CA2426430C - Biaryl compounds as serine protease inhibitors - Google Patents
Biaryl compounds as serine protease inhibitors Download PDFInfo
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- CA2426430C CA2426430C CA2426430A CA2426430A CA2426430C CA 2426430 C CA2426430 C CA 2426430C CA 2426430 A CA2426430 A CA 2426430A CA 2426430 A CA2426430 A CA 2426430A CA 2426430 C CA2426430 C CA 2426430C
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- C07—ORGANIC CHEMISTRY
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- 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
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- 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
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- 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
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- 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
- A61K31/38—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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- A61K31/00—Medicinal preparations containing organic active ingredients
- 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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- 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
- A61K31/395—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
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- 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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- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
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- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—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
- 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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- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C251/48—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
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- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
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- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
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- C07C257/00—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
- 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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- C07C259/00—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
- 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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- C07C259/12—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
- C07C259/20—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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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- 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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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
- C07C271/64—Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates
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- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
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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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- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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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. One example of a compound according to formula (I) is:
(see formula I) wherein R is -OSO2CF3; and R' is selected from the group consisting of -CHO, -CO2H, and (see formula II) ; and pharmaceutically acceptable salts thereof.
(see formula I) wherein R is -OSO2CF3; and R' is selected from the group consisting of -CHO, -CO2H, and (see formula II) ; and pharmaceutically acceptable salts thereof.
Description
DEMANDES OU BREVETS VOLUMINEUX
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BIARYL COMPOUNDS AS SERLNE PROTEASE INHIBITORS
DESCRIPTION
=
Technical Field The present invention relates to the identification, through synthesis and testing, of heretofore unreported 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.
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.
JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.
NOTE: For additional volumes please contact the Canadian Patent Office.
BIARYL COMPOUNDS AS SERLNE PROTEASE INHIBITORS
DESCRIPTION
=
Technical Field The present invention relates to the identification, through synthesis and testing, of heretofore unreported 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 suben.dothelium. TF then acts upon factor VII to form __ the TF/FVIIa complex (where Vila designates the activated factor rather than the zymogen form). This complex initiates coagulation by activating factors IX 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 __ subendothelial connective tissue. In the sequence that follows, contact factors XII and XI
are activated. The resulting factor Xla activates factor DC; then factor IXa activates factor X thereby intersecting with the extrinsic pathway.
With time, the TF/FVIlla 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 __ 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.
The initiation of the coagulation cascade involves the release of tissue factor (TF) from injured vessel endothelial cells and suben.dothelium. TF then acts upon factor VII to form __ the TF/FVIIa complex (where Vila designates the activated factor rather than the zymogen form). This complex initiates coagulation by activating factors IX 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 __ subendothelial connective tissue. In the sequence that follows, contact factors XII and XI
are activated. The resulting factor Xla activates factor DC; then factor IXa activates factor X thereby intersecting with the extrinsic pathway.
With time, the TF/FVIlla 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 __ 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.
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 =
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 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 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 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 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 VIIa or factor Xa, prevents clot =
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 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 that would be safe and effective in situations where the present drugs of choice, heparin and related sulfated polysaccharides, are no better than marginally effective.
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 unwanted side effects.
Figure 1. Pathways of Coagulation Extrinsic Pathway Intrinsic Pathway Release of TF Release of Contact Factors XII and XI
VIIXLIa XII
TF/FVIIaXI
Xla-4 __________________________________________________ _____________________________________________ IX
______________ X µc X
Common Pathway Prothrombin ______________ Thrombin _________ Fibrinogen _____ > Fibrin The figure illustrates the extrinsic and intrinsic pathways of blood coagulation.
Summary of Invention In a broad aspect, the present invention relates to a compound represented by the structure R R' wherein R is selected from the group consisting of -0Bn, -OH, -0S02CF3, .)CH 9 ) S
CH
OHC
CHO
OHC
N3H2C\ CH2OH HOH2C
_____________________________________________ -0 11 0 , and -OCH3; and R is selected from the group consisting of -CHO, -CO2H, and -0O2MEM;
and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure R 40 R' * H
1\I
BnO2C
wherein R is selected from the group consisting of -0Bn, -OH, -0S02CF3, .-----s , s) , ______________________________ / __ \ =
3, , 0 0 s , N ' N ' N
H3C & __ ) CH2 I¨ \ _ SN'TµI
S, 0 , N , IT
I , 7---17NCH v--- CH2 __________________________ /-CH3 ,.//=OH ¨
3, 7 H3r OH CH3 ./H2 z ______________________ _ -,....,.....70H 7(,...CH 2 /=-TMS , , /
CHO
OH, , S
..__,,.
\ CHO ' S
OHC / OHC
i / \
, -----S ' OHC---- 3.----- ' S S ' N , I
Boc / __ OH
¨7 ' =
S)/." __ ' S ___ OH' BnO2V
CH , 0H .,1\13 ;
, and HoH2c , s S
and R' is selected from the group consisting of -CHO, -CO2H, and -0O2MEM; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure NH
lel NH2 R
H
OH
N
BnO2C
wherein R is selected from the group consisting of 3, el , --) , fi3c-s3 , s S
S .1 l I
N
H3CN____,.._._., & ) CH2 I_\
N
S , N 7 5 1 S z N
0 I l CH3 OH ¨CH2 7¨NCH3 H3r OH
CH3 , , CH2 7== CH , __ --, / __ .7,OH , ' CH3' .(OH
OH BnCO2 ) ...,./-. \,..,....., ' \ OH ' & ' s \ , - OH
S S
/
II T OH
i OH
HOH2C s , S , , Boc and ; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure NH
I.
N NH, R elH
40 NHR' wherein R is selected from the group consisting of , S ' el ' 0 ' ' s s =%/ H3 c \------ I
. , L s , , , S , N N 0 N
CH2 si \N /7=N
CH, CH
3 , < , N ' N ' H
C
V ______ Nz7CH3 OH ¨ 2 ___________________ - OH
H3/ / , 9a K CH (CH3 OH ' ¨
/
\ al 3 , ______,,OH
OH
OH' S , A, HOH2C sk ' S
S
OH OH
.,,.,-.CH3 ,., , N N3 CH3 OH' , /CH3, , * 'CH2 \ -pH
, , , \o 41 CH2 11 ¨OCH3 ft 0 ¨0 /NS
and NH2 ; and R' is selected from the group consisting of ¨0 /-\ CH3 / CH3 CH3 CF 3 CH3 ' 9b CH2 CH3 OH , CH3 ' _________________________ CH3 '<1 CHI ,vCH3 0 , , CH3, .,Xci-:3 , CH3 CH3 -.,/,7NH2 "OH ___< ____<>
OH <CH3.
,and CH3' and pharmaceutically acceptable salts thereof.
In another broad aspect the present invention relates to a compound represented by the structure NH
R *
N H, H
lei H
N
wherein R is selected from the group consisting of 9c CHõ CH3 XS'/ 401 =CH2 S
-0Bn, -OCH3, and ; and pharmaceutically acceptable salts thereof In another broad aspect, the present invention relates to a compound represented by the structure NH
NHR' wherein R is selected from the group consisting of -0S02CF3, / N
, and _________________________ Cr , = and R' is -H or OBn ;
and pharmaceutically acceptable salts thereof.
9d In another broad aspect, the present invention relates to a compound represented by the structure 1.
H3CO2C R"
wherein R is selected from the group consisting of -0Bn, -OH, -0S02CF3, 0 , S , -CH=CH2, and -H; R' is selected from the group consisting of -CHO, -CO2H, and -0O2MEM; and R" is selected from the group consisting of 0 CH3 CH3 rC CH3 H
7....v.', CH =--0O2MEM, N 3 N CH3 H CH3 , CH H
H , N,7CF3 , H
N CH3 , N
E
IN CH3 and CO2H ;
and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure 9e NH
NHR' H3CO2C R"
wherein R is selected from the group consisting of -0Bn, -OH, -0S02CF3, 0 and -CH=CH2; R' is -H or -Boc; and R" is -0O2MEM or -CO2H; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure NII
1.1 NHBoc NHR' wherein R is -CH3; and ¨N
NHR' is \- ___ , or , or R' is selected from the group consisting of 9f CT-13 , (----043 CH3 CH3 CH3 CH3 0 ' C:3 c..
, _________________________________________________ I \CH3 ' CH3' 0 .,,CF3 W CH3 CH3 CH3 , Th<CH3 .,-OH 0 \
CH3 , 0H
N.,,-CH3 CH
, , , , OH
OH, =, OH; --0 , and and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure 9g NH
H
NHR' CC( wherein R is ¨ ; and R' is selected from the group consisting of CH3 ' CH3, CH2 , 1.1 CH3' CH3 .,,,,,.,..,..../.4...--CH3 C113 5 CH3 ' _____O , CH3 ,cõ--CH3, 5, =CF3 WCH3 CH3 -=<CH3 ) , CH3 ' \ N
OH, ...,..õ..õ,.......,õ...OH
N----1/ , 9h OH
.,- CH
Cli3 OH
and ; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure NH
401 NHR' R
H
* NHR' wherein R is o or ¨CH=CH2 and R' is selected from the group consisting of ,CH3 CH3 5 X> , , and ci-i, ; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure 9i NH
S NHBoc ON
H
401 NHR' wherein R is -CH3 and R' is selected from the group consisting of CH3' , cH3 f----\
,.CF3 5 ------\ __________________________________ / ' CH2 ' ,<,C113 KC/13 '''-\
OH W OH
, ilk, , , CH3 , CH3 CH3 /CH3 -41D ,,CH3 CH3 , \_--CH3 ¨0 and --.<CH3 , CH3 ' and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure 9j 4 0 6 11?
R
2 (10H
R"02C
wherein R is selected from the group consisting of -OCH3, -OH, -0S02CF3, -CH=CH2, -OCH2CO2C2H5, -OCH2CONH2, s , ii, ., ,..3 , 0 _0 0 0 .3 ,...... , 00Ac , 0 OAc , -0Bn , -OH, -0S02CF3, -OCH3, -0Bn, -H, and -CH=CH2; R' is selected from the group S
consisting of NH
NHBoo -CHO, -0O2H, -0O2MEM, NH NH
CH3 el NHBoc ' el NH2 ' ''0 0 9k NH NH
CH3 . NH2 CH3 1.11 NHBoc 0 N , , H
N
NH H
7N = NHBoc N H
H
, , NH
N =
C N
N¨OH
-----=_-_ 0 0 . H
, H
, N
H
N
C -==---=.N H
. N¨OH
H
N
= , , H N
H
N
NH H
= NH2 N el NHBoc , and NH
, H
NH
N =
H
and R" is selected from the group consisting of ¨H, -CH3 and -Bn; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure NH
R 4 el 6 1}1 R'02C
wherein R is selected from the group consisting of -CH=CH2, -0S02CF3, -OCH2CO2C2115, -OCH2CONH2, p -OCH3, CH3 ,CF13 0 CH3, 0 ,-0-CH2-CH2-0Ac, -OH, Cl-i3 -OCH2CO2H, -0-CH2-CH2-0H, -CH(OH)CH2OH, -CH2OH, -CO2H, S , -0Bn, -0C2H5, and -CH(OH)CH3; and R' is selected from the group consisting of -CH3, -Bn, and -H;
and pharmaceutically acceptable salts thereof.
9m In another broad aspect, the present invention relates to a compound represented by the structure NH
1401 NHBoc R N
H
3. 40 H
N
wherein R is selected from the group consisting of -CH=CH2, -CH(OH)CH2OH, -CH=0, -CH2OH, -CO2H, and -OCH3; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure NH
* N
H
0 * H
and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure 9n W 10 R"
RO
le NHR"
wherein R is selected from the group consisting of -C113, -C2H5, -CH(CH3)2, and R' is selected from the group consisting of -0Bn, -OH, -0S02CF3, and -CH=CH2;
R" is selected from the group consisting of -CO2H, -0O2MEM, and -CHO; and R"' is selected from the group consisting of < ____________________ CH3 CH3 ' CH3 ' //,,,..CH3 , ,CH , ' CF ' ' 3 CH3 _.0 , CH3 , , and CH3 ; and pharmaceutically acceptable salts thereof wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure NH
RO
1101 NI-ER"
R'0,C
wherein R is selected from the group consisting of -C7115, -CH(C113)2, 'C(CH3)3 , and -H; R' is -H or alkyl; and R" is selected from the group consisting of CH, CH_ < ________________________________ CH, CH, CF
C
CR.3 H
, and ; and pharmaceutically acceptable salts thereof.
9p In another broad aspect, the present invention relates to a compound represented by the structure R' 0R
* H
N
R"02C
wherein R is selected from the group consisting of H
/ \ N N,., /
it N ) /}11 40 ¨N\ / N
NN---- H
, H ' CF3 , /IN . CF3 \N 40 CF3 , N
H
F F
H / \o H
/N
il 40 ¨N
\ __________________________________________ / , /N = , N
¨ \ NH, N \N-4 , /111 = , \ ______ , N¨ H
9q N /\ N_\
H
Ll 0 I , -N
_______________________________________________ , / , / \ __ /N /2N .\
S OMe õN
N
H
OH
H
N . NH2 H
N H
N\
/ N ' H
/
N____ N __ H t\IT H e \
,N
, , %
_, , N , H
OH
N
L
( ________________________ , / H 40 _____________________________________ N N
- / /N OH
N N , H , H , /III = OH NI
/
N NI
/ 4101 I\1/N
____________________________________________________ lel \:_-_-__---/
, N
OH /
H
N H H
\N/ le /N
. OH
N, , , . jl \ I
H
I\ 11 Li . H
N
N
H NN "'N N
/
N-----1''NH2' \ __ / \
, , 9r N N a ¨OH, / ____________________ /
4 _______________ , __ NH2 II ___ C )-NH2 H
N = , H H
,N 10 CH2CN , /I
/N \II 4110 40 NH, ' / ) .
and ; R' is -H, or -CH=CH2; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure NH
lei NH, R
H
III
R'02C R"
wherein R is selected from the group consisting of .k 0 , S , -CH=CH2, and -H; R is -H or alkyl; and R" is selected from the group consisting of NCH,' CH3 /N-C7 I
, , H H Boc CH3 9s N
and H ; and pharmaceutically acceptable salts thereof.
cH3 In a broad aspect, the present invention relates to a compound represented by the structure R
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 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 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 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 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 VIIa or factor Xa, prevents clot =
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 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 that would be safe and effective in situations where the present drugs of choice, heparin and related sulfated polysaccharides, are no better than marginally effective.
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 unwanted side effects.
Figure 1. Pathways of Coagulation Extrinsic Pathway Intrinsic Pathway Release of TF Release of Contact Factors XII and XI
VIIXLIa XII
TF/FVIIaXI
Xla-4 __________________________________________________ _____________________________________________ IX
______________ X µc X
Common Pathway Prothrombin ______________ Thrombin _________ Fibrinogen _____ > Fibrin The figure illustrates the extrinsic and intrinsic pathways of blood coagulation.
Summary of Invention In a broad aspect, the present invention relates to a compound represented by the structure R R' wherein R is selected from the group consisting of -0Bn, -OH, -0S02CF3, .)CH 9 ) S
CH
OHC
CHO
OHC
N3H2C\ CH2OH HOH2C
_____________________________________________ -0 11 0 , and -OCH3; and R is selected from the group consisting of -CHO, -CO2H, and -0O2MEM;
and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure R 40 R' * H
1\I
BnO2C
wherein R is selected from the group consisting of -0Bn, -OH, -0S02CF3, .-----s , s) , ______________________________ / __ \ =
3, , 0 0 s , N ' N ' N
H3C & __ ) CH2 I¨ \ _ SN'TµI
S, 0 , N , IT
I , 7---17NCH v--- CH2 __________________________ /-CH3 ,.//=OH ¨
3, 7 H3r OH CH3 ./H2 z ______________________ _ -,....,.....70H 7(,...CH 2 /=-TMS , , /
CHO
OH, , S
..__,,.
\ CHO ' S
OHC / OHC
i / \
, -----S ' OHC---- 3.----- ' S S ' N , I
Boc / __ OH
¨7 ' =
S)/." __ ' S ___ OH' BnO2V
CH , 0H .,1\13 ;
, and HoH2c , s S
and R' is selected from the group consisting of -CHO, -CO2H, and -0O2MEM; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure NH
lel NH2 R
H
OH
N
BnO2C
wherein R is selected from the group consisting of 3, el , --) , fi3c-s3 , s S
S .1 l I
N
H3CN____,.._._., & ) CH2 I_\
N
S , N 7 5 1 S z N
0 I l CH3 OH ¨CH2 7¨NCH3 H3r OH
CH3 , , CH2 7== CH , __ --, / __ .7,OH , ' CH3' .(OH
OH BnCO2 ) ...,./-. \,..,....., ' \ OH ' & ' s \ , - OH
S S
/
II T OH
i OH
HOH2C s , S , , Boc and ; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure NH
I.
N NH, R elH
40 NHR' wherein R is selected from the group consisting of , S ' el ' 0 ' ' s s =%/ H3 c \------ I
. , L s , , , S , N N 0 N
CH2 si \N /7=N
CH, CH
3 , < , N ' N ' H
C
V ______ Nz7CH3 OH ¨ 2 ___________________ - OH
H3/ / , 9a K CH (CH3 OH ' ¨
/
\ al 3 , ______,,OH
OH
OH' S , A, HOH2C sk ' S
S
OH OH
.,,.,-.CH3 ,., , N N3 CH3 OH' , /CH3, , * 'CH2 \ -pH
, , , \o 41 CH2 11 ¨OCH3 ft 0 ¨0 /NS
and NH2 ; and R' is selected from the group consisting of ¨0 /-\ CH3 / CH3 CH3 CF 3 CH3 ' 9b CH2 CH3 OH , CH3 ' _________________________ CH3 '<1 CHI ,vCH3 0 , , CH3, .,Xci-:3 , CH3 CH3 -.,/,7NH2 "OH ___< ____<>
OH <CH3.
,and CH3' and pharmaceutically acceptable salts thereof.
In another broad aspect the present invention relates to a compound represented by the structure NH
R *
N H, H
lei H
N
wherein R is selected from the group consisting of 9c CHõ CH3 XS'/ 401 =CH2 S
-0Bn, -OCH3, and ; and pharmaceutically acceptable salts thereof In another broad aspect, the present invention relates to a compound represented by the structure NH
NHR' wherein R is selected from the group consisting of -0S02CF3, / N
, and _________________________ Cr , = and R' is -H or OBn ;
and pharmaceutically acceptable salts thereof.
9d In another broad aspect, the present invention relates to a compound represented by the structure 1.
H3CO2C R"
wherein R is selected from the group consisting of -0Bn, -OH, -0S02CF3, 0 , S , -CH=CH2, and -H; R' is selected from the group consisting of -CHO, -CO2H, and -0O2MEM; and R" is selected from the group consisting of 0 CH3 CH3 rC CH3 H
7....v.', CH =--0O2MEM, N 3 N CH3 H CH3 , CH H
H , N,7CF3 , H
N CH3 , N
E
IN CH3 and CO2H ;
and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure 9e NH
NHR' H3CO2C R"
wherein R is selected from the group consisting of -0Bn, -OH, -0S02CF3, 0 and -CH=CH2; R' is -H or -Boc; and R" is -0O2MEM or -CO2H; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure NII
1.1 NHBoc NHR' wherein R is -CH3; and ¨N
NHR' is \- ___ , or , or R' is selected from the group consisting of 9f CT-13 , (----043 CH3 CH3 CH3 CH3 0 ' C:3 c..
, _________________________________________________ I \CH3 ' CH3' 0 .,,CF3 W CH3 CH3 CH3 , Th<CH3 .,-OH 0 \
CH3 , 0H
N.,,-CH3 CH
, , , , OH
OH, =, OH; --0 , and and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure 9g NH
H
NHR' CC( wherein R is ¨ ; and R' is selected from the group consisting of CH3 ' CH3, CH2 , 1.1 CH3' CH3 .,,,,,.,..,..../.4...--CH3 C113 5 CH3 ' _____O , CH3 ,cõ--CH3, 5, =CF3 WCH3 CH3 -=<CH3 ) , CH3 ' \ N
OH, ...,..õ..õ,.......,õ...OH
N----1/ , 9h OH
.,- CH
Cli3 OH
and ; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure NH
401 NHR' R
H
* NHR' wherein R is o or ¨CH=CH2 and R' is selected from the group consisting of ,CH3 CH3 5 X> , , and ci-i, ; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure 9i NH
S NHBoc ON
H
401 NHR' wherein R is -CH3 and R' is selected from the group consisting of CH3' , cH3 f----\
,.CF3 5 ------\ __________________________________ / ' CH2 ' ,<,C113 KC/13 '''-\
OH W OH
, ilk, , , CH3 , CH3 CH3 /CH3 -41D ,,CH3 CH3 , \_--CH3 ¨0 and --.<CH3 , CH3 ' and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure 9j 4 0 6 11?
R
2 (10H
R"02C
wherein R is selected from the group consisting of -OCH3, -OH, -0S02CF3, -CH=CH2, -OCH2CO2C2H5, -OCH2CONH2, s , ii, ., ,..3 , 0 _0 0 0 .3 ,...... , 00Ac , 0 OAc , -0Bn , -OH, -0S02CF3, -OCH3, -0Bn, -H, and -CH=CH2; R' is selected from the group S
consisting of NH
NHBoo -CHO, -0O2H, -0O2MEM, NH NH
CH3 el NHBoc ' el NH2 ' ''0 0 9k NH NH
CH3 . NH2 CH3 1.11 NHBoc 0 N , , H
N
NH H
7N = NHBoc N H
H
, , NH
N =
C N
N¨OH
-----=_-_ 0 0 . H
, H
, N
H
N
C -==---=.N H
. N¨OH
H
N
= , , H N
H
N
NH H
= NH2 N el NHBoc , and NH
, H
NH
N =
H
and R" is selected from the group consisting of ¨H, -CH3 and -Bn; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure NH
R 4 el 6 1}1 R'02C
wherein R is selected from the group consisting of -CH=CH2, -0S02CF3, -OCH2CO2C2115, -OCH2CONH2, p -OCH3, CH3 ,CF13 0 CH3, 0 ,-0-CH2-CH2-0Ac, -OH, Cl-i3 -OCH2CO2H, -0-CH2-CH2-0H, -CH(OH)CH2OH, -CH2OH, -CO2H, S , -0Bn, -0C2H5, and -CH(OH)CH3; and R' is selected from the group consisting of -CH3, -Bn, and -H;
and pharmaceutically acceptable salts thereof.
9m In another broad aspect, the present invention relates to a compound represented by the structure NH
1401 NHBoc R N
H
3. 40 H
N
wherein R is selected from the group consisting of -CH=CH2, -CH(OH)CH2OH, -CH=0, -CH2OH, -CO2H, and -OCH3; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure NH
* N
H
0 * H
and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure 9n W 10 R"
RO
le NHR"
wherein R is selected from the group consisting of -C113, -C2H5, -CH(CH3)2, and R' is selected from the group consisting of -0Bn, -OH, -0S02CF3, and -CH=CH2;
R" is selected from the group consisting of -CO2H, -0O2MEM, and -CHO; and R"' is selected from the group consisting of < ____________________ CH3 CH3 ' CH3 ' //,,,..CH3 , ,CH , ' CF ' ' 3 CH3 _.0 , CH3 , , and CH3 ; and pharmaceutically acceptable salts thereof wherein MEM designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure NH
RO
1101 NI-ER"
R'0,C
wherein R is selected from the group consisting of -C7115, -CH(C113)2, 'C(CH3)3 , and -H; R' is -H or alkyl; and R" is selected from the group consisting of CH, CH_ < ________________________________ CH, CH, CF
C
CR.3 H
, and ; and pharmaceutically acceptable salts thereof.
9p In another broad aspect, the present invention relates to a compound represented by the structure R' 0R
* H
N
R"02C
wherein R is selected from the group consisting of H
/ \ N N,., /
it N ) /}11 40 ¨N\ / N
NN---- H
, H ' CF3 , /IN . CF3 \N 40 CF3 , N
H
F F
H / \o H
/N
il 40 ¨N
\ __________________________________________ / , /N = , N
¨ \ NH, N \N-4 , /111 = , \ ______ , N¨ H
9q N /\ N_\
H
Ll 0 I , -N
_______________________________________________ , / , / \ __ /N /2N .\
S OMe õN
N
H
OH
H
N . NH2 H
N H
N\
/ N ' H
/
N____ N __ H t\IT H e \
,N
, , %
_, , N , H
OH
N
L
( ________________________ , / H 40 _____________________________________ N N
- / /N OH
N N , H , H , /III = OH NI
/
N NI
/ 4101 I\1/N
____________________________________________________ lel \:_-_-__---/
, N
OH /
H
N H H
\N/ le /N
. OH
N, , , . jl \ I
H
I\ 11 Li . H
N
N
H NN "'N N
/
N-----1''NH2' \ __ / \
, , 9r N N a ¨OH, / ____________________ /
4 _______________ , __ NH2 II ___ C )-NH2 H
N = , H H
,N 10 CH2CN , /I
/N \II 4110 40 NH, ' / ) .
and ; R' is -H, or -CH=CH2; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure NH
lei NH, R
H
III
R'02C R"
wherein R is selected from the group consisting of .k 0 , S , -CH=CH2, and -H; R is -H or alkyl; and R" is selected from the group consisting of NCH,' CH3 /N-C7 I
, , H H Boc CH3 9s N
and H ; and pharmaceutically acceptable salts thereof.
cH3 In a broad aspect, the present invention relates to a compound represented by the structure R
3 Ilk 1110 H
N..-R'02C
wherein N is located at position 3 or 4 in the phenyl ring; R is selected from the group consisting of -CHO, -CO2H, and NH
1.1 NH2 N =
H , and R' is -H or alkyl; and pharmaceutically acceptable salts thereof.
In a broad aspect, the present invention relates to a compound represented by the structure I
IIIII NH OR
* N
H
H
N
R'02C
9t wherein R is selected from the group consisting of -CH3, -C2H5, -CH2C6H5, -C(CH3)3, -CH2-CC13, . OMe , ilk F, 0CH3 0/\<cH3 ,and = and R' is -H or ' ,v"\ ' cH3 alkyl; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure 4NHR' R
.
3 ei NHR"
R"'02C
wherein R is selected from the group consisting of -CH=CH2, -OCH3, -0Bn, -OH, and -H; Rt is NH NH
lei NH2 , or -iel NH2 I
N =
, R" is selected from the group consisting of .,v"--=cH3 '.
CF
, and CH3 ;
and R"' is -H; and pharmaceutically , 9u acceptable salts thereof.
In a broad aspect, the present invention relates to a compound represented by the structure R.' si R
I H
/ s,7 R"02C N N
wherein R is selected from the group consisting of -CHO, -CO2H, -0O2MEM, NH
NH
H ,and =
, R' is selected from the group consisting of -0Bn, -OH, -0S02CF3, and -CH=CH2;
and R"
is -H or alkyl; and pharmaceutically acceptable salts thereof; wherein MEM
designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure 40 Ri CO2R"
1.1 H
R
wherein R is -H or -CO2H; R' is selected from the group consisting of -CHO, -CO2H, and 9v NH
N ; and R" is -H or alkyl; and pharmaceutically acceptable H
salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure NH
1401 NHR' R
* N
H
* H
R"02C
wherein R is selected from the group consisting of -CH(OH)-CH2OH, -CHO, and -CH(OH)-CH=CH2; R' is -Boc or -H; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
In a broad aspect, the present invention relates to a compound represented by the structure NH
el NHBoc ISI N
H
401 NHR' 9w wherein R is alkyl; and /---N \.,---CH3 ¨N
NHR' is ) \ __ ,or or R' is selected from the group consisting of -.õ,...õ.õ,.....,,,...,,,cH3 -..,..,.._,,---õ, CH3 , ` CH2 , CH3 /
(CH3 7.----CH3 CH3 CH3 ' CH3 OH
c_CH3 CH
el cF,3 wcH3 CH3 OH _____...--,...,,OH
r\N
¨2N
CH '',/CH3 OH, , OH it -- OH
0 ;
and 9x and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to the compound represented by the structure NH
RO
NHR"
R'02C X
wherein X is CH or N;
R is -CH3;
R' is -H or ¨CH3; and Rn is selected from the group consisting of CH3 CH3 < __ CH3 CH3 ,CH3 CH3 CF3, CH , and ; and pharmaceutically acceptable salts thereof. Preferably X is N; R' is H and R" is .
The present invention also relates to pharmaceutical compositions containing at least one of the above disclosed compounds and their prodrugs.
9y A further aspect of the present invention relates to 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.
9z 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: B1 (R1)- El- W E2- B
X (R2) ; pharmaceutically acceptable salts thereof;
V1¨ L¨V and prodrugs thereof.
X
(I) ( A )o 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, 0, S, S(0), and S(02) which may be saturated or unsaturated.
=
R is -CH---CH-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 RI, R2, or R3. Preferably, these R, RI, R2, or R3 do not include -(C2-4 alkeny1)-0O2-C1-s alkyl, -(C2.4 alkeny1)-0O2-C1_8 alkyl-phenyl, and -(C2.4 alkeny1)-0O2-C1.5 alkyl-O-Ci _4 alkyl.
RI is H, -R, -NO2, -CN, -halo, -N3, -C i_g alkyl, -(CH2).0O2R2, -C2.5 alkenyl-0O2R2, -0(CH2)õCO2R2, -C(0)NR2R3, -P(0)(0R2)2, alkyl substituted tetrazol-5-yl, -(CH2).0(CH2). aryl, -NR2R3, -(CH2). OR2, -(CH2)õ SR2, -N(R2)C(0)R3, -S(02)NR2R3, -N(R2)S(02)R3, 4CHR2)õ NR2R3, -C(0)R3, (CH2). N(R3)C(0)R3, -N(R2)CR2R3 substituted or unsubstituted (CH2).-cycloalkyl, substituted or unsubstituted (CH2)n-phenyl, or substituted or unsubstituted (CH2).-heterocycle which may be saturated or unsaturated.
m is 1 except that when EI 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). -phenyl, -(CH2)1_3-biphenyl, -(CH2)14-Ph-N(S02-C1..2-alky1)2, -CO(CHRI).-ORI, -(CHRI).-heterocycle, -(CHRI).-NH-CO-RI, -(CHR1)n-NH-S02R1, -(CILR1)õ-Ph-N(S02-Ci_2-alkyl)2, -(CHRI)õ-C(0)(CHR1)-NHR1, -(CHRI)-C(S)(CHR1)-NHR1, -(CH2)O(CH2)CH3, -CF3, -C2..5 acyl, -(CHRI)õOH, -(CHR1)CO2R1, -(CHR1)õ-0-alkyl, -(CHR1)õ-O-(CH2)-0-alky1, -(CHRI).-S(0)-a1kyl, -(CHRI).-S(02)-a1kyl, -(CHR1).-S(02)-NHR3, -(CHR3)õ-N3, -(CHR3)NHR4, 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted-(CHR3)n heterocycle, or substituted or unsubstituted-(CHR3),-, 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(R1)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-, -0-CHR2-, -CHR2-0-, -N(R2)-C(0)-, -C(0)-N(R2)-, -N(R2)-CH-(R3)-, -CH(R1)-N(R2)-, -S-CHR2-, -CHR2-S-, -S(02)-N(R2)-, -C(0)N(R2)-(CHR2)n-, -C(R1R2)n-NR2-, -N(R2)-S(02)-, -R2C(0)NR2-, -R2NC(0 )NR2-, -CONR2C0-, -c"R2)NR2_, _NR2c(=NR2)NR2...2 u 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, C2.8 alkenyl, C2_8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
each X individually is a direct bond, substituted or unsubstituted C1_4 methylene chain; 0, S, NR2 , S(0), S(02), or N(0) containing one or two C1..4 substituted or =substituted methylene chains. X at different places may be same or different.
B is H, -halo, -CN, -NH2, -(CH2)õ-C(=NR4)NHR5, -(CH2),1-NHR4, -(CH2)nNHC(=NR4)NR5, -(CH2),-OR4, C1-8 substituted or unsubstituted alkyl, substituted or =substituted 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 F2, 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 RI.
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 VI individually is selected from Ri and N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic;
N,N-disubstituted carboxamidyl (-CONR1R2 where R1 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)õOH, -C(0)0R6, -C(0)SR6, -(CHA
C(0)NR7R8, -0-C(0)-0-R7, an amino acid or a dipeptide, Each R6 is H, R7, -C(R7)(R8)-(CH2)n-O-C(0)-R9, -(CH2)n-C(R7)(R8)-0-C(0)R9, -(CH2)n-C(R7)(R8)-0-C(0)-0-R9, or -C(R7)(R8)-(CH2),-,-0-C(0)-0-R9, Each R7, RR 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 CH2CO2alkyl.
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 terms 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 teims "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, trifiuoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, 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, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), 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 imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
Where noted above where the sub stituent 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 sub stituents such as alkyl;
substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, azido, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, hydroxyalkyl, amino alkyl, 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 sub stituent 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 alkyl 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, fhryl, 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 and tetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl and triazolyl and the like.
Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chrom.onyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolapridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b)pyridinyl, 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, indolinyl, 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 C 1 ..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 0 in the ring. Examples of suitable preferred heterocyclic groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2-methylpiperidino and 2-ethylpiperidino. In addition, the above substitutions can include halo such as F, Cl, 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)OR
(c) (Acyloxy)alkyl carbamates, -NHC(0)0ROC(0)R
(d) Enamines, -NHCR(=CHCRO2R) 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 are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO pp/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.
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 G/
RC(=0)0CHN- X
I \
of structure described by Boder et al., S. Med. Chem. 1980, 23, 469.
Examples of some preferred groups for W are ¨CH2CH2-, -CH=CH-, -CH2CH2CH2-, -CH2CH=CH-, -CONH, -CH2CONH-, -NHCONH-, -CONHCO-, -CONHCH2-, -C(=NH)NH-, -CH2C(=NH)NH-, -NHC(=NH)NH-, -NHNH-, -NHO-, -CONHS02-, -SO2NEI-, -NHSO2CH2-, -SO2NHCH2-, -CH20-, -CH2OCH2-, -OCH2CH2-, -CH2NH-, -CH2CH2NH-, -CH2NHCH2-, -CH2S-, -SCH2CH2, -CH2SCH2-, -CH2S02CH2-, -CH2SOCH2-, -CH(CO2H)0 and ¨CH(CO2H)OCH2.
Examples of some preferred groups for V and V1 are N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic, and typically containing up to ten carbons; N,N-disubstituted carboxamidyl (-CONR1R2 where R1 and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or ¨SO2NRIR2);
methylene- or polymethylene chain- extended variants thereof such as ¨(CH2)C01\THR1, -(CH2),ICONRIR2, -(CH2)SO2NHR1, -(CH2)nS02NR1R2 (where n = 1-4), -NHC(0)R, N(R1)C(0)R2, NHSO2R, CH2NHR, CH2NR1R2.
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.
The synthetic routes leading to the compounds in formula (I) are described in the following schemes.
Scheme 1 OH = H OSO2CF3 CO2CH3 A-1 or CO2CH3 B..1 or CO2CH3 0 N¨R 0 N¨R
H3C,,,CH3 OH = SO2CF3 CF3 2a, 3a, R = _____________________________________________ 2f, 3f, R =
CO2CH3 13-1 or 2b,3b, R ¨ ____________________________________ CH3 2g, 3g, R = \\X
CO2MEM CO2MEM 2, 3c, R=---<¨ CH3 2h, 3h, R=
MEM = CH2-0-CH2-C112-0-CH3 2d, 3d, R = 2i, 31, R = --2e, 3e, R 2j, 3j, R=
2, c02.3 AK
0 N¨R
6a Cl-i3 R =
CH.
Scheme 2 =
fan Bn0 0 CHO Bn0 0 CO2H
D-1 or = ell +3a D-2 E 2 CHO
1.I H S H
N...õ,,,..."-.....õ
B(0H)2 N...,........,..-,õõ
H3CO,C
H2CO,C
N..-R'02C
wherein N is located at position 3 or 4 in the phenyl ring; R is selected from the group consisting of -CHO, -CO2H, and NH
1.1 NH2 N =
H , and R' is -H or alkyl; and pharmaceutically acceptable salts thereof.
In a broad aspect, the present invention relates to a compound represented by the structure I
IIIII NH OR
* N
H
H
N
R'02C
9t wherein R is selected from the group consisting of -CH3, -C2H5, -CH2C6H5, -C(CH3)3, -CH2-CC13, . OMe , ilk F, 0CH3 0/\<cH3 ,and = and R' is -H or ' ,v"\ ' cH3 alkyl; and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure 4NHR' R
.
3 ei NHR"
R"'02C
wherein R is selected from the group consisting of -CH=CH2, -OCH3, -0Bn, -OH, and -H; Rt is NH NH
lei NH2 , or -iel NH2 I
N =
, R" is selected from the group consisting of .,v"--=cH3 '.
CF
, and CH3 ;
and R"' is -H; and pharmaceutically , 9u acceptable salts thereof.
In a broad aspect, the present invention relates to a compound represented by the structure R.' si R
I H
/ s,7 R"02C N N
wherein R is selected from the group consisting of -CHO, -CO2H, -0O2MEM, NH
NH
H ,and =
, R' is selected from the group consisting of -0Bn, -OH, -0S02CF3, and -CH=CH2;
and R"
is -H or alkyl; and pharmaceutically acceptable salts thereof; wherein MEM
designates a methoxyethoxymethyl group.
In another broad aspect, the present invention relates to a compound represented by the structure 40 Ri CO2R"
1.1 H
R
wherein R is -H or -CO2H; R' is selected from the group consisting of -CHO, -CO2H, and 9v NH
N ; and R" is -H or alkyl; and pharmaceutically acceptable H
salts thereof.
In another broad aspect, the present invention relates to a compound represented by the structure NH
1401 NHR' R
* N
H
* H
R"02C
wherein R is selected from the group consisting of -CH(OH)-CH2OH, -CHO, and -CH(OH)-CH=CH2; R' is -Boc or -H; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
In a broad aspect, the present invention relates to a compound represented by the structure NH
el NHBoc ISI N
H
401 NHR' 9w wherein R is alkyl; and /---N \.,---CH3 ¨N
NHR' is ) \ __ ,or or R' is selected from the group consisting of -.õ,...õ.õ,.....,,,...,,,cH3 -..,..,.._,,---õ, CH3 , ` CH2 , CH3 /
(CH3 7.----CH3 CH3 CH3 ' CH3 OH
c_CH3 CH
el cF,3 wcH3 CH3 OH _____...--,...,,OH
r\N
¨2N
CH '',/CH3 OH, , OH it -- OH
0 ;
and 9x and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to the compound represented by the structure NH
RO
NHR"
R'02C X
wherein X is CH or N;
R is -CH3;
R' is -H or ¨CH3; and Rn is selected from the group consisting of CH3 CH3 < __ CH3 CH3 ,CH3 CH3 CF3, CH , and ; and pharmaceutically acceptable salts thereof. Preferably X is N; R' is H and R" is .
The present invention also relates to pharmaceutical compositions containing at least one of the above disclosed compounds and their prodrugs.
9y A further aspect of the present invention relates to 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.
9z 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: B1 (R1)- El- W E2- B
X (R2) ; pharmaceutically acceptable salts thereof;
V1¨ L¨V and prodrugs thereof.
X
(I) ( A )o 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, 0, S, S(0), and S(02) which may be saturated or unsaturated.
=
R is -CH---CH-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 RI, R2, or R3. Preferably, these R, RI, R2, or R3 do not include -(C2-4 alkeny1)-0O2-C1-s alkyl, -(C2.4 alkeny1)-0O2-C1_8 alkyl-phenyl, and -(C2.4 alkeny1)-0O2-C1.5 alkyl-O-Ci _4 alkyl.
RI is H, -R, -NO2, -CN, -halo, -N3, -C i_g alkyl, -(CH2).0O2R2, -C2.5 alkenyl-0O2R2, -0(CH2)õCO2R2, -C(0)NR2R3, -P(0)(0R2)2, alkyl substituted tetrazol-5-yl, -(CH2).0(CH2). aryl, -NR2R3, -(CH2). OR2, -(CH2)õ SR2, -N(R2)C(0)R3, -S(02)NR2R3, -N(R2)S(02)R3, 4CHR2)õ NR2R3, -C(0)R3, (CH2). N(R3)C(0)R3, -N(R2)CR2R3 substituted or unsubstituted (CH2).-cycloalkyl, substituted or unsubstituted (CH2)n-phenyl, or substituted or unsubstituted (CH2).-heterocycle which may be saturated or unsaturated.
m is 1 except that when EI 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). -phenyl, -(CH2)1_3-biphenyl, -(CH2)14-Ph-N(S02-C1..2-alky1)2, -CO(CHRI).-ORI, -(CHRI).-heterocycle, -(CHRI).-NH-CO-RI, -(CHR1)n-NH-S02R1, -(CILR1)õ-Ph-N(S02-Ci_2-alkyl)2, -(CHRI)õ-C(0)(CHR1)-NHR1, -(CHRI)-C(S)(CHR1)-NHR1, -(CH2)O(CH2)CH3, -CF3, -C2..5 acyl, -(CHRI)õOH, -(CHR1)CO2R1, -(CHR1)õ-0-alkyl, -(CHR1)õ-O-(CH2)-0-alky1, -(CHRI).-S(0)-a1kyl, -(CHRI).-S(02)-a1kyl, -(CHR1).-S(02)-NHR3, -(CHR3)õ-N3, -(CHR3)NHR4, 2 to 8 carbon atom alkene chain having 1 to 5 double bonds, 2 to carbon atom alkyne chain having 1 to 5 triple bonds, substituted or unsubstituted-(CHR3)n heterocycle, or substituted or unsubstituted-(CHR3),-, 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(R1)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-, -0-CHR2-, -CHR2-0-, -N(R2)-C(0)-, -C(0)-N(R2)-, -N(R2)-CH-(R3)-, -CH(R1)-N(R2)-, -S-CHR2-, -CHR2-S-, -S(02)-N(R2)-, -C(0)N(R2)-(CHR2)n-, -C(R1R2)n-NR2-, -N(R2)-S(02)-, -R2C(0)NR2-, -R2NC(0 )NR2-, -CONR2C0-, -c"R2)NR2_, _NR2c(=NR2)NR2...2 u 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, C2.8 alkenyl, C2_8 alkynyl, alkylaryl, aralkyl, aralkenyl, aralkynyl, alkoxy, alkylthio, or alkylamino.
each X individually is a direct bond, substituted or unsubstituted C1_4 methylene chain; 0, S, NR2 , S(0), S(02), or N(0) containing one or two C1..4 substituted or =substituted methylene chains. X at different places may be same or different.
B is H, -halo, -CN, -NH2, -(CH2)õ-C(=NR4)NHR5, -(CH2),1-NHR4, -(CH2)nNHC(=NR4)NR5, -(CH2),-OR4, C1-8 substituted or unsubstituted alkyl, substituted or =substituted 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 F2, 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 RI.
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 VI individually is selected from Ri and N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic;
N,N-disubstituted carboxamidyl (-CONR1R2 where R1 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)õOH, -C(0)0R6, -C(0)SR6, -(CHA
C(0)NR7R8, -0-C(0)-0-R7, an amino acid or a dipeptide, Each R6 is H, R7, -C(R7)(R8)-(CH2)n-O-C(0)-R9, -(CH2)n-C(R7)(R8)-0-C(0)R9, -(CH2)n-C(R7)(R8)-0-C(0)-0-R9, or -C(R7)(R8)-(CH2),-,-0-C(0)-0-R9, Each R7, RR 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 CH2CO2alkyl.
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 terms 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 teims "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, trifiuoromethyl, trifluoromethoxy, hydroxy, alkoxy, cycloalkyloxy, 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, aralkylthio, cycloalkylthio, heterocyclothio, alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), 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 imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
Where noted above where the sub stituent 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 sub stituents such as alkyl;
substituted alkyl, halo, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, azido, cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, hydroxyalkyl, amino alkyl, 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 sub stituent 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 alkyl 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, fhryl, 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 and tetrahydro-1, 1-dioxothienyl, dioxanyl, isothiazolidinyl, thietanyl, thiiranyl, triazinyl and triazolyl and the like.
Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chrom.onyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolapridyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b)pyridinyl, 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, indolinyl, 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 C 1 ..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 0 in the ring. Examples of suitable preferred heterocyclic groups are pyrrolidino, azetidino, piperidino, 3,4-didehydropiperidino, 2-methylpiperidino and 2-ethylpiperidino. In addition, the above substitutions can include halo such as F, Cl, 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)OR
(c) (Acyloxy)alkyl carbamates, -NHC(0)0ROC(0)R
(d) Enamines, -NHCR(=CHCRO2R) 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 are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO pp/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.
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 G/
RC(=0)0CHN- X
I \
of structure described by Boder et al., S. Med. Chem. 1980, 23, 469.
Examples of some preferred groups for W are ¨CH2CH2-, -CH=CH-, -CH2CH2CH2-, -CH2CH=CH-, -CONH, -CH2CONH-, -NHCONH-, -CONHCO-, -CONHCH2-, -C(=NH)NH-, -CH2C(=NH)NH-, -NHC(=NH)NH-, -NHNH-, -NHO-, -CONHS02-, -SO2NEI-, -NHSO2CH2-, -SO2NHCH2-, -CH20-, -CH2OCH2-, -OCH2CH2-, -CH2NH-, -CH2CH2NH-, -CH2NHCH2-, -CH2S-, -SCH2CH2, -CH2SCH2-, -CH2S02CH2-, -CH2SOCH2-, -CH(CO2H)0 and ¨CH(CO2H)OCH2.
Examples of some preferred groups for V and V1 are N-alkyl substituted carboxamidyl (-CONHR) where the alkyl group may be straight, branched, cyclic, or bicyclic, and typically containing up to ten carbons; N,N-disubstituted carboxamidyl (-CONR1R2 where R1 and R2 may be substituted or unsubstituted alkyl or aryl and may be the same or different); mono- or disubstituted sulfonamides (SO2NHR or ¨SO2NRIR2);
methylene- or polymethylene chain- extended variants thereof such as ¨(CH2)C01\THR1, -(CH2),ICONRIR2, -(CH2)SO2NHR1, -(CH2)nS02NR1R2 (where n = 1-4), -NHC(0)R, N(R1)C(0)R2, NHSO2R, CH2NHR, CH2NR1R2.
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.
The synthetic routes leading to the compounds in formula (I) are described in the following schemes.
Scheme 1 OH = H OSO2CF3 CO2CH3 A-1 or CO2CH3 B..1 or CO2CH3 0 N¨R 0 N¨R
H3C,,,CH3 OH = SO2CF3 CF3 2a, 3a, R = _____________________________________________ 2f, 3f, R =
CO2CH3 13-1 or 2b,3b, R ¨ ____________________________________ CH3 2g, 3g, R = \\X
CO2MEM CO2MEM 2, 3c, R=---<¨ CH3 2h, 3h, R=
MEM = CH2-0-CH2-C112-0-CH3 2d, 3d, R = 2i, 31, R = --2e, 3e, R 2j, 3j, R=
2, c02.3 AK
0 N¨R
6a Cl-i3 R =
CH.
Scheme 2 =
fan Bn0 0 CHO Bn0 0 CO2H
D-1 or = ell +3a D-2 E 2 CHO
1.I H S H
N...õ,,,..."-.....õ
B(0H)2 N...,........,..-,õõ
H3CO,C
H2CO,C
, CF3S020 CO2MEM HO 0001 CO2MEM Bn0 0 CO,MEM
la. B-2 G
01N.. H õ,...õõ---...,,, 40 H
..."...---,..%
Fl N......,..õ.......
H3CO2C H,CO2C 83CO2C
' Scheme 3 all OH = SO,CF, = SO,CF, so CO211 . CO,Bn ao CO2Bn CO2Bn H B-2 g 411 CHO CHO CHO CO,H
1A-3 or = SO,CF3 0 CO,Bn H
=
Scheme 4 = SO,CF, Bn0 0 CO214 so CO,Bn D-1 or 13n0 CHO
-, 0 , ., D-2 E
-----).-H SL
1µ1...,-, BnO2C
0 1\"11 BnO,C 11111 1, F
_ HO is CO2MEM HO el CO2MEM ...,__....2_Bn0 0 CO2MEM
H
.0----, * 11 N.õ.....õ...--...õ...
BnO,C HO2C BnO2C
21 ._... _ 20 19 0C11110 .
H
BnO2 , , , -Scheme 5 F,CO2S0 CO,MEM
is + R _ Dx-1, D-2, D-3, D-4, D-5, D-10, D-11, or D-12 R
_____________________________________________ 1 23 X --= H, B-(OH)2, Sn(Bu),, Sn(Me),,or Si(Me)3 0 CO2MEM
110 *\/).\. 4 Sk,_.
BnO2C BnO2C
R
NH
.1, 411 NH2 14õ,.....õ..õ
BnO2C BnO2C
:6 . 25 NH
R elH
HO,C
24, R -= , H3C
a___ A __ -. c,, d,... _14 , e,4µ.
H,C s h, =-"..,-1 i, !%'-'"----1 j, k, Ki".--0 H3C
T N
N 0 CH, i n, ,====õ,,_,,..2-.CH2 0, /7-=Nal, q' - CH
r'OH
SNe õ...,.."-N".õ 3 w,H2 =TMS
s,t' ___________________ H2 U, z OH v, OH /
CH, 25 CH, 24, R = (continued) CHO
X, /_<
y, ---s-.. OH z, )1 aa, ¨
N ab, .,,, ,...C..
CH3 \ OH .---S
OHC
ac, /....,, ad, \ .,..,\// ae, //
,,,,\........___ ag , ..., .,' ah, ---N\ CH, S
CHO OHC-- s N
S
Boo 25, R = H3C
c, c1,_____Q........
H3C s S . S 0 0 S
h, /V.::.i i,,V j, H3C .._.,_, =:,- /-.,,, 1. .,,.) I
/3, ,,.CH2 0, i¨ \ 1), (1, -----CH3 r, '7'- OH
/= N CH3 N
SN/Z
/ -OH
CH, CH2 v w, ,,= CH
s, -,__.-1/2 t, __ < it, /_0R, -....õ.õ..., OR /,, OH
CH, OH z, z li x, z _ <CH, y, ..,,,,-µ-..,....õ...-\ OH aa,,¨N ab, &.
...
S
BnO,C / HOH2C
ad, ae, HOH2CNs / af, ( ag , i j / \
OR N
S S CS) c)c ah , ai, OH
----, 26, R = H,C
a b, ______________ cio d, .,\..., e, H,C s S7 0 0 S
h, -'1 1 i,--`Y--1 j, 1 k, H,C, .,,,..\ 11 111, &
N) --:,,, 7---..,,, ===:,-,..,.. .õ--N
N N I S
I
N 0 CH, n, .õ,--,....-,,CH, 0, /¨ \ P, //=-----\----- CH q, N< CH, r, 7-.,.,'=-,,,. OH
S Ne 3 H,C/ -OH
CH ____/<C1,,,, 2 w, //,,=_- CH
s, ,..,,... ____ ,..,,,..., CH, t, ______________ u, z____ ,õ.µ..7 OH v, OH
CH, CH, CH, X, / __ <CH, y, ._..,z, OH )1____\ aa,._,-N ab, 4/\
S
BnO,C /
ae, ,_._..,_ at HOH,C
( ag , & ........_ ad, i HOH,C s OH N
Boc OH
ah, ai, OH
27, R=
c, V s S7 0 0 S
N N N
I
'ThµK 0 CH, n, ,..,-=,,,,, CH2 o,, ¨
P /¨`,. q, 7,--Nv CH, r,OH
Ss'N CH3 / .(:)14 HC
CH, CH, OH w, /CH, s, "..,,, ,,,,,....õ 2 CH t, __ < u,, õ,./¨`====,_,,- v, ----/.v OH
CH, CH, 27 27, R = (continued) , CH2 OH
x, _______________ yv zaa OH ab, ac, ______________ ad, ae, HOH2C at HOH2C
ag , OH
ah, OH ai,N2 Conversion of 24ab K I-I25ab = 24ac 25ac 24ae 25ae =
24ad 25af The reduction of the formyl group of 24ab, 24ac, 24ae, and 24ad was accomplished with NaBH4 to give corresponding alcohols 242134, 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 25ah The vinyl compound 24ah was oxidized with 0504 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 NaI04 produced aldehyde 24ah-ii. The aldehyde on reduction gave alcohol 24ah-iii, which on further reaction with methane sulfonyl chloride yielded mesylate 24ah-iv. The mesylate on further reaction with sodium azide gave the corresponding azide 24ah-v, which on acidic hydrolysis produced 25ai.
Conversion of 24w 25w =
Scheme 6 CF,S0,0 01 CO,MEM D-1, D-2, D-3, D-4, or D-5 = CO,MEM
+ R - X ______________________________________ s 28 X = H, B-(OH)2, Sn(Bu)3, or Sn(Me), 113CO,C S II
H3CO2C S {I
NH
7, el NH, R 0 C0,1-1 -..(---110 14\, Slk.
H3CO2C 1-1,002C
= 31 30 11-2 .
NH
NH, Ho2c 29, R=
a, 0 b, ,.,..õ, ' c, .,,.,,, CH2 cl, ,..... ) e, CH,r S
OHC CHO OHC\ /
g, h, ,.....,.. i, s o o r 29 30, R=
a, b, c, d, = e, t CH, CH,=
NHC
CH OH HOH,C
g 13, __________________ 31, R=
''C H3 a, b, c, 0H2 d, e, cH20H HOH,C
g ,1\131-12.
32, R=
a, b, 0H, c, d, e, 1110 c H2 c H, g K, N, 0,1-i Conversion of 29g 30g Aldehyde 29g was converted to alcohol 29g-i by reduction with NaBH4, followed by the reaction of 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.
K, I-1 Conversion of 29h----)- 30h K, I-1 29i 30i The reduction of the formyl group of 29h and 291 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 30h and 301, respectively.
Compounds of the type 23 and 28, where X = -Sn(Bu)3, are prepared using the methods AG-1 or AG-2 Scheme 7 11 .....-_L_ * H
N........,,,..,--..,,, H,CO2C
Si NH
I 0 N laill NH2 CF3 S020 is CBz CF3S020 0 N P
H H
N-- ..,.....õ,õ,..õ....õ . H
= 0 0 35 0 . 34 B(OH)2 / \
CBz e CH2C6H5 . =
I
TIPS
TIPS = Tri-isopropylsilyl TIPS NH TIPS NH
I I
N N
\/
CBz * N
H G
N
H
* H
N,,,,,_.,, 01 H
N.õ,,....õ..--..,,, NH NH
H H
N N
\ /
\ /
OHN*
H
,..,, .
I\I,s.,,,.=., Scheme 8A
0 0 CO,MEM
+ 1411 H
10 B(011)2 H,CO2C
NH
401 = 1-1 illt NH, IP 1 0 C0,11 =
H J
*
H
1110 11õ,...... 5 H,CO,C H,CO,C
* 11-2 NH
0 Sp NH, N
H
1$1 14,..õ_v.--HO,C
Scheme 8B
IP NH
S.
= N 4111 0 N NH, -1-3.-el H
N,,.,,. 411 H
H,CO,C HO,C
Scheme 8C
CHO
Me0 40 CHO Me0 +3a D-2 3a __ J2:,/_,,.
(11101 H
B(OH)2 47 H3CO,C
, 0 NH
/ E
0 NH, 111111 Me0 40 CO,H
Me0 H 0 N J
* H
N,.,,..7,---,,, 1.13CO2C
25 . 11-2 NH
30 Me0 0 ill 2 N
H
35 HO,C Si H
N. \
40 Scheme 8D
NH
S
S 0 4111 NH2 = 4110 NH, G 0110 14 1-2 (101 h 31g ---3.
H2N I-1,N
H3c02c H02c Scheme 8E
raj (R... ) 26n 32f 27ak (R = ) 26a1 27al(R ) 26u 27am (R= OH) Scheme 9 . le * 0 NH
0 NH, 0 CHO 0 Oil CO,H 0 5 + 6 ..J:L_,..
H
11101Oil 116 H,CO,C CO,MEM H,CO,C CO,MEM H,CO,C
CO,MEM
IR .
NH NH
41111 NHBoc 0 git 0 SI N NHBoc HO, 0 N
H ___ so H
Oil 110 H,CO,C CO,MEM H,CO,C CO,MEM
. 58 57 NH NH
¨ 0 5 NHBoc N Sp NHBoc / 0 la H,CO,C 1111111 CO,MEM H3CO2C CO,MEM
NH NH
/ = 0 N
1410 NHBoc /
¨0O
N
0 el NHBoc (16/
____.
H
H1CO1C H3CO2C CO,H
. 11-2 ¨
NH NH
/ = 0 5 NHI30c / 0 0 II NH, ¨
H S
la N
H
Lail NHR 411 NHR
HO,C HO,C
63 0 . 0 62, R =
' a, ,,,,--..,,CH3 b' CH, c' .'.CF12 d' e,`...,...c..-CH3 f 4---CH3 ' CH3 CH3 CH, OH
g , \/'\(CH3 }:..,,.,70 i CH
14¨) 0 CH, . CH, m,=-,CH3 ,, ,,,,..<3 0, *
P> ..CF3 q, r' CH, OH
t''OH 11, CH, OH
,,,(.JD y, z, .õ.7 CH3 aa, ,.,--cOH ab, w, -'"--,_/\/14--41 ' ac,, ad _0 OH ae, NHR = ¨N/
\ af, Niirt \.------", 63, R =
e,.CH, f; A--"CH, a, ......õ..õ,......cHa b' CH3 d, cHa d' CH, CH, OH
g, \ ,,,3h,) CH )1___C) i, CH, 0 1), =,.7.CF, 9, '..,.\.--''\CH3 r, m, \ n,,,C3 0, CH3 t CH3 II, OH , =%.,,,)(23 CH, OH
CH, OH
y' Z,7-...%,.CH CH3 aa, -õ,.......,,,--cy.,OH ab, II
w, af, NHR = ae, NTIR = --N --IN
ac, ___-.0 ad, OH \ \-----A7, ' 36 , 64, 12 =
0, ..,.<CH3 f ,,,----- CH3 a, ,..-,..7=CH3 b' CF13 c' C11, d, g , "\s,C1-13 1,1:_Nf) i, CH3 =
OH
1.1_0 m' CH3 n'-'=C
CH3 0, P, -..,,,.=CF3 q, ,,-"-.,V,,, r, CH, CH3 CH, s, t, ...õ..,, ,,...,...õ. u, CH3 -`.- -OH =,,, OH
_, CH
w, r\N x, y, =r''-'s-% z, -,,.C113 aa, ,.,cOH ab, 44I
a0,ad, _0 OH/
ae, NHR = --N( af, MR
,.
\-----v7, NH
-el NHR
¨
IS N
H
NHR
HO,C
65 ,õCH3 65' R = CH3 Scheme 10 NH
N II NHBoc 59 + (Bu),Sn. D-3 H3CO2C CO,MEM
H NH
N 411:1 NHBoc N 411 NHBoc * H A-4 la 1 . 5 NHR
H3CO2C 113CO2C CO,H
= 680 67 NH NH
NH
N 4111 Boc I
N I. 2 HO,C HO,C
, 68,R ----a, -,.,.,..,CH, b, CH3 c, ¨0 d, ,,,,,,,,..,õe, CH, CH, CH, CH3 CH, g, '-CF, h,. OH
i, k, \ CH3 1, m, _______________ n, /---,'II3 0, 7r' \/-*''''',.." CH3 P, 0 C 'CH
CH, cl, X------ CH, .-0.. 110H 11, --1 vy --<>
r'NHBoc s, ---0 t .
IN, ,..-. x, CH , CH, 38 69, R =
a, ..--",,,CH3 b, CH3 c, ¨0 d CH3 f ..,<3 _1 ' CH, e' 'X ' . CH, CH, CH, g, ==õ,CF h, i' -'OH j, k, `--., CH, 1, =,,,CH3 CH, 0, .,---.. CH, //¨ CH, CH3 ci' CH X---- 3 r,..õ,õ,-,,,..õ....A4H2 s, __.0 t, ...._<---),,,,i OH
u, w, -.....,.õ.CH
OH x' 3 CH, 70, R =
a, =õ--...,,C113 b, CH3 c, --- d, e CH
..,õ_,< t `,., 3 ' '''CF12 ' CH3 CH, CH, -CH3 g, -CF h, it 1, \,^\OR j, --"IC
CH, m, 0, .,.,--..,,,,CH, 0, ,,-..,_CH3 CH, q' X---- CH, r,..,,,...7-,NH2 s, ¨0 t, ¨O. , i 'OH u, _______________ < v, w' OH x' Cli3 NH
! 0 II NHR
1110 HO,C NI
71 o 71, R=
a, --<> b, --1 c, Scheme 11 CHO * CHO
1110 U-2 or T and U-3 ' 73 -I- 3a Me0 Me0 B(OH)2 0 CHO V-1 or V-2 so CHO
andHorW
-.E----HO
le 11 Me0 * 1\1,.,,,=\õ
12.02C H3CO2C
75a, R' = Me 75 0 74 0 75b, R = Bn 0 CHO si CHO
D-2,D-3, or D-8 ---).-F,CO2S0 * H R
* H
N..õ,õ......õ.^-,.., N,N....õ...---.õ,..
R'02C
76a, R. = Me 76 077 0 76b, R' = Bn NH
41) el CO21-1 1.1 N
H J
= Ill H
R 0 .2 R
0 ' 1\11,..õ, R'02C
ROS
11-2 or G
NH
R * N
0 4111 NH, H
SL=--,õ., HOS
77a, 78a, 79a, 80a, R = -C-77-- CH2; R' = CH3 H
78b, 79b, P. OSO2CF3; R' = Bn; 80b, R = OH
7713, 78c, 79c, R = -0-CH2CO2C2H5; R' = Bn; 80c, R= -O-CH2CO2H
77c, 78d, 79d, 80d, R = -0-CH2CONH2; R' = Bn 77d, 78e, 79e, 80e, R = ; R' = Bn S
77e, 78f, 79f, 80f, R = -o=; R' = Bn 74 B 78g ._f___.)... 79g___12_,... 80g 78g, 79g, 80g, R = OCH3, R' = CH3 77f, 78h, 79h, 80h, R = -- ,-,,,,--- CH3; R' = Bn .,,,,.0,,,CH3;
77g, 781, 791, 801, R = ' Bn 77h, 78j, 79j, 80j, R ----, :
CH3- R.' = Bn , 771,78k, 79k, R = OCH2-CH2-0Ac; R' = Bn; 80k, R = -0-CH2-CH2-0H
, , , -Scheme 12 .
NH NH
N
II NH, 0 N 410 NHBoc I.
I.
H R
H
/µI.- I
H,CO,C 01 H
, 79, NH IL
NH
N
el NHBoc 0 1.11 NHBoc H
el H M
* H
1110 }-1 0 14 ,,,,,., N -,7,k-,, H,CO2C HO 113CO2C
NH K
NH
41111 NHBoc 0 lel NHBoc N
II N
H
0 Oil gill' OH iglr H H
OH
N,..,7-.,. 11101 H,CO,C H,CO2C
NH
R *
N
=NH, 82, 84, 85-=----,-H
86a, R= CH(OH)CH,OH
86b, R = C1-120H
86c, R= CO21-1 , Scheme 13 ell OBn OBn X T, U- 1 lip CHO
_____ 40 CHO --3== CHO 89 + 3a Br Br B(OH)2 ' a Bn /13n . OBn los CO2MEM 40 co2H CHO
F E
-c------ ...E-------_ II N (101 ''-=,..,"'xi' '`,. .
H3CO2C . - s'-`-'--.-- 1-13CO,C .',,.-V- H3CO2C
=1-1 = SO2CF3 los B-2 D-3 $
---N.-410 14 14 /1õ,,,r H,CO,C -x" H3CO2C . '--`- 143CO,C .
NH NH
R
7,1 II. NH2 CO211 01 P 1-2 (10 HI
_____ t\i HO2C fl H3CO2C . 1-13CO2C
0 ' 0 0 , j.
95a, 96a, 97a, 98a, R= ) S
,......._ _is.9:L.. / \
iS S
91 ----,..- 97b ¨3..1-2 = 98h, R.= -0-CH2C6H5 Br SnBu3 98b ¨g---).- 98c, R.---- -OH
, Scheme 14 CHO CHO
II T, U-3 ----i.
41111 B(OH)2 OMe OMe leo CHO
I.
100 + 3a _______,.... D-2 E OH
-.-OMe OMe 1110 ,CO,C \ \/
H,CO,C 11 it NH it NH
ill t N 0 ti NH, OMe S14.õ........... OMe OP *
'=.,, õ/ \
HO2C H,CO,C
-Scheme 15 0 mo . CHO CHO
X T, U-I .
I I I. B(OH)2 OH OBn OBn 107 + 3a NH
, ON
4111 NH, 0 H ..,.... õI__ 5 OH E
H H H
OBn 5 N.,.....,.y" OBn el N.,,,,,..--.. OBn *
H3CO2C H,CO,C H,CO,C
NH NH
*
II NH, 0 0 NH, N
H I-2 1. N
H
H
H
OH 5 N.., 0 01 N
H,CO,C
Scheme 16 Ko 40 CHO HO
110 CHO X or Bn0 CHO
Z or Z-1 X, V-4, AR
RO
= ------3I .
Br Br Br 6a IT, U-I
Bn0 10 CO21-1 Bn0 op CHO
E -*---- Bn0 ii. CHO
RO RO ' CF RO 30S,0 ip = 40 B(OH)2 NHR H
NHR' 40 ' ,CO,C NHR' 11,CO2C H,CO,C
=
3a-j = 0 0 , Bn0 CO2MEM
. G HO CO2MEM
110 NHR' RO
NI-1R' RO
11,CO2C H3CO2C H3CO,C
. 0 0 0 .
NH
I 0 igli NH, 1 I .
lip CO2H CO2MEM
0 NHR' RO
IR
RO ' H,CO,C
0 0 , 0 NH
. 0N
H
RO
4101 ' if 114a, 115a, 116a, R = CH3; 114b, 115b, 116b, R= C2115; 114c, 115c, 116e, R = -CH(CH3)2; 115d, R = C---C(CH3)3 117a -- 125a, R = CH3; 12' = =,..,, 117b¨ 125b, R = C21-15, R' =
'CH3 CH
117c -- 125c, R = CH(CH3)2; 12' =
117d -- 125d, R ¨ CH3; R.' = <
117e -- 125e, R = CH3; R.<
' =
..,.,..,.,7,-.,..7 117f ¨ 125f, R = CH3; R' = .-CH3 117g ¨ 125g, R = CH3; R' = .'''CF3 117h -- 125h, R = CH3; R.' = 'CH3 117i -- 1251, R = CH3; RI=
117j -- 125j, R = CH3; R' 117k-- 125k, R = CH3; R' = ---'CH3 1171-- 1251, R = CH3; RI=
117m -- 124m, R = C¨C(CH3)3; R1= ; 125m, R = H; 12.' =
`===..,.,/,, "
Scheme 16a NH . NH
NH, B el Bn0 n0 it N N
118b---1--)- H 1-2 H
RO RO
1110 NHR' 01 1\11111' H,CO,C HO,C
CH, 126, 127, R = C2H5; W =
''''-----''''CH, Scheme 16b =
NH NH
1 0 ep NHBoc 0 N Ili NH2 124a R 1 40 n 1-2, S HO el 14 ---3===
RO Me0 CH, 128, R = CH3; RI = CH, , =
, Scheme 17 CHO
lel E
+ 3a CO,H
lel D-2 B(OH)2 --)--=
CHO 0 11 \./'\. H3CO,C =130 H3CO,C
1 jA-5, A-4, or R R
.
la 111101 HO,C H,CO,C
. 133, 134, R=
II
/ _____________ \
N __________________ D N-..,..
c, ,,...,, a, ¨N b, ti = /
CF
41 d, 41 3 \ _____________ / N
CF, CF CF,, F
e, 411 CF, f, 41100 g' 14 4110 /14 it .., ,.., / h, 7 , II 11 F
0 j, K /\__ k,___N/ \N____(7 ) I, ti . NH
i, ¨N\ ________ / /
\ ________________________________________ / N¨ /
in, ti . n, fq $ 0, ¨N
/ _________________________________________________ \ N.._ N ____________________________________________________ K ) 13, /II 41 / / S OMe _____________________________ 1 ,-N
OH
cl, 11 110 I r' 14110 NH, s, u, 4 /
/ N
v, ________ / (/ %N w, i' II x, 7----(-) Y, OH
133, 134, R= (continued) / __________ \\N aa, 14 il ab, 14 11 OH ac, 14.____(i z, ...,...
