclic or a benzofused bicyclic ring contain restraining, slowing or reversing the progression, or reducing ing 1-5 heteroatoms selected from N, S or O, wherein said the severity of a pathological symptom related to or resultant heterocycle is optionally Substituted at carbon or nitrogen from the modulation of CETP activity, especially as related to atom(s) unless otherwise specified. Most preferred heterocy raising plasma levels of HDL, or lowering LDL-cholesterol 50 clic groups include pyrrolidinyl, piperidinyl, hexamethylene levels or raising the HDL/LDL ratio or controlling athero immino, morpholino, benzthiophene, indolyl, quinolyl, iso Sclerosis, hyperlipidemia and/or hypercholesterolemia. quinolyl, tetrazolyl, and pyridinyl. As a corollary, the term Generally, one of skill in the art is aware that valency must “alkylheterocyclic' or “alkylheterocycle” is understood to be conserved (complete) for all stable molecules. Therefore, mean that the alkyl group is attached to the heterocycle and the necessary implication that hydrogenatoms are necessary 55 the point of attachment to the molecular backbone or nucleus and available to complete valency in all structures including is the alkyl group. formula I unless expressly indicated otherwise, is imputed to The term “haloalkoxyalkyl as used herein include for the general knowledge of one of skill in the art. example trifluoromethoxy, pentafluoroethoxy, trifluoroet General chemical terms used in the description of com hoxy (OCHCF) and the like. Similarly, the term “holaoalkyl pounds herein described bear their usual meanings. For 60 alcohol implies compounds such as CFCH-OH and the example, the term "C. alkyl or “(C-C)alkyl” or "C-C, like. alkyl refers to a straight or branched aliphatic chain of 1 to 6 The term “Prodrugs’ describes derivatives of the com carbon atoms including but not limited to methyl, ethyl, pro pounds of the invention that have chemically or metabolically pyl, iso-propyl. n-butyl, pentyl, and hexyl. Unless otherwise cleavable groups and become by Solvolysis or under physi stated, the term “alkyl means C-C alkyl. Similarly, the 65 ological conditions the compounds of the invention, which term “Co-Co alkyl implies an alkyl group as indicated are pharmaceutically active, in vivo. Derivatives of the com wherein when the term Co applies, the alkyl group is not pounds of this invention have activity in both their acid and US 7,749,992 B2 10 base derivative forms, but the acid derivative form often offers cal isomers or regio-isomers, all of which are objects of the advantages of Solubility, tissue compatibility, or delayed invention. Certain compounds of the invention may possess release in a mammalian organism (see, Bundgard, H., Design one or more chiral centers, and thus, may exist in optically of Prodrugs, pp. 7-9, 21-24. Elsevier, Amsterdam 1985). Pro active forms. Likewise, when the compounds contain an alk drugs include acid derivatives, such as, esters prepared by reaction of the parent acidic compound with a suitable alco enyl or alkenylene group, there exist the possibility of cis- and hol, or amides prepared by reaction of the parent acid com trans-isomeric forms of the compounds. The R- and S-iso pound with a suitable amine. Simple aliphatic esters (e.g., mers and mixtures thereof, including racemic mixtures as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) well as mixtures of enantiomers or cis- and trans-isomers, are or aromatic esters derived from acidic groups pendent on the contemplated by this invention. Additional asymmetric car compounds of this invention are preferred prodrugs. Other 10 bon atoms can be present in a substituent group Such as an preferred esters include morpholinoethyloxy, diethylglycola alkyl group. All Such isomers as well as the mixtures thereof mide and diethylaminocarbonylmethoxy. In some cases it is are intended to be included in the invention. If a particular desirable to prepare double ester type prodrugs such as (acy stereoisomer is desired, it can be prepared by methods well loxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. known in the art by using stereo-specific reactions with start As used herein, the term “protecting group' refers to a 15 group useful for masking reactive sites in a molecule to ing materials that contain the asymmetric centers and are enhance the reactivity of another group or allow reaction at already resolved. Alternatively desired stereoisomers may be another desired site or sites following which the protecting prepared by methods that lead to mixtures of the stereoiso group may be removed. Protecting groups are usually used to mers and Subsequent resolution by known methods. For protect or mask groups including but not limited to —OH, example, a racemic mixture may be reacted with a single —NH, and —COOH. Suitable protecting groups are known enantiomer of Some other compound i.e. a chiral resolving to one of skill in the art and are described in Protecting groups agent. This changes the racemic form into a mixture of Ste in Organic Synthesis, 3' edition, Greene, T. W.; Wuts, P.G.M. reoisomers and diastereomers, because they have different Eds. John Wiley and Sons, New York, 1999. melting points, different boiling points, and different solu As used herein, the term "solvate” is a form of the com 25 bilities and can be separated by conventional means, such as pound of the invention wherein a crystal or crystals of a crystallization. compound of the invention have been formed from a stoichio metric or non-stoichiometric amount of the compound of PREFERRED EMBODIMENTS OF THE formula I and a stoichiometric or non-stoichiometric amount INVENTION of a solvent. Typical Solvating solvents include for example, water, methanol, ethanol, acetone and dimethylformamide. 30 In those instances where a compound of the invention Preferred n, m, p, t and q possesses acidic or basic functional groups, various salts may Preferably n is 0, or 1. More preferably, n is 0. be formed which are more water soluble and/or more physi Preferably m is 0, or 1. ologically suitable than the parent compound. Representative 35 Preferably p is 1, or 2. pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, Sodium, Preferably t is 0, 1 or 2. More preferably t is 1 or 2 potassium, calcium, magnesium, aluminum and the like. Preferably, q is 0, 1 or 2. More preferably q is 1 or 2. Most Salts are conveniently prepared from the free acid by treating preferably, q is 1. the acid in Solution with a base or by exposing the acid to an ion-exchange resin. 40 Preferred R' Included within the definition of pharmaceutically accept A preferredR'groups is selected from the group consisting able salts are the relatively non-toxic, inorganic and organic of aryloxy, —OC-Chaloalkyl, —OC-C alkylcycloalkyl, base or acid addition salts of compounds of the present inven —C-C alkylcycloalkyl, C-C alkylcycloalkylNRR, tion. Base addition salts include for example, ammonium, —OC-C alkylcycloalkylNR'R''. C-C alkoxy, OC-C, quaternary ammonium, and amine cations, derived from 45 alkylaryl, and—OC-C alkylheterocyclic. More preferred is nitrogenous bases of sufficient basicity to form salts with the an R' group selected from C-C alkyl, C-C alkoxy, —OC compounds of this invention (see, for example, S. M. Berge, C alkylaryl, and —OC-C alkylcycloalkylNR'R''. Most et al., “Pharmaceutical Salts.” J. Phar. Sci., 66:1-19 (1977)). preferred is an R' group represented by C-C alkoxy or Moreover, the basic group(s) of the compound of the inven C-C alkylcycloalkyl, or C-C cycloalkyl. tion may be reacted with Suitable organic or inorganic acids to 50 form salts such as acetate, benzenesulfonate, benzoate, bicar Preferred R' bonate, bisulfate, bitartrate, borate, hydrobromide, camsy A preferredR groups is selected from the group consisting late, carbonate, clavulanate, citrate, chloride, edetate, edisy late, estolate, esylate, fluoride, fumarate, gluceptate, of hydrogen, hydroxy, C-C haloalkyl, C-C alkyl, halo, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, C-C alkylhalide, —OC-C alkyl, —OC-C haloalkyl, hydrochloride, hydroxynaphthoate, hydroiodide, isothionate, 55 —OC-Cs alkylcycloalkyl, Co-C alkylNR'R''. —OC-C, lactate, lactobionate, laureate, maleate, mandelate, mesylate, alkylaryl, and—OC-C alkylheterocyclic. More preferred is methylbromide, methylnitrate, methylsulfate, mucate, nap an R group selected from hydroxy, C-C alkyl, halo C-C, Sylate, nitrate, oleate, oxalate, palmitate, pantothenate, phos alkylhalide and C-C alkoxyalkyl. Most preferred is an R phate, polygalacturonate, Salicylate, Stearate. Subacetate. Suc group represented by hydrogen or C-C alkyl. cinate, tannate, tartrate, tosylate, trifluoroacetate, 60 trifluoromethane sulfonate, and Valerate. Preferred salts for Preferred R' the purpose of the invention include the hydrochloride salt, R is hydrogen. the hydrobromide salt, the bisulfate salt, the methane sulfonic acid salt, the p-toluenesulfonic acid salt, bitartrate, the acetate Preferred R' and the citrate salt. 65 Preferred R is the group - NR'R''. The group - NR'R'' A compound of the invention as illustrated by formula I is preferably represented by a group selected from the group may occur as any one of its positional isomers, Stereochemi consisting of: US 7,749,992 B2 12 aryl, C-C haloalkyl, C-C alkoxy, aryloxy, —OC-C alk enyl, OC-C haloalkyl, —CHNRR, NH, —CN, OCF OCF -COOH, benzyl, and NO; Preferred R' R is at each occurrence independently selected preferably from a group consisting of hydrogen, C-C alkyl, and C-C, alkoxy, C-C cycloalkyl, C-C alkylaryl, C-C alkylhet erocyclic, and aryloxy. F A. N C. F A N o 10 Preferred R7 ?' X- R7 ?' X- R7 Preferred R is a group selected from the group consisting O O of C-C alkyl, C-C alkenyl, C-C alkylaryl, C-C alkyl OCF CF cycloalkyl, C-C cycloalkyl, phenyl, heterocyclic, and C-Calkylheterocyclic, OC-C alkyl, OC-C alkenyl, 15 OC-C alkylaryl, Oaryl, C-C alkylcycloalkyl, Oheterocy clic, and OC-Calkylheterocyclic wherein each aryl or het erocyclic group is optionally substituted with 1-3 groups independently selected from C-C alkyl, halo, and C-C, A ClCN, haloalkyl. More preferably, R is selected from the group consisting of C-C alkyl, C-C alkenyl, C-C alkylaryl, and phenyl. Preferred R' CN Preferred R is a group selected from the group consisting 25 of C-C alkyl, C-C alkenyl, C-C alkylaryl, phenyl, het erocyclic, and C-Calkylheterocyclic, wherein each aryl or heterocyclic group is optionally Substituted with 1-3 groups / CF3, independently selected from C-C alkyl, halo, and C-C, v-N haloalkyl. More preferably, R is selected from the group 30 consisting of C-C alkyl, C-C alkenyl, C-C alkylaryl, and w R7 R7 phenyl. O O Preferred R' C A preferred R is the group COR7 wherein R is selected from the group consisting of C-C alkyl, C-C alkenyl, 35 C-C alkylaryl, C-C alkylcycloalkyl, C-C cycloalkyl, phenyl, heterocyclic, and C-Calkylheterocyclic, OC-C, alkyl, OC-C alkenyl, OC-C alkylaryl, Oaryl, C-C alky / Cl, lcycloalkyl, Oheterocyclic, and OC-Calkylheterocyclic N wherein each aryl or heterocyclic group is optionally Substi Ny 40 A. tuted with 1-3 groups independently selected from C-C, A. O F O alkyl, halo, and C-C haloalkyl. CF Preferred R' R" is preferably the group optionally substituted aryl, 21 21 NN 45 alkylaryl, heterocyclic oralkylheterocyclic. More preferred is an optionally Substituted aryl or alkylaryl. N N CF, , N CF, Preferred R'' and R'? F N w N Preferred R'' and R'' are independently selected from a group consisting of C-C alkyl, C-C alkenyl, C-C alky 50 laryl, and C-Calkylheterocyclic, wherein each aryl group is OX-R OX-R optionally substituted with 1-3 groups independently CF3 CF3 selected from C-C alkyl, halo, and C-C haloalkyl. A preferred compound of the invention is a compound selected from the group consisting of: N1 N 55 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7-trif 2 ? luoromethyl-2,3,4,5-tetrahydro-benzoblazepine-1-car N CF, ? CF boxylic acid isopropyl ester, R N. ' F ? A- N / 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl Ny F S-R7 60 amino-7-trifluoromethyl-2,3,4,5-tetrahydro-benzob. ? / aZepine-1-carboxylic acid isopropyl ester, O A. 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl amino-7-trifluoromethyl-2,3,4,5-tetrahydro-benzob. aZepine-1-carboxylic acid ethyl ester, Preferred R 65 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7-trif R is preferably selected from a group consisting of hydro luoromethyl-2,3,4,5-tetrahydro-benzoblazepine-1-car gen, hydroxy, C-C alkyl, C-C alkenyl, halo, heterocylic, boxylic acid ethyl ester, US 7,749,992 B2 13 14 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-2,3,4,5- by procedures which are selected from standard techniques of tetrahydro-benzoblazepine-1-carboxylic acid isopropyl organic and heterocyclic chemistry, techniques which are ester, analogous to the syntheses of known structurally similar 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl intermediates, and in the procedures described in the prepa amino-2,3,4,5-tetrahydro-benzoblazepine-1-carboxylic 5 rations and examples below, including any novel procedures. acid isopropyl ester, This includes, but is not limited to, esterification of a carboxy 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl lic acid, hydrolysis of a nitrile to a carboxylic acid, and amino-7-bromo-2,3,4,5-tetrahydro-benzoblazepine-1- Subsequent esterification. In addition, one of ordinary skill in carboxylic acid isopropyl ester, the art will appreciate that many of the necessary reagents or 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl 10 starting materials can be readily obtained from commercial amino-7-bromo-2,3,4,5-tetrahydro-benzoblazepine-1- suppliers. The R, R1,R2, R3, R4, R5, R6, etc, used within this carboxylic acid ethyl ester, section for the purpose of illustrating the various methods of 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7- synthesizing compounds of the invention are not necessarily bromo-2,3,4,5-tetrahydro-benzoblazepine-1-carboxylic synonymous in scope or meaning with similar groups used in acid ethyl ester, 15 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7-meth the generic structure for compounds of formula I. However, oxy-2,3,4,5-tetrahydro-benzoblazepine-1-carboxylic groups in similar positions for final compounds (compounds acid ethyl ester, of the invention) of the schemes are co-extensive in scope and 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-8-trif meaning compared to groups occupying similar positions as luoromethyl-2,3,4,5-tetrahydro-benzoblazepine-1-car defined for the generic structure of compounds of formula I. boxylic acid isopropyl ester, Intermedaite compounds of formula 1 or 4 useful for pre 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-8- paring compounds of the invention may be prepared as shown fluoro-7-trifluoromethyl-2,3,4,5-tetrahydro-benzob. in Scheme 1. aZepine-1-carboxylic acid isopropyl ester, 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-2-me 25 thyl-7-trifluoromethyl-2,3,4,5-tetrahydro-benzob. Scheme 1 aZepine-1-carboxylic acid isopropyl ester, 1 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-4,4-dim O R1 ethyl-7-trifluoromethyl-2,3,4,5-tetrahydro-benzob. R3 aZepine-1-carboxylic acid isopropyl ester, 30 6-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-8-trif C N o1 luoromethyl-3,4,5,6-tetrahydro-2H-benzoblazocine-1- yea N1 R4 carboxylic acid isopropyl ester, R2 6-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-9-trif R5 luoromethyl-3,4,5,6-tetrahydro-2H-benzoblazocine-1- 35 R1 carboxylic acid isopropyl ester, X N R6 R5 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-9-trif luoromethyl-3,4,5,6-tetrahydro-2H-benzoblazocine-1- A. 21 F R41 NH carboxylic acid isopropyl ester, R2 4-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7-trif 40 luoromethyl-2,3,4,5-tetrahydro-benzoblazepine-1-car 2 3 boxylic acid isopropyl ester, 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-8- chloro-2,3,4,5-tetrahydro-benzoblazepine-1-carboxylic 45 C 2 - R5 acid isopropyl ester, R2C 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl amino-8-chloro-2,3,4,5-tetrahydro-benzoblazepine-1- R4 carboxylic acid isopropyl ester, or a pharmaceutically 4 R6 = CN acceptable salt, Solvate enantiomer or diastereomer or mix 1 R6 = COR3 ture thereof. 50 The geometric isomers associated with the asymmetric carbon atoms of compounds of formula I are also within the According to Scheme 1, the nucleophilic aromatic Substi scope of the current invention as useful for the treatment of tution occurs by methods known in the art, (Wells, K. M. et al. diseases related to CETP modulation. Tetrahedron Letters, 1996, 37(36), 6439-6442). The appro 55 priately substituted amine is dissolved in a suitable solvent, Synthesis of Compounds of the Invention such as DMF or DMSO, with a base, such as cesium carbon ate, and the appropriately substituted fluorobenzoate or ben Intermediates and compounds of the instant invention can Zonitrile (R6=CN or COR3). The reaction proceeds at 0°C. be synthesized as illustrated in the following schemes. to elevated temperatures in anywhere from ten minutes to Anthranilate intermediates of Formula 1 can be chemically 60 several days depending on the stability of the starting mate prepared, for example, by following the synthetic routes set rials. The product of structure 4 (R6=CN) or 1 (R6=COR) forth in the schemes below. However, the following discus can then be isolated by a standard aqueous workup, followed sion is not intended to be limiting to the Scope of the present by normal phase chromatographic methods or recrystalliza invention in any way. The reagents and starting materials are tion techniques commonly employed in the art. readily available commercially or by derivation from other 65 Intermedaite compounds of formula 1 or 4 useful for pre available starting materials to one of ordinary skill in the art. paring compounds of the invention may also be prepared as Other necessary reagents and starting materials may be made shown in Scheme 2. US 7,749,992 B2 15 16 anywhere from ten minutes to several days depending on the stability of the starting materials. The product of structure 1 Scheme 2 may then be isolated by a standard aqueous workup, option R1 ally followed by normal phase chromatographic methods or recrystallization techniques commonly employed in the art. A-4N Ra1‘Sh R2CC. s I. Intermedaite compounds of formula 1 or 4 useful for pre 5 6 10 paring compounds of the invention may also be prepared as shown in Scheme 4.

Scheme 4 15 O 2 R5 CY R1 R1 R4 C N Br C N -R 4 R6 = CN A-4 -Rs A-4 -Rs 1 R6 = COR3 R2 R2

In Scheme 2, the N-Aryl coupling occurs by methods 7 1 known in the art, (Hartwig, J. F. et al. Angew. Chem. Int. Ed. 25 Engl. 1998, 37, 2046-2067). The appropriately substituted In Scheme 4, the aromatic carboxylation occurs by meth amine is dissolved in a suitable solvent, such as DMF, with a ods known in the art, (Boger, D. L. et al., Journal of Organic base. Such as cesium carbonate or sodium tert-butoxide, the Chemistry, 1994, 59(17), 4943-4949, Volpin et al. Orga appropriately Substituted halogenated benzoate or benzoni trile (R6=CN or COR3), and a suitable catalyst complex, 30 nomet. Reactions, 1975, 5,313-386). The appropriately sub Such as palladium acetate and diphenyl phospino ferrocene. stituted aryl bromide is dissolved in a suitable solvent, such as The reaction proceeds at 0° C. to elevated temperatures in diethyl ether or tetrahydrofuran, with an alkyl lithium, such as anywhere from ten minutes to several days depending on the n-butyl lithium or ter-butyl lithium or magnesium turnings. The resulting anion is quenched with a Suitable carbon diox stability of the starting materials. The product of structure 4 35 (R6-CN) or 1 (R6=COR3) canthen be isolated by a standard ide source, such as dry ice, or dimethyl carbonate. The reac aqueous workup, followed by normal phase chromatographic tion proceeds at -78° C. to room temperature in anywhere methods or recrystallization techniques commonly employed from about five minutes to several hours depending on the in the art. stability of the starting materials. The product of structure 1 40 can then be isolated by a standard aqueous workup, followed Intermediate compounds of formula 1 or 4 useful for pre by normal phase chromatographic methods or recrystalliza paring compounds of the invention may also be prepared as tion techniques commonly employed in the art. shown in Scheme 3. 45 Synthetic Scheme 5 shows preparation of the benzazepine Scheme 3 intermediates for compounds of the invention depicted by O Formula 1. R1 R1 50 Scheme 5 2n-R5 2n-R5 R Y-->C - YC COOMe R4 R4 He 55 7 1 CC p-TsCl, pyr. NH RA4 2 In Scheme 3, the carbonylation occurs by methods known 1 R in the art, (Heck, Palladium Reagents in Organic Synthesis: COOMe Academic Press: New York, 1985, p. 348-358). The appro 60 X^n K2CO3, priately substituted aryl bromide is dissolved in a suitable --- Solvent, such as DMF, with a base. Such as cesium carbonate R or sodium tert-butoxide, and a suitable catalyst complex, Such A 2 NHTS --> Br COOEt as palladium acetate and diphenylphospino ferrocene, appro 65 priate alcohol (R3-OH) and saturated with carbon monoxide. 8 9 The reaction proceeds at 0° C. to elevated temperatures in US 7,749,992 B2 17 18

-continued -continued O COOMe x N R t-BuOK, R ~. toluene 5 C N C N COOEt tosyl RA4 N R 10 10 13 COOEt

Xs HCHOAC For example, substituted anthranilic esters 1 that are either 15 commercially available or prepared as set forth in the litera C N ture or in schemes 1-4, can be N-sulfonylated to provide 8. to s' R which in turn may be alkylated with appropriately substi tuted, or unsubstituted 3-bromopropanoic acid esters 9 thus 8 affording 10. Dieckmann condensation/cyclization of inter ' mediate 10 yields N-tosylbenzazepine 11, which is subjected x N to acid hydrolysis and de-carboxylation to give benzodiaz PPA or TMSI epin-5-one derivatives 12. Removal oftosyl group with either acid (e.g. PPA (polyphosphoric acid)) or TMSI (trimethylsi C N 25 lyliodide) provides intermediate benzazepin-5-one 13. tosyl R 12 Benzazepine-5-ones of general structure 13 are converted to compounds of formula I utilizing the steps outlined in Scheme 6.

Scheme 6 O O R RCOCl, base: R O

C N HerRCOH, C N carbodiimide reagent; A. 2 O A. 2 R N RNCO R N R R R O

13 14

1)NHOH, R-NH TA(O-i-PSE NaOAc, O EtOH, H.O. NaCNBH 2) H, Ra-Nior Pd/C

O

Rus N1 HN-R HN R R R * N * N RCHO, NaCNBH; or * N a- se 2 2 R-Br, I, OMs, OTs (LG) 21 A. N A. N NaH, or K2CO3 A. N R R DMF or DMSO R -Q R -Q R -Q R O O O

17 16 15 US 7,749,992 B2 19 20 N-acylation of 13 to afford carbamates of structure 14 is accomplished by treatment with an appropriately substituted -continued R aryl or alkyl chloroformate in the presence of an organic base COOMe Such as pyridine. Alternatively, treatment with an acid chlo Xs R t-BuOK, ride or an appropriate activated ester, Such as those generated toluene in-situ from the reaction of an appropriately substituted aryl A. 21 COOEt Her or alkyl carboxylic acid Generation of urea derivatives from 13 is accomplished by treatment with a carbamoyl chloride in gr the presence of base such as pyridine and DMAP (dimethy tosyl R lamino pyridine) or an alternative base such as NaH in DMF. Alternatively treatment with phosgene, or carbodiimide 10 31 (CDI) reagent such as cyclohexylcarbodiimide or analog O COOEt thereof, followed by the addition of an appropriately di-sub R stituted amine will afford ureas of structure 14. Formation of Xs HCl, HOAC sulfonamide derivatives from 13 can be accomplished by -- reaction with appropriately substituted sulfonyl chlorides in 15 A4 R the presence of base. Conversion of ketone 14 to 17 may be R N performed either through direct reductive amination with an W appropriately substituted alkyl orarylamine to directly afford tosyl R 16, or alternatively through formation of the amine derivate 32 15 by reduction of an intermediate oxime, followed by alky O lation with an appropriately substituted benzylic halide, R mesylate or tosylate, or reductive alkylation with the appro Xs priate aldehyde or ketone in the presence of a reducing PPA or TMSI reagent such as NaCNBH. 16 is converted to 17 (a com He pound of the invention) by acylation with an appropriately A-4 R substituted symmetrical anhydride or acid halides to afford 25 R N amides, or chloroformates to afford carbamates, or isocyan M ates, carbamoyl chlorides, etc. to form ureas, or appropriately tosyl R substituted sulfonyl chlorides to afford sulfonamides. 33 Scheme 7 shows, for example, the synthesis of intermedi O ates used for the preparation of 1-benzazacines of Formula I. 30 R Scheme 7 R C N COOMe A4 R --- R N CC p-TsCl, pyr. M H R RA4 NH2 34 1 R COOMe Xs 40 K2CO3, For example, tosylation of 1 to give 8, followed by alkyla -- R tion with 30 provides 31. Deickmann cyclization (Leonard, et A 41 yr. al.; J. Org. Chem., 1969, 34, 1066) of 31 provides 1-benza Br Zacin-6-one 32, which is further elaborated to 34 after decar COOEt 45 boxylation and tosylate removal. R 1-Benzazacin-6-one compounds of general structure 34 8 30 are converted to compounds of formula I (38) utilizing the steps outlined in Scheme 8. Scheme 8 O R RCOCl, base: * N RCOH,O or X N He carbodiimide reagent; A. 2 R O R ? RNCO H R C. , -( R O

34 35

Ti4(O-i-Pr)4 1)NH2OH, NaBH4 NaOAc, O EtOH, HO NaCNBH4 2) H2, Ra-Nior Pd/C US 7,749,992 B2 21

-continued O R N(, H / N1 NN HN R R R RCHO, NaCNBH; or C N a R-Br, I, OMs, OTs (LG) 2 21 NaH, or K2CO3 A. 2 R A 1-\ ^ A1\ ^ DMF or DMSO R N R-( R R-( R R-( R O O O

38 37 36

N-acylation of 34 to afford carbamates of structure 35 is accomplished by treatment with an appropriately substituted 20 -continued aryl or alkyl chloroformate in the presence of an organic base O Such as pyridine. Alternatively, treatment with an acid chlo 1. O CrO3 ride or an appropriate activated ester, Such as those generated Hess in situ from the reaction of an appropriately substituted aryl or 25 AcOH, H2O alkyl carboxylic acid Generation of urea derivatives from 34 NH is accomplished by treatment with a carbamoyl chloride in the presence of base such as pyridine and DMAP oran alternative base such as NaH in DMF. Alternatively treatment with phos- 3 gene, or CDI, oran analog thereof, followed by the addition of O an appropriately di-substituted amine will afford ureas of 42 structure 35. Formation of sulfonamide derivatives from 34 can be accomplished by reaction with appropriately Substi tuted sulfonyl chlorides in the presence of base. Conversion 35 of ketone 35 to 38 can be performed either through direct O O reductive amination with an appropriately Substituted alkyl or aryl amine to directly afford 37, or alternatively through 1 1. formation of the amine derivate 36 by reduction of an inter- 40 mediate oxime, followed by alkylation with an appropriately substituted benzylic halide, mesylate or tosylate, or reductive alkylation with the appropriate aldehyde or ketone in the presence of a reducing reagent such as NaCNBH. 37 is 45 converted to 38 (a compound of the invention) by acylation with and appropriately substituted symmetrical anhydride or acid halides to afford amides, or chloroformates to afford carbamates, or isocyanates, carbamoyl chlorides, etc. to form Separation by chromatography ureas, or appropriately substituted Sulfonyl chlorides to afford sulfonamides. Compounds of formula I wherein two Rgroups combineto form a cyclopentane or other cycloalkyl ring may be prepared according to the following scheme 9 or known variations thereof. 55

FSN(CH2CH2OCH3)2 --- DCM, rt 60

O iPrCOCI --- Py, DCM, 0° C.-rt NH 2 65 41 US 7,749,992 B2 24

-continued -continued O F F OMe O CF Br -O- Cs2CO3, DMF NH CF 10

44 15

48

O F F According to Scheme 9, 6-aminoindane-5-carboxylic acid o1 1. KOtBu, methylester (42) is N-protected by reacting with isopropyl toluene, OMe 700 C. chloroformate to afford compound 42. Compound 42 is oxi --- N 2. AcOHHCl, dized at the benzylic carbon atoms to afford the indanone H2O mixtures 43A and 43B. The mixture may be separated by O 3. CICOiPr, 25 chromatography or other techniques known to one of skill in O O Py. DCM the art. The compound 43A is reacted with Deoxo-Fluor R (registered trademark of Aldrich Chemical company) avail able from Aldrich Chemical Company, Milwaukee Wis., 45 30 USA, 2004-2005 catalog of fine chemicals, number 49, 411 9. The fluorination reaction is performed in the presence of a suitable solvent such as dichloromethane to afford the diflu orinated compound 44. Compound 44 is N-alkylated with 1. CF 4-bromobutyl methyl ester in the presence of a mild base such HN 35 as cesium carbonate to afford the diester 45. The diester is O cyclized by decarboxylation in the presence of a strong protic F F base such as for example potassium t-butoxide. The reaction CF is worked up using aqueous extraction conditions followed by Ti(OiPr)4, MeOH 40 isolation of the intermediate keto azepine as the salt, prefer 2. NaBH4, MeOH ably the hydrochloride salt. The intermediate ketoazepine is N protected as the isopropylcarbamate 46 by reaction with iso g propylchloroformate in the presence of a base Such as, for example, pyridine in a suitable solvent Such as dichlo 45 romethane. The carbamate 46 is then reductively aminated - " with the desired substituent such as for example an optionally 46 substituted benzylamine (e.g. 3,5-bistrifluoromethylbenzy lamine shown) or other desired substituent. Amine 47 may be acylated, or Sulfonylated as shown, for example, by the treat 50 ment of an appropriate reagent such as acetic anhydride to provide 48. CF Scheme 10 shows the conversion of the other indene iso mer to a compound of formula I (for example, compounds HN F F 55 54).

CF Acetic anyodride He Scheme 1() O N 60 g 1. iPrCOCI He Py, DCM, 0° C. rt - " NH2 65 41 US 7,749,992 B2 26

-continued -continued O

1. 1. KOtBu, toluene, CrO3 OMe 700 C. Her -r NH AcOH, H2O ~ 2. AcOH HCl, H2O 3. CICOiPr, Py, DCM

10

42 15 O CF HN

CF Ti(OiPr)4, MeOH O 2. NaBH4, MeOH

25

43A

30 CF

35 CF Acetic anhydride He

F 40 Separation by chromatography O 1. 45 FSN(CH2CH2OCH3)2 CF ...... DCM.

50 CF

43B

O 55 1 OMe NH ~~ O 60 He F F 1. CsCO3, DMF According to Scheme 10, the other difluoro isomer 43B O - may be converted to a compound of formula I using proce dures analogous to those described for Scheme 9. 65 N-acyl analogs of compound of formula 55 and 49 may be 50 prepared as shown in Scheme 11 for preparing an analog of compound 55.

