Language selection

Search

Patent 2426430 Summary

Third-party information liability

Some of the information on this Web page has been provided by external sources. The Government of Canada is not responsible for the accuracy, reliability or currency of the information supplied by external sources. Users wishing to rely upon this information should consult directly with the source of the information. Content provided by external sources is not subject to official languages, privacy and accessibility requirements.

Claims and Abstract availability

Any discrepancies in the text and image of the Claims and Abstract are due to differing posting times. Text of the Claims and Abstract are posted:

  • At the time the application is open to public inspection;
  • At the time of issue of the patent (grant).
(12) Patent: (11) CA 2426430
(54) English Title: BIARYL COMPOUNDS AS SERINE PROTEASE INHIBITORS
(54) French Title: COMPOSES BIARYLE UTILISES COMME INHIBITEURS DE SERINE PROTEASE
Status: Expired
Bibliographic Data
(51) International Patent Classification (IPC):
  • C07C 229/38 (2006.01)
  • A61K 31/155 (2006.01)
  • A61K 31/192 (2006.01)
  • A61K 31/24 (2006.01)
  • A61K 31/255 (2006.01)
  • A61K 31/27 (2006.01)
  • A61K 31/34 (2006.01)
  • A61K 31/341 (2006.01)
  • A61K 31/38 (2006.01)
  • A61K 31/381 (2006.01)
  • A61K 31/40 (2006.01)
  • A61K 31/415 (2006.01)
  • A61K 31/425 (2006.01)
  • A61K 31/426 (2006.01)
  • A61K 31/44 (2006.01)
  • A61K 31/4418 (2006.01)
  • A61K 31/495 (2006.01)
  • A61K 31/505 (2006.01)
  • A61K 31/535 (2006.01)
  • A61K 31/55 (2006.01)
  • A61K 31/69 (2006.01)
  • C07C 63/04 (2006.01)
  • C07C 233/54 (2006.01)
  • C07C 235/84 (2006.01)
  • C07C 251/48 (2006.01)
  • C07C 255/57 (2006.01)
  • C07C 255/58 (2006.01)
  • C07C 257/00 (2006.01)
  • C07C 257/18 (2006.01)
  • C07C 259/18 (2006.01)
  • C07C 259/20 (2006.01)
  • C07C 271/22 (2006.01)
  • C07C 271/64 (2006.01)
  • C07C 309/65 (2006.01)
  • C07C 317/22 (2006.01)
  • C07D 207/08 (2006.01)
  • C07D 207/30 (2006.01)
  • C07D 207/337 (2006.01)
  • C07D 209/08 (2006.01)
  • C07D 211/70 (2006.01)
  • C07D 213/40 (2006.01)
  • C07D 213/56 (2006.01)
  • C07D 213/74 (2006.01)
  • C07D 213/75 (2006.01)
  • C07D 213/78 (2006.01)
  • C07D 213/79 (2006.01)
  • C07D 213/80 (2006.01)
  • C07D 213/81 (2006.01)
  • C07D 213/82 (2006.01)
  • C07D 231/56 (2006.01)
  • C07D 233/54 (2006.01)
  • C07D 235/14 (2006.01)
  • C07D 235/30 (2006.01)
  • C07D 235/32 (2006.01)
  • C07D 239/02 (2006.01)
  • C07D 239/14 (2006.01)
  • C07D 239/42 (2006.01)
  • C07D 239/48 (2006.01)
  • C07D 265/30 (2006.01)
  • C07D 277/30 (2006.01)
  • C07D 277/62 (2006.01)
  • C07D 277/82 (2006.01)
  • C07D 307/02 (2006.01)
  • C07D 307/54 (2006.01)
  • C07D 311/78 (2006.01)
  • C07D 311/80 (2006.01)
  • C07D 317/44 (2006.01)
  • C07D 317/46 (2006.01)
  • C07D 317/68 (2006.01)
  • C07D 333/22 (2006.01)
  • C07D 333/24 (2006.01)
  • C07D 333/38 (2006.01)
  • C07D 521/00 (2006.01)
(72) Inventors :
  • BABU, YARLAGADDA S. (United States of America)
  • ROWLAND, SCOTT R. (United States of America)
  • CHAND, POORAN (United States of America)
  • KOTIAN, PRAVIN L. (United States of America)
  • EL-KATTAN, YAHYA (United States of America)
  • NIWAS, SHRI (United States of America)
(73) Owners :
  • BIOCRYST PHARMACEUTICALS, INC. (United States of America)
(71) Applicants :
  • BIOCRYST PHARMACEUTICALS, INC. (United States of America)
(74) Agent: MOFFAT & CO.
(74) Associate agent:
(45) Issued: 2014-10-07
(86) PCT Filing Date: 2001-10-22
(87) Open to Public Inspection: 2002-05-02
Examination requested: 2006-07-25
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/US2001/032582
(87) International Publication Number: WO2002/034711
(85) National Entry: 2003-04-17

(30) Application Priority Data:
Application No. Country/Territory Date
60/241,848 United States of America 2000-10-20
60/281,735 United States of America 2001-04-06

Abstracts

English 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.


French Abstract

La présente invention concerne des composés représentés par la formule (I) qui conviennent comme inhibiteurs de trypsine comme les enzymes sérine protéases telles que la thrombine, le facteur VIIa, le facteur Xa, TF/FVIIa et la trypsine. Ces composés peuvent convenir pour traiter et/ou pour prévenir des troubles de la coagulation, et comme agents anticoagulants.

Claims

Note: Claims are shown in the official language in which they were submitted.


What is claimed is
1. A compound represented by the structure
Image
wherein R is selected from the group consisting of
-OBn, -OH, -OSO2CF3,
Image, 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.
287

2. A compound represented by the structure
Image
wherein R is selected from the group consisting of
-OBn, -OH, -OSOCF3,
Image
288


Image
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
289

Image
wherein R is selected from the group consisting of
Image
290


Image
and Image ; and pharmaceutically acceptable salts thereof
4. A compound represented by the structure
Image
wherein R is selected from the group consisting of
291

Image
292


Image
and R' is selected from the group consisting of
Image
293

Image
and pharmaceutically acceptable salts thereof.
5. A compound represented by the structure
Image
wherein R is selected from the group consisting of
Image
294


Image
-OBn, -OCH3, and Image ; and pharmaceutically acceptable salts thereof.
6. A compound represented by the structure
Image
wherein R is selected from the group consisting of
-OSO2CF3, Image
and R' is -H or Image ; and pharmaceutically acceptable salts thereof.
295

7. A compound represented by the structure
Image
wherein R is selected from the group consisting of
-OBn, -OH, -OSO2CF3, Image , -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,
Image
and CO2H
and pharmaceutically acceptable salts thereof; wherein MEM designates a
methoxyethoxymethyl group.
8. A compound represented by the structure
296

Image
wherein R is selected from the group consisting of
-OBn, -OH, -OSO2CF3, Image , 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.
9. A compound represented by the structure
Image
297


wherein R is -CH3; and
NHR' is Image , or R'
is selected from the group consisting
of
Image
298


Image
and pharmaceutically acceptable salts thereof.
10. A compound represented by the structure
Image
wherein R is Image ; and R' is selected from the group consisting of
Image
299


Image
and pharmaceutically acceptable salts thereof.
11. A compound represented by the structure
300

Image
wherein R is Image or -CH=CH2 and R' is selected from the group consisting of
Image
and pharmaceutically acceptable salts thereof.
12. A compound represented by the structure
Image
wherein R is -CH3 and R' is selected from the group consisting of

301


Image
and pharmaceutically acceptable salts thereof.
13. A compound represented by the structure
Image
302


wherein R is selected from the group consisting of
-OCH3, -OH, -OSO2CF3, -CH=CH2, -OCH2CO2C2H5,
-OCH2CONH2, Image ,
Image
Image , -OBn , -OH, -OSO2CF3,
Image , -OCH3, -OBn, -H, and -CH=CH2;
R' is selected from the group consisting of
-CHO, -CO2H, -CO2MEM, Image
Image
303

Image
304

Image
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
Image
wherein R is selected from the group consisting of
-CH=CH2,-OSO2CF3, -OCH2CO2C2H5, -OCH2CONH2,
Image
305


-OCH2CO2H, -O-CH2-CH2-OH, -CH(OH)CH2OH, -CH2OH, -CO2H,
Image , -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
Image
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

306

Image
and pharmaceutically acceptable salts thereof.
17. A compound represented by the structure
Image
wherein R is selected from the group consisting of
Image
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
307

Image
Image and pharmaceutically acceptable salts thereof
wherein MEM designates a methoxyethoxymethyl group.
18. A compound represented by the structure
Image
wherein R is selected from the group consisting of
Image
308


R' is -H or alkyl; and R" is selected from the group consisting of
Image
Image , and Image ; and
pharmaceutically acceptable salts
thereof
19. A compound of claim 18 wherein said alkyl is -CH3.
20. A compound represented by the structure
Image
309


wherein R is selected from the group consisting of
Image
310


Image
311


Image
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
Image
wherein R is selected from the group consisting of
Image , -CH=CH2, and -H; R' is -H or alkyl; and R" is
selected
from the group consisting of
312


Image
and Image ; and pharmaceutically acceptable salts thereof.
23. The compound of claim 22 wherein said alkyl is -CH3.
24. A compound represented by the structure
Image
wherein N is located at position 3 or 4 in the phenyl ring; R is selected from
the group
consisting of -CHO, -CO2H, and
Image
and R' is -H or alkyl; and pharmaceutically acceptable salts thereof.
25. The compound of claim 24 wherein said alkyl is -CH3.
313


26. A compound represented by the structure
Image
wherein R is selected from the group consisting of
-CH3, -C2H5, -CH2C6H5, -C(CH3)3, -CH2-CCl3, Image,
Image
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
Image
314

wherein R is selected from the group consisting of -CH=CH2, -OCH3, -OBn, -OH,
and -
H; R' is
Image
R" is selected from the group consisting of
Image; and R"' is -H; and pharmaceutically
acceptable salts thereof.
29. A compound represented by the structure
Image
wherein R is selected from the group consisting of -CHO, -CO2H, -CO2MEM,
Image
315


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.
30. The compound of claim 29 wherein said alkyl is -CH3.
31. A compound represented by the structure
Image
wherein R is -H or -CO2H;
R' is selected from the group consisting of -CHO, -CO2H, and
Image
and R" is -H or alkyl; and pharmaceutically acceptable salts thereof.
32. The compound of claim 31 wherein said alkyl is -CH3.
316


33. A compound represented by the structure
Image
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.
34. A compound of claim 33 wherein said alkyl is -CH3.
35. A compound represented by the structure
Image
wherein R is alkyl; and
317

Image
NHR' is , or R' is
selected from the group
consisting of
Image
318


and pharmaceutically acceptable salts thereof.
36. The compound represented by the structure
Image
wherein X is CH or N;
R is -CH3;
R' is -H or ¨CH3; and R" is selected from the group consisting of
Image
Image ; and pharmaceutically acceptable salts
thereof.
37. The compound of claim 36, wherein X is N; R' is H and R" is
Image
319


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.
320

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.
321

Description

Note: Descriptions are shown in the official language in which they were submitted.


DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
CECI EST LE TOME 1 DE 2
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.
THIS IS VOLUME 1 OF 2
NOTE: For additional volumes please contact the Canadian Patent Office.

CA 02426430 2009-09-03
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.

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
2

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
3

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Need for the prevention of intravascular blood clots or for anti-coagulant
treatment in many clinical situations is well known. Drugs in use today are
often not
satisfactory. A high percentage of patients who suffer internal injuries or
undergo certain
=
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
4
=

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
formation and does not produce bleeding side effects observed with direct
thrombin
inhibitors.
Several preclinical studies reveal that inhibition of TF/FVIIa offers the
widest
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

CA 02426430 2011-12-08
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'
H3CO2C
0
wherein R is selected from the group consisting of
0
-0Bn, -OH, -0S02CF3,
.)CH 9 ) S
CH
3 3
OHC
CHO
OHC
0 0
N3H2C\ CH2OH HOH2C
_____________________________________________ -0 11
0 , and
0
-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
6

CA 02426430 2011-12-08
R 40 R'
* H
1\I
BnO2C
0
wherein R is selected from the group consisting of
-0Bn, -OH, -0S02CF3, .-----s , s) ,
______________________________ / __ \ =
3,
,
H3C S
H3C
0 0 s
, N ' N ' N
H3C & __ ) CH2 I¨ \ _
SN'TµI
S,
0 , N , IT
I ,
CH3
7---17NCH v--- CH2
__________________________ /-CH3 ,.//=OH ¨
3, 7
H3r OH CH3
./H2
z ______________________ _ -,....,.....70H 7(,...CH 2
CH3
/=-TMS ,
, /
OH CH3
7

CA 02426430 2011-12-08
CHO
CH2
OH, , S
..__,,.
\ CHO '
S
OHC / OHC
CH2
i / \
, -----
S ' OHC---- 3.----- '
S S '
N ,
I
Boc
/ __ OH
¨7 ' =
S)/." __ ' S ___ OH' BnO2V
CH ,
HOH2C / OH
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
0
lel NH2
R
1101 N
H
OH
N
BnO2C
0
8

CA 02426430 2011-12-08
wherein R is selected from the group consisting of
3, el , --) , fi3c-s3 ,
s
S
H3 C
S .1
l I
N 1
N
0
H3CN____,.._._., & ) CH2 I_\
N
S , N 7
5 1 S z N
NZ 7
0 I l
CH3
CH3 OH ¨CH2
7¨NCH3
H3r OH
CH3 ,
CH3
,
CH2
CH2 7== CH , __ --
, / __ .7,OH ,
' CH3'
.(OH
CH3
OH BnCO2
)
OH CI H2
...,./-. \,..,.....,
' \ OH ' & ' s \ ,
- OH
S S
HOH2C
/
II T OH
i OH
HOH2C s
, S , ,
Boc
9

CA 02426430 2011-12-08
N3
and ; and pharmaceutically
acceptable salts thereof.
In another broad aspect, the present invention relates to a compound
represented
by the structure
NH
0
I.
N NH,
R elH
40 NHR'
HO2C
0
wherein R is selected from the group consisting of
, S ' el
' 0 '
'

s s
H3 C
=%/ H3 c \--
---- I
. , L s
, , ,
S , N N 0
N
CH2 si \N /7=N
CH,
CH
3 , < ,
N ' N '
CIH3 I CH3
H
C
V ______ Nz7CH3 OH ¨ 2 ___________________
- OH
H3/ / ,
CH3
9a

CA 02426430 2011-12-08
CH2 CH2
K CH (CH3
OH ' ¨
/
\ al 3 , ______,,OH
OH
OH'
S ,
A, HOH2C sk '
S
HO2C
S
HOH2C
OH OH
.,,.,-.CH3 ,.,
, N N3 CH3
S I I 5 5 5 5 5
0 CH2
OH' , /CH3, ,
CH3
N3H2C CH2OH
* 'CH2
\ -pH
S S0
, , ,
HOH2C /
\o 41 CH2
11 ¨OCH3 ft
0 ¨0
/NS
and
NH2 ; and R' is selected from the group consisting of
CH3
¨0
/-\ CH3 / CH3 CH3 CF 3
5 5
CH3 '
9b

