BENZODIAZEPINE DERIVATIVES, PREPARATION THEREOF AND USE THEREOF BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is directed to compounds that are useful in treating or preventing pain, septic shock, pancreatitis, edema, rhinitis, asthma, colitis, arthritis, hepatorenal syndrome, cancer, bacterial and viral infections, ulcerative colitis, and Alzheimer's Disease. More particularly, the present invention is directed to benzodiazepine derivatives that useful in treating pain.

2. Discussion of Relevant Art Two types of bradykinin receptor are known : The B 1 receptor and the B2 receptor. A number of reports indicate an important role for the B2 receptor in the pathophysiology of pain. [e. g Hall, J. M., Morton, I. K. M. The pharmacology and immunopharmacology ou kinn receptors. In : Farmer SG (Ed). The kinin system. London : Academic Press, 1997 ; 9-44]. Hence, compounds that are B2 antagonists are useful in the relief of pain, including chronic pain and acute pain, e. g., chronic inflammatory pain, neuropathic pain, back pain, migraine, cancer pain, visceral pain, arthritis pain and post- operative pain.

DETAILED DESCRIPTION OF THE INVENTION Thus, the problem underlying the present invention was to develop new compounds that are novel kinin B2 antagonists.

Accordingly, in one aspect, the present invention provides compounds that are useful in treating pain.

Definitions Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a

chemical naming program : ACD/ChemSketch, Version 5. 09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.

The term"Cm n"or"Cm n group"used alone or as a prefix, refers to any group having m to n carbon atoms, and having 0 to n multivalent heteroatoms selected from O, S, N and P, wherein m and n are 0 or positive integers, and n>m. For example,"Cl 6" would refer to a chemical group having 1 to 6 carbon atoms, and having 0 to 6 multivalent heteroatoms selected from O, S, N and P.

The term"hydrocarbon"used alone or as a suffix or prefix, refers to any structure comprising only carbon and hydrogen atoms up to 14 carbon atoms.

The term"hydrocarbon radical"or"hydrocarbyl"used alone or as a suffix or prefix, refers to any structure as a result of removing one or more hydrogens from a hydrocarbon.

The term"alkyl"used alone or as a suffix or prefix, refers to monovalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms. Unless otherwise specifieds"alkyl"general includes both saturated alkyl and unsaturated alkyl.

The term"alkylene"used alone or as suffix or prefix, refers to divalent straight or branched chain hydrocarbon radicals comprising 1 to about 12 carbon atoms, which serves to links two structures together.

The term"alkenyl"used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 2 up to about 12 carbon atoms.

The term"alkynyl"used alone or as suffix or prefix, refers to a monovalent straight or branched chain hydrocarbon radical having at least one carbon-carbon triple bond and comprising at least 2 up to about 12 carbon atoms.

The term"cycloalkyl,"used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical comprising at least 3 up to about 12 carbon atoms.

The term"cycloalkenyl"used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon double bond and comprising at least 3 up to about 12 carbon atoms.

The term"cycloalkynyl"used alone or as suffix or prefix, refers to a monovalent ring-containing hydrocarbon radical having at least one carbon-carbon triple bond and comprising about 7 up to about 12 carbon atoms.

The term"aryl"used alone or as suffix or prefix, refers to a monovalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e. g, 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms.

The term"arylene"used alone or as suffix or prefix, refers to a divalent hydrocarbon radical having one or more polyunsaturated carbon rings having aromatic character, (e. g., 4n + 2 delocalized electrons) and comprising 5 up to about 14 carbon atoms, which serves to links two structures together.

The term"heterocycle"used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring (s). Heterocycle may be saturated or unsaturated, containing one or more double bonds, and heterocycle may contain more than one ring. When a heterocycle contains more than one ring, the rings may be fused or unused. Fused rings generally refer to at least two rings share two atoms therebetween.

Heterocycle may have aromatic character or may not have aromatic character.

The term"heteroalkyl"used alon or as a suffix or prefix, refers to a radical formed as a result of replacing one or more carbon atom of an alkyl with one or more heteroatoms selected from N, O, P and S.

The term"heteroaromatic"used alone or as a suffix or prefix, refers to a ring- containing structure or molecule having one or more multivalent heteroatoms, independently selected from N, O, P and S, as a part of the ring structure and including at least 3 and up to about 20 atoms in the ring (s), wherein the ring-containing structure or molecule has an aromatic character (e. g., 4n + 2 delocalized electrons).

The term"heterocyclic group,""heterocyclic moiety,""heterocyclic,"or "heterocyclo"used alone or as a suffix or prefix, refers to a radical derived from a heterocycle by removing one or more hydrogens therefrom.

The term"heterocyclyl"used alone or as a suffix or prefix, refers a monovalent radical derived from a heterocycle by removing one hydrogen therefrom.

The term"heterocyclylene"used alone or as a suffix or prefix, refers to a divalent radical derived from a heterocycle by removing two hydrogens therefrom, which serves to links two structures together.

The term"heteroaryl"used alone or as a suffix or prefix, refers to a heterocyclyl having aromatic character.

The term "heterocycloalkyl" used alone or as a suffix or prefix, refers to a heterocyclyl that does not have aromatic character.

The term"heteroarylene"used alone or as a suffix or prefix, refers to a heterocyclylene having aromatic character.

The term"heterocycloalkylene"used alone or as a suffix or prefix, refers to a heterocyclylene that does not have aromatic character.

The term"six-membered"used as prefix refers to a group having a ring that contains six ring atoms.

The term"five-membered"used as prefix refers to a group having a ring that contains five ring atoms.

A five-membered ring heteroaryl is a heteroaryl with a ring having five ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.

Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1, 2, 3-triazolyl, tetrazolyl, 1, 2, 3- thiadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-triazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-triazolyl, 1, 3, 4-thiadiazolyl, and 1, 3, 4- oxadiazolyl.

A six-membered ring heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are independently selected from N, O and S.

Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term"substituted"used as a prefix refers to a structure, molecule or group, wherein one or more hydrogens are replaced with one or more Cl l2hydrocarbon groups, or one or more chemical groups containing one or more heteroatoms selected from N, O, S, F, Cl, Br, I, and P. Exemplary chemical groups containing one or more heteroatoms include heterocyclyl,-NO2,-OR,-Cl,-Br,-I,-F,-CF3,-C (=O) R,-C (=O)OH, -NH2, -SH, - NHR,-NR2,-SR,-S03H,-SOzR,-S (=O) R,-CN,-OH,-C (=O) OR,-C (=O) NR2,- NRC (=O) R, oxo (=O), imino (=NR), thio (=S), and oximino (=N-OR), wherein each"R" is a C1-12hydrocarbyl. For example, substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring.

The term"substituted"used as a suffix of a first structure, molecule or group, followed by one or more names of chemical groups refers to a second structure, molecule or group, which is a result of replacing one or more hydrogens of the first structure, molecule or group with the one or more named chemical groups. For example, a"phenyl substituted by nitro"refers to nitrophenyl.

The term"optionally substituted"refers to both groups, structures, or molecules that are substituted and those that are not substituted.

Heterocycle includes, for example, monocyclic heterocycles such as : aziridin, oxirane, thiirane, azetidine, oxetan, thietane, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazoline, dioxolane, sulfolan 2, 3-dihydrofuran, 2, 5-dihydrofuran tetrahydrofuran, thiophane, piperidine, 1, 2, 3, 6-tetrahydro-pyridine, piperazine, morpholine, thiomorpholine, pyran, thiopyran, 2, 3-dihydropyran, tetrahydropyran, 1, 4- dihydropyridine, 1, 4-dioxan, 1, 3-dioxan, dioxan, homopiperidine, 2, 3, 4, 7-tetrahydro- lH-åzepine homópiperazine, 1, 3-dioepane, 4, 7-dihydro-1, 3-dioxepin, and hexamethylene oxide.

In addition, heterocycle includes aromatic heterocycles, for example, pyridine, pyrazin, pyrimidine, pyridazine, thiophene, furan, furazan, pyrrole, imidazole, thiazole, oxazol, pyrazol, isothiazole, isoxazole, 1, 2, 3-triazole, tetrazol, 1, 2, 3-thiadiazole, 1, 2, 3- oxadiazole, 1, 2, 4-triazole, 1, 2, 4-thiadiazole, 1, 2, 4-oxadiazole, 1, 3, 4-triazole, 1, 3, 4- thiadiazole, and 1, 3, 4- oxadiazole.

Additionally, heterocycle encompass polycyclic heterocycles, for example, indole, indoline, isoindoline, quinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, 1, 4-benzodioxan, cumarin, dihydrocoumarin, benzofuran, 2, 3- dihydrobenzofuran, isobenzofuran, chromene, chroman, isochroman, xanthene, phenoxathiin, thianthrene, indolizine, isoindol, indazole, purine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, phenanthridine, perimidine, phenanthroline, phenazine, phenothiazine, phenoxazine, 1, 2-benzisoxazole, benzothiophene, benzoxazole, benzthiazole, benzimidazole, benztriazole, thioxanthine, carbåzole, carboline, acridine, pyrolizidine, and quinolizidine.

In addition to the polycyclic heterocycles described above, heterocycle includes polycyclic heterocycles wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings.

Examples of such bridged heterocycles include quinuclidine, diazabicyclo [2. 2. 1] heptane and 7-oxabicyclo [2. 2. 1] heptane.

Heterocyclyl includes, for example, monocyclic heterocyclyls, such as : aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2, 3-dihydrofuranyl, 2, 5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1, 2, 3, 6-tetrahydro-pyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2, 3-dihydropyranyl, tetrahydropyranyl, 1, 4-dihydropyridinyl, 1, 4-dioxanyl, 1, 3-dioxanyl, dioxanyl, homopiperidinyl, 2, 3, 4, 7-tetrahydro-lH-azepinyl, homopiperazinyl, 1, 3-dioxepanyl, 4, 7- dihydro-l, 3-dioxepinyl, and hexamethylene oxidyl.

In addition, l1eterocyclyl includes aromatic heterocyclyls or heteroaryl, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, fury, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1, 2, 3-triazolyl, tetrazolyl, 1, 2, 3-thiadiazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-triazolyl, 1, 2, 4-thiadiazolyl, 1, 2, 4- oxadiazolyl, 1, 3, 4-triazolyl, 1, 3, 4-thiadiazolyl, and 1, 3, 4 oxadiazolyl.

Additionally, heterocyclyl encompasses polycyclic heterocyclyls (including both aromatic or non-aromatic), for example, indolyl, indolinyl, isoindolinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, 1, 4-benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2, 3-dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indolizinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, phenanthridinyl, parimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1, 2-benzisoxazolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrolizidinyl, and quinolizidinyl.

In addition to the polycyclic heterocyclyls described above, heterocyclyl includes polycyclic heterocyclyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include quinuclidinyl, diazabicyclo [2. 2. 1] heptyl ; and 7-oxabicyclo [2. 2. 1] heptyl.

The term"alkoxy"used alone or as a suffix or prefix, refers to radicals of the general formula-O-R, wherein R is selected from a hydrocarbon radical. Exemplary

aLkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy, and propargyloxy.

The term"amine"or"amino"used alone or as a suffix or prefix, refers to radicals of the general formula-NRR', wherein R and R'are independently selected from hydrogen or a hydrocarbon radical.

"Acyl"used alone, as a prefix or suffix, means-C (=O)-R, wherein R is an optionally substituted hydrocarbyl, hydrogen, amino or alkoxy. Acyl groups include, for example, acetyl, propionyl, benzoyl, phenyl acetyl, carboethoxy, and dimethylcarbamoyl.

Halogen includes fluorine, chlorine, bromine and iodine.

"Halogenated,"used as a prefix of a group, means one or more hydrogens on the group is replaced with one or more halogens.

"RT"or"rt"means room temperature.

A first ring group being"fused"with a second ring group means the first ring and the second ring share at least two atoms therebetween.

"Link,""linked,"or"linking,"unless otherwise specified, means covalently linked or bonded.

Description of Preferred Embodiments In one aspect, the present invention provides a compound of formula (I), pharmaceutically acceptable salts thereof, diasteriomers thereof, enantiomers thereof, or mixtures thereof : wherein Ru ils selected from optionally substituted acyl, optionally substituted alkyl- oxycarbonyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted aryl ; optionally substituted heterocyclyl ; optionally substituted aryl-Cl 6alkyl, and optionally substituted heterocyclyl-Cl, alkyl ; or a divalent Cl-12 group that together with a second nitrogen of X to form a ring ;

X is a divalent group including a first nitrogen atom and the second nitrogen atom, wherein a first group (e. g., the ZH-1, 4-benzodiazepin-2-one group of formula (I)) is linked to the first nitrogen atom and R1 is linked to the second nitrogen atom, and wherein the first and second nitrogen atoms are separated by either one carbon atom, or two carbon atoms wherein said two carbon atoms have a double bond therebetween ; R3 is optionally substituted aryl, optionally substituted Cl l2alkyl, optionally substituted C3 l2cycloalkyl, or optionally substituted heterocyclyl ; R4 is, at each position, independently-H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, nitro, cyano, hydroxy,-oR6,-SR6,-S (=O) R6, -S(=O)2R6, -C(=O)R6, -C(=S)R6, -NR7R6, -C(=O)NR7R6, -NR7C(=O)R6, -SO2NR7R6, -NR7SO2R6, or-C (=0) OR" ; and R5, R6 and R7 are independently-H, optionally substituted C, 6alkyl.

In another aspect, the compounds of the present invention are those of formula (I), pharmaceutically acceptable salts thereof, diasteriomers thereof, enantiomers thereof, or mixtures thereof, wherein R is selected from optionally substituted acyl, optionally substituted alkyl- oxycarbonyl, optionally substituted alkyl, optionally substituted heteroàlkyl, optionally substituted cycloalkyl, optionally substituted aryl ; optionally substituted heterocyclyl ; optionally substituted aryl-Cl 6alkyl, and optionally substituted heterocyclyl-Cl 6alkyl ; or a divalent C1-12 group that together with a divalent R2 of X forms a portion of a ring ; X is represented by (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), or (xvii) below : wherein R2 is selected from-H, optionally substituted Cl z2alkyl, optionally substituted Cl 12heteroalkyl, optionally substituted aryl, optionally substituted heterocyclyl, and a divalent C0 6group together with a divalent Rl to form the portion of the ring, wherein said divalent C0-6 group optionally includes one or more heteroatoms ; R3 is optionally substituted aryl, optionally substituted Cs 2alkyl, optionally substituted C3-12cycloalkyl, or optionally substituted heterocyclyl ; R4 is, at each position, independently,-H, halogen, optionally substituted alkyl, optionally substituted heteroalkyl, nitro, cyano, hydroxy,-oR6,-SR6,-S (=O) R6, -S(=O)2R6, -C(=O)R6, -C (=S) R6, -NR7R6, -C(=O)NR7R6, -NR7C(=O)R6, -SO2NR7R6, -NR7So2R6, or-C (=O)OR6 ; and

R5,R6 and R7 are independently-H, optionally substituted Cl 6alkyl.

More particularly, the compound of the present invention is a compound of formula (I), wherein R is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted isoquinolyl, optionally substituted acridinyl, optionally substituted coumarinyl, optionally substituted carbazolyl, or a first divalent group selected from optionally substituted C1-12alkylene and optionally substituted C1-12heteroalkylene ; wherein said phenyl, naphthyl, isoquinolyl, acridinyl, coumarinyl, and carbazolyl are optionally substituted by Cl 6alkyl, Cl 6heterocyclyl or amino, wherein said C1-12alkylene and Cl 12heteroalkylene are optionally substituted by C1-6alkyl, aryl-C1-6alkyl, aryl or heterocyclyl ; X is selected from formulas (i), (ii), (iii), (vi) and (xvii) below : R2 is -H, C1-3alkyl, or a second divalent group selected from a single bond, an optionally substituted alkylen and an optionally substituted heteroalkylene ; wherein said second divalent group together with said first divalent group forms a portion of a ring ; R3 is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cycloalkyl ; R4 is halogen, or C1-3alkyl ; and R5 is C1-3alkyl.

Most particularly, the compound of the present invention is a compound of formula (I), wherein -X-Rl of formula (I) is selected from formulas (a), (b), (c), (d), (e), (f) and (g) below :

Rl is optionally substituted phenyl, optionally substituted naphthyl, optionally substituted isoquinolyl, wherein said phenyl, naphthyl and isoquinolyl are optionally substituted by C1-6alkyl, C1-6heterocyclyl or amino ; R2 is-H, or C1-3alkyl ; is a nitrogen containing heterocyclyl, which may be optionally substituted by one or more-R8, and which includes a bond on the nitrogen that links to other group of formula (I). Exemplary nitrogen containing heterocyclyls include, but is not limited to, piperazinyl, morpholinyl, poperidyl, and pyrrolidinyl.

R8 is-H, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted C, 6alkyl,-OH, or C, 6alkoxy, wherein R8 is optionally fused with the ring of R3 iS optionally substituted cyclohexyl, optionally substituted phenyl, optionally substituted pyridyl, optionally substituted thienyl, or optionally substituted pyrimidinyl, wherein said cyclohexyl, phenyl, pyridyl, thienyl and pyrimidinyl are optionally substituted by halogen, methoxy, or C1-3alkyl ; R4 is halogen ; and R5 is methyl.

Specific examples of compounds of the present invention that may be used in practicing the present invention are listed in Table 1, below.