US 7,749,992 B2 29 30 Assay Assay of CETP Activity In Vivo The following assay protocols and result(s) thereof dem A strain of transgenic mice that express both human CETP onstrating the utility and efficacy of the compounds and/or and human apolipoprotein A-1 (Taconic, Germantown, N.Y.) methods of the current invention are given for the purpose of 5 is used to test compounds of this invention. Test compounds illustration and are not meant to be limiting in any way. are administered once orally or IV in selected aqueous or oil based vehicles. At various times after dosing, ranging from 4 h to 24 h, blood is obtained. Blood is allowed to clot and In Vitro CETP Inhibitor Assay:Spa Assay serum is obtained by centrifugation. CETP activity is deter mined by a method similar to that described for the in vitro An in vitro scintillation proximity assay (SPA) has been 10 CETP activity assay, except that plasma from treated animals used to test the ability of compounds of this invention to is used as the CETP source in the assay. inhibit the transfer of radiolabeled cholesterol esters between The efficacy of compounds of the invention in vivo may HDL and LDL. This assay monitors the inhibition of the also be determined utilizing Syrian Golden Hamsters, which transfer of Hicholesterol esters from HDL (Amersham) to express endogenous CETP. Test compounds are administered biotinylated LDL (Amersham) by a CETP source. CETP 15 orally in selected aqueous or oil based vehicles for up to one produced by AV-12 cells that have been created to express week. At various times after dosing, ranging from 4h to 24, human CETP has been used to mediate the transfer. After a blood is obtained. Blood is allowed to clot and serum is 30-minute incubation at 37 C in which the radiolabeled cho obtained by centrifugation. CETP activity is determined by a lesterol ester is transferred in a HEPES-NaCl based buffer, method similar to that described for the invitro CETP activity the reaction is stopped and the biotinylated LDL is bound to assay, except that serum from treated animals is used as the streptavidin/scintillant coated SPA beads (Amersham). Then CETP source in the assay. the radioactive signal is measured in a Packard 96-well scin Alternatively, a strain of transgenic mice that express tillation TopCounter with window settings fully open. Com human CETP (Taconic, Germantown, N.Y.) is used to test pounds of this invention can be added to the reaction mixture compounds of this invention. Test compounds are adminis in an appropriate solvent to assess their ability to inhibit the 25 tered once orally or IV in selected aqueous or oil based transfer of the radiolabeled cholesterol esters by CETP rep vehicles. At various times after dosing, ranging from 4h to 24 resented by a decrease in radioactive signal. The activity h, blood is obtained. Blood is allowed to clot and serum is transferred in the reaction mixtures with control solvents is obtained by centrifugation. CETP activity is determined by a rated as 100% transfer. The compound concentration at which method similar to that described for the invitro CETP activity the activity is midway between 100% and the lowest recorded 30 assay, except that serum from treated animals is used as the activity is indicated as the IC50 value. A three-parameter CETP source in the assay. fixed top logistic curve-fitting algorithm is used to generate Assay of Plasma Lipids In Vivo the IC50 value. Examine of IC50 values determined by these methods are Activity of compounds of this invention in vivo can be summarized in Table 1. 35 determined by the level of elevation of HDL cholesterol rela tive to control by a given amount of compound in a CETP TABLE 1. containing animal species. A strain of transgenic mice that express both human CETP and human apolipoprotein A-1 Inhibition of CETP Activity (SPA assay (Taconic, Germantown, N.Y.) is used to test compounds of 40 this invention. Test compounds are administered once orally Compound of in selected aqueous or oil based vehicles. At various times example No. ICSOM after dosing, ranging from 4 h to 24 h, blood is obtained. 1 293 Blood is allowed to clot and serum is obtained by centrifuga 117 65 tion. HDL cholesterol levels in the serum is determined by 111 68 45 119 42 HDL-C plus reagents (Roche/Hitachi, Indianapolis, Ind.) 129 S4 with a clinical chemistry analyzer (Roche/Hitachi, India 182 191 napolis, Ind.). Additional serum lipids can be analyzed by enzymatic methods. Lipids in the VLDL, LDL and HDL fractions are analyzed by enzymatic methods after precipita Alternatively, additional CETP sources can be used to 50 tion or size exclusion chromatography. An example of the mediate the transfer of radiolabeled cholesterol ester in this elevation of HDL cholesterol levels at 8 hr are summarized in assay. Endogenous CETP from human plasma, CETP from table 2 mice made to express human CETP, endogenous CETP from hamsters, and CETP from additional mammalian species can TABLE 2 be used as the CETP source in this assay. 55 Elevation of HDL cholesterol levels at Alternatively, other sources may be used as the buffer. In 8 hr by example 98 of the invention addition to the HEPES-NaCl based buffer that has been used in this assay, human plasma, mouse plasma or a Tris-buffer Compound % HDL of Example Single Oral cholesterol that may be high in albumin may be used as the buffer in No. Dose (mg/kg) increase which the transfer of radiolabeled cholesterol esters from 60 HDL to LDL may occur. 119 30 123 Alternatively, other sources of radioactivity and or accep tors may be used to track the CETP activity in this assay. The efficacy of compounds of the invention in vivo may Alternatively, radiolabeled-LDL may be used in this assay. also be determined utilizing Syrian Golden Hamsters. The One of skill in the art is able to practice the different assay 65 compounds can be tested in hamsters made hypercholester methodologies disclosed herein with minimal experimenta olemic by feeding a high fat high cholesterol diet for a mini tion. mum of two weeks or in non-hypercholesterolemic hamsters US 7,749,992 B2 31 32 fed normal chow for two weeks. Test compounds can be priate for parenteral administration, for example, by intra administered orally in selected aqueous or oil based vehicles muscular, Subcutaneous or intravenous routes. Additionally, for up to 1 week. Serum can be obtained and lipids can be the compounds may be formulated as Sustained release dos analyzed by enzymatic methods. Lipids in the VLDL, LDL age forms and the like. The formulations can be so constituted and HDL fractions are analyzed by enzymatic methods after that they release the active ingredient only or preferably in a precipitation or size exclusion chromatography. particular physiological location, possibly over a period of Alternatively, a strain of transgenic mice that express time. The coatings, envelopes, and protective matrices may be human CETP (Taconic, Germantown, N.Y.) is used to test the made, for example, from polymeric Substances or waxes. efficacy of the compounds of this invention. The hCETP mice Compounds of formula I, generally, will be administered in can be made hypercholesterolemic by feeding a high fat chow a convenient formulation as determined by the attending phy diet such as TD 88051, as described by Nishina et al. (J Lipid 10 sician. The following formulation examples are only illustra Res., 31, 859-869 (1990)) for at least two weeks before the tive and are not intended to limit the scope of the present start of the study. Test compounds can be administered orally invention. in selected aqueous or oil based vehicles for up to 1 week. Serum can be obtained and lipids can be analyzed by enzy Formulations matic methods. Lipids in the VLDL, LDL and HDL fractions 15 are analyzed by enzymatic methods after precipitation or size In the formulations which follow, “Active Ingredient' exclusion chromatography. means a compound of formula I, a salt, Solvate, racemate, enantiomer diastereomer or mixture of diastereomers, or pro Method of Treatment drug thereof, or a combination of a compound of formula I As used herein, the term “effective amount’ means an and other effective agent for the treatment or prevention of amount of compound of the present invention, i.e., formula I, dyslipidemia or atherosclerosis. which is capable of alleviating the symptoms of the various pathological conditions herein described. The specific dose of a compound administered according to this invention will, of Formulation 1: Gelatin Capsules course, be determined by the particular circumstances Sur 25 Hard gelatin capsules are prepared using the following: rounding the case including, for example, the compound administered, the route of administration, the state of being of Ingredient Quantity (mg capsule) the patient, and the pathological condition being treated. A Active ingredient O.1-1000 typical daily dose will contain a nontoxic dosage level of from Starch, NF O-6SO about 0.01 mg to about 100 mg/day of a compound of the 30 Starch flowable powder O-6SO present invention. Preferred daily doses generally will be Silicone fluid 350 centistokes O-15 from about 1 mg to about 250 mg/day. The compounds of this invention can be administered by a variety of routes including oral, rectal, transdermal, Subcuta The formulation above may be changed in compliance with neous, intravenous, intramuscular, and intranasal. These the reasonable variations provided. compounds preferably are formulated prior to administration, 35 A tablet formulation is prepared using the ingredients the selection of which will be decided by the attending phy below: sician. Thus, another aspect of the present invention is a pharmaceutical composition comprising an effective amount of a compound of Formula I, or a pharmaceutically accept able salt thereof. Solvate, prodrug, enantiomer or prodrug 40 Formulation 2: Tablets thereof, and a pharmaceutically acceptable carrier, diluent, or Ingredient Quantity (mg tablet) excipient. Active ingredient 2.5-1000 The total active ingredients in Such formulations comprises Cellulose, microcrystalline 200-650 from 0.1% to 99.9% by weight of the formulation. By “phar Silicon dioxide, fumed 10-650 maceutically acceptable' it is meant the carrier, diluent, 45 Stearate acid 5-15 excipients and salt must be compatible with the other ingre dients of the formulation, and not deleterious to the recipient thereof. The components are blended and compressed to form tablets. Pharmaceutical formulations of the present invention can Alternatively, tablets each containing 2.5-1000 mg of be prepared by procedures known in the art using well-known 50 and readily available ingredients. For example, the com active ingredient are made up as follows: pounds of formula I can be formulated with common excipi ents, diluents, or carriers, and formed into tablets, capsules, Suspensions, powders, and the like. Examples of excipients, Formulation 3: Tablets diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, 55 Ingredient Quantity (mg tablet) Sugars, mannitol, and silicic derivatives; binding agents such Active ingredient 2S-1000 as carboxymethyl cellulose and other cellulose derivatives, Starch 45 alginates, gelatin, and polyvinyl-pyrrolidone; moisturizing Cellulose, microcrystalline 35 agents such as glycerol, disintegrating agents such as calcium Polyvinylpyrrollidone 4 carbonate and sodium bicarbonate; agents for retarding dis 60 (as 10% solution in water) Solution Such as paraffin, resorption accelerators such as qua Sodium carboxymethyl cellulose 4.5 ternary ammonium compounds; Surface active agents such as Magnesium stearate O.S cetyl alcohol, glycerol monostearate; adsorptive carriers such Talc 1 as kaolin and bentonite; and lubricants such as talc, calcium and magnesium Stearate, and Solid polyethylglycols. 65 The active ingredient, starch, and cellulose are passed The compounds also can be formulated as elixirs or solu through a No. 45 mesh U.S. sieve and mixed thoroughly. The tions for convenient oral administration or as solutions appro solution of polyvinylpyrrolidone is mixed with the resultant US 7,749,992 B2 33 34 powders that are then passed through a No. 14 mesh U.S. reagent is not taught it is presumed that such reagent may be sieve. The granules so produced are dried at 50°-60° C. and made by one of skill in the art following procedures to make passed through a No. 18 mesh U.S. sieve. The sodium car analogous reagents taught in the available literature and stan boxymethyl starch, magnesium Stearate, and talc, previously dard reference texts and/or procedures involving minimal passed through a No. 60 U.S. sieve, are then added to the experimentation known to one of skill in the art. granules, which after mixing, are compressed on a tablet machine to yield tablets. Example 1 Suspensions each containing 0.1-1000 mg of medicament per 5 ml dose are made as follows: Synthesis of 5-Acetyl-(3,5-bis-trifluoromethyl-ben 10 Zyl)-amino-2,3,4,5-tetrahydro-benzoblazepine-1- carboxylic acid isopropyl ester Formulation 4: Suspensions Step 1. Preparation of Ingredient Quantity (mg 5 ml) 2-(Toluene-4-sulfonylamino)-benzoic acid methyl 15 ester Active ingredient 0.1-1000 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 mg To a mixture of 2-Amino-benzoic acid methyl ester (900 g, Benzoic acid solution 0.10 mL. 6 mol) in pyridine (6 L) was added p-Toluenesulfonyl chlo Flavor G.V. ride (1500 g, 7.5 mol). The mixture was stirred overnight at Color G.V. room temperature. The mixture was poured into ice water, Purified water to 5 mL. and the resultant precipitates were collected by filtration. The filtrates were dissolved in CHCl, and the solution washed The medicament is passed through a No. 45 mesh U.S. with diluted HCl, HO, and dried over MgSO. The residue sieve and mixed with the sodium carboxymethyl cellulose thus obtained was crystallized from ethanol to give 2-(Tolu and syrup to form a smooth paste. The benzoic acid solution, 25 ene-4-Sulfonylamino)-benzoic acid methyl ester (1454 g. flavor, and color are diluted with some of the water and added, 80%). with stirring. Sufficient water is then added to produce the required Volume. Step 2. Preparation of 2-(3-Ethoxycarbonyl-propyl)- An aerosol Solution is prepared containing the following (toluene-4-Sulfonyl)-amino-benzoic acid methyl ingredients: 30 ester A mixture of 2-(Toluene-4-sulfonylamino)-benzoic acid methyl ester (1000 g, 3.27 mol), ethyl 4-bromobutyrate (639 Formulation 5: Aerosol g, 3.45 mol) in 2-butanone (5.6 L) was heated at reflux for 24 Ingredient Quantity (% by weight) 35 hours. After the reaction was completed, the mixture was poured into ice-water, and the resultant precipitates were Active ingredient O.25 collected by filtration. The filtrates were washed with ethyl Ethanol 25.75 acetate to give 2-(3-Ethoxycarbonyl-propyl)-(toluene-4-Sul Propellant 22 (Chlorodifluoromethane) 7O.OO fonyl)-amino-benzoic acid methyl ester (890 g. 65%). 40 The active ingredient is mixed with ethanol and the mixture Step 3. Preparation of 5-Oxo-1-(toluene-4-sulfonyl)- added to a portion of the propellant 22, cooled to 30°C., and 2,3,4,5-tetrahydro-1H-benzoblazepine-4-carboxylic transferred to a filling device. The required amount is then fed acid ethyl ester to a stainless steel container and diluted with the remaining propellant. The valve units are then fitted to the container. 45 To a heated mixture of potassium t-butoxide (371 g, 3.58 mol) in toluene (41) at 70° C. was added 2-(3-Ethoxycarbo nyl-propyl)-(toluene-4-Sulfonyl)-amino-benzoic acid methyl ester (750 g, 1.79 mol). After the addition was com Formulation 6: Intravenous Solution pleted, the mixture was cooled to room temperature then Ingredient Quantity 50 poured into ice water. The extraction with CHC1 was suc cessively done, and organic layer was dried over MgSO and Active ingredient 50 mg concentrated under reduced pressure to afford crude com Isotonic Saline 1,000 mL. pound 5-Oxo-1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H benzoblazepine-4-carboxylic acid ethyl ester (450 g) as a The solution of the above ingredients is intravenously 55 mixture of Me and Etesters. administered to a patient at a rate of about 1 mL per minute. Step 4. Preparation of 1-(Toluene-4-sulfonyl)-1.2.3, EXAMPLES 4-tetrahydro-benzoblazepin-5-one

The following examples include actual and prophetic 60 To the mixture of 5-Oxo-1-(toluene-4-sulfonyl)-2,3,4,5- examples. The examples herein are not all-inclusive and are tetrahydro-1H-benzoblazepine-4-carboxylic acid ethyl ester not intended to limit the scope of the invention but to provide thus obtained, were added AcOH (2.41), conc.HCl (800 ml) an illustration of the breadth and scope of the compounds and HO (240ml). The mixture was heated at reflux for 5 h falling within the scope of the invention. In general, commer and poured into ice water. The pH was adjusted to about 7-8 cially available reagents have been used. Every attempt has 65 by adding diluted aqueous NaOH. The mixture was extracted been made to teach processes and/or procedures for preparing with CH2Cl2. The organic layer was separated, dried over non-commercial reagents. Where a procedure for making a MgSO4, concentrated, and the residue was crystallized from US 7,749,992 B2 35 36 the mixture (4:1 n-hexane: AcOEt) to give 1-(Toluene-4-sul ml, 10.5 mmol) in dichloromethane (2 ml) at room tempera fonyl)-1,2,3,4-tetrahydro-benzoblazepin-5-one (278 g. ture was treated with acetic anhydride (0.79 ml, 8.4 mmol) via 60%) as a white powder. dropwise addition over 4 minutes. The mixture was stirred at room temperature for 20 hours. The mixture was cooled (0° Step 5. Preparation of C.) and treated with 1NNaOH and stirred for 30 minutes. The 1,2,3,4-Tetrahydro-benzoblazepin-5-one aqueous layer was extracted with dichloromethane. The com bined organic phases were washed with 1N HCl, dried To preheated polyphosphoric acid (PPA, 220 g) at 70-80° (NaSO) and concentrated to an oil. Purification by silica gel C. was added 1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahydro 10 chromatography (eluent, 2:1 n-hexanes:ethyl acetate) pro benzoblazepin-5-one (50.0 g, 0.16 mol). The mixture was vided 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-2, stirred for 3.0 hat the same temperature and then poured into 3,4,5-tetrahydro-benzoblazepine-1-carboxylic acid isopro ice water. After the pH was adjusted to about 8-9 by adding aq pyl ester (144 mg). NaOH, the mixture was extracted with ethyl acetate. The Additional compounds were prepared utilizing this same organic layer was separated, dried over MgSO4, and concen 15 trated. The residue was purified by silica gel column chroma methodology in which R1 is variable and is introduced by tography (eluent, 3:1 n-hexanes:ethyl acetate) to give 1.2.3, replacement of acetic anhydride with alternative reagents 4-Tetrahydro-benzoblazepin-5-one (22 g). following the procedure of Example 1, Step 8 for the synthe sis of 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-2, Step 6. Preparation of 5-Oxo-2,3,4,5-tetrahydro 3,4,5-tetrahydro-benzoblazepine-1-carboxylic acid isopro benzoblazepine-1-carboxylic acid isopropyl ester pyl ester. To a cooled (0°C.) solution of 1,2,3,4-Tetrahydro-benzo blazepin-5-one (1.5g, 9.3 mmol) and pyridine (2.26 ml, 27.9 25 mmol) in dichloromethane (30 ml) was added 1M isopropy F F lchloroformate (solution in toluene) dropwise over 10 min utes. After addition was completed, the mixture was removed F from the cold bath and stirred for 18 hours at room tempera ture. The mixture was cooled to 0° C., then treated with Rls. N aqueous 1N NaOH and stirred for 30 minutes. After layer 30 separation, the aqueous layer was extracted with dichlo romethane. The combined organic phases were washed with F 1N HCl, saturated aqueous NaHCO, brine, then dried F F (NaSO) and concentrated to an oil. Purification by silica gel N chromatography (eluent, 3:1 n-hexanes:ethyl acetate) pro 35 vided 5-Oxo-2,3,4,5-tetrahydro-benzoblazepine-1-car boxylic acid isopropyl ester (1.91 g). o O Step 7. Preparation of 5-(3.5-Bis-trifluoromethyl benzylamino)-2,3,4,5-tetrahydro-benzoblazepine-1- 40 Example # Reagent RI MS (ES+) carboxylic acid isopropyl ester Example 2 methylchloroformate methoxycarbonyl 533 (M+H) A mixture of 5-Oxo-2,3,4,5-tetrahydro-benzoblazepine 1-carboxylic acid isopropyl ester (283 mg, 1.14 mmol), 3.5- 45 Bis(trifluoromethyl)benzylamine (304 mg, 1.25 mmol) and Example 3 titanium(IV) isopropoxide (0.43 ml, 1.43 mmol) was stirred at room temperature for 6 hours. The mixture was diluted with methanol (5 ml) and treated with sodium borohydride (65 mg. 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino 8-chloro-2,3,4,5-tetrahydro-benzoblazepine-1-car 1.71 mmol), then stirred at room temperature for 18 hours. 50 The mixture was treated with 0.1N NaOH (25 ml) and stirred boxylic acid isopropyl ester for 10 minutes, then filtered through Celite. The filtered resi due washed successively with diethyl ether and dichlo romethane. The filtrate was transferred to a separatory funnel CF and the organic layer was separated, dried (NaSO) and O 3 concentrated to provide crude 5-(3.5-Bis-trifluoromethyl 55 benzylamino)-2,3,4,5-tetrahydro-benzoblazepine-1-car boxylic acid isopropyl ester, which was elaborated without y purification. 60 CF Step 8. Preparation of 5-Acetyl-(3,5-bis-trifluorom ethyl-benzyl)-amino)-2,3,4,5-tetrahydro-benzob. azepine-1-carboxylic acid isopropyl ester C N

A solution of crude 5-(3.5-Bis-trifluoromethyl-benzy 65 lamino)-2,3,4,5-tetrahydro-benzoblazepine-1-carboxylic o-Sl acid isopropyl ester (200 mg, 0.42 mmol) and pyridine (0.85 US 7,749,992 B2 37 38 The titled compounds was prepared following the proce Example 5 dures described in Example 1 by replacing 2-Amino-benzoic acid methyl ester with 2-Amino-4-chloro-benzoic acid Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) methyl ester in Example 1, step 1. MS (ES+): 551 (M+H). aminol-7-methyl-2,3,4,5-tetrahydrobenzoblazepine 1-carboxylate Example 4

5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbo CF O 3 nyl-amino-8-chloro-2,3,4,5-tetrahydro-benzob 10 azepine-1-carboxylic acid isopropyl ester

CF 15 N CH O - O O CF CH3

C N Purge a mixture of isopropyl-5-acetyl-(3.5-bistrifluorom ethylbenzyl)amino-7-bromo-2,3,4,5-tetrahydrobenzob 25 azepine-1-carboxylate (0.400 g, 0.672 mmol), trimethyl o-Sl boroxine (0.084 g. 0.672 mmol), and potassium carbonate (0.279 g, 2.02 mmol) in anhydrous tetrahydrofuran (5 mL) with nitrogen, then add tetrakis(triphenylphosphine)palla The titled compounds was prepared following the proce dium(0) (0.077g, 0.067 mmol) and stir at reflux for 1 h. Cool dures described in Example 1 by replacing 2-Amino-benzoic 30 the mixture to room temperature and dilute with ethyl acetate acid methyl ester with 2-Amino-4-chloro-benzoic acid (30 mL) and wash with water and brine (10 mL each). Dry the methyl ester in Example 1, step 1 as well as replacing acetic organic layer over anhydrous sodium Sulfate, filter and anhydride with methyl chloroformate in Example 1, Step 8. remove the solvent under reduced pressure. Chromatograph MS (ES+): 567 (M+H). the residue over silica gel, eluting with hexanes/ethyl acetate The following Examples were prepared utilizing the same 35 (20:1 to 3:1), to provide the title compound as a white solid methodology described in Example 1 wherein R1 is a variable (0.156 g., 44%): ESI MS 531 (M+H). and is introduced by replacement of 2-amino-benzoic acid The following Examples were prepared utilizing the same methyl ester with alternative reagents following the proce methodology described in Example 5 wherein R1 is a variable dure of Example 1, Steps 1-8 for the synthesis of 5-acetyl 40 and is introduced by replacement of trimethylboroxine with (3,5-bistrifluoromethylbenzyl)amino-2,3,4,5-tetrahy alternative reagents following the procedure of Example 5 for drobenzoblazepine-1-carboxylic acid isopropyl ester. the synthesis of Isopropyl 5-acetyl-(3,5-bistrifluoromethyl benzyl)aminol-7-methyl-2,3,4,5-tetrahydrobenzob. azepine-1-carboxylate. 45 CF O CF X- N O 3 HC R 50 X CF H3C R CF N CH 55 O N O CH CH O O Example # Reagent R1 MS (ES+) CH3 60 Example 4A 2-amino-5- bromo 595 (M+H) Example # Reagent R1 MS (ES+) bromobenzoic acid methyl ester Example 5a 4-methylphenylboronic 4-methylphenyl 607 (M+H) Example 4B 2-amino-5- trifluoromethoxy 601 (M+H) acid trifluoromethoxybenzoic Example 5b 4-chlorophenylboronic 4-chlorophenyl 627 (M+H) acid methyl ester acid 65 Example 5c 4-methoxyphenylboronic 4-methoxyphenyl 624 (M+H) acid US 7,749,992 B2 40 The following Examples were prepared utilizing the same -continued methodology described in Example 6 wherein R' is a variable CF and is introduced by replacement of morpholine with alter O native reagents following the procedure of Example 6 for the X- N synthesis of Isopropyl 5-acetyl-(3,5-bistrifluoromethylben H3C Zyl)aminol-7-morpholino-2,3,4,5-tetrahydrobenzob. R azepine-1-carboxylate. CF 10 N CF CH3 O O O H3CX CH 15 R Example # Reagent R1 MS (ES+) CF Example 5d 4-fluorophenylboronic 4-fluorophenyl 611 (M+H) acid N Example 5e 2-fluorophenylboronic 2-fluorophenyl 611 (M+H) CH3 acid O Example 5f 2- 2-trifluoro- 662 (M + H) O trifluoromethylphenyl- methylphenyl CH bornonic acid Example 5g 2-methylphenylboronic 2-methylphenyl 607 (M+H) acid Example # Reagent R1 MS (ES+) 25 Example 5h phenylboronic acid Phenyl 593 (M+H) Example 6a 4-methylpiperazine N-methylpiperazinyl 615 (M+ H) Example 5i 4- 4-(trifluoro- 661 (M+H) Example 6b benzophenoneimine benzhydrylideneamino 696 (M+H) (trifluoromethyl)phenyl- methyl)phenyl Example 6c Aniline phenylamino 609 (M+) boronic acid Example 6d Pyrrollidine pyrrollidin-1-yl 586 (M+H) Example 6e azetidin-2-one 2-oxo-azetidin-1-yl 586 (M+H) Example 7 pyrrollidin-2-one 2-oxo-pyrrollidin-1-yl 600 (M+H) 30 Example 8 AZetidine aZetidin-1-yl 572 (M+H) Example 6 Example 9 Methanol Methoxy 547 (M+H) Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) aminol-7-morpholino-2,3,4,5-tetrahydrobenzob. azepine-1-carboxylate 35 Example 10 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) amino-7-amino-2,3,4,5-tetrahydrobenzoblazepine CF 1-carboxylate 40

CF O 3 CF 45 X- N N H3C CH HN O CF O CH 50 N CH3 Combine tris(dibenzylideneacetone)dipalladium (O) O O (0.031 g, 0.034 mmol), racemic-2,2'-bis(diphenylphos CH phino)-1,1'-binaphy1 (0.064g, 0.102 mmol) and sodium t-bu 55 toxide (0.045 g, 0.470 mmol) in toluene (2 mL) and purge this Suspension with nitrogen at room temperature for 5 min. Add Add 2N hydrochloric acid (2 mL) to a solution ofisopropyl morpholine (0.033 mL, 0.369 mmol) followed by isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-7-(benzhy 5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-7-bromo-2, drylideneamino)-2,3,4,5-tetrahydrobenzoblazepine-1-car 3,4,5-tetrahydrobenzoblazepine-1-carboxylate (0.200 g, 60 0.336 mmol) and heat this mixture at 80° C. under nitrogen boxylate (example 6b) (0.920 g, 1.32 mmol) in tetrahydrofu for 1 h. Cool the reaction mixture to room temperature, dilute ran (10 mL) at room temperature and stir for 15 min. Dilute the mixture with dichloromethane, filter through Celite, and the mixture with ethyl acetate (20 mL) and wash with satu concentrate under reduced pressure. Chromatograph the resi rated Sodium hydrogen carbonate solution and brine (10 mL due over silica gel, eluting with hexanes/ethyl acetate (20:1 to 65 each). Dry the organic layer over anhydrous Sodium sulfate, 1:2), to provide the title compound as an off-white solid filter and remove the solvent under reduced pressure. Chro (0.130 g. 64%): APCI MS 603 (M+H). matograph the residue over silica gel, eluting with hexanes/ US 7,749,992 B2 41 42 ethyl acetate (1:1), to provide the title compound as an off remove the cooling bath and warm to room temperature while white solid (0.526g, 75%); APCI MS 531 (M+H). stirring overnight. Dilute the mixture with dichloromethane (30 mL) and wash with 2 N hydrochloric acid, water, and Example 11 brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) pressure. Chromatograph the residue over silica gel, eluting amino-7-dimethylamino-2,3,4,5-tetrahydrobenzob with ethyl acetate/hexanes (10:1 to 1:2), to provide the title azepine-1-carboxylate compound as a white solid (0.037 g. 65%): ESI MS 610 (M+H). 10 The following Examples were prepared utilizing the same CF methodology described in Example 12 wherein R1 is a vari HC able and is introduced by replacement of methanesulfonyl CH p- N chloride with alternative reagents following the procedure of O 15 Example 19 for the synthesis of Isopropyl 5-acetyl-(3.5- bistrifluoromethylbenzyl)amino-7-dimethylamino-2,3,4,5- 1. HC CF tetrahydrobenzoblazepine-1-carboxylate.

N CH CF O O O CH3 X HC3 Add sodium cyanoborohydride (0.035 g, 0.564 mmol) in 25 R1 one portion to a solution of isopropyl-5-(acetyl-(3,5-bistrif CF luoromethylbenzyl)amino-7-amino-2,3,4,5-tetrahy drobenzoblazepine-1-carboxylate (0.100 g, 0.188 mmol) N and 37% aqueous formaldehyde (0.020 mL, 0.621 mmol) in CH3 30 O acetonitrile (6 mL) at room temperature. Addacetic acid over O 40 minto the resulting clear solution and stir for 2 h. Dilute CH the reaction with ethyl acetate (30 mL) and wash with 2 N sodium hydroxide (10 mL) and brine (20 mL). Dry the Example # Reagent R1 MS (ES+) organic layer over anhydrous Sodium Sulfate, filter and 35 Example 13 acetic anhydride Acetyl 574 (M+H) remove solvent under reduced pressure. Chromatograph the Example 14 benzenesulfonyl benzenesulfonyl 672 (M + H) residue over silica gel, eluting with hexanes/ethyl acetate chloride (20:1 to 3:1), to provide the title compound as a colorless gum Example 15 benzoyl chloride Benzoyl 636 (M+H) (0.059 g, 56%), APCI MS 560 (M+H). Example 12 40 The following Examples were prepared utilizing the same methodology described in Example 5 wherein R1 is a variable Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) and is introduced by replacement of trimethylboroxine with amino-7-methanesulfonylamino-2,3,4,5-tetrahy alternative reagents following the procedure of Example 5 for drobenzoblazepine-1-carboxylate the synthesis of Isopropyl 5-acetyl-(3,5-bistrifluoromethyl 45 benzyl)aminol-7-methyl-2,3,4,5-tetrahydrobenzob. azepine-1-carboxylate.

CF O 3 CF 50 O 3 HCX HC 3 Ns1 CF MV 3 O O 55 CF N CH3 O O CH 60 Add methanesulfonyl chloride (8 ul, 0.103 mmol) drop wise to a suspension of isopropyl-5-acetyl-(3,5-bistrifluo Example # Reagent R1 MS (ES+) romethylbenzyl)amino-7-amino-2,3,4,5-tetrahydrobenzo Example 16 tributyl (vinyl)tin Vinyl 543 (M+H) blazepine-1-carboxylate (0.050 g., 0.094 mmol) and pyridine 65 Example 17 tributyl (1-methoxyvinyl)tin 7-acetyl 559 (8 ul, 0.103 mmol) in dichloromethane (2 mL) at 0°C. under atmosphere of nitrogen. Stir the suspension for 30 min, then US 7,749,992 B2 43 44 Example 18 Example 20 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) aminol-7-methylcarboxylate-2,3,4,5-tetrahy amino-7-carboxy-2,3,4,5-tetrahydrobenzob drobenzoblazepine-1-carboxylate aZepine-1-carboxylate

CF O 3 10 O CF X- N HC ) N H3COC H3C CF HOC 15 CF N CH N O CH O O CH O CH3 Purge with a suspension ofisopropyl-5-acetyl-(3,5-bistri fluoromethylbenzyl)amino-7-bromo-2,3,4,5-tetrahy Add 2N sodium hydroxide solution (2 mL) to a solution of drobenzoblazepine-1-carboxylate (0.400 g, 0.671 mmol), 25 isopropyl-5-acetyl-(3,5-bistrifluoromethylbenzyl)amino triethylamine (0.20 mL, 1.48 mmol), and tetrakis(triph 7-bromo-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate enylphosphine)palladium(0) (0.080 g, 0.070 mmol) in aceto nitrile (3 mL) and methanol (1 mL) with carbon monoxide gas (0.100 g, 0.174 mmol) in methanol (5 mL) at 0°C. and allow at room temperature in a high pressure vessel for 5 min. to stir for 30 min. Acidify to pH 4 with 2N hydrochloric acid Pressurize the vessel with carbon monoxide gas to 20 psi and Solution and extract the aqueous mixture with ethyl acetate heat the mixture at 60° C. for 16 h. Cool the mixture to room 30 (3x10 mL). Wash the organic layer with water and brine (10 temperature and dilute with ethyl acetate (30 mL) and wash mL each). Dry the organic layer over anhydrous Sodium with water (3x10 mL) and brine (25 mL). Dry the organic sulfate, filter and remove the solvent under reduced pressure. layer over anhydrous sodium sulfate, filter and remove the Purify the residue by triturating with water, to provide the title Solvent under reduced pressure. Chromatograph the residue 35 compound as a white solid (0.091 g, 96%): APCI MS 561 over silica gel, eluting with hexanes/ethyl acetate (20:1 to (M+H). 3:1), to provide the title compound as a white solid (0.320 g, 83%): APCI MS 575 (M+H). The following Example was prepared utilizing the same methodology described in Example 1 wherein R1 is a variable Example 19 and is introduced by replacement of 2-amino-benzoic acid 40 methyl ester with alternative reagents following the proce Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) dure of Example 1, Steps 1-8 for the synthesis of 5-acetyl amino-7-formyl-2,3,4,5-tetrahydrobenzoblazepine (3,5-bistrifluoromethylbenzyl)amino-2,3,4,5-tetrahy 1-carboxylate drobenzoblazepine-1-carboxylic acid isopropyl ester. 45

CF O CF O 3

X- N 50 H3C H3C X OHC R CF CF

N 55 N CH3 CH O O O O CH3 CH3 60 This compound was prepared utilizing the same method Example # Reagent R1 MS (ES+) ology described in Example 18 wherein replacement of methanol with triethylsilane following the procedure of Example 21 2-amino-5- Fluoro 535 (M+H) fluorobenzoic acid Example 18 for the synthesis of Isopropyl 5-acetyl-(3.5- methyl ester bistrifluoromethylbenzyl)aminol-7-methylcarboxylate-2,3, 65 4,5-tetrahydrobenzoblazepine-1-carboxylate. ESIMS m/z 545 CHFNO+H" US 7,749,992 B2 45 46 Example 22 Step 4. Preparation of Methyl 4-bromo-2-isopro poxycarbonyl-(3-methoxycarbonylpropyl)amino Isopropyl 5-Acetyl-(3,5-bistrifluoromethylbenzyl) benzoate amino-8-bromo-2,3,4,5-tetrahydrobenzoblazepine 1-carboxylate 5 Heat a Suspension of methyl 4-bromo-2-isopropoxycarbo nylaminobenzoate (19.2 g, 60.7 mmol), methyl 4-iodobu tyrate (16.4 mL, 121 mmol) and cesium carbonate (39.6 g. 121 mmol) in N,N-dimethylformamide (240 mL) under nitrogen at 80° C. for 24 h. Cool the mixture to room tem O CF perature and pour into a saturated ammonium chloride solu 10 tion (500 mL) and extract with ethyl acetate (3x200 mL). X- N Combine the organic extracts and wash with water (2x400 H3C mL), brine (100 mL), then dry the solution over sodium sulfate, filter and remove the solvent under reduced pressure. CF Purify the residue using chromatography on silica gel, eluting 15 with hexanes/ethyl acetate (60:40), to provide the title com Br N pound as an orange oil (15.9 g, 63%): APCI MS 416 (M+H CH O Step 5. Preparation of Isopropyl 8-bromo-5-oxo-2,3, O 4,5-tetrahydrobenzoblazepine-1-carboxylate CH3 Adda Solution of methyl 4-bromo-2-isopropoxycarbonyl (3-methoxycarbonylpropyl)aminobenzoate (15.9 g, 38.2 Step 1. Preparation of Methyl mmol) in toluene (500 mL) over 0.5 h to a suspension of 4-bromo-2-nitrobenzoate potassium t-butoxide (8.57 g, 76.4 mmol) in toluene (1800 25 mL) at 70° C. under nitrogen. After 7 h, cool the mixture to Add concentrated sulfuric acid (7 mL) to a solution of room temperature and pour the Suspension into ice water commercially available 4-bromo-2-nitrobenzoic acid (25.0g, (2000 mL) and adjust the pH of the solution to 3 with 2 NHCl 102 mmol) in methanol (150 mL), and heat at reflux for 16 (25 mL) and separate the layers. Extract the aqueous layer hours. Cool the reaction to room temperature and pour into with ethyl acetate (3x200 mL), then combine the organic 30 extracts, dry the solution over sodium sulfate, filter and water (500 mL) and adjust the pH of the suspension to 9 with remove the solvent under reduced pressure to provide 1-iso solid sodium carbonate. Extract the solution with ethyl propyl-4-methyl-8-bromo-5-oxo-2,3,4,5-tetrahydrobenzo acetate (2x250 mL), then combine the organic extracts and blazepine-1,4-dicarboxylate as an orange semi-solid (11.8g. wash with brine (100 mL), dry over sodium sulfate, filter and 80%). Dissolve 1-isopropyl-4-methyl-8-bromo-5-oxo-2,3,4, remove the solvent under reduced pressure to afford the title 5-tetrahydrobenzoblazepine-1,4-dicarboxylate (11.8 g. 30.7 compound as a pale amber oil, which crystallizes upon stand 35 mmol) in glacial acetic acid (72 mL) and add water (6.5 mL) ing (20.5 g., 78%) followed by concentrated hydrochloric acid (22.6 mL) and heat the resulting solution at reflux for 45 min. Cool the Step 2. Preparation of Methyl mixture to room temperature and pour the Solution into ice 2-amino-4-bromobenzoate water (500 mL) and adjust the pH to 8 with potassium hydrox 40 ide (85g) in water (200 uL). Extract this mixture with ethyl Add tin(II) chloride (65.9 g, 292 mmol) to a suspension of acetate (3x150 mL) and combine the organic extracts and dry methyl 4-bromo-2-nitrobenzoate (15.2g, 58.4 mmol) in con them over sodium sulfate, filter and remove the solvent under centrated hydrochloric acid (120 mL) at room temperature reduced pressure. The crude material is purified using chro and stirfor 24h. Slowly pour the mixture into water (700 mL) matography on silica gel eluting with hexanes/ethyl acetate and adjust the pH to 9 with solid potassium hydroxide. Filter 45 (60:40), to afford the title compound as a yellow solid (5.24g, the white suspension through Celite, then stir the filter cake 52%): ESI MS 326 (M+H). with ethyl acetate and filter that suspension. Separate the Step 6. Preparation of Isopropyl 5-acetyl-(3,5-bistri filtrate and extract the aqueous layer with ethyl acetate (200 fluoromethylbenzyl)amino-8-bromo-2,3,4,5-tet mL). Combine the organic layers, dry over sodium Sulfate, rahydrobenzoblazepine-1-carboxylate filter and remove the solvent under reduced pressure to afford 50 the title compound as an off-white solid (11.3 g, 84%) Add 3,5-bis(trifluoromethyl)benzylamine (5.47 g. 22.5 Step 3. Preparation of Methyl mmol) followed by titanium isopropoxide (5.98 mL. 20.1 4-bromo-2-isopropoxycarbonylaminobenzoate mmol) to a solution of isopropyl 8-bromo-5-oxo-2,3,4,5-tet 55 rahydrobenzoblazepine-1-carboxylate (5.24 g. 16.1 mmol) Addisopropylchloroformate (104 mL, 104 mmol. 1.0M in in tetrahydrofuran (20 mL) at room temperature under nitro gen was and stir the solution for 4 h. Dilute the reaction with toluene) dropwise to a solution of methyl 2-amino-4-bro methanol (40 mL) and slowly add sodium borohydride (0.912 mobenzoate (14.5 g. 63.0 mmol) and pyridine (10.3 mL, g, 24.1 mmol) over 15 minto the reaction and stir at room 126.0 mmol) in dichloromethane (210 mL) at room tempera temperature for 3.5h. Quench the reaction with addition of 2 ture under nitrogen and stir for 5.5 h. Pour the reaction into 60 NNaOH (56 mL) and water (50 mL) and stir for 0.5 h. Filter water (500 mL) and separate the layers. Extract the aqueous the mixture and wash the solids with ethyl acetate/ethanol layer with dichloromethane (2x100 mL) and combine the (4:1, 3x100 mL). Separate the filtrate and wash the organic organic extracts and wash with 2 NHCl, saturated sodium layer with 2 NNaOH, 2 NHCl, and brine (50 mL each), then bicarbonate and brine (100 mL each), then dry over sodium dry the solution over sodium sulfate, filter and remove the sulfate, filter and remove the solvent under reduced pressure 65 solvent under reduced pressure to afford isopropyl-5-(3.5- to afford the title compound as a pale orange Solid (19.2 g, bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahy 96%) drobenzoblazepine-1-carboxylate as a white solid. Addace US 7,749,992 B2 47 48 tic anhydride (22.6 mL. 241 mmol) dropwise to a suspension Add a solution of isopropyl-5-acetyl-(3,5-bistrifluorom of isopropyl 5-(3,5-bistrifluoromethylbenzylamino)-8- ethylbenzyl)amino-8-bromo-2,3,4,5-tetrahydrobenzob bromo-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate azepine-1-carboxylate (0.080 g, 0.134 mmol) in tetrahydro (8.89 g, 16.1 mmol) and pyridine (19.6 mL g, 241 mmol) in furan (1 mL) to phenylboronic acid (0.024g, 0.202 mmol), dichloromethane (64 mL) under nitrogen cooled to 0° C. 5 After the addition is complete, remove the cooling bath and palladium acetate (0.0015g, 0.0067 mmol), 2-(dicyclohexy warm the reaction to room temperature and stir for 12 h. lphosphino)biphenyl (0.0047g, 0.013 mmol) and potassium Dilute the mixture with dichloromethane (100 mL) and wash fluoride (0.023 g, 0.403 mmol) and purge with nitrogen and with 2 N hydrochloric acid (2x50 mL), saturated aqueous stir for 2 hat room temperature, then at 50° C. for 12 h. After sodium bicarbonate (50 mL) and brine (50 mL). Dry the 10 this initial period, additional phenylboronic acid (0.024 g. organic layer over Sodium Sulfate, filter and remove the Sol 0.202 mol), palladium acetate (0.0015 g, 0.0067 mmol), vent under reduced pressure. Purify the residue using chro matography on silica gel, eluting with hexanes/ethyl acetate 2-(dicyclohexylphosphino)biphenyl (0.0047 g., 0.013 mmol) and potassium fluoride (0.023 g, 0.403 mmol) is added and (60:40), to afford the title compound as a white solid (7.60 g, 15 79%, 2 steps): ESI MS 595 (M+H). the reaction is heated at 50° C. for 1 h. Cool the reaction to room temperature and dilute with ethyl acetate (30 mL) and Example 23 wash with 2 Nsodium hydroxide and brine (10 mL each). Dry the organic layer over Sodium sulfate, filter and remove the Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) solvent under reduced pressure. Purify the residue using chro amino-8-fluoro-2,3,4,5-tetrahydrobenzoblazepine 1-carboxylate matography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a white solid (0.058 g, 72%): ESI MS 593 (M+H). O CF 25 Example 25 X- N H3C Synthesis of Isopropyl 5-acetyl-(3,5-bistrifluorom ethylbenzyl)amino-8-cyano-2,3,4,5-tetrahydrobenzo CF 30 blazepine-1-carboxylate