CA 02426430 2011-12-08
H3
CH2 CH3 OH ,
CH3 ' _________________________ 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
0
001 N
R *
N H,
H
lei H
N
H3CO2C
0
wherein R is selected from the group consisting of
9c

CA 02426430 2011-12-08
0
CH2
CHõ CH3 XS'/ 401
N3H2C CH2OH HOH2C
=CH2
S 0 0
S
-0Bn, -OCH3, and ; and pharmaceutically acceptable salts thereof
CH2NH2
In another broad aspect, the present invention relates to a compound
represented
by the structure
NH
0
NHR'
H3CO2C
0
wherein R is selected from the group consisting of
TIPS 0
-0S02CF3, / N
, and _________________________ Cr ,
= and R' is -H or OBn ;
and
pharmaceutically acceptable salts thereof.
9d

CA 02426430 2011-12-08
In another broad aspect, the present invention relates to a compound
represented
by the structure
R 40 RP
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 ,
0
CH H
H , N,7CF3 , H
N CH3 ,
N
CH3 0 0
06
CH3
E
IN CH3 and CO2H ;
0
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

CA 02426430 2011-12-08
NH
0
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
/ 0
1.1 NHBoc
0
NHR'
RO2C
0
wherein R is -CH3; and
¨N
NHR' is \- ___ , or , or R'
is selected from the group consisting
of
CH3 CH29
CH3
9f

CA 02426430 2011-12-08
CT-13 , (----043 CH3
CH3 CH3 CH3 0 '
CH3 OH
C:3
c..
CH3 1 CH3 -----0
, _________________________________________________ I \CH3 ' CH3'
0 .,,CF3 W CH3 CH3
CH3 ,
Th<CH3
.,-OH 0 \
CH3 , 0H
CH3
N.,,-CH3
CH
, , , ,
OH
OH, =, OH; --0 ,
and
0
and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound
represented
by the structure
9g

CA 02426430 2011-12-08
NH
0
001 N
R 0
N H2
H
NHR'
HO2C
0
CC(
wherein R is ¨ ; and R' is selected from the group consisting of
CH3 ' CH3, CH2 , 1.1
CH3'
CH3
CH3 .,,,,,.,..,..../.4...--CH3 C113 5
CH3 '
CH3 CH3 CH3
OH CH3
_____O , CH3 ,cõ--CH3, 5,
CH3
=CF3
WCH3 CH3 -=<CH3
) , CH3 '
CH3 CH3
\ N
OH, ...,..õ..õ,.......,õ...OH
N----1/ ,
9h

CA 02426430 2011-12-08
OH
.,- CH
Cli3
OH
and ; and
pharmaceutically acceptable
0
salts thereof.
In another broad aspect, the present invention relates to a compound
represented
by the structure
NH
0
401 NHR'
R
110 N
H
* NHR'
HO2C
0
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

CA 02426430 2011-12-08
NH
1 0
S NHBoc
ON
H
401 NHR'
RO2C
0
wherein R is -CH3 and R' is selected from the group consisting of
CH3'
,
cH3 f----\
,.CF3 5
------\ __________________________________ / ' CH2 '
CH3
,<,C113 KC/13 '''-\
OH W OH
, ilk, , ,
CH3 , CH3
CH3 /CH3 -41D ,,CH3
5 5 / 5
CH3 CH3 X------CH3
NH2
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

CA 02426430 2011-12-08
4 0 6 11?
R
3 1
2 (10H
R"02C
0
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

CA 02426430 2011-12-08
NH NH
CH3 . NH2 CH3 1.11 NHBoc
0 N ,
, H
N
NH H
CH3 14111 NH2 0
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
NH2
N =
H
91

CA 02426430 2012-08-16
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
0
1401 NH2
R 4 el 6 1}1
3 1 110
2
R'02C
0
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

CA 02426430 2011-12-08
In another broad aspect, the present invention relates to a compound
represented
by the structure
NH
0
1401 NHBoc
4
R N
H
3. 40
2
H
N
H3CO2C
0
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
0
1401 NH2
* N
H
0 * H
0 0
and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to a compound
represented
by the structure
9n

CA 02426430 2011-12-08
W 10 R"
RO
le NHR"
H3CO2C
0
wherein R is selected from the group consisting of
0
-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 ' CH3 ' //,,,..CH3 ,
,CH ,
3
'

CF ' '
3 CH3 _.0 , CH3 ,
CH3 CH3
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

CA 02426430 2014-04-25
NH
0
NH2
RO
1101 NI-ER"
R'0,C
0
wherein R is selected from the group consisting of
0
-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
9
CH3
C
CR.3 H
CH3 CH
, and ; and
pharmaceutically acceptable salts
thereof.
9p

CA 02426430 2011-12-08
In another broad aspect, the present invention relates to a compound
represented
by the structure
0
R' 0R
* H
N
R"02C
0
wherein R is selected from the group consisting of
H
/ \ N N,.,
/
it
N ) /}11 40
¨N\ / N
NN---- H
, H ' CF3 ,
CF3
/IN . CF3 \N 40 CF3
, N
H
F F
CF3
H / \o H
/N
il 40 ¨N
\ __________________________________________ / , /N = ,
N
¨ \ NH,
N \N-4 , /111 = ,
\ ______ , N¨ H
9q

CA 02426430 2011-12-08
N /\ N_\
H
Ll
0 I , -N
_______________________________________________ , / ,
/ \ __ /N /2N .\
S OMe õN
N
H
OH
H
N . NH2
H
/ 411
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 /
H3C
H
N H H
\N/ le /N
4OH /N
. OH
N,
,
,
H CH3
. jl \ I
H
I\ 11
Li . H
N
N
H NN "'N N
/
N-----1''NH2' \ __ / \
, ,
9r

CA 02426430 2011-12-08
N N a
¨OH, / ____________________ /
4 _______________ , __ NH2 II ___ C )-NH2
H
N = ,
0
H H
,N 10 CH2CN , /I
/N \II 4110
CH2NH2
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
0
lei NH,
R
401 N
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
0 CH3 0
NCH,' CH3 /N-C7
I
, ,
H H Boc CH3
CH3
9s

CA 02426430 2011-12-08
CH3
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
4
6
3 Ilk 1110
H
N..-
R'02C
0
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
0
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
0 NH 0
I
IIIII NH OR
* N
H
H
N
R'02C
0
9t

CA 02426430 2011-12-08
wherein R is selected from the group consisting of
-CH3, -C2H5, -CH2C6H5, -C(CH3)3, -CH2-CC13, . OMe ,
ilk F,
0 0 CH3 9
0CH3 0/\<cH3 ,and = and R' is -H or
' ,v"\ '
cH3
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
2
NHR"
R"'02C
0
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
CH3
.,v"--=cH3 '.

CF

3

, and CH3 ;
and R"' is -H; and pharmaceutically
,
9u

CA 02426430 2011-12-08
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
0
wherein R is selected from the group consisting of -CHO, -CO2H, -0O2MEM,
NH
NH
0 NH2 H
N NH2
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"
0
1.1 H
R
0
wherein R is -H or -CO2H; R' is selected from the group consisting of -CHO, -
CO2H, and
9v

CA 02426430 2011-12-08
NH
0
1401 NH2
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
0
1401 NHR'
R
* N
H
* H
R"02C
0
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
/ 1 0
el NHBoc
0
ISI N
H
401 NHR'
RO2C
0
9w

CA 02426430 2011-12-08
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
CH3 0
OH
c_CH3
CH

CH3 -0 CH3
CH3 / 5 5
CH3
el cF,3 wcH3 CH3
OH _____...--,...,,OH
0
CH3
r\N
¨2N

CH '',/CH3
OH, ,
OH it -- OH
0 ;
and
9x

CA 02426430 2014-04-25
and pharmaceutically acceptable salts thereof.
In another broad aspect, the present invention relates to the compound
represented
by the structure
NH
0
NH 2
RO
NHR"
R'02C X
0
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

9 7
CF3, CH , and
013
; 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

CA 02426430 2011-12-08
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

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Still other objects and advantages of the present invention will become
readily
apparent by those skilled in the art from the following detailed description,
wherein it is
shown and described preferred embodiments of the invention, simply by way of
illustration of the best mode contemplated of carrying out the invention. As
will be
realized the invention is capable of other and different embodiments, and its
several
details are capable of modifications in various obvious respects, without
departing from
the invention. Accordingly, the description is to be regarded as illustrative
in nature and
not as restrictive.
Best and Various Modes for Carrying Out Invention
An aspect of the present invention relates to compounds represented by the
formula: B1
(R1)- El- W E2- B
1
X (R2) ; pharmaceutically
acceptable salts thereof;
V1¨ L¨V and prodrugs thereof.
1
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.

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
=
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
8
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.
11

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
12

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
13

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
14

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
16

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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
17

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
18

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
19

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
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
A-2 B-2
CO211
0 N¨R 0 N¨R
1
2 3
H3C,,,CH3
OH = SO2CF3 CF3
2a, 3a, R = _____________________________________________ 2f, 3f, R =
CO2CH3 13-1 or
13-2
2b,3b, R ¨ ____________________________________
CO2CH /C143 3
CH3
CH3 2g, 3g, R = \\X
CO2MEM CO2MEM 2, 3c, R=---<¨ CH3 2h, 3h, R=
4 5
MEM = CH2-0-CH2-C112-0-CH3 2d, 3d, R = 2i, 31, R = --
CH2CH3
CH3 CH3
2e, 3e, R 2j, 3j, R=
CH3
2, c02.3
AK
0 N¨R
6a
Cl-i3
R =
CH.
21

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
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
6 0 0
7 8
,
1 F
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
0 0 0
9
11 10
'
22

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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
14 15
12 13
1A-3 or
A4
= SO,CF3
0 CO,Bn
H
0
16
=
23

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
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
0
16 0
18
17
1, F
_
HO is CO2MEM HO el CO2MEM ...,__....2_Bn0 0 CO2MEM
H
.0----
110 H
011 H
,
* 11
N.õ.....õ...--...õ...
BnO,C HO2C BnO2C
0 0 0
21 ._... _ 20 19
1B-2
F3CO280 CO2MEM
0C11110 .
H
BnO2
0
22
,
,
24

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
,
-
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
0 0
22 24
R
NH
1 I-1
0
.1, 411 NH2
R CO2H
41111 E J
0
0 14 110
14õ,.....õ..õ
BnO2C BnO2C
0 0
:6 . 25
1 1-2
NH
0 N/12
R elH
HO,C
0
27
24, R -= , H3C
a___ A __ -. c,, d,... _14 , e,4µ.
H,C s
0 0 S
h, =-"..,-1 i, !%'-'"----1 j, k,
Ki".--0 H3C
N N 1 S
T N
N 0 CH, i
n, ,====õ,,_,,..2-.CH2 0, /7-=Nal, q' - CH
r'OH
SNe õ...,.."-N".õ 3
H3C/011
CH2
w,H2 =TMS
s,t' ___________________ H2 U, z OH v,
OH /
CH, 25
CH,

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
24, R = (continued)
CHO
CH3 912
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 .._.,_,
0
=:,- /-.,,, 1. .,,.)
N N 1 S N
I
1
0 CH3
/3, ,,.CH2 0, i¨ \ 1), (1, -----
CH3 r, '7'- OH
/= N CH3
N
SN/Z
/ -OH
H3C
CH,
CH2 v w,
,,= CH
s, -,__.-1/2 t, __ < it, /_0R, -....õ.õ...,
OR /,,
CH3
CH3
OH
CH,
OH z, z li
x, z _ <CH,
y, ..,,,,-µ-..,....õ...-
\ OH aa,,¨N ab, &.
...
CH3
S
BnO,C / HOH2C
ad, ae, HOH2CNs / af, ( ag ,
i j / \
OR N
S S CS)
c)c
ah
,
ai,
OH
26
----
,

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
26, R = H,C
a b, ______________ cio d, .,\..., e,
S7
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
1
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/\
CH3 OH
S
BnO,C /
ae, ,_._..,_ at HOH,C
( ag , & ........_
ad,
i
HOH,C s
OH N
Boc
OH
ah, ai,
OH
27, R=
H3C
c,
S7
V s S7 0 0 S
N N N
N 1 S
I
1
'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

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
27, R = (continued)
CH3
, CH2 OH
x, _______________ yv zaa
OH ab,
CH3

ac, ______________ ad,
ae, HOH2C at HOH2C
ag ,
OH
HO2C
ah, OH ai,N2
Conversion of 24ab K I-I25ab
K I-1
= 24ac 25ac
K I-1
24ae 25ae
=
K I-1
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.
L I-1
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.
I-1 Q
Conversion of 24w 25w
28

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
=
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
11 0 29 0
NH
R 0
7, el NH,
R 0 C0,1-1
411 F J
-..(---
110 14\, Slk.
H3CO2C 1-1,002C
0 0
= 31 30
11-2 .
NH
R 0
NH,
41 H
101 14
14
Ho2c
0
32
29, R=
a, 0 b, ,.,..õ, ' c, .,,.,,, CH2 cl, ,..... )
e,
CH3
CH,r S
OHC CHO OHC\ /
g, h, ,.....,.. i,
s o o
r 29

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
30, R=
0
a, b, c, d, = e, t
CH,
CH,=
NHC
CH OH HOH,C
g
13, __________________
0 0
31, R=
''C H3 a, b, c, 0H2 d, e,
CH3
cH20H HOH,C
g ,1\131-12.
0 0
32, R=
0
a, b,
0H, c, d, e, 1110
c H2
c H,
C H20 H HO H2C
g
0
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

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 7
CF3S020 CO2H
11 .....-_L_
* H
N........,,,..,--..,,,
H,CO2C
0
33
NH 1 J NH
0
Si NH
I 0 N laill NH2
CF3 S020 is CBz CF3S020 0
N P
H H
0 H
N-- ..,.....õ,õ,..õ....õ . H
H3CO2C H3CO2C
= 0 0
35 0 . 34
B(OH)2
/ \
CBz e CH2C6H5
. =
N D-2
I
TIPS
36
TIPS = Tri-isopropylsilyl
TIPS NH TIPS NH
I I
N N
0 4
\/
0 NHI 0 NH
CBz
* N
H G
N
H
* H
N,,,,,_.,, 01 H
N.õ,,....õ..--..,,,
H3CO2C H3CO2C
0 0
37 38
1 Q
NH NH
H H
N N
0 NI-12 0 NH2
\ /
\ /
OHN*
1-2
5 N0
H
1
1110 H
,..,, .
5 H
I\I,s.,,,.=.,
HO2C H3CO2C
0 0
40 39
31

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 8A
0
0 0 CO,MEM
D-8
+ 1411
H
10 B(011)2
H,CO2C
0
41
NH
401 = 1-1
illt NH, IP 1
0 C0,11
=
0
0 N
H J
*
H
1110 11õ,...... 5
H,CO,C H,CO,C
0 0
43 42
* 11-2
NH
0 Sp NH,
N
0O
H
1$1 14,..õ_v.--
HO,C
0
44
Scheme 8B
10 NH
IP NH
S.
= N 4111 0 N NH,
0 NH2
0
-1-3.-
el
8
H 1-2
01
H
1110 H
N,,.,,. 411 H
H,CO,C HO,C
0 0
46
32