/ *
/
7.--------- N
ad, fl Of N ae, f 11101 af, 1;1 40 OH
/ \_..-------- /
ag,/ / /I 00 OH ai, Y 40 4 ..
CH3 N 1\11-12/NHBoc Scheme 17a .
I o I o A-3, A-4, A-5, or J R 1-2 R
30f ________ y 0---30.
01 ._ 11101 14 \-1-1,CO,C HO2C
135, 136, R=
14 N __________________ N
a' 13 =-N'\ 7. , NHHBoc c' 2 __ d' / / 11-- ) NH, /N
\ --/
11 N / ¨N
Cl e' /14 . f) 40 NH2 g, 11 it cH2eN h, / 4 01 CH2NH2/NHBoc /
Scheme 18 NH, ri n Bn0 41 CHO Bn0 ei CO2H
140 + 6 4101 , \,..... 0 H 3 CO 2 C H3c02c h HO CO,MEM 13n0 CO2MEM
G
112CO2C . V='.= 113CO2C 5 =
F3CO2S0 CO,MEM R gab CO,MEM
D-2 or 0-3 WI.---0.-vo,C lei 11--' H3co2c õ
.
H NH
R
Nj 10111 R
-.(-----I. It ..c-----41. N-= .I K.---HO2C H3c02c ri V 113CO2C
' 149 148 147 =
146a -- 149a, R = 146b -- 1496, R = r$ 146c--149c, R = -CH=CH2 Scheme 19 ...,. CHO / CHO
a D-9 +3a -a N
Sn(Me)3 H,CO2C
NH , 151 41 ./ NH2 1 CO2H
N .
J
I H
N =,, N
. 0 H
.1 N
H
le HO,C
154 0 .
, Scheme 19a CHO
N i I +3a D-9 3 .
I
Sn(Me), H
155 N,....,..õ,..---H,CO,C
NH
illi NH2 CO,H
NH - N
I
-, N.,....õ....õ..-* H
H3CO2C H,CO,C
' 0 NH
111 NH, N
I H
, .-HO,C
, Scheme 20 , NH 0 i 0 I. õ....---...õ
H
lei .1_ 3ifAB-1 or AB-2 _____________________________ 1 H
0 0 el H
N.,...,....õ..----..õ, -.......õ.." -...__ R , 12R. Cl or ., (RN, .,,A.... N N1OR
) 0 0 H
H
160a, 161a, R = -CH3 1411) 4101 114.,....
160, 161b, R = -C2115 HO2C
160c, 161c, R = -CH2C6H5 162a, R = -CH3 160d, 161d, R = -C(CH3)3 162b, P. -C2115 160e, 161e, R = -CH2-CC13 45, 160f, 161f, R = OMe 162c, R = -CH2C6H5 160g, 161g, R = 41 F 162d, R = -C(CH3)3 160h, 161h, R ----- CH
..,7 2.,.... ., = ._ ,,, CH, ..... s ...0-.CH3 160i, 1611, R
I
160j, 161j, R ,.,.,C1-1,,,... .7õ.., Scheme 21 Br 404_ 130 I_ H3 C 0 2 CH2 C H,CO,CH,C
NH
410 NH, is OS
NH
NH, So HO,C112C
Scheme 22 HO * HO* HO 0 AC G
õ. NOH NH, H,CO,C CHO H3CO2C H;CO,C
IAA
H *
H
Ns.,,,, H H3CO,C
,CO2C
172 + 130 - - 40 - 2 E
la H
H,CO2C H,CO2C
173 '4 NH I j NH .
ell NH, 0 el NH2 H 1-2 * N
H
* H
N., H
HO,C H3CO2C
, Scheme 23 168 AE-1 > - H B-2 H =
N
11,CO2C H2CO2C
177 178 .
IR
F3CO2S0 0 roc 11,CO2C
179 + 130 E 1-2-12---N,-1101 Hoc 11,CO2C lel Hoc I
11,CO,C
NH NH
0 - el H IP
1-2, S 0 N 140 NH2 Hoc N
11,CO2C
, Scheme 24 F3CO293 ea H,C,H,C0 Cl-b H5C6H2C0 0 CHO
H +
R
H3CO,C
IP H
B(OH)2 0 N., 3a, 3f, 3i, 3j 6 1-13CO2C R
CHO F3C0,80 CHO HO
N
R
Nõ
l'\I
'''' NH, 187 186 185 1 HN NH, NH
141111 õ
SI N
H
H
1\1_ 3a, 184a, 185a, 186a, 187a, 188a, 3f, 184b, 185b, 186b, 187b, 188b, R= CH,CF, 31, 184c, 185c, 186c, 187c, 188c, R = CH,CH, CH, 3j, 184d, 185d, 186d, 187d, 188d, R = CH, =
Scheme 25 NH
X
HO,C
189a, 189b, 189; 189d AE-4, 74 189a 184a AE-3 189b _G 189c 189a, X = H, Y = OCH3 189b, X = OCH2C61-15, Y = H
189c, X = OH, Y H
131_AE-3 NH, I (Prepared by method AJ-1, AJ-2, or AJ-3) HN NH, NH
189d,X=Y=H
is CHO
NH, µ\
[xi H3c02c HO,C
HN NH, 189e =
Scheme 26 NH
NH R 411 NHBoc Br = +
NHBoc X
Br HO Br \c, 192 B..
40 cocn, 6a NH NH
NH, R NHBoc 110 114 \/
H3CO2C 1-1,CO2C
NH
R= NH
SL
HO,C
190a, 192a - 195a, R = H
190b, 192b - 195b, R= CH3 Scheme 27 . NH . NH . NH
NH, R. G H,N NHBoc NHBoc NH NH
H, 411 NHBoc 6a CH, II NHBoc Ill V D-7 41111 D
11101 11...õ,...7.--.......õ Br H,CO,C
NHNH, H, /01111 NHBoc H, 411 = t s ---, S11,,,,,,,,õ,, la ti...
HOC
HO2C , =
, , , Scheme 28 ell NH
II NHBoc 0 0 NHBoc 0 0 ei Vi , N
* H
N....,,,--, N,,,,,....õ...-H,CO,C HO,C
Ill NH
el NH
0 NHBoc 0 NHBoc 0 el 0 II
' N Ill el N
H H
*H
INI.,,µõõ...---...,õ H2N
II NH
lel NH
N
lel NH, *
Ill N
H H
*H
N...=-=-,., H2N
IP H
N..., , Scheme 29 , 3,T 1411) CN
R el CO2H R
----). 11 11,CO2C Si il H,CO,C 4101 1\'-132, 30f 209 NH NH
01H R so CI
R
411) 14 1-2 , *{4 * 1.
H02c H30020 209a, R = H
209b -211b, R =
, Scheme 30 I
I si CN 0 H
----31. rah IV .\
-14.....,_õ.õ, 01 K.
187a 212 NH NH
N ill NH
N el N, H
01.I
-.(-----01,. le HO,C H3CO2C
Scheme 31 Me0..,...õõõ--- Me0 Me0.., I H
Br 1µ1.- CO2H BrNN ____õ--...,....N..7.,...(N., 216 . 0 I 0 E-2, ..., .
F,CO2S0.õ--,..,,,,N, :-3, 1 , H B-2 .---' 11,...õ..,õ--',.õ, + 6.-2--yN.....,....õ,, H2CO2C N H3CO2C N H,CO2C N
. 0 221 220 .
' I E .
PhH2C0 0 CO21-1 PhH2C0 CO2MEM .
F G
-....,_ -.......
I ' H I H
I
1.1 .--" N...õ.....õ..- ./ N.,..,.,,, I I
0 CO2H 00 CO2MEM Di3 0F COS0 5 CO,MEM
I H I H I H
N..,..,....,, ..' N...,õ.....7- ./
11,CO2C N
. 1 J
NH NH
, ell NH, 0 NH, * N
H
.....,. 1-2 lei N
H
-.......
/ --N.,....õ...õ
, , Scheme 32 CO2CH, CHO
II CHO D-6 or --I.-4- 6a I. CHO
------).-Br HO Br a 0 OP
)--- 0 )--- 0 OH
'\.
R = H R =H 232 0 R = CO2CH3 R = CO2H
E
NH
1\1112 el g I.
CC/2CH, J
-*---CO2CH, o 0 o . )¨o ,)---o R R
R = H 234 0 R = CO2H R = H
R = CO21-1 Y
NH
4111 ti I.
R
R = H
231a, 232a, 233a, 234a, 235a, R = H
231b, R -- CO2CH3 232b, 233b, 234b, R = CO2H
Scheme 33 NH
CN
I NH2 +187a 1-121µ1N
Scheme 34 NH NH
40 NHBoc OH 0 el NHBoc ./ 0111 N L N
H OH H
* H
N.,,,, SIP
* H
N.,,,,,,,, H,CO2C H3CO2C
161d 240 NH /1\4 NH
S
NHBoc 0 0 i NHBoc l I
,HN
AG H el H
, H
N..,,,..õ....." . ell H
NH NH
lall NH2 OH 0 el H 112_ NH2 H
* H 1110 N.õ H
H,CO2C
Scheme 35 HO el CHO F3C0,80 opo CHO
221--L-1 ) B-2 I H I ," H
./ l'qõ,..,,-H,CO,C N 1-1,CO,C N
0, 0 245 ' 246 NH, CHO
H
I H
I H
HO,C N lei 1-1,CO,C N
248 HN NH, . .
' NH NH
I. NH, Bn0 si 4111 Bn0 opi N
222 -----3.- H 1-2 H
=,,, I HI H
,--- 2µ1,_õ--- ,---H,CO,C N HO,C N
NH' Ill NH, N
H
=
I H
./ N..õ...............---HO,C N
NH .
i I \TH2 i / illip NV
247 ---1=-.0 ...tn;
-,õ
I H
N.õ,,,,,......--...õ....
HO,C N
HN NI4, 0 252 .
Scheme 36 NH
CHO AE-3 NHz NH, Br Br HN NH, R
it NH it NH
NHBoc D-6 NHBoc + 6a Br H3CO,C
I-2, S
N NH
NH, HO,C
General Methods of Preparation The 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: Methoxyethoxyrnethyl; 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 folinula (I) are given below:
A-1: 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 water and amine (5 mmol) was added. The reaction mixture was stirred at room temperature overnight, washed with 1N 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 chloroformate (3 mmol). The reaction mixture was stirred at the same temperature for 30 mm and the corresponding amine (6 nunol) was added. The reaction mixture was stirred at room temperature overnight and quenched with 1N HC1. The organic layer was separated, washed with water, brine, dried and concentrated in vacua. The product obtained was purified by crystallization or flash 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 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 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 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 purified by crystallization or flash column chromatography to furnish the desired amide.
72 .
A-5: Conversion of acid to amide A mixture of carboxylic acid (1 mmol), amine (1.1 mmol), 1-hydroxybenzotriazole (1 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide methiodide (1.1 mmol) in pyridine (10 mL) was stirred overnight at room temperature and was concentrated in vacua 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 or .THF (10 inL) at 0 C was added triethylamine (1.2 mmol) and ethyl chlorofounate 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 and quenched with 1N 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-dimethylaminopyridine (0.12 mmol) in xylene (10 rnL) was stirred at 80 C for 10 min.
Phosphorus trichloride (1 romol) was added and the reaction mixture was heated with stirring at 150 C for 2 hr. After cooling, the product was extracted with Et0Ac. The organic layers were combined, washed with water, brine, dried and concentrated in vacua. The product obtained was purified by flash column chromatography to furnish the desired amide.
B-1: 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 added dropwise triflic anhydride (2 mmol) in dichloromethane (2.5 mL) over a period of 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 1N 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 triflate.
13-2: Conversion of phenolic hydroxyl to triflate To a solution of substituted phenol (1 mmol) in DMF (10 mL) was added N-phenylbis(trifluoromethanesulphonimide) (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 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.
=
D-1: 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(triphen.ylphosphine)palladium (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) 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 vacua.
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 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-4: Coupling of trimethyltin derivative with triflate A mixture of triflate (1 mmol), trimethyltin derivative (3 mmol), and bis(triphenylphosphine)palladium(II)chloride (0.05 mmol) in THF (10 mL) was heated at 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 rnmol), 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 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-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 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.
=
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(I1)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-8: Coupling of phenol with boronic acid =
A mixture of phenol (1 mmol), aryl boronic acid (3 mmol), molecular sieves (4.e), pyridine (5 mmol), copper(1)acetate (1 mmol) and bis(triphenylphosphine)-panadiumRchloride (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 Celitermand 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), LiC1 (4 mmol), PPh3 (0.15 mmol), CuBr (0.2 mmol), and bis(triphenylphosphine)palladium(11)chloride (0.07 g) in DMF (10 mL) under an atmosphere of argon was added trimethylstsnnyl compound (0.8 mmol) and a crystal of 2,6-di-t-butyl-4-rnethylphenol. After the mixture was stirred at 90 C for 3 h, a second portion of aryl-trimethylstannyl compound (0.5 mrnol) was added. The reaction mixture was stirred at 90 C overnight. Water was added and extracted with ethyl acetate. The organic layer was dried (114gSO4), concentrated and purified by flash column chromatography or crystallization to furnish the desired coupled product.
D-10: Coupling of amine with triflate A mixture of triflate (0.75 mmol), amine (0.9 mmol), potassium phosphate (1.1 mmol), 2-(di-t-butylphosphino)biphenyl (0.015 mmol) and tris(dibenzylideneacetone) dipalladiurn(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-11: 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-tert-butylphosphine)biphenyl ( 0.016 mmol) and N-methyl pyiTolidine (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 DMT (5 mL) were added LiC1 (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 (MgSO4). After evaporating the solvent in vacuo, the compound was purified by flash-column chromatography to give the desired product.
E: Oxidation of aryl aldehyde to acid A mixture of aldehyde (1 mmol), tert-butanol (5 mL), water (2 mL) and acetonitrile (1 mL, additional amount may be added until the reaction mixture was 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 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 KM.n04 (4 mrnol). The reaction mixture was stirred for 3 h (the reaction is exothermic, and refluxed on its own during the addition of KMn04). The reaction mixture was diluted 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 (MgSO4) to furnish the desired acid.
F: Conversion of aromatic acid to MEM ester To a solution of aromatic acid (1 rntnol) in THF (10 mL) was added diisopropylethylamine (2 mmol) and 2-methoxyethoxymethylchloride (1.1 rnmol).
The reaction mixture was stirred a room temperature for 3 h and diluted with ether (25 mL).
=
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 cobimn 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 ininol) in ethanol (10 mL) was added 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 ceiitermunder nitrogen.
The filtrate was ccincentrated 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 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 cohmm chromatography gave the desired ester.
1-1: Hydrolysis of MEM ester to acid To a solution of MEM ester (1 mmol) in MAE (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 mixture was acidified with 0.5 N HC1 (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 Me0H (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 Me0H. 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 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 HC1 (10 mL), diluted with ice cold water (10 mL) and extracted with chlorofoini (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 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.
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 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/tert-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 tert-butanol, 0.1 mmol). The reaction mixture was stirred at room 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 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 metaperiodate (3 mmol) and stirred at room temperature for 30 mm. The reaction mixture was quenched 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. The crude product was purified by flash column chromatography to furnish the desired aldehyde.
N: Conversion of alcohol to mesylate To a solution of alcohol (1 mmol) in DME (10 mL) was added 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 by column chromatography to furnish the desired mesylate.
0: Conversion of mesylate to azide To a solution of mesylate (1 mmol) in DMSO (10 mL) was added sodium azide (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 (2 X 15 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 chloroforrnate (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 HC1 (10 mL). The product was extracted with chloroform (2 X 10 mL), dried, filtered and concentrated in vacuo. The residue obtained was purified by column chromatography to furnish the desired carbamate.
Q: Conversion of silyl protected amine to amine A mixture of silyl protected amine (1 mmol), tetrabutylammonium fluoride (1.0 M in THE, 2 mmol) in THE (10 mL) was stirred at room temperature for 1.5 h.
The reaction mixture was concentrated in vacuo and purified by column chromatography to obtain the desired product.
R: Proteetion of amine as tert-butyl 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 (MgSO4), and the solvent was evaporated in -mato to furnish tert-butyl carbamate. If needed, the product 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 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 HC1 (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, 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, 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-1: 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 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 HC1 (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 1N NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 N HC1 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 (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
U-2: Synthesis of boronic acid by ortho lithiation of aryl aldehyde To a solution of N,N,N'-trimethylethylenediamine (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 (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 C 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 reaction and stirred at 4 C for 12 h. The reaction mixture was allowed to warm to 0 C
and quenched with 2 M HC1 (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 HC1 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 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 lithiation of aryl acetal To a solution of aryl acetal compound (1 mmol) M 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 HC1 (10 mL). The reaction mixture was stirred at room temperature for lh. The aqueous layer was separated and the organic layer was extracted twice with 1N NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 N HC1 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 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-1: Demethylation of aryl methyl ether to phenol In a round bottom flask (50 mL), pyridine hydrochloride (10g) was heated in an oil bath at 180 C. After the entire solid had melted, the corresponding aryl methyl ether (1 mmol) was added in small portions over a period of 20 mm. 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 10mL). The combined organic layers were washed with brine, dried over MgSO4, 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 tribromide (3 mmol). The reaction mixture was allowed to warm to 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 MgSO4, and concentrated to give the desired phenol. This can be further purified if needed by crystallization or column chromatography.
V-3: Demethylation of aryl methyl ether to phenol To a solution of aryl methyl ether (1 mmol) in dichloromethane (5 mL) was added AlC13 (8.5 mmol). The reaction mixture was heated to reflux for 12 h under nitrogen. To this mixture was added 12 mL of 1 N HC1 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 (MgSO4), 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 (2 mmol) in toluene (5 mL) was added dropwise over a period of 30 min. A
solution of aryl ether (1 rnmol) 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 organic layers were combined, washed with water, dried (MgSO4) and concentrated in vacua. 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 cone HC1 (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 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 HC1 or ethanolic HC1 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 HC1 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 nitrite 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.
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 50 C for 30 mm. 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 hydi-oxide (16 mL). The reaction m mixture was washed with ether (2 X 10 mL) and acidified to pH 4 using cone HC1. The solid obtained was collected by filtration to furnish the desired product.
Z-1: Opening of aromatic methylene dioxy compound with alcohol To a mixture of methylene dioxy compound (1 mmol) in HMPA (2.5 mL) were 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 mm. It was then extracted with ether and the aqueous layer was acidified to pH
4 with HC1 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 and was then poured into ice water and acidified with 1 N HC1. The precipitated solid was collected by filtration, washed with 1N HC1, 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 vacua. The residue 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 (MgSO4) 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 residue was added alkyl or aryl 4-nitrophenyl 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 X 100 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 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 triethylarnine (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 column chromatography to furnish the desired product.
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 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 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 aldehyde =
AE-1: Reductive amination of aldehyde To a stirred solution of aldehyde (1 mmol) in methanol (40 mL) was added amine (3.3 mmol) followed by the addition of glacial acetic acid (0.3 mL). The reaction mixture was stirred for 30 mm 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 filtration. The pH of the aqueous phase was adjusted to 7 with 1N NaOH and was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated in vacuo to furnish crude product. The crude product was purified by crystallization or flash column chromatography.
AE-2: Reductive amination 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) was added a solution of aldehyde (1 mmol) in THY (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 nimol) and stirred for additional 2 h and concentrated in vacuo to remove methanol. The mixture was diluted with water (15 mL) and washed with ether (2 x 10 mL). The aqueous layer was acidified to pH 2 using 6 N HC1 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 animation 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 THY, 5 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with 5 N NaOH (30 nunol) and stirred for additional 2 h. The reaction mixture was filtered through CeIiteTM (to remove molecular sieves) and concentrated to remove methanol. The mixture was diluted with water (15 mL) and washed with ether (2 X 10 mL). The aqueous layer was filtered and solid obtained was kept aside (mainly product). The aqueous layer was acidified to pH 2 using 6 N HC1 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 amination of aldehyde To a mixture of aldehyde (1 mmol) and aminoarylamidine (1.1 mmol) in Me0H
at room temperature was added triethyl amine (2.75 mmol), sodium cyanoborohydride = (0.83 mmol) and zinc chloride (0.9 nun.o1). The reaction mixture was stirred at room temperature overnight and concentrated to remove methanol. The reaction mixture was quenched with 1 N NaOH (10 mL), diluted with water (10 mL), and extracted with Et0Ac (5 X 20 mL). The combined organic extracts were washed with brine (15 mL), dried (MgSO4), filtered throughceiitermand concentrated to give the product.
Purification 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 Me0H (10 mL) was added aldehyde (1 mmol) in 'rHF (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 (MgSO4) and evaporated in vacuo. The residue was purifeid by flash column chromatography to furnish the desired amine.
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 HC1 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 HC1 (10 mL), brine (20 mL), dried and concentrated in vacuo to furnish 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 to ¨78 C was added dropwise tert-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 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 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 overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ether (2 X 10 mL). The organic layers were combined, washed with brine (10 mL), dried, filtered and concentrated in vacuo to furnish desired tributyltinalkyl and was used as such without further purification.
AG-3: 4-Bromo-5-formyl-benzo[1,31dioxole-2-carboxylic acid methyl ester To a mixture of 2-bromo-3,4-dihydroxy-benza1dehyde (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, 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
HC1 and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were dried (MgSO4) and evaporated in vacuo to afford crude 4-bromo-5-formyl-benzo[1,3]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 mL X 3). The combined organic layers were dried (MgSO4) and evaporated in vacuo.
The residue was purified by flash column chromatography (ethyl acetate:hexane = 5:95) to furnish 4-bromo-5-formyl-benzo[1,3]dioxole-2-carboxylic acid methyl ester as a white solid.
All: 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 ethyl acetate (3 X 50 mL). The organic layers were combined and washed with aqueous 0.5 N HC1 (100 mL), water, brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash column chromatography to furnish the desired ester.
la. B-2 G
01N.. H õ,...õõ---...,,, 40 H
..."...---,..%
Fl N......,..õ.......
H3CO2C H,CO2C 83CO2C
' Scheme 3 all OH = SO,CF, = SO,CF, so CO211 . CO,Bn ao CO2Bn CO2Bn H B-2 g 411 CHO CHO CHO CO,H
1A-3 or = SO,CF3 0 CO,Bn H
=
Scheme 4 = SO,CF, Bn0 0 CO214 so CO,Bn D-1 or 13n0 CHO
-, 0 , ., D-2 E
-----).-H SL
1µ1...,-, BnO2C
0 1\"11 BnO,C 11111 1, F
_ HO is CO2MEM HO el CO2MEM ...,__....2_Bn0 0 CO2MEM
H
.0----, * 11 N.õ.....õ...--...õ...
BnO,C HO2C BnO2C
21 ._... _ 20 19 0C11110 .
H
BnO2 , , , -Scheme 5 F,CO2S0 CO,MEM
is + R _ Dx-1, D-2, D-3, D-4, D-5, D-10, D-11, or D-12 R
_____________________________________________ 1 23 X --= H, B-(OH)2, Sn(Bu),, Sn(Me),,or Si(Me)3 0 CO2MEM
110 *\/).\. 4 Sk,_.
BnO2C BnO2C
R
NH
.1, 411 NH2 14õ,.....õ..õ
BnO2C BnO2C
:6 . 25 NH
R elH
HO,C
24, R -= , H3C
a___ A __ -. c,, d,... _14 , e,4µ.
H,C s h, =-"..,-1 i, !%'-'"----1 j, k, Ki".--0 H3C
T N
N 0 CH, i n, ,====õ,,_,,..2-.CH2 0, /7-=Nal, q' - CH
r'OH
SNe õ...,.."-N".õ 3 w,H2 =TMS
s,t' ___________________ H2 U, z OH v, OH /
CH, 25 CH, 24, R = (continued) CHO
X, /_<
y, ---s-.. OH z, )1 aa, ¨
N ab, .,,, ,...C..
CH3 \ OH .---S
OHC
ac, /....,, ad, \ .,..,\// ae, //
,,,,\........___ ag , ..., .,' ah, ---N\ CH, S
CHO OHC-- s N
S
Boo 25, R = H3C
c, c1,_____Q........
H3C s S . S 0 0 S
h, /V.::.i i,,V j, H3C .._.,_, =:,- /-.,,, 1. .,,.) I
/3, ,,.CH2 0, i¨ \ 1), (1, -----CH3 r, '7'- OH
/= N CH3 N
SN/Z
/ -OH
CH, CH2 v w, ,,= CH
s, -,__.-1/2 t, __ < it, /_0R, -....õ.õ..., OR /,, OH
CH, OH z, z li x, z _ <CH, y, ..,,,,-µ-..,....õ...-\ OH aa,,¨N ab, &.
...
S
BnO,C / HOH2C
ad, ae, HOH2CNs / af, ( ag , i j / \
OR N
S S CS) c)c ah , ai, OH
----, 26, R = H,C
a b, ______________ cio d, .,\..., e, H,C s S7 0 0 S
h, -'1 1 i,--`Y--1 j, 1 k, H,C, .,,,..\ 11 111, &
N) --:,,, 7---..,,, ===:,-,..,.. .õ--N
N N I S
I
N 0 CH, n, .õ,--,....-,,CH, 0, /¨ \ P, //=-----\----- CH q, N< CH, r, 7-.,.,'=-,,,. OH
S Ne 3 H,C/ -OH
CH ____/<C1,,,, 2 w, //,,=_- CH
s, ,..,,... ____ ,..,,,..., CH, t, ______________ u, z____ ,õ.µ..7 OH v, OH
CH, CH, CH, X, / __ <CH, y, ._..,z, OH )1____\ aa,._,-N ab, 4/\
S
BnO,C /
ae, ,_._..,_ at HOH,C
( ag , & ........_ ad, i HOH,C s OH N
Boc OH
ah, ai, OH
27, R=
c, V s S7 0 0 S
N N N
I
'ThµK 0 CH, n, ,..,-=,,,,, CH2 o,, ¨
P /¨`,. q, 7,--Nv CH, r,OH
Ss'N CH3 / .(:)14 HC
CH, CH, OH w, /CH, s, "..,,, ,,,,,....õ 2 CH t, __ < u,, õ,./¨`====,_,,- v, ----/.v OH
CH, CH, 27 27, R = (continued) , CH2 OH
x, _______________ yv zaa OH ab, ac, ______________ ad, ae, HOH2C at HOH2C
ag , OH
ah, OH ai,N2 Conversion of 24ab K I-I25ab = 24ac 25ac 24ae 25ae =
24ad 25af The reduction of the formyl group of 24ab, 24ac, 24ae, and 24ad was accomplished with NaBH4 to give corresponding alcohols 242134, 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 25ah The vinyl compound 24ah was oxidized with 0504 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 NaI04 produced aldehyde 24ah-ii. The aldehyde on reduction gave alcohol 24ah-iii, which on further reaction with methane sulfonyl chloride yielded mesylate 24ah-iv. The mesylate on further reaction with sodium azide gave the corresponding azide 24ah-v, which on acidic hydrolysis produced 25ai.
Conversion of 24w 25w =
Scheme 6 CF,S0,0 01 CO,MEM D-1, D-2, D-3, D-4, or D-5 = CO,MEM
+ R - X ______________________________________ s 28 X = H, B-(OH)2, Sn(Bu)3, or Sn(Me), 113CO,C S II
H3CO2C S {I
NH
7, el NH, R 0 C0,1-1 -..(---110 14\, Slk.
H3CO2C 1-1,002C
= 31 30 11-2 .
NH
NH, Ho2c 29, R=
a, 0 b, ,.,..õ, ' c, .,,.,,, CH2 cl, ,..... ) e, CH,r S
OHC CHO OHC\ /
g, h, ,.....,.. i, s o o r 29 30, R=
a, b, c, d, = e, t CH, CH,=
NHC
CH OH HOH,C
g 13, __________________ 31, R=
''C H3 a, b, c, 0H2 d, e, cH20H HOH,C
g ,1\131-12.
32, R=
a, b, 0H, c, d, e, 1110 c H2 c H, g K, N, 0,1-i Conversion of 29g 30g Aldehyde 29g was converted to alcohol 29g-i by reduction with NaBH4, followed by the reaction of 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.
K, I-1 Conversion of 29h----)- 30h K, I-1 29i 30i The reduction of the formyl group of 29h and 291 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 30h and 301, respectively.
Compounds of the type 23 and 28, where X = -Sn(Bu)3, are prepared using the methods AG-1 or AG-2 Scheme 7 11 .....-_L_ * H
N........,,,..,--..,,, H,CO2C
Si NH
I 0 N laill NH2 CF3 S020 is CBz CF3S020 0 N P
H H
N-- ..,.....õ,õ,..õ....õ . H
= 0 0 35 0 . 34 B(OH)2 / \
CBz e CH2C6H5 . =
I
TIPS
TIPS = Tri-isopropylsilyl TIPS NH TIPS NH
I I
N N
\/
CBz * N
H G
N
H
* H
N,,,,,_.,, 01 H
N.õ,,....õ..--..,,, NH NH
H H
N N
\ /
\ /
OHN*
H
,..,, .
I\I,s.,,,.=., Scheme 8A
0 0 CO,MEM
+ 1411 H
10 B(011)2 H,CO2C
NH
401 = 1-1 illt NH, IP 1 0 C0,11 =
H J
*
H
1110 11õ,...... 5 H,CO,C H,CO,C
* 11-2 NH
0 Sp NH, N
H
1$1 14,..õ_v.--HO,C
Scheme 8B
IP NH
S.
= N 4111 0 N NH, -1-3.-el H
N,,.,,. 411 H
H,CO,C HO,C
Scheme 8C
CHO
Me0 40 CHO Me0 +3a D-2 3a __ J2:,/_,,.
(11101 H
B(OH)2 47 H3CO,C
, 0 NH
/ E
0 NH, 111111 Me0 40 CO,H
Me0 H 0 N J
* H
N,.,,..7,---,,, 1.13CO2C
25 . 11-2 NH
30 Me0 0 ill 2 N
H
35 HO,C Si H
N. \
40 Scheme 8D
NH
S
S 0 4111 NH2 = 4110 NH, G 0110 14 1-2 (101 h 31g ---3.
H2N I-1,N
H3c02c H02c Scheme 8E
raj (R... ) 26n 32f 27ak (R = ) 26a1 27al(R ) 26u 27am (R= OH) Scheme 9 . le * 0 NH
0 NH, 0 CHO 0 Oil CO,H 0 5 + 6 ..J:L_,..
H
11101Oil 116 H,CO,C CO,MEM H,CO,C CO,MEM H,CO,C
CO,MEM
IR .
NH NH
41111 NHBoc 0 git 0 SI N NHBoc HO, 0 N
H ___ so H
Oil 110 H,CO,C CO,MEM H,CO,C CO,MEM
. 58 57 NH NH
¨ 0 5 NHBoc N Sp NHBoc / 0 la H,CO,C 1111111 CO,MEM H3CO2C CO,MEM
NH NH
/ = 0 N
1410 NHBoc /
¨0O
N
0 el NHBoc (16/
____.
H
H1CO1C H3CO2C CO,H
. 11-2 ¨
NH NH
/ = 0 5 NHI30c / 0 0 II NH, ¨
H S
la N
H
Lail NHR 411 NHR
HO,C HO,C
63 0 . 0 62, R =
' a, ,,,,--..,,CH3 b' CH, c' .'.CF12 d' e,`...,...c..-CH3 f 4---CH3 ' CH3 CH3 CH, OH
g , \/'\(CH3 }:..,,.,70 i CH
14¨) 0 CH, . CH, m,=-,CH3 ,, ,,,,..<3 0, *
P> ..CF3 q, r' CH, OH
t''OH 11, CH, OH
,,,(.JD y, z, .õ.7 CH3 aa, ,.,--cOH ab, w, -'"--,_/\/14--41 ' ac,, ad _0 OH ae, NHR = ¨N/
\ af, Niirt \.------", 63, R =
e,.CH, f; A--"CH, a, ......õ..õ,......cHa b' CH3 d, cHa d' CH, CH, OH
g, \ ,,,3h,) CH )1___C) i, CH, 0 1), =,.7.CF, 9, '..,.\.--''\CH3 r, m, \ n,,,C3 0, CH3 t CH3 II, OH , =%.,,,)(23 CH, OH
CH, OH
y' Z,7-...%,.CH CH3 aa, -õ,.......,,,--cy.,OH ab, II
w, af, NHR = ae, NTIR = --N --IN
ac, ___-.0 ad, OH \ \-----A7, ' 36 , 64, 12 =
0, ..,.<CH3 f ,,,----- CH3 a, ,..-,..7=CH3 b' CF13 c' C11, d, g , "\s,C1-13 1,1:_Nf) i, CH3 =
OH
1.1_0 m' CH3 n'-'=C
CH3 0, P, -..,,,.=CF3 q, ,,-"-.,V,,, r, CH, CH3 CH, s, t, ...õ..,, ,,...,...õ. u, CH3 -`.- -OH =,,, OH
_, CH
w, r\N x, y, =r''-'s-% z, -,,.C113 aa, ,.,cOH ab, 44I
a0,ad, _0 OH/
ae, NHR = --N( af, MR
,.
\-----v7, NH
-el NHR
¨
IS N
H
NHR
HO,C
65 ,õCH3 65' R = CH3 Scheme 10 NH
N II NHBoc 59 + (Bu),Sn. D-3 H3CO2C CO,MEM
H NH
N 411:1 NHBoc N 411 NHBoc * H A-4 la 1 . 5 NHR
H3CO2C 113CO2C CO,H
= 680 67 NH NH
NH
N 4111 Boc I
N I. 2 HO,C HO,C
, 68,R ----a, -,.,.,..,CH, b, CH3 c, ¨0 d, ,,,,,,,,..,õe, CH, CH, CH, CH3 CH, g, '-CF, h,. OH
i, k, \ CH3 1, m, _______________ n, /---,'II3 0, 7r' \/-*''''',.." CH3 P, 0 C 'CH
CH, cl, X------ CH, .-0.. 110H 11, --1 vy --<>
r'NHBoc s, ---0 t .
IN, ,..-. x, CH , CH, 38 69, R =
a, ..--",,,CH3 b, CH3 c, ¨0 d CH3 f ..,<3 _1 ' CH, e' 'X ' . CH, CH, CH, g, ==õ,CF h, i' -'OH j, k, `--., CH, 1, =,,,CH3 CH, 0, .,---.. CH, //¨ CH, CH3 ci' CH X---- 3 r,..õ,õ,-,,,..õ....A4H2 s, __.0 t, ...._<---),,,,i OH
u, w, -.....,.õ.CH
OH x' 3 CH, 70, R =
a, =õ--...,,C113 b, CH3 c, --- d, e CH
..,õ_,< t `,., 3 ' '''CF12 ' CH3 CH, CH, -CH3 g, -CF h, it 1, \,^\OR j, --"IC
CH, m, 0, .,.,--..,,,,CH, 0, ,,-..,_CH3 CH, q' X---- CH, r,..,,,...7-,NH2 s, ¨0 t, ¨O. , i 'OH u, _______________ < v, w' OH x' Cli3 NH
! 0 II NHR
1110 HO,C NI
71 o 71, R=
a, --<> b, --1 c, Scheme 11 CHO * CHO
1110 U-2 or T and U-3 ' 73 -I- 3a Me0 Me0 B(OH)2 0 CHO V-1 or V-2 so CHO
andHorW
-.E----HO
le 11 Me0 * 1\1,.,,,=\õ
12.02C H3CO2C
75a, R' = Me 75 0 74 0 75b, R = Bn 0 CHO si CHO
D-2,D-3, or D-8 ---).-F,CO2S0 * H R
* H
N..õ,õ......õ.^-,.., N,N....õ...---.õ,..
R'02C
76a, R. = Me 76 077 0 76b, R' = Bn NH
41) el CO21-1 1.1 N
H J
= Ill H
R 0 .2 R
0 ' 1\11,..õ, R'02C
ROS
11-2 or G
NH
R * N
0 4111 NH, H
SL=--,õ., HOS
77a, 78a, 79a, 80a, R = -C-77-- CH2; R' = CH3 H
78b, 79b, P. OSO2CF3; R' = Bn; 80b, R = OH
7713, 78c, 79c, R = -0-CH2CO2C2H5; R' = Bn; 80c, R= -O-CH2CO2H
77c, 78d, 79d, 80d, R = -0-CH2CONH2; R' = Bn 77d, 78e, 79e, 80e, R = ; R' = Bn S
77e, 78f, 79f, 80f, R = -o=; R' = Bn 74 B 78g ._f___.)... 79g___12_,... 80g 78g, 79g, 80g, R = OCH3, R' = CH3 77f, 78h, 79h, 80h, R = -- ,-,,,,--- CH3; R' = Bn .,,,,.0,,,CH3;
77g, 781, 791, 801, R = ' Bn 77h, 78j, 79j, 80j, R ----, :
CH3- R.' = Bn , 771,78k, 79k, R = OCH2-CH2-0Ac; R' = Bn; 80k, R = -0-CH2-CH2-0H
, , , -Scheme 12 .
NH NH
N
II NH, 0 N 410 NHBoc I.
I.
H R
H
/µI.- I
H,CO,C 01 H
, 79, NH IL
NH
N
el NHBoc 0 1.11 NHBoc H
el H M
* H
1110 }-1 0 14 ,,,,,., N -,7,k-,, H,CO2C HO 113CO2C
NH K
NH
41111 NHBoc 0 lel NHBoc N
II N
H
0 Oil gill' OH iglr H H
OH
N,..,7-.,. 11101 H,CO,C H,CO2C
NH
R *
N
=NH, 82, 84, 85-=----,-H
86a, R= CH(OH)CH,OH
86b, R = C1-120H
86c, R= CO21-1 , Scheme 13 ell OBn OBn X T, U- 1 lip CHO
_____ 40 CHO --3== CHO 89 + 3a Br Br B(OH)2 ' a Bn /13n . OBn los CO2MEM 40 co2H CHO
F E
-c------ ...E-------_ II N (101 ''-=,..,"'xi' '`,. .
H3CO2C . - s'-`-'--.-- 1-13CO,C .',,.-V- H3CO2C
=1-1 = SO2CF3 los B-2 D-3 $
---N.-410 14 14 /1õ,,,r H,CO,C -x" H3CO2C . '--`- 143CO,C .
NH NH
R
7,1 II. NH2 CO211 01 P 1-2 (10 HI
_____ t\i HO2C fl H3CO2C . 1-13CO2C
0 ' 0 0 , j.
95a, 96a, 97a, 98a, R= ) S
,......._ _is.9:L.. / \
iS S
91 ----,..- 97b ¨3..1-2 = 98h, R.= -0-CH2C6H5 Br SnBu3 98b ¨g---).- 98c, R.---- -OH
, Scheme 14 CHO CHO
II T, U-3 ----i.
41111 B(OH)2 OMe OMe leo CHO
I.
100 + 3a _______,.... D-2 E OH
-.-OMe OMe 1110 ,CO,C \ \/
H,CO,C 11 it NH it NH
ill t N 0 ti NH, OMe S14.õ........... OMe OP *
'=.,, õ/ \
HO2C H,CO,C
-Scheme 15 0 mo . CHO CHO
X T, U-I .
I I I. B(OH)2 OH OBn OBn 107 + 3a NH
, ON
4111 NH, 0 H ..,.... õI__ 5 OH E
H H H
OBn 5 N.,.....,.y" OBn el N.,,,,,..--.. OBn *
H3CO2C H,CO,C H,CO,C
NH NH
*
II NH, 0 0 NH, N
H I-2 1. N
H
H
H
OH 5 N.., 0 01 N
H,CO,C
Scheme 16 Ko 40 CHO HO
110 CHO X or Bn0 CHO
Z or Z-1 X, V-4, AR
RO
= ------3I .
Br Br Br 6a IT, U-I
Bn0 10 CO21-1 Bn0 op CHO
E -*---- Bn0 ii. CHO
RO RO ' CF RO 30S,0 ip = 40 B(OH)2 NHR H
NHR' 40 ' ,CO,C NHR' 11,CO2C H,CO,C
=
3a-j = 0 0 , Bn0 CO2MEM
. G HO CO2MEM
110 NHR' RO
NI-1R' RO
11,CO2C H3CO2C H3CO,C
. 0 0 0 .
NH
I 0 igli NH, 1 I .
lip CO2H CO2MEM
0 NHR' RO
IR
RO ' H,CO,C
0 0 , 0 NH
. 0N
H
RO
4101 ' if 114a, 115a, 116a, R = CH3; 114b, 115b, 116b, R= C2115; 114c, 115c, 116e, R = -CH(CH3)2; 115d, R = C---C(CH3)3 117a -- 125a, R = CH3; 12' = =,..,, 117b¨ 125b, R = C21-15, R' =
'CH3 CH
117c -- 125c, R = CH(CH3)2; 12' =
117d -- 125d, R ¨ CH3; R.' = <
117e -- 125e, R = CH3; R.<
' =
..,.,..,.,7,-.,..7 117f ¨ 125f, R = CH3; R' = .-CH3 117g ¨ 125g, R = CH3; R' = .'''CF3 117h -- 125h, R = CH3; R.' = 'CH3 117i -- 1251, R = CH3; RI=
117j -- 125j, R = CH3; R' 117k-- 125k, R = CH3; R' = ---'CH3 1171-- 1251, R = CH3; RI=
117m -- 124m, R = C¨C(CH3)3; R1= ; 125m, R = H; 12.' =
`===..,.,/,, "
Scheme 16a NH . NH
NH, B el Bn0 n0 it N N
118b---1--)- H 1-2 H
RO RO
1110 NHR' 01 1\11111' H,CO,C HO,C
CH, 126, 127, R = C2H5; W =
''''-----''''CH, Scheme 16b =
NH NH
1 0 ep NHBoc 0 N Ili NH2 124a R 1 40 n 1-2, S HO el 14 ---3===
RO Me0 CH, 128, R = CH3; RI = CH, , =
, Scheme 17 CHO
lel E
+ 3a CO,H
lel D-2 B(OH)2 --)--=
CHO 0 11 \./'\. H3CO,C =130 H3CO,C
1 jA-5, A-4, or R R
.
la 111101 HO,C H,CO,C
. 133, 134, R=
II
/ _____________ \
N __________________ D N-..,..
c, ,,...,, a, ¨N b, ti = /
CF
41 d, 41 3 \ _____________ / N
CF, CF CF,, F
e, 411 CF, f, 41100 g' 14 4110 /14 it .., ,.., / h, 7 , II 11 F
0 j, K /\__ k,___N/ \N____(7 ) I, ti . NH
i, ¨N\ ________ / /
\ ________________________________________ / N¨ /
in, ti . n, fq $ 0, ¨N
/ _________________________________________________ \ N.._ N ____________________________________________________ K ) 13, /II 41 / / S OMe _____________________________ 1 ,-N
OH
cl, 11 110 I r' 14110 NH, s, u, 4 /
/ N
v, ________ / (/ %N w, i' II x, 7----(-) Y, OH
133, 134, R= (continued) / __________ \\N aa, 14 il ab, 14 11 OH ac, 14.____(i z, ...,...
/ *
/
7.--------- N
ad, fl Of N ae, f 11101 af, 1;1 40 OH
/ \_..-------- /
ag,/ / /I 00 OH ai, Y 40 4 ..
CH3 N 1\11-12/NHBoc Scheme 17a .
I o I o A-3, A-4, A-5, or J R 1-2 R
30f ________ y 0---30.
01 ._ 11101 14 \-1-1,CO,C HO2C
135, 136, R=
14 N __________________ N
a' 13 =-N'\ 7. , NHHBoc c' 2 __ d' / / 11-- ) NH, /N
\ --/
11 N / ¨N
Cl e' /14 . f) 40 NH2 g, 11 it cH2eN h, / 4 01 CH2NH2/NHBoc /
Scheme 18 NH, ri n Bn0 41 CHO Bn0 ei CO2H
140 + 6 4101 , \,..... 0 H 3 CO 2 C H3c02c h HO CO,MEM 13n0 CO2MEM
G
112CO2C . V='.= 113CO2C 5 =
F3CO2S0 CO,MEM R gab CO,MEM
D-2 or 0-3 WI.---0.-vo,C lei 11--' H3co2c õ
.
H NH
R
Nj 10111 R
-.(-----I. It ..c-----41. N-= .I K.---HO2C H3c02c ri V 113CO2C
' 149 148 147 =
146a -- 149a, R = 146b -- 1496, R = r$ 146c--149c, R = -CH=CH2 Scheme 19 ...,. CHO / CHO
a D-9 +3a -a N
Sn(Me)3 H,CO2C
NH , 151 41 ./ NH2 1 CO2H
N .
J
I H
N =,, N
. 0 H
.1 N
H
le HO,C
154 0 .
, Scheme 19a CHO
N i I +3a D-9 3 .
I
Sn(Me), H
155 N,....,..õ,..---H,CO,C
NH
illi NH2 CO,H
NH - N
I
-, N.,....õ....õ..-* H
H3CO2C H,CO,C
' 0 NH
111 NH, N
I H
, .-HO,C
, Scheme 20 , NH 0 i 0 I. õ....---...õ
H
lei .1_ 3ifAB-1 or AB-2 _____________________________ 1 H
0 0 el H
N.,...,....õ..----..õ, -.......õ.." -...__ R , 12R. Cl or ., (RN, .,,A.... N N1OR
) 0 0 H
H
160a, 161a, R = -CH3 1411) 4101 114.,....
160, 161b, R = -C2115 HO2C
160c, 161c, R = -CH2C6H5 162a, R = -CH3 160d, 161d, R = -C(CH3)3 162b, P. -C2115 160e, 161e, R = -CH2-CC13 45, 160f, 161f, R = OMe 162c, R = -CH2C6H5 160g, 161g, R = 41 F 162d, R = -C(CH3)3 160h, 161h, R ----- CH
..,7 2.,.... ., = ._ ,,, CH, ..... s ...0-.CH3 160i, 1611, R
I
160j, 161j, R ,.,.,C1-1,,,... .7õ.., Scheme 21 Br 404_ 130 I_ H3 C 0 2 CH2 C H,CO,CH,C
NH
410 NH, is OS
NH
NH, So HO,C112C
Scheme 22 HO * HO* HO 0 AC G
õ. NOH NH, H,CO,C CHO H3CO2C H;CO,C
IAA
H *
H
Ns.,,,, H H3CO,C
,CO2C
172 + 130 - - 40 - 2 E
la H
H,CO2C H,CO2C
173 '4 NH I j NH .
ell NH, 0 el NH2 H 1-2 * N
H
* H
N., H
HO,C H3CO2C
, Scheme 23 168 AE-1 > - H B-2 H =
N
11,CO2C H2CO2C
177 178 .
IR
F3CO2S0 0 roc 11,CO2C
179 + 130 E 1-2-12---N,-1101 Hoc 11,CO2C lel Hoc I
11,CO,C
NH NH
0 - el H IP
1-2, S 0 N 140 NH2 Hoc N
11,CO2C
, Scheme 24 F3CO293 ea H,C,H,C0 Cl-b H5C6H2C0 0 CHO
H +
R
H3CO,C
IP H
B(OH)2 0 N., 3a, 3f, 3i, 3j 6 1-13CO2C R
CHO F3C0,80 CHO HO
N
R
Nõ
l'\I
'''' NH, 187 186 185 1 HN NH, NH
141111 õ
SI N
H
H
1\1_ 3a, 184a, 185a, 186a, 187a, 188a, 3f, 184b, 185b, 186b, 187b, 188b, R= CH,CF, 31, 184c, 185c, 186c, 187c, 188c, R = CH,CH, CH, 3j, 184d, 185d, 186d, 187d, 188d, R = CH, =
Scheme 25 NH
X
HO,C
189a, 189b, 189; 189d AE-4, 74 189a 184a AE-3 189b _G 189c 189a, X = H, Y = OCH3 189b, X = OCH2C61-15, Y = H
189c, X = OH, Y H
131_AE-3 NH, I (Prepared by method AJ-1, AJ-2, or AJ-3) HN NH, NH
189d,X=Y=H
is CHO
NH, µ\
[xi H3c02c HO,C
HN NH, 189e =
Scheme 26 NH
NH R 411 NHBoc Br = +
NHBoc X
Br HO Br \c, 192 B..
40 cocn, 6a NH NH
NH, R NHBoc 110 114 \/
H3CO2C 1-1,CO2C
NH
R= NH
SL
HO,C
190a, 192a - 195a, R = H
190b, 192b - 195b, R= CH3 Scheme 27 . NH . NH . NH
NH, R. G H,N NHBoc NHBoc NH NH
H, 411 NHBoc 6a CH, II NHBoc Ill V D-7 41111 D
11101 11...õ,...7.--.......õ Br H,CO,C
NHNH, H, /01111 NHBoc H, 411 = t s ---, S11,,,,,,,,õ,, la ti...
HOC
HO2C , =
, , , Scheme 28 ell NH
II NHBoc 0 0 NHBoc 0 0 ei Vi , N
* H
N....,,,--, N,,,,,....õ...-H,CO,C HO,C
Ill NH
el NH
0 NHBoc 0 NHBoc 0 el 0 II
' N Ill el N
H H
*H
INI.,,µõõ...---...,õ H2N
II NH
lel NH
N
lel NH, *
Ill N
H H
*H
N...=-=-,., H2N
IP H
N..., , Scheme 29 , 3,T 1411) CN
R el CO2H R
----). 11 11,CO2C Si il H,CO,C 4101 1\'-132, 30f 209 NH NH
01H R so CI
R
411) 14 1-2 , *{4 * 1.
H02c H30020 209a, R = H
209b -211b, R =
, Scheme 30 I
I si CN 0 H
----31. rah IV .\
-14.....,_õ.õ, 01 K.
187a 212 NH NH
N ill NH
N el N, H
01.I
-.(-----01,. le HO,C H3CO2C
Scheme 31 Me0..,...õõõ--- Me0 Me0.., I H
Br 1µ1.- CO2H BrNN ____õ--...,....N..7.,...(N., 216 . 0 I 0 E-2, ..., .
F,CO2S0.õ--,..,,,,N, :-3, 1 , H B-2 .---' 11,...õ..,õ--',.õ, + 6.-2--yN.....,....õ,, H2CO2C N H3CO2C N H,CO2C N
. 0 221 220 .
' I E .
PhH2C0 0 CO21-1 PhH2C0 CO2MEM .
F G
-....,_ -.......
I ' H I H
I
1.1 .--" N...õ.....õ..- ./ N.,..,.,,, I I
0 CO2H 00 CO2MEM Di3 0F COS0 5 CO,MEM
I H I H I H
N..,..,....,, ..' N...,õ.....7- ./
11,CO2C N
. 1 J
NH NH
, ell NH, 0 NH, * N
H
.....,. 1-2 lei N
H
-.......
/ --N.,....õ...õ
, , Scheme 32 CO2CH, CHO
II CHO D-6 or --I.-4- 6a I. CHO
------).-Br HO Br a 0 OP
)--- 0 )--- 0 OH
'\.
R = H R =H 232 0 R = CO2CH3 R = CO2H
E
NH
1\1112 el g I.
CC/2CH, J
-*---CO2CH, o 0 o . )¨o ,)---o R R
R = H 234 0 R = CO2H R = H
R = CO21-1 Y
NH
4111 ti I.
R
R = H
231a, 232a, 233a, 234a, 235a, R = H
231b, R -- CO2CH3 232b, 233b, 234b, R = CO2H
Scheme 33 NH
CN
I NH2 +187a 1-121µ1N
Scheme 34 NH NH
40 NHBoc OH 0 el NHBoc ./ 0111 N L N
H OH H
* H
N.,,,, SIP
* H
N.,,,,,,,, H,CO2C H3CO2C
161d 240 NH /1\4 NH
S
NHBoc 0 0 i NHBoc l I
,HN
AG H el H
, H
N..,,,..õ....." . ell H
NH NH
lall NH2 OH 0 el H 112_ NH2 H
* H 1110 N.õ H
H,CO2C
Scheme 35 HO el CHO F3C0,80 opo CHO
221--L-1 ) B-2 I H I ," H
./ l'qõ,..,,-H,CO,C N 1-1,CO,C N
0, 0 245 ' 246 NH, CHO
H
I H
I H
HO,C N lei 1-1,CO,C N
248 HN NH, . .
' NH NH
I. NH, Bn0 si 4111 Bn0 opi N
222 -----3.- H 1-2 H
=,,, I HI H
,--- 2µ1,_õ--- ,---H,CO,C N HO,C N
NH' Ill NH, N
H
=
I H
./ N..õ...............---HO,C N
NH .
i I \TH2 i / illip NV
247 ---1=-.0 ...tn;
-,õ
I H
N.õ,,,,,......--...õ....
HO,C N
HN NI4, 0 252 .
Scheme 36 NH
CHO AE-3 NHz NH, Br Br HN NH, R
it NH it NH
NHBoc D-6 NHBoc + 6a Br H3CO,C
I-2, S
N NH
NH, HO,C
General Methods of Preparation The 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: Methoxyethoxyrnethyl; 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 folinula (I) are given below:
A-1: 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 water and amine (5 mmol) was added. The reaction mixture was stirred at room temperature overnight, washed with 1N 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 chloroformate (3 mmol). The reaction mixture was stirred at the same temperature for 30 mm and the corresponding amine (6 nunol) was added. The reaction mixture was stirred at room temperature overnight and quenched with 1N HC1. The organic layer was separated, washed with water, brine, dried and concentrated in vacua. The product obtained was purified by crystallization or flash 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 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 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 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 purified by crystallization or flash column chromatography to furnish the desired amide.
72 .
A-5: Conversion of acid to amide A mixture of carboxylic acid (1 mmol), amine (1.1 mmol), 1-hydroxybenzotriazole (1 mmol) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide methiodide (1.1 mmol) in pyridine (10 mL) was stirred overnight at room temperature and was concentrated in vacua 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 or .THF (10 inL) at 0 C was added triethylamine (1.2 mmol) and ethyl chlorofounate 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 and quenched with 1N 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-dimethylaminopyridine (0.12 mmol) in xylene (10 rnL) was stirred at 80 C for 10 min.
Phosphorus trichloride (1 romol) was added and the reaction mixture was heated with stirring at 150 C for 2 hr. After cooling, the product was extracted with Et0Ac. The organic layers were combined, washed with water, brine, dried and concentrated in vacua. The product obtained was purified by flash column chromatography to furnish the desired amide.
B-1: 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 added dropwise triflic anhydride (2 mmol) in dichloromethane (2.5 mL) over a period of 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 1N 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 triflate.
13-2: Conversion of phenolic hydroxyl to triflate To a solution of substituted phenol (1 mmol) in DMF (10 mL) was added N-phenylbis(trifluoromethanesulphonimide) (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 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.
=
D-1: 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(triphen.ylphosphine)palladium (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) 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 vacua.
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 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-4: Coupling of trimethyltin derivative with triflate A mixture of triflate (1 mmol), trimethyltin derivative (3 mmol), and bis(triphenylphosphine)palladium(II)chloride (0.05 mmol) in THF (10 mL) was heated at 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 rnmol), 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 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-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 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.
=
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(I1)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-8: Coupling of phenol with boronic acid =
A mixture of phenol (1 mmol), aryl boronic acid (3 mmol), molecular sieves (4.e), pyridine (5 mmol), copper(1)acetate (1 mmol) and bis(triphenylphosphine)-panadiumRchloride (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 Celitermand 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), LiC1 (4 mmol), PPh3 (0.15 mmol), CuBr (0.2 mmol), and bis(triphenylphosphine)palladium(11)chloride (0.07 g) in DMF (10 mL) under an atmosphere of argon was added trimethylstsnnyl compound (0.8 mmol) and a crystal of 2,6-di-t-butyl-4-rnethylphenol. After the mixture was stirred at 90 C for 3 h, a second portion of aryl-trimethylstannyl compound (0.5 mrnol) was added. The reaction mixture was stirred at 90 C overnight. Water was added and extracted with ethyl acetate. The organic layer was dried (114gSO4), concentrated and purified by flash column chromatography or crystallization to furnish the desired coupled product.
D-10: Coupling of amine with triflate A mixture of triflate (0.75 mmol), amine (0.9 mmol), potassium phosphate (1.1 mmol), 2-(di-t-butylphosphino)biphenyl (0.015 mmol) and tris(dibenzylideneacetone) dipalladiurn(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-11: 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-tert-butylphosphine)biphenyl ( 0.016 mmol) and N-methyl pyiTolidine (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 DMT (5 mL) were added LiC1 (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 (MgSO4). After evaporating the solvent in vacuo, the compound was purified by flash-column chromatography to give the desired product.
E: Oxidation of aryl aldehyde to acid A mixture of aldehyde (1 mmol), tert-butanol (5 mL), water (2 mL) and acetonitrile (1 mL, additional amount may be added until the reaction mixture was 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 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 KM.n04 (4 mrnol). The reaction mixture was stirred for 3 h (the reaction is exothermic, and refluxed on its own during the addition of KMn04). The reaction mixture was diluted 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 (MgSO4) to furnish the desired acid.
F: Conversion of aromatic acid to MEM ester To a solution of aromatic acid (1 rntnol) in THF (10 mL) was added diisopropylethylamine (2 mmol) and 2-methoxyethoxymethylchloride (1.1 rnmol).
The reaction mixture was stirred a room temperature for 3 h and diluted with ether (25 mL).
=
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 cobimn 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 ininol) in ethanol (10 mL) was added 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 ceiitermunder nitrogen.
The filtrate was ccincentrated 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 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 cohmm chromatography gave the desired ester.
1-1: Hydrolysis of MEM ester to acid To a solution of MEM ester (1 mmol) in MAE (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 mixture was acidified with 0.5 N HC1 (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 Me0H (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 Me0H. 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 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 HC1 (10 mL), diluted with ice cold water (10 mL) and extracted with chlorofoini (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 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.
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 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/tert-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 tert-butanol, 0.1 mmol). The reaction mixture was stirred at room 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 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 metaperiodate (3 mmol) and stirred at room temperature for 30 mm. The reaction mixture was quenched 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. The crude product was purified by flash column chromatography to furnish the desired aldehyde.
N: Conversion of alcohol to mesylate To a solution of alcohol (1 mmol) in DME (10 mL) was added 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 by column chromatography to furnish the desired mesylate.
0: Conversion of mesylate to azide To a solution of mesylate (1 mmol) in DMSO (10 mL) was added sodium azide (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 (2 X 15 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 chloroforrnate (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 HC1 (10 mL). The product was extracted with chloroform (2 X 10 mL), dried, filtered and concentrated in vacuo. The residue obtained was purified by column chromatography to furnish the desired carbamate.
Q: Conversion of silyl protected amine to amine A mixture of silyl protected amine (1 mmol), tetrabutylammonium fluoride (1.0 M in THE, 2 mmol) in THE (10 mL) was stirred at room temperature for 1.5 h.
The reaction mixture was concentrated in vacuo and purified by column chromatography to obtain the desired product.
R: Proteetion of amine as tert-butyl 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 (MgSO4), and the solvent was evaporated in -mato to furnish tert-butyl carbamate. If needed, the product 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 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 HC1 (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, 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, 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-1: 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 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 HC1 (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 1N NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 N HC1 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 (2 X 10 mL). The organic layers were combined, dried and concentrated in vacuo to furnish boronic acid.
U-2: Synthesis of boronic acid by ortho lithiation of aryl aldehyde To a solution of N,N,N'-trimethylethylenediamine (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 (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 C 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 reaction and stirred at 4 C for 12 h. The reaction mixture was allowed to warm to 0 C
and quenched with 2 M HC1 (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 HC1 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 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 lithiation of aryl acetal To a solution of aryl acetal compound (1 mmol) M 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 HC1 (10 mL). The reaction mixture was stirred at room temperature for lh. The aqueous layer was separated and the organic layer was extracted twice with 1N NaOH (2 X 10 mL). The basic extracts were combined and washed with ether (10 mL). The basic layer was acidified to pH 4 using 6 N HC1 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 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-1: Demethylation of aryl methyl ether to phenol In a round bottom flask (50 mL), pyridine hydrochloride (10g) was heated in an oil bath at 180 C. After the entire solid had melted, the corresponding aryl methyl ether (1 mmol) was added in small portions over a period of 20 mm. 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 10mL). The combined organic layers were washed with brine, dried over MgSO4, 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 tribromide (3 mmol). The reaction mixture was allowed to warm to 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 MgSO4, and concentrated to give the desired phenol. This can be further purified if needed by crystallization or column chromatography.
V-3: Demethylation of aryl methyl ether to phenol To a solution of aryl methyl ether (1 mmol) in dichloromethane (5 mL) was added AlC13 (8.5 mmol). The reaction mixture was heated to reflux for 12 h under nitrogen. To this mixture was added 12 mL of 1 N HC1 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 (MgSO4), 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 (2 mmol) in toluene (5 mL) was added dropwise over a period of 30 min. A
solution of aryl ether (1 rnmol) 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 organic layers were combined, washed with water, dried (MgSO4) and concentrated in vacua. 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 cone HC1 (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 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 HC1 or ethanolic HC1 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 HC1 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 nitrite 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.
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 50 C for 30 mm. 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 hydi-oxide (16 mL). The reaction m mixture was washed with ether (2 X 10 mL) and acidified to pH 4 using cone HC1. The solid obtained was collected by filtration to furnish the desired product.
Z-1: Opening of aromatic methylene dioxy compound with alcohol To a mixture of methylene dioxy compound (1 mmol) in HMPA (2.5 mL) were 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 mm. It was then extracted with ether and the aqueous layer was acidified to pH
4 with HC1 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 and was then poured into ice water and acidified with 1 N HC1. The precipitated solid was collected by filtration, washed with 1N HC1, 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 vacua. The residue 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 (MgSO4) 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 residue was added alkyl or aryl 4-nitrophenyl 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 X 100 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 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 triethylarnine (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 column chromatography to furnish the desired product.
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 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 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 aldehyde =
AE-1: Reductive amination of aldehyde To a stirred solution of aldehyde (1 mmol) in methanol (40 mL) was added amine (3.3 mmol) followed by the addition of glacial acetic acid (0.3 mL). The reaction mixture was stirred for 30 mm 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 filtration. The pH of the aqueous phase was adjusted to 7 with 1N NaOH and was extracted twice with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated in vacuo to furnish crude product. The crude product was purified by crystallization or flash column chromatography.
AE-2: Reductive amination 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) was added a solution of aldehyde (1 mmol) in THY (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 nimol) and stirred for additional 2 h and concentrated in vacuo to remove methanol. The mixture was diluted with water (15 mL) and washed with ether (2 x 10 mL). The aqueous layer was acidified to pH 2 using 6 N HC1 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 animation 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 THY, 5 mmol) was added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was quenched with 5 N NaOH (30 nunol) and stirred for additional 2 h. The reaction mixture was filtered through CeIiteTM (to remove molecular sieves) and concentrated to remove methanol. The mixture was diluted with water (15 mL) and washed with ether (2 X 10 mL). The aqueous layer was filtered and solid obtained was kept aside (mainly product). The aqueous layer was acidified to pH 2 using 6 N HC1 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 amination of aldehyde To a mixture of aldehyde (1 mmol) and aminoarylamidine (1.1 mmol) in Me0H
at room temperature was added triethyl amine (2.75 mmol), sodium cyanoborohydride = (0.83 mmol) and zinc chloride (0.9 nun.o1). The reaction mixture was stirred at room temperature overnight and concentrated to remove methanol. The reaction mixture was quenched with 1 N NaOH (10 mL), diluted with water (10 mL), and extracted with Et0Ac (5 X 20 mL). The combined organic extracts were washed with brine (15 mL), dried (MgSO4), filtered throughceiitermand concentrated to give the product.
Purification 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 Me0H (10 mL) was added aldehyde (1 mmol) in 'rHF (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 (MgSO4) and evaporated in vacuo. The residue was purifeid by flash column chromatography to furnish the desired amine.
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 HC1 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 HC1 (10 mL), brine (20 mL), dried and concentrated in vacuo to furnish 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 to ¨78 C was added dropwise tert-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 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 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 overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ether (2 X 10 mL). The organic layers were combined, washed with brine (10 mL), dried, filtered and concentrated in vacuo to furnish desired tributyltinalkyl and was used as such without further purification.
AG-3: 4-Bromo-5-formyl-benzo[1,31dioxole-2-carboxylic acid methyl ester To a mixture of 2-bromo-3,4-dihydroxy-benza1dehyde (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, 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
HC1 and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were dried (MgSO4) and evaporated in vacuo to afford crude 4-bromo-5-formyl-benzo[1,3]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 mL X 3). The combined organic layers were dried (MgSO4) and evaporated in vacuo.
The residue was purified by flash column chromatography (ethyl acetate:hexane = 5:95) to furnish 4-bromo-5-formyl-benzo[1,3]dioxole-2-carboxylic acid methyl ester as a white solid.
All: 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 ethyl acetate (3 X 50 mL). The organic layers were combined and washed with aqueous 0.5 N HC1 (100 mL), water, brine, dried (MgSO4) and concentrated in vacuo. The crude residue was purified by flash column chromatography to furnish the desired ester.
9'7 Al: Preparation of 2-bromo-5-hydroxy benzakiehyde =
=
To a solution 3-hydroxybenzaldehyde (Aldrich, 101.39 g, 805 mmol) in chloroform (1000 mL), 'vim added bromine (45 mL, 845 mmol) in chloroform (200 mL) 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 pact of ceiitemand 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 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 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 Et0H (15 mL) was refluxed for 3 h and concentrated in vacuo. To the residue obtained was added Et0H (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 HC1 solution (freshly prepared by bubbling HC1 gas or prepared in-situ by premixing methanol and acetyl 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 Me0H (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 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.
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 the reaction was complete. The reaction mixture was concentrated in vacuo and purified by flash column chromatography to obtain the corresponding amidine, AK: Conversion of aryl triflates or halides to boronate ester To dichloro [1,1' -bis(diphenylphosphino)ferrocene]palladium (II) dichloro-methane 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) dichloro-methane adduct (0.03 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.03 mmol) under argon in dioxane (100 mL) was added aryl triflate (1 mmol), bis(pinacolata)diboron (1.1 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.
=
R
o n.) = 'W."
.6.
1-, 1-, R' Cpd. Starting Method -R -R' Analytical Data No. From Used .
_ 0113 11--1NMR (DMSO-d6): 8 10.26 (s, 1 H), 9.84 (s, 1 H
H), 8.15 (d, J= 3.0 Hz, 1 H), 7.64 (dd, J¨ 2.0 Hz 2a -OH 1 A-1 or A-\,.õ.,--,,, 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 (m, J= 6.9 Hz, n 1 H), 0.93 (d, J= 6.9 Hz, 1 H), 0.93 (d, J ---- 6 Hz, = 0 6H); MS (ES): 252.12 I.) a, I.) (5) a, 1¨
o co 2b -OH1 A-1 or A-2 Characterized in the next step co FP
I
H
=
'-ri-Lc' CH3 2c -OH / CH3 1 A-1 or A-2 MS (ES+): 294.54 H
'A
=,µõ,,/%1_, 2d -OH 1 A-1 or A-2 MS (ES): 288.49 (M+Na) cp 0 ---,----1¨
i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used =
2e -OH 1 A-1 or A-2 Characterized in the next step 2f -OH 1 A-1 or A-2 MS (ES): 300.40 (M+Na) H
1.) 2g -OH 1 A-1 or A-2 MS (ES): 272.48 (M+Na)+; MS (ES): 248.66 (5) 2h -OH 1 A-1 or A-2 MS (ES"): 286.48 (M+Na) 2i -OH
1 A-1 or A-2 MS (ES): 224.54 1-d CH, 2j -OH 1 A-1 or A-2 Characterized in the next step oe Cpd. Starting Method -R
Analytical Data No. From Used o t..) H
3a -OS 02CF3 yNcii3 2a B-1 or B-2 MS (BS): 384.37 .6.