F N CH O O CF O 35 CH3 This compound was prepared utilizing the same method ology described in Example 22 by replacement of methyl 2-amino-4-bromobenzoate with 2-amino-4-fluorobenzoate 40 CF following the procedure of Example 22, Steps 1-6 for the synthesis of isopropyl 5-acetyl-(3,5-bistrifluoromethylben NC N Zyl)amino-8-bromo-2,3,4,5-tetrahydrobenzoblazepine-1- CH carboxylate. EI MS 535 (M+H). O 45 O Example 24 CH3 Synthesis of Isopropyl 5-acetyl-(3,5-bistrifluorom Purge with nitrogen, a solution of isopropyl-5-acetyl-(3. ethylbenzyl)amino-8-phenyl-2,3,4,5-tetrahy 5-bistrifluoromethylbenzyl)amino-8-bromo-2,3,4,5-tet drobenzoblazepine-1-carboxylate 50 rahydrobenzoblazepine-1-carboxylate (0.074 g., 0.124 mmol) and Zinc cyamide (0.014 g., 0.124 mmol) in N.N- dimethylformamide (2 mL) in a 10 mL microwave vial. Add tetrakis(triphenylphosphine)palladium (O) (0.0043 g, 0.0037 55 mmol) and irradiate the mixture at 175° C. for 0.5 h (60-80 Watts). Add a second portion of zinc cyamide (0.014g, 0.124 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.0043 g, 0.0037 mmol) and continue irradiating for 8 min. Cool the mixture to room temperature and dilute with ethyl 60 acetate (35 mL) and wash with water (3x25 mL) and brine (25 mL each), then dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with 65 hexanes/ethyl acetate (60:40), to provide the title compound as a crushable white foam (0.034 g. 51%): ESI MS 542 (M+H). US 7,749,992 B2 49 50 Example 26 Example 27 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) amino-8-amino-2,3,4,5-tetrahydrobenzoblazepine amino-8-methanesulfonylamino-2,3,4,5-tetrahy 1-carboxylate drobenzoblazepine-1-carboxylate

O CF CF 10 O 3

H3CX HC O. O CF CF 15 \/ HC1 SN N HN N CH3 CH3 O O O O CH3 CH Add methanesulfonyl chloride (13 ul, 0.170 mmol) drop wise to a suspension of isopropyl-5-acetyl-(3,5-bistrifluo Step 1. Preparation of Isopropyl 5-acetyl-(3,5-bistri 25 romethylbenzyl)amino-8-amino-2,3,4,5-tetrahydrobenzo fluoromethylbenzyl)amino-8-(benzhydrylidene blazepine-1-carboxylate (0.082g, 0.154 mmol) and pyridine amino)-2,3,4,5-tetrahydrobenzoblazepine-1-car (15ul, 0.185 mmol) in dichloromethane (2 mL) at 0°C. under boxylate nitrogen. Stir the orange suspension for 0.5h, then remove the cooling bath and warm the mixture to room temperature and 30 stir overnight. Dilute the mixture with dichloromethane (30 Combine tris(dibenzylideneacetone)dipalladium (O) mL) and wash with 2 NHCl, water and brine (10 mL each), (0.077 g., 0.084 mmol), 2,2'-bis(diphenylphosphino)-1,1'-bi then dry the organic layer over Sodium Sulfate, filter and naphyl (0.157g, 0.252 mmol) and sodium t-butoxide (0.113 remove the solvent under reduced pressure. Purify the residue g, 1.18 mmol) in toluene (5 mL) and purge this suspension 35 using chromatography on silica gel, eluting with ethyl with nitrogen at room temperature for 5 min. Add benzophe acetate/hexanes (70:30), to provide the title compound as a noneimine (0.155 mL, 0.924 mmol) followed by isopropyl white solid (0.055 g, 58%): ESIMS 610 (M+H). 5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-8-bromo-2, The following Examples were prepared utilizing the same 3,4,5-tetrahydrobenzoblazepine-1-carboxylate (0.500 g, methodology described in Example 27 wherein R1 is a vari 40 able and is introduced by replacement of methanesulfonyl 0.840 mmol) and heat this mixture at 80° C. under nitrogen chloride with alternative reagents following the procedure of for 1 h. Cool the mixture to room temperature, dilute with Example 27 for the synthesis of Isopropyl 5-acetyl-(3.5- dichloromethane and filter through Celite. Remove the filtrate bistrifluoromethylbenzyl)amino-8-methanesulfonylamino Solvent under reduced pressure and purify the residue using 2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate. chromatography on silica gel, eluting with hexanes/ethyl 45 acetate (60:40), to provide the title compound as an orange oil (0.520 g, 89%): APCI MS 696 (M+H). CF O Step 2. Preparation of Isopropyl 5-acetyl-(3,5-bistri fluoromethylbenzyl)amino-8-amino-2,3,4,5-tetrahy X drobenzoblazepine-1-carboxylate H3C CF Add 2 N hydrochloric acid (0.19 mL) to a solution of 55 RIn isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-8- N N (benzhydrylideneamino)-2,3,4,5-tetrahydrobenzob. CH3 O azepine-1-carboxylate (0.520 g, 0.747 mmol) in tetrahydro O furan (5 mL) at room temperature and stir for 3 h. Dilute the CH mixture with ethyl acetate (20 mL) and wash with saturated 60 sodium bicarbonate solution and brine (10 mL each), then dry Example # Reagent R1 MS (ES+) the organic layer over sodium sulfate, filter and remove the Example 28 acetic anhydride Acetyl 574 (M+H) Example 29 benzenesulfonyl benzenesulfonyl 670 (M+H) solvent under reduced pressure. Purify the residue using chro chloride matography on silica gel, eluting with hexanes/ethyl acetate 65 Example 30 benzoyl chloride Benzoyl 636 (M+H) (1:1), to provide the title compound as an off-white solid (0.297 g, 75%): 530 (M-H). US 7,749,992 B2 51 52 Example 31 Example 34 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) amino-8-methyl-2,3,4,5-tetrahydrobenzoblazepine amino-8-dimethylamino-2,3,4,5-tetrahydrobenzob 1-carboxylate aZepine-1-carboxylate

CF CF 10 O 3 X- N H3C

CF 15 CF H3C N N N f CH CH3 H3C O O O O CH3 CH3

Purge with nitrogen, a Suspension ofisopropyl-5-acetyl Add sodium cyanoborohydride (0.011 g, 0.175 mmol) in one portion to a solution of isopropyl-5-acetyl-(3,5-bistrif (3,5-bistrifluoromethylbenzyl)amino-8-bromo-2,3,4,5-tet 25 rahydrobenzoblazepine-1-carboxylate (0.153 g, 0.257 luoromethylbenzyl)amino-8-amino-2,3,4,5-tetrahy mmol), trimethylboroxine (36 ul, 0.257 mmol), and potas drobenzoblazepine-1-carboxylate (0.031 g, 0.058 mmol) sium carbonate (0.106 g. 0.771 mmol) in N,N-dimethylfor and 37% aqueous formaldehyde (0.014 mL, 0.192 mmol) in mamide (2 mL) in a 10 mL microwave vessel. Add tetrakis acetonitrile (3.2 mL) at room temperature. Add acetic acid (triphenylphosphine)palladium (O) (0.030 g, 0.026 mmol) 30 over 40 minto the resulting clear solution and stir for 2 h. and irradiate the mixture at 150° C. for 20 min (50W). Dilute Dilute the reaction with methylene chloride (30 mL) and the mixture with ethyl acetate (20 mL), wash with water and wash with 2 N NaOH (10 mL) and brine (20 mL), then dry brine (10 mL each), then dry the organic layer over sodium over sodium sulfate, filter and remove solvent under reduced pressure. Purify the residue using chromatography on silica sulfate, filter and remove the solvent under reduced pressure. 35 Purify the residue first using chromatography on silica gel. gel, eluting with hexanes/ethyl acetate (60:40), to provide the eluting with hexanes/ethyl acetate (60:40), to provide the title title compound as a white solid (0.021 g, 64%): ESIMS 560 compound as a white solid (0.056 g., 41%): 531 (M--H). (M+H). The following Examples were prepared utilizing the same Example 35 methodology described in Example 31 wherein R1 is a vari 40 able and is introduced by replacement of trimethylboroxine Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) with alternative reagents following the procedure of Example amino-8-diethylamino-2,3,4,5-tetrahydrobenzob. 31 for the synthesis of Isopropyl 5-acetyl-(3,5-bistrifluo aZepine-1-carboxylate romethylbenzyl)amino-8-methyl-2,3,4,5-tetrahydrobenzo 45 blazepine-1-carboxylate.

CF O 3 CF O 50 X- N X- N HC HC CF CF 55 He1N N Ri N u - CH CH3 H3C O O -Q O CH O 60 CH This compound was prepared utilizing the same method Example # Reagent R1 MS (ES+) ology described in Example 34 wherein replacement of form Example 32 tributyl (vinyl)tin Vinyl 543 (M+H) aldehyde with acetaldehyde following the procedure of Example 33 ethylboronic acid Ethyl 545 (M+H) 65 Example 34 for the synthesis of Isopropyl 5-acetyl-(3.5- bistrifluoromethylbenzyl)amino-8-dimethylamino-2,3,4,5- tetrahydrobenzoblazepine-1-carboxylate. US 7,749,992 B2 53 54 Example 36 Combine tris(dibenzylideneacetone)dipalladium (O) (0.015 g, 0.017 mmol), 2,2'-bis(diphenylphosphino)-1,1'-bi Synthesis of (+/-)-Isopropyl 5-acetyl-(3,5-bistrif naphyl (0.031 g, 0.050 mmol) and sodium t-butoxide (0.023 luoromethylbenzyl)amino-8-hydroxymethyl-2,3,4, g, 0.235 mmol) in toluene (3 mL) in a 10 mL microwave 5-tetrahydrobenzoblazepine-1-carboxylate vessel and purge this suspension with nitrogen at room tem perature for 5 min. Add morpholine (0.016 mL, 0.185 mmol) followed by isopropyl-5-acetyl-(3,5-bistrifluoromethylben Zyl)amino-8-bromo-2,3,4,5-tetrahydrobenzoblazepine-1- CF O 3 carboxylate (0.100 g, 0.168 mmol) and irradiate this mixture 10 at 110° C. for 15 min. Dilute the cooled mixture with dichlo ly N romethane and filter through Celite. Remove the filtrate sol HC vent under reduced pressure and purify the residue using chromatography on silica gel, eluting with hexanes/ethyl CF 15 acetate (60:40), to provide the title compound a yellow solid HO (0.041 g, 40%): ESI MS 602 (M+H) N The following Examples were prepared utilizing the same CH methodology described in Example 37 wherein R1 is a vari O able and is introduced by replacement of morpholine with O alternative reagents following the procedure of Example 37 CH3 for the synthesis of Isopropyl 5-acetyl-(3,5-bistrifluorom ethylbenzyl)amino-8-morpholin-4-yl-2,3,4,5-tetrahy Add butyl lithium (0.157 mL, 0.252 mmol, 1.6M in hex drobenzoblazepine-1-carboxylate. anes) dropwise to a solution of isopropyl-5-acetyl-(3,5-bis trifluoromethylbenzyl)amino-8-bromo-2,3,4,5-tetrahy 25 drobenzoblazepine-1-carboxylate (0.100 g, 0.168 mmol) in CF tetrahydrofuran (2 mL) under nitrogen at -78°C. and stir for O 1 h. Add N,N-dimethylformamide (0.052 mL, 0.672 mmol) dropwise to the cold solution and stir for 40 min at -78°C. X- N then warm to room temperature. Quench the reaction with 30 H3C saturated aqueous ammonium chloride (10 mL) and dilute with ethyl acetate (20 mL). Separate the layers and wash the CF organic layer with water (2x30 mL) and brine (30 mL), then dry over sodium sulfate, filter and remove solvent under N N reduced pressure to provide the crude aldehyde. Dissolve the 35 CH3 crude aldehyde (0.091 g, 0.167 mmol) in methanol (3 mL) O and add sodium borohydride (0.019 g, 0.501 mmol) in one O portion at room temperature. After stirring for 3 h, dilute the CH reaction with ethyl acetate (25 mL) and wash with brine (40 Example # Reagent R1 MS (ES+) mL), then dry the organic layer over Sodium sulfate, filter and 40 remove the solvent under reduced pressure. Purify the crude Example 38 Pyrrollidine pyrrollidin-1-yl 586 (M+H) material by chromatography on silica gel, eluting with aceto Example 39 Ethylamine ethylamino nitrile to provide the title compound as an off-white solid Example 40 Azetidine aZetidin-1-yl 572 (M+H) (0.008 g, 8%): ESI MS 547 (M+H). 45 Example 37 Example 41 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) amino-8-morpholin-4-yl-2,3,4,5-tetrahydrobenzob. amino-8-methoxy-2,3,4,5-tetrahydrobenzob. azepine-1-carboxylate 50 aZepine-1-carboxylate

CF O CF 55 X- N H3C

CF CF 60 H3CO N CH3 O O 65 CH3 US 7,749,992 B2 55 56 Combine isopropyl-5-acetyl-(3,5-bistrifluoromethylben temperature and stir for 1 h. Dilute the reaction with water (25 Zyl)amino-8-bromo-2,3,4,5-tetrahydrobenzoblazepine-1- mL) and extract with ethyl acetate (2x10 mL). Dry the com carboxylate (0.100 g, 0.168 mmol), palladium acetate (0.001 bined organic extracts over Sodium sulfate, filter and remove g, 0.0033 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopro the solvent under reduced pressure. Purify the residue using pylbiphenyl (0.002 g, 0.0041 mmol), cesium carbonate chromatography on silica gel, eluting with ethyl acetate/hex (0.082 g, 0.252 mmol), and methanol (0.03 mL, 0.67 mmol) in toluene (1 mL) in a 10 mL microwave vessel and irradiate anes (70:30), to provide the title compound as a white solid the mixture at 110° C. for 30 min (45 W). Dilute the mixture (0.016 g., 44%): ESI MS 595 (M+H). with ethyl acetate (20 mL), filter through Celite(R) and remove the solvent under reduced pressure. Purify the residue using Example 44 chromatography on silica gel, eluting with hexanes/ethyl 10 acetate (60:40), to provide the title compound as a white solid Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) (0.028 g., 30%): ESI MS 547 (M+H) amino-8-benzyloxy-2,3,4,5-tetrahydrobenzob. aZepine-1-carboxylate Example 42 15 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) amino-8-thiomethyl-2,3,4,5-tetrahydrobenzob azepine-1-carboxylate CF CF O 3

CF

CF 25 O N CH HCS N O CH3 O CH3 O O 30 CH3 Combine isopropyl-5-acetyl-(3,5-bistrifluoromethylben Combine isopropyl-5-acetyl-(3,5-bistrifluoromethylben Zyl)amino-8-bromo-2,3,4,5-tetrahydrobenzoblazepine-1- Zyl)amino-8-bromo-2,3,4,5-tetrahydrobenzoblazepine-1- carboxylate (0.100 g, 0.168 mmol), tris(dibenzylideneac carboxylate (0.100 g, 0.168 mmol) and sodium thiomethox etone)dipalladium (O) (0.0031 g, 0.0033 mmol), 2-di-tert ide (0.018 g., 0.252 mmol) in N,N-dimethylformamide (0.34 35 butylphosphino-2',4',6'-triisopropylbiphenyl (0.0043 g, mL) in a 10 mL microwave vessel and irradiate at 100° C. for 0.010 mmol), cesium carbonate (0.082 g, 0.252 mmol) and 40 min (50 W). Dilute the mixture with ethylacetate (20 mL) benzyl alcohol (0.035 mL, 0.336 mmol) in toluene (0.67 mL) and wash with water (2x25 mL) and brine (25 mL). Dry the in a sealed tube and heat at 110°C. for 20h. Dilute the cooled organic layer over Sodium Sulfate, filter and remove the Sol mixture with dichloromethane (50 mL) and filter through vent under reduced pressure. Purify the crude material using 40 Celite. Remove the filtrate solvent under reduced pressure chromatography on silica gel, eluting with hexanes/ethyl: and first purify the residue using chromatography on silica acetate (60:40), to provide the title compound as a white solid gel, eluting with hexanes/ethyl acetate (60:40), to provide the (0.033 g, 35%).0. ESI MS 563 (M+H)-. title compound as a white solid (0.054g, 52%): ESIMS 623 (M+H). Example 43 45 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) Example 45 amino-8-methanesulfonyl-2,3,4,5-tetrahydrobenzo blazepine-1-carboxylate Isopropyl 5-acetyl-(3,5'-bistrifluoromethylbenzyl) amino-8-hydroxy-2,3,4,5-tetrahydrobenzob. CF 50 O 3 aZepine-1-carboxylate X- N H3C O CF CF 55 H3CN X- N H3C 7\ N CH O O 3 O CF O 60 CH HO N Add a solution of oxone (0.111 g, 0.181 mmol) in water (1 CH mL) dropwise to a solution ofisopropyl 5-acetyl-(3,5-bistri O O fluoromethylbenzyl)amino-8-thiomethyl-2,3,4,5-tetrahy 65 drobenzoblazepine-1-carboxylate (0.034g, 0.060 mmol) in CH3 methanol (2 mL) at 0°C. Warm the white suspension to room US 7,749,992 B2 57 58 Combine isopropyl-5-acetyl-(3,5-bistrifluoromethylben Step 3. Preparation of tert-Butyl 5-acetyl-(3,5-bistri Zyl)amino-8-benzyloxy-2,3,4,5-tetrahydrobenzob. fluoromethylbenzyl)amino-8-bromo-2,3,4,5-tet azepine-1-carboxylate (0.050 g, 0.080 mmol) and 10% pal rahydrobenzoblazepine-1-carboxylate ladium on carbon (50% wet, 10 mg) in ethanol (3 mL) and stir at room temperature under an atmosphere of hydrogen (1 5 Add 3,5-bis(trifluoromethyl)benzylamine (1.49 g, 6.13 atm) for 19 h. Filter the reaction through Celite, rinse the filter mmol) followed by titanium isopropoxide (1.60 mL, 5.47 cake with ethyl acetate and remove the filtrate solvent under mmol) to a solution of tert-butyl 8-bromo-5-oxo-2,3,4,5-tet reduced pressure. Purify the crude material using chromatog rahydrobenzoblazepine-1-carboxylate (1.49 g, 4.38 mmol) raphy on silica gel, eluting with hexanes/ethyl acetate (60: in tetrahydrofuran (17.5 mL) at room temperature under 40), to provide the title compound as a white solid (0.054g, 10 nitrogen and stir the solution for 14h. Dilute the reaction with 52%): ESIMS 533 (M+H). methanol (35 mL) and slowly add sodium borohydride (0.248 g, 6.57 mmol) to the reaction and stir at room temperature for Example 46 3 h. Add 2 NNaOH (20 mL) and water (20 mL) to the reaction and stir for 0.5 h. Filter the mixture and wash the solids with tert-Butyl-5-acetyl-(3,5-bistrifluoromethylbenzyl) ethyl acetate (3x75 mL). Separate the filtrate and wash the amino-8-bromo-2,3,4,5-tetrahydrobenzoblazepine organic layer with brine (25 mL), then dry the solution over 1-carboxylate sodium sulfate, filter and remove the solvent under reduced pressure to afford tert-butyl 5-(3,5-bistrifluoromethylbenzy lamino)-8-bromo-2,3,4,5-tetrahydrobenzoblazepine-1-car boxylate as a white solid. Add acetic anhydride (6.0 mL. 64.0 CF mmol) dropwise to a suspension of tert-butyl 5-(3,5-bistrif luoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahy drobenzoblazepine-1-carboxylate (2.42 g, 4.26 mmol) and pyridine (5.2 mL, 64.0 mmol) in dichloromethane (17 mL) 25 under nitrogen cooled to 0°C. After the addition is complete, CF remove the cooling bath and warm the reaction to room tem perature and stir for 12 h. Dilute the mixture with dichlo Br N romethane (25 mL) and wash with 2 M potassium hydrogen CH Sulfate and Saturated aqueous Sodium bicarbonate (25 mL O CH 30 each). Dry the organic layer over sodium Sulfate, filter and O remove the solvent under reduced pressure. Purify the residue CH3 using chromatography on silica gel, eluting with hexanes/ ethyl acetate (60:40), to afford the title compound as a white solid. Step 1. Preparation of 35 8-Bromo-1,2,3,4-tetrahydrobenzoblazepin-5-one Example 47 Dissolve 1-isopropyl-4-methyl-8-bromo-5-oxo-2,3,4,5- tert-Butyl-5-acetyl-(3.5-bistrifluoromethylbenzyl) tetrahydrobenzoblazepine-1,4-dicarboxylate (4.47 g, 11.6 amino-8-methyl-2,3,4,5-tetrahydrobenzoblazepine mmol) in glacial acetic acid (32 mL). Add water (2.9 mL) 40 1-carboxylate followed by concentrated HCl (9.9 mL) and heat the orange solution at reflux for 24 h. Cool the mixture to room tempera ture and remove the solvents under reduced pressure. Add 2 N NaOH to the residue and extract this mixture with ethyl CF acetate (3x100 mL), then combine the organic extracts, dry 45 the solution over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the crude material using chro matography on silica gel eluting with hexanes/ethyl acetate (60:40), to provide 8-bromo-1,2,3,4-tetrahydrobenzob CF azepin-5-one as an orange solid (1.39 g, 50%). 50 Step 2. Preparation of tert-Butyl 8-bromo-5-oxo-2.3, N 4,5-tetrahydrobenzoblazepine-1-carboxylate CH O CH3 O Add di-tert-butyl-dicarbonate (0.189 g, 0.866 mmol) to a 55 solution of 8-bromo-1,2,3,4-tetrahydrobenzoblazepin-5- CH3 one (0.104g, 0.433 mmol), N,N-diisopropylethylamine (0.15 mL, 0.866 mmol) and 4-(dimethylamino)pyridine (0.010 g, Combine tert-butyl-5-acetyl-(3,5-bistrifluoromethylben 0.087 mmol) in dichloromethane (1 mL) at 0°C. and slowly Zyl)amino-8-bromo-2,3,4,5-tetrahydrobenzoblazepine-1- warm to room temperature. After 6 hadd more di-tert-butyl 60 carboxylate (0.438 g. 0.719 mmol), methylboronic acid dicarbonate (0.189 g, 0.866 mmol) and N,N-diisopropylethy (0.086 g, 1.44 mmol), 1,1'-bis(diphenylphosphino)fer lamine (0.15 mL, 0.866 mmol) and stir at room temperature rocenedichloropalladium(II), complex with dichlo for 15 h. Remove the solvent under reduced pressure and romethane (1:1) (0.059 g, 0.072 mmol) and cesium fluoride purify the crude material using chromatography on silica gel. (0.328 g, 2.16 mmol) in dioxane (2.5 mL) in a 10 mL micro eluting with hexanes/ethyl acetate (60:40), to afford tert-butyl 65 wave vessel and irradiate this mixture at 110° C. for 80 min. 8-bromo-5-oxo-2,3,4,5-tetrahydrobenzoblazepine-1-car Dilute the cooled mixture with dichloromethane and filter boxylate as an off-white solid (0.097 g. 66%). through Celite(R). Remove the filtrate solvent under reduced US 7,749,992 B2 59 60 pressure and purify the residue first using chromatography on 160° C. for 60 min (170 W). Cool the mixture to room tem silica gel, eluting with hexanes/ethyl acetate (60:40), to afford perature and dilute with ethyl acetate (30 mL) and wash with the title compound as a white solid (0.116 g. 30%). water (2x30 mL) and brine (30 mL), then dry the organic layer over sodium sulfate, filter and remove the solvent under Example 48 reduced pressure. Purify the mixture using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), ESI Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) MS 585 (M+H). amino-8-chloro-7-cyano-2,3,4,5-tetrahydrobenzob. azepine-1-carboxylate Example 50 10 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) amino-8-chloro-7-dimethylamino-2,3,4,5-tetrahy CF drobenzoblazepine-1-carboxylate O 3

X- N 15 HC NC O CF CF ly N H3C C N CH3 (H3C)N CF O O CH3 C N 25 CH O Purge with nitrogen a suspension of isopropyl-5-acetyl O (3,5-bistrifluoromethylbenzyl)amino-7-bromo-8-chloro-2, CH3 3,4,5-tetraydrobenzoblazepine-1-carboxylate (0.100 g, 0.159 mmol) and zinc cyamide (0.023 g, 0.198 mmol) in N,N-dimethylformamide (3 mL) at room temperature in a 10 30 Combine isopropyl-5-acetyl-(3,5-bistrifluoromethylben mL microwave vessel. Add tetrakis(triphenylphosphine)pal Zyl)amino-7-bromo-8-chloro-2,3,4,5-tetrahydrobenzob. ladium (0) (0.006 g., 0.0047 mmol) and irradiate the mixture azepine-1-carboxylate (0.075 g, 0.119 mmol), tris(diben at 175° C. for 5 min (50-75 W). Cool the mixture to room Zylideneacetone)dipalladium (O) (0.003 g, 0.0029 mmol), temperature and dilute with ethyl acetate (30 mL) and wash 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl with water (3x10 mL) and brine (25 mL), then dry the organic 35 (0.006 g., 0.012 mmol), sodium tert-butoxide (0.029 g, 0.298 layer over sodium sulfate, filter and remove the solvent under mmol) and dimethylamine (0.071 mL, 0.143 mmol. 2.0 M in reduced pressure. Purify the residue using chromatography THF) in toluene (0.5 mL) in a 10 mL microwave vessel and on silica gel, eluting with hexanes/ethyl acetate (60:40), to irradiate at 110°C. for 20 min (50 W). Add a large excess of provide the title compound as a white solid (0.051 g, 56%): dimethylamine (2 mL, 4 mmol. 2.0 M in THF) and irradiate at ESI MS 576 (M+H). 40 110° C. for 20 min. Dilute the cooled mixture with ethyl acetate (25 mL) and filter through Celite. Remove the filtrate Example 49 Solvent under reduced pressure and purify the residue using chromatography on silica gel, eluting with hexanes/ethyl Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) acetate (60:40), to provide the title compound as an off-white amino-7,8-dichloro-2,3,4,5-tetrahydrobenzob solid (0.037 g., 52%): ESI MS 594 (M+H). azepine-1-carboxylate 45 Example 51 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) CF amino-8-chloro-7-methoxy-2,3,4,5-tetrahydrobenzo O 3 50 blazepine-1-carboxylate

HCX C CF O 3 CF 55 X- N C N H3C CH HCO O CF O 60 CH3 C N CH3 Irradiate a suspension of isopropyl-5-acetyl-(3,5-bistrif O luoromethylbenzyl)amino-7-bromo-8-chloro-2,3,4,5-tet O rahydrobenzoblazepine-1-carboxylate (0.100 g, 0.159 65 CH mmol) and copper(I) chloride (0.017 g., 0.175 mmol) in N.N- dimethylformamide (1.5 mL) in a 10 mL microwave vessel at US 7,749,992 B2 61 62 Combine isopropyl-5-acetyl-(3,5-bistrifluoromethylben rahydrobenzoblazepine-1-carboxylate (0.053 g, 0.087 Zyl)amino-7-bromo-8-chloro-2,3,4,5-tetrahydrobenzob. mmol) and copper(I) chloride (0.013 g, 0.130 mmol) in N.N- azepine-1-carboxylate (0.050 g, 0.079 mmol), tris(diben dimethylformamide (0.35 mL) in a 10 mL microwave vessel Zylideneacetone)dipalladium (O) (0.0014 g., 0.0015 mmol), at 160° C. for 20 min (110 W). Cool the mixture to room 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl (0.002 temperature and dilute with ethyl acetate (30 mL) and wash g, 0.0047 mmol), cesium carbonate (0.039 g, 0.119 mmol) with water (2x40 mL) and brine (25 mL), then dry the organic and methanol (0.016 mL, 0.397 mmol) in toluene (1 mL) in a layer over sodium sulfate, filter and remove the solvent under sealed tube and heat at 110° C. for 24 h. Dilute the cooled reduced pressure. The crude material was first purified using mixture with ethyl acetate (25 mL) and filter through Celite. chromatography on silica gel, eluting with hexanes/ethyl Remove the filtrate solvent under reduced pressure and first purify the residue using chromatography on silica gel, eluting 10 acetate (60:40), to provide the title compound as a white solid with hexanes/ethyl acetate (60:40), to provide the title com (0.014g, 29%): ESI MS 565 (M+H). pound as a white solid (0.017 g., 37%): ESI MS 581 (M+H). Example 54 Example 52 15 Isopropyl 5-Acetyl-(3,5-bis-trifluoromethyl-ben Isopropyl-5-acetyl-(3,5-bistrifluoromethylbenzyl) Zyl)-amino-7-amino-8-methyl-2,3,4,5-tetrahydro amino-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo benzoblazepine-1-carboxylate blazepine-1-carboxylate

CF O 3 CF X- N HC Br 25 CF CF

HC N N CH3 CH O 30 O ---> CH3 Add bromine (0.016 mL, 0.303 mmol) dropwise to a solu This compound was prepared utilizing the same method tion of isopropyl-5-acetyl-(3,5-bistrifluoromethylbenzyl) ology described in Example 26 wherein replacement of iso amino-8-methyl-2,3,4,5-tetrahydrobenzoblazepine-1-car 35 propyl-5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-8- boxylate (0.153 g, 0.288 mmol) in glacial acetic acid (2.8 mL) bromo-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate and heat at 50° C. under nitrogen for 18 h. Cool the mixture to with isopropyl-5-acetyl-(3,5-bistrifluoromethylbenzyl) room temperature, dilute with ethyl acetate (50 mL) and wash amino-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzob. with saturated sodium bicarbonate (2x50 mL) and 10% aque azepine-1-carboxylate following the procedure of Example ous sodium thiosulfate (50 mL), then dry the organic layer 40 26, Steps 1-2 for the synthesis of isopropyl 5-acetyl-(3.5- over sodium sulfate, filter and remove the solvent under reduced pressure to provide the title compound as a white bistrifluoromethylbenzyl)amino-8-amino-2,3,4,5-tetrahy solid (0.176 g, >99%): ESIMS 609 (M+H). drobenzoblazepine 1-carboxylate. CIMS 546 (M+H). Example 55 Example 53 45 Isopropyl-5-acetyl-(3,5-bistrifluoromethylbenzyl) Isopropyl-5-acetyl-(3,5-bistrifluoromethylbenzyl) amino-7-chloro-8-methyl-2,3,4,5-tetrahydrobenzo amino-7-dimethylamino-8-methyl-2,3,4,5-tetrahy blazepine-1-carboxylate drobenzoblazepine-1-carboxylate 50

CF O 3 O CF

X- N 55 X- N HC HC C (H3C)N CF CF

HC N 60 HC N CH CH O O O O CH3 CH3 65 Irradiate a suspension of isopropyl-5-acetyl-(3,5-bistrif This compound was prepared utilizing the same method luoromethylbenzyl)amino-7-bromo-8-methyl-2,3,4,5-tet ology described in Example 50 wherein replacement of iso US 7,749,992 B2 63 64 propyl-5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-7- This compound was prepared utilizing the same method bromo-8-chloro-2,3,4,5-tetrahydrobenzoblazepine-1- ology described in Example 56 wherein replacement of iso carboxylate with isopropyl-5-acetyl-(3.5- propyl-5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-8- bistrifluoromethylbenzyl)amino-7-bromo-8-methyl-2,3,4, methyl-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate 5-tetrahydrobenzoblazepine-1-carboxylate the procedure of 5 with isopropyl-5-acetyl-(3,5-bistrifluoromethylbenzyl) Example 50 for the synthesis of isopropyl 5-acetyl-(3.5- amino-8-fluoro-2,3,4,5-tetrahydrobenzoblazepine-1-car bistrifluoromethylbenzyl)amino-8-chloro-7-dimethy boxylate following the procedure of Example 56 for the syn lamino-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate. thesis of isopropyl-5-acetyl-(3,5-bistrifluoromethylbenzyl) ESI MS m/z 574 (M+H). amino-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzob. 10 azepine-1-carboxylate. ESIMS 613 (M+H). Example 56 Example 58 Isopropyl-5-acetyl-(3,5-bistrifluoromethylbenzyl) amino-7,8-dimethyl-2,3,4,5-tetrahydrobenzob. Isopropyl 5-Acetyl-(3,5-bis-trifluoromethyl-ben azepine-1-carboxylate 15 Zyl)-amino-8-fluoro-7-methyl-2,3,4,5-tetrahydro benzoblazepine-1-carboxylate

O CF CF X- N O 3 H3C X- N H3C H3C CF 25 HC CF H3C N CH F N O CH3 O 30 O CH3 O CH3 Combine isopropyl-5-acetyl-(3,5-bistrifluoromethylben Zyl)amino-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzob. This compound was prepared utilizing the same method azepine-1-carboxylate (0.058 g., 0.095 mmol), methylboronic 35 ology described in Example 56 wherein replacement of iso acid (0.011 g, 0.190 mmol), palladium acetate (0.0009 g, propyl-5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-7- 0.004 mmol), 2-dicyclohexylphosphino-2,6'-dimethoxybi bromo-8-methyl-2,3,4,5-tetrahydrobenzoblazepine-1- phenyl (0.0036 g., 0.0087 mmol) and potassium phosphate carboxylate with isopropyl-5-acetyl-(3.5- monohydrate (0.044 g., 0.190 mmol) in toluene (2 mL) and bistrifluoromethylbenzyl)amino-7-bromo-8-fluoro-2,3,4,5- heat in a sealed tube at 100° C. for 24 h. Dilute the cooled 40 tetrahydrobenzoblazepine-1-carboxylate following the mixture with ethyl acetate (30 mL) and filter through Celite. procedure of Example 56 for the synthesis of isopropyl Remove the filtrate solvent under reduced pressure and purify 5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-7,8-dim the residue using chromatography on silica gel, eluting with ethyl-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate. ESI hexanes/ethyl acetate (60:40), to provide the title compound MS 549 (M+H). as a white solid (0.020 g, 38%): ESIMS 545 (M+H). 45 Example 59 Example 57 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) Isopropyl-5-acetyl-(3,5-bistrifluoromethylbenzyl) amino-7,8-dimethoxy-2,3,4,5-tetrahydrobenzob. amino-7-bromo-8-fluoro-2,3,4,5-tetrahydrobenzob. 50 aZepine-1-carboxylate azepine-1-carboxylate

O CF CF 55 O 3 X- N H3C H3C Br HCO CF 60 CF

F N CH O O CH3 65 US 7,749,992 B2 65 66 This compound was prepared utilizing the same method 1-8 for the synthesis of 5-acetyl-(3,5-bistrifluoromethylben ology described in Example 1 wherein replacement of Zyl)amino-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylic 2-amino-benzoic acid methyl ester with methyl 2-amino-4,5- acid isopropyl ester. CIMS 531 (M+H). dimethoxybenzoate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-acetyl-(3,5-bistrifluorometh 5 Example 62 ylbenzyl)amino-2,3,4,5-tetrahydrobenzoblazepine-1-car boxylic acid isopropyl ester. CIMS 577 (M+H). Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) amino-9-methoxy-2,3,4,5-tetrahydrobenzob. Example 60 10 aZepine-1-carboxylate Isopropyl 5-Acetyl-(3,5-bis-trifluoromethyl-ben Zyl)-amino-2,3,4,5-tetrahydro-naphtho2,3-b CF azepine-1-carboxylate 15 O 3 X- N HC CF O 2O y CF H3C N CH3

H3CO O1. O lsCH3

OC)N CH3 This compound was prepared utilizing the same method O O -Q ology described in Example 1 wherein replacement of CH 30 2-amino-benzoic acid methyl ester with methyl 2-amino-3- methoxybenzoate following the procedure of Example 1, This compound was prepared utilizing the same method Steps 1-8 for the synthesis of 5-acetyl-(3,5-bistrifluorometh ology described in Example 1 wherein replacement of ylbenzyl)amino-2,3,4,5-tetrahydrobenzoblazepine-1-car 2-amino-benzoic acid methyl ester with methyl 3-amino 35 boxylic acid isopropyl ester. CIMS 547 (M+H). naphthalene-2-carboxylate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-acetyl-(3.5- Example 63 bistrifluoromethylbenzyl)amino-2,3,4,5-tetrahydrobenzo blazepine-1-carboxylic acid isopropyl ester. CI MS 567 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) (M+H). 40 amino-9-chloro-2,3,4,5-tetrahydrobenzoblazepine Example 61 1-carboxylate

Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) 45 amino-9-methyl-2,3,4,5-tetrahydrobenzoblazepine CF 1-carboxylate O 3

50 H3C X CF O 3 CF

H3CX 55 N CH3 CF 'llO O CH3

N CH 60 This compound was prepared utilizing the same method ology described in Example 1 wherein replacement of 2-amino-benzoic acid methyl ester with methyl 2-amino-3- This compound was prepared utilizing the same method chlorobenzoate following the procedure of Example 1, Steps ology described in Example 1 wherein replacement of 65 1-8 for the synthesis of 5-acetyl-(3,5-bistrifluoromethylben 2-amino-benzoic acid methyl ester with methyl 2-amino-3- Zyl)amino-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylic methylbenzoate following the procedure of Example 1, Steps acid isopropyl ester. CIMS 551 (M+H). US 7,749,992 B2 67 68 Example 64 Example 66 Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) Isopropyl 5-Acetyl-(3,5-bis-trifluoromethyl-ben amino-9-bromo-2,3,4,5-tetrahydrobenzoblazepine Zyl)-amino-9-amino-2,3,4,5-tetrahydro-benzob. 1-carboxylate aZepine-1-carboxylate

CF 10 CF

15

Br O1. O lsCH 2O This compound was prepared utilizing the same method This compound was prepared utilizing the same method ology described in Example 26 wherein replacement of iso ology described in Example 1 wherein replacement of 25 propyl-5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-8- 2-amino-benzoic acid methyl ester with methyl 2-amino-3- bromo-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate bromobenzoate following the procedure of Example 1, Steps with isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) 1-8 for the synthesis of 5-acetyl-(3,5-bistrifluoromethylben amino-9-bromo-2,3,4,5-tetrahydrobenzoblazepine-1-car Zyl)amino-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylic boxylate following the procedure of Example 26, Steps 1-2 acid isopropyl ester. CIMS 595 (M+H). 30 for the synthesis of isopropyl 5-acetyl-(3,5-bistrifluorom ethylbenzyl)amino-8-amino-2,3,4,5-tetrahydrobenzob. azepine-1-carboxylate. CIMS 532 (M+H).

