NZ526003A - Biaryl compounds as serine protease inhibitors - Google Patents

Biaryl compounds as serine protease inhibitors

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Publication number
NZ526003A
NZ526003A NZ526003A NZ52600301A NZ526003A NZ 526003 A NZ526003 A NZ 526003A NZ 526003 A NZ526003 A NZ 526003A NZ 52600301 A NZ52600301 A NZ 52600301A NZ 526003 A NZ526003 A NZ 526003A
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NZ
New Zealand
Prior art keywords
compound
group
alkyl
pct
usol
Prior art date
Application number
NZ526003A
Inventor
Yarlagadda S Babu
Scott R Rowland
Pooran Chand
Pravin L Kotian
Yahya El-Kattan
Shri Niwas
Original Assignee
Biocryst Pharm Inc
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Publication date
Application filed by Biocryst Pharm Inc filed Critical Biocryst Pharm Inc
Publication of NZ526003A publication Critical patent/NZ526003A/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
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    • C07C259/20—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines with at least one nitrogen atom of hydroxamidine groups bound to another nitrogen atom
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    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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    • C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Abstract

Compounds of formula (I) are useful as inhibitors of trypsin like serine protease enzymes such as thrombin, factor VIIa, factor Xa, TF/FVIIa, and trypsin. These compounds could be useful to treat and/or prevent clotting disorders, and as anticoagulating agents.

Description

New Zealand Paient Spedficaiion for Paient Number 526003 5260 BIARYL COMPOUNDS AS SERINE PROTEASE INHIBITORS DESCRIPTION Cross-Reference to Related Applications This application is a continuation-in-part of copending U. S. applications S.N. 60/241,848 filed October 20,2000 and entitled "Inhibitors for Activated Blood Coagulation Factor Vila (FVHa)" and S.N. 60/281,735 filed April 6,2001 and entitled "Biaryl Compounds as Serine Protease Inhibitors" Technical Field The present invention relates to the identification, through synthesis and testing, of heretofore vmreported compounds which, in appropriate pharmaceutical compositions, exert a therapeutic effect through reversible inhibition of serine proteases.
Background of Invention Serine proteases make up the largest and most extensively studied group of proteolytic enzymes. Their critical roles in physiological processes extend over such diverse areas as blood coagulation, fibrinolysis, complement activation, reproduction, digestion, and the release of physiologically active peptides. Many of these vital processes begin with cleavage of a single peptide bond or a few peptide bonds in precursor protein or peptides. Sequential limited proteolytic reactions or cascades are involved in blood clotting, fibrinolysis, and complement activation. The biological signals to start these cascades can be controlled and amplified as well. Similarly, controlled proteolysis can shut down or inactivate proteins or peptides through single bond cleavages.
While serine proteases are physiologically vital, they also can be hazardous.
Their proteolytic action, if uncontrolled, can destroy cells and tissues through degradation of proteins. As a natural safeguard in normal plasma, 10% of the protein matter is composed of protease inhibitors. The major natural plasma inhibitors are specific for serine proteinases. Diseases (associated protease given in the parentheses) such as pulmonary emphysema (cathepsin G), adult respiratory distress syndrome (chymases), and pancreatitis (trypsin, chymotrypsin, and others) are characterized by uncontrolled serine proteases. Other proteases appear to be involved in tumor invasion (plasmin, plasminogen activator), viral transformation, and inflammation (kallikrein). Thus the design and synthesis of specific inhibitors for this class of proteinases could offer major therapeutic benefits.
Thrombus formation, that is blood coagulation, is normally initiated by tissue injury; its normal purpose is to slow or prevent blood loss and facilitate wound healing. There are other conditions, however, not directly connected with tissue injury that may promote the coagulation process and lead instead to harmful consequences; examples of such conditions are atherosclerosis and inflammation.
The complex pathways of blood coagulation involve a series of enzyme reactions in which plasma coagulation factors, actually enzyme precursors or zymogens, are sequentially activated by limited proteolysis. Blood coagulation, or the coagulation cascade, is viewed mechanistically as two pathways, the extrinsic and the intrinsic (Fig. 1). Each pathway proceeds through a sequence of the Roman-numeral-designated factors until they converge at the activation of factor X after merger of the pathways. Thrombin generation proceeds stepwise through a common pathway. Thrombin then acts on the solution plasma protein, fibrinogen, to convert it to stable insoluble fibrin clots, thus completing the coagulation cascade.
The extrinsic pathway is vital to the initiation phase of blood coagulation while the intrinsic pathway provides necessary factors in the maintenance and growth of fibrin. The initiation of the coagulation cascade involves the release of tissue factor (TF) from injured vessel endothelial cells and subendothelium. TF then acts upon factor VII to form 5 the TF/FVIIa complex (where Vila designates the activated factor rather than the zymogen form). This complex initiates coagulation by activating factors DC and X. The resulting factor Xa forms a prothrombinase complex that activates prothrombin to produce the thrombin that converts fibrinogen to insoluble fibrin. In contrast, the intrinsic system is activated in vivo when certain coagulation proteins contact ^ 10 subendothelial connective tissue. In the sequence that follows, contact factors XH and XI are activated. The resulting factor XIa activates factor IX; then factor JKa activates factor X thereby intersecting with the extrinsic pathway.
With time, the TF/FVlUa complex (of the extrinsic pathway) loses activity due to the action of tissue factor pathway inhibitor (TFPI), a Kunitz-type protease inhibitor protein which, when complexed with factor Xa, can inhibit the proteolytic activity of TF/FVIIa. If the extrinsic system is inhibited, additional factor Xa is produced through the thrombin-mediated action in the intrinsic pathway. Thrombin, therefore, exerts a dual catalytic role in (a) the conversion of fibrinogen to fibrin and (b) mediating its own production. The autocatalytic aspect of thrombin production affords an important safeguard against excessive blood loss, and, assuming presence of a threshold level of prothrombinase, ensures that the blood coagulation process will go to completion.
While the ability to form blood clots is vital to survival, there are disease states 25 • wherein the formation of blood clots within the circulatory system can cause death.
When patients are afflicted with such disease states, it is not desirable to completely inhibit the clotting system because life-threatening hemorrhage would follow. Thus, it is highly desirable to develop agents that inhibit coagulation by inhibition of factor Vila without directly inhibiting thrombin. 3 PCT/USO1/32582 Need for the prevention of intravascular blood clots or for anti-coagulant treatment in many clinical situations is well known. Drugs in use today are often not satisfactory. A high percentage of patients who suffer internal injuries or undergo certain 5 surgical procedures develop intravascular blood clots which, if unchecked, cause death. In total hip replacement surgery, for example, it is reported that 50% of the patients develop deep vein thrombosis (DVT). Current approved therapies involve administration of heparin in various forms, but results are not entirely satisfactory; 10-20% of patients suffer DVT and 5-10% have bleeding complications. Along these lines, see International 10 Publication No. WO 00/15658.
Other examples of clinical situations for which better anticoagulants would be of great value are when patients undergo transluminal coronary angioplasty and treatment. for myocardial infarction or crescendo angina. The present therapy for these conditions 15 is administration of heparin and aspirin, but this treatment is associated with a 6-8% abrupt vessel closure rate within 24 hours of the procedure. Transfusion therapy due to bleeding complications is required in approximately 7% of cases following the use of heparin. Occurrences of delayed vessel closures are also significant, but administration of heparin after termination of the procedure affords little beneficial effect and can be 20 detrimental.
Heparin and certain derivatives thereof are the most commonly used anti-clotting agents. These substances exert their effects mainly through inactivation of thrombin, which is inactivated 100 times faster than factor Xa. Two other thrombin-specific 25 anticoagulants, hirudin and hirulog, are in clinical trials (as of September 1999). However, bleeding complications are associated with these agents.
In preclinical studies in baboons and dogs, the targeting of enzymes involved in earlier stages of the coagulation cascade, such as factor Vila or factor Xa, prevents clot 4 PCT/USOl/32582 formation and does not produce bleeding side effects observed with direct thrombin inhibitors.
Several preclinical studies reveal that inhibition of TF/FVIIa offers the widest 5 window of therapeutic effectiveness and safety with respect to bleeding risk of any anticoagulant approach tested including thrombin, platelet, and factor Xa inhibition.
A specific inhibitor of factor Vila would provide clinicians with a valuable and needed agent feat would be safe and effective in situations where the present drugs of 10 choice, heparin and related sulfated polysaccharides, are no better than marginally There exists a need for a low molecular weight specific serine protease inhibitors specific toward various enzymes, particularly for factor Vila that does not cause 15 unwanted side effects.
Figure 1. Pathways of Coagulation effective.
Extrinsic Pathway Intrinsic Pathway Release of TF Release of Contact Factors XXX and XI XHa-* XH TF/FVIIa IX XI X* X Common Pathway Prothrombin- Thrombin Fibrinogen Fibrin The figure illustrates the extrinsic and intrinsic pathways of blood coagulation.
Summary of Invention An aspect of the present invention relates to compounds represented by the formula: R B1 (R1)_— w |2 B ; pharmaceutically acceptable salts thereof; and prodrugs thereof.
X | (I) (A) O Each E1 and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ting, or 1-8 hydrocarbon chain which may be substituted with one or more hetero groups selected from N, O, S, S(0), and S(02) which may be saturated or unsaturated. The bicyclic rings typically contain 7-13 atoms in the ring.
R is -CH=CH:R2, -C-C-R2, -C(Ri)=CH2j -C(R2)=C(R3), -CH=NR2, -C(R>N-R3,4-7 membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from R1, R2, or R3.
X V1 L V (R2X s R1 is H, -R, -N02, -CN, -halo, -N3, -C i.8 alkyl, -(CH2)nC02R2, -C2.8 alkenyl~C02R2, -0(CH2)nC02R2, -C(0)NR2R3, -P(0)(0R2)2, alkyl substituted tetrazol-5-yl, -(CH2)nO(CH2)„ aryl, -NR2R3, -(CH2)n OR2, -(CH2)n SR2, -N(R2)C(0)R3, -S(02>NR2R3, -N(R2)S(02)R3, -(CHR2)n NR2R3, -C(0)R3, (CH2)„ N(R3)C(0)R3, -N(R2)CR2R3 substituted or unsubstituted (CH2)n-cycloaIkyl, substituted or unsubstituted (CH2)„-phenyl, or substituted or unsubstituted (GEfeVheterocycle which may be saturated or unsaturated. m is 1 except that when El is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring.
R2 is H, -halo, -alkyl, -haloalkyl, -(CH2)n-phenyl, -(CH2)i-3-biphenyl, -(CH2)M-Ph-N(S02-Ci-2-alkyl)2, -CXKCHRVOR1, -(CHR^-heterocycle, -(CHR^-NH-CO-R1, -(CHRVNH-SOaR1, -(CHR,)n-Ph-N(S02-C].2-alkyl)2, -(CHRt)n-C(0)(CHR!)-NHR1, -(CHR1)n-C(S)(CHR1)-NHR1, -(CH2)nO(CH2)nCH3, -CF3, -C2.5 acyl, -(CHRl)nOH, -(CHRt)„C02Rl, -(CHRVO-aJkyl, -(CHR1)n-0-(CH2)n-0-alkyl, -(CHR'VS-alkyI, -(CHR^n-S^-alkyl, -(CHR1)„-S(02)-alkyl5 -(CHRVS(02)-NHR3, -(CHR3)n-N3, -(CHR3)nNHR4i 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted-(CHR3)n heterocycle, or substituted or unsubstituted-(CHR3)n cycloalkyl which may be saturated or unsaturated.
When n is more than 1, the substitutions R1 and R3 may be same or different.
R3 is H, -OH, -CN, substituted alkyl, -C2-8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R')R2, or 5-6 membered saturated substituted or unsubstituted hetero ring.
-NR2R3 may form a ring system having 4 to 7 atoms or may be bicyclic ring. The ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also maybe substituted or unsubstituted.
PCT/USO1/32582 W is a direct bond, -CHR2-, -CH=CR2-, -CR2=CH-, -CR2=CR2-, -C=C-, -O-CHR2-, -CHR2-0-, -N(R2)-C(0)-, -C(0)-N(R2)-, -N(R2)-CH-(R3)-, -CH2-N(R2)-, -CH(Rl)-N(R2)-, -S-CHR2-, -CHR2-S-, -S(02)-N(R2)-, -C(0)N(R2)-(CHR2)n-, -CCR'RVNR2-, -N(R2)-S(02)-, -R2C(0)NR2-, -R2NC(0)NR2-, -CONR2CO-, -C(=NR2)NR2-, -NR2C(==NR2)NR2-, -NR20-, -N=NCHR2-, or -C(0)NR2S02-.
E2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Ci-s alkyl, C2.s alkenyl, C2-s alkynyl, alkylaiyl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino. each X individually is a direct bond, substituted or unsubstituted Cw methylene chain; O, S, NR2, S(O), S(02), or N(0) containing one or two Cm substituted or unsubstituted methylene chains. X at different places may be same or different.
B is H, -halo, -CN, -NH2, -(CH2)n-C(=NR4)NHR5, -(CH2)n-NHR4, -(CH2)nNHC(=NR4)NR5, -(CH2)n-OR4 Ci.g substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated.
B1 is selected from B; B1 and B may be same or different.
There may be more than one similar or different R2 groups present on E2, when E2 is a cyclic group of more than 5 atoms. In particular, p is 1 except that when E2 is a cyclic ring of mor e than 5 atoms, p is 1 or higher depending upon the size of the ring. n is 0-4 A is selected from R\ 8 / o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring.
Each V and V1 individually is selected from R1 and N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group maybe straight, branched, cyclic, or bicyclic; N.N-disubstituted carboxamidyl (-CONR1R2 where Ri and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or -SO2NR1R2); and methylene- or polymethylene chain-extended variants thereof.
Each R4 and R5 individually is H, -(CH2)„OH, -C(0)0R6, -C(0)SR6, -(CH2)„ €(0)NR7R8, -0-C(0)-0-R7, an amino acid or a (^peptide, Each R6 is H, R7, -C(R7)(R8)-(CH2)n-0-C(0)-R9, -(CH2)n-C(R7)(R8)-0-C(0)R9, -(CH2)„-15 C(R7)(R8)-0-C(0)-0-R9,or-C(R7)(R8)-(CH2)n-0-C(0)-0-R9, Each R7, R8 and R9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or 20 CH2C02alkyl.
The present invention also relates to pharmaceutical compositions containing at least one of the above disclosed compounds and their prodrugs, , 25 The present invention also relates to uses of the compounds of the invention in the manufacture of medicaments.
Also described is a method for inhibiting trypsin-like serine protease enzymes, such as thrombin, factor Xa, factor Vila, TF/VIIa, and trypsin in a patient which comprises administering to the patient an effective serine protease inhibiting amount of at least one of the above disclosed compounds. 9 I " 8 JUN 2005 1 '—ERcetved I PCT/USO1/32582 Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
Best and Various Modes for Carrying Out Invention An aspect of the present invention relates to compounds represented by the formula: r (R1)- m E1' W B1 E2 g V- -V (R2) ' P acceptable salts thereof; and prodrugs thereof.
X (A) 0) Each El and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which may be substituted with one or more hetero groups selected from N, O, S, S(O), and S(02) which may be saturated or unsaturated.
Ris -CH-CH-R2, -C-C-R2, -C(R2)=CH2, -C(R2)=C(R3), -CH=NR2, -C(R2)=N-R3,4-7 membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions selected from R1, R2, or R3. Preferably, these R, R1, R2, or R3 do not include -(C2-4 alkenyl)-C02-Ci.8 alkyl, -(C2-4 alkenyl)-C02-Ci.g alkyl-phenyl, and -(C2.4 alkenyl)-C02-C1-8 alkyl-O-Ci.4 alkyl.
R1 is H, -R, -NO2, -CN, -halo, ~N3, -C i_8 alkyl, -(CH2)nC02R2, -C2.8 alkenyl-C02R2, -0(CH2)nC02R2, -C(0)NR2R3, -P(OKOR2>2, alkyl substituted tetrazol-5-yl, -(CH2)nO(CH2)„ aryl, -NR2R3, -(CH2)n OR2, -(CH2)n SR2, -N(R2)C(0)R3, -S(02)NR2R3, -N(R2)S(02)R3, '-(CHR2)n NR2R3, -C(0)R3, (CH2)n N(R3)C(0)R3, -N(R2)CR2R3 substituted or unsubstituted (CH2)n-cycloalkyl, substituted or unsubstituted (CH2)n-phenyl, or substituted or unsubstituted (CH2)n-heterocycle which may be saturated or unsaturated. m is 1 except that when E1 is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring. For instance if the ring is 6 atoms, m can be 1 or 2.
R2 is H, -halo, -alkyl, -haloalkyl, -(CH2)n -phenyl, -(CH2)i-3-biphenyl, -(CH2)i-4-Ph-N(S02-Ci_2-alkyl)2, -CCKCHRVOR1, -(CHRVheterocycle, -(CHRVNH-CO-R1, -(CHR1)n-NH-S02R1, -(CHR^n-Ph-NCSOz-Ci-j-alkyl)^ -(CHR VQOXCHRVNHR1, -(CHR^n-CCSXCHR^-NHR1, -(CH2)nO(CH2)nCH3, -CF3, -C2-5 acyl, -(CHR^nOH, -(CHR^nCOjR1, -(CHR^-O-alkyl, -(CHRVOKCH2)n-0-alkyl, -(CHR^n-S-alkyl, -(CHR1 )n~S (O)-alkyl, -(CHRI)„-S(02)-alkyl, -(CHRJ)n-S(02)-NHR3, -(CHR3)„-N3, -(CHR3)nNHR4,2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted-(CHR3)n heterocycle, or substituted or unsubstituted-(CHR3)n cycloalkyl which may be saturated or unsaturated. 11 WO 02/3471-1 When n is more than 1, the substitutions R1 and R3 may be same or different.
R3 is H, -OH, -CN, substituted alkyl, -C2.8 alkenyl, substituted or unsubstituted cycloalkyl, -N(R!)R2, or 5-6 membered saturated substituted or unsubstituted hetero ring.
-NR2R3 may form a ring system having 4 to 7 atoms or may be bicyclic ring. The ring system may be of carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted.
W is a direct bond, -CHR2-, -CH=CR2-, -CR2=CH-, -CR2=CR2-, -C=C-, -O-CHR2-, -CHR2-0-, -N(R2)-C(0)-, -C(0)-N(R2)-, -N(R2)-CH-(R3K -CH2-N(R2)-, -CHCR^-NCR2)-, -S-CHR2-, -CHR2-S-, -S(02)-N(R2)-, -C(0)N(R2)-(CHR V, -C(RlR2)n-NR2-, -N(R2)-S(02)-, -R2C(0)NR2-, -R2NC(0)NR2-, -CONR2CO-, -C(=NR2)NR2-, -NR2C(=NR2)NR2-, -NR20-, -N=NCHR2-, or -C(0)NR2S02-.
E2 is-5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Ci_g alkyl, C2-8 alkenyl, C2-8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkyltbio, or alkylamino. each X individually is a direct bond, substituted or unsubstituted Cm methylene chain; O, S, NR2, S(O), S(02), orN(0) containing one or two Cm substituted or unsubstituted methylene chains. X at different places may be same or different.
B is H, -halo, -CN, -NH2, -(CH2)n-C(=NR4)NHR5, -(CH2)»-NHR4, -(CH2)nNHC(=NR4)NR5, -(CH2)n~OR4, Ci_g substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated.
B! is selected from B; B1 and B may be same or different. 12 There may be more than one similar or different R2 groups present on E2, when E2 is a cyclic system of more than 5 atoms, p is 1 or higher if E2 is a cyclic ring of more than 5 atoms. For example, if the ring is 6 atoms, p can be 1 or 2. n is 0-4 A is selected from R1. o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending upon the size of the ring. For instance, if the ring is 6 atoms, o can be 1 or 2.
Each V and V1 individually is selected from R1 andN-alkyl substituted carboxamidyl (~ CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; N.N-disubstituted carboxamidyl (-CONR1R2 where Ri and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or -SO2NR1R2); and methylene- or polymethylene chain-extended variants thereof.
Each R4 and R5 individually is H, -(CH2)nOH, -C(0)0R6, -C(0)SR6, -(CH2)„ C(0)NR7R8, -0-C(0)-0-R7, an amino acid or a dipeptide, EachR6is H, R7,-C(R7)(R8)-(CH2)n-0-C(0)-R9,-(CH2)„-C(R7)(R8)-0-C(0)R9,-(CH2)n-C(R7)(R8)-0-C(0)-0-R9, or -C(R7)(R8)-(CH2)n-0-C(0)-0-R9, Each R7, R8 and R9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH2C02alkyl. 13 R substituent groups employed pursuant to the present invention contribute to significantly enhanced activity of the compounds of the present invention.
Listed below are definitions of various tenns used to describe this invention. These definitions apply to the terms as they are used throughout this specification, unless otherwise limited in specific instances, either individually or as part of a larger group.
The term "alkyl" refers to straight or branched chain unsubstituted hydrocarbon groups of 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms. The expression "lower alkyl" refers to unsubstituted alkyl groups of 1 to 4 carbon atoms.
The terms "alkenyl" and "alkynyl" refer to straight or branched chain unsubstituted hydrocarbon groups typically having 2 to 8 carbon atoms.
The terms "substituted alkyl", "substituted alkenyl" or substituted alkynyl" refer to an alkyl, alkenyl or alkynyl group substituted by, for example, one to four substituents, such as halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloaikyloxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which the 2 amino substituents are selected from alkyl, aryl or aralkyl, alkanoylamine, aroylamino, aralkanoylamino, substituted alkanolamino, substituted arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkyUMo, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SC^NEfe). substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. CONH2), substituted carbamyl (e.g. CONH alkyl, CONH aryl, CONH aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclos, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. 14 Where noted above where the substituent is further substituted it will be with halogen, alkyl, alkoxy, aryl or aralkyl. • The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.
The term "aralkyl" or "alkylaryl" refers to an aryl group bonded directly through an alkyl group, such as benzyl or phenethyl.
The term "substituted aryl" or "substituted alkylaryl" refers to an aryl group or alkylaryl group substituted by, for example, one to four substituents such as alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, azido, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, hydroxyalkyl, aminoalkyl, azidoalkyl, alkenyl, alkynyl, allenyl, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono, arylthiono, alkysulfonyl, sulfonamido, aryloxy and the like. The substituent may be further substituted by halo, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl. "Substituted benzyl" refers to a benzyl group substituted by, for example, any of the groups listed above for substituted aryl.
The term "cycloalkyl" refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring which may be further fused with an unsaturated C3-C7 carbocyclic ring. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. Exemplary substituents include one or more PCT/USO1/32582 alky] groups as described above, or one or more groups described above as alkyl substituents.
The term "cycloalkenyl" refers to optionally substituted, unsaturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3-7 carbons per ring. Exemplary groups include cyclopentenyl and cyclohexenyl.
The terms "heterocycle", "heterocyclic" and "heterocyclo" refer to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, for example, which is 4 to 7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1,2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized and the nitrogen heteroatoms may also optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atoms.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, thiophenyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, dihydropyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dixolane andtetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl and triazolyl and the like. is PCT/USO1/32582 Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolapridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3}l-b3pyridinyl, or furo[2,3-b]pyridinyl), dihydroisoindolyl, diyhydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzothrasolyl, benzpyrasolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indohnyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, theinofuryl, thienopyridyl, thienothienyl, and the like.
Exemplary substituents include one or more alkyl groups as described above or one or more groups described above as alkyl substituents.
Within the above-described definitions, certain embodiments are preferred. Preferred alkyl groups are lower alkyl groups containing 1 to about 8 carbon, and more preferably 1 to about 5 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups.
Examples of suitable alkyl groups include methyl, ethyl and propyl. Examples of branched alkyl groups include isopropyl and t-butyl. An example of a suitable alkylaryl group is phenethyl. Examples of suitable cycloalkyl groups typically contain 3-8 carbon atoms and include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The aromatic or aryl groups are preferably phenyl or alkyl substituted aromatic groups (aralkyl) such as phenyl C1-3 alkyl such as benzyl.
The N-heterocyclic rings preferably contain 3-7 atoms in the ring and a heteroatom such as N, S or O in the ring. Examples of suitable preferred heterocyclic 17 groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2-methylpiperidino and 2-ethylpiperidino. In addition, the above substitutions can include halo such as F, CI, Br, lower alkyl, lower alkoxy and halo substituted lower alkoxy.
Examples of some preferred B groups include -NHC(=NH)NH2, -C(=NH)NH2, NH2, various N-substituted variants, and assorted prodrug derivatives.
Prodrug forms of the compounds bearing various nitrogen functions (amino, hydroxyamino, hydrazino, guanidino, amidino, amide, etc.) may include the following types of derivatives where each R group individually may be hydrogen, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl, heterocycle, alkylaryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, or cycloalkenyl groups as defined beginning on page 7. (a) Carboxamides, -NHC(0)R (b) Carbamates, -NHC(0)0R (c) (Acyloxy)alkyl carbamates,-NHC(0)0R0C(0)R (d) Enamines, -NHCR(=CHCR02R) or -NHCR(=CHCRONR2) (e) Schiff bases, -N=CR2 (f) Mannich bases (from carboximide compounds), RCONHCH2NR2 Preparations of such prodrug derivatives are discussed in various literature sources (examples axe: Alexander etal, J. Med. Chem. 1988, 31, 318; Aligas-Martin et at, PCTWOpp/41531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the invention. 18 Prodrug forms of carboxyl-bearing compounds of the invention include esters (-CO2R) where the R group corresponds to any alcohol whose release in the body through enzymatic or hydrolytic processes would be at pharmaceutically acceptable levels. Another prodrug derived from a carboxylic acid form of the invention may be a quaternary salt type ®/ 0 RC(=0)0CHN-— I x R of structure described by Boder et al.,5. Med. Chem. 1980,23,469.
Examples of some preferred groups for W are -CH2CH2-, -CH=CH-, -OC-, -CH2CH2CH2-, -CH2CH=CH-, -CH2C=C-, -CONH, -CH2CONH-, -NHCONH-, -CONHCO-, -CONHCH2-, -C(=NH)NH-, -CH2C(=NH)NH-, -NHC(=NH)NH-, -NHNH-, -NHO-, -CONHSO2-, -SO2NH-, -NHSO2CH2-, -SO2NHCH2-, -CH2O-, -CH2OCH2-, -OCH2CH2-9 -CH2NH-, -CH2CH2NH-, -CH2NHCH2-5 -CH2S-, -SCH2CH2, -CH2SCH2-, -CH2SO2CH2-, -CH2SOCH2-, -CH(C02H)0 and -CH(C02H)0CH2.
Examples of some preferred groups for V and V1 are N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group maybe straight, branched, cyclic, or bicyclic, and typically containing up to ten carbons; N.N-disubstituted carboxamidyl (-CONR1R2 where Ri and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or -SO2NR1R2); methylene- or polymethylene chain- extended variants thereof such as -(CH2)nCONHRi, -(CH2)„CONRiR2> -(CH2)nS02NHR1, -(CH2)nS02NRlR2 (where n = 1-4), -NHC(0)R, N(Ri)C(0)R2, NHSO2R, CH2NHR, CH2NR1R2. 19 Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable, inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, trifluoroacetic and benzenesulphonic acids.
Salts derived from appropriate bases include alkali such as sodium and ammonia.
It is of course understood that the compounds of the present invention relate to all optical isomers and stereo-isomers at the various possible atoms of the molecule.
PCT/US01/32S82 The synthetic routes leading to the compounds in formula (I) are described in the following schemes.
Scheme 1 COjCHJ MEM = CHj-0-CH2-CH2-0-CH3 3g, CH, 2h, 3h, R = (^3 2i,3i,R= —CHjCH3 2j, 3j, R = n -CHj 21 PCT/USOl/32582 Scheme 2 D-l or *3a P'-2 »■ CHO S{OH), 6 22 PCT/USOl/32582 Scheme 3 A-3or A-4 23 PCT/USOl/32582 Scheme 4 F 22 24 PCT/USOl/32582 Scheme 5 < CO MEM D-l, D-2, D-3, D-4, D-5, D-10, D-l 1, or D-12 * + R, • y _ ■ ...» 23 X = H, B-(OH)2, Sn(Bu)3, Sn(Me)j,or Si(Me)3 BnOjC H02C 24,R = •-O 'O Ml V h.
N' V>- "? ^CH, °. P, s. X.N / CH3 HjC CHj OH >CH2 .CH, CH.
.OH v.
CH, =TMS OH PCT/USOl/32582 24, R= (continued) x, /=< CH, CH, .OH ae, OHC' aa, 'j=vi ab, OH CHO -o- "Q- ah, 'CH^ , Rs '-O *D r) 4-0- H3C, h, N' V>- m, CH, Q» H.
•CH, OH x, ac, j-CHj CH3 -CH, "CH, £H» CH, u, „OH .OH w, ECH "OH aa, j=n ab, OH / BnO,Cv Ti_ 3d' —OH V/ ae' ^ ^ ^ ^ HOH.C^Xg. af, HOH^q ii \ V s> *x- "N, 26 PCT/USOl/32582 26, R= a, ■jry '.(i d, HjC' h.
N' N' o IT^ <y> CHj "> /^N^CH2 O, /^X p, SV^,N CH, q.
H,C /PHj sffl, t, ^ * », ,OH -CH3 "OH CH, v, X. ac, CH, ,CH3 "CHj CH, w, -OH OH aa, ab, / BnO,C cv^ OH ECH OH ft \ ad, \ / -OH 0 -cy ah, OH ai, X Boc 27, R a, ■-O '-o 4 H,C' U) ^ n k, H,CS c^'(X -Q f CH, a. o, / \ p, SV^N CHj s,.
,CEL ^CHj t, // 11 «,■ ,OH CH, CHj 27 PCT/USOl/32582 27, R= (continued) ,CH, x, CH, *=N ab, J/ S OH - *„ n --. O ""X 'V ah, OH ' N, Conversion of 24ab K,I-1 s 25ab 24ac 25ac 24ae K,l-1 j 25ae 24ad K, 1-11 25af The reduction of the formyl group of 24ab, 24ae, 24ae, and 24ad was accomplished with NaBH4 to give corresponding alcohols 24ab-i, 24ac-i, 24ae-i, and 24ad-i, respectively. Later, the MEM group was removed under acidic conditions to give 25ab, 25ac, 25ae, and 25af, respectively.
E, H, 1-1 Conversion of 24ad 25ad The aldehyde 24ad was oxidized to acid 24ad-i which was protected as benzyl ester to give 24ad~ii. MEM deprotection under acidic conditions produced 25ad.
Conversion of 24ah J'l > 25ah The vinyl compound 24ah was oxidized with 0s04 to give diol 24ah-i, followed by acidic hydrolysis of the MEM group to produce 25ah.
L,M,K,N,0,1-1 Conversion of 24ah 25ai The vinyl compound 24ah on dihydroxylation with 0s04 gave diol 24ah-i. Oxidative cleavage of the diol with NalOi nroduced aldehyde 24ah-ii. The aldehyde on reduction gave alcohol 24ah-iii, which on further PCT/USOl/32582 Scheme 6 29, R = ■X ch3 ohc / ch, \o 'd <3, .CHO OHC. i, // w V f, ch, 29 PCT/USOl/32582 , R = 31, r= ' d> FA " O S C' /^CHa d> jr\ chjoh hohjc ' // w 4 ch, f, ch, Conversion of K, N, 0,1-1 29g »- 30g > f' '^^CH2 Aldehyde 29g was converted to alcohol 29g-i by reduction with NaBE^t, followed by the reaction of 35 methanesulfonyl chloride to give mesylate 29g-ii. The mesyl group was displaced with azide to give 29g-iii and finally, the MEM group was removed under acidic conditions to give 30g.
Conversion of K, 1-1 29h 30h K,I-1 29i — *- 30i The reduction of the formyl group of 29h and 29i was accomplished with NaBH4 to give corresponding alcohols 29h-i and 29i-i, respectively. Later, the MEM group was removed under acidic conditions to give 40 30h and 30i, respectively.
Compounds of the type 23 and 28, where X = -Sn(Bu)3l are prepared using the methods AG-1 or AG-2 PCT/USOl/32582 Scheme 7 it l-i CFjSOJO.
HjCOJC TIPS 36 TIPS Tri-isopropylsilyl HOjC' wo 02/34711 PCT/USOl/32582 Scheme 8A + D-8 B(OH), PCT/USOl/32582 Scheme 8C MeCk /cn. ^CHO B(OH)2 MeCX vCHO + 3a D-2 47 MeCL /COjH h3cojc' 51 40 Scheme 8D 31g 33 PCT/USOl/32582 Scheme 8E 26n—2—*► 27aj (R= ) 32f —227ak ) 26ai ———*" 27al (R = ) 26u —-—27am (R = qr ) 34 PCT/USOl/32582 PCT/USOl/32582 PCT/USOl/32582 37 PCT/USOl/32582 PCT/USOl/32582 PCT/USOl/32582 Scheme 11 PCT/USOl/32582 77a, 78a, 79a, 80a, R « C~CH2; R' = CH3 H 78b, 79b, R=0S02CF3; R' = Bn; 80b, R = OH 77b, 78c, 79c, R= -0-CH2C02C2H5; R1 = Bn; 80c, R= -0-CH2C02H 77c, 78d, 79d, 80d, R = -0-CH2C0NH2; R' = Bn 77d, 78e, 79e, 80e, R = ; R' = Bn 77e, 78f, 79f, 80f, R O—(/ y; R' =* Bn 74 78g J > 79g 1-2 > 80g 78g, 79g, 80g, R=OCHj, R' = CH3 77f, 78h, 79h, 80h,R = NCH3;R'=Bn 77g, 78i, 79i, 80i, R = -O^ /CH, ;R' = Bn CH, 77h, 78j, 79j, 80j, R =.0.
CHj ;R' = Bn 77i, 78k, 79k, R= OCH2-CH2-OAc; R' = Bn; 80k, R = -0-CH2-CH2-OH 41 PCT/USOl/32582 Scheme 12 NHBoc NHBoc NHBoc 85 ° 84 O 82,84,85 S, 1-2 86 0 86a, R=CH(OH)CH2OH 86b, R= CHjOH 86c, R= C02H 42 1 PCT/USOl/32582 43 PCT/USOl/32582 Scheme 14 ,cho b(oh)2 jMe too 100 + 3a D-2 101 102 1-2 HjCOJC 103 44 PCT/USOl/32582 Scheme 15 CHO oc T, U-l.
CHO B(OH)j OH 105 OBn 106 OBn 107 110 109 108 1-2 111 45 PCT/USOl/32582 Scheme 16 BnO.
NHR1 ■NHR' PCT/USOl/32582 114a, 115a, 116a, R = CH3; 114b, 115b, 116b,R=C2Hs; 114c, 115c, 116c, R= -CH(CH3)2; 115d, R= C—C(CH3)3 CH, 117a -- 125a, R= CH3; R' = 117b - 125b, R = C2Hs,R" 117c - 125c, R = CH(CH3)2; R' = 117d - 125d, R= CH3; R' = 117e -- 125e, R = CH3; R1 = 117f-125f,R=CH3;R' = 117k- 125k, R = CH3;R' = 1171-1251, R=CH3;R' = O CF, lng-nSg.R^CHjSR^ 117h-125h,R = CH3;R,= 1171 --1251, R = CH3; R' = 117J -- 125j, R = CH3; R1« "CH, II 117m - 124m, R = C 0(0*,).,; R' = CH, ;125m,R = H;R' = CH, 47 PCT/USOl/32582 Scheme 16a H8b- ch, 126,127, R = CjH5; R' = Scheme 16b 124a- 128, R = CH3; R' = 48 PCT/USOl/32582 Scheme 17 134 J33 49 PCT/USOl/32582 133,134, R= (continued) K> "/""O'v™ "V9"^ ^ / ag,^H OH ai' \ CH, N NHj/NHBoc 30f A-3.A-4, A-5, or J Scheme 17a 135 136 135,136, R = b, '? N -v. \=/ "l .CI 6' —<\ ^ f'/^ C—^ 8' ^ CHjCN h' ^ CHjNHJ/NHBoc 50 PCT/USOl/32582 I46a-149a,R= JO 146b--149b, R= -xy 146c-- 149c,R=-CH=CHj 51 PCT/USOl/32582 Scheme 19 a CHO .u-U.
Sn(Me)3 ISO -cho h02c h3co,c 154 52 pCT/US01/32S82 53 PCT/USOl/32582 Scheme 20 AB-1 or AB-2 +31f *- 160a, 161a, R = -CH3 160b, 161b, R = -CjH5 160c, 161c, R = -CH2C6H5 160d, 161d, R = -C(CH3)3 160e, 161 e, R = -CH2-CC13 162 162a, R = -CHj 162b, R = -CjH5 162 c, R = -CHjC6H5 162d, R = -C(CH3)3 54 Wo 02134711 Scheme 21 PCT/USOl/32582 X) 163 + 130 -^l ho2ch2c 167 55 PCT/USOl/32582 Scheme 22 HO HjCOJC' AC CHO 168 172 + 130 D-2 HO.
NOH 169 H;co2C IX. 170 AA HO.
B-2 i. A 1-2 171 175 56 PCT/USOl/32582 Scheme 23 177 B-2 HjCOJC' 178 |r h3c02c' 179 co2H 179 + 130 183 182 57 PCT/USOl/32582 Scheme 24 3a, 184a, 185a, 186a, 187a, 188a, R= 3f, 184b, 185b, 186b, 187b, 188b, R=CH2CF3 3i, 184c, 185c, 186c, 187c, 188c, R = CHjCH, 3j, lS4d, 185d, 18«d, 1870,188d, R =v 58 PCT/USOl/32582 Scheme 25 189a, 189b, 189c, 189d ae-4, 1-2 74 189a 184a_^l», 189b 5—»»189c 189a, X = H, Y = OCH3 189b, X = OCH2C6H5, Y = H 189c,X=OH, Y = H ,CHO h3co2c- 131 AE~3 »■ 189d NH, 1*^1] (Prepared by method AJ-l.AJ-2, or AJ-3) hn^tjh, 189d, X=Y = H AE-3 189e 59 PCT/USOl/32582 Scheme 26 Br Br 190 HO' 191 194 1-2 O NH NHBoc x S-2 193 195 190a, 192a- 195a, R=H 190b, 192b-195b, R-CEj 60 PCT/USOl/32582 61 PCT/USOl/32582 62 PCT/USOl/32582 Scheme 29 A-7 1-2 211 O HjCOJC' 209a, R = H 209b - 211b, 63 PCT/USOl/32582 64 PCT/USOl/32582 PCT/USOl/32582 Scheme 32 R = H 231a, 232a, 233a, 234a, 23Sa, R - H 231b, R = C02CHj 232b, 233b, 234b, R = C02H 66 PCT/USOl/32582 Scheme 33 CN AF-l HjN N 236 NHj -j-lS7a_A£-2 H2N' N 237 67 PCT/USOl/32582 68 PCT/USOl/32582 Scheme 35 hn nh, PCT/USOl/32582 70 PCT/USOl/32582 General Methods of Preparation Hie following abbreviations have been used: THF: Tetrahydrofuran; DMF: Dimethylformamide DME: 1,2-Dimethoxyethane; DMAP: 4-(Dimethylamino)pyridine Boc anhydride: Di-tert-butyl dicarbonate; TIPS: Triisopropylsilyl MEM: Methoxyethoxymethyl; Bn: Phenylmethyl or Benzyl The organic extracts were dried over sodium sulfate or magnesium sulfate.
The general methods for the preparation of the compounds of formula (I) are given below: A-l: Conversion of acid to amide To derivative (1 mmol), was added thionyl chloride (12.6 mmol) and a few drops of DMF. The reaction mixture was refluxed for 2 h and concentrated in vacuo to obtain an oily residue. The residue was dissolved in dichloromethane (3 mL); cooled with ice 20 water and amine (5 mmol) was added. The reaction mixture was stirred at room temperature overnight, washed with IN HC1, saturated sodium hydrogen carbonate, water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash column chromatography to furnish the desired amide.
A-2: Conversion of acid to amide To a solution of acid derivative (1 mmol) in dichloromethane (10 mL) at 0 °C was added triethylamine (3 mmol) and ethyl chlorofoimate (3 mmol). The reaction mixture was stirred at the same temperature for 30 min and the corresponding amine (6 71 WO 02/34711 PCT/USOl/32582 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with IN HC1. The organic layer was separated, washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by crystallization or flash i i column chromatography to furnish the desired amide.
A-3: Conversion of acid to amide To a solution of acid (1 mmol) in dichloromethane (5 mL) was added 2M oxalyl chloride in dichloromethane (2.5 mmol), followed by a drop of DMF. The reaction 10 mixture was stirred for 2h at room temperature and concentrated in vacuo. The residue was co-evaporated once with dichloromethane (5 mL) and then dried in vacuo. To the residue in dichloromethane (10 mL) were further added triethylamine (3 mmol) and the corresponding amine (1.2 mmol). The reaction mixture was stirred for 16 h and washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by 15 crystallization or flash column chromatography to furnish the desired amide.
A-4: Conversion of acid to amide To a solution of acid (1 mmol) in dichloromethane or THF (10 mL) cooled with 20 an ice bath was added triethylamine (1.2 mmol) and ethyl chloroformate or isobutyl chloroformate (1.2 mmol). The reaction mixture was stirred at 0°C for 30 min and the corresponding amine (2.5 mmol) was added. The reaction mixture was stirred at room temperature overnight and quenched with IN HC1. The organic layer was separated, washed with water, brine, dried and concentrated in vacuo. The product obtained was 25 purified by crystallization or flash column chromatography to furnish the desired amide. 72 PCT/USOl/32582 A-5: Conversion of acid to amide A mixture of carboxylic acid (1 mmol), amine (1.1 mmol), 1-hydroxybenzotriazole (1 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (1.1 mmol) in pyridine (10 mL) was stirred overnight at room temperature and was concentrated in vacuo to dryness. The residue obtained was purified by column chromatography or used as such for the next step, A-6: Reduction of acid to alcohol To a solution of acid (1 mmol) in dichloromethane ot .THF (10 mL) at 0 °C was added triethylamine (1.2 mmol) and ethyl chloroformate or isobutyl chloroformate (1.2 mmol). The reaction mixture was stirred at 0 °C for 30 min and sodium borohydride (1.25 mmol) was added. The reaction mixture was stirred at room temperature overnight 15 and quenched with IN HC1. The reaction mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried and concentrated in vacuo to furnish the desired alcohol. This can be purified further, if needed, by crystallization or column chromatography.
A-7: Conversion of acid to amide A mixture of carboxylic acid (1 mmol), amine (1 mmol), and 4-dimethylaminopyridie (0.12 mmol) in xylene (10 mL) was stirred at 80 °C for 10 min. Phosphorus trichloride (1 mmol) was added and the reaction mixture was heated with 25 stirring at 150 °C for 2 hr. After cooling, the product was extracted with EtOAc. The organic layers were combined, washed with water, brine, dried and concentrated in vacuo. The product obtained was purified by flash column chromatography to furnish the desired amide. 73 PCT/USOl/32582 B-l: Conversion of phenolic hydroxyl to triflate To a phenol (1 mmol) in dichloromethane (2.5 mL) was added pyridine (5 mmol) under a nitrogen atmosphere and cooled to -10 C. To the cold reaction mixture was 5 added dropwise triflic anhydride (2 mmol) in dichloromethane (2.5 mL) over a period of 10 mins and allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and the organic layer was separated. The organic layer was washed with IN HC1, saturated sodium hydrogen carbonate, water, brine, dried and concentrated in vacuo. The product 10 obtained was purified by crystallization or flash column chromatography to furnish the desired triflate.
B-2: Conversion of phenolic hydroxyl to triflate To a solution of substituted phenol (1 mmol) in DMF (10 mL) was added N- phenylbis(trifluoromethanesuiphonimide) (1.1 mmol), and triethylamine (2 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with ice water and extracted twice with ether. The organic layers were combined, washed with brine, dried and concentrated in vacuo to furnish the desired triflate.
C: Conversion of acid to MEM ester To a solution of acid derivative (1 mmol) in DMF (10 mL) was added sodium bicarbonate (1.05 mmol), and MEM-C1 (1.05 mmol) and was stirred at room temperature 25 for 24 h. The reaction mixture was quenched with ice water and extracted twice with ether. The organic layers were combined, washed with brine, dried and concentrated in vacuo to furnish crude product. Purification by flash column chromatography or crystallization gave the desired MEM ester. 74 PCT/USOl/32582 D-l: Coupling of boronic acid with triflate A mixture of triflate (1 mmol), aryl boronic acid (1.5 mmol), potassium phosphate (3 mmol), potassium bromide (2.4 mmol) and tetrakis(triphenylphosphine)palladium 5 (0.05 mmol) in dioxane (10 mL) was heated at reflux overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water and was extracted with ethyl acetate. The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-2: Coupling of boronic acid with triflate A mixture of triflate (1 mmol), aryl boronic acid (2 mmol), sodium hydrogen carbonate (3 mmol) and tetrakis(triphenylphosphine)palladium (0.05 mmol) or bis(triphenylphosphine)palladium(II)chloride (0.05 mmol) in DME/water (9:1, 10 mL) 15 was heated at reflux overnight. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-3: Coupling of tributyltin derivative with triflate A mixture of triflate (1 mmol), tributyltin derivative (3 mmol), tetraethylammonium chloride (6 mmol), and bis(triphenylphosphine)palladium(II)-chloride (0.05 mmol) in DMF (10 mL) was heated at 70 °C overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and 25 extracted with ethyl acetate (2X10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product. 75 PCT/USOl/32582 D-4: Coupling of trimethyltin derivative with triflate A mixture of triflate (1 mmol), trimethyltin derivative (3 mmol), and bis(triphenylphosphine)palladium(Il)chloride (0.05 mmol) in THF (10 mL) was heated at 5 70 °C overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-5: Coupling of alkyne with triflate A mixture of triflate (1 mmol), triethylamine (4.5 mmol), substituted alkyne (3.5 mmol), and bis(triphenylphosphine)palladium(II)chloride (0.05 mmol) in DMF (10 mL) was heated at 70 °C overnight under an argon atmosphere. The reaction mixture was 15 cooled, quenched with water (20 mL) and extracted with ethyl acetate (2X10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-6: Coupling of boronate ester with aryl bromides A mixture of boronate ester (2 mmol)," aryl bromide (1 mmol), potassium phosphate (3 mmol) and bis(diphenylphosphinoferrocene)palladium(II)chloride (0.05 mmol) in DMF (10 mL) was heated at 100 °C for overnight under an argon atmosphere. The reaction mixture was cooled, quenched' with water (20 mL) and extracted with ethyl 25 acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the desired product. 76 PCT/USOl/32582 D-7: Coupling of boronate ester with aryl bromides A mixture of boronate ester (2 mmol), aryl bromide (1 mmol), sodium hydrogen carbonate (3 mmol) and bis(diphenylphosphinoferrocene)palladium(II)chloride (0.05 mmol) in DME/water (9:1,10 mL) was heated at 50-70 °C for overnight under an argon atmosphere. The reaction mixture was cooled, quenched with water (20 mL) and was extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo. Purification by flash column chromatography or crystallization gave the coupled product.
D-S: Coupling of phenol with boronic acid A mixture of phenol (1 mmol), aryl boronic acid (3 mmol), molecular sieves (4A°), pyridine (5 mmol), copper(II)acetate (1 mmol) and bis(triphenylphosphine)-palladium(II)chloride (0.05 mmol) in dichloromethane (10 mL) was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was cooled, filtered through a pad of Celite and concentrated in vacuo. Purification of the crude by flash column chromatography gave the coupled aryl ether.
D-9: Coupling of trimethyltin derivative with triflate To a solution of triflate (1 mmol), LiCl (4 mmol), PPh3 (0.15 mmol), CuBr (0.2 mmol), andbis(triphenylphosphine)palladmm(n)chloride (0.07 g) in DMF (10 mL) under an atmosphere of argon was added trimethylstannyl compound (0.8 mmol) and a crystal of 2,6-di-f-butyl-4-methylphenol. After the mixture was stirred at 90 °C for 3 h, a second portion of aryl-trimethylstannyl compound (0.5 mmol) was added. The reaction mixture was stirred at 90 °C overnight. Water was added and extracted with ethyl acetate. The organic layer was dried (MgSCU), concentrated and purified by flash column chromatography or crystallization to furnish the desired coupled product. 77 PCT/USOl/32582 D-10: Coupling of amine with triflate A mixture of triflate (0.75 mmol), amine (0.9 mmol), potassium phosphate (1.1 5 mmol), 2-(di-t-butylphosphino)biphenyl (0.015 mmol) and tris(dibenzylideneacetone) dipalladium(0) (10 mg) in DME (10 mL) was heated at reflux overnight under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography to furnish the desired coupled product.
D-ll: Conversion of triflate to cyano compound To a solution of triflate (0.84 mmol), zinc cyanide (0.54 mmol), Palladium acetate (0.016 mmol), 2-(di-ter^butylphospMne)biphenyl ( 0.016 mmol) and N-methyl-pyrrolidine (10 mL) was heated under argon at 160 °C for 48 h. The reaction mixture was cooled to room temperature and quenched with water (50 mL). The reaction mixture was extracted with ethyl acetate (2 X 25 mL). The organic layers were combined, dried, filtered and concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired cyano compound.
D-12: Coupling of tetravinyltin with triflate or halide To a solution of aryl triflate or bromide (1 mmol) in DMF (5 mL) were added LiCl (5 mmol), tetravinyltin (2 mol), and dichlorbis(triphenylphosphine)palladium (II) (0.01 mmol). The reaction mixture was stirred at 70 °C under nitrogen for 5 h and then diluted with ethyl acetate and filtered. The organic layer was washed with water and brine and dried (MgSCH). After evaporating the solvent in vacuo, the compound was purified by flash-column chromatography to give the desired product. 78 WO 02/34711 E: Oxidation of aryl aldehyde to acid PCT/USOl/32582 A mixture of aldehyde (1 mmol), fert-butanol (5 mL), water (2 mL) and acetonitrile (1 mL, additional amount may be added until the reaction mixture was 5 homogenous) was stirred at room temperature. The solution was cooled in ice-bath and 2-methyl-2-butene (1 mL), sodium chlorite (6 mmol) and sodium dihydrogenphosphate (1.6 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. If the solid separated out, the mixture was filtered to collect the solid, the desired product. If no solid separated out, then the reaction mixture was concentrated in vacuo to remove 10 acetonitrile, diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, washed with water, brine, dried and concentrated in vacuo to furnish crude acid. Purification was achieved, if needed, by crystallization or using flash column chromatography to obtain pure acid.
E-2: Oxidation of vinyl compound to acid To a solution of vinyl compound (1 mmol) in acetone (5 mL) was added KM11O4 (4 mmol). The reaction mixture was stirred for 3 h (the reaction is exothermic, and refluxed on its own during the addition of KM11O4). The reaction mixture was diluted 20 with methanol and water and filtered. The organic solvents were evaporated in vacuo and the aqueous layer was acidified to pH 1 and extracted several times with ethyl acetate/DME. The combined organic layers were dried (MgS04) to furnish the desired acid.
F: Conversion of aromatic acid to MEM ester To a solution of aromatic acid (1 mmol) in THF (10 mL) was added diisopropylethylamine (2 mmol) and 2-methoxyethoxymethyIchloride (I.I mmol). The reaction mixture was stirred a room temperature for 3 h and diluted with ether (25 mL). 79 PCT/USOl/32582 The reaction mixture was washed with water (10 mL), brine (10 mL), dried and concentrated in vacuo to obtain product as colorless oil. The product was purified by flash column chromatography to furnish desired product.
G: Conversion of aromatic benzyl ether to aromatic phenol, benzyl ester to acid, benzyl carbamate to amine, alkene to alkane, azide to amine, nitro to amine, and oxime to amine To a solution of appropriate substrate (1 mmol) in ethanol (10 mL) was added 10 10% palladium on carbon (10-wt%). The reaction mixture was hydrogenated at 50 psi for 2 to 24 h (until all starting material disappeared as confirmed by MS and TLC analysis). The catalyst was removed by filtration through a pad of Celite under nitrogen. The filtrate was concentrated in vacuo to furnish the product, which was purified by flash column chromatography or crystallization.
H: Conversion of aromatic acid to benzyl ester To a solution of aromatic acid (1 mmol) in DMF (10 mL) was added sodium bicarbonate (1.05 mmol), and benzyl bromide (1.05 mmol) and stirred at room 20 temperature for 24 h. The reaction mixture was quenched with ice water and extracted twice with ethyl acetate. The organic layers were combined, washed with water and brine, dried and concentrated in vacuo to furnish crude product. Purification by crystallization or flash column chromatography gave the desired ester. 1-1: Hydrolysis of MEM ester to acid •I To a solution of MEM ester (1 mmol) in DME (8 mL) was added 6 N HC1 (2 mL) and stirred at room temperature overnight. The reaction mixture was neutralized with solid sodium hydrogen carbonate (18 mmol) and concentrated in vacuo. The reaction 80 PCT/USOl/32582 mixture was acidified with 0.5 N HCl (20 mL) and extracted with ethyl acetate (2 X 20 mL). The organic layers were combined, washed with brine (20 mL), dried and concentrated in vacuo to furnish crude product. Purification of the crude by flash column chromatography gave the product. Alternatively the crude reaction mixture was diluted with water (10 mL) and concentrated in vacuo to remove DME. The solid obtained was collected by filtration and dried in vacuo to furnish pure acid. 1-2: Hydrolysis of ester to acid To a solution of ester (1 mmol) in MeOH (10 mL) was added 1 N NaOH (10 mmol). The reaction mixture was stirred at room temperature for 2-3 h, filtered through a plug of cotton, and concentrated in vacuo to remove MeOH. The pH of the aqueous layer was adjusted to below 7. The solid that separated, was collected by filtration, washed with water and dried in vacuo to furnish the desired acid.
J: Coupling of acid with amino compounds To a solution of acid (1 mmol) in DMF (5 mL) was added corresponding amine (1.1 mmol) and stirred at room temperature until homogenous. Pyridine (5 mL) was 20 added to the reaction mixture followed by 1,3-dicyclohexylcarbodiimide (1.2 mmol) and stirred overnight at room temperature. The mixture was quenched with 6 N HCl (10 mL), diluted with ice cold water (10 mL) and extracted with chloroform (2 X 10 mL). The organic layers were combined washed with brine (10 mL), dried and filtered. Purification of the crude by flash column chromatography gave the product as a solid. If 25 the product was soluble in water, then the reaction mixture was concentrated in vacuo to remove pyridine and DMF and purified by flash column chromatography. 81 PCT/USOl/32582 K: Reduction of aldehyde to alcohol To a solution of aldehyde (1 mmol) in THF (10 mL) was added sodium borohydride (0.4 mmol). The reaction mixture was stirred for 30 mins and quenched 5 with glacial acetic acid (0.3 mL). The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL).. The organic layers were combined and washed with brine (10 mL), dried, filtered and concentrated in vacuo to obtain crude product which was purified by flash column chromatography.
L: Conversion of vinyl group to diol To a solution of vinyl compound (1 mmol) in THF/fert-butanol (1:1,10 mL) and water (2 mL) was added 4-methylmorpholine N-oxide (2.5 mmol) and osmium tetraoxide (1 mL, 2.5 wt% in teri-butanol, 0.1 mmol). The reaction mixture was stirred at room 15 temperature for 2 h and quenched with saturated aqueous solution of sodium sulfite (5 mL). The reaction was stirred at room temperature for 30 mins and diluted with brine (10 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL). The organic layers were combined and washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was 20 purified by flash column chromatography to furnish the desired diol.
M: Conversion of diol to aldehyde To a solution of diol (1 mmol) in DME/water (9:1, 10 mL) was added sodium 25 metaperiodate (3 mmol) and stirred at room temperature for 30 min. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2X10 mL). The organic layers were combined and washed with brine (10 mL), dried, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography to furnish the desired aldehyde. 82 PCT/USOl/32582 N: Conversion of alcohol to mesylate To a solution of alcohol (1 mmol) in DME (10 mL) was added 5 dimethylaminopyridine (0.1 mmol), methane sulfonyl chloride (3 mmol) and diisopropylethylamine or triethylamine (5 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 X 10 mL). The combined organic layers were washed with brine, dried, filtered and concentrated in vacuo. The residue obtained, was purified 10 by column chromatography to furnish the desired mesylate.