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 8C
CHO
Me0 40 CHO Me0
+3a D-2
3a __ J2:,/_,,.
(11101 H
B(OH)2
47 H3CO,C
, 0
48
NH
/ E
0 NH,
111111 Me0 40 CO,H
Me0 H 0
N J
* H
N,.,,..7,---,,,
H3CO2C H
1.13CO2C
0
0
49
25 . 11-2
NH
0 NH
30 Me0 0 ill 2
N
H
35 HO,C Si H
N. \
0
51
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
0 0
52 53
33

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 8E
raj (R... )
26n
32f 27ak (R = )
26a1 27al(R )
26u 27am (R= OH)
34

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 9
. le * 0 NH
0 NH,
0 CHO 0 Oil CO,H 0
5 + 6 ..J:L_,..
1101 E 3
H
11101Oil 116
H,CO,C CO,MEM H,CO,C CO,MEM H,CO,C
CO,MEM
54 55 56
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
1B-2
NH NH
¨ 0 5 NHBoc
0
CF302S0 01
N Sp NHBoc / 0
110 N
H D-2 H
la
H,CO,C 1111111 CO,MEM H3CO2C CO,MEM
59 60
11-1
NH NH
/ = 0
N
1410 NHBoc /
¨0O
N
0 el NHBoc
(16/
H A-4
101
____.
H
11101 NI-1R
H1CO1C H3CO2C CO,H
62 0 61
. 11-2
¨
NH NH
/ = 0 5 NHI30c / 0 0
II NH,
¨
01 N
H S
la N
H
Lail NHR 411 NHR
HO,C HO,C
63 0 . 0
64

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
62, R =
'
a, ,,,,--..,,CH3
b' CH, c' .'.CF12 d' e,`...,...c..-
CH3 f 4---CH3
' CH3
CH3 CH,
OH
g , \/'\(CH3 }:..,,.,70 i CH
3
14¨)
0 CH,
CH3
. CH,
m,=-,CH3 ,, ,,,,..<3 0, *
P> ..CF3 q, r' CH,
CH3
CH3
CH3
OH
t''OH 11,
CH,
CH3
OH
,,,(.JD y,
z, .õ.7 CH3 aa, ,.,--cOH ab,
w,
-'"--,_/\/14--41
' ac,, ad
_0 OH ae, NHR = ¨N/
\ af, Niirt
\.------",
0
63, R =
e,.CH, f; A--"CH,
a, ......õ..õ,......cHa b' CH3 d, cHa d'
CH3
CH, CH,
OH
g, \ ,,,3h,) CH )1___C)
CH3
i,
0 CH3
CH,
0 1), =,.7.CF, 9, '..,.\.--''\CH3 r,
m, \ n,,,C3 0,
CH3 t CH3
CH3
CH3
II, OH , =%.,,,)(23
CH, OH
CH,
OH
1--
y' Z,7-...%,.CH CH3 aa, -
õ,.......,,,--cy.,OH ab,
II
w,
af, NHR = ae, NTIR = --N --IN
ac, ___-.0 ad, OH \ \-----A7,
0
'
36 ,

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
64, 12 =
0, ..,.<CH3 f ,,,----- CH3
a, ,..-,..7=CH3
b' CF13 c' C11, d,
CH3
CH3 CH3
g , "\s,C1-13 1,1:_Nf) i, CH3 =
OH
1.1_0
CH3
CH3
m' CH3 n'-'=C
CH3 0,
P, -..,,,.=CF3 q, ,,-"-.,V,,, r,
CH, CH3
CH3
CH3
CH,
s, t, ...õ..,, ,,...,...õ. u,
CH3 -`.- -OH =,,,
CH3
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,
0
NH
-
/ 0 0
el NHR
¨
IS N
H
1110
NHR
HO,C
0
65 ,õCH3
65' R = CH3
37

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 10
NH
I 0
N II NHBoc
59 + (Bu),Sn. D-3
111101
H3CO2C CO,MEM
66
11-1
H NH
I 0
N 411:1 NHBoc
I 0
N 411 NHBoc
* H A-4
-4----
401 II
la 1
. 5
NHR
H3CO2C 113CO2C CO,H
= 680 67
1I-2
NH NH
I 0
NH
NH 0
N 4111 Boc
I
N I. 2
5 H
IP NHR 4101 NHR
HO,C HO,C
69 0 70 0
,
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
3
CH, cl, X------ CH,
.-0.. 110H 11, --1 vy --<>
r'NHBoc s, ---0 t .
IN, ,..-. x, CH ,
CH, 38

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
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
CH3
CH, q' X---- CH,
r,..,,,...7-,NH2 s, ¨0 t, ¨O. , i 'OH u, _______________ < v,
w' OH x' Cli3
CH3
NH
! 0 II NHR
110 VI
1110 HO,C NI
71 o
71, R=
a, --<> b, --1 c,
39

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 11
CHO * CHO
1110 U-2 or
T and U-3 ' 73 -I- 3a
Me0 Me0 B(OH)2
1 D-2
72 73
0 CHO V-1 or V-2 so CHO
andHorW
-.E----
HO
le 11 Me0
1-1
* 1\1,.,,,=\õ
12.02C H3CO2C
75a, R' = Me 75 0 74 0
1
75b, R = Bn
B-2 X
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
R102C
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
79 0 78 0
11-2 or G
NH
R * N
0 4111 NH,
H
SL=--,õ.,
HOS
80 0

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
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
CH3
77h, 78j, 79j, 80j, R ----, :
CH3- R.' = Bn ,
771,78k, 79k, R = OCH2-CH2-0Ac; R' = Bn; 80k, R = -0-CH2-CH2-0H
,
41
,
,

CA 0242 6430 2003-04-17
WO 02/34711 PCT/US01/32582
-
Scheme 12
.
NH NH
0
N
II NH, 0
N 410 NHBoc
I.
I.
H R
H
I 0 5 H
/µI.- I
H,CO,C 01 H
OCH 81 0
, 79,
NH IL
NH
0
N
el NHBoc 0
1.11 NHBoc
H
el
H M
HO 4111 N
1
* H
1110 }-1
0 14 ,,,,,., N -,7,k-,,
H,CO2C HO 113CO2C
83 0 82 0
1E
NH K
NH
0
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
85 0 84 0
NH
R *
0
N
=NH,
S 1-2
82, 84, 85-=----,-
H
1110 H
HO2C
86 0
86a, R= CH(OH)CH,OH
86b, R = C1-120H
86c, R= CO21-1
42

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
,
Scheme 13
ell OBn OBn
X T, U- 1
lip CHO
_____ 40 CHO --3== CHO 89 + 3a
11111 1D-2
Br Br B(OH)2
87 88 89
'
a Bn /13n . OBn
los CO2MEM 40 co2H CHO
F E
-c------ ...E-------
_
II N (101 ''-
=,..,"'xi' '`,. .
H3CO2C . - s'-`-'--.-- 1-13CO,C .',,.-V- H3CO2C
0 0 0
92 91 90
1G
=1-1 = SO2CF3
los
CO2MEM 5 CO2MEM CO2MEM
B-2 D-3 $
---N.-
410 14 14 /1õ,,,r
H,CO,C -x" H3CO2C . '--`- 143CO,C .
0 0 0
93 94 95
NH NH
R
R 0 4111 NH2 0
7,1 II. NH2 CO211
01 P 1-2 (10 HI
_____
t\i
HO2C fl H3CO2C . 1-13CO2C
0 ' 0 0
98 97 96
, 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
43
,

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 14
CHO CHO
II T, U-3
----i.
41111 B(OH)2
OMe OMe
99 100
0
leo CHO
I.
100 + 3a _______,.... D-2 E OH
-.-
OMe OMe 1110
,CO,C \ \/
H,CO,C 11
0 0
101 102II
0 0
it NH it NH
ill t
1-12 1-2
N 0 ti
NH,
OMe S14.õ........... OMe OP *
'=.,, õ/ \
HO2C H,CO,C
0 0
104 103
44

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
-
Scheme 15
0 mo . CHO CHO
X T, U-I .
I I I. B(OH)2
OH OBn OBn
105 106 107
107 + 3a
NH
,
1D-2
101
ON
4111 NH, 0
0 CHO
H ..,.... õI__ 5 OH E
H H H
OBn 5 N.,.....,.y" OBn el N.,,,,,..--.. OBn *
H3CO2C H,CO,C H,CO,C
0 0 0
110 109 108
NH NH
*
0
II NH, 0
0 NH,
N
H I-2 1. N
H
H
H
OH 5 N.., 0 01 N
H,CO,C
0 0 0
111 112

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 16
Ko 40 CHO HO
110 CHO X or Bn0
CHO
Z or Z-1 X, V-4, AR
RO
0101
= ------3I .
0 RO
Br Br Br
113 114 115
6a IT, U-I
D-6
Bn0 10 CO21-1 Bn0 op CHO
D-2
E -
*---- Bn0 ii. CHO
RO RO ' CF RO 30S,0 ip
= 40
B(OH)2
NHR H
NHR' 40 '
,CO,C NHR'
116
11,CO2C H,CO,C
=
3a-j
= 0 0
118 117
,
1 F
Bn0 CO2MEM
. G HO CO2MEM
B-2 F3CO2S0 CO2MEM
110 NHR' RO
10 RO
4101
NI-1R'
RO
11,CO2C H3CO2C H3CO,C
. 0 0 0
.
119 120 121
NH
ID-3
I 0 igli NH, 1
I .
lip CO2H CO2MEM
10 N
H J I-1
1101
1110 NFIR1 RO
0 NHR' RO
11111 NI-
IR
RO '
H,CO,C
H3CO2C H3CO2C
0 0 , 0
124 123 122
1 1-2
NH
I 0
0 NH2
. 0N
H
RO
4101 '
HO2C NHR
0
125
46

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
0
if
114a, 115a, 116a, R = CH3; 114b, 115b, 116b, R= C2115; 114c, 115c, 116e, R = -
CH(CH3)2; 115d, R = C---C(CH3)3
CH3
117a -- 125a, R = CH3; 12' = =,..,,
1-111
C 3
117b¨ 125b, R = C21-15, R' =
'CH3
CH
117c -- 125c, R = CH(CH3)2; 12' =
CH3
CH3
117d -- 125d, R ¨ CH3; R.' = <
CH3
117e -- 125e, R = CH3; R.<
' =
CH3
..,.,..,.,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
CH3
1171-- 1251, R = CH3; RI=
0
I 1 CH3 CH3
117m -- 124m, R = C¨C(CH3)3; R1= ; 125m, R = H; 12.' =
`===..,.,/,,
CH3 CH3
47

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
"
Scheme 16a
NH . NH
0
NH,
0 NH2
II 4111
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
126 0 127 0
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
1110 MIR
113CO2C 1102C
128 0 129 0
CH,
128, R = CH3; RI = CH,
,
=
48

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
,
Scheme 17
CHO
lel
E
+ 3a CO,H
lel D-2
B(OH)2 --)--
=
CHO 0 11 \./'\. H3CO,C =130
H3CO,C
0 0
131 132
1 jA-5,
A-4, or
0 0 A-3
R R
1-2 411
141111
.
la 111101
HO,C H,CO,C
0 0
134 133
. 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 11 /
/ N
v, ________
/ (/ %N w, i' II x, 7----(-) Y,
OH
49

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
133, 134, R= (continued)
/ __________
\\N aa, 14 il ab, 14 11 OH ac, 14.____(i
z, ...,...
/ *
14 N
/
14 OH H3C
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
411
30f ________ y
0---30.
01 ._ 11101
14 \-
1-1,CO,C HO2C
0 0
135 136
135, 136, R=
14 N __________________ N
a' 13
=-N'\ 7. , NHHBoc c' 2 __
d' / / 11-- ) NH,
/N
\ --/
11 N / ¨N
Cl
0
e' /14 . f) 40 NH2 g, 11 it cH2eN h, / 4 01 CH2NH2/NHBoc
/

CA 0242 6430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 18
CO2H 020-13 02CH3 CO2CH3
11040 HO 5 HO CF302S0
0 0
W AA 1101
NH,
N112 N N
ri n
137 138 139 140
Bn0 41 CHO Bn0 ei CO2H
D-2 E
140 + 6
0
4101 , \,..... 0
H 3 CO 2 C H3c02c
h
141 142
HO CO,MEM 13n0 CO2MEM
G
0 0
112CO2C . V='.= 113CO2C 5
=
144 143
1B-2
F3CO2S0 CO,MEM R gab CO,MEM
D-2 or 0-3
WI.---0.-
0 NJU
vo,C lei 11--' H3co2c
õ
145 146
1 1-1
.
H NH
NH2
0
NH2 0
R
Nj 10111
R 5 CO211
R
ID 11
0 1-2
-.(-----
I. It
0 J
..c-----
0
41. N-= .I K.---
HO2C H3c02c
ri V 113CO2C
' 149 148 147
=
146a -- 149a, R = 146b -- 1496, R = r$ 146c--
149c, R = -CH=CH2
0 S
51

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 19
...,. CHO / CHO
1
a D-9
+3a -a
N
Sn(Me)3
01 H
150
H,CO2C
0
NH , 151
1E
0
41 ./ NH2 1 CO2H
N .
J
1
I H
N =,, N
. 0
H
01 H
.1
H3CO2C H3CO2C
153 0
152 0
11-2
1 NH
4111
0 NH2
N
1 H
H
le
HO,C
154 0 .
,
52

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 19a
CHO
N 1
N i
I +3a D-9 3 .
I
Sn(Me),
H
155 N,....,..õ,..---
H,CO,C
0
156
NH
1E
0
illi NH2
CO,H
NH - N
H 3
I
-,
01 H
N.,....õ....õ..-
* H
H3CO2C H,CO,C
' 0
158 0 157
11-2
NH
0
111 NH,
N
I H
,
.-
1101 H 1
HO,C
0
159
,
53

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 20
, NH 0
NO2
i 0
I. õ....---...õ
H
lei .1_ 3ifAB-1 or AB-2
_____________________________ 1
1110 N N OR
H
0 0 el H
N.,...,....õ..----..õ,
-.......õ.." -...__
H3CO2C
R ,
0 0
161
0
12R. Cl or
0 NH 0
0
.,
(RN, .,,A.... N N1OR
) 0 0
0 2 1
H
160
H
160a, 161a, R = -CH3 1411)
4101 114.,....
160, 161b, R = -C2115 HO2C
0
162
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
0
160h, 161h, R ----- CH
..,7 2.,.... .,
0 CH3
0
= ._ ,,, CH, ..... s ...0-.CH3
160i, 1611, R
CI-13
CH3
CH3 0
I
160j, 161j, R ,.,.,C1-1,,,... .7õ..,
0 CH3
54

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 21
40 CHO
Br 404_ 130 I_
H3 C 0 2 CH2 C H,CO,CH,C
163 164
NH
1E
0
410 NH,
CO211
is
OS
FI3CO2CH2C 113CO2CH2C
166 165
I-2
NH
0
NH,
So
HO,C112C
167

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 22
HO * HO* HO 0
AC G
õ. NOH NH,
H,CO,C CHO H3CO2C H;CO,C
168 169 170
IAA
F3CO2S0 0 HO
H *
B-2
H
Ns.,,,,
H H3CO,C
,CO2C
O 0
172 171
CHO CO213
172 + 130 - - 40 - 2 E
1101 H
la H
H,CO2C H,CO2C
O 0
17
173 '4
NH I j NH .
0
ell NH, 0
el NH2
11010 N
H 1-2 * N
H
* H
N., H
HO,C H3CO2C
O 0
176 175
,
56