35 Example 67 Example 65 Isopropyl 5-Acetyl-(3,5-bis-trifluoromethyl-ben Zyl)-amino-9-dimethylamino-2,3,4,5-tetrahydro Isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) benzoblazepine-1-carboxylate amino-9-trifluoromethoxy-2,3,4,5-tetrahydrobenzo 40 blazepine-1-carboxylate

CF

CF 45 yO 3 H3C CF 50 CF N CH (H3C)N 1. ls N CH3 O O CH3 FCO 1. ls 55 O O CH 3 This compound prepared utilizing the same methodology described in Example 50 wherein replacement of isopropyl This compound was prepared utilizing the same method 5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-7-bromo-8- ology described in Example 1 wherein replacement of 60 chloro-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate 2-amino-benzoic acid methyl ester with methyl 2-amino-3- with isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) trifluoromethoxybenzoate following the procedure of amino-9-bromo-2,3,4,5-tetrahydrobenzoblazepine-1-car Example 1, Steps 1-8 for the synthesis of 5-acetyl-(3.5- boxylate following the procedure of Example 50 for the syn bistrifluoromethylbenzyl)amino-2,3,4,5-tetrahydrobenzo 65 thesis of isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl) blazepine-1-carboxylic acid isopropyl ester. CI MS 601 amino-8-chloro-7-dimethylamino-2,3,4,5-tetrahydrobenzo (M+H). blazepine-1-carboxylate. CIMS 560 (M+H). US 7,749,992 B2 69 70 Example 68 Example 70 Isopropyl 5-Acetyl-(3,5-bis-trifluoromethyl-ben Isopropyl 5-Acetyl-(3,5-bis-trifluoromethyl-ben Zyl)-amino-9-bromo-7-methyl-2,3,4,5-tetrahydro Zyl)-amino-9-dimethylamino-7-methyl-2,3,4,5-tet benzoblazepine-1-carboxylate rahydro-benzoblazepine-1-carboxylate

CF 10 CF O 3 X- N HC HC CF 15 CF

N N CH Br CH3 O (H3C)N O1. O lsCH O 3 CH3 This compound prepared utilizing the same methodology This compound prepared utilizing the same methodology described in Example 51 wherein replacement of isopropyl described in Example 1 wherein replacement of 2-amino 25 5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-7-bromo-8- benzoic acid methyl ester with methyl 2-amino-3-bromo-5- chloro-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate methylbenzoate following the procedure of Example 1, Steps with isopropyl 5-acetyl-(3,5-bis-trifluoromethyl-benzyl)- amino-9-bromo-7-methyl-2,3,4,5-tetrahydro-benzob. 1-8 for the synthesis of 5-acetyl-(3,5-bistrifluoromethylben azepine-1-carboxylate following the procedure of Example Zyl)amino-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylic 30 51 for the synthesis ofisopropyl 5-acetyl-(3,5-bistrifluorom acid isopropyl ester. ESIMS 609 (M+H). ethylbenzyl)amino-8-chloro-7-dimethylamino-2,3,4,5-tet rahydrobenzoblazepine-1-carboxylate. CIMS 574 (M+H).

Example 69 35 Example 71 Isopropyl 5-Acetyl-(3,5-bis-trifluoromethyl-ben Isopropyl 5-Acetyl-(3,5-bis-trifluoromethyl-ben Zyl)-amino-9-amino-7-methyl-2,3,4,5-tetrahydro Zyl)-amino-7,9-dimethyl-2,3,4,5-tetrahydro-benzo benzoblazepine-1-carboxylate blazepine-1-carboxylate 40

CF CF O 3 O 3 X- N 45 X- N HC H3C HC HC CF CF 50 N N CH3 HC CH3 O HN O1. O 1.CH3 O CH 55 This compound prepared utilizing the same methodology This compound prepared utilizing the same methodology described in Example 26 wherein replacement of isopropyl described in Example 56 wherein replacement of isopropyl 5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-8-bromo-2, 5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-7-bromo-8- 3,4,5-tetrahydrobenzoblazepine-1-carboxylate with isopro 60 methyl-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate pyl 5-acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-9- with isopropyl 5-acetyl-(3,5-bis-trifluoromethyl-benzyl)- bromo-7-methyl-2,3,4,5-tetrahydro-benzoblazepine-1- amino-9-bromo-7-methyl-2,3,4,5-tetrahydro-benzob. carboxylate following the procedure of Example 26, Steps azepine-1-carboxylate following the procedure of Example 1-2 for the synthesis of isopropyl 5-acetyl-(3,5-bistrifluo 65 56 for the synthesis ofisopropyl 5-acetyl-(3,5-bistrifluorom romethylbenzyl)amino-8-amino-2,3,4,5-tetrahydrobenzo ethylbenzyl)amino-7,8-dimethyl-2,3,4,5-tetrahydrobenzo blazepine-1-carboxylate. CIMS 546 (M+H). blazepine-1-carboxylate. ESI MS 545 (M+H). US 7,749,992 B2 71 72 Example 72 The titled compounds was prepared following the proce dures described in Example 1 by replacing 2-Amino-benzoic (S)-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- acid methyl ester with 2-Amino-4-trifluoromethyl-benzoic amino-8-chloro-2,3,4,5-tetrahydro-benzob. acid methyl ester in Example 1, step 1. MS (ES+): 585 aZepine-1-carboxylic acid isopropyl ester(isomer 1) (M+H). Preparation of 2-Aminos-trifluoromethyl-benzoic CF acid methyl ester O 3 A solution of 2-amino-4-trifluoromethyl-benzoic acid (9.15 g, 44.6 mmol) in THF/MeOH (300 ml/75.0 ml) was treated with trimethylsilyldiazonium methane (2.00 M in hexane, 10 23.0 ml) and stirred at room temperature for an hour. The reaction was quenched by acetic acid (3.00 ml). The solvent CF was evaporated in vacuo and the residue was purified by silica gel chromatography eluting with 0-10% ethyl acetate in hex C N ane to provide 8.55 g (88%) white crystalline of the titled 15 compound. The structure was confirmed by 'H-NMR. o O Example 75 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbo - nyl-amino-8-trifluoromethyl-2,3,4,5-tetrahydro The title compound was obtained by chiral resolution of benzoblazepine-1-carboxylic acid isopropyl ester Example 3 on a Chiralpak AD-H (0.46x150 mm), flow rate: 1.0 ml/min, solvents: 40% propan-2-ol in heptane, R, 2.72 min, wavelength: 225 nm. EE=100%. MS (ES+):551 (M,H). Example 73 CF 25 (R)-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- amino-8-chloro-2,3,4,5-tetrahydro-benzob. O - azepine-1-carboxylic acid isopropyl ester CF CF 30 CF N s - O CF 35 -Q C N The titled compounds was prepared following the proce 40 dures described in Example 1 by replacing 2-Amino-benzoic acid methyl ester with 2-Amino-4-trifluoromethyl-benzoic acid methyl ester in Example 1, step 1 as well as replacing acetic anhydride with methyl chloroformate in Example 1, The title compound was obtained by chiral resolution of Step 8. MS (ES+): 601 (M+H). Example 3 on a Chiralpak AD-H (0.46x150 mm), flow rate: 45 Example 76 1.0 ml/min, solvents: 40% propan-2-ol in heptane, R, 3.74 ml, wavelength: 225 nm. EE=100%. MS (ES+): 551 (M,H). 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino Example 74 8-trifluoromethyl-2,3,4,5-tetrahydro-benzob. azepine-1-carboxylic acid ethyl ester 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino 50 8-trifluoromethyl-2,3,4,5-tetrahydro-benzob. azepine-1-carboxylic acid isopropyl ester CF CF O 3 O 3 y 55 y

CF 60 CF N CF N

O - -, O -Q 65 US 7,749,992 B2 73 The titled compounds was prepared following the proce dures described in Example 1 by replacing 2-Amino-benzoic -continued acid methyl ester with 2-Amino-4-trifluoromethyl-benzoic acid methyl ester in Example 1, step 1 as well as replacing CF isopropylchloroformate with ethyl chloroformate in Example 1, Step 6. MS (ES+): 571 (M+H). Rl's N Example 77 CF 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbo 10 nyl-amino-8-trifluoromethyl-2,3,4,5-tetrahydro C N benzoblazepine-1-carboxylic acid ethyl ester o 15 CF - Example # Reagent R1 MS (ES+) O - Example 80 Ethyl chloroformate ethoxycarbonyl 581 (M+H) Example 81 Isopropyl isopropoxycarbonyl 595 (M+H) chloroformate CF Example 82 Ethyl isocyanate 3-ethyl-ureido 580 (M+H)

CF N 25 o Example 83 O 5-Acetyl-(4-fluoro-benzyl)-amino-8-chloro-2,3,4, 5-tetrahydro-benzoblazepine-1-carboxylic acid iso 30 propyl ester The titled compounds was prepared following the proce dures described in Example 1 by replacing 2-Amino-benzoic acid methyl ester with 2-Amino-4-trifluoromethyl-benzoic acid methyl ester in Example 1, step 1; replacing isopropyl chloroformate with ethylchloroformate in Example 1, Step 6; 35 as well as replacing acetic anhydride with methyl chlorofor mate in Example 1, Step 8. MS (ES+): 587 (M+H). The following Examples 78-82 were prepared utilizing the same methodology described in Example 1 wherein R1 is 40 variable and is introduced by replacement of acetic anhydride with alternative reagents following the procedure of Example C N 1, Step 8 for the synthesis of 5-Acetyl-(3,5-bis-trifluorom ethyl-benzyl)-amino)-2,3,4,5-tetrahydro-benzoblazepine 1-carboxylic acid isopropyl ester 45

CF 50 Step 1. Preparation of 8-Chloro-5-oxo-2,3,4,5-tet Rls-- N rahydro-benzoblazepine-1-carboxylic acid isopro pyl ester CF 55 The titled compound was prepared following the proce C N dures described in Example 1 from step 1 to step 6 by replac ing 2-Amino-benzoic acid methyl ester with 2-Amino-4- chloro-benzoic acid methyl ester in Example 1, step 1. MS - (ES+): 282 (M+H). 60 - Step 2. Preparation of 8-Chloro-5-hydroxyimino-2,3, 4,5-tetrahydro-benzoblazepine-1-carboxylic acid Example # Reagent R1 MS (ES+) isopropyl ester Example 78 Propionyl chloride propionyl 565 (M+H) Example 79 Trifluoroacetic 2.2.2-trifluoro- 605 (M+H) 65 anhydride acetyl To a solution of 8-Chloro-5-oxo-2,3,4,5-tetrahydro-benzo blazepine-1-carboxylic acid isopropyl ester (3.40 g, 12.1 US 7,749,992 B2 75 76 mmole) in EtOH/HO (96.0 ml/24.0 ml) was added hydroxy fluoro-benzyl)-amino-8-chloro-2,3,4,5-tetrahydro-benzo lamine hydrochloride (8.39 g, 121 mmole) followed by blazepine-1-carboxylic acid isopropyl ester. sodium acetate (9.93 g, 121 mmole). The reaction was heated under 60° C. for 3 hours. The mixture was partitioned between ethylacetate (100ml) and 1.00NHCl (100ml). After separated the two layers, the aqueous layer was extracted with more acetate (2x100 ml). The combined organics washed with NaHCO (aq) and followed by brine (2x200 ml). Dried over NaSO filtered and concentrated to provide the crude product (3.45 g, 96%), which was used directly for the next 10 step without further purification. MS (ES+): 297 (M+H). Step 3. Preparation of 5-Amino-8-chloro-2,3,4,5- tetrahydro-benzoblazepine-1-carboxylic acid iso C N propyl ester 15 To a mixture of 8-chloro-5-hydroxyimino-2,3,4,5-tetrahy dro-benzoblazepine-1-carboxylic acid isopropyl ester (3.33 g, 11.2 mmole) and MoO (2.45 g, 17.0 Lummole) in MeOH (50.0 ml) was added a solution of sodium borohydride (2.13 g, 56.2 mmole) in DMF (50.0 ml). The reaction was stirred at Exam eii Reagent R2 MS (ES+) room temperature overnight. To the reaction mixture was Exam e 83 4-trifluoromethyl 4-trifluoromethyl 483 added 2.0N NaOH (aq) (100 ml). The precipitate was benzaldenyde benzyl (M+H) 25 removed by filtration, and the filtrate was extracted with ethyl Exam e 84 4-trifluoromethoxy 4-trifluoromethoxy 499 acetate (5x100 ml). The combined organics was washed with benzaldenyde benzyl (M+H) brine (3x500 ml). Dried over NaSO, filtered and concen Exam e 85 3-trifluoromethyl 3-trifluoromethyl 483 trated to 100 ml, which was then treated with 4.0N HCl in benzyl benzyl (M+H) dioxane (3.50 ml). Removal of solvents in vacuo gave a white Exam e 86 3,5-dimethoxy 3,5-dimethoxy 475 30 benzaldenyde benzyl (M+H) solid, which washed with ethyl ether and dried under vacuum Exam e 87 3,5-dibromo 3,5-dibromo-benzyl 571,573 to provide the titled compound as hydrochloride salt (2.87 g, benzaldenyde (M+H) 80%). MS (ES+): 283 (M+H). Exam e 88 3,5-dimethyl 3,5-dimethyl-benzyl 443 benzaldenyde (M+H) Step 4. Preparation of 8-Chloro-5-(4-fluoro-benzy 35 Exam e 89 3,5-dichloro-benzyl 483,485 lamino)-2,3,4,5-tetrahydro-benzoblazepine-1-car (M+H) Exam e 90) 3,5-difluoro-benzyl 451 boxylic acid isopropyl ester (M+H) Exam e 91 3-fluoro-5- To a solution of 5-Amino-8-chloro-2,3,4,5-tetrahydro trifluoromethyl benzoblazepine-1-carboxylic acid isopropyl ester hydro 40 benzy Exam e 92 24-bis 550 chloride (0.100 g, 0.313 mmole) in DMF/HOAc (3.00 trifluoromethyl (M+H) ml/0.300 ml) was added 4-fluoro-benzyaldehyde (0.0388 g. benzy 0.313 mmole). The mixture was stirred at room temperature Exam e 93 4-fluoro-2- for an hour. To it was added sodium triacetoxyborohydride 45 trifluoromethyl (0.265 g, 1.25 mmole) in one portion and the reaction was benzy Exam e 94 2-fluoro-4- continued at room temperature overnight. The mixture was trifluoromethyl partitioned between ethyl acetate (10.0 ml) and saturated benzy Na2CO (aq) (10 ml). The organic layer was separated and Exam e 95 4-fluoro-3- 50 trifluoromethyl washed with brine (3x10.0 ml). Dried over NaSO filtered benzy and concentrated to provide the crude product (0.147 g. Exam e 96 3-fluoro-4- 100%), which was used directly for the next step without trifluoromethyl further purification. MS (ES+): 391 (M+H). benzy 55 Exam e 97 4-chloro-3- 517,519 Step 5. Preparation of 5-Acetyl-(4-fluoro-benzyl)- trifluoromethyl (M+H) amino-8-chloro-2,3,4,5-tetrahydro-benzob. benzy Exam e 98 2-chloro-5- 517,519 azepine-1-carboxylic acid isopropyl ester trifluoromethyl (M+H) benzy 60 Exam e 99 2-fluoro-5- The titled compound was prepared following the proce trifluoromethyl dures described in Example 1 Step 8. MS (ES+): 433 (M+H). benzy The following Examples 83-100 were prepared utilizing Exam e 1OO 5-fluoro-2- this same methodology described in Example 61, in which R2 trifluoromethyl benzy is variable and is introduced by replacement of 4-fluoro 65 benzaldehyde with alternative reagents following the proce dure of Example 61, Step 4 for the synthesis of 5-Acetyl-(4- US 7,749,992 B2 77 78 Example 101 and concentrated to provide the crude product (2.08 g., 78%), which was used directly for the next step without further 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino purification. MS (ES+): 264, 266 (M+H). 8-chloro-2,3,4,5-tetrahydro-benzoblazepine-1-car boxylic acid benzyl ester Step 2. Preparation of 5-Bromo-4-chloro-2-isopropoxycarbonylamino-benzoic acid methyl ester CF To a solution of 2-Amino-5-bromo-4-chloro-benzoic acid O 3 methyl ester (2.08 g, 7.86 mmol) and pyridine (1.91 ml, 23.6 10 mmol) in dichloromethane (75.0 ml) was added 1.00N iso y propylchloroformate in toluene dropwise. The mixture was stirred for 16 hours at room temperature. The mixture washed with 0.500N HCl(aq) (100 ml), and brine (3x100 ml), then CF dried (NaSO) and concentrated to an oil. Purification by 15 silica gel chromatography (gradient eluent, 0-10% ethyl C N acetate in hexane) provided 5-Bromo-4-chloro-2-isopro poxycarbonylamino-benzoic acid methyl ester (2.53 g.92%) o as a white crystalline material. MS (ES+): 350, 352 (M+H). O Step 3. Preparation of 5-Bromo-4-chloro-2-isopro poxycarbonyl-(3-methoxycarbonyl-propyl)-amino benzoic acid methyl ester To a mixture of 5-Bromo-4-chloro-2-isopropoxycarbony 25 lamino-benzoic acid methyl ester (2.52 g, 7.19 mmol) and cesium carbonate (4.68 g. 14.4 mmol) in DMF (35 ml) under The titled compound was prepared following the proce nitrogen was added methyl 4-bromobutyrate (2.60 g, 14.4 dures described in Example 1 by replacing 2-Amino-benzoic mmol) dropwise. The reaction mixture was heated to 60° C. acid methyl ester with 2-Amino-4-chloro-benzoic acid for 4 hours and then cooled to room temperature. The mixture methyl ester in Example 1, step 1 as well as replacing isopro was diluted with ethyl acetate (100 ml), and thenwashed with pyl chloroformate with benzyl chloroformate in Example 1, 30 0.1N HCl(aq) (100 ml) and brine (3x100 ml). The organic Step 6. MS (ES+): 599 (M+H). layer was dried over NaSO and concentrated under reduced pressure. Purification by silica gel chromatography (gradient Example 102 eluent, 0-20% ethyl acetate in hexane) provided 5-Bromo-4- chloro-2-isopropoxycarbonyl-(3-methoxycarbonyl-pro 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino 35 7-bromo-8-chloro-2,3,4,5-tetrahydro-benzob. pyl)-amino-benzoic acid methyl ester (2.78 g, 86%) as oil. azepine-1-carboxylic acid isopropyl ester MS (ES+): 450, 452 (M+H). Step 4. Preparation of 7-Bromo-8-chloro-5-oxo-2.3, 4,5-tetrahydro-benzoblazepine-1,4-dicarboxylic 40 CF acid 1-isopropyl ester 4-methyl ester O 3 To a heated mixture of potassium t-butoxide (1.27 g, 11.3 mmol) in toluene (50 ml) at 70° C. was added a solution of y 5-Bromo-4-chloro-2-isopropoxycarbonyl-(3-methoxycar Br 45 bonyl-propyl)-amino-benzoic acid methyl ester (2.55 g, 5.66 CF mmol) in toluene (50.0 ml) over 30 minutes. After the addi tion was completed, the mixture was cooled to room tempera C N ture and diluted with ethyl acetate (100 ml), and then washed with 1.00N HCl(aq) (120 ml) and brine (3x120 ml). The - 50 organic layer was dried over Na2SO4 and concentrated under O reduced pressure. Purification by Silica gel chromatography (gradient eluent, 0-15% ethyl acetate in hexane) provided 7-Bromo-8-chloro-5-oxo-2,3,4,5-tetrahydro-benzob. -Q azepine-1,4-dicarboxylic acid 1-isopropyl ester 4-methyl 55 ester (1.46g, 62%) as oil. MS (ES+): 418, 420 (M+H). Step 1. Preparation of Step 5. Preparation of 7-Bromo-8-chloro-5-oxo-2.3, 2-Amino-5-bromo-4-chloro-benzoic acid methyl 4,5-tetrahydro-benzoblazepine-1-carboxylic acid ester isopropyl ester To a solution of 2-Amino-4-chloro-benzoic acid methyl 60 A mixture of 7-Bromo-8-chloro-5-oxo-2,3,4,5-tetrahydro ester (1.85g. 10.0 mmole) in HOAc (20.0 ml) was injected benzoblazepine-1,4-dicarboxylic acid 1-isopropyl ester bromine (0.512 ml, 10.0 mmole) dropwise. The reaction was 4-methyl ester (1.43 g, 3.42 mmol) in HOAc (30.0 ml), con stirred at room temperature for an hour. The mixture was centrated HCl (9.00 ml) and water (3.00 ml) was heated at diluted with ethyl ether (200 ml) and then the solvents were 100° C. for 4 hours and then cooled down to room tempera decanted. The residue was partitioned between ethyl acetate 65 ture overnight. The solvents were evaporated under reduced (200 ml) and 0.100N NaOH(aq) (200 ml). After separated the pressure, and the residue was partitioned between ethyl two layers, the organic layer was dried over NaSO, filtered acetate (100 ml) and saturated NaHCO (aq) (100 ml). The US 7,749,992 B2 79 80 aqueous layer was extracted with more ethyl acetate (20.0 A mixture of 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- ml). The combined organics washed with brine (3x120 ml), amino-7-bromo-8-chloro-2,3,4,5-tetrahydro-benzob. dried over NaSO filtered and concentrated. The material azepine-1-carboxylic acid isopropyl ester (0.118 g., 0.187 obtained was subjected to the conditions described in step 2 to mmol), methyl boronic acid (0.0340 g, 0.561 mmol) and provide 7-Bromo-8-chloro-5-oxo-2,3,4,5-tetrahydro-benzo cesium fluoride (0.0990 mg, 0.655 mmol) in dioxane (2.00 blazepine-1-carboxylic acid isopropyl ester (0.990 g, 80%) ml) was purged with nitrogen for 10 minutes. To it was added as white solid. MS (ES+): 360,362 (M+H). PdCl(dppf) (0.0240 g) in one portion. The mixture was Step 6. Preparation of 5-(3.5-Bis-trifluoromethyl heated at 100° C. overnight. The solid was removed by filtra benzylamino)-7-bromo-8-chloro-2,3,4,5-tetrahydro tion, washed with ethyl acetate (30.0 ml) and the filtrate was 10 concentrated in vacuo. Purification by silica gel chromatog benzoblazepine-1-carboxylic acid isopropyl ester raphy (gradient eluent, 0-35% ethyl acetate in hexane) pro A mixture of 7-Bromo-8-chloro-5-oxo-2,3,4,5-tetrahydro vided the titled compound (0.0820 g, 77%) as white foamy benzoblazepine-1-carboxylic acid isopropyl ester (0.98 g. solid. MS (ES+): 565 (M+H). 2.72 mmole), 3.5-bistrifluoromethylbenzyl amine (0.682 g, 2.72 mmol) and titanium(IV) isopropoxide (1.00 ml, 3.26 15 Example 104 mmol) was stirred at room temperature overnight. To it was added sodium cyanoborohydride (0.684 g, 10.9 mmole) in (R)-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- MeOH (20.0 ml) and the reaction was continued at room amino-8-chloro-7-methyl-2,3,4,5-tetrahydro-benzo temperature for 6 hours. The mixture was partitioned between blazepine-1-carboxylic acid isopropyl ester) ethyl acetate (50.0 ml) and water (50.0 ml). The precipitate was removed by filtration. The aqueous layer was extracted with more ethyl acetate (2x50.0 ml). The combined organics washed with brine (3x150 ml). Dried over NaSO, filtered CF and concentrated to provide the crude product (1.47g, 88%), which was used directly for the next step without further 25 purification. MS (ES+): 587, 589 (M+H). Step 7. Preparation of 5-Acetyl-(3,5-bis-trifluorom ethyl-benzyl)-amino-7-bromo-8-chloro-2,3,4,5- CF tetrahydro-benzoblazepine-1-carboxylic acid iso 30 propyl ester (2312873) C N A mixture of crude 5-(3.5-Bis-trifluoromethyl-benzy lamino)-7-bromo-8-chloro-2,3,4,5-tetrahydro-benzob azepine-1-carboxylic acid isopropyl ester (1.40 g, 2.38 mmol) and pyridine (5.00 ml) was treated with acetic anhy 35 dride (5.00 ml) via dropwise addition. The mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50.0 ml), washed with 1.00N HCl (2x50.0 ml) The title compound was obtained by chiral resolution of and brine (3x150 ml). Dried over NaSO, filtered and con Example 103 on a Chiralcel OD-H(0.46x250mm), flow rate: centrated. Purification by silica gel chromatography (gradient 40 1.0 ml/min, solvents: 5%3A alcoholin heptane, R-6.54 min, eluent, 0-40% ethyl acetate in hexane) provided the titled wavelength: 220 nm. EE=98.0%. MS (ES+): 564 (M+H). compound (1.28 g. 85%) as white foamy solid. MS (ES+): 629, 631 (M+H). Example 105

Example 103 45 (S)-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- amino-8-chloro-7-methyl-2,3,4,5-tetrahydro-benzo 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino blazepine-1-carboxylic acid isopropyl ester 8-chloro-7-methyl-2,3,4,5-tetrahydro-benzob. azepine-1-carboxylic acid isopropyl ester 50 CF O 3 O CF

y 55

CF C N C N 60 - o O O -Q 65 -Q The title compound was obtained by chiral resolution of Example 103 on a Chiralcel OD-H(0.46x250mm), flow rate: US 7,749,992 B2 81 82 1.0 ml/min, solvents: 5%3A alcoholin heptane, R,-7.55 min, Example 108 wavelength: 220 nm. EE=99.5%. MS (ES+): 551 (M+H). 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino Example 106 7-chloro-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino blazepine-1-carboxylic acid isopropyl ester 8-chloro-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo blazepine-1-carboxylic acid isopropyl ester

10 O CF O CF y y C 15 CF CF CF CF N C N - - O

-Q 25 The titled compound was prepared following the proce dures described in Example 102 by replacing 5-acetyl-(3.5- To aheated mixture of 5-Acetyl-(3,5-bis-trifluoromethyl bis-trifluoromethyl-benzyl)-amino-7-bromo-8-chloro-2.3, benzyl)-amino-7-bromo-8-chloro-2,3,4,5-tetrahydro-benzo 4.5-tetrahydro-benzoblazepine-1-carboxylic acid isopropyl blazepine-1-carboxylic acid isopropyl ester (Example 48) ester with 5-acetyl-(3,5-bis-trifluoromethyl-benzyl)- (0.335 g, 0.532 mmol) and CuI (0.101 mg, 0.532 mmol) in 30 DMF (5.00 ml)/HMPA (1.00 ml) at 80°C., was added methyl amino-7-bromo-8-trifluoromethyl-2,3,4,5-tetrahydro fluorosulphonyl difluoroacetate (0.410 ml, 3.19 mmol). The benzoblazepine-1-carboxylic acid isopropyl ester. MS reaction was continued at 80°C. for an hour. The mixture was (ES+): 619 (M+H). partitioned between ethyl acetate (50.0 ml) and brine (50.0 ml). The organic layer was washed with brine (2x150 ml). 35 Example 109 Dried over NaSO filtered and concentrated. Purification by silica gel chromatography (gradient eluent, 0-35% ethyl 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino acetate in hexane) provided the titled compound (0.00520 g, 7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo 1.6%) as white solid. MS (ES+): 619 (M+H). blazepine-1-carboxylic acid isopropyl ester 40 Example 107 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino 7-bromo-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo CF blazepine-1-carboxylic acid isopropyl ester 45

O CF CF 50 y CF N Br CF 55 CF N

- O The titled compound was prepared following the proce 60 dures described in Example 103 by replacing 5-Acetyl-(3.5- -Q bis-trifluoromethyl-benzyl)-amino-7-bromo-8-chloro-2.3, 4.5-tetrahydro-benzoblazepine-1-carboxylic acid isopropyl The titled compounds was prepared following the proce ester (Example 103) with 5-Acetyl-(3,5-bis-trifluoromethyl dures described in Example 102 by replacing 2-amino-4- 65 benzyl)-aminol-7-bromo-8-trifluoromethyl-2,3,4,5-tetrahy chloro-benzoic acid methyl ester with 2-amino-4-trifluorom dro-benzoblazepine-1-carboxylic acid isopropyl ester. MS ethyl-benzoic acid methyl ester. MS (ES+): 663, 665 (M+H). (ES+): 599 (M+H). US 7,749,992 B2 83 84 Example 110 Example 112

(R)-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino 7-amino-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahy blazepine-1-carboxylic acid isopropyl ester dro-benzoblazepine-1-carboxylic acid isopropyl ester

CF 10 O 3

CF y- N HN y s CF CF N CF

CF o O - -Q O

25 The titled compound was prepared following the proce -Q dures described in Example 26 by replacing 5-acetyl-(3.5- bis-trifluoromethyl-benzyl)-amino-8-bromo-2,3,4,5-tet The title compound was obtained by chiral resolution of rahydro-benzoblazepine-1-carboxylic acid isopropyl ester Example 109 on a Chiralpak AD-H (0.46x150 mm), flow with 5-(acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7- rate: 1.0 ml/min, solvents: 10% propan-2-ol in heptane, 30 bromo-8-trifluoromethyl-2,3,4,5-tetrahydro-benzob. R-2.88 min, wavelength: 225 nm. EE=100%. MS (ES+): azepine-1-carboxylic acid isopropyl ester. MS (ES+): 600 599 (M+H). (M+H). Example 113 Example 111 35 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino (S)-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- 7-dimethylamino-8-trifluoromethyl-2,3,4,5-tetrahy amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahy dro-benzoblazepine-1-carboxylic acid isopropyl dro-benzoblazepine-1-carboxylic acid isopropyl 40 ester ester

CF 45 CF O 3 - 1 > CF 50

CF CF

CF N o O - 55 O -Q The titled compound was prepared following the proce 60 dures described in Example 34 by replacing 5-Acetyl-(3.5- The title compound was obtained by chiral resolution of bis-trifluoromethyl-benzyl)-amino-8-amino-2,3,4,5-tet Example 109 on a Chiralpak AD-H (0.46x150 mm), flow rahydro-benzoblazepine-1-carboxylic acid isopropyl ester with 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7- rate: 1.0 ml/min, solvents: 10% propan-2-ol in heptane, 65 amino-8-trifluoromethyl-2,3,4,5-tetrahydro-benzob R-4.37 min, wavelength: 225 nm. EE=100%. MS (ES+): azepine-1-carboxylic acid isopropyl ester. MS (ES+): 628 599 (M+H). (M+H). US 7,749,992 B2 85 86 Example 114 Example 116 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino- 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino 8-trifluoromethyl-7-vinyl-2,3,4,5-tetrahydro-benzo 5 7-bromo-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo blazepine-1-carboxylic acid isopropyl ester blazepine-1-carboxylic acid tert-butyl ester

CF 10 CF O O 3 y- N y- N

21 15 Br CF CF

CF N CF N

o- 2O O -Q

The titled compound was prepared following the proce- 25 dures described in Example 32 by replacing 5-Acetyl-(3.5- The titled compound was prepared following the proce bis-trifluoromethyl-benzyl)-amino-8-bromo-2,3,4,5-tet- dures described Example 1 by replacing 2-Amino-4-trifluo rahydro-benzoblazepine-1-carboxylic acid isopropyl ester romethyl-benzoic acid methyl ester with 2-Amino-5-bromo with 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7- 30 4-trifluoromethyl-benzoic acid methyl ester in step 1. MS bromo-8-trifluoromethyl-2,3,4,5-tetrahydro-benzob. (ES+): 677, 679 (M+H). azepine-1-carboxylic acid isopropyl ester (Example 107). MS (ES+): 611 (M+H). Example 117 Example 115 35 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino 7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino- blazepine-1-carboxylic acid tert-butyl ester 7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo blazepine-1-carboxylic acid isopropyl ester 40

CF yO CF 3 45 X CF

CF 50 CF N CF N o o-s,-Q 55 -NO The titled compound was prepared following the proce The titled compound was prepared following the proce- 60 dures described in Example 109 by replacing 5-Acetyl-(3.5- dures described in Example 33 by replacing 5-Acetyl-(3.5- bis-trifluoromethyl-benzyl)-amino-7-bromo-8-trifluorom bis-trifluoromethyl-benzyl)-amino-8-vinyl-2,3,4,5-tetrahy- ethyl-2,3,4,5-tetrahydro-benzoblazepine-1-carboxylic acid dro-benzoblazepine-1-carboxylic acid isopropyl ester with isopropyl ester with 5-Acetyl-(3,5-bis-trifluoromethyl-ben 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-8-trif. Zyl)-aminol-7-bromo-8-trifluoromethyl-2,3,4,5-tetrahydro luoromethyl-7-vinyl-2,3,4,5-tetrahydro-benzoblazepine-1- benzoblazepine-1-carboxylic acid tert-butyl ester. MS carboxylic acid isopropyl ester. MS (ES+): 613 (M+H). (ES-): 611 (M-H). US 7,749,992 B2 87 88 Example 118 Example 120 (R)-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- (S)-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahy aminol-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahy dro-benzoblazepine-1-carboxylic acid tert-butyl dro-benzoblazepine-1-carboxylic acid tetrahydro ester pyran-4-yl ester

10 CF O 3 CF

15 CF CF CF CF

- O

25

The title compound was obtained by chiral resolution of Example 117 on a Chiralpak AD-H (0.46x150 mm), flow Step 1. Preparation of N-(3.5-Bis-trifluoromethyl rate: 1.0 ml/min, solvents: 10% propan-2-ol in heptane, 30 benzyl)-N-(7-methyl-8-trifluoromethyl-2,3,4,5-tet R-2.54 min, wavelength: 225 nm. EE=100%. MS (ES-): rahydro-1H-benzoblazepin-5-yl)-acetamide 611 (M-H).