H
-.,,.,,NCH3 3b -OS 02CF3 2b B-1 or B-2 MS (ES): 370.36 0 CH, H
,,,- CH, 3e -0S02CF3 / CH, 2c B-1 or B-2 MS (ES): 426.37 IV
FP
IV
o H co o CH, 3d -0S02CF3 2d B-1 or B-2 Characterized in the next step I.) 0 -----...,-, CA
I
FP
I
H
H
1H NMR (CDC13): 5 8.41 (d, J=2.3 Hz, 1 H), 8.10 (dd, .1= 8.5, 2.4 Hz, 1 H), 7.37 (d, .1= 8.5 Hz, 1 H), 3e -0S02CF3 0 ... CH, 2e B-1 or B-2 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, .1= 7.2 Hz, 3 H); MS (ES): 384.1 1-d H
1H NMR (CDC13): 5 8.45 (d, .1= 2.4 Hz, 1 H), 8.14 n =-..,,,.N...CF, 1-3 3f -0S02CF3 2f B-1 or B-2 (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 H); MS
cp o (ES): 410.2 c.:.) t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data o No. From Used o t..) IHNMR (CDC13): 5 8.42 (d, J= 2.3 Hz, 1 H), 8.12 .6.
H (dd, J= 8.5, 2.3 Hz, 1 H), 7.39 (d, J= 8.7 Hz, 1 H), -4 3g -0S02CF3 ,..2g B-1 or B-2 6.31 (broad, 1 H), 4.00 (s, 3 H), 3.34 (dd, J-= 7.2, 1-5.5 Hz, 2 H), 1.07 (m, 1 H), 0.59 (m, 2 H), 0.30 (m, 0 2 H);
MS (ES+): 382.2 =
H
. 3h _oso2cF3 ,Nn 2h B-1 or B-2 MS (ES+): 396.36 1HNMR (DMSO-d6): 5 8.85 (t, J= 5.5 Hz, 1 H), n H 8.49 (d, .1- 2.3 Hz, 1 H), 8.23 (dd, J= 8.7, 2.3 Hz, 3i -0S02CF3 -,,.N.,Ncii3 2i B-1 or B-2 1 H), 7.70 (d, J= 8.7 Hz, 1 H), 3.92(s, 3 H), 3.31 0 "
a, (m, 2 H), 1.14 (t, J= 7.2 Hz, 3 H); MS (ES+): 356.1 I.) (5) a, o (A
.6. iHNMR
(DMSO-d6): 5 8.81 (t, J= 6.0 Hz, 1 H), 0 CH, 8.49 (d, J-= 2.3 Hz, 1 H), 8.24 (dd, J= 8.7, 2.4 Hz, I.) 3j -0S02CF3H 2j B-1 or B-2 1 H), 7.71 (d, J= 8.7 Hz, 1 H), 3.92 (s, 3 H), 3.15 0 (m, 2 H), 1.64(m, 1H), 1.41 (m, 1 II), 1.12(m, 1 a, H), 0.88 (m, 6 H); MS (ES+): 398.2 H
-,1 1H NMR (DMSO-d6): 5 8.52 (d, J= 2.0 Hz, 1 H), 8.32 (dd, J= 2.0 and 8.9 Hz, 1 H), 7.72 (d, J=7.9 -0S02CF3 -0O2MEM 4 B-2 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 (ES): 439.1 (M+Na) CH3 iHNMR
(CDC13): 8 8.29 (d, J = 1.6 Hz, 1 H), 7.96 /0 H j-.
1-d o n (dd, J = 7.5 & 1.6 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 1 -,,...1\1,.
6a -B \ 3a AK H), 6.24 (bs, 1 H), 3.94 (s, 3 H), 3.30 (t, J = 6.5 Hz, 0 2 H), 1.92 (m, 1 H), 1.43 (s, 12 H), 0.99 (d, J = 6.5 cp =
0 Hz, 6 H); MS (ES+) 362.2 t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used NMR (DMSO-d6): 5 10.26 (s, 1 H), 9.84 (s, 1 t..) H), 8.15 (d, J=3.0 Hz, 1 H), 7.64 (dd, J=2.0 Hz .6.
139 -OH \ N./..µ\.,'\ CH3 138 AA and 8.9 Hz, 1 H), 6.94 (d, J= 8.9 Hz, 1 H), 3.90 (s, --.1 H 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 NMR (DMSO-d6): 5 10.38 (s, 1 H), 8.36 (d, J=
2.8 Hz, 1 H), 7.99 (dd, J= 2.6 and 8.9 Hz, 1 H), 140 -.....õ ...........õ....-.õ, -OSO2CF3 N CH3 139 B-2 7.52 (d, J---- 9.0 Hz, 1 H), 3.89 (s, 3 H), 2.23 (d, J--H 7.0 Hz, 2 H), 2.09 (m, J= 6.6 Hz, 1 H), 0.94 (d, J=
6.6 Hz, 6 H); MS (ES): 384.0 n I.) a, I.) 111. NMR (CDC13): 6 8.08 (s, 1 H), 8.00 (d,J= 2.3 (5) a, 169 168 AC Hz, 1 H), 7.75 (dd, J= 2.3 and 8.7 Hz, 1 H), 7.01 u.) vi -OH -,..NOH (d, J=8.7 Hz, 1 I), 3.97 (s, 3 H), 3.50 (s, 1 H); MS 0 I.) (ES): 196.1 u.) 1HNMR (DMSO-d6): 5 7.79 (d, J= 2.0 Hz, 1 H), a, H
170 -OH -CH2NH2 169 G 7.51 (dd, J= 2.3 and 8.5 Hz, 1 H), 6.95 (d, J= 8.5 --1 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 (ES): 182.12 H
.,>N
(ES): 250.50; MS (ES): 274.50 (M+Na)+ 1-d n o cp =
t..) u, oe-t..) Cpd. Starting 1 Method -R -R' No. From Used Analytical Data _ _ o cii, 1H
NMR (CDC13): 5 7.96 (d, J= 2.3 Hz, 1 H), 7.55 t..) i-,.)--H (d, J= 2.3 and 8.3 Hz, 1 H), 7.26 (d, J= 8.3 Hz, 1 .6.
172 -0S02CF3 õ.,7-,...'CH 171 B-2 H), 5.90 (br s, 1 H), 4.50 (d, J= 4.1 Hz, 2 H), 3.97 1-(s, 3 H), 2.44 (sep, J= 7.0 Hz, 1 H), 1.20 (d, J---- 7.0 Hz, 6 H); MS (ES ): 384.1 MR (DMSO-d6): 5 10.62 (s, 1 H), 8.88 (m, 2 177 -OH H 168 AE-1 H), 7.99 (d, J=
2.3 Hz, 1 H), 7.70 (dd, J= 2.3 and .NCH3 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=
n 6.8 Hz), 0.93 (d, J= 6.8 Hz, 6 H); MS (ES): 238.1 11-1NMR (CDC13): 5 8.05 (d, J= 2.3 Hz, 1 H), 7.63 I.) a, I.) (dd, J= 2.3 and 8.3 Hz, 1 H), 7.25 (d, J= 8.3 Hz, 1 (5) a, o 178 -0S02CF3 177 B-2 H), 3.96 (s, 3 H), 3.85 (s, 2 H), 2.43 (d, J= 6.8 Hz, u.) o `CH o N
3 2 H), 1.77 (m, J= 6.6 Hz, 1 H), 0.93 (d, J= 6.6 Hz, I.) 1 H); MS (ES+): 370.2 u.) Boc 111 NMR (DMSO-d6): 5 7.93 (m, 1 H), 7.47 (m, 1 0 CH
.i.
I
179 -0S02CF3 1 178 R H), 7.26 (m, 1 H), 4.48 (m, 2 H), 3.96 (s, 3 H), 3.03 '-' (m, 2 H), 1.91 (m, 1 H), 1.52 (m, 9 H), 0.89 (d, J=
CH3 6.6 Hz, 6 H); MS (ES+): 492.2 (M+Na) 1-d n ,-i cp =
t..) u, oe t..) R R' Cpd. Starting Method -R -R' Analytical Data No. From Used 111 NIVIR (DMSO-d6): 0.78 (s, 1H), 8.85 (t, 1= 5.7 Hz, 1H), 8.50 = (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 8.2, 1.9 Hz, 111), 7.55 (m, 9H), 7 -0Bn -CHO 6 + 3a D-2 5.35 (s, 2H), 3.69 (s, 3H), 3.23 (t, J = 6.5 Hz, 2H), 1.98 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H); MS (ES+): 446.3 8 -0Bn -CO2H 7 E MS (BS): 484.33 (M+Na) (5) 9 -0Bn -0O2MEM 8 F MS (ES): 572.2 (M+Na) -OH -0O2MEM 9 G MS (BS): 482.33 (M-MEM) +Nal+
IHNIVIR (DMSO-d6): ,58.75 (t, J = 5.6 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.11 (dd, J = 8.0, 1.9 Hz, 1H), 8.01 (d, J. =2.9 Hz, 1H), 7.84 (dd, J= 8.4, 2.6 Hz, 1H), 7.47 (d, J = 8.5 Hz, 111), 7.41 (d, J =
11 -0S02CF3 -0O2MEM 10 B-2 8.0 Hz, 1H), 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, 1H), 0.91 (d, J = 6.7 Hz, 6H); MS (ES+): 614.3 (M+Na)+
1-d 29a -0O2MEM 11 D-3 Characterized in the next step cH3 oe Cpd. Starting Method Analytical Data No. From Used 29b CH3 -0O2MEM 11 D-3 MS
(BS): 520.2 (M+Na) 29c -0O2MEM 11 D-3 MS
(ES): 482.3 29d -0O2MEM 11 D-3 MS
(ES): 562.3 (M+Na) 29e -0O2MEM 11 D-3 MS (ES): 556.4 (M+Na)+ 0 (5) oe 1H NMR (DMSO-d6): 8.50 (t, J = 5.6 Hz, 111), 8.18 (d, J = 1.9 Hz, 1H), 7.86 (dd, J = 7.9, 1.9 Hz, 1H), 7.78 (d, J =1.7 Hz, 111), 7.56 (dd, J = 8.0, 1.8 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.00 (d, J =
29f -CO2MEM 11 D-3 7.9 Hz' 1H), 6.67 (dd, J = 17.6, 11.1 Hz, 111), 5.76 (d, J = 17.6 Hz, 1H), 5.19 (d, J = 11.1 Hz, 1H), 4.99 (q, AB system, 2H), 3.37 (s, 3H), 3.20 (m, 2H), 3.11 (m, 211), 2.97 (s, 311), 2.91 (t, J = 6.7 Hz, 2H), 1.67 (m, 1H), 0.70 (d, J = 6.6 Hz, 611); MS (ES+): 492.3 (M+Na) OHC
29g -0O2MEM 11 D-2 MS (ES): 576.2 (M+Na) ; MS (ES): 552.2 oe Cpd. Starting Method -R -IV
Analytical Data . No. From Used CHO
o , n.) 29h // .........,_ -0O2MEM 11 D-2 MS
(ES): 538.2 1-, 1-, OHC
291 \k \ -0O2MEM 11 D-2 MS (ES): 560.4 (M+Na)+
-30a -CO2H 29a I-I MS (ES): 398.3 ;
MS (ES): 396.3 0 --CH, IV
FP
30b .--',-- --,.
I\) (5) o CH3 -CO2H 29b I-1 Characterized in the next step Lo vD
IV
CA
30c.,... CH2 -CO2H 29c I-1 MS (ES): 392.1 a, H
-,1 30d S -CO2H 29d I-1 MS (ES): 452.1 30e II -CO2H 29e I-1 MS (ES): 446.2 Iv n ,-i cp =
i-,.,--t..) u, .
oe t..) Cpd.Starting Method -R -12' No. From Used Analytical Data 30f -.--'''.-- CH2 -CO2H 29f I-1 MS
(ES): 380.1 t..) i-,.)--.6.
N3H2C\ /
30g 0 -CO2H 29g K, N, 0, I-1 MS (ES): 515.3 (M+Na) ; MS (ES): 491.2 S
CH20H 1,µ
30h -CO2H 29h K, I-1 MS (ES): 450.1 , n IV
FP
IV
I-, 1..,30i \ -CO2H 29i K, I-1 MS (ES): 450.3 a, co o 0 "
CA
Characterized in the next step I
FP
I
H
41 --0 . -0O2MEM 10 D-8 MS (ES): 534.30 42 -CO2H 41 I-1 MS (ES):
446.30 1-d 48 -OCH3 -CHO 47+ 3a D-2 MS (ES): 392.2 (M+Na)+ n ,-i 49 -OCH3 -CO2H 48 E MS (ES): 386.1;
408.1 (M+Na)+
cp o 1¨
t..) vi oe t..) CO,Bn W."
R' Cpd.Starting Method -R
Analytical Data No. From Used 14 -0S02CF3 -CHO 13 B-2 Characterized in the next step -0S02CF3 -CO2H 14 E MS (ES): 403.58 cH3 11-IN4R (DMSO-d6): .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), 16 -0S02CF3CH3 15 A-3 or A-4 "
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).
(5) 1.) oe R R' OH
W."
BnO,C
Cpd. Starting Method -R -R' No. From Used Analytical Data 1HN4R (DMSO-d6): !S 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, 1=13 and 2.5 Hz, 2 H), 5.18 (s, 2 17 -0Bn -CHO 16 + 6 D-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 (5) 1HNMR (DMSO-d6): 6 0.86 (d, J = 6.9 Hz, 6 H), 1.85 (m, 1 H), 3.09 (t, 3= 6.9 Hz, 2 H), 5.01 (d, J = 5.01 Hz, 2 H), 5.14 (s, 2 H), 18 -0Bn -CO2H 17 E 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 IHNMR (DMSO-d6): El 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 19 -0Bn -0O2MEM 18 F H), 3.36 (dd, J = 3 and 6 Hz, 2 H), 5.02 (d, J = 3.8 Hz, 2 H), 5.12 (d, 3= 15 Hz, 2 H), 5.64 (s, 2 H), 7.11 (m, 3 H), 7.24 (dd, 3= 8.25 and 2.75 Hz, 1 H), 7.29 (m, 4 H), 7.35 (m, 1 H), 7.42 (m, 3 H), 1-d 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 oe Cpd.Starting Method -R -R' Analytical Data No. From Used 1HNMR (DMSO-d6): 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 21 -OH -0O2MEM 19 G, H (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%; M+1) (DMSO-d6): 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 (m, 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 (m, 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, I = 2.6 Hz, 1 H), 8.07 (5) (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 11-INMR (DMSO-d6): 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 (m, 2 H), 5.05 (d, J = 2.6 Hz, 2 H), 5.16 (d, J = 17 Hz, 2 H), 7.08 (m, 2 H), 24a -0O2MEM 22 + 23 D-1 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, I = 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 1-d oe =
Cpd. Starting Method -R -R' Analytical Data No. From Used o IHNMR (DMSO-d6): 5 0.89 (d, J = 6.8 Hz, 6 H), 1.87 (m, 1 H), .6.
3.12(t, J = 6 and 6.8 Hz, 2 H), 3.16 (s, 3 H), 3.30 (m, 2 H), 3.39 24b ' (dd, J = 5.2 and 3.4 Hz, 2 H), 5.04 (d, J = 4.3 Hz, 2 H), 5.16 (d, J =
-0O2MEM 22 + 23 D-1 16 Hz, 2 H), 7.08 (m,2 H), 7.20 (m, 3 H), 7.24 (d, J = 8.6 Hz, 1 S 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, 1 H), 8.14 (d, J = 1.7 Hz, 1 H), 8.41 (d, J = 1.7 Hz, 1 H), 8.68 (t, J = 6 Hz, 1 H); MS (ES+) 602.27 .1,.
u.) 5.53Hollz(8d,9,2 J(Hdl)i:71.67 Hz, 1 H), 7.37 (d, J ---- 7.7 Hz, -57. 167. 807;.6 H), 1.87 27 H(m),, 71.H09),(m, I.) .6. 24c I.1 3.12 (t, J = 6 and 6.8 Hz, 2 H), 3 (s, 3 H), 3.30 (m, 2 H), 3.40 .1,.
I.) (5) -0O2MEM 22 4- 23 D-1 2(inaHNMRH, 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 u.) Hz, 1 H), 8.11 (d, J = L7 Hz, 1 H), 8.42 (d, J = 1.7 Hz, 1 H), 8.72 .1,.
(t, J = 6 Hz, 1 H); MS (ES+) 596.45 H
)2, 7H.2)715(.:05:3(::J:=)7:
-A
24d -0O2MEM 22 + 23 D-1 MS (ES+) 616 , H3C s 1-d 24e -0O2MEM 22 + 23 D-1 MS (ES+) 586.4 n ,-i o cp =
t..) u, oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used 24f -0O2MEM 22 + 23 D-1 MS (ES): 586.39 11,C
24g -0O2MEM 22 + 23 D-1 MS (ES): 616.63 24h -0O2MEM 22 + 23 D-1 MS (ES): 597.25 1.) 1.) (5) 24i -0O2MEM 22 + 23 D-1 MS (ES): 597.4 1.) 24j -0O2MEM 22 +23 D-1 MS (ES): 597.4 24k H3C iS -0O2MEM 22 + 23 D-1 MS (ES): 644.3 oe Cpd. Starting Method -R -R' Analytical Data No. From Used 241 N -0O2MEM 22+ 23 D-3 Characterized at the next step cH3 24m -0O2MEM 22 + 23 D40 Characterized at the next step 24n CH2 -0O2MEM 22 +23 D-3 MS (ES): 560.74 (5) 24o S.Nv N
-0O2MEM 22 +23 D-4 MS (ES): 603.72 24p /=NcH3 -0O2MEM 22 + 23 D-5 MS (ES): 558.3 CH
24q Ni< -0O2MEM 22 + 23 D-5 Characterized in the next step OH
24r -0O2MEM 22 + 23 D-5 MS (ES): 610.4 (M+Na) oe Cpd. Starting Method -R -IV
Analytical Data No. From Used CH
t..) 24s -0O2MEM 22 + 23 D-3 Characterized in the next step 4,.
I-, I-, }12 24t ------4 -0O2MEM 22 + 23 D-3 Characterized in the next step CH, _____ OH
24u / -0O2MEM 22 + 23 D-3 MS (ES): 598.4 (M+Na) CH, n 24v --7<\, -0O2MEM 22 + 23 D-3 MS (ES): 500.4 KM-MEM)-1r IV
I\) (5) --4 /=TMS
24w -0O2MEM 22 +23 D-5 Characterized in the next step I.) CA
I
24x / ¨ \ -0O2MEM 22 + 23 D-3 MS (ES): 610.5 (M Na) CH,+
a, , H
24y ......õ--_ -......õ,. OH -0O2MEM 22 +23 D-5 MS
(ES): 596.4 (M+Na)+
CH, 24z -0O2MEM 22 + 23 D-3 MS (ES): 576.3 (M+Na)+
OH
IV
n ,-i 24aa ______N -0O2MEM 22 +23 D-11 Characterized in the next step cp o 1-, i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. , From , Used CHO
0o t..) 24ab -0O2MEM 22 + 23 D-2 MS (ES): 630.55 4,.
--.1 1-, 1-, S
24ac _.,_.. -0O2MEM 22 + 23 D-2 MS (ES): 630.74 S CHO
OHC /
n 24ad -0O2MEM 22 + 23 D-2 MS (ES): 652.3 0 IV
FP
IV
S
FP
I..
Pe IV
CA
I
24ae OHC"--- \------- -0O2MEM 22 + 23 D-2 Characterized in the next step 0 FP
I
S
H
-,1 24ag N -0O2MEM 22 +23 D-1 MS (ES): 685.01 I
Boc IV
n 24ah ----\\, = CH2 -0O2MEM 22 23 D-3 MS (ES): 546.49 cp o 1-, i-,.)--t..) vi oe t..) Cpd.Starting Method -R -R' Analytical Data No. From Used 1HNMR (DMSO-d6): 5 0.91 (d, J = 6.9 Hz, 6 H), 1.88 (m, 1 H), o , t..) 3.13 (t, J = 6.9 and 6 Hz, 2 H), 5.07(d, J = 11.2 Hz, 2 H), 7.09 (m, . 2 H), 7.22 (m, 5 H), 7.35 (d, 7.7 Hz, 1 H), 7.63 (d, 2.6 Hz, 1 H), .6.
--.1 25a CO2H 24a I-1 s 7.65 (d, J = 5.2 Hz, 1 H), 7.82 (dd, J = 7.7 and 1.7 Hz, 1 H), 8.05 1-(d, J = L7 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 _ 1HNMR (DMSO-d6): 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 25b CO2H 24b I-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 n S
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 I.) .1, I.) (5) .1, 1- 1HNMR (DMSO-d6):
5 12.73 (bs, 1 H), 8.73 (t, .1. = 6 Hz, 1 H), u.) VD
8.41 (d, J = 1.7 Hz, 1 H), 8.12 (d, J = 1.7 Hz, 1 H), 8.07 (dd, J =
I.) 7.7 & 1.7 Hz, 1 H), 7.83 (dd, J - 7.7 & 1.7 Hz, 1 H), 7.72 (d, J =
25c (m, 2 H), 5.08 (d, J = 14 Hz, 2 H), 3.13 (t, J
III CO2H 24c I-1 6.9 Hz, 2 H), 7.54 (t, J = 7.7, 2 H), 7.44 (t, J = 7.7 Hz, 1 H), 7.37 I., , (d, J. = 7.7 Hz, 1 H), 7.28 (d, J. = 7.7 Hz, 1 H), 7.21 (m, 3 H), 7.09 -= 6.5 Hz, 2 H), 1.88 L.
,i, I
H
-,1 (rn, 1 H), 0.91 (d, 6.8 Hz, 6 H); MS (ES+) 507.93 1HNMR (DMSO-d6): 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, 25d ---3_ CO2H 24d I-1 1 H), 7.34 (d, J = 7.7 Hz, 1 H), 7.22 (m, 3 H), 7.19 (d, J. = 8.6 Hz, H,C s , 1 H), 7.09 (m, 2 H), 6.95 (d, J =3.4 Hz, 1 H), 5.06 (d, J = 11 Hz, 2 1-d n 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 cp o i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used iHNMR. (DMSO-d6): 8 0.89 (d, J = 6 Hz, 6 H), 1.86 (m, 1 H), 3.12 25e CO2H 24e (t, J = 6.8 and 6.0 Hz, 2 H), 5.03 (d, J =1:D Hz, 2 H), 7.02 (s, 1 H), I-1 7.06 (m' 211), 7.16 (d, = 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 0 Hz, 1 H), 8.04 (m, 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 CO211 24f I-1 MS (ES): 498.36 H3C 1HNMR (DMSO-d6): 8 12.72 (bs, 1 H), 8.69 (t, J = 6 Hz, 1 H), (5) 8.39 (d, J = 1.7 Hz, 1 H), 8.06 (m, 2 H), 7.79 (dd, J - 1.7 & 7.7 25g CO2H 24g I-1 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, 211), 5.07(d, J = 8.6 Hz, 2 H), 3.12(t, J = 6.5 Hz, 2H) 2.29 (s, 3 H), 1.89 (m, 1 H), 0.91 (d, 6.8 Hz, 6 H); MS (ES+) 528.38 1HNMR (DMSO-d6): 6 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, 1 H), 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), 25h CO2H 24h I-1 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, 211), 5.01 (q, J = 10 & 25 Hz, 211), 3.13 (t, J = 6.9 and 6 1-d Hz, 2 H), 1.89 (m, 1 H), 0.92 (d, J = 6.9 Hz, 611); MS (ES+) 509.58 oe Cpd.Starting Method -R -R' Analytical Data No. From-Used 1HNMR (DMSO-d6): 6 12.70 (bs, 1 H), 8.91 (d, J = 2.6 Hz, 1 H), =
t..) 8.68 (t, J = 6 & Hz, 1 H), 8.62 (d, J = 2 Hz, 1 H), 8.4 (d, J = 1.7 .6.
Hz, 1 H), 8.12 (m, 2 H), 8.05 (dd, J = 8.6 & 1.7 Hz, 1 H), 7.88 (d, --.1 251 1 CO2H 241 1-1 8.5 & 1.7 Hz, 1 H), 7.53 (dd, J = 8.6 & 5.2 Hz, 1 H), 7.34 (d, J =
,-, N 7.7 Hz, 1 H), 7.28 (d, J = 8.6 Hz, 1 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 IHNMR (DMSO-d6): 6 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 25j CO2H 24j (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), n 8.18 (s, 1 H), 8.40 (d, J =2 Hz, 1 H), 8.71 (m, 4 H); MS (ES+) I.) 509.49 a, I.) (5) a, I.) 25k H3c CO2H 24K 1-1 Characterized in the next step 0 s u.) a, .
H
I . CO2H 241 I-1 MS (ES+):
511.54 25m ) N CO2H 24m I-1 MS (ES+):
501.66 1-d n ,-i I
cp =
t..) u, oe t..) Cpd.Starting Method -R -R' Analytical Data No. From Used 25n CO2H 24n I-1 MS (BS): 472.4 25oSN77 CO2H 24o I-1 MS (ES+): 515.65 /=-N
25p CH3 CO2H 24p I-1 Characterized in the next step 25q HrOH CO2H 24q I-I MS (ES4): 536.3 (M+Na)+
(5) 25r CO2H 24r I-1 MS (ES): 500.4 /¨*CH2 25s CO2H 24s I-1 Characterized in the next step 25t /<\ CO2H 24t I-1 Characterized in the next step CH, 25u CO2H 24u 1-1 MS (ES): 486.4 oe Cpd. Starting Method -R
No. From Used Analytical Data 25v OH CO2H 24v I-1 MS (ES): 524.3 (M+Na) 25w CO2H 24w 1-4, Q Characterized in the next step 25x cH3 CO2H 24x I-1 MS (ES): 498.3 (5) 25y OH CO2H 24y I-1 MS (ES): 484.3 CH
25z )-L¨\\ CO2H 24z I-1 MS (ES): 488.3 OH
25aa CO2H 24aa 1-1 Characterized in the next step OH
1-d 25ab CO2H 24ab K, I-1 MS (ES): 544.27 Ns oe Cpd.Starting Method -R -R' Analytical Data No. From Used 25ac 24ac K, I-1 MS (ES): 544.2 t..) i-,.)--.6.
OH
S
1¨, 1¨, BnO,C /
25ad i CO2H 24ad E, H, I-1 MS (ES): 670.3 (M+Na)+
S
IHNMR (DMSO-d6): 8 9.1 (bs, 2 H), 8.8 (bs, 2 H), 8.5 (t, J = 6 25ae HOH,C s CO2H Hz, 1 H), 8.02 (s, 1 H), 7.68 (s, 1 H), 7.62 (m, 6 H), 7.53 (d, .1=
24ae K, I-1 5.8 Hz, 1 H), 7.15 (d, J = 6 Hz, 1 H),), 7.13 (m, 1 H), 7.01 (s, 1 n 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) IV
FP
I\)/61 N
CA
' 25af i CO2H 24ad K, I-1 MS (ES):
566.2 (M+Na)+ I.) S
CA
I
FP
I
.----"----H
25ag III CO2H 24ag I-I MS (ES):
597.7 Boc OH
25ah CO2H 24ah L, I-1 MS (ES):
492.54 -IV
n L, m 25ai l'13 CO2H 24ai K, N,, Characterized in the next step cp 0,1-1 o 1¨
i-,.)--t..) vi oe t..) NH
0 411) NH2 R
H
o n.) .6.
1-, H
1-, BnO2C
Cpd. Starting Method -R
Analytical Data = No. From Used 1HNMR (DMSO-do): 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 n 3 (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, 0 26a 25a J
"
FP
s 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 I.) (5) a, t..) 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); u.) vi MS (ES+) 631.05 I.) CA
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 26b IHNMR (DMSO-do): 8 0.88 (d, J "6.9 Hz, 6 H), 1.84 (m, 1 H), 3.07 (t, J = 6.8 -,1 S and 7.7 Hz, 1 H), 8.05 (m, 3 H), 8.23 (d, J = 1.7 Hz, 1 H), 8.68 (t, 3 = 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 IHNMR (DMSO-do): 8 10.75 (s, 1 H), 9.19 (s, 2 H), 8.89 (s, 2 H), 8.69 (t, J =
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
26c 1411 25c J = 1.7 Hz, 1 H),7.87 (dd, .1 = 7.7 & 1.7 Hz, 1 H), 7.83 (d, J = 7.7 Hz, 2 H), 7.77 (m 5 H), 7.54 (t, J = 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, IV
n ,-i 6.8 Hz, 6 H); MS (ES+) 625.81 cp o i-,.)--t..) vi oe t..) Cpd. Starting Method -R
Analytical Data No. From Used o 1HNMR (DMSO-d6): 8 10.7 (s, 1 H), 9.14 (s, 2 H), 8.82 (s, 2 H), 8.64 (t, J = 6 t..) i-,.)--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), .6.
--.1 26d 25d J 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, 1-.
H3C s 7.8 Hz, 1 H), 7.27 (d, J
= 7.7 Hz, 1 H), 7.16 (rn, 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 IHNMR (DMSO-d6): 8 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 26e \.(:) 25e J 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 n =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 0 I.) a, (bs, 2 H), 10.67 (s, 1 H); MS (ES+) 615.75 I.) (5) o 0 1HNMR (DMSO-d6): 8 0.87 (d, J = 6.7 Hz, 6 H), 1.83 (m, 1 H), 3.06 (t, J = 6.7 I.) 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), 26f 251 J 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 u.) a, , co 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, H
-,1 1 H); MS (ES+) 615.75 H3C IHNMR (DMSO-d6): 8 10.67 (s, 1 H), 9.12 (s, 2 H), 8.78 (s, 2 H), 8.61 (t, J = 6 26g ' 25g 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), J 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 s (m, 4H), 7.01(s, 1 H), 6.99 (s, 1 H), 5.0 (s, 2 H), 3.03 (t, J = 6.5 Hz, 2 H), 2.23 1-d n (s, 3 H), 1.79 (m, 1 H), 0.83 (d, 6.8 Hz, 6 H); MS (ES+) 645.77 cp o 1-.
i-,.)--t..) vi oe t..) Cpd. Starting Method -R Analytical Data No. From Used -1HNMR (DMSO-d6): 8 10.77 (bs, 1 H), 8.95 (bs, 4 H), 8.76 (d, J = 4.3 Hz, 1 o t..) ..--%-i i-,.)--, 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 .6.
26h ----<:.. _....--....... 25h N ' 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 1H2'4MR (DMSO-d6): 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), 26i 25i 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 &
I J
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, n N
2 H), 7.18 (m, 3 H), 7.0 (m, 2 H), 5.0 (s, 2 H), 3.08 (t, 3 = 6.5 Hz, 2 H), 1.82 (m, 1 H), 0.88 (d, 6.8 Hz, 6 H);; MS (ES+) 626.44 I.) a, I.) (5) --4 IHNMR (DMSO-d6): 8 0.87 (d, J = 6.9 Hz, 6 H), 1.75 (m, 1 H), 3.08 (t, J = 6.9 u.) 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 I.) 26j I 25j J 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, 0 l A
N 1 H), 8.05 (dd, 3 = 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+) a, H
626.76 -A
IHNMR (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 =
26k N----ks 25k J 4 Hz, 1 H), 7.74 (s, 4 H), 7.42 (d, 3 = 7.9 Hz, 1 H), 7.38 (d, 3 = 7.9 Hz, 1 H), 0 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 Iv H), 1.83 (m, 1 H), 0.87 (d, J = 6.8 Hz, 6 H); MS (ES+) 673.7 n ,-i cp =
t..) u, oe t..) Cpd. Starting Method -R
Analytical Data No. From Used 8 10z, 1 H
.66(s), 15 ,18.11), (9d.d,j=.88LHz, 1 11 20 (s, 72H), 82.86(s, 211), o)7, .86.9n,4H
66(t, J =),6 H1HNMRz, 1 H),(D8.1\424S(?1,-c16J-1-:2H
261 N 251 J 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), CH3 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 25m J MS (ES+) : 618.91 11-11M1 (DMSO-d6): 8 10.56 (s, 1 H), 9.15 (bs, 2 H), 8.84 (bs, 2 H), 8.64 (t, J
(5) -= 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), oe 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, 0 26n CH, 25n 1 H), 5.18 (d, J = 16 Hz, 1 H), 5.10 (d, J 11 Hz, 1 H), 5.0 (s, 2H), 3.47 (d, = 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 IHNMR (DMSO-d6): 8 10.84 (s, 1 H), 9.16 (s, 2 H), 8.78 (s, 2 H), 8.69 (t, J =
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), 26o S Nz-V. N 25o 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, 3= 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 1-d 26p /--NcH3 25p J MS (ES): 609.3 (M+Na) oe Cpd. Starting 1 Method -R
Analytical Data No. From Used . 0 o t..) 26q Nz CH3 H3 C7 -' cm 25q J MS (ES+) 631.5 .6.
IHNMR (DMSO-d6): 6 10.71 (s, 1 H), 9.16 (s, 2 H), 8.81 (s, 2 H), 8.68 (t, J =--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), 26r 25r .,,,. OH
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, J
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 n I.) a, 1HNMR (DMSO-d6): 6 0.89 (d, J = 6.8 Hz, 6 H), 1.84 (m, 1 H), 1.99 (s, 3 H), I.) (5) t..) --- Cii, 3.09 (t, J = 6 Hz, 2 H), 5.04 (s, 211), 5.18 (s, 1 H), 5.28 (s, 1 H), 6.73 (d, J = 16 a, o 26s -25s J 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 u.) I.) cH3 (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), 0 8.69 (t, J = 6 Hz, 1 H), 8.87 (bs, 4 H), 10.91 (s, 1 H); MS (ES+) 615.4 u.) a, H
1HNMR (DMSO-d6): 6 10.8 (br s, 1 H), 9.1 and 8.9 (2 br s, 4 H), 8.6 (m, 1 H), -A
26t 25t iICH2 8.2 (s, 1 H), 8.0 (m, 1 H), 7.8-7.6 (m, 611), 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 CH3 H), 2.2 ( s, 3 H), 1.8 (m, 1 H), 0.95 (d, 6 H); MS (ES+) 589.4, MS (ES-) 587.5 -=.
1HNMR (DM50-d6): 6 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 1-d 26u z_ ,,,..,,,. OH
25u j (m, 1 H), 6.57 (d, J.----11.5 Hz, 1 H), 7.04 (d, J = 6.7 Hz, 2 H), 7.25 (m, 3 H), n ,-i 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
cp --= 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 t..) vi oe Cpd. Starting Method -R Analytical Data No. From Used 111NMR (DMSO-d6): 8 0.88 (d, J = 6.8 Hz, 6 H), 1.84 (m, 1 H), 2.75 (t, J = 7 cH2 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, 25v 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, 26v OH = 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 1HNMR (DMSO-d6): 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 26w /CH 25w (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, 1 H), 7.75 (s, 4 H), 7.79 (s, 1 H), 8.05 (dd, J = 8 and 2 Hz, 1 H), 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 (5) IHNMR (DMSO-d6): 8 0.86 (d, J = 6.8 Hz, 6 H), 1.47 (s, 3 H), 1.74 (s, 3 H), CH 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), 25x J 5.11 (m, 1 H),7.03 (m, 2 H), 7.23 (m, 5 H), 7.52 (m, 2 H), 7.72 (m, 5H), 8.02 0 26x <CH: (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 1HNMR (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 H), 7.03 (d, OH
= 7 Hz, 2 H), 7.25 (m, 3 H), 7.31 (d, J = 8 Hz, 1 H), 7.39 (d, J = 8 Hz, 1 H), 26y 25y 7.58 (d, J = 8 Hz, 1 H), 7.73 (m, 5 H), 8.02 (dd, 3 = 10 and 2 Hz, 1 H), 8.23 (s, 1-d 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 oe _ Cpd. Starting Method -R
Analytical Data No. From . Used _ _ o 1HNMR (DMSO-d6): 5 10.6 (s, 1 H), 9.17 (s, 1 H), 8.85 (s, 1 H), 8.68 (d, J =
t..) W."
26z 711-\ OH 25z 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 1-1), 7.41 (d, J = 7.87 Hz, 4 H), 7.25 (m, 1 .6.
--.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, 3= 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 1HNMR (DMSO-d6): 5 10.70 (s, 1 H) 9.15 (bs, 2 H), 8.77 (bs, 2 H), 8.67 (t, J =
OH
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 0 26ab ,,......,... 25ab j (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, I.) a, I.) 1- S H), 5.31 (t, J = 6 Hz, 1H), 5.04 (bs, 2 H), 4.51 (d, J. = 6 Hz, 2 H), 3.07 (t, J = (5) a, 1- 6 Hz, 2 H), 1.82 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES+) 661.74 u.) I.) 1HNMR (DMSO-d6): 8 0.87 (d, J = 6.8 Hz, 6 H), 1.83 (m, 1 H), 3.07 (t, J = 6 u.) I
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 a, 26ac 25ac j (d, 3 = 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
-A
OH H), 7.44 (m, d, 3 = 8 Hz, 1 H), 7.58 (d, J = 5 Hz, 1 H), 7.74 (m, 6 H), 8.03 (d, J
S = 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 1HNMR (DMSO-d6): 5 9.65 (s, 1 H), 8.71 (t, 3 =5.15 Hz, 1 H) 8.39 (d, J. =
BnCO2 \ /
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 1-d & i 25ad J. = 7.77 Hz, 2 H), 7.29 (s, 2 H), 7.19 (m, 2 H), 7.08 (m, 2 H), 5.03 (d, I = 2.58 26ad 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 = n ,-i cp s 6.87 Hz, 6 H); MS (ES+) 765.4 t..) vi .
oe t..) , Cpd. Starting Method -R
Analytical Data No. From Used IHNMR (DMSO-d6): 5 9.1 (bs, 2 H), 8.8 (bs, 2 H), 8.5 (t, J = 6 Hz, 1 H), 8.02 o t..) 26ae HoHC 25ae (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 .6.
2ds J
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, 1-2 H), 3.01 (m, 2 H), 1.8 (m, 1 H), 0.85 (d, J= 6.8 Hz, 6 H); MS (ES+) 571.2 1HNMR (DMSO-d6): 5 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
--26af 3 25af 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 =
S 5.9 Hz, 6 H).
=
To a solution 3-hydroxybenzaldehyde (Aldrich, 101.39 g, 805 mmol) in chloroform (1000 mL), 'vim added bromine (45 mL, 845 mmol) in chloroform (200 mL) 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 pact of ceiitemand 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 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 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 Et0H (15 mL) was refluxed for 3 h and concentrated in vacuo. To the residue obtained was added Et0H (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 HC1 solution (freshly prepared by bubbling HC1 gas or prepared in-situ by premixing methanol and acetyl 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 Me0H (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 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.
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 the reaction was complete. The reaction mixture was concentrated in vacuo and purified by flash column chromatography to obtain the corresponding amidine, AK: Conversion of aryl triflates or halides to boronate ester To dichloro [1,1' -bis(diphenylphosphino)ferrocene]palladium (II) dichloro-methane 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) dichloro-methane adduct (0.03 mmol), 1,1'-bis(diphenylphosphino)ferrocene (0.03 mmol) under argon in dioxane (100 mL) was added aryl triflate (1 mmol), bis(pinacolata)diboron (1.1 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.
=
R
o n.) = 'W."
.6.
1-, 1-, R' Cpd. Starting Method -R -R' Analytical Data No. From Used .
_ 0113 11--1NMR (DMSO-d6): 8 10.26 (s, 1 H), 9.84 (s, 1 H
H), 8.15 (d, J= 3.0 Hz, 1 H), 7.64 (dd, J¨ 2.0 Hz 2a -OH 1 A-1 or A-\,.õ.,--,,, 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 (m, J= 6.9 Hz, n 1 H), 0.93 (d, J= 6.9 Hz, 1 H), 0.93 (d, J ---- 6 Hz, = 0 6H); MS (ES): 252.12 I.) a, I.) (5) a, 1¨
o co 2b -OH1 A-1 or A-2 Characterized in the next step co FP
I
H
=
'-ri-Lc' CH3 2c -OH / CH3 1 A-1 or A-2 MS (ES+): 294.54 H
'A
=,µõ,,/%1_, 2d -OH 1 A-1 or A-2 MS (ES): 288.49 (M+Na) cp 0 ---,----1¨
i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used =
2e -OH 1 A-1 or A-2 Characterized in the next step 2f -OH 1 A-1 or A-2 MS (ES): 300.40 (M+Na) H
1.) 2g -OH 1 A-1 or A-2 MS (ES): 272.48 (M+Na)+; MS (ES): 248.66 (5) 2h -OH 1 A-1 or A-2 MS (ES"): 286.48 (M+Na) 2i -OH
1 A-1 or A-2 MS (ES): 224.54 1-d CH, 2j -OH 1 A-1 or A-2 Characterized in the next step oe Cpd. Starting Method -R
Analytical Data No. From Used o t..) H
3a -OS 02CF3 yNcii3 2a B-1 or B-2 MS (BS): 384.37 .6.
H
-.,,.,,NCH3 3b -OS 02CF3 2b B-1 or B-2 MS (ES): 370.36 0 CH, H
,,,- CH, 3e -0S02CF3 / CH, 2c B-1 or B-2 MS (ES): 426.37 IV
FP
IV
o H co o CH, 3d -0S02CF3 2d B-1 or B-2 Characterized in the next step I.) 0 -----...,-, CA
I
FP
I
H
H
1H NMR (CDC13): 5 8.41 (d, J=2.3 Hz, 1 H), 8.10 (dd, .1= 8.5, 2.4 Hz, 1 H), 7.37 (d, .1= 8.5 Hz, 1 H), 3e -0S02CF3 0 ... CH, 2e B-1 or B-2 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, .1= 7.2 Hz, 3 H); MS (ES): 384.1 1-d H
1H NMR (CDC13): 5 8.45 (d, .1= 2.4 Hz, 1 H), 8.14 n =-..,,,.N...CF, 1-3 3f -0S02CF3 2f B-1 or B-2 (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 H); MS
cp o (ES): 410.2 c.:.) t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data o No. From Used o t..) IHNMR (CDC13): 5 8.42 (d, J= 2.3 Hz, 1 H), 8.12 .6.
H (dd, J= 8.5, 2.3 Hz, 1 H), 7.39 (d, J= 8.7 Hz, 1 H), -4 3g -0S02CF3 ,..2g B-1 or B-2 6.31 (broad, 1 H), 4.00 (s, 3 H), 3.34 (dd, J-= 7.2, 1-5.5 Hz, 2 H), 1.07 (m, 1 H), 0.59 (m, 2 H), 0.30 (m, 0 2 H);
MS (ES+): 382.2 =
H
. 3h _oso2cF3 ,Nn 2h B-1 or B-2 MS (ES+): 396.36 1HNMR (DMSO-d6): 5 8.85 (t, J= 5.5 Hz, 1 H), n H 8.49 (d, .1- 2.3 Hz, 1 H), 8.23 (dd, J= 8.7, 2.3 Hz, 3i -0S02CF3 -,,.N.,Ncii3 2i B-1 or B-2 1 H), 7.70 (d, J= 8.7 Hz, 1 H), 3.92(s, 3 H), 3.31 0 "
a, (m, 2 H), 1.14 (t, J= 7.2 Hz, 3 H); MS (ES+): 356.1 I.) (5) a, o (A
.6. iHNMR
(DMSO-d6): 5 8.81 (t, J= 6.0 Hz, 1 H), 0 CH, 8.49 (d, J-= 2.3 Hz, 1 H), 8.24 (dd, J= 8.7, 2.4 Hz, I.) 3j -0S02CF3H 2j B-1 or B-2 1 H), 7.71 (d, J= 8.7 Hz, 1 H), 3.92 (s, 3 H), 3.15 0 (m, 2 H), 1.64(m, 1H), 1.41 (m, 1 II), 1.12(m, 1 a, H), 0.88 (m, 6 H); MS (ES+): 398.2 H
-,1 1H NMR (DMSO-d6): 5 8.52 (d, J= 2.0 Hz, 1 H), 8.32 (dd, J= 2.0 and 8.9 Hz, 1 H), 7.72 (d, J=7.9 -0S02CF3 -0O2MEM 4 B-2 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 (ES): 439.1 (M+Na) CH3 iHNMR
(CDC13): 8 8.29 (d, J = 1.6 Hz, 1 H), 7.96 /0 H j-.
1-d o n (dd, J = 7.5 & 1.6 Hz, 1 H), 7.58 (d, J = 7.5 Hz, 1 -,,...1\1,.
6a -B \ 3a AK H), 6.24 (bs, 1 H), 3.94 (s, 3 H), 3.30 (t, J = 6.5 Hz, 0 2 H), 1.92 (m, 1 H), 1.43 (s, 12 H), 0.99 (d, J = 6.5 cp =
0 Hz, 6 H); MS (ES+) 362.2 t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used NMR (DMSO-d6): 5 10.26 (s, 1 H), 9.84 (s, 1 t..) H), 8.15 (d, J=3.0 Hz, 1 H), 7.64 (dd, J=2.0 Hz .6.
139 -OH \ N./..µ\.,'\ CH3 138 AA and 8.9 Hz, 1 H), 6.94 (d, J= 8.9 Hz, 1 H), 3.90 (s, --.1 H 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 NMR (DMSO-d6): 5 10.38 (s, 1 H), 8.36 (d, J=
2.8 Hz, 1 H), 7.99 (dd, J= 2.6 and 8.9 Hz, 1 H), 140 -.....õ ...........õ....-.õ, -OSO2CF3 N CH3 139 B-2 7.52 (d, J---- 9.0 Hz, 1 H), 3.89 (s, 3 H), 2.23 (d, J--H 7.0 Hz, 2 H), 2.09 (m, J= 6.6 Hz, 1 H), 0.94 (d, J=
6.6 Hz, 6 H); MS (ES): 384.0 n I.) a, I.) 111. NMR (CDC13): 6 8.08 (s, 1 H), 8.00 (d,J= 2.3 (5) a, 169 168 AC Hz, 1 H), 7.75 (dd, J= 2.3 and 8.7 Hz, 1 H), 7.01 u.) vi -OH -,..NOH (d, J=8.7 Hz, 1 I), 3.97 (s, 3 H), 3.50 (s, 1 H); MS 0 I.) (ES): 196.1 u.) 1HNMR (DMSO-d6): 5 7.79 (d, J= 2.0 Hz, 1 H), a, H
170 -OH -CH2NH2 169 G 7.51 (dd, J= 2.3 and 8.5 Hz, 1 H), 6.95 (d, J= 8.5 --1 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 (ES): 182.12 H
.,>N
(ES): 250.50; MS (ES): 274.50 (M+Na)+ 1-d n o cp =
t..) u, oe-t..) Cpd. Starting 1 Method -R -R' No. From Used Analytical Data _ _ o cii, 1H
NMR (CDC13): 5 7.96 (d, J= 2.3 Hz, 1 H), 7.55 t..) i-,.)--H (d, J= 2.3 and 8.3 Hz, 1 H), 7.26 (d, J= 8.3 Hz, 1 .6.
172 -0S02CF3 õ.,7-,...'CH 171 B-2 H), 5.90 (br s, 1 H), 4.50 (d, J= 4.1 Hz, 2 H), 3.97 1-(s, 3 H), 2.44 (sep, J= 7.0 Hz, 1 H), 1.20 (d, J---- 7.0 Hz, 6 H); MS (ES ): 384.1 MR (DMSO-d6): 5 10.62 (s, 1 H), 8.88 (m, 2 177 -OH H 168 AE-1 H), 7.99 (d, J=
2.3 Hz, 1 H), 7.70 (dd, J= 2.3 and .NCH3 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=
n 6.8 Hz), 0.93 (d, J= 6.8 Hz, 6 H); MS (ES): 238.1 11-1NMR (CDC13): 5 8.05 (d, J= 2.3 Hz, 1 H), 7.63 I.) a, I.) (dd, J= 2.3 and 8.3 Hz, 1 H), 7.25 (d, J= 8.3 Hz, 1 (5) a, o 178 -0S02CF3 177 B-2 H), 3.96 (s, 3 H), 3.85 (s, 2 H), 2.43 (d, J= 6.8 Hz, u.) o `CH o N
3 2 H), 1.77 (m, J= 6.6 Hz, 1 H), 0.93 (d, J= 6.6 Hz, I.) 1 H); MS (ES+): 370.2 u.) Boc 111 NMR (DMSO-d6): 5 7.93 (m, 1 H), 7.47 (m, 1 0 CH
.i.
I
179 -0S02CF3 1 178 R H), 7.26 (m, 1 H), 4.48 (m, 2 H), 3.96 (s, 3 H), 3.03 '-' (m, 2 H), 1.91 (m, 1 H), 1.52 (m, 9 H), 0.89 (d, J=
CH3 6.6 Hz, 6 H); MS (ES+): 492.2 (M+Na) 1-d n ,-i cp =
t..) u, oe t..) R R' Cpd. Starting Method -R -R' Analytical Data No. From Used 111 NIVIR (DMSO-d6): 0.78 (s, 1H), 8.85 (t, 1= 5.7 Hz, 1H), 8.50 = (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 8.2, 1.9 Hz, 111), 7.55 (m, 9H), 7 -0Bn -CHO 6 + 3a D-2 5.35 (s, 2H), 3.69 (s, 3H), 3.23 (t, J = 6.5 Hz, 2H), 1.98 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H); MS (ES+): 446.3 8 -0Bn -CO2H 7 E MS (BS): 484.33 (M+Na) (5) 9 -0Bn -0O2MEM 8 F MS (ES): 572.2 (M+Na) -OH -0O2MEM 9 G MS (BS): 482.33 (M-MEM) +Nal+
IHNIVIR (DMSO-d6): ,58.75 (t, J = 5.6 Hz, 1H), 8.44 (d, J = 1.6 Hz, 1H), 8.11 (dd, J = 8.0, 1.9 Hz, 1H), 8.01 (d, J. =2.9 Hz, 1H), 7.84 (dd, J= 8.4, 2.6 Hz, 1H), 7.47 (d, J = 8.5 Hz, 111), 7.41 (d, J =
11 -0S02CF3 -0O2MEM 10 B-2 8.0 Hz, 1H), 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, 1H), 0.91 (d, J = 6.7 Hz, 6H); MS (ES+): 614.3 (M+Na)+
1-d 29a -0O2MEM 11 D-3 Characterized in the next step cH3 oe Cpd. Starting Method Analytical Data No. From Used 29b CH3 -0O2MEM 11 D-3 MS
(BS): 520.2 (M+Na) 29c -0O2MEM 11 D-3 MS
(ES): 482.3 29d -0O2MEM 11 D-3 MS
(ES): 562.3 (M+Na) 29e -0O2MEM 11 D-3 MS (ES): 556.4 (M+Na)+ 0 (5) oe 1H NMR (DMSO-d6): 8.50 (t, J = 5.6 Hz, 111), 8.18 (d, J = 1.9 Hz, 1H), 7.86 (dd, J = 7.9, 1.9 Hz, 1H), 7.78 (d, J =1.7 Hz, 111), 7.56 (dd, J = 8.0, 1.8 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.00 (d, J =
29f -CO2MEM 11 D-3 7.9 Hz' 1H), 6.67 (dd, J = 17.6, 11.1 Hz, 111), 5.76 (d, J = 17.6 Hz, 1H), 5.19 (d, J = 11.1 Hz, 1H), 4.99 (q, AB system, 2H), 3.37 (s, 3H), 3.20 (m, 2H), 3.11 (m, 211), 2.97 (s, 311), 2.91 (t, J = 6.7 Hz, 2H), 1.67 (m, 1H), 0.70 (d, J = 6.6 Hz, 611); MS (ES+): 492.3 (M+Na) OHC
29g -0O2MEM 11 D-2 MS (ES): 576.2 (M+Na) ; MS (ES): 552.2 oe Cpd. Starting Method -R -IV
Analytical Data . No. From Used CHO
o , n.) 29h // .........,_ -0O2MEM 11 D-2 MS
(ES): 538.2 1-, 1-, OHC
291 \k \ -0O2MEM 11 D-2 MS (ES): 560.4 (M+Na)+
-30a -CO2H 29a I-I MS (ES): 398.3 ;
MS (ES): 396.3 0 --CH, IV
FP
30b .--',-- --,.
I\) (5) o CH3 -CO2H 29b I-1 Characterized in the next step Lo vD
IV
CA
30c.,... CH2 -CO2H 29c I-1 MS (ES): 392.1 a, H
-,1 30d S -CO2H 29d I-1 MS (ES): 452.1 30e II -CO2H 29e I-1 MS (ES): 446.2 Iv n ,-i cp =
i-,.,--t..) u, .
oe t..) Cpd.Starting Method -R -12' No. From Used Analytical Data 30f -.--'''.-- CH2 -CO2H 29f I-1 MS
(ES): 380.1 t..) i-,.)--.6.
N3H2C\ /
30g 0 -CO2H 29g K, N, 0, I-1 MS (ES): 515.3 (M+Na) ; MS (ES): 491.2 S
CH20H 1,µ
30h -CO2H 29h K, I-1 MS (ES): 450.1 , n IV
FP
IV
I-, 1..,30i \ -CO2H 29i K, I-1 MS (ES): 450.3 a, co o 0 "
CA
Characterized in the next step I
FP
I
H
41 --0 . -0O2MEM 10 D-8 MS (ES): 534.30 42 -CO2H 41 I-1 MS (ES):
446.30 1-d 48 -OCH3 -CHO 47+ 3a D-2 MS (ES): 392.2 (M+Na)+ n ,-i 49 -OCH3 -CO2H 48 E MS (ES): 386.1;
408.1 (M+Na)+
cp o 1¨
t..) vi oe t..) CO,Bn W."
R' Cpd.Starting Method -R
Analytical Data No. From Used 14 -0S02CF3 -CHO 13 B-2 Characterized in the next step -0S02CF3 -CO2H 14 E MS (ES): 403.58 cH3 11-IN4R (DMSO-d6): .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), 16 -0S02CF3CH3 15 A-3 or A-4 "
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).
(5) 1.) oe R R' OH
W."
BnO,C
Cpd. Starting Method -R -R' No. From Used Analytical Data 1HN4R (DMSO-d6): !S 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, 1=13 and 2.5 Hz, 2 H), 5.18 (s, 2 17 -0Bn -CHO 16 + 6 D-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 (5) 1HNMR (DMSO-d6): 6 0.86 (d, J = 6.9 Hz, 6 H), 1.85 (m, 1 H), 3.09 (t, 3= 6.9 Hz, 2 H), 5.01 (d, J = 5.01 Hz, 2 H), 5.14 (s, 2 H), 18 -0Bn -CO2H 17 E 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 IHNMR (DMSO-d6): El 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 19 -0Bn -0O2MEM 18 F H), 3.36 (dd, J = 3 and 6 Hz, 2 H), 5.02 (d, J = 3.8 Hz, 2 H), 5.12 (d, 3= 15 Hz, 2 H), 5.64 (s, 2 H), 7.11 (m, 3 H), 7.24 (dd, 3= 8.25 and 2.75 Hz, 1 H), 7.29 (m, 4 H), 7.35 (m, 1 H), 7.42 (m, 3 H), 1-d 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 oe Cpd.Starting Method -R -R' Analytical Data No. From Used 1HNMR (DMSO-d6): 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 21 -OH -0O2MEM 19 G, H (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%; M+1) (DMSO-d6): 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 (m, 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 (m, 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, I = 2.6 Hz, 1 H), 8.07 (5) (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 11-INMR (DMSO-d6): 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 (m, 2 H), 5.05 (d, J = 2.6 Hz, 2 H), 5.16 (d, J = 17 Hz, 2 H), 7.08 (m, 2 H), 24a -0O2MEM 22 + 23 D-1 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, I = 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 1-d oe =
Cpd. Starting Method -R -R' Analytical Data No. From Used o IHNMR (DMSO-d6): 5 0.89 (d, J = 6.8 Hz, 6 H), 1.87 (m, 1 H), .6.
3.12(t, J = 6 and 6.8 Hz, 2 H), 3.16 (s, 3 H), 3.30 (m, 2 H), 3.39 24b ' (dd, J = 5.2 and 3.4 Hz, 2 H), 5.04 (d, J = 4.3 Hz, 2 H), 5.16 (d, J =
-0O2MEM 22 + 23 D-1 16 Hz, 2 H), 7.08 (m,2 H), 7.20 (m, 3 H), 7.24 (d, J = 8.6 Hz, 1 S 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, 1 H), 8.14 (d, J = 1.7 Hz, 1 H), 8.41 (d, J = 1.7 Hz, 1 H), 8.68 (t, J = 6 Hz, 1 H); MS (ES+) 602.27 .1,.
u.) 5.53Hollz(8d,9,2 J(Hdl)i:71.67 Hz, 1 H), 7.37 (d, J ---- 7.7 Hz, -57. 167. 807;.6 H), 1.87 27 H(m),, 71.H09),(m, I.) .6. 24c I.1 3.12 (t, J = 6 and 6.8 Hz, 2 H), 3 (s, 3 H), 3.30 (m, 2 H), 3.40 .1,.
I.) (5) -0O2MEM 22 4- 23 D-1 2(inaHNMRH, 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 u.) Hz, 1 H), 8.11 (d, J = L7 Hz, 1 H), 8.42 (d, J = 1.7 Hz, 1 H), 8.72 .1,.
(t, J = 6 Hz, 1 H); MS (ES+) 596.45 H
)2, 7H.2)715(.:05:3(::J:=)7:
-A
24d -0O2MEM 22 + 23 D-1 MS (ES+) 616 , H3C s 1-d 24e -0O2MEM 22 + 23 D-1 MS (ES+) 586.4 n ,-i o cp =
t..) u, oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used 24f -0O2MEM 22 + 23 D-1 MS (ES): 586.39 11,C
24g -0O2MEM 22 + 23 D-1 MS (ES): 616.63 24h -0O2MEM 22 + 23 D-1 MS (ES): 597.25 1.) 1.) (5) 24i -0O2MEM 22 + 23 D-1 MS (ES): 597.4 1.) 24j -0O2MEM 22 +23 D-1 MS (ES): 597.4 24k H3C iS -0O2MEM 22 + 23 D-1 MS (ES): 644.3 oe Cpd. Starting Method -R -R' Analytical Data No. From Used 241 N -0O2MEM 22+ 23 D-3 Characterized at the next step cH3 24m -0O2MEM 22 + 23 D40 Characterized at the next step 24n CH2 -0O2MEM 22 +23 D-3 MS (ES): 560.74 (5) 24o S.Nv N
-0O2MEM 22 +23 D-4 MS (ES): 603.72 24p /=NcH3 -0O2MEM 22 + 23 D-5 MS (ES): 558.3 CH
24q Ni< -0O2MEM 22 + 23 D-5 Characterized in the next step OH
24r -0O2MEM 22 + 23 D-5 MS (ES): 610.4 (M+Na) oe Cpd. Starting Method -R -IV
Analytical Data No. From Used CH
t..) 24s -0O2MEM 22 + 23 D-3 Characterized in the next step 4,.
I-, I-, }12 24t ------4 -0O2MEM 22 + 23 D-3 Characterized in the next step CH, _____ OH
24u / -0O2MEM 22 + 23 D-3 MS (ES): 598.4 (M+Na) CH, n 24v --7<\, -0O2MEM 22 + 23 D-3 MS (ES): 500.4 KM-MEM)-1r IV
I\) (5) --4 /=TMS
24w -0O2MEM 22 +23 D-5 Characterized in the next step I.) CA
I
24x / ¨ \ -0O2MEM 22 + 23 D-3 MS (ES): 610.5 (M Na) CH,+
a, , H
24y ......õ--_ -......õ,. OH -0O2MEM 22 +23 D-5 MS
(ES): 596.4 (M+Na)+
CH, 24z -0O2MEM 22 + 23 D-3 MS (ES): 576.3 (M+Na)+
OH
IV
n ,-i 24aa ______N -0O2MEM 22 +23 D-11 Characterized in the next step cp o 1-, i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. , From , Used CHO
0o t..) 24ab -0O2MEM 22 + 23 D-2 MS (ES): 630.55 4,.
--.1 1-, 1-, S
24ac _.,_.. -0O2MEM 22 + 23 D-2 MS (ES): 630.74 S CHO
OHC /
n 24ad -0O2MEM 22 + 23 D-2 MS (ES): 652.3 0 IV
FP
IV
S
FP
I..
Pe IV
CA
I
24ae OHC"--- \------- -0O2MEM 22 + 23 D-2 Characterized in the next step 0 FP
I
S
H
-,1 24ag N -0O2MEM 22 +23 D-1 MS (ES): 685.01 I
Boc IV
n 24ah ----\\, = CH2 -0O2MEM 22 23 D-3 MS (ES): 546.49 cp o 1-, i-,.)--t..) vi oe t..) Cpd.Starting Method -R -R' Analytical Data No. From Used 1HNMR (DMSO-d6): 5 0.91 (d, J = 6.9 Hz, 6 H), 1.88 (m, 1 H), o , t..) 3.13 (t, J = 6.9 and 6 Hz, 2 H), 5.07(d, J = 11.2 Hz, 2 H), 7.09 (m, . 2 H), 7.22 (m, 5 H), 7.35 (d, 7.7 Hz, 1 H), 7.63 (d, 2.6 Hz, 1 H), .6.
--.1 25a CO2H 24a I-1 s 7.65 (d, J = 5.2 Hz, 1 H), 7.82 (dd, J = 7.7 and 1.7 Hz, 1 H), 8.05 1-(d, J = L7 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 _ 1HNMR (DMSO-d6): 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 25b CO2H 24b I-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 n S
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 I.) .1, I.) (5) .1, 1- 1HNMR (DMSO-d6):
5 12.73 (bs, 1 H), 8.73 (t, .1. = 6 Hz, 1 H), u.) VD
8.41 (d, J = 1.7 Hz, 1 H), 8.12 (d, J = 1.7 Hz, 1 H), 8.07 (dd, J =
I.) 7.7 & 1.7 Hz, 1 H), 7.83 (dd, J - 7.7 & 1.7 Hz, 1 H), 7.72 (d, J =
25c (m, 2 H), 5.08 (d, J = 14 Hz, 2 H), 3.13 (t, J
III CO2H 24c I-1 6.9 Hz, 2 H), 7.54 (t, J = 7.7, 2 H), 7.44 (t, J = 7.7 Hz, 1 H), 7.37 I., , (d, J. = 7.7 Hz, 1 H), 7.28 (d, J. = 7.7 Hz, 1 H), 7.21 (m, 3 H), 7.09 -= 6.5 Hz, 2 H), 1.88 L.
,i, I
H
-,1 (rn, 1 H), 0.91 (d, 6.8 Hz, 6 H); MS (ES+) 507.93 1HNMR (DMSO-d6): 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, 25d ---3_ CO2H 24d I-1 1 H), 7.34 (d, J = 7.7 Hz, 1 H), 7.22 (m, 3 H), 7.19 (d, J. = 8.6 Hz, H,C s , 1 H), 7.09 (m, 2 H), 6.95 (d, J =3.4 Hz, 1 H), 5.06 (d, J = 11 Hz, 2 1-d n 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 cp o i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used iHNMR. (DMSO-d6): 8 0.89 (d, J = 6 Hz, 6 H), 1.86 (m, 1 H), 3.12 25e CO2H 24e (t, J = 6.8 and 6.0 Hz, 2 H), 5.03 (d, J =1:D Hz, 2 H), 7.02 (s, 1 H), I-1 7.06 (m' 211), 7.16 (d, = 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 0 Hz, 1 H), 8.04 (m, 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 CO211 24f I-1 MS (ES): 498.36 H3C 1HNMR (DMSO-d6): 8 12.72 (bs, 1 H), 8.69 (t, J = 6 Hz, 1 H), (5) 8.39 (d, J = 1.7 Hz, 1 H), 8.06 (m, 2 H), 7.79 (dd, J - 1.7 & 7.7 25g CO2H 24g I-1 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, 211), 5.07(d, J = 8.6 Hz, 2 H), 3.12(t, J = 6.5 Hz, 2H) 2.29 (s, 3 H), 1.89 (m, 1 H), 0.91 (d, 6.8 Hz, 6 H); MS (ES+) 528.38 1HNMR (DMSO-d6): 6 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, 1 H), 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), 25h CO2H 24h I-1 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, 211), 5.01 (q, J = 10 & 25 Hz, 211), 3.13 (t, J = 6.9 and 6 1-d Hz, 2 H), 1.89 (m, 1 H), 0.92 (d, J = 6.9 Hz, 611); MS (ES+) 509.58 oe Cpd.Starting Method -R -R' Analytical Data No. From-Used 1HNMR (DMSO-d6): 6 12.70 (bs, 1 H), 8.91 (d, J = 2.6 Hz, 1 H), =
t..) 8.68 (t, J = 6 & Hz, 1 H), 8.62 (d, J = 2 Hz, 1 H), 8.4 (d, J = 1.7 .6.
Hz, 1 H), 8.12 (m, 2 H), 8.05 (dd, J = 8.6 & 1.7 Hz, 1 H), 7.88 (d, --.1 251 1 CO2H 241 1-1 8.5 & 1.7 Hz, 1 H), 7.53 (dd, J = 8.6 & 5.2 Hz, 1 H), 7.34 (d, J =
,-, N 7.7 Hz, 1 H), 7.28 (d, J = 8.6 Hz, 1 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 IHNMR (DMSO-d6): 6 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 25j CO2H 24j (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), n 8.18 (s, 1 H), 8.40 (d, J =2 Hz, 1 H), 8.71 (m, 4 H); MS (ES+) I.) 509.49 a, I.) (5) a, I.) 25k H3c CO2H 24K 1-1 Characterized in the next step 0 s u.) a, .
H
I . CO2H 241 I-1 MS (ES+):
511.54 25m ) N CO2H 24m I-1 MS (ES+):
501.66 1-d n ,-i I
cp =
t..) u, oe t..) Cpd.Starting Method -R -R' Analytical Data No. From Used 25n CO2H 24n I-1 MS (BS): 472.4 25oSN77 CO2H 24o I-1 MS (ES+): 515.65 /=-N
25p CH3 CO2H 24p I-1 Characterized in the next step 25q HrOH CO2H 24q I-I MS (ES4): 536.3 (M+Na)+
(5) 25r CO2H 24r I-1 MS (ES): 500.4 /¨*CH2 25s CO2H 24s I-1 Characterized in the next step 25t /<\ CO2H 24t I-1 Characterized in the next step CH, 25u CO2H 24u 1-1 MS (ES): 486.4 oe Cpd. Starting Method -R
No. From Used Analytical Data 25v OH CO2H 24v I-1 MS (ES): 524.3 (M+Na) 25w CO2H 24w 1-4, Q Characterized in the next step 25x cH3 CO2H 24x I-1 MS (ES): 498.3 (5) 25y OH CO2H 24y I-1 MS (ES): 484.3 CH
25z )-L¨\\ CO2H 24z I-1 MS (ES): 488.3 OH
25aa CO2H 24aa 1-1 Characterized in the next step OH
1-d 25ab CO2H 24ab K, I-1 MS (ES): 544.27 Ns oe Cpd.Starting Method -R -R' Analytical Data No. From Used 25ac 24ac K, I-1 MS (ES): 544.2 t..) i-,.)--.6.
OH
S
1¨, 1¨, BnO,C /
25ad i CO2H 24ad E, H, I-1 MS (ES): 670.3 (M+Na)+
S
IHNMR (DMSO-d6): 8 9.1 (bs, 2 H), 8.8 (bs, 2 H), 8.5 (t, J = 6 25ae HOH,C s CO2H Hz, 1 H), 8.02 (s, 1 H), 7.68 (s, 1 H), 7.62 (m, 6 H), 7.53 (d, .1=
24ae K, I-1 5.8 Hz, 1 H), 7.15 (d, J = 6 Hz, 1 H),), 7.13 (m, 1 H), 7.01 (s, 1 n 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) IV
FP
I\)/61 N
CA
' 25af i CO2H 24ad K, I-1 MS (ES):
566.2 (M+Na)+ I.) S
CA
I
FP
I
.----"----H
25ag III CO2H 24ag I-I MS (ES):
597.7 Boc OH
25ah CO2H 24ah L, I-1 MS (ES):
492.54 -IV
n L, m 25ai l'13 CO2H 24ai K, N,, Characterized in the next step cp 0,1-1 o 1¨
i-,.)--t..) vi oe t..) NH
0 411) NH2 R
H
o n.) .6.