Table 1 : Spreadsheet of combinatorially prepared compounds with LCMS analysis of the reaction product. Corn-n,. , f Mass RtnTime Structur Target Mass Mass Rtn Time ound # ''YN tC I ci s e N > 474. 13 Yes 3. 92 . je/ f 9 s 9 X ou- 2 471. 15 Yes 2. 9 o i N - C'Yc. _ \S N CI 3 449. 11 Yes 2. 93 o, N N woNN \ N S CI 4 °/466. 13 No , N y-N N II o 483. 15 Yes 2. 85 /\ CIs<N \J X ci 517. 17 Yes 3. 97 N * o 7 cri 627. 16 No . o ci W$N S 525. 2 Yes 3. 47 cl i N _N N-. N-1 9477. 14 Yes 3. 11 Com-Struchue Target Mass Mass Rtn Time O Cl@$N » NE N e 1 " CI/ LJ N O 10/o 503. 15 No ° \ _N YNJ cri/1 N (O 11 543. 19 Yes 4. 24 N N °/ I CI' 12 468. 08 Yes 3. 55 cl N N k J NJO o/ N \=Ja N-CI S 14 455. 15 Yes 3. 11 cru N IS N\ \ N CI 15 W 463. 12 Yes 3. 05 o/ N N- (Y, N\S N IC N 16 U 449. 11 Yes 2. 94 NJLN N aN ep CI 17 _ 478. 12 Tentative o/ o/~ N- \ N N \S N \ I CI 18 449. 11 Yes 2. 89 Corn-.-,.. ,, Mass RtnTime pound # c. P 0 I i c \ I \\ NJLN/I N 19 552. 17 Yes 4. 5 NXN X °N IS N\ \ 20 469. 17 Yes 2. 85 o N \ CI S 21 21 469. 13 Yes 2. 78 Y ° N 0 --. - N_ CI O 22 499. 14 Yes 3. 3 r \. r FF S-F N N O CI 23 586. 14 Yes 3. 75 o S N _N, ''YY. jr n a N t N _ Q 24 532. 17 Yes 3. 7 i <N JN 45 C jus \ 25 561. 16 Yes 3. 87 .. _ _ / N 26 o 477 14 Yes 3. 17 X S N m I \ S i CI 27 469. 17 Yes 2. 78 Corn-,-.., rp. T., Mass RtnTime , Structure Target Mass Mass Rtn Time omd # Fotmd ? (MS) 1 . s Cl<$N » N3 U N 28/o 509. 2 Yes 2. 74 zu Clt FNs Nt zu 29/o 504. 15 Yes 3. 43 v/ s CI/N -N ! w N N 30/o 502. 13 Yes 2. 96 i W F F C' I N N N/\ F 31 °571. 14 Yes \ s LJ LJ 32 509. 2 Yes 4. 05 F -N ' IL N-- (I CI S 33 F 629. 18 Yes 1 ci O cl VN CI Nr /0 34 571. 08 No 01 s O \ N 35 ° 531. 19 Yes 4. 8 i '/°1 o- CI/-N -j N NN 36/o 565. 19 No Corn-e,,. ,.,, Mass RtnTime pound # Found ? (MS) xi i 0 s CI \ I NW 37/o 533. 17 Yes 3. 87 su ) )-N - \=/ - I 0 38 547. 18 Yes 3. 98 s F S (; 3 F }-N N l 39/o 521. 15 Yes 4. 02 (3 - s ci o _N, N N, o o N O 40 513. 16 Yes 3. 22 /\ ° ri N\, CI S 41 593. 2 Yes o/ zon N'll N \S N CI 42 455. 15 Yes 2. 79 o/ N N-- (I w o Ni NCCI S 43 o/428. 11 Yes 2. 91 o/ N N N N CI s b 44 495. 19 Yes 2. 62 9 0 ce u-u 45 ° 538. 16 Yes 4. 64 Corn-.. .., Mass RtnTimc Com-Structure Target Mass Mass Rtn Time pound #°Found ? (MS) zu Cl/ 'C N V N N 46 I o 46 _ 505. 15 Yes 3. 31 o\, --N N- ! N N N~ S FCI 47 457. 17 Yes 3. 02 cri e - 48 o 477. 14 Yes 3. 17 i Nez C N S\ N/\ F r \ I N 571. 14 Yes 4. 49 p S p 1 N -N - N CI 50 471. 19 Yes 1 F Cl N 51/o 521. 15 Yes 4. 02 1 s t N < NN N 52< °519. 19 Yes 3. 97 v 7 h)-N --=-0 b 53 545. 17 Yes 3. 49 01 s "c I N 54441. 14 Yes 2. 94 Corn-n. . n. f Mass RtnTime Com-Mass Rtn Time pound # Found ? (MS) 1 CI \ I u 55'521. 15 Yes 3. 92 55 {o 521. 15 Yes 3. 92 ri. ci tNe \ N 56 ° 477. 14 Yes 3. 08 o i o/. \ "Y) s 57 456. 14 Yes 3. 34 c cl pN S O 58°492. 14 Yes 3. 47 t _ s o N v1-. N N N O/ O 59 521. 13 Yes 3. 04 . N N N N CI 60'497. 2 Yes 2. 7 e/. N <N ,/'15 N S N X X 61 452. 12 Yes 2. 69 o v k ° J N \S N'i v CI 62 443 15 Yes 2. 51 .---. CI. \ I'N N N , N' p 63'513. 14 Yes 3. 97 Corn-n,. .,., Mass RtnTime Com-. Mass Rtn Time ound # Fotmd ? (MS) xi ci aN tN < 0 64 483. 19 Tentative 1. 63 N NSDN i N ß Cl S 65 455. 15 Yes 2. 8 o N (, I cl Y S 66 o/455. 15 Yes 2. 77 o I N O N-- N'-'S L 67 1' 469. 13 Yes 2. 69 ? 0 68 515. 15 Yes 3. 59 " Q % NN 69'o | 515. 15 Yes 3. 59 O N v CI . ° Nt O ; NZNi Nf 70469. 13 Yes 2. 73 o i -N zon Y ou V O N N-- N CI S s 72471. 15 Tentative 72-\-N/N- (N D C I 471 15 I c ma h 9 c _ Corn-pt j- t Mass RtnTime Com-Stn. icture Target Mass Mass Rtn Time ound # Fotmd ? (MS) 0. P @4N 9 . N u. Nv 0 73 442. 12 No 1 o s o _N . N' N e v O o C) NON T 74 °519. 15 Tentative zu CI \ N N Nez /O 75 533. 17 No \ '0 N NO I 76 538. 19 No - s CI/ ! ° i 77 512. 21 No \ _ s -- ° cl o I N O 78 525. 16 Yes 6. 5 i O N 1 CI J 79 574. 19 No s1 s C @S F N N CN V 'N 80/° 504. 15 Tentative _ u 81 505. 15 No Corn-c,,. rp,., Mass RtnTime Com-Mass Rtn Time pound # Found ? (MS) O N \ CI S 82 495 19 No O-cl. ci ) Nx N < LA/'" Cl 571. 08 No N CI _ S 84531. 19 Yes 4. 18 o "Y f N, Ni NCCI S 85 469. 17 Yes 3. 28 /\ F F CI/N N^N I N-C N O=N. F O O 86 616. 13 No o i N , '\ Yc. 87 455. 15 Yes . _ 1 \ CI, V 503. 15 Yes. 5. 38 o/ \NN \ OtN NiS Nf CI / $9 483. 15 No y F F S 622. 15 Yes 6. 44 Corn-n., ,,,, Mass RtnTime Com-Stnictme Target Mass Mass Rtn Time ound # Found ? (MS) n o 5 -- F C \ I N N.-/N/ F F 91 i o 571. 14 No o s - N N'N \ I Cl'SF n W F 620. 1 Yes 4. 37 o/ /cl rs 531. 19 No zu . _. \ I N N N 9453119 No o i v \ O N \S N C' 95 428. 11 Tentative \ s/N v v CI W 1 O F F 96 572. 14 Tentative 6. 45 1 N o 518. 13 No m CI S 98 Cl 661. 12 Yes 0 0 s" C'N N0 l... _ zu 99 613. 23 Yes 6. 59 Com-Mass Rtn Time Com Structure Target Mass MaSS Rtn Time pound #°Found ? (MS) \ s 3t N w I N 100 _ 532. 17 No ° N N N N S N I 101 558. 16 No N N N CI I N I O , i p I 101558. 16 No 1 s/ CI, N N^N N I nu 103 o 519. 15 No y °-NN=a . ( N N CI S 104 ° . 470. 15 Yes o/ N N i CI O 105456. 14 Yes NJLN f X at 106 463. 12 Yes o s N N N IS e \. CI 107 _N/463. 12 Yes 5. 94 N N i 469. 17 Yes 2. 7 Com-Structure Target Mass MaSS Rtn Time ound # Found ? (MS) NJLN N-/s TC ! CI 109 485. 17 No I AN » N 4 N N 110 ° 498. 2 No jLJO" N-N'"N" NNN 111 o513. 16 Tentative Xi ce 1 s . N N f 512. 14 Yes 4. 21 o rk C) N IS N\ \ CI 113 469. 17 Yes 2. 55 xi ci i N s v/NN o \ 114 o512. 14 No -/ N N , 115 469. 17'No 'Y. -0- (- . _.. /O 116504. 17 No I N\. 6 /'-< N N N' 117 ° 476. 08 Tentative Corn-,. .,, Mass RtnTime Com-Stnicture Target Mass Mass Rtn Time otmd # _ Found ? (MS) XI ci S s $N 9 xN o 118 490. 12 No . . JL CI 119 457. 17 Yes 2. 68 I ci N J. 'O (- zu 120 499. 22 No . N N NN. I \ 121 455. 15 Yes 2. 63 . . ci \ \N NNV aN e N 122'o497. 2 No o N N Ft - Nv I N IS Nw \ CI 123 439. 09 Yes 3. 34 N e N N N N Il \ e Cl 124 469. 17 No 0 N CI c1 \ I N N 125/o 467. 15 No N N O Nr- J 126 443 15 No Com-Structure Target Mass Mass Rtn Time pound # Found ? (MS) °/ N N , 127 469. 17 No ci N I/ - 128 o 505. 17 No . CI N g N N $ 4 N- ( 129/o 569. 22 No I o /0 130 555. 21 Yes 3. 99 I CI-/ non , Nj-N 131 ° 555. 21 Yes 4. 03 N N . f k N X S cl 132529. 19 Yes 3. 74 oXN X g ? CI 133 527. 18 No CLo O CIN\ 134541. 19 No / CIJ 3 CI N. 5 135 541. 19 Yes 3. 84 < WN EN) (N GN J (o5< 541. 19 < 3. 84 Corn-n,, ,,., Mass RtnTime pound# Structure TargetMass Mass (MS) pound #°Found ? (MS) <. "0 CI/N, J N i r-N 136527. 18 Tentative I Io' ci s _\ te SNwN ot N- 137 b 541. 19 Yes 3. 84 0 s ClAt FNuNffl + 138 N* t 599. 2 Yes 3. 87 Os'Io. CI I N S\\ N Nu0 --Nr O O 139 541. 19 Yes 3. 75 . Cl H 140 539. 18 No / 0 0 p"° 'o. 140 539 18 No \ I NN Ct FNuNt + 141 ß O 599 2 Yes 3. 87 9 Q ci !' N \ N N !'-N. 1t N 142'°°572. 18 No o yyyN a N N4NA NCCI O 143556. 14 No o . N' fN- I cl / 144 558. 16 No Com-Mass Rtn Time , Structure Target Mass Mass Rtn Time N N pound # Found ? (MS) o, zon \ N r'O CI 145 501. 16 No Q, , . S N - N cri/ 146 577. 19 No O CI S N O, i N \\ o 147 527. 18 Yes 3. 46 . y\ o /s/\ r0 S 148 587. 2 No . CI 4N O < CI . 0 NO 149 541. 19 Yes 3. 59 S A W e, ci NJLN II Nv 150 474. 13 No I N os f) F 151 466. 1 Yes 3. 54 I \ NNI N I ! _S i 50- cl 152 541. 1 Yes 2. 63, 2. 81 ce N NNNv 153 ° 553. 17 Tentative 4. 13 Corn-n,, ,. n, f Mass RtnTime , Structure Target Mass Mass Rtn Time ound # Found ? (MS) xi N-\ <k N N ?'w I 154 154412. 11 Tentative 2. 21 xi c 0 j ! ; yn0 ""'r\ N 155 ° 471. 15 Yes 2. 9 w 0 i CI N \ I 1 156 453. 14 Yes 3 3r o 15 s d 157441. 14 Yes 2. 61 I ce N N / N 158°442. 12 No /1T ° \ N N zu 159 470. 19 Yes 4'5 a 56 , -N' s CN- N-, CI N 160426. 13 Yes 3. 27 vl s /CI NrN I O 161 _ _ 504. 17 Yes 4. 52 i ci o. l w s - 162-° 536. 16 Yes 3. 46 Com-Structure Target Mass Mass Rtn Time o I s \ I N-Q N /N AT o, _. ; 163°476. 14 Yes 3. 97 /v I WE qS X /N-C w pl \ 164 562. 16 Yes 3. 1, 3. 35 . O \ ce -N oJ v 165 462. 13 Yes 3. 64 . O s. a NN j 166 414. 13 No Xi V\ 166414. 13 No _O QC ./N- w 167°460. 13 Yes 3. 08 I s fJ-, CI N 168 427. 12 Yes 2. 63 o O. 0 J N/CI N I r NAX o 169 416. 11 Yes 2. 7 1 'L of 170 440. 14 Yes 3. 59 I _ _ N w I N XY 171454. 16 No Corn-n.. ,,,, Mass RtnTime Com-Structure Target Mass M Rtn Time ound # Found ? (MS) I a ci zu 172c'398. 1 No I ci \ I N C N 1/N 173 O 538. 16 Yes 4. 35 _ s N- N-, I CI N _O N O 1 174 474. 15 Yes 3. 23 xi \/s . o N XT 175424. 11 Yes 3. 66 c {_%, N OS XNTN NAOD _N N OJ 176 484. 13 Yes 3. 13 I s /_, N-t N TCI N 177 454. 16 Yes 3. 87 N- S N a t Cl N'4J' 498. 15 Yes 3. 44 I S N/I CI N CF Nez o 179438. 09 Yes 2. 66, 3. 16 I s 9 cl . X N N 180480. 12 Yes 3. 68 Corn-e,,. , T Mass RtnTime , Structure Target Mass Mass Rtn Time omd # Found ? (MS) xi //NA 5S 'J o 181 492. 14 Yes 3. 44 Q Cl S N N N nu 3. 68, 4. 04, 182 494. 19 Yes 4. 78 zu s ci - N I o 183 440. 14 Yes 3. 5 's Cl N 184440. 14 Yes 3. 59 1 ci o 185 X \ 414 13 No . ci e v N 186 454. 16 No I bS N /CI /q XWCI '-N N 187° 410. 1 Tentative 2. 81, 3. 33 / s , CI 188 188410. 1 Yes 3. 03, 6. 5 1 1 . ci o I N N Nv 492. 14 Yes 3. 59 Com-Structure Target Mass Mass Rtn Time ound # Found ? (MS) N% ~ N ci 0' 190 494. 19 Yes 4. 73 s '<h - N I 191 548. 14 Yes 3. 62 xi cri u NN N 192o498. 13 Yes 4. 06 ci L./N-'tN N o l A NAT 193 456 : 14 Yes 3. 21 I -N O \ I N 'C N/I N 194 o \ 492. 1 Yes 3. 4 N t v/N N, 0 1 N 195 476. 14 Yes 3. 88 I N CI / 5 501. 14 Yes 3. 22, 3. 43 ci J (N, 1 197 197o512. 14 Yes 4. 26 O _ zu N N i CI N \ I 198 ° 474. 13 Yes 3. 83 Com-Structure Tar et Mass Mass Rtn Time ound # g Found ? (MS) I ci /N- ( 0 \ r-N 412. 11 Tentative 1 -N NN N 200 o \ 498. 15 Yes 3. 39 ... _ s /, I ci N 201 o \ 458. 12 Yes 2. 96 N S XNfO Sx X F F F 202532. 09 Yes 4. 16 I ci N-v 203°538. 14 Yes 3. 24 I F S N CI I F Q O \ 204440. 07 No _ I N 205°516. 17 Yes 4. 45 .... N- NN- ( I CI SO N \ 206608. 2 Yes 4. 22 .. g CI 207443. 15 Yes 2. 57 Corn-n.. , T., Mass RtnTime Com-Structure Target Mass Foumd ? (MS) pound #°Found ? (MS) i c ANS A X N N'N 208 517. 17. Yes 9 73 I r' Nr'C N w 209°'474. 15 Yes 3. 39 I ci Ni/ N 466. 16 Yes 4. 22 xi ce N l N \ 211466. 16 Yes 3. 99 oui ci -N N 212 o \ 508. 13 Yes 3. 19 I s c s N. r o 0 0 213 524. 14 Yes 4. 17 I s ci \ I N 214 °'538. 16 Yes 4. 39 v ci 215o492. 14 Yes 3. 64 . I -N N \ N-'C N I 216463. 12 Yes 2. 56, 2. 82 Com-Mass Rtn Time , Structure Target Mass , n. ound # Folmd ? (MS) v/ N_ CI N \ 217 552. 17 Yes 4. 82 o. LJ F° N A t -° - N 218 o \ 516. 12 Yes 3. 37 CIXNXO S F F N NriN/ F F 219 534. 09 Yes 4. 24 xi ci N-N N A 220-o 428. 14 Yes 3. 61 I N S CI _ ( 221 o \ 478. 12 Yes 3. 41 I '\ NJLN//N 222 540. 04 Yes 4. 21 a-vyo o_ 0 NXNJ (N S O 223 500. 13 Yes 3. 08 I o ci , - N 224o472. 13 Tentative 3. 13 / s ce 225 502. 16 No Corn-n,, .,., Mass RtuTime Com-Mass Rtn Time pound # Found ? (MS) 1 I \ N O S CI _N N N 226 506. 19 Yes 4. 8 s 9 s 9 //N- i N 227438. 13 Yes 3. 52 I b R5 CI 228 o \ 490. 16 Yes 4. 19 / s C tS X N \ 229 440. 14 Yes 3. 52 zu o ci - NN I/N- 230 o 622. 15 Yes 3. 32 I S a y\ N 231°478. 12 Yes 3. 49 43 s N CT -N 232°'396. 08 No I o a ^o, w N 233 O \ 458 12 Yes 3. 12 v ci \ N/ ! Nv 234 474. 13 No i Com-Mass Rtn Time pound # Found ? (MS) r N ors CI- JN 235 482. 07 Yes 3. 29, 3. 86 O. a N s v 1 2Q N< 236 o 464. 14 Yes 2. 68, 4. 77 _,. tE qS XCI 237 o \ 442. 12 Yes 3. 02 I \ cri 238 o \ 398. 1 No xi o ci I N 'v\ 239o502. 18 Tentative 4. 31 sl ce I s l N/\ N N n_. tJ. 240 508. 12 Yes 3. 99 su ci ci s N. \ N 241. 496. 09 Yes 4. 09 . I NN 242oJ446. 1 Yes 3. 38 I -\ N 243 ° 471. 19 Yes 2. 86 Corn-e.,. ,,, Mass RtnTime Com-Structtre Tar et Mass MSS Rtn Time ound # g Found ? (MS) / /N. N S CI 244 N o z 529. 15 Yes 3. 41 os N C/ NN N'' (' N FI XN a° S F 245572. 14 Yes 4. 16 zu jus 0 o 246538. 11 Yes 4 e Br 1. 0 N XJ 247 526. 02 No I N CT N-y 248 o \ 468. 17 No zu s CI I N 249 518. 17 Yes 3. 85 0 a o N N N _ 250 _ 492. 14 Yes 3. 74 /'o NN jON - SN t 4 ? n 251 516. 1 'es 3, g . '\ N 252 ° \ 462. 13 Yes 3. 68 Com-Mass Rtn Time , Structure Target Mass Po md ? h ri" O 1N M NX '°-° 253 430. 12 Yes 3. 03 xi i ci <\ NE AS NYS Cl 254°443. 15 Yes 2. 77 Xi NJCN N 426. 13 Yes 3. 4 / s l _. /N XX 256 256_ 400. 11 No I /'s ci N 257°466. 1 Yes 2. 83, 3. 54 xi _o S ci N At 258 0 416. 11 Yes 2. 86 I /CI I 'ruz 259 448. 11 Yes 3. 45 v ci o ?"0 c. s 260 600. 06 Yes 2. 43, 3. 84 ci o i N zoos non 261626. 28 Yes 6. 29 Corn-.-,.. . , Mass RtnTime IDotund # Structure Target Mass Mass (MS) ound # Found ? (MS) ti ,,/CI N w zon 262 386. 1 No I N N O Cl /N % t 263 r cl 425. 11 Yes 2. 84 ri ce I s NN//N 264 o 506. 15 Yes 4. 05 xi o Ocl 265°456. 14 Yes 2. 77 / / s "'Cr I 266 X. 454. 16 Yes 3. 79 s ßN t CI 267P \454. 16 Yes 3. 97 I y-\ 268 444. 14 Yes 3. 28 I N-\/ N 269o\444. 1 Yes 2. 8 (DN- "YT° N 270 o v 270476. 14 Yes 3. 86 Com-Structure Target Mass Mass Rtn Time pound # Found ? (MS) , zu s N-, CI 0 271 4. 56. 14 Yes 3. 32 s N N-, CI N 272 442. 16 Yes 3. 8 / N I N \ 273°470. 19 Yes 4. 39 zu s ci N N N q N t Cl I N-\ ' -N 275 454. 07 Yes 3. 35 X N N cl N 276 466. 13 Yes 2. 81 I N o N-QN N \ . 277 442. 12 Yes 3. 01 xi o ci N 278 0 456. 14 Tentative 3. 13 xi zon N w 279 o v 508. 13 Yes. 3. 48 Com-Struchlre Target Mass Mass Rtn Time Xo AS NW xi s oNN. ( N 280 O 430. 12 Yes 2. 95 I Cl PN q N 9 N- - 281 482. 07 Yes 3. 89 xi a s N. i 1 NN \ N . 282 428. 14 Yes 3. 53 I y-\ NN 283°412. 11 Yes 3. 19 Xi ce s N, NN N 284o454. 16 Yes 3. 84 xi 0 v I ci 3. 03, 3. 16, 285478. 12 Yes 4. 05 / s N- (N e CI I 286 538. 16 Yes 4. 6 'I CL I N//N\_ 287 476. 14 Yes 3. 87 xi N N N 440. 14 Yes 3. 68 Com-Mass Rtn Time Com-Structure TargetMass Mass (MS) pi f s., <'<TC (/ 289 442. 16 Yes 3. 91 ce/ sII /NNN 0 290 456. 14 Yes 3. 16 N. S CI " N 291 455. 06 No /. s r CI N 414. 13 Tentative 3. 12 S\ I \ N O CI N - N 293 518. 15 Yes 3. 51 0X N\ N-\ 466.'I Yes 3. 5 . o X N\ N"N N w I 295 470. 15 No F I CI O \ d 296 _ 494. 13 Yes 3. 99 / N 6A"N 297 297440. 14 Yes 3. 61 Corn-.,-.., Mass RtnTime Com-Stnicture Target Mass Mss Rtn Time ound # Found ? (MS) v/ 0'- CI NO 1 \ 298 398. 1 No I 0 N/'S N /CI N y- I 299°'452. 11 No I °''a d o v 300452. 11 No xi s N-N N CT 30 442. 12 Yes 3. 02 I N ß non 302 452. 11 Yes 2. 78, 3. 41 SNA N\ ' (f\ N 303 ° 303416. 11 Yes 2. 68 Si w ci 52 tCI y\ 304 458. 06 No 1 yN t Cl \==/J N 305 512. 14 Yes 4. 17 '\ s N. m \ NN//N 306 ° \ 478. 12 Yes 3. 01 Corn-c,.. .. , Mass RtnTime N NSS I o ci N 307 _ 458. 12 Yes 2. 86 I N N N I// I 308 454. 16 Yes 4. 01 N N S "'r\ N 456. 14 Yes 2. 77 Xi N-"C, N'/I CI X N -N 310476. 14 Yes 3, g I n cl 311 ° 412. 11 Yes 3. 18, 6. 2 0s, NaNt oLJ'fj) = cl 312476. 07 Yes 2. 75 N=S c ! eNANW "=s ci an N 313 ° 492. 06 Yes 3. 77 O \ d- N N'/I I 314 314484. 09 Yes 3. 45 xi ce r N 315476. 14 Yes 3. 9 Corn- t t Mass RtnTime , Structure Target Mass Mass Rtn Time ound # Found ? (MS) xi o s b-y t~ N N 316°492. 14 Yes 3. 77 I ci 9 -N 317 o 454. 16 Yes 3. 91 sUcl \ N- (N N \ I N 318 517. 17 No N OS CIN F F CI N. s wF 319 586. 14 Yes 4 I o ci . a S CI 320o'490. 12 Yes 3. 41, 3. 63 Xi N. p CI y "-\ N 321 o 439. 09 Yes 3. 33 I S N I CI O \ 322°'446. 12 Yes 2. 96 CI I \ N'p O N O 323 472. 13 Yes 3. 14 , _ n e N/ f)' 324476. 14 Yes 3. 99 Cam-e-.. rp. T,., Mass RtnTime Structure Target Mass Mass Rtn Time ound # Found ? (MS) ci N o NY 325 _ 494. 19 No o //cri \ I. NN N' I N 326 o \ 506. 12 Yes 3. 83 NSSt ci N'\/' y-\ 327°443. 12 Yes I Cl i zon 464. 12 Yes 2. 92 cl N O 329 535. 18 Yes 2. 99 XN 0 5 CI - N NJLN w I F F F 330 516. 1 Yes 4. 03 I o ci N O 331 529. 19 Yes 3. 51 N ou ci ° 1 . 332 _ 555. 21 Yes 3. 91, 4. 15 j v v No S cl _N F F 333517. 1 Yes 3. 44 Com-Stnictur Target Mass RtnTime , Stmcture Target Mass.-., n/Ac'\ ound # Found ? (MS) xi cl - N-1 334 531. 19 Yes 3. 6, 3. 76 CI/ NNN-Y'' S N X 335573. 16 Yes 4. 27 F F, N'F I --N S 336 615. 17 Yes 4. 19 I v ci. ci N 337 539. 13 Yes 3. 94 ci ci r"NJ (N' s 1 338 °'565. 15 Yes 4. 19, 4. 36 O-a 0 v ci ci $ o \ fiN 339/561. 14 Yes 3. 9 I ° ci Jl N N N Nv N\ 340° 535. 18 Yes 3. 43 I N I r--N _S N,/I CI 341o 488. 12 No I 0 N-<. -N O. N I 342. o v 527. 09 Yes 2. 73 Corn-n.. , T., Mass RtnTime Com-Stnicture Targe Mas Rtn Time t ound #-Foimd ? (MS) T N'C 343 469. 17 Yes 2. 58 ri ci ci ci N N WN jr 344 _ _ 530. 05 Yes 4. 59 ci N N N 0 345 480. 12 Yes 3. 73 F zu I N N//N-_. 346 sSc'460. 12 Yes 3. 06, 3. 76 1" N Yr N 20+, 347"573. 16 Yes 3. 02 o. ''u i CI 348 518. 19 Yes 4. 85 'I ce N M/- N N- 2. 69, 3 3. 25, 349 531. 15 Yes 3. 36 Xi ci e A 9 NJLN//N 350o477. 14 Yes 2. 94 SM XN AN X _ i. N N N' Cl 351 496. 09 Yes 4. 02 Corn-n.. ..., Mass RtnTime Com-Mass Rtn Time ound # Found ? (MS) I N CI O NN / 2. 59, 3. 2, 352531. 15 Yes 3. 31 i ci S N- 353 559. 22 Yes 3. 37 Xi N-. ' N v"w I 354o 456. 14 Yes 3. 01 I '\ N N N 355 442. 12 Yes 2. 97 xi ce '''\-\ 356 o 470. 15 Yes 3. 15 n N N SN NJLN//N _, 357o496. 09 Yes 4. 11 I \ J --vNN w 1 358 o 471. 19 Yes 2. 6 xi N CI N N//N 0 359 515. 15 Yes 3. 49, 3. 69 ci " NJLN/l N 360 ° \ 476. 14 Yes 4. 01 Com-Stnicture Target Mass RtnTime , Structure Target Mass . n/n, fci\ ound # Found ? (MS) XI ^N. ci s N \ NN=NN 361 O \ 425. 08 Yes 2. 7 N 362 o 452 12 Yes 2. 94 o N N N Ct 363497. 11 Yes 4. 37 xi ce S N N NJ (// '\ 364°438. 1 Yes 3. 45 ce N N 365 O \ 441. 05 Yes 3. 27 xi - (f S CI " 366 465. 06 Yes 3. 49 I ce 367 o 471 07 No 1 zip N N Nv 368 509. 05 No Xi w fN. N ci "y-\ 424. 09 Yes 3. 15 369 tdN A S < Yes 3 1 S Corn-t t, t Mass RtnTime Com-Structure Target Mass Mass Rtn Time pound #°Found ? (MS) xi c s e N S t / 370508. 09 No Acl. CI Ton F 371/o 500. 06 Yes 3. 59 0 NNN CI 0 CI 372 575. 06 Yes 2. 87 CY"r N"NN SN ; NSN C$3 373587. 13 No o/ N iS tCI "\S N CI CI 374 446 07 No o, f 9 s 0 °\-, ° oJ 375 505. 11 Yes 2. 96 zu cy. N s CI N N I 376 i 487. 1 Yes 3. 29, 4. 02 N N N I/ N >\ IN W J S CI E 377 475. 1 Yes 2. 68 zu N N O°N \S T")"' 378476. 08 No Com-Structure Target Mass Mass Rtn Time rNXN$CI N- \ S CI CI i 379 504. 15 Yes 4. 64 o I N Nez cl S CI 380'460. 09 Yes 3. 29 1 cri/\ ce I)--N nez 381 538. 14 Yes-4. 51 cyc. 4 X n° v/ 382 cl 670. 13 Yes 3. 49 ce ci s N- 383 °510. 1 Yes 3. 96 I ci 384596. 12 Yes I /-N \ N 385/o 496. 09 Yes 3 66 / N e lgCl 386448. 09 No o./ N - O N \ cl cl 387494. 09 Yes 3. 12 Corn-n,. . T,, Mass RtnTime Com-Struc Target Mass Mass Rtn Time ovmd # Found ? (MS) o/ NtN NX NI CCI S CI 388 461. 08 Yes 2. 71 o i N N \5 N CI CI 389"'450. 07 Yes 2. 77 .. I cl S CI 390 474. 1 Yes 3. 6 xi CI N 5 A/-N N 391 °488. 12 No o N u \S N CI 392 c 432. 06 No ci ci . N s we N Jt N t3 393 572. 12 Yes 4. 36 i Y s/-' s Sc O UL h NN - 394/o 508. 11 Yes 3. 24 o i N N- \ , 395'458. 07 Yes 3. 55 o. CI/N -N X \.-/O \ N 396 518. 09 Yes 3. 16 Corn-.. ,., Mass RtnTime Com-Mass Rtn Time ound # Found ? (MS) o N. \ N I cl CI 397 488. 12 Yes 3. 88 o, N N O S S cl 0 CI \ 398J-532. 11 Yes 3. 44 o o/ -N tS N >te Cl 399 472. 05 Yes 3. 21 ol ci ci N s Scl &N 400/o 514. 08 Yes 3. 72 I - ° i NJLN I)--N Nez 401 °526. 1 Yes 3. 46 ci - ci i N N 402 528. 15 No ° N I \ N \S CI CI 403 474. 1 Yes 3. 51 o/ \ . _ S CI 404 o/474. 1 Yes 3. 59 0/ N \ INC N \ N i , s-ci ci clt 405 448. 