O: Conversion of mesylate to azide To a solution of mesylate (1 mmol) in DMSO (10 mL) was added sodium azide 15 (25 mmol) and heated at 100 °C overnight. The reaction mixture was cooled and diluted with cold water (25 mL). The reaction mixture was extracted with ethyl acetate (2X15 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried, filtered and concentrated in vacuo The residue obtained was purified by column chromatography to furnish the desired azido compound.
P: Protection of amine as benzyl carbamate A mixture of amino compound (1 mmol), benzyl chloroformate (2 mmol) and triethylamine (10 mL) in pyridine (10 mL) was stirred at room temperature overnight.
The reaction mixture was concentrated in vacuo to remove organic solvents and diluted with 0.1 N HCl (10 mL). The product was extracted with chloroform (2 X10 mL), dried, filtered and concentrated in vacuo. The residue obtained was purified by column chromatography to furnish the desired carbamate. 83 PCT/USOl/32582 Q: Conversion of silyl protected amine to amine A mixture of silyl protected amine (1 mmol), tetrabutylammonium fluoride (1.0 M in THF, 2 mmol) in THF (10 mL) was stirred at room temperature for 1.5 h. The 5 reaction mixture was concentrated in vacuo and purified by column chromatography to obtain the desired product.
R: Protection of amine as tert-hniyl carbamate To a solution of amino compound (1 mmol) in acetonitrile (5 mL) was added triethylamine (2 mmol) and BOC anhydride (1.2 mmol). The reaction mixture was stirred for 2 h and-concentrated in vacuo. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSC>4), and the solvent was evaporated in vacuo to furnish tert-butyl carbamate. If needed, the product 15 was purified by crystallization or column chromatography.
S: Conversion of tert-butyl carbamate to amine To a solution of tert-butyl carbamate (1 mmol) in dichloromethane (10 mL) was 20 added trifluoroacetic acid (2 mL). The solution was stirred at room temperature for 4 h and concentrated in vacuo. The residue was purified by column chromatography or crystallization to give the desired amine.
S-2: Conversion of tert-butyl carbamate to amine To a solution of tert-butyl carbamate (1 mmol) in methanol (13 mL) was added 6 N HCl (8.75 mL, 52 mmol) and water (4.25 mL). The reaction mixture was stirred at room temperature for 2 days. The pH was adjusted to 7 using conc. ammonium hydroxide and the solid that separated out, was collected by filtration, washed with ether, 84 PCT/USOl/32582 dried in vacuo to furnish the desired product. If no solid separated out, the product was isolated by extraction with chloroform and evaporating the organic layer.
T: Protection of aldehyde as acetal To a solution of aldehyde (1 mmol) in ethanol (5 mL) was added triethyl orthoformate (1.4 mmol), ammonium nitrate (0.2 mmol) and stirred at room temperature overnight (if reaction was not complete by TLC and NMR analysis of an aliquot, the reaction mixture was heated at 50 °C until complete). After completion of the reaction, 10 the mixture was quenched with triethylamine (0.2 mmol) and concentrated in vacuo to remove ethanol. The residue was dissolved in ether, filtered to remove any insoluble inorganic impurities, and evaporated to dryness. The product obtained was used as such without further purification.
U-l: Conversion of bromide to boronic acid To a mixture of bromo compound (1 mmol) in ether (10 mL), cooled to -78 °C, n-butyl lithium (1.2 mmol) was added dropwise and the reaction mixture was stirred for 30 mins after the addition was completed. Tributyl borate (1.3 mmol) in ether (10 mL) was 20 added to the reaction and stirred at -78 °C for 2 h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCl (10 mL). The reaction mixture was stirred at • room temperature for lh and cooled with ice. The aqueous layer was separated and the organic layer was extracted twice with IN NaOH (2X10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 25 N HCl and the solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid product is obtained then the basic layer was extracted with ether (2X10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid. 85 PCT/USOl/32582 U-2: Synthesis of boronic acid by ortho Iithiation of aryl aldehyde To a solution of N;N,N'-trimethylethylenediamjne (1 mmol) in THF/ether (10 mL, 1:1) cooled to -20 °C was added dropwise, over a period of 15 mins, n-butyl lithium 5 (1 mmol) and stirred at -20 °C for 15 mins. Aldehyde (1 mmol) at -20 °C was added dropwise over a period of 10 mins to this mixture. The reaction mixture was further stirred for 15 mins at -20 °G followed by the addition of n-butyl lithium (2.8 mmol) dropwise over a period of 15 mins and stirred at 4 °C overnight The reaction mixture was cooled to -40 °C and tributyl borate (5.6 mmol) in ether (20 mL) was added to the 10 reaction and stirred at 4 °C for 12 h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCl (3 mmol) and heated at reflux for 2 h and added to ice water (25 mL). The aqueous layer was separated and the organic layer extracted twice with IN NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 3 using 6 N HCl and the solid that separated out was 15 collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid product was obtained, then the basic layer was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
U-3: Synthesis of boronic acid by ortho Iithiation of aryl acetal To a solution of aryl acetal compound (1 mmol) in ether (10 mL) at -78 °C, tert- butyl lithium (1.1 mmol) was added dropwise and the reaction mixture was stirred for 3 h at -20 °C after the addition was completed. Tributyl borate (1.2 mmol) in ether (10 mL) was added to the reaction and stirred at -20 °C for 1 h. The reaction mixture was allowed to warm to 0 °C and quenched with 2 M HCl (10 mL). The reaction mixture was stirred at room temperature for Ih. The aqueous layer was separated and the organic layer was extracted twice with IN NaOH (2X10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 N HCl and the 86 PCT/USOl/32582 solid that separated out was collected by filtration, washed with water and hexane and dried in vacuo to furnish boronic acid as a solid. If no solid'product was obtained then the mixture was extracted with ether (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
V-l: Demethylation of aryl methyl ether to phenol In a round bottom flask (50 mL), pyridine hydrochloride (lOg) was heated in an oil bath at 180 °C. After the entire solid had melted, the corresponding aryl methyl ether 10 (1 mmol) was added in small portions over a period of 20 min. The reaction mixture was heated at 180 °C for 4 h, cooled and quenched with water (100 mL). The reaction mixture was extracted with ethyl acetate (3 X lOmL). The combined organic layers were washed with brine, dried over MgSCU, concentrated to give phenol. This can be further purified if needed by crystallization or column chromatography.
V-2: Demethylation of aryl methyl ether to phenol To a solution of aryl ether (1 mmol) in dichloromethane (10 mL) cooled to -78 °C was added boron tribtomide (3 mmol). The reaction mixture was allowed to warm to 20 room temperature overnight and quenched with water (10 mL). The solid obtained was collected by filtration to give the desired product. More product was obtained after evaporation of the organic layer and washing the residue with water. Alternatively, if a homogenous biphasic mixture was obtained on addition of water, the organic layer was separated, washed with brine, dried over MgSC>4, and concentrated to give the desired 25 phenol. This can be further purified if needed by crystallization or column chromatography. 87 PCT/USOl/32582 V-3: Demethylation of aryl methyl ether to phenol To a solution of aryl methyl ether (1 mmol) in dichloromethane (5 mL) was added AICI3 (8.5 mmol). The reaction mixture was heated to reflux for 12 h under nitrogen. To 5 this mixture was added 12 mL of 1 N HCl slowly and the organic layer was separated. The aqueous layer was re-extracted several times with ethyl acetate/DME. The combined organic layers were washed with brine, dried (MgSC>4), and evaporated in vacuo to furnish the desired phenol, which was purified by column chromatography.
V-4: Demethylation of aryl methyl ether to phenol To a stirred slurry of NaH (2 mmol) in anhydrous toluene (5 mL) under nitrogen atmosphere was added para-thiocresol (2 mmol) dissolved in toluene (40 mL). The mixture was stirred at room temperature for 30 min and hexamethylphosphoric triamide 15 (2 mmol) in toluene (5 mL) was added dropwise over a period of 30 min. A solution of aryl ether (1 mmol) in toluene (5 mL) was added in one portion. The reaction mixture was stirred at reflux for 9.5 h, cooled to room temperature and diluted with ethyl acetate (40 mL). The organic layer was extracted with 1 N aqueous NaOH solution (2 X 20 mL). The basic layer was acidified to pH 5 and extracted with ethyl acetate (2 X 20 mL). The 20 organic layers were combined, washed with water, dried (MgS04) and concentrated in vacuo. The residue obtained was purified by flash column chromatography to afford the desired phenol compound.
W: Conversion of acid to methyl ester A mixture of acid (1 mmol), conc. H2SO4 or conc HCl (0.5 mL) and methanol (10 mL) was heated at reflux for 16 h. The mixture was concentrated to half of its volume and the residue poured into a saturated sodium bicarbonate solution. The precipitate was collected by filtration, washed with water and dried to give the desired ester. If the ester 88 PCT/USOl/32582 did not come as solid, it was extracted with ethyl acetate. The organic layer was dried, filtered and concentrated to give the desired ester.
W-2: Conversion of acid to ester A solution of methanolic HCl or ethanolic HCl was prepared by the addition of acetyl chloride (1 mL) to methanol/ethanol (9 mL) at 0 °C and stirred for 30 mins. To the solution of anhydrous methanolic HCl was added acid (1 mmol) and stirred at room temperature (or reflux if needed) overnight. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by column chromatography or crystallization to furnish the desired ester.
X: Conversion of phenol to alkyl aryl ethers or alkylation of amines To a solution phenol or amine (1 mmol) in DMF (10 mL) was added cesium carbonate (1.25 mmol) and corresponding bromide (1.1 mmol). The reaction mixture was stirred at room temperature overnight and quenched with water (25 mL). The product was extracted with ether (2 X 25 mL), the organic layers were combined and washed with water (25 mL), brine (25 mL), dried and concentrated in vacuo to furnish crude product. The crude was purified by crystallization or flash column chromatography.
Y: Conversion of nitrile to hydroxycarbamimidoyl To a solution of nitrile compound (1 mmol) in ethyl alcohol (10 mL) was added hydroxylamine (50% aqueous solution, 5 mmol). The mixture was stirred at reflux for 2-5 h. The reaction mixture was concentrated in vacuo to furnish the desired hydroxycarbamimidoyl compound. 89 PCT/USOl/32582 Z: Opening of aromatic methylene dioxy compound with alcohol A solution of potassium tert-butoxide (2.25 mmol) in DMSO (1.25 mL) was heated at 50 °C for 30 min. Methanol (1.25 mL) was added to it and continued heating at 5 50 °C for 30 min. To the reaction mixture was added 1,2-methylenedioxy aromatic compound (1 mmol) and continued heating at 50 °C for 30 min. The reaction mixture was cooled to room temperature and quenched with water (10 mL) and 1 N sodium hydroxide (16 mL). The reaction m mixture was washed with ether (2X10 mL) and acidified to pH 4 using conc HCl. The solid obtained was collected by filtration to 10 furnish the desired product.
Z~l: Opening of aromatic methylene dioxy compound with alcohol To a mixture of methylene dioxy compound (1 mmol) in HMPA (2.5 mL) were I added sodium methoxide (2.5 mmol) and heated with stirring at 150 °C for 12 min. The mixture was cooled and poured into ice water (20 mL), NaOH (30 mg) and stirred for 10 min. It was tihen extracted with ether and the aqueous layer was acidified to pH 4 with HCl and extracted with ether. The later ethereal extracts were combined, dried and concentrated. The residue was purified by crystallization or column chromatography.
AA: Conversion of amine to amide in the presence of a phenol To a solution of amino compound (1 mmol) in pyridine (5 mL) was added, dropwise, acid chloride (2 mmol) at 0 °C under N2. The mixture was stirred for 45 min 25 and was then poured into ice water and acidified with 1 N HCl. The precipitated solid was collected by filtration, washed with IN HCl, hexane, and then dried in vacuo to give crude product. The crude product was added to freshly prepared sodium methoxide solution (0.1 M, 10 mL) and stirred for 30 min at room temperature. The reaction ( mixture was quenched with acetic acid (1 mmol) and concentrated in vacuo. The residue 90 PCT/USOl/32582 was dissolved in ethyl acetate and washed with water. The water layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSC>4) and evaporated to yield a solid. The solid was washed with hexane and dried in vacuo to furnish the desired amide.
AB-1: Conversion of amino of amidine to amino carbamate To amidine compound (1 mmol) was added 0.1N NaOH (10 mL) and stirred at room temperature for 5 min. The reaction mixture was concentrated in vacuo and to the 10 residue was added alkyl or aryl 4-mtrophenyl carbonate (2 mmol) in 20 mL of hexamethylphosphoramide and stirred at 45 °C for 24 h. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (2 X100 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was purified by flash 15 column chromatography to furnish the desired product.
AB-2: Conversion of amino of amidine to amino carbamate To a solution of amidine compound (1 mmol) in acetonitrile (25 mL) was added 20 triethylamine (5 mL) and aryl/alkyl chloroformate (2 mmol) or dialkyl/aryl carbonate. The reaction mixture was stirred at room temperature for 16 h and quenched with water (100 mL). The reaction mixture was extracted with ethyl acetate (2 X 100 mL). The combined extracts were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was purified by flash 25 column chromatography to furnish the desired product. 91 PCT/USOl/32582 AC: Conversion of aldehyde to oxime To a stirred solution of aldehyde (1 mmol) in ethanol (10 mL) was added pyridine (10 mL) and hydroxylamine hydrochloride (1.25 mmol). The reaction mixture was 5 stirred overnight at room temperature under nitrogen and then concentrated in vacuo to one third of its original volume. Water (10 mL) was added and the precipitated solid was collected by filtration and dried in vacuo. The product was used as such for next step without further purification.
AD: Debenzylation in the presence of aldehyde To a solution of phenyl methoxyaryl aldehyde (1 mmol) in dichloromethane (10 mL) cooled to -78 °C was added dropwise under a nitrogen atmosphere boron tribromide (1M solution in dichloromethane, 1.2 mmol). The reaction mixture was allowed to warm 15 to room temperature and stirred at room temperature overnight. The reaction mixture was quenched with water (10 mL) and the layers were separated. The aqueous layer was extracted with chloroform (10 mL). The organic layers were combined, washed with brine (10 mL), dried, filtered and concentrated in vacuo to furnish crude product. Purification of the crude by flash column chromatography furnished the desired phenolic 20 aldehyde AE-1: Reductive amination of aldehyde To a stirred solution of" aldehyde (1 mmol) in methanol (40 mL) was added amine 25 (3.3 mmol) followed by the addition of glacial acetic acid (0.3 mL). The reaction mixture was stirred for 30 min under nitrogen at room temperature, and then sodium cyanoborohydride (1.5 mmol) was added. After stirring for 20 min, the solvent was evaporated in vacuo, and the residue was taken in ethyl acetate. The organic layer was washed with water, and the insoluble material was removed from the organic layer by 92 PCT/USOl/32582 filtration. The pH of the aqueous phase was adjusted to 7 with IN NaOH and was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (MgS04). The solvent was evaporated in vacuo to furnish crude product. The crude product was purified by crystallization or flash column chromatography.
AE-2: Reductive animation of aldehyde To a mixture of aminoarylamidine (1.2 mmol), 4A° molecular sieves, and sodium hydroxide (1 N solution in anhydrous methanol, 1.2 mL, 1.2 mmol) in methanol (10 mL) 10 was added a solution of aldehyde (1 mmol) in THF (10 mL). The reaction mixture was heated for 15 mins at reflux temperature and was cooled to room temperature. Acetic acid (1 %) and sodium cyanoborohydride (1 M solution in THF, 5 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with 1 N NaOH (30 mmol) and stirred for additional 2 h and concentrated in 15 vacuo to remove methanol. The mixture was diluted with water (15 mL) and washed with ether (2x10 mL). The aqueous layer was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration, washed with ether, dried in vacuo to furnish product, which was purified by flash column chromatography, if needed.
AE-3: Reductive amination of aldehyde A mixture of aminoarylamidine (2 mmol), 4A° molecular sieves, pyridine (6 mL) in methanol (9 mL) was heated at 50 °C for one hour. A solution of aldehyde (1 mmol) in methanol (7.5 mL) containing acetic acid (1 %) was added and continued heating for 4 h to 12 h. The reaction mixture was cooled and sodium cyanoborohydride (1 M solution in THF, 5 -mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with 5 N NaOH (30 mmol) and stirred for additional 2 h. The reaction mixture was filtered through Celite (to remove molecular sieves) and concentrated to remove methanol. The mixture was diluted with water (15 93 PCT/USOl/32582 mL) and washed with ether (2 X 10 mL). The aqueous layer was filtered and solid obtained was kept aside (mainly product). The aqueous layesr was acidified to pH 2 using 6 N HCl and the solid that separated out was collected by filtration. The combined solid materials were purified, if needed, by flash column chromatography.
AE-4: Reductive ammation of aldehyde To a mixture of aldehyde (1 mmol) and aminoarylamidine (1.1 mmol) in MeOH at room temperature was added triethyl amine (2.75 mmol), sodium cyanoborohydride 10 (0.83 mmol) and zinc chloride (0.9 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to remove methanol. The reaction mixture was quenched wife 1 N NaOH (10 mL), diluted with water (10 mL), and extracted with EtOAc (5 X 20 mL). The combined organic extracts were washed with brine (15 mL), dried (MgS04), filtered through Celite and concentrated to give the product. Purification 15 of the crude by flash column chromatography gave the desired product.
AE-5: Reductive amination of aldehyde To a solution of amine (1.2 mmol) in MeOH (10 mL) was added aldehyde (1 20 mmol) in THF (10 mL) containing acetic acid (0.1 mL) drop-wise. The mixture was stirred at 50 °C for 4-12 h and then cooled to room temperature. Sodium cyanoborohydride (1.5 mmol) was added to the reaction mixture and stirred at room temperature overnight. Water was added and pH of the solution was adjusted to 7. The solution was extracted with ethyl acetate. The organic layer was dried (MgS04) and 25 evaporated in vacuo. The residue was purifeid by flash column chromatography to furnish the desired amine. 94 PCT/USOl/32582 AF-1; Synthesis of amidine from nitrile Acetyl chloride (5 mL) was added to methanol (5 mL) at 0 °C drop-wise and stirred at room temperature for 15 mins. To this solution of methanolic HCl was added nitrile compound (1 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and dried. The residue obtained of the resulting methyl imidate was dissolved in methanol (10 mL). Dry ammonia gas was bubbled into the reaction mixture at reflux temperature for 5 h. The reaction mixture was concentrated to furnish the required amidine.
AG: Addition of Grignard reagent to aryl aldehyde To a solution of aryl aldehyde (1 mmol) in THF (15 mL) cooled to -78 °C was added drop wise under a nitrogen atmosphere, vinyl magnesium bromide (1 M solution in THF, 5 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 48 h. The reaction was quenched carefully with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (2 X 10 mL). The organic layers were combined, washed with brine (10 mL), dried and concentrated in vacuo. The residue obtained was purified by flash column chromatography to obtain the desired addition product.
AG-1: Synthesis of tributylvinyltin compounds from vinyl bromide containing hydroxyl To a solution of vinyl bromide with hydroxyl (1 mmol) in dichloromethane (20 ml,) was added tert-butyldimethylsilyl chloride (1.5 mmol) and DMAP (1.5 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with water (20 ml.) and the aqueous layer separated. The organic layer was washed with 0.1 N aqueous HCl (10 mL), brine (20 mL), dried and concentrated in vacuo to furnish 95 PCT/USOl/32582 corresponding tert-butyldimethylsilyloxy compound as an oil which was used as such for the next step.
To a solution of the above oily residue (1 mmol) in diethyl ether (20 mL) cooled 5 to -78 °C was added dropwise Zert-butyllithium (1.7 M in pentane, 2 mmol) over a period of 15 mins. The reaction mixture was stirred at -78 °C for 3 h and quenched at -78 °C with 2 N aqueous sulfuric acid (2 mL) and water (18 mL). The reaction mixture was neutralized using 2 N NaOH and the organic layer was separated. The organic layer was washed with water (20 mL), brine (20 mL), dried and concentrated in vacuo. Purification 10 of the crude residue obtained by flash column chromatography furnished the desired tributyltin compound.
AG-2: Synthesis of tributylmethyltin compounds from arylmethyl bromides or allyl bromides To lithium clippings (10 mmol) in THF (10 mL) cooled to -40 °C was added dropwise tributyltin chloride (0.27 mL, 1 mmol) in THF (5 mL) over a period of 15 min. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was filtered through glass wool to remove insoluble impurities and 20 cooled to -40 °C. A freshly prepared solution of arylmethyl bromide or allyl bromide (1 mmol) was added dropwise over a period of 10 mins and stirred at room temperature I overnight. The reaction mixture was quenched with saturated aqueous ammonium 4> chloride solution (10 mL) and extracted with ether (2 X10 mL). The organic layers were combined, washed with brine (10 mL), dried, filtered and concentrated in vacuo to 25 furnish desired tributyltinalkyl and was used as such without further purification. 96 PCT/USOl/32582 AG-3:4-Bromo-5-formyI-benzo[l,3]dioxole-2-carboxyIic acid methyl ester To a mixture of 2-bromo-3,4-dihydroxy-benzaldehyde (2.17 g, 10.0 mmol) and K2CO3 (5.56 g, 40.2 mmol) in n-propanol (25 mL) was added dibromoacetic acid (2.18, 5 10.0 mmol) and the mixture was heated at reflux temperature for 24 h. After cooling to room temperature, another portion of dibromoacetic acid (1.75 g, 8.0 mmol) was added. The mixture was stirred at reflux for 46 h. n-Propanol was evaporated and water (30 mL) was added. The resulting aqueous solution was acidified to pH 2 by adding 1 N HCl and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were dried 10 (MgSC>4) and evaporated in vacuo to afford crude 4-bromo-5-formyl-benzo[l,3]dioxole-2-carboxylic acid (1.34 g) as a brownish solid. This crude product was dissolved in anhydrous methanol (50 mL) and conc. H2SO4 (5 mL) was added drop by drop. The resulting mixture was refluxed overnight and cooled to room temperature. Water (50 mL) was added and the resulting aqueous solution was extracted with ethyl acetate (100 15 mL X 3). The combined organic layers were dried (MgS04) and evaporated in vacuo. The residue was purified by flash column chromatography (ethyl acetate:hexane = 5:95) to furnish 4-bromo-5-formyl-benzo[l,3]dioxole-2-carboxylic acid methyl ester as a white solid.
AH: Synthesis of tert-butyl ester of phenol To a solution of phenol (1 mmol) in pyridine (10 mL) was added 2,2-dimethyl-propionyl chloride (1.2 mmol) dropwise. The mixture was stirred at room temperature for overnight and diluted with water (100 mL). The reaction mixture was extracted with 25 ethyl acetate (3 X 50 mL). The organic layers were combined and washed with aqueous 0.5 N HCl (100 mL), water, brine, dried (MgSO*) and concentrated in vacuo. The crude residue was purified by flash column chromatography to furnish the desired ester. 97 PCT/USOl/32582 AI: Preparation of 2-bromo-5-hydroxy benzaldehyde To a solution 3-hydroxybenzaldehyde (Aldrich, 101.39 g, 805 mmol) in chlorofoim (1000 mL), was added bromine (45 mL, 845 mmol) in chloroform (200 mL) 5 drop wise over a period of 2 h at room temperature. The reaction mixture was stirred at room temperature overnight and filtered to collect crude 2-bromo-5-hydroxy benzaldehyde (32 g) as a dark brown solid. The filtrate was concentrated to 200 mL, filtered through a pad of Celite and silica gel (40 g) and washed with ether (1000 mL). The filtrate was concentrated in vacuo to give a second crop of the crude desired 10 aldehyde (60 g) as a dark brown solid. The above solids were combined and dissolved in glacial acetic acid (360 mL) by heating. Water (840 mL) was added and the solution was filtered hot. The solution was allowed to attain room temperature and kept in a refrigerator overnight. The crystals obtained were collected by filtration and washed with water, dried overnight in vacuo to furnish (60 g, 37%) of the desired product as a purplish 15 brown crystalline solid, mp: 135 °C.
AJ-1: Amidine from nitrile A mixture of nitrile (1 mmol) and hydroxylamine (aqueous 50%, 1.8 mL) in 20 EtOH (15 mL) was refluxed for 3 h and concentrated in vacuo. To the residue obtained was added EtOH (20 mL), acetic acid (2 mL) and a small amount of Raney nickel. The reaction mixture was hydrogenated (50 psi) for 14-24 h, filtered and concentrated in vacuo. The residue obtained, was purified by flash column chromatography to obtain the corresponding amidine.
AJ-2: Amidine from nitrile A mixture of nitrile (1 mmol) and saturated methanolic HCl solution (freshly prepared by bubbling HCl gas or prepared in-situ by premixing methanol and acetyl 98 PCT/USOl/32582 chloride at ice cold temperature) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to furnish methyl imidate. To the residue of methyl imidate was added MeOH (40 mL) and ammonia gas was bubbled at reflux temperature for 16 h or till the reaction was complete. The reaction mixture was concentrated in 5 vacuo and dried to furnish the desired amidine. Alternatively, the methyl imidate was dissolved in methanol and ammonium acetate (10 mmol) was added. The reaction mixture was concentrated in vacuo and purified by flash column chromatography to obtain the corresponding amidine. ^ 10 AJ-3: Amidine from nitrile To a solution of nitrile (1 mmol) dissolved in methanol (5 mL) was added N-acetyl cystein (0.1 or 1 mmol) and ammonium acetate (5 mmol) and heated at reflux till tiie reaction was complete. The reaction mixture was concentrated in vacuo and purified 15 by flash column chromatography to obtain the corresponding amidine.
AK: Conversion of aryl triflates or halides to boronate ester To dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.75 mmol) under argon in dioxane (100 mL) was added aryl triflate (25 mmol), pinacolborane (31.5 mmol) and triethylamine (75 mmol). The reaction mixture was heated under argon at 100 °C for 3h or until complete as evidenced from TLC analysis. The reaction mixture was concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired boronate ester. Alternatively, the following method can be used.
To dichloro [1,1' -bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.03 mmol), l,l'-bis(diphenylphosphino)ferrocene (0.03 mmol) under argon in dioxane (100 mL) was added aryl triflate (1 mmol), bis(pinacolata)diboron (1.1 99 PCT/USOl/32582 mmol) and potassium acetate (3 mmol). The reaction mixture was heated under argon at 100 °C for 3h or until complete as evidenced from TLC analysis. The reaction mixture was concentrated in vacuo. The residue obtained was purified by flash column chromatography to furnish the desired boronate ester.
The examples of the compounds prepared are given in the following tables. The tables describe the compounds, their method of preparation, the starting material, and the analytical data. In some cases, where analytical data have not been given, those compounds were characterized at the later step in the synthesis. 100 COjCHJ r' Cpd. No.
-R -R' Starting From Method Used Analytical Data 2a -OH ch3 0 1 A-lorA-2 'H NMR (DMSO-dfi): 8 10.26 (s, 1 H), 9.84 (s, 1 H), 8.15 (d, 7 = 3.0 Hz, 1 H), 7.64 (dd, /= 2.0 Hz and 8.9 Hz, 1 H), 6.94 (d, J= 8.9 Hz, 1 H), 3.90 (s, 3 H), 2.15 (d, J= 6.9 Hz, 2 H), 2.06 (in, J= 6.9 Hz, 1 H), 0.93 (d, J= 6.9 Hz, 1 H), 0.93 (d, J = 6 Hz, 6H); MS (ES"*): 252.12 2b / -OH -Y^CH3 0 ch, * 1 A-lorA-2 Characterized in the next step 2c -OH h ch3 T nLx-®* 0 1 A-1 or A-2 MS (ES"1): 294.54 2d -OH Yu* 1 A-1 or A-2 MS (ES+): 288.49 (M+Naf 101 Cpd. No.
-R -R' Starting From Method Used Analytical Data 2e -OH 1 A-1 or A-2 Characterized in the next step 2f -OH H Ny^CF3 o 1 A-1 or A-2 MS (ES4): 300.40 (M+Na)+ 2g -OH O 1 A-1 or A-2 MS (ES4): 272.48 (M+Na)+; MS (ES'): 248.66 2h -OH 1 A-1 or A-2 MS (ES+): 286.48 (M+Na)+ 2i -OH H \^Zn\/CH3 o 1 A-1 or A-2 MS (ES+): 224.54 2j -OH CHj o 1 A-1 or A-2 Ch£ racterized in the next step 102 o Cpd. No.
-R -R' Starting From Method Used Analytical Data 3a -OSO2CF3 h 0 9*3 2a B-l orB-2 MS (ES"): 384.37 3b -oso2cf3 h Vs 0 ^ch3 ch3 2b B-l or B-2 MS (ES+): 370.36 3c -0S02CF3 h vx 0 —ch3 / ch3 2c B-l orB-2 MS (ES"): 426.37 3d -0S02CF3 J- 2d B-l or B-2 Characterized in the next step 3e -0S02CF3 h T\ _/ch3 2e B-l orB-2 lHNMR (CDCI3): 8 8.41 (d, J=2.3 Hz, 1 H), 8.10 (dd, J= 8.5,2.4 Hz, 1H), 7.37 (d, J= 8.5 Hz, 1H), 6.48 (broad, 1 H), 3.98 (s, 3 H), 3.46 (q, J =7.2 Hz, 2 H), 1.62 (m, 2 H), 1.42 (m, 2H), 0.96 (t, J= 7.2 Hz, 3 H); MS (ES"): 384.1 3f -0S02CF3 V" 0 2f B-l or B-2 'HNMR (CDCfe): 8 8.45 (d, J= 2.4 Hz, 1 H),- 8.14 (dd, J= 8.7,2.4 Hz, 1 H), 7.42 (d, J= 8.7 Hz, 1 H), 6.52 (broad, 1 H), 4.14 (m, 2 H), 4.00 (s, 3 Pi); MS. (ES"): 410.2 103 Cpd. No.
-R -R' Starting From Method Used Analytical Data 3g -0S02CF3 0 2g B-l orB-2 'HNMR (CDCI3): 8 8.42 (d, /= 2.3 Hz, 1 H), 8.12 (dd, J= 8.5,2.3 Hz, 1 H), 7.39 (d, 8.7 Hz, 1 H), 6.31 (broad, 1 H), 4.00 (s, 3 H), 3.34 (dd, J= 7.2, 5.5 Hz, 2 H), 1.07 (m, 1 H), 0.59 (m, 2 H), 0.30 (m, 2 H); MS (ES4): 382.2 3 b -oso2cf3 2h B-l orB-2 MS (ES4): 396.36 3i -0S02CF3 h O 2i B-l orB-2 lHNMR (DMSO-rftf): 5 8.85 (t, J= 5.5 Hz, 1 H), 8.49 (d, J=2.3 Hz, 1 H), 8.23 (dd, J= 8.7,2.3 Hz, 1 H), 7.70 (d, J= 8.7 Hz, 1 H), 3.92 (s, 3 H), 3.31 (m, 2 H), 1.14 (t, J= 12 Hz, 3 H); MS (ES j: 356.1 3j -0S02CF3 ch3 h i o 2j B-l orB-2 'HNMR (DMSO-rf6): 8 8.81 (t, J= 6.0 Hz, 1 H), 8.49 (d, 2.3 Hz, 1 H), 8.24 (dd, J= 8.7,2.4 Hz, 1 H), 7.71 (d, J= 8.7 Hz, 1 H), 3.92 (s, 3 H), 3.15 (m, 2 H), 1.64 (m, 1 H), 1.41 (m, 1 H), 1.12 (m, 1 H), 0.88 (m, 6 H); MS (ES4): 398.2 -0S02CF3 -CO2MEM 4 B-2 'H NMR (DMSO-dfj): 8 8.52 (d,J= 2.0 Hz, 1H), 8.32 (dd, J=2.0 and 8.9 Hz, 1 H), 7.72 (d,/= 7.9 Hz, 1 H), 5.50 (s, 2 H), 3.88 (s, 3 H), 3.78 (t, J= 4.9 Hz, 2 H), 3.44 (d, J= 4.9 Hz, 2 H), 3.17 (s, 3 H); MS (ES4): 439.1 (M+Na)4* 6a i 0' No 1 1 ch, 0 3a AIC 'HNMR (CDCI3): 8 8.29 (d, J = 1.6 Hz, 1 H), 7.96 (dd, J = 7.5 & 1.6 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 1 H), 6.24 (bs, 1 H), 3.94 (s, 3 H), 3.30 (t, J = 6.5 Hz, 2 H), 1.92 (in, 1 H), 1.43 (s, 12 H), 0.99 (d,J = 6.5 Hz, 6 H); MS (ES+) 362.2 104 Cpd. No.
-R -R' Starting From Method Used Analytical Data 139 -OH o ch, H 3 138 aa lH NMR (DMSO-de): 8 10.26 (s, 1 H), 9.84 (s, 1 H), 8.15 (d, 7=3.0 Hz, 1 H), 7.64 (dd, .7=2.0 Hz and 8.9 Hz, 1H), 6.94 (d, J= 8.9 Hz, 1 H), 3.90 (s, 3 H), 2.15 (d, J= 6.9 Hz, 2 H), 2.06 (m, J= 6.9 Hz, 1 H), 0.93 (d, J= 6.9 Hz, 6 H); MS (ES+): 252.12 140 -OSO2CF3 IX H 3 139 B-2 !H NMR (DMSO-ds): 8 10.38 (s, 1 H), 8.36 (d, 2.8 Hz, 1 H), 7.99 (dd, J=* 2.6 and 8.9 Hz, 1 H), 7.52 (d, J= 9.0 Hz, 1 H), 3.89 (s, 3 H), 2.23 (d, 7.0 Hz, 2 H), 2.09 (m, J=6.6 Hz, 1 H), 0.94 (d, J= 6.6 Hz, 6 H); MS (ES4): 384.0 169 -OH \^NOH 168 ac 'H NMR (CDCI3): 8 8.08 (s, 1 H), 8.00 (d, J= 2.3 Hz, 1 H), 7.75 (dd, 2.3 and 8.7 Hz, 1 H), 7.01 (d, J ='8.7 Hz, 1 H), 3.97 (s, 3 H), 3.50 (s, 1 H); MS (ES4): 196.1 170 -OH -ch2nh2 169 G 'H NMR (DMSO-Jtf): 5 7.79 (d, J= 2.0 Hz, 1 H), 7.51 (dd, J= 2.3 and 8.5 Hz, 1 H), 6.95 (d, /= 8.5 Hz, 1 H), 7.01 (d, J= 8.7 Hz, 1 H), 3.90 (s, 3 H), 3.72 (s, 2 H), 3.50 (bs, 2H); MS (ES4): 182.12 171 -OH CH3 Y ^ 0 170 aa MS (ES"): 250.50; MS (ES4): 274.50 (M+Na)+ 105 Cpd. No.
-R -R' Starting From 171 Method Used Analytical Data 172 -OSO2CF3 ch3 0 B-2 'H NMR (CDCI3): 6 7.96 (d, J= 2.3Hz, 1 H), 7.55 (d, /= 2.3 and 8.3 Hz, 1 H), 7.26 (d, J= 8.3 Hz, 1 H), 5.90 (br s, 1 H), 4.50 (d, J= 4.1 Hz, 2 H), 3.97 (s, 3 H), 2.44 (sep, J= 7.0 Hz, 1 H), 1.20 (d, /= 7.0 Hz, 6 H); MS (ES4): 384.1 177 -OH ch3 h ch3 168 AE-1 lH NMR (DMSO-de): 5 10.62 (s, 1 H), 8.88 (m, 2 H), 7.99 (d, J= 2.3 Hz, 1 H), 7.70 (dd, J= 2.3 and 8.5 Hz, 1 H), 7.06 (d, J= 8.7 Hz, 1 H), 4.09 (m, 2 H), 3.91 (s, 3 H), 2.70 (m, 2 H), 1.98 (m, 1 H, J= 6.8 Hz). 0.93 (d. 7= 6.8 Hz, 6 H); MS (ES4): 238.1 178 -OSO2CF3 9h3 ch3 177 B-2 JH NMR (CDCI3): 5 8.05 (d, J= 2.3 Hz, 1 H), 7.63 (dd, J= 2.3 and 8.3 Hz, 1 H), 7.25 (d, J= 8.3 Hz, 1 H), 3.96 (s, 3 H), 3.85 (s, 2 H), 2.43 (d, J= 6.8 Hz, 2 H), 1.77 (m, J= 6.6 Hz, 1 H), 0.93 (d,J= 6.6 Hz, 1 H); MS (ES+): 370.2 179 -OSO2CF3 boc ch3 ch3 178 r !H NMR (DMSO-de): 5 7.93 (m, 1 H), 7.47 (m, 1 H), 7.26 (m, 1 H), 4.48 (m, 2 H), 3.96 (s, 3 H), 3.03 (nx, 2 H), 1.91 (m, 1 H), 1.52 (m, 9 H), 0.89 (d, 6.6 Hz, 6 H); MS (ES4): 492.2 (M+Na)+ 106 Cpd. No.
-R -R* Starting From Method Used Analytical Data 7 -OBn -CHO 6 + 3a D-2 'H NMR (DMSO-d6): 89.78 (s,'lH), 8.85 (t, J = 5.7 Hz, IH), 8.50 (d, J = 2.0 Hz, IH), 8.20 (dd, J = 8.2,1.9 Hz, IH), 7.55 (m, 9H), 5.35 (s, 2H), 3.69 (s, 3H), 3.23 (t, J = 6.5 Hz, 2H), 1.98 (m, IH), 1.02 (d, J = 6.8 Hz, 6H); MS (ES+): 446.3 8 -OBn -CO2H 7 E MS (ES""): 484.33 (M+Na)+ 9 -OBn -CO2MEM 8 F MS (ES4): 572.2 (M+Na)+ -OH -CO2MEM 9 G MS (ES4): 482.33 [(M-MEM) + Na]+ 11 -OSO2CF3 -CO2MEM B-2 'H NMR (DMSO-d6): 58.75 (t, J = 5.6 Hz, IH), 8.44 (d, J = 1.6 Hz, IH), 8.11 (dd, J = 8.0,1.9 Hz, IH), 8.01 (d, J = 2.9 Hz, IH), 7.84 (dd, J = 8.4,2.6 Hz, IH), 7.47 (d, J = 8.5 Hz, IH), 7.41 (d, J = 8.0 Hz, IH), 5.23 (q, AB system, 2H), 3.59 (s, 3H), 3.44 (m, 2H), 3.30 (m, 2H), 3.18 (s, 3H), 3.13(t, J = 6.6 Hz, 2H), 1.88 (m, IH), 0.91 (d, J = 6.7 Hz, 6H); MS (ES+): 614.3 (M+Na)+ 29a O A* -COzMEM 11 D-3 Characterized in the next step Cpd. No.
-R -R' Starting From Method Used Analytical Data 29b -CO2MEM 11 D-3 MS (ES4): 520.2 (M+Na)4" 29c ^^CH2 -CO2MEM 11 D-3 MS (ES4): 482.3 29d r^> -CO2MEM 11 D-3 MS (ES4): 562.3 (M+Na)4" 29e -CO2MEM 11 D-3 MS (ES4): 556.4 (M+Na)4" 29f /^CH2 -CO2MEM 11 D-3 lH NMR (DMSO-d6): 88.50 (t, J = 5.6 Hz, IH), 8.18 (d, J = 1.9 Hz, IH), 7.86 (dd, J = 7.9,1.9 Hz, IH), 7.78 (d, J =1.7 Hz, IH), 7.56 (dd, J = 8.0,1.8 Hz, IH), 7.13 (d, J = 8.0 Hz, IH), 7.00 (d, J = 7.9 Hz, IH), 6.67 (dd, J = 17.6,11.1 Hz, IH), 5.76 (d, J = 17.6 Hz, IH), 5.19 (d, J = 11.1 Hz, IH), 4.99 (q, AB system, 2H), 3.37 (s, 3H), 3.20 (m, 2H), 3.11 (m, 2H), 2.97 (s, 3H), 2.91 (t, J = 6.7 Hz, 2H), 1.67 (m, IH), 0.70 (d, J = 6.6 Hz, 6H); MS (ES+): 492.3 (M+Na)4" 29g "¥ -CO2MEM 11 D-2 MS (BS4): 576.2 (M+Na)+; MS (ES"): 552.2 108 Cpd. No.
-R -R" Starting From Method Used Analytical Data 29h CHO -co2mem 11 d-2 ms (es*): 538.2 291 -co2mem 11 d-2 MS (ES"1): 560.4 (M+Naf 30a -K -co2h 29a 1-1 ms (es4): 398.3 ; ms (es"): 396.3 30b -co2h 29b 1-1 Characterized in the next step 30c -co2h 29c 1-1 ms (es"): 392.1 30d fQ -co2h 29d 1-1 ms (es4): 452.1 30e ~0 -co2h 29e 1-1 MS (ES4): 446.2 109 Cpd. No.
-R -R' Starting From Method Used Analytical Data 30f -cozh 29f I-l MS (ES"): 380.1 30g N3H,Q / Q -co2h 29g K, N, 0, I-l MS (ES"'): 515.3 (M+Na)+; MS (ES"): 491.2 30b ch2oh -co2b 29h K, I-l MS (ES"): 450.1 30i hoh2c / 0 -co2h 29i K, I-l MS (ES-): 450.3 33 -0SO2CF] -co2h 11 I-l Characterized in the next step 41 -°~0 -co2mem D-8 MS (ES): 534.30 42 -cojh 41 I-l MS (ES"): 446.30 48 -OCH3 -cho 47 +3a D-2 MS (ES"): 392.2 (M+Na)+ 49 -OCH3 -c02h 48 E MS (ES+): 386.1; 408.1 (M+Na)+ 110 Cpd. No.
-R -R' Starting From Method Used Analytical Data 14 -OSO2CF3 -CHO 13 B-2 Characterized in the next step -OSO2CF3 -COzH 14 E MS (ES"): 403.58 16 -OSO2CF3 ch3 Ys^c^ 0 A-3 or A-4 'HNMR (DMSO-dg): 5 8.83 (t, J = 6 Hz, 1 H), 8.49 (d, J = 2.6 Hz, 1 H), 8.23 (dd, J = 8.6 Hz, 1 H), 7.72 (d, J = 8.6 Hz, 1 H), 7.49 (m, 2 H), 7.41 (m, 3 H), 5.43 (s, 2 H), 3.1 (t, J = 6.9 Hz, 2 H), 2.29 (m, 1 H), 0.89 (d, J - 6.9 Hz, 6 H). 111 hd o 63 € o 'Ji Cpd. No.
-R -R' Starting From Method Used Analytical Data 17 -OBn -CHO 16 + 6 D-2 'HNMR (DMSO-dfi): 8 0.88 (d, J = 6.0 Hz, 6 H), 1.85 (m, 1 H), 3.1 (t, J - 6.0 Hz, 2 H), 5.02 (q, J = 13 and 2.5 Hz, 2 H), 5.18 (s, 2 H), 6.88 (m, 2 H), 7.17 (d, J = 8.6 Hz, 1 H), 7.26 (m, 4 H), 7.35 (m, 1 H), 7.40 (m, 4 H), 7.49 (d, J = 7.7 Hz, 2 H), 8.07 (dd, J = 7.7 and 1.7 Hz, 1 H), 8.38 (d, J = 1.7 Hz, 1 H), 8.72 (t, J = 6 Hz, 1 H), 9.63 (s, 1 H); MS (ES+):522.89 18 -OBn -CO2H 17 E 'HNMR (DMSO-dg): § 0.86 (d, J = 6.9 Hz, 6 H), 1.85 (m, 1 H), 3.09 (t, J = 6.9 Hz, 2 H), 5.01 (d, J = 5.01 Hz, 2 H), 5.14 (s, 2 H), 7.08 (m, 3 H), 7.14 (dd, J = 8.6 and 2.6 Hz, 1 H), 7.27 (m, 4 H), 7.34 (m, 1 H), 7.41 (m, 3 H), 7.48 (m, 2 H), 7.99 (dd, J = 6.9 and 1.8 Hz, 1 H), 8.32 (s, 1 H), 8.64 (t, J = 6 Hz, 1 H), 12.57 (s, 1 H); MS (ES+):538.86 19 -OBn -CO2MEM 18 F 'HNMR (DMSO-de): 8 0.90 (d, J = 6.8 Hz, 6 H), 1.86 (m, 1 H), 3.10 (t, J = 6.5 Hz, 2 H), 3.16 (s, 3 H), 3.28 (dd, J = 3 and 6 Hz, 2 H), 3.36 (dd, J » 3 and 6 Hz, 2 H), 5.02 (d, J = 3.8 Hz, 2 H), 5.12 (d, J = 15 Hz, 2 H), 5.64 (s, 2 H), 7.11 (m, 3 H), 7.24 (dd, J = 8.25 and 2.75 Hz, 1 H), 7.29 (m, 4 H), 7.35 (m, 1 H), 7.42 (m, 3 H), 7.49 (m, 2 H), 8.02 (dd, J = 1.7 and 8.2 Hz, 1 H), 8.36 (d, 1.7 Hz, 1 H), 8.68 (t, J = 6 Hz, 1 H); MS (ES+): 626.44 112 Cpd. No.
-R -R' Starting From Method Used Analytical Data 21 -OH -co2mem 19 G, H 'HNMR (DMSO-de): 8 0.88 (d, J = 6 Hz, 6 H), 1.85 (m, 1 H) 3.10 (t, J = 6 Hz, 2 H) 3.16 (s, 3 H), 3.28 (m 2 H), 3.35 (m, 2 H), 5.04 (d, J = 3.5 Hz, 2 H) 5.11 (d, J = 14 Hz, 2 H), 6.98 (m, 2 H), 7.11 m, 2 H), 7.29 (m, 5 H), 8.03 (dd, J = 8 and 2 Hz, 1 H), 8.32 (d, J = 2 Hz, 1 H), 8.67 (t, J = 6 Hz, 1 H), 9.9 (s, 1 H); MS (ES+) 536.30 (100%: M4"1) 22 -oso2cf3 -COaMEM 21 B-2 'HNMR (DMSO-dfi): 8 0.89 (d, J = 6.8 Hz, 6 H), 1.86 (m, 1 H), 3.12 (t, J = 6.5 Hz, 2 H), 3.16 (s, 3 H), 3.29 (in, 2 H), 3.40 (m, 2 H), 5.04 (s, 2 H), 5.16 (dd, J = 18 and 6 Hz, 2 H), 7.15 (m, 2 H), 7.31 (rn, 3 H), 7.36 (d, J = 8.5 Hz, 1 H), 7.41 (d, J = 8.5 Hz, 1 H), 7.73 (dd, J = 8.6 and 2.6 Hz, 1 H), 7.85 (d, J = 2.6 Hz, 1 H), 8.07 (dd, J = 7.7and 1.7 Hz, 1 H), 8.45 (d, J - 1.7 Hz, 1 H), 8.73 (t, J = 6 Hz, 1 H); MS (ES+) 668.15 24a jcy s -COjMEM 22 + 23 D-l 1HNMR (DMSO-dg): 8 0.89 (d, J = 6.8 Hz, 6 H), 1.87 (m, 1 H), 3.12 (t, J = 6 Hz, 2 H), 3.16 (s, 3 H), 3.29 (m, 2 H), 3.39 (ra, 2 H), 5.05 (d, J = 2.6 Hz, 2 H), 5.16 (d, J = 17 Hz, 2 H), 7.08 (m, 2 H), 7.21 (m, 4 H), 7.24 (d, J = 7.7 Hz, 1 H), 7.35 (d, J = 7.7 Hz, 1 H), 7.62 (d, J = 3.5 Hz, 1 H), 7.64 (d, J = 5 Hz, 1 H), 7.86 (d, J = 8.6 Hz, 1 H), 8.06 (m, 2 H), 8.42 (s, 1 H), 8.73 (t, J = 6 Hz, 1 H); MS (ES+) 602.52 113 Cpd.
No.
-R -R' Starting From Method Used Analytical Data 24b 0 -c02mem 22 + 23 D-l- 'HNMR (DMSO-de): 5 0.89 (d, J = 6.8 Hz, 6 H), 1.87 (m, 1 H), 3.12 (t, J = 6 and 6.8 Hz, 2 H), 3.16 (s, 3 H), 3.30 (m, 2 H), 3.39 (dd, J = 5.2 and 3.4 Hz, 2 H), 5.04 (d, J = 4.3 Hz, 2 H), 5.16 (d, J = 16 Hz, 2 H), 7.08 (m, 2 H), 7.20 (m, 3 H), 7.24 (d, J = 8.6 Hz, 1 H), 7.35 (d, J = 8.6 Hz, 1 H), 7.61 (d, J = 5 Hz, 1 H), 7.71 (dd, J = 4.8 and 3 Hz, 1 H), 7.91 (dd, J = 1.7 and 7.7 Hz, 1 H), 8.00 (m, 1 H), 8.06 (dd, J = 2 and 8 Hz, IH), 8.14 (d, J = 1.7 Hz, 1H), 8.41 (d, J = 1.7 Hz, 1 H), 8.68 (t, J = 6 Hz, 1 H); MS (ES+) 602.27 24c 6 -co2mem 22 + 23 D-l 'HNMR (DMSO-dfi): 8 0.89 (d, J = 6.8 Hz, 6 H), 1.87 (m, 1 H), 3.12 (t, J = 6 and 6.8 Hz, 2 H), 3.16 (s, 3 H), 3.30 (m, 2 H), 3.40 (m, 2 H), 5.05 (d, J = 5 Hz, 2 H), 5.17 (d, J = 17 Hz, 2 H), 7.09 (m, 2 H), 7.21 (m, 3 H), 7.30 (d, J = 7.7 Hz, 1 H), 7.37 (d, J = 7.7 Hz, 1 H), 7.44 (m, 1 H), 7.54 (t, J = 7.7 Hz, 2 H), 7.73 (d, J = 6.8 Hz, 2 H), 7.88 (dd, J = 1.7 and 7.7 Hz, 1 H), 8.07 (dd, J = 7.7 and 1.7 Hz, 1 H), 8.11 (d, J = 1.7 Hz, 1 H), 8.42 (d, J = 1.7 Hz, 1 H), 8.72 (t, J = 6 Hz, 1 H); MS (ES+) 596.45 24d -co2mem 22 + 23 D-l MS (ES+) 616 24e b o -C02MEM 22 + 23 D-l MS (ES+) 586.4 114 Cpd. No.
-R -R' Starting From Method Used Aaalytical Data 24f jcy o -CO2MEM 22 + 23 D-l MS (ES4): 586.39 24g h3c -CO2MEM 22 + 23 D-l MS (ES+): 616.63 24h a -CO2MEM 22 + 23 D-l MS (ES4): 597.25 24i cx -CO2MEM. 22 + 23 D-l MS (ES4): 597.4 24j C1) n -CO2MEM 22 + 23 D-l MS (ES4): 597.4 24k "Yv^ 0 -CO2MEM 22 + 23 D-l MS (ES+): 644.3 115 Cpd. No.
-R -R* Starting From Method Used Analytical Data 241 cx n 1 ck, -C02MEM 22 + 23 D-3 Characterized at the next step 24m O n 1 -CO2MEM 22 + 23 D-10 Characterized at the next step 24n -CO2MEM 22 + 23 D-3 MS (ES+): 560.74 24o r=\ S^N -CO2MEM 22 + 23 D-4 MS (ES4): 603.72 24p ch3 -CO2MEM 22 + 23 D-5 MS (ES4): 558.3 24q / \/ch3 /^oh h3c -COzMEM 22 + 23 D-5 Characterized in the next step 24r -CO2MEM 22 + 23 D-5 MS (ES4): 610.4 (M+Na)+ 116 Cpd. No.
-R -R' Starting From Method Used Analytical Data 24s CH, -COzMEM 22+23 D-3 Characterized in the next step 2 4t CHj -COzMEM 22 + 23 D-3 Characterized in the next step 24u -C02MEM 22 + 23 D-3 MS (ES*): 598.4 (M+Na)+ 24v ,cb.2 -COzMEM 22 + 23 D-3 MS (ES"): 500.4 [(M-MEM)-1]' 24w ^/=TMS -COzMEM 22 + 23 D-5 Characterized in the next step 24x /CH3 —^ CH3 -COzMEM 22 + 23 D-3 MS (ES+): 610.5 (M+Naf 24y i^==\^-OH -COzMEM 22 + 23 D-5 MS (ES*): 596.4 (M+Naf 24z A OH -COzMEM 22 + 23 D-3 MS (ES+): 576.3 (M+Naf 24aa -COzMEM 22 + 23 D-ll Characterized in the next step 117 Cpd. No.
-R -R' Starting From Method Used Analytical Data 24ab CHO -CO2MEM 22 + 23 D-2 MS (ES4): 630.55 24ac cC.
\ / ^CHO P -COaMEM 22 + 23 D-2 MS (ES4"): 630.74 24ad OHCv/ ¥ -CO2MEM 22 + 23 D-2 MS (ES4): 652.3 24ae ohcA^ -CO2MEM 22 + 23 D-2 Characterized in the next step 24ag CA N 1 Boc -CO2MEM 22 + 23 D-l MS (ES4): 685.01 24ah ^CH2 -CO2MEM 22 + 23 D-3 MS (ES4"): 546.49 118 Cpd. No.
-R -R' Starting From Method Used Analytical Data 25a ■■*> co2h 24a I-l 'HNMR (DMSO-dfi): 5 0.91 (d, J = 6.9 Hz, 6 H), 1.88 (m, 1 H), 3.13 (t, J = 6.9 and 6 Hz, 2 H), 5.07 (d, J = 11.2 Hz, 2 H), 7.09 (in, 2 H), 7.22 (m, 5 H), 7.35 (d, 7.7 Hz, 1 H), 7.63 (d, 2.6 Hz, 1 H), 7.65 (d, J = 5.2 Hz, 1 H), 7.82 (dd, J = 7.7 and 1.7 Hz, 1 H), 8.05 (d, J = 1.7 Hz, 1 H), 8.07 (s, 1 H), 8.40 (s, 1 H), 8.72 (t, J = 6 Hz, 1 H), 12.77 (brs, 1 H); MS (ES+) 514.19 25b co2h 24b I-l 'HNMR (DMSO-de): 5 0.92 (d, J = 6.9 Hz, 6 H), 1.88 (m, 1 H), 3.12 (t, J = 6.9 and 6 Hz, 2 H), 5.07 (d, J = 13 Hz, 2 H), 7.09 (m, 2 H), 7.22 (m, 4 H), 7.35 (d, J = 8.6 Hz, 1 H), 7.63 (d, J = 5.2 Hz, 1 H), 7.70 (dd, J = 2.6 and 4.3 Hz, 1 H), 7.88 (dd, J = 7.2 and 1.7 Hz, 1 H), 8.02 (d, J = 1.7 Hz, 1 H), 8.07 (dd, J = 1.7 and 7.7 Hz, 1 H), 8.15 (m, 1 H), 8.39 (d, J = 1.7 Hz, 1 H), 8.72 (t, J = 6 Hz, 1 H), 12.70 (brs, 1 H); MS (ES+) 514.06 25c 6 co2h 24c I-l 'HNMR (DMSO-ds): 8 12.73 (bs, 1 H), 8.73 (t, J = 6 Hz, 1 H), 8.41 (d, J = 1.7 Hz, 1 H), 8.12 (d, J = 1.7 Hz, 1 H), 8.07 (dd, J = 7.7 & 1.7 Hz, 1 H), 7.83 (dd, J = 7.7 & 1.7 Hz, 1 H), 7.72 (d, J = 6.9 Hz, 2 H), 7.54 (t, J = 7.7,2 H), 7.44 (t, J = 7.7 Hz, 1 H), 7.37 (d, J - 7.7 Hz, 1 H), 7.28 (d, J = 7.7 Hz, 1 H), 7.21 (m, 3 H), 7.09 (m, 2 H), 5.08 (d, J = 14 Hz, 2 H), 3.13 (t, J = 6.5 Hz, 2 H), 1.88 (m, 1 H), 0.91 (d, 6.8 Hz, 6 H); MS (ES+) 507.93 25d co2h 24d I-l 'HNMR (DMSO-de): 8 12.75 (bs, 1 H), 8.71 (t, J = 6 Hz, 1 H), 8.39 (d, J = 1.7 Hz, 1 H), 8.05 (dd, J = 1.7 & 7.7 Hz, 1 H), 8.01 (d, J = 2.5 Hz, 1 H), 7.75 (dd, J =2.5 & 7.7 Hz, 1 H), 7.42 (d, 3.4 Hz, 1 H), 7.34 (d, J = 7.7 Hz, 1 H), 7.22 (m, 3 H), 7.19 (d, J = 8.6 Hz, 1 H), 7.09 (m, 2 H), 6.95 (d, J = 3.4 Hz, 1 H), 5.06 (d, J = 11 Hz, 2 H), 3.12 (t, J = 6.5 Hz, 2 H), 2.52 (s, 3 H), 1.89 (m, 1 H), 0.81 (d, 6.8 Hz, 6 H); MS (ES+) 528.51 119 Cpd. No.
