(12) United States Patent (10) Patent No.: US 7,119,196 B2 Cook Et Al

US007 119196B2

(12) United States Patent (10) Patent No.: US 7,119,196 B2 Cook et al. (45) Date of Patent: Oct. 10, 2006

(54) ANXIOLYTIC AGENTS WITH REDUCED Armin Walser, et al., “Triazolobenzo- and Triazolothienodiazepines SEDATIVE AND ATAXC EFFECTS as Potent Antagonists of Platelet Activating Factor,” “Journal of Medicinal Chemistry,” 1991, pp. 1209-1221, vol. 34, No. 3, Ameri (75) Inventors: James M. Cook, Whitefish Bay, WI can Chemistry Society. (US); Qi Huang, Moorpark, CA (US); Qi Huang, “Part One: A Chemical and Computer Assisted Approach to Pharmacophore/Receptor Models for GABAaBZ Receptor Sub Xiaohui He, San Diego, CA (US); types; Part Two: Predictive Models for GABAaBZR Subtypes Via Xioayan Li, Milwaukee, WI (US); Comparative Molecular Field Analysis.” DISSERTATION, UW Jianming Yu, Princeton, NJ (US); Milwaukee, 1998, pp. 1-296. Dongmei Han, Milwaukee, WI (US); Shu Yu, et al., “Studies in the Search for a5 Subtype Selective Snjezana Lelas, Middletown, CT (US); Agonists for GABAaBZR Sites,” “Medicinal Chemistry Research.” John F. McElroy, Wilmington, DE 1999, pp. 71-88, Birkhauser Boston. (US) Qi Huang, et al., “Pharmacophore Receptor Models for GABAa? BZR Subtypes (alB3y2, aSB3y2, and aoB3y2) via a Comprehensive (73) Assignee: Wisys Technology Foundation, Inc., Ligand Mapping Approach.” “J. Med. Chem.” 2000, pp. 71-95, Madison, WI (US) American Chemical Society. Xiaohui He, et al., “Pharmacophore/Receptor Models for GABAa? (*) Notice: Subject to any disclaimer, the term of this BZRa2B3y2, a3B3y2 and a4B3y2 Recombinant Subtypes. Induced patent is extended or adjusted under 35 Volume Analysis and Comparison to alB3y2, aSB3y2 and aoB3y2 U.S.C. 154(b) by 198 days. Subtypes,” “Drug Design and Discovery,” 2000, pp. 131-171, vol. 17, Overseas Publishers Association. (21) Appl. No.: 10/402,538 Xiaohui He, “Studies of Molecular Phamracophore/Receptor Mod els for GABAaBZR Subtypes: Chemical and Computer Assisted Approach in Search of Selective Ligands for GABAaBZR Sub (22) Filed: Mar. 28, 2003 types.” DISSERTATION, UW-Milwaukee, 2000, pp. 1-300. (65) Prior Publication Data Le Solleu, et al., “Determination of a PAF Antagonist Pharmacophore Using Combined Molecular Electrostatic Potential US 2004/0082573 A1 Apr. 29, 2004 and Molecular Lipophilicity Potential.” “Drug Design and Discov ery,” 1994, pp. 149-167, vol. 12, Harwood Academic Publishers Related U.S. Application Data GmbH. Yu, et al., “Studies in Search of alpha2 Selective Ligands for (60) Provisional application No. 60/368,408, filed on Mar. GABAaBZR Receptor Subtypes. Part I. Evidence for the Conser 28, 2002. vation of Pharmacophoric Desciptors for DS Subtypes”, “Med. Chem. Res.” 1999, pp. 186-202, vol. 9, No. 3, Birkhauser, Boston. (51) Int. Cl. Bundgaard, H., “Design of prodrugs: Bioreversible derivatives for CO7D 487/12 (2006.01) various functional groups and chemical entities, pp. 1-92 in (52) U.S. Cl...... 54.0/S62 Bundgaard, H., ed., Design of Prodrugs, Elsevier Science Publishers B.V., Amsterdam 1985. (58) Field of Classification Search ...... 54O7562 Chambon, J.P. et al., Ethyl loflazepate: a prodrug from the See application file for complete search history. benzodiazepine series designed to dissociate anxiolytic and sedative (56) References Cited activities. Arzneimittelforschung. 1985:35(10): 1573-7. Cho, M.J., et al., Sequentially labile water-soluble prodrugs of U.S. PATENT DOCUMENTS alprazolam. J Med Chem. Aug. 1986; 29(8): 1346-50. Han, K.-Y., & Amidon, G.L., Targeted prodrug design to optimize 2,893,992 A 7, 1959 Sternbach drug delivery, AAPS Pharmsci. 2000; 2(1): 1-11, article 6, http:// 4,280,957 A 7, 1981 Walser et al. www.pharmsci.org/. 4,401,597 A 8, 1983 Walser et al. Mussini, E., et al., Hydroxylation of three benzodiazepines in vitro. 4.959,361 A 9, 1990 Walser J. Pharm Sci. Oct. 1977;66(10): 1482-3. Simon-Trompler, E., et al., Lorazepam and oxazepam esters. Hydro phobicity, hydrolysis rates and brain appearance. Arzneimit FOREIGN PATENT DOCUMENTS telforschung. 1982:32(2):102-5. Tegyey, Z. et al., Comparison of dihydrodiazepam enantiomers: EP O 320992 6, 1989 metabolism, serum binding and brain receptor binding. Experientia. WO WO O2/O83652 A1 10, 2002 Sep. 15, 1980:36(9): 103.1-2. Primary Examiner Bruck Kifle OTHER PUBLICATIONS (74) Attorney, Agent, or Firm Godfrey & Kahn, S.C.; Sonali S. Srivastava Camille G. Wermuth, “Molecular Variations Based on Isosteric Replacements.” “The Practice of Medicinal Chemistry.” 1996, pp. 203-237, Academic Press Limited. (57) ABSTRACT Qi Huang, et al., “BenZo-fused Benzodiazepines Employed as Topological Probes for the Study of Benzodiazepine Receptor Orally active benzodiazepine derivatives and their salts are Subtypes,” “Medicinal Chemistry Research.” 1996, pp. 384-391. Birkhauser Boston. disclosed. These compounds and their salts have anxiolytic Ruiyan Liu, et al., “Synthesis and Pharmacological Properties of and anticonvulsant activity with reduced sedative/hypnotic/ Novel 8-Substituted Imidazobenzodiazepines: High-Affinity, Selec muscle relaxant/ataxic effects. tive Probes for a5-Containing GABAa Receptors,” “J. Med. Chem.” 1996, pp. 1928-1934. 5 Claims, No Drawings US 7,119,196 B2 1. 2 ANXOLYTIC AGENTS WITH REDUCED receptor modulatory sites, and is the site through which SEDATIVE AND ATAXC EFFECTS benzodiazepine-based anxiolytic drugs exert their effect. Before the cloning of the GABA receptor gene family, the CROSS-REFERENCE TO RELATED benzodiazepine binding site was historically subdivided into APPLICATIONS two subtypes, BENZODIAZEPINE1 and BENZODIAZ EPINE2, on the basis of radioligand binding studies on This application claims benefit of U.S. Provisional Patent synaptosomal rat membranes. The BENZODIAZEPINE1 Application No. 60/368,408 filed Mar. 28, 2002. Subtype has been shown to be pharmacologically equivalent to a GABA receptor comprising the C.1 subunit in combi STATEMENT REGARDING FEDERALLY 10 nation with a B subunit and Y2. This is the most abundant SPONSORED RESEARCH OR DEVELOPMENT GABA receptor subtype, and is believed to represent almost This invention was made with Government support under half of all GABA receptors in the brain, as stated. NIMH grant number MH46851. The Government has cer Two other major populations are the C.232/3y2 and C3f2/ tain rights to this invention. 15 3y2/3 subtypes. Together these constitute approximately a further 35% of the total GABA receptor population. Phar BACKGROUND OF THE INVENTION macologically this combination appears to be equivalent to the BENZODIAZEPINE2 subtype as defined previously by The present invention relates to a class of benzodiazepine radioligand binding, although the BENZODIAZEPINE2 derivatives which possess anxiolytic activity with decreased Subtype may also include certain C5-containing Subtype sedative, hypnotic, and ataxic side effects. assemblies. The physiological role of these subtypes has The most frequently prescribed medication for treatment hitherto been unclear because no sufficiently selective ago of anxiety disorders (such as phobias, obsessive compulsive nists or antagonists were known. disorders) and seizure disorders are benzodiazepines such as It is now believed that agents acting as benzodiazepine diazepam (Valium), triazolam (Halcion), midazolam 25 agonists at GABA/C2, GABA/o3, and/or GABA/O5 (Versed), lorazepam (Ativan), chlordiazepoxide (Librium), receptors, will possess desirable anxiolytic properties. Com alprazolam (Xanax), and other benzodiazepine-based medi pounds which are modulators of the benzodiazepine binding cations. However, these benzodiazepine-based medications site of the GABA receptor by acting as benzodiazepine have side effects such as drowsiness, sedation, motor inco agonists are referred to hereinafter as “GABA receptor ordination, memory impairment, potentiation of effects of 30 agonists.” The GABA/O. 1-selective (C.132y2) agonists alpi alcohol, tolerance and dependence, and abuse potential. dem and Zolpidem are clinically prescribed as hypnotic Buspirone, tandospirone, and other serotonergic agents have agents, Suggesting that at least Some of the sedation asso been developed as anxiolytics with a potentially reduced ciated with known anxiolytic drugs which act at the BEN profile of side effects. However, while these medications do ZODIAZEPINE1 binding site is mediated through GABA show a reduced profile of side effects, they have other 35 receptors containing the C.1 Subunit. Accordingly, it is con characteristics which make them less than ideal for treat sidered that GABA/C2, GABA/C3, and/or GABA/O.5 ment of anxiety disorders. In some cases, these agents cause receptor agonists rather than GABA/O.1 receptors will be anxiety before a therapeutic dose can be obtained or require effective in the treatment of anxiety with a reduced propen dosing of the drug for several days before a therapeutic sity to cause sedation. For example, QH-ii-066 binds with effect is seen. Development of anxiolytics with even fewer 40 high affinity to GABA/O.5 receptors (Ki-10 nM), interme side effects is desired. diate affinity to GABA/C2 and GABA/C3 (Ki-S0 nM), Receptors for the major inhibitory neurotransmitter, and lower affinity to GABA/O.1 receptors (Ki>70 nM), gamma-aminobutyric acid (GABA), are divided into three unlike diazepam which binds with high affinity to all four main classes: (1) GABA receptors, which are members of diazepam-sensitive GABA receptors (Ki-25 nM), as dis the ligand-gated ion channel Superfamily; (2) GABA recep 45 closed in Huang, et al., J. Med. Chem. 2000, 43, 71-95. tors, which may be members of the G-protein linked recep Also, agents which are antagonists or inverse agonists at C.1 tor superfamily; and (3) GABA, receptors, also members of receptors might be employed to reverse sedation or hypnosis the ligand-gated ion channel Superfamily, but their distribu caused by C.1 agonists. tion is confined to the retina. BenZodiazepine receptor Since the compounds of the present invention exhibit ligands do not bind to GABA and GABA, receptors. Since 50 increased agonist efficacy at only a few GABA types of the first cDNAs encoding individual GABA receptor sub receptors and/or selective efficacy at one or more ion chan units were cloned the number of known members of the nels and have been shown to be effective in animal models mammalian family has grown to 21 including C, B, and Y of anxiety and seizures, with reduced severity and/or inci subunits (6C., 4f3, 4y, 16, 1e, 17t, 10, and 3p). dence of side effects, they are useful in the treatment and/or Subtype assemblies containing an O.1 subunit (C.132y2) 55 prevention of a variety of disorders of the central nervous are present in most areas of the brain and are thought to system. Such disorders include anxiety disorders, such as account for 40–50% of GABA receptors in the rat. Subtype panic disorder with or without agoraphobia, agoraphobia assemblies containing C.2 and C3 Subunits respectively are without history of panic disorder, animal and other phobias thought to account for about 25% and 17% GABA recep including Social phobias, obsessive-compulsive disorder, tors in the rat. Subtype assemblies containing an O.5 subunit 60 general anxiety disorder, attention deficit disorders, stress (C533y2) are expressed predominately in the hippocampus disorders including post-traumatic and acute stress disorder, and cortex and are thought to represent about 4% of GABA and generalized or Substance-induced anxiety disorder, neu receptors in the rat. roses, convulsions; migraine; depressive or bipolar disor A characteristic property of all known GABA receptors ders, for example single episode or recurrent major depres is the presence of a number of modulatory sites, one of 65 sive disorder, dysthymic disorder, bipolar I and bipolar II which is the benzodiazepine binding site. The benzodiaz manic disorders, and cyclothymic disorder, psychotic disor epine binding site is the most explored of the GABA ders including Schizophrenia. US 7,119,196 B2 3 4 SUMMARY OF THE INVENTION wherein Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and In consideration of this situation, the problem to be solved thienyl, which ring is substituted at the C(7) position with at by the present invention is to provide a medication which least the substituent —C=C R, where R is H, Si(CH), can be used for the treatment of anxiety neurosis, general 5 t-butyl, isopropyl, methyl, or cyclopropyl; R is one of H, anxiety disorder, panic disorder, phobias, obsessive-compul CH, CHN(CHs), CHCF CH-C=CH, or an alkyl cyclopropyl; R is a substituted or unsubstituted at least sive disorders, Schizophrenia, post-cardiac trauma stress partially unsaturated 5 or 6 membered cyclic or heteorcyclic disorders, depression disorders, psychosomatic disorders, ring, wherein if substituted the substituent is one or more of and other psychoneurotic disorders, eating disorders, meno 10 F, Cl, Br, or NO at the 2'-position; and R is one of H, OH, pausal disorders, infantile autism and other disorders, and OCON(CH), COOCH, or COOCHs. Preferred com also emesis with fewer side effects. pounds according to formula I include: The present inventors engaged in repeated extensive studies to develop a superior medication free from the above problems. They found that the compounds of the present 15 CH O invention, that is, the novel benzodiazepine derivatives and N their salts, have beneficial pharmacological and behavioral effects, that is, the compounds of the present invention show anxiolytic and anticonvulsant activity with greatly decreased or no sedative/hypnotic/muscle relaxant/ataxic side effects. 2C eN The compounds described in the present invention have H F, been synthesized based on a modified version of the com puter modeling disclosed in Cook, et al.J. Med. Chem., 1996, 39, 1928–1934. These compounds obtained by modifying 25 CH3 elements, described herein, of the known benzodiazepine O, and agents, have increased binding selectivity for the GABA/ N C2, GABA/C3, and/or GABA/O.5 receptors described above, and/or altered efficacy at one or more GABA receptors described above, and/or altered selectivity at one 30 or more ion channels. These compounds, which have been C S eN tested in animal models of anxiety in rats and seizures in H 2 mice, and side effect models in rats, have been found to be orally active and have anxiolytic and anticonvulsant activity, with reduced severity and/or incidence of side effects. 35 One object of the present invention is to identify medi CH cations containing these benzodiazepine derivatives or their O pharmaceutically acceptable salts as essential ingredients N that are usable for the treatment of anxiety neurosis, phobias, obsessive-compulsive disorders, panic disorder, generalized 40 anxiety disorder, Schizophrenia, post-cardiac trauma stress C disorders, depression disorders, psychosomatic disorders, 2 and other psychoneurotic disorders, eating disorders, meno H1 pausal disorders, infantile autism, and other disorders. The present invention describes a class of benzodiazepine 45 5. derivatives which possess desirable enhanced agonist effi cacy at various GABA receptors and desirable behavioral profile with respect to anxiolytic and anticonvulsant efficacy The invention provides in another aspect a compound of and reduced side effect efficacy. The compounds in accor formula II, or a salt or prodrug thereof, dance with the present invention have agonist efficacy at the 50 GABA/C2, GABA/C3, and GABA/C.5 receptors. The compounds of this invention have anxiolytic and anticon (II) Vulsant effects with decreased sedative-hypnotic activity. R 9 The present invention provides a compound of formula I, Y. N or a salt or prodrug thereof, 55

(I) Z N R Y 9 60 R Y. N R3 wherein Y and Z are taken together with the two intervening Z eN carbon atoms to form a ring selected from phenyl and 65 thienyl, which ring is substituted at the C(7) position with at R least the substituent —C=C R, where R is H, Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl; R is one of H, US 7,119,196 B2 5 CH, CHN(CHs), CHCF CH-C=CH, or an alkyl cyclopropyl; and R is a Substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic NHCH, ring, wherein if substituted the substituent is one or more of NS F, Cl, Br, or NO at the 2'-position. Preferred compounds 5 according to formula II include: C eN % N H1 O CH O 10

NHCH, 2C Y C N NS 15 H % O, 2 2N. (H,C),S1 O CH O, and

NHCH, and NS 2 N 25 (H3C)3Si c? O %C eNN H1 O 30 F CH" O. NHCH. H-CEC 35 // C 2 S eN H1 N O 40

The present invention provides in yet another aspect a compound of formula III, or a salt or prodrug thereof, 45 Further, the present invention provides a compound of formula IV, or a salt or prodrug thereof, (III) NHCH Y. NS (IV) 50

Z eN N O R2 55 wherein Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7) position with at wherein R is H, Si(CH), t-butyl, isopropyl, methyl, or least the substituent —C=C R, where R is H. Si(CH), 60 cyclopropyl; R is one of H, CH, CHN(CHs), CHCF, thutyl, isopropyl, methyl, or cyclopropyl; and R is a Sub CHC=CH, or an alkyl cyclopropyl; R is a substituted or stituted or unsubstituted at least partially unsaturated 5 or 6 unsubstituted at least partially unsaturated 5 or 6 membered membered cyclic or heterocyclic ring, wherein if substituted cyclic or heterocyclic ring, wherein if substituted the sub the substituent is one or more of F, Cl, Br, or NO, at the 65 stituent is one or more of F, Cl, Br, or NO, at the 2'-position; 2'-position. Preferred compounds according to the formula and A is an ethoxide or a propoxide. Preferred compounds III include: according to the formula IV include: US 7,119,196 B2 8

-continued CH3 J/t CO2-CH2CH3,

d H-CEC / 2C N 8. S eN 1 2 H O 10 F O CH p N N 15 e r-/ CO-C(CH3)3, and

C N 2 O C eN H O le H 2 CH In a still further aspect, the present invention provides a 25 compound of formula V, or a salt or prodrug thereof, N tJ/ CO2-CH2CH3. (V) R N 30 e Y / CO Rs C eN Y. N 1. % H F

35 Z eN

R2 In yet another aspect, the present invention provides a 40 wherein Y and Z are taken together with the two intervening compound of formula VI, or a salt or prodrug thereof, carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at (VI) least the substituent —C=C R, where R is H, Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl; R is one of H. 45 CH, CF, CHCH, CHCF CH-C=CH, an alkyl, or cyclopropyl; R is a substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO, at the 2'-position; and Rs is a branched or 50 straight chain C to Chalogenated or unhalogenated alkyl or a methyl cyclopropyl. Preferred compounds according to formula V include:

55 wherein Y and Z are taken together with the two intervening N carbon atoms to form a ring selected from phenyl and CO-CHCH, thienyl, which ring is substituted at the C(8) position with at O least the substituent —C=C R, where R is H, Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl; R is one of H. 60 CH, CF, CHCH, CHCF, or cyclopropyl; R is a C eN substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substi tuted the substituent is one or more of F, Cl, Br, or NO, at 65 the 2'-position; and R is a branched or straight chain C to C alkyl or a methyl cyclopropyl. Preferred compounds according to formula VI include: US 7,119,196 B2 9 10 least the substituent —C=C R, where R is H, Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl; and R is a N N CHCH, substituted or unsubstituted at least partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substi N(1) / ( o-N tuted the substituent is one or more of F, Cl, Br, or NO at the 2'-position. Preferred compounds according to formula VII include: 2C eN 10 H % . os A N\ /N-CH 15 N / and

N N CH3, and N(1) / (o-N

C eN 1 % 25 H

N N-CH. 30

N N CH2CH3. / 35

40 H F

The present invention still further provides a compound of 45 formula VIII, or a salt or prodrug thereof, The present invention also provides a compound of for mula VII, or a salt or prodrug thereof, (VIII)

50 (VII)

N N-CH O S- \ / " 55 Y.

Z wherein Y and Z are taken together with the two intervening 60 carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) position with at least the substituent—C=C R, where X is N or CH, where R is H. Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl; wherein Y and Z are taken together with the two intervening 65 R is H, CH, CF, CHCH, CHCF, or cyclopropyl; R is carbon atoms to form a ring selected from phenyl and a substituted or unsubstituted at least partially unsaturated 5 thienyl, which ring is substituted at the C(8) position with at or 6 membered cyclic or heterocyclic ring, wherein if US 7,119,196 B2 11 12 substituted the substituent is one or more of F, Cl, Br, or NO at the 2'-position. Preferred compounds according to for -continued mula VIII include:

10 eN

C eN 1 % H Cl, 15

Yet another aspect of the present invention provides a compound of formula IX, or a salt or prodrug thereof,

HC N (IX) Y.J/ 25 R N N R y Y.--/ CO21N-1- OC \-s y

C eN % 30 H1 D.R2 R"

35 wherein n is 0 to 4: Y and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(8) 40 position with at least the substituent —C=C R, where R is HC N H. Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl: Y Y. N N, and and Z are taken together with the two intervening carbon NN / atoms to form a ring selected from phenyl and thienyl, which R-CC 7 ring is substituted at the C(8)' position with at least the 45 substituent —C=C R', where R' is H, Si(CH), t-butyl, S eN isopropyl, methyl, or cyclopropyl; R and R' are indepen dently one of H, CH, CF, CHCF, CHCH, or cyclo propyl; and R and R are independently a substituted or unsubstituted at least partially unsaturated 5 or 6 membered 50 cyclic or heterocyclic ring, wherein if substituted the sub stituent is one or more of F, Cl, Br, or NO at the 2'-position. Preferred compounds according to formula IX include:

N J/r co1N1 Noc H-CC / S eN US 7,119,196 B2 13 14

-continued

N N CO OC J/ \ N

%C eN N S. C& R1 R is Hor Si(CH3)3 n R R is Hor Si(CH3)

A still further aspect of the present invention provides a thienyl, which ring is substituted at the C(8) position with at compound of formula X, or a salt or prodrug thereof, least the substituent —C=C R, where R is H, Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl: Y and Z are taken together with the two intervening carbon atoms to (X) form a ring selected from phenyl and thienyl, which ring is R 2N N R substituted at the C(8)' position with at least the substituent Y. co1Sp1N1 Soc s 25 —C=C R' where R' is H, Si(CH), t-butyl, isopropyl, y -/ \- y methyl, or cyclopropyl; R and Rare independently one of H, CH, CF, CHCH, CHCF, or cyclopropyl; R and R' are independently a substituted or unsubstituted at least Z eN C. 30 partially unsaturated 5 or 6 membered cyclic or heterocyclic ring, wherein if substituted the substituent is one or more of R2 R" F, Cl, Br, or NO, at the 2'-position; and B is O or NH and wherein—BCH-B is optionally replaced with N(R,)— wherein Y and Z are taken together with the two intervening N(R)—, where R is one of H, CH, alkyl, or cycloalkyl. carbon atoms to form a ring selected from phenyl and Preferred compounds according to formula X include:

and N i NS %2C e independentlyX and X’ are Horeach F C&s H X X H

2N N J/r CO1so1N1Noe \- H-CEC 7 N CEC-H S eN X and X are each NS S independently H or F US 7,119,196 B2 15 16 The present invention further provides a compound of Yet another aspect of the present invention provides a formula XI, or a salt or prodrug thereof, compound of formula XII, or a salt or prodrug thereof,

(XI) (XII) R R’ R R NeN 1N1- N1 O O / CO in B in OC \ Y. N N Yi Y. N N Yi 10 co1N11 Noc NS- Z D R2 R" R R.' 15 wherein n is 1 or 2; wherein Yand Z are taken together with wherein n is 0 to 4: Y and Z are taken together with the two the two intervening carbon atoms to form a ring selected intervening carbon atoms to form a ring selected from from phenyl and thienyl, which ring is substituted at the C(8) phenyl and thienyl, which ring is substituted at the C(7) position with at least the substituent —C=C R, where R is position with at least the substituent —C=C R, where R is H, Si (CH), t-butyl, isopropyl, methyl, or cyclopropyl: Y' H. Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl: Y and Z are taken together with the two intervening carbon and Z are taken together with the two intervening carbon atoms to form a ring selected from phenyl and thienyl, which 25 ring is substituted at the C(8)' position with at least the atoms to form a ring selected from phenyl and thienyl, which substituent —C=C R', where R' is H, Si(CH), t-butyl, ring is substituted at the C(7)' position with at least the isopropyl, methyl, or cyclopropyl; R and R' are indepen substituent —C=C R', where R' is H, Si(CH), t-butyl, dently one of H, CH, CF, CHCH, CHCF, or cyclo isopropyl, methyl, or cyclopropyl; R and R' are indepen propyl; R and Rare independently a Substituted or unsub 30 dently one of H, CH, CF, CHCF, CHCH, or cyclo stituted at least partially unsaturated 5 or 6 membered cyclic propyl; and R and R are independently a Substituted or or heterocyclic ring, wherein if substituted the Substituent is unsubstituted at least partially unsaturated 5 or 6 membered one or more of F, Cl, Br, or NO at the 2'-position; and B is cyclic or heterocyclic ring, wherein if substituted the O, NH, or N(R.) N(R,)—, where R, is one of H, CH, substituent is one or more of F, Cl, Br, or NO at the alkyl, or cycloalkyl. Preferred compounds according to 2'-position. Preferred compounds according to formula XII formula XI include: include:

H-CEC 7 N CEC-H X and X’ are each S eN independently Hor F Sr. S and

N N ?e co1 No1 Noc S J/ \ N

X and X’ are each eN independently Hor F NS US 7,119,196 B2 17 18

CH CH O R N N H-CEC 7 co1N1 Soc N CEC-H and S eN NS S

CH3 O O CH3 N N co1 N1) oc %C eN NS C& R1 R is Hor Si(CH3)3 NR R is Hor Si (CH3)

A still further aspect of the present invention provides a 35 thienyl, which ring is substituted at the C(7) position with at compound of the formula XIII, or a salt or prodrug thereof, least the substituent —C=C R, where R is H, Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl: Y and Z are taken together with the two intervening carbon atoms to (XIII) form a ring selected from phenyl and thienyl, which ring is R R’ 40 substituted at the C(7)' position with at least the substituent O O —C=C R, where R' is H. Si(CH), t-butyl, isopropyl, Y. N N Yi methyl, or cyclopropyl; R and Rare independently one of co1\p1N1 Soc H, CH, CF, CHCH, CHCF, or cyclopropyl; R and R' Z eN NS Z. are independently a substituted or unsubstituted at least 45 partially unsaturated 5 or 6 membered cyclic or heterocyclic R2 R" ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO, at the 2'-position; and B is O or NH and wherein—BCH-B is optionally replaced with N(R,)— wherein Y and Z are taken together with the two intervening N(R,)—, where R, is one of H, CH, alkyl, or cycloalkyl. carbon atoms to form a ring selected from phenyl and Preferred compounds according to formula XIII include:

C H CH 3 O O 3 N N

CO1so1N1Noe and C e N NS

X X X and X’ are each independently Hor F US 7,119,196 B2 19 20

-continued

CH3 CH3 9 R N N H-CEC 7 co1\o1\o1 Noe N CEC-H S eN NS S

X X X and X’ are each independently H or F

Yet another aspect of the present invention provides a thienyl, which ring is substituted at the C(7) position with at compound of the formula XIV, or a salt or prodrug thereof, least the substituent —C=C R, where R is H, Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl: Y and Z are taken together with the two intervening carbon atoms to (XIV) form a ring selected from phenyl and thienyl, which ring is substituted at the C(7)' position with at least the substituent 25 —C=C R', where R is H, Si(CH), t-butyl, isopropyl. Yi methyl, or cyclopropyl; R and Rare independently one of H, CH, CF, CHCH, CHCF, or cyclopropyl; R and R' are independently a substituted or unsubstituted at least Z partially unsaturated 5 or 6 membered cyclic or heterocyclic 30 ring, wherein if substituted the substituent is one or more of F, Cl, Br, or NO at the 2'-position; and B is O. NH, or —N(R) N(R)—, where R is one of H, CH, alkyl, or wherein Y and Z are taken together with the two intervening cycloalkyl. Preferred compounds according to formula XIV carbon atoms to form a ring selected from phenyl and include:

CH CH 3 O O 3 N N H-CEC / co1 No1 Noe N CEC-H S eN NS S and

X X X and X’ are each independently Hor F

CH CH 3 O O 3 N N co1 No1 Noc 2C e N NS C&

H 2 X X s H X and X’ are each independently Hor F US 7,119,196 B2 21 22 Another compound (XV) of the present invention is Another compound (XVIII) of the present invention is:

15 n=1, n=2; R=H. SiMes, tBu, CH, n=0, n=1; R=H, SiMe, thBu, CH, -4. 2O -4. Ar phenyl. 2'-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-pyridyl N-O; X=N or CH Arphenyl. 2'-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, Yet another compound (XVI) of the present invention is: 2-pyridyl N-O; Y=O, S, NHCH,

25 Yet another compound (XIX) of the present invention is: (H3 N 30

2^ N N-N R 35

R=H, SiMe, tRu, CH, R=H, SiMe, tRu, CH,

Ar phenyl. 2'-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-pyridyl N-O; X=N or CH Ar phenyl, 2'-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 45 2-pyridyl N. O: Y=O, S, NHCH Stillill anothanother compoundd (XVII)( ) of theth presentt iinvention tion isis: Still another compound (XX) of the present invention is:

CH Y 50 N / O 2^ - 4- 55 R

R=H, SiMes, tBu, CH, 60 R=H, SiMes, tBu, CH,

65 Ar phenyl. 2'-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, Arphenyl. 2'-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-pyridyl N. O: Y=O, S, NHCH 2-pyridyl N-O; Y=O, S, NHCH, US 7,119,196 B2 23 24 A further compound (XXI) of the present invention is: the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts. ": y alkaline earth metal salts, e.g. calcium or magnesium salts: N and salts formed with suitable organic ligands, e.g. quater nary ammonium salts. The present invention includes within its scope prodrugs 2 N O of the compounds of formulas (I)-(XXI) above. In general, N such prodrugs will be functional derivatives of the com 10 pounds of formulas (I)-(XXI) which are readily convertible in vivo into the required compound of formulas (I)-(XXI). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. R=H. SiMes, thBu, CH, 15 Where the compounds according to the invention have at least one asymmetric center, they may accordingly exist as enantiomers. Where the compounds according the invention -4. possess two or more asymmetric centers, they may addi tionally exist as diastercoisomers. It is to be understood that Ar phenyl, 2'-flurophenyl, 2-thienyl, 3-thienyl, 2-pyridyl, all such isomers and mixtures thereof in any proportion are 2-pyridyl N-O; Y=O, S, NHCH encompassed within the scope of the present invention. Compounds (XV) to (XXI) above can also have Ras CF, The compounds according to the present invention exhibit CC1, or CBr. anxiolytic activity, as may be demonstrated in rats by a A still further aspect of the present invention provides positive response in a preclinical test for anti-anxiety effi compositions comprising compounds of the above kind in a 25 cacy (e.g., situational anxiety or defensive withdrawal). pharmaceutically acceptable carrier. Such pharmaceutically Moreover, the compounds of the invention are substantially acceptable carriers are well known in the art. non-sedating and non-ataxic as may be confirmed by an Another aspect of the invention provides a method for the appropriate result obtained from the locomotor activity test treatment and/or prevention of anxiety which comprises and rotorod paradigm, respectively. administering to a patient in need of such treatment an 30 The compounds according to the present invention may effective amount of a compound of the above kinds, or a also exhibit anticonvulsant activity. This can be demon pharmaceutically acceptable salt thereof or a prodrug strated by the ability to block pentylenetetrazole-induced thereof. seizures in rodents. In the above embodiments by “alkyl we mean a straight The invention also provides pharmaceutical compositions or branched halogenated or unhalogenated alkyl group hav 35 comprising one or more compounds of this invention in ing 1–6 carbon atoms. By “cycloalkyl we mean one con association with a pharmaceutically acceptable carrier. Pref taining 3-7 carbon atoms. Also, in the above embodiments erably these compositions are in unit dosage forms such as by “cyclic” we prefer a phenyl group and by "heterocyclic” tablets, pills, capsules, powders, granules, sterile parenteral we prefer a 2-pyridine or a 2- or 3-thiophene. solutions or suspensions, metered aerosol or liquid sprays, The compounds of the present invention are GABA 40 drops, ampoules, auto-injector devices or suppositories; for receptor ligands which exhibit anxiolytic activity due to oral, parenteral, intranasal, Sublingual or rectal administra increased agonist efficacy at GABA/C2, GABA/C3 and/or tion, or for administration by inhalation or insufflation. It is GABA/O.5 receptors. The compounds in accordance with also envisioned that the compounds of the present invention this invention may possess at least 2-fold, suitably at least may be incorporated into transdermal patches designed to 5-fold, and advantageously at least a 10-fold, selective 45 deliver the appropriate amount of the drug in a continuous efficacy for the GABA/c2, GABA/o3, and/or GABA/O.5 fashion. For preparing solid compositions such as tablets, receptors relative to the GABA/o.1 receptors. However, the principal active ingredient is mixed with a pharmaceu compounds which are not selective in terms of their agonist tical carrier, e.g. conventional tableting ingredients such as efficacy for the GABA/o.2, GABA/o3, and/or GABA/o.5 corn starch, lactose, sucrose, sorbitol, talc, stearic acid, receptors are also encompassed within the scope of the 50 magnesium stearate, dicalcium phosphate or gums, and present invention. Such compounds will desirably exhibit other pharmaceutical diluents, e.g. water, to form a solid functional selectivity by demonstrating anxiolytic activity preformulation composition containing a homogeneous with decreased sedative-hypnotic/muscle relaxant/ataxic mixture for a compound of the present invention, or a activity due to decreased efficacy at GABA/C.1 receptors. pharmaceutically acceptable salt thereof. When referring to For use in medicine, the salts of the compounds of 55 these preformulation compositions as homogeneous, it is formulas (I)-(XXI) will be pharamaceutically acceptable meant that the active ingredient is dispersed evenly through salts. Other salts may, however, be useful in the preparation out the composition so that the composition may be easily of the compounds according to the invention or of their subdivided into equally effective unit dosage forms such as pharamaceutically acceptable salts. Suitable pharmaceuti tablets, pills and capsules. This solid performulation com cally acceptable salts of the compounds of this invention 60 position is then subdivided into unit dosage forms of the type include acid addition salts which may, for example, be described above containing from 0.1 to about 500 mg of the formed by mixing a solution of the compound according to active ingredient of the present invention. Typical unit the invention with a solution of a pharmaceutically accept dosage forms contain from 1 to 100 mg, for example, 1, 2. able acid such as hydrochloric acid, Sulphuric acid, meth 5, 10, 25, 50 or 100 mg. of the active ingredient. The tablets anesulphonic acid, fumaric acid, malcic acid, succinic acid, 65 or pills of the novel composition can be coated or otherwise acetic acid, benzoic acid, oxalic acid, citric acid, tartaric compounded to provide a dosage from affording the advan acid, carbonic acid or phosphoric acid. Furthermore, where tage of prolonged action. For example, the tablet or pill can US 7,119,196 B2 25 26 comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. -continued The two components can be separated by an enteric layer which, serves to resist disintegration in the stomach and permits the inner component to pass intact into the duode num or to be delayed in release. A variety of materials can be used for Such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with Such materials as shellac, cetyl alcohol and cellulose acetate. 10 The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous Solutions, Suitably 4 (QHII-066) flavored syrups, aqueous or oil Suspensions, and flavored emulsions with edible oils such as cottonseed oil, Sesame oil, 15 coconut oil or peanut oil, as well as elixirs and similar The bromide 1 available from reference' was reacted with pharmaceutical vehicles. Suitable dispersing or Suspending trimethylsilyacetylene in the presence of a palladium cata agents for aqueous Suspensions include synthetic and natural lyst to provide trimethylsilyl analog 2. This product was gums such as tragacanth, acacia, alginate, dextran, Sodium methylated with methyl iodide/sodium hydride to give the caboxymethylcellulose, methylcellulose, polyvinylpyrroli N-methylbenzodiazepine 3. This was subjected to fluoride done or gelatin. mediated desilation to furnish 4 (QHII-066). In the treatment of anxiety, suitable dosage level is about Procedure for QHII-066 0.01 to 250 mg/kg, per day, preferably about 0.05 to 100 7-Trimethylsilylacetyleno-5-phenyl-1,3-dihydrobenzo mg/kg per day, and especially about 0.05 to 5 mg/kg per day. 25 el-1,4-diazepin-2-one 2. A mixture of 1 (1 g, 3.17 The compounds may be administered on a regimen of 1 to mmole available from reference 1) in triethylamine (30 mL) 4 times per day, or on a continuous basis via, for example, and CHCN (20 mL) with trimethylsilylacetylene (622.7 the use of a transdermal patch. mg, 6.34 mmole) and bis(tri-phenylphosphine)-palladium (II) acetate (118 mg, 0.16 mmol) was heated to reflux under DETAILED DESCRIPTION OF THE 30 nitrogen. After 12 hours, the reaction mixture was cooled to INVENTION room temperature and filtered. The filtrate was concentrated in vacuum and the residue was treated with a saturated aqueous solution of NaHCO (30 mL), and extracted with Scheme 1 (OHII-066) CHCl (3x50 mL). The organic layers were combined and O 35 washed with brine and dried (NaSO). After removal of H N solvent under reduced pressure, the residue was purified via flash chromatography (silica gel, EtOAC/hexanes: 1/1) to furnish 3 as a yellow powder (791 mg, 75%); mp: Pd(OAc)2(PPh3)2 190-191.5° C.; IR (KBr) 3011, 2281, 1686, 1610, 1486, Br eN H Si(CH3)3 EtN, CHCN 40 1325, 1249, 839, 700 cm; 1H NMR (CDC1) & 0.21 (s, Reflux 9H), 4.31 (s. 2H), 7.09 (d. 1H, J=8.25 Hz), 7.21–7.61 (br. 7H), 10.17 (s, 1H); MS (CI) m/e (relative intensity) 333 (M"+1, 100). This material was used in the next step. O O 1-Methyl-7-trimethylsilylacetyleno-5-phenyl-1,3-dihy H 45 drobenzoel-1,4-diazepin-2-one 3. A mixture of 2 (485 mg. 1 N 1.46 mmol) was dissolved in dry THF (20 mL) at 0°C. and NaH (60% in mineral oil, 70 mg, 1.75 mmol) was added to the solution in one portion. The slurry was then stirred for 20 C 2 N NaH/CHI He min at 0° C. and CHI (311 mg, 2.19 mmol) was added to 4 THF 50 the mixture and it was warmed up to room temperature. After the mixture stirred for 3 hours at room temperature, the THF was then removed under reduced pressure. The residue (H3C)Si O was purified by flash chromatography hexanes/EtOAc 2 (1:4) to provide the title compound 3 (303 mg, 60%) as a HC O 55 white solid: mp: 177-178° C.: IR (KBr) 2954, 2147, 1687, V 1612, 1491, 1382, 1115, 1075, 839, 700 cm; 1HNMR N (CDC1) 8(ppm), 3.18 (s.3H), 3.54 (d. 1H, J=10.8 Hz), 4.60 (d. 1 H. J=10.8 Hz), 7.05 (s, 1H), 7.07 (d. 1H, J=8.58 Hz), 7.20 7.27 (m, 3H), 7.37 7.42 (m, 3H); MS (EI) m/e 346 C 2N TBAF, THF/H2O 60 (M',90), 318 (100), 303(19), 165(22), 151(20). Anal. Calcd. for CHNOSi: C, 72.79; H, 6.40; N, 8.08: Found: C, 72.50; H, 6.68; N, 8.04. 1-Methyl-7-acetyleno-5-phenyl-1,3-dihydro-benzoe-1, (H3C)Si 4-diazepin-2-one 4 (QHII-066). A solution of 3 (100 mg.) 65 in THF (30 mL) was treated with tetrabutylammonium fluoride (1M in THF). The mixture was stirred for 20 minutes at room temperature before water (30 mL) was US 7,119,196 B2 27 28 added. The mixture was then extracted with EtOAc (3x30 mL). The combined organic extracts were washed with brine -continued and dried (NaSO). The solvent was removed under ?aN CO2: 1) NaH, THF/DMF vacuum and the residue which resulted was passed through N CIPO(OEt), 0° C. a wash column (silica gel, EtOAC/hexanes: 4/1) to give 4 2) NaH, DMF (QHII-066) as light yellow crystals (71 mg, 90%): mp: CNCHCOEt 163–165° C.; IR (KBr) 2965, 1680, 1605, 1387, 1121, 833, eN 747 cm; 1HNMR (CDC1) & (ppm) 3.38 (s.3H), 3.75 (d. 1H, J=10.8 Hz), 4.80 (d. 1H, J=10.9 Hz), 5.28 (s, 1H), 7.29 10 (d. 1H, J=8.5 Hz), 7.35 7.45 (m, 4H), 7.55-7.59 (m, 2H), 7.62 (dd. 1H, J=8.5 Hz, 2.0 Hz); MS (EI) m/e (relative intensity) 274 (M', 100), 259 (12), 246 (100), 189 (12), 122(19), 105 (42). Anal. Calcd. for CHNO.2/3H2O, Calculated: C, 75.51; H, 4.89: N, 9.78. Found: C, 75.59; H, 15 5.17; N, 9.62.