09 No _ . _ Com-Mass Rtn Time pound # Found ? (MS) °., N X N tm N. N-N IS N\ ci cl 406 _ 488. 12 No o i N \N-/Y =4 S XCI CI 407 444. 06 Yes 2. 84, 3. 26 o I N _ "Y S 408 444. 06 Yes 3. 06 ci cl gCl os CrY /r 409 o 526. 1 Yes 3. 64 ACI CIXNXo S 4 N 410 528. 15 Yes 4. 73 1 ci s % 0' 411 582. 1 Yes 3. 63 zu a \ s CI N -N- /O 412532. 09 Yes 4. 08 ce 1 zu 413 490. 1 Yes 3. 23 .-.-- - ci S/\ o CI, N -N ou N 414 ° 414 526. 06 Yes 3. 44 Corn-,-,.. rr.. nT Mass RtnTime Com-Mass Rtn Time ound # Foimd ? (MS) I ce ci "rt NN 415 r C 510. 1 Yes 3. 92 ci ci. 4 Jk @ i N) HN N 2. 86, 3. 28, 416 535. 1 Yes 3. 48 1 s CI 3 417/o 4 546. 1 Yes 4. 25 0/ N N N N t.. __ CI w / 418 508. 09 Yes 3. 81 0/ N \N- (V) 'Tc, S-C CI f 419 446. 07 Tentative 3. 1 tO N t FCN iS C o"° S CI 420 o/532. 11 Yes 3. 41 y. zon Is 421 _ 492. 08. Yes 3. 03 c. -<Yo Scl @t FN<+F i. N TN FF \ I N F N 422 _ _ 566. 06 Yes 4. 19 Xi ce cl Sc \o 423 572. 11 Yes 3. 3 Corn-.. .., Mass RtnTmie Com-Mass Rtn Time ound # Found ? (MS) -N. N 9 S tCI F N \5 N \ I CI 424 474. 03 No ce s - N CI O' OCss Cl >@ L N Ab 425 550. 14 Yes 4. 43 b Cl C CI O v Ci. 426 o/642. 16. Yes 4. 22 Cl f N N I\ N \ N i g. I CI 427 477. 12 Yes 2. 65 ci ci/ N s 428 o 551. 13 Yes 3. 74 su ce ci S oJ XNE X 429508. 11 Yes 3. 42 C S S N IS ci cl 430 500. 12 Yes 4. 24 cl Cl, 3tN 0 431°. 500. 12 Yes 4 viz - cri N-/ 432 °542. 09 Yes 3. 25 Com-Structu-e Target Mass Mass Rtn Time ound # Fomd ? (MS) 00. 0 ci-ci N Ny (J/ % 433 558. 1 Yes 4. 2 Xi NIN 434 °572. 12 Yes 4. 4 ct I ci R N \ N- N 435 Scg 526. 1 Yes 3. 69 I a ci s\ \ I NlN N 436/o 497. 08 Yes 2. 68 /. v o /cri N- S CI 437586. 14 Yes 4. 83 0 c Cl+ N-<' ci , N s , ° NJwN' 438550. 08 Yes 3. 41 I CI F F cl \ N N 439 o 568. 05 Yes 4. 27 N t w o, N N cJL 440 cl 462. 1 Yes --c r_N N 441 ° 512. 08 Yes 3. 46 Corn-n. t, rr tf Mass RtnTime Structure Target Mass Mass Rtn Time ound # Found ? (MS) c ' sr zon s \\ N N 442°574 Yes 4. 24 I o_ N S e 443/O 534. 09 Yes 3. 14 xi a ce o, f a Sx 02 444 0 506. 09 Yes 3. 24 N zizi \/N' N ci s a 1 445 536. 12 No Xi ci ci -r1 Nec 446/O 540. 15 Yes 4. 79 t S f C-, N _/-I. N- N='a 5 iv c 447 472. 09 Yes 3. 55 xi a'ci S r N y-N N t 524. 12 Yes 4. 19 o/ yin / I. N-- N CI U S CI 449 474. 1 Yes 3. 53 ") ==" Q.- NN I. 1 450 ° 556. 11 Yes 3. 38 Corn-c', . f Mass RtnTime . Structure Target Mass Mass Rtn Time pound#°Found ? (MS) zu cri \ m o 0 N-y \ 451 512. 08 Yes 3. 52 --N N- (I \ s N CI a I 452-430. 04 Yes 3. 11, 6. 48 o N Py-N 1 v v0° S N V a CI 453492. 08 Yes 3. 16 ce 'ci v zu /NNJLN 454 9 s 508. 09 Yes 3. 9 I . c s \ . \ I N CI N 455/o 516. 03 Yes 3. 9 ici NNJ\N 4Db Cv tc 4sa1 Yes 4. 65, 6. 23 o/ N \S N CI CI 457-476. 08 Yes 3. 08 o i N 0 !/\S N i CI cl 458 432. 06 No xi o ci N \ I _l\ Y-NO 459 ° 536. 14 No Corn-n t Mass RtnTime pound # Stmcture Target Mass Mass (MS) pound #°Found ? (MS) ci 'ci \/N s s I i NNN 460, O 542. 08 Yes. 3. 25, 4. 03 rAE N N - ci /r' N N 461./530. 05 Yes 4. 12 o, N N \. CI CI 462 480. 06 Yes 2. 81, 3. 43 o, N \S N i . . 463 o/505. 15 Yes 2. 93 o/ cl \N CI I w 464 563. 11 Yes 3. 43 Scl C odS F NwN >F T 1 h'' 465606. 1 Yes 4. 14 1 Sc c cri \\ N T-N N I rN N O 466 a 572. 07 Yes 3. 96 /\ ci _ N N N I i CI Np S Br 1 467 559. 98 Yes 3. 86 xi . \ I N NIN V 468, 502. 14 No Com-Stnicture Target Mass RtuTime Cl e 5S n 4 f N \ S/-\ N- ! < IN 469/o 552. 13 Yes 3. 83 I . N s \ v Ou N 470 cl 526. 1 Yes 3. 75 ci I N N N r CI F 471 550. 06 Yes 3. 92 cr N IS CI CI 472 WN/496. 09 Yes 3. 72 i N NN O \S 'C CI 473 464. 08 Yes 3. 08 , / N Ns'\SN N I i "r o 474 477. 12 Yes 2. 85 o ° NS "N CI CI 475"460. 09 Yes 3. 44 o/ i5 f CI JN \ N CI. S CI 476 4. 34. 07 No I CI, N S zu 477 500. 06 Yes 3. 59 Com-Stnictue Target Mass Mass Rtn Time pound # o N N 0 N CI CI 478 450. 07 Yes 2. 93 xi ci N s N t je 479 482. 07 Yes 3. 49 a o Cri - zu N O 480 o 634. 02 Yes 3. 89 0 NNNs cl cl . r) o i N \S N . i CI 482 420. 06 No o, non \S N i cl "° 483 459. 07 Yes 2. 89 I ci i N S zon NN 484 °540. 12 Yes 4. 07 rS ° [/N 1S Nw J/I ' ct 485 490. 1 Yes 2. 85 o/ N N, I CI S CI 1 f 486 488. 12 Yes 1. 84, 3. 8 Corn-.-,.. ., Mass RtnTime , Structure Target Mass Mass Rtn Time ound # Found ? (MS) 1 ce 0 CI/N -N \ I N N 487 o 487 488. 12 Yes 3. 93 zu N N Cl 488 478. 1-Yes 3. 32 o/ N 0 N N- \ C » XCI ce 489 489 478. 06 Yes 2. 87 . N*. CI 490 °510. 1 Yes 3. 87 1 s N-4' N 491 o/490. 1 Yes 3. 3 o/ \ J""Y N i5 ttWCI . J cl 492 t/476. 12 Yes 3 s 1 o/ "Yt » 4 C / 493 504. 15 Yes 4. 39 o/ N N NY CCI S CI 1 494475. 1 Yes 2. 99 o i -N N- \ I d N't N I s-a I 495 488. 03 Yes 3. 37 Corn-n., , T., Mass RtnTime , Structure Target Mass Mass Rtn Time ound # Found ? (MS) o N N S CI CI 496 500. 1 Yes 2. 88 o i N ., N ci ci I 497 476. 08 Yes 3. 08 Xi ci ci N'N O O 498°490. 1 No xi o_ O 499 542. 09 Yes 3. 53 N ON \S I \ CI CI c) jL ' 500 464. 08 Yes 3 OL. WNO- rv $N N 501/o 516. 03 Yes 3. 92 / N Y-N N \\ 5 nez CI CI 502"462. 1 Yes 3. 58 N N Ef '1 CI CI i 503 446. 07 Yes 3. 24 o \ NN 0\ "vS" vi ci i I 504 488. 12 Yes 3. 86 Corn-n.. ,., Mass RtnTime Com-Mass Rtn Time pound # Found ? (MS) Sclo / sN o N NIN \ 505 512. 08 Yes 3. 16 5 's D I N N o 8 506 572. 12 Yes 4. 56 I ci ci e zu NN 1 507'o 510. 1 Yes 3. 89 o N N \ r, N 1S N. I V CI CI 508 °/474. 1 Yes 3. 7 x N y_-N ^'NyP S N CI CI 509 476. 12 Yes 3. 94 XI ci ^ c Vcl / 510 490. 1 Yes 3. 21 ' N y--N S N\ I Nls N\ \ NH Y $ 511 489. 03 No tN \ iN » -SCtt 5 CI 1 s 512 448. 09 Tentative 2. 76 ruz ce - S o N-0 w N t 513. 552. 12 Yes 3. 53 Corn- . t. f Mass RtnTime Com-Stmcture Target Mass Mass Rtn Time poimd # Found ? (MS) OCI _ N N N I i CtXNXOf X a-. NoS 514 500. 06 Yes 3. 54 F9CI N a-os A Cl<_N o S o 515 504. 12 Yes 3. 34 I F N N- Lj !)-N'- I)--N 516 528. 1 Yes 3. 98 o zon N- (I w '-'s L U S CI 517 474. 1 Yes 3. 61 o/ zu . N- (JJ (N IN cl Ccl S 518 cl, 432. 06 No 0./ S XCI \0'"' CI 519 486. 07 No o i O/ O N \ ci ci I 520 486. 07 No N' N Cl f _ N \S N' CI 521 o/476. 08 Yes 3. 07 o i y-N N clX CI w 522 486. 07 Yes 3. 46 Com-Stn, icture Target Mass Mass Rtn Time P N N >4Z cle c N , N N I \ \S N CI V CI 523 °/450. 07 Yes 2. 75 . N N , S N S O CI CI 524 492. 02 Tentative 6. 5 I ce ci N NN / 525/o 546. 1 Yes 4. 2 °'Ici ° cri 4 X X N \\ N N 526 ° 512. 08 Yes 3. 08 a rc) n'x < s ~L) N- N 527'o 492. 08 Yes 2. 93 a \ 'N-/N - N N 528'o 488. 12 Yes 4. 04 o N N CI 529 490. 1 Yes 2. 85 WT N ci s 530 r o 510. 1 Yes 3. 84 N f N tX o, N N , ci'ci 531 446. 07 Yes 3. 3 Corn-e,,. . , Mass RtnTime '; 5S 5 9 o N N N \ CI l 532 510. 04 Yes 2. 82 I C 0 \ I N \\ NN N_S 533 o 526. 02 Yes 3. 76 SCl cl F CI g\\ N F ,/O 534 518. 05 Yes 3. 47 ci 'ci N N 535'o 510. 1 Yes 3. 91 xi - c \ ce UL' o 536/o 526. 1 Yes 3. 8 ce . /e N N N 537°488. 12 Yes 3. 93 a S NA ; O 0 538'551. 13 No F F CI S N o N O 539 620 1 Yes 4. 03 ci ci 1 s O 540 524. 08 Yes 3. 57 Com-Stnicture Target Mass Mass Rtn Time P e/ V 0 N IS N\ \ C CI, 541 473. 05 Yes 2. 79, 3. 36 0/ N N- \ cl CI 542 at 480. 08 Yes 3. 02 Acl CIwN Ss \ N1N O 543 °506. 09 Yes 3. 19 Zip a'cri /-<" N N 544, O 510. 1 Yes 4. 02 I a ce " N N 545/o 528. 15 No I w 4 SN< C3 \NN-O N 4 546/o 540. 08 Yes 3. 86 / \ N p C CI Yj 547-477. 08 Yes 2. 76 _. /-N" 548 498. 08 Yes 2. 97 1 zoo C/N. -N \ I N % _ po I a 549, 569. 14 Yes 3. 06 Com-Structure Target Mass Mss Rtn Time Cl C2 5> F xi ci CI \ N S F F \ I Nr_N F 550 r o 550. 06 Yes 4. 06 nu -Q O N o N X N CI CI 551 563. 15 Yes 3. 57 ci N NN/N O WN Y Wo 552 589. 17 Yes 3. 89, 4. 18 SclS ce CI N S \ F F - N \ I NT F 553551. 06 Yes 3. 49 Sc,'O, t$N e ce I N N \/ 554 °565. 15 Yes 3. 68 CI 'F F CL ' i 1\ N Nw 555607. 12 Yes 4. 24 F F F CI _N, I yN CI N O S N 556 tO 649. 13 Yes 4. 2 xi ce ci e s N y'-N'\ C N N 557/o 573. 09 Yes 3. 92 I ! ci CI . 558 599. 11 Yes 4. 3 Corn-n. . f Mass RtnTime ,, Structure Target Mass Mass Rtn Time ound # Fomd ? (MS) o --N N N- (\ CI N \ N'i cl CI 559615. 1 Yes 3 job C CI w / N 560 o 569. 14 Yes 3. 46 I ci N CI N S NN i \ I Nr_ 561/o 522. 08 Yes 3. 32 Su N \ ! CI O 562 561. 05 Yes 2. 79 N N °, _NAN INC D 159 \N S >g4CI 561. 05 Yes < 79 563503. 13 Tentative 2. 68 ci ci ce N_f'N N CI O 564 564. 01 Yes 4. 61 /-<" NN N F 565°514. 08 Yes 3. 75 xi ci ci /v N N 566 514. 08 Yes 3. 8 N 'cl i NNYN S CI/\ o O \ 567 607. 12 Yes 3. 86 Com-Structure Target Mass Mass Rtn Time ound # Found ? (MS) ci N NN I N CI 568 552. 15 Yes 4. 85 c O O ci o_ ce N s N NN 569 °565. 11 Yes 3. 41 ce v/ N . 570511. 1 Yes 3 /N e N N ./. N. s 1 CI 571 530. 05 Yes 4. 03 i ClAN SN - ci/ N S w 572 o, 565. 11 Yes 3. 36 0 """vS NI J S CI CI 573 593. 18 Yes 3. 43 ex a s, _/ N $ 574/o 490 1 Yes 3. 08 °/. X S S \L ° CI CI 575 476. 08 Yes 3. 03 o N N v/CI CI 504. 12 Yes 3. 21 Corn-n., .., Mass RtnTime . Structure Target Mass Foumd ? U ht 4 k X "=\J ' Q N 577 o 530. 05 Yes 4. 14 o, 0/. N N \g cl n 578 505. 15 Yes 2. 69 , ce v iN 11 NJLN CI4NX 579 549. 12 Yes 3. 54, 3. 74 a 'cri /r'' N 580 ° 10. 1 Yes 4. 03 N N \ N N CI CI 581J472. 06 Yes 2. 87 I )-N N /O 582 483. 19 Yes 2. 57 I N- 583/o 477. 1 Yes 2. 38, 2. 62 e/ N yy--N N IS N CI 584'469. 2 Yes 2. 63, 5. 03 o N N~ S XCI CI 585 401. 11 Yes 2. 45 Com-Structure Target Mass Mass Rtn Time ound # Found ? (MS) zu f s \ I N NT_'N N Q N Uk) 586477. 1 Yes 2. 67, 3. 16 )-/ N o . '6 N I. w J/473 13 No l o i N N-/"L I N 588'455. 2 Yes 2. 56, 3. 84 o, N N L CI 589429. 14 Yes 2. 48 Nez Nu \ 590"-427. 12 Yes 2. 49 . N N r ° N, S N. CI 591 441. 14 Yes 2. 5 i N N 1S N 'CI 592-441. 1 Yes 2. 48, 2. 92 o/ Nain NV- N-CI' S ho 593 427. 12 Yes 2. 62 o I N N/N i N DCI S 594 441. 14 Yes 2. 58 Com-Structure Target Mass Mass Rtn Time O>, N f Ng o , - Y N I i VCI 595. 499. 1 Yes 2. 81, 3. 84 o/ ' N > ZCN i5 N eCI N S 596 ° N/427. 12 Yes 2. 53 o -N,. N > N ZCN i5 NiCI 597'441. 14 Yes 2. 59 s w 0 CI , . N y... N O N_ N 598 °487. 14 No o/ Nez N- ( N 599 439. 12 Yes 2. 56 i N 'ruz , S N O \ CI O 600 499. 14 Yes 2. 81 \ s/ CI/- -N rN CN t N 601441. 14 Yes 2. 53 I N S CI N-N N 0 602 497. 2 No xi < 603 491. 15 Tentative 2. 87 Corn-.. ,,,, Mass RtnTime , Structure Target Mass Mass Rtn Time 1 A3cl Found ? (MS), 'I 5 N./ /NN \ O 604 483. t 9 Tentative 2. 63 I N g CI N Ct 605 o 415. 1 Yes 2. 49, 3. 01 s N-- N/CI N NEZ 606 ° X 491. 15 No CI f I O 607487. 14 No Xi ci 'NJ N--Q N N 608 o \ 469. 17 Yes 2. 64 I ci N 609 443. 15 Yes C3. N N'/ N N N 610°441. 14 Yes 2. 76 I ci N 611. 455. 15 Yes 2. 68 xi ce '-\ > N N 455. 15 Yes 2. 76 Corn-n, . f Mass RtnTime Com-Structtre Target Mass Mass Rtn Time ound # Found ? (MS) zu N 613°J441. 14 Yes 2. 93 s r\ s r N 614455. 15 Yes 2. 8 N N S N N_. õ oXNg O O OI \ 615 513. 16 Yes 3. 13 's 9 w N N, CI O 616 44'1. 14 Tentative 2. 9 / s CI N 617'455. 15 Yes 2. 9 /S N/CI /y N l - N O/ 618 501. 16 No vl N'S N-/CI nez N \ 619453. 14 Yes 2. 73 N 8 9 \ N/ CI / O ; O o i \ 620 S 513. 16 Yes 3. 13 xi s CI "N N 621455. 15 No Cam-.-,,. , T., Mass RtnTime , Structure Target Mass Mass (MS) pound #°Found ? (MS) I V-N N 622°525. 23 Yes 3. 15 I TNX N « NSf 623 519. 19 Yes 2. 72 O '" S A st 624 o 511. 22 Yes 3. 19 I NN N/ n N f B 625 443. 15 Yes 2. 64 /=\ 0 s CI . O 626519. 19 Tentative o 0n ce XN N 627 o 515. 18 Tentative 3. 73 I s CI A N X 628 _ 497. 2 Yes 2. 66, 2. 88 w ci 1N _l (S NS N- 629o471. 19 Yes 2. 76 I ce N N N 630° 469. 17 Yes 2. 76 Corn- Mass RtnTime Com-s. cture Target Mass Mass Rtn Time round # ! P I ci /N S Ni/ NN I/N- 631o483. 19 Yes 2. 68 N ci /"\. / -\ 632 o 483. 19 Yes 2. 78 I \ s r VN- tV-, CI N N 633 ° 469. 2 Yes 2. 51, 3. 27 !'s '' N 634 483. 2 Yes 2. 54, 2. 91 Cl X X° S X N NN 635 541. 19 Yes 3. 79 s CI N w I 0 636 469. 2 Yes 2. 76, 3. 1 / 's - i I CI 637'483. 2 Yes 2. 5, 3. 09 o 0 s t°H s 9 S S \ or 1 638 529. 19 No zu UN=C. NU ! ! '639 639481. 2 Yes 2. 5, 2. 97 Corn-n.. . T., Mass RtnTime , Structure Target Mass Mass Rtn Time pound #°Found ? (MS) /°'" 0 . o N N N 640 541. 2 Yes 3. 79, 4. 07 4 s ? 4 N sX N N 641 o \ 483. 2 Tentative 2. 4, 2. 98 . O. I 5 CI r eN<N S y-N 642 524. 21 Yes 2. 82 I t + N Cb 643 o \ 518. 17 Yes 2. 64 I N NS Nt 644 O \ 510. 2 Tentative 2. 9 I CI y-\ N l_ \w 645°442. 13 Yes 2. 48 s CI N 646'518. 17 Yes 2. 68 ° oI ce S Il N N//N 647 o 514. 16 No xi s ''t J' 'N * N 648496. 18 Yes 2. 6 Corn-,-,,, ,.., Mass RtnTime , Structure Target Mass Mass Rtn Time N1 Çcl poimd # Found ? (MS) - r N 649 470. 17 Yes 2. 52 N CI f Na A5 NS N 650 o \ 468. 2 Yes 2. 24, 2. 53 1 N ci N N JY N NN//N- 651o482. 2 Yes 2. 15, 2. 52 Xi CI -N 5 \ 652°482. 17 Yes 2. 65 / N- 653468. 15 Yes 2. 52 s N N 654 482. 17 Yes 2. 55 osa S Cl X 655 N 540. 17 Yes 2. 66 v/.. o N NNN N, i CI 656'_ 468. 15 Yes 2. 52 n 'c 657482. 17 Yes 2. 52 Corn-.-,., . T,, Mass RtnTime , Structure Target Mass MaSS Rtn Time pound #°Found ? (MS) ! S O N-- N-, CI N/'J N 658 °528. 17 No N N-, CI N-h-I zu 659°480. 15 Yes 2 51 . O, 0 c S \ ri o o N N N o v 660 N 540. 17 Yes _ s -N N 66 661°482. 17 Yes 2. 58 0 NNN S Nw i p . J 662 492. 16 Yes 3. 63 F Q F F gNeNyN t 663 663 468. 12 Yes 2. 99 \ NN p o-N % nez r) 664 o 537. 15 Yes 3. 64 0 N NN s N./v v 1 665 430. 15 Yes 2. 78 0 C IS N/\ CI 666"468. 06 Tentative 3. 33 w Corn-c... . n. Mass RtnTime , Structure Target Mass Rtn Time Ja 0 N non ci ci 667 468. 06 Yes 3. 76 " . s oow aN 11 NN 668 o 460. 16 Yes 2. 76 o , N.. N-N w I C IS N w I \ 669468. 06 Yes 0 /NNN vNy NS \ 670 430. 15 No o NN AY N at s 671 428. 17 Yes 3. 08 o, N 672 445.'12 Yes 3. 03 o\ N (- N N Isl N 673-478. 05 No 0 /N II N 1 N vNyNS 674 _ 425. 13 Yes 2. 89 o 0 i 675 ° 458. 14 No Cam-.. ,.,, Mass RtnTime , Structure Target Mass Mass Rtn Time pound # Found ? (MS) i N , 676471. 21 Yes 3. 41 vol /-/ v/N S I , NNJN 677 o 444. 16 Yes 3. 01 v/o YN v/'N S I N NN 460. 16 Yes 2. 68 678 N N" !-N N J CI N 434. 1 Tentative 3. 32 o Or 680 418. 13 Yes 3. 01 F F N N N/ F 'NO"W 681468. 12 Yes 3. 44 o qY3 682 434. 1 Yes 3. 21, 6. 45 (T '/a r CI 683434. 1 Yes 2. 93, 6. 48 Yi o- 0 NN- 684 ° 444. 13 Yes 2. 73 Corn-,-,,. , Mass RtnTime Com-Mass Rtn Time ound # Found ? (MS) . °/. '\ N N/ Nz e v N I 685 493. 19 Yes 3. 31 o N N eN lys N o v I I 686"430. 15 Yes 2. 79 \ I NNI' /-0 N t N Ni O 687 506. 18 Yes 3. 7 F9 F N NN /Y T IT ! ! CI<N o S Cl 688 536. 05 Yes 4. 46 ci I Agop % \\ N N 689 o 526. 1 Yes 2. 53, 4. 15 @ F F F F N N u i CI Cìe_ N ; O S U 690 502. 08 Yes 3. 39 p-r.- _O_Nts 691 °571. 11 No o ° cl 'g Nw cl 0-" ° s L s N N \ ct ci w t 1 693 502. 02 Yes 3. 81 5 9 w % Y N X L Y S 3 B 1 - Com-Structtue Target Mass Mass Rtn Time ound # Found ? (MS) o NXN X CI \ CI'\ CI 694 502. 02 Yes ci o v/N I, % \1 N N 695 ° 494. 1 Yes 3. 14, 3. 45 N IS N ft CI 696502. 02 No 0 S nez O ! \ CI 464. 11 Yes 3. 34 jazz N'''N /1 N IS N CI 698 t 462. 13 Yes 3. 49 , y-N CI 699 479. 08 No . . /I N 1s N Br CI 700 (d 512. 01 Yes 3. 36 uN'N S N/\ cl f 701 459. 09 Yes 3. 27 a y o. N s N N 702 ° 492. 1 Yes 3. 37s 6. 53 Com-Structure Target Mass Mass R e ound # Found ? (MS) ci li NS Q i rT NN'N' 703 o 505. 17 Yes 3. 86 ci o . _ Q /hr" 478. 12 Yes 3. 46 cl O so " v/N S I NN-N 705 o'494. 12 Yes 2. 99 ° fS ° w CI CI 706 468. 06 Yes 3. 76 N N / N IS N CI 707 452. 09 Yes 3. 45 /v F'F N N N 'lf ci v 708 502. 08 Yes 3. 92 o N N nez il \ 'r"' 709 468. 06 Yes 3. 74 o N N N 'ci 710468. 06 Yes 3. 34 o NuNN \ S nez CI L 71 1 Yes 3. 12 ; 3. 49 Corn-.-,, . n. f Mass RtnTime Com-Stnicttre Target Mass Mass Rtn Time pound # Found ? (MS) ce . N s 1 712 527. 2 Yes 3. 76, 4. 81 wNicl ,, N N v 1 N ao 713 464. 1 Yes 3. 19, 3. 53 . P . 1 v O f NA n 540. 1, 714 ° N blank Tentative 6. 4 F n F 1. F y 715 508. 13 Yes 4. 35, 6. 57 0 NN Nw avb 716 498. 21 Yes 4. 18 F Q F F N NN i 717 474. 17 Yes 3. 4 °e t ßN S l-N Nv ! non 718 o N 543. 19 Yes 2. 52, 4. 19 i N y r 719 436. 19 Yes 2. 7, 3. 18 N N'N yb ct r\ CI 720474. 1 Yes 3. 76 Corn- f Mass RtnTime Com-Structure Target Mass Mass Rtn Time pound # Found ? (MS) 0 cb /\ S N CI CI 721 474. 1 Yes 4. 21 S o. NNN i 11 722 o 466. 2 Yes 3. 2 y 'g N CI J CI 723 474. 1 Yes 3. 96 0 rS S N 724 436. 19 Yes 3. 4 0 N w 725 434. 21 Yes 3. 57 °/ N O e N, S, N u 726 451. 17 Yes 3. 45 CB (N t J er 727 484. 09 Yes 3. 37 0 o S nez N 728 431. 18 Yes 3. 23 t 0 0 'N s sN NN I , 729 464. 19 Yes 3. 34 Corn-n,, . n. f Mass RtnTime Com-Mass Rtn Time otmd # Found ? (MS) N ; 730 477. 26 Yes 3. 98 o v/N s i N) e N N Ja 731 o 450. 21 Yes 3. 48 0 Q A P o 732o466. 2 Yes 3. 04 Nu NN Nw 733 440. 14 Yes 3. 72 o Nu N'N 1S N w U vNYN 734 424. 17 Yes 3. 41 9. F F N N N^ F 'NO"U 735 474. 17 Yes 3. 87 o N N-N ce 736 440. 14 Yes 3. 7 o N'N f N 1S N\ CI 737 440. 14 Yes 3. 35 Q.-. quiz P on iN 11 NJLN I/ 738 ° 450. 17 Yes 3. 09 Corn-. (-,.. ., Mass RtnTime Com-Structue Target Mass Mass Rtn Time NXN t "D UN XN Neo7 e 1 4 9 9 Z4 Yes 3 W ound # Found ? (MS) o R » ß \ Zon I, 739 499. 24 Yes 3. 87 0 s NN g f '6 1 740436. 19 Yes 3. 18 \ I N-N O , P- /\ , 0/ NL '''N 742449. 11 No cri NY i fS" CI CI 743 498. 07 Yes 3. 74 r" i N N, NJLN ici)' cl 744 581. 11 No 0 s N'N C 745"482. 07 Yes 4 NL N N N N CI 746 _ 436. 09 Yes 2. 98 xi o, zizi O j' N 747 ° 492. 1 Yes 3. 1 Corn-.. ,, Mass RtnTime Com-Stnichre Target Mass Mass Rtn Time pound #°Found ? (MS) ce I ci Is NNN 748 o518. 07 Yes I /-< N NyNN 749 °485. 11 Yes 3. 02 r O * u ;'- N O 750. 485. 1'1 Yes 3. 63 ci N zu ./-V' 751 499. 12 Yes 3. 42 I GQ N CW NN N/I N \ 752°'488. 14 Yes 3. 86 xi j Nr, l l N./\ N N N 753o469. 05 Yes 3. 4 o f ci s N' 754 516. 1 No I ce N N 755o459. 09 Yes 3. 27 1 ci \ NNNv 756 ° 536. 11 Yes 3. 51 Com-Mass Rtn Time strtlcttlre Target Mass ound # Found ? (MS) rYn vNNN i CI 757 490. 16 Yes 4. 28 ° Ne QN xN Nt J'a N 758 612. 14 Yes 2. 89 I - N 1 N r NsN '" 759 448. 11 Yes 3. 44 N C !, jL s \ S c I 760 546. 22 Tentative 6. 44 o NYNVo i O \NN II N CI p F 761 532. 09 Yes 4. 11 ° s N-/\ 'NN\N' 762°526. 12 No 0-jQ "f 762 o 526. 12 No xi ci o 763 526. 12 Yes 4. 19 o i C !/ F ,, N g I F CI F 764 502. 08 Yes 4. 11 a--/ y osez . NNNJ 765 482. 07 Yes 3. 67 \ Com-scture Target Mass Mass Rtn Time omd # _ Found ? (MS) o oQ O ci I v 766°526. 12 Yes 3. 31 ce ce N_N JLN N I c 1S1 S N Ce 767 o \ 483. 07 Yes 3. 44 zu I i N N//N 768 o 526. 02 Yes 4. 15 I o o N N sS N 769 \ 506. 12 No Xi /s N i ci S 45 NtCI N 770°473. 11 No e ru w s N' I/NN II Nv 771 522. 13 Yes 3. 06 , I - 772°'483. 07 No f 0 \-/g ci N N- ( 773526. 12 Yes 3. 37 Xi ce '\ N 774 ° \ 559. 99 Yes 3. 93 Com-Mass Rtn Time Com-Structure Target Mass Mass Rtn Time ound #--_ Found ? (MS) zu ce i NLN II N 775 o 510. 13 Yes 4. 2 /\ ci /\ 0 I/NriN II Nw 776 534. 15 Yes 4. 55 'I s n N N 777o462. 13 Yes ar. f) a w S N- <N NW 'cc 778 600. 04 No N CI N f N N//N VN 779°509. 11 Yes 3. 57 OX cl /\ S N I/NJLN 11 N_ 780 o 524. 14 Yes 3. 92 0 o s a XN NÇN p 781 o 550. 11 Yes 3. 55 ci N N N 782 478. 12 No zu Ni e i N N N ° 473. 11 Tentative 2. 93 Corn-e,,. . T., Mass RtnTime Com-Mass Rtn Time ound # Found ? (MS) 1 ci N N Ni/\ S $eN W U i O 784 549. 14 Yes 3. 87 / 0 I ce , <sL A S NS 785. 550. 11 Yes 3. 57 i a X A W . 514. 12 Yes I S Ç \ X N N N//_ 787 434. 1 Yes 3. 21, 6. 52 I '\ CI N N /N 788 o 452. 09 Yes 3. 45 xi . ci 04 _QS, NS N N 464. 11 Yes 3. 27, 3. 62 a tNANX '\ N N N _ 790 o 512. 01 Yes 3. 82 i JD s N. \ 10elNANW 791 o 524. 