-R -R' Starting From Method Used Analytical Data 25e b co2h 24e I-l 'HNMR (DMSO-d6): 5 0.89 (d, J = 6 Hz, 6 H), 1.86 (m, 1 H), 3.12 (t, J = 6.8 and 6.0 Hz, 2 H), 5.03 (d, J = 10 Hz, 2 H), 7.02 (s, 1 H), 7.06 (m, 2 H), 7.16 (d, J = 8.6 Hz, 1 H), 7.21 (m, 3 H), 7.31 (d, J = 7.7 Hz, 1 H), 7.75 (dd, J = 8.5 and 1.7 Hz, 1 H), 7.78 (t, J -1.7 Hz, 1 H), 8.04 (in, 2 H), 8.29 (s, 1 H), 8.36 (d, J = 1.7 Hz, 1 H), 8.66 (t, J = 6 and 5.2 Hz, 1 H), 12.58 (bs, 1 H); MS (ES+) 498.49 25f o co2h 24f I-l MS (ES*): 498.36 25g 1 1 CO 3- " co2h 24g I-l 'HNMR (DMSO-dfi): 5 12.72 (bs, 1 H), 8.69 (t, J = 6 Hz, 1 H), 8.39 (d, J = 1.7 Hz, 1 H), 8.06 (m, 2 H), 7.79 (dd, 1 = 1.7 & 7.7 Hz, 1 H), 7.45 (s, 1 H), 7.35 (d, J = 7.7 Hz, 1 H), 7.21 (m, 5 H), 7.1 (m, 2 H), 5.07 (d, J = 8.6 Hz, 2 H), 3.12 (t, J = 6.5 Hz, 2 H), 2.29 (s, 3 H), 1.89 (m, 1 H), 0.91 (d, 6.8 Hz, 6 H); MS (ES+) 528.38 25h c02h 24h I-l 'HNMR (DMSO-d6): 8 12.74 (bs, 1 H), 8.73 (m, 2 H), 8.63 (d, J = 1.7 Hz, 1 H), 8.41 (d, J = 1.7 Hz, 1 H), 8.23 (dd, J = 1.7 and 7.7 Hz, 1 H), 8.08 (dd, J = 1.7 & 7.7 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1 H), 7.96 (dt, J = 7.7 & 1.7 Hz, 1 H), 7.43 (dd, J == 6 & 7 Hz, 1 H), 7.37 (d, J = 7.7 Hz, 1 H), 7.29 (d, J = 8.6 Hz, 1 H), 7.18 (m, 3 H), 7.08 (m, 2 H), 5.01 (q, J = 10 & 25 Hz, 2 H), 3.13 (t, J = 6.9 and 6 Hz, 2 H), 1.89 (m, 1 H), 0.92 (d, J = 6.9 Hz, 6 H); MS (ES+) 509.58 120 Cpd. No.
-R -R' Starting From Method Used Analytical Data 25i cr co2h 24i I-l 'HNMR (DMSO-ds): 512.70 (bs, 1 H), 8.91 (d, J = 2.6 Hz, 1 H), 8.68 (t, J = 6 & Hz, 1 H), 8.62 (d, J = 2 Hz, 1 H), 8.4 (d, J = 1.7 Hz, 1 H), 8.12 (m, 2 H), 8.05 (dd, J = 8.6 & 1.7 Hz, 1 H), 7.88 (d, 8.5 & 1.7 Hz, 1 H), 7.53 (dd, J = 8.6 & 5.2 Hz, 1 H), 7.34 (d, J = 7.7 Hz, 1 H), 7.28 (d, J = 8.6 Hz, I H), 7.18 (m, 3 H), 7.08 (m, 2 H), 5.04 (d, J = 12 Hz, 2 H), 3.11 (t, J = 6.5 Hz, 2 H), 1.87 (m, 1 H), 0.9 (d, 6.8 Hz, 6 H); MS (ES+) 509.11 25j 6 co2h 24j I-l 'HNMR (DMSO-dg): 5 0.90 (d, J = 6.9 Hz, 6 H), 1.88 (m, 1 H), 3.11 (t, J = 6.9 and 6 Hz, 2 H), 5.03 (s, 2 H), 7.06 (m, 2 H), 7.18 (m, 3 H), 7.33 (d, 8.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 6.2 Hz, 2 H), 7.85 (m, 1 H), 8.05 (dd, J = 7.6 and 1.7 Hz, 1 H), 8.18 (s, 1 H), 8.40 (d, J=2 Hz, 1 H), 8.71 (m, 4 H); MS (ES+) 509.49 25k o COaH 24K 1-1 Characterized in the next step 251 1 ch3 co2h 241 I-l MS (ES+): 511.54 25m o T co2h 24m I-l MS (ES*): 501.66 121 Cpd. No.
-R -R' Starting From Method Used Analytical Data 25n co2h 24n I-l MS (ES*): 472.4 25o 155 co2h 24o I-l MS (ES*): 515.65 25p / vch3 co2h 24p I-l Characterized in the next step 25q // \zCH3 h3c/^oh co2h 24q I-l MS (ES*): 536.3 (M+Na)+ 25r oh co2h 24r I-I MS (ES-): 500.4 25s ch3 co2h 24s I-l Characterized in the next step 25t ch, ch3 co2h 24t I-l Characterized in the next step 25u yr=7\^-OH co2h 24u I-l MS (ES"): 486.4 122 Cpd. No.
-R -R' Starting From Method Used Analytical Data 25v , ch, C02H ' 24v . I-l MS (ES*): 524.3 (M+Na)* 25w y=cn C02H 24w i-l.Q Characterized in the next step 25x /ch3 — ch3 C02H 24x I-l MS (ES"): 498.3 25y C02H 24y I-l MS (ES"): 484.3 25z ch, A OH C02H 24z I-l MS (ES*): 488.3 25aa CO2H 24aa I-l Characterized in the next step 25ab y OH Q~ C02H 24ab K, I-l MS (ES*): 544.27 123 Cpd. No.
-R -R* Starting From Method Used Analytical Data 25ac ci-— OH co2h 24ac k, i-l MS (ES"1): 544.2 25ad BnOzC / co2h 24ad E,H, i-l MS (ES4): 670.3 (M+Na)+ 25ae HOHaC— co2h 24ae k, i-l 'HNMR (DMSO-dfi): 8 9.1 (bs, 2 H), 8.8 (bs, 2 H), 8.5 (t, J = 6 Hz, 1 H), 8.02 (s, 1 H), 7.68 (s, 1 H), 7.62 (m, 6 H), 7.53 (d, J = 5.8 Hz, 1 H), 7.15 (d, J = 6 Hz, 1 H),), 7.13 (m, 1 H), 7.01 (s, 1 H), 5.5 (t, J = 5 Hz, 1 H), 4.7 (d, J = 5 Hz, 2 H), 3.01 (m, 2 H), 1.8 Cm, 1 H), 0.85 fd, J = 6.8 Hz, 6 H) 25af HOHjC / ¥ co2h 24ad k, i-l MS (ES4): 566.2 (M+Na)4 25ag * l Boc co2h 24ag i-l MS (ES4): 597.7 25ah OH /Is^oa co2h 24ah l, i-l MS (ES4): 492.54 • 25ai ^n3 co2h 24ai ' L, M, K,N, 0,1-1 Characterized in the next step 124 Cpd. No.
-R Starting From Method Used Analytical Data 26a 25a J 'HNMR (DMSO-de): 5 0.88 (d, J « 6.9 Hz, 6 H), 1.84 (m, 1 H), 3.07 (t, J = 6.9 and 6.0 Hz, 2 H), 5.05 (s, 2 H), 7.04 (d, J = 6.9 Hz, 2 H), 7.20 (m, 4 H), 7.35 (d, J = 7.7 Hz, 1 H), 7.43 (d, J = 7.7 Hz, 1 H), 7.66 (d, J » 5.2 Hz, 1 H), 7.70 (d, J = 4.3 Hz, 1 H), 7.75 (m, 4 H), 7.82 (dd, J = 7.7 and 1.7 Hz, 1 H), 7.94 (d, J = 1.7 Hz, 1 H), 8.03 (dd, J = 7.7 and 1.7 Hz, 1 H), 8.26 (dd, J = 7.7. and 1.7 Hz, 1 H), 8.69 (t, J = 6 Hz, 1 H), 8.80 (s, 2 H), 9.17 (s, 2 H), 10.76 (s, 1 H); MS (ES+) 631.05 26b b 25b J 'HNMR (DMSO-d6): 8 0.88 (d, J = 6.9 Hz, 6 H), 1.84 (m, 1 H), 3.07 (t, J - 6.8 and 6.0 Hz, 2 H), 5.04 (s, 2 H), 7.02 (d, J = 6.8 Hz, 2 H), 7.20 (m, 3 H), 7.34 (d, J = 7.7 Hz, 1 H), 7.43 (d, J = 8.6 Hz, 1 H), 7.72 (m, 6 H), 7.90 (dd, J = 1.7 and 7.7 Hz, 1 H)s 8.05 (m, 3 H), 8.23 (d, J = 1.7 Hz, 1 H), 8.68 (t, J = 6 and 5.2 Hz, 1 H), 8.82 (s, 2 H), 9.17 (s, 2 H), 10.73 (s, 1 H); MS (ES+) 631.82 26c 6 25c J 'HNMR (DMSO-dfi): 8 10.75 (s, 1 H), 9.19 (s, 2 H), 8.89 (s, 2 H), 8.69 (t,J = 6 Hz, 1 H), 8.29 (d, J = 1.7 Hz, 1 H), 8.07 (dd, J = 7.7 & 1.7 Hz, 1 H), 7.99 (d, J = 1.7 Hz, 1 H), 7.87 (dd, J = 7.7 & 1.7 Hz, 1 H), 7.83 (d, J = 7.7 Hz, 2 H), 7.77 (m 5 H), 7.54 (t, 3 = 7.7,2 H), 7.43 (m, 3 H), 7.19 (m, 3 H), 7.03 (d, J = 6.9 Hz, 2 H); 5.04 (bs, 2 H), 3.09 (t, J - 6.5 Hz, 2 H), 1.84 (m, 1 H), 0.89 (d, 6.8 Hz, 6 H); MS (ES+) 625.81 125 Cpd. No.
-R Starting From Method Used Analytical Data 26d 25d J 'HNMR (DMSO-dfi): 5 10.7 (s, 1 H), 9.14 (s, 2 H), 8.82 (s, 2 H), 8.64 (t, J = 6 Hz, 1 H), 8.21 (s, 1 H), 7.98 (dd, J = 7.8 & 2 Hz, 1 H), 7.8 (d, J = 2 Hz, 1 H), 7.7 (m, 4 H), 7.68 (dd, J = 2 & 7.8 Hz, 1 H), 7.44 (d, J = 3 Hz, 1 H), 7.37 (d, 7.8 Hz, 1 H), 7.27 (d, J = 7.7 Hz, 1 H), 7.16 (m, 3 H), 7.0 (s, 1 H), 6.99 (s, 1 H), 6.86 (d, J = 3 Hz, 1 H), 5.0 (s,-2 H), 3.03 (t, J = 6.5 Hz, 2 H), 2.46 (s, 3 H), 1.78 (m, 1 H), 0.83 (d, 6.8 Hz, 6 H); MS (ES+) 645.77 26e b 25e J 'HNMR (DMSO-de): 5 0.87 (d, J = 6.2 Hz, 6 H), 1.73 (m, 1 H), 3.07 (t, J = 6.7 and 6.2 Hz, 2 H), 5.05 (s, 2 H), 7.03 (dd, J -1.7 and 8 Hz, 2 H), 7.11 (d, J 1.7 Hz, 1 H), 7.21 (m, 3 H), 7.31 (d, J = 8 Hz, 1 H), 7.42 (d, J = 8 Hz, 1 H), 7.78 (m, 5 H), 7.92 (d, J = 1.7 Hz, 1 H), 8.02 (dd, J = 8 and 1.7 Hz, 1 H), 8.25 (d, J = 1.9 Hz, 1 H), 8.33 (s, 1 H), 8.63 (t, J = 6 and 5 Hz, 1 H), 8.80 (bs, 2 H), 9.14 (bs, 2 H), 10.67 (s, 1 H); MS (ES+) 615.75 26f 2Sf J 'HNMR (DMSO-de): 6 0.87 (d, J = 6.7 Hz, 6 H), 1.83 (m, 1 H), 3.06 (t, J = 6.7 and 6.2 Hz, 2 H), 5.04 (s, 2 H), 6.67 (m, 1 H), 7.03 (m, 2 H), 7.16 (m, 3 H), 7.35 (d, J = 8.6 Hz, 1 H), 7.42 (d, J = 8 Hz, 1 H), 7.74 (m, 4 H), 7.85 (m, 2 H), 7.98 (d, J = 1.2 Hz, 1 H), 8.03 (dd, J = 1.7 and 8 Hz, 1 H), 8.25 (d, J= 1.8 Hz, 1 H), 8.67 (t, J = 6.2 and 5.5 Hz, 1 H), 8.88 (bs, 2 H), 9.12 (bs, 2 H), 10.772 (bs, 1 H); MS (ES+) 615.75 26g H3C '25g J 'HNMR (DMSO-de): 8 10.67 (s, 1 H), 9.12 (s, 2 H), 8.78 (s, 2 H), 8.61 (t, J = 6 Hz, 1 H), 8.21 (s, 1 H), 7.98 (dd, J = 7.8 & 2 Hz, 1 H), 7.84 (d, J - 2 Hz, 1 H), 7.7 (m, 5 H), 7.46 (s, 1 H), 7.39 (d, 7.8 Hz, 1 H), 7.29(d, J = 7.7 Hz, 1 H), 7.16 (m, 4H), 7.0l(s, 1 H), 6.99 (s, 1 H), 5.0 (s, 2 H), 3.03 (t, J = 6.5 Hz, 2 H), 2.23 (s, 3 H), 1.79 (m, 1 H), 0.83 (d, 6.8 Hz, 6 H); MS (ES+) 645.77 126 Cpd. No.
-R Starting From Method Used Analytical Data 26h a 25h J 'HNMR (DMSO-dfi): 5 10.77 (bs, 1 H), 8.95 (bs, 4 H), 8.76 (d, J = 4.3 Hz, 1 H), 8.69 (t, J = 6 Hz, 1 H), 8.4 (s, 1 H), 8.29 (m, 2 H), 8.15 (d, J = 7.7 Hz, 1 H), 8.07 (dd, J = 1.7 and 7.7 Hz, 1 H), 7.99 (dt, J = 1.7 & 7.7 Hz, 1 H), 7.76 (m, 4 H), 7.46 (m, 2 H), 7.18 (m,.3 H), 7.05 (s, 1 H), 7.03 (s, 1 H), 5.06 (s, 2 H), 3.10 (t, J = 6.9 and 6 Hz, 2 H), 1.86 (m, 1 H), 0.89 (d, J = 6.9 Hz, 6 H); MS (ES+) 626.69 26i cy 25i J 'HNMR (DMSO-de): 8 10.73 (bs, 1 H), 9.16 (bs, 2 H), 9.05 (d, J = 1.9 Hz, 1 H), 8.79 (s, 2 H), 8.69 (t, J = 6 & Hz, 1 H), 8.64 (dd, J = 1.2 & 5 Hz, 1 H), 8.29 (d, J = 1.7 Hz, 1 H), 8.24 (d, J = 8 Hz, 1 H), 8.05 (m, 2 H), 7.93 (dd, 8 & 1.8 Hz, 1 H), 7.76 (m, 5 H), 7.56 (dd, J = 8 & 4.3 Hz, 1 H), 7.44 (d, J = 7.4 Hz, 2 H), 7.18 (m, 3 H), 7.0 (m, 2 H), 5.0 (s, 2 H), 3.08 (t, J = 6.5 Hz, 2 H), 1.82 (m, 1 H), 0.88 (d, 6.8 Hz, 6 H);; MS (ES+) 626.44 26j 25j J 'HNMR (DMSO-d6): 5 0.87 (d, J = 6.9 Hz, 6 H), 1.75 (m, 1 H), 3.08 (t, J = 6.9 and 6.0 Hz, 2 H), 5.03 (s, 2 H), 7.03 (m, 1 H), 7.18 (m, 3 H), 7.45 (t, J = 7.8 and 7 Hz, 2 H), 7.76 (s, 4 H), 7.87 (d, J = 6 Hz, 2 H), 7.94 (dd, J = 8 and 2 Hz, 1 H), 8.05 (dd, J = 8 and 2 Hz, 1 H), 8.08 (d, J=2 Hz, 1 H), 8.29 (d, J = 2 Hz, 1 H), 8.70 (m, 3 H), 8.84 (s, 2 H), 9.11 (s, 2 H), 10.76 (s, 1 H); MS (ES+) 626.76 26k h,cY^ 0 25k J 'HNMR (DMSO-d6): 8 10.72 (bs, 1 H), 9.15 (bs, 2 H), 8.81 (bs, 2 H), 8.86 (t, J = 6 Hz, 1 H), 8.28 (s, 1 H), 8.03 (m, 3 H), 7.91 (d, J = 7.9 Hz, 1 H), 7.81 (d, J = 4 Hz, 1 H), 7.74 (s, 4 H), 7.42 (d, J = 7.9 Hz, 1 H), 7.38 (d, J = 7.9 Hz, 1 H), 7.18 (m, 3 H), 7.04 (m, 2 H), 5.04 (bs, 2 H), 3.07 (t, J = 6 Hz, 2 H), 2.57 (s, 3 H), 1.83 (m, 1 H), 0.87 (d, J = 6.8 Hz, 6 H); MS (ES+) 673.7 127 Cpd. No.
-R Starting From Method Used Analytical Data 261 N 1 CH3 251 J 'HNMR (DMSO-d6): 5 10.66 (s, 1 H), 9.20 (s, 2 H), 8.86 (s, 2 H), 8.66 (t, J = 6 Hz, 1 H), 8.24 (d, J = 2 Hz, 1 H), 8.15 (dd, J = 7.8 & 2 Hz, 1 H), 7.69 (m, 4 H), 7.68 (d, J = Hz, 1 H), 7.63 (d, J = 7.9 Hz, 1 H), 7.43 (d, J = 7.9 Hz, 1 H), 7.37 (d, J = 7.9 Hz, 1 H), 7.24 (m, 3 H), 7.09 (m, 2 H), 6.92 (s, 1 H), 6.40 (s, 1 H), 6.17 (t, J = 4 Hz, 1 H), 5.10 (bs, 2 H), 3.74 (s, 3 H), 3.09 (t, J = 6 Hz, 2 H), 1.83 (m, 1 H), 0.88 (d, J = 6.8 Hz, 6 H); MS (ES+) 628.65 26m Q 1 25m J MS (ES+): 618.91 26a 25n J 'HNMR (DMSO-d6): 8 10.56 (s, 1 H), 9.15 (bs, 2 H), 8.84 (bs, 2 H), 8.64 (t, J = 6 Hz, 1 H), 8.19 (d, J = 2 Hz, 1 H), 7.99 (d, J = 7 Hz, 1 H), 7.70 (m, 4 H), 7.46 (s, 1 H), 7.36 (m, 2 H), 7.24 (m, 3 H), 7.05 (s, 1 H), 7.00 (s, 1 H), 6.0 (m, 1 H), 5.18 (d, J = 16 Hz, 1 H), 5.10 (d, J = 11 Hz, 1 H), 5.0 (s, 2 H), 3.47 (d, J = 6 Hz, 1 H), 3.03 (t, J = 6 Hz, 2 H), 1.79 (m, 1 H), 0.83 (d, J = 6.8 Hz, 6 H); MS (ES+) 589.5 26o r=\ s\^n 25o J 'HNMR (DMSO-de): 8 10.84 (s, 1 H), 9.16 (s, 2 H), 8.78 (s, 2 H), 8.69 (t, J = 6 Hz, 1 H), 8.27 (d, J = 2 Hz, 1 H), 8.19 (s, 1 H), 8.09 (dd, J = 2 & 7.7 Hz, 1 H), 8.04 (dd, J = 2 & 7.7 Hz, 1 H), 8.01 (d, J = 4 Hz, 1 H), 7.89 (d, J = 3 Hz, 1 H), 7.73 (m, 4 H), 7.44 (dd, J = 3 & 7.8 Hz, 2 H), 7.16 (m, 3 H), 7.30 (s, 1 H), 7.05 (s, 1 H), 5.03 (bs, 2 H), 3.06 (t, J = 6.5 Hz, 2 H), 1.82 (m, 1 H), 0.86 (d, 6.8 Hz, 6 H); MS (ES+) 632.4 26p ch3 25p J MS (ES4): 609.3 (M+Na)+ 128 Cpd. No.
-R Starting From Method Used Analytical Data 26q 25q J MS (ES+) 631.5 26r 25r J 'HNMR (DMSO-ds): 5 10.71 (s, 1 H), 9.16 (s, 2 H), 8.81 (s, 2 H), 8.68 (U = 6 Hz, 1 H), 8.25 (s, 1 H), 8.03 (d, J = 7.8 Hz, 1 H), 7.73 (m, 5 H), 7.69 (s, 1 H), 7.55 (d, J = 7.8 Hz, 1 H), 7.39 (d,J = 8.9 Hz, 1 H), 7.26 (m, 3 H), 7.03 (m, 2 H), 5.02 (bs, 2 H), 4.95 (t, J = 5 Hz, 1 H), 3.62 (q, J « 6 & 12.8 Hz, 2 H), 3.07 (t, J = 6 Hz, 2 H), 2.62 (t, J = 6 Hz, 2 H), 1.83 (m, 1 H), 0.88 (d, J = 6.8 Hz, 6 H); MS (ES+) 617.4 26s ^-=\^CH2 CHJ 25s J 'HNMR (DMSO-de): 5 0.89 (d, J = 6.8 Hz, 6 H), 1.84 (m, 1 H), 1.99 (s, 3 H), 3.09 (t, J = 6 Hz, 2 H), 5.04 (s, 2 H), 5.18 (s, 1 H), 5.28 (s, 1 H), 6.73 (d, J = 16 Hz, 1 H), 7.04 (d, J = 6 Hz, 2 H), 7.23 (m, 5 H), 7.42 (d, J = 9 Hz, 1 H), 7.73 (m, 5 H), 7.85 (s, 1 H), 8.03 (dd, J = 9 and 2 Hz, 1 H), 8.26 (d, J = 2 Hz, 1 H), 8.69 (t, J = 6 Hz, 1 H), 8.87 (bs, 4 H), 10.91 (s, 1 H); MS (ES+) 615.4 26t CHL, 25t J 'HNMR (DMSO-de): S 10.8 (br s, 1 H), 9.1 and 8.9 (2 br s, 4 H), 8.6 (m, 1 H), 8.2 (s, 1 H), 8.0 (m, 1 H), 7.8-7.6 (m, 6 H), 7.40 (, J « 6.9 Hz, 1 H ), 7.3 (m, 4 H), 7.0 (d, 1 H), 5.6 (m, 1 H), 5.2 (m, 1 H), 5.0 (br s, 1 H), 3.1 (t, J = 6.8 Hz, 2 H ), 2.2 ( s, 3 H), 1.8 (m, 1 H), 0.95 (d, 6 H); MS (ES+) 589.4, MS (ES-) 587.5 26u //==\/OH 2Su J 'HNMR (DMSO-dfi): 5 0.88 (d, J = 6.8 Hz, 6 H), 1.84 (m, 1 H), 3.09 (t, J = 6 Hz, 2 H), 4.33 (t, J = 5.5 Hz, 2 H), 5.02 (s, 2 H), 5.01 (t, J — 5.5 Hz, 1 H), 5.95 (m, 1 H), 6.57 (d, J = 11.5 Hz, 1 H), 7.04 (d, J - 6.7 Hz, 2 H), 7.25 (in, 3 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.43 (m, 2 H), 7.54 (s, 1 H), 7.74 (s, 4 H), 8.05 (dd, J = 7.8 and 2 Hz, 1 H), 8.23 (d, J = 2 Hz, 1 H), 8.69 (t, J = 6 Hz, 1 H), 8.83 (bs, 2 H), 9.18 (bs, 2 H), 10.66 (s, 1 H); MS (ES+) 605.3 129 Cpd. No.
-K Starting From Method Used Analytical Data 26v ^OH 25v J 'HNMR (DMSO-de): 8 0.88 (d, J = 6.8 Hz, 6 H), 1.84 (m, 1 H), 2.75 (t, J = 7 Hz, 2 H), 3.09 (t, J - 6 Hz, 2 H), 3.60 (m, 2 H), 4.65 (t, J - 5 Hz, 1 H), 5.05 (s, 2 H), 7.05 (d, J = 7 Hz, 2 H), 7.29 (m, 5 H), 7.42 (d, J = 7.8 Hz, 1 H), 7.66 (dd, J = 7.8 and 2 Hz, 1 H), 7.75 (m, 6 H), 8.03 (dd, J = 7.8 and 2 Hz, 1 H), 8.25 (s, 1 H), 8.68 (t, J = 6 Hz, 1 H), 8.82 (bs, 2 H), 9.18 (bs, 2 H), 10.68 (s, 1 H); MS (ES+) 619.4 26w y^CH 25w J 'HNMR (DMSO-de): 8 0.88 (d, J = 6.8 Hz, 6 H), 1.84 (m, 1 H), 3.09 (t, J = 6 Hz, 2 H), 4.41 (s, 1 H), 5.04 (d, J = 11 Hz, 2 H), 7.05 (d,J = 5.5 Hz, 2 H), 7.29 (m, 3 H), 7.34 (d, J = 8 Hz, 1 H), 7.40-(d, J = 8 Hz, 1 H), 7.65 (dd, J = 8 and 2 Hz, 1H), 7.75 (s, 4 H), 7.79 (s, 1 H), 8.05 (dd, J = 8 and 2 Hz, 1H), 8.28 (d, J = 2 Hz, 1 H), 8.71 (t, J = 6 Hz, 1 H), 8.82 (bs, 2 H), 9.17 (bs, 2 H), 10.73 (s, 1 H); MS (ES+) 573.3 26x /CH3 CH, 25x J lHNMR (DMSO-d6): 8 0.86 (d, J = 6.8 Hz, 6 H), 1.47 (s, 3 H), 1.74 (3, 3 H), 1.85 (m, 1 H), 3.06 (t, J = 6 Hz, 2 H), 3.43 (d, J = 8 Hz, 1 H), 5.04 (s, 2 H), 5.11 (m, 1H), 7.03 (m, 2 H), 7.23 (m, 5 H), 7.52 (m, 2 H), 7.72 (m, 5 H), 8.02 (m, 1 H), 8.21 (s, 1 H), 8.66 (t, J = 6 Hz, 1 H), 8.81 (bs, 2 H), 9.23 (bs, 2 H), 10.52 (s, 1 H); MS (ES+) 617.6 26y 25y J 'HNMR (DMSO-d6): 8 0.87 (d, J = 6.8 Hz, 6 H), 1.72 (m, 1 H), 3.07 (t, J = 6 Hz, 2 H), 4.36 (d, J " 6 Hz, 2 H), 5.0 (m, 2 H), 5.42 (t, J = 6 Hz, 1 K), 7.03 (d, J = 7 Hz, 2 H), 7.25 (m, 3 H), 7.31 (d, I = 8 Hz, 1 H), 7.39 (d, J = 8 Hz, 1 H), 7.58 (d, J = 8 Hz, I H), 7.73 (m, 5 H), 8.02 (dd, J = 10 and 2 Hz, 1 H), 8.23 (s, 1 H), 8.68 (t, J = 6 Hz, 1 H), 8.76 (bs, 2 H), 9.15 (bs, 2 H), 10.71 (s, 1 H); MS (ES+) 603.4 130 Cpd. No.
-R . Starting From Method Used Analytical Data 26z CH, OH 25z J 'HNMR (DMSO-de): 8 10.6 (s, 1 H), 9.17 (s, 1 H), 8.85 (s, 1 H), 8.68 (d, J = 5.9 Hz, 2 H), 8.25 (d, 1.98 Hz, 1 H), 8.05 (d, J = 1.96 Hz, 1 H), 8.03 (d, J = 1.9 Hz, 1 H), 7.75 (m, 4 H), 7.65 (m, 4 H), 7.41 (d, J = 7.87 Hz, 4 H), 7.25 (m, 1 H) 5.4 (s, 1 H), 5.2 (d, J = 5.9 Hz, 2 H), 4.44 (d, J = 5.9 Hz, 1 H), 3.09 (d, J = 6.89 Hz, 2 H), 1.89 (d, J = 6.89 Hz, 2 H) 0.88 (d, J = 5.9 Hz, 6 H); MS (ES+) 605.69 26aa _ =N 25aa J Characterized in the next step 26ab y "OH 0- 25ab J 'HNMR (DMSO-ds): 8 10.70 (s, 1 H) 9.15 (bs, 2 H), 8.77 (bs, 2 H), 8.67 (t, J = 6 Hz, 1 H), 8,25 (s, 1 H), 8.04 (d, J = 7 Hz, 1 H), 7.77 (d, J -2 Hz, 1 H), 7.71 (m 4 H), 7.70 (d, J = 2 Hz, 1 H), 7.59 (d, J = 6 Hz, 1 H), 7.46 (d, J = 8 Hz, 1 H), 7.41 (d, J = 8 Hz, 1 H), 7.22 (m, 3 H), 7.05 (s, 1 H), 7.03 (d, J = 2 Hz, 1 H), 5.31 (t, J = 6 Hz, 1 H), 5.04 (bs, 2 H), 4.51 (d, J = 6 Hz, 2 H), 3.07 (t, J = 6 Hz, 2 H), 1.82 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES+) 661.74 26ac ,nC_ OH 25ac J 'HNMR (DMSO-dfi): 8 0.87 (d, J = 6.8 Hz, 6 H), 1.83 (m, 1 H), 3.07 (t, J = 6 Hz, 2 H), 4.71 (d, J = 5 Hz, 2 H), 5.04 (bs, 2 H), 5.69 (t, J — 5 Hz, 1 H), 7.03 (d, J - 5.8 Hz, 2 H), 7.21 (m, 3 H), 7.35 (d, J - 5 Hz, 1 H), 7.38 (d, J = 8 Hz, 1 H),7.44(m,d, J = 8Hz, 1 H),7.58(d,J = 5Hz,l H),7.74(m,6H),8.03 (d, J => 8 Hz, 1 H), 8,24 (s, 1 H), 8.67 (t, J = 6 Hz, 1 H), 8.79 (bs, 2 H), 9.14 (bs, 2 H), 10.64 (s, 1 H); MS (ES+) 661.74 26ad BnC02 / Q 25ad J 'HNMR (DMSO-dfi): 8 9.65 (s, 1 H), 8.71 (t, J = 5.15 Hz, 1H) 8.39 (d, J = 2.57 Hz, 4 H), 8.09 (d, J = 1.79 Hz, 4 H), 8.05 (d, J = 1.79 Hz, 4 H), 7.43 (d, J = 7.77 Hz, 2 H), 7.29 (s, 2 H), 7.19 (m, 2 H), 7.08 (m, 2 H), 5.03 (d, J = 2.58 Hz, 2 H) 3.29 (m, 2 H), 3.12 (s, 4 H), 2.49 (m, 2 H), 1.87 (m, 2 H), 0.90 (d,J = 6.87 Hz, 6 H); MS (ES+) 765.4 131 Cpd. No.
-R Starting From Method Used Analytical Data 26ae 25ae J 'HNMR (DMSO-de): 8 9.1 (bs, 2 H), 8.8 (bs, 2 H), 8.5 (t, J = 6 Hz, 1H), 8.02 (s, 1 H), 7.68 (s, 1 H), 7.62 (m, 6 H), 7.53 (d, J = 5.8 Hz, 1 H), 7.15 (d, J « 6 Hz, 1 H),), 7.13 (m, 1 H), 7.01 (s, 1 H), 5.5 (t, J = 5 Hz, 1 H), 4.7 (d, J = 5 Hz, 2 H), 3.01 (m, 2 H), 1.8 (m, 1 H), 0.85 (d, J = 6.8 Hz, 6 H); MS (ES+) 571.2 26af HOH2C / ¥ 25af J 'HNMR (DMSO-de): 8 10.6 (s, 1 H), 9.17 (s, 1 H), 8.85 (s, 1 H), 8.68 (d, J = 5.9 Hz, 2 H), 8.25 (d, 1.98 Hz, 1 H), 7.75 (m, 4 H), 7.65 (m, 4 H), 7.41 (d, J = 7.87 Hz, 4 H), 7.25 (m, 4 H), 5.4 (s, 1 H), 5.2 (d, J = 5.9 Hz, 2 H), 4.44 (d, J = 5.9 Hz, 1 H), 3.09 (d, J = 6.89 Hz, 2 H), 1.89 (d, J = 6.89 Hz, 2 H), 0.88 (d, J = 5.9 Hz, 6 H). 26ag 1 Boc 25ag J 'HNMR (DMSO-de): 8 0.90 (d, J = 6.9 Hz, 6 H), 1.41 (s, 9 H), 1.87 (in, 1 H), 3.11 (t, J = 6.9 and 6 Hz, 2 H), 5.07 (s, 2 H), 6.37 (t, J = 3.4 Hz, 1 H), 6.51 (s, 1 H), 7.11 (m, 2 H), 7.26 (m, 3 H), 7.33 (d, 7.7 Hz, 1 H), 7.41 (d, J - 8.6 Hz, 1 H), 7.45 (d, J = 1.7 Hz, 1 H), 7.61 (dd, J = 1.7 and 7.7,1 H), 7.74 (m, 5 H), 8.05 (dd, J = 8.6 and 1.7 Hz, 1 H), 8.26 (d, J = 1.7 Hz, 1 H), 8.66 (t, J = 5 and 6 Hz, 1 H), 8.77 (bs, 2 H), 9.15 (bs, 2H), 10.58 (s, 1H); MS (ES+) 714.78 26ah X- 25ah J MS (ES4): 609.6 26ai 25ai J 'HNMR (DMSO-d6): 8 10.8 (s, 1 H), 6.2 and 8.9 (2 br s, 2 H each, 4H), 8.7 (t, 1 H), 8.2 (s, 1 H), 8.0 (d, J = 6 Hz, 1 H), 7.7 (m, 5 H), 7.6 (d, J = 5 Hz, 1 H), 7.4 (d, J = 5.8 Hz, 1 H), 7.35 (d, J = 6.9 Hz, 1 H), 7.29 (m, 3 H), 7.0 (m, 2 H), 5.0 (m, 2 H), 4.6 (s, 2 H), 3.01 (t, J = 6.8 Hz, 2 H), 1.81 (m, 1 H), 0.95 (d, J ~ 6.8 Hz, 6 H); MS (ES+) 604.3 132 Cpd. No.
-R -R' Starting From Method Used Analytical Data 27a -<> ch3 26a 1-2 'H NMR (DMSO-de): 8 14.95 (s, 1 H), 8.97 (s, 4 H), 8.5 (t, J = 6 Hz, 1 H), 7.97 (d, J = 2 Hz, 1 H), 7.80 (d, J = 2 Hz, 1 H), 7.73 (dd, J = 7.9 and 2 Hz, 1H), 7.61 (m, 7 H), 7.18 (t, J - 3.9 Hz, 1 H), 7.05 (d, J = 7.9 Hz, 1 H), 6.93 (d, J = 7.9 Hz, 1 H), 3.01 (t, J = 6.9 and 6.0 Hz, 2 H), 1.81 (m, 1 H), 0.84 (d, J = 6.9 Hz, 6 H); MS (ES4): 541.17 27b CH3 26b 1-2 :H NMR (DMSO-de): 5 13.24 (s, 1 H), 9.05 (s, 2 H), 8.9 (s, 2 H), 8.49 (t, J = 6 and 5.2 Hz, 1 H), 7.97 (s, 1 H), 7.99 (s, 1 H), 7.87 (s, IH), 7.75 (d, J = 7.7 Hz, 1 H), 7.65 (m, 1 H), 7.62 (m, 6 H), 7.05 (d,J = 7.7 Hz, 1 H), 6.93 (d, J = 7.7 Hz, 1H), 3.01 (t, J « 6.9 and 6.0 Hz, 2 H), 1.81 (m, 1 H), 0.85 (d, J = 6.9 Hz, 6 H); MS (ES4): 541.42 27c 6 ch3 \^ch3 26c 1-2 'H NMR (DMSO-de): 8 13.28 (s, 1 H), 9.04 (s, 4 H), 8.5 (t, J = 6 Hz, 1 H), 7.97 (s, 1 H), 7.82 (s, 1 H), 7.74 (m, 3 H), 7.62 (m, 5 H), 7.5 (t, J = 7.7 Hz, 2 H), 7.4 (t, J = 7.7, 1H), 7.1 (d, J = 7.7 Hz, 2 H), 6.97 (d, J = 7.7. Hz, 1H), 3.01 (t, J = 6.5 Hz, 2 H), 1.8 (m, 1 H), 0.85 (d, 6.8 Hz, 6 H); MS (ES4): 535.48 133 Cpd. No.
-R -R' Starting From Method Used Analytical Data 27d ch3 x~-/^ch3 26d 1-2 "H NMR (DMSO-de): 5 9.03 (s, 2 H), 8.89 (s, 2 H), 8.49 (t, J = 6 Hz, 1 H), 7.99 (s, 1 H), 7.65 (m, 8 H), 7.37 (d, J = 3 Hz, 1 H), 7.04 (d> J = 7.7 Hz, 1 H), 6.98 (s, 1 H), 6.82 (d, J = 3 Hz, 1 H), 2.98 (t, J = 6.5 Hz, 2 H), 2.46 (s, 3 H), 1.76 (m, 1 H), 0.81 (d, 6.8 Hz, 6 H); MS (ES^SS^l 27e b ch, 26e 1-2 'H NMR (DMSO-dfi): 8 14.10 (s, 1 H), 9.05 (bs, 2 H), 8.79 (bs, 2 H), 8.47 (t, J - 5.6 Hz, 1 H), 8.3 (s, 1 H), 7.96 (d, J = 2 Hz, 1 H), 7.78 Cm, 1 H), 7.63 (m, 7 H), 7.05 (m, 1 H), 7.01 (d, J = 7.7 Hz, 1 H), 6.92 (d, J - 7.7 Hz, 1 H), 3.02 (t, J « 4.9 Hz, 2 H), 1.81 (m, 1 H), 0.85 (d, J = 6.3 Hz, 6 H); MS (ES4): 525.36 27f -o O ch, 26f 1-2 'H NMR (DMSO-de): 8 9.07 (s, 2 H), 8.86 (s, 2 H), 8.53 (t, J = 5 Hz, 1 H), 8.03 (s, 1 H), 7.89 (d, J = 1.4 Hz, 1 H), 7.78 (m, 2 H), 7.65 (m, 6 H), 7.1 (m, 2 H), 7.08 (d, J = 7 Hz, 1 H), 6.64 (dd, J = 3.5 and 2 Hz, 1 H), 3.03 (t, J = 6.9 and 6.0 Hz, 2 H), 1.81 (m, 1 H), 0.86 (d, J = 6.9 Hz, 6 H); MS (ES4): 525.43 27g h3c. ch3 ^\:H3 26g 1-2 lH NMR (DMSO-de): 8 13.81 (s, 1 H), 8.74 (bs, 4 H), 8.43 (t, J = 6 Hz, 1 H), 7.92 (d, J = 2 Hz, 1 H), 7.69 (d,J = 2 Hz, 1 H), 7.62 (dd, J = 7.7 & 2 Hz, 1 H), 7.54 (m, 5 H), 7.38 (s, 1 H), 7.15 (s, 1 H), 6.99 (d, J = 7.8 Hz, 1 H), 6.89 (d, J = 6.8 Hz, 1 H), 2.97 (t, J = 6.5 Hz, 2 H), 2.20 (s, 3 H), 1.76 (m, 1 H), 0.8 (d, 6.8 Hz, 6 H); MS (ES4): 555.67 134 Cpd. No.
-R -R' Starting From Method Used Analytical Data 27h a ch3 ^^ch3 26h 1-2 lH NMR (DMSO-de): 8 13.95 (bs, 1 H), 8.99 (bs, 2 H), 8.79 (bs, 2 H), 8.65 (d, J = 5 Hz, 1 H), 8.43 (t, J = 6 Hz, 1 H), 8.25 (s, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.00 (d, J = 7.8 Hz, 1 H), 7.94 (s, 1 H), 7.87 (t, J - 7.8 Hz, 1 H), 7.58 (m, 5 H), 7.34 (dd, j = 7.8 & 5 Hz, 1 H), 7.09 (dd, J = 7.7 Hz, 1 H), 6.90 (d, J = 7.8 Hz, 1 H), 2.97 (t, J = 5 Hz, 2 H), 1.76 (m, 1 H), 0.81 (d, 6.8 Hz, 6 H); MS (ES4): 268.64 (m/2) 27i CJ ch3 \^ch3 26i 1-2 !H NMR (DMSO-d6): 8 9.05 (bs, 2 H), 8.95 (d, J=2.1 Hz, 1 H), 8.75 (s, 2 H), 8.65 (dd, J = 5 & 1.4 Hz, 1 H), 8.5 (t, J = 5.6 Hz, 1H), 8.2 (dt, J = 1.8 & 7.7 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.9 (d, J = 2.1 Hz, 1 H), 7.85 (dd, J = 7.7 &2.2 Hz, 2 H), 7.65 (m, 5 H), 7.55 (dd, J = 7.7 & 4.5 Hz, 1 H), 7.15 (d, J - 7.7 Hz, 1 H), 6.95 (d, J = 7.7 Hz, 1 H), 3.08 (t, J = 5 Hz, 2 H), 1.82 (m, 1 H), 0.9 (d, 6.8 Hz, 6 H); MS (ES4): 268.85 (m/2) 27j 6 N ch3 26j 1-2 'H NMR (DMSO-de): 8 14.19 (s, 1 H), 9.06 (bs, 2 H), 8.67 (bs, 2 H), 8.67 (d, J = 6 Hz, 2 H), 8.50 (t, J = 6 Hz, 1 H), 7.97 (m, 2 H), 7.91 (dd, J = 7.7 and 2 Hz, 1 H), 7.80 (d, J = 6 Hz, 2 H), 7.64 (m,6H), 7.18 (d, J = 7.7 Hz, 1 H), 6.95 (d, J = 7.7 Hz, 1 H), 3.02 (t, J = 5.0 Hz, 2 H), 1.82 (m, 1 H), 0.80 (d, J = 6.9 Hz, 6 H); MS (ES4): 536.43 27k 0 ch, . ^c„, 26k 1-2 'H NMR (DMSO-ds): 8 9.04 (bs, 2 H), 8.78 (bs, 2 H), 8.55 (t, J = 6 Hz, 1H), 8.1 (s, 1H), 7.98 (d, J=4 Hz, 1 H), 7.95 (s, 1 H), 7.87 (d, J = 7.9 Hz, 1 H), 7.75 (d, J = 6.9 Hz, 1 H), 7.66 (m, 4 H), 7.2 (m, 2 H), 7.09 (s, 1 H), 3.03 (t, J = 6 Hz, 2 H), 2.55 (s, 3 H), 1.81 (m, 1 H), 0.85 (d, J = 6.8 Hz, 6 H); MS (ES4): 583.59 135 Cpd. No. -r -r' Starting From Method Used Analytical Data 271 T ch3 ch3 ^^ch3 261 1-2 'H NMR (DMSO-de): 6 9.1 (s, 2 H), 8.84 (s, 2 H), 8.56 (t, J = 6 Hz, 1 H), 8.08 (bs, 1 H), 7.67 (in, J = 7 H), 7.58 (d, J = 7.9 Hz, 1 H), 7.11 (tn, 2 H), 6.91 (bs, 1 H), 6.31 (bs, 1 H), 6.11 (t, J = 3 Hz, 1 H), 3.74 (s, 3 H), 3.05 (t, J = 6 Hz, 2 H), 1.83 (m, 1 H), 0.88 (d, J = 6.8 Hz, 6 H); MS (ES+): 538.64 27m V 1 ch3 ^Sh3 26m 1-2 'H NMR (DMSO-de): 5 9.04 (s, 2 H), 8.94 (s, 2 H), 8.46 (t, J = 6 Hz, 1 H), 7.96 (s, 1 H), 7.63 (xn, 6 H), 6.94 (s, 1 H), 6.83 (d, J = 7.7 Hz, 1 H), 6.7 (d, J = 2,1 H), 6.62 (dd, J = 7.7 and 2 Hz, 1 H), 3.28 (m, 4 H), 3.02 (t, J = 6.5 Hz, 2 H), 1.98 (m, 4 H), 1.82 (m,lH), 0.82 (d, 6.8 Hz, 6 H); MS (ES4): 528.76 27n ch3 26n 1-2 'H NMR (DMSO-de): 5 13.96 (s, 1 H), 9.02 (s, 2 H), 8.85 (s, 2 H), 8.46 (t, J = 6 Hz, 1 H), 7.91 (s, 1 H), 7.58 (m, 4 H), 7.39 (s, 1H), 7.25 (d, J = 7.8 Hz, 1 H), 6.92 (d, J = 7.7,1 H), 6.87 (d, J = 7.7 Hz, 1 H), 6.01 (m, 1 H), 5.17 (d, J = 16.7 Hz, 1 H), 5.08 (d, J = 10 Hz, 1 H), 3.45 (d, J = 6 Hz, 2H), 2.99 (t, J = 6 Hz, 2 H), 1.78 (m, 1 H), 0.83 (d, J = 6.8 Hz, 6 H); MS (ES1): 499.3 27o r=\ s\^N ch3 -^ch3 26o 1-2 'H NMR (DMSO-d6): 5 14.08 (bs, 1 H), 9.06 (s, 2 H), 8.79 (s, 2 H), 8.51 (t, J = 6 Hz, 1 H), 8.11 (d, J = 2 Hz, 1 H), 8.01 (m, 3 H), 7.85 (d, J = 3 Hz, 1 H), 7.63 (m, 6 H), 7.17 (d, J = 7.8 Hz, 1 H), 6.97 (d, J = 7.8 Hz, 1 H), 3.02 (t, J = 6.5 Hz, 2 H), 1.81 (m, 1 H), 0.86 (d, 6.8 Hz, 6 H); MS (ES*): 542.2) 136 Cpd. No.
-R -R' Starting From Method Used Analytical Data 27p ch3 ch3 \^ch3 26p 1-2 'H NMR (DMSO-de): 5 9.1 and 9.2 (2 br s, 4 H, NH proton), 8.6 (m, 1 H), 8.3 (m, 1 H), 8.0-7.6 (m, 8 H, aromatic proton), 7.3 (m, 2 H), 3.1 (t, 2 H), 2.2 (s, 3 H), 1.8 (m, 1 H), 0.9 (2s, 6 H); IR (KBr Pellets) 2957,1676, 1480,1324, 844 cm"1. MS (ES+) : 497 27q /—\/CH.
H/^ ch, 26q 1-2 'H NMR (DMSO-d6): 5 9.06 (s, 2 H), 8.77 (s, 2 H), 8.53 (t, J = 6 Hz, 1 H), 8.03 (m, 1 H), 7.64 (m, 6 H), 7.46 (d, J = 6.9 Hz, 1 H), 7.05 (s, 2 H), 6.96 (s, 1 H), 5.52 (s, 1H), 3.02 (t, J = 6.8 Hz, 2 H), 1.81 (m, 1 H), 1.48 (s, 6 H),0.85 (d, J= 6.8 Hz, 6 H); MS (ES"): 539.4 27r ch3 ^^ch3 26r 1-2 'H NMR (DMSO-de): 5 9.06 (s, 2 H), 8.78 (s, 2 H), 8.52 (t, J = 6 Hz, 1 H), 8.01 (d, J = 6.8 Hz, 1 H), 7.62 (m, 7 H), 7.46 (d, J = 6.8 Hz, 1 H), 7.0 (m, 2 H), 4.94 (t, J = 6 Hz, 1 H), 3.60 (q, J = 6 & 12.8 Hz, 2 H), 3.01 (t, J = 6 Hz, 2 H), 2.58 (t, J = 6 Hz, 2 H), 1.82 (m, 1 H), 0.85 (d, J = 6.8 Hz, 6 H); MS (ES"): 525.4 27s ^=\^ch2 ch3 CH, 26s 1-2 !H NMR (DMSO-de): 8 9.01 (s, 2 H), 8.88 (s, 2 H), 8.5 (t, J = 6 Hz, 1 H), 8.07 (m, 1 H), 7.73 (m, 1 H), 7.63 (in, 7 H), 7.11 (d, J = 17 Hz, 1 H), 7.01 (d, J = 17 Hz, 1 H), 6.97 (m, 1 H), 6.69 (d, J = 17 Hz, 1 H), 5.24 (s, IH), 5.14 (s, IH), 3.03 (t, J = 6.9 and 6.0 Hz, 2 H), 1.92 (s, 3 H), 1.81 (m, 1 H), 0.84 (d, J = 6.9 Hz, 6 H); MS (ES"1): 525.4 27t /(H1 ch3 • f*3 ^Nh3 26t 1-2 'H NMR (DMSO-dfi): 8 9.08 (s, 2 H), 8.82 (s, 2 H), 8.53 (t, J = 6 Hz, 1 H), 8.04 (m, 1 H), 7.67 (m, 7 H), 7.04 (m, 2 H), 5.55 (s, IH), 5.20 (s, IH), 3.04 (t, J = 6.9 and 6.0 Hz, 2 H), 2.19 (s, 3 H), 1.81 (m, 1 H), 0.87 (d, J = 6.9 Hz, 6 H); MS (ES+): 499.4 137 Cpd. No.
-R -R' Starting From Method Used Analytical Data 27H ch3 ^N;h3 26u 1-2 ]H NMR (DMSO-de): 8 9.11 (s,2 H), 8.86 (s, 2 H), 8.57 (t, J = 6 Hz, 1 H), 8.13 (m,l H), 7.53 (m, 2 H), 7.74 (m, 6 H), 7.37 (d, J=7 Hz, 1 H), 7.17 (m, 2 H), 6.54 (d, J = 12 Hz, 1 H), 5.91 (m, 1 H), 4.99 (m, 1 H), 4.31 (m, 2 H), 3.06 (t, J = 6.9 and 6.0 Hz, 2 H), 1.83 (m, 1H), 0.87 (d, J = 6.9 Hz, 6 H); MS (ES4): 515.4 27v ,ch, ch3 ^^ch3 26v 1-2 'H NMR (DMSO-d6): 8 9.08 (s, 2 H), 8.82 (s, 2 H), 8.54 (t, J - 6 Hz, 1 H), 8.05 (m, 1 H), 7.63 (m, 8 H), 7.06 (m, 2 H), 5.52 (s, 1 H), 5.2 (s, 1 H), 4.63 (t, J = 5 Hz, 1 H), 3.56 (m, 2 H), 3.05 (t, J = 6.9 and 6.0 Hz, 2 H), 2.71 (t, J = 7 Hz, 2 H), 1.82 (m, 1 H), 0.87 (d, J = 6.9 Hz, 6 H); MS (ES4): 529.4 27w ^/=ch ch, 26w 1-2 'H NMR (DMSO-de): 8 9.08 (s, 2 H), 8.86 (s, 2 H), 8.54 (t, J = 6 Hz, 1 H), 8.03 (m, 1 H), 7.62 (m, 7 H), 7.08 (d, J = 7.5 Hz, 1 H), 6.99 (m, 1 H), 4.32 (s, 1 H), 3.03 (t, J = 6.9 and 6.0 Hz, 2 H), 2.71 (t, J = 7 Hz, 2 H), 1.82 (m, 1 H), 0.87 (d, J = 6.9 Hz, 6 H); MS (ES4): 483.3 27x /ch3 <( xch3 ch, 26x 1-2 'H NMR (DMSO-de): 8 13.8 (s, 1 H), 9.04 (s, 2 H), 8.96 (s, 2 H), 8.47 (t, J = 6 Hz, 1 H), 7.93 (s, 1 H), 7.61 (m, 6 H), 7.42 (m, 1 H), 6.91 (m, 2 H), 6.07 (dd, J = 17 and 9 Hz, 1 H), 5.35 (m, 1 H), 5.09 (dd, J = 17 and 11 Hz, 1 H), 3.38 (d, J = 6.5 Hz, 1 H), 3.0 (t, J = 7 Hz, 2 H), 1.78 (m, 1 H), 1.72 (s, 3 H), 1.41 (s, 3 H), 0.84 (d, J = 6.9 Hz, 6 H); MS (ES4): 527.5 138 Cpd. No.
-R -R' Starting From Method Used Analytical Data 27y ch3 \^ch3 26y 1-2 :H NMR (DMSO-d5): 8 8.99 (s, 2 H), 8.86 (s, 2 H), 8.52 (t, J == 6 Hz, 1 H), 8.03 (m, 1 H), 7.63 (m, 6 H), 7.50 (d, J = 7 Hz, 1 H), 7.07 (d, J = 7 Hz, 1 H), 7.12 (m, 1 H), 5.40 (t, J = 6 Hz, 1 H), 4.33 (d, J = 6.0-Hz, 2 H), 3.01 (t, J = 7 Hz, 2 H), 1.80 (ra, 1H), 0.84 (d, J = 6.9 Hz, 6 H); MS (ES4): 513.4 27z A oh CH3 ■^^•ch3 26z 1-2 !H NMR (DMSO-de): 8 9.50 (bs, 1 H), 8.77 (bs, 2 H), 8.49 (t, J = 6 Hz, 1 H), 7.98 (m, 1 H), 7.63 (m, 6 H), 7.55 (d, J = 6.9 Hz, 1 H), 7.01 (d, J = 7.9 Hz, 1 H), 6.99 (m, 1 H), 5.55 (s, 1 H), 5.38 (s, 1 H), 5.-13 (t, J = 5 Hz, 1 H), 4.39 (d, J = 5 Hz, 2 H), 3.02 (t, J = 6.9 and 6.0 Hz, 2 H), 1.81 (m, 1 H), 0.86 (d, J = 6.9 Hz, 6 H); MS (ES4): 515.4 27aa ch, 26aa 1-2 'H NMR (DMSO-de): 8 9.08 (s, 2 H), 8.73 (s, 2 H), 8.53 (t, J = 6 Hz, 1 H), 8.06 (s, 1 H), 8.02 (bs, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.62 (m, 6 H), 7.24 (d, J = 7.8 Hz, 1 H), 6.95 (d, J = 7.8 Hz, 1 H), 3.03 (t,J = 6Hz,2H), 1.82 (m, 1 H), 0.87 (d, J = 6.8 Hz, 6 H); MS (ES4): 484.3 27ab / oh Q- chu 26ab 1-2 !H NMR (DMSO-de): 8 9.05 (bs, 2 H), 8.81 (bs, 2 H), 8.49 (t, J = 6 Hz, 1 H), 8.02 (s, 1 H), 7.68 (s, 1 H), 7.62 (m, 6 H), 7.53 (d, J = 6 Hz, 1 H), 7.21 (d, J = 6 Hz, 1 H), 7.13 (d, J = 7 Hz, 1 H), 7.01 (s, 1 H), 5.25 (t, J = 5 Hz, 1 H), 4.51 (d, J == 5 Hz, 2 H), 3.01 (t, J = 6 Hz, 2 H), 1.81 (m, 1 H), 0.85 (d, J = 6.8 Hz, 6 H); MS (ES4): 571.64 139 Cpd. No.