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 23
HO 0 F3CO2S0
168 AE-1 > - H B-2
H =
N
11,CO2C H2CO2C
177 178 .
IR
F3CO2S0 0 roc
11,CO2C
179
0 CHO 0 CO2H
179 + 130 E 1-2-12---N,-
1101 Hoc
1
11,CO2C lel Hoc
I
11,CO,C
180 181
1 J
NH NH
0 - el H IP
N N112 0
1-2, S 0 N 140 NH2
11
Hoc
N
11,CO2C
HO2C
183 182
,
57

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 24
F3CO293 ea H,C,H,C0 Cl-b H5C6H2C0 0 CHO
D-2
H +
R
H3CO,C
IP H
B(OH)2
0 N.,
3a, 3f, 3i, 3j 6 1-13CO2C R
0
184
CHO F3C0,80 CHO HO
0 0 CHO
D-3 B-2
4
11101 H
N
110 H
R

01 H
l'\I
''''
H3CO2C H3CO2C R H3CO2C R
0 0 0
NH, 187 186 185
40 1 AE-3 NH
1 HN NH,
NH
141111 õ
SI N
H
H
1\1_
1-102C 11 -R
0
188
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, =
58

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 25
NH
X
4111 NI-12
HO,C
0
189a, 189b, 189; 189d
AE-4,
1-2
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
NH2
is CHO
AE-3
NH,
101
µ\
[xi
H3c02c HO,C
HN NH,
0
131
189e
59
=

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 26
NH
NH R 411 NHBoc
Br
= +
NHBoc X
0
Br HO Br
190 191
\c, 192
B..
40 cocn,
6a
NH NH
NH, R NHBoc
0
S-2 0
110 114 \/
H3CO2C 1-1,CO2C
O 0
194 193
11-2
NH
R= NH
0
SL
HO,C
0
195
190a, 192a - 195a, R = H
190b, 192b - 195b, R= CH3

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 27
. NH . NH . NH
02N
NH, R. G H,N NHBoc NHBoc
196 197 193
4- 190131X
NH NH
H, 411 NHBoc 6a CH, II NHBoc
Ill V D-7 41111
D
11101 11...õ,...7.--.......õ Br
199
H,CO,C
0
200
11-2
NHNH,
H, /01111 NHBoc H, 411
NH2
= t s
---,
410N
S11,,,,,,,,õ,, la ti...
HOC
HO2C ,
0 0
201 202
=
61
,

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
,
,
Scheme 28
4111 NH
ell NH
0
II NHBoc 0
0 NHBoc
0 0 ei
Vi
I-2
, N
45---0R- H
* H
N....,,,--,
1110 H
N,,,,,....õ...-
H,CO,C HO,C
0 0
203 204
Ill NH
el NH
0 NHBoc 0
NHBoc
0 el 0 II
' N Ill
el N
H H
*H
INI.,,µõõ...---...,õ H2N
1101 H
OH 0 0 0
206 205
1 S-2
II NH
lel NH
0
N
lel NH,
0
14111 NH2
*
0 0
Ill N
H H
*H
N...=-=-,., H2N
IP H
N...,
OH 0 0 0
207 208
62

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
,
Scheme 29
,
0
3,T 1411) CN
R el CO2H R
A-7
410
----). 11
11,CO2C Si il H,CO,C 4101 1\'-
0 0
132, 30f 209
1 Y
NH NH
0
N 411 NH
01H R so CI
-NT 40 NH
01H
R
411) 14 1-2
,
*{4 * 1.
H02c H30020
0 0
211 210
209a, R = H
209b -211b, R =
,
63

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 30
I
I si CN 0
H
IS 411 AE-5
----31. rah
IV .\
-
14.....,_õ.õ, 01 K.
H3CO2C H3CO2C
0 0
187a 212
1Y
NH NH
1
N ill NH
01H I
N el N, H
01.I
1410 H I-2
-.(-----
11111 H
01,. le
HO,C H3CO2C
0 0
214 213
64

CA 02426430 2003-04-17
WO 02/34711 PCT/US01/32582
Scheme 31
Me0..,...õõõ--- Me0 Me0..,
I A-3
I H D-12
I H
Br 1µ1.- CO2H BrNN ____õ--...,....N..7.,...(N.,
216 . 0 I 0
217 218
E-2,
1
H2C6H2C0 CHO
..., .
F,CO2S0.õ--,..,,,,N, :-3,
W-2
1H D-2
1 , H B-2
1 H
.---' 11,...õ..,õ--',.õ, + 6.-2--yN.....,....õ,,
H2CO2C N H3CO2C N H,CO2C N
0 0
. 0
219
221 220 .
'
I E .
PhH2C0 0 CO21-1 PhH2C0 CO2MEM .
HO0 CO2MEM
F G
-....,_ -.......
I ' H I H
I
1.1
.--" N...õ.....õ..- ./ N.,..,.,,,
H2CO2C N H2CO2C N H3CO2C N
0 0 0
222 223 224
1B-2
I I
0 CO2H 00 CO2MEM Di3 0F COS0 5 CO,MEM
1-1 D 12
I H I H I H
N..,..,....,,
..' N...,õ.....7- ./
11,CO2C N
0 0 0
227 226 225
. 1 J
NH NH
,
I 0
ell NH,
I 0
0 NH,
* N
H
.....,. 1-2
lei N
H
-.......
1 H I H
/ --
N.,....õ...õ
H3CO2C N HO2C N
0 0
228 229
,
,

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 32
CO2CH,
D-7
CHO
II CHO D-6 or
--I.-4- 6a I. CHO
40 AG-3
------).-
Br
HO Br a 0
OP
)--- 0 )--- 0
OH
'\.
230 R R
231
R = H R =H 232 0
R = CO2CH3 R = CO2H
E
NH
1\1112
0
el g I.
CC/2CH, J
-*---
CO21-1
CO2CH,
o
0 o
. )¨o ,)---o
5
R R
R = H 234 0
233 0
R = CO2H R = H
R = CO21-1
1-2
Y
NH
NI-12
0
4111 ti I.
CO2H
0
R
0
235
R = H
231a, 232a, 233a, 234a, 235a, R = H
231b, R -- CO2CH3
232b, 233b, 234b, R = CO2H
66

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 33
NH
NH NH2
CN
AF-1
I NH2 +187a
AE-2
1-121µ1N
H2N N
236 237
HO2C
238 0
67

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 34
NH NH
0
40 NHBoc OH 0
el NHBoc
./ 0111 N L N
H OH H
* H
N.,,,, SIP
* H
N.,,,,,,,,
H,CO2C H3CO2C
0 0
161d 240
NH /1\4 NH
OH 0
S
14111 NH N
NHBoc 0 0 i NHBoc
l
I
,HN
AG H el
H
,
H
N..,,,..õ....." . ell H
H3CO2C H3 CO2C
0
242 0 241
1 S
NH NH
OH 0
lall NH2 OH 0
el
41IP N
H 112_ NH2
1 1
0111 N
H
* H 1110
N.õ H
HO2C
H,CO2C
243 0 244 0
68

CA 0242 6430 2003-04-17
WO 02/34711
PCT/US01/32582
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 1 D-3
NH,
CHO
H
AE-3
I H
I H
HO,C N lei 1-1,CO,C N
0
247
0
248 HN NH,
. .
' NH NH
0
N NH2 0
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
0 0
249 250
NH'
0
Ill NH,
HO 0
N
H
=
I H
./ N..õ...............---
HO,C N
0
251
NH .
i I \TH2
i
/ illip NV
AE-3 H
247 ---1=-
.0 ...tn;
-,õ
I H
N.õ,,,,,......--...õ....
HO,C N
HN NI4, 0
252 .
69

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Scheme 36
NH
11111
CHO AE-3 NHz
NH,
Br Br
253
254
HN NH,
R
it NH it NH
NHBoc D-6
NHBoc
+ 6a
Br
4101
255
H3CO,C
0
256
I-2, S
N NH
NH,
HO,C
0
257

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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
71

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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 .

CA 02426430 2009-09-03
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.
73

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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
10
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.
=
74

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
76
=

CA 02426430 2009-09-03
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.
77

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
78

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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).
79

CA 02426430 2009-09-03
=
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

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
81

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
K: Reduction of aldehyde to alcohol
To a solution of aldehyde (1 mmol) in THF (10 mL) was added sodium
borohydride (0.4 mmol). The reaction mixture was stirred for 30 mins and
quenched
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.
82

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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.
83

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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,
84

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
dried in vacuo to furnish the desired product. If no solid separated out, the
product was
isolated by extraction with chloroform and evaporating the organic layer.
T: Protection of aldehyde as acetal
To a solution of aldehyde (1 mmol) in ethanol (5 mL) was added triethyl
orthoformate (1.4 mmol), ammonium nitrate (0.2 mmol) and stirred at room
temperature
overnight (if reaction was not complete by TLC and NMR analysis of an aliquot,
the
reaction mixture was heated at 50 C until complete). After completion of the
reaction,
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.

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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
86

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
solid that separated out was collected by filtration, washed with water and
hexane and
dried in vacuo to furnish boronic acid as a solid. If no solid product was
obtained then
the mixture was extracted with ether (2 X 10 mL). The organic layers were
combined,
dried and concentrated in vacuo to furnish boronic acid.
V-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.
87

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
V-3: Demethylation of aryl methyl ether to phenol
To a solution of aryl methyl ether (1 mmol) in dichloromethane (5 mL) was
added
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
88

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
did not come as solid, it was extracted with ethyl acetate. The organic layer
was dried,
filtered and concentrated to give the desired ester.
W-2: Conversion of acid to ester
A solution of methanolic 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.
89

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
Z: Opening of aromatic methylene dioxy compound with alcohol
A solution of potassium tert-butoxide (2.25 mmol) in DMSO (1.25 mL) was
heated at 50 C for 30 min. Methanol (1.25 mL) was added to it and continued
heating at
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

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
was dissolved in ethyl acetate and washed with water. The water layer was
extracted
with ethyl acetate, and the combined organic layers were washed with brine,
dried
(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.
92

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
AC: Conversion of aldehyde to oxime
To a stirred solution of aldehyde (1 mmol) in ethanol (10 mL) was added
pyridine
(10 mL) and hydroxylamine hydrochloride (1.25 mmol). The reaction mixture was
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
92

CA 02426430 2009-09-03
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
93

CA 02426430 2009-09-03
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.
94

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
AF-1: Synthesis of amidine from nitrile
Acetyl chloride (5 mL) was added to methanol (5 mL) at 0 C drop-wise and
stirred at room temperature for 15 mins. To this solution of methanolic 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

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
corresponding tert-butyldimethylsilyloxy compound as an oil which was used as
such for
the next step.
To a solution of the above oily residue (1 mmol) in diethyl ether (20 mL)
cooled
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.
96

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
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

CA 02426430 2009-09-03
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
98

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
chloride at ice cold temperature) was stirred at room temperature overnight.
The reaction
mixture was concentrated in vacuo to furnish methyl imidate. To the residue of
methyl
imidate was added 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
99

CA 02426430 2003-04-17
WO 02/34711
PCT/US01/32582
mmol) and potassium acetate (3 mmol). The reaction mixture was heated under
argon at
100 C for 3h or until complete as evidenced from TLC analYsis. The reaction
mixture
was concentrated in vacuo. The residue obtained was purified by flash column
chromatography to furnish the desired boronate ester.
The examples of the compounds prepared are given in the following tables. The
tables describe the compounds, their method of preparation, the starting
material, and the
analytical data. In some cases, where analytical data have not been given,
those
compounds were characterized at the later step in the synthesis.
=
100

R
0 CO2CH3
0
o
n.)
= 'W."
.6.
-4
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-
2
\,.õ.,--,,, and 8.9 Hz, 1 H), 6.94 (d, J-- 8.9 Hz, 1 H), 3.90 (s,
CH3
3 H), 2.15 (d, J= 6.9 Hz, 2 H), 2.06 (m, J= 6.9 Hz,
n
0
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,


o co
H 0
0
0
2b -OH1 A-1 or A-
2 Characterized in the next step co
1
0 0113
0
FP
I
H
=
'-ri-Lc' CH3
2c -OH / CH3 1 A-1 or A-
2 MS (ES+): 294.54
0
H
'A
=,µõ,,/%1_,
0113
1-3
2d -OH 1 A-1 or A-
2 MS (ES): 288.49 (M+Na)
cp
0 ---,----


i-,.)--
t..)
vi
oe
t..)
101

Cpd. Starting Method
-R -R' Analytical Data
No. From Used
=
2e -OH 1 A-1 or A-2 Characterized
in the next step
0
2f -OH 1 A-1 or A-2 MS (ES): 300.40
(M+Na)
0
0
H
1.)
2g -OH 1 A-1 or A-2 MS (ES): 272.48
(M+Na)+; MS (ES): 248.66 (5)
0
0
0
0
2h -OH 1 A-1 or A-2 MS (ES"): 286.48
(M+Na)
0
2i -OH
1 A-1 or A-2 MS (ES): 224.54
0
1-d
CH,
2j -OH 1 A-1 or A-2 Characterized in
the next step
oe
102

Cpd. Starting Method
-R
Analytical Data
No. From Used
0
CH3
o
t..)
H
3a -OS 02CF3 yNcii3 2a B-1 or B-2 MS (BS): 384.37
.6.
--4
1-
1-
0
H
-.,,.,,NCH3
3b -OS 02CF3 2b B-1 or B-2 MS (ES): 370.36
0 CH,
H
,,,- CH,
0
3e -0S02CF3 / CH, 2c B-1 or B-2 MS (ES): 426.37
0
IV
0
FP
IV
61
o
H co
o
CH,
3d -0S02CF3 2d B-1 or B-2 Characterized in the
next step I.)
0
0
0 -----...,-,
CA
I
0
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
0
(ES): 410.2
1-
c.:.)
t..)
vi
oe
t..)
103

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
1-
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
0
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)
1- 0
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.)
0
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
0
a,
1
H), 0.88 (m, 6 H); MS (ES+): 398.2
H
0
-,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,
CH3
0 2 H),
1.92 (m, 1 H), 1.43 (s, 12 H), 0.99 (d, J = 6.5 cp
=
1-
0 Hz, 6
H); MS (ES+) 362.2

t..)
vi
oe
t..)
104

Cpd. Starting Method
-R -R' Analytical Data
No. From Used
0
0 CH3 1H
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
1-
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
0 CH3 IH
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
0
I.)
a,
I.)
111. NMR (CDC13): 6 8.08 (s, 1 H), 8.00 (d,J= 2.3
(5)
1-
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.)
0
(ES): 196.1
0
u.)
1
0
1HNMR (DMSO-d6): 5 7.79 (d, J= 2.0 Hz, 1 H),
a,
1
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
CH3
H
.,>N
171 -OH CH3 170 AA MS
(ES): 250.50; MS (ES): 274.50 (M+Na)+ 1-d
n
o
cp
=
t..)
u,
oe-
t..)
105

Cpd. Starting 1 Method
-R -R'
No. From Used
Analytical Data
_
_
0
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.
--4
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-
1-
(s, 3 H), 2.44 (sep, J= 7.0 Hz, 1 H), 1.20 (d, J---- 7.0
0
Hz, 6 H); MS (ES ): 384.1
CH3 11-1N-
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
0
11-1NMR (CDC13): 5 8.05 (d, J= 2.3 Hz, 1 H), 7.63
I.)
a,
CH3
I.)
(dd, J= 2.3 and 8.3 Hz, 1 H), 7.25 (d, J= 8.3 Hz, 1
(5)
1- H
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
0
0
u.)
1
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..)
106