13 Yes 3. 11, 3. 58 . _ _ _ I / w S N I/NNNv 538. 12 Yes 4. 05 Corn-.. .,, Mass RtnTime Com-Structure Target Mass Mass Rtn Time round ? (MS) xi ci ci cri i N N/I N 793o502. 02 Yes 4. 3 1 a I \ NS N i NJLN//N- 794 ° 485. 11 Yes. 3. 62 a °s1I . NNN' F 795"-466. 1 Yes 3. 43 ce J N N-\-N, 796 ° \ 460. 11 Yes 3. 66 J'-Y a ce a s N "ruz N -N J r a ci I ce \ N N N// 79$ 502. 02 Yes 4. 55 N -N ci /s /NN N N -N 493. 05 Yes 3. 41 zu ci w ci sur Ni N 545. 97 Yes 4. 41 ci I o a O N N-N 801 ° 528. 08 Yes 3. 39 7 9 B S N T 1 S O Z w t C s 4 W |/W F f 493. 05 f Yes f 3. 41 I X S NS Corn-,-.., . T,, Mass RtnTime Com-Structure TargetMass Found ? (MS) C NXo F ,/\ _ CN N N Cl 802-cl 482. 07 Yes S44 571 . \. 0'1 ci S N' 803 553. 11 Yes 3. 65 I ci y N. W CI "\ 0 804 493. 05 Yes 3. 9 Q, N a , i \ N 805 o 524. 12 Yes 4. 35, 6. 49 . t A W - 806 o 498. 07 Yes 3. 42 I ci ci tN A N < '"'y\ 807 o 482. 07 Yes 3. 99 cl Ocl dNANS . j) ==/ '\ 808 o 468. 06 Yes 3. 74 ci \ N ci °s \= °s. . Jp 809"502. 02 Yes 3. 92 CI AN o os'I e _ NNIN I 1 810 \ 482. 07 Yes 3. 68 Corn-.. , T... Mass RtnTime Com-Mass Rtn Time ound # Found ? (MS) zu YS s,. ci- ci ce 811 o 502. 02 Yes 4. 32 N F iN 'F . S r C 0/ 812 550. 09 No ci I s N 'Q ns 813 o \ 482. 07 Yes. 3. 84 xi v/s , Dì, 9 S NkCt , 0 0 r NiN 814 506. 12 Yes 3. 25 N N N I 815 482. 07 Yes 3. 62 1 o ci N/\ "NN N 816 506. 12 Yes 3. 57, 4. 02 0 c, \ Q O Cl Q A NX 817 ° ° 572. 08 Yes 4. 36 F "Y o fS' N Nl \ CI N 818 551. 06 Yes 3. 92 I I N cl n' 819 ° 516. 03 Yes Corn-,-,,. ,, Mass RtnTime Com-sc. e Target Mass Mass Rtn Time pound #°Found ? (MS) I N N 820 O \ 463. 12 Yes 3. 69 I ce '\ N 821 o 449. 11 Yes 3. 39 ' N N < 435. 09 Yes 3. 14 1 ci I. N S N./ .. _. 823J477. 14 Yes 4. 18 0 ci os N Y I N NN II Nw 824 N o 609. 06 Tentative 3. 91 . Ni N 825o485. 11 Yes 3. 69 I I s N NNN . 45. 11 Yes 3. 82 I ce N N 827o449. 11 Yes 3. 37 ci I a N N 482. 07 Yes 3. 86 Corn-n . n Mass RtnTime Com-. Structure Target Mass , n/n. fc'\ pound #°Found ? (MS) xi N LN _ W9'6312 Yes 3. 64 \ ce Fiv N o s NN II Nv N 830 541. 13 No /Q a a I N. Ni f N . "yN, xi ce UJO '-\-\ i 832 463. 12 | Yes 3. 81 ci ci /'s N. O=_ I N//N 833 ° 527. 06 No S N \ II I, N NN : 834 449. 11 Yes 3. 45 s ce NN'N 835 485. 11 No s ce \ NJLN 836 486. 1 No I o ci l'N S Ni v \ p N @' 837 ° 496. 11 No Corn-n,. .,, Mass RtnTime Com-tructure Target Mass Mass Rtn Time pound #°Found ? (MS) ci N N N 838 464. 11 Yes 3. 15 xi o ci lyl N./\ N 2. 76, 3. 53, 839°478. 12 Yes 3. 93 " a ci 1 s 840 o513 Yes 3. 75 xi Nb yNtCt N i I CI S O I \ 841 608. 14 Yes 3. 96 1 N, N CI A NNNv ° 518. 08 Yes 3. 29 a / ci . s , N-N N\ \ 843 592. 04 Yes 3. 8 J 0 a f s. J' d A S 844°462. 13 Yes 3. 76, 4. 37 " N O 845 498. 13 Yes 3. 99, 4. 74 / I F p F 846"516. 1 No Corn-p,. . , Mass RtuTime pound # C-VY/F. F N F F F 0'- 847 °'°561. 08 No 847 I \ NO S CI / XNXN Npo F I o F F 848 532. 09 Tentative 3. 92 $NANV X X - oS I F /N NhN F 484. 09 Yes 3. 56 0 e S ao , N S FF CI 850 532. 09 No ci ci N NN 851 ° 522. 1 No V-C / N IS N CI N CI 852 503. 01 Yes 3. 44 ci c °'< S \ O O CI/ O 853 550. 06 No 0 \ CL'==\. V S $ X cri C cl 854 493. 05 Yes 3. 3 v ci \ o ci - i N N 855 ° 570. 07 No Corn-c,.. , T,, Mass RtnTime , Structure Target Mass Mass Rtn Time pound #°Found ? (MS) ce N F N I S CI \ O 856 524. 12 Yes 4. 3 DYN X °Y N 0 N ru 646. 1 Yes 2. 96 i \ \ y cri 858 482. 07 Yes 3. 47 ci XN xN X N t CI 859 580. 18 Yes 5. 17 ci i N NN/I S NlO F F 860 566. 06 Yes tclsR ! n$ SN ot 861 xi 560. 08 No ce N ci o /e N zQ N 4 X v 862 cl 560. 08 Yes . s i N NN/I F CI 863 536. 05 Yes 4. 12 . ßNXSN NtX I Nl ( N I \ ci \ ci I 864 516. 03 Tentative 3. 67 Cam-n,. ,, Mass RtnTime Com-Mass Rtn Time ound # Found ? (MS) o f VclS ß tJT' vN SN WreN b 865560. 08 Yes 3. 33 3. 33 ACI N NN. N I i CI IN S I 866 517. 03 Yes 3. 38, 3. 96 A X 5 N < Br \. 867 559. 98 Tentative 4. 16 c. Q' a-cri \/ NU 0 540. 08 No N NeN . N N_ lN CQ TS III N 869 507. 07 No ce o / s 870 556. 09 Yes 4. 26 Sc. CI N S N N CI N$N 871/o 517. 03 No zu a o ci \\ i N lN I N 0 872 560 08 Yes 3. 39 ... '\ - °\k ° CI CI 873 593. 95 No Corn-n., ., Mass RtnTime Com-Mass Rtn Time pound # Found ? (MS) ci / - ci Cl4NJH I N 11 NAN/ 874 o 544. 09 Yes 4. 21 a, o ce v/N s lu 875 o 568. 11 Yes 4. 55 ce ce v/ i N_/NN 876 o496. 09 No. % XN S su i "N i N-N \ I CI 877 634 No /" ci iN 11 N N w 878°543. 07 Yes 3. 59 1 Vcl O . N $ N 879 cl o 558. 1 Yes 3. 94 ci o fY"JL. 5 .-j-o'Y p O 880 l 584. 07 Yes 3. 57 xi ci ci cg Vcß O 881 512. 08 No ci ' cl' N /N 11 NJLN 882 ° 507. 07 Yes 3. 01 Com-Mass Rtn Time ound # Found ? (MS) Acl O XÑ to % CI/ 883 O 8 583. 1 Yes 3. 93 \ . N D-N I/ aNeN N o 884 o 584. 07 Yes 3. 5 ci ° I ci 4 Cl @ X NNJLN O 885o548. 08 Tentative 4. 47 o, 0 U S $ 886 468. 06 Yes 3. 24 o, N- \ CI CI 887 486. 05 Yes 3. 48 cl X o' ci v/N i NNN 498. 07 Yes 3. 29 o, , -N -, ! 1 \ C, C. CI I CI 889 545. 97 No po ci 0 cl a ~o a R C0 NeN N \ 2. 02, 3. 17, 890'o 558. 09 Yes 3. 48 ce 'a v/N I NN N 891 XN 572 08 Yes 4. 07 Corn-n,, rr. f Mass RtnTime , Structure Target Mass Found ? (MS) pound # Found ? (MS) / "W'S CIXNXCN$CI 892 535. 98 Yes 4. 31 I ce U (/-J \ I N-N Na/ N- 893 °519. 07 Yes 3. 61 PNaSN Clt cl e 1 ci ci I 894 500. 06 Yes 3. 46 ci . Qi-o N je % N N 895'494. 07 Yes 3. 69 ./ N CI N CI 896 537. 97 No . - c L CI/1 N IS N CI 897 535. 98 No a - ce \/ N JNN \ N 898°. 527. 01 Yes 3. 44 o N'N Cri/1 g ''CI \ CI $99'579. 93 Tentative 4. 41 /hr' CI 900°562. 04 Yes 3. 41 Com-Mass Rtn Time pound # Found ? (MS) zu N N b N a N a CI I CI 901 516. 03 Tentative 3. 71 ce ci ° ) =\ CI NS N7eNANgCI 902 o 587. 07 Yes 3. 68 o , \ N, NN /S CI CI C Cl 903 527. 01 Yes 3. 9 I s \ ci eN SCI N 904 558. 08 Yes 4. 37 ci ci \ o ci N 905 o 532 03 Yes 3. 46 °/. N y-N "TS f"CI r CI 906 516 03 Tentative 3. 99 NL °\\ s O S NX CI e N 1S N\/\ CI CI 907 502. 02 Yes 3. 76 o cit c CI CI zu 908 535. 98 Yes 3. 93 _ y-N N CI CI CI 909516. 03 Tentative 3. 68 Com-Structure Target Mass'Mass Rtn Time X S $ N zu "W'U CI CI 910535. 98 Yes ci N"NN/OF iJtr 911 584. 05 No 0 I N_ l-N X 15 $ o 912 516 03 Yes 3. 84 n... a ci. s \ A. i N \ N- 913/o 540. 08 Yes 3. 29 °/ N CI 1, ci cl 914 516. 03 Yes 3. 64 1 j0 - i NN 915 °540. 08 Yes 3. 58 fY/-\ f C s N-'. O N 916/o 606. 05 Yes 4. 4 F F CI '. F I CI N_/N N 917 585. 02 Yes 3. 92 ce pizza ce 918 ° 550 Yes 4. 25 Corn-,. ..,, Mass RtnTime N O>N/ o N N N \ 919 497. 08 Yes 3. 67 fuzz N °/. /"CI CI 920 483. 07 Yes 3. 36 N- /I N \ CI CI 921 469. 05 Yes 3. 14 I ci ci s \ \ N NyN N. aN eCN 922 511. 1 Yes 4. 05 c, N,./ O "'YIJT'Y SN o Cl Cl 923 l 643. 02 No ci a il MYifY +eNCaN @ 924 519. 07 Yes 3. 65 ci - ci I \/N S N / sN 11 N N. NYN-N 925 o 519. 07 Yes 3. 83 0 N N N i I N IS N w. \ CI CI 926 483. 07 Yes 3. 35 N t) r ci cl C !. l a 927 516. 03 Yes 3. 85 Corn-n,. ., Mass RtnTime Com-Structtlre Target Mass Mass Rtn Time pound #°Found ? (MS) n CI N \ I N N \ O 928'o 497. 08 Yes 3. 59 SCI NR oe SF o N 929 575. 09 No zu N (N X Nt "vS"' CI 'CI 930 459. 04 Yes 3. 11 o O N. Y) r CI CI 931 483. 07 Yes 3. 4 - N N N N I i CI 932 486. 08 Yes 2. 99 ci ci aN eCN N N-., 933'o 497. 08 Yes 3. 71 rya N"NNYN_ \. c ' 934531. 07. Yes 4. 27 o, N --N S N. I \ CI CI 935 475. 01 Yes 3. 28 ce N'0 ci N I N3'- OeO 936 561. 02 No Com-Structure Target Mass Mass Rtn Time bNN a5N f Cl o, "CkJ. C. CI CI 937 483. 07 Yes 3. 42 N N cri 938 489. 03 Yes 3. 47 o N NN NY N ISI N w I \ FN S S 505. 03 Yes ci /. ci cl v/N s o v/ S A 1v. 940 543. 01 No I a ci s N \ . N-< 941'°519. 07 Yes 3. 87 I Ci \ I N NN 942b520. 06 No o, N y-N N 1 "ifs" N S CI CI 943 458 05 Yes 2. 78 r I o' ci ci N \/wN NJLNN°'O 944 o530. 07 No o s N O !, \SN' CI CI 945 498. 07 Yes 3. 2 Corn-e,,. ., Mass RtnTime , Structure Target Mass Fotmd ? (MS) S R g ci . ci o N-/"N NN 1 946'o 512. 08 Yes 3. 55 o $ N NstN _ '\ 947 546. 96 Yes 3. 69 X$cl ozon N_ /CI N SCI 948 642. 1 Yes 3. 98 ci v s cl Q's N S N N NN I/ e 949°552. 04 Yes 3. 34 / ci c-/)-. os kjr OS \ I Br 950 °/626. 01 Yes 3. 79 i N \ N \S N I CI CI 951 951 496. 09 Yes 3. 77, 4. 2 I ci 532. 09 Yes 4, 4. 52 I F F F f_ 953 o550. 06 Yes 3. 74 F F /N 1 N 1 O : O 954 ° 595. 05 No Corn-n,, ., Mass RtnTime , Structure Target Mass Mass Rt e ound # Found ? (MS) I CI, N S Fj 955 566. 06 Yes 3. 91 ce W lN \\ N \ F 956 ° 518. 05 Yes 3. 59 ci i N 11 O CI \ 957 566. 06 No i N I 15 N CI 958'474. 13 Yes 4 r-\ s 0 NoX N Cl \ 460. 11 Yes 3. 9 / N . /N \S N'i CI CI 960 494. 07 Yes 3. 9 xi o 961°350. 17 Tentative 2. 46 I NDO \ N NN i J 962 466. 2 Yes 3. 55, 6. 41 I o v, N O 963 364. 19 Tentative 2. 68 ! Com- n,, . , Mass RtnTime Com-Structure Target Mass Mass Rtn Time otmd # Found ? (MS) o N N O N H H'" 964 442. 24 Yes 3. 55 / °o 0 NXNQN O 0 965 412. 15 Tentative 2. 78 S N N N N iN 966 O 390. 21 Tentative 2. 86 N st N Ir 1 967 O \ 420. 25 Tentative 3. 55 o N N N O O w 968 412. 19 Tentative 2. 88 Q"o. N N N s \ I 969 462. 21 Yes 3. 21 Xi \ 970 o 378. 21 Tentative 2. 91 I C CIxN- ( ; 971o 424. 03 No I -y O N N l-o 972° 394. 16 Tentative 2. 4 Corn-,-,,.-. , Mass RtnTime Com-Structure Trt bss Found ? (MS) ound # Found ? (MS) xi 0 0 973o\422. 2 Tentative 2. 63 o N N 974 472. 2 Yes 2. 15, 3. 38 O Q NN O 975 474. 21 Yes 3. 23 . CI N st \ 384. 1 Tentative 2. 75, 3. 26 , 6 C 11 @N N NY 0 977 500. 2 Yes 36 : 40Z I o ci N Cy N 978 0 978398. 2 Tentative 3. 02, 3. 66 0 N / sN O H NSN. ,- (Y. 476. 2 Yes 4. 06 : N NIN/I . 446. 11 Yes 3. 11 0 C I CI Is 424. 2 Tentative 3. 23, 3. 88 Corn-., . , Mass RtnTime Com-Structure Target M Mass Rtn Time pound #°Found ? (MS) . _ N Ce 982 Ns 454. 2 Yes 4. 06, 4. 8 . r-o N ci I I 446. 2 Yes 3. 22, 3. 85 'C)"°o. N N N/, I SN N NJb3 984 496. 2 Yes 3. 6, 3. 71 N C O 985412. 2 Tentative 3 28 3 93 ..... ci ci ci CI, N N I/ 986 457. 99 No I » N A N se ° N"" 428. 1 Yes 2. 68, 3. 08 O o_, o a _otN qN Ct N 2. 89, 3. 34, 988°'456. 2 Yes 3. 73 _.. N. N 1 N X O X CI 989506. 15 Yes 3. 84 o NJLN e r N/ ci I w 99° 508. 17 Yes 3. 65 Com-Mass Rtn Time , Structure Target M MaSS Rtn Time 3ound #°Found ? (MS) o N-\3J ~ O h__. N o Nx 991 356. 22 Tentative 2. 81 VNtANW \/ N NN i' 992 472. 28 Yes 4. 11, 6. 46 Q < N Ce 370. 24 Tentative 3. 05 S 0" H H 994 448. 28 Yes 4. 07 l l N °o 0 N NN I 995 418. 2 Tentative 3. 22 o N N N iN Q 996 396. 25 Tentative 3. 29 Q N Ct 997° 426. 3 Yes 4. 09 - Y N N i 998418. 24 Yes 3. 29 / \/ N° i N N. N Y 468. 25 Yes 3. 67 tCom-.-.,. .,, Mass RtnTime pound #-.-_ Found ? (MS) 0 N N Ct "- 1000o384. 25 Tentative 3. 35 ci i o cWNJ ( 1/ CXC° NX 0 1001°430. 07 No Q rO 1002 O 400. 21 Yes 2. 72 o _o N Nt 1003 O \ 428. 24 Tentative 3. 08 o N N N b 1004 478. 24 Yes 3. 85 g NXN o Q o. p 1005cT480. 25 Yes 2. 7 3. 73 -N N i N _ ST N ot N O 1006-384. 16 Tentative 2. 74 P I ou N Nv 1007o474. 19 Yes 2. 7 N ozon \e r/0 1008 468. 25 Yes 3. 73 Cam-n.. ,,,, Mass RtnTime Com-Structure Target Mass Mass Rtn Time . NyN N S F N N O F 1009 402. 15 Yes 2. 81 0 N"N NF cl 1010 \ 502. 1 Yes 3. 06, 3. 9 I o NN 1011o456. 2 Yes 2. 15, 3 : 05 o N-. N N 0 \=/\ r-F N O I F e F F 1012 452. 15 Yes 3. 32 N NEZ /I N F F iN 0 I F 1013 452. 15 No o NJ (\ F O/-N F F N 1014452. 15 Yes 2. 96 N N i N lI i 1015 398. 17 Tentative 2. 8 \ O s tNtNt N i N p O 1016 444. 18 Yes 2. 76 ! NN-N-Y. 1017 434. 17 Tentative 3. 03 Com-Mass Rtn Time Com-Structure Target Mass Mass Rtn Time pound # Found ? (MS) N NN cr 0 1018 C 402 15 Tentative 2. 9 o N N N \ O. 1019 412. 1. 9 Yes 2. 97 oX N N N_ w o 1020 l 460. 19 Yes 3. 3 Q lo t c) 1 fM tN N$N\ 1021 ° 456. 18 Yes 3. 1 o / tN Y N a 1022 \ ° 428. 18 Tentative 2. 88 o c a F . XN b 1023 428. 18 Yes 3. 01 N NorX N O i 1'0 24 412. 19 Tentative 2. 86 0 "'fus (O NI \ 1025 409. 15 Yes 2. 74 0 \NN II N F F N O \ I F F F N O 1026 520. 13 No Corn-,-,., .,, Mass RtnTime , Structure Target Mass Fo md ? (MS) 3ound#°Found ? (MS) K NSNtNa N p 1027 O 398. 17 Tentative 2. 93 , o VN o CI i N j. Cl 1028 452. 08 Yes 3. 36 o O N N I Br 1029 \ ° 462. 07 Yes 3. 2 N Nor N t 0 1030 462. 07 Yes 3. 02 N i S N Y N bu 1031 462. 07 Tentative 3. 21 \,. M N t N e 'N o N l ci I 1032 418. 12 Yes N NW ce '\ 1033 o 432. 1 Yes 3. 36, 6. 43 N CI iN p 1034 418. 12 No xi o N. cW J N 1035452. 08 Yes 3. 53 Com-Mass Rtn Time Com Struchue Target Mass Mass Rtn Time ound # Fomd ? (MS) 0 \NNN i N 0 1036 440. 22 Yes 3. 66 o N-r (N CI Y b 1037 452. 08 Yes S O S YN N F i N/'i F F w CI 1038 486. 11 No \ 1-- Ni \ '1 N Nr 3. 21, 3. 49, 1039 476. 2 Yes 6. 51 N N 1040 W 412. 19 Tentative 2. 95 0 N-l xo O 1041 L 444. 18 Yes 2. 84 0 \N YN N v ? 1\ o 1042 9 428. 18 Tentative 2. 74 N N N 1043 412. 19 No 0 NNN O i u N 1044 409. 2 Yes 2. 75, 3. 22 Com-Mass Rtn Time pound # Found ? (MS) o 'b N CI 1045 418. 1 Tentative 3. 1, 3. 5 i o I ct \ O N O ''\ 1046 \ o 508. 2 Yes 3. 01, 3. 39 o N CI 1047 502. 2 Yes 4. 18, 4. 67 o N O i CI F 1048 436. 1 Yes 3. 18, 3. 61 non N 0 TiN o CI J 1049 U 490. 1 Yes 3. 48, 3. 99 tNrWF \N-YN N i a F CI 1 F 1050 486. 11 Yes 3. 79 ft-F N N , l N. F F O CI (J 2. 79, 3. 73, 1051 486. 1 Yes 4. 25 \ o N- F S \ X CI 1052486. 11 Yes 3. 33 non zon cl 1053432. 1 Tentative 3. 16, 3. 62 tCom-c.. ,.,, Mass RtnTime Com-Mass Rtn Time ound # Fotmd ? (MS) 0 vN/N S O t r P O 1054 478. 14 Yes 3. 09 I ci N o o w N NLN I I SN NANB 1055 468. 14 Yes 3. 42 N N CINotNiF CI 1056 W 436. 1 Yes 3. 27, 3. 73 N VN t S Cl I'\ 1057 446. 2 Yes 3. 36, 3. 87 zu J Scl 19 N \ 1058 g 494. 15 Yes 3. 73 o vNNN/ N S Nr N oSp ci 1059 490. 14 Yes 3. 52 0 NN N O CI 1060 462. 2 Yes 3. 24, 3. 75 \ o o . Y- 7 cl 1061462. 2 Yes 3. 43, 4. 17 ß N tX / cl b CI 1062 446. 2 Yes 3. 21, 3. 7 Corn-.. , , Mass RtnTime Stnicture Target Mass Mass Rtn Time potuid #°Found ? (MS) YN NN O Nw NI'\ CI 1063 443. 11 Yes 3. 08 o NN N F F i N O F CI w F F F 1064 554. 09 Yes 4. 59 o . N N N ° CI 1065 432. 1 Tentative 3. 32, 3. 82 razz e NN N ci ci a \ o 1066 486. 04 Yes 3. 85 . N N N tN or Br CI 1067 496. 03 Yes 3. 65 N X NN Br N N S O t 1068 496. 03 Yes 3. 39 o N a Br Cl C Br 1069 496 Yes 3. 65, 4. 15 o -rv-N Nj N o JL. -- CI 1070452. 08 Yes 3. 55 N N N c'A 0 CI Is 1071466. 1 Yes 3. 83, 6. 53 Com-Mass Rtn Time ound # Found ? (MS) J (o AoN o t ion O cri 1072 cl b 452. 08 Yes 3. 37 o N N C N « N o C cl O cl 1073 486. 04 No o \N'YN N i / iN O CI 1074 474. 18 Yes 4. 14 S rNd N N N iN O CI I w CI 1075 486. 04 Yes 4. 01 o N N S r F in O CI \ F CI 1076 520. 07 Yes 4. 15 f 0 ' \-ci I- O w N 1077 o 510. 15 Yes 3. 96 Nt A O S cl {k, CI 1078 v 446. 2 Yes 3. 31, 3. 8 N CI tN o t 1079 _ 478. 1 Yes 3. 2, 3. 79 Y O CI I 1080 462. 2 Yes 3. 04, 3. 49 Corn-n,. .,,, Mass RtnTime , Structure Target Mass Mass Rtn Time pound # Foimd ? (MS) o N N N lI CI 1081 446. 15 No 0 NN"N O Nw cl 1082 443. 1 Yes 3. 07, 3. 47 o o N e d 1083 Q 390. 21 Tentative 3. 1 10-O °l) dNJ (NSNu N N/ ! N 1084, o 480. 24 Yes 2. 71, 3. 05 N N 1085 474. 3 Yes 4. 39 o XNtNuF i N O b 1086 408. 2 Tentative 3. 19 " II NN N. l' N 1087 o 462. 23 Yes 3. 5 o "T N I N Y 1088458. 19 Yes 3. 77 o. N N F F N F 1089 458. 19 Yes 2. 7, 3. 72 Com-Structure Target Mass Mass Rtn Time ound # Found ? (MS) - N F X O C h N O 1090 458. 19 Yes 3. 38 \ ° zon il i O 1091 U 404. 22 Tentative 3. 21 0 c 6 O I 1092 450. 23 Yes 3. 12 l \/N° N N N Y U 1093 440. 22 Yes 3. 48 o o F O 1094 408. 2 Tentative 3. 27 N N \N rVN. T Wt tN' A 1095 kJ 418. 24 Yes 3. 44 n-O N N N_ w o N 1096 466. 24 Yes 3. 81 o N'\/ tN Jk N C O 1097 462. 23 Yes 3. 53 o / -N 0 J b 1098 434. 23 Yes 3. 28, 6. 53 Com-Structure Target Mass Mass Rtn Time ound # Found ? (MS) / _ J \I N o N 1099 kJ 434. 23 Yes 3. 45, 6. 47 \ S N iN O 110 0 4 18. 24 Tentative 3. 33 o N NJLN ur c vs tNyNS 1101415. 2 Tentative 3. 09 N-. M., F c N F F zu F F F F 1 102 526. 18 Tentative 2. 96 eNtN N N N p \ 1103 404. 22 Tentative 3. 35 \.' Cl V N tN W 1 104. 458. 13 Yes 2. 7, 3. 86 , N iN o N /Br 1105 468. 12 No Br N O 1 106 468. 12 Yes 3. 42 ffi B N N iN O \ Br 1107 468. 12 Yes 3. 64 Com-Mass Rtn Time , Stmcture Target Mass , ..., ound # Fotuid ? (MS) o N N iN N /CI 1108 424. 17 Yes 3. 55 Q ci N N N 1109 -438. 18 Yes 3. 83 o NN N CI i N 1110 424. 17 Yes 3. 4 CI' 1111 458. 13 Yes 4. 01 o N-\N N /\ N p 1112446. 27 Yes 4. 17 0 NN CI N f) 1113 458. 13 Yes 2. 7, 4. 01 o 6 i N/, i F F CI 1114 492. 15 No Ni \ O11, 0 I f NIN OI N 1115 482. 23 Yes 3, gg N N N Or 1116""418. 24 No Corn-.-,.. ..., Mass RtnTime > Structure Target Mass Mass Rtn Time Found ? (MS) o C N iN 0 1117. 450. 23 Yes 3. 23, 6. 51 v o N i O 1118 434. 23 Tentative 3. 15 . o NtNW N i N O 1119'418. 24 Tentative 3. 48 , _ N II N 11 N O N 1120 415. 2 Yes 3. 09 The additional exam les below were prepared by individual syntheses. , o N N 1. N v CI 'N H CI S 1121 604. 56 es .. H3C l CI) NX X v. S 1122. 570 11 es HC H3C N) CI tN FHNX CI \ N H CIv S 1123. 602-59 yes X. Corn-n. . . f Mass RtnTime Com-Stn. icture Target Mass Mass Rtn Time Mund#°Found ? (MS) C, $s » N t 0 -/razz CI S H 1124 645. 66 yes hic N-CH3 HaC O W N N Br F 1125 590. 52 yes .. r, a f 1 NH F G N CN 1126 \ polar 612. 52 es 0 HC, 1 H. F j \ t CI// (/ i : _ : 1127 nonpolar 678. 07 yes r. ; 0, M N. O t o sas ., \ t iN NH, ! Cv HN. 1128 \ 587. 51 yes a 3N hic a'/iN NH H, v 1129 \ 568. 53 yes H¢ N-CN HG N\H Cv 5, 1130 526. 49 yes Corn-n,, ,,., Mass RtnTime Com-Structure Tar ass Mass Rtn Time ound # Found ? (MS) N-CH HC H X f H 1131J526. 49 yes N-CH3 Hic CI i r--NH y N 1-NH Cv 5 i 1132 546. 9 1 yes,, H7 NH ; s¢C I X, 1 Cl CI S/ 1133 580. 46 yes, ;"" Ha ; a N NH r CL N h--NH N-CH3 1 CI. S H3C 1134 \ 546. 91 yes Ha N-CH" HC 1< -NH y' N fVH/N CI S H3 /Ha v, : I Ck j s CH M 1135 583. 59 yes X N N, f% 1 1 36 CI tN FHt 612. 51 8 yes'' VN ; e Hc o X, O u z 1137 CI<N FNt 630. 53 | yes cl CI N o Xn ., Com-Structure Mass Rtn Time _ Found ? (MS) oimd # Target Mass Found ? ( Ha N O/ 1138 576. 485 e 1138 jfY)-H W 576. 485 yes -.'" CI N -l CH Y S HC 1 139 Cl kN CH, 562 653 yes A cri _-. \/. N N-'S-. - 57. 508 yes CI rr'N -N CI/ HN H. 1 v u t rv 1141 y N ,-N CH 551. 475 yes CI HN H' H, C N).. _ S FIC /O. 1142 HC-N,, N S 582. 126 yes v i ^- |, 4. S1 zozo O N / x. n \ \ 1143. n, c-, 632. 142 yes, v i"--' vi a -| Cl--. _ X ,. s"r. H C_ \ 1144 N N"S 596. 109 yes H/\ hic ; s 1145 H'C'NN/S 576. 142 yes ° H/=\/ :-''. M-°- :. ;'. i t-. A1 Cam-n., .., Mass RtnTime Com-Structure Mass Rtn Time H, C, ~ Found ?- (MS) O NO Zon 1146 c, NN. 582. 082 yes s o- \/U°,,. c H'c, o \ I. cH, N DN l i,,. f 616. 527 yes ci"s, H 1148 jrY"')- = ( 571. 102 yes S% 'N O "-b ta 1148 a<WSHS ! 571. 10 yes FX f. . : S zu N 1 Y k < _Ck 521. 06 yes X . H Az a CH HC a o Y iN . X. X o p- 614. 555 yes cl v v a j° X h v o p- 580. 11 yes a, ; ,. _ r v 1152 af FH CH, 565 09 yes ; 0 0 yes 0 HC p N 1153 - N --N CH 534. 081 yes H' Com-Mass Rtn Time °m Stnicture Target Mass Mass Rtn Time pound #°Found ? (MS) . N 1154 f) Y)-H) == ( 513. 663 yes a--N CH,. 5 H n N W Q'J 517. 626 yeã '. 00 ? X ; F N l/1 CHa S . HN o (/ E a ; | 1156 X CH, 535. 069 yeS CI N/'H CH.. :'' \N l The compounds listed in Table 1, or their pharmaceutically acceptable salts, may be used in the methods described herein to treat or prevent pain.