The bromide 1 was reacted with diethylphosphorochlori date in the presence of sodium hydride, followed by addition 1) NaH, THF/DMF of ethyl isocyanoacetate to provide the ester 5. This was CIPO(OEt), 0° C. 25 --- converted to the trimethylsilylacetyleno compound 6 2) NaH, DMF (XLiXHeII-048) under standard conditions (Pd-mediated, CNCHCOEt Heck-type coupling). Treatment of 6 with fluoride gave the title compound 7 (XHeII-053). 30 Procedure for XHe-II-053 1 Ethyl 8-bromo-6-phenyl-4H-benzofimidazo 1.5-a1,4 diazepine-3-carboxylate 5. This benzodiazepine 5 was obtained in 45% yield from 1 analogous to the literature 35 procedure as a white solid. 2: mp: 174–175° C.: IR (KBr) r N COEt 2978, 1712, 1609, 1491 cm': "H NMR (CDC1) & 1.44 (t, 3H, J=7.1 Hz), 4.09 (d. 1H, J=12.1 Hz), 4.38–449 (m, 2H), -/ 6.08 (d. 1H, J=12.3 Hz), 7.40 7.53 (m, 6H), 7.60 (d. 1H, J=2.2 Hz), 7.82 (dd. 1H, J=8.6 Hz and 2.2 Hz), 7.95 (s, 1H): Br O eN (CH3)Si-E-H 40 MS (EI) m/e (relative intensity) 411 (34), 410 (M", 8), 409 Pol(OAc)2(PPh) (34), 365 (61), 363 (61), 337 (100), 335 (100), 285 (21), 232, TEA (17). Anal. Calcd. for CHBrNO: C, 58.55; H, 3.93: N, 10.24. Found: C, 58.30; H, 3.91: N, 9.90. O reflux 45 Ethyl 8-trimethylsilylacetylenyl-6-phenyl-4H-benzof imidazo 1.5-a1,4diazepine-3-carboxylate 6 (XLiXHeII 5 048). A mixture of bromide 5 (0.3 g, 0.73 mmol), trimethylsilylacetylene (0.143 g, 1.46 mmol) and bis(triph enylphosphine)-palladium-(II) acetate (55 mg, 0.073 mmol) N 50 in a mixed solvent system of toluene (20 mL) and anhydrous COEt TEA (50 mL) was heated to reflux under argon. After stirring for 12 hours at reflux, the mixture was cooled to room temperature and the precipitate which formed was removed by filtration. The filtrate was concentrated under reduced 55 pressure and the residue was treated with a saturated aque ous solution of NaHCO (20 mL), and extracted with CHCl (3x25 mL). The combined extracts were washed with brine and dried (NaSO). After removal of solvent under reduced 60 pressure, the residue was purified by flash chromatography (silica gel, EtOAc) to afford 6 (XLiXHeII-048) as a white 6 (XLiHeII-048) solid (0.29 g, 93%). This benzodiazepine can also be obtained from 2 in 45% yield by following the same TBAF procedure 6 (XLiXHeII-048): mp: 170–172° C.; IR (KBr) THF, 10 min 65 2958, 2152, 1718 cm; H NMR (CDC1) & 0.23 (s, 9H), 1.42 (t, 3H, J–7.2 Hz), 4.04 (d. 1H, J=12.6 Hz), 4.41 (m, 2H, J=7.2 Hz), 6.23 (d. 1H, J=12.6 Hz), 7.35 7.55 (m, 7H), 7.73 US 7,119,196 B2 29 30 (dd. 1H, J=8.3 Hz, J=1.9 Hz), 7.93 (s, 1H); MS (EI) m/e (relative intensity) 427 (M', 76), 412 (5), 381 (55), 353 -continued (100) 303 (10), 287 (7). Anal. Calcd. for CHNO.Si./3EtOAc: C, 69.22; H, 6.01: N, 9.20. Found: Y NN C, 68.87; H, 5.81; N, 9.37. 5 NN / Ethyl 8-acetylenyl-6-phenyl-4H-benzofimidazo 1.5-a 1,4-diazepine-3-carboxylate 7 (XHeII-053)." A solution of 6 (XLiXHeII-048) (0.17g, 0.41 mmol), in THF (15 mL) was 2 O eN treated with BuNF.HO (0.16 g. 0.62 mmol). The mixture 10 which resulted was allowed to stir for 30 min at room temperature after which the mixture was added to HO (10 mL) and extracted with EtOAc (3x25 mL). The combined organic extracts were washed with brine (25 mL) and dried 10 (XLi270) (NaSO). After removal of solvent under reduced pressure, 15 the residue was purified by a wash column (silica gel. EtOAc) to furnish 7 (XHeII-053) (0.12 g, 85%) as a white The bromide 1, available from reference 1, was stirred solid: mp 237 239° C.; IR (KBr) 3159, 3107, 2092, 1721, with the di-4-morpholino-phosphinic chloride, followed by 1606 cm; H NMR (CDC1) & 144 (t,3H, J=7.1 Hz), 3.20 addition of acetylhydrazide to furnish triazolo-benzodiaz (s, 1H), 4.13 (d. 1H, J=10.22 Hz), 4.41–4.48 (m, 2H), 6.11 epine 8. This material 8 was subjected to a Heck-type (d. 1H, J=12 Hz), 7.42 7.63 (m, 7H), 7.81 (dd. 1H, J=8.3 Hz coupling reaction (TMS-C=CH, Pd-mediated)''' to furnish and 1.8 Hz), 8.03 (s, 1H); MS (EI) m/e (relative intensity) ligand 9. This analog was converted into 10 (XLi270) on 355 (M', 83), 309 (70), 281 (100), 253 (12), 231 (18), 178 stirring with fluoride anion as shown in Scheme 3. (20). Anal. Calcd. for C.H.N.O.34HO: C, 71.63; H, 25 5.05; N, 11.39. Found: C, 71.27; H, 4.71: N, 11.03. Procedure for XLi 270 8-Bromo-1-methyl-6-phenyl-4H-s-triazolo 4.3-a 1.4 benzodiazepine 8. A solution of 1 (1 g, 3.07 mmol of Scheme 3 (XLi270) 7-bromo-5-phenyl-1,4-benzodiazepine-2-one) in dry THF 30 (20 mL) was cooled in an ice-water bath and a 60% O O dispersion of sodium hydride (152.2 mg) was added in one 1. N portion. After 20 minutes, di-4-morpholinylphosphinic chlo C11 N YN SoS. ride (943.9 mg, 4.76 mmol) was added at 0°C. and this was 1) NaH, THF, stirred for 30 minutes and allowed to warm to room tem Br eN O 35 perature. The mixture was stirred for 1.5 hours. To this 2) NaH, BuOH mixture was then added a solution of acetylhydrazide (521.9 CHCONHNH mg, 7.14 mmol) in dry butanol (5 mL) and stirring was continued at room temperature for 10 min. The solvents 40 were evaporated and the residue was dissolved in butanol 1 (10 mL) and heated to reflux for 5 hours. Butanol was H3C N removed under reduced pressure and the residue was parti 21 N. N tioned between CHCl (50 mL) and water (50 mL). The N/ water layer was extracted by CHCl (3x30 mL). The combined organic layer was washed by brine (30 mL). The organic layer was dried (NaSO) and the solvent was Br O eN (CH3)3SiCHS-s- H 45 removed under vacuum. The residue was purified by flash Pd(OAc)2(PPh) chromatography (silica gel) to provide pure 8539.5 mg TEA (40% yield) as a white solid: mp 268.5–270° C.; IR (KBr) 2358, 1607, 1538, 1484, 1311, 1000, 801, 697 cm; 1H O reflux 50 NMR (CDC1) & 2.82(s, 3H), 4.11(d.1 H, J=12.8 Hz), 5.49 (d.1 H, J=12.8 Hz), 7.21–7.68(m, 7H), 7.75 (dd. 1H, J=0.58 8 HZ, J=1.5 Hz); MS (EI) m/e (relative intensity) 354 (34), H3C N (M, 16), 352 (34), 325(33), 323 (34), 273 (63), 245 (31), Y NN 55 232 (19), 204 (100), 183(23), 177 (36), 151 (24). Anal. N-/ Calcd. for CHBrN: C, 57.81; H, 3.71: N, 15.86. Found C, 57.57; H, 3.64: N, 15.70. TBAF He 8-Trimethylsilylacetylenyl-1-methyl-6-phenyl-4H-s-tria THF, 10 min Zolo4.3-a 1,4-benzodiazepine 9." (XLi269). A mixture 2 eN 60 of 8 (8-bromo-1-methyl-6-phenyl-4-H-s-triazolo-4.3-a1, 4benzodiazepine, 300 mg. 0.85 mmol), trimethylsilylacety (H3C)Si t lene (208.5 mg, 2.12 mmol) and bis(triphenylphosphine)- palladium(II) acetate in a mixed solvent system of EtN (5 65 mL) and CHCN (8 mL) was heated to reflux under nitro 9 (XLi269) gen. After stirring for 6 hours at reflux. The mixture was cooled to room temperature. The mixture was concentrated US 7,119,196 B2 31 32 under reduced pressure and H2O (30 mL) was added. The mixture was extracted with CHCl (3x50 mL). The com -continued bined extracts were washed with brine and dried (Na2SO). After removal of solvent under reduced pressure, the residue COEt was purified by flash chromatography (silica gel, EtOH/ EtOAc) to afford benzodiazepine 9 (185 mg, 60% yield) as (CH3)Si-E-H (trimethylsilyl)acetylene a white solid: mp 229–233° C.: IR (KBr) 2957, 2156, 1609, Pd(PPh3)2(OAc) 1537, 1491, 1424, 1315, 1249, 881, 844, 750 cm; H NMR Br eN NEt3, CH3CN (CDC1) & 0.23 (s, 9H), 2.68 (s, 3H), 4.11 (d. 1H, J=12.5 reflux Hz), 5.49 (d. 1H, J=13.0 Hz), 7.21–7.68(m,7H), 7.75(dd, 10 1H, J–8.5 Hz, J=1.5 Hz); MS (EI) m/e (relative intensity) 370 (M", 80), 355 (44), 341 (60), 286 (34), 177 (51), 163 O F (52) 143 (100), 129 (19), 115 (28). Anal. Calcd. for 13 (JYI-032) C.H.N. Si: C, 71.31; H, 5.98: N, 15.12. Found: C, 70.90; 15 H, 5.93: N, 15.08. 8-Acetylenyl-1-methyl-6-phenyl-4H-s-triazolo 4.3-a1, 4)benzodiazepine 10 (Xli-270). A solution of 9 trimethyl N silylacetylenyl-1-methyl-6-phenyl-4H-s-triazolo-4.3-a-1, r COEt 4-benzodiazepine (106.4 mg., 0.288 mmol) in dry THF (20 J/ mL) was treated with BuNF (1.0 M in THF, 112.8 mg, 0.431 mmol). The mixture which resulted was allowed to stir O n-BuNFTHF for 5 min at room temperature after which the mixture was 2 eN added to H2O (10 mL) and extracted with CHCl (3x25 (CH3)3Si F mL). The combined organic extracts were washed with brine 25 (25 mL) and dried (NaSO). After removal of solvent under reduced pressure, the residue was crystallized from EtOAc to provide benzodiazepine 10 (XLi270) (66.8 mg, 80% yield) as a white solid: mp-250° C. (dec); IR (KBr) 3198, 14 (JYI-038) 2158, 1609, 1538, 1491, 1425, 1317, 1002, 838, 748, 695 30 cm': "H NMR (CDC1) & 2.78 (s, 3H), 3.15 (s, 1H), 4.11 (d. 2H, J=12.8 Hz), 5.91 (d. 1H, J=12.8 Hz), 7.35 7.85 (m, N 8H); MS (EI) (relative intensity) 298 (M', 100), 269 (78), COEt 230 (48), 228 (65), 201 (20), 127 (65), 115 (42), 101 (54). Anal. Calcd. for C.H.N./2CHOH: C, 74.50; H, 5.13: N, 35 17.82. Found: C, 74.33; H, 4.83; N, 17.77,

Scheme 4 40 NH2 1. BrCH2COBr O NaHCO3, CH2Cl2 He 15 (JY-XHE-053) Br 2. NH, MeOH F reflux 45 The 7-bromo-2'-fluorobenzodiazepine 12 (available from reference 1) was reacted with sodium hydride and dieth ylphosphorochloridate and this was followed by addition of ethyl isocyanoacetate to provide benzimidazo intermediate 1 50 13 (JYI-032), as illustrated in Scheme 4. This material was heated with trimethysilylacetylene in a Heck-type coupling reaction to provide the trimethylsilyl analog 14 (JYI-038). The silyl group was removed from 14 on treatment with O H fluoride anion to furnish 15, a 2'-fluoro analog of XHeII-053, N 55 in excellent yield. Procedure: 1. NaH, (EtO)2POCI Ethyl 8-bromo-6-(2'-fluorophenyl)-4H-benzofimidazo Br eN ---THF, 0° C. 2. NaH, CNCH2COEt 1.5-a 1,4-diazepine-3-carboxylate 13 (JYI-032). A solu F 60 tion of 12' (7.0g, 21.0 mmol) in THF (50 mL) was cooled in ice-water, and sodium hydride (1.0 g, 25.2 mmol) was added in one portion. After 30 min, diethyl phosphorochlo ridate (5.62 g, 31.5 mmol) was added dropwise, and the 12 solution which resulted was stirred continuously for 30 min (this material available 65 with cooling from an ice bath. A solution of ethyl isocy from reference one) anoacetate (4.22 g, 25.2 mmol) and sodium hydride (1.17 g. 29.4 mmol) in THF (10 mL), which had stirred for 30 min US 7,119,196 B2 33 34 with ice-bath cooling, was added slowly via a cannula. After stirring for another 30 min with cooling, the reaction mixture was allowed to stir at room temperature overnight. The Scheme 5 mixture was then added to H2O (10 mL) and extracted with 5 H O EtOAc (3x50 mL). The combined organic extracts were N washed with brine (2x50 mL) and dried (NaSO). The 1. NaH Solvent was evaporated under reduced pressure and the di-4-morpholinylphosphinic residue was purified by flash chromatography (silica gel. chloride hexanes/EtOAc: 2/1) to afford 13 (JYI-032, 5.2g, 58%) as Br eN THF, 0° C. a white solid: mp 200–201.5° C.; IR (KBr) 2977, 1718, 10 2. CHCONHNH 1610, 1491, 1450 cm; H NMR (DMSO-d) & 1.30 (t,3H, F reflux J–4.2 Hz), 4.28 (bs, 1H), 4.30 (q, 2H, J–4.2 Hz), 5.75 (bs, 1H), 7.20 (t, 1H, J=5.6 Hz), 7.30 (t, 1 H, J=4.5 Hz), 7.40 (s, 1 H), 7.54 (m, 2 H), 7.85 (d. 1 H, J=5.2 Hz), 7.96 (dd. 1 H, 15 12 J=5.2 Hz and 1.3 Hz), 8.44 (s, 1 H); MS (EI) m/e (relative intensity) 428 (7), 381 (58), 355 (100), 303 (37), 274 (36), 247 (35), 234 (52), 154 (71), 127 (62). Anal Calcd. for CHNOFBr: C, 56.09: H, 3.53: N, 9.81. Found: C, (CH)Si-E-H 56.02; H, 3.51; N, 9.58. (trimethylsilyl)acetylene Ethyl 8-trimethylsilylacetylenyl-6-(2'-fluorophenyl)-4H Pd(PPh3)2(OAc) benzof-imidazo 1.5-a 1,4-diazepine-3-carboxylate 14 Br eN NEt3, CH3CN (JYI-038). A mixture of bromide 13 (JYI-032, 1.40 g, 3.3 reflux mmol), trimethylsilylacetylene (0.65 g. 6.6 mmol) and bis (triphenylphosphine)-palladium (II) acetate (0.25 g, 0.33 25 mmol) in a mixed solvent system of CHCN (80 mL) and O F anhydrous triethylamine (50 mL) was heated to reflux under 16 (JYI-73) argon. After stirring for 2 hat reflux, the mixture was cooled H3C N to room temperature and the precipitate which formed was 30 removed by filtration. The filtrate was concentrated under Y. NN reduced pressure and the residue was treated with a saturated N/ aqueous solution of NaHCO (40 mL), and extracted with n-Bu-NF He CHCl (3x50 mL). The combined organic extracts were THF washed with brine (2x20 mL) and dried (NaSO). After 35 2 eN removal of solvent under reduced pressure, the residue was purified by flash chromatography (silica gel, hexanes/ (CH3)3Si F EtOAc: 3/1) to afford 14 (JYI-038, 1.2g, 82%) as a white solid: mp 196-197.5°C.: IR (KBr) 2959, 2157, 1709, 1613, 1494, 1451, 1252 cm; H NMR (DMSO-d) & 0.20 (s, 9 40 H), 1.32 (t, 3 H, J=7.1 Hz), 4.18 (bs, 1 H), 4.32 (q, 2 H, J–7.1 17 (JYI-72) Hz), 5.78 (bs, 1 H), 7.25 (t, 1 H, J=11.5 Hz), 7.30 7.35 (m, 4 H), 7.81 (d. 1 H, J=6.6 Hz), 7.93 (d. 1 H, J=8.4 Hz), 8.49 (s, 1 H); MS (EI) m/e (relative intensity) 445 (37), 399 (51), 371 (100), 235 (71), 192 (66), 178 (75). Anal. Calcd. for 45 CHNOFSi: C, 67.39; H, 5.42: N, 9.43. Found: C, 66.98; H, 5.46; N, 9.19. 8-Acetyleno-6-(2'-fluorophenyl)-4H-benzofimidazol, 5-a 1.4 diazepine-3-carboxylate 15 (JY-XHE-053). A solu tion of 14 (JYI-038, 80 mg, 0.18 mmol) in THF (5 mL) was 50 treated with BuNF (0.5 mL, 1.0M solution in THF). The mixture which resulted was allowed to stir for 5 min at room temperature after which the mixture was added to H2O (5 mL) and extracted with EtOAc (3x10 mL). The combined 18 (JYI-70) organic extracts were washed with brine (2x10 mL) and 55 dried (NaSO). The solvent was removed under reduced pressure and the residue was purified by flash chromatog The 7-bromo-2'-fluorobenzodiazepine 12 was stirred with raphy (silica gel, EtOAc) to afford 15 (JY-XHE-053, 67 mg, Sodium hydride and di-4-morpholinylphosphinic chloride, 80%) as a white solid: mp 223.5-224.5°C.: IR (KBr)3288, followed by addition of acetic hydrazide, according to the 2979, 1712, 1621, 1491, 1255, 1190 cm; H NMR 60 published procedure to provide triazolobenzodiazepine 16 (DMSO-d) & 1.34 (t, 3 H, J=7.1 Hz), 4.27 (bs, 1 H), 4.36 (q, 2 H, J=7.1 Hz), 4.47 (s, 1 H), 5.80 (bs, 1 H), 7.22 (t, 1 (JYI-73), as illustrated in Scheme 5. This compound 16 H, J=8.4 Hz), 7.30 7.60 (m, 4H), 7.85 (d. 1 H, J=6.6 Hz), underwent the palladium-mediated Heck-type coupling 7.92 (d. 1 H, J=8.4 Hz), 8.83 (s, 1 H); MS (EI) m/e (relative reaction with trimethylsilylacetylene to furnish the 8-trim intensity) 373 (28), 327 (47), 299 (100), 249(22), 178 (50). 65 ethylsilyl substituted analog 17 (JYI-72). Removal of the Anal. Calcd. for CHNO.F./2H2O: C, 69.10; H, 4.48: N, silyl group from 17 furnished the 8-acetyleno triazoloben 10.99. Found: C, 69.19; H, 4.39; N, 10.68. Zodiazepine 18 (JYI-70). US 7,119,196 B2 35 36 Procedure: (100), 246 (69), 153 (16), 127 (62). Anal. Calcd. for 8-Bromo-1-methyl-6-(2'-fluorophenyl)-4H-s-triazolo4. CHN.F.0.6CHOH: C, 70.16; H, 4.37; N, 16.55. Found: 3-a 1,4-benzodiazepine 16 (JYI-73). A solution of 12 (JYI C, 69.98; H, 4.3.1: N, 16.70. 032, 7.0 g, 21.0 mmol) in THF (50 mL) was cooled in ice-water, and sodium hydride (0.72 g, 18 mmol) was added 5 in one portion. After 1 hour, di-4-morpholinylphosphinic chloride (4.84 g. 22.5 mmol) was added, and the solution which resulted was stirred continuously for 2 hours at room temperature. To this mixture was then added a solution of COC acetic hydrazide (2.47 g., 30 mmol) in n-BuOH (20 mL) and 10 stirring was continued at room temperature for 15 min. The C solvents were evaporated and the residue was dissolved in anhydrous ZnCl2: n-BuOH (25 mL) and heated to reflux for 2 hours. n-Butanol n-( )- NH2 12% HCl; 7 2% H2SO4 was evaporated and the residue was partitioned between 15 CHCl, and brine. The CHCl, layer was dried and removed NH2 under reduced pressure after which the residue was purified by flash chromatography (silica gel, EtOAc) to afford 16 1. BrCOCHBr/NaHCO (JYI-73, 2.2g, 40%) as a white solid: mp 213–214° C.; IR Br O O --- (KBr) 1610, 1484, 1426, 1314 cm; H NMR (DMSO-d) 2. NH/CH3OH 8 2.56 (s.3 H), 4.28 (d. 1 H, J=12.9 Hz), 5.26 (d. 1 H, J=12.9 C Hz), 7.24 (t, 1 H, J=8.3 Hz), 7.29 (t, 1 H, J–7.2 Hz), 7.35 (s, 1 H), 7.43–7.60 (m, 2 H), 7.83 (d. 1 H, J–8.7 Hz), 7.98 (dd, 1 H, J=8.7 Hz and 2.3 Hz); MS (EI) m/e (relative intensity) 371 (5), 341 (34), 222 (100), 195 (19), 181 (28), 111 (72). 19 Anal. Calcd. for CHNFBr: C, 55.01; H, 3.26: N, 15.09. 25 Found: C, 54.76; H, 3.29; N, 14.74. 8-Trimethylsilylacetylenyl-1-methyl-6-(2'-fluorophenyl)- 4H-s-triazolo 4.3-a 1,4-benzodiazepine 17 (JYI-72). A IL-N mixture of bromide 16 (JYI-73, 1.40 g, 3.8 mmol), trimeth 30 H O NaHC-K ylsilylacetylene (0.65 g. 6.6 mmol) and bis(triphenylphos N s N phine)palladium (II) acetate (0.25 g, 0.33 mmol) in a mixed y solvent system of CHCN (80 mL) and anhydrous triethy Br eN S lamine (50 mL) was heated to reflux under argon. After CHCONHNH stirring for 2 hours at reflux, the mixture was cooled to room 35 temperature and the precipitate which formed was removed C by filtration. The filtrate was concentrated under reduced pressure and the residue was treated with a Saturated aque ous solution of NaHCO, (40 mL), and extracted with CHCl 2O (3x50 mL). The combined organic extracts were washed 40 with brine (2x10 mL) and dried (NaSO). After removal of CH N solvent under reduced pressure, the residue was purified by 2 N flash chromatography (silica gel, EtOAc) to afford 17 (JYI N 72, 1.15g, 77%) as a gray solid: mp 218–219°C.; IR (KBr) N/ 2958, 2157, 1612, 1537, 1493, 1452, 1317, 1249 cm; H 45 NMR (DMSO-d) & 0.21 (s, 9 H), 2.56 (s, 3 H), 4.23 (s, 1 Br eN He H, J=12.9 Hz), 7.26 (t, 1 H, J=8.4 Hz), 7.29-7.83 (m, 6 H): TMS H, reflux MS (EI) m/e (relative intensity) 388 (65), 373 (14), 359 (77), 304 (44), 152 (100). Anal. Calcd. for CHNSiF.0.7H2O: C C, 65.87; H, 5.62: N, 13.94. Found: C, 65.88; H, 5.34; N, 50 13.94. 8-Acetyleno-1-methyl-6-(2'-fluorophenyl)-4H-s-triazolo 4.3-a1,4)benzodiazepine 18 (JYI-70). A solution of 17 21 (dim-II-90) (JYI-72, 2.0 g, 5 mmol) in THF (20 mL) was treated with CH3 N 55 2 N BuNF (4 mL, 1.0M solution in THF). The mixture which N resulted was allowed to stir for 5 min at room temperature N/ after which the mixture was added to H2O (20 mL) and extracted with CHCl (3x50 mL). The combined organic TBAF*xH2O extracts were washed with brine (2x15 mL) and dried He (NaSO). After removal of solvent under reduced pressure, 60 the residue was purified by flash chromatography (silica gel. -O- EtOAc/MeOH: 100/1) to afford 18 (JYI-70, 1.1 g, 70%) as TMS C a pale yellow solid: mps250° C. (dec); IR (KBr) 3205, 1612, 1493, 1426, 1317 cm; H NMR (DMSO-d) & 2.54 (s, 3 H), 4.22 (d. 1 H, J=12.9 Hz), 4.39 (s, 1 H), 5.26 (d. 1 H, 65 J=12.9 Hz), 7.22 (t, 1 H, J=8.3 Hz), 7.32 7.55 (m, 4H), 7.97 (m, 2 H); MS (EI) m/e (relative intensity) 316 (72), 287 US 7,119,196 B2 37 38 mmol) was added in one portion. The mixture was allowed -continued to warm to rt with stirring and the stirring was continued at rt until no more bubbles were evolved. The suspension was cooled to -5° C. after which di-4-morpholinylphosphinic chloride (21.8 g. 86 mmol) was added and this mixture was stirred for 30 min and allowed to warm to rt. The mixture was stirred for an additional 1.5 hr. To the mixture was then added a solution of acetylhydrazide (9.42 g, 114 mmol) in butanol (60 mL) and stirring was continued at rt for 10 min. H C 10 The solvent was removed under reduced pressure and the residue was taken up in butanol (100 mL) and held at reflux for 2 hr. Butanol was removed under reduced pressure and the residue was partitioned between CHCl (200 mL) and HO (100 mL). The aqlayer was extracted 4 times and the 23 (XLi-JY-DMH) 15 organic layers combined. The organic layer was washed 2-Amino-5-bromo-2'-chlorobenzophenone 19 was with brine and dried (NaSO). After the solvent was obtained from simple starting materials, 4-bromoaniline and removed under reduced pressure, the residue was crystal 2-chlorobenzoyl chloride, according to the improved con lized from EtOAc-EtO to provide the pure triazolobenzo ditions in the literature. The benzodiazepine 20, available diazepine 21 (dim-II-90, 14 g. 63.2%) as a yellow solid: mp from reference 1, was stirred with sodium hydride and 265-267° C. lit 274–275° C.I; IR (KBr) 3120 (br), di-4-morpholinophosphinic chloride, followed by addition 1686, 1479, 1386, 1014, 827, 747 cm; H NMR (300 of acetylhydrazide to furnish triazolobenzodiazepine 21 MHz, CDC1) & 2.42 (s, 1H), 4.18 (d. 1H, J=12.9 Hz), 5.56 (dim-II-90). The ligand 22 (XLi-JY-DMH-TMS) was (d. 1H, J=12.9 Hz), 7.36 (m, 3H), 7.43 (m, 2H), 7.61 (m, obtained by a Heck coupling reaction of 21 (dim-II-90) with 1H), 7.80 (dd. 1H, J–2.1 Hz, 8.7 Hz); MS (EI) m/e (rel trimethylsilylacetylene."' This compound was converted 25 intensity) 386 (M', 45), 357 (100); Anal. Calcd. For into acetylene 23 (XLi-JY-DMH) on stirring with fluoride CHNBrC1.0.5H2O: C, 51.65; H, 3.32: N, 14.18: Found anion as shown in Scheme 6. C, 51.95; H, 2.97; N, 13.91. 2-Amino-5-bromo-2'-chlorobenzophenone 19. 8-Trimethylsilylacetylenyl-5-(2-chlorophenyl)-1-me 2-Chlorobenzoyl chloride (177 mL, 1.4 mol) was cooled in thyl-4H-s-triazolo-4.3-a-1,4-benzodiazepine 22 (XLi-JY a 2-L flask equipped with a condenser and a thermometer to 30 DMH-TMS).-78 0°C. with an ice-water bath and 4-bromoaniline (100 g, 0.58 A mixture of 21 (7.75 g, 20 mmol), acetonitrile (600 mL), mol) was added to the cooled solution. The mixture was triethylamine (500 mL) and bis(triphenylphosphine)-palla heated to 120° C. and kept at this temperature for 1 h until dium (II) acetate (1.2g, 1.6 mmol) was degassed. Trimeth analysis by TLC indicated 4-bromoaniline had been con ylsilylacetylene (5.65 mL, 40 mmol) was then added and the sumed (EtOAc:hexane, 1:4). The solution was heated to 35 160° C. and anhydrous ZnCl2 (95 g, 0.70 mol, flamed dried) Solution was degassed again. The Solution was then heated was added in one portion. The temperature was increased to to reflux for 4 hr until analysis by TLC indicated the starting 195° C. and stirring was maintained at this temperature for material had disappeared. The mixture was cooled to rt and 3 hr until no more bubbles were evolved. The mixture was concentrated under reduced pressure. The residue was par cooled to 120° C. and aq. HCl (12%, 350 mL) was added titioned between HO (50 mL) and EtOAc (2x200 mL). The dropwise slowly. The mixture was kept at reflux for 20 min, 40 combined organic layer was washed with brine and dried after which the aqlayer was poured off. This procedure with (NaSO). The residue was purified by flash chromatogra aq HCl was repeated 4 times. Water (350 mL) was then phy on silica gel (CHCl) to furnish the trimethylsilyl added, and the mixture held at reflux for 20 min and then the analogue 22 (XLi-JY-DMH-TMS, 3 g, 37.0%) as white water was poured off. This was repeated several times until solid: mp 265-267° C.: IR (KBr) 2930, 1618, 1554, 1497, the solid was not a block any more. Then HSO (72%. 700 45 1429, 1316, 885, 847 cm': "H NMR (300 MHz, CDC1) & mL) was added to the residue and the mixture was heated to 0.24 (s, 9H), 2.65 (s, 3H), 4.15 (d. 1H, J=12.9 Hz), 5.52 (d. reflux for about 1 hr until the reaction mixture became a 1H, J=12.9 Hz), 7.35 7.45 (m, 5H), 7.61 (m. 1H), 7.72 (dd, homogeneous dark colored solution. The hot acidic Solution 1H, J=1.8 Hz, 8.4 Hz); MS (EI) m/e (rel intensity) 404 (M', was poured into a mixture of ice and water with stirring. The 90),375 (100); Anal. Calcd. For CH, NSiCl: C, 65.33; H, precipitate which resulted was filtered and washed with a 50 5.24; N, 13.86. Found: C, 64.99; H, 4.98: N, 13.79. large amount of cold water until the pH value of the solid 8-Acetyleno-5-(2-chlorophenyl)-1-methyl-4H-s-triazolo was about 6. The solid was then suspended in ice water and aq NaOH (40%, 290 mL) was added carefully. The mixture 1,4-a-1,4-benzodiazepine 23 (XLi-JY-DMH)." which resulted was stirred for 2 hrs. The solid was filtered A solution of benzodiazepine 22 (1.25 g, 31 mmol) in THF and washed with ice water. The suspension of the solid in ice 55 (250 mL) was cooled to -30° C. and treated with water was adjusted carefully to approximately pH-3 with aq BuNFXHO (0.97 g., 37 mmol). After the mixture was HSO (40%) dropwise. The solid which remained was stirred for 5 min, analysis by TLC (silica gel; EtOAc:EtOH filtered and washed with water to neutrality. The yellow 4:1) indicated starting material had disappeared. Water (70 solid 19 (66.1 g, 37.0%) was dried and used directly in the mL) was then added and the mixture was allowed to warm next step without further purification. H NMR (300 MHz, 60 to rt. The mixture was then extracted with EtOAc (2x200 CDC1) & 6.49 (s. br, 2H), 6.65 (d. 1H, J=8.82 Hz), 7.26–7.8 mL). The organic layer was washed with brine and dried (m, 6H). (NaSO). After removal of the solvent under reduced 8-Bromo-5-(2-chlorophenyl)-1-methyl-4H-s-triazolo.4, pressure, the residue was washed successively with ethyl 3-a-1,4-benzodiazepine 21 (dim-II-90). ether, ethyl acetate and chloroform. After drying, the title A solution of benzodiazepine 20 (20g, 57 mmol, available 65 compound 23 (XLi-JY-DMH) was obtained (1.0 g, 97.3%) from reference 1) in dry THF (250 mL) was cooled to -5° as a white solid: mps250° C. (dec); IR (KBr) 3185, 1623, C. and a 60% dispersion of sodium hydride (3.66 g. 92 1543, 1497, 1429, 756 cm': "H NMR (300 MHz, CDC1) US 7,119,196 B2 39 40 8 2.65 (s, 3H), 3.17 (s, 1H), 4.18 (d. 1H, J=12.9 Hz), 5.54 quenched by adding water. The solid which precipitated was (d. 1H, 12.9 Hz), 7.34(m, 2H), 7.41–7.45 (m, 3H), 7.6 (m, filtered and washed with ethyl ether. It was purified by flash 1H), 7.75 (dd. 1H, J=1.8 Hz, 8.4 Hz); MS (EI) m/e (rel chromatography (EtOAc) on silica gel or neutral aluminum intensity) 332 (M', 78) 303 (100). oxide for ester 38. Scheme 7 r N COOH r N COOCH2CF N / N / CDI/DMF; He CFCHOH Br eN DBU Br eN

27 37 (dim-II-30)

(HC). Si-E-H CDI/DMF; Pd(OAc)2(PPh3)2 CCICH2OH EtN, CHCN DBU reflux r N COOCHCCl3 r N COOCHCF J/ J/

Br eN 2 eN TMS

38 (dm-II-33) 39 (dim-II-35) ? N COOH r N COOCHCF N / N / CDI/DMF; Her CFCHOH eN DBU eN H H O 40 41 (dim-II-20)

Esters 37 (dim-II-30), 38(dm-II-33) and 41 (dim-II-20) Trifluoroethyl 8-bromo-6-phenyl-4H-benzofimidazo1, were prepared according to the general procedure described 5-a1,4diazepine-3-carboxylate 37 (dim-II-30). in item 0067 from the starting acids and different alcohols, 55 respectively. The bromide 37 was converted into the tri A white solid (69.1%) from acid 27 and 2.2.2-trifluoroetha methilyacetylenyl compound 39 (dim-II-35) under standard nol: mp 202-204° C.; IR (KBr) 3114, 1711, 1608, 1495, conditions (Pd-mediated, Heck-type coupling)''' (Scheme 1368, 1288, 1158 cm; H NMR (300 MHz, CDC1) & 4.10 7). (d. 1H, J=12.6 Hz), 4.68 (m, 1H), 4.85 (m, 1H), 6.02 (d. 1H, General Procedure for Preparing the Esters. 60 J=12.6 Hz), 741-7.54 (m, 6H), 7.62 (d. 1H, J=2.1 Hz), 7.83 (dd. 1H, J=2.1 Hz, 8.4 Hz), 7.97 (s, 1H); MS (EI) m/e (rel The acid was dissolved in DMF (10 mL/mmol S.M.) and intensity) 463 (M", 14), 465 (14). CDI (1.2 eq) was added. The reaction mixture was stirred at Trichloroethyl 8-bromo-6-phenyl-4H-benzofimidazo1, room temperature for 3 h followed by addition of the alcohol 5-a1,4diazepine-3-carboxylate 38 (dim-II-33). (10 eq) and DBU (1 eq). The stirring was maintained until 65 the disappearance of all the starting material as determined A white solid (90.9%) from acid 27 and 2.2.2-trichloroet by TLC (EtOAc:EtOH 4:1). The reaction mixture was then hanol: mp 113-116° C.: IR (KBr) 3434, 1728, 1610, 1493, US 7,119,196 B2 41 42 1270, 1146, 1128 cm; H NMR (300 MHz, CDC1) & 4.11 (d. 1H, J=12.6 Hz), 4.91 (d. 1H, J=12.0 Hz), 5.19 (d. 1H, -continued COtBu J=12.0 Hz), 6.12 (d. 1H, J=12.6 Hz), 741-7.54 (m, 6H), NO) 7.61 (d. 1H, J=2.1 Hz), 7.83 (dd. 1H, J=2.1 Hz, 8.4 Hz). MS (EI) m/e (rel intensity) 511 (M', 45). 5 Trifluoroethyl 8-trimethylsilylacetylenyl-6-phenyl-4H eN benzofimidazo 1.5-a1,4diazepine-3-carboxylate 39 2 (dm-II-35). A white solid (49.8%); mp 107–110° C.; IR (KBr) 2961, 10 1734, 1611, 1560, 1497, 1251, 1159, 1120, 846 cm; H O NMR (300 MHz, CDC1) & 0.25 (s.9H), 4.08 (d. 1H, J=12.3 Hz), 4.69 (m, 1H), 4.84 (m, 1H), 5.98 (d. 1H, J=12.3 Hz), 44 (XLi 225) m/e739 (rel7.57 intensity) (m, 7H), 4817.76 (M", (dd. 1H,100). J–1.8 Hz, 8.4 Hz). MS (EI), The bromide 1 was reacted with diethylphosphorochlori date in the presence of sodium hydride, followed by addition Trifluoroethyl 8-acetylenyl-6-phenyl-4H-benzofimi of t-butyl isocyanoacetate to provide the ester 42. This was dazo 1.5-a 1,4-diaze-pine-3-carboxylate 41 (dim-II-20). converted into the trimethylsilylacetyleno compound 43 A white solid (36.9%) from acid 40 and 2.2.2-trifluoroetha under standard conditions (Pd-mediated, Heck-type cou nol: mp 188–190° C.; IR (KBr) 3443, 3277, 1710, 1600, pling). Treatment of 43 with fluoride gave the title com 1492, 1366, 1280, 1156 cm; H NMR (500 MHz, CDC1,) pound 44. & 3.18 (s, 1H), 4.08 (d. 1H, J–12.5 Hz), 4.67 (m, 1H), 4.82 Procedure for XLi225 (m. 1H), 5.98 (d. 1H, J=12.5 Hz), 7.37 7.40 (m, 2H), t-Butyl 8-bromo-6-phenyl-4H-benzofimidazo 1.5-a1, 7.44 7.51 (m, 3H), 7.56 7.59 (m, 2H), 7.78 (dd. 1H, J=1.5 25 4diazepine-3-carboxylate 42. This benzodiazepine 42 was Hz, 8.5 Hz); MS (EI) m/e (rel intensity) 409 (M", 28). Anal. obtained in 40% yield from 1' analogous to the literature Calcd. For CHNOF.0.25H2O: C, 63.82; H, 3.72: N, procedure as a white solid. 42 (XLi223): mp: 222° 223°C.; 10.16. Found: C, 63.89; H, 3.37; N, 9.94. IR (KBr) 2975, 2358, 1717, 1608, 1557, 1277, 1073, 908, Scheme 8: 696, 652 cm; H NMR (CDC1) & 1.60 (s, 9H), 4.03 (d. 30 1H, J=12.5 Hz), 6.08 (d. 1H, J=12.4 Hz), 7.35 7.52 (m, 7H), O H 7.58 (d. 1H, J–2.2 Hz), 7.80 (dd. 1H, J=2.22 Hz and 8.55 N Hz), 7.93 (s, 1H): t-Butyl-8-trimethylsilylacetylenyl-6-phenyl-4H-benzof O 1) NaH, THF/DMF imidazo 1.5-a 1,4-diazepine-3-carboxylate 43 (XLi Br eN CIPO(OEt), 0° C. 35 224). A mixture of bromide 42 (1 g, 2.28 mmol, trim 2) NaH, DMF ethylsilylacetylene (559 mg, 5.69 mmol) and bis(triph CNCH2COEt enylphosphine)-palladium-(II) acetate (55 mg, 0.073 mmol) in a mixed solvent system of CHCN (15 mL) and anhy drous TEA (25 mL) was heated to reflux under argon. After 40 stirring for 6 hours at reflux, the mixture was cooled to room 1 temperature and the precipitate which formed was removed N by filtration. The filtrate was concentrated under reduced r COtBu pressure and the residue was treated with a saturated aque J/ ous solution of NaHCO, (20 mL), and extracted with CHCl 45 (3x25 mL). The combined extracts were washed with brine and dried (NaSO). After removal of solvent under reduced Br O eN (CH)Si-E-H pressure, the residue was purified by flash chromatography Pd(OAc)2(PPh) (silica gel, EtOAc) to afford 43 (XLi224) as a white solid TEA (710 mg, 68.9%). mp: 234° 236° C.; IR (KBr) 2973, 2357, 50 2154, 1719, 1611, 1493, 1366, 1250, 1152, 1075,946, 880 cm': "H NMR (CDC1) & 0.23 (s, 9H), 1.64 (s, 9H), 4.05 O reflux (d. 1H, J=12.7 Hz), 6.06 (d. 1H, J=12.4), 7.37 7.53 (m, 7H), 42 (XLi 223) 7.73 (dd. 1H, J=1.95 and 8.25 Hz), 7.92 (s, 1 H); MS (EI) N m/e (relative intensity) 427 (M', 76), 412 (5), 381 (55), 353 55 (100) 303 (10), 287 (7). r COtBu t-Butyl 8-acetylenyl-6-phenyl-4H-benzofimidazo 1.5- J/ a 1,4diazepine-3-carboxylate 44 (XLi 225). A solution of 43 (128 mg 0.281 mmol), in THF (15 mL) was treated with BuNF.HO (100.04 mg., 0.38 mmol). The mixture which O -asTBAF 2^ eN THF, 10 min 60 resulted was allowed to stir for 5 min at room temperature after which the mixture was added to HO (10 mL) and (H3C)3Si extracted with EtOAc (3x15 mL). The combined organic extracts were washed with brine (15 mL) and dried (NaSO). After removal of solvent under reduced pressure, 65 the residue was purified by a wash column (silica gel. 43 (XLi224) EtOAc) to furnish 44 (XLi225) (92 mg. 85.4%) as a white solid: mp: 221° 223° C.: IR (KBr) 3159,3107, 2092, 1721, US 7,119,196 B2 43 44 1606 cm; H NMR (CDC1) & 1.62 (s, 9H), 3.21 (s, 1H), 7-Bromo-2'-fluorobenzodiazepine 13 was hydrolyzed 4.12 (d. 1H, J=10.2 Hz), 6.07 (d. 1H, J=12.5 Hz), 7.35-7.53 with aq. 2 N sodium hydroxide in EtOH and acidified to pH (m, 7H), 7.73 (dd. 1H, J=1.8 Hz and 8.3 Hz), 7.92 (s, 1H). 4 by adding 1 NHCl to afford the acid 45. The acid, obtained from the ester 13, was stirred with CDI in DMF, followed by Scheme 9 stirring with trifluoroethanol and DBU to provide the ester N 46 (JYI-049). This material 46 was heated with trimethysi r COEt lylacetylene in a Heck-type coupling reaction to provide the J/ trimethylsilyl analog 47 (JYI-053). The silyl group was removed from 47 on treatment with tetrabutylammonium 1 N NaOH: 10 fluoride to furnish 48 (JYI-059) in 70% yield. He Br eN 1 NHCI Procedure: 8-Bromo-6-(2'-fluorophenyl)-4H-benzofimidazo 1.5-a F 1,4-diazepine-3-carboxylic acid 45. The ester 13 (1.0 g, 15 2.36 mmol) was dissolved in EtOH (80 mL) and 2 N aq NaOH (8 mL) was added to the solution. The mixture was stirred at rt for 4 hours. After the EtOH was removed under 13 (JYI-032) reduced pressure, the solution was allowed to cool. The pH N value was adjusted to 4 by adding 1 NHCl dropwise. The ? COOH mixture was filtered and the solid was washed with cold -/ water and ethyl ether. The solid was dried to afford 45 (0.96 g, 97%) as a white solid: mp 280° C. (dec); IR (KBr) 3419, 1740, 1611, 1491 cm': "H NMR (DMSO-d) & 4.11 (bs, 1 O HeCDI Br eN CFCHOH H), 5.99 (bs, 1 H), 7.20 (t, 1 H, J=8.5 Hz), 7.32 (t, 1 H, J–7.5 DBU 25 Hz), 7.38 (d. 1 H, J=1.8 Hz), 7.55 (m, 2 H), 7.84 (d. 1 H, J=8.7 Hz), 7.95 (dd. 1 H, J=8.6, 19 Hz), 8.35 (s, 1 H). MS (EI) m/e (relative intensity) 400 (72), 399 (85), 381 (100), 355 (82). O F Trifluoroethyl-8-bromo-6-(2'-fluorophenyl)-4H-benzof 45 30 imidazo 1.5-a1,4diazepine-3-carboxylate 46 (JYI-049). N The carboxylic acid 45 (0.89 g, 2.23 mmol) was dissolved r COCH2CF in dry DMF (20 mL), after which CDI (0.72g, 4.45 mmol) / was added at rt and the mixture was stirred for 12 hours. The trifluoroethanol (0.49 mL, 6.68 mmol) in DMF (1 mL) and 35 DBU (0.37 mL, 2.45 mmol) in DMF (1 mL) were then added Br eN trimethylsilylacetylene to the mixture and stirring continued overnight. The solvent -- Pd(PPh3)2(OAc) was evaporated under reduced pressure and the residue was F NEt3. CHCN, A purified by flash chromatography (silica gel, hexanes/ EtOAc: 3/1) to afford 46 (JYI-049, 0.81 g, 76%) as a white 40 solid: mp 223-224° C.; IR (CHC1) 3063, 1732, 1611, 1492 cm'; H NMR (CDC1) & 4.16 (bs, 1 H), 4.80 (bs, 2 H), 6.07 46 (JYI-049) N (bs, 1 H), 7.06 (dt, 1 H, J=8.3, 0.9 Hz), 7.30 (m, 2 H), 7.48 r COCH2CF (m, 2 H), 7.68 (dt, 1 H, J=7.6, 1.8 Hz), 7.80 (dd. 1 H, J=8.6, J/ 2.1 Hz), 8.11 (s, 1H). MS (EI) m/e (relative intensity) 483 45 (38), 383 (64), 355 (100). Anal. Calcd. for CHNOFBr: C, 49.81; H, 2.51; N, 8.71. Found: C, O Hen-Bu-NF 49.97; H, 2.44; N, 8.68. 2 eN THF Trifluoroethyl-8-trimethylsilylacetylenyl-6-(2'-fluo (H3C)Si F rophenyl)-4H-benzofimidazo 1.5-a1,4diazepine-3-car 50 boxylate 47 (JYI-053). A mixture of bromide 46 (JYI-049, 482 mg, 1.0 mmol), trimethylsilylacetylene (0.28 mL, 2.0 mmol) and bis(triphenylphosphine)palladium (II) acetate 47 (JYI-053) (75 mg 0.11 mmol) in a mixed solvent system of CHCN N (25 mL) and anhydrous triethylamine (25 mL) was heated to COCH2CF 55 reflux under argon. After stirring for 12 h at reflux, the / mixture was cooled to room temperature and the precipitate which formed was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was treated with a saturated aqsolution of NaHCO (40 mL), and eN 60 extracted with CHCl (3x100 mL). The combined organic 2 extracts were washed with brine (2x50 mL) and dried (NaSO). After removal of solvent under reduced pressure, the residue was purified by flash chromatography (silica gel. O F hexanes/EtOAc: 3/1) to afford 47 (JYI-053, 360 mg, 76%) 65 as a gray solid: mp 220–221° C.; IR (CHC1) 2960, 1741, 48 (JY-059) 1612, 1496 cm; H NMR (CDC1) & 0.25 (s, 9 H), 4.12 (bs, 1 H), 4.82 (bs, 2 H), 6.10 (bs, 1 H), 7.06 (t, 1 H, J=8.3 Hz), US 7,119,196 B2 45 46 7.30 (m, 1 H), 7.48 (m, 2 H), 7.56 (d. 1 H, J=8.3 Hz), 7.67 (2x10 mL) and dried (Na2SO). The solvent was removed (m. 1 H), 7.73 (dd. 1 H, J=8.3, 1.8 Hz), 8.02 (s, 1 H); MS under reduced pressure and the residue was recrystallized (EI) m/e (relative intensity) 499 (52), 399 (45), 371 (100), from ethyl acetate/hexanes to afford 48 (JYI-059, 299 mg, 235 (21), 178 (36). Anal. Calcd. for CHNOFSi: C, 70%) as a pale yellow solid: mp 192–193° C.: IR (CHCI) 60.11; H, 4.24; N, 8.41. Found: C, 60.27; H, 4.22: N, 8.33. Trifluoroethyl-8-acetyleno-6-(2'-fluorophenyl)-4H-benzo 3295, 3052, 1741, 1612, 1494, 1277, 1159 cm; H NMR fimidazo 1.5-a 1,4-diazepine-3-carboxylate 48 (JYI (CDC1) & 3.14 (s, 1 H), 4.17 (bs, 1 H), 4.78 (bs 2 H), 4.47 059). A solution of 47 (JYI-053, 475 mg, 1.0 mmol) in THF (s, 1 H), 6.05 (bs, 1 H), 7.05 (dt, 1 H, J=8.3, 0.8 Hz), 7.30 (15 mL) was treated with BuNF (2 mL, 1.0M solution in (m. 1 H), 7.48 (m, 2 H), 7.60 (d. 1 H, J=8.3 Hz), 7.68 (dt, THF). The mixture, which resulted, was allowed to stir for 10 1H, J=7.6, 1.8 Hz), 7.76 (dd. 1 H, J=10.1, 1.8 Hz), 8.02 (s, 5 min at room temperature after which the mixture was 1 H); MS (EI) m/e (relative intensity) 427 (37), 327 (26), added to H2O (5 mL) and extracted with EtOAc (3x10 mL). 299 (100), 178 (50). Anal. Calcd. for CHNOF: C, The combined organic extracts were washed with brine 61.83; H, 3.07: N, 9.83. Found: C, 61.94; H, 3.03; N, 9.68.