R R'
H3CO2C
0
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
0
8 -0Bn -CO2H 7 E MS (BS): 484.33 (M+Na)
(5)
9 -0Bn -0O2MEM 8 F MS (ES): 572.2 (M+Na)
0
-OH -0O2MEM 9 G MS (BS): 482.33 (M-MEM) +Nal+
0
0
IHNIVIR (DMSO-d6): ,58.75 (t, J = 5.6 Hz, 1H), 8.44 (d, J = 1.6
0
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)+
0
1-d
29a -0O2MEM 11 D-3 Characterized in the next
step
cH3
oe
107

Cpd. Starting Method
-R -R1
Analytical Data
No. From Used
29b CH3 -0O2MEM 11 D-3 MS
(BS): 520.2 (M+Na)
CH2
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
0
1H NMR (DMSO-d6): 8.50 (t, J = 5.6 Hz, 111), 8.18 (d, J = 1.9
0
0
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 =
0
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,
CH2
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
108

Cpd. Starting Method
-R -IV
Analytical Data
. No. From Used
0
CHO
o
,
n.)
29h // .........,_ -0O2MEM 11 D-2 MS
(ES): 538.2
--4
1-,
1-,
0
OHC
291 \k \ -0O2MEM 11 D-2 MS (ES): 560.4 (M+Na)+
-
0
0
30a -CO2H 29a I-I MS (ES): 398.3 ;
MS (ES): 396.3 0
--CH,
0
IV
FP
30b .--',-- --,.
I\)
(5)
o CH3 -CO2H 29b I-1 Characterized in
the next step Lo
vD
0
IV
0
0
CA
30c.,... CH2 -CO2H 29c I-1 MS (ES): 392.1
1
0
a,
1
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..)
109

Cpd.Starting Method
-R -12'
No. From Used
Analytical Data
0
30f -.--'''.-- CH2 -CO2H 29f I-1 MS
(ES): 380.1
t..)
i-,.)--
.6.
--4
N3H2C\ /
1-
1-
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
0
0
HOH20
IV
FP
IV
61
I-,
1..,30i
\ -CO2H 29i K, I-1 MS (ES): 450.3
a,
co
o 0
0
"
0
0
CA
33 -0S02CF3 -CO2H 11 I-1
Characterized in the next step
I
0
FP
I
H
--1
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


t..)
vi
oe
t..)
110

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
0
H), 2.29 (m, 1 H), 0.89 (d, J = 6.9 Hz, 6 H).
0
(5)
1.)
oe
111

R R'
OH
W."
BnO,C
0
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),
0
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),
0
3.09 (t, 3= 6.9 Hz, 2 H), 5.01 (d, J = 5.01 Hz, 2 H), 5.14 (s, 2 H),
0
0
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
112

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
22 -0S02CF3 -0O2MEM 21 B-2
H), 5.04 (s, 2 H), 5.16 (dd, J = 18 and 6 Hz, 2 H), 7.15 (m, 2 H),
0
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 =
0
6 Hz, 1 H); MS (ES+) 668.15
0
0
0
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
113
=

Cpd. Starting Method
-R -R'
Analytical Data
No. From Used
0
o
IHNMR (DMSO-d6): 5 0.89 (d, J = 6.8 Hz, 6 H), 1.87 (m, 1 H),
.6.
--4
3.12(t, J = 6 and 6.8 Hz, 2 H), 3.16 (s, 3 H), 3.30 (m, 2 H), 3.39
1-
1-
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-
.1,.
1-
u.)
5.53Hollz(8d,9,2 J(Hdl)i:71.67 Hz, 1 H), 7.37 (d, J ---- 7.7 Hz,
0
-57. 167. 807;.6 H), 1.87 27 H(m),, 71.H09),(m,
0
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)
0
-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
"
0
H), 7.88 (dd, J = 1.7 and 7.7 Hz, 1 H), 8.07 (dd, J = 7.7 and 1.7
0
u.)
1
Hz, 1 H), 8.11 (d, J = L7 Hz, 1 H), 8.42 (d, J = 1.7 Hz, 1 H), 8.72
0
.1,.
(t, J = 6 Hz, 1 H); MS (ES+) 596.45
1
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..)
114

Cpd. Starting Method
-R -R' Analytical
Data
No. From Used
24f -0O2MEM 22 + 23 D-1 MS (ES): 586.39
0
11,C
24g
-0O2MEM 22 + 23 D-1 MS (ES): 616.63
24h -0O2MEM 22 + 23 D-1 MS (ES): 597.25
0
1.)
1.)
(5)
24i -0O2MEM 22 + 23 D-1 MS (ES): 597.4
0
1.)
0
0
0
24j
-0O2MEM 22 +23 D-1 MS (ES): 597.4
24k H3C iS -0O2MEM 22 + 23 D-1 MS (ES): 644.3
oe
115

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
0
(5)
24o
S.Nv N
-0O2MEM 22 +23 D-4 MS (ES): 603.72
0
0
0
0
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
H3 C
24r -0O2MEM 22 + 23 D-5 MS (ES): 610.4 (M+Na)
oe
116

Cpd. Starting Method
-R -IV
Analytical Data
No. From Used
0
CH
t..)
24s -0O2MEM 22 + 23 D-3 Characterized in the next step

4,.
CH3
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
0
IV
I\)
(5)
--4 /=TMS
0
24w -0O2MEM 22 +23 D-5 Characterized in the next step
I.)
0
0
CA
CH3
I
0
24x / ¨ \ -0O2MEM 22 + 23 D-3 MS (ES): 610.5 (M Na)
CH,+
a,
,
H
--1
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..)
117

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
61
FP
I..
Pe
0
IV
0
0
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..)
118

Cpd.Starting Method
-R -R'
Analytical Data
No. From Used
0
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
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),
0
12.70 (brs, 1 H); MS (ES+) 514.06
I.)
.1,
I.)
(5)
.1,
1-
1- 1HNMR (DMSO-d6):
5 12.73 (bs, 1 H), 8.73 (t, .1. = 6 Hz, 1 H), u.)
0
VD
8.41 (d, J = 1.7 Hz, 1 H), 8.12 (d, J = 1.7 Hz, 1 H), 8.07 (dd, J =
I.)
0
7.7 & 1.7 Hz, 1 H), 7.83 (dd, J - 7.7 & 1.7 Hz, 1 H), 7.72 (d, J =
0
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.
0
,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
1-
i-,.)--
t..)
vi
oe
t..)
119

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
0
0
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
0
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),
0
7.1 (m, 211), 5.07(d, J = 8.6 Hz, 2 H), 3.12(t, J = 6.5 Hz, 2H)
0
2.29 (s, 3 H), 1.89 (m, 1 H), 0.91 (d, 6.8 Hz, 6 H); MS (ES+)
0
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
120

Cpd.Starting Method
-R -R'
Analytical Data
No. From-Used
-0
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
I I-1
= 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+)
0
I.)
509.49
a,
I.)
(5)
1-
a,
1-
0
I.)
25k H3c CO2H 24K 1-1 Characterized
in the next step 0
0
s
u.)
1
0
0
a,
.
1
H
251 N
I . CO2H 241 I-1 MS (ES+):
511.54
CH3
25m )
N CO2H 24m I-1 MS (ES+):
501.66 1-d
n
,-i
I
cp
=
t..)
u,
oe
t..)
121

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)+
0
(5)
25r CO2H 24r I-1 MS (ES): 500.4
0
0
0
/¨*CH2
25s CO2H 24s I-1 Characterized in the next
step
CH3
H2
25t /<\ CO2H 24t I-1 Characterized in the next
step
CH,
25u CO2H 24u 1-1 MS (ES): 486.4
oe
122

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
0
(5)
25y OH CO2H 24y I-1 MS (ES): 484.3
0
0
0
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
123

Cpd.Starting Method
-R -R'
Analytical Data
No. From Used
0
25ac 24ac
K, I-1
MS (ES): 544.2 t..)
i-,.)--
.6.
OH
-4
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)
0
IV
FP
I\)/61
N
CA
FP HOH2C
0
'
25af i CO2H 24ad K, I-1 MS (ES):
566.2 (M+Na)+ I.)
0
S
0
CA
I
0
FP
I
.----"----
H
--1
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


i-,.)--
t..)
vi
oe
t..)
124

NH
0 411) NH2
R
0
11101 N
H
o
n.)
.6.
-4
1-,
H
1-,
BnO2C
0
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)
1-
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
0
MS (ES+) 631.05 I.)
0
0
CA
1
7
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 =
6
Hz, 1 H), 8.29 (d, J = 1.7 Hz, 1 H), 8.07 (dd, J = 7.7 & 1.7 Hz, 1 H), 7.99
(d, J
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..)
125

Cpd. Starting Method
-R
Analytical Data
No. From Used
0
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),
0
0
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.)
1
0
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..)
126

Cpd. Starting Method
-R Analytical Data
No. From Used
-
0
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.
--4
1-
26h ----<:.. _....--....... 25h
J 1-
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
0
(m, 1 H), 0.88 (d, 6.8 Hz, 6 H);; MS (ES+) 626.44
I.)
a,
I.)
1-
(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.)
0
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
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, '
0
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,
1
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..)
127

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
0
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,
J 0
0
= 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
0
IHNMR (DMSO-d6): 8 10.84 (s, 1 H), 9.16 (s, 2 H), 8.78 (s, 2 H), 8.69 (t, J =
6
Hz, 1 H), 8.27 (d, J = 2 Hz, 1 H), 8.19 (s, 1 H), 8.09 (dd, J 2 & 7.7 Hz, 1
H),
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
128

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.
--4
1-
1-
IHNMR (DMSO-d6): 6 10.71 (s, 1 H), 9.16 (s, 2 H), 8.81 (s, 2 H), 8.68 (t, J =--
6
Hz, 1 H), 8.25 (s, 1 H), 8.03 (d, J = 7.8 Hz, 1 H), 7.73 (m, 5 H), 7.69 (s, 1
H),
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,
2
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
0
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)
1-
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.)
0
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
0
8.69 (t, J = 6 Hz, 1 H), 8.87 (bs, 4 H), 10.91 (s, 1 H); MS (ES+) 615.4
u.)
1
0
a,
1
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
---1 J
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 =
1-
H), 9.18 (bs, 2 H), 10.66 (s, 1 H); MS (ES+) 605.3
t..)
vi
oe
129

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
0
= 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)
0
IHNMR (DMSO-d6): 8 0.86 (d, J = 6.8 Hz, 6 H), 1.47 (s, 3 H), 1.74 (s, 3 H),
0
0
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
130

_
Cpd. Starting Method
-R
Analytical Data
No. From . Used
_ _
0
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..)
CH2
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
1-
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,
1 0
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.)
0
I.)
0
0
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
0
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,
1
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
1-
t..)
vi
.
oe
t..)
131

,
Cpd. Starting Method
-R
Analytical Data
No. From Used
0
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
--4
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-
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 =-
HOH2 C /
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).
0
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
0
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.)
0
0
OH
u.)
1
o
26ah 25ah J. MS (ES): 609.6
a,
1
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..)
132

NH
0 4111 NH,
0
o
n.)
.6.
-4
1410 HN
1-,
1-,
NBR'
la
HO,C
0
- 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,
1- CT-13
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
0
0
(s, 2 H), 8.49 (t, J = 6 and 5.2 Hz, 1 H), 7.97 (s, 1 H), 7.99
u.)
1
0
\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
1-
c.:.)
tµ.)
vi
oe
tµ.)
133

Cpd.Starting Method
-R -R'
Analytical Data
No. From Used
0
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
--1
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-
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),
0
0
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
0
I.)
a,
I.)
c7,
1-
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.)
0
0
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.)
'
0
a,
and 6.0 Hz, 2 H), 1.81 (m, 1 H), 0.86 (d, J = 6.9 Hz, 6 H);
1
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
1-
l= . )
C. if I
0 0
l= . )
' 134
_

Cpd. 1 Starting Method
-R -R' Analytical Data
No. From Used
0
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
1-
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
-7M--/
271
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
0
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)
1-
a,
vi H), 3.08
(t, J = 5 Hz, 2 H), 1.82 (m, 1 H), 0.9 (d, 6.8 Hz, 6 u.)
0
H); MS (ESI): 268.85 (m1 2)
I.)
0
1H NMR (DMSO-d6): 6 14.19(s, 1 H), 9.06 (bs, 2 H),
0
u.)
1
cH3 8.67 (bs, 2 H), 8.67 (d, J = 6 Hz, 2 H), 8.50 (t, J =
6 Hz, 1 0
a,
1
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
1-
i-,.)--
t..)
vi
oe
t..)
135

Cpd. Starting Method
-R -R'
Analytical Data
No. From Used
0
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
271
H), 6.11 (t, J= 3 Hz, 1 H), 3.74 (s, 3 H), 3.05 (t, J = 6 Hz,
.6.
--4
1-
1-
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);
0
MS (ES): 528.76
0
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.)
0
--.,õ..--C11.2
CH, H), 7.39 (s, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 6.92 (d, I
0
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
1
J = 16.7 Hz, 1 H), 5.08 (d, J = 10 Hz, 1 H), 3.45 (d, J = 6
0
a,
Hz, 211), 2.99 (t, J = 6 Hz, 2 H), 1.78 (m, 1 H), 0.83 (d, J
1
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..)
136

Cpd. Starting _ Method
-R -R'
Analytical Data
No. From Used
0
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.
--4
CH, 1.8 (m, 1
H), 0.9 (2s, 6 H); IR (K.Br Pellets) 2957, 1676, 1-
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
CH3
= 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
0
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.)
--4
0
611); MS (ES): 525.4
I.)
0
0
11-1NMR (DMSO-d6): 8 9.01 (s, 2 H), 8.88 (s, 2 H), 8.5 (t,
u.)
1
0
CH, I = 6 Hz, 1
H), 8.07 (In, 1 H), 7.73 (m, 1 H), 7.63 (in, 7 a,
1
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
1-
c.:.)
t..)
vi
oe
t..)
137

Cpd. Starting Method
-R -R' Analytical Data
No. From Used
0
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
--4
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-
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
0
I.)
a,
(ES): 529.4
I.)
1-
(5)
0
1H NMR (DMSO-d6): 5 9.08 (s, 2 H), 8.86 (s, 2 H), 8.54
I.)
cH3
0
/=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
0
'-ci-i3
a,
6.9 and 6.0 Hz, 2 H), 2.71 (t, J ----- 7 Hz, 2 H), 1.82 (m, 1
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
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
1-
t..)
vi
oe
t..)
138

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
--4
1-
26y 1-2 = 7 Hz, 1
H), 7.07 (d, J = 7 Hz, 1 H), 7.12 (in, 1 H), 5.40 1-
CH3
(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),
0
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)
1-
a,
o 0
IV
0
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
'
.
0
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,
1
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
1-
i-,.)--
t..)
vi
oe
t..)
139

Cpd. Starting Method
-R -R'
Analytical Data
No. From Used
0
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.
--4
1-
= 5 Hz, 1 H), 7.54 (d, J =5 Hz, 1 H), 7.26 (d, J = 5 Hz, 1
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
0
'CH3
I.)
a,
I.)
1-,
(5)
o u.)
0
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
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.,
0
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
1-
c.:.)
t..)
vi
oe
t..)
140