It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I. The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.

It will also be appreciated that certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of aLkenes. The present invention includes any geometrical isomer of a compound of Formula I. It will further be understood that the present invention encompasses tautomers of the compounds of the formula I.

It will also be understood that certain compounds of the present invention may exist in solvate, for example hydrated, as well as unsolvated forms. It will further be

understood that the present invention encompasses all such solvate forms of the compounds of the formula I.

Within the scope of the invention are also salts of the compounds of the formula I.

Generally, phanmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCl or acetic acid, to afford a physiologically acceptable anion. It may also be possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.

In one embodiment, the compound of formula I above may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleat, tartrate, citrate, methanesulphonate orp-toluenesulphonate.

The novel compounds of the present invention are useful in therapy, especially for the treatment of various pain conditions such as chronic pain, neuropathic pain, acute pain, cancer pain, pain caused by rheumatoid arthritis, migraine, visceral pain etc. This list should however not be interpreted as exhaustive.

Compounds of the invention are useful in disease states where degeneration or dysfunction of Bradykinin receptors is present or implicated in that paradigm. This may involve the use of isotopically labeled versions of the compounds of the invention in diagnostic techniques and imaging applications such as positron emission tomography (PET).

Compounds of the invention are useful for the treatment of septic shock, pancreatitis, edema, rhinitis, asthma, colitis, arthritis, hepatorenal syndrome, cancer, (including but not restricted to SCLC, prostrate cancer), bacterial and viral infections, ulcerative colitis, and Alzheimer's Disease.

Compounds of the invention are useful as an analgesic agent for use during general anesthesia and monitored anesthesia care. Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anesthetic

state (e. g. amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers and opioids.

Also within the scope of the invention is the use of any of the compounds according to the formula I above, for the manufacture of a medicament for the treatment of any of the conditions discussed above.

A further aspect of the invention is a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such treatment.

Thus, the invention provides a compound of formula I, or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.

In a further aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term"therapy"also includes"prophylaxis" unless there are specific indications to the contrary. The term"therapeutic"and "therapeutically"should be construed accordingly. The term"therapy"within the context of the present invention further encompasses to administer an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.

The compounds of the present invention are useful in therapy, especially for the therapy of various pain conditions including, but not limited to : acute pain, chronic pain, neuropathic pain, acute pain, back pain, cancer pain, and visceral pain.

In use for therapy in a warm-blooded animal such as a human, the compound of the invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.

In one embodiment of the invention, the route of administration may be orally, intravenously or intramuscularly.

The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level at the most appropriate for a particular patient.

For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents ; it can also be an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture in then poured into convenient sized moulds and allowed to cool and solidify.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.

The term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets arc included.

Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.

Depending on the mode of administration, the pharmaceutical composition will preferably include from 0. 05% to 99% w (per cent by weight), more preferably from 0. 10 to 50% w, of the compound of the invention, all percentages by weight being based on total composition.

A therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented, by one of ordinary skills in the art.

Within the scope of the invention is the use of any compound of formula I as defined above for the manufacture of a medicament.

Also within the scope of the invention is the use of any compound of formula I for the manufacture of a medicament for the therapy of pain.

Additionally provided is the use of any compound according to Formula I for the manufacture of a medicament for the therapy of various pain conditions including, but not limited to : acute pain, chronic pain, neuropathic pain, acute pain, back pain, cancer pain, and visceral pain.

A further aspect of the invention is a method for therapy of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to the formula I above, is administered to a patient in need of such therapy.

Additionally, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

Particularly, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier for therapy, more particularly for therapy of pain.

Further, there is provided a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier use in any of the conditions discussed above.

In a further aspect, the present invention provides a method of preparing a compound of formula I.

Methods of preparation The compounds listed in Table 1 were prepared as single compounds in a combinatorial array. The Table 1, column 4 designation of"yes"indicates that the target mass of the designated compound was found in >50% abundance in the MS spectrum.

Similarly, the designation of"tentative"indicates that that the target mass of the designated compound was found in 15-50% abundance in the MS spectrum. Likewise the designation"no"indicates that the target mass of the designated compound was found in <15% abundance in MS spectrum. It will be understood by those of ordinary skill in the art that a chemical reaction which fails to efficiently yield the desired product within the context of a combinatorial protocol may nonetheless efficiently yield the desired product when the reaction is performed in a single reaction or parallel reaction format, without undue experimentation on the part of the chemist. In this regard, several of the compounds which were not prepared efficiently in the combinatorial array, were subsequently prepared in separate syntheses as shown in the Examples.

The reaction sequence depicted in Scheme 1, infra, describes a process for preparing compounds of formula (I) wherein X is represented by formula (i) òr (ii), comprising reacting a compound of general formula II wherein Y is a protecting group such as CBZ or FMOC, with an alkyl or alkenyl halide, such as allyl bromide in the presence of a base such as cesium carbonate to give compounds of general formula III ;

deprotecting the compounds of formula III under standard conditions and then acylated the deprotected products of formula IV with thiophosgene or phosgene to yield isothiocyanates or isocyanates of formula V, respectively : and subsequently animating the compounds of formula V combinatorially in a multiwell plate with a selection of different amines to yield compounds of formula I wherein X is represented by formula (i) or (ii) shown above.

The general protocol for the preparation of the combinatorial library is depicted in Scheme 1 and specific experimental details are provided in the Examples below.

Scheme 1 5 5 O S R' HNR R N (R4) b N--S DCE, 60°C R4 z / b/H plate format -i R V R3 s s O O RINCO N (R4) b DCE, 60°C Ra N H plate format R3 IV R3 b is 0, 1, or 2 ; Rl, R2, R3, R4, and R5 are as defined above.

In addition, certain compounds of the present invention and certain intermediates used in the preparation of the compounds of the present invention maybe prepared according to one or more of the following general procedures, wherein, unless specified otherwise, b, R1, R2, R3, R4 and R5 are defined as above.

General Procedure 1 : 5' 5 R^b I -N concHBr/AcOH N Y -N H r. t, 3h R'R. Br,"R' R3 RSBr, 3 II Cs, CO, P IV DMF, r. t, 5h Y = protecting groups R4 =H Cl, F R$=Me, R'=H, R3=Cyciohexyl such as CBZ or FMOC RS=Me, R^=H, R3=Phenyl R5=Me, R4=CI, R3=Phenyl RS=Me, R4=Cl, R3=2-ClPhenyi R5=Me, R4-F, R3=2-BrPhenyl R5=Allyl, R4=CI, R3=Phenyl As illustrated in the scheme above, to a stirred solution of (7-chloro-2, 3-dihydro-2-oxo-5- phenyl-1H-1, 4-benzodiazepin-3-yl)-, phenylmethyl ester-carbamic acid (lOmmol) in DMF (140mol) was added cesium carbonate (3, 72g, 11. 4mol) followed by methyl iodide (2. 0g, 14mmol). The reaction mixture was stirred at room temperature for 5 hours then concentrated in vacuo. The residue was taken in EtOAc (200mol) and washed with brine (2x30ml). The organic phase was then dried over MgS04, filtered and concentrated in vacuo. The products were purified by flash chromatography using dichloromethane as the eluent. The products (8mmol) were added with conc HBr (33% in acetic acid) (50ml) and were stirred at room temperature for 3 hours. The reaction mixture was poured into ether (300 ml), the precipitate was collected, and then taken in dichloromethane (250 ml) and washed with 2N NaOH (2x50ml). The organic phase was dried over MgS04, filtered and concentrated in vacuo to provide the desired compound.

General Procedure 2 : 5 5 . R O sat NaC03 (ac N thiophosgene b/ /N DCE r. t, 3h iR R3 IV R V

As illustrated in the scheme above, to a solution of 3-aminobenzodiazepines (3 mmol) in dichloroethane (20mol) and saturated aqueous Na2CO3(20ml) was added dropwise thiophosgene (0. 7g, 6 mmol). and the The reaction mixture was stirred at room temperature for 3 hours. The organic phase was separated and the aqueous phase was extracted with dichloromethane (50ml). The combined organic phases were dried over MgS04, filtered and concentrated in vacuo. The product was purified by flash chromatography (100% CH2Cl2) to yield a compound of formula V.

General Procedure 3 : F RaRbN RaRbN \ HNRaRb SnCl2 R-N=C=S DCE 70C Ethanol/Hz0 Ethanol/cHCI Y Ethano !/H, 0 j Ethane !/cHa"Y" NOZ 90C N2 reflux NH2 i He R"R" \ fY \-H Y-x F F F F CI _NJ F F ß ß F C Cl lNJ F u Nez NOZ NOZ NOZ NOZ Npz NOZ NOz H3C f N RN=C=S - CI CI'S

As illustrated in the scheme above, to a solution of 4-fluoro-2-methyl-1-nitro-benzene (0. 155g, lmmol) in a 1 : 1 mixture of ethanol and water (20 ml) was added morpholine (0. 435g, 5 mmol). The reaction mixture was heated at 90°C for 16 h. The solvent was evaporated in vacuo, the residue was taken in dichloromethane (50 ml) and washed with brine (3x 10ml). The organic phase was dried over MgS04, filtered, and concentrated in vacuo. The product was taken up in ethanol (20 ml) and heated at reflux. A solution of tin chloride (2M, 2. 5 ml) in conc. HCl was added dropwise and heated at reflux for another

30 minutes. The solvent was then evaporated in vacuo, and the residue was treated with a 2M solution of sodium hydroxide until the pH of the solution was >10. The mixture was extracted with dichloromethane (50 ml) and the organic phase was dried over MgS04, filtered, and concentrated in vacuo. The product (0. 032g, 0. 2 mmol) ((ESI) (M+H) +=192) was taken up in dichloroethane (5 ml), and 7-chloro-5- (2-chlorophenyl)-1, 3-dihydro-3- isothiocyanato-1-rnethyl-2H 1, 4-benzodiazepin-2-one (0. 075g, 0. 2 mmol) was added.

The reaction mixture was heated at 70C for 16 h. The solvent was evaporated in vacuo, and the residue was washed with ether (2 x 10 ml) to yield the desired compound.

General Procedure 4 :

As illustrated in the scheme above, N2 gas was bubbled through both DME and water for at least 3 hours. A solution of the imidoyl chloride (1 equiv.) in DME (1. 5 mL/mmol imidoyl chloride) was placed in a N2 purged flask. Na2CO3 (1 equiv.), PdCl2(dppf) (0. 05 equi.), boronic acid (1 equiv.) and water (0. 5 mL/mmol imidoyl chloride) were added sequentially, and the resulting mixture was heated at 100 °C until the imidoyl chloride was consumed (typically 16 h). The reaction was then cooled, diluted with CH2Cl2 and water, and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3x), and the combined organic phases were dried over Na2S04, filtered, and concentrated in vacua. The crude product was purified by silica gel column chromatography to provide the desired compound.

General Procedure 5 :

As illustrated in the scheme above, boronic acid (1. 15 equi.), Pd2 (dba) 3 (0. 015 equi.), and dry KF (3. 3 equiv.) were placed in an oven-dried, N2 purged flask. A solution of the imidoyl chloride (1 equiv.) in dry THF (2 mL/mmol imidoyl chloride) was added followed by a solution of P (t-Bu) 3 (0. 045 equiv., 10 % solution in hexanes) in dry THF (1. 6 mL/mmol imidoyl chloride). The resulting mixture was heated at reflux until the imidoyl chloride was consumed (typically 16 h). The reaction was then cooled, diluted with EtOAc, and filtered through a small pad of silica gel. The silica was washed well with EtOAc, and the combined organic phases were concentrated in vacDo. The product was purified by silica gel column chromatography to provide the desired compound.

General Procedure 6 : As illustrated in the scheme above, a solution of the benzodiazepine compound (1 equiv.) in dry THF (4 mL/mmol benzodiazepine, or slightly more if solubility was low) was added to a mixture of KHMDS (l. 05 equiv., 0. 5 M in toluene) and dry THF (2 mL/mmol benzodiazepine) immersed in a-78 °C cooling bath. After stirring for 5 min., a solution of trisyl azide (2. 5 equiv) in dry THF (4 mL/mmol benzodiazepine) was added to the reaction, and stirring was continued until all the starting benzodiazepine had been consumed (typically 10 min.). Glacial acetic acid (4. 4 equiv) was then added, and the mixture was warmed to 30 °C for 2 h. Saturated NaHCO3 was added, the layers were separated, and the aqueous phase was extracted with CH2Cl2 (4x). The combined organic phases were dried over Na2S04, filtered, and concentrated in vacuo. The product was purified by silica gel column chromatography to provide the corresponding azide compound.

General Procedure 7 :

As illustrated in the scheme above, polymer supported triphenylphosphine (Argonaut Technologies, 5-10 equiv) was added to a solution of the azide (1 equiv.) in THF (10 mL/g polymer) and water (0. 8 mL/g polymer). The resulting mixture was stirred at room temperature until all of the azide had been consumed (typically overnight). The polymer resin was then removed by filtration, and was washed well with CH2Cl2 and MeOH (3x each). The filtrate was concentrated in vacuo, and the residue was redissolved in CH2Cl2.

Any remaining water was removed with the aid of a separator funnel, and the organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The amine was purified using a"catch and release"strategy with MP-TsOH resin (Argonaut Technologies) : The product was dissolved in CHzClz (10 mL/mmol product), and MP- TsOH resin (2. 3 equiv) was added. The mixture was stirred for 1 h, and the solvent was removed by filtration and discarded. The resin was rinsed with CH2Cl2 and MeOH (3x each), and the washing were discarded as well. The product was then released from the resin by washing with 2M NH3 in MeOH and CHUCK (3x each). Concentration of the filtrate in vacuo provided the corresponding amine compound.

Additional compounds of the present invention may also be prepared according to the methods represented in Schemes 2-4 below, wherein, unless specified otherwise, b, Rl, R2, R3, R4 and R5 are defined as above.

Scheme 2 H 0 N O N 1. NaH, R51, DMF /O 2. glycine, AcOH, d Ra/ °" R R3BH2'R O Pd2 (dba) 3, P (t-Bu) Q KF, THF, 0 ou Ra Ra 1. KHMDS, TrisN3, 0 R, 3 (0H) 2, XN - rue 70 of*/\ fry z 3' 2. AcOH, 30 °C R3 3 : 1DME=H, O. A C. Rs o Rs o '' PS-PPh3, N sat'd Na2C03, THF/Ha0 (CH2CI) 2, RT Ra/Ns or _ Ra./NHZ NH HCO, N or a z CSz, EDCI, Et3N, PciIC, MeOH THF,-15 °C to RT R3 R3 | R1NCS, (CH2C1) 2, A R O N H RRZNH, \ DCC, WzNCN, R4/N RZ -R NCS Et3N, CH2CI2 D R3 S R, R3 S RUZ 'R zoo O N N N Ra TFA, H20, THF, 0 R N R /N \ N z 1 CN N \R 3 kNH2 0 Scheme 3 razz L J/ 1. CH30COCI, iPraNEt, CHaCl2 2. LiAIH4, Et20/THF, cX Cri S N NCS CI N CI CL (CHC) A Scheme 4 Br \ O 1. n-BuLi, EtzO,-40 °C. N fw N 2. B (OMe),-40 °C to RT 41s 3. Evaporate solvent Cl/<N 1. KHMDS, TrisN3, OMe 4. Pd (PPh3) 4, CsF, DME, A/THF,-78 °C 2. AcOH, 30 °C 3. NHQHCO2, PdIC, MeOH 4. C/N OMe \ N \ NCS CI icH2cy2, e 0 N N CI N Jr-N NX w lN OMe Biological Evaluation I. B2 bradvkinin Binding Assav A. Human Bradykinin B2 (hB2) receptor expression and membrane preparation

The cloned human Bradykinin B2 (hB2) receptor in the pCIN vector was purchased from Receptor Biology. The hB2 receptor was stably transfected into HEK 293 S cells and a clonal cell line was generated. Cells were grown in T-flasks with DMEM culture media containing 10% FBS, 2 mM glutamin, 60011g/ml neomycin and an antibiotic cocktail (100 IU penicillin, lOOlg/ml streptomycin, 0. 25 µg/ml amphotericin B). Membranes, expressing the hB2 receptor, were prepared from this cell line according to this protocol : Cells are harvested at 1 to 1. 2 million cells/ml, pelleted, and resuspended in ice-cold lysis buffer (50 mM Tris, pH 7. 0, 2. 5 mM EDTA, with PMSF added just prior to use to 0. 5 mM from a 0. 5 M stock in UMSO. After lysis on ice for 15 min, the cells are homogenized with a poltron for 10 sec. The suspension is spun at lOOOg for 10 min at 4°C. The supernatant is saved on ice and the pellets resuspended and spun as before. The supernatånts from both spins are combined and spun at 46, 000g for 10-30 min. The pellets are resuspended in cold Tris buffer (50 mM Tris/Cl, pH 7. 0) at a dilution of 0. 2-1 ml per 40 million cells and spun again. The final pellets are resuspended in membrane buffer (50 mM Tris, 0. 32 M sucrose, pH 7. 0). Aliquots are frozen in dry ice/ethanol and stored at-70°C until use. The protein concentrations are determined by a modified Lowry with SDS.