-R -R' Starting From Method Used Analytical Data 27ac CH, ^CH, 26ac 1-2 'H NMR (DMSO-de): 5 9.05 (bs, 2 H), 8.78 (s, 2 H), 8.52 (t, J = 6 Hz, 1 H), 8.02 (bs, 1 H), 7.65 (m, 6 H), 7.53 (d, J = 5 Hz, 1H), 7.54 (d, J = 5 Hz, 1 H), 7.26 (d, J = 5 Hz, 1 H), 7.10 (m, 1 H), 6.99 (m, 1 H), 5.64 (t, J - 5 Hz, IH), 4.71 (d, J = 5 Hz, 2H), 3.07 (t, J = 6.9 and 6.0 Hz, 2 H), 1.73 (m, 1 H), 0.84 (d, J = 6.9 Hz, 6 H); MS (ES+): 571.56 27ad H03c \g/ GH3 '^^V"CHJ 26ad 1-2 MS (ES"*): 585.4 27ae .it CH, "^^^CH, 26ae 1-2 lH NMR (DMSO-de): 6 14.11 (bs, 1 H), 9.05 (bs, 2 H), 8.75 (bs, 2 H), 8.5 (m, 1 H), 8.0 (s, 1 H), 7.8-7.6 (m, 8 H), 7.49 (d, J = 3 Hz, 1 H), 7.1 (d, J = 6.9 Hz, 1 H), 7.0 (m, 1 H), 5.5 (m,l H), 4.7 (m, 2 H), 3.09 (m, 2 H), 1.74 (m, 1 H) 0.86 (d, J « 6.9 Hz, 6 H); MS (ES+) 571.2 27af HOH2C / CH, 26af 1-2 'H NMR (DMSO-d6): 5 14.11 (bs, 1 H), 9.05 (bs, 2 H), 8.75 (bs, 2 H), 8.49 (t, J = 6 Hz, 1 H), 7.97 (s, 1 H), 7.67 (d, J = 3 Hz, 1 H), 7.61 (m, 7 H), 7.54 (d, J = 3 Hz, 1 H), 7.06 (d, J = 6.9 Hz, 1 H), 6.89 (d, J = 6.9 Hz, 1 H), 5.23 (t, J - 5 Hz, 1 H), 5.42 (d, J = 5 Hz, 2 H), 3.09 (t, J = 6.9 and 6.0 Hz, 2 H), 1.74 (m, 1 H) 0.86 (d, J = 6.9 Hz, 6 H); MS (ES4): 571.3 140 Cpd. No.
-R -R1 Starting From Method Used Analytical Data 27ag.
N H CHj 26ag 1-2 'H NMR (DMSO-d6): 8 11.45 (s,1 H), 9.08 (bs, 2 H), 8.88 (bs, 2 H), 8.75 (t, J = 6Hz, ZH), 8.04 (bs, 1 H), 7.88 (m, 1H), 7.7 (m, 7 H), 7.03 (m, 2 H), 6.9 (m, 1 H), 6.62 (ra, 1 H), 6.17 (m, 1H), 3.07 (t, J = 6.9 and 6.0 Hz, 2 H), 1.84 (m, 1 H), 0.86 (d, J = 6.9 Hz, 6 H); MS (ES4): 524.65 27ah OH CH3 ^^CH3 26ah 1-2 'H NMR (DMSO-d6): 8 13.83 (s, 1 H), 8.9 (bs, 4 H), 8.47 (t, J = 6 Hz, 1 H), 7.95 (s, 1 H), 5.3 (s, 1 H), 7.61 (m, 6 H), 7.4 (m, 1 H), 6.95 (d, 3 = 7.7 Hz, 1 H), 6.85 (d, J - 7.7 Hz, 1 H), 6.64 (d, J = 9 Hz, 1 H), 6.22 (s, 1 H), 4.6 (t, J = 5.1 Hz, 1 H), 3.51 (d, J = 5.6 Hz, 2 H), 3.01 (t, J = 7 Hz, 2 H), 1.8 (m, 1 H), 0.85 (d, J - 6.9 Hz, 6 H); MS (ES4): 519.52 27ai CH, 26ai 1-2 MS (ES+) 514.25 27ai CH, 26n G 'H NMR (DMSO-d6): 8 9.05 (s, 2 H), 8.67 (s, 2 H), 8.47 (t, J = 6 and 5 Hz, 1H), 7.95 (m, 1 H), 7.95 (m, 1 H), 7.63 (tn, 5H), 7.40 (s, 1 H), 7.38 (d, J = 7.7 Hz, 1 H), 6.92 (m, 2 H), 3.02 (t, J = 6.8 Hz, 2 H), 2.64 (m, 2 H), 1.80 (m, 1 H), 1.66 (m, 2 H), 0.96 (t, J = 8 and 6.5 Hz, 3 H), 0.85 (d, J = 6.8 Hz, 6 H); MS (ES-) 499.31 141 Cpd. No.
-R -R' Starting From Method Used Analytical Data 27ak -"/^CH3 CH, 32f G 'H NMR (DMSO-de): 8 14.3 (bs, 1 H), 9.05 (bs, 2 H), 8.75 (bs, 2 H), 8.5 (m, 1 H), 8.0 (s, 1 B), 7.8-7.6 (m, 8 H), 7.49 (d, J = 3 Hz, 1 H), 7.1 (d, J = 6.9 Hz, 1 H), 7.0 (m, 1 H), 5.5 (m,l H), 4.7 (m, 2 H), 3.09 (m, 2 H), 1.74 (m, 1 H), 0.86 (d, J = 6.9 Hz, 6 H); MS (ES+) 487.2 27al CH, 26ai G MS (ES+) 488.3 (100%: M1"1) 27am CH, 26u G 'H NMR (DMSO-de): 8 13.9 (bs, 1 H>, 9.05 (2 bs, 4 H), 8.5 (in, 1H), 7.9 (s, 1 H), 7.7-7.5 (m, 8 H), 7.3 (d, J = 3 Hz, 1 H), 6.9 (m, 2 H), 4.6 (m, IH), 3.5 (m, 2 H), 3.09 (m, 2 H), 2.6 (m, 2 H), 1.8 (m, 1 H) 0.85 (d, J - 6.9 Hz, 6 H); MS (ES+) 517.3 32a A* CH, 31a 1-2 'H NMR (DMSO-de): 8 9.84 (bs, 1 H), 9.07 (bs, 2 H), 8.87 (bs, 2 H), 8.51 (t, J = 6 and 5 Hz, I H), 8.13 (m, 1 H), 8.03 (m, 2 H), 7.65 (m, 5 H), 7.20 (d, J = 7.7 Hz, 1 H), 6.94 (d, J = 7.7.Hz, 1 H), 3.04 (t, J = 6.8 Hz, 2 H), 2.66 (s, 3 H), 1.83 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES-) 499.4, (ES+) 501.4 32b ch3 ■^^CH3 31b 1-2 Characterized in the next step 142 Cpd. No.
-R -R' Starting From Method Used Analytical Data 32c ch, 31c 1-2 'H NMR (DMSO-dfi): 8 14.24 (s, 1 H), 9.29 (bs, 2 H), 9.01 (bs, 2 H), 8.73 (t, J = 6 Hz, 1 H), 8.2 (d, J = 2 Hz, 1 H), 7.85 (m, 5 H), 7.74 (d, 2 Hz, 1 H), 7.4 (d, J = 8 Hz, 1 H), 7.22 (d, J = 7.4 Hz, 1 H), 7.13 (d, J = 7.5,1 H), 6.73 (t, J = 6.8 Hz, 1 H), 5.59 (d, J = 6.8 Hz, 2 H), 3.25 (t, J = 6.8 Hz, 2 H), 2.04 (m, 1 H), 1.08 (d, J = 6.8 Hz, 6 H); MS (ES-) 495.1, (ES+) : 497.2 32d fQ 0*3 \^ch3 31d 1-2 MS (ES-): 553.3 32e ^0 ch3 31e 1-2 JH NMR (DMSO-d6): 8 13.642 (bs, 1 H), 9.06 (s, 2 H), 8.89 (s, 2 H), 8.50 (t, J = 6 and 5 Hz, 1 H), 7.98 (s, 1 H), 7.62 (m, 7 H), 7.43 (s, 1 H), 7.33 (m, 4 H), 6.95 (m, 2 H), 4.04 (s, 2 H), 3.02 (t, J = 6.8 Hz, 2 H), 1.80 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES"): 547.4 32f -^ch2 ch, 31f 1-2 JH NMR (DMSO-d6): 8 0.85 (d, J = 6.9 Hz, 6 H), 1.81 (m, 1 H), 3.03 (t, J = 7 Hz, 2 H), 5.35 (d, J = 11 Hz, 1 H), 5.94 (d, J = 17 Hz, 1 H), 6.84 (dd, J = 17 and 11 Hz, 2 H), 7.0 (m, 2 H), 7.64 (m, 8 H), 8.01 (s, 1 H), 8.54 (t, J = 6 Hz, 1 H), 8.77 (s, 2 H), 9.06 (s, 2 H); MS (ES+) :485.57 32g W, y .
Q ch, 31g 1-2 MS (ES+) 596..2 143 Cpd.
No.
-R -R' Starting From Method Used Analytical Data 32h ch,oh ch3 31b 1-2 "H NMR (DMSO-dfi): 8 14.2 (bs, 1 H), 9.1 (bs, 4 H), 8.6 (m, 1 H), 8.15 (s, 1 H), 7.9-7.6 (m, 8 H), 7.2 (m, 2 H), 6.7 (s, 1 H), 5.3 (br s, 1 H), 4.6 (m, 2 H), 3.1 (m, 2 H), 1.9 (m, 1 H), 0.9 (d, J = 6.7 Hz, 6 H); MS (ES+) 555.1 32i HOH.C , 9 ch3 31i 1-2 'H NMR (DMSO-dfi): 8 13.84 (bs, IH), 9.01 (bs, 2 H), 8.80 (bs, 2 H), 8.46 (t, J = 6 and 5 Hz, 1 H), 8.03 (s, 1 H), 7.95 (s, 1 H), 7.77 (s, 1 H), 7.67 (m, 2 H), 7.61 (m, 5 H), 7.02 (d, J = 7.7 Hz, 1 H), 6.94 (m, 1 H), 5.13 (t, J = 5 Hz, 1 H), 4.47 (m, 2 H), 2.97 (t, J = 6.8 Hz, 2 H), 1.78 (m, 1 H), 0.80 (d, J = 6.8 Hz, 6 H); MS (ES-) 553.3, (ES+) 555.3 40 "O" ch3 39 1-2 MS (ES+) 524.3 44 ch3 \^ch3 43 1-2 'H NMR (DMSO-d6): 8 13.82 (s, 1 H), 9.20 (bs, 1 H), 9.10 (bs, 1 H), 8.51 (t, J == 6 Hz, 1 H), 7.97 (s, 1 H), 7.73-7.45 (m, 5 H), 7.43-7.39 (m, 2 H), 7.20 (t, J = 8 Hz, 1 H), 7.10 (m, 6 H), 6.96 (d, J = 8 Hz, 1 H), 3.0 (t, J = 6 Hz, 2 H), 1.80 (m, 1 H), 0.68 (d, J = 6.8 Hz, 6 H); MS (ES+) 551.30 46 j o ch3 45 1-2 'H NMR (DMSO-de): 8 9.21 (2 bs, 2 H each, 4 H), 8.61 (m, 1 H), 8.1 (s, IH), 7.8-7.4 (m, 10 H), 7.3 (s, 1 H), 7.2 (d, J = 7 Hz, 1 H), 7.1 (m, 2 H), 52 (s, 2 H), 3.1 (m, 2 H), 1.8 (m, 1 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES4) 565.27 144 Cpd. No.
-R -R' Starting From Method Used Analytical Data 51 oca, 50 1-2 'H NMR (CF3CO2D): 8 8.43 (s, 1 H), 8.01 (d,. J = 7.5 Hz, 1 H), 7.67 (q, J = 24 and 8.4 Hz, 4 H), 7.56 (d, J = 7.7 Hz, 1 H), 7.38 (s, 1 H), 7.23 (s, 2 H), 3.98 (s, 3 H), 3.43 (d, J = 7 Hz, 2 H), 2.01 (m, 1 H), 1.01 (d, J = 6.8 Hz, 6 H); MS (ES-) 487., (ES+) 489.3 53 CH, 52 1-2 !H NMR (DMSO-de): 8 14.00 (bs, 1 H), 8.52 (t, J = 6 and 5 Hz, 1 H), 7.98 (s, 1 H), 7.63'(m, 8 H), 7.07 (d, J = 7.7 Hz, 1 H), 6.96 (d, J = 7.7 Hz, 1 H), 3.83 (s, 2 H), 3.02 (t, J = 6.8 Hz, 2 H), 1.81 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES-) 568.1 70a 68a 1-2, S !H NMR (DMSO-d6): 8 13.84 (br s, 1 H), 9.05 (s, 2 H), 8.94 (s, 2 H), 8.48 (t, J= 5.7 Hz, 1 H), 7.97 (d, J= 1.9 Hz, 1 H), 7.70 (m, 7 H), 7.00 (d, J= 7.9 Hz, 1 H), 6.92 (d, J= 7.9 Hz, 1 H), 6.84 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.93 (d,J= 17.7 Hz, 1 H), 5.34 (d, J= 10.9 Hz, 1 H), 3.19 (m, 2 H), 1.46 (qui, J=7.0 Hz, 2 H), 1.29 (sex, 7.0 Hz, 2 H), 0.87 (t, J= 7.3 Hz, 3 H); MS (ES"*): 485.2 70b ~\</\_^CH3 CHj 68b 1-2, S 'HNMR(DMSO-de): 8 12.71 (brs, I H), 9.12 (s, 2 H), 8.93 (s, 2 H), 8.20 (m, 2 H), 7.86 (m, 1 H), 7.70 (m, 6 H), 7.20 (m, 2 H), 6.87 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.99 (d, /= 17.7 Hz, 1H), 5.40 (d, J= 10.9 Hz, 1 H), 3.97 (m, 1 H), 1.50-1.20 (m, 8 H) 0.86 (t, J= 7.2 Hz, 6 H); MS (ES4): 527.3 145 Cpd. No.
-R -R* Starting From Method Used Analytical Data 70c 68c 1-2, S 'HNMR(DMSO-de): 6 12.84 (br s, 1 H), 9.08 (ra, 3 H), 8.36 (d, J= 7.7 Hz, 1 H), 8.18 (s, 1 H), 7-83 (m, 1 H), 7.67 (m, 6 H), 7.15 (m, 3 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J= 17.7 Hz, 1 H), 5.39 (d, J= 10.9 Hz, 1 H), 3.74 (m, 1 H), 1.84-1.55 (m, 5 H), 1.38-1.04 (m, 5 H); MS (ES4): 511.3 70d 68d 1-2, S 'H NMR (DMSO-d6): 8 9.11 (s, 2 H), 8.89 (s, 2 H), 8.81 (t, ,7=5.7 Hz, 1 H), 8.21 (s, 1 H), 7.85 (m, 1 H), 7.68 (m, 7 H), 7.17 (m, 3 H), 6.87 (dd,J= 10.9 and 17.7 Hz, 1 H), 5.99 (d, J= 17.7 Hz, 1 H), 5.88 (in, 1 H), 5.39 (d, /= 10.9 Hz, 1 H), 5.12 (m, 2 H), 3.88 (t, J= 5.0 Hz, 1 H); MS (ES4): 469.2 70e \^,CH3 CH, 68e 1-2, S 'HNMR (DMSO-de): 8 9.11 (s, 2H), 9.01 (s, 2H), 8.38 (d, 7=7.5 Hz, 1 H), 8.18 (s, 1 H), 7.83 (m, 1 H), 7.67 (m, 6 H), 7.16 (m, 3 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J= 11.1 Hz, 1 H), 5.39 (d, 10.9 Hz, 1 H), 4.09 (m, 1 H), 1.15 (d, 7= 6.6 Hz, 6 H); MS (ES4): 471.3 70f t "\/CH3 ^—CH, 68f 1-2, S 'HNMR (DMSO-de): 8 9.11 (s, 2 H), 9.05 (s, 2 H), 8.31 (d, 7= 8.1 Hz, 1 H), 8.20 (s, 1 H), 7.85 (d, /= 7.7 Hz, 1 H), 7.69 (m, 6 H), 7.17 (m, 3 H), 6.86 (dd, 10.9 and 17.7 Hz, 1 H), 5.98 (d, 17.7 Hz, 1 H), 5.39 (d, /= 10.9 Hz, 1 H), 3.91 (m, 1 H), 1.50 (m, 2 H), 1.12 (d, J= 6.6 Hz, 3 H). 0.85 (t, J= 13 Hz, 3 H); MS (ES4): 485.3 Cpd. No.
-R -R' Starting From Method Used Analytical Data 70g "\/CF3 68g 1-2, S t 'H NMR (DMSO-d6): 5 12.82 (br s, 1 H), 9.25 (m, 1 H), 9.12 (s, 2 H), 8.91 (s, 2 H), 8.23 (s, 1 H), 7.87 (m, 1 H), 7.68 (m, 7 H), 7.18 (m, 3 H), 6.87 (dd, J= 10.9 and 17.7 Hz, i H), 5.99 (d, J= 17.7 Hz, 1 H), 5.40 (d, J= 10.9 Hz, 1 H), 4.07 (m, 2 H); MS (ES4): 511.2 70h "O 68h 1-2, S !H NMR (DMSO-de): 8 10.34 (s, 1 H), 9.05 (m, 4 H) 8.18 (s, 1H), 7.71 (m, 11 H), 7.34 (t, 7.8 Hz, 2 H), 7.09 (m, 3 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J = 17.7 Hz, 1 H), 5.39 (d, J= 10.9 Hz, 1 H); MS (ES'): 505.3 70i Nv/Ss/^S0H 68i 1-2, S 'H NMR (DMSO-de): 8 12.64 (br s, 1 H), 9.09 (m, 4 H), 8.56 (m, 1 H), 8.09 (s, 1 H), 7.66 (m, 9 H), 7.08 (m, 3 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.96 (d, J= 17.7 Hz, 1 H), 5.37 (d, J= 10.9 Hz, 1 H), 4.40 (m, 2 H) 3.39 (m, 2 H), 3.22 (m, 2 H), 1.48 (m, 4 H); MS (ES4): 501.3 (100%: M41) 70j t 68j 1-2, S 'H NMR (DMSO-dfi): 8 9.08 (m, 4 H), 8.69 (t, J = 6.0 Hz, 1 H), 8.16 (s, 1 H), 7.69 (m, 5 H), 7.13 (d, J= 7.7 Hz, 2 H), 7.09 (m, 3 H), 6.86 (dd,J= 10.9 and 17.7 Hz, 1 H), 5.97 (d, 17.7 Hz, 1 H), 5.38 (d, 7= 10.9 Hz, 1 H), 3.U (t, J= 6.0 Hz, 2 H), 1.01 (m, 1 H), 0.41 (m, 2 H), 0.21 (m, 2 H); MS (ES4): 483.3 70k ^CHL, 68k 1-2, S 'H NMR (DMSO-de): 8 9.11 (s, 2 H), 8.97 (s, 2 H), 8.54 (m, 1 H), 8.12 (s, 1 H), 7.68 (m, 7 H), 7.17 (m, 4 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.97 (d, 17.7 Hz, 1 H), 5.38 (d, J= 10.9 Hz, 1 H), 2.75 (d, 7=4.3 Hz, 1 H); MS (ES4): 443.26 Cpd. No.
-R -R' Starting From Method Used Analytical Data 701 ch, t 681 1-2, S 'H NMR (DMSO-dfi): 8 9.07 (s, 2 H), 8.92 (s, 2 H), 8.53 (t, 7= 5.5 Hz, 1 H), 8.02 (s, 1 H), 7.62 (m, 7 H), 7.01 (m, 2 H), 6.85 (dd, 7- 10.9 and 17.7 Hz, 1 H), 5.95 (d, 7= 17.7 Hz, 1 H), 5.36 (d, 7= 10.9 Hz, 1 H), 3.24 (qui, 7= 6.7 Hz, 2 H), 1.08 (t, 7= 7.2 Hz, 3 H); MS (ES ): 457.2 70m ch, c ^0 68m 1-2, S 'H NMR (DMSO-d6): S 12.53 (br s, 1 H), 9.10 (m, 3 H), 8.38 (d, 7= 7.9 Hz, 1 H), 8.11 (s, 1 H), 7.68 (m, 7 H), 7.12 (m, 3 H), 6.86 (dd, 7= 10.9 and 17.7 Hz, 1 H), 5.96 (d, 7= 17.7 Hz, 1 H), 5.37 (d, 7= 10.9 Hz, 1 H), 3.94 (m, 1 H), 1.88-1.33 (m, 12 H); MS (ES4): 525.3 70n /\^ch3 68n 1-2, S !H NMR (DMSO-d6): 8 9.09 (m, 4 H), 8.59 (t, 5.2 Hz, 1 H), 8.17 (s, 1 H), 7.70 (m, 7 H), 7.16 (m, 4 H), 6.87 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J= 17.7 Hz, 1 H), 5.39 (d, J= 10.9 Hz, 1 H), 3.20 (q, J= 6.7 Hz, 2 H), 1.52 (sex, J= 7.2 Hz, 2 H), 0.87 (t, 7= 7.3 Hz, 3 H); MS (ES+): 471.3 i- 70o *9 ch, C — 68o 1-2, S JH NMR (DMSO-dfi): 8 12.97 (br s, I H), 9.08 (s, 2 H), 8.99 (s, 2 H), 8.53 (t, 7= 5.1 Hz, 1 H), 8.06 (s, 1 H), 7.64 (m, 7 H), 7.06 (m, 2 H), 6.85 (dd, 7= 10.9 and 17.7 Hz, 1 H), 5.96 (d, 7= 17.7 Hz, 1 H), 5.36 (d, 7= 10.9 Hz, 1 H), 3.20 (q, 7= 6.5 Hz, 2 H), 1.49 (qui, 7= 6.6 Hz, 2 H), 1.27 (m, 4 H), 0.86 (t, 7= 6.6 Hz, 3 H); MS (ES4): 499.3 70p ch, c ch3 68p 1-2, S 'H NMR (DMSO-ds): 8 9.10 (s, 2 H), 8.91 (s, 2 H), 8.55 (t, 7= 5.5 Hz, 1 H), 8.13 (s, 1 H), 7.68 (m, 7 H), 7.12 (m, 2 H), 6.86 (dd, 7= 10.9 and 17.7 Hz, 1 H), 5.98 (d, 7= 17.7 Hz, 1 H), 5.38 (d, 7= 10.9 Hz, 1 H), 3.10 (m, 2 H), 1.62 (m, 1 H), 1.39 (in, 1 H), 1.10 (m, 1 H), 0.86 (m, 6 H); MS (ES4): 499.3 148 Cpd. No.
-R -R' Starting From Method Used Analytical Data 70q t "chj ^—-ch3 68q 1-2, S 'H NMR (DMSO-d6): 8 9.06 (s, 2 H), 8.82 (s, 2 H), 8.11 (t,J= 7.9 Hz, 1 H), 8.00 (s, 1 H), 7.62 (m, 7 H), 6.99 (m, 2 H), 6.85 (dd, 7= 10.9 and 17.7 Hz, 1 H), 5.95 (d, /= 17.7 Hz, 1 H), 5.35 (d, 7= 10.9 Hz, 1 H), 3.81 (q, 7= 7.5 Hz, 1 H), 1.45 (m, 4 H), 1.24 (m, 4 H), 0.82 (m, 6 H); MS (ES4): 527.3 70r — 68r 1-2, S 'H NMR (DMSO-de): 8 13.81 (s, 1 H), 8.44 (m, 4 H), 7.97 (s, 1 H), 7.61 (m, 7 H), 6.90 (m, 3 H), 5.93 (d, 7= 17.7 Hz, 1 H), 5.34 (d, 7= 10.9 Hz, 1 H), 3.22 (m, 5 H), 2.73 (m, 2 H), 1.52 (m, 4 H); MS (ES4): 500.3 70s 68s 1-2, S 'H NMR (DMSO-de): 8 9.09 (s, 2 H), 8.86 (s, 2 H), 8.42 (d, 7= 7.5 Hz, 1 H), 8.11 (s, 1 H), 7.68 (m, 8 H), 7.10 (m, 2 H), 6.86 (dd, 7= 10.9 and 17.7 Hz, 1 H), 5.97 (d, 7= 17.7 Hz, 1 H), 5.38 (d, 7= 10.9 Hz, 1 H), 4.20 (q, J= 7.2 Hz, 1 H), 1.93-1.44 (in, 8 H); MS (ES4): 497.2 70t ■ y> OH 68t 1-2, S 'H NMR (DMSO-dg): 8 13.78 (br s, 1 H), 9.07 (s, 2 H), 8.87 (s, 2 H), 8.25 (d,J= 8.1 Hz, 1 H), 8.00 (s, 1 H), 7.62 (m, 7 H), 6.98 (m, 2 H), 6.85 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.94 (d, 17.7 Hz, 1 H), 5.35 (d, 10.9 Hz, 1 H), 4.55 (d, J= 4.1 Hz, 1 H), 3.68 (m, 1 H), 3.39 (m, 1 H), 1.79 (m, 4 H), 1.28 (m, 4 H); MS (ES4): 527.2 70u 68u 1-2, S 'H NMR (DMSO-de): 8 13.36 (br s, 1 H), 9.05 (m, 3 H), 8.49 (s, 1 H), 7.98 (s, 1 H), 7.61 (m, 8 H), 6.92 (m, 3 H), 5.94 (d, J = 17.7 Hz, 1 H), 5.35 (d, 7== 10.9 Hz, 1 H), 2.81 (m, 1 H), 0.69-0.48 (m, 4 H); MS (ES4): 469.3 Cpd. No.
-R -R' Starting From Method Used Analytical Data 70v ch, c 68v 1-2, S 'H NMR (DMSO-d6): 5 9.05 (m, 4 H), 8.75 (d, J= 7.5 Hz, 1 H), 8.15 (s, 1 H), 7.70 (m, 7 H), 7.14 (d,J= 7.9 Hz, 2 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1H), 5.97 (d, J= 17.7 Hz, 1 H), 5.39 (d, J= 10.9 Hz, 1 H), 4.40 (q, J = 8.2 Hz, 1 H), 2.12 (m, 4 H) 1.65 (m, 2 H); MS (ES*): 483.3 70w 68w 1-2, S 'H NMR (DMSO-de): 8 13.17 (br s, 1 H), 9.05 (m, 4 H), 8.51 (t, J= 5.8 Hz, 1 H), 8.06 (s, 1 H), 7.64 (m, 7 H), 7.03 (m, 2 H), 6.85 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.95 (d, J = 17.7 Hz, 1 H), 5.36 (d, J= 10.9 Hz, 1 H), 4.72 (t, J= 5.4 Hz, 1 H) 3.47 (q, J= 5.7 Hz, 2 H), 3.28 (m, 2 H); MS (ES+): 473.2 70x t ch3 68x 1-2, S 'H NMR (DMSO-de): 8 9.07 (s, 2 H), 8.90 (s, 2 H), 8.50 (t, J =5.5 Hz, 1 H), 8.04 (s, 1 H), 7.63 (m, 7 H), 7.03 (m, 2 H), 6.85 (dd, J = 10.9 and 17.7 Hz, 1 H), 5.96 (d, J= 17.7 Hz, 1 H), 5.36 (d, J= 10.9 Hz, 1 H),3.23 (q, 7= 6.5 Hz, 2 H), 1.59 (in, J= 7.0 Hz, 1 H), 1.39 (q, J= 6.8 Hz, 2 H), 0.88 (d, J = 6.6 Hz, 6 H).
Cpd. No.
-R Starting From Method Used Analytical Data 31a 30a J 'HNMR (DMSO-de): 510.85 (s, 1 H), 9.21(s, 2 H), 8.91 (s, 2 H), 8.71 (t, J = 5.9 Hz, 1 H), 8.21 (d, J = 1.96 Hz, 1 H), 8.23 (d, J = 1.96 Hz, 1 H), 8.19 (d, J-2.19 Hz, 1 H), 8.17 (d, J = 1.97 Hz, 1 H), 8.09 (d, J = 1.91 Hz, 1 H), 7.77 (s, 4 H), 7.53 (d, J - 7.53 Hz, 1 H), 3.57 (s, 3 H), 3.11 (q, J = 6.89 Hz, 1 H), 2.71 (s, 3 H), 1.86 (m, 1 H), 3.88 (d, 6.87 Hz, 6H); MS (ES+) 515.3 31b CH3 30b J MS (ES+): 527.2 31c /^5^cH2 30c J Characterized in the next step 31d rO 30d J 'HNMR (DMSO-de): 8 10.59 (bs, 1 H), 9.16 (s, 2 H), 8.85 (s, 2 H), 8.69 (t, J = 6 and 5 Hz, 1 H), 8.21 (s, 1 H), 8.04 (d, J - 1.5 Hz, 1 H), 7.73 (m, 4 H), 7.58 (s, 1 H), 7.50-7.38 (m, 3 H), 7.32 (m, 1 H), 7.03 (d, J = 7.5 Hz, 2 H), 4.31 (s, 2 H), 3.55 (s, 2 H), 3.07 (t, J = 6.8 Hz, 2 H), 1.85 (m, 1H), 0.87 (d, J = 6.8 Hz, 6 H),; MS (ES-) 567.3, (ES+) 569.3 31e 30e J MS (ES"): 561.4; MS (ES+): 563.4 151 Cpd. No. 31f -R Starting From Method Used Analytical Data ^^ch2 30f J 'H NMR (DMSO-d6): 8 10.73 (s, IH), 9.24 (s, 2H), 9.00 (s, 2H), 8.71 (t, J = 5.7 Hz, IH), 8.24 (d, J = 1.9 Hz, IH), 8.05 (dd, J = 8.0,1.9 Hz, IH), 7.77 (m, 5H), 7.71 (dd, J = 7.9,1.5 Hz, 1H), 7.42 (d, J = 7.9 Hz, IH), 7.31 (d, J = 7.9 Hz, IH), 6.89 (dd, J = 17.6,11.0 Hz, IH), 6.04 (d, J = 17.6 Hz, IH), 5.42 (d, J = 11.0 Hz, IH), 3.56 (s, 3H), 3.10 (t, J = 6.4 Hz, 2H), 1.85 (m, IH), 0.89 (d, J = 6.7 Hz, ' 6H); MS (ES+): 499.3 31g n3h2c , Q 30g J !HNMR (DMSO-de): 8 10.73 (s, 1 H), 9.19 (bs, 2 H), 8.88 (bs, 2 H), 8.71 (t, J = 6 Hz, 1 H), 8.27 (d, J = 2 Hz, 1 H), 8.07 (dd, J = 7.7 and 2 Hz, 1 H), 7.88 (d, 2 Hz, 1 H), 7.8 (d, J = 2 Hz, 1 H), 7.83 (m, 4 H), 7.72 (dd, J=2 and 7.7 Hz, 1 H), 7.46 (d, J = 7.7,1 H), 7.41 (d, J = 7.7 Hz, 1 H), 4.56 (s, 2 H), 3.56 (s, 3 H), 3.11 (t, J = 6.8 Hz, 2 H), 1.87 (m, 1 H), 0.92 (d, J = 6.8 Hz, 6 H); MS (ES-) 608.2, (ES+) 610.3 31h ch2oh ft 0 30h J Characterized at the next step 311 hoh-c / o 30i J 'HNMR (DMSO-de): 8 10.68 (s, 1 H), 9.17 (bs, 2 H), 8.82 (bs, 2 H), 8.68 (t, J = 6 Hz, 1 H), 8.25 (d, J = 2 Hz, 1 H), 8.16 (d, J = 2 Hz, 1 H), 8.05 (dd, J = 8 and 2 Hz, 1 H), 7.87 (m, 1 H), 7.89 (dd, J = 8 and 2 Hz, 1 H), 7.75 (m, 5 H), 7.44 (d, J = 9 Hz, 1 H), 7.36 (d, J = 8 Hz, 1 H), 5.22 (t, J = 5 Hz, 1H), 4.54 (d, J = 5 Hz, 2 H), 3.57 (s, 3 H), 3.10 (t, J = 6.8 Hz, 2 H), 1.84 (m, 1 H), 0.88 (d, J = 6.8 Hz, 6 H; MS (ES-) 567.4, (ES+) 569.4 43 -°-0 42 J MS (ES"): 563.4 45 -Obn 8 J Characterized in the next step 50 -och3 49 J MS (ES+): 503.1 152 Cpd. No.
-R Starting From Method Used Analytical Data -f* I - 52 }=J 31g G Characterized in the next stq) NHLj 153 Cpd. No.
-R -R' Startmg From Method Used Analytical Data 34 -oso2cf3 -h 33 j ms (es4): 621.2 -oso2cf3 34 p ms (es4): 755.2; (es1) 753.3 37 TIPS O x ^ OBn + 36 d-2 ms (es4): 828.5 38 TIPS -o -h 37 g ms (es4): 694.4; (es") 692.4 39 -O- -h 38 Q Characterized in the next step 154 in Ui Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 54 -OBn -CHO -COzMEM + 6 D-2 lH NMR (DMSO-de): 8 9.69 (s, 1 H), 8.49 (d, J=2.0 Hz, 1 H), 8,22 (d, /= 6.9 Hz, 1 H), 7.53 (xn, 4 H), 7.43 (m, 2 H), 7.37 (m, 2 H), 7.24 (d, 7= 8.9 Hz, 1 H), 5.57 (s, 2 H), 5.26 (s, 2 H), 3.85 (t, J= 4.9 Hz, 2 H), 3.60 (s, 3 H), 3.51 (t, /= 4.9 Hz 2 H), 3.32 (s, 3 H); MS (ES+): 501.02 (M+Na)+ 55 -OBn -CO2H -CO2MEM 54 E NMR (DMSO-de): 8 12.65 (s, 1 H), 8.41 (d, J= 2.0 Hz 1 H), 8.14 (dd, J= 2.0 and 7.9 Hz, 1 H), 7.50 (m, 3 H), 7.38 (m, 4 H), 7.24 (dd, J= 3.0 and 8.9 Hz, 1 H), 7.11 (d, /= 8.9 Hz, 1 H), 5.54 (s, 2 H), 5.20 (s, 2 H), 3.82 (t, J= 4.9 Hz, 2 H), 3.57 (s, 3 H), 3.49 (t, /=4.9 Hz, 2 H), 3.23 (s, 3 H); MS (ES"): 493.2 141 -OBn -CHO H 4 140 + 6 D-2 JH NMR (DMSO-de): 8 10.2 (s, 1 H), 9.65 (s, 1 H), 8.25 (d, J= 2.0 Hz, 1 H), 7.85 (dd,J= 2.0 and 8.9 Hz, 1H), 7.51 (d, J=7.9 Hz, 2 H), 7.45 (m, 2 H), 7.35 (m, 3 H),7.29 (d, J= 1.9 Hz, 1 H) 7.2 (d, J= 7.9 Hz, 1H), 5.24 (s, 2 H), 3.55 (s, 3 H), 2.3 (d, J= 6.9 Hz, 2 H) 2.1 (m, J = 6.9 Hz, 1 H), 1.0 (d,/= 6.9 Hz, 6 H); MS (ES*): 446.31 155 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 142 -OBn -C02H 0 ch, h 3 141 E 'HNMR(DMSO-d6): 5 12.38 (s, 1 H), 10.01 (s, 1 H), 8.05 (s, 1 H), 7.68 (d, 7= 7.9 Hz, 1 H), 7.41 (d, /= 7.9 Hz, 2 H), 7.35 (m, 5 H), 7.27 (m, 1 H), 7.11 (d, J= 8.9 Hz, 1 H), 7.04 (d, J= 8.9 Hz, 1 H), 6.99 (d, J= 8.9 Hz, 1 H), 5.11 (s, 2 H), 2.13 (d, J=6.9 Hz, 2 H), 2.02 (m, .7=6.9 Hz, 1 H), 0.852 (d, J= 6.9 Hz, 6 H); MS (ES"): 460.2 143 -OBn -CO2MEM h 3 142 F 'H NMR (DMSO-de): 810.12 (s, 1 H), 8.16 (d, J= 1.9 Hz, 1 H), 7.80 (dd, J= 1.9 and 8.3 Hz, 1 H), 7.42 (m, 6 H), 7.26 (dd, J=2.8 and 8.3 Hz, 1 H), 7.13 (m, 2 H), 5.21 (s, 2 H), 5.17 (s, 2 H), 3.54 (s, 3 H), 3.40 (m, 2 H), 3.32 (m, 2 H), 2.22 (d, 7.0 Hz, 2 H), 2.10 (m, 4H), 0.95 (d, J= 6.4 Hz, 6H); MS (ES*): 572.3 (M+Naf 144 -OH -C02MEM .XA h 3 143 G 'H NMR (DMSO-de): 5 12.7 (br s, 1 H), 9.09 (s, 2 H), 8.91 (s, 2 H), 8.57 (m, 1 H), 8.11 (s, 1 H), 7.92 (d, J= 1.9 Hz, 1 H), 7.81 (m, 3 H), 7.67 (m, 5 H), 7.14 (m, 3 H), 6.66 (m, 1 H), 4.40 (t, /= 5.3 Hz, 1 H), 3.39 (m, 2 H), 3.22 Cm, 2 H), 1.48 (in, 4 H); MS (ES"): 592.2. 145 -OSO2CF3 -CO2MEM 0 ch, h 3 144 B-2 MS (ES4):. 592.2 146a -Q -CO2MEM .XX h 3 145 D-2 MS (ES+): 532.5 (M+Na)+ 156 Cpd. No.
-R -R* -R" Starting From Method Used Analytical Data 146b ■*> -COzMEM O CH, vU.
H 3 145 D-2 'HNMR(DMSO-d6): 8 10.1 (s, 1 H), 8.21 (d, 7= 2.0 Hz, 1 H), 8.10 (d, 7=2.0 Hz, 1 H), 7.89 (dd, J~ 2.0 and 7.9 Hz, 1 H), 7.84 (d, 7=3.0 and 8.9 Hz, 1 H), 7.63 (m, 2 H), 7.25 (d, 7= 7.9 Hz, 1 H), 7.19 (m, 2 H), 5.22 (d, 7= 14.8 Hz, 2 H), 3.57 (s, 3 H), 3.43 (t, 7=4.9 Hz, 2 H), 3.34 (t, 7= 4.9 Hz, 2 H), 3.20 (s, 3H), 2.23 (d, 7= 6.9 Hz, 2 H), 2.11 (m, 7= 6.9 Hz, 1 H), 0.96 (d, 7= 5.9 Hz, 6 H); MS (ES4): 526.48 146c -ch=ch2 -COzMEM H 3 145 D-3 MS (ES*): 470.2 (M+Na)+ 147a JC\ o -co2h O CH, H 3 146a I-l MS (ES"): 420.29 147b -O -co2h O CH, H 3 146b I-l 'HNMR(DMSO-de): 8 12.65 (s, 1 H), 10.12 (s, 1 H), 8.18 (d, 7= 1.9 Hz, 1 H), 8.07 (d, 7= 3.0 Hz, 1 H), 7.83 (m, 2 H), 7.61 (m, 2 H), 7.19 (m, 3 H), 3.56 (s, 3 H), 2.22 (d, 7= 6.9 Hz, 2 H), 2.11 (m, 7= 6.9 Hz, 1 H), 0.96 (d, 7= 6.9 Hz, 6H); MS (ES4): 438.52 147c -ch=ch2 -co2h 0 CH, H 3 146c I-l MS (ES"): 380.32 157 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 173 -H -CHO ch3 0 172 + 130 D-2 *H NMR (DMSO-ds): 5 9.70 (s, 1 H), 8.42 (t, J= 6.2 Hz, 1 H), 7.90 (dd, J= 1.1 & 6.6 Hz, l' H), 7.82 (d, J =3.9 Hz, 1 H), 7.72-7.50 (m, 3 H), 7.34 (d, J= 7.7 Hz, 1 H), 7.27 (dd, J= 1.3 & 6.2 Hz, 1 H), 4.38 (d, J= 6.0 Hz, 2 H), 3.53 (s, 3 H), 2.47 (m, 1 H),, 1.07 (d, /= 7.0 Hz, 6 H); MS (ES4): 340.05 174 -H -COzH ch3 0 . 173 E 'H NMR (DMSO-de): 8 12.35 (hr s, 1H), 8.31 (t, J= 7.5 Hz, 1 H), 7.80-7.31 (m, 5 H), 7.06 (m, 2 H), 4.25 (d, /= 6.0 Hz, 2 H), 3.41 (s, 3 H), 2.37 (m, 1 H), 0.97 (d, /= 7.0 Hz, 6 EQ; MS (ES"): 353.83 180 -H -CHO poc ch3 179 + 130 D-2 lH NMR (DMSO-de): 8 9.70 (s, 1 H), 7.87 (m, 2 H), 7.69 (m, 1H), 7.55 (m, 2 H), 7.35 (d, J= 7.9 Hz, 1 H), 7.27 (d, J= 7.5 Hz, 1 H), 4.51 (s, 2 H), 3.52 (s, 3 H), 3.05 (in, 2 H), 1.92 (m, 1 H), 1.40 (m, 9 H), 0.85 (d ,J= 6.8 Hz, 6 H); MS (ES4): 448.3 (M+Na)4" 181 -H -COzH p00 ch3 ^N^SH3 180 E tH NMR (DMSO-dfi): § 7.81 (m, 2 H), 7.56 (m, 1 H), 7.44 (m, 2 H), 7.16 (m, 2 H), 4.47 (s, 2 H), 3.51 (s, 3 H), 3.02 (m, 2 H), 1.92 (m, J= 7.0 Hz, 1 H), 1.41 (m, 9 H), 0.85 (d, J= 6 Hz, 6 H); MS (ES"): 440.2 184a -OBn -CHO ch3 0 3a+ 6 D-2 'HNMR (DMSO-d6): 59.78 (s, IH), 8.85 (t, J - 5.7 Hz, IH), 8.50 (d, J = 2.0 Hz, IH), 820 (dd, J = 8.2,1.9 Hz, IH), 7.55 (m, 9H), 5.35 (s, 2H), 3.69 (s, 3H), 3.23 (t, J = 6.5 Hz, 2H), 1.98 (m, IH), 1.02 (d, J = 6.8 Hz, 6H); MS (ES+): 446.3 158 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 184b -OBn -CHO h o 3f+6 D-2 MS (ES"): 470.2 184c -OBn -CHO 0 3i + 6 D-2 MS (ES"): 418.3 184d -OBn -CHO <fH3 0 3j + 6 D-2 MS (ES4): 460.3 185a -OH -CHO ch3 Y H3 o 184a AD 'HNMR (DMSO-dfi): 8 10.06 (s, 1 H), 9.63 (s, 1 H), 8.73 (t, J = 6.5 Hz, 1 H), 8.36 (d, J « 2 Hz, 1 H), 8.09 (dd, J - 2 and 8 Hz, 1 H), 7.45 (d, J = 8 Hz, 1 H), 7.28 (s, 1 H), 7.11 (s, 2 H), 3.58 (s, 3 H), 3.13 (d, J = 7 Hz, 2 H), 1.87 (m, 1 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES-): 354.2 and (ES4) 378.2 (M+Na)+) 185b -OH -CHO h \^N^CF3 0 184b AD MS (ES"): 380.1 185c -OH -CHO "vn^'n-v—,ch3 O 184c AD 'HNMR (DMSO-de): 8 10.21 (s, 1H), 9.78 (s, 1 H), 8.87 (t, J = 5.80 Hz, LH), 8.51 (s, 1 H), 8.23 (d, J = 7.92 Hz, 1 H), 7.60 (d, J = 7.9 Hz, 1 H), 7.43 (s, 1 H), 7.25 (s, 2 H), 3.74 (s, 3 H), 3.46 (q, J =» 5.65,2 H), 1.32(t, J = 7.8 Hz, 3 H) 159 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 185d -OH -CHO 9h3 0 184d AD "HNMR (DMSO-d6): 5 10.06 (s, 1 H), 9.62 (s, 1 H), 8.69 (t, J = 5.90 Hz, 1 H), 8.36 (s, 1 H), 8.08 (d, J = 7.92 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1 H), 7.28 (s, 1 H), 7.10 (s, 2 H), 3.58 (s, 3 H), 3.22 (m, 1H), 3.11 (m, 1 H), 1.66 (m, 1 H), 1.44 (m, 1 H), 1.18 (m, 1 H), 0.89(t, J = 6.4 Hz, 6H). 186a -OSO2CF3 -CHO ch, 0 185a B-2 MS (ES-1): 488.24 186b -OSO2CF3 -CHO h \^n\^-cf3 o 185b B-2 'HNMR (DMSO-dfi): 8 9.74 (s, 1 H), 9.44 (t, J - 5.90 Hz, 1 H), 8.51 (s, 1 H), 8.11 (d, J = 7.91 Hz, 1 H), 7.54 (m, 4 H), 4.18 (m, 2 H), 3.59 (s, 3 H). 186c -oso2cf3 -CHO h \^n\/"ch3 0 185c B-2 1HNMR (DMSO-d6): 6 9.45 (s, 1H), 8.59 (t, J - 5.90 Hz, 1 H), 8.28 (s, 1 H), 7.94 (d, J - 8.10 Hz, 1H), 7.79 (d, J = 2.8 Hz, 1 H), 7.67 (d, J = 7.9 Hz, 1 H), 7.32 (d, J = 7.9 Hz, 2 H), 3.40 (s, 3 H), 3.12 (q, J - 7.1 Hz, 2 H), 0.97 (t, J = 7.16 Hz, 3 H). 186d -OSO2CF3 -CHO ch3 0 185d B-2 !HNMR (DMSO-de): 8 9.71 (s, 1 H), 8.78 (t, J = 5.90 Hz, 1 H), 8.49 (s, 1 H), 8.18 (d, J = 7.92 Hz, 1 H), 8.00 (s, 1 H), 7.88 (4 J = 8.51 Hz, 1 H), 7.52 (q, J = 8.1 Hz, 2 H), 3.67 (s, 3 H), 3.22 (m, 1 H), 3.16 (m, 1 H), 1.68 (m, 1H), 1.44 (m, 1 H), 1.18 (m, 1 H), 0.89(t, J = 6.4 Hz, 6 H). 160 Cpd. No.- -R -R' -R" Starting From Method Used Analytical Data 187a -ch=ch2 -CHO ch3 0 186a D-3 'HNMR CDMSO-ds): 5 9.74 (s, 1 H), 8.76 (t, J = 6.5 Hz, 1 H), 8.42 (d, J = 2 Hz, 1 H), 8.11 ■ (dd, J = 2 and 8 Hz, 1 H), 8.00 (d, J = 1.7 Hz, 1 H), 7.84 (dd, J = 8 and 2 Hz, 1H), 7.47 (d, J = 8 Hz, 1H), 7.27 (d, J = 8 Hz, 1H), 6.90 (dd, J = 11 and 17.7 Hz, 1 H), 6.01 (d, J = 17.7 Hz, 1 H), 5.42 (d, J = 11 Hz, 1 H), 3.59 (s, 3 H), 3.14 (d, J = 7 Hz, 2 H), 1.88 (m, 1 H), 0.92 (d, J = 6.8 Hz, 6 H); MS (ES-): 364.2 and (ES4) 388.2 (M+Na)4 187b -ch=ch2 -CHO H o 186b D-3 MS (ES"): 390.1 187c -ch=ch2 -CHO h \^xn^ch3 o 186c D-3 MS (ES"): 336.2 187d -ch=ch2 -CHO h fh' 0 186d D-3 MS (ES0: 378.2 161 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 56 -OBn K -H -CO2MEM 55 J 'H NMR (DMSO-de): 5 10.67 (s, 1 H), 9.2 (s, 2 H), 8.87 (s, 2 H), 8.33 (d, /= 2.0 Hz, 1 H), 8.17 (dd, /= 2.0 and 7.9 Hz, 1 H), 7.77 (s, 4 H), 7.49 (m, 4 H), 7.39 (m, 2 H), 7.30 (s, 2 H), 5.54 (s, 2 H), 5.27 (s, 2 H), 3.83 (t, J= 4.9 Hz, 2 H); 3.57 (s, 3 H), 3.49 (t, J=4.9 Hz, 2 H), 3.23 (s, 3 H); MS (Esi: 612.4 57 -OBn -Boc -CO2MEM 56 R MS (ES+): 712.4 58 -OH -Boc -CO2MEM 57 G 'H NMR (DMSO-de): 8 10.4 (s, 1 H), 10.0 (s, 1 H), 8.9 (s, IH), 8.28 (d, J =2.0 Hz, 1H), 8.12 (dd, J=2.1 and 7.7 Hz, 1 H), 7.89 (d, J= 8.4 Hz, 2 H), 7.61 (d, J= 8.4 Hz, 2 H), 7.45 (d, J=7.7 Hz, 1H), 7.13 (d, 8.4 Hz, 1 H), 7.06 (s, 1 H), 6.98 (dd, J= 2.8 and 8.4 Hz, 1 H), 5.52 (s, 2 H), 3.81 (t, J= 4.9 Hz, 2 H), 3.56 (s, 3 H), 3.46 (t, J = 4.9 Hz, 2 H), 3.20 (s, 3 H), 1.43 (s, 9 H); MS (ES"): 620.5 162 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 59 -OSO2CF3 -Boc -CO2MEM 58 B-2 'H NMR (DMSO-de): 5 10.55 (s, 1 H), 8.38 (d, 7= 2.0 Hz, 1H), 8.18 (dd, 7=2.0 and 7.9 Hz, 1 H), 7.86 (m, 4 H), 7.75 (dd, 7=2.0 and 8.9 Hz, 1 H), 7.54 (m, 5 H), 5.51 (s, 2 H), 3.77 (t, 7= 4.9 Hz, 2 H), 3.55 (s, 3 H), 3.46 (t, 7= 4.9 Hz, 2 H), 3.18 (s, 3 H) 1.41 (s, 9 H); MS (ES+): 754.3 60 -Boc -CO2MEM 59 D-2 'H NMR (DMSO-d6): 5 10.61 (s, 1 H), 8.94 (s, 1 H), 8.37 (s, 1 H), 8.19 (dd, 7= 2.0 and 7.9 Hz, 1 H), 8.02 (s, 1 H), 7.89 (m, 5 H), 7.65 (d, 7= 8.9 Hz, 2 H), 7.54 (d, 7 = 7.9 Hz, 1 H), 7.39 (d, 7= 7.9 Hz, 1 H), 7.17 (d, 7=3.9 Hz, 1 H), 6.68 (m, 1 H), 5.54 (s, 2 H), 3.82 (t, 7= 4.9 Hz, 2 H), 3.58 (s, 3 H), 3.49 (t, 7= 4.9 Hz, 2 H), 3.22 (s, 3 H), 1.45 fs, 9 H); MS <ES^): 672.5 61 -O 0 -Boc -COzH 60 I-l 'HNMR(DMSO-de): 8 10.50 (s, 1 H), 8.96 (s, 1 H), 8.32 (s, 1 H), 8.07 (d, 7= 7.9 Hz, 1 H), 7.98 (s, 1 H), 7.87 (m, 5 H), 7.63 (d, 7= 8.9 Hz, 2 H), 7.38 (m, 2 H), 7.15 (d, 7= 3.0 Hz, 1 H), 6.67 (m, 1 H), 3.57 (s, 3 H), 1.45 fs, 9 H); MSCES1): 582.4 66 -CH=CH3 -Boc -COzMEM 59 D-3 !H NMR (DMSO-de): 8 10.56 (s, 1 H), 9.02 (br s, 1 H), 8.35 (d, 7= 1.7 Hz, 1H), 8.18 (dd, 7= 1.9 and 6.0 Hz, 1 H), 7.88 (d, 7= 9.0 Hz, 2 H), 7.80 (d, 7== 1.3 Hz, 1 H), 7.71 (dd, 7= 1.7 and 6.2 Hz, 1 H), 7.63 (d, 7= 8.9 Hz, 2 H), 7.50 (d, 7= 8.3 Hz, 1 H), 7.32 (d, 7=8.1 Hz, 1 H), 6.89 (dd, 7= 10.7 and 17.7 Hz, 1 H), 6.04 (d, 7= 17.4 Hz, 1 H), 5.54 (s, 2 H), 5.43 (d, 7= 11.7 Hz, 1 H), 3.82 (t, 7= 4.5 Hz, 2 H), 3.57 (s, 3 H), 3.48 (t, 7=4.5 Hz, 2 H), 3.22 (s, 3 H), 1.44 (s, 9 H); MS (ES*): 632.1 163 Cpd. No.
-R -R' -R" Starting From Metbod Used Analytical Data 67 -CH=CH2 -Boc -COaH 66 I-l 'H NMR (DMSO-de): 5 10.49 (s, 1 H), 8.99 (br s, 1 H), 8.31 (s, 1 H), 8.07 (d, J= 8.3 Hz, 1 H), 7.87 (d, J= 9.0 Hz, 2 H), 7.77 (m, 2 H), 7.66 (m, 3 H), 7.38 (d, J-7.7 Hz, 1 H), 7.29 (d, J= 7.7 Hz, 1 H), 6.88 (dd, J= 10.7 and 17.7 Hz, 1 H), 6.03 (d, J= 17.4 Hz, 1 H), 5.41 (d, J= 10.9 Hz, 1 H), 3.56 (s, 3 H), 1.43 (s, 9 H); MS (ES"): 542.1 164 9\ (Ji Cpd. No.
-R -R' Starting From Method Used Analytical Data 62a -ch3 61 A-4 'H NMR (DMSO-de): 8 10.57 (s, 1 H), 8.92 (s, 1 H), 8.64 (t, J= 5.4 Hz, 1 H), 8.24 (d, J= 2.0 Hz, 1 H), 8.02 (dd, J= 2.0 and 7.9 Hz, 1 H), 7.98 (s, 1 H), 7.88 (m, 3 H) 7.84 (s, 1 H), 7.64 (d,J= 8.9 Hz, 2 H), 7.42 (d, 7.9 Hz, 1 H), 7.36 (d, J= 7.9 Hz, 1 H), 7.14 (d, J=3.0 Hz, 1 H), 6.67 (m, 1 H), 3.55 (s, 3 H), 3.26 (m, 2 H), 1.50 (m, J= 7.4 Hfe, 2 H), 1.43 ($, 9 H), 1.32 (m, J= 7.4 Hz, 2 H), 0.89 (t, 3 H); MS (ES"): 639.5 62b -ch3 61 A-4 MS (ES+): 625.5 62c -ch3 ^^CH2 61 A-4 MS (ES+): 623.4 62d -ch3 -XK 61 A-4 MS (ES*): 687.4 Ct ►H a *z> o w 00 165 Cpd. No.
-R -R' Starting From Method Used Analytical Data 62e -ch3 \^ch3 ch, 61 a-4 ms (es*): 625.4 62f -ch3 /^CH, ^-^^CH3 61 a-4 ms (es+): 653.5 62g -ch3 ch3 61 a-4 ms (es*): 653.5 62h -CHj 61 a-4 ms (es*): 667.3 62i -ch3 ch3 61 a-4 ms (es*): 681.5 62j -ch3 61 a-4 ms (es*): 637.3 62k -ch3 oh \^ch3 61 a-4 ms (es*): 640.3 621 -ch3 -O 61 a-4 ms (es*): 665.4 166 Cpd. No.
-R -R' Starting From Method Used Analytical Data 62m -chj ^ch3 61 A-4 MS (ES*): 597.3 62n -ch3 \/ch3 V-ch3 61 A-4 MS (ES*): 639.4 62o -ch3 -jo 61 A-4 MS (ES*): 695.4 (M+Na)* 62p -ch3 \^cf3 61 A-4 MS (ES'): 665.4 62q -ch3 61 A-4 MS (ES*): 653.4 62r -ch3 \_. chj 61 A-4 MS (ES*): 567.3 62s -ch3 ch3 61 A-4 MS (ES*): 667.5 62t -ch3 61 A-4 MS (ES*): 641.3 62u -ch3 61 A-4 MS (ES*): 655.3 167 Cpd.
