Sulfonamide lactam inhibitors of FXa and method

Abstract

Sulfonamide lactams of the following formula 1

Description

FIELD OF THE INVENTION

[0002] The present invention relates to sulfonamide lactam inhibitors of the enzyme Factor Xa which are useful as anticoagulants in the treatment of cardiovascular diseases associated with thromboses.

BRIEF DESCRIPTION OF THE INVENTION

[0003] In accordance with the present invention, novel lactam derivatives are provided which are inhibitors of the enzyme Factor Xa and have the structure I 2

[0004] including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrugs thereof, wherein

[0005] X is defined as:

[0006] —(CH2)m—

[0007] where m is an integer between 1 and 3 and which may be optionally mono- or di-substituted on 1 to 3 of the methylenes with oxo, lower alkyl, and aryl;

[0008] R1 is selected from alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl and substituted cycloheteroalkyl;

[0009] R2 and R3 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or substituted heteroaryl;

[0010] R4, R4a, R5, and R5a are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, hydroxy, alkoxy, 3

[0011] R6 and R6a are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, cycloheteroalkyl;

[0012] R7 and R8 are independently chosen from

[0013] —(CH2)n—H

[0014] where n is an integer between 1 and 4 and which may be optionally mono- or di-substituted on 1 to 4 of the methylenes with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and heteroaryl, and which may be optionally substituted with 1 to 4 halogens except on a carbon that is directly bonded to a nitrogen;

[0015] or R7 and R8 together with the nitrogen atom to which they are attached may form an optionally substituted cycloheteroalkyl group;

[0016] Ra and Rb are the same or different and are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, substituted alkyl-carbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkylaminocarbonyl, substituted alkylaminocarbonyl, dialkylaminocarbonyl, and substituted dialkylaminocarbonyl.

[0017] Compounds within the scope of the present invention include compounds of the following formula II 4

[0018] including pharmaceutically acceptable salts thereof and all stereoisomers thereof, and prodrugs thereof, wherein

[0019] Y and Ya are independently a bond, alkyl, alkenyl or alkynyl;

[0020] X and Xa are independently

[0021] —(CH2)m—

[0022] where m is an integer between 1 and 3 and where each methylene group of X may be optionally substituted with oxo, or mono- or di-substituted with lower alkyl or aryl;

[0023] Q is a group A or B 5

[0024] where

[0025] (1) n, p, q and r are each independently 0 to 2, provided that at least one of n, p, q and r is other than zero;

[0026] (2) X1 is —O—, R14R15—, —NR14—, or —S(O)t— where t is 1 or 2;

[0027] (3) the group B ring system optionally contains one or more double bonds where valence allows; and

[0028] (4) optionally fused to the group B ring system is an optionally substituted cycloalkyl ring, an optionally substituted cycloheteroalkyl ring, an optionally substituted heteroaryl ring, or an optionally substituted aryl ring;

[0029] R1 and R1a are independently aryl, heteroaryl, cycloalkyl or cycloheteroalkyl any of which may be optionally substituted with one or more groups Z1, Z2 or, Z3;

[0030] R2, R2a, R3 and R3a are independently selected from

[0031] (1) hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, cycloheteroalkyl, or heteroaryl any of which may be optionally substituted with one or more groups Z1a, Z2a or Z3a; or

[0032] (2) —C(O)tH, or C(O)tZ6 where t is 1 or 2; or

[0033] (3) -Z4-NZ7Z8;

[0034] R4, R4a, R4b, R4c, R5, R5a, R5b and R5c are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloheteroalkyl, hydroxy, alkoxy, 6

[0035] which may be optionally substituted with one or more groups Z1b, Z2b or Z3b;

[0036] R6 and R6a are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or cycloheteroalkyl any of which may be optionally substituted with one or more groups Z1c, Z2c or Z3c;

[0037] R7 and R8 are independently chosen from optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl or

[0038] —(CH2)n—H

[0039] where n is an integer between 1 and 4 and wherein 1 to 4 of the methylene groups may be optionally mono- or di-substituted with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and heteroaryl, and which may be optionally substituted with 1 to 4 halogens except on a carbon that is directly bonded to a nitrogen;

[0040] or R7 and R8 together with the nitrogen atom to which they are attached may form an optionally substituted cycloheteroalkyl group;

[0041] Ra and Rb are the same or different and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloheteroalkyl, cycloalkyl, alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, cycloheteroalkylcarbonyl, heteroarylcarbonyl, aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl.

[0042] R9 is H, Z3d or when a group R11 is present R9 combines with R11 to form a bond;

[0043] R10 is H, Z1f, —Y2—R11, —Y2—N(R11)(Z4-Z9a), —Y2—OR11—Y2—C(O)R11, —Y2—C(O)OR11, Y2—OC(O)R1, —Y2—N(Z4-Z9a)-C(O)R11, —Y2—N(Z4-Z9a)-C(O)OR11, —Y2—S(O)tR11 where t is 0 to 2, or —Y2—R12;

[0044] Y2 is —(CH2)u—, —O—(CH2)u—, —C(O)—(CH2)u—, —C(O)O—(CH2)u—, —OC(O)—(CH2)u— where u is 0 to 3;

[0045] R11 when present combines with R9 to form a bond;

[0046] R12 is 7

[0047] R13 is H, Z2f,

[0048] R14 is H, Z3f or a group D 8

[0049] or R13 and R14 combine to form ═O or ═S;

[0050] Z1, Z1a, Z1b, Z1c, Z1d, Z1e, Z1f, Z2, Z2a, Z2b, Z2c, Z2d, Z2e, Z2f, Z3, Z3a, Z3b, Z3c, Z3d, Z3e, Z3f, Z13 and Z14 are each independently

[0051] (1) hydrogen or Z6, where Z6 is

[0052] (i) alkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl or heteroarylalkyl;

[0053] (ii) (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or

[0054] (iii) (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of Z1 through Z3f,

[0055] (2)—OH or —OZ6,

[0056] (3) —SH or —SZ6,

[0057] (4) —C(O)tH, —C(O)tZ6, or —O—C(O)Z6,

[0058] (5) —SO3H, —S(O)tZ6, or S(O)tN(Z9)Z6,

[0059] (6) halo,

[0060] (7) cyano,

[0061] (8) nitro,

[0062] (9) -Z4-NZ7Z8,

[0063] (10) -Z4-N(Z9)-Z5-NZ7Z8,

[0064] (11) -Z4-N(Z10)-Z5-Z6,

[0065] (12) -Z4-N(Z10)-Z5-H,

[0066] (13) oxo,

[0067] Z4 and Z5 are each independently

[0068] (1) a single bond,

[0069] (2) -Z11-S(O)t-Z12-,

[0070] (3) -Z11-C(O)-Z12-,

[0071] (4) -Z11-C(S)-Z12-,

[0072] (6) -Z11-S-Z12-,

[0073] (7)-Z11-O—C(O)-Z12-,

[0074] (8)-Z11-C(O)—O-Z12-,

[0075] (9)-Z11-C(═NZ9a)-Z12-, or

[0076] (10)-Z11-C(O)—C(O)-Z12-

[0077] Z7, Z8, Z9, Z9a and Z10

[0078] (1) are each independently hydrogen or a group provided in the definition of Z6,

[0079] (2) Z7 and Z8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups provided in the defintion of Z1 through Z3,

[0080] (3) Z7 or Z8, together with Z9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups provided in the defintion of Z1 through Z3, or

[0081] (4) Z7 and Z8 or Z9 and Z10 together with the nitrogen atom to which they are attached may combine to form a group —N═CZ13Z14;

[0082] Z11 and Z12 are each independently

[0083] (1) a single bond,

[0084] (2) alkylene,

[0085] (3) alkenylene, or

[0086] (4) alkynylene.

[0087] In addition, in accordance with the present invention, a method for preventing, inhibiting or treating cardovascular diseases associated with thromboses is provided, wherein a compound of formula I or II is administered in a therapeutically effective amount which inhibits Factor Xa.

DETAILED DESCRIPTION OF THE INVENTION

[0088] The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.

[0089] The term “alkyl” or “alk” as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons containing 1 to 20 carbons, preferably 1 to 12 carbons, more preferably 1 to 8 carbons in the normal chain. Examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the various additional branched chain isomers thereof. The term “lower alkyl” includes both straight and branched chain hydrocarbons containing 1 to 4 carbons.

[0090] The term “alkenyl” as employed herein alone or as part of another group includes both straight and branched hydrocarbons having one or more double bonds, preferably one or two, and being of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain. Examples include 9

[0091] The term “alkynyl” as employed herein alone or as part of another group includes both straight and branched hydrocarbons having one or more triple bonds, preferably one or two, and being of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain. Examples include 10

[0092] The terms “substituted alkyl”, “substituted lower alkyl”, “substituted alkenyl” and “substituted alkynyl” refer to such groups as defined above having one, two, or three substituents independently selected from the groups listed in the description of T1, T2 and T3.

[0093] The term “halo” refers to chloro, bromo, fluoro and iodo.

[0094] The term “cycloallyl” as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds and/or 1 or 2 triple bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 4 to 12 carbons forming the rings. Also included within the definition of “cycloalkyl” are such rings fused to an aryl, cycloheteroalkyl, or heteroaryl ring and bridged multicyclic rings containing 5 to 20 carbons, preferably 6 to 12 carbons, and 1 or 2 bridges. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, 11

[0095] cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, cycloheptadienyl, cyclopentynyl, cyclohexynyl, cycloheptynyl, cyclooctynyl, etc. Cycloalkyl groups may be optionally substituted with one, two or three substituents independently selected from the groups listed in the description of T1, T2 and T3.

[0096] The term “aryl” or “ar” as employed herein alone or as part of another group refers to phenyl, 1-naphthyl, and 2-naphthyl as well as such rings fused to a cycloalkyl, aryl, cycloheteroalkyl, or heteroaryl ring.

[0097] Examples include 12

[0098] etc.

[0099] Aryl rings may be optionally substituted with one, two or three substituents independently selected from the groups listed in the description of T1, T2 and T3.

[0100] The term “cycloheteroalkyl” as used herein alone or as part of another group refers to 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated rings which includes 1 or more hetero atoms such as nitrogen, oxygen and/or sulfur (preferably 1 to 3 heteroatoms), linked through a carbon atom or an available nitrogen atom. Also included within the definition of cycloheteroalkyl are such rings fused to a cycloalkyl or aryl ring and spiro cycloheteroalkyl rings. One, two, or three available carbon or nitrogen atoms in the cycloheteroalkyl ring can be optionally substituted with substituents listed in the description of T1, T2 and T3. Also, an available nitrogen or sulfur atom in the cycloheteroalkyl ring can be oxidized. Examples of cycloheteroalkyl rings include 1314

[0101] etc. Depending on the point of attachment, a hydrogen may be missing from the nitrogen atom in the above rings.

[0102] The term “heteroaryl” as used herein alone or as part of another group refers to a 5-6- or 7-membered aromatic rings containing from 1 to 4 nitrogen atoms and/or 1 or 2 oxygen or sulfur atoms provided that the ring contains at least 1 carbon atom and no more than 4 heteroatoms. The heteroaryl ring is linked through an available carbon or nitrogen atom. Also included within the definition of heteroaryl are, such rings fused to a cycloalkyl, aryl, cycloheteroalkyl, or another heteroaryl ring. One, two, or three available carbon or nitrogen atoms in the heteroaryl ring can be optionally substituted with substituents listed in the description of T1, T2 and T3. Also an available nitrogen or sulfur atom in the heteroaryl ring can be oxidized. Examples of heteroaryl rings include 1516

[0103] Again, depending on the point of attachment, a hydrogen may be missing from the nitrogen atom in the above rings.

[0104] The term “alkoxy” as employed herein alone or as part of another group includes “alkyl” groups as defined above bonded to an oxygen. Similarly, the term “alkylthio” as employed herein above or as part of another group includes “alkyl” groups as defined above bonded to a sulfur.

[0105] Unless otherwise indicated, the term “substituted amino” as employed herein alone or as part of another group refers to amino substituted with one or two substituents, which may be the same or different, such as alkyl (optionally substituted), aryl (optionally substituted), arylalkyl (optionally substituted), arylalkyl (optionally substituted), heteroaryl (optionally substituted), heteroarylalkyl (optionally substituted), cycloheteroalkyl (optionally substituted), (cycloheteroalkyl)alkyl (optionally substituted), cycloalkyl (optionally substituted), cycloalkylalkyl (optionally substituted), haloalkyl (optionally substituted), hydroxyalkyl (optionally substituted), alkoxyalkyl (optionally substituted) or thioalkyl (optionally substituted). In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, substituted alkyl, alkoxy, alkylthio, halo, trifluoromethyl, hydroxy, aryl or substituted aryl.

[0106] T1, T2 and T3 are each independently

[0107] (1) hydrogen or T6, where T6 is

[0108] (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, cycloheteroalkyl, (cylcloheteroalkyl)alkyl, heteroaryl, or (heteroaryl)alkyl;

[0109] (ii) (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or

[0110] (iii) (iii) a group (i) or (ii) which is independently substituted by one or more (preferably 1 to 3) of the following groups (2) to (13) of the definition of T1, T2 and T3,

[0111] (2) —OH or T6,

[0112] (3) —SH or ST6,

[0113] (4) —C(O)tH, —C(O)tT6, or —O—C(O)T6,

[0114] (5) —SO3H, —S(O)tT6, or S(O)tN(T9)T6,

[0115] (6) halo,

[0116] (7) cyano,

[0117] (8) nitro,

[0118] (9) -T4-NT7T8,

[0119] (10) -T4-N(T9)-T5-NT7T8,

[0120] (11) -T4-N(T10)-T5-T6,

[0121] (12) -T4-N(T10)-T5-H,

[0122] (13) oxo,

[0123] T4 and T5 are each independently

[0124] (1) a single bond,

[0125] (2) -T11-S(O)t-T12-,

[0126] (3) -T11-C(O)-T12-,

[0127] (4) -T11-C(S)-T12-,

[0128] (5) -T11-O-T12-,

[0129] (6) -T11-S-T12-,

[0130] (7) -T11-O—C(O)-T12-,

[0131] (8) -T11-C(O)—O-T12-,

[0132] (9) -T11-C(═NT9a)-T12-, or

[0133] (10) -T11-C(O)—C(O)-T12-

[0134] T7, T8, T9 and T10

[0135] (1) are each independently hydrogen or a group provided in the definition of T6, or

[0136] (2) T7 and T8 may together be alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1, T2 and T3, or

[0137] (3) T7 or T8, together with T9, may be alkylene or alkenylene completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atoms to which they are attached, which ring is unsubstituted or substituted with one or more groups listed in the description of T1, T2 and T3, or

[0138] (4) T7 and T8 or T9 and T10 together with the nitrogen atom to which they are attached may combine to form a group —N═CT13T14 where T13 and T14 are each independently H or a group provided in the definition of T6;

[0139] T11 and T12 are each independently

[0140] (1) a single bond,

[0141] (2) alkylene,

[0142] (3) alkenylene, or

[0143] (4) alkynylene;

[0144] The compounds of formula I can be prepared as salts, in particular pharmaceutically acceptable salts. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, with amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluene sulfonic acid. Corresponding acid addition salts can also be formed if the compounds of formula I have an additional basic center. The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.

[0145] Preferred salts of the compounds of formula I include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate.

[0146] All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents. Consequently, compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers or diastereomers as starting materials. When enantiomeric or diastereomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.

[0147] It should be understood that the present invention includes prodrug forms of the compounds of formula I such as alkylesters of acids or any known prodrugs for lactam derivatives.

[0148] The compounds of the instant invention may, for example, be in the free or hydrate form, and may be obtained by methods exemplified by the following descriptions.

[0149] The compounds of formula I may be prepared by the exemplary processes described in the following reaction schemes. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples.

[0150] The compounds of formula I can be prepared using the reactions shown in the schemes below using techniques known to those skilled in the art of organic synthesis. Additional compounds within formula I can be generated from compounds disclosed in the schemes through conversion of the substituent groups to other functionality by the usual methods of chemical synthesis. In generating compounds of the present invention one skilled in the art will recognize that it may be necessary to protect reactive functionalilty such as hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in reactions. The introduction and removal of protecting groups are well known to those skilled in the art (for example see Green, T. W., “Protective Groups in Organic Synthesis”, John Wiley and Sons 1991).

[0151] In one method, lactam II, the preparations of which are know in the literature to those skilled in the art, shall be protected on the nitrogen atom alpha to the carbonyl by the Cbz group to produce lactam III. The Boc and other protecting groups may also be used. Lactam III may then be derivatized by alkylation with appropriately substituted alpha-halo esters such as methyl bromoacetate, methyl 2-bromopropionate, or methyl 2-bromo-2-phenylacetate to yield lactam IV, where X is defined as in structure I. Hydrolysis of the ester with LiOH and the like will give the acid V. 17

[0152] The coupling of V with various amines to produce product amides can be accomplished using numerous procedures known to those skilled in the art. A suitable example employs ethyl 3-(dimethylamino)propylcarbodiimide hydrochloride (WSC, EDCI) and 1-hydroxybenzotriazole hydrate (HOBt).

[0153] The Cbz protecting group can be removed, for example with hydrogen over palladium, to give amine compound VII. Reaction of VII with sulfonyl chlorides in the presence of triethylamine or other base will provide the product VIII. 18

[0154] Alternatively, the Cbz-protecting group of compound IV can be removed with hydrogen and palladium to give compound IX. This compound can then be sulfonylated to yield compound X, which can be hydrolyzed with lithium hydroxide and the like to produce the acid XI. Compound XI can then be coupled with various amines as described above to yield products of formula VIII. 19

[0155] In addition to the methods already described, compounds of formula I wherein R2 is other than hydrogen can be prepared as shown in the following scheme. Compounds of formula VIIIa are sequentially treated with a base such as NaH or the like and then with an alkylating agent R2-halogen (for example; methyl iodide, methyl bromoacetate, benzyl bromide and the like) to provide the title compounds. Similarly, compounds of formula VIIIa are treated with an acylating agent, for example methyl chloroformate, to provide the title compounds. 20

[0156] In a similar fashion, compounds of formula IVa are treated with a base (cesium carbonate and the like) and an alkylating agent such as methyl iodide to provide compounds of formula IV which are transformed using aformentioned procedures. 21

[0157] R2 other then Hydrogen may also be introduced by reductive amination procedures. For example, compounds of formula IXa are treated with an aldehyde and a reducing agent such as sodium triacetoxyborohydride to produce compounds of the type IXb. The aldehyde may be attached to a polymer support to provide resin-bound intermediates which can be treated using the other described procedures. Resin cleavage techniques are well known to those skilled in the art. 22

[0158] In a similar fashion compounds of formula VIIa may be resin bound or functionalized to produce compounds of formula VIIb. 23

[0159] Preferred compounds of this invention are those of claim 1 including a pharmaceutically acceptable salt thereof wherein:

[0160] X is CH2;

[0161] R1 is selected from alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alknyl, cycloalkyl, substituted cycloalkyl, aryl, cycloheteroalkyl, and heteroaryl;

[0162] R2 is H, alkyl or substituted alkyl;

[0163] R3, R4, R4a, R5, R5a, R6, and R6a are H or alkyl;

[0164] R7 and R8 are independently chosen from

[0165] —(CH2)n—H

[0166] where n is an integer between 1 and 4 and which may be optionally mono- or di-substituted on 1 to 4 of the methylenes with alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and heteroaryl, and which may be optionally substituted with 1 to 4 halogens except on a carbon that is directly bonded to a nitrogen;

[0167] or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted cycloheteroalkyl group;

[0168] More preferred compounds of this invention are those of formula I or a pharmaceutically acceptable salt thereof wherein:

[0169] X is CH2;

[0170] R1 is selected from, substituted alkyl (especially (heteroaryl)alkyl or (aryl)alkyl), substituted alkenyl (especially (heteroaryl)alkenyl or (aryl)alkenyl), substituted alkynyl (especially (heteroaryl)alkynyl or arylalkynyl), substituted cycloalkyl, aryl, cycloheteroalkyl, and heteroaryl;

[0171] R2 is H, alkyl or substituted alkyl;

[0172] R3, R4, R4a, R5, R5a, R6, and R6a are H.

[0173] R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted cycloheteroalkyl group (especially pyrolidine, piperadine, piperazine, morpholine, thiomorpholine or thiazolidine).

[0174] More preferred compounds include compounds of formula II wherein

[0175] X is CH2;

[0176] Y is a bond or alkyenyl (when alkenyl, Y is preferably —CH═CH—, and more preferably, 24

[0177] R1 is aryl or heteroaryl, either of which may be optionally substituted with one or more groups Z1, Z2, Z3 (especially where Z1, Z2 and Z3 are independently halo, cyano, —OH, OZ6, alkyl, aryl, heteroaryl, or -Z4-NZ7Z8, any of which may be further substituted where valence allows as provided in the definition of Z1, Z2 and Z3);

[0178] R2 is H, alkyl, —C(O)tH, —C(O)tZ6, -Z4-NZ7Z8, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, or -(alkyl)-Z4-NZ7Z8;

[0179] R3, R4, R4a, R5, R5a, R6, and R6a are H;

[0180] Q is a group B;

[0181] R9 is H, Z3d or when a group R11 is present R9 combines with R1 to form a single bond;

[0182] R10 is H, Z1f, —Y2—R11, Y2—R12 or Y2—N(R11)-Z4-Z9a;

[0183] Y2 is —(CH2)u— or —C(O)—(CH2)—;

[0184] Z3d and Z1f are each independently H, halo, oxo, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, -(alkyl)-cycloalkyl, -(alkyl)-cycloheteroalkyl, -(alkyl)-aryl, -(alkyl)-heteroaryl, —OH, OZ6, —C(O)tH, —C(O)tZ6, —S(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, -(alkyl)-S(O)tZ6, -Z4-NZ7Z8, -Z4-N(Z10)-Z5-Z6, -Z4-N(Z10)-Z5-H, -Z4-N(Z9)-Z5-NZ7Z8, -(alkyl)-Z4-NZ7Z8, -(alkyl)-Z4-N(Z10)-Z5-Z6, -(alkyl)-Z4-N(Z10)-Z5-H, or -(alkyl)-Z4-N(Z9)-Z5-NZ7Z8 any of which may be optionally further substituted where valence allows as provided in the respective definitions of Z3d and Z1f;

[0185] R14 is a group D or H, halo, oxo, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, -(alkyl)-cycloalkyl, -(alkyl)-cycloheteroalkyl, -(alkyl)-aryl, -(alkyl)-heteroaryl, —OH, —OZ6, —C(O)tH, —C(O)tZ6, —S(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, -(alkyl)-S(O)tZ6, -Z4-NZ7Z8, -Z4-N(Z10) Z5-Z6, -Z4-N(Z10)-Z5-H, -Z4-N(Z9)-Z5-NZ7Z8, -(alkyl)-Z4-NZ7Z8, -(alkyl)-Z4-N(Z10)-Z5-Z6, -(alkyl)-Z4-N(Z10)-Z5-H, or -(alkyl)-Z4-N(Z9)-Z5-NZ7Z8 any of which may be optionally further substituted where valence allows as provided in the definition of R14;

[0186] Z4 is a bond —C(O)—, —C(═NZ9a)-, —C(O)—C(O)— or —C(O)O—; and

[0187] Z5 is —C(O)— or —SO2—.

[0188] The most preferred compounds are those of formula I or a pharmaceutically acceptable salt thereof wherein:

[0189] X is CH2;

[0190] R1 is selected from, optionally substitued heteroaryl, optionally substituted (heteroaryl)alkenyl, optionally substituted aryl or optionally substituted (aryl)alkenyl (especially where the aryl and heteroaryl groups are optionally substituted with one or more halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl);

[0191] R2 is H, alkyl or substituted alkyl;

[0192] R3, R4, R4a, R5, R5a, R6, and R6a are H;

[0193] R7 and R8 together with the nitrogen atom to which they are attached form a cycloheteroalkyl group (especially pyrrolidine) which may be optionally substituted (especially with one or more (amino)alkyl, or (substituted amino)alkyl.

[0194] Most preferred compounds include compounds of formula II wherein

[0195] X is CH2;

[0196] Y is a bond or 25

[0197] R1 is aryl or heteroaryl, either of which may be optionally substituted with one or more halo, cyano, —OH, —OZ6 (especially alkoxy), optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, or -Z4-NZ7Z8;

[0198] R2 is H, alkyl, —C(O)tH, —C(O)tZ6, -Z4-NZ7Z8, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, or -(alkyl)-Z4-NZ7Z8;

[0199] R3, R4, R4a, R5, R5a, R6, and R6a are H;

[0200] Q is a group B;

[0201] R9 is H, Z3dor, when a group R11 is present R9 combines with R11 to form a single bond;

[0202] R10 is H, Z1f, —Y2—R11 or —Y2—R2;

[0203] Y2 is —(CH2)u— or —C(O)—(CH2)—;

[0204] Z3d and Z1f are each independently H, alkyl, heteroaryl, -(alkyl)-cycloheteroalkyl, -(alkyl)-Z4-NZ7Z8, -Z4-NZ7Z8, -(alkyl)-Z4-N(Z10)-Z5-Z6, -(alkyl)-Z4-N(Z9)-Z5-NZ7Z8, —C(O)tZ6, -(alkyl)-C(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, or —S(O)tZ6;

[0205] R14 is a group H, -(alkyl)-cycloheteroalkyl, -(alkyl)-Z4-NZ7Z8, -Z4-NZ7Z8, -(alkyl)-Z4-N(Z10)-Z5-Z6, -(alkyl)-Z4-N(Z9)-Z5-NZ7Z8, —C(O)tZ6, -(alkyl)-C(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, —S(O)tZ6 or a group D;

[0206] Z4 is a bond —C(O)—, —C(═NZ9a)-, —C(O)—C(O)—, or —C(O)O—; and

[0207] Z5 is —(O)— or —SO2—.

Utility

[0208] The compounds of the present invention are inhibitors of the activated coagulation serine protease known as Factor Xa and thus are useful for the treatment or prophylaxis of those processes which involve activation of the coagulation cascade and especially those which involve the production and/or action of Factor Xa. Thus the compounds of the present invention are useful in the prevention and treatment of all Factor Xa-associated conditions. An “Factor Xa-associated condition” is a disorder which may be prevented, partially alleviated or cured by the administration of an inhibitor of Factor Xa. Such diseases include arterial thrombosis, coronary artery disease, acute coronary syndromes, myocardial infarction, unstable angina, ischemia resulting from vascular occlusion cerebral infarction, stroke and related cerebral vascular diseases (including cerebrovascular accident and transient ischemic attack). Additionally, the compounds are useful in treating or preventing formation of atherosclerotic plaques, transplant atherosclerosis, peripheral arterial disease and intermittent claudication. In addition, the compounds can be used to prevent restenosis following arterial injury induced endogenously (by rupture of an atherosclerotic plaque), or exogenously (by invasive cardiological procedures such as vessel wall injury resulting from angioplasty).

[0209] In addition, the inventive compounds are useful in preventing venous thrombosis, coagulation syndromes, deep vein thrombosis (DVT), disseminated intravascular coagulopathy, Kasabach-Merritt syndrome, pulmonary embolism, cerebral thrombosis, atrial fibrillation, and cerebral embolism. The compounds are useful in treating peripheral arterial occlusion, thromboembolic complications of surgery (such as hip replacement, endarterectomy, introduction of artificial heart valves, vascular grafts, and mechanical organs), implantation or transplantation of organ, tissue or cells, and thromboembolic complications of medications (such as oral contraceptives, hormone replacement, and heparin, e.g., for treating heparin-induced thrombocytopenia). The inventive compounds are useful in preventing thrombosis associated with artificial heart valves, stents, and ventricular enlargement including dilated cardiac myopathy and heart failure. The compounds are also useful in treating thrombosis due to confinement (i.e. immobilization, hospitalization, bed rest etc.).

[0210] These compounds are also useful in preventing thrombosis and complications in patients genetically predisposed to arterial thrombosis or venous thrombosis (including activated protein C resistance, FVleiden, Prothrombin 20210 elevated coagulation factors FVII, FVIII, FIX, FX, FXI, prothrombin, TAFI and fibrinogen), elevated levels of homocystine, and deficient levels of antithrombin, protein C, and protein S. The inventive compounds may be used for treating heparin-intolerant patients, including those with congenital and acquired antithrombin III deficiencies, heparin-induced thrombocytopenia, and those with high levels of polymorphonuclear granulocyte elastase.

[0211] The present compounds may also be used to inhibit blood coagulation in connection with the preparation, storage, fractionation, or use of whole blood. For example, the compounds may be used to maintain whole and fractionated blood in the fluid phase such as required for analytical and biological testing, e.g., for ex vivo platelet and other cell function studies, bioanalytical procedures, and quantitation of blood-containing components. The compounds may be used as anticoagulants in extracorpeal blood circuits, such as those necessary in dialysis and surgery (such as coronary artery bypass surgery); for maintaining blood vessel patency in patients undergoing transluminal coronary angioplasty, vascular surgery including bypass grafting, arterial reconstruction, atherectomy, vascular graft and stent patency, tumor cell metastesis, and organ, tissue, or cell implantation and transplantation. The inventive compounds may also be inhibitors of the activated coagulation serine proteases known as Factor VIIa, Factor XIa, and thrombin and also inhibit other serine proteases, such as trypsin, tryptase, and urokinase. Thus, the compounds are useful for treating or preventing those processes, which involve the production or action of Factor VIIa, Factor XIa, thrombin, trypsin, and/or tryptase. Inventive compounds with urokinase inhibitory activity are useful as metastasis inhibitors in treating cancer. As used herein with reference to the utilities described below other than metastasis, the term “treating” or “treatment” encompasses prevention, partial alleviation, or cure of the disease or disorder.

[0212] In view of their above-referenced serine protease inhibitory activity, the inventive compounds are useful in treating consequences of atherosclerotic plaque rupture including cardiovascular diseases associated with the activation of the coagulation cascade in thrombotic or thrombophilic states.