B. hB2 recentor bindinq Membranes expressing the hB2 receptor are thawed at 37°C, passed 3 times through a 25- gauge blunt-end needle, diluted in the bradykinin binding buffer (50 mM Tris, 3mM MgCl2, and 1 mg/ml BSA, pH 7. 4, 0. 02 mg/ml Phenanthroline, 0. 25 mg/ml Pefabloc) and 80 pL aliquots containing the appropriate amount of protein (final concentration of 0. 25pg/ml) are distributed in 96-well polystyrene plates (Treff Lab). The IC50 of compounds are evaluated from 10-point dose-response curves, where the serial dilutions are done on a final volume of 150pL, with 70µL of 125I-Desamino-TyrHOE140 (Kd=0. 05) at 50, 000 to 60, 000 dpm per well (0. 03-0. 04nM) in a final volume of 300p1.

The total and non-specific binding are determined in the absence and presence of 0. 1 uM (150µL) of Bradykinin respectively. The plates are vortexed and incubated for 60 minutes at room temperature, filtered through Unifilters-96 GF/B (Canberra Packard), which were presoaked in 0. 1 % polyethyleneimine, with a harvester using 3ml of wash buffer (50 mM Tris, pH 7. 0, 3mM Cl2). The filters are dried for 1 hour at 55°C. The radioactivity (cpm) is counted in a TopCount (Canberra Packard) after adding 65 ptl/well

of MS-20 scintillation liquid (Canberra Packard). Compounds of the present invention have demonstrated hB2 receptor binding at concentrations less than 10 M.

Based on the above assays, the dissociation constant (Ki) for a particular compound of the invention towards a particular receptor is determined using the following equation : Ki = ICSO/ (l+ [rad]/Kd), Wherein IC50 is the concentration of the compound of the invention at which 50% displacement has been observed ; [rad] is a standard or reference radioactive ligand concentration at that moment ; and Kd is the dissociation constant of the radioactive ligand towards the particular receptor.

II. GTP[γ]35S binding experiments on BradvEnin @2) receptors A. General Information The procedures below describe how to perform and interpret GTP [r] 35S binding experiments designed to determine the activity of new compounds on the human B2 receptor.

B. General procedure of the assay Human Bradykinin-2 GTP[γ]35S Binding Human Bradykinin-2 membranes (hB2 293s) are thawed at 37°C, passed 3 times through a 25-gauge blunt-end needle and diluted in the GTPrS binding buffer for the assay (50 mM Hepes, pH 7. 4 ; 200 mM NaCl ; 1 mM EDTA ; 5 mM MgCl2. To this added freshly prepared 1 mM DTT, 0. 5% BSA, luM GDP. The EC50 and Emax of compounds are evaluated from 10-point dose-response curves done in 300p1 with the appropriate amount of membrane protein and 100, 000-120, 000 dpm of GTPy35S perwell (0. 11-0. 14 nM). Bradykinin (1-9) is used as the standard agonist at hB2. The ranges of concentrations tested should include a maximal concentration of 0.1µM bradykinin in order to establish the EmaX- The plates are vortexed and incubated for 60 minutes at room temperature, filtered on GF/B Unifilters (presoaked in water) with the Packard harvester using 4 ml/well of

wash buffer (50 mM Tris, 5 mM MgCl2, 50 mM Nail, pH 7. 0), minimum. The filters are dried for 1 hour at 55°C. The radioactivity (cpm) is counted in a TopCount (Packard) after adding 65 pLl/well of MS-20 scintillation liquid.

Antagonist reversal studies are done in a similar manner except that the compound dose-response curve's are performed in the presence of a constant concentration of agonist (approx. 80% bradykinin Emax; #5 nM). A standard B2 Antagonist is used as the reference antagonist at hB2. The ranges of antagonist concentrations tested should include a maximal concentration of 3 µM of the standard B2 Antagonist in order to establish the maximal displacement (Dmax).

C. Radioligand : Preparation of GTP[γ]35S GTP [Y] 35S is acquired from Perkin-Elmer (250 µCi/20 µl). It is diluted from with 10 mM DTT, 50 mM Tris, pH 7 (dilute in 2 ml, 1. 0 mCI/20µ). Sonicate the solution, filter through a 0. 45, um filter, and freeze aliquots at-70°C. For the experiment, use ~ 0. 3 nM dilution of this tracer in the GTP binding buffer.

D. Data analysis The ECso and EmaX of compounds are evaluated from 10-point dose-response curves done in 300p1 with the appropriate amount of membrane protein and GTPy35S per well and are calculated in Activity base with ExcelFit. The basal and maximal stimulated binding are determined in the absence and presence of standard reference compounds, respectively.

The stimulation (Stim) in the presence of compounds is expressed as the percentage of Dmax of the reference antagonist. Values of IC50, Ki' and Dmax for ligands capable of competing for agonist stimulated binding are calculated in Activity Base.

Mean ~ S. E. M. values of IC50, Ki' and % Dmax are reported for ligands tested in at least three dose-response curves.

Biological data for particular testing samples (aS listed in Table 2) of the compounds of the invention are listed in Table 3 below.

Table 2 : List of the test samples used in the Biological Evaluation Test Sample Nos : Structure of the Test Sample 7l 2 1 N ci J H N 3 X NX cl NI hic P O 4 U 2Fr F c HC/'C , FNHs 0 N H, C - CI o nr zon 5 fY-0 S pf b v i H, c t, c N o M 7 ( W __ _.. H3C Xi c 8 0 c G H. C u N-CH, HC p /I N q S H H, C N-CN 'CI 77--N N N .... ; CI N Ha N °\-/" CI CI. HN N Ha O 12'I CL/S" CI S HC N-CH3 - C Q/ 11 12 CItN FH C CI S H3C N-CH3 HC c 15 c NXNS, g CI N 5 JC (Y-W - t ' CH3 cl c N 16 Nb v 16 A, R CI r S CH, CL/S CHj 17'i 18 ~ 0-N N O 19 Clt SN N O zu H, C H, C \ 0 rH Cr 20 clf3/' H, C H Hic N-CH2 21 Cl 4 >l 9 9 ce H. C H3C H3C, -Y uC ob 0 CI -N ---- N-CN jazz H (. N _1 N 22 y S 23 H C 0X CI, a N 0 /=\ /\ n ( ci I 24 H'GNN S O Fi O ----- HaC 0 25 I N-b N/v CL y S" cl 0 N . ZON 26 /SN \ I H a 26 @9 27 t tCH /-cl, -cH, H, C 28 - o 2 8 H tC) H, C 0 29 y 30 iz cri Mr/' /I N 31 fY)-H w 31 H'CzN4NH f Cg CI S H H3C cl a T ? H-N ° zu O N a 31 i i-N , cH, CI HN CI 32 tt C N \N CI s i v n . HC s o , N N a b L 33 Table 3 Biological Data for the testing samples as listed in Table 2 Test Sample Nos. Ki (hB2) (nM) 1-33 43 - 3110

EXAMPLES The invention will further be described in more detail by the following Examples which describe methods whereby compounds of the present invention may be prepared, purified, analyzed and biologically tested, and which are not to be construed as limiting the invention.

INTERMEDIATE 1 : 3-amino-7-chloro-1, 3-dihydro-1-methyl-5-phenyl-2H-1, 4- benzodiazepin-2-one.

Following General Procedure 1, INTERMEDIATE 1 was obtained as pale brown solid (2. 5g, 77%) and used for the subsequent reaction without further purification. MS (ESI) (M+H) +-300.

INTERMEDIATE 2 : 3-Amino-5-(2-bromophenyl)-7-fluoro-1,3-dihydro-1-methyl- 2H-1, 4-benzodiazepin-2-one. Following General procedure 1, INTERMEDIATE 2. was obtained as a thick pale brown oil (0. 5g, 17%) and used for the subsequent reaction without further purification. INTERMEDIATE 3 : 3-amino-5-cyclohexyl-1,3-dihydro-1-methyl-2H-1, 4- benzodiazepin-2-one.

Following General Procedure 1, after flash chromatography (100% EtOAc), INTERMEDIATE 3 was obtained as a pale brown solid (1. 25g, 45%). MS (ESI) (M+H) +-272 INTERMEDIATE 4 : 3-amino-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1-methyl- 2H-1, 4-benzodiazepin-2-one.

Following General Procedure 1, INTERMEDIATE 4 was obtained as a thick pale brown oil (1. 8g, 65%) and used for the subsequent reaction without further purification. MS (ESp (M+H) +=334 INTERMEDIATE 5 : 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1, 4- benzodiazepin-2-one.

To a stirred solution of (2, 3-dihydro-2-oxo-5-phenyl-lH-1, 4-benzodiazepin-3-yl)-, phenylmethyl ester-carbamic acid, (4. 0g, 10. 3mmol) in toluene (100ml) was added Aliquat336 (l. Og) and 50% aqueous sodium hydroxide (20mol) followed by methyl iodide (5.0g, 35mmol). The reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated in vacuo and the residue was taken in dichloromethane (150mol).

The organic phase was washed with 2N sodium hydroxide (soma) and brine (soma) ; the organic phase was dried over MgS04, filtered and concentrated in vacuo. The residue was triturated with hexane and the precipitate was treated with cone. HBr as in General

Procedure 1. INTERMEDIATE 5 was obtained as a pale brown solid (1. 63g, 59%) and used for the subsequent reaction without further purification. MS (ESI) (M+H) +=266 INTERMEDIATE 6 : 3-amino-7-chloro-1,3-dihydro-5-phenyl-1-(2-propenyl)-2H- 1, 4-b enzodiazepin-2-one.

To a stirred solution of (7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1, 4-benzodiazepin-3- yl)-, phenylmethyl ester-carbamic acid (1mmol) in DMF (10mol) was added cesium carbonate (0. 370g, 1. 14mmol) followed by allyl bromide (0. 134g, 1. 1mmol). The reaction mixture was stirred at room temperature for 5 hours. The solvent was evaporated in vacuo and the residue was taken in EtOAc (50m1). The. organic phase was washed with brine (2xlOm1) ; the organic phase was dried over MgSO4, filtered and concentrated in vacuo.

The crude products were purified by flash chromatography using dichloromethane as the eluent. The crude product was added to cone. HBr (33% in acetic acid) (10mol) and stirred at room temperature for 3 hours. The reaction mixture was poured into ether (100 ml), the precipitate was collected and then taken in dichloromethane (50 ml) and washed with 2N NaOH (2x10ml). The organic phase dried over MgS04, filtered and concentrated in vacua. The title compound was obtained as a pale yellow solid (0. 19g, 60%) and used for the subsequent reaction without further purification. MS (ESI) (M+H) +-326 INTERMEDIATE 7 : 7-chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-phenyl-2H- 1, 4-benzodiazepin-2-one.

Following General Procedure 2, INTERMEDIATE 7 was obtained as a pale yellow solid (0. 7g, 69%). 1H-NMR (CDCl3) : # 7. 66-7. 64 (m, 2H), 7. 60-7. 57 (dd, J=2. 4Hz and 8. 8Hz, 1H), 7. 55-7. 51 (m, 1H), 7. 47-7. 43 (m, 2H), 7. 36-7. 34 (m, 2H) and 3. 48 (s, 4H) MS (ESI) (M+H)+=342

INTERMEDIATES : 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-isothiocyanato-1- methyl-2H-1, 4-benzodiazepin-2-one.

Following General Procedure 2, after flash chromatography (dichloromethane), the title compound was obtained as pale yellow solid (2. 2g, 65%). 1H-NMR (CDCl3) : # 7. 66-7. 64 (m, 1H), 7. 56-7. 53 (dd, J=2. 4Hz and 8. 8Hz, 1H), 7. 46-7. 43 (m, 2H), 7. 39-7. 37 (m, 1H), 7. 05 (d, J=2. 0Hz, 1H), 3. 73 (s, 1H) and 3. 51 (s, 3H). MS (ESI) (M+H) +-376 EXAMPLE 1 : N-(7-chloro-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4- benzodiazepin-3-yl)-N'-(5-isoquinolinyl)- thiourea.

Scheme : o \ o s /%, NS HNR1R2/%, NS SNR1R2 NCS DCE, 70C | N or DCM, reflux CI -N X X= H, halogen As illustrated in the scheme above, to a solution of 7-chloro-1, 3-dihydro-3- isothiocyanato-1-methyl-5-phenyl-21I 1, 4-benzodiazepin-2-one (INTERMEDIATE 7) (0. 035g, O. lmmol) in dichloromethane (5mol) was added 5-isoquinolinamine (0. 015g, O. lmmol). The reaction mixture was heated at reflux for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (20mg, 40%). IH-NMR (CDC13) : 6 9. 33 and 9. 19 (2xs, 1H), 8. 63 and 8. 49 (2xd, J=5. 6Hz and J=6. 0Hz, 1H), 8. 34 (br s, 1H), 8. 02 (d, J=8. 4Hz, 1H), 7. 92 (t, J=1 1. 6Hz, 2H), 7. 58-7. 32 (mn lOH), 6. 03 (d, J=7. 6Hz, 1H) and 3. 3 (s, 3H). MS (ESI) (M+H)+=486

EXAMPLE 2: N-(7-chloro-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4- benzodiazepin-3-yl)-N'-[4-(dimethylamino)phenyl]- thiourea.

To a solution of 7-chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-phenyl-2H-1 , 4- benzodiazepin-2-one (INTERMEDIATE 7) (0. 342g, 1mol) in dichloromethane (20mol). was added N,N-dimethyl-1, 4-benzenediamine (0. 136g, 1mmol). The reaction mixture was heated at reflux for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0. 167g, 35%). IH-NMR (CDC13) : # 7. 70-7. 22 (m, lOH), 6. 75 (d, J=8. 8Hz, 2H), 6. 05 (d, J=7. 6Hz, 1H), 3. 42 (s, 3H) and 2. 98 (s, 6H). MS (ESI), (M+H) += 478.

EXAMPLE 3 : N-(7-chloro-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4- benzodiazepin-3-yl)-N'-[4-(dimethylamino)-1-naphthalenyl]-N- methyl- thiourea.

To a stirred solution of carboxybenzyl-3-amino-7-chloro-5-phenyl-2-oxo-1, 4- benzodiazepine (EXAMPLE 6) (1mmol) in DMF (10mol) was added cesium carbonate (5mol) followed by methyl iodide (2. 2mmol). The reaction mixture was stirred at room temperature for S hours. The solvent was evaporated in vacuo and the residue was taken in EtOAc (50ml). The organic phase was washed with brine (2xlOml) ; the organic phase was dried over MgS04, filtered and concentrated in vacuo. The product (O. Smmol) was added to cone. HBr (35% in acetic acid) (10ml) and was stirred at room temperature for 3 hours. The reaction mixture was poured into ether (30mol), the precipitate was collected, and taken in dichloromethane (25 ml) and washed with 2N NaOH (2xlOml). The organic phase was dried over MgS04, filtered and concentrated in vacuo. The product was used for the subsequent steps without further purification.

To a solution of the product above (0. 03g, 1mmol) in dichloroethane (5mol) was added 4- isothiocyanato-N,N-dimethyl-1-naphthalenamine (0. 025g, 1mmol). The reaction mixture

was stirred at 70C for 4 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (28mg, 52%). 1H-NMR(CDCl3) : 6 8. 24 (m, 1H), 7. 92 (m, 1H), 7. 67 (d, J=7. 2Hz, 2H), 7. 52-7. 40 (m, 8H), 7. 31 (d, J=1. 6Hz, 1H), 7. 05 (d, J=8. 0Hz, 2H), 3. 78 (s, 3H), 3. 41 (s, 3H) and 2. 91 (s, 6H). MS (ESI) (M+H) +-542.

'EXAMPLE 4 : N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H -1, 4- benzodiazepin-3-yl]-N'-[4-(dimethylamino)-1-naphthalenyl]- thiourea.

To a solution of 3-amino-7-chloro-5-(2-chlorophenyl)-1,3-dihydro-1-methyl-2H- 1, 4- benzodiazepin-2-one (INTERMEDIATE 8) (0. 03g, 1mmol) in dichloroethane (5mol) was added 4-isothiocyanato-N,N-dimethyl-1-naphthalenamine (0. 025g, lmmol). The reaction mixture was stirred at 70°C for 4 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (35mg, 60%). 1H-NMR (CDC13) : # 8. 26 (d, J=8. 4Hz, 1H), 8. 03 (d, J=7. 6Hz, 1H), 7. 93 (br s, 1H), 7. 73-7. 06 (m, 11H) 6. 10 (d, J=7. 6Hz, 1H), 3. 40 (s, 3H) and 2. 92 (s, 6H). MS (ESI) (M+H)+=562.

EXAMPLE 5 : N-[7-chloro-2,3-dihydro-2-oxo-5-phenyl-1-(2-propenyl)-1H-1, 4- benzodiazepin-3-yl]-N'-[4-(dimethylamino)-1-naphthalenyl]- thiourea.

A solution of 3-amino-7-chloro-1,3-dihydro-5-phenyl-1-(2-propenyl)-2H-1, 4- benzodiazepin-2-one (INTERMEDIATE 6) (0. 162g, 0. 5mol) in dichloroethane (5ml) was added 4-isothiocyanato-N, N dimethyl-1-naphthalenamine (0. 115g, 0. 5mol). The reaction mixture was stirred at 70°C for 4 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0. 152g, 55%). 1H-NMR (CDCl3) : 8 8. 29-8. 27 (m, 1H), 8. 08-8. 06 (m, 1H), 7. 90 (s,

1H), 7. 60-7. 36 (m, lOH), 7. 32 (d, J=2. 4Hz, 1H), 7. 09 (d, J=8Hz, 1H), 6. 14 (d, J=7. 6Hz, 1H), 5. 76-5, 69 (m, 1H), 5, 15 (s, 1H), 5. 12 (dd, J=1. 2 and 7. 0 Hz, 1H), 4. 57-4. 39 (m, 2H) and 2. 93 (s, 6H). MS (ESI) (M+H)+=554.

EXAMPLE 6 : N-(7-chloro-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4- benzodiazepin-3-yl)-N'- [4- (dimethylamino)-1-naphthalenyl]-thiourea.

To a solution of 3-amino-7-chloro-5-phenyl-1,3-dihydro-1-methyl-2H-1, 4-benzodiazepin- 2-one (INTERMEDIATE 1) (0. 299g, 1mmol) in dichloroethane (15mol) was added 4- isothiocyanato-N,N-dimethyl-1-naphthalenamine (0. 230g, lmmol). The reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0. 345g, 65%). 1H-NMR (CD3OD) : # 8. 25 (d, 8. 4Hz, 2H), 8. 00(d, J=8. 4Hz, 1H), 7. 88 (d, J=8. 4Hz, 1H), 7. 85-7. 81 (m, 2H), 7. 77-7. 72 (m, 2H), 7. 65 (d, J=8. 8Hz, 1H), 7. 61-7. 58 (m, 4H), 7. 51-7. 47 (m, 2H), 7. 29 (d, J=2. 4Hz, 1H), 6. 01 (s, 1H) and 3. 49 (s, 9H). MS (ESI) (M+H)+=528.

EXAMPLE 7 : N-(7-chloro-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4- benzodiazepin-3-yl)-N'-(4-methoxy-2-methylphenyl)- urea.

To a solution of 3-amino-7-chloro-5-phenyl-1,3-dihydro-1-methyl-2H-1, 4-benzodiazepin- 2-one (INTERMEDIATE 1) (0. 299g, 1mmol) in dichloromethane (15mol) was added 1- isocyanato-4-methoxy-2-methyl-benzene (0. 163g, lmmol). The reaction mixture was stirred at room temperature for 17 hours. The solvent was evaporated in vacuo, the residue was triturated with ether and the title compound was obtained as a colorless solid (0. 197g, 42%). 1H-NMR(CDCl3) : # 7.57-7.48 (m, 3H), 7. 47-7. 44 (m, 1H), 7. 39-7. 38 (m, 3H), 7. 36-7. 29 (m, 2H), 6. 77-6. 73 (m, 2H), 6. 71 (d, J=2. 8Hz, 1H), 6. 61 (s, 1H), 5. 51 (d, J=8. 4Hz, 1H), 3. 78 (s, 3H), 3. 39 (s, 3H) and 2. 29 (s, 3H). MS (ESI) (M+H) += 463 EXAMPLE 8 : N-(7-chloro-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4- benzodiazepin-3-yl)-N'-[4-(dimethylamino)-1-naphthalenyl]- urea.

Scheme : HO O NCO N N W DPPA, NEt3 0 N X ? . CI v-N Toluene, reflux \/E N N As illustrated in the scheme above, a mixture of 4-(dimethylamino)-1- naphthalenecarboxylic acid (O. lmmol), diphenylphosphoryl azide (0. 15mmol) ånd triethylamine (0. 3mmol) in toluene (10mol) was heated at reflux overnight. The solvent was evaporated in vacuo, and then the residue was redissolved in dichloroethane, added to INTERMEDIATE 1 (0. 08mmol) and heated at 70°C for 4 hours. The solvent was evaporated in vacuo and the residue was taken in dichloromethane (50ml). The organic phase was washed with brine (2x10m1) ; the organic phase was dried over MgS04, filtered and concentrated in vacuo. The residue was triturated with ether and the title compound was obtained as a colorless solid (9mg, 22%) ; IH-NMR (CDC13) : # 8. 27 (m, 1H), 8. 11 (m, 1H), 7. 60 (d, J=8Hz, 1H), 7. 77-7. 29 (m, 10H0, 7. 08 (d, J=8. 4Hz, 1H), 6. 75 (br s, 2H), 5. 56 (d, J=8. 4Hz, 1H), 3. 39 (s, 3H) and 2. 90 (s, 6H) ; MS (ESI) (M+H) += 512.

EXAMPLE 9 : N-[5-(2-bromophenyl)-7-fluoro-2,3-dihydro-1-methyl-2-oxo-1H- 1, 4- benzodiazepin-3-yl)-N'-[4-(dimethylamino)-1-naphthalenyl]- thiourea.

Scheme :

As illustrated in the scheme above, INTERMEDIATE 2 (0. 018g, 0. 05mmol) and 4- isothiocyanato-N,N-dimethyl-1-naphthalenamine (0.011g, 0. 05mmol) was heated in dichloroethane (4 mL) at 70°C overnight. The solvent was evaporated in vacuo and the residue was trituated with ether (2 x 10 ml). The title compound (0. 021g, 72%) was obtained as a cotorless solid. IH-NMR (CDC13) : # 8. 26 (m, 1H), 8. 06 (m, 1H), 7. 85 (s, 1H), 7. 79 (m, 1H), 7. 69-7. 24 (m, 8H), 7. 08 (d, J=8. 0Hz, 1H), 7. 02 (t, J=8. 4Hz, 1H), 6. 06 (d, J=8. 0 Hz, 1H), 3. 39 (s, 3H), 2. 93 (s, 6H). (EST (M+H) +=591.

EXAMPLE 10 : N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H -1, 4- benzo-diazepin-3-yl]-N"-cyano-N'-[4-(4-morpholinyl)-1-naphth alenyl]- guanidine (E and Z isomers separated but not identified).

Scheme : As illustrated in the scheme above, a solution of N-[7-chloro-5-(2-chlorophenyl)-2, 3- dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[4-[4-m orpholinyl)-1- naphthalenyl]-thiourea (EXAMPLE 11, made according toGeneral Procedure 3) (0. 058g, 0. 1 mmol) and silver triflate (0. 077g, 0. 3 mmol) in dichloromethane (2 ml) was combined with cyanamide disodium salt (1 mmol) and stirred at room temperature for 3h.

The reaction mixture was then diluted with dichloromethane (10 ml) and washed with brine (2x5 ml). The organic phase was dried over MgS04, filtered and concentrated in vacuo. The residue was washed with ether (2 x 10 ml) and the polar isomer of the title compound (0. 023g, 38%) was obtained as pale yellow solid. The ether layer was concentrated i7 vacuo and purified by column chromatography (1 : 1 EtOAc : CH2Cl2) to give the non-polar isomer of the title compound (0. 009g, 15%) as a colorless solid.

EXAMPLE 10A : N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H - 1,4-benzo-diazepin-3-yl]-N"-cyano-N'-[4-(4-morpholinyl)-1-na phthalenyl]- guanidine (polar isomer) iH-NMR (CDC13) : 8 8. 26 (m, 1H), 7. 9 (m, 2H), 7. 69 (d, J=12. 0Hz, 2H), 7. 53-7. 46 (m, 4H), 7. 39 (m, 1H), 7. 30-7. 23 (m, 4H), 7. 11 (m, 2H), 3. 98 (t, J=9. 2Hz, 2H), 3. 48 (s, 3H) and 3. 12 (br. s, 6H). (ESI) (M+H) +-612

EXAMPLE 10B : N [7-chloro-5- (2-chlorophenyl)-2, 3-dihydro-1-methyl-2-oxo-1H 1,4-benzo-diazepin-3-yl]-N"-cyano-N'-[4-(4-morpholinyl)-1-na phthalenyl]- guanidine (nonpolar isomer).

'H-NMR (CDC13) : 6 8. 25 (m, 1H), 8. 03 (m, 1H), 7. 66-7. 53 (m, 5H), 7. 44-7. 40 (m, 3H), 7. 39-7. 30 (m, 2H), 7. 09 (m, 2H), 6. 54 (d, J=7. 6Hz, 1H), 5. 48 (d, J=7. 6Hz, 1H), 3. 99 (t, J=9. 2Hz, 4H), 3. 39 (s, 3H) and 3. 15 (br. s, 4H). (ESI) (M+H)+=612.