Scheme 1()

N N N e- e- / / COOCH5 / N N suc N O-1 Br eN —N - Br eN 4A molecular sieves NaH, THF O 47% O 5 (dim-I-70) 49 (PS-I-27)

TMS- E -HPd(OAc)(PPh3) EtN, CH3CN 7396 r N /N ? /N N / o-N N / o-N

TMS

51(PS-I-26) 50(PS-I-28)

NOH 4A molecular sieves N-( NaH,40% THF

7 (XHe-II-053) US 7,119,196 B2 47 48 Ethyl amido oxime (59.5 mg, 0.676 mmol) was added to This compound 49 (PS-I-27) was obtained in 47% yield a stirred suspension of powdered 4 A molecular sieves (75 from 5 (dim-I-70) analogous to the procedure employed in mg) in anhydrous THF (15 mL) under nitrogen. After the 0085 as a white solid. mp: 210°C.; IR (KBr) 3106, 1631, mixture was stirred at rt for 10 min, NaH (27 mg of 60% in 1563, 1493, 1147, 931, 698 cm; H NMR (CDC1) & 8.06 5 (s, 1H), 7.84 (dd. 1H, J=8.6 Hz, J=2.25 Hz), 7.63–7.38 (m, mineral oil, 0.676 mmol) was added to the mixture. After the 7H), 6.13 (d. 1H1, J=12.911z), 4.21 (d. 1H, J=12.9 Hz), 3.20 mixture was stirred for a further 30 min, a solution of the (s, 1H), 2.88 and 2.83 (ABq, 2H, J=7.6 Hz), 1.41 (t, 3H, forgoing ester 7 (XHeII-053, 120 mg, 0.338 mmol) in THF J=7.6 Hz); MS (m/z) 435 (100). (20 mL) was added. The mixture which resulted was heated To the suspension of compound 49 (PS-I-27, 0.5 g, 1.15 to reflux for 8 hr. It was cooled to rt, after which acetic acid 10 mmol) in acetonitrile (30 mL) and triethylamine (80 mL) (40.6 mg, 0.676 mmol) was added. After the solution was was added bis(triphenylphosphine)palladium(II) acetate stirred for 10 min, the mixture was filtered through celite. (0.086 g., 0.115 mmol). The solution was degassed and The filtrate was diluted with CHCl (50 mL) and washed trimethylsilylacetylene (0.33 mL, 2.3 mmol) added. The with water, brine and dried (KCO). Evaporation of the mixture was heated to reflux and stirred overnight. After solvent under reduced pressure afforded a pale yellow solid, 15 removal of the solvent, the residue was dissolved in CHC1. which was purified by flash column chromatography (silica and washed with a saturated aqueous solution NaHCO, and gel, EtOAc/hexane, 2:3) to furnish 51 as a white solid brine. The organic layer was dried (NaSO) filtered and (PS-I-26, 52 mg, 40%). mp: 221–222° C.: IR (KBr) 3297, concentrated under vacuum. The residue was purified by 3105, 1631, 1570, 1495, 1310,938 cm; H NMR (CDC1,) flash column chromatography (EtOAc:hexane 2:3) to fur & 8.07 (s, 1H), 7.80 (dd. 1H, J=8.4 Hz, J=1.8 Hz), 7.64 7.60 20 nish the trimethylsilyl analog 50 (PS-I-28, 380 mg, 73%) as (m. 2H), 7.53-7.37 (m, 5H), 6.12 (d. 1H, J=12.9 Hz), 4.21 a pale yellow solid: mp: 193–194° C.; IR (KBr) 3106, 2960, (d. 1H, J=12.9 Hz), 3.20 (s, 1H), 2.88 and 2.83 (ABq, 2H, 2149, 1630, 1567, 1493, 938, 851, 701 cm; H NMR (300 J=7.6 Hz), 1.41 (t, 3H, J–7.6 Hz); C NMR (CDC1,) & Hz, CDC1) & 8.07 (s, 1H), 7.78 (dd. 1H, J=1.86, 8.34 Hz), 171.8, 170.6, 168.8, 139.1, 136.6, 135.8, 135.4 (2C), 135.1, 7.6.1-7.38 (m, 7H), 6.11 (d. J=112.78 Hz), 4.19 (d. J=12.78 130.7, 129.3 (2C), 128.3 (2C), 128. 1, 124.7, 122.7, 121.6, 25 Hz), 2.88 and 2.83 (ABq, 2H, J=7.56 Hz), 1.41 (t, 3H, 81.2, 80.0, 44.7, 19.7, 11.5; MS (m/z) 379 (100). J=7.56 Hz), 0.25 (s, 9H). Scheme 11

H O N O H N

Br eN Pd(OAc)2(PPh3)2 2N H Si(CH3)3 O C EtN,Reflux CHCN 4 C (H3C)Si

2O 52 (XLi343) H3C O V N

NaH/CHI TBAF, THF/H2O THF 2N 4 C (H3C)Si O 54 (XLi351) H N O 2 N TBAF, THF/HO --- -, A O 53 (XLi350) H 4. O C

55 (XL352) US 7,119,196 B2 49 50 The bromide 20 available from references 9 and 10 was tetrabutylammonium fluoride (1M in THF). The mixture reacted with trimethylsilyacetylene in the presence of a was stirred for 20 minutes at room temperature before water palladium catalyst to provide trimethylsilyl analog 52. This (30 mL) was added. The mixture was then extracted with product was methylated with methyl iodide/sodium hydride EtOAc (3x30 mL). The combined organic extracts were to give the N-methylbenzodiazepine 54 (XLi 351). This was washed with brine and dried (NaSO). The solvent was subjected to fluoride-mediated desilation to furnish 53 (XLi removed under vacuum and the residue which resulted was 350) and 55 (XLi 352). passed through a wash column (silica gel, EtOAC/hexanes: Procedure for XLi 350 and XLi 352 4/1) to give 55 as light yellow crystals (71 mg, 90%): mp: 7-Trimethylsilylacetyleno-5-phenyl-(2-chlorophenyl) 1, 95.6 98.1° C.; IR (KBr) 2953, 1677, 1489, 1346, 1091,791, 3-dihydrobenzoel-1,4-diazepin-2-one 52 (XLi 343). A 10 749 cm', 'H NMR (CDC1) & (ppm) 3.05(s, 1H), 3.46 (s, mixture of 20' (500 mg, 1.43 mmole) available from refer 3H), 3.83 (d. 1H, J=10.5 Hz), 4.87 (d. 1H, J=9.33 Hz), 5.28 ences 9 and 10 in triethyl amine (10 mL) and CHCN (16 (s, 1H), 7.20 7.43 (m, 5H), 7.58 7.86 (m, 2H); MS (EI) m/e mL) with trimethyl-silylacetylene (126 mg, 1.28 mmole) (relative intensity) 308(M', 100), 294(19), 280(82), 273 (99), 249(28), 245(61), 229(29), 201(32), 189(43). and bis(triphenylphosphine)palladium (II) acetate (64.3 mg, 15 0.086 mmol) was heated to reflux under nitrogen. After 6 hours, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was treated with a saturated aqueous NaHCO solution (15 mL), and extracted with CHCl (3x20 mL). The organic layers were combined and washed with brine and dried (NaSO). After removal of solvent under reduced trimethylsilylacetylene pressure, the residue was purified via flash chromatography He Pd(PPh3)2(OAc) (silica gel, EtOAc/hexanes: 1/1) to furnish 52 as a yellow NEt3. CHCN, A powder (310 mg, 59%): mp: 225.8–228.2° C.: IR (KBr) 25 2953, 2358, 1685, 1616, 1490, 1328, 1248, 1058, 1011, 841, 746 cm', 'H NMR (CDC1,) & 0.21 (s, 9H), 4.38 (s. 2H), 7.41 (d. 1H, J=8.37 Hz), 7.19 7.52 (br. 7H), 8.11 (s, 1H): MS (EI) m/e (relative intensity) 366 (M", 100), 331(59), 12 229(18), 161(26). 30 7-Acetyleno-5-phenyl-(2-chlorophenyl)-1,3-dihydro benzole-1,4-diazepin-2-one 53 (XLi 350): A solution of 52 O H (150 mg, 0.408 mol) in THF (30 mL) was treated with N tetrabutylammonium fluoride (1M in THF). The mixture was stirred for 20 minutes at room temperature before water 35 (30 mL) was added. The mixture was then extracted with 2 O eN n-Bu-NF EtOAc (3x30 mL). The combined organic extracts were 21 THF washed with brine and dried over (Na2SO). The solvent (H3C)Si F was removed under vacuum and the residue which resulted was passed through a wash column (silica gel, EtOAC/ 40 hexanes: 4/1) to give 55 as light yellow crystals (110 mg. 95.2%); mp: 215° C.; IR (KBr) 3290, 1685, 1615, 1491, 1328, 731 cm', 'H NMR (CDC1) & 3.06 (s, 1H), 4.40 (s, 56 (JYI-55) 3H), 7.03–7.61 (m, 7H), 7.58 7.86 (m, 2H), 7.99 (s, 1H): MS (EI) m/e (relative intensity) 294 (M', 100), 266(75), 45 H O 265(87), 259(83), 231(40), 201(24), 176(23). N 1-Methyl-7-trimethylsilylacetyleno-5-phenyl-(2-chlo rophenyl)-1,3-dihydro-benzoe-1,4-diazepin-2-one 54 (XLi 351). A mixture of 52 (300 mg. 0.82 mmol) was dissolved in dry THF (40 mL) at 0° C. and NaH (60% in mineral oil, 50 2^ O eN 50 mg, 1.25 mmol) was added to the solution in one portion. F The slurry was then stirred for 20 min at 0°C. and CHI (139 mg, 0.98 mmol) was added to the mixture and it was warmed up to room temperature. After the mixture stirred for 3 hours at room temperature, the THF was then removed under 55 reduced pressure. The residue was purified by flash chro 57 (JYI-60) matography hexanes/EtOAc (1:4) to provide the title com pound 54 (260 mg, 83%) as a white solid: mp: 1969–198° 7-Trimethylsilylacetyleno-5-(2'-fluorophenyl)-1,3-dihy C.; IR (KBr) 2953, 1676, 1611, 1489, 1346, 1125, 1078, drobenzoe-1,4-diazepine-2-one 56 (JYI-55). A mixture of 913, 742 cm-1; H NMR (CDC1)8(ppm) 0.21 (s, 9H)3.46 60 bromide 12 (1.6 g. 5.0 mmol), trimethylsilylacetylene (3.0 (s, 3H), 3.54 (d. 1H, J=10.9 Hz), 4.60 (d. 1H. J=10.8 Hz), mL, 21.0 mmol) and bis(triphenylphosphine)palladium (II) 7.20 7.43 (m, 5H), 7.58 7.65 (m, 3H). MS (EI) m/e (rela acetate (375 mg, 0.5 mmol) in a mixed solvent system of tive intensity) 380(M., 8), 366(10), 308(100), 280(88), CHCN (60 mL) and anhydrous triethylamine (40 mL) was 273(97), 245(61). heated to reflux under argon. After stirring for 3 hat reflux, 1-Methyl-7-acetyleno-5-phenyl-(2-chlorophenyl)-1,3-di 65 the mixture was cooled to room temperature and the pre hydro-benzoel-1,4-diazepin-2-one 55 (XLi 352): A solu cipitate which formed was removed by filtration. The filtrate tion of 54 (100 mg, 0.262) in THF (30 mL) was treated with was concentrated under reduced pressure and the residue US 7,119,196 B2 51 52 was treated with a saturated aq solution of NaHCO (100 mL), and extracted with CHCl (3x200 mL). The combined -continued organic extracts were washed with brine (2x100 mL) and dried (NaSO). After removal of solvent under reduced pressure, the residue was purified by flash chromatography 5 (silica gel, hexanes/EtOAc: 2/1) to afford 56 (JYI-55, 794 mg, 47%) as a gray solid: mp 168.5–169.5°C.; IR (CHCl) 3202, 3113, 2955, 1686, 1612, 1490 cm; H NMR (CDC1) & 0.22 (s, 9 H), 4.38 (s, 2 H), 704–7.33 (m, 3 H), 10 7.34 (s, 1 H), 7.45 7.53 (m, 1 H), 7.56 7.62 (m, 2 H), 8.73 (bs, 1 H). MS (EI) m/e (relative intensity) 350 (94), 322 (100), 167 (41), 153 (37). Anal. Calcd. for CHNOFSi: C, 68.54; H, 5.46; N, 7.99. Found: C, 68.23; H, 5.40; N, 62, R = I (Hz120) 8.34. 15 63, R = CI (Hz111) 7-Acetyleno-5-(2'-fluorophenyl)-1,3-dihydrobenzoel, 4-diazepine-2-one 57 (JYI-60). A solution of 56 (JYI-55, 2-Amino-5-iodo-benzophenone was prepared from p-io 700 mg, 2.0 mmol) in THF (200 mL) was treated with donitrobenzene and phenylacetonitrile according to the lit BuNF (2 mL, 1.0M solution in THF). The mixture, which erature.' 2-Amino-5-chloro-benzophenone was commer resulted, was allowed to stir for 5 min at room temperature cially available from Acros. The benzodiazepine 60 was after which the mixture was added to H2O (5 mL) and reacted with diethylphosphorochloridate in the presence of extracted with EtOAc (3x10 mL). The combined organic sodium hydride, followed by the addition of ethyl isocy extracts were washed with brine (2x10 mL) and dried 25 anoacetate to provide the ester 62 (HZ120), as shown in (NaSO). After the solvent was removed under reduced Scheme 13. pressure, the residue was purified by flash chromatography Ethyl 8-iodo-6-phenyl-4H-benzofimidazo 1.5-a 1.4 (silica gel, hexanes/EtOAc: 2/1) to afford 57 (JYI-60, 400 diazepine-3-carboxylate 62. A solution of benzodiazepine 60 mg, 72%) as a pale yellow solid: mp 208–209.5° C.; IR (3 g, 8.3 mmol) in dry THF (36 mL) was cooled to 0°C. and (CHC1) 3290, 3110, 2930, 1685, 1612, 1489 cm; H 30 a 60% dispersion of sodium hydride (0.70 g, 17.4 mmol) NMR (CDC1) & 3.04 (s, 1 H), 4.40 (s, 2 H), 7.06–7.28 (m, was added in one portion. The mixture was allowed to warm 3 H), 7.38 (s, 1 H), 7.44 7.51 (m. 1 H), 7.59 7.62 (m, 2 H), to rt with stirring and the stirring was continued at rt until no 9.43 (bs, 1 H). MS (EI) m/e (relative intensity) 278 (80), 250 more bubbles were evolved. The suspension was cooled to (100). Anal. Calcd. for CHNOF: C, 73.37; H, 3.98: N, 0° C. after which diethylphosphorochloridate (2.29 g, 13.3 10.07. Found: C, 73.64; H, 3.92: N, 9.78. 35 mmol) was added and this mixture was stirred for 30 min and allowed to warm to rt. The mixture was stirred for an additional 1.5 hr. In another flask, a 60% dispersion of sodium hydride (0.70 g, 17.4 mmol) in mineral oil was added in dry THF (36 mL) and cooled to 0° C. Ethyl NH2 40 isocyanoacetate (1.13 g, 9.94 mmol) was added and the stirring was continued until no more bubbles were evolved. O O This mixture was transferred to the above mixture at 0° C. R 1) BrCOCHBr, NaHCO He The mixture was then stirred at rt for 6 hand quenched with 2) NH, MeOH 45 HOAc (3.2 mL). The mixture was partitioned between EtOAc (200 mL) and HO (50 mL). The organic layer was washed with brine and dried (NaSO). After the solvent was removed under reduced pressure, the residue was purified by flash chromatography (silica gel, gradient elution, EtOAc: 50 hexane 1:4, 1:1, 4:1) to provide the ester 62 (HZ120) in 43% yield as a light brown solid. mp: 221–222 C.; IR (KBr) 2977, 1717, 1608, 1489 cm; H NMR (DMSO-d) & 1.31 (t,3H, J–7.1 Hz), 4.10 (d. 1H, J=12.5 Hz), 4.29 (q, 2H, J=6.7 Hz), 5.75 (d. 1H, J=12.4 Hz), 7.40 7.50 (m, 5H), 7.63 (d. 55 1H, J=1.8 Hz), 7.69 (d. 1H, J=8.5 Hz), 8.13 (dd. 1H, J=1.9, 8.5 Hz), 8.36 (s, 1H); MS (EI) m/e (relative intensity) 458 (23), 457 (M', 100), 411 (62), 384 (29), 383 (100), 257 (29) Anal. Calcd. for CHINO: C, 52.53; H, 3.53: N, 9.19. NaH, CIPO(OEt) Found: C, 52.57, H, 3.73; N, 8.64. Her 60 CNCHCOEt, THF Ethyl 8-chloro-6-phenyl-4H-benzofimidazo 1.5-a 1.4 diazepine-3-carboxylate 63. This ester 63 was obtained in 52% yield from 61 analogous to the procedure employed in 0092) as a white solid. mp: 174–175° C. (lit.' 174–175° 60, R = I 65 C.); H NMR (DMSO-d) & 1.32 (t, 3H, J=7.1 Hz), 4.13 (d. 61, R = Cl 1H, J=12.3 Hz), 4.32 (q, 2H, J=6.7 Hz), 5.76 (d. 1H, J=12.3 Hz), 7.37 7.50 (m, 6H), 7.86–8.38 (m, 2H), 8.74 (s, 1H).

US 7,119,196 B2 55 56

-continued 2N. - COEt N N-/ 2

TBAF, r THF/HO 2 eN 2 eN MeSi H 4Ns a S

75 (JC220) 76 (JC221)

6-Bromo-2-phenyl-4H-benzo[2,3-d-1,3-oxazin-4-one Sure, and the residue was purified via a wash column (silica 64. The 2-amino-5-bromobenzoic acid (5g, 23.1 mmol) was gel, hexanes/EtOAc: 11:1 to 4:1) to provide 67 as a bright treated with benzoyl chloride (237 mL, 2.04 mol) at 140°C. yellow solid: "H NMR (DMSO-d) & 6.28 (brs, 2H), 6.82 for 3 h. After the reaction mixture was cooled to rt, the (s, 11–1), 6.90 (s, 1H), 7.26 (dd. 1H, J=3.8, 5.0 Hz), 7.42 crystals that formed were collected by filtration and were (dd. 1H, J=2.4, 8.9 Hz), 7.61 (dd. 1H, J=1.1, 3.8 Hz), 7.69 washed with hexanes to provide 64 as light brown needles (dd. 1H, J=2.4 Hz), 8.04 (dd. 1H, J=10.1, 5.0 Hz); C NMR (6.8 g.97%): 'H NMR (CDC1) & 7.51–7.2 (m, 4H), 7.9 (dd, (DMSO) & 187.42, 150.09, 143.87, 136.46, 134.75, 13441, 1H, J=2.3, 8.6 Hz), 8.30–8.33 (m, 2H), 8.8 (d. 1H, J–2.2 25 133.93, 128.78, 119.36, 119.17, 104.95; MS (EI) m/e (rela Hz); 'C NMR (CDC1,) & 158.19, 157.35, 145.75, 139.58, tive intensity) 283 (M",59), 282 (M., 87), 281 (M',59), 280 132.82, 130.97, 129.77, 128.82, 128.73, 128.29, 121.37, (M, 79), 250 (23), 248 (23), 201 (13), 199 (49), 197 (48), 118.27; MS (EI) m/e (relative intensity) 303 (M", 36), 301 172 (25), 170 (23), 145 (13), 140 (1), 111 (100), 101 (33). (M, 36), 259 (14), 257 (14), 226 (6), 224 (6), 178 (9), 170 4-Bromo-2-(2-thienylcarbonyl)-N-bromoacetylaniline (9), 168 (9), 151 (4), 105 (100). 30 68. The thienylaniline 67 (3.3 g, 11.7 mmol) and NaHCO 4-Bromo-2-(2'-thienylcarbonyl)-N-benzoylaniline 66 and (2.9 g, 34.5 mmol) were suspended in dry CHCl (180 mL) bis-(2 '-thienyl)-5-bromo-2-(N-benzoyl)-aminophenyl and cooled to 0°C. A solution of bromoacetyl bromide (1.12 methanol 65. The benzo-xazinone 64 (5.0 g, 16.6 mmol) was mL, 12.9 mmol) in dry CHCl (30 mL) was added dropwise dissolved in dry THF (250 mL) and cooled to -78° C. for 45 over 20 min at 0° C. and the mixture was stirred at rt for 3 min. The 2-thienylithium (18.21 mL of 1M solution in THF) 35 h. The CHCl solution was then washed with aq NaHCO was added dropwise over 35 min and the reaction was stirred (5%) and dried (NaSO). The CHCl was removed under at -78° C. for 1.2 h. Saturated aq NHCl solution (25 mL) reduced pressure, and EtO was added to the flask. The and EtO (30 mL) were then added. The organic layer was solution was sonicated and filtered to provide 68 as a light separated, washed with brine and dried (MgSO). The solid: mp: 1440–146.5° C.; H NMR (CDC1) & 4.01 (s, Solvent was removed under reduced pressure, and the resi 40 2H), 7.23 7.26 (m. 1H), 7.24 (d. 1H), 7.65 (d. 1H), 7.74 (d. due was purified via flash chromatography (silica gel, hex 1H), 7.84 (d. 1H), 8.46 (d. 1H), 10.85 (brs, 1H); MS (EI) anes/EtOAc: 1:0, 49:1, 20:1, 11:1, 5:1) to provide 66 as m/e (relative intensity) 405 (M", 69), 404 (40), 403 (M", yellow crystals and the alcohol 65.66: "H NMR (CDC1) & 100), 401 (M', 66), 324 (39), 322 (38), 310 (33), 308 (33), 7.23 (dd. 1H), 7.52 7.56 (m, 3H), 7.66 (dd. 1H, J=0.99, 3.8 292 (32), 283 (65), 282 (72), 281 (65), 280 (67), 266 (10), Hz), 7.82 (d. 1H, J=5.0 Hz), 7.998.02 (m, 3H), 7.75 (d. 1H, 45 264 (10), 250 (34), 248 (35), 226 (55), 224 (55), 201 (43), J=9.0 Hz), 11.2 (s, 1H); 'C NMR (CDC1) & 188.82, 199 (27), 197 (27), 173 (32), 111 (73). 165.45, 143.24, 138.79, 136.57, 135.90, 135.51, 134.25, 7-Bromo-5-(2'-thienyl)-1,3-dihydrobenzoe 1.4 diaz 134.03, 132.17, 128.81, 128.31, 127.26, 125.65, 123.45, epine 69 (JC184). The bromoacetylamide 68 (0.236g, 0.586 114.95: MS (EI) m/e (relative intensity) 387 (M", 12), 385 mmol) was dissolved in a saturated Solution of anhydrous (M', 12), 276 (18), 274 (18), 201 (7), 172 (7), 105 (100). 65: 50 ammonia in MeOH (50 mL) and the mixture was heated to "H NMR (CDC1,) & 4.20 (s, 1H), 6.82 (s, 2H), 6.96 701 (m, reflux for 6 h. After the MeOH was removed under reduced 3H), 7.33 7.38 (m, 7H), 7.65 (d. 2H, J=7.23 Hz), 8.43 (d. pressure, EtOAc was added to the residue. The solution was 1H, J=8.8 Hz), 9.92 (s, 1H); 'C NMR(CDC1,) & 165.04, sonicated and then filtered to provide 69 (JC184) as a light 148.94, 136.44, 135.49, 134.49, 132.34, 131.59, 131.40, solid: MS (EI) m/e (relative intensity) 322 (M", 54), 320 128.40, 127.20, 126.89, 126.58, 124.18, 116.00, 79.35, 55 (M., 53), 294 (100), 292 (98), 211 (24), 185 (31), 140 (21). 76.92, 76.50; MS (EI) m/e (relative intensity) 471 (M", 54), The material was used directly in the next step. 469 (M', 51), 453 (100), 451 (93), 348 (98), 346 (92), 316 7-Trimethylsilylacetylenyl-5-(2'-thienyl)-1,3-dihy (54), 314 (58), 282 (20), 280 (19), 267 (88), 235 (12), 234 drobenzoe 1.4 diazepine 70 (JC207). A mixture of 69 (1 g, (12), 223 (15), 222 (17), 201 (56), 173 (20), 172 (12), 158 3.12 mmol) in CHCN (20 mL) and Et-N (30 mL) was (10), 129 (10). 60 degassed and heated to reflux under nitrogen. Bis(triph 5-Bromo-2-(2-thienylcarbonyl)aniline 67. The amide 66 enylphosphine)-palladium (11) acetate (0.26g, 0.347 mmol) (2 g, 635 mmol) was dissolved in EtOH (150 mL) and 20% was then quickly added, followed by the addition of TMS NaOH solution (30 mL) was added. The mixture was heated acetylene (0.76 g, 7.78 mmol). The mixture was stirred at to reflux for 5 h and the EtOH was removed under reduced reflux for 4 h and the solvent was removed under reduced pressure. The mixture was extracted with EtOAc and the 65 pressure. Water (25 mL) and EtOAc (25 mL) were added to organic phases were combined, washed with brine and dried the residue and the mixture was filtered through celite to (NaSO). The solvent was removed under reduced pres remove the organometallic species. The filtrate was then US 7,119,196 B2 57 58 extracted with EtOAc and the organic phases were com Prior to adding ClPO(OEt) (1.06 g. 6.35 mmol), the mixture bined, washed with brine and dried (NaSO). The solvent was again pre-cooled to 0° C. The solution was stirred was removed under reduced pressure and the residue was another 3 has the ice bath warmed to rt. Meanwhile, dry purified via flash chromatography (silica gel, hexanes/ THF (10 mL) was added to a second flask containing NaH EtOAc: 11:1, 5:1) to provide 70 (JC207) as a light yellow (60% in mineral oil, 0.229 g, 5.72 mmol). After the second solid: mp: 198.5-201° C.; MS (EI) m/e (relative intensity) mixture was cooled to 0° C., CNCHCOEt was added 338 (M, 68), 337 (M", 28), 310 (100), 295 (13), 161 (13), dropwise and the solution continued to stir for 30 min at 0° 147 (33), 105 (17). The material was used directly in the next C. After both reaction mixtures were again pre-cooled to 0° step. 10 C., the two solutions were combined under Ar via cannula 7-Acetylenyl-5-(2'-thienyl)-1,3-dihydrobenzoe 1.4di and the solution stirred at rt overnight. The reaction was azepine 72(JC208). A solution of 70 (150 mg, 0.457 mmol) quenched with ice water and worked up with EtOAc, and the in THF (30 mL) was treated with tetrabutylammonium combined organic phases were washed with brine and dried fluoride (1M in THF) at 0°C. for 5 minutes. Water (20 mL) (NaSO). The solvent was removed under reduced pressure was subsequently added to quench the reaction and the THF 15 was removed under reduced pressure. The remaining aq and the residue was purified via flash chromatography (silica solution was then extracted with EtOAc and the organic gel, hexanes: EtOAc 4:1, 1:1, 1:3) to provide the title com phases were combined, washed with brine and dried pound 74 (JC217) as an ivory solid (500 mg. 30% yield): (NaSO). Upon removal of the solvent, EtO was added to mp: 2040 205.3°C.; H NMR (CDC1) & 1.45 (t,3H, J=7.1, the residue which was sonicated and then filtered to provide 14.3 Hz), 4.07 (d. 1H, J=8.8 Hz), 4.44 (dd, 2H, J–3.8, 4.7 the title compound 72 (JC208, 111 mg, 91%) as an ivory Hz), 5.98 (d. 1H, J=12.8 Hz), 7.05 (d. 1H, J=1.0 Hz), 7.07 colored solid: mp: 214–216° C.; MS (EI) m/e (relative (s, 1H), 7.46–7.49 (m, 2H), 7.83 (dd. 1H, J–2.2, 8.5 Hz), intensity) 266 (M', 61), 265 (M', 30), 238 (100), 237 (49), 7.91 (s, 1H), 7.96 (d. 1H, J–2.2 Hz): MS (EI) m/e (relative 210 (13), 209 (10), 164 (6), 153 (7), 139 (7). This material intensity) 418 (M", 15), 417 (M, 68), 416 (M", 15), 415 was used in the next step. 25 (M, 64), 407 (22), 344 (26), 343 (100), 342 (30), 341 (93), 1-N-methyl-7-trimethylsilylacetylenyl-5-(2'-thienyl)-1,3- 293 (15), 291 (21), 262 (18), 235 (15), 211 (12), 154 (10), dihydrobenzoel 1,4-diazepine 71 (JC209). Thiophere 70 127 (11). (500 g, 1.52 mmol) was dissolved in dry THF (25 mL) at 0° Ethyl 8-trimethylsilylacetylenyl-6-(2-thienyl)-4H-benzo C. and NaH (60% in mineral oil, 76 mg, 1.50 mmol) was 30 fimidazo 1.5-a 1,4-diazepine-3-carboxylate 75 (JC220). added to the solution in one portion. After the mixture was The same procedure for preparing 70 (JC207) was applied to stirred at 0°C. for 30 min, Mel (0.14 mL, 2.25 mmol) was 75 (JC220) and an ivory colored solid resulted: "H NMR added and the ice bath was allowed to warm to rt. The (CDC1) & 0.29 (s.9H), 1.45 (t, 3H, J=7.1, 14.3 Hz), 4.0 (d. mixture was allowed to stir for 3 h and the THF was then 1H, J=18.1 Hz), 4.45 (dd, 2H, J=7.2, 8.5 Hz), 5.97 (d. 1H, removed under reduced pressure. The residue was purified 35 J=12.8 Hz), 7.06 7.11 (m, 2H), 7.49 (dd. 1H, J=1.2, 5.0 Hz), via flash chromatography (silica gel, hexanes/EtOAc 8:1, 7.52 (d. 1H, J=8.3 Hz), 7.77 (dd. 1H, J=1.9, 8.3 Hz), 7.90 (d. 4:1) to provide the title compound 71 (JC209) as a white 1H, J=1.8 Hz), 7.93 (s, 1H). MS (EI) m/e (relative intensity) solid: mp: 171.3–173.6° C.; H NMR (CDC1) & 0.26 (brs, 433 (M', 74), 387 (49), 359 (100), 277 (28), 262 (19), 235 9H), 3.38 (s.3H), 4.71 (d. 1H), 7.09 (dd. 1H, J–3.7, 5.0 Hz), (24), 172 (19), 129(17). 7.17 (dd. 1H, J=1.1, 3.7 Hz), 7.30 (s, 1H), 7.49 (dd. 1H, 40 Ethyl 8-acetyleno-6-(2'-thienyl)-4H-benzofimidazo1, J=1.1, 5.0 Hz), 7.65 (dd. 1H, J=2.0, 8.5 Hz), 7.75 (d. 1H): 5-a1,4diazepine-3-carboxylate 76 (JC221). The same pro 'C NMR (CDC1) 8(CDC1) & 170.12, 163.22, 143.65, cedure for preparing 72 (JC208) was applied to 76 (JC221) 143.14, 134.69, 133.12, 131.38, 130.14, 127.77, 127.47, and an ivory colored solid resulted: mp: >198° C.; H NMR 121.01, 119.10, 103.01, 95.66, 56.38, 34.67; MS (EI) m/e 45 (CDC1) & 1.43 (t,3H, J=4.3, 11.4 Hz), 3.25 (s, 1H), 4.10 (d. (relative intensity)352 (M",71), 351 (M", 60), 337 (10), 324 1H, J=12.8 Hz), 4.40-449 (m, 2H), 5.99 (d. 1H, J=12.9 Hz), (100), 309 (24), 168 (28), 154 (38). 7.50 (d. 1H, J=5.0 Hz), 7.56 (d. 1H, J=8.3 Hz), 7.81 (dd. 1H, 1-N-methyl-7-acetyleno-5-(2'-thienyl)-1,3-dihydrobenzo J=1.8, 8.3 Hz), 7.95 (s, 1H); MS (EI) m/e (relative intensity) e1.4 diazepine 73 (JC222). The same procedure for pre 361 (M', 24), 315 (35), 287 (100), 237 (26), 178 (30), 153 paring 72 (JC208) was applied to 73 (JC222) and a very light 50 (21), 126 (18). MS (EI) m/e (relative intensity) 361 (M',29), brown solid resulted: mp: 218.3–220.4° C.; H NMR 315 (41), 287 (100), 237 (31), 178 (40), 153 (26), 126 (21). (CDC1) & 3.16 (s, 1H), 3.39 (s.3H), 3.78 (d. 1H, J=11.07 Hz), 4.72 (d. 1H, J=5.9 Hz), 7.08 (dd. 1H, J=3.8, 5.0 Hz), 7.31 (d. 1H, J=8.6 Hz), 7.49 (dd. 1H, J=1.0, 50 Hz), 7.67 (dd. 1H, J=2.0, 8.5 Hz), 7.79 (d. 1H, J=1.9 Hz); 'C NMR 55 (CDC1) D 171.04, 170.07, 163.12, 143.49, 134.79, 133.50, 131.34, 130.25, 127.85, 127.46, 121.16, 117.99, 81.83, 78.30, 56.34, 34.69. MS (EI) m/e (relative intensity) 281 (13), 280 (M', 60), 279 (51), 253(19), 252 (100), 251(2), mCPBA 235 (11), 209(10). 60 He O CHCl2 Ethyl 8-bromo-6-(2'-thienyl)-4H-benzofimidazo 1.5-a Br 1,4-diazepine-3-carboxylate 74 (JC217). Dry THF (30 mL) was added to a flask containing the benzodiazepine 69 (1.27 g, 3.96 mmol) and the solution was allowed to cool to 0°C. and NaH (60% in mineral oil, 0.191 g, 4.76 mmol) was 65 O quickly added. The mixture was stirred for 30 min at 0°C. and then removed from an ice bath to stir another 1 h at rt. US 7,119,196 B2

-continued -continued O NHCH N HN 5

N O 4 y NHCH/THF O 2N -e-n-BuNFenH2O Her Br O TiCl4 4 THF O 10 s 77 82 (HZ141) NHCH NHCH 15 N N

N Pd(OAc)2(PPh3)2 4-y TMS H, 2O Br O CHCN, EtN

25 83 (Hz148) 78 NHCH The benzodiazepine 1 was oxidized with 3-chloroperoxy NS benzoic acid (mCPBA) to form 77, followed by the addition of methylamine to afford amidine 78. N-Oxide 78 was 30 reacted with trimethylsilyacetylene in the presence of a a v n-Bu-NFenH2O palladium catalyst to provide the trimethylsilyl analog 79 O THF (HZ146) which was subjected to fluoride-mediated desila tion to afford 80 (HZ147), as shown in Scheme 15. In a related route, bromide 81 was converted into the trimethyl silylacetylene 82 (HZ141). This analog was then trans s O 35 formed into target 79 (HZ146) with mCPBA or the key target 79 (Hz146) (HZ148) or treatment with fluoride (Scheme 16). NHCH 7-Bromo-4-oxy-5-phenyl-1,3-dihydro-benzoe 1.4diaz N 40 epin-2-one 77. Bromide 1 (1.88 g, 5.95 mmol) was dissolved in CHCl (50 mL) and mOPBA (77% max) (1.76 g) was added at rt. The reaction mixture was stirred overnight. The mixture was diluted with CHCl (80 mL) and washed with a N a sat. solution of NaHCO (50 mL), water (50 mL) and brine O y (40 mL). The organic layer was dried (NaSO) and con 4. 45 centrated. The residue was purified by flash chromatography (silica gel, EtOAc) to afford compound 77 in 90% yield as a white solid. mp: 230 231° C. (lit.' 230-231° C.); H NMR (CDC1) & 4.69 (s. 2H), 7.16 (d. 1H, J=8.7 Hz), 7.24 80 (Hz147)(HZ147 50 (d. 1H, J=2.1 Hz), 7.45 (m, 3H), 7.54 (dd. 1H, J=8.6, 2.2 Hz), 7.64 (dd, 2H, J=7.3, 3.6 Hz), 10.02 (s, 1H). (7-Bromo-4-oxy-5-phenyl-3H-benzoe 1.4 diazepin-2- yl)-methyl-amine 78. Methylamine (50 mL, 2 M in THF) Scheme 16 was added to 77 (1.9 g, 5.7 mmol) in a 100 mL round-bottom flask. The mixture was cooled to 0° C. after which TiCla NHCH 55 (0.54 g, 2.86 mmol) was added dropwise. The reaction N mixture was allowed to warm to rt and stirred for 4 h. The Pol(OAc)2(PPh3)2 mixture was quenched with water (5 mL), diluted with CH3CN EtOAc (100 mL) and washed with dilute NHOH. The 2N HeTMS-E-H, 60 organic layer was washed with water, brine and dried EtN (NaSO). After the solvent was removed under reduced pressure, the residue was purified by flash chromatography (silica gel, gradient elution, EtOAc, EtOAc:MeOH 10:1) to provide 78 in 86% yield as a white solid. mp: 236-237° C. 65 (lit. 242-243° C); H NMR (300 MHz, CDC1,) & 0.21 (s, 81 (Hz.135) 9H), 2.91 (s, 3H), 4.17 (s, 1H), 4.85 (s, 1H), 7.13–7.66 (m, 9H).