1-, H
1-, BnO2C
Cpd. Starting Method -R
Analytical Data = No. From Used 1HNMR (DMSO-do): 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 n 3 (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, 0 26a 25a J
"
FP
s 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 I.) (5) a, t..) 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); u.) vi MS (ES+) 631.05 I.) CA
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 26b IHNMR (DMSO-do): 8 0.88 (d, J "6.9 Hz, 6 H), 1.84 (m, 1 H), 3.07 (t, J = 6.8 -,1 S and 7.7 Hz, 1 H), 8.05 (m, 3 H), 8.23 (d, J = 1.7 Hz, 1 H), 8.68 (t, 3 = 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 IHNMR (DMSO-do): 8 10.75 (s, 1 H), 9.19 (s, 2 H), 8.89 (s, 2 H), 8.69 (t, J =
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
26c 1411 25c J = 1.7 Hz, 1 H),7.87 (dd, .1 = 7.7 & 1.7 Hz, 1 H), 7.83 (d, J = 7.7 Hz, 2 H), 7.77 (m 5 H), 7.54 (t, J = 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, IV
n ,-i 6.8 Hz, 6 H); MS (ES+) 625.81 cp o i-,.)--t..) vi oe t..) Cpd. Starting Method -R
Analytical Data No. From Used o 1HNMR (DMSO-d6): 8 10.7 (s, 1 H), 9.14 (s, 2 H), 8.82 (s, 2 H), 8.64 (t, J = 6 t..) i-,.)--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), .6.
--.1 26d 25d J 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, 1-.
H3C s 7.8 Hz, 1 H), 7.27 (d, J
= 7.7 Hz, 1 H), 7.16 (rn, 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 IHNMR (DMSO-d6): 8 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 26e \.(:) 25e J 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 n =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 0 I.) a, (bs, 2 H), 10.67 (s, 1 H); MS (ES+) 615.75 I.) (5) o 0 1HNMR (DMSO-d6): 8 0.87 (d, J = 6.7 Hz, 6 H), 1.83 (m, 1 H), 3.06 (t, J = 6.7 I.) 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), 26f 251 J 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 u.) a, , co 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, H
-,1 1 H); MS (ES+) 615.75 H3C IHNMR (DMSO-d6): 8 10.67 (s, 1 H), 9.12 (s, 2 H), 8.78 (s, 2 H), 8.61 (t, J = 6 26g ' 25g 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), J 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 s (m, 4H), 7.01(s, 1 H), 6.99 (s, 1 H), 5.0 (s, 2 H), 3.03 (t, J = 6.5 Hz, 2 H), 2.23 1-d n (s, 3 H), 1.79 (m, 1 H), 0.83 (d, 6.8 Hz, 6 H); MS (ES+) 645.77 cp o 1-.
i-,.)--t..) vi oe t..) Cpd. Starting Method -R Analytical Data No. From Used -1HNMR (DMSO-d6): 8 10.77 (bs, 1 H), 8.95 (bs, 4 H), 8.76 (d, J = 4.3 Hz, 1 o t..) ..--%-i i-,.)--, 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 .6.
26h ----<:.. _....--....... 25h N ' 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 1H2'4MR (DMSO-d6): 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), 26i 25i 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 &
I J
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, n N
2 H), 7.18 (m, 3 H), 7.0 (m, 2 H), 5.0 (s, 2 H), 3.08 (t, 3 = 6.5 Hz, 2 H), 1.82 (m, 1 H), 0.88 (d, 6.8 Hz, 6 H);; MS (ES+) 626.44 I.) a, I.) (5) --4 IHNMR (DMSO-d6): 8 0.87 (d, J = 6.9 Hz, 6 H), 1.75 (m, 1 H), 3.08 (t, J = 6.9 u.) 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 I.) 26j I 25j J 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, 0 l A
N 1 H), 8.05 (dd, 3 = 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+) a, H
626.76 -A
IHNMR (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 =
26k N----ks 25k J 4 Hz, 1 H), 7.74 (s, 4 H), 7.42 (d, 3 = 7.9 Hz, 1 H), 7.38 (d, 3 = 7.9 Hz, 1 H), 0 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 Iv H), 1.83 (m, 1 H), 0.87 (d, J = 6.8 Hz, 6 H); MS (ES+) 673.7 n ,-i cp =
t..) u, oe t..) Cpd. Starting Method -R
Analytical Data No. From Used 8 10z, 1 H
.66(s), 15 ,18.11), (9d.d,j=.88LHz, 1 11 20 (s, 72H), 82.86(s, 211), o)7, .86.9n,4H
66(t, J =),6 H1HNMRz, 1 H),(D8.1\424S(?1,-c16J-1-:2H
261 N 251 J 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), CH3 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 25m J MS (ES+) : 618.91 11-11M1 (DMSO-d6): 8 10.56 (s, 1 H), 9.15 (bs, 2 H), 8.84 (bs, 2 H), 8.64 (t, J
(5) -= 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), oe 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, 0 26n CH, 25n 1 H), 5.18 (d, J = 16 Hz, 1 H), 5.10 (d, J 11 Hz, 1 H), 5.0 (s, 2H), 3.47 (d, = 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 IHNMR (DMSO-d6): 8 10.84 (s, 1 H), 9.16 (s, 2 H), 8.78 (s, 2 H), 8.69 (t, J =
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), 26o S Nz-V. N 25o 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, 3= 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 1-d 26p /--NcH3 25p J MS (ES): 609.3 (M+Na) oe Cpd. Starting 1 Method -R
Analytical Data No. From Used . 0 o t..) 26q Nz CH3 H3 C7 -' cm 25q J MS (ES+) 631.5 .6.
IHNMR (DMSO-d6): 6 10.71 (s, 1 H), 9.16 (s, 2 H), 8.81 (s, 2 H), 8.68 (t, J =--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), 26r 25r .,,,. OH
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, J
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 n I.) a, 1HNMR (DMSO-d6): 6 0.89 (d, J = 6.8 Hz, 6 H), 1.84 (m, 1 H), 1.99 (s, 3 H), I.) (5) t..) --- Cii, 3.09 (t, J = 6 Hz, 2 H), 5.04 (s, 211), 5.18 (s, 1 H), 5.28 (s, 1 H), 6.73 (d, J = 16 a, o 26s -25s J 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 u.) I.) cH3 (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), 0 8.69 (t, J = 6 Hz, 1 H), 8.87 (bs, 4 H), 10.91 (s, 1 H); MS (ES+) 615.4 u.) a, H
1HNMR (DMSO-d6): 6 10.8 (br s, 1 H), 9.1 and 8.9 (2 br s, 4 H), 8.6 (m, 1 H), -A
26t 25t iICH2 8.2 (s, 1 H), 8.0 (m, 1 H), 7.8-7.6 (m, 611), 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 CH3 H), 2.2 ( s, 3 H), 1.8 (m, 1 H), 0.95 (d, 6 H); MS (ES+) 589.4, MS (ES-) 587.5 -=.
1HNMR (DM50-d6): 6 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 1-d 26u z_ ,,,..,,,. OH
25u j (m, 1 H), 6.57 (d, J.----11.5 Hz, 1 H), 7.04 (d, J = 6.7 Hz, 2 H), 7.25 (m, 3 H), n ,-i 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
cp --= 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 t..) vi oe Cpd. Starting Method -R Analytical Data No. From Used 111NMR (DMSO-d6): 8 0.88 (d, J = 6.8 Hz, 6 H), 1.84 (m, 1 H), 2.75 (t, J = 7 cH2 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, 25v 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, 26v OH = 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 1HNMR (DMSO-d6): 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 26w /CH 25w (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, 1 H), 7.75 (s, 4 H), 7.79 (s, 1 H), 8.05 (dd, J = 8 and 2 Hz, 1 H), 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 (5) IHNMR (DMSO-d6): 8 0.86 (d, J = 6.8 Hz, 6 H), 1.47 (s, 3 H), 1.74 (s, 3 H), CH 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), 25x J 5.11 (m, 1 H),7.03 (m, 2 H), 7.23 (m, 5 H), 7.52 (m, 2 H), 7.72 (m, 5H), 8.02 0 26x <CH: (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 1HNMR (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 H), 7.03 (d, OH
= 7 Hz, 2 H), 7.25 (m, 3 H), 7.31 (d, J = 8 Hz, 1 H), 7.39 (d, J = 8 Hz, 1 H), 26y 25y 7.58 (d, J = 8 Hz, 1 H), 7.73 (m, 5 H), 8.02 (dd, 3 = 10 and 2 Hz, 1 H), 8.23 (s, 1-d 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 oe _ Cpd. Starting Method -R
Analytical Data No. From . Used _ _ o 1HNMR (DMSO-d6): 5 10.6 (s, 1 H), 9.17 (s, 1 H), 8.85 (s, 1 H), 8.68 (d, J =
t..) W."
26z 711-\ OH 25z 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 1-1), 7.41 (d, J = 7.87 Hz, 4 H), 7.25 (m, 1 .6.
--.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, 3= 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 1HNMR (DMSO-d6): 5 10.70 (s, 1 H) 9.15 (bs, 2 H), 8.77 (bs, 2 H), 8.67 (t, J =
OH
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 0 26ab ,,......,... 25ab j (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, I.) a, I.) 1- S H), 5.31 (t, J = 6 Hz, 1H), 5.04 (bs, 2 H), 4.51 (d, J. = 6 Hz, 2 H), 3.07 (t, J = (5) a, 1- 6 Hz, 2 H), 1.82 (m, 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES+) 661.74 u.) I.) 1HNMR (DMSO-d6): 8 0.87 (d, J = 6.8 Hz, 6 H), 1.83 (m, 1 H), 3.07 (t, J = 6 u.) I
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 a, 26ac 25ac j (d, 3 = 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
-A
OH H), 7.44 (m, d, 3 = 8 Hz, 1 H), 7.58 (d, J = 5 Hz, 1 H), 7.74 (m, 6 H), 8.03 (d, J
S = 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 1HNMR (DMSO-d6): 5 9.65 (s, 1 H), 8.71 (t, 3 =5.15 Hz, 1 H) 8.39 (d, J. =
BnCO2 \ /
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 1-d & i 25ad J. = 7.77 Hz, 2 H), 7.29 (s, 2 H), 7.19 (m, 2 H), 7.08 (m, 2 H), 5.03 (d, I = 2.58 26ad 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 = n ,-i cp s 6.87 Hz, 6 H); MS (ES+) 765.4 t..) vi .
oe t..) , Cpd. Starting Method -R
Analytical Data No. From Used IHNMR (DMSO-d6): 5 9.1 (bs, 2 H), 8.8 (bs, 2 H), 8.5 (t, J = 6 Hz, 1 H), 8.02 o t..) 26ae HoHC 25ae (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 .6.
2ds J
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, 1-2 H), 3.01 (m, 2 H), 1.8 (m, 1 H), 0.85 (d, J= 6.8 Hz, 6 H); MS (ES+) 571.2 1HNMR (DMSO-d6): 5 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
--26af 3 25af 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 =
S 5.9 Hz, 6 H).
11-11\1114R. (DMSO-d6): 5 0.90 (d, J--= 6.9 Hz, 6 H), 1.41 (s, 9 H), 1.87 (m, 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 I.) a, 26ag N 25ag J 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 I.) .
,T
I 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), u.) t..) Boc 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 0 Hz, 1 H), 8.77 (bs, 2 H), 9.15 (bs, 2 H), 10.58 (s, 1 H); MS (ES+) 714.78 I.) OH
u.) o 26ah 25ah J. MS (ES): 609.6 a, H
-A
1HNMR (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), 26a1 25ai J 7.4 (d, S = 5.8 Hz, 1 H), 7.35 (d, 3 = 6.9 Hz, 1 H), 7.29 (m, 3 H), 7.0 (m, 2 H), N3 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 1-d n ,-i cp =
t..) u, oe t..) NH
0 4111 NH, o n.) .6.
1-, 1-, NBR' la HO,C
- Cpd. Starting Method -R -R' Analytical Data No. From Used 1HNMR (DMSO-d6): 5 14.95 (s, 1 H), 8.97 (s, 4 H), 8.5 n (t, J = 6 Hz, 1 H), 7.97 (d, J = 2 Hz, 1 H), 7.80 (d, J =- 2 CH3 Hz, 1 H), 7.73 (dd, J = 7.9 and 2 Hz, 1 H), 7.61 (m, 7 H), 0 I.) 27a 26a 1-2 7.18 (t, J = 3.9 Hz, 1 H), 7.05 (d, J= 7.9 Hz, 1 H), 6.93 a, N) c7, a, (d, J = 7.9 Hz, 1 H), 3.01 (t, J = 6.9 and 6.0 Hz, 2 H), 1.81 u.) - (m, 1 H), 0.84 (d, J = 6.9 Hz, 6 H); MS (ES): 541.17 0 I.) IHNMR (DMSO-d6): 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 u.) \N 3 26b 1-2 (s, 1 H), 7.87 (s, 1H), 7.75 (d, J = 7.7 Hz, 1 H), 7.65 (m, 1 27b .3 a, ' H), 7.62 (m, 6 H), 7.05 (d, J = 7.7 Hz, 1 H), 6.93 (d, J --H
--.1 S
CH3 7.7 Hz, 1 H), 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 (ES): 541.42 Ill NMR (DMSO-d6): 5 13.28 (s, 1 H), 9.04 (s, 4 H), 8.5 CH3 (t, J = 6 Hz, 1 H), 7.97 (s, 1 H), 7.82 (s, 1 H), 7.74 (m, 3 lei CH3 26c 1-2 H), 7.62 (m, 5 H), 7.5 (t, J = 7.7 Hz, 2 H), 7.4 (t, J = 7.7, 27c 1 H), 7.1 (d, J = 7.7 Hz, 2 H), 6.97 (d, J = 7.7. Hz, 1 H), 3.01 (t, J = 6.5 Hz, 2 H), 1.8 (m, 1 H), 0.85 (d, 6.8 Hz, 6 Iv n H); MS (ES): 535.48 cp o c.:.) tµ.) vi oe tµ.) Cpd.Starting Method -R -R' Analytical Data No. From Used o 1H NMR (DMSO-d6): 8 9.03 (s, 2 H), 8.89 (s, 2 H), 8.49 t-.) j/N CH, (t, J = 6 Hz, 1 H), 7.99 (s, 1 H), 7.65 (m, 8 H), 7.37 (d, J
27d H3C s26d 1-2 3 Hz, 1 H), 7.04 (d, J = 7.7 Hz, 1 H), 6.98 (s, 1 H), 6.82 1-.'-- CH3 (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+):555.61 1H NMR (DMSO-d6): 8 14.10 (s, 1 H), 9.05 (bs, 2 H), cH3 8.79 (bs, 2 H), 8.47 (t, J = 5.6 Hz, 1 H), 8.3 (s, 1 H), 7.96 27e ), cii3 26e 1-2 (d, J. =
2 Hz, 1 H), 7.78 (m, 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 (ES): 525.36 I.) a, I.) c7, a, 4,. 1H NMR
(DMSO-d6): 8 9.07 (s, 2 H), 8.86 (s, 2 H), 8.53 0 cH3 (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 I.) 27f 0 'CH3 26f 1-2 Hz, 1 H), 6.64 (dd, J = 3.5 and 2 Hz, 1 H), 3.03 (t, J. = 6.9 u.) ' a, and 6.0 Hz, 2 H), 1.81 (m, 1 H), 0.86 (d, J = 6.9 Hz, 6 H);
H
MS (ES): 525.43 HC
CH, 1H NMR
(DMSO-d6): 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 =
27g CiT3 26g 1-2 s\t3, 2 Hz, 1 H), 7.62 (dd, J -- 7.7 & 2 Hz, 1 H), 7.54 (m, 5 H), s 7.38 (s, 1 H), 7.15 (s, 1 H), 6.99 (d, J = 7.8 Hz, 1 H), 6.89 Iv (d, 3 = 6.8 Hz, 1 H), 2.97 (t, J -- 6.5 Hz, 2 H), 2.20 (s, 3 n ,-i H), 1.76 (m, 1 H), 0.8 (d, 6.8 Hz, 6 H); MS (ES): 555.67 cp o l= . ) C. if I
l= . ) ' 134 _ Cpd. 1 Starting Method -R -R' Analytical Data No. From Used 1H NMR (DMSO-d6): 6 13.95 (bs, 1 H), 8.99 (bs, 2 H), o t..) 8.79 (bs, 2 H), 8.65 (d, J = 5 Hz, 1 H), 8.43 (t, J = 6 Hz, 1 .6.
CH3 H), 8.25 (s, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.00 (d, J = --.1 I .\-C1-1, 26h 1-2 7.8 Hz, 1 H), 7.94 (s, 1 H), 7.87 (t, .1-- 7.8 Hz, 1 H), 7.58 27h (m, 5 H), 7.34 (dd, J = 7.8 & 5 Hz, 1 H), 7.09 (dd, J = 7.7 -..z...... _...---..õ
N' 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 (ES+): 268.64 (m/2) 111 NMR (DMSO-d6): 6 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 CH3 (t, J --5.6 Hz, 1 H), 8.2 (dt, J - 1.8 & 7.7 Hz, 1 H), 7.99 n 1 CH3 261 1-2 (d, 3 =2.1 Hz, 1 H), 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 I.) a, I.) N Hz, 1 H), 7.15 (d, J = 7.7 Hz, 1 H), 6.95 (d, J = 7.7 Hz, 1 (5) a, vi H), 3.08 (t, J = 5 Hz, 2 H), 1.82 (m, 1 H), 0.9 (d, 6.8 Hz, 6 u.) H); MS (ESI): 268.85 (m1 2) I.) 1H NMR (DMSO-d6): 6 14.19(s, 1 H), 9.06 (bs, 2 H), u.) cH3 8.67 (bs, 2 H), 8.67 (d, J = 6 Hz, 2 H), 8.50 (t, J =
6 Hz, 1 0 a, 1 H), 7.97 (m, 2 H), 7.91 (dd, J = 7.7 and 2 Hz, 1 H), 7.80 H
27j i CH3 26j 1-2 (d, J = 6 Hz, 2 H), 7.64 (m, 6 H), 7.18 (d, J = 7.7 Hz, 1 -A
N 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 (ES+):
536.43 111 NMR (DMSO-d6): 6 9.04 (bs, 2 H), 8.78 (bs, 2 H), H3C = jli 3 8.55 (t, J
= 6 Hz, 1 H), 8.1 (s, 1 H), 7.98 (d, J = 4 Hz, 1 27k 26k 1-2 H), 7.95 (s, 1 H), 7.87 (d, J = 7.9 Hz, 1 H), 7.75 (d, J =
1-d n S CH3 6.9 Hz, 1 H), 7.66 (in, 4 H), 7.2 (m, 2 H), 7.09 (s, 1 H), 0 3.03 (t, J
= 6 Hz, 2 H), 2.55 (s, 3 H), 1.81 (m, 1 H), 0.85 cp (d, J = 6.8 Hz, 6 H); MS (ES): 583.59 o i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used 1H NMR (DMSO-d6): 8 9.1 (s, 2 H), 8.84 (s, 2 H), 8.56 (t, o t..) -\------- CH, \L-CH, 261 1-2 J = 6 Hz, 1 H), 8.08 (bs, 1 H), 7.67 (m, J = 7 H), 7.58 (d, J
= 7.9 Hz, 1 H), 7.11 (m, 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, .6.
N
1 2 H), 1.83 (m, 1 H), 0.88 (d, J = 6.8 Hz, 6 H); MS (ES):
cH3 538.64 )1H NMR (DMSO-d6): 8 9.04 (s, 2 H), 8.94 (s, 2 H), 8.46 CH, (t, J = 6 Hz, 1 H), 7.96 (s, 1 H), 7.63 (m, 6 H), 6.94 (s, 1 I N CH3 26m 1-2 H), 6.83 (d, J = 7.7 Hz, 1 H), 6.7 (d, J = 2, 1 H), 6.62 (dd, 27m 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,1H), 0.82 (d, 6.8 Hz, 6 H);
MS (ES): 528.76 I.) a, I.) 1-(5) CH, 1H NMR (DMSO-d6): 8 13.96 (s, 1 H), 9.02 (s, 2 H), 8.85 a, o, (s, 2 H), 8.46 (t, I = 6 Hz, 1 H), 7.91 (s, 1 H), 7.58 (m, 4 u.) --.,õ..--C11.2 CH, H), 7.39 (s, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 6.92 (d, I
27n 26n 1-2 7.7, 1 H), 6.87 (d, J = 7.7 Hz, 1 H), 6.01 (m, 1 H), 5.17 (d, 0 CA
J = 16.7 Hz, 1 H), 5.08 (d, J = 10 Hz, 1 H), 3.45 (d, J = 6 a, Hz, 211), 2.99 (t, J = 6 Hz, 2 H), 1.78 (m, 1 H), 0.83 (d, J
H
= 6.8 Hz, 611); MS (ES): 499.3 -A
111 NMR (DMSO-d6): 8 14.08 (bs, 1 H), 9.06 (s, 2 H), "
CH, 8.79 (s, 2 H), 8.51 (t, J = 6 Hz, 1 H), 8.11 (d, J = 2 Hz, 1 ,77 CH, 26o 1-2 H), 8.01 (m, 3 H), 7.85 (d, J = 3 Hz, 1 H), 7.63 (m, 6 H), 27o N
S
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, 211), 1.81 (m, 1 H), 0.86 (d, 6.8 Hz, 6 H);
MS (ES+): 542.2) 1-d n ,-i cp =
t..) u, oe .
t..) Cpd. Starting _ Method -R -R' Analytical Data No. From Used 1H NMR (DMSO-d6): 69.1 and 9.2 (2 br s, 4H, NH
o CH, proton), 8.6 (m, 1 H), 8.3 (m, 1 H), 8.0-7.6 (in, 8 H, t..) c.:.) 27p /7-:-TN CH, 26p 1-2 aromatic proton), 7.3 (m, 211), 3.1 (t, 2 H), 2.2 (s, 3 H), .6.
CH, 1.8 (m, 1 H), 0.9 (2s, 6 H); IR (K.Br Pellets) 2957, 1676, 1-1480, 1324, 844 cm-1. MS (ES+) : 497 11-1NMR (DMSO-d6): 5 9.06 (s, 2 H), 8.77 (s, 2 H), 8.53 ,- N/CH3 cH3 (t, J - 6 Hz, 1 H), 8.03 (n, 1 H), 7.64 (m, 6 H), 7.46 (d, J
26q 1-2 = 6.9 Hz, 1 H), 7.05 (s, 2 H), 6.96 (s, 1 H), 5.52 (s, 1 H), 27q H3C OH
= 3.02 (t, J = 6.8 Hz, 211), 1.81 (m, 1 H), 1.48 (s, 6 H),0.85 (d, .1= 6.8 Hz, 6 H); MS (ES): 539.4 111NMR (DMSO-d6): 5 9.06 (s, 2 H), 8.78 (s, 2 H), 8.52 n CH3 (t, J -----6 Hz, 1 H), 8.01 (d, J = 6.8 Hz, 1 H), 7.62 (m, 7 H), .-',,..., OH
7.46 (d, J = 6.8 Hz, 1 H), 7.0 (m, 211), 4.94 (t, J = 6 Hz, 1 I.) a, 27r NCH- 26r 1-2I.) H), 3.60 (q, J = 6 & 12.8 Hz, 2 H), 3.01 (t, J. = 6 Hz, 2 1-1), (5) 1-a, 2.58 (t, J = 6 Hz, 2 H), 1.82 (m, 1 H), 0.85 (d, I = 6.8 Hz, u.) 611); MS (ES): 525.4 I.) 11-1NMR (DMSO-d6): 8 9.01 (s, 2 H), 8.88 (s, 2 H), 8.5 (t, u.) CH, I = 6 Hz, 1 H), 8.07 (In, 1 H), 7.73 (m, 1 H), 7.63 (in, 7 a, H), 7.11 (d, J = 17 Hz, 1 H), 7.01 (d, J. = 17 Hz, 1 H), 6.97 H
27s 26s 1-2 -A
CH, CH, (n, 1 H), 6.69 (d, J = 17 Hz, 1 H), 5.24 (s, 111), 5.14 (s, 111), 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): 525.4 ziCH2 27t 0-1 1H NMR (DMSO-d6): 8 9.08 (s, 2 H), 8.82 (s, 2 H), 8.53 ---4c . 3 26t (t, I =6 Hz, 1 H), 8.04 (n, 1 H), 7.67 (m, 7H), 7.04 (m, 2 1-2 H), 5.55 (s, 1H), 5.20 (s, 11-1), 3.04 (t, J = 6.9 and 6.0 Hz, 1-d 1-i H); MS (ES+): 499.4 i cp o c.:.) t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used o t..) 1H NMR (DMSO-d6): 5 9.11 (s, 2 H), 8.86 (s, 2 H), 8.57 cH3 .6.
(t, J ---- 6 Hz, 1 H), 8.13 (m, 1 H), 7.53 (m, 2 H), 7.74 (m, 6 27u z-OH
'\CH3 26u 1-2 H), 7.37 (d, J = 7 Hz, 1 H), 7.17 (m, 2 H), 6.54 (d, J
= 12 1-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, 1 H), 0.87 (d, J
= 6.9 Hz, 6 H); MS (ES): 515.4 cH3 1H NMR
(DMSO-d6): 5 9.08 (s, 2 H), 8.82 (s, 2 H), 8.54 CH: (t, 3 = 6 Hz, 1 H), 8.05 (m, 1 H), 7.63 (m, 8 H), 7.06 (m, 2 27v õ....õ, -.,,.,,-"\C}13 26v 1-2 H), 5.52 (s, 1 H), 5.2 (s, 1 H), 4.63 (t, J =
5 Hz, 1 H), 3.56 n OH (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
I.) a, (ES): 529.4 I.) (5) 1H NMR (DMSO-d6): 5 9.08 (s, 2 H), 8.86 (s, 2 H), 8.54 I.) cH3 /=CH (t, J ---6 Hz, 1 H), 8.03 (m, 1 H), 7.62 (m, 7 H), 7.08 (d, J 0 u.) 27w 26w 1-2 = 7.5 Hz, 1 H), 6.99 (m, 1 H), 4.32 (s, 1 H), 3.03 (t, J = 1 '-ci-i3 a, 6.9 and 6.0 Hz, 2 H), 2.71 (t, J ----- 7 Hz, 2 H), 1.82 (m, 1 H
H), 0.87 (d, J = 6.9 Hz, 6 H); MS (ES): 483.3 -A
1H NMR (DMSO-d6): 5 13.8 (s, 1 H), 9.04 (s, 2 H), 8.96 CH3 (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 -.,/'-27x. ---C-K- cH3 .CH3 26x 1-2 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 1-d H), 1.72 (s, 3 H), 1.41 (s, 3 H), 0.84 (d, J = 6.9 Hz, 6 H);
n ,-i MS (ES): 527.5 cp o t..) vi oe t..) Cpd.Starting Method -R -R' Analytical Data No. From Used o o t..) 1H NMR (DMSO-d6): 5 8.99 (s, 2 H), 8.86 (s, 2 H), 8.52 CH, .6.
(t, J = 6 Hz, 1 H), 8.03 (m, 1 H), 7.63 (m, 6 H), 7.50 (d, J
26y 1-2 = 7 Hz, 1 H), 7.07 (d, J = 7 Hz, 1 H), 7.12 (in, 1 H), 5.40 1-(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 (m, 1 H), 0.84 (d, J = 6.9 Hz, 6 H); MS
(ES): 513.4 -, CH2 1H NMR
(DMSO-d6): 5 9.50 (bs, 1 H), 8.77 (bs, 2 H), cH3 8.49 (t, J
=6 Hz, 1 H), 7.98 (m, 1 H), 7.63 (n, 6 H), 7.55 Z N (d' J = 6.9 Hz, 1 H), 7.01 (d, J -- 7.9 Hz, 1 H), 6.99 (m, 1 0 ' 27z OH 26z 1-2 ' ''''-CH3 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), I.) a, I.) 1.81 (m, 1 H), 0.86 (d, J = 6.9 Hz, 6 H); MS (ES): 515.4 (5) a, o 0 IV
CH, 1H NMR
(DMSO-d6): 5 9.08 (a, 2 H), 8.73 (s, 2 H), 8.53 0 CA
(t, J ----- 6 Hz, 1 H), 8.06 (s, 1 H), 8.02 (bs, 1 H), 7.94 (d, J
' .
27aa '''''''CH3 26aa 1-2 = 7.8 Hz, 1 H), 7.62 (m, 6 H), 7.24 (d, J = 7.8 Hz, 1 H), a, H
6.95 (d, J = 7.8 Hz, 1 H), 3.03 (t, J = 6 Hz, 2 H), 1.82 (m, -A
1 H), 0.87 (d, J = 6.8 Hz, 6 H); MS (ES): 484.3 1H NMR (DMSO-d6): 5 9.05 (bs, 2 H), 8.81 (bs, 2 H), ,_....,_...-OH CH, 8.49 (t, J
= 6 Hz, 1 H), 8.02 (s, 1 H), 7.68 (s, 1 H), 7.62 27ab (m, 6 H), 7.53 (d, J = 6 Hz, 1 H), 7.21 (d, J. = 6 Hz, 1 H), \
'cH3 26ab 1-2 7.13 (d, J
= 7 Hz, 1 H), 7.01 (s, 1 H), 5.25 (t, J = 5 Hz, 1 1-d n S H), 4.51 (d, J = 5 Hz, 2 H), 3.01 (t, J = 6 Hz, 2 H), 1.81 (n, 1 H), 0.85 (d, J = 6.8 Hz, 6 H); MS (ES+): 571.64 cp o i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used o IHNMR (DMSO-d6): 5 9.05 (bs, 2 H), 8.78 (s, 2 H), 8.52 t..) c.:.) CH3 (t, J = 6 Hz, 1 H), 8.02 (bs, 1 H), 7.65 (m, 6 H), 7.53 (d, J .6.
= 5 Hz, 1 H), 7.54 (d, J =5 Hz, 1 H), 7.26 (d, J = 5 Hz, 1 OH
27ac S 26ac 1-2 H), 7.10 (m, 1 H), 6.99 (m, 1 H), 5.64 (t, J = 5 Hz, 1H), cH3 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 A .3 26ad 1-2 MS (ES: 585.4 n HO2c s 'CH3 I.) a, I.) 1-, (5) o u.) IHNMR (DMSO-d6): 8 14.11 (bs, 1 H), 9.05 (bs, 2 H), I.) CH, 8.75 (bs, 2 H), 8.5 (m, 1 H), 8.0 (s, 1 H), 7.8-7.6 (m, 8 H), 0 26ae 1-2 7.49 (d, J
= 3 Hz, 1 H), 7.1 (d, J = 6.9 Hz, 1 H), 7.0 (m, 1 L.I., 27ae HoH2c s CH3 H), 5.5 (m,1 H), 4.7 (m, 2 H), 3.09 (m, 2 H), 1.74 (m, 1 a, I
H
H) 0.86 (d, J = 6.9 Hz, 6 H); MS (ES+) 571.2 -.-1 ill NMR (DMSO-d6): 8 14.11 (bs, 1 H), 9.05 (bs, 2 H), HOH,C / 8.75 (bs, 2 H), 8.49 (t, J = 6 Hz, 1 H), 7.97 (s, 1 H), 7.67 , CH3 (d, J = 3 Hz, 1 H), 7.61 (m, 7 H), 7.54 (d, J = 3 Hz, 1 H), i 26af 1-2 7.06 (d, J
= 6.9 Hz, 1 H), 6.89 (d, J = 6.9 Hz, 1 H), 5.23 27af 1-d 'cli3 (t, J = 5 Hz, 1 H), 5.42 (d, J = 5 Hz, 2 H), 3.09 (t, J = 6.9 n s and 6.0 Hz, 211), 1.74 (m, 1 H) 0.86 (d, J = 6.9 Hz, 6 H);
MS (ES): 571.3 cp o c.:.) t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used o CH, 1H NMR
(DMSO-d6): 5 11.45 (s, 1 H), 9.08 (bs, 2 H), .6.
N.)*\ -------- 8.88 (bs, 2 H), 8.75 (t, J. = 6 Hz, 1 H), 8.04 (bs, 1 H), 7.88 --.1 ci=-i 26ag 1-2 3 (m, 1 H), 7.7 (m, 7 H), 7.03 (m, 2 H), 6.9 (m, 1 H), 6.62 27ag H (m, 1 H), 6.17 (m, 1 H), 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 (ES):
524.65 (DMSO-d6): 5 13.83 (s, 1 H), 8.9 (bs, 4 H), 8.47 CH, (t, J = 6 Hz, 1 H), 7.95 (s, 1 H), 5.3 (s, 1 H), 7.61 (m, 6 n .). OH H), 7.4 (m, 1 H), 6.95 (d, J = 7.7 Hz, 1 H), 6.85 (d, 1= 7.7 27ah Ci-1, 26ah 1-2 Hz, 1 H), 6.64 (d, J =9 Hz, 1 H), 6.22 (s, 1 H), 4.6 (t, J = 0 N
FP
1- 5.1 Hz, 1 H), 3.51 (d, J = 5.6 Hz, 2 H), 3.01 (t, J = 7 Hz, K) (5) .6.
a, 1- 2 H), 1.8 (m, 1 H), 0.85 (d, J = 6.9 Hz, 6 H); MS (ES): u.) 519.52 0I.) u.) CH, I
Fi.
27ai 1'43 26ai 1-2 MS (ES+) 514.25 H-,1 1H NMR (DMSO-d6): 5 9.05 (s, 2 H), 8.67 (s, 2 H), 8.47 CH:. (t, J = 6 and 5 Hz, 1 H), 7.95 (m, 1 H), 7.95 (m, 1 H), 7.63 CH3 (m, 5H), 7.40 (s, 1 H), 7.38 (d, J = 7.7 Hz, 1 H), 6.92 (m, 1-d 27aj 26n G
n cH3 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, cp J = 6.8 Hz, 6 H); MS (ES-) 499.31 i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used CH, 1H NMR (DMSO-d6): 5 14.3 (bs, 1 H), 9.05 (bs, 2 H), ./CH3 8.75 (bs, 2 H), 8.5 (m, 1 H), 8.0 (s, 1 H), 7.8-7.6 (m, 8 H), 27ak 32f G 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,1 H), 4.7 (m, 2 H), 3.09 (m, 2 H), 1.74 (m, 1 FE), 0.86 (d, J = 6.9 Hz, 6 H); MS (ES+) 487.2 CH, 27a1 N112 26ai G MS (ES+) 488.3 (100%:
M+1) CH3 1H N1VIR. (DMSO-d6): 5 13.9 (bs, 1 H), 9.05 (2 bs, 4 H), 8.5 (m, 1 H), 7.9 (s, 1 H), 7.7-7.5 (m, 8 H), 7.3 (d, I = 3 (5) 27am CH3 26u G Hz, 1 H), 6.9 (m, 2 H), 4.6 (m, 1H), 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 1H NMR (DMSO-d6): 5 9.84 (bs, 1 H), 9.07 (bs, 2 H), 0 CH3 8.87 (bs, 2 H), 8.51 (t, J = 6 and 5 Hz, 1H), 8.13 (m, 1 32a 31a 1-2 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 1-d cH3 32b 31b 1-2 Characterized in the next step oe Cpd. -R -R' Starting Method Analytical Data No. From Used o t..) 1H NMR (DMSO-d6): 8 14.24 (s, 1 H), 9.29 (bs, 2 H), .6.
CH, 9.01 (bs, 2 H), 8.73 (t, J --- 6 Hz, 1 H), 8.2 (d, J = 2 Hz, 1 --.1 .,,-----,..,v.CH2 H), 7.85 (m, 5 H), 7.74 (d, 2 Hz, 1 H), 7.4 (d, J = 8 Hz, 1 1-32c .C1.13 31e 1-2 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 CH3 31d 1-2 MS (ES") :
553.3 S
n CH, _ I.) a, I.) (5) 1-, a, .6. 1HNMR (DMSO-d6): 8 13.642 (bs, 1 H), 9.06 2 H), u.) CH, (s, 0 la .'-cii3 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), I.) 32e 31e 1-2 CA
I
0.86 (d, J = 6.8 Hz, 6 H); MS (ES): 547.4 a, I
H
-A
1H 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), cii, --CH, 31f 1-2 5.94 (d, J = 17 Hz, 1 H), 6.84 (dd, J. =
17 and 11 Hz, 2 H), 32f scH, 7.0 (m, 2 H), 7.64 (m, 8 H), 8.01 (s, 1 H), 8.54 (t, J =
Hz, 1 H), 8.77 (s, 2 H), 9.06 (s, 2 H); MS (ES+) :485.57 N,H2C /
IV
CH, n 32g \CH3 31g 1-2 MS (ES+) 596..2 cp =
t..) vi oe t..) , Cpd. Starting Method -R -R' Analytical Data k No. From Used o CH2OH CH, 1H NMR (DMSO-d6): 5 14.2 (bs, 1 H), 9.1 (bs, 4 H), 8.6 .6.
32h .,...s..._, -Cii, 31h 1-2 (m, 1 H), 8.15 (s, 1 H), 7.9-7.6 (m, 8 H), 7.2 (m, 2 H), 6.7 1--, 1--, (s, 1 H), 5.3 (br s, 1 H), 4.6 (m, 2 H), 3.1 (m, 2 H), 1.9 (m, 0 1 H), 0.9 (d, J = 6.7 Hz, 6 H); MS (ES+) 555.1 1H NMR (DMSO-d6): 5 13.84 (bs, I H), 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), H0H2C / CH37.95 (s, 1 H), 7.77 (s, 1 H), 7.67 (in, 2 H), 7.61 (m, 5 H), 32i 31i 1-2 7.02 (d, J = 7.7 Hz, 1 H), 6.94 (n, 1 H), 5.13 (t, I =5 Hz, \k -C1-13 1 H), 4.47 (m, 2 H), 2.97 (t, J = 6.8 Hz, 2 H), 1.78 (m, 1 n 0 H), 0.80 (d, 1 -- 6.8 Hz, 6 H); MS (ES-) 553.3, (ES+) 555.3 I.) a, CH
I.) 1--, 3 0, .6.
a, .6. 40 - NH 39 1-2 MS (ES+) 524.3 u.) -/ '-'Cii3 I.) 1H NMR (DMSO-d6): 5 13.82 (s, 1 H), 9.20 (bs, 1 H), u.) CH3 9.10 (bs, 1 H), 8.51 (t, 3 = 6 Hz, 1 H), 7.97 (s, 111), 7.73- H
a, \ 0 11 7.45 (m, 5 H), 7.43-7.39 (m, 2 H), 7.20 (t, J = 8 Hz, 1 H), 1 -A
CH3 7.10 (m, 6 H), 6.96 (d, J = 8 Hz, 1 H), 3.0 (t, J = 6 Hz, H), 1.80 (m, 1 H), 0.68 (d, J = 6.8 Hz, 6 H); MS (ES) 551.30 CH, 1H NMR (DMSO-d6): 5 9.21 (2 bs, 2 H each, 4 H), 8.61 46 lik '-'CH3 45 1_2 (m, 1 H), 8.1 (s, 111), 7.8-7.4 (in, 10 H), 7.3 (s, 1 H), 7.2 1-d n (d, 1 =- 7 Hz, 1 H), 7.1 (m, 2 H), 5.2 (s, 2 H), 3.1 (m, 2 H), 1.8 (m, 1 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES) 565.27 cp o 1--, i-,.)--t..) vi oe t..) _ Cpd.Starting Method -R -R' Analytical Data No. From Used o o 111 NMR (CF3CO2D): 5 8.43 (s, 1 H), 8.01 (d, J = 7.5 Hz, t..) c.:.) .6.
1 H), 7.67 (q, J = 24 and 8.4 Hz, 411), 7.56 (d, J = 7.7 Hz, CH,1-, 51 50 1-2 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 111NMR (DMSO-d6): 5 14.00 (bs, 1 H), 8.52 (t, J. = 6 and T S CH, 5 Hz, 1 H), 7.98 (s, 1 H), 7.63 (m, 8 H), 7.07 (d, J = 7.7 - 53-/ 52 1-2 Hz, 1 H), 6.96 (d, J = 7.7 Hz, 1 H), 3.83 (s, 2 H), 3.02 (t, J
c11.3 = 6.8 Hz, 211), 1.81 (m, 1 H), 0.86 (d, J = 6.8 Hz, 611);
NH, MS (ES-) 568.1 11-1 NMR (DMSO-d5): 5 13.84 (br s, 1 H), 9.05 (s, 2 H), I.) I.) 1-, 8.94 (s, 2 H), 8.48 (t, J= 5.7 Hz, 1 H), 7.97 (d, J= 1.9 (5) .6.
vi CH, Hz, 1 H), 7.70 (m, 7 H), 7.00 (d, J= 7.9 Hz, 1 H), 6.92 (d 68a 1-2, S
, u.) -.....,..___,õõõ..cH3 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, .1= 10.9 Hz, 1 H), 70a N
CA
3.19 (m, 2 H), 1.46 (qui, J = 7.0 Hz, 2 H), 1.29 (sex, J=
7.0 Hz, 2 H), 0.87 (t, J= 7.3 Hz, 3 H); MS (ES+): 485.2 , H
-A
111 NMR (DMSO-d6): 5 12.71 (br s, 1 H), 9.12 (s, 2 H), CH, 8.93 (s, 2 H), 8.20 (m, 2 H), 7.86 (m, 1 H), 7.70 (m, 6 H), 70b 68b 1-2, ' 7.20 (m 211), 6.87 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.99 ..., CH3 (d, J= 17.7 Hz, 1 H), 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, 611); MS
(ES ): 527.3 1-d n 1-i cp .
o ,-, t..) u, oe t..) 145 .
, Cpd. Starting Method -R -R' Analytical Data No. From Used o tµ.) 111 NMR (DMSO-d6): 8 12:84 (br s, 1 H), 9.08 (m, 3 H), '(;) 4=, 8.36 (d, .1= 7.7 Hz, 1 H), 8.18 (s, 1 H), 7.83 (m, 1 H), 70c CIH, -0 68c 1-2, S
7.67 (m, 6 H), 7.15 (m, 3 H), 6.86 (dd, J= 10.9 and 17.7 1-.. 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 (ES): 511.3 1H NMR (DMSO-d6): 69.11 (s, 2 H), 8.89 (s, 2 H), 8.81 I (t, J= 5.7 Hz, 1 H), 8.21 (s, 1 H), 7.85 (m, 1 H), 7.68 (m, CH, 70d ..,, CH2 68d 1-2, S 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 (m, 1 H), 5.39 (d, J= 10.9 Hz, 1 11), 5.12 (m, 2 H), 3.88 (t, J= 5.0 Hz, 1 H); MS
I.) (ES): 469.2 a, I.) c7, a, .6.
u.) c7, 1H NMR
(DMSO-d6): 5 9.11 (s, 2 H), 9.01 (s, 2 H), 8.38 0 70e N,cõ..CH, (d, J= 7.5 Hz, 1 H), 8.18 (s, 1 H), 7.83 (m, 1 H), 7.67 (m, I.) CIH, 68e 1-2, S
6 H), 7.16 (m, 3 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 0 CH, 5.98 (d, J= 17.7 Hz, 1 H), 5.39 (d, J--- 10.9 Hz, 1 H), u.) I
4.09 (m, 1 H), 1.15 (d, J= 6.6 Hz, 6 H); MS (ES): 471.3 a, I
H
--.1 1H NMR (DMSO-d6): 69.11 (s, 2 H), 9.05 (s, 2 H), 8.31 CH,I
<H (d, J= 8.1 Hz, 1 H), 8.20 (s, 1 H), 7.85 (d, J= 7.7 Hz, 1 H), 7.69 (m, 6 H), 7.17 (m, 3 H), 6.86 (dd, .1.--=- 10.9 and 70f --, ________________ CH3 68f 1-2, S
17.7 Hz, 1 H), 5.98 (d, J= 17.7 Hz, 1 H), 5.39 (d, J=
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= 7.3 Hz, 3 H); MS (ES): 485.3 1-lo n ,-i cp =
l=.) Cif I
l=.) _______________________________________________________________________________ ____________________________ -, Cpd. Starting Method -R -R' Analytical Data No. From Used o 11-1 NMR (DMSO-d6): 8 12.82 (br s, 1 H), 9.25 (m, 1 H), t..) c.:.) CH2 9.12 (s, 2 H), 8.91 (s, 2 H), 8.23 (s, 1 H), 7.87 (m, 1 H), .6.
70g I CF, 68g 1-2, S
7.68 (m, 7 H), 7.18 (m, 3 H), 6.87 (dd, J= 10.9 and 17.7 --4 Hz, 1 H), 5.99 (d, J= 17.7 Hz, 1 H), 5.40 (d, J= 10.9 Hz, 9140z5, 2 H), 7.09 H); MS (ES+):
' , __=((11Hs ,H1,NmR17).,H74)H.,)0;77(:D7(1m1mH,(sm)(2,0,H5-1.d)31;69)MH:
()IS,17(JE0.3=.S34+41)(0:t(,:59.1,1Hz1=1}{.27:81, (m, 4 H) 8.18 70h --. 68h 1-2 S m 3 H
6.86 dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J
505.3 n 11-1 NMR (DMSO-d6): 8 12.64 (br s, 1 H), 9.09 (m, 4 H), I.) a, c/H2 8.56 (m, 1 H), 8.09 (s, 1 H), 7.66 (m, 9 H), 7.08 (m, 3 H), N) OH
1-, .iT
.6. 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.96 (d, J= 17.7 Hz, u.) --4 70i -,,. 68i 1-2, S
1 H), 5.37 (d, J= 10.9 Hz, 1 H), 4.40 (m, 2 H) 3.39 (m, 2 I.) H), 3.22 (m, 2 H), 1.48 (m, 4 H); MS (ES): 501.3 (100%:
1\4+1) LO
I
FP
11-1 NMR (DMSO-d6): 8 9.08 (m, 4 H), 8.69 (t, J=. 6.0 Hz, H
CH, 1 H), 8.16 (s, 1 H), 7.69 (m, 5 H), 7.13 (d, J-- 7.7 Hz, 2 --1 70j 68j 1-2, S H), 7.09 (m, 3 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.97 (d, J= 17.7 Hz, 1 H), 5.38 (d, .1= 10.9 Hz, 1 H), 3.11 (t, J= 6.0 Hz, 2 H), 1.01 (m, 1 H), 0.41 (m, 2 H), 0.21 (m, 2 H); MS (ES+): 483.3 CH, . 11-1 NMR
(DMSO-d6): 8 9.11 (s, 2 H), 8.97 (s, 2 H), 8.54 70k (m, 1 H), 8.12 (s, 1 H), 7.68 (m, 7 H), 7.17 (m, 4 H), 6.86 1-d -,, c113 68k 1-2, S
(dd, J= 10.9 and 17.7 Hz, 1 H), 5.97 (d, J= 17.7 Hz, 1 n ,-i H), 5.38 (d, J= 10.9 Hz, 1 H), 2.75 (d, J=4.3 Hz, 1 H);
MS (ES ): 443.26 cp o c.:.) t..) vi oe t..) Cpd.Starting Method -R -R' Analytical Data No. From Used o t..) 1H NMR (DMS0415): 5 9.07 (s, 2 H), 8.92 (s, 2 H), 8.53 .6.
(t, J= 5.5 Hz, 1 H), 8.02 (s, 1 H), 7.62 (m, 7 H), 7.01 (m, --.1 701 T2 ..,, CH3 681 1-2, S
2 H), 6.85 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.95 (d, J--= 1-.õ,. 17.7 Hz, 1 H), 5.36 (d, J= 10.9 Hz, 1 H), 3.24 (qui, J=
6.7 Hz, 2 H), 1.08 (t, J= 7.2 Hz, 3 H); MS (ES+): 457.2 1H NMR (DMSO-d6): 5 12.53 (br s, 1 H), 9.10 (m, 3 H), - 70m CIH2 -CD 8.38 (d, J= 7.9 Hz, 1 H), 8.11 (s, 1 H), 7.68 (m, 7 H), 68m 1-2, S 7.12 (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), 3.94 (m, 1 H), 1.88-1.33 (m, 12 H); MS (ES4): 525.3 n 1H NIVIR (DMSO-do): 8 9.09 (tn, 4 H), 8.59 (t, J= 5.2 Hz, I.) 1 H), 8.17 (s, 1 H), 7.70 (m, 7 H), 7.16 (m, 4 H), 6.87 a, CH, "
--,,.Cli, (dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J= 17.7 Hz, 1 (5) .6. 70n 11 68n 1-2, S
a, u.) oe H), 5.39 (d, J= 10.9 Hz, 1 H), 3.20 (q, J= 6.7 Hz, 2 H), 0 1.52 (sex, J= 7.2 Hz, 2 H), 0.87 (t, J= 7.3 Hz, 3 H); MS
"
(ES): 471.3 CA
I
(DMSO-do): 8 12.97 (br s, 1 H), 9.08 (s, 2 H), a, -8.99 (s, 2 H), 8.53 (t, J= 5.1 Hz, 1 H), 8.06 (s, 1 H), 7.64 (m, 7 H), 7.06 (m, 2 H), 6.85 (dd, J= 10.9 and 17.7 Hz, 1 IL
,1 70o .µ 68o 1-2, S
H), 5.96 (d, J= 17.7 Hz, 1 H), 5.36 (d, J= 10.9 Hz, 1 H), 3.20 (q, J= 6.5 Hz, 2 H), 1.49 (qui, J= 6.6 Hz, 2 H), 1.27 (m, 4 H), 0.86 (t, J= 6.6 Hz, 3 H); MS (ES): 499.3 1H NMR (DMSO-do): 8 9.10 (s, 2 H), 8.91 (s, 2 H), 8.55 CI
H2 .,.CCH3 (t, J= 5.5 Hz, 1 H), 8.13 (s, 1 H), 7.68 (m, 711), 7.12 (m, 1-d CH, 1-2, 2 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J= n ,-i 70p === 68p S
17.7 Hz, 1 H), 5.38 (d, J= 10.9 Hz, 1 H), 3.10 (m, 211), cp 1.62(m, 1 H), 1.39(m, 1 H), 1.10(m, 1 H), 0.86 (m, 6 H); MS (ES ): 499.3 t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used o t..) CH2 1H NMR (DMSO-d6): 69.06 (s, 2 H), 8.82 (s, 2 H), 8.11 I CH, (t, .1= 7.9 Hz, 1 H), 8.00 (s, 1 H), 7.62 (m, 7 H), 6.99 (m, .6.
--.1 -, 2 H), 6.85 (dd, J.=-. 10.9 and 17.7 Hz, 1 H), 5.95 (d, J= 1-70q 68q 1-2, S
-CH, 17.7 Hz, 1 H), 5.35 (d, J= 10.9 Hz, 1 H), 3.81 (q, J= 7.5 Hz, 1 H), 1.45 (m, 4 H), 1.24 (m, 4 H), 0.82 (m, 6 H);
MS (ES): 527.3 _ 0-12 1H NMR (DMSO-d6): 5 13.81 (s, 1 H), 8.44 (m, 4 H), 70r l is1}{2 68r 1-2, S
7.97 (s, 1 H), 7.61 (m, 7 H), 6.90 (m, 3 H), 5.93 (d, J=
.,, 17.7 Hz, 1 H), 5.34 (d, J= 10.9 Hz, 1 H), 3.22 (m, 5 H), n 2.73 (m, 2 H), 1.52 (m, 4 H); MS (ES): 500.3 -I \ ) FP
1H NMR (DMSO-d6): 5 9.09 (s, 2 H), 8.86 (s, 2 H), 8.42 I.) (5) 1- cH2 a, .6. (d, J-----.
7.5 Hz, 1 H), 8.11 (s, 1 H), 7.68 (m, 8 H), 7.10 (m, u.) o 70s -0 68s 1-2, S 2 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.97 (d, .1-.-L) 17.7 Hz, 1 H), 5.38 (d, J= 10.9 Hz, 1 H), 4.20 (q, J= 7.2 \) \
Hz, 1 H), 1.93-1.44 (m, 8 H); MS (ES): 497.2 u.) FP
I
1H NMR (DMSO-d6): 5 13.78 (br s, 1 H), 9.07 (s, 2 H), H
-.-1 70t 68t 1-2, S
.1 8.87 (s, 2 H), 8.25 (d, = 8.1 Hz, 1 H), 8.00 (s, 1 H), 7.62 I,L, (m, 7 H), 6.98 (m, 2 H), 6.85 (dd, J=
10.9 and 17.7 Hz, 1 H), 5.94 (d, J= 17.7 Hz, 1 H), 5.35 (d, J= 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 (ES): 527.2 cH2 51794NMR0, j(=DM17S.70H-dz6,)1:
5H1),35.3.365(bor,s J., 1,1: 11)0,.99.H05z,(m1 H, 3),H), 1-d I
n 8.49 (s, 1 H), 7.98 (s, 1 H), 7.61 (m, 8 H), 6.92 (m, 3 H), 70u 68u 1-2, S
cp o 2.81 (m, 1 H), 0.69-0.48 (m, 4 H); MS (ES): 469.3 t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used 11-1NMR (DMSO-d6): 8 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, 70v Cr, 68v 1-2, S 2 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 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 1H NMR (DMSO-d6): 8 13.17 (br s, 1 H), 9.05 (m, 4 H), CI
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
70w 68w 1-2, S
= 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 11-1NMR (DMSO-d6): 8 9.07 (s, 2 H), 8.90 (s, 2H), 8.50 (5) CH, (t, J = 5.5 Hz, 1 H), 8.04 (s, 1 H), 7.63 (m, 7 H), 7.03 (m, cH3 2 H), 6.85 (dd, J = 10.9 and 17.7 Hz, 1 H), 5.96 (d, 0 70x 68x 1-2, S
17.7 Hz, 1 H), 5.36 (d, J= 10.9 Hz, 1 H), 3.23 (q, J= 6.5 Hz, 2 H), 1.59 (m, J= 7.0 Hz, 1 H), 1.39 (q, J= 6.8 Hz, 2 H), 0.88 (d, J= 6.6 Hz, 6 H).
=
oe NH
o 0 40 NH, n.) W."
.6.
R
le N
H
1-, 1-, OH 1.4 = H3CO2C
Cpd. Starting Method 1 -R
Analytical Data No. ____________________________ From Used IHNMR. (DMSO-d6): 8 10.85 (s, 1 H), 9.21(s, 2 H), 8.91 (s, 2 H), 8.71 (t, J =
5.9 o 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 I.) 31a ..'LC1-1, 30a J 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), a, "
(5) a, 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), u.) 1.86 (m, 1 H), 3.88 (d, 6.87 Hz, 6H); MS (ES+) 515.3 I.) 31b .-''' .µ--c}13 30b J
MS (ES): 527.2 u.) a, H
31c./.--\,/-- CH2 30c J Characterized in the next step -A
IHNMR (DMSO-d6): 8 10.59 (bs, 1 H), 9.16 (s, 2 H), 8.85 (s, 2 H), 8.69 (t, J =
31d_______ 30d J 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), s 3.55 (s, 2 H), 3.07 (t, J = 6.8 Hz, 2 H), 1.85 (m, 1 H), 0.87 (d, J = 6.8 Hz, 6 H),;
MS (ES-) 567.3, (ES+) 569.3 1-d n ,-i 31e IO 30e J MS (ES): 561.4; MS (ES):
563.4 cp o i-4.)--t..) vi oe t..) Cpd. Starting Method -R
Analytical Data No. From Used o 11-1 NMR (DMSO-d6): 8 10.73 (s, 1H), 9.24 (s, 2H), 9.00 (s, 2H), 8.71 (t, J =
5.7 t..) Hz, 1H), 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.05 (dd, J = 8.0, 1.9 Hz, 1H), 7.77 (m, 5H), .6.
--.1 31f ----CH2 30f J 7.71 (dd, J = 7.9, 1.5 Hz, 1H), 7.42 (d, J =7.9 Hz, 1H),7.31 (d, J = 7.9 Hz, 1H), 1-6.89 (dd, J = 17.6, 11.0 Hz, 1H), 6.04 (d, J =17.6 Hz, 1H), 5.42 (d, J = 11.0 Hz, 1H), 3.56 (s, 3H), 3.10 (t, J = 6.4 Hz, 2H), 1.85 (m, 1H), 0.89 (d, J = 6.7 Hz, 6H); MS (ES+): 499.3 1HNMR (DMSO-d6): 5 10.73 (s, 1 H), 9.19 (bs, 2 H), 8.88 (bs, 2 H), 8.71 (t, I
=
N3H2C / 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 31g i 30g J 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 s (t, I = 6.8 Hz, 2 H), 1.87 (m, 1 H), 0.92 (d, J = 6.8 Hz, 6 H); MS (ES-) 608.2, n (ES+) 610.3 I.) N) (5) a,.
t..) 31h 30h J Characterized at the next step 0 IV
LO
1HNMR. (DMSO-d6): 5 10.68 (s, 1 H), 9.17 (bs, 2 H), 8.82 (bs, 2 H), 8.68 (t, J
= 1 FP
6 Hz, 1 H), 8.25 (d, J. = 2 Hz, 1 H), 8.16 (d, J = 2 Hz, 1 H), 8.05 (dd, I = 8 and 2 1 H
30i J 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, 3= 5 Hz, 1 H), 4.54 (d, J. = 5 Hz, 2 --1 0 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 -o lip 42 J MS (ES): 563.4 1-d 45 -Obn 8 J Characterized in the next step n ,-i . .
cp 50 -OCH3 49 J MS (ES): 503.1 o i-,.)--t..) vi oe t..) Cpd. Starting Method -R Analytical Data No. From Used Iss 52 31g G Characterized in the next step 1.) 1`) (5) 1.) oe NH
o R' n.) W."
R si 4.
--.1 1-, N
1-, H
H
CO,CSI
11, _ 0 Cpd.Starting Method -R -R' Analytical Data No. From Used n 34 -0S02CF3 -H 33 J MS (ES): 621.2 I.) a, I.) (5) 1¨ 0 a, vi Lo 4,. 35 -0S02CF3 34 P MS (ES): 755.2;
(ES-) 753.3 0 OBn 1.) o o co i /
C 35 + 36 D-2 MS (ES): 828.5 ' H
OBn TIPS
, /
38 CN -H 37 G MS (ES): 694.4; (ES") 692.4 OH
IV
39 -H 38 Q Characterized in the next step n ,-i cp 1-, W."
n.) vi oe n.) R a R' o 11101 n.) .6.
--.1 1-, 1-, H3CO2C R" c.:.) , Cpd. Starting Method -R -R' -R"
Analytical Data No. From Used 1HNMR (DMSO-d6): 8 9.69 (s, 1 H), 8.49 (d, J= 2.0 Hz, 1 H), 8.22 (d, J= 6.9 Hz, 1 H), 7.53 (in, 4 H), 7.43 (m, 2 H), 7.37 (m, 2 H), 7.24 (d, 54 -0Bn -CHO -0O2MEM 5 + 6 D-2 J=
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, n J= 4.9 Hz 2 H), 3.32 (s, 3 H); MS (ES):
I.) 501.02 (M+Na)+
a, I.) 1-(5) vi 111 NMR (DMSO-d6): 8 12.65 (s, 1 H), 8.41 (d, a, vi u.) J2.0 Hz 1 H), 8.14 (dd, J---- 2.0 and 7.9 Hz, 1 H), 7.50(m, 3 H), 7.38(m, 4H), 7.24 (dd, J=
I.) 55 -0Bn -CO2H -0O2MEM 54 E 3.0 and 8.9 Hz, 1 H), 7.11 (d, J= 8.9 Hz, 1 H), 0 u.) 5.54 (s, 2 H), 5.20 (s, 2 H), 3.82 (t, J4.9 Hz, a, 2 H), 3.57 (s, 3 H), 3.49 (t, J=4.9 Hz, 2 H), , -,1 3.23 (s, 3 H); MS (ES): 493.2 1HNMR (DMSO-d6): 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, 1 H), 7.51 (d, J= 7.9 Hz, 2 H), 141 -0Bn -CHO 140 +6 D-2 7.45 (m, 2 H), 7.35 (m, 3 H),7.29 (d, J= 7.9-. --.NCH3 Hz, 1 H) 7.2 (d, J= 7.9 Hz, 1 H), 5.24 (s, 2 H), H
3.55 (s, 3 H), 2.3 (d, J= 6.9 Hz, 2 H) 2.1 (m, J 1-d = 6.9 Hz, 1 H), 1.0 (d, J= 6.9 Hz, 6 H); MS
n 1-i , (ES+): 446.31 cp .
o ,-, t..) u, oe t..) Cpd.
Starting Method -R -R' -R" Analytical Data No. From Used o 1H NMR (DMSO-d6): 6 12.38 (s, 1 H), 10.01 t..) (s, 1 H), 8.05 (s, 1 H), 7.68 (d, J= 7.9 Hz, 1 H), .6.
7.41 (d, J= 7.9 Hz, 2 H), 7.35 (m, 5 H), 7.27 1-, 1-, 142 -0Bn -CO2H 141 E (m, 1 H), 7.11 (d, J= 8.9 Hz, 1 H), 7.04 (d, J-o CH, 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, J= 6.9 3 Hz, 1 H), 0.852 (d, J= 6.9 Hz, 6 H); MS (ES-):
H
460.2 11-1NMR (DMSO-d6): 5 10.12(s, 1 H), 8.16 (d, J= 1.9 Hz, 1 H), 7.80 (dd, J= 1.9 and 8.3 o cH3 Hz, 1 H), 7.42 (m, 6 H), 7.26 (dd, J= 2.8 and n 8.3 Hz, 1 H), 7.13 (m, 2 H), 5.21 (s, 2 H), 5.17 143 -0Bn -0O2MEM --, ,-.. 142 F
N CH, (s, 2 H), 3.54 (s, 3 H), 3.40 (m, 2 H), 3.32 (m, 2 I.) H
H), 2.22 (d, J- 7.0 Hz, 211), 2.10 (m, 4H), a, I.) (5) 1-, vi 0.95 (d, .1= 6.4 Hz, 6H); MS (ES): 572.3 a, u.) c7, (M+Na)+
I.) 111 NMR (DMSO-d6): 8 12.7 (br s, 1 H), 9.09 O CH, (s, 2 H), 8.91 (s, 211), 8.57 (m, 1 H), 8.11 (s, 1 u.) , 144 -OH -0O2MEM ,, ...-,,,., 143 G H), 7.92 (d, J-- 1.9 Hz, 1 H), 7.81 (m, 3 H), a, 7.67 (m, 5 H), 7.14 (m, 311), 6.66 (m, 1 H), H
-,1 H
4.40 (t, J= 5.3 Hz, 1 H), 3.39 (m, 211), 3.22 (m, 2 H, 1.48 (m, 4 H) ; MS (ES"): 592.2.
O CH, .
145 -0S02CF3 -0O2MEM -, ,,,,,.". 144 B-2 MS (ES):, 592.2 , H
O CH, IV
n 146a ..\ -0O2MEM -,õ ..,--.L.,,,-. 145 D-2 MS
(ES: 532.5 (M+Na) N CH, cp o 1-, W."
n.) vi oe n.) Cpd. Starting Method -R -R' -R" Analytical Data No. _____________________________________________________ From Used o t..) Ili NMR (DMSO-d6): 5 10.1 (s, 1 H), 8.21 (d, .6.
J= 2.0 Hz, 1 H), 8.10 (d, J=2.0 Hz, 1 H), 7.89 O cH3 (dd, J=2.0 and 7.9 Hz, 1 H), 7.84 (d, J=3.0 and 8.9 Hz, 1 H), 7.63 (m, 2 H), 7.25 (d, J
H
=
146b -0O2MEM -i\I--- CH 3 145 D-2 7.9 Hz, 1 H), 7.19 (m, 2 H), 5.22 (d,J= 14.8 S Hz, 2 H), 3.57 (s, 3 H), 3.43 (t, J- 4.9 Hz, 2 H), 3.34 (t, J-- 4.9 Hz, 2 H), 3.20 (s, 3H), 2.23 (d, J= 6.9 Hz, 2 H), 2.11 (m, J= 6.9 Hz, 1 H), .
0.96 (d, J= 5.9 Hz, 6 H); MS (ES): 526.48 146c -CH=CH2 -0O2MEM -- j---..._,r--..CH3 145 D-3 MS (ES): 470.2 (WNW
N
I\) H
.i.
I\) (5) 1-, 0 CH, .i.
vi Lo --4 147a _- -CO2H146a I-1 MS (ES): 420.29 0 ',....., ,,.......".........
IV
H
_ Lo 11-1NMR (DMSO-d6): 5 12.65 (s, 1 H), 10.12 I
FP
0 CH3 (s, 1 H), 8.18 (d, J= 1.9 Hz, 1 H), 8.07 (d, J= I
H
147b -CO2H \ I-1 3.0 Hz, 1 H), 7.83 (m, 2 H), 7.61 (m, 2 H), 7.19 N 146b -,1 CH3 (m, 3 H), 3.56 (s, 3 H), 2.22 (d, J= 6.9 Hz, 2 S H H), 2.11 (m, J= 6.9 Hz, 1 H), 0.96 (d, J= 6.9 Hz, 6 H); MS (BS): 438.52 O CH, 147c -CH=CH2 -CO2H -- .,,,-- 146c I-1 MS (ES): 380.32 H
n ,-i cp =
i-,.,--t..) u, oe t..) Cpd. Starting Method -R -R' -R"
Analytical Data 0 No. From Used o 1H NMR (DMSO-d6): 8 9.70 (s, 1 H), 8.42 (t, t..) c.:.) CH, J=
6.2 Hz, 1 H), 7.90 (dd, J= 1.1 & 6.6 Hz, 1 .6.
--.1 H H), 7.82 (d, J= 1.9 Hz, 1 H), 7.72-7.50 (m, 3 1---, ,N
173 -H -CHO ---'-cii3 1/7320+ D-2 H), 7.34 (d, J= 7.7 Hz, 1 H), 7.27 (dd, J= 1.3 O
' &
6.2 Hz, 1 H), 4.38 (d, J= 6.0 Hz, 2 H), 3.53 (s, 3 H), 2.47 (m, 1 H)õ 1.07 (d, J= 7.0 Hz, 6 H); MS (ES ): 340.05 CH, 1H
NMR (DMSO-d6): 8 12.35 (br s, 1 H), 8.31 H (t, J= 7.5 Hz, 1 H), 7.80-7.31 (m, 5 H), 7.06 174 -H -CO2H '--,.2',1, 173 E (m, 2 H), 4.25 (d, J- 6.0 Hz, 2 H), 3.41 (s, 3 cH3 H), 2.37 (m, 1 H), 0.97 (d, J= 7.0 Hz, 6 H);
n 0 MS (ES): 353.83 0 1H NMR (DMSO-d6): 8 9.70 (s, 1 H), 7.87 (m, I.) .1,.
I.) 2 H), 7.69 (m, 1 H), 7.55 (in, 2 1-1), 7.35 (d, J=
(5) , 1-, a, 180 -H -CHO CH 179 +
D-2 7.9 Hz' 1 H), 7.27 (d, J= 7.5 Hz, 1 H), 4.51 (s, u.) H), 3.52 (s, 3 H), 3.05 (m, 2 H), 1.92 (m, 1 I.) CH3 H), 1.40 (m, 9 H), 0.85 (d, J= 6.8 Hz, 6 H); 0 ig u.) MS (ES): 448.3 (M+Na)+
.1,.
1H NMR (DMSO-d6): 8 7.81 (m, 2 H), 7.56 (m, H
H), 7.44 (m, 211), 7.16 (m, 211), 4.47 (s, 2 181 -H -CO2H 180 E H), 3.51 (s, 311), 3.02(m, 211), 1.92 (m, J.=--NCH, 7.0 Hz, 111), 1.41 (m, 9 H), 0.85 (d, J= 6 Hz, 6 H); MS (ES): 440.2 1H NMR (DMSO-d6): 89.78 (s, 1H), 8.85 (t, J
cH3 =
5.7 Hz, 111), 8.50 (d, J = 2.0 Hz, 1H), 8.20 H (dd J ---'- 8.2, 1.9 Hz 7., 9H), 5., 184a -0Bn -CHO '`_..1"1,--'"\, 3a + 6 D-2 ' ' " 1H)55 (m 35 (s 1-d 2H), 3.69 (s, 3H), 3.23 (t, J = 6.5 Hz, 211), 1.98 n (m, 111), 1.02 (d, J = 6.8 Hz, 611); MS (ES+):
446.3 cp o c.:.) t..) vi oe t..) Cpd. Starting Method -R -IV -R"
Analytical Data No. From Used o H
n.) 1"s1.-CF3 .6.