EXAMPLE 11 : N-(7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H -1, 4- benzodiazepin-3-yl]-N'-[4-(4-morpholinyl)-1-naphthalenyl]-th iourea

Following General Procedure 3, the title compound (0. 078g, 65%) was obtained as a white solid. 1H-NMR (CDCl3): # 8. 4 (m, 1H), 8. 08 (m, 2H), 7. 72 (m, 1H), 7. 64 (d, J=8Hz, 1H), 7. 6-7. 5 (m, 4H), 7. 39 (t, J=4. 4Hz, 2H), 7. 30 (d, J=8. 8Hz, 2H), 7. 10 (m, 2H), 6. 09 (d, J=7. 6 Hz, 1H), 3. 98 (t, J=4. 4Hz, 4H) 3. 40 (s, 3H), and 3. 13 (m, 4H). (EST) (M+H)+=604.

EXAMPLE 12 : N-(7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H -1, 4- benzodiazepin-3-yl]-N'-[4-(4-morpholinyl)-1-naphthalenyl]- guanidine.

As illustrated in the scheme above, to a solution of N-[7-chloro-5-(2-chlorophenyl)-2, 3- dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[4-(4-m orpholinyl)-1- naphthalenyl]-thiourea (EXAMPLE 11) (0. 029g, 0.05 mmol) and silver triflate (0. 038g, 0. 15 mmol) in dichloromethane (2 ml) was added a solution of ammonia (0. 25mol, 2M in methanol). Thereactiomn mixture was stirred at room temperature for 3h, diluted with dichloromethane (10 ml) and washed with brine (2x5 ml). The organic layer was dried with MgS04 filtered, concentrated in vacuo. The residue was triturated with ether to give the title compound (0. 008g, 28%) as a pale yellow solid. IH-NMR (CDC13) : # 8. 22 (d, J= 9. 2Hz, 1H), 8. 11 (d, J=8. 4Hz, 1H), 7. 75 (br. s, 1H), 7. 50-7. 41 (m, 7H), 7. 31 (d, J=8. 8Hz,

1H), 7. 04 (m, 2H), 5. 8 (br. s, 1H), 3. 96 (t, J=9. 2Hz, 4H) 3. 51 (s, 3H) and 3. 05 (br. s, 4H).).

(ESI) (M+H)+=587.

EXAMPLE 13 : N [7-chloro-5- (2-chlorophenyl)-2, 3-dihydro-1-methyl-2-oxo-lH-1, 4- benzo-diazepin-3-yl]-N'- [2-methyl-4- (4-morpholinyl) phenyl]-thiourea.

Following General Procedure 3, the title compound (0. 096g, 85%) was obtained as a colorless solid. 1H-NMR(CDCl3) : # 7. 74 (m, 1H), 7. 54 (s, 1H), 7. 51 (m, 1H), 7. 42-7. 39 (m, 3H), 7. 34-7. 31 (m, 2H), 7. 24 (d, J=8. 8Hz, 1H), 7. 09 (d, J=2. 4Hz, 1H), 6. 80-6. 76 (m, 2H), 6. 09 (d, J=7. 6Hz, 1H), 3. 85 (t, J=9. 6Hz, 4H), 3. 44 (s, 3H), 3. 17 (t, J=10.0Hz, 4H) and 2. 32 (s, 3H). (ESI) (M+H) +=568.

EXAMPLE 14 : N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H -1, 4- benzodiazepin-3-yl]-N'-[4-(4-dimethylamino)-2-methylphenyl]- thiourea Following the General Procedure 3, the title compound (0. 052g, 51%) was obtained as a pale brown solid. IH-NMR (CDC13) : # 7. 75 (m, 1H), 7. 52 (dd, J=8. 8Hz, 1H), 7. 47 (s, 1H), 7. 42-7. 40 (m, 3H), 7. 34-7. 31 (m, 2H), 7. 19 (d, J=8. 0Hz, 1H), 7. 09 (d, J=2. 0Hz, 1H), 6. 60 (br. s, 1H), 6. 58 (br. s, 1H), 6. 09 (d, J=8. 0Hz, 1H), 3. 44 (s, 3H), 2. 97 (s, 6H) and 2. 30 (s, 3H). (ESI) (M+H) +=526.

EXAMPLE 15 : N [7-chloro-5- (2-chlorophenyl)-2, 3-dihydro-1-methyl-2-oxo-lH-1, 4- benzodiazepin-3-yl]-N'-[4-(4-dimethylamino)-3-methylphenyl]- thiourea

Following General Procedure 3, the title compound (0. 034g, 35%) was obtained as a pale brown solid.'H-NMR (CDCI3) : # 7. 86 (d, J=7. 6Hz, 1H), 7. 76 (m, 1H), 7. 53 (dd, J=8. 8Hz, 1H), 7. 42-7. 39 (m, 2H), 7. 36-7. 32 (m, 2H), 7. 17 (dd, J=8. 8Hz, 1H), 7. 12 (d, J=2. 0Hz, 1H), 7. 10 (d, J=2. 4Hz, 1H), 7. 06 (d, J=8. 4Hz, 1H), 6. 09 (d, J=7. 6Hz, 1H), 3. 46 (s, 3H), 2. 71 (s, 6H) and 2. 33 (s, 3H). (ESI) (M+H) +-526.

EXAMPLE 16 : N-[7-chloro-5-(2-chlorophenyl-2,3-dihydro-1-methyl-2-oxo-1H- 1, 4- benzo-diazepin-3-yl]-N'- [3-chloro-4- (dimethylamino) phenyl]-thiourea.

Following the General Procedure 3, the title compound (0. 025g, 23%) was obtained as a pale brown solid. 1H-NMR (CDCl3) : # 7. 86 (s, 1H), 7. 83 (d, J=7. 2Hz, 1H), 7. 5 (m, 1H), 7. 53 (dd, J=8. 8Hz, 1H), 7. 43-7. 40 (m, 2H), 7. 35-7. 33 (m, 2H), 7. 28 (m, 1H), 7. 10 (s, J=2. 0Hz, 1H), 7. 05 (d, J=7. 2Hz, 1H), 6. 06 (d, J=7. 2Hz, 1H), 3. 47 (s, 3H) and 2. 82 (s, 6H). (ESI) (M+H) +=546.

EXAMPLE 17 : N [7-chloro-5- (2-chlorophenyl)-2, 3-dihydro-1-methyl-2-oxo-lH-1, 4- benzodiazepin-3-yl]-N'-[4-(4-dimethylamino)-3-(trifluorometh yl)phenyl]- thiourea.

Following General Procedure 3, the title compound (0. 017g, 18%) was obtained as a pale brown solid. lH-NMR (CDC13) : # 7. 93 (s, 1H), 7. 85 (d, J=7. 2Hz, 1H), 7. 38 (m, 1H), 7. 58 (d, J=8. 4Hz, 1H), 7. 55-7. 53 (m, 2H), 7. 42-7. 40 (m, 2H), 7. 34 (m, 3H), 7. 10 (s, J=2. 0Hz, 1H), 6. 06 (d, J=7. 6Hz, 1H), 3. 47 (s, 3H) and 2. 76 (s, 6H). (ESI) (M+H) +=580.

EXAMPLE 18 : N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H -1, 4- benzo-diazepin-3-yl]-N'-(4-chloro-2-(dimethylamino) phenyl]-thiourea.

Following the General Procedure 3, the title compound (0. 024g, 22%) was obtained as a pale brown solid. IH-NMR (CDC13) : # 8. 55 (d, J=7. 2Hz, 1H), 7. 84 (s, 1H), 7. 77 (t, J=4. 8Hz, 1H), 7. 53 (dd, J=8. 8Hz, 1H), 7. 46 (d, J=8. 4Hz, 1H), 7. 42-7. 41 (m, 2H), 7. 36- 7. 34 (m, 3H), 7. 11-7. 02 (m, 2H), 60. 6 (d, J=7. 2Hz, 1H), 3. 48 (s, 3H) and 2. 75 (s, 6H)..

(ESI) (M+H) +-546.

EXAMPLE 19 : N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H -1, 4- benzo-diazepin-3-yl]-N'-[4-(diethylamino)-2-(dimethylamino)p henyl]- thiourea.

Following the General Procedure 3, the title compound (0. 040g, 35%) was obtained as a pale gray solid. IH-NMR (CDC13) : 8 9. 4 (s, 1H), 8. 22 (s, 1H), 7. 76 (m, 1H), 7. 52 (dd, J=8. 8Hz, 1H), 7. 40 (m, 2H), 7. 35 (m, 2H), 7. 10 (d, J=2. 4Hz, 1H), 7. 03 (d, J=8. 8 Hz, 1H), 6. 84 (s, 1H), 6. 49 (dd, J=8. 8 Hz, 1H), 6. 11 (d, J=7. 2Hz, 1H), 3. 47 (s, 3H) 3. 33 (m, 4H), 2. 65 (s, 6H) and 1. 38 (t, J=14. 0 Hz, 6H). (ESI) (M+H) +=583.

EXAMPLE 20 : N-[(1E)-[[7-Chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2 -oxo- 1H-1, 4-benzodiazepin-3-yl] amino][[4-(4-morpholinyl)-1- naphthalenyl] amino] methylene] urea

A mixture of N-[7-chloro-5-(2-chlorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H -1, 4- benzodiazepin-3-yl]-N"-cyano-N'-[4-(4-morpholinyl)-1-naphtha lenyl] guanidine (EXAMPLE 10) (21. 9 mg, 35. 8 mol), water (4. 6 µL, 260 µmol) and trifluoroacetic acid (19. 8 µL, 257 µmol) in THF (3 mL) was heated to reflux for 43 h. The reaction was concentrated in vacuo, and the residue was purified by reverse phase HPLC (gradient 20- 70% CH3CN in H20) to provide the title compound (0. 0092 g, 35%) as its TFA salt. lH- NMR (CD30D) : # 8. 37 (br s, 1H), 8. 06 (br s, 1H), 7. 75-7. 41 (br m, 9H), 7. 26 (br s, 1H), 7. 04 (br s, 1H), 5. 66 (br s, 1H), 4. 00 (br s, 4H), 3. 58 (br s, 3H), 3. 17 (br s, 4H). HRMS calculated for (C32H29Cl2N7O3+H)(M+H)+ : 630. 1787. Found (ESI) : 630. 1800.

EXAMPLE 21 : N'- [7-Chloro-5- (2-chlorophenyl)-2, 3-dihydro-1-methyl-2-oxo-lH 1,4-benzodiazepin-3-yl]-N-methyl-N-[2-methyl-4-(4-morpholiny l) phenyl] thiourea A solution of 2-methyl-4- (4-morpholinyl) benzenamine (53. 3 mg, 0. 277 mmol) and diisopropylethylamine (0. 063 mL, 0. 36 mmol) in CH2Cl2 (1 mL) was cooled to 0 °C.

Methyl chloroformate (0. 024 mL, 0. 31 mmol) was added dropwise, and then the reaction was allowed to warm to room temperature and stir overnight. The reaction was diluted with CH2C12 (20 mL) and washed with brine (10 mol). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was then suspended in a 1 : 2 mixture of Et20 : THF (6 mL). A solution of LiAlH4 in Et20 (0. 34 mL of a 1 M solution, 0. 34 mol) wus added dropwise, and then the reaction mixture was heated to reflux for 1. 5 h. The reaction was cooled, diluted with additional Et20 (8 mL), and quenched with Na2SO4 5H20 (0. 98 g, 4. 2 mmol). After stirring for 15 minutes, the

mixture was filtered and the reaction was concentrated i7 vacuo. A portion of this crude aniline (0. 0580 g, 0. 281 mmol) was dissolved in (CH2C1) 2 (8 mL), and 7-chloro-5- (2- chlorophenyl)-1, 3-dihydro-3-isothiocyanato-1-methyl-2H-1, 4-benzodiazepin-2-one (0. 106 g, 0. 281 mmol) was added. The resulting mixture was heated at 70 °C for 14 h.

The reaction was cooled and concentrated in vacuo. and the residue was purified by silica gel column chromatography (7 : 1 CH2C12 : EtOAc) to provide the title compound (0. 1211 g, 74%). Due to hindered rotation about one of the bonds, rotamers were observed in the 1H-NMR spectrum. 1H-NMR(CDCl3) : # 7. 77-7. 68 (m, 1H), 7. 51 (dd, J=2. 4 Hz, J=8. 8 Hz, 1H), 7. 43-7. 36 (m, 2H), 7. 34-7. 28 (m, 2H), 7. 16 (t, J=8. 4 Hz, 1H), 7. 10-7. 01 (m, 2H), 6. 86-6. 76 (m, 2H), 6. 14 and 6. 10 (2 x d, J=8 0 Hz, J=7. 6 Hz, 1H), 3. 88-3. 82 (br m, 4H), 3. 60 and 3. 59 (2 x s, 3H), 3. 41 (s, 3H), 3. 19 (br s, 4H), 2. 24 and 2. 23 (2 x s, 3H). MS (ESI) (M+H) + = 582. HRMS calculated for (C29H29C12N502S+H) (M+H) + : 582. 1497.

Found (ESI) : 582. 1448.

INTERMEDIATE 9 : 6-Chloro-l-methyl-2H-3, 1-benzoxazine-2, 4 (1H)-dione As illustrated in the scheme above, NaH (2. 43 g of a 60% dispersion, 60. 8 mmol) was added to a solution of 6-chloro-2H-3, 1-benzoxazine-2, 4 (1H)-dione (10. 0 g, 50. 6 mmol) dissolved in DMF (200 mL). The resulting mixture was stirred at room temperature for 30 min., and then methyl iodide (6. 3 mL, 101 mmol) was added dropwise. After the reaction had stirred at room temperature overnight, it was concentrated in vacuo. Water and brine were added to the residue, and the aqueous layer was extracted With CH2Cl2 (2x). The combined organic phases were dried overNa2S04, filtered, and concentrated i72 vacuo. The crude product was triturated with 3 : 1 hexanes : EtOAc. The solvent was removed by filtration, and the resulting solid was washed with additional 3 : 1 hexanes : EtOAc, followed by 100% hexanes. The product was dried briefly under vacuum to produce the title compound as a pale yellow solid. (8. 59 g, 80 %). IH-NMR (DMSO-d6) : # 7. 96 (d,J=2. 6 Hz, 1H), 7. 89 (dd, J=2. 6 Hz, J=9. 0 Hz, 1H), 7. 48 (d, J=9. 0 Hz, 1H), 3. 45 (s, 3H). MS (ESI) (M+H)+ = 212. INTERMEDIATE 10 : 7-Chloro-3, 4-dihydro-1-methyl-1H-1,4-benzodiazepine-2, 5- dione i o glycine, AcOH CI/ CI N 0 0 As illustrated in the scheme above, a mixture of 6-chloro-1-methyl-2H-3, 1-benzoxazine- 2, 4 (1H)-dione (6. 00 g, 28. 4 mmol) and glycine (2. 14 g, 28. 4 mmol) in glacial acetic acid ' (72 mL) was heated at reflux for 4 h. The reaction was cooled and concentrated in vacuo.

Water was added to the residue, and the mixture was cooled to 0 °C. NaHCO3 was added to adjust the pH of the aqueous layer to approximately 8, and then the aqueous layer was extracted with CH2Clz (3x). The combined organic phases were dried over Na2S04, filtered, and concentrated in vacuo. The crude product was triturated with Et20, the solvent was removed by filtration, and the resulting solid was washed with additional Et20 to provide the title compound as a slightly yellow solid (5. 657 g, 89%).'H-NMR (Cl3) : # 7. 88 (d, J=2. 5 Hz, 1H), 7. 57 (br s, 1H), 7. 53 (dd, J=2. 6 Hz, J=8. 7 Hz, 1H), 7. 19 (d, J=8. 6 Hz, 1H), 3. 84 (d, J=6. 1 Hz, 2H), 3. 39 (s, 3H). MS (ESI) (M+H)+= 225.

INTERMEDIATE 11 : 5, 7-Dichloro-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2- one As illustrated in the scheme above, 7-chloro-3, 4-dihydro-1-methyl-1H 1, 4- benzodiazepine-2, 5-dione (5. 00 g, 22. 3 mmol) was suspended in POC13 (100 mL) and heated at 100 °C for 30 min. The reaction was cooled and concentrated in vacuo. Traces of POCl3 were removed by adding toluene and concentrating the mixture in vacuo (2x).

The residue was dissolved in CHZCla, the solution was cooled to 0 °C, and Et3N (6. 8 mL, 48. 8 mmol) was added dropwise. The mixture was stirred for 1 h and allowed to slowly

warm to room temperature, and was then concentrated in vacua once again. The residue was purified by silica gel column chromatography (5 : 1 CH2Cl2 : EtOAc + 0. 5% Et3N) to provide the title compound as an orange solid (4. 68 g, 86%). H-NMR (CDC13) : # 7. 79 (d, J=2. 5 Hz, 1H), 7. 55 (dd, J=2. 4 Hz, J--8. 9 Hz, 1H), 7. 23 (d, J=8.8 Hz, 1H), 4. 67 (br s, 1H), 3. 72 (br s, 1H), 3. 39 (s, 3H). MS (ESI) (M+H)+= 243.

INTERMEDIATE 12 : 7-Chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-1,3-dihydro-1- methyl-2H-1, 4-benzodiazepin-2-one As illustrated in the scheme above and following General Procedure 5, (2, 4-dimethoxy-5- pyrimidinyl) boronic acid (0. 939 g, 5. 10 mmol), Pd2 (dba) 3 (0. 064 g, 0. 07 mmol), dry KF (0. 890 g, 15. 3 mmol), 5, 7-dichloro-1,3-dihydro-1-methyl-2H-1, 4-benzodiazepin-2-one (1. 12 g, 4. 61 mmol) and P (t-Bu)3 (0. 42 mL of a 10 % solution in hexanes, 0. 21 mmol) were combined and heated for 20 h. After workup, purification of the crude product by silica gel column chromatography (1 : 3 hexanes : EtOAc) provided the title compound as a pale orange solid (1. 20 g, 75%). 1H-NMR(CDCl3) : # 8. 50 (s, 1H), 7. 49 (dd, J=2. 4 Hz, J=8. 8 Hz, 1H), 7. 29 (d, J=8. 8 Hz, 1H), 7. 13 (d, J=2. 4 Hz, 1H), 4. 84 (d, J=10. 8 Hz, 1H), 4. 06 (s, 3H), 3. 79 (s, 3H), 3. 76 (d, J=10. 8 Hz, 1H), 3. 42 (s, 3H). MS (ESI) (M+H) + = 347.

INTERMEDIATE 13 : 3-Azido-7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-1, 3- dihydro-l-methyl-2H-1, 4-benzodiazepin-2-one

As illustrated in the scheme above and following General Procedure 6, KHMDS (7. 0 mL of 0. 5 M in toluene, 3. 5 mmol), 7-chloro-5- (2, 4-dimethoxy-5-pyrimidinyl)-1, 3-dihydro- 1-methyl-2H-1, 4-benzodiazepin-2-one (1. 16 g, 3. 35 mmol), trisyl azide (2. 60 g, 8. 40 mmol) and acetic acid (0. 85 mL, 14. 8 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (2 : 3 hexanes : EtOAc) provided the title compound as a pale yellow solid (1. 23 g, 95%). 1H-NMR (CDCl3) : # 8. 64 (s, 1H), 7. 54 (dd, J=2. 3 Hz, J=8. 8 Hz, 1H), 7. 33 (d, J=8. 8 Hz, 1H), 7. 19 (d, J=2. 3 Hz, 1H), 4. 51 (s, 1H), 4. 08 (s, 3H), 3. 78 (s, 3H), 3. 47 (s, 3H). MS(ESI)(M+H)+= 388.

INTERMEDIATE 14 : 3-Amino-7-chloro-5-(2, 4-dimethoxy-5-pyrimidinyl)-1, 3- dihydro-1-methyl-2H-1,4-benzodiazepin-2-one As illustrated in the scheme above and following General Procedure 7, 3-azido-7-chloro- 5- (2, 4-dimethoxy-5-pyrimidinyl)-1, 3-dihydro-1-methyl-2H 1, 4-benzodiazepin-2-one (1. 22 g, 3. 15 mmol) and PS-PPh3 (23. 0 g of 1. 37 mmol/g, 31. 5 mmol) were combined.

After workup and purification by"catch and release,"the title compound was obtained as a brown solid (1. 15 g, quantitative). IH-NMR (CDC13) : õ 8. 56 (s, 1H), 7. 50 (dd, J=2. 4 Hz, J=8. 9 Hz, 1H), 7. 30 (d, J=8. 8 Hz, 1H), 7. 15 (d, J=2. 5 Hz, 1H), 4. 46 (s, 1H), 4. 06 (s, 3H), 3. 77 (s, 3H), 3. 46 (s, 3H), 2. 85-2. 12 (br s, 2H). MS (ESp (M+H) + = 362 INTERMEDIATE 15 : 7-Chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-1, 3-dihydro-3- isothiocyanato-l-methyl-2H-1, 4-benzodiazepin-2-one

As illustrated in the scheme above and following General Procedure 2, 3-amino-7-chloro- 5- (2, 4-dimethoxy-5-pyrimidinyl)-1, 3-dihydro-1-methyl-2H-1, 4-benzodiazepin-2-one (1. 15 g, 3. 18 mmol) and thiophosgene (0. 49 mL, 6. 4 mmol) were combined. Purification of the crude product by silica gel column chromatography (9 : 1 CH2Cl2 : EtOAc) provided the title compound as a viscous dark yellow oil (0. 560 g, 44%). 1H-NMR (CDCl3) : # 8. 60 (s, 1H), 7. 55 (dd, J=2. 5 Hz, J=8. 8 Hz, 1H), 7. 33 (d, J=8. 8 Hz, 1H), 7. 17 (d, J=2. 5 Hz, 1H), 5. 16 (s, 1H), 4. 07 (s, 3H), 3. 78 (s, 3H), 3. 49 (s, 3H). MS (ESI) (M+H) + = 404.

EXAMPLE 22 : N-[7-chloro-5-(2, 4-dimethoxy-5-pyrimidinyl)-2, 3-dihydro-1-methyl- 2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-[4-(diethylamino)-2-meth ylphenyl]- thiourea

As illustrated in the scheme above, a solution of 7-chloro-5-(2, 4-dimethoxy-5- pyrimidinyl)-1, 3-dihydro-3-isothiocyanato-1-methyl-2H-1, 4-benzodiazepin-2-one (0. 069 g, 0. 146 mmol) and N4,N4-diethyl-2-methyl-1,4-benzenediamine (0. 029 g, 0. 161 mmol) in

(CH2C1) 2 (5. 0 mL) was heated at 70 °C for 16 h. The reaction was cooled and concentrated in vacuo, and the residue was purified by silica gel column chromatography (7 : 3 CHOC12 : EtOAc) to provide the title compound as a light orange solid (0. 074 g, 87%).

IH-NMR (CDC13) : 8 8. 64 (s, 1H), 7. 52 (dd, J=2. 5 Hz, J--8. 8 Hz, 1H), 7. 40 (s, 1H), 7. 35 (d, J=7.8 Hz, 1H), 7. 32 (d, J=9. 0 Hz, 1H), 7. 20 (d, J=2. 2 Hz, 1H), 7. 17-7. 13 (m, 1H), 6. 54-6. 51 (m, 2H), 6. 06 (d, J=8. 0 Hz, 1H), 4. 05 (s, 3H), 3. 74 (s, 3H), 3. 42 (s, 3H), 3. 40- 3. 27 (m, 4H), 2. 30 (s, 3H), 1. 17 (t, J=7. 1 Hz, 6H). HRMS calculated for (C28H32ClN7O3S+H)(M+H)+ : 582. 2054. Found (ESI) : 582. 2076.

INTERMEDIATE 16: 7-Chloro-1,3-dihydro-1-methyl-5-(3-thienyl)-2H-1, 4- benzodiazepin-2-one As illustrated in the scheme above and following General Procedure 5, 3-thienylboronic acid (1. 15 g, 9. 01 mmol), Pd2 (dba) 3 (0. 113 g, 0. 123 mmol), dry kif (1. 57 g, 27. 0 mmol), 5, 7-dichloro-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (1. 98 g, 8. 15 mmol) and P (t-Bu) 3 (0. 75 mL of a 10 % solution in hexanes, 0. 37 mmol) were combined and heated for 16 h. After workup, purification of the crude product by silica gel column chromatography (9 : 1 CH2Cl2:EtOAc) provided the title compound as a yellow solid (1. 44 g, 61%). 1H-NMR(CDCl3) : 8 7. 54-7. 49 (m, 4H), 7. 37 (dd, J=3. 0 Hz, J=5. 0 Hz, 1H), 7. 29 (d, J=9. 4 Hz, 1H), 4. 76 (d, J=10. 9 Hz, 1H), 3. 77 (d, J=10. 9 Hz, 1H), 3. 38 (s, 3H).

MS (ESI) (M+H)+=291.

INTERMEDIATE 17 : 3-Azido-7-chloro-1,3-dihydro-1-methyl-5-(3-thienyl)-2H-1, 4- benzodiazepin-2-one

As illustrated in the scheme above and following General Procedure 6, KHMDS (10. 4 mL of 0. 5 M in toluene, 5. 20 mmol), 7-chloro-1, 3-dihydro-1-methyl-5-(3-thienyl)-2H- 1, 4-benzodiazepin-2-one (1. 44 g, 4. 95 mmol), trisyl azide (3. 83 g, 12. 4 mmol) and acetic acid (1. 25 mL, 21. 8 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (7 : 3 hexanes : EtOAc) provided the title compound as a pale yellow solid (1. 60 g, 98%). 1H-NMR (CDC13) : # 7. 61-7. 55 (m, 4H), 7. 40 (dd, J=2. 9 Hz, J=5. 1 Hz, 1H), 7. 33 (dd, J=1. 0 Hz, J=8. 2 Hz, 1H), 4. 54 (s, 1H), 3. 44 (s, 3H). MS (ESI) (M+H) += 332.