35 Example 119 O CF (S)-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- y amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahy 40 dro-benzoblazepine-1-carboxylic acid tert-butyl CF ester CF N

45 A solution of (S)-5-Acetyl-(3,5-bis-trifluoromethyl-ben CF Zyl)-amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro benzoblazepine-1-carboxylic acid tert-butyl ester (0.920 g, 1.50 mmol) (Example 110) in 1:1 TFA/DCM (10.0 ml) was 50 stirred at room temperature for 2 hours. The solvents were evaporated on a (rotary evaporation). Purification by silica gel CF chromatography (gradient eluent, 0-30% ethyl acetate in hex ane) provided the titled compound (0.736 g. 96%) as white CF solid. MS (ES+): 513 (M+H). 55 Step 2. Preparation of (S)-5-Acetyl-(3,5-bis-trifluo romethyl-benzyl)-amino-7-methyl-8-trifluorom ethyl-2,3,4,5-tetrahydro-benzoblazepine-1-carboxy lic acid tetrahydro-pyran-4-yl ester 60 To a mixture of tetrahydro-pyran-4-ol (0.0830 ml, 0.876 The title compound was obtained by chiral resolution of mmol) and di-isopropyl ethylamine (0.153 ml, 0.876 mmol) Example 117 on a Chiralpak AD-H (0.46x150 mm), flow in DCM (2.00 ml) at 0°C., was added a solution of phosgene rate: 1.0 ml/min, solvents: 10% propan-2-ol in heptane, 65 in toluene (0.384 ml, 0.730). The reaction mixture was stirred R, 3.24 min, wavelength: 225 nm. EE=100%. MS (ES-): for 2 hours. To it was added N-(3.5-Bis-trifluoromethyl-ben 611 (M-H). Zyl)-N-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H US 7,749,992 B2 89 90 benzoblazepin-5-yl)-acetamide (Step 1) followed by pyri 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7-trif dine (0.059 ml, 0.730 mmol) and then warmed up to room luoromethyl-2,3,4,5-tetrahydro-benzoblazepine-1-car temperature overnight. The reaction mixture washed with boxylic acid tert-butyl ester (0.118 g., 0.197 mmol) was water (3x2.00 ml), dried over NaSO and concentrated fol treated with 1:1 TFA/DCM (2.00 ml) at room temperature. lowed by purification by silica gel chromatography. MS Evaporation of solvents provided the titled compound, which (ES+): 641 (M+H). was used directly for the next step without further purifica The following Examples were prepared utilizing this same tion. MS (ES+): 499 (M+H). methodology described in Example 120 wherein R30 is vari able and is introduced by replacement of tetrahydro-pyran-4- Step 2. Preparation of N-(3.5-Bis-trifluoromethyl ol (Example 120, Step 2) with corresponding alcohol. 10 benzyl)-N-(9-bromo-7-trifluoromethyl-2,3,4,5-tet rahydro-1H-benzoblazepin-5-yl)-acetamide

CF O 3 15 > yO CF CF CF CF CF: N o N Br 25 R3f To a solution of crude N-(3.5-Bis-trifluoromethyl-benzyl)- Example # Reagent R30 MS (ES+) N-(7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzob. Example 121 Cyclobutanol Cyclobutyl 627 (M+H) azepin-5-yl)-acetamide (0.0980 mg, 0.197 mmol) in HOAc Example 122 Cyclopentanol Cyclopentyl 627 (M+H) 30 (2.00 ml), was added bromine (0.01.06 ml, 0.207 mmol) drop wise. The reaction mixture was stirred at room temperature overnight. Remove the solvent on a rotary evaporator. Puri Example 123 fication by silica gel chromatography (eluent, 0-40% ethyl acetate in hexane) provided the titled compound (0.0850 mg. 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino 35 75%). MS (ES+): 577, 579 (M+H). 9-methyl-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo blazepine-1 carboxylic acid isopropyl ester Step 3. Preparation of N-(3.5-Bis-trifluoromethyl benzyl)-N-(9-methyl-7-trifluoromethyl-2,3,4,5-tet 40 rahydro-1H-benzoblazepin-5-yl)-acetamide

CF CF CF O 3 45 y N CF o CF O 50 -Q N Step 1. Preparation of N-(3.5-Bis-trifluoromethyl benzyl)-N-(7-trifluoromethyl-2,3,4,5-tetrahydro-1H 55 A mixture of N-(3.5-Bis-trifluoromethyl-benzyl)-N-(9- benzoblazepin-5-yl)-acetamide bromo-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzob. azepin-5-yl)-acetamide (0.0830 g, 0.144 mmol), methyl CF O 3 boronic acid (0.0260 g, 0.432 mmol) and cesium fluoride (0.0770 mg, 0.504 mmol) in dioxane (2.00 ml) was purged 60 with nitrogen for 10 minutes. To it was added PdCl2(dppf) y (0.0170 g) in one portion. The mixture was heated at 80°C. CF overnight. The solid was removed by filtration, washed with CF ethyl acetate (30.0 ml) and the filtrate was concentrated in vacuo. Purification by silica gel chromatography (gradient 65 eluent, 0-40% ethyl acetate in hexane) provided the titled N compound (0.0460 g, 63%) as white solid. MS (ES+): 513 (M+H). US 7,749,992 B2 91 92 Step 4. Preparation of 5-Acetyl-(3,5-bis-trifluorom Step 1. Preparation of N-(3-Fluoro-4-methyl-phe ethyl-benzyl)-amino-9-methyl-7-trifluoromethyl-2, nyl)-2-hydroxyimino-acetamide 3,4,5-tetrahydro-benzoblazepine-1-carboxylic acid isopropyl ester To a solution of N-(3.5-Bis-trifluoromethyl-benzyl)-N-(9- methyl-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzob. F N-OH azepin-5-yl)-acetamide (0.0210 g, 0.0410 mmol) and pyri dine (0.0100 ml, 0.123 mmol) in dichloromethane (1.00 ml) was added 1M isopropylchloroformate (solution in toluene) O (0.120 ml), 0.123 mmol) dropwise. The mixture was stirred at 10 oN room temperature overnight. The solvents were evaporated on a rotavapor (rotary evaporator). Purification by Silica gel chromatography (gradient eluent, 0-30% ethyl acetate in hex To a solution of chloral hydrate (2.97g, 17.98 mmol) and ane) provided the titled compound (0.0180 g, 72%) as white anhydrous sodium sulfate (15.20 g, 107 mmol) in water (50 crystalline. MS (ES+): 599 (M+H). 15 mL) add a mixture of hydroxylamine sulfate (13.67 g. 83.23 mmol), 3-Fluoro-4-methyl-phenylamine (2 g, 15.98 mmol), Example 124 concentrated hydrochloric acid (1.67 mL) in water (17 mL). 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7, Heat the mixture at 45° C. for 2 h and at 75° C. for 1 hr. Cool 9-dimethyl-8-trifluoromethyl-2,3,4,5-tetrahydro the mixture to room temperature and filter the solid. Wash the benzoblazepine-1-carboxylic acid isopropyl ester solid with water and ethyl ether. Dry the solid under vacuum CF to yield the title compound (2.96 g.94%). H NMR (DMSO O 3 d,300 MHz) & 2.08 (d.J=1.0Hz,3H), 7.12 (t, J=8.8 Hz, 1H), 7.25 (dd, J=2.1, 8.2 Hz, 1H), 7.36 (dd, J=1.6, 12.4 Hz, 1H), y 25 10.18 (s, 1H), 12.11 (s, 1H). MS (ES-): 195 (M-H). Step 2. Preparation of CF 6-Amino-2-fluoro-3-methyl-benzoic acid methyl ester CF -N 30 O

-Q 35 The titled compound was prepared using the method described in Example 123 by replacing 5-Acetyl-(3,5-bis trifluoromethyl-benzyl)-amino-7-trifluoromethyl-2,3,4,5- tetrahydro-benzoblazepine-1-carboxylic acid tert-butyl 40 ester with 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- Add of N-(3-Fluoro-4-methyl-phenyl)-2-hydroxyimino aminol-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro acetamide (2.96 g. 15.10 mmol) in small portions at 65°C. to benzoblazepine-1-carboxylic acid tert-butyl ester in concentrated sulfuric acid (15 mL) and heat the mixture at 80° Example 117, step 1. C. for 10 minutes. Cool to room temperature, pour into ice 45 water (100 mL) and filter the precipitate and wash with water. Example 125 Dry the solid to yield 4-Fluoro-5-methyl-1H-indole-2,3-di Synthesis of (+/-)-5-Acetyl-(3,5-bis-trifluorom one and 6-Fluoro-5-methyl-1H-indole-2,3-dione. ethyl-benzyl)-amino-6-fluoro-7-methyl-2,3,4,5- Add 30% aqueous hydrogen peroxide Solution (4 mL) to a tetrahydro-benzoblazepine-1-carboxylic acid iso solution of the isatin mixture (2.70 g. 15.10 mmol) in 2 N propyl ester 50 sodium hydroxide (30 mL) over a period of 5 minutes, stir the F mixture at room temperature for 1 h. Add 1N hydrochloric acid to pH=5 and extract with ethyl acetate (3x20 mL). Wash O F with brine, dry the organic layer over anhydrous Sodium -- F sulfate, filter and remove the solvent under reduced pressure. F N Chromatograph the residue over silica gel, eluting with hex anes/ethyl acetate (3:1), to afford 6-Amino-2-fluoro-3-me thyl-benzoic acid and 2-Amino-4-fluoro-5-methyl-benzoic F F acid (1.91 g, 75%). F 60 Dissolve in ethylacetate (1 mL) and ethanol (1 mL) N 6-Amino-2-fluoro-3-methyl-benzoic acid and 2-Amino-4- fluoro-5-methyl-benzoic acid (240 mg, 1.42 mmol) and add o (trimethylsilyl) diazomethane (0.7 mL, 1.4 mmol, 2M in hex O ane) at room temperature and stir the solution for 16 h. 65 Remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (10:1), to afford the titled compound (50 mg). H NMR US 7,749,992 B2 93 94 (CDC1,300 MHz) & 2.13 (d. J=2.4 Hz,3H), 3.9 (s.3H), 6.39 Step 5. Preparation of Isopropyl 6-fluoro-7-methyl (dd, J=0.8, 8.5 Hz, 1H), 7.04 (t, J=8.1 Hz, 1H). MS (ES+): 184 5-oxo-2,3,4,5-tetrahydrobenzoblazepine-1-carboxy (M+H). late Step 3. Preparation of Methyl 6-fluoro-5-methyl-2-isopropoxycarbonyl aminobenzoate

10

COMe

15 Add a solution of Methyl 6-fluoro-5-methyl-2-isopro - O poxycarbonyl-(3-methoxycarbonylpropyl)aminobenzoate (66 mg, 0.18 mmol) in THF (3 mL) to a solution of potassium tert-butoxide (0.36 mL, 0.36 mmol, 1M in THF) in THF (2.5 -Q mL) at room temperature under an atmosphere of nitrogen. Add isopropyl chloroformate (0.27 mL, 0.27 mmol. 1.0 M After 15 min, add a saturated solution of ammonium chloride in toluene) dropwise to a solution of methyl 2-amino-6- and extract with ethyl acetate (3x10 mL). Dry the organic fluoro-5-methylbenzoate (50 mg, 0.27 mmol) and pyridine layer over anhydrous sodium sulfate, filter, and remove the (0.055 mL, 0.68 mmol) in dichloromethane (1 mL) at 0°C. 25 Solvent under reduced pressure to provide 1-isopropyl-4-me under an atmosphere of nitrogen and stir at room temperature thyl-6-fluoro-7-methyl-5-oxo-2,3,4,5-tetrahydrobenzob. azepine-1,4-dicarboxylate (61 mg, 100% crude). Dissolve for 24 h. Add 1N HCl and separate the layers. Extract the the dicarboxylate (61 mg 0.18 mmol) in DMSO (1.5 mL) and aqueous layer with dichloromethane (3x10 mL). Dry the add water (1 drop) followed by addition of lithium chloride organic layer over anhydrous sodium sulfate, filter, and (19 mg, 0.45 mmol) and heat the resulting solution at 160° C. remove the solvent under reduced pressure. Filter through 30 for 45 minutes. Cool the mixture to room temperature and silica cartridge eluting with hexanes/ethyl acetate (8:1), to pour into brine. Extract the mixture with ethyl acetate (3x10 afford the title compound (65 mg, 90%): 'H NMR (CDC1) 8 mL). Chromatograph the residue over silica cartridge eluting 1.30 (d. J=6.5 Hz, 6H), 2.21 (d. J=2.4 Hz, 3H), 3.95 (s.3H), with hexanes/ethyl acetate (8:1), to afford the title compound 4.99 (septet, J=6.5 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H), 8.05 (d. (24 mg., 48% over two steps): MS (ES+): 280 (M+H) J=8.5 Hz, 1H), 9.56 (brs, 1H); MS (ES+): 270 (M+H) 35 Step 6. Preparation of (+/-)-Isopropyl 5-acetyl-(3.5- Step 4. Preparation of Methyl 6-fluoro-5-methyl-2- bistrifluoromethylbenzyl)amino-6-fluoro-7-methyl isopropoxycarbonyl-(3-methoxycarbonylpropyl) 2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate aminobenzoate 40 - O CF F N

45 CF

50 o O

Heat a suspension of Methyl 6-fluoro-5-methyl-2-isopro -Q poxycarbonyl aminobenzoate (65 mg, 0.24 mmol), methyl 55 Add 3,5-bis(trifluoromethyl)benzylamine (23 mg, 0.095 4-bromobutyrate (174 mg. 0.96 mmol) and cesium carbonate mmol) followed by titanium isopropoxide (0.035 mL, 0.12 (313 mg, 0.96 mmol) in N,N-dimethylformamide (1.2 mL) mmol) to isopropyl 6-fluoro-7-methyl-5-oxo-2,3,4,5-tet under nitrogen at 80° C. for 3 h. Cool the mixture to room rahydro benzoblazepine-1-carboxylate (24 mg. 0.086 temperature and pour into water (5 mL). Extract with ethyl mmol) at room temperature under an atmosphere of nitrogen acetate (3x10 mL). Dry the organic layer over anhydrous and stir the solution for 2 days. Filter the residue over silica sodium sulfate, filter and remove the solvent under reduced 60 cartridge, eluting with hexanes/ethyl acetate (8:1) to afford pressure. Chromatograph the residue over silica cartridge, 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-7-me eluting with hexanes/ethyl acetate (6:1), to provide the title thyl-2,3-dihydro-benzoblazepine-1-carboxylic (34 mg. compound (66 mg, 75%): 'H NMR (CDC1, 300 MHz) & 79%). Add methanol (1 mL) and platinum oxide (2 mg, 0.007 1.11-1.28 (m, 6H), 1.85-2.04 (m, 2H), 2.29-2.46 (m, 2H), mmol) and hydrogenate the mixture at 1 atmosphere and 3.41 (m, 1H), 3.66(s.3H), 3.78 (m, 1H), 3.87 (s.3H), 4.87(m, 65 room temperature for 7 h. Filter through celite and remove the 1H), 6.90 (brid, 1H), 7.26 (t, J=6.5 Hz, 1H). MS (ES+): 370 solvent under reduced pressure to afford 5-(3.5-Bis-trifluo (M+H) romethyl-benzylamino)-6-fluoro-7-methyl-2,3,4,5-tetrahy US 7,749,992 B2 95 96 dro-benzoblazepine-1-carboxylic acid isopropyl ester (36 Add 2-Hydroxyimino-N-indan-5-yl-acetamide (4.66 g. mg, quantitative). Add acetic anhydride (0.1 mL, 1.07 mmol) 22.84 mmol) in small portions at 65° C. to concentrated dropwise to a suspension of the amine (36 mg, 0.071 mmol) and pyridine (0.1 mL g, 1.07 mmol) in dichloromethane (0.5 sulfuric acid (22 mL) and heat the mixture at 80° C. for 15 mL) under nitrogen cooled to 0° C. After the addition is minutes. Cool to room temperature, pour into ice water (200 complete, remove the cooling bath and warm the reaction to mL) and filter the precipitate. Dissolve the solid in warmed room temperature and stirfor 12 h. Add 1 Nhydrochloric acid ethanol and leave to cool overnight. Filter the precipitate and and extract with dichloromethane (3x10 mL). Dry the organic wash with ethyl ether. Dry the solid to yield the title com layer over anhydrous sodium sulfate, filter and remove the Solvent under reduced pressure. Chromatograph the residue pound (3.3 g, 77%). "H NMR (DMSO-d 300 MHz) & 1.98 over silica cartridge, eluting with hexanes/ethyl:acetate (6:1), 10 (quintuplet, J–7.7 Hz, 2H), 2.76 (t, J=7.7 Hz, 2H), 2.85 (t, to afford the title compound (18 mg, 46%); MS (ES+): 549 J=7.7 Hz, 2H), 6.74 (s, 1H), 7.28 (s, 1H). MS (ES-): 186 (M+H) (M-H). Example 126 Step 3. Preparation of 6-Amino-indan-5-carboxylic 15 acid methyl ester Synthesis of (+/-)-9-Acetyl-(3,5-bis-trifluorom ethyl-benzyl)-amino)-2,3,6,7,8,9-hexahydro-1H-5- aza-cyclohepta findene-5-carboxylic acid isopropyl ester COMe

O CF NH2 N4 N

25 Add 30% aqueous hydrogen peroxide solution (3 mL) to a solution of 1,5,6,7-Tetrahydro-1-aza-s-indacene-2,3-dione CF (2.18 g, 11.66 mmol) in 2 N sodium hydroxide (23 mL) over a period of 5 minutes, stir the mixture at room temperature for 3 h. Add 1N hydrochloric acid to pH=5 and extract with ethyl 30 acetate (3x20 mL). Wash with brine, dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent s under reduced pressure to afford 6-Amino-indan-5-carboxy lic acid (1.7 g, 86%). Dissolve in ethylacetate (2 mL) and Step 1. Preparation of 35 ethanol (2 mL) and add (trimethylsilyl) diazomethane (9.6 2-Hydroxyimino-N-indan-5-yl-acetamide mL, 19.2 mmol, 2M in hexane) at room temperature and stir the solution for 16 h. Remove the solvent under reduced --OH pressure. Chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (9:1), to afford the title compound 40 (1.19 g, 66%). H NMR (CDC1, 300 MHz) & 2.05 (quintu plet, J–7.3 Hz, 2H), 2.80 (q, J=7.7 Hz, 4H), 6.59 (s, 1H), 7.69 CO (s, 1H). MS (ES+): 192 (M+H). To a solution of chloral hydrate (5.56 g. 33.63 mmol) and 45 Step 4. Preparation of 9-Oxo-2,3,6,7,8,9-hexahydro anhydrous sodium sulfate (28.58 g, 201.20 mmol) in water 1H-5-aza-cyclohepta findene-5-carboxylic acid iso (90 mL) add a mixture of hydroxylamine sulfate (25.63 g, propyl ester 156.16 mmol), 5-aminoindane (4 g. 30.03 mmol), concen trated hydrochloric acid (3.14 mL) in water (30 mL). Heat the mixture at 45° C. for 1 h and at 75° C. for 2 hr. Cool the mixture to room temperature and filter the solid. Wash the 50 solid with water and ethyl ether. Dry the solid under vacuum to yield the title compound (4.98g, 81%). H NMR (DMSO de 300 MHz) & 1.90 (quintuplet, J–7.8 Hz, 2H), 2.72 (q, J=7.8 Hz, 4H), 7.06 (d.J=8.2 Hz, 1H), 7.28 (dd, J=1.5, 8.2 Hz, 1H), 7.49 (bs, 1H), 9.94 (s, 1H), 12.02 (s, 1H). MS (ES-): 203 55 (M-H). Step 2. Preparation of 1,5,6,7-Tetrahydro-1-aza-s-indacene-2,3-dione 60 The titled compound was prepared following the proce O dure described for the preparation of isopropyl 6-fluoro-7- methyl-5-oxo-2,3,4,5-tetrahydrobenzoblazepine-1-car boxylate (example 132, from step 3 to 5) by replacing methyl 65 2-amino-6-fluoro-5-methylbenzoate with 6-Amino-indan-5- N carboxylic acid methyl ester in example 132 step 3. MS (ES+): 288 (M+H). US 7,749,992 B2 97 98 Step 5. Preparation of (+/-)-9-Acetyl-(3,5-bis-trif example 3) (40 mg, 0.078 mmol) in formic acid (0.5 mL) and luoromethyl-benzyl)-amino-2,3,6,7,8,9-hexahydro stir at room temperature for 16 h. Chromatograph the residue 1H-5-aza-cyclohepta findene-5-carboxylic acid iso over silica cartridge, eluting with hexanes/ethyl acetate (5:1). propyl ester to afford the title compound (27 mg, 64%). H NMR (DMSO de 300 MHz, 100° C.) & 1.14 (d. J=6.5 Hz, 6H), 1.63-2.05 (m, O 2H), 3.43 (m. 1H), 3.63 (m, 1H), 4.56-4.61 (m. 1H), 4.70-4.72 (m. 1H), 4.77-4.89 (m, 2H) 7.09 (d. J=8.3 Hz, 1H), 7.23-7.26 N4 CF (m. 2H), 7.80-7.86 (m, 3H), 8.46 (s, 1H). MS (ES+): 537 N (M+H). 10 Example 128 CF Synthesis of (+/-)-5-[(3.5-Bis-trifluoromethyl-ben Zyl)-ethyl-amino-8-chloro-2,3,4,5-tetrahydro-benzo g 15 blazepine-1-carboxylic acid isopropyl ester ls" Add 3,5-bis(trifluoromethyl)benzylamine (187 mg, 0.77 1n CF mmol) followed by titanium isopropoxide (835 mg, 2.94 mmol) to 9-Oxo-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclo hepta findene-5-carboxylic acid isopropyl ester (200 mg. 0.7 mmol) at room temperature under an atmosphere of nitro CF gen and stir the solution for 3 days. Add methanol (3 mL) and C N sodium borohydride (40 mg, 1.05 mmol) and stir the mixture 25 under nitrogen at room temperature for 16 hours. Add sodium bicarbonate saturated solution. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aque ous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous Sodium sulfate. Filter and 30 remove the solvent under reduced pressure. Purify the residue by silica cartridge, eluting with hexanes/ethyl acetate 9:1, to Add acetic acid (0.05 mL, 0.078 mmol) and acetaldehyde afford of (+/-)-9-(3,5-bis-trifluoromethyl-benzylamino)-2,3, (34 mg. 0.78 mmol) to a solution of 5-(3.5-Bis-trifluorom 6,7,8,9-hexahydro-1H-5-aza-cyclohepta findene-5-car ethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydro-benzob. boxylic acid isopropyl ester (220 mg). Add acetic anhydride azepine-1-carboxylic acid isopropyl ester (see example 3) (40 (0.22 mL, 2.33 mmol) dropwise to a solution of the amine (80 35 mg, 0.078 mmol) in dimethylformamide (1 mL). Stir at room mg, 0.155 mmol) and pyridine (0.18 mL, 2.33 mmol) in temperature for 2 h. Add sodium triacetoxyborohydride (33 dichloromethane (1 mL). Stir under nitrogen at room tem mg, 0.16 mmol) and stir the mixture at room temperature for perature for 14 h. Add 1 Mhydrochloric acid and extract with 2h. Add saturated solution of sodium bicarbonate and extract dichloromethane. Dry the organic layer over anhydrous with ethyl acetate (3x10 mL). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced 40 anhydrous sodium sulfate, filter and remove the solvent under pressure. Purify the residue by silica gel cartridge, eluting reduced pressure. Chromatograph the residue over silica car with hexanes/ethyl acetate 4:1, to afford the title compound tridge, eluting with hexanes/ethyl acetate (10:1), to afford the (64 mg, 74%); MS (ES+): 579 (M+H+Na). title compound (11 mg, 26%). MS (ES+): 537 (M+H). Example 127 45 Example 129 Synthesis of (+/-)-5-[(3.5-Bis-trifluoromethyl-ben Synthesis of (+/-)-6-Acetyl-(3,5-bis-trifluorom Zyl)-formyl-amino-8-chloro-2,3,4,5-tetrahydro ethyl-benzyl)-amino-2,3,6,7,8,9-hexahydro-1H-10 benzoblazepine-1-carboxylic acid isopropyl ester aza-cycloheptaeindene-10-carboxylic acid isopro 50 pyl ester O H-4 CF N O us CF CF C N -Q 60 CF - Add acetic anhydride (0.22 mL, 2.34 mmol) and sodium formate (26 mg, 0.39 mmol) to a solution of 5-(3.5-Bis 65 S. trifluoromethyl-benzylamino)-8-chloro-2,3,4,5-tetrahydro benzoblazepine-1-carboxylic acid isopropyl ester (see US 7,749,992 B2 99 100 Step 1. Preparation of acid (3.13 g, 87%). Dissolve 4-Amino-indan-5-carboxylic 2-Hydroxyimino-N-indan-4-yl-acetamide acid (3.07 g. 17.3 mmol) in ethyl acetate (87 mL) and ethanol (87 mL) and add (trimethylsilyl) diazomethane (17.3 mL, 34.6 mmol, 2M in hexanes) at room temperature and stir the solution for 1 hour. Remove the solvent under reduced pres sure. Purify the residue by flash chromatography, eluting with -OH hexanes/ethyl acetate, to afford the title compound (2.50 g, W 76%). "H NMR (MeOD,300 MHz) & 2.12 (quintuplet, J=7.6 O Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5 Hz, 2H), 3.83 10 (s, 3H), 6.53 (d. J=8.1 Hz, 1H), 7.66 (d. J=8.1 Hz, 1H). MS N (ES+): 192 (M+H). Step 4. Preparation of 4-Isopropoxycarbonylamino-indan-5-carboxylic acid To a solution of chloral hydrate (5.46g, 33 mmol) and 15 methyl ester anhydrous sodium sulfate (25.6 g., 180 mmol) in water (92 mL) add a mixture of hydroxylamine sulfate (25.6 g. 156 mmol), 4-aminoindane (4.g., 30 mmol), concentrated hydro chloric acid (3.1 mL) in water (30.8 mL). Heat the mixture up COMe to 45° C. for 90 min, to 52° C. over 45 min and to 75° C. for 60 min. Cool the mixture to room temperature and filter the solid. Wash the solid with water and hexane. Dry the solid under vacuum to yield the title compound (5.54 g.90%). MS (ES-): 203 (M-H). o O 25 Step 2. Preparation of 1,6,7,8-Tetrahydro-1-aza-as-indacene-2,3-dione -Q Add isopropyl chloroformate (2.22 mL, 2.22 mmol. 1.0 M 30 in toluene) dropwise to a solution of 4-Amino-indan-5-car boxylic acid methyl ester (425 mg, 2.22 mmol) and pyridine (0.44 mL, 5.5 mmol) in dichloromethane (4.4 mL) at 0°C. under an atmosphere of nitrogen and stir at room temperature for 24 h. Add 1M HCl and separate the layers. Extract the N 35 aqueous layer with dichloromethane. Dry the organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure, to afford the title compound (576 mg, 93%); H NMR (MeOD) & 1.37 (d. J=6.5 Hz, 6H), 2.16 Add 2-Hydroxyimino-N-indan-4-yl-acetamide (5.54 g. (quintuplet, J–7.7 Hz, 2H), 2.97 (t, J=7.3 Hz, 2H), 3.05 (t, 27.1 mmol) in small portions at 80° C. to methanesulfonic 40 acid (21 mL). Stir the mixture at this temperature for 25 min. J–7.3 Hz, 2H), 3.94 (s.3H), 4.97 (m, 1H), 7.22 (d. J=8.1 Hz, Cool to room temperature, pour into ice water and filter the 1H), 7.80 (d. J=8.1 Hz, 1H). MS (ES+): 278 (M+H). precipitate. Dissolve the solid in warmed 1N NaOH, and Step 5. Preparation of 4-(3-Ethoxycarbonyl-propyl)- neutralize with acetic acid. Filter the resulting solid and isopropoxycarbonyl-amino-indan-5-carboxylic acid acidify the filtrate with concentrated HC1. Filter the precipi 45 methyl ester tate and wash with water. Dry the solid to yield the title compound (3.80 g, 72%). MS (ES-): 186 (M-H). Step 3. Preparation of 4-Amino-indan-5-carboxylic acid methyl ester 50

COMe 55

NH2

60 Add a solution of 4-Isopropoxycarbonylamino-indan-5- Add 30% aqueous hydrogen peroxide solution (5 mL) in carboxylic acid methyl ester (570 mg, 2.1 mmol) in DMF (8.2 water (44 mL) to a solution of 1,6,7,8-Tetrahydro-1-aza-as mL) to a suspension of sodium hydride 60% dispersion min indacene-2,3-dione (3.80 mg, 20.3 mmol) and sodium eral oil (82 mg, 2.1 mmol) in DMF (8.2 mL) at 0°C. under an hydroxide (5.03 g, 126 mmol) in water (97 uL) over a period atmosphere of nitrogen and allow to reach room temperature of 30 minutes, stir the mixture at room temperature for 1 h. 65 over 1 h. Add ethyl 4-bromobutyrate (0.44 mL, 3.09 mmol) Acidulate with 1N hydrochloric acid, filter the solid, wash and stir at room temperature for 14 h, then heat at 65° C. for with water and dry to afford 4-Amino-indan-5-carboxylic 2 h. Cool the mixture to room temperature, dilute with ethyl US 7,749,992 B2 101 102 acetate, wash with 1M HCl, water and brine. Dry the organic mmol) to 6-Oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclo layer over anhydrous sodium sulfate, filter and remove the heptaeindene-10-carboxylic acid isopropyl ester (300 mg. solvent under reduced pressure. Purify the residue by flash 1.04 mmol) at room temperature under an atmosphere of chromatography, eluting with hexanes/ethyl acetate, to pro nitrogen and stir the solution for 14 h. Add methanol (4.3 mL) vide the title compound (651 mg, 81%): 'H NMR (MeOD, and sodium borohydride (59 mg, 1.56 mmol) and stir the 300 MHz) & 1.03-1.34 (m, 9H), 1.85 (m, 2H), 2.10 (m, 2H), mixture under nitrogen at room temperature for 45 min. Add 2.30 (m, 2H), 2.82-3.01 (m, 4H), 3.32 (m. 1H), 3.68 (m, 1H), 0.1M NaOH, stir for 30 min. Filter through celite and wash 3.86 (s.3H), 4.08 (m, 2H), 4.91 (m. 1H), 7.19 (d. J–7.7 Hz, the residue with AcOEt. Separate organic layer, extract aque 1H), 7.77 (d. J=7.7 Hz, 1H). MS (ES+): 392 (M+H). ous with AcOEt. Wash organic layer with brine and dry the 10 organic layers over anhydrous Sodium sulfate. Filter and Step 6. Preparation of 6-Oxo-2,3,6,7,8,9-hexahydro remove the solvent under reduced pressure. Purify the residue 1H-10-aza-cycloheptaeindene-10-carboxylic acid by flash chromatography, eluting with hexanes/ethyl acetate, isopropyl ester to afford (+/-)-6-(3.5-Bis-trifluoromethyl-benzylamino)-2, 3,6,7,8,9-hexahydro-1H-10-aza-cycloheptaeindene-10 O 15 carboxylic acid isopropyl ester (443 mg, 83%). Add acetic anhydride (0.24 mL, 2.52 mmol) dropwise to a solution of the amine (184 mg. 0.36 mmol) and pyridine (0.25 mL, 3.06 mmol) in dichloromethane (3.1 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under o reduced pressure. Purify the residue by flash chromatogra O phy, eluting with hexanes/ethyl acetate, to afford the title compound (149 mg, 74%); MS (ES+): 557 (M+H). 25 -Q Example 130 Add a solution of 4-(3-Ethoxycarbonyl-propyl)-isopro poxycarbonyl-amino-indan-5-carboxylic acid methyl ester Synthesis of (+/-)-Isopropyl 5-acetyl-(3,5-bistrif. (510 mg, 1.30 mmol) in THF (20.4 mL) to a solution of luoromethylbenzyl)amino-6-methyl-tetrahy potassium tert-butoxide (2.60 uL. 2.60 mmol. 1 Min THF) in 30 drobenzoblazepine-1-carboxylate THF (18 mL) at room temperature under an atmosphere of nitrogen. After 30 min, pour the mixture into ice/water. Treat aqueous phase with 1M HCl to pH neutral and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced 35 pressure. Dissolve the former crude in DMSO (11 mL) and add water (2 drops) followed by addition of lithium chloride (134 mg, 3.2 mmol) and heat the resulting solution at 160° C. for 30 minutes. Cool the mixture to room temperature and pour into brine. Extract the mixture with ethyl acetate. Dry the organic layers over anhydrous Sodium Sulfate, filter and 40 remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (302 mg, 81% over two steps): MS (ES+): 288 (M+H). 45 Step 7. Preparation of (+/-)-6-Acetyl-(3,5-bis-trif luoromethyl-benzyl)-amino-2,3,6,7,8,9-hexahydro 1H-10-aza-cycloheptaeindene-10-carboxylic acid isopropyl ester 50 Step 1. Preparation of 2-Amino-6-methyl-benzoic O CF -- acid methyl ester 55

CF COMe

o 60 NH2 O Dissolve 2-Amino-6-methyl-benzoic acid (3.00 g, 19.8 -Q mmol) in ethylacetate (100 mL) and ethanol (100 mL) and 65 add (trimethylsilyl) diazomethane (19.8 mL, 39.7 mmol, 2M Add 3,5-bis(trifluoromethyl)benzylamine (349 mg, 1.15 in hexane) at room temperature and stir the solution for 1 h 30 mmol) followed by titanium isopropoxide (414 mg, 1.46 min. Remove the solvent under reduced pressure to afford the US 7,749,992 B2 103 104 title compound (3.30 g, quantitative). H NMR (CDC1,300 300 MHz) & 1.05-1.30 (m, 9H), 1.90 (m, 2H), 2.32 (m, 2H), MHz) & 2.43 (s, 3H), 3.89 (s.3H), 5.11 (brs, 2H), 6.52 (m, 2.36 (s, 3H), 3.85 (s, 3H), 4.11 (q, J–7.3 Hz, 2H), 4.88 (m, 2H), 7.08 (t, J=7.7 Hz, 1H). MS (ES+): 166 (M+H). 1H), 7.02 (m. 1H), 7.16 (d. J–7.7 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H). MS (ES+):366 (M+H). Step 2. Preparation of 2-Isopropoxycarbonylamino-6-methyl-benzoic acid Step 4. Preparation of 6-Methyl-5-oxo-2,3,4,5-tet methyl ester rahydro-benzoblazepine-1-carboxylic acid isopro pyl ester

10

COMe

15 o O o -Q O Add isopropyl chloroformate (19.8 mL, 19.8 mmol. 1.0 M -Q in toluene) dropwise to a solution of 2-Amino-6-methyl benzoic acid methyl ester (3.27 g. 19.8 mmol) and pyridine 25 Add a solution of 2-(3-Ethoxycarbonyl-propyl)-isopro (4.0 mL, 50 mmol) in dichloromethane (39 mL) at 0°C. under poxycarbonyl-amino-6-methyl-benzoic acid methyl ester an atmosphere of nitrogen and stir at room temperature for 14 (4.60 g, 12.6 mmol) in THF (197 mL) to a solution of potas h. Add 1M HCl and separate the layers. Extract the aqueous sium tert-butoxide (25.2 mL, 25.2 mmol, 1 Min THF) in THF layer with dichloromethane. Dry the organic layer over anhy (175 mL) at room temperature under an atmosphere of nitro drous sodium sulfate, filter, and remove the solvent under 30 gen. After 30 min, pour the mixture into ice/water. Treat reduced pressure. Purify the residue by flash chromatogra aqueous phase with 1M HCl to pH neutral and extract with phy, eluting with hexanes/ethyl acetate, to afford the title dichloromethane. Dry the organic layer over anhydrous compound (3.80 g, 76%): 'H NMR (CDC1) & 1.29 (d. J=6.5 sodium sulfate, filter, and remove the solvent under reduced HZ, 6H), 2.43 (s.3H), 3.94 (s.3H), 5.00 (septuplet, J=6.5 Hz, pressure. Dissolve the former crude in DMSO (101 mL) and 1H), 6.90 (d. J=8.1 Hz, 1H), 7.32 (t, J=8.1 Hz, 1H), 8.07 (d. 35 add water (8 drops) followed by addition of lithium chloride J=8.1 Hz, 1H), 8.86 (brs, 1H). MS (ES+): 252 (M+H). (1.32g, 31.5 mmol) and heat the resulting solution at 160° C. for 45 minutes. Cool the mixture to room temperature and Step 3. Preparation of 2-(3-Ethoxycarbonyl-propyl)- pour into brine. Extract the mixture with ethyl acetate. Dry the isopropoxycarbonyl-amino-6-methyl-benzoic acid organic layers over anhydrous Sodium Sulfate, filter and methyl ester 40 remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (903 mg, 27% over two steps): MS (ES+): 262 (M+H). Step 5. Preparation of (+/-)-Isopropyl 5-acetyl-(3.5- 45 bistrifluoromethylbenzyl)amino-6-methyl-tetrahy drobenzoblazepine-1-carboxylate