No.
-R -R' Starting From Method Used Analytical Data 62v -ch3 61 a-4 ms (es"*): 663.1 62w -ch3 1 /n 61 a-4 ms (eso: 577.2 62x -ch3 61 a-4 ms (es4): 679.2 62y -ch3 61 a-4 ms (es+): 621.1 62z -ch3 \^CH3 61 a-4 ms (es4): 611.1 62aa -ch3 OH 61 a-4 ms (es4): 657.1 62ab -ch3 0 T 61 a-4 ms (es4): 659.1 62ac -ch3 o 61 a-4 ms (es4): 679.3 168 Cpd. No.
-R -R1 Starting From Method Used Analytical Data 62ad -ch3 o 61 a-4 ms (eso: 695.3 62ae -ch3 NHR"''— 61 a-4 ms (es4): 651.3 62af -ch3 nhr' NCf^XTCH3 61 a-4 ms (es1): 679.4 169 NH Cpd. No.
-R -R' Starting From Method Used Analytical Data 64a — 62a 1-2, S 'H NMR (DMSO-ds): 8 12.80 (s, 1 H), 9.09 (s, 2 H), 8.91 (s, 2 H), 8.57 (m, 1 H), 8.15 (s, 1 H), 7.91 (s, 1 H), 7.80 (m, 3 H), 7.67 (m, 4 H), 7.20 (m, 2 H), 7.07 (s, 1 H), 6.63 (s, 1 H) 3.21 (m, J= 5.9 Hz, 2 H), 1.46 (m, J= 7.4 Hz, 2 H), 1.28 (m,/= 7.4 Hz, 2 H) 0.86 (t, /= 7.4 Hz, 3 H); MS (ES4): 525.3 64b a. 62b 1-2, S 'H NMR (DMSO-dfi): 8 12.76 (s, 1 H), 9.10 (s, 2 H), 8.82 (s, 2 H), 8.59 (m, 1 H), 8.20 (s, 1 H), 7.95 (s, 1 H), 7.83 (m, 3 H), 7.70 (s, 4 H), 7.25 (m, 2 H), 7.10 (s, 1 H), 6.65 (s, 1 H), 3.20 (q, J= 6.0 Hz, 2 H), 1.51 (m, 7= 7.4 Hz, 2 H), 0.87 (t, J= 7.4 Hz, 3 H); MS (ES4): 511.2 64c 62c 1-2, S 'H NMR (DMSO-de): 8 12.84 (s, 1 H), 9.11 (s, 2 H), 8.84 (m, 2 H), 8.26 (m, 1 H), 7.94 (m, 2 H), 7.83 (xn, 3 H), 7.71 (s, 4 H), 7.28 (m, 2 H), 7.12 (s, 1 H), 6.65 (s, 1 H), 5.87 (xn, 1 H), 5.15 (d, J= 17.2 Hz, 1 H), 5.07 (d, 10.3 Hz, 1 H) 3.88 (t, J= 5.2 Hz, 2 H); MS (ES4): 509.2 170 Cpd. No.
-R -R' Starting From Method Used Analytical Data 64d \^C^-ch3 62d 1-2, S ]H NMR (DMSO-de): 5 12.78 (s, IH), 9.11 (m, 2 H), 8.85 (s, 2 H), 8.22 (s, 1 H), 7.93 (s, 1 H), 7.83 (m, 3 H), 7.68 (s, 4 H), 7.19 (m, 3 H), 7.10 (m, 5 H), 6.65 (s, 1 H), 4.41 (s, 2 H), 2.27 (s, 3 H); MS (ES4): 573.3 64e Q.
^CH, CHj 62e 1-2, S "H NMR (DMSO-de): 8 12.82 (s, 1 H), 9.11 (s, 2 H), 8.86 (s, 2 H), 8.39 (d, J= 7.7 Hz, 1 H), 8.24 (s, 1 H), 7.95 (s, 1 H), 7.90 (m, 1 H), 7.84 (m, 2 H), 7.71 (s, 4 H), 7.28 (m, 2 H), 7.11 (m, 1 H), 6.65 (s, 1 H), 4.08 (m, 7= 6.9 Hz, 1 H), 1.14 (d, J- 6.9 Hz, 6 H); MS (ES+): 511.3 64f /~-ch3 ^^ch3 62f 1-2, S *H NMR (DMSO-de): 8 13.28 (br s, 1 H), 9.05 (m, 2 H), 8.84 (s, 2 H), 8.46 (m, 1 H), 7.99 (s, 1 H), 7.88 (s, 1 H), 7.77 (m, 2 H), 7.63 (m, 5 H), 7.07 (m, 2 H), 6.96 (m, 1 H), 6.63 (s, 1 H), 3.16-2.96 (m, 2 H), 1.65-1.03 (m, 3 H), 0.85 (m, 6 H); MS (ES4): 539.3 64g ch3 62g 1-2, S lH NMR (DMSO-d6): 8 13.37 (s, 1 H), 9.06 (s, 2 H), 8.84 (s, 2 H), 8.47 (m, 1 H), 8.00 (s, 1 H), 7.88 (s, 1 H), 7.78 (m, 2 H), 7.70 (m, 5 H), 7.08 (m, 2 H), 6.97 (s, 1 H), 6.63 (s, 1 H), 3.22 (m, 2 H), 1.58 (m, 6.0 Hz, 1 H), 1.38 (m, J=6.9 Hz, 2 H), 0.87 (d, /= 6.9 Hz, 6 H); MS (ES4): 539.3 64b <5. 62h 1-2, S 'H NMR (DMSO-de): 8 12.71 (br s, 1 H), 9.13 (s, 1 H), 8.75 (m, 3 H), 8.31 (xn, 1 H), 7.97 (m, 2 H), 7.86 (in, 2 H), 7.73 (m, 4 H), 7.64 (m, 2 H), 7.33 (m, 2 H), 7.13 (m, 1 H), 6.67 (m, 1 H), 3.98 (m, 1 H), 3.77 (q, J= 6.9 Hz, 1 H), 3.62 (q, J= 6.9 Hz, 1 H), 3.29 (xn, 2 H), 1.86 (m, 3 H), 1.59 (m, 1 H); MS (ES4): 553.3 171 Cpd. No.
-R -R' Starting From Method Used Analytical Data 64 i CH3 62i 1-2, S 'H NMR (DMSO-dfi): 8 12.81 (br s, 1 H), 9.13 (s, 2 H), 8.85 (s, 2 H), 8.26 (in, 2 H), 7.96 (m, 2 H), 7.86 (m, 2 H), 7.74 (m, 5 H), 7.32 (m, 1 H), 7.13 (m, 1 H), 6.67 (m, 1 H), 3.99 (m, 1 H), 1.5-0.85 (m, 14 H); MS (ES4): , 567.3 64j Q. 62j 1-2, S 'H NMR (DMSO-d6): 8 13.74 (br s, 1 H), 9.07 (s, 2 H), 8.92 (s, 2 H), 8.62 (t,7=5.6 Hz, 1 H), 8.03 (s, 1 H), 7.89 (d, 7= 1.7 Hz, 1 H), 7.79 (m, 2 H), 7.64 (m, 4 H), 7.10 (m, 3 H), 6.99 (d, 7= 8,5 Hz, 1 H), 6.64 (m, 1 H), 3.08 (t, 7= 6.0 Hz, 2 H), 1.00 (m, 1 H), 0.40 (m, 2 H), 0.20 (m,2H);MS(ES">523.4 64k o.
OH 62k 1-2, S 'H NMR (DMSO-de): 8 9.12 (s, 2 H), 8.88 (s, 2 H), 8.52 (m, 1 H), 8.12 (m, 1 H), 7.92 (m, 2 H), 7.81 (m, 3 H), 7.67 (m, 4 H), 7.14 (xn, 3 H), 6.66 (ra, 1 H), 4.75 (d, 7= 4.5 Hz, 1 H), 3.77 (m, 1 H), 3.17 (m, 1 H), 1.04 (d, 7= 6.0 Hz, 3 H); MS (ES4): 527.2 641 a ~K3 621 1-2, S 'H NMR (DMSO-dfi): 8 13.91 (br s, 1 H), 9.07 (s, 2 H), 8.90 (s, 2 H), 8.29 (d,7= 8.1 Hz, 1 H), 8.00 (s, 1 H), 7.89 (m, 1 H), 7.78 (m, 2 H), 7.64 (m, 5 H), 7.08 (m, 2 H), 6.96 (d, 7= 7.7 Hz 1 H), 6.64 (m, 1 H), 3.71 (m, 1 H), 1.82-1.03 (m, 10 H)p; MS (ES4): 551.33 64m C^ ^CH3 62m 1-2, S lH NMR (DMSO-de): 813.87 (br s, 1 H), 9.07 (s, 2 H), 8.90 (s, 2 H), 8.48 (m, 1 H), 7.99 (s, 1 H), 7.89 (m, 1 H), 7.79 (m, 2 H), 7.62 (m, 5 H), 7.10 (m, 2 H), 6.97 (d, 7= 7.9 Hz 1 H), 6.64 (m, 1 H), 2.73 (d,7-4.5 Hz, 3 H); MS (ES4): 483.2 172 Cpd. No.
-R -R' Starting From Metbod Used Analytical Data 64n V-ch3 62n 1-2, S 'H NMR (DMSO-d6): 8 9.08 (s, 2 H), 8.85 (s, 2 H), 8.26 (d, J= 8.7 Hz, 1 H), 8.07 (s, 1 H), 7.91 (s, 1 H), 7.80 (m, 2 H), 7.67 (m, 5 H), 7.09 (xn, 3 H), 6.65 (m, 1 H), 3.89 (m, J= 7.0 Hz, 1 H), 1.49 (m, J= 6.9 Hz, 2 H), 1.10 (d, J= 6.6 Hz, 3 H), 0.85 (t, J=7.2 Hz, 3 H); MS (ES"*): 525.2 64o <5.
JO 62o 1-2, S 'HNMR(DMSO-de): 8 9.19 (m, 2 H), 9.10 (s, 2 H), 8.82 (s, 2 H), 8.19 (in, 1 H), 7.94 (s, 1 H), 7.83 (m, 2 H), 7.68 (m, 4 H), 7.33-7.10 (in, 8 H), 6.66 (m, 1 H), 4.45 (d, J=5.7 Hz, 2 Hz); MS (ES4): 559.2 64p Ct \zct3 62p 1-2, S 'H NMR (DMSO-de): 8 9.22 (m, 2 H), 9.09 (s, 2 H), 8.81 (s, 2 H), 8.17 (m, 1 H), 7.95 (s, 1 H), 7.82 (m, 2 H), 7.68 (tn, 4 H), 7.16 (m, 4 H), 6.66 (m, 1 H), 4.06 (m, 2 H); MS (ES"): 551.22 64q a. 62q 1-2, S "H NMR (DMSO-de): 8 9.10 (s, 2 H), 8.86 (s, 2 H), 8.56 (m, 1 H), 8.13 (m, 1 H), 7.93 (s, 1 H), 7.82 (m, 2 H), 7.67 (m, 5 H), 7.15 (m, 3 H), 6.66 (ra, 1 H), 3.19 (tn, 2 H), 1.50 (m, 2 H), 1.28 (m, 4 H), 0.87 (t, J=7.0 Hz, 3 H); MS (ES*): 539.3 64r a. x> 62r 1-2, S lH NMR (DMSO-de): 8 9.09 (s, 2 H), 8.90 (m, 2 H), 8.15 (m, 2 H), 7.93 (s, 1 H), 7.81 (m, 3 H), 7.68 (m, 4 H), 7.13 (m, 3 H), 6.66 (m, 1 H), 3.83 (m, 1 H), 1.47 (m, 4 H), 1.25 (m, 4 H), 0.83 (m, 6 H); MS (ES+): 567.3 Cpd. No.
-R -R' Starting From Method Used Analytical Data 64s 0. >ch3 ch3 62s 1-2, S 'H NMR (DMSO-dfi): 8 9.08 (s, 2 H), 8.86 (s, 2 H), 8.48 (m, 1 H), 8.03 (m, 1 H), 7.90 (s, 1 H), 7.79 (m, 2 H), 7.65 (m, 5 H), 7.12 (m, 2 H), 7.02 (m, 1 H), 6.65 (m, 1 H), 3.22 (m, 2 H), 1.42 (t,7= 8.2 Hz, 2 H), 0.91 (s, 9 H); MS (ES+): 553.4 64t Q, 62t 1-2, S 'H NMR (DMSO-de): 8 13.61 (br s, 1 H), 9.07 (s, 2 H), 9.00 (s, 2 H), 8.52 (t,7= 5.5 Hz, 1 H), 8.02 (s, 1 H), 7.90 (d, 7= 1.9 Hz, 1 H), 7.79 (m, 2 H), 7.64 (m, 5 H), 7.10 (m, 2 H), 7.00 (d, 7=7.7 Hz, 1 H), 6.64 (m, 1 H), 4.47 (t, 7= 5.3 Hz, 1 H), 3.43 (m, 2 H), 3.27 (m, 2 H), 1.64 (qui, 7= 6.8 Hz, 2 H); MS (ES+): 527.23 64u 0. 62u 1-2, S 'H NMR (DMSO-de): 8 12.7 (br s, 1 H), 9.09 (s, 2 H), 8.91 (s, 2 H), 8.57 (m, 1 H), 8.11 (s, 1 H), 7.92 (d, 7= 1.9 Hz, 1 H), 7.81 (m, 3 H), 7.67 (m, 5 H), 7.14 (m, 2 H), 6.66 (m, 1H), 4.40 (t, 7= 5.3 Hz, 1 H), 3.39 (m, 2 H), 3.22 (m, 2 H), 1.48 (m, 4 H); MS (ES*): 541.34 64v 62v 1-2, S !H NMR (DMSO-de): 8 9.16-8.89 (ra, 4 H), 8.16 (m, 1 H), 7.93 (s, 1 H), 7.81 (m, 3 H), 7.67 (m, 4 H), 7.56 (s, 1 H), 7.15 (m, 5 H), 6.65 (m, 1 H), 6.38 (m, 1H), 6.26 (m, 1 H), 4.42 (d, 7=4.9 Hz, 2 H); MS (ES+): 549.27 64w a —// 62w 1-2, S 'H NMR (DMSO-de): 8 11.59 (br s, 1 H), 9.14 (s, 2 H), 8.98 (s, 2 H), 8.70 (t, 7= 5.7 Hz, 1 H), 8.24 (s, 1 H), 7.99 (m, 2 H), 7.87 (m, 3 H), 7.71 (m, 3 H), 7.36 (s, 1 H), 7.27 (m, 2 H), 7.10 (m, 2 H), 6.67 (m, 1 H), 4.07 (t, 7= 6.9 Hz, 2 H), 3.24 (q, 7= 6.5 Hz, 2 H), 1.98 (qui, 7= 6.7 Hz, 2 H); MS (ES4): 577.17 174 Cpd. No.
. -R -R' Starting From Method Used Analytical Data 64x oo 62 x 1-2, S 'H NMR (DMSO-de): 5 13.72 (br s, 1 H), 9.13 (s, 2 H), 9.06 (s, 2 H), 8.50 (t, 7= 5.7 Hz, 1 H), 8.00 (d, 7=1.3 Hz, 1 H), 7.89 (d, 7= 1.9 Hz, 1 H), 7.78 (m, 2 H), 7.62 (xn, 4 H), 7.08 (m, 2 H), 6.96 (d, 7= 7.9 Hz, 1 H), 6.64 (tn, 1 H), 3.04 (t, 7= 6.5 Hz, 2 H), 1.72-1.43 (in, 6 H), 1.25-1.08 (m, 3 H), 0.88 (m, 2 H); MS (ES*): 565.25 64y 62y 1-2, S 'H NMR (DMSO-de): 5 9.16-8.87 (m, 4 H), 8.09 (s, 1 H), 7.91 (s, 1 H), 7.80 (m, 2 H), 7.65 (in, 5 H), 7.12 (xn, 5 H), 6.65 (m, 1 H), 4.01 (m, 2 H), 3.10 (m, 1 H); MS (ES ): 507.2 64z \^CH3 62z 1-2, S 'H NMR (DMSO-de): 8 9.10 (s, 2 H), 8.97 (s, 2 H), 8.59 (t, 7= 5.7 Hz, 1 H), 8.13 (s, 1 H), 7.93 (s, 1 H), 7.80 (xn, 3 H), 7.68 (m, 4H), 7.16 (m, 4H), 6.65 (m, 1 H), 3.26 (qui, 7= 6.0 Hz, 2 H), 1.10 (t, 7= 7.2 Hz, 3 H); MS (ES*): 497.2 64aa q.
OK ^X^0H 62aa 1-2, S 'H NMR (DMSO-de): 8 14.1 (br s, 1 H), 9.08 (s, 2 H), 8.79 (s, 2 H), 8.45 (m, 1 H), 8.01 (s, 1 H), 7.90 (s, 1 H), 7.79 (m, 3 H), 7.63 (m, 5 H), 7.09 (in, 2 H), 6.98 (in, 1 H), 6.65 (m, 1 H), 4.80 (d, 7= 4.7 Hz, 1 H), 4.56 (t, 7= 6.8 Hz, 1 H), 3.60 (m, 1 H), 3.32-2.90 (m, 3 H); MS (ES*): 543.2 64ab <x. -o 62ab 1-2, S 'H NMR (DMSO-de): 8 10.34 (s, 1 H), 9.07 (s, 2 H), 8.85 (s, 2 H), 8.18 (s, 1 H), 7.93 (s, 1 H), 7.80 (xn, 6 H), 7.66 (m, 4 H), 7.34 (m, 2 H), 7.11 (m, 4 H), 6.65 (m, 1 H); MS (ES"1): 545.2 175 Cpd. No.
-R -R' Starting From Method Used Analytical Data 64 ac C?. -o 62ac 1-2, S 'H NMR (DMSO-dfi): 8 9.07 (m, 4 H), 8.38 (d, J= 8.5 Hz, 1 H), 8.10 (s, 1 H), 7.92 (s, i H), 7.84-7.62 (m, 7 H), 7.11 (m, 3 H), 6.66 (m, 1 H), 3.94 (m, 1 H), 1.88-1.35 (m, 12 H); MS (ES*): 565.3 64ad <3.
O 62ad 1-2, S 'HNMR(DMSO-de): 8 13.71 (m, 2H), 9.36-8.57 (m, 4 H), 8.50 (m, 1 H), 7.98 (s, 1 H), 7.89 (s, 1 H), 7.78 (2 H), 7.61 (m, 5 H), 7.08 (m, 2 H), 6.95 (d, J=7.9 Hz, 1 H), 6.63 (m, 1 H), 3.19 (xn, 2 H), 2.16 (t, /= 7.2 Hz, 2 H), 1.48 (in, 4 H), 1.28 (m, 2 H); MS (ES"): 581.2 64ae Q.
NHR= ?/ 62ae 1-2, S 'H NMR (DMSO-d6): 8 9.12 (s, 2 H), 8.89 (s, 2 H), 7.91 (m, 1 H), 7.81 (m, 2 H), 7.70 (d, 8.7 Hz, 2 H), 7.62 (d, J=8.9 Hz, 2 H), 7.48 (m, 1 H), 7.22 (m, 2 H), 7.11 (d, J= 3.4 Hz, 1 H), 7.05 (d, /= 7.2 Hz, 1 H), 6.65 (m, 1 H), 3.53 (m, 2 H), 3.08 (m, 2 H), 1.62-1.21 (m, 6 H); MS (ES*): 537.20 64af CL N0^H3 62af 1-2, S 'H NMR (DMSO-de): 8 12.81 (br s, 1 H), 9.13 (s, 2 H), 8.82 (s, 2 H), 7.95 (s, 1 H), 7.85 (m, 2 H), 7.71 (m, 5 H), 7.43 (m, 1 H), 7.29 (m, 2 H), 7.13 (in, 1 H), 6.67 (m, 1 H), 3.49-2.97 (in, 4 H), 1.67-1.37 (m, 2 H), 1.08 (tn, 1 H), 0.90 (m, 3 H), 0.61-0.26 (m, 4 H); MS (ES*): 565.3 <1 <1 Cpd. No.
-R -R' Starting From Method Used Analytical Data 65 -O /CH3 \^CH3 61 A-4,1-2, S 'H NMR (DMSO-dfi, d2o): 8 13.87 (br s, 1 H), 9.56 (m, 2 H) 9.21 (s, 1 H), 8.74 (s, 1 H), 8.47 (m, 1 H), 7.97 (m, 1 H), 7.88 (s, 1 H), 7.78 (m, 3 H), 7.58 (m, 7 H), 7.09 (m, 3 H), 6.96 (m, 1 H), 6.65 (m, 1 H), 3.14 (xn, 4 H), 1.77-0.80 (m, 18 H); MS (ES"*): 609.4 71a -ch=ch2 x> 67 A-4,1-2, S lH NMR (DMSO-de): 8 13.80 (br s, 1 H), 9.91 (s, 1 H), 9.41 (s, I H), 8.63 (m, 2 H), 8.07 (s, 1 H), 7.98 (s, 1 H), 7.60 (m, 8 H), 6.90 (m, 3 H), 5.94 (d, /= 17.7 Hz, 1 H), 4.37 (m, 1 H), 4.16 (m, 1 H), 2.41-1.58 (m, 12 H); MS (ES1): 537.4 71b -ch=ch2 67 A-4,1-2, S *H NMR (DMSO-de): 8 9.76 (s, 1 H), 9.41 (s, 1 H), 8.95 (s, 1 H), 8.53 (m, 1 H), 8.07 (s, 1 H), 7.65 (m, 8 H), 7.08 (in, 2 H), 6.85 (dd, /== 10.9 and 17.7 Hz, 1 H), 6.92 (m, 3 H), 5.97 (d, J= 17.7 Hz, 1 H), 5.37 (d, 10.9 Hz, 1 H), 2.84 (m, 1 H), 2.70 (m, 1 H), 0.98-0.51 (m, 8H); MS (ES*): 509.4 *0 o C3 Ul © KJ Vl 00 K> 177 Cpd. No.
-R -R' Startmg From Method Used Analytical Data 71c -ch=ch2 67 A-4,1-2, S !H NMR (DMSO-de): 8 12.51 (br s, 1 H), 9.59 (s, 1 H), 9.22 (s, 1 H), 8.79 (s, 1 H), 8.58 (t, J= 5.5 Hz, 1 H), 8.17 (s, 1 H), 7.67 (m, 8 H), 7.12 (m, 2 H), 6.86 (dd, /= 10.9 and 17.7 Hz, 1H), 5.98 (d, J= 17.7 Hz, 1 H), 5.38 (d, /= 10.9 Hz, 1 H), 3.27 (m, 4 H), 1.20 (t, 7= 7.2 Hz, 1 H), 1.09 (t, J== 7.2 Hz, 1 H); MS (ES+): 485.3 178 NHBoc R02C Cpd. No.
-R -R' Starting From Method Used Analytical Data 68a -ch3 67 A-4 MS (ES4): 599.4 68b rCH3 CHj - 67 A-4 MS (ES4): 641.4 68c -ch3 -<) 67 A-4 MS (ES4): 625.3 68d -CHj Nx,/X^CH2 67 A-4 MS (ES4): 583.3 68e -ch3 ' •v^CH, CH, 67 A-4 MS (ES4): 585.3 68f -ch3 \^ch3 CHj 67 A-4 MS (ES4): 599.4 179 Cpd. No.
-R -R' Starting From Method Used Analytical Data 68g -ch3 \/cf3 67 a-4 MS (ES*): 625.2 68b -ch3 -O 67 a-4 MS (ES*): 619.2 68i -ch3 67 a-4 MS (ES*): 615.3 68j -ch3 67 a-4 MS (ES*): 597.3 68k -ch3 ^CH3 67 a-4 MS (ES*): 557.3 681 -ch3 \^ch3 67 a-4 MS (ES*): 571.4 68m -ch3 ~o. 67 a-4 MS (ES*): 639.4 68n -ch3 67 a-4 Characterized in the next step 68o -ch3 67 a-4 MS (ES*): 613.5 180 Cpd. No.
-R -R' Starting From Method Used Analytical Data 68p -ch3 y—ch3 67 A-4 ms (es*): 613.5 68q -ch3 \_—ch3 67 A-4 ms (es*): 641.5 68r -ch3 67 A-4 ms (es*): 714.5 68s -ch3 ~~o 67 A-4 ms (es*): 611.4 68t ~ch3 y>-"oh 67 A-4 ms (es*): 641.4 68u -ch3 67 A-4 ms (es*): 583.3 68v -ch3 -o 67 A-4 ms (es*): 597.4 68w -ch3 vx-^voh 67 A-4 ms (es*): 587.4 68x -ch3 CHj 67 A-4 ms (es*): 613.5 181 oe R"02C Cpd. No.
-R (Position with Respect to Phenyl Ring) -R' -R" Starting From Method Used Analytical Data 74 -och3 (3) -cho -ch3 73 +3a d-2 MS (ES"): 368.2 75a -oh (3) -cho -ch3 74 v-2,w MS (ES"): 354.1 75b -oh (3) -cho -b11 74 v-1,h MS (ES-): 430.2 76a -oso2cf3 (3) -cho -ch3 75a b-2 MS (ES*): 488.1 76b -oso2cf3 (3) -cho -Bn 75b b-2 MS (ES"): 562.3; MS (ES*): 586.3 (M+Na)* 77a -ch=ch2 (3) -cho -ch3 76a d-3 MS (ES*): 366.38 77b -och2co2c2h5 (3) -cho -Bn 75b X Characterized in the next step 77c -och2conh2(3) -cho -Bn 75b X MS (ES"): 487.3; MS (ES*): 511.35 (M+Na)* 77d -cho -Bn 76b d-2 Characterized in the next step 77e -—O" -cho -Bn 75b d-8 MS (ES*): 530.3 (M+Na)*); MS (ES"): 506.3 3 o o O? hS n |H Cl <ZJ o 182 <*> CA 00 K> Cpd. No.
-R (Position with Respect to Phenyl Ring) -R' -R" Starting From Method Used Analytical Data 77f (3) -CHO -Bn 75b x MS (ES*): 496.3 (M+Na)+ 77g ^o^ch3 <3> -CHO -Bn 75b x MS (ES+): 482.4 (M+Na)* 77h 0 { (3) ch3 -CHO -Bn 75b x MS (ES*): 510.4 (M+Na)* 77i \ ^oac ° ^ (3) -CHO -Bn 75b x 'HNMR (cdci3): 5 9.59 (s, 1 H), 8.39 (d, J = 2 Hz, 1 H), 8.03 (m, 2 H), 7.84 (d, J = 8.9 Hz, 1 H), 7.35 (d, J = 8 Hz, 1 H), 7.28 (m, 2 H), 7.12 (m, 2 H), 6193 (dd, J=2.5 and 8.8 Hz, 1 H), 6.64 (d, J = 2.5 Hz, 1 H), 6.31 (t, J = 6 and 5 Hz, 1 H), 5.06 (m, 2 H), 4.42 (t, J = 4.5 Hz, 2 H), 4.13 (m, 2 H), 3.34 (t, J =6.8 Hz, 2 H), 2.11 (s, 3 H), 1.94 (m, 1 H), 1.01 (d, J = 6.8 Hz, 6H) 78a -CH=CH2 (3) -C02H -ch3 77a E MS (ES"): 380.1 78b -OSOsCF3 (3) -C02H -Bn 76b E Characterized in the next step 78c -0CH2C02C2Hs(3) -co2h -Bn 77b E Characterized in the next step ,78d -OCH2CONH2 (3) -co2h -Bn 77c E MS (ES*): 52735 (M+Na)* 183 Cpd. No.
-R (Position with Respect to Phenyl Ring) -R' -R" Starting From Method Used Analytical Data 78e JL}a -co2h -Bn 77d E MS (ES+): 536.4 (M+Na)+ 78f —°-^f y(3) -CO2 h -Bn 77e E MS (ESO: 522.3 78g -och3 (3) -c02h -ch3 74 E MS (ES-): 384.1 78h / 0 » 1 -co2h -Bn 77f E MS (ES-): 488.3 78i / o > uP 1 ^ -co2h -Bn 77g E MS (ES"): 474.4 78j vy1 (3) CH, -co2h -Bn 77h E MS (ES"): 502.4 78k (3) -co2h -Bn 771 E Characterized in the next step 90 -OBn (5) -CHO -ch3 89 +3a D-2 1HNMR (CDCI3): 8 10.47 (s, 1 H), 8.36 (d, J = 2 Hz, 1 H), 7.96 (dd, J = 2.2 and 7.7 Hz, 1H), 7.68 (m, 2 H), 7.46 (m, 5 H), 7.23 (d, J - 8 Hz, 1 H), 7.12 (d, J = 8.7 Hz, 1 H), 6.73 (d, J = 7.2 Hz, 1 H), 5.23 (q, J = 11 and 15 Hz, 2 H), 3.67 (s, 3 H), 3.31 (t, J = 6.8 Hz, 2 H), 1.94 (m, 1 H), 1.01 (d, J = 6.8 Hz, 6 H), MS (ES+) 468.2 (M+Naf (ES-) 444.2 ' 184 Cpd. No.
-R (Position with Respect to Phenyl Ring) -R' -R" Starting From Method Used Analytical Data 91 -OBn (5) -COzH -ch3 90 E 'HNMR (CDClj): 8 8.22 (s, 1 H), 7.83 (d, J = 7.2 Hz, 1 H), 7.34 (m, 8 H), 7.02 (d, J = 8.1 Hz, 1 H), 6.75 (d, J = 7.4 Hz, 1 H), 5.16 (s, 2 H), 3.66 (s, 3 H), 3.21 (t, J = 6.8 Hz, 2 H), 1.85 (m, 1 H), 0.94 (d, J = 6.8 Hz, 6 H), MS (ES+) 484.1 (M+Na)+ 92 -OBn (5) -COzMEM -ch3 91 F MS (ES+): 572.2 (M+Na)+ 93 -OH (5) -co2mem -ch3 92 G MS (ES4): 482. (M+Na)4 94 -oso2cf3 (5) -COzMEM -CHj 93 B-2 MS (ES4): 614.3 (M+Na)+ 95a vOb s -co2mem -ch3 94 D-3 MS (ES+) 562.3 (M+Na)+ 96a s -co2h -CHj 95a I-l MS (ES+) 452.1 (M+Na)+ 101 -OCHa (2) -CHO -ch3 100 + 3a D-2 MS (ES+) 370.1 102 -och3 (2) -co2h -ch3 101 E MS (ES-) 384.2; MS (ES+) 386.2 108 -OBn (2) -CHO -ch3 107 +3a D-2 MS (ES4): 446.2 109 -OBn (2) -co2h -ch3 108 E MS (ES"): 460.1 185 Cpd. No.
-R (Position with Respect to Phenyl Ring) -R' -R" Starting From Method Used Analytical Data 131 -h -CHO -ch3 130 + 3a D-2 'HNMR (CDCl3-di): 6 9.79 (s, 1 H), 8.39 (d, J = 1.88 Hz, 1 H), 8.02 (t, J = 6.0 Hz, 2 H), 7.59 (m, 2 H), 7.38 (d, J = 7.9 Hz, 1 H), 7.22 (d, J - 8.1 Hz, 1 H), 6.30 (b, 1 H), 3.72 (s, 3 H), 3.36 (t, J = 6.6 Hz, 2 H), 1.96 (m, 1H), 1.02 (d, J = 6.8 Hz, 6 H), MS (ES+): 340.1 132 -H -co2h -ch3 131 E 'HNMR (DMSO-dfi): 5 12.28 (b, 1 H), 8.52 (d, J = 6.03 Hz, 1 H), 8.12 (s, 1 H), 7.86 (d, J = 8.1 Hz, 1 H), 7.74 (d, J = 7.74 Hz, 1 H), 7-41 (t, J = 8.67 Hz, 1 H), 7.31 (t, J = 7.9Hz, IH),7.12(d, J = 8.1 Hz, 1 H), 6.97 (d, J = 7.5 Hz, 1 H), 3.39 (s, 3 H), 2.92 (t, J = 6.0 Hz, 2 H), 1.66 (m, 1H), 0.78 (d, J - 7.4 Hz, 6 H), MS (ES-): 354.1 NH 193a -H || jMHBoc -ch3 192a + 6a D-7 MS (ES"*): 560.5 f 193b -H CH3 -ch3 192b + 6a D-7 MS (ES+): 574.5) IBS Cpd. No.
-R (Position with Respect to Phenyl Ring) -R' -R" Starting From Method Used Analytical Data' r 194a -h -ch3 193a S-2 MS (ES*): 460.3 NH Jl 194b -h -ch3 193b S-2 MS (ES*): 474.3 195a -H NH -H 194a 1-2 'HNMR (DMSO-de): 5 8.79 (bs, 4H), 8.63 (t, J = 6.5 Hz, I H), 8.35 (s, 1H), 7.85 (d, J = 6 Hz, 1 H), 7.62 (d, J = 8.2 Hz, 2 HQ, 7.26 (m, 5 H), 7.06 (m, 1 H), 5.0 (xn, 2 H), 3.09 (t, J = 6.2 Hz, 2 H), 1.86 (m, 1 H), 0.89 (d, J = 6.6 Hz, 6 H); MS (ES-): 444.3 and (ES*) 446.3 187 Cpd. No.
-R (Position with Respect to Phenyl Ring) -R' -R" Starting From Method Used Analytical Data 'HNMR (DMSO-dg/DCl): 8 8.24 (d, J = 1.6 Hz, 1 H), 7.91 (dd, J = 7.7 and 1.6 Hz, 1 H), 7.56 (d, J = 195b -H xXy1*' -H 194b 1-2 8.7 Hz, 1 H), 7.48 (d, J = 8.7 Hz, 1 H), 7.32 (t, J = 8 Hz, 1 H), 7.16 (m, 3 H), 6.91 (t, J = 7.5 Hz, 1 H), 6.76 (d, J = 8.5 Hz, 1 H), 6.66 (d, J = 8.5Hz, IH),4.99(m, 1 H), 2.92 (d, J = 6.9 Hz, 2 H), 1.68 (m, IH), 1.33 (d, J = 6 Hz, 1.2 H), 1.27 (d, J = 6 Hz, 1.8 H), 0.71 (d, J = 6.5 Hz, 6 H); MS (ES-): 458.2 and (ES4) 460.3 NH J] 200 -h AA! H -ch3 199 +6a D-7 MS (ES4): 573.5 188 Cpd. No.
-R (Position with Respect to Phenyl Ring) -R' -R" Starting From Method Used Analytical Data 201 -H H H NHBoc -H 200 1-2 'HNMR (DMSO-dg/DCl): 5 8.49 (t, J = 5.6 Hz, 1H), 8.18 (d, J = 6.9 Hz, 1H), 7.84 (t, J = 7.8 Hz, I H), 7.23 (m, 4 H), 7.01 (m, 2 H), 6.82 (d, J = 7 Hz, 1 H), 6.22 (d, J = 8.5 Hz, 1 H), 6.15 (d, J = 8.5 Hz, 1H), 3.95 (m, 1 H), 2.85 (t, J = 5.8 Hz, 1 H), 1.62 (m, 1 H), 1.23 (s, 9 H), 1.1 (d, J = 6.7 Hz, 1.2 H), 1.05 (d, J = 6.7 Hz, 1.8 H), 0.67 (d, J = 6.6 Hz, 6 H); MS (ES+): 559.4 202 -H NH jjryK, H -H 201 S MS (ES+): 459-3 203 -OBn (4) AXr H :mh ^"NHBoc -CH3 45 R MS (ES4): 679.4 204 -OBn (4) o .^tf nhboc A.XJ H -H 203 1-2 MS (ES")'- 663.4 189 Cpd. No. 209a -R (Position with Respect to Phenyl Ring) -R' -R" -ch3 Starting From Method Used Analytical Data -H H 132 A-7 MS (ES*): 454.3 209b -CH==CH2 (4) sC N xxr H -ch3 30f A-7 'HNMR (DMSO-ds): 5 10.72 (s, 1 H), 8.65 (d, J = 6.03 Hz, 1 H), 8.24 (s, 1 H), 8.03 (d, J=8.3 Hz, 1 H), 7.75 (m, 6 H), 7.40 (d, J = 7.90 Hz, 1 H), 7.34 (d, J = 8.1 Hz, IH), 6.88 (q, J = 11.2 Hz, IH), 6.04 (d, J = 7.5 Hz, 1H), 5.41 (d, J = 11.1 Hz, 1 H), 3.55 (s, 3 H), 3.10 (t, J —6.6 Hz, 2 H), 1.86 (xn, IH), 0.88 (d, J = 6.6 Hz, 6 H); MS (ESI: 480.3 210b -CH-CH2 (4) 0 A^N-OH AAi ■ H -ch3 209b Y 1HNMR (DMSO-d6): 5 10.12 (s, 1 H), 9.37 (b, 1 H), 8.48 (t, J=6.1 Hz, 1 H), 8.05 (d, J=1.9 Hz, 1 H), 7.85 (d, J=7.9 Hz, 1 H), 7.56 (d, J=7.8 Hz, 1 H), 7.49 (d, J=7.9 Hz, 1 H), 7.36 (s, 4 H), 7.21 (d, J=7.9 Hz, 1 H), 7.10 (d, J=2.8 Hz, 1 H), 6.69 (in, 1 H), 5.84 (d, J=15.5 Hz, 1 H), 5.60 (b, 1 H), 5.22 (d, J=11.4Hz, IH),3.38(s,3H), 2.91 (t, J - 6 Hz, 2 H), 1.66 (m, 1 H), 0.71 (d, J = 6.8 Hz, 6 H); MS (ES+) 515.40 190 Cpd.
No.
-R (Position with Respect to Phenyl Ring) -R' -R" Starting From Method Used Analytical Data 211b -CH=CH2 (4) NH 0 r^V^^N-OH AAJ ' H -H 210b 1-2 'HNMR (DMSO-dg): 8 12.62 (bs, IH), 10.24 (s, 1 H), 8.48 (t, J=5.65 Hz, 1 H), 8.15 (s, 1 H), 7.81 (d, J=10.9 Hz, 1 H), 7.61 (s, IH), 7.50 (d, J=7.9 Hz, 1 H), 7.49 (s, 6 H), 7.16 (d, J=8.1 Hz, 1 H), 7.08 (d, J=8.1 Hz, 1H), 6.72 (m, 1 H), 5.85 (d, J=13.7 Hz, 1 H), 5.24(d,J=11.5Hz, IH), 2.93 (t, J = 6 Hz, 2 H), 1.68 (m, 1 H), 0.72 (d, J = 6.8 Hz, 6 H); MS (ES+) 501.40, (ES-) 499.2 212 -CH=CH2 (4) ^xr™ H -CH3 187a AE-5 'H NMR (DMSO): 8 8.70 (t, J = 5.6 Hz, 1 H), 8.36 (d, J= 1.7 Hz, 1 H), 8.07 (dd, J = 8.1,1.9 Hz, 1 H), 7.42 (m, 4H), 7.09 (d, J-5.5 Hz, 1 H), 7.04 (d, /= 7.7 Hz, 1 H), 6.74 (dd, J= 17.5,10.9 Hz, 1 H), 6.49 (d, J= 8.8 Hz, 2 H), 5.79 (d, J= 17.7 Hz, 1 H), 5.27 (d, /= 10.9 Hz, 1 H), 4.0 (t, J= 6.0 Hz, 2 H), 3.62 (s, 3 H), 3.11 (t, J= 6.2,2 H), 1.86 (in, 1 H), 0.90 (d, J= 6.6 Hz, 6 H) 191 Cpd. No.
-R (Position with Respect to Phenyl Ring) -R' -R" -ch3 Starting From Method Used Analytical Data 213 -CH=CH2(4) NH H 212 Y 'HNMR (DMSO): 8 9.23 (s, 1 H), 8.71 (t, 7= 6.2 Hz, 1 H), 8.36 (d, 7= 1.9 Hz, 1 H), 8.09 (dd, J = 7.9,1.7 Hz, 1H), 7.49 (d, J = 7.9 Hz, 2H), 7.40 (d, 7= 8.3 Hz, 1 H), 7.32 (d, 7= 8.8 Hz, 2 H), 7.04 (d, 7= 7.9 Hz, 1 H), 6.73 (dd, 7= 17.7,11.1 Hz, IH),6.40 (d, 7= 8.5 Hz, 2 H), 6.33 (t, 7= 7.0 Hz, 1 H), 5.78 (d, 7= 17.7 Hz, 1 H), 5.58 (b,lH), 5.26 (d, 7= 11.1 Hz, 1 H), 3.96 (m. 2 H), 3.64 (s, 3 H), 3.11 (t, 7= 6.4 Hz, 2 H), 1.86 (m„ 1 H), 0.90 (d, 7= 6.8 Hz, 6 H); MS (ES*): 501.3 214 ~CH=CH2 (4) NH * H -H 213 1-2 ^NMR (DMSO): 5 8.76 (t, 7= 5.8 Hz, 1 H), 8.37 (s, IH), 8.04 (d, 7= 8.7 Hz, 1 H), 7.39 (m, 5 H), 7.06 (d, 7= 8.3 Hz, 1 H), 6.72 (dd, J= 17.9,11.3 Hz, 1 H), 6.43 (d, 7= 8.5 Hz, 3 H), 5.76 (d, 7= 17.9 Hz, 1 H), 5.24 (d, 7=11.1 Hz, 1 H), 3.98 (m. 2 H), 3.11 (t, 7 = 6.6 Hz, 2 H), 1.86 (h, 7= 6.8 Hz, IH),0.90(d,7= 6.8,6H); MS (ES4): 487.2 192 Cpd. No.
-R (Position with Respect to Phenyl Ring) -R' -R" Starting From Method Used Analytical Data 238 -CH=CH2 (4) NH sJZr* H -H 237 + 187a AE-2 'HNMR (DMSO-de): 8 8.68-8.60 (m, IH), 8.50 (d, J=2.4 Hz, 1 H), 7.90-7.80 (m, 1 H), 7.76-7.70 (m, 1 H), 7.56-7.50 (m, 1 H), 7.48-7.42 (d, J = 7.7 Hz, 1H), 7.30-7.22 (d, J = 7.9 Hz, 1 H), 7.10-7.02 (d, J=7.7 Hz, 1 H), 6.90-6.75 (dd, J = 17,11 Hz, 1 H), 6.5 (bs, 1 H), 5.92-5.80 (d,J = 17 Hz, 1 H), 5.40-5.30 (d, 11 Hz, 1 H), 4.50-4.20 (m, 2 H), 3.20-3.10 (t, J = 6.6 Hz, 2 H), 2.10-1.88 (m, 1 H), 1.2-0.94 (d, J = 6.6 Hz, 6 H); MS (ES+) 471.3 N[H 256 -H NHBoc -ch3 255 + 6a D-6 MS (ES+): 573.3 « 257 -h wcr H -H 256 1-2, S MS (ES*): 459.1 193 Cpd. No.
-R -R' Starting From Method Used Analytical Data 79a -ch=ch2 (3) -ch3 78a J MS (ES*): 499.2 79b -0S02CF3 (3) -ch2c6h5 78b J Characterized in the next step 79c -och2co2c2h5 (3) -ch2c6h5 78c J Characterized in the next step 79d -och2conh2 (3) -ch2c6h5 78d J MS (ES*): 622.4; (ES") 620.4 79e (3) o -ch2c6h5 78e J Characterized in the next step 79f / \=/ (3) -ch2c6h5 78f J Characterized in the next step 194 Cpd. No.
-R -R' Starting From Method Used Analytical Data 79g -OCH3 (3) -CH3 78g J 'HNMR (DMSO-de): 5 10.6 (bs, 1 H), 9.29-9.32 (bs, 1 H), 9.06 (bs, 1 H), 8.82-8.75 (t, J = 5.84 Hz, 1 H), 8.32 (d, J = 1.88 Hz, 1 H), 8.13 (d, J =1.7 Hz, 1 H), 7.83 (s, 4 H), 7.78 (d, J = 8.67 Hz, 1 H), 7.50 (d, J = 7.9 Hz, 1 H), 7.20-7.15 (dd, J = 8.67,2.3 Hz, 1 H), 6.92 (d, J = 2.4 Hz, 1 H), 3.94 (s, 3 H), 3.64 (s, 3 H), 3.21-3.14 (t, J = 6 Hz, 2 H), 2.0-1.86 (m, 1 H), 1.0-0.94 (d, J = 6.5 Hz, 6 H); MS (ES+ ) 503.3 79h \0^x^CH3 (3) -Bn 78h J MS (ES+): 607.3 79i (3) -Bn 781 J MS (ES+): 593.4 79j "\ ^CH3 (3) CHj -Bn ? f- J MS (ES*): 621.4 79k -0-CH2-CH2-0Ac (3) -Bn 78k J MS (ES*): 651.4 80a -CH=CH2 (3) -H 79a 1-2 'HNMR (DMSO-de): 5 9.1 (s, 2 H), 8.87 (s, 2 H), 8.53 (t, J = 6 Hz, 1 H), 8.02 (s, 1 H), 7.64 (m, 7 H), 7.1 (s, 1 H), 6.98 (d, 7.4 Hz, 1 H), 6.80 (dd, J = 11 Hz, J = 17:6 Hz, 1 H), 5.90 (d, J = 17.6 Hz, 1 H), 5.35 (d, J = 12 Hz, 1H), 3.03 (t, 6 Hz, 2 H), 1.83 (m, 1 H), 0.86 (d, J = 6.7 Hz, 6 H); MS (ES+ ) 485.2 80b -OH (3) -H 79b 1-2 'HNMR (DMSO-de): 5 10.37 (s, 1 H), 9.20 (m, 3 H), 8.72 (t, J = 6 Hz, 1H), 8.2 (s, 1 H), 8.85 (in, 6 H), 7.65 (d, J - 8 Hz, 1 H), 7.12 (d, 8 Hz, 1 H), 7.02 (dd, J = 2.5 Hz, J = 8 Hz, 1 H), 6.60 (d, J = 2.5 Hz, 1 H), 3.25 (t, J = 6.5 Hz, 2 H), 2.0 (m, 1 H), 1.07 (d, J = 6.8 Hz, 6 H); MS (ES+ ) 475.2 195 Cpd.
No.
-R -R' Starting From Method Used Analytical Data 80c -OCH2CO2H (3) -H 79c 1-2 !H NMR (DMSO-de): 8 12.7 (2H, bs, 1 H), 9.01, 8.87 (2 bs, 4 H), 8.36 (m, IH), 7.83 (s, 1H), 7.44 (m, 6 H), 6.75 (xn, 2H), 6.31 (d, J=2.2 Hz, IH), 4.42 (s, 2H), 2.84 (tn, 2H), 1.63 (m, IH), 0.67 (d, J=6.5 Hz, 6H); MS(ES+): 533.4 80d -OCH2CONH2 (3) -H 79d G !H NMR (DMSO-de): S 9.13 (bs, 5H), 8.59 (t, J=6.28 Hz, IH), 8.14 (d, J =* 1.7 Hz, IH), 7.63 (m, 9H), 7.42 (s, IH), 7.09 (d, J = 7.5 Hz, IH), 7.03 (dd, J = 2.5,12.7 Hz, IH), 6.70 (d, J =2.5 Hz, IH), 4.48 (s, 2H), 3.05 (t, J= 6.6 Hz, 2H), 1.83 (m, IH), 0.87 (d, J=6.8 Hz, 6H); MS(ES+): 532.4 80e JL) (3) -H 79e 1-2 *H NMR (DMSO-ds): 5 12.6 (IH, bs, COOH), 8.98, 8.67 (2 bs, 4H), 8.46 (m, IH), 8.08 (ra,IH), 7.76 (m, IH), 7.53 (in, 6 H), 7.39 (in, 2H), 7.06. (m; IH), 7.04 (m, IH), 2.89 (m, 2H), 1.66 (m, IH), 0.69 (d, 3=6.5 Hz, 6H); MS(ES+): 541.4 80f />~o® -H 79f 1-2 'HNMR (DMSO-dfi): 8 9.14 (d, J = 10 Hz, 4 H), 8.60 (t, J = 6 Hz, 1 H), 8.22 (bs, 1 H), 7.87-7.62 (m, 7 H), 7.47 (t, J = 8 Hz, 2 H), 7.26 (t, 7 Hz, 1 H), 7.22 (m, 4 H), 6.70 (bs, 1 H), 3.09 (t, J = 6 Hz, 2 H), 1.83 (m, 1 H); 0.91 (d, 3 = 6.8 Hz, 6 H); MS (ES+) 551.4 80g -OCHj (3) -H 79g 1-2 'HNMR (DMSO-ds): 8 9.13 (bs, 2 H), 8.78 (bs, 2H), 8.65 (t, J = 6 Hz, 1 H), 8.25 (bs, 1 H), 7.78 (in, 1 H), 7.76 (in, 5 H), 7.25 (s, 1 H), 7.17 (m, 1 H), 6.73 (bs, 1 H), 3.83 (s, 3 H), 3.10 (t, J = 6 Hz, 2 H), 1.80 (m, 1 H), 0.88 (d, J = 6.8 Hz, 6 H); MS (ES+) 489.3 Cpd. No.
-R -R' Starting From Method Used Analytical Data 80h -H 79h 1-2 MS (ES*): 517.7 80i / o > Q 1 12 -H 79i 1-2 MS (ES+): 503.4 ; MS (ES"): 501.4 80j (3) ch3 -H 79] 1-2 MS (ES4): 531.4; MS (ES-): 529.4 80k -O-CH2-CH2-OH (3) -H 79k 1-2 'HNMR (DMSO-dg): 5 13.52 (bs, 1 H), 9.16 (bs, 2 H), 9.03 (bs, 2 H), 8.50 (t, J = 6 Hz, 1 H), 7.96 (d, J -1.7 Hz, 1 H), 7.56 (m, 6 H), 7.00 (dd, J = 2.5 and 8.5 Hz, 1 H), 6.90 (d, J = 8 Hz, 1 H), 6.48 (d, J = 2.5 Hz, 1 H), 4.91 (t, J = 5.5 Hz, 1 H), 4.00 (t, J = 4.5 Hz, 2 H), 3.69 (q, J = 5.5 and 10 Hz, 2 H), 3.05 (t, J = 6.8 Hz, 2 H), 1.80 (m, 1 H), 0.84 (d, I = 6.8 Hz, 6 H); MS (ES+): 519.3, (ES-) 517.3 86a -CH(OH)CH2OH (3) -H 82 S, 1-2 'HNMR (DMSO-de): 5 9.15 (bs, 3 H), 8.65 (t, J = 6 Hz, 1 H), 8.12 (s, 2 H), 7.82-7.56 (m, 7 H), 7.55-6.96 (m, 4 H), 5.5 (bs, 1 H), 4.90 (bs, 1 H), 4.65 (bs, 1 H), 3.10 (t, J = 6 Hz, 2 H),-1.90 (m, 1 H), 0.92 (d, J = 6.8 Hz, 6 H); MS (ES+) 519.3 86b -CH2OH (3) -H 84 S, 1-2 'HNMR (DMSO-d6): 8 8.82 (bs, 2 H), 8.68 (bs, 2 H), 8.40 (t, J = 6 Hz, 1 H), 7.88 (bs, 1 H), 7.53 (m, 5 H), 7.45 (d, 8 Hz, 1 H), 7.25 (d, J = 8 Hz, 1 H), 6.81 (m, 2 H), 5.22 (d, J = 5.5 Hz, 1 H), 4.41 (d, J = 5.5 Hz, 2 H), 2.88 (t,J = 6 Hz, 2 H), 1.65 (m, 1 H), 0.71 (d, J = 6.8 Hz, 6 H); MS (ES+ ) 489.2 197 Cpd. No. -r -r' Starting From Method Used Analytical Data 86c -C02H(3) -H 85 S, 1-2 1HNMR.(DMSO-dfrD20): 8 13.7 (bs, 1 H), 8.32 (t, J=6 Hz, 1 H), 7.63-7.17 (m, 7 H), 6.72 (d, 7.0 Hz, 1 H), 2.81 (t, J = 6 Hz, 2 HJ, 1.53 (m, 1 H), 0.64 (d, J = 6.8 Hz, 6 H); MS (ES+) 503.2 97a -ch3 96a J MS (ES4): 569.2 97b -OBn (5) -ch3 91 J 'HNMR (DMSO-dfi): 8 10.62 (s, 1 H), 9.15 (bs, 2 H), 8.82 (bs, 2 H), 8.67 (t, J = 6 Hz, 1 H), 8.25 (d, J = 2 Hz, 1 H), 7.99 (dd, J = 8.1 and 2 Hz, 1 H), 7.69 (q, 8.8 and 16.2 Hz, 4 H), 7.44 (m, 3 H), 7.28 (m, 3 H), 6.89 (d, J = 7.7 Hz, 1 H), 5.5 (s, 2 H), 3.6 (s, 3 H), 3.08 (t, J = 5.8 and 6.8 Hz, 2 H), 1.83 (m, 1 H), 0.87 (d, J = 6.8 Hz, 6 H); MS (ES-) 577.2, (ES+) 579.3 98a S (5) -H 97a 1-2 'HNMR (DMSO-d6): 8 13.45 (bs, 1 H), 9.06 (s, 2 H), 8.99 (s, 2 H), 8.51 (t, J = 6 and 5 Hz, 1 H), 7.99 (s, 1 H), 7.62 (m, 5 H), 7.47 (s, 1 H), 7.36 (m, 2 H), 6.99 (m, 4 H), 4.26 (s, 2 H), 3.02 (t, J = 6.8 Hz, 2 H), 1.80 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES-) 553.2, (ES+) 555.2 98b -OBn (5) -H 97b 1-2 'HNMR (DMSO-dfi): 8 13.52 (bs, 1 H), 9.09 (bs, 2 H), 9.04 (bs, 2 H), 8.48 (t, J = 6 Hz, 1 H), 7.94 (s, 1 H), 7.61 (m, 4 H), 7.49 (s, 1 H), 7.46 (s, 1 H), 7.34 (m, 5 H), 7.15 (d, J = 8.2 Hz, 1 H), 7.00 (d, J - 8.2,1 H), 6.02 (d, J = 7.4 Hz, I H), 5.21 (s, 2 H), 3.01 (t, J = 6.8 Hz, 2 H), 1.80 (m, 1 H), 0.85 (d, J = 6.8 Hz, 6 H); MS (ES-) 563.2, (ES+) 565.2 198 Cpd. No.
-R -R' Starting From Method Used Analytical Data 98c -OH (5) -H 98b G 'HNMR (DMSO-dfi): 8 9.85 (s, 1 H), 9.07 (s, 2 H), 8.98 (s, 2 H), 8.50 (t, J = 6 and 5 Hz, 1 H), 7.99 (d, J = 1.7 Hz, 1 H), 7.63 (m, 5 H), 7.20 (t, J = 8 Hz, 2 H), 6.90 (d, J = 7.9 Hz, 1 H), 6.49 (d, J = 7.2 Hz, 1 H), 3.21 (t, J = 6.8 Hz, 2 H), 1.80 (m, 1H), 0.85 (d, J = 6.8 Hz, 6 H); MS (ES+) 475.2; (ES-) 473.2 103 -OCH3 (2) -ch3 102 J MS (ES+) 503.1 104 -OCH3 (2) -h 103 1-2 'HNMR (DMSO-dfi): 8 9.08 (bs, 2 H), 8.80 (bs, 2 H), 8.52 (t, J = 6 Hz, 1 H), 8.02 (s, 1 H), 7.64 (ro, 5 H), 7.16 (m, 2 H), 7.03 (m, 2 H), 3.84 (s, 3 H), 3.03 (t, J = 6.8 Hz, 2 H), 1.81 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES-) 487.3, (ES+) 489.3 110 -OBn (2) -ch3 109 J MS (ES4): 579.3 111 -OH (2) -ch3 110 G MS (ES4): 489.3 126 -OC2Hs<3V -OBn (4) J -ch3 118b J Characterized in flie next step 127 -OC2H5 (3)i -OBn{4)jb0111 -H 126 1-2 'H NMR (DMSO-d6): 8 9.06-9.09 (m, 3H), 8.56-8.50 (m, IH), 8.05 (s, IH), 7.71-7.58 (m, 6H), 7.55-7.28 (xn, 6H), 7.10-7.01 (in, IH), 6.63 (s, IH), 5.19 (s, 2H), 4.05-3.97 (m, 2H), 3.05-3.01 (in, 2H), 1.86-1.77 (m, IH), 1.29 (t, 7=6.7 Hz, 3H), 0.87 (d, 7=6.8 Hz, 6H) 129 j-both -OCH3 (3) J -CH(OH)CH3 (4) -h 128 1-2, S 'H NMR (DMSO-c?tf): 13.64 (br s, 1 H), 8.99 (br s, 2 H), 8.49 (t, 7= 5.1 Hz, 1 H), 7.99 (s, 1 H), 7.73-7.56 (m, 5 H), 7.32-6.83 (in, 5 H), 6.50 (s, 1 H), 5.17 (d, 7= 4.3 Hz, 1 H), 5.01 (m, 1 H), 3.75 (s, 3 H), 3.03 (t, 7= 6.0 Hz, 1 H), 1.81 (m, 1 H), 1.32 (d, 7= 6.2 Hz, 3 H), 0.86 (d, 7= 6.6 Hz, 6 H); MS (ES4): 533.4 (100% M+') 199 o.