US 7,119,196 B2 63 64

-continued

N N-CH

90 (PS-1-37)

A suspension of 7-bromo-1,3-dihydro-5-phenyl-2H-1,4- 25 was added bis(triphenylphosphine)-palladium (II) acetate benzodiazepin-2-thione 84' (1.6 g. 4.83 mmol), glycine (22.6 mg, 0.03 mmol). The solution was degassed and (1.81 g, 24.2 mmol) and NaCO (1.84 g. 17.4 mmol) in trimethylsilylacetylene (0.1 mL, 0.7 mmol) was added. The EtOH (38 mL)-HO (16 mL) was stirred at reflux for 5 h, mixture was heated to reflux and stirred overnight. After poured into water (100 mL), and then filtered to remove a 30 removal of the solvent in vacuum, the residue was dissolved small amount of 7-bromo-1,3-dihydro-5-phenyl-2H-1,4- in CH2Cl and washed with a saturated aqueous solution of benzodiazepin-2-one which remained. The filtrate was NaHCO and brine. The organic layer was dried (NaCO), extracted with CHC1. The CHCl extract was discarded; the filtered and concentrated under vacuum. The residue was aqueous layer was adjusted to pH 4 with 2N HCl and then 35 purified by flash column chromatography (EtOAc:MeOH extracted with CHCl (3x25 mL). Evaporation of the CHCl 9:1) to furnish the trimethylsilyl analogue 89 (PS-I-36, 100 solution gave pure acid 85 (1.2g, 67%) as a yellow solid. mg, 69%) as a pale yellow solid. mps250° C.; IR (KBr) Acid 85 (350 mg. 0.941 mmol) was suspended in dry 3436, 2936, 2794, 2154, 1682, 1625, 1489, 1136, 847 cm; CHCl (10 mL) and DCC (223 mg, 1.08 mmol) was added. The suspension which resulted was stirred at 40° C. for 2 h 40 "H NMR (CDC1,) & 8.0 (d. 1H, J=8.5 Hz), 7.68 (dd. 1H1, and then cooled to 0°C. It was filtered, and the solvent was J=1.9 Hz, J=8.5 Hz), 7.55 7.59 (m, 2H), 7.37 7.49 (m, 4H), removed in vacuum to give 8-bromo-2,4-dihydro-6-phenyl 7.16 (s, 1H), 4.99 (d. 1H, J=12 Hz), 4.50–4.60 (m. 1H), 1H-imidazo[1,2-a 1,4-benzodiazepin-1-one 3 as a brown 4.20 4.30 (m, 1H), 4.13 (d. 1H, J=12.4 Hz), 3.483.58 (m, oil. The cyclized product 86 (ca. 250 mg) was dissolved in 45 2H), 2.4-2.6 (m, 4H), 2.35 (s, 3H), 0.23 (s, 9H); MS (m/z) dry benzene (6 mL), dimethylformamide diethylacetal (130 482 (100). mg, 0.883 mmol) and triethylamine (89 mg, 0.883 mmol) A solution of the trimethylsilyl analog 89 (PS-I-36, 65 were added. The solution which resulted was stirred at room mg, 0.135 mmol) in THF (15 mL) was stirred with tetrabu temperature for 1 h and the solvent was removed in vacuum, 50 tylammonium fluoride hydrate (45 mg, 0.175 mmol) at -5° The residue was then crystallized from EtOAc-MeOH to C. for 5 min. After this, H2O (5 mL) was added to the give 87 (200 mg, 70%). A solution of 87 (180 mg, 0.440 Solution to quench the reaction and stirring continued at low mmol) in dry toluene (5 mL) was treated with 1-methyl temperature for one half hour. The solution was extracted piperazine (1 mL) and heated to reflux for 5 h. The solvent with EtOAc (3x40 mL), and the organic layer was washed was removed in vacuum to give a gum which crystallized 55 with water. After removal of the solvent under reduced from CHC1-EtO to furnish 88 (PS-I-35, 146 mg, 72%). pressure, ethyl ether was added to the residue to precipitate mpa250° C.; IR (KBr) 3324, 2932, 2787, 1692, 1624, 1475, a solid. The mixture was filtered and the solid was washed 1402, 1297, 1137,933 cm; H NMR (CDC1,) & 7.95 (d. with CHC1-EtO (ca 1:15) to provide the acetyl target 90 1H, J=8.8 Hz), 7.72 (dd. 1H, J=2.3 Hz, J=8.8 Hz), 7.58 7.55 60 (PS-I-37, 40 mg, 73%). mp 223-224° C.; IR (KBr) 3298, (m. 2H), 7.49–7.37 (m, 4H), 7.17 (s, 1H), 5.01 (d. 1H, J=12 2935, 2786, 1695, 1628, 1364, 1136, 1002, 778 cm; H Hz), 4.50–4.60 (m, 1H), 4.20 4.30 (m. 1H), 4.16 (d. 1H, NMR (CDC1) & 8.04 (d. 1H, J=8.5 Hz), 7.71 (dd. 1H, J=12 Hz), 3.50–3.58 (m, 2H), 2.40 2.60 (m, 4H), 2.34 (s, J=10.9 Hz, J=8.5 Hz), 7.55 7.58 (m, 2H), 7.36 7.48 (m, 3H); MS (m/z) 465 (100). 65 4H), 7.17 (s, 1H), 5.0 (d. 1H, J=12.1 Hz), 4.5–4.6 (m. 1H), To the suspension of compound 88 (PS-I-35, 140 mg. 4.2–4.3 (m, 1H), 4.16 (d. 1H, J=12.1 Hz), 3.5–3.6 (m, 2H), 0.302 mmol) in acetonitrile (4 mL) and triethylamine (3 mL) 3.08 (s, 1H), 2.4-2.6 (m, 4H), 2.35 (s.3H); MS (m/z) (100). US 7,119,196 B2 65 66

r N COOCHs ? N COOH N J/ 2N NaOH/EtOH, O Br eN --10% aq. HCI B. eN -1,3-propanediol SPPMI DBU

5 (dim-I-70) 27 O O N N O O N / \ N (HC)Si-E-H Pol(OAc)2(PPh3)2 He EtN, CHCN Br eN NS- B reflux

91 (DMH-D-070) O O e N N / O 1N1 ao V TBAFoxH2O, THF 2 eN NS S - - 2 N (H3C)Si

92 (DMH-D-048)

O O - 93 (DMH-D-053) is

The acid 27, obtained from the ester 5 (dim-I-70), was 60 the dimer of XHeII-053) was easily obtained by treatment of stirred with CDI in DMF, followed by stirring with 1,3- trimethylsilyl compound 92 with fluoride anion as shown in propanediol and DBU to provide 91 (DMH-D-070, the Scheme 18.7 dimer of dm-I-70). This was converted into the trimethyl 8-Bromo-6-phenyl-4H-benzofimidazo 1.5-a 1,4-diaz silylacetylenyl compound 92 (DMH-D-048, the dimer of 65 epine-3-carboxylic acid 27. The ester 5 (2 g) was dissolved XLiXHe048) under standard conditions (Pd-mediated, in EtOH (50 mL) and aqsodium hydroxide (10 mL 2N) was Heck-type coupling).'The bisacetylene 93(DMH-D-053, added to the solution. The mixture was heated to reflux for US 7,119,196 B2 67 68 half an hour. After the EtOH was removed under reduced under reduced pressure, the residue was dissolved in CHC1. pressure, the solution was allowed to cool. The pH value was and washed with water. 3-Mecaptopropyl functionalized adjusted to 4 by adding 10% aq. HCl dropwise. The mixture silica gel (0.6 g) was added into the organic layer and stirring was filtered and the solid was washed with water and ethyl continued for 1 hour. The silica gel/Pd complex was ether. The solid was dried to provide 27 (1.8 g., 96.6%): removed by filtration and the filtrate was concentrated under mpa250° C.; IR (KBr) 3450 (b), 2844, 1707, 1615, 1493, reduced pressure. The residue was purified by flash column 1166,700 cm; H NMR (300 MHz, DMSO-d) & 4.14 (d. chromatography on silica gel (gradient elution, EtOAc: 1H, J=12.6 Hz), 5.79 (d. 1H, 12.6 Hz), 7.41-7.54 (m, 6H), EtOH20:1, 15:1, 10:1) to furnish the bistrimethylsilyl dimer 7.88 (d. 1H, J–8.7 Hz), 8.03 (dd. 1H, J=8.7 Hz, J-2.1 Hz), 92 (DMH-D-048, 680 mg, 60.8%) as a white solid: mp 8.47 (s, 1H); MS (EI) m/e (rel intensity) 381 (M", 20), 383 10 169-172° C.; IR (KBr)3449,2950, 1725, 1720, 1715, 1496, (19). 1250, 1160, 1080, 847 cm; H NMR (300 MHz, CDC1) 1,3-Bis(8-bromo-6-phenyl-4H-benzofimidazo 1.5-a1, 8 0.25 (s, 18H), 2.35 (m, 2H), 4.05 (d. 2H, J=12.6 Hz), 4.55 4diazepine-3-carboxy) propyl diester 91 (DMH-D-070). (m, 4H), 6.02 (d. 2H, J=12.6 Hz), 7.37 7.55 (m, 14H), 7.75 The carboxylic acid 27 (2 g, 5.2 mmol) was dissolved in (dd, 2H, J=1.8 Hz, 8.4 Hz), 7.94 (s. 2H); 'C NMR (75.5 DMF (20 mL), after which CDI (1.02 g, 6.3 mmol) was 15 MHz, CDC1) 8 -0.3, 28.3, 44.9, 61.4, 97.4, 102.3, 122.4, added at rt and the mixture was stirred for 2 h. Then 122.6, 128.0, 128.3, 129.0, 129.4, 130.5, 134.1, 134.9, 1,3-propanediol (0.19 mL, 2.6 mmol) and DBU (0.78 mL, 135.1, 139.0, 139.2, 139.2, 162.6, 168.5: MS (FAB, NBA) 5.2 mmol) were added to the mixture and stirring continued m/e (rel intensity) 839 (M"+1, 100); Anal. Calcd. For overnight. The reaction Solution was then cooled with an CHNOSi: C, 70.14; H, 5.53: N, 10.02. Found: C, ice-water bath, after which water was added to precipitate a 69.97; H, 5.35; N, 9.77. solid. This material was purified further by flash chroma 1,3-Bis(8-acetylenyl-6-phenyl-4H-benzofimidazo 1.5- tography on silica gel (gradient elution, EtOAc:EtOH 20:1, a 1,4-diazepine-3-carboxy) propyl diester 93 (DMH-D- 15:1, 10:1) to provide the bisbromide 91 (DMH-D-070) as 053).7 a white solid (1.3 g, 61.9%); mp 187.5–189° C.; IR (KBr) A solution of bistrimethylsilyl dimer 92 (330 mg, 0.4 mmol) 3112, 2968, 1708, 1610, 1559, 1491, 1269, 1160, 1123, 1073 25 in THF (70 mL) was stirred with tetrabutylammonium cm'; H NMR (300 MHz, CDC1) & 2.35 (m, 2H), 4.08 (d. fluoride hydrate (250 mg, 0.96 mmol) at -78°C. for 5 min. 2H, J–12.6 Hz), 4.55 (m, 4H), 6.05 (d. 2H, J=12.6 Hz), After this, HO (35 mL) was added to the solution to quench 7.37 7.53 (m, 12H), 7.6 (d. 2H, J=2.1 Hz), 7.81 (dd, 2H, the reaction and stirring continued at low temperature for J=2.1 Hz, 8.6 Hz), 7.93 (s. 2H); 'C NMR (75.5 MHz, one half hour. The solution was extracted with EtOAc CDC1) & 28.2, 44.9, 61.4, 120.7, 124.2, 128.3, 129.0, 129.3, 30 129.6, 130.6, 134.1, 1344, 134.7, 135.0, 138.9, 138.9, (3x100 mL), and the organic layer was washed with water. 162.6, 167.9; MS (FAB, NBA) m/e (rel intensity) 803 After removal of the solvent under reduced pressure, ethyl (M"+1, 15); Anal. Calcd. For CHNOBr: C, 58.23; H, ether was added to the residue to precipitate a solid. The 3.51; N, 10.45. Found: C, 57.92; H, 3.43; N, 10.29. mixture was filtered and the solid was washed with CHC1 1,3-Bis(8-trimethylsilylacetylenyl-6-phenyl-4H-benzof 35 EtO (ca 1:15), the bisacetylenyl dimer 93 (DMH-D-053, imidazo 1.5-a 1,4-diazepine-3-carboxy) propyl diester 92 220 mg, 80%) was obtained as a yellow solid: mp 172–175° C.; IR (KBr) 3450, 3280, 2950, 1720, 1715, 1495, 1250, (DMH-D-048).78 1120, 1050 cm; H NMR (300 MHz, CDC1,) & 2.35 (m, To a suspension of bisbromide 91 (1.005 g, 1.25 mmol) in 2H), 3.18 (s. 2H), 4.08 (d. 2H, J=12.3 Hz), 4.56 (m, 4H), acetonitrile (50 mL) and triethylamine (65 mL), was added 6.04 (d. 2H, J=12.6 Hz), 7.36 7.59 (m, 14H), 7.78 (dd, 2H, bis(triphenylphosphine)-palladium (II) acetate (0.15 g, 0.2 40 J=8.4 Hz, 1.7 Hz), 7.95 (s. 2H); 'C NMR (75.5 MHz, mmol). The solution was degassed and trimethylsilylacety CDC1) & 28.8, 45.4, 61.9, 80.2, 81.3, 121.4, 122.7, 128.1, lene (0.7 mL, 5 mmol) was added after which it was 128.3, 129.0, 129.3, 130.5, 134.2, 135.2, 135.3, 135.6, degassed again. The mixture was heated to reflux and 138.9, 139.2, 162.6, 168.5: MS (FAB, NBA) m/e (rel stirring maintained overnight. After removal of the solvent intensity) 695 (M+1, 100).

27 --1,5-pentanediol DBU O O N N J/ O O \- O O HerEtN, CHCN Br eN Ns- B reflux O 94 (dim-II-26) US 7,119,196 B2 69 70

-continued

or's TBAFoxH2O, THF OO eN is 95 (dim-II-41)

2 H CCO Ois 96 (dim-III-97)

The 5-carbon linker bisbromide 94 (dim-II-26), bis-trim 1.5-Bis(8-trimethylsilylacetylenyl-6-phenyl-4H-benzof ethylsilylacetylenyl dimer 95 (dim-II-41) and bisacetylene imidazo 1.5-a 1,4-diazepine-3-carboxy) pentyl diester 95 dimer 96 (dim-II-97), which are analogues of dimers DMH 45 (dim-II-41). D-070, DMH-D-048 and DMH-D-053, respectively, were A yellow solid (58.1%): mp 154–156° C.; IR (KBr) 3426, prepared from acid 27 under the same conditions employed 2955, 1727, 1720, 1612, 1495, 1251, 1174, 1076, 846 cm; for preparing dimers 91 (DMH-D-070), 92 (DMH-D-048) H NMR (300 MHz, CDC1) & 0.25 (s, 18H), 1.63(m, 2H), and 93 (DMH-D-053), respectively, by using 1,5-pen 1.90 (m, 4H), 4.05 (d. 2H, J=12.6 Hz), 4.39 (m, 4H), 6.03 (d. tanediol in place of 1,3-propanediol (Scheme 19). 50 2H, J=12.6 Hz), 7.40 7.54 (m, 14H), 7.75 (dd, 2H, J=1.8 Hz, 8.4 Hz), 7.93 (s. 2H); C NMR (75.5 MHz, CDC1) & 1.5-Bis(8-bromo-6-phenyl-4H-benzofimidazo 1.5-a1, -0.3, 22.5, 28.4, 44.9, 64.5, 97.4, 102.3, 122.4, 122.6, 128.0, 4diazepine-3-carboxy) pentyl diester 94 (dim-II-26). 128.3, 129.2, 129.4, 130.5, 134.1, 135.0, 135.1, 135.1, 138.9, 139.3, 162.8, 168.5: MS (FAB, NBA) m/e (rel A yellow powder (63.2%); mp 172–175° C.; IR (KBr) 3112, 55 intensity) 867 (M1, 100). 2970, 1721, 1609, 1490, 1267, 1158, 1075, 754, 697 cm; 1.5-Bis(8-acetylenyl-6-phenyl-4H-benzofimidazo 1.5- "H NMR (300 MHz, CDC1,) & 1.62 (m, 2H), 1.90 (m, 4H), a 1,4-diazepine-3-carboxy) pentyl diester 96 (dim-III-97). A 4.07 (d. 2H, J=12.6 Hz), 4.39 (m, 4H), 6.05 (d. 2H, J=12.6 yellow solid: mp 150–153° C.; IR (KBr) 3290, 2953, 1718, Hz), 7.37 7.53 (m, 12H), 7.58 (d. 2H, J=2.1 Hz), 7.78 (dd, 1611, 1493, 1253, 1172, 1120, 1076 cm; H NMR (300 60 MHz, CDC1)ö 1.62 (m, 2H), 1.90 (m, 4H), 3.18 (s. 2H), 2H, J=2.1 Hz, 8.6 Hz), 7.92 (s. 2H); 'C NMR (75.5 MHz, 4.07 (d. 2H, J=12.3 Hz), 4.38 (m, 4H), 6.04 (d. 2H, J=12.3 CDC1) & 22.5, 28.4, 44.9, 64.5, 120.7, 124.2, 128.3, 129.2, Hz), 7.36 7.58 (m, 14H), 7.77 (dd, 2H, J=8.4 Hz, 1.6 Hz), 129.3, 129.6, 130.6, 134.0, 134.5, 134.6, 135.0, 138.8, 7.94 (s. 2H); 'C NMR (75.5 MHz, CDC1,) & 22.5, 28.4, 138.9, 162.8, 167.9; MS (FAB, NBA) m/e (rel intensity) 831 44.9, 64.5, 79.8, 81.3, 121.3, 122.7, 128.1, 128.3, 129.2, (M+1, 5). Anal. Calcd. For CHNOBr.0.25H2O: 65 129.3, 130.5, 134.1, 135.2, 135.3, 135.6, 138.8, 139.2, C, 58.95; H, 3.89; N, 10.07: Found: C, 58.69; H, 3.74; N, 162.8, 168.5: MS (FAB, NBA) m/e (rel intensity) 723 9.70. (M"+1, 13). US 7,119,196 B2 71 72

27 Hediethylene glycol DBU O ClN (HC)Si-E-H Pd(OAc)2(PPh3)2 -> EtN, CHCN co s B reflux

97 (dim-III-93) O O J/ C TBAFoxH2O, THF He r N-1N -78° C. 2 eN COs (H3C)Si

98 (dim-III-94) O r N-1 no ClN Cy - 99 (dim-III-96)

50 In order to improve the water solubility of the dimers, the 129.6, 130.6, 134.1, 1344, 134.6, 135.0, 138.9, 139.0, oxygen-containing 5-atom linked dimers 97 (dm-III-93), 98 162.5, 167.9; MS (FAB, NBA) m/e (rel intensity) 833 (dm-II-94) and 99 (dim-II-96), were designed and prepared (M*--1, 5). from acid 27 under the same conditions employed for Bis(8-trimethylsilylacetylenyl-6-phenyl-4H-benzofimi preparation of dimers DMH-D-070, DMH-D-048 and DMH-D-053, respectively, by replacing 1,3-propanediol 55 daZo 1.5-a 1.4 diazepine-3-carboxy) diethylene glycol with diethylene glycol (Scheme 20). diester 98 (dm-II-94). Bis(8-bromo-6-phenyl-4H-benzofimidazo 1.5-a 1.4 A yellow solid (49.5%); mp 205-208° C.; IR (KBr) 3433, diazepine-3-carboxy) diethylene glycol diester 97 (dim-III 2960, 1730, 1700, 1612, 1493, 1255, 1169, 1120, 1071,847 93). 60 cm; H NMR (300 MHz, CDC1,) & 0.25 (s, 18H), 3.93 (t, A yellow solid (93.7%); mp 165–168° C.; IR (KBr) 3060, 4H, J–5.4 Hz), 4.04 (d. 2H, J=12.6 Hz), 4.55 (m, 4H), 6.04 2956, 1725, 1610, 1558, 1491, 1267, 1161, 1123, 1074 (d. 2H, J=12.6 Hz), 7.37 7.53 (m. 14H), 7.74 (dd, 2H, J=1.2 cm': "H NMR (300 MHz, CDC1,) & 3.93 (t, 4H, J=4.8 Hz), Hz, 8.4 Hz), 7.91 (s. 2H); 'C NMR (75.5 MHz, CDC1,) & 4.06 (d. 2H, J=12.6 Hz), 4.54 (m, 4H), 6.05 (d. 2H, J=12.6 -0.3, 45.0, 63.6, 69.0, 97.5, 102.4, 122.5, 122.7, 128.1, Hz), 7.39 7.50 (m, 12H), 7.57 (d. 2H, J=2.7 Hz), 7.80 (dd, 65 128.3, 129.0, 129.4, 130.5, 134.2, 135.0, 135.1, 135.2, 2H, J=2.1 Hz, 8.4 Hz), 7.90 (s. 2H); 'C NMR (75.5 MHz, 139.1, 139.3, 162.7, 168.6; MS (FAB, NBA) m/e (rel CDC1) & 44.9, 63.6, 69.0, 120.7, 124.2, 128.3, 129.0, 129.3, intensity) 869 (M"+1, 100).

US 7,119,196 B2 75 76 stituent at C(8) with a 6-phenyl group (alprazolam number -continued ing system). For example, we claim any benzodiazepine O N structurally related to analogs (and other related compounds) to diazepam, alprazolam, medazolam, and triazolam in ?J/ o-r which the C(7) or C(8) substituent has been replaced with an acetylene or trimethylsilylacetylene substituent. -BuNFenH2O 2 eN l THF

Ns e 10 / \ N Nu 105 (Hz165) 15

O r N

2 reeN 25 COEt(R") e N ) N

30 106 (Hz166)

The benzodiazepine 100 (bromazepam) was reacted with diethylphosphorochloridate, followed by the addition of ethyl isocyanoacetate to provide the ester 104. This was then 35 reacted with trimethylsilyacetylene in the presence of a palladium catalyst to provide trimethylsilyl analog 105 7. (HZ165) which was subjected to fluoride-mediated desily 6 lation to furnish analog 106 (HZ166). 8-Trimethylsilylacetylenyl-6-pyridin-2-yl-4H-benzof 40 imidazo 1.5-a1,4diazepine-3-carboxylic acid ethyl ester 105 (HZ165). Trimethylsilyacetylenyl analog 105 (HZ165) was obtained in 73% yield from 104 analogous to the procedure employed in 0047 as a white solid. mp: 205 206° C.; H NMR (300 MHz, CDC1) & 0.25 (s, 9H), 45 1.44 (t, 3H, J–7.1 Hz), 4.14 (d. 1H, J–11.0 Hz), 4.44 (In, 2H), 6.11 (d. 1H, J=10.9 Hz), 7.38 (ddd, 1H, J=7.5, 4.8, 1.1 Hz), 7.51 (s, 1H), 7.54 (d. 1H, J=8.4 Hz), 7.74 (dd, J=8.3, 1.8 Hz), 7.83 (td, 1H, J=7.7, 1.7 Hz), 7.93 (s.1H), 8.05 (m. 1H), 8.61 (m, 1H). 50 8-Acetylenyl-6-pyridin-2-yl-4H-benzofimidazo 1.5-a 1,4-diazepine-3-carboxylic acid ethyl ester 106 (HZ166). The 7-acetyleno analog 106 (HZ166) was obtained in 98% yield from 105 analogous to the procedure employed in 0048 as a white solid. mp: 243–244° C.; H NMR (300 55 MHz, CDC1,) & 145 (t,3H, J=7.1 Hz), 3.17 (s, 1H), 4.17 (d. 1H, J=10.0 Hz), 4.45 (m, 2H), 6.13 (d. 1H, J=10.4 Hz), 7.38 (ddd, 1H, J–7.5, 4.8, 1.1 Hz), 7.56 (d. 1H, J=8.2 Hz), 7.58 (s, 1H), 7.77 (dd. 1H, J=8.6, 1.8 Hz), 7.83 (td, 1H, J=7.7, 1.8 60 Hz), 7.93 (s, 1H), 8.08 (m. 1H), 8.59 (m. 1H). Generally, we contemplate all analogs of 1–4 above with Some exemplary compounds falling under the scope of X-F, Cl, Br, NO, and/or R"=CH, isopropyl, 1-butyl, isox the present invention are as follows: azoles. Also, all analogs of R-C=C- with R=t-butyl, In general, any 1,4-benzodiazepine with a 5-phenyl-like isopropyl, cyclopropyl. We believe that replacement of the substituent in which C(7) has been replaced with an acety 65 halogen atom in 1,4-benzodiazepines or the related triazolo lene substituent or a trimethylsilyl acetylene substituent or 1,4-benzodiazepines at C(7) or C(8) generally results in any triazolo benzodiazepine that has a corresponding Sub anxiolytic activity with greatly decreased sedative/hypnotic/

US 7,119,196 B2 81 82

-continued -continued CH O 9 N CH 5 Ocoy 2 O eN MCH3 2 C N 21 R (U) R O 10 ( ) O NHCH O seN 15 O 2 N R C R O 2O O O t O t O 25 N N O 2^ FN 2 N 30 R R O O H3C

H O 35 N - N / 2 FN 40 2 FN R C R

45 O O

O COOKoKOH O COOCHs 50 2^ FN 2^ o N

R R F 55 O CH 9 N

2 FN F US 7,119,196 B2 83 84

-continued -continued US 7,119,196 B2 85 86

-continued -continued

R = Hor R = (CH3)Si 15

25 st O 30 2 FN 35 R 21 NN N 40

CH 9 N 45

OH 2^ FN 4 NN 50 N

55 CH N

65 US 7,119,196 B2 87 88 from death. The data were analyzed by Chi Square statistics. -continued The significance level was set at p-0.05. HC Protection from Electroshock-Induced Seizures 3 N-yN Male CF1 mice weighing 20–22 g at the time of the N-N / experiment were purchased from Charles River Laboratories (Wilmington, Mass.). Electroshock is administered using a Ugo Basile ECT, Unit 7801 seizure apparatus (Ugo Basile, 2 FN Italy) and corneal electrodes soaked in 0.9% saline. Mice 10 received a shock of 30 mA for 0.3 seconds. Drug Admin R C istration: All experimental compounds were administered PO 60 minutes before administration of electroshock. Data Analysis: The data are presented as the percent of animals protected from the hind-limb extensor component of the seizure. The data were analyzed by Chi Square statistics. 15 The significance level was set at p-0.05. Experimental Methods Open-Field Locomotor Activity in Rats Situational Anxiety Model in Rats Male Sprague-Dawley rats, weighing 250–290 grams at Male Sprague-Dawley rats weighing 180–200 grams the beginning of the experiment were purchased from were purchased from Charles River Laboratories (Wilming Charles River Laboratories (Wilmington, Mass.). The ani ton, Mass.). The rats were housed individually in suspended mals were housed in groups of four in a colony room wire cages in a colony room maintained at constant tem maintained at constant temperature (21+2°C.) and humidity perature (21+2°C.) and humidity (50+10%). The room was (50+10%). The room was illuminated 12 hours per day illuminated 12 hours per day (lights on at 0600 h). The rats (lights on at 0600h). The rats had ad libitum access to food had ad libitum access to food and water throughout the 25 and water. The testing apparatus consisted of plexiglas study. Behavioral studies were conducted between 0600 and chambers (42x42x30 cm) equipped with Digiscan activity 1300 hours. Testing: A modification of the Defensive With monitors (Omnitech Electronics, Columbus, Ohio) that drawal procedure, as originally described by Takahashi et al. detect interruptions of 16 photobeams spaced 2.5 cm apart (1989), was employed. The testing apparatus consisted of an and 2.5 cm above the floor. Horizontal activity was moni opaque plexiglass open field (106 cm lengthx92 cm width:X 30 tored for 60 minutes. Drug Administration: All drugs were 50 cm height), containing a cylindrical galvanized chamber administered PO 20-60 minutes before behavioral testing. (14 cm length, 10 cm diameter) that was positioned length Data Analysis: Results were expressed as the mean+1 SEM. wise against one wall, with the open end 40 cm from the All data were subjected to analysis of variance (ANOVA) corner. The open field was illuminated by a 60 watt incan followed by individual mean comparisons using Fisher's descent bulb, and illumination was titrated by a powerstat 35 Least Significant Difference Test (Kirk, 1968) where appro transformer to a 23 lux reading at the entrance to the priate. The significance level was set at p-0.05. cylinder. Rats were habituated to handling by gently strok Rotorod Performance in Rats ing their dorsal Surface for approximately one minute daily Male Sprague-Dawley rats, weighing 180–200 grams at for 5–6 consecutive days before testing. To initiate testing of the beginning of the experiment were purchased from exploratory behavior in this unfamiliar environment, each 40 Charles River Laboratories (Wilmington, Mass.). The ani rat was placed within the cylinder, which was then secured mals were housed in groups of four in a colony room to the floor. Behavior was assessed for 15 minutes by a maintained at constant temperature (21+2°C.) and humidity trained observer (unaware of treatment assignment) via a (50+10%). The room was illuminated 12 hours per day Video monitor in an adjacent room. The latency to emerge (lights on at 0600h). The rats had ad libitum access to food from the cylinder, defined by the placement of all four paws 45 and water. The degree of muscle coordination or balance into the open field, was recorded for each rat. After testing (i.e., ataxia) was determined using a standard accelerating each rat, the plexiglass chamber and the cylinder were rotorod treadmill (Ugo Basile, Comerio-Varese, Italy or cleaned with 1.0% glacial acetic acid to prevent olfactory Columbus Instruments, Columbus, Ohio) that was 6 cm in cues from influencing the behavior of subsequently tested diameter, 24 cm above the base, and run from an initial rats. Drug Administration: All drugs were administered PO 50 speed of 2 rpm to a maximum speed of 20 rpm. The time 20–60 minutes prior to behavioral testing. Data Analysis: each animal remained on the rotating rod was automatically Results were expressed as the Mean+1 SEM. All data were recorded, up to a maximum of 5 minutes. Each rat had three subjected to analysis of variance (ANOVA) followed by pretest acclimation trials, and the latency from the third trial individual mean comparisons using Fisher's Least Signifi was used to counterbalance rats for Subsequent drug testing. cant Difference Test (Kirk, 1968) where appropriate. The 55 Drug Administration: All drugs were administered PO significance level was set at p-0.05. 20–60 minutes before behavioral testing. Data Analysis: Protection from Pentylenetetrazole-Induced Seizures Results were expressed as the meant1 SEM. All data were subjected to analysis of variance (ANOVA) followed by Male CF1 mice weighing 20–22 g at the time of the individual mean comparisons using Fisher's Least Signifi experiment were purchased from Charles River Laboratories 60 (Wilmington, Mass.). Pentylenetetrazole (Sigma Chemical cant Difference Test (Kirk, 1968) where appropriate. The Co.) was administered at 125 mg/kg, s.c. The number of significance level was set at p-0.05. animals surviving was recorded at 30 minutes and 60 Discriminative Stimulus Effects of Chlordiazepoxide in Rats minutes after administration of pentylenetetrazole. Drug Male Sprague-Dawley rats weighing 240 to 300 g at the Administration: All drugs were administered PO 60 minutes 65 start of the experiment were purchased from Charles River before administration of pentyenetetrazole. Data Analysis: Laboratories (Wilmington, Mass.). Animals were housed The data are presented as the percent of animals protected singly in hanging wire cages in a room maintained at US 7,119,196 B2 89 90 constant temperature (21–23°C.) and humidity (50+10%) with lowest effective doses producing side effects in three and illuminated 12 hours per day (lights on at 0600 h). different models: locomotor activity (LMA), rotorod (RR), Throughout the study rats were restricted to 12 g of labo and chlordiazepoxide-like subjective effects as measured by ratory rodent chow pellets (Bio-Serv, Frenchtown, N.J.) per the drug discrimination method (DD). day, while access to water was unlimited. All training and Table 2 (below) shows effective doses in a model of testing was done Monday through Friday of each week. epilepsy (pentylenetetrazole-induced seizures) in mice (mg/ Twelve model E10-10 Coulbourn operant chambers (28x kg, PO) for QH-ii-066, Xli-JY-DMH, and XHe-ii-053 in 26x31 cm) were housed in light-proof, sound-attenuated, comparison with diazepam, triazolam, and DM-i-070. and fan-ventilated chambers. Each operant chamber was equipped with two non-retractable levers, requiring a down 10 EXAMPLE 1. ward force equivalent to 15 g (0.15 N), that were mounted 3 cm from the side wall, 3 cm above the metal grid floor, and Situational Anxiety in Rats 5 cm from a centrally placed dipper that delivered one 45 mg food pellet (Dustless Precision Pellets, Bio-Serv, French Rats were handled daily for at least 5–6 days. They were town, N.J.). The experimental chambers were connected to 15 then placed in a dark cylinder in an illuminated open field. a Micro PDP11/73 computer using a LAB LINC interface. The time for the rats to exit the dark cylinder was then A SKED-11 operating system (State System, Kalamazoo, measured. Vehicle-treated animals remain within the dark Mich.) was used to record and control behavior. Discrimi cylinder for 10–15 minutes (total test duration is 15 min nation training: After habituation to the operant chamber, utes). This high latency to exit the dark chamber is an index rats were trained to alternate daily between response levers of a heightened State of anxiety. Compounds with anxiolytic on a Fixed Ratio 1 (FR 1) schedule of reinforcement. Once efficacy reduce latency to exit the dark chamber. Table 1 lever pressing was well established, the reinforcement con shows that QH-i-066, XLi-JY-DMH, and XHe-ii-053 show tingency was increased incrementally to an FR 10 schedule, anxiolytic effects in the situational anxiety test at doses while maintaining the lever alternation. Next, rats were >100-fold lower than doses producing sedative and ataxic trained to discriminate between drug (5.0 mg/kg, IP, chlor 25 effects (see examples 2 and 3). diazepoxide) and drug vehicle (0.9% saline). Half of the rats were randomly assigned the left lever as “drug-correct” and EXAMPLE 2 the right lever as "saline-correct.” The lever assignments were reversed for the remaining animals. Every tenth Locomotor Activity in Rats response on the drug-correct lever was reinforced on days 30 when the rats were pretreated with drug, whereas every tenth Rats were placed in an open field and the total distance response on the opposite lever was reinforced after saline covered by the rat was measured. The test duration was 60 injections. In each 2-week period there were 5 drug days and minutes. Compounds producing sedative effects decrease 5 saline days, with the constraint that there not be more than the distance covered. Table 1 shows that QH-ii-066, XLi 3 consecutive drug or vehicle days. Discrimination sessions 35 JY-DMH, and XHe-ii-053 are less effective in producing were continued until each rat reached the criterion of no sedative or hypnotic effects than diazepam or triazolam. more than three incorrect responses before first food pre sentation in 9 out of 10 consecutive sessions. Test sessions: EXAMPLE 3 Once criterion for testing was met, stimulus Substitution tests were conducted on Friday of each week. Test sessions 40 Rotorod Performance in Rats were 10 minutes in duration. During the test sessions, the lever on which the rat first responded 10 times resulted in Rats were placed on a slowly rotating rod and the speed reinforcement and subsequent FR 10 reinforcement was of rotation was gradually increased. The time on the rod for made contingent upon pressing this “selected' lever. The each rat was recorded. Compounds producing ataxia (motor lever on which the rat first made 10 responses (the selected 45 incoordination) decrease the time spent on the rod compared lever) and the total number of responses in the session were with vehicle-treated animals. Table 1 shows that QH-ii-066, recorded. On Monday through Thursday of each week, XLi-JY-DMH, and XHe-ii-053 are less potent in producing training sessions were conducted to ensure that criterion for ataxia than diazepam or triazolam. Thus, they are likely testing was met. If any rat failed to meet the criterion for better drugs clinically because they have decreased side testing, testing with that animal was postponed and discrimi 50 effects decreased sedation (example 2) and ataxia (example nation training continued until the performance criterion was 3). attained. Data analysis: Drug discrimination results are expressed as the percentage of animals selecting the chlor EXAMPLE 4 diazepoxide-correct lever. REFERENCES 55 Drug Discrimination in Rats Kirk RE (1968) Experimental Design: Procedures for the Animals are taught to emit one response if they just Behavioral Sciences. Brooks/Cole, Belmont, Calif. received drug and a different response if they just received Takahashi L. K. Kalin NH, Vanden Burgt JA, Sherman J E saline. The animals learn to discriminate between a "drug 60 state' and a “no drug state'. The rats were trained to (1989) Corticotropin-releasing factor modulates defen discriminate between a state induced by a typical benzodi sive-withdrawal and exploratory behavior in rats. Behav azepine chlordiazepoxide (CDP; "drug state') and a state Neurosci 103:648-654 induced by vehicle (methocel: “no drug state'). Table 1 Experimental Results shows that QH-ii-066, XLi-JY-DMH, and XHe-ii-053 are 65 less potent in producing CDP-like effects than diazepam or Table 1 (below) shows ratios of lowest effective anxi triazolam and thus may have reduced abuse potential com olytic doses in the situational anxiety (SA) assay compared pared with CDP. US 7,119,196 B2 91 92 EXAMPLE 5 15. G. A. Archer and L. H. Sternbach, J. Org. Chem., 29, 231 (1964). Seizure Protection in Mice 16. Fryer, R. I. Zhang, P.; Rios, R. Synth. Commun. 1993, 23,985-992. Mice treated with certain compounds of the present 5 17. U.S. Pat. No. 3,886,141, 1975. invention were subjected to pentylenetetrazole (PTZ) at 125 mg/kg to induce seizures. The percent of animals protected The invention claimed is: from death within one hour of PTZ was measured. Table 2 1. A compound of formula V. or a salt thereof, shows that QH-ii-066 and XLi-JY-DMH have anticonvul sant effects against PTZ-induced seizures at doses compa 10 rable to those for diazepam and triazolam. Table 2 also (V) shows that XHe-ii-053 is effective against PTZ-induced seizures.

TABLE 1. 15 Antianxiety. Antianxiety. Antianxiety abuse sedation ataxia liability Diazepam 10 100 5 QH-ii-066 100 >100 30 Triazolam 3OO 100 30 XL-Y-DMH 1OOOO 1OOOO 1OOO wherein: DM-1-070 >1OO >100 10 Y and Z are taken together with the two intervening XHe-ii-053 >3OO >300 >300 carbon atoms to form a phenyl ring, which is Substi tuted at the C(8) position with at least the substituent 25 —C=C R, where R is H. Si(CH), t-butyl, isopropyl, TABLE 2 methyl, or cyclopropyl;

PTZ Seizures R is one of H, CH, CF, CHCF, CHCH, CHC=CH, (mg/kg, PO or cyclopropyl; R is a substituted or unsubstituted at least partially Diazepam &10 30 unsaturated 5 membered or 6 membered carbocyclic QH-ii-066 &30 Triazolam <1.0 ring or 5 membered or 6 membered heterocyclic ring XL-Y-DMH <1.0 having at least one heteroatom selected from N, O and DM-1-070 &1OO S, wherein if substituted the substituent is one or more XHe-ii-053 is 100 of F, Cl, Br, or NO, at the 2'-position; 35 Rs is a branched or straight chain C to Chalogenated or unhalogenated alkyl or a methyl cyclopropyl. REFERENCES 2. A compound of formula VI, or a salt thereof,

1. Sternbach, L. H.; Fryer, R. I.; Metlesics, W.; Reeder, E.; 40 Sach, G.; Saucy, G.; Stempel, A.J. Org. Chem. 1962, 27. (VI) 3788 3796. 2. Gu, Q.: Wang, G.; Dominguez, C.: Costa, B. R.; Rice, K. C.; Skolnick, P. J. Med. Chem. 1993, 36, 1001-1006. 3. Ning, R.Y.; Fryer, R. I. Madan, P. B.; Sluboski, B. C. J. 45 Org. Chem. 1976, 41, 2724–2727. 4. Liu, R.; Zhang, P.; Skolnick, P.; McKernan, R.; Cook, J. M. J. Med. Chem. 1996, 39, 1928-1934. 5. Austin, W. B.: Bilow, N.; Kelleghan, W. J.; Lau, K. S. Y. J. Org. Chem. 1981, 46, 2280–2286. 50 6. Sternbach, L. H.; Reeder, E.; Archer, G. A. J. Org. Chem. 1963, 28, 2456 2459. wherein: . He, X. Ph.D. Thesis, UW-Milwaukee, 2000. Y and Z are taken together with the two intervening . Heck, R. F. Palladium Reagents in Organic Synthesis: carbon atoms to form a phenyl ring, which is Substi Academic Press, Orlando, Fla.: Academic Press, 1985. 55 tuted at the C(8) position with at least the substituent 9. Bogatskii, A. V.; Andronati, S. A.; Vikhlyaev, Yu. I.: —C=C R, where R is H, Si(CH), t-butyl, isopropyl. Voronina, T. A.; Yakubovskaya, L. N.; Behko, A. V. methyl, or cyclopropyl; Pharm. Chem. J. (Engl. Transl.) 1977, 11, 1520–1525 R is one of H, CH, CF, CHCH, CHCF, or cyclo 10. Vejdelek, Zdenek; Protiva, Miroslav. Collect. Czech. propyl; Chem. Commun. 1983, 48, 1477–1482 60 R is a substituted or unsubstituted at least partially 11. Hester, J. B. Ludens, J. H.; Emmert, D. E.; West, B. E. unsaturated 5 membered or 6 membered carbocyclic J. Med. Chem. 1989, 32, 1157-1163. ring or 5 membered or 6 membered heterocyclic ring 12. Fryer, R.I.; Kudzma, L. K. Gu, Z. Lin, K.J. Org. Chem. having at least one heteroatom selected from N, O and 1991, 56, 3715. 3719. S, wherein if substituted the substituent is one or more 13. Patent, Hoffmann-LaRoche, 1963, DE 1145625. 65 of F, Cl, Br, or NO at the 2'-position; 14. Patent, Hoffmann-LaRoche, 1958, U.S. Pat. No. 2,893, R is a branched or straight chain C to C alkyl or a 992. methyl cyclopropyl. US 7,119,196 B2 93 94 3. A compound of formula IX, or a salt thereof, Y" and Z are taken together with the two intervening carbon atoms to form a phenyl ring, which is Substi tuted at the C(8)' position with at least the substituent (IX) —C=C R', where R is H, Si(CH), t-butyl, isopropyl, R 5 methyl, or cyclopropyl; R and R' are independently one of H, CH, CF, CHCH, CHCF or cyclopropyl; R and R are independently a Substituted or unsubsti tuted at least partially unsaturated 5 membered or a 6 Y. ra Yi 10 membered carbocyclic ring or 5 membered or 6 mem bered heterocyclic ring having at least one heteroatom selected from N, O and S, wherein if substituted the D. C. substituent is one or more of F, Cl, Br, or NO at the 2'-position; wherein: 15 B is O or NH and wherein —BCH-B is optionally n is 0 to 4: replaced with —N(R) N(R)—, where R is one of Y and Z are taken together with the two intervening H, CH, alkyl, or cycloalkyl. carbon atoms to form a phenyl ring, which is Substi 5. A compound of formula XI, or a salt thereof, tuted at the C(8) position with at least the substituent —C=C R, where R is H, Si(CH), t-butyl, isopropyl, 2O methyl, or cyclopropyl; (XI) Y" and Z are taken together with the two intervening R N N R carbon atoms to form a phenyl ring, which is Substi / CO in B in OC \ tuted at the C(8)' position with at least the substituent 25 Y. N N Y! —C=C R', where R is H. Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl; R and R' are independently one of H, CH, CF, Z eN NS Z. CHCF, CHCH, or cyclopropyl; R and R' are independently a Substituted or unsubsti 30 R2 R" tuted at least partially unsaturated 5 membered or 6 membered carbocyclic ring or 5 membered or 6 mem bered heterocyclic ring having at least one heteroatom wherein: selected from N, O and S, wherein if substituted the n is 1 or 2 substituent is one or more of F, Cl, Br, or NO at the 35 Y and Z are taken together with the two intervening 2'-position. carbon atoms to form a phenyl ring, which is Substi 4. A compound of formula X, or a salt thereof, tuted at the C(8) position with at least the substituent —C=C R, where R is H, Si(CH), t-butyl, isopropyl. methyl, or cyclopropyl; (X) 40 Y" and Z are taken together with the two intervening carbon atoms to form a phenyl ring, which is Substi R 2N N R tuted at the C(8)' position with at least the substituent Y. / co1YB-1Sp1\oc \ s —C=C R', where R is H, Si(CH), t-butyl, isopropyl. Y. N N Yi methyl, or cyclopropyl; 45 R and R' are independently one of H, CH, CF, CHCH, CHCF or cyclopropyl: Z eN C. R and R are independently a Substituted or unsubsti tuted at least partially unsaturated 5 membered or 6 R R.' membered carbocyclic ring or 5 membered or 6 mem 50 bered heterocyclic ring having a heteroatom selected wherein: from N, O and S, wherein if substituted the substituent Y and Z are taken together with the two intervening is one or more of F, Cl, Br, or NO at the 2'-position; carbon atoms to form a phenyl ring, which is Substi B is O, NH, or - N(R) N(R)—, where R is one of H, tuted at the C(8) position with at least the substituent CH, alkyl, or cycloalkyl. —C=C R, where R is H, Si(CH), t-butyl, isopropyl, methyl, or cyclopropyl; k k k k k UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7,119,196 B2 Page 1 of 53 APPLICATIONNO. : 10/402538 DATED : October 10, 2006 INVENTOR(S) : Cook et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Please delete title page and insert title page as attached Please delete column 1 line 1 through column 94 line 54 and insert column 1 line 1 through column 102 line 20 as attached