50 - O CF N

55 Add a solution of 2-isopropoxycarbonylamino-6-methyl benzoic acid methyl ester (3.77 g, 15.0 mmol) in DMF (60 mL) to a suspension of sodium hydride 60% dispersion min N eral oil (600 mg, 15.0 mmol) in DMF (60 mL) at 0°C. under an atmosphere of nitrogen and allow to reach room tempera 60 ture over 1 h. Add ethyl 4-bromobutyrate (3.2 mL, 22 mmol) o O and stir at room temperature for 14 h. Dilute with ethyl acetate, wash with 1M HCl, water and brine. Dry the organic layer over anhydrous sodium sulfate, filter and remove the -Q solvent under reduced pressure. Purify the residue by flash 65 chromatography, eluting with hexanes/ethyl acetate, to pro Add 3,5-bis(trifluoromethyl)benzylamine (423 mg, 1.62 vide the title compound (4.60 mg, 84%); H NMR (CDC1, mmol) followed by titanium isopropoxide (645 mg, 2.27 US 7,749,992 B2 105 106 mmol) to 6-Methyl-5-oxo-2,3,4,5-tetrahydro-benzob. methyl-benzoic acid methyl ester (3.54 g. 14.5 mmol) and azepine-1-carboxylic acid isopropyl ester (423 mg, 1.62 pyridine (2.9 mL, 36.25 mmol) in dichloromethane (29 mL) mmol) at room temperature under an atmosphere of nitrogen at 0°C. under an atmosphere of nitrogen and stir at room and stir the solution for 14 h. Add methanol (6.7 mL) and temperature for 14 h. Add 1M HCl and separate the layers. sodium borohydride (92 mg, 2.43 mmol) and stir the mixture Extract the aqueous layer with dichloromethane. Dry the under nitrogen at room temperature for 45 min. Add 0.1M organic layer over anhydrous magnesium Sulfate, filter, and NaOH, stir for 30 min. Filter through celite and wash the remove the solvent under reduced pressure. Purify the residue residue with AcOEt. Separate organic layer, extract aqueous by flash chromatography, eluting with hexanes/ethyl acetate, with AcOEt. Wash organic layer with brine and dry the to afford the titled compound (3.36 g. 70%): MS (ES+): 331 organic layers over anhydrous Sodium sulfate. Filter and 10 (M+H). remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, Step 3. Preparation of 2-(3-Ethoxycarbonyl-propyl)- to afford (+/-)-5-(3.5-Bis-trifluoromethyl-benzylamino)-6- isopropoxycarbonyl-amino-4-bromo-3-methyl-ben methyl-2,3,4,5-tetrahydro-benzoblazepine-1-carboxylic Zoic acid methyl ester acid isopropyl ester (27 mg. 3%). Add acetic anhydride 15 (0.037 mL, 0.39 mmol) dropwise to a solution of the amine Add a solution of 2-Isopropoxycarbonylamino-4-bromo (27 mg, 0.055 mmol) and pyridine (0.038 mL, 0.43 mmol) in 3-methyl-benzoic acid methyl ester (3.36 g. 10.18 mmol) in dichloromethane (0.5 mL). Stir under nitrogen at room tem DMF (37 mL) to a suspension of sodium hydride 60% dis perature for 14 h. Add 1 Mhydrochloric acid and extract with persion mineral oil (407 mg, 10.18 mmol) in DMF (37 mL) at dichloromethane. Dry the organic layer over anhydrous 0° C. under an atmosphere of nitrogen and allow to reach sodium sulfate, filter and remove the solvent under reduced room temperature over 1 h. Add ethyl 4-bromobutyrate (2.2 pressure. Purify the residue by flash chromatography, eluting mL, 15.27 mmol) and stir at room temperature for 14 h. Dilute with hexanes/ethyl acetate, to afford the title compound (28 with ethyl acetate, wash with 1M HCl, water and brine. Dry mg, 96%); MS (ES+): 531 (M+H). the organic layer over anhydrous magnesium sulfate, filter 25 and remove the solvent under reduced pressure. Purify the Example 131 residue by flash chromatography, eluting with hexanes/ethyl Synthesis of (+/-)-Isopropyl 5-acetyl-(3,5-bistrif acetate, to provide the titled compound (3.47 g, 77%); MS luoromethylbenzyl)amino-8-bromo-9-methyl-tet (ES+): 445 (M+H). rahydrobenzoblazepine-1-carboxylate 30 Step 4. Preparation of 8-Bromo-9-methyl-5-oxo-2.3, 4,5-tetrahydro-benzoblazepine-1-carboxylic acid isopropyl ester Add a solution of 2-(3-Ethoxycarbonyl-propyl)-isopro 35 poxycarbonyl-amino-4-bromo-3-methyl-benzoic acid methyl ester (3.47 g, 7.81 mmol) in THF (120 mL) to a solution of potassium tert-butoxide (15.6 mL, 15.62 mmol. 1 M in THF) in THF (120 mL) at room temperature under an atmosphere of nitrogen. After 2 h, pour the mixture into 40 ice/water. Treat aqueous phase with 1M HCl to pH neutral and extract with dichloromethane. Dry the organic layer over anhydrous magnesium Sulfate, filter, and remove the solvent Br N under reduced pressure. Dissolve the former crude in DMSO (66 mL) and add water (4 drops) followed by addition of 45 lithium chloride (0.882 g, 20.8 mmol) and heat the resulting solution at 160° C. for 2 h. Cool the mixture to room tem perature and pour into brine. Extract the mixture with ethyl acetate. Dry the organic layers over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Step 1. Preparation of 50 Purify the residue by flash chromatography, eluting with hex 2-Amino-4-bromo-3-methyl-benzoic acid methyl anes/ethyl acetate, to afford the title compound (2.0 g, 72% ester over two steps): MS (ES+): 341 (M+H). Step 5. Preparation of (+/-)-5-Acetyl-(3,5-bis-trif Prepare the title compound in a manner analogous to the 55 luoromethyl-benzyl)-amino-8-bromo-9-methyl-2,3, procedure set forth in the preparation of 4-Amino-indan-5- 4,5-tetrahydro-benzoblazepine-1-carboxylic acid carboxylic acid methyl ester (see Example 129, step 3) by replacing 4-bromoindane with 3-bromo-2-methyl-pheny isopropyl ester lamine in Example 129 step 1 and replacing methanesulfonic Inject titanium isopropoxide (1.1 mL, 3.89 mmol) to a acid by concentrated sulfuric acid in Example 129, step 2. MS 60 mixture of 8-bromo-9-methyl-5-oxo-2,3,4,5-tetrahydro (ES+): 245 (M+H). benzoblazepine-1-carboxylic acid isopropyl ester (88.2 mg, Step 2. Preparation of 2.59 mmol) and 3.5-bis(trifluoromethyl)benzylamine (866 2-Isopropoxycarbonylamino-4-bromo-3-methyl-benzoic mg, 2.85 mmol) at room temperature under an atmosphere of acid methyl ester nitrogen and stir the solution for 14 h. Add methanol (11.3 65 mL) and sodium borohydride (245 mg, 6.47 mmol) and stir Add isopropyl chloroformate (14.5 mL, 14.5 mmol. 1.0 M the mixture under nitrogen at room temperature for 2 h. Add in toluene) dropwise to a solution of 2-Amino-8-bromo-9- 0.1MNaOH (61 mL), stirfor 30 min. Filter through celite and US 7,749,992 B2 107 108 wash the residue with AcOEt. Separate organic layer, extract 0.30 mmol) and 3.5-bis(trifluoromethyl)benzylamine (137 aqueous with AcOEt. Wash organic layer with brine and dry mg, 0.45 mmol) at room temperature under an atmosphere of the organic layers over anhydrous magnesium Sulfate. Filter nitrogen and stir the solution for 14 h. Add methanol (1.3 mL) and remove the solvent under reduced pressure. To the former and sodium borohydride (28 mg, 0.75 mmol) and stir the crude in dichloromethane (9.8 mL), add acetic anhydride mixture under nitrogen at room temperature for 2 h. Add (0.980 mL, 10.36 mmol) dropwise and pyridine (0.980 mL. 0.1M NaOH, stir for 30 min. Filter through celite and wash 10.36 mmol), stir under nitrogen at room temperature for 14 the residue with AcOEt. Separate organic layer, extract aque h. Add 1 M hydrochloric acid and extract with dichlo ous with AcOEt. Wash organic layer with brine and dry the romethane. Dry the organic layer over anhydrous sodium organic layers over anhydrous Sodium sulfate. Filter and sulfate, filter and remove the solvent under reduced pressure. 10 remove the solvent under reduced pressure. Purify the residue Purify the residue by flash chromatography, eluting with hex by flash chromatography, eluting with hexanes/ethyl acetate, anes/ethyl acetate, to afford the title compound (162 mg, 10% to afford (+/-)-5-(3.5-Bis-trifluoromethyl-benzylamino)-8- over two steps); MS (ES+): 610 (M+H). chloro-9-methyl-2,3,4,5-tetrahydro-benzoblazepine-1-car Example 132 15 boxylic acid isopropyl ester (90 mg, 57%). Add acetyl chlo ride (0.025 mL, 0.34 mmol) dropwise to a solution of the Synthesis of (+/-)-Isopropyl 5-acetyl-(3,5-bistrif amine (90 mg, 0.17 mmol) and pyridine (0.025 mL, 0.34 luoromethylbenzyl)amino-8-chloro-9-methyl-tet mmol) in dichloromethane (1.2 mL) at 0°C. Stir under nitro rahydrobenzoblazepine-1-carboxylate gen at room temperature for 1 h 30 min. Add water and extract with dichloromethane. Dry the organic layer over anhydrous magnesium Sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatogra CF O 3 phy, eluting with hexanes/ethyl acetate, to afford the title compound (40 mg. 42%); MS (ES+): 565 (M--H). -- 25 Example 133 CF Synthesis of (+/-)-Isopropyl 5-acetyl-(3,5-bistrif. luoromethylbenzyl)amino-8,9-dimethyl-tetrahy 30 C N drobenzoblazepine-1-carboxylate

O

CF 35 4O Step 1. Preparation of 8-Chloro-9-methyl-5-oxo-2.3, 4,5-tetrahydro-benzoblazepine-1-carboxylic acid 40 CF isopropyl ester N In a 10 mL. glass tube, 8-Bromo-9-methyl-5-oxo-2,3,4,5- tetrahydro-benzoblazepine-1-carboxylic acid isopropyl O ester (162 mg, 0.47 mmol), dry DMF (1 mL), NiC1 (247 mg, 45 1.9 mmol) and a magnetic stirring bar were placed. The vessel was sealed with a septum and placed into the microwave cavity. Microwave irradiation of 100W was used, the tem perature being ramped from RT to 170° C. Once this tem perature was reached, the reaction mixture was held at this 50 Mixina 10 mL. glass tube provided with a magnetic stirring temperature for 15 min. After allowing the mixture to cool to bar (+/-)-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- room temperature, the reaction vessel was opened and the amino-8-bromo-9-methyl-2,3,4,5-tetrahydro-benzob. contents poured into a separating funnel and the tube washed azepine-1-carboxylic acid isopropyl ester (46 mg, 0.075 with water and then ether. The organic phase was separated mmol), trimethylboroxine (0.011 mL, 0.075 mmol), KCO, and dried over magnesium sulfate, filtered and removed the 55 (31 mg, 0.225 mmol) and DMF (0.6 mL). Purge the suspen solvent under reduced pressure. Purify the residue by flash sion with nitrogen. Add tetrakis(triphenylphosphine)palla chromatography, eluting with hexanes/ethyl acetate, to afford dium (O) (9 mg, 0.0075 mmol). Place the vessel into the the title compound (94 mg, 68%); MS (ES+): 296 (M+H). microwave cavity. Irradiate with 50 W, with a temperature ramp from RT to 150° C. Maintain the temperature at 150° C. Step 2. Preparation of (+/-)-5-Acetyl-(3,5-bis-trif 60 for 20 min. Cool the mixture to room temperature, open the luoromethyl-benzyl)-amino-8-chloro-9-methyl-2,3, reaction vessel and pour the contents into a separating funnel 4,5-tetrahydro-benzoblazepine-1-carboxylic acid and wash the tube with water and then ethyl acetate. Separate isopropyl ester the layers, wash the organic phase with brine and dry over magnesium Sulfate, filter and remove the solvent under Inject titanium isopropoxide (0.176 mL, 0.60 mmol) to a 65 reduced pressure. Purify the residue by flash chromatogra mixture of 8-chloro-9-methyl-5-oxo-2,3,4,5-tetrahydro phy, eluting with hexanes/ethyl acetate, to afford the title benzoblazepine-1-carboxylic acid isopropyl ester (90 mg. compound (7 mg, 17%); MS (ES+): 545 (M+H). US 7,749,992 B2 109 110 Example 134 eral oil (471 mg, 11.76 mmol) in DMF (43 mL) at 0°C. under an atmosphere of nitrogen and allow to reach room tempera Synthesis of (+/-)-Isopropyl 5-acetyl-(3,5-bistrif ture over 1 h. Add ethyl 4-bromobutyrate (2.5 mL, 17.64 luoromethylbenzyl)amino-6-fluor-tetrahydrobenzo mmol) and stir at room temperature for 14 h. Dilute with ethyl blazepine-1-carboxylate acetate, wash with 1M HCl, water and brine. Dry the organic layer over anhydrous magnesium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to pro 10 vide the title compound (2.96, 68%). MS (ES+): 370 (M+H).

Step 4. Preparation of 6-Fluor-5-oxo-2,3,4,5-tetrahy 15 dro-benzoblazepine-1-carboxylic acid isopropyl ester

Add a solution of 2-(3-Ethoxycarbonyl-propyl)-isopro poxycarbonyl-amino-6-fluor-benzoic acid methyl ester (2.96g, 8.01 mmol) in THF (123 mL) to a solution of potas sium tert-butoxide (16 mL, 16 mmol, 1 M in THF) in THF (123 mL) at room temperature under an atmosphere of nitro 25 gen. After 2 h, pour the mixture into ice/water. Treat aqueous phase with 1M HCl to pH neutral and extract with dichlo Step 1. Preparation of 2-Amino-6-fluor-benzoic acid romethane. Dry the organic layer over anhydrous magnesium methyl ester sulfate, filter, and remove the solvent under reduced pressure. 30 Dissolve the former crude in DMSO (58 mL) and add water (4 Dissolve 2-Amino-6-fluoro-benzoic acid (3.00 g, 19.3 drops) followed by addition of lithium chloride (773 mg, mmol) in ethylacetate (59 mL) and ethanol (59 mL) and add 18.23 mmol) and heat the resulting solution at 160° C. for 2 h. (trimethylsilyl) diazomethane (19.3 mL, 38.68 mmol, 2M in Cool the mixture to room temperature and pour into brine. hexane) at room temperature and stir the solution for 1 h 30 35 Extract the mixture with ethyl acetate. Dry the organic layers min. Remove the solvent under reduced pressure to afford the over anhydrous magnesium sulfate, filter the mixture and title compound (3.26g, quantitative). MS (ES+): 170 (M--H). evaporate the solvent under reduced pressure. Purify the resi due by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (1.0 g, 47% over two Step 2. Preparation of 40 steps): MS (ES+): 266 (M+H). 2-Isopropoxycarbonylamino-6-fluor-benzoic acid methyl ester Step 5. Preparation of (+/-)-5-Acetyl-(3,5-bis-trif Add isopropyl chloroformate (20.7 mL. 20.7 mmol. 1.0 M 45 luoromethyl-benzyl)-amino-6-fluor-2,3,4,5-tetrahy in toluene) dropwise to a solution of 2-Amino-6-fluor-ben dro-benzoblazepine-1-carboxylic acid isopropyl Zoic acid methyl ester (3.5g, 20.7 mmol) and pyridine (4.2 ester mL, 51.75 mmol) in dichloromethane (41 mL) at 0°C. under an atmosphere of nitrogen and stir at room temperature for 14 50 Inject titanium isopropoxide (1.3 mL, 4.32 mmol) to a h. Add 1M HCl and separate the layers. Extract the aqueous mixture of 6-fluor-5-oxo-2,3,4,5-tetrahydro-benzob. layer with dichloromethane. Dry the organic layer over anhy azepine-1-carboxylic acid isopropyl ester (572 mg, 2.16 drous sodium sulfate, filter, and remove the solvent under mmol) and 3,5-bis(trifluoromethyl)benzylamine (972 mg, reduced pressure. Purify the residue by flash chromatogra 55 3.2 mmol) at room temperature under an atmosphere of nitro phy, eluting with hexanes/ethyl acetate, to afford the title gen and stir the solution for 14 h. Purify the residue by flash compound (3.00 g, 63%). MS (ES+): 256 (M+H). chromatography, eluting with hexanes/ethyl acetate, to afford 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-2,3-dihy Step 3. Preparation of 2-(3-Ethoxycarbonyl-propyl)- 60 dro-benzoblazepine-1-carboxylic isopropyl ester (820 mg. isopropoxycarbonyl-amino-6-fluor-benzoic acid 77%). Add methanol (9.3 mL) and platinum oxide (37 mg, methyl ester 0.16 mmol) to 5-(3.5-Bis-trifluoromethyl-benzylamino)-6- fluoro-2,3-dihydro-benzoblazepine-1-carboxylic isopropyl

Add a solution of 2-Isopropoxycarbonylamino-6-fluor 65 ester (742 mg, 1.5 mmol) and hydrogenate the mixture at 1 benzoic acid methyl ester (3.0 g, 11.76 mmol) in DMF (43 atmosphere and room temperature for 2 h. Filter through mL) to a suspension of sodium hydride 60% dispersion min celite and remove the solvent under reduced pressure to afford US 7,749,992 B2 111 112 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-2,3,4,5- small portions at 60° C. to concentrated sulfuric acid (44 mL) tetrahydro-benzoblazepine-1-carboxylic acid isopropyl and heat the mixture at 80°C. for 1 h. Cool to room tempera ester (730 mg, quantitative). Add acetic anhydride (0.5 mL, ture, pour into ice water (100 mL) and filter the precipitate. 5.78 mmol) dropwise to a suspension of the amine (190 mg. Wash the solid with cool water twice. Dry the solid to afford 0.385 mmol) and pyridine (0.5 mL, 5.78 mmol) in dichlo the title compound (3.54 g. 46% two steps). MS (ES-): 228 romethane (1.5 mL), stir under nitrogen at room temperature (M-H). for 14 h. Add 1 M hydrochloric acid and extract with dichlo romethane. Dry the organic layer over anhydrous sodium 10 sulfate, filter and remove the solvent under reduced pressure. Step 2. Preparation of Purify the residue by flash chromatography, eluting with hex anes/ethyl acetate, to afford the title compound (141 mg, 2-Amino-3-methyl-4-trifluoromethyl-benzoic acid 68%); MS (ES+): 535 (M+H). 15

Example 135 Synthesis of (+/-)-Isopropyl 5-acetyl-(3,5-bistrif luoromethylbenzyl)amino-9-methyl-8-trifluorom ethyl-tetrahydrobenzoblazepine-1-carboxylate

F 25 F Add 30% aqueous hydrogen peroxide solution (3.8 mL) in - 4 F water (33 mL) to solution of 7-methyl-6-trifluoromethyl-1H N indole.2,3-dione (3.54 g. 15.46 mmol) and sodium hydroxide

30 (3.83 g, 95.84 mmol) in water (74 mL) slowly. Then stir the F F mixture at room temperature for 1 h. Add 1N hydrochloric F F acid to acidulate the mixture. Filter the resulting solid and N F wash with water. Dry the solid to afford the title compound F 35 O (1.7g, 50%). MS (ES+): 218 (M-H). O Step 3. Preparation of (+/-)-Isopropyl 5-acetyl-(3.5- 40 bistrifluoromethylbenzyl)amino-9-methyl-8-trifluo Step 1. Preparation of romethyl-tetrahydrobenzoblazepine-1-carboxylate 7-methyl-6-trifluoromethyl-1H-indole.2,3-dione

45

CF

50 N F CF F

To a solution of chloral hydrate (6.08 g. 36.74 mmol) and 55 anhydrous sodium sulfate (28.5g, 200.4 mmol) in water (102 mL) add a mixture of hydroxylamine sulfate (28.5g, 173.68 mmol), 2-methyl-3-trifluoromethyl-phenylamine (5.85 g, The titled compound was prepared following the proce 33.4 mmol), concentrated hydrochloric acid (3.5 mL) in 60 water (34 mL). Heat the mixture at 35° C. for 1 h, then heat up dures described for the preparation of (+/-)-Isopropyl to 52° C. for 90 min and at 75° C. for 1 hr. Cool the mixture 5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-6-methyl to room temperature and filter the solid. Wash the solid with tetrahydrobenzoblazepine-1-carboxylate (Example 130, water and hexane. Dry the solid under vacuum to afford from step 1 to step 5) by replacing 2-Amino-6-methyl-ben 2-hydroxyimino-N-(2-methyl-3-trifluoromethyl-phenyl)- 65 Zoic acid with 2-Amino-3-methyl-4-trifluoromethyl-benzoic acetamide. MS (ES+): 245 (M-H). Add the former crude in acid in Example 130, step 1. MS (ES+): 599 (M+H). US 7,749,992 B2 113 114 Example 136 methyl-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate (example 132, from step 3 to 6) by replacing methyl 2-amino Synthesis of (+/-)-6-Acetyl-(3,5-bis-trifluorom 6-fluoro-5-methylbenzoate with 4-Amino-7-bromo-indan-5- ethyl-benzyl)-amino-4-bromo-2,3,6,7,8,9-hexahy carboxylic acid methyl ester in example 132 step 3. MS dro-1H-10-aza-cycloheptaeindene-10-carboxylic 5 (ES+): 635.64 (M+H). acid isopropyl ester Example 137 O CF Synthesis of (+/-)-6-Acetyl-(3,5-bis-trifluorom - 10 ethyl-benzyl)-amino-4-methyl-2,3,6,7,8,9-hexahy N dro-1H-10-aza-cycloheptaeindene-10-carboxylic acid isopropyl ester Br CF 15 N CF O

- O 4

-Q 2O CF

Step 1. Preparation of N 4-Amino-7-bromo-indan-5-carboxylic acid methyl 25 ester O

Br COMe

30 NH2 The titled compound was prepared in a manner analogous to the procedure for the preparation of N-(3.5-Bis-trifluorom ethyl-benzyl)-N-(9-methyl-7-trifluoromethyl-2,3,4,5-tet Add N-bromosuccinimide (1.99 g, 11.2 mmol) to rahydro-1H-benzoblazepin-5-yl)-acetamide (example 123, 4-Amino-indan-5-carboxylic acid methyl ester (2.15g, 11.2 35 step 3) by replacing N-(3.5-Bis-trifluoromethyl-benzyl)-N- mmol) in acetic acid (13 mL). Stir the mixture at room tem (9-bromo-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo perature for 48 h. Pour the mixture into ice-water and add blazepin-5-yl)-acetamide with (+/-)-6-Acetyl-(3,5-bis-tri ethyl acetate. Separate the layers and wash the organic phase fluoromethyl-benzyl)-amino-4-bromo-2,3,6,7,8,9- with sat NaHCO and brine and dry over sodium sulfate. hexahydro-1H-10-aza-cycloheptaeindene-10-carboxylic Remove the solvent under reduced pressure to afford the title 40 acid isopropyl ester (example 144, step 2) compound (3.10, quantitative). MS (ES+): 271 (M+H). MS (ES+): 570 (M+H). Step 2. (+/-)-6-Acetyl-(3,5-bis-trifluoromethyl benzyl)-amino-4-bromo-2,3,6,7,8,9-hexahydro-1H Example 138 10-aza-cycloheptaeindene-10-carboxylic acid iso- 45 Synthesis of (+/-)-9-Acetyl-(3,5-bis-trifluorom propyl ester ethyl-benzyl)-amino-4-methyl-2,3,6,7,8,9-hexahy dro-1H-5-aza-cyclohepta findene-5-carboxylic acid isopropyl ester CF O 3 50

4- N CF O Br CF 55 -4-

N CF

O -, 60

-Q o O The titled compound was prepared following the proce- 65 dure described for the preparation of (+/-)-Isopropyl -Q 5-acetyl-(3,5-bistrifluoromethylbenzyl)amino-6-fluoro-7- US 7,749,992 B2 115 116 The titled compound was prepared following the proce and remove solvent under vacuum. Chromatograph the prod dures described for the preparation of (+/-)-6-Acetyl-(3.5- uct on silica gel using hexane/ethyl acetate (gradient, 2-10% bis-trifluoromethyl-benzyl)-amino-4-methyl-2,3,6,7,8,9- ethyl acetate/hexane) to elute. This provides the title com hexahydro-1H-10-aza-cycloheptaeindene-10-carboxylic pound as a colorless solid (1.43 g, 4.9%); H NMR (CDC1, acid isopropyl ester (example 137) by replacing 4-amino 5 400MHz) & 1.54 (s.9H), 3.99 (s.3H), 7.75 (dd, J=2.0,9.2 Hz, indan-5-carboxylic acid methyl ester by 6-amino-indan-5- 1H), 8.30 (d. J=1.6 Hz, 1H), 8.64 (d. J=9.2 Hz), 10.48 (s, 1H). carboxylic acid methyl ester in example 136 step 1. Step 3. Preparation of 2-tert-Butoxycarbonyl-(3- Example 139 10 methoxycarbonyl-propyl)-amino-5-trifluoromethyl benzoic acid methyl ester Synthesis of 5-Acetyl-(3,5-bis-trifluoromethyl-ben Zyl)-amino-7-trifluoromethyl-2,3,4,5-tetrahydro Add 50 mL of DMF to a mixture of methyl-3-trifluorom benzoblazepine-1-carboxylic acid tert-butyl ester ethyl-2-t-butoxycarbonylaminobenzoate (3.0 g, 9.4 mmol) 15 and methyl 4-bromobutyrate (2.6 g., 14.1 mmol) under an atmosphere of nitrogen. To this, add cesium carbonate (9.2g, 28.2 mmol) and heat the suspension to 60° C. for 6h then cool F to room temperature. Dilute the reaction with water (200 mL) O F and ethyl acetate (300 mL). Separate the organic phase and F wash with water (100 mL) followed by brine (100 mL). Dry F F y the organics over Sodium Sulfate, filter, and remove solvent under vacuum. Chromatograph the reaction over silica gel F using ethylacetate/hexane (0-10%) to elute. This provides the F F 25 title compound as an oil (3.8 g.97%); H NMR (CDC1, 400 F MHz) & 1.33 (s, 6H), 1.54 (s, 3H), 1.97 (bm, 2H), 2.41 (bt, N J=7.2 Hz, 2H), 3.56-3.85 (m, 5H), 3.94 (bs, 3H), 7.40 (bt, o J=8.0 Hz, 1H), 7.78 (dd, J=2.0, 8.0 Hz, 1H), 8.19 (bs, 1H). O 30 Step 4. Preparation of 7-Trifluoromethyl-1,2,3,4- tetrahydro-benzoblazepin-5-one Add a solution of methyl 2-tert-Butoxycarbonyl-(3-meth 35 oxycarbonyl-propyl)-amino-5-trifluoromethyl-benzoic acid Step 1. Preparation of methyl ester (0.5g, 1.3 mmol) in toluene (25 mL) to a sus Methyl-3-trifluoromethyl-2-aminobenzoate pension of potassium tert-butoxide (0.3 g, 2.6 mmol) in tolu ene (75 mL) at 70°C., under an atmosphere of nitrogen, over Add palladium (II) acetate (1.89 g, 8.4 mmol), 1,1-bis a period of 30 min. After 2 h, cool the reaction to room (diphenylphosphino) ferrocene (6.83 g, 12.3 mmol), and tri 40 temperature and quench the reaction with acetic acid (2.6 ethylamine (32 mL, 44.0 mmol) to a solution of 2-bromo-4- mmol). Dilute the reaction with water (100 mL) and dichlo trifluoromethylanaline (10.0 g, 42.0 mmol) in romethane (100 mL). Separate the organic phase, dry over dimethylsulfoxide (283 mL) and methanol (187 mL). At 100 sodium sulfate, and filter. Remove the solvent under vacuum psi of carbon monoxide, heat the mixture to 80° C. After 45 then dissolve the crude intermediate in acetic acid (20 mL). heating for 14-16 h cool the reaction to room temperature and Dilute with conc. HCl (20 mL) and water (10 mL) and heat the filter. Dilute the organics with ethyl acetate (500 mL), wash mixture to 100° C. for 4 h. After cooling to room temperature with water (3x200 mL) and brine (200 mL). Dry the organics neutralize the reaction with 5N NaOH while cooling in an ice over sodium sulfate and filter. Remove solvent under vacuum bath. Extract the organics with ethyl acetate (3x100 mL), dry and chromatograph the crude product using ethyl acetate/ 50 over sodium sulfate, and filter. Remove the solvent under hexane (10%) to elute. This provides the title compound (8.0 vacuum and chromatograph the product over silica gel using g, 88%) as an off white solid; H NMR (CDC1, 400 MHz) & ethyl acetate/hexane (5-20%) to elute. This provides the title 3.93 (s.3H), 6.11 (bs, 2H), 6.73 (d. J=8.4 Hz, 1H), 7.49 (dd. compound as an off white solid (0.13 g, 45%); H NMR J=2.0, 8.4 Hz, 1H), 8.17 (d. J=2.0 Hz, 1H). 55 (CDC1, 400 MHz) & 2.22-2.29 (m, 2H), 2.88 (t, J=6.4 Hz), 3.35 (t, J=6.8 Hz), 4.96 (bs, 1H), 6.84 (d. J=8.8 Hz, 1H), 7.46 Step 2. Preparation of Methyl-3-trifluoromethyl-2-t- (dd, J-2.0, 8.8 Hz, 1H), 8.02 (s, 1H). butoxycarbonylaminobenzoate Step 5. Preparation of 5-Oxo-7-trifluoromethyl-2,3, Add di-t-butyl dicarbonate (2.0 g, 9.1 mmol) to a solution 60 4,5-tetrahydro-benzoblazepine-1-carboxylic acid of methyl-3-trifluoromethyl-2-aminobenzoate (2.0 g, 9.1 tert-butyl ester mmol) in dichloromethane (20 mL). To this mixture, add triethylamine (9.1 mmol) and stir at room temperature under Add di-t-butyldicarbonate (0.68 mmol) to a solution of an atmosphere of nitrogen for 72 h. Dilute the reaction with 65 7-trifluoromethyl-1,2,3,4-tetrahydro-benzoblazepin-5-one dichloromethane (100 mL) and wash with water (100 mLx2). (0.1 g, 0.44 mmol) in dichloromethane (10 mL). To this Dry the separated organic phase over Sodium sulfate, filter, Solution add dimethylaminopyridine (0.22 mmol) and diiso US 7,749,992 B2 117 118 propyl ethylamine (0.68 mmol). Stir the resulting mixture at dicarbonate (21.5 g., 0.0985 mol) and continue heating for 5 room temperature overnight. Remove solvent under vacuum days. Concentrate the contents in vacuo. Recrystallize the and chromatograph the product over silica gel using ethyl title compound from Methanol to give a colorless solid (86.2 acetate/hexane (5-20%) to elute. This provides the title com g, 45%). Remove solvent from the filtrate, under vacuum, and pound as an oil (0.13 g, 90%): MS (ES+): 330 (M+H). 5 chromatograph over silica gel using ethyl acetate/hexane (0-10%) to elute. This affords an additional 13.5 g (7%) of the Step 6. Preparation of 5-Acetyl-(3,5-bis-trifluorom title compound: H NMR (CDC1, 300 MHz) & 1.53 (s, 9H), ethyl-benzyl)-amino-7-trifluoromethyl-2,3,4,5-tet 3.91 (s.3H), 6.96 (dd, J=1.8, 8.7 Hz, 1H), 7.92 (d. J=8.7 Hz, rahydro-benzoblazepine-1-carboxylic acid tert-butyl 1H), 8.54 (d. J=2.4 Hz, 1H). ester 10 Step 2. Preparation of 2-tert-Butoxycarbonyl-(3- Add 3,5-bis(trifluoromethyl)benzylamine (0.1 g, 0.4 methoxycarbonyl-propyl)-amino-4-chloro-benzoic mmol) followed by titanium isopropoxide (1.0 mL) to 5-Oxo acid methyl ester 7-trifluoromethyl-2,3,4,5-tetrahydro-benzoblazepine-1- carboxylic acid tert-butyl ester (0.13 g, 0.4 mmol) and stir at 15 Add methyl 4-bromobutyrate (54.4 mL, 0.437 mol) to a room temperature overnight. Dilute the mixture with 5 mL of mixture of 2-tert-butoxycarbonylamino-4-chloro-benzoic Methanol and add sodium borohydride (0.8 mmol). Stir the acid methyl ester (96.15g, 0.337 mol) and CsCO (274.10g, suspension at room temperature for 30 min then dilute with 0.841 mol) in DMF (1.3 L). Heat the suspension at 55° C. water (20 mL) and ethyl acetate (20 mL). Filter the resulting overnight. Remove DMF under vacuum. Dilute the organics emulsion through celite and wash with ethyl acetate (3x20 with ethyl acetate (1.5 L) and water (1.5 L). Separate the mL). Separate the organics, dry over Sodium Sulfate, and organic layer and extract the aqueous with ethyl acetate filter. Remove the solvent under vacuum to afford (+/-)-t- (2x0.5 L). Combine the organics and wash with half saturated butyl-5-(3,5-bistrifluoromethylbenzylamino)-7-trifluorom potassium bicarbonate (1 L), water (2x0.5 L) and brine (0.5 ethyl-2,3,4,5-tetrahydrobenzoblazepine-1-carboxylate L). Dry the organics over Sodium Sulfate, filter, and remove crude (0.2g, MS (ES+): 557 (M+H)). Without further purifi 25 Solvent under vacuum. This provides the title compound as a cation, add acetyl chloride (0.8 mmol) and pyridine (0.8 yellow oil crude (141.8 g): mmol) to a solution of (+/-)-t-butyl-5-(3,5-bistrifluorometh H NMR (CDC1, 300 MHz) & 1.28 (s, 6H), 1.48 (s, 3H), ylbenzylamino)-7-trifluoromethyl-2,3,4,5-tetrahydrobenzo 1.87-1.98 (m,2h), 2.33-2.43 (m, 2H),341-3.80 (m, 5H), 3.86 blazepine-1-carboxylate in dichloromethane. After stirring (s, 3H), 7.22-7.31 (m, 2H), 7.85 (d. J=8.1 Hz, 1H). for 2 h remove solvent under vacuum and chromatograph 30 over silica gel using ethyl acetate/hexane (5-40%) to elute. Step 3. Preparation of This affords the title compound as an oil (0.2g, 83%) which 8-Chloro-1,2,3,4-tetrahydro-benzoblazepin-5-one foams under vacuum: MS (ES-): 597 (M-H). Add a mixture of crude 2-tert-Butoxycarbonyl-(3-meth Example 140 35 oxycarbonyl-propyl)-amino-4-chloro-benzoic acid methyl ester (141.5g, ~0.337 mol) in toluene to potassium t-butoxide Synthesis of 5-Acetyl-(3,5-bis-trifluoromethyl-ben (95%, 100 g, 0.847 mol) in anhydrous toluene (4.5 L) at 60° Zyl)-amino-8-chloro-2,3,4,5-tetrahydro-benzob C. over 1 h. After heating of 24 h concentrate the mixture azepine-1-carboxylic acid tert-butyl ester 40 under vacuum. Partition the residue between ethyl acetate (1.5 L) and saturated KHPO (1.5 L). Separate the aqueous layer and extract with ethyl acetate (2x0.5 L). Combine the organics and wash with water (2x0.5 L). Remove solvent F under vacuum. Dissolve the residue in acetic acid (250 mL) and dilute with 5N HCl (1 L). After heating at 85°C. for 4 h, O F 45 cool the mixture to room temperature. Basify (pH=10) with F 5N sodium hydroxide (ca. 1.8 L) while cooling in an ice bath. Extract the organics with ethyl acetate (3x0.5 L) and wash y with brine (0.75 L). Dry over sodium sulfate, filter and con F centrate under vacuum. Pass the beige crude product through 50 F a pad of silica (8 cmDx3 cmH), eluting with DCM/hexanes F (2/1, ca. 3.5 L). Concentrate the crude product under vacuum to give a yellow solid. Recrystallize from EtOAc/hexanes C N (1/4) to give the title compound (42.85g. 65%) as an off white solid; H NMR (CDC1, 300 MHz) & 4.20 (m, 2H), 4.85 (t, o O 55 J=4.2 Hz, 2H), 5.29 (t, J=4.2 Hz, 2H), 6.71 (bs, 1H),8.79-8.82 (m. 2H), 9.68 (d. J=5.1 Hz, 1H). Step 4. Preparation of 8-Chloro-5-oxo-2,3,4,5-tet rahydro-benzoblazepine-1-carboxylic acid tert-butyl 60 ester Step 1. Preparation of 2-tert-Butoxycarbonylamino-4-chloro-benzoic acid Add dichloromethane (DCM) (100 mL) to a mixture of methyl ester 8-Chloro-1,2,3,4-tetrahydro-benzoblazepin-5-one (3.0 g, 15.4 mmol) and di-t-butyl dicarbonate (38.5 mmol). To this Heat a mixture of methyl 4-chloro-2-aminobenzoate 65 mixture add dimethylaminopyridine (7.7 mmol) and diiso (124.8 g., 0.672 mol) and di-tert-butyl dicarbonate (161.4g, propyl ethylamine (38.5 mmol) and stir at room temperature 0.740 mol) at 70° C. After 48 h, add additional di-t-butyl under an atmosphere of nitrogen for 24 h. Concentrate the US 7,749,992 B2 119 120 reaction under vacuum and chromatograph the product over silica gel using ethyl acetate/hexane (0-20%) to elute. This provides the title compound (3.6 g. 79%) as an oil which crystallizes upon standing: HNMR (CDC1,400MHz) & 1.53 Example # Reagent R MS (ES+) (s, 9H), 2.15 (m, 2H), 2.75 (t, J=6.8 Hz, 2H), 3.73 (bt, J=6.8 141 Propionyl chloride Propane-1-carbonyl 577 (M-H) 142 Isovaleryl chloride 3-methylbutyl-1- 605 (M-H) Hz, 2H), 7.22 (dd, J-2.0, 8.8 Hz, 1H), 7.49 (bs, 1H), 7.80 (d. carbonyl J=8.8 Hz, 1H). MS (ES+): 296 (M+H). 143 Cyclopropanecarbonyl Cyclopropanecarbonyl 589 (M-H) chloride Step 5. Preparation of 5-(3.5-Bis-trifluoromethyl 144 Cyclopentanecarbonyl Cyclopentanecarbonyl 617 (M-H) 10 chloride benzylamino)-8-chloro-2,3,4,5-tetrahydro-benzob 145 Benzoyl chloride Benzoyl 625 (M-H) azepine-1-carboxylic acid tert-butyl ester 146 Methoxyacetyl Methoxyacetyl 593 (M-H) chloride Add 3,5-bis(trifluoromethyl)benzylamine (3.2 g, 13.1 147 2-Furoyl chloride Furan-2-carbonyl 615 (M-H) mmol) followed by titanium isopropoxide (5.0 mL) to 15 8-Chloro-5-oxo-2,3,4,5-tetrahydro-benzoblazepine-1-car boxylic acid tert-butyl ester (3.5 g., 11.9 mmol) and stir at Example 148 room temperature overnight. Dilute the mixture with 20 mL Synthesis of 5-Acetyl-(3,5-bis-trifluoromethyl-ben of Methanol and add sodium borohydride (23.8 mmol). Stir Zyl)-amino-8-chloro-2,3,4,5-tetrahydro-benzob the suspension at room temperature for 1 h then dilute with aZepine-1-carboxylic acid cyclopentyl ester water (200 mL) and ethyl acetate (200 mL). Filter the result ing emulsion through celite and wash with ethyl acetate (3x100 mL). Separate the organics and dry over sodium sul fate. Remove the Solvent under vacuum and chromatograph F the product over silica gel using ethyl acetate/hexane (5-30%) 25 to elute. This affords the title compound (5.7g.93%) as an off O F white solid: MS (ES+): 523 (M+H). y F Step 6. Preparation of 5-Acetyl-(3,5-bis-trifluorom ethyl-benzyl)-amino-8-chloro-2,3,4,5-tetrahydro 30 F benzoblazepine-1-carboxylic acid tert-butyl ester F F Add acetyl chloride (0.3 mmol) followed by pyridine (0.3 C N mmol) to a solution of 5-(3.5-Bis-trifluoromethyl-benzy 35 o lamino)-8-chloro-2,3,4,5-tetrahydro-benzoblazepine-1-car O boxylic acid tert-butyl ester (0.05 g, 0.1 mmol) in dichlo romethane (1 mL). After stirring at room temperature for 24h remove solvent under vacuum. Chromatograph the product over silica gel using ethyl acetate/hexane (10-40%) to elute. 40 This affords the title compound (0.04g, 71%) as an oil which foams under vacuum: MS (ES+): 563 (M-H). Step 1. Preparation of N-(3.5-Bis-trifluoromethyl benzyl)-N-(8-chloro-2,3,4,5-tetrahydro-1H-benzob. F 45 aZepin-5-yl)-acetamide F F RNN