184b -0Bn -CHO 3f 6 D-2 MS
(ES): 470.2 --4 1-, 1-, H
,.,_,7NCH, 184c -0Bn -CHO 3i + 6 D-2 MS (ES): 418.3 _ CH, H
184d -0Bn -CHO ,.,..õ,--,,,.,õ,3j 6 (ES): 460.3 o 11INMR (DMSO-d6): 6 10.06 (s, 1 H), 9.63 (s, I.) a, H), 8.73 (t, J = 6.5 Hz, 1 H), 8.36 (d, J = 2 I.) (5) 1-, H Hz, 1 H), 8.09 (dd, J = 2 and 8 Hz, 1 H), 7.45 a, u.) vD
o 185a -OH -CHO --.' '-''CH, 184a AD (d, J = 8 Hz, 1 H), 7.28 (s, 1 H), 7.11 (s, 2 H), I.) 3.58 (s, 3 H), 3.13 (d, 3- = 7 Hz, 2 H), 1.87 (m, 1 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES-):
u.) , 354.2 and (ES) 378.2 (M+Na)) a, H
H
-,1 185b -OH -CHO 184b AD MS
(ES-): 380.1 0 _ H
1HNMR (DMSO-d6): 8 10.21 (s, 1 H), 9.78 (s, -,r.T=TCH, 1 H), 8.87 (t, J = 5.80 Hz, 1_H), 8.51 (s, 1 H), 185c -OH -CHO 184c AD
8.23 (d, J = 7.92 Hz, 1 H), 7.60 (d, J = 7.9 Hz, 0 1 H), 7.43 (s, 1 H), 7.25 (s, 2 H), 3.74 (s, 3 H), 1-d 3.46 (q, J = 5.65, 2 H), 1.32(t, J = 7.8 Hz, 3 H) n ,-i cp =
t..) u, oe t..) Cpd.Starting Method -R -R' -R"
Analytical Data No. From Used o IHNMR (DMSO-d6): 5 10.06 (s, 1 H), 9.62 (s, t..) i-,.)--H), 8.69 (t, J = 5.90 Hz, 1 H), 8.36 (s, 1 H), .6.
H .
1-, . -....,,,_õN........--....,....õ, CH, 8.08 (d, J = 7.92 Hz, 1 H), 7.45 (d, J = 8.1 Hz, 1-185d -OH -CHO 184d AD 1 H), 7.28 (s, 1 H), 7.10 (s, 2 14), 3.58 (s, 3 H), 3.22 (m, 1 H), 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).
_ H, 186a -0S02CF3 -CHO .--Nci13 185a B-2 MS
(ES): 488.24 H
1FINMR (DMSO-d6): 5 9.74 (s, 1 H), 9.44 (t, J 0 N
FP
\,,(1\1,CF3 .--5.90 Hz, 1 H), 8.51 (s, 1 H), 8.11 (d, J = 7.91 I.) 186b -0S02CF3 -CHO 185b B-2 (5) 1 4 4 H 418 2 H 359 Hz, H), 7.5 (m, ), . (m, ), . (s, a, c7, u.) o 0 311). 0 IV
1HNMR (DMSO-d6): 6 9.45 (s, 1 H), 8.59 (t, J
H -=
5.90 Hz, 1 H), 8.28 (s, 1 H), 7.94 (d, J = 8.10 u.), 186c -0S02CF3 -CHO -,,,..1\ICH, 185c B-2 Hz, 1 H), 7.79 (d, I = 2.8 Hz, 1 H), 7.67 (d, J = a, 7.9 Hz, .1 H), 7.32 (d, J = 7.9 Hz, 2 H), 3.40 (s, H
-.-1 H), 3.12 (q, J = 7.1 Hz, 211), 0.97 (t, J = 7.16 Hz, 3 H).
IHNMR (DMSO-d6): 5 9.71 (s, 1 H), 8.78 (t, J
oH3 =
5.90 Hz, 1 H), 8.49 (s, 1 H), 8.18 (d, J = 7.92 H
Hz, 1 H), 8.00 (s, 1 H), 7.88 (d, J = 8.51 Hz, 1 186d -0S02CF3 -CHO --..õ..r.N.,-...,,,........, CH3 185d B-2 H), 7.52 (q, J = 8.1 Hz, 211), 3.67 (s, 311), 3.22 o (m, 1 H), 3.16 (m, 1 H), 1.68 (m, 1 H), 1.44 (m, 1-d n 1 H), 1.18 (m, 1 H), 0.89(t, J = 6.4 Hz, 6 H).
cp o i-,.)--t..) vi oe t..) Cpd. -R -R" Starting Method Analytical Data No. From Used 1141\TMR. (DMSO-d6): 8 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, 1 H), 7.47 (d, J =
8 Hz, 1 H), 7.27 (d, J = 8 Hz, 1 H), 6.90 (dd, 187a -CH¨CH2 -CHO 186a D-3 = 11 and 17.7 Hz, 1 H), 6.01 (d, J = 17.7 Hz, 1 0 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 (BS) 388.2 (M+Na)+
187b -CH=CH2 -CHO 186b D-3 MS
(ES): 390.1 0 (5) c7, 187c -CH=CH2 -CHO 186c 0-3 MS
(ES): 336.2 CH, 187d -CH=CH2 -CHO
186d 0-3 MS
(ES): 378.2 =
oe NH
0 410 NBR' gal H,CO2C R"
Cpd. Starting Method -R -R' -R"
Analytical Data No. From Used 1H NMR (DMSO-d6): 6 10.67 (s, 1 H), 9.2 (s, 2 H), 8.87 (s, 2 H), 8.33 (d, J= 2.0 Hz, 1 H), 8.17 (dd, J= 2.0 and -7.9 Hz, 1 H), 7.77 (s, 4 H), 7.49 (m, 4 H), 7.39 (m, 2 H), 56 -0Bn -H -0O2MEM 55 7.30 (s, 2 H), 5.54 (s, 2 H), 5.27 (s, 2 H), 3.83 (t, J4.9 (5) Hz, 2 H); 3.57 (s, 3 H), 3.49 (t, J- 4.9 Hz, 2 H), 3.23 (s, c7, 3 H); MS (BS): 612.4 57 -0Bn -Boc -0O2MEM 56 R MS (BS):
712.4 0 1H NMR (DMSO-d6): 8 10.4 (s, 1 H), 10.0 (s, 1 H), 8.9 (s, 1H), 8.28 (d, J= 2.0 Hz, 1 H), 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 58 -OH -Boc -0O2MEM 57 Hz, 2 H), 7.45 (d, J= 7.7 Hz, 1 H), 7.13 (d, J= 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 1-d oe Cpd. Starting Method -R -R' -R" Analytical Data No. From Used 11-1NMR (DMSO-d6): 610.55 (s, 1 H), 8.38 (d, J.= 2.0 Hz, 1 H), 8.18 (dd, J= 2.0 and 7.9 Hz, 1 H), 7.86 (m, 4 59 -0S02CF3 -Boc -0O2MEM 58 B-2 H), 7.75 (dd, J= 2.0 and 8.9 Hz, 1 H), 7.54 (m, 5 H), 5.51 (s, 2 H), 3.77 (t, .1= 4.9 Hz, 2 H), 3.55 (s, 3 H), 3.46 (t, J= 4.9 Hz, 2 H), 3.18 (s, 3 H) 1.41 (s, 9 H); MS
_ (ES+): 754.3 1HNMR (DMSO-d6): 5 10.61 (s, 1 H), 8.94 (s, 1 H), 8.37 (s, 1 H), 8.19 (dd, J= 2.0 and 7.9 Hz, 1 H), 8.02 (s, 1 H), 7.89 (m, 5 H), 7.65 (d, J-= 8.9 Hz, 2 H), 7.54 (d, J
60 -Boc -0O2MEM 59 D-2 = 7.9 Hz, 1 H), 7.39 (d, J= 7.9 Hz, 1 H), 7.17 (d, J= 3.9 0 Hz, 1 H), 6.68 (m, 1 H), 5.54 (s, 2 H), 3.82 (t, J= 4.9 Hz, 2 H), 3.58 (s, 3 H), 3.49 (t, J= 4.9 Hz, 2 H), 3.22 (s, 3 H), 1.45 (s, 9 H); MS (ES): 672.5 1H NMR (DMSO-d6): 6 10.50 (s, 1 H), 8.96 (s, 1 H), (5) 8.32 (s, 1 H), 8.07 (d, J= 7.9 Hz, 1 H), 7.98 (s, 1 H), 61 -Boc -CO2H 60 I-1 7.87 (m, 5 H), 7.63 (d, J= 8.9 Hz, 2 H), 7.38 (m, 2 H), o 7.15 (d, J= 3.0 Hz, 1 H), 6.67 (m, 1 H), 3.57 (s, 3 H), 1.45 (s, 9H); MS (ES): 582.4 1HNMR (DMSO-d6): 6 10.56 (s, 1 H), 9.02 (br s, 1 H), 8.35 (d, J- 1.7 Hz, 1 H), 8.18 (dd, 1.9 and 6.0 Hz, 1 H), 7.88 (d, J= 9.0 Hz, 2 H), 7.80 (d, J= 1.3 Hz, 1 H), 7.71 (dd, J= 1.7 and 6.2 Hz, 1 H), 7.63 (d, J= 8.9 Hz, 2 66 -CH=CH2 -Boc -0O2MEM 59 D-3 H), 7.50 (d, J= 8.3 Hz, 1 H), 7.32 (d, J= 8.1 Hz, 1 H), 6.89 (dd, J= 10.7 and 17.7 Hz, 1 H), 6.04 (d, J= 17.4 Hz, 1 H), 5.54 (s, 2 H), 5.43 (d, J= 11.7 Hz, 1 H), 3.82 (t, J= 4.5 Hz, 2 H), 3.57 (s, 3 H), 3.48 (t, J=4.5 Hz, 2 H), 3.22 (s, 3 H), 1.44 (s, 9 H); MS (ES): 632.1 1-d oe Cpd. Starting Method -R -R' -R" Analytical Data No. From Used (DMSO-d6): 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, 2H), 7.66(m, 3H), 7.38 (d, J= 7 .7 67 -CH=CH2 -Boc -CO2H 66 I-1 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 (5) oe NH
13oc o n.) H
.6.
1-, 1-, 0 NHEZ!
RO,C
.
Cpd. _R
-R' Starting Method Analytical Data No. From Used n 1H NMR (DMSO-d6): 6 10.57 (s, 1 H), 8.92 (s, 1 H), 8.64 (t, J=
I.) 5.4 Hz, 1 H), 8.24 (d, J= 2.0 Hz, 1 H), 8.02 (dd, J= 2.0 and 7.9 a, I.) (5) o, Hz, 1 H), 7.98 (s, 1 H), 7.88 (m, 3 H) 7.84 (s, 1 H), 7.64 (d, J= a, vi u.) 62a -CH3 -,,,.,-cH3 61 A-4 8.9 Hz, 2 H), 7.42 (d, J= 7.9 Hz, 1 H), 7.36 (d, J=7.9 Hz, 1 H), 0 7.14 (d, J= 3.0 Hz, 1 H), 6.67 (m, 1 H), 3.55 (s, 3 H), 3.26 (m, 2 I.) H), 1.50 (m, J= 7.4 Hz, 2 H), 1.43 (s, 9 H), 1.32 (m, J= 7.4 Hz, u.) 2 H), 0.89 (t, 3 H); MS (ES"): 639.5 a, -H
-,1 Cli.3 62b -CH3 61 A-4 MS (ES):
625.5 ''.-CH2 62c -CH3 61 A-4 MS (ES):
623.4 =
62d -CH3 lel CH3 61 A-4 MS (ES):
687.4 1-d n ,-i cp I.., W.
N
N
Cpd. 41 -R' Starting Method Analytical Data o No. From Used o t.) -...,,,CH3 4= , 62e -CH3 61 A-4 MS (ES): 625.4 621 -CH3 ,3 61 A-4 MS (ES): 653.5 -_,,=-=õ,.CH3 62g -CH3 61 A-4 MS (ES): 653.5 n I.) a, I.) c7, o 62h -CH3 61 A-4 MS (ES): 667.3 a, c:
Lo I.) 62i -CH3 61 A-4 MS (ES): 681.5 Lo a, H
--J
62j -CH3 61 A-4 MS (ES): 637.3 OH
62k -CH3 61 A-4 MS (ES): 640.3 'CH3 n 1-i 621 -CH3 ¨0 61 A-4 MS (ES): 665.4 cp o l=.) -CA
l=.) Cpd.
Starting Method No. From Used Analytical Data 62m -CH3 CH3 61 A-4 MS (ES): 597.3 62n -CH3 61 A-4 MS (ES): 639.4 - 62o -CH3 10111 61 A-4 MS (ES): 695.4 (M+Na) 62p -CH3 61 A-4 MS (ES): 665.4 (5) 62q -CH3 WcH, 61 A-4 MS (ES): 653.4 cH3 62r -CH3 61 A-4 MS (ES): 567.3 62s -CH3 61 A-4 MS (ES): 667.5 62t -CH3 OH 61 A-4 MS (ES): 641.3 OH
62u -CH3 61 A-4 MS (ES): 655.3 oe Cpd. ..R
-R' Starting Method Analytical Data No. From Used o t..) 62v -CH3\ 61 A-4 MS (ES): 663.1 1¨
62w -CH3 61 A-4 MS (ES): 577.2 1¨
r\z N
"4---__V
62x -CH3 \/0 61 A-4 MS (ES): 679.2 n I.) a, I.) 62y -CH3 .,õ,--,,,.OH 61 A-4 MS (ES): 621.1 (5) 1¨
a, o Lo oe I.) 62z -CH3 -..,,0H3 61 A-4 MS (ES): 611.1 Lo a, OH
H
-,1 62 aa -CH3 -,,,,..,...OH 61 A-4 MS (ES): 657.1 62 ab -CH3 4. 61 A-4 MS (ES): 659.1 1-d n 62 ac -CH3 ¨61 A-4 MS (ES): 679.3 cp o 1¨
i-,.)--t..) vi oe t..) -Cpd.
-R' Starting Method Analytical Data No. From Used 62ad -CH3 61 A-4 MS (ES): 695.3 62ae -CH3 NHR, _N 61 A-4 MS (ES): 651.3 NHR' 62af -CH3 61 A-4 MS (ES): 679.4 (5) oe NH
o n.) c.:.) .6.
R is N
H
1-, 1-, 1101 NHR' _ _ Cpd. Starting Method .
-R -R' Analytical Data No.From Used _ _ n 1H NMR (DMSO-d6): 8 12.80 (s, 1 H), 9.09 (s, 2 H), CC( 8.91 (s, 2 H), 8.57 (m, 1 H), 8.15 (s, 1 H), 7.91 (s, 1 H), 0 IV
7.80 (m 3 H), 7.67 (m, 4 H), 7.20 (m, 2 H), 7.07 (s, 1 a, I.) 1- 64a - 62a I-2, S ' (5) --4 H), 6.63 (s, 1 H) 3.21 (m, J= 5.9 Hz, 2 H), 1.46 (m, J= a, o u.) 7.4 Hz, 2 H), 1.28 (m, J= 7.4 Hz, 2 H) 0.86 (t, J= 7.4 Hz, 3 H); MS (ES): 525.3 I.) CA
I
1H NMR (DMS0416): 8. 12.76 (s, 1 H), 9.10 (s, 2 H), a, Cc( CI-1, 8.82 (s, 2 H), 8.59 (m, 1 H), 8.20 (s, 1 H), 7.95 (s, 1 H), H
-A
64b - 62b 1-2, S 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, J= 7.4 Hz, 2 H), 0.87 (t, J= 7.4 Hz, 3 H); MS (ES): 511.2 1H NMR (DMSO-d6): 8 12.84 (s, 1 H), 9.11 (s, 2 H), CO
'-'-'.-"cH2 8.84 (m, 2 H), 8.26 (m, 1 H), 7.94 (m, 2 H), 7.83 (m, 64c __ 62e 1-2, S H), 7.71 (s, 4 H), 7.28 (m, 2 H), 7.12 (s, 1 H), 6.65 (s, 1 1-d n H), 5.87 (m, 1 H), 5.15 (d, J= 17.2 Hz, 1 H), 5.07 (d, J.=
10.3 Hz, 1 H) 3.88 (t, J= 5.2 Hz, 2 H); MS (ES): 509.2 cp o c.:.) t..) vi oe t..) _ Cpd. -R
-R' Starting Method Analytical Data No. From Used _ - 4111 CH, =
81H.85NMR(s, 2 (HD)M, 8S.202-d(s6,):1 6H1),27.7.983(s(,s,11H)H,),97.1.813(m,on,23HH),), 64d 62d 1-2, S
7.68 (s, 4 H), 7.19 (m, 3 H), 7.10 (m, 5 H), 6.65 (s, 1 H), .6.
--.1 1-.
1-.
4.41 (s, 2 H), 2.27 (s, 3 H); MS (ES): 573.3 1H NMR (DMSO-d6): 8 12.82 (s, 1 H), 9.11 (s, 2 1-1), 64e C7 0 -....,,,\.õ-CH3 8.86 (s, 2 H), 8.39 (d, J--- 7.7 Hz, 1 H), 8.24 (s, 1 H), .___Q 62e 1-2, S
7.95 (s, 1 H), 7.90 (m, 1 H), 7.84 (m, 2 H), 7.71 (s, 4 H), CH3 7.28 (m, 2 H), 7.11 (m, 1 H), 6.65 (s, 1 H), 4.08 (m, J=-6.9 Hz, 1 H), 1.14 (d, J= 6.9 Hz, 6 H); MS (ES): 511.3 o (DMSO-d6): 5 13.28 (br s, 1 H), 9.05 (m, 2 H), Co 8.84 (s, 2 H), 8.46 (m, 1 H), 7.99 (s, 1 H), 7.88 (s, 1 H), 0 I.) 64f - Q CH, 62f 1-2, S 7.77 (m, 2 H), 7.63 (m, 5 H), 7.07 (m, 2 H), 6.96 (m, 1 I.) (5) 1-.
--.1 H), 6.63 (s, 1 H), 3.16-2.96 (m, 2 H), 1.65-1.03 (m, 3 u.) 1-.
H), 0.85 (m, 6 H); MS (BS): 539.3 I.) 1H NMR (DMSO-d6): 5 13.37 (s, 1 H), 9.06 (s, 2 H), u.) 8.84 (s, 2 H), 8.47 (m, 1 H), 8.00 (s, 1 H), 7.88 (s, 1 H), a,.
64g -Q 62g 1-2, S 7.78 (m, 2 H), 7.70 (m, 5 H), 7.08 (m, 2 H), 6.97 (s, 1 1 H
-,1 CH3 H), 6.63 (s, 1 H), 3.22 (m, 2 H), 1.58 (m, .1= 6.0 Hz, 1 H), 1.38 (m, J= 6.9 Hz, 2 H), 0.87 (d, J= 6.9 Hz, 6H);
MS (ES): 539.3 1H NMR (DMSO-d6): 5 12.71 (br s, 1 H), 9.13 (s, 1 H), 8.75 (m, 3 H), 8.31 (m, 1 H), 7.97 (m, 2 H), 7.86 (m, 2 ,,,,C) 64h n H), 7.73 (m, 4 H), 7.64 (m, 2 H), 7.33 (m, 2 H), 7.13 (m, -- 0 62h 1-2, S
1 H), 6.67 (m, 1 H), 3.98 (m, 1 H), 3.77 (q, f= 6.9 Hz, 1 1-d n ,-i H), 3.62 (q, J= 6.9 Hz, 1 H), 3.29 (m, 2 H), 1.86 (m, 3 H), 1.59 (m, 1 H); MS (ES): 553.3 cp o 1-.
c.:.) t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used o t..) 1H NMR (DMSO-d6): 612.81 (br s, 1 H), 9.13 (s, 2H), .6.
64iC
8.85 (s, 2 H), 8.26 (m, 2 H), 7.96 (m, 2 H), 7.86 (m, 2 1-2, S H), 7.74 (m, 5 H), 7.32 (m, 1 H), 7.13 (m, 1 H), 6.67 (m, --4 CH, 1 H), 3.99 (m, 1 H), 1.5-0.85 (m, 14 H); MS (ES):
567.3 Ili NMR (DMSO-d6): 5 13.74 (br s, 1 H), 9.07 (s, 2 H), 8.92 (s, 2 H), 8.62 (t, J=5.6 Hz, 1 H), 8.03 (s, 1 H), 7.89 64j ( /.\.<
62j 1-2, S (d, J= 1.7 Hz, 1 H), 7.79 (m, 2 H), 7.64 (m, 4 H), 7.10 -Q (m, 3 H), 6.99 (d, J= 8.5 Hz, 1 H), 6.64 (m, 1 H), 3.08 (t, J= 6.0 Hz, 2 H), 1.00 (m, 1 H), 0.40 (m, 2 H), 0.20 n (m, 2 H); MS (ES): 523.4 _ I.) a, OH 'H NMR
(DMSO-d6): 8 9.12 (s, 2 H), 8.88 (s, 2 H), 8.52 I.) (5) Coa, t..) (m, 1 H), 8.12 (m, 1 H), 7.92 (m, 2 H), 7.81 (m, 3 H), 64k -Q -...,...õ...õ----..., CH, 62k 1-2, S 7.67 (m, 4 H), 7.14 (m, 3 H), 6.66 (m, 1 H), 4.75 (d, J= (8) I.) 4.5 Hz, 1 H), 3.77 (m, 1 H), 3.17 (m, 1 H), 1.04 (d, J=
LO
6.0 Hz, 3 H); MS (ES+): 527.2 FP
I
Ili NMR (DMSO-d6): 8 13.91 (br s, 1 H), 9.07 (s, 2 H), H
621 1-2, S
-,1 641 (-( -0 8.90 (s, 2 H), 8.29 (d, J= 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, J= 7.7 Hz 1 H), 6.64 (m, 1 H), 3.71 (in, 1 H), 1.82-1.03 (m, 10 H)p; MS (BS): 551.33 ill NMR (DMSO-d6): 8 13.87 (br s, 1 H), 9.07 (s, 2 H), Co 8.90 (s, 2 H), 8.48 (m, 1 H), 7.99 (s, 1 H), 7.89 (m, 1 H), 1-d 64m -Q -õ, 62m 1-2, S 7.79 (in, 2 H), 7.62 (m, 5 H), 7.10 (m, 2 H), 6.97 (d, J= n 1-i cH3 7.9 Hz 1 H), 6.64 (m, 1 H), 2.73 (d, J= 4.5 Hz, 3 H);
cp MS (ES): 483.2 c.:.) t..) vi oe t..) _ Cpd.Starting Method Analytical Data No. From Used .
o t..) 1H NMR (DMSO-d6): 5 9.08 (s, 2 H), 8.85 (s, 2 H), 8.26 .6.
C (3( CH, (d, J=
8.7 Hz, 1 H), 8.07 (s, 1 H), 7.91 (s, 1 H), 7.80 (m, --4 64n - 62n 1-2, S 2 H), 7.67 (m, 5 H), 7.09 (m, 3 H), 6.65 (m, 1 H), 3.89 1-CH3 (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+):
CC( lall (DMSO-d6): 8 9.19 (m, 2 H), 9.10 (s, 2 H), 58.852 114 NMR (s, 2 H), 8.19 (m, 1 H), 7.94 (s, 1 H), 7.83 (m, 2 H), 7.68 (m, 4 H), 7.33-7.10 (m, 8 H), 6.66 (m, 1 H), 4.45 n 64o 62o 1-2, S
(d, J=5.7 Hz, 2 Hz); MS (E5+): 559.2 I.) a,.
I.) (5) (DMSO-d6): 8 9.22 (m, 2 H), 9.09 (s, 2 H), u.) w 8.81 (s, 2 H), 8.17 (m, 1 H), 7.95 (s, 1 H), 7.82 (m, 2 H), 64p 1-2, S I.) H); MS (ES): 551.22 7.68 (m, 4 H), 7.16 (m, 4 H), 6.66 (m, 1 H), 4.06 (m, 2 -+
u.) a,.
H
-,1 1H NMR (DMSO-d6): 8 9.10 (s, 2 H), 8.86 (s, 2 H), 8.56 C:( (m, 1 H), 8.13 (m, 1 H), 7.93 (s, 1 H), 7.82 (m, 2 H), 64q ci-I3 62q 1-2, S 7.67 (m, 5 H), 7.15 (m, 3 H), 6.66 (rn, 1 H), 3.19 (rn, 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 1-d Cc( 1H NMR
(DMSO-d6): 8 9.09 (s, 2 H), 8.90 (m, 2 H), n ,-i 64r - CH, 62r 1-2, S 8.15 (m, 2 H), 7.93 (s, 1 H), 7.81 (m, 3 H), 7.68 (m, 4 cp H), 7.13 On, 3 H), 6.66 (m, 1 H), 3.83 (m, 1 H), 1.47 (m, CH, 1-, 4 H), 1.25 (m, 4 H), 0.83 (m, 6 H); MS (E8+): 567.3 t..) vi oe t..) , Cpd. ' Starting =' Method -R -Re Analytical Data No. From Used o 11-1 NMR (DMSO-d6): 5 9.08 (s, 2 H), 8.86 (s, 2 H), 8.48 t..) .6.
(m, 1 H), 8.03 (m, 1 H), 7.90 (s, 1 H), 7.79 (m, 2 H), 64s --.1 - -,,,,<cH, 62s 1-2, S 7.65 (m, 5 H), 7.12 (m, 2 H), 7.02 (m, 1 H), 6.65 (m, 1 1-cH3 cH3 H), 3.22 (m, 2 H), 1.42 (t, J= 8.2 Hz, 2 H), 0.91 (s, 9 H);
MS (ES): 553.4 111 NMR (DMSO-d6): 5 13.61 (br s, 1 H), 9.07 (s, 2 H), C:( 64t 62t 1-2, S 9.00 (s, 2 H), 8.52 (t, J= 5.5 Hz, 1 H), 8.02 (s, 1 H), 7.90 - /\.--OH (d, J= 1.9 Hz' 1 H), 7.79 (m, 2 H), 7.64 (m, 5 H), 7.10 (m, 2 H), 7.00 (d, J = 7.7 Hz, 1 H), 6.64 (m, 1 H), 4.47 (t, J= 5.3 Hz, 1 H), 3.43 (m, 2 H), 3.27 (m, 2 H), 1.64 n (qui, J= 6.8 Hz, 2H); MS (ES): 527.23 , I\) FP
C l( Ili NMR
(DMSO-d6): 5 12.7 (br s, 1 H), 9.09 (s, 2 H), I.) (5) a, --.1 8.91 (s, 2 H), 8.57 (m, 1 H), 8.11 (s, 1 H), 7.92 (d, J= u.) .6. -64u .,-,.,.,,..,,.=,,,OH 62u 1-2, S 1.9 Hz, 1 H), 7.81 (m, 3 H), 7.67 (m, 5 H), 7.14 (m, 2 I.) H), 6.66 (m, 1 H), 4.40 (t, J= 5.3 Hz, 1 H), 3.39 (m, 2 H), 3.22 (in, 2 H), 1.48 (m, 4 H); MS (ES): 541.34 u.) FP
I
'H NMR (DMSO-d6): 5 9.16-8.89 (m, 4 H), 8.16 (m, 1 H
C( \
-,1 64v 62v 1-2, S 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, 1 H), 6.26 (m, 1 H), 4.42 (d, J.= 4.9 Hz, 2 H); MS (ES): 549.27 11-1 NMR (DMSO-d6): 5 11.59 (br s, 1 H), 9.14 (s, 2 H), , N 8.98 (s, 2 H), 8.70 (t, J= 5.7 Hz, 1 H), 8.24 (s, 1 H), 7.99 64w - N.-1/ 62w 1-2, S (m, 2 H), 7.87 (m, 3 H), 7.71 (m, 3 H), 7.36 (s, 1 H), 1-d n 7.27 (m, 2 H), 7.10 (m, 2 H), 6.67 (m, 1 H), 4.07 (t, J=
6.9 Hz, 2 H), 3.24 (q, J= 6.5 Hz, 2 H), 1.98 (qui, J= 6.7 cp Hz, 2 H); MS (ES): 577.17 =
c.:.) t..) vi oe t..) Cpd. Starting Method -R -R.' Analytical Data No. From Used o t..) (3D.0M4 (t SO, J- 6.5 .: H13z.,722H(b)r, s1,.712H)-1.,493.1(m3 (, s6, 2H)H, ), .6.
C
9.06 (s, 2 H), 8.50 (t, J= 5.7 Hz, 1 H), 8.00 (d, J= 1.3 --.1 Hz, 1 H), 7.89 (d, Jr- 1.9 Hz, 1 H), 7.78 (m, 2 H), 7.62 64x 62x 1-2, S
- (lnimil:
NMR 41 HH)),, 7.08 (m, 2 H), 6.96 (d, J= 7.9 Hz, 1 H), 6.64 ( 1.25-1.08 (m, 3 H), 0.88 (m, 2 H); MS (ES): 565.25 1H NMR (DMSO-d6): 5 9.16-8.87 (m, 4 H), 8.09 (s, 1 C.C( H), 7.91 (s, 1 H), 7.80 (m, 2 H), 7.65 (m, 5 H), 7.12 (m, 64y -,,,.,, .,.,CH 62y 1-2, S
- 5 H), 6.65 (m, 1 H), 4.01 (m, 2 H), 3.10 (m, 1 H); MS
(ES): 507.2 I.) Cc( 1H NMR
(DMSO-d6): 5 9.10 (s, 2 H), 8.97 (s, 2 H), 8.59 a, I.) , (t, J=
5.7 Hz, 1 H), 8.13 (s, 1 H), 7.93 (s, 1 H), 7.80 (m, (5) a, u.) vi 64z 62z 1-2, S 3 H), 7.68 (m, 4H), 7.16 (m, 4H), 6.65 (m, 1 H), 3.26 0 (qui, J= 6.0 Hz, 2 H), 1.10 (t, J= 7.2 Hz, 3 H); MS
"
(ES): 497.2 CA
I
FP
I
C 0( OH 1H NMR
(DMSO-d6): 5 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), H
-.-1 64aa _ 62aa 1-2, S 7.79 (m' 3 H), 7.63 (m, 5 H), 7.09 (m, 2 H), 6.98 (m, 1 H), 6.65 (m, 1 H), 4.80 (d, J= 4.7 Hz, 1 H), 4.56 (t, J=
6.8 Hz, 1 H), 3.60 (m, 1 H), 3.32-2.90 (m, 3 H); MS
(ES): 543.2 Cc( 40 1H NMR
(DMSO-d6): 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 (m, 6 H), 64ab 62ab 1-2, S
7.66 (m, 4 H), 7.34 (m, 2 H), 7.11 (m, 4 H), 6.65 (m, 1 1-d n g c 4 . H); MS
(ES): 545.2 c.:.) .
t..) vi .
oe t..) Cpd. Starting Method -R = -R' Analytical Data No. From Used CC( -0 1H NMR
(DMSO-d6): 8 9.07 (m, 4 H), 8.38 (d, J= 8.5 Hz, 1 H), 8.10 (s, 1 H), 7.92 (s, 1 H), 7.84-7.62 (m, 7 H), o t..) i-,.)--12.6' 64ac 62ac 1-2, S
- 7.111(mH, )3; MS H), 6(.E6s): .3 6 (m5, 615H), 3.94 (m, 1 H), 1.88-1.35 (11, 2 1H NMR (DMSO-d6): 8 13.71 (m, 2 H), 9.36-8.57 (m, 4 (0 H), 8.50 (m, 1 H), 7.98 (s, 1 H), 7.89 (s, 1 H), 7.78 (2 64ad ______Q ____-.õ..õ,,,,,,,,,.õ,õõõOH
62ad 1-2, S 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 (m, 2 H), 2.16 (t, J= 7.2 Hz, 2 H), 1.48 (m, 4H), 1.28 (m, 2 H); MS (ES): 581.2 1H NMR (DMSO-d6): 8 9.12 (s, 2 H), 8.89 (s, 2 H), 7.91 n / (m, 1 H), 7.81 (m, 2 H), 7.70 (d, J= 8.7 Hz, 2 H), 7.62 0 C(. NHR = -N ) (d, J= 8.9 Hz, 2 H), 7.48 (m, 1 H), 7.22 (m, 2 H), 7.11 I.) a, 64ae 62ae 1-2, S
I.) (d, J= 3.4 Hz, 1 H), 7.05 (d, J= 7.2 Hz, 1 H), 6.65 (m, 1 (5) --,1 a, o H), 3.53 (m, 2 H), 3.08 (m, 2 H), 1.62-1.21 (m, 6 H); MS u.) (ES): 537.20 I.) u.) 1H NMR (DMSO-d6): 8 12.81 (br s, 1 H), 9.13 (s, 2 1-1), C0( 8.82 (s, 2 H), 7.95 (s, 1 H), 7.85 (m, 2 H), 7.71 (m, 5 H), a, 64af ,,.3 H
- 62af 1-2, S 7.43 (m, 1 H), 7.29 (m, 2 H), 7.13 (m, 1 H), 6.67 (m, 1 -A
NHR = -N\----A;7.
H), 3.49-2.97 (m, 4 H), 1.67-1.37 (m, 2 H), 1,08 (m, 1 H), 0.90 (m, 3 H), 0.61-0.26 (m, 4 H); MS (ES): 565.3 1-d n ,-i cp =
t..) u, oe t..) NH
=
n.) R c.:.) mat LW N NBR
H .6.
1-, 1-, 0 NHR' HO,C
Cpd. Starting Method -R -R' Analytical Data No. From Used CH3 111 NMR (DMSO-d6, D20): 5 13.87 (br s, 1 H), 9.56 (m, 2 H) 0 9.21 (s, 1 H), 8.74 (s, 1 H), 8.47 (m, 1 H), 7.97 (m, 1 H), 7.88 (s, 1 I.) a, I.) 65 61 A-4, I-2, S H), 7.78 (m, 3 H), 7.58 (m, 7 H), 7.09 (m, 3 H), 6.96 (m, 1 H), (5) 1- 0 \/- CH, .i.
u.) --.1 6.65 (in, 1 H), 3.14 (m, 4 H), 1.77-0.80 (in, 18 H); MS (ES): 0 609.4 I.) CA
I
11-1 NMR (DMSO-d6): 8 13.80 (hr s, 1 H), 9.91 (s, 1 H), 9.41 (s, 1 a, 71a -C1-1.----CH2 ..'0* 67 A-4, 1-2, S H), 8.63 (m, 2 H), 8.07 (s, 1 H), 7.98 (s, 1 H), 7.60 (m, 8 H), 6.90 H
-A
(in, 3 H), 5.94 (d, J= 17.7 Hz, 1 H), 4.37 (m, 1 H), 4.16 (m, 1 H), 2.41-1.58 (m, 12 H); MS (ES): 537.4 IHNIVIR (DMSO-d6): 5 9.76 (s, 1 H), 9.41 (s, 1 H), 8.95 (s, 1 H), 71b -CF1=--CH2 ..(/ 8.53 (m, 1 H), 8.07 (s, 1 H), 7.65 (m, 8 H), 7.08 (m, 2 H), 6.85 67 A-4, 1-2, S (dd, J= 10.9 and 17.7 Hz, 1 H), 6.92 (in, 3 H), 5.97 (d, J=17.7 1-d Hz, 1 H), 5.37 (d, J= 10.9 Hz, 1 H), 2.84 (m, 1 H), 2.70 (m, 1 H), n 0.98-0.51 (m, 8H); MS (ES): 569.4 cp o c.:.) t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used 1HNMR (DMSO-d6): 5 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, 71c -CH=CH2 67 A-4, 1-2, S 8 H), 7.12 (m, 2 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J=17.7 Hz, 1 H), 538 (d, J= 10.9 Hz, 1 H), 3.27 (m, 4 H), 1.20 (t, J= 7.2 Hz, 1 H), 1.09 (t, J= 7.2 Hz, 1 H); MS (ES): 485.3 (5) oe oe NH
I o N Si NHBoc o n.) W."
4.
0 ii --101 NHR`
_ Cpd....R
-11.1 Starting Method Analytical Data No. From Used 68a -CH3 --...,õõ,-.õõ,,3 67 A-4 MS (ES): 599.4 I.) I\),-, 68b 67 A-4 MS (ES): 641.4 a, (5) a, Lo o I.) 68c -CH3 ¨0 67 A-4 MS (ES): 625.3 a, H
-,1 , 68d -CH3 " CH, 67 A-4 MS (ES): 583.3 ....,<CH3 68e -CH3 67 A-4 MS (ES): 585.3 1-d n -...,.....,K7H, 681 -CH3 CH3 67 A-4 MS (ES): 599.4 cp o i-,.)--t..) vi oe t..) Cpd.
-R' Starting Method Analytical Data No. From Used tµ.) 68g -CH3 67 A-4 MS (ES): 625.2 =
= =
68h -CH3 67 A-4 MS (ES): 619.2 681 -CH3 WOH 67 A-4 MS (ES):
615.3 68j -CH3 /\.< 67 A-4 MS (ES): 597.3 o.
oe 68k -CH3 CH3 67 A-4 MS (ES): 557.3 67 A-4 MS (ES): 571.4 68m -CH3 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 = .) = .) = , Cpd. -R
-R' Starting Method Analytical Data ' No. , From , Used o .,,,, CH, l= . ) 68p -CH3 CH, 67 A-4 MS (ES): 613.5 .6.
1--, 1--, 68q -CH3 67 A-4 .MS (ES): 641.5 68r -CH3 ./\./.\--NIIBIDc 67 A-4 MS (ES): 714.5 68s -CH3 ¨0 67 A-4 MS (ES): 611.4 I.) a, I.) c7, 1--, 0H
.i.
oe 68t -CH3 67 A-4 MS (ES): 641.4 co 1--, I.) co 68u -CH3 < 67 A-4 MS (ES): 583.3 H
68v -CH3 ----<> 67 A-4 MS (ES): 597.4 -.../.= OH
68w -CH3 67 A-4 MS (ES): 587.4 Iv_ n ,-i -__,<
68x -CH3 CH3 67 A-4 MS (ES.): 613.5 cp =
CH3 o 1--, l= . ) ( A
l= . ) 4 0 6 11' R
o 3n.) 2 1, H
.6.
R"O,C
-R (Position with Cpd. Starting Method Respect to Phenyl -R' -R" Analytical Data No. From Used Ring) 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 n 75b -OH (3) -CHO -Bn 74 V-1, H MS (ES):
430.2 0 I.) 76a -0S02CF3 (3) -CHO -CH3 75a B-2 MS (ES):
488.1 a, I.) 1¨
MS (ES): 562.3 ; MS (ES): (5) a, oe 76b -0S02CF3 (3) -CHO -Bn 75b B-2 co t..) 586.3 (M+Na)+ 0 I.) 77a -CH=CH2 (3) -CHO -CH3 76a D-3 MS (ES ):
366.38 0 co 77b -OCH2CO2C2H5 (3) -CHO -Bn 75b X
Characterized in the next step 0 MS (ES): 487.3; MS (ES):
a, 77c -OCH2CONH2 (3) -CHO -Bn 75b X H
511.35 (M+Na) 77d ----I\ s (3) -CHO -Bn 76b D-2 Characterized in the next step MS (ES ): 530.3 (M+Na)+); MS
77e ¨0 . (3) -CHO -Bn 75b D-8 (ES): 506.3 1-d n ,-i cp =
i-,.,--u, oe t..) -R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data 0 No. From Used Ring) o t..) i-,.)--77f 0 -CHO -Bn 75b X MS (ES):
496.3 (M+Na)4" -4 1¨
(3) 77g \ 0/\ CH3 (3) -CHO -Bn 75b X MS (ES+):
482.4 (M+Na)+ .
..,..-...CH, 77h (3) -CHO -Bn 75b X MS (ES):
510.4 (M+Na) 111N-MR (CDC13): 5 9.59 (s, 1 H), 8.39 (d, J = 2 Hz, 1 H), 8.03 (m, 2 n ' H), 7.84 (d, J = 8.9 Hz, 1 H), 7.35 0 I.) (d, J = 8 Hz, 1 H), 7.28 (m, 2 H), a, "
1¨
7.12 (m, 2H), 6.93 (dd, J = 2.5 (5) a, u.) and 8.8 Hz, 1 H), 6.64 (d, J = 2.5 (3) -CHO -Bn 75b X
Hz, 1 H), 6.31 (t, J = 6 and 5 Hz, "
.
1 H), 5.06 (m, 2 H), 4.42 (t, J = 0 u.) 4.5 Hz, 2 H), 4.13 (m, 2 H), 3.34 a, (t, J =6.8 Hz, 2 H), 2.11 (s, 3 H), ' , 1.94 (m, 111), 1.01 (d, J = 6.8 Hz, 6H) 78a -CH=CH2 (3) -CO2H -CH3 77a E MS (ES):
380.1 78b -0S0sCF3 (3) -CO2H -Bn 76b E
Characterized in the next step 78c -OCH2CO2C2H5 (3) = -CO2H -Bn 77b E
Characterized in the next step Iv n 78d -OCH2CONH2 (3) -CO2H -Bn 77c E MS (ES):
52735 (M+Na)+
cp o 1¨
i-,.)--t..) vi oe t..) -R (Position with Cpd. Starting Method Respect to Phenyl -IV -R"
Analytical Data No.
From Used 0 Ring) o i-,.)--.6.
78e (3) -CO2H -Bn 77d E MS (ES): 536.4 (M+Na)+ -4 1.., 1.., S
78f ¨0 41 (3) -CO2H -Bn 77e E MS (ES): 522.3 _ - 78g -OCH3 (3) -CO2H -CH3 74 E MS (ES): 384.1 78h -....,s0,--_,....õ.õCH3 (3) -CO2H
-Bn 77f E MS (ES): 488.3 781 (:)C1.13 (3) -CO2H -Bn 77g E MS (ES): 474.4 0 I.) a, "
0, 1¨
a, oe 78j (3) -CO2H -Bn 77h E MS (ES): 502.4 co .6.
CH, N
78k '-'-1:y' \ OAc (3) -CO2H -Bn 771 E Characterized in the next step co ' a, IHNMR. (CDC13): 5 10.47 (s, 1 IH
H), 8.36 (d, J = 2 Hz, 1 H), 7.96 -A
(dd, I = 2.2 and 7.7 Hz, 1 H), 7.68 (m, 2 H), 7.46 (m, 5 H), 7.23 (d, J
= 8 Hz, 1 H), 7.12 (d, I = 8.7 Hz, 90 -0Bn (5) -CHO -CH3 89 + 3a D-2 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, I = 6.8 Hz, 2 H), 1.94 (m, 1 H), 1.01 (d, I =
1-d n 6.8 Hz, 6 H), MS (ES+) 468.2 (M+Na)+ (ES-) 444.2 cp o 1¨
i-,.)--t..) vi oe t..) Cpd -R (Position with .
Respect to Phenyl -R' -R" Starting Method Analytical Data o No.
From Used Ring) o t.) IHNMR (CDC13): 5 8.22 (s, 1 H), .6.
--.1 7.83 (d, J = 7.2 Hz, 1 H), 7.34 (m, 8 H), 7.02 (d, J = 8.1 Hz, 1 H), 91 -0Bn (5) -CO2H -CH3 90 E 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 -0Bn (5) -0O2MEM -CH3 91 F MS (ES): 572.2 (M+Na)+
93 -OH (5) -0O2MEM -CH3 92 G MS (ES+): 482. (M+Na) n 94 -0S02CF3 (5) -0O2MEM -CH3 93 B-2 MS (ES): 614.3 (M+Na)+ 0 I.) a, I.) 1¨
D-3 MS (ES+) 562.3 (M+Na)+ T
L., c'e u, 95a \ (5) s I.) co 96a \\,¨) (5) -CO2H -CH3 95a I-1 MS (ES+) 452.1 (M+Na)+ 1 a, S
H
-1 .
101 -OCH3 (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 -0Bn (2) -CHO -CH3 107 + 3a D-2 MS (ES+): 446.2 109 -0Bn (2) -CO2H -CH3 108 E MS (ES"): 460.1 . .
1-lo n ,-i cp =
e l= . ) ( A
l= . ) -R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data o No. From Used Ring) o t..) iHNMR (CDC13-di): 5 9.79 (s, 1 .6.
H), 8.39 (d, J =-- 1.88 Hz, 1 H), 8.02 (t, J = 6.0 Hz, 2 H), 7.59 (m, 131 -H -CHO -CH3 130 + 3a D-2 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, 1 H), 1.02 (d, J
= 6.8 Hz, 6 H), MS (ES+): 340.1 iHNMR (DMSO-d6): 8 12.28 (b, 1 H), 8.52(d, J = 6.03 Hz, 111), n 8.12 (s, 1 H), 7.86 (d, .1 = 8.1 Hz, 1 H), 7.74 (d, J = 7.74 Hz, 1 H), N
E 7.41 (t, J = 8.67 Hz, 1 H), 7.31 (t, a, I.) (5) oe J = 7.9 Hz, 1 H), 7.12 (d, J -= 8.1 a, c7, u.) Hz, 1 H), 6.97 (d, J - 7.5 Hz, 1 H), 3.39 (s, 3 H), 2.92 (t, 3 --- 6.0 I.) Hz, 2 H), 1.66 (m, 1 H), 0.78 (d, J
u.) -- 7.4 Hz, 6 H), MS (ES-): 354.1 a, NH
H
-.-1 192a+
193a -H ei NHBoc -CH3 6a D-7 MS (ES): 560.5 NH
193b -H CH, 00 NHBoc -CH3 192b+
MS (ES): 574.5) 1-d n 6a 1-i cp o i-,.)--t..) vi oe t..) -R (Position with Cpd. Starting Method Respect to Phenyl -R.' -R"
Analytical Data No. From Used 0 Ring) _______________________________________________________________________________ ____________________________________ o _ t..) NE
i-,4--.6.
1-, 194a -H 1.1 NH2 -CH3 193a S-2 MS (ES): 460.3 1-NH
- 194b -H CH3 NH2 -CH3 193b S-2 MS (ES): 474.3 -'0 = 0 IHNMR (DMSO-d6): 8 8.79 (bs, I.) 4H), 8.63 (t, J --- 6.5 Hz, 1 H), a, I\) NH
1¨
8.35 (s, 1 H), 7.85 (d, J = 6 Hz, 1 (5) oe a, H), 7.62 (d, J = 8.2 Hz, 2 H), 7.26 Lo l 195a -H el NH2 -H 194a 1-2 (m, 5 H), 7.06 (m, 1 H), 5.0 (m, 2 H), 3.09 (t, J = 6.2 Hz, 2 H), 1.86 N
CA
(n, 1 H), 0.89 (d, J = 6.6 Hz, 6 I0 H); MS (ES-): 444.3 and (ES) a, H
446.3 -A
.0 n ,-i cp =
i-,.,--t..) u, oe t..) -R (Position with Cnd Starting Method - = Respect to Phenyl -R' -R"
Analytical Data No. From Used Ring)tµ.) 11INTMR (DMSO-d6/DC1): 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 =
8.7 Hz, 1 H), 7.48 (d, J = 8.7 Hz, NH
1 H), 7.32 (t, J = 8 Hz, 1 H),7.16 (m, 3 H), 6.91 (t, S = 7.5 Hz, 1 H), 195b -H CH, el NH, -H 194b 1-2 6.76 (d, J = 8.5 Hz, 1 H), 6.66 (d, = 8.5 Hz, 1 H), 4.99 (m, 1 H), 2.92 (d, J= 6.9 Hz, 2 H), 1.68 (m, 111), 1.33 (d, J = 6 Hz, 1.2H), 1.27 (d, 5= 6 Hz, 1.8 H), 0.71 (d, J = 6.5 Hz, 6 H); MS (ES-): 458.2 and (ES) 460.3 c7, oe NH
oe CH, NHBoc _CH3 199 6a 200 -H MS (ES):
573.5 0 C. I
-R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data No. From Used 0 Ring) _ o tµ.) 11-11\IMR. (DMSO-d6/DC1): 5 8.49 '(;) (t, J = 5.6 Hz, 1 H), 8.18 (d, J =
.6.
NH
6.9 Hz, 1 H), 7.84 (t, J= 7.8 Hz, 1 H), 7.23 (m, 4 H), 7.01 (m, 2 H), 6.82 (d, J =7 Hz, 1 H), 6.22 (d, J
CH, NHBoc =--- 8.5 Hz, 1 H), 6.15 (d, J = 8.5 Hz, 1 H), 3.95 (m, 1 H), 2.85 (t, J
H =-- 5.8 Hz, 1 H), 1.62 (m, 1 H), 1.23 (s, 9 H), 1.1 (d, J = 6.7 Hz, 1.2H), 1.05 (d, J = 6.7 Hz, 1.8 H), 0.67 (d, J ---- 6.6 Hz, 6 H); MS
n (ES+): 559.4 o NH
1.) .i.
1.) 1-, = o) o CH3 u.) 202 -H lep NH2 .4-1 201 S MS (ES+): 459.3 0 I.) o N
o u.) H
o NH
.i.
H
203 -0Bn (4) 0 = NHBoc R MS (ES+): 679.4 N
H
NH
204 -0Bn (4) 0 NHBoc -H 203 1-2 MS (ES): 663.4 1-lo n ,-i N
ci) H
o 1-, l = . ) l = . ) --R (Position with Cnd= Starting Method -No. Respect to Phenyl -R' -R" From Used Analytical Data Ring)-0 c _N
I
-209a -H II ----=-_--A-7 MS (ES): 454.3 N
H
IHNMR (DMSO-d6): 5 10.72 (s, 1 H), 8.65 (d, J = 6.03 Hz, 1 H), = c ----____T- N 8.24(s, 1 H), 8.03 (d, J =8.1 Hz, 141111 1 H), 7.75 (m, 6 H), 7.40 (d, J =
7.90 Hz, 1 H), 7.34 (d, J = 8.1 Hz, N
209b -CH=CH2 (4) -CH3 30f A-7 1 H), 6.88 (q, J = 11.2 Hz, 1 H), n H
6.04 (d, J = 7.5 Hz, 1 H), 5.41 (d, J = 11.1 Hz, 1 H), 3.55(s, 3 H), I.) .1, I.) 3.10 (t, J = 6.6 Hz, 2 H), 1.86(m, (5) vD
.1, , MS (ES): 480.3 I.) 11-1N4R (DMSO-d6): 5 10.12 (s, u.) 1 H), 9.37 (b, 1 H), 8.48 (t, 3=6.1 .1, Hz, 1 H), 8.05 (d, 3=1.9 Hz, 1 H), H
NH
7.85 (d, 3=7.9 Hz, 1 H), 7.56 (d, 3=7.8 Hz, 1 H), 7.49 (d, 3=7.9 Hz, 1 H), 7.36 (s, 4 H), 7.21 (d, 3=7.9 210b -CH=CH2 (4) H -CH3 209b Y Hz, 1 H), 7.10 (d, J=2.8 Hz, 1 H), -'N 6.69 (m, 1 H), 5.84 (d, 3=15.5 Hz, H 1 H), 5.60 (b, 1 H), 5.22 (d, J=11.4 Hz, 1 H), 3.38 (s, 3 H), 2.91 (t, J = 6 Hz, 2 H), 1.66 (m, 1 1-d n H),0.71 (d, J = 6.8 Hz, 6 H); MS
(ES+) 515.40 cp o i-,.)--t..) vi oe t..) , i -R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data 0 No. From Used Ring) o t..) IHNMR.(DMSO-d6): 5 12.62 .6.
--.1 (bs, 1H), 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, NH
1 H), 7.50 (d, J=7.9 Hz, 1 H), 7.49 (s, 6 H), 7.16 (d, J=8.1 Hz, 1 211b -CH=CH2 (4) 0 410 N-OH
H -H 210b 1-2 H), 7.08 (d, J=8.1 Hz, 1 H), 6.72 (m, 1 H), 5.85 (d, J=13.7 Hz, 1 N
H), 5.24 (d, J-41.5 Hz, 1 H), H
2.93 (t, J = 6 Hz, 2 H), 1.68(m, 1 0 H), 0.72 (d, J ---- 6.8 Hz, 6 H); MS
(ES+) 501.40, (ES-) 499.2 I.) a, IHNMR (DMS0): 5 8.70 (t, J =
I.) (5) 1-a, vD
5.6 Hz, 1 H), 8.36 (d, J=1.7 Hz, u.) 1 H), 8.07 (dd, J = 8.1, 1.9 Hz, 1 I.) . c .N H), 7.42 (m, 4H), 7.09 (d, J= 5.5 0 Hz, 1 H), 7.04 (d, J= 7.7 Hz, 1 u.) H), 6.74 (dd, J= 17.5, 10.9 Hz, 1 a, 212 -CH=CH2 (4) -CH3 187a AE-5 N
H), 6.49 (d, J= 8.8 Hz, 2 H), 5.79 H
-,1 H
(d, J= 17.7 Hz, 1 H), 5.27 (d, J-10.9 Hz, 1 H), 4.0 (t, J- 6.0 Hz, 211), 3.62 (s, 3 H), 3.11 (t, J=
6.2, 2 H), 1.86 (m, 1 H), 0.90 (d, J= 6.6 Hz, 6 H) 1-d n ,-i cp =
t..) u, oe t..) , -R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data No. From Used 0 Ring), _______________________________________________________________________________ ___________________________________ o t..) 1H NMR (DMS0): 3 9.23 (s, 1 .6.
H), 8.71 (t, J- 6.2 Hz, 1 H), 8.36 (d, J= 1.9 Hz, 1 H), 8.09 (dd, J =
7.9, 1.7 Hz, 1 H), 7.49 (d, J = 7.9 Hz, 2 H), 7.40 (d, J= 8.3 Hz, 1 NH
H), 7.32 (d, J= 8.8 Hz, 2 H), 7.04 (d, J= 7.9 Hz, 1 H), 6.73 (dd, J=
213 -CH=CH2 (4) N-OH -CH3 212 Y 17.7, 11.1 Hz, 1 H), 6.40 (d, J=
H
.
8.5 Hz, 2 H), 6.33 (t, J= 7.0 Hz, N
1 H), 5.78 (d, J= 17.7 Hz, 1 H), H
5.58 (b, 1 H), 5.26 (d, J= 11.1 n Hz, 1 H), 3.96 (m. 2 H), 3.64 (s, 3 I.) H),3.11 (t, J-- 6.4 Hz, 2 H), 1.86 a, I.) (mõ 1 H), 0.90 (d, J= 6.8 Hz, 6 (5) a, vDu.) t..) H); MS (ES): 501.3 0 11-1NMR (DMS0): 68.76 (t, J=
"
5.8 Hz, 1 H), 8.37 (s, 1 H), 8.04 u.) (d, J= 8.7 Hz, 1 H), 7.39 (m, 5 H), 7.06 (d, J-- 8.3 Hz, 1 H), 6.72 H
-,1 (dd, 1 = 17.9, 11.3 Hz, 1 H), 6.43 214 -CH=CH2 (4) 1-2 (d, J= 8.5 Hz, 3 H), 5.76 (d, J=
H
17.9 Hz, 1 H), 5.24 (d, J= 11.1 N =
Hz, 1 H), 3.98 (m. 2 H), 3.11 (t, J
H
= 6.6 Hz, 2 H), 1.86 (h, J.-- 6.8 Hz, 1 H), 0.90 (d, J= 6.8, 6 H);
.
MS (ES): 487.2 1-d n 1-i = cp o ,-, t..) u, oe t..) -R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data No. From Used Ring 1HNMR (DMSO-d6): 8 8.68-8.60 (m, 1 H), 8.50 (d, J = 2.4 Hz, 1 NH H), 7.90-7.80 (m, 1 H), 7.76-7.70 (m, 1 H), 7.56-7.50 (m, 1 H), 011p NH2 237 + 7.48-7.42 (d, J ¨7.7 Hz, 1 H), 7.30-7.22 (d, J = 7.9 Hz, 1 H), 7.10-7.02 (d, J = 7.7 Hz, 1 H), 238 -CH=CH2 (4) H -H AE-2 187a 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, = 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 (5) NH
1.) 256 -H 410 NHB" -CH3 255 + 6a D-6 MS (BS):
573.3 NH
NH2 -H 256 1-2, S MS
(ES): 459.1 oe NH
0 4111) NH, 3 2 1 la R'02C
Cpd.Starting Method -R -R' Analytical Data No. From Used 79a -CH=CH2 (3) -CH3 78a J MS (ES): 499.2 c7, 79b -OS02CF3 (3) -CH2C6H5 78b J Characterized in the next step 79C OCH2C 02 C2115. (3) -CH2C6H5 78c J Characterized in the next step 79d -OCH2CONH2 (3) -CH2C6H5 78d J MS (ES.): 622.4; (ES") 620.4 79e (3) -CH2C6H5 78e J Characterized in the next step 79f0 -CH2C6H5 78f 3 Characterized in the next step 1-3 / 11 ar (3) oe Cpd. Starting Method -R -R' Analytical Data No. From Used IHNMR (DMSO-d6): 8 10.6 (bs, 1 H), 9.29-9.32 (bs, 1 H), o 9.06 (bs, 1 H), 8.82-8.75 (t, J. = 5.84 Hz, 1 H), 8.32 (d, J =
.6.
1.88 Hz, 1 H), 8.13 (d, J = 1.7 Hz , 1 H), 7.83 (s, 4 H), 7.78 (d, --.1 -OCH3 (3) 79g -CH3 78g J 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 --.., ...õ---.....,_7CH3 (3) -Bn 78h J MS
(ES): 607.3 791 -"OCH3 (3) -Bn 781 J MS (ES):
593.4 n I.) 793 0 (3) -Bn 78j J MS (ES):
621.4 . a, "
(5) o a, vi CH, u.) o 79k -0-CH2-CH2-0Ac (3) -Bn 78k 1 MS (ES):
651.4 "
u.) IHNMR (DMSO-d6): 8 9.1 (s, 2 H), 8.87 (s, 2 H), 8.53 (t, J =
a, -CH=CH2 (3) . 6 Hz, 1 H), 8.02 (s, 1 H), 7.64 (m, 7 H), 7.1 (s, 1 H), 6.98 (d, HI
80a -H 79a 1-2 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, 1 H), 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 IHNMR (DMSO-d6): 8 10.37 (s, 1 H), 9.20 (m, 3 H), 8.72 (t, , -OH (3) 1 = 6 Hz, 1 H), 8.2 (s, 1 H), 8.85 (m, 6 H), 7.65 (d, I = 8 Hz, 1 80b -H 79b . 1-2 H), 7.12 (d, 8 Hz, 1 H), 7.02 (dd, J = 2.5 Hz, J = 8 Hz, 1 H), 1-d n 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 cp o c.:.) t..) vi oe t..) -Cpd. Starting Method -R -W
Analytical Data No. From Used 11-1 NMR. (DMSO-d6): 6 12.7 (211, bs, 1 H), 9.01, 8.87 (2 bs, 4 80c -OCH2CO2H (3) -H 79c 1-2 H), 8.36 (m, 1H), 7.83 (s, 1H), 7.44 (m, 6 H), 6.75 (m, 2H), 6.31 (d, J=2.2 Hz, 111), 4.42 (s, 2H), 2.84 (m, 2H), 1.63 (m, 1H), 0.67 (d, J=6.5 Hz, 6H); MS(ES+): 533.4 1HNMR (DMSO-d6): 5 9.13 (bs, 5H), 8.59 (t, J=6.28 Hz, 111), 8.14 (d, J= 1.7 Hz, 1H), 7.63 (m, 9H), 7.42 (s, 1H), 7.09 - 80d -OCH2CONH2 (3) -H 79d G (d, .1 = 7.5 Hz, 1H), 7.03 (dd, J = 2.5, 12.7 Hz, 1H), 6.70 (d, J
=2.5 Hz, 1H), 4.48 (s, 2H), 3.05 (t, J= 6.6 Hz, 2H), 1.83 (m, 1H), 0.87 (d, J=6.8 Hz, 6H); MS(ES+): 532.4 11-1 NMR (DMSO-d6): 5 12.6 (1H, bs, COOH), 8.98, 8.67 (2 80e (3) -H 79e 1-2 bs, 4H), 8.46 (m, 1H), 8.08 (m,1H), 7.76 (m, 111), 7.53 (m, 6 H), 7.39 (m, 2H), 7.06 (m; 1H), 7.04 (m, 111), 2.89 (m, 211), (5) 1.66 (m, 1H), 0.69 (d, J=6.5 Hz, 6H); MS(ES+): 541.4 IHNMR (DMSO-d6): 5 9.14 (d, J = 10 Hz, 4 H), 8.60 (t, J = 6 801 II Hz, 1 H), 8.22 (bs, 1 H), 7.87-7.62 (m, 7 H), 7.47 (t, = 8 Hz (3) , -H 79f 1-2 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, J = 6.8 Hz, 6 H); MS
(ES) 551.4 11-1NMR (DMSO-d6): 6 9.13 (bs, 2 H), 8.78 (bs, 2H), 8.65 (t, J
= 6 Hz, 1 H), 8.25 (bs, 1 H), 7.78 (m, 1 H), 7.76 (m, 5 H), 80g -OCH3 (3) -H 79g 1-2 7.25 (s, 1 H), 7.17 (m, 1 H), 6.73 (bs, 1 H), 3.83 (s, 3 H), 3.10 1-d (t, J = 6 Hz, 2 H), 1.80 (m, 1 H), 0.88 (d, J = 6.8 Hz, 6 H);
MS (ES) 489.3 oe Cpd.Starting Method -R -R' Analytical Data No. From Used 80h(3) 4.1 79h 1-2 MS (ES): 517.7 80i \ 0./\CH3 (3) -H 79i 1-2 MS (ES): 503.4 ; MS (ES):
501.4 80j 0 (3) -H 79j 1-2 MS (ES): 531.4 ; MS (ES):
529.4 IHNMR (DMSO-d6): 6 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
80k -H 79k 1-2 8 Hz, 1 H), 6.48 (d, J = 2.5 Hz, 1 H), 4.91 (t, J = 5.5 Hz, 1 H), 0 -0-CH2-CH2-0H (3) 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 (5) H); MS (ES): 519.3, (ES-) 517.3 IHNMR (DMSO-d6): 5 9.15 (bs, 3 H), 8.65 (t, J = 6 Hz, 1 H), -CH(OH)CH2OH (3) 8.12 (s, 2 H), 7.82-7.56 (m, 7 H), 7.55-6.96 (m, 4 H), 5.5 (bs, 86a -H 82 S, 1-2 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 IHNMR (DMSO-d6): 6 8.82 (bs, 2 H), 8.68 (bs, 2 H), 8.40 (t, -CH2OH (3) J = 6 Hz, 1 H), 7.88 (bs, 1 H), 7.53 (m, 5 H), 7.45 (d, 8 Hz, 1 =
86b -H 84 S, 1-2 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-d 1 H), 0.71 (d, J = 6.8 Hz, 6 H); MS (ES) 489.2 oe -, Cpd. Starting Method -R -R' Analytical Data No. From Used o 1HNMR (DMSO-d6_D20): 5 13.7 (bs, 1 H), 832 (t, J -= 6 Hz, t..) 86c -CO2H (3) -H 85 S, 1-2 i-,.)--1 H), 7.63-7.17 (m, 7 H), 6.72 (d, 7.0 Hz, 1 H), 2.81 (t, J = 6 .6.
Hz, 2 H), 1.53 (m, 1 H), 0.64 (d, J = 6.8 Hz, 6 H); MS (ES) 503.2 97a ) -CH 3 96a J MS (ES): 569.2 (5) s 1HNMR (DMSO-d6): 5 10.62 (s, 1 H), 9.15 (bs, 2 H), 8.82 n (bs, 2 H), 8.67 (t, J = 6 Hz, 1 H), 8.25 (d, J = 2 Hz, 1 H), 7.99 97b -0Bn (5) -CH3 91 J (dd, J = 8.1 and 2 Hz, 1 H), 7.69 (q, 8.8 and 16.2 Hz, 4 H), "
a, I.) 1- 7.44 (m, 3 H), 7.28 (m, 3 H), 6.89 (d, J = 7.7 Hz, 1 H), 5.5 (s, (5) o a, oe 2 H), 3.6 (s, 3 H), 3.08 (t, J = 5.8 and 6.8 Hz, 2 H), 1.83 (m, 1 u.) H), 0.87 (d, J = 6.8 Hz, 6 H); MS (ES-) 577.2, (ES+) 579.3 I.) u.) 11-INMR (DMSO-d6): 5 13.45 (bs, 1 H), 9.06 (s, 2 H), 8.99 (s, a, -, 3 2 H), 8.51 (t, J = 6 and 5 Hz, 1 H), 7.99 (s, 1 H), 7.62 (m, 5 I-.H), 7.47 (s, 1 H), 7.36 (m, 2 H), 6.99 (m, 4 H), 4.26 (s, 2 H), 1 98a -H 97a 1-2 -,1 S (5) 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 = 11-1NMR (DMSO-d6): 5 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), =98b -0Bn (5) -H 97b 1-2 7.49 (s, 1 H), 7.46 (s, 1 H), 7.34 (m, 5 H), 7.15 (d, J = 8.2 Hz, 1-d n 1 H), 7.00 (d, J - 8.2, 1 H), 6.02 (d, J - 7.4 Hz, 1 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 cp Hz, 6 H); MS (ES-) 563.2, (ES+) 565.2 t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used IHNMR (DMSO-d6): 5 9.85 (s, 1 H), 9.07 (s, 2 H), 8.98 (s, 2 o t..) H), 8.50 (t, J = 6 and 5 Hz, 1 H), 7.99 (d, J = 1.7 Hz, 1 H), .6.
98c -OH(5) -H 98b G 7.63 (m, 5 H), 7.20 (t, J = 8 Hz, 2 H), 6.90 (d, J = 7.9 Hz, 1 --4 1-, 1-, H), 6.49 (d, J = 7.2 Hz, 1 H), 3.21 (t, J = 6.8 Hz, 2 H), 1.80 (m, 1 H), 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 iHNMR (DMSO-d6): 5 9.08 (bs, 2 H), 8.80 (bs, 2 H), 8.52 (t, 104 -OCH3 (2) -H 103 1-2 J = 6 Hz, 1 H), 8.02 (s, 1 H), 7.64 (m, 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, n 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES-) 487.3, (ES+) 489.3 I.) a, 110 -0Bn (2) -CH3 109 J MS (ES):
579.3 I.) (5) o a, 111 -OH (2) -CH3 110 G MS (ES):
489.3 0 I.) -0C2H5 (3)1 .
LO
' both -CH3 118b J Characterized in the next step -0Bn (4) 0 FP
I
H
1H NMR (DMSO-d6): 8 9.06-9.09 (m, 3H), 8.56-8.50 (m, 1H), 8.05 (s, 1H), 7.71-7.58 (m, 6H), 7.55-7.28 (m, 6H), 7.10-127 -0C2H5 (31 -H 126 1-2 7.01 (m, 1H), 6.63 (s, 1H), 5.19 (s, 2H), 4.05-3.97 (m, 2H), .
both 3.05-3.01 (m, 2H), 1.86-1.77 (m, 1H), 1.29 (t, J=6.7 Hz, 3H), -0Bn (4)j 0.87 (d, J=6.8 Hz, 6H) 111 NMR (DMSO-do): 13.64 (hr s, 1 H), 8.99 (br s, 2 H), 8.49 }both (t, .1=5.1 Hz, 1 H), 7.99 (s, 1 H), 7.73-7.56 (m, 5 H), 7.32--0CH3 (3) 6.83 (m, 5 H), 6.50 (s, 1 H), 5.17 (d, J= 4.3 Hz, 1 H), 5.01 1-d 129 -H 128 I-2, S
n -CH(OH)CH3 (4) (m, 1 H), 3.75 (s, 3 H), 3.03 (t, J= 6.0 Hz, 1 H), 1.81 (m, 1 H), 1.32 (d, J = 6.2 Hz, 3 H), 0.86 (d, J- 6.6 Hz, 6 H); MS
cp (ES): 533.4 (100% M+1) o .
i-,.)--t..) vi oe t..) NH
0 NHBoc W."
= H
Cpd. -R (With Respect to Starting Method No. , Phenyl Ring) , From , 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 (ES): 601.3 (5) 84 -CH2OH (3) 83 K MS (ES-1): 601.4 85 -CO2H (3) 83 E MS (ES-1): 615.3 -OCH3 (3) 128 both 124a R MS (ES): 629.4 -CH=CH2 (4) oe . 0 5 o n.) c.:.) .6.