[0213] The inventive compounds with tryptase inhibitory activity are useful as anti-inflammatory agents, in treating chronic asthma, allergic rhinitis, inflammatory bowel disease, psoriasis, conjunctivitis, atopic dermatitis, pancreatis, rheumatoid arthritis, osteoarthritis, septic shock, and chronic inflammatory joint diseases, diseases of joint cartilage destruction, and/or vascular damage due to bacterial and/or viral infections. Additionally, the inventive compounds may be useful for treating diabetic retinopathy or motor neuron diseases such as amyotrophic lateral sclerosis, progressive muscular atrophy, and primary lateral sclerosis. Additionally, the inventive compounds may be useful for tissue remodeling diseases and for treating plaque instability and sequelli. In addition, these compounds may be useful for treating fibrotic diseases and conditions, for example, fibrosis, scleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas, and hypertrophic scars.

[0214] In addition, the compounds of the present invention are useful in treating cancer and preventing the prothrombotic complications of cancer. In view of their metastasis inhibition activity, the compounds are useful in treating tumor growth, as an adjunct to chemotherapy, and for treating diseases involving metastases including, but not limited to cancer, more particularly, cancer of the lung, prostate, colon, breast, ovaries, and bone. These compounds may also be useful in preventing angiogenesis.

[0215] The inventive compounds may also be used in combination with other antithrombotic or anticoagulant drugs such as thrombin inhibitors, platelet aggregation inhibitors such as aspirin, clopidogrel, ticlopidine or CS-747, warfarin, low molecular weight heparins (such as LOVENOX), GPIIb/GPIIIa blockers, PAI-1 inhibitors such as XR-330 and T-686, inhibitors of α-2-antiplasmin such as anti-α-2-antiplasmin antibody and thromboxane receptor antagonists (such as ifetroban), prostacyclin mimetics, phosphodiesterase (PDE) inhibitors, such as dipyridamole or cilostazol, PDE inhibitors in combination with thromboxane receptor antagonists/thromboxane A synthetase inhibitors (such as picotamide), serotonin-2-receptor antagonists (such as ketanserin), fibrinogen receptor antagonists, hypolipidemic agents, such as HMG-CoA reductase inhibitors, e.g., pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin, AZ4522, itavastatin (Nissan/Kowa), and compounds disclosed in U.S. provisional applications No. 60/211,594 filed Jun. 15, 2000, and No. 60/211,595 filed Jun. 15, 2000; microsomal triglyceride transport protein inhibitors (such as disclosed in U.S. Pat. Nos. 5,739,135, 5,712,279 and 5,760,246), antihypertensive agents such as angiotensin-converting enzyme inhibitors (e.g., captopril, lisinopril or fosinopril); angiotensin-II receptor antagonists (e.g., irbesartan, losartan or valsartan); and/or ACE/NEP inhibitors (e.g., omapatrilat and gemopatrilat); β-blockers (such as propranolol, nadolol and carvedilol), PDE inhibitors in combination with aspirin, ifetroban, picotamide, ketanserin, or clopidogrel and the like. The inventive compounds are also useful in combination with anti-arrhythmic agents such as for atrial fibrillation, for example, amiodarone or dofetflide.

[0216] The inventive compounds may be used in combination with prothrombolytic agents, such as tissue plasminogen activator (natural or recombinant), streptokinase, reteplase, activase, lanoteplase, urokinase, prourokinase, anisolated streptokinase plasminogen activator complex (ASPAC), animal salivary gland plasminogen activators, and the like. The inventive compounds may also be used in combination with β-adrenergic agonists such as albuterol, terbutaline, formoterol, salmeterol, bitolterol, pilbuterol, or fenoterol; anticholinergics such as ipratropium bromide; anti-inflammatory cortiocosteroids such as beclomethasone, triamcinolone, budesonide, fluticasone, flunisolide or dexamethasone; and anti-inflammatory agents such as cromolyn, nedocromil, theophylline, zileuton, zafirlukast, monteleukast and pranleukast.

[0217] The inventive compounds may also be useful in combination with other anticancer strategies and chemotherapies such as taxol and/or cisplatin.

[0218] The compounds may act synergistically with one or more of the above agents. For example, the inventive compounds may act synergistically with the above agents to prevent reocclusion following a successful thrombolytic therapy and/or reduce the time to reperfusion. Thus, reduced doses of thrombolytic agent(s) may be used, therefore minimizing potential hemorrhagic side effects.

[0219] The compounds of this invention may be administered by any means suitable for the condition to be treated, which may depend on the need for site-specific treatment or quantity of drug to be delivered. Systematic treatment is typically preferred for cancerous conditions, although other modes of delivery are contemplated. The compounds may be delivered orally, such as in the form of tablets, capsules, granules, powders, or liquid formulations including syrups; sublingually; bucally; transdermally; parenterally, such as by subcutaneous, intravenous, intramuscular or intrasternal injection or infusion (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; rectally such as in the form of suppositories; or liposomally. Dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents may be administered. The compounds may be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved with suitable pharmaceutical compositions or, particularly in the case of extended release, with devices such as subcutaneous implants or osmotic pumps.

[0220] Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The inventive compounds may be orally delivered by sublingual and/or buccal administration, e.g., with molded, compressed, or freeze-dried tablets. Exemplary compositions may include fast-dissolving diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (AVICEL) or polyethylene glycols (PEG); an excipient to aid mucosal adhesion such as hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (SCMC), and/or maleic anhydride copolymer (e.g., GANTREZ); and agents to control release such as polyacrylic copolymer (e.g., CARBOPOL 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.

[0221] Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.

[0222] Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

[0223] Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures but liquefy and/or dissolve in the rectal cavity to release the drug.

[0224] The effective amount of a compound of the present invention may be determined by one of ordinary skill in the art. The specific dose level and frequency of dosage for any particular subject may vary and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition. An exemplary effective amount of compounds of formula I may be within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) on a regimen in single or 2 to 4 divided daily doses.

[0225] The ability of compounds of the present invention to inhibit Factor Xa can be determined using methods well known to those skilled in the art, such as methods that measure FXa amidolytic (Balasubramanian et al., J. Med. Chem. 36:300-303, 1993; Combrink et al., J. Med. Chem. 41:4854-4860, 1998), clotting time (Balasubramanian, N. et al., J. Med. Chem. 36:300-303, 1993) and in vivo models of arterial and venous thrombosis (Schumacher et al., Eur. J. Pharm. 259:165-171, 1994).

[0226] General Experimental and Definitions:

[0227] The following examples and preparations describe the manner and process of making and using the invention and are illustrative rather than limiting. It is to be understood that there may be other embodiments which fall within the spirit and scope of the invention as defined by the claims appended hereto. Abbreviations and terms employed herein are defined below.

[0228] brine=saturated aqueous sodium chloride

[0229] Dess-Martin periodinane=1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-Benziodoxol-3(1H)-one

[0230] DMF=N,N-dimethylformamide

[0231] EDCI=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride.

[0232] PS-PB-CHO=1% Cross linked polystyrene with (4-formyl-3-methoxyphenoxy)methyl linker.

[0233] PyBOP=(T-4)-(1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-phosphorus(1+) hexafluorophosphate(1−)=Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate

[0234] TFA=trifluoroacetic acid

[0235] TFFH=Tetramethylfluoroformamidinium hexafluorophosphate.

[0236] THF=tetrahydrofuran

[0237] WSC=1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride.

[0238] Unless otherwise noted all mass spectral data are positive ion spectra.

[0239] The following conditions were used for HPLC:

[0240] Method 1: column-YMC S5 C18 ODS 4.6×50 mm; flow-4.0 mL/min.; detection at 220 nm; solvent-A=90:10/water:methanol+0.2% phosphoric acid, B=10:90/water:methanol+0.2% phosphoric acid; gradient-linear, 0% B to 100% B over 4 min and hold at 100% B for 1 min.

[0241] Method 2: column-YMC (ODS) S-5, 4.6 mm×33 mm; flow-5.0 mL/min.; detection at 220 nm; solvent-A=10% methanol/water+0.2% phosphoric acid, B=90% methanol/water+0.2% phosphoric acid; gradient-linear, 0% B to 100% B over 2 min and 100% B for 1 min.

[0242] Method 3: column-YMC A-ODS S-5, 4.6 mm×50 mm; flow-4 mL/min.; detection at 220 nm; solvent-A=90:10 water:methanol, solvent B=10:90 water:methanol (both containing 0.1% trifluoroacetic acid); 0% B to 100% B (4 min linear gradient) and 100% B for 1 min.

[0243] Method 4: column-YMC (ODS-A) S-5, 4.6 mm×33 mm; flow-5 mL/min.; detection at 220 nm; solvent-A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; gradient-linear, 0% B to 100% B over 2 min and 100% B for 1 min.

[0244] Method 5: column-YMC (S3 ODS column) 3 mm×50 mm; detection at 220 nm; flow-5 mL/min; solvent-A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; linear gradient, 0% B to 100% B over 2 min and 100% B for 1 min.

[0245] Method 6: column-Phenomenex (5 micron ODS column) 4.6 mm×30 mm; detection at 220 nm; flow-5 mL/min.; solvent-A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; linear gradient, 0% B to 100% B over 2 min and 100% B for 1 min.

[0246] Method 7: column-Shimadzu VP-ODS, 4.6 mm×50 mm; flow-4 mL/min.; detection at 220 nm; solvent-A=10% methanol/water+0.1% TFA, B=90% methanol/water+0.1% TFA; linear gradient, 0% B to 100% B over 4 min and 100% B for 2 min.

[0247] Method 8: Luna (5 micron ODS column) 2×30 mm; flow-1 ml/min; detection at 220 nm; solvent-A=10 mM ammonium acetate in 98% water/acetonitrile; solvent B=10 mM ammonium acetate in 90% MeCN/water; 3 min linear gradient 0%-100% B and 0.4 min hold at 100% B.

[0248] Method 9: column-Waters Xterra, 4.6 mm×50 mm; flow-5.0 mL/min.; detection at 220 nm; solvent-A=10% methanol/water+0.2% phosphoric acid, B=90% methanol/water+0.2% phosphoric acid; gradient-linear, 0% B to 100% B over 2 min.

[0249] Method 10: column-YMC S5 C18 ODS 4.6×50 mm; flow-2.5 mL/min.; detection at 220 nm; solvent-A=90:10/water:methanol+0.2% phosphoric acid, B=10:90/water:methanol+0.2% phosphoric acid; gradient-linear, 40% B to 60% B over 10 min.

[0250] Intermediates used in the preparation of the example compounds are provided in Table 1, followed by a description of relevant procedures. The example compounds are provided in Table 2 followed by a description of relevant procedures.

TABLE 1
#	Structure	Characterization	Method
INT1	26		Title compound of Example INT1
INT2	27		Title compound of Example INT2
INT3	28	HPLC (Method 2) tR = 2.0 min	Title compound of Example INT3
INT4	29	HPLC (Method 2) tR = 2.0 min	Title compound of Example INT4
INT5	30		Title compound of Example INT5
INT6	31	HPLC (Method 2) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 430/432 (M + 1)	Title compound of Example INT6
INT7	32		Title compound of Example INT7
INT8	33	HPLC (Method 2) tR = 0.12 min	Title compound of Example INT8
INT9	34		Title compound of Example INT9
INT10	35	LCMS (method 4) tR = 1.6 min (ESI, pos. ion spectrum) m/z 441/443	Prepared using the methods described in Example INT3
INT11	36	LCMS (method 4) (ESI, pos. ion spectrum) m/z 379/381 (M + 1)	Prepared using the methods described in Example INT3
INT12	37	LCMS (method 4) (ESI, pos. ion spectrum) m/z 424/426 (M + 1)	Prepared using the methods described in Exampl INT3 using INT28
INT13	38	LCMS (method 3) (ESI, pos. ion spectrum) m/z 404/406 (M + 1)	Prepared using the methods described in Example INT3
INT14	39	LCMS (method 3) (ESI, pos. ion spectrum) m/z 404/406 (M + 1)	Prepared using the methods described in Example INT3
INT15	40	LCMS (method 3) (ESI, pos. ion spectrum) m/z 397/399 (M + 1)	Prepared using the methods described in Example INT3
INT16	41	LCMS (method 3) (ESI, pos. ion spectrum) m/z 403/405 (M + 1)	Prepared using the methods described in Example INT3
INT17	42	LCMS (method 3) (ESI, pos. ion spectrum) m/z 403/405 (M + 1)	Prepared using the methods described in Example INT3
INT18	43	LCMS (method 3) (ESI, pos. ion spectrum) m/z 435/437 (M + 1)	Prepared using the methods described in Example INT3
INT19	44	LCMS (method 3) (ESI, pos. ion spectrum) m/z 404/406 (M + 1)	Prepared using the methods described in Example INT3
INT20	45	LCMS (method 3) (ESI, pos. ion spectrum) m/z 516/518 (M + 1)	Title compound of Example INT20
INT21	46	LCMS (method 4) (ESI, pos. ion spectrum) m/z 485/487 (M + 1)	Prepared using the methods described in Example INT20 using INT14
INT22	47	LCMS (method 3) (ESI, pos. ion spectrum) m/z 460/462 (M + 1)	Prepared using the methods described in Example INT20 using INT11
INT23	48	LCMS (method 3) (ESI, pos. ion spectrum) m/z 484/486 (M + 1)	Prepared using the methods described in Example INT20 using INT17
INT24	49		Title compound of Example INT24
INT25	50		Title compound of Example INT25
INT26	51		Title compound of Example INT26
INT27	52		Title compound of Example INT27
INT28	53		Prepared using the methods described in Example INT27
INT29	54		Title compound of Example INT29
INT30	55		Prepared using the methods described in Example INT29
INT31	56		Title compound of Example INT31
INT32	57		Prepared using the method described in Example INT5
INT33	58		Prepared using the method described in Example INT5
INT34	59		Prepared using the method described in Example INT5
INT35	60		Prepared using the method described in Example INT5
INT36	61		Prepared using the method described in Example INT5
INT37	62		Prepared using the method described in Example INT5
INT38	63		Prepared using the method described in Example INT5
INT39	64		Prepared using the method described in Example INT5
INT40	65		Prepared using the method described in Example INT5
INT41	66		Prepared using the method described in Example INT5
INT42	67		Prepared using the method described in Example INT5
INT43	68		Prepared using the method described in Example INT7 parts C-D from INT60
INT44	69		Prepared using the method described in Example INT3
INT45	70		prepared using methods described in the literature
INT46	71		prepared using methods described in the literature
INT47	72		prepared using methods described in the literature
INT48	73		prepared using methods described in the literature
INT49	74		Prepared using methods described in: Tetrahedron: Asymmetry 1900, 1(12), 877.
INT50	75		Prepared using methods described in: Tetrahedron: Asymmetry 1900, 1(12), 877.
INT51	76		Prepared using methods described in: Tetrahedron: Asymmetry 1900, 1(12), 877.
INT52	77		Prepared using methods described in: Tetrahedron: Asymmetry 1900, 1(12), 877.
INT53	78		Prepared using methods described in: Tetrahedron: Asymmetry 1900, 1(12), 877.
INT54	79		title compound of Example INT54
INT55	80		title compound of Example INT55
INT56	81	HPLC (method 1) tR = 2.6 min LRMS (ESI, pos. ion spectrum) m/z 355 (M + H)	prepared using the method described in Example INT8 using INT55
INT57	82	HPLC (method 1) tR = 2.4 min LRMS (ESI, pos. ion spectrum) m/z 321 (M + H)	prepared using the method described in Example INT3 part B using INT56
INT58	83	HPLC (method 1) tR = 0.2 min LRMS (ESI, pos. ion spectrum) m/z 323 (M + H)	prepared using the method described in Example INT7 parts C and D using INT57
INT59	84		compound of Example INT7 part A
INT60	85		compound of Example INT7 part B
INT61	86		compound of Example INT7 part C
INT62	87		Title compound of Example INT62
INT63	88		Title compound of Example INT63
INT64	89		Title compound of Example INT64
INT65	90		Title compound of Example INT65
INT66	91		Title compound of Example INT66
INT67	92		Title compound of Example INT67
INT68	93		Prepared using the method described in Example INT5

EXAMPLE INT1

[0251] t-Butyl lithium (1.7 M in pentane, 0.78 mL, 1.3 mmol) was added over 5 min to a solution of 5-bromo-2-chlorobenzo[b]thiophene (0.17 g, 0.68 mmol) in ether (6 mL) stirring under nitrogen at −100° C. After stirring at −100° C. for 30 min, sulfur dioxide was bubbled into the reaction for about 3 min whereupon a white precipitate formed. After stirring at −100° C. for an additional 30 min, N-chlorosuccinimide (0.11 g, 0.84 mmol) in THF (1 ml) was added. The reaction was allowed to very slowly warm to ambient temperature. After stirring overnight the reaction was transferred to a separatory funnel with ether and water. Extraction with ether (2×15 ml), washing the combined organic layers with brine and drying over magnesium sulfate afforded 0.20 g of crude product. Purification over silica gel afforded 0.10 g (55%) of 2-chlorobenzo[b]thiophene-5-sulfonyl chloride. 1H-NMR (CDCl3) δ 8.34 (1H, s), 8.05 (1H; d, J=7.5 Hz), 7.93 (1H, d, J=7.5 Hz), and 7.38 (1H, s).

EXAMPLE INT2

[0252] Part A: A suspension of 3-bromothiophenol (15.2 g, 81 mmol), bromoacetaldehyde dimethylacetal (9.5 mL, 81 mmol) and potassium carbonate (12.2 g, 88 mmol) in acetone (90 mL) was stirred at ambient temperature overnight. The solid was filtered and rinsed with ether. Evaporation of the filtrate afforded 23 g of 1-bromo-3-((2,2-dimethoxyethyl)thio)benzene which was carried forward without further purification.

[0253] Part B: A solution of 1-bromo-3-((2,2-dimethoxyethyl)thio)benzene (23 g, 81 mmol theory) in chlorobenzene (100 mL) was slowly added over 1 h to polyphosphoric acid (62 g) in chlorobenzene (500 mL) stirring vigorously at 140° C. under nitrogen. After refluxing for 4.5 h, the reaction was slowly poured into 1.5 L of ice water. Extraction with methylene chloride (2×700 mL) and washing the combined organic layers with water and saturated sodium bicarbonate solution and drying over magnesium sulfate afforded 17 g of crude product after evaporation of the solvent. Distillation (20 mm Hg) afforded 9.7 g (156-165° C., 55%) of a 50/50 mixture of 4-bromobenzo[b]thiophene and 6-bromobenzo[b]thiophene.

[0254] Part C: A portion of the part B product (2.1 g, 10 mmol) was slowly added over 20 min to a solution of LDA (2 M in THF/hexane, 5.5 mL, 11 mmol) stirring under argon at −78° C. After stirring at −78° C. for 40 min, this solution was transferred over 10 min via cannula to a solution of carbon tetrachloride (3.0 mL, 38 mmol) in THF (40 mL) stirring at −78° C. After stirring at −78° C. for 1.5 h, the reaction was quenched with sat. ammonium chloride and allowed to warm to room temperature and, transferred to a separatory funnel with methylene chloride/water. Extraction with methylene chloride (2×100 mL) and drying the combined organic layers over magnesium sulfate afforded 3.7 g of crude product after evaporation of the solvent. Purification over silica gel gave 2.1 g (87%) of a mixture of 4-bromo-2-chlorobenzo[b]thiophene and 6-bromo-2-chlorobenzo[b]thiophene.

[0255] Part D: t-Butyl lithium (1.7 M in pentane, 11 mL, 19 mmol) was slowly added over 30 min, to a solution of the part C product (2.1 g, 8.7 mmol) in ether (20 mL) stirring under nitrogen at −78° C. After stirring at −78° C. for 1 h, sulfur dioxide (150 drops, ˜55 mmol) was added dropwise to the reaction by condensing the vapor onto a −78° C. cold finger and allowing it to drip into the reaction from the tip of the cold finger. The cold bath was removed after 1 h. After stirring an additional 2 h at ambient temperature, the reaction was evaporated in vacuo. Hexanes (22 mL) was added to the resultant residue and the reaction was cooled to 0° C. before adding sulfuryl chloride (0.83 mL, 10 mmol) over 10 min. The reaction was stirred at 0° C. for 30 min and then at ambient temperature overnight. The reaction was then purified over silica gel to afford 0.24 g (10%) of 2-chlorobenzo[b]thiophene-6-sulfonyl chloride: 1H-NMR (CDCl3) δ 8.42 (1H, s), 7.98 (1H, d, J=7.6 Hz), 7.86 (1H, d, J=7.6 Hz), and 7.34 (1H, s).

EXAMPLE INT3

[0256] Preparation of [(3S)-3-(2-Chlorobenzo[b]thiophene-5-sulfonylamino)-2-oxo-piperidin-1-yl]acetic acid. Part A: Using the method described in Example 1 and using INT1 and methyl ((3S)-3-amino-2-oxopiperidin-1-yl)acetate, 0.18 g (73%) of methyl [(3S)-3-(2-chlorobenzo[b]thiophene-5-sulfonylamino)-2-oxo-piperidin-1-yl]acetate was prepared: 1H-NMR (CDCl3) δ 8.13 (1H, s), 7.80 (2H, s), 7.18 (1H, s), 5.98 (1H, broad s), 4.02 (1H, d, J=15.3 Hz), 3.82 (1H, d, J=15.3 Hz), 3.61 (3H, s), 3.35 (1H, m), 3.32 (1H, m), 3.20 (1H, m), 1.90 (4H, m).

[0257] Part B: The compound of part A (0.44 mmol) was dissolved in THF (2.2 mL) and stirred at 0° C. Lithium hydroxide (2.0 N, 2.2 mL, 4.4 mmol) was then added. After stirring at 0° C. for 1 h, the reaction was quenched with 6 N HCl (0.7 mL) and transferred to a separatory funnel. Extraction with ethyl acetate (3×30 mL), washing the combined organic layers with brine, and drying over magnesium sulfate afforded 0.17 g (98%) of the title compound: HPLC (method 2) tR=2.0 min.

EXAMPLE INT4

[0258] Preparation of [(3S)-3-(2-Chlorobenzo[b]thiophene-6-sulfonylamino)-2-oxo-piperidin=1-yl]acetic acid. Part A: Using the method described in Example 1 and using INT2 and methyl ((3S)-3-amino-2-oxopiperidin-1-yl)acetate, 0.26 g (100%) of methyl [(3S)-3-(2-chlorobenzo[b]thiophene-6-sulfonylamino)-2-oxo-piperidin-1-yl]acetate was prepared: 1H-NMR (CDCl3) δ 8.27 (1H, s), 7.82 (1H, d, J=8.4 Hz), 7.74 (1H, d, J=8.4 Hz), 7.23 (1H, s), 6.20 (1H, broad s), 4.11 (1H, d, J=17.3 Hz), 3.90 (1H, d, J=17.3 Hz), 3.65 (3H, s), 3.60 (1H, m), 3.38 (1H, m), 3.28 (1H, m), 1.85 (4H, m).

[0259] Part B: Using the method of Example INT3 Part B, the compound of Part A (0.60 mmol) was converted to 0.24 g (100%) of the title compound: HPLC (method 2) tR=2.0 min.

EXAMPLE INT5

[0260] Part A. Morpholine (7.1 g, 7.1 mL, 82 mmol) was added to a stirring solution of N-BOC-(S)-prolinal (3.3 g, 17 mmol) in methylene chloride (83 mL) followed by zinc chloride (0.5 M in THF, 100 mL, 50 mmol). After stirring at ambient temperature for 5 h, borane-pyridine (ca. 8 M, 2 mL, 16 mmol) was added. After stirring at ambient temperature overnight, the reaction was evaporated in vacuo. Methanol was added to the residue and the solids were filtered. Evaporation of the filtrate afforded 13 g of crude product. Purification over silica gel afforded 3.9 g (87%) of 1,1-dimethylethyl (S)-2-(4-morpholinylmethyl)-1-pyrrolidinecarboxylate: 1H-NMR (CDCl3) δ 3.90 (1H, m), 3.69 (4H, m), 3.34 (2H, m), 2.57 (2H, m), 3.40 (2H, m), 2.18 (1H, m), 1.90 (4H, m), 1.74 (1H, m), 1.47 (9H, s).

[0261] Part B: A portion of Part A amine (14 mmol) was stirred in methylene chloride (44 mL) and TFA (22 mL). After stirring at ambient temperature for 2.5 h, the reaction was evaporated in vacuo. The residue was sequentially coevaporated twice with methylene chloride and once with methanol. The residue was loaded onto a column of AG 50W-X2 resin (160 g, prewashed with 480 mL of MeOH, 480 mL water, and 480 mL of 1/1 MeOH/water). The column was washed with MeOH (480 mL) and was then eluted with 2N ammonia in methanol to afford 2.0 g (82%) (S)-4-(2-pyrrolidinylmethyl)morpholine, the title compound: 1H-NMR (CDCl3) δ 3.70 (4H, m), 3.46 (1H, s), 3.27 (1H, m), 2.96 (1H, m), 2.86 (1H, m), 2.53 (2H, m), 2.42 (2H, m), 2.30 (2H, m), 1.86 (1H, m), 1.74 (2H, m), 1.35 (1H, m).

EXAMPLE INT6

[0262] Preparation of ((3S)-3-[6-(5-Chlorothiophen-2-yl)pyridine-3-sulfonylamino]-2-oxopiperidin-1-yl)-acetic acid. Part A: Using the method described in Example 1 and using 2-chloro-5-pyridinesulfonyl chloride and methyl ((3S)-3-amino-2-oxopiperidin-1-yl)acetate, 0.16 g (83%) methyl [(3S)-3-(6-chloropyridine-3-sulfonylamino)-2-oxopiperidin-1-yl]acetate was prepared: HPLC (method 2) tR=1.5 min; LCMS (ESI, pos. ion specturm) m/z 362/364 (M+1).

[0263] Part B: Using the method described in Example 421, Part A compound was converted to 89 mg (45%) of methyl [(3S)-3-[6-(5-chlorothiophen-2-yl)pyridine-3-sulfonylamino]-2-oxopiperidin-1-yl]acetate: HPLC (method 2) tR=2.10 min; LCMS (ESI, pos. ion specturm) m/z 444/446 (M+1).

[0264] Part C: Using the method of Example INT3 Part B, Part B compound (0.20 mmol) was converted to 86 mg (100%) of the title compound: HPLC (method 2) tR=2.0 min; LCMS (ESI, pos. ion specturm) m/z 430/432 (M+1).

EXAMPLE INT7

[0265] Preparation of (3R)-3-amino-1-[((2S)-2-(4-morpholinylmethyl)-1-pyrrolidinyl)-2-oxoethyl]piperidin-2-one. Part A: INT59 was prepared from D-ornithine using the procedures described in Example INT54 and Example INT55.

[0266] Part B. Using the procedures described in Example INT3 Part B and using Part A compound, INT60 was prepared

[0267] Part C. Using the procedure described in Example 1 and using part B compound and INT5, INT61 was prepared: HPLC (method 2) tR=1.4 min.

[0268] Part D. Part C compound (0.47 g, 1.0 mmol) was dissolved in methanol (14 mL) and 10% palladium on carbon (100 mg) was added. After stirring under hydrogen (50 psi) for 2 h, the reaction was filtered through CELITE. The pad was rinsed with methanol and the combined filtrates were concentrated to afford 0.33 g (100%) of (3R)-3-amino-1-[2-((2S)-2-(4-morpholinylmethyl)-1-pyrrolidinyl)-2-oxoethyl]piperidin-2-one after evaporation of the solvent: 1H-NMR (CDCl3) δ 4.26 (1H, broad s), 4.07 (1H, d, J=13 Hz), 4.01 (1H, d, J=13 Hz), 3.69 (4H, m), 3.44 (2H, m), 2.60 (2H, m), 2.46 (2H, m), 2.27-1.92 (12H, m), 1.7 (2H, m).

EXAMPLE INT8

[0269] Preparation of (3R)-3-methylamino-1-[((2S)-2-(4-morpholinylmethyl)-1-pyrrolidinyl)-2-oxoethyl]piperidin-2-one (INT8). Part A: Cesium carbonate (1.9 g, 6.0 mmol) and tetrabutylammonium iodide (2.2 g, 6.0 mmol) were added to a stirring solution of INT59 (0.63 g, 2.0 mmol) in DMF (23 mL). After stirring at ambient temperature for 30 min, methyl iodide (filtered through basic alumina, 0.86 g, 0.38 mL, 6.0 mmol) was added. After stirring at ambient temperature for 3 d, the reaction was transferred to a separatory funnel with ethyl acetate/water. Extraction with ethyl acetate (3×140 mL), washing the combined organic layers with water (2×140 mL) and brine (140 mL), and drying over magnesium sulfate afforded 1.1 g of crude product. Purification over silica gel gave 0.33 g (50%) of methyl ((3R)-N-benzyloxycarbonyl-N-methylamino-2-oxopiperidin-1-yl)acetate. HPLC (method 2) tR=1.8 min; LCMS (ESI, pos. ion specturm) m/z 335 (M+1); Chiral HPLC (Chiralcel OD; 4.6×250 mm; 2 mL/min; detection at 220 nm; isocratic, 15% isopropyl alcohol in hexane) tR=11.0 min.

[0270] Part B: Part A compound was saponified using the procdure described in Example INT3 Part B using 2.0 equivalents of lithium hydroxide to afford ((3R)-N-benzyloxycarbonylmethylamino-2-oxopiperidin-1-yl)acetic acid.

[0271] Part C: Using the method described in Example 1 and using Part B compound and INT5 provided phenylmethyl R-methyl[1-[2-((2S)-2-(4-morpholinylmethyl)-1-pyrrolidinyl)-2-oxoethyl]-2-oxopiperidin-3-yl]carbamate. HPLC (method 2) tR=1.6 min; LCMS (ESI, pos. ion specturm) m/z 474 (M+1); Chiral HPLC (Chiralcel AD; 4.6×250 mm; 2 mL/min; detection at 220 nm; isocratic,25% isopropyl alcohol in hexane) tR=6.2 min.