F

F F C N o 55

C N

60 To a solution of 5-Acetyl-(3,5-bis-trifluoromethyl-ben Additional compounds (Examples 141-147) were pre Zyl)-amino-8-chloro-2,3,4,5-tetrahydro-benzoblazepine pared using the methodology described in step 6 (5-Acetyl 1-carboxylic acid tert-butyl ester (7.9 g, 14.0 mmol) in (3,5-bis-trifluoromethyl-benzyl)-amino-8-chloro-2,3,4,5- dichloromethane (100 mL) add a solution of trifluoroacetic tetrahydro-benzoblazepine-1-carboxylic acid tert-butyl 65 acid (50 mL) in dichloromethane (50 mL). After stirring at ester) above. The R group is varied by replacing acetyl chlo room temperature for 1 h, neutralize the reaction with con ride with the appropriate Reagent. centrated Sodium bicarbonate. Separate the organic phase and US 7,749,992 B2 121 122 wash with water (100 mL) and brine (100 uL). Dry the organ ics over sodium sulfate, filter, and remove solvent under vacuum. Crystallize the compound from dichloromethane/ hexane. This provides the title compound (5.3 g, 81%) as a Exam colorless solid: MS (ES+): 465 (M+H). ple # Reagent R1 MS (ES+) 49 cyclobutanol cyclobutyloxy 563 (M+H) Step 2. Preparation 5-Acetyl-(3,5-bis-trifluorom 50 Cyclohexanol Cyclohexyloxy 591 (M+H) ethyl-benzyl)-amino-8-chloro-2,3,4,5-tetrahydro 51 3-pentanol pentyloxy 579 (M+H) benzoblazepine-1-carboxylic acid cyclopentyl ester 52 2,4-dimethyl-3- 2,4-dimethyl-3- 607 (M+H) 10 pentanol pentyloxy 53 1,3-difluoro-2- 1,3-difluoro-2- 587 (M+H) butanol butyloxy F 54 3-methyl-2-butanol 3-methyl-2-butyloxy 579 (M+H) 55 2-methyl-3-pentanol 2-methyl-3-pentyloxy 593 (M+H) 56 1,1,1-trifluoro-2- 1,1,1-trifluoro-2- 605 (M+H) O F F 15 propanol propyloxy 57 2-butanol 2-butyloxy 565 (M+H) y 58 3-methylcyclo- 3-methylcyclo- 591 (M+H) pentanol pentyloxy F 59 1-methoxy-2-butanol 1-methoxy-2-butyloxy 595 (M+H) 60 Tetrahydrothiophene- Tetrahydrothiophene- 627 (M+H) F F 3-ol-1,1-dioxide 3-oxy-1,1-dioxide 61 Tetrhydro-3- Tetrhydro-3- 593 (M+H) C N furanmethanol furanmethyloxy 62 (S)-(+)-3- (S)-(+)-3- 579 (M+H) o hydroxytetra- tetrahydrofuranyloxy O 25 hydrofuran 63 (R)-(-)-3- (R)-(-)-3- 579 (M+H) hydroxytetra- tetrahydrofuranyloxy hydrofuran 64 2-propanethiol 2-propanethioxy 567 (M+H) 30 Add phosgene (0.5 mmol) to a solution of cyclopentanol (0.5 mmol) in DCM (1 mL) at 0°C. under nitrogen. To this Example 165 cooled solution add diisopropyl ethylamine (0.5 mmol) drop wise. After stirring for 1 h with cooling, warm the mixture to Synthesis of N-(1-Acetyl-8-chloro-2,3,4,5-tetrahy room temperature and add N-(3.5-Bis-trifluoromethyl-ben 35 Zyl)-N-(8-chloro-2,3,4,5-tetrahydro-1H-benzoblazepin-5- dro-1H-benzoblazepin-5-yl)-N-(3,5-bis-trifluorom yl)-acetamide (0.05 g, 0.11 mmol) in dichloromethane (0.5 ethyl-benzyl)-acetamide mL) and pyridine (0.5 mmol). After stirring at room tempera ture for 14-16 h dilute the reaction with dichloromethane (2 mL) and wash with 5% HCl (2 mL) followed by water (2 mL) 40 and brine (2 mL). Dry the organics over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the crude mixture over silica gel using ethyl acetate/hexane (10-30%) to elute. This affords the title compound (0.06 g.95%) as an oil which crystallizes upon standing: MS (ES+): 577 (M--H). 45

F

O F C N y F F

F 55 Add acetyl chloride (0.3 mmol) followed by dimethylami F nopyridine (cat.) and pyridine (0.3 mmol) to a solution of C N N-(3.5-Bis-trifluoromethyl-benzyl)-N-(8-chloro-2,3,4,5-tet o rahydro-1H-benzoblazepin-5-yl)-acetamide (0.05 g, 0.11 R1 mmol) in dichloromethane (1 ml). After stirring for 14-16 h 60 dilute with dichloromethane (2 mL) and wash with 5% HCl (2 Additional compounds (examples 149-164) were prepared mL), water (2 mL) and brine (2 mL). Dry the organics over using the methodology described in step 2 (Preparation of Sodium Sulfate, filter, and remove solvent under vacuum. 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-8- Chromatograph the crude product over silica gel using ethyl chloro-2,3,4,5-tetrahydro-benzoblazepine-1-carboxylic 65 acetate/hexane (10-30%) to elute. This afford the title com acid cyclopentyl ester) above. R1 is varied by replacing pound (0.04 g., 89%) as a colorless solid: MS (ES+): 507 cyclopentanol with the appropriate reagent. (M+H). US 7,749,992 B2 123 124 Step 1. Preparation of 5-Acetyl-(3,5-bis-trifluorom ethyl-benzyl)-amino-8-chloro-2,3,4,5-tetrahydro benzoblazepine-1-carbonyl chloride

Add phosgene (1.1 mmol. 1.93 M solution in toluene) followed by diisopropyl ethylamine (1.1 mmol) to a toluene (15 mL) solution of N-(3.5-Bis-trifluoromethyl-benzyl)-N- (8-chloro-2,3,4,5-tetrahydro-1H-benzoblazepin-5-yl)-ac 10 etamide (0.50 g, 1.1 mmol) under nitrogen. After stirring at room temperature for 1 h, remove solvent under vacuum. C N Chromatograph the crude product over silica gel using ethyl I acetate/hexane (10-30%) to elute. This provides the title com R2 pound (0.55g.96%) as an oil which solidifies upon standing: Additional compounds (examples 166-177) were prepared 15 MS (ES+): 527 (M+H). using the same methodology described for the (synthesis of N-(1-Acetyl-8-chloro-2,3,4,5-tetrahydro-1H-benzob. Step 2. Preparation of 5-Acetyl-(3,5-bis-trifluorom azepin-5-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-acetamide. ethyl-benzyl)-amino-8-chloro-2,3,4,5-tetrahydro R2 is varied by replacing acetylchloride with the appropriate benzoblazepine-1-carboxylic acid isopropylamide reagent. Add isopropyl amine (0.3 mmol) to a dichloromethane solution of 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- Example # Reagent R2 MS (ES+) amino-8-chloro-2,3,4,5-tetrahydro-benzoblazepine-1-car 25 bonyl chloride (0.050 g, 0.11 mmol) at room temperature 66 Isobutyryl chloride isobutylcarbonyl 535 (M+H) 67 Propionyl chloride Propane-1-carbonyl 521 (M+H) under nitrogen. After stirring for 1 h remove solvent under 68 DL-2-methylbutyryl DL-2-methylbutyl-1- 549 (M+H) vacuum and chromatograph the crude product over silica gel chloride carbonyl using ethyl acetate/hexane (30-40%) to elute. This provides 69 Isovaleryl chloride 3-methylbutyl-1- 549 (M+H) carbonyl 30 the title compound (0.052 g, 87%) as a colorless solid: MS 70 2-ethylbutyryl 2-ethylbutyl-1- 563 (M+H) (ES+): 550 (M+H). chloride carbonyl 71 Cyclopropanecarbonyl Cyclopropanecarbonyl 533 (M+H) chloride 72 Cyclopentanecarbonyl Cyclopentanecarbonyl 561 (M+H) F chloride 35 73 Cyclohexanecarbonyl Cyclohexanecarbonyl 575 (M+H) O F chloride 74 Benzoyl chloride Benzoyl 569 (M+H) F 75 Methoxyacetyl Methoxyacetyl 537 (M+H) N chloride 76 3,3-dimethylacryloyl 3,3-dimethylacryloyl- 547 (M+H) 40 F chloride 1-carbonyl 77 2-Furoyl chloride Furan-2-carbonyl 559 (M+H) F F C N Example 178 45 - -R4 Synthesis of 5-Acetyl-(3,5-bis-trifluoromethyl-ben Zyl)-amino-8-chloro-2,3,4,5-tetrahydro-benzob R3 aZepine-1-carboxylic acid isopropylamide 50 Additional compounds (examples 179-181) are prepared F using the same methodology described in Example 178 above (Preparation of 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- O F F amino-8-chloro-2,3,4,5-tetrahydro-benzoblazepine-1-car N 55 boxylic acid isopropylamide). R3 and R4 is varied by replac ing isopropylamine with the appropriate reagent. F

F F C N 60 Example # Reagent R3 R4 MS (ES+) 179 t-butylamine H t-butyl 564 (M+H) o 18O N,N- Ethyl Ethyl 564 (M+H) N diethylamine 181 pyrrollidine 562 (M + H) 65 US 7,749,992 B2 125 126 Example 182 Step 4. Preparation of 2-Amino-5-methyl-4-trifluoromethoxy-benzoic acid Synthesis of 5-Acetyl-(3,5-bis-trifluoromethyl-ben methyl ester Zyl)-amino-7-methyl-8-trifluoromethoxy-2,3,4,5- tetrahydro-benzoblazepine-1-carboxylic acid cyclo Add 1,1-bis(diphenylphosphino) ferrocene palladium (II) pentyl ester chloride (0.92 g, 1.1 mmol), potassium carbonate (23.4 mmol), and triethylamine (1.1 mL, 7.8 mmol) to a solution of 2-iodo-4-methyl-5-trifluoromethoxyanaline (2.5 g, 7.8 mmol) in dimethylsulfoxide (30 mL) and methanol (18 mL). Using a balloon of carbon monoxide, vacuum purge the reac 10 tion mixture several times. After heating at 70° C. under carbon monoxide for 1.5 h cool the reaction to room tempera ture. Dilute the reaction with ethyl acetate (300 mL), wash with water (3x100 mL) followed by brine. Dry the organics over Sodium sulfate, filter, and remove solvent under vacuum. 15 This provides the title compound (1.34g, 69%) as an oil: MS (ES+): 250 (M+H). Step 5. Preparation of 2-tert-Butoxycarbonyl-(3- methoxycarbonyl-propyl)-amino-5-methyl-4-trif luoromethoxy-benzoic acid methyl ester Add methyl 2-Amino-5-methyl-4-trifluoromethoxy-ben Zoic acid methyl ester (1.3 g, 5.2 mmol) in dichloromethane (10 mL) to a solution of di-tert-butyl dicarbonate (21 mmol) in dichloromethane (10 mL), pyridine (10.4 mmol), and dim Step 1. Preparation of 25 ethylaminopyridine (catalytic). After stirring at room tem 4-iodo-3-trifluoromethoxyanaline perature for 2h concentrate the mixture under vacuum. Chro matograph the crude intermediate, 2-bis(tert Add iodine monochlorinde (5.5 g., 33 mmol) in dichlo butoxycarbonyl)amino-5-methyl-4-trifluoromethoxy romethane (10 mL) to a dichloromethane (40 mL) solution of benzoic acid methyl ester (bis-Boc), over silica gel using 3-trifluoromethoxyanaline (5.0g, 28 mmol) at room tempera 30 ethyl acetate/hexane to elute. Add 1% TFA in dichlo ture under nitrogen. To this, add methanol (10 mL) followed romethane (40 mL) to the bis-Boc intermediate. After stirring by sodium bicarbonate (33 mmol) and stir for 2 h. Quench the at room temperature for 0.5 h, quench the reaction with reaction with concentrated sodium metabisulfite (100 mL). Sodium bicarbonate. Separate the organics and wash with Separate the organics, wash with brine (50 mL), and dry over water (50 mL) followed by brine (50 mL). Dry the organics Sodium sulfate. Chromatograph the crude product over silica over Sodium sulfate, filter, and remove solvent under vacuum. gel using ethyl acetate/hexane (2-25%) to elute. This provides 35 This provides 2-(tert-butoxycarbonylamino)-5-methyl-4-tri the title compound (5.8 g. 68%) as a tan oil: H NMR (CDC1, fluoromethoxy-benzoic acid methyl ester (1.4 g) as a color 400 MHz) & 3.85 (bs, 2H), 6.38 (dd, J=2.8, 8.4 Hz, 1H), 6.61 less solid. (m. 1H), 7.51 (d. J=8.4 Hz, 1H). Add methyl 4-bromobutyrate (1.1 g, 6.0 mmol) and cesium Step 2. Preparation of carbonate (3.9 g, 12.0 mmol) to a DMF solution of 2-(tert 4-methyl-3-trifluoromethoxyanaline 40 butoxycarbonylamino)-5-methyl-4-trifluoromethoxy-ben Zoic acid methyl ester (1.4g, 4.0 mmol) under nitrogen. After Add 1,1-bis(diphenylphosphino)ferrocene palladium (II) stirring at 60° C. for 5 hours, the reaction mixture is cooled to chloride (0.8 g., 0.1 mmol), methylboronic acid (1.8 g. 29.7 room temperature and diluted with ethyl acetate (150 mL). mmol) and cesium fluoride (5.2g, 34.6 mmol) to a solution of Wash the organics with water (2x150 mL) followed by brine 4-iodo-3-trifluoromethoxyanaline (3.0 g, 9.9 mmol) in diox 45 (100 mL), dry over sodium sulfate, and filter. Remove the ane under nitrogen. After heating at 80°C. for 3 h, cool the Solvent under vacuum and chromatograph the crude product reaction to room temperature and dilute with ethyl acetate over silica gel using ethyl acetate/hexane (5-30%) to elute. (100 mL) and water (100 mL). Separate the organics, wash This provides the title compound (1.1 g, 61%) as an oil: H with brine, dry over sodium sulfate, and filter. Remove the NMR (CDC1,400MHz) & 1.28 (s, 6H), 1.49 (s.3H), 1.91 (m, Solvent under vacuum and chromatograph the crude product 2H), 2.33 (m, 5H), 3.39 (m. 1H), 3.63 (s.3H), 3.77 (m. 1H), over silica gel using ethyl acetate/hexane (5-20%) to elute. 50 3.86 (bs, 3H), 7.06 (m, 1H), 7.80 (m, 1H). MS (ES+): 350 This provides the title compound (1.5g, 79%) as a tan oil: MS (M+H-100). (ES+): 192 (M+H). Step 6. Preparation of 7-Methyl-8-trifluoromethoxy Step 3. Preparation of 1,2,3,4-tetrahydro-benzoblazepin-5-one 2-iodo-4-methyl-5-trifluoromethoxyanaline 55 Add a solution of 2-tert-Butoxycarbonyl-(3-methoxycar Add iodine monochloride (1.3 g 7.8 mmol) in dichlo bonyl-propyl)-amino-5-methyl-4-trifluoromethoxy-ben romethane (10 mL) to a dichloromethane (40 mL) solution of Zoic acid methyl ester (1.1 g, 2.4 mmol), in toluene (25 mL) 4-methyl-3-trifluoromethoxyanaline (1.5 g, 7.8 mmol) at to a solution of potassium t-butoxide (0.51 g, 4.9 mmol) in room temperature under nitrogen. To this add methanol (10 toluene (75 mL) at 100° C. over 30 min. After heating for 1 h mL) followed by sodium bicarbonate (8.0 mmol) and stir for 60 cool the reaction to room temperature and quench the reaction 2 h. Quench the reaction with concentrated sodium met with acetic acid (5.0 mmol). Dilute the reaction with ethyl abisulfite (100 mL). Separate the organics, wash with brine acetate (100 mL) and wash with water (2x200 mL) followed (50 mL), dry over sodium sulfate, and filter. Remove solvent by brine (200 mL). Dry the organics over sodium sulfate and under vacuum and the crude material (2.5 g) crystallizes upon remove solvent under vacuum. Dissolve the residue in acetic standing. The title compound is used without further purifi 65 acid (25 mL) and dilute with concentrated HCl (15 mL) and cation: H NMR (CDC1, 400 MHz) & 2.15 (s.3H), 4.10 (bs, water (10 mL). Heat the mixture at 100° C. for 2 h then cool 2H), 6.61 (m. 1H), 7.51 (s, 1H). to room temperature. While cooling in an ice bath neutralize US 7,749,992 B2 127 128 the reaction with 5 N NaOH. Extract the organics with ethyl Step 1. Preparation of 2,2-Difluoro-9-oxo-6,7,8,9- acetate (200 mL) and wash the organic with brine (100 mL). tetrahydro-1,3-dioxa-5-aza-cyclohepta findene-5- Remove solvent under vacuum and chromatograph the crude carboxylic acid tert-butyl ester product over silica gel using ethyl acetate/hexane (5-20%) to elute. This provides the title compound (0.28 g. 44%) as an oil that crystallizes upon standing: H NMR (CDC1, 400 MHz) & The title compound was prepared using procedures analo 2.11-2.18 (m, 5H), 2.81 (t, J=6.8 Hz, 2H), 3.24 (t, J=6.8 Hz, gous to Example 182 (Synthesis of 5-Acetyl-(3,5-bis-trif 2H), 6.61 (m. 1H), 7.59 (s, 1H). MS (ES+): 260 (M+H). luoromethyl-benzyl)-aminol-7-methyl-8-trifluoromethoxy 2,3,4,5-tetrahydro-benzoblazepine-1-carboxylic acid Step 7. Preparation of 5-Acetyl-(3,5-bis-trifluorom 10 cyclopentylester, steps 3-7), starting with 2,2-difluoro-benzo ethyl-benzyl)-amino-7-methyl-8-trifluoromethoxy 1.3dioxol-5-ylamine in step 3 and replacing phosgene/cy 2,3,4,5-tetrahydro-benzoblazepine-1-carboxylic clopropanol with di-t-butyl dicarbonate in step 7. acid cyclopentyl ester Step 2. Preparation of (R)-2,2-Difluoro-9-hydroxy-6, Add phosgene (1.5 mmol. 1.93 Msolution in toluene) to a 15 7,8.9-tetrahydro-1,3-dioxa-5-aza-cycloheptafin solution of cyclopentanol (0.17g, 1.9 mmol) in DCM (3 mL) dene-5-carboxylic acid tert-butyl ester at 0°C. under nitrogen. To this cooled solution add diisopro pyl ethylamine (0.26 mL, 1.5 mmol) dropwise. After stirring Add a solution of 2,2-Difluoro-9-oxo-6,7,8,9-tetrahydro for 1 h with cooling, warm the mixture to room temperature and add 7-Methyl-8-trifluoromethoxy-1,2,3,4-tetrahydro 1,3-dioxa-5-aza-cyclohepta findene-5-carboxylic acid tert benzoblazepin-5-one (0.10 g, 0.38 mmol) in dichlo butyl ester (2.2 mmol) in THF (20 mL), to a cooled (-78°C.) romethane (2 mL). After stirring for 1 hat room temperature, solution of Borane-methyl sulfide (2.6 mmol) and (R)-2- dilute with dichloromethane (5 mL) and wash with 5% HCl (5 methyl-CBS-oxazaborolidine (3.3 mmol) in THF (20 mL). mL) followed by water (5 mL) and brine (5 mL). Dry the After warming slowly to 0°C. for 1 h, quench the reaction organics over Sodium Sulfate, filter, and remove solvent under 25 vacuum. To this residue, add titanium isopropoxide (1 mL) with methanol (2 mL). Remove solvent under vacuum and and 3,5-bis(trifluoromethyl)benzylamine (0.18 g., 0.76 chromatograph using ethyl acetate/hexane (2-35%) to elute. mmol). After stirring at room temperature over night dilute This gives the title compound as a colorless Solid. with methanol (3 mL) and add sodium borohydride (3.0 mmol). After 1 h of stirring at room temperature dilute the Step 3. Preparation of (S)-9-Amino-2,2-difluoro-6,7, reaction with water (5 mL) and ethyl acetate (10 mL). Filter 30 8.9-tetrahydro-1,3-dioxa-5-aza-cyclohepta findene the resulting emulsion through a pad of celite and rinse with 5-carboxylic acid tert-butyl ester ethyl acetate (3x5 mL). Separate the organics and wash with water (10 mL) followed by brine (10 mL). Dry the organics over Sodium sulfate, filter, and concentrate under vacuum. To To a solution of (R)-2,2-Difluoro-9-hydroxy-6,7,8,9-tet This residue in dichloromethane (5 mL), add acetyl chloride 35 rahydro-1,3-dioxa-5-aza-cyclohepta findene-5-carboxylic (2.3 mmol) followed by pyridine (2.3 mmol). After stirring acid tert-butyl ester (1.9 mmol) in Toluene, add DPPA (2.5 for 0.5 h dilute with dichloromethane (5 mL), wash with 5% HCl (5 mL), water (5 mL) and brine (5 mL). Dry the organics mmol) and DBU (2.5 mmol). After heating the mixture at 65° over Sodium sulfate and concentrate under vacuum. Chro C. for 14h, remove solvent under vacuum and chromatograph matograph the crude product over silica gel using ethyl 40 the intermediate using ethyl acetate/hexane (5-20%) to elute. acetate/hexane (10-30%) to elute. This provides the title com This provides (S)-9-Azido-2,2-difluoro-6,7,8,9-tetrahydro pound (0.14 g. 60%) as an oil that solidifies upon standing: 1,3-dioxa-5-aza-cyclohepta findene-5-carboxylic acid tert MS (ES+): 641 (M+H). butyl ester as a colorless oil. To a solution of (S)-9-Azido-2, 2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cycloheptaf Example 185 45 indene-5-carboxylic acid tert-butyl ester (1.8 mmol) in Synthesis of (S)-9-Acetyl-(3,5-bis-trifluoromethyl methanol (20 mL) add a catalytic amount of Pd/C after purg benzyl)-amino-2,2-difluoro-6,7,8,9-tetrahydro-1,3- ing the solution with nitrogen. Place a balloon of hydrogen on dioxa-5-aza-cyclohepta findene-5-carboxylic acid the reaction and purge the Solution several times. After stir tert-butyl ester ring for 1 h, purge the solution with nitrogen then filter 50 through celite. Collect the filtrate and remove solvent under vacuum to provide the title compound as a colorless oil. Step 4. Preparation of (S)-9-Acetyl-(3,5-bis-trifluo 55 romethyl-benzyl)-amino-2,2-difluoro-6,7,8,9-tet rahydro-1,3-dioxa-5-aza-cyclohepta findene-5-car F O F boxylic acid tert-butyl ester F F F To a solution of (S)-9-Amino-2,2-difluoro-6,7,8,9-tetrahy 60 dro-1,3-dioxa-5-aza-cyclohepta findene-5-carboxylic acid tert-butyl ester (1.8 mmol) in DCE (20 mL), add 3,5-bis (trifluoromethyl)benzylaldehyde (2.8 mmol), acetic acid (cat.), and Sodium triacetoxyborohydride (5.7 mmol). After stirring for 14 h, dilute with DCM (100 mL) and quench with 65 concentrated Sodium carbonate (50 mL). Separate the organ ics, dry over Sodium Sulfate, and remove solvent under vacuum. Chromatograph using ethyl acetate/hexane (5-25%) US 7,749,992 B2 129 130 to elute. This provides (S)-9-(3.5-Bis-trifluoromethyl-benzy Example 188 lamino)-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa-5-aza-cy clohepta findene-5-carboxylic acid tert-butyl ester as an oil. Synthesis of (+/-)5-Acetyl-(3,5-bis-trifluoromethyl MS (ES+): 569 (M+H). To a solution of (S)-9-(3.5-Bis-trif benzyl)-amino-7-trifluoromethyl-2,3,4,5-tetrahydro luoromethyl-benzylamino)-2,2-difluoro-6,7,8,9-tetrahydro 5 benzoblazepine-1-carboxylic acid isopropyl ester 1,3-dioxa-5-aza-cyclohepta findene-5-carboxylic acid tert butyl ester (0.35 mmol) in DCM (5 mL), add pyridine (1.06 mmol) and acetyl chloride (1.06 mmol). After stirring for 1.5 h remove solvent under vacuum and chromatograph using ethyl acetate/hexane (5-25%) to elute. This provides the title 10 compound as a foam. MS (ES+): 609 (M-H). Example 186 (R)-6-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- amino-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta 15 elindene-10-carboxylic acid isopropyl ester F

O --l F us y CF 25 Step 1. Preparation of N-(2-Bromo-4-trifluorom ethyl-phenyl)-4-methyl-benzenesulfonamide CF N To a solution of 4-amino-3-bromobenzotrifluoride (20.0 g, 83.3 mmol) in pyridine at room temperature is added p-tolu 30 O enesulfonyl chloride (19.8 g. 104.1 mmol) in portions over 3 minutes, and the resulting mixture stirred for 52 hours. The suspension is poured into an ice-water mix (300 ml), filtered; and the filtered solid is washed with water (250 ml). The solid The title compound is obtained by chiral resolution of 35 is dissolved in dichloromethane (200 ml) and the resulting Example 129 on a Chiralpak AD (4.6x250 mm), flow rate 1 solution is washed with 1N HCl (2x150 ml), water (2x200 mL/min, solvents: 5% propan-2-ol in hexane 0.05% TFA, ml), dried (NaSO), and concentrated to a solid. The solid is R-12.1 min, wavelength: 215.16. EE>95%. MS (ES+): 557 suspended in ethanol (700 ml) and heated at reflux for 10 (M+H). minutes, filtered while hot to remove insolubles, and the 40 filtered solids washed with ethanol (250 ml). After concen Example 187 tration of the filtrate, the resulting solid is suspended in methanol (500 ml), treated with KCO (2.0 g, 14.4 mmol), (S)-6-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- and the mixture is stirred at room temperature for 46 hours. amino-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta After filtration of the suspension, the filtered solid is washed elindene-10-carboxylic acid isopropyl ester 45 with methanol (150ml), and the filtrate is concentrated to give the title compound as a foam. Mass spectrum (ES+): 394 (M+). O Step 2. Preparation of 2-(Toluene-4-sulfonylamino)- ---, 50 5-trifluoromethyl-benzoic acid methyl ester To a solution of N-(2-Bromo-4-trifluoromethyl-phenyl)-4- methyl-benzenesulfonamide (1.0 g, 2.53 mmol) in CH-OH (11 ml) and DMSO (17 ml) is added triethylamine (2.0 ml, CF 14.3 mmol), palladium (II) acetate (115 mg, 0.5 mmol) and 1,1'-Bis(diphenylphosphino) ferrocene (416 mg, 0.75 mmol). The mixture is heated at 80°C. for 24 hours under an atmo sphere of carbon monoxide (100 psi). After cooling to room O temperature the mixture is partially concentrated in vacuo to 60 remove CH-OH. The residual mixture is cooled to 0°C. and diluted with water (120 ml) and 1N HCl (300 ml), then extracted with ethyl acetate (3x70 ml). The combined ethyl The title compound is obtained by chiral resolution of acetate extracts are washed with water, brine, dried (NaSO), Example 129 on a Chiralpak AD (4.6x250 mm), flow rate 1 and concentrated to an oil. The oil is purified by silica gel mL/min, solvents: 5% propan-2-ol in hexane 0.05% TFA, 65 column chromatography (eluent, 15% ethyl acetate in hex R-13.8 min, wavelength: 215.16. EE>90%. MS (ES+): 557 anes) to give the title compound as a white solid. Mass spec (M+H). trum (ES-): 372 (M-H). US 7,749,992 B2 131 132 The titled compound was Subsequently prepared following Example 191 the procedures described in Example 1, Steps 2-8, by replac ing 2-(Toluene-4-Sulfonylamino)-benzoic acid methyl ester Synthesis of (+/-)N-(3.5-Bis-trifluoromethyl-ben with 2-(Toluene-4-sulfonylamino)-5-trifluoromethyl-ben Zyl)-N-1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro zoic acid methyl ester. MS (ES+): 585 (M+H). 1H-benzoblazepin-5-yl)-acetamide Example 189