Signed and Sealed this Sixth Day of May, 2008 WDJ

JON. W. DUDAS Director of the United States Patent and Trademark Office

Page 2 of 53

12 United States Patent (a) Patent No.: US 7,119,196 B2 Cook et ai. (45) Date of Patent: Oct. 0, 2006 Amir Walse, et al., “Iriszolobenzo-sld Tria2.jottierodiazepines (54) ANXIoIYTICAGENES WITH RECE as potent Antagonists of Platelet Activating factor." tria of SEAVE, ANS) AFAXICEFFECTS edicipal Chetnistry. E998, pp. 239-3223, vol.34, 80. S. Aisei can Chemistry Society, Investors: James M. Cook, Wastefish Bay, Wi cititang.* Part one: A Chemical and Computer Assisted APPS (US), Qi Huang, McGipark, CA (US); to Pharacophore Receptor Models for GAB&alA Rector St. Xiaohui He, Sail:)iego, CA (JS); types: part Two: Predictive Models for ABAs Subtypes Wii. Xiosyati Li, Miwaukee, WI (US); comparative Molecu at Field Ataiysis," ISSERTATION, W Jiataming Yu, Princetoa, N: IS); Milwaukee, 1998, pp. 1-296, Fongmei Hau, Miwaukee, WI (US) Shu Yu, et al., "Stities in the Search for as Subtype Selective Agonists fix GABAaB2R Sites, "Medicin83 Certistry R&search, Assignee: Wisys Technology foliidation, iss, 1999, pp. 71-88, Birkhause Boston, Qi Huang, et al., “Pharmacophere Receptor vicdels for GABA a Madiscil, WiS R subtypes (ai B3y2, a3B3y2, and 2683y2) visa Comptehetisive Notice: Subject to any disclaimer, the tests of this Ligaad Mappias Approach," "I. Xei, Chelix,” 2009, PP. SS, American Chemical Society, pstent is extended of 8djusted under 35 xiii. He, et al., “Pharmacophore/8cceptcy Models ft (A& U.S.C. 54(h) by 198 days. Bzia:B3y2, a383y2 and a BSy2Recobinstitsubtypes, induced volune Analysis and Comparison to ai B$y, SB3y and asts Appl. No. 81402,538 subtypes,” “Drug Design and Discovers," 2099, pg. 13- 171, vv. 17, verseas Fubishes Associatics, Fied; Mar 28, 2803 Xiaxinife, studies of Molecular Pitamracophore R&ceptor Mod: els for si3AaB2R Subtypes: Chemical and Computer Assisted Prior blication Data Approach it search of Selective i.igrds for GAB&BER Sh, US 2004,238.2573 Al Apr. 29, 2004 types." DissERTARON, Liv-Milwaukee, 2000, pg. 1-508. Le soleu et al., "etermination of a PAF Attigrist Related U.S. Application. Data Pharmacophore Using Combined Molecula: Electrostatic oteiia and Molecular ?paghilicity Potential," ":rigiesign aidisciv provisiona: 8pplication No. 60,368,438, filed on M3), ery," 1994, pp. 49-36, vol. 2, Harwood Academic Polishers 28, 2002, b. Yu, et al., "sadies in Search of alpha2 Selective Ligards for it, C. GABAa3a, Receptor Subtypes. Part E. Evidcace for the Conse City 487/12 2006(3) vision of Pharmacophoric escitors for DS Sisypes", "vlei. R.S.C...... SS62 chem. Res. 3999, pp. 186-202, voi. 9, No. 3, Birkha:3cs, Boston. Bundgaard, ii., "Design of protrugs: Bioreversitile derivative3 for Field of Classification Search . 5-552 various functional groups arti cheritical exities,” p. 93 it See application file for complete search sistory. Bandgaard, Hei.esign of Prodrugs, $3sevief Science Publishers B.W., Amsterda $985, References Cited Chariboa Ji, et a, Ethyl kiiazepate: 4 prodrig fion the S. FENT DEMEN'S benzodiazepine series designed to issociate anxiolytic and sciative activities. Arzreisite:firschaig. 19853S(i93.3-7. 2.893,892 A 959 Siriac Cho, X.3, et al., Sequentially lattie water-Šible prodigs of 4,280,957 A. T98 Salse et a. alpraxian. J Med Chem. Aug. 1986, 29(8): 346.50, 4,439. A 8.983 Waser et al. Hat, K.Y., & Aridon, (ii., Targeted proding design to optirri2. 4,9536. A 9.99 Waset drug delivers, AAPS Pharisci. 2008, (1): -i, article 8, http: www.phanics.org. Mussiri, E., et al., Hydroxylation of three heriod:8:6311es it sits. J. Sarm Sti. Oct. 1985 18:14:32-3. simirroriple, E., et al., Scrazepam and oxazepam esters. Ely OREG: PAEEN'S SCCSEENES phobicity, hydrolysis rates and brain appearance. Afzines:- E. 32 S9. 1989 te:firschtig. E982:32:2):332-5. Eegyey, 2., e: ai Corugatigon of dihydrodiazepart ensitioners: W S. 2835. A metabolism, serum binding and haia receptor biasinsixperiests. sep, 15, 1980,36(9): 1031-2, Prinary Examiner-8ruck. Xife CEER PUBLICAEONS (74) Attorney, Agent, or Firm-iodirey & Kaha, S.C. camie G. Wemuth, Slolecular variators Sased oth isosterie Somali S. Srivastava Replacemests.” “The Practice of Medicinal Cienistry, 3998, pp. 2C3.237, Acadetti: regs Limited. {57) ABSTRACE c iusing, ct al., “Benz-fused Benzodiaspiries Euployed as topological Probes for the Study of Benzodiazepine gigg or by active benzodiazepine derivatives and their salts are sites." Meicinal Chemistry Research." 996, pp. 384-39, disclosed. These compounds and their salts have anxiolyte Bikase Bostol. an anticonvulsant activity with seduced sedative bypilotic Ruiyan iu, et al., “synthesis and Pharinacological roperties of Novel 8-substitutedlutidazobenzodiazepines: High-\finity, See auscle relaxantataxic effects. tive robes for as-Containing GABAA :exploss," . Med. Chen," 396, pp. 928-1934, Clairs, NY Drawings Page 3 of 53

i:S 7,139, 96 B2 1 1. ANXO3 ECAGENTS WHRE)CES receptor modulatory sites, axi is the site through whic: SEAVE AN ATAXEC EFFECTS benzodiazepine-based axiolytic drugs exert th&ir effect,

Before the closing of the GABA rexceptor gene family, the

CROSS-REFERENCE TO BELAEE) benzodiazepine binding site was historically $1shivided into APPICATOXS two sitypes, BENZODIAZEPINE1 and BENZOE):AZ

EENE2, on the basis of radio:igand binding studies on

This application clais is benefit of U.S. 3rovisional Pales: synaptosomal rat incanbranes, 'ihe BEN2O3);AZEPINE1

Appication No. 60,368,408 Siled Mar. 28, 2002. subtype has been shown to 8& phaisacoicgically equivalent

to a GABA receptor comprisiag the U. SLiunit is coabi STAEMENE RECARENG FEER ALLY 8.

:ation with a 3 subunit atti Y2. iiis is the most abundant SPONSORED RESEARC8 OR DEWELOPMEN: (ABA receptor subtype, a tail is believed to represen airlost

half of a: GABA receptors is the 8:ain, as stated. isis invention was 2.8de with Governinet support under Two other major populations are the X28232 and 332; NEM: grant aunter MH4685l. The Governaen: has cer. 3.273 Sabtypes. Together these constitute approximately a tain tights to this investion, s fi:Ether 35% of the total GABA receptor population. ;har

BACKGRC) JN3 ()3F HE INVENTION: inacologically this combination appears to be ex; siva)& it to

the BENZODIAZEPINE2 subtype as defined previously by

radioigand binding, although the SENZOD:AZEPINE2 The present invention relates to aciass of benzodiazepine subtype may also inchide certain g5-containing 5 type derivatives which possess anxiolytic activity with decreased sexdative, hypnotic, and ataxic side effects. asseublies. The physiologica: Fle of these subtypes has site Host frequently prescribed medication for treatmeat inichetto bee unclear because Bo sufficietty selective ago {farxiety disorders (such as pilobias, obsessive compulsive aists or antagonists were knowil, disorders) and seizure disorders are benzoiazepiles such as it is tow believed that agents acting as benzodiazepine diazepam (Valium), triazolam (Hacioli), midazola agonists at GAA foa, GABA fox3, accior GABAeS (Versed), crazepam. (Ativan), chloridiazepoxide (Liriuli, receptors, wil: possess desitable aaxciyilic properties. Co.;1- alprazolan (Xanax), and other benzodiazepine-based aedi pounds which are accusators of the benzodiazepine binding cations. However, these beinzodiazepine-based mexications site of the GABA receptar by acting as benzodiazepine have site effects such as drowsiness, sedation, motor inco E.gc.nists are referred io hereafter as "GABA receptor ordinatios), Eric mory inspilingnt, potentiation of effects of 30 agonists." The GABA fol-selective (cyl B223 againists alpi alcoho, ifierance and depeiaeace, and abuse potential. deri act 2.0lpiden are ci:icality prescribed as hypotic

BEEspirot, 3.IIdospirome, and other serotonergic agents have agents, Stiggesting that at cast solate of the Sciatics asso been developed as a1,xiolytics with a potentially reisced ciated with known anxiolytic strugs which act at title: 3EN profile of side effects. However, wixieties Baetications do 2ODIAZEPENE: binding site is neiated through GABA siaow a reduced profile of side effects, they have other 35 receptors containing the X: subunit. Accordingly, it is co characteristics which take them less that idea for treat sisterex that GABAfc.2, GA8 Aio.3, atci?or GABAct 5 IIIent of anxiety dis(3rders. in some cases, these agents cause receptor agexists rather than GABA to recepts will be 2:1%ity before a tietapcuti: dose cast be oktained or require effective it the treatmento: anxiety with a reduced propen

dosing of the drug for seveal days before a therapeutic sity to cause sedatio. For example, Qi-ii-866 incis with effect is seca. )evelopment of anxiolytics with even fewer 4) thigh afficity to GABAfc5 receptors (Kiai () aks, internac side effects is desire. diate affinity to GABAc2 and GABAf{y} {Ki-53 M), Receptors for the aajor inhibitory aerotransmitter, and lower afinity to GABA receptors (Ki>7) M3, gamma-aminobutyric acid (GABA), are 3ivitici into ihree unlike diazepin which binds with high a finity to all four It air casses: (1) GABA receptors, which are members of &azepan1-seasitive GABA recep?ors (Kiz25 &?), as dis the igsix-gated ion chamei superia:aily; (2) GABA recep- 45 closed its Huang, et al., J kied. Chen. 2000, 43, 7-95. tors, wiich may be members of the G-protein linked recep Assc, agents which 8re antagonists of is verse agonists at (l or superfamiyani (3) GABA receptors, also members of receptors night be eraployed to reverse sedation or hygosis the Eig&3d-gated ion channe: superian:ly, but their distribu caused by agoEtists. tion is confined to the retina. Benzodiazepine receptor Since the compounds of the present inverticit exhibit

ligards do not bind to GABA assi GABA receptors, Siace so increased agonist efficacy at only a few GABA types of

tle first cDNAs cacoding is dividua: GABA receptor sub receptors and/or selective eficagy at be or more ion chitti

units were ciorked the tufather of klow remiers of the reis and have been shown to be effective it animal models Baminatian as:ily has growa to 2 isci:cing (X, f, and Y of axxiety and seizu:res, with reduced severity and/or inci

subunits (6, 48, 4, 8, le. if, 8, and 3p}. deace of side effects, they are useful in the treatient and/or Subtype assemblies containing as Cal subunit (ca.1822) ss prevention of a variety of disorders of the central nervous

8te present in test areas of the brain &nd are thought to systeix. Such disorders include anxiety disorders, such as account for 48-50% of GABA receptors in the rat. Subtype pagic disorder with it without agoraphobia, age apicbia

assemblies containing c2 and Q3 subunits respectively are without history of panic disottier, animal and othcrphibias thought to account for about 25% aac. 17% GABA recep inclkiing social phobias, obsessive-compulsive disorder. tors in the rat. Subtypic assets::ies containing sn (5 subunit so general anxiety disorder, attentics deficit disqtders, stress (oS83y2) are expressed predicinitiately in the bippocampus disorders iscluding post-trauiatic and acute stress disoeder,

and cortex anxi are thought to represent about 4% of GABA and generalized or substance-induced anxiety disordes, ex

receptors in the rat. roses, convisions, aigraine, depressive 3 bipolar disor A characteristic property of all known GABA receptors ders, for exaltiple single episode or recurrent Rajor depres is 8xe prese:Ice of a number of acduatory sites, one of 65 sive disorder, dysthymic disorder, bipolar I and bipolar E.I. which is the benzodiazepine binding site. The benzodia. imanic disoriers, and cyclothymic disode, psychotic disor egie indig site is the aost expicted of the GABA ders :::cluding schizophiesia.

Page 4 of 53

US 7, 9,196 B2 4 3. wherein Y and Z are taken together with the two intetvetting SMARY OF EHE INVENTON carton atoms to form a ring selected from phenyl and thienyl, which ring is substituted at the C(7) position with at It consideration of this situatics, the probleak be solved east the substituent -CxC-R, where R is H, Si(OHsis by the present inventios is te provide a medication which t-styl, isopropyi, nethyl, or cyclopropy; R1 is one of , can be used for he treatmeist of anxiety neurosis, general CH, CHN(C.H.). CHCFCH.C. Ci, Crail aikyi anxiety disorder, panic disorder, phobias, obsessive-compil cyclopropyi; R. is a substituted or unsubstituted at least sive disorders, schizophrenia, post-cardiac trainia stress partially unsaturated 5 or 6 cabered cyclic or heteorcyclic (isorders, depression disorders, psychosomatic disorders, ing, wiereis if substituted the substituent is eteers' f and other psycionaliroic disciders, eating disorders, tero , , , Br, or NO, at the 2-position; and R, is one of H, OH, pausal disorders, infantile altisa aski other distiers, and OCON(CH, (OOCH, or COOC.H. Prefered c.18 also enesis with fewer side effects, pounds according to formula : include: be present inventists engaged in repeated extensive studies to develop a superior medicatios free from the above problems. They found that 3e conpounds of the pressilt invention, that is, the novel benzodiazepine derivatives and their saits, have beneficial pha:Tuacological and behavicial effects, that is, the coalpouncis of the reset: invention show anxiolytic and anticonvulsant activity with greaty decreases or no sedative hypnoticimuscle relaxantataxic side effects. ?ite compounds described in the present invertion have been synthesized based on a modified versio: if the cog piteriodicing disclosed in Cook, et ald Med. Chen, 996, 39, 1928-1934. These compounds obtaiased by stifying cements, described erein, of the kilowa bet:2Odiazepine agents, have increased binding selectivity or the GABA ca, Ag3A/o3, and/or GABAoS receptors described above, and or altered eificacy at one or more GABA receptors described agove, and for 3ltered selectivity atoire or more ion channels, These compounds, which have bell tested in animal models of 3nxiety is rats and seizures in mice, and side effect models in rais, have been found to be orally active and have anxiolytic aid anticovisast activity, sit reduced severity anior incidence of side effects. One object of the present invention is to identify ared cations containing these benzodiazepise derivatives of 3eir pharisiaceutical:y acceptable sails as essential ingredients that are usable for the treatinent of anxiety neurosis, photias, obsessive-compulsive disordier8, panic disrder, generalized anxiety disorder, schizophrenia, post-cardiac Ealina stress disorders, depression disorders, psychosotiatic disorders, and other psychothetirotic disorders, eating distries, Ineo pausa disorders, infartile autism, and other disordes. the present inventioidescribes ackass of benzodiazepile derivatives which possess desirable eahanced ageaist eli cacy at various GABA receptors and desirable behavioral prof:e with respect to anxiolytic and atticonvulsant efficacy and reduced side etect eticacy, the co8pxitxis in acco: The inventiot provides in acthes aspect a compound of dance with the presentitivention have agonist eiticacy at the formula : i, or 8. Salt os produg hereof, GABAct, GABA(x3, and GABA5 receptors. 30 componds of this invention have axxiolytic a1:d anticon vulsant effects wit: decreased sedative-hypnotic activity. R ise present invention provides 3 compound of formula I, ; or a salt r prodrug thereof, D . R.

wherein Yang Zaretaken together with the two intervening carbon atoms to form a ring selected fro13. phony &nd 65 thienyi, which ring is substituted at the C(7) positios with at least the substituen: -C:C.R, where R is ii, Si(Cis). -butyl, isopropy, methy}, or cyclopropyt, R, is Be &f H,

Page 5 of 53

US 7, 19,96 B2 5 CH, C,8.N.C.Els). CHCP3, CHCs:CH, or an alkyi cyclopropyl; and it is 8 substituted or insubstituted 8 least partially utisatxirated 3 or 6 membered cyclic or heterocyclic ring, wherein if substituted the Substituent is one or more of g, C, B, or NC, at the 2'-position. Preferred compositids 5 according to fo:mula II include:

he present invention provides in yet assother aspect 8 compound of formula TTE, at a sait or prodrug thereof, Further, the present inversion provides it compound of foriaula IV, or a salt of prodrug thereof,

wherein Y and Z are taken together with the two intervesing carbon atoms to form a ring selected from phenyl and thieny, which ring is substituted at the C(7) position wili: a wherein R is is, Si(CH,), t-butyl, is propy, lethyl or east the substitiest-CeC-K, where R is 8, Si(OH)3 cycopropyl, R is one of H. Chi, C.H.N.C.E.): {CECF, truty, is propyi, methyl, or cyclopropy, and R. is a Sub CHCsCE, as an alkyl cyclopropyl, R: is a Susitated of stituted or asbstituted at lea: partially unsaturated 5 or 6 basibstituted at east partially unsaturated 5 or 6 itembered isenbered cyslie or heterocyclic ring, whereiki substituted cyclic or heterocyclic rig, whereill if substituted in Sub the substituent is one or more of F, C, Br, of NO: 8: the stituent is one or more of F, Cl, Br, or NO, at the 2'-positio:}; 3'-position. Preferred compouncis according to the fortia and A is an ethexide or a propoxide. Preserted ceilipGuids include: according to the femala Winelude:

Page 6 of 53

US 7,119,196 B2 8

-contified

in a still further aspect, the present invetition provides 8. compound of formula V, or a sait or prodrig thereof.

In yet another aspect, the presert Eventicit provides a compouad of fortriula V. or 8 sait {}r podrug thereof, wherein Yard Z are taken together with the two interveiling carbon atoms to form a ring 8:lected foll phenyl &nd thienyi, which ring is substituted at the C8} positio: with at least the substitueat-CaeC R, whire R is H. Si(CFs): t-buyi, isopropyl, retity}, or cyclopropy; R is one of H, CH, CF,{HCH, CHCF, CHCsCfi, an 8ky, or cycopropy); R is a substituted or unsubstituted at least partially unsaturated S or 6 (Leibered cyclic or heterocyclic 53 ring, wherein if substituted the substitueat is orc or more Of F.C., Br, or N{}, at the 2'-position; asid Rs is a bfanched og straight chain C, to Chalogenated o: unhalogenated alkyi orformula a methyl W incide: cyclopropyl. Preferred compoathis according to wherein Y and Z are takeatogether with ihe two is tervening carbon stoms to form a ring selected from phenyl and Co-CHCH thienyi, which ring is substituted at the C8} positiot withi Beast the substitueat...-C:C-8, where 8 is H, Si(OH}s: t-butyl, isopropy, meiyi, or cyclopropy; R is one fH, CH, CF, CHCH, CHCF or cyclopropy, R is a substituted or ursubstitutei at least partiaily st:3aturated 5 of 6 membered cyclic or heterocyclic ring, wheréill if substi tuted the substituett is one or nore of F, Ci, Bi, or NOx at the 2'-position; and &s is a branched is straight chair C to C, alkyl or a methyl cyclopropyi. Preferred Colapunds according to formula W include:

Page 7 of 53

US 7,119,396 B2 ) east the substituent ...-C:C-R, where R is ii. Si{Clds, t-butyl, isopropy, nettiyi, or cyclopropyl; 33rd R2 is a substituted or insubstituted at least partially utisaturated of 6 mentered cyclic or heterocyclic rig. wherein if sisti tute the substituent is one (it more aff, Cl, Br or NO at the 2-position. Preferred coin, inds according to fitinua Wi include:

r-CH

The present inventists still further provides a compound of formula Viti, or 8 salt or prodrug thereof, Eise present invention also provides is compound for maia VI, or a salt (; prodrig there3,

wherein Y and Zaretaken together with the two intervestig carbon atoms to form a ring selected Bell phony and thiery, which ring is substituted at the C(8) position with is: least the substitueta. --Czec-R, where X is No CH, whereins and 2 are taken together with the tw8 intervettig 55 wbore R is H, Si(CH, t-butyl, isopropyi, aethyl 8 carbon atoms to forta a ring selected from pheny and cyclopropyi; R. is H, CH, CFs. CECH, CHCF or thicayi, which ring is suistituted at the C(8) position with at cyclopropyl; R. is a substituted or unsubstituted at east

Page 8 of 53

US 7, 19,96 B2 partially insaturated 5 or 6 incubered cyclic or heterocycic ring, wherein if substituted the substituel) is one of fore f -continued , c. 3r, or No, at the 2'-position. Preferred compounds according to formala VII is:clude:

5. Yet another aspect of the present investical provides a compound of £3rmia X, or a Saitor prodiring thereof,

R cy-, Y N: . N Cg

whereina is 0 to 4; Yard Z, are taken together with the two intervening carbon atoms to form a ring selected irom pheny aid thienyl, which ring is sistituted at the C8) position with at least the substituent C:C-R, where R is bi, Si(CH, t-butyl, is propyl, methyi, or cyclopropyi, Y. and are takes together with the two intervening carto: atoms to formating selected fro: phenyl and thienyl, whic: ring is substituted at the C8)' position with at least the substituent CsC-R, where R is H, S (CH3)3 -butyl, isopropyl, aethyi, or cyclopropyl R. aid R." are indepen deity one of H, CH, CF, Cil:CF, CHCH or cyclo propyl; and R. and 8, are indepe3dents substituted or instituted at east partially unsaturated 5 or 618erbed cyclic or heterocyclic ring, wherein itsubstitute the Sut stituent is one or ?acre off, Cl, Bi, or NO, at the 'position. referred compounds according to Rimlila IX include:

Page 9 of 53

US 7, 9,196 B2

-contified

Risar Sick: is :: SCEs. O

5 A still frther aspect of the present inverticiptovides & thienyl, which ring is substitisted at the C(8) position. Witt at least the substituent –CaC-R, where R is H, Si(Chs)4, compound of formula X, or it salt (st proxirug thereoi, t-buty, isopropyi, methyl, or cyclopropy: Y" (3d 2 are takea together with the two interveiling carbon atoms to form a ring selected from phenylalithienyl, which ring is substituted at the C(8) position with at east the substituent ...C:C-R were R is H, Si(Cii,), t-b13ty, isopropy, methyl, or cyclopropyl, R, and R, are independently 98e 8f H, CH, CF, CHCH, CH,C#, or cyclopropyl, Ratsl R: are independently a substituted of ims:bstituted at least partially unsaturated 5 of 618&mie'eicSctic or heterocyclic ring, where: if substituted the Stittstituent is one or more of E. C. Br, or NO, at the 2-position, and 8 is O or NH and wherein-BCHB–is optionally replaced with ri(R)- whercis Yard?, are taken together with he two it:ervening N{R-, where R is one of Ei, Chi, alkyl, 8 cycloalkyl. carbon atoms to form a ring selected for phenyl and Preferred compounds accoring to faratsla X include:

X and X’ are sh: indepetitly lar

ceno-Yo.1\oc s8

sitd are each i:iegedently Eff s

Page 10 of 53

US 7,119,196 B2 5 6 The present invention further provides a compound of Yet another aspect of the prese: invention p:Ovides & formula X, or a sat or prodrug thereof, compeund of formula X:l, or a sal: (fp:(drug thereof,

wherein aisl or 2; wherein Y and are taket 80gether with whereinnis () to 4, Y and Z are taken togethex with the tw8 the two intervening carbon atoms to fort), a ring Selected intervening carbo:3 atoms to fortil a tag selected iro1. from phenyianisheryl, which ring is substituted at the C(8) phenyi and thienyi, which sing is substituted at the C) position with at least he substituent - CsC-R, where R positioa with at Beast the substituent --CeC-R, where R is H, Si (CH,), t-buty, isopsopyl, methyl, or cyclopropy: is I, Si(CH,), t-butyl, is propy, methyl, or cyclopropyi;Y" Yad Zaretaken together with the two intervening carto: and Z are taken together with the two intervenig carbon atons to xm a ring sciected froxypheny and thiefly, which ring is substituted at the CC83 position with a least the atoms to for: aring selected foil: phenyi and thienyi, which substituent - C:C-R, where R is ti, Si(CH), t-butyl, ring is substituted at the C(7) p.sition with at least t isopropy, gethyl, or cyclopsopyl; R and Rare indepel substituent ...Casc-R, where R is H, Si{CH3, -butyl, dently one of H, CH, CF, CHCH, CHCF or cyclo isopropyl, methyi, os cyclopropyi; R. and Ri'ite indepe:- propyl; RandR, are independently a substituted of 1:Sub dently one of H, CEI, CF, Chi;(F, CHCHs or cyclo stituted at east partially usasaturated 5 or 6 metabered cyclic propyl; and R. and Rate independently & substituted of orbeterocyclicting, wherein if substituted the Substituent is one or gore of F, Cl, B, or NO at the 2'-position; and B is unsubstituted at least partially 3Saturated of 618embered (, NH, or -N(R-N(R} , where R is one of H, CH, cyclic or heterocyclic ring, wherein if substituted the sub alkyl, or cycloatkyi. Preferred compounds according to stituent is one of inore of F, Cl, B, or NOa: the 2'-position fini: X it clie: preferre: compounds according is formula X inckde:

coyo Yoc W ss N

X3X are sch independentiy Hof Ns.

co1 Ye1No. ss

Xanxier ch independent:y Here s

Page 11 of 53

US 7,19,196 B2

Ris Her St. 3R & Hi Si (CH,

A stilitarter aspect of the present invention provides a tieryl, which ring is substituted at the C7) position with at compound of the fiximula X:li, or a salt or geocirug thereof, so east the substituent --CeC-R, where R is i. Si(CH), t-hayl, isopropyl, imethyl, or cyciopropyl, Y and 2 3Te take; together with the two interversing carbo) as(EBS to xii; foran a ring selected from phenyi 3rd thienyi, which sing is R. substituted at the C(7) position with at least the substituent 81I E. 3S -C:C.R, where R is ii, Si(CH), t-butyl, isogiopyl, . NY methyi, or cyclopropyl; R. and Rare independently onco c1a1a1\ce H, C, CF, CH-CH, CBCF, or cyclopropy, 8: Rad R s are andependently a substituted or unsubstituted at leasi partially unsaturated 5 or 6 metailered cyclic or heterocycic R ring, wherein if substituted the substitueat is otle or more of R F.C., Bi, or NO, at the 2-positio8; and B is O or NEi 3.8d wherein...BCHB- is optionally replaced with “NR}- wherein Y and Zare taken together with the two intervering N(R:)-, where R, is one of Ce: alkyi, or cyclaikyl. carbon atoms to form a ring selected fro: phenyi aid Preferri compounds according to foratia XBi isletude:

X and X’ are &etch independer:ly 83. F

Page 12 of 53

US 7,119,196 B2

-continued

X and Kare each: independentiy EE or F

Yet another aspect of the present invenfict p3ovides a takery, whichring is substituted at the C7 position with 3: soupound of the Érauia XFV, of a Sa: }; prodrug theref, : east the substituent ....C:C-8, where k is H, Si(CH3)3; t-butyl, isopropyl, methyi, or cycloprogyi; Y and Z are taken together with the two intervening carbon atoms to in a ring selected from phenyi and thienyl, which ring is substituted at the C(7) position with at least the Substituent v. c -CsC.R, where R is H, Si(CII) -butyl, is propyl, ---- aethyl, or cyclopropyl; R and Rare isiependentiy ()ise of H, CH, CF, CE: CH, CHCF, or cyclopropy, RandR . as are independentiy a substituted or unsubstituted at east partially unsaturated 5 or 6 Bielsbeted cylic or heteroglycic R ring, wherein if substituted the substituent is one or more {: , C:, Bt, or NO. 3: the 2-position; and B is (), NE. or ...N(R-N(R)-..., where R, is one of H, CHs, alkyl, or wherein Y and Z are taken together with the two intervening cycloalkyl, Preferred compounds according to £38:a XV carbon atoms to form a ring selected fica: phenyl and include:

X and X’ are each independently Haif

X and X’ are eech independently 3:3: F

Page 13 of 53

US 7, 19, 196 B2 22 Another corapeutid (XV) of the present invention is Arsenyi, 2.Éturophery), 2-thiesy, 3-thic:y, 2-pyridyl, 2-pyridy: N-O; Y-O, S, NEC3, Another compound (XVII) of the present invention is:

msl, re2; Rii, Silvie, tRa. CH -4. Arphenyl, -irophenyl, 2-lixienyl, 3-thienyl, 2-pyridy, 3-pyridy: X-Q; X=N or CSi n=3, it: ; R-H, Sisse, 8, CH, Yet attether cattp::ict XVI) of the presett svention is:

Ar:phenyi, 2'-fluroghenyl, 2-tienyi, 3-thiessy), pytidy. 2-pyridy: N. O, Ye-O, S, NHCH, Yet 8:other compound (XX) of the preser: investic:3 is:

R-H, SiMe, 8, CH, -4. th Ar:phenyl, 2'-itutophetyl, 2-thictyl, 3-thicily, 2-pyridy, 2-pyridyl N-0; X-N or CH was see Still another compound (XVII) of the paese: invention is: : N -

R-H, SiMe, BL, CSI,

R-H, SiMe. Bu, CH, -4. s s Ar=pliery, 2'-fluropheny, 3-thienyi, 3-tixietyl, 2-pyridy, 2-pyrily: N-0; Y-O, S, NHCH Page 14 of 53

{jS 7, 19, 96 B2 23 24 Still another citripound (XX) of the present invention is: The coilpotasis of the presert invention arc (i?t A

receptor ligands which exhibit anxic:ytic activity due to increased agonist cficacy at GABA'oZ, iABAf{3 and or

s GABAeS receptors. The compounds in accorda:3ce with

this invention may possess at least 2-fold, suitably at least

5-fold, and advantageously at least a 10-fold. selective efficacy for the GABAct 2, GABA(3, Ead'or (ARA ($ receptors relative to the GABA foll receptors, Fiowever,

compounds which 3:e not selective inter&s if ticis agonist

efficacy for the CiA3Ac2, GABAe3, and/or (i.ABA fos

receptors are also encompassed within tie scope {f the

present invention. Such compounds will desirably exhibit functional selectivity by dict:(instrating at xiolytic activity

with decreased sedative-hypnotic muscle relaxantialaxic

activity due to decreased efficacy at 3ABA'(x: receptors. For use in aedicine, the salts of the compouilds of

formulas () XX}} will be haraxiaceutically acceptable 8-1, SiMe. Bu, CH, salts. Other salts 131ay, however, be usef: in the preparation at the computids according to the inventical or of their

phazamaceutically acceptable saits. Suitable shariaceuti 2. cally acceptabie saits of the compounds of this Eventic: -4. actude acid addition salts which may, for example, he fornied by mixing a solution of the compound according to

the invention with a solution of a bariaceutically accipit Arphenyl. 2'-fluophery, 3-hieryl, 3-thiety, 2-pyridyli, abie acid such as hydrochloric acid, sulphuric acid, meth

2-pyridiyl N-O; Yr-O, S, NEHC, 25 anesulphonic acid, fumaric acid, 3.8lcic acid, succinic acid,

acetic acid, benzoic acid, (xatic acid, citric icid, tartaric A further catapould (XX) of the present invention is: acid, carbonic acid (; plosphoric acid. Furthermore, where the compounds of the invention carry an acidic aciety,

suitaisie pharinaceutically 8ccaptable salts thereof Inay include alkali metai salts, e.g. sodium or potassita). Salts, 3. alkaline earth metai sails, e.g. calcit:38 or tragacsi:11 salts; and saits formed with suitable orgatic ligands, e.g. quatex nary at Iristill salts, The present invexation includes within its scopic prodrugs of the compounds of ionoukas (E)-(XXI) above. In general, such prodrugs wi: be functional derivatives of the com loo pounds of formulas ()-(XXI) which are readily coEvertible in vivo into the reg:ed compound (if fotnias (I)-XXE}. {Coventional procedures for the selection and preparatic: of suitable prodrug derivatives are described, for example, in 40 design of Prodrugs, ed., H. Bundgaard, Elsevict, 1985. Where the compounds according to the investion have at R-31, S&Me E3: C: least one asymmetric center, they may accordingly exist. 38 en3ntioners. Where the compouilds according tie invention possess two or more asymmetric centess, they may addi ticially exist as diastercoisoisets. It is to the ukierstood that -4. all such isoxers agxi inixtures thereof: any preportion are

encottipassed within the scope of the present investion, the cottigounds according to the present invexion exhibit Arphenyl, 3'-fluropheryl 2-thienyl, 3-thicinyl, 2-pyridyl, 3.Bxiolytic activity, as may be dery (instrated in rats by a 2-pyridyl N-0; Y-O, S, NHCH, positive response in a preclinical test for anti-aixiety fi

Compounds XV} to (XX) above can also have Ras CF, cacy (e.g., situational anxiety (if deficisive withdrawal), CCs, or CBr. Moreover, the coopounds of the inventios are substantially A stil: Rather aspect of the present invention provides non-sedating and on-ataxic as Bay be confirmed ty an

coalpositions comprisiag compounds of the 8bove kind in a appropriatic res: obtained from the locomotor activity test pharaceutica:ly acceptable carrier. Such plariaceutically a Eld retorod paradigm, respectively.

acceptable carriers are we: known in the 3rt. 3 he cortigourds according to the present invent:31) may Another aspect office inventioi provides a method for the also exhibit anticoriyuis&int activity. This can be cleaka treatment and or prevetition of anxiety which comprises strated by the ability to block peatyenetetra:le-induced airfissistering to 3. patient in need (if such treatmeat ai. seizures in rodents. cfictive aimount {}f a compound of the above kinds, or a The invexation also peovides pharmaceutical compositions

giarillaceistically acceptable sal: thereof or a proxirug comprising oae or more collipoliticis of this invetation a

tiereof association with a pharmaceuticaliy acceptable catrix, Frei

fi the above Inbodiments by "aikyt we meat a straight. erably these compositions are in unit dosage fo:ms such as

or braached halogenated or unhaiogenated alkyl group hav tablets, pills, capstiles, powders, grarities, settle paretteral ing 1-6 catbi atoms. By "cycloa:yi" we mean one con solutions or suspeasions, metered aerosol at Eiguidi spray3, taining 3-7 cartoon ators. Also, is: the above entxodine; its 63 drops, ampoules, auto-injector devices or suppositories; fox by "cycic" we prefer a phenyi group and by "heterocyclic” ora, part:grai, iittanasal, subtingual or rectai adit:aistia

we prefer a 2-pyridine or a 2- or 3-thiophene. tion, or for 3dininistratics by inhalation of insuitatiot. it is

Page 15 of 53

US 7, 19, 196 B2 25 2 also envisione: ;hat the compoulds of the present invention may be incorporated into transdermal p3:cks designed ti -cintinuxi deliver the appropriate amount of the drug in a centitless fashion. For preparing solid 20:33positions such as tablets, the principal active ingredient is sixed with a sharinacci tica carrier, e.g. conversional tableting ingreients such as corn starch, actose, sucrose, sorbitoi, tale, Stearic acid. tragnesium stearate, discaleiun phosphate or guins, and SC a Net-CHsiles-e- other pharmaceutical diluents, e.g. Water, to fixin a said preformulatiot composition cottaining 3. E1030gie is mixture for a corpound of the presert investigii, of 3 pharmaceutically acceptabies: thereof. Whell referring to these presennulation cottpositions as hogsteeleos, it is meant that the active ingrexient is dispersed ever:y throught out the composition, so that the couposition lay be easily subdivided into equally effective unit dosage forms such as tables, pills atti capstics. This solid perforanulation cott position is then subdivided into unit dosage folls if the type RAF, EFE described above containing fro: ), 1 to 8b{xt 5 laggi the sur-rava-e- active ingredient of the present investigB. Typical li: dosage forms contain from to 388 ing, for example, 2. 5,625, 53 or 100 mg. of the active ::geciet. The tablets or pills of the novel composition can be coated 3r otherwise coupoundeiko provide a dosage from affording the avail tage of prokage: action. fox example, the table; or pil car. cimprise as inner dosage and &n Outer dosage citipolent, the atter being in the firingfan envelope over the foiler. The two components can be separated by an enteric layer which serves te resist tisintegration is: the stolnach and permits the inner coup Exeat to pass intactite the ducd turn or to be delayed ia release. A variety of Eaterials cat: he used for such enteric layers of coatings, such laterias including a mumber of polytizic acids and mixties of polymeric acids with such materials as sheilac, cetyl alcolio as cellulose 3C:. The liquid forms in which the Eawei compositions of ic present invention may be incorporated for administration rally or by itjection include aqueous solations, suitably 4 CEE-858: fiavored syrups, aqueous or oil suspensio3s, 3d favored emulsions with edible oils such as cottoiseed oil, Sesaime (i. coconut oil or pearxt oil, as well as eixirs aid similar The bromise available fictin reference' was eacted with pharn:ceutical vehicles. Suitable dispessing or suspe:cing trimethylsilyacetylene in the presence of a paladiuin cata agents for aqueous suspensions include synthetic and Bahiral lyst to provide timethylsily analog 2." This product was gins such as tragacaith, acacis, algitate, dextrati, sodium methylated with methyl iodickeisodius: hydride to give the caboxymethylcellulose, aethylceBulose, polyvinylpyrroli N-methylbenzodiazegius: 3, his was subsected to fluoride dose or gekatia. in the treatinent of anxiety, suitable dosage level is about mediated des:lation to furnishi (QH-366). 0.01 to 250 trigg, per day, preferably about 0.05 to 0. Procesire for QHi-f)66 ing/kg per day, and especially about 0.05 to 5 3g?kg persy, 7.irimethylsily:acetyle:no-5-phenyl-3.3-ditStrobets? the composids may be administered on a regimen efito e-i,4-diazepin-3-one 2.' A mixture f * 1 g, 3.7 4 tiraes er day, or on a coatia:Ects basis via, for example, inmale availabic from reference i} it trietylainine (303.) tie use of a tatasier:rial patci. and C, CN 20 mi.) with trimethylsilyiacetyleile (622.7 IAEE) DESCRIPTEON OF THE tag, 6.34 minole) and bis(tri-phenylphosphine-paladium NENTON (II) acetate (18 mg, 0.5 minoi) was heated it refix (de: nitrogers. After 12 hours, the reaction mixture was coo::ce to regatemperature and filterei. 3 he filtrate was c{1}centrated in vacuura and the residue was treated with a Saturated aqueous sciution of Nai:Co. (38 mil), 88d extracted with CHC (3x50 mL). The organic ayers were contised aiki FiAeach r washed with brine and dried (Na,S8.). After removal of SiCE: saveat under reduced pressure, the residue was purified via Et, CHCN flash chrogatography (silica gei, EtOAcihexanes; iii) to Rays furnish 3 as a yelow powder (91 ing, 75%); itp: 99-915 C. R. KBr) 30:3, 228, 1686, 16 (), 1486, 325, 249, 839, 700 car; : NMR (CDC & .21 (s, 9H, 431 (s, 2EE), 7.09 (c., E.H. J-8.25 i2), 7.21-7.6 g. H., 10, it is, Ia); MS (CE) ane (relative intensity} 333 (Me, 00). This materia: was used in the text step,

Page 16 of 53

US 7,139,196 B2 27 Methyl-7-trimethylsilylacetylen- 5-phenyl-3,3-dity drobenzole-1,4-diazepin-2-one 3. A list chi: 4.85 Eng, 46 mino) was dissolved in dry HF {20 mL) at C. aid Nah; 6% in mineraioii, 7 Rg, is amo) w83 &ticed to the solution inorseportion. The slurry w88 the stirred for 20 in at (C. aid CHI (3 mg, 2.19 anol) was added to he mixture and it was warned up to root temport After the mixture stirred for 3 hours at rcontemperitute he TH was best emoved under reduced press. The residue was purified by flash chromatography g;exanes;Et)Ac (::4}} to provide the title compound 3 (333 mg, 50%) as a white scii; imp. 177.178°C, IR (KBE) 2954, 247, if:87, 1612,Cispin, 149, 382, 3.8 1:5, (3,3H),354 3075, 839, (d. 701H, cm98) ; BNMR : Six Lief-043) id, H, -io.8 Hz), 705 (s, 1H), 70 (c. H, -8.5& H), BAF 7.297.27 m, 38, 7.37-42 (m, 3H); MS (EI) nie 346 HF, 33 air (Mt,90), 38 (100),393(9), 5(22), 151 (20). Ana. Caled. for C.H.N.O.si: C, 72.79; ii, 6.48, N. 8.08; Ford: C, 2.5; H, 6.68; N, 8.4, 1.x:H, TEFINEF Methyl-7-acetylene-5-phenyl- 1,3-di:ydro-benzoic-, (OxCE: C. 4-diazepin-3-one 4 (Q:El-966). A solutio of 3:00 ing.) in TER (33 in; ) was treated with tetrabutylasiaoxi.1113 auoride (M in THF). The mixture was stirred for 20 minutes at room temperature before water (3) iil) was added. The mixture was then extracted with E9 (3x30 m.). The combined organic extracts were wasted with title as dried (NaSO). The Sovent w88 retroved under vacuu and the residue wick resulted was passed 3rough awasa colustin (silica gei, EiOA&hexanes: 8 give 4 (QHEI-066) as tight Sellow crystas (73 mg, 90%), p. 65 C.ERKBy 2965, 3680, 180S, 133,12 833, in NM8 (CDC), 8 (ppm) 3.38 (s.3H),375 (d, ,0s Hz, 480 td, H, 3:30.9 hz), 528 (3. 1H), 7.29 (d. 14, J-8.5 Hz), 7 35-743 (,4H), 7.55-7.5% m, 2i}, i 62 did, II, J-85 Hz, 2.0 Hz; MS (E) gift relative intensity 374 (M', 138), 258 (2), 26 (100), 189 (12), 'he bromide was reacted with diethylpho spivorochlori 22:9), 105 (42). Atal, Caled for {i, N.C.?stio, date in the presence of sodium bydride: followed by addition died., 5.5; H, 4.89: N,978. Fou3d: C, 75.59, H, of ethyl isocyanoacetate to provide the ester 5. This was 5.17; N, 3.62. converted to the kirbethylsilyacetyle:30 compound is (xiXHe:3-148) under standard conditions (d-mediated, eck-type coupling). Treatment of 6 with fluorixie gave the title compound 7 XHeli-053). procedure if XHe-Il-953 NaH, HFDMF £iyi 8tronic-6-phenyl-48-benzettitudazol 5-al4 Cleo(OEy,... elser-ge 3 C, diazepine-3-carboxylate 5, his benzodiazepise S was 2NE, DEF obtained in 45% yield forn attalogous to the litesature CNCEXE: procedure as 8 white solid, 8: p. 74.175 C.; ER (KBr) is, 172, is09, 1491 cm; H NMR (PCs) 8 .44 (t, 3H, J-7. Hz), 4.09(d. 1, j-2. Hz, 4.38-449 (n,2), 608 (d, H. J-12.3 Bia), 740-53 (it, 6H, 7.60 (d. iii, 3-2.2iz,782secreative (ck, EI, intensity) -8.5 Fizaldi), 4:1 (34), 7.95M3, (s, ill); 34,365 (61),363 (63), 337 (38),335 ())), 285 (21), 233, (7), Ana: Calcd. for C.Hafn,0: C, 58.55, Fl, 3.93, N, 4. Found: C, 58.30; H, 393; N, 9.98. Ethyi 8-trimethylsiyiacetylenyl-6-phenyl-4-benzo EES: agrue imidaze: 5-a(3,4-diazepine-3-carboxylate 6 (XLIXHel:- iOAPPh3 048's. A sixture of bromide 5 (0.3 g, 8.73 it:o), EA. trimethylsilylacetylene (0.143 g. 1.46 mitos and bis(triph refs enyipkosphine)palladiuri-Racetate (55 pag, 8,873 in 38) is nixed solvent system of toluene (20 ti) aid at:ydrills TEA(50 mL) was heated to reflux indes ago. Afte: stiring ir boss at refux, the mixture was cooled to rol teaperature and the precipitate which formed was religvedi