[0272] Part D: Hydrogenation of Part C amine using the method described in Example INT7 Part D afforded the title compound: HPLC (method 2) tR=0.12 min.

[0273] 5

EXAMPLE INT9

[0274] Part A: To a suspension of (3S)-2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-piperidineacetic acid (955 mg, 3.12 mmol) in acetonitrile (10 mL) was added WSC (899 mg, 4.68 mmol) and 1-hydroxy-7-azabenzotriazole (424 mg, 3.12 mmol) producing a homogeneous solution. After 10 minutes, 1-[(2S)-2-pyrrolidinylmethyl]pyrrolidine (721 mg, 4.68 mmol) was added. After an additional 20 minutes, the reaction was quenched with water (10 mL). This mixture was then added to a 10-g C-18 cartridge (Varian part no. 1425-6031). The cartridge was washed with water (100 mL). The product was then eluted with 60% acetonitrile in water (100 mL). Concentration of this solution provided phenylmethyl S-[2-Oxo-1-[2-oxo-2-((2S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)ethyl]piperidin-3-yl]carbamate (663 mg, 1.50 mmol, 48%) as a yellow foam: LCMS (method 3) m/z 443 (M+H), tR=2.0 min.

[0275] Part B: To a solution of Part A compound (643 mg, 1.45 mmol) in methanol (20 mL) was added 10% palladium on carbon (200 mg). The mixture was stirred under an atmosphere of hydrogen (50 psi) for 17 hours. The reaction mixture was then filtered though CELITE (20 mm i.d.×10 mm). The pad was rinsed with methanol (20 mL). Concentration of the combined filtrates provided the title compound (430 mg, 1.40 mmol, 96%) as a light yellow foam.

EXAMPLE INT20

[0276] Part A: Using INT18 and (S)-2-hydroxymethylpyrrolidine and using the methods described in Example 130, N-([(S)-1-[2-[(S)-(2-hydroxymethyl)-1-pyrrolidinyl]-2-oxoethyl]-2-oxo-piperidin-3-yl]) 5′-Chloro-[2,2′]bithienyl-5-sulfonamide was prepared: LCMS (method 4, ESI, pos. ion. spectrum), m/z 518/520).

[0277] Part B: The compound of part A (10.8 g, 20.9 mmol) was dissolved in 200 mL of “wet” methylene chloride. “Wet” methylene chloride is the lower layer produced by shaking equal amounts of methylene chloride and water in a separatory funnel. To this solution was added Dess-Martin periodinane (17.7 g, 41.8 mmol). After 80 minutes, the reaction was quenched with ether (100 mL) and 100 mL of a solution of 48 g of sodium thiosulfate in 80% saturated aqueous sodium bicarbonate/20% water. Some foaming occured, however after 10 minutes the layers separated. The upper organic layer was subsequently washed with saturated aqueous sodium bicarbonate (75 mL) followed by water (50 mL). The combined aqueous washes were backwashed with ether (100 mL) and the combined ether layers were dried over sodium sulfate. The filtrate was concentrated and purified by silica gel chromatography using 2% methanol in chloroform to provide N-[S-1-[2-[(S)-(2-formyl)-1-pyrrolidinyl]-2-oxoethyl]-2-oxo-piperidin-3-yl] 5′-Chloro-[2,2′]bithienyl-5-sulfonamide as a yellow foam (10.5 g): LCMS (method 3) (ESI, pos. ion. spectrum), m/z 516/518).

EXAMPLE INT24

[0278] Part A, Preparation of 5-Chloro-[2,2′]bithiazole: To a solution of 2,2′-bithiazole (340 mg, 2.0 mmol) in THF (4 mL) at −78° C. was added n-butyllithium (0.85 mL, 2.5 M in hexanes). After 5 min, CCl4 (310 mg, 2.0 mmol) was added and the mixture was brought to 0° C. After one hour, the reaction was quenched with saturated aqueous ammonium chloride (5 mL) and extracted with ether (20 mL+10 mL). The combined organic extracts were dried over magnesium sulfate and concentrated to yield 270 mg of crude material. This material was purified using preparative silica TLC (chloroform) to produce 5-Chloro-[2,2′]bithiazole (76 mg, 0.37 mmol, 19%).

[0279] Part B, Preparation of 5′-Chloro-[2,2′]bithiazole-5-sulfonyl chloride: To 5-Chloro-[2,2′]bithiazole (76 mg, 0.37 mmol) in 2 mL of THF at −78° C. was added 1.6 M n-butyl lithium in hexane solution (0.25 mL, 0.41 mmol) dropwise. The reaction mixture was stirred at −78° C. for another 30 min. Sulfur dioxide gas was added at the surface of the reaction mixture for 30 min. The dry-ice cooling bath was removed and the reaction mixture was warmed to room temperature over 1 h. The reaction mixture was concentrated and 2 mL of hexanes was added. The reaction was cooled to 0° C. Sulfuryl chloride (56 mg, 0.41 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was loaded on a silica gel pad and eluted with 100 mL of a 1:1 mixture of hexanes and ethyl acetate to give the title compound as a yellow solid (110 mg, 98%) after concentration: 1H-NMR (CDCl3) δ 7.83 (1H, s), 8.44 (1H, s).

EXAMPLE INT25

[0280] INT25 was prepared from 5-chlorobenzothiazole using the method described in the following reference: Vedejs, E., Kongkittingam, C. J. Org. Chem. 2000, 65, 2309. The crude product was used without purification.

EXAMPLE INT26

[0281] INT26 was prepared from 6-chlorobenzothiazole using the method described in the following reference: Vedejs, E., Kongkittingam, C. J. Org. Chem. 2000, 65, 2309. The crude product was used without purification.

EXAMPLE INT27

[0282] A. 2-(5-Methyl-thiophen-2-yl)-ethenesulfonic acid, ethyl ester.

[0283] n-Butyl lithium (1.6 mL of a 2.5 M solution in hexanes, 4.0 mmol) was added dropwise to a solution of ethyl diethylphosphorylmethanesulfonate (1.0 g, 3.8 mmol), prepared as described in Tetrahedron, 1987, 43(21), 5125, at −78° C. in THF (15 mL). The mixture was stirred for 20 min. then 5-methyl-2-thiophenecarboxaldehyde (460 mg, 4.2 mmol) was slowly added. The mixture was stirred at −78° C. for 1 h. then allowed to warm to room temperature overnight. The bulk of the solvents were evaporated and the residue was treated with water (2 mL) and extracted with CH2CL2. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography eluting with CH2CL2 to give the title compound.

[0284] B. 2-(5-Methyl-thiophen-2-yl)-ethenesulfonic acid, tetra-n-butylammonium salt.

[0285] 2(5-Methyl-thiophen-2-yl)-ethenesulfonic acid, ethyl ester (0.92 g. 3.2 mmol) in acetone (16 mL) was treated with tetrabutylammonium iodide (1.3 g, 3.5 mmol) and heated to reflux for 19 h. The mixture was concentrated to dryness then diluted with CH2CL2 and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound which was taken on to the next step without further purification.

[0286] C. 2-(5-Methyl-thiophen-2-yl)-ethenesulfonyl chloride.

[0287] Sulfuryl chloride (0.61 mL, 7.6 mmol) was added to a solution of triphenylphosphine (1.8 g, 6.9 mmol) in CH2CL2 (8.6 mL) at 0° C. The ice bath was removed and part B compound (1.6 g, 3.4 mmol) in CH2CL2(17 mL) was added to the reaction mixture via cannula. The resulting solution was stirred for 1.5 h then hexane/ether (1:1 v/v, 200 mL) was added until the solution was no longer cloudy and two layers formed. The solution was decanted and the lower oily layer was discarded. The solution was concentrated to dryness and the product was purified by column chromatograph eluting with CH2CL2 to give the title compound; LRMS (ESI, pos. ion spectrum 223/225 (M+H).

EXAMPLE INT29

[0288] Sulfuryl chloride (2.87 mL, 35.7 mmol) was added dropwise to DMF (3.8 mL) at 0° C. The resulting mixture was stirred at room temperature for 50 min. To the mixture was added 3-bromostyrene (2.7 mL, 21 mmol). The mixture was then heated to 90° C. for 4 h, cooled to room temperature and poured into 50 mL of ice/water. The precipitate was collected by filtration, washed with water (2×), and dried by lyophilization to afford 3.54 g (60%) of the title compound: 1H-NMR (CD3OD) δ 7.55-7.65 (3H, m), 7.38-7.44 (1H, d, m), 7.27 (1H, t, 7.9), 7.16 (1H, d, J=11.3 Hz).

EXAMPLE INT31

[0289] To a solution of 1,1-dimethylethyl (S)-2-thiomorpholin-4-ylmethyl-pyrrolidine-1-carboxylate (90 mg, 0.32 mmol) in dichloromethane (1.5 mL) was added 3-chloroperoxybenzoic acid (114 mg, 0.660 mmol). The mixture was stirred at room temperature until monitoring indicated that the oxidation was complete. The reaction was then diluted with dichloromethane and washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified over silica gel to afford 61 mg (61%) of the title compound.

EXAMPLE INT54

[0290] A suspension of L-Ornithine hydrochloride (102 g, 600 mmol) in MeOH (600 mL) was cooled to 0° C. Thionyl chloride (54.7 mL, 750 mmol) was added dropwise over 30 min maintaining an internal reaction temperature of <10° C. The cooling bath was removed and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to afford a white solid (131 g). The solid was dissolved in water (600 mL) and 4N NaOH (160 mL, 640 mmol) was added to bring the pH to 8-9. After 4 h the reaction mixture was cooled to 0° C. and benzyl chloroformate (102 mL, 717 mmol) was added over 30 min. After the addition, the pH was maintained at ca. 8-9 by addition of 4N NaOH (160 mL, 640 mmol) until the pH stabilized. The reaction mixture was stirred an additional 30 min during which time the product began to precipitate as a sticky solid. Diethyl ether (500 mL) was added, and the resulting mixture was vigorously stirred for 30 min. The solid was filtered, washed with water and diethyl ether, then dried in vacuo. The title compound was obtained as a white solid (61.6 g, 41%): HPLC (method 1) tR=2.7 min, >99% pure; (HPLC; Chiralcel AD, 4.6 mm×250 mm; 1 mL/min; 220 nm, 40% EtOH/hexanes, tR(S)=9.9 min, tR(R)=13.2 min)>99% ee; LRMS (ESI, pos. ion spectrum) m/z 249 (M+H).

EXAMPLE INT55

[0291] The title compound of Example INT54 (59.6 g, 240 mmol) was dissolved in anhydrous THF (672 mL) then cooled to −78° C. A solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 288 mL, 288 mmol) was added dropwise over 1 h. The reaction was stirred an additional 30 min, then methyl bromoacetate (27.3 mL, 288 mmol) was added dropwise over 15 min. The reaction mixture was stirred at −78° C. for 1 h before being quenched with aqueous saturated ammonium chloride solution (20 mL). The reaction mixture was warmed to room temperature then partitioned between aqueous 50% saturated ammonium chloride solution (400 mL) and ethyl acetate (200 mL). The organic phase was collected, and the aqueous phase extracted with ethyl acetate (200 mL). The organic layers were combined, dried (MgSO4), and concentrated in vacuo to afford a semi-solid (78.9 g). This residue was triturated with ethyl acetate/hexanes (1:1, 100 mL) to afford a tan solid (65.4 g). This solid was triturated with ME (3×150 mL) to afford the title compound as an off-white solid (51.3 g, 67%): HPLC (method 1) tR=2.9 min, 96% pure; HPLC (Chiralcel OD, 4.6 mm×250 mm; 2 mL/min; 220 nm, 20% isopropanol/hexanes, tr(S)=14.7 min)>99% ee; LRMS (ESI, pos. ion spectrum) m/z 321 (M+H).

EXAMPLE INT62

[0292] Part A. Phosphorus trichloride (0.08 mL, 0.4 mmol) was added to a solution of part B compound of Example INT65 (58 mg, 0.19 mmol) in chloroform (1 mL). The reaction mixture was heated to 75° C. for 1 h and the solvents removed yielding benzyl (S)-2-pyrimidin-2-yl-pyrrolidine-1-carboxylate as an orange oil (55 mg, crude quantative yield): HPLC (method 1) tR=2.54 min, Purity 97%; LCMS (method 4) tR=1.32 min, m/z 284 (M+H).

[0293] (S)-2-Pyrrolidin-2-yl-pyrimidine. Part B. Using the method described in Example INT66 part C, the bis HBr salt of (S)-2-pyrrolidin-2-ylpyrimidine isolated as a yellow solid (52 mg, 89% yield): 1H-NMR H (d4-MeOH) δ 2.2 (3H, m), 2.8 (1H, m), 3.8 (2H, m), 5.10 (1H, t, J=7.2 Hz), 7.55 (1H, t, J=4.0 Hz), 8.90 (2H, d, J=4.0 Hz).

EXAMPLE INT63

[0294] Part A. Lawesson's reagent (90 mg, 0.22 mmol) was added to a stirred slurry of benzyl (S)-2-carbamoyl-pyrrolidine-1-carboxylate (100 mg, 0.40 mmol) in toluene (3 mL) at ambient temperature. The reaction mixture was heated to 100° C. for 3 h then the solvents were removed. The residue was purified by flash silica gel chromatography yielding benzyl (S)-2-thiocarbamoylpyrrolidine-1-carboxylate as white solid (108 mg, crude quantative yield): HPLC (method 1) tR=2.55 min, Purity 100%; LCMS (method 4) tR=1.34 min, m/z 287 (M+H).

[0295] Part B. to a solution of part A compound (108 mg, 0.41 mmol) in dry ethanol (1 mL) was added 3-bromo-2-butanone (68 mg, 0.45 mmol). The resulting solution was heated to reflux for 4 h then passed through a short silica gel pad then concentrated yielding benzyl (S)-2-(4,5-Dimethyl-thiazol-2-yl)-pyrrolidine-1-carboxylate as a colorless oil (130 mg, crude quantative yield): HPLC (method 1) tR=3.19 min, Purity 100%; LCMS (method 4) tR=1.73 min, m/z 317 (M+H).

[0296] (S)-4,5-Dimethyl-2-pyrrolidin-2-ylthiazole. Part C. Using the method described in Example INT66 part C, the HBr salt of (S)-4,5-dimethyl-2-pyrrolidin-2-ylthiazole was isolated as a pale brown precipitate (85 mg, 79%): 1H-NMR (d4-MeOH) δ 2.3 (3H, m), 2.39 (3H, s), 2.44 (3H, s), 2.65 (1H, m), 3.49 (2H, m), 5.19 (1H, brs).

EXAMPLE INT64

[0297] Part A. Chloroacetone (36 mg, 0.37 mmol) was added to a solution of benzyl (S)-2-thiocarbamoyl-pyrrolidine-1-carboxylate (90 mg, 0.34 mmol) in dry chloroform (2 mL). The resulting solution was heated to reflux for 24 h then purified by preparative HPLC yielding benzyl (S)-2-(4-methylthiazol-2-yl)-pyrrolidine-1-carboxylate as a colorless oil (55 mg, 54% yield): HPLC (method 1) tR=3.11 min, Purity 100%; LCMS (method 4) tR=1.57 min, m/z 303 (M+H).

[0298] (S)-4-Methyl-2-pyrrolidin-2-ylthiazole. Part B. Using the method described in Example INT66 part C, the HBr salt of (S)-4-methyl-2-pyrrolidin-2-ylthiazole isolated as an orange oil (45 mg, 100%): 1H-NMR(d4-MeOH) δ 2.2 (2H, m), 2.6 (1H, m), 3.36 (3H, s), 3.5 (2H, m), 5.20 (1H, t, J=7.2 Hz) 7.44 (1H, s).

EXAMPLE INT65

[0299] Part A. Benzyl (S)-2-cyanopyrrolidine-1-carboxylate (500 mg, 2.17 mmol) was dissolved in aqueous ethanol (3 m-L) and water (1 mL). Hydroxylamine hydrochloride (152 mg, 2.17 mmol) and Na2CO3 (115 mg, 1.08 mmol) were added and the reaction mixture heated to 100° C. for 1 h. The ethanol was removed and the aqueous residue was extracted with dichloromethane (3×25 mL), dried over Na2SO4 decanted and concentrated yielding benzyl (S)-2-(N-hydroxycarbamimidoyl)pyrrolidine-1-carboxylate as a pale yellow gum (428 mg, 75% yield): HPLC (method 1) tR=1.40 min, Purity 76%; LCMS (method 4) tR=0.81 min, m/z 264 (M+H).

[0300] Part B. Trifluoroacetic acid (0.24 mL) and tetramethoxypropane (400 mg, 2.43 mmol) were added to a solution of part A compound (428 mg, 1.63 mmol) in 2-propanol (5 mL). The resulting solution was heated to reflux for 13 h then concentrated and purified by preparative HPLC yielding benzyl (S)-2-(1-oxypyrimidin-2-yl)pyrrolidine-1-carboxylate as colorless oil (105 mg, 28%): HPLC (method 1) tR=2.35 min, Purity 100%; LCMS (method 4) tR=1.21 min, m/z 300 (M+H).

[0301] (S)-2-Pyrrolidin-2-yl-pyrimidine 1-oxide. Part C. Using the method described in Example INT66 part C, the HBr salt of (S)-2-pyrrolidin-2-ylpyrimidine 1-oxide isolated as a yellow oil (32 mg, 88% yield): 1H-NMR (d4-MeOH) δ 2.4 (2H, m), 2.6 (1H, m), 2.9 (1H, m), 3.8 (2H, m), 5.20 (1H, t, J=7.2 Hz), 7.95 (1H, dd, J=4.4 and 6.4 Hz), 8.76 (1H, d, J=4.4 Hz), 8.96 (1H, dd, J=6.4 Hz.

EXAMPLE INT66

[0302] Part A: N,N-Dimethylformamide dimethyl acetal (5 mL) was added to benzyl (2S)-2-carbamoyl-pyrrolidine-1-carboxylate (1.05 g, 4.23 mmol) at ambient temperature. The resulting slurry was heated to 120° C. for 2 h then allowed to cool and poured into hexane (50 mL). The solvents were removed under reduced pressure yielding benzyl (2S)-2-(dimethylaminomethylenecarbamoyl)pyrrolidine-1-carboxylate as a colorless oil (1.35 g, crude quantative yield). HPLC (method 1) tR=1.70 min, Purity 100%; LCMS (method 4) tR=0.94 min, m/z 304 (M+1)

[0303] Part B. Part A compound (427 mg, 1.41 mmol) was dissolved in acetic acid (1.2 mL) and added to a solution of anhydrous hydrazine (52 mg, 1.6 mmol) in acetic acid (0.8 mL). The reaction mixture was heated to 90° C. for 1.5 h then poured into water (20 mL). The aqueous portion was extracted with chloroform (3×20 mL) and the combined organic portions washed with sat. NaHCO3 (20 mL), dried over Na2SO4, and concentrated to provide benzyl (2S)-2-(4H-[1,2,4]triazol-3-yl)pyrrolidine-1-carboxylate was obtained as a colorless oil (351 mg, 92% crude yield): HPLC (method 1) tR=2.76 min, Purity 100%; LCMS (method 4) tR=1.15 min, m/z 273 (M+H).

[0304] (S)-3-Pyrrolidin-2-yl-4H-[1,2,4]triazole. Part C. To a portion of part B compound (76 mg, 0.28 mmol) was added HBr in acetic acid (30%, 1.0 mL). After 1 h, ether (70 mL) was added and the product precipitated as a white solid. The precipitate was filtered then washed from the frit with methanol (ca. 10 mL) and concentrated under reduced pressure yielding the HBr salt of (S)-3-pyrrolidin-2-yl-4H-[1,2,4]triazole as a pale yellow oil (55 mg, 90% yield): 1H-NMR (d4-MeOH) δ 2.24 (2H, m), 2.35 (1H, m), 2.61 (1H, m), 3.55 (2H, m), 5.10 (1H, t, J=7.2 Hz) 9.46 (1H, s).

EXAMPLE INT67

[0305] Part A. Using the methods described in Example INT66 parts A and B, benzyl (2S)-2-(2-phenyl-2H-[1,2,4]triazol-3-yl)pyrrolidine-1-carboxylate was obtained from phenylhydrazine as a pale yellow oil after purification by preparative HPLC (250 mg, 51% yield): HPLC (method 1) tR=3.51 min, Purity 99%; LCMS (mehtod 4) tR=1.24 min, m/z 349 (M+H).

[0306] (S)-1-Phenyl-5-pyrrolidin-2-yl-1H-[1,2,4]triazole. Part B. Using the method described in Example INT66 part C, the HBr salt of (S)-1-phenyl-5-pyrrolidin-2-yl-1H-[1,2,4]triazole was isolated as a white powder: 210 mg, 100% yield; HPLC (method 1) tR=0.70 min, Purity 90%; LCMS (method 4) tR=0.57 min, m/z 214 (M+H).