Cpd. Starting Method
-R -R'
Analytical Data
No. From Used
0
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
1-
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
OH 1H NMR
(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.)
0
0
u.)
CH,
I
0
Fi.
1
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
1-
i-,.)--
t..)
vi
oe
t..)
141

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
0
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,
0
2 H), 2.6 (m, 2 H), 1.8 (m, 1 H) 0.85 (d, J = 6.9 Hz, 6 H);
0
MS (ES+) 517.3
0
0
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
142

Cpd. -R -R' Starting Method
Analytical Data
No. From Used
0
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
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,
0
_
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),
0
4.04 (s, 2 H), 3.02 (t, J = 6.8 Hz, 2 H), 1.80 (m, 1 H),
I.)
0
32e 31e 1-2
CA
I
0
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 =
6
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
=
1-
t..)
vi
oe
t..)
143

,
Cpd. Starting Method
-R -R'
Analytical Data
k No. From Used
0
o
CH2OH CH,
1H NMR (DMSO-d6): 5 14.2 (bs, 1 H), 9.1 (bs, 4 H), 8.6
.6.
--4
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
0
I.)
a,
CH
I.)
1--, 3
0,
.6.
a,
.6. 40 - NH 39 1-2 MS (ES+)
524.3 u.)
0
-/ '-'Cii3
I.)
0
0
1H NMR (DMSO-d6): 5 13.82 (s, 1 H), 9.20 (bs, 1 H),
u.)
1
0
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
44 43 1-2
-A
CH3 7.10 (m, 6 H), 6.96 (d, J = 8 Hz, 1 H), 3.0 (t, J = 6 Hz,
2
H), 1.80 (m, 1 H), 0.68 (d, J = 6.8 Hz, 6 H); MS (ES)
551.30
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),
-0
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..)
144

_
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,
--4
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
-OCH3
= 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
0
0
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),
0
70a
N
0
0
CA
3.19 (m, 2 H), 1.46 (qui, J = 7.0 Hz, 2 H), 1.29 (sex, J=
I0
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
1 S
..., 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
0
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),
-4
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-
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
0
Hz, 1 11), 5.12 (m, 2 H), 3.88 (t, J= 5.0 Hz, 1 H); MS
0
I.)
(ES): 469.2
a,
I.)
c7,
1-
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
0
CH, 5.98 (d, J= 17.7 Hz, 1 H), 5.39 (d, J--- 10.9 Hz, 1 H),
u.)
I
0
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
00
l=.)
146

_______________________________________________________________________________
____________________________ -,
Cpd. Starting Method
-R -R'
Analytical Data
No. From Used
0
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
1-
1-
Hz, 1 H), 5.99 (d, J= 17.7 Hz, 1 H), 5.40 (d, J= 10.9 Hz,
T211
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
0
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
0
I.)
H), 3.22 (m, 2 H), 1.48 (m, 4 H); MS (ES): 501.3 (100%:
0
0
1\4+1)
LO
I
0
FP
11-1 NMR (DMSO-d6): 8 9.08 (m, 4 H), 8.69 (t, J=. 6.0 Hz,
1
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
1-
c.:.)
t..)
vi
oe
t..)
147

Cpd.Starting Method
-R -R' Analytical Data
No. From Used
0
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
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,
0
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
"
0
(ES): 471.3
0
CA
I
I0
4 1H NMR
(DMSO-do): 8 12.97 (br s, 1 H), 9.08 (s, 2 H), a,
-
CIH2
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
1-
H); MS (ES ): 499.3

t..)
vi
oe
t..)
148

Cpd. Starting Method
-R -R' Analytical Data
No. From Used
0
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
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
0
-
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
I 0
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
\)
0
\
Hz, 1 H), 1.93-1.44 (m, 8 H); MS (ES): 497.2
u.)
1
0
FP
I
1H NMR (DMSO-d6): 5 13.78 (br s, 1 H), 9.07 (s, 2 H),
H
-.-1
CH2
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
---1
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
1-
t..)
vi
oe
t..)
149

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
0
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
0
17.7 Hz, 1 H), 5.36 (d, J= 10.9 Hz, 1 H), 3.23 (q, J= 6.5
0
Hz, 2 H), 1.59 (m, J= 7.0 Hz, 1 H), 1.39 (q, J= 6.8 Hz, 2
0
H), 0.88 (d, J= 6.6 Hz, 6 H).
=
oe
150

NH
0
o
0 40 NH,
n.)
W."
.6.
R
le N
H
-4
1-,
1-,
OH 1.4
= H3CO2C
0
Cpd. Starting Method 1
-R
Analytical Data
No. ____________________________ From Used
0
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
0
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)
1-
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-
0
1.86 (m, 1 H), 3.88 (d, 6.87 Hz, 6H); MS (ES+) 515.3
I.)
0
0
31b .-''' .µ--c}13 30b J
MS (ES): 527.2 u.)
1
0
a,
1
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 =
6
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
1-
i-4.)--
t..)
vi
oe
t..)
151

Cpd. Starting Method
-R
Analytical Data
No. From Used
0
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-
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
0
I.)
CH20H
N)
(5)
1-
a,.
t..) 31h
30h J Characterized at the next
step 0
IV
0
0
0
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
0
HOH2C /
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
311
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
1-
i-,.)--
t..)
vi
oe
t..)
152

Cpd. Starting Method
-R Analytical Data
No. From Used
Iss
52 31g G Characterized in the next step
NH2
0
1.)
1`)
(5)
0
1.)
0
0
0
oe
153

NH
o
0 0 NU
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
0
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
TIPS 9
i
0
/
37
C 35 + 36 D-2 MS (ES): 828.5
'
H
OBn
--1
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.)
154

R a R'
0
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):
0
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
0
H), 7.50(m, 3 H), 7.38(m, 4H), 7.24 (dd, J=
I.)
0
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,
0
a,
2 H), 3.57 (s, 3 H), 3.49 (t, J=4.9 Hz, 2 H),
1
,
-,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),
0 CH3
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..)
155

Cpd.
Starting Method
-R -R' -R" Analytical Data
No. From Used
0
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.
--4
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
0
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,
0
(M+Na)+
I.)
111 NMR (DMSO-d6): 8 12.7 (br s, 1 H), 9.09
0
0
O CH, (s,
2 H), 8.91 (s, 211), 8.57 (m, 1 H), 8.11 (s, 1 u.)
,
0
144 -OH -0O2MEM ,, ...-,,,.,
143 G H), 7.92 (d, J-- 1.9 Hz,
1 H), 7.81 (m, 3 H), a,
1
N CH3
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 ,
N CH3
H
O CH,
IV
n
146a ..\ -0O2MEM -,õ ..,--.L.,,,-. 145 D-2 MS
(ES: 532.5 (M+Na)
N CH,
cp
0 H
o
1-,
W."
n.)
vi
oe
n.)
156

Cpd. Starting Method
-R -R' -R" Analytical Data
0
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
--4
O cH3
1-
(dd, J=2.0 and 7.9 Hz, 1 H), 7.84 (d, J=3.0
1-
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
O CH3
0
146c -CH=CH2 -0O2MEM -- j-
--..._,r--..CH3 145 D-3 MS (ES): 470.2 (WNW
N
0
I\)
H
.i.
I\)
(5)
1-, 0 CH,
.i.
vi
Lo
--4 147a _- -CO2H146a I-
1 MS (ES): 420.29 0
',....., ,,.......".........
IV
0 N CH3
0
H
0
_
Lo
11-1NMR (DMSO-d6): 5 12.65 (s, 1 H), 10.12
I
0
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..)
157

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-
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.)
0
130 2
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
0
u.)
1
MS (ES): 448.3 (M+Na)+
0
.1,.
1H NMR (DMSO-d6): 8 7.81 (m, 2 H), 7.56 (m,
1
H
13 C CH3 1
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
CH3
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+):
0
446.3
cp
o
1-
c.:.)
t..)
vi
oe
t..)
158

Cpd. Starting Method
-R -IV -R"
Analytical Data
No. From Used
0
o
H
n.)
1"s1.-CF3
.6.
184b -0Bn -CHO 3f 6 D-2 MS
(ES): 470.2 --4
1-,
1-,
0
H
,.,_,7NCH,
184c -0Bn -CHO 3i + 6 D-2
MS (ES): 418.3
_
0
CH,
H
184d -0Bn -CHO ,.,..õ,--,,,.,õ,3j 6
D-2 MS
(ES): 460.3
0
o
11INMR (DMSO-d6): 6 10.06 (s, 1 H), 9.63 (s,
0
I.)
a,
CH3 1
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,
0
0
0
1 H), 0.91 (d, J = 6.8 Hz, 6 H); MS (ES-):
u.)
,
354.2 and (ES) 378.2 (M+Na))
0
a,
1
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..)
159

Cpd.Starting Method
-R -R' -R"
Analytical Data
No. From Used
0
o
IHNMR (DMSO-d6): 5 10.06 (s, 1 H), 9.62 (s,
t..)
i-,.)--
CH3 1
H), 8.69 (t, J = 5.90 Hz, 1 H), 8.36 (s, 1 H), .6.
H .
-4
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),
0
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).
_
CH3
H,
186a -0S02CF3 -CHO .--Nci13 185a B-2 MS
(ES): 488.24
0
0
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-
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
0
0
H -=
5.90 Hz, 1 H), 8.28 (s, 1 H), 7.94 (d, J = 8.10 u.),
0
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,
1
7.9 Hz, .1 H), 7.32 (d, J = 7.9 Hz, 2 H), 3.40 (s,
H
-.-1
0 3
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
1-
i-,.)--
t..)
vi
oe
t..)
160

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
CH3
(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
0
(5)
c7,
187c -CH=CH2 -CHO 186c 0-3 MS
(ES): 336.2
0
0
0
CH,
187d -CH=CH2 -CHO
186d 0-3 MS
(ES): 378.2
0
=
oe
161

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),
0
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
0
57 -0Bn -Boc -0O2MEM 56 R MS (BS):
712.4 0
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
162

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
0
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),
0
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
0
7.15 (d, J= 3.0 Hz, 1 H), 6.67 (m, 1 H), 3.57 (s, 3 H),
0
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
163

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
0
(5)
0
0
0
0
oe
164

NH
0
/ I 0 410 NH
13oc
o
n.)
0 40 N
H
.6.
--4
1-,
1-,
0 NHEZ!
RO,C
0
.
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=
0
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.)
1-
(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.)
0
0
H), 1.50 (m, J= 7.4 Hz, 2 H), 1.43 (s, 9 H), 1.32 (m, J= 7.4 Hz,
u.)
1
2 H), 0.89 (t, 3 H); MS (ES"): 639.5
0
a,
1
-
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
0
I..,
W.
N
00
N
165

Cpd. 41
-R' Starting Method
Analytical Data
o
No. From Used
o
t.)
-...,,,CH3
4= ,
62e -CH3 61 A-4 MS (ES): 625.4
-4
CH3
621 -CH3 ,3
61 A-4 MS (ES): 653.5
CH3
-_,,=-=õ,.CH3
62g -CH3 61 A-4 MS (ES): 653.5
n
CH3
0
I.)
a,
I.)
c7,
o 62h -CH3 61
A-4 MS (ES): 667.3 a,
c:
Lo
0
0
I.)
0
0
62i -CH3
61 A-4 MS (ES): 681.5
Lo
1
0
a,
1
CH3
H
--J
62j -CH3 61 A-4 MS (ES): 637.3
OH
62k -CH3 61 A-4 MS (ES): 640.3
'CH3
00
n
1-i
621 -CH3 ¨0 61 A-4 MS (ES): 665.4
cp
o
l=.)
-
CA
00
l=.)
166

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
CH3
- 62o -CH3
10111 61 A-4 MS (ES): 695.4 (M+Na)
0
62p -CH3 61 A-4 MS (ES): 665.4
(5)
0
62q -CH3 WcH, 61 A-4 MS (ES): 653.4
0
0
0
cH3
62r -CH3 61 A-4 MS (ES): 567.3
CH3
CH3
62s -CH3 61 A-4 MS (ES): 667.5
CH3
CH3
62t -CH3 OH 61 A-4 MS (ES): 641.3
OH
62u -CH3 61 A-4 MS (ES): 655.3
oe
167

Cpd. ..R
-R' Starting Method
Analytical Data
No. From Used
0
o
t..)
62v -CH3\ 61 A-4 MS (ES): 663.1
--4

62w -CH3 61 A-4 MS (ES): 577.2

r\z N
"4---__V
62x -CH3 \/0 61 A-4 MS (ES): 679.2
n
0
I.)
a,
I.)
62y -CH3 .,õ,--,,,.OH 61 A-4 MS (ES): 621.1
(5)

a,
o Lo
oe
0
I.)
0
62z -CH3 -..,,0H3 61 A-4 MS (ES): 611.1
0
Lo
1
0
a,
1
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


i-,.)--
t..)
vi
oe
t..)
168
-

Cpd.
-R' Starting Method Analytical Data
No. From Used
62ad -CH3 61 A-4 MS (ES): 695.3
0
62ae -CH3 NHR, _N 61 A-4 MS (ES): 651.3
NHR'
62af -CH3 61 A-4 MS (ES): 679.4
0
(5)
0
0
0
0
oe
169

NH
0 411 NH2 0
o
n.)
c.:.)
.6.
R is
N
H
-4
1-,
1-,
1101 NHR'
HO2C
0
_
_
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
0
Hz, 3 H); MS (ES): 525.3
I.)
0
0
CA
I
0
1H NMR (DMS0416): 8. 12.76 (s, 1 H), 9.10 (s, 2 H),
a,
1
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,
3
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
1-
c.:.)
t..)
vi
oe
t..)
170
_

Cpd. -R
-R' Starting Method
Analytical Data
No. From Used
0
_
- 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
CH3 1H NMR
(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
0
I.)
0
1H NMR (DMSO-d6): 5 13.37 (s, 1 H), 9.06 (s, 2 H),
0
u.)
1
8.84 (s, 2 H), 8.47 (m, 1 H), 8.00 (s, 1 H), 7.88 (s, 1 H),
0
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..)
171

Cpd. Starting Method
-R -R'
Analytical Data
No. From Used
0
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
621
1-2, S H), 7.74
(m, 5 H), 7.32 (m, 1 H), 7.13 (m, 1 H), 6.67 (m, --4
1-
1-
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
0
_
I.)
a,
OH 'H NMR
(DMSO-d6): 8 9.12 (s, 2 H), 8.88 (s, 2 H), 8.52 I.)
(5)
1-
--4
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=
0
0
LO
6.0 Hz, 3 H); MS (ES+): 527.2
1
0
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
1-
c.:.)
t..)
vi
oe
t..)
172

_
Cpd.Starting Method
Analytical Data
No. From Used
0
.
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
1-
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

2
(DMSO-d6): 8 9.19 (m, 2 H), 9.10 (s, 2 H),
58.852
2
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
0
I.)
a,.
I.)
(5)
1- 1H NMR
(DMSO-d6): 8 9.22 (m, 2 H), 9.09 (s, 2 H),
--4
u.)
w
0
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
0
-
0
+
u.)
1
0
a,.
1
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..)
173