RI CHO --.1 1-, 1-, R
, Cpd. _R
-R1 -R2-R3 -R4 Starting 1 Method Analytical Data No. From Used 1HNMR (CDC13): 6 10.48 (s, 1 H), 7.42 -7.25 (m, 7 H), 7.00 (dd, J = 2 and 7.4 88 -Br -H -H -H -0Bn 87 X Hz, 1 H), 5.19 (s, 2 H); IR (I<Br) 1701, 1585, 1452, 1262, 1009 crn-1; MS
(ES+) 313.0, 315.0 (M+Na)-1 n ....
1HNMR (CDC13): 8 10.61 (s, 1 H), 7.65 (d, J = 7.2 Hz, 1 H), 7.60 (t, J = 7.9 and "
a, t..) 89 -B(OH)2 -H -H -H -0Bn 88 T, U-1 7.2 Hz, 1 H), 7.41 (m, 5 H), 7.19 (d, J = I.) (5) o a, 7.9 Hz, 1 H), 6.81 bs, 2 H), 5.20 (s, 2 u.) H) I.) 1HNMR (DMSO-d6): 6 10.2 (s, 1 H), u.) 100 -B(OH)2 -OCH3 -H -H -H 99 T, U-3 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-) a, H
179.0 107 -B(OH)2 -0Bn -H -H -H 106 T, U-1 1HNMR (DMSO-d6): 8 10.1 (s, 1 H), .
7.3-7.6 (m, 8 H), 5.3 (m, 2 H) 114a -Br -H -OCH3 -OH -H 113 Z MS (ES):
229.0 and 231.0) _ 114b -Br -H -0C2H5 -OH -H 113 Z-1 MS (ES):
242.9 and 244.9 114c -Br -H -OCH(CH3)2 -OH -H 113 Z-1 MS (ES):
257.0 and 259.0 115a -Br -H ' -OCH3 -0Bn -H 114a X MS
(ES): 321.0 and 323.0 115b -Br -H - -0C2H5 -0Bn -H 114b X
MS (ES): 335.0 and 337.0 Iv n 115c -Br -H -OCH(CH3)2 -0Bn -H 114c X , MS (ES+):
349.0 and 351.0 cp o t..) vi oe t..) Cpd.
-R1-R2 -R3 -R4 Starting Method Analytical Data No. From Used X, V-4, 1151 -Br -H -0Bn -H 115a Characterized in the next step All 0 C(CH3)3 116a -B(OH)2 -H -OCH3 -0Bn -H 115a T, U-1 Characterized in the next step 116b -B(OH)2 -H -0C2H5 -0Bn -H 115b T, U-1 Characterized in the next step 116c -B(OH)2 -H -OCH(CH3)2 -0Bn -H 115c T, U-1 Characterized in the next step =
(5) oe NH
0 = N112 -Cpd. Starting Method Analytical Data No. From Used 11INMR (DMSO-d6): 11.28 (s, 1 H), 9.31 (s, 2 H), 9.0 (s, 2 H), 8.88 (d, J =
11.30 Hz, 0 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), (5) 112 111 1-2 8.04 (d, J = 8.47 Hz, 1H), 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 0 =3.5 Hz, 1 H), 1.8 (m, J = 19.9 Hz, 2 H), 0.88 (m, J = 6.6 Hz, 6 H).
oe R' RO =
n.) 40 NHR"' .6.
H3CO,C --4 1¨, 1¨, i Cpd. I
-R -R' -R" -R"' 1 Starting Method ' No.
Analytical Data From Used 117a -CH3 -0Bn -CHO 3a D-2 D-2 MS (ES-): 474.2 CH3 116a 117b -C2H5 -0Bn -CHO 3a I.) -'=,,.,./---,.CH3 116b D-2 MS (ES):
488.2 a, t..) I.) o (5) CH3 Lo 117c -CH(CH3)2 -0Bn -CHO 3a+
I.) MS (ES): 502.3 0 116c Lo a, ' IHNMR (CDC13): 8 9.56 (s, 1 H), 8.34 (d, J = 1.7 Hz, 1H), 8.5 -A
(s, 1 H), 8.01 (dd, J =7.9 and 1.9 117d -CH3 -0Bn -CHO CH3 3b +
Hz, 1 H), 7.40 (m, 7 H), 6.9 (s, 1 116a H), 5.24 (m, 2 H), 4.2 (m, 1 H), 'cH3 3.80 (s, 3 H), 3.52 (s, 3 H), 1.02 (d, J = 7 Hz, 6 H); MS (ES+) :
=
484.3 (M+Na) Iv n 1-i cp .
o ,-, t..) u, oe t..) Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used IHNMR (DMSO
0-d6): 5 8.43 (d, J o = 1.65 Hz, 1 H), 8.31 (d, J = 8.66 t..) c.:.) Hz, 1), 8.12 (dd, J =1.69 Hz, .6.
1H), 7.98 (s, 1H), 7.41 (d, J = 8 CH3 and and 10 Hz, 1H), 7.19 (d, J = 8.1 117e -CH3 -0Bn -CHO
3c Hz, 111), 5.20 (dd, J = 6.2 Hz, CH, 116a 1H), 3.98 (dd, J = 7.75 Hz, 311), 3.94 (s, 3H), 3.42 (m, 311), 3.32 (m, 3H), 3.19 (s, 3H), 2.5 (m, 3H), 2.0 (s, 4H), 1.5 (m, 211), 1.28 (m, 3H), 0.88 (d, J = 6.59 Hz, 311); MS (ES ): 664.3 n , 1HNMR (CDC13): 5 9.50 (s, 1 H), 8.40 (d, J = 2.1 Hz, 111), 8.04 I.) a, I.) t..) (dd, J= 8.1, 2.1 Hz, 111), 7.57 (s, (5) oa, 1 H), 7.48 (m, 5 H), 7.38 (m, 5 u.) ....,,...--.....,.....õ,-...,.....CH3 3d H), 6.67 (s, 1 H), 6.50 (broad, 1 I.) 117f -CH3 -0Bn -CHO
116a H),) 5.27 (d, J----- 11.9 Hz, 1 H), 0 u.) ' 5.22 (dd, J= 11.7, 1 1-1), 4.63,(m,3H) 4.17 (m, 4 H), 3.92 a, H
(s, 3 H), 3.66 (s, 3 H); MS (ES):
488.3 IH NMR (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 117g -CH3 -0Bn -CHO 3 D-2 (m, 3 H), 6.67 (s, 1 H), 6.50 116a 1-d 'cF3 (broad, 1 H), 5.27 (d, J= 11.9 n Hz, 1 H), 5.22 (dd, J = 11.7, 2 H), 4.17 (m, 2 H), 3.92 (s, 3 H), cp o 3.66 (s, 3 H); MS (ES): 500 c.:.) t..) vi oe t..) , Cpd.Starting Method -R -R' -R" -R"' Analytical Data No. From Used _____________________ IHNMR (CDC13): 5 9.56 (s, 1 o H), 8.34 (d, J-- 1.7 Hz, 1 H), =
t..) 8.01 (dd, J= 7.9, 1.9 Hz,'1 H), .6.
7.57 (s, 1 H), 7.50 (dd, J= 7.2, 3e +
1.5, 2 H), 7.40 (m, 4 H), 6.67 (s, 117h -CH3 -0Bn -CHO
116a 1 H), 6.21 (broad, 1 H), 5.24 (d, J
= 2.8 Hz, 2 H), 3.92 (s, 3 H), 3.65 (s, 311), 3.52 (m, 2 H), 1.65 (m, 2 H), 1.46 (m, 2 H), 0.99 (t, 3 = 7.3 Hz, 3 H).
11-1NMR (CDC13): 8 9.57 (s, 1 H), 8.37 (d, J= 1.9 Hz, 1 H), n 8.03 (dd, J= 7.9, 1.9 Hz, 1 H), 7.58 (s, 1 H), 7.50 (d, J= 7.2 Hz, I.) 2 H), 7.38 (m, 3 H), 6.68 (s, 1 H), .1,.
I.) t.) 117i -CH3 -0Bn -CHO /\, 3ff +
-D-2 6.33 (broad, 1 H), 5.26 (d, J=
116a (5) a, =
u.) c7, 11.5 Hz, 1 H), 5.21 (d, J= 11.9 0 Hz, 1 H), 3.92 (s, 3 H), 3.65 (s, 3 "
H), 3.37 (dd, J= 7.2, 5.3 Hz, 2 Lo H), 1.09 (m, 1 H), 0.60 (m, 2 H), .1,.
' 0.32 (m, 2 H); MS (ES): 474.2 , -,1 1H NAIR (CDC13): 5 9.55 (s, 1 H), 8.32 (d, J= 1.9 Hz, 1 H), 8.00 (dd, J= 1.9 and 7.9 Hz, 1 117j -CH3 -0Bn -CHO -0 3h +
116a D-2 H 7.59-7.30 m 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
1-d (ES+): 510.3 (M + Na)+
n 1-i cp o ,-, t..) u, oe 206 n.) Cpd. Starting Method -R -R' -R"
Analytical Data No. From Used 0 1H NMR (CDC13): 8 9.56 (s, 1 o t..) H), 8.35 (d, J= 1.9 Hz, 1 H), .6.
8.02 (dd, f= 1.9 and 7.9 Hz, 1 1-, 1-, 3i +
H), 7.58-7.33 (m, 7 H), 6.68 (s, 1 117k -CH3 -0Bn -CHO
cti3 116a H), 5.24 (m, 2 H), 3.92 (s, 3 H), 3.65 (s, 3 H), 3.56 (m, 2 H), 1.30 (t, J= 7.2 Hz, 3 H); MS (ES):
470.3 (M Na) 1H NMR (CDC13): 8 9.56 (s, 1 H), 8.35 (d, J= 1.9 Hz, 1 H), 8.02 (dd, J= 1.9 and 7.9 Hz, 1 3j +
H), 7.58-7.33 (m, 7 H), 6.68 (s, 1 1171 -CH3 . -0Bn -CHO
116a H), 5.24 (m, 2 H), 3.92 (s, 3 H), 0 IV
3.65 (s, 3 H), 3.40 (m, 2 H), 1.80-a, I.) (5) t..) 0.94 (m, 9 H); MS (ES): 512.2 a, o u.) (M+ Na) 0 I.) 1HNMR (DMSO-d6): 8 9.73 (s, 1 .
H), 8.86 (t, J = 5.7 Hz, 1 H), 8.52 u.) (d, J = 1.5 Hz, 1 H), 8.22 (dd, J =
FP
I
8 and 2 Hz, 1 H), 7.79 (s, 1 H), H
-.-1 6a +
7.60 (d, J = 8 Hz, 1 H), 7.5 (m, 5 117m -0Bn -CHO \,./`-..
--..---.C. (CH3)3 CH3 115d H), 7.22 (s, 1 H), 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 (ES): 546.4 .
_ CH3 1-d n 118a -CH3 -0Bn -CO2H 117a E MS (ES): 490.2 cp o i-,.)--t..) vi oe t..) Cpd. Starting Method -R -12.' -R" -R"' Analytical Data No. From Used _ -CH
5 =
t..) 118b -C2H5 -0Bn -CO2H 117b E MS (ES): 504.2 4,.
'--'CH3 --.1 1¨
cH3 118e -CH(CH3)2 -0Bn -CO2H 117c E . MS (ES): 518.2 118d -CH3 -0Bn -CO2H 117d E Characterized in the next step -clI3 118e -CH3 -0Bn -CO2H ____<---CH3 117e E MS (ES): 534.3 0 IV
FP
IV
0) FP
la IV
1181 -CH3 -0Bn -CO2H .,---..,..---..,.,,,c1-13 117f E MS (ES): 506.3 la I
FP
I
118g -CH3 -0Bn -CO2H /CF3 117g E Characterized in the next step H
118h -CH3 -0Bn -CO2H .--'''cli3 117h E MS (ES-1): 490.2 118i -CH3 -0Bn -CO2H /<1 117i E MS (ES-1): 488.3 1-d n ,-i cp =, i-,.,--t..) u, oe t..) .
, Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used 0 1H NMR (DMSO-d6): 6 12.19 o t..) (br s, 1 H), 8.50 (d, J= 7.4 Hz, 1 .6.
H), 8.31 (d, J= 1.9 Hz, 1 H), --.1 118j -CH3 -0Bn -CO2H -0 117j E 8.02 (dd, J= 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, J= 6.4 Hz, 1 H), 3.80 (s, 3 H), 3.57 (s, 3 H), 1.97-1.51 (m, 8 H) -_.
118k -CH3 -0Bn -CO2H C1.1, 117k E MS (ES): 462.3 n 1H NMR (CDC13): 8 8.30 (d, J=
1.9 Hz, 1 H), 7.95 (dd, J= 1.7 N
and 7.9 Hz, 1 H), 7.66 (s, 1 H), I.) t..) CH3 7.52-7.27 (m, 6 H), 6.62 (s, 1 H), (5) a,.
vD 1181 -CH3 -0Bn -CO2H 1171 E u.) 6.49 (m, 1 H), 5.21 (s, 2 H), 3.88 1.) (s, 3 H), 3.61 (s, 3 H), 3.38 (m, 2 H), 1.79-0.94 (m, 9 H); MS (ES):
u.) 504.4 c) a,.
H
CH, -A
118m-0Bn -CO2H 117m E Characterized in the next step C(CH3)3 CH3 _ CH, 119a -CH3 -0Bn -0O2MEM 118a F MS (ES): 578.3 1-d CH, n ,-i 119b -C2H5 -0Bn -0O2MEM \_/\ CH3 118b F MS (ES): 592.3 cp o . i I I
t..) vi oe t..) Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used CH, 119c -CH(CH3)2 -0Bn -0O2MEM 118c F MS (ES):
606.3 cH3 119d -CH3 -0Bn -0O2MEM 118d F MS (ES):
564.2 '"CH3 119e -CH3 -0Bn -0O2MEM 118e F MS (ES):
620.1 119f -CH3 -0Bn -0O2MEM 118f F MS (ES):
592.3 0 (5) 119g -CH3 -0Bn -0O2MEM 118g F
Characterized in the next step 1H NMR (CDC13): 5 8.32 (d, J=
1.9 Hz, 1 H), 7.96 (dd, J= 7.9, 1.9 Hz, 1 H), 7.68 (s, 1 H), 7.50 (m, 2 H), 7.35 (m, 4 H), 6.62 (s, 1 119h -CH3 -0Bn -0O2MEM 118h F 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) oe Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used 1HNMR (CDC13): 8 8.34 (d, L9 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 119i -CH3 -0Bn -0O2MEM 1181 F H), 6.42 (broad, 1 H), 524 (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, 1H), 0.58 (m, 2 H), 0.30 (m, 2H) 1H NMR (DMSO-d6): 5 8.55 (d, J= 7.4 Hz, 1 H), 8.39 (d, J= 1.9 Hz, 1 H), 8.10 (dd, J= 1.7 and 7.9 Hz, 1 H), 7.63-7.35 (m, 7 H), 119j -CH3 -0Bn -0O2MEM 118j F 6.81 (s, 1 H), 5.25-5.12 (m, 4 H), 4.31 (q, J= 6.4 Hz, 1 H), 3.86 (s, (5) 3 H), 3.62 (s, 3 H), 3.3 (s, 3 H), 3.23 (s, 3 11)1.99-1.53 (m, 8 H);
MS (BS): 614.3 (M+ Na) 1H NMR (DMSO-d6): 5 8.70 (t, J= 5.5 Hz, 1 H), 8.35 (d, J= 1.9 Hz, 1 H), 8.05 (dd, J= 1.7 and 7.9 Hz, 1 H), 7.59-7.30 (m, 7 H), 119k -CH3 -0Bn -0O2MEM 118k F 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= 7.2 Hz, 3 H); MS (ES):
574.3 (M+ Na) 1-d oe , Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used .1= 5.8 Hz, 1 H), 8.35 (d, J= 1.9 t..) i-,.)--, Hz, 1 H), 8.05 (dd, .1= 1.7 and .6.
--.1 7.9 Hz, 1 H), 7.63-7.33 (m, 7 H), 1191 -CH3,,,.).____, -0Bn -0O2MEM CH31181 F 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 (m, 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
=
(ES): 616.3 (M+ Na)+
1HNMR (DMSO-d6): 8 8.72 (t, J
= 5.6 Hz, 1 H), 8.38 (d, J = 1.8 n Hz, 1 H), 8.70 (dd, 3 = 1.8 and 8.1 Hz, 1 H), 7.71 (s, 1 H), 7.40 I.) a, I.) (m, 6 H), 7.02 (s, 1 H), 5.20 (m, 4 (5) t..) a, 1- 119m -0Bn -0O2MEM 118m F H), 3.59 (s, 3 H), 3.37 (m, 2 H), u.) t.) C(CH3)3 CH3 3.31 (m, 2 H), 3.17 (s, 3 H), 3.12 N) (t, J =6.5 Hz, 2 H), 1.87 (m, 1 u.) H), 1.21 (s, 9 H), 0.91 (d, J = 6.8 .
Hz, 6 H); MS (ES+): 650.4 and a, H
672.3 (M+ NO+
-A
120a -CH3 -OH -0O2MEM 119a G MS (ES): 488.1 120b -C2H5 -OH -0O2MEM \,..,/\ CH3 119b G MS (ES): 502.2 1-d n 1-i cp o i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used 0 CH, =
n.) W."
120c -CH(CH3)2 -OH -0O2MEM 119c G MS (ES): 516.3 120d -CH3 -OH -0O2MEM 119d G MS (ES): 474.3 120e -CH3 -OH -0O2MEM ____<--CH3 119e G MS (ES): 530.4 CH, n 120f -CH3 -OH -0O2MEM --,,,.c1-13 119f G MS (ES): 502.3 a, I.) (5) a, t..) Lo 120g -CH3 -OH -0O2MEM /..--CF3 119g G Characterized in the next step "
Lo a, 120h -CH3 -OH -0O2MEM3 119h G Characterized in the next step H
-,1 120i -CH3 -OH -0O2MEM /.<
119i G MS (ES): 486.3 120j -CH3 -01-r1 -0O2MEM ¨0 119j G MS (ES): 524.3 (M+ Na)+
od n 1-i 120k -CH3 -OH -0O2MEM .,--"CH3 119k G MS (ES): 484.2 (M+ Na) cp o . .
t..) vi oe t..) s _______________________________________________________________________________ ___________________________ Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From-Used ¨0 CH
o n.) G MS (ES): 502.3 .6.
'\/\/CH3 I-, I-, 1HNMR (DMSO-d6): 5 10.83 (bs, 1 H), 8.77 (t, J =5.6 Hz, 1 H), 8.42 (d, J = 1.8 Hz, 1 H), 8.12 (dd, J = 1.8 and 8.1 Hz, 1H), 7.68 (s, 1 H), 7.41 (d, J =8.1 Hz, 1 H), 6.73 (s, 1 H), 5.21 (q, J =
120m ...-., -OH -0O2MEM CH3 119m G 21 and 6 Hz, 2 H), 3.65 (s, 3 H), C(CH3)3 3.48 (m, 2 H), 3.37 (m, 2 H), 3.24 n (s, 3 H), 3.18 (t, J = 6.5 Hz, 2 H), 1.94 (m, 1 H), 1.39 (s, 9 H), 0.97 I.) a, (d, J = 6.8 Hz, 6 H); MS (ES+):
I.) (5) t..) a, 1¨
560.5 and 582.4 (M+ Na), (ES) co .6.
558.4 I.) CH
CA
I
121a -CH3 -0S02CF3 -0O2MEM 120a B-2 MS (ES-3): 644.1 (M+ Na) 0 .P
I
H
-A
121b -C2H5 -0S02CF3 -0O2MEM 120b B-2 MS (ES+): 658.2 (M+ Na)+
CH, 121c -CH(CH3)2 -0S02CF3 -0O2MEM
120c B-2 MS (EST): 672.2 (M+Na)+ 1-d n ,-i cp =
i-,.,--t..) u, oe t..) Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From __________________________________________________________________ Used _ IHNMR (DMSO-d6): 8 8.43 (d, J
o .---- 1.9 Hz, 1 H), 8.31 (s, 1 H), 8.12 t..) CH3 (d, J = 1.69 Hz, 1 H), 7.98 (s, 1 .6.
H), 7.41 (d, J --- 8.1 Hz, 1 H), 7.19 --.1 121d -CH3 -0S02CF3 -0O2MEM CH3 120d B-2 (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 _ IHNMR (DMSO-d6): 8 8.49 (s, 1 H), 8.34 (d, J = 1.8 Hz, 1 H), 8.2 (d, J = 1.8 Hz, 1 H), 7.97 (s, 1 H), 121e -CH3 -0S02CF3 -0O2MEM ____<-- CH, 7.4 (d, J = 7.8 Hz, 1 H), 7.2 (s, 1 120e B-2 H), 5.2 (q, J -= 6 and 10 Hz, 2 H), I.) 4.0 (m, 3 H), 3.6 (s, 3 H), 3.4 (m, a, I.) t..) (5) 4 H), 3.2 (s, 3 H), 1.5 (m, 4 H), a, vi u.) 1.3 (m, 4 H), 0.85 (m, 6 H); MS
(ES+): 664.3 I.) IHNMR (DMSO-d6): 8 8.83 (d, J
u.) = 5.46, 1 H), 8.55 (d, J = 1.88 Hz, a, 1 H), 8.23 (dd, J = 1.88 Hz, 1 H), H
-,1 8.19(s, 111), 7.73 (d, J = 7.93 Hz, 1 H), 7.29 (s, 1 H), 5.29 (dd, 121f -CH3 -0S02CF3 -0O2MEM 120f B-2 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
1-d (ES+) 636.6 n , i .
1-i cp o t..) u, oe t..) Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used iHNMR (CDC13): 68.43 (d, J=---tµ.) 1.9 Hz, 1 H), 8.03 (dd, 7.9 Hz, 2.1 Hz, 1 H), 8.00 (s, 1 H), 7.35 (d, J= 7.9 Hz, 1 H), 6.79 121g -CH3 -0S02CF3 -0O2MEM ./"-CF3 120g B-2 (m, 2 H), 5.29 (d, J= 6.2 Hz, 1 H), 5.26 (d, J= 6.2 Hz, 1 H), 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 1HNMR (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, 121h -CH3 -0S02CF3 -0O2MEM120h B-2 1 H), 5.32 (m, 2 H), 3.90 ( s, 3 0 H), 3.66 (s, 3 H), 3.55 (m, 6 H), tµ.) 3.4 ( s, 3 H), 1.7 (m,.2 H), 1.45 c7, c7, (m, 2 H), 0.98 (t, J = 7.3 Hz, 3 H); MS (ES): 620 1H NMR (CDC13): 68.41 (d, 2.1 Hz, 1 H), 8.03 (dd, J= 7.9, 1.9 Hz, 1 H), 8.00 (s, 1 H), 7.32 (d, J= 7.9 Hz, 1 H), 6.43 (t, J=
1211 -CH3 -0S02CF3 -0O2MEM /<1 1201 B-2 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 oe Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used . 0 1H NMR (CDC13): 8 8.35 (d, J=
=
tµ.) 1.9 Hz, 1 H), 8.00 (m, 2 H), 7.31 '(;) 4 = , (d, J= 7.9 Hz, 1 H), 6.77 (s, 1 H), 121j -CH3 -0S02CF3 -0O2MEM ----0 120j B-2 6.27 (m, 1 H), 5.28 (m, 2 H), 4.44 (q, J= 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 (ES): 656.3 (M+Na) ' IH NMR (CDC13): 68.38 (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 121k -CH3 -0S02CF3 -0O2MEM 120k B-2 H), 5.27 (m, 2 H), 3.94 (s, 3 H), 0 3.66 (s, 3 H), 3.59-3.43 (m, 6 H), 0 I.) 3.35 (s, 3 H), 1.28 (t, J= 7.2 Hz, a, I.) tµ.) 3 H); MS (ES+): 616.3 (M+Na)+ c7, a, u.) 111 NMR (CDC13): 8 8.38 (s, 1 H), 8.00 (m, 2 H), 7.31 (d, J= 7.9 0 I.) cH3 -Hz, 1 H), 6.78 (s, 1 H), 6.37 (m, 1 u.) 1211 -CH3 -0S02CF3 -0O2MEM --,.----\,-cF13 1201 B-2 H), 5.27 (m, 2 H), 3.94 (s, 3 H), 0 a, 3.66 (s, 3 H), 3.57-3.25 (m, 9 H), H
1.78-0.92 (m, 9 H); MS (ES+):
658.4 (M+ Na)+
1-lo n ,-i cp =
l= . ) C. if I
l= . ) ' Cpd. Starting Method -R -R' -R" -R"
Analytical Data No. From Used IHNMR (DMSO-d6): 5 8.75 (t, J.
o t..) = 5.6 Hz, 1 H), 8.45 (d, J = 1.8 .6.
Hz, 1 H), 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), 121m -OS 02CF3 -0O2MEM --...õ),,.... 121m B-2 5.23 (q, J =21 and 6 Hz, 2 H), /..C(CH3)3 CH3 3.60 (s, 3 H), 3.41 (m, 2 H), 332 (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 -C 02MEM 121a D-3 Characterized in the next step 0 IV
FP
IV
N
OCI
CA
IV
122b -C2H5 -CH=CH2 -0O2MEM 121b D-3 MS (ES):
536.3 (M+Na)+ 0 CA
I
FP
CH
HI
122c -CH(CH3)2 -CH=CH2 -0O2MEM 121c D-3 MS (ES): 550.3 (M+ Na) 122d -CH3 -CH=CH2 -0O2MEM 121d D-3 MS (ES+):
486.2 1-d n cH3 ,-i 122e -CH3 -CH=CH2 -0O2MEM 121e D-3 MS (ES):
564.5 (M+ Na) cp CH, =
1¨, n.) vi oe n.) Cpd.Starting Method -R -R" -R" ' Analytical Data No. From Used 122f -CH3 -CH=CH2 -0O2MEM 121f D-3 MS
(ES+): 514.4 (M+ Na) 122g -CH3 -CH=CH2 -0O2MEM CF3 121g D-3 Characterized in the next step 122h -CH3 -CH=CH2 -0O2MEM CH3 121h D-3 Characterized in the next step 122i -CH3 /\<1 -CH=CH2 -0O2MEM 1211 D-3 Characterized in the next step 122j -CH3 - -CH=CH2 -0O2MEM 121j D-3 MS
(ES-): 422.3 [(M-MeM)-1]
(5) 122k -CH=CH2 -0O2MEM CH3 121K D-3 MS
(ES): 494.2 (M+ Na)+
CH, 1221 -CH3 -CH=CH2 -0O2MEM 'CH1211 D-3 MS (ES): 536.42 (M+ Na) 1-d oe Cpd. Starting Method -R -R' -R" -R"' Analytical Data 0 No. From Used o t..) 1HNMR (DMSO-d6): 8 8.73 (t, J
.6.
= 5.6 Hz, 1H), 8.43 (d, J = 1.8 --.1 Hz, 111), 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 122m ..)4'-C(CH3)3 -CH=CH2 -0O2MEM CH3 121m D-3 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), I.) 0.91 (d, J = 6.8 Hz, 6 H); MS
I.) t..) (ES-): 480.4 [(M-MEM)-1]
o u.) CH, iv 123a -CH3 -CH=CH2 CO2H 122a I-1 MS (ES): 410.2 0 CA
CH
I
FP
I
H
-,1 123b -C2115 -CH=CH2 CO2H 122b I-1 MS (ES): 424.2 123c -CH(CH3)2 -CH=CH2 CO2H122c I-1 MS (ES): 438.2 .-CH3 1-d n 123d -CH3 -CH=CH2 CO2H 122d I-1 MS (ES): 396.2 cp i-,.)--t..) vi oe t..) , Cpd. Starting Method ical Data o No. From Used o t..) CH, FP
123e -CH3 -CH=CH2 CO2H -----c ...-._ 122e I-1 MS (ES): 454.3 --4 ' CHõ
=
1231 -CH3 -CH=CH2 CO2H .-/-\/---./CH3 122f 1-1 MS (ES): 426.3 1HNMR (DMS0): 8 12.37 (s, 1 H), 9.35 (t, .1= 6.0 Hz, 1 H), 8.42 (d, J= 1.7 Hz, 1 H), 8.10 (dd, j=
8.1 Hz, 1.9 Hz, 1 H), 8.06 (s, 1 H), 7.40 (d, J= 7.9 Hz, 1 H), 123g -CH3 -CH=CH2 CO2H 122g I-1 6.98 (dd, J= 17.9, 11.5 Hz, 1 H), I\) a, ./ CF 3 "
t..) 6.77 (s, 1 H), 5.89 (dd, J=17.7, (5) t..) .1,.
1.3 Hz, 1 H), 5.37 (dd, J = 11.1, u.) 1.3 Hz, 1 H), 4.14 (m, 2 H), 3.84 I.) (s, 3 H), 3.61 (s, 3 H); MS (ES):
u.) 436.3 ' FP
1FINMR (DMS0): 8 8.66 (t, .1=
I
H
5.5 Hz, 1 H), 8.35 (d, J= 1.7 Hz, 1 H), 8.05 (s, 1 H), 8.03 (dd,J=
8.1, 1.9 Hz, 1 H), 7.34 (d, J= 7.9 Hz, 1 H), 6.98 (dd, J= 17.9, 11.3 123h -CH3 -CH=CH2 CO2H122h I-1 Hz, 1 H), 6.75 (s, 1 H), 5.88 (dd, J=17.7, 1.3, 1H), 5.36 (dd, J=
11.3, 1.3 Hz, 1 H), 3.84 (s, 3 H), 1-d 3.60 (s, 3 H), 3.30 (q, .1= 5.6 Hz, n 2H), 1.52 (m, 2 H), 1.33 (m, 2 H), 0.96 (t, .1= 7.3 Hz, 3 H); MS
cp o (ES): 410A.
-c.:.) t..) vi oe t..) Cpd.Starting Method Analytical Data 0 -R -R' -R" -R"' No. , From Used o 1HNMR (DMS0): 5 12.34 (s, 1 .6.
H), 8.80 (t, J= 6.1 Hz, 1 H), 8.37 --.1 1--, 1--, (d, J=1.9 Hz, 1H), 8.06 (dd, J=
9.8, 7.9 Hz, 1 H), 8.05 (s, 1 H), = 7.36 (d, J=7.9 Hz, 1 H), 6.98 (dd, J- 17.9, 11.3 Hz, 1 H), 6.76 123i -CH3 -CH=CH2 CO2H /\.<I 122i 1-1 (s, 1 H), 5.89 (dd, J= 17.9, 1.5 Hz, 1 H), 5.36 (dd, J= 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);
n MS (ES): 408.4 I.) 1H NMR (DMSO-d6): 5 12.31 a, I.) t..) (br s, 1 H), 8.52 (d, J= 7.3 Hz, 1 (5) a, t..) u.) t..) H), 8.34 (d, J= 1.7 Hz, 1 H), 0 8.05 (m, 2 H), 7.34 (d, J= 7.9 "
123j -CH3 -CH=CH2 CO21-1 -0 122j Hz, 1 H), 6.97 (dd, J=11.5 and 17.9 Hz, 1 H), 6.74 (s, 1 H), 5.89 7 us, (d, J= 17.9 Hz, 1 H), 5.37 (d, J=
, 11.5 Hz, 1 H), 4.27 (q, J= 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 11-1NMR (DMSO-d6): 8 12.27 (br s, 1 H), 8.58 (m, 1 H), 8.23 (s, 1 H), 7.92 (m, 2 H), 7.47 (m, 1 1-d H), 7.22 (m, 1 H), 6.84 (m, 1 H), n 123k -CH3 -CH=CH2 CO2H ci-i, 122k 6.63 (s, 1 H), 5.76 (d, J= 17.9 Hz, 1 H), 5.24 (d, J-- 11.5 Hz, 1 cp o 1--, H), 3.71 (s, 3 H), 3.47 (s, 3 H), 1.02 (m, 3 H); MS (ES): 382.2 t..) vi oe t..) Cpd.
-R -R' -R" -R Starting Method "' Analytical Data No. From Used 1H NMR (DMSO-d6): ö 12.30 (br s, 1 H), 8.52 (d, J= 6.0 Hz, 1 H), 8.33 (d, J=1.7 Hz, 1 H), 8.02 (m, 2 H), 7.31 (d, J= 7.9 Hz, 1 H), 6.95 (dd, J= 11.5 and 1231 -CH3 -CH=CH2 CO2H 1221 1-1 17.9 Hz, 1 H), 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) (DMSO-d6): 8 12.81 (bs, 1 H), 8.72 (t, J = 5.6 Hz, 1 H), 8.38 (d, J= 1.8 Hz, 1 H), 8.08 (5) (dd, J = 1.8 and 8.1 Hz, 1 H), CH, 7.61 (s, 1 H), 7.57 (s, 1 H), 7.39 123m -CH=CH2 -CO2H 122m I-1 (d, J
=8 Hz, 1 H), 6.72 (dd, J = 0 0 11 and 17.5 Hz, 1 H), 5.99 (d, J
17.5 Hz, 1 H), 5.49 (d, 1=11 Hz, A
1 H), 3.57 (s, 3 H), 3.13 (t, J =
6.5 Hz, 2 H), 1.87 (in, 1 H), 1.37 (s, 9 H), 0.91 (d, J = 6.8 Hz, 6 H);
MS (ES-): 480.3 1-d oe DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
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JUMBO APPLICATIONS / PATENTS
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,T
I 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), u.) t..) Boc 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 0 Hz, 1 H), 8.77 (bs, 2 H), 9.15 (bs, 2 H), 10.58 (s, 1 H); MS (ES+) 714.78 I.) OH
u.) o 26ah 25ah J. MS (ES): 609.6 a, H
-A
1HNMR (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), 26a1 25ai J 7.4 (d, S = 5.8 Hz, 1 H), 7.35 (d, 3 = 6.9 Hz, 1 H), 7.29 (m, 3 H), 7.0 (m, 2 H), N3 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 1-d n ,-i cp =
t..) u, oe t..) NH
0 4111 NH, o n.) .6.
1-, 1-, NBR' la HO,C
- Cpd. Starting Method -R -R' Analytical Data No. From Used 1HNMR (DMSO-d6): 5 14.95 (s, 1 H), 8.97 (s, 4 H), 8.5 n (t, J = 6 Hz, 1 H), 7.97 (d, J = 2 Hz, 1 H), 7.80 (d, J =- 2 CH3 Hz, 1 H), 7.73 (dd, J = 7.9 and 2 Hz, 1 H), 7.61 (m, 7 H), 0 I.) 27a 26a 1-2 7.18 (t, J = 3.9 Hz, 1 H), 7.05 (d, J= 7.9 Hz, 1 H), 6.93 a, N) c7, a, (d, J = 7.9 Hz, 1 H), 3.01 (t, J = 6.9 and 6.0 Hz, 2 H), 1.81 u.) - (m, 1 H), 0.84 (d, J = 6.9 Hz, 6 H); MS (ES): 541.17 0 I.) IHNMR (DMSO-d6): 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 u.) \N 3 26b 1-2 (s, 1 H), 7.87 (s, 1H), 7.75 (d, J = 7.7 Hz, 1 H), 7.65 (m, 1 27b .3 a, ' H), 7.62 (m, 6 H), 7.05 (d, J = 7.7 Hz, 1 H), 6.93 (d, J --H
--.1 S
CH3 7.7 Hz, 1 H), 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 (ES): 541.42 Ill NMR (DMSO-d6): 5 13.28 (s, 1 H), 9.04 (s, 4 H), 8.5 CH3 (t, J = 6 Hz, 1 H), 7.97 (s, 1 H), 7.82 (s, 1 H), 7.74 (m, 3 lei CH3 26c 1-2 H), 7.62 (m, 5 H), 7.5 (t, J = 7.7 Hz, 2 H), 7.4 (t, J = 7.7, 27c 1 H), 7.1 (d, J = 7.7 Hz, 2 H), 6.97 (d, J = 7.7. Hz, 1 H), 3.01 (t, J = 6.5 Hz, 2 H), 1.8 (m, 1 H), 0.85 (d, 6.8 Hz, 6 Iv n H); MS (ES): 535.48 cp o c.:.) tµ.) vi oe tµ.) Cpd.Starting Method -R -R' Analytical Data No. From Used o 1H NMR (DMSO-d6): 8 9.03 (s, 2 H), 8.89 (s, 2 H), 8.49 t-.) j/N CH, (t, J = 6 Hz, 1 H), 7.99 (s, 1 H), 7.65 (m, 8 H), 7.37 (d, J
27d H3C s26d 1-2 3 Hz, 1 H), 7.04 (d, J = 7.7 Hz, 1 H), 6.98 (s, 1 H), 6.82 1-.'-- CH3 (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+):555.61 1H NMR (DMSO-d6): 8 14.10 (s, 1 H), 9.05 (bs, 2 H), cH3 8.79 (bs, 2 H), 8.47 (t, J = 5.6 Hz, 1 H), 8.3 (s, 1 H), 7.96 27e ), cii3 26e 1-2 (d, J. =
2 Hz, 1 H), 7.78 (m, 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 (ES): 525.36 I.) a, I.) c7, a, 4,. 1H NMR
(DMSO-d6): 8 9.07 (s, 2 H), 8.86 (s, 2 H), 8.53 0 cH3 (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 I.) 27f 0 'CH3 26f 1-2 Hz, 1 H), 6.64 (dd, J = 3.5 and 2 Hz, 1 H), 3.03 (t, J. = 6.9 u.) ' a, and 6.0 Hz, 2 H), 1.81 (m, 1 H), 0.86 (d, J = 6.9 Hz, 6 H);
H
MS (ES): 525.43 HC
CH, 1H NMR
(DMSO-d6): 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 =
27g CiT3 26g 1-2 s\t3, 2 Hz, 1 H), 7.62 (dd, J -- 7.7 & 2 Hz, 1 H), 7.54 (m, 5 H), s 7.38 (s, 1 H), 7.15 (s, 1 H), 6.99 (d, J = 7.8 Hz, 1 H), 6.89 Iv (d, 3 = 6.8 Hz, 1 H), 2.97 (t, J -- 6.5 Hz, 2 H), 2.20 (s, 3 n ,-i H), 1.76 (m, 1 H), 0.8 (d, 6.8 Hz, 6 H); MS (ES): 555.67 cp o l= . ) C. if I
l= . ) ' 134 _ Cpd. 1 Starting Method -R -R' Analytical Data No. From Used 1H NMR (DMSO-d6): 6 13.95 (bs, 1 H), 8.99 (bs, 2 H), o t..) 8.79 (bs, 2 H), 8.65 (d, J = 5 Hz, 1 H), 8.43 (t, J = 6 Hz, 1 .6.
CH3 H), 8.25 (s, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.00 (d, J = --.1 I .\-C1-1, 26h 1-2 7.8 Hz, 1 H), 7.94 (s, 1 H), 7.87 (t, .1-- 7.8 Hz, 1 H), 7.58 27h (m, 5 H), 7.34 (dd, J = 7.8 & 5 Hz, 1 H), 7.09 (dd, J = 7.7 -..z...... _...---..õ
N' 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 (ES+): 268.64 (m/2) 111 NMR (DMSO-d6): 6 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 CH3 (t, J --5.6 Hz, 1 H), 8.2 (dt, J - 1.8 & 7.7 Hz, 1 H), 7.99 n 1 CH3 261 1-2 (d, 3 =2.1 Hz, 1 H), 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 I.) a, I.) N Hz, 1 H), 7.15 (d, J = 7.7 Hz, 1 H), 6.95 (d, J = 7.7 Hz, 1 (5) a, vi H), 3.08 (t, J = 5 Hz, 2 H), 1.82 (m, 1 H), 0.9 (d, 6.8 Hz, 6 u.) H); MS (ESI): 268.85 (m1 2) I.) 1H NMR (DMSO-d6): 6 14.19(s, 1 H), 9.06 (bs, 2 H), u.) cH3 8.67 (bs, 2 H), 8.67 (d, J = 6 Hz, 2 H), 8.50 (t, J =
6 Hz, 1 0 a, 1 H), 7.97 (m, 2 H), 7.91 (dd, J = 7.7 and 2 Hz, 1 H), 7.80 H
27j i CH3 26j 1-2 (d, J = 6 Hz, 2 H), 7.64 (m, 6 H), 7.18 (d, J = 7.7 Hz, 1 -A
N 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 (ES+):
536.43 111 NMR (DMSO-d6): 6 9.04 (bs, 2 H), 8.78 (bs, 2 H), H3C = jli 3 8.55 (t, J
= 6 Hz, 1 H), 8.1 (s, 1 H), 7.98 (d, J = 4 Hz, 1 27k 26k 1-2 H), 7.95 (s, 1 H), 7.87 (d, J = 7.9 Hz, 1 H), 7.75 (d, J =
1-d n S CH3 6.9 Hz, 1 H), 7.66 (in, 4 H), 7.2 (m, 2 H), 7.09 (s, 1 H), 0 3.03 (t, J
= 6 Hz, 2 H), 2.55 (s, 3 H), 1.81 (m, 1 H), 0.85 cp (d, J = 6.8 Hz, 6 H); MS (ES): 583.59 o i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used 1H NMR (DMSO-d6): 8 9.1 (s, 2 H), 8.84 (s, 2 H), 8.56 (t, o t..) -\------- CH, \L-CH, 261 1-2 J = 6 Hz, 1 H), 8.08 (bs, 1 H), 7.67 (m, J = 7 H), 7.58 (d, J
= 7.9 Hz, 1 H), 7.11 (m, 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, .6.
N
1 2 H), 1.83 (m, 1 H), 0.88 (d, J = 6.8 Hz, 6 H); MS (ES):
cH3 538.64 )1H NMR (DMSO-d6): 8 9.04 (s, 2 H), 8.94 (s, 2 H), 8.46 CH, (t, J = 6 Hz, 1 H), 7.96 (s, 1 H), 7.63 (m, 6 H), 6.94 (s, 1 I N CH3 26m 1-2 H), 6.83 (d, J = 7.7 Hz, 1 H), 6.7 (d, J = 2, 1 H), 6.62 (dd, 27m 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,1H), 0.82 (d, 6.8 Hz, 6 H);
MS (ES): 528.76 I.) a, I.) 1-(5) CH, 1H NMR (DMSO-d6): 8 13.96 (s, 1 H), 9.02 (s, 2 H), 8.85 a, o, (s, 2 H), 8.46 (t, I = 6 Hz, 1 H), 7.91 (s, 1 H), 7.58 (m, 4 u.) --.,õ..--C11.2 CH, H), 7.39 (s, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 6.92 (d, I
27n 26n 1-2 7.7, 1 H), 6.87 (d, J = 7.7 Hz, 1 H), 6.01 (m, 1 H), 5.17 (d, 0 CA
J = 16.7 Hz, 1 H), 5.08 (d, J = 10 Hz, 1 H), 3.45 (d, J = 6 a, Hz, 211), 2.99 (t, J = 6 Hz, 2 H), 1.78 (m, 1 H), 0.83 (d, J
H
= 6.8 Hz, 611); MS (ES): 499.3 -A
111 NMR (DMSO-d6): 8 14.08 (bs, 1 H), 9.06 (s, 2 H), "
CH, 8.79 (s, 2 H), 8.51 (t, J = 6 Hz, 1 H), 8.11 (d, J = 2 Hz, 1 ,77 CH, 26o 1-2 H), 8.01 (m, 3 H), 7.85 (d, J = 3 Hz, 1 H), 7.63 (m, 6 H), 27o N
S
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, 211), 1.81 (m, 1 H), 0.86 (d, 6.8 Hz, 6 H);
MS (ES+): 542.2) 1-d n ,-i cp =
t..) u, oe .
t..) Cpd. Starting _ Method -R -R' Analytical Data No. From Used 1H NMR (DMSO-d6): 69.1 and 9.2 (2 br s, 4H, NH
o CH, proton), 8.6 (m, 1 H), 8.3 (m, 1 H), 8.0-7.6 (in, 8 H, t..) c.:.) 27p /7-:-TN CH, 26p 1-2 aromatic proton), 7.3 (m, 211), 3.1 (t, 2 H), 2.2 (s, 3 H), .6.
CH, 1.8 (m, 1 H), 0.9 (2s, 6 H); IR (K.Br Pellets) 2957, 1676, 1-1480, 1324, 844 cm-1. MS (ES+) : 497 11-1NMR (DMSO-d6): 5 9.06 (s, 2 H), 8.77 (s, 2 H), 8.53 ,- N/CH3 cH3 (t, J - 6 Hz, 1 H), 8.03 (n, 1 H), 7.64 (m, 6 H), 7.46 (d, J
26q 1-2 = 6.9 Hz, 1 H), 7.05 (s, 2 H), 6.96 (s, 1 H), 5.52 (s, 1 H), 27q H3C OH
= 3.02 (t, J = 6.8 Hz, 211), 1.81 (m, 1 H), 1.48 (s, 6 H),0.85 (d, .1= 6.8 Hz, 6 H); MS (ES): 539.4 111NMR (DMSO-d6): 5 9.06 (s, 2 H), 8.78 (s, 2 H), 8.52 n CH3 (t, J -----6 Hz, 1 H), 8.01 (d, J = 6.8 Hz, 1 H), 7.62 (m, 7 H), .-',,..., OH
7.46 (d, J = 6.8 Hz, 1 H), 7.0 (m, 211), 4.94 (t, J = 6 Hz, 1 I.) a, 27r NCH- 26r 1-2I.) H), 3.60 (q, J = 6 & 12.8 Hz, 2 H), 3.01 (t, J. = 6 Hz, 2 1-1), (5) 1-a, 2.58 (t, J = 6 Hz, 2 H), 1.82 (m, 1 H), 0.85 (d, I = 6.8 Hz, u.) 611); MS (ES): 525.4 I.) 11-1NMR (DMSO-d6): 8 9.01 (s, 2 H), 8.88 (s, 2 H), 8.5 (t, u.) CH, I = 6 Hz, 1 H), 8.07 (In, 1 H), 7.73 (m, 1 H), 7.63 (in, 7 a, H), 7.11 (d, J = 17 Hz, 1 H), 7.01 (d, J. = 17 Hz, 1 H), 6.97 H
27s 26s 1-2 -A
CH, CH, (n, 1 H), 6.69 (d, J = 17 Hz, 1 H), 5.24 (s, 111), 5.14 (s, 111), 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): 525.4 ziCH2 27t 0-1 1H NMR (DMSO-d6): 8 9.08 (s, 2 H), 8.82 (s, 2 H), 8.53 ---4c . 3 26t (t, I =6 Hz, 1 H), 8.04 (n, 1 H), 7.67 (m, 7H), 7.04 (m, 2 1-2 H), 5.55 (s, 1H), 5.20 (s, 11-1), 3.04 (t, J = 6.9 and 6.0 Hz, 1-d 1-i H); MS (ES+): 499.4 i cp o c.:.) t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used o t..) 1H NMR (DMSO-d6): 5 9.11 (s, 2 H), 8.86 (s, 2 H), 8.57 cH3 .6.
(t, J ---- 6 Hz, 1 H), 8.13 (m, 1 H), 7.53 (m, 2 H), 7.74 (m, 6 27u z-OH
'\CH3 26u 1-2 H), 7.37 (d, J = 7 Hz, 1 H), 7.17 (m, 2 H), 6.54 (d, J
= 12 1-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, 1 H), 0.87 (d, J
= 6.9 Hz, 6 H); MS (ES): 515.4 cH3 1H NMR
(DMSO-d6): 5 9.08 (s, 2 H), 8.82 (s, 2 H), 8.54 CH: (t, 3 = 6 Hz, 1 H), 8.05 (m, 1 H), 7.63 (m, 8 H), 7.06 (m, 2 27v õ....õ, -.,,.,,-"\C}13 26v 1-2 H), 5.52 (s, 1 H), 5.2 (s, 1 H), 4.63 (t, J =
5 Hz, 1 H), 3.56 n OH (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
I.) a, (ES): 529.4 I.) (5) 1H NMR (DMSO-d6): 5 9.08 (s, 2 H), 8.86 (s, 2 H), 8.54 I.) cH3 /=CH (t, J ---6 Hz, 1 H), 8.03 (m, 1 H), 7.62 (m, 7 H), 7.08 (d, J 0 u.) 27w 26w 1-2 = 7.5 Hz, 1 H), 6.99 (m, 1 H), 4.32 (s, 1 H), 3.03 (t, J = 1 '-ci-i3 a, 6.9 and 6.0 Hz, 2 H), 2.71 (t, J ----- 7 Hz, 2 H), 1.82 (m, 1 H
H), 0.87 (d, J = 6.9 Hz, 6 H); MS (ES): 483.3 -A
1H NMR (DMSO-d6): 5 13.8 (s, 1 H), 9.04 (s, 2 H), 8.96 CH3 (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 -.,/'-27x. ---C-K- cH3 .CH3 26x 1-2 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 1-d H), 1.72 (s, 3 H), 1.41 (s, 3 H), 0.84 (d, J = 6.9 Hz, 6 H);
n ,-i MS (ES): 527.5 cp o t..) vi oe t..) Cpd.Starting Method -R -R' Analytical Data No. From Used o o t..) 1H NMR (DMSO-d6): 5 8.99 (s, 2 H), 8.86 (s, 2 H), 8.52 CH, .6.
(t, J = 6 Hz, 1 H), 8.03 (m, 1 H), 7.63 (m, 6 H), 7.50 (d, J
26y 1-2 = 7 Hz, 1 H), 7.07 (d, J = 7 Hz, 1 H), 7.12 (in, 1 H), 5.40 1-(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 (m, 1 H), 0.84 (d, J = 6.9 Hz, 6 H); MS
(ES): 513.4 -, CH2 1H NMR
(DMSO-d6): 5 9.50 (bs, 1 H), 8.77 (bs, 2 H), cH3 8.49 (t, J
=6 Hz, 1 H), 7.98 (m, 1 H), 7.63 (n, 6 H), 7.55 Z N (d' J = 6.9 Hz, 1 H), 7.01 (d, J -- 7.9 Hz, 1 H), 6.99 (m, 1 0 ' 27z OH 26z 1-2 ' ''''-CH3 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), I.) a, I.) 1.81 (m, 1 H), 0.86 (d, J = 6.9 Hz, 6 H); MS (ES): 515.4 (5) a, o 0 IV
CH, 1H NMR
(DMSO-d6): 5 9.08 (a, 2 H), 8.73 (s, 2 H), 8.53 0 CA
(t, J ----- 6 Hz, 1 H), 8.06 (s, 1 H), 8.02 (bs, 1 H), 7.94 (d, J
' .
27aa '''''''CH3 26aa 1-2 = 7.8 Hz, 1 H), 7.62 (m, 6 H), 7.24 (d, J = 7.8 Hz, 1 H), a, H
6.95 (d, J = 7.8 Hz, 1 H), 3.03 (t, J = 6 Hz, 2 H), 1.82 (m, -A
1 H), 0.87 (d, J = 6.8 Hz, 6 H); MS (ES): 484.3 1H NMR (DMSO-d6): 5 9.05 (bs, 2 H), 8.81 (bs, 2 H), ,_....,_...-OH CH, 8.49 (t, J
= 6 Hz, 1 H), 8.02 (s, 1 H), 7.68 (s, 1 H), 7.62 27ab (m, 6 H), 7.53 (d, J = 6 Hz, 1 H), 7.21 (d, J. = 6 Hz, 1 H), \
'cH3 26ab 1-2 7.13 (d, J
= 7 Hz, 1 H), 7.01 (s, 1 H), 5.25 (t, J = 5 Hz, 1 1-d n S H), 4.51 (d, J = 5 Hz, 2 H), 3.01 (t, J = 6 Hz, 2 H), 1.81 (n, 1 H), 0.85 (d, J = 6.8 Hz, 6 H); MS (ES+): 571.64 cp o i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used o IHNMR (DMSO-d6): 5 9.05 (bs, 2 H), 8.78 (s, 2 H), 8.52 t..) c.:.) CH3 (t, J = 6 Hz, 1 H), 8.02 (bs, 1 H), 7.65 (m, 6 H), 7.53 (d, J .6.
= 5 Hz, 1 H), 7.54 (d, J =5 Hz, 1 H), 7.26 (d, J = 5 Hz, 1 OH
27ac S 26ac 1-2 H), 7.10 (m, 1 H), 6.99 (m, 1 H), 5.64 (t, J = 5 Hz, 1H), cH3 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 A .3 26ad 1-2 MS (ES: 585.4 n HO2c s 'CH3 I.) a, I.) 1-, (5) o u.) IHNMR (DMSO-d6): 8 14.11 (bs, 1 H), 9.05 (bs, 2 H), I.) CH, 8.75 (bs, 2 H), 8.5 (m, 1 H), 8.0 (s, 1 H), 7.8-7.6 (m, 8 H), 0 26ae 1-2 7.49 (d, J
= 3 Hz, 1 H), 7.1 (d, J = 6.9 Hz, 1 H), 7.0 (m, 1 L.I., 27ae HoH2c s CH3 H), 5.5 (m,1 H), 4.7 (m, 2 H), 3.09 (m, 2 H), 1.74 (m, 1 a, I
H
H) 0.86 (d, J = 6.9 Hz, 6 H); MS (ES+) 571.2 -.-1 ill NMR (DMSO-d6): 8 14.11 (bs, 1 H), 9.05 (bs, 2 H), HOH,C / 8.75 (bs, 2 H), 8.49 (t, J = 6 Hz, 1 H), 7.97 (s, 1 H), 7.67 , CH3 (d, J = 3 Hz, 1 H), 7.61 (m, 7 H), 7.54 (d, J = 3 Hz, 1 H), i 26af 1-2 7.06 (d, J
= 6.9 Hz, 1 H), 6.89 (d, J = 6.9 Hz, 1 H), 5.23 27af 1-d 'cli3 (t, J = 5 Hz, 1 H), 5.42 (d, J = 5 Hz, 2 H), 3.09 (t, J = 6.9 n s and 6.0 Hz, 211), 1.74 (m, 1 H) 0.86 (d, J = 6.9 Hz, 6 H);
MS (ES): 571.3 cp o c.:.) t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used o CH, 1H NMR
(DMSO-d6): 5 11.45 (s, 1 H), 9.08 (bs, 2 H), .6.
N.)*\ -------- 8.88 (bs, 2 H), 8.75 (t, J. = 6 Hz, 1 H), 8.04 (bs, 1 H), 7.88 --.1 ci=-i 26ag 1-2 3 (m, 1 H), 7.7 (m, 7 H), 7.03 (m, 2 H), 6.9 (m, 1 H), 6.62 27ag H (m, 1 H), 6.17 (m, 1 H), 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 (ES):
524.65 (DMSO-d6): 5 13.83 (s, 1 H), 8.9 (bs, 4 H), 8.47 CH, (t, J = 6 Hz, 1 H), 7.95 (s, 1 H), 5.3 (s, 1 H), 7.61 (m, 6 n .). OH H), 7.4 (m, 1 H), 6.95 (d, J = 7.7 Hz, 1 H), 6.85 (d, 1= 7.7 27ah Ci-1, 26ah 1-2 Hz, 1 H), 6.64 (d, J =9 Hz, 1 H), 6.22 (s, 1 H), 4.6 (t, J = 0 N
FP
1- 5.1 Hz, 1 H), 3.51 (d, J = 5.6 Hz, 2 H), 3.01 (t, J = 7 Hz, K) (5) .6.
a, 1- 2 H), 1.8 (m, 1 H), 0.85 (d, J = 6.9 Hz, 6 H); MS (ES): u.) 519.52 0I.) u.) CH, I
Fi.
27ai 1'43 26ai 1-2 MS (ES+) 514.25 H-,1 1H NMR (DMSO-d6): 5 9.05 (s, 2 H), 8.67 (s, 2 H), 8.47 CH:. (t, J = 6 and 5 Hz, 1 H), 7.95 (m, 1 H), 7.95 (m, 1 H), 7.63 CH3 (m, 5H), 7.40 (s, 1 H), 7.38 (d, J = 7.7 Hz, 1 H), 6.92 (m, 1-d 27aj 26n G
n cH3 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, cp J = 6.8 Hz, 6 H); MS (ES-) 499.31 i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used CH, 1H NMR (DMSO-d6): 5 14.3 (bs, 1 H), 9.05 (bs, 2 H), ./CH3 8.75 (bs, 2 H), 8.5 (m, 1 H), 8.0 (s, 1 H), 7.8-7.6 (m, 8 H), 27ak 32f G 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,1 H), 4.7 (m, 2 H), 3.09 (m, 2 H), 1.74 (m, 1 FE), 0.86 (d, J = 6.9 Hz, 6 H); MS (ES+) 487.2 CH, 27a1 N112 26ai G MS (ES+) 488.3 (100%:
M+1) CH3 1H N1VIR. (DMSO-d6): 5 13.9 (bs, 1 H), 9.05 (2 bs, 4 H), 8.5 (m, 1 H), 7.9 (s, 1 H), 7.7-7.5 (m, 8 H), 7.3 (d, I = 3 (5) 27am CH3 26u G Hz, 1 H), 6.9 (m, 2 H), 4.6 (m, 1H), 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 1H NMR (DMSO-d6): 5 9.84 (bs, 1 H), 9.07 (bs, 2 H), 0 CH3 8.87 (bs, 2 H), 8.51 (t, J = 6 and 5 Hz, 1H), 8.13 (m, 1 32a 31a 1-2 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 1-d cH3 32b 31b 1-2 Characterized in the next step oe Cpd. -R -R' Starting Method Analytical Data No. From Used o t..) 1H NMR (DMSO-d6): 8 14.24 (s, 1 H), 9.29 (bs, 2 H), .6.
CH, 9.01 (bs, 2 H), 8.73 (t, J --- 6 Hz, 1 H), 8.2 (d, J = 2 Hz, 1 --.1 .,,-----,..,v.CH2 H), 7.85 (m, 5 H), 7.74 (d, 2 Hz, 1 H), 7.4 (d, J = 8 Hz, 1 1-32c .C1.13 31e 1-2 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 CH3 31d 1-2 MS (ES") :
553.3 S
n CH, _ I.) a, I.) (5) 1-, a, .6. 1HNMR (DMSO-d6): 8 13.642 (bs, 1 H), 9.06 2 H), u.) CH, (s, 0 la .'-cii3 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), I.) 32e 31e 1-2 CA
I
0.86 (d, J = 6.8 Hz, 6 H); MS (ES): 547.4 a, I
H
-A
1H 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), cii, --CH, 31f 1-2 5.94 (d, J = 17 Hz, 1 H), 6.84 (dd, J. =
17 and 11 Hz, 2 H), 32f scH, 7.0 (m, 2 H), 7.64 (m, 8 H), 8.01 (s, 1 H), 8.54 (t, J =
Hz, 1 H), 8.77 (s, 2 H), 9.06 (s, 2 H); MS (ES+) :485.57 N,H2C /
IV
CH, n 32g \CH3 31g 1-2 MS (ES+) 596..2 cp =
t..) vi oe t..) , Cpd. Starting Method -R -R' Analytical Data k No. From Used o CH2OH CH, 1H NMR (DMSO-d6): 5 14.2 (bs, 1 H), 9.1 (bs, 4 H), 8.6 .6.
32h .,...s..._, -Cii, 31h 1-2 (m, 1 H), 8.15 (s, 1 H), 7.9-7.6 (m, 8 H), 7.2 (m, 2 H), 6.7 1--, 1--, (s, 1 H), 5.3 (br s, 1 H), 4.6 (m, 2 H), 3.1 (m, 2 H), 1.9 (m, 0 1 H), 0.9 (d, J = 6.7 Hz, 6 H); MS (ES+) 555.1 1H NMR (DMSO-d6): 5 13.84 (bs, I H), 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), H0H2C / CH37.95 (s, 1 H), 7.77 (s, 1 H), 7.67 (in, 2 H), 7.61 (m, 5 H), 32i 31i 1-2 7.02 (d, J = 7.7 Hz, 1 H), 6.94 (n, 1 H), 5.13 (t, I =5 Hz, \k -C1-13 1 H), 4.47 (m, 2 H), 2.97 (t, J = 6.8 Hz, 2 H), 1.78 (m, 1 n 0 H), 0.80 (d, 1 -- 6.8 Hz, 6 H); MS (ES-) 553.3, (ES+) 555.3 I.) a, CH
I.) 1--, 3 0, .6.
a, .6. 40 - NH 39 1-2 MS (ES+) 524.3 u.) -/ '-'Cii3 I.) 1H NMR (DMSO-d6): 5 13.82 (s, 1 H), 9.20 (bs, 1 H), u.) CH3 9.10 (bs, 1 H), 8.51 (t, 3 = 6 Hz, 1 H), 7.97 (s, 111), 7.73- H
a, \ 0 11 7.45 (m, 5 H), 7.43-7.39 (m, 2 H), 7.20 (t, J = 8 Hz, 1 H), 1 -A
CH3 7.10 (m, 6 H), 6.96 (d, J = 8 Hz, 1 H), 3.0 (t, J = 6 Hz, H), 1.80 (m, 1 H), 0.68 (d, J = 6.8 Hz, 6 H); MS (ES) 551.30 CH, 1H NMR (DMSO-d6): 5 9.21 (2 bs, 2 H each, 4 H), 8.61 46 lik '-'CH3 45 1_2 (m, 1 H), 8.1 (s, 111), 7.8-7.4 (in, 10 H), 7.3 (s, 1 H), 7.2 1-d n (d, 1 =- 7 Hz, 1 H), 7.1 (m, 2 H), 5.2 (s, 2 H), 3.1 (m, 2 H), 1.8 (m, 1 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES) 565.27 cp o 1--, i-,.)--t..) vi oe t..) _ Cpd.Starting Method -R -R' Analytical Data No. From Used o o 111 NMR (CF3CO2D): 5 8.43 (s, 1 H), 8.01 (d, J = 7.5 Hz, t..) c.:.) .6.
1 H), 7.67 (q, J = 24 and 8.4 Hz, 411), 7.56 (d, J = 7.7 Hz, CH,1-, 51 50 1-2 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 111NMR (DMSO-d6): 5 14.00 (bs, 1 H), 8.52 (t, J. = 6 and T S CH, 5 Hz, 1 H), 7.98 (s, 1 H), 7.63 (m, 8 H), 7.07 (d, J = 7.7 - 53-/ 52 1-2 Hz, 1 H), 6.96 (d, J = 7.7 Hz, 1 H), 3.83 (s, 2 H), 3.02 (t, J
c11.3 = 6.8 Hz, 211), 1.81 (m, 1 H), 0.86 (d, J = 6.8 Hz, 611);
NH, MS (ES-) 568.1 11-1 NMR (DMSO-d5): 5 13.84 (br s, 1 H), 9.05 (s, 2 H), I.) I.) 1-, 8.94 (s, 2 H), 8.48 (t, J= 5.7 Hz, 1 H), 7.97 (d, J= 1.9 (5) .6.
vi CH, Hz, 1 H), 7.70 (m, 7 H), 7.00 (d, J= 7.9 Hz, 1 H), 6.92 (d 68a 1-2, S
, u.) -.....,..___,õõõ..cH3 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, .1= 10.9 Hz, 1 H), 70a N
CA
3.19 (m, 2 H), 1.46 (qui, J = 7.0 Hz, 2 H), 1.29 (sex, J=
7.0 Hz, 2 H), 0.87 (t, J= 7.3 Hz, 3 H); MS (ES+): 485.2 , H
-A
111 NMR (DMSO-d6): 5 12.71 (br s, 1 H), 9.12 (s, 2 H), CH, 8.93 (s, 2 H), 8.20 (m, 2 H), 7.86 (m, 1 H), 7.70 (m, 6 H), 70b 68b 1-2, ' 7.20 (m 211), 6.87 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.99 ..., CH3 (d, J= 17.7 Hz, 1 H), 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, 611); MS
(ES ): 527.3 1-d n 1-i cp .
o ,-, t..) u, oe t..) 145 .
, Cpd. Starting Method -R -R' Analytical Data No. From Used o tµ.) 111 NMR (DMSO-d6): 8 12:84 (br s, 1 H), 9.08 (m, 3 H), '(;) 4=, 8.36 (d, .1= 7.7 Hz, 1 H), 8.18 (s, 1 H), 7.83 (m, 1 H), 70c CIH, -0 68c 1-2, S
7.67 (m, 6 H), 7.15 (m, 3 H), 6.86 (dd, J= 10.9 and 17.7 1-.. 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 (ES): 511.3 1H NMR (DMSO-d6): 69.11 (s, 2 H), 8.89 (s, 2 H), 8.81 I (t, J= 5.7 Hz, 1 H), 8.21 (s, 1 H), 7.85 (m, 1 H), 7.68 (m, CH, 70d ..,, CH2 68d 1-2, S 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 (m, 1 H), 5.39 (d, J= 10.9 Hz, 1 11), 5.12 (m, 2 H), 3.88 (t, J= 5.0 Hz, 1 H); MS
I.) (ES): 469.2 a, I.) c7, a, .6.
u.) c7, 1H NMR
(DMSO-d6): 5 9.11 (s, 2 H), 9.01 (s, 2 H), 8.38 0 70e N,cõ..CH, (d, J= 7.5 Hz, 1 H), 8.18 (s, 1 H), 7.83 (m, 1 H), 7.67 (m, I.) CIH, 68e 1-2, S
6 H), 7.16 (m, 3 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 0 CH, 5.98 (d, J= 17.7 Hz, 1 H), 5.39 (d, J--- 10.9 Hz, 1 H), u.) I
4.09 (m, 1 H), 1.15 (d, J= 6.6 Hz, 6 H); MS (ES): 471.3 a, I
H
--.1 1H NMR (DMSO-d6): 69.11 (s, 2 H), 9.05 (s, 2 H), 8.31 CH,I
<H (d, J= 8.1 Hz, 1 H), 8.20 (s, 1 H), 7.85 (d, J= 7.7 Hz, 1 H), 7.69 (m, 6 H), 7.17 (m, 3 H), 6.86 (dd, .1.--=- 10.9 and 70f --, ________________ CH3 68f 1-2, S
17.7 Hz, 1 H), 5.98 (d, J= 17.7 Hz, 1 H), 5.39 (d, J=
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= 7.3 Hz, 3 H); MS (ES): 485.3 1-lo n ,-i cp =
l=.) Cif I
l=.) _______________________________________________________________________________ ____________________________ -, Cpd. Starting Method -R -R' Analytical Data No. From Used o 11-1 NMR (DMSO-d6): 8 12.82 (br s, 1 H), 9.25 (m, 1 H), t..) c.:.) CH2 9.12 (s, 2 H), 8.91 (s, 2 H), 8.23 (s, 1 H), 7.87 (m, 1 H), .6.