Cpd. No.
-R (With Respect to Phenyl Ring) Starting From Method Used Analytical Data 81 -CH=CH2 (3) 79a R MS (ES"): 597.2 82 -CH(OH)CH2OH (3) 81 L MS (ES"1): 631.3 83 -CH=0 (3) 82 M MS (ES4): 601.3 84 ~CH2OH (3) 83 K MS (ES"1): 601.4 85 -C02H (3) 83 E MS (ES"1): 615.3 128 -OCB3 (3) "I r both -CH=CH2(4)J 124a R MS (ES"1): 629.4 200 R3 Cpd. No.
-R -R1 -R2 -R3 -R4 Starting From Method Used X Analytical Data 88 -Br -H -H -H -OBn 87 'HNMR (CDC13): 5 10.48 (s, 1 H), 7.42 - 7.25 (m, 7 H), 7.00 (dd, J = 2 and 7.4 Hz, 1 H), 5.19 (s, 2 H); 3R (KBr) 1701, 1585,1452,1262,1009 cm'1; MS (ES+) 313.0,315.0 (M+Naf 89 -B(OH)2 -H -H -H -OBn 88 T, U-l 1HNMR (CDC13): 8 10.61 (s, 1 H), 7.65 (d, J = 7.2 Hz, 1 H), 7.60 (t, J = 7.9 and 7.2 Hz, 1 H), 7.41 (m, 5 H), 7.19 (d, J = 7.9 Hz, 1 H), 6.81 bs, 2 H), 5.20 (s, 2 H) 100 -B(OH)2 -OCH3 -H -H -H 99 T, U-3 lHNMR (DMSO-de): 8 10.2 (s, 1 H), 8.34 (s, 2 H), 7.92 (d, J = 9.4 Hz, 1 H), 7.13 (m, 2 H), 3.92 (s, 3 H); MS (ES") 179.0 107 -B(OH)2 -OBn -H -H -H 106 T, U-l 'HNMR (DMSO-d6): 8 10.1 (s, 1 H), 7.3-7.6 (m, 8 H), 5.3 (m, 2 H) 114a -Br -H -OCHj -OH -H 113 Z MS (ES"): 229.0 and 231.0) 114b -Br -h -oc2h5 -OH -H 113 Z-l MS (ES"): 242.9 and 244.9 114c -Br -H -OCH(CH3)2 -OH -H 113 Z-l MS (ES"): 257.0 and 259.0 115a -Br -H -och3 -OBn -H 114a X MS (ES4): 321.0 and 323.0 115b -Br -H -oc2h5 -OBn -H 114b X MS (ES1): 335.0 and 337.0 115c -Br -H -OCH(CH3)2 -OBn -H 114c X MS (ES"1): 349.0 and 351.0 201 Cpd. No.
-R -R1 -R2 -R3 -R4 Starting From Metbod Used Analytical Data 115d -Br -h o . I O C(CH3)3 -OBn -h 115a X.V-4, ah Characterized in the next step 116a -b(oh)2 -h -och3 -OBn -h 115a T, U-l Characterized in the next step 116b -b(oh)2 -h -oc2h5 -OBn -h 115b T,U-1 Characterized in the next step 116c -b(oh)2 -h -och(ch3)2 -OBn -h 115c T, U-l Characterized in the next step 202 Cpd. No.
Starting From Method Used Analytical Data 112 111 1-2 'HNMR (DMSO-ds): 5 11.28 (s, 1 H ), 9.31 (s, 2 H), 9.0 (s, 2 H), 8.88 (d, J = 11.30 Hz, 1 H), 8.82 (d, J = 1.88 Hz, 1 H), 8.25 (d, J = 1.88 Hz, 1 H), 8.18 (d, J = 1.88 Hz, 1 H), 8.04 (d, J = 8.47 Hz, IH), 7.92 (m, J =24.48 Hz, 2H), 7.75 (m, J = 15.82,1 H), 7.75 (m, J = 8.28 Hz, 1 H), 7.55 (m, J = 8.66 Hz, 1 H), 3.10 (m, J = 12.6 Hz, 1 H), 2.5 (m, J = 3.5 Hz, 1 H), 1.8 (m, J = 19.9 Hz, 2 H), 0.88 (m, J = 6.6 Hz, 6 H). 203 o Cpd. No.
-R -R' -R" -R1" Starting From Method Used Analytical Data 117a -ch3 -OBn -cho ch3 \^-ch3 3a + 116a D-2 MS (ES"): 474.2 117b -c2h5 -OBn -cho ch, \Ach3 3a + 116b D-2 MS (ESO: 488.2 117c -ch(ch3)2 -OBn -cho CH3 ^^^ch3 3a + 116c D-2 MS (ES-): 502.3 117d -ch3 -OBn -CHO ch, 3b + 116a D-2 'HNMR (CDC13): 8 9.56 (s, 1 H), 8.34 (d, J = 1.7 Hz, 1H), 8.5 (s, 1 H), 8.01 (dd, J = 7.9 and 1.9 Hz, 1 H), 7.40 (m, 7 H), 6.9 (s, 1 H), 5.24 (m, 2 H), 4.2 (tn, 1 H), 3.80 (s, 3 H), 3.52 (s, 3 H), 1.02 (d, J = 7 Hz, 6 H); MS (ES+): 484.3 (M+Naf 204 Cpd. No.
-R -R' -OBn -R" -R"» Starting From Method Used Analytical Data 117e -ch3 -CHO y CH3 ^ 3c+ 116a D-2 'HNMR (DMSO-dfi): 8 8.43 (d, J = 1.65 Hz, 1 H), 8.31 (d, J = 8.66 Hz, 1), 8.12 (dd, J =1.69 Hz, IH), 7.98 (s, IH), 7.41 (d, J = 8 and 10 Hz, IH), 7.19 (d, J = 8.1 Hz, IH), 5.20 (dd, J = 6.2 Hz, IH), 3.98 (dd, J = 7.75 Hz, 3H), 3.94 (s, 3H), 3.42 (m, 3H), 3.32 (m, 3H), 3.19 (s, 3H), 2.5 (m, 3H), 2,0 (s, 4H), 1.5 (m, 2H), 1.28 (m, 3H), 0.88 (d, J = 6.59 Hz, 3H); MS (ES+): 664.3 117f -ch3 -OBn -CHO 3d + 116a D-2 'HNMR (CDC13): 8 9.50 (s, 1 H), 8.40 (d, J = 2.1 Hz, 1 H), 8.04 (dd, J= 8.1,2.1 Hz, 1 H), 7.57 (s, 1 H), 7.48 (m, 5 H), 7.38 (xn, 5 H), 6.67 (s, 1 H), 6.50 (broad, 1 H),) 5.27 (d,J= 11.9 Hz, IH), 5.22 (dd,J= 11.7,1 H), 4.63,(m,3H) 4.17 (ra, 4 H), 3.92 (s, 3 H), 3.66 (s, 3 H); MS (ES"): 488.3 117g -ch3 -OBn -CHO ^^CF3 3f+ 116a D-2 'HNMR (CDC13): 8 9.50 (s, 1 H), 8.40 (d, J=2.1 Hz, 1 H), 8.04 (dd, J— 8.1,2.1 Hz, 1 H), 7.57 (s, 1 H), 7.48 (m, 2 H), 7.38 (in, 3 H), 6.67 (s, 1 H), 6.50 (broad, 1 H), 5.27 (d,J= 11.9 Hz, 1 H), 5.22 (dd, J= 11.7,2 H), 4.17 (m, 2 H), 3.92 (s, 3 H), 3.66 (s, 3 H); MS (ES"): 500 205 Cpd. No.
-R -R' -R" -R,M Starting From Method Used Analytical Data 117b -CH3 -OBn -CHO 3e + 116a D-2 !HNMR (CDC13): 5 9.56 (s, 1 H), 8.34 (d, J= 1.7 Hz, 1 H), 8.01 (dd, /= 7.9,1.9 Hz; 1 H), 7.57 (s, IH), 7.50 (dd, .7=7.2, 1.5,2 H), 7.40 (m, 4 H), 6.67 (s, 1 H), 6.21 (broad, 1H), 5.24 (d, J =2.8 Hz, 2 H), 3.92 (s, 3 H), 3.65 (s, 3 H), 3.52 (m, 2 H), 1.65 (xn, 2 H), 1.46 (m, 2 H), 0.99 (t, J = 7.3 Hz, 3 H). 117i -ch3 -OBn -CHO 3g + 116a D-2 'HNMR (CDCI3): 5 9.57 (s, 1 H), 8.37 (d, J~ 1.9 Hz, 1 H), 8.03 (dd, J= 7.9,1.9 Hz, 1 H), 7.58 (s, 1 H), 7.50 (d, J= 12 Hz, 2 H), 7.38 (m, 3 H), 6.68 (s, 1 H), 6.33 (broad, 1 H), 5.26 (d, J= 11.5 Hz, IH), 5.21 (d, J= 11.9 Hz, 1 H), 3.92 (s, 3 H), 3.65 (s, 3 H), 3.37 (dd, J= 12,5.3 Hz, 2 H), 1.09 (m, 1 H), 0.60 (m, 2 H), 0.32 (in, 2 H); MS (esi: 474.2 H7j -ch3 -OBn -CHO -o 3h + 116a D-2 'H NMR (CDCI3): 8 9.55 (s, 1 H), 8.32 (d, 7= 1.9 Hz, IH), 8.00 (dd, 7 = 1.9 and 7.9 Hz, 1 H), 7.59-7.30 (in, 7 H), 6.67 (s, 1 H), 5.23 (m, 2 H), 4.45 (q,J= 7.0 Hz, 1 H), 3.91 (s, 3 H), 3.64 (s, 3 H), 2.21-1.46 (m, 8 H); MS (ES4): 510.3 (M + Naf 206 Cpd. No.
-R -R' -R" -R"' Starting From Method Used Analytical Data 117k -ch3 -OBn -CHO 3i + 116a D-2 'H NMR (CDC13): 8 9.56 (s, 1 H), 8.35 (d, J= 1.9 Hz, 1 H), 8.02 (dd,7= 1.9 and 7.9 Hz, 1 H), 7.58-7.33 (m, 7 H), 6.68 (s, 1 H), 5.24 (m, 2 H), 3.92 (s, 3 H), 3.65 (s, 3 H), 3.56 (m, 2 H), 1.30 (t, 7= 7.2 Hz, 3 H); MS (ES4): 470.3 (M+Naf 1171 -ch3 .-OBn -CHO 9h3 3j + 116a D-2 lH NMR (CDC13): 8 9.56 (s, 1 H), 8.35 (d,/= 1.9 Hz, IH), 8.02 (dd, 7= 1.9 and 7.9 Hz, 1 H), 7.58-7.33 (xn, 7 H), 6.68 (s, 1 H), 5.24 (in, 2 H), 3.92 (s, 3 H), 3.65 (s, 3 H), 3.40 (m, 2 H), 1.80-0.94 (in, 9 H); MS (ES*): 512.2 (M+ Na)+ 117m o x -OBn -CHO ch, 6a + 115d D-6 'HNMR (DMSO-d6): 8 9.73 (s, 1 H), 8.86 (t, J = 5.7 Hz, 1 H), 8.52 (d, J = 1.5 Hz, 1 H), 8.22 (dd, J = 8 and 2 Hz, 1 H), 7.79 (s, 1 H), 7.60 (d, J « 8 Hz, 1 H), 7.5 (m, 5 H), 7.22 (s, IH), 5.35 (q, J = 11 and 17 Hz, 1 H), 3.70 (s, 3 H), 3-23 (t, J = 6.5 Hz, 2 H), 1.98 (m, 1 H), 1.3 (s, 9 H), 1.01 (d, J = 6.8 Hz, 6 H); MS (ES4): 546.4 118a -CH3 -OBn -co2h ch3 ^^^ch3 117a E MS (ES"): 490.2 207 ■ Cpd. No.
-R -R' -R" _r»> Startmg From Method Used Analytical Data 118b -C2H5 -OBn -co2h ch, 117b E MS (ES> 504.2 118c -ch(ch3)2 -OBn -co2h 9h3 ^^CH3 117c E .
MS (ES-): 518.2 118d -ch3 -OBn -co2h CR3 117d E Characterized in the next step 118e -ch3 -OBn -co2h y—CH3 117e E MS (ES4): 534.3 118f -ch3 -OBn -co2h 117f E MS (ES4): 506.3 nsg -ch3 -OBn -cozh /^xcf3 U7g E Characterized in the next step 118b -ch3 -OBn -co2h 117h E MS (ES-1): 490.2 118i -ch3 -OBn -co2h 117i E MS (ES"1): 488.3 208 Cpd. No.
-R -R' -R" -R"' Startmg From Method Used Analytical Data 118j -ch3 -OBn -co2h 117j E *H NMR (DMSO-dd): 8 12.19 (br s, 1 H), 8.50 (d, J= 7.4 Hz, 1 H), 8.31 (d,J= 1.9 Hz, IH), 8.02 (dd, /= 1.7 and 7.9 Hz, 1 H), 7.58-7.29 (m, 7 H), 6.71 (s, 1 H), 5.17 (s, 2 H), 4.27 (q, /= 6.4 Hz, 1 H), 3.80 (s, 3 H), 3.57 (s, 3 H), 1.97-1.51 (m, 8 H) 118k -ch3 -OBn -co2h 117k E MS (ES"): 462.3 1181 -ch3 -OBn „v -co2h ch3 1171 E 'H NMR (CDC13): 8 8.30 (d, J-1.9 Hz, 1.H), 7.95 (dd, 7= 1.7 and 7.9 Hz, 1 H), 7.66 (s, 1 H), 7.52-7.27 (m, 6 H), 6.62 (s, 1 H), 6.49 (m, 1 H), 5.21 (s, 2 H), 3.88 (s, 3 H), 3.61 (s, 3 H), 3.38 (m, 2 H), 1.79-0.94 (m, 9 H); MS (ES"): 504.4 118m x -OBn -co2h ch, 117m E Characterized in the next step 119a -CH3 -OBn -co2mem ch, \^ch3 118a f MS (ES"): 578.3 119b -c2h5 -OBn -co2mem ch, x^/^ch3 118b f MS (ESI: 592.3 209 Cpd. No.
-R -R' -R" -R"* Starting From Method Used Analytical Data 119c -ch(ch3)2 -OBn -coamem cb, 118c f ms (eso: 606.3 119d -ch3 -OBn -CO2MEM 118d f ms (es"): 564.2 119e -ch3 -OBn -CO2MEM ^ 118e ' f ms (es"): 620.1 1191 -ch3 -OBn -CO2MEM 118f f ms (es-): 592.3 119g -ch3 -OBn -CO2MEM ^^CF3 118g f Characterized in the next step 119h -ch3 -OBn -c02mem 118b f 'HNMR (CDCI3): 8 8.32 (d; J-= 1.9 Hz, IH), 7.96 (dd, J= 7.9, 1.9Hz, IH),7.68 (s,lH),7.50 (m, 2 H), 7.35 (m, 4 H), 6.62 (s, 1 H), 6.33 (t, J= 5.4 Hz, 1 H), 5.24 (m, 4 H), 3.88 (s, 3 H), 3.63 (s, 3 H), 3.46 (m, 6 H), 3.34 (s, 3 H), 1.63 (m, 2 H), 1.44 (m, 2 H), 0.98 (t, J= 7.3 Hz, 3 H) 210 Cpd. No. -r -r* -r" -r»< Starting From Method Used Analytical Data 119i -ch3 -OBn -co2mem 1181 F 'HNMR (CDC13): 6 8.34 (d, J= 1.9 Hz, 1 H), 8.00 (dd,J=7.9, 2.1 Hz, 1 H), 7.68 (s, 1 H), 7.50 (m, 2 H), 7.36 (m, 4 H), 6.63 (s, 1 H), 6.42 (broad, 1 H), 5.24 (m, 4 H), 3.89 (s, 3 H), 3.64 (s, 3 H), 3.45 (s, 3 H), 3.35 (m, 5 H), 1.07 (m, 1 H), 0.58 (m, 2 H), 0.30 (m, 2H) U9j -ch3 -OBn -co2mem -0 118J F !H NMR (DMSO-^): 8 8.55 (d, /= 7.4 Hz, 1 H), 8.39 (d, /= 1.9 Hz, 1 H), 8.10 (dd, J= 1.7 and 7.9 Hz, 1 H), 7.63-7.35 (m, 7 H), 6.81 (s, 1 H), 5.25-5.12 (m, 4 H), 4.31 (q, J= 6.4 Hz, 1 H), 3.86 (s, 3 H), 3.62 (s, 3 H), 3.3 (s, 3 H), 3.23 (s, 3 H) 1.99-1.53 (m, 8 H); MS (ES4): 614.3 (M+Na)4 119k -ch3 -OBn -COzMEM •^^CH3 118k F 'H NMR (DMSO-4s): 8 8.70 (t, J—5.5 Hz, 1 H), 8.35 (d, J= 1.9 Hz, 1 H), 8.05 (dd, 7= 1.7 and 7.9 Hz, 1 H), 7.59-7.30 (m, 7 H), 6.77 (s, 1 H), 5.21-5.08 (m, 4 H), 3.82 (s, 3 H), 3.58 (s, 3 H), 3.40-3.29 (m, 6 H), 3.18 (s, 3 H), 1.14 (t, J= 12 Hz, 3 H); MS (ES4): 574.3 (M+Na)4 211 Cpd. No. -r -r' -r" -r1" Starting From Method Used Analytical Data 1191 -ch3 -OBn -co2mem ch, 1181 f 'H NMR (DMSO-4;): 8 8.68 (t, J=5.8 Hz, 1 H), 8.35 (d, ./= 1.9 Hz, 1 H), 8.05 (dd, /= 1.7 and 7.9 Hz, 1H), 7.63-7.33 (m, 7 H), 6.77 (s, 1 H), 5.22-5.08 (m, 4 H), 3.82 (s, 3 H), 3.58 (s, 3 H), 3.39-3.22 (xn, 6 H), 3.18 (s, 3 H), 1.56 (qui, J= 7.0 Hz, 2 H), 1.27 (m, 1 H), 0.94-0.75 (m, 6 H); MS (ES4): 616.3 (M+Na)+ 119m 0 x ^c(ch3)3 -OBn -co2mem ch3 \^ch3 118m f 'HNMR (DMSO-d6): 8 8.72 (t, J = 5.6 Hz, 1 H), 8.38 (d, J = 1.8 Hz, 1H), 8.70 (dd, J = 1.8 and 8.1 Hz, 1 H), 7.71 (s, 1H), 7.40 (m, 6 H), 7.02 (s, 1 H), 5.20 (in, 4 H), 3.59 (s, 3 H), 3.37 (m, 2 H), 3.31 (m, 2 H), 3.17 (s, 3 H), 3.12 (t, J = 6.5 Hz, 2 H), 1.87 (m, 1 H), 1.21 (s, 9 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES+): 650.4 and 672.3 (M+Na)+ 120a -ch3 -OH -co2mem ch3 ^^ch3 119a g MS (ES"): 488.1 120b -C2hs -OH -co2mem ch3 119b g MS (ES"): 502.2 212 Cpd. No.
-R -R' -R" ~R"' Starting From Method Used Analytical Data 120c -ch(ch3)2 -oh -COzMEM ch3 \^ch3 119c G ms (es"): 516.3 120d -ch3 -oh -co2mem ch3 /"^CH3 119d G ms (es-): 474.3 120e -CHj -oh -coiMEM y chj ^ ^^chj 119e G ms (es-): 530.4 120f -ch3 -oh -coamem 119f G MS (ESO: 502.3 120g -ch3 -oh -C02MEM /^cf3 119g G Characterized in the next step 120h -ch3 -oh -C02MEM /^x/^ch3 119h G Characterized in the next step 120i -ch3 -oh -co2mem 119i G MS (ESy. 486.3 120j -ch3 -oh -co2mem -0 119j G MS (ES4): 524.3 (M+ Na)+ 120k -ch3 -oh -co2mem ^~^ch3 119k G MS (ES4): 484.2 (M+ Na)4 213 Cpd. No.
-R -R? -R" -R'" Starting From Method Used Analytical Data 1201 -ch3 -OH -COzMEM chj 1191 G MS (ES^: 502.3 120m x -^^c(ch3)3 -OH -CO2MEM 119m G 'HNMR (DMSO-d6): 8 10.83 (bs, IH), 8.77 (t, J = 5.6 Hz, IH), 8.42 (d, J = 1.8 Hz, 1H), 8.12 (dd, J = 1.8 and 8.1 Hz, 1 H), 7.68 (s, 1 H), 7.41 (d, J = 8.1 Hz, 1 H), 6.73 (s, 1 H), 5.21 (q, J = 21 and 6 Hz, 2 H), 3.65 (s, 3 H), 3.48 (m, 2 H), 3.37 (m, 2 H), 3.24 (s, 3 H), 3.18 (t, J = 6.5 Hz, 2 H), 1.94 (xn, 1 H), 1.39 (s, 9 H), 0.97 (d, J = 6.8 Hz, 6 H); MS (ES+): 560.5 and 582.4 (M+ Na)+, (ES-) 558.4 121a -ch3 -oso2cf3 -CO2MEM ch, 120a B-2 MS (ES4): 644.1 (M+Na)+ 121b -C2H5 -oso2cf3 -CO2MEM ch3 \^CH. 120b B-2 MS (ES4): 658.2 (M+Na)+ 121c -CH(CH3)2 -OSO2CF3 -COzMEM ch3 \^ch3 120c B-2 MS (ES4): 672.2 (M+Na)+ 214 Cpd. No.
-R -R' -R" -R*" Starting From Method Used Analytical Data 121d -ch3 -OSO2CF3 -COzMEM ch3 ^"ch3 120d B-2 'HNMR (DMSO-de): 6 8.43 (d, J — 1.9 Hz, 1 H), 8.31 (s, 1 H), 8.12 (d, J = 1.69Hz, l.H),7.98 (s, 1 H), 7.41 (d, J = 8.1 Hz, 1 H), 7.19 (s, 1 H), 5.20 (m, 2 H), 3.98 (m, 1 H), 3.94 (s, 3 H), 3.42 (s, 3 H), 3.19 (s, 3 H), 2.50 (m, 2 H), 1.08 (d, J = 6.59, 6 H); MS (ES+) 608.3 121e -ch3 -oso2cf3 -CO2MEM /—ch3 120e B-2 'HNMR (DMSO-de): 5 8.49 (s, 1 H), 8.34 (d, J = 1.8 Hz, 1 H), 8.2 (d, J = 1.8 Hz, 1H), 7.97 (s, 1 H), 7.4 (d, J = 7.8 Hz, 1 H), 7.2 (s, 1 H), 5.2 (q, J - 6 and 10 Hz, 2 H), 4.0 (m, 3 H), 3.6 (s, 3 H), 3.4 (m, 4 H), 3.2 (s, 3 H), 1.5 (m, 4 H), 1.3 (m, 4 H), 0.85 (m, 6 H); MS (ES+): 664.3 121f -ch3 -oso2cf3 -co2mem 120f B-2 'HNMR (DMSO-de): 5 8.83 (d, J - 5.46,1 H), 8.55 (d, J = 1.88 Hz, 1 H), 8.23 (dd, J = 1.88 Hz, 1 H), 8.19 (s, 1 H), 7.73 (d, J = 7.93 Hz, 1 H), 7.29 (s, 1 H), 5.29 (dd, J = 6.217 Hz, 2 H), 4.06 (s, 3 H), 3.71 (s, 2 H), 3.54 (m, 5 H), 2.62 (t, J = 3.57 Hz, 3 H), 1.66 (t, J = 6.59 Hz, 2 H), 1.42 (m, 6 H), 0.99 (t, J = 6.79 Hz, 3 H); MS (ES+) 636.6 215 Cpd. No. -r -r* -r" -r"' Starting From Method Used Analytical Data 121g -ch3 -oso2cf3 -C02MEM /^cf3 120g B-2 !HNMR (CDCI3): 5 8.43 (d,«/= 1.9 Hz, 1 H), 8.03 (dd, .7=7.9 Hz, 2.1 Hz, 1 H), 8.00 (s, 1 H), 7.35 (d, J— 7.9 Hz, 1 H), 6.79 (m, 2 H), 5.29 (d, J= 6.2 Hz, 1 H), 5.26 (d, J=6.2 Hz, 1H), 4.16 (m, 2 H), 3.94 (s, 3 H), 3.67 (s, 3 H), 3.48 (m, 4 H), 3.36 (s, 3 H); MS (ES"): 646.3 121h -ch3 -oso2cf3 -c02mem 1201.
B-2 'HNMR (CDC13): 8 8.41 (s, 1 H), 7.96 (d, J = 8.3 Hz, 2 H), 7.8 (m, 1 H), 6.80 ( s, 1 H), 6.34 (m, IH), 5.32 (m, 2 H), 3.90 (s, 3 H), 3.66 (s, 3 H), 3.55 (m, 6 H), 3.4 (s, 3 H), 1.7 (m,.2H), 1.45 (m3 2 H), 0.98 (t, J = 7.3 Hz, 3 H); MS (ES-): 620 1211 -ch3 -0s02cf3 -co2mem 120i B-2 'HNMR (CDC13): 8 8.41 (d, J= 2.1 Hz, 1 H), 8.03 (dd, J= 7.9, 1.9 Hz, 1 H), 8.00 (s, 1 H), 7.32 (d, 7 = 7.9 Hz, 1 H), 6.43 (t, J= 4.9 Hz, 1 H), 5.30 (q, J= 6.0 Hz, 2 H), 3.94 (s, 3 H), 3.67 (s, 3 H), 3.55 (m, 2 H), 3.48 (m, 2 H), 3.35 (m, 5 H), 1.09 (m, 1 H), 0.59 (m, 2 H), 0.31 (m, 2 H); MS (ES"): 618.4 21S Cpd. No.
-R -R' -R" -r'» Starting From Method Used Analytical Data 121j -ch3 -oso2cf3 -co2mem -0 120J B-2 'H NMR (cdci3): 8 8.35 (d, J= 1.9 Hz, 1 H), 8.00 (m, 2 H), 7.31 (d, J= 7.9 Hz, 1 H), 6.77 (s, 1 H), 6.27 (m, 1H), 5.28 (m, 2 H), 4.44 (q, /= 7.0 Hz, 1 H), 3.94 (s, 3 H), 3.66 (s, 3 H), 3.57-3.45 (m, 4 H), 3.35 (s, 3 H), 2.19-1.45 (m, 8 H); MS (ES4): 656.3 (M+Naf 121k -ch3 -oso2cf3 -COzMEM 120k B-2 ''H NMR (cdci3): 8 8.38 (s, 1 H), 8.00 (m, 2 H), 7.31 (d, J =7.9 Hz, 1 H), 6.78 (s, 1 H), 6.37 (m, 1 H), 5.27 (m, 2 H), 3.94 (s, 3 H), 3.66 (s, 3 H), 3.59-3.43 (m, 6 H), 3.35 (s, 3 H), 1.28 (t, J= 7.2 Hz, 3 H); MS (ES4): 616.3 (M+Na)4 1211 -ch3 -oso2cf3 -COzMEM ch3 1201 B-2 'H NMR (cdci3): 5 8.38 (s, 1 H), 8.00 (m, 2 H), 7.31 (d, J= 7.9 Hz, 1 H), 6.78 (s, 1 H), 6.37 (in, 1 H), 5.27 (m, 2 H), 3.94 (s, 3 H), 3.66 (s, 3 H), 3.57-3.25 (m, 9 H), 1.78-0.92 (m, 9 H); MS (ES4): 658.4 (M+Naf 217 Cpd. No.
-R -R' -R" -R1" Starting From Method Used Analytical Data 121m V- 1 I -oso2cf3 -COaMEM CH3 121m B-2 'HNMR (DMSO-de): 5 8.75 (t, I = 5.6 Hz, 1H), 8.45 (d, J = 1.8 Hz, IH), 8.11 (dd, J = 1.8 and 8.1 Hz, 1 H), 8.04 (s, 1 H), 7.57 (s, 1 H), 7.42 (d, J = 8.1 Hz, 1 H), 5.23 (q, J = 21 and 6 Hz, 2 H), 3.60 (s, 3 H), 3.41 (m, 2 H), 3:32 (m, 2 H), 3.17 (s, 3 H), 3.13 (t,J = 6.5 Hz, 2 H), 1.87 (m, 1 H), 1.37 (s, 9 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES-): 690.4 122a -ch3 -ch=ch2 -co2mem CH3 121a D-3 Characterized in the next step 122b -c2h5 -ch=ch2 -COaMEM ch, \^ch3 121b D-3 MS (ES+): 536.3 (M+Na)+ 122c -CH(CH3)2 -ch=ch2 -COaMEM ch, 121c D-3 MS (ES1): 550.3 (M+Na)4" 122d -ch3 -ch=ch2 -COaMEM ch3 ^ch, I21d D-3 MS (ES"*): 486.2 122e -ch3 -ch=ch2 -co2mem / chj ^^ ^ch. 121e D-3 MS (ES"1): 564.5 (M+Na)+ 228 Cpd. No.
-R -R1 -R" -R»" Starting From Method Used Analytical Data 122f -ch3 -ch=ch2 -co2mem 121f d-3 MS (ES"1): 514.4 (M+Na)+ 122g -ch3 -ch=ch2 -co2mem ^"cf3 121g d-3 Characterized in the next step 122h -ch3 -ch=ch2 -co2mem 121h d-3 Characterized in the next step 122i -ch3 -ch=ch2 -co2mem 1211 d-3 Characterized in the next step 122j -ch3 - -ch=ch2 -co2mem 121j d-3 MS (ES"): 422.3 [(M-MeM)-l] 122k -ch3 -ch=ch2 -co2mem 121K d-3 MS (ES+): 494.2 (M+Na)+ 1221 -ch3 -ch=ch2 -co2mem ch3 1211 d-3 MS (ES+): 536.42 (M+Na)+ 219 Cpd. No.
-R -R' -R" -R'" Starting From Method Used Analytical Data 122m O x ^^C(CH3)3 -CH=CH2 -co2mem ch3 ^^ch3 121m D-3 'HNMR (DMSO-d6): 8 8.73 (t, J = 5.6 Hz, 1 H), 8.43 (d, J = 1.8 Hz, IH), 8.11 (dd, J =1.8 and 8.1 Hz, 1 H), 7.61 (s, 1 H), 7.57 (s, 1 H), 7.42 (d, J = 8.1 Hz, 1 H), 6.72 (dd, J = 11 and 17.5 Hz, 1 H), 6.03 (d, J = 17.5 Hz, 1 H), 5.52 (d, J = 11 Hz, 1 H), 5.19 (q, J = 18 and 6 Hz, 2 H), 3.60 (s, 3 H), 3.41 (m, 2 H), 3.32 (m, 2 H), 3.18 (s, 3 H), 3.13 (t, J = 6.5 Hz, 2 H), 1.89 (m, 1 H), 1.38 (s, 9 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES-): 480.4 r(M-MEM)-ll 123a -ch3 -ch=ch2 co2h ch3 122a I-l MS (ES'): 410.2 123b -c2h5 -ch=ch2 COzH ch3 122b I-l MS (ES"): 424.2 123c -CH(CH3)2 -ch=ch2 co2h ch3 122c I-l MS (ESO: 438.2 123d -ch3 -ch=ch2 COzH ch3 -^^ch3 122d I-l MS (ES"): 396.2 220 Cpd. No. 123e -R -ch3 -R' -ch=ch2 -R" co2h -R" ch, Starting From 122e Method Used I-l Analytical Data MS (ES+): 454.3 123f -CH3 -ch=ch2 co2h 122f I-l MS (ES4): 426.3 123g -ch3 -ch=ch2 co2h cf, 122g I-l 'HNMR (DMSO): 8 12.37 (s, 1 H), 9.35 (t, 7= 6.0 Hz, 1 H), 8.42 (d, 7= 1.7 Hz, 1 H), 8.10 (dd, 7= 8.1 Hz, 1.9 Hz, 1 H), 8.06 (s, 1 H), 7.40 (d, 7= 7.9 Hz, 1 H), 6.98 (dd, 7= 17.9,11.5 Hz, 1 H), 6.77 (s, 1 H), 5.89 (dd, 7= 17.7, 1.3 Hz, IH), 5.37 (dd, 7=11.1, 1.3 Hz, 1 H), 4.14 (m, 2 H), 3.84 (s, 3 H), 3.61 (s, 3 H); MS (ES"): 436.3 123h -CH3 -ch=ch2 co2h ^CHj 122h I-l 'HNMR (DMSO): 8 8.66 (t, 7= 5.5 Hz, 1 H), 8.35 (d, 7= 1.7 Hz, 1 H), 8.05 (s, 1 H), 8.03 (dd, 7= 8.1,1.9 Hz, 1 H), 7.34 (d, 7= 7.9 Hz, 1 H), 6.98 (dd,J= 17.9,11.3 Hz, 1 H), 6.75 (s, 1 H), 5.88 (dd, 7=17.7,1.3, IH), 5.36 (dd,7= 11.3, 1.3 Hz, IH), 3.84 (s, 3 H), 3.60 (s, 3 H), 3.30 (q, 7= 5.6 Hz, 2 H), 1.52 (m, 2 H), 1.33 (m, 2 H), 0.96 (t, 7= 7.3 Hz, 3 H); MS (ES"): 410.4 221 Cpd. No.
-R -R' -R" -R"' Starting From Metbod Used Analytical Data 123i -ch3 -ch=ch2 COzH 122i I-l 'HNMR (DMSO): 5 12.34 (s, 1 H), 8.80 (t, 7= 6.1 Hz, 1 H), 8.37 (d, 7= 1.9 Hz, 1 H), 8.06 (dd, 7= 9.8, 7.9 Hz, 1 H), 8.05 (s, 1 H), 7.36 (d, 7= 7.9 Hz, 1 H), 6.98 (dd, 7= 17.9,11.3 Hz, 1 H), 6.76 (s, 1H), 5.89 (dd, 7= 17.9,1.5 Hz, 1 H), 5.36 (dd, 7= 10.9,1.5 Hz, 1 H), 3.84 (s, 3 H), 3.60 (s, 3 H), 3.18 (t, 6.2,2 H), 1.06 (m, 1 H), 0.45 (m, 2 H), 0.25 (m, 2 H); MS (ES"): 408.4 123j -ch3 -ch=ch2 co2h -O 122] I-l 'H NMR (DMSO-rftf): 612.31 (br s, 1 H), 8.52 (d, 7=7.3 Hz, 1 H), 8.34 (d, 7= 1.7 Hz, 1 H), 8.05 (m, 2 H), 7.34 (d, 7= 7.9 Hz, 1 H), 6.97 (dd, 7= 11.5 and 17.9 Hz, 1 H), 6.74 (s, 1 H), 5.89 (d, 7= 17.9 Hz, 1 H), 5.37 (d, 7= 11.5Hz, IH),4.27(q,7= 7.3 Hz, 1 H), 3.84 (s, 3 H), 3.60 (s, 3 H), 1.98-1.50 (m, 8 H); MS (ES"): 422.3 123k -ch3 -ch=ch2 co2h /^CH3 122k I-l "H NMR (DMSO-<&): 512.27 (brs, 1 H), 8.58 (m, 1 H), 8.23 (s, IH), 7.92 (m, 2 H), 7.47 (m, 1 H), 7.22 (m, 1 H), 6.84 (m, 1 H), 6.63 (s, 1 H), 5.76 (d, 7= 17.9 Hz, 1 H), 5.24 (d, J- 11.5 Hz, 1 H), 3.71 (s, 3 H), 3.47 (s, 3 H), 1.02 (m, 3 H); MS (ES"): 382.2 222 Cpd. No. 1231 -R -R' -R" -R"' Starting From Metbod Used Analytical Data -ch3 -ch=ch2 co2h ch3 1221 I-l !H NMR (DMSO-^s): 512.30 (br s, 1 H), 8.52 (d, 7= 6.0 Hz, 1 H), 8.33 (d, J= 1.7 Hz, 1 H), 8.02 (m, 2 H), 7.31 (d, 7=7.9 Hz, 1 H), 6.95 (dd, J= 11.5 and 17.9 Hz, IH), 6.73 (s, 1 H), 5.86 (d, J= 17.9 Hz, 1 H), 5.33 (d, J= 11.5 Hz, 1 H), 3.81 (s, 3 H), 3.57 (s, 3 H), 3.14 (m, 2 H), 1.65 (m, 1 H), 1.39 (m, 1 H), 1.11 (m, 1 H), 0.87 (m, 6 H) 123m x ^^c(ch3)3 -ch=ch2 -co2h ch3 ^Nh3 122m I-l 'HNMR (DMSO-dfi): 512.81 (bs, IH), 8.72 (t, J = 5.6 Hz, 1 H), 8.38 (d, J = 1.8 Hz, 1 H), 8.08 (dd, J =1.8 and 8.1 Hz, 1 H), 7.61 (s, 1 H), 7.57 (s, 1 H), 7.39 (d, J = 8 Hz, 1 H), 6.72 (dd, J = 11 and 17.5 Hz, 1 H), 5.99 (d, J = 17.5 Hz, 1 H), 5.49 (d, J -11 Hz, 1 H), 3.57 (s, 3 H), 3.13 (t, J = 6.5 Hz, 2 H), 1.87 (m, 1H), 1.37 (s, 9 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES-): 480.3 223 nhr" r'02c' Cpd. No.
-R -R' R" Starting From Method Used Analytical Data 124a -ch3 -ch3 ch3 123a J MS (ES+): 529.3 124b -c2h5 -ch3 ch, \>-ch3 123b J MS (ES4): 543.3 124c -ch(ch3)2 -ch3 ch, 123c J MS (ES4): 557.3 124d -ch3 -ch3 ch, ^^ch3 123d J Characterized in the next step 124e -CHs -ch3 / ch, ^ 123e J MS (ES4): 571.6 224 Cpd. No.
-R -R' -ch3 R" Starting From Method Used Analytical Data 124f -ch3 123f J MS (ES4): 543.6 124g -ch3 -ch3 ^CP3 123g J 'HNMR (DMSO): 5 10.62 (s, 1 H), 9.35 (t,/= 6.6 Hz, 1 H), 9.20 (s, 2 H), 8.90 (s, 2 H), 8.30 (d, J= 1.9 Hz, 1 H), 8.11 (dd, J= 8.1,1.9 Hz, 1 H), 7.86 (s, 1 H), 7.76 (s, 4 H), 7.50 (d, J= 8.1 Hz, 1 H), 7.04 (dd, J= 17.9,11.5 Hz, 1 H), 6.94 (s, 1 H), 6.01 (dd, J= 17.7,1.3, 1 H), 5.42 (dd, J= 11.3,1.3 Hz. 1H), 4.11 (m, 2 H), 3.89 (s, 3 H), 3.57 {s, 3 H) 124h -ch3 -ch3 123h J 'HNMR (DMSO): 8 9.03 (broad, 3 H), 8.49 (broad, 1 H), 8.04 (s, 1 H), 7.65 (m, 6 H), 6.99 (m, 2 H), 6.61 (s, 1 H), 5.90 (d, J= 17.5 Hz, 1 H), 5.35 (d,7= 11.5 Hz, 1 H), 3.78 (s, 3 H), 3.20 (m, 2 H), 1.46 (m5 2 H), 1.28 (m, 2 H), 0.87 (t, J= 7.3 Hz, 3 H) 124i -ch3 -CHj 123i J MS (ES4): 527.4 t 124j -ch3 -ch3 123j J MS (ES4): 541.4 124k -ch3 -ch3 -^~^ca2 123K J MS (ES4): 501.3 1241 -ch3 -CHj ch3 1231 J MS (ES4): 543.3 225 Cpd. No. -r -r' r" Starting From Metbod Used Analytical Data 124m x -ch3 ch3 123m j 'HNMR (DMSO-d6): 8 10.67 (s, IH), 9.19 (bs, 2 H), 8.88 (bs, 2 H), 8.71 (t, J = 5.6 Hz, 1 H), 8-25 (d, J = 1.8 Hz, 1 H), 8.07 (dd, J = 1.8 and 8.1 Hz, 1 H), 7.73 (m, 4 H), 7.65 (s, 1 H), 7.50 (d, J = 8 Hz, 1 H), 7.45 (s, 1 H), 6.73 (dd, J = 11 and 17.5 Hz, 1 H), 6.03 (d, J = 17.5 Hz, 1H), 5.49 (d, J = 11 Hz, 1 H), 3.56 (s, 3 H), 3.09 (t, J = 6.5 Hz, 2 H), 1.85 (m, 1 H), 1.37 (s, 9 H), 0.89 (d, J = 6.8 Hz, 6 H); MS (ES-): 597.3 and (ES+) 599.5 125a -ch3 -h ch3 124a 1-2 'HNMR (DMSO): 5 13.40 (bs, IH), 9.26 and 9.03 (2s, 4H), 8.53-8.49 (t, J = 6 Hz, IH), 8.02 (d, 7=1.28 Hz, IH), 7.71-7.53 (m, 6H), 7.0-6.9 (m, 2H), 6.5 (s, IH), 5.89 (d, 7=17.6 Hz, IH), 5.33 (d, 7=12.4 Hz, IH), 3.77 (s, 3H), 3.04-2.99 (m, 2H), 1.85-1.75 (m, IH), 0.86-0.84 (d, 7=76.8 Hz, 6H); MS (ES*): 515.3 125b -c2h5 -H ch3 124b 1-2 'HNMR (DMSO): 8 9.17 and 8.92 (s, 3H), 8.67-8.63 (m, IH), 8.28 (s, IH), 7.95-7.93 (m, IH), 7.83 (s, IH), 7.73 (s, 5H), 7.29 (d, 7-8.1 Hz, IH), 7.02 (dd, 7=17.7 Hz, 11.3 Hz, IH), 6.82 (s, IH), 6.00 (d, 17.7 Hz, IH), 5.38 (d, 11.3 Hz, IH), 4.14-4.06 (m, 2H), 3.11-3.04 (q, 7=6.8 Hz, 2H), 1.89-1.80 (m, IH), 1.35 (t, 7=6.8 Hz, 3H), 0.88 (d, 7=6.8 Hz, 6H); MS (ES+): 529.2 125c -CH(CH3)2 -H CH, 124c 1-2 1HNMR (DMSO): 8 13.74 (s, IH), 8.99 (s, 3H), 8.59-8.41 (m, IH), 7.95 (s, IH), 7.69 (s, IH), 7.65- 7.53 (m, 6H), 7.06-6.91 (m, 2H), 6.53 (s, IH), 5.89 (d, 7=17.7 Hz, IH), 5.32 (d, 7=11.5 Hz, IH), 4.62- 4.54 (m, IH), 3.03-2.99 (m, 2H), 1.87-1.71 (m, IH), 1.25 (d, 7=6.1 Hz, 6H), 0.85 (d, 7=6.8 Hz, 6H); MS (ES"): 541.2 226 Cpd. No.
-R -R' R" Starting From Method Used Analytical Data 125d -ch3 -H ch3 ^ch3 124d 1-2 'HNMR (DMSO-de): 8 8.9 (d, J = 33.74,4 H), 8.08 (d, J = 7.91,1 H), 7.81 (s, 1 H), 7.51 (s, 1 H), 7.4l(s, 4 H), 6.78 (s, 1 H), 6.3 (s, 2 H), 5.70 (d, J = 7.78 Hz, 1 H), 5.15 (d, J = 11.8 Hz, 2 H),) 3.82 (m, J = 20.34 Hz, 2 H), 3.56 (bs, 3 H) 0.92 (d, 6H); MS (ES+) 501.3 125e -ch3 -h / CH3 124e 1-2 'HNMR (DMSO-de): 8 9.05 (s, 2 H), 8.85 (s, 2 H), 7.96 (d, J = 9.04 Hz, 1 H), 7.88 (s, 1 H), 6,86 (m, J = 17.8 Hz, 3 H), 7.62 (m, 1 H), 7.24 (d, J = 7.8 Hz, 1 H), 6.95 (d, J = 7.8 Hz, 1 H), 7.45 (m, J = 28.63 Hz, 5 H), 7.55 (s, 1 H), 5.75 (d, J = 17.5 Hz, 1 H); 5.61 (d, J= 11.11, 1 H) 3.61(s, 3H) 1.30 (bs, 3 H) 1.05 (s, 4 H) 0.66 (m, 6 H); MS (ES+) 555.3(100% M4"') 125f -ch3 -H 124f 1-2 'H NMR (DMSO-de): S 12.7 (bs, IH), 9.01 (bs, 2H), 8.87 (bs, 2H), 8.36 (t, J = 6 Hz, IH), 7.83 (s, IH), 7.44 (m, 6H), 6.75 (m, 2H), 6.31 (d, J = 2.2 Hz, IH), 5.7 (d, J -17 Hz, IH), 5.1 (d, J = 11 Hz, IH), 3.5 (s, 3H), 2.84 (m, 2H), 1.3 (m, 2H), 1.1 (m, 4H), 0.7 (tn, 3H); MS (ES+) : 529.4 125g -ch3 -h -^cF3 124g 1-2 'HNMR (DMSO): 8 9.22 (broad, 1 H), 9.09 (s, 2 H), 8.9 (s, 2 H), 8.18 (s, 1 H), 7.80 (m, 2 H), 7.66 (m, 4 H), 7.16 (s, 1 H), 7.00 (dd, J= 17.7,11.1 Hz, 1 H), 6.70 (s, 1 H), 5.94 (d, J= 17.7 Hz, 1 H), 5.37 (d, J= 10.9 Hz, 1 H), 4.07 (m, 2 H), 3.81 (s, 3 H); MS (ES") 539.3 Cpd. No.
-R -R' R" Starting From Method Used Analytical Data 125h -ch3 -h 124h 1-2 'HNMR (DMSO): 8 9.03 ( bs, 4 H), 8.49 (bs, 1 H), 8.04 (s, 1 H), 7.65 (m, 6 H), 6.99 (m, 2 H), 6.61 (s, 1 H), 5.90 (d, 7= 17.5 Hz, 1 H), 5.35 (d, J = 11.5 Hz, 1 H), 3.78 (s, 3 H), 3.20 (m, 2 H), 1.46 (m, 2 H), 1.28 (m, 2 H), 0.87 (t, 7= 7.3 Hz, 3 H); MS (ES"1) 515.4 125i -ch3 -H 124i 1-2 'HNMR (DMSO): 8 8.86 (s, 2 H), 8.78 (s, 2 H), 8.44 (broad, 1 H), 7.89 (s, 1 H), 7.53 (m, 2 H), 7.43 (m, 4 H), 6.86 (s, 1 H), 6.78 (dd, J= 17.5, 11.3 Hz, 1 H), 6.44 (s, IH), 5.71 (d,J= 17.5 Hz, 1 H), 5.14 (d, 7= 11.1 Hz, 1 H), 3.59 (s, 3 H), 2.89 (m, 2H), 0.79 (m, 1 H), 0.20 (m, 2 H), 0.01 (m, 2 H); MS (ES-) 513.4 125j -ch3 -H 124j 1-2 'HNMR (DMSO): 8 13.14 (br s, 1 H), 8.84 (m, 3 H), 8.12 (d, J= 7.3 Hz, 1 H), 7.79 (s, 1 H), 7.40 (m, 8 H), 6.74 (m, 2 H), 6.33 (s, 1 H), 5.66 (d, J= 19.2 Hz, 1 H), 5.10 (d, /= 11.7 Hz, 1H), 3.94 (m, 1 H), 3.54 (s, 3 H), 1.66-0.93 (m, 8 H); MS (ES4) 527.4 125k -ch3 -H /^•ch3 124k 1-2 'H NMR (DMSO): 8 9.25 (m, 4 H), 8.73 (t, J= 5.7 Hz, 1 H), 8.28 (s, 1 H), 7.86 (m, 7 H), 6.84 (s, I H), 6.10 (d, J = 17.7 Hz, 1 H), 5.55 (&,J= 11.3 Hz, 1 H), 3.99 (s, 3 H), 3.43 (qui, 6.2 Hz, 2 H), 1.28 (t, J= 7.2 Hz, 3 H); MS (ES4): 487.2 1251 -ch3 -H CH3 1241 1-2 'H NMR (DMSO): 8 8.91 (m, 4 H), 8.38 (t, J= 5.5 Hz, 1 H), 7.96 (s, 1H), 7.53 (m, 5 H), 6.86 (m, 2 H), 6.52 (s, 1 H), 5.77 (d, 7= 17.7 Hz, 1 H), 5.21 (d, J= 11.5 Hz, 1 H), 3.65 (s, 3 H), 2.94 (tn, 1 H), 1.57-0.56 (m, 11 H); MS (ES"): 529.3 Cpd. No.
-R -R' R" Starting From Method Used Analytical Data 125m -H -H ch3 124m 1-2 1HNMR (DMSO-de): 8 10.07 (bs, IH), 9.05 (bs, 2 H), 8.98 (bs, 2 H), 8.49 (t, J = 5.6 Hz, 1 H), 7.96 (s, 1 H), 7.62 (m, 5 H), 7.06 (s, 1 H), 7.03 (s, 1 H), 6.94 (dd, J = 11 and 18 Hz, 1 H), 5.78 (d, J -18 Hz, 1 H), 5.26 (d, J = 11 Hz, 1 H), 3.02 (t, J = 5.7 Hz, 2 H), 1.81 (xn, 1 H), 0.85 (d, J = 6.8 Hz, 6 H); MS (ES-): 499.2 and (ES^ 501.3 229 Cpd. No.
-R H ~ / \ -R' -h -R" -ch3 Starting From Method Used Analytical Data 133a 132 A-5 MS (ES4): 506.4 133b H ^~\ H -h -ch3 132 J MS (ES4): 499.3 133c cfj -h -ch3 132 A-5 Characterized in the next step 133d ^n—^ y~~ cfs -h -ch3 132 A-5 Characterized in the next step 133e -.-o- h -h -ch3 132 A-5 Characterized in the next step 230 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 133f cf, H -h -ch3 132 A-5 Characterized in the next step 133g cf3 ■ s-O -H I tS o , i 132 A-5 Characterized in the next step 133h -h -ch3 132 A-5 Characterized in the next step 133i -o -h -ch3 132 A-5 Characterized in the next step 133j -h -ch3 132 A-5 Characterized in the next step 133k -OO -h -ch3 132 J MS (ES"1"): 502.3 231 Cpd. No.
-R -R' -R" -ch3 Starting From 132 Method Used Analytical Data 1331 -h j ms (es+): 470.2 133m -rO -h -ch3 132 j ms (es4): 437.3 133n MXX -h -ch3 132 j ms (es4): 518.2 133o / \ N=r\ -h -ch3 132 j ms (es4): 501.3 133p \ ^-N N H -h -ch3 132 j ms (es"): 469.1 133q -h -ch3 132 j ms (ESy. 469.1; MS (es4): 471.2 133r H ~h -ch3 132 a-5 Characterized in the next step 232 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 133s \ i(y» i -h -chj 132 A-5 MS (ES"*): 483.2 (M+Na) 133u -H -ch3 132 A-5 MS (ES4): 432.2 133v \ '6 1 -H -ch3 132 A-5 MS (ES4): 432.2 133w OH -H -ch3 132 A-5 MS (ES+): 447.2 133x H -h -CHj 132 A-5 Characterized in the next step 133y ?: /*! -h -ch3 132 A-5 MS (ES4): 446.3 133z >s-0 H -H -CHj 132 A-5 MS (ES4): 446.2 233 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 133aa H // \ N V V v / \ / N OH -h -ch3 132 A-4 MS (ES*): 475.3 133ab V—OH ^—OH -h -ch3 132 J MS (ES+): 499.3 (M+Na) 133ac /"-CO / H3C -h -ch3 132 A-4 MS (ES"): 483.2; MS (ES+): 485.2 133ad h/~\ ^ H" (f V—N\J -h -ch3 132 A-4 MS (ES*): 497.2; MS (ES"): 495.2 133ae H -h -ch3 132 A-4 MS (ES"): 483.2; MS (ES*): 485.2 133af (/ y-^-OA.c ~h -ch3 132 J MS (ES*): 511.3 (M+Na)*; MS (ES"): 487.3 o K) Si ■fr.
-J o H XSl o hi CA oo Ki 234 Cpd. No.
-R -R* -R" Starting From Method Used Analytical Data 133ag ^,n ^ ^ oh ch3 -H -ch3 132 j ms (es~): 451.3 133ai n-^^nhboc -H -CHj 132 j MS (ES"): 584.4 134a OO -H -H 133a 1-2 'HNMR (DMSO-d6): 8 13.13 (bs, 1 H), 8.76 (t, J = 6 and 5 Hz, 1 H), 8.32 (m, 2 H), 8.02 (dd, J = 1.9 and 8.1 Hz, 1 H), 7.42 (m, 4 H), 7.25 (m, 1 H), 3.62-3.19 (xn, 12 H), 3.11 (t, J = 6.8 Hz, 2 H), 1.87 (m, 1 H), 1.76 (m, 2 H), 0.90 (d, J = 6.8 Hz, 6 H); MS (ES-) 490.3; (ES+) 492.3 134b s-O-O h -H -H 133b 1-2 'HNMR (DMSO-d6): 5 13.82 (bs, 1 H), 10.57 (bs, 2 H), 8.50 (t, J = 6 and 5 Hz, 1 H), 7.99 (d, J = 1.5 Hz, 1 H), 7.83 (s, 1 H), 7.8 (s, 1 H), 7.59 (m, 4 H), 7.46 (m, 2 H), 7.03 (m, 1 H), 6.92 (d, J = 7.9 Hz, 1 H), 3.89 (s, 4 H), 3.02 (t, J = 6.8 Hz, 2 H), 1.81 (m, 1 H), 0.8 (d, J = 6.8 Hz, 6 H);MS (ES"): 483.3; MS (ES*): 485.4 134c cf/ -H -H 133c 1-2 'HNMR (DMSO-de): 8 8.71 (t, J=5.5 Hz, 1 H), 8.40 (t, J=5.3 Hz, IH), 8.30 (s, 1 H), 8.00(d, J= 7.8 Hz, 1 H), 7.63 (d, J=4.3 Hz, 2 H), 7.40 (d, J=7.4 Hz, 4 H), 7.27(d, J=8.1 Hz, 1 H), 7.18 (s, 1 H), 6.91 (d, J=7.1 Hz, 1 H), 4.42 (b, 2 H), 3.13 (t, J - 6.5 Hz, 2 H), 1.93 (m, 1 H), 0.91 (d, J - 6.8 Hz, 6 H); MS (ES-) 497.3 235 Cpd. No. 134d ~R -R' -R" -H Starting From Method Used Analytical Data ^ CF3 -H 133d 1-2 'HNMR (DMSO-de): 5 10.45 (s, 1 H), 8.63 (s, 1 H), 8.27 (s, 1 H), 7.93 (d, J=8.1Hz, 1 H), 7.67 (t, J=6.8 Hz, 2 H), 7.55 (m, 2 H), 7.27 (m 3 H), 7.12 (m, 2 H), 3.06 (t, J = 6 Hz, 2 H), 1.82 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS(ES-) 483.3 134e H -H -H 133e 1-2 'HNMR (DMSO-dfi): 5 12.92 (bs, 1H), 8.71 (t, J=5.8Hz, 1H), 8.49(t, J=6.2 Hz, 1 H), 8.32 (s, 1 H), 8.01 (d, J= 7.8 Hz, 1 H), 7.52 (xn, 5 H), 7.27 (d, J=7.9 Hz, 1 H), 7.18 (m, 1 H), 7.08 (d, J=8.2 Hz, 2 H), 4.32 (d, J=4.2 Hz, 2 H), 3.12 (t, J « 6.5 Hz, 2 H), 1.88 (xn, 1 H), 0.91 (d, J - 6.8 Hz, 6 H); MSfES-) 498.2 134f H -H -H 133f 1-2 'HNMR (DMSO-ds): 8 8.66 (t, J=5.7 Hz, 1 H), 8.27 (s, 1 H), 7.92 (d, J=8.1 Hz, 1 H), 7.45 (xn, 7 H), 7.18 (m, 3 H), 4.32 (d, J=5.9 Hz, 2 H), 3.12 (t, J = 6 Hz, 2 H), 1.89 (m, 1 H), 0.91 (d, J = 6.8 Hz, 6 H); MS(ES-) 497.2 134g -H -H 133g 1-2 'HNMR (DMSO-de): 8 13.1 (s, 1 H), 9.58 (s, 1 H), 8.65 (s, 1 H), 8.29 (s, 1 H), 7.98 (d, J=5.9Hz, 1 H), 7.75 (d, J-5.2 Hz, 2 H), 7.30 (d, J=S Hz, 2 H), 7.12 (d, JM12.0 Hz, 1 H), 7.12 (m, 4 H), 3.06 (t, J = 6Hz,2H), 1.85 (m, 1 H), 0.86(d, J = 6.8 Hz, 6 H); MS (ES-) 483.2 134h mJ -H -H 133h 1-2 'HNMR (DMSO-de): 8 10.31 (s, 1 H), 8.65 (t, J=6.2 Hz, 1 H), 8.31 (s, 1 H), 7.98 (d, J= 7.9 Hz, 1 H), 7.66 (m, 1 H), 7.53 (m, 3 H), 7.27 (m, 4 H), 6.85 (m, 1 H), 3.09 (t, J = 6.5 Hz, 2 H), 1.86 (m, 1 H), 0.89 (d, J - 6.8 Hz, 6 H); MS (ES-) 433.1(M"') 236 Cpd.