Page 17 of 53

US 7, 9,196 B2 9 30 by filtration. The filtrate was concentratei under reduced -co; tired pressure aid tie residue was treated with a saturated aque cus sciution of NaliCO, (20: al., and extracted with. CHCi (3x25m), the combined extracts were washed with brine and dried (Na SC. After reanowai of solvent under reduced s 3A pressure, the residue was purifixi by lash chromatography ------a- (silica ge:, EQA) to airti 6 (XLEXHell-048) as a white 3.E, (; xis: solid {0,29 g, 93%). This benzodiazepine can also be obtailed from 2 in 45% yield by following the same procedure 6 (XTiX3eiI-848}: Lisp. 170-172 C.; ER (KBry 2958. 2152, 1718 cm; H NMR (CDC) 3 0.23 (s, 9H), 3.42 (t, 3E3, le7.2 Hz), 4.34 (d, F, 3-2.6 Hz, 4.41 (as, 2EE, 3-2 Hz), 8.23 (c. 13, J-2.6Hz), 7.35-7.55 (m, EI), 7,73 (&, 143, 3-83 Hz, 321.9 FIz), 793 (s, JH); MS (E) me S. FR (relative intensity) 427 (M', 763, 412 (5), 38l (55), 353 { } {{1} 303 (10), 287 (7). Ana E. Cakd, for "Y,- / C.H.N.C.Si./.EtOAc: C, 69.23; H, 601; N, 9.20. Found: C, 68.87; H, 5.81; N, 9.37. Ethyl 8-acetylenyl-6-phenyl-4E-benzo(fiquidazo 3,5-ad 2. 1,4-diazepine-3-carboxylate 7 XEici I-853). A solution of e 6 (XLIXHeIT-848} {0.7 g (3.4 mmol), iaTHF (i.5 till was treated with 33.N.F.H.C) (). 16 g (3.62 smol). The mixture which resultex was allowed to stir for 38 ania at room temperature after which the mixture was added to HO (10 s Sl 3:) and extracted with EtOAc (3x25m?...}. The combined : 3 X 323, organic extracts were washed with brine (25 mL) and died (NaSO,}. After renova of soiset under reduced pressure, the residue was parified by a wash co838 (silica gei, The Ironide , available from reference l, was stirrex E3Ac} to fittish 7 (XHell-053) (0.12 g, 85%) as a white with the di-4-morpholic-phosphinic chloride, illowed by solid: mp 237-239° C., R (KBr) 359, 3307, 2092, 1721, addition of acetylhydrazide to furnisi triazok-benzodiaz 1606 cm.; El NMR (CXC: & 1448,3H, Je7.1 Hz), 3.29 epine 8. This Eilateria: 8 was subjected to a Heck-type {3, iH, 4.13 (di, H, 3- 0.22 82), 4.43-448 {, 2H), 5.31 coupling reaction (TMS-CeCH, Pd-mediated)''' to fur (d, H, 3-82II2), 742-7.63 (m, 7H), 7.81 (id, il, J-8.3}{z. nisis ligand 9. This agaiog was converted into () Xi27}} and 8:32), 8.03 s, EI), MS (EI) me (relative intensity) 35 on stirrig with fluoride airl as shown in Schene 3, 355 (3', 83,339 (70), 28 (100), 253 (12), 231 (18), 178 Procedure or XL 270 (20). Anai. Cascd. for Cii, N.O.%HO: C, 7.63; H, 8-Broac-i-methyl-6-phenyl-4H-s-triazol-4,3-a8,4 535; N, .39. Round: C, i.27; {i, 4.7; N, ; 133, benzodiazepic 8. A solutioa of (ig, 3.07 mmol of 4. 7-brose-5-phenyl-3,4-8c712odiazepine-2-one) in dry Ei (20 mi.) was cooled in an ice-water that is aid a 63% Schemi:... i2. dispersion of sodium hydriie (iš2.2 rag) was a died in one portios. After 20 minutes, di-4-ab?orptoliyiphosphinicchio i-A i side (343.9 ting, 4.76ramol was added at 8°C. and this was --a 35 stirred for 30 minutes and allowed to warm to room ten 1 Ns, perature. The mixture was stirred for 1.5 hours. To this w NaH, 31E, mixture was then added a solution of acetylhydrazide (52:.9 Er eas mg, 7.4 mmol) in dry btaiaoi (5 ml.) and stirring was 2) Ngh, Bucs: toxinued at run temperature for ; ) iii. This solycats C:{ONEEN}}, were evaporatex and the residue was disso:ved in butanol (5 mL) : 1st Eleated to reflux for 5 hours. Butaol was removed under reduced pressure actise residue was parti tie aed between CHCl (50 m3.} &nd water (50 mi.). The water layer was extracted by CHC (3x30 T3.), the HC N s coabited organic layer was washed by brine (3) ini.}, i he organic layer was dried (NaSO) and the solvct was Y- /Y removed 33der vacuati. The residue was purified by fashi chromatography (silica ge) to provide pure 8539.5 mg (40% yield); as a while solid: up 268.5-270° C.; ER (KBry O eat re-eless-a-wu(CHSi-ex-H S. 2358, 1607, 3538. 1484, 1331, 2008, 801, 89'i cin; : II Bt pd(OAc{PPH), NMR (CDC), 82.82s, 3}}}, 4.11(i,i}}, jel2.8 Éiz., 5.4% EA (d,lii, i=2.8 Hz), 7.2-7.68(8,7H, 7.75 (dd. ii, Fe3.58 reflux Hz, e3.5 Hz); MS (EI) i.e. elative intensity) 354 (34), (M, 16), 352 (34), 325(33), 323 (34), 273 (63), 245 (31), O 232 (19), 204 (303), 83(23), 77 (36), 35 (24). Anai, Calcd, for C.H.BN: C, 5.81; H, 3,7; N, 1586. Folid

C, 57.57; i, 3.64; N, 15.70.

Page 18 of 53

US 7, 9,196 B2 3. 3. 8-trimethylsilyacetylienyl-1-Etiethyl-6-phenyi-4H-Stria zoo.4,3-ai,4-benzodiazepine 9.'" (XI.i.269). A mixture -continued of 8 8-brotno-1-methyl-6-phenyl-4-H-s-triazolorf, 3-al, 4;benzodiazepine, 30. Eig, 8.85 milliol), trimethys:ylacety etxe (208.5 mg, 2, 2 B}}}ol atd bis(triphesyiphosphire)- - 1. N.E.E. (EEOC pastadium(II) acetate in a mixed solvest system of Ethi, (5 e8 BE, or C. n; as CHCN 8 ai.} was heated to reflux 33dier nitro ;&isis, Notice gea. After stirring for 6 hours at reflux. The fixture S&S cooked to room temperature. She mixtute was concentrated under reduced pressure and iO (3 mi} was added. The mixture was extracted with CH.C. 3x30 ml), the corn l2 bined extracts were washed with brine and dried Na:SO4). this tie:::clastiable After removal of solvent under reixed pressure, the residue irot, reissnet of: was purified: by flash chromatography (sica gel, OE EtOAc) to a lord beix2 diazepine 9 (185 mg, 60% yield) as a white sid: mp 229-233°C.; ER (K8x) 2957,256, 1609, CE:38: ser 537, 49, 424, 1315, 1249,881, 844,750 cm; HiSMR rix:hylsily::::::yely (CDC, 68.23 (s, 9H), 2.68 (s, 3H), 4.1 (d. H. 125 File:A: hiz, S.49 (ci, H, 3-3.0 Fiz), 7.21-7.6863, FI), 7.753, XEs, CEN its, -85 Hz, 3-3.5 Hz); MS (EE} Eye relative intensity) 379 (x, 80), 355 (44), 343 (60), 286 (34), 177 (51), 163 52) 143 (100), 129 (19), i5 (28), Anxi Caked, for ci.N.si: C, 73.31; H, 5.98; N, 5.32. Found: C, 70.90, B, 5.93, N, 15.08. 8-Acetyltyl- 1-tiethyl-6-phetyl-3H-s-triazolol.43-83, 4 benzodiazepine 18 (Xi- 270). A solutio: of 9 timethyl silylaceyjenyl-1-methyl-6-phenyl-4:i-5- triazoic-43-a-i, 4-benzodiazepine (106.4 Eg, (.288 manoi) in dry H. (20 mi.) was treated with BuNF (30 M in Ei $2.8 g. (3.43 mmol). The mixture which resulted was kilowed to stir for stin at roots temperature after whic: the mixture Was acked to H.O. (30 mL) aid extracted with CHCl: (3x25 tal). the combined organic extracts westwa shed with bine (25 mL) and dried (NaSO). After removal of solvent slider reduced pressure, tie residue was crystallized fixin EtOAC to provide benzodiazepine 3 (XI.370 (66.8 mg, 80% 143YT-38) yield) as a white solid; ap-250° C (dee); R (KBr) 398, 258, 699, 1538, 1491, i425, 137, 2002, 838, 748, 695 en', H NMR CE}{l} & 2.78 is, 3H), 3.15 s, 1H), 4il (3,2H, -12.8 Hz), 5.91 (d, H, J-12.8 Hz), .3585 (al 83; MS Ei) retative intersity} 298 (M', 108}, 269 (78), 230 (48), 228 (65), 20: 28), 27 (65), iis (42), 101 (54). Ana, Calcá, for C.H.N.Y:CH, H. C.74.50; H, 3.13: N, 782. Find: C, 74.33; 3, 4.83; N, 77.

3rcBr

...------Niscs. rrrrrrrra-exEx: 2. NH, MeOH The i-broao-2'-fluorobenzodiazepine 12 (available from resis. reierence :) was seacted with sediuill hydride and dieth yphasphorochioridate and this was followed by addition of ethyl isocyanoacetate to provide benzinidazo intertaköiate 3 (Y-932), as iustrated in Scheme 4. This material was heated with trimethysityacetylene in a 3eck-type coupling reactions to provide the trimethylsily anasog 4 (Y-38). Page 19 of 53

US 7, 19,196 B2 33 34

The silyl group was removed from 14 on treatment with raphy (silica gel, BOAc) to aford 15 (JYXHE-QS3,6; urg, fit oride anion to finish 5, a 3'-fluoro analog of XHef-053. 2979,80%) as 7:3,a white 362, solid: 491,mp 223.5-224.5° 12S5, 190 C.; can'; TR{KBr)3288, 'EI NMR in exclient yield, (MSO)-d) 8,34 (t, 3 ::, 3-71 Hz), 4.27 (3s, i ly), 4.36

Procedure: - 5. {q, 2 H, Jr.: Hz), 4.47 (s, 1 H, 5.80 (bs, H), 7.22 kt, Ethyl 8-brino-6-2-Euorophetyl)-4t-benzel finidazo H, 3-84 Hz), 7.30-7.60 m, 4H), 785 (d, H, 3-6.6 jiz),

E1,5-aidiazepige-3-carboxylate 133Yi-032). A scu- 792 (d. 1 R, J-84 Hz), 8.83 (s, H); MS (EI) ri?e (relative tion of 12' (70 g, 21.0 maic) in THF (50 mL) was cooked intensity).373 (28), 327 (47), 299 (160), 249(22), 378 (50),

in ice-water, and sodiug hydride (i,0g, 25.2 audiol) was Anai, Calcd. for C.H.N.G.F. A. Ho: C, 69.30; H, 4.48; N. added in ore perior. After 30 min, diethyi phosphotochlo- it).99. Found: C, 63.3; i, 4.39, N, 10.68,

ridate (5.62 g, 33.5 Euncil) was added dropwise, 33d the solution which resulted was stirred continuously for 33 mir Sctics

with cooling from an ice bath. A solution of ethyl isocy

anoacetate (4.22 g, 252 giguei) and sodium hydride (i.l7g, E. 29.4 mm.of) in : HF (30 mi), which had stirred for 30 min s O 1, at

with ice-bah cooling, was added slowly via a caatia. After 8-4. Aft:32 Easylphospitti:ic

stirring for arsother 30 min with cooling, the reaction inixture teN choid

was allowed to stir at room temperature overnight. The R -- -E, (; c. mixture was than acided to i) (18 rall) and extracted with Chitii, Et()Ac (3x30 mL}. The coabilkeci organic extracts were R res:

washed with brine (2x50 m3.) and dried (NaSO). The 23 solvent was evapotated undes redisced pressure and the

residue was purified by flash chtomatography (silica gei. hexanes, EtOAc: 2 to afford 3 (JY1-032, 5.2 g 58%) as a white solic: pp. 299-208.5° C.; IR (KBr). 2977, 1728, 1628, 1493, 1450 cm; H NMR (DMSc)-d) 8 130 (t,3H, is

J-4.2 Hz), 4.28 {bs, EEI), 4.38 (c. 2F, J-4.2 E2), 5.75 (bs, -r H

}}E), 7.23 (t, 1H, J-36 Hz), 7.30{t, H, 3-4.5Hz), 2.43 is, CSi

1 H), 7.54 (at, 2 H), 7.85 (d, H, 3-5.2 Hz), 7.96 (dd, H, (trirasitby:silyl)acetylete

3-5.2 Hz and 1.3 Hz), 8.44 (s, H; MS (EE) me (relative Pigp3s2CAc: intersity) 428 (7), 381 (58), 355 {1}{3), 303 (37), 274 (36. 3) N8ts. CHCN refox 247 (35), 234 (52), S4 (7i), 127 (62), Anal Calcd.ir CoHNO*8t: C, 56.39; H, 3.53; N, 9.81. Found: C, 5632; H, 3.5i, N, 9.58. Ethyl 3-tiethylsiliyiacetylenyl-6-2'-fluorophenyl)-4}{-

benzofirinidazo 3,5-aii,4}diazepine-3-carboxylate 34 3S (3Y1-038). A mixture of broaide 3 (JY-032, 40 g, 3.3 16 JY-3) J33mci}, trimethylsily:acety:ene (8,65g, 8.6 minol) and bis

(triphenylphosphine)-paliakitu (EI acetate (0.25 g, (.33 inci) in a mixed solvent systeal of CH,CN (80 mi) and

arhydrous triethyianne (50 13.) was heated to refux under

a gon. After stirring for 2 hatrefix, the mixtute was cooked

to rCoin teasperature and the precipitate which formed was

fellowed by filtration. The filtrate was concentrated under reduced pressure and the residue was treated with a saturated aqueous solution of Kia CC (40 mi), and extracted with {33}ss: CfiCl, {3x50 mi.). The combined crganic extracts were 4:

washed with brine (2x2 mi) and dried (NaSO.). After

reEEC was of soveat under reiuced pressure, the residue was

putified by flash chromatography (silica gel, hexanes? r

Et0Ac: 3/2) to a firi 4 {}Y1-038, i.2g, 82%) as a white 7 (YE-72) HC N solid: gp96-97.5°C.; RK3r) 2959,257, 709, 3653, ne }494, :45, i252 cm; 8 NMR (DSO)-d) 80.20 (s, 9 N

H), 1.32 (, 3 H, 3-7, 1 Hz), 4.18 (bs, : EE), 4.32(q, 2H, -7. S

Hz), 5.78 (bs, H), 7.25 (t, H, 3-15 Hz), 7.30-7.35 (n,

4H), 7,8: d, i H, -66 Hz, 7.93 (di, H, J-8.432), 8.49 a

(s, 1 H; MS (EI)afe (relative intensity) 445(37), 399 (5), a e

37 (300), 235 (73, 192 (66), 78 (S. Arsa). Calci. for (shinoFSi: C, 67.39, H, 5.42; N, 9.43, Faund: C,

66.38; H, 3.46; 8, 9, 19,

8-Acetylene-6-2'-fluorophets)-4H-benzofiaidazoli,

S-a: , kiiazepige-3-carboxylate 15 $YXIIE-53). Asia tion of 14 (Y-838, 80 mg 0.18 attnai) in F8F (5 mi) was 8. & JY3.70)

treated with BuNF (O.S. m. , 1.0&1 solution in EHF). The inixtakeerapezature which after resulted which was the allowed mixtute to was stir foradded Smit: to atrocinHQ {5 The 7-bromo-2'-fluorobenzodiazepinef ... - 12 was stirred with

will and extracted with EtOAC (3x30 mL). The coaiined sodiual hydride and di-Eksphelinyiphosphinic chloride,

organic extracts were washed with brine (2x30 mi) and 65 followed by addition facetic hydrazide, according to the died NaSO). 3 he solvent was removed up:der reduced published procedure to provide triaclobcagodiazepine &

pressure and the residue was purified by flash chromatog- (JY.73, as illustrated it. Scheme 5. } his coupouild 6 Page 20 of 53

US 7,119,196 B2 35 13derwent be pailadium-mediated Heck-type couping is 32.9Hz), 7.22 {t, 1H, F-8.3 Hz), 732.7.55 m, 4H, 7.97 reaction with trimacthylsilylacetylene to furnish the 8-trim {m, 2 A); MS E3 mile (relative intensity) 316 (72), 287

(301), 246 (69), 53 (36), 27 (62), Aria:... Caicci, for ethylsily: substitute: analog 17 (FY1-72). Removal of the C3HN.F.0.6CHOH: C, 70.16; H, 4.37; N, 6.55. Found: sily group from 7 finished the 8-acetyleno triazoic-te s C, 69.98; H, 4.33; N, 16.70. zodiazepine i8 JYl-733.

Procedure:8-Broac-i-uiethyl-6-(2'-fluorophenyl)-41-s-triazoo.4, 3-ai,4-benzodiazepine 6 (YI-73). A solution of 2 (3Y:- O32, 7.9 g, 21.0 mmol) in ELF 50 mL) was cooled in Coci ice-water, and socium Sydride (0.2 g 18 nanol) was added in one portion, Aiter 1 hour, di-4-norphosinylphosphinic chloride (4.84 g, 22.5 mioi) was added, aid the soil.tion --arrrrrrl-resser--- which resuited was stirred coatiaosiy for 2 hours at room a .N. erthsidrus 2ncl: tertiperature. To this mixture was then added a solution of 28 BC: acetic hydrazide (2.47 g, 30 minol) it: n-BuOH (20 mL) and 72% iS).

stirring was continued at room temperature for 15 1xia. Etic N3 solvents were evaporated and the residue was dissolved in -i}{30}:{25 is:} and heated to reflux for 2 hours, n-Butano: i & Co.CHEsthyaHCO3 was evaporated and the residue was partitioacci between samer-ur-R-arrrrrr-ar CBC1 aa?s briae. The CHC layer was dried and removed 20 2. NFC:CH Rinder reduced pressure after which the residue was purified by fiash chromatography (silica ge:, EtOAc) to aiford 6

(3Y3-73, 2.2g, 4.0%) as a white solid; rap 213-24°C.; IR KB) 16, 1484, 1426,134 cm; iiN.MR (DMSod)

$2.56(s, 3:33,428 (d, F, J-12.3 Hz), 5.26 (, l H, in 12.9 xs H23, 7.34 (t, H, -8.3 Hz), 7.29 (i, H, J-7.2:2), 735 is, H, 7.43-7, 68 (n,2i), 7.83 (i, H, J-8.7 Hz), 7.98 (di, : H, 3-3.7 Hz and 2.3 Hz); MS (E) infe (relative intensity)

371 (5), 34 (34), 222 (100), 395 (19), 181 (28), ill (72). H. :- Anai. Calcd to C, FNFBr: C, 5591; H, 3.26, N, 15,09. sha-kN. Found:8-Friulethylsilyacetylenyl-1-tiethyl-6-2'-fuorophenyl)- C, 54.76; H, 3,29; N, 4.4. ry 4H-s-triazolo 4,3-at,4-benzodiazepine 17 (jYI-72). A S sixture of bromide i8 (JY-73, 40 g, 3.8 mao:), trimeth rwar-rriremar yisilylacetylene (9.5 g. 6.6 pol) and bis(trighenylphos cEi(ON::NE phie)pai?adium (E) acetate (0.25 g, 8.33 innol) in a mixed

solveat systeux of CHCN 80 mi.) and anhydrous triethy.

a?uise (58 B.E.} was heatei to reflux under arga. After stirring for 2 tours atrethix, the mixture, was cooked to room teinperature at the precipitate wick foraeci was removed 4) by filtration. The filtrate was concentrated under reduced pressure and the residue was treated with a satirated aque ous soiution of Naft C (40 mi.), and extracted with CEC (3x58 rail), The combied organic extracts were washed with brine (2x10 mi) and dried (NaSO). After removal of

soiveti u ider reduced pressure, the residue was purified by 45 flash ciromatography (silica ge: it{Ac} to afford 7 (BY PiCAc)??h: CHy(R.Ety S-a-E, reux 22, 2.5g, 77%) as a gray solid: inp2i 8-219 C.; IR (KBry 2958, 2157, 6.2, 537, 3493, 1452, 1337, 3249 crat; ; NMR (EMS?)-d) & 8.2 s, 9 ii), 2.56 (s, 33), 4.23 (s, 1 it, 3- 12.9 Hz), 7.26 it, l H, 3-8.4H2), 7.29 7,83 (m, 63); MS (En?e (relative iniensity). 388 (553,373 i4), 359 (77), 304 (44), 52 (100), Anal. Calci fit CEN.S.0.7HO:

(6ssifican, 9...f.i.538,534'N, 33.93,

4,3-ai1,4-benzodiazepine3-Acetylene-i-methyl-6-(2-fluoroghenyl)-4H-s-triazole : 8 (YT-78). A solution of 17 (JYI-72, 2.0 g, 5 airinol) in TEEE (2 m) was treated with

BNF (4 EE (34 solation in HF. & II.ix:re whicl:

TEAixF) resulted was allowed to stir for 5 miti at room temperature -r-arms ailer whic: the inixture was added to HO {2 in) and 3. extractext with CHC: {3x59 mi.). The combined organic extracks were washed with brile (2xiš a) and dried (NasO). After removal: if soivcut under reduced pressure,

t3& residue was puried by flash chromatography (silica gel,

EtOAcMetJH: 00ft) to attird i8 (YI-70, E. g., 70%) as a pale yellow sosid:mp>250° C. (dec); ER (K3r)3285, 1612, 65 22 XLE-JY-SA-3AS 1493, i426, 13 i7 en'; H NMR (DMSO-i} 82.54 s, 3 H), 4.23 (d. 1 H, a 2.9 iiz), 439 {s, H), 5.26 (d. 1 H,

Page 21 of 53

US 7, 19,196 B2

C. aai a 60% dispersion of sodium hydride {3.86 g, 92 axanol) was added in one partion. the mixture was a towed to warm to it with stirring aid the stirring was continued at rt stiliositore bubbles were evolved. The suspe:sio was cooied to -5° C. after which di.4-morpholinylp:Exgiriaic

chloride (2.8 g., 86 mac:) was aided and is alixtire was stirred for 30 min and a:Wed E?warm to ?t. She alixture

was stirred for an additionai 3.5 hr. To the mixture was thei).

added a solution of acetylhydrazide (9.42 g, 34 mExcl. ii.

butanoi (60 E.8ai stirring was continued at it for it tail,

The solvent was removed side reduced pressure and the

residue was take up in butaiaoi (100 m?...} and held at effux

for 2 hr. Butano was resnoved under reduced pressite a list at a tie residue was partitio:ed between ChiCl. (200 ai) and

23 xLi-Y.EMH) 1s HO (100 ml), Tile 33 layer was extracted 4 times and the organic layers combitted. The orgagic layer was washex: 2-Amino-5-brorso-2'-chlorobenzophenone 19 was with brine aad dried (N&SC). After tie 36:veit was obtaired from simple starting Eaterials. 4-bromosailine and removed sider reduced pressure, the residue was crystal

2-chlorobenzoyl chioride, according to the improved con- lized from EtOAc-Etc. to provide the pure triazolobenzo ditions in the literature.” The benzodiazepine 20, available 20 diazepite 23 (dim-11.90, 14g, 63.2%) as a yellow solid: ; p. iron reference i, was stirred with sodiata isydride and 265-267 (, lit 274.275° C3°; IR (KBry 3:20 br}, di-4-morphinophosphinic chloride, foilowed by additig. 686, 479. 1386, 1834, 827, 747 cm; F NMR (30) of acetylhydrazides furnish Bia?olobrazdiazepine 23 MHz, CDC), 82.42 (s, EH), 4.18 (d, H, Jel 2.3 Hz), 5.56

(in-il-90), he ligand 22 (XLi-Y-OMH-FMS) was (d. 1:, .29 Hz), 736 (m, 3H), 7.43 m, 2H), 761 (m. obtained by a Beck copigg reaction of 2i (ilia-i?-90) with as iti, iso (di, Ei, J-2 Hz, 8.7 Hz; MS (EI) nie (re tirety syllacetylessengend was covered intensity) 385 (M', 45,357 (100, Ana, Caled For into acetylne 23 (X-Y-IMH) on stirring with fluoride crisis,cisio. 6 si65.H. Sai, N. a.is. Found asion as shows in Scheme 6. (, 5.95; H, 2,97; N, 3,91 2-Amino-5-broaq-2'-chiorcherzophenote 19. 8-Trimethylsiyiacetykesyl-5-(2-chlorophecy:)-1-(i.e- 3-Chlorobenzoyl choriie (177 mi., 4 moi) was cooled in 33 thy-4H-s-triazol-4,3-3-1,4-be:32ediaepine 23 XI.i-JY a 3-, task equipped with a coticlenser and ather:Ometer to DMi-MS).'"

{{, with an ice-water bathaadi-biomoaime (100 g, 0.58 T i--. -- "f Y ..

tol) was added to the cooled soit:tion, The mixture was G f.A.R. SR SE SE analysisheated by29 ic andindicated kaisterprisis bromotine had been til cons E.diacetate E. E.Emali was degassed. ise - sned to Acie ancii), the solution was heated yisilylacetylene (5.6 mi., it anol) was then added adhe

60 candanhydroasznci, (95g, 07) mol, famoi died) solution was degassed again. The solio was then heated was ided in oxie portion. The temperature was increased to reflux f3 4. hrutil 8talysis by il Cindicated the stating

35° C. and stirrig was saintained at this temperature for 11laterialconcentrated had disappeated.inder reduced The press mixture tre. The was residuecooled wascr; parand 3coxled hr until to 1120° more C. bubblesBraq FC were (12%, evolved. 350 The mL) aixture was added was titioned between H0(58 mi) and EtGAc{2x200 mi.).3 he

dropwise slow}y, he mixture was kept at reflux for 20 min, cabined organic layer was washed with brine agd dried

aftet which the acayer was poured off. '88is procedure with (NaSO). The residuc was purified by flash chromatogra

3g HCl was repeated 4 times, Water (350 nt) was then phy on silica gel (CHC,) to furnish the triaethylsily: added, and the mixture held at reflux for 20 mi;3 and then the anakogue 22 (XLi-YDM:I-TMS, 3 g, 37.0%) as white water was poured of his was repeated several times until ' solid mp. 265-267 c.; ER (KB 2936,1618, 558, :49, the solid was to a lock any mere. Thea i...SO.(72%, 09 1429, 315,885, 847 cm; H NMR (30 MHz, Caci,) 8 m) was 8died to the residue and the mixture was heated to ().24ts, 9H, 2.65 (s.3H), 4.15 (d, H, J-2.9 He, 5.52td,

elius or abey bruntil the reaction sixturbecame a iii.; i39,735.74s (SH), 76 (ra, H}, 7.72 (dd homogeneous dark colored solutios, the hot acidic solution H.3x3 8 d 84 ity. MS RE) mic (rel intensity i): (M.

was poured into a mixture of ice and water with stirring the 30 56). 375 (3 o, Anal Cascarorchisicissisi, precipitatetarge arolift which of coki resulted water was until filtered the pH and value washed of the with solid AcetylenosN,386. Found (6.... 99. "...i.2.98. N. ... a.k.

was aboutT 6, he solid was ther suspended in ice wateris yiri, and 4-a-3,4-benzodiazepine-Acetyleno-5-2'-chlorophesy-lethyl 23 XI. JY-DM). H-s-triazole adkarao. 296 was addedicarcity imitre it's which resulted was stired for 2 hrs, lic sold was filtered ss Asok:tion of betwodiazepine 22 (1,25g, 31 rurao) in H}.

aid washed with ice water, ihe E.Solidia ice (250 mL) was cooled to -30° C. and treated with

Walt was used carefully to appxiately pH-3 with 89 BaNRxHo (0.9 g, 37 mil). After the mixture was

*:SO (40%) lipwise. The solid which resisted was sticed for 5 min, analysis by c(sibcage; EtoAcEto:

is: it. sh was it acut;Fa y 4:ii) indicated starting material had disappeared water (70

solid 1966, g33) was tried andlessly the mi was then added and the mixture was a:owed to wat:3: E. girl prisis E. NE t tart, 3 he mixture was then extracted with 3:EOAe (2x300 35.49 {s, ty, 2H), 5.65 (d, H, J-8.82 Hz), 7.26-7.8 33.3. The organic layer was washed with briie and died

{a,8 6H).Bromo-5-(2-chorophenyl-3-methyl-4sis-triazolots, (NSO). It

3-al-i,4-benzodiazepine 21 din-II-90). pressure, the residue was washed successively with ethyl

is ether, ethyl acetate and chlor(form. After drying, the title A solution of benzodiazepine 20 (20 g, 57 mmol, available compound 23 (X13-JY-i}^48) was obtaisied (1.8 g. 97.3%)

from rešerence l) in dry iHF (250 on...} was cooled to -5° as a white solid: mp-259° C. (dec), IR (KBr} 385, 3623,

Page 22 of 53

US 7,119, 196 B2 39 4. 543, 1497, 429, 756 ca'; 'HNMR (300 M CEC) goom temperature for 3h followed by acidition of th: alcohei si, 37 (s,t), 4.18 (, i. i2).55 {o eq} and IBU ( ea). The stirrig was trait:tained until air, 2.3 Hz), 7.34 m, ii), 4:Sh, 7.5 m, the disappearance of at the starting materia: as desertained i.75dd, H, J-18 Hz, 84 Hz). MS (E) tie rei by LC(E:OAc:EtOH 4:E), The reaction taixture was the intensity) 332 (M',78) 303 (38). quenckei by aciding water. The solid which precipitated was

S? --

GCSi it, CECS sex

3g cir-E-33 33-3-35) C.C.Hi.F.

------arr FCC

41 di-,-20)

Esters 37 tim-i-30). 38(da-1-33) and 41 (d.1-20 attered and washed with ethyl ether, it was purified by fash were prepared according to the getgrai procedure described chromatography (E10Ac) on silica geet restral ailinitial isitein 6087 from the starting acids and different alcohols oxiie for ester 38. respective:y. The promide 3 was converted into the tri Tiflaroethyl 8-brono-6-phenyl-4H-benzo finidazoli, methilyacetylenyi compoutsi 38 (din-I-35) under staikdard 5-aii,43diazepine-3-cartoxylate 37 (dru-33-30}. coctioned-mediated, ileck-type coupling" * (Scheiae A white solid (69.1%) from acid; 27 and 2,22-trificroetha 7). pol; mp 202-204°C. R. (KB) 3114, 1711, 68, 495, Geaera procedure for Prepasing the Estes. is 38,288, tissem, EINMR (30 MEE, CECs), The acid was dissolved in DM: (i) ilihinmol S.M.) and (8, ti, 3-2.6 Hz, 4.68 (mi), 4.85, EI), 6.03 (d. 1, CDI (3.2e was addict. The reactical fixture was stified at 126 Hz), 7.4-7.54 (m, 51), 7.62 {d, H. - Hey, .83

Page 23 of 53

US 7, 19,196 B2 4. 42 (dd, 3-, 3-2. Hz, 8.4 Hz), 7.97 (s, iii); MS {E} Efe (rel intersity) 453 (M', 14), 483 {34}. -contined Erichoroethy: 8-brome-6-paenyl-4H-be:3zotilitiidazoli, say 1,4-diazepine-3-carboxylate 38 (dim-li-33), A white solid (90.9%) from acid 27 Lad 2,2,3-tricitor hapoi, p 3.15° C.; R (KBr) 3434, 1728, 610, 93, 10, 136, 128 cm; NMR 30)MHz, CDCl3) 84.1 (i, H, J-126 Hz), 49 (d. lti, -1282), 5.19 (d. iii, HCSi43 -:20 Hz, 5.2 (d, FI, J-2.5 Hz), 741-7.54 (m, 6H), 76 (d, H, 3-2. Elz), i.83 (dd, H, J-2. Hz, 8.4 Hz); MS (E) use (rel intensity) 54 (M', 4S). misheroethyl 8-trimethylsitylacetylesyl-6-phenyl 8cizo::::Ficiazil,5-aifi 43iazepine-3-carboxylate 39 5 kia-I-35). A white solid (49.8%: mg 107-10°C.; 18 (KB) 296. 734, 6, 1560, 1497, 3251, 359, 1120,846 car; B. NMR 300 MHz, CDC, 80.25 45,9H), 4.08 (d. 1, 2.3 ii., 469 (in, E1), 4.84 (i, H), 5.98 (di, H. 123 Hz), 739 7.37 m, 7}}, 7.75 (dd, H, -1.8 Hz, 8.4Hz); &S Ei mere intensity) 48l (M', 188). 3riuoroethy: 8-acetyltenyl-6-phenyl-4H-beExotin:- dazo:S-aii,4}ctiaze-pine-3-carboxyiate 41 (du-I-20). A white said (36.9%) from acid 48 and 2,2,3-trifluoroetha' g4 XL 225) noi; mp 188-90° C.; :R (KBr}3443, 3377, 1713, 1600, she bronicle 1 was reacted with diethylphosphortchlori 1492, $366, 1280, 1156 cris, ENMR (508 MHz, CDC,) date in the presence of sodiufi sydide, followed by aiditio: 83.8 (s, 1H), 4.08 d, H, -12.5 Hz), 4.67 (ira, H), 4.83 ort-butyl isocyanoacetate to provide the ester 42. This was (n : H], 5.98 d, lil, 3-13.5 Hz), 7.37-7.40 (in, 2), converted into the trimethylsilylacetylcito Coalposed 43 in 44.75 m, 3H, 7.56-59 km, 2H), 7.78 (dd, lii, is under standard conditious (Pai-lediated, tieck-type co Hz, 8.5 Hg), 8iS (EI) 3fe (re::itensity} {29 M, 28), Aaal. ping) treatment of 43 with flurride gave the title con calci. For C.H.N.O.F, 0.25H2O: C, 63.82; i. 3.72; N, potted 44. 0.16. Round: C, 63.89; , 3,37; N, 9.94, Procedure f: Xii.225 3utyi 8-brome-6-phexyl-4H-benzo finidazoli, 4.d38zepine-3-carboxylate 42-isis enzodiazepine 4 was obtained in 48% yield in analogous to the literature Scene S; procedure as a white solid, 42(Xii.22). TE 2229.3°C. ER (KBr 2975,2358, 1717, 1608, i557, 277, 1973, 908, 696, 65.2 cm; H. N&ER (COCl) 8.68 s. 91), 483 {d, H.-12.5Hz), 6.08 (d, 3H, j-12.4 Hz), 3532 (iii) )waii, THFAMF 7.58 (d. 33, J-22 Hz), 788 (dd, H, - 22 x and 8.55 CEPCOEL, OC,lw! Hg, 7.93 (s, H.), 2NiH, Mif -Butyl-8-triaeisylsilylacety:enyl-6-phetyl-H-benzo f CNCHCCE 8 inidazol,5-3,4-diazepine-3-carboxylate 43 (xiii.224).3.timethylsilyacetylese A fixture (559 of mg, brotide 569 42anal) (2,228 aid bistripil ture, enylphosphiae)-palladium-(l)aceta (55 mg 0.073 stimol} in mixed soivient systein of Chicx (15 ai) and any dross EA (25 mL) was heated to Felix uder aga, Afte: stirring for 5 hours at refix, the mixture was coolist FC temperature and the precipitate which ormed was renovel by filtration, The filtrate was concentrated acter reduced pressure and the reside was treated with & satirated agit (CHsi-e-E: silion of Natico, (20 mL), 3rd extracted with CBC's soap...“ (3x25m). The combined extracts were washed with brige E. and dried NaSO.). After estigwai.of solves upierreduced reflux pressure, the residue was psited by flash chromatography silica gel, EtOAc) to afford 3 XLi224) as a white Soid song, 68.9%). pp: 234-235 C. R. KB 293.2 18, 9.16, 1493, 366, 1250, :52, 1975,946, 88 32 & 23) c: NMR (CDC), 8 0.23 (8, 9H}, i.6

Page 24 of 53

US 7,1 i9,196 B2 4. 44 7.37.7.53s, 93, 4.65 m, 7:3),(d, 7,73dd,F, J-32.7 H,Hz), Jr.95 686 abd (d. 8.2SHz), Hi2). 7.9. -continued (s, H, MS (EI) me{relative intersity) 427 (M', 753,432 5,381 (SS), 353 (139303 (10), 287 (7). -Buty 8-acetylienyl-6-phenyl-AH-benzolinidazolls a .43diazepine-3-carboxylate 44 (Xi 225). A solution of 4328 mg 0.281 mmol), in THF (5 mL) w88 treated wit: pxFH3 (0.04 mg, 2.38 mmol). The mixture which sited was allowed to stir for 5 min at root temperatt after which the mixture was added to Ho (10 mi) and extracted with :OAe 3x5 mi). The coilbined organic extracts were washed with brine (15 mi.) asid dried Naso. After removal of solventucker reduced pessure. the residue was purified by a wash count silica gel, OAc) to firsaigh 44 (Xili225) (92 1112, 85.4%) as B white solid; mp: 221-223 C., R. (KBr3159,3107,2092, 172, 66 en; ENMR (CDCl3) 8 i.6. (s, 9H, 3.21 (s, H), 4.2d, 31, -33,282), 687 (di, H,-12.5 Hz, 35-7.53 (m, n, 773 (8d, H., f=}.8 Hz and 8.3 Hz), 7.92 s, E).

4s. T-33) 7-Bromo-3'-fluorobenzodiazepine 13 was hydroly? with a 2N sodium hydroxide in Etoil and acidified to pH s 4 by adding 1 NHCl to afford the acid 45. he acid, obtained from the ester 3, was stirrect with Ci in DMF, followed y stirring with trigoroethailol and EBU to provide the ester 46 (JY-049). This material 46 was theated with trimethysi yacetylene inatieck-type couping reaction to provisie the trimethyisilyl amalog 47 (Y- (53). The silyl group was removed from 7 on treatment with tetrabuty:Enhygium iuoride to furnish 48 (YI-359) in 70% yiei. rocedure:8-gromo-5-(2-iluorophenyl)-4H-heaZofiliilidazol, 14 diazepine-3-carboxylic acid is. The ster 3 (3.0 g, 2.36 mino) was dissolved in Etobi (80 tal.) 3rd a NaOH. (8 anil) was added to the solution, the isixtire was sited at it for 4 hours. After the EtOH was regioved 1Biker reduced pressure, the sciution was 8lowed to cool. She pH OCH CE value was adjusted to 4 by adding NHC dropwise, the mixture was filtered and the solid was washed with cki water and ethyl ether. She solid was tried to afford 45 (3.96 g, 97%) as a white solid; mp 280° C. (sec); ER (KB) 349, trieststyle:Syers 740, 63, 491 cm '; 'A NMR (DMSO-da} 84.11 (bs, XE1iPascarts C: E, & H,599 (bs, 1 Fry, 7.20 (t, a1H, J-8.5H2), 7.32 (t. H, i. Hz), .38 (d, 1 E, F-1.8 Hz}, 7.55 (in, 2H), 7.84 (d, H, -8.7 Hz, 3.95 (di, H, -86, 39 ig), 8.35 (s, II). MS (E) use (reiative intensity) 400 (72), 399 (85). 381 (108), 35S (82).