70g I CF, 68g 1-2, S
7.68 (m, 7 H), 7.18 (m, 3 H), 6.87 (dd, J= 10.9 and 17.7 --4 Hz, 1 H), 5.99 (d, J= 17.7 Hz, 1 H), 5.40 (d, J= 10.9 Hz, 9140z5, 2 H), 7.09 H); MS (ES+):
' , __=((11Hs ,H1,NmR17).,H74)H.,)0;77(:D7(1m1mH,(sm)(2,0,H5-1.d)31;69)MH:
()IS,17(JE0.3=.S34+41)(0:t(,:59.1,1Hz1=1}{.27:81, (m, 4 H) 8.18 70h --. 68h 1-2 S m 3 H
6.86 dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J
505.3 n 11-1 NMR (DMSO-d6): 8 12.64 (br s, 1 H), 9.09 (m, 4 H), I.) a, c/H2 8.56 (m, 1 H), 8.09 (s, 1 H), 7.66 (m, 9 H), 7.08 (m, 3 H), N) OH
1-, .iT
.6. 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.96 (d, J= 17.7 Hz, u.) --4 70i -,,. 68i 1-2, S
1 H), 5.37 (d, J= 10.9 Hz, 1 H), 4.40 (m, 2 H) 3.39 (m, 2 I.) H), 3.22 (m, 2 H), 1.48 (m, 4 H); MS (ES): 501.3 (100%:
1\4+1) LO
I
FP
11-1 NMR (DMSO-d6): 8 9.08 (m, 4 H), 8.69 (t, J=. 6.0 Hz, H
CH, 1 H), 8.16 (s, 1 H), 7.69 (m, 5 H), 7.13 (d, J-- 7.7 Hz, 2 --1 70j 68j 1-2, S H), 7.09 (m, 3 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.97 (d, J= 17.7 Hz, 1 H), 5.38 (d, .1= 10.9 Hz, 1 H), 3.11 (t, J= 6.0 Hz, 2 H), 1.01 (m, 1 H), 0.41 (m, 2 H), 0.21 (m, 2 H); MS (ES+): 483.3 CH, . 11-1 NMR
(DMSO-d6): 8 9.11 (s, 2 H), 8.97 (s, 2 H), 8.54 70k (m, 1 H), 8.12 (s, 1 H), 7.68 (m, 7 H), 7.17 (m, 4 H), 6.86 1-d -,, c113 68k 1-2, S
(dd, J= 10.9 and 17.7 Hz, 1 H), 5.97 (d, J= 17.7 Hz, 1 n ,-i H), 5.38 (d, J= 10.9 Hz, 1 H), 2.75 (d, J=4.3 Hz, 1 H);
MS (ES ): 443.26 cp o c.:.) t..) vi oe t..) Cpd.Starting Method -R -R' Analytical Data No. From Used o t..) 1H NMR (DMS0415): 5 9.07 (s, 2 H), 8.92 (s, 2 H), 8.53 .6.
(t, J= 5.5 Hz, 1 H), 8.02 (s, 1 H), 7.62 (m, 7 H), 7.01 (m, --.1 701 T2 ..,, CH3 681 1-2, S
2 H), 6.85 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.95 (d, J--= 1-.õ,. 17.7 Hz, 1 H), 5.36 (d, J= 10.9 Hz, 1 H), 3.24 (qui, J=
6.7 Hz, 2 H), 1.08 (t, J= 7.2 Hz, 3 H); MS (ES+): 457.2 1H NMR (DMSO-d6): 5 12.53 (br s, 1 H), 9.10 (m, 3 H), - 70m CIH2 -CD 8.38 (d, J= 7.9 Hz, 1 H), 8.11 (s, 1 H), 7.68 (m, 7 H), 68m 1-2, S 7.12 (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), 3.94 (m, 1 H), 1.88-1.33 (m, 12 H); MS (ES4): 525.3 n 1H NIVIR (DMSO-do): 8 9.09 (tn, 4 H), 8.59 (t, J= 5.2 Hz, I.) 1 H), 8.17 (s, 1 H), 7.70 (m, 7 H), 7.16 (m, 4 H), 6.87 a, CH, "
--,,.Cli, (dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J= 17.7 Hz, 1 (5) .6. 70n 11 68n 1-2, S
a, u.) oe H), 5.39 (d, J= 10.9 Hz, 1 H), 3.20 (q, J= 6.7 Hz, 2 H), 0 1.52 (sex, J= 7.2 Hz, 2 H), 0.87 (t, J= 7.3 Hz, 3 H); MS
"
(ES): 471.3 CA
I
(DMSO-do): 8 12.97 (br s, 1 H), 9.08 (s, 2 H), a, -8.99 (s, 2 H), 8.53 (t, J= 5.1 Hz, 1 H), 8.06 (s, 1 H), 7.64 (m, 7 H), 7.06 (m, 2 H), 6.85 (dd, J= 10.9 and 17.7 Hz, 1 IL
,1 70o .µ 68o 1-2, S
H), 5.96 (d, J= 17.7 Hz, 1 H), 5.36 (d, J= 10.9 Hz, 1 H), 3.20 (q, J= 6.5 Hz, 2 H), 1.49 (qui, J= 6.6 Hz, 2 H), 1.27 (m, 4 H), 0.86 (t, J= 6.6 Hz, 3 H); MS (ES): 499.3 1H NMR (DMSO-do): 8 9.10 (s, 2 H), 8.91 (s, 2 H), 8.55 CI
H2 .,.CCH3 (t, J= 5.5 Hz, 1 H), 8.13 (s, 1 H), 7.68 (m, 711), 7.12 (m, 1-d CH, 1-2, 2 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J= n ,-i 70p === 68p S
17.7 Hz, 1 H), 5.38 (d, J= 10.9 Hz, 1 H), 3.10 (m, 211), cp 1.62(m, 1 H), 1.39(m, 1 H), 1.10(m, 1 H), 0.86 (m, 6 H); MS (ES ): 499.3 t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used o t..) CH2 1H NMR (DMSO-d6): 69.06 (s, 2 H), 8.82 (s, 2 H), 8.11 I CH, (t, .1= 7.9 Hz, 1 H), 8.00 (s, 1 H), 7.62 (m, 7 H), 6.99 (m, .6.
--.1 -, 2 H), 6.85 (dd, J.=-. 10.9 and 17.7 Hz, 1 H), 5.95 (d, J= 1-70q 68q 1-2, S
-CH, 17.7 Hz, 1 H), 5.35 (d, J= 10.9 Hz, 1 H), 3.81 (q, J= 7.5 Hz, 1 H), 1.45 (m, 4 H), 1.24 (m, 4 H), 0.82 (m, 6 H);
MS (ES): 527.3 _ 0-12 1H NMR (DMSO-d6): 5 13.81 (s, 1 H), 8.44 (m, 4 H), 70r l is1}{2 68r 1-2, S
7.97 (s, 1 H), 7.61 (m, 7 H), 6.90 (m, 3 H), 5.93 (d, J=
.,, 17.7 Hz, 1 H), 5.34 (d, J= 10.9 Hz, 1 H), 3.22 (m, 5 H), n 2.73 (m, 2 H), 1.52 (m, 4 H); MS (ES): 500.3 -I \ ) FP
1H NMR (DMSO-d6): 5 9.09 (s, 2 H), 8.86 (s, 2 H), 8.42 I.) (5) 1- cH2 a, .6. (d, J-----.
7.5 Hz, 1 H), 8.11 (s, 1 H), 7.68 (m, 8 H), 7.10 (m, u.) o 70s -0 68s 1-2, S 2 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.97 (d, .1-.-L) 17.7 Hz, 1 H), 5.38 (d, J= 10.9 Hz, 1 H), 4.20 (q, J= 7.2 \) \
Hz, 1 H), 1.93-1.44 (m, 8 H); MS (ES): 497.2 u.) FP
I
1H NMR (DMSO-d6): 5 13.78 (br s, 1 H), 9.07 (s, 2 H), H
-.-1 70t 68t 1-2, S
.1 8.87 (s, 2 H), 8.25 (d, = 8.1 Hz, 1 H), 8.00 (s, 1 H), 7.62 I,L, (m, 7 H), 6.98 (m, 2 H), 6.85 (dd, J=
10.9 and 17.7 Hz, 1 H), 5.94 (d, J= 17.7 Hz, 1 H), 5.35 (d, J= 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 (ES): 527.2 cH2 51794NMR0, j(=DM17S.70H-dz6,)1:
5H1),35.3.365(bor,s J., 1,1: 11)0,.99.H05z,(m1 H, 3),H), 1-d I
n 8.49 (s, 1 H), 7.98 (s, 1 H), 7.61 (m, 8 H), 6.92 (m, 3 H), 70u 68u 1-2, S
cp o 2.81 (m, 1 H), 0.69-0.48 (m, 4 H); MS (ES): 469.3 t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used 11-1NMR (DMSO-d6): 8 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, 70v Cr, 68v 1-2, S 2 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 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 1H NMR (DMSO-d6): 8 13.17 (br s, 1 H), 9.05 (m, 4 H), CI
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
70w 68w 1-2, S
= 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 11-1NMR (DMSO-d6): 8 9.07 (s, 2 H), 8.90 (s, 2H), 8.50 (5) CH, (t, J = 5.5 Hz, 1 H), 8.04 (s, 1 H), 7.63 (m, 7 H), 7.03 (m, cH3 2 H), 6.85 (dd, J = 10.9 and 17.7 Hz, 1 H), 5.96 (d, 0 70x 68x 1-2, S
17.7 Hz, 1 H), 5.36 (d, J= 10.9 Hz, 1 H), 3.23 (q, J= 6.5 Hz, 2 H), 1.59 (m, J= 7.0 Hz, 1 H), 1.39 (q, J= 6.8 Hz, 2 H), 0.88 (d, J= 6.6 Hz, 6 H).
=
oe NH
o 0 40 NH, n.) W."
.6.
R
le N
H
1-, 1-, OH 1.4 = H3CO2C
Cpd. Starting Method 1 -R
Analytical Data No. ____________________________ From Used IHNMR. (DMSO-d6): 8 10.85 (s, 1 H), 9.21(s, 2 H), 8.91 (s, 2 H), 8.71 (t, J =
5.9 o 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 I.) 31a ..'LC1-1, 30a J 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), a, "
(5) a, 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), u.) 1.86 (m, 1 H), 3.88 (d, 6.87 Hz, 6H); MS (ES+) 515.3 I.) 31b .-''' .µ--c}13 30b J
MS (ES): 527.2 u.) a, H
31c./.--\,/-- CH2 30c J Characterized in the next step -A
IHNMR (DMSO-d6): 8 10.59 (bs, 1 H), 9.16 (s, 2 H), 8.85 (s, 2 H), 8.69 (t, J =
31d_______ 30d J 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), s 3.55 (s, 2 H), 3.07 (t, J = 6.8 Hz, 2 H), 1.85 (m, 1 H), 0.87 (d, J = 6.8 Hz, 6 H),;
MS (ES-) 567.3, (ES+) 569.3 1-d n ,-i 31e IO 30e J MS (ES): 561.4; MS (ES):
563.4 cp o i-4.)--t..) vi oe t..) Cpd. Starting Method -R
Analytical Data No. From Used o 11-1 NMR (DMSO-d6): 8 10.73 (s, 1H), 9.24 (s, 2H), 9.00 (s, 2H), 8.71 (t, J =
5.7 t..) Hz, 1H), 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.05 (dd, J = 8.0, 1.9 Hz, 1H), 7.77 (m, 5H), .6.
--.1 31f ----CH2 30f J 7.71 (dd, J = 7.9, 1.5 Hz, 1H), 7.42 (d, J =7.9 Hz, 1H),7.31 (d, J = 7.9 Hz, 1H), 1-6.89 (dd, J = 17.6, 11.0 Hz, 1H), 6.04 (d, J =17.6 Hz, 1H), 5.42 (d, J = 11.0 Hz, 1H), 3.56 (s, 3H), 3.10 (t, J = 6.4 Hz, 2H), 1.85 (m, 1H), 0.89 (d, J = 6.7 Hz, 6H); MS (ES+): 499.3 1HNMR (DMSO-d6): 5 10.73 (s, 1 H), 9.19 (bs, 2 H), 8.88 (bs, 2 H), 8.71 (t, I
=
N3H2C / 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 31g i 30g J 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 s (t, I = 6.8 Hz, 2 H), 1.87 (m, 1 H), 0.92 (d, J = 6.8 Hz, 6 H); MS (ES-) 608.2, n (ES+) 610.3 I.) N) (5) a,.
t..) 31h 30h J Characterized at the next step 0 IV
LO
1HNMR. (DMSO-d6): 5 10.68 (s, 1 H), 9.17 (bs, 2 H), 8.82 (bs, 2 H), 8.68 (t, J
= 1 FP
6 Hz, 1 H), 8.25 (d, J. = 2 Hz, 1 H), 8.16 (d, J = 2 Hz, 1 H), 8.05 (dd, I = 8 and 2 1 H
30i J 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, 3= 5 Hz, 1 H), 4.54 (d, J. = 5 Hz, 2 --1 0 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 -o lip 42 J MS (ES): 563.4 1-d 45 -Obn 8 J Characterized in the next step n ,-i . .
cp 50 -OCH3 49 J MS (ES): 503.1 o i-,.)--t..) vi oe t..) Cpd. Starting Method -R Analytical Data No. From Used Iss 52 31g G Characterized in the next step 1.) 1`) (5) 1.) oe NH
o R' n.) W."
R si 4.
--.1 1-, N
1-, H
H
CO,CSI
11, _ 0 Cpd.Starting Method -R -R' Analytical Data No. From Used n 34 -0S02CF3 -H 33 J MS (ES): 621.2 I.) a, I.) (5) 1¨ 0 a, vi Lo 4,. 35 -0S02CF3 34 P MS (ES): 755.2;
(ES-) 753.3 0 OBn 1.) o o co i /
C 35 + 36 D-2 MS (ES): 828.5 ' H
OBn TIPS
, /
38 CN -H 37 G MS (ES): 694.4; (ES") 692.4 OH
IV
39 -H 38 Q Characterized in the next step n ,-i cp 1-, W."
n.) vi oe n.) R a R' o 11101 n.) .6.
--.1 1-, 1-, H3CO2C R" c.:.) , Cpd. Starting Method -R -R' -R"
Analytical Data No. From Used 1HNMR (DMSO-d6): 8 9.69 (s, 1 H), 8.49 (d, J= 2.0 Hz, 1 H), 8.22 (d, J= 6.9 Hz, 1 H), 7.53 (in, 4 H), 7.43 (m, 2 H), 7.37 (m, 2 H), 7.24 (d, 54 -0Bn -CHO -0O2MEM 5 + 6 D-2 J=
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, n J= 4.9 Hz 2 H), 3.32 (s, 3 H); MS (ES):
I.) 501.02 (M+Na)+
a, I.) 1-(5) vi 111 NMR (DMSO-d6): 8 12.65 (s, 1 H), 8.41 (d, a, vi u.) J2.0 Hz 1 H), 8.14 (dd, J---- 2.0 and 7.9 Hz, 1 H), 7.50(m, 3 H), 7.38(m, 4H), 7.24 (dd, J=
I.) 55 -0Bn -CO2H -0O2MEM 54 E 3.0 and 8.9 Hz, 1 H), 7.11 (d, J= 8.9 Hz, 1 H), 0 u.) 5.54 (s, 2 H), 5.20 (s, 2 H), 3.82 (t, J4.9 Hz, a, 2 H), 3.57 (s, 3 H), 3.49 (t, J=4.9 Hz, 2 H), , -,1 3.23 (s, 3 H); MS (ES): 493.2 1HNMR (DMSO-d6): 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, 1 H), 7.51 (d, J= 7.9 Hz, 2 H), 141 -0Bn -CHO 140 +6 D-2 7.45 (m, 2 H), 7.35 (m, 3 H),7.29 (d, J= 7.9-. --.NCH3 Hz, 1 H) 7.2 (d, J= 7.9 Hz, 1 H), 5.24 (s, 2 H), H
3.55 (s, 3 H), 2.3 (d, J= 6.9 Hz, 2 H) 2.1 (m, J 1-d = 6.9 Hz, 1 H), 1.0 (d, J= 6.9 Hz, 6 H); MS
n 1-i , (ES+): 446.31 cp .
o ,-, t..) u, oe t..) Cpd.
Starting Method -R -R' -R" Analytical Data No. From Used o 1H NMR (DMSO-d6): 6 12.38 (s, 1 H), 10.01 t..) (s, 1 H), 8.05 (s, 1 H), 7.68 (d, J= 7.9 Hz, 1 H), .6.
7.41 (d, J= 7.9 Hz, 2 H), 7.35 (m, 5 H), 7.27 1-, 1-, 142 -0Bn -CO2H 141 E (m, 1 H), 7.11 (d, J= 8.9 Hz, 1 H), 7.04 (d, J-o CH, 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, J= 6.9 3 Hz, 1 H), 0.852 (d, J= 6.9 Hz, 6 H); MS (ES-):
H
460.2 11-1NMR (DMSO-d6): 5 10.12(s, 1 H), 8.16 (d, J= 1.9 Hz, 1 H), 7.80 (dd, J= 1.9 and 8.3 o cH3 Hz, 1 H), 7.42 (m, 6 H), 7.26 (dd, J= 2.8 and n 8.3 Hz, 1 H), 7.13 (m, 2 H), 5.21 (s, 2 H), 5.17 143 -0Bn -0O2MEM --, ,-.. 142 F
N CH, (s, 2 H), 3.54 (s, 3 H), 3.40 (m, 2 H), 3.32 (m, 2 I.) H
H), 2.22 (d, J- 7.0 Hz, 211), 2.10 (m, 4H), a, I.) (5) 1-, vi 0.95 (d, .1= 6.4 Hz, 6H); MS (ES): 572.3 a, u.) c7, (M+Na)+
I.) 111 NMR (DMSO-d6): 8 12.7 (br s, 1 H), 9.09 O CH, (s, 2 H), 8.91 (s, 211), 8.57 (m, 1 H), 8.11 (s, 1 u.) , 144 -OH -0O2MEM ,, ...-,,,., 143 G H), 7.92 (d, J-- 1.9 Hz, 1 H), 7.81 (m, 3 H), a, 7.67 (m, 5 H), 7.14 (m, 311), 6.66 (m, 1 H), H
-,1 H
4.40 (t, J= 5.3 Hz, 1 H), 3.39 (m, 211), 3.22 (m, 2 H, 1.48 (m, 4 H) ; MS (ES"): 592.2.
O CH, .
145 -0S02CF3 -0O2MEM -, ,,,,,.". 144 B-2 MS (ES):, 592.2 , H
O CH, IV
n 146a ..\ -0O2MEM -,õ ..,--.L.,,,-. 145 D-2 MS
(ES: 532.5 (M+Na) N CH, cp o 1-, W."
n.) vi oe n.) Cpd. Starting Method -R -R' -R" Analytical Data No. _____________________________________________________ From Used o t..) Ili NMR (DMSO-d6): 5 10.1 (s, 1 H), 8.21 (d, .6.
J= 2.0 Hz, 1 H), 8.10 (d, J=2.0 Hz, 1 H), 7.89 O cH3 (dd, J=2.0 and 7.9 Hz, 1 H), 7.84 (d, J=3.0 and 8.9 Hz, 1 H), 7.63 (m, 2 H), 7.25 (d, J
H
=
146b -0O2MEM -i\I--- CH 3 145 D-2 7.9 Hz, 1 H), 7.19 (m, 2 H), 5.22 (d,J= 14.8 S Hz, 2 H), 3.57 (s, 3 H), 3.43 (t, J- 4.9 Hz, 2 H), 3.34 (t, J-- 4.9 Hz, 2 H), 3.20 (s, 3H), 2.23 (d, J= 6.9 Hz, 2 H), 2.11 (m, J= 6.9 Hz, 1 H), .
0.96 (d, J= 5.9 Hz, 6 H); MS (ES): 526.48 146c -CH=CH2 -0O2MEM -- j---..._,r--..CH3 145 D-3 MS (ES): 470.2 (WNW
N
I\) H
.i.
I\) (5) 1-, 0 CH, .i.
vi Lo --4 147a _- -CO2H146a I-1 MS (ES): 420.29 0 ',....., ,,.......".........
IV
H
_ Lo 11-1NMR (DMSO-d6): 5 12.65 (s, 1 H), 10.12 I
FP
0 CH3 (s, 1 H), 8.18 (d, J= 1.9 Hz, 1 H), 8.07 (d, J= I
H
147b -CO2H \ I-1 3.0 Hz, 1 H), 7.83 (m, 2 H), 7.61 (m, 2 H), 7.19 N 146b -,1 CH3 (m, 3 H), 3.56 (s, 3 H), 2.22 (d, J= 6.9 Hz, 2 S H H), 2.11 (m, J= 6.9 Hz, 1 H), 0.96 (d, J= 6.9 Hz, 6 H); MS (BS): 438.52 O CH, 147c -CH=CH2 -CO2H -- .,,,-- 146c I-1 MS (ES): 380.32 H
n ,-i cp =
i-,.,--t..) u, oe t..) Cpd. Starting Method -R -R' -R"
Analytical Data 0 No. From Used o 1H NMR (DMSO-d6): 8 9.70 (s, 1 H), 8.42 (t, t..) c.:.) CH, J=
6.2 Hz, 1 H), 7.90 (dd, J= 1.1 & 6.6 Hz, 1 .6.
--.1 H H), 7.82 (d, J= 1.9 Hz, 1 H), 7.72-7.50 (m, 3 1---, ,N
173 -H -CHO ---'-cii3 1/7320+ D-2 H), 7.34 (d, J= 7.7 Hz, 1 H), 7.27 (dd, J= 1.3 O
' &
6.2 Hz, 1 H), 4.38 (d, J= 6.0 Hz, 2 H), 3.53 (s, 3 H), 2.47 (m, 1 H)õ 1.07 (d, J= 7.0 Hz, 6 H); MS (ES ): 340.05 CH, 1H
NMR (DMSO-d6): 8 12.35 (br s, 1 H), 8.31 H (t, J= 7.5 Hz, 1 H), 7.80-7.31 (m, 5 H), 7.06 174 -H -CO2H '--,.2',1, 173 E (m, 2 H), 4.25 (d, J- 6.0 Hz, 2 H), 3.41 (s, 3 cH3 H), 2.37 (m, 1 H), 0.97 (d, J= 7.0 Hz, 6 H);
n 0 MS (ES): 353.83 0 1H NMR (DMSO-d6): 8 9.70 (s, 1 H), 7.87 (m, I.) .1,.
I.) 2 H), 7.69 (m, 1 H), 7.55 (in, 2 1-1), 7.35 (d, J=
(5) , 1-, a, 180 -H -CHO CH 179 +
D-2 7.9 Hz' 1 H), 7.27 (d, J= 7.5 Hz, 1 H), 4.51 (s, u.) H), 3.52 (s, 3 H), 3.05 (m, 2 H), 1.92 (m, 1 I.) CH3 H), 1.40 (m, 9 H), 0.85 (d, J= 6.8 Hz, 6 H); 0 ig u.) MS (ES): 448.3 (M+Na)+
.1,.
1H NMR (DMSO-d6): 8 7.81 (m, 2 H), 7.56 (m, H
H), 7.44 (m, 211), 7.16 (m, 211), 4.47 (s, 2 181 -H -CO2H 180 E H), 3.51 (s, 311), 3.02(m, 211), 1.92 (m, J.=--NCH, 7.0 Hz, 111), 1.41 (m, 9 H), 0.85 (d, J= 6 Hz, 6 H); MS (ES): 440.2 1H NMR (DMSO-d6): 89.78 (s, 1H), 8.85 (t, J
cH3 =
5.7 Hz, 111), 8.50 (d, J = 2.0 Hz, 1H), 8.20 H (dd J ---'- 8.2, 1.9 Hz 7., 9H), 5., 184a -0Bn -CHO '`_..1"1,--'"\, 3a + 6 D-2 ' ' " 1H)55 (m 35 (s 1-d 2H), 3.69 (s, 3H), 3.23 (t, J = 6.5 Hz, 211), 1.98 n (m, 111), 1.02 (d, J = 6.8 Hz, 611); MS (ES+):
446.3 cp o c.:.) t..) vi oe t..) Cpd. Starting Method -R -IV -R"
Analytical Data No. From Used o H
n.) 1"s1.-CF3 .6.
184b -0Bn -CHO 3f 6 D-2 MS
(ES): 470.2 --4 1-, 1-, H
,.,_,7NCH, 184c -0Bn -CHO 3i + 6 D-2 MS (ES): 418.3 _ CH, H
184d -0Bn -CHO ,.,..õ,--,,,.,õ,3j 6 (ES): 460.3 o 11INMR (DMSO-d6): 6 10.06 (s, 1 H), 9.63 (s, I.) a, H), 8.73 (t, J = 6.5 Hz, 1 H), 8.36 (d, J = 2 I.) (5) 1-, H Hz, 1 H), 8.09 (dd, J = 2 and 8 Hz, 1 H), 7.45 a, u.) vD
o 185a -OH -CHO --.' '-''CH, 184a AD (d, J = 8 Hz, 1 H), 7.28 (s, 1 H), 7.11 (s, 2 H), I.) 3.58 (s, 3 H), 3.13 (d, 3- = 7 Hz, 2 H), 1.87 (m, 1 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES-):
u.) , 354.2 and (ES) 378.2 (M+Na)) a, H
H
-,1 185b -OH -CHO 184b AD MS
(ES-): 380.1 0 _ H
1HNMR (DMSO-d6): 8 10.21 (s, 1 H), 9.78 (s, -,r.T=TCH, 1 H), 8.87 (t, J = 5.80 Hz, 1_H), 8.51 (s, 1 H), 185c -OH -CHO 184c AD
8.23 (d, J = 7.92 Hz, 1 H), 7.60 (d, J = 7.9 Hz, 0 1 H), 7.43 (s, 1 H), 7.25 (s, 2 H), 3.74 (s, 3 H), 1-d 3.46 (q, J = 5.65, 2 H), 1.32(t, J = 7.8 Hz, 3 H) n ,-i cp =
t..) u, oe t..) Cpd.Starting Method -R -R' -R"
Analytical Data No. From Used o IHNMR (DMSO-d6): 5 10.06 (s, 1 H), 9.62 (s, t..) i-,.)--H), 8.69 (t, J = 5.90 Hz, 1 H), 8.36 (s, 1 H), .6.
H .
1-, . -....,,,_õN........--....,....õ, CH, 8.08 (d, J = 7.92 Hz, 1 H), 7.45 (d, J = 8.1 Hz, 1-185d -OH -CHO 184d AD 1 H), 7.28 (s, 1 H), 7.10 (s, 2 14), 3.58 (s, 3 H), 3.22 (m, 1 H), 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).
_ H, 186a -0S02CF3 -CHO .--Nci13 185a B-2 MS
(ES): 488.24 H
1FINMR (DMSO-d6): 5 9.74 (s, 1 H), 9.44 (t, J 0 N
FP
\,,(1\1,CF3 .--5.90 Hz, 1 H), 8.51 (s, 1 H), 8.11 (d, J = 7.91 I.) 186b -0S02CF3 -CHO 185b B-2 (5) 1 4 4 H 418 2 H 359 Hz, H), 7.5 (m, ), . (m, ), . (s, a, c7, u.) o 0 311). 0 IV
1HNMR (DMSO-d6): 6 9.45 (s, 1 H), 8.59 (t, J
H -=
5.90 Hz, 1 H), 8.28 (s, 1 H), 7.94 (d, J = 8.10 u.), 186c -0S02CF3 -CHO -,,,..1\ICH, 185c B-2 Hz, 1 H), 7.79 (d, I = 2.8 Hz, 1 H), 7.67 (d, J = a, 7.9 Hz, .1 H), 7.32 (d, J = 7.9 Hz, 2 H), 3.40 (s, H
-.-1 H), 3.12 (q, J = 7.1 Hz, 211), 0.97 (t, J = 7.16 Hz, 3 H).
IHNMR (DMSO-d6): 5 9.71 (s, 1 H), 8.78 (t, J
oH3 =
5.90 Hz, 1 H), 8.49 (s, 1 H), 8.18 (d, J = 7.92 H
Hz, 1 H), 8.00 (s, 1 H), 7.88 (d, J = 8.51 Hz, 1 186d -0S02CF3 -CHO --..õ..r.N.,-...,,,........, CH3 185d B-2 H), 7.52 (q, J = 8.1 Hz, 211), 3.67 (s, 311), 3.22 o (m, 1 H), 3.16 (m, 1 H), 1.68 (m, 1 H), 1.44 (m, 1-d n 1 H), 1.18 (m, 1 H), 0.89(t, J = 6.4 Hz, 6 H).
cp o i-,.)--t..) vi oe t..) Cpd. -R -R" Starting Method Analytical Data No. From Used 1141\TMR. (DMSO-d6): 8 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, 1 H), 7.47 (d, J =
8 Hz, 1 H), 7.27 (d, J = 8 Hz, 1 H), 6.90 (dd, 187a -CH¨CH2 -CHO 186a D-3 = 11 and 17.7 Hz, 1 H), 6.01 (d, J = 17.7 Hz, 1 0 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 (BS) 388.2 (M+Na)+
187b -CH=CH2 -CHO 186b D-3 MS
(ES): 390.1 0 (5) c7, 187c -CH=CH2 -CHO 186c 0-3 MS
(ES): 336.2 CH, 187d -CH=CH2 -CHO
186d 0-3 MS
(ES): 378.2 =
oe NH
0 410 NBR' gal H,CO2C R"
Cpd. Starting Method -R -R' -R"
Analytical Data No. From Used 1H NMR (DMSO-d6): 6 10.67 (s, 1 H), 9.2 (s, 2 H), 8.87 (s, 2 H), 8.33 (d, J= 2.0 Hz, 1 H), 8.17 (dd, J= 2.0 and -7.9 Hz, 1 H), 7.77 (s, 4 H), 7.49 (m, 4 H), 7.39 (m, 2 H), 56 -0Bn -H -0O2MEM 55 7.30 (s, 2 H), 5.54 (s, 2 H), 5.27 (s, 2 H), 3.83 (t, J4.9 (5) Hz, 2 H); 3.57 (s, 3 H), 3.49 (t, J- 4.9 Hz, 2 H), 3.23 (s, c7, 3 H); MS (BS): 612.4 57 -0Bn -Boc -0O2MEM 56 R MS (BS):
712.4 0 1H NMR (DMSO-d6): 8 10.4 (s, 1 H), 10.0 (s, 1 H), 8.9 (s, 1H), 8.28 (d, J= 2.0 Hz, 1 H), 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 58 -OH -Boc -0O2MEM 57 Hz, 2 H), 7.45 (d, J= 7.7 Hz, 1 H), 7.13 (d, J= 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 1-d oe Cpd. Starting Method -R -R' -R" Analytical Data No. From Used 11-1NMR (DMSO-d6): 610.55 (s, 1 H), 8.38 (d, J.= 2.0 Hz, 1 H), 8.18 (dd, J= 2.0 and 7.9 Hz, 1 H), 7.86 (m, 4 59 -0S02CF3 -Boc -0O2MEM 58 B-2 H), 7.75 (dd, J= 2.0 and 8.9 Hz, 1 H), 7.54 (m, 5 H), 5.51 (s, 2 H), 3.77 (t, .1= 4.9 Hz, 2 H), 3.55 (s, 3 H), 3.46 (t, J= 4.9 Hz, 2 H), 3.18 (s, 3 H) 1.41 (s, 9 H); MS
_ (ES+): 754.3 1HNMR (DMSO-d6): 5 10.61 (s, 1 H), 8.94 (s, 1 H), 8.37 (s, 1 H), 8.19 (dd, J= 2.0 and 7.9 Hz, 1 H), 8.02 (s, 1 H), 7.89 (m, 5 H), 7.65 (d, J-= 8.9 Hz, 2 H), 7.54 (d, J
60 -Boc -0O2MEM 59 D-2 = 7.9 Hz, 1 H), 7.39 (d, J= 7.9 Hz, 1 H), 7.17 (d, J= 3.9 0 Hz, 1 H), 6.68 (m, 1 H), 5.54 (s, 2 H), 3.82 (t, J= 4.9 Hz, 2 H), 3.58 (s, 3 H), 3.49 (t, J= 4.9 Hz, 2 H), 3.22 (s, 3 H), 1.45 (s, 9 H); MS (ES): 672.5 1H NMR (DMSO-d6): 6 10.50 (s, 1 H), 8.96 (s, 1 H), (5) 8.32 (s, 1 H), 8.07 (d, J= 7.9 Hz, 1 H), 7.98 (s, 1 H), 61 -Boc -CO2H 60 I-1 7.87 (m, 5 H), 7.63 (d, J= 8.9 Hz, 2 H), 7.38 (m, 2 H), o 7.15 (d, J= 3.0 Hz, 1 H), 6.67 (m, 1 H), 3.57 (s, 3 H), 1.45 (s, 9H); MS (ES): 582.4 1HNMR (DMSO-d6): 6 10.56 (s, 1 H), 9.02 (br s, 1 H), 8.35 (d, J- 1.7 Hz, 1 H), 8.18 (dd, 1.9 and 6.0 Hz, 1 H), 7.88 (d, J= 9.0 Hz, 2 H), 7.80 (d, J= 1.3 Hz, 1 H), 7.71 (dd, J= 1.7 and 6.2 Hz, 1 H), 7.63 (d, J= 8.9 Hz, 2 66 -CH=CH2 -Boc -0O2MEM 59 D-3 H), 7.50 (d, J= 8.3 Hz, 1 H), 7.32 (d, J= 8.1 Hz, 1 H), 6.89 (dd, J= 10.7 and 17.7 Hz, 1 H), 6.04 (d, J= 17.4 Hz, 1 H), 5.54 (s, 2 H), 5.43 (d, J= 11.7 Hz, 1 H), 3.82 (t, J= 4.5 Hz, 2 H), 3.57 (s, 3 H), 3.48 (t, J=4.5 Hz, 2 H), 3.22 (s, 3 H), 1.44 (s, 9 H); MS (ES): 632.1 1-d oe Cpd. Starting Method -R -R' -R" Analytical Data No. From Used (DMSO-d6): 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, 2H), 7.66(m, 3H), 7.38 (d, J= 7 .7 67 -CH=CH2 -Boc -CO2H 66 I-1 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 (5) oe NH
13oc o n.) H
.6.
1-, 1-, 0 NHEZ!
RO,C
.
Cpd. _R
-R' Starting Method Analytical Data No. From Used n 1H NMR (DMSO-d6): 6 10.57 (s, 1 H), 8.92 (s, 1 H), 8.64 (t, J=
I.) 5.4 Hz, 1 H), 8.24 (d, J= 2.0 Hz, 1 H), 8.02 (dd, J= 2.0 and 7.9 a, I.) (5) o, Hz, 1 H), 7.98 (s, 1 H), 7.88 (m, 3 H) 7.84 (s, 1 H), 7.64 (d, J= a, vi u.) 62a -CH3 -,,,.,-cH3 61 A-4 8.9 Hz, 2 H), 7.42 (d, J= 7.9 Hz, 1 H), 7.36 (d, J=7.9 Hz, 1 H), 0 7.14 (d, J= 3.0 Hz, 1 H), 6.67 (m, 1 H), 3.55 (s, 3 H), 3.26 (m, 2 I.) H), 1.50 (m, J= 7.4 Hz, 2 H), 1.43 (s, 9 H), 1.32 (m, J= 7.4 Hz, u.) 2 H), 0.89 (t, 3 H); MS (ES"): 639.5 a, -H
-,1 Cli.3 62b -CH3 61 A-4 MS (ES):
625.5 ''.-CH2 62c -CH3 61 A-4 MS (ES):
623.4 =
62d -CH3 lel CH3 61 A-4 MS (ES):
687.4 1-d n ,-i cp I.., W.
N
N
Cpd. 41 -R' Starting Method Analytical Data o No. From Used o t.) -...,,,CH3 4= , 62e -CH3 61 A-4 MS (ES): 625.4 621 -CH3 ,3 61 A-4 MS (ES): 653.5 -_,,=-=õ,.CH3 62g -CH3 61 A-4 MS (ES): 653.5 n I.) a, I.) c7, o 62h -CH3 61 A-4 MS (ES): 667.3 a, c:
Lo I.) 62i -CH3 61 A-4 MS (ES): 681.5 Lo a, H
--J
62j -CH3 61 A-4 MS (ES): 637.3 OH
62k -CH3 61 A-4 MS (ES): 640.3 'CH3 n 1-i 621 -CH3 ¨0 61 A-4 MS (ES): 665.4 cp o l=.) -CA
l=.) Cpd.
Starting Method No. From Used Analytical Data 62m -CH3 CH3 61 A-4 MS (ES): 597.3 62n -CH3 61 A-4 MS (ES): 639.4 - 62o -CH3 10111 61 A-4 MS (ES): 695.4 (M+Na) 62p -CH3 61 A-4 MS (ES): 665.4 (5) 62q -CH3 WcH, 61 A-4 MS (ES): 653.4 cH3 62r -CH3 61 A-4 MS (ES): 567.3 62s -CH3 61 A-4 MS (ES): 667.5 62t -CH3 OH 61 A-4 MS (ES): 641.3 OH
62u -CH3 61 A-4 MS (ES): 655.3 oe Cpd. ..R
-R' Starting Method Analytical Data No. From Used o t..) 62v -CH3\ 61 A-4 MS (ES): 663.1 1¨
62w -CH3 61 A-4 MS (ES): 577.2 1¨
r\z N
"4---__V
62x -CH3 \/0 61 A-4 MS (ES): 679.2 n I.) a, I.) 62y -CH3 .,õ,--,,,.OH 61 A-4 MS (ES): 621.1 (5) 1¨
a, o Lo oe I.) 62z -CH3 -..,,0H3 61 A-4 MS (ES): 611.1 Lo a, OH
H
-,1 62 aa -CH3 -,,,,..,...OH 61 A-4 MS (ES): 657.1 62 ab -CH3 4. 61 A-4 MS (ES): 659.1 1-d n 62 ac -CH3 ¨61 A-4 MS (ES): 679.3 cp o 1¨
i-,.)--t..) vi oe t..) -Cpd.
-R' Starting Method Analytical Data No. From Used 62ad -CH3 61 A-4 MS (ES): 695.3 62ae -CH3 NHR, _N 61 A-4 MS (ES): 651.3 NHR' 62af -CH3 61 A-4 MS (ES): 679.4 (5) oe NH
o n.) c.:.) .6.
R is N
H
1-, 1-, 1101 NHR' _ _ Cpd. Starting Method .
-R -R' Analytical Data No.From Used _ _ n 1H NMR (DMSO-d6): 8 12.80 (s, 1 H), 9.09 (s, 2 H), CC( 8.91 (s, 2 H), 8.57 (m, 1 H), 8.15 (s, 1 H), 7.91 (s, 1 H), 0 IV
7.80 (m 3 H), 7.67 (m, 4 H), 7.20 (m, 2 H), 7.07 (s, 1 a, I.) 1- 64a - 62a I-2, S ' (5) --4 H), 6.63 (s, 1 H) 3.21 (m, J= 5.9 Hz, 2 H), 1.46 (m, J= a, o u.) 7.4 Hz, 2 H), 1.28 (m, J= 7.4 Hz, 2 H) 0.86 (t, J= 7.4 Hz, 3 H); MS (ES): 525.3 I.) CA
I
1H NMR (DMS0416): 8. 12.76 (s, 1 H), 9.10 (s, 2 H), a, Cc( CI-1, 8.82 (s, 2 H), 8.59 (m, 1 H), 8.20 (s, 1 H), 7.95 (s, 1 H), H
-A
64b - 62b 1-2, S 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, J= 7.4 Hz, 2 H), 0.87 (t, J= 7.4 Hz, 3 H); MS (ES): 511.2 1H NMR (DMSO-d6): 8 12.84 (s, 1 H), 9.11 (s, 2 H), CO
'-'-'.-"cH2 8.84 (m, 2 H), 8.26 (m, 1 H), 7.94 (m, 2 H), 7.83 (m, 64c __ 62e 1-2, S H), 7.71 (s, 4 H), 7.28 (m, 2 H), 7.12 (s, 1 H), 6.65 (s, 1 1-d n H), 5.87 (m, 1 H), 5.15 (d, J= 17.2 Hz, 1 H), 5.07 (d, J.=
10.3 Hz, 1 H) 3.88 (t, J= 5.2 Hz, 2 H); MS (ES): 509.2 cp o c.:.) t..) vi oe t..) _ Cpd. -R
-R' Starting Method Analytical Data No. From Used _ - 4111 CH, =
81H.85NMR(s, 2 (HD)M, 8S.202-d(s6,):1 6H1),27.7.983(s(,s,11H)H,),97.1.813(m,on,23HH),), 64d 62d 1-2, S
7.68 (s, 4 H), 7.19 (m, 3 H), 7.10 (m, 5 H), 6.65 (s, 1 H), .6.
--.1 1-.
1-.
4.41 (s, 2 H), 2.27 (s, 3 H); MS (ES): 573.3 1H NMR (DMSO-d6): 8 12.82 (s, 1 H), 9.11 (s, 2 1-1), 64e C7 0 -....,,,\.õ-CH3 8.86 (s, 2 H), 8.39 (d, J--- 7.7 Hz, 1 H), 8.24 (s, 1 H), .___Q 62e 1-2, S
7.95 (s, 1 H), 7.90 (m, 1 H), 7.84 (m, 2 H), 7.71 (s, 4 H), CH3 7.28 (m, 2 H), 7.11 (m, 1 H), 6.65 (s, 1 H), 4.08 (m, J=-6.9 Hz, 1 H), 1.14 (d, J= 6.9 Hz, 6 H); MS (ES): 511.3 o (DMSO-d6): 5 13.28 (br s, 1 H), 9.05 (m, 2 H), Co 8.84 (s, 2 H), 8.46 (m, 1 H), 7.99 (s, 1 H), 7.88 (s, 1 H), 0 I.) 64f - Q CH, 62f 1-2, S 7.77 (m, 2 H), 7.63 (m, 5 H), 7.07 (m, 2 H), 6.96 (m, 1 I.) (5) 1-.
--.1 H), 6.63 (s, 1 H), 3.16-2.96 (m, 2 H), 1.65-1.03 (m, 3 u.) 1-.
H), 0.85 (m, 6 H); MS (BS): 539.3 I.) 1H NMR (DMSO-d6): 5 13.37 (s, 1 H), 9.06 (s, 2 H), u.) 8.84 (s, 2 H), 8.47 (m, 1 H), 8.00 (s, 1 H), 7.88 (s, 1 H), a,.
64g -Q 62g 1-2, S 7.78 (m, 2 H), 7.70 (m, 5 H), 7.08 (m, 2 H), 6.97 (s, 1 1 H
-,1 CH3 H), 6.63 (s, 1 H), 3.22 (m, 2 H), 1.58 (m, .1= 6.0 Hz, 1 H), 1.38 (m, J= 6.9 Hz, 2 H), 0.87 (d, J= 6.9 Hz, 6H);
MS (ES): 539.3 1H NMR (DMSO-d6): 5 12.71 (br s, 1 H), 9.13 (s, 1 H), 8.75 (m, 3 H), 8.31 (m, 1 H), 7.97 (m, 2 H), 7.86 (m, 2 ,,,,C) 64h n H), 7.73 (m, 4 H), 7.64 (m, 2 H), 7.33 (m, 2 H), 7.13 (m, -- 0 62h 1-2, S
1 H), 6.67 (m, 1 H), 3.98 (m, 1 H), 3.77 (q, f= 6.9 Hz, 1 1-d n ,-i H), 3.62 (q, J= 6.9 Hz, 1 H), 3.29 (m, 2 H), 1.86 (m, 3 H), 1.59 (m, 1 H); MS (ES): 553.3 cp o 1-.
c.:.) t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used o t..) 1H NMR (DMSO-d6): 612.81 (br s, 1 H), 9.13 (s, 2H), .6.
64iC
8.85 (s, 2 H), 8.26 (m, 2 H), 7.96 (m, 2 H), 7.86 (m, 2 1-2, S H), 7.74 (m, 5 H), 7.32 (m, 1 H), 7.13 (m, 1 H), 6.67 (m, --4 CH, 1 H), 3.99 (m, 1 H), 1.5-0.85 (m, 14 H); MS (ES):
567.3 Ili NMR (DMSO-d6): 5 13.74 (br s, 1 H), 9.07 (s, 2 H), 8.92 (s, 2 H), 8.62 (t, J=5.6 Hz, 1 H), 8.03 (s, 1 H), 7.89 64j ( /.\.<
62j 1-2, S (d, J= 1.7 Hz, 1 H), 7.79 (m, 2 H), 7.64 (m, 4 H), 7.10 -Q (m, 3 H), 6.99 (d, J= 8.5 Hz, 1 H), 6.64 (m, 1 H), 3.08 (t, J= 6.0 Hz, 2 H), 1.00 (m, 1 H), 0.40 (m, 2 H), 0.20 n (m, 2 H); MS (ES): 523.4 _ I.) a, OH 'H NMR
(DMSO-d6): 8 9.12 (s, 2 H), 8.88 (s, 2 H), 8.52 I.) (5) Coa, t..) (m, 1 H), 8.12 (m, 1 H), 7.92 (m, 2 H), 7.81 (m, 3 H), 64k -Q -...,...õ...õ----..., CH, 62k 1-2, S 7.67 (m, 4 H), 7.14 (m, 3 H), 6.66 (m, 1 H), 4.75 (d, J= (8) I.) 4.5 Hz, 1 H), 3.77 (m, 1 H), 3.17 (m, 1 H), 1.04 (d, J=
LO
6.0 Hz, 3 H); MS (ES+): 527.2 FP
I
Ili NMR (DMSO-d6): 8 13.91 (br s, 1 H), 9.07 (s, 2 H), H
621 1-2, S
-,1 641 (-( -0 8.90 (s, 2 H), 8.29 (d, J= 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, J= 7.7 Hz 1 H), 6.64 (m, 1 H), 3.71 (in, 1 H), 1.82-1.03 (m, 10 H)p; MS (BS): 551.33 ill NMR (DMSO-d6): 8 13.87 (br s, 1 H), 9.07 (s, 2 H), Co 8.90 (s, 2 H), 8.48 (m, 1 H), 7.99 (s, 1 H), 7.89 (m, 1 H), 1-d 64m -Q -õ, 62m 1-2, S 7.79 (in, 2 H), 7.62 (m, 5 H), 7.10 (m, 2 H), 6.97 (d, J= n 1-i cH3 7.9 Hz 1 H), 6.64 (m, 1 H), 2.73 (d, J= 4.5 Hz, 3 H);
cp MS (ES): 483.2 c.:.) t..) vi oe t..) _ Cpd.Starting Method Analytical Data No. From Used .
o t..) 1H NMR (DMSO-d6): 5 9.08 (s, 2 H), 8.85 (s, 2 H), 8.26 .6.
C (3( CH, (d, J=
8.7 Hz, 1 H), 8.07 (s, 1 H), 7.91 (s, 1 H), 7.80 (m, --4 64n - 62n 1-2, S 2 H), 7.67 (m, 5 H), 7.09 (m, 3 H), 6.65 (m, 1 H), 3.89 1-CH3 (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+):
CC( lall (DMSO-d6): 8 9.19 (m, 2 H), 9.10 (s, 2 H), 58.852 114 NMR (s, 2 H), 8.19 (m, 1 H), 7.94 (s, 1 H), 7.83 (m, 2 H), 7.68 (m, 4 H), 7.33-7.10 (m, 8 H), 6.66 (m, 1 H), 4.45 n 64o 62o 1-2, S
(d, J=5.7 Hz, 2 Hz); MS (E5+): 559.2 I.) a,.
I.) (5) (DMSO-d6): 8 9.22 (m, 2 H), 9.09 (s, 2 H), u.) w 8.81 (s, 2 H), 8.17 (m, 1 H), 7.95 (s, 1 H), 7.82 (m, 2 H), 64p 1-2, S I.) H); MS (ES): 551.22 7.68 (m, 4 H), 7.16 (m, 4 H), 6.66 (m, 1 H), 4.06 (m, 2 -+
u.) a,.
H
-,1 1H NMR (DMSO-d6): 8 9.10 (s, 2 H), 8.86 (s, 2 H), 8.56 C:( (m, 1 H), 8.13 (m, 1 H), 7.93 (s, 1 H), 7.82 (m, 2 H), 64q ci-I3 62q 1-2, S 7.67 (m, 5 H), 7.15 (m, 3 H), 6.66 (rn, 1 H), 3.19 (rn, 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 1-d Cc( 1H NMR
(DMSO-d6): 8 9.09 (s, 2 H), 8.90 (m, 2 H), n ,-i 64r - CH, 62r 1-2, S 8.15 (m, 2 H), 7.93 (s, 1 H), 7.81 (m, 3 H), 7.68 (m, 4 cp H), 7.13 On, 3 H), 6.66 (m, 1 H), 3.83 (m, 1 H), 1.47 (m, CH, 1-, 4 H), 1.25 (m, 4 H), 0.83 (m, 6 H); MS (E8+): 567.3 t..) vi oe t..) , Cpd. ' Starting =' Method -R -Re Analytical Data No. From Used o 11-1 NMR (DMSO-d6): 5 9.08 (s, 2 H), 8.86 (s, 2 H), 8.48 t..) .6.
(m, 1 H), 8.03 (m, 1 H), 7.90 (s, 1 H), 7.79 (m, 2 H), 64s --.1 - -,,,,<cH, 62s 1-2, S 7.65 (m, 5 H), 7.12 (m, 2 H), 7.02 (m, 1 H), 6.65 (m, 1 1-cH3 cH3 H), 3.22 (m, 2 H), 1.42 (t, J= 8.2 Hz, 2 H), 0.91 (s, 9 H);
MS (ES): 553.4 111 NMR (DMSO-d6): 5 13.61 (br s, 1 H), 9.07 (s, 2 H), C:( 64t 62t 1-2, S 9.00 (s, 2 H), 8.52 (t, J= 5.5 Hz, 1 H), 8.02 (s, 1 H), 7.90 - /\.--OH (d, J= 1.9 Hz' 1 H), 7.79 (m, 2 H), 7.64 (m, 5 H), 7.10 (m, 2 H), 7.00 (d, J = 7.7 Hz, 1 H), 6.64 (m, 1 H), 4.47 (t, J= 5.3 Hz, 1 H), 3.43 (m, 2 H), 3.27 (m, 2 H), 1.64 n (qui, J= 6.8 Hz, 2H); MS (ES): 527.23 , I\) FP
C l( Ili NMR
(DMSO-d6): 5 12.7 (br s, 1 H), 9.09 (s, 2 H), I.) (5) a, --.1 8.91 (s, 2 H), 8.57 (m, 1 H), 8.11 (s, 1 H), 7.92 (d, J= u.) .6. -64u .,-,.,.,,..,,.=,,,OH 62u 1-2, S 1.9 Hz, 1 H), 7.81 (m, 3 H), 7.67 (m, 5 H), 7.14 (m, 2 I.) H), 6.66 (m, 1 H), 4.40 (t, J= 5.3 Hz, 1 H), 3.39 (m, 2 H), 3.22 (in, 2 H), 1.48 (m, 4 H); MS (ES): 541.34 u.) FP
I
'H NMR (DMSO-d6): 5 9.16-8.89 (m, 4 H), 8.16 (m, 1 H
C( \
-,1 64v 62v 1-2, S 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, 1 H), 6.26 (m, 1 H), 4.42 (d, J.= 4.9 Hz, 2 H); MS (ES): 549.27 11-1 NMR (DMSO-d6): 5 11.59 (br s, 1 H), 9.14 (s, 2 H), , N 8.98 (s, 2 H), 8.70 (t, J= 5.7 Hz, 1 H), 8.24 (s, 1 H), 7.99 64w - N.-1/ 62w 1-2, S (m, 2 H), 7.87 (m, 3 H), 7.71 (m, 3 H), 7.36 (s, 1 H), 1-d n 7.27 (m, 2 H), 7.10 (m, 2 H), 6.67 (m, 1 H), 4.07 (t, J=
6.9 Hz, 2 H), 3.24 (q, J= 6.5 Hz, 2 H), 1.98 (qui, J= 6.7 cp Hz, 2 H); MS (ES): 577.17 =
c.:.) t..) vi oe t..) Cpd. Starting Method -R -R.' Analytical Data No. From Used o t..) (3D.0M4 (t SO, J- 6.5 .: H13z.,722H(b)r, s1,.712H)-1.,493.1(m3 (, s6, 2H)H, ), .6.
C
9.06 (s, 2 H), 8.50 (t, J= 5.7 Hz, 1 H), 8.00 (d, J= 1.3 --.1 Hz, 1 H), 7.89 (d, Jr- 1.9 Hz, 1 H), 7.78 (m, 2 H), 7.62 64x 62x 1-2, S
- (lnimil:
NMR 41 HH)),, 7.08 (m, 2 H), 6.96 (d, J= 7.9 Hz, 1 H), 6.64 ( 1.25-1.08 (m, 3 H), 0.88 (m, 2 H); MS (ES): 565.25 1H NMR (DMSO-d6): 5 9.16-8.87 (m, 4 H), 8.09 (s, 1 C.C( H), 7.91 (s, 1 H), 7.80 (m, 2 H), 7.65 (m, 5 H), 7.12 (m, 64y -,,,.,, .,.,CH 62y 1-2, S
- 5 H), 6.65 (m, 1 H), 4.01 (m, 2 H), 3.10 (m, 1 H); MS
(ES): 507.2 I.) Cc( 1H NMR
(DMSO-d6): 5 9.10 (s, 2 H), 8.97 (s, 2 H), 8.59 a, I.) , (t, J=
5.7 Hz, 1 H), 8.13 (s, 1 H), 7.93 (s, 1 H), 7.80 (m, (5) a, u.) vi 64z 62z 1-2, S 3 H), 7.68 (m, 4H), 7.16 (m, 4H), 6.65 (m, 1 H), 3.26 0 (qui, J= 6.0 Hz, 2 H), 1.10 (t, J= 7.2 Hz, 3 H); MS
"
(ES): 497.2 CA
I
FP
I
C 0( OH 1H NMR
(DMSO-d6): 5 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), H
-.-1 64aa _ 62aa 1-2, S 7.79 (m' 3 H), 7.63 (m, 5 H), 7.09 (m, 2 H), 6.98 (m, 1 H), 6.65 (m, 1 H), 4.80 (d, J= 4.7 Hz, 1 H), 4.56 (t, J=
6.8 Hz, 1 H), 3.60 (m, 1 H), 3.32-2.90 (m, 3 H); MS
(ES): 543.2 Cc( 40 1H NMR
(DMSO-d6): 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 (m, 6 H), 64ab 62ab 1-2, S
7.66 (m, 4 H), 7.34 (m, 2 H), 7.11 (m, 4 H), 6.65 (m, 1 1-d n g c 4 . H); MS
(ES): 545.2 c.:.) .
t..) vi .
oe t..) Cpd. Starting Method -R = -R' Analytical Data No. From Used CC( -0 1H NMR
(DMSO-d6): 8 9.07 (m, 4 H), 8.38 (d, J= 8.5 Hz, 1 H), 8.10 (s, 1 H), 7.92 (s, 1 H), 7.84-7.62 (m, 7 H), o t..) i-,.)--12.6' 64ac 62ac 1-2, S
- 7.111(mH, )3; MS H), 6(.E6s): .3 6 (m5, 615H), 3.94 (m, 1 H), 1.88-1.35 (11, 2 1H NMR (DMSO-d6): 8 13.71 (m, 2 H), 9.36-8.57 (m, 4 (0 H), 8.50 (m, 1 H), 7.98 (s, 1 H), 7.89 (s, 1 H), 7.78 (2 64ad ______Q ____-.õ..õ,,,,,,,,,.õ,õõõOH
62ad 1-2, S 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 (m, 2 H), 2.16 (t, J= 7.2 Hz, 2 H), 1.48 (m, 4H), 1.28 (m, 2 H); MS (ES): 581.2 1H NMR (DMSO-d6): 8 9.12 (s, 2 H), 8.89 (s, 2 H), 7.91 n / (m, 1 H), 7.81 (m, 2 H), 7.70 (d, J= 8.7 Hz, 2 H), 7.62 0 C(. NHR = -N ) (d, J= 8.9 Hz, 2 H), 7.48 (m, 1 H), 7.22 (m, 2 H), 7.11 I.) a, 64ae 62ae 1-2, S
I.) (d, J= 3.4 Hz, 1 H), 7.05 (d, J= 7.2 Hz, 1 H), 6.65 (m, 1 (5) --,1 a, o H), 3.53 (m, 2 H), 3.08 (m, 2 H), 1.62-1.21 (m, 6 H); MS u.) (ES): 537.20 I.) u.) 1H NMR (DMSO-d6): 8 12.81 (br s, 1 H), 9.13 (s, 2 1-1), C0( 8.82 (s, 2 H), 7.95 (s, 1 H), 7.85 (m, 2 H), 7.71 (m, 5 H), a, 64af ,,.3 H
- 62af 1-2, S 7.43 (m, 1 H), 7.29 (m, 2 H), 7.13 (m, 1 H), 6.67 (m, 1 -A
NHR = -N\----A;7.
H), 3.49-2.97 (m, 4 H), 1.67-1.37 (m, 2 H), 1,08 (m, 1 H), 0.90 (m, 3 H), 0.61-0.26 (m, 4 H); MS (ES): 565.3 1-d n ,-i cp =
t..) u, oe t..) NH
=
n.) R c.:.) mat LW N NBR
H .6.
1-, 1-, 0 NHR' HO,C
Cpd. Starting Method -R -R' Analytical Data No. From Used CH3 111 NMR (DMSO-d6, D20): 5 13.87 (br s, 1 H), 9.56 (m, 2 H) 0 9.21 (s, 1 H), 8.74 (s, 1 H), 8.47 (m, 1 H), 7.97 (m, 1 H), 7.88 (s, 1 I.) a, I.) 65 61 A-4, I-2, S H), 7.78 (m, 3 H), 7.58 (m, 7 H), 7.09 (m, 3 H), 6.96 (m, 1 H), (5) 1- 0 \/- CH, .i.
u.) --.1 6.65 (in, 1 H), 3.14 (m, 4 H), 1.77-0.80 (in, 18 H); MS (ES): 0 609.4 I.) CA
I
11-1 NMR (DMSO-d6): 8 13.80 (hr s, 1 H), 9.91 (s, 1 H), 9.41 (s, 1 a, 71a -C1-1.----CH2 ..'0* 67 A-4, 1-2, S H), 8.63 (m, 2 H), 8.07 (s, 1 H), 7.98 (s, 1 H), 7.60 (m, 8 H), 6.90 H
-A
(in, 3 H), 5.94 (d, J= 17.7 Hz, 1 H), 4.37 (m, 1 H), 4.16 (m, 1 H), 2.41-1.58 (m, 12 H); MS (ES): 537.4 IHNIVIR (DMSO-d6): 5 9.76 (s, 1 H), 9.41 (s, 1 H), 8.95 (s, 1 H), 71b -CF1=--CH2 ..(/ 8.53 (m, 1 H), 8.07 (s, 1 H), 7.65 (m, 8 H), 7.08 (m, 2 H), 6.85 67 A-4, 1-2, S (dd, J= 10.9 and 17.7 Hz, 1 H), 6.92 (in, 3 H), 5.97 (d, J=17.7 1-d Hz, 1 H), 5.37 (d, J= 10.9 Hz, 1 H), 2.84 (m, 1 H), 2.70 (m, 1 H), n 0.98-0.51 (m, 8H); MS (ES): 569.4 cp o c.:.) t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used 1HNMR (DMSO-d6): 5 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, 71c -CH=CH2 67 A-4, 1-2, S 8 H), 7.12 (m, 2 H), 6.86 (dd, J= 10.9 and 17.7 Hz, 1 H), 5.98 (d, J=17.7 Hz, 1 H), 538 (d, J= 10.9 Hz, 1 H), 3.27 (m, 4 H), 1.20 (t, J= 7.2 Hz, 1 H), 1.09 (t, J= 7.2 Hz, 1 H); MS (ES): 485.3 (5) oe oe NH
I o N Si NHBoc o n.) W."
4.
0 ii --101 NHR`
_ Cpd....R
-11.1 Starting Method Analytical Data No. From Used 68a -CH3 --...,õõ,-.õõ,,3 67 A-4 MS (ES): 599.4 I.) I\),-, 68b 67 A-4 MS (ES): 641.4 a, (5) a, Lo o I.) 68c -CH3 ¨0 67 A-4 MS (ES): 625.3 a, H
-,1 , 68d -CH3 " CH, 67 A-4 MS (ES): 583.3 ....,<CH3 68e -CH3 67 A-4 MS (ES): 585.3 1-d n -...,.....,K7H, 681 -CH3 CH3 67 A-4 MS (ES): 599.4 cp o i-,.)--t..) vi oe t..) Cpd.
-R' Starting Method Analytical Data No. From Used tµ.) 68g -CH3 67 A-4 MS (ES): 625.2 =
= =
68h -CH3 67 A-4 MS (ES): 619.2 681 -CH3 WOH 67 A-4 MS (ES):
615.3 68j -CH3 /\.< 67 A-4 MS (ES): 597.3 o.
oe 68k -CH3 CH3 67 A-4 MS (ES): 557.3 67 A-4 MS (ES): 571.4 68m -CH3 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 = .) = .) = , Cpd. -R
-R' Starting Method Analytical Data ' No. , From , Used o .,,,, CH, l= . ) 68p -CH3 CH, 67 A-4 MS (ES): 613.5 .6.
1--, 1--, 68q -CH3 67 A-4 .MS (ES): 641.5 68r -CH3 ./\./.\--NIIBIDc 67 A-4 MS (ES): 714.5 68s -CH3 ¨0 67 A-4 MS (ES): 611.4 I.) a, I.) c7, 1--, 0H
.i.
oe 68t -CH3 67 A-4 MS (ES): 641.4 co 1--, I.) co 68u -CH3 < 67 A-4 MS (ES): 583.3 H
68v -CH3 ----<> 67 A-4 MS (ES): 597.4 -.../.= OH
68w -CH3 67 A-4 MS (ES): 587.4 Iv_ n ,-i -__,<
68x -CH3 CH3 67 A-4 MS (ES.): 613.5 cp =
CH3 o 1--, l= . ) ( A
l= . ) 4 0 6 11' R
o 3n.) 2 1, H
.6.
R"O,C
-R (Position with Cpd. Starting Method Respect to Phenyl -R' -R" Analytical Data No. From Used Ring) 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 n 75b -OH (3) -CHO -Bn 74 V-1, H MS (ES):
430.2 0 I.) 76a -0S02CF3 (3) -CHO -CH3 75a B-2 MS (ES):
488.1 a, I.) 1¨
MS (ES): 562.3 ; MS (ES): (5) a, oe 76b -0S02CF3 (3) -CHO -Bn 75b B-2 co t..) 586.3 (M+Na)+ 0 I.) 77a -CH=CH2 (3) -CHO -CH3 76a D-3 MS (ES ):
366.38 0 co 77b -OCH2CO2C2H5 (3) -CHO -Bn 75b X
Characterized in the next step 0 MS (ES): 487.3; MS (ES):
a, 77c -OCH2CONH2 (3) -CHO -Bn 75b X H
511.35 (M+Na) 77d ----I\ s (3) -CHO -Bn 76b D-2 Characterized in the next step MS (ES ): 530.3 (M+Na)+); MS
77e ¨0 . (3) -CHO -Bn 75b D-8 (ES): 506.3 1-d n ,-i cp =
i-,.,--u, oe t..) -R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data 0 No. From Used Ring) o t..) i-,.)--77f 0 -CHO -Bn 75b X MS (ES):
496.3 (M+Na)4" -4 1¨
(3) 77g \ 0/\ CH3 (3) -CHO -Bn 75b X MS (ES+):
482.4 (M+Na)+ .
..,..-...CH, 77h (3) -CHO -Bn 75b X MS (ES):
510.4 (M+Na) 111N-MR (CDC13): 5 9.59 (s, 1 H), 8.39 (d, J = 2 Hz, 1 H), 8.03 (m, 2 n ' H), 7.84 (d, J = 8.9 Hz, 1 H), 7.35 0 I.) (d, J = 8 Hz, 1 H), 7.28 (m, 2 H), a, "
1¨
7.12 (m, 2H), 6.93 (dd, J = 2.5 (5) a, u.) and 8.8 Hz, 1 H), 6.64 (d, J = 2.5 (3) -CHO -Bn 75b X
Hz, 1 H), 6.31 (t, J = 6 and 5 Hz, "
.
1 H), 5.06 (m, 2 H), 4.42 (t, J = 0 u.) 4.5 Hz, 2 H), 4.13 (m, 2 H), 3.34 a, (t, J =6.8 Hz, 2 H), 2.11 (s, 3 H), ' , 1.94 (m, 111), 1.01 (d, J = 6.8 Hz, 6H) 78a -CH=CH2 (3) -CO2H -CH3 77a E MS (ES):
380.1 78b -0S0sCF3 (3) -CO2H -Bn 76b E
Characterized in the next step 78c -OCH2CO2C2H5 (3) = -CO2H -Bn 77b E
Characterized in the next step Iv n 78d -OCH2CONH2 (3) -CO2H -Bn 77c E MS (ES):
52735 (M+Na)+
cp o 1¨
i-,.)--t..) vi oe t..) -R (Position with Cpd. Starting Method Respect to Phenyl -IV -R"
Analytical Data No.
From Used 0 Ring) o i-,.)--.6.
78e (3) -CO2H -Bn 77d E MS (ES): 536.4 (M+Na)+ -4 1.., 1.., S
78f ¨0 41 (3) -CO2H -Bn 77e E MS (ES): 522.3 _ - 78g -OCH3 (3) -CO2H -CH3 74 E MS (ES): 384.1 78h -....,s0,--_,....õ.õCH3 (3) -CO2H
-Bn 77f E MS (ES): 488.3 781 (:)C1.13 (3) -CO2H -Bn 77g E MS (ES): 474.4 0 I.) a, "
0, 1¨
a, oe 78j (3) -CO2H -Bn 77h E MS (ES): 502.4 co .6.
CH, N
78k '-'-1:y' \ OAc (3) -CO2H -Bn 771 E Characterized in the next step co ' a, IHNMR. (CDC13): 5 10.47 (s, 1 IH
H), 8.36 (d, J = 2 Hz, 1 H), 7.96 -A
(dd, I = 2.2 and 7.7 Hz, 1 H), 7.68 (m, 2 H), 7.46 (m, 5 H), 7.23 (d, J
= 8 Hz, 1 H), 7.12 (d, I = 8.7 Hz, 90 -0Bn (5) -CHO -CH3 89 + 3a D-2 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, I = 6.8 Hz, 2 H), 1.94 (m, 1 H), 1.01 (d, I =
1-d n 6.8 Hz, 6 H), MS (ES+) 468.2 (M+Na)+ (ES-) 444.2 cp o 1¨
i-,.)--t..) vi oe t..) Cpd -R (Position with .
Respect to Phenyl -R' -R" Starting Method Analytical Data o No.
From Used Ring) o t.) IHNMR (CDC13): 5 8.22 (s, 1 H), .6.
--.1 7.83 (d, J = 7.2 Hz, 1 H), 7.34 (m, 8 H), 7.02 (d, J = 8.1 Hz, 1 H), 91 -0Bn (5) -CO2H -CH3 90 E 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 -0Bn (5) -0O2MEM -CH3 91 F MS (ES): 572.2 (M+Na)+
93 -OH (5) -0O2MEM -CH3 92 G MS (ES+): 482. (M+Na) n 94 -0S02CF3 (5) -0O2MEM -CH3 93 B-2 MS (ES): 614.3 (M+Na)+ 0 I.) a, I.) 1¨
D-3 MS (ES+) 562.3 (M+Na)+ T
L., c'e u, 95a \ (5) s I.) co 96a \\,¨) (5) -CO2H -CH3 95a I-1 MS (ES+) 452.1 (M+Na)+ 1 a, S
H
-1 .
101 -OCH3 (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 -0Bn (2) -CHO -CH3 107 + 3a D-2 MS (ES+): 446.2 109 -0Bn (2) -CO2H -CH3 108 E MS (ES"): 460.1 . .
1-lo n ,-i cp =
e l= . ) ( A
l= . ) -R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data o No. From Used Ring) o t..) iHNMR (CDC13-di): 5 9.79 (s, 1 .6.
H), 8.39 (d, J =-- 1.88 Hz, 1 H), 8.02 (t, J = 6.0 Hz, 2 H), 7.59 (m, 131 -H -CHO -CH3 130 + 3a D-2 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, 1 H), 1.02 (d, J
= 6.8 Hz, 6 H), MS (ES+): 340.1 iHNMR (DMSO-d6): 8 12.28 (b, 1 H), 8.52(d, J = 6.03 Hz, 111), n 8.12 (s, 1 H), 7.86 (d, .1 = 8.1 Hz, 1 H), 7.74 (d, J = 7.74 Hz, 1 H), N
E 7.41 (t, J = 8.67 Hz, 1 H), 7.31 (t, a, I.) (5) oe J = 7.9 Hz, 1 H), 7.12 (d, J -= 8.1 a, c7, u.) Hz, 1 H), 6.97 (d, J - 7.5 Hz, 1 H), 3.39 (s, 3 H), 2.92 (t, 3 --- 6.0 I.) Hz, 2 H), 1.66 (m, 1 H), 0.78 (d, J
u.) -- 7.4 Hz, 6 H), MS (ES-): 354.1 a, NH
H
-.-1 192a+
193a -H ei NHBoc -CH3 6a D-7 MS (ES): 560.5 NH
193b -H CH, 00 NHBoc -CH3 192b+
MS (ES): 574.5) 1-d n 6a 1-i cp o i-,.)--t..) vi oe t..) -R (Position with Cpd. Starting Method Respect to Phenyl -R.' -R"
Analytical Data No. From Used 0 Ring) _______________________________________________________________________________ ____________________________________ o _ t..) NE
i-,4--.6.