INTERMEDIATE 18 : 3-Amino-7-chloro-1,3-dihydro-1-methyl-5-(3-thienyl)-2H-1, 4- benzodiazepin-2-one As illustrated in the scheme above and following General Procedure 7, 3-azido-7-chloro- 1, 3-dihydro-1-methyl-5- (3-thienyl)-2H 1, 4-benzodiazepin-2-one (1. 60 g, 4. 82 mmol). and PS-PPh3 (30. 0 g of 1. 37 mmol/g, 41. 1 mmol) were combined. After workup and purification by"catch and release,"the title compound was obtained as a brown solid (1. 35 g, 92%). 1H-NMR(CDCl3) : 8 7. 56-7. 50 (m, 4H), 7. 36 (dd, J=3. 1 Hz, J=4. 9 Hz, 1H), 7. 29 (d, J=8. 8 Hz, 1H), 4. 46 (s, 1H), 3. 43 (s, 3H), 2. 35-2. 15 (br s, 2H). MS (ESI) (M+H) += 306.

INTERMEDIATE 19 : 7-Chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-(3- thienyl)-2H-1, 4-benzodiazepin-2-one As illustrated in the scheme above and following General Procedure 2, 3-amino-7-chloro- 1,3-dihydro-1-methyl-5-(3-thienyl)-2H-1, 4-benzodiazepin-2-one (1. 35 g, 4. 41 mmol) and thiophosgene (0. 67 mL, 8. 8 mmol) were combined. Purification of the crude product by silica gel column chromatography (100% CH2C12) provided the title compound as a yellow solid (1. 04 g, 68%). 1H-NMR (CDCl3) : # 7. 61-7. 54 (m, 4H), 7. 39 (dd, J=2. 9 Hz, J=5. 3 Hz, 1H), 7. 33 (d, J=8. 8 Hz, 1H), 5. 20 (s, 1H), 3. 46 (s, 3H). MS (ESI) (M+H) += 348.

Example 23 : N-[7-Chloro-2,3-dihydro-1-methyl-2-oxo-5-(3-thienyl)-1H-1, 4- benzodiazepin-3-yl]-N'-[4-(4-morpholinyl)-1-naphthalenyl] thiourea 0 N N N f NCS N u Cl J4N DMAI (CH2CI) 2, A S S 2. Polyamine resin, (CHZCI) 2 tus s This reaction was carried out in a multiwell plate. As illustrated in the scheme above, aA mixture of 7-chloro-1, 3-dihydro-3-isothiocyanato-1-methyl-5- (3-thienyl)-2H-1, 4- benzodiazepin-2-one (156 pL of a 0. 128 M solution in (CH2C1) 2, 0. 020 mmol), 4-(4- morpholinhyl)- 1-naphthalenamine (44 µL of a 0. 5 M solution in DMA, 0. 022 mmol), and (CH2C1) 2 (300 CL) was agitated and heated at 70 °C for 22 h. The reaction was cooled and concentrated in vacuo, and the residue was redissolved in DMA (25 pL) and

(CH2C1) 2 (275 aL). Polyamine resin HL (NovaBiochem) was added (20 mg of 4. 53 mmol/g, 0. 091 mmol), and the mixture was agitated at room temperature overnight. The resin was removed by filtration and washed with additional (CH2C1) 2 and MeOH. The filtrate was concentrated in vacuo to provide the title compound. MS (ESI) (M+H) + = 576.

INTERMEDIATE 20 : 7-Chloro-1,3-dihydro-1-methyl-5-(3-pyridinyl)-2H-1, 4- benzodiazepin-2-one As illustrated in the scheme above and following General Procedure 4, 5, 7-dichloro-1, 3- dihydro-1-methyl-2H-1, 4-benzodiazepin-2-one (1. 99 g, 8. 19 mmol), Na2CO3 (0. 868 g, 8. 19 mmol), PdCl2 (dppf) (0. 335 g, 0. 410 mmol) and (3-pyridinyl) boronic acid (1. 01 g, 8. 19 mmol) were combined and heated for 14 h. After workup, purification of the crude product by silica gel column chromatography (100% EtOAc) provided the title compound (1. 51 g, (64%). 1H-NMR (CDCl3) : # 8. 78 (d, J=1. 6 Hz, 1H), 8. 72 (dd, J=1. 6 Hz, J=4. 8 Hz, 1H), 8. 02 (dt, J=1. 6 Hz, J=8. 0 Hz, 1fui), 7. 56 (dd, J=2. 4 Hz, J=8. 8 Hz, 1H), 7. 39 (dd, J=4.8 Hz, J=8. 0 Hz, 1H), 7. 34 (d, J=8. 8 Hz, 1H), 7. 28 (d, J=2. 4 Hz, 1H), 4. 89 (d, J=10. 4 Hz, 1H), 3. 80 (d, J=10. 8 Hz, 1H), 3. 41 (s, 3H). MS (ESI) (M+H) +=286.

INTERMEDIATE 21 : 3-Azido-7-chloro-1,3-dihydro-1-methyl-5-(3-pyridinyl)-2H- 1,4-benzodiazepin-2-one

As illustrated in the scheme above and following General Procedure 6, KHMDS (10. 5 mL of 0. 5 M in toluene, 5. 25 mmol), 7-chloro-1, 3-dihydro-1-methyl-5- (3-pyridinyl)-2H 1, 4-benzodiazepin-2-one (1. 43 g, 4. 99 mmol), trisyl azide (3. 86 g, 12. 5 mmol) and acetic acid (1. 26 mL, 22. 0 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (1 : 1 CH2Cl2 : EtOAc) provided the title compound as a yellow foam (1. 47 g, 90%). 1H-NMR (CDCl3) : # 8. 80 (s, 1H), 8. 76 (d, J-3. 6 Hz, 1H), 8. 14 (dt, J=1. 6 Hz, J--8. 0 Hz, 1H), 7. 61 (dd, J=2. 0 Hz, J=8. 4 Hz, 1H), 7. 44 (ddd, J=0. 8 Hz, J=4 8 Hz, J=8. 0 Hz, 1H), 7. 38 (d, J=8. 8 Hz, 1H), 7. 35 (d, J=2. 4 Hz, 1H), 4. 56 (s, 1H), 3. 48 (s, 3H). MS (ESI) (M+H) + = 327.

INTERMEDIATE 22 : 3-Amino-7-chloro-1,3-dihydro-1-methyl-5-(3-pyridinyl)-2H- 1, 4-benzodiazepin-2-one As illustrated in the scheme above and following General Procedure 7, 3-azido-7-chloro- 1,3-dihydro-1-methyl-5-(3-pyridinyl)-2H-1, 4-benzodiazepin-2-one (1. 47 g, 4. 49 mmol) and PS-PPh3 (16. 4 g of 1. 37 mmol/g, 22. 4 mmol) were combined. After workup and purification by "catch and release," the title compound was obtained as a slightly brown solid (1. 46 g, quantitative). 1H-NMR (CDCl3) : # 8.76 (d, J=2. 4 Hz, 1H), 8. 72 (dD, J=1.6 Hz, J=5. 2 Hz, 1H), 8. 06 (dT, J=2. 4 Hz, J=7. 6 Hz, 1H), 7. 58 (dd,. l=2. 4 Hz, J=8. 8 Hz, 1H), 7. 40 (dd, J=4. 8 HZ, J=8. 0 Hz, 1H), 7. 35 (d, J=8.8 Hz, 1H), 7. 29 (d, J=2. 4 Hz, 1H), 4. 51 (s, 1H), 3. 46 (s, 3H), 2. 41 (br s, 2H). MS (ESI) (M+H) += 301.

INTERMEDIATE 23 : 7-Chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-(3- pyridinyl)-2H-1, 4-benzodiazepin-2-one As illustrated in the scheme above, a solution of 3-amino-7-chloro-1,3-dihydro-1-methyl- 5-(3-pyridinyl)-2H-1, 4-benzodiazepin-2-one (1. 36 g, 4. 52 mmol) in dry THF (55 mL) was cooled to-15 °C. Carbon disulfide (2. 7 mL, 45 mmol) was added, followed by EDCI (1. 73 g, 9. 03 mmol). The mixture was stirred for 10 min., and then Et3N (1. 26 mL, 9. 04 mmol) was added. The reaction was stirred for 16 h while it was allowed to slowly warm to room temperature. The precipitated solid was removed by filtration and was washed well with CH2Cl2 and then discarded. The filtrate was concentrated in vacuo, and the residue was dissolved in CH2C12. The organic phase was washed with water, saturated NaHC03, and brine, and was then dried over Na2S04, filtered, and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (3 : 1 CH2Cl2 : EtOAc) provided the title compound as a solid (0. 652 g, 42%). 1H-NMR (Cl3) : # 8. 75 (s, 2H), 8. 12 (dt,. 7=2. 0 Hz, J=8. 0 Hz, 1H), 7. 63 (dd, J=2. 0 Hz, J=8. 8 Hz, 1H), 7. 43 (dd, J=4. 8 Hz, J=8. 0 Hz, 1H), 7. 39 (d, J=8. 8 Hz, 1H), 7. 33 (d, J=2. 4 Hz, 1H), 5. 22 (s, 1H), 3. 50 (s, 3H). MS (ESI) (M+H) + = 343.

EXAMPLE 24 : N-[7-Chloro-2,3-dihydro-1-methyl-2-oxo-5-(3-pyridinyl)-1H-1, 4- benzodiazepin-3-yl]-N'-[4-(4-morpholinyl)-1-naphthalenyl] thiourea

A solution of 7-chloro-1,3-dihydro-3-isothiocyanato-1-methyl-5-(3-pyridiny l)-2H-1, 4- benzodiazepin-2-one (0. 0282 g, 0. 0823 mmol) and 4-(4-morpholinyl)-1-naphthalenamine (0. 0188 g, 0. 0823 mmol) in (CH2C1) 2 (2. 5 mL) was heated at 70 °C for 24 h. The reaction was cooled and concentrated i7Z vacuo, and the residue was purified by silica gel column chromatography (1 : 2 CH2Cl2 : EtOAc) to provide the title compound (0. 0263 g, 56%). lH-NMR (CDC13) : # 8. 72-8. 68 (m, 2H), 8. 29-8. 25 (m, 1H), 8. 11-8. 07 (m, 1H), 8. 05-8. 00 (m, 2H), 7. 64-7. 55 (m, 5H), 7. 38-7. 33 (m, 3H), 7. 15 (d, J=8. 0 Hz, 1H), 6. 08 (d, J=7. 6 Hz, 1H), 4. 03-3. 96 (br m, 4H), 3.39 (s, 3H), 3. 15. (br s, 4H). HRMS calculated for (C3oH27ClN602S+H) (M+H) + : 571. 1683. Found (ESI) : 571. 1699. Anal. Calcd for C3oH27ClN602S + 0. 7 H20 : C, 61. 73 ; H, 4. 90 ; N, 14. 40. Found : C, 61. 93 ; H, 4. 79 ; N, 13. 87.

INTERMEDIATE 24 : 6-Fluoro-1-methyl-2H-3,1-benzoxazine-2, 4 (1H)-dione As illustrated in the scheme above, NaH (0. 312 g of a 60% dispersion, 7. 80 mmol) was added to a solution of 6-fluoro-2H-3, 1-benzoxazine-2, 4 (1H)-dione (1. 176 g, 6. 49 mmol) dissolved in DMF (60 mL). The resulting mixture was stirred at room temperature for 30 min., and then methyl iodide (0. 81 mL, 13 mmol) was added dropwise. After the reaction had stirred at room temperature overnight, it was concentrated in vacuo. Water and brine were added to the residue, and the aqueous layer was extracted with CH2Cl2 (3x). The combined organic phases were dried over Na2S04, filtered, and concentrated in vacuo.

The crude product was triturated with Et2O. The solvent was removed by filtration, and the resulting solid was washed with additional Et20. The product was dried briefly under vacuum to produce the title compound as a white solid (1. 00 g, 79%). 1H-NMR(CDCl3) : 8 7. 86-7. 82 (m, 1H), 7. 55-7. 48 (m, 1H), 7. 22-7. 17 (m, 1H), 3. 61 (s, 3H)-MS (ESD (M+H) += 196.

INTERMEDIATE 25 : 7-Fluoro-3, 4-dihydro-1-methyl-1H-1, 4-benzodiazepine-2, 5- dione

i v o N O glycine, AcOH 0 F N o o As illustrated in the scheme above, a mixture of 6-fluoro-1-methyl-2H-3, 1-benzoxazine- 2, 4 (1I1)-dione (1. 00 g, 5. 12 mmol) and glycine (0. 385 g, 5. 13 mmol) in glacial acetic acid (13 mL) was heated at reflux for 4 h. The reaction was cooled and concentrated in vacuo.

Water was added to the residue, and the mixture was cooled to 0 °C. NaHCO3 was added to adjust the. pH of the aqueous layer to approximately 8, and then the aqueous layer was extracted with CH2C12 (4x). The combined organic phases were dried over Nazis04, filtered, and concentrated n vacuo. The crude product was triturated with Et2O, the solvent was removed by filtration, and the resulting solid was washed with additional Et20 to provide the title compound as a slightly yellow solid (0. 560 g, 52%). IH-NMR (DMSO-d6) : # 8. 80 (br s, 1H), 7. 49-7. 38 (m, 3H), 3. 76 (br d, 1H), 3. 47 (br d, 1H), 3. 26 (s, 3H). MS (ESI) (M+H) + = 209.

INTERMEDIATE 26 : 5-Chloro-7-fluoro-1,3-dihydro-1-methyl-2H-1, 4- benzodiazepin-2-one As illustrated in the scheme above, 7-fluoro-3, 4-dihydro-1-methyl-1H-1, 4- benzodiazepine-2, 5-dione (0. 495 g, 2. 38 mmol) was suspended in POCK3 (10. 6 mL) and heated at 100 °C for 30 min. The reaction was cooled and concentrated in vacuo. Traces of POC13 were removed by adding toluene and concentrating the mixture in vacuo (2x).

The residue was dissolved, in CH2Cl2, the solution was cooled to 0 °C, and Et3N (0. 75 mL, 5. 4 mmol) was added dropwise. The mixture was stirred for 0. 5 h and allowed to slowly warm to room temperature, and was then concentrated in vacuo once again. The residue was purified by silica gel column chromatography (9 : 1 CH2Cl2:EtOAc + 0. 5% Et3N) to provide the title compound as a light tan solid (0. 422 g, 78%). 1H-NMR (CDCl3) : # 7. 53-

7. 48 (m, 1H), 7. 34-7. 24 (m, 2H), 4. 66 (br s, 1H), 3. 72 (br s, 1H), 3. 39 (s, 3H). MS (ESI) (M+H) + = 227.

INTERMEDIATE 27 : 7-Fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1, 4- benzodiazepin-2-one As illustrated in the scheme above and following General Procedure 4, 5-chloro-7-fluoro- 1,3-dihydro-1-methyl-2H-1, 4-benzodiazepin-2-one (0. 201 g, 0. 887 mmol.), Na2CO3 (0. 0940 g, 0. 887 mmol), PdCl2(dppf) (0. 0362 g, 0. 0443 mmol) and phenylboronic acid (0. 108 g, 0. 886 mmol) were combined and heated for 13 h. After workup, purification of the crude product by silica gel column chromatography (3 : 1 CH2Cl2 EtOAc) provided the title compound (0. 180 g, 76%). 1H-NMR (CDCl3) : 6 7. 64-7. 60 (m, 2H), 7. 51-7. 45 (m, 1H), 7. 44-7. 39 (m, 2H), 7. 34 (dd, J=4. 8 Hz, J--9. 2 Hz, 1H), 7. 31-7. 25 (m, 1H), 7. 02 (dd, J=2.8 Hz, J=8.8 Hz, 1H), 4. 84 (d, J=10.8Hz, 1H), 3. 78 (d, J=10.8Hz, 1H), 3. 40 (s, 3H).

MS (ESI) (M+H)+=269.

INTERMEDIATE 28 : 3-Azido-7-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1, 4- benzodiazepin-2-one As illustrated in the scheme above and following General Procedure 6, KHMDS (1. 34 mL of 0. 5 M in toluene, 0. 670 mmol), 7-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1, 4- benzodiazepin-2-one (0. 171 g, 0. 637 mmol), trisyl azide (0. 493 g, 1. 59 mmol) and acetic acid (0. 16 mL, 2. 8 mmol) were combined. After workup, purification of the crude

product by silica gel column chromatography (100% CH2C12 to 9 : 1 CH2Cl2 : EtOAc) provided the title compound as a pale yellow solid (0. 163 g, 83%). 1H-NMR(CDCl3) : # 7. 72-7. 67 (m, 2H), 7. 54-7. 49 (m, 1H), 7. 47-7. 42 (m, 2H), 7. 39 (dd, J=4. 8 Hz, J=9. 2 Hz, 1H), 7. 36-7. 30 (m, 1H), 7. 08 (dd, J=2.8 Hz, J=8. 4 Hz, 1H), 4. 55 (s, 1H), 3. 45 (s, 3H).

MS (ESI) (M+H) +=310.

INTERMEDIATE 29 : 3-Amino-7-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1, 4- benzodiazepin-2-one As illustrated in the scheme above and following General Procedure 7, 3-azido-7-fluoro- 1, 3-dihydro-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2-one (0. 0826 g, 0. 267 mmol) and PS-PPh3 (1. 63 g of 1. 64 mmol/g, 2. 67 mmol) were combined. After workup and purification by"catch and release,"the title compound was obtained as a slightly yellow solid (0. 0450 g, 59%). 1H-NMR (CDC13) : (# 7. 65-7. 60 (m, 2H), 7. 51-7. 46 (m, 1H), 7. 44- 7. 39 (m, 2H), 7. 36 (dd, J=4. 8 Hz, J--9. 2 Hz, 1H), 7. 33-7. 26 (m, 1H), 7. 03 (dd, J=2. 4 Hz, J=8. 4 Hz, 1H), 4. 48 (s, 1H), 3. 45 (s, 3H), 2. 30-1. 60 (br s, 2H). MS (ESI) (M+H) + = 284.

EXAMPLE 25 : N-(7-Fluoro-2,3-dihydro-1-methy-2-oxo-5-phenyl-1H-1, 4- benzodiazepin-3-yl)-N'- [2-methyl-4- (4-morpholinyl) phenyl] thiourea

As illustrated in the scheme above, a solution of 3-amino-7-fluoro-1,3-dihydro-1-methyl- 5-phenyl-2H-1, 4-benzodiazepin-2-one (0. 0056 g, 0. 020 mmol) and 4-(4-isothiocyanato-3- methylphenyl) morpholine (0. 0048 g, 0. 020 mmol) in DMA (0. 5 mL) was heated at 70 °C for 16 h. The reaction was cooled and concentrated in vacuo, and the residue was lyophilized to provide the title compound (0. 0104 g, quantitative). 1H-NMR (CDCl3) : # 7. 63-7. 58 (m, 2H), 7. 50-7. 45 (m, 1H), 7. 44-7. 36 (m, 4H), 7. 36-7. 26 (m, 3H), 7. 09 (dd, J=2. 4 Hz, J=8. 4 Hz, 1H), 6. 85-6. 78 (m, 2H), 6. 09-6. 05 (m, 1H), 3. 90-3. 83 (bru, 4H), 3. 41 (s, 3H), 3. 21-3. 15 (br s, 4H), 2. 36 (s, 3H). MS (ESD (M+H) + = 518. HRMS calculated for (C28H28FN5O2S+H)(M+H)+ : 518. 2026. Found (ESI) : 518. 2117.

INTERMEDIATE 30 : 7-Chloro-1,3-dihydro-5-(6-methoxy-2-pyridinyl)-1-methyl- 2H-1, 4-benzodiazepin-2-one Br 1. n-BuLi, Et20,-40 °C N// C/N 2. B (OMe) ,-40 °C to RT I \ 3. Evaporate solvent OMe 4. Pd (PPh3) 4, CsF, DME, A CI<N iN N OMe cl As illustrated in the scheme above, a. solution of 2-bromo-6-methoxypyridine (0. 022 mL, 0. 18 mmol) in dry Et20 (0. 3 mL) was added to a solution of n-BuLi (0. 12 mL of 1. 6 M in hexanes, 0. 19 mmol) maintained at-40 °C. The reaction was stirred at-40 °C for 20 min., and then B (OMe) 3 (0. 022 mL, 0. 19 mmol) was added dropwise. The reaction was stirred at-40 °C for 30 min., and then at room temperature for 3. 5 h. The reaction was concentrated in vacuo, anhydrous MeOH was added to the residue, and the reaction was concentrated in vacuo once again. Dry DME (0. 8 mL), 5, 7-dichloro-1, 3-dihydro-1- methyl-2H-1, 4-benzodiazepin-2-one (0. 0392 g, 0. 161 mmol), Pd (PPh3) 4 (0. 0093 g, 0. 0080 mmol) and CsF (0. 0612 g, 0. 403 mmol) were added to the residue, and the mixture was heated to reflux for 15 h. Water (5 mL) and CH2Cl2 (5 mL) were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with additional CH2Cl2 (3x), and the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude product by silica gel column

chromatography (2 : 1 CH2Cl2 : EtOAc) provided the title compound (0. 029 g, 57%). 1H- NMR (CDC13) : # 7. 77 (d, J=7. 6 Hz, 1H), 7. 71-7. 64 (m, 2H), 7. 49 (dd, J=2. 4 Hz, J--8. 8 Hz, 1H), 7. 27 (d, J=8. 8 Hz, 1H), 6. 83 (d, J=8. 0 Hz, 1H), 4. 85 (d, J=10. 8 Hz, 1H), 3. 86 (d, J=10. 4 Hz, 1H), 3. 81 (s, 3H), 3. 39 (s, 3H). MS (ESI) (M+H) + = 316.

INTERMEDIATE 31 : 3-Azido-7-chloro-1, 3-dihydro-5-(6-methoxy-2-pyridinyl)-1- methyl-2H-1, 4-benzodiazepin-2-one As illustrated in the scheme above and following General Procedure 6, KHMDS (0. 19 mL of 0. 5 M in toluene, 0. 095 mmol), 7-chloro-1,3-dihydro-5-(6-methoxy-2-pyridinyl)-1- methyl-2H-1, 4-benzodiazepin-2-one (0. 0290 g, 0. 0918 mmol), trisyl azide (0. 0710 g, 0. 229 mmol) and acetic acid (0. 023 mL, 0. 40 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (49 : 1 CH2Cl2 : EtOAc) provided the title compound (0. 0204 g, 62%). 1H-NMR(CDCl3) : #7. 95 (d, J=7. 2 Hz, 1H), 7. 78-7. 70 (m, 2H), 7. 54 (dd, J=2. 4 Hz, J=8. 8 Hz, 1H), 7. 31 (d, J=8. 8 Hz, 1H), 6. 87 (d, J=8. 4 Hz, 1H), 4. 64 (s, 1H), 3. 80 (s, 3H), 3. 44 (s, 3H). MS (ESI) (M+H) +=357.

INTERMEDIATE 32 : 3-Amino-7-chloro-1,3-dihydro-5-(6-methoxy-2-pyridinyl)-1- methyl-2H-1, 4-benzodiazepin-2-one

As illustrated in the scheme above, a suspension of Pd/C (0. 005 g of 10% on C) in MeOH (0. 5 mL) under N2 was treated with ammonium formate (0. 0252 g, 0. 400 mmol). The mixture was stirred for 10 min. and then transferred via Pasteur pipette to a suspension of 3-azido-7-chloro-1, 3-dihydro-5- (6-methoxy-2-pyridinyl)-1-methyl-2F1=1, 4- benzodiazepin-2-one (0. 0204 g, 0. 0572 mmol) in MeOH (1. 2 mL). The resulting mixture was stirred at room temperature for 3h and was then filtered through a small pad of Celite. The filtrate was concentrated i7 vacuo, and the residue was purified by silica gel column chromatography (100% EtOAc, followed by 4 : 1 CH2Cl2:EtOAc) to provide the title compound (0. 0148 g, 78%). IH-NMR (CDC13) : # 7. 82 (dd, J=0. 8 Hz, J=7. 6 Hz, 1H), 7. 71-7. 66 (m, 2H), 7. 51 (dd, J=2. 4 Hz, J=8. 8 Hz, 1H), 7. 28 (d, J=8. 8 Hz, 1H), 6. 83 (dd, J=0. 8 Hz, J=8. 4 Hz, 1H), 4. 56 (s, 1H), 3. 80 (s, 3H), 3. 44 (s, 3H), 2. 53 (br s, 2H). MS (ESI) (M+H) +-331.

EXAMPLE 26 : N-[7-Chloro-2, 3-dihydro-5-(6-methoxy-2-pyridinyl)-1-methyl-2-oXo- 1H-1,4-benzodiazepin-3-yl]-N'-[2-methyl-4-(4-morpholinyl)phe nyl] thiourea As illustrated in the scheme above, a solution of 3-amino-7-chloro-1,3-dihydro-5-(6- methoxy-2-pyridinyl)-1-methyl-2H-1, 4-benzodiazepin-2-one (0. 0113 g, 0. 0342 mmol) and 4-(4-isothiocyanato-3-methylphenyl) morpholine (0. 0080 g, 0. 034 mmol) in (CH2C1) 2 (0. 9 mL) was heated at 70 °C for 20 h. The reaction was cooled and concentrated in vacua, and the residue was purified by silica gel column chromatography (2 : 1 CHUCK : EtOAc) to provide the title compound (0. 0172 g, 89%) as a slightly yellow solid. 1H- NMR (CL,) : # 7. 79 (dd, J=0. 8 Hz, J=7. 2 Hz, 1H), 7. 70-7. 65 (m, 2H), 7. 54 (dd, J=2. 4 Hz, J=8. 8 Hz, 1H), 7. 42 (br s, 1H), 7. 30 (d, J=8. 8 Hz, 1H), 7. 28-7. 25 (m partially hidden under CHCIs, 2H), 6. 85-6. 80 (m, 3H), 6. 14 (m, 1H), 3. 88-3. 85 (m, 4H), 3. 78 (s, 3H), 3. 40 (s, 3H), 3. 22-3. 18 (m, 4H), 2. 36 (s, 3H). MS (ESI) (M+H)+= 565.