,
Cpd. ' Starting =' Method
-R -Re Analytical Data
No. From Used
0
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-
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
0
,
I\)
FP
C l( Ili NMR
(DMSO-d6): 5 12.7 (br s, 1 H), 9.09 (s, 2 H), I.)
(5)
1-
a,
--.1 8.91 (s,
2 H), 8.57 (m, 1 H), 8.11 (s, 1 H), 7.92 (d, J= u.)
.6. -
0
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
0
0
H), 3.22 (in, 2 H), 1.48 (m, 4 H); MS (ES): 541.34
u.)
1
0
FP
I
0
'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
=
1-
c.:.)
t..)
vi
oe
t..)
174

Cpd. Starting Method
-R -R.'
Analytical Data
No. From Used
0
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
0
0
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
"
0
(ES): 497.2
0
CA
I
0
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..)
175

Cpd. Starting Method
-R = -R'
Analytical Data
No. From Used
0
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'
1-
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
0
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.)
0
(ES): 537.20
I.)
0
0
u.)
1H NMR (DMSO-d6): 8 12.81 (br s, 1 H), 9.13 (s, 2 1-1),
1
0
C0( 8.82 (s,
2 H), 7.95 (s, 1 H), 7.85 (m, 2 H), 7.71 (m, 5 H), a,
1
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..)
176

NH
=
0
n.)
R c.:.)
mat
LW N NBR
H .6.
--4
1-,
1-,
0 NHR'
HO,C
0
Cpd. Starting Method
-R -R'
Analytical Data
No. From Used
0
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.
--4
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.)
0
0
CA
I
0
11-1 NMR (DMSO-d6): 8 13.80 (hr s, 1 H), 9.91 (s, 1 H), 9.41 (s, 1
a,
1
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
1-
c.:.)
t..)
vi
oe
t..)
177

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
0
(5)
oe
0
0
0
0
oe
178

NH
0
I o
N Si NHBoc
o
n.)
W."
4.
0 ii
-4
-
-
101 NHR`
RO2C
0
_ Cpd....R
-11.1 Starting Method
Analytical Data
No. From Used
0
68a -CH3 --...,õõ,-.õõ,,3 67 A-4 MS (ES): 599.4
0
I.)
I\),-, 68b
-CH3
67 A-4 MS (ES): 641.4
a,
(5)
a,
--4
Lo
o
CH3
0
I.)
0
0
68c -CH3 ¨0 67 A-4 MS (ES): 625.3
0
a,
1
H
-,1
,
68d -CH3 " CH, 67 A-4 MS (ES): 583.3
....,<CH3
68e -CH3 67 A-4 MS (ES): 585.3
CH3
1-d
n
-...,.....,K7H,
1-3
681 -CH3 CH3 67 A-4 MS (ES): 599.4
cp
o
1-
i-,.)--
t..)
vi
oe
t..)
179

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
0
o.
oe
68k -CH3 CH3 67 A-4 MS (ES): 557.3
0
0
0
681 -CH3
67 A-4 MS (ES): 571.4
0
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
= .)
0 0
= .)
180

= ,
Cpd. -R
-R' Starting Method
Analytical Data '
No. , From , Used
0
o
.,,,, CH,
l= . )
68p -CH3 CH, 67 A-4 MS (ES): 613.5
.6.
--1
1--,
1--,
CH3
68q -CH3 67 A-4 .MS (ES): 641.5
CH3
68r
-CH3 ./\./.\--NIIBIDc 67 A-4 MS (ES): 714.5
68s -CH3 ¨0 67 A-4 MS (ES): 611.4
0
0
I.)
a,
I.)
c7,
1--, 0H
.i.
oe 68t -CH3 67 A-4 MS (ES): 641.4
co
1--,
0
I.)
0
0
co
68u -CH3
< 67 A-4 MS (ES): 583.3
1
7
H
- 1
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
0 0
l= . )
181

5
4 0 6 11'
R
0
o
3n.)
2 1,
H
.6.
-4
R"O,C
0
-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.)

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
0
co
1
77b -OCH2CO2C2H5 (3) -CHO -Bn 75b X
Characterized in the next step 0
MS (ES): 487.3; MS (ES):
a,
1
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..)
182

-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


(3)
1-
77g \ 0/\ CH3 (3) -CHO -Bn 75b X MS (ES+):
482.4 (M+Na)+ .
..,..-...CH,
0
77h (3) -CHO -Bn 75b X MS (ES):
510.4 (M+Na)
CH3
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,
"

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
0
771
(3) -CHO -Bn 75b X
Hz, 1 H), 6.31 (t, J = 6 and 5 Hz,
"
0
.
1 H), 5.06 (m, 2 H), 4.42 (t, J = 0
u.)
1
4.5 Hz, 2 H), 4.13 (m, 2 H), 3.34
0
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


i-,.)--
t..)
vi
oe
t..)
183

-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
0
781 (:)C1.13 (3) -CO2H -Bn 77g
E MS (ES): 474.4 0
I.)
a,
3
"
0,

a,
oe 78j (3) -CO2H -Bn 77h
E MS (ES): 502.4 co
.6.
0
CH,
N
0
0
78k '-'-1:y' \ OAc (3) -CO2H -Bn 771
E Characterized in the next step co
'
0
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


i-,.)--
t..)
vi
oe
t..)
184

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,
1-
1-
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.)

-0O2MEM -CH3 94
D-3 MS (ES+) 562.3 (M+Na)+ T
L.,
c'e
u, 95a \ (5)
0
s
I.)
0
0
co
96a \\,¨) (5) -CO2H -CH3 95a
I-1 MS (ES+) 452.1 (M+Na)+ 1
0
a,
1
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
0 0
l= . )
185

-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),
--4
1-
1-
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),
0
N
132 -H -CO2H -CH3 131
E 7.41 (t, J = 8.67 Hz, 1 H), 7.31 (t, a,
I.)
(5)
1-
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
0
H), 3.39 (s, 3 H), 2.92 (t, 3 --- 6.0
I.)
0
0
Hz, 2 H), 1.66 (m, 1 H), 0.78 (d, J
u.)
1
-- 7.4 Hz, 6 H), MS (ES-): 354.1
0
a,
1
NH
H
-.-1
192a+
193a -H ei NHBoc -CH3 6a
D-7 MS (ES): 560.5
0
NH
193b -H CH, 00 NHBoc -CH3 192b+
D-7
MS (ES): 574.5) 1-d
n
6a
1-i
cp
o
1-
i-,.)--
t..)
vi
oe
t..)
186

-R (Position with
Cpd. Starting
Method
Respect to Phenyl -R.' -R"
Analytical Data
No. From
Used 0
Ring)
_______________________________________________________________________________
____________________________________ o
_
t..)
NE
i-,4--
.6.
--4
1-,
194a -H 1.1 NH2 -CH3 193a
S-2 MS (ES): 460.3 1-
--0
NH
- 194b -H CH3 NH2 -CH3 193b
S-2 MS (ES): 474.3
-'0 = 0
IHNMR (DMSO-d6): 8 8.79 (bs,
0
I.)
4H), 8.63 (t, J --- 6.5 Hz, 1 H),
a,
I\)
NH

8.35 (s, 1 H), 7.85 (d, J = 6 Hz, 1 (5)
oe
a,
--4
H), 7.62 (d, J = 8.2 Hz, 2 H), 7.26 Lo
l
0
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
0
0
CA
0
(n, 1 H), 0.89 (d, J = 6.6 Hz, 6 I0
H); MS (ES-): 444.3 and (ES)
a,
1
H
446.3
-A
.0
n
,-i
cp
=
i-,.,--
t..)
u,
oe
t..)
187

-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
0
and (ES) 460.3
c7,
oe NH
oe
CH, NHBoc _CH3 199 6a
D-7 0
200 -H MS (ES):
573.5 0
0
C. I
0 0
188

-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.
-4
NH
1-
6.9 Hz, 1 H), 7.84 (t, J= 7.8 Hz, 1
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
201 -H -H 200
1-2
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
1
o
NH
.i.
1
H
203 -0Bn (4) 0 = NHBoc
-CH3 45
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 = . )
0 0
l = . )
189

-
-R (Position with
Cnd= Starting
Method
-
No. Respect to Phenyl -R' -R" From
Used Analytical Data
Ring)-0
c _N
I
0
-
209a -H II ----=-_--
-CH3 132
A-7 MS (ES): 454.3
1-
1-
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,
0
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,
0
J = 11.1 Hz, 1 H), 3.55(s, 3 H),
I.)
.1,
I.)
1-
3.10 (t, J = 6.6 Hz, 2 H), 1.86(m, (5)
vD
.1,
0
,
MS (ES): 480.3
I.)
0
11-1N4R (DMSO-d6): 5 10.12 (s,
0
u.)
1 H), 9.37 (b, 1 H), 8.48 (t, 3=6.1
1
0
.1,
Hz, 1 H), 8.05 (d, 3=1.9 Hz, 1 H),
1
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
0 411 N-OH
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
1-
i-,.)--
t..)
vi
oe
t..)
190

,
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,
1-
1-
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
0
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.)
1-0
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
0
Hz, 1 H), 7.04 (d, J= 7.7 Hz, 1
u.)
1
H), 6.74 (dd, J= 17.5, 10.9 Hz, 1
0
a,
212 -CH=CH2 (4) -CH3 187a AE-5
1
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..)
191
,

-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
--4
1-
(d, J= 1.9 Hz, 1 H), 8.09 (dd, J =
1-
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
0
I.)
H),3.11 (t, J-- 6.4 Hz, 2 H), 1.86
a,
I.)
1-
(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=
"
0
5.8 Hz, 1 H), 8.37 (s, 1 H), 8.04
0
u.)
1
(d, J= 8.7 Hz, 1 H), 7.39 (m, 5
0
H), 7.06 (d, J-- 8.3 Hz, 1 H), 6.72
1
H
N-OH -H 213
-,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..)
192

-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-
0
1.88 (m, 1 H), 1.2-0.94 (d, J = 6.6
Hz, 6 H); MS (ES) 471.3
(5)
NH
0
1.)
0
0
256 -H 410 NHB" -CH3 255 + 6a D-6 MS (BS):
573.3
0
NH
257 -H
NH2 -H 256 1-2, S MS
(ES): 459.1
oe
193

NH
0 4111) NH,
5
R 4 401 6 N
3 2 1 la
R'02C
0
Cpd.Starting Method
-R -R'
Analytical Data
No. From Used
79a -CH=CH2 (3) -CH3 78a J MS (ES): 499.2
0
c7,
79b -OS02CF3 (3) -CH2C6H5 78b J Characterized in the
next step
0
0
0
79C OCH2C 02 C2115. (3) -CH2C6H5 78c J Characterized
in the next step
0
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
194

Cpd. Starting Method
-R -R'
Analytical Data
No. From Used
0
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-
, 1 H), 7.83 (s, 4 H), 7.78 (d,
--.1
-OCH3 (3)
1-
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
0
791 -"OCH3 (3) -Bn 781 J MS (ES):
593.4 n
0
CH3
I.)
793 0 (3) -Bn 78j J MS (ES):
621.4 . a,
"
1-
(5)
o a,
vi CH,
u.)
o
79k -0-CH2-CH2-0Ac (3) -Bn 78k 1 MS (ES):
651.4 "
0
0
u.)
1
IHNMR (DMSO-d6): 8 9.1 (s, 2 H), 8.87 (s, 2 H), 8.53 (t, J =
0
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
1-
c.:.)
t..)
vi
oe
t..)
195
-

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
0
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
0
0
0
IHNMR (DMSO-d6): 5 9.14 (d, J = 10 Hz, 4 H), 8.60 (t, J = 6
0
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
196

Cpd.Starting Method
-R -R' Analytical
Data
No. From Used
80h(3) 4.1 79h 1-2 MS (ES): 517.7
-0
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
CH3
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
0
0
0
IHNMR (DMSO-d6): 5 9.15 (bs, 3 H), 8.65 (t, J = 6 Hz, 1 H),
0
-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
197

-
,
Cpd. Starting Method
-R -R'
Analytical Data
No. From Used
0
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.
---1
1-
Hz, 2 H), 1.53 (m, 1 H), 0.64 (d, J = 6.8 Hz, 6 H); MS (ES)
1-
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
0
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.)
0
H), 0.87 (d, J = 6.8 Hz, 6 H); MS (ES-) 577.2, (ES+) 579.3
I.)
0
0
u.)
1
11-INMR (DMSO-d6): 5 13.45 (bs, 1 H), 9.06 (s, 2 H), 8.99 (s,
0
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
1-
t..)
vi
oe
t..)
198

Cpd. Starting Method
-R -R'
Analytical Data
No. From Used
0
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
0
I.)
a,
110 -0Bn (2) -CH3 109 J MS (ES):
579.3 I.)
1-
(5)
o
a,
111 -OH (2) -CH3 110 G MS (ES):
489.3 0
I.)
126
-0C2H5 (3)1 .
0
0
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,
--1
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
1-
.
i-,.)--
t..)
vi
oe
t..)
199

NH
0 NHBoc
5
4
W."
= H
3
2
H3CO2C
0
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
0
83 -CH=0 (3) 82 M MS (ES): 601.3
(5)
84 -CH2OH (3) 83 K MS (ES-1): 601.4
0
85 -CO2H (3) 83 E MS (ES-1): 615.3
0
0
-OCH3 (3)
128 both 124a R MS (ES): 629.4
0
-CH=CH2 (4)
oe
200

R3
R2 R4
. 0 5
0
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
0
(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,
1-
7.9 Hz, 1 H), 6.81 bs, 2 H), 5.20 (s, 2 u.)
0
H)
I.)
0
1HNMR (DMSO-d6): 6 10.2 (s, 1 H),
0
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), '
0
7.13 (m, 2 H), 3.92 (s, 3 H); MS (ES-)
a,
1
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
1-
t..)
vi
oe
t..)
201

Cpd.
-R1-R2 -R3 -R4 Starting Method
Analytical Data
No. From Used
0
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
=
0
(5)
0
0
0
0
oe
202

NH
0 = N112
0
0 0
-
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).
0
0
0
oe
203

R'
0
RO =
n.)
40 NHR"'
.6.
H3CO,C --4
1¨,
1¨,
0
i
Cpd. I
-R -R' -R" -R"' 1
Starting Method '
No.
Analytical Data
From Used
CH3
117a -CH3 -0Bn -CHO 3a D-2
D-2 MS (ES-): 474.2
CH3 116a
CH3 0
117b -C2H5 -0Bn -CHO 3a
0
I.)
-'=,,.,./---,.CH3 116b D-2 MS (ES):
488.2 a,
t..)
I.)
o
(5)
CH3 Lo
0
117c -CH(CH3)2 -0Bn -CHO 3a+
I.)
D-2
MS (ES): 502.3 0
CH3 0
116c
Lo
1
0
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 +
D-2
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..)
204

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.
--4
1-
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
D-2
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
0
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.)
0
....,,...--.....,.....õ,-...,.....CH3 3d H), 6.67
(s, 1 H), 6.50 (broad, 1 I.)
117f -CH3 -0Bn -CHO
D-2 0
116a
H),) 5.27 (d, J----- 11.9 Hz, 1 H), 0
u.)
'
5.22 (dd, J= 11.7, 1 1-1),
0
4.63,(m,3H) 4.17 (m, 4 H), 3.92
a,
1
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
1-
c.:.)
t..)
vi
oe
t..)
205