1-, 194a -H 1.1 NH2 -CH3 193a S-2 MS (ES): 460.3 1-NH
- 194b -H CH3 NH2 -CH3 193b S-2 MS (ES): 474.3 -'0 = 0 IHNMR (DMSO-d6): 8 8.79 (bs, I.) 4H), 8.63 (t, J --- 6.5 Hz, 1 H), a, I\) NH
1¨
8.35 (s, 1 H), 7.85 (d, J = 6 Hz, 1 (5) oe a, H), 7.62 (d, J = 8.2 Hz, 2 H), 7.26 Lo l 195a -H el NH2 -H 194a 1-2 (m, 5 H), 7.06 (m, 1 H), 5.0 (m, 2 H), 3.09 (t, J = 6.2 Hz, 2 H), 1.86 N
CA
(n, 1 H), 0.89 (d, J = 6.6 Hz, 6 I0 H); MS (ES-): 444.3 and (ES) a, H
446.3 -A
.0 n ,-i cp =
i-,.,--t..) u, oe t..) -R (Position with Cnd Starting Method - = Respect to Phenyl -R' -R"
Analytical Data No. From Used Ring)tµ.) 11INTMR (DMSO-d6/DC1): 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 =
8.7 Hz, 1 H), 7.48 (d, J = 8.7 Hz, NH
1 H), 7.32 (t, J = 8 Hz, 1 H),7.16 (m, 3 H), 6.91 (t, S = 7.5 Hz, 1 H), 195b -H CH, el NH, -H 194b 1-2 6.76 (d, J = 8.5 Hz, 1 H), 6.66 (d, = 8.5 Hz, 1 H), 4.99 (m, 1 H), 2.92 (d, J= 6.9 Hz, 2 H), 1.68 (m, 111), 1.33 (d, J = 6 Hz, 1.2H), 1.27 (d, 5= 6 Hz, 1.8 H), 0.71 (d, J = 6.5 Hz, 6 H); MS (ES-): 458.2 and (ES) 460.3 c7, oe NH
oe CH, NHBoc _CH3 199 6a 200 -H MS (ES):
573.5 0 C. I
-R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data No. From Used 0 Ring) _ o tµ.) 11-11\IMR. (DMSO-d6/DC1): 5 8.49 '(;) (t, J = 5.6 Hz, 1 H), 8.18 (d, J =
.6.
NH
6.9 Hz, 1 H), 7.84 (t, J= 7.8 Hz, 1 H), 7.23 (m, 4 H), 7.01 (m, 2 H), 6.82 (d, J =7 Hz, 1 H), 6.22 (d, J
CH, NHBoc =--- 8.5 Hz, 1 H), 6.15 (d, J = 8.5 Hz, 1 H), 3.95 (m, 1 H), 2.85 (t, J
H =-- 5.8 Hz, 1 H), 1.62 (m, 1 H), 1.23 (s, 9 H), 1.1 (d, J = 6.7 Hz, 1.2H), 1.05 (d, J = 6.7 Hz, 1.8 H), 0.67 (d, J ---- 6.6 Hz, 6 H); MS
n (ES+): 559.4 o NH
1.) .i.
1.) 1-, = o) o CH3 u.) 202 -H lep NH2 .4-1 201 S MS (ES+): 459.3 0 I.) o N
o u.) H
o NH
.i.
H
203 -0Bn (4) 0 = NHBoc R MS (ES+): 679.4 N
H
NH
204 -0Bn (4) 0 NHBoc -H 203 1-2 MS (ES): 663.4 1-lo n ,-i N
ci) H
o 1-, l = . ) l = . ) --R (Position with Cnd= Starting Method -No. Respect to Phenyl -R' -R" From Used Analytical Data Ring)-0 c _N
I
-209a -H II ----=-_--A-7 MS (ES): 454.3 N
H
IHNMR (DMSO-d6): 5 10.72 (s, 1 H), 8.65 (d, J = 6.03 Hz, 1 H), = c ----____T- N 8.24(s, 1 H), 8.03 (d, J =8.1 Hz, 141111 1 H), 7.75 (m, 6 H), 7.40 (d, J =
7.90 Hz, 1 H), 7.34 (d, J = 8.1 Hz, N
209b -CH=CH2 (4) -CH3 30f A-7 1 H), 6.88 (q, J = 11.2 Hz, 1 H), n H
6.04 (d, J = 7.5 Hz, 1 H), 5.41 (d, J = 11.1 Hz, 1 H), 3.55(s, 3 H), I.) .1, I.) 3.10 (t, J = 6.6 Hz, 2 H), 1.86(m, (5) vD
.1, , MS (ES): 480.3 I.) 11-1N4R (DMSO-d6): 5 10.12 (s, u.) 1 H), 9.37 (b, 1 H), 8.48 (t, 3=6.1 .1, Hz, 1 H), 8.05 (d, 3=1.9 Hz, 1 H), H
NH
7.85 (d, 3=7.9 Hz, 1 H), 7.56 (d, 3=7.8 Hz, 1 H), 7.49 (d, 3=7.9 Hz, 1 H), 7.36 (s, 4 H), 7.21 (d, 3=7.9 210b -CH=CH2 (4) H -CH3 209b Y Hz, 1 H), 7.10 (d, J=2.8 Hz, 1 H), -'N 6.69 (m, 1 H), 5.84 (d, 3=15.5 Hz, H 1 H), 5.60 (b, 1 H), 5.22 (d, J=11.4 Hz, 1 H), 3.38 (s, 3 H), 2.91 (t, J = 6 Hz, 2 H), 1.66 (m, 1 1-d n H),0.71 (d, J = 6.8 Hz, 6 H); MS
(ES+) 515.40 cp o i-,.)--t..) vi oe t..) , i -R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data 0 No. From Used Ring) o t..) IHNMR.(DMSO-d6): 5 12.62 .6.
--.1 (bs, 1H), 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, NH
1 H), 7.50 (d, J=7.9 Hz, 1 H), 7.49 (s, 6 H), 7.16 (d, J=8.1 Hz, 1 211b -CH=CH2 (4) 0 410 N-OH
H -H 210b 1-2 H), 7.08 (d, J=8.1 Hz, 1 H), 6.72 (m, 1 H), 5.85 (d, J=13.7 Hz, 1 N
H), 5.24 (d, J-41.5 Hz, 1 H), H
2.93 (t, J = 6 Hz, 2 H), 1.68(m, 1 0 H), 0.72 (d, J ---- 6.8 Hz, 6 H); MS
(ES+) 501.40, (ES-) 499.2 I.) a, IHNMR (DMS0): 5 8.70 (t, J =
I.) (5) 1-a, vD
5.6 Hz, 1 H), 8.36 (d, J=1.7 Hz, u.) 1 H), 8.07 (dd, J = 8.1, 1.9 Hz, 1 I.) . c .N H), 7.42 (m, 4H), 7.09 (d, J= 5.5 0 Hz, 1 H), 7.04 (d, J= 7.7 Hz, 1 u.) H), 6.74 (dd, J= 17.5, 10.9 Hz, 1 a, 212 -CH=CH2 (4) -CH3 187a AE-5 N
H), 6.49 (d, J= 8.8 Hz, 2 H), 5.79 H
-,1 H
(d, J= 17.7 Hz, 1 H), 5.27 (d, J-10.9 Hz, 1 H), 4.0 (t, J- 6.0 Hz, 211), 3.62 (s, 3 H), 3.11 (t, J=
6.2, 2 H), 1.86 (m, 1 H), 0.90 (d, J= 6.6 Hz, 6 H) 1-d n ,-i cp =
t..) u, oe t..) , -R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data No. From Used 0 Ring), _______________________________________________________________________________ ___________________________________ o t..) 1H NMR (DMS0): 3 9.23 (s, 1 .6.
H), 8.71 (t, J- 6.2 Hz, 1 H), 8.36 (d, J= 1.9 Hz, 1 H), 8.09 (dd, J =
7.9, 1.7 Hz, 1 H), 7.49 (d, J = 7.9 Hz, 2 H), 7.40 (d, J= 8.3 Hz, 1 NH
H), 7.32 (d, J= 8.8 Hz, 2 H), 7.04 (d, J= 7.9 Hz, 1 H), 6.73 (dd, J=
213 -CH=CH2 (4) N-OH -CH3 212 Y 17.7, 11.1 Hz, 1 H), 6.40 (d, J=
H
.
8.5 Hz, 2 H), 6.33 (t, J= 7.0 Hz, N
1 H), 5.78 (d, J= 17.7 Hz, 1 H), H
5.58 (b, 1 H), 5.26 (d, J= 11.1 n Hz, 1 H), 3.96 (m. 2 H), 3.64 (s, 3 I.) H),3.11 (t, J-- 6.4 Hz, 2 H), 1.86 a, I.) (mõ 1 H), 0.90 (d, J= 6.8 Hz, 6 (5) a, vDu.) t..) H); MS (ES): 501.3 0 11-1NMR (DMS0): 68.76 (t, J=
"
5.8 Hz, 1 H), 8.37 (s, 1 H), 8.04 u.) (d, J= 8.7 Hz, 1 H), 7.39 (m, 5 H), 7.06 (d, J-- 8.3 Hz, 1 H), 6.72 H
-,1 (dd, 1 = 17.9, 11.3 Hz, 1 H), 6.43 214 -CH=CH2 (4) 1-2 (d, J= 8.5 Hz, 3 H), 5.76 (d, J=
H
17.9 Hz, 1 H), 5.24 (d, J= 11.1 N =
Hz, 1 H), 3.98 (m. 2 H), 3.11 (t, J
H
= 6.6 Hz, 2 H), 1.86 (h, J.-- 6.8 Hz, 1 H), 0.90 (d, J= 6.8, 6 H);
.
MS (ES): 487.2 1-d n 1-i = cp o ,-, t..) u, oe t..) -R (Position with Cpd. Starting Method Respect to Phenyl -R' -R"
Analytical Data No. From Used Ring 1HNMR (DMSO-d6): 8 8.68-8.60 (m, 1 H), 8.50 (d, J = 2.4 Hz, 1 NH H), 7.90-7.80 (m, 1 H), 7.76-7.70 (m, 1 H), 7.56-7.50 (m, 1 H), 011p NH2 237 + 7.48-7.42 (d, J ¨7.7 Hz, 1 H), 7.30-7.22 (d, J = 7.9 Hz, 1 H), 7.10-7.02 (d, J = 7.7 Hz, 1 H), 238 -CH=CH2 (4) H -H AE-2 187a 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, = 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 (5) NH
1.) 256 -H 410 NHB" -CH3 255 + 6a D-6 MS (BS):
573.3 NH
NH2 -H 256 1-2, S MS
(ES): 459.1 oe NH
0 4111) NH, 3 2 1 la R'02C
Cpd.Starting Method -R -R' Analytical Data No. From Used 79a -CH=CH2 (3) -CH3 78a J MS (ES): 499.2 c7, 79b -OS02CF3 (3) -CH2C6H5 78b J Characterized in the next step 79C OCH2C 02 C2115. (3) -CH2C6H5 78c J Characterized in the next step 79d -OCH2CONH2 (3) -CH2C6H5 78d J MS (ES.): 622.4; (ES") 620.4 79e (3) -CH2C6H5 78e J Characterized in the next step 79f0 -CH2C6H5 78f 3 Characterized in the next step 1-3 / 11 ar (3) oe Cpd. Starting Method -R -R' Analytical Data No. From Used IHNMR (DMSO-d6): 8 10.6 (bs, 1 H), 9.29-9.32 (bs, 1 H), o 9.06 (bs, 1 H), 8.82-8.75 (t, J. = 5.84 Hz, 1 H), 8.32 (d, J =
.6.
1.88 Hz, 1 H), 8.13 (d, J = 1.7 Hz , 1 H), 7.83 (s, 4 H), 7.78 (d, --.1 -OCH3 (3) 79g -CH3 78g J 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 --.., ...õ---.....,_7CH3 (3) -Bn 78h J MS
(ES): 607.3 791 -"OCH3 (3) -Bn 781 J MS (ES):
593.4 n I.) 793 0 (3) -Bn 78j J MS (ES):
621.4 . a, "
(5) o a, vi CH, u.) o 79k -0-CH2-CH2-0Ac (3) -Bn 78k 1 MS (ES):
651.4 "
u.) IHNMR (DMSO-d6): 8 9.1 (s, 2 H), 8.87 (s, 2 H), 8.53 (t, J =
a, -CH=CH2 (3) . 6 Hz, 1 H), 8.02 (s, 1 H), 7.64 (m, 7 H), 7.1 (s, 1 H), 6.98 (d, HI
80a -H 79a 1-2 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, 1 H), 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 IHNMR (DMSO-d6): 8 10.37 (s, 1 H), 9.20 (m, 3 H), 8.72 (t, , -OH (3) 1 = 6 Hz, 1 H), 8.2 (s, 1 H), 8.85 (m, 6 H), 7.65 (d, I = 8 Hz, 1 80b -H 79b . 1-2 H), 7.12 (d, 8 Hz, 1 H), 7.02 (dd, J = 2.5 Hz, J = 8 Hz, 1 H), 1-d n 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 cp o c.:.) t..) vi oe t..) -Cpd. Starting Method -R -W
Analytical Data No. From Used 11-1 NMR. (DMSO-d6): 6 12.7 (211, bs, 1 H), 9.01, 8.87 (2 bs, 4 80c -OCH2CO2H (3) -H 79c 1-2 H), 8.36 (m, 1H), 7.83 (s, 1H), 7.44 (m, 6 H), 6.75 (m, 2H), 6.31 (d, J=2.2 Hz, 111), 4.42 (s, 2H), 2.84 (m, 2H), 1.63 (m, 1H), 0.67 (d, J=6.5 Hz, 6H); MS(ES+): 533.4 1HNMR (DMSO-d6): 5 9.13 (bs, 5H), 8.59 (t, J=6.28 Hz, 111), 8.14 (d, J= 1.7 Hz, 1H), 7.63 (m, 9H), 7.42 (s, 1H), 7.09 - 80d -OCH2CONH2 (3) -H 79d G (d, .1 = 7.5 Hz, 1H), 7.03 (dd, J = 2.5, 12.7 Hz, 1H), 6.70 (d, J
=2.5 Hz, 1H), 4.48 (s, 2H), 3.05 (t, J= 6.6 Hz, 2H), 1.83 (m, 1H), 0.87 (d, J=6.8 Hz, 6H); MS(ES+): 532.4 11-1 NMR (DMSO-d6): 5 12.6 (1H, bs, COOH), 8.98, 8.67 (2 80e (3) -H 79e 1-2 bs, 4H), 8.46 (m, 1H), 8.08 (m,1H), 7.76 (m, 111), 7.53 (m, 6 H), 7.39 (m, 2H), 7.06 (m; 1H), 7.04 (m, 111), 2.89 (m, 211), (5) 1.66 (m, 1H), 0.69 (d, J=6.5 Hz, 6H); MS(ES+): 541.4 IHNMR (DMSO-d6): 5 9.14 (d, J = 10 Hz, 4 H), 8.60 (t, J = 6 801 II Hz, 1 H), 8.22 (bs, 1 H), 7.87-7.62 (m, 7 H), 7.47 (t, = 8 Hz (3) , -H 79f 1-2 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, J = 6.8 Hz, 6 H); MS
(ES) 551.4 11-1NMR (DMSO-d6): 6 9.13 (bs, 2 H), 8.78 (bs, 2H), 8.65 (t, J
= 6 Hz, 1 H), 8.25 (bs, 1 H), 7.78 (m, 1 H), 7.76 (m, 5 H), 80g -OCH3 (3) -H 79g 1-2 7.25 (s, 1 H), 7.17 (m, 1 H), 6.73 (bs, 1 H), 3.83 (s, 3 H), 3.10 1-d (t, J = 6 Hz, 2 H), 1.80 (m, 1 H), 0.88 (d, J = 6.8 Hz, 6 H);
MS (ES) 489.3 oe Cpd.Starting Method -R -R' Analytical Data No. From Used 80h(3) 4.1 79h 1-2 MS (ES): 517.7 80i \ 0./\CH3 (3) -H 79i 1-2 MS (ES): 503.4 ; MS (ES):
501.4 80j 0 (3) -H 79j 1-2 MS (ES): 531.4 ; MS (ES):
529.4 IHNMR (DMSO-d6): 6 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
80k -H 79k 1-2 8 Hz, 1 H), 6.48 (d, J = 2.5 Hz, 1 H), 4.91 (t, J = 5.5 Hz, 1 H), 0 -0-CH2-CH2-0H (3) 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 (5) H); MS (ES): 519.3, (ES-) 517.3 IHNMR (DMSO-d6): 5 9.15 (bs, 3 H), 8.65 (t, J = 6 Hz, 1 H), -CH(OH)CH2OH (3) 8.12 (s, 2 H), 7.82-7.56 (m, 7 H), 7.55-6.96 (m, 4 H), 5.5 (bs, 86a -H 82 S, 1-2 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 IHNMR (DMSO-d6): 6 8.82 (bs, 2 H), 8.68 (bs, 2 H), 8.40 (t, -CH2OH (3) J = 6 Hz, 1 H), 7.88 (bs, 1 H), 7.53 (m, 5 H), 7.45 (d, 8 Hz, 1 =
86b -H 84 S, 1-2 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-d 1 H), 0.71 (d, J = 6.8 Hz, 6 H); MS (ES) 489.2 oe -, Cpd. Starting Method -R -R' Analytical Data No. From Used o 1HNMR (DMSO-d6_D20): 5 13.7 (bs, 1 H), 832 (t, J -= 6 Hz, t..) 86c -CO2H (3) -H 85 S, 1-2 i-,.)--1 H), 7.63-7.17 (m, 7 H), 6.72 (d, 7.0 Hz, 1 H), 2.81 (t, J = 6 .6.
Hz, 2 H), 1.53 (m, 1 H), 0.64 (d, J = 6.8 Hz, 6 H); MS (ES) 503.2 97a ) -CH 3 96a J MS (ES): 569.2 (5) s 1HNMR (DMSO-d6): 5 10.62 (s, 1 H), 9.15 (bs, 2 H), 8.82 n (bs, 2 H), 8.67 (t, J = 6 Hz, 1 H), 8.25 (d, J = 2 Hz, 1 H), 7.99 97b -0Bn (5) -CH3 91 J (dd, J = 8.1 and 2 Hz, 1 H), 7.69 (q, 8.8 and 16.2 Hz, 4 H), "
a, I.) 1- 7.44 (m, 3 H), 7.28 (m, 3 H), 6.89 (d, J = 7.7 Hz, 1 H), 5.5 (s, (5) o a, oe 2 H), 3.6 (s, 3 H), 3.08 (t, J = 5.8 and 6.8 Hz, 2 H), 1.83 (m, 1 u.) H), 0.87 (d, J = 6.8 Hz, 6 H); MS (ES-) 577.2, (ES+) 579.3 I.) u.) 11-INMR (DMSO-d6): 5 13.45 (bs, 1 H), 9.06 (s, 2 H), 8.99 (s, a, -, 3 2 H), 8.51 (t, J = 6 and 5 Hz, 1 H), 7.99 (s, 1 H), 7.62 (m, 5 I-.H), 7.47 (s, 1 H), 7.36 (m, 2 H), 6.99 (m, 4 H), 4.26 (s, 2 H), 1 98a -H 97a 1-2 -,1 S (5) 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 = 11-1NMR (DMSO-d6): 5 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), =98b -0Bn (5) -H 97b 1-2 7.49 (s, 1 H), 7.46 (s, 1 H), 7.34 (m, 5 H), 7.15 (d, J = 8.2 Hz, 1-d n 1 H), 7.00 (d, J - 8.2, 1 H), 6.02 (d, J - 7.4 Hz, 1 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 cp Hz, 6 H); MS (ES-) 563.2, (ES+) 565.2 t..) vi oe t..) Cpd. Starting Method -R -R' Analytical Data No. From Used IHNMR (DMSO-d6): 5 9.85 (s, 1 H), 9.07 (s, 2 H), 8.98 (s, 2 o t..) H), 8.50 (t, J = 6 and 5 Hz, 1 H), 7.99 (d, J = 1.7 Hz, 1 H), .6.
98c -OH(5) -H 98b G 7.63 (m, 5 H), 7.20 (t, J = 8 Hz, 2 H), 6.90 (d, J = 7.9 Hz, 1 --4 1-, 1-, H), 6.49 (d, J = 7.2 Hz, 1 H), 3.21 (t, J = 6.8 Hz, 2 H), 1.80 (m, 1 H), 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 iHNMR (DMSO-d6): 5 9.08 (bs, 2 H), 8.80 (bs, 2 H), 8.52 (t, 104 -OCH3 (2) -H 103 1-2 J = 6 Hz, 1 H), 8.02 (s, 1 H), 7.64 (m, 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, n 1 H), 0.86 (d, J = 6.8 Hz, 6 H); MS (ES-) 487.3, (ES+) 489.3 I.) a, 110 -0Bn (2) -CH3 109 J MS (ES):
579.3 I.) (5) o a, 111 -OH (2) -CH3 110 G MS (ES):
489.3 0 I.) -0C2H5 (3)1 .
LO
' both -CH3 118b J Characterized in the next step -0Bn (4) 0 FP
I
H
1H NMR (DMSO-d6): 8 9.06-9.09 (m, 3H), 8.56-8.50 (m, 1H), 8.05 (s, 1H), 7.71-7.58 (m, 6H), 7.55-7.28 (m, 6H), 7.10-127 -0C2H5 (31 -H 126 1-2 7.01 (m, 1H), 6.63 (s, 1H), 5.19 (s, 2H), 4.05-3.97 (m, 2H), .
both 3.05-3.01 (m, 2H), 1.86-1.77 (m, 1H), 1.29 (t, J=6.7 Hz, 3H), -0Bn (4)j 0.87 (d, J=6.8 Hz, 6H) 111 NMR (DMSO-do): 13.64 (hr s, 1 H), 8.99 (br s, 2 H), 8.49 }both (t, .1=5.1 Hz, 1 H), 7.99 (s, 1 H), 7.73-7.56 (m, 5 H), 7.32--0CH3 (3) 6.83 (m, 5 H), 6.50 (s, 1 H), 5.17 (d, J= 4.3 Hz, 1 H), 5.01 1-d 129 -H 128 I-2, S
n -CH(OH)CH3 (4) (m, 1 H), 3.75 (s, 3 H), 3.03 (t, J= 6.0 Hz, 1 H), 1.81 (m, 1 H), 1.32 (d, J = 6.2 Hz, 3 H), 0.86 (d, J- 6.6 Hz, 6 H); MS
cp (ES): 533.4 (100% M+1) o .
i-,.)--t..) vi oe t..) NH
0 NHBoc W."
= H
Cpd. -R (With Respect to Starting Method No. , Phenyl Ring) , From , 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 (ES): 601.3 (5) 84 -CH2OH (3) 83 K MS (ES-1): 601.4 85 -CO2H (3) 83 E MS (ES-1): 615.3 -OCH3 (3) 128 both 124a R MS (ES): 629.4 -CH=CH2 (4) oe . 0 5 o n.) c.:.) .6.
RI CHO --.1 1-, 1-, R
, Cpd. _R
-R1 -R2-R3 -R4 Starting 1 Method Analytical Data No. From Used 1HNMR (CDC13): 6 10.48 (s, 1 H), 7.42 -7.25 (m, 7 H), 7.00 (dd, J = 2 and 7.4 88 -Br -H -H -H -0Bn 87 X Hz, 1 H), 5.19 (s, 2 H); IR (I<Br) 1701, 1585, 1452, 1262, 1009 crn-1; MS
(ES+) 313.0, 315.0 (M+Na)-1 n ....
1HNMR (CDC13): 8 10.61 (s, 1 H), 7.65 (d, J = 7.2 Hz, 1 H), 7.60 (t, J = 7.9 and "
a, t..) 89 -B(OH)2 -H -H -H -0Bn 88 T, U-1 7.2 Hz, 1 H), 7.41 (m, 5 H), 7.19 (d, J = I.) (5) o a, 7.9 Hz, 1 H), 6.81 bs, 2 H), 5.20 (s, 2 u.) H) I.) 1HNMR (DMSO-d6): 6 10.2 (s, 1 H), u.) 100 -B(OH)2 -OCH3 -H -H -H 99 T, U-3 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-) a, H
179.0 107 -B(OH)2 -0Bn -H -H -H 106 T, U-1 1HNMR (DMSO-d6): 8 10.1 (s, 1 H), .
7.3-7.6 (m, 8 H), 5.3 (m, 2 H) 114a -Br -H -OCH3 -OH -H 113 Z MS (ES):
229.0 and 231.0) _ 114b -Br -H -0C2H5 -OH -H 113 Z-1 MS (ES):
242.9 and 244.9 114c -Br -H -OCH(CH3)2 -OH -H 113 Z-1 MS (ES):
257.0 and 259.0 115a -Br -H ' -OCH3 -0Bn -H 114a X MS
(ES): 321.0 and 323.0 115b -Br -H - -0C2H5 -0Bn -H 114b X
MS (ES): 335.0 and 337.0 Iv n 115c -Br -H -OCH(CH3)2 -0Bn -H 114c X , MS (ES+):
349.0 and 351.0 cp o t..) vi oe t..) Cpd.
-R1-R2 -R3 -R4 Starting Method Analytical Data No. From Used X, V-4, 1151 -Br -H -0Bn -H 115a Characterized in the next step All 0 C(CH3)3 116a -B(OH)2 -H -OCH3 -0Bn -H 115a T, U-1 Characterized in the next step 116b -B(OH)2 -H -0C2H5 -0Bn -H 115b T, U-1 Characterized in the next step 116c -B(OH)2 -H -OCH(CH3)2 -0Bn -H 115c T, U-1 Characterized in the next step =
(5) oe NH
0 = N112 -Cpd. Starting Method Analytical Data No. From Used 11INMR (DMSO-d6): 11.28 (s, 1 H), 9.31 (s, 2 H), 9.0 (s, 2 H), 8.88 (d, J =
11.30 Hz, 0 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), (5) 112 111 1-2 8.04 (d, J = 8.47 Hz, 1H), 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 0 =3.5 Hz, 1 H), 1.8 (m, J = 19.9 Hz, 2 H), 0.88 (m, J = 6.6 Hz, 6 H).
oe R' RO =
n.) 40 NHR"' .6.
H3CO,C --4 1¨, 1¨, i Cpd. I
-R -R' -R" -R"' 1 Starting Method ' No.
Analytical Data From Used 117a -CH3 -0Bn -CHO 3a D-2 D-2 MS (ES-): 474.2 CH3 116a 117b -C2H5 -0Bn -CHO 3a I.) -'=,,.,./---,.CH3 116b D-2 MS (ES):
488.2 a, t..) I.) o (5) CH3 Lo 117c -CH(CH3)2 -0Bn -CHO 3a+
I.) MS (ES): 502.3 0 116c Lo a, ' IHNMR (CDC13): 8 9.56 (s, 1 H), 8.34 (d, J = 1.7 Hz, 1H), 8.5 -A
(s, 1 H), 8.01 (dd, J =7.9 and 1.9 117d -CH3 -0Bn -CHO CH3 3b +
Hz, 1 H), 7.40 (m, 7 H), 6.9 (s, 1 116a H), 5.24 (m, 2 H), 4.2 (m, 1 H), 'cH3 3.80 (s, 3 H), 3.52 (s, 3 H), 1.02 (d, J = 7 Hz, 6 H); MS (ES+) :
=
484.3 (M+Na) Iv n 1-i cp .
o ,-, t..) u, oe t..) Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used IHNMR (DMSO
0-d6): 5 8.43 (d, J o = 1.65 Hz, 1 H), 8.31 (d, J = 8.66 t..) c.:.) Hz, 1), 8.12 (dd, J =1.69 Hz, .6.
1H), 7.98 (s, 1H), 7.41 (d, J = 8 CH3 and and 10 Hz, 1H), 7.19 (d, J = 8.1 117e -CH3 -0Bn -CHO
3c Hz, 111), 5.20 (dd, J = 6.2 Hz, CH, 116a 1H), 3.98 (dd, J = 7.75 Hz, 311), 3.94 (s, 3H), 3.42 (m, 311), 3.32 (m, 3H), 3.19 (s, 3H), 2.5 (m, 3H), 2.0 (s, 4H), 1.5 (m, 211), 1.28 (m, 3H), 0.88 (d, J = 6.59 Hz, 311); MS (ES ): 664.3 n , 1HNMR (CDC13): 5 9.50 (s, 1 H), 8.40 (d, J = 2.1 Hz, 111), 8.04 I.) a, I.) t..) (dd, J= 8.1, 2.1 Hz, 111), 7.57 (s, (5) oa, 1 H), 7.48 (m, 5 H), 7.38 (m, 5 u.) ....,,...--.....,.....õ,-...,.....CH3 3d H), 6.67 (s, 1 H), 6.50 (broad, 1 I.) 117f -CH3 -0Bn -CHO
116a H),) 5.27 (d, J----- 11.9 Hz, 1 H), 0 u.) ' 5.22 (dd, J= 11.7, 1 1-1), 4.63,(m,3H) 4.17 (m, 4 H), 3.92 a, H
(s, 3 H), 3.66 (s, 3 H); MS (ES):
488.3 IH NMR (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 117g -CH3 -0Bn -CHO 3 D-2 (m, 3 H), 6.67 (s, 1 H), 6.50 116a 1-d 'cF3 (broad, 1 H), 5.27 (d, J= 11.9 n Hz, 1 H), 5.22 (dd, J = 11.7, 2 H), 4.17 (m, 2 H), 3.92 (s, 3 H), cp o 3.66 (s, 3 H); MS (ES): 500 c.:.) t..) vi oe t..) , Cpd.Starting Method -R -R' -R" -R"' Analytical Data No. From Used _____________________ IHNMR (CDC13): 5 9.56 (s, 1 o H), 8.34 (d, J-- 1.7 Hz, 1 H), =
t..) 8.01 (dd, J= 7.9, 1.9 Hz,'1 H), .6.
7.57 (s, 1 H), 7.50 (dd, J= 7.2, 3e +
1.5, 2 H), 7.40 (m, 4 H), 6.67 (s, 117h -CH3 -0Bn -CHO
116a 1 H), 6.21 (broad, 1 H), 5.24 (d, J
= 2.8 Hz, 2 H), 3.92 (s, 3 H), 3.65 (s, 311), 3.52 (m, 2 H), 1.65 (m, 2 H), 1.46 (m, 2 H), 0.99 (t, 3 = 7.3 Hz, 3 H).
11-1NMR (CDC13): 8 9.57 (s, 1 H), 8.37 (d, J= 1.9 Hz, 1 H), n 8.03 (dd, J= 7.9, 1.9 Hz, 1 H), 7.58 (s, 1 H), 7.50 (d, J= 7.2 Hz, I.) 2 H), 7.38 (m, 3 H), 6.68 (s, 1 H), .1,.
I.) t.) 117i -CH3 -0Bn -CHO /\, 3ff +
-D-2 6.33 (broad, 1 H), 5.26 (d, J=
116a (5) a, =
u.) c7, 11.5 Hz, 1 H), 5.21 (d, J= 11.9 0 Hz, 1 H), 3.92 (s, 3 H), 3.65 (s, 3 "
H), 3.37 (dd, J= 7.2, 5.3 Hz, 2 Lo H), 1.09 (m, 1 H), 0.60 (m, 2 H), .1,.
' 0.32 (m, 2 H); MS (ES): 474.2 , -,1 1H NAIR (CDC13): 5 9.55 (s, 1 H), 8.32 (d, J= 1.9 Hz, 1 H), 8.00 (dd, J= 1.9 and 7.9 Hz, 1 117j -CH3 -0Bn -CHO -0 3h +
116a D-2 H 7.59-7.30 m 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
1-d (ES+): 510.3 (M + Na)+
n 1-i cp o ,-, t..) u, oe 206 n.) Cpd. Starting Method -R -R' -R"
Analytical Data No. From Used 0 1H NMR (CDC13): 8 9.56 (s, 1 o t..) H), 8.35 (d, J= 1.9 Hz, 1 H), .6.
8.02 (dd, f= 1.9 and 7.9 Hz, 1 1-, 1-, 3i +
H), 7.58-7.33 (m, 7 H), 6.68 (s, 1 117k -CH3 -0Bn -CHO
cti3 116a H), 5.24 (m, 2 H), 3.92 (s, 3 H), 3.65 (s, 3 H), 3.56 (m, 2 H), 1.30 (t, J= 7.2 Hz, 3 H); MS (ES):
470.3 (M Na) 1H NMR (CDC13): 8 9.56 (s, 1 H), 8.35 (d, J= 1.9 Hz, 1 H), 8.02 (dd, J= 1.9 and 7.9 Hz, 1 3j +
H), 7.58-7.33 (m, 7 H), 6.68 (s, 1 1171 -CH3 . -0Bn -CHO
116a H), 5.24 (m, 2 H), 3.92 (s, 3 H), 0 IV
3.65 (s, 3 H), 3.40 (m, 2 H), 1.80-a, I.) (5) t..) 0.94 (m, 9 H); MS (ES): 512.2 a, o u.) (M+ Na) 0 I.) 1HNMR (DMSO-d6): 8 9.73 (s, 1 .
H), 8.86 (t, J = 5.7 Hz, 1 H), 8.52 u.) (d, J = 1.5 Hz, 1 H), 8.22 (dd, J =
FP
I
8 and 2 Hz, 1 H), 7.79 (s, 1 H), H
-.-1 6a +
7.60 (d, J = 8 Hz, 1 H), 7.5 (m, 5 117m -0Bn -CHO \,./`-..
--..---.C. (CH3)3 CH3 115d H), 7.22 (s, 1 H), 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 (ES): 546.4 .
_ CH3 1-d n 118a -CH3 -0Bn -CO2H 117a E MS (ES): 490.2 cp o i-,.)--t..) vi oe t..) Cpd. Starting Method -R -12.' -R" -R"' Analytical Data No. From Used _ -CH
5 =
t..) 118b -C2H5 -0Bn -CO2H 117b E MS (ES): 504.2 4,.
'--'CH3 --.1 1¨
cH3 118e -CH(CH3)2 -0Bn -CO2H 117c E . MS (ES): 518.2 118d -CH3 -0Bn -CO2H 117d E Characterized in the next step -clI3 118e -CH3 -0Bn -CO2H ____<---CH3 117e E MS (ES): 534.3 0 IV
FP
IV
0) FP
la IV
1181 -CH3 -0Bn -CO2H .,---..,..---..,.,,,c1-13 117f E MS (ES): 506.3 la I
FP
I
118g -CH3 -0Bn -CO2H /CF3 117g E Characterized in the next step H
118h -CH3 -0Bn -CO2H .--'''cli3 117h E MS (ES-1): 490.2 118i -CH3 -0Bn -CO2H /<1 117i E MS (ES-1): 488.3 1-d n ,-i cp =, i-,.,--t..) u, oe t..) .
, Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used 0 1H NMR (DMSO-d6): 6 12.19 o t..) (br s, 1 H), 8.50 (d, J= 7.4 Hz, 1 .6.
H), 8.31 (d, J= 1.9 Hz, 1 H), --.1 118j -CH3 -0Bn -CO2H -0 117j E 8.02 (dd, J= 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, J= 6.4 Hz, 1 H), 3.80 (s, 3 H), 3.57 (s, 3 H), 1.97-1.51 (m, 8 H) -_.
118k -CH3 -0Bn -CO2H C1.1, 117k E MS (ES): 462.3 n 1H NMR (CDC13): 8 8.30 (d, J=
1.9 Hz, 1 H), 7.95 (dd, J= 1.7 N
and 7.9 Hz, 1 H), 7.66 (s, 1 H), I.) t..) CH3 7.52-7.27 (m, 6 H), 6.62 (s, 1 H), (5) a,.
vD 1181 -CH3 -0Bn -CO2H 1171 E u.) 6.49 (m, 1 H), 5.21 (s, 2 H), 3.88 1.) (s, 3 H), 3.61 (s, 3 H), 3.38 (m, 2 H), 1.79-0.94 (m, 9 H); MS (ES):
u.) 504.4 c) a,.
H
CH, -A
118m-0Bn -CO2H 117m E Characterized in the next step C(CH3)3 CH3 _ CH, 119a -CH3 -0Bn -0O2MEM 118a F MS (ES): 578.3 1-d CH, n ,-i 119b -C2H5 -0Bn -0O2MEM \_/\ CH3 118b F MS (ES): 592.3 cp o . i I I
t..) vi oe t..) Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used CH, 119c -CH(CH3)2 -0Bn -0O2MEM 118c F MS (ES):
606.3 cH3 119d -CH3 -0Bn -0O2MEM 118d F MS (ES):
564.2 '"CH3 119e -CH3 -0Bn -0O2MEM 118e F MS (ES):
620.1 119f -CH3 -0Bn -0O2MEM 118f F MS (ES):
592.3 0 (5) 119g -CH3 -0Bn -0O2MEM 118g F
Characterized in the next step 1H NMR (CDC13): 5 8.32 (d, J=
1.9 Hz, 1 H), 7.96 (dd, J= 7.9, 1.9 Hz, 1 H), 7.68 (s, 1 H), 7.50 (m, 2 H), 7.35 (m, 4 H), 6.62 (s, 1 119h -CH3 -0Bn -0O2MEM 118h F 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) oe Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used 1HNMR (CDC13): 8 8.34 (d, L9 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 119i -CH3 -0Bn -0O2MEM 1181 F H), 6.42 (broad, 1 H), 524 (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, 1H), 0.58 (m, 2 H), 0.30 (m, 2H) 1H NMR (DMSO-d6): 5 8.55 (d, J= 7.4 Hz, 1 H), 8.39 (d, J= 1.9 Hz, 1 H), 8.10 (dd, J= 1.7 and 7.9 Hz, 1 H), 7.63-7.35 (m, 7 H), 119j -CH3 -0Bn -0O2MEM 118j F 6.81 (s, 1 H), 5.25-5.12 (m, 4 H), 4.31 (q, J= 6.4 Hz, 1 H), 3.86 (s, (5) 3 H), 3.62 (s, 3 H), 3.3 (s, 3 H), 3.23 (s, 3 11)1.99-1.53 (m, 8 H);
MS (BS): 614.3 (M+ Na) 1H NMR (DMSO-d6): 5 8.70 (t, J= 5.5 Hz, 1 H), 8.35 (d, J= 1.9 Hz, 1 H), 8.05 (dd, J= 1.7 and 7.9 Hz, 1 H), 7.59-7.30 (m, 7 H), 119k -CH3 -0Bn -0O2MEM 118k F 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= 7.2 Hz, 3 H); MS (ES):
574.3 (M+ Na) 1-d oe , Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used .1= 5.8 Hz, 1 H), 8.35 (d, J= 1.9 t..) i-,.)--, Hz, 1 H), 8.05 (dd, .1= 1.7 and .6.
--.1 7.9 Hz, 1 H), 7.63-7.33 (m, 7 H), 1191 -CH3,,,.).____, -0Bn -0O2MEM CH31181 F 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 (m, 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
=
(ES): 616.3 (M+ Na)+
1HNMR (DMSO-d6): 8 8.72 (t, J
= 5.6 Hz, 1 H), 8.38 (d, J = 1.8 n Hz, 1 H), 8.70 (dd, 3 = 1.8 and 8.1 Hz, 1 H), 7.71 (s, 1 H), 7.40 I.) a, I.) (m, 6 H), 7.02 (s, 1 H), 5.20 (m, 4 (5) t..) a, 1- 119m -0Bn -0O2MEM 118m F H), 3.59 (s, 3 H), 3.37 (m, 2 H), u.) t.) C(CH3)3 CH3 3.31 (m, 2 H), 3.17 (s, 3 H), 3.12 N) (t, J =6.5 Hz, 2 H), 1.87 (m, 1 u.) H), 1.21 (s, 9 H), 0.91 (d, J = 6.8 .
Hz, 6 H); MS (ES+): 650.4 and a, H
672.3 (M+ NO+
-A
120a -CH3 -OH -0O2MEM 119a G MS (ES): 488.1 120b -C2H5 -OH -0O2MEM \,..,/\ CH3 119b G MS (ES): 502.2 1-d n 1-i cp o i-,.)--t..) vi oe t..) Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used 0 CH, =
n.) W."
120c -CH(CH3)2 -OH -0O2MEM 119c G MS (ES): 516.3 120d -CH3 -OH -0O2MEM 119d G MS (ES): 474.3 120e -CH3 -OH -0O2MEM ____<--CH3 119e G MS (ES): 530.4 CH, n 120f -CH3 -OH -0O2MEM --,,,.c1-13 119f G MS (ES): 502.3 a, I.) (5) a, t..) Lo 120g -CH3 -OH -0O2MEM /..--CF3 119g G Characterized in the next step "
Lo a, 120h -CH3 -OH -0O2MEM3 119h G Characterized in the next step H
-,1 120i -CH3 -OH -0O2MEM /.<
119i G MS (ES): 486.3 120j -CH3 -01-r1 -0O2MEM ¨0 119j G MS (ES): 524.3 (M+ Na)+
od n 1-i 120k -CH3 -OH -0O2MEM .,--"CH3 119k G MS (ES): 484.2 (M+ Na) cp o . .
t..) vi oe t..) s _______________________________________________________________________________ ___________________________ Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From-Used ¨0 CH
o n.) G MS (ES): 502.3 .6.
'\/\/CH3 I-, I-, 1HNMR (DMSO-d6): 5 10.83 (bs, 1 H), 8.77 (t, J =5.6 Hz, 1 H), 8.42 (d, J = 1.8 Hz, 1 H), 8.12 (dd, J = 1.8 and 8.1 Hz, 1H), 7.68 (s, 1 H), 7.41 (d, J =8.1 Hz, 1 H), 6.73 (s, 1 H), 5.21 (q, J =
120m ...-., -OH -0O2MEM CH3 119m G 21 and 6 Hz, 2 H), 3.65 (s, 3 H), C(CH3)3 3.48 (m, 2 H), 3.37 (m, 2 H), 3.24 n (s, 3 H), 3.18 (t, J = 6.5 Hz, 2 H), 1.94 (m, 1 H), 1.39 (s, 9 H), 0.97 I.) a, (d, J = 6.8 Hz, 6 H); MS (ES+):
I.) (5) t..) a, 1¨
560.5 and 582.4 (M+ Na), (ES) co .6.
558.4 I.) CH
CA
I
121a -CH3 -0S02CF3 -0O2MEM 120a B-2 MS (ES-3): 644.1 (M+ Na) 0 .P
I
H
-A
121b -C2H5 -0S02CF3 -0O2MEM 120b B-2 MS (ES+): 658.2 (M+ Na)+
CH, 121c -CH(CH3)2 -0S02CF3 -0O2MEM
120c B-2 MS (EST): 672.2 (M+Na)+ 1-d n ,-i cp =
i-,.,--t..) u, oe t..) Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From __________________________________________________________________ Used _ IHNMR (DMSO-d6): 8 8.43 (d, J
o .---- 1.9 Hz, 1 H), 8.31 (s, 1 H), 8.12 t..) CH3 (d, J = 1.69 Hz, 1 H), 7.98 (s, 1 .6.
H), 7.41 (d, J --- 8.1 Hz, 1 H), 7.19 --.1 121d -CH3 -0S02CF3 -0O2MEM CH3 120d B-2 (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 _ IHNMR (DMSO-d6): 8 8.49 (s, 1 H), 8.34 (d, J = 1.8 Hz, 1 H), 8.2 (d, J = 1.8 Hz, 1 H), 7.97 (s, 1 H), 121e -CH3 -0S02CF3 -0O2MEM ____<-- CH, 7.4 (d, J = 7.8 Hz, 1 H), 7.2 (s, 1 120e B-2 H), 5.2 (q, J -= 6 and 10 Hz, 2 H), I.) 4.0 (m, 3 H), 3.6 (s, 3 H), 3.4 (m, a, I.) t..) (5) 4 H), 3.2 (s, 3 H), 1.5 (m, 4 H), a, vi u.) 1.3 (m, 4 H), 0.85 (m, 6 H); MS
(ES+): 664.3 I.) IHNMR (DMSO-d6): 8 8.83 (d, J
u.) = 5.46, 1 H), 8.55 (d, J = 1.88 Hz, a, 1 H), 8.23 (dd, J = 1.88 Hz, 1 H), H
-,1 8.19(s, 111), 7.73 (d, J = 7.93 Hz, 1 H), 7.29 (s, 1 H), 5.29 (dd, 121f -CH3 -0S02CF3 -0O2MEM 120f B-2 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
1-d (ES+) 636.6 n , i .
1-i cp o t..) u, oe t..) Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used iHNMR (CDC13): 68.43 (d, J=---tµ.) 1.9 Hz, 1 H), 8.03 (dd, 7.9 Hz, 2.1 Hz, 1 H), 8.00 (s, 1 H), 7.35 (d, J= 7.9 Hz, 1 H), 6.79 121g -CH3 -0S02CF3 -0O2MEM ./"-CF3 120g B-2 (m, 2 H), 5.29 (d, J= 6.2 Hz, 1 H), 5.26 (d, J= 6.2 Hz, 1 H), 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 1HNMR (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, 121h -CH3 -0S02CF3 -0O2MEM120h B-2 1 H), 5.32 (m, 2 H), 3.90 ( s, 3 0 H), 3.66 (s, 3 H), 3.55 (m, 6 H), tµ.) 3.4 ( s, 3 H), 1.7 (m,.2 H), 1.45 c7, c7, (m, 2 H), 0.98 (t, J = 7.3 Hz, 3 H); MS (ES): 620 1H NMR (CDC13): 68.41 (d, 2.1 Hz, 1 H), 8.03 (dd, J= 7.9, 1.9 Hz, 1 H), 8.00 (s, 1 H), 7.32 (d, J= 7.9 Hz, 1 H), 6.43 (t, J=
1211 -CH3 -0S02CF3 -0O2MEM /<1 1201 B-2 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 oe Cpd. Starting Method -R -R' -R" -R"' Analytical Data No. From Used . 0 1H NMR (CDC13): 8 8.35 (d, J=
=
tµ.) 1.9 Hz, 1 H), 8.00 (m, 2 H), 7.31 '(;) 4 = , (d, J= 7.9 Hz, 1 H), 6.77 (s, 1 H), 121j -CH3 -0S02CF3 -0O2MEM ----0 120j B-2 6.27 (m, 1 H), 5.28 (m, 2 H), 4.44 (q, J= 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 (ES): 656.3 (M+Na) ' IH NMR (CDC13): 68.38 (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 121k -CH3 -0S02CF3 -0O2MEM 120k B-2 H), 5.27 (m, 2 H), 3.94 (s, 3 H), 0 3.66 (s, 3 H), 3.59-3.43 (m, 6 H), 0 I.) 3.35 (s, 3 H), 1.28 (t, J= 7.2 Hz, a, I.) tµ.) 3 H); MS (ES+): 616.3 (M+Na)+ c7, a, u.) 111 NMR (CDC13): 8 8.38 (s, 1 H), 8.00 (m, 2 H), 7.31 (d, J= 7.9 0 I.) cH3 -Hz, 1 H), 6.78 (s, 1 H), 6.37 (m, 1 u.) 1211 -CH3 -0S02CF3 -0O2MEM --,.----\,-cF13 1201 B-2 H), 5.27 (m, 2 H), 3.94 (s, 3 H), 0 a, 3.66 (s, 3 H), 3.57-3.25 (m, 9 H), H
1.78-0.92 (m, 9 H); MS (ES+):
658.4 (M+ Na)+
1-lo n ,-i cp =
l= . ) C. if I
l= . ) ' Cpd. Starting Method -R -R' -R" -R"
Analytical Data No. From Used IHNMR (DMSO-d6): 5 8.75 (t, J.
o t..) = 5.6 Hz, 1 H), 8.45 (d, J = 1.8 .6.
Hz, 1 H), 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), 121m -OS 02CF3 -0O2MEM --...õ),,.... 121m B-2 5.23 (q, J =21 and 6 Hz, 2 H), /..C(CH3)3 CH3 3.60 (s, 3 H), 3.41 (m, 2 H), 332 (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 -C 02MEM 121a D-3 Characterized in the next step 0 IV
FP
IV
N
OCI
CA
IV
122b -C2H5 -CH=CH2 -0O2MEM 121b D-3 MS (ES):
536.3 (M+Na)+ 0 CA
I
FP
CH
HI
122c -CH(CH3)2 -CH=CH2 -0O2MEM 121c D-3 MS (ES): 550.3 (M+ Na) 122d -CH3 -CH=CH2 -0O2MEM 121d D-3 MS (ES+):
486.2 1-d n cH3 ,-i 122e -CH3 -CH=CH2 -0O2MEM 121e D-3 MS (ES):
564.5 (M+ Na) cp CH, =
1¨, n.) vi oe n.) Cpd.Starting Method -R -R" -R" ' Analytical Data No. From Used 122f -CH3 -CH=CH2 -0O2MEM 121f D-3 MS
(ES+): 514.4 (M+ Na) 122g -CH3 -CH=CH2 -0O2MEM CF3 121g D-3 Characterized in the next step 122h -CH3 -CH=CH2 -0O2MEM CH3 121h D-3 Characterized in the next step 122i -CH3 /\<1 -CH=CH2 -0O2MEM 1211 D-3 Characterized in the next step 122j -CH3 - -CH=CH2 -0O2MEM 121j D-3 MS
(ES-): 422.3 [(M-MeM)-1]
(5) 122k -CH=CH2 -0O2MEM CH3 121K D-3 MS
(ES): 494.2 (M+ Na)+
CH, 1221 -CH3 -CH=CH2 -0O2MEM 'CH1211 D-3 MS (ES): 536.42 (M+ Na) 1-d oe Cpd. Starting Method -R -R' -R" -R"' Analytical Data 0 No. From Used o t..) 1HNMR (DMSO-d6): 8 8.73 (t, J
.6.
= 5.6 Hz, 1H), 8.43 (d, J = 1.8 --.1 Hz, 111), 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 122m ..)4'-C(CH3)3 -CH=CH2 -0O2MEM CH3 121m D-3 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), I.) 0.91 (d, J = 6.8 Hz, 6 H); MS
I.) t..) (ES-): 480.4 [(M-MEM)-1]
o u.) CH, iv 123a -CH3 -CH=CH2 CO2H 122a I-1 MS (ES): 410.2 0 CA
CH
I
FP
I
H
-,1 123b -C2115 -CH=CH2 CO2H 122b I-1 MS (ES): 424.2 123c -CH(CH3)2 -CH=CH2 CO2H122c I-1 MS (ES): 438.2 .-CH3 1-d n 123d -CH3 -CH=CH2 CO2H 122d I-1 MS (ES): 396.2 cp i-,.)--t..) vi oe t..) , Cpd. Starting Method ical Data o No. From Used o t..) CH, FP
123e -CH3 -CH=CH2 CO2H -----c ...-._ 122e I-1 MS (ES): 454.3 --4 ' CHõ
=
1231 -CH3 -CH=CH2 CO2H .-/-\/---./CH3 122f 1-1 MS (ES): 426.3 1HNMR (DMS0): 8 12.37 (s, 1 H), 9.35 (t, .1= 6.0 Hz, 1 H), 8.42 (d, J= 1.7 Hz, 1 H), 8.10 (dd, j=
8.1 Hz, 1.9 Hz, 1 H), 8.06 (s, 1 H), 7.40 (d, J= 7.9 Hz, 1 H), 123g -CH3 -CH=CH2 CO2H 122g I-1 6.98 (dd, J= 17.9, 11.5 Hz, 1 H), I\) a, ./ CF 3 "
t..) 6.77 (s, 1 H), 5.89 (dd, J=17.7, (5) t..) .1,.
1.3 Hz, 1 H), 5.37 (dd, J = 11.1, u.) 1.3 Hz, 1 H), 4.14 (m, 2 H), 3.84 I.) (s, 3 H), 3.61 (s, 3 H); MS (ES):
u.) 436.3 ' FP
1FINMR (DMS0): 8 8.66 (t, .1=
I
H
5.5 Hz, 1 H), 8.35 (d, J= 1.7 Hz, 1 H), 8.05 (s, 1 H), 8.03 (dd,J=
8.1, 1.9 Hz, 1 H), 7.34 (d, J= 7.9 Hz, 1 H), 6.98 (dd, J= 17.9, 11.3 123h -CH3 -CH=CH2 CO2H122h I-1 Hz, 1 H), 6.75 (s, 1 H), 5.88 (dd, J=17.7, 1.3, 1H), 5.36 (dd, J=
11.3, 1.3 Hz, 1 H), 3.84 (s, 3 H), 1-d 3.60 (s, 3 H), 3.30 (q, .1= 5.6 Hz, n 2H), 1.52 (m, 2 H), 1.33 (m, 2 H), 0.96 (t, .1= 7.3 Hz, 3 H); MS
cp o (ES): 410A.
-c.:.) t..) vi oe t..) Cpd.Starting Method Analytical Data 0 -R -R' -R" -R"' No. , From Used o 1HNMR (DMS0): 5 12.34 (s, 1 .6.
H), 8.80 (t, J= 6.1 Hz, 1 H), 8.37 --.1 1--, 1--, (d, J=1.9 Hz, 1H), 8.06 (dd, J=
9.8, 7.9 Hz, 1 H), 8.05 (s, 1 H), = 7.36 (d, J=7.9 Hz, 1 H), 6.98 (dd, J- 17.9, 11.3 Hz, 1 H), 6.76 123i -CH3 -CH=CH2 CO2H /\.<I 122i 1-1 (s, 1 H), 5.89 (dd, J= 17.9, 1.5 Hz, 1 H), 5.36 (dd, J= 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);
n MS (ES): 408.4 I.) 1H NMR (DMSO-d6): 5 12.31 a, I.) t..) (br s, 1 H), 8.52 (d, J= 7.3 Hz, 1 (5) a, t..) u.) t..) H), 8.34 (d, J= 1.7 Hz, 1 H), 0 8.05 (m, 2 H), 7.34 (d, J= 7.9 "
123j -CH3 -CH=CH2 CO21-1 -0 122j Hz, 1 H), 6.97 (dd, J=11.5 and 17.9 Hz, 1 H), 6.74 (s, 1 H), 5.89 7 us, (d, J= 17.9 Hz, 1 H), 5.37 (d, J=
, 11.5 Hz, 1 H), 4.27 (q, J= 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 11-1NMR (DMSO-d6): 8 12.27 (br s, 1 H), 8.58 (m, 1 H), 8.23 (s, 1 H), 7.92 (m, 2 H), 7.47 (m, 1 1-d H), 7.22 (m, 1 H), 6.84 (m, 1 H), n 123k -CH3 -CH=CH2 CO2H ci-i, 122k 6.63 (s, 1 H), 5.76 (d, J= 17.9 Hz, 1 H), 5.24 (d, J-- 11.5 Hz, 1 cp o 1--, H), 3.71 (s, 3 H), 3.47 (s, 3 H), 1.02 (m, 3 H); MS (ES): 382.2 t..) vi oe t..) Cpd.
-R -R' -R" -R Starting Method "' Analytical Data No. From Used 1H NMR (DMSO-d6): ö 12.30 (br s, 1 H), 8.52 (d, J= 6.0 Hz, 1 H), 8.33 (d, J=1.7 Hz, 1 H), 8.02 (m, 2 H), 7.31 (d, J= 7.9 Hz, 1 H), 6.95 (dd, J= 11.5 and 1231 -CH3 -CH=CH2 CO2H 1221 1-1 17.9 Hz, 1 H), 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) (DMSO-d6): 8 12.81 (bs, 1 H), 8.72 (t, J = 5.6 Hz, 1 H), 8.38 (d, J= 1.8 Hz, 1 H), 8.08 (5) (dd, J = 1.8 and 8.1 Hz, 1 H), CH, 7.61 (s, 1 H), 7.57 (s, 1 H), 7.39 123m -CH=CH2 -CO2H 122m I-1 (d, J
=8 Hz, 1 H), 6.72 (dd, J = 0 0 11 and 17.5 Hz, 1 H), 5.99 (d, J
17.5 Hz, 1 H), 5.49 (d, 1=11 Hz, A
1 H), 3.57 (s, 3 H), 3.13 (t, J =
6.5 Hz, 2 H), 1.87 (in, 1 H), 1.37 (s, 9 H), 0.91 (d, J = 6.8 Hz, 6 H);
MS (ES-): 480.3 1-d oe DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
NOTE: Pour les tomes additionels, veillez contacter le Bureau Canadien des Brevets.
JUMBO APPLICATIONS / PATENTS
THIS SECTION OF THE APPLICATION / PATENT CONTAINS MORE
THAN ONE VOLUME.
NOTE: For additional volumes please contact the Canadian Patent Office.
Claims (51)
1. A compound represented by the structure wherein R is selected from the group consisting of -OBn, -OH, -OSO2CF3, , and -OCH3;
and R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
and R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
2. A compound represented by the structure wherein R is selected from the group consisting of -OBn, -OH, -OSOCF3, and R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
3. A compound represented by the structure wherein R is selected from the group consisting of and ; and pharmaceutically acceptable salts thereof
4. A compound represented by the structure wherein R is selected from the group consisting of and R' is selected from the group consisting of and pharmaceutically acceptable salts thereof.
5. A compound represented by the structure wherein R is selected from the group consisting of -OBn, -OCH3, and ; and pharmaceutically acceptable salts thereof.
6. A compound represented by the structure wherein R is selected from the group consisting of -OSO2CF3, and R' is -H or ; and pharmaceutically acceptable salts thereof.
7. A compound represented by the structure wherein R is selected from the group consisting of -OBn, -OH, -OSO2CF3, , -CH=CH2, and -H;
R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM;
and R" is selected from the group consisting of -CO2MEM, and CO2H
and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
R' is selected from the group consisting of -CHO, -CO2H, and -CO2MEM;
and R" is selected from the group consisting of -CO2MEM, and CO2H
and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
8. A compound represented by the structure wherein R is selected from the group consisting of -OBn, -OH, -OSO2CF3, , and -CH=CH2;
R' is -H or -Boc; and R" is -CO2MEM or -CO2H; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
R' is -H or -Boc; and R" is -CO2MEM or -CO2H; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
9. A compound represented by the structure wherein R is -CH3; and NHR' is , or R' is selected from the group consisting of and pharmaceutically acceptable salts thereof.
10. A compound represented by the structure wherein R is ; and R' is selected from the group consisting of and pharmaceutically acceptable salts thereof.
11. A compound represented by the structure wherein R is or -CH=CH2 and R' is selected from the group consisting of and pharmaceutically acceptable salts thereof.
12. A compound represented by the structure wherein R is -CH3 and R' is selected from the group consisting of and pharmaceutically acceptable salts thereof.
13. A compound represented by the structure wherein R is selected from the group consisting of -OCH3, -OH, -OSO2CF3, -CH=CH2, -OCH2CO2C2H5, -OCH2CONH2, , , -OBn , -OH, -OSO2CF3, , -OCH3, -OBn, -H, and -CH=CH2;
R' is selected from the group consisting of -CHO, -CO2H, -CO2MEM, and R" is selected from the group consisting of ¨H, -CH3 and -Bn; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
R' is selected from the group consisting of -CHO, -CO2H, -CO2MEM, and R" is selected from the group consisting of ¨H, -CH3 and -Bn; and pharmaceutically acceptable salts thereof; wherein MEM designates a methoxyethoxymethyl group.
14. A compound represented by the structure wherein R is selected from the group consisting of -CH=CH2,-OSO2CF3, -OCH2CO2C2H5, -OCH2CONH2, -OCH2CO2H, -O-CH2-CH2-OH, -CH(OH)CH2OH, -CH2OH, -CO2H, , -OBn, -OC2H5, and -CH(OH)CH3; and R' is selected from the group consisting of -CH3, -Bn, and -H; and pharmaceutically acceptable salts thereof.
15. A compound represented by the structure wherein R is selected from the group consisting of -CH=CH2, -CH(OH)CH2OH, -CH=O, -CH2OH, -CO2H, and -OCH3; and pharmaceutically acceptable salts thereof.
16. A compound represented by the structure and pharmaceutically acceptable salts thereof.
17. A compound represented by the structure wherein R is selected from the group consisting of R' is selected from the group consisting of -OBn, -OH, -OSO2CF3, and -CH=CH2;
R" is selected from the group consisting of -CO2H, -CO2MEM, and -CHO;
and R"' is selected from the group consisting of and pharmaceutically acceptable salts thereof wherein MEM designates a methoxyethoxymethyl group.
R" is selected from the group consisting of -CO2H, -CO2MEM, and -CHO;
and R"' is selected from the group consisting of and pharmaceutically acceptable salts thereof wherein MEM designates a methoxyethoxymethyl group.
18. A compound represented by the structure wherein R is selected from the group consisting of R' is -H or alkyl; and R" is selected from the group consisting of , and ; and pharmaceutically acceptable salts thereof
19. A compound of claim 18 wherein said alkyl is -CH3.
20. A compound represented by the structure wherein R is selected from the group consisting of R' is -H, or -CH=CH2; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
21. The compound of clam 20 wherein said alkyl is -CH3.
22. A compound represented by the structure 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 and ; and pharmaceutically acceptable salts thereof.
23. The compound of claim 22 wherein said alkyl is -CH3.
24. A compound represented by the structure wherein N is located at position 3 or 4 in the phenyl ring; R is selected from the group consisting of -CHO, -CO2H, and and R' is -H or alkyl; and pharmaceutically acceptable salts thereof.
25. The compound of claim 24 wherein said alkyl is -CH3.
26. A compound represented by the structure wherein R is selected from the group consisting of -CH3, -C2H5, -CH2C6H5, -C(CH3)3, -CH2-CCl3, , and R' is -H or alkyl; and pharmaceutically acceptable salts thereof.
27. The compound of claim 26 wherein alkyl is CH3.
28. A compound represented by the structure wherein R is selected from the group consisting of -CH=CH2, -OCH3, -OBn, -OH, and -H; R' is R" is selected from the group consisting of ; and R"' is -H; and pharmaceutically acceptable salts thereof.
29. A compound represented by the structure wherein R is selected from the group consisting of -CHO, -CO2H, -CO2MEM, R' is selected from the group consisting of -OBn, -OH, -OSO2CF3, and -CH=CH2;
and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; wherein MEM
designates a methoxyethoxymethyl group.
and R" is -H or alkyl; and pharmaceutically acceptable salts thereof; wherein MEM
designates a methoxyethoxymethyl group.
30. The compound of claim 29 wherein said alkyl is -CH3.
31. A compound represented by the structure wherein R is -H or -CO2H;
R' is selected from the group consisting of -CHO, -CO2H, and and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
R' is selected from the group consisting of -CHO, -CO2H, and and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
32. The compound of claim 31 wherein said alkyl is -CH3.
33. A compound represented by the structure wherein R is selected from the group consisting of -CH(OH)-CH2OH, -CHO, and -CH(OH)-CH=CH2;
R' is -Boc or -H; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
R' is -Boc or -H; and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
34. A compound of claim 33 wherein said alkyl is -CH3.
35. A compound represented by the structure wherein R is alkyl; and NHR' is , or R' is selected from the group consisting of and pharmaceutically acceptable salts thereof.
36. The compound represented by the structure wherein X is CH or N;
R is -CH3;
R' is -H or ¨CH3; and R" is selected from the group consisting of ; and pharmaceutically acceptable salts thereof.
R is -CH3;
R' is -H or ¨CH3; and R" is selected from the group consisting of ; and pharmaceutically acceptable salts thereof.
37. The compound of claim 36, wherein X is N; R' is H and R" is
38. A pharmaceutical composition containing at least one compound according to any one of claims 1-37, and a pharmaceutically acceptable carrier.
39. Use of a compound according to any one of claim 1-37 in a medicament for inhibiting a serine protease.
40. Use of a compound according to any one of claim 1-37 in a medicament for inhibiting the coagulation cascade and preventing or limiting coagulation.
41. Use of a compound according to any one of claim 1-37 in a medicament for inhibiting the formation of emboli or thromboli in blood vessels.
42. Use of a compound according to any one of claim 1-37 in a medicament for treating at least one condition selected from the group consisting of thrombolymphangitis, thrombosinusitis, thromboendocarditis, thromboangitis, and thromboarteritis.
43. Use of a compound according to any one of claim 1-37 in a medicament for inhibiting thrombus formation following angioplasty.
44. Use of a compound according to any one of claim 1-37 and at least another antithromolytic agent in a medicament for preventing arterial occlusion following thrombolytic therapy.
45. The use of claim 44 wherein said other antithrombolytic agent is selected from the group consisting of tissue plasminogen activators, streptokinase and urokinase, and functional derivatives thereof.
46. Use of a compound according to any one of claim 1-37 in a medicament for treating metastatic diseases.
47. The use of claim 46 comprising an further anticoagulant agent.
48. The use of claim 47 wherein said further anticoagulant agent is selected from the group consisting of heparin, aspirin, and warfarin.
49. A method for inhibiting in vitro clotting of blood which comprises contacting said blood with at least one compound according to any one of claims 1-37.
50. The method of claim 49 which comprises inhibiting said blood clotting in tubes.
51. An extracorporeal device having a coating thereon which comprises a compound according to any one of claims 1-37.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24184800P | 2000-10-20 | 2000-10-20 | |
| US60/241,848 | 2000-10-20 | ||
| US28173501P | 2001-04-06 | 2001-04-06 | |
| US60/281,735 | 2001-04-06 | ||
| PCT/US2001/032582 WO2002034711A1 (en) | 2000-10-20 | 2001-10-22 | Biaryl compounds as serine protease inhibitors |
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| CA2426430C true CA2426430C (en) | 2014-10-07 |
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| DK (1) | DK1383731T3 (en) |
| HK (1) | HK1062676A1 (en) |
| IL (1) | IL155202A0 (en) |
| MX (1) | MXPA03009130A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4551279A (en) * | 1984-01-09 | 1985-11-05 | G. D. Searle & Co. | Protease inhibitors |
| KR20010082515A (en) * | 1998-02-17 | 2001-08-30 | 우에노 도시오 | Amidino derivatives and drugs containing the same as the active ingredient |
| EP0987274A1 (en) | 1998-09-15 | 2000-03-22 | Hoechst Marion Roussel Deutschland GmbH | Factor VIIa Inhibitors |
| DE60023266T2 (en) | 1999-01-13 | 2006-07-13 | Genentech Inc., San Francisco | Serine protease inhibitors |
-
2001
- 2001-10-22 NZ NZ526003A patent/NZ526003A/en not_active IP Right Cessation
- 2001-10-22 AU AU1339302A patent/AU1339302A/en active Pending
- 2001-10-22 WO PCT/US2001/032582 patent/WO2002034711A1/en active IP Right Grant
- 2001-10-22 IL IL15520201A patent/IL155202A0/en unknown
- 2001-10-22 DK DK01981772T patent/DK1383731T3/en active
- 2001-10-22 MX MXPA03009130A patent/MXPA03009130A/en active IP Right Grant
- 2001-10-22 AU AU2002213393A patent/AU2002213393B2/en not_active Expired
- 2001-10-22 CA CA2426430A patent/CA2426430C/en not_active Expired - Lifetime
-
2004
- 2004-07-28 HK HK04105585.6A patent/HK1062676A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| HK1062676A1 (en) | 2004-11-19 |
| NZ526003A (en) | 2005-09-30 |
| AU2002213393B2 (en) | 2007-02-15 |
| CA2426430A1 (en) | 2002-05-02 |
| MXPA03009130A (en) | 2004-02-26 |
| AU1339302A (en) | 2002-05-06 |
| WO2002034711A1 (en) | 2002-05-02 |
| DK1383731T3 (en) | 2009-12-07 |
| IL155202A0 (en) | 2003-11-23 |
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