Page 25 of 53

US 7, 9,196 B2 S 46 Trifluoroethyl-8-bromo-5-(2-fikorophenyi)-4H-benzo(i) extracts were washed with tie (2x50 m...} and dried imidazo,5-ai,4-diazepine-3-carboxylate 46 (Y-349), (NaSO.). After renova: of stylved under reduced pressure, The carboxylic acid 45 0.89 g, 2.23 uncil was dissolved tise residue was purified by flash caromatography (silicagci, it dry IXff (20 ml), after which CD: (.72g, 4.45 mmol) hexages.EtOAc: 3:1) to afford 47 (JYJ-053, 360 mg, 76%) was added at raid the mixture was stirred for 2 hours. The as a gray sciiti II; 220-221 C.; ER (CHC) 3:60, 741, trifluoroethanoi (0.49 mi., 6.68 malol) in DMF (i mi.a3d 1612, 1496cm; H NMR (CDC,89.25{s, 9H, 4.12(bs, DBi ().37BL., 2.45 anol) in D&F (lini) were the 8cided H, 4.82 (bs, 2 H, 6.18 (is, H), 7.06 (t, E3, 3-8.3 Hz), to the Hixture and stirring continued overnight, the silverit. 7.30 (m, 1 }I), 748 (1, 2 H, 7.56 (d. 1 H, J-8.3 Hz, 7.67 was evaporated under texticed pressure and the reside was (m, 3 H), 7.73 (dd, F, J-8.3, 1.8 Hz), 8.02 (s, H. MS purified by flash chromatography (silica gel, hexanesi (Ei} mate (relative intersity) 439 (52), 339 (45), 37 (90), EtOA: 3 E} {{afford 46 (3 Y-049, 3.81 g, 76%) as a white 235 (2i}, 78 (36). Anai. Cakcd, for CiNOFSi: C, solid: np 223-224°C.; ER(CHC) 3363, 1732, 611, 1492 60.1; H, 4.24; N, 8.43. Found: C, 69.27; H, 4.22; N, 8.33. cin; H NMR{C}}C., 34.i 6 (bs, 3 H),483 (bs, 2H), 6.87 s Trifluoroethyl-8-acetyleno-6-(2-fluorophenyl)-4H-benzo (bs, H), 706 (d:, ; H, -8.3, 0.982), 7.30 (m, 2H), 7.48 finidazolS-a:4iiazepite-3-carboxylate 48 (Y- (al, 2 3i), 7.68 (dt, 1 {I, Je?.6, 3.8 biz), 7,88 (di, H, J-86, 859). A solution of 47 (JY3-053,475 mg, 1.0 m3)}ol) in THF 2. Hz), 8.: (s, lid. MS (EI) m?e (retative intensity) 483 (15 ml) was treated with BuNP (2 till, .3i solution: in (38, 383 (64), 335 (180). Aral. Calcd, for IHF). The mixtuae, which resultai, was awed to stir or CHN.O.F, Br: C, 49.81; i, 2.5l; 8, 8.7, Found: C, 5 mi) at coal tet: ;erature after which the mixture was 49.97; 8, 2.34; N, 8.68. added to 3.5 m. and extracted with EtOAC (3x} (ti). Iri?hBoroethyl-8-timethyisily:acetyleay-6-2'-fluy the coabined organic extracts were washed with brine rophenyl)-4-benzo finida2O,5-aii,43diazepine-3-car (2x0 mL) and dried (NaSO.), The solvent was regioved boxylate 47 (FY-053), A Faixture of bromide 46 (Y-049, wder reduced pressure and the residue was recrystallized 482 ag, .0 minol), trimethylsilyacetylene (3.28 m, 2.( from ethyl acetateihexanes to afford 48 (JY-359, 299 mg, me!) and bis(triphecylphosphine)paladian (l) acetate 70%) as a pale yelow solid: np i92-193 {..., R. (CHCi,) (75 rig, 3.1 mitici) in a mixed solvent system of CHCN 30 3295,3052, 743, 1612, 1494, 277, 359 cm, H NMR (25:ii) atkia:ydrous triethylaimine (25 mi) was heated to (CESC, 33, 4 (s, H), 4, 7 (bs, H), 4.78 (bs 2H), 4,47 reflux under argon, After stiring for 12 h at reflux, the (S, ) H), 6.05 (bs, : H), 7,05 (dt, H, J-8.3, 3.8 Hz), 7.30 inixture was cooled to room tetapezature and the Fecipitate (us, H), 748 (ra, 2 H), 7.60 (ii, H, Ja-83 Hz), .68 (dt, which forted was reakoved by filtration. The fitrate was 35 1H, Jai,6, i.8 Hz), 7.76 (di, B, Jri{3.1, 8 Hz), 8.92 (s, coEaccitrated under reduced pressure and the residue was Fi); MS (EI) infe (reiative intensity) 427 {37), 337 (26), ticated with a saturatedaq solution of NaHCO(40:E.}, and 299 (2003, 178 (50), Anai, Caici, if ChiN,9.F. C., extracted with CHC, {3x300 mi.). The combined organic 53.83; H, 3.07; N, 9.83, Found: C, 61.94; H, 303; N, 968,

8E. icers.

Xah, THE

5 (in-3-73) 49 PS1.27)

ma &ES xual

EN. (HCN

Page 26 of 53

US 7, 19, 196 B2

-cottiliucci

TBAE3, TE

5iS-3.363 53(PS-I-28)

Ns 4A molecular sieves E.THF a;

C-3:His

i XH-E-53) This compound 49 (PSI-27 was obtained ia 47% yied Ethy amido oxiute (59.5 sig, ),676 moi) was added to from 5 (dan--70) analogous to the procedure et:ployed a stirred suspension of powdered 4 Å molecular sieves (75 0885; as a white solici. Eup: 218 CFR (KBI) 31 G6, 63i, ang) in aailydrous TBF (15 mL) untier nitrogen. After the 563,493, 147,931,698 cm; 'H&MR (CECs) 58.06 mixture was stirred at rt for $0ttin, Nah (27 Sag of 68% in (s, iH), 7.84 (di, H, 3:8,6Elz, J-2.25:iz}, 3.63-7.38 (iii, mineral oil, 0.676muel) was added to the mixture. After the it), 6.33 (i, H1, -12.9 lz), 4.23 (i, H, J-32.9 high, 3.23 mixture was stirrei for a further 30 gia, a Solution of the (s, iH), 2.88 and 2.83 (AB3. 2, J-76 Hz), 1.4 (.3H, forgoing esteri (Xie I-953, E2 mg 0.338 milk:) is: HF j:76 six; his (niz) 435 (0). (20 mL) was added. The trixxxe which resulted was heisted To the suspension of collapouad 49 (PS-3-27, 3.5g, 1.15 to reflux for 8 hit. It was cooled to rt, after which acetic acid macy in acetonitriie (30 mL) and triethylamine (8) LE.) 43.6 ing, 8.676 innaci) was added. After the slitic was was added bis(triphenylpix.csphiae)palladiutil{ii} acetate stirred for 10 tuin, tie axixture was filesed through celite. (0.086 g. (3,115 ruino), he solutics: was degassed Biki the filtrate was diluted with CHC (50 mL) and washed trimethylsilyacetylese (0.33 mi, 2.3 mmol) added, he with water, brine and dried (KCO.). Evaporation of the aixture was heated to refux and stined overnight. Afte: solvent inder reduced pressure afforded 3 pale yellow solid, removal of the solvent, the residue was dissolved in CH-Cl: which was purified by flash colunxin chronatography (silica and washed with a saturated agacous solution Nahcos asid gel, EtoAc:hexane, 2:3) to firgish Si as 8 white solid brine. Fhe organic layer was driexi (Na2SO4} filtered azid (Ps.i.26, 52 mg, 40%), inp: 221-222" C.; ER (KBr) 3297. concentrated under vacuu:1. The iesidue was purified by 365,163,570, 3495, 318,338 cai'; ': NMR (CDCs) fiash coluaia chromatography (ECAchexane 2330 fir 8807 (s, E), 7.8() (dd, H, J-8.4 Hz, F-18 Hz), 7.34-7.63 nish the trimethylsilyl analog 50 (PS-3-28,389 mg, 73%. 88 {m, 2EE), 7,53-7.37 (m, SH), 6.2 (d, Ei, I-32.9 Hz), 4.21 a pale yellow solid: rap. 93-194°C.; ER (KBE) 3:08, 29.50, {d, ; H, -12.9 Ex, 3.20 (s, H}, 2.88 and 2.83 (AB4. 23, 249, 1630, 1567,3493, 938,851, 70 cm; 'h MMR (300 J-7.6 Hz, 3.4 (t, 3H, J-76 Hz); C NMR (CDCl3) is H, CBC, S 8.07 (s, iH), 2.78 (dd, H, J-1.86, 834 lz), 178, iii.6, 168.8, 39.1, 1366, 35.8, 35.4 (2C), 35.l., 7.6.1-7.38 m, 7H), 6.1 d, J-2.78 Hz), 4.39 (d, J-2.78 30.7, 293 (2C), 128.3 (2C), 28.3, 24.7, 122.7, 12,6, Hz), 2.88 and 3.83 (ABq 2R, 3-7.56 Fig), 4k (, 3H, 812, 80.3, 44.7, 19.7, ii.5; MS (m/z. 379 (100). 1-7.56 Ez), (3.25 s, 9H).

Page 27 of 53

US 7, 19,196 B2

FOAPE's --e-Sis EN, CHN Rix -Si

53 (XL:33G)

55:352.

the broutide 20 available from refereuces 9 and 0 was * (silica ge. EtoAchexapes: 1,1} to furnish, 528S 8 yellow reacted with triraethylsilyacetylene in the prese:Ice of a powder (310 mg, 59%: mi: 25.8-2.28.2° C. R. KBr} paitadium catalyst to provide trimethylsilyl analog i. iii.3 3953,2358, 685, 66,3490, 328, 1248, 1858, 3.841, product was methylated with methy: glide's dium hydrie 46 cm, H NMR (CEC) & 0.21 (8, 91, 4.38 (s. 2::), to give the N-tethylbenzodiazepine S4 (Xli35). This is 741 d, H, -8.37 Hz), 7.9–7.53 (br, H), 8.il (s. H), subjected to fluoride-mediated desilation to furnish 53 (XLi MS (E3) infe (relative intensity} 366 (Mi', iO6), 33 (59), 350 and 5S Xii. 352). 229(38), 6-26), grocedure for XEL: 35 and Xii 352 i-Acetyleno-5-phenyi-(2-chloropheny) 3-dihydri 7-trimethylsily:acetylene-3-phenyl-(2-chlorophety) benzoej-3,4-diazepin-2-cite 53 (Xli 35(3): Asylution of 52 3-dihydrobenzole),4-diazepin-3-one 52 Xi 343).388 A . 150 g (.408 inol) is HF (30 mi.) was treated with sixtire of 20' (500 mg, 1.43 amoke) available ion fier tetrabusyammonium fluoride (M is iii). The fixture cnces 9 and 18 it triethy: arisine (10 mi.) and CN 6 was stirred for 2) Bainutes at roots temperature before water mL) with trimethyl-silyacetylene 126 gig. 1.28 minole and bis(triphetyphosphine)paitadium(II) acetate (64.3 mg, (36 in: ) was added, The Luixture was the extracted with. 3.86 nano was beated to reflux under nitrogen. After 6 tCAc (3x33 m3), The consibited organic extracts were huts, the reactic trixiute was cooleito Rom experature washes with brine and dried over (Na:S0). Rh8 Scivett and filtered. The filtrate was concentrated under vacuutti 8td was renoved under vacuum and the sesidue which resulted the residue was treated with a Saturated aqueous Natics was passed through 3 Wash column (silica gei, EtOAC/ solution (5 mL), and extracted with Chic: (3x2 m). hexanes: 43) to give $5 as sight yellow crystals ig. The organic layers were collibiised 83d washed with xine 95.2%); rip: 25° C.; R (KB) 3290, 1685, 1815, 49 and 3rica (Naso). After retieval of solventuader reduced 1328, 13 ca, HMMR (CDC1,) 3306 is, 1 EI), 4,4} {s, pressure, the residue was purified via flash chrottacgraphy 34, 7 O3-7.61 (m, 7H), 7.58-786 (iii, 2H), 7.99 (s, if);

Page 28 of 53

US 7, 19.96 B2 5. 52 MS (E1 Erie (relative intensity). 29. {M, 300), 266(75). -coatinued 26587),Methyl-7-triglethylsilyacetylene-3- 259(83), 23i (40), 201(24), 623). ghenyl-(2-chlo raphenyl- 3-dihydro-benzo(e-1,4-diazepin-2-one 5 X:...i 351). A mixture of 52 (300 mg,0.82 mino) was dissolved it iry HF 40 int.) at ()" C, and Nali (68% in mineral oil, song, 3.25 nanol) was added to the solution in the portio, The slurry was the stirred for 28 min at 6'C, and CHI (139 sg, 3.98 inmoy was added to the mixture and it was warried up to room tettiperature. After the sixture stirres for hours at rooan terriperature, the Thi? was the renovec ide: reduced pressure. The residue was parified by flash citro matography hexages.E.A. (3:4) to provide the title coin pound 54 (360 ing, 83%) as 3 white solid; trap: 96.9-98 57 (Y-53) C ER (KBr) 2953, 1676, 1618, 1489, 3346, 325, 178, 93,742 cm-1; H NMR (CDC,Šppm} 0.2}{s, 9H)3.6 7-iximethylsilylacotyleno-5-(3'-fluorophenyl- 3-dihy (s.3H), 3.54 (d, iH, J-3.9 Hz), 4.50 (d. H. J-10.8 Hz), drobenzoie-i,4-diazepine-2-0:1e S6 YT-55). A fixture of 7.28.7.43 m, 5H, 7.58-65 (g), 3EE). MS (E) u?e (rela bromide 2 (1.6 g., 5.0 inmol), trimethylsilylacetylee. tive intensity) 380(M., 8), 366(t)), 308(380), 280(88), in: 2.0 Enc:) and bis(triphetylphosphine)palladian () 27397), 245(61), -Mety .7-acetyleno-5-phenyl-(2-chlorophenyl,3-di accitate 375 mg, 0.5 minol) is a mixed ${ive1st Syster s hydro-benzoie-1,4-diazepin-2-Qae SS {X11 35): A solu CHCN (60 mL) and anhyixous riethylaxine (4) ml) was tion of 54 (300 trig. 3262) in IHF (30 mL) was treated with beated to reiux under argon. After stirring for 3 h 8 refix: tetrabutylammonium fiacride (IM in Elf. he aixi Ere the mixture was cooled to roora temperature and the pre was stirred for 20 minutes atrocal temperature before water cipitate which formed was removed by filtration, The filtra (30 mL) was added, site inixture was the extracted with was concentrated urder reduced pressure and the residt Es(Ac 3x30 mi). The combined (Eganic extracts were was treated with a saturated aq. Soiution of NaCOs (9) washed with brine as dried (Na2SO.). The Sovett was mi.), and extracted with CHC (3x200 (Eii). The coined removed under vacuum and the residue which resulted was organic extracts were washed with brine (2xt{ {ii} and passed through a wast; coluxili) (silica gel, iCAchexities: dried (Naso,). After removal of sovent under reduced 4) to give SS as light yetlow crystals (71 mg, 93%); mp; pressure, the residue was purified by flash chromatography 956.98°C, IR (KBr; 2953, 1677, 1489, 1346, 309;,791, (sica gel, hexanes EtOAc: 27) to atford 56 (YI-55, 794 749 cm-, 3 NMR (CDC) & (ppm} 3.850s, lii). 3.46 (s, ag, 47%) as a gray solid: mp368.5- 59.5° C.; ER. (CEil) 3H), 383 (c., H, J-10.5 Hz, 4.87 (d, H, J-933 Hz), 5,28 3202, 3313, 2955, 1686, 1632, 3490 car; E: SMR ts, 1H), 7.2.7.43 (al, SH), 7.58.786 (n,2H), 3:S (Enge C: C1,) 58.22 (s, 9 H, 4.38 (s, 2 H), 7.34-7 33 {a, 3 H. (relative intensity) 308CM, 30), 2949), 28882), 273 7.34 ts, 1 H, 7.45-7.53 (u, i :), 7.56-7.62 (ins, 2H), 3.3 (99,249(28), 245(6), 229(29), 201 (32), 189(43). its, H. MS (EI) me (relative iatensity) 350 (94), 322 (00), 167 (43), 153 (37). Anal. Caled. for {{i,NOFSi. C, 68.s: -, 5.46; N, 7.99. Found: C, 68.23; fl. 5.40; N, 8.34. 7-Acetyleno-S-(2'-fluorophenyl)-l 3-dihydrobenzofei, 4-diazepine-2-one S7 (JYI-68). A solution of 56 (Y-55, triraethylsily:acetylete 79 mg, 2.3 minol) in THF (200 sili) was treated with 3Pic) BNF (2 al., 1084 soitatic:1 in fitF). Tie inixture, wikich. NEts C-CN. A resu:ted, was a lowed to stir for 5 min a rocit camperatus: after which the mixture was ackies; to Ho (5 ni-) at extracted with EtoAc 3xi{ inl). The cottsbined organic extracts were washed with brine (2xi8 in I.) and dried (NaSO). After the solvent was retroved under educed pressure, the residue was purified by fast citromatography (silica gel, hexanes/E:OAc: 21) to afford 57 (JYi-60, 400 mg, 72%) as a paie yellow solid; ing 208-09.5° C.; 38 (CBC, 3290, 30, 2930, 1685, iéi2, 489 can'; 'H NMR (CDC1, S3.04 (s, H), 4,4} {s, 2 ti), 706-728 (). 3 : ), 7.38 (s, ID, 7,44-7.5i (m, lil), 759-7.62(n), 2 H), 943 (bs, 3 H). MS (Ei) rate (relative instersity). 278 (8), 250 33 (180), Anal. Caica, for CIA, NOF: C, 73.37; i. 3.38; N. 56 (3.55 37. Fostd: C, 73.64; H, 3.92, N. 9.8.

Page 29 of 53

US 7, 9,196 B2 cially awaiiable item Acros. The benzodiazepine 6 W3S eace with diethylphosphorochioidate in the prostic of sidium hydride, followed by the adition of ethyl isoxy anoacetate to provide the esta 63 (H2O), is shown in Scheie 13, Ethyl 8-iodo-8-phenyl-4H-benzofimidazoil,5-8: diazepine-3-cartoxylate 62. A solutier ofbenzodiazepite 60 Br(OCBI, 8:C: (38.3 mmol) in iry 'HF (36 mL) was cooled to ( C is 2NE: MeOH a 60% isspersion of sodius) hydrisie (0.7 g : mo) was aideinoise portion. The sixture was allowed to WR with stirring ad tie stirrig w88 continued at it until moebbies were evolved the suspension was coole 6.C. after which diethylphosphorachioridate (239 g, 3. namo) was added and this sixture was stirred for 30 shi: and allowed to warm to it. The mixture was stirred for as nical 15 hr in another task, a 60% dispersity of sodium hydride (0.70 g. 17.4 milio) in fit. oil was diary rif (36 mi) and cooled to C. Ety isocyanoacetate (3.13 g, 3.94 mrae) as adied and the stiming was contiaued antil 1.5 mre bubbles were evolved, sE, PCE. this sixture was transferred to the 8bove sixture at 0. thenixture was then stirred at it for 5h883 aucteed with CNECOE, EHF RA (3.2 mL). The sixture was partitiongxi betwee: Ac (200 mL) and H.0 (50 mi), he organic layes was washedoved with underreduced brine and dried pressure:e (NaSO.). residues Afte: the 8 spurified Stivist was by flash chromatography (silica gel, gradientists: EA. ean, 4:ii) to provice the este: 62 (iii.28) in: yield as a sight bfossi scid : 2.222 C.; ER (KB) 35i, iii. 608,489 cm; if NMR (DySQ-813 ,3}, j-7.ihiz,410 (d. 18, 32.5Hz), 429 (l 3H, -6.7 ii, 5.7s id, lii, e124 Hz, 47.5g in, H, 7.63 (d, E-18 ft), 769 (ci, H, -8.5H2), 8.3 (dé, iii, 3-39, 3.5Hz), 8.36 (s, 1H); MS (8) u?e (relative intensity) 458 (23), 457 (M', 100), 411 (62), 384 (2),383 (X3), 257 (29} Card for CH,i,0: C, 52.53; i, 3.53, N, 9.8. Found: C, 52.57, Ei, 3.73; N, 8.64. Ethyl 8-chloro-6-phenyl-4:i-benzoiliidazol 5-a:. 32R wil2) disetae-3-carboxylate 63. This ester 63 was obtained it. 53, Raf all 52% sicid for 61 analogous to the procedure employed in 0092 as a white soi, mp. ; S. (lit.: 74-75° 2-Amino-5-iodo-benzopaenose was prepared from pig iSMR (DMSO-d) & 132,3H, J.H. i.i. ionitrobenzee stics phensiacetoaitrike according to the li i,j:23:2, 432(q,23, J-6.7 Hz), 576 (, H, J3 crate, 2-Arino-5-chloro-beagherOile WES costinct H, 737-7.56 ca. 6H, 7.86-8.38 (18, 28, 8.78 ($, 1F).

See:...

COC 2-shienyihilar all lev-weeks r 38 C. tip, .73 C, CQR

scpsral; ------SaHCO 2: 3, ECH

Page 30 of 53

US 7,119,196 B2

castinued

disc-E3 exe-sists Ets. CBN Mesi a S

2. JC288 S C2.84 iO C2S) NBE, CEFOCE M , ics 2. CNCCQEt 9° C. tor

33 (EC222 74 (EC337 it (EC299) P:CacPh3 gest-8Mes EN, CEON

32. 7S (iO2)

4-Broino-2-(2-thienylcarbonyl)-N-beiizoyianit: 66 and 6-Broine-2-pheny}-4:H-benzo[2,3-di-1,3-oxazit-one ...thienyl-(5-iromo-2-(N-benzyl)trinciple 64. The 2-amino-5-bromobenzoic acici (Sg, 23.1 mbol) was 55 bis-(2methanoló5. The te:20-Xazilians 6 (5.0g, 26,638) was treated with beargy: chloride (237 ml, 2.04 mo) at 1: . dissolved in dry IHF (2500xi) and cooledo -8°C for 45 for 3 h. After the reaction mixture was cooled to rt, the min. The 2thisayilithium (38.23 mi. of MSolution in HF crystals that formed were collected by filtration Bad were was added dropwise over 35min and the reaction was stirred washed with hexages to provisie 64 as light brown cedes is forth. Saturated aq. NEC: Solution (25 m) (6.8g.97%): 'H&MR (CDCs) 67.5-7.2 m, 4H), 79 (did, and 8to (30 mL) were then added organic layer was 13, -2.3, 8.6 Hz), 8.30-8.33 (m, 2H), 8.3 (d. H, s2.2 separated, washed with bisc and dried (MgSO4). Eise Hz); c XMR (cDC1,) & 15819, 5.35, 45.75, 139.58, solvent was removed untier reduced tesSite. and the resi 33.82. 30.92, 29.77, 12882, 128.73. 28.29, 213, due was purified via flash chaoimatogaghy (silica gei, hex 1827; MS (ET) rife relative intensity). 303 (M", 36,391 anes EtOAc: 1:0, 49:1, 20:1, 1:1, 5: c provide 66 88 Mr. 36,253 (14), 257 (14), 226 (6), 224 (6), 178 ($), 70 yellow crystals and the 8teolics. 55; *ENMR (CEC, 8 (9), 68 (9), :53 (4), 105 (109). i.23 (8d, 3 H), 7.52-7.56(3), 23), 7.66 (di, H, J-0,99, 38 Page 31 of 53

US 7, 19,196 B2 57 58 Hz), 7.82 (d. 1F, is 50Hz), 799-8.02 (m, 38), 7.75 (ci, iii, was then quickly added, fo:kowick by the additiot of iMS J-90 Hz), ii.2 (s, H); C NMR (CDC, 6 88.82, acetylcne (0.76e, 7.78 mraot). The mixture was stirred 3: l65.45, i43.34, 38.79, 36.57, 35,90, 135.5i, 3425, reflux for 4 h aid the solves was removed under reduced

pressure. Water (25 mL) and Ét()Ac (25 mi.) were added to 34,03, 32.37, 28.8, :28.33, 27.26, 25.65, 12345, the residize and the mixture was filtered through cetite to 1495; MS (EI) gle (relative itizensity) 387 (M', 12), 385 s retrove the organoneta Elic species. 3 he filtrate was ther: (M', 12), 276 (18,274 (8), 203 (?), 172(7), 30S (iO3). 65: extracted with ExCAc and the crganic phases were com H NMR (CBC), 84.20 is, H), 6.82 (s, 2H), 6.96-7.0i (m, bined, washeck with briie and dried NaSO). The solvent 3H), 7.33.7.38 m, lif., 7.65 (d. 2H, J-7.23 Eliz), 8,43 (d, was removed under reduced pressure and the residuc was {{, -8.8 Hz), 9,92 {s, E); C NMR(CIOC, 8 iá5.04, purified via flash chromatography (si:ica gel, hexanes. 148,94, 36.44, 35.49, 3.34.49, 32.34, 13.59, 33.40, 13 EtOAc: ::::, 5:}} to provide 70 (C207) as a light yellow 28.40, 27.20, 126.83, 26.58, 24.8, 18.x, 73.35, soid: inp: $98.5-201 C.; MS (EE). Elle (reiative ixtensity) 76.92, 78.50; MS (E) 11:e (relative intensity) 47 (M', 54), 338 (M, 68), 337 (M', 28), 318 (ECO), 295 (13), 16: (13), 369 (M", Sl), 453 (300), 453 (93), 348 (98), 346 (92), 326 147 {33}, {}5 (17), he aateria was used directly in the next (54), 314 (58), 282 (23), 280 (39), 267 (88), 23S (2), 234 step. (12), 223 (15), 222 (17), 202 (56), 173 (20), 372 (12), 158 is

7-Acetyietyl-5-(2-flienyl-2,3-dihydrobetzke;i,43di (38), 29 (). azepine 72(JC208. A solution of 70 (iš0 Big, (.457 3moi) 5-Bromo-2-(2-thie: lycarbirylaniile 67. lae amide 66 in 'HF (38 mi) was treated with tetratutylatiotix: (2g, 635 minoi) was dissolved in E:Oh (250 mi) and 20% fluoride (1 M in THF) at {}* C, fit 5 minutes. Water (20 sai. NaOH sciution (30 mi.) was added. The mixture was heated was subsequetitly added to greich the reaction and tile lif to reflux for Sil 38 the ECH was rived under reduced 28

was emoved untier reduce pressure. The remaining as pressure. Ehe Enixture was extracted with 30Ac aid the solution was the extracted with EtOA aid the organic organic phases were combiei, washed with brine anxi dried phases were combinei, washed with trine aid citied (NaSO. She solve was rethoved under reduced pres (NaSO). Upon renova: of the solvent, Et () was added to sure, and the residibe was purified via a wash colu:11E (silica the residue which was sonicated and then filtered to provide gel, hexaaesEtOAc: li: to 4:) to provide 67 as a bright 23 the title compound 72 {3C238, lil ing, 3% as an ivory yelkow solid; H NMR (DMSE)-d) S 8.23 (brs. 2H), 6.82 cored solid: sip: 24-26° C.; MS (EI) nate (relative (s, li-1), 6.90 (s, iH), 7.26 (dci, H, -3.8, 5.3 H2}, 7.42 intensity). 266 (M', 61), 265 (M', 30}, 238 (i{}(3), 237 (49), (cki, H, -2.4, 8.9 Fix), 7.6 t (iii, Fl, 3-li, 3.8 Hz), 7.69 28 (3.3), 209 (20), 64 (6), 53 (7), 39 {3}. This materia: (ck, H, Jr.-24H2), 8.04 (cki, H, J-13., 50 Hz); CNAMR was usei is tie text step. {DMSO)8187.42, 50.09, 43.87, 136.46, 34.75, :34,4}, 33 -N-methyl-7-tricuetlaysilylacetyletyl-3-(2-hienyl)-3- 133,93, 28.78, 1936, 39.17, 134.95: MS (EI) n?e (rela dihydrobenzoeii,4-diazepine 7 (JC209). Thicphere 73 tive intensity).283 (M', 39), 282 (M',87), 28E (M',59), 280 (S00 g, i.52 alrao:) was diss):ved in dry EHF (25 mi.) at {} (84', '79), 250 (23), 248 (23), 23: 13), 199 (49), 97 (48), C, aiki Nali (60% a mineral oii, 76 mg, i.5 minol was 372 (25), 73 (23), :45 (3), i40 (!), El (180), Oi (33). added to tie solutics: in cine portion. After the riixture was 4-Bromo-2-(2-thienylcarbonyl)-N-bromoacetylaniirie stirred at O'C. for 38 min, Mei (0.14 E., 2.25 mmol) was 68. The hienylatine 67 (3.3 g, 1.7 minol) and NaHCO, added and the ice that was allowed to Wa:Tl to it. "ae (2.9 g, 34.5 inol) were suspexed its dry CHCl (30m) Fixture was allowei to stir for 3 had the TEF was then and cooled to {} C, Aschatic of bronoacetyl bromide {{...}.2 re:Eoved untier reduced pressure. She residuc was puried al., 2.93mol) in dry CHCls (3) mL) was added dropwise Es via flash chromatography (silica gel, hexanes; E:0Ac: 8:l, over 28) iii.; at 8° C. ataxi the mixture was sized at ris far 3 $::) $o provide ite: title cottipou.3d 7 (JC239} as a white h. The CHCl, solution was ther washed with sq Na3C(3. solid; mp. 171.3-173.6° C.; if NMK (C)Ci & 3.26 brs, (5%) and dried (N&SO). The CHC), was removed under 9H), 3.38 (s, 3EI, 4.7 (d. 3), 7.39 (d:l, 333, 3-3, 5.8 Hz, reduced pressure, and EtO was added to the ask, The 7, 7 (dd, H, J, 1.1, 3.7 Hz), .30 (8, E), 7.49 (cid, H, solution was scaicated and fittered to provide 68 as a Bight soid: mp: 448-146.5°C.; H NMR (CDC), 84.01 (s, 4s J-1,*C NMR 50 Hz},CE)C1,) 7.65 (di,8(CDCs) 3 FE, F:2.0, 8 170, 8.5:{z}, 2, 163.22, 7.75 (d,43.55, H}; 2H), 723-7.26 (m, iH), 7.24 (ci, H), 7.65 (d, J.H), 7.74 (ci, 43,34, 134,59, 33.32, 131. 38, 30.4, 12777, 127.47, 18), i.84 (3, 38, 8.46 {d, H), 30.85 (by s, iii); MS (EI) 12101, 1:9, 10, 103.01, 95.66, 56.38, 34,67; MS (EI) use nate (relative intersity) 405 (M, 69), 434 (40), 483 (M', (relative intensity).352 (31,71),35i (M', 60), 337 (10), 324 100), 403 (M', 66), 324 (39), 322 (38), 330 (33), 308 (33), 292 (32), 283 (63), 282 (72), 283 (55), 283 (67), 266 (10), 50 (300),-N-methy}-7-acetyleno-5-(2-thienyl)-3,3-dihydrotezzo 309 (24), 168 (28), 154 (38). 264 (30), 250 (34), 248 (35), 226 (55), 224 (55), 201 (43), {e},43diazepine 73 (C232). The saline procedure for re j99 (37), 97 (27), 373 (32), 1: (73). paring 72. JC208 was applied to 73 (C222) as a very light 7-Bromo-5-(2-thie Ey)-3,3-dihydrobenzoel 4 diaz brown solii resulted, mp. 28.3-220.4° C.; Ei NMR epire 69 {}C184). Stiebronoacetylastice 68 (0.236g, 3,586 s5 (CIC) 83.36 (s, 1}{), 3.39 (s.3H), 3.78 (i, 3H, F-13.87 minol was issolved in a saturated solution of anhydrous Hz), 4.72 (d. 1H, J-5.3 Hz), 7,08 (dd, H, J-3.8, 5.0 Hz), 3T3:Ionia is MeOH (53 i: ) and the laixture was heated to 7.3) (d : H, j-8.8 Hz), 7.49 (did, :IH, Je.(3, 5.3 Hz), 7.67 refix for 6th. After the McC3H was removed uBder reduced (di, Ei, J-2 (), 8.5 Hz), 2.79 {{i, lii, Jr.93 Iz), C NMR pressure, E:OAC was aided to the residue. The solution was (CDCL) 17:04, 17().0?, 163.12, 43.49, 34.79, 133.50, sonicated asid then fittered to provide 69 (JCl84) as a ligit 6(; 31.34, 130.25, 127,85, 27.46, 23.16, 17.99, 81.83, solid; MS (EE) me (relative intensity; 322 (M., 54), 320 78.33, 56.34, 34.69. MS (EE) rate (relative intensity) 281 (M', 53), 294 (20), 292 (98), 21 (24), 85 (31), 40 (21), (3), 283 (M', 60), 279 (51), 253(9), 252 (130), 251(2), The 3ateriai was used directiy in the next step, 7-Eislethylsilyacetylcyl-5-(2-tienyl)-3-dihy 235Ethyi (3), 8-bromo-6-(2-thietyl)-4H-betzofiahidazo:209{10}, 5-3 drobenzoe, 1,4-diazepisoe 7 (JC237). A mixture of 69 (ig, 55 43diazepile-3-carboxylate 74 (EC2:7). Dry THF (30 ml) 3.32 nanol in CHCN (20 mi.) and EtN (30 mL) was was added to a fask containing the benzodiazepine 69 (1.27 degassed and hexed to 'efix uncker :roge:3. Bis(triph g, 3.96 aiio) and the solution was allowed to cool fo to C. enylp:hos; hike-palladium () acetate 3.26g, .347 mmol)

Page32 of 53

US 7, 19.96 B2 59 60 and Xiah (60% in Irineral oil, 3.191 g, 4.76 attrao) was quickly aidx. She mixture was stirred for 30 is at 3 C, -Continusck and then retroved from an ice hath to stir another 3 is at it, Prior to adding CPO(OEt) (1.05 g. 6.35 Eunoi), the mixture was again pre-cooled to 3° C. The solution was stirred another 3 as tie ice bath warried to r. Meanwhile, dry IHF (30 mL) was aided to a second fiask containing Nai (60% it miteral cii, ().229 g, 5.72 IElinoi). After the second alma-rrore-reg Frixture was cooled to ). C., CNCHCC.Et was added E. dropwise and the schution continued to stir for 30 nain a C C. After both reactics: ixties were again pre-cociled to C C., he two solutions were contined utiéies. At via cannula and the solution stirred at rt owcraight, he reactica was quetched with ice water axi worked up with EtOAc, asid the coatined organic phases were washed with brine and dried (NaSO). She solvent was removed under reduced pressure and the residue was pitfied via flash chromatography (silica gei, hexahes:E(OAc 4:3, 1:3, 3} to provide the title con ------assessessmallF3A is mallaxam pound 74 (3C27 as an ivory solid {508 mg, 30% yield): MS-err. trip; 2040-205.3°C.; H NMR (CECs) & 145 (t,3H, -7., ci. EN 14.3 Hz), 4.87 (d, H, -8.8 Fitz}, 4.44 (dd, 2H, -38, 4.7 Hz, 5.98 (d. 18, 3-12.8 Hz), 7.05 (d, lith, Jr.0 Hz), 7.87 {s, EH), 7.46.7.49 (ii, 2H), 783 (dd, 1:H, J-2.2, 8.5 Hz), 7.91 (s, H, 7.96 (d, 134, J-2.2 Hz}: MS (EE) age (relative intensity) 48 (M', 5), 417 (M', 68, 436 (38, :53, 415 (M', 54), 407 (22), 344 (26), 343 (330), 342 (38), 34 (93), 293 (5). 291 (21), 262 (38), 235 (15), 21 (33), 154 (10), 127 (1). Ethyl 8-tristiethylsilyacetylenyi-6-(2-thietyl)-4:i-benzo finidazo,5-383,4}diazepine-3-carboxylate 75 (C220). ti-SEFes-C 3 he same procedure for prepating 70 (IC207) was appieito arryman 75 K220 at aa ivory colored solid resulted: Ei NMR 3E (CEC, 80.23 (s, 9H, 145 (t, 3H, J-i, l, 14.3 biz), 40 (d, 1II, fx-18, Hz, 445 (dd, 23.I. J=7.2, 8.5 Hz), 5.97 (i, H, Je2,8EEz), 7,06-7, (i,2i), 7.49 did, lBE, Je1.2, S.C. Hz). 752 (d. 1H, 3-8.3 Hz), 7.77 (cki, H, Jel 9, 8.3 Hz), 7.90 (ci, 1FI, J-E.8 Hz, 7.93 s, 3 H). MS (EI me (relative intensity} 433 (M', 74), 387 (49), 359 (300), 277 (28), 252 (9), 235 (34), 72 (E9), 2917). Ethy 8-acetyle:no-6-2'-thienyl)-4-benzofimidazol, 5-ai,4-diazepine-3-carboxylate 75 JC221). The same pro cedure for preparing 73 (30208) was applied to 76 (C221) and an ivory coiored solid resulted; tip: Y98 C.; HRMR (CEC), 3143 (t, 3H, -4.3, 31.4 Ha), 3,25s, iH), 4.0 (é, iH, -12.8:2), 4.4.4.4.9, 2E, 599 (i, H, 3-2.9 Ha), 7.50 (di, 1EI, JsS.0 Hz), 7.56 (i, H, Jes.3 H2}, 7.81 (cid, iii, 3-8.8, 8.3 {z}, 7.95 (s, H); MS (Earte (relative itersity 363 (M', 24), 35 (35), 237 (80), 237 (26), 78 (30), 353 (2)}, 26 (38), MS (Ernie (relative intensity} 363 (M',2S), 315 (4), 287 (30), 237 (3), 7840, i53 (26), 126 (23).

Schemes Sea. NHHis

Fi:CAccP3: -wawaararerrarHer S-ea,

8 (132:35}

Page 33 of 53

;S 7,1 19,196 B2 6 62 organic layer was washed with water, brine and citiexi -citined (NaSO). After the Scivet was removed Lander reducei pressure, the feside was purified by fast chrottlit tography (silica gel, gracient eatics, E:OAc, 80Acivic fi : 3:3 to provide 78 it 86% yield as a white sciii. pp: 236-237°C. it 242-243° C); 'I: N3AR (30 M332, CEE) 88.21 is, 9H, 2.91 is, 3H, 4. ii (s, 3 H), 4.85 (5, EI), 7.3.7.66 (n, (j-iii-ethylsilyacetylenyi-4-cxy-5-phety-313-tier82.Ée E4kiazepin-2-yl)-abethyl-amine 79 (tizi:45}. Irillethysi lyiacetsiety: analog 79 (Tzi-46) was obtained in: 58% yield fort: 78 atalogous to the procedure employed in 19047 as 82. 33a): a sight gray solid. Ep: 239-240° C.; : R (KBr) 3229, 306, 2952, 21.49, 1516, 593, 462, 1238, 868 ea; H N&SR (300 MHz, CDC, 82.89 (d, 3:H, a 1.4 Hz, 4.14 (d, Ei, Js C6Hz, 4.78 (ci, E3, Je), 4 Hz), .35 (d, H, F-17 3-iz), ( 7.24-728 (a 2H), i.45 (rs, 43-3, 7.56 (m. 2H, MS (EI) infe (relative intensity) 36: M', 483, 344 (30), 393 (3)}, 16533}. (7-Acetylenyl-4-oxy-5-phenyl-3H-be: zoel,4 diaz is epia-2-y}}-methyl-amine S8 (Hz:47). The 7-acetyleno target 8) was obtained in 90% yield iron 39 anasogeus to the procedure employed in 8483 as a light yellow solici, mg: 23-24°C.; R (KBr)3242, 3068,2977, 16:9, 1589, 1460, 83 (Hai-38) 44 cm: ; H NMR (300 MHz, CBC3) & 2.89 (ci, 2ki, s3. He, 2.98 (s, 333), 4.13 (bs, A, 478 hs, H., Tie benzodiazepine i was oxidized with 3-chloroperoxy 7.8-7.7 (na, 9F); MS 321 mile relative intensity). 389 teacic acid (CPBA) to fom 77, foilowed try the addition. M, 47), 272 {10}, 31 (42. af methytailine to afford amidine 78. N-Oxide 78 was 7-Broino-S-pitcyl-3H-benzei,4-diazepin-2-yl)-te ireacted with trimethylsilyacity: i.e : the presece of 8. thyl-armine 8 (Fiz.135), Brotide 8 was obtaileci in 70% paliadinal catalyst to provide the trimet:ylsilyl ana:(g 79 yield for t analogous to tile procedure eployed it. :)f Rzi 45) which was subjectesi to fuoride-mediated diesia as a white said imp: 234-235°C; ER (KBr) 3253, 30.78, tion to affix: 80 Hz: 47), as shown in Scheme 15. In a 1699, $7, 435, 326, 233 cm; H NMR (30G Miz, related route, bromise 8 was coverted into the trimethyl CDC,) 82.62 (s, 3H), 3.56 (bs, 1H), 4,68(bs. H), 6.34 (s. siyiacetyle: le 82 (Eizia). This analog was ties, trans 1, 7.17 (d, H, J=8.7 Hz), 1.36-78; (m, 73); MS (EE) formed into target 79 (Bizit) with a? PBA or the key target afe relative intensity 329 {80}, 328 (v3, 8), 32? (82), (Eiz:48) or treatinent with fluorice (Scheme 16). 326 (92), 320 (38), 25(48), 21846, 205 (38. 7-Bronn-4-oxy-5-phenyl-1,3-dihydro-benzo:e,4öiaz 7-Trimethylsilyiacetyenyl-5-picay:-3-tet Zoe, epin-3-one 77. Bramidel 3.88 g, 5.95 anac was dissoiwei diazepin-2-yl)-ukethyiannine 82 (Hz 4). Triaethylsily ix. CETC (S. n.) aid taCPBA, (77% Blax} 1.76 g was lacetylienyi analog 82 (H234) was ottained is 73% yield added at rit. The reactics: mixture was stirred overnight. The for; 8 analogous to the procedure employexiii. 804 as mixture was diluted with CiCl (80 mE} aid washed with a light ye:ow solid. ap: 218-21°C.; R (KBE) 3257,378, a sat. soition of NaliCO (5):3E), water 5:... and barrie 2956, 2:50, 619, 1610, 580, 1426, 1237,880, 8:43 cm; 40 m3), the tigatic ayer was citied NaSO) aid co centrated. The reside was purified by flash chromatography H NMR (30 &Hz, CDC 80.22 s, 9:), 2.59 (ii. 3:3, silica gi. Eit Ac) to aifyrd compound in 90% yield as J-3.5 Hz), 3.56 (bs, 3 H),466 (bs, bi), 6.39 (5, li), 7.2: (i, a white soii. trip: 330-23° C. (iii. 238-231° C.; it } H, J-84 Hz, 2.33-7.65 (a, ii); MS (EE) inje (reiative NMR (CDC, 6 4,69 {s, 2E, 7.6 d, H, 3-8.7 Hz), .24 irstensity 345 (M', 100), 344 (98), 15450). ci, H, 3:3. He), 7.45 m, 3H, 7.54 did, 1H, J-8, 6, 2.2 (7-Acetylenyl-4-oxy-3-phenyl-3B-besiei,4ciaz Fix, 3.64 (dii. 2H, 3-7.3, 3.6 Hz), 10.82 (s, H. epin-2-yl)-Eaethylaxine 83 (Hz 43). The 7-acetylene analog (7-Broino-4-oxy-5-pietyl-3Ei-henzoe,4-diazepin-2- 83 (EE-38) was obtainedia 92% yielki from 82 analogous to yl)-methyl-aniac 78. Methylamine (50 mi., 2 Mia HF the procedure enployed in 8048 as a white solid. Irip: was added to 77 (2.9 g, 5.7 manoi) is a 100 mL road-botto. 226.227 C.; ER (KB) 3275,3245,3875, 2102, 638, 3599, flask. The mixture was cooled to 3' C. after wirich Eic: 1580, 467, 4:5, 333, 3235 cm; H NM8. 303 Miz. {.5 g, 2.86 irraol) was added dropwise, he reaction CIC), 82.65 (ci, 3H, i.e4.4 Hz), 2.97 (s, EI), 3.57 (bs, H), aixture was allowed to warn to it atti stirred for 4. The 465ts, 1H), 6.20 (ci,}{, -3.7 Hz), 7.22(d, H, 3-84 Hz), Elixture was quented with water (5 Iti), dited with 3.42-7.58 (ai, H). MS (El) we (relative intensity) 273 EtOA: (200 mE atti washed with dilute NEIOE. The (M, (30), 272 (98).