,
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,
--4
1-
1-
3e +
1.5, 2 H), 7.40 (m, 4 H), 6.67 (s,
117h -CH3 -0Bn -CHO
D-2
116a
1 H), 6.21 (broad, 1 H), 5.24 (d, J
CH3
= 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,
0
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
"
0
0
H), 3.37 (dd, J= 7.2, 5.3 Hz, 2
Lo
1
H), 1.09 (m, 1 H), 0.60 (m, 2 H),
0
.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
--4
1-,
1-,
3i +
H), 7.58-7.33 (m, 7 H), 6.68 (s, 1
117k -CH3 -0Bn -CHO
D-2
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
CH3
0
3j +
H), 7.58-7.33 (m, 7 H), 6.68 (s, 1
1171 -CH3 . -0Bn -CHO
D-2
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.)
--4
(M+ Na) 0
I.)
1HNMR (DMSO-d6): 8 9.73 (s, 1
0
.
0
H), 8.86 (t, J = 5.7 Hz, 1 H), 8.52
u.)
1
(d, J = 1.5 Hz, 1 H), 8.22 (dd, J =
0
FP
I
0 CH3
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 \,./`-..
D-6
--..---.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
CH3
cp
o
1-
i-,.)--
t..)
vi
oe
t..)
207

Cpd. Starting
Method
-R -12.' -R" -R"'
Analytical Data
No. From
Used
_
0
-
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
CH3
CH3
118d -CH3 -0Bn -CO2H 117d
E Characterized in the next step
-clI3
0
118e -CH3 -0Bn -CO2H ____<---CH3
117e
E MS (ES): 534.3 0
IV
FP
IV
0)
N CH3
FP
0
la
00
0
IV
1181 -CH3 -0Bn -CO2H .,---..,..-
--..,.,,,c1-13 117f E MS (ES): 506.3
0
0
la
I
0
FP
I
118g -CH3 -0Bn -CO2H /CF3 117g
E Characterized in the next step H
--1
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..)
208

.
,
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
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
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
0
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.)
0
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
0
0
H), 1.79-0.94 (m, 9 H); MS (ES):
u.)
504.4
c)
a,.
0
1
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
CH3
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..)
209

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
CH3
119d -CH3 -0Bn -0O2MEM 118d F MS (ES):
564.2
'"CH3
119e -CH3 -0Bn -0O2MEM 118e F MS (ES):
620.1
CH3
119f -CH3 -0Bn -0O2MEM 118f F MS (ES):
592.3 0
(5)
119g -CH3 -0Bn -0O2MEM 118g F
Characterized in the next step
0
0
1H NMR (CDC13): 5 8.32 (d, J=
1.9 Hz, 1 H), 7.96 (dd, J= 7.9,
0
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
210

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),
0
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),
0
3.23 (s, 3 11)1.99-1.53 (m, 8 H);
0
MS (BS): 614.3 (M+ Na)
0
1H NMR (DMSO-d6): 5 8.70 (t,
0
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
211

,
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
CH3
7.9 Hz, 1 H), 7.63-7.33 (m, 7 H),
1-
1-
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
0
8.1 Hz, 1 H), 7.71 (s, 1 H), 7.40
I.)
a,
I.)
0 CH3
(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.)
0
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
0
0
u.)
1
H), 1.21 (s, 9 H), 0.91 (d, J = 6.8
0
.
Hz, 6 H); MS (ES+): 650.4 and a,
1
H
672.3 (M+ NO+
-A
CH3
120a -CH3 -OH -0O2MEM 119a
G MS (ES): 488.1
C1-13
CH3
120b -C2H5 -OH -0O2MEM \,..,/\ CH3
119b G MS (ES): 502.2 1-d
n
1-i
cp
o
1-
i-,.)--
t..)
vi
oe
t..)
212

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
--4
CH3
CH3
120d -CH3 -OH -0O2MEM 119d
G MS (ES): 474.3
CH3
120e -CH3 -OH -0O2MEM ____<--CH3
119e
G MS (ES): 530.4
CH,
n
2
120f -CH3 -OH -0O2MEM --,,,.c1-13 119f
G MS (ES): 502.3 a,
I.)
(5)
a,
t..)
Lo
0
120g -CH3 -OH -0O2MEM /..--CF3 119g
G Characterized in the next step "
0
0
Lo
1
0
a,
1
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..)
213

s
_______________________________________________________________________________
___________________________
Cpd. Starting
Method
-R -R' -R" -R"'
Analytical Data
No. From-
Used
¨0
CH
o
n.)
1201 -CH3 -OH -0O2MEM 1191
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),
CH3
7.68 (s, 1 H), 7.41 (d, J =8.1 Hz,
0
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),
0
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,

560.5 and 582.4 (M+ Na), (ES) co
.6.
0
558.4
I.)
0
0
CH
CA
I
121a -CH3 -0S02CF3 -0O2MEM 120a
B-2 MS (ES-3): 644.1 (M+ Na) 0
.P
I
CH3
H
-A
CH3
121b -C2H5 -0S02CF3 -0O2MEM 120b
B-2 MS (ES+): 658.2 (M+ Na)+
CH,
CH3
121c -CH(CH3)2 -0S02CF3 -0O2MEM
120c B-2 MS (EST): 672.2 (M+Na)+ 1-d
CH3
n
,-i
cp
=
i-,.,--
t..)
u,
oe
t..)
214

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
1-
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),
0
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),
0
I.)
CH3
4.0 (m, 3 H), 3.6 (s, 3 H), 3.4 (m, a,
I.)
t..)
(5)
1-
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
0
(ES+): 664.3
I.)
0
0
IHNMR (DMSO-d6): 8 8.83 (d, J
u.)
1
= 5.46, 1 H), 8.55 (d, J = 1.88 Hz,
0
a,
1
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..)
215

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
0
H); MS (ES): 620
0
1H NMR (CDC13): 68.41 (d,
0
2.1 Hz, 1 H), 8.03 (dd, J= 7.9,
0
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
216

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),
-4
1-
1-
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
CH3
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,
1-
u.)
-4
111 NMR (CDC13): 8 8.38 (s, 1
0
H), 8.00 (m, 2 H), 7.31 (d, J= 7.9
0 I.)
cH3
0
-
Hz, 1 H), 6.78 (s, 1 H), 6.37 (m, 1 u.)
1
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),
1
H
1.78-0.92 (m, 9 H); MS (ES+):
658.4 (M+ Na)+
1-lo
n
,-i
cp
=
l= . )
C. if I
0 0
l= . )
217

' Cpd. Starting Method
-R -R' -R" -R"
Analytical Data
No. From Used
0
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
--4
1-
8.1 Hz, 1 H), 8.04 (s, 1 H), 7.57
1-
0 CH3
(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
0
CH3
122a -CH3 -CH=CH2 -C 02MEM 121a D-3
Characterized in the next step 0
IV
FP
CH3
IV
N
61
OCI
CA
0
CH3
IV
122b -C2H5 -CH=CH2 -0O2MEM 121b D-3 MS (ES):
536.3 (M+Na)+ 0
0
CA
CH3
I
0
FP
CH
HI
--1
122c -CH(CH3)2 -CH=CH2 -0O2MEM 121c D-3
MS (ES): 550.3 (M+ Na)
CH3
CH3
122d -CH3 -CH=CH2 -0O2MEM 121d D-3 MS (ES+):
486.2
CH3
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.)
218

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
0
122j -CH3 - -CH=CH2 -0O2MEM 121j D-3 MS
(ES-): 422.3 [(M-MeM)-1]
(5)
0
0
-CH3
0
122k -CH=CH2 -0O2MEM CH3 121K D-3 MS
(ES): 494.2 (M+ Na)+
0
CH,
1221 -CH3 -CH=CH2 -0O2MEM 'CH1211 D-3
MS (ES): 536.42 (M+ Na)
1-d
oe
219

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
1-
1-
Hz, 111), 8.11 (dd, J= 1.8 and
8.1 Hz, 1 H), 7.61 (s, 1 H), 7.57
CH3
0
(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,
0
2 H), 1.89 (m, 1 H), 1.38 (s, 9 H),
0
I.)
0.91 (d, J = 6.8 Hz, 6 H); MS
I.)
t..)
(ES-): 480.4 [(M-MEM)-1]
o
u.)
0
CH,
iv
123a -CH3 -CH=CH2 CO2H 122a
I-1 MS (ES): 410.2 0
0
CA
CH
I
0
FP
I
CH3
H
-,1
123b -C2115 -CH=CH2 CO2H 122b
I-1 MS (ES): 424.2
CH3
CH3
123c -CH(CH3)2 -CH=CH2 CO2H122c
I-1 MS (ES): 438.2
.-CH3
1-d
n
CH3
123d -CH3 -CH=CH2 CO2H 122d
I-1 MS (ES): 396.2
cp
CH3
1-
i-,.)--
t..)
vi
oe
t..)
220

,
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
1-
1-
' 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
0
H), 7.40 (d, J= 7.9 Hz, 1 H),
0
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-
1.3 Hz, 1 H), 5.37 (dd, J = 11.1,
u.)
0
1.3 Hz, 1 H), 4.14 (m, 2 H), 3.84
I.)
0
(s, 3 H), 3.61 (s, 3 H); MS (ES):
0
u.)
436.3
'
0
FP
1FINMR (DMS0): 8 8.66 (t, .1=
I
H
5.5 Hz, 1 H), 8.35 (d, J= 1.7 Hz,
--1
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.
1-
-
c.:.)
t..)
vi
oe
t..)
221

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
0
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
"
0
123j -CH3 -CH=CH2 CO21-1 -0 122j
Hz, 1 H), 6.97 (dd, J=11.5 and
I-1
17.9 Hz, 1 H), 6.74 (s, 1 H), 5.89 7
us,
0
(d, J= 17.9 Hz, 1 H), 5.37 (d, J=
1
,
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
I-1
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..)
222

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
CH3
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,
0
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),
0
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
0 11 and
17.5 Hz, 1 H), 5.99 (d, J
CH3 7
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
223

DEMANDES OU BREVETS VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVETS
COMPREND PLUS D'UN TOME.
CECI EST LE TOME 1 DE 2
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.
THIS IS VOLUME 1 OF 2
NOTE: For additional volumes please contact the Canadian Patent Office.

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Administrative Status , Maintenance Fee  and Payment History  should be consulted.

Administrative Status

Title Date
Forecasted Issue Date 2014-10-07
(86) PCT Filing Date 2001-10-22
(87) PCT Publication Date 2002-05-02
(85) National Entry 2003-04-17
Examination Requested 2006-07-25
(45) Issued 2014-10-07
Expired 2021-10-22

Abandonment History

Abandonment Date Reason Reinstatement Date
2013-05-09 R30(2) - Failure to Respond 2014-04-25

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $300.00 2003-04-17
Maintenance Fee - Application - New Act 2 2003-10-22 $100.00 2003-10-15
Registration of a document - section 124 $100.00 2003-10-17
Maintenance Fee - Application - New Act 3 2004-10-22 $100.00 2004-10-08
Maintenance Fee - Application - New Act 4 2005-10-24 $100.00 2005-10-24
Request for Examination $800.00 2006-07-25
Maintenance Fee - Application - New Act 5 2006-10-23 $200.00 2006-10-03
Maintenance Fee - Application - New Act 6 2007-10-22 $200.00 2007-10-22
Maintenance Fee - Application - New Act 7 2008-10-22 $200.00 2008-10-01
Maintenance Fee - Application - New Act 8 2009-10-22 $200.00 2009-10-08
Maintenance Fee - Application - New Act 9 2010-10-22 $200.00 2010-10-05
Maintenance Fee - Application - New Act 10 2011-10-24 $250.00 2011-09-28
Maintenance Fee - Application - New Act 11 2012-10-22 $250.00 2012-10-16
Maintenance Fee - Application - New Act 12 2013-10-22 $250.00 2013-10-11
Reinstatement - failure to respond to examiners report $200.00 2014-04-25
Final Fee $1,782.00 2014-07-24
Maintenance Fee - Patent - New Act 13 2014-10-22 $250.00 2014-10-09
Maintenance Fee - Patent - New Act 14 2015-10-22 $250.00 2015-10-07
Maintenance Fee - Patent - New Act 15 2016-10-24 $450.00 2016-09-28
Maintenance Fee - Patent - New Act 16 2017-10-23 $450.00 2017-09-27
Maintenance Fee - Patent - New Act 17 2018-10-22 $450.00 2018-09-26
Maintenance Fee - Patent - New Act 18 2019-10-22 $450.00 2019-10-02
Maintenance Fee - Patent - New Act 19 2020-10-22 $450.00 2020-10-02
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
BIOCRYST PHARMACEUTICALS, INC.
Past Owners on Record
BABU, YARLAGADDA S.
CHAND, POORAN
EL-KATTAN, YAHYA
KOTIAN, PRAVIN L.
NIWAS, SHRI
ROWLAND, SCOTT R.
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
Documents

To view selected files, please enter reCAPTCHA code :



To view images, click a link in the Document Description column. To download the documents, select one or more checkboxes in the first column and then click the "Download Selected in PDF format (Zip Archive)" or the "Download Selected as Single PDF" button.

List of published and non-published patent-specific documents on the CPD .

If you have any difficulty accessing content, you can call the Client Service Centre at 1-866-997-1936 or send them an e-mail at CIPO Client Service Centre.


Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Abstract 2003-04-17 1 8
Claims 2003-04-17 51 796
Description 2003-04-17 286 8,934
Cover Page 2003-06-20 2 37
Claims 2009-09-03 36 686
Description 2009-09-03 286 8,851
Abstract 2009-09-03 1 14
Claims 2011-02-16 31 525
Description 2011-02-16 309 9,200
Claims 2011-12-08 35 497
Description 2011-12-08 312 9,171
Claims 2012-08-16 35 493
Description 2012-08-16 312 9,169
Representative Drawing 2014-08-06 1 2
Description 2014-04-25 251 7,251
Description 2014-04-25 65 1,984
Claims 2014-04-25 35 496
Cover Page 2014-09-04 2 70
Correspondence 2005-02-14 1 23
PCT 2003-04-17 4 194
Assignment 2003-04-17 3 103
Correspondence 2003-06-18 1 24
PCT 2003-04-17 1 55
PCT 2003-04-17 1 39
Assignment 2003-10-17 3 89
Fees 2003-10-15 1 35
Fees 2004-10-08 1 36
Fees 2005-10-24 1 35
Prosecution-Amendment 2006-07-25 1 42
Fees 2006-10-03 1 55
Fees 2007-10-22 1 60
Fees 2008-10-01 1 52
Prosecution-Amendment 2009-03-05 4 179
Prosecution-Amendment 2009-09-03 53 1,331
Fees 2009-10-08 1 70
Prosecution-Amendment 2010-08-27 6 287
Fees 2010-10-05 1 60
Prosecution-Amendment 2011-02-16 93 1,716
Prosecution-Amendment 2011-06-08 3 130
Fees 2011-09-28 1 43
Fees 2012-10-16 1 48
Prosecution-Amendment 2011-12-08 100 1,632
Prosecution-Amendment 2012-02-16 2 103
Prosecution-Amendment 2012-08-16 9 214
Prosecution-Amendment 2012-11-09 2 111
Fees 2013-10-11 1 46
Prosecution-Amendment 2014-04-25 11 304
Correspondence 2014-07-24 1 45
Fees 2014-10-09 1 51
Maintenance Fee Payment 2015-10-07 1 59