TABLE 2
Ex #	Structure	characterization	method
1	94	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 416 (M + H)	title compound of Example 1
2	95	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 456/458 (M + H)	prepared using the method described in Example 1
3	96	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 456/458 (M + H)	prepared using the method described in Example 1
4	97	HPLC (method 1) tR = 1.9 min LCMS (ESI, pos. ion spectrum) m/z 372 (M + H)	prepared using the method described in Example 1
5	98	HPLC (method 1) tR = 2.5 min LCMS (ESI, pos. ion spectrum) m/z 456/458 (M + H)	prepared using the method described in Example 1
6	99	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 450/452 (M + H)	prepared using the method described in Example 1
7	100	HPLC (method 1) tR = 2.3 min LCMS (ESI, pos. ion spectrum) m/z 456/458 (M + H)	prepared using the method described in Example 1
8	101	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 470/472 (M + H)	prepared using the method described in Example 1
9	102	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 446 (M + H)	prepared using the method described in Example 1
10	103	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 450/452 (M + H)	prepared using the method described in Example 1
11	104	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 422 (M + H)	prepared using the method described in Example 1
12	105	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 436 (M + H)	prepared using the method described in Example 1
13	106	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 470/472 (M + H)	Title compound of Example 13
14	107	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 432/434 (M + H)	prepared using the method described in Example 1
15	108	HPLC (method 3) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	prepared using the method described in Example 130 using INT16
16	109	HPLC (method 3) tR = 3.9 min LCMS (ESI, pos. ion spectrum) m/z 655/657 (M + 1)	prepared using the method described in Example 130 using INT16
17	110	HPLC (method 3) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 474/476 (M + 1)	prepared using the method described in Example 130 using INT16
18	111	HPLC (method 3) tR = 3.5 min LCMS (ESI, pos. ion spectrum) m/z 520/522 (M + 1)	prepared using the method described in Example 130 using INT16
19	112	HPLC (method 3) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 470/472 (M + 1)	prepared using the method described in Example 130 using INT16
20	113	HPLC (method 3) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 499/501 (M + 1)	prepared using the method described in Example 130 using INT16
21	114	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 450/452 (M + 1)	Title compound of Example 21
22	115	HPLC (method 3) tR = 3.6 min LCMS (ESI, pos. ion spectrum) m/z 540/542 (M + 1)	prepared using the method described in Example 130 using INT16
23	116	HPLC (method 3) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 470/472 (M + 1)	prepared using the method described in Example 130 using INT16
24	117	HPLC (method 1) tR = 2.5 min LCMS (ESI, pos. ion spectrum) m/z 392 (M + H)	prepared using the method described in Example 1
25	118	HPLC (method 1) tR = 1.9 min LCMS (ESI, pos. ion spectrum) m/z 418/420 (M + H)	prepared using the method described in Example 1
26	119	HPLC (method 1) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 385 (M + H)	prepared using the method described in Example 1
27	120	HPLC (method 1) tR = 2.1 min LCMS (ESI, pos. ion spectrum) m/z 424 (M + H)	prepared using the method described in Example 1
28	121	HPLC (method 1) tR = 2.1 min LCMS (ESI, pos. ion spectrum) m/z 408 (M + H)	prepared using the method described in Example 1
29	122	HPLC (method 1) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 370 (M + H)	prepared using the method described in Example 1
30	123	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 456/458 (M + H)	prepared using the method described in Example 1
31	124	HPLC (method 3) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 584/586 (M + H)	prepared using the method described in Example 130 using INT16
32	125	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 412 (M + H)	prepared using the method described in Example 1 using INT27
33	126	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 476/478 (M + H)	prepared using the method described in Example 1 using INT28
34	127	HPLC (method 3) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 484/486 (M + H)	prepared using the method described in Example 130 using INT16
35	128	HPLC (method 3) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 533/535 (M + 1)	prepared using the method described in Example 130 using INT16
36	129	HPLC (method 1) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 391 (M + H)	prepared using the method described in Example 1
37	130	HPLC (method 1) tR = 1.7 min LCMS (ESI, pos. ion spectrum) m/z 395 (M + H)	Title compound of example 37
38	131	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 579/581 (M + H)	prepared using the method described in Example 1
39	132	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 440/442 (M + H)	prepared using the method described in Example 1
40	133	HPLC (method 1) tR = 3.5 min LCMS (ESI, pos. ion spectrum) m/z 494/496 (M + 1)	Prepared using the method described in Example 21
41	134	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 426/428 (M + H)	Title compound of Example 41
42	135	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 426/428 (M + H)	Prepared using the method described in Example 41
43	136	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 439/441 (M + H)	Title compound of Example 43
44	137	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 439/441 (M + H)	prepared using the method described in Example 43
45	138	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 470/472 (M + H)	Prepared using the method described in Example 41 and INT29
46	139	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 470/472 (M + H)	Prepared using the method described in Example 41 and INT30
47	140	HPLC (method 1) tR = 3.6 min LCMS (ESI, pos. ion spectrum) m/z 508/510 (M + 1)	Prepared using the method described in Example 13 using Example 40 title compound
48	141	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 482/484 (M + 1)	Title compound of Example 48
49	142	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 498/500 (M + 1)	Title compound of Example 49
50	143	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 514/516 (M + 1)	Title compound of Example 50
51	144	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 468/470 (M + 1)	Prepared using the method described in Example 48
52	145	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 484/486 (M + 1)	Prepared using the method described in Example 49
53	146	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 500/502 (M + 1)	Prepared using the method described in Example 50
54	147	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 442 (M + H)	prepared using the method described in Example 1
55	148	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 444/446 (M + H)	prepared using the method described in Example 1
56	149	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 444/446 (M + H)	prepared using the method described in Example 1
57	150	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 456/458 (M + H)	prepared using the method described in Example 1
58	151	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 496 (M + H)	prepared using the method described in Example 1
59	152	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 498/500 (M + 1)	prepared using the method described in Example 130 using INT16
60	153	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 454/456 (M + 1)	prepared using the method described in Example 130 using INT16
61	154	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 503/505 (M + 1)	prepared using the method described in Example 130 using INT16
62	155	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 488/490 (M + 1)	prepared using the method described in Example 130 using INT16
63	156	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 484/486 (M + 1)	prepared using the method described in Example 130 using INT16
64	157	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 484/486 (M + 1)	prepared using the method described in Example 130 using INT16
65	158	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 518/520 (M + 1)	prepared using the method described in Example 130 using INT16
66	159	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 484/486 (M + 1)	prepared using the method described in Example 130 using INT16
67	160	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 506/508 (M + 1)	prepared using the method described in Example 130 using INT16
68	161	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 519/521 (M + 1)	prepared using the method described in Example 130 using INT16
69	162	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 458/46o (M + 1)	prepared using the method described in Example 130 using INT16
70	163	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 574/576/578/580 (M + 1)	prepared using the method described in Example 130 using INT16
71	164	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 556/558 (M + 1)	prepared using the method described in Example 130 using INT16
72	165	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 589/591 (M + 1)	prepared using the method described in Example 130 using INT16
73	166	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 469/471 (M + 1)	prepared using the method described in Example 130 using INT16
74	167	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 544/546 (M + 1)	prepared using the method described in Example 130 using INT16
75	168	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 602/604 (M + 1)	prepared using the method described in Example 130 using INT16
76	169	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 543/545 (M + 1)	prepared using the method described in Example 130 using INT16
77	170	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 472/474 (M + 1)	prepared using the method described in Example 130 using INT16
78	171	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 542/544 (M + 1)	prepared using the method described in Example 130 using INT16
79	172	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 578/580 (M + 1)	prepared using the method described in Example 130 using INT16
80	173	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 500/502 (M + 1)	prepared using the method described in Example 130 using INT16
81	174	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 580/582 (M + 1)	prepared using the method described in Example 130 using INT16
82	175	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	prepared using the method described in Example 130 using INT16
83	176	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 559/561 (M + 1)	prepared using the method described in Example 130 using INT16
84	177	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 577/579 (M + 1)	prepared using the method described in Example 130 using INT16
85	178	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 485/487 (M + 1)	prepared using the method described in Example 130 using INT16
86	179	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 561/563 (M + 1)	prepared using the method described in Example 130 using INT16
87	180	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 582/584 (M + 1)	prepared using the method described in Example 130 using INT16
88	181	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 598/600 (M + 1)	prepared using the method described in Example 130 using INT16
89	182	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 548/550 (M + 1)	prepared using the method described in Example 130 using INT16
90	183	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 521/523 (M + 1)	prepared using the method described in Example 130 using INT16
91	184	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 547/549 (M + 1)	prepared using the method described in Example 130 using INT16
92	185	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 553/555 (M + 1)	prepared using the method described in Example 130 using INT16
93	186	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 563/565 (M + 1)	prepared using the method described in Example 130 using INT16
94	187	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 539/541 (M + 1)	prepared using the method described in Example 130 using INT16
95	188	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 501/503 (M + 1)	prepared using the method described in Example 130 using INT16
96	189	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 561/563 (M + 1)	prepared using the method described in Example 130 using INT16
97	190	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 533/535 (M + 1)	prepared using the method described in Example 130 using INT16
98	191	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 521/523 (M + 1)	prepared using the method described in Example 130 using INT16
99	192	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 584/586 (M + 1)	prepared using the method described in Example 130 using INT16
100	193	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 557/559 (M + H)	prepared using the method described in Example 130 using INT16
101	194	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 546/548 (M + 1)	prepared using the method described in Example 130 using INT16
102	195	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 521/523 (M + 1)	prepared using the method described in Example 130 using INT16
103	196	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 597/599 (M + 1)	prepared using the method described in Example 130 using INT16
104	197	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 584/586 (M + 1)	prepared using the method described in Example 130 using INT16
105	198	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 499/501 (M + 1)	prepared using the method described in Example 130 using INT16
106	199	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 499/501 (M + 1)	prepared using the method described in Example 130 using INT16
107	200	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 533/535 (M + 1)	prepared using the method described in Example 130 using INT16
108	201	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 523/525 (M + 1)	prepared using the method described in Example 130 using INT16
109	202	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 533/535 (M + 1)	prepared using the method described in Example 130 using INT16
110	203	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 533/535 (M + 1)	prepared using the method described in Example 130 using INT16
111	204	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 562/564 (M + 1)	prepared using the method described in Example 130 using INT16
112	205	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 625/627 (M + 1)	prepared using the method described in Example 130 using INT16
113	206	HPLC (method 3) LCMS (ESI, pos. ion spectrum) m/z 514/516 (M + 1)	prepared using the method described in Example 130 using INT16
114	207	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 456/458 (M + H)	prepared using the method described in Example 1 using INT43
115	208	HPLC (method 3) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 559/561 (M + 1)	prepared using the method described in Example 1 using INT9 and INT28
116	209	HPLC (method 3) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 533/535 (M + 1)	prepared using the method described in Example 1 using INT9
117	210	HPLC (method 4) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 553/555 (M + 1)	prepared using the method described in Example 1 using INT9 and INT30
118	211	HPLC (method 4) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 509/511 (M + 1)	prepared using the method described in Example 1 using INT9
119	212	HPLC (method 3) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 539/541 (M + 1)	prepared using the method described in Example 1 using INT9
120	213	HPLC (method 3) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 515/517 (M + 1)	prepared using the method described in Example 1 using INT9
121	214	HPLC (method 3) tR = 2.3 min LCMS (ESI, pos. ion spectrum) m/z 523/525 (M + 1)	prepared using the method described in Example 1 using INT9
122	215	HPLC (method 1) tR = 2.5 min LCMS (ESI, pos. ion spectrum) m/z 539/541 (M + H)	prepared using the method described in Example 1 using INT9
123	216	HPLC (method 4) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 547/549 (M + 1)	prepared using the method described in Example 130 using INT12
124	217	HPLC (method 4) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 587/589 (M + 1)	prepared using the method described in Example 130 using INT12
125	218	HPLC (method 1) tR = 3.0 min (55%) and 3.27 (45%) LCMS (ESI, pos. ion spectrum) m/z 521/523 (M + 1)	Prepared using the method described in Example 48
126	219	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 491/493 (M + 1)	Prepared using the method described in Example 48
127	220	HPLC (method 1) tR = 3.5 min LCMS (ESI, pos. ion spectrum) m/z 590/592 (M + 1)	Prepared using the method described in Example 48
128	221	HPLC (method 1) tR = 3.6 min LCMS (ESI, pos. ion spectrum) m/z 574/576 (M + 1)	Prepared using the method described in Example 48
129	222	HPLC (method 3) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 559/561 (M + 1)	prepared using the method described in Example 130 using INT12 and INT50
130	223	HPLC (method 1) tR = 2.1 min LCMS (ESI, pos. ion spectrum) m/z 506/508 (M+)	Title compound of Example 130
131	224	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 520/522 (M+)	prepared using the method described in Example 130 using INT12
132	225	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 544/546 (M + H)	prepared using the method described in Example 130 using INT12
133	226	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 506/508 (M + H)	prepared using the method described in Example 130 using INT12
134	227	HPLC (method 1) tR = 2.2 min LCMS (ESI, pos. ion spectrum) m/z 509/511 (M + H)	prepared using the method described in Example 1 using INT9
135	228	HPLC (method 1) tR = 2.3 min LCMS (ESI, pos. ion spectrum) m/z 553/555 (M + H)	prepared using the method described in Example 1 using INT9 and INT29
136	229	HPLC (method 1) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 495 (M + H)	prepared using the method described in Example 1 using INT9 and INT27
137	230	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 529 (M + H)	prepared using the method described in Example 1 using INT9
138	231	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 533/535 (M + H)	prepared using the method described in Example 1 using INT9
139	232	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 519 (M + H)	prepared using the method described in Example 1 using INT9
140	233	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 553/555 (M + H)	prepared using the method described in Example 1 using INT9
141	234	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 480/482 (M + 1)	Prepared using the method described in Example 48
142	235	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 537/539 (M + 1)	Prepared using the method described in Example 50
143	236	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 499/501 (M + H)	prepared using the method described in Example 130 using INT17
144	237	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 523/525 (M + H)	prepared using the method described in Example 130 using INT17 and INT66
145	238	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 567/569 (M + H)	prepared using the method described in Example 130 using INT17 and INT63
146	239	HPLC (method 1) tR = 3.7 min LCMS (ESI, pos. ion spectrum) m/z 577/579 (M + 1)	Prepared using the method described in Example 48
147	240	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 599 (M + H)	prepared using the method described in Example 130 using INT17 and INT67
148	241	HPLC (method 9) tR = 1.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 657/659 (M + 1)	Title compound of Example 148
149	242	HPLC (method 1) tR = 4.1 min LCMS (ESI, pos. ion spectrum) m/z 593/595 (M + 1)	Prepared using the method described in Example 48
150	243	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 493/495 (M + 1)	Prepared using the method described in Example 178 Step B using Example 149 title compound
151	244	HPLC (method 1) tR = 3.6 min LCMS (ESI, pos. ion spectrum) m/z 627/629 (M + 1)	Prepared using the method described in Example 48
152	245	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 459 (M + 1)	Title compound of Example 152
153	246	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 587/589/591 (M + 1)	Prepared using the method described in Example 48
154	247	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 500/502 (M + H)	prepared using the method described in Example 130 using INT17
155	248	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 577/579 (M + H)	prepared using the method described in Example 1 using INT9
156	249	HPLC (method 1) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 540/542 (M + H)	prepared using the method described in Example 1 using INT9
157	250	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 553/555 (M + H)	prepared using the method described in Example 130 using INT17
158	251	HPLC (method 1) tR = 2.5 min LCMS (ESI, pos. ion spectrum) m/z 457/459 (M + H)	prepared using the method described in Example 1
159	252	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 527/529 (M + H)	prepared using the method described in Example 613 part A and INT49
160	253	HPLC (method 1) tR = 2.6 min LRMS (ESI, pos. ion spectrum) m/z 531/533 (M + H)	prepared using the method described in Example 613 part A and INT5
161	254	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 547/549 (M + H)	prepared using the method described in Example 613 part A and INT32
162	255	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 484/486 (M + H)	prepared using the method described in Example 130 using INT17
163	256	HPLC (method 1) tR = 2.3 min LCMS (ESI, pos. ion spectrum) m/z 540/542 (M + H)	prepared using the method described in Example 1using INT9
164	257	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 464/466 (M + H)	prepared using the method described in Example 130 using INT15
165	258	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 547/549 (M + H)	prepared using the method described in Example 130 using INT15
166	259	HPLC (method 1) tR = 2.3 min LCMS (ESI, pos. ion spectrum) m/z 529/531 (M + H)	prepared using the method described in Example 130 using INT11
167	260	HPLC (method 1) tR = 3.8 min LRMS (ESI, pos. ion spectrum) m/z 543/545 (M + H)	prepared using the method described in Example 613 part A using INT42
168	261	HPLC (method 1) tR = 3.5 min LRMS (ESI, neg. ion spectrum) m/z 511/513 (M − H)	prepared using the method described in Example 613 part A using INT36
169	262	HPLC (method 1) tR = 2.6 min LRMS (ESI, pos. ion spectrum) m/z 572/574 (M + H)	prepared using the method described in Example 613 part A using INT37
170	263	HPLC (method 1) tR = 2.6 min LRMS (ESI, pos. ion spectrum) m/z 593/595 (M + H)	prepared using the method described in Example 613 part A using INT35
171	264	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 529/531 (M + H)	prepared using the method described in Example 613 part A using INT38
172	265	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 572/574 (M + H)	prepared using the method described in Example 613 part A and INT33
173	266	HPLC (method 3) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 577/579 (M + 1)	prepared using the method described in Example 130 using INT11
174	267	HPLC (method 4) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 494/496 (M + 1)	prepared using the method described in Example 130 using INT11
175	268	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 571/573 (M + H)	prepared using the method described in Example 1 using INT9
176	269	HPLC (method 1) tR = 2.2 min LCMS (ESI, pos. ion spectrum) m/z 540/542 (M + H)	prepared using the method described in Example 1 using INT9
177	270	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 506/507 (M + 1)	Title compound of Example 177
178	271	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 493/495 (M + 1)	Title compound of Example 178
179	272	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 529/531 (M + H)	prepared using the method described in Example 130 using INT11 and INT64
180	273	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 510/512 (M + H)	prepared using the method described in Example 130 using INT11 and INT65
181	274	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 526/528 (M + H)	prepared using the method described in Example 130 using INT11
182	275	HPLC (method 3) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 486/488 (M + 1)	prepared using the method described in Example 130 using INT16
183	276	LCMS (method 4) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 589/591 (M + 1)	Title compound of Example 183
184	277	LCMS (method 4) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 524/526 (M + 1)	Prepared using the method described in Example 183
185	278	LCMS (method 4) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 599/601 (M + 1)	Prepared using the method described in Example 183
186	279	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 600/602 (M + 1)	Prepared using the method described in Example 183
187	280	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 478/480 (M + 1)	Prepared using the method described in Example 183
188	281	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	Prepared using the method described in Example 183
189	282	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	Prepared using the method described in Example 183
190	283	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 542/544 (M + 1)	Prepared using the method described in Example 183
191	284	LCMS (method 4) tR = 1.6 min (ESI, pos. ion spectrum) m/z 532/534 (M + 1)	Prepared using the method described in Example 183
192	285	LCMS (method 4) tR = 1.6 min (ESI, pos. ion spectrum) m/z 540/542 (M + 1)	Prepared using the method described in Example 183
193	286	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 493/495 (M + 1)	Prepared using the method described in Example 183
194	287	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 521/523 (M + 1)	Prepared using the method described in Example 183
195	288	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 571/573 (M + 1)	Prepared using the method described in Example 183
196	289	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 494/496 (M + 1)	Prepared using the method described in Example 183
197	290	LCMS (method 4) tR = 1.1 min (ESI, pos. ion spectrum) m/z 477/479 (M + 1)	Prepared using the method described in Example 183
198	291	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 567/569 (M + 1)	Prepared using the method described in Example 183
199	292	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 478/480 (M + 1)	Prepared using the method described in Example 183
200	293	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 589/591 (M + 1)	Prepared using the method described in Example 183
201	294	LCMS (method 4) tR = 1.2 min (ESI, pos. ion specturm) m/z 493/495 (M + 1)	Prepared using the method described in Example 183
202	295	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 595/597 (M + 1)	Prepared using the method described in Example 183
203	296	LCMS (method 4) tR = 1.1 min (ESI, pos. ion spectrum) m/z 493/495 (M + 1)	Prepared using the method described in Example 183
204	297	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 479/481 (M + 1)	Prepared using the method described in Example 183
205	298	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 481/483 (M + 1)	Prepared using the method described in Example 183
206	299	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 507/509 (M + 1)	Prepared using the method described in Example 183
207	300	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 547/549 (M + 1)	Prepared using the method described in Example 183
208	301	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 524/526 (M + 1)	Prepared using the method described in Example 183
209	302	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 561/563 (M + 1)	Prepared using the method described in Example 183
210	303	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 533/535 (M + 1)	Prepared using the method described in Example 183
211	304	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 493/495 (M + 1)	Prepared using the method described in Example 183
212	305	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 557/559 (M + 1)	Prepared using the method described in Example 183
213	306	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 541/543 (M + 1)	Prepared using the method described in Example 183
214	307	LCMS (method 4) tR = 1.6 min (ESI, pos. ion spectrum) m/z 534/536/538 (M + 1)	Prepared using the method described in Example 183
215	308	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 507/509 (M + 1)	Prepared using the method described in Example 183
216	309	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 514/516 (M + 1)	Prepared using the method described in Example 183
217	310	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 452/454 (M + 1)	Prepared using the method described in Example 183
218	311	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 528/530 (M + 1)	Prepared using the method described in Example 183
219	312	LCMS (method 4) tR = 1.7 min (ESI, pos. ion spectrum) m/z 478/480 (M + 1)	Prepared using the method described in Example 183
220	313	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 555/557 (M + 1)	Prepared using the method described in Example 183
221	314	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 576/578 (M + 1)	Prepared using the method described in Example 183
222	315	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 494/496 (M + 1)	Prepared using the method described in Example 183
223	316	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 507/509 (M + 1)	Prepared using the method described in Example 183
224	317	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 559/561 (M + 1)	Prepared using the method described in Example 183
225	318	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 612/614 (M + 1)	Prepared using the method described in Example 183
226	319	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 507/509 (M + 1)	Prepared using the method described in Example 183
227	320	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 578/580 (M + 1)	Prepared using the method described in Example 183
228	321	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 516/518 (M + 1)	Prepared using the method described in Example 183
229	322	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 557/559 (M + 1)	Prepared using the method described in Example 183
230	323	LCMS (method 4) tR = 1.6 min (ESI, pos. ion spectrum) m/z 540/542 (M + 1)	Prepared using the method described in Example 183
231	324	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 526/528 (M + 1)	Prepared using the method described in Example 183
232	325	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 583/585 (M + 1)	Prepared using the method described in Example 183
233	326	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 492/494 (M + 1)	Prepared using the method described in Example 183
234	327	LCMS (method 4) tR = 1.6 min (ESI, pos. ion spectrum) m/z 506/508 (M + 1)	Prepared using the method described in Example 183
235	328	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 508/510 (M + 1)	Prepared using the method described in Example 183
236	329	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 494/496 (M + 1)	Prepared using the method described in Example 183
237	330	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 478/480 (M + 1)	Prepared using the method described in Example 183
238	331	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 464/466 (M + 1)	Prepared using the method described in Example 183
239	332	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 480/482 (M + 1)	Prepared using the method described in Example 183
240	333	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 602/604 (M + 1)	Prepared using the method described in Example 183
241	334	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 670/672 (M + 1)	Prepared using the method described in Example 183
242	335	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 555/557 (M + 1)	Prepared using the method described in Example 183
243	336	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 495/497 (M + 1)	Prepared using the method described in Example 183
244	337	LCMS (method 4) tR = 1.1 min (ESI, pos. ion spectrum) m/z 556/558 (M + 1)	Prepared using the method described in Example 183
245	338	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 556/558 (M + 1)	Prepared using the method described in Example 183
246	339	LCMS (method 4) tR = 1.1 min (ESI, pos. ion spectrum) m/z 556/558 (M + 1)	Prepared using the method described in Example 183
247	340	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 612/614 (M + 1)	Prepared using the method described in Example 183
248	341	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	Prepared using the method described in Example 183
249	342	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	Prepared using the method described in Example 183
250	343	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	Prepared using the method described in Example 183
251	344	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 569/571 (M + 1)	Prepared using the method described in Example 183
252	345	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 538/540 (M + 1)	Prepared using the method described in Example 183
253	346	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 538/540 (M + 1)	Prepared using the method described in Example 183
254	347	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 464/466 (M + 1)	Prepared using the method described in Example 183
255	348	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 536/538 (M + 1)	Prepared using the method described in Example 183
256	349	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 466/468 (M + 1)	Prepared using the method described in Example 183
257	350	LCMS (method 4) tR = 1.6 min (ESI, pos. ion spectrum) m/z 506/508 (M + 1)	Prepared using the method described in Example 183
258	351	LCMS (method 4) tR = 1.7 min (ESI, pos. ion spectrum) m/z 632/634 (M + 1)	Prepared using the method described in Example 183
259	352	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 508/510 (M + 1)	Prepared using the method described in Example 183
260	353	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 492/494 (M + 1)	Prepared using the method described in Example 183
261	354	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 536/538 (M + 1)	Prepared using the method described in Example 183
262	355	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 478/480 (M + 1)	Prepared using the method described in Example 183
263	356	LCMS (method 4) tR = 1.7 min (ESI, pos. ion spectrum) m/z 532/534 (M + 1)	Prepared using the method described in Example 183
264	357	HPLC (method 1) tR = 2.4 min LRMS (ESI, pos. ion spectrum) m/z 544/546 (M + H)	prepared using the method described in Example 613 part A using INT39
265	358	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 543/545 (M + H)	prepared using the method described in Example 613 part A using INT40
266	359	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 579/581 (M + H)	prepared using the method described in Example 613 part A using and INT41
267	360	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 538/540 (M + H)	prepared using the method described in Example 613 part A using and INT34
268	361	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 506/508 (M + H)	prepared using the method described in Example 130 using INT12
269	362	HPLC (method 1) tR = 2.1 min LCMS (ESI, pos. ion spectrum) m/z 552/554 (M + H)	prepared using the method described in Example 130 using INT14 and INT49
270	363	HPLC (method 1) tR = 2.2 min LCMS (ESI, pos. ion spectrum) m/z 552/554 (M + H)	prepared using the method described in Example 130 using INT13 and INT49
271	364	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 583/585 (M + H)	prepared using the method described in Example 130 using INT18 and INT49
272	365	HPLC (method 1) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 543/545 (M + H)	prepared using the method described in Example 130 using INT11 and INT51
273	366	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 484/486 (M + 1)	Prepared using the method described in Example 48 using INT17
274	367	HPLC (method 1) tR = 3.8 min LCMS (ESI, pos. ion spectrum) m/z 595/597 (M + 1)	Prepared using the method described in Example 48 using INT17
275	368	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 497/499 (M + 1)	Prepared using the method described in Example 48 using INT17
276	369	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 511/513 (M + 1)	Prepared using the method described in Example 48 using INT17
277	370	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 575/577 (M + 1)	prepared using the method described in Example 130 using INT17
278	371	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 484/485 (M + 1)	Prepared using the method described in Example 48 using INT17
279	372	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 505/507 (M + 1)	Prepared using the method described in Example 48 using INT15
280	373	HPLC (method 1) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 551/553 (M + H)	prepared using the method described in Example 130 using INT17 and INT49
281	374	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 601/603 (M + H)	prepared using the method described in Example 130 using INT17 and INT52
282	375	HPLC (method 1) tR = 4.0 min LCMS (ESI, pos. ion spectrum) m/z 601/603 (M + H)	prepared using the method described in Example 130 using INT17 and INT53
283	376	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 567/569 (M + H)	prepared using the method described in Example 130 using INT17 and INT51
284	377	HPLC (method 1) tR = 3.8 min LCMS (ESI, pos. ion spectrum) m/z 577/579 (M + 1)	prepared using the method described in Example 130 using INT11 and INT53
285	378	HPLC (method 1) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 602/604 (M + H)	prepared using the method described in Example 130 using INT14 and INT52
286	379	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 602/604 (M + H)	prepared using the method described in Example 130 using INT13 and INT52
287	380	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 633/635 (M + H)	prepared using the method described in Example 130 using INT18 and INT52
288	381	HPLC (method 1) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 576/578 (M + H)	prepared using the method described in Example 130 using INT14
289	382	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 576/578 (M + H)	prepared using the method described in Example 130 using INT13
290	383	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 607/609 (M + H)	prepared using the method described in Example 130 using INT18
291	384	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 551/553 (M + H)	prepared using the method described in Example 613 part A
292	385	HPLC (method 1) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 513/515 (M + H)	Title compound of Example 292
293	386	HPLC (method 1) tR = 2.5 min LCMS (ESI, pos. ion spectrum) m/z 541/543 (M + H)	prepared using the method described in Example 292 using INT23
294	387	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 537/539 (M + H)	prepared using the method described in Example 130 using INT11
295	388	HPLC (method 1) tR = 3.5 min LCMS (ESI, pos. ion spectrum) m/z 745/747/749 (M + 1)	Prepared using the method described in Example 48 using INT10
296	389	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 625/627 (M + 1)	Prepared using the method described in Example 48 using INT10
297	390	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 550/552 (M + 1)	Prepared using the method described in Example 48 using INT10
298	391	HPLC (method 1) tR = 3.6 min LCMS (ESI, pos. ion spectrum) m/z 636/638 (M + 1)	Prepared using the method described in Example 48 using INT10
299	392	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 613/615 (M + 1)	Prepared using the method described in Example 48 using INT10
300	393	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 561/563 (M + 1)	From title compound of Example 278 using the using the method described in Example 21
301	394	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 535/537 (M + 1)	Prepared using INT10 using the methods described in Example 48 and Example 178 part B
302	395	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 497/499 (M + 1)	Prepared using INT17 using the methods described in Example 48 and Example 178 part B
303	396	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 596/598 (M + H)	prepared using the method described in Example 613 part A and INT33 and INT17
304	397	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 603/605 (M + H)	prepared using the method described in Example 613 part A and INT41 and INT17
305	398	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 555/557 (M + H)	prepared using the method described in Example 613 part A and INT17 and INT5
306	399	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 571/573 (M + H)	prepared using the method described in Example 613 part A and INT17 and INT32
307	400	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 561/563 (M + H)	prepared using the method described in Example 130 using INT17
308	401	HPLC (method 3) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 589/591 (M + 1)	prepared using the method described in Example 400 using INT23
309	402	HPLC (method 9) tR = 1.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 685 (M + 1)	prepared using the methods described in Example 148 Part A using the title compound of Example 299
310	403	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 548/550 (M + 1)	Prepared using the method described in Example 48 using INT10
311	404	HPLC (method 1) tR = 3.5 min LCMS (ESI, pos. ion spectrum) m/z 520/522 (M + 1)	Title compound of Example 311
312	405	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 563/565 (M + 1)	Prepared using the method described in Example 48 using INT10
313	406	HPLC (method 4) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 555/557 (M + 1)	prepared using the method described in Example 400 using INT23
314	407	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 613/615 (M + 1)	Prepared From the title compound of Example 301 using the method described in Example 21
315	408	HPLC (method 3) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 632/634 (M + 1)	prepared using the method described in Example 400 using INT23
316	409	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 578/580 (M + 1)	Title compound of Example 316
317	410	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 577/579 (M + 1)	Title compound of Example 317
318	411	HPLC (method 1) tR = 2.1 min LCMS (ESI, pos. ion spectrum) m/z 489/491 (M + H)	prepared using the method described in Example 130 using INT11
319	412	HPLC (method 1) tR = 2.2 min LCMS (ESI, pos. ion spectrum) m/z 517/519 (M + H)	prepared using the method described in Example 130 using INT11
320	413	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 561/563 (M+)	prepared using the method described in Example 613 part A and INT17 and INT34
321	414	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 587/589 (M + H)	prepared using the method described in Example 400 using INT23
322	415	HPLC (method 2) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 625/627 (M + H)	prepared using the method described in Example 400 using INT23
323	416	HPLC (method 2) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 661/663 (M + H)	prepared using the method described in Example 400 using INT23
324	417	HPLC (method 2) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 575/577 (M + H)	prepared using the method described in Example 400 using INT23
325	418	HPLC (method 2) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 583/585 (M + H)	prepared using the method described in Example 400 using INT23
326	419	HPLC (method 2) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 610/612 (M + H)	prepared using the method described in Example 400 using INT23

[0307]