Page 34 of 53

US 7,119,196 B2

NCHCOOH

HNo.3 NaCOs EE:-3C 6%

Me:NCERCHs. Ersk, Renzene Ex

Nies 3. A s X-CH Pd(PPh2OAc); sesser-sala EN, CHCN tiere, SS

SS PS.:-36) 83 (S.333

g) Ps, t-3

A suspeasion of 7-broa10-3,3-dihydro-5-phenyl-2H-4- Acid 85 (350 ag, 0.94l mini) was suspended it dry benzodiazepin-2-thioak 84 (.6 g., 4.83 shuto3), glycine CHC, (10 mi) and DCC (22.3 mg, 3,838 IEEE) was added. {1.8 g. 28.2 mino:) and NaCO, (1.84 g, 7.4 innol in The suspension which resulted was stirred at 40° C. for 2 h. ECES (38. 3.}-ii) 8 in; ) was stirred at refux for 5E, s aid ther coolecy 0°C, it was filtered, and the Sovent was pourei into water (10 i.), aid the filtered to restove a removed in vacuuEI) to give 8-kiromo-2,4-dihydro-3-phenyl snai alount of 7-broto-3,3-dihydro-3-phenyl-2-4- H-imidazo:2-81.43benzodiazepin-4-oxe 3 as a brows benzodiazepin-2-cine which regained. The filtrate was oil. The cyclized product 86 (ca. 250 ng) was dissolved is extracted with CHC, The CiCl, extract was discarded; the dry benzene (6 m), dinethylfortnanide diethylacetal (33 aqueous layer was adjusted to pH 4 with 2 C and ther s png, 0.883 ruoi) and tiethylamine (89 trg, 8.883 mini) extracted with CHC, {3x25ml), Evaporation of the CHCi, were added. The solution which resitesi was stirred at: root: so:utici gave pure acid 85 E.2g, 67%) as a ye:low so:id. tersperature for th and the soiwent was retroved in vacuuin,

Page 35 of 53

US 7, 19,196 B2 65 66 The reside was thea crystallized from ECAC-MeOH 336,2936,2794, 254, 1682, 1825, 1489, $36,84 c1; give 87 (200 mg, 76%). A solution of Si (180 rig, 0.84 3H NMR (CDC1,) 880 (ii, 1F. -8.5 ft2), 7.68 (3d, 3 stic:) in dry toilete (5 :-) was treated with I-IIaethy J-siz, J-8.5Hz), 7,55-7.59 (1,2h), 7.37 7.49 (T3, 4:ii), piperazine (1 ini aiki heated to reflux for Sh, Ike Siwent 7.16 s, H, 4.99 (i, H, J-12 Hz), 450-60 (in ), was removed in vacuum to give a gum which crystalized 420.430 (in, H), 4.3 ki, 8, a 24 Hz, 3,48-3.58 (tal, from CFC-2:0 to fixinish 88 (PS-3-35, 146 ing, 72%), 2H), 24-26 (m, 4ii), 2.35 (s, 3H), 3.23 (s.9H}; MS (n.2) sup>250° C.; R (KBr}3324, 2932,2787, 1692, 1624, 475, 482 (100). 1.03, 297,137,933 en'; H NMR (CDCs) 57.95 d, A solution of the trimethylsily: analog 89 (PS-36, 6 13, 3-8.8 Hz), 7.72 (dd, Ei, J-2.3H2, -3.8 Hz), 7.58-7.5S ago.35 mmol) in THF (15 mi.) was stirred with tetrab tin, 23, 7,49-7.37 (m, 4ff), 7, 17 (s, lii), 5.{ {d, H, J-l3. tylammonium fuoride hydrate (45:g, 3.175 133aol) at -5 itz, 450.4.6) (m. H). 4.2C-4.30 (m, H), 4.6 (d. ii, C. for S. mia. After this, HO (5 mi} was adid to the J-2 Hz). 3.50.358 (m, 2H), 2.8-2.6 (m, 4}, 2.34 (s, solution to quiesch the reaction and stirring coli:itued at if 3);is MSthe (af2)suspension 465 (100), of compound 88 (PS-33, 8 Eng. temperature for olie ha: hour. The solution was extracted (.303 msa1y in acetotitriie (4 f.) and triety assile (3 : ) with EtOAc (3x40 sal), assi the orgassic layer w888 sited was added bistriphenylphosphine-paladiu!h (l) actite with water. After renova of the solvent utilder reduced (22.6 msg, {}{3 miliol), the solution was degassed and pressure ethy: (ther was added to the residue to precipitate trimethylsiliyiacetylene (9.1 mL, 0. ruinol) was addex. The a solid, he mixture was filtered and the Seid was washed mixture was heated to reflux and stirred overnight. After with CHC, 3:0 (ca 1:15} to provide the acety: target renewal of the solvent in vacuugi, the residue was dissolved (PS-3.37, 40 mg, 73%). tap 223-224 C. R. (KB) 3298, is CHC, and washed with a saturated aqueous solution of 2935, 2786, 695, 1628, 1354, 1136, {{2,778 cm; H NaHCO, and brise. The organic layer was drick (NaCO), NMR (CDC) & 804 (d, Fi, -8.5 Hz}, i (dd. hi, filtered and concentrated Elder vacuum, The sesidue was Ja-109 Hz, J-8.5 Hz), 7.55-7.58 (ril, 2), 7.36.88 (I, puried by fash; colux: chromatography (EtOAcMcOh 4E), 7.17 (s, H), 5.0 (d, iH, I-12. 1 Hz), 45.4.6 (rri, H). 9:1) to furnish the trimethylsilyl analogue 89 (PS-1-36, 80 42-43 (un, H, 4.16 (i, 3H, -12. HE), 3.5.3.6 (ril, 2:3. mg, 89%) as a paie yellow Seli. mpx250° C.; IR (KBr) 3.98 (s, H, 2.4-2.6 (m, 4H), 2.35 (s.33: MS. 12; i30).

2NEEEEEEE, reux, ------war3,3-preseds: 30%. 3, HC :

5 (3ri-I-70

ls).S. P.A. (PEs: Et, CEEN Felix,

Page 36 of 53

US 7, 19.196 B2

-cottissued

23 MH-E-8)

93 &AH-E-SS)

tography on silica gei (gradient elution, EOEt). he acid: 27, obtained for the ester 5 (dan-i-8), was 151,13:1) to provide the bisorcinide 9 (DMH-370), as stirred with CDE in IMF, flowed by stirrigg with 1.3 a white solid (1.3 g, 61.9%); Ip 87.5-i89 C.; IR (KBr) propatseio and DR3 to provide 93 (DMH-D-070, the s 312,2968,3708, 1623, 1559, 493,3269, 6,123, 3. ciner of dim-I-70). This was converted into the trimethyl ca-i, ii. M.R (30 MHz, CDC,) & 2.35 (m. 2H), 4.08 ci, silylacetylienyl compound 92 (DMH-E-048, the diner (f 2H, J-26 Hz, 4.55 (all, 4H), 6.05 (i,2H, 12.6 i. XiXHe48 under standaxi conditions (Pd-mediated, 737.3.53 (ta, 2H), 76 (d, 234, J-21 Hz), 7,8: {dd, 2, Heck-type coupling).'The bisacetylene 93(EMB-E-053, -2. He, 8.6 Hz, 93 (s, Sii); 3C NMR 75.5 MHz, the dimer of XHea:353) was easily obtained by treatinent of CEC)328.2, 44.9,834, 1207, 24, 28.3, 29.0, 29.3, trinetylsily compound 92 with fiboride anion 88 showa in 29.6, 30.8, 34.1, 344, 34.7, 1358, 38.9, 38.9, Scheme 18. 62.6, 679, MS (FAB, NBA) mile (re intensity) 83 8-Brome-6-phenyl-4E-benzo(fittiidazo[15-aliidiaz M", 15); Anal, Calci. for CHNOB2, 58.23; i. epise-3-carboxyzic acid 27. She ester 5 (2 g) was dissolved 3.5, N, 45. Foxrd: C, 57,92; li, 3.43; N, 0.29. in EtOH.50 m) and as sodium hydroxide (Qini, 2N) was 1,3-Bisig-triaethylsilylaceyienyl-6-pheryl-it-benzoli added to the solution. The mixture was heated to reflux for imidazo,5-al-diazepine-3-carboxy} propy diestes 32 half an hour. After the EtOH was renoved under reduced pressure, the solution was allowed to cool. The pivakue was (DM:-)-048)." adjusted to 4 by adding 30% aqBC dropwise. The Enixlise to a suspension of bisbronide 9} (i,005g, 1251)}inoi is was filtered and the solid was washed with water and ethyl acetonitrile (50 mL) and triethylainine (65 mi.), was added ether. The solid was dried to provide 27 (1.8 g., 96.6%); bis(triphenyiphosphixe-paiiadium (ii) acetate 8.5 s. (). mps250° C.; R (KB) 3450 (b), 2844, 1787,165,493. mncl. he solution was degassed and trimethylsilyacety 3.66,700 cl, 3 NMR 303 MHz, DMSO-3) 54.4 (i. lene (3.7 iii., 5 minol) was added: after with it was H, -12.6 Ez), 5,79 (ci, 1H, 12.5 Hz), .41-7.54 (8,6H), degassed again. The mixture w85 heated to reflux aid 788 (d, H, 3-8.7 Hz), 8.03 (did, lii, Js-8.7 Hz, J-21 Hz, stirring maintained overnight. After retival of the sevent 847 ts, its); MS (EE) me (rel intensity) 38 (M'. 20),383 inderreduced pressure, the residue was dissolved in CB-Cl (13). and washed with water. 3-Mecaptoprogy fuactionalized 1,3-Bis(8-brono-6-phenyl-4H-benzo: timidazol-5-all silica gel(0.6 g) was added into the creasiayer ani stirring 4 diazepine-3-carboxy) propy: diester 9: (EMH--070). continued for hour. Tise silica gel/Pd couplex was The carboxylic acid 27 2 g, 5.2 mEol) was disseived in removed by filtratiot and the filtrate was concentrated indef IMF (20 mE), after which CEi (1.02 g. 6.3 intact was reduced pressure. The residue was purified try ash counts added at it and the mixture was stirred for 2 h, keta chromatography en silica gel (gradict elution, FCAc: 1,3-propanediol (0.19 mi., 2.6 minos) and OBR (0.78:1 L, Etop 20, is, 0:1) to furnish the bistrinetylsily difief 5.2 inni) were added to the Rixtute and stiring continued 92 (DM:-D-Q48, 68 mg, 60.8%) as a white solici; mg overnight. The reaction sciution was the cooled with at 169-72 CIR (KBr) 3449,2950, 3725, 720, 5, 496, ice-water bath, after which water was added to precipitate 8 25C, 363,080, 847 cm"; 1H NMR (30 MHz, CDC1,) solid. This material was purified further by flash chronia 38.25ts, 38H), 2.35 (n,2EE), 405 (d. 231, -12.6:3z), 4.SS

Page 37 of 53

US 7, 19,196 B2 70 69 one half tour. The sciition was extracted with ECAC (r1, 4:1), 6.02 (d. 2H, J-12s Fiz), 737-7.55 m, i4H), 7 is (3x00 al.), and the orgasic layer was washed with Water. ai, ii-18 Hz, 8.4 biz), 7.9 s 2H NMRC After removal of the solvent under reduced press city. Miz., CC1, S -0.3, 28.3, 44.9, 64.4, 97.4, (2.3, 22.4, ether was added to the residue to precipitals 3 said. The 26, 1288, 1283, 129.0, 39.3, 30.5, 134.1, i34.9, mixture was filtered and the Solid was washed with CHEC 35, 336, 1392,339.2, 62.6, 1685, MS (FA, NBA) EtO (ca 1:53, the bisacetylenyi diet 93 (DMEi-I)-053, merel intensity 839 (Mi-108; Asia, Caki. For 2 tag, 83%) was obtained as 3. yellow solid: 3p 72- 7.58 chixosis: C, 70.14; it, 5.53, N, 802. Found: C, C. :8 (KBr; 3453, 3280, 2950. 1720, 1715, 495, 258, 6997;,3-Bis(8-8cetyliety-6-phenyl-4-ft-be:20 3,535; N, 3.77. finidazol-5- li:), isoch; a NMR (300 MFiz, CECs) S 2.35 (n, a; 1,4-diazepine-3-carboxy} propy) diester 93 (DME-D- 2,318 (s, 2H), 408 (d. 21, 12.3 Fiel's, 0.53). 604 (d. 2E, J={2.6 Hz), 7.36 759 (ta, 14E), 7.78 (dii, 21, Asolution of bistrimethylsilyi dime: 92 (330:18, 8. immol) 8 . Hz), 795 (s. 28); C NMR 755, in TBF (70 mL) was stirred with tetrabutyla EGEiura CDC1, 328.8, 454,619,802,813, 24, 22.7, 33, fooride hydrate (250mg,096 milliol) at -78° C. & 5 air. 283, 3298, :29.3, 138.5, 334.2, 135.2 35,3, 35.6, After this, HO(35 mL) was added to the solution to quesich 138.9, 39.2, 62.6, $88.5: MS (FAB, NBA) me (rel the eaction and stirring continued at low temperature for intensity) 695 (M'+, lit}}.

EMF re-arrors1,5-penteredic

Hasi-ce- H disAchi EN, CFCN rolix

33 in-E-2)

TAFerH), 3F ae-rr-se go E.

9s dis-I-41

S-6 (is--

Page 41 of 53 US 7, 9,396 B2 77 (Hz 65) which was subjected to fluoride-mediated desily lationstrinethysilylacetyleryl-6-pyridin-2-y-4-benzil to furnish analog 106 (Hz:66). raidazol,5-aii-diazepine-3-carboxylic acid ethyi ester 105 H65), trimethylsilyacetylery analog 105 (Haif.5) as obtainei is 73% yield fiosis (+ 8talogous to the procedure singloyed in 004.7 as a white solid, up: cas M.R (360 MHz, CPC1) 8025 (3,93. 34 (t, 3H, J-7, fiz), 4.4 td, 1H, -1.8 Hz), 4,44 (in, 2H), 6.3 (i, H, J-30.9 Hz), 7.38 (ddd, H, -7.5, 4.8, 8. Hay, 3.5 (s, Hi, 7.54 (d. 1B: J-8.: iz), 7.74 (di,J-8.3, 18 , 7.83 (tal, H., f= 7, 1.7 Hz), 7.93 is, H, 8.05 (in, H.), 8.6ls.Aceyenyl-6-pyridin-3-yl (ii, H), 4H-benzaffimia.o. diazepine-3-carboxylic acid ety este 08 (HE2:36). the 7-acetyeno analog 106 (iiz166) was obtained a 98% yield frott: 185 analoge:8 to the procedure employed in ois as a white soli, rap. 243.244. HNMR cil,81.45 (t,3H, -7.1 Hz), 3.37 (s,t). 1.-10 (six), 445 m, 2H), 6.3 (i, H). 38. (did, 1H, -7.5, 48, 1. H, 7.56 (d. iii, as .237), 7.58 R., iii. 777 (ck, H, J-3,6, 1.8 Hz,783 (td. ii, -77, 18 Generally, we contemplate &liataegs of 1-4 above with Some, 793 exemplary is, iH), 838 compounds (m, H), failing8.59 (m, wilder H). the scope of X-R, C, B, NO, andfork":CH isopropyl, 1-butyl, is Xr s azoles. Also, all anakg3 of R-C-C- with 8xt-buty, theit present generai, invention any ;4-benzodiazepine are as illows: with a 5-phenyl-like sistituent in which C(7) has been replaced with 8 8vey isopropyl, cyciopropy. We believe that replaceaet: of th: lene substitueat or a trittiethylsiyl acetyletic substituent of halogen atoa in 1,4-benzodiazepines or tie relatecitta2.co any triazolo benzodiazepine that has a coiresponding Sub 3,4-benzodiazepines at C(7) or C(8) generally results in tient at C(8) with a 6-phenyi group {aiprazolar sub anxiolytic activity with greatly deceasci sedativelypnotic ing system. For example, we clair any benzodiazepine suscle relaxant activity or, in Some ciscs, 10 seative straturally seiated to analogs and other related cagounds: to diazepaal, alprazolam, illed320ial, and triazolata is: bypnotic activity compared to known agents. which the C(7) or C(8) substitutea has beet replaced with an acetylene or trimethylsilyacetylene substite it. 35

4, Ro, HRH106) 3.33. , S:C

CER N t e

R - , Kr. Si(His R - Her CH K'-F.C., Br, 8.3:

Page 44 of 53

US 7, 19, 196 B2 8. -contigli

Page 45 of 53

US 7,119,396 B2 8S 86 continuesi -continued

Page 46 of 53

US 7,119,196 B2 8 88

-coatinued -continued

Ric Hors. CES Experigeriai Methods 3:Crch Situational Anxiety Model in its iale Sprague-Dawley as weighing 180–20 grams were purchased fian Charies River Eaxratories (Wilting tin, Mass.), The rats were housed individually in suspended wise cages in a colony rocin itaintained at constait is perature (21:2 C.) and huntidify (50-30%). The rooa was illuminated 12 hours per day (lights or at 0600 b). he rats had ad libiium access to food and water throughout the study, Behavioral studies were conducted betwo if a 1396 hours. Festing. A modification of the Defensive Wit drawal procedure, as originally desctibed by iakahashi et ai. (1989), was employed the testing apparatus insisted of all opaque plexiglass open fieidi (106 call length:X92 cit: width x so cm height), containing a cylindricii galvanized charater 14 cm length, 10 cm diarietes) that was positioned length wise against one waii, with th& Qpe end $0 cm ion the cerer. The open field was illuminated by a 6 Wattical descent bulb, and illuriation was titrated by a powersa transforiter to a 23 hux reading at the entrance to the cylinder, Rats were habituated to haaciling by getty strok tag their dorsak surface for approxiraately one minute daily 85-6 consecutive days beiore testing, to initiate testing of exploratory behavior in this usianiar enviroient, each rat was placed within the cylinder, wiich was the secured s to the floor. Behavior was assessex for 15 Tititutics by 8. trained observer (unaware qi treatiricit assignetis) via a video monitor in an adjacent room. The latency to crier8 from the cylinder, defise by the placement of a four as into the open field, was recorded for each at After testig each rat, the plexiglass camber and the cylinder wer cleaned with .0% glacial acetic acid to prevent olfactor cues from influencing the behavior of subsequently tested rats. Drug Administration: Ali drugs were adalinisterc PO 5 2.60 minutes prior to behavioral testing. T38 Analysis: Results were expressed as the Mean: SEM. A data were subjected to analysis of variance (ANOVA) followed y individai mean comparisons using fishe's east Sgif capt. Difference rest (Kirk, 1968) where appropsiate. 8 significance level was set al. ps3.05. Protection from Peatyeyetetrazole-induced Seizures Male CF mice weighing 20.32 g at the time of the experiment were purchased from Charles River Laboratories (winnington, Mass.). Penyleaetetracoke Sigma {Clhetical Cay was ideninistered at 125 Bigkg 3-c. The immixer of

Page 47 of 53

US 7, 19,196 B2 9th 89 catal lifference Test (Kirk, 968) whete appropriate. She animalsHinutes survivingafter administration was recorded of penlyleaetetrazole.at 30 minutes and Drug 60 significance level was set at p-t}{5. Administration:refore administration Ai drugs of pettyenetetiazole,were aiministered?O Data 68 Analysis: minutes Discriminative Stirtuius Effects of Chlardiazepoxide in Rats EFE E. SSR. t 3. Male Sprague-Dawcy rats weighing 249 to 30 g at the The significance level was seap-50s. starttaboratories of the experiment Wiimingto, were Mass.) perchased Anitials from Charleswere housei River Protection from Electrick's Seizares singly in hanging wire eages in a roofia islaintained at

E.3. andconstant i:luminated temperatre 2 hosts (21-23 per c) day and (lights humidity cn & (stio)600 h). {Wilmington,Ugo Basile ECT, Mass.). (Epit Electroshock 780 seizuxe isappatatus administered (3 go usingBasile, a Throughout the study rats were restricted to 2 g of labc Italy) 8ad corneal electrodes, soaked 30.9% saline, Mice ratory rodent chow pe:lets (Bio-Serv, Freichtown, N.J.) per Yet lock of for 93 solds. Pig Adi is day, while access to water was unlimited. All training and pigminutesistration: Ail experitaeata eforeaninistration c3rapouilds of werecrosocial administered testing was done Moriday through Friday of each wick.---- Analysis: The data are presented as the percent of atimals Twelve modei E18-10 Coubout cpcrant chambers {28x protected from the bird-limb extensor component of the 26x3 cm) were hosised in tight-proof, sound-attentiated, seizure. The data were analyzed by Square statistics. and fan-ventilated chambers. Each operant chamber was The significaEcce level was set at p4(3.05. equipped with two non-retractabic levers, requiring a town Open-Field locomotor Activity in Rats ward force equivalent to is g (.35N), that were sounted Male Sprague-Bawiey rats, weighing 250-290 grams at 3 cm from thesidewall, 3 cu above the petal grid floor, and tle beginning of the experimeat were purchased from 5 cm fro: a centraliy placed dipper that delivered one 45 ing Charles River Laboratories {Wiknington, Mass), he ani- 25 food pellet (Bustless Precision Pelets, Bio-Setv, *rench mals were housed in groups of four in a colony room towa, N.J.), The experimental chambers were co8nected to maintained at coastant te:perature (2it+2°C) and hutnidity a Micro PDP: 1/73 computer using a ..AB LINC interface. (50.10%. She roo: was illuminated 12 hours per day A SKED-3 oper sing system (State Systein, Kalanaeso, (lights on at 2600h. The rats has ad ibilum access to food Mich.) was used to record and control behavior. biscrimi and water. The testing apparatus consisted of pixiglas aation training: After labituation to the operatt chatibet, ch3mbers (2x42x39 CE) equipped with Digiscal activity rats were trained to alerate daily between response Revers ilsonitors (Omnitech Electronics, Columbus, Ohio) iiii on a Fixed Ratio (FR) schedule of reinforcement. Once detect interruptio33 of 16 photobeans spaced 2.5 CIn spast lever pressing was well established, the reinforcement con and 2 cl above the foot. Hosizontal activity was moni- tirgency was increased increasentally to an FR 10 schedule, toged for 69 lites. Brug Administration: Ali drigs were ' while maintaining the lever atternatica. Next, rats were administered PO 20-63 finites before behavioral testing. traiad to discrimitate between drug (5.0 Tigkg, P. chlor All dataAssis. were subjectedRise to analysis exposed of stemaS,variance (ANOVA) diazepoxidecrerandomly and assigned drug vehicleros::stineiai?oftheats the fi crasing-correct and foikowed byr. insiividual Dean comparisoas--- using Fisher's werethe right randomly lever assigas "saline-correct. gineer sever The a leverdrug-cor: assign:leaks 3 east. Significant Difference test (Kisk, 1968) where appro- - - priste. The significance Revei was set at p-0.054At wereresponse reversed of the fordrug-correct the remaining ever wasazimals, reinforced Every on tenthdays Rorod Performance in Rats whenresponse the ratscy: the were opposite pretreated lever with was drug, reinforced whereas afterevery saliae tenth theMale begiuling Sprague-Dawley of the experimeat rais, weighing were 80–200purch&sed grams from at 43 injectious. each 2-week period there were 5 drug days and Charles River Laboratories (Wilmingoa, Mass.). The ani- 5 sailine days, with the constraint that there not be more tha}). mais were housed in groups of four in a colony room 3 consecutive drug or vehic!e days. Piscrimination sessions maintained at coastant temperature (21+2°C) and humidity were continued until each rat reached the criteriod of no (5:10%).(ights on at The 0600 room b). The was rats illuminated had ad ibibiri 12 hoursaccess per to foodday 'Sentatiothan in three 9 out incorrect of to consecutive respouses sessions. before first Test food sessions: pre and water. The degree of muscle coordination or balance Otice criterion for esting was et stimuli substitution (i.e., ataxia) was determined using a standard accelerating conducted on Friday of each week test sessions tolorod tradinil (igo Basile, Cornerio-Wrese, italy or were : minutes in d Ei test so Columbus list::getts, Columbus, Ohio) that was 6 can in 53 keye on which th tas first responded 10 times resulte diametex, 24 cm above the base, and rur: iron an initia: reinforcement and subsequeat FR, reinforcetient was speed of2pm anasium speed c20pf20 rpm, hilehe sila madeicy coatingeetwith uponanoesponse, pressing is "selected' checlected lever. The achinal raised on theating rod was automatically and becamber of response in the session were recordicci, up to a tilaxtauru (f5 minutes. Each rat had three recorded. On Xionday through. Thursday of each week, pretest acclimation trials, and the latency from the third trial C training sessions were conducted to ensure that citerica ir was sised to counterbalance rats for subsequeli drug testing, testing was sue. If any rat failed to meet the criterion for Drug Administration. All drugs were admissistered PO testing, testing with that animal was postponed and discrimi 20-60 animates before behavioral testing. Data Analysis: nation training continued unti: the performance criterion was Results were expressed as the neartl SEM. Aidata were is attained. Eata analysis: Drug discrimination results are Subjected to analysis of waiiance (ANOVA) followed by expressed as the percentage of animais selecting the chlor

individual Betia cottiparisons using Fisher's 3-cast Sigrif- diazepoxide-correct levex. Page 48 of 53

US 7,139,196 B2 9. 92.

REFERENCES EXAMPLE 4

Drug Discritination it. Rats Kirk R. E. (1968} Experiental I)esigs: procedures for the Behaviora: Sciences. Brooks:Coks, Belmoat, Calif. s at t i: if they just

kakashi. E An:alais are taught to crai: one response if they jus Takahashi L. K. Kaia N ii, Vander Burgti A, Sh H received drug and a difierent response if they just received (1989) Corticotropin-releasing factor modulates defeu- line. The anials to discriminate betw “if

S-ive-withdrawalad explorate behavior in rats. Behav state' and a ''''""to drug state". The rats were trained to Nesios: 03:648-553 discriminate betweg 8 state indiced by a typical benzodi

- - 38 a zepine chlordiazepoxide (C3):; "drug state”) and a state

Experimeits: Resists induced by vehicle (aethocei: "no drag state). Table 1

shows that QH-i-066, Xii-FY-ESMli, and Xite-ii-853 are

Eable i below) shows ratios of lowest effective anxi less pote: it a producing Ci P-like effects ibi diazepam (t olytic doses in the situational anxiety (SA) assay compared triazolam and this may have reduced abuse potential coin witi owest effective doses producing side effects in three 15 pared with CDP. citierest models: locomotor activity (LMA), rotorod (RR), and chloriazepoxide-like subjective effects as measured by EXAMP.E 5 the drug discrimination. Eitetloci (T: ). Sei Protection in Mi

fable 2 (below) shows effective doses in a node of are Poctor Mice epilepsy (petity lectetrazole-induced seiz:res) it mice (agf raries yy' kg, fos for 3-i-666,-- A. xypyi,- and X-ie-ins; in investionMissippi; were subjected to pentyienctetrazile (PF) at 125 comparisc; with diazepam, triazolars, and M-i-073. gig to induce seizures. She percent of aniaals protected

fio; death, withi; one hour of PT. was neasured. Eithie 2 25 EXAME shows that QH-i-066 and XLi-JY-DMH have anticonvul

- - - - sant effects against P2-induced seizures at doses colpa Situational Anxiety in Rais rable to those for diazepam aid triazoian, fable 2 also

shows that XHe-ji-053 is effective against 32-induced Rats were hat died daily for at least 5–6 days. Eacy were seizures. then placed in a dark cylinder in at life:Yinated open fieki.

the time for the rats to exit the dark cylinder was then ABLE Ireasured. Vehicle-treate animals retail within the dark

cylinder for 10.15 minutes (tastal test duration is 15 amis- Aatistsy Antigeriety Antibilgecie utes). This high iatency to exitine dark chamber is an index seiaison atteX. iaidity of a heightened state of anxiety, Compounds with anxiolytic digiper 1. c s efficacy reduce agicy to exit the dark haber. Table St. 3. > shows that QEi-ii-066, XLi-Y-DMii, and XHe-3-353 show El ox x3 1st 3)xiolytic effects in the situational anxiety tes; a doses M-- al - 0

>100-fold lower tha: doses producing sedative and ataxic 4) Xe-ii-053 s303 >30 3. effects (see exauples 2 arci 3).

EXAMPLE 2 A3LE 2

Locomotor Activity in Rats

Rats were placed in an oper field and the total distance Diazepam

covered by the rat was Bleasured. The test duration was 60 &Ei-ice ass minutes. Cornpourkis producing sedative effects decrease SEEa 3

the distance covered. Eable 1 shows that Q:i-i-t}66, Xi- Ciao JY-DMH, and XFie-ii-053 are 3ess effective in producing Xe-CS3 313)

sedative or hypnotic effects than diazepair or triaxo:aua. EXAMPLE 3 REFERENCES

Rotorod Periorixaace is. Rats l, Ster:83ch, E. H.; Frye, R. l. Metlesics, W.; Reeder, E., Siliy J. ei, A. J. Og, Chasis, 362,27, Rats were placed on a sowly rotating rod and the speed Salley, G.; Stet::pei, A. J. Org. Chans, 362,27 of rotation was g3Rduallyw increased. The time of the rod for 2. G), Q.; Wang, G.; C.; Costa, B. R., &ice, K.

i.S.S.ulcoordination) decrease startisting the tirise spent on the rock compa S.S.;* ... gigto sil. is: with vehicle treated animalsTable shows actios. 3. ng Egil B. Sloboski, B.C., d. XL.Y.DME, and XHeii.53 are less potent introducing Og. Chin 927. y ataxia than diazepara or triazolam. Thus, they are ikely 4. iliu, R. Zhang, P:Skoiick, McKerra1), R.; Cook, i.M. better drugs clipsically because they have decreased side 65 J. Med, Chen. 3996, 39, 928-3934.

effects decreased sedation (exaggie2) and ataxia (example 5. Austis, W. B.; Bilow, N.; Kelleghaa. W. 3.; :..au, K. S.Y. 3. J. Org. Chen. 1981. 46, 22.80.2286. Page 49 of 53

US 7, 9,96 B2 93 94

6. Steubach, i. H.; Reexier, E.; Arcier, G. A. J. Org. Chen). with at east the skibstituent -CxcC-R, where R is H, 3963, 28, 2456-2459, SECH), t-buyi, isopropyi, actinyl, or cyclopropy;

7. He, X. Ph.d. They is, UW-Missaukee, 2003). 3R is cast of H, CE3 C3N{CEis), CHCF, CHCCfi.

8. Eieck, R. F. Paiiadium. Reager: in Organic Synthesis; is aa alkyl cyclopropy;

R is a substituted or unsubstituted at cast partially Academic Press, Orlaado, Fla.: Academic Press, 1985. 5. irisatirated 5 or 6 membered cyclic or heterocyclic 9. Bogatskii, A. W.; Andronati, S. A.; Wikilyaev, Yu. ...;

Wororin3, T. A.; Yakkirovskaya, i. N. Bef ko, A. W. ring, whexcit: if substituted the substituen: is tile or

Ficini. Cheii. i. (Engl. iiansl., 1977, 1 }, i.520.1525 Enore of F, Ci, Bt, or NO at the 2-position.

t{3, Weidelek, 2 delek; Protiva, Miroslav, Collect, Czech 3. A compouni (ffonmula i, or a salt or prodrig there.cf. Chena. Copysyster. 3983, 48, :47-1483. 3i, Hester, J, 8.; Lucie is, J. E.; Eminert, I, E. West, 8, E, ... fed. Chepp. 989, 32, 57.63, XHHYrk. E}

12. Fryer, R.I. Kudzmai. K; Gu, 2.; i3, K.J. Org, Cherr, $93,56, 375-37.9. Y -'s 13. Paterst, Hoffmann-LaRoche, 1963, DE 145625, s 4. Patent, of:inam-LaRoche, 1958, i.S. Pat, Xy, 2,893, 992. 2. es 5. G. A. Archer and L. H. Sterabach, J. Org. Chen. 29, 23i ' (1964). R 16. £ryer, R. E.; Zhang, P.; Rios, R. Syrith. Comun, 1993, 2, 33,985-992. wileein: 7. U.S. Pat. No. 3,886,41, 1975. Y and Z are takea togethe, with the iwo intervening The invention claimed is: carbon atons to form a rig selected from pElenyk and

1. A compound of formuia, or a sait or prodrug thereaf, thienyl, which fig is substituted: at the C(7) position 25 with at least the substituent -C=e:C-R, where R is E,

Si(OH, -butyl, isopropyl, methyl, or cyclopropyl; R R is a substituted or unsubstituted at least partially : us)saturated 5 or 6 meElbered cyclic or hetergyclic ring, wixercia if substituted the substitueat is one or

3C more of F, Ci, B, or NQ at the 2-position, R 4. A compound of frauia IV, or a salt or pro-drug thereof,

tw.

whereint:

Y axi Z. &re taken together with the two intervening

carbor: atolls to form a ring selected fral pheny and

thienyl, which ring is substituted at the C(7) p.sitiox. 4: a

with at east the substituent -C-C-R, where R is 3, -er R {

Si(C3,}, t-butyl, isopropyl, methyl, or cyclopropyi; R is cise off, Ci, CHN (CH), CSICF, CHCCH,

or an alky: cycopropyl; wherein:

R is a substitutei or unsubstituted at least partially as R is H, Si(CE), t-buty, isopicgyi, methyi, or cyclopro usisatirated 5 or 6 actsabered cyclic or heterocyclic pyl;

ring, whereis) if substituted the substituent is one or R is one ofH, CH, ChiN (C.H.), CHCF, Ci:CCEi, Exore of F, Cl, Br, or NO at the 2' position; or an aikyl cyclopropyl;

R is oxe of ti, OH, OCONCH, COOCH, or R is a substituted or usubstitute at least artially COOCEi. s utxsafurated 5 or 6 membered cyclic or keterocyclic 2. A compound {}f for Etula E, or s. salt or pro-drug thereof, ring, wherein: if substituted the substituent is tie or more of F, Cl, Br, or NO. at the 2'-position; A is an ethoxide or a propoxide.

{} 5. A coungkuid of formula W, or a sait or prodrug thereof,

wiereira:

Y and Z are taken together with the two intervettig ós R carbon atoans to form a ring selected ion phenyi and

thie:yl, which ring is substituted at the C(7) position

Page 50 of 53 US 7,119, 196 B2 96 95. R is a substituted os tasubstituted at 3eas: patially wierciaY and 2 are taken together with the two intervening unsatisfied 5 or 5 membered cyclic or heterocyclic carton atoms to for a ring selected foil phenylind ring, whereirs if substituted be substituett is 33 of thienyi, which ring is substituted at the C8 position. ce of F, C, Br, or NC, at the 2'-positios, with at east the substituent -C-C-R, where R is H. 8. A compound of formula Will, or sailor prodrug thereof, si(CEI), t-b:y, is popyl, methyi, of cycopropyl; R, is one of H, CH, CF, CHCF, C:Chi, C-x CH, an alkyl, or cyclopsopyl, VEST R is a substituted of unsubstituted at least partially unsatistated 5 or 6 membered cyclic or heterocytic ring, wherein if substituted the substitueat is one of sacre of F, Cl, Br, or NO at the 3' position; R is a branchci or straight C to C. halogenated or unhakeenated alkyl or a racity! cyclopropy. 6. A compound offortula VI, or a Salt (if prodrig thereof,

Y. wherein: X is N or CE, Y and Z are taken together with the two interveilig carbon atoms to form a rig sciected from pheny aid thienyl, which ring is substituted at the C(8) position. with at least the substituent CeC-R, whete R is is SiCE, t-butyl, isopropyl, aethyl, or cyckpropy: R, is one of H, CH, CF, CH3i (H-CF3 of cyclo propy; R, is a substituted or usubstituted at east patia:y unsaturated 5 or 6 incziibee cyclic or heterocyclic whitein: ring wherein if substituted the substituent is of f Y and Z are taken together with the two interversing more of F, Cl, Br, or NO, at the 2-positie3. carbut atoms to form a ring selected for phenyl and aienyi, which ring is substituted at the C(8) position 9. A corporadofformula X, erit Saitor prodrug thereof, with at least the substituent -C=C-R, where Rish, Si(OH), t-butyl, isopropyl, tethyl, or cyclopropyl R, is one of E3, CH, CP, CHCH, CHCF. (f cyclo propy; R is a substituted or unsuistituted at least partially unsaturated S or 6 membered cyclic or heterocyclic ring, whereii: if substituted the substitue: is tie of rare of F, Cl, Br, or NO, at the 3'-position; R is 3 brancised or straight C, to Ca alky of a Tethyl cyclopropy. 7. A compound of farasia Wii, or a salt 3E prodrug tiereof, were:: n is to 4; Yaad Z are taken together with the two interveiling carbonatoras to &om a ring selected from phenyi and thienyi, which ring is substituted at the C(8) position. with at least the substituent -C-C-R, whese R is . Si(CH, 3-butyl, isopropyi, akchyi, tor cyclopropyi, Yard 2 are takes together with the two intervais-g carboa atoms to form a ring selected fork phenyi and thienyl, which ring is substituted at the C(8) positio: with at east the substituent -C-C-R', whese Risi, Si(CH, t-butyl, isopropyl, lethyl, or cyclopropy: R, and R." are independently one af Ei. Chi, Cif whereit CHCF. CHOH, or cyclopropyl Y and Z are takers togetier with the two intervening R, and R are independently 8 substitutes: crunsubst:- carbon atoms to foran a ring selected fictis phenylalki buted a Beast partia:y unsatugated 5 of 6 1ucherd thienyi, which ring is substituted at the C8) position cyclic or heterocycie sing, where if substituted the with at least the substituent -C-cC-R, where R is H. abstituent is ose or more of F.C. Br, or NO: 8 the 2 Si(CH, -butyl, isopropyl, methyl, or cyclopropy: position,

Page 51 of 53

US 7,139,196 B2 98 97 cyclic or heterocyclic ring, wherein if substitiated the 16, Acompound offoriaula X, or a salt or predirig thereof, bstituent is one or more of F,C), 3r, otho: at the 2'- positions, X) Bisc, NH, or -N(R-NCR}, where R is 888 of H, Cii, s alkyl, or cylioakyi. R 12. A compouni of fox33mia Xi, or a s: (; grottig 1Noc. W s thereof, 3 y"

1. s C whereitand z are taken togetber with the two intervering carbon assins to form a ring selected ios) pheny and thienyi, which ring is substituted at the C8) position with at east the substitgeit -C=C-R, where R is . si(CH, t-butyi, isopropy, resbyi, or cyclopropyl. Yi and Ž are taken together with the two intervening itvanda is to 4;are taken together with the two servetting carbon atons to form a ring selected 30m pitchy and carbon atoms to fom a fine selected fictitenylaid thienyl, which ring is st:bstitute at the C(8 position. thienyi, which ring is substituted at the {c'} position with at east the substituent -C:C-R, where R is H. with at least the substituent -C-C-R, where Risk Si(CH, t-buiyi, isopropy, whethyi, gif cyckpiogy, Si{C}},, t-buty, isopropyi, aethyi, or cyclopropyl R, and R. are independently ope of H, CH, CF yadi are takes together with the two interving CHC3, CHCF, or cyclopropy; carton atoms to form a sing selected from pietistic R, and Rare independently a substituted or wnsubsti thienyl, which ring is 3:bstituted at the C(7) position atted at east partially unsaturated 5 or 6 pembered withs east the substituent -Co-C-R, where R is, cyclic or xeterocyclic ine, where if substituted the Si(CH, t-butyl, 1soprogs, Betty, if cyclopropy: gostituent is one of more of F.C., Br, or NO at the 2'- R, and R' are independerly one of I, CH, CFs, position: CHCF, CHCH, or cyclopsopy, Biso or NH and wherein -8CH3- is optionally replaced R and R are independently a substituted or uns:sti with NR-N(R-, where R. is one of H, Clls, alky, tuted a cast partially unsaturated 58 6 membed or cycloaky, cyclic or beterocyclic ring, where if substituted the 11. A compound of formatia Xi, or a salt of prodrug sittent is one or more of F, C, B, of NOx at the 2 thereof, positius. 13. A compound of formula XBI, or a salt or portg thereof,

r)--sis.N

2. e werein: is or whereiz: Y and Z are takes together with the two servening y aid Z are taken together with the two interve: ing carbon atoms to form a ring selected fo:Tl phenyland carbonacas to form a ring selected item phenyl aft thienyl, which ring is substituted at the (8) posities: thienyi, which ting is substituted at the 7 positio. with at least the substituent -CeC-R, where R is , with a cast the substituent -CrcC-R, where Risi, SCH.) :-butyl, isopropyl, methyi, (x cyclopropy, si(CH, -butyl, isopropyl, pethyi, ir cyclopropy; Y' and Z are taken together with the two intervesing Yi and fare takes together with the two intervening carton atoms to for a ring selected from phenyl and carbon atoms to for: a ring selected for phenyl 8:3i thienyl, which ring is st:stituted at the C(8) position thiery, which ring is substituted at tic C(7) position with at east the substituest-C-C-R, where R is H, what cast the substituent CeC-R, where R is H, Si(CH, t-butyi is propyl, methyl, of cyclopropy; si(CEI), t-buyi, isoprayi. Inethyl, or cycopropyi; R, and R, are independently one of Ei, CH, CF R, and R, are independently cite of El, CFI CF, CHCI, CHCF or cyclopropy; s CHC3, CHCF, or cyclepropy: R. and Rare independently a substituted or itsubsti R, and R. are isdependently a substituted or itsubsti tuted at east parisaily unsaturated 5 or & Enembered tuted at least partially uBSakurated S or 6 m&miered

Page 52 of 53

US 7, 19,196 B2 99 cyclic or heterocyclic ring, wherein if substituted the substituent is one (; Rose of F, Cl, Br, or NOz at the 2'- position; Biso or NH and wherein-BCH.B. is optionally replaced : with N(R)-N(R)-, where R is one of H, C, askyi, or cycloalkyl. 14. A coupound of formula XIV, at 8 sait or to-drug thereof,

(XV) whereia: 8. R Risi, Sixte iBE, C$3 methy cyclopropyl, CF, Cis . s' s CB, Arispiety,3'-flux spheryl,2-thienyl, 3-thienyl, co-Yp1No. Y- ii.2-pyridy, A compoutd. 2-pyrity: of XVII, N-O, or X a issalt N ofor froirugCE. thereof, e Nase R R XII.

whereig: Y and 2 are taken together with the tw8 intervening carbonators to form a ring selected froís, phery and s thienyi, which ring is substituted at the C7 position with at least the su?ystituett-C-C-R, where Risi, Si(CH, t-butyl, isopropy, methyl, or cyclopropy; y and 2 are taken together with the two intervetting 3 whereig e carbonatoms to form a ring selected from betty and Risi, Silvie B, Eley E. CFCCl3 thienyl, watch rise is substituted at the C7) position E.G. ity: S. 3-thienyl, with at east the substituent -C-C-R, where R is , 3 E. R NAVKirodrug si(CH, t-butyl, isopropyl, methyi, orr cyclogropyl as theref, ck R, and R are independently one of H, CH, CF C:CH, CHCF, or cyclopropyl R, and R. are independently a st:stituted of insisti tuted a cast partially unsaturated 5 or 6 Benbered cyclic or heterocyclic ring, wherein if substituted the substituent is one or acre of F, Cl, Bt, or MO: at the: g(sition; piso, NH, or N(R)-N(R)-, where R is oae of H, CH, alky, or cycloalkyl. 1s. A compound of 83ruaula XV, or a Salt or prodrug tiereo, wiercia: n is or l;R is H, S:Me, Bu, CH, methylcyclopropy, CE, CC1, CB, Aris phenyl, 2'-flurophenyi, 2-thie ny), 3-tienyl, 3-yridyl, 2-pyridyl N-0; Y is Q, S, NEC; i. 19. A compoxiad of forussia XX, at a sa kt or proxirag thereif, 55

Ea w x: wherein, O sees is or 2; Risi, SiMetBig, CH, methylcyclopropy, r Cr, cc, CBra; Ar is ghenyi, 2-Europhery, 2-thie e -\s sy, 3-taienyl, 2-pyridy, 2-pyridyl N-0: X is NorCE. as R 6. A compound of formula XV, or a $8to: prodrig thirteli,