No.
-R -R' -R" Starting From Method Used Analytical Data 134i —\ /° -H -H 1331 1-2 'HNMR (DMSO-dfi): 8 8.71 (t, J=5.7 Hz, 1 H), 8.31 (s, 1H), 8.01 (d, J= 7.9 Hz, 1H), 7.46 (m, 2 H), 7.39 (m, 2 H), 7.24 (s, 1 H), 3.38 (b, 8 H), 3.11 (t, J = 6.5 Hz, 2 H), 1.86 (m, 1 H), 0.91(d, J = 6.8 Hz, 6 H); MS(ES-) 409.3 134j -H -H 133j 1-2 'HNMR (DMSO-d6): 8 9.61 (s, 1 H), 8.67 (t, J=5.5 Hz, 1 H), 8.32 (s, 1 H), 7.98 (d, J- 7.9 Hz, 1H), 7.71 (m, 2 H), 7.54 (m, 2 H), 7.29 (d, J=7.9 Hz, 1 H), 7.04 (m, 4 H), 3.10 (t, J = 6.5 Hz, 2 H), 1.86 (m, 1 H), 0.89 (d, J = 6.8 Hz, 6 H); MS (ES-) 433.3 134k -OO -H -H 133k 1-2 'HNMR (DMSO-de): 5 8.59 (t, J = 6 and 5 Hz, 1 H), 8.3 (d, J = 5 Hz, 2 H), 8.18 (s, 1 H), 7.86 (d, J = 8 Hz, 1 H), 7.36 (m, 5 H), 6.6 (t, J = 4.7 Hz, 1 H), 4.0 (m, 1 H), 3.75 (m, 2 H), 3.37 (m, 5 H), 3.07 (t, J = 6.8 Hz, 2 H), 1.81 (m, 1 H), 0.85 (d, J = 6.8 Hz, 6 H) 1341 -H -H 1331 1-2 'HNMR (DMSO-de): 8 10.92 (bs, 1 H), 8.55 (t, J = 6 and 5 Hz, 1 H), 8.14 (s, 1 H), 7.76 (d, J = 7 Hz, 1 H), 7.68 (m, 1 H), 7.62 (m, 1 H), 7.45 (m, 2 H), 7.24 (t, J = 2.6 Hz, 1 H), 7.19 (s, 1H), 7.15 (s, 1 H), 7.10 (m, 2 H), 6.95 (dd, J = 1.5 and 8.7 Hz, 1H), 6.28 (s, 1H), 3.04 (t, J = 6.8 Hz, 2 H), 1.82 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES-) 454.3; (ES+) 456.3 134m JO -H -H. 133m 1-2 'HNMR (DMSO-dfi): 8 13.30 (bs, 1 H), 8.62 (t, J = 6 and 5 Hz, 1 H), 8.18 (s, 1 H), 7.87 (d, J = 7.9. Hz, 1 H), 7.42 (m, 3 H), 7.09 (m, 2 H), 3.03 (in, 1 H), 3.1 (t, J = 6.8 Hz, 2 H), 1.86 (m, 1 H), 1.4 (m, 4 H), 1.09 (ra, 1 H), 0.89 (d, J = 6.8 Hz, 6 H); MS (ES-) 421.2; (ES+) 423.2 237 Cpd. No. -r -r' -r" Starting From Method Used Analytical Data 134n H // 11 M / VU^ s OMe -H -H 133n 1-2 'HNMR (DMSO-ds): S 15.89 (bs, 1 H), 8.56 (t, J = 6 and 5 Hz, 1 H), 8.06 (s, 1 H), 7.67 (m, 2 H), 7.54 (d, J = 8.8 Hz, 1 H), 7.48 (m, 4 H), 7.05 (m, 1 H), 6.96 (in, 2 H), 3.77 (s, 3 H), 3.03 (t, J = 6.8 Hz, 2 H), 1.81 (m, 1 H), 0.84 (d, J - 6.8 Hz, 6 H); MS (ES-) 502.3; (ES+) 504.3 134o y -H -H 133o 1-2 'HNMR (DMSO-d6): 5 13.07 (bs, 1 H), 8.63 (t, J = 6 and 5 Hz, 1 H), 8.26 (s, 1 H), 8.05 (d, J = 4 Hz, 1 H), 7.94 (d, J = 8 Hz, 1 H), 7.43 (m, 5 H), 7.28 (m, 1 H), 6.72 (d, J = 8.8 Hz, 1 H), 6.62 (dd, J = 5.5 and 6.5 Hz, 1 H), 3.34 (m, 8 H), 3.07 (t, J = 6.8 Hz, 2 H), 1.82 (m, 1 H), 0.85 (d, J = 6.8 Hz, 6 H); MS (ES-) 486.3; (ES+) 488.3 134p H / \ S~\jti N N H -H -H 133p 1-2 lHNMR (DMSO-de): 5 12.94 (bs, 1 H), 10.20 (bs, 1 H), 8.63 (t, J = 6 and 5 Hz, 1 H), 8.28 (d, J = 1.5 Hz, 1 H), 7.96 (m, 2 H), 7.92 (d, J = 8.3 Hz, 1 H), 7.68 (ra, 1 H), 7.52 (m, 2 H), 7.4 (m, 1 H), 7.3 (xn, 2 H), 7.24 (m, 1 H), 3.08 (t,J = 6.8 Hz, 2 H), 1.84 (in, 1 H), 0.88 (d, J - 6.8 Hz, 6 H); MS (ES-) 455.2; (ES+) 479.2 (M+Na) 134q -H -H 133q 1-2 'HNMR (DMSO-de): S 12.84 (bs, 1 H), 10.45 (bs, 1 H), 8.62 (t, J = 6 and 5 Hz, 1 H), 8.27 (d, J = ,1.5 Hz, 1 H), 8.01 (s, 1 H), 7.93 (s, 2 H), 7.9 (d, J = 1.5 Hz, 1 H), 7.69 (in, 1 H), 7.57 (d, J = 8.7 Hz, 1 H), 7.52 (m, 2 H), 7.29 (d, J = 8 Hz, 1 H), 7.23 (m, 1 H), 7,02 (dd, J -1.5 and 8.7 Hz, 1 H), 3.07 (t, J = 6.8 Hz, 2 H), 1.83 (m, 1 H), 0.87 (d, J = 6.8 Hz, 6 H), MS (ES-) 455.2; (ES+) 479.3 (M+Na) 238 Cpd.
No.
-R -R' -R" -H Starting From Method Used Analytical Data 134r H -H 133r 1-2 'HNMR (DMSO-de): 5 8.64 (t, J=5.5 Hz, 1 H), 8.16 (s, 1 H), 7.87 (d, J=7.1 Hz, IH), 7.50 (m, 1 H), 7.40 (d, J=4.1 Hz, 2 H), 7.19 (b, 3 H), 7.07 (m, 2 H), 6.51 (m, 2 H), 6.35 (d, J=7.8 Hz, 2 H), 3.97 (d, J=5.6 Hz, 2 H), 3.13 (t, J = 6.5 Hz, 2 H), 1.90 (m, 1 H), 0.91(d. J = 6.8 Hz, 6 H) 134s -H -H 133s 1-2 'HNMR (DMSO-de): 8 9.53 (bs, 1 H), 8.67 (t, J=4.7 Hz, 1 H), 8.32 (s, 1 H), 7.99 d, J=8.1 Hz, 1 H), 7.70 (d, J=7.6 Hz, 1 H), 7.52 (m, 2 H), 7.46 (d, J=11.5 Hz, 1 H), 7.32 (m, 3 H), 7.18 (m, 3 H), 4.33 (s, 2 H), 3.10 (t, J = 6.5 Hz, 2 H), 1.86 (m, 1 H), 0.89 fd, J = 6.8 Hz, 6 H); MS (ES-) 445.2 134t OH -H -H 132 1-2 'HNMR (DMSO-de): 8 12.57 (b, 1 H), 8.69 (t, J=5.6 Hz, 1 H), 8.36 (s, 1 H), 7.99 (d, J= 7.9 Hz, 1 H), 7.92 (d, J=7.7 Hz, 1 H), 7.57(t, J=7.5 Hz, IH), 7.46 (t, 1=1.1 Hz, IH), 7.23 (d, J=5.2 Hz, IH), 7.17 (d, J=7.5 Hz, IH), 3.12 (t, J = 6.5 Hz, 2 H), 1.88 (m, 1 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES-) 340.2 134u >o- -H -H 133u 1-2 'HNMR (DMSO-de): 8 8.56 (t, J=5.0 Hz, 1 H), 8.16 (d, J=7.0 Hz, 2 H), 7.94 (d, J=8.4 Hz, 1 H), 7.75 (d, J=7.4 Hz, 1 H), 7.63 (m, 2 H), 7.46 (m, 2 H), 7.21 (b, 1 H), 7.07 (s, 2 H), 6.99 (t, J=5.1 Hz, 1 H), 3.05 (t, J = 6.5 Hz, 2 H), 1.83 (m, 1 H), 0.86(d, J = 6.8 Hz, 6 H); MS (ES-) 416.3 134v ,*-0 -H -H 133v 1-2 'HNMR (DMSO-de): 8 8.60 (t, J=5.6 Hz, 1 H), 8.32 (d, J=5.3 Hz, 2 H), 8.11(s, 1 H), 7.78 (d, 1=1.1 Hz, 1 H), 7.65 (d, J=5.5 Hz, 1 H), 7.55 (m, 2 H), 7.43 (d, J=4.5 Hz, 2 H), 7.14 (m, 3 H), 3.06 (t, J = 6.5 Hz, 2 H), 1.83 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES-) 416.2 239 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 134w OH -H -H 133w 1-2 'HNMR (DMSO-de): 8 10.10 (bs, 1 H), 9.31 (s, 1 H), 8.65 (t, J=5.7 Hz, 1 H), 8.27 (s, 1 H), 7.93 (d, J=8.1 Hz, 1 H), 7.62 (d, J=5.3 Hz, 1 H), 7.48 (m, 2 H), 7.28(s, 1 H), 7.20 (d, J=12.0 Hz, 1 H), 7.09 (s, 1 H), 6.98 (d, J=7.0 Hz, 1 H), 6.81 (d, J=7.3 Hz, 1 H), 6.37 (t, J=7.6 Hz, 1 H), 3.09 (t, J = 6.5 Hz, 2 H), 1.85 (m, 1 H), 0.90(d, J - 6.8 Hz, 6 H); MS (ES-) 431.1 134x ^-O H -H -H 133x 1-2 'HNMR (DMSO-de): 8 10.28 (bs, 1 H), 8.63 (t, J=5.3 Hz, 1 H), 8.34 (d, J=4.7 Hz, 1 H), 8.06 (s, 1 H), 7.82 (d, J=6.6 Hz, 1 H), 7.53 (m, 1 H), 7.42 (m, 2 H), 7.34 (t, J=8.6 Hz, 1 H), 7.18 (s, 1 H), 7.07 (d, J=2.7Hz, 2 H)s 6.10 (b; 1 H), 4.43 (b; 1 H), 4.12 (b, 1H), 3.12 (t, J = 6.5 Hz, 2 H), 1.89 (m, 1 H), 0.90(d, J = 6.8 Hz, 6 H); MS (ES+) 432.3, (ES-) 430.2 . 134y r—N w-o H -H -H 133y 1-2 'HNMR (DMSO-d6): 8 9.79 (bs, 1 H), 8.62 (t, J=6.0 Hz, 1 H), 8.31 (d, J=4.5 Hz, 1 H), 8.20 (s, 1 H), 8.08 (s, 1 H), 7.78 (d, J=2.1 Hz, 1 H), 7.51 (m, 1 H), 7.42 (m, 2 H), 7.06 (m, 3 H), 6.88 (m, 1 H), 4.02 (b, 2 H), 3.13 (t, J = 6.5 Hz, 2 H), 1.90 (m, 1 H), 0.93 (d, J = 6.8 H2,6 H); MS (ES+) 432.3, (ES-) 430.3 134z H -H -H 133z 1-2 'HNMR (DMSO-de): 8 10.71 (bs, 1 H), 8.64 (t, J=5.9 Hz, 1 H), 8.21 (d, J=5.2 Hz, 2 H), 8.05 (s, 1 H), 7.81 (d, J=7.7 Hz, 1H), 7.51 (m, 1 H), 7.42 (m, 2 H), 7.18 (s, 1 H), 7.04 (t, J=1.4Hz, 2 H), 6.51 (b, 2H), 4.41 (b, 1 H), 4.01 (b, 1 H), 3.13 (t, J = 6.5 Hz, 2 H), 1.91 (m, 1 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES+) 432.2, (ES-) 430.2 240 Cpd. No. 134aa -R -R' -R" Starting From Method Used Analytical Data H // \ N (' V v / \ / \ OH -H -H 133aa 1-2 'HNMR (DMSO-dfi): 8 10.02 (bs, 1 H), 8.65 (t, J = 5.7 Hz, 1 H), 8.26(s, 1 H), 7.94(d, J= 7.7 Hz, 1 H), 7.66(d, J=5.8 Hz, 1 H), 7.51(m, 2 H), 7.36 (d, J=8.4 Hz, 2 H), 7.29 (d, J=7.9 Hz, 1 H), 7.22 (d, J=5.5 Hz, 1 H), 7.07(d, J=8.3 Hz, 2 H), 4.57 (t, J=9.0 Hz, 1 H), 3.51 (m, 2 H), 3.09 (t, J = 6.5 Hz, 2 H), 2.62 (t, J=6.6 Hz, 2 H), 1.85 (m, 1 H), 0.90(d, J = 6.8 Hz, 6 H), MS(ES-) 459.2 134ab H jF~\_ N—(/ y—OH ^ OH -H -H 133ab 1-2 'HNMR (DMSO-ds): 8 9.05 (s, 1 H), 8.70 (t, J=5.7 Hz, 1 H), 8.56 (s, 1 H), 8.36 (s, 1 H), 8.12 (m, 2 H), 7.79 (m, 1 H), 7.60 (m, 1 H), 7.44 (s, 2 H), 7.09 (m, 2 H), 6.56 (d, J=8.9 Hz, 1H), 4.89 (t, J=4.4 Hz, 1 H), 4.38 (d, J=5.6 Hz, 2 H), 3.11 (t, J = 6.5 Hz, 2 H), 1.84 (m, 1 H), 0.90 (d, J = 6.8 Hz, 6 H), MS(ES-) 461.1 134ac S_<f 1 n / H*C -H 133ac 1-2 'HNMR (DMSO-de): 8 8.60 (t, J = 6 and 5 Hz, 1 H), 8.13 (s, 2 H), 7.85 (d, J = 2 Hz, 1 H), 7.46 (m, 4 H), 7.36 (d, J = 7.7 Hz, 1 H), 7.16 (m, 4 H), 7.10 (m, 1 H), 3.17 (s, 3 H), 3.08 (t, J = 6.8 Hz, 2 H), 1.85 (m, 1 H), 0.89 (d, J = 6.8 Hz, 6 H), MS (ES-) 469.2; (ES+) 471.3 134ad -H -H 133ad 1-2 'HNMR (DMSO-de): 8 8.55 (t, J = 6 and 5 Hz, 1 H), 8.10 (s, 2 H), 7.73 (d, J = 7.2 Hz, 1H), 7.54 (m, 4 H), 7.46 (m, 5 H), 7.08 (m, 3 H), 3.04 (t, J = 6.8 Hz, 2 H), 1.82 (m, 1 H), 0.86 (d, J - 6.8 Hz, 6 H), MS (ES-) 481.1; (ES+) 483.3 241 Cpd. No.
-R -R' -H -R" Starting From Method Used Analytical Data 134ae jh v~vQ h -H 133ae 1-2 'HNMR (DMSO-d6): 5 9.66 (bs, IH), 8.54 (t, j = 6 and 5 Hz, 1 H), 8.12 (s, 2 H), 7.77 (dd, J = 8 and 2 Hz, 1 H), 7.6 (dd, J = 7 and 2 Hz, 1 H), 7.45 (m, 5 H), 7.10 (m, 4 H), 4.36 (bs, 2 H), 3.09 (t, J = 6.8 Hz, 2 H), 1.86 (m, 1 H), 0.89 (d, J = 6.8 Hz, 6 H), MS (ES-) 469.2; (ES+) 471.3 134af ^jn oh -H -H 133af 1-2 'HNMR (DMSO-de): 5 9.76 (s, 1 H), 9.17 (s, 1 H), 8.63 (t, J=5.0 Hz, 1 H), 8.29 (s, 1 H), 7.90 (d, J=1.6 Hz, 1 H), 7.60 (s, 1 H), 7.51 (d, J=8 Hz 1 H), 7.30 (d, J=3.6 Hz, 2 H), 7.28 (d, J=8.2Hz, 1 H), 7.22 (t, 3 H), 6.60 (d, J=8.9 Hz, 1 H), 3.06 (t, J == 6 Hz, 2 H), 1.85 (m, 1 H), 0.86 (d, J « 6.8 Hz, 6H); MS (ES-) 431.2 134ag ^ oh chj -H -H 133ag 1-2 'HNMR (DMSO-dfi): 5 9.64 (s, 1 H), 9.06 (s, 1 H), 8.66 (t, J=5.6 Hz, 1 H), 8.29 (s, 1 H), 7.95 (d, J=7.9 Hz, 1 H), 7.63 (m, 1 H), 7.50 (m, 2 H), 7.29 (d, J—3.1 Hz, 1 H), 7.20 (d, J=8.9 Hz, 1 H), 7.11 (m, 1 H), 7.03 (m, 1 H), 6.60 (d, J=8.9 Hz, 1 H), 3.08 (t, J = 6 Hz, 2 H), 2.05 (s, 3 H), 1.85 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES-) 445.2, MS (ES+) 469.3 (M+Na) 134ai n nblj -H -H 133ai 1-2, S MS (ES+): 472.2; MS (ES"): 470.2 135a w -ch=ch2 -ch3 30f A-4 MS (ES"): 489.3 242 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 135b H -ch=ch2 -ch3 30f a-4 ms (es*): 475.3; ms (es"): 473.3 135c r—N ft \ NHBoc , -ch=ch2 -ch3 30f j ms (es*): 573.5; ms (es"): 571.3 135d \=N -ch=ch2 -ch3 30f a-4 ms (es"): 472.2 135e -ch=ch2 ~ch3 30f j ms (es"): 489.1 135f / \=/ NH2 -ch=ch2 -ch3 30f j ms (es"): 498.1 135g ^,N ^ ^ CH2CN -ch=ch2 -ch3 30f j ms (es"): 494.3 13Sh CHjNHBoc -ch=ch2 -ch3 30f j ms (es"): 584.2 243 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 136a -ch=ch2 -H 135a 1-2 'HNMR (DMSO-ds): 6 8.66 (t, J = .55 Hz, 1 H), 8.35 (t, J = 4 and 6.4 Hz, 1 H), 8.28 (d, J=2 Hz, 1 H), 7.95 (dd, J = 7.9 and 2 Hz, 1 H), 7.69 (s, 1 H), 7.59 (m, 2 H), 7.25 (d, J = 8.1 Hz, 2H), 7.15 (xn, 2 H), 6.93 (s, .1 H), 6.88 (dd, J =17.7 and 11.5 Hz, 1 H), 5.95 (d, J = 17.7 Hz, 1 H), 5.37 (d, J = 11.5 Hz, 1H), 3.76 (t, J = 6.8 Hz, 2 H), 3.10 (t, J = 6.4 Hz, 2 H), 2.96 (m, 2 H), 1.86 (m, 1 H), 1.67 (m, 2 H), 0.89 (d, J = 6.8 Hz, 6 H); MS (ES-) 473.3; (ES+) 475.3 136b -ch=ch2 -H 135b 1-2 'HNMR (DMSO-de): 8 8.64 (t, 1 H), 8.51 (s, 1 H), 8.21 (s, 1 H), 7.88 (d, J-7.8 Hz, 1 H), 7.74 (s, 1 H), 7.56 (s, 2 H), 7.15 (m, 2 H), 6.80 (t, 2 H), 5.90 (d, J—17 Hz, 1 H), 5.36 (d, J=11.0Hz, 1 H), 3.18 (m, 2 H), 3.06 (t, J = 6 Hz, 2 H), 2.43 (m, 2 H), 1.85 (m, 1H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES+) 461.2, MS (ES-) 459.2 136c n (/ V—nhj -ch=ch2 -H 135c 1-2, S 'HNMR (DMSO-ds/DzO): 5 8.71 (t, 1 H), 8.27 (d, J= 3 Hz, 1 H), 8.2l(d, J=3 Hz, 1 H), 7.96 (q, 1 H), 7.79 (q, 1 H), 7.72 (s, 1 H), 7.63 (d, J=8 Hz 1 H), 7.30 (d, J=6 Hz, 1 H), 7.24 (d, J=7 Hz, 1 H), 6.87 (q, 2 H), 6.00 (d, J=8 Hz, 1 H), 5.41 (d, J=8 Hz, 1 H), 3.06 (t, J = 6 Hz, 2 H), 1.85 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES+) 459.2 244 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 136d rl V tE2;\ ~ch=ch2 -h 135d 1-2 'HNMR (DMSO-dfi): 5 12.86 (bs,1 H), 9.17 (s, 1 H), 8.65 (t, J = 6 Hz, 1 H), 8.29 (d, J = 2 Hz, 1 H), 8.26 (s, 2 H), 7.97 (dd, J = 8 and 2 Hz, 1 H), 7.76 (s, 1 H), 7.63 (d, 8 Hz, 1 H), 7.31 (d, J = 8 Hz, 1 H), 7.24 (d, J = 8 Hz, 1 H), 6.86 (dd, J = 10.7 and 17.5 Hz, 1 H), 6.49 (s, 1 H), 5.99 (d, J = 17.5,1 H), 5.40 (d, J = 10.7 Hz, 1 H), 3.10 (t, J = 6.8 Hz, 2 H), 1.86 (m, 1 H), 0.89 (d, J - 6.8 Hz, 6 H); MS (ES-) 458.2, (ES+) 460.3 136e -ch=ch2 -H 135e 1-2 'HNMR (DMSO-de): 8 12.72 (s, broad, 1 H), 8.65(t, J=5.7 Hz, 1 H), 8.29 (s, 1 H), 7.93 (d, J=7.9 Hz, 1 H), 7.74 (m, 2 H), 7.65 (d, J=6 Hz 1 H), 7.42 (d, J=7.9 Hz, 1 H), 7.24 (m, 3 H), 7.11 (m, 1 H), 6.84 (q, J=ll.l, 17.8 Hz, 1 H), 5.97 (d, J=18 Hz, 1 H), 5.58 (d, 1H), 5.41 (d, 1 H), 3.08 (t, J = 6 Hz, 2 H), 1.85 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES-) 475.1 136f / \ / NH2 -ch=ch2 -H 135f 1-2 'HNMR (DMSO-dfi): 8 8.67 (t, J=6.06 Hz, 1 H), 8.28 (s, 1 H), 7.90 (d, J=7.7Hz, 1 H), 7.67 (m, 4 H), 7.32 (m, 5 H), 7.09 (d, J=7.9 Hz 1 H), 6.89 (q, J=10.9 & 18.0 Hz, 1 H), 5.99 (d, J=17.5Hz, 1 H), 5.42 (d, J=ll Hz, 1H), 3.08-(t, J=6.3 Hz, 2 H), 1.88 (m, 1 H), 0.87 (d, J = 6.8 Hz, 6 H); MS (ES-) 484.2 245 Cpd. No. 136g -R -R' -R" Starting From Method Used Analytical Data ^.N——CH2CN -ch=ch2 -h 13Sg 1-2 'HNMR (DMSO-de): 8 10.38 (s, 1 H), 8.66 (t, J=6.06 Hz, 1 H), 8.29 (s, 1 H), 7.95 (d, J=6.1 Hz, 3 h), 7.75 (s, 1 H), 7.63 (d, 2 h), 7.43 (d, 2 h), 7.26 (m, 3 H), 7.00 (d, J=7.7 Hz, 1 H), 6.85 (q, J=10.9 & 18.0 Hz, 1 H), 5.98 (d, J=17.5Hz, 1 H), 5.40 (d, J=ll Hz, 1 H), 3.98 (s, 2 H), 3.08 (t, J=6.3 Hz, 2 H), 1.86 (m, 1 H), 0.88 (d, J- 6.8 Hz, 6 H); MS (ES-) 480.2 136h H // N <7 V CH2NH2 -ch=ch2 -H 135h S, 1-2 'HNMR (DMSO-de): 8 8.55 (t, J=6.06 Hz, 1 H), 8.02 (s, 1 H), 7.60(m, 4H), 7.21 (t, J=7.1,2 H), 6.99(m, 2 H), 6.83 (d, J=6.8 Hz, IH), 6.81 (q, J=10.9 & 18.0 Hz, IH), 5.92 (d, J=17.5Hz, 1 H), 5.35 (d, J=ll Hz, 1 H), 3.89 (s, 2H), 3.03 (t, J=6.3 Hz, 2 H), 1.36 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6H) 246 Cpd. No.
-R -R' -R" Starting From Metbod Used Analytical Data 148a -ch3 IX H 3 147a J >H NMR (DMSO-dfi): § 10.65 (s, 1 H), 10.15 (s, 1 H), 9.19 (s, 2 H), 8.88 (s, 2 H), 8.10 (d, J= 2.1 Hz, 1 H), 7.92 (s, 1 H), 7.93-7.75 (m, 6 H), 7.31 (dd, J= 8.4 and 23.9 Hz, 1 H), 7.12 (d, J= 3.5 Hz, 1 H), 6.67 (m, 1 H), 3.53 (s, 3 H), 2.20 (d, 7= 7.0 Hz, 2 H), 2.07 (m, 1 H), 0.94 (d, J= 6.3 Hz, 6 H). 148b -Q -ch3 0 CH, "^lA-^CH, H 3 147b J 'H NMR (DMSO-d6): 8 10.65 (s, 1 H), 10.09 (s, 1 H), 9.17 (s, 1 H), 8.83 (s, 1 H), 8.10 (d,J=2.0Hz, 1 H), 7.85 (d, J=2.0 Hz, 2 H), 7.81 (d, J= 2.0 and 7.9 Hz, 2 H), 7.76 (m, 5 H), 7.66 (d, J= 3.9 Hz, 1 H), 7.62 (d, J= 4.9 Hz, 1 H), 7.31 (d, J= 7.9 Hz, 1 H), 7.26 (d, /= 7.9 Hz, 1 H), 7.19 (t, J= 3.9 Hz, 1 H), 3.53 (s, 1 H), 2.19 (d, J= 6.9 Hz, 2 H), 2.06 (m, J= 6.9 Hz, 1 H), 0.92 (d, J= 6.9 Hz, 6 H); MS (ES*): 555.67 148c -ch=ch2 -ch3 0 CH, nA-^CH, H 3 147c 3 Characterized in the next step o H Cpd. No.
-R -R' -H -R" Starting From Method Used Analytical Data 149a O CH, H 3 148a 1-2 MS (ES*): 525.3 149b A} -H OA • H 3 148b 1-2 lH NMR (DMSO-ds): 8 13.95 (s, 1H), 9.79 (s, 1 H), 8.87 (s, 4 H), 7.76 (s, 1 H), 7.65 (m, 8 H), 7.46 (dd, J= 2.1 and 8.4 Hz, 1 H), 7.16 (t, J= 4.2 Hz, 1 H), 7.04 (d, /= 7.7 Hz, 1 H), 6.76 (d, J= 8.4 Hz, 1 H), 2.13 (d, J= 7.0 Hz, 2 H), 2.03 (m, J= 6.3 and 7.0 Hz, 1 H), 0.90 (d, J— 6.3 Hz, 6 H); MS (ES*): 541.62 149c -ch=ch2 -H O CH, H 5 148c 1-2 MS (ES*): 485.6 175 -H -ch3 CH3 174 j 'H NMR (DMSO-de): 8 8.81 (m, 4 H), 8.37 (t, J= 6.0 Hz, 1H), 7.74-7.:23 (m, 11 H), 4.31 (d, J= 6.2 Hz, 2 H), 3.51 (s, 3 H), 2.44 (m, 1 H), 1.04 (d, J= 7.0 Hz, 6 H); MS (ES*): 473.3 176 -H -H o CHj 175 1-2 'H NMR (DMSO-d5): 8 13.79 (br s, 1 H), 9.03 (m, 3 H), 8.25 (m, 1 H), 7.78-7.35 (m, 7 H), 6.99 (m, 2 H), 6.79 (m, 1 H), 4.20 (br s, 2 H), 3.51 (s, 3 H), 2.39 (m, 1 H), 1.00 (d, J= 6.8 Hz, 6 H); MS (ES*): 459.3 182 -H -ch3 Boc CH3 178 j 'H NMR (DMSO-ds): 8 8.96 (m, 2 H), 7.79-7.38 (m, 9 H), 7.29 (dd, J= 7.5 and 1.7 Hz, 2 H), 4.42 (s, 2 H), 3.50 (s, 3 H), 2.97 (s, 2 H), 1.87 (m, 1 H), 1.36 (m, 9 H), 0.81 (d, J= 6.8 Hz, 6 H); MS (ES*): 559.5 248 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 183 -H -H H 1 ch3 182 1-2, S 'H NMR (DMSO-de): 8 9.11 (m, 4 H), 7.86 (s, 1 H), 7.66 (m, 5 H), 7.49 (m, 2 H), 7.38 (m, 1 H), 7.08 (m, 2 H), 4.12 (s, 2 H), 2.59 (m, 2 H), 1.87 (m, 1 H), 0.81 (d, J=6.6Hz,6H);MS(ES+): 445.32 249 Cpd. No.
N (in Ring With Respect to Phenyl) -R -R' Starting From Method Used Analytical Data 151 3 -cho -ch3 150 + 3a D-9 MS (ES"): 339.3 152 3 -co2h -ch, 151 E 'HNMR (CDCI3): 8 8.69 (t, J= 5.8 Hz, 1 H), 8.50 (d, /= 4.9 Hz, 1 H), 8.33 (d, 1.7 Hz, 1 H), 8.24 (s, 1 H), 8.01 (dd, J= 7.9,1.9 Hz, 1 H), 7.53 (d,J=5.lHz, i H), 7.34 (d,7=8.1 Hz, 1 H), 3.56 (s, 3 H), 3.12 (m, 2 H), 1.87 (m, 1 H), 0.91 (d, 7=6.6 Hz, 6 H) 153 3 ax/"1 H -ch, 152 J 'HNMR (CD3OD): 8 8.75 (d, J = 4.7 Hz, 2 H), 8.55 (s, 1 H), 8.42 (d, J= 1.9 Hz, 1 H), 8.07 (dd, J = 8.1,1.9,1 H), 7.74 (s, 3 H), 7.70 (d, 5.1 Hz, 1 H), 7.51 (d, /= 8.1 Hz, 1 H), 3.69 (s, 3 H), 3.21 (m, 2 H), 1.94 (m, 1 H), 0.98 (d, J= 6.6 Hz, 6 H); MS (ES+): 474 2S0 Cpd. No.
N (in Ring With Respect to Phenyl) -R -R' Starting From Method Used Analytical Data 154 3 !fh AAJ H -h 153 1-2 'HNMR (DMSO): 8 11.18 (s, 1H), 9.31 (s, 2 H), 9.10 (s, 2 H), 8.92 (d, 7=5.1 Hz, 1 H), 8.78 (m, 2 H), 8.43 (d, 7= 1.5 Hz, 1 H), 8.07 (dd, 7= 7.9,1.3 Hz, 1 H), 7.97 (d, 7= 5.3 Hz, 1 H), 7.82 (d, 7= 8.7 Hz, 2 H), 7.72 (d,7= 8.8 Hz, 2 H), 7.50 (d, 7= 7.9 Hz, 1 H), 3.10 (t, 7= 6.0 Hz, 2 H), 1.86 (m, 1 H), 0.89 (d, 7-6.6 Hz, 6 H); MS (ES^ 460 156 4 -CHO -ch3 155+3a D-9 MS(ES*): 341.4 157 4 -co2h -ch3 156 E lHNMR (CDC13): 8 8.80 (s, 1 H), 8.46 (d, 7= 5.1 Hz, 1 H), 8.29 (s, 1 H), 7.85 (d, 7= 7.9 Hz, 1 H), 7.13 (d, 7= 7.9 Hz, 1H), 7.00 (d, 7= 5.1 Hz, 1 H), 6.83 (bs, 2 H), 3.45 (s, 3 H), 3.15 (m, 2 H), 1.84 (m, 1 H), 0.90 (d, 7= 6.6 Hz, 6 H); MS (ES* ): 355.2 158 4 NH aXj-- H -ch3 157 J 'HNMR (CD3OD): 8 8.85 (s, 1 H), 8.75 (d, 7= 5.3 Hz, 1 H), 8.41 (d, J = 1.9 Hz, 1H), 8.07 (dd, J-8.1,2.1,1 H), 7.74 (s, 4 H), 7.48 (d, 7= 8.1 Hz, 1H), 7.45 (d, 7= 5.1 Hz, 1 H), 3.69 (s, 3 H), 3.21 (m, 2 H), 1.94 (m, 1 H), 0.97 (d, 7= 6.8 Hz, 6 H); MS (ES"): 472.4 159 4 axA- H -h 158 1-2 'HNMR (DMSO): 8 10.97 (s, 1 H), 9.24 (s, 2 H), 8.96 (s, 3 H), 8.79 (m, 2 H), 8.40 (d, 7= 1.8 Hz, 1H), 8.06 (d, 7= 7.7 Hz, 1 H), 7.77 (s, 4 H), 7.52 (m, 1 H), 7.38 (d, 7= 7.5 Hz, 1 H), 3.10 (m, 2 H), 1.85 (m, 1 H), 0.89 (d, 7= 5.3,6 H); MS (ES") 460.2 251 o.
Cpd. No.
-R -R' Starting From Method Used Analytical Data 161a -CHj -CHj 31f AB-2 'H NMR (DMSO-d6): 8 10.55 (s, IH), 9.00 (bs, 2H), 8.68 (t, J = 5.8 Hz, IH), 8.24 (d, J = 1.9 Hz, IH), 8.04 (d, J « 8.1 Hz, IH), 7.91 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 1.3 Hz, IH), 7.67 (m, 3H), 7.40 (d, J = 7.9 Hz, IH), 7.29 (d, J = 7.9 Hz, IH), 6.90 (dd, J = 17.7,11.0 Hz, IH), 6.03 (d, J = 17.7 Hz, IH), 5.42 (d, J = 11.0 Hz, IH), 3.61 (s, 3H), 3.56 (s, 3H), 3.10 (t, J = 6.4 Hz, 2H), 1.85 (m, IH), 0.90 (d, J = 6.5 Hz, 6H); MS (ES+): 557.3 161b -C2Hs 'CHj 31f AB-2 lH NMR (DMSO-d6): 8 10.54 (s, IH), 9.20 (bs, 4H), 8.67 (t, 3=6 Hz, IH), 8.24 (IH), 8.02 (IH), 7.91 (2H), 7.77 (IH), 7.66 (m, 3H), 7.40 (IH), 7.29 (IH), 6.88 (dd, J = 17.3,10.7 Hz, IH), 6.03 (d, J = 17.3 Hz, IH), 5.42 (d, J = 10.7 Hz, IH), 3.56 (s, 3H), 3.5 (m, 3H), 3.09 (2H), 1.85 (m, IH), 0.89 (6H); MS (ES+): 571.3 161c -ch2c6h5 -CHj 31f AB-2 'H NMR (DMSO-d6): 8 10.54 (s, IH), 9.20 (bs, 2H), 8.68 (t, J = 5.8 Hz, IH), 8.24 (d, J = 1.9 Hz, IH), 8.03 (d, J = 8.1 Hz, IH), 7.92 (d, J = 8.8 Hz, 2H), 7.77 (s, IH), 7.68 (m, 4H), 7.36(m, 6H), 6.89 (dd, J = 17.7,11.2 Hz, IH), 5.05 (s, 2H), 6.03 (d, 3 = 17.7 Hz, IH), 5.42 (d, J = 11.2 Hz, IH), 3.56 (s, 3H), 3.09 (t, J = 6.6 Hz, 2H), 1.84 (m, IH), 0.89 (d, J = 6.6 Hz, 6H); MS (ES+): 633.3 252 Cpd. No.
-R -R' Startmg From Method Used Analytical Data 16Id -C(CH3)3 -ch3 31f AB-2 MS (ES"*): 599.3 and 499.3 161 e -CH2-CC13 -ch3 31f AB-2 'HNMR (DMSO-d6): 8 10.59 (s, IH), 9.24(s, 2H), 8.68 (t, J = 5.6 Hz, IH), 8.24 (d, J = 1.8 Hz, IH), 8.03 (dd, J = 8.9,1.9 Hz, IH), 7.96 (d, J = 8.9 Hz, 2H), 7.79 (d, J = 1.5 Hz, IH), 7.69 (m, 3H), 7.41 (d, J - 8.1 Hz, IH), 7.29 (d, J = 8.0 Hz, IH), 6.89 (dd, J = 17.7,11.1 Hz, IH), 6.03 (d, J = 17.7 Hz, IH), 5.42 (d, J -11.1 Hz, IH), 4.88 (s, 2H), 3.56 (s, 3H), 3.10 (t, J = 6.6 Hz, 2H), 1.85 (m, IH), 0.89 (d, J = 6.6 Hz, 6H); MS (ES+): 674.97 161f ^ OMe -CHj 31f AB-2 'H NMR (DMSO-d6): 8. 10.58 (s, IH), 9.15 (s, 2H), 8.69 (t, J = 5.4 Hz, IH), 8.25 (d, J = 1.8 Hz, IH), 8.04 (dd, J = 8.1,1.9 Hz, IH), 7.95 (d, J = 8.9 Hz, 2H), 7.78 (s, IH), 7.68 (m, 3H), 7.40 (d, J = 8.0 Hz, IH), 7.29 (d, J = 8.0 Hz, IH), 7.07 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 17.7,11.1 Hz, IH), 6.03 (d, J = 17.7 Hz, IE), 5.42 (d, J = 11.1 Hz, IH), 3.75 (s, 3H), 3.57 (s, 3H), 3.10 (t, J = 6.6 Hz, 2H), 1.85 (m, IH), 0.89 (d, J = 6.6 Hz, 6H); MS (ES+): 649.3 161g -ch3 31f AB-2 'H NMR (DMSO-d6): 8 10.59 (s, IH), 9.19 (s, 2H), 8.68 (t,J = 5.7 Hz, IH), 8.25 (d, J = 1.8 Hz, IH), 8.03 (dd, J - 8.1,1.9 Hz, IH), 7.95 (d, J = 8.9 Hz, 2H), 7.78 (d, J = 1.7 Hz, IH), 7.70 (m, 3H), 7.41 (d, J = 8.1 Hz, IH), 7.29 (d, J = 7.9 Hz, IH), 7.20 (m, 4H), 6.90 (dd, J = 17.9,11.1 Hz, IH), 6.03 (d, J = 17.9 Hz, IH), 5.42 (d, J = 11.1 Hz, IH), 3.57 (s, 3H), 3.10 (t, J = 6.8Hz, 2H), 1.85 (m, IH), 0.89 (d, J = 6.6 Hz, 6H); MS (ES+): 637.5 Cpd. No.
-R -R' Starting From Method Used Analytical Data 1611v 0 ^ x chj -ch3 31f AB-1 'H NMR (DMS0-d6): 8 10.58 (s, IH), 9.00 (bs, 2H), 8.68 (t, J = 5.9 Hz, 1H), 8.24 (d, J = 1.9 Hz, IH), 8.03 (d, J = 8.1 Hz, IH), 7.94 (d, J = 8.9 Hz, 2H), 7.78 (d, J-1.5 Hz, IH), 7.68 (m, 3H), 7.40 (d, J = 8.1 Hz, IH), 7.29 (d, J = 8.1 Hz, IH), 6.89 (dd, J = 17.5,11.0 Hz, IH), 6.03 (d, J = 17.5 Hz, IH), 5.71 (s, 2H), 5.42 (d, J = 11.0 Hz, IH), 3.56 (s, 3H), 3.10 (t,J = 6.2 Hz, 2H), 2.07 (s, 3H), 1.85 (m, IH), 0.89 (d, J = 6.6 Hz, 6H); MS (ES+): 615.3 161i 1 ch3 CHj -ch3 31f AB-1 'H NMR (DMSO-d6): 8 10.57 (s, IH), 9.22 (s, 2H), 8.67 (t, J = 5.9 Hz, IH), 8.24 (d, J = 1.9 Hz, IH), 8.03 (dd, J = 8.1,1.9 Hz, IH), 7.94 (d, J = 8.9 Hz, 2H), 7.78 (d, J = 1.5 Hz, IH), 7.69 (m, 3H), 7.41 (d, J = 7.9 Hz, IH), 7.29 (d, J = 7.9 Hz, IH), 6.89 (dd, J = 17.7,11.1 Hz, IH), 6.03 (d, J = 17.7 Hz, IH), 5.73 (s, 2H), 5.42 (d,J= 11.1 Hz, IH),3.56 (s, 3H), 3.09 (t, J - 6.6 Hz, 2H), 1.85 (m, IH), 1.14 (s, 9H), 0.89 (d, J = 6.7 Hz, 6H); MS (ES+): 657.52 161j ch, o aa* -ch3 31f AB-1 'H NMR(DMSO-d6): § 10.57 (s, IH), 9.24 (s, 1 H), 9.17 (s, IH), 8.68 (t, J = 6.2 Hz, IH), 8.25 (s, IH), 8.04 (d» J = 8.2Hz, IH), 7.94 (d, J = 7.5 Hz, 2H), 7.67 (s, IH), 7.67 (m, 3H), 7.40 (d, J = 7.9 Hz, IH), 7.29 (d, J = 7.9 Hz, IH), 6.90 (dd, J = 17.8,11.1 Hz, IH), 6.71 (q, J = 5.5 Hz, IH), 6.03 (d, J = 17.7 Hz, IH), 5.42 (d, J = 11.1 Hz, IH), 3.56 (s, 3H), 3.10 (t, J = 6.6 Hz, 2H), 2.00 (s, 3H), 1.85 (m, IH), 1.43 (d, J = 5.5 Hz, 3H), 0.89 (d, J = 6.7 Hz, 6H); MS (ES+): 629.4 254 Cpd. No. -r -r' Startmg From Method Used Analytical Data 162a -CH3 -H 161a 1-2 lH NMR (DMSO-46): 5 9.04 (bs, 3H), 8.57 (t, J = 5.4 Hz, IH), 8.16 (s, IH), 7.86 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 7.9 Hz, IH), 7.72 (s, IH), 7.58 (m, 3H), 7.12 (d, J = 8.0 Hz, 2H), 6.87 (dd, J = 17.7,11.0 Hz, IH), 5.97 (d, J = 17.7 Hz, IH), 5.37 (d, J = 11.0 Hz, IH), 3.59 (s, 3H), 3.05 (t, J = 6.6 Hz, 2H), 1.83 (m, IH), 0.87 (d, J = 6.6 Hz, 6H); MS (ES+): 543.38 162b -C2H5 -H 161b 1-2 !H NMR (DMSO-d6): 6 12.8 (bs, IH), 10.8 (bs, IH), 9.20 (bs, 2H), 8.68 (t, J = 5.9 Hz, IH), 8.24 (d, J = 1.9 Hz, IH), 7.91 (m, 3H), 7.77 (d, J = 1.5 Hz, IH), 7.64 (m, 3H), 7.28 (d, J = 8.1 Hz, IH), 7.22 (d, J = 8.1 Hz, IH), 6.87 (dd, J = 17.7,11.4 Hz, IH), 6.01 (d, J = 17.7 Hz, IH), 5.42 (d, J = 11.4 Hz, IH), 4.05 (q, J = 7.2 Hz, 2H), 3.08 (t, J = 6.4 Hz, 2H), 1.84 (m, IH), 1.21 (t, J = 7.2 Hz, 3H), 0.88 (d, J = 6.6 Hz, 6H); MS (ES"): 555.2 162c -CHzCsHs -H 161c 1-2 'H NMR (DMSO-d6): 5 12.7 (bs, IH), 10.75 (bs, IH), 9.15 (b, 2H), 8.63 (t, J = 5.8 Hz, IH), 8.27 (bs, IH), 7.90 (d, J = 8.3 Hz, 2H), 7.77 (s, IH), 7.43-7.15 (m, 8H), 7.40 (d, J = 8.1 Hz, IH), 7.29 (d, J = 8.1 Hz, IH), 6.87 (dd, J = 17.4,11.0 Hz, IH), 6.03 (d, J = 17.5 Hz, 1H), 5.71 (s, 2H), 5.42 (d, J = 11.0 Hz, IH), 5.09 (s, 2H), 3.08 (t, J = 6.4 Hz, 2H), 1.85 (ra, IH), 0.88 (d, J = 6.6 Hz, 6H); MS (ES+l): 619.2 162d -C(CH3)3 -H 161d 1-2 !H NMR (DMSO-d6): 812.6 (bs, IH), 11.0 (bs, IH), 9.04 (b, 2H), 8.62 (t, J = 5.4 Hz, IH), 8.24 (s, IH), 7.86 (m, 3H), 7.77 (s, IH), 7.62 (m, 3H), 7.24 (d, J = 8.2 Hz, IH), 7.20 (d,J = 8.0 Hz, IH), 6.87 (dd, J = 17.2,11.0 Hz, IH), 6.00 (d, J = 17.7 Hz, IH), 5.40 (d, J = 11.0 Hz, IH), 3.07 (t, J = 6.3 Hz, 2H), 1.84 (m, IH), 1.44 (s, 9H), 0.88 (d, J=6.6 Hz, 6H); MS (ES+l): 585.4 Cpd.
No. -r -r' Starting From Method Used Analytical Data 164 -CHO -ch3 163 +130 D-2 'HNMR (DMSO-dg): 6 9.58 (s, 1 H), 7.91 (dd, J = 1,2, 8.0 Hz, 1 H), 7.71 (dt, J = 1.2 and 7.4 Hz, 1 H), 7.58 (t, J = 7.4 Hz, 1 H), 7.41 (m, 2 H), 7.38 (m, 1 H), 7.32 (d, J = 8 Hz, 1 H), 7.24 (d, J = 7.4 Hz, 1 H), 3.52 (q,3 = 16 and 26 Hz, 2 H), 3.35 (s, 3 H); MS (ES+): 255.32 165 -co2h -ch3 164 E Characterized in the next step 166 NH xXT* H -ch3 165 J 'HNMR (DMSO-de): 8 10.34 (s, 1 H), 9.18 (s, 2 H), 8.92 (s, 2 H), 7.72-7.5 (m, 7 H), 7-34-7.14 (m; 5 H), 3.60 (q, J = 17 & 40 Hz, 2 H), 3.48 (s, 3 H); MS (ES+) 388.67 167 NH JUT"' H -h 166 1-2 'HNMR (DMSO-dfi): 6 11.74 (bs, 1 H), 9.90 (s, 1 H), 8.79 (bs, 2 H), 7.64 (m, 1 H), 7.50 (m, 7 H), 7.33 (d, J = 8.6 Hz, 1 H), 7.26 (d, J = 7.4 Hz, 1 H), 7.12 (t, J = 7.4 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1 H), 6.89 (d, J = 6.8 Hz, 1 H), 3.83 (d, J = 15 Hz, 2 H); MS (ES+) 374.79 256 o Cpd. No.
-R -R' -R" -R'" Starting From Method Used Analytical Data 188a -CH=CH2(4) X) Mi chj \^~~-ch3 -H 187a AE-3 MS (ES^ i: 485.4 (100% M1"1) 188b -CH=CH2 (4) NH \^CF3 -H 187b AE-3 'HNMR J = 2 Hz, H), 7.65 ( d, J = 8 7.14 (d,. J = 11 aa 9bz, 1 H 5.33 (d, J 9hz, 1 H : 497.3 DMS0-d6/D20): 8 8.5 (d; IH), 8.17 (dd, J = 8 Hz, 2 s, 1 H), 7.63 (s, 1 H), 7.54 Hz, 1 H), 7.49 (bs, 2 H), i = 7.7 Hz, 1 H), 6.78 (dd, 117 Hz, 1 H), 6.62 (d, J = ), 5.83 ( d, J = 17 hz, 1 H), = 11 hz, 1 H), 4.17 (d, J = 1,4.12 (s, 2 H); MS (ES+) 257 Cpd. No.
-R -R' -R" -R'" Starting From Method Used Analytical Data 'HNMR (DMSO-de/DaO): 5 8.6 (m, 3 H), 8.3 (m, 3 H), 7.9 (d, J = 7.9 Hz, 1 H), 7.45 (d, J = 8.8 Hz, 1 H), 7.3 (m, 3 H), 7.1 (m, 1 H), 7.0 (d, J = 8.1 Hz, 1 H), 6.6 (dd, J = 6 and 28 Hz, 1 H), 6.4 (d, J = 8.8 Hz, 2 H), 5.7 (d, J = 17 Hz, 1 H), 5.15 (d, J= 11 Hz, 1 H), 3.9 (m, 2 H), 3.25 (m, 2 H), 1.1 (t,J==&Hz,3 H); MS (ES+) : 443.3 188c -CH=CH2 (4) xA \^/CH3 -H 187c AE-3 188d -CH=CH2(4) NH CHj H 187d AE-3 'HNMR (DMSO-dfi): 8 8.8 (m, 2 H), 8.7 (m, 1 H), 8.4 (m, 2 H), 8.1 (m, 1 H), 7.6 (m, 2 H), 7.5 (m, 3 H), 7.3 (m, 1 H), 7.2 (m, 1 H), 6.8 (m, 1H), 6.6 (m, 2 H), 5.8 (m, 1 H), 5.3 (m, 1 H), 4.1 (m, 2 H), 3.31 (m, 1 H), 3.2 (m, 1 H), 1.7 (m, 1 H), 1.6 (m, 1 H), 1.3 (m, 1 H), 1.0 (m, 6 H); MS (ES+) : 485 189a -OCH3 (3) i xr~- ch3 -H 74 AE-4, 1-2 'HNMR (DMSO-d6): 8 8.60 (t, J = 6 Hz, 1 H), 8.39 (bs, 2 H), 8.28 (bs, 1 H), 7.78 (m, 1H), 7.56 (m, 1 H), 7.43 (dd, J = 5.8 Hz, 3.8 Hz, 2 H), 7.18 (m, 2 H), 6.80 (m, 3 H), 6.51 (bs, 1 H), 4.10 (m, 1 H), 3.85 (m, 1 H), 3.70 (s, 3 H), 3.17 (t, J = 6 Hz, 2 H), 1.80 (m, 1 H), 0.89 (d, J = 6.8 Hz, 6 H); MS (ES+ ) 475.2 • 258 Cpd. No.
-R -R' -R" -R'" Starting From Metbod Used Analytical Data 189b -OBn (4) NH X \x^CH3 -H 184a AE-3 1HNMR (DMSO-dg/DaO): 6 8.24 (d, J = 1.5 Hz, 1 H), 7.86 (d, J = 7 Hz, 1 H), 7.49 (m, 2 H), 7.36 (xn, 4 H), 7.26 (d, J = 8.3 Hz, 1 H), 6.94 (m, 3 H), 6.66 (d, J = 8.7 Hz, 2 Hz, 2 H), 5.03 (s, 2 H), 4.06 (q, J =16 and 21 Hz, 2 H), 3.02 (d, J = 7 Hz, 2 H), 1.86 (m, 1H), 0.89 (d, J = 6.8 Hz, 6 H); MS (ES-): 549.2 and (ES+) 551.4 189c -OH (4) NH CHj \Z^CH3 -H 189b G 'HNMR (DMSO-dfi): 5 11.3 (bs, 1 H), 9.07 (s, 1 H), 8.46 (t, J = 6 Hz, 1 H), 8.27 (bs, 2 H), 8.15 (bs, 2 H), 7.66 (d, J - 7.7 Hz, 1 H), 7.36 (d, J = 8.5 Hz, 2 H), 7.03 (d, J = 8.1 Hz, 1 H), 6.77 (m, 2 H), 6.68 (d, J = 8.3 Hz, 2 Hz, 2 H), 6.6 (s, 1 H), 6.47 9d, J = 8.2 Hz, 1 H), 4.05 (d, J = 14 Hz, 1 H), 3.09 (d, J = 14 Hz, 1 H), 3.01 (t, J = 7 Hz, 2 H), 1.79 (m, 1 H), 0.82 (d, J=6.8 Hz, 6 H); MS (ES-): 459.2 and (ES4) 461.4 189d -H NH ot3 -H 131 AE-3 MS (ES4): 445.4; MS (ES"): 443.3 259 PCT/USOl/32582 Analytical Data Q B on 3 vo 12 ? Is 13 Method Used AE-3 Starting From f0 h ■ h k £ i Cpd. No. 00 r-< o 10 03 260 Cpd. No. -r -r' Starting From.
Method Used Analytical Data 205 X.