Ex #	Structure	characterization	method
327	420	HPLC (method 2) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 625/627 (M + H)	prepared using the method described in Example 400 using INT23
328	421	HPLC (method 1) tR = 2.9 min LRMS (ESI; pos. ion spectrum) m/z 616/618 (M + H)	prepared using the method described in Example 613 part A and INT17 and INT35
329	422	HPLC (method 9) tR = 1.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 671 (M + 1)	prepared using the methods described in Example INT3 part B using the title compound of Example 309
330	423	HPLC (method 10) tR = 7.2 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 684 (M + 1)	prepared using the methods described in Example 130 using the title compound of Example 329
331	424	HPLC (method 5) tR = 1.0 min LCMS (ESI, pos. ion spectrum) m/z 509/511 (M + 1)	Title compound of Example 331
332	425	HPLC (method 5) tR = 1.1 min LCMS (ESI, pos. ion spectrum) m/z 503/505 (M + 1)	prepared using the method described for Example 331
333	426	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 476/478 (M + 1)	prepared using the method described for Example 331
334	427	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 476/478 (M + 1)	prepared using the method described for Example 331
335	428	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 490/492 (M + 1)	prepared using the method described for Example 331
336	429	HPLC (method 5) tR = 1.1 min LCMS (ESI, pos. ion spectrum) m/z 489/491 (M + 1)	prepared using the method described for Example 331
337	430	HPLC (method 5) tR = 1.0 min LCMS (ESI, pos. ion spectrum) m/z 475/477 (M + 1)	prepared using the method described for Example 331
338	431	HPLC (method 5) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 601/603 (M + 1)	prepared using the method described for Example 331
339	432	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 533/535 (M + 1)	prepared using the method described for Example 331
340	433	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	prepared using the method described for Example 331
341	434	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 500/502 (M + 1)	prepared using the method described for Example 331
342	435	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 500/502 (M + 1)	prepared using the method described for Example 331
343	436	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 514/516 (M + 1)	prepared using the method described for Example 331
344	437	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 513/515 (M + 1)	prepared using the method described for Example 331
345	438	HPLC (method 5) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 625/627 (M + 1)	prepared using the method described for Example 331
346	439	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 520 (M + 1)	prepared using the method described for Example 331
347	440	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 603 (M + 1)	prepared using the method described for Example 331
348	441	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 639 (M + 1)	prepared using the method described for Example 331
349	442	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 591 (M + 1)	prepared using the method described for Example 331
350	443	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 564 (M + 1)	prepared using the method described for Example 331
351	444	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 564 (M + 1)	prepared using the method described for Example 331
352	445	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 578 (M + 1)	prepared using the method described for Example 331
353	446	HPLC (method 5) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 577 (M + 1)	prepared using the method described for Example 331
354	447	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 563 (M + 1)	prepared using the method described for Example 331
355	448	HPLC (method 5) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 689 (M + 1)	prepared using the method described for Example 331
356	449	HPLC (method 5) tR = 1.1 min LCMS (ESI, pos. ion spectrum) m/z 462/464 (M + 1)	prepared using the method described for Example 331
357	450	HPLC (method 5) tR = 1.1 min LCMS (ESI, pos. ion spectrum) m/z 476/478 (M + 1)	prepared using the method described for Example 331
358	451	HPLC (method 5) tR = 1.1 min LCMS (ESI, pos. ion spectrum) m/z 462/464 (M + 1)	prepared using the method described for Example 331
359	452	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 500/502 (M + 1)	prepared using the method described for Example 331
360	453	HPLC (method 6) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 486/488 (M + 1)	prepared using the method described for Example 331
361	454	HPLC (method 6) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 550 (M + 1)	prepared using the method described for Example 331
362	455	HPLC (method 6) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 550 (M + 1)	prepared using the method described for Example 331
363	456	HPLC (method 2) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	prepared using the method described for Example 1 using INT9
364	457	HPLC (method 5) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 584/586 (M + 1)	prepared using the method described for Example 331
365	458	HPLC (method 5) tR = 1.1 min LCMS (ESI, pos. ion spectrum) m/z 415/417 (M + 1)	prepared using the method described for Example 331
366	459	HPLC (method 5) tR = 1.0 min LCMS (ESI, pos. ion spectrum) m/z 498/500 (M + 1)	prepared using the method described for Example 331
367	460	HPLC (method 5) tR = 1.0 min LCMS (ESI, pos. ion spectrum) m/z 534/536 (M + 1)	prepared using the method described for Example 331
368	461	HPLC (method 5) tR = 1.0 min LCMS (ESI, pos. ion spectrum) m/z 486/488 (M + 1)	prepared using the method described for Example 331
369	462	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 459/461 (M + 1)	prepared using the method described for Example 331
370	463	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 459/461 (M + 1)	prepared using the method described for Example 331
371	464	HPLC (method 5) tR = 1.0 min LCMS (ESI, pos. ion spectrum) m/z 472/474 (M + 1)	prepared using the method described for Example 331
372	465	HPLC (method 5) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 626/628 (M + 1)	Title compound of Example 372
373	466	HPLC (method 5) tR = 1.0 min LCMS (ESI, pos. ion spectrum) m/z 457/459 (M + 1)	prepared using the method described for Example 372
374	467	HPLC (method 5) tR = 1.0 min LCMS (ESI, pos. ion spectrum) m/z 540/542 (M + 1)	prepared using the method described for Example 372
375	468	HPLC (method 5) tR = 1.0 min LCMS (ESI, pos. ion spectrum) m/z 576/578 (M + 1)	prepared using the method described for Example 372
376	469	HPLC (method 5) tR = 1.0 min LCMS (ESI, pos. ion spectrum) m/z 528/530 (M + 1)	prepared using the method described for Example 372
377	470	HPLC (method 5) tR = 1.1 min LCMS (ESI, pos. ion spectrum) m/z 501/503 (M + 1)	prepared using the method described for Example 372
378	471	HPLC (method 5) tR = 1.1 min LCMS (ESI, pos. ion spectrum) m/z 501/503 (M + 1)	prepared using the method described for Example 372
379	472	HPLC (method 5) tR = 0.9 min LCMS (ESI, pos. ion spectrum) m/z 514/516 (M + 1)	prepared using the method described for Example 372
380	473	HPLC (method 5) tR = 1.7 min LCMS (ESI, pos. ion spectrum) m/z 652/654 (M + 1)	prepared using the method described for Example 372
381	474	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 483/485 (M + 1)	prepared using the method described for Example 372
382	475	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 566/568 (M + 1)	prepared using the method described for Example 372
383	476	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 602/604 (M + 1)	prepared using the method described for Example 372
384	477	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 554/556 (M + 1)	prepared using the method described for Example 372
385	478	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	prepared using the method described for Example 372
386	479	HPLC (method 5) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	prepared using the method described for Example 372
387	480	HPLC (method 5) tR = 1.2 min LCMS (ESI, pos. ion spectrum) m/z 540/542 (M + 1)	prepared using the method described for Example 372
388	481	HPLC (method 1) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 514 (M + 1)	Prepared using the method described in Example 48 using INT68
389	482	HPLC (method 1) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 514 (M + 1)	Prepared using the method described in Example 48 using INT69
390	483	HPLC (method 1) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 550 (M + 1)	Prepared using the method described in Example 48 using INT68
391	484	HPLC (method 2) tR = 1.9 min LCMS (ESI, pos. ion spectrum) m/z 559/561 (M + 1)	Title compound of Example 391
392	485	HPLC (method 2) tR = 1.9 min LCMS (ESI, pos. ion spectrum) m/z 565/567 (M + 1)	prepared using the method described in Example 391
393	486	HPLC (method 1) tR = 3.6 min LCMS (ESI, pos. ion spectrum) m/z 578/580 (M + 1)	Prepared using the method described in Example 48 using INT10
394	487	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 474/476 (M + 1)	Prepared using the method described in Example 48 using INT11
395	488	HPLC (method 1) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 550 (M + 1)	Prepared using the method described in Example 48 using INT69
396	489	HPLC (method 2) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 533/535 (M + 1)	prepared using the method described in Example 1 using INT9
397	490	HPLC (method 2) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 484/486 (M + 1)	prepared using the method described in Example 1 using INT9
398	491	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 518/520 (M + H)	prepared using the method described in Example 130 using INT18
399	492	HPLC (method 1) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 540/542 (M + H)	prepared using the method described in Example 1 using INT9
400	493	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 599/601 (M + H)	Title compound of Example 400
401	494	HPLC (method 2) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 555 (M + 1)	Title compound of Example 401
402	495	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 657/659 (M + H)	prepared using the method described in Example 400 using INT20
403	496	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 559/561 (M + H)	prepared using the method described in Example 400 using INT20
404	497	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 557/559 (M + H)	prepared using the method described in Example 400 using INT20
405	498	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 615/617 (M + 1)	prepared using the method described in Example 400 using INT20
406	499	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 597/599 (M + H)	prepared using the method described in Example 400 using INT20
407	500	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 621/623 (M + 1)	Title compound of Example 407
408	501	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 549/551 (M + 1)	Prepared using the method described in Example 407
409	502	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 592/594 (M + 1)	Title compound of Example 409
410	503	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	Title compound of Example 410
411	504	LCMS (Conditon YS1) tR = 2.9 min (ESI, pos. ion spectrum) m/z 670/672 (M + 1)	Prepared using example 409 using the method described in Example 21
412	505	HPLC (method 1) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 565 (M + 1)	Title compound of Example 412
413	506	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 549/551 (M + 1)	Prepared using the method described in Example 48 using INT10
414	507	HPLC (method 2) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 555 (M + 1)	Title compound of Example 414
415	508	HPLC (method 2) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 527/529 (M + 1)	Title compound of Example 414
416	509	HPLC (method 2) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 565/567 (M + 1)	prepared using the method described in Example 414
417	510	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 545/547 (M + H)	prepared using the method described in Example 400 using INT20
418	511	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 599/601 (M + H)	prepared using the method described in Example 400 using INT20
419	512	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 563/565 (M + 1)	Prepared using the method described in Example 407
420	513	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 629/631 (M + H)	prepared using the method described in Example 400 using INT20
421	514	HPLC (method 1) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 514 (M + 1)	prepared using the method described in Example 48 using INT69
422	515	HPLC (method 2) tR = 1.9 min LCMS (ESI, pos. ion spectrum) m/z 566/568 (M + 1)	prepared using the method described in Example 421 using the title compound of Example 397
423	516	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 635/637 (M + 1)	Prepared using title compound of Example 409 using the method described in Example 316
424	517	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 634/636 (M + 1)	Prepared using title compound of Example 409 using the method described Example 317
425	518	HPLC (method 3) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 587/589 (M + 1)	prepared using the method described in Example 400 using INT18
426	519	HPLC (method 2) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 539/541 (M + 1)	prepared using the method described in Example 1 with INT1 and INT9
427	520	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 606/608 (M + 1)	Prepared using title compound of Example 409 using the method described in Example 407
428	521	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 678/680 (M + 1)	Prepared using title compound of Example 409 using the method described in Example 407
429	522	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 505/507 (M + 1)	Title compound of Example 429
430	523	HPLC (method 10) tR = 6.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 697 (M + 1)	prepared using the methods described in Example 130 using the title compound of Example 329
431	524	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 575/577 (M + H)	Title compound of Example 431
432	525	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 524/526 (M + H)	prepared using the method described in Example 613 part A using INT18 and Example 431 part C compound and 2 equiv. of triethylamine
433	526	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 492/494 (M + H)	prepared using the method described in Example 613 part A using INT17 and Example 431 part C compound and 2 equiv. of triethylamine
434	527	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 603/605 (M + H)	prepared using the method described in Example 400 using INT20
435	528	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 589/591 (M + H)	prepared using the method described in Example 400 using INT20
436	529	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 545/547 (M + H)	prepared using the method described in Example 400 using INT20
437	530	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 573/575 (M + H)	prepared using the method described in Example 400 using INT20
438	531	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 561/563 (M + H)	prepared using the method described in Example 400 using INT20
439	532	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 603/605 (M + H)	prepared using the method described in Example 400 using INT20
440	533	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 665/667 (M + H)	prepared using the method described in Example 400 using INT20
441	534	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 685/687 (M + H)	prepared using the method described in Example 400 using INT20
442	535	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 684/686 (M + H)	prepared using the method described in Example 400 using INT20
443	536	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 607/609 (M + H)	prepared using the method described in Example 400 using INT20
444	537	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 608/610 (M + H)	prepared using the method described in Example 400 using INT20
445	538	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 647/649 (M + H)	prepared using the method described in Example 400 using INT20
446	539	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 674/676 (M + H)	prepared using the method described in Example 400 using INT20
447	540	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 501/503 (M + 1)	Prepared using the method described in Example 410
448	541	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 541/543 (M + 1)	Prepared using the method described in Example 410
449	542	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 543/545 (M + 1)	Prepared using the method described in Example 410
450	543	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 640/642 (M + H)	prepared using the method described in Example 400 using INT20
451	544	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 585/587 (M + H)	prepared using the method described in Example 400 using INT20
452	545	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 599/601 (M + H)	prepared using the method described in Example 400 using INT20
453	546	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 628/630 (M + H)	prepared using the method described in Example 400 using INT20
454	547	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 680/682 (M + H)	prepared using the method described in Example 400 using INT20
455	548	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 603/605 (M + H)	prepared using the method described in Example 400 using INT20
456	549	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 594/596 (M + H)	prepared using the method described in Example 400 using INT20
457	550	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 487/489 (M + 1)	Prepared using the method described in Example 429 using INT11
458	551	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 601/603 (M + H)	prepared using the method described in Example 400 using INT20
459	552	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 601/603 (M + H)	prepared using the method described in Example 400 using INT20
460	553	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 573/575 (M + H)	prepared using the method described in Example 400 using INT20
461	554	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 569/571 (M + H)	prepared using the method described in Example 400 using INT20
462	555	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 585/587 (M + H)	prepared using the method described in Example 400 using INT20
463	556	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 615/617 (M + H)	prepared using the method described in Example 400 using INT20
464	557	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 587/589 (M + H)	prepared using the method described in Example 400 using INT20
465	558	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 649/651 (M + H)	prepared using the method described in Example 400 using INT20
466	559	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 628/630 (M + H)	prepared using the method described in Example 400 using INT20
467	560	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 642/644 (M + H)	prepared using the method described in Example 400 using INT20
468	561	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 457/459 (M + H)	prepared using the method described in Example 130 using INT13
469	562	HPLC (method 2) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 561 (M + 1)	prepared using the method described in Example 421 using the title compound of Example 396
470	563	HPLC (method 2) tR = 1.9 min LCMS (ESI, pos. ion spectrum) m/z 571/573 (M + 1)	prepared using the method described in Example 421 using the title compound of Example 396
471	564	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 628/630 (M + H)	prepared using the method described in Example 400 using INT20
472	565	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 614/616 (M + H)	prepared using the method described in Example 400 using INT20
473	566	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 629/631 (M + H)	prepared using the method described in Example 400 using INT20
474	567	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 662/664 (M + H)	prepared using the method described in Example 400 using INT20
475	568	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 657/659 (M + H)	prepared using the method described in Example 400 using INT20
476	569	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 628/630 (M + H)	prepared using the method described in Example 400 using INT20
477	570	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 645/647 (M + H)	prepared using the method described in Example 400 using INT20
478	571	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 643/645 (M + H)	prepared using the method described in Example 400 using INT20
479	572	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 628/630 (M + H)	prepared using the method described in Example 400 using INT20
480	573	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 575/577 (M + H)	prepared using the method described in Example 400 using INT20
481	574	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 589/591 (M + H)	prepared using the method described in Example 400 using INT20
482	575	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 589/591 (M + H)	prepared using the method described in Example 400 using INT20
483	576	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 599/601 (M + H)	prepared using the method described in Example 400 using INT20
484	577	HPLC (method 2) tR = 1.9 min LCMS (ESI, pos. ion spectrum) m/z 559/561 (M + 1)	prepared using the method described in Example 421 using the title compound of Example 363
485	578	HPLC (method 2) tR = 1.9 min LCMS (ESI, pos. ion spectrum) m/z 593/595 (M + 1)	prepared using the method described in Example 421 using the title compound of Example 363
486	579	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 531/533 (M + H)	prepared using the method described in Example 400 using INT20
487	580	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 615/617 (M + H)	prepared using the method described in Example 400 using INT20
488	581	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 659/661 (M + H)	prepared using the method described in Example 400 using INT20
489	582	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 715/717 (M + H)	prepared using the method described in Example 400 using INT20
490	583	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 689/691/693 (M + H)	prepared using the method described in Example 400 using INT20
491	584	HPLC (method 1) tR = 2.5 min LCMS (ESI, pos. ion spectrum) m/z 600/602 (M + H)	prepared using the method described in Example 400 using INT20
492	585	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 642/644 (M + H)	prepared using the method described in Example 400 using INT20
493	586	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 488/490 (M + H)	prepared using the method described in Example 400 using INT20
494	587	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 631/633 (M + 1)	Title compound of Example 494
495	588	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 616/618 (M + 1)	Prepared using the methods described in Example 494
496	589	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 594/596 (M + 1)	Prepared using the methods described in Example 494
497	590	HPLC (method 6) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 602/604 (M + 1)	Prepared using the methods described in Example 494
498	591	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 602/604 (M + 1)	Prepared using the methods described in Example 494
499	592	HPLC (method 6) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 559/561 (M + 1)	Prepared using the methods described in Example 494
500	593	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 529/531 (M + 1)	Prepared using the methods described in Example 494
501	594	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 602/604 (M + 1)	Prepared using the methods described in Example 494
502	595	HPLC (method 6) tR = 1.7 min LCMS (ESI, pos. ion spectrum) m/z 565/567 (M + 1)	Prepared using the methods described in Example 494
503	596	HPLC (method 6) tR = 1.7 min LCMS (ESI, pos. ion spectrum) m/z 572/574 (M + 1)	Prepared using the methods described in Example 494
504	597	HPLC (method 6) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 649/651 (M + 1)	Prepared using the methods described in Example 494
505	598	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 587/589 (M + 1)	Prepared using the methods described in Example 494
506	599	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 591/593 (M + 1)	Prepared using the methods described in Example 494
507	600	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 591/593 (M + 1)	Prepared using the methods described in Example 494
508	601	HPLC (method 6) tR = 1.7 min LCMS (ESI, pos. ion spectrum) m/z 591/593 (M + 1)	Prepared using the methods described in Example 494
509	602	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 552/554 (M + 1)	Prepared using the methods described in Example 494
510	603	HPLC (method 6) tR = 1.7 min LCMS (ESI, pos. ion spectrum) m/z 618/620 (M + 1)	Prepared using the methods described in Example 494
511	604	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 609/611 (M + 1)	Prepared using the methods described in Example 494
512	605	HPLC (method 6) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 631/633 (M + 1)	Prepared using the methods described in Example 494
513	606	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 616/618 (M + 1)	Prepared using the methods described in Example 494
514	607	HPLC (method 6) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 594/596 (M + 1)	Prepared using the methods described in Example 494
515	608	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 602/604 (M + 1)	Prepared using the methods described in Example 494
516	609	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 602/604 (M + 1)	Prepared using the methods described in Example 494
517	610	HPLC (method 6) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 559/561 (M + 1)	Prepared using the methods described in Example 494
518	611	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 529/531 (M + 1)	Prepared using the methods described in Example 494
519	612	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 602/604 (M + 1)	Prepared using the methods described in Example 494
520	613	HPLC (method 6) tR = 1.7 min LCMS (ESI, pos. ion spectrum) m/z 565/567 (M + 1)	Prepared using the methods described in Example 494
521	614	HPLC (method 6) tR = 1.7 min LCMS (ESI, pos. ion spectrum) m/z 572/574 (M + 1)	Prepared using the methods described in Example 494
522	615	HPLC (method 6) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 649/651 (M + 1)	Prepared using the methods described in Example 494
523	616	HPLC (method 6) tR = 1.7 min LCMS (ESI, pos. ion spectrum) m/z 587/589 (M + 1)	Prepared using the methods described in Example 494
524	617	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 591/593 (M + 1)	Prepared using the methods described in Example 494
525	618	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 552/554 + C94 (M + 1)	Prepared using the methods described in Example 494
526	619	HPLC (method 6) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 591/593 (M + 1)	Prepared using the methods described in Example 494
527	620	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 552/554 (M + 1)	Prepared using the methods described in Example 494
528	621	HPLC (method 6) tR = 1.7 min LCMS (ESI, pos. ion spectrum) m/z 618/620 (M + 1)	Prepared using the methods described in Example 494
529	622	HPLC (method 2) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 560/562 (M + 1)	prepared using the method described in Example 421
530	623	HPLC (method 2) tR = 2.1 min LCMS (ESI, pos. ion spectrum) m/z 594/596 (M + 1)	prepared using the method described in Example 421
531	624	HPLC (method 2) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 560/562 (M + 1)	prepared using the method described in Example 421
532	625	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 559/561 (M + 1)	Title compound of Example 532
533	626	LCMS (method 4) tR = 1.6 min (ESI, pos. ion spectrum) m/z 567 (M + 1)	prepared using the method described in Example 532
534	627	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 589/591 (M + H)	Title compound of Example 534
535	628	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 651/653 (M + H)	prepared using the title compound of Example 440 and INT20 using the method described in Example 534
536	629	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 681/683 (M + H)	prepared using the method described in Example 400 using INT20
537	630	HPLC (method 1) tR = 2.3 min LCMS (ESI, pos. ion spectrum) m/z 545/547 (M + H)	prepared using the method described in Example 400 using INT22
538	631	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 559/561 (M + 1)	prepared using the method described in Example 421 using the title compound of Example 415
539	632	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 521 (M + 1)	prepared using the method described in Example 421 using the title compound of Example 415
540	633	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 555 (M + 1)	prepared using the method described in Example 421 using the title compound of Example 415
541	634	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 539 (M + 1)	prepared using the method described in Example 421 using the title compound of Example 415
542	635	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 539 (M + 1)	prepared using the method described in Example 532
543	636	HPLC (method 2) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 490/492 (M + 1)	prepared using the method described in Example 1 using INT9
544	637	HPLC (method 1) tR = 2.3 min LCMS (ESI, pos. ion spectrum) m/z 501/503 (M + 1)	Prepared using the method described in Example 410
545	638	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 577/579 (M + 1)	Prepared using the method described in Example 410
546	639	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 555/557 (M + 1)	Prepared using the method described in Example 410
547	640	HPLC (method 1) tR = 2.2 min LCMS (ESI, pos. ion spectrum) m/z 605/607 (M + 1)	Prepared using the method described in Example 410
548	641	HPLC (method 1) tR = 2.3 min LCMS (ESI, pos. ion spectrum) m/z 541/543 (M + 1)	Prepared using the method described in Example 410
549	642	HPLC (method 1) tR = 2.2 min LCMS (ESI, pos. ion spectrum) m/z 525/527 (M + 1)	Prepared using the method described in Example 410
550	643	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 631/633 (M + 1)	Prepared using the method described in Example 410
551	644	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 603/605 (M + 1)	Prepared using the method described in Example 410
552	645	HPLC (method 1) tR = 2.2 min LCMS (ESI, pos. ion spectrum) m/z 556/558 (M + 1)	Prepared using the method described in Example 410
553	646	HPLC (method 1) tR = 2.5 min LCMS (ESI, pos. ion spectrum) m/z 613/615 (M + 1)	Prepared using the method described in Example 410
554	647	HPLC (method 1). tR = 2.5 min LCMS (ESI, pos. ion spectrum) m/z 613/615 (M + 1)	Prepared using the method described in Example 410
555	648	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 640/642 (M + 1)	Prepared using the method described in Example 410
556	649	HPLC (method 1) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 584/586 (M + 1)	Prepared using the method described in Example 410
557	650	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 555/557 (M + 1)	Prepared using the method described in Example 410
558	651	HPLC (method 1) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 555/557 (M + 1)	Prepared using the method described in Example 410
559	652	HPLC (method 1) tR = 3.6 min LCMS (ESI, pos. ion spectrum) m/z 476/478 (M + 1)	Prepared using the methods described in Example INT3 and Example 48
560	653	HPLC (method 1) tR = 3.5 min LCMS (ESI, pos. ion spectrum) m/z 595/597 (M + 1)	Prepared using the methods described in Example INT3 and Example 48
561	654	HPLC (method 1) tR = 3.6 min LCMS (ESI, pos. ion spectrum) m/z 510 (M + 1)	Prepared using the methods described in Example INT3 and Example 48
562	655	HPLC (method 1) tR = 3.5 min LCMS (ESI, pos. ion spectrum) m/z 629 (M + 1)	Prepared using the method described in Example 48
563	656	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 548/550 (M + 1)	Prepared using the method described in Example 316 using the title compound of Example 429
564	657	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 547/549 (M + 1)	Prepared using the method described in Example 317 using the title compound of Example 429
565	658	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 576/578 (M + 1)	Prepared using the method described in Example 48 using the title compound of Example 429
566	659	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 583/585 (M + 1)	Prepared using the method described in Example 21 using the title compound of Example 429
567	660	HPLC (method 1) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 649/561 (M + 1)	Prepared using the method described in Example 21 using the title compound of Example 429
568	661	HPLC (method 1) tR = 2.6 min LRMS (ESI, pos. ion spectrum) m/z 554/556 (M + H)	Prepared using the method described in Example 613
569	662	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 592/594 (M + H)	Prepared using the method described in Example 613
570	663	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 640/642 (M + H)	Title compound of Example 570
571	664	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 632/634 (M + H)	Title compound of Example 571
572	665	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 698/700 (M + H)	Prepared using the method described in Example 571
573	666	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 712/714 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 615
574	667	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 552/554 (M + 1)	Title compound of Example 574
575	668	HPLC (method 6) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 459/461 (M + 1)	Title compound of Example 575
576	669	HPLC (method 6) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 501/503 (M + 1)	Prepared using the method described in Example 575
577	670	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 563/565 (M + 1)	Prepared using the method described in Example 575
578	671	HPLC (method 1) tR = 4.0 min LCMS (ESI, pos. ion spectrum) m/z 649/651 (M − H)	Title compound of Example 578
579	672	HPLC (method 3) tR = 2.6 min LCMS (ESI, pos. ion spectrum) m/z 457/459 (M + 1)	prepared using the method described in Example 1 using INT25
580	673	HPLC (method 6) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 680/682 (M + 1)	Prepared using the methods described in Example 494
581	674	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 616/618 (M + 1)	Prepared using the method described in Example 48 using the title compound of Example 429
582	675	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 616/618 (M + 1)	Prepared using the methods described in Example 48 and 178 part B using the title compound of Example 429 and 1-(1,1-dimethyl- ethyl) 1,4- Piperidinedi- carboxylate
583	676	HPLC (method 1) tR = 3.0 min LCMS (ESI, pos. ion spectrum) m/z 616/618 (M + 1)	From EXAMPLE 429 Prepared using the method described in Examples 48 and 178 part B1-(1,1- dimethylethyl) 1,3-Piperidinedi- carboxylate
584	677	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 670/672 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 569
585	678	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 684/686 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 569
586	679	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 698/700 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 569
587	680	HPLC (method 1) tR = 3.1 min LCMS (ESI, pos. ion spectrum) m/z 614/616 (M + 1)	Prepared using the method described in Example 48 using the title compound of Example 429
588	681	HPLC (method 1) tR = 3.21 min LRMS (ESI, pos. ion spectrum) m/z 736/738 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 569
589	682	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 660/662 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 568 at elevated temperature
590	683	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 699/701 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 569 at elevated temperature
591	684	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 660/662 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 615
592	685	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 674/676 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 615
593	686	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 646/648 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 568
594	687	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 660/662 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 568
595	688	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 622/624 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 613
596	689	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 650/652 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 613
597	690	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 688/690 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 613
598	691	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 636/638 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 613
599	692	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 690/692 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 613
600	693	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 703/705 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 613
601	694	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 706/708 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 614
602	695	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 708/710 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 614
603	696	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 721/723 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 614
604	697	HPLC (method 2) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 551 (M − 1)	Title compound of Example 604
605	698	HPLC (method 2) tR = 1.9 min LCMS (ESI, pos. ion spectrum) m/z 551 (M + 1)	prepared using the method described in Example 604
606	699	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 654/656 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 614
607	700	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 721/723 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 614
608	701	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 654/656 (M − H)	Title compound of Example 608
609	702	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 599/601 (M + H)	prepared using the method described in Example 400 using INT20
610	703	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 559/561 (M + H)	prepared using the method described in Example 400 using INT20
611	704	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 668/670 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 614
612	705	HPLC (method 1) tR = 2.2 min LRMS (ESI, pos. ion spectrum) m/z 530/532 (M + H)	Prepared using the method described in Example 613
613	706	HPLC (method 1) tR = 2.1 min LRMS (ESI, pos. ion spectrum) m/z 544/546 (M − H)	Title compound of Example 613
614	707	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 562/564 (M − H)	Prepared using the method described in Example 613 part A using INT15
615	708	HPLC (method 1) tR = 2.5 min LRMS (ESI, pos. ion spectrum) m/z 568 (M − H)	Prepared using the method described in Example 613 part A using INT17
616	709	HPLC (method 2) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 539/541 (M + 1)	prepared using the method described in Example 1 with INT 2 and INT9
617	710	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 616/618 (M + 1)	Prepared using the method described in Example 48 using the title compound of Example 429
618	711	HPLC (method 7) tR = 3.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 608/610 (M − 1)	Title compound of Example 618
619	712	HPLC (method 7) tR = 3.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 608/610 (M − 1)	Title compound of Example 619
620	713	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 635/637/639 (M − 1)	Title compound of Example 620
621	714	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 635/637/639 (M − 1)	Title compound of Example 621
622	715	HPLC (method 7) tR = 2.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 517/519 (M − 1)	Title compound of Example 622
623	716	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 572/574 (M + 1)	Prepared using the methods described in Example 494
624	717	HPLC (method 7) tR = 2.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 517/519 (M − 1)	Title compound of Example 624
625	718	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 599/601/603 (M + 1)	Prepared using the procedures described in Example 622
626	719	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 599/601/603 (M + 1)	Prepared using the procedures described in Example 622
627	720	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 685/687 (M + 1)	Prepared using the procedures described in Example 620
628	721	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 685/687 (M + 1)	Prepared using the procedures described in Example 620
629	722	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 576/578 (M + H)	prepared using the method described in Example 130 using INT19
630	723	HPLC (method 1) tR = 3.5 min LCMS (ESI, pos. ion spectrum) m/z 601/603 (M − H)	Title compound of Example 630
631	724	HPLC (method 3) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 490/492 (M + 1)	prepared using the method described in Example 1
632	725	HPLC (method 6) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 545/547 (M + 1)	Prepared using the methods described in Example 494
633	726	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 557/559 (M + 1)	Prepared using the methods described in Example 494
634	727	HPLC (method 6) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 559/561 (M + 1)	Prepared using the methods described in Example 494
635	728	HPLC (method 6) tR = 1.5 min LCMS (ESI, pos. ion spectrum) m/z 638/640 (M + 1)	Prepared using the methods described in Example 494
636	729	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 586/588 (M + 1)	Prepared using the methods described in Example 494
637	730	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 587/589 (M + 1)	Prepared using the methods described in Example 494
638	731	HPLC (method 6) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 606/608 (M + 1)	Prepared using the methods described in Example 494
639	732	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 572/574 (M + 1)	Prepared using the methods described in Example 494
640	733	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 544/546 (M + 1)	Prepared using the methods described in Example 494
641	734	HPLC (method 6) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 611/613 (M + 1)	Prepared using the methods described in Example 494
642	735	HPLC (method 6) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 593/595 (M + 1)	Prepared using the methods described in Example 494
643	736	HPLC (method 6) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 579/581 (M + 1)	Prepared using the methods described in Example 494
644	737	HPLC (method 6) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 579/581 (M + 1)	Prepared using the methods described in Example 494
645	738	HPLC (method 6) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 542/544 (M + 1)	Prepared using the methods described in Example 494
646	739	HPLC (method 6) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 567/569 (M + 1)	Prepared using the methods described in Example 494
647	740	HPLC (method 6) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 573/575 (M + 1)	Prepared using the methods described in Example 494
648	741	HPLC (method 6) tR = 1.6 min LCMS (ESI, pos. ion spectrum) m/z 543/545 (M + 1)	Prepared using the methods described in Example 494
649	742	HPLC (method 6) tR = 1.3 min LCMS (ESI, pos. ion spectrum) m/z 558/560 (M + 1)	Prepared using the methods described in Example 494

[0308]

Ex #	Structure	characterization	method
650	743	HPLC (method 4) tR = 1.4 min LCMS (ESI, pos. ion spectrum) m/z 573/575 (M + 1)	prepared using the method described in Example 1 using INT9
651	744	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 645/647 (M + 1)	Prepared using the procedures described in Example 620
652	745	HPLC (method 7) tR = 3.4 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 645/647 (M + 1)	Prepared using the procedures described in Example 620
653	746	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 714/716/718 (M + 1)	Prepared using the procedures described in Example 620
654	747	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 714/716/718 (M + 1)	Prepared using the procedures described in Example 620
655	748	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 655 (M + H)	Title compound of Example 655
656	749	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 669 (M + H)	Prepared using the procedure described in Example 655
657	750	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 629/631 (M + H)	Prepared using the procedure described in Example 655
658	751	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 615/617 (M + H)	Prepared using the procedure described in Example 655
659	752	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 601/603 (M + H)	Prepared using the procedure described in Example 655
660	753	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 629/631 (M + H)	Prepared using the procedure described in Example 655
661	754	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 673/675 (M + H)	Prepared using the procedure described in Example 655
662	755	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 663/665 (M + H)	Prepared using the procedure described in Example 655
663	756	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 643/645 (M + H)	Prepared using the procedure described in Example 655
664	757	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 673/675 (M + H)	Prepared using the procedure described in Example 655
665	758	HPLC (method YW1) tR = 2.6 min LRMS (ESI, pos. ion spectrum) m/z 587/589 (M + H)	Prepared using the procedure described in Example 655
666	759	HPLC (method 1) tR = 3.4 min LRMS (ESI, pos. ion spectrum) m/z 679/681 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 615
667	760	HPLC (method 1) tR = 3.5 min LRMS (ESI, pos. ion spectrum) m/z 693/695 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 615
668	761	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 653/655 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 615
669	762	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 639/641 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 615
670	763	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 625/627 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 615
671	764	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 653/655 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 615
672	765	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 697/699 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 615
673	766	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 687/689 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 615
674	767	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 667/669 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 615
675	768	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 697/699 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 615
676	769	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 611/613 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 615
677	770	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 641/643 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 612
678	771	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 655/657 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 612
679	772	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 615/617 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 612
680	773	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 601/603 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 612
681	774	HPLC (method 1) tR = 2.6 min LRMS (ESI, pos. ion spectrum) m/z 587/589 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 612
682	775	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 615/617 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 612
683	776	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 659/661 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 612
684	777	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 649/651 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 612
685	778	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 629/631 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 612
686	779	HPLC (method 1) tR = 2.5 min LRMS (ESI, pos. ion spectrum) m/z 573/575 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 612
687	780	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 649/651 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 569
688	781	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 663/665 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 569
689	782	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 677/679 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 569
690	783	HPLC (method 1) tR = 3.4 min LRMS (ESI, pos. ion spectrum) m/z 703/705 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 569
691	784	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 635/637 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 569
692	785	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 611/613 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 568
693	786	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 625/627 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 568
694	787	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 639/641 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 568
695	788	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 665/667 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 568
696	789	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 597/599 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 568
697	790	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 683/685 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 568
698	791	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 605/607 (M + H)	Prepared using the procedure described in Example 655 using the title compound of Example 614
699	792	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 623/625 (M + 1)	Prepared using the method described in Examples 48 and 178 part B using title compound of Example 702 and 1-(1,1-dimethyl- ethyl) (2R)-1,2- piperidinedi- carboxylate
700	793	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 554/556 (M + 1)	Prepared using the method described in Example 317 using the title compound of Example 702
701	794	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 555/557 (M + 1)	Prepared using the method described in Example 316 using the title compound of Example 702
702	795	HPLC (method 1) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 512/514 (M + 1)	Prepared using the method described in Example 429 using INT14
703	796	HPLC (method 1) tR = 2.2 min LCMS (ESI, pos. ion spectrum) m/z 556/558 (M + H)	prepared using the method described in Example 130 using INT19
704	797	HPLC (method 1) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 556/558 (M + H)	prepared using the method described in Example 130 using INT14
705	798	HPLC (method 1) tR = 2.1 min LCMS (ESI, pos. ion spectrum) m/z 570/572 (M + H)	prepared using the method described in Example 400 using INT21
706	799	HPLC (method 1) tR = 2.5 min LCMS (ESI, pos. ion spectrum) m/z 653/655 (M + H)	prepared using the method described in Example 400 using INT21
707	800	HPLC (method 6) tR = 1.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 610/612 (M + 1)	Prepared using the procedures described in Example 618
708	801	HPLC (method 7) tR = 3.2 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 610/612 (M + 1)	Prepared using the procedures described in Example 618
709	802	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 581/583 (M + 1)	Prepared using the procedures described in Example 620
710	803	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 601/603 (M + 1)	Prepared using the procedures described in Example 620
711	804	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 635/637/639 (M + 1)	Prepared using the procedures described in Example 620
712	805	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 669/671/673 (M + 1)	Prepared using the procedures described in Example 620
713	806	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 629/631 (M + 1)	Prepared using the procedures described in Example 620
714	807	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 669/671 (M + 1)	Prepared using the procedures described in Example 620
715	808	HPLC (method 6) tR = 1.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 658/660 (M + 1)	Prepared using the procedures described in Example 620
716	809	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 646/648 (M + 1)	Prepared using the procedures described in Example 620
717	810	HPLC (method 6) tR = 1.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 679/681 (M + 1)	Prepared using the procedures described in Example 620
718	811	HPLC (method 6) tR = 2.0 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 675/677/679 (M + 1)	Prepared using the procedures described in Example 620
719	812	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 620/622 (M + 1)	Prepared using the procedures described in Example 620
720	813	HPLC (method 6) tR = 2.0 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 705/707/709 (M + 1)	Prepared using the procedures described in Example 620
721	814	HPLC (method 6) tR = 1.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 545/547 (M + 1)	Prepared using the procedures described in Example 622
722	815	HPLC (method 6) tR = 1.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 547/549 (M + 1)	Prepared using the procedures described in Example 622
723	816	HPLC (method 6) tR = 1.4 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 612/614 (M + 1)	Prepared using the procedures described in Example 622
724	817	HPLC (method 6) tR = 1.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 657/659 (M + 1)	Prepared using the procedures described in Example 622
725	818	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 571/573 (M + 1)	Prepared using the procedures described in Example 622
726	819	HPLC (method 6) tR = 1.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 529/531 (M + 1)	Prepared using the procedures described in Example 622
727	820	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 633/635/637 (M + 1)	Prepared using the procedures described in Example 622
728	821	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 617/619/621 (M + 1)	Prepared using the procedures described in Example 622
729	822	HPLC (method 6) tR = 2.0 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 633/635/637 (M + 1)	Prepared using the procedures described in Example 622
730	823	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 585/587 (M + 1)	Prepared using the procedures described in Example 622
731	824	HPLC (method 6) tR = 1.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 584/586 (M + 1)	Prepared using the procedures described in Example 622
732	825	HPLC (method 6) tR = 1.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 600/602/604 (M + 1)	Prepared using the procedures described in Example 622
733	826	HPLC (method 6) tR = 1.3 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 566/568 (M + 1)	Prepared using the procedures described in Example 622
734	827	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 605/607 (M + 1)	Prepared using the procedures described in Example 622
735	828	HPLC (method 6) tR = 1.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 632/634 (M + 1)	Prepared using the procedures described in Example 622
736	829	HPLC (method 6) tR = 1.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 641/643 (M + 1)	Prepared using the procedures described in Example 622
737	830	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 580/582 (M + 1)	Prepared using the procedures described in Example 618
738	831	HPLC (method 6) tR = 1.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 614/616/618 (M + 1)	Prepared using the procedures described in Example 618
739	832	HPLC (method 6) tR = 1.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 648/650 (M + 1)	Prepared using the procedures described in Example 618
740	833	HPLC (method 6) tR = 1.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 648/650 (M + 1)	Prepared using the procedures described in Example 618
741	834	HPLC (method 6) tR = 1.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 630/632 (M + 1)	Prepared using the procedures described in Example 618
742	835	HPLC (method 6) tR = 2.1 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 648/650/652 (M + 1)	Prepared using the procedures described in Example 618
743	836	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 622/624 (M + 1)	Prepared using the procedures described in Example 618
744	837	HPLC (method 8) tR = 1.8 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 670/672 (M − 1)	Prepared using the procedures described in Example 618
745	838	HPLC (method 8) tR = 1.6 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 624/626 (M − 1)	Prepared using the procedures described in Example 618
746	839	HPLC (method 8) tR = 1.5 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 636/638 (M − 1)	Prepared using the procedures described in Example 618
747	840	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 581/583 (M + 1)	Prepared using the procedures described in Example 620
748	841	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 601/603 (M + 1)	Prepared using the procedures described in Example 620
749	842	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 635/637/639 (M + 1)	Prepared using the procedures described in Example 620
750	843	HPLC (method 6) tR = 1.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 669/671/673 (M + 1)	Prepared using the procedures described in Example 620
751	844	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 629/631 (M + 1)	Prepared using the procedures described in Example 620
752	845	HPLC (method 6) tR = 1.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 669/671 (M + 1)	Prepared using the procedures described in Example 620
753	846	HPLC (method 6) tR = 1.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 658/660 (M + 1)	Prepared using the procedures described in Example 620
754	847	HPLC (method 8) tR = 1.6 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 644/646 (M − 1)	Prepared using the procedures described in Example 620
755	848	HPLC (method 6) tR = 1.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 679/681 (M + 1)	Prepared using the procedures described in Example 620
756	849	HPLC (method 6) tR = 2.0 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 675/677/679 (M + 1)	Prepared using the procedures described in Example 620
757	850	HPLC (method 6) tR = 1.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 620/622 (M + 1)	Prepared using the procedures described in Example 620
758	851	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 674/676 (M + 1)	Prepared using the procedures described in Example 620
759	852	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 681/683/685 (M + 1)	Prepared using the procedures described in Example 620
760	853	HPLC (method 5) tR = 2.1 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 705/707/709 (M + 1)	Prepared using the procedures described in Example 620
761	854	HPLC (method 8) tR = 1.4 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 543/545 (M − 1)	Prepared using the procedures described in Example 622
762	855	HPLC (method 8) tR = 1.3 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 545/547 (M − 1)	Prepared using the procedures described in Example 622
763	856	HPLC (method 8) tR = 1.4 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 612/614 (M − 1)	Prepared using the procedures described in Example 622
764	857	HPLC (method 8) tR = 1.5 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 655/657 (M − 1)	Prepared using the procedures described in Example 622
765	858	HPLC (method 8) tR = 1.5 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 569/571 (M − 1)	Prepared using the procedures described in Example 622
766	859	HPLC (method 8) tR = 1.3 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 527/529 (M − 1)	Prepared using the procedures described in Example 622
767	860	HPLC (method 8) tR = 1.6 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 631/633/635 (M − 1)	Prepared using the procedures described in Example 622
768	861	HPLC (method 8) tR = 1.6 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 615/617/619 (M − 1)	Prepared using the procedures described in Example 622
769	862	HPLC (method 8) tR = 1.8 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 631/633/635 (M − 1)	Prepared using the procedures described in Example 622
770	863	HPLC (method 6) tR = 1.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 554/556 (M + 1)	Prepared using the procedures described in Example 622
771	864	HPLC (method 8) tR = 1.5 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 583/585 (M − 1)	Prepared using the procedures described in Example 622
772	865	HPLC (method 8) tR = 1.4 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 582/584 (M − 1)	Prepared using the procedures described in Example 622
773	866	HPLC (method 8) tR = 1.4 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 597/599/601 (M − 1)	Prepared using the procedures described in Example 622
774	867	HPLC (method 8) tR = 1.3 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 564/566 (M − 1)	Prepared using the procedures described in Example 622
775	868	HPLC (method 8) tR = 1.6 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 603/605 (M − 1)	Prepared using the procedures described in Example 622
776	869	HPLC (method 8) tR = 1.3 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 630/632 (M − 1)	Prepared using the procedures described in Example 622
777	870	HPLC (method 8) tR = 1.3 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 638/640 (M − 1)	Prepared using the procedures described in Example 622
778	871	HPLC (method 6) tR = 1.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 580/582 (M + 1)	Prepared using the procedures described in Example 618
779	872	HPLC (method 6) tR = 1.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 614/616/618 (M + 1)	Prepared using the procedures described in Example 618
780	873	HPLC (method 6) tR = 1.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 648/650 (M + 1)	Prepared using the procedures described in Example 618
781	874	HPLC (method 6) tR = 1.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 648/650 (M + 1)	Prepared using the procedures described in Example 618
782	875	HPLC (method 8) tR = 1.6 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 628/630 (M − 1)	Prepared using the procedures described in Example 618
783	876	HPLC (method 6) tR = 2.1 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 648/650/652 (M + 1)	Prepared using the procedures described in Example 618
784	877	HPLC (method 8) tR = 1.4 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 620/622 (M − 1)	Prepared using the procedures described in Example 618
785	878	HPLC (method 8) tR = 1.8 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 670/672 (M − 1)	Prepared using the procedures described in Example 618
786	879	HPLC (method 8) tR = 1.6 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 624/626 (M − 1)	Prepared using the procedures described in Example 618
787	880	HPLC (method 8) tR = 1.5 min LCMS (method 8) (ESI, neg. ion spectrum) m/z 636/638 (M − 1)	Prepared using the procedures described in Example 618
788	881	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 634/636 (M + H)	Title compound of Example 788
789	882	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 648/650 (M + H)	Prepared using the procedure described in Example 788
790	883	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 662/664 (M + H)	Prepared using the procedure described in Example 788
791	884	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 660/662 (M + H)	Prepared using the procedure described in Example 788
792	885	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 664/666 (M + H)	Prepared using the procedure described in Example 788
793	886	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 678/680 (M + H)	Prepared using the procedure described in Example 788
794	887	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 712/714 (M + H)	Prepared using the procedure described in Example 788
795	888	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 687/689 (M + H)	Prepared using the procedure described in Example 788
796	889	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 702/704 (M + H)	Prepared using the procedure described in Example 788
797	890	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 596/598 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 568
798	891	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 610/612 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 568
799	892	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 624/626 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 568
800	893	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 622/624 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 568
801	894	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 626/628 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 568
802	895	HPLC (method 2) tR = 2.1 min LCMS (ESI, pos. ion spectrum) m/z 456/458 (M + 1)	prepared using the method described in Example 130 with INT3
803	896	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 640/642 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 568
804	897	HPLC (method 2) tR = 2.0 min LCMS (ESI, pos. ion spectrum) m/z 456/458 (M + 1)	prepared using the method described in Example 130 with INT4
805	898	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 674/676 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 568
806	899	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 649/651 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 568
807	900	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 664/666 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 568
808	901	HPLC (method 2) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 555/557 (M + 1)	prepared using the method described in Example 130 with INT4 and INT5
809	902	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 658/660 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 568
810	903	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 604/606 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 614
811	904	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 618/620 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 614
812	905	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 632/634 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 614
813	906	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 630/632 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 614
814	907	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 634/636 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 614
815	908	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 648/650 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 614
816	909	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 682/684 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 614
817	910	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 657/659 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 614
818	911	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 654/656 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 615
819	912	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 638/640 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 615
820	913	HPLC (method 1) tR = 3.4 min LRMS (ESI, pos. ion spectrum) m/z 664/666 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 615
821	914	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 678/680 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 615
822	915	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 672/674 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 615
823	916	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 663/665 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 615
824	917	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 680/682 (M + H)	Prepared using the procedure described in Example 613 Part A using the title compound of Example 615 and using 1/1 DMF/acetonitrile for solvent
825	918	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 624/626 (M + H)	Prepared using the procedure described in Example 613 Part A using the title compound of Example 615 and using 1/1 DMF/acetonitrile for solvent
826	919	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 688/690 (M + H)	Prepared using the procedure described in Example 613 Part A using the title compound of Example 615 and using 1/1 DMF/acetonitrile for solvent
827	920	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 636/638 (M + H)	Prepared using the procedure described in Example 613 Part A using the title compound of Example 615 and using 1/1 DMF/acetonitrile for solvent
828	921	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 640/642 (M + H)	Prepared using the procedure described in Example 788 using the title compound of Example 615
829	922	HPLC (method 1) tR = 3.5 min LRMS (ESI, pos. ion spectrum) m/z 751/753 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 569
830	923	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 738/740 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 569
831	924	HPLC (method 1) tR = 3.4 min LRMS (ESI, pos. ion spectrum) m/z 713/715 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 568
832	925	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 700/702 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 568
833	926	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 714/716 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 615
834	927	HPLC (method 1) tR = 3.3 min LRMS (ESI, pos. ion spectrum) m/z 727/729 (M + H)	Prepared using the method described in Example 571 using the title compound of Example 615
835	928	HPLC (method 2) tR = 1.8 min LCMS (ESI, pos. ion spectrum) m/z 555/557 (M + 1)	prepared using the method described in Example 130 with INT3 and INT5
836	929	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 517/519 (M + H)	Title compound of Example 836
837	930	HPLC (method 1) tR = 2.5 min LCMS (ESI, pos. ion spectrum) m/z 573/575 (M + H)	prepared using the method described in Example 1 using INT9 and INT24
838	931	HPLC (method 2) tR = 2.1 min LCMS (ESI, pos. ion spectrum) m/z 483/485 (M + 1)	prepared using the method described in Example 130 using INT6
839	932	HPLC (method 3) tR = 2.2 min LCMS (ESI, pos. ion spectrum) m/z 556/558 (M + 1)	prepared using the method described in Example 130 using INT5 and INT13
840	933	HPLC (method 1) tR = 2.9 min LCMS (ESI, pos. ion spectrum) m/z 511/513 (M + 1)	Prepared using the method described in Example 429 using INT17
841	934	HPLC (method 1) tR = 3.3 min LCMS (ESI, pos. ion spectrum) m/z 553/555 (M + 1)	Prepared using the method described in Example 317 using the title compound of Example 840
842	935	HPLC (method 1) tR = 3.2 min LCMS (ESI, pos. ion spectrum) m/z 543/545 (M + 1)	Prepared using the method described in Example 429 using INT18
843	936	HPLC (method 1) tR = 2.7 min LCMS (ESI, pos. ion spectrum) m/z 598/600 (M + 1)	From title compound of Example 702 using using the method described in Example 407
844	937	HPLC (method 6) tR = 1.2 min LCMS (method 6) (ESI, pos. ion spectrum) m/z	Title compound of Example 844
845	938	HPLC (method 6) tR = 1.3 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 461/463 (M + 1)	Title compound of Example 845
846	939	HPLC (method 1) tR = 3.6 min LCMS (ESI, pos. ion spectrum) m/z 585/587 (M + 1)	Prepared using the method described in Example 317 using the title compound of Example 842
847	940	HPLC (method 1) tR = 3.6 min LCMS (ESI, pos. ion spectrum) m/z 627/629 (M + 1)	Title compound of Example 847
848	941	HPLC (method 1) tR = 3.5 min LCMS (ESI, pos. ion spectrum) m/z 569/571 (M + 1)	Title compound of Example 848
849	942	HPLC (method 3) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 556/558 (M + 1)	prepared using the method described in Example 130 using INT5 and INT19
850	943	LCMS (method 4) tR = 1.7 min (ESI, pos. ion spectrum) m/z 593/595 (M + 1)	Title compound of Example 850
851	944	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 539 (M + 1)	prepared using the method described in Example 850
852	945	LCMS (method 4) tR = 1.7 min (ESI, pos. ion spectrum) m/z 593/595 (M + 1)	prepared using the method described in Example 850
853	946	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 585 (M + 1)	prepared using the method described in Example 850
854	947	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 545 (M + 1)	prepared using the method described in Example 850
855	948	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 545 (M + 1)	prepared using the method described in Example 850
856	949	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 525 (M + 1)	prepared using the method described in Example 850
857	950	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 539 (M + 1)	prepared using the method described in Example 850
858	951	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 539 (M + 1)	prepared using the method described in Example 850
859	952	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 555 (M + 1)	prepared using the method described in Example 850
860	953	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 539 (M + 1)	prepared using the method described in Example 850
861	954	LCMS (method 4) tR = 1.6 min (ESI, pos. ion spectrum) m/z 593/595 (M + 1)	prepared using the method described in Example 850
862	955	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 567 (M + 1)	prepared using the method described in Example 850
863	956	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 585 (M + 1)	prepared using the method described in Example 850
864	957	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 545 (M + 1)	prepared using the method described in Example 850
865	958	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 545 (M + 1)	prepared using the method described in Example 850
866	959	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 531 (M + 1)	prepared using the method described in Example 850
867	960	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 565/567 (M + 1)	prepared using the method described in Example 850
868	961	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 545 (M + 1)	prepared using the method described in Example 850
869	962	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 565/567 (M + 1)	prepared using the method described in Example 850
870	963	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 545 (M + 1)	prepared using the method described in Example 850
871	964	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 561 (M + 1)	prepared using the method described in Example 850
872	965	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 561 (M + 1)	prepared using the method described in Example 850
873	966	LCMS (method 4) tR = 1.7 min (ESI, pos. ion spectrum) m/z 599/601 (M + 1)	prepared using the method described in Example 850
874	967	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 545 (M + 1)	prepared using the method described in Example 850
875	968	LCMS (method 4) tR = 1.7 min (ESI, pos. ion spectrum) m/z 599/601 (M + 1)	prepared using the method described in Example 850
876	969	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 573 (M + 1)	prepared using the method described in Example 850
877	970	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 591 (M + 1)	prepared using the method described in Example 850
878	971	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 551 (M + 1)	prepared using the method described in Example 850
879	972	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 551 (M + 1)	prepared using the method described in Example 850
880	973	LCMS (method 4) tR = 1.3 min (ESI, pos. ion spectrum) m/z 531 (M + 1)	prepared using the method described in Example 850
881	974	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 565/567 (M + 1)	prepared using the method described in Example 850
882	975	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 545 (M + 1)	prepared using the method described in Example 850
883	976	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 565/567 (M + 1)	prepared using the method described in Example 850
884	977	LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 545 (M + 1)	prepared using the method described in Example 850
885	978	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 561 (M + 1)	prepared using the method described in Example 850
886	979	LCMS (method 4) tR = 1.7 min (ESI, pos. ion spectrum) m/z 599/601 (M + 1)	prepared using the method described in Example 850
887	980	LCMS (method 4) tR = 1.4 min (ESI, pos. ion spectrum) m/z 545 (M + 1)	prepared using the method described in Example 850
888	981	LCMS (method 4) tR = 1.6 min (ESI, pos. ion spectrum) m/z 599/601 (M + 1)	prepared using the method described in Example 850
889	982	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 573 (M + 1)	prepared using the method described in Example 850
890	983	LCMS (method 4) tR = 1.2 min (ESI, pos. ion spectrum) m/z 591 (M + 1)	prepared using the method described in Example 850
891	984	HPLC (method 3) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 570/572 (M + 1)	prepared using the method described in Example 130 using INT13
892	985	HPLC (method 7) tR = 3.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 637/639 (M + 1)	Title compound of Example 892
893	986	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 714/716 (M + 1)	Prepared using the method described in Example 892
894	987	HPLC (method 7) tR = 3.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 702/704 (M + 1)	Prepared using the method described in Example 892
895	988	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 605/607 (M + 1)	Prepared using the method described in Example 892
896	989	HPLC (method 7) tR = 3.3 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 682/684 (M + 1)	Prepared using the method described in Example 892
897	990	HPLC (method 7) tR = 3.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 670/672 (M + 1)	Prepared using the method described in Example 892
898	991	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 603/605 (M + 1)	Title compound of Example 898
899	992	HPLC (method 7) tR = 2.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 668/670 (M + 1)	Prepared using the method described in Example 898
900	993	HPLC (method 7) tR = 3.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 713/715 (M + 1)	Prepared using the method described in Example 898
901	994	HPLC (method 7) tR = 3.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 627/629 (M + 1)	Prepared using the method described in Example 898
902	995	HPLC (method 7) tR = 3.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 656/658/660 (M + 1)	Prepared using the method described in Example 898
903	996	HPLC (method 7) tR = 3.2 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 622/624 (M + 1)	Prepared using the method described in Example 898
904	997	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 688/690 (M + 1)	Prepared using the method described in Example 898
905	998	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 697/699 (M + 1)	Prepared using the method described in Example 898
906	999	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 573/575 (M + 1)	Prepared using the method described in Example 898
907	1000	HPLC (method 7) tR = 3.3 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 571/573 (M + 1)	Title compound of Example 907
908	1001	HPLC (method 7) tR = 2.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 636/638 (M + 1)	Prepared using the method described in Example 907
909	1002	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 681/683 (M + 1)	Prepared using the method described in Example 907
910	1003	HPLC (method 7) tR = 3.9 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 595/597 (M + 1)	Prepared using the method described in Example 907
911	1004	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 624/626/628 (M + 1)	Prepared using the method described in Example 907
912	1005	HPLC (method 7) tR = 3.2 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 590/592 (M + 1)	Prepared using the method described in Example 907
913	1006	HPLC (method 7) tR = 3.3 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 656/658 (M + 1)	Prepared using the method described in Example 907
914	1007	HPLC (method 7) tR = 3.2 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 665/667 (M + 1)	Prepared using the method described in Example 907
915	1008	HPLC (method 7) tR = 3.2 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 541/543 (M + 1)	Prepared using the method described in Example 907
916	1009	HPLC (method 1) tR = 3.4 min LRMS (ESI, pos. ion spectrum) m/z 450/452 (M + H)	Prepared using the method described in Example 613 Part A and INT44
917	1010	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 605/607 (M + H)	Prepared using the procedures described in Example 613 and Example 655 and using INT44
918	1011	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 619/621 (M + H)	Prepared using the procedures described in Example 613 and Example 655 and using INT44
919	1012	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 604/606 (M + H)	Prepared using the procedures described in Example 613 and Example 788 and using INT44
920	1013	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 682/684 (M + H)	Prepared using the procedures described in Example 613 and Example 788 and using INT44
921	1014	HPLC (method 1) tR = 2.2 min LRMS (ESI, pos. ion spectrum) m/z 554/556 (M + H)	Title compound of Example 921
922	1015	HPLC (method 1) tR = 2.2 min LRMS (ESI, pos. ion spectrum) m/z 519 (M + H)	Prepared using the method described in Example 921
923	1016	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 585/587	Prepared using the method described in Example 921
924	1017	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 553/555 (M + H)	Prepared using the method described in Example 921
925	1018	HPLC (method 1) tR = 2.2 min LRMS (ESI, pos. ion spectrum) m/z 554/556 (M + H)	Prepared using the method described in Example 921
926	1019	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 591/593 (M + H)	Prepared using the method described in Example 921
927	1020	HPLC (method 7) tR = 2.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 517/519 (M + 1)	Title compound of Example 927
928	1021	HPLC (method 7) tR = 2.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 485/487 (M + 1)	Title compound of Example 928
929	1022	LCMS (method 4) tR = 1.6 min (ESI, pos. ion spectrum) m/z 601/603 (M + 1)	prepared using the method described in Example 1 with INT8
930	1023	HPLC (method 7) tR = 2.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 517/519 (M + 1)	Title compound of Example 930
931	1024	HPLC (method 7) tR = 3.7 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 637/639 (M + 1)	Title compound of Example 931
932	1025	HPLC (method 7) tR = 3.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 714/716 (M + 1)	Prepared using the method described in Example 931
933	1026	HPLC (method 7) tR = 3.8 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 702/704 (M + 1)	Prepared using the method described in Example 931
934	1027	HPLC (method 1) tR = 3.6 min LCMS (ESI, pos. ion spectrum) m/z 540/542 (M + 1)	Prepared using the method described in Example 48 using INT17
935	1028	HPLC (method 2) tR = 1.9 min LCMS (method 4) tR = 1.5 min (ESI, pos. ion spectrum) m/z 587/589 (M + 1)	prepared using the method described in Example 1 using INT7
936	1029	HPLC (method 3) tR = 3.4 min LCMS (ESI, pos. ion spectrum) m/z 677/679 (M + 1)	Title compound of Example 936
937	1030	HPLC (method 7) tR = 2.5 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 485/487 (M + 1)	Prepared using the method described in Example 930
938	1031	HPLC (method 7) tR = 3.6 min LCMS (method 6) (ESI, pos. ion spectrum) m/z 670/672 (M + 1)	Prepared using the method described in Example 931
939	1032	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 646/648 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 615
940	1033	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 659/661 (M + H)	prepared using the methods described in Example 608 using the title compound of Example 612
941	1034	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 586/588 (M + H)	prepared using the methods described in Example 788 using the title compound of Example 612
942	1035	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 600/602 (M + H)	prepared using the methods described in Example 788 using the title compound of Example 612
943	1036	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 598/600 (M + H)	prepared using the methods described in Example 788 using the title compound of Example 612
944	1037	HPLC (method 1) tR = 2.6 min LRMS (ESI, pos. ion spectrum) m/z 602/604 (M + H)	prepared using the methods described in Example 788 using the title compound of Example 612
945	1038	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 616/618 (M + H)	prepared using the methods described in Example 788 using the title compound of Example 612
946	1039	HPLC (method 1) tR = 2.5 min LRMS (ESI, pos. ion spectrum) m/z 650/652 (M + H)	prepared using the methods described in Example 788 using the title compound of Example 612
947	1040	HPLC (method 1) tR = 2.6 min LRMS (ESI, pos. ion spectrum) m/z 625/627 (M + H)	prepared using the methods described in Example 788 using the title compound of Example 612
948	1041	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 640/642 (M + H)	prepared using the methods described in Example 788 using the title compound of Example 612
949	1042	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 654/656 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 613
950	1043	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 612/614 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 613
951	1044	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 639/641 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 613
952	1045	HPLC (method 1) tR = 3.1 min LRMS (ESI, pos. ion spectrum) m/z 648/650 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 613
953	1046	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 664/666 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 613
954	1047	HPLC (method 1) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 686/588 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 613
955	1048	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 616/618 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 613
956	1049	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 630/632 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 613
957	1050	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 614/616 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 613
958	1051	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 600/602 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 613
959	1052	HPLC (method 1) tR = 3.2 min LRMS (ESI, pos. ion spectrum) m/z 640/642 (M + H)	prepared using the methods described in Example 571 using the title compound of Example 613
960	1053	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 533/535 (M + H)	prepared using the methods described in Example 613 Part A using INT44
961	1054	HPLC (method 1) tR = 2.9 min LRMS (ESI, pos. ion spectrum) m/z 549/551 (M + H)	prepared using the methods described in Example 613 Part A-C using INT44
962	1055	HPLC (method 1) tR = 2.8 min LRMS (ESI, pos. ion spectrum) m/z 562/564 (M + H)	prepared using the methods described in Example 613 Part A-C using INT44
963	1056	HPLC (method 1) tR = 3.0 min LRMS (ESI, pos. ion spectrum) m/z 563/565 (M + H)	prepared using the methods described in Example 613 Part A-C using INT44
964	1057	HPLC (method 3) tR = 2.5 min LRMS (ESI, pos. ion spectrum) m/z 569/571 (M + H)	prepared using the method described in Example 130 using INT17 and INT68
965	1058	HPLC (method 3) tR = 2.6 min LRMS (ESI, pos. ion spectrum) m/z 569/571 (M + H)	prepared using the method described in Example 130 using INT17
966	1059	HPLC (method 4) tR = 1.5 min LRMS (ESI, pos. ion spectrum) m/z 569/571 (M + H)	prepared using the method described in Example 130 using INT16 and INT68
967	1060	HPLC (method 3) tR = 2.7 min LRMS (ESI, pos. ion spectrum) m/z 569/571 (M + H)	prepared using the method described in Example 130 using INT16
968	1061	HPLC (method 1) tR = 2.8 min LCMS (ESI, pos. ion spectrum) m/z 660/662 (M + 1)	Obtained as a co- product with the title compound of Example 429
969	1062	HPLC (method 1) tR = 2.4 min LCMS (ESI, pos. ion spectrum) m/z 642/644 (M + 1)	Obtained as a co- product with the title compound of Example 457
970	1063	HPLC (method 1) tR = 4.0 min LCMS (ESI, pos. ion spectrum) m/z 855/857/859 (M + 1)	Title compound of Example 970
971		LCMS (ESI, pos.	Obtained as a co-
		ion spectrum) m/z	product with the
		819/821/823	title compound of
		(M + 1)	Example 575
	1064
972		LCMS (ESI, pos.	Prepared using
		ion spectrum) m/z	the method
		867/869/871	described in
		(M + 1)	Example 575
	1065
973	1066	HPLC (method 1) tR = 4.1 min LCMS (ESI, pos. ion spectrum) m/z 883/885/887 (M + 1)	Obtained as a co- product with the title compound of Example 429
974	1067	HPLC (method 1) tR = 3.8 min LCMS (ESI, pos. ion spectrum) m/z 847/849/851 (M + 1)	Obtained as a co- product with the title compound of Example 457

EXAMPLE 1

[0309] A mixure of INT48 (45 mg, 0.20 mmol), naphthalene-2-sulfonyl chloride (68 mg, 0.30 mmol) and triethylamine (61 mg, 0.60 mmol) were dissolved in methylene chloride (1 mL). After stirring at room temperature for 0.5 h, the reaction mixture was diluted with 20 mL of ethyl acetate. The organic solution was washed with 0.1N HCl (10 mL) and saturated aqueous sodium bicarbonate (10 mL). The organic layer was collected and concentrated. The residue was purified by reverse phase chromatography to afford the title compound (51 mg, 66%): HPLC (method 1) tR=2.7 min; LCMS (ESI, pos. ion spectrum) m/z 416 (M+H).

EXAMPLE 13

[0310] To the title compound of Example 3 (130 mg, 0.29 mmol) in 2 mL of DMF was added sodium hydride (14 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 10 min. Iodomethane (82 mg, 0.58 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and quenched with 1 mL of water. Then the reaction mixture was extracted with 10 mL of methylene chloride. The organic layer was dried and concentrated. The residue was purified by reverse phase chromatography to give the title compound (15 mg, 11%): HPLC (method 1) tR=3.2 min; LCMS (ESI, pos. ion spectrum) m/z 470/472 (M+H).

EXAMPLE 21

[0311] To a solution of INT48 (20 mg, 0.089 mmol) in dichloromethane (0.5 mL) was added triethylamine (0.013 mL, 0.089 mmol) and 6-chloronaphthalene-2-sulfonyl chloride (23 mg, 0.089 mmol). The reaction was stirred at room temperature for 1 h. The solvent was evaporated in vacuo to afford the crude product. Purification of the crude product over silica gel afforded the title compound (31 mg, 77%).

EXAMPLE 37

[0312] To 21 mL of a mixture of methanol and ethanol (1:2) was added the title compound of Example 36 (66 mg, 0.17 mmol), trifluoroacetic acid (0.3 mL) and 5 mg of 10% palladium on carbon. The reaction mixture was stirred under a hydrogen atmosphere (50 psi) for 24 h. The reaction mixture was filtered through CELITE and concentrated to provide the title compound (60 mg, 90%): HPLC (method 1) tR=1.7 min; LCMS (ESI, pos. ion spectrum) m/z 395 (M+H).

EXAMPLE 41

[0313] To a solution of INT46 (47.4 mg, 0.20 mmol) in 2 mL of dichloromethane was added INT48 (47.8 mg, 0.20 mmol) and triethylamine (0.084 mL, 0.60 mmol). After stirring at room temperature for 1 h, the mixture was concentrated. The residue was purified by reverse phase chromatography. Product-containing fractions were combined, and concentrated and dried by lyophilization to provide the title compound (46 mg, 54%): LRMS (ESI, pos. ion spectrum) m/z 426/428 (M+H); HPLC (method 1) tR=3.2 min

EXAMPLE 43

[0314] The title compound of Example 38 (43 mg, 0.074 mmol) was dissolved in 1.5 mL of THF and 1.5 mL of 1N sodium hydroxide solution. The reaction mixture was stirred at 60° C. for 9 h and then at room temperature overnight. The reaction mixture was extracted with 10 mL of ethyl acetate. The organic layer was washed with 10 mL of brine, dried and concentrated. The residue was purified by reverse phase chromatography to give the title compound (11 mg, 33%): HPLC (method 1) tR=3.0 min; LCMS (ESI, pos. ion spectrum) m/z 439/441 (M+H).

EXAMPLE 48

[0315] To a solution of INT15 (85 mg, 0.22 mmol) in dichloromethane (2 mL) was added triethylamine (0.031 mL, 0.22 mmol), thiomorpholine (0.024 mL, 0.26 mmol), a catalytic amount of 4-dimethylaminopyridine, 1-hydroxy-7-azabenzotriazole (36 mg, 0.26 mmol) and EDCI (49 mg, 0.26 mmol) in that order. The reaction was stirred at room temperature for 2 h. The reaction was then quenched with water and extracted with methylene chloride (2×5 mL). The organic layers were combined, dried over magnesium sulfate, and evaporated in vacuo to afford the crude product. Purification of the crude product over silica gel afforded the title compound (85 mg, 80%).

EXAMPLE 49

[0316] To a solution of the title compound of Example 48 (80 mg, 0.17 mmol) in methylene chloride (2 mL) at −10° C. was added slowly 3-chloroperoxybenzoic acid (37 mg, 77% pure, 0.17 mmol). After stirring for 2 h, the reaction was quenched with saturated sodium thiosulfate solution. The mixture was extracted with methylene chloride (2×5 mL). The organic fractions were combined, dried over magnesium sulfate, and evaporated in vacuo to afford the crude product. RP-HPLC purification of the crude material afforded 40 mg (47%) of the title compound.

EXAMPLE 50

[0317] To a solution of the title compound of Example 49 (27 mg, 0.054 mmol) in methylene chloride (1 mL) was added 3-chloroperoxybenzoic acid (37 mg, 77% pure, 0.17 mmol). After stirring for 1 h, the reaction was quenched with saturated sodium thiosulfate solution, and extracted with methylene chloride (2×5 mL). The organic fractions were combined, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and evaporated in vacuo to afford the the title compound (18 mg, 65%) as a white solid.

EXAMPLE 130

[0318] INT12, EDCI (29 mg, 0.15 mmol) and HOBT (14 mg, 0.10 mmol) were dissolved in 0.5 mL of acetonitrile and stirred at room temperature for 5 min. Then, N,N,N′-trimethylethane-1,2-diamine (15 mg, 0.15 mmol) was added and the reaction mixture was stirred at room temperature for an additional 30 min. The reaction mixture was quenched with 0.5 mL of water and purified by reverse phase chromatography to give the title compound (32 mg, 62%): HPLC (method 1) tR=2.1 min; LCMS (ESI, pos. ion spectrum) m/z 506/508 (M+).

EXAMPLE 148

[0319] Part A: The title compound of Example 299 (49 mg, 0.08 mmol) was dissolved in anhydrous DMF (0.4 mL). To this solution was added cesium carbonate (78 mg, 0.24 mmol), tetrabutylammonium iodide (89 mg, 0.24 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (0.052 mL, 0.24 mmol). The reaction mixture was warmed to 50° C. After 6 h the reaction mixture was partitioned between water and ethyl acetate. The organic phase was collected, and the aqueous phase extracted with ethyl acetate. The organic layers were combined, dried (sodium sulfate), and concentrated in vacuo to afford a semi-solid (75 mg).

[0320] Part B: The compound of part A was dissolved in THF (0.8 mL) and cooled to 0° C. A solution of tetrabutylammonium flouride in THF (1.0 M, 0.8 mL, 0.8 mmol) was added. After 1 h the reaction mixture was partitioned between aqueous 50% saturated ammonium chloride solution and ethyl acetate. The organic phase was collected, and the aqueous phase extracted with ethyl acetate. The organic layers were combined, dried (sodium sulfate), and concentrated in vacuo to afford a semi-solid. Purification by flash chromatography (silica, 5-10% methanol/dichloromethane) provided the title compound: 10 mg, 20%; HPLC (method 9) tR=1.5 min; LRMS (ESI, pos. ion spectrum) 657/659 (M+H).

EXAMPLE 152

[0321] A solution of the title compound of Example 151 (17 mg, 0.027 mmol) and palladium activated carbon (10%, 5 mg) in methanol (0.5 mL) was stirred under one atmosphere of hydrogen at room temperature for 2 h. The reaction was diluted with methylene chloride (1 mL) and filtered through a pad of CELITE. The filtrate was evaporated in vacuo to afford the title compound 12 mg (99%).

EXAMPLE 177

[0322] Part A. Preparation of rel-(1R,2S,4S)-2-(((1,1-dimethylethyl)diphenylsilyl)oxymethyl)-7-aza-bicyclo[2.2.1]heptane. To a solution of ethyl rel-(1R,2S,4S)-2-(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (386 mg, 1.94 mmol) in methylene chloride (3 mL) was added chloro(1,1-dimethylethyl)diphenylsilane (0.61 mL, 2.3 mmol) and triethylamine (0.33 mL, 2.3 mmol). The reaction was stirred overnight and concentrated in vacuo. The residue was dissolved in 4 mL of dry chloroform. To the solution was added dropwise iodotrimethylsilane (0.33 mL, 2.3 mmol) under argon at room temperature. The reaction was refluxed for 2 h and then quenched with methanol. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated sodium carbonate solution, dried over magnesium sulfate, and evaporated in vacuo to afford the crude product. RP-HPLC purification of the crude product afforded 200 mg (42%) of rel-(1R,2S,4S)-2-(((1,1-dimethylethyl)diphenylsilyl)oxymethyl)-7-aza-bicyclo[2.2.1]heptane.

[0323] Part B: N-((S)-1-{[rel-(1R,2S,4S)-2-(tert-butyldiphenylsilanyloxymethyl)-7-aza-bicyclo[2.2.1]hept-7-yl]-2-oxoethyl}-2-oxopiperidin-3-yl) 6-chloronaphthalene-2-sulfonamide was prepared from part A compound and INT15 using the method described in Example 48.

[0324] Part C: To a solution of part B compound (2 mg, 0.003 mmol) in THF (0.1 mL) was added tetrabutylammonium fluoride (0.004 mL, 1M in THF). The reaction was stirred overnight, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate (2×2 mL). The organic fractions were combined, dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified by RP-HPLC to provide 1 mg (88%) of the title compound.

[0325] note: the rel-descriptor indicates that the substance is racemic but has the relative chirality indicated.

EXAMPLE 178

[0326] Part A. 1,1-dimethylethyl ((1-[2-[(3S)-3-(6-chloronaphthalene-2-sulfonylamino)-2-oxo-piperidin-1-yl]acetyl]piperidin-4-yl)methyl)carbamate was prepared using the method described in

EXAMPLE 48

[0327] Part B. To a solution of part A compound (21 mg, 0.036 mmol) in methylene chloride (0.5 mL) was added trifluoroacetic acid (TFA, 0.5 mL). After stirring for 1 h, the TFA and methylene chloride were evaporated in vacuo to afford 17 mg (97%) of the title compound.

EXAMPLE 183

[0328] A solution of INT15 (23 mg, 0.058 mmol) and triethylamine (0.016 mL, 0.12 mmol) in acetonitrile (0.2 mL) was added to 2-(4-nitrophenyl)thiazolidine (18 mg. 0.087 mmol) in a test tube. A solution of 1-hydroxy-7-azabenzotriazole (14 mg, 0.10 mmol) in DMF (0.1 mL) and a solution of EDCI (free base) (17 mg, 0.087 mmol) in DMF (0.1 mL) were added to above mixture in that order. The test tube was shaken overnight. The crude mixture was loaded onto a C-18 cartridge. The cartridge (2.5 g of C18 packing) had been previously pre-washed with 10 mL of MeOH and 10 mL of water and had the bulk solvent removed with air. The tube was rinsed with acetonitrile (0.1 mL) which was added to the top of the column. The cartridge was washed with water (30 mL), and 4% of acetonitrile in water (20 mL). The column was then eluted with acetonitrile (5 mL) to provide the title compound (26 mg, 77%).

EXAMPLE 292

[0329] To 0.2 mL of methanol containing 22 mg of 4 Å molecular sieves was added, sequentially, INT23 (25 mg, 0.05 mmol), dimethylamine (0.03 mL, 0.05 mmol) and borane-pyridine complex (ca. 8 M, 0.006 mL, 0.05 mmol). The reaction mixture was stirred at room temperature for 16 h. Then, 6N HCl (0.1 mL) was added. The reaction was stirred at room temperature for 1 h and was brought to pH 14 with 2N sodium hydroxide. The reaction mixtrue was extracted 3×1 mL with methylene chloride. The combined organic layers were dried and concentrated. The residue was purified by reverse phase chromatography to give the title compound (6 mg, 24%): HPLC (method 1) tR=2.4 min; LCMS (ESI, pos. ion spectrum) m/z 513/515 (M+H).

EXAMPLE 311

[0330] Sodium metal (3 mg, 0.13 mmol) was added to ammonia (2 mL) at −33° C. and stirred for 10 min. A solution of the title compound of Example 298 (7 mg, 0.01 mmol) in dry THF (1 mL) was then added to the above solution. The reaction was stirred at −33° C. for 3 h, quenched with solid ammonium chloride, and stirred overnight at room temperature. The mixture was diluted with water (1 mL), and extracted with ethyl acetate (2×3 mL). The organic fractions were combined, dried over magnesium sulfate, and evaporated in vacuo to afford the crude product. Preparative HPLC purification over C18 silica gel afforded 1 mg (23%) of the title compound.

EXAMPLE 316

[0331] To a solution of the title compound of Example 301 (12 mg, 0.023 mmol) in methylene chloride (0.5 mL) was added triethylamine (0.007 mL, 0.05 mmol) and trimethylsilyl isocyanate (0.007 mL, 0.05 mmol). After stirring for 3 h, the reaction was concentrated. The residue was purified by RP-HPLC to afford 6 mg (47%) of the title compound.

EXAMPLE 317

[0332] To a solution of the title compound of Example 301 (10 mg, 0.019 mmol) in methylene chloride (0.5 mL) were added triethylamine (0.005 mL, 0.04 mmol) and 1-acetylimidazole (5 mg, 0.04 mmol). After stirring for 3 h, the reaction was concentrated. The residue was purified by RP-HPLC to afford 3 mg (27%) of the title compound.

EXAMPLE 331

[0333] A mixture of INT47 (1.5 g, 8.1 mmol), PS-MB-CHO resin (Argonaut Technologies Inc., 3.2 g, 1.26 mmol/g), and sodium triacetoxyborohydride (1.72 g, 8.1 mmol) in DMF-trimethyl orthoformate-acetic acid 49:49:2 (50 mL) was agitated at room temperature for 48 h. The mixture was filtered and the resin was subjected to 3 sequential washing cycles. In each cycle, the resin was washed sequentially with 6/3/1 THF/water/AcOH (3×), DMF (3×), methylene chloride (3×), and methanol (3×). The polymer supported amino ester (3.8 g) thus prepared was divided into 48 equal portions and each portion was suspended in methylene chloride (1.5 mL) and a sulfonyl chloride (1.5 equivalents based on the initial aldehyde resin is loading, chosen from INT45, 5-chlorobenzo[b]thiophene-2-sulfonyl chloride, 5-(1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-sulfonyl chloride or 4-acetylamino-3-chloro-benzenesulfonyl chloride) and Hunig's base (3 equivalents) were added. The reactions were agitated for 3 h at room temperature. The reaction mixtures were individually filtered and washed with methylene chloride. A second coupling was performed as described above. The reaction mixtures were filtered. The resins were subjected to two sequential washing cycles. In each cycle, the resins were washed with methylene chloride (2×), methanol (2×), DMF (2×), and THF (2×). The resultant polymer supported sulfonylamino esters were treated, under agitation, with 2 N LiOH (1 mL) in THF (1 mL) for 36 h at room temperature. The resins were subjected to 3 sequential washing cycles. In each cycle, the resins were washed sequentially with 6/3/1 THF/water/AcOH (3 x), DMF (3×), methylene chloride (3×), and methanol (3×). The resins were then washed with THF. The polymer supported acids thus obtained were suspended in DMF (1 mL). Various commercially available amines (3 equivalents), PyBOP (3.4 equivalents) and N-methylmorpholine (0.3 mL) were added and the mixtures were agitated for 14 h at room temperature. The resins were subjected to two sequential washing cycles. In each cycle, the resins were washed with methylene chloride (2×), methanol (2×), DMF (2×), and THF (2×). In the final step the resins were agitated with a 1:1 mixture of methylene chloride-TFA (1.5 mL) for 30 min, filtered and washed with methylene chloride. Concentration of each of the individual combined filtrates afforded the title compounds.

EXAMPLE 372

[0334] The title compounds were prepared using the procedures described in Example 331 with the following modifications:

[0335] a) only 4-acetylamino-3-chlorobenzenesulfonyl chloride was used in the sulfonylation step; b) before the final TFA cleavage step, the resins were agitated with acetyl chloride or cyclopropanecarbonyl chloride (3 equivalents, based on the initial loading of the aldehyde resin) in the presence of pyridine (5 equivalents) in methylene chloride (1.5 mL) for 15 min and then filtered and washed with methylene chloride.

EXAMPLE 391

[0336] A solution of (3-chlorophenyl)boronic acid (19 mg, 0.12 mmol) in ethanol (0.4 mL, sparged with argon for 30 min) was added to a stirring solution of the title compound of Example 363 (52 mg, 0.10 mmol) in toluene (0.8 mL, sparged with argon for 30 min). Sodium carbonate (23 mg, 0.20 mmol) in water (0.40 mL sparged with argon for 30 min) was then added followed by Pd(PPh3)4 (7 mg). After refluxing under argon for 2 h, the reaction was poured into brine and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate to afford 60 mg of crude product. Purification over C18 silica gel afforded 15 mg (27%) of the title compound.

EXAMPLE 400

[0337] A mixture of INT20 (78 mg, 0.15 mmol) and azepane (23 mg, 0.23 mmol) in 0.3 mL of 1,2-dichloroethane was stirred at room temperature for 10 min. To the reaction was added sodium triacetoxyborohydride (48 mg, 0.23 mmol). The reaction was stirred at room temperature for an additional 20 minutes. The volatiles were removed with a stream of nitrogen and the residue was purified by reverse phase chromatography to afford the title compound (62 mg, 69%): HPLC (method 1) tR=3.0 min; LCMS (ESI, pos. ion spectrum) m/z 599/601 (M+H).

EXAMPLE 401

[0338] A mixture of the title compound of Example 363 (52 mg, 0.10 mmol), (3-methoxyphenyl)boronic acid (23 mg, 0.10 mmol), cesium carbonate (65 mg, 0.20 mmol), N,N′-dicyclohexyl-1,4-diaza-1,3-butadiene (0.66 mg), and palladium acetate (0.67 mg) in dioxane (1 mL) was stirred at 80° C. After 4.5 h, the reaction was transferred to a separators funnel with ethyl acetate/water and extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate to afford 84 mg of crude product. Purification over silica gel afforded 45 mg (81%) of the title compound.

EXAMPLE 407

[0339] To a solution of the title compound of Example 301 (10 mg, 0.019 mmol) in 1,2-dichloroethane (0.3 mL) was added acetic acid (0.1 mL) and ethyl oxoacetate (10 mg, 0.1 mmol, 50% in toluene). After stirring for 30 min, sodium triacetoxyborohydride (8 mg, 0.037 mmol) was added. The reaction mixture was stirred for 2 h, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (2×1 mL). The organic fractions were combined, dried over magnesium sulfate, and evaporated in vacuo to afford the crude product. Preparative HPLC Purification afforded 7 mg (61%) of the title compound.

EXAMPLE 409

[0340] Part A. 4-(11,1-dimethyl)ethyl 1-(9H-fluoren-9-ylmethyl) 2-((1-pyrrolidinyl)carbonyl)piperazine-1,4-dicarboxylate was prepared from 1-(9H-fluoren-9-ylmethyl) 4-(1,1-dimethyl)ethyl 1,2,4-piperazinetricarboxylate and pyrrolidine according to the method described in Example 48.

[0341] Part B. Part A compound was treated with a solution (20% v/v) of piperazine in DMF for 10 min. The reaction was concentrated and purified over silica gel afford (1,1-dimethylethyl) 3-((1-pyrrolidinyl)carbonyl)-piperazine-1-carboxylate.

[0342] Part C. To a solution of lithium aluminum hydride (0.18 g, 4.7 mmol) in THF (2 mL) at 0° C. was added dropwise a solution of part B compound (0.88 g, 3 mmol) in THF (1 mL). The reaction was stirred for 3 h at room temperature and was quenched at 0° C. with 10 drops of MeOH. To the reaction were sequentially added NaOH solution (2 mL, 5%),THF (50 mL) and MeOH (10 mL) at 0° C. The mixture was stirred at room temperature for 1 h. Sodium sulfate was added to absorb water and mixture filtered through a plug of CELITE. The filtrate was concentrated and coevaporated with toluene three times to afford (1,1-dimethyl)ethyl 3-(pyrrolidin-1-ylmethyl)-piperazine-1-carboxylate (0.60 g, 74%) which was used immediately without further purification.

[0343] Part D. 4-{2-[(3S)-(6-Bromo-naphthalene-2-sulfonylamino)-2-oxo-piperidin-1-yl]-acetyl}-3-pyrrolidin-1-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from INT10 and part C compound using the method described in Example 48.

[0344] Part E. The title compound was prepared from part D compound using the method described in Example 178 part B.

EXAMPLE 410

[0345] Part A. To a solution of the title compound of Example 394 (100 mg, 0.21 mmol) in dichloromethane (1.5 mL) was added Dess-Martin reagent in dichloromethane (1.5 mL). After stirring at room temperature for 30 min, the mixture was concentrated and purified over silica gel afford 50 mg (50%) of N-[(S)-1-[2-(rel-(1S,2S,5R)-2-formyl-3-aza-bicyclo[3.1.0]hex-3-yl)-2-oxo-ethyl]-2-oxo-piperidin-3-yl] ((E)-2-(5-chloro-thiophen-2-yl)ethenesulfonamide).

[0346] Part B. The title compound was prepared from the part A aldehyde using the methods described in Example 407.

[0347] the rel-descriptor indicates that the bicyclic portion is racemic but has the relative stereochemistry shown.

EXAMPLE 412

[0348] Part A. A solution of the title compound of Example 390 (20 mg, 0.037 mmol) in methylene chloride (1 mL) was cooled to 0° C. 3-Chloroperoxybenzoic acid (10 mg, 57%, 0.026 mmol) was added. The mixture was allowed to warm to room temperature and was stirred overnight. The reaction was concentrated in vacuo to afford the crude product. Preparative HPLC purification over C18 silica gel afforded 4 mg (19%) of Example 390 title compound N-oxide: LCMS (method 4) tR=0.84 min; LCMS (ESI, pos. ion spectrum) m/z 566 (M+1).

[0349] Part B. To part A compound (3 mg, 0.005 mmol) in dry pyridine (0.5 mL) at 0° C. was added p-toluenesulfonyl chloride (1.5 mg). The reaction was stirred at 0° C. for 2.5 h and the solvent was removed in vacuo. To the residue was added 2-aminoethanol (0.5 mL) and the mixture was stirred overnight. Preparative HPLC purification afforded 1 mg (39%) the title compound: LCMS (method 4) tR=0.88 min; LCMS (ESI, pos. ion spectrum) m/z 565 (M+1).

EXAMPLE 414

[0350] Part A. INT9 (0.31 g, 1.0 mmol) and PS-MB-CHO (1.26 mmol/g, 0.40 g, 0.50 mmol) were suspended in 1/1 DMF/trimethylorthoformate containing 2% acetic acid (6.3 mL). Sodium triacetoxyborohydride (0.22 g, 1.0 mmol) was then added and the mixture was agitated at ambient temperature. After 2 days, the solid was filtered and subjected to 3 sequential washing cycles. In each cycle, the resin was washed sequentially with 6/3/1 THF/water/AcOH (3×), DMF (3×), methylene chloride (3×), and methanol (3×). The resin was then washed with THF (2×), and the solid was dried under vacuum to afford 0.41 g of resin-supported amine.

[0351] Part B. A portion of Part A amine resin (0.10 g, 0.12 mmol), diisopropylethylamine (48 mg, 0.38 mmol), and (4-bromophenyl)sulfonyl chloride (48 mg, 0.19 mmol) were suspended in methylene chloride (1.5 mL). The mixture was agitated at ambient temperature overnight. The resin was filtered and rinsed with methylene chloride. A second coupling was performed for 5 h. The resin was subjected to two sequential washing cycles. In each cycle, the resin was washed with methylene chloride (2×), methanol (2×), DMF (2×), and THF (2×). Finally, the resin was dried to provide part B resin-bound sulfonamide

[0352] Part C: A portion of Part B sulfonamide resin (0.12 mmol theory) was suspended in dioxane (1.5 mL) (3-Methoxyphenyl)boronic acid (30 mg, 0.13 mmol), cesium carbonate (81 mg, 0.25 mmol), N,N′-dicyclohexyl-1,4-diaza-1,3-butadiene (0.80 mg), and palladium acetate (0.80 mg) were then added and the resultant mixture was agitated at 75° C. overnight. The solid was filtered and subjected to 3 sequential washing cycles and was dried. In each cycle, the resin was washed sequentially with methylene chloride (3×), methanol (3×), DMF (3×), and THF (3×). Methylene chloride (0.50 mL) and trifluoroacetic acid (0.50 mL) were added to the solid resin. After 15 min, the reaction was filtered and rinsed with methylene chloride. The combined filtrates were evaporated in vacuo to afford the crude product. Purification over C18 silica gel afforded 6 mg (9%) of Example 414 title compound BMS-525150.

EXAMPLE 415

[0353] The title compound (4 mg, 4%) was isolated from the product-containing fractions obtained during the purification of the title compound of Example 414.

EXAMPLE 421

[0354] A mixture of Example 397 title compound (48 mg, 0.10 mmol), (3-methoxyphenyl)boronic acid (25 mg, 0.12 mmol), 2 N potassium carbonate (0.14 mL, 0.28 mmol) in dimethoxyethane (1.0 mL) was sparged with argon for 20 min. Tetrakis(triphenylphosphine)palladium (6 mg) was added. After refluxing for 4 h, the reaction was transferred to a separatory funnel with ethyl acetate/water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine and dried over magnesium sulfate to afford 51 mg of crude product. Purification over silica gel afforded 23 mg (36%) of Example 421 title compound.

EXAMPLE 429

[0355] To a solution of INT15 (41 mg, 0.10 mmol) in acetonitrile (1 mL) were added diisopropylethylamine (0.036 mL, 0.21 mmol), 3,7-Diaza-bicyclo[3.3.1]nonane (13 mg, 0.10 mmol), a catalytic amount of 4-dimethylaminopyridine, 1-hydroxy-7-azabenzotriazole. (28 mg, 0.20 mmol) and EDCI (39 mg, 0.20 mmol) in that order. The reaction was stirred at room temperature overnight. Preparative HPLC purification afforded the title compound (11 mg, 22%).

EXAMPLE 431

[0356] Part A: To a solution of oxalyl chloride (1.3 mL, 15 mmol) in 20 mL of dichloromethane at −60° C. was added methyl sulfoxide dropwise over period of 10 min. After stirring at −60° C., a solution of 1,1-dimethylethyl 3-hydroxypyrrolidine-1-carboxylate (1.87 g, 10 mmol) in 20 mL of dichloromethane was added over 20 min. Then, diisopropylethylamine (8.8 mL, 50 mmol) was added over 5 min. The resulting mixture was stirred at −60° C. for 25 min, and at room temperature for 30 min. The reaction was diluted with dichloromethane (100 mL). The organic layer was washed sequentially with saturated sodium bisulfate solution (2×), saturated sodium bicarbonate solution, water, and brine; dried over sodium sulfate; and concentrated to afford 1.8 g (97%) of 1,1-dimethylethyl 3-oxo-pyrrolidine-1-carboxylate: 1H-NMR (CDCl3) δ 3.75 (4H, m), 2.58 (2H, t, J=7.8 Hz), 1.49 (9H, s).

[0357] Part B: To a solution of part A compound (1.8 g, 9.7 mmol) in 2 mL of toluene was added a solution of (diethylamino)sulfur trifluoride (1.3 mL, 9.7 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and at room temperature for 22 h. The resulting mixture was then poured onto ice and extracted with ethyl acetate (3×). The organic layer was washed with saturated sodium bicarbonate aqueous solution, brine and dried over magnesium sulfate. The crude product was purified over silica gel to afford 1.1 g (54.7%) of 1,1-dimethylethyl 3,3-difluoropyrrolidine-1-carboxylate: 1H-NMR (CDCl3, δ) 3.62 (4H, m), 2.34 (2H, m), 1.48 (9H, s).

[0358] Part C: To a solution of 1,1-dimethylethyl 3,3-difluoropyrrolidine-1-carboxylate (0.868 g, 4.19 mmol) in 1.5 mL of 1,4-dioxane was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 11 mL, 44 mmol) at 0° C. The mixture was stirred at 0° C. for 40 min, at room temperature for 1 h and was then concentrated to afford 0.65 g (100%) of 3,3-difluoropyrrolidine hydrochloride: 1H-NMR (CD3OD) δ 3.54 (2H, t, J=11.9 Hz), 3.43 (2H, t, J=7.8 Hz), 2.40 (2H, m).

[0359] Part D: The title compound was prepared using the procedures described in Example 613 Parts A-C employing part C compound and INT17.

EXAMPLE 494

[0360] The title compounds were prepared using the procedures described in Example 331 with the following modifications:

[0361] a) only (E)-2-(5-Chlorothien-2-yl)ethenesulfonyl chloride was used in the sulfonylation step; b) in the coupling step, the polymer supported acid was condensed with either D-proline methyl ester or L-proline methyl ester; c) the resulting polymer supported methyl esters were hydrolyzed by using lithium hydroxide as described in Example 331 and coupled (by using 5 equivalents PyBOP and 10 equivalents N-methylmorpholine) with 5 equivalents of various commercially available amines, anilines or aminoheterocyclic compounds as previously described.

EXAMPLE 532

[0362] Resin-supported sulfonamide Example 414 Part B (0.12 mmol) was suspended in dimethoxyethane (1.5 mL). (3-Chlorophenyl)boronic acid (23 mg, 0.15 mmol), 2 N potassium carbonate (0.10 mL, 0.20 mmol), and tetrakis(triphenylphosphine)palladium (4 mg) were then added and the resultant mixture was agitated at 80° C. overnight. The solid was filtered and subjected to 3 sequential washing cycles. In each cycle, the resin was washed sequentially with 6/3/1 THF/water/AcOH (3×), DMF (3×), methylene chloride (3×), and methanol (3×). The solid was subjected to 5 sequential washing cycles. In each cycle, the resin was washed sequentially with methanol (2×) and methylene chloride (2×). The resin was then washed with THF (3×). An aliquot of this resin was cleaved with 1/1 methylene chloride/TFA as described below. HPLC analysis of the residue indicated incomplete reaction, so the resin was resubmitted to the preceding reaction conditions and washing cycles. Methylene chloride (0.50 mL) and trifluoroacetic acid (0.50 mL) were added to the solid resin. After 30 min, the reaction was filtered and rinsed with methylene chloride and the combined filtrates were evaporated in vacuo to afford the crude product. Purification over C18 silica gel afforded 49 mg (58%) of Example 532 title compound.

EXAMPLE 534

[0363] The title compound of Example 439 (43 mg, 0.07 mmol) was dissolved in 0.4 mL of THF and cooled to 0° C. Then, 2 N lithium hydroxide (0.4 mL) was added. The reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was neutralized with 6 N HCl and then was purified using reverse phase chromatography to give the title compound (36 mg, 86%): HPLC (method 1) tR=2.8 min LCMS (ESI, pos. ion spectrum) m/z 589/591 (M+H).

EXAMPLE 570

[0364] To a solution of the title compound of Example 568 (95 mg, 0.17 mmol) in 1 mL of dichloromethane at 0° C. was added diisopropylethylamine (0.05 mL, 0.52 mmol) and 2-bromoethyl acetate (0.02 mL, 0.18 mmol). The mixture was stirred at room temperature for 2 h, heated at reflux for 2 h and cooled to room temperature. To the mixture were added additional portions of diisopropylethylamine, and 2-bromoethyl acetate as used above. The resulting mixture was heated at reflux for an additional 2 h. The solvent was exchanged for 1,2-dichloroethane and the mixture was heated at reflux for 2 h. The mixture was then diluted with dichloromethane (15 mL) and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified over silica gel to afford 55 mg (50%) of the title compound: LRMS (ESI, pos. ion spectrum) m/z 640/642 (M+H); HPLC (method 1) tR=2.9 min.

EXAMPLE 571

[0365] To a solution of the title compound of Example 568 (23 mg, 0.042 mmol) in dichloromethane (0.4 mL) was added, sequentially, diisopropylethylamine (0.010 mL, 0.058 mmol) and methanesulfonyl chloride (7 mg, 0.05 mmol). The mixture was shaken for 30 min and the volatiles were removed under a stream of nitrogen. The residue was purified by RP-HPLC chromatography to afford 6 mg (22%) of the title compound: LRMS (ESI, pos. ion spectrum) m/z 632/634 (M+H); HPLC (method 1) tR=2.7 min.

EXAMPLE 574

[0366] The title compounds were prepared using the procedures described in Example 331 with the following modifications:

[0367] a) in the coupling step, the resin supported acid (10 mg) was treated with tetramethylfluoroforamidinium hexafluorophosphate (TFFH, 20 mg) in the presence of triethylamine (0.1 mL) in 1:1 THF-acetonitrile (0.5 mL) for 1 minute prior to the addition of 2-aminopyridine hydrochloride (25 mg). The mixture was agitated at RT for 14 h, washed and subjected to the cleavage conditions as described in the general procedure Example 331.

EXAMPLE 575

[0368] The title compounds were prepared using the procedures described in Example 331 with the following modifications:

[0369] a) only E-2-(5-Chlorothien-2-yl)ethenesulfonyl chloride was used in the sulfonylation step; b) in the coupling step, the polymer supported acid was condensed only with tert-butyl (1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate; c) the title compound of Example 575 was obtained by TFA cleavage of the above adduct; d) prior to the cleavage step, the resin was treated with trimethylsilyl triflate (0.1 mL) and 2,6-lutidine (0.1 mL) in methylene chloride (1 mL) for 3 h to remove the BOC protecting group. The resin was washed with methylene chloride, MeOH, DMF and acylated with acetyl chloride or benzoyl chloride as described in the general procedure Example 372 (Examples 115-116).

EXAMPLE 578

[0370] A mixture of INT20 (77 mg, 0.15 mmol), carbamic acid benzyl ester (68 mg, 0.45 mmol), triethylsilane (0.072 mL, 0.45 mmol) and trifluoroacetic acid (0.023 mL, 0.30 mmol) in 0.65 mL of acetonitrile was stirred at room temperature for 3 h. The reaction mixture was purified by reverse phase chromatography to give the title compound (59 mg, 60%): HPLC (method 1) tR=4.0 min; LCMS (ESI, pos. ion spectrum) m/z 649/651 (M+H).

EXAMPLE 604

[0371] A mixture of Example 396 title compound (0.16 g, 0.30 mmol), 5-methylthiophene-2-boronic acid (48 mg, 0.34 mmol), and 2N potassium carbonate (0.45 mL, 0.90 mmol) in dimethoxyethane (4.5 mL) was sparged with argon for 20 min. Bis(triphenylphosphine)palladium chloride (17 mg) was added. After refluxing for 5 h, the reaction was transferred to a separatory funnel with ethyl acetate/water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine and dried over magnesium sulfate to afford 0.14 g of crude product. Sequential purification over silica gel and C18 silica gel afforded 18 mg (11%) of Example 604 title compound.

EXAMPLE 608

[0372] To a solution of the title compound of Example 615 (50 mg, 0.088 mmol) in 1 mL of 1,2-dichloroethane at 0° C. was added diisopropylethylamine (0.03 mL, 0.3 mmol), and 2-bromoethyl acetate (0.015 mL, 0.14 mmol). The mixture was stirred at room temperature for 2 h, at reflux for 4 h and was cooled to room temperature. To the reaction was added an additional portion of 2-bromoethyl acetate as used above. The resulting mixture was heated at reflux for additional 4 h; diluted with dichloromethane (15 mL); and washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was purified over silica gel to afford 22 mg (38%) of the title compound: LRMS (ESI, pos. ion spectrum) m/z 654/656 (M+H); HPLC (method 1) tR=3.1 min.

EXAMPLE 613

[0373] Part A: A mixture of INT11 (2.26 g, 5.98 mmol), (S)-2-pyrrolidinylmethanol (0.89 mL, 8.97 mmol), WSC (1.72 g, 8.97 mmol), and 1-hydroxy-7-azabenzotriazole (0.81 g, 5.98 mmol) in 5 mL of DMF was stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate and then washed with brine. The organic layer was concentrated and purified over silica gel to provide 2.16 g (78%) of N-((S)-[1-[2-((2S)-2-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl]-2-oxopiperidin-3-yl]) ((E)-2-(5-chlorothiophen-2-yl)ethenesulfonamide): LRMS (ESI, pos. ion spectrum) m/z 462 (M+H); HPLC (method 1) tR=2.5 min.

[0374] Part B: To a solution of part A compound (2.16 g, 4.68 mmol) in 10 mL of dichloromethane was added a suspension of Dess-Martin periodinane (3.77 g, 8.89 mmol) in 20 mL of dichloromethane. The mixture was stirred at room temperature for 30 min and diluted with ethyl ether (60 mL). The reaction was then quenched with a solution of sodium thiosulfate (8.13 g, 51.5 mmol) in saturated sodium bicarbonate. The resulting mixture was stirred at room temperature for 15 min and was then extracted with ethyl ether (3×). The aqueous layer was further extracted with dichloromethane (2×). The combined ether layers and combined methylene chloride layers were separately washed with brine, combined, dried over magnesium sulfate and concentrated. The crude product was purified over silica gel provide 1.7 g (79%) of INT22: LRMS (ESI, pos. ion spectrum) m/z 460/462 (M+H); HPLC (method 1) tR=3.1 min.

[0375] Part C: A mixture of part B compound (1.00 g, 2.17 mmol) and 1,1-dimethylethyl methyl(3-pyrrolidinyl)carbamate (0.64 mL, 3.26 mmol) in 15 mL of 1,2-dichloroethane was stirred at room temperature for 10 min. To the reaction was added sodium triacetoxyborohydride (0.69 g, 3.3 mmol). The resulting mixture was stirred at room temperature for 30 min and concentrated. The crude product was purified over silica gel to afford 1.32 g (94%) of 1,1-dimethylethyl {1-[1-((2S)-2-{(3S)-3-[(E)-2-(5-Chloro-thiophen-2-yl)-ethenesulfonylamino]-2-oxo-piperidin-1-yl}-acetyl)-pyrrolidin-2-ylmethyl]-pyrrolidin-3-yl}-methyl-carbamate: HPLC (method 1) tR=3.2 min.

[0376] Part D: To a solution of Part C compound (1.32 g, 2.05 mmol) in 5 mL of dichloromethane was added trifluoroacetic acid (2.0 mL). The mixture was stirred at room temperature for 1 h, and concentrated. The residue was then dissolved in ethyl acetate (40 mL), washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to afford 0.92 g (84%) of the title compound: LRMS (ESI, pos. ion spectrum) m/z 544/546 (M+H); HPLC (method 1) tR=2.1 min.

EXAMPLE 618-619

[0377] Part A: A One-third portion of Example 844 Part C resin was divided into 20 mg (ca. 0.022 mmol) portions. Each portion was shaken for 16 h to 28 h with Hunig's base (3 equivalents based on initial aldehyde loading) and an isocyanate (3 equivalents based on initial aldehyde loading) in dichloroethane or methylene chloride (1 mL). The resins were filtered and washed and then shaken with a solution of either TFA:methylene chloride or TFA:dichloroethane (1:1 mixture, 1.5 mL). The reactions were individually filtered and the individual filtrates were concentrated in vacuo to provide the title compounds. If the purity of the title compound was less than 90%, purification was performed (RP-HPLC [YMC Pack C18, 20 mm×100 mm; 20 mL/min; detection at 220 nm; 10-90% aqueous MeOH containing 0.1% TFA, 10.0 min linear gradient and then 2 min hold]). The title compound of Example 619 was prepared using this method and 3-ethylphenyl isocyanate.

[0378] Part B: A One-third portion of Example 844 Part D resin was divided into 20 mg (ca. 0.022 mmol) portions. Each portion was shaken for 16 h to 28 h with Hunig's base (3 equivalents) and an isocyanate (3 equivalents based on initial aldehyde loading) in dichloroethane or methylene chloride (1 mL). The resins were filtered and washed and then shaken with a solution of either TFA:methylene chloride or TFA: dichloroethane and (1:1 mixture, 1.5 mL). The reactions were filtered and the filtrates were concentrated in vacuo to provide the title compounds. If the purity of the title compound was less than 90%, purification was performed (RP-HPLC [YMC Pack C18, 20 mm×100 mm; 20 mL/min; detection at 220 nm; 10-90% aqueous MeOH containing 0.1% TFA, 10.0 min linear gradient and then 2 min hold]). The title compound of Example 618 was prepared using this method and 3-ethylphenyl isocyanate.

EXAMPLE 620-621

[0379] Part A: A One-third portion of Example 844 Part C resin was divided into 20 mg (ca. 0.022 mmol) portions. Each portion was shaken for 16 h to 28 h with pyridine (6 equivalents based on initial aldehyde loading) and a sulphonyl chloride (3 equivalents based on initial aldehyde loading) in either dichloroethane or methylene chloride (1 mL). The resins were filtered and washed and then shaken with a solution of either TFA:methylene chloride or TFA:dichloroethane (1:1 mixture, 1.55 mL). The reactions were filtered and the filtrates were concentrated in vacuo to provide the title compounds. If the purity of the title compound was less than 90%, purification was done as described in Example 618-619. The title compoun of Example 619 was prepared using this method and 3-chlorophenylsulfonyl chloride.

[0380] Part B: A One-third portion of Example 844 Part D resin was divided into 20 mg (ca. 0.022 mmol) portions. Each portion was shaken for 16 h to 28 h with pyridine (6 equivalents) and a sulphonyl chloride (3 equivalents based on initial aldehyde loading) in either dichloroethane or methylene chloride (1 mL). The resins were filtered and washed and then shaken with a solution of either TFA:methylene chloride or TFA:dichloroethane (1:1 mixture, 1.5 mL). The reactions were filtered and the filtrates were concentrated in vacuo to provide the title compounds. If the purity of the title compound was less than 90%, purification was done as described in Example 618-619. The title compoun of Example 620 was prepared using this method and 3-chlorophenylsulfonyl chloride.

EXAMPLE 622

[0381] A One-third portion of Example 844 Part D resin was divided into 20 mg (ca. 0.022 mmol) portions. Each portion was shaken for 16 h to 28 h with a carboxylic acid (3 equivalents based on initial aldehyde loading), PyBOP (3 equivalents based on initial aldehyde loading) and N-methylmorpholine (6 equivalents based on initial aldehyde loading) in either dichloroethane or methylene chloride (1 mL). The resins were filtered and washed and then shaken with a solution of either TFA:methylene chloride or TFA:dichloroethane (1:1 mixture, 1.5 mL). The reactions were filtered and the filtrates were concentrated in vacuo to provide the title compounds. If the purity of the title compund was less than 90%, purification was done as described in Example 618-619.

EXAMPLE 624

[0382] A One-third portion of Example 844 Part C resin was divided into 20 mg (ca. 0.022 mmol) portions. Each portion was shaken for 16 h to 28 h with a carboxylic acid (3 equivalents based on initial aldehyde loading), PyBOP (3 equivalents based on initial aldehyde loading) and N-methylmorpholine (6 equivalents based on initial aldehyde loading) in either dichloromethane or methylene chloride (1 mL). The resins were filtered and washed and then shaken with a solution of either TFA:methylene chloride or TFA:dichloroethane and (1:1 mixture, 1.5 mL). The reactions were filtered and the filtrates were concentrated in vacuo to provide the title compounds. If the purity of the title compound was less than 90%, purification was done as described in Example 618-619.

EXAMPLE 630

[0383] The title compound of Example 610 (19 mg, 0.034 mmol), triethylamine (5.0 mg, 0.040 mmol) and acetyl chloride (4.0 mg, 0.050 mmol) were dissolved in 0.5 mL of methylene chloride and stirred at room temperature for 1 h. Additional one equivalent-portions of acetyl chloride and triethylamine were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by reverse phase chromatography to provide the title compound (11 mg, 51%): HPLC (method 1) tR=3.5 min; LCMS (ESI, pos. ion spectrum) m/z 601/603 (M+H).

EXAMPLE 655

[0384] To a solution of the title compound of Example 613 (20 mg, 0.037 mmol) in 0.1 mL of a mixture of acetonitrile and tetrahydrofuran (1:1) was added a solution of cyclopentylisocyanate (4.5 mg, 0.04 mmol) in 0.1 mL of acetonitrile and tetrahydrofuran (1:1). The resulting mixture was stirred at room temperature overnight. The solvent was removed on a Savant Speedvac® to afford 24 mg (99%) of the title compound: LRMS (ESI, pos. ion spectrum) m/z 655 (M+H); HPLC (method 1) tR=3.2 min.

EXAMPLE 788

[0385] A solution of 1,1′-carbonyldiimidazole (8.2 mg, 0.051 mmol) in 0.2 mL of acetonitrile was added to acetic acid (3.3 mg, 0.055 mmol). The mixture was stirred at room temperature for 40 min. A solution of title compound of Example 569 (25 mg, 0.042 mmol) in 0.2 mL of dichloromethane was then added. The resulting mixture was stirred at room temperature for 2 d. The crude product was purified by C-18 chromatography to afford 21 mg (78%) of the title compound: LRMS (ESI, pos. ion spectrum) m/z 634/636 (M+H); HPLC (method 1) tR=3.0 min.

EXAMPLE 836

[0386] To the title compound of Example 578 (56 mg, 0.086 mmol) was added 0.17 mL of 30% HBr in acetic acid. The mixture was stirred at room temperature for 1 hour and purified by reverse phase chromatography to give the title compound (9 mg, 20%): HPLC (method 1) tR=3.3 min; LCMS (ESI, pos. ion spectrum) m/z 517/519 (M+H).

EXAMPLE 844

[0387] Part A. Preparation of resin-bound sulfonamide: A polymer-supported amino ester (2.4 g) was prepared using the procedures described in Example 331 from INT47 and PS-MB-CHO resin. The resin was shaken on a platform shaker for 16 h at room temperature with INT45 (1.3 equivalents based on the initial aldehyde resin loading) and Hunig's base (4 equivalents based on the initial aldehyde resin loading) in methylene chloride (25 mL). The resin filtered and washed repeatedly with, in sequence, methylene chloride, MeOH, DMF and THF and then dried. A total of 500 mL-1 L (approx.) of each solvent was used for the washing.

[0388] Part B. Preparation of resin-bound acid: The part A polymer-supported methyl ester was shaken for 2 h at room temperature with LiOH (10 equivalents based on the initial aldehyde resin loading) in a 1:1 THF:water mixture. The resin was filtered and was washed repeatedly with, in sequence, THF:water:acetic acid (6:3:1), DMF, methylene chloride, methanol and THF and then dried. A total of 500 ml-1 L (approx.) of each solvent was used for the washing.

[0389] Part C: One half of the part B polymer-supported acid was shaken for 16 h at room temperature with (R)-2-(azidomethyl)pyrrolidine (3 equivalents based on initial aldehyde loading), PyBOP (3 equivalents based on initial aldehyde loading) and N-methylmorpholine (6equivalents based on initial aldehyde loading) in DMF (15 mL). The resin was filtered and washed with THF:water:acetic acid (6:3:1), DMF, methylene chloride, methanol and THF and then dried. A total of 500 mL-1 L (approx.) of each solvent was used for the washing. The resultant resin was shaken for 72 h with triphenylphosphine (6 equivalents based on initial aldehyde loading) in THF:water (9:1, 20 mL). The resin was filtered and was washed repeatedly with, in sequence, methylene chloride, MeOH, DMF and THF and then dried. A total of 500 mL-1 L (approx.) of each solvent was used for the washing.

[0390] Part D: One half of the part B polymer supported acid was shaken for 16 h at room temperature with (S)-2-(azidomethyl)pyrrolidine (3 equivalents based on initial aldehyde loading), PyBOP (3 equivalents based on initial aldehyde loading) and N-methylmorpholine (6 equivalents based on initial aldehyde loading) in DMF (15 mL). The resin was filtered and washed with THF:water:acetic acid (6:3:1), DMF, methylene chloride, methanol and THF and then dried. A total of 500 mL-1 L (approx.) of each solvent was used for the washing. The resultant resin was shaken for 72 h with triphenylphosphine (6 equivalents based on initial aldehyde loading) in THF:water (9:1, 20 mL). The resin was filtered and was washed repeatedly with, in sequence, methylene chloride, MeOH, DMF and THF and then dried. A total of 500 mL-1 L (approx.) of each solvent was used for the washing.

[0391] Part E. the Part D resin (20 mg) was treated with a solution of methylene chloride and TFA (1:1 mixture, 1.5 mL) and filtered. The filtrate was concentrated in vacuo to provide the title compound.

EXAMPLE 845

[0392] The Example 844 Part Cousin (20 mg) was treated with a solution of methylene chloride and TFA (1:1 mixture, 1.5 mL) and filtered. The filtrate was concentrated in vacuo to provide the title compound.

EXAMPLE 847

[0393] To a solution of the title compound of Example 840 (14 mg, 0.028 mmol) in methylene chloride (1 mL) was added triethylamine (0.007 mL, 0.055 mmol) and methyl chloroformate (0.005 mL, 0.055 mmol). After stirring at room temperature for 1 h, the mixture was concentrated and the residue was purified over C18 silica gel afforded 14 mg (80%) of the title compound.

EXAMPLE 848

[0394] A mixture of the title compound of Example 847 (10 mg, 0.016 mmol) and lithium hydroxide dihydrate (5 mg, 0.086 mmol) in 1 mL of THF-water (1:1) solution was stirred for 2 h. The mixture was extracted with ethyl acetate (2×3 mL). The organic fractions were combined, dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo to afford the crude product. Preparative HPLC purification over C18 silica gel afforded 2.4 mg (23%) of the title compound.

EXAMPLE 850

[0395] Part A: (3S)-3-Amino-1-[2-oxo-2-((2S)-2-pyrrolidin-1-ylmethyl-1-pyrrolidinyl)ethyl]piperidine-2-one (5.4 g, 17 mmol) and PS-MB-CHO (1.26 mmol/g, 13 g, 16 mmol) were suspended in 1/1 DMF/trimethylorthoformate with 2% acetic acid (125 mL). Sodium triacetoxyborohydride (3.9 g, 18 mmol) was then added and the was filtered and subjected to 3 sequential washing cycles. In each cycle, the resin was washed sequentially with 6/3/1 THF/water/AcOH (3×), DMF (3×), methylene chloride (3×), and methanol (3×). The solid was subjected to 5 sequential washing cycles. In each cycle, the resin was washed sequentially with methylene chloride (2×) and methanol (2×). The isolated resin was is then resubmitted to the above reaction conditions and agitated for 3 days and washed again as above. After drying under vacuum 16 g of resin-supported amine was isolated.

[0396] Part B: Part A resin-bound amine (1.7 g, 1.7 mmol theory), diisopropylethylamine (0.88 mL, 5.1 mmol), and (4-bromophenyl)sulfonyl chloride (0.64 g, 2.5 mmol) were suspended in dichloroethane (17 mL). After agitating at ambient temperature for 4 d, the resin was filtered and rinsed with DMF (4×), methanol (3×), THF (3×) and methylene chloride (3×). The resin was again sulfonylated (3 d reaction time) and washed as described and dried.

[0397] Part C: A portion of Part B resin-bound sulfonamide (0.19 mmol theory) was suspended in dimethoxyethane (1.5 mL). (3,5-Dichlorophenyl)boronic acid (0.30 mmol), 2 N potassuim carbonate (0.30 mL, 0.60 mmol), and bis(triphenylphosphine)palladium chloride (5 mg) were then added and the resultant mixture was agitated at 75° C. overnight before the solid was filtered and washed with DMF (3×), methanol (3×), THF (3×) and methylene chloride. Methylene chloride (0.50 mL) and trifluoroacetic acid (0.50 mL) were added to the solid resin. After 30 min, the reaction was filtered and rinsed with methylene chloride and the combined filtrates were evaporated in vacuo to afford 32 mg (24%) of Example 850 BMS-543947 title compound. LCMS (method 4) tR=1.7 min; LCMS (ESI, pos. ion specturm) m/z 593/595 (M+1).

EXAMPLE 892

[0398] The title compound was prepared using the procedures described in Example 620-621 using Example 927-928 part A resin.

EXAMPLE 895

[0399] The title compound was prepared using the procedures described in Example 620-621 using Example 927-928 part B resin.

EXAMPLE 898

[0400] The title compound was prepared using the procedures described in Example 622 using Example 927-928 part A resin.

EXAMPLE 907

[0401] The title compound was prepared using the procedures described in Example 622 using Example 927-928 part B resin.

EXAMPLE 921

[0402] INT58 (19.3 mg, 0.06 mmol) was dissolved in pyridine (0.6 mL) and cooled to 0° C. 6-Chloro-thieno[2,3-b]pyridine-2-sulfonyl chloride (24.1 mg, 0.09 mmol) was added, and the reaction mixture allowed to slowly warm to RT overnight without removal of the cooling bath. After 16 h the reaction mixture was concentrated in vacuo and the residue purified via preparative HPLC to afford the title compound as an off-white white solid (24.5 mg, 74%); HPLC (method 1), t4=2.2 min., 90% pure; LRMS (ESI, pos. ion spectrum) m/z 554 (M+H).

EXAMPLE 927 and 928

[0403] Part A: The same procedure as Example 844 was followed using 5′-Chloro-[2,2′]bithienyl-5-sulfonyl chloride in place of INT45 and (S)-2-(azidomethyl)pyrrolidine

[0404] Part B: The same procedure as Example 844 was followed using 5-chlorobenzo[b]thiophene-2-sulphonyl chloride in place of INT45 and (S)-2-(azidomethyl)pyrrolidine

EXAMPLE 930

[0405] The title compound was prepared using the procedures described in Example 927-928 except that the reactions were carried out in solution phase. The isolation of product was done using prep HPLC as described earlier.

EXAMPLE 931

[0406] The title compound was prepared using the procedures described in Example 892 except that the reactions were carried out in solution phase. The isolation of product was done using prep HPLC as described earlier.

EXAMPLE 936

[0407] To a solution of the title compound of Example 425 (59 mg, 0.10 mmol) in DMF (0.3 mL) was added NaH as a 60% dispersion in oil (4.4 mg). After 15 minutes, benzyl bromide (17 mg, 0.10 mmol) was added. After 15 hours, the reaction was quenched with 3 drops of water and the solvent removed in vacuo. The residue was purified by reverse phase chromatography to provide 38 mg of the title compound: LCMS (method 3, ESI, pos. ion. spectrum), m/z 677/679.

EXAMPLE 970

[0408] To a solution of INT15 (30 mg, 0.08 mmol) in dichloromethane (1 mL) were added triethylamine (0.033 mL, 0.24 mmol), (1S, 4S)-(+)-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (10 mg, 0.04 mmol), a catalytic amount of 4-(dimethylamino)pyridine, 1-hydroxy-7-azabenzotriazole (14 mg, 0.10 mmol) and WSC (23 mg, 0.12 mmol) in that order. The reaction was stirred at room temperature for 2 h, quenched with water, and extracted with methylene chloride (2×5 mL). The combined organic fractions were dried over magnesium sulfate and evaporated in vacuo. Purification of the residue over silica gel afforded the title compound: 42 mg (49%).

Claims

1. A compound of formula I

2. A compound of claim 1 including a pharmaceutically acceptable salt thereof wherein X is CH2; R1 is selected from alkyl, alkenyl, alkynyl, substituted alkyl, substituted alkenyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl and substituted heteroaryl; R2 is H, alkyl or substituted alkyl; and R3, R4, R4a, R5, R5a, R6, and R6a are H or alkyl.

3. A compound of claim 2 including a pharmaceutically acceptable salt thereof wherein R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted cycloheteroalkyl group.

4. A compound of claim 3 wherein R1 is aryl, -(alkenyl)-aryl, heteroaryl, or -(alkenyl)-heteroaryl.

5. A compound of formula II

6. A compound of claim 5 wherein Q is a group B.

7. A compound of claim 6 wherein Y is bond or alkenyl.

8. A compound of claim 7 wherein R1 is aryl or heteroaryl either of which may be optionally substituted with one or more groups Z1, Z2 or Z3.

9. A compound of claim 8 wherein R9 is H, Z3d or when a group R11 is present R9 combines with R11 to form a single bond; R10 is H, Z1f, —Y2—R11, Y2—R2 or —Y2—N(R11)-Z4-Z9a; Y2 is —(CH2)u— or —C(O)—(CH2)—; Z3d and Z1f are each independently H, halo, oxo, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, -(alkyl)-cycloalkyl, -(alkyl)-cycloheteroalkyl, -(alkyl)-aryl, -(alkyl)-heteroaryl, —OH, OZ6, —C(O)tH, —C(O)tZ6, —S(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, -(alkyl)-S(O)tZ6, -Z4-NZ7Z8, -Z4-N(Z10) Z5-Z6, -Z4-N(Z10)-Z5-H, -Z4-N(Z9)-Z5-NZ7Z8, -(alkyl)-Z4-NZ7Z8, -(alkyl)-Z4-N(Z10)-Z5-Z6, -(alkyl)-Z4-N(Z10)-Z5-H, or -(alkyl)-Z4-N(Z9)-Z5-NZ7Z8 any of which may be optionally further substituted where valence allows; R14 is a group D or H, halo, oxo, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, -(alkyl)-cycloalkyl, -(alkyl)-cycloheteroalkyl, -(alkyl)-aryl, -(alkyl)-heteroaryl, —OH, OZ6, —C(O)tH, —C(O)tZ6, —S(O)tZ6, -(alkyl)-OH, -(alkyl) OZ6, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, -(alkyl)-S(O)tZ6, -Z4-NZ7Z8, -Z4-N(Z10) Z5-Z6, -Z4-N(Z10)-Z5-H, -Z4-N(Z9)-Z5-NZ7Z8, -(alkyl)-Z4-NZ7Z8, -(alkyl)-Z4-N(Z10)-Z5-Z6, -(alkyl)-Z4-N(Z10)-Z5-H, or -(alkyl)-Z4-N(Z9)-Z5-NZ7Z8 any of which may be optionally further substituted where valence allows.

10. A compound of claim 9 wherein Z4 is a bond, —C(O)—, —C(═NZ9a)-, —C(O)—C(O)— or —C(O)O—; and Z5 is —C(O)—, —C(O)O—— or —SO2—.

11. A compound of claim 10 wherein Z3d and Z1f are each independently H, alkyl, heteroaryl, -(alkyl)-cycloheteroalkyl, -(alkyl)-Z4-NZ7Z8, -Z4—NZ7Z8, -(alkyl)-Z4-N(Z10)-Z5-Z6, -(alkyl)-Z4-N(Z9)-Z5-NZ7Z8, —C(O)tZ6, -(alkyl)-C(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, or —S(O)tZ6; and R14 is a group H, -(alkyl)-cycloheteroalkyl, -(alkyl)-Z4-NZ7Z8, -Z4-NZ7Z8, -(alkyl)-Z4-N(Z10)-Z5-Z6, -(alkyl)-Z4-N(Z9)-Z5-NZ7Z8, —C(O)tZ6, -(alkyl)-C(O)tZ6, -(alkyl)-OH, -(alkyl)-OZ6, —S(O)tZ6 or a group D;

12. A compound of claim 11 wherein R2 is H, alkyl, —C(O)tH, —C(O)tZ6, -Z4-NZ7Z8, -(alkyl)-C(O)tH, -(alkyl)-C(O)tZ6, or -(alkyl)-Z4-NZ7Z8; and R3, R4, R4a, R5, R5a, R6, and R6a are H.

13. A compound of claim 12 wherein R1 is

14. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable vehicle or carrier therefor.

15. A pharmaceutical composition of claim 14 further comprising at one additional therapeutic agent selected from prothrombolytic agents, thrombin inhibitors, platelet aggregation inhibitors, PAI-1 inhibitors, thromboxane receptor antagonists, prostacyclin mimetics, phosphodiesterase inhibitors, fibrinogen antagonists, thromboxane receptor antagonists, thromboxane synthase inhibitors, serotonin-2-receptor antagonists, aspirin, hypolipodemic agents, antihypertensive agents, or combinations thereof.

16. A pharmaceutical combination of claim 15 wherein the additional therapeutic agent is streptokinase, releplase, activase, lanoteplase, urokinase, prourokinase, ASPAC, animal salivary gland plasminogen activators, warfarin, clopidogrel, aspirin, ticlopidine, ifetroban, XR-330, T-686, dipyridamole, cilostazol, picotamide or ketanserin or combinations thereof.

17. A method for preventing or treating Factor Xa-associated disorders, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of at least one compound of formula 1

18. A method of claim 17 wherein the Factor Xa-associated disorder is selected from thromboses, coronary artery disease or cerebrovascular disease.