Synthesis of (+/-) 6-Acetyl-(3,5-bis-trifluorom F F ethyl-benzyl)-amino-8-bromo-3,4,5,6-tetrahydro 2H-benzoblazocine-1-carboxylic acid isopropyl 10 F ester yO F F 15 F F F F O ul N OFSFO Br F F F -- 25 Step 1. Preparation of (+/-)1-(Toluene-4-sulfonyl)-1, The titled compound may be prepared following the pro 30 2,3,4-tetrahydro-benzoblazepin-5-one cedures described for the synthesis of (+/-)-5-Acetyl-(3.5- bis-trifluoromethyl-benzyl)-amino-6-fluoro-7-methyl-2,3, To a solution of 1,2,3,4-Tetrahydro-benzoblazepin-5-one 4.5-tetrahydro-benzoblazepine-1-carboxylic acid isopropyl (500 mg, 3.1 mmol) in pyridine (2 ml) is added p-toluene ester (example 125 Steps 1-4) and replacing 3-fluoro-4-me sulfonyl chloride (650 mg, 3.4 mmol), and the mixture is thylphanylamine with 4-methylaniline and also replacing 35 heated at 50° C. for 1 hour. The reaction mixture is poured methyl 4-bromobutyrate with methyl 5-bromovalerate. The into 1N HCl (100 ml) and extracted with ethyl acetate (3x20 reaction is worked up analogously or by methods known to ml). The combined organic extracts are washed with brine, one of skill in the art to afford the title compound. MS (ES+): dried (NaSO), and concentrated to a solid. The solid is 609(M+). purified by silica gel column chromatography (eluent, 30% ethyl acetate in hexanes) to give the title compound as a solid. Example 190 40 Mass spectrum (ES+): 316 (M--H). Synthesis of (+/-)5-(3.5-Bis-trifluoromethyl-ben Step 2. Preparation of (+/-) (3,5-Bis-trifluoromethyl Zyl)-methanesulfonyl-amino-2,3,4,5-tetrahydro benzyl)-1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro benzoblazepine-1-carboxylic acid isopropyl ester 1H-benzoblazepin-5-yl)-amine 45 A mixture of (+/-)1-(Toluene-4-sulfonyl)-1,2,3,4-tetrahy dro-benzoblazepin-5-one (500 mg, 1.58 mmol), 3.5-Bis(tri fluoromethyl)benzylamine (423 mg, 1.74 mmol) and tita nium(IV) isopropoxide (0.59 ml, 1.97 mmol) in diglyme (2 ml) is stirred at room temperature for 22 hours. The mixture is 50 diluted with methanol (7 ml) and treated with sodium boro hydride (90 mg, 2.37 mmol), then stirred at room temperature for 6 hours. The mixture is treated with 0.1N aqueous NaOH (15 ml) and stirred for 10 minutes, then filtered. The filter cake is washed with 1:1 ethanol:diethyl ether. The filtrate is diluted 55 with water (70 ml) and extracted with ethyl acetate (2x30 ml). F F The combined organic extracts are washed with brine, dried N (NaSO) and concentrated to an oil. The oil is purified by silica gel column chromatography (eluent, 15% ethyl acetate o in hexanes) to give the title compound as a Solid. Mass spec - 60 trum (ES+): 543 (M+H). Step 3. Preparation of (+/-)N-(3.5-Bis-trifluorom The titled compound was prepared following the proce ethyl-benzyl)-N-1-(toluene-4-sulfonyl)-2,3,4,5-tet dures described in Example 1 for the synthesis of 5-Acetyl rahydro-1H-benzoblazepin-5-yl)-acetamide (3,5-bis-trifluoromethyl-benzyl)-amino-2,3,4,5-tetrahydro benzoblazepine-1-carboxylic acid isopropyl ester in step 8, 65 To a solution of (+/-) (3.5-Bis-trifluoromethyl-benzyl)-1- by replacing acetic anhydride with methanesulfonyl chloride. (toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzoblazepin MS (ES+):553(M+). 5-yl)-amine (149 mg, 0.27 mmol) and pyridine (0.33 ml, 4 US 7,749,992 B2 133 134 mmol) in dichloromethane (1.5 ml) at room temperature is bonyl chloride (1.0 mmol. 0.52 g) and hydrazine hydrate added acetic anhydride (0.38 ml. 4.1 mmol) via dropwise (50.0 mmol. 1.56 mL) in MeOH (5 mL) was refluxed at 70° C. addition over 2 minutes. The mixture is stirred at room tem for 12 h with vigorous stirring. The solvent was removed in perature for 20 hours. The mixture is treated with 1 Naqueous vacuo and the crude product was purified by crystallization NaOH (4 ml) and stirred for 10 minutes, then diluted with 1N HCl (15 ml) and dichloromethane (15 ml). The organic layer using EtOAc. The product was obtained as white solid; R0.2 is washed with water, dried (NaSO), and concentrated to a (EtOAc); MS (ES+): 523 (M+H"). Solid. Purification by silica gel column chromatography (elu ent, 35% ethyl acetate in hexanes) gives the title compound as Step 2. Preparation of N-(3.5-Bistrifluoromethyl a solid. Mass spectrum (ES+): 585 (M+H). benzyl)-N-(8-chloro-1-(5-ethoxy-1,3,4-oxadiazol-2- 10 yl)-2,3,4,5-tetrahydro-1H-benzoblazepin-5-yl)-ac Example 192 etamide Synthesis of (+/-) (3.5-Bis-trifluoromethyl-benzyl)- 1-(toluene-4-sulfonyl)-2,3,4,5-tetrahydro-1H-benzo To a stirring solution of N-(3.5-Bistrifluoromethyl-ben blazepin-5-yl-carbamic acid methyl ester Zyl)-N-(8-chloro-1-hydrazinocarbonyl-2,3,4,5-tetrahydro 15 1H-benzoblazepin-5-yl)-acetamide (0.13 mmol. 73 mg) in F F MeOH (1 mL) was added ethyl chloroformate (0.41 mmol. F 45.0LL) and the reaction mixture was refluxed for 12 h. After completion (by TLC), the mixture was cooled, diluted with O EtOAc (20 mL), washed with water and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product as viscous oil. Purification by flash No X silica gel column chromatography gave the title compound as F colorless foam; R, 0.40 (EtOAc/Hexane, 1:1, v/v); MS (ES+): F F 599 (M+Na"). 25 N Example 194 OFSFO N-(3.5-Bis-trifluoromethyl-benzyl)-N-8-chloro-1- (5-phenyl-1,3,4-oxadiazol-2-yl)-2,3,4,5-tetrahydro 30 1H-benzoblazepin-5-yl)-acetamide O CF Me us N The titled compound was prepared following the proce 35 dures described for the preparation of (+/-) N-(3,5-Bis-trif luoromethyl-benzyl)-N-1-(toluene-4-sulfonyl)-2,3,4,5-tet rahydro-1H-benzoblazepin-5-yl)-acetamide (example 191, CF step 3) by replacing acetic anhydride with methyl chlorofor C N mate. MS (ES+): 601(M+H). 40 Example 193 -, -N N-(3.5-Bis-trifluoromethyl-benzyl)-N-8-chloro-1- (5-ethoxy-1,3,4-oxadiazol-2-yl)-2,3,4,5-tetrahydro 1H-benzoblazepin-5-yl)-acetamide 45

CF To a solution of N-(3.5-Bistrifluoromethyl-benzyl)-N-(8- 50 chloro-1-hydrazinocarbonyl-2,3,4,5-tetrahydro-1H-benzo blazepin-5-yl)-acetamide (0.23 mmol, 0.12 g) in CHCl (3 mL) was added pyridine (0.5 mL) and catalytic amount of CF DMAP (2 mg). The reaction mixture was cooled to 0°C. and C N treated with benzoyl chloride (0.34 mmol. 40.0 uL). The 55 resulting Solution was warmed to room temperature and kept at that temperature for 12 h. After completion, the reaction s N mixture was diluted with CHCl (20 mL), washed with )=N water, and brine. The organic layer was dried over NaSO, EtO 60 filtered, and concentrated in vacuo. The crude product was stirred with Con. HSO at room temperature for 12 h. The Step 1. Preparation of N-(3.5-Bistrifluoromethyl reaction mixture was basified with aqueous NaHCO, benzyl)-N-(8-chloro-1-hydrazinocarbonyl-2,3,4,5- extracted with EtOAc (3x30 mL). The combined organic tetrahydro-1H-benzoblazepin-5-yl)-acetamide layers were washed with water and brine. Removal of the 65 Solvent and purification by flash column chromatography A mixture of 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- gave the pure compound as a white solid; RO.21 (EtOAc amino-8-chloro-2,3,4,5-tetrahydro-benzoblazepine-1-car Hexane, 1:3, V/v); MS (ES+): 610 (M+H"). US 7,749,992 B2 135 136 Example 195 ture for 1 h. After completion, the reaction mixture was diluted with EtOAc (50 mL), washed with water and brine. N-(3.5-Bis-trifluoromethyl-benzyl)-N-8-chloro-1- The organic phase was separated and dried over NaSO4. (4-isopropyl-4H-1,2,4-triazol-3-yl)-2,3,4,5-tetrahy Removal of the solvent and purification on flash column dro-1H-benzoblazepin-5-yl)-acetamide chromatography provided the pure compound as a colorless foam; R, 0.20 (EtOAc-Hexane, 1:1, v/v), MS (ES+): 549 (M+H"). 10 Step 2. N-(3,5-Bis-trifluoromethyl-benzyl)-N-8- CF chloro-1-(5-methyl-1H-pyrazol-3-yl)-2,3,4,5-tetrahy dro-1H-benzoblazepin-5-yl)-acetamide

15 To a mixture of N-(3.5-Bis-trifluoromethyl-benzyl)-N-8- CF chloro-1-(3-oxo-butyryl)-2,3,4,5-tetrahydro-1H-benzob azepin-5-yl)-acetamide (0.13 mmol. 72 mg), hydrazine hydrate (1.3 mmol. 40.0 uL) in MeOH (2 mL) was added POo (0.5 g) at room temperature. The resulting Suspension )- was stirred vigorously at 70° C. for 12 h. After completion, the mixture was diluted with water (20 mL), and extracted The title compound could be prepared as described for the with EtOAc (3x20 mL). The combined organic layers were synthesis of Example 194 for N-3,5-Bis-trifluoromethyl-ben washed with water and brine, dried over NaSO and evapo Zyl)-N-8-chloro-1-(5-phenyl-1,3,4-oxadiazol-2-yl)-2,3,4, 25 rated to dryness. Flash chromatography (EtOAc-Hexane as 5-tetrahydro-1H-benzoblazepin-5-yl)-acetamide, using, eluent 1:1) afforded the title compound as viscous foam; R, N-(3.5-Bistrifluoromethyl-benzyl)-N-(8-chloro-1-hydrazi 0.28 (EtOAc-Hexane, 1:1, v/v); MS (ES+): 545 (M+H"). nocarbonyl-2,3,4,5-tetrahydro-1H-benzoblazepin-5-yl)-ac etamide, dimethylacetamide dimethyl acetal, and isopropy 30 Example 197 lamine. N-(3.5-Bis-trifluoromethyl-benzyl)-N-8-chloro-1- Example 196 (3-methyl-isoxazol-5-yl)-2,3,4,5-tetrahydro-1H benzoblazepin-5-yl)-acetamide N-(3.5-Bis-trifluoromethyl-benzyl)-N-8-chloro-1- 35 (5-methyl-1H-pyrazol-3-yl)-2,3,4,5-tetrahydro-1H benzoblazepin-5-yl)-acetamide

40 CF

CF Me 45 CF C

CF C N 50

To a mixture of N-(3.5-Bis-trifluoromethyl-benzyl)-N-8- 55 chloro-1-(3-oxo-butyryl)-2,3,4,5-tetrahydro-1H-benzob azepin-5-yl)-acetamide (0.13 mmol. 72 mg), hydroxylamine Step 1. Preparation of N-(3.5-Bis-trifluoromethyl hydrochloride (1.3 mmol, 90 mg) in MeCH (2 mL) was added benzyl)-N-8-chloro-1-(3-oxo-butyryl)-2,3,4,5-tet NaOAc (20 mg) at room temperature. The resulting Suspen rahydro-1H-benzoblazepin-5-yl)-acetamide 60 sion was stirred vigorously at 70° C. for 12 h. After comple tion, the mixture was diluted with water (20 mL), extracted To a solution of N-(3.5-Bis-trifluoromethyl-benzyl)-N-(8- with EtOAc (3x20 mL). The combined organic layers were chloro-2,3,4,5-tetrahydro-1H-benzoblazepin-5-yl)-aceta washed with water and brine, dried over NaSO and evapo mide (1.0 mmol. 465 mg) and DMAP (0.1 mmol. 12 mg) in 65 rated to dryness. Flash chromatography (EtOAc-Hexane as THF (5 mL) was added diketene (1.1 mmol. 86.0 LL) at 0°C. eluent 1:1) afforded the title compound as viscous foam; R, The reaction mixture was stirred vigorously at that tempera 0.35 (EtOAc-Hexane, 1:1, v/v); MS (ES+): 564 (M+HO). US 7,749,992 B2 137 138 Example 198 above mixture, MeOH (2.75 mmol, 0.11 uL) was added and warmed to room temperature for 48 h. After completion, the N-(3.5-Bis-trifluoromethyl-benzyl-N-8-chloro-1-(2- reaction mixture was diluted with water (20 mL), extracted methyl-2H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H with EtOAC (3x25 mL) and the combined organic layers benzoblazepin-5-yl)-acetamide were washed with water and brine. The organic phase was dried (NaSO) and concentrated in vacuo. The crude com pound was purified by flash column chromatography to afford O the title compound as colorless foam; R, 0.60 (EtOAc-Hex CF ane, 1:1, v/v); MS (ES+): 547 (M+H"). Me ul N 10 Example 199 N-(3.5-Bis-trifluoromethyl-benzyl-N-8-chloro-1-(3- methyl-1,2,4-oxadiazol-5-yl)-2,3,4,5-tetrahydro CF 1H-benzoblazepin-5-yl)-acetamide C N 1. 15 N1 N V / O N-N CF Me/ Me us N

Step 1. Preparation of N-(3.5-Bis-trifluoromethyl benzyl)-N-(8-chloro-1-cyano-2,3,4,5-tetrahydro-1H CF benzoblazepin-5-yl)-acetamide 25 C N To a solution of N-(3.5-Bis-trifluoromethyl-benzyl)-N-(8- chloro-2,3,4,5-tetrahydro-1H-benzoblazepin-5-yl)-aceta mide (1.0 mmol. 465 mg) in THF (5 mL) was added n-BuLi (1.0 mmol, 0.62 mL, 1.6M in THF) at -78°C. and stirred for 30 20 min. The above dark brown solution was treated with a solution of cyanogens bromide (2.0 mmol, 0.21 g) in THF (1 Me mL). The reaction mixture was stirred vigorously at that temperature for 1 h and slowly warmed to room temperature for 12 h. After completion, the reaction mixture was diluted Step 1. Preparation of 5-Acetyl-(3,5-bis-trifluorom with EtOAc (50 mL), washed with water and brine. The 35 ethyl-benzyl)-amino-8-chloro-2,3,4,5-tetrahydro organic phase was separated and dried over NaSO. benzoblazepine-1-carboxylic acid amide Removal of the solvent and purification on flash column chromatography provided the pure title compound as a col A mixture of 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- orless foam; R, 0.20 (EtOAc-Hexane, 4:1, v/v); MS (ES+): amino-8-chloro-2,3,4,5-tetrahydro-benzoblazepine-1-car 490 (M+H"). 40 bonyl chloride (0.1 mmol, 50.0 mg) and ammonia (1.0 mmol. 1.0 mL, 1M in MeOH) was refluxed at 70° C. for 6 h with Step 2. Preparation of N-(3.5-Bis-trifluoromethyl vigorous stirring. The solvent was removed in vacuo and the benzyl-N-8-chloro-1-(1H-tetrazol-5-yl)-2,3,4,5- crude product was purified by crystallization using EtOAc. tetrahydro-1H-benzoblazepin-5-yl)-acetamide The product was obtained as a white solid; R, 0.1 (EtOAc); 45 MS (ES+): 508 (M+H"). A solution of N-(3.5-Bis-trifluoromethyl-benzyl)-N-(8- chloro-1-cyano-2,3,4,5-tetrahydro-1H-benzoblazepin-5- Step 2. Preparation of N-(3.5-Bis-trifluoromethyl yl)-acetamide (0.92 mmol, 0.45 g) in toluene (5 mL) was benzyl-N-8-chloro-1-(3-methyl-1,2,4-oxadiazol-5- treated with tributyltin azide (1.8 mmol, 0.49 mL) at room yl)-2,3,4,5-tetrahydro-1H-benzoblazepin-5-yl)-ac temperature. The reaction mixture was kept at reflux tempera 50 etamide ture for 12 h. After completion, the mixture was diluted with water (20 mL), extracted with EtOAC (3x25 mL) and the A mixture of 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- combined organic layers were washed with water and brine. amino-8-chloro-2,3,4,5-tetrahydro-benzoblazepine-1-car The organic phase was dried (Na2SO4) and concentrated in boxylic acid amide (0.1 mmol, 51 mg) and 85% dimethyl vacuo. The crude compound was purified by flash column acetamide dimethylacetal (1.5 mmol, 0.22 mL) was heated at chromatography to afford the title compound as colorless 55 reflux for 1 h and then evaporated in vacuo. Dioxane (1 mL), foam; R, 0.40 (EtOAc-Hexane, 1:1, v/v); MS (ES+): 533 hydroxylamine hydrochloride (0.2 mmol. 14 mg), acetic acid (M+H"). (0.4 mL), and a 2N NaOH (0.2 ml) solution were added and the mixture was stirred at room temperature for 2 h. Then the Step 3. Preparation of N-(3.5-Bis-trifluoromethyl reaction mixture was refluxed for 1 h, cooled to room tem benzyl-N-8-chloro-1-(2-methyl-2H-tetrazol-5-yl)-2, 60 perature and poured into ice water (10 mL). After the pH of 3,4,5-tetrahydro-1H-benzoblazepin-5-yl)-acetamide the solution had been adjusted to 7-8 using 1 NNaOH, it was extracted with EtOAc (2x20 mL). The combined organic To a solution of N-(3.5-Bis-trifluoromethyl-benzyl-N-8- layers were dried over NaSO and the solvent evaporated in chloro-1-(1H-tetrazol-5-yl)-2,3,4,5-tetrahydro-1H-benzob. vacuo. The pure compound was obtained by flash column azepin-5-yl)-acetamide (0.55 mmol, 0.29 g) in CHCl (5 65 chromatography (EtOAc-Hexane 1:1) to afford the title com mL) was added triphenyl phosphine (0.55 mmol, 0.14 g) and pound as colorless oil. R,0.6 (EtOAc-Hexane, 1:1, v/v), MS diethylazo dicarboxylate (0.55 mmol, 90.0 uL) at 0°C. To the (ES+): 547 (M+H"). US 7,749,992 B2 139 140 Example 200 Example 202 N-(3.5-Bis-trifluoromethyl-benzyl-N-8-chloro-1- (S)-N-(3,5-bis-trifluoromethyl-benzyl)-N-(1-cyclo methanesulfonylaminocarbonyl-2,3,4,5-tetrahydro pentyl-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahy 1H-benzoblazepin-5-yl)-acetamide dro-1H-benzoblazepin-5-yl)-acetamide

CF CF 10 Me

CF CF C N 15

Method A: To a solution of (S)-N-(3.5-Bis-trifluorom ethyl-benzyl)-N-(7-methyl-8-trifluoromethyl-2,3,4,5-tet Me rahydro-1H-benzoblazepin-5-yl)-acetamide (0.15 mmol. To a solution of 5-Acetyl-(3,5-bis-trifluoromethyl-ben 80.0mg) in CHCl (2 mL) was added cyclopentane carboxy Zyl)-amino-8-chloro-2,3,4,5-tetrahydro-benzoblazepine aldehyde (0.23 mmol. 22 LL), followed by dropwise addition of TiCl, (0.23 mmol, 0.23 mL, 1M in CHCl). The reaction 1-carboxylic acid amide (0.1 mmol, 51.0 mg) in CHCl (1 mixture was stirred at room temperature for 12 h. After mL) was added pyridine (0.5 mL) at room temperature. The 25 completion, the solvent was removed in vacuo. The resulting reaction mixture was cooled to 0°C. and treated with meth crude imine was dissolved in MeCH (2 mL) and treated with ansulfonyl chloride (0.3 mmol. 25.0LL). Stirring was contin NaBH (1.5 mmol. 60mg) at 0°C. After, stirring for 1 at 0°C., ued at room temperature for 12 h. The reaction mixture was the reaction was diluted with saturated NHCl (10 mL) and diluted with water (5 mL), and extracted with EtOAc (3x10 extracted with EtOAc (3x10 mL). The combined organic mL). The combined organic layers were washed with water 30 layers were washed with water, brine and dried (NaSO). and brine. The pure compound was obtained by flash column Removal of the solvent and further purification on flash col chromatography (EtOAc-Hexane 1:1) to provide the title umn chromatography provided the title compound as a vis compound as a white solid; R, 0.48 (EtOAc-Hexane, 1:1, cous oil; R, 0.58 (EtOAc-Hexane, 1:1, v/v); MS (ES+): 594 v/v); MS (ES+): 586 (M+H"). (M+H") 35 Method B: To a solution of (S)-N-(3.5-Bis-trifluorom ethyl-benzyl)-N-(7-methyl-8-trifluoromethyl-2,3,4,5-tet Example 201 rahydro-1H-benzoblazepin-5-yl)-acetamide (0.15 mmol. 80.0 mg) in CHCl (2 mL) was added cyclopentane carbox N-(3.5-Bis-trifluoromethyl-benzyl-N-8-chloro-1- aldehyde (0.23 mmol, 22 uL), AcOH (10 uL), and NaBH (toluene-4-Sulfonylaminocarbonyl)-2,3,4,5-tetrahy (OAc). (0.45 mmol. 95.0 mg). After stirring overnight at dro-1H-benzoblazepin-5-yl)-acetamide 40 room temperature, the reaction mixture was poured in to saturated NaHCO solution and extracted with CHCl (3x10 mL). The organic extracts were dried and concentrated. Flash chromatography on silica gel (EtOAc-Hexane) afforded the CF title compound as viscous oil; R, 0.58 (EtOAc-Hexane, 1:1, 45 v/v); MS (ES+): 594 (M+H"). Example 203 (S)-2-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- CF aminol-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahy C N 50 dro-benzoblazepin-1-ylmethyl)-cyclopropanecar boxylic acid

55 CF Me > Me

60 CF FC N The title compound was prepared by similar procedure as described in Example 200 (0.1 mmol scale of 5-Acetyl-(3. 5-bis-trifluoromethyl-benzyl)-amino-8-chloro-2,3,4,5-tet rahydro-benzoblazepine-1-carboxylic acid amide). The title 65 compound was obtained as a white solid; R, 0.58 (EtOAc MeOC Hexane, 1:1, v/v); MS (ES+): 662 (M+H"). US 7,749,992 B2 141 142 The title compound prepared by similar procedure azepine-1-carboxylic acid tert-butyl ester (Example 140), (Method B) as described in Example 202 for (S)-N-(3,5-bis starting with 5,6,7,8-Tetrahydro-naphthalen-2-ylamine and trifluoromethyl-benzyl)-N-(1 cyclopentyl-7-methyl-8-trif. isopropyl chloroformate. luoromethyl-2,3,4,5-tetrahydro-1H-benzoblazepin-5-yl)- acetamide, using, (S)-N-(3.5-Bis-trifluoromethyl-benzyl)- Example 206 N-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H benzoblazepin-5-yl)-acetamide and 2-formyl Synthesis of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(5- cyclopropanecarboxylic acid methyl ester, R, 0.46 (EtOAc cyclopentylmethyl-2,2-difluoro-6,7,8,9-tetrahydro Hexane, 1:1, v/v); MS (ES+): 639.3 (M+H"). 5H-1,3-dioxa-5-aza-cyclohepta finden-9-yl)-amine Example 204 10 F (S)-5-5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)- amino-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahy O F dro-benzoblazepin-1-yl)-3,3-dimethyl-pentanoic F acid 15 N

F O F F O F F O CF N N Me Me

CF 25 To a solution of (S)-9-Acetyl-(3,5-bis-trifluoromethyl FC N benzyl)-amino-2,2-difluoro-6,7,8,9-tetrahydro-1,3-dioxa 5-aza-cyclohepta findene-5-carboxylic acid tert-butyl ester (0.26 mmol) in DCM (5 mL) add trifluoroacetic acid (1 mL). vos-X- After stirring for 1 h, quench the reaction with sodium bicar 30 bonate (5 mL) and dilute with DCM (20 mL). Separate and The title compound prepared by similar procedure dry the organics over sodium sulfate. Remove the solvent and (Method B) as described in Example 202 for (S)-N-(3,5-bis chromatograph the product using ethyl acetate/hexane trifluoromethyl-benzyl)-N-(1-cyclopentyl-7-methyl-8-trif (5-20%) to elute. This provides N-(3.5-Bis-trifluoromethyl luoromethyl-2,3,4,5-tetrahydro-1H-benzoblazepin-5-yl)- benzyl)-N-(2,2-difluoro-6,7,8,9-tetrahydro-5H-1,3-dioxa-5- acetamide, using, N-(3.5-Bis-trifluoromethyl-benzyl)-N-(7- 35 aza-cyclohepta finden-9-yl)-acetamide as an oil. To this methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzob. crude intermediate in DCE (dichloroethane) (5 mL), add azepin-5-yl)-acetamide and 3.3-dimethyl-5-oxo-pentanoic cyclopentylcarbaldehyde (1.3 mmol), acetic acid (cat.), and acid methyl ester; R 0.41 (EtOAc-Hexane, 1:1, V/v); MS sodium triacetoxyborohydride (1.6 mmol). After stirring for (ES+): 655.2 (NH3. 14h, dilute the reaction with DCM (20 mL) and quench with concentrated Sodium carbonate (5 mL). Separate the organ Example 205 40 ics, dry over Sodium Sulfate, and remove solvent under vacuum. Chromatograph the product using ethyl acetate/hex Synthesis of 5-Acetyl-(3,5-bis-trifluoromethyl-ben ane (5-20%) to elute. This provides the title compound as a Zyl)-amino-2,3,4,5,7,8,9,10-octahydro-naphtho2,3- foam. MS (ES+): 593 (M+H). blazepine-1-carboxylic acid isopropyl ester 45 Example 207 Synthesis of N-(3.5-Bis-trifluoromethyl-benzyl)-N- F (5-cyclopentylmethyl-3,5,6,7,8,9-hexahydro-1H-2- oxa-5-aza-cyclohepta finden-9-yl)-acetamide O F F N

F F F N

- 60 O

The title compound can be prepared using procedures 65 analogous to the synthesis of 5-Acetyl-(3,5-bis-trifluorom ethyl-benzyl)-amino-8-chloro-2,3,4,5-tetrahydro-benzob. US 7,749,992 B2 143 144 Step 1. Preparation of The title compound could be prepared using procedures 1,3-Dihydro-isobenzofuran-5-ylamine described in Example 185 (Synthesis of 9-Acetyl-(3,5-bis trifluoromethyl-benzyl)-amino-2,2-difluoro-6,7,8,9-tet rahydro-1,3-dioxa-5-aza-cyclohepta findene-5-carboxylic N acid tert-butyl ester) and Example 207 (Synthesis of (3.5-Bis trifluoromethyl-benzyl)-(5-cyclopentylmethyl-2,2-difluoro 6,7,8,9-tetrahydro-5H-1,3-dioxa-5-aza-cyclohepta finden 9-yl)-amine) starting with 9-Oxo-1,3,6,7,8,9-hexahydro-2- To a solution of 1,3-dihydro-isobenzofuran (83.2 mmol) in oxa-5-aza-cyclohepta findene-5-carboxylic acid tert-butyl sulfuric acid (75 mL) cooled in an ice bath, add a solution of 10 ester. potassium nitrate (83.2 mmol) in sulfuric acid (25 mL) drop wise. After stirring for 30 min. pour the reaction mixture over We claim: ice and collect the resulting precipitate on a glass frit. Wash 1. A compound of a formula below: the precipitate with water (200 mL) and dry under vacuum. Dissolve the precipitate in ethanol (250 mL) and add tin 15 chloride dihydrate (273.6 mmol). After heating at 70° C. for 2 h dilute with water (200 mL), cool to room temperature and neutralize the reaction with 5 N sodium hydroxide. Extract the mixture with ethyl acetate (3x200 mL) and dry the organ ics over sodium sulfate. Remove solvent to afford the title compound as a tan solid. H NMR (CDC1, 400 MHz) & 3.50 (bs, 2H), 5.02 (s, 4H), 6.56 (d. J=2.4 Hz, 1H), 6.60 (dd, J=2.4, 8.0 Hz, 1H), 7.01 (d. J=8.0 Hz, 1H). Step 2. Preparation of 9-Oxo-1,3,6,7,8,9-hexahydro 2-oxa-5-aza-cyclohepta findene-5-carboxylic acid 25 tert-butyl ester wherein n is 0, 1, 2, or 3: q is 0, 1, 2, or 3; Y is a bond, C=O, or S(O), whereint is 0, 1, or 2: 30 R" is selected from a group consisting of C-C alkyl, aryl, C-C alkenyl, C-C alkylbeterocyclic, C-Cs cycloalkyl, C-C alkylcycloalkyl, C-C alkylaryl, heterocyclyl, C-C alkoxy, aryloxy, OC-C, haloalkyl, —OCs-Cs cycloalkyl, —OC-C alkylcy 35 cloalkyl, - NR7R, OC-C alkylaryl, -O-hetero cyclic, and —OC-C alkylheterocyclic; and wherein each of cycloalkyl, aryl and heterocyclic group is optionally Substituted with 1 to 3 groups indepen dently selected from oxo, halo, C-C alkyl, C-C, The title compound was prepared using procedures analo 40 alkoxy, C-C haloalkyl, CONR'R''. Co-C, gous to Example 182 (Synthesis of 5-Acetyl-(3,5-bis-trif alkylNR'R''. Co-C alkylCOOR'', cyano, and phe luoromethyl-benzyl)-amino-7-methyl-8-trifluoromethoxy nyl: 2,3,4,5-tetrahydro-benzoblazepine-1-carboxylic acid each R is selected from a group consisting of hydroxy, cyclopentyl ester, steps 3-7), starting with 1,3-Dihydro halogen, C-C haloalkyl, aryl, heterocyclic, cyano, isobenzofuran-5-ylamine in step 3 and replacing phosgene/ 45 C-C alkyl, C-C alkenyl, C-C alkoxy, —OC-C, cyclopropanol with di-t-butyl dicarbonate in step 7. haloalkyl, Co-C alkylNR'R''. Co-C alkylCOR". C-C alkylCOR7, NR'SOR, NR7COR, S(O).R7, Step 3. Preparation of N-(3.5-Bis-trifluoromethyl and—OC-C alkylaryl wherein each of the aryland benzyl)-N-(5-cyclopentylmethyl-3,5,6,7,8,9-hexahy heterocyclic groups is optionally substituted by oxo dro-1H-2-oxa-5-aza-cyclohepta finden-9-yl)-aceta 50 or alkyloxy; mide R is hydrogen or C-C alkyl; each R" is independently selected from a group consist F ing of hydrogen, C-C alkyl, OC-C alkyl, C-C, 55 haloalkyl, -C-C cycloalkyl, heterocyclic, and aryl, O F wherein each alkyl, is optionally substituted with 1-3 F groups independently selected from C-C alkoxy, N SOR'', and NR''R. each R is independently selected from a group consist 60 ing of hydrogen, C-C alkyl, and aryl; F O F R is COR7 wherein R is as defined above: F R" is benzyl, optionally substituted with 1 or 2 groups N selected from halo, C-Calkyl, haloalkyl, C-Calkoxy, and C-C haloalkoxyalkyl, 65 R'' and R'' are independently selected from a group consisting of hydrogen, C-C alkyl, and aryl; or a pharmaceutically acceptable salt thereof. US 7,749,992 B2 145 146 2. The compound according to claim 1 wherein R' is 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl selected from a group consisting of C-C alkoxy, C-C, amino-2,3,4,5-tetrahydro-benzoblazepine-1-car alkylcycloalkyl, C-C cycloalkyl, C-C alkylheterocyclic, boxylic acid isopropyl ester, aryloxy, —OC-Chaloalkyl, —OCs-Cs cycloalkyl, —OC 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl C alkylaryland—OC-C alkylheterocyclic wherein each 5 amino-7-bromo-2,3,4,5-tetrahydro-benzoblazepine of cycloalkyl, aryl and heterocyclic group is optionally Sub 1-carboxylic acid isopropyl ester, stituted with 1 to 3 groups independently selected from oxo, 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl halo, C-C alkyl, C-C alkoxy, C-C haloalkyl, amino-7-bromo-2,3,4,5-tetrahydro-benzoblazepine CONR'R'' and C-C alkylCOOR''. 1-carboxylic acid ethyl ester, 3. A compound according to claim 1 wherein R' is selected 10 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7- from a group consisting of aryloxy, —OC-C haloalkyl, bromo-2,3,4,5-tetrahydro-benzoblazepine-1-carboxy —OCs-Cs cycloalkyl, —OC-C alkylaryl, -Oheterocyclic, lic acid ethyl ester, and—OC-C alkylheterocyclic; wherein each of cycloalkyl, 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7- aryland heterocyclic group is optionally Substituted with 1 to methoxy-2,3,4,5-tetrahydro-benzoblazepine-1-car 15 boxylic acid ethyl ester, 3 groups independently selected from halo, C-C alkyl, 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-8-trif C-C alkoxy, C-Chaloalkyl, and C-C alkylCOOR''. luoromethyl-2,3,4,5-tetrahydro-benzoblazepine-1- 4. The compound according to claim 1 wherein R' is carboxylic acid isopropyl ester, selected from a group consisting of C-C alkylcycloalkyl, 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-8- C-C alkylheterocyclic, C-C cycloalkyl and aryloxy, fluoro-7-trifluoromethyl-2,3,4,5-tetrahydro-benzo wherein each of cycloalkyl, aryl and heterocyclic group is blazepine-1-carboxylic acid isopropyl ester, optionally substituted with 1 to 3 groups independently 4-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7-trif selected from halo, C-C alkyl, C-C alkoxy, C-C, luoromethyl-2,3,4,5-tetrahydro-benzoblazepine-1- haloalkyl, and Co-Co alkylCOOR''. carboxylic acid isopropyl ester, 5. The compound according to claim 1Y is a bond; and R' 25 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-8- is alkylaryl, alkylheterocyclic, C-C alkylcycloalkyl chloro-2,3,4,5-tetrahydro-benzoblazepine-1-carboxy wherein the aryl, cycloalkyl and heterocyclic groups are each lic acid isopropyl ester, and optionally substituted with 1, 2 or 3 groups independently 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl selected from oxo. —COOH, C-C alkyl, and C-C alkoxy. amino-8-chloro-2,3,4,5-tetrahydro-benzoblazepine 6. The compound of claim 1, wherein n is 0 or 1 and q is 1. 30 1-carboxylic acid isopropyl ester, 2, or 3. or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 1 wherein n is 0 or 1; 9. A method of treating dyslipidemia comprising adminis and q is 2 or 3. tering a compound of claim 1, or a pharmaceutically accept 8. A compound selected from the group consisting of able salt thereof, to a patient in need thereof. 35 10. A method of treating artherosclerosis comprising 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7-trif administering a compound of claim 1, or a pharmaceutically luoromethyl-2,3,4,5-tetrahydro-benzoblazepine-1- acceptable salt thereof, to a patient. carboxylic acid isopropyl ester, 11. A method of according to claim 9 comprising lowering 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl plasma LDL-cholesterol in a mammal. amino-7-trifluoromethyl-2,3,4,5-tetrahydro-benzob. 40 12. A method of treating pathological sequelae due to low azepine-1-carboxylic acid isopropyl ester, levels of plasma HDL-cholesterol in a mammal comprising 5-(3.5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl administering a pharmaceutically effective amount of a com amino-7-trifluoromethyl-2,3,4,5-tetrahydro-benzob. pound of claim 1, or a pharmaceutically acceptable salt azepine-1-carboxylic acid ethyl ester, thereof, to a patient in need thereof. 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-7-trif 45 13. A pharmaceutical formulation comprising a compound luoromethyl-2,3,4,5-tetrahydro-benzoblazepine-1- according to claim 1 and at least one of a carrier, a diluent and carboxylic acid ethyl ester, an excipient. 5-Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino-2,3,4, 14. A method according to claim 9 comprising raising 5-tetrahydro-benzoblazepine-1-carboxylic acid iso plasma HDL-cholesterol in a mammal. propyl ester, k k k k k UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7,749,992 B2 Page 1 of 2 APPLICATIONNO. : 10/574649 DATED : March 30, 2006 INVENTOR(S) : Guoqing Cao et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

In the issued patent, please note the following corrections:

S. No. PAA Original Issued Patent Page Line Column Line Description of Error 1 P Page 1 1 Title page 2 Delete DISLIPIDEMIA Specification Col. 1 and insert (03/30/2006) (Title) -- DYSLIPIDEMIA --, therefor. 2 P Page 1 1 Title page 2 Delete Abstract (Approx.) item 57 (Approx.) “ 99 (03/30/2006) (Structure) Col. 2 R. (Abstract)Abstract (Abstract)Abstract Ys K (R', i. City N -Yu. ches. - it

and insert --,

YS W (R)- s:a C.).Y(a), (CHP's therefor.

3 P Page 1 2 Title page 3 Delete “y, R' and Abstract (Abstract) item 57 insert - Y, R', --, therefor. (03/30/2006) Col. 2 (Abstract) 4. A Page 1 4. 5 Delete “artherosclerosis' Abstract (Abstract) Col. 2 and insert -- atherosclerosis --, (03/30/2006) therefor.

Signed and Sealed this Seventh Day of September, 2010

David J. Kappos Director of the United States Patent and Trademark Office CERTIFICATE OF CORRECTION (continued) Page 2 of 2 U.S. Pat. No. 7,749,992 B2

5 P Page 1 Delete DISLIPIDEM1A Specification and insert (03/30/2006) -- DYSLIPIDEM1A-, therefor. 6 P Page 2 Claim 1 144 32 In Claim 1, delete Claims Line 8 “alkylbeterocyclic, and (02/10/2010) (Including insert --alkylheterocyclic, --, Structure) therefor. 7 P Page 2 Claim 1 144 58 In Claim 1, delete Claims Line 23 “NRR, and (02/10/2010) (Including insert-NR'R'', --, Structure) therefor. 8 P Page 3 Claim 2 145 In Claim 2, delete “—OC1-C 6 Claims Lines 3-4 and insert -- —OC1-C5 --, (02/10/2010) therefor. 9 A Page 3 Claim 3 145 13 In Claim 3, delete Claims Line 3 “-Oheterocyclic, and insert (02/10/2010) ---O-heterocyclic, --, therefor. 10 A Page 5 Claim 16 146 35 In Claim 10, delete Claims Line 1 “artherosclerosis' and insert (02/10/2010) -- atherosclerosis -, therefor. 11 A Page 5 Claim 18 146 38 In Claim 11, after “method Claims Line 1 delete “of”. (02/10/2010)