-Boc 204 A-4 1HNMR {DMSO-d6): 5 11.04 (s, 0.6 H), 10.97 (bs, 0.4 H), 8.66 (t, J = 5.6 Hz, 0.6 H), 8.56 (t, J = 5.6 Hz, 0.4 H), 8.22 (s, 1 H), 8.11 (d, J = 2 Hz, 0.6 H), 8.03 (d, J = 2 Hz, 0.4 H), 7.94 (dd, J = 2 and 8 Hz, 1 H), 7.82 (m, 4 H), 7.40 (m, 8 H), 7.18 (m, 2 H), 7.04 (m, 2 H), 5.21 (s, 0.8 H), 5.11 (s, 1.2 H), 3.1I (t, J = 6.2 Hz, 1.2 H), 3.06 (t, J = 6.2 Hz, 0.8 H), 1.84 (ra, 1 H), 1.43 (s, 5.4 H), 1.42 (s, 3.6 H), 0.91 (d, J = 6.8 Hz, 3.6 H), 0.88 (d, J=6.8 Hz, 2.4 H); MS (ES+): 665.5 206 -CH2OH -Boc 204 A-6 'HNMR (DMSO-d6): 8 12.15 (bs, 1 H), 11.07 (bs, 1 H), 10.69 (s, 1 H), 10.38 (bs, 1 H), 8.68 (t, J = 5.6 Hz, 1 H), 8.12 (d, J = 1.7 Hz, 1 H), 8.00 (dd, 1.8, 8 Hz, 1 H), 7.68 (m, 4 H), 7.46-7.30 (m, 6 H), 7.16 (d, J = 2.8 Hz, 1 H), 7.01 (d, J = 8.5 Hz, 1 H), 6.86 (dd, J = 8.5 and 2.8 Hz, 1 H), 5.07 (s, 2 H), 4.30 (d, J =7.4 Hz, 2 H), 3.15 (t, J = 6.2 Hz, 2 H), 1.86 (m, 1 H), 1.53 (s, 9 H), 0.89 (d, J = 6.8 Hz, 6 H); MS (ES-): 649.4 207 -ch2oh -H 206 S-2 'HNMR (DMS0-dfi/D20): § 10.66 (s, 1 H), 9.19 (bs, 2 H), 8.86 (bs, 2 H), 8.69 (t, J = 5.5 Hz, 1 H), 8.13 (d, J = 2 Hz, 1 H), 8.02 (dd, J = 8 and 2 Hz, 1 H), 7.72 (m, 4 H), 7.38 (m, 6 H), 7.17 (d, J=2.6 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 6.87 (dd, J = 8.5 and 2.5 Hz, 1 H), 5.39 (t, J = 4.7 Hz, 1H), 5.08 (s, 2 H), 4.30 (xn, 2 H), 3.13 (t3J = 6.5 Hz, 2 H), 1.87 (in, 1 H), 0.91 (d, J = 6.5 Hz, 6 H); MS (ES"*) 551.4 261 Cpd.
No.
-R -R' Starting From Method Used Analytical Data 208 x -^NH2 -H 205 S-2 'HNMR (DMSO-de): 5 11.26 (s, 0.6 H), 11.20 (bs, 0.4 H), 9.15 (bs, 1.2 H), 9.11 (bs, 0.8 H), 8.84 (bs, 1.2 H), 8.82 (bs, 0.8 H), 8.67 (t, J = 5.6 Hz, 0.6 H), 8.58 (t, J = 5.6 Hz, 0.4 H), 8.3 (s, 1 H), 8.12 (d, J = 2 Hz, 0.6 H), 8.04 (d, J = 2 Hz, 0.4 H), 7.96 (dd, J=2 and 8 Hz, 1 H), 7.84 (m, 1 H), 7.70 (m, 2 H), 7.57 (m, 3 H), 7.40 (m, 4 H), 7.22 (m, 2 H), 7.02 (m, 2 H), 5.21 (s, 0.8 H), 5.11 (s, 1.2 H), 3.12 (t, J = 6.5 Hz, 1.2 H), 3.06 (t, J = 6.5 Hz, 0.8 H), 1.84 (m, 1 H), 0.90 (d, J = 6.5 Hz, 3.6 H), 0.86 (d, J = 6.5 Hz, 2.4 H); MS (ES+): 564.5 262 Cpd. No.
-R -R' -R" Starting Flora Method Used Analytical Data 217 -och3 V- O ch, . ch3 -Br 216 A-3 JH NMR (DMSO-ds): 8 8.48 (t, 7= 6.2 Hz, 1H), 8.06 (d, 7= 8.3 Hz, 1 B), 7.69 (d, 7= 8.5 Hz, 1 H), 4.01 (s, 3 H), 3.15 (t, 7=6.5 Hz, 2 H), 1.91 (m, 1 H), 0.91 (d, 7= 6.6 Hz, 6 H); MS (ES*): 287.1 218 -och3 V- 0 ch, -CH=CH2 217 D-12 'H NMR (CDC13): 8 8.08 (m, 2 H), 7.20 (m, 2 H), 6.39 (dd, 7== 2.0 and 17.3 Hz, 1 H), 5.53 (dd, 7=2.0 and 10.9 Hz, 1 H), 4.01 (s, 3 H), 3.15 (t, 7 = 6.5 Hz, 2 H), 1.91 (m, 1 H), 0.91 (d, 7=6.6 Hz, 6H) 219 -OH V- 0 ch.
-CO2CH3 218 E-2, V-3, W-2 'H NMR (DMSO-cftf): 511.05 (s, 1 H), 8.48 (t, 7 = 6.2 Hz, 1 H), 8.06 (d, 7= 8.7 Hz, 1 H), 7.53 (d, 7= 8.5 Hz, 1 H), 3.90 (s, 3 H), 3.12 (t, 7= 6.6 Hz, 2 H), 1.85 (m, 1 H), 0.86 (d, 7= 6.6 Hz, 6 H); MS (ES ): 253.2 220 -OSO2CF3 V- 0 ch3 ^^ch3 -C02CH3 219 B-2 MS (ES"): 407.2 (M+Na)+ 237 ,nh nhlj -nh2 -h 236 AF-1 MS (ES+): 137.1 263 K) CN Cpd.
No.
-R -R' -R" Starting From Method Used Analytical Bata 221 -CHO -OBn -ch3 220 + 6 D-2 'H NMR (CDCI3): 5 9.77 (s, 1H)', 8.40 (d, J=> 7.9 Hz, 1 H), 8.13 (d, J-6.8 Hz, 1 H), 7.83 (d, /= 7.9 Hz, 1 H), 7.61 (d, J-2.60 Hz, 1 H), 7.20 (m, 5 H), 7.21 (m, 1 H), 7.18 (d, J= 8.3 Hz, 1 H), 5.18 (s, 2 H), 3.72 (s, 3 H), 3.35 (q, J= 5.8 Hz, 2 H), 1.96 (m, 1 H), 1.01 (d, J=» 6.8 Hz, 6 H); MS (ES+): 447.4 222 -co2h -OBn -ch3 221 e MS (ES"): 461.3 223 -co2mem -OBn -ch3 222 F MS (ES+): 573.33 (M+Na)+ 224 -COzMEM -OH -ch3 223 g MS (ES+): 461.36 225 -c02mem -OSO2CF3 -ch3 224 B-2 MS (ES+): 615.58 (M+Na)+ 226 -cozmem -ch=ch2 -ch3 225 D-3 or D-12 MS (ES"): 381.35 [(M-MEM)-l] 227 -co2h -ch=ch2 -ch3 226 I-l MS (ES"): 381.35 hs n jH ■a o 264 U> 00 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 228 mh o aXX h -ch=ch2 -ch3 227 j ms (es1): 500.35 ■ 229 nh AXj* h -ch=ch2 -h 228 1-2 ms (es4): 486.32 245 -cho -oh -ch3 221 ad ms (es*): 357.40 246 -cho -oso2cf3 -ch3 245 b-2 Characterized in the next step 247 -cho -ch=ch2 -ch3 246 d-3 ms (es"1): 367.42 248 /=\ ,nh n ' nhj -ch=ch2 -h 247 ae-3 ms (es"'): 472.39 249 nh \£r- H -OBn -ch3 222 j ms (es+): 580.4 265 Cpd. No. 250 -R -R' -R" Starting From Method Used Analytical Data NH XXT* H -OBn -h 249 1-2 MS (ES*): 566.4 MS (ES"): 564.3 251 NH xXA H -oh -H . 250 G MS (ES*): 476.3 MS (ES"): 474.2 252 /==\ /NH H N—J NH2 -ch=ch2 -h 247 AE-3 MS (ES*): 473.44 MS (ES"): 471.43 266 Cpd. No.
-R Starting From Method Used Analytical Data 231b -CO2CH3 230 AG-3 'HNMR (CDCI3): 8 10.17 (d, J = 0.75 Hz, 1 H), 7.62 (d, J « 8.3 Hz, 1 H), 6.94 (dd, J = 8.3,0.75 Hz, 1 H), 6.51 (s, 1 H), 3.90 (s, 3 H) 267 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 232a -H -CHO -CH3 231a + 6a D-6 or D-7 'HNMR (CDC13): 8 9.64 (s, 1 H), 8.44 (d, J = 2 Hz, 1H), 8.02 (dd, J = 8 and 2 Hz, 1 H), 7.60 (d, J = 8.3 Hz, 1 H), 7.40 (d, J = 8 Hz, 1 H), 6.96 (d, J = 8 Hz, 1 H), 6.32 (t, J = 6 and 5 Hz, 1 H), 6.01 (s, 2 H), 3.72 (s, 3 H), 3.33 (t, J = 6.5 Hz, 2 H), 1.93 (m, 1 H), 1.00 (d, J = 6.8 Hz, 6 H); MS (ES+): 384.3 and 406.3 (M+Naf 232b -co2h -CHO -ch3 231b + 6a D-6 or D-7 'HNMR (DMSO-d6): 8 9.87 (s, 1 H), 9.49 (s, 1 H), 8.64 (d, J = 2 Hz, 1 H), 8.3 (s, 1 H), 7.97 (d, J = 8 Hz, 1 H), 7.43 (dd, J = 8 and 2.6 Hz, 1 H), 7.35 (m, 2 H), 6.94 (m, 1 H), 6.05 (s, 0.4 H), 5.98 (s, 0.6 H), 3.55 (s, 1.8 H), 3.52 (s, 1.2 H), 3.02 (t, J = 6.5 Hz, 2 H), 1.78 (m, 1 H), 0.81 (d, J = 6.6 Hz, 6 H); MS (ES"): 426.2 233a -h -co2h -ch3 232a E 'HNMR (DMSO-de): 8 12.29 (bs, 1 H), 8.69 (t, J - 5.5 Hz, 1 H), 8.38 (d, J = 2 Hz, 1 H), 8.03 (dd, J = 8 and 2 Hz, 1 H), 7.58 (d, J = 8.5 Hz, 1 H), 7.36 (d, J = 8 Hz, 1 H), 7.00 (d, J = 8.5 Hz, 1 H), 6.02 (s, 2 H), 3.64 (s, 3 H), 3.12 (t, J = 6.5 Hz, 2 H), 1.87 (m, 1 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES"): 398.2 n C3 <Z> O Ui C/l 00 268 Cpd. No.
-R -R* -R" Starting From Method Used Analytical Data 233b -COzH -COzH -ch3 232b E 'HNMR (DMSO-de): 8 8.64 (t, J = 5.5 Hz, 1 H), 8.38 (d, J = 4 Hz, 1 H), 8.00 (dd, J = 8.5 and 4 Hz, 1 H), 7.59 (dd, J = 8.5 and 4 Hz, 1 H), 7.30 (dd, J = 8 and 2.5 Hz, 1H), 6.52 (s, 0.5 H), 6.48 (s, 0.5 H), 3.60 (s, 1.5 H), 3.58 (s, 1.5 H), 3.08 (t, J = 6.5 Hz, 2 H), 1.84 (m, 1 H), 0.88 (d, J = 6.8 Hz, 6 H) 234a -H NH jUT- H -ch3 233a J MS (ES4): 517.4 234b -COzH juof1"" H -ch3 233b J 'HNMR (DMSO-de): 8 12.41 (bs, 1 H), 11.09 (s, 1 H), 10.96 (s, 1 H), 9.22 (bs. 2 H), 8.96 (bs, 2 H), 8.70 (xn, 1 H), 8.38 (dd, J = 2 and 13 Hz, 1 H), 8.04 (d, J = 8 Hz, 1 H), 7.82 (m, 4 H), 7.65 (dd, J = 8 and 5 Hz, 1 H), 7.39 (dd, J = 8 and 2.'5 Hz, 1 H), 7.11 (dd, J = 8.5 and 1.7 Hz, 1 H), 6.05 (s, 1 H), 3.67 (s, 1.5 H), 3.50 (s, 1.5 H), 3.10 (t, J = 6.5 Hz, 2 H), 1.88 (m, I H), 0.90 (d, J = 6.8 Hz, 6 H) 235a -H NH H -H 234a 1-2 1HNMR (DMSO-dfi+DCl one drop): 8 8.34 (d, J = 2 Hz, 1 H), 7.97 (dd, J = 8 and 2 Hz, 1 H), 7.75 (m, 4 H), 7.33 (dd, J = 3.8 and 8.1 Hz, 2 H), 7.04 (d, J = 8.1 Hz, 1 H), 6.01 (d, J = 6 Hz, 2 H), 3.07 (t, J = 6.5 Hz, 2 H), 1.83 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES-) 501.3; (ES+) 503.3 269 Cpd. No.
-R -R' -R" Starting From Method Used Analytical Data 240 -CH(OH)-CH2OH -Boc -ch3 161d L 'H NMR (DMSO-d6): 8 10.47 (s, IH), 9.07 (s, 2H), 8.72 (t,J = 5.7 Hz, IH), 8.29 (d, J = 2 Hz, IH), 8.08 (dd, J = 8.0,2 Hz, IH), 7.95 (s, IH), 7.92 (s, 1 H), 7.67 (m, 2 H), 7.62 (d, J = 6.5 Hz, 1 H), 7.46 (d, J = 8 Hz, IH), 7.31 (d, J = 8 Hz, IH), 5.50 (d, J = 4.5 Hz, IH), 4.91 (t, J = 5.7 Hz, IH), 4.74 (m, 1 H), 4.25 (s, 1 H), 3.63 (s, 3H), 3.15 (t, J = 6.4 Hz, 2H), 1.91 (m, 1H), 1.50 (s, 9 H), 0.95 (d, J = 6.7 Hz, 6H) 241 -CHO -Boc -ch3 240 M 'H NMR (DMSO-d6): 8 10.69 (s, IH), 10.17 (s, 1 H), 9.10 (bs, 2 H), 8.72 (t, J = 5.7 Hz, IH), 8.30 (d, J = 1.5 Hz, IH), 8.22 (d, J = 1.5 Hz, IH), 8.22 (dd, J = 1.5 and 8 Hz, 1 H), 8.07 (dd, J = 1.5 and 8 Hz, 1 H), 7.89 (s, IH), 7.86 (s, 1 H), 7.65 (s, 1 H), 7.62 (s, 1 H), 7.57 (d, J = 8 Hz, IH), 7.44 (d, J = 8 Hz, IH), 3.57 (s, 3H), 3.11 (t, J = 6.4 Hz, 2H), 1.85 (m, IH), 1.44 (s, 9 H), 0.89 (d, J = 6.7 Hz, 6H) 242 -CH(OH)-CH=CH2 -Boc -ch3 241 AG MS (ES*): 629.39 243 -CH(OH)-CH=CH2 -h -ch3 242 S MS (ES*): 529.38 244 -CHfOH)-CH=CH2 -H -H 243 1-2 MS (ES"): 515.35 270 oc Starting Method Cpd. No. 254 -R Starting From Method Used Analytical Data t -\ ,NH NS— NH2 253 AE-3 MS (ES*): 318.2,320.2 255 /=\ ,NH x / NHBoc 254 R MS (ES*): 418 o !H Cl Ifl o w (A oo 271 PCT/USOl/32582 The following non-limiting examples are presented to further illustrate the present invention. 2'-[( {4-[Amino(imino)methyl]phenyl} atnino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-thien-2-yl-1,1 '-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-thien-3-yl-l, 1 -biphenyl-2-carboxylic acid 2-[({4-[Amino(imino)methyl]phenyl} amino)carbonyl j -4-[(isobutylamino)carbonyl]-l,r:4',l "-teiphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} ammo)carbonyl]-4'-(3-furyl)-4-[(isobutylamino)caxbonyl]-l,r-biphenyl-2-carboxylic acid 2-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-pyridin-4-yl-1,1 '-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl] -4-[(isobutylamino)carbonyl]-4,-(lH-pyrrol-2-yl)-l,r-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-[2-(hydroxymethyl)thien- 3-yl]-4-[(isobutylamino)carbonyl]-1,1 '-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-[3-(hydroxymethyl)thien-2-yl]-4-[(isobutylamino)carbonyl]-l,r-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-vinyl-l,l -biphenyl-2-carboxylic acid 272 PCT/USOl/32582 4*-Allyl-2'-[({4-[amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylaxnino)carbonyl]-1,1 '-biphenyl-2-carboxylate 2'-[( {4-[Amino(imino)metiiyl]p]ienyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-(l,3-thiazol-2-yl)-l,r-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-[3-(hydroxymethyl)-2-furyl]-4-[(isobutylamino)carbonyl]-l, 1 -biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl] -4'-prop-1 -ynyl-1,1 '-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4'-(3-hydroxy-3-methylbut-l-ynyl)-4-[(isobutylamino)carbonyl]-l,l'-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)methyl]plienyl}amiiio)carbonyl]-4-[(3-methylbutanoyl)amino]-4,-vinyl-l,r-biphenyl-2-carboxylic acid 2I-[({4-[Ammo(imino)methyl]phenyl}amino)carbonyl]-4,-(4-hydroxybut-l-ynyl)-4-[(isobutylamino)carbonyl] -1,1 -biphenyl-2-carboxylic acid 2'- [({4- [ Ammo(imino)methyl]phenyl} amino)carbonyl] -4-[(isobutylamino)carbonyl]-4'-[(lE)-3-methylbuta-l,3-dienyl]-l,r-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)methyl]phenyl}axnino)carbonyl]-41-(3-hydroxyprop-l-ynyl)-4-[(isobutylamino)carbonyl]-l, 1 '-biphenyl-2-carboxylic acid 273 PCT/USOl/32582 2'-[({4-[Amino(imino)methyl]phenyl}amino)carboiiyl]-4'-(2-furyl)-4-f(propylamino)carbonyI]-l,r-biphenyI-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(sec-butylamino)carbonyl]-4'-(2-furyI)-1,1 -biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-(2-fiaryl)-4- {[(2,2,2-trifluoroethyl)amino]carbonyl}-l,r-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(iraino)methyl]phenyl} amino)carbonyl3-4'-(2-furyl)-4- {[(4-hydroxybutyl)amino]carbonyl}-l,r-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)methyl]phenyl}amino)carbonyl]-4-[(ethylamino)carbonyl]-4'-(2-furyl)-1,1 '-biphenyl-2-carboxylic acid 2'-[( {4-[Ammo(imino)methyl3phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-5'-methoxy-4 Vinyl-1,1 '-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(immo)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-4'-(thien-2-ylmethyl)-1,1 -biphenyl-2-carboxylic acid 2- (3-[( {4-[Amino(iniino)methyl]phenyl} atnino)carbonyl]pyxidm-4-yl} -5-[(isobutylamino)carbonyl]benzoic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4-[(cyclopentylamino)carbonyl]-4'-vinyl-l,r-biplienyl-2-carboxylic acid 274 PCT/USOl/32582 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-5'-ethoxy-4-[(isobutylamino)carbonyl]-4'-vinyl-1,1 -biphenyl-2-carboxylic acid Methyl 2'-[( {4-[( {[(acetyloxy)methoxy]carbonyI}amino)(immo)methyl]phenyl} amino)carbonyI]-4-[(isobutylamino)carbonyl]-4'-vinyl-l,r-biphenyl-2-carboxylate Methyl 2'-[({4-[ {[(benzyloxy)carbonyl]ammo}(imino)methyl]phenyl}amino) carbonyl]-4-[(isobutylamino)carbonyl]-4'-vinyl-l5r-biphenyl-2-carboxylate N1-{4-[Amino(imino)methyl]phenyl}-N8-isobutyl-6-oxo-6H-benzo[c]chromene-1,8-dicarboxamide 2'-[({4-[Amino(imino)methyl]phenyl}amino)methyl]-4-[(isobutylamino)carbonyl]-4-vinyl-1,1 '-biphenyl-2-carboxylic acid 2'-({[4-(4,5-Dihydro-lH-imidazol-2-yl)pbenyl]ammo}carbonyl)-4-[(isobutylamino)carbonyl]-l,r-biphenyl-2-carboxylic acid 2'-[( {4-[ Amino(ixniEo)methyl]phenyl} amino)carbonyl]-4-[(isobutylamino)carbonyl]-5'-thien-2-yl-l, 1 '-biphenyl-2-carboxylic acid 2'-[({4-[Amino(imino)methyl]phenyl}ammo)carbonyl]-5'-(2-amino-2-oxoethoxy)-4-[(isobutylainino)carbonyl]-1,1 !-biphenyl-2-carboxylic acid 2'-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-4'-ethoxy-4-[(isobutylamino)carbonyl]-l,r-biphenyl-2-carboxylic acid 275 PCT/USOl/32582 2- {5-[( {4-[Amino(imino)methyl]phenyl} amino)carbonyl]-1,3-benzodioxoI-4-y!} -5-[(isobutylamino)carbonyl]benzoic acid 2'-[ 1 -({4-[ Amino(imino)methyl]phenyl} amino)ethyl] -4-[(isobutylamino)carbonyl] -l,l'-biphenyl-2-carboxylic acid 3-[2-[({4-[Ammo(imino)methyl]phenyl}amino)carbonyl]-4-(benzyloxy)phenyl]-6-[(isobutylamino)carbonyl]pyridine-2-carboxylic acid 3-[2-(4-Carbamimidoyl-phenylcarbamoyl)-4-vinyl-phenyl]-6-isobutylcarbamoyl-pyridine-2-carboxylic acid 2'-[(5-Carbamimidoyl-pyridin-2-ylamino)-methyl]-4-isobutylcarbamoyl-4,-vinyl-biphenyl-2-carboxylic acid 2,-{[4-(N-Hydroxycarbamimidoyl)-phenylammo]-methyl}-4-isobutyIcarbamoyl-4'-vinyl-biphenyl-2-carboxylic acid 2'-{[4-(N-Hydroxycarbamimidoyl)-phenylamino]-methyl}-4-isobutylcarbamoyl-4l-vinyl-bipbenyl-2-carboxylic acid methyl ester 3- {2-[(4-Carbaxnimidoyl-phenylamino)-methyl]-4-vinyl-phenyl} -6-isobutylcarbamoyl-pyridine-2-carboxylic acid 276 WO 02/34711 PCT/USOl/32582 Biological Assay Methods In Vitro Assay for Inhibition of TF/FVIIa To assess the inhibition of the test compounds against the target enzyme, TF/FVIIa, an amidolytic assay based upon the absorbance of p-Nitroanalide (pRA) at OD405 was utilized. The IC50 of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Vmax values.
TF/FVIIa assay reactions were performed in a 200 jj,L mixture containing 4 nM FVIIa, 10 nM lipidated tissue factor, in an assay buffer containing 100 mM Tris, pH 7.2, 150 mM NaCl, 5 mM calcium chloride, 0.1 % bovine serum albumin (BSA), and 10% dimethyl sulfoxide (DMSO). TF and FVIIa were allowed to equilibrate at room 15 temperature for 15 minutes. Test compounds dissolved in DMSO were incubated at varied concentrations with TF/FVIIa for 10 minutes, followed by addition of 500 DM substrate Spectrozyme-FVIIa. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD405 nm for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
In Vitro Assay for Human Thrombin This colorimetric assay was used to assess the ability of the test compounds to inhibit the human thrombin enzyme. IC50 of the test compounds was determined by 25 using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Vmax values.
Thrombin assay reactions were performed in a 200 pL mixture containing human thrombin at (1 U/mL) in an assay buffer containing 100 mM HEPES, 10 mM calcium 277 PCT/USOl/32582 chloride, and 10 % DMSO, pH 7.5. Test compounds dissolved in DMSO were added to thrombin enzyme reactions at varied concentrations, followed by the addition of substrate Na-Benzoyl-Phe-Val-Arg p-Nitroanilide at a final concentration of 1 mM. Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD4os 5 nm for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader.
In Vitro Assay for Human Trypsin This enzymatic assay was employed to evaluate the ability of the test compounds to inhibit human pancreatic trypsin. IC50 of the test compounds was determined by using KC4A data reduction software (Bio-Tek Instruments) to interpolate percent inhibition from observed Vmax values.
Trypsin assay reactions were performed in a 200 fiL mixture containing human pancreatic trypsin at 1 jig/mL in an assay buffer containing 200 mM triethanolamine (TEA), 10 mM calcium chloride, 10 % DMSO, pH 7.8. Test compounds dissolved in DMSO were added to trypsin enzyme reactions at varied concentrations, followed by the addition of substrate Na-Benzoyl-L-Arginine p-Nitroanilide (L-BAPNA) at a final concentration of (0.25 mg/mL). Reactions were incubated for 5 minutes at room temperature prior to measuring the change in OD405 nm for 10 minutes at 21 second intervals with a Powerwave x (Bio-Tek Instruments) microplate reader. 278 PCT/USOl/32582 Biological Data IC50 Values of Some Selected Compounds on Different Serine Protease Enzymes R (With Respect to Phenyl Ring R' TF/FVUa Trypsin Thrombin — y «i ch3 ++ + + s \^ch3 ++ + + /^il —;—(\ |j (4) TSS cm, ++ 4* + ch, v 3 QH (4) ch3 ch3 +4* - - -o-O ch3 + - - ,^3 (3) ch3 ++ - - +++ ++ 4* 279 PCT/USOl/32582 \^cha |c4) /CH' +++ ++ + .o. +++ ++ + \^ch2 (4) ch3 \>-ch3 +++ ++ + IC50 values: + means >1 |iM; ++ means >100 nM; +++ means <100 nM 280 PCT/USOl/32582 A comparison of Examples with R group and without R group illustrates the greatly-enhanced activity achieved pursuant to the present invention.
Compounds of the present invention are useful as inhibitors of trypsin-like serine 5 protease enzymes such as thrombin, factor Vila, TF/FVIIa, and trypsin.
These compounds may be employed to inhibit the coagulation cascade and prevent or limit coagulation.
These compounds may be used to inhibit the formation of emboli or thromboli in blood vessels.
These compounds may be used to treat tbrombolymphangitis, tbrombosinusitis, thromboendocarditis, thromboangitis, and thromboarteritis.
These compounds may be used to inhibit thrombus formation following angioplasty. These may be used in combination with other antithrombolytic agents such as tissue plasminogen activators and their derivatives, streptokinase and its derivatives, or urokinase and its derivatives to prevent arterial occlusion following thrombolytic therapy.
These compounds may also be used in matastatic diseases, or for any disease where inhibition of coagulation is indicated.
These compounds may be used as diagnostic reagents in vitro for inhibiting clotting of blood in the tubes.
These compounds may be used alone or in combination with other compounds such as heparin, aspirin, or warfarin and any other anticoagulant agents. 281 PCT/USOl/32582 These compounds may be used as anti-inflammatory agents.
According to a further aspect of the invention, compounds may be employed in preventing ex vivo coagulation such as that encountered in the extracorporeal perfusion 5 of blood through for example artificial valves, prothesis, stents or catheters. According to this aspect of the invention the extracorporeal device may be coated with the compositions of the invention resulting in a lower risk of clot formation due to extrinsic pathway activation.
Dosage and Formulation The compounds of this invention can be administered by any means that produces contact of the active agent's site of action with factor Vila and other serine proteases in the body of a human, mammal, bird, or other animal. They can be administered by any 15 conventional means, such as oral, topical, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. Parenteral infusion includes intramuscular, intravenous, and intraarterial. They can be administered alone, but generally administered with a pharmaceutical carrier 20 elected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage administered will, or course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and 25 route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms, the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.0001 to 1000 milligram (mg) per kilogram (kg) of body weight, with the preferred dose being 0.1 to about 30 mg/kg. 2 82 WO 02/34711 PCT/USOl/32582 Dosage forms (compositions suitable for administration) contain from about mg to about 500 mg of compound per unit. In these pharmaceutical compositions, the compound of the present invention will ordinarily be present in an amount of about 0.5-5 95% by weight based on the total weight of the composition.
The daily dose of the compounds of the invention that is to be administered can be a single daily dose or can be divided into several, for example, two, three or four, part administrations. The pharmaceutical compositions or medicaments of the invention can 10 be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion 15 solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
Gelatin capsules contain a compound of the present invention and powdered 20 carriers, such as lactose, starch, cellulose derivatives, biocompatible polymers, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated to mask by unpleasant taste and protect the tablet 25 from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. They may also contain buffering agents, surfactants and 283 PCT/USOl/32582 preservatives. Liquid oral products can be developed to have sustained-release properties. They may also contain cyclodextrin derivatives to enhance the solubility of the active ingredient and to promote its oral uptake.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffering agents. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company and in the Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association, both standard reference texts in this field.
Useful pharmaceutical dosage forms for administration of the compounds according to the present invention can be illustrated as follows: Hard Shell Capsules A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered 1500 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate. 284 PCT/USOl/32582 Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The prodrug can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.
Tablets ' A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocystalline cellulose, 11 mg of starch, and 9.98 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase 15 palatability improve elegance and stability or delay absorption.
Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. 20 These units are taken orally without water for immediate dissolution and delivery of the medication. The drug is mixed containing ingredient such as sugar, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
Moreover, the compounds of the present invention can be administered in the foim of nose drops, metered dose nasal or buccal inhalers. The drug is delivered from a nasal solution as a fine mist or from a powder as an aerosbl. 285

Claims (67)

WO 02/34711 PCT/USOl/32582 In another embodiment of the invention, a compound of the invention can be used in an assay to identify the presence of factor Vila and other serine protease or to isolate , factor Vila and other serine protease in a substantially purified form. For example, the compound of the invention can be labeled with, for example, a radioisotope, and the 5 labeled compound is detected using a routine method useful for detecting the particular label. In addition, £ compound the invention can be used advantageously as a probe to detect the location or amount of factor Vila and other serine protease activity in vivo, in vitro or ex vivo. 10 Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in flie art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. The foregoing disclosure includes all the information deemed essential to enable IS those skilled in the art to practice the claimed invention. The foregoing description of the invention illustrates and describes the present invention. Additionally, the disclosure shows and describes only the preferred embodiments of the invention but, as mentioned above, it is to be understood that the invention is capable of use in various other combinations, modifications, and environments and is capable of changes or 20 modifications within the scope of the inventive concept as expressed herein, commensurate with the above teachings and/or the skill or knowledge of the relevant art. The embodiments described hereinabove are further intended to explain best modes known of practicing the invention and to enable others skilled in the art to utilize the invention in such, or other, embodiments and with the various modifications required by 25 the particular applications or uses of the invention. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended that the appended claims be construed to include alternative embodiments; 286 What is claimed is 10
1. Compound having the structure (I) shown below: B1 R (R1) E*- m X w V1 L V X (A) £2 B (R2). (I) ; pharmaceutically P acceptable salts thereof; and prodrugs thereof; 15 each E and L individually is a 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic saturated or unsaturated carbon ring, bicyclic saturated or unsaturated hetero ring, or 1-8 hydrocarbon chain which may be substituted with one or more hetero groups selected from N, O, S, S(O), and S(02) which may be saturated or unsaturated; 20 R is -CH=CH-R2, -QfC-R2, -C(R2)=CH2, -C(R2)=C(R3), -CH=NR2, -C(R2)=N-R3,4-7 membered saturated or unsaturated carbon ring system with or without substitution, 4-7 membered saturated or unsaturated hetero ring system with or without substitution, or chain of 2 to 8 carbon atoms having 1 to 5 double or triple bonds with substitutions 25 selected from R1, R2, or R3. Preferably, these R, R1, R2, or R3 do not include -(C2-4 alkenyl)-C02-Ci-8 alkyl, -(C2-4 alkenyl)-C02-Ci.8 alkyl-phenyl, and-(C2-4 alkenyl)-C02-Ci-8 alkyl-O-Ci.4 alkyl; Rl is H, -R, -N02, -CN, -halo, -N3, -C ,.8 alkyl, -(CH2)nC02R2, -C2.8 alkenyl-C02R2, 30 -0(CH2)„C02R", -C(0)NR2R3, -P(0)(0Rz)2, alkyl substituted tetrazol-5-yl, 287 -(CH2)nO(CH2)n aryl, -NR2R3, -(CH2)n OR2, -(CH2)n SR2, -N(R2)C(0)R3, -S(02)NR2R3, -N(R2)S(02)R3, -(CHR2)n NR2R3, -C(0)R3, (CH2)n N(R3)C(0)R3, -N(R2)CR2R3 substituted or unsubstituted (CH2)n-cycloalkyl, substituted or unsubstituted (CH2)n-phenyl, or substituted or xmsubstituted (CEbVhetesrocycle which may be saturated or unsaturated; m is 1 except that when E1 is a cyclic ring of more than 5 atoms, then m is 1 or higher, depending upon the size of the ring; R2 is H, -halo, -alkyl, -haloalkyl, -(CH2)n -phenyl, -(CH2),.3-biphenyl, -(CH2),.4-Ph-N(S02-Ci-2-alkyl)2, -COCCHR'VOR1, -(CHR^-heterocycle, -(CHR^-NH-CO-R1, -(CHRl)n-HH-S02R13-(CHR1)n-Ph-N(S02-Ci.2-alkyl)2, -(CHRVCtOXCHR^-NHR1, -(CHR1)„-C(S)(CHR')-NHR1, -(CH2)nO(CH2)nCH3, -CF3, -C2.5 acyl, -(CHR')nOH, -(CHR^COzR1, -(CHRVO-alkyl, -(CHR')n-0-(CH2)n-0-alkyl, -(CHR')n-S-alkyl, -(CHR1 )n-S(0)-alkyl, -(CHR!)n-S(02)-alkyl, -(CHR'VS^-NHR3, -(CHR3)n-N3, -(CHR3)nNHR4,2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to 8 carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted-(CHR3)n heterocycle, or substituted or unsubstituted-(CHR3)n cycloalkyl which may be saturated or unsaturated; when n is more than 1, the substitutions R1 and R3 may be same or different; R3 is H, -OH, -CN, substituted alkyl, -C2.s alkenyl, substituted or unsubstituted cycloalkyl, -N(R!)R2, or 5-6 membered saturated substituted or unsubstituted hetero ring; -NR2R3 may form a ring system having 4 to 7 atoms or may be bicyclic ring; wherein said ring system comprises carbon or hetero atoms and further it may saturated or unsaturated and also may be substituted or unsubstituted; 288 INTELLECTUAL PROWv nFclGE of >'1/ - 8 JUN 2005 RECEIVED WO 02/34711 PCT/USOl/32582 W is a direct bond, -CHR2-, -CH=CR2-, -CR2=CH-, -CR2=CR2-, -C=C-, -O-CHR2-, -CHR2-0-, -N(R2)-C(0)-, -C(0)-N(R2)-, -N(R2)-CH-(R3)-, -CH2-N(R2)-, -CH^-NCR2)-, -S-CHR2-, -CHR2-S-, -S(02)-N(R2)-s -C(0)N(R2)-(CBR2)n-, -C(R1R2)n-NR2-, -N(R2)-S(02)-, -R2C(0)NR2-, -R2NC(0)NR2-, -CONR2CO-, 5 -C(=NR2)NR2-, -NR2C(=NR2)NR2-, -NR20-, -N=NCHR2-, or -C(0)NR2S02-; E2 is 5 to 7 membered saturated or unsaturated carbon ring, 5 to 7 membered saturated or unsaturated hetero ring, bicyclic ring system, Ci.g alkyl, C2-8 alkenyl, C2„8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino; 10 each X individually is a direct bond, substituted or unsubstituted Cm methylene chain, O, S, NR.2, S(O), S(02), or N(O) containing one or two Cm substituted or unsubstituted methylene chains; X at different places may be same or different; 15 B is H, -halo, -CN, -NH2, -(CH2)„-C(=NR4)NHR5, -(CH2)n-NHR4, -(CH2)nNHC(=NR4)NR5, -(CH2)n-OR4, Ci-8 substituted or unsubstituted alkyl, substituted or unsubstituted ring system having 4 to 7 carbon or hetero atoms which may be saturated or unsaturated; 20 B1 is selected from B; B1 and B may be same or different; N?}iere may be more than one similar or different R2 groups present on E2, when E2 is a cyclic group of more than 5 atoms; p is 1 except that when E2 is a cyclic ring of more than 5 atoms, p is 1 or higher depending upon the size of the ring; 25 n is 0-4; A is selected from R1; o is 1 except that when L is a cyclic ring of more than 5 atoms, o is 1 or higher depending 3 0 upon the size of the ring; 289 each V and V1 individually is selected from R1 and N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic; N.N-disubstituted carboxamidyl of the formula -CONRiR2 where Ri and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different; mono- or disubstituted sulfonamides of the formula SO2NHR or -SO2NR1R2; and methylene- or polymethylene chain-extended variants thereof; each R4 and R5 individually is H, -(CH2)„OH, -C(0)0R6, -C(0)SR6, -(CH2)„ C(0)NR7R8, -0-C(0)-0-R7, an amino acid or a dipeptide; each R6is H, R7, -C(R7)(R8)-(CH2)n-0-C(0)-R9, -(CH2)„-C(R7)(R8)-0-C(0)R9, -(CH2)„-C(R7)(R8)-0-C(0)-0-R9, or-C(R7)(R8)-(CH2)n-0-C(0)-0-R9; and each R7, R8 and R9 individually is H, alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heterocycle, substituted heterocycle, alkylaryl, substituted alkylaryl, cycloalkyl, substituted cycloalkyl, or CH2C02alkyl. 290 INTELLECTUAL PROPERTY OFFICE OF AI.Z -8 JUN 2005 RECEIVED WO 02/34711 PCT/USOl/32582
2. The compound of claim 1 represented by the structure R co2ch3 r" wherein R is selected from the group consisting of 10 ch, .0- -OH, -OSO2CF3, and —B 15 -ch3 -ch3 ch, and R' is selected from the group consisting of 20 YN « r ssv//^ch.' h ^gh, o ch, 25 YS T' • Y8"^' ■ Y YY o o o o ^—' 30 ch, \^n^/ch3 s 0 o ch ■3 ,-co2mem, ,ch, 35 40 o ch, AY . \^N0H. ch, ch, h ,n- h ,n. ch3 ioc 9^ ch3 ' ,n. ch, ch3 , and -CH2NH2; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 291 WO 02/34711 PCT/USOl/32582
3. The compound of claim 1 represented by the structure Rs. 1 o wherein R is selected from the group consisting of 0 -OBn, -OH, -OSO2CF3, a*' "CE, I > 15 OHC CHO OHC ^^ch2 ' ft \\ ' U \ // \\ . v 20 25 N3H2C. -OCH3; CHjOH HOH2C. and and R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM; and 30 pharmaceutically acceptable salts thereof; and prodrugs thereof. 292
4. The compound of claim 1 represented by the structure C02Bn r' wherein R is -oso2cf3; and R' is selected from the group consisting of 10 -CH0,-C02H, and h f ; and pharmaceutically acceptable salts thereof; o 15 and prodrugs thereof. 293 'NTELLECTUAL^PROPERTV OFFICE, - 8 JUN 2005 -jjjcef vgn I WO 02/34711 PCT/USOl/32582
5. The compound of claim 1 represented by the structure 10 wherein R is selected from the group consisting of 294 WO 02/34711 PCT/USOl/32582 OHC. OHC. y ohc -s 10 :CH Boc BnO.C. CH, j OH / BnU2C / . CX • Cl-oh. o. 15 HOH2C. hoh2c o ■ and N, 20 and R' is selected from the group consisting of -CHO, -CO2H, and -C02MEM; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 295 WO 02/34711 PCT/USOl/32582
The compound of claim 1 represented by the structure NH 10 Bn02C' 15 . wherein R is selected from the group consisting of ' o H,C -s 20 \ H C O' JJ-'tK- 25 n N n 30 ' n CH, 'CH2 sv n ' 35 CH, H,C /"oh ' -==\ ^.ch, CH, 40 /ghz -< ■ CH, ^oh CH, :ch OH ,CH, CH, 296 WO 02/34711 PCT/USOl/32582 .OH CEL. 9 OH HOHjC 10 HOH2C II w •s' OH n OH Boc and n3 ; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 15 297 WO 02/34711 PCT/USOl/32582
7. The compound of claim 1 represented by the structure 10 NH, NHR' H02C 15 wherein R is selected from the group consisting of 20 . // w. S' s" H3C ,s. 0 H,C. 25 o . Cx. 30 N Q--Q- >CH, f=\ , S. , CH, . • /* CH,, , ■ CH, 35 =\/ch, H/"OH ,OH CH, /= .oh CH, 40 CH, :CH OH < \ ,OH CH, OH 298 WO 02/34711 PCT/USOl/32582 (X_ c en oh h02c ,g. hoh2c 10 hoh.c / oh s n h oh n3 , sch3, 15 NH2 , o "oh , ch, ^ch3 , /^v^ch; 20 n3h2c, ,ch2oh ^ O Cx ^Cr , » s ' o ' ' 25 hoh2c // w \, -J ^ J~\ // ch, -OCHj ^ 30 35 and <7 -nh, and R' is selected from the group consisting of ch, 40 ch, ,ch, ch, ch, ,cf, 299 WO 02/34711 PCT/USOl/32582 300 WO 02/34711 PCT/USOl/32582
The compound of claim 1 represented by the structure NH 10 H3COj wherein R is selected from the group consisting of 15 x vch JQ- 20 n3h2c. ch, 25 ch,oh hoh,c // \\ . -0^ ^ 0 -OBn, -OCH3, and prodrugs thereof. ; and pharmaceutically acceptable salts thereof; and 30 ch2nh2 301 WO 02/34711 PCT/USOl/32582
9. The compound of claim 1 represented by the structure NH 10 h3co2c wherein R is selected from the group consisting of 15 tips -OSO2CF3, / ? , and / nh . 20 A, and R1 is -H or ; and pharmaceutically acceptable salts thereof; and prodrugs OBn thereof. 25 302 WO 02/34711 PCT/USOl/32582 10
10. The compound of claim 1 represented by the structure Rv h3co2c wherein R is selected from the group consisting of -OBn, -OH, -OSO2CF3, , -CH==CH2, and -H; 0' S 15 R' is selected from fee group consisting of -CHO, -CO2H, and -C02MEM; 20 25 35 and R" is selected from the group consisting of o -CO2MEM, H CH, CH, 30 chj Y CH, X \ .n CH, ' o o 0 H n\^ch3 CHj and C02H . and pharmaceutically acceptable salts thereof; and prodrugs thereof. CH3 ' 303
11. The compound of claim 1 represented by the structure NH 10 h3co2c nhr' wherein R is selected from the group consisting of 15 -OBn, -OH, -OSO2CF3, , and -CH=CH2; 20 R1 is -H or -Boc; and R" is -CO2MEM or -CO2H; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 304 I INTELLECTUAL PROPFRTv QFRCEl i of n7 - 8 JUN 2005 RECEIVED WO 02/34711 PCT/USOl/32582
12. The compound of claim 1 represented by the structure 10 wherein R is 15 20 nhr' R02C -CH3 and R' is selected from the group consisting of 305 WO 02/34711 PCT/USOl/32582 10 and pharmaceutically acceptable salts thereof; and prodrugs thereof. 306 WO 02/34711 PCT/USOl/32582
13. The compoimd of claim 1 represented by the structure 10 ho2c' wherein R is 15 and R' is selected from the group consisting of 20 25 30 chj ch3 ' ch, ch, , oh ch, ' ^chj ' ch, 35 40 ch -ch, \ // 307 WO 02/34711 PCT/USO1/32582
14. The compound of claim 1 represented by the structure NH . 10 nhr' ho2c; wherein R is J) and -CH=CH2 and R' is selected from the group consisting of 15 X0 ,ch, 20 "ch. ' X>' ^<7 , and "ch,' and pharmaceutically acceptable salts thereof; and prodrugs thereof. 25 309
15. The compound of claim 1 represented by the structure NH 10 InHBoc r02c wherein R is -CHj and R' is selected from the group consisting of 15 ,CHj ■x^-O CH, N ' •CH, 'CF, 20 CH, CH, .ch, -CH, \ //' OH 25 30 ,CH, CH, CH, 35 , and 40 and pharmaceutically acceptable salts thereof; and prodrugs thereof. nh2 , .CH, . s i SCH, 310 INTELLECTUAL PROPERTY OFFICE OF NZ - 8 JUN 2005 RECEIVED WO 02/34711 PCT/US01/32582
16. The compound of claim 1 represented by the structure 5 r"02c 10 wherein at least one R is selected from the group consisting of -OCH3, -OH, -0S02CF3, -CH=CH25 -0CH2C02C2H5, 15 -OCH2CONH2, 20 CH, CH, 25 'OAc: \ s \ , -OBn, -OH, -OSO2CF3, 0 v 0 OAc 30 , -OCH3, -OBn, -H, -OBn, and -CH=CH2; R' is selected from the group consisting of 35 NH -CHO, -CO2H, -CO2MEM, 40 NHBoc 3X1 WO 02/34711 PCT/USO1/32582 312 WO 02/34711 PCT/USOl/32582 acceptable salts thereof; and prodrugs thereof. 313 WO 02/34711 PCT/USOl/32582
17. The compound of claim 1 represented by the structure NH 10 R'02C 15 wherein at least one R is selected from the group consisting of -ch=ch2, -OSO2CF3, -OCH2CO2C2H5, -och2conh2, 20 ' / w , -OCH3, \0 o ch3 » ,-0-ch2-ch2-0Ac, -oh, 25 CH3 -0ch2c02h, -o-CH2-CH2-oh, -ch(oh)ch2oh, -ch2oh, -co2h, 30 , -OBn, -OH, -0CH3, -OBn, -OH, -OC2H5, 35 -OBn, -OCH3, and -CH(OH)CH3; and R1 is selected from the group consisting of -CH3, -CHzCeHs, -Bn, -H; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 3X4
18. The compound of claim 1 represented by the structure NH wherein at least one R is selected from the group consisting of -CH=CH2) -CH(OH)CH2OH, -CH=0, -CH2OH, -C02H, -OCH3, -CH=CH2; and -CH=CH2; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 315 IfcLLECTUAL^PROPERTY OFFICE " 8 JUN 2005 D r> a I
19. The compound of claim 1 represented by the structure 10 wherein R is selected from the group consisting of halo and -B(OH)2; R1 is selected from the group consisting of-H, -OCH3, and -OBn; R2 is selected from the group consisting of -H, -OCH3, -OC2H5, -OCH(CH3>2, and \ , ; 15 ^ c(ch3j3. R3 is selected from the group consisting of -H, -OH, -OBn; and R4 is -OBn or -H; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
20 20. The compound of claim 19 wherein said halo is -Br. 315 flNTELLEC, I (ML PROPERTY OFFICE I OF N.Z - 8 JUN 2005 D r rt r- WO 02/34711 PCT/USOl/32582
21. The compound of claim 1 represented by the structure nh 10 15 and pharmaceutically acceptable salts thereof; and prodrugs thereof. 317
22. The compound of claim 1 represented by the structure 15 nhr" h3c02c 10 wherein R is selected from the group consisting of o -CH3,-C2H5,-CH(CH3)2, and 11 ; ^ c(ch3)3 R' is selected from the group consisting of -OBn, -OH, -OSO2CF3, and -CH==CH2; 20 R" is selected from the group consisting of -CO2H, -C02MEM, and -CHO; and R"1 is selected from the group consisting of 25 h, ch3 , ch, ch,' ,ch, ch, 30 cf, ch, 35 :h, ch,,and ;and pharmaceutically acceptable salts thereof; ch, and prodrugs thereof. 3x8 INTELLECTUAL PROPERTTorcF] OF |\)^ ur ,W: - 8 JUN 2005 —Q-ECETVED WO 02/34711 PCT/USOl/32582
23. The compound of claim 1 represented by the structure NH 10 NHR" R'02C 15 wherein R is selected from the group consisting of o -CH3, -C2H5, -CH(CH3)2, , and -H; c(ch3)3 20 R' is -H or alkyl; and R" is selected from the group consisting of CH, 25 chj CH3 , CH, "CH, 30 CH, ; and pharmaceutically acceptable salts 35 thereof; and prodrugs thereof.
24. The compound of claim 23 wherein said alkyl is -CH3. 319 WO 02/34711 PCT/USOl/32582
25. The compound of claim 1 represented by the structure 10 R"02C wherein R is selected from the group consisting of 15 20 -N V \\ n- 25 . ^,N V CF. .CF, ■ H 3 ^ / / V—CF, H // \\ n H CF' .CF, N H / // \\ 30 / 8-V/ W _ JH-J ^ 35 / \ -N V 9 \ n= -N-H 40 N= \ 6 OMe n H ■N 320 WO 02/34711 PCT/USOl/32582 /""a // r in N H // ^ NH, /K3 , 10 /s-0 • /B_0, / -Q. 15 \ r\ y N H O / \^-oh 20 25 r -< H n- 30 N H N' H [/ \ H f/ ^,N—(J J—OH J OH CH, 35 / ^Qz N' H N . H NH2 "o. N 40 -OH, / At NH2 . ,N s-^rv- NH, ' / / 2' / w \=N — .ci 321 WO 02/34711 PCT/USOl/32582 H f/ \_jf H f/ H f/ ^ y \ , y CHjCN , y CH2NH. 5 and 10 R' is -H, -CH=CH2; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
26. The compound of claim 25 wherein said alkyl is -CH3. 322 WO 02/34711 PCT/USOl/32582
27. The compound of claim 1 represented by the structure NH 10 nh, 15 r-o2c wherein R is selected from the group consisting of , -CH=CH2, and -H; R' is -H or alkyl; and R" is selected from the group consisting of 20 o chj 25 and N ch3> CHj n' CH, CH, Boc CH3 CH, ; and pharmaceutically acceptable salts thereof; and prodrugs CH, 30 thereof.
28. The compound of claim 27 wherein said alkyl is -CH3. 35 323 WO 02/34711 PCT/USOl/32582
29. The compound of claim 1 represented by the structure 10 wherein N is located at position 3 or 4 in the phenyl ring; R is selected from the group consisting of -CHO, -CO2H, and 20 and R' is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
30. The compound of claim 29 wherein said alkyl is -CH3. 324 WO 02/34711 PCT/USOl/32582
31. The compound of claim 1 represented by the structure NH O 10 OR R'OjC 15 wherein R is selected from the group consisting of -ch* -c2h5, -chzcehs, -c(ch3)3, -ch2-cc13, \ // -OMe ^ // 20 m m 9^ 0 ,and •/^0'^vsch ' I CH, CH, 25 and R' is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
32. The compound of claim 31 wherein alkyl is CH3. 30 325 WO 02/34711 PCT/USOl/32582
33. The compound of claim 1 represented by the structure ,R wherein R is selected from the group consisting of 10 -CHO, -C02H: 15 ; and R' is -H or alkyl; and phannaceutically acceptable salts thereof; and prodrugs thereof. 20
34. The compound of claim 33 wherein said alkyl is -CH3. 326 WO 02/34711 PCT/USOl/32582
3 5. The compound of claim 1 represented by the structure 5 rb,o2c nhr" 10 wherein at least one R is selected from the group consisting of -CH=CH2, -OCH3, -OBn, -OH, and -H; R' is 15 (H ""NH, or "nh, n 20 R" is selected from the group consisting of ch, 25 ch, , \^/,CF3 , and ; and R'" is -H; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 30 327 WO 02/34711 PCT/USOl/32582
36. The compound of claim 1 represented by the structure NH NHR' BnO 10 15 wherein R is -CH2OH or NHn and R' is -Boc, or -H; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 20 328 WO 02/34711 PCT/USOl/32582
37. The compound of claim 1 represented by the structure Rs , R" N R' wherein R is -OCH3, -OH, -0S02CF3, -C(=NH)NH2, and -H; 10 R' 15 -is Y Alkyl o . NH and R" is halo, -CH=CH2, -C02CH3, and —\ ; NH, and pharmaceutically acceptable salts thereof; and prodrugs thereof. 20
38. The compound of claim 37 wherein said halo is -Br. 329
39. The compound of claim 1 represented by the structure r"02c n 0 10 wherein R is selected from the group consisting of -CHO, -CO2H, -CO2MEM, nh 15 nh, , and h „N \\ // nh nh2 20 R1 is selected from the group consisting of -OBn, -OH, -OSO2CF3, and -CH=CH2; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 25
40. The compound of claim 39 wherein said alkyl is -CH3. 330 intellectual property office of - 8 JUN 2005 __EEC E1 v e n WO 02/34711 PCT/USOl/32582
41. The compound of claim 1 represented by the structure /wCH° 0 f Br \—o r wherein R is -CO2CH3; and pharmaceutically acceptable salts thereof; and prodrugs 10 thereof. 331 WO 02/34711 PCT/USOl/32582
42. The compound of claim 1 represented by the structure CO2R" o 10 wherein R is -H or -CO2H; R1 is selected from the group consisting of -CHO, -COaH, and NH 15 O A, H ^nh2 20 and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof.
43. The compound of claim 42 wherein said alkyl is -CH3. 25 332 WO 02/34711 PCT/USOl/32582
44. The compound of claim 1 represented by the structure NH wherein R is selected from the group consisting of -CH(0H)-CH20H, -CHO, and 15 -CH(OH)~CH=CH2; R' is -Boc or -H; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; and prodrugs thereof. 20
45. The compound of claim 44 wherein said alkyl is -CH3. 333
46. The compound of claim 1 represented by the structure ,r 5 wherein R is \nh 10 15 nh2 or and pharmaceutically acceptable salts thereof; and prodrugs thereof.
47. A pharmaceutical composition containing at least one compound according to claim 1.
48. A use of at least one compound according to claim 1 in the manufacture of a 20 medicament for inhibiting serine protease in a patient.
49. A use of at least one compound according to claim 1 in the manufacture of a medicament for inhibiting the coagulation cascade and preventing or limiting coagulation.
50. A use of at least one compound according to claim 1 in the manufacture of a 25 medicament for inhibiting the formation of emboli or thromboli in blood vessels.
51. A use of at least one compound according to claim 1 in the manufacture of a medicament for treating at least one condition selected from the group consisting of thrombolymphangitis, thrombosimisitis, thromboendocarditis, thromboangitis, and thromboarteritis. 30
52. A use of at least one compound according to claim 1 in the manufacture of a medicament for inhibiting thrombus formation following angioplasty. 334 INTELLECTUAL PROPERTY OFFICE OF i\I.Z - 8 JUN 2005 5
53. A use of at least one compound according to claim 1 and an effective amount of at least another antithrombolytic agent in the manufacture of a medicament for preventing arteria occlusion following thrombolytic therapy. 10
54. The use of claim 53 wherein said other antithrombolytic agent is selected from the group consisting of tissue plasminogen activators, streptokinase and urokinase, and functional derivatives thereof. j5
55. A use of at least one compound according to claim 1 in the manufacture of a medicament for treating metastatic diseases.
56. A use of claim 49 wherein the medicament is formulated for administration with a further anticoagulant agent. 20
57. The use of claim 56 wherein said further anticoagulant agent is selected from the group consisting of heparin, aspirin, and warfarin.
58. A use of at least one of the compounds according to claim 1 in the manufacture of a medicament for treating a patient in need of an anti-inflammatory agent. 25
59. A method for inhibiting in vitro clotting of blood which comprises contacting said blood with at least one compound according to claim 1. 335 INTELLECTUAL PROPERTV OFRCE OF N.Z - 8 JUN 2005 RECFIVFn
60. The method of claim 59 which comprises inhibiting said blood in tubes.
61. An extracorporeal device having a coating therein which comprises a compound according to claim 1.
62. The compound of claim 1 represented by the structure wherein R is alkyl and R' is selected from the group consisting of ,ch3 "CH, •ch, ch, ch, ch, ch, -ch, ' ch, ch, ch, >h ch, ch. ' ch3 ' '3 CHj 336 intellectual property office of n.z - 7 JUL 2005 RECEIVED and pharmaceutically acceptable salts thereof; and prodrugs thereof.
63. A compound as claimed in claim 1 substantially as herein described with reference to any example thereof.
64. A pharmaceutical composition as claimed in claim 47 substantially as herein described with reference to any example thereof.
65. A use as claimed in any one of claims 48 to 53, 55 and 58 substantially as herein described with reference to any example thereof.
66. A method as claimed in claim 59 substantially as herein described with reference to any example thereof.
67. An extracorporeal device as claimed in claim 61 substantially as herein described with reference to any example thereof. 337 INTELLECTUAL PROPERTY OFFICE OF N.Z - 7 JUL 2005 RECEIVED
NZ526003A 2000-10-20 2001-10-22 Biaryl compounds as serine protease inhibitors NZ